Aryl tricyclic derivative, preparation method therefor, and use thereof

Abstract

Provided are an aryl tricyclic derivative, a preparation method therefor, and a use of a pharmaceutical composition containing the derivative in medicine. Specifically, provided are an aryl tricyclic derivative represented by general formula (I), a preparation method therefor and a pharmaceutically acceptable salt thereof, and a use of the aryl tricyclic derivative and the pharmaceutically acceptable salt as a therapeutic agent, especially as a Kv1.3 potassium ion channel inhibitor, wherein the definition of each substituent in general formula (I) is the same as that in the description.

Description

Aryltricyclic derivatives, processes for their preparation and uses thereof TECHNICAL FIELD

[0001] The present invention relates to a class of aryltricyclic derivatives, processes for their preparation and pharmaceutical compositions containing the derivatives and their use as therapeutic agents, in particular as Kv1.3 inhibitors. BACKGROUND

[0002] Ion channels are proteins located in the cell membrane that selectively control the flow of ions (e.g. potassium, sodium, calcium) across the membrane, thus creating a concentration gradient between the intracellular components of the cell and the extracellular fluid surrounding it. Because ion concentrations directly participate in the electrical activity of excitable cells, ion channels can significantly control the electrical properties and state of the cell. Ion channels that can open and close are termed "gated". Voltage-gated channels are found on neurons, muscle cells and non-excitable cells such as lymphocytes. They respond to changes in the electrical charge across the membrane to open and close, and play an important role in cell communication, signal transduction pathways, and the overall homeostasis of tissues and various organ functions.

[0003] Potassium ion is one of the main cations in the body, which plays an important role in maintaining the membrane potential of the cell, and also plays an indispensable role in cell proliferation, activation and apoptosis. Kv1.3 channel is a member of the voltage-gated potassium channel (Kv) family, which is encoded by the KCNA3 gene and located at 1p13.3 of human chromosome. It is composed of four similar subunits, each of which contains a main part composed of six transmembrane structural elements (S1-S6), and an N-terminal and a C-terminal connected to S1 and S6, respectively. The transmembrane structural elements (S1-S4) form the voltage-sensitive region of the channel, and the S5-S6 of the four subunits and the S5-S6 connecting segment (P-loop) embedded in the membrane form the pore diameter of the channel. Each S4 in the voltage-sensitive region contains a large number of positive charges, which are necessary for the channel to respond to the depolarization voltage of the cell membrane.

[0004] Kv1.3 channel was first discovered in human T lymphocytes, and it is also expressed in the immune system, central nervous system and vascular smooth muscle cells. Kv1.3 plays an important role in regulating resting membrane potential, apoptosis, regulation of cell volume, activation and proliferation of immune cells. In T cells, cell membrane depolarization leads to the activation of calcium channels (Ca 2+ 2+ 2+ channel, CRAC) into the cell, leading to an increase in intracellular Ca 2+ ​​With the increase of the concentration, the cell membrane is depolarized, thereby mediating the activation of intracellular calmodulin and calcineurin and the like to activate the downstream signal path, so that the expression amount of Kv1.3 on the cell membrane is increased. Therefore, the intracellular potassium ions outflow, so as to maintain the osmotic pressure balance between the inside and outside of the cell. This is a necessary condition in the transcription-dependent step in the T cell activation. The Kv1.3 potassium ion channel is the key to the sustained activation of the effector T cells. In the microglial cells, the Kv1.3 participates in the process of killing neurons in the burst respiratory burst neuroinflammation. In the dendritic cells, together with Kv1.5, the Kv1.3 participates in the secretion of inflammatory cytokines. Since the Kv1.3 participates in these key roles, it is related to many autoimmune diseases, such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis, or chronic kidney disease and the like.

[0005] Studies have shown that selectively inhibiting the Kv1.3 channel can achieve the purpose of selectively inhibiting the activation process of the effector T cells, which provides a new idea for the treatment of autoimmune diseases related to the effector T cells. Therefore, the Kv1.3 has become a new target protein for treating autoimmune diseases. In addition, the Kv1.3 also participates in the neurotoxic effect of the body and the occurrence and development of cancer and the like. The abnormal expression of the Kv1.3 is detected in many tumor cells such as breast cancer, prostate cancer, ovarian cancer and microglial cells. Experiments have shown that inhibiting the activity of the Kv1.3 can induce the apoptosis of tumor cells. Therefore, the drug taking the Kv1.3 as the target has important clinical value.

[0006] There is no new drug for the inhibitor of the Kv1.3 target on the market. At present, only two small molecule compounds DES-7114 and YR-001 enter the clinical phase I, and three polypeptide clinical compounds, in which the highest clinical stage is dalazatide developed by Kv1.3Therapeutics company in the phase II, is a polypeptide compound derived from sea anemone toxin. As a more advanced research direction, there is a great exploration space for the research related to the Kv1.3 target, and it is necessary to continue to study the mechanism and develop new inhibitors. SUMMARY

[0007] In order to solve the above technical problems, the present application provides an aryl tricyclic derivative or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt thereof shown in the general formula (I):

[0008] In which:

[0009] According to the need, it is selected from a single bond or a double bond, so that each atom thereof presents a normal valence;

[0010] is selected from a single or double bond as necessary to render each atom thereof a normal valency state;

[0011] is selected from a single or double bond as necessary to render each atom thereof a normal valency state;

[0012] n is 0 or 1 ;

[0013] with the proviso that when n is 1, is a double bond (to form ); and when n is 0, is a single bond (to form );

[0014] R B is independently selected from the group consisting of a hydroxyl group, a halogen, a cyano group, a C 1-6 alkyl group or a C 1-6 alkoxy group, wherein said C 1-6 alkyl group or C 1-6 alkoxy group is optionally further substituted by one or more substituents selected from the group consisting of a halogen, a hydroxyl group, a cyano group, =0, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a haloC 1-6 alkyl group or a haloC 1-6 alkoxy group.

[0015] when Y is a single bond, Y is selected from CR a R b , NR c or O;

[0016] R a , R b are the same or different, each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, or, R a and R b together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group or a 3-7 membered heterocyclyl group, wherein said heterocyclyl group contains one or more N, O or S(=O) r ;

[0017] R c is selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group or a C 3-7 cycloalkyl group;

[0018] Y is selected from N or CR d ;

[0019] R d is selected from a hydrogen atom, halogen, C 1-6 alkyl or C 1-6 alkoxy;

[0020] X is each independently selected from N or CH;

[0021] Z, T are each independently selected from N or CR d when a single bond;

[0022] Z, T are each independently selected from N or C

[0023] ring A is selected from C 6-10 aryl, 5-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C 6-10 aryl is preferably phenyl;

[0024] R 1 is selected from a hydrogen atom or C 1-6 alkyl;

[0025] R 2 , R 3 , R 4 , R 5 are each independently selected from a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, halogenated C 3-7 cycloalkyl or halogenated C 1-6 alkyl;;

[0026] or, R 2 and R 3 , R 3 and R 4 are each independently taken together with the carbon atom to which they are attached to form a C 3-6 cycloalkyl, C 6-10 aryl, 5-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C 3-6 cycloalkyl, C 6-10 aryl, 5-8 membered heterocyclyl or 5-8 membered heteroaryl is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, =0, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy.

[0027] R A each independently is selected from the group consisting of deuterium atom, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -OC(=O)R 6 , -C(=O)R 6 , -NR 7 C(=O)R 8 , -NR 7 C(=O)OR 8 , -NR 7 R 8 , -C(=O)NR 7 R 8 , -S(=O) r NR 7 R 8 or -S(=O) r R 6 ; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more R AA ;

[0028] or, two R A together with the same carbon atom to which they are attached form a -C(=O)-;

[0029] R AA are the same or different, each independently is selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 9 , =O, -C(=O)R 9 , -S(=O) r R 9 , -C(=O)OR 9 , -OC(=O)R 9 , -NR 10 R 11 , -C(=O)NR 10 R 11 , -SO2NR 10 R 11 , -NR 10 C(=O)R 11 or -NR 10 C(=O)OR 11 ; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -S(=O) r R 9 , -S(=O)(=NR 10)R 11 , -C(=O)R 9 , -C(=O)OR 9 , -OC(=O)R 9 , -NR 10 R 11 , -C(=O)NR 10 R 11 , -SO2NR 10 R 11 , -NR 10 C(=O)R 11 or -NR 10 C(=O)OR 11 ;

[0030] R 6 each independently is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(=O)R 9 , -C(=O)OR 9 , -OC(=O)R 9 , -NR 10 R 11 , -C(=O)NR 10 R 11 , -SO2NR 10 R 11 , -NR 10 C(=O)R 11 or -NR 10 C(=O)OR 11 ;

[0031] R 7 and R 8 each independently is selected from a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(=O)R 9 , -C(=O)OR 9 , -OC(=O)R 9 , -NR 10 R 11 , -C(=O)NR 10 R 11 , -SO2NR 10 R 11 , -NR10 C(=O)R 11 or -NR 10 C(=O)OR 11 substituted;

[0032] or, R 7 and R 8 together with the atom to which they are attached form a 3-12 membered heterocyclyl, wherein the 3-12 membered heterocyclyl contains one or more N, O, or S(O)r, and said 3-12 membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(=O)R 9 , -C(=O)OR 9 , -OC(=O)R 9 , -NR 10 R 11 , -C(=O)NR 10 R 11 , -SO2NR 10 R 11 , -NR 10 C(=O)R 11 or -NR 10 C(=O)OR 11 substituted;

[0033] R 9 , R 10 and R 11 are each independently selected from the group consisting of hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxy, or carboxylate;

[0034] m is 0, 1, 2, 3, or 4;

[0035] t is 0, 1, or 2 and

[0036] each r is independently 0, 1, or 2;

[0037] In a preferred embodiment of the present application, a compound of general formula (I) or a stereoisomer, a tautomer, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a hydrogen atom.

