Aryl nitrogen-containing heterocyclic compound, pharmaceutical composition, and use

Abstract

Disclosed in the present invention are an aryl nitrogen-containing heterocyclic compound, a pharmaceutical composition, and a use. Specifically, the present invention provides a compound as shown in general formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound as shown in general formula (I), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof has good Kv1.3 potassium channel inhibitory activity.

Description

Aryl nitrogen-containing heterocyclic compound, pharmaceutical composition and application

[0001] This application claims priority to Chinese Patent Application No. 2023109191450, filed on July 26, 2023, and priority to Chinese Patent Application No. 2024106568695, filed on May 24, 2024. The entire text of the aforementioned Chinese patent application is incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of drug synthesis, and in particular relates to an aromatic nitrogen-containing heterocyclic compound, a drug composition and an application thereof. Background Art

[0003] Voltage-gated Kv1.3 potassium (K+) channels are expressed in lymphocytes (T and B lymphocytes), the central nervous system, and other tissues, and regulate a large number of physiological processes such as neurotransmitter release, heart rate, insulin secretion, and neuronal stress. Kv1.3 channels can adjust membrane potential and thereby indirectly affect calcium signaling in human effector memory T cells. Effector memory T cells are mediators of several conditions, including multiple sclerosis, type I diabetes, psoriasis, spondylitis, periodontitis, and rheumatoid arthritis. After activation, effector memory T cells increase the expression of Kv1.3 channels. In human B cells, young and early memory B cells express a small amount of Kv1.3 channels when they are inactive. In contrast, class-switched memory B cells express a large amount of Kv1.3 channels. In addition, Kv1.3 channels promote T-cell receptors to regulate calcium homeostasis required for cell activation, gene transcription, and proliferation (Panyi, G. et al., 2004, Trends Immunol, 565-569). Blockade of Kv1.3 channels in effector memory T cells inhibits activities such as calcium signaling, cytokine production (interferon-γ, interleukin-2), and cell proliferation.

[0004] Basic research on autoimmune diseases has found that the voltage-gated potassium channel Kv1.3 on the T lymphocyte membrane plays an important role in many autoimmune diseases. In the immune response process related to T lymphocytes, the voltage-gated potassium channel Kv1.3 and the calcium-activated potassium channel Kca jointly regulate the membrane potential and Ca of T lymphocytes. 2+ signals, thereby affecting the activation, proliferation and cytokine secretion of T lymphocytes. Among them, the Kv1.3 potassium channel is specifically related to the body's abnormal autoimmunity.

[0005] Furthermore, there are indications that Kv1.3 channels also play a role in body weight regulation, making them a promising target for the treatment of obesity.

[0006] Therefore, there is a continuing need for Kv1.3 channel-specific therapeutic compounds that exhibit strong and specific interactions with Kv1.3 channels and are able to block or reduce their activity.

[0007] Summary of the Invention

[0008] The technical problem to be solved by the present invention is to overcome the problem of single structure of Kv1.3 channel inhibitors in the prior art, and to provide an aromatic nitrogen-containing heterocyclic compound and its preparation method and application; the aromatic nitrogen-containing heterocyclic compound provided by the present invention can be used as a PRMT5 inhibitor, which has good inhibitory activity or selectivity against human colon cancer cells with stable MTAP protein knockout (HCT-116-MTAP-KO-1A2) and can inhibit the proliferation of tumor cells.

[0009] The present invention solves the above technical problems through the following methods.

[0010] A compound represented by general formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

[0011] in:

[0012] M is -CH2-, -C(=O)- or -C(=N-L4-R2)-; L4 is a bond or -CH2-; R2 is C 1-3 Alkyl, C 1-3 Halogenated alkyl, pyrazolyl or phenyl; the pyrazolyl and phenyl are optionally substituted by halogen, amino, C 1-3 Alkyl or C 1-3 One or two substitutions of hydroxyalkyl groups;

[0013] L1 is a bond, -(CH2) n3 - or -C(O)-; n3 is 1 or 2;

[0014] L2 is a bond, -(CH2) n5 -、-CH2-NH-、C 4-6 Cycloalkylene, pyridylene or 4-membered heterocyclylene; n5 is 1 or 2;

[0015] L3 is -CH2-, -S(O) n4 -、-C(=NH)-、 R L3 For hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl; the C 1-3 The alkyl group is optionally substituted with a cyano group; n4 is 1 or 2;

[0016] R1 is hydroxyl, amino, C 1-3 Alkyl or C1-3 Halogenated alkyl; the C 1-3 The alkyl group is optionally substituted with a cyano group.

[0017] In some preferred embodiments, the general formula (I) is further represented by the general formula (I-1):

[0018] Where: L1 is a bond, -(CH2) n3 -, n3 is 1 or 2; L2 is -CH2- or pyridinyl; L3 is -CH2-, -S(O) n4 -、-C(=NH)-、 R L3 For hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl; the C 1-3 The alkyl group is optionally substituted with a cyano group; n4 is 1 or 2; R1 is hydroxyl, amino, C 1-3 Alkyl or C 1-3 Halogenated alkyl; the C 1-3 The alkyl group is optionally substituted with a cyano group.

[0019] In some preferred embodiments, the general formula (I) is further represented by the general formula (I-2):

[0020] Where: L1 is -(CH2) n3 -, n3 is 1 or 2; L2 is -(CH2) n5 -, n5 is 1 or 2; L3 is -CH2-, -S(O)2- or -C(=NH)-; R1 is hydroxyl, amino, C 1-3 Alkyl or C 1-3 Halogenated alkyl; L4 is a bond or -CH2-; R2 is C 1-3 Alkyl, C 1-3 Halogenated alkyl, pyrazolyl or phenyl; the pyrazolyl and phenyl are optionally substituted by halogen, amino, C 1-3 Alkyl or C 1-3 One or two of the hydroxyalkyl groups are substituted.

[0021] In some preferred embodiments, the general formula (I) is further represented by the general formula (I-3):

[0022] Among them: L2 is a bond, -(CH2) n5 -、-CH2-NH-、C 4-6 Cycloalkylene, pyridylene or 4-membered heterocyclylene; n5 is 1 or 2; L3 is -CH2-, -S(O)2- or -C(=NH)-; R L3 is hydrogen or C1-3 Alkyl; R1 is hydroxyl, amino, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

[0023] In some preferred embodiments, the C 1-3 Alkyl is independently methyl, ethyl, n-propyl or isopropyl; preferably methyl.

[0024] In some preferred embodiments, the C 1-3 Haloalkyl is -CF3 or -CH2CF3; preferably -CH2CF 3。

[0025] In some preferred embodiments, the C 4-6 Cycloalkylene is

[0026] In some preferred embodiments, the pyridinylene group is Preferred

[0027] In some preferred embodiments, the 4-membered heterocyclylene group is Preferred

[0028] In some preferred embodiments, the halogen is fluorine, chlorine, or bromine; preferably chlorine.

[0029] In some preferred embodiments, L1 is a bond, or -(CH2) n3 -; n3 is 1 or 2;

[0030] In some preferred embodiments, L2 is -CH2-, -CH2-CH2-, pyridinyl, C 4-6 Cycloalkylene or 4-membered heterocyclylene; preferably -CH2-, -CH2-CH2-,

[0031] In some preferred embodiments, said L3 is -CH2-, -S(O)-, -S(O)2-, -C(=NH)-,

[0032] In some preferred embodiments, the R L3 It is hydrogen, methyl, ethyl, n-propyl, isopropyl, -CF3, -CH2CF3 or -CH2CN; preferably hydrogen, methyl, -CF3, -CH2CF3 or -CH2CN.

[0033] In some preferred embodiments, R1 is hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, -CF3, -CH2CF3 or CH2CN; preferably hydroxy, amino, methyl, -CF3, -CH2CF3 or CH2CN.

[0034] In some preferred embodiments, said L4 is a bond or -CH2-; preferably -CH2-.

[0035] In some preferred embodiments, R2 is methyl, ethyl, propyl, -CF3, -CH2CF3, pyrazolyl or phenyl, and the pyrazolyl and phenyl are optionally substituted with chlorine, amino, methyl or Preferably, R2 is methyl, -CF3, -CH2CF3,

[0036] In some preferred embodiments, said L1 is a bond.

[0037] In some preferred embodiments, L1 is -(CH2) n3 -, n3 is 1 or 2.

[0038] In some preferred embodiments, said L2 is -CH2-.

[0039] In some preferred embodiments, L2 is

[0040] In some preferred embodiments, said L3 is -S(O)2-, -C(=NH)-.

[0041] In some preferred embodiments, L3 is -CH2-, -S(O)2-, or -C(=NH)-.

[0042] In some preferred embodiments, said L3 is -S(O)2- or -C(=NH)-.

[0043] In some preferred embodiments, said R1 is methyl or amino;

[0044] In some preferred embodiments, said R1 is hydroxyl or amino;

[0045] In some preferred embodiments, said R1 is amino;

[0046] In some preferred embodiments, said L4 is -CH2-;

[0047] In some preferred embodiments, said R2 is -CF3,

[0048] In some preferred embodiments, in the general formula (I-1), L1 is a bond, -CH2- or -CH2-CH2-; L2 is a bond, -CH2- or L3 is -S(O)2- or -C(=NH)-; R1 is amino or methyl.

[0049] In some preferred embodiments, in the general formula (I-1), L1 is a bond, -CH2- or -CH2-CH2-; L2 is a bond, -CH2- or L3 is -S(O)2-; R1 is amino or C 1-3 Alkyl; preferably amino or methyl.

[0050] In some preferred embodiments, in the general formula (I-1), L1 is -CH2-CH2-; L2 is a bond or -CH2-; L3 is -S(O)2-; R1 is an amino group or C 1-3 Alkyl; preferably amino or methyl.

[0051] In some preferred embodiments, in the general formula (I-1), L1 is a bond; L2 is L3 is -S(O)2-; R1 is amino or C 1-3 Alkyl; preferably amino or methyl.

[0052] In some preferred embodiments, in the general formula (I-2), L1 is -(CH2) n3 -, n3 is 1 or 2; L2 is -CH2-; L3 is -CH2-, -S(O)2- or -C(=NH)-; R1 is hydroxyl, amino, C 1-3 Alkyl or C 1-3 Halogenated alkyl, preferably hydroxy, amino or methyl, more preferably hydroxy or amino; L4 is a bond or -CH2-; R2 is C 1-3 Halogenated alkyl, pyrazolyl or phenyl; the pyrazolyl and phenyl are optionally substituted by halogen, amino, C 1-3 Alkyl or C 1-3 One or two of the hydroxyalkyl groups are substituted; preferably, R2 is -CF3, More preferably -CF3,

[0053] In some preferred embodiments, in the general formula (I-3), L2 is -(CH2)2-, -CH2-NH-, Preferred are -(CH2)2-, -CH2-NH-, L3 is -S(O)2- or -C(=NH)-; R1 is amino or C 1-3 Alkyl group, preferably amino or methyl group.

[0054] The present invention also relates to a compound represented by general formula (II):

[0055] In a preferred embodiment of the present invention, the R a 、R b 、R c 、R d and R e are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, amino, hydroxyl or alkyl;

[0056] Preferably hydrogen, deuterium, fluorine, chlorine, cyano, amino, hydroxyl or C 1-6 alkyl;

[0057] For example, hydrogen, chlorine or hydroxyl.

[0058] In a preferred embodiment of the present invention, X3 is (C=NR 32 ), CO or CH2.

[0059] In a preferred embodiment of the present invention, the R 32 is hydrogen, alkyl, aryl, arylalkyl or heteroarylalkyl, wherein the alkyl, arylalkyl or heteroarylalkyl is optionally substituted with one or more substituents selected from deuterium, amino, halogen, alkyl, and alkyl substituted with hydroxy;

[0060] Preferably; said R 32 For hydrogen, C 1-6 Alkyl, C 6-10 Aryl, C 6-10 Aryl-substituted C 1-6 Alkyl or 5-10 membered heteroaryl substituted C 1-6 Alkyl, the C 1-6 Alkyl, C 6-10 Aryl-substituted C 1-6 Alkyl or 5-10 membered heteroaryl substituted C 1-6 The alkyl group is optionally selected from deuterium, amino, halogen, C 1-6 Alkyl, C substituted by hydroxy 1-6 The alkyl group is substituted by one or more substituents.

[0061] In a preferred embodiment of the present invention, the R 32 For hydrogen, C 1-3 Alkyl, phenyl, phenyl-substituted C 1-3 Alkyl or 5-6 membered heteroaryl substituted C 1-3 Alkyl, the C 1-3 Alkyl, phenyl substituted C 1-3Alkyl or 5-6 membered heteroaryl substituted C 1-3 The alkyl group is optionally selected from deuterium, amino, halogen, C 1-3 Alkyl, C substituted by hydroxy 1-3 The alkyl group is substituted by one or more substituents;

[0062] Preferably, the R 32 is hydrogen, methyl, ethyl, phenyl, phenyl-substituted methyl, phenyl-substituted ethyl, Substituted methyl or substituted ethyl; said methyl, ethyl, phenyl substituted methyl, phenyl substituted ethyl, Substituted methyl or The substituted ethyl group is optionally substituted with one or more substituents selected from deuterium, amino, F, Cl, methyl, ethyl, isopropyl substituted with hydroxy.

[0063] In a preferred embodiment of the present invention, the R 32 For hydrogen,

[0064] In a preferred embodiment of the present invention, the R 41 Selected from C 1-6 Alkyl, C 1-6 Alkylcarbonyl, C 3-6 Cycloalkylcarbonyl, 3-6 membered heterocyclylcarbonyl, 5-10 membered heteroarylcarbonyl or 5-10 membered heteroaryl, the C 1-6 Alkyl, C 1-6 Alkylcarbonyl, C 3-6 Cycloalkylcarbonyl, 3-6 membered heterocyclylcarbonyl, 5-10 membered heteroarylcarbonyl and 5-10 membered heteroaryl are optionally selected from deuterium, halogen, amino, hydroxy, alkyl, -(C=NH)NH2, -S(=O)(=NR7)R8, -S(=O)2R9, NHS(=O)2R 16 or -C(=NR7)R 12 is substituted by one or more substituents.

