Polysubstituted aryl derivative and preparation method therefor and use thereof

Abstract

The present invention relates to a polysubstituted aryl derivative, a preparation method therefor, and the use of a pharmaceutical composition containing the derivative in medicine. Specifically, the present invention relates to a polysubstituted aryl derivative as shown in general formula (I), a preparation method therefor, a pharmaceutically acceptable salt thereof, and the use thereof as a therapeutic agent, in particular as a Kv1.3 potassium ion channel inhibitor, wherein the definition of each substituent in general formula (I) is the same as defined in the description.

Description

Polysubstituted aryl derivatives and preparation methods and uses thereof Technical Field

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

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

[0003] Potassium ions are one of the body's major cations, playing a crucial role in maintaining cell membrane potential and influencing cell proliferation, activation, and apoptosis. The Kv1.3 channel is a member of the voltage-gated potassium channel (Kv) family, encoded by the KCNA3 gene, located on human chromosome 1p13.3. It is composed of four similar subunits, each of which consists of a main body composed of six transmembrane structural elements (S1-S6) and N- and C-termini connected to S1 and S6, respectively. The transmembrane structural elements (S1-S4) constitute the voltage-sensitive region of the channel, while the S5-S6 segments of the four subunits, along with the membrane-embedded S5-S6 connecting segment (P-loop), form the channel pore. Each S4 segment in the voltage-sensitive region contains a significant positive charge, which is essential for the channel's response to depolarizing voltages on the cell membrane.

[0004] Kv1.3 channels were first discovered in human T lymphocytes and are also expressed in the immune system, central nervous system, and vascular smooth muscle cells. Kv1.3 plays an important role in regulating resting membrane potential, cell apoptosis, cell volume regulation, and immune cell activation and proliferation. In T cells, cell membrane depolarization leads to Ca 2+ Activates calcium channels through calcium ion release (Ca 2+ release-activated Ca 2+ channel, CRAC) into the cell, leading to intracellular Ca 2+Increased concentrations depolarize the cell membrane, mediating the activation of downstream signaling pathways such as calmodulin and calmodulin within the cell, leading to increased expression of Kv1.3 on the cell membrane. This leads to an efflux of intracellular potassium ions, maintaining osmotic pressure balance within and outside the cell. This is essential for the transcription-dependent steps of T cell activation. The Kv1.3 potassium channel is crucial for sustained activation of effector T cells. In microglia, Kv1.3 participates in neuronal killing during the respiratory burst neuroinflammation. In dendritic cells, it participates, along with Kv1.5, in the secretion of inflammatory cytokines. Because of these key roles, Kv1.3 has been implicated in numerous autoimmune diseases, such as rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type 1 diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis, and chronic kidney disease.

[0005] Studies have shown that selectively inhibiting Kv1.3 channels can selectively inhibit the activation of effector T cells, providing new insights into the treatment of autoimmune diseases associated with effector T cells. Kv1.3 has therefore become a novel target protein for the treatment of autoimmune diseases. Furthermore, Kv1.3 is also involved in the body's neurotoxic effects and the development and progression of cancer. Abnormal expression of Kv1.3 has been detected in a variety of tumor cells, including breast cancer, prostate cancer, ovarian cancer, and microglia. Experiments have shown that inhibiting Kv1.3 activity can induce apoptosis in tumor cells. Therefore, drugs targeting Kv1.3 have important clinical value.

[0006] No new Kv1.3 inhibitors have been marketed. Currently, only two small molecule compounds, DES-7114 and YR-001, have entered Phase I clinical trials. Three peptide compounds are also in clinical trials, the most advanced of which is dalazatide, a peptide derived from sea anemone toxin, developed by Kv1.3 Therapeutics, currently in Phase II clinical trials. As a cutting-edge research area, Kv1.3 research still has significant room for exploration, and further research into its mechanism of action and the development of new inhibitors is crucial.

[0007] Summary of the Invention

[0008] In order to solve the above technical problems, the present invention provides a polysubstituted aryl derivative represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

[0009] in:

[0010] Ring A is selected from a 6- to 14-membered fused heterocyclic group, a 6- to 14-membered fused cycloalkyl group, a 6- to 10-membered heteroaryl group, or a 6- to 14-membered fused ring;

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

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

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

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

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

[0016] R A The same or different, each independently selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 、=O、-C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more groups selected from =O, -C 1-6 Alkylene-R B , halogen, hydroxyl, cyano, -NR 9 R 10 , alkoxy, aryl or heteroaryl substituents;

[0017] R B Selected from hydrogen, halogen, hydroxy, cyano, amino, alkoxy, -S(=O) r R 8 or -S(=O)(=NH)R 8 ; R 3 are the same or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group, a cycloalkyl group or an alkoxy group; wherein the alkyl group, the cycloalkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an amino group, an alkyl group or an alkoxy group;

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

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

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

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

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

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

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

[0025] Provided that: when ring A is selected from the following structures, the two R 3 The carbon atom to which it is connected does not form -C(=O)-: wherein, ring B is selected from a 5-6 membered heterocyclic group, and n1, n2, and n3 are each independently 0, 1, or 2.

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

[0027] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein X1, X2 and X3 are each independently selected from a hydrogen atom or a halogen.

[0028] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein X1 is selected from a hydrogen atom, and X2 and X3 together with the carbon atoms to which they are attached form a phenyl group.

[0029] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of formula (IIA), (IIB) or (IIC) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0030] Wherein: X3 is selected from hydrogen atom or halogen;

[0031] R 4 is selected from a hydrogen atom, a deuterium atom or a halogen;

[0032] Ring A, R 2 、R 3 and n are as defined in the general formula (I).

[0033] A preferred embodiment of the present invention is a compound of formula (I), (IIA), (IIB) or (IIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 A hydrogen atom.

[0034] A preferred embodiment of the present invention is a compound of formula (I) or (IIA) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0035] Among them: Ring A, R 2 、R 3 and n are as defined in the general formula (I).