[0038] In a preferred embodiment of the present application, a compound of general formula (I) or a stereoisomer, a tautomer, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, is a compound of general formula (II) or a stereoisomer, a tautomer, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof:

[0039] wherein:

[0040] R 2 , R 3 each independently is selected from a hydrogen atom or a halogen; the halogen is preferably chlorine;

[0041] R 4 is a hydrogen atom or a halogen;

[0042] ring A, X, Y, Z, T, R A , R 5 , R B , t, m and n are as defined in general formula (I).

[0043] According to a preferred embodiment of the application, a compound according to general formula (I) or (II), or a stereoisomer, a tautomer, a deuterated analogue or a pharmaceutically acceptable salt thereof, is a compound according to general formula (III), or a stereoisomer, a tautomer, a deuterated analogue or a pharmaceutically acceptable salt thereof:

[0044] wherein:

[0045] R 5 is selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-6 alkynyl group, a C A alkoxy group;

[0046] ring A, X, Y, Z, T, R A , R B , t, m and n are as defined in general formula (I).

[0047] According to a preferred embodiment of the application, a compound according to general formula (I) or (II), or a stereoisomer, a tautomer, a deuterated analogue or a pharmaceutically acceptable salt thereof, is a compound according to general formula (IV-1) or (IV-2), or a stereoisomer, a tautomer, a deuterated analogue or a pharmaceutically acceptable salt thereof:

[0048] wherein: ring B is a phenyl group or a 5-6 membered heteroaryl group;

[0049] R j is selected from a hydroxyl group, a halogen, a cyano group, a C 1-6 alkyl group or a C 1-6 alkoxy group;

[0050] q is 0, 1 or 2;

[0051] R 2 , R 4 each independently is selected from a hydrogen atom or a halogen, the halogen is preferably chlorine;

[0052] R 5 is selected from a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkoxy;

[0053] ring A, X, Y, Z, T, R A , R B , t, m and n are as defined in general formula (I).

[0054] A preferred embodiment of the present application is a compound according to general formula (I), (II), (III), (IV-1) or (IV-2), wherein R 5 is selected from a hydrogen atom, fluorine, chlorine, cyano, methyl, ethynyl or methoxy.

[0055] A preferred embodiment of the present application is a compound according to general formula (I), (II), (III), (IV-1) or (IV-2), wherein is selected from the following groups:

[0056] ring A, R A , R B , t and m are as defined in general formula (I).

[0057] A preferred embodiment of the present application is a compound according to general formula (I), (II), (III), (IV-1) or (IV-2), wherein t is 1 and R B is selected from C 1-6 alkyl.

[0058] A preferred embodiment of the present application is a compound according to general formula (I), (II), (III), (IV-1) or (IV-2), wherein t is 0.

[0059] A preferred embodiment of the present application is a compound according to general formula (I), (II), (III), (IV-1) or (IV-2), wherein ring A is selected from

[0060] In a preferred embodiment of the present application, a compound of general formula (I), (II), (III), (IV-1) or (IV-2) or a stereoisomer, a tautomer, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, wherein R A each independently is selected from the group consisting of hydroxy, halogen, cyano, C 1-6 alkyl or 3- to 12-membered heterocyclyl; wherein said C 1-6 alkyl or 3- to 12-membered heterocyclyl is optionally further substituted with one or more R AA ;

[0061] or two R A together with the carbon atom to which they are attached form a -C(=O)-;

[0062] R AA are the same or different, each independently selected from the group consisting of hydroxy, halogen, cyano, C 3～6 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, -NR 10 R 11 or -SO2NR 10 R 11 wherein said C 3～6 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl or C 1-6 alkoxy, NR 10 R 11 , -S(=O) r R 9 , -SO2NR 10 R 11 , or -S(=O)(=NR 10 )R 11 ;

[0063] R 9 is selected from the group consisting of C 3～6 cycloalkyl or C 1-6 alkyl;

[0064] R 10 , R 11 are each independently selected from the group consisting of a hydrogen atom or C 1-6 alkyl;

[0065] r is 0 or 2.

[0066] In a preferred embodiment of the present application, a compound of general formula (I), (II), (III), (IV-1) or (IV-2) or a stereoisomer, a tautomer, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, wherein RA selected from methyl, hydroxy,

[0067] or, two R A together with the same carbon atom to which they are attached form a -C(=0)-.

[0068] In a preferred embodiment of the present application, a compound of general formula (I), (II), (III), (IV-1) or (IV-2) or a stereoisomer, a tautomer, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0069] In a preferred embodiment of the present application, a compound of general formula (I), (II), (III), (IV-1) or (IV-2) is selected from:

[0070] or a stereoisomer, a tautomer thereof, or a pharmaceutically acceptable salt thereof. Note: If there is a discrepancy between a depicted structure and a name given for that structure, the depicted structure will control.

[0071] Further, the present application provides a pharmaceutical composition comprising an effective amount of a compound of general formula (I), (II), (III), (IV-1) or (IV-2) or a stereoisomer, a tautomer, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

[0072] The present application provides the use of a compound of general formula (I), (II), (III), (IV-1) or (IV-2) or a stereoisomer, a tautomer, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a Kv1.3 inhibitor.

[0073] The present application also provides the use of a compound of general formula (I), (II), (III), (IV-1) or (IV-2) or a stereoisomer, a tautomer, a deuterated compound thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment of a Kv1.3 mediated disease, wherein the Kv1.3 mediated disease is preferably an autoimmune disease; wherein the Kv1.3 mediated disease is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis, or chronic kidney disease.

[0074] The present application further provides use of a compound according to Formula (I), (II), (III), (IV-1), or (IV-2), or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer.

[0075] The present application provides use of a compound according to Formula (I), (II), (III), (IV-1), or (IV-2), or a stereoisomer, a tautomer, a deuterated analog, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis, or chronic kidney disease.

[0076] DETAILED DESCRIPTION

[0077] Unless otherwise indicated, the following terms used in the specification and claims have the following meanings:

[0078] "Alkyl" when used as a group or part of a group refers to a straight-chain or branched- chain saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is C1-C6alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups can be substituted or unsubstituted. 20 "Alkyl" when used as a group or part of a group refers to a straight-chain or branched- chain saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is C1-C6alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups can be substituted or unsubstituted. 10 "Alkyl" when used as a group or part of a group refers to a straight-chain or branched- chain saturated hydrocarbon group having 1 to 6 carbon atoms. Preferred is C1-C6alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. Alkyl groups can be substituted or unsubstituted.

[0079] "Cycloalkyl" refers to non-aromatic cyclic alkyl groups in which one or more ring-forming atoms are carbon atoms, the ring contains 0, 1, or multiple double bonds, and includes monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably having 3 to 7 members in a monocyclic ring or 4 to 18 members in a bicyclic or tricyclic ring. Examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, norcaryl, and the like. Cycloalkyl groups can be substituted or unsubstituted. "Cycloalkyl" refers to non-aromatic cyclic alkyl groups in which one or more ring-forming atoms are carbon atoms, the ring contains 0, 1, or multiple double bonds, and includes monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably having 3 to 7 members in a monocyclic ring or 4 to 18 members in a bicyclic or tricyclic ring. Examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, norcaryl, and the like. Cycloalkyl groups can be substituted or unsubstituted.

[0080] "Spiroalkyl" refers to a polycyclic group of 5 to 18 members, having two or more cyclic structures sharing a single carbon atom (referred to as a spiro atom) between the rings, containing 0, 1, or multiple double bonds within the rings, but no ring having a fully conjugated pi-electron system. Preferably 6 to 14 members, more preferably 7 to 10 members. Spiroalkyl groups are classified as mono-, bi-, or polycyclic depending on the number of spiro atoms shared between the rings, preferably mono- and bi-cyclic, preferably 4 / 5-, 4 / 6-, 5 / 5-, or 5 / 6-membered. Non-limiting examples of "spiroalkyl" groups include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0081] "Fused cycloalkyl" refers to a all-carbon polycyclic group of 4 to 18 members, having two or more cyclic structures sharing a pair of carbon atoms between the rings, one or more rings can contain 0, 1, or multiple double bonds within the rings, but no ring having a fully conjugated pi-electron system, preferably 6 to 14 members, more preferably 7 to 10 members. Fused cycloalkyl groups are classified as bi-, tri-, tetra-, or polycyclic depending on the number of rings comprising the group, preferably bi- or tri-cyclic, more preferably 5 / 5- or 5 / 6- membered bi-cyclic fused cycloalkyl groups. Non-limiting examples of "fused cycloalkyl" groups include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradeca-hydrophenanthryl.

[0082] "Bridged cycloalkyl" refers to a all-carbon polycyclic group of 5 to 18 members, having two or more cyclic structures sharing two non-adjacent carbon atoms between the rings, one or more rings can contain 0, 1, or multiple double bonds within the rings, but no ring having a fully conjugated pi-electron system, preferably 6 to 14 members, more preferably 7 to 10 members. Bridged cycloalkyl groups are classified as bi-, tri-, tetra-, or polycyclic depending on the number of rings comprising the group, preferably bi-, tri-, or tetra-cyclic, more preferably bi- or tri-cyclic. Non-limiting examples of "bridged cycloalkyl" groups include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.

[0083] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably herein and refer to non-aromatic heterocyclic groups, including mono-, polycyclic, fused, bridged, and spirocyclic rings, which can contain 1 or more double bonds within the ring but no ring having a fully conjugated pi-electron system, wherein one or more of the atoms in the ring is an element selected from the group consisting of nitrogen, oxygen, or S(O) r (wherein r is selected from 0, 1, or 2) heteroatom. Preferably 3 to 7 membered monocyclic or 4 to 18 membered bi- or tri-cyclic.

[0084] Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, azetidinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidinyl,

[0085] Heterocyclyl groups can be substituted or unsubstituted.

