6,7-dihydro-5h-pyrrolo[1,2-a]imidazole derivative, preparation method therefor, and use thereof

Abstract

The present invention relates to a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole derivative, a preparation method therefor, and a medical use of a pharmaceutical composition containing the derivative. Specifically, the present invention relates to a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole derivative as shown in general formula (I), a preparation method therefor, and a pharmaceutically acceptable salt thereof, as well as a use thereof as a therapeutic agent, particularly as a Kv1.3 potassium channel inhibitor. The definitions of the substituents in general formula (I) are the same as those defined in the description.

Description

6,7-dihydro-5h-pyrrolo[1,2-a]imidazole derivatives, processes for their preparation and uses thereof TECHNICAL FIELD

[0001] The present invention relates to 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole 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, etc.) across the membrane, thus creating a concentration gradient between the intracellular components of the cell and the extracellular fluid surrounding it. Because ion concentrations are directly involved 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". Among them, voltage-gated channels are found in 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 ions are 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 one of the members 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 N-terminal and C-terminal connected to S1 and S6, respectively. Among them, the transmembrane structural elements (S1-S4) constitute the voltage-sensitive region of the channel, and the S5-S6 of the four subunits and the S5-S6 connecting segment (P-loop) embedded in the membrane polymerize to 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 Ca 2+ Calcium channels are activated by the release of calcium ions (Ca 2+ release-activated Ca 2+channel, CRAC) into the cell, resulting in intracellular Ca 2+ The concentration increases, the cell membrane depolarizes, thereby mediating intracellular calmodulin and calcineurin and the like to activate the downstream signal pathway, so that the expression amount of Kv1.3 on the cell membrane is increased. Thus, the intracellular potassium ion outflows, 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 T cell activation. Kv1.3 potassium ion channel is the key to the sustained activation of effector T cells. In microglial cells, Kv1.3 participates in the process of killing neurons in the burst respiratory burst neuroinflammation. In dendritic cells, Kv1.3 participates in the secretion of inflammatory cytokines together with Kv1.5. Since 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 Kv1.3 channels can selectively inhibit the activation process of effector T cells, which provides a new idea for the treatment of autoimmune diseases related to effector T cells. Kv1.3 has thus become a new target protein for the treatment of autoimmune diseases. In addition, Kv1.3 also participates in the process of neurotoxicity effect of the body and the occurrence and development of cancer, and abnormal expression of Kv1.3 has been detected in many tumor cells such as breast cancer, prostate cancer, ovarian cancer and microglial cells. Experiments have shown that inhibiting the activity of Kv1.3 can induce apoptosis of tumor cells. Therefore, drugs targeting Kv1.3 have important clinical value.

[0006] There is no drug on the market for Kv1.3 inhibitors, and there is still a lack of effective treatment drugs for autoimmune diseases, which seriously threatens human health, and there is still a huge unmet clinical need. SUMMARY

[0007] In order to solve the above technical problems, the present application provides a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazole derivative or its stereoisomer, tautomer, deuterium or pharmaceutically acceptable salt thereof represented by general formula (I):

[0008] Wherein:

[0009] L is selected from a bond, -C(R aa R bb )- and -C(=O)-;

[0010] R aa and R bbeach independently is selected from the group consisting of a hydrogen atom, a hydroxy group, and a methyl group;

[0011] R 1 is selected from the group consisting of a hydrogen atom and a C 1-6 alkyl group;

[0012] R 2 , R 3 , R 4 , R 5 each independently is selected from the group consisting of a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 1-6 alkenyl group, a C 2-6 alkynyl group, a C 2-6 cycloalkyl group, and a halogenated C 3-6 alkyl group; 3-6 cycloalkyl group, and a halogenated C 1-6 alkyl group;

[0013] R a is selected from the group consisting of a hydrogen atom, a C 1-6 alkyl group, a C 2-6 alkenyl group, and a C 2-6 alkynyl group, wherein said C 1-6 alkyl group, C 2-6 alkenyl group, or C 2-6 alkynyl group is optionally further substituted by one or more substituents selected from the group consisting of a deuterium atom, a hydroxy group, a halogen, a cyano group, an amino group, a halogenated C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, and a SF5 group;

[0014] R b , R c , R d , R e each independently is selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkenyl group, and a C 1-6 alkynyl group; 1-6 alkoxy group;

[0015] or, R b and R c , R d and R e each independently, together with the same carbon atom to which they are attached, form a -C(=O)- or a C 3-6 cycloalkyl group, wherein said C 3-6 cycloalkyl group is optionally further substituted by one or more substituents selected from the group consisting of a deuterium atom, a hydroxy group, a halogen, a cyano group, an amino group, a halogenated C 1-6 alkyl group, a halogenated C 1-6 alkoxy group, and a SF5 group;

[0016] or, R a and Rb R a R d each independently with the carbon atom to which they are attached form a C 3-6 cycloalkyl group, wherein said C 3-6 cycloalkyl group is optionally further substituted by one or more substituents selected from a deuterium atom, a hydroxyl group, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkyl group, a halogenated C 1-6 alkoxy group and a SF5 group;

[0017] R B is selected from a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, a SF5 group, a C 1-6 alkyl group, a C 1-6 alkoxy group and a halogenated C

[0018] R A is selected from a hydrogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-10 aryl group, a 5-6 membered heteroaryl group, a 6-10 membered fused ring, a SF5 group, -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 and -S(=O) r R 5 ; wherein said C 1-6 alkyl group, C 2-6 alkenyl group, C 2-6 alkynyl group, C 3-6 cycloalkyl group, 3-12 membered heterocyclyl group, C 6-10 aryl group, 5-6 membered heteroaryl group, 6-10 membered fused ring is optionally further substituted by one or more R AA ;

[0019] R AA are the same or different, each independently selected from a hydroxyl group, a halogen, a nitro group, a cyano group, a C 1-6 alkyl group, a C1-6 alkyl, C 3-6 alkoxy, C 9 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, -OR 9 , =0, -C(=0)R r , -S(=0) 9 R 9 , -C(=0)OR 9 , -OC(=0)R 10 , -NR 11 R 10 , -C(=0)NR 11 R 10 , -SO2NR 11 R 10 , -NR 11 C(=0)R 10 , and -NR 11 C(=0)OR 1-6 ; wherein said C 1-6 alkyl, C 3-6 alkoxy, C 1-6 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, or 5- to 6-membered heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, 5- to 6-membered 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 , and -NR 10 C(=0)OR 11 ;

[0020] or, two R AA together with the carbon atom to which they are attached form a -C(=0)-;

[0021] or, two R AAtogether with the carbon atom to which they are attached form a C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl; wherein said C 3-6 cycloalkyl or 3- to 12-membered heterocyclyl is optionally further substituted with one or more substituents independently selected from the group consisting of 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, =0, -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 , and -NR 10 C(=O)OR 11 ;

[0022] R 6 each independently is selected from the group consisting of hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 9 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 9 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 9 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 10 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 11 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 10 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 11 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 10 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 11 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 10 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 11 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 10 hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents independently selected from the group consisting of 11 ;

[0023] R 7 and R 8each independently selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, wherein said alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of 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, =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 , and -NR 10 C(=0)OR 11 ;

[0024] or, R 7 and R 8 together with the atom to which they are attached form a 3- to 12-membered heterocyclyl group, wherein the 3- to 12-membered heterocyclyl group contains one or more N, O, or S(0)r, and said 3- to 12-membered heterocyclyl group is optionally further substituted by one or more substituents selected from the group consisting of 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, =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 , and -NR 10 C(=0)OR 11 ;

[0025] R 9 , R 10 , and R 11 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and 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 the group consisting of a hydroxy 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, and a carboxylate group;

[0026] each r is independently 0, 1 or 2;

[0027] with the proviso that the compound of general formula (I) does not include the following structure:

[0028] In a preferred embodiment of the present application, a 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole derivative of general formula (I) or a stereoisomer, a tautomer, a deuterated 1 is a hydrogen atom.

[0029] In a preferred embodiment of the present application, a 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole derivative of general formula (I) or a stereoisomer, a tautomer, a deuterated B is a hydrogen atom.

[0030] In a preferred embodiment of the present application, a 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole derivative of general formula (I) or a stereoisomer, a tautomer, a deuterated

[0031] wherein:

[0032] R 2 is selected from a hydrogen atom and a halogen; said halogen is preferably chlorine;

[0033] R 3 is selected from a C 1-4 alkyl and a halogen; said halogen is preferably chlorine; said C 1-4 alkyl is preferably a methyl group;

[0034] R 4 is selected from a hydrogen atom, a C 1-4 alkyl and a halogen; said halogen is preferably chlorine; said C 1-4 alkyl is preferably a methyl group;

[0035] L, R a , R b , R c , R d , R e , R A , R 5 and R B are as defined in general formula (I).

[0036] A preferred embodiment of the present invention is a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium derivative of general formula (I) or (II) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof, which is a compound of general formula (III-1) or (III-2) or its stereoisomers, tautomers, deuterated derivatives or pharmaceutically acceptable salts thereof:

[0037] in:

[0038] R 3 Selected from methyl and chlorine;

[0039] R 4 Selected from methyl and chlorine;

[0040] R 5 Selected from hydrogen atom, deuterium atom, halogen, cyano group, C 1-6 Alkyl, C 2-6 alkynyl group and C 1-6 Alkoxy;

[0041] L, R a R b R c R d R e R A and R B The definition is as stated in general formula (I).

[0042] A preferred embodiment of the present invention is a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium derivative of general formula (I), (II), (III-1) or (III-2) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R b R c R d R e For hydrogen atoms, R a Selected from hydrogen atoms, C 1-6 Alkyl or C 2-6 alkenyl, wherein the C 1-6 Alkyl or C 2-6 The alkenyl group may be further replaced by one or more atoms selected from deuterium or halogens.

[0043] A preferred embodiment of the present invention is a 6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium derivative of general formula (I), (II), (III-1) or (III-2) or a stereoisomer, tautomer, deuterated derivative or pharmaceutically acceptable salt thereof, wherein R a It is selected from hydrogen atoms, methyl, deuterated methyl, ethyl or vinyl.

[0044] In a preferred embodiment of the present application, a 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole derivative of the general formula (I), (II), (III-1) or (III-2) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, wherein R c , R d , R e is a hydrogen atom, R a and R b together with the carbon atom to which they are attached form a cyclopropyl group.

[0045] In a preferred embodiment of the present application, a 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole derivative of the general formula (I), (II), (III-1) or (III-2) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, is a compound of the general formula (IV-1), (IV-2), (IV-3) or (IV-4) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof:

[0046] wherein:

[0047] R 3 each independently is selected from the group consisting of a methyl group and a chlorine atom;

[0048] R 4 each independently is selected from the group consisting of a methyl group and a chlorine atom;

[0049] R 5 is selected from the group consisting of a hydrogen atom, a deuterium atom, a fluorine atom or a chlorine atom, preferably from the group consisting of a hydrogen atom, a fluorine atom and a chlorine atom;

[0050] R a is selected from the group consisting of a hydrogen atom, a methyl group, a deuterated methyl group, an ethyl group and a vinyl group;

[0051] L and R A are as defined in claim 1.

[0052] In a preferred embodiment of the present application, a 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole derivative of the general formula (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3) or (IV-4) or a stereoisomer, a tautomer, a deuterated derivative or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, -CH2-, -C(CH3)2-, -C(CH3)(OH)- or -C(=O)-.