[0036] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB) or (IIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from a 5-membered / 5-membered bicyclic fused heterocyclic group, a 5-membered / 6-membered bicyclic fused heterocyclic group, a 5-membered / 5-membered bicyclic fused cycloalkyl group or a 5-membered / 6-membered bicyclic fused cycloalkyl group.

[0037] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB) or (IIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the following groups:

[0038] in represents the connection site between Ring A and the benzene ring in Formula (I), (II), (IIA), (IIB) or (IIC); Indicates that ring A and R in general formula (I), (II), (IIA), (IIB) or (IIC) 2 connection site.

[0039] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB) or (IIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from an 8-10 membered bicyclic heteroaryl group.

[0040] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB) or (IIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the following groups:

[0041] in represents the connection site between Ring A and the benzene ring in Formula (I), (II), (IIA), (IIB) or (IIC); Indicates that ring A and R in general formula (I), (II), (IIA), (IIB) or (IIC) 2 connection site.

[0042] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB) or (IIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from an 8- to 10-membered bicyclic fused ring.

[0043] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB) or (IIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the following groups:

[0044] in represents the connection site between Ring A and the benzene ring in Formula (I), (II), (IIA), (IIB) or (IIC); Indicates that ring A and R in general formula (I), (II), (IIA), (IIB) or (IIC) 2 connection site.

[0045] A preferred embodiment of the present invention is a compound of formula (I), (IIA), (IIB) or (IIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0046] wherein X3 is selected from a hydrogen atom or chlorine;

[0047] R 4 is selected from hydrogen atom, deuterium atom, fluorine or chlorine; preferably hydrogen atom;

[0048] R 2 and R 3 The definition is as stated in claim 1.

[0049] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atom, -OR 5 、-C(=O)OR 5 、-C(=O)R 5 、-NR 6 R 7 、-C(=O)NR 6 R 7 、C 1-6 alkyl, 3-10 membered heterocyclic group, 3-6 membered cycloalkyl or 5-6 membered heteroaryl, wherein the C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-10 membered heterocyclic group or 5-6 membered heteroaryl group may be further substituted with one or more R A replaced by;

[0050] RA the same or different, each independently selected from -C(=O)R 8 、-C(=O)NR 9 R 10 , =O, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered heterocyclic group or 3-6 membered cycloalkyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered heterocyclyl or 3-6 membered cycloalkyl are optionally further substituted with one or more selected from =O, halogen, -NR 9 R 10 , hydroxyl, cyano, -C 1-6 Alkylene-R B 、C 1-6 substituted by an alkoxy or phenyl substituent;

[0051] R B Selected from hydrogen, halogen, hydroxy, cyano, amino, alkoxy, -S(=O) r R 8 or -S(=O)(=NH)R 8 ;

[0052] m is 1, 2, or 3;

[0053] r is 0, 1 or 2;

[0054] R 5 Each independently selected from a hydrogen atom, C 1-6 Alkyl or 3-10 membered heterocyclic group, wherein the C 1-6 The alkyl or 3-10 membered heterocyclic group is optionally further substituted by one or more radicals selected from =O, halogen, hydroxy, cyano, amino, C 1-6 Alkyl or C 1-6 substituted by an alkoxy substituent.

[0055] R 6 are each independently selected from a hydrogen atom;

[0056] R 7 Each independently selected from a hydrogen atom, C 1-6 Alkyl or 3-10 membered heterocyclic group, wherein the C 1-6 The alkyl group or the 3-10 membered heterocyclyl group is optionally further substituted with one or more substituents selected from =0, halogen, hydroxy, cyano, amino or 3-10 membered heterocyclyl.

[0057] R 8 Selected from C 1-6 Alkyl or 3-10 membered heterocyclic group, wherein the C 1-6The alkyl group or the 3-10 membered heterocyclyl group is optionally further substituted with one or more substituents selected from =0, halogen, hydroxy, cyano, amino or 3-10 membered heterocyclyl.

[0058] R 9 、R 10 are each independently selected from a hydrogen atom or a methyl group.

[0059] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the following groups:

[0060] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from the following groups: hydrogen atom, carboxyl group, amino group,

[0061] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 For hydrogen atoms, C 1-6 Alkyl or C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or amino.

[0062] Or, two R 3 Together with the carbon atom to which it is attached, it forms a -C(=O)-.

[0063] A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, a methyl group, a cyclopropyl group,

[0064] Or, two R 3 Together with the carbon atom to which it is attached, it forms a -C(=O)-.

[0065] In a preferred embodiment of the present invention, the compound described by the general formula is selected from:

[0066] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0067] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0068] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I) or (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0069] The present invention provides a compound of formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing a Kv1.3 inhibitor.

[0070] The present invention also provides a compound of general formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or its pharmaceutical composition for use in preparing a medicament for treating a disease mediated by Kv1.3, wherein the disease mediated by Kv1.3 is preferably an autoimmune disease; wherein the disease mediated by Kv1.3 is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis or chronic kidney disease.

[0071] The present invention further provides use of a compound of formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating cancer.

[0072] The present invention provides a compound of general formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preparing a medicament for treating rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis or chronic kidney disease.

[0073] Detailed Description of the Invention

[0074] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0075] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0076] "Alkylene" refers to a saturated C1-C 20 A straight-chain or branched aliphatic hydrocarbon group having a residue derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, preferably C1-C 10 Alkylene, more preferably C1-C6 alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. Alkylene groups may be substituted or unsubstituted. "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the ring atoms is a carbon atom, including 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" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.

[0077] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing 0, 1 or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into single spiro, double spiro or multiple spiroalkyl groups, preferably single spiro and double spiroalkyl groups, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0078] "Fused cycloalkyl" refers to a 4 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more rings may contain 0, 1 or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused cycloalkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetradecahydrophenanthrenyl,

[0079] "Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures, sharing two carbon atoms that are not directly connected to each other. One or more rings may contain 0, 1, or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6 to 14 members, and more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic, or tetracyclic group, and more preferably a bicyclic or tricyclic group. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r,5r)-bicyclo[3.3.2]decyl.