[0065] In a preferred embodiment of the present invention, the R 41 Selected from C 1-3 Alkyl, C 1-3 Alkylcarbonyl, C 4-6 Cycloalkylcarbonyl, 3-4 membered heterocyclylcarbonyl or 5-6 membered heteroaryl; the C 1-3 Alkyl, C 1-3 Alkylcarbonyl, C 4-6Cycloalkylcarbonyl, 3-4 membered heterocyclylcarbonyl and 5-6 membered heteroaryl are optionally selected from deuterium, halogen, amino, hydroxy, alkyl, -(C=NH)NH2, -S(=O)(=NR7)R8, -S(=O)2R9, NHS(=O)2R 16 or -C(=NR7)R 12 is substituted by one or more substituents;

[0066] Preferably, the R 41 Selected from n-propyl, methylcarbonyl, ethylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, The R 41 Selected from n-propyl, methylcarbonyl, ethylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, is optionally selected from deuterium, halogen, amino, hydroxy, alkyl, -(C=NH)NH2, -S(=O)(=NR7)R8, -S(=O)2R9, NHS(=O)2R 16 or -C(=NR7)R 12 is substituted by one or more substituents.

[0067] In a preferred embodiment of the present invention, the R 41 for

[0068] In a preferred embodiment of the present invention, for or a combination thereof, e.g.

[0069] In the preferred embodiment of the present invention, R7, R8, R9, R 11 、R 12 and R 16 is hydrogen, deuterium, amino or alkyl;

[0070] Preferably hydrogen, deuterium, amino or C 1-6 alkyl;

[0071] More preferably, hydrogen, deuterium, amino or C 1-3 alkyl;

[0072] For example, hydrogen, amino or methyl.

[0073] In a preferred embodiment of the present invention, n1 is 1.

[0074] In a preferred embodiment of the present invention, n2 is 0.

[0075] In a preferred embodiment of the present invention, the R 41 -C(=O)R 411 -R412 ;

[0076] R 411 is an alkyl group, a cycloalkyl group, a heterocyclic group or a heteroaryl group,

[0077] R 412 -(C=NH)NH2, -S(=O)(=NR7)R8, -S(=O)2R9, -S(=O)R 11 or NHS(=O)2R 16 ;

[0078] Preferably, the alkyl group is C 1-6 Alkyl; for example, C 1-3 Alkyl; preferably methyl or ethyl;

[0079] The cycloalkyl group is C 3-6 Cycloalkyl; for example, C 4-6 Cycloalkyl; preferably cyclobutyl, cyclohexyl or cyclopentyl;

[0080] The heterocyclic group is a 3-6 membered heterocyclic group; for example, a 3-4 membered heterocyclic group; for example

[0081] The heteroaryl group is a 5-10 membered heteroaryl group; for example, a 5-6 membered heteroaryl group; for example

[0082] R7, R8, R9, R 11 and R 16 is hydrogen, deuterium or alkyl; preferably hydrogen, deuterium or C 1-6 Alkyl; further preferably hydrogen, deuterium or C 1- 3 Alkyl; for example, hydrogen or methyl.

[0083] In a preferred embodiment of the present invention, the R 41 -R 413 -R 414 ;

[0084] R 413 is an alkyl group, a cycloalkyl group, a heterocyclic group, or a heteroaryl group,

[0085] R 414 -(C=NH)NH2, -S(=O)(=NR7)R8, -S(=O)2R9, -S(=O)R 11 or NHS(=O)2R 16 ;

[0086] Preferably, the alkyl group is C 1-6 Alkyl; for example, C 1-3 Alkyl; preferably methyl or ethyl;

[0087] The cycloalkyl group is C3-6 Cycloalkyl; for example, C 4-6 Cycloalkyl; preferably cyclobutyl, cyclohexyl or cyclopentyl; the heterocyclic group is a 3-6 membered heterocyclic group; for example a 3-4 membered heterocyclic group; for example

[0088] The heteroaryl group is a 5-10 membered heteroaryl group; for example, a 5-6 membered heteroaryl group; for example

[0089] R7, R8, R9, R 11 and R 16 is hydrogen, deuterium or alkyl; preferably hydrogen, deuterium or C 1-6 Alkyl; further preferably hydrogen, deuterium or C 1- 3 Alkyl; for example, hydrogen or methyl.

[0090] In a preferred embodiment of the present invention, the compound represented by general formula (II) is further represented by general formula (III), a compound represented by general formula (IV), or a compound represented by general formula (V):

[0091] Among them, R a 、R b 、R c 、R d 、R e 、R 41 、R 32 、R 411 、R 412 、R 413 and R 414 As defined above.

[0092] In a preferred embodiment of the present invention, the compound represented by general formula (III) is or a combination thereof; for example

[0093] In a preferred embodiment of the present invention, the compound represented by general formula (IV) is or a combination thereof; for example

[0094] In a preferred embodiment of the present invention, the compound represented by general formula (V) is or a combination thereof, e.g.

[0095] In a preferred embodiment of the present invention, the structural unit for Among them, R c 、R d and R eis hydrogen or halogen,

[0096] Preferably, the halogen is Cl,

[0097] For example, the structural unit for

[0098] In a preferred embodiment of the present invention, the compound is selected from the compounds shown in Table 1 below:

[0099] Table 1

[0100] The present invention also provides a pharmaceutical composition comprising the compound of the aforementioned general formulae and its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients.

[0101] The present invention also provides the use of the compounds of the aforementioned general formulae and their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof in the preparation of Kv1.3 potassium channel inhibitors.

[0102] The present invention also provides the use of the compounds of the aforementioned general formulae and their stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical compositions thereof, in the preparation of drugs for treating or preventing diseases;

[0103] The drug may be a drug for inhibiting Kv1.3 potassium channels;

[0104] The disease may be a Kv1.3 potassium channel-related disease, such as cancer, immunological disorders, central nervous system disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and renal diseases;

[0105] The compound of the aforementioned general formulae and its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition may be in a therapeutically effective amount.

[0106] The present invention also provides a method for treating Kv1.3 potassium channel-related diseases, which comprises administering the compounds of the aforementioned general formulas, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition to a subject in need thereof (e.g., a human or mouse); preferably, the compounds of the aforementioned general formulas, their stereoisomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition are in a therapeutically effective amount.

[0107] In a preferred embodiment of the present invention, the Kv1.3 potassium channel-related disease is selected from cancer, immunological disorders, central nervous system disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders and renal diseases.

[0108] The present invention also provides the intermediate 2 compound shown below,

[0109] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0110] The reagents and raw materials used in the present invention are commercially available.

[0111] the term

[0112] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0113] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 6 carbon atoms, and more preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, and the like.

[0114] The term "alkylcarbonyl" refers to a -C(O)alkyl group, wherein the alkyl group is as defined above. Non-limiting examples of alkylcarbonyl groups include -C(O)CH3, -C(O)CH2CH3.

[0115] The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 12 carbon atoms, preferably 3 to 6 carbon atoms, and more preferably 3 to 4 carbon atoms. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0116] The term "cycloalkylcarbonyl" refers to a -C(O)cycloalkyl group, wherein the cycloalkyl group is as defined above. Non-limiting examples of cycloalkylcarbonyl groups include -C(O)-cyclopentane, -C(O)-cyclohexane.

[0117] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 12 ring atoms, one or more of which is selected from nitrogen, oxygen, C(O), S(O)(=NH) or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, excluding the ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 8 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 6 ring atoms, of which 1 to 2 are heteroatoms; and most preferably, it contains 3 to 4 ring atoms, of which 1 heteroatom is included. Non-limiting examples of monocyclic heterocyclic groups include oxirane, aziridine, oxetanyl, azetidinyl, azepanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and the like.

[0118] The term "heterocyclylcarbonyl" refers to a -C(O)heterocyclyl group, wherein the heterocyclyl group is as defined above.

[0119] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably a 6- to 10-membered, more preferably a phenyl group.

[0120] The term "arylalkyl" refers to an alkyl group substituted by an aryl group, wherein the aryl and alkyl groups are as defined above. Non-limiting examples include:

[0121] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably a 5- to 8-membered heteroaryl group; more preferably a 5-membered heteroaryl group or a 6-membered heteroaryl group, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl and the like.

[0122] The term "heteroarylalkyl" refers to an alkyl group substituted by a heteroaryl group, wherein heteroaryl and alkyl are as defined above.

[0123] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are as defined above. Non-limiting examples of alkoxy include methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy.

[0124] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above. Non-limiting examples include: trifluoromethyl, difluoromethyl.

[0125] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above. Non-limiting examples include trifluoromethoxy, trifluoroethoxy, difluoromethoxy, and the like.

[0126] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0127] "Hydroxy" refers to an -OH group.

[0128] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0129] In the present invention Indicates that the key does not exist;

[0130] Unless otherwise specified, the chiral carbon atoms in the compounds of the present invention are in the R or S configuration.

[0131] The hydrogen atoms described in the present invention may be replaced by their isotope deuterium. Any hydrogen atom in the example compounds of the present invention may also be replaced by a deuterium atom.

[0132] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0133] "Pharmaceutical composition" means a composition containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, and at least one pharmaceutically acceptable excipient. Excipients are a general term for all pharmaceutical materials other than the principal ingredient added to a formulation to enhance the formability, efficacy, stability, and safety of the formulation, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, promote absorption of the active ingredient, and thereby exert its biological activity.

[0134] "Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is safe and effective when used in mammals and has the desired biological activity, and the salt is selected from an organic salt or an inorganic salt.

[0135] The positive progress of the present invention is that the compound provided by the present invention has good inhibitory activity on Kv1.3 potassium channel. DETAILED DESCRIPTION

[0136] The present invention is further illustrated by way of examples below, but the invention is not limited to the scope of the examples. The starting materials and reagents used in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art. For example, intermediate 1 was synthesized according to the method described in WO2022076285A1.

[0137] Example 1 Preparation of Compound 1

[0138] Step 1: Synthesis of intermediate 2

[0139] Intermediate 1 (200 mg, 0.53 mmol, 1 eq) and Na2CO3 (110.24 mg, 1.06 mmol, 2 eq) were dissolved in dichloromethane (5 ml), and Et3OBF4 (0.64 mmol, 1.2 eq) was added portionwise at zero temperature. The reaction solution was then slowly warmed to room temperature and stirred for 3 hours. The reaction was completed. The mixture was quenched with saturated aqueous ammonium chloride (20 ml) and extracted with ethyl acetate (20 ml x 3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified on a preparative plate (PE / EA = 1:1) to obtain Intermediate 2 (130 mg, yield: 60.87%) as a colorless oil.

[0140] 1 H NMR (400MHz, CDCl3) δ7.25(d,1H),7.02(d,J=9.0Hz,1H),5.22–5.14(m,2H),4.45–4.35(m,1H),4.26(qd,J=7.1,2.5Hz,2H),4.01(ddd,J=13.5,9.4, 1.9Hz,1H),3.81–3.75(m,1H),3.74–3.68(m,2H),3.66–3.52(m,1H),2.92 –2.67(m,2H),1.35(dd,J=8.9,5.3Hz,3H),0.96–0.86(m,2H),0.01(s,9H).

[0141] Step 2: Synthesis of intermediate 3

[0142] Intermediate 2 (40 mg, 0.099 mmol, 1 eq) and compound 1-1 (1 ml) were dissolved in anhydrous ethanol (2 ml), then heated to 80°C and stirred for 24 hours. After completion of the reaction, the crude product was concentrated and purified on a preparative plate (PE / EA = 1:1) to afford Intermediate 3 (24 mg, 53.3% yield), a colorless liquid.

[0143] 1 H NMR (400MHz, MeOD) δ7.45(d,J=9.0Hz,1H),7.21(t,J=6.1Hz,1H),5.25(d,J=23.1Hz,2H),4.64(d,J=39.0Hz,1H),4.12(dd, J=18.9,9.4Hz,3H),3.85–3.70(m,3H),3.32(s,1H),3.13(dd,J=12.3,7.3Hz,1H),0.94(dd,J=8.4,7.3Hz,2H),0.01(s,9H).

[0144] Step 3: Synthesis of Compound 1-3

[0145] First, intermediate 3 (24 mg, 0.052 mmol, 1 eq) and K2CO3 (18.2 mg, 0.13 mmol, 2.5 eq) were dissolved in DMF (5 ml), and then compound 1-2 (19.66 mg, 0.078 mmol, 1.5 eq) was slowly added. The reaction solution was stirred at 80°C for 48 hours. After completion of the reaction, the solution was quenched with saturated aqueous ammonium chloride (20 ml) and then extracted with ethyl acetate (20 ml * 3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain crude compound 1-3 (27 mg, content: 75%, yield: 62.1%) as a yellow oil. ESI-MS m / z = 629.2 [MH] - .

[0146] Step 4: Synthesis of Compound 1

[0147] First, compound 1-3 (27 mg, 0.043 mmol, 1 eq) was dissolved in dioxane (2 ml). Then, at zero degrees Celsius, aqueous hydrochloric acid (6 M, 0.5 ml) was added to the solution. After the addition was complete, the reaction solution was warmed to room temperature and stirred for 30 minutes. After completion of the reaction, the reaction mixture was quenched and extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by preparative chromatography (ACN / H2O, 0.1% FA) to obtain compound 1 (1.98 mg, yield: 11.96%). ESI-MS m / z = 385.1 [MH] - .

[0148] 1 H NMR(400MHz,MeOD)δ8.44(s,1H),7.21(d,J=4.0Hz,1H),6.70(d,J=8Hz,1H),4.47-4.10(m,1H), 4.10-4.03(m,3H),3.84-3.83(m,1H),3.55-3.35(m,5H),3.22-3.17(m,1H),1.28-1.17(m,2H).

[0149] Example 2 Preparation of Compound 2

[0150] Step 1: Synthesis of compound 2-2

[0151] Intermediate 3 (200 mg, 0.44 mmol, 1 eq), K2CO3 (151.8 mg, 1.1 mmol, 2.5 eq), and compound 2-1 (78.15 mg, 0.53 mmol, 1.2 eq) were dissolved in DMF (5 mL), then heated to 80 degrees and stirred for 16 hours. The reaction was completed. The mixture was quenched with saturated aqueous ammonium chloride (20 mL) and then extracted with ethyl acetate (20 mL*3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by preparative plate (PE / EA=1:1) to obtain compound 2-2 (154 mg, yield: 89%) as a colorless oil. ESI-MS m / z=524.1[M+H] + .