[0086] "Spiroheterocyclyl" refers to a polycyclic group of 5 to 18 members, two or more cyclic structures, and sharing one atom between single rings, which can contain 1 or more double bonds within the ring, but none of the rings have a fully conjugated system of π electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r wherein r is selected from 0, 1, or 2, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Spirocycloalkyl groups are classified as mono-, bi-, or polyspirocycloalkyl groups, preferably mono- and bi-spirocycloalkyl groups, more preferably 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5-, 5 / 6-, or 6 / 6- membered mono-spirocycloalkyl groups, based on the number of spiro atoms shared between rings. Non-limiting examples of "spiroheterocyclyl" groups include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0087] "Fused heterocyclyl" refers to a polycyclic group of two or more cyclic structures sharing a pair of atoms between single rings, one or more rings which can contain 0, 1, or more double bonds, but none of the rings have a fully conjugated system of π electrons, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r wherein r is selected from 0, 1, or 2, and the remaining ring atoms are carbon, preferably 6 to 14 members, more preferably 7 to 10 members. Fused heterocyclyl groups are classified as bi-, tri-, tetra-, or polycyclic, preferably bi- or tri-cyclic, more preferably 5 / 5- or 5 / 6- membered bi-cyclic fused heterocyclyl groups, based on the number of rings. Non-limiting examples of "fused heterocyclyl" groups include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxine,

[0088] "Bridged heterocyclic group" refers to a polycyclic group with 5 to 18 members, containing two or more ring structures that share two atoms that are not directly connected. One or more rings may contain 0, 1 or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen or S(O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

[0089] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0090] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" compounds include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridyl, pyridine- 2(1H)-keto, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyrimidin-2(1H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl

[0091] Heteroaryl groups can be substituted or unsubstituted.

[0092] "Fused ring" means a polycyclic group in which two or more cyclic structures share a pair of atoms with each other, at least one of which rings has a fully conjugated pi-electron aromatic system, while one or more rings can contain 0, 1 or multiple double bonds, but at least one ring does not have a fully conjugated pi-electron aromatic system, wherein the ring atoms are selected from 0, 1 or more heteroatoms selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Fused rings preferably include bicyclic or tricyclic fused rings, with bicyclic fused rings preferably being a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclyl or monocyclic cycloalkyl group, preferably 6 to 14 membered, more preferably 8 to 10 membered. Examples of "fused rings" include, but are not limited to:

[0093] "Alkoxy" means a group of the formula (alkyl-O-). Alkyl is as defined above. C1-C6alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, and the like.

[0094] "Nitro" means a -NO2group.

[0095] "Hydroxy" means an -OH group.

[0096] "Halo" means fluoro, chloro, bromo, and iodo.

[0097] "Amino" means -NH2.

[0098] "Cyano" means -CN.

[0099] "Benzyl" means -CH2-phenyl.

[0100] "Carboxy" means -C(=O)OH.

[0101] "Carboxylate" means -C(=O)O-alkyl or -C(=O)O-cycloalkyl, wherein alkyl and cycloalkyl are as defined above.

[0102] "Hydroxyalkyl" means an alkyl group as defined above substituted with a hydroxyl group.

[0103] "Aminoalkyl" means an alkyl group as defined above substituted with an amino group.

[0104] "Haloalkyl" means an alkyl group as defined above substituted with a halo group.

[0105] "Haloalkoxy" means an alkoxy group as defined above substituted with a halo group.

[0106] "DMSO" refers to dimethyl sulfoxide.

[0107] “BOC” refers to tert-butoxycarbonyl.

[0108] “Bn” refers to benzyl.

[0109] "THP" refers to 2-tetrahydropyranyl.

[0110] "TFA" refers to trifluoroacetic acid.

[0111] “FA” stands for nail acid.

[0112] “ACN” refers to acetonitrile.

[0113] “Ts” refers to p-toluenesulfonyl group.

[0114] “Bn” refers to benzyl.

[0115] “SEM” refers to (trimethylsilyl)ethoxymethyl.

[0116] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0117] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene). Unless otherwise specified, "substituted" or "substituted" as used in this specification means that a group can be substituted by one or more groups selected from: deuterium, alkyl, alkenyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocyclic alkoxy, cycloalkylthio, heterocyclic alkylthio, amino, haloalkyl, halocycloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylic acid ester, =O, -OR 6 -OC(=O)R 6 -C(=O)R 6 -C(=O)OR 6 -NR 7 C(=O)R 8 -NR 7 C(=O)OR 8 -NR 7 R 8 -C(=O)NR 7 R 8 -S (=O) r NR 7 R 8 -S(=O)(=NR) 10 )R 11 Or -S (=O) r R 6 The substituents are replaced;

[0118] R 6 Each is independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 9 -C(=O)OR 9 -OC(=O)R 9 -NR 10 R 11 -C(=O)NR 10 R 11 -SO2NR 10 R 11 -NR10 C(=O)R 11 or -NR 10 C(=O)OR 11 The substituents are replaced;

[0119] R 7 and R 8 Each is independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R 9 -C(=O)OR 9 -OC(=O)R 9 -NR 10 R 11 -C(=O)NR 10 R 11 -SO2NR 10 R 11 -NR 10 C(=O)R 11 or -NR 10 C(=O)OR 11 The substituents are replaced;

[0120] Or, R 7 and R 8 The atoms bonded to them together form a 3- to 12-membered heterocyclic group, wherein the 3- to 12-membered heterocyclic group contains one or more N, O, or S(O)r, and the 3- to 12-membered heterocyclic group is optionally further composed of one or more elements selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(=O)R. 9 -C(=O)OR 9 -OC(=O)R 9 -NR 10 R 11 -C(=O)NR 10 R 11 -SO2NR 10 R 11 -NR 10 C(=O)R 11 or -NR 10 C(=O)OR 11 The substituents are replaced;

[0121] R 9 R 10 and R 11Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group;

[0122] r can be 0, 1, or 2 independently.

[0123] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, atropisomers, and geometric (conformal) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0124] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, and trans-isomers, and geometric (conformal) isomers; for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0125] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0126] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and its biological activity.

[0127] Method for synthesizing the compounds of the present invention

[0128] To achieve the objectives of this invention, the following technical solution is adopted:

[0129] This invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, the method comprising:

[0130] Compound of general formula (Ia) undergoes a coupling reaction with compound (Ib), and optionally a further substitution reaction is carried out to give compound of general formula (I).

[0131] in:

[0132] Y1 is selected from halogens;

[0133] W is selected from boric acid or

[0134] R 1 Selected from hydrogen atoms;

[0135] Rings A, X, Y, Z, T, R 2 R 3 R 4 R 5 R A R B The definitions of t, m and n are as described in general formula (I). Detailed Implementation

[0136] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0137] Example

[0138] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0139] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0140] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0141] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0142] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0143] CD3OD: Deuterated methanol.

[0144] CDCl3: Deuterated chloroform.

[0145] DMSO-d6: Deuterated dimethyl sulfoxide.

[0146] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0147] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0148] The compounds were purified using silica gel column chromatography and reversed-phase column chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile. The volume ratio of the solvent varied depending on the polarity of the compound and could be adjusted by adding small amounts of acidic or basic reagents, such as acetic acid or triethylamine.

[0149] Example 1

[0150] 6-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one

[0151] 6-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one

[0152] first step

[0153] diethyl 7-bromoimidazo[1,2-a]pyridine-2,3-dicarboxylate

[0154] 7-Bromoimidozop[1,2-a]pyridine-2,3-dicarboxylic acid diethyl ester

[0155] To a 50 mL ethanol solution of 4-bromopyridin-2-amine 1a (5 g, 28.90 mmol, commercially available), diethyl 2-chloro-3-oxosuccinate 1b (6.43 g, 28.90 mmol, commercially available) was added. Under nitrogen protection, the mixture was heated to 100 °C and reacted for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give diethyl 7-bromoimidazolo[1,2-a]pyridine-2,3-dicarboxylic acid 1c (4 g), with a yield of 40.5%.

[0156] MS m / z(ESI): 340.9 [M+1]

[0157] Step 2

[0158] ethyl 7-bromo-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate

[0159] 7-Bromo-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

[0160] 1 g (2.93 mmol) of 7-bromoimidozolo[1,2-a]pyridine-2,3-dicarboxylic acid diethyl ester 1c was added to tetrahydrofuran (10 mL), the mixture was cooled to 0 °C, and lithium borohydride solution (2 M, 2.2 mL) was added. The mixture was then heated to room temperature and the reaction was continued for 16 hours. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (25 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1 d (400 mg) of 7-bromo-2-(hydroxymethyl)imidozolo[1,2-a]pyridine-3-carboxylic acid diethyl ester, yield 45.6%. MS m / z (ESI): 299.0 [M+1]

[0161] Step 3

[0162] ethyl 7-bromo-2-(((methylsulfonyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate

[0163] 7-Bromo-2-(((methanesulfonyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

[0164] Ethyl 7-bromo-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate 1d (350 mg, 1.17 mmol), methanesulfonyl chloride (268 mg, 2.34 mmol), and triethylamine (177 mg, 1.76 mmol) were sequentially added to dichloromethane (5 mL). The reaction mixture was subjected to nitrogen protection and reacted at 25 °C for 16 hours. The reaction solution was quenched with water (10 mL), extracted with dichloromethane (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give ethyl 7-bromo-2-(((methanesulfonyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylate 1e (220 mg), yield 49.8%. The crude product was used directly in the next reaction without purification.

[0165] MS m / z(ESI): 376.9 [M+1]

[0166] Step 4

[0167] ethyl 7-bromo-2-(((2,4-dimethoxybenzyl)amino)methyl)imidazo[1,2-a]pyridine-3-carboxylate

[0168] 7-Bromo-2-(((2,4-dimethoxybenzyl)amino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

[0169] Ethyl 7-bromo-2-(((methanesulfonyl)oxy)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid ester 1e (220 mg, 0.58 mmol) was added to 1,4-dioxane (5 mL), followed by N,N-diisopropylethylamine (151 mg, 1.17 mmol) and 2,4-dimethoxybenzylamine (195 mg, 1.17 mmol). The mixture was then heated to 80 °C for 16 hours under nitrogen protection. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (10 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1f (100 mg) of ethyl 7-bromo-2-(((2,4-dimethoxybenzyl)amino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid, with a yield of 38.2%.