[0080] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring atoms is selected from nitrogen, oxygen, or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, including monocycles, polycycles, condensed rings, bridged rings and spirocycles, preferably having 3 to 7 membered monocycles or 4 to 18 membered bicyclic or tricyclic rings, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "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, hexahydropyrimidine,

[0081] The heterocyclic group may be substituted or unsubstituted.

[0082] "Spiro heterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, which may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spiroalkyl is divided into monospiro heterocyclic group, dispiro heterocyclic group or polyspiro heterocyclic group, preferably monospiro heterocyclic group and dispiro heterocyclic group, more preferably 3 yuan / 6 yuan, 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan, 5 yuan / 6 yuan or 6 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0083] "Fused heterocyclic group" refers to a polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain zero, one or more double bonds, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r(wherein r is selected from 0, 1 or 2) heteroatom, the remaining ring atoms are carbon, preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin,

[0084] "Bridged heterocyclic group" refers to a polycyclic group of 5 to 18 members, containing two or more ring structures, sharing two atoms that are not directly connected to each other, one or more rings may contain 0, 1 or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl,

[0085] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0086] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridinyl, pyridinyl- 2(1H)-one, pyrimidinyl, pyrazin-2(1H)-one, pyrimidin-4(3H)-one, pyrimidin-2(1H)-one, pyridazin-3(2H)-one, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furo[3,2-b]pyridinyl, furo[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl,

[0087] Heteroaryl groups can be substituted or unsubstituted.

[0088] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, wherein at least one ring has a completely conjugated π-electron aromatic system, and at the same time, one or more rings may contain 0, 1 or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system, wherein the ring atoms are selected from 0, 1 or more nitrogen, oxygen or S(O) r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclyl or monocyclic cycloalkyl group, preferably 6 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include but are not limited to:

[0089] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0090] "Nitro" refers to a -NO2 group.

[0091] "Hydroxy" refers to an -OH group.

[0092] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0093] "Amino" refers to -NH2.

[0094] "Cyano" refers to -CN.

[0095] "Benzyl" refers to -CH2-phenyl.

[0096] "Carboxyl" refers to -C(=O)OH.

[0097] "Carboxylate" refers to a -C(=O)O-alkyl group or a -C(=O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0098] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0099] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0100] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0101] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0102] "DMSO" refers to dimethyl sulfoxide.

[0103] "BOC" refers to tert-butoxycarbonyl.

[0104] "Bn" refers to benzyl.

[0105] "THP" refers to 2-tetrahydropyranyl.

[0106] "TFA" refers to trifluoroacetic acid.

[0107] “FA” stands for formic acid.

[0108] "Ts" refers to p-toluenesulfonyl.

[0109] "Bn" refers to benzyl.

[0110] "SEM" refers to (trimethylsilyl)ethoxymethyl.

[0111] "Leaving group", or leaving group, is an atom or functional group that breaks away from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that easily accept electrons and have a strong ability to withstand negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break away from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to bind to other atoms, and the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, methylsulfonyl, -OTs or -OH.

[0112] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (such as olefinic) bond. "Substituted" or "substituted" as described in this specification, unless otherwise specified, means that the group can be substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, halocycloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylate, =O, OR 5 、OC(=O)R 5 、-C(=O)R 5 、-C(=O)OR 5 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 7 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-S(=O) r NR 6 R 7 or -S(=O) r R 5 substituted by a substituent;

[0113] R 5Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 Substituted by a substituent; R 6 and R 7 Each independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent;

[0114] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group contains one or more N, O or S(O)r, and the 3-12 membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent;

[0115] R 8 、R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0116] r is independently 0, 1 or 2.

[0117] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0118] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0119] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0120] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0121] Synthesis method of the compound of the present invention

[0122] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0123] The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, the method comprising:

[0124] The compound of formula (Ia) is coupled with the compound of formula (Ib), and optionally further subjected to a deprotection reaction to obtain the compound of formula (I)

[0125] in:

[0126] Y is selected from halogen;

[0127] W is selected from boric acid or

[0128] PG is selected from hydroxyl protecting groups, preferably methyl or -SEM;

[0129] R 1 selected from hydrogen atoms;

[0130] X1, X2, X3, R 2 、R 3 、R 4 and n are as defined in the general formula (I). DETAILED DESCRIPTION

[0131] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0132] Example

[0133] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0134] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0135] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0136] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0137] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise indicated. Commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0138] CD3OD: deuterated methanol.

[0139] CDCl3: deuterated chloroform.

[0140] DMSO-d6: deuterated dimethyl sulfoxide.

[0141] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1 L.

[0142] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0143] The compound was purified using silica gel column chromatography and reverse phase column chromatography, with the eluent system selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; and D: aqueous trifluoroacetic acid and acetonitrile. The volume ratio of the solvents varied depending on the polarity of the compound and could be adjusted by adding a small amount of an acidic or alkaline reagent, such as acetic acid or triethylamine.

[0144] Example 1

[0145] 3,4-dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0146] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0147] first step

[0148] 3-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methoxy-3,4-dihydro-2H-pyrrole

[0149] 3-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methoxy-3,4-dihydro-2H-pyrrole

[0150] 4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidin-2-one 1a (300 mg, 797.13 μmol, prepared according to WO2021183994) was added to dichloromethane (3 mL). Trimethyloxonium tetrafluoroborate (117.90 mg, 797.13 μmol) was added under ice-cooling conditions, and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methoxy-3,4-dihydro-2H-pyrrole 1b (300 mg), which was used directly in the next reaction.

[0151] MS m / z(ESI):390.1[M+1]

[0152] Step 2

[0153] 4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidin-2-imine

[0154] 4-(2,3-Dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidin-2-imine

[0155] 3-(2,3-Dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-5-methoxy-3,4-dihydro-2H-pyrrole 1b (200 mg, 512.33 μmol) was added to amine methanol (3 mL), heated to 60°C for 16 hours, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column: Waters 3767 Column: SunFire Sunfire C18, 19*250 mm, 10 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidine-2-imine 1c (130 mg) in a yield of 67.6%.