[0053] In a preferred embodiment of the present application, a 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole derivative of general formula (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3) or (IV-4), wherein R A is selected from the group consisting of hydroxy, amino, phenyl, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered heterocyclyl or 5-6 membered heteroaryl, wherein said phenyl, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered heterocyclyl or 5-6 membered heteroaryl are optionally further substituted with one or more R AA ;

[0054] R AA are the same or different, each independently selected from the group consisting of halogen, hydroxy, amino, C 1-6 alkyl, halogenoC 1-6 alkyl and hydroxyC 1-6 alkyl;

[0055] or two R AA together with the same carbon atom to which they are attached form a -C(=0)-;

[0056] or two R AA together with the same carbon atom to which they are attached form a C 3-6 cycloalkyl, 3-12 membered heterocyclyl.

[0057] In a preferred embodiment of the present application, a 6,7-dihydro-5H-pyrrolo[l,2- a]imidazole derivative of general formula (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3) or (IV-4), wherein is selected from the group consisting of ethyl, ethenyl, wherein the wavy line indicates the position of attachment to the compound.

[0058] In a preferred embodiment of the present application, the compound of general formula is selected from the group consisting of:

[0059] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0060] Note: If there is a discrepancy between the structure drawn and the name given for the structure, the structure drawn is considered correct.

[0061] Further, the present application provides a pharmaceutical composition comprising an effective amount of a compound according to Formula (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), or (IV-4), or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0062] The present application provides use of a compound according to Formula (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), or (IV-4), or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a Kv1.3 inhibitor.

[0063] The present application also provides use of a compound according to Formula (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), or (IV-4), or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in 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, and chronic kidney disease.

[0064] The present application further provides use of a compound according to Formula (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), or (IV-4), or a stereoisomer, a tautomer, a deuterated isotope, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer.

[0065] The present application provides use of a compound according to Formula (I), (II), (III-1), (III-2), (IV-1), (IV-2), (IV-3), or (IV-4), or a stereoisomer, a tautomer, a deuterated isotope, 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.

[0066] Detailed description of the application

[0067] Unless otherwise indicated, the following terms are defined throughout this application:

[0068] "Alkyl" when used as a group or part of a group refers to a straight or branched chain aliphatic group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. 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 or branched chain aliphatic group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. 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 or branched chain aliphatic group having 1 to 20 carbon atoms, preferably 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. 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.

[0069] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group 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 a 3- to 7-membered monocyclic ring or a 4- to 18-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, and the like. Cycloalkyl groups can be substituted or unsubstituted. "Cycloalkyl" refers to a non-aromatic cyclic alkyl group 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 a 3- to 7-membered monocyclic ring or a 4- to 18-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" groups include, but are not limited to, cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclotridecyl, cyclotetradecyl, cyclopentadecyl, cyclohexadecyl, and the like. Cycloalkyl groups can be substituted or unsubstituted.

[0070] "Spirocycloalkyl" refers to a polycyclic group of 5 to 18 members, two or more cyclic structures, and single rings sharing one carbon atom with each other (referred to as a spiro atom), the ring contains 0, 1, or multiple double bonds, but none of the rings has a fully conjugated pi-electron aromatic system. Preferably, 6 to 14 members, more preferably 7 to 10 members. Spirocycloalkyl is classified as a single-, bi-, or multi-spirocycloalkyl depending on the number of spiro atoms shared between the rings, preferably single- and bi-spirocycloalkyl, preferably 4 / 5, 4 / 6, 5 / 5, or 5 / 6. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0071] "Condensed ring alkyl" refers to a fully carbon polycyclic group of 4 to 18 members, containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings can contain 0, 1 or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system, preferably 6 to 14 members, more preferably 7 to 10 members. It can be classified as bi-, tri-, tetra- or polycyclic condensed ring alkyl according to the number of rings, preferably bi- or tri-cyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bi-cyclic condensed ring alkyl. Non-limiting examples of "condensed ring alkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthalenyl, tetradeca-hydrophenanthryl.

[0072] "Bridged ring alkyl" refers to a fully carbon polycyclic group of 5 to 18 members, containing two or more cyclic structures sharing two non-directly connected carbon atoms with each other, one or more rings can contain 0, 1 or more double bonds, but none of the rings has a fully conjugated π-electron aromatic system, preferably 6 to 14 members, more preferably 7 to 10 members. It can be classified as bi-, tri-, tetra- or polycyclic bridged ring alkyl according to the number of rings, preferably bi-, tri- or tetra-cyclic, more preferably bi- or tri-cyclic. Non-limiting examples of "bridged ring alkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r,5r)-bicyclo[3.3.2]decyl.

[0073] "Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably in the present application and refer to non-aromatic heterocyclic groups, including monocyclic, polycyclic, condensed, bridged and spirocyclic, which can contain 1 or more double bonds in the ring, but none of the rings has a fully conjugated π-electron aromatic system, wherein 1 or 2 or 3 or 4 ring-forming atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms. Preferably 3 to 7 membered monocyclic or 4 to 18 membered bi- or tri-cyclic.

[0074] 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,

[0075] The heterocyclyl group can be substituted or unsubstituted.

[0076] "Spiroheterocyclyl" refers to a polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing one atom between single rings, which can contain 1 or more double bonds, but no ring has a fully conjugated pi-electron system of aromaticity, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r having the indicated number of carbon atoms, and 0 to 4 heteroatoms, selected from nitrogen, oxygen or S(O)0-2, wherein r is selected from 0, 1 or 2, and the remaining ring atoms are carbon. Preferred are 6 to 14 membered rings, more preferred are 7 to 10 membered rings. Spiroheterocyclyl groups are classified as mono-, bi- or polyspiroheterocyclyl groups, preferably mono- and bi-spiroheterocyclyl groups, more preferably 3 / 6-, 4 / 4-, 4 / 5-, 4 / 6-, 5 / 5-, 5 / 6- or 6 / 6- membered mono-spiroheterocyclyl groups, according to the number of spiro atoms shared between the 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,

[0077] "Fused heterocyclyl" refers to a polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing a pair of atoms between the rings, one or more rings can contain 0, 1 or more double bonds, but no ring has a fully conjugated pi-electron system of aromaticity, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) r having the indicated number of carbon atoms, and 0 to 4 heteroatoms, selected from nitrogen, oxygen or S(O)0-2, wherein r is selected from 0, 1 or 2, and the remaining ring atoms are carbon, preferably 6 to 14 membered rings, more preferred are 7 to 10 membered rings. Fused heterocyclyl groups are classified as bi-, tri-, tetra- or polycyclic, preferably bi- or tri-cyclic, more preferred are 5 / 5- or 5 / 6- membered bi-cyclic fused heterocyclyl groups, according to 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,

[0078] "Bridged heterocyclyl" refers to a polycyclic group of 5 to 18 members, containing two or more cyclic structures, sharing two non-adjacent atoms between the rings, one or more rings can contain 0, 1 or more double bonds, but no ring has a fully conjugated pi-electron system of aromaticity, wherein 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 a bicyclic, tricyclic, tetracyclic, or polycyclic bridged heterocyclic group, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of the "bridged heterocyclic group" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl,

[0079] "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.

[0080] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 (1, 2, 3 or 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

[0081] The heteroaryl group can be substituted or unsubstituted.

[0082] "Heteroatom" means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and S(O) r (wherein r is selected from 0, 1, or 2) and the remaining ring atoms are carbon. A fused ring preferably includes bicyclic or tricyclic fused rings, wherein a bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group with a monocyclic heterocyclyl or monocyclic cycloalkyl group, preferably a 6- to 14-membered ring, more preferably an 8- to 10-membered ring. Examples of "fused rings" include, but are not limited to:

[0083] "Alkoxy" means a group of the formula (alkyl-O-). Alkyl is as defined herein. Preferred is C1-C6alkoxy. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, t-butoxy, and the like.

[0084] "Carboxy" means a -C(=O)OH group.

[0085] "Halo" means fluoro, chloro, bromo, and iodo.

[0086] "Amino" means -NH2.

[0087] "Cyano" means -CN.

[0088] "Benzyl" means -CH2-phenyl.

[0089] "Carboxy" means a -C(=O)OH group.

[0090] "Carboxy" means a -C(=O)OH group.

[0091] "Carboxy" means a -C(=O)OH group.

[0092] "Hydroxyalkyl" means an alkyl group as defined above substituted with a hydroxyl group.

[0093] "Aminoalkyl" means an alkyl group as defined above substituted with an amino group.

[0094] "Haloalkyl" means an alkyl group as defined above substituted with a halo group.

[0095] "Haloalkoxy" means an alkoxy group as defined above substituted with a halo group.

[0096] "DMSO" means dimethyl sulfoxide.

[0097] "BOC" means tert-butyloxycarbonyl.

[0098] "Bn" means benzyl.

[0099] "THP" means 2-tetrahydropyranyl.

[0100] "TFA" means trifluoroacetic acid.

[0101] "FA" means formic acid.

[0102] "Ts" means p-toluenesulfonyl.

[0103] "Bn" means benzyl.

[0104] "SEM" means (trimethylsilyl)ethoxymethyl.

[0105] A "leaving group", or leaving group, is an atom or functional group that departs from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant that is attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that readily accept electrons and bear a negative charge well are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the more likely the leaving group is to depart from other molecules. This is because the smaller the pKa of the conjugate acid, the more the corresponding leaving group tends to exist as an anion (or a neutral leaving group) without bonding to other atoms. Common leaving groups include, but are not limited to, halogen, mesylate, -OTs, or -OH.

[0106] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1, 2, or 3, of a group are independently of one another replaced by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, which can or cannot be possible, can be determined (experimentally or theoretically) by a person skilled in the art without undue effort. For example, an amino group with a free hydrogen or a hydroxyl group can not be stable when bound to a carbon atom with an unsaturated (e.g., olefinic) bond.

[0107] "Substituted" or "substitution" as used herein, unless otherwise indicated, means that a group can be substituted with one or two or three or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, halocycloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylate, fused ring, =0, -OR 6 , SF5, -OC(=0)R6 -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 5 ;

[0108] 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 -NR 10 C(=O)R 11 and -NR 10 C(=O)OR 11 The substituents are replaced;

[0109] R 7 and R 8 Each is independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, and 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 10C(=O)R 11 and -NR 10 C(=O)OR 11 substituted;

[0110] or, R 7 and R 8 together with the atom to which they are attached form a 3- to 12-membered heterocyclyl group, wherein the 3- to 12-membered heterocyclyl group contains one or more N, O, or S(O)r, and said 3- to 12-membered heterocyclyl group 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 , and -NR 10 C(=O)OR 11 substituted;

[0111] R 9 , R 10 , and R 11 are each independently selected from the group consisting of a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, and 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, and carboxylate;

[0112] each r is independently 0, 1, or 2.

[0113] The compounds of the present application can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the present application, including but not limited to, diastereomeric, enantiomeric, and atropisomeric forms, and geometric (conformational) isomers, and mixtures thereof, such as racemic mixtures, are within the scope of the present application.

[0114] Unless otherwise indicated, structures depicted throughout this specification are also meant to include all isomeric (e.g., enantiomeric, enantiomeric, and atropisomeric and geometric (conformational) isomeric) forms of the structure; for example, the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (conformational) mixtures of the present compounds are within the scope of the application. Unless otherwise stated, the present compounds can exist as single stereoisomers or as mixtures of stereoisomers.

[0115] "Pharmaceutically acceptable salt" refers to those salts which retain the biological activity of the parent compound and which are suitable for medical use. The pharmaceutically acceptable salts of the compounds of Formula (I) can be metal salts, amine salts with suitable acids.