[0152] Step 2: Synthesis of compound 2-3

[0153] Compound 2-2 (154 mg, 0.29 mmol, 1 eq) was dissolved in anhydrous ethanol (5 mL), cooled to 0 degrees, and then hydrochloric acid gas was introduced for 20 minutes. After the reaction was completed, anhydrous ethanol (15 mL) was added, nitrogen was purged, and after stirring for 2 hours, compound 2-3 was obtained, which was directly used in the next step.

[0154] Step 3: Synthesis of Compound 1

[0155] The reaction mixture of compound 2-3 in step 2 was first introduced into NH3 and stirred at 0°C for 1 hour. After completion of the reaction, the concentrate was directly dried to dryness. Water (5 mL) was then added and lyophilized to obtain a white solid. This solid was then dissolved in methanol / dichloromethane and filtered. The mother liquor was then dried to dryness to obtain the crude product. This was then preparatively purified (ACN / water, 0.1% FA) to afford compound 2 (3.57 mg, two-step yield: 3%). ESI-MS m / z = 411.0 [M+H] + .

[0156] 1 H NMR(400MHz,MeOD)δ8.46(s,0.65H FA),7.30(d,J=8.8Hz,1H),6.82(d,J=8.8Hz,1H),4.58(td,J=10.4,5.2Hz,2H),4.12(dd,J=21.1,9.9Hz,2H),3.91(dd,J=10 .2,5.9Hz,1H),3.76–3.53(m,2H),3.49–3.36(m,1H),3.25(d,J=6.1Hz,1H),2.57(dd,J=14.4,6.7Hz,2H),2.22–1.83(m,2H).

[0157] Example 3 Preparation of Compound 3

[0158] Step 1: Synthesis of compound 3-2

[0159] Intermediate 2 (130 mg, 0.32 mmol, 1 eq) was dissolved in ethanol (5 mL), and 3-chlorobenzylamine (3-1, 45 mg, 0.32 mmol, 1 eq) was added at 25°C. The mixture was stirred at 80°C for 20 hours. After completion of the reaction, the reaction mixture was concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain compound 3-2 (80 mg) as a white oil. ESI-MS m / z = 499.0 [M+1] + .

[0160] Step 2: Synthesis of compound 3-4

[0161] Compound 3-2 (70 mg, 0.14 mmol, 1 eq) and compound 3-3 (43 mg, 0.17 mmol, 1.2 eq) were dissolved in DMF (2 mL), potassium carbonate (39 mg, 0.28 mmol, 2 eq) was added at 25°C, and the mixture was stirred at 80°C for 6 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture and extracted three times with ethyl acetate (20 mL). The organic layer was dried and concentrated to obtain a crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 4:1) to obtain compound 3-4 (55 mg) as a yellow oil. ESI-MS m / z = 673.1 [M+1] + .

[0162] Step 3: Synthesis of compound 3

[0163] Compound 3-4 (55 mg, 0.07 mmol, 1 eq) was dissolved in 1,4-dioxane solution (1 mL) and 6 M aqueous hydrochloric acid solution (0.5 mL) was added with stirring at 25°C. The reaction mixture was stirred at 25°C for 2 hours. Compound 3 (7 mg) was obtained by purification via reverse phase preparative chromatography (acetonitrile / 0.05% formic acid). ESI-MS m / z = 427.0 [M+1] + .

[0164] 1H NMR (400MHz, CD3OD) δ7.39(dd,J=14.4,7.0Hz,3H),7.32–7.28(m,2H),6.80(d,J=8.8Hz,1H),4.58(d,J=6.2Hz,3H),4. 14(t,J=10.3Hz,1H),3.94(dd,J=10.5,5.9Hz,1H),3.73–3.56(m,5H),3.48–3.42(m,1H),1.90(dd,J=13.0,6.8Hz,2H).

[0165] Example 4 Preparation of Compound 4

[0166] Step 1: Synthesis of compound 4-1

[0167] Intermediate 1 (500 mg, 1.33 mmol, 1 eq) was dissolved in THF (20 mL), and then BH3 (13.3 mL, 1 M in THF, 10 eq) was slowly added at room temperature. The reaction solution was slowly heated to 70°C and reacted at 70°C for 12 hours. The reaction was completed. The mixture was quenched with saturated aqueous ammonium chloride (20 mL) and then extracted with ethyl acetate (20 mL*3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by preparative plate (PE / EA = 1:1) to obtain compound 4-1 (310 mg, 70% content, 70.6% yield) as a colorless oil. ESI-MS m / z = 232.1 [M+H] + .

[0168] Step 2: Synthesis of compound 4-3

[0169] Compound 4-1 (250 mg, 1.08 mmol, 1 eq), EDCI (249.21 mg, 1.3 mmol, 1.2 eq), HOBT (175.5 mg, 1.3 mmol, 1.2 eq), and DIPEA (278.64 mg, 2.16 mmol, 2 eq) were dissolved in DMF (15 mL) and stirred at room temperature for 20 minutes. The reaction was completed. The mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL*3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by preparative plate (PE / EA = 1:1) to obtain compound 4-3 (140 mg, yield: 41.7%) as a colorless oil. ESI-MS m / z = 313.0 [M+H] + .

[0170] Step 3: Synthesis of compound 4-4

[0171] Compound 4-3 (140 mg, 0.45 mmol, 1 eq) was dissolved in anhydrous ethanol (5 mL), cooled to 0°C, and then hydrochloric acid gas was introduced for 20 min. After the reaction was complete, anhydrous ethanol (15 mL) was added, purged with nitrogen, and stirred for 2 hours to obtain compound 4-4, which was used directly in the next step.

[0172] Step 4: Synthesis of Compound 4

[0173] The reaction mixture of compound 4-4 in step 3 was first introduced into NH3 and stirred at 0°C for 30 minutes. After completion of the reaction, the concentrate was directly dried to dryness. Water (5 mL) was then added and lyophilized to obtain a white solid. The solid was then dissolved in methanol / dichloromethane and filtered. The mother liquor was then dried to dryness to obtain the crude product. This was then preparatively purified (ACN / water, 0.1% FA) to afford compound 4 (6.31 mg, two-step yield: 4.3%). ESI-MS m / z = 330.0 [M+H] + .

[0174] 1 H NMR (400MHz, MeOD) δ8.53 (s, 0.21H, FA), 7.24 (dd, J=8.8, 4.3Hz, 1H), 6.75 (dd, J=8.8, 5.6Hz, 1H), 4.31–4.10 (m, 1H), 4.0 8–3.87(m,1H),3.81(dd,J=17.5,8.3Hz,1H),3.72–3.53(m,2H),3.49–3.37(m,1H),2.87–2.71(m,4H),2.15–1.98(m,1H).

[0175] Example 5 Preparation of Compound 5

[0176] Compound 5-1 (5 g, 0.02 mol, 1 eq) was dissolved in toluene (50 mL), followed by the addition of p-toluenesulfonic acid (0.08 g, 0.4 mmol, 0.02 eq) and ethylene glycol (2.83 g, 0.04 mol, 3 eq). The reaction mixture was allowed to react at 110°C for 16 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by a normal silica gel column (petroleum ether:ethyl acetate = 20:1) to afford compound 5-2 (5 g, yield: 66.67%) as a clear oil.

[0177] 1H NMR (400MHz, CDCl3) δ7.51 (dt, J=3.7, 1.6Hz, 2H), 7.41 (t, J=1.5Hz, 1H), 5.77 (s, 1H), 4.09 (ddd, J = 7.1, 5.9, 3.8 Hz, 2H), 4.04 ( ddd, J = 8.2, 5.9, 3.8 Hz, 2H).

[0178] Compound 5-2 (5 g, 0.02 mol, 1 eq) was dissolved in tetrahydrofuran (50 mL), cooled to -70°C, and then n-butyllithium (28.5 mL, 0.06 mol, 3 eq, 2.5 M) was slowly added dropwise. After the addition was complete, the reaction mixture was allowed to react at -70°C for 30 minutes. Acetone (3.31 g, 0.057 mol, 3 eq) was then slowly added at -70°C. Stirring was continued at this temperature for 1 hour. After the reaction was complete, the mixture was quenched with water and extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by a normal phase silica gel column to obtain compound 5-3 (2.2 g, yield: 43.16%) as a transparent liquid.

[0179] 1 H NMR (400MHz, CDCl3) δ7.50–7.44(m,2H),7.36(s,1H),5.77(s,1H),4.15–4.10(m,2H),4.07–3.99(m,2H),1.56(s,6H).

[0180] Compound 5-3 (2.1 g, 8.7 mmol, 1.0 eq) was dissolved in acetone (15 mL), followed by the addition of p-toluenesulfonic acid (0.3 g, 1.7 mmol, 0.2 eq). After the addition was complete, the reaction mixture was allowed to react at 20°C for 1 hour. After the reaction was complete, the mixture was quenched with water and extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by a normal phase silica gel column to obtain compound 5-4 (1.2 g, P: 70%, yield: 62.07%) as a yellow oil. ESI-MS m / z = 181.1 [M-OH] + .

[0181] Compound 5-4 (1 g, 0.01 mol, 1.0 eq) was dissolved in an amine methanol solution (30 mL) and stirred overnight at room temperature. Sodium borohydride (0.57 g, 15.1 mmol, 1.5 eq) was then added at 0°C. The reaction mixture was allowed to react at 20°C for 2 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by a normal phase silica gel column to obtain compound 5-5 (1.2 g, yield: 47.52%) as a transparent oil. ESI-MS m / z = 200.1 [M+H]+ .

[0182] Compound 5-5 (350 mg, 1.75 mmol, 1.0 eq) was dissolved in ethanol (1 mL), followed by the addition of intermediate 2 (708 mg, 1.75 mmol, 1 eq). After the addition was complete, the reaction mixture was allowed to react at 80°C for 8 hours. After completion of the reaction, the mixture was extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was chromatographed on a silica gel plate (PE:EA = 1:2) to obtain compound 5-6 (600 mg, yield: 55.21%) as a transparent oil. ESI-MS m / z = 557.2 [M+H] + .

[0183] Compound 5-6 (600 mg, 1.08 mmol, 1.0 eq) was dissolved in di-N, N-dimethylformamide (5 mL), 4-bromobutane trinitrile (175 mg, 1.18 mmol, 1.1 eq) and potassium carbonate (445 mg, 3.23 mmol, 3 eq). The mixture was stirred at 60 ° C for 5 hours. After completion, the mixture was cooled with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by chromatography on silica gel plates (DCM: MeOH = 20: 1) to give 5-7 (430 mg, yield: 51.18%) as a yellow oil. ESI-MS m / z = 624.2 [M + H] + .

[0184] Trimethylaluminum (1.6 ml, 3.20 mmol, 10 eq, 2 M in THF) was added to a solution of ammonium chloride (85 mg, 1.60 mmol, 5 eq) in toluene (3 ml) at 0°C under nitrogen protection. The mixture was stirred at this temperature for 30 minutes, then heated to 20°C and stirred at this temperature for 2 hours. Then, a solution of compound 5-7 (200 mg, 0.32 mmol, 1 eq) in toluene (1 mL) was added. The mixture was stirred at 80°C for 16 hours. After the reaction was completed, the mixture was quenched with water and then extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was subjected to acid-phase reverse-phase preparation to obtain compound 5 (4.38 mg, yield: 2.59%, FA salt) as a white solid. ESI-MS m / z = 513.2 [M+H] + .

[0185] 1H NMR (400MHz, MeOD) δ7.44(d,J=12.6Hz,2H),7.32–7.20(m,2H),6.78(d,J=8.8Hz,1H),4.12-3.92(m,3H),3.78–3. 57(m,3H),3.44(dd,J=17.5,10.3Hz,3H),2.59(dd,J=15.8,7.2Hz,2H),2.11(dd,J=15.7,8.0Hz,2H),1.51(s,6H).

[0186] Example 6 Preparation of Compound 6

[0187] Intermediate 2 (200 mg, 0.49 mmol, 1 eq) was dissolved in ethanol (4 mL), and 3-chloroaniline (252 mg, 1.96 mmol, 4 eq) was added at 25°C. The mixture was sealed and stirred at 100°C for 3 days. After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL). The organic layer was dried and concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 6-1 (150 mg, 56% yield) as a yellow oil. ESI-MS m / z = 487.0 [M+1] + .

[0188] Compound 6-1 (150 mg, 0.31 mmol, 1 eq) and 4-bromobutyronitrile (229 mg, 1.55 mmol, 5 eq) were dissolved in DMF (3 mL). Potassium carbonate (214 mg, 1.55 mmol, 3 eq) was added at 25°C, and the mixture was stirred at 80°C in a sealed tube for 16 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL). The organic layer was dried and concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 6-2 (200 mg, P: 70%, 73% yield) as a yellow oil. ESI-MS m / z = 552.1 [M+1] + .

[0189] Ammonium chloride (82 mg, 1.5 mmol, 5 eq) was dissolved in toluene (2 mL). Trimethylaluminum (1.5 mL, 3 mmol, 10 eq, 2 mol / L) was added at 0°C under nitrogen. The mixture was stirred at 0°C for half an hour and at 20°C for 2 hours. A 1 mL toluene solution of compound 6-2 (170 mg, 0.30 mmol, 1 eq) was added dropwise to the reaction mixture, and the mixture was stirred at 80°C for 16 hours. After completion of the reaction, methanol (10 mL) was added to quench the reaction mixture. The reaction mixture was filtered, washed three times with methanol, and the filtrate was dried to give the crude product. Reverse preparative chromatography (acetonitrile / 0.05% FA) afforded compound 6 (13.3 mg, P: 99.57%, 9.95% yield) as a light pink solid. MS m / z = 439.0 [M+1] + .

[0190] 1 H NMR(400MHz,MeOD)δ8.54(s,1.46H,FA),7.58(dd,J=12.7,5.6Hz,3H),7.45–7.36(m,1H),7.29(d,J=8.8Hz,1H),6.84(d, J=8.8Hz,1H),4.63(s,1H),4.09(t,J=10.4Hz,1H),3.95–3.73(m,3H),3.24(s,2H),2.57–2.44(m,2H),2.18–1.86(m,2H).