[0170] MS m / z (ESI): 448.0 [M+1]

[0171] Step 5

[0172] 7-bromo-2-(((2,4-dimethoxybenzyl)amino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid

[0173] 7-Bromo-2-(((2,4-dimethoxybenzyl)amino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid

[0174] Ethyl 7-bromo-2-((((2,4-dimethoxybenzyl)amino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid ester 1f (50 mg, 0.11 mmol) was added to a mixed solvent of tetrahydrofuran (5 mL), methanol (0.5 mL), and water (0.5 mL), followed by the addition of sodium hydroxide (23 mg, 0.56 mmol). The reaction was carried out at 25 °C for 16 hours. The solution was concentrated under reduced pressure to give 1 g (25 mg) of 7-bromo-2-(((2,4-dimethoxybenzyl)amino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid, with a yield of 53.3%. The crude product was used directly in the next reaction without purification.

[0175] MS m / z(ESI): 420.2 [M+1]

[0176] Step 6

[0177] 6-bromo-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one

[0178] 6-Bromo-2-(2,4-Dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one

[0179] 1 g (25 mg, 0.06 mmol) of 7-bromo-2-(((2,4-dimethoxybenzyl)amino)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid was added to N,N-dimethylformamide (1 mL), followed by O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (34 mg, 0.09 mmol) and N,N-diisopropylethylamine (15 mg, 0.12 mmol). The mixture was reacted at 25 °C for 1 hour. The reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 6-bromo-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one (15 mg) for 1 h, yield 62.6%. The crude product was used directly in the next reaction without purification.

[0180] MS m / z(ESI): 402.0 [M+1]

[0181] Step 7

[0182] 6-bromo-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one

[0183] 6-Bromo-2,3-dihydro-1H-pyrrole[3',4':4,5]imidazo[1,2-a]pyridin-1-one

[0184] 300 mg (0.74 mmol) of 6-bromo-2-(2,4-dimethoxybenzyl)-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one was added to a mixed solvent of dichloromethane (1 mL) and trifluoroacetic acid (1 mL) and reacted at 50 °C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography (eluent: system D) to give 160 mg (1i) of 6-bromo-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one, with a yield of 85.1%.

[0185] MS m / z(ESI): 252.0 [M+1]

[0186] 1H NMR (400MHz, DMSO-d6) δ8.52(dd,J=7.2,0.8Hz,1H),8.20(s,1H),8.16–8.08(m,1H),7.27(dd,J=7.2,2.0Hz,1H),4.37(d,J=0.8Hz,2H).

[0187] Step 8

[0188] 6-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one

[0189] 6-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one

[0190] 6-Bromo-2,3-dihydro-1H-pyrrole[3',4':4,5]imidazo[1,2-a]pyridin-1-one 1i (100 mg, 0.39 mmol), (2,3-dichloro-6-hydroxyphenyl)boronic acid 1j (123 mg, 0.59 mmol, commercially available), cesium carbonate (258 mg, 0.79 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride(II) (29 mg, 0.04 mmol) were added sequentially to a mixed solvent of 1,4-dioxane (3 mL) and water (0.3 mL). Under nitrogen protection, the mixture was heated to 110 °C and reacted for 2 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (Column: XBridge C18; 250 × 19 mm ID; 10 μm, 20 mL / min; Mobile phase A: 0.1% NH4HCO3 + H2O, Mobile phase B: CH3CN) to give 1 (2 mg) of 6-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-pyrrolo[3',4':4,5]imidazo[1,2-a]pyridin-1-one, with a yield of 1.5%.

[0191] MS m / z(ESI): 333.9 [M+1]

[0192] 1H NMR(400MHz,DMSO-d6)δ10.23(br s,1H),8.62(d,J=6.8Hz,1H),8.15(s,1H),7.66(s,1H),7.51(d,J=8.8Hz,1H),7.01(dd,J=6.8,1.6Hz,1H),6.98(d,J=8.8Hz,1H),4.38(s,2H).

[0193] Example 2

[0194] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4-methylpiperidin-4-ol

[0195] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4-methylpiperidin-4-ol

[0196] first step

[0197] 3-bromo-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one

[0198] 3-Bromo-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one

[0199] 4-Bromopyridin-2-amine 1a (1 g, 5.78 mmol) was added to isobutyric acid (10 mL), followed by cyclohexanone 2a (1.13 g, 11.56 mmol) and elemental iodine (146 mg, 0.57 mmol). The reaction mixture was heated to 110 °C for 16 hours under an oxygen atmosphere. The reaction solution was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (50 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 3-bromo-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one 2b (400 mg), with a yield of 26.1%.

[0200] MS m / z(ESI): 265.0 [M+1]

[0201] Step 2

[0202] 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one

[0203] 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one

[0204] 3-Bromo-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one 2b (100 mg, 0.37 mmol), (2,3-dichloro-6-hydroxyphenyl)boronic acid 1j (117 mg, 0.56 mmol), cesium carbonate (245 mg, 0.75 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride(II) (27.6 mg, 0.04 mmol) were added sequentially to a mixed solvent of 1,4-dioxane (2 mL) and water (0.2 mL). Under nitrogen protection, the mixture was heated to 110 °C and reacted for 2 hours. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: system B) to give 2c (60 mg) of 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one, with a yield of 45.8%.

[0205] MS m / z(ESI): 347.0 [M+1]

[0206] Step 3

[0207] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4-methylpiperidin-4-ol

[0208] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4-methylpiperidin-4-ol

[0209] 200 mg (0.57 mmol) of 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one 2c was added to tetrahydrofuran (5 mL), followed by 132 mg (1.15 mmol) of 4-methylpiperidin-4-ol 2d and tetraisopropyl titanate (818 mg, 2.88 mmol, commercially available). The mixture was reacted at 70 °C for 16 hours. The temperature was then lowered to 0 °C, and sodium cyanoborohydride (181 mg, 2.88 mmol) was added. The mixture was then heated to 70 °C and the reaction was continued for 2 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (Column: XBridge C18; 250 × 19 mm ID; 10 μm, 20 mL / min; Mobile phase A: 0.1% NH4HCO3 + H2O, Mobile phase B: CH3CN) to give 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4-methylpiperidin-4-ol 2 (17 mg), yield 6.6%.

[0210] MS m / z(ESI): 446.3 [M+1]

[0211] 1 H NMR (400MHz, DMSO) δ10.16(s,1H),8.21(d,J=7.2Hz,1H),7.47(d,J=8.8Hz,1H),7.35(s,1H),6.96(d,J=8.8Hz,1H),6.74(d,J=8.0Hz,1H),4 .03(s,1H),3.81–3.68(m,1H),2.81–2.51(m,6H),2.18–2.07(m,1H), 2.01–1.90(m,1H),1.88–1.74(m,2H),1.51–1.38(m,4H),1.09(s,3H).

[0212] Example 3

[0213] 3-(2,3-dichloro-6-hydroxyphenyl)-6-methyl-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-ol

[0214] 3-(2,3-Dichloro-6-hydroxyphenyl)-6-methyl-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-6-ol

[0215] 20 mg (0.05 mmol) of 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridine-6(7H)-one 2c was added to tetrahydrofuran (2 mL), the mixture was cooled to 0 °C, methyl magnesium bromide (3 M, 192 μL) was added, and the mixture was heated to room temperature and the reaction was continued for 16 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (Column: XBridge C18; 250 × 19 mm ID; 10 μm, 20 mL / min; Mobile phase A: 0.1% NH4HCO3 + H2O, Mobile phase B: CH3CN) to give 3-(2,3-dichloro-6-hydroxyphenyl)-6-methyl-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridine-6-ol 3 (9 mg), yield 43.0%.

[0216] MS m / z(ESI): 363.0 [M+1]

[0217] 1H NMR (400MHz, DMSO-d6) δ10.16(s,1H),8.21(dd,J=7.2,0.8Hz,1H),7.47(d,J=8.8Hz,1H),7.38–7.33(m,1H),6.96(d,J=8.8Hz,1H),6.75(dd, J=7.2,1.6Hz,1H),4.76(s,1H),2.89–2.81(m,1H),2.74–2.66(m,1H), 2.16–2.04(m,1H),1.96–1.86(m,2H),1.78–1.70(m,1H),1.52(s,3H).

[0218] Example 4

[0219] 3,4-dichloro-2-(7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-7-yl)phenol

[0220] 3,4-Dichloro-2-(7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-7-yl)phenol

[0221] first step

[0222] 4-(6-(allyloxy)-2,3-dichlorophenyl)-1-(3-nitropyridin-2-yl)pyrrolidin-2-one

[0223] 4-(6-(allyloxy)-2,3-dichlorophenyl)-1-(3-nitropyridin-2-yl)pyrrolidine-2-one

[0224] 4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidone-2-one 4a (400 mg, 1.40 mmol, prepared using patent CN117946111), 2-bromo-3-nitropyridine (425 mg, 2.10 mmol), cuprous iodide (53 mg, 0.28 mmol), potassium carbonate (386 mg, 2.80 mmol), and 1,2-diaminocyclohexane (8 mg, 0.07 mmol) were sequentially added to 1,4-dioxane (5 mL), and the mixture was heated to 110 °C for 2 hours under nitrogen protection. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (eluent: system A) to give 4-(6-(allyloxy)-2,3-dichlorophenyl)-1-(3-nitropyridin-2-yl)pyrrolidine-2-one 4c (300 mg), yield 52.5%.

[0225] MS m / z(ESI): 408.0 [M+1]

[0226] Step 2

[0227] 7-(6-(allyloxy)-2,3-dichlorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine

[0228] 7-(6-(allyloxy)-2,3-dichlorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine

[0229] 4-(6-(allyloxy)-2,3-dichlorophenyl)-1-(3-nitropyridin-2-yl)pyrrolidine-2-one 4c (300 mg, 0.73 mmol) was added to acetic acid (5 mL), followed by iron powder (410 mg, 7.35 mmol). The mixture was heated to 120 °C and reacted for 2 hours. The pH of the reaction mixture was adjusted to 7–8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-(6-(allyloxy)-2,3-dichlorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine 4d (100 mg), with a yield of 37.7%. The crude product was used directly in the next reaction without purification.