[0156] MS m / z(ESI):375.1[M+1]

[0157] Step 3

[0158] 1-(4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-iminopyrrolidin-1-yl)-4-hydroxybutan-2-one

[0159] 1-(4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-iminopyrrolidin-1-yl)-4-hydroxybutan-2-one

[0160] 1-Bromo-4-hydroxybutan-2-one 1d (69.40 mg, 415.60 μmol, commercially available) was dissolved in acetonitrile (2 mL), and sodium carbonate (73.42 mg, 692.66 μmol) and 4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidin-2-imine 1c (130 mg, 346.33 μmol) were added. The mixture was heated to 60°C for 6 h. After the reaction was complete after mass spectrometry detection, the product was filtered and concentrated under reduced pressure. The residue was subjected to preparative liquid separation (separation column: Waters 3767 Column: SunFire Sunfire C18, 19*250 mm, 10 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 1-(4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-iminopyrrolidin-1-yl)-4-hydroxybutan-2-one 1e (20 mg) in a yield of 12.5%.

[0161] MS m / z(ESI):461.1[M+1]

[0162] Step 4

[0163] 2-(6-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)ethan-1-ol

[0164] 2-(6-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)ethan-1-ol

[0165] 1-(4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-iminopyrrolidin-1-yl)-4-hydroxybutan-2-one 1e (20 mg, 43.34 μmol) was added to anhydrous ethanol (2 mL), sealed and heated at 150°C for 2 hours, and concentrated under reduced pressure to obtain 2-(6-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)ethan-1-ol 1f (30 mg), which was used directly in the next reaction.

[0166] MS m / z(ESI):443.4[M+1]

[0167] Step 5

[0168] 3,4-dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0169] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol

[0170] 2-(6-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-2-yl)ethan-1-ol 1f (6 mg, 13.53 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was added dropwise. The reaction was carried out at room temperature for 16 hours. After concentration, preparative liquid separation (separation column: Waters 3767 Column: SunFire Sunfire C18, 19*250 mm, 10 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) was performed to obtain 3,4-dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 1 (2.6 mg) in a yield of 57.1%.

[0171] MS m / z(ESI):313.0[M+1]

[0172] Example 2 and Example 3

[0173] (R)-3,4-dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 2

[0174] (S)-3,4-dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 3

[0175] (R)-3,4-dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 2

[0176] (S)-3,4-dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 3

[0177] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-6-yl)phenol 1 (210 mg, 673.08 μmol) was chirally resolved by SFC (system: Waters SFC 150, separation column: Column volume: 250*25mm 10μm, mobile phase A: supercritical CO2, mobile phase B: MeOH + 0.1% 7.0mol / L NH3H2O ​​in MeOH, detection wavelength: 214nm, flow rate: 120mL / min, column temperature: RT, column pressure: 100bar) After purification, a single configuration compound (shorter retention time) and a single configuration compound (longer retention time) were obtained.

[0178] Single configuration compound (shorter retention time):

[0179] MS m / z(ESI):313.2[M+1]

[0180] 99 mg; retention time: 0.918 min, chiral purity: 99.9% ee.

[0181] 1 H NMR (400MHz, DMSO-d6) δ10.42(s,1H),7.37(d,J=8.8Hz,1H),6.84(d,J=8.8Hz,1H),6.79(s,1H),4.80-4.69 (m,1H),4.61-5.55(m,1H),4.22-4.05(m,2H),3.64-3.58(m,2H),3.03-2.94(m,2H),2.59(t,J=7.2Hz,2H).

[0182] Single configuration compound (longer retention time):

[0183] MS m / z(ESI):313.2[M+1]

[0184] 78 mg; retention time: 1.471 minutes, chiral purity: 99.2% ee.

[0185] 1 H NMR (400MHz, DMSO-d6) δ10.49(s,1H),7.39(d,J=8.8Hz,1H),6.92(s,1H),6.86(d,J=8.8Hz,1H),4.86–4.73(m, 1H),4.26-4.19(m,1H),4.13-4.05(m,1H),3.61(t,J=7.2Hz,2H),3.06(d,J=7.6Hz,2H),2.63(t,J=7.2Hz,2H).

[0186] Example 4

[0187] 3,4-dichloro-2-(2-(2-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)phenol

[0188] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)phenol

[0189] first step

[0190] 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0191] 2-(7-Bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0192] 1-Bromo-4-hydroxybutan-2-one 1d (723.95 mg, 4.33 mmol), 4-bromopyridin-2-amine 4a (500 mg, 2.89 mmol, commercially available), and sodium bicarbonate (485.58 mg, 5.78 mmol) were dissolved in ethanol (10 mL), and the reaction mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluent: System B) to afford 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4b (380 mg) in a 54.54% yield.

[0193] MS m / z(ESI):240.8[M+1]

[0194] Step 2

[0195] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0196] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0197] 2-(7-Bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4b (360 mg, 1.49 mmol), (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (494.67 mg, 2.24 mmol, commercially available), cesium carbonate (973.06 mg, 2.99 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (109.16 mg, 149.33 μmol) were dissolved in dioxane (10 mL) and water (1 mL) and stirred at 100°C for 12 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: System B) to give 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4d (230 mg) in a yield of 45.68%.

[0198] MS m / z(ESI):337.1[M+1]

[0199] Step 3

[0200] 2-(7-(2,3-dichloro-6-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0201] 2-(7-(2,3-dichloro-6-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0202] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4d (120 mg, 355.87 μmol) was dissolved in acetic acid (2 mL) and ethyl acetate (2 mL). Platinum dioxide (80.78 mg, 355.87 μmol) was then added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to provide 2-(7-(2,3-dichloro-6-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4e (100 mg) in an 82.35% yield.