[0116] "Pharmaceutical composition" means a mixture of one or more of the compounds described herein or physiologically acceptable salts or prodrugs thereof with other chemical components, such as physiologically acceptable carriers. The purpose of a pharmaceutical composition is to facilitate administration of the active ingredient to an organism. DETAILED DESCRIPTION

[0117] The following examples are intended to further describe the present application, but are not intended to limit the scope of the present application.

[0118] Examples

[0119] The examples below provide the preparation of representative compounds of Formula (I) and related structural identification data. It must be understood that the examples below are intended to illustrate the present application and are not intended to limit the present application. 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are reported in ppm using tetramethylsilane as internal standard (0.00 ppm). 1 H NMR spectra were recorded on a Bruker instrument (400 MHz) and chemical shifts are reported in ppm using tetramethylsilane as internal standard (0.00 ppm).

[0120] Mass spectra were recorded on a LC / MS instrument and ionization can be ESI or APCI.

[0121] Thin layer chromatography silica gel plates were Yantai Huanghai HSG F254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin layer chromatography (TLC) were 0.15 mm to 0.2 mm in thickness. The silica gel plates used for thin layer chromatography separation and purification of products were 0.4 mm to 0.5 mm in thickness.

[0122] Column chromatography generally used Yantai Huanghai silica gel 200 to 300 mesh silica gel as the carrier.

[0123] 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.

[0124] CD3OD: Deuterated methanol.

[0125] CDCl3: Deuterated chloroform.

[0126] DMSO-d6: Deuterated dimethyl sulfoxide.

[0127] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0128] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0129] 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.

[0130] Example 1

[0131] 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0132] first step

[0133] 2,3-dichloro-6-methoxybenzaldehyde

[0134] 2,3-Dichloro-6-methoxybenzaldehyde

[0135] 1,2-Dichloro-4-methoxybenzene 1a (50 g, 282.44 mmol) was dissolved in tetrahydrofuran (700 mL), cooled to -78 °C, and n-butyllithium (2.5 M, 124.27 mL) was added under a nitrogen atmosphere. The reaction mixture was stirred at -78 °C for 1 hour, and N,N-dimethylformamide (22.71 g, 310.69 mmol) was added, followed by stirring for another hour. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, concentrated, and the residue was purified by column chromatography (eluent: system A) to give 2,3-dichloro-6-methoxybenzaldehyde 1b (33.2 g), with a yield of 57.33%.

[0136] MS m / z(ESI): 205.0 [M+1]

[0137] Step 2

[0138] ethyl(E)-3-(2,3-dichloro-6-methoxyphenyl)acrylate

[0139] Ethyl (E)-3-(2,3-dichloro-6-methoxyphenyl)acrylate

[0140] 2,3-Dichloro-6-methoxybenzaldehyde 1b (15 g, 73.16 mmol), ethyl 2-diethoxyphosphate (24.60 g, 109.74 mmol), and lithium hydroxide monohydrate (4.60 g, 109.74 mmol) were dissolved in tetrahydrofuran (200 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was quenched with water, extracted with ethyl acetate (200 mL × 3), and the organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system A) to give (E)-3-(2,3-dichloro-6-methoxyphenyl)acrylate 1c (9.6 g), yield 47.70%.

[0141] MS m / z(ESI): 275.0 [M+1]

[0142] Step 3

[0143] ethyl 3-(2,3-dichloro-6-methoxyphenyl)-4-nitrobutanoate

[0144] Ethyl 3-(2,3-dichloro-6-methoxyphenyl)-4-nitrobutyrate

[0145] Ethyl (E)-3-(2,3-dichloro-6-methoxyphenyl)acrylate 1c (9.6 g, 34.89 mmol) was dissolved in dimethyl sulfoxide (10 mL), followed by the addition of nitromethane (10.65 g, 174.46 mmol) and cesium carbonate (9.10 g, 27.91 mmol). The reaction mixture was stirred at 70 °C for 18 hours. The mixture was quenched with water, extracted with ethyl acetate, and the organic phase was dried and concentrated to give ethyl 3-(2,3-dichloro-6-methoxyphenyl)-4-nitrobutyrate 1d (9.6 g), in 81.84% yield.

[0146] MS m / z(ESI): 336.2 [M+1]

[0147] Step 4

[0148] ethyl 4-amino-3-(2,3-dichloro-6-methoxyphenyl)butanoate

[0149] Ethyl 4-amino-3-(2,3-dichloro-6-methoxyphenyl)butyrate

[0150] Ethyl 3-(2,3-dichloro-6-methoxyphenyl)-4-nitrobutyrate 1d (9.6 g, 28.56 mmol) and zinc powder (18.67 g, 285.57 mmol) were dissolved in acetic acid (50 mL), and the reaction solution was reacted at 50 °C for 2 hours. After the reaction was complete, the mixture was filtered, the pH was adjusted to 8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate, and the organic phase was dried and concentrated to give ethyl 4-amino-3-(2,3-dichloro-6-methoxyphenyl)butyrate 1e (8 g), with a yield of 91.49%.

[0151] MS m / z(ESI): 306.0 [M+1]

[0152] Step 5

[0153] 4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-one

[0154] 4-(2,3-Dichloro-6-methoxyphenyl)pyrrolidine-2-one

[0155] Ethyl 4-amino-3-(2,3-dichloro-6-methoxyphenyl)butyrate 1e (8 g, 26.13 mmol) and cesium carbonate (25.54 g, 78.38 mmol) were dissolved in methanol (100 mL). The reaction mixture was stirred at 50 °C for 18 hours, filtered, concentrated, and the residue was purified by column chromatography (eluent: system B) to give 4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-one 1f (6.2 g), with a yield of 91.23%.

[0156] MS m / z(ESI): 260.0 [M+1]

[0157] Step 6

[0158] methyl 2-(4-(2,3-dichloro-6-methoxyphenyl)-2-oxopyrrolidin-1-yl)acetate

[0159] 2-(4-(2,3-dichloro-6-methoxyphenyl)-2-oxopyrrolidone-1-yl)methyl acetate

[0160] 4-(2,3-dichloro-6-methoxyphenyl)pyrrolidone-2-one 1f (600 mg, 2.31 mmol) and potassium tert-butoxide (516.69 mg, 4.61 mmol) were dissolved in N,N-dimethylformamide (4 mL). The mixture was stirred at room temperature for 20 minutes under nitrogen protection, and then cooled to 0 °C. A solution of methyl bromoacetate (519 mg, 3.41 mmol) in N,N-dimethylformamide (2 mL) was added dropwise to the reaction mixture. After the addition was complete, the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water, extracted with ethyl acetate (15 mL × 3), the organic phases were combined, washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (eluent: system D) to give 1 g (490 mg) of methyl 2-(4-(2,3-dichloro-6-methoxyphenyl)-2-oxopyrrolidine-1-yl)acetate, yield 64.0%.

[0161] MS m / z(ESI): 332.0 [M+1]

[0162] Step 7

[0163] 2-(4-(2,3-dichloro-6-methoxyphenyl)-2-oxopyrrolidin-1-yl)acetamide

[0164] 2-(4-(2,3-dichloro-6-methoxyphenyl)-2-oxopyrrolidone-1-yl)acetamide

[0165] Under nitrogen protection, a methanol solution of ammonia (4 mL, 4 M) was added to a methanol solution of 1 g (490 mg, 1.48 mmol) of methyl 2-(4-(2,3-dichloro-6-methoxyphenyl)-2-oxopyrrolidone-1-yl)acetate at 0 °C and stirred at 40 °C under nitrogen protection for 16 h. The reaction solution was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (eluent: system D) to give 2-(4-(2,3-dichloro-6-methoxyphenyl)-2-oxopyrrolidone-1-yl)acetamide 1 h (360 mg), yield 77.0%. MS m / z (ESI): 316.7 [M+1]

[0166] Step 8

[0167] 2-bromo-6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0168] 2-Bromo-6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0169] 2-(4-(2,3-dichloro-6-methoxyphenyl)-2-oxopyrrolidine-1-yl)acetamide 1h (360 mg, 1.14 mmol) and phosphorus tribromooxyphosphine (967.06 mg, 3.41 mmol) were dissolved in acetonitrile (2 mL), and the mixture was heated to 85 °C and stirred for 3 hours under nitrogen protection. The reaction mixture was cooled to room temperature, filtered, and the solid was washed with methanol (5 mL) and dried under reduced pressure to give 2-bromo-6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5h-pyrrolo[1,2-a]imidazole 1i (300 mg), yield 73.0%.

[0170] MS m / z(ESI): 361.0 [M+1]

[0171] Step 9

[0172] 2-(2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol

[0173] 2-(2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol

[0174] 2-Bromo-6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5h-pyrrolo[1,2-a]imidazol 1i (7.83 g, 21.63 mmol) was added to dichloromethane (80 mL), and boron tribromide (27.09 g, 108.13 mmol) was added at 0 °C. The reaction was carried out at 0 °C for 1 hour. The mixture was cooled to -7 °C, quenched with methanol, and then heated to 0 °C. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution. The mixture was filtered, and the solid was dried under reduced pressure to give 2-(2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol 1j (6.23 g), with a yield of 82.8%.

[0175] MS m / z (ESI): 347.0 [M+1]

[0176] Step 10

[0177] 2-bromo-6-(6-((tert-butyldimethylsilyl)oxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0178] 2-Bromo-6-(6-((tert-butyldimethylsilyl)oxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0179] 2-(2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol 1j (6.23 g, 17.90 mmol) was added to N,N-dimethylformamide (70 mL), followed by imidazole (2.56 g, 37.59 mmol) and tert-butyldimethylchlorosilane (4.05 g, 26.85 mmol). The reaction mixture was allowed to react for 12 hours at room temperature. Water (700 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phase was washed with saturated sodium chloride solution (500 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 A) to give 2-bromo-6-(6-((tert-butyldimethylsilyl)oxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole 1k (8.02 g), with a yield of 96.9%.

[0180] MS m / z (ESI): 461.2 [M+1]

[0181] Step 11

[0182] methyl 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate

[0183] 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylic acid methyl ester

[0184] 2-Bromo-6-(6-((tert-butyldimethylsilyl)oxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole 1k (1g, 2.16mmol) was added to a mixture of dichloromethane and methanol (30mL, V / V = 1:1). Then, triethylamine (459.67mg, 4.54mmol) and 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16.56mg, 432.64μmol) were added to the system. The reaction was carried out at 80°C for 16 hours under a carbon monoxide atmosphere (30psi). The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (eluent: system D) to obtain 1l (532mg) of methyl 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylate, with a yield of 75.2%.

[0185] MS m / z (ESI): 327.0 [M+1]

[0186] Step Twelve

[0187] 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0188] 1 L (2 g, 6.11 mmol) of methyl 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylate was added to tetrahydrofuran (100 mL) under nitrogen protection. Methyl magnesium bromide (3 M, 30.57 mL) was added dropwise at -78 °C, and the temperature was raised to 50 °C for 4 hours. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (100 mL × 3), washed with saturated sodium chloride solution (200 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (Separation column: SunFire Sunfire C18; 19*250 mm, 10 μm, 20 mL / min; Mobile phase A: 0.1% FA / H2O, Mobile phase B: CH3CN) to give 3,4-dichloro-2-(2-(2-hydroxypropyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 1 (513.5 mg), yield 25.7%.