[0230] MS m / z(ESI): 360.0 [M+1]

[0231] Step 3

[0232] 3,4-dichloro-2-(7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-7-yl)phenol

[0233] 3,4-Dichloro-2-(7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-7-yl)phenol

[0234] 7-(6-(allyloxy)-2,3-dichlorophenyl)-7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridine 4d (100 mg, 0.27 mmol) was added to 1,4-dioxane (2 mL), the mixture was cooled to 0 °C, sodium borohydride (21 mg, 0.55 mmol) and tetrakis(triphenylphosphine)palladium (6.4 mg, 0.05 mmol) were added, and the mixture was heated to room temperature and the reaction was continued for 1 hour. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (15 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (Column: XBridge C18; 250 × 19 mm ID; 10 μm, 20 mL / min; Mobile phase A: 0.1% FA + H2O, Mobile phase B: CH3CN) to give 3,4-dichloro-2-(7,8-dihydro-6H-pyrrolo[2',1':2,3]imidazo[4,5-b]pyridin-7-yl)phenol 4 (1.66 mg), yield 1.8%.

[0235] MS m / z(ESI): 319.9 [M+1]

[0236] 1H NMR (400MHz, MeOD) δ8.27(d,J=4.8Hz,1H),8.00(d,J=8.4Hz,1H),7.33–7.28(m,2H),6.78(d,J= 8.8Hz,1H),5.21–5.13(m,1H),4.57(t,J=10.0Hz,1H),4.42–4.35(m,1H),3.43(d,J=8.8Hz,2H).

[0237] Example 5

[0238] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazetidin-3-ol

[0239] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazacyclobutane-3-ol

[0240] 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridine-6(7H)-one 2c (30 mg, 0.08 mmol) was added to tetrahydrofuran (2 mL), followed by 3-methylazacyclobutane-3-ol hydrochloride 5a (21 mg, 0.17 mmol) and tetraisopropyl titanate (122 mg, 0.43 mmol). The mixture was reacted at 70 °C for 16 hours. The mixture was cooled to 0°C, and sodium cyanoborohydride (27 mg, 0.43 mmol) was added. The temperature was raised to 70°C and the reaction was continued for 2 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL × 2). The mixture was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column: Boston Uni C18; 250 × 21.2 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.1% FA + H2O, mobile phase B: CH3CN) to give 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazacyclobutane-3-ol 5 (8 mg), yield 22.1%.

[0241] MS m / z(ESI): 417.7 [M+1]

[0242] 1H NMR (400MHz, DMSO-d6) δ10.19 (s, 1H), 8.22 (d, J = 7.2Hz, 1H), 7.47 (d, J = 8. 8Hz,1H),7.36(s,1H),6.96(d,J=8.8Hz,1H),6.79–6.73(m,1H),5.17(s,1H ),3.44–3.39(m,1H),3.30–3.15(m,3H),3.01–2.95(m,1H),2.87–2.78(m, 1H),2.74–2.66(m,1H),2.12–2.01(m,1H),1.86–1.68(m,3H),1.32(s,3H).

[0243] Example 6

[0244] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylpyrrolidin-3-ol

[0245] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylpyrrolidine-3-ol

[0246] 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridine-6(7H)-one 2c (50 mg, 0.14 mmol) was added to tetrahydrofuran (2 mL), followed by 3-methylpyrrolidine-3-ol 6a (14 mg, 0.14 mmol) and tetraisopropyl titanate (204 mg, 0.72 mmol). The mixture was reacted at 70 °C for 16 hours. The mixture was cooled to 0°C, and sodium cyanoborohydride (45 mg, 0.72 mmol) was added. The temperature was raised to 70°C and the reaction was continued for 2 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated sodium chloride solution (20 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (QdaColumn: Agilent C18; 250 × 19 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.1% FA + H2O, mobile phase B: CH3CN) to give 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylpyrrolidine-3-ol 6 (27 mg), yield 43.3%. MS m / z(ESI): 432.0 [M+1]

[0247] 1H NMR(400MHz,DMSO)δ10.22(br s,1H),8.23(d,J=7.2Hz,1H),7.47(d,J=8.8Hz,1H),7.35(s,1H),6.97( d,J=8.8Hz,1H),6.78(d,J=6.8Hz,1H),3.74–3.68(m,1H),3.11–3.04(m ,1H),2.94–2.89(m,1H),2.87–2.76(m,4H),2.22–2.12(m,1H),1.99–1. 92(m,1H),1.89–1.80(m,2H),1.75–1.66(m,2H),1.23(d,J=9.2Hz,3H).

[0248] Example 7

[0249] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylpiperidin-3-ol

[0250] 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylpiperidin-3-ol

[0251] 200 mg (0.57 mmol) of 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridine-6(7H)-one 2c was added to tetrahydrofuran (4 mL), followed by 3-methylpiperidin-3-ol 7a (66 mg, 0.57 mmol) and tetraisopropyl titanate (818 mg, 2.88 mmol). The mixture was reacted at 70 °C for 16 hours. The mixture was cooled to 0°C, and sodium cyanoborohydride (181 mg, 2.88 mmol) was added. The temperature was raised to 70°C and the reaction was continued for 2 hours. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated sodium chloride solution (20 mL × 2). The solution was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (Column: XBridge C18; 250 × 19 mm ID; 10 μm, 20 mL / min; Mobile phase A: 0.1% NH4HCO3 + H2O, Mobile phase B: CH3CN) to give 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylpiperidin-3-ol (15 mg), yield 5.8%.

[0252] MS m / z(ESI): 446.0 [M+1]

[0253] 1H NMR (400MHz, DMSO) δ 10.20 (br s,1H),8.21(d,J=7.2Hz,1H),7.47(d,J=8.8Hz,1H),7.35(s,1H),6.96(d,J=8. 8Hz,1H),6.74(dd,J=6.8,1.6Hz,1H),4.00(s,1H),3.87–3.81(m,1H),2.81–2. 73(m,3H),2.59–2.52(m,1H),2.43–2.38(m,1H),2.30–2.24(m,1H),2.16–2.08 (m,1H),1.94–1.75(m,3H),1.68–1.58(m,1H),1.47–1.26(m,3H),1.06(s,3H).

[0254] Example 8

[0255] 2-(6-(3-amino-3-methylazetidin-1-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0256] first step

[0257] tert-butyl

[0258] (1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazetidin-3-yl)carbamate

[0259] (1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazacyclobutane-3-yl)tert-butyl carbamate

[0260] 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one 2c (100 mg, 0.28 mmol) was added to tetrahydrofuran (3 mL), followed by (3-methylazacyclobutane-3-yl)carbamate tert-butyl ester 8a (128 mg, 0.57 mmol, commercially available) and tetraisopropyl titanate (409 mg, 1.44 mmol). The reaction mixture was reacted at 70 °C for 16 hours under nitrogen protection. The temperature was then lowered to 0 °C, sodium cyanoborohydride (90 mg, 1.44 mmol) was added, and the reaction mixture was heated to 70 °C and reacted for another 2 hours. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give tert-butyl carbamate 8b (50 mg), yield 33.5%.

[0261] MS m / z (ESI): 517.2 [M+1]

[0262] Step 2

[0263] 2-(6-(3-amino-3-methylazetidin-1-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0264] 2-(6-(3-amino-3-methylazacyclobutane-1-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0265] 50 mg (0.09 mmol) of 1-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazacyclobutane-3-yl) tert-butyl carbamate 8b was added to a mixed solvent of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was adjusted to pH 7–8 with saturated sodium carbonate solution, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (XBridge C18 column; 250 × 19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3 / H2O, mobile phase B: CH3CN) to give 2-(6-(3-amino-3-methylazacyclobutane-1-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol 8 (8 mg), yield 19.8%.

[0266] MS m / z (ESI): 417.0 [M+1]

[0267] 1H NMR (400MHz, DMSO-d6) δ8.20(d,J=6.8Hz,1H),7.47(d,J=8.8Hz,1H),7.34(s,1H),6.96(d,J=9.2Hz,1H),6.74(d,J=6.8Hz,1H),3.41–3.39(m,1H), 3.26–3.23(m,1H),3.19–3.12(m,2H),2.89–2.78(m,2H),2.76–2.69(m,1 H),2.12–2.03(m,1H),1.86–1.76(m,1H),1.74–1.67(m,2H),1.24(s,3H).

[0268] Example 9

[0269] 2-(6-(4,7-diazaspiro[2.5]octan-7-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0270] 2-(6-(4,7-diazaspiro[2.5]octane-7-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0271] first step

[0272] tert-butyl

[0273] 7-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0274] 7-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4,7-diazaspiro[2,5]octane-4-carboxylic acid tert-butyl ester

[0275] 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one 2c (100 mg, 0.28 mmol) was added to tetrahydrofuran (3 mL), followed by (4,7-diazaspiro[2,5]octane-4-carboxylic acid tert-butyl ester 9a (122 mg, 0.57 mmol, commercially available) and tetraisopropyl titanate (409 mg, 1.44 mmol). The reaction mixture was reacted at 70 °C for 16 hours under nitrogen protection. The mixture was then cooled to 0 °C, and sodium cyanoborohydride (90 mg, 1.44 mmol) was added. The mixture was then heated to... The reaction was continued at 70℃ for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase preparation (C18) (eluent: system D) to give 7-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4,7-diazaspiro[2,5]octane-4-carboxylic acid tert-butyl ester 9b (70 mg), yield 44.7%.

[0276] MS m / z (ESI): 543.0 [M+1]

[0277] Step 2

[0278] 2-(6-(4,7-diazaspiro[2.5]octan-7-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0279] 2-(6-(4,7-diazaspiro[2.5]octane-7-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0280] 7-(3-(2,3-dichloro-6-hydroxyphenyl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4,7-diazaspiro[2,5]octane-4-carboxylic acid tert-butyl ester 9b (70 mg, 0.12 mmol) was added to a mixed solvent of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was reacted at 25 °C for 2 hours. The reaction solution was adjusted to pH 7–8 with saturated sodium carbonate solution, extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (XBridge C18 column; 250 × 19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol NH4HCO3 / H2O, mobile phase B: CH3CN) to give 2-(6-(4,7-diazaspiro[2.5]octane-7-yl)-6,7,8,9-tetrahydrobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol 9 (22 mg), yield 38.5%.