[0203] MS m / z(ESI):341.2[M+1]

[0204] Step 4

[0205] 3,4-dichloro-2-(2-(2-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)phenol

[0206] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)phenol

[0207] Dissolve 2-(7-(2,3-dichloro-6-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4e (110 mg, 322.36 μmol) in dichloromethane (1 mL), cool to -78°C, and add boron tribromide (2 mL). Incubate the mixture on ice for 1 hour. Methanol (2 mL) was added to the reaction solution to quench the reaction, and the reaction solution was concentrated. The residue was separated by preparative liquid phase separation (separation column: Waters 3767 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-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-7-yl)phenol 4 (4.45 mg) with a yield of 4.22%.

[0208] MS m / z(ESI):327.0[M+1]

[0209] 1 H NMR (400MHz, MeOD) δ7.26(d,J=8.8Hz,1H),6.92(s,1H),6.76(d,J=8.8Hz,1H),4.21-4.14(m,1H),4.07-3.94( m,2H),3.77(t,J=6.4Hz,2H),3.64-3.55(m,1H),2.97-2.87(m,2H),2.76(t,J=6.4Hz,2H),2.04-1.98(m,1H).

[0210] Example 5

[0211] 3,4-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0212] 3,4-Dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0213] 2-(7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4d (70 mg, 207.59 μmol) was dissolved in dichloromethane (1 mL), cooled to -78°C, and then boron tribromide (2 mL) was added. The reaction was allowed to react in an ice bath for 1 hour. Methanol (2 mL) was added to the reaction solution to quench the reaction. The reaction solution was concentrated, and the resulting residue was separated by preparative liquid phase separation (Waters 3767 SunFire C18 column, 19*250 mm, 10 μm, 20 mL / min; mobile phase A: 0.1% FA + H2O, mobile phase B: CH3CN) to afford 3,4-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 5 (20.15 mg) in a 30.04% yield.

[0214] MS m / z(ESI):323.0[M+1]

[0215] 1 H NMR (400MHz, MeOD) δ8.63(d,J=8.0Hz,1H),7.94(s,1H),7.62(s,1H),7.44(d,J=8.8Hz,1H),7.20 -7.13(m,1H),6.92(d,J=8.8Hz,1H),3.93(t,J=6.4Hz,2H),3.06(t,J=6.4Hz,2H).

[0216] Example 6

[0217] 3,4-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-6-yl)phenol

[0218] 3,4-Dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-6-yl)phenol

[0219] first step

[0220] 2-(6-bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0221] 2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0222] 5-Bromopyridin-2-amine 6a (1.0 g, 5.78 mmol) was dissolved in ethanol (10 mL), and 1-bromo-4-hydroxybutan-2-one 1d (1.45 g, 8.67 mmol) and sodium bicarbonate (971.16 mg, 11.56 mmol) were added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated under reduced pressure, and the pH was adjusted to 8-9 by adding 10% aqueous sodium bicarbonate. The mixture was extracted with n-butanol (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 2-(6-bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 6b (717 mg) in a yield of 51.45%.

[0223] MS m / z(ESI):241.0[M+1]

[0224] Step 2

[0225] 2-(6-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0226] 2-(6-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0227] 2-(6-Bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 6b (667 mg, 2.77 mmol) was dissolved in 1,4-dioxane (10 mL) and water (1 mL). (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (916.51 mg, 4.15 mmol), cesium carbonate (1.80 g, 5.53 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (202.44 mg, 276.67 μmol) were added to the reaction mixture. The atmosphere was replaced with nitrogen 3 to 5 times, and the reaction mixture was stirred at 100 °C under nitrogen for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (eluent: System B) to give 2-(6-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 6c (253 mg) in a yield of 27.12%.

[0228] MS m / z(ESI):337.0[M+1]

[0229] Step 3

[0230] 3,4-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-6-yl)phenol

[0231] 3,4-Dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-6-yl)phenol

[0232] 2-(6-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 6c (50 mg, 148.28 μmol) was dissolved in dichloromethane (1 mL). The reaction solution was cooled to -78°C. Boron tribromide (0.5 mL) was slowly added to the reaction mixture and stirred at 0°C for 1 hour. The reaction solution was quenched by adding methanol (2 mL) at -78°C, and aqueous ammonia was added to adjust the pH to 7-8. The mixed solution was concentrated under reduced pressure, and the residue was purified by preparative liquid separation (separation column: Waters 3767 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-hydroxyethyl)imidazo[1,2-a]pyridin-6-yl)phenol 6 (21.3 mg) with a yield of 44.45%.

[0233] MS m / z(ESI):323.1[M+1]

[0234] 1 H NMR (400MHz, MeOD) δ8.48(s,1H),7.85(s,1H),7.68(d,J=9.2Hz,1H),7.45(dd,J=9.2,1.6Hz,1 H),7.42(d,J=8.8Hz,1H),6.91(d,J=8.8Hz,1H),3.93(t,J=6.4Hz,2H),3.04(t,J=6.4Hz,2H).

[0235] Example 7

[0236] 3,4-dichloro-2-(2-(2-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)phenol

[0237] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)phenol

[0238] first step

[0239] 2-(6-(2,3-dichloro-6-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0240] 2-(6-(2,3-dichloro-6-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0241] 2-(6-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 6c (170 mg, 504.15 μmol) was dissolved in ethyl acetate (4 mL) and acetic acid (4 mL). Platinum dioxide (28.62 mg, 126.04 μmol) was added, and the mixture was stirred at 30°C under a hydrogen atmosphere for 12 hours. The reaction solution was diluted with ethyl acetate (15 mL), filtered, and the filtrate was concentrated under reduced pressure to provide 2-(6-(2,3-dichloro-6-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 7a (172 mg) in a yield of 99.98%.

[0242] MS m / z(ESI):341.1[M+1]

[0243] Step 2

[0244] 3,4-dichloro-2-(2-(2-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)phenol

[0245] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)phenol

[0246] 2-(6-(2,3-Dichloro-6-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 7a (120 mg, 175.83 μmol) was dissolved in dichloromethane (3 mL). The reaction solution was cooled to -78 °C. Boron tribromide (1.5 mL) was slowly added to the reaction mixture and stirred at 0 °C for 1 hour. The reaction solution was quenched with methanol (2 mL) at -78 ° C., the pH was adjusted to 7-8 with aqueous ammonia, and the mixed solution was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column: Waters 3767 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-hydroxyethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)phenol 7 (5.02 mg) with a yield of 8.73%.