[0189] MS m / z (ESI): 327.2 [M+1]

[0190] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.14(s,1H),7.38(d,J=8.0Hz,1H),6.86(d,J=8.0Hz,1H),6.84 (s,1H),4.81-4.73(m,1H),4.57(s,1H),4.18-4.06(m,2H),3.04-2.98(m,2H),1.38(d,J=8.0Hz,6H).

[0191] Example 2 and Example 3

[0192] (S)-3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0193] (S)-3,4-Dichloro-2-(2-(2-hydroxypropyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 2

[0194] (R)-3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0195] (R)-3,4-Dichloro-2-(2-(2-hydroxypropyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 3

[0196] 3,4-Dichloro-2-(2-(2-hydroxypropyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 1 (260 mg) was purified by chiral preparation (gradient column: The mixture was separated and purified using a 250*30mm, 10μm filter, at a flow rate of 140mL / min, with a gradient of 20% MeOH (+0.1% 7.0mol / L ammonia methanol): 80% CO2, to obtain compounds 2 and 3.

[0197] SFC analysis method: 100*30mm, 3.0μm, wavelength: 214nm, flow rate: 1.5mL / min; gradient: 85% supercritical CO2, 15% MeOH (0.1% DEA); column temperature: 35℃.

[0198] Single-configuration compounds (shorter retention time):

[0199] MS m / z (ESI): 327.1 [M+1]

[0200] 104.78 mg, yield 40.3%; retention time 2.393 minutes, chiral purity 100% ee

[0201] 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),8.15(s,1H,HCOOH),7.38(d,J=8.0Hz,1H),6.86(d,J=8.0Hz,1H),6 .83(s,1H),4.84-4.70(m,1H),4.56(s,1H),4.20-4.04(m,2H),3.07-2.92(m,2H),1.38(d,J=8.0Hz,6H).

[0202] Single-configuration compounds (longer retention time):

[0203] MS m / z (ESI): 327.1 [M+1]

[0204] 93.13 mg, yield 35.82%; retention time 4.126 minutes, chiral purity 98% ee

[0205] 1H NMR (400MHz, DMSO-d6) δ10.46(s,1H),8.14(s,1H,HCOOH),7.38(d,J=8.0Hz,1H),6.86(d,J=8.0Hz,1H),6 .83(s,1H),4.83-4.71(m,1H),4.57(s,1H),4.18-4.04(m,2H),3.07-2.92(m,2H),1.38(d,J=8.0Hz,6H).

[0206] Example 2: Preparation method of compound 2

[0207] first step

[0208] (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole

[0209] (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole

[0210] Cesium carbonate (11.96 g, 36.69 mmol) was added to a solution of (S)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidone-2-one 2a (3.5 g, 12.23 mmol, prepared according to CN117946111) in 50 mL of dichloromethane. The reaction was stirred at room temperature for 5 min, followed by the addition of triethylonium tetrafluoroborate (2.79 g, 14.68 mmol), and the reaction was allowed to proceed at room temperature for 12 h. Water (50 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (80 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 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 A) to give (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole 2b (2.4 g), with a yield of 62.5%.

[0211] MS m / z (ESI): 314.1 [M+1]

[0212] Step 2

[0213] (S)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidin-2-imine

[0214] (S)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-imine

[0215] (S)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole 2b (2.5 g, 7.96 mmol) was added to methanol (15 mL), followed by ammonium bicarbonate (1.89 g, 23.87 mmol). The reaction was continued at room temperature for 18 hours. After the reaction was complete, the solution was directly concentrated by rotary evaporation, washed with dichloromethane (30 mL), filtered, and the filtrate was evaporated to dryness to give (S)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrole-2-imine 2c (1.8 g), with a yield of 79.3%.

[0216] MS m / z (ESI): 285.1 [M+1]

[0217] Step 3

[0218] (S)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propan-2-ol

[0219] (S)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)prop-2-ol

[0220] To a solution of (S)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-imine 2c (1.8 g, 6.31 mmol) in ethanol (30 mL), 1-bromo-3-hydroxy-3-methylbut-2-one 2d (3.43 g, 18.94 mmol, prepared according to the method disclosed in US2008 / 269279) and sodium bicarbonate (1.59 g, 18.94 mmol) were added. The system was reacted at 80 °C for 12 hours. After the reaction, the mixture was directly evaporated to dryness, and the residue was purified by silica gel column chromatography (eluent: system A) to give (S)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)prop-2-ol 2e (1.5 g), in a yield of 64.7%.

[0221] MS m / z (ESI): 367.2 [M+1]

[0222] Step 4

[0223] (S)-3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0224] (S)-3,4-Dichloro-2-(2-(2-hydroxypropyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0225] At room temperature, under nitrogen protection, tetrakis(triphenylphosphine)palladium (378 mg, 326.74 μmol) was added to a solution of (S)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)prop-2-ol 2e (1.2 g, 3.27 mmol) and morpholine (313.12 mg, 3.59 mmol) in N,N-dimethylformamide (15 mL). The mixture was heated to 80 °C and stirred for 3 hours. After the reaction was complete, the mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by silica gel column chromatography (eluent: system D) to give (S)-3,4-dichloro-2-(2-(2-hydroxypropyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 2 (709.65 mg), with a yield of 66.4%.

[0226] MS m / z (ESI): 327.1 [M+1]

[0227] 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),7.38(d,J=8.8Hz,1H),6.89–6.81(m,2H),4.81–4.72(m,1H),4.56(br s,1H),4.18–4.05(m,2H),3.04–2.93(m,2H),1.38(d,J=5.6Hz,6H).

[0228] SFC analysis method: Rt = 2.227 min (gradient column: 100*30mm, 3.0μm, wavelength: 214nm, flow rate: 1.5mL / min; gradient: 85% supercritical CO2, 15% MeOH (0.1% DEA); column temperature: 35℃.

[0229] Example 3: Preparation method of compound 3 (II)

[0230] first step

[0231] (R)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole

[0232] (R)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole

[0233] Cesium carbonate (1.02 g, 3.15 mmol) was added to an 8 mL solution of (R)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidone-2-one 3a (300 mg, 1.05 mmol, prepared according to CN117946111), and the reaction was carried out at room temperature for 5 minutes. Then, triethylonium tetrafluoroborate (239.02 mg, 1.26 mmol) was added, and the mixture was stirred for 12 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 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 A) to give (R)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole 3b (182 mg), yield 55.3%.

[0234] MS m / z (ESI): 314.1 [M+1]

[0235] Step 2

[0236] (R)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidin-2-imine

[0237] (R)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-imine

[0238] Ammonium bicarbonate (140.40 mg, 1.78 mmol) was added to methanol (5 mL) containing (R)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole 3b (186.00 mg, 591.97 μmol). The reaction was continued at room temperature for 18 hours. After the reaction was completed, the mixture was directly concentrated by rotary evaporation, washed with dichloromethane (30 mL), filtered, and the filtrate was concentrated under reduced pressure to give (R)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrole-2-imine 3c (132 mg), with a yield of 78.2%.

[0239] MS m / z (ESI): 285.1 [M+1]

[0240] Step 3

[0241] (R)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)propan-2-ol

[0242] (R)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)prop-2-ol

[0243] To (R)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidine-2-imine 3c (132 mg, 462.88 μmol) in ethanol (3 mL), 1-bromo-3-hydroxy-3-methylbut-2-one 2d (251.38 mg, 1.39 mmol) and sodium bicarbonate (116.66 mg, 1.39 mmol) were added. The system was reacted at 80 °C for 12 h. After the reaction, the mixture was directly evaporated to dryness and purified by thin-layer chromatography (developing solvent: system A) to give (R)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)prop-2-ol 3d (128 mg), yield 75.3%.

[0244] MS m / z (ESI): 367.2 [M+1]

[0245] Step 4

[0246] (R)-3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0247] (R)-3,4-Dichloro-2-(2-(2-hydroxypropyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0248] (R)-2-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)prop-2-ol 3d (128.00 mg, 348.52 μmol) was added to tetrahydrofuran (4 mL), followed by sodium borohydride (26.37 mg, 697.04 μmol) and tetratetraphenylphosphine palladium (201.37 mg, 174.26 μmol). The reaction was carried out at room temperature under a nitrogen atmosphere for 2 hours. After the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (using a SunFire C10 column). 18 ; 19*250mm, 10um, 20mL / min; mobile phase A: 0.1% FA / H2O, mobile phase B: CH3CN, gradient: 20%-30%), to obtain (R)-3,4-dichloro-2-(2-(2-hydroxypropyl-2-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 3 (21.6 mg), yield 18.9%.

[0249] MS m / z (ESI): 327.1 [M+1]

[0250] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),7.38(d,J=8.0Hz,1H),6.87(d,J=8.0Hz,1H),6.82(s,1H ),4.84-4.69(m,1H),4.57(s,1H),4.17-4.06(m,2H),3.06-2.92(m,2H),1.38(d,J=8.0Hz,6H).

[0251] SFC analysis method: Rt = 4.039 min (gradient column: 100*30mm, 3.0μm, wavelength: 214nm, flow rate: 1.5mL / min; gradient: 85% supercritical CO2, 15% MeOH (0.1% DEA); column temperature: 35℃.

[0252] Example 4

[0253] 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-4-methylpiperidin-4-ol

[0254] 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-4-methylpiperidin-4-ol

[0255] first step

[0256] 3,4-dichloro-2-(2-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0257] 3,4-Dichloro-2-(2-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0258] 1 g (3.06 mmol) of methyl 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-carboxylate was added to tetrahydrofuran (20 mL), followed by the addition of lithium aluminum hydride solution (3.36 mL, 3.36 mmol, 1 M) under nitrogen protection at 0 °C. The reaction was carried out at 0 °C for 0.5 h. After the reaction was complete, the mixture was quenched with water (30 mL) at 0 °C, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography (eluent: system D) to give 4a (508 mg) of 3,4-dichloro-2-(2-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol, with a yield of 55.6%.

[0259] MS m / z (ESI): 299.1 [M+1]

[0260] Step 2

[0261] 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carbaldehyde

[0262] 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-carboxaldehyde

[0263] 3,4-Dichloro-2-(2-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 4a (508 mg, 1.70 mmol) was added to 1,4-dioxane (10 mL), followed by the addition of manganese dioxide (2.95 g, 33.96 mmol) at 0 °C. The reaction mixture was then heated to 80 °C and reacted for 3 hours. After the reaction was complete, the mixture was filtered, the filter cake was washed with dichloromethane, and the filtrate was collected and concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography (eluent: system D) to obtain 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-carboxaldehyde 4b (80 mg), with a yield of 15.9%.

[0264] MS m / z (ESI): 297.1 [M+1]

[0265] Step 3

[0266] 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-4-methylpiperidin-4-ol

[0267] 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-4-methylpiperidin-4-ol

[0268] 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxaldehyde 4b (25 mg, 84.14 μmol) was added to methanol (2 mL), followed by the addition of 4-methylpiperidin-4-ol (14.54 mg, 126.20 μmol) and sodium cyanoborohydride (26.44 mg, 420.68 μmol). The reaction mixture was allowed to react at 70 °C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative liquid chromatography (Waters 3767 / Qda column: SunFire C18, 19*250mm, 10um; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20mL / min) to obtain 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-4-methylpiperidin-4-ol 4 (8.8mg), yield 26.4%.

[0269] MS m / z (ESI): 396.1 [M+1]

[0270] 1 H NMR (400MHz, DMSO-d6) δ8.25(s,1H),7.37(d,J=8.8Hz,1H),7.00(s,1H),6.87(d,J=8.8Hz,1H),4.87–4.70(m,1H),4.2 2–4.16(m,1H),4.13–4.07(m,1H),3.56(s,2H),3.07–2.95(m,2H),2.73–2.58(m,4H),1.54–1.46(m,4H),1.11(s,3H).