[0191] Example 7 Preparation of Compound 7

[0192] Compound 3-2 (200 mg, 0.4 mmol, 1 eq) and 4-bromobutyronitrile (237 mg, 1.6 mmol, 4 eq) were dissolved in DMF (5 mL). Potassium carbonate (166 mg, 1.2 mmol, 3 eq) was added at 25°C and stirred at 80°C for 6 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture and the mixture was extracted three times with ethyl acetate (20 mL). The organic layer was dried and concentrated to obtain a crude product. Column chromatography (petroleum ether:ethyl acetate = 10:1) afforded compound 7-1 (200 mg, P: 80%, 78.55% yield) as a yellow oil. ESI-MS m / z = 566.0 [M+1] + .

[0193] Ammonium chloride (81 mg, 1.5 mmol, 5 eq) was dissolved in toluene (2 mL), and trimethylaluminum (1.5 mL, 3 mmol, 10 eq, 2 mol / L) was added at 0°C under nitrogen. The mixture was stirred at 0°C for half an hour and at 20°C for 2 hours. A 1 mL toluene solution of compound 7-1 (170 mg, 0.30 mmol, 1 eq) was added dropwise to the reaction mixture and stirred at 80°C for 16 hours. After the reaction was completed, methanol (10 mL) was added to the reaction mixture to quench the mixture. The reaction mixture was filtered, washed three times with methanol, and the filtrate was dried to give the crude product. The product was then prepared by reverse reaction (acetonitrile / 0.05% FA) to give compound 7 (18.16 mg, P: 92.60%, 12.27% yield) as a light pink solid. ESI-MS m / z = 453.1 [M+1] + .

[0194] 1 H NMR(400MHz,MeOD)δ8.54(s,1.53H,FA),7.43(d,J=8.9Hz,1H),7.38(d,J=7.3Hz,1H),7.36–7.32(m,2H),7.30(t,J=3.7Hz,1H),6.81(d,J=8.8Hz,1H) ,4.65–4.54(m,3H),4.15(t,J=10.2Hz,1H),3.94(dd,J=10.4,5.8Hz,1H),3 .74–3.39(m,3H),3.30–3.22(m,1H),2.66–2.45(m,2H),2.21–2.01(m,2H).

[0195] Example 8 Preparation of Compound 8

[0196] Compound 3-2 (400 mg, 0.80 mmol, 1 eq) was dissolved in N,N-dimethylformamide (10 mL), followed by the addition of compound 8-0 (657.6 mg, 2.4 mmol, 3 eq), cesium carbonate (780 mg, 2.4 mmol, 3 eq), and sodium iodide (119.2 mg, 0.8 mmol, 1 eq). After the addition was complete, the reaction mixture was allowed to react at 20°C for 4 hours. After completion, the reaction was quenched with water and then extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was chromatographed on silica gel (PE:EA = 1:2) to obtain compound 8-1 (357 mg, yield: 16.93%) as a yellow oil. ESI-MS m / z = 693.2 [M+H] + .

[0197] Compound 8-1 (357 mg, 0.51 mmol, 1 eq) was dissolved in dichloromethane / 1M hydrochloric acid (5 mL / 5 mL), followed by the addition of 10% sodium hypochlorite (1.13 g, 1.53 mmol, 3 eq) at -10°C. The reaction mixture was allowed to react at -10°C for 20 minutes, then extracted with dichloromethane and ammonia gas was introduced, followed by a half-hour reaction at room temperature. Upon completion, the reaction mixture was dried to afford crude compound 8-2, which was used directly in the next reaction. ESI-MS m / z = 620 [M+1] + .

[0198] Compound 8-2 (86 mg, 0.14 mmol, 1.0 eq) was dissolved in 1,4-dioxane (3 mL), followed by the addition of 6 M hydrochloric acid (3 mL). After the addition was complete, the reaction mixture was allowed to react at 20°C for half an hour. After the reaction was complete, the mixture was quenched with water and then extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was subjected to acid-phase reverse-phase purification to obtain compound 8 (5 mg, yield: 7.08%) as a white solid. ESI-MS m / z = 490.0 [M+H] + .

[0199] 1 H NMR (400MHz, MeOD) δ8.54(s,1H,FA),7.43–7.34(m,3H),7.31(d,J=2.5Hz,1H),7.29(s,1H),6.81(d,J=8.8Hz,1H),4.65–4.53(m,3H),4. 16(t,J=10.3Hz,1H),3.95(dd,J=10.4,5.7Hz,1H),3.76–3.55(m,2H),3.52–3.43(m,1H),3.15(dt,J=5.0,4.5Hz,3H),2.32–2.11(m,2H).

[0200] Example 9 Preparation of Compound 9

[0201] Compound 9-1 (5 g, 24.8 mmol, 1 eq) was dissolved in THF (100 mL), cooled to 0°C, and then a solution of borane in tetrahydrofuran (124 mL, 124 mmol, 5 eq, 1 mol / L) was slowly added. The reaction was allowed to react at room temperature for 4 hours until the reaction was complete. The mixture was quenched with water and then extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The product 9-2 (4.6 g, yield: 98.5%) was obtained after purification by a normal phase column chromatography (PE / EA = 1:0 to 5:1). ESI-MS m / z = 188.1 [M+H] + .

[0202] Compound 9-2 (4.6 g, 24.5 mmol, 1 eq) was dissolved in dichloromethane (50 mL), cooled to 0°C, and triphenylphosphine (9.6 g, 36.75 mmol, 1 eq) was added and stirred for 5 minutes. Carbon tetrabromide (12.2 g, 36.75 mmol, 1 eq) was then added. The reaction was stirred at room temperature for 16 hours. Upon completion, the mixture was directly wet-loaded and purified by normal phase column chromatography (PE) to obtain product 9-3 (5 g, yield: 82%).

[0203] Compound 9-3 (5 g, 20 mmol, 1 eq) was slowly added to a 200 mL methanol solution of NH3 at room temperature and stirred for 4 hours. After the reaction was complete, the crude product was directly concentrated by rotary evaporation and then slurried with ethyl acetate (3 mL) to obtain product 9-4 (2.1 g, yield: 100%). ESI-MS m / z = 186 [M+H] +

[0204] 1 H NMR (400MHz, MeOD) δ8.29-8.28(m,2H),7.9(s,1H),4.17(m,2H).

[0205] Compound 9-4 (360 mg, 1.9 mmol, 1.2 eq) and intermediate 2 (639.7 mg, 1.58 mmol, 1 eq) were dissolved in anhydrous ethanol (5 mL), then heated to 80°C and stirred for 3 hours. After completion of the reaction, the mixture was concentrated to obtain a crude product, which was then purified on a preparative plate (PE / EA = 1:1) to afford a colorless liquid, compound 9-5 (410 mg, yield: 47.7%). ESI-MS m / z = 544.0 [M+H] + .

[0206] Compound 9-5 (510 mg, 0.94 mmol, 1 eq), K2CO3 (323.4 mg, 2.34 mmol, 2.5 eq), and 1876-6A (346.3 mg, 2.34 mmol, 2.5 eq) were dissolved in DMF (25 mL) and then heated to 80°C with stirring for 12 hours. After completion, the reaction was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL*3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by preparative plate (PE / EA = 1:1) to obtain compound 9-6 (310 mg, yield: 53.9%) as a colorless oil. ESI-MS m / z = 611.1 [M+H] + .

[0207] Compound 9-6 (310 mg, 0.51 mmol, 1 eq) and Zn (160.65 mg, 2.55 mmol, 5 eq) were reacted in glacial acetic acid (35 mL) at room temperature for 15 min. The pH was adjusted to 8-9 with saturated aqueous sodium carbonate (20 mL), followed by extraction with ethyl acetate (20 mL x 3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified on a preparative plate (PE / EA = 1:1) to afford compound 9-7 (200 mg, yield: 67.6%) as a colorless oil. ESI-MS m / z = 581.2 [M+H] + .

[0208] Compound NH4Cl (51 mg, 0.96 mmol, 6.5 eq) was dissolved in anhydrous toluene (5 mL). The mixture was cooled to 0°C under nitrogen, and then a solution of trimethylaluminum in tetrahydrofuran (0.96 mL, 1.92 mmol, 13 eq) was slowly added dropwise. After the addition was complete, the mixture was slowly warmed to room temperature and stirred for 2 hours. 9-7 (80 mg, 0.14 mmol, 1 eq) was added. The reaction mixture was then stirred at 80°C overnight. After the reaction was complete, the mixture was cooled to room temperature and slowly quenched with methanol. The reaction mixture was filtered and the mother liquor was dried to obtain the crude product. The crude product was subjected to reverse phase purification (ACN / water, 0.1% FA) to afford compound 9 (2.1 mg, pH 92.84%, yield 3.2%). ESI-MS m / z = 470.1 [M+H] + .

[0209] 1 H NMR (400MHz, MeOD) δ8.53 (s, 2.92H, FA), 7.29 (dd, J=8.8, 4.8Hz, 1H), 6.80 (dd ,J=12.4,8.8Hz,1H),6.67–6.48(m,3H),4.68(d,J=10.3Hz,1H),4.44(s,1H), 4.10(t,J=10.1Hz,1H),3.94(dd,J=10.5,6.5Hz,1H),3.54–3.41(m,3H),2.61 (dd, J = 19.9, 12.8 Hz, 2H), 2.03 ( d, J = 5.8 Hz, 2H), 1.89 ( dd, J = 13.7, 6.3 Hz, 2H).

[0210] Example 10 Preparation of Compound 10

[0211] Compound 10-1 (26 g, 88.7 mmol, 1 eq) was dissolved in THF (300 mL). The reaction mixture was cooled to -60°C under nitrogen, followed by the slow dropwise addition of LDA (66.5 mL, 133.05 mmol, 1.5 eq). The mixture was stirred at this temperature for 30 min. Iodine (33.5 g, 133.05 mmol, 1.5 eq, dissolved in 50 mL of THF) was then slowly added dropwise to the reaction mixture. The reaction was allowed to react for 1.5 hours until completion. After the addition of the ingredients, the reaction mixture was allowed to react at 20°C for 2 hours. After completion, the reaction was quenched with water and extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 10:1) to afford compound 10-2 (31 g, yield: 83.8%) as a yellow oil.

[0212] 1 H NMR (400MHz, MeOD) δ7.50 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.34 (s, 2H), 3.79-3.83 (m, 2H), 1.21-1.29 (m, 2H), 0.01 (s, 9H).

[0213] Compound 10-2 (15 g, 35.8 mmol, 1 eq), 10-3a (10.56 g, 35.8 mmol, 1 eq), Pd(dppf)Cl2 (2.62 g, 3.58 mmol, 0.1 eq), and K2CO3 (12.35 g, 89.5 mmol, 2.5 eq) were added to dioxane and water (150 mL / 20 mL) and reacted at 70°C for three hours under nitrogen. After completion, the reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (200 mL x 3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by normal phase column chromatography (PE / EA = 1:0 to 1:1) to obtain compound 10-3 (10.2 g, 90% content, 61% yield) as a colorless oil. ESI-MS m / z = 360 [M-Boc] + .

[0214] Compound 10-3 (9.5 g, 20.6 mmol, 1.0 eq) was dissolved in a 1,4-dioxane solution (100 mL, 4 M) in hydrochloric acid and stirred at 20°C for 6 hours. After completion of the reaction, the mixture was concentrated by rotary evaporation to afford crude product 10-4 (5.6 g, yield: 100%). ESI-MS m / z = 230 [M+H] + .

[0215] Compound 10-4 (5.6 g, 24.5 mmol, 1 eq) and PtO2 (4.6 g, 20.3 mmol, 0.83 eq) were added to methanol (50 mL). The reaction mixture was stirred in a 30°C oil bath under hydrogen (0.1 MPa) for 12 hours. After completion of the reaction, the mixture was filtered and the filtrate was dried to afford compound 10-5 (4.9 g, 90% content, 94.8% yield) as a colorless oil. ESI-MS m / z = 232 [M+H] + .

[0216] 3-Chlorocyclobutane-1-carboxylic acid (185.9 mg, 1.39 mmol, 1 eq), HATU (633.84 mg, 1.67 mmol, 1.2 eq), and DIPEA (448.3 mg, 3.48 mmol, 2.5 eq) were stirred in DMF (15 mL) at room temperature for 10 minutes. 10-5 (322 mg, 1.39 mmol, 1.0 eq) was then slowly added. The reaction mixture was allowed to react at 25°C for 30 minutes until completion. The mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified on a preparative plate (PE / EA = 1:1) to afford compound 10-6 (189 mg, 41.7% yield) as a colorless oil. ESI-MS m / z = 348 [M+H] + .

[0217] Compound 10-6 (140 mg, 0.4 mmol, 1 eq), 4-methoxybenzyl mercaptan (61.6 mg, 0.4 mmol, 1 eq), Cs2CO3 (390 mg, 1.2 mmol, 3 eq), and NaI (17.9 mg, 0.12 mmol, 0.3 eq) were reacted in DMF (15 mL) at 80°C for 3 hours. The reaction was completed. The mixture was quenched with saturated aqueous ammonium chloride (20 mL) and then extracted with ethyl acetate (20 mL x 3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified on a preparative plate (PE / EA = 1:1) to obtain compound 10-7 (140 mg, yield: 75.2%) as a colorless oil. ESI-MS m / z = 466.1 [M+H] + .

[0218] Compound 10-7 (130 mg, 0.28 mmol, 1.0 eq) was dissolved in dichloromethane / 1M hydrochloric acid (3 / 3 mL), and then 10% sodium hypochlorite (621.6 mg, 0.84 mmol, 3 eq) was added at -10 degrees. After the addition was complete, the reaction solution was reacted at -10 degrees for 20 minutes, and then the reaction solution was extracted with dichloromethane and ammonia gas was introduced to react at room temperature for half an hour. After the reaction was completed, the reaction solution was dried to obtain a crude product, which was then subjected to reverse phase preparation (ACN / water, 0.1 FA) to obtain the racemate compound 10 (20.58 mg, P: 95.37%, yield: ESI-MS m / z = 393.0 [M+H] + .