[0247] MS m / z(ESI):327.0[M+1]

[0248] 1 H NMR(400MHz,MeOD)δ7.19(d,J=8.8Hz,1H),6.96(s,1H),6.69(d,J=8.8Hz,1H),4.61(t,J=11.6Hz,2H),4.08-3.9 5(m,2H),3.70(t,J=6.4Hz,2H),3.09-2.98(m,1H),2.95-2.84(m,1H),2.84-2.75(m,1H),2.72(t,J=6.4Hz,2H).

[0249] Example 8

[0250] 3,4-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-b]pyridazin-6-yl)phenol

[0251] 3,4-Dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-b]pyridazin-6-yl)phenol

[0252] first step

[0253] 2-(6-bromoimidazo[1,2-b]pyridazin-2-yl)ethan-1-ol

[0254] 2-(6-Bromoimidazo[1,2-b]pyridazin-2-yl)ethan-1-ol

[0255] 6-Bromopyridazin-3-amine 8a (500 mg, 2.87 mmol) and 1-bromo-4-hydroxybutan-2-one 1d (719.84 mg, 4.31 mmol) were dissolved in ethanol (10 mL), followed by the addition of sodium bicarbonate (482.82 mg, 5.75 mmol), and the mixture was stirred at 80°C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure, and the resulting residue was purified by column chromatography (eluent: System B) to afford 2-(6-bromoimidazo[1,2-b]pyridazin-2-yl)ethan-1-ol 8b (500 mg) in a yield of 77.18%.

[0256] MS m / z(ESI):242.0[M+1]

[0257] Step 2

[0258] 2-(6-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl)ethan-1-ol

[0259] 2-(6-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl)ethan-1-ol

[0260] 2-(6-Bromoimidazo[1,2-b]pyridazin-2-yl)ethan-1-ol 8b (0.85 g, 3.51 mmol), (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (930.56 mg, 4.21 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (256.93 mg, 351.13 μmol) and cesium carbonate (3.43 g, 10.53 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL) and reacted at 100°C for 16 hours. The reaction mixture was filtered and concentrated, and the residue was separated and purified by column chromatography (eluent: System B) to give 2-(6-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl)ethan-1-ol 8c (0.345 g) in a yield of 29.05%.

[0261] MS m / z(ESI):338.0[M+1]

[0262] Step 3

[0263] 3,4-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-b]pyridazin-6-yl)phenol

[0264] 3,4-Dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-b]pyridazin-6-yl)phenol

[0265] 2-(6-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-b]pyridazin-2-yl)ethan-1-ol 8c (345 mg, 1.02 mmol) was dissolved in dichloromethane (5 mL), cooled to -78°C, and then boron tribromide (2 mL) was added. The reaction was allowed to react on ice for 1 hour. The reaction solution was quenched with methanol (2 mL) at -78°C and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (Waters 3767 Column: SunFire Sunfire C18, 19*250 mm, 10 μm, 20 mL / min; Mobile phase A: 0.1% FA + H2O, Mobile phase B: CH3CN) to afford 3,4-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-b]pyridazin-6-yl)phenol 8 (5.1 mg) in an 8.79% yield.

[0266] MS m / z(ESI):324.0[M+1]

[0267] 1 H NMR (400MHz, MeOD) δ8.08-7.99(m,2H),7.48(d,J=8.8Hz,1H),7.26(d,J=9.6Hz,1H),6.93(d,J=8.8Hz,1H),3.94(t,J=6.4Hz,2H),3.06(t,J=6.4Hz,2H).

[0268] Example 9

[0269] 3-chloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0270] 3-Chloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0271] first step

[0272] 2-(7-(2-chloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0273] 2-(7-(2-chloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0274] 2-(7-Bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4b (200 mg, 829.59 μmol), 2-(2-chloro-6-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 9a (268 mg, 995.50 μmol), cesium carbonate (811 mg, 2.49 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (61 mg, 82.96 μmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL). The mixture was sealed under nitrogen and heated to 100°C with stirring overnight. The reaction solution was concentrated under reduced pressure, water (20 mL) was added, and the aqueous phase was extracted with ethyl acetate (20 mL × 3). The obtained organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (eluent: System B) to give 2-(7-(2-chloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 9b (107 mg) in a yield of 42.60%.

[0275] MS m / z(ESI):302.7[M+1].

[0276] Step 2

[0277] 3-chloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0278] 3-Chloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0279] 2-(7-(2-chloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 9b (50 mg, 165.15 μmol) was added to dichloromethane (1 mL), cooled to -78°C, and boron tribromide (0.5 mL) was slowly added. The mixture was stirred for 1 hour. The reaction mixture was quenched with methanol (2 mL) at -78°C and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (Waters 3767 SunFire C18 column, 19*250 mm, 10 μm, 20 mL / min; mobile phase A: 0.1% FA + H2O, mobile phase B: CH3CN) to afford chloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 9 (7.03 mg) in a 14.74% yield.

[0280] MS m / z(ESI):289.2[M+1].

[0281] 1H NMR(400MHz,MeOD)δ8.49(d,J=6.8Hz,1H),7.81(s,1H),7.50(s,1H),7.22(t,J=8.0Hz,1H ),7.04–6.99(m,2H),6.89(d,J=8.0Hz,1H),3.92(t,J=6.4Hz,2H),3.02(t,J=6.4Hz,2H).