[0271] Example 5

[0272] 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-3-methylazetidin-3-ol

[0273] 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-3-methylazacyclobutane-3-ol

[0274] 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxaldehyde 4b (20 mg, 67.31 μmol) was added to methanol (1 mL), followed by the addition of 3-methylazacyclobutane-3-ol (8.80 mg, 100.96 μmol) and sodium cyanoborohydride (21.15 mg, 336.55 μmol). The reaction mixture was reacted at 70 °C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative liquid chromatography (Waters 2767 / Qda column: SunFire C18, 19*250mm, 10um; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20mL / min) to obtain 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-3-methylazacyclobutane-3-ol 5 (8.88mg), yield 35.8%.

[0275] MS m / z (ESI): 368.1 [M+1]

[0276] 1H NMR(400MHz,MeOD-d4)δ7.29(d,J=8.8Hz,1H),7.25(s,1H),6.79(d,J=8.8Hz,1H),5.04–4.95(m,1H),4. 30(d,J=8.8Hz,2H),4.22(s,2H),4.08–4.01(m,2H),3.99–3.90(m,2H),3.26–3.06(m,2H),1.49(s,3H).

[0277] Example 6

[0278] 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-3-(trifluoromethyl)azetidin-3-ol

[0279] 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-3-(trifluoromethyl)azacyclobutane-3-ol

[0280] 6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxaldehyde 4b (20 mg, 67.31 μmol) was added to methanol (1 mL), followed by the addition of 3-(trifluoromethyl)azacyclobutane-3-ol (14.25 mg, 100.96 μmol) and sodium cyanoborohydride (21.15 mg, 336.55 μmol). The reaction mixture was reacted at 70 °C under nitrogen protection for 1 hour. After the reaction was completed, the reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative liquid chromatography (Waters 2767 / Qda column: SunFire C18, 19*250mm, 10um; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20mL / min) to obtain 1-((6-(2,3-dichloro-6-hydroxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)methyl)-3-(trifluoromethyl)azacyclobutane-3-ol 6 (10.93mg), yield 38.5%.

[0281] MS m / z (ESI): 422.1 [M+1]

[0282] 1H NMR(400MHz,MeOD-d4)δ7.31(d,J=8.8Hz,1H),7.30(s,1H),6.80(d,J=8.8Hz,1H),5.13–5.04(m,1H),4.4 5–4.38(m,1H),4.37–4.30(m,1H),4.03–3.95(m,2H),3.93(s,2H),3.66–3.58(m,2H),3.35–3.31(m,2H).

[0283] Examples 7-13 were synthesized according to the synthesis method of Example 4; Examples 14-18 were synthesized according to the synthesis method of Example 1. The specific structures and characterizations of Examples 7-18 are shown in Table 1 below:

[0284] Table 1. Specific structures and characterizations of Examples 7-18

[0285] Example 19

[0286] 3,4-dichloro-2-(2-(pyrrolidin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0287] 3,4-Dichloro-2-(2-(pyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0288] first step

[0289] 3-(2,3-dichloro-6-methoxyphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole

[0290] 3-(2,3-dichloro-6-methoxyphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole

[0291] 4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-one 1f (5.5 g, 21.14 mmol) was dissolved in dichloromethane (100 mL), and then trimethyloxonium tetrafluoroboric acid (5.99 g, 42.29 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the solution was concentrated to obtain 3-(2,3-dichloro-6-methoxyphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole 19a (5.8 g), which was directly used in the next step of the reaction.

[0292] MS m / z(ESI): 274.0 [M+1]

[0293] Step 2

[0294] 4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-imine

[0295] 4-(2,3-Dichloro-6-methoxyphenyl)pyrrolidine-2-imine

[0296] 3-(2,3-dichloro-6-methoxyphenyl)-5-methoxy-3,4-dihydro-2H-pyrrole 19a (4.4 g, 16.05 mmol) was dissolved in methanol (20 mL), and sodium bicarbonate (3.81 g, 48.15 mmol) was added. The reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluent: system B) to give 4-(2,3-dichloro-6-methoxyphenyl)pyrrolidin-2-imine 19b (1.1 g), in 26.45% yield.

[0297] MS m / z(ESI): 258.9 [M+1]

[0298] Step 3

[0299] tert-butyl 3-(6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)pyrrolidine-1-carboxylate

[0300] 3-(6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)pyrrolidin-1-carboxylic acid tert-butyl ester

[0301] Sodium bicarbonate (97.48 mg, 1.16 mmol) was added to an ethanol (4 mL) solution of tert-butyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 19c (226 mg, 773.53 μmol, prepared according to published patent "WO2010051245") and 4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-imine 19b (100.22 mg, 386.76 μmol). The reaction mixture was stirred at 80 °C for 16 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 19d (80mg) of tert-butyl 3-(6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)pyrrolidine-1-carboxylate, with a yield of 45.72%.

[0302] MS m / z(ESI): 452.1 [M+1]

[0303] Step 4

[0304] 3,4-dichloro-2-(2-(pyrrolidin-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0305] 3,4-Dichloro-2-(2-(pyrrolidine-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0306] At -78°C, boron tribromide (100 mg, 0.4 mmol) was added to a dichloromethane solution of 19d (70 mg, 154.74 μmol) of 3-(6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 19d. The reaction mixture was then stirred at 0°C for 10 min. After the reaction was complete, it was quenched with methanol at -78°C, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The system was filtered, and the filter cake was washed with dichloromethane. The filtrates were combined, and the solvent was removed under reduced pressure. The residue was purified by preparative liquid chromatography (using a SunFire C10 column). 18 [UNK] 19*250mm [UNK] 10μm; 20ml / min; mobile phase A: 10mmol / L, 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 20mL / min), yielded 19 (17.8mg) of 3,4-dichloro-2-(2-(pyrrolidone-3-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol, yield 34.01%.

[0307] MS m / z(ESI): 337.8 [M+1]

[0308] 1 H NMR(400MHz, DMSO-d6)δ8.30(s,1H),7.37(dd,J=8.8,1.8Hz,1H),7.01–6.95(m,1H),6.88(dd,J=8.7,3.7Hz,1H),4.83–4.70( m,1H),4.21–4.04(m,2H),3.46–3.23(m,4H),3.26–3.09(m,2H),3.10–2.91(m,2H),2.24–2.12(m,1H),2.04–1.89(m,1H)ppm.

[0309] Example 20

[0310] 3,4-dichloro-2-(2-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0311] 3,4-Dichloro-2-(2-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0312] first step

[0313] 6-(2,3-dichloro-6-methoxyphenyl)-2-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0314] 6-(2,3-dichloro-6-methoxyphenyl)-2-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0315] Sodium bicarbonate (97.26 mg, 1.16 mmol) was added to an ethanol (4 mL) solution of 4-(2,3-dichloro-6-methoxyphenyl)pyrrolidine-2-imine 19b (100 mg, 385.90 μmol) and 1-bromobut-2-one 20a (116.54 mg, 771.81 μmol). The reaction mixture was then stirred at 80 °C under nitrogen protection for 16 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: system B) to give 6-(2,3-dichloro-6-methoxyphenyl)-2-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium 20b (50 mg) in 41.63% yield.

[0316] MS m / z(ESI): 311.0 [M+1]

[0317] Step 2

[0318] 3,4-dichloro-2-(2-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0319] 3,4-Dichloro-2-(2-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0320] At -78°C, boron tribromide (80 mg, 321.32 μmol) was added to a solution of 6-(2,3-dichloro-6-methoxyphenyl)-2-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole 20b (40 mg, 128.53 μmol) in dichloromethane (2 mL). The reaction mixture was then stirred at 0°C for 10 minutes. After the reaction was complete, methanol was added at -78°C to quench the reaction, and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The mixture was filtered, the filter cake was washed with dichloromethane, and the solvent was removed from the filtrate under reduced pressure. The residue was purified by preparative liquid chromatography (Waters 3767 / QDA column: SunFire C). 18 The sample was prepared by mixing 19*250mm, 10um; mobile phase A: 10mmol / L, A: 0.1% formic acid / water, B: acetonitrile; flow rate: 20mL / min, yielding 20 (13.1mg) of 3,4-dichloro-2-(2-ethyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol, with a yield of 34.30%.

[0321] MS m / z(ESI): 297.0 [M+1]

[0322] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),7.41(d,J=8.8Hz,1H),7.19(s,1H),6.87(d,J=8.8Hz,1H),4.98–4.83(m,1H),4. 39(t,J=10.2Hz,1H),4.15(dd,J=10.4,7.0Hz,2H),3.22–3.10(m,2H),2.59(q,J=7.5Hz,4H),1.19(t,J=7.5Hz,3H)ppm.

[0323] Example 21

[0324] 2-(2-(1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol

[0325] 2-(2-(1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol

[0326] first step

[0327] tert-butyl 4-(6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1H-pyrazole-1-carboxylate

[0328] 4-(6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester

[0329] 2-(2-bromo-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol 1j (100 mg, 276.21 μmol), 1-Boc-pyrazole-4-boronic acid pinacol ester 21a (162.49 mg, 552.41 μmol, commercially available), cesium carbonate (359.97 mg, 1.10 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (40.98 mg, 55.24 μmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL), and the mixture was stirred at 100 °C for 18 hours. After the reaction was complete, the mixture was filtered, concentrated, and purified by silica gel column chromatography (eluent: system B) to obtain 21b (124 mg) of 4-(6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester, with a yield of 99.91%.

[0330] MS m / z(ESI): 349.0 [M-100].

[0331] Step 2

[0332] 2-(2-(1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol

[0333] 2-(2-(1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol

[0334] 4-(6-(2,3-dichloro-6-methoxyphenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester 21b (124 mg, 275.97 μmol) was dissolved in dichloromethane (1 mL), and boron tribromide (206.98 mg, 827.90 μmol) was added dropwise under ice bath, with stirring for 2 hours. After the reaction was complete, water was added to quench (15 mL), and the mixture was neutralized with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative liquid chromatography (using SunFire C column). 18 [UNK] 19*250mm [UNK] 10μm; 20mL / min; mobile phase A: 10mmol / L, 0.1% formic acid / water, mobile phase B: acetonitrile, flow rate: 20mL / min), yielded 21 (19.8mg) of 2-(2-(1H-pyrazol-4-yl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol, yield 20.85%.

[0335] MS m / z(ESI): 335.0 [M+1].

[0336] 1 H NMR (400MHz, DMSO-d6) δ7.74(s,2H),7.16(s,1H),7.10(d,J=8.8Hz,1H),6.52(d,J=8.8Hz,1H),4.80–4.66(m,1 H), 4.21 (t, J = 8.8Hz, 1H), 4.09 (t, J = 9.6Hz, 1H), 3.17 (dd, J = 15.1, 8.2Hz, 1H), 2.88 (dd, J = 15.2, 9.7Hz, 1H) ppm.