[0219] 1 H NMR (400MHz, MeOD) δ7.23 (dd, J=8.8, 3.9Hz, 1H), 6.73 (dd, J=8.8, 3.6Hz, 1H), 4.28–4. 08(m,1H),4.05–3.70(m,3H),3.63–3.24(m,3H),2.78–2.42(m,5H),2.12–1.95(m,1H).

[0220] Example 11 Preparation of Compound 11

[0221] 3-(Methylthio)propionic acid (310 mg, 2.59 mmol, 1 eq), triethylamine (1090 mg, 10.77 mmol, 4 eq), and HATU (1064 mg, 2.8 mmol, 1.1 eq) were dissolved in DMF (10 mL). 10-5 (500 mg, 2.15 mmol, 1 eq) was added at 25°C, and the mixture was stirred at 20°C for 1 hour. After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (20 mL). The organic layer was dried and concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 11-1 (550 mg, 68.74% yield) as a yellow oil. ESI-MS m / z = 334.1 [M+1] + .

[0222] Compound 11-1 (430 mg, 1.29 mmol, 1 eq) was dissolved in acetonitrile (5 mL) / water (5 mL). Potassium peroxymonosulfate (395 mg, 0.64 mmol, 0.5 eq) was added at 25°C and stirred at 20°C for 1 hour. After completion of the reaction, water (10 mL) was added to the reaction mixture and the mixture was extracted three times with ethyl acetate (20 mL). The organic layer was dried and concentrated to obtain the crude product. Column chromatography (petroleum ether:ethyl acetate = 1:1) afforded compound 11-2 (280 mg, 61.52% yield) as a yellow oil. ESI-MS m / z = 350.0 [M+1] + .

[0223] Compound 11-2 (200 mg, 0.57 mmol, 1 eq) and ammonium carbonate (220 mg, 2.23 mmol, 4 eq) were dissolved in methanol (10 mL). Iodobenzene acetate (552 mg, 1.71 mmol, 3 eq) was added at 25°C and stirred at 25°C for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture and extracted three times with dichloromethane (20 mL). The organic layer was dried and concentrated to obtain a crude product, which was then prepared by reverse reaction (acetonitrile / 0.05% FA) to obtain a white solid racemate of compound 11 (75.9 mg, P: 97.03%, 35.60% yield). ESI-MS m / z = 365.1 [M+1] + .

[0224] 1 H NMR(400MHz,MeOD)δ7.25(dd,J=8.8,4.2Hz,1H),6.76(dd,J=8.8,5.5Hz,1H),4.35–3.81(m,3H),3.79–3.59(m,2H), 3.51(ddd,J=19.5,12.5,5.5Hz,2H), 3.07(d,J=8.0Hz,3H), 3.00–2.85(m,2H), 2.82–2.60(m,1H), 2.18–1.99(m,1H).

[0225] Example 12 Preparation of Compound 12

[0226] Compound 12-1 (5 g, 39 mmol, 1 eq) was dissolved in methanol (50 mL), followed by the dropwise addition of concentrated sulfuric acid (5 mL) at room temperature. The reaction mixture was heated to 60°C and stirred overnight. The reaction was complete. The mixture was cooled to room temperature and concentrated by rotary evaporation. The concentrate was dissolved in ethyl acetate and the pH was adjusted to 9-8 with saturated aqueous sodium carbonate. The mixture was then extracted with ethyl acetate (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by rotary evaporation to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 1:0 to 10:1) to afford compound 12-2 (4.5 g, yield: 83.6%) as a yellow oil. ESI-MS m / z = 143.1 [M+H] + .

[0227] Compound 12-2 (4.2 g, 29.6 mmol, 1 eq) was dissolved in methanol (20 mL), then cooled to 0°C and slowly added with sodium borohydride (3.18 g, 88.8 mmol, 3 eq). The reaction mixture was slowly warmed to room temperature and stirred for 3 hours. After completion, the mixture was quenched with saturated aqueous ammonium chloride (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by normal phase column chromatography (PE / EA = 1:0 to 1:1) to obtain compound 12-3 (3.6 g, 90% content, 85.7% yield) as a colorless oil. ESI-MS m / z = 145.2 [M+H] + .

[0228] Compound 12-3 (1.8 g, 12.5 mmol, 1.0 eq) and triethylamine (3.79 g, 37.5 mmol, 3 eq) were added to dichloromethane (20 mL). The mixture was then cooled to 0°C and methylsulfonyl chloride (2.85 g, 25.0 mmol, 2 eq) was added. The reaction mixture was stirred for 1 hour. Upon completion of the reaction, the mixture was concentrated by rotary evaporation to afford crude product 12-4 (2 g, 100% yield).

[0229] Compound 12-5a (2.1 g, 13.5 mmol, 1.5 eq) and K2CO3 (3.1 g, 22.5 mmol, 2.5 eq) were stirred in DMF (20 mL) at room temperature for 10 min. Compound 12-4 (2 g, 9 mmol, 1 eq) was then added to the reaction mixture at room temperature, and the reaction mixture was stirred at 40°C for 4 hours. After completion of the reaction, the mixture was quenched with saturated sodium chloride aqueous solution and extracted with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and dried to obtain the crude product. The crude product was purified on a preparative plate (PE / EA = 1:1) to obtain product 12-5 (1.5 g, content: 40%, yield: 25.6%). ESI-MS m / z = 303 [M+Na] + .

[0230] Compound 12-5 (1.6 g, 5.7 mmol, 1 eq, content: 40%) was dissolved in methanol (20 mL), followed by the slow addition of lithium hydroxide (273 mg, 11.4 mmol, 5 eq, dissolved in 1 mL of water). The mixture was stirred at room temperature for one hour. Upon completion, the reaction solution was extracted with ethyl acetate (20 mL x 3). The aqueous layer was then adjusted to pH 2-3 with dilute hydrochloric acid (2 M) and extracted with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and dried to afford crude product 12-6 (560 mg, yield: 83.2%). ESI-MS m / z = 289.1 [M+Na] + .

[0231] Compound 12-6 (100 mg, 0.38 mmol, 1 eq), HATU (171 mg, 0.45 mmol, 1.2 eq), and DIPEA (123 mg, 0.95 mmol, 2.5 eq) were stirred in DMF (15 mL) at room temperature for 10 minutes. 1877-5 (88 mg, 0.38 mmol, 1.0 eq) was then slowly added, and the reaction mixture was allowed to react at 25°C for 20 minutes until complete. The mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified on a preparative plate (PE / EA = 1:1) to afford compound 12-7 (80 mg, yield: 41.7%) as a colorless oil. ESI-MS m / z = 480.0 [M+H] + .

[0232] Compound 12-7 (80 mg, 0.17 mmol, 1.0 eq) was dissolved in dichloromethane / 1M hydrochloric acid (3 / 3 mL), and then 10% sodium hypochlorite (377.4 mg, 0.51 mmol, 3 eq) was added at -10°C. After the addition was complete, the reaction solution was reacted at -10°C for 20 minutes, then the reaction solution was extracted with dichloromethane and ammonia gas was introduced and reacted at room temperature for half an hour. After the reaction was completed, the reaction solution was dried to obtain a crude product, which was then subjected to reverse phase purification (ACN / water, 0.1 FA) to obtain compound 12 (1.26 mg, P: 95.37%. ESI-MS m / z = 407 [M+H] + .

[0233] 1H NMR(400MHz,MeOD)δ8.50(s,0.38H,FA),7.23(dd,J=8.8,4.2Hz,1H),6.74(dd,J=8.8,4.1Hz,1H),4.17(dq,J=37.3,9.7Hz,1H),3. 96–3.69(m,2H),3.68–3.33(m,4H),3.16–3.01(m,1H),2.67(ddd,J=59.1,25.3,14.2Hz,1H),2.40–2.26(m,1H),2.23–1.86(m,5H).

[0234] Example 13 Preparation of Compound 13

[0235] Compound 13-1 (2.5 g, 8.8 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of 4-methoxybenzylmercaptan (1.49 g, 9.6 mmol, 1.1 eq) and potassium carbonate (3.65 g, 26.4 mmol, 3 eq). The reaction mixture was allowed to react at 60°C for 2 hours. After completion, the mixture was quenched with water and extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified by a normal silica gel column (petroleum ether:ethyl acetate = 10:1) to afford compound 13-2 (1.9 g, yield: 62.5%) as a clear oil. ESI-MS m / z = 332.1 [M+Na] + .

[0236] Compound 13-2 (1.9 g, 6.1 mmol, 1.0 eq) was dissolved in dichloromethane (8 mL), followed by the addition of trifluoroacetic acid (2 mL). The reaction mixture was allowed to react at 20°C for 1 hour. After the reaction was complete, the compound was freed with saturated sodium bicarbonate aqueous solution and then dried to give crude product 13-3 (1.35 g). ESI-MS m / z = 209.3 [M+H] + .

[0237] Compound 13-3 (1.2 g, 5.7 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), followed by the addition of triethylamine (2.31 g, 22.8 mmol, 4 eq) and compound 13-3B (1.38 g, 6.8 mmol, 1.2 eq). After the addition was complete, the reaction mixture was allowed to react at 20°C for half an hour. After completion, the reaction was quenched with water and extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to give crude product 13-3A (1.6 g, P: 70%, yield: 52.63%). ESI-MS m / z = 397.1 [M+Na] + .

[0238] Compound 13-3A (1.6 g, 4.3 mmol, 1.0 eq) was dissolved in tetrahydrofuran (10 mL), followed by the addition of triethylamine (1.74 g, 17.2 mmol, 4 eq) and compound 10-5 (1.2 g, 5.1 mmol, 1.2 eq). After the addition was complete, the reaction mixture was allowed to react at 80°C for 20 hours. After the reaction was complete, the mixture was extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was purified by a normal phase silica gel column to obtain compound 13-4 (1.3 g, yield: 51.16%) as a yellow oil. ESI-MS m / z = 467.1 [M+H] + .

[0239] Compound 13-4 (300 mg, 0.64 mmol, 1.0 eq) was dissolved in dichloromethane / 1M hydrochloric acid (4 mL / 4 mL), and then 10% sodium hypochlorite (11.6 g, 12.8 mmol, 20 eq) was added at 0°C. After the addition was complete, the reaction solution was reacted at 0°C for half an hour. After the reaction was complete, the mixture was extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain 300 mg of crude yellow oily compound. The crude product was dissolved in 20 mL of an amine solution in tetrahydrofuran, and the reaction solution was reacted at 20°C for 1 hour. After the reaction was complete, the mixture was extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain the crude product. The crude product was subjected to acid-based reverse phase purification to obtain compound 13 (11.7 mg, yield: 4.62%) as a white solid. ESI-MS m / z = 394.0 [M+H] + .

[0240] 1 H NMR (400MHz, MeOD) δ7.22(d,J=8.8Hz,1H),6.72(d,J=8.8Hz,1H),4.36(t,J=8.8Hz,1H),4.26(dd,J=6.9,3.2Hz,2H),4.20–4. 03(m,3H),3.90(t,J=9.7Hz,1H),3.66(t,J=8.6Hz,1H),3.52–3.39(m,2H),2.68(d,J=1.9Hz,1H),1.98(dd,J=8.5,3.3Hz,1H).

[0241] Example 14 Preparation of Compound 14

[0242] Compound 14-1 (5 g, 35.7 mmol, 1 eq) and sodium iodide (2.68 g, 17.9 mmol, 0.5 eq) were dissolved in THF (10 mL). Lithium bistrimethylsilylamide (1 mol / L) (43 mL, 42.8 mmol, 1.2 eq) and 4-methoxybenzyl chloride (6.7 g, 42.8 mmol, 1.2 eq) were added at 0°C and stirred at 60°C for 2.5 hours. After completion of the reaction, water (100 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (100 mL). The organic layer was dried and concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to afford compound 14-2 (4.5 g, 43.7% yield) as a yellow oil. ESI-MS m / z = 275.1 [M+1] + .

[0243] Compound 14-2 (4.5 g, 16.2 mmol, 1 eq) was dissolved in ethanol (20 mL), and aqueous ammonia (10 mL) was added at 25°C. The mixture was stirred at 70°C for 16 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product. Column chromatography (pure ethyl acetate) afforded compound 14-3 (3 g, 64.29% yield) as a yellow oil. ESI-MS m / z = 246.1 [M+1] + .

[0244] Compound 14-3 (1 g, 4.1 mmol, 1 eq) was dissolved in THF (10 mL), and lithium aluminum tetrahydride (0.5 g, 12.3 mmol) was added at 0°C. The mixture was stirred at 25°C for 16 hours. After the reaction was completed, aqueous ammonium chloride (50 mL) was added to the reaction mixture and extracted three times with ethyl acetate (100 mL). The organic layer was dried and concentrated to obtain a crude product. Column chromatography (dichloromethane:methanol = 10:1) afforded compound 14-4 (0.8 g, 39.2% yield) as a yellow oil. ESI-MS m / z = 232.3 [M+1] + .

[0245] Compound 14-4 (200 mg, 0.5 mmol, 1 eq) and intermediate 2 (229 mg, 1 mmol, 2 eq) were dissolved in ethanol (5 mL) and stirred at 80°C for 2 days. After the reaction was completed, the reaction solution was concentrated to obtain a crude product, which was purified by column chromatography (dichloromethane:methanol=20:1) to obtain compound 14-5 (150 mg, 80.42% yield) as a yellow oil. ESI-MS m / z=589.2[M+1] + .

[0246] Compound 14-5 (130 mg, 0.22 mmol, 1 eq) and (3-bromopropoxy) (tert-butyl) dimethylsilane (168 mg, 0.66 mmol, 3 eq) were dissolved in DMF (5 mL), potassium carbonate (61 mg, 0.44 mmol, 2 eq) was added at 25 ° C and stirred at 80 ° C for 4 hours. After the reaction was completed, water (50 mL) was added to the reaction mixture and extracted three times with ethyl acetate (50 mL). The organic layer was dried and concentrated to obtain a crude product, which was then purified by column chromatography (pure ethyl acetate) to obtain compound 14-6 (200 mg, 85.24% yield) as a yellow oil. ESI-MS m / z = 761.4 [M + 1] + .