[0281] MS m / z (ESI): 443.0 [M+1]

[0282] 1 H NMR (400MHz, MeOD) δ8.50(d,J=6.4Hz,1H),7.69(s,1H),7.46(d,J=8.8Hz,1H),7.26(d,J=6.4Hz,1H),6.93(d,J=8.8Hz,1H),4.35–4.25(m,1H),3.39 –3.34(m,2H),3.07–2.97(m,2H),2.94–2.82(m,4H),2.31–2.55(m,1H),2. 19–2.12(m,1H),2.05–1.98(m,2H),1.05–1.00(m,2H),0.95–0.91(m,2H).

[0283] Example 10

[0284] 2-(6-(4,7-diazaspiro[2.5]octan-7-yl)benzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0285] 2-(6-(4,7-diazaspiro[2.5]octane-7-yl)benzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0286] first step

[0287] tert-butyl

[0288] 7-(3-(2,3-dichloro-6-hydroxyphenyl)benzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4,7-diazaspiro[2.5]octane-4-carboxylate

[0289] 7-(3-(2,3-dichloro-6-hydroxyphenyl)benzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4,7-diazaspiro[2,5]octane-4-carboxylic acid tert-butyl ester

[0290] 3-(2,3-dichloro-6-hydroxyphenyl)-8,9-dihydrobenzo[4,5]imidazo[1,2-a]pyridin-6(7H)-one 2c (100 mg, 0.28 mmol) was added to tetrahydrofuran (3 mL), followed by (4,7-diazaspiro[2,5]octane-4-carboxylic acid tert-butyl ester 9a (122 mg, 0.57 mmol) and tetraisopropyl titanate (409 mg, 1.44 mmol). The reaction mixture was reacted at 70 °C for 16 hours. The mixture was then cooled to 0 °C, and sodium cyanoborohydride (90 mg, 1.44 mmol) was added. The reaction was continued at 70°C for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The organic phases were washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to obtain 10b (70 mg) of (7-(3-(2,3-dichloro-6-hydroxyphenyl)benzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4,7-diazaspiro[2,5]octane-4-carboxylic acid tert-butyl ester, yield 45.0%.

[0291] MS m / z (ESI): 539.2 [M+1]

[0292] Step 2

[0293] 2-(6-(4,7-diazaspiro[2.5]octan-7-yl)benzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0294] 2-(6-(4,7-diazaspiro[2.5]octane-7-yl)benzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0295] (7-(3-(2,3-dichloro-6-hydroxyphenyl)benzo[4,5]imidazo[1,2-a]pyridin-6-yl)-4,7-diazaspiro[2,5]octane-4-carboxylic acid tert-butyl ester 10b (70 mg, 0.12 mmol) was added to a mixed solvent of dichloromethane (2 mL) and trifluoroacetic acid (0.5 mL), and the reaction mixture was reacted at 25 °C for 2 hours. The pH of the reaction solution was adjusted to 7–8 with saturated sodium carbonate solution. Extracted with ethyl acetate (10 mL × 3), the organic phases were combined and washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reverse-phase separation to give 10 (3 mg) of 2-(6-(4,7-diazaspiro[2.5]octane-7-yl)benzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol, yield 4.1%. MS m / z (ESI): 439.0 [M+1]

[0296] 1 H NMR (400MHz, DMSO) δ9.00(d,J=7.2Hz,1H),7.76(d,J=8.0Hz,1H),7.54–7.49(m,2H),7.23(t,J=8.0Hz,1H),7.00(d,J=8.8H z,1H),6.85(d,J=7.2Hz,1H),6.76(d,J=7.6Hz,1H),3.61–3.56(m,2H),3.36(s,2H),3.04–2.98(m,2H),0.59–0.52(m,4H).

[0297] Example 11

[0298] 1-(3-(2,3-dichloro-6-hydroxyphenyl)benzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazetidin-3-ol

[0299] 1-(3-(2,3-dichloro-6-hydroxyphenyl)benzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazacyclobutane-3-ol

[0300] first step

[0301] 6-bromo-3-methoxybenzo[4,5]imidazo[1,2-a]pyridine

[0302] 6-Bromo-3-methoxybenzo[4,5]imidazo[1,2-a]pyridine

[0303] At room temperature, cesium carbonate (3.90 g, 11.96 mmol), cuprous iodide (379.5 mg, 1.99 mmol), and o-phenanthroline (71.7 mg, 398.5 μmol, commercially available) were added to a xylene (30 mL) solution of 2-bromo-4-methoxypyridine 11a (1.50 g, 7.97 mmol, commercially available) and 2,6-dibromoaniline 11b (1 g, 3.99 mmol, commercially available). The reaction mixture was stirred at 120 °C under nitrogen protection for 8 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 6-bromo-3-methoxypyridano[1,2-a]benzimidazole 11c (300 mg), in 27.2% yield.

[0304] MS m / z(ESI): 277.0 [M+1]

[0305] Step 2

[0306] 6-bromobenzo[4,5]imidazo[1,2-a]pyridin-3-ol

[0307] 6-Bromobenzo[4,5]imidazo[1,2-a]pyridine-3-ol

[0308] A mixture of 6-bromo-3-methoxypyridano[1,2-a]benzimidazole 11c (500 mg, 1.80 mmol) and pyridine hydrochloride (5 g) was stirred at 150 °C for 16 hours. The reaction mixture was cooled to room temperature, and the residue was purified directly by reverse-phase preparation (C18) (eluent: system D) to give 6-bromopyridano[1,2-a]benzimidazole-3-ol 11d (320 mg), yield 67.4%.

[0309] MS m / z(ESI): 262.9 [M+1]

[0310] Step 3

[0311] 6-bromobenzo[4,5]imidazo[1,2-a]pyridin-3-yl trifluoromethanesulfonate

[0312] 6-Bromobenzo[4,5]imidazo[1,2-a]pyridin-3-yltrifluoromethanesulfonate

[0313] Under nitrogen protection at 0°C, 4-dimethylaminopyridine (23.2 mg, 190.0 μmol, commercially available) and triethylamine (384.6 mg, 3.8 mmol) were added to a solution of 6-bromopyrido[1,2-a]benzimidazole-3-ol 11d (500 mg, 1.90 mmol) and N-phenylbis(trifluoromethane)sulfonylimide (1.02 g, 2.85 mmol, commercially available) in dichloromethane (8 mL). The reaction mixture was heated to room temperature and stirred for 2 hours. The reaction mixture was quenched with water (10 mL), extracted with dichloromethane (20 mL × 3), the combined organic phases were washed with saturated sodium chloride (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (6-bromopyrido[1,2-a]benzimidazol-3-yl)trifluoromethanesulfonate 11e (1 g, 1.90 mmol) in 99.8% yield, which was used directly in the next step.

[0314] MS m / z(ESI): 395.0 [M+1]

[0315] Step 4

[0316] 2-(6-bromobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0317] 2-(6-bromobenzo[4,5]imidazo[1,2-a]pyridin-3-yl)-3,4-dichlorophenol

[0318] To a solution of (6-bromopyrido[1,2-a]benzimidazol-3-yl)trifluoromethanesulfonate 11e (300 mg, 759.2 μmol) and (2,3-dichloro-6-hydroxyphenyl)boronic acid (157.0 mg, 759.2 μmol) in 1,4-dioxane (3 mL) and water (0.5 mL), potassium carbonate (314.3 mg, 2.28 mmol) and tetraphenylphosphine palladium (87.7 mg, 75.9 μmol, commercially available) were added. The reaction mixture was stirred at 80 °C under nitrogen protection for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 2-(6-bromopyrido[1,2-a]benzimidazol-3-yl)-3,4-dichlorophenol 11f (120 mg), in 38.7% yield.

[0319] MS m / z(ESI): 407.0 [M+1]

[0320] Step 5

[0321] 1-(3-(2,3-dichloro-6-hydroxyphenyl)benzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazetidin-3-ol

[0322] 1-(3-(2,3-dichloro-6-hydroxyphenyl)benzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazacyclobutane-3-ol

[0323] To a solution of 2-(6-bromopyrido[1,2-a]benzimidazol-3-yl)-3,4-dichlorophenol 11f (50 mg, 122.5 μmol) and 3-methylazacyclobutane-3-ol (32.0 mg, 367.6 μmol, commercially available) in 1,4-dioxane (3 mL), cesium carbonate (199.6 mg, 612.6 μmol) and (2-dicyclohexylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II)methanesulfonate (19.9 mg, 12.3 μmol, commercially available) were added. The reaction mixture was stirred at 110 °C under nitrogen protection for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 3767 / Qda column: SunFire C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20ml / min) to give 1-(3-(2,3-dichloro-6-hydroxyphenyl)benzo[4,5]imidazo[1,2-a]pyridin-6-yl)-3-methylazacyclobutane-3-ol 11 (1.72mg, 4.2μmol), yield 3.4%.

[0324] MS m / z(ESI): 414.2 [M+1]

[0325] 1H NMR(400MHz,MeOD)δ8.76(d,J=7.2Hz,1H),7.57–7.47(m,2H),7.42(d,J=8.8Hz,1H),7.27(t,J=7.6Hz,1 H),6.94–6.84(m,2H),6.51(d,J=7.6Hz,1H),4.25(d,J=8.4Hz,2H),4.05(d,J=8.0Hz,2H),1.64(s,3H).