[0282] Example 10

[0283] 7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid

[0284] 7-(2,3-Dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid

[0285] first step

[0286] ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[0287] Ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[0288] (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (295.45 mg, 1.34 mmol) and ethyl 7-bromoimidazo[1,2-A]pyridine-2-carboxylate 10a (300 mg, 1.11 mmol, commercially available) were dissolved in 1,4-dioxane (4 mL) and water (1 mL). Sodium carbonate (236.33 mg, 2.23 mmol) and tetrakis(triphenylphosphine)palladium (128.83 mg, 111.49 μmol) were added, and the mixture was heated to 100 °C under argon protection for 18 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3) and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (eluent: System A) to give ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 10b (320 mg) in a yield of 78.59%.

[0289] MS m / z(ESI):365.1[M+1]

[0290] Step 2

[0291] 7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid

[0292] 7-(2,3-Dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid

[0293] Ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 10b (230 mg, 629.77 μmol) was dissolved in dichloromethane (2 mL), cooled to 0°C, and boron tribromide (315.54 mg, 1.26 mmol) was added dropwise. The mixture was allowed to react slowly at room temperature for 18 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 3) and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 10 (20 mg) in a 9.34% yield.

[0294] MS m / z(ESI):323.1[M+1]

[0295] 1H NMR (400MHz, DMSO-d6) δ10.60(brs,1H),9.22(brs,2H),8.82(s,1H),7.91(d,J=9.3Hz,1H),7.65(d,J=9.2Hz,1H),7.55(d,J=8.9Hz ,1H),7.05(d,J=8.9Hz,1H),3.82(p,J=7.9Hz,1H),3.75–3.63(m,1H),3.48–3.28(m,3H),2.49–2.38(m,1H),2.25–2.13(m,1H)ppm.

[0296] Example 11

[0297] 3,4-dichloro-2-(2-(hydroxymethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0298] 3,4-Dichloro-2-(2-(hydroxymethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0299] 7-(2,3-Dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 10 (60 mg, 185.68 μmol) was added to tetrahydrofuran (2.00 mL), cooled to 0°C, and borane tetrahydrofuran complex (557.05 μmol, 557.05 μL, 1 M) was added dropwise. The mixture was heated to 60°C and reacted for 3 hours. After the reaction, ice water was added to quench the reaction, and the reaction solution was concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 3,4-dichloro-2-(2-(hydroxymethyl)imidazo[1,2-a]pyridin-7-yl)phenol 11 (8.36 mg) with a yield of 13.40%.

[0300] MS m / z(ESI):309.1[M+1]

[0301] 1H NMR (400MHz, DMSO-d6) δ10.60(brs,1H),9.22(brs,2H),8.82(s,1H),7.91(d,J=9.3Hz,1H),7.65(d,J=9.2Hz,1H),7.55(d,J=8.9Hz ,1H),7.05(d,J=8.9Hz,1H),3.82(p,J=7.9Hz,1H),3.75–3.63(m,1H),3.48–3.28(m,3H),2.49–2.38(m,1H),2.25–2.13(m,1H)ppm.

[0302] Example 12

[0303] phenol

[0304] phenol

[0305] first step

[0306] benzyl 3-(chlorocarbonyl)pyrrolidine-1-carboxylate

[0307] Benzyl 3-(chlorocarbonyl)pyrrolidine-1-carboxylate

[0308] 1-(Benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid 12a (1.5 g, 6.02 mmol, commercially available) was added to dichloromethane (14.66 mL). Oxalyl chloride (1.53 g, 12.04 mmol, 1.02 mL) was added dropwise under an ice bath, followed by one drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure to afford benzyl 3-(chlorocarbonyl)pyrrolidine-1-carboxylate 12b, which was used directly in the next step.

[0309] Step 2

[0310] benzyl 3-(2-diazoacetyl)pyrrolidine-1-carboxylate

[0311] Benzyl 3-(2-diazoacetyl)pyrrolidine-1-carboxylate

[0312] Benzyl 3-(chlorocarbonyl)pyrrolidine-1-carboxylate 12b (1.6 g, 5.98 mmol) was added to a mixed solution of tetrahydrofuran (10 mL) and acetonitrile (10 mL). Trimethylsilylated diazomethane (2 M, 11.95 mL) was added dropwise at -20°C. The mixture was stirred at -10°C for 2 h to obtain benzyl 3-(2-diazoacetyl)pyrrolidine-1-carboxylate 12c, which was used directly in the next step.

[0313] Step 3

[0314] benzyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate

[0315] Benzyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate

[0316] To a solution of benzyl 3-(2-diazoacetyl)pyrrolidine-1-carboxylate 12c (1.62 g, 5.93 mmol) in tetrahydrofuran (10 mL) and acetonitrile (10 mL) was added dropwise an aqueous solution of hydrogen bromide (11.99 g, 59.28 mmol, 10 mL, 40% purity) and stirred at room temperature for 2 hours. After the reaction was complete, water (50 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 (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and dried. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford benzyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 12d (1.42 g) in a yield of 73.44%.

[0317] Step 4

[0318] benzyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

[0319] Benzyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

[0320] 4-Bromopyridin-2-amine 4a (500 mg, 2.89 mmol), benzyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate 12d (1.13 g, 3.47 mmol), and sodium bicarbonate (728.37 mg, 8.67 mmol) were added to acetonitrile (8 mL) and toluene (8 mL) and stirred at 80°C for 18 hours. After the reaction was complete, the reaction mixture was filtered to remove insoluble matter and purified by silica gel column chromatography (eluent: System A) to obtain benzyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate 12e (506 mg) in a 43.74% yield. MS m / z (ESI): 399.8 [M+1]

[0321] Step 5

[0322] benzyl

[0323] 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

[0324] Benzyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate

[0325] (2,3-Dichloro-6-methoxy-phenyl)boronic acid 4c (150 mg, 679.21 μmol), benzyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate 12e (271.87 mg, 679.21 μmol), cesium carbonate (442.60 mg, 1.36 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (49.70 mg, 67.92 μmol) were added to 1,4-dioxane (1 mL). The air was replaced with nitrogen, and the reaction was stirred at 80°C for 18 hours. The insoluble matter was removed by filtration and the residue was purified by silica gel column chromatography (eluent: System A) to give benzyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate 12f (256 mg) in a yield of 75.93%.