[0247] Compound 14-6 (150 mg, 0.2 mmol, 1 eq) was dissolved in trifluoroacetic acid (10 mL) and stirred at 100°C for 16 hours. After completion of the reaction, the reaction solution was concentrated to obtain a crude product. The reverse reaction was used to obtain compound 14 (1.7 mg, 2.08% yield, 95.24% purity at 214 nm) as a white solid. ESI-MS m / z = 397.1 [M+1] + .

[0248] 1 H NMR (400MHz, CD3OD) δ8.54 (s, 0.46H, FA), 7.47–7.09 (m, 1H), 6.80 (t, J = 9.1Hz, 1H), 6.10 (m, 1 H),4.55–4.46(m,2H),4.15–4.01(m,1H),3.99–3.85(m,1H),3.71–3.60(m,3H),3.48(dddd,J= 47.6, 36.7, 13.9, 7.3Hz, 4H), 2.29 (d, J = 4.4Hz, 3H), 1.96–1.78 (m, 2H).

[0249] Example 15 Preparation of Compound 15

[0250] Compound 14-1 (5 g, 35.7 mmol, 1 eq) was dissolved in tetrahydrofuran (50 mL) and then cooled to zero degrees Celsius. NaH (2.85 g, 71.4 mmol, 2 eq, 60% content) was slowly added. The reaction solution was stirred at this temperature for 10 min, and then SEMCl (8.89 g, 53.55 mmol, 1.5 eq) was slowly added dropwise. The temperature was slowly raised to room temperature and then stirred for 3 hours. After completion of the reaction, water (100 mL) was added to the reaction mixture and the mixture was extracted three times with ethyl acetate (100 mL). The organic layer was dried and concentrated to obtain the crude product, which was then purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to afford compound 15-1 (4.3 g, 43% yield) as a yellow oil. ESI-MS m / z = 256 [M-Me] + .

[0251] Compound 15-1 (3.2 g, 11.3 mmol, 1 eq) was dissolved in ethanol (20 mL), and aqueous ammonia (10 mL) was added at 25°C. The mixture was stirred at 80°C for 12 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product. Column chromatography (pure ethyl acetate) afforded compound 15-2 (0.52 g, yield: 18.6%) as a yellow oil. ESI-MS m / z = 256.2 [M+1] + .

[0252] Compound 15-2 (0.52 g, 2.04 mmol, 1 eq) was dissolved in THF (40 mL), and lithium aluminum tetrahydride (0.5 g, 12.3 mmol, 6 eq) was added at 0°C and stirred at 60°C for 12 hours. After the reaction was completed, the reaction mixture was allowed to cool to room temperature, and then aqueous ammonium chloride (50 mL) was added to the reaction mixture and extracted three times with ethyl acetate (100 mL). The organic layer was dried and concentrated to obtain a crude product, which was then purified by column chromatography (dichloromethane:methanol=10:1) to obtain compound 15-3 (0.31 g, yield: 67.5%) as a yellow oil. ESI-MS m / z=242.3[M+1] + .

[0253] Compound 15-3 (520 mg, 2.15 mmol, 1 eq) and intermediate 2 (868 mg, 2.15 mmol, 1 eq) were dissolved in ethanol (8 mL) and reacted at 80°C for 8 hours. After completion of the reaction, the reaction solution was concentrated to obtain a crude product. Column chromatography (dichloromethane:methanol = 20:1) afforded compound 15-4 (270 mg, yield: 23%) as a yellow oil. ESI-MS m / z = 599.2 [M+1] + .

[0254] Compound 15-4 (270 mg, 0.45 mmol, 1 eq), cesium carbonate (443 mg, 1.35 mmol, 3 eq), sodium iodide (20.25 mg, 0.135 mmol, 0.3 eq) and compound 8-0 (371.25 mg, 1.35 mmol, 3 eq) were dissolved in DMF (15 mL) and then stirred at 60 ° C for 12 hours. After the reaction was completed, water (50 mL) was added to the reaction mixture and extracted three times with ethyl acetate (50 mL). The organic layer was dried and concentrated to obtain a crude product, which was then purified by column chromatography (pure ethyl acetate) to obtain compound 15-5 (210 mg, 85.24% yield) as a yellow oil. ESI-MS m / z = 793.2 [M + 1] + .

[0255] Compound 15-5 (210 mg, 0.26 mmol, 1 eq) was dissolved in dichloromethane / 1M hydrochloric acid (5 / 5 ml), and then 10% sodium hypochlorite (260 mg, 0.26 mmol, 10 eq) was added at -10°C. After the addition was complete, the reaction solution was reacted at -10°C for 20 minutes. The reaction solution was then extracted with dichloromethane and ammonia gas was introduced, and the reaction was allowed to proceed for half an hour at room temperature. After the reaction was complete, the reaction solution was spin-dried to obtain the crude product, which was then purified on a preparative plate (DCM / MeOH = 10:1) to obtain product 15-6 (40 mg). ESI-MS m / z = 720.2 [M+1] + .

[0256] Compound 15-6 (40 mg, 0.056 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 ml), followed by the addition of 6 M hydrochloric acid (2 mL). After the addition was complete, the reaction mixture was allowed to react at 20°C for half an hour. After the reaction was complete, the mixture was quenched with water and then extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was subjected to an acid-based reverse phase reaction to obtain compound 15 (1.7 mg, yield: 6.8%) as a white solid. ESI-MS m / z = 460.0 [M+H] + .

[0257] 1 H NMR (400MHz, MeOD) δ7.30(d,J=8.8Hz,1H),6.81(d,J=8.8Hz,1H),6.09(s,1H),4.52(s,2H),4.12(t,J=10.3Hz,1H),3.96(dd ,J=10.5,6.1Hz,1H),3.74–3.57(m,3H),3.52–3.43(m,2H),3.16(dd,J=15.3,8.0Hz,2H),2.29(s,3H),2.19(d,J=4.3Hz,2H).

[0258] Example 16 Preparation of Compound 16

[0259] Compound 10-5 (500 mg, 2.15 mmol, 1 eq) and triethylamine (436 mg, 4.3 mmol, 2 eq) were dissolved in dichloromethane (5 mL). Chloroacetyl chloride (268 mg, 2.37 mmol, 1.1 eq) was added at 0°C and stirred at 0°C for 0.5 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product of compound 16-1 (500 mg), which was used directly in the next step. ESI-MS m / z = 308.0 [M+1] + .

[0260] Compound 16-2 (318 mg, 1.62 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL), sodium hydride (130 mg, 3.24 mmol, 2 eq, 60% purity) was added at 0 ° C, stirred at 0 ° C for 0.5 hours, compound 16-1 (500 mg, 1.62 mmol, 1 eq) was added, and stirred at 60 ° C for 16 hours. After the reaction was completed, water (50 mL) was added to the reaction mixture and extracted three times with ethyl acetate (100 mL). The organic layer was dried and concentrated to obtain a crude compound 16-3 (300 mg), which was used directly in the next step. ESI-MS m / z = 490.0 [M + 23] + .

[0261] Compound 16-3 (200 mg, 0.43 mmol, 1 eq) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 ml) was added at 20°C, and the mixture was stirred at 20°C for 30 minutes. After the reaction was completed, sodium bicarbonate aqueous solution (10 mL) was added to the reaction mixture to adjust the pH to 8 and the mixture was extracted three times with ethyl acetate (50 mL). The organic layer was dried and concentrated to obtain a crude product, which was then prepared by reverse reaction (acetonitrile / 0.05% formic acid) to obtain compound 16 (2.14 mg, 1.33% yield) as a white solid. ESI-MS m / z=368.0[M+1] + .

[0262] 1H NMR(400MHz,CD3OD)δ7.23(dd,J=8.8,3.5Hz,1H),6.73(dd,J=8.8,4.8Hz,1H),4.33–4.09(m,1 H),4.07–3.88(m,2H),3.88–3.74(m,2H),3.66(dd,J=18.6,9.1Hz,1H),3.59–3.38(m,1H),2.86 –2.55(m,1H),2.05(ddt,J=13.1,7.3,6.3Hz,1H).

[0263] Example 17 Preparation of Compound 17

[0264] Compound 17-1 (2.6 g, 16.5 mmol, 1.0 eq) and DIPEA (6.34 g, 49.5 mmol, 3 eq) were added to dichloromethane (30 mL), then cooled to 0°C and methylsulfonyl chloride (5.6 g, 49.5 mmol, 3 eq) was added. The reaction solution was stirred at 20°C for 12 hours. After completion of the reaction, the product was concentrated by rotary evaporation to afford crude product 17-2 (3.6 g, yield: 92%). ESI-MS m / z = 259 [M+Na] + .

[0265] Compound 4-methoxybenzylmercaptan (2.9 g, 19.05 mmol, 1.5 eq) and K2CO3 (4.39 g, 31.78 mmol, 2.5 eq) were stirred in DMF (20 mL) at room temperature for 10 min. 1887-2 (3 g, 12.7 mmol, 1 eq) was then added to the reaction mixture at room temperature, and the reaction mixture was stirred at 60°C for 12 hours. After completion of the reaction, the mixture was quenched with saturated sodium chloride solution and extracted with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and dried to obtain the crude product. The crude product was purified on a preparative plate (PE / EA = 1:1) to obtain product 17-3 (0.86 g, yield: 23.4%). ESI-MS m / z = 317.1 [M+Na] + .

[0266] Compound 17-3 (760 mg, 2.58 mmol, 1 eq) was dissolved in methanol (20 mL), followed by the slow addition of lithium hydroxide (273 mg, 11.4 mmol, 4.4 eq, dissolved in 1 mL of water). The mixture was stirred at room temperature for one hour. Upon completion, the reaction solution was extracted with ethyl acetate (20 mL x 3). The aqueous layer was then adjusted to pH 2-3 with dilute hydrochloric acid (2 M) and extracted with ethyl acetate (20 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and spun down to afford crude product 17-4 (490 mg, yield: 68%). ESI-MS m / z = 303.1 [M+Na] + .

[0267] Compound 17-4 (230 mg, 0.82 mmol, 1 eq), HATU (374.6 mg, 0.99 mmol, 1.2 eq), and DIPEA (264.5 mg, 2.05 mmol, 2.5 eq) were stirred in DCM (15 mL) at room temperature for 10 minutes. Compound 17-5 (190.24 mg, 0.82 mmol, 1.0 eq) was then slowly added, and the reaction mixture was allowed to react at 20°C for 20 minutes. The reaction was quenched with saturated aqueous ammonium chloride (20 mL), followed by extraction with ethyl acetate (20 mL x 3). The organic solvents were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was purified on a preparative plate (PE / EA = 1:1) to afford compound 17-5 (290 mg, yield: 71.6%) as a colorless oil. ESI-MS m / z = 494.1 [M+H]+.

[0268] Compound 17-5 (280 mg, 0.57 mmol, 1.0 eq) was dissolved in dichloromethane / 1M hydrochloric acid (10 / 10 mL), followed by the addition of 10% sodium hypochlorite (1.2 g, 1.7 mmol, 3 eq) at -10°C. The reaction mixture was allowed to react at -10°C for 3 hours. After completion, the reaction was quenched with water and then washed with dichloromethane (10 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and then spin-dried to obtain crude product 17-6 (160 mg crude), which was used directly in the next step. ESI-MS m / z = 440 / 442 [M+H] + .

[0269] Compound 17-6 (160 mg, 0.36 mmol, 1.0 eq) was dissolved in dichloromethane (10 ml), followed by the addition of ammonia in dioxane (20 mL, 0.4 M / L). The reaction mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the crude product was directly spin-dried and purified by preparative purification (ACN / H2O, 0.1% FA) to afford compound 17 (5.02 mg, yield: 3.3%). ESI-MS m / z = 421.1 [M+H] +.

[0270] 1 H NMR(400MHz,MeOD)δ7.23(dd,J=8.8,5.0Hz,1H),6.74(dd,J=8.8,4.6Hz,1H),4.34–4.03(m,1H),3.94–3.53(m,3H),3.43–3.36(m ,1H),2.81(dddd,J=65.7,60.6,14.5,7.0Hz,2H),2.35–1.95(m,6H),1.65(dddd,J=13.7,11.4,7.1Hz,2H),0.90(t,J=6.8Hz,2H).

[0271] Example 18 Preparation of Compound 19

[0272] Intermediate 1 (0.5 g, 1.33 mmol, 1 eq), compound 19-1 (255 mg, 1.33 mmol, 1 eq), Ruphos (62 mg, 0.13 mmol, 0.1 eq), Pd2(dba)3 (121.7 mg, 0.133 mmol, 0.1 eq), and cesium carbonate (1.08 g, 3.33 mmol, 2.5 eq) were dissolved in dioxane (15 mL). The reaction mixture was stirred at 100°C under nitrogen for 12 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched with water (20 mL). The mixture was then extracted with ethyl acetate (30 mL x 3). The organic layer was dried over anhydrous sodium sulfate, filtered, and dried to dryness to obtain the crude product, which was then purified on a preparative plate (PE / EA = 1:1) to obtain compound 19-2 (350 mg). ESI-MS m / z = 487.0 [M+H] + .

[0273] Compound 4-methoxybenzyl mercaptan (145 mg, 0.9 mmol, 1.3 eq), tBuOK (243 mg, 2.16 mmol, 3 eq), and compound 19-2 (350 mg, 0.72 mmol, 1 eq) were dissolved in dioxane (4 mL) and stirred at 80° C. for 2 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture and extracted three times with ethyl acetate (20 mL). The organic layer was dried and concentrated to obtain a crude product, which was purified by column chromatography (pure ethyl acetate) to obtain compound 19-3 (269 mg, yield: 61.8%) as a yellow oil. ESI-MS m / z=605.1[M+1] + .

[0274] Compound 19-3 (200 mg, 0.33 mmol, 1 eq) was dissolved in dichloromethane / 1M hydrochloric acid (5 / 5 mL), followed by the addition of 10% sodium hypochlorite (3.57 g, 4.96 mmol, 15 eq) at -10°C. The reaction mixture was allowed to react for 20 minutes at -10°C, then extracted with dichloromethane and introduced with ammonia gas for half an hour at room temperature. Upon completion of the reaction, the reaction mixture was spin-dried to obtain the crude product, which was then purified on a preparative plate (DCM / MeOH = 10:1) to afford product 19-4 (160 mg, 91% yield). ESI-MS m / z = 534.0 [M+1]. + .