[0326] Example 12

[0327] 1-(2-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-3-methylazetidin-3-ol

[0328] 1-(2-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-3-methylazacyclobutane-3-ol

[0329] first step

[0330] 4-(6-(allyloxy)-2,3-dichlorophenyl)-1-(3-bromo-2-nitrophenyl)pyrrolidin-2-one

[0331] 4-(6-(allyloxy)-2,3-dichlorophenyl)-1-(3-bromo-2-nitrophenyl)pyrrolidine-2-one

[0332] Under nitrogen protection at 0°C, sodium hydride (279.6 mg, 6.99 mmol, 60%) and 1-bromo-3-fluoro-2-nitrobenzene 12a (1.15 g, 5.24 mmol, commercially available) were added to a solution of 4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidone-2-one 4a (1.0 g, 3.49 mmol) in N,N-dimethylformamide (6 mL). The reaction mixture was stirred at 60°C under nitrogen protection for 16 hours. The reaction mixture was cooled to 0°C, quenched with water (10 mL), extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed with saturated sodium chloride (60 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 4-(6-allyloxy-2,3-dichloro-phenyl)-1-(3-bromo-2-nitro-phenyl)pyrrolidine-2-one 12b (950 mg), yield 55.9%.

[0333] MS m / z(ESI): 484.9 [M+1]

[0334] Step 2

[0335] 2-(6-(allyloxy)-2,3-dichlorophenyl)-5-bromo-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

[0336] 2-(6-(allyloxy)-2,3-dichlorophenyl)-5-bromo-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazole

[0337] 4-(6-allyloxy-2,3-dichlorophenyl)-1-(3-bromo-2-nitro-phenyl)pyrrolidine-2-one 12b (400 mg, 822.8 μmol) and iron powder (459.5 mg, 8.23 ​​mmol) were added sequentially to an acetic acid (8 mL) solution. The reaction mixture was stirred at 120 °C under nitrogen protection for 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 2-(6-allyloxy-2,3-dichlorophenyl)-5-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole 12c (140 mg, 319.5 μmol), yield 38.8%.

[0338] MS m / z(ESI): 436.8 [M+1]

[0339] Step 3

[0340] 1-(2-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-3-methylazetidin-3-ol

[0341] 1-(2-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-3-methylazacyclobutane-3-ol

[0342] Cesium carbonate (223.1 mg, 684.7 μmol) and palladium(II) methanesulfonate (22.2 mg, 13.7 μmol) were added to a solution of 2-(6-allyloxy-2,3-dichlorophenyl)-5-bromo-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole 12c (60 mg, 136.9 μmol) and 3-methylazacyclobutane-3-ol (35.8 mg, 410.8 μmol) in 1,4-dioxane (2 mL). The reaction mixture was stirred at 110 °C under nitrogen protection for 4 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters 3767 / Qda column: SunFire C18, 19*250mm, 10µm; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20ml / min) to give 1-(2-(2,3-dichloro-6-hydroxyphenyl)-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-5-yl)-3-methylazacyclobutane-3-ol 12 (3.18 mg), yield 5.7%.

[0343] MS m / z(ESI): 404.1 [M+1]

[0344] 1 H NMR (400MHz, DMSO-d6) δ10.59(s,1H),7.39(d,J=8.8Hz,1H),6.94(t,J=7.6Hz,1H),6.86(d,J=8.8Hz,1H),6.72(d,J=7.6Hz,1H),6.06(d,J=7.2Hz,1 H),5.41(s,1H),4.99–4.83(m,1H),4.35(t,J=9.6Hz,1H),4.18–4.07(m,1 H),4.06–3.96(m,2H),3.88–3.81(m,2H),3.24–3.15(m,2H),1.48(s,3H).

[0345] Example 13

[0346] 3,4-dichloro-2-(1,3,8-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),8,10,12-tetraen-11-yl)phenol

[0347] 3,4-Dichloro-2-(1,3,8-triazacyclo[7.4.0.0])2,7 [Tetane-2(7),8,10,12-tetraen-11-yl)phenol]

[0348] first step

[0349] tert-butyl 11-bromo-1,3,8-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),8,10,12-tetraene-3-carboxylate

[0350] 11-Bromo-1,3,8-triazacyclo[7.4.0.0] 2,7 [Tetrazane-2(7),8,10,12-tetraene-3-carboxylic acid tert-butyl ester]

[0351] 4-Bromopyridine-2-amine 1a (1 g, 5.78 mmol) and tert-butyl 3-oxopiperidinium-1-carboxylic acid 13b (1.15 g, 5.78 mmol, commercially available) were added to acetic acid (0.5 mL) and toluene (15 mL), and the mixture was heated to 135 °C to separate the water. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: system A) to give product 11-bromo-1,3,8-triazacyclo[7.4.0.02, 7]tridecane-2(7),8,10,12-tetraene-3-carboxylic acid tert-butyl ester 13c (2.6 g), yield: 25.5%.

[0352] MS m / z (ESI): 352.1 [M+1]

[0353] Step 2

[0354] tert-butyl

[0355] 11-(2,3-dichloro-6-methoxy-phenyl)-1,3,8-triazatricyclo[7.4.0.0 2,7 ]trideca-2(7),8,10,12-tetraene-3-carboxylate

[0356] 11-(2,3-dichloro-6-methoxy-phenyl)-1,3,8-triazacyclo[7.4.0.0] 2,7 [Tetrazane-2(7),8,10,12-tetraene-3-carboxylic acid tert-butyl ester]

[0357] (2,3-Dichloro-6-methoxy-phenyl)boronic acid (141.1 mg, 638.8 μmol), 11-bromo-1,3,8-triazacyclo[7.4.0.0] 2,7 [1,1'-Tetrane-2(7),8,10,12-tetraen-3-carboxylic acid tert-butyl ester 13c (150 mg, 425.9 μmol), cesium carbonate (152.6 mg, 468.5 μmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (31.6 mg, 42.6 μmol, commercially available) were added to dioxane (10 mL), and the mixture was heated to 100 °C under argon protection. The mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (eluent: system A) to obtain 11-(2,3-dichloro-6-methoxy-phenyl)-1,3,8-triazacyclo[7.4.0.0] 2,7 [Tetrazane-2(7),8,10,12-tetraen-3-carboxylic acid tert-butyl ester 13d (110mg), yield: 57.6%]

[0358] MS m / z (ESI): 448.1 [M+1]

[0359] Step 3

[0360] tert-butyl

[0361] 3,4-dichloro-2-(1,3,8-triazatricyclo[7.4.0.02,7]trideca-2(7),8,10,12-tetraen-11-yl)phenol

[0362] 3,4-Dichloro-2-(1,3,8-triazacyclo[7.4.0.0]) 2,7 [Tetane-2(7),8,10,12-tetraen-11-yl)phenol]

[0363] 11-(2,3-dichloro-6-methoxy-phenyl)-1,3,8-triazacyclo[7.4.0.0] 2,7 13d (100 mg, 223 μmol) of tridecane-2(7),8,10,12-tetraen-3-carboxylic acid tert-butyl ester was added to dichloromethane (1 mL), the mixture was cooled to 0 °C, boron tribromide (55.9 mg, 223 μmol) was added, and the mixture was slowly brought to room temperature and reacted overnight. The mixture was concentrated under reduced pressure, and the residue was used to prepare 3,4-dichloro-2-(1,3,8-triazine) [7.4.0.0] 2,7 [Tetrazane-2(7),8,10,12-tetraen-11-yl)phenol 13 (2.35 mg), yield 2.2%.]

[0364] MS m / z (ESI): 334.1 [M+1]

[0365] Biological evaluation

[0366] Test Example 1: Manual patch-clamp method for detecting the effect of the compound of this invention on the hKv1.3 potassium ion channel.

[0367] 1.1 Cells

[0368] The HEK293 cell line stably expressing the hKv1.3 ion channel used in this experiment was constructed by Kanglong Chemical. This cell line was cultured in a medium containing 90% DMEM (Thermo Fisher Scientific), 10% fetal bovine serum, 100 U / mL penicillin-streptomycin solution (Thermo Fisher Scientific), and 6 μg / mL puromycin (Sigma-Aldrich). Before the experiment, the cells were digested and cultured at a density of 5 × 10⁶ cells / mL. 5 The samples were seeded at a density in 3.5 cm culture dishes containing coverslips for subsequent manual patch-clamp experiments.

[0369] 1.2 Experimental Solution

[0370] 1) Extracellular fluid: 132mM sodium chloride, 4mM potassium chloride, 3mM calcium chloride, 0.5mM magnesium chloride, 11.1mM glucose and 10mM HEPES (pH adjusted to 7.35 using sodium hydroxide).

[0371] 2) Intracellular fluid: 10mM EGTA, 10mM HEPES, 10mM potassium chloride, 10mM sodium chloride, 110mM potassium fluoride (pH adjusted to 7.2 using potassium hydroxide).

[0372] Note: The osmotic pressure of the solution should be controlled between 280 and 300 mOsmol / kg. The solution needs to be filtered and stored at 4°C before use.

[0373] 1.3 Solution of the compound to be tested

[0374] The test compound was dissolved in DMSO to prepare a stock solution with a final concentration of 10 mM. The stock solution was then serially diluted, and further diluted in extracellular fluid to obtain five test solutions with the desired final concentrations (μM): 30, 10, 3.33, 1.11, and 0.37. The concentration of DMSO in the test solutions ranged from 0.1% to 0.3% (volume ratio).

[0375] 1.4 Experimental Procedure

[0376] 1) The hKv1.3 current test method is as follows: Apply a depolarization command voltage for 2 seconds to depolarize the membrane potential from -80mV to +50mV, thereby allowing the hKv1.3 current to be observed. The peak value of the current is the magnitude of the hKv1.3 current.

[0377] 2) The hKv1.3 current used to detect the test compound was continuously recorded for 120 seconds before drug administration to assess the stability of the hKv1.3 current generated by the test cells. Only stable cells within the acceptable range of the evaluation criteria were allowed to proceed to the subsequent compound detection.

[0378] 3) Test of the inhibitory effect of the test compound on hKv1.3 current: First, the hKv1.3 current measured in extracellular fluid containing 0.1% DMSO was used as the baseline. After the hKv1.3 current stabilized for at least 5 minutes, the solution containing the test compound was sequentially perfused around the cells from low to high concentration. After each perfusion, approximately 5 minutes were allowed for the compound to fully act on the cells while simultaneously recording the hKv1.3 current. After the recorded current stabilized, the last 5 hKv1.3 current values ​​were recorded, and their average value was taken as the final current value at the specific concentration. After testing the compound, 100 μM carvedilol was added to the same cell to completely inhibit its current, serving as a positive control for that cell.