[0337] Example 22

[0338] 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0339] 3,4-Dichloro-2-(2-(2-hydroxypropyl-2-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0340] first step

[0341] (2,3-dichloro-6-methoxyphenyl)methanol

[0342] (2,3-Dichloro-6-methoxyphenyl)methanol

[0343] 2,3-Dichloro-6-methoxybenzaldehyde 1b (20 g, 97.54 mmol) was dissolved in tetrahydrofuran (200 mL). Sodium borohydride (7.38 g, 195.09 mmol) was added under nitrogen protection at 0 °C, and the mixture was then heated to 25 °C and reacted for 16 hours. The reaction solution was diluted with water (400 mL), extracted with ethyl acetate (400 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (600 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 A) to give (2,3-dichloro-6-methoxyphenyl)methanol 22a (20 g), with a yield of 99.0%.

[0344] MS m / z (ESI): 207.0 [M+1]

[0345] Step 2

[0346] 1,2-dichloro-3-(chloromethyl)-4-methoxybenzene

[0347] 1,2-Dichloro-3-(chloromethyl)-4-methoxybenzene

[0348] (2,3-Dichloro-6-methoxyphenyl)methanol 22a (20 g, 96.59 mmol), methanesulfonyl chloride (22.13 g, 193.19 mmol), and triethylamine (24.44 g, 241.48 mmol) were added sequentially to dichloromethane (200 mL). The reaction mixture was reacted at 25 °C for 16 hours under nitrogen protection. After the reaction was complete, water (300 mL) was added to quench the reaction mixture, and the mixture was extracted with dichloromethane (300 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (400 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 1,2-dichloro-3-(chloromethyl)-4-methoxyphenyl 22b (14 g), with a yield of 64.2%.

[0349] MS m / z (ESI): 225.0 [M+1]

[0350] Step 3

[0351] 2-(2,3-dichloro-6-methoxyphenyl)acetonitrile

[0352] 2-(2,3-Dichloro-6-methoxyphenyl)acetonitrile

[0353] 1,2-Dichloro-3-(chloromethyl)-4-methoxyphenyl 22b (14 g, 62.08 mmol) was dissolved in dimethyl sulfoxide (140 mL), and sodium cyanide (9.88 g, 186.25 mmol) was added. The reaction mixture was heated to 90 °C and reacted for 4 hours. After the reaction was complete, the reaction solution was diluted with saturated sodium bicarbonate solution (400 mL), extracted with ethyl acetate (400 mL × 3), and the combined organic phases were washed with saturated sodium chloride solution (500 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 A) to give 2-(2,3-dichloro-6-methoxyphenyl)acetonitrile 22c (12 g), with a yield of 89.4%.

[0354] MS m / z (ESI): 216.0 [M+1]

[0355] Step 4

[0356] 2-(2,3-dichloro-6-methoxyphenyl)propanenitrile

[0357] 2-(2,3-Dichloro-6-methoxyphenyl)propionitrile

[0358] 2-(2,3-dichloro-6-methoxyphenyl)acetonitrile 22c (12 g, 55.54 mmol) was dissolved in N,N-dimethylformamide (120 mL), and iodomethane (11.82 g, 83.31 mmol) and cesium carbonate (36.19 g, 111.08 mmol) were added. The reaction mixture was reacted at room temperature under nitrogen protection for 16 hours. After the reaction was complete, the reaction solution was diluted with water (200 mL), extracted with ethyl acetate (200 mL × 3), and the organic phase was washed with saturated sodium chloride solution (300 mL × 2). The solution was 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 2-(2,3-dichloro-6-methoxyphenyl)propionitrile 22d (10.5 g), with a yield of 82.1%.

[0359] MS m / z (ESI): 230.0 [M+1]

[0360] Step 5

[0361] ethyl 3-cyano-3-(2,3-dichloro-6-methoxyphenyl)butanoate

[0362] Ethyl 3-cyano-3-(2,3-dichloro-6-methoxyphenyl)butyrate

[0363] 2-(2,3-dichloro-6-methoxyphenyl)propionitrile 22d (10.5 g, 45.63 mmol) was dissolved in tetrahydrofuran (110 mL). The mixture was cooled to -70 °C under nitrogen protection. Bistrimethylsilylaminolithium (1 M, 68 mL) was slowly added dropwise to the reaction mixture. After the addition was complete, the reaction mixture was stirred at -70 °C for 1 hour. Then, ethyl bromoacetate (15.24 g, 91.27 mmol) was added. After the addition was complete, the reaction mixture was slowly heated to 25 °C and stirred for 16 hours. After the reaction was complete, water (200 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phase was washed with saturated sodium chloride solution (400 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 A) to give ethyl 3-cyano-3-(2,3-dichloro-6-methoxyphenyl)butyrate 22e (10 g), with a yield of 69.3%.

[0364] MS m / z (ESI): 316.0 [M+1]

[0365] Step 6

[0366] 4-(2,3-dichloro-6-methoxyphenyl)-4-methylpyrrolidin-2-one

[0367] 4-(2,3-Dichloro-6-methoxyphenyl)-4-methylpyrrolidone-2-one

[0368] Ethyl 3-cyano-3-(2,3-dichloro-6-methoxyphenyl)butyrate 22e (5 g, 15.81 mmol) was dissolved in methanol (50 mL), and Raney nickel (928 mg, 15.81 mmol) was added. The reaction mixture was stirred at 25 °C for 2 hours under a hydrogen atmosphere (30 psi). After the reaction was complete, the reaction solution was filtered, the residue was washed with methanol, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 4-(2,3-dichloro-6-methoxyphenyl)-4-methylpyrrolidone-2-one 22f (2 g), with a yield of 46.1%.

[0369] MS m / z (ESI): 274.0 [M+1]

[0370] Step 7

[0371] methyl 2-(4-(2,3-dichloro-6-methoxyphenyl)-4-methyl-2-oxopyrrolidin-1-yl)acetate

[0372] 2-(4-(2,3-dichloro-6-methoxyphenyl)-4-methyl-2-oxopyrrolidone-1-yl)methyl acetate

[0373] 22f of 4-(2,3-dichloro-6-methoxyphenyl)-4-methylpyrrolidone-2-one (2 g, 7.30 mmol) was dissolved in N,N-dimethylformamide (20 mL), followed by the addition of potassium tert-butoxide (1.64 g, 14.59 mmol) and methyl bromoacetate (1.67 g, 10.94 mmol), respectively. The reaction mixture was stirred at 60 °C for 16 hours under nitrogen protection. After the reaction was complete, water (50 mL) was added to dilute the reaction solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (80 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 A) to obtain 22 g (1.5 g) of methyl 2-(4-(2,3-dichloro-6-methoxyphenyl)-4-methyl-2-oxopyrrolidine-1-yl)acetate, with a yield of 59.3%.

[0374] MS m / z (ESI): 346.0 [M+1]

[0375] Step 8

[0376] 2-(4-(2,3-dichloro-6-methoxyphenyl)-4-methyl-2-oxopyrrolidin-1-yl)acetamide

[0377] 2-(4-(2,3-dichloro-6-methoxyphenyl)-4-methyl-2-oxopyrrolidone-1-yl)acetamide

[0378] 22 g (2 g, 5.78 mmol) of methyl 2-(4-(2,3-dichloro-6-methoxyphenyl)-4-methyl-2-oxopyrrolidone-1-yl)acetate was dissolved in methanol (5 mL), and a methanol solution of ammonia (4 M, 15 mL) was added. The reaction mixture was reacted at 40 °C for 16 h. After the reaction was complete, the reaction mixture was concentrated under reduced pressure to give 22 h (1.5 g) of 2-(4-(2,3-dichloro-6-methoxyphenyl)-4-methyl-2-oxopyrrolidone-1-yl)acetamide, yield 78.4%, which was used directly in the next step without further purification. MS m / z (ESI): 331.0 [M+1]

[0379] Step 9

[0380] 2-bromo-6-(2,3-dichloro-6-methoxyphenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0381] 2-Bromo-6-(2,3-dichloro-6-methoxyphenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0382] 2-(4-(2,3-dichloro-6-methoxyphenyl)-4-methyl-2-oxopyrrolidine-1-yl)acetamide 22h (1.50 g, 4.53 mmol) was dissolved in acetonitrile (15 mL), and phosphorus tribromooxyphosphine (3.90 g, 13.59 mmol) was added. The reaction mixture was reacted at 85 °C for 3 hours. After the reaction was complete, the reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was washed with saturated sodium chloride solution (60 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 2-bromo-6-(2,3-dichloro-6-methoxyphenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium 22i (1.4 g), yield 82.1%.

[0383] MS m / z (ESI): 375.0 [M+1]

[0384] Step 10

[0385] 2-(2-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol

[0386] 2-(2-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol

[0387] Under nitrogen protection, 1.4 g (3.72 mmol) of 2-bromo-6-(2,3-dichloro-6-methoxyphenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium 22i was dissolved in 14 mL of dichloromethane. The reaction mixture was cooled to -78 °C, and then 4 mL of boron tribromide was added dropwise at -78 °C. After the addition was complete, the reaction mixture was heated to 0 °C and reacted for 30 minutes. After the reaction was complete, the reaction mixture was cooled to -78 °C, and then the reaction solution was quenched with 30 mL of methanol. Ammonia was added to adjust the pH to 8-9, and the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give 600 mg (600 mg) of 2-(2-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol 22j, with a yield of 44.5%.

[0388] MS m / z (ESI): 360.8 [M+1]

[0389] Step 11

[0390] 2-bromo-6-(6-((tert-butyldimethylsilyl)oxy)-2,3-dichlorophenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0391] 2-Bromo-6-(6-((tert-butyldimethylsilyl)oxy)-2,3-dichlorophenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole

[0392] 2-(2-bromo-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)-3,4-dichlorophenol 22j (600 mg, 1.66 mmol) was dissolved in N,N-dimethylformamide (5 mL), and imidazole (225 mg, 3.31 mmol) and tert-butyldimethylchlorosilane (299 mg, 1.99 mmol) were added respectively. The reaction mixture was then reacted at 25 °C for 16 hours under nitrogen protection. After the reaction was complete, water was added to dilute the reaction solution (30 mL), and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 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 A) to give 2-bromo-6-(6-((tert-butyldimethylsilyl)oxy)-2,3-dichlorophenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole 22k (300 mg), with a yield of 38.0%.

[0393] MS m / z (ESI): 475.0 [M+1]

[0394] Step Twelve

[0395] methyl 6-(2,3-dichloro-6-hydroxyphenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-2-carboxylate

[0396] 6-(2,3-Dichloro-6-hydroxyphenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylic acid methyl ester

[0397] 2-Bromo-6-(6-((tert-butyldimethylsilyl)oxy)-2,3-dichlorophenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazole 22k (300 mg, 0.62 mmol), tritert-butylphosphine tetrafluoroborate (36 mg, 0.12 mmol), molybdenum hexacarbonyl (166 mg, 0.62 mmol), triethylamine (127 mg, 1.26 mmol), and 1,1'-bis(diphenylphosphino)ferrocene palladium dichloride (II) (51 mg, 0.06 mmol) were added sequentially to a mixed solvent of N,N-dimethylformamide (2 mL) and methanol (2 mL). The reaction mixture was reacted at 90 °C for 1 hour under nitrogen protection. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was washed with saturated sodium chloride solution (15 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 give 22 μL (80 mg) of methyl 6-(2,3-dichloro-6-hydroxyphenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylate, with a yield of 37.2%. MS m / z (ESI): 340.9 [M+1]

[0398] Step Thirteen

[0399] 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0400] 3,4-Dichloro-2-(2-(2-hydroxypropyl-2-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0401] Under nitrogen protection, 22 μL (60 mg, 0.17 mmol) of methyl 6-(2,3-dichloro-6-hydroxyphenyl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazolium-2-carboxylate was dissolved in tetrahydrofuran (2 mL). The reaction system was cooled to 0 °C, and then methyl magnesium bromide (3 M, 586 μL) solution was added. After the addition was complete, the reaction mixture was heated to 50 °C and stirred for 3 hours. After the reaction was complete, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (using a SunFire Sunfire C column). 18; 250×19mm ID; 10μm, 20mL / min; mobile phase A: 0.1% FA / H2O, mobile phase B: CH3CN), to give 22 (7 mg) of 3,4-dichloro-2-(2-(2-hydroxypropyl-2-yl)-6-methyl-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol, yield 11.6%.