[0275] Compound 19-4 (160 mg, 0.3 mmol, 1 eq) was dissolved in 1,4-dioxane (2 mL), followed by the addition of 6 M hydrochloric acid (2 mL). After the addition was complete, the reaction mixture was allowed to react at 20°C for half an hour. After the reaction was complete, the mixture was quenched with water and then extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was subjected to reverse phase purification to obtain compound 19 (6.07 mg, yield: 5%) as a white solid. ESI-MS m / z = 402.0 [M+H] + .

[0276] 1 H NMR (400MHz, MeOD) δ8.58(d,J=5.6Hz,1H),8.54(d,J=1.7Hz,1H),7.82(dd,J=5.6,2.1 Hz,1H),7.28(d,J=8.8Hz,1H),6.78(d,J=8.8Hz,1H),4.24(t,J=9.6Hz,1H),4.13(dd,J=9.4,6.8Hz,1H),3.15–2.86(m,3H).

[0277] Example 19 Preparation of Compound 20

[0278] Compound 20-1 (2 g, 14.2 mmol, 1 eq) and 4-methoxybenzyl mercaptan (2.4 g, 15.6 mmol, 1.1 eq) were dissolved in dioxane (10 mL). Potassium tert-butoxide (4.8 g, 42.6 mmol, 3 eq) was added at 25°C, and the mixture was stirred at 80°C for 16 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (100 mL). The organic layer was dried and concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to afford compound 20-2 (3.3 g, 84.51% yield) as a yellow oil. ESI-MS m / z = 276.1 [M+1] + .

[0279] Compound 20-2 (600 mg, 1.82 mmol, 1 eq), HATU (760 mg, 2 mmol, 1.1 eq), and N,N-diisopropylethylamine (704 mg, 5.45 mmol, 3 eq) were dissolved in N,N-dimethylformamide (5 mL). Compound 10-5 (422 mg, 1.82 mmol, 1 eq) was added at 20°C and stirred at 20°C for 1 hour. After completion of the reaction, water (50 mL) was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate (100 mL). The organic layer was dried and concentrated to obtain the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to afford compound 20-3 (800 mg, 81.01% yield) as a yellow oil. ESI-MS m / z = 489.0 [M+1] + .

[0280] Compound 20-3 (200 mg, 0.41 mmol, 1 eq) was dissolved in dichloromethane (2 mL) and 1 molar hydrochloric acid (2 mL). Sodium hypochlorite (3042 mg, 4.1 mmol, 10 eq) was added at 0°C and stirred at 0°C for 2 hours. After the reaction was completed, the reaction solution was spin-dried to obtain a crude product. The crude product was added to a solution of ammonia in dioxane (10 mL) and stirred at 20°C for 5 minutes. The reaction solution was spin-dried to obtain a crude product, which was then prepared by reverse reaction (acetonitrile / 0.05% FA) to obtain compound 20 (20.5 mg, 11.94 yield) as a white solid. ESI-MS m / z = 416.0 [M+1] + .

[0281] 1 H NMR (400MHz, CD3OD) δ8.84(dd,J=15.7,1.4Hz,1H),8.19(ddd,J=18.4,8.1,2.1Hz,1H),8.09–7.96(m,1H),7.22(dd,J=18.1,8.8Hz ,1H),6.73(dd,J=19.8,8.8Hz,1H),4.38–4.15(m,1H),4.10–3.93(m,1H),3.86–3.49(m,3H),2.81–2.48(m,1H),2.22–1.97(m,1H).

[0282] Example 20 Preparation of Compound 21

[0283] Compound 21-1A (500 mg, 3.22 mmol, 1 eq) was dissolved in 1,4-dioxane (10 mL), followed by the addition of 4-methoxybenzylmercaptan (547 mg, 3.55 mmol, 1.1 eq) and potassium tert-butoxide (1.09 g, 9.70 mmol, 3 eq). The reaction mixture was sealed and reacted at 80°C for 12 hours. After completion, the reaction was quenched with water, the pH was adjusted to 4-5 with 1M hydrochloric acid, and then extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by a normal flow silica gel column (DCM:MeOH = 10:1) to afford Compound 21-1 (250 mg, yield: 24.13%) as a yellow oil. ESI-MS m / z = 276.1 [M+H] + .

[0284] Compound 21-1 (220 mg, 0.80 mmol, 1 eq) was dissolved in dichloromethane (5 mL), followed by the addition of compound 10-5 (223 mg, 0.96 mmol, 1.2 eq), HATU (608 mg, 1.60 mmol, 2 eq), and N,N-diisopropylethylamine (413 mg, 3.20 mmol, 4 eq). After the addition was complete, the reaction mixture was allowed to react at 20°C for 1 hour. After completion, the mixture was quenched with water and extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by chromatography on silica gel (PE:EA = 3:1) to afford compound 21-2 (170 mg, 30.42% yield) as a white solid. ESI-MS m / z = 489.1 [M+H] + .

[0285] Compound 21-2 (150 mg, 0.31 mmol, 1.0 eq) was dissolved in dichloromethane / 1M hydrochloric acid (4 mL / 4 mL), followed by the addition of 10% sodium hypochlorite (4.56 g, 6.13 mmol, 20 eq) at 0°C. After the addition was complete, the reaction mixture was allowed to react at 0°C for 20 minutes. After completion of the reaction, the mixture was extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain 200 mg of the crude compound as a yellow oil. The crude product was dissolved in a solution of amine in tetrahydrofuran (20 mL), and the reaction mixture was allowed to react at 20°C for 20 minutes. After completion of the reaction, the mixture was extracted with dichloromethane. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was subjected to an acid-based reverse phase reaction to obtain Compound 21 (5.73 mg, yield: 4.49%) as a white solid. ESI-MS m / z = 416.0 [M+H] + .

[0286] 1H NMR(400MHz,MeOD)δ8.79(dd,J=13.8,4.9Hz,1H),8.09(d,J=12.7Hz,1H),7.72(ddd,J=16.4,4.9,1.5Hz,1H),7.28–7 .17(m,1H),6.74(dd,J=19.4,8.8Hz,1H),4.35–3.98(m,2H),3.87–3.46(m,3H),2.74–2.58(m,1H),2.20–2.02(m,1H).

[0287] Example 21 Preparation of Compound 22

[0288] Step 1: Synthesis of compound 22-2

[0289] Compound 22-1 (1 g, 9.4 mmol, 1 eq) and triethylamine (1.90 g, 0.019 mol, 2 eq) were dissolved in dichloromethane (10 mL). p-Toluenesulfonyl chloride (2.15 g, 11.3 mol, 1.2 eq) was added with stirring at 30°C. The reaction mixture was stirred at 30°C for 16 h. After completion of the reaction, water (60 mL) was added to the reaction mixture, and the mixture was extracted three times with dichloromethane (50 mL). The organic layer was dried and concentrated to obtain crude product 22-2, which was used directly in the next step without purification.

[0290] 1 H NMR (400MHz, CDCl3) δ7.79(d,J=8.2Hz,2H),7.35(d,J=8.0Hz,2H),4.14(t,J=6.1Hz ,2H),2.51(t,J=7.1Hz,2H),2.45(s,3H),2.03(s,3H),1.94(dd,J=13.2,6.6Hz,2H).

[0291] Step 2: Synthesis of compound 22-3

[0292] Compound intermediate 1 (100 mg, 0.26 mmol, 1 eq) was dissolved in tetrahydrofuran (3 mL), and sodium hydride (42.5 mg, 1.06 mmol, 4 eq, 60% purity) was added to the solution. The reaction mixture was stirred at 25 ° C for 0.5 hours. To the above mixture was added compound 22-2 (207 mg, 0.79 mmol, 3 eq). The reaction mixture was stirred at 60 ° C for 16 hours. After the reaction was completed, water (60 mL) was added to the reaction mixture and extracted three times with ethyl acetate (50 mL). The organic layer was dried and concentrated to obtain a crude product. The crude product was purified by preparative plate (petroleum ether: ethyl acetate = 5:1) to obtain compound 22-3 (170 mg, purity 80%).

[0293] MS m / z (ESI) = 464.1 [M+1] + .

[0294] Step 3: Synthesis of compound 22-4.

[0295] Compound 22-3 (170 mg, 0.37 mmol, 1 eq) and ammonium carbonate (141 mg, 1.47 mmol, 4 eq) were dissolved in methanol (2 mL) and iodobenzene diacetate (355 mg, 1.10 mmol, 3 eq) was added with stirring at 25°C. The reaction mixture was stirred at 25°C for 4 h. The mixture was evaporated under reduced pressure to obtain a crude product. Compound 22-4 (75 mg) was obtained by purification on a preparative plate (dichloromethane:ethanol = 20:1).

[0296] MS m / z (ESI) = 495.1 [M+1] + .

[0297] Step 4: Preparation of compound 22

[0298] Compound 22-4 (75 mg, 0.15 mmol, 1 eq) was dissolved in 1,4-dioxane solution (1 mL), and 6 M aqueous hydrochloric acid solution (0.5 mL) was added with stirring at 25°C. The reaction mixture was stirred at 25°C for 1 hour. Compound 22 (9 mg) was obtained by reverse preparation (acetonitrile / 0.05% formic acid).

[0299] MS m / z (ESI) = 365.0 [M+1] + .

[0300] 1H NMR(400MHz,dmso-d6)δ10.51(s,1H),7.35(d,J=8.8Hz,1H),6.85(d,J=8.8Hz,1H),4.22(dt,J=15.9,7.9Hz,1H),3.65-3.58(m,2H),3.54–3.46(m ,1H),3.39(dt,J=12.6,6.4Hz,1H),3.30–3.23(m,1H),3.02(dd,J=10.2, 5.9Hz, 2H), 2.90 (s, 3H), 2.58 (dd, J=16.4, 9.5Hz, 2H), 1.98–1.85 (m, 2H).

[0301] Example 22 Preparation of Compound 23

[0302] Step 1: Synthesis of compound 23-2

[0303] Dissolve compound intermediate 1 in tetrahydrofuran (4 mL), cool to 0°C, and then slowly add sodium hydroxide (31.88 mg, 0.80 mmol, 3 eq, 60% purity) in portions. After addition, the reaction mixture was allowed to react at zero degrees for 30 minutes. Then, slowly add compound 23-1 (149 mg, 0.80 mmol, 3 eq) dropwise at zero degrees. After addition, slowly warm the temperature to room temperature and stir for 1 hour. After the reaction is complete, quench with saturated aqueous ammonium chloride solution and extract with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to dryness to obtain the crude product. The crude product was chromatographed on a silica gel plate to obtain compound 23-2 (90 mg, yield: 63.19%) as a clear liquid. MS m / z (ESI) = 504.0 [M+Na] + .

[0304] 1 H NMR (400MHz, CDCl3) δ7.31(d,J=9.0Hz,1H),7.07(d,J=9.0Hz,1H),5.22(q,J=7.1Hz,2H),4.44(t,J=8.9Hz,1H),3.91–3.64(m,6H ),3.39–3.26(m,2H),3.01(s,3H),2.80(dd,J=17.1,8.2Hz,1H),2.66(dd,J=17.1,10.7Hz,1H),0.97–0.90(m,2H),-0.00(s,9H).

[0305] Step 2: Preparation of compound 23

[0306] Compound 23-2 (90 mg, 0.19 mmol, 1.0 eq) was dissolved in 1,4-dioxane (4 mL), and 6 M hydrochloric acid (2 mL) was slowly added dropwise. After the addition was complete, the reaction solution was reacted at room temperature for 1 hour. After the reaction was complete, the reaction was quenched with water and then extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was then subjected to the reverse reaction to obtain compound 23 (33.35 mg). MS m / z (ESI) = 352.0 [M+H] + .

[0307] 1 H NMR (400MHz, MeOD) δ7.27(d,J=8.8Hz,1H),6.78(d,J=8.8Hz,1H),4.44(tt,J=10.4,7.4Hz,1H),3.93 –3.69(m,4H),3.43(t,J=7.0Hz,2H),3.06(s,3H),2.89–2.77(m,1H),2.69(dd,J=17.0,10.8Hz,1H).

[0308] Example 23 Preparation of Compound 24

[0309] Step 1: Synthesis of compound 24-2

[0310] Compound Intermediate 1 (400 mg, 1.06 mmol, 1.0 eq) was dissolved in tetrahydrofuran (5 mL) and cooled to 0°C. Sodium hydroxide (102.03 mg, 4.25 mmol, 4 eq) was then added portionwise. The reaction mixture was stirred at 0°C for half an hour. Compound 24-1 (1.1 g, 4.15 mmol, 4 eq) was then slowly added at 0°C. After the addition was complete, the temperature was raised to 60°C and stirred for 3 hours. After the reaction was complete, the mixture was quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was chromatographed on silica gel (petroleum ether:ethyl acetate = 2:1) to obtain compound 24-2 (380 mg). MS m / z (ESI) = 474.1 [M+Na] + .

[0311] 1H NMR (400MHz, CDCl3) δ7.31(d,J=9.0Hz,1H),7.08(d,J=9.0Hz,1H),5.21(q,J=7.2Hz,2H),4.47–4.36(m,1H),3.75–3.63(m,3H) ,3.58(t,J=6.7Hz,3H),3.50–3.46(m,2H),2.81–2.63(m,2H),2.05(p,J=6.9Hz,2H),0.97–0.90(m,2H),-0.00(d,J=2.5Hz,9H).

[0312] Step 2: Synthesis of compound 24-3

[0313] Compound 24-2 (150 mg, 0.33 mmol, 1.0 eq) was dissolved in ethanol (5 mL), followed by the addition of thiourea (30 mg, 0.40 mmol, 1.2 eq). The reaction mixture was allowed to react at 90°C for 3 hours. After completion of the reaction, the reaction mixture was dried to give compound 24-3 (150 mg). MS m / z (ESI) = 492.0 [M+H] + .