[0326] MS m / z(ESI):495.8[M+1]

[0327] Step 6

[0328] 3,4-dichloro-2-(2-(pyrrolidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0329] 3,4-Dichloro-2-(2-(pyrrolidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0330] Benzyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylate 12f (256 mg, 515.73 μmol) was added to dichloromethane (2 mL), and boron tribromide (515.73 mg, 2.06 mmol) was added dropwise under ice-cooling. The mixture was slowly heated to room temperature and stirred for 6 hours. After the reaction was complete, the solvent was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give 3,4-dichloro-2-(2-(pyrrolidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol 12 (84 mg) in a yield of 34.61%.

[0331] MS m / z(ESI):347.8[M+1]

[0332] 1 H NMR (400MHz, DMSO-d6) δ10.60(brs,1H),9.22(brs,2H),8.82(s,1H),7.91(d,J=9.3Hz,1H),7.65(d,J=9.2Hz,1H),7.55(d,J=8.9Hz ,1H),7.05(d,J=8.9Hz,1H),3.82(p,J=7.9Hz,1H),3.75–3.63(m,1H),3.48–3.28(m,3H),2.49–2.38(m,1H),2.25–2.13(m,1H)ppm.

[0333] Example 13

[0334] 2-(2-(2-aminoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0335] 2-(2-(2-aminoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0336] first step

[0337] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethyl methanesulfonate

[0338] Ethyl 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanesulfonate

[0339] 2-(7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4d (28 mg, 83.04 μmol) was dissolved in dichloromethane (5 mL), and methanesulfonyl chloride (19.02 mg, 166.07 μmol, 12.85 μL) and triethylamine (16.80 mg, 166.07 μmol, 23.15 μL) were added and reacted at room temperature for 18 hours. Water (15 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: System B) to give ethyl 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanesulfonate 13a (34 mg) in a yield of 98.60%.

[0340] MS m / z(ESI):414.7[M+1]

[0341] Step 2

[0342] 2-(2-azidoethyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[0343] 2-(2-Azidoethyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[0344] Ethyl 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanesulfonate 13a (90 mg, 216.72 μmol) was dissolved in N,N-dimethylformamide (5 mL) and sodium azide (42.27 mg, 650.15 μmol) was added. The mixture was heated to 80°C for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 2-(2-azidoethyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 13b (65 mg) in an 82.81% yield.

[0345] MS m / z(ESI):361.8[M+1]

[0346] Step 3

[0347] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-amine

[0348] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-amine

[0349] 2-(2-Azidoethyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 13b (65 mg, 179.45 μmol) was dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (109.22 mg, 358.91 μmol) was added. The mixture was heated to 60°C for 6 hours. The reaction solution was concentrated, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-amine 13c (25 mg) in a 41.44% yield.

[0350] MS m / z(ESI):335.8[M+1]

[0351] Step 4

[0352] 2-(2-(2-aminoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0353] 2-(2-(2-aminoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0354] 2-(7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-amine 13c (25 mg, 74.36 μmol) was dissolved in dichloromethane (5 mL) and boron tribromide (186.28 mg, 743.57 μmol) was added. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was quenched with methanol and concentrated. The resulting residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to afford 2-(2-(2-aminoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 13 (10 mg) in a 30.21% yield.

[0355] MS m / z(ESI):321.8[M+1]

[0356] 1 H NMR (400MHz, DMSO-d6) δ10.55(brs,1H),8.76(d,J=7.0Hz,1H),8.07(s,1H),7.96(brs,3H),7.70(s,1H),7. 53(d,J=8.9Hz,1H),7.12(d,J=7.0Hz,1H),7.02(d,J=8.8Hz,1H),3.30–3.18(m,2H),3.16–3.07(m,2H)ppm.

[0357] Example 14

[0358] 3,4-dichloro-2-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-7-yl)pheno

[0359] 3,4-Dichloro-2-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0360] first step

[0361] 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one

[0362] 2-Bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one

[0363] 1-(1-Methyl-1H-pyrazol-4-yl)ethanone 14a (1 g, 8.06 mmol) was dissolved in dichloromethane (2 mL) and ethanol (0.5 mL), and pyridinium tribromide (4.25 g, 8.86 mmol) was added. After stirring at room temperature for 2 hours, the mixture was quenched by addition of saturated sodium bisulfite solution. Extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one 14b (1.05 g, 5.17 mmol) in a yield of 64.20%.

[0364] MS m / z(ESI):203.1[M+1].

[0365] Step 2

[0366] 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine

[0367] 7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine

[0368] 4-Bromopyridin-2-amine 4a (1.47 g, 8.51 mmol) and 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one 14b (1.92 g, 9.45 mmol) were added to acetonitrile (5 mL) and toluene (5 mL). Sodium bicarbonate (1.59 g, 18.91 mmol) was added, and the mixture was heated to 90°C for 18 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine 14c (1.5 g, 5.41 mmol) in a 57.26% yield.

[0369] MS m / z(ESI):277.2[M+1]

[0370] Step 3

[0371] 7-(2,3-dichloro-6-methoxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine

[0372] 7-(2,3-Dichloro-6-methoxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine

[0373] (2,3-Dichloro-6-methoxy-phenyl)boronic acid 4c (145.42 mg, 658.45 μmol) and 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine 14c (200.72 mg, 724.29 μmol) were added to 1,4-dioxane (2 mL) and water (0.5 mL), and cesium carbonate (429.07 mg, 1.32 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (48.18 mg, 65.84 μmol) were added. The mixture was heated to 100 °C under argon protection and reacted for 4 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: System A) to give 7-(2,3-dichloro-6-methoxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine 14d (200 mg) in a yield of 81.38%.

[0374] MS m / z(ESI):373.1[M+1]

[0375] Step 4

[0376] 3,4-dichloro-2-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0377] 3,4-Dichloro-2-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0378] 7-(2,3-Dichloro-6-methoxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine 14d (200 mg, 535.85 μmol) was added to dichloromethane