[0402] MS m / z (ESI): 340.9 [M+1]

[0403] 1 H NMR (400MHz, DMSO-d6) δ10.70(brs,1H),8.38(brs,1H),7.35(d,J=8.8Hz,1H),6.89(d,J=8.8Hz,1H),6.87(s,1H),4.51(d,J =11.4Hz,1H),4.26(d,J=11.5Hz,1H),3.44(d,J=15.9Hz,1H),3.21(d,J=16.0Hz,1H),1.39(s,3H),1.38(s,3H),1.37(s,3H).

[0404] Examples 23-25, 27, and 28-31 were synthesized according to the synthesis method of Example 21; Example 26 was synthesized according to the synthesis method of Example 20; and Example 32 was synthesized according to the synthesis method of Example 22. The specific structures and characterizations of Examples 23-32 are shown in Table 2 below:

[0405] Table 2. Specific structures and characterizations of Examples 23-32

[0406] Synthesis of control compound A

[0407] (R)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol

[0408] (R)3,4-Dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol

[0409] first step

[0410] (R)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole

[0411] (R)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole

[0412] (R)-4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidone-2-one A-01 (1 g, 3.49 mmol, prepared according to CN117946111) was added to dichloromethane (20 mL), followed by the addition of cesium carbonate (3.42 g, 10.48 mmol) and triethyloxonium tetrafluoroborate (995.86 mg, 5.24 mmol). The reaction mixture was reacted at room temperature under nitrogen protection for 12 hours. After the reaction was complete, water (100 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (80 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give (R)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole A-02 (901 mg), with a yield of 81.53%.

[0413] MS m / z (ESI): 313.9 [M+1]

[0414] Step 2 (R)-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methanol

[0415] (R)-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methanol

[0416] (R)-3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole A-02 (500 mg, 1.59 mmol) was added to n-butanol (20 mL), followed by the addition of 2-hydroxyacetylhydrazine (430.04 mg, 4.77 mmol). The reaction mixture was reacted at 140 °C for 12 hours under nitrogen protection. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give (R)-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methanol A-03 (360 mg), in 66.50% yield.

[0417] MS m / z (ESI): 340.1 [M+1]

[0418] Step 3

[0419] (R)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol

[0420] (R)-3,4-Dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol

[0421] (R)-(6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methanol A-03 (180 mg, 529.09 μmol) was added to tetrahydrofuran (10 mL), followed by the addition of sodium borohydride (40.21 mg, 1.06 mmol) and tetra(triphenylphosphine)palladium (61.14 mg, 52.91 μmol). The reaction mixture was reacted at room temperature for 4 hours under nitrogen protection. After the reaction was complete, water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was 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 preparative liquid chromatography (Waters 3767 / QDA column: SunFire Sunfire C18, 19*250 mm, 10 μm; mobile phase A: 0.1% FA / H2O, B: CH3CN; flow rate: 20 mL / min; gradient: 23-33%; retention time: 9.1-11 min, 16 min) to obtain (R)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol A (48.88 mg), with a yield of 30.78%.

[0422] MS m / z (ESI): 300.0 [M+1]

[0423] 1 H NMR (400MHz, DMSO-d6) δ10.58(s,1H),7.40(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),5.49(t,J=5.8Hz,1H),5.02– 4.91(m,1H),4.54(d,J=5.3Hz,2H),4.26(t,J=10.0Hz,1H),4.16–4.07(m,1H),3.15–3.07(dd,J=9.0,4.6Hz,2H).

[0424] SFC analysis method: Rt = 1.505 min (gradient column: 100*30mm, 3.0μm, wavelength: 214nm, flow rate: 1.5mL / min; gradient: 85% supercritical CO2, 15% MeOH (0.1% DEA); column temperature: 35℃.

[0425] Synthesis of control compound B

[0426] (S)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol

[0427] (S)3,4-Dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol

[0428] first step

[0429] 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole

[0430] 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole

[0431] 4-(6-(allyloxy)-2,3-dichlorophenyl)pyrrolidone-2-one AB-1 (500 mg, 1.75 mmol, prepared according to CN117946111) was added to dichloromethane (15 mL), followed by the addition of cesium carbonate (1.71 g, 5.24 mmol) and triethyloxonium tetrafluoroborate (398.36 mg, 2.1 mmol). The reaction mixture was allowed to react at room temperature for 12 hours. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole AB-2 (458 mg), with a yield of 83.42%.

[0432] MS m / z (ESI): 314.2 [M+1]

[0433] Step 2

[0434] (6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methanol

[0435] (6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methanol

[0436] 3-(6-(allyloxy)-2,3-dichlorophenyl)-5-ethoxy-3,4-dihydro-2H-pyrrole AB-2 (408 mg, 1.38 mmol) was added to n-butanol (10 mL), followed by the addition of 2-hydroxyacetylhydrazine (350.91 mg, 3.90 mmol). The reaction mixture was reacted at 140 °C for 12 hours. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give (6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methanol AB-3 (385 mg), in 87.15% yield.

[0437] MS m / z (ESI): 340.1 [M+1]

[0438] Step 3

[0439] (S)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol

[0440] (S)-3,4-Dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol

[0441] (6-(6-(allyloxy)-2,3-dichlorophenyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl)methanol AB-3 (355 mg, 1.04 mmol) was added to tetrahydrofuran (10 mL), followed by the addition of sodium borohydride (78.96 mg, 2.09 mmol) and tetra(triphenylphosphine)palladium (120.58 mg, 104.35 μmol). The reaction mixture was reacted at room temperature for 4 hours under nitrogen protection. After the reaction was complete, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by preparative liquid chromatography (Waters 3767 / QDA column: XBridge C). 18Purification was performed using a 19*250mm, 10µm mobile phase (A: 0.1% FA / H2O, B: ACN; flow rate: 20mL / min; gradient: 26-36%; retention time: 7.1-8.7min, 17min) to obtain a racemic mixture (98mg). This mixture was then resolved by chiral preparative chromatography (instrument: Waters SFC 150, gradient column: ). Two compounds were obtained using a 250*30mm, 10µm column, flow rate of 50mL / min, gradient of 70% supercritical CO2: 30% MeOH (+0.1% 7.0mol / L ammonia-methanol); column temperature: room temperature. These two compounds were then purified by preparative liquid chromatography (using a SunFire C400 column). 18 ; 19*250mm, 10um, 20mL / min; mobile phase A: 0.1% FA / H2O, mobile phase B: CH3CN), yielding (R)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol A (38.56 mg), yield 39.11%; and (S)-3,4-dichloro-2-(3-(hydroxymethyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol B (35.72 mg), yield 36.20%.

[0442] Reference compound A

[0443] MS m / z (ESI): 300.0 [M+1]

[0444] 1 H NMR (400MHz, DMSO-d6) δ10.66(s,1H),7.39(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),5.49(brs,1H),5.03–4.90( m,1H),4.54(d,J=3.4Hz,2H),4.26(t,J=10.0Hz,1H),4.11(dd,J=10.5,7.9Hz,1H),3.11(dd,J=9.0,3.4Hz,2H).

[0445] SFC analysis method: RT = 1.531 min (gradient column: 100*30mm, 3.0um, wavelength: 214nm, flow rate: 1.5mL / min; gradient: 85% supercritical CO2, 15% MeOH (0.1% DEA); column temperature: 35℃.

[0446] Reference compound B

[0447] MS m / z (ESI): 300.0 [M+1]

[0448] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),7.40(d,J=8.8Hz,1H),6.86(d,J=8.8Hz,1H),5.49(t,J=5.8Hz,1H),5.02–4. 90(m,1H),4.54(d,J=5.5Hz,2H),4.26(t,J=10.0Hz,1H),4.11(dd,J=10.5,7.9Hz,1H),3.11(dd,J=9.0,4.4Hz,2H).

[0449] SFC analysis method: RT = 2.482 min (gradient column: 100*30mm, 3.0m, wavelength: 214nm, flow rate: 1.5mL / min; gradient: 85% supercritical CO2, 15% MeOH (0.1% DEA); column temperature: 35℃.

[0450] The absolute configurations of compounds A and B were confirmed by combining the two control synthesis methods described above.

[0451] Reference compound C

[0452] 3,4-dichloro-2-(3-(2-hydroxy-2-methylpropyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-6-yl)phenol

[0453] 3,4-Dichloro-2-(3-(2-hydroxy-2-methylpropyl)-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazole-6-yl)phenol

[0454] The control compound C was prepared according to the synthesis method of Example 3 of WO2024088343A1.

[0455] Biological evaluation

[0456] Test Example 1: Manual patch-clamp method for detecting the effect of the compound of this invention on the hKv1.3 potassium ion channel.

[0457] 1.1 Cells

[0458] 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.

[0459] 1.2 Experimental Solution

[0460] 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).

[0461] 2) Intracellular fluid: 10mM EGTA, 10mM HEPES, 10mM potassium chloride, 10mM sodium chloride, 110mM potassium fluoride (pH adjusted to 7.2 using potassium hydroxide).

[0462] 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.

[0463] 1.3 Solution of the compound to be tested

[0464] 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).

[0465] 1.4 Experimental Procedure

[0466] 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.

[0467] 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.

[0468] 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.

[0469] 1.5 Data Analysis

[0470] Note: Data is output by PatchMaster software.

[0471] 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 ".

[0472] The current suppression percentage is calculated using the following formula.

[0473] 2) The dose-response curve was fitted using Graphpad Prism 8.0 software and the IC was calculated. 50 value.

[0474] 3) The standard deviation of the three sets of data is less than 15 (SD<15).

[0475] 1.6 Experimental Results

[0476] This experiment used a manual patch-clamp technique to evaluate whether the test compound had a potential inhibitory effect on the voltage-gated potassium ion channel hKv1.3. The results are shown in Table 3.

[0477] Table 3 shows the IC50 of the inhibitory activity of the compounds of the present invention for the hKv1.3 potassium ion channel. 50

[0478] Note: Control compounds A, B and C are from WO2024088343A1.

[0479] The results showed that, compared with the control compound, the compound of the present invention had a significantly better inhibitory effect on the hKv1.3 potassium ion channel.

[0480] Test Example 2: Manual patch-clamp method for detecting the effect of the compound of this invention on the hKv1.3 potassium ion channel (two concentration points)

[0481] 1.1 Cells

[0482] 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.

[0483] 1.2 Experimental Solution

[0484] 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).

[0485] 2) Intracellular fluid: 10mM EGTA, 10mM HEPES, 10mM potassium chloride, 10mM sodium chloride, 110mM potassium fluoride (pH adjusted to 7.2 using potassium hydroxide).

[0486] 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.

[0487] 1.3 Solution of the compound to be tested

[0488] 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 two final concentrations of test solutions, namely (μM): 0.1 and 0.001 or 0.01 and 1. The concentration of DMSO in the test solutions was 0.1-0.3% (volume ratio).

[0489] 1.4 Experimental Procedure

[0490] 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.

[0491] 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.

[0492] 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.