[0379] 1.5 Data Analysis

[0380] Note: Data is output by PatchMaster software.

[0381] 1) After injecting blank solvent or compound gradient solution, calculate the average of five consecutive current values ​​obtained at a stable state, and use these averages as the "current magnitude". 空白 "and current magnitude" 化合物 ".

[0382] The current suppression percentage is calculated using the following formula.

[0383] 2) The dose-response curve was fitted using Graphpad Prism 8.0 software and the IC50 value was calculated.

[0384] 3) The standard deviation of the three sets of data is less than 15 (SD < 15).

[0385] 1.6 Experimental Results

[0386] This experiment used a manual patch-clamp technique to evaluate whether the test compounds had a potential inhibitory effect on the voltage-gated potassium ion channel hKv1.3. The results are shown in Tables 1 and 2.

[0387] Table 1. Inhibitory activity of the compounds of this invention against hKv1.3 potassium ion channels (two concentration points, 0.001 μM / 0.1 μM)

[0388] The results showed that the compounds of the present invention exhibited 1 nM inhibitory activity against the hKv1.3 potassium ion channel. <IC 50 <100nM, exhibiting good inhibitory effect.

[0389] Table 2. Inhibitory activity of the compounds of this invention against hKv1.3 potassium ion channels (two concentration points, 0.01 μM / 1 μM).

[0390] The results showed that the compounds of the present invention exhibited IC50 inhibitory activity against hKv1.3 potassium ion channels. 50 <1μM, exhibiting good inhibitory effect.

Claims

1. A compound of Formula (I) or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof: ###0001### (I) ​ wherein: is selected from a single or double bond as necessary such that each atom thereof assumes a normal valency; is selected from a single or double bond as necessary such that each atom thereof assumes a normal valency; is selected from a single or double bond as necessary such that each atom thereof assumes a normal valency; n is 0 or 1 ; with the proviso that n is 1 when for a double bond (to form ) ; n is 0, for a single bond (to form )； R B each independently is selected from the group consisting of hydroxy, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy, wherein said C 1-6 alkyl or C 1-6 alkoxy is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, =0, amino, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy. Y is selected from CR a R b , NR c , or O; R a , R b are the same or different, each independently selected from a hydrogen atom, a hydroxyl group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, or, R a and R b together with the carbon atom to which they are attached form a C 3-7 cycloalkyl group or a 3-7 membered heterocyclyl group, wherein the heterocyclyl group contains one or more N, O or S(=O) r atoms within the ring; R c selected from a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl or C 3-7 cycloalkyl; Y is selected from N or CR when the double bond is present d ; X is each independently selected from N or CH; Z, T are each independently selected from N or CR d ; Z, T are each independently selected from N or C when is a double bond; R d each independently is selected from a hydrogen atom, a halogen, a C 1-6 alkyl group or a C 1-6 alkoxy group; Ring A is selected from C 6-10 aryl, 5-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein the C 6-10 aryl is preferably phenyl; R 1 selected from a hydrogen atom or C 1-6 alkyl group; R 2 , R 3 , R 4 , R 5 are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-7 cycloalkyl group, a halogenated C 3-7 cycloalkyl group or a halogenated C 1-6 alkyl group; or R 2 and R 3 , R 3 and R 4 each independently form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl, C 6-10 aryl, 5-8 membered heterocyclyl or 5-8 membered heteroaryl, wherein said C 3-6 cycloalkyl, C 6-10 aryl, 5-8 membered heterocyclyl or 5-8 membered heteroaryl is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, =0, C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkyl or halogenated C 1-6 alkoxy. R A each independently is selected from the group consisting of a deuterium atom, halogen, cyano, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 6 , -OC(=O)R 6 , -C(=O)R 6 , -NR 7 C(=O)R 8 , -NR 7 C(=O)OR 8 , -NR 7 R 8 , -C(=O)NR 7 R 8 , -S(=O) r NR 7 R 8 or -S(=O) r R 6 ; wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R AA ; or two R A with the same carbon atom to which they are attached forms a -C(=0)-; R AA the same or different, each independently selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 9 , =0, -C(=0)R 9 , -S(=0) r R 9 , -C(=0)OR 9 , -OC(=0)R 9 , -NR 10 R 11 , -C(=0)NR 10 R 11 , -SO2NR 10 R 11 , -NR 10 C(=0)R 11 or -NR 10 C(=0)OR 11 ; wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =0, -S(=0) r R 9 , -S(=0)(=NR 10 )R 11 , -C(=0)R 9 , -C(=0)OR 9 , -OC(=0)R 9 , -NR 10 R 11 , -C(=0)NR 10 R 11 , -SO2NR 10 R 11 , -NR 10 C(=0)R 11 or -NR 10 C(=0)OR 11 ; R 6 each independently is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 9 , -C(=0)OR 9 , -OC(=0)R 9 , -NR 10 R 11 , -C(=0)NR 10 R 11 , -SO2NR 10 R 11 , -NR 10 C(=0)R 11 , or -NR 10 C(=0)OR 11 ; R 7 and R 8 are each independently selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =0, -C(=0)R 9 , -C(=0)OR 9 , -OC(=0)R 9 , -NR 10 R 11 , -C(=0)NR 10 R 11 , -S02NR 10 R 11 , -NR 10 C(=0)R 11 , or -NR 10 C(=0)OR 11 ; or R 7 and R 8 together with the atom to which they are attached form a 3- to 12-membered heterocyclyl, wherein the 3- to 12-membered heterocyclyl contains one or more N, O, or S(O)r, and said 3- to 12-membered heterocyclyl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(=O)R 9 , -C(=O)OR 9 , -OC(=O)R 9 , -NR 10 R 11 , -C(=O)NR 10 R 11 , -SO2NR 10 R 11 , -NR 10 C(=O)R 11 , or -NR 10 C(=O)OR 11 ; R 9 , R 10 , and R 11 are each independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxyl group, or a carboxylate ester group; m is 0, 1, 2, 3 or 4; t is 0, 1 or 2 and r is each independently 0, 1 or 2; 2. The compound according to claim 1, or a stereoisomer, tautomer, deuterated analog, or pharmaceutically acceptable salt thereof, wherein R 1 is a hydrogen atom.

3. The compound according to claim 1 or 2, or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, which is a compound according to general formula (II) or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof: ###00006### (II) wherein: R 2 , R 3 each independently is selected from a hydrogen atom or a halogen; the halogen preferably is chlorine; R 4 is a hydrogen atom or a halogen; A, X, Y, Z, T, R A , R 5 , R B , t, m and n are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof, wherein it is the compound according to general formula (III), or its stereoisomer, tautomer, deuterated derivative, or pharmaceutically acceptable salt thereof: wherein: R 5 Selected from hydrogen atom, halogen, cyano group, C 1-6 Alkyl, C 2-6 alkynyl group, C 1-6 Alkoxy; A, X, Y, Z, T, R A , R B , t, m and n are as defined in claim 1.

5. The compound according to claim 1 or 2, or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, which is a compound according to Formula (IV-1) or (IV-2), or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof: ###00032### (IV-1) (IV-2) 5 wherein: Ring B is phenyl or 5-6 membered heteroaryl; R j selected from hydroxy, halogen, cyano, C 1-6 alkyl or C 1-6 alkoxy; q is 0, 1 or 2; R 2 , R 4 each independently is selected from a hydrogen atom or a halogen, said halogen preferably being chlorine; R 5 selected from a hydrogen atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-6 alkynyl group, a C 1-6 alkoxy group; A, X, Y, Z, T, R A , R B , t, m and n are as defined in claim 1.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R 5 is selected from a hydrogen atom, fluoro, chloro, cyano, methyl, ethynyl, or methoxy.

7. The compound according to any one of claims 1 to 6, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of: Rings A and R A R B The definitions of t and m are as described in claim 1.

8. The compound of any one of claims 1-7, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein t is 1, R B selected from C 1-6 alkyl.

9. The compound according to any one of claims 1-7 or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, wherein t is 0.

10. The compound according to any one of claims 1-9, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein ring A is selected from 11. The compound according to any one of claims 1 to 10, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R A is each independently selected from hydroxy, halogen, cyano, C 1-6 alkyl or 3- to 12-membered heterocyclyl; wherein said C 1-6 alkyl or 3- to 12-membered heterocyclyl is optionally further substituted with one or more R AA . or two R A with the same carbon atom to which they are attached forms a -C(=0)-; R AA the same or different, each independently selected from the group consisting of hydroxy, halogen, cyano, C 3～6 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, -NR 10 R 11 or -SO2NR 10 R 11 wherein said C 3～6 cycloalkyl, C 1-6 alkyl, C 1-6 alkoxy is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, C 1-6 alkyl or C 1-6 alkoxy, NR 10 R 11 , -S(=O) r R 9 , -SO2NR 10 R 11 , or -S(=O)(=NR 10 )R 11 ; R 9 selected from C 3～6 cycloalkyl or C 1-6 alkyl; R 10 , R 11 are each independently selected from a hydrogen atom or a C 1-6 alkyl group; r is 0 or 2.

12. The compound as claimed in claim 11, wherein R A selected from the group consisting of methyl, hydroxy, or two R A with the same carbon atom to which they are attached forms a -C(=O)-.

13. The compound according to any one of claims 1-12 or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, wherein m is 0.

14. The compound according to any one of claims 1-13, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein the compound is:

15. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1-14 or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

16. Use of a compound according to any one of claims 1-14 or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 for the manufacture of a Kv1.3 potassium channel inhibitor.

17. Use of a compound according to any one of claims 1-14 or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 for the manufacture of a medicament for the treatment of a disease mediated by Kv1.3 potassium channel; preferably, the disease mediated by Kv1.3 potassium channel is an autoimmune disease; further preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis, or chronic kidney disease.

18. Use of a compound according to any one of claims 1-14 or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15 for the manufacture of a medicament for the treatment of an autoimmune disease; preferably, the autoimmune disease is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis, or chronic kidney disease.

Images