[0314] Step 3: Synthesis of compound 24-4

[0315] Compound 24-3 (150 mg, 0.30 mmol, 1.0 eq) was dissolved in acetonitrile / water (2 mL / 0.2 mL), followed by the addition of tert-butyl hypochlorite (165 mg, 1.52 mmol, 5 eq) at 0°C. After completion of the addition, the reaction mixture was allowed to react at 0°C for 10 minutes. After completion, the reaction was quenched with 10 mL of water and extracted three times with 10 mL of petroleum ether. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. To the crude product was added 1 mL of aqueous ammonia, the reaction was allowed to react at room temperature for 10 minutes, followed by quenching with 10 mL of water and extraction three times with 20 mL of ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain the crude product. The crude product was chromatographed on silica gel (dichloromethane:methanol = 10:1) to obtain compound 24-4 (60 mg). MS m / z (ESI) = 497.1 [M+H] + .

[0316] Step 4: Synthesis of compound 24

[0317] Compound 24-4 (40 mg, 0.08 mmol, 1.0 eq) was dissolved in 1,4-dioxane (2 mL), and 6 M hydrochloric acid (1 mL) was slowly added dropwise. After the addition was complete, the reaction solution was reacted at room temperature for 3 hours. After the reaction was complete, the solution was quenched with water and then extracted with ethyl acetate. The organic solvent was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was then subjected to reverse preparation to obtain compound 24 (10.11 mg) as a white solid. MS m / z (ESI) = 367.1 [M+H] + .

[0318] 1 H NMR (400MHz, MeOD) δ7.26(d,J=8.8Hz,1H),6.78(d,J=8.8Hz,1H),4.52–4.38(m,1H),3.74(dd,J=11.7,4.4Hz,2H),3.59(dt,J=14.1,7 .1Hz,1H),3.43(dt,J=13.6,6.7Hz,1H),3.20–3.08(m,2H),2.85(dd,J=17.0,7.7Hz,1H),2.70(dd,J=17.0,10.9Hz,1H),2.11(s,2H).

[0319] Referring to the synthesis of compound 22, 23 or 24, the following compounds were prepared:

[0320] Table 2

[0321] Test Case Biological Test Evaluation

[0322] Test Example 1 QPatch 48X (Sophion) fully automated patch clamp assay for Kv1.3 inhibitory activity

[0323] 1. Cell culture

[0324] Compounds were evaluated for their inhibitory activity against Kv1.3 using a HEK-293 cell line stably expressing the Kv1.3 potassium channel. The Kv1.3 cell line was established by Beijing Aisiyipu Biotechnology Co., Ltd. Cells were cultured in DMEM supplemented with 10% fetal bovine serum at 37°C and 5% CO2. Cells were passaged regularly, and the cell density must not exceed 80% to maintain electrophysiological activity.

[0325] Before the automated patch clamp assay, cells were stained with TrypLE TM Express separation, add culture medium to terminate digestion and centrifuge, resuspend cells and count, adjust the cell density to 2-3×10 6cells / mL, and then gently mix the cells on a balanced shaker at room temperature for 15-20 minutes before testing on the instrument.

[0326] 2. Preparation of Compounds

[0327] Compounds were dissolved in DMSO and prepared into 10 mM stock solutions, which were stored at -20°C. On the day of the experiment, the test compound stock solutions were removed from -20°C and diluted into the appropriate amount of extracellular fluid as working solutions. The default test concentrations for the test compounds were set at 10 and 100 nM. The blank control extracellular solution consisted of 0.3% DMSO. The test compound working solutions were sonicated for 20 minutes prior to testing. The extracellular solution consisted of: 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, with NaOH adjusting the pH to 7.4. The intracellular solution consisted of: 145 mM KF, 10 mM HEPES, 10 mM EGTA, 2 mM MgCl2, with KOH adjusting the pH to 7.2.

[0328] 3. Patch clamp detection

[0329] When performing electrophysiological testing with a fully automated patch clamp, prepared cells are first placed in the centrifuge of the Qpatch workstation. The cells are then washed using multiple centrifugation / suspension cycles, and the cell culture medium is replaced with extracellular fluid. Subsequent steps include aspirating the cell suspension from the centrifuge's cell container and positioning the cells onto the chip wells using a pressure controller, establishing a high-resistance seal and enabling whole-cell recording. Once a stable control current baseline is achieved, the test substances are then applied to the cells in order of concentration.

[0330] Each drug concentration was administered twice over a minimum of 5 minutes. Blank control solutions and test compound working solutions were applied to cells sequentially from low to high concentrations. The current measured in each cell in the compound-free solution served as its own control. After whole-cell seal, the cell membrane voltage was clamped at -80 mV and then stepped to +40 mV for 200 ms. Data were collected repeatedly at 20-s intervals to observe the effect of the drug on the peak Kv1.3 current. All electrophysiological experiments were performed at room temperature.

[0331] 4. Data Analysis

[0332] The second of the two drug administrations was used for data analysis. The average of the last three data points before the next drug administration concentration was taken for each drug concentration to represent the current value after the action of that concentration. The current value representing each drug concentration was normalized with the reference current value as the blank control, and then the inhibition rate corresponding to each drug concentration was calculated.

[0333] The experimental results are shown in Tables 3 and 4:

[0334] Table 3 Inhibitory activity of the compounds of the present invention on Kv1.3 potassium channels at 10 nM and 100 nM concentrations / : indicates not measured; A: inhibition rate ≥ 85%; B: 75% ≤ inhibition rate < 85%; C: 50% ≤ inhibition rate < 75%; D: 30% ≤ inhibition rate < 50%.

[0335] Table 4 Inhibitory activity of the compounds of the present invention on Kv1.3 potassium channels at 10 nM and 100 nM concentrations

[0336] The experimental results show that the compound of the present invention has good inhibitory activity on Kv1.3 potassium channel.

[0337] Test Example 2: Study on the pharmacokinetic behavior of the compound of the present invention in mice

[0338] Experimental drugs: Compounds of the present invention, homemade.

[0339] Experimental plan:

[0340] Three healthy male ICR mice (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), weighing 18-25 g, were intravenously injected with 1 mg / kg of the compound in a volume of 5 ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0341] Three healthy male ICR mice (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), weighing 18-25 g, were orally administered with 5 mg / kg of the compound in a volume of 10 ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0342] Blood samples (approximately 0.05 mL) were collected from the cheek at 5, 15, 30, 1, 2, 4, 6, 8, and 24 hours after intravenous administration and at 5, 15, 30, 1, 2, 4, 6, 8, and 24 hours after oral administration. Blood samples were anticoagulated with sodium heparin and placed on ice. Plasma was separated by centrifugation within 1 hour (6000 g, 3 minutes, 2-8°C). Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. Plasma samples were stored at -80°C until analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 using plasma concentration data at different time points.

[0343] The experimental results show that the compound of the present invention has a low clearance rate, a high plasma exposure, and good oral availability in rodent ICR mice, and has good pharmacokinetic properties.

[0344] Table 5

[0345] Test Example 3: Study on the pharmacokinetic behavior of the compound of the present invention in rats

[0346] Experimental drugs: Compounds of the present invention, homemade.

[0347] Experimental plan:

[0348] Three healthy male SD rats (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), weighing 180-250 g, were intravenously injected with 1 mg / kg of the compound in a volume of 2 ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0349] Three healthy male SD rats (SPF grade, source: Beijing Weitonglihua Experimental Animal Technology Co., Ltd.), weighing 180-250 g, were orally administered with 5 mg / kg of the compound in a volume of 10 ml / kg. The compound was prepared using 5% DMSO + 10% Solutol + 85% Saline (w / v). The animals were not fasted before the experiment.

[0350] Blood samples were collected venously at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after intravenous administration and at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, and 24 hours after oral administration. Approximately 0.25 mL of blood was collected for each sample. Blood samples were anticoagulated with sodium heparin and placed on ice. Plasma was separated by centrifugation within 1 hour (centrifugation conditions: 6000g, 3 minutes, 2-8°C). Plasma compound concentrations were determined by liquid chromatography-tandem mass spectrometry. Plasma samples were stored at -80°C prior to analysis. Pharmacokinetic parameters were calculated using Phoenix WinNonlin 8.2.0 using plasma drug concentration data at different time points. The experimental results are as follows:

[0351] Table 6

[0352] Control compound A0: It was synthesized by referring to the preparation method in patent WO2022076285A1.

Claims

1. A compound represented by general formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof: in: M is -CH2-, -C(=O)- or -C(=N-L4-R2)-; L4 is a bond or -CH2-; R2 is C 1-3 Alkyl, C 1-3 haloalkyl, pyrazolyl or phenyl; the pyrazolyl and phenyl are optionally substituted with halogen, amino, C 1-3 Alkyl or C 1-3 One or two substitutions of hydroxyalkyl; L1 is a bond, -(CH2) n3 - or -C(O)-; n3 is 1 or 2; L2 is a bond, -(CH2) n5 -、-CH2-NH-、C 4-6 Cycloalkylene, pyridylene or 4-membered heterocyclylene; n5 is 1 or 2; L3 is -CH2-, -S(O) n4 -、-C(=NH)-、 R L3 For hydrogen, C 1-3 Alkyl or C 1-3 haloalkyl; said C 1-3 The alkyl group is optionally substituted with a cyano group; n4 is 1 or 2; R1 is hydroxyl, amino, C 1-3 Alkyl or C 1-3 haloalkyl; said C 1-3 The alkyl group is optionally substituted with a cyano group.

2. The compound represented by formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) is further shown in the general formula (I-1): Where: L1 is a bond, -(CH2) n3 -, n3 is 1 or 2; L2 is -CH2- or pyridinyl; L3 is -CH2-, -S(O) n4 -、-C(=NH)-、 R L3 For hydrogen, C 1-3 Alkyl or C 1-3 haloalkyl; said C 1-3 The alkyl group is optionally substituted with a cyano group; n4 is 1 or 2; R1 is hydroxyl, amino, C 1-3 Alkyl or C 1-3 haloalkyl; said C 1-3 The alkyl group is optionally substituted with a cyano group.

3. The compound represented by formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) is further shown in the general formula (I-2): Where: L1 is -(CH2) n3 -, n3 is 1 or 2; L2 is -CH2-; L3 is -CH2-, -S(O)2- or -C(=NH)-; R1 is hydroxyl, amino, C 1-3 Alkyl or C 1-3 Haloalkyl; L4 is a bond or -CH2-; R2 is C 1-3 Alkyl, C 1-3 haloalkyl, pyrazolyl or phenyl; the pyrazolyl and phenyl are optionally substituted with halogen, amino, C 1-3 Alkyl or C 1-3 One or two of the hydroxyalkyl groups are substituted.

4. The compound represented by formula (I) according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The general formula (I) is further shown in general formula (I-3): Where: L2 is a bond, -(CH2) n5 -、-CH2-NH-、C 4-6 Cycloalkylene, pyridylene or 4-membered heterocyclylene; n5 is 1 or 2; L3 is -CH2-, -S(O)2- or -C(=NH)-; R L3 is hydrogen or C 1-3 Alkyl; R1 is hydroxyl, amino, C 1-3 Alkyl or C 1-3 Halogenated alkyl.

5. The compound of general formula (I) as claimed in claims 1 to 4, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) C 1-3 Alkyl is independently methyl, ethyl, n-propyl or isopropyl; preferably methyl; (2) C 1-3 The haloalkyl group is -CF3 or -CH2CF3; preferably -CH2CF3; (3) C 4-6 Cycloalkylene is (4) The pyridylene group is Best (5) The 4-membered heterocyclic group is Best (6) The halogen is fluorine, chlorine or bromine; preferably chlorine.

6. The compound according to any one of claims 1 to 5, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) L1 is a bond or -(CH2) n3 -; n3 is 1 or 2; (2) L2 is -CH2-, -CH2-CH2-, pyridylene, C 4-6 Cycloalkylene or 4-membered heterocyclylene; preferably -CH2-, -CH2-CH2-, (3) L3 is -CH2-, -S(O)-、-S(O)2-、-C(=NH)-、 (4)R L3 is hydrogen, methyl, ethyl, n-propyl, isopropyl, -CF3, -CH2CF3 or -CH2CN; preferably hydrogen, methyl, -CF3, -CH2CF3 or -CH2CN; (5) R1 is hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, -CF3, -CH2CF3 or CH2CN; preferably hydroxy, amino, methyl, -CF3, -CH2CF3 or CH2CN; (6) L4 is a bond or -CH2-; preferably -CH2-; (7) R2 is methyl, ethyl, propyl, -CF3, -CH2CF3, pyrazolyl or phenyl, wherein the pyrazolyl and phenyl are optionally substituted with chlorine, amino, methyl or Preferably, R2 is methyl, -CF3, -CH2CF3, 7. The compound according to any one of claims 1 to 6, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: It meets one or more of the following conditions: (1) L1 is a bond; (2) L1 is -(CH2) n3 -, n3 is 1 or 2; (3) L2 is -CH2-; (4) L2 is (5) L3 is -S(O)2-, -C(=NH)-; (6) L3 is -CH2-, -S(O)2-, -C(=NH)-; (7) L3 is -S(O)2- or -C(=NH)-; (8) R1 is methyl or amino; (9) R1 is hydroxyl or amino; (10) R1 is amino; (11) L4 is -CH2-; (12) R2 is -CF3, 8. The compound according to any one of claims 1 to 7, its stereoisomer or a pharmaceutically acceptable salt thereof; characterized in that: It is any one of the compounds in Table 1, its stereoisomers or pharmaceutically acceptable salts thereof.

9. A pharmaceutical composition, characterized in that It contains substance X and at least one pharmaceutically acceptable excipient, The substance X is a compound according to any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

10. Use of the pharmaceutical composition or substance X as claimed in claim 9 in the preparation of a Kv1.3 potassium channel inhibitor; the substance X is a compound as claimed in any one of claims 1 to 8, a stereoisomer thereof or a pharmaceutically acceptable salt thereof.

11. A use of the pharmaceutical composition or substance X according to claim 9 in the preparation of a drug for treating or preventing a disease; the substance X is a compound according to any one of claims 1 to 8, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof; The drug may be a drug for inhibiting Kv1.3 potassium channel; The disease may be a Kv1.3 potassium channel-related disease, such as cancer, immunological disorders, central nervous system disorders, inflammatory disorders, gastrointestinal disorders, metabolic disorders, cardiovascular disorders, and renal diseases; The pharmaceutical composition or the substance X may be in a therapeutically effective amount.

12. An intermediate 2 compound as shown below,

Images