[0493] 1.5 Data Analysis

[0494] Note: Data is output by PatchMaster software.

[0495] 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 ".

[0496] The current suppression percentage is calculated using the following formula.

[0497] 2) The dose-response curve was fitted using Graphpad Prism 8.0 software and the IC50 value was calculated.

[0498] 3) The standard deviation of the three sets of data is less than 15 (SD<15).

[0499] 1.6 Experimental Results

[0500] 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 4 and 5.

[0501] Table 4. Inhibitory activity of the compounds of this invention against hKv1.3 potassium ion channels (two concentration points, 0.001 μM / 0.1 μM)

[0502] 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.

[0503] Table 5. Inhibitory activity of the compounds of this invention against hKv1.3 potassium ion channels (two concentration points, 0.01 μM / 1 μM).

[0504] The results showed that the compounds of the present invention exhibited IC50 inhibitory activity against hKv1.3 potassium ion channels. 50 <10nM, exhibiting good inhibitory effect.

[0505] Test Example 3: Rat Pharmacokinetic Study of the Compounds of the Invention

[0506] 1. Experimental Objective

[0507] Using SD rats as test animals, the drug concentration in plasma at different time points after injection of the compound of the present invention (Example 2) and control compounds 8343-01 and 8343-03 was determined by LC / MS / MS to study the pharmacokinetic characteristics of the compound of the present invention in mice.

[0508] 2. Experimental Design

[0509] 2.1 Experimental drugs and animals;

[0510] Control compound 8343-01, control compound 8343-03, Example 2;

[0511] Male SD rats, 269-306g, were purchased from Vital River Laboratory Animal Technology Co., Ltd.

[0512] 2.2 Drug Preparation

[0513] Intravenous injection group: Weigh an appropriate amount of drug and add DMA: 30% solubil HS15: saline = 10:10:80 (v / v / v) to prepare a solution with a final concentration of 0.2 mg / mL;

[0514] Oral gavage group: Weigh an appropriate amount of drug and add DMA: 30% solubil HS15: saline = 10:10:80 (v / v / v) to prepare a solution with a final concentration of 1 mg / mL;

[0515] 2.3 Administration

[0516] Twelve SD rats were used, divided into four groups of three groups each. After fasting overnight, the rats were administered the drugs via intravenous injection or gavage. The rats were fed four hours after administration. The dosages of each compound are shown in Table 6 below.

[0517] Table 6 Dosage of each compound

[0518] 3. Operation

[0519] 150 μL of blood was collected via the jugular sinus before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after administration, and anticoagulated with EDTA-K2. After collection, blood samples were placed on ice and centrifuged within 30 minutes to separate the plasma (centrifugation conditions: 1500g, 10 minutes). Collected plasma was stored at –40 to –20°C before analysis.

[0520] The levels of the target compounds in rat plasma after intravenous injection and gavage administration were determined by LC-MS / MS.

[0521] 4. Pharmacokinetic Parameter Results

[0522] Oral bioavailability is the percentage of AUC (area under the curve) after oral administration of an equal amount of drug and the AUC (area under the curve) after intravenous administration of an equal amount of drug. The formula for calculation is as follows: In the formula, AUC represents the area under the blood drug concentration-time curve, the subscripts ig and iv represent oral gavage and intravenous injection, respectively, and D represents the dosage.

[0523] The pharmacokinetic parameters of the compounds of the present invention in mice are shown in Table 7 below.

[0524] Table 7. Pharmacokinetic parameters of the compounds of the present invention in mice.

[0525] Note: N / A indicates no relevant results.

[0526] Conclusion: Compared with the control compound, Compound Example 2 of the present invention exhibits better pharmacokinetic absorption, higher bioavailability, and better pharmacokinetic properties.

Claims

1. A compound of Formula (I) or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof: ###00001### (I) ​ wherein: L is selected from the group consisting of a bond, -C(R aa R bb )- and -C(=O)-; R aa and R bb are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, and a methyl group; R 1 selected from a hydrogen atom and C 1-6 alkyl; R 2 , R 3 , R 4 , R 5 are each independently selected from the group consisting of a hydrogen atom, a deuterium 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 3-6 cycloalkyl group, a haloC 3-6 cycloalkyl group, and a haloC 1-6 alkyl group; R a is selected from the group consisting of a hydrogen atom, C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl, wherein said C 1-6 alkyl, C 2-6 alkenyl or C 2-6 alkynyl is optionally further substituted by one or more substituents selected from the group consisting of a deuterium atom, hydroxyl, halogen, cyano, amino, haloC 1-6 alkyl, haloC 1-6 alkoxy and SF5; R b , R c , R d , R e are each independently selected from the group consisting of a hydrogen atom, a halogen, a C 1-6 alkyl group, a C 1-6 alkoxy group, a haloC 1-6 alkyl group and a haloC 1-6 alkoxy group; or R b with R c , R d with R e each independently form together with the same carbon atom to which they are attached a -C(=0)- or C 3-6 cycloalkyl, wherein said C 3-6 cycloalkyl is optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, hydroxy, halogen, cyano, amino, haloC 1-6 alkyl, haloC 1-6 alkoxy and SF5; or R a and R b , R a and R d each independently form, together with the carbon atom to which they are attached, a C 3-6 cycloalkyl group, wherein said C 3-6 cycloalkyl group is optionally further substituted by one or more substituents selected from the group consisting of a deuterium atom, a hydroxyl group, a halogen, a cyano group, an amino group, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halogenated C 1-6 alkyl group, a halogenated C 1-6 alkoxy group and a SF5 group; R B selected from the group consisting of a hydrogen atom, a hydroxyl group, a halogen, a cyano group, an amino group, SF5, C 1-6 alkoxy group and a halogenated C 1-6 alkoxy group; R A is selected from the group consisting of hydrogen atom, hydroxyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, 6-10 membered fused ring, SF5, -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 and -S(=O) r R 5 ; wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-6 membered heteroaryl, 6-10 membered fused ring is optionally further substituted with one or more R AA ; R AA are the same or different, each independently selected from the group consisting of hydroxy, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, 5- to 6-membered 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 and -NR 10 C(=0)OR 11 ; wherein said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl or 5- to 6-membered heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, 5- to 6-membered 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 and -NR 10 C(=0)OR 11 ; or two R AA with the same carbon atom to which they are attached forms a -C(=0)-; or two R AA form together with the carbon atom to which they are attached a C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl; wherein said C 3-6 cycloalkyl or 3- to 12-membered heterocyclyl is optionally further substituted with one or more substituents independently selected from the group consisting of hydroxy, halogen, nitro, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, 3- to 12-membered heterocyclyl, phenyl, 5- to 6-membered heteroaryl, =0, -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 and -NR 10 C(=O)OR 11 ; R 6 each independently is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and 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 the group consisting of 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 , and -NR 10 C(=0)OR 11 ; R 7 and R 8 are each independently selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, wherein said alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted by one or more substituents selected from the group consisting of 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 , -SO2NR 10 R 11 , -NR 10 C(=0)R 11 and -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 , and -NR 10 C(=O)OR 11 ; R 9 , R 10 , and R 11 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group, and 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 the group consisting of 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, and a carboxylate ester group; each r is independently 0, 1 or 2; with the proviso that the compound of formula (I) does not include the following structures:

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, tautomer, deuterated analog, or pharmaceutically acceptable salt thereof, wherein R B is a hydrogen atom.

4. The compound according to any one of claims 1-3, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, which is a compound according to Formula (II), or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof: ###00003### (II) wherein: R 2 is selected from a hydrogen atom and a halogen; said halogen is preferably chlorine; R 3 selected from C 1-4 alkyl and halogen, preferably chlorine, the C 1-4 alkyl is preferably methyl; R 4 selected from the group consisting of a hydrogen atom, a C 1-4 alkyl group and a halogen, said halogen being preferably chlorine, said C 1-4 alkyl group being preferably a methyl group; L, R a R b R c R d R e R A R 5 and R B The definition is as described in claim 1.

5. The compound according to any one of claims 1 to 4, which is a compound according to general formula (III-1) or (III-2) or a stereoisomer, a tautomer, a deuterated analogue or a pharmaceutically acceptable salt thereof: ###00019### (III-1) (III-2) ​ wherein: R 3 selected from methyl and chloro; R 4 selected from methyl and chloro; R 5 selected from a hydrogen atom, a deuterium atom, a halogen, a cyano group, a C 1-6 alkyl group, a C 2-6 alkenyl group and a C 1-6 alkynyl group; and a C L, R a R b R c R d R e R A and R B The definition is as described in claim 1.

6. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R b , R c , R d , R e is a hydrogen atom, R a is selected from a hydrogen atom, C 1-6 alkyl, or C 2-6 alkenyl, wherein said C 1-6 alkyl or C 2-6 alkenyl is optionally further substituted with one or more selected from a deuterium atom or a halogen.

7. The compound according to claim 6, or a stereoisomer, tautomer, deuterated analog, or pharmaceutically acceptable salt thereof, wherein R a is selected from a hydrogen atom, a methyl group, a deuterated methyl group, an ethyl group, and an ethenyl group.

8. The compound according to any one of claims 1-5, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R c , R d , R e is a hydrogen atom, R a and R b together with the carbon atom to which they are attached form a cyclopropyl group.

9. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof, wherein the compound is a stereoisomer, tautomer, deuterated product, or pharmaceutically acceptable salt thereof of general formula (IV-1), (IV-2), (IV-3), or (IV-4): wherein: R 3 each independently selected from methyl or chloro; R 4 each independently selected from methyl or chloro; R 5 selected from a hydrogen atom, a deuterium atom, fluorine or chlorine, preferably from a hydrogen atom, fluorine or chlorine; R a is selected from a hydrogen atom, a methyl group, a deuterated methyl group, an ethyl group or a vinyl group; L and R A The definitions are as in claim 1.

10. The compound according to any one of claims 1-9, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of a bond, -CH2-, -C(CH3)2-, -C(CH3)(OH)-, and -C(=0)-.

11. The compound according to any one of claims 1-10, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein R A is selected from the group consisting of hydroxy, amino, phenyl, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered heterocyclyl, and 5-6 membered heteroaryl, wherein said phenyl, C 1-6 alkyl, C 2-6 alkenyl, 3-12 membered heterocyclyl, or 5-6 membered heteroaryl is optionally further substituted with one or more R AA . R AA the same or different, each independently selected from halogen, hydroxyl, amino, C 1-6 alkyl, haloC 1-6 alkyl, hydroxylC 1-6 alkyl; or two R AA with the same carbon atom to which they are attached forms a -C(=0)-; or two R AA with the same carbon atom to which they are attached form a C 3-6 cycloalkyl, 3-12 membered heterocyclyl.

12. The compound according to claim 10 or 11, or a stereoisomer, tautomer, deuterated isomer, or pharmaceutically acceptable salt thereof, wherein is selected from the group consisting of ethyl, ethenyl, 13. The compound according to any one of claims 1 to 12, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, wherein the compound is selected from:

14. A pharmaceutical composition comprising a compound according to any one of claims 1-13, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. Use of a compound according to any one of claims 1-13, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a Kv1.3 potassium channel inhibitor.

16. Use of a compound according to any one of claims 1-13, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, 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 the group consisting of rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis, and chronic kidney disease.

17. Use of a compound according to any one of claims 1-13, or a stereoisomer, tautomer, deuterated isotope, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14, for the manufacture of a medicament for the treatment of an autoimmune disease, preferably, the autoimmune disease is selected from the group consisting of rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis, and chronic kidney disease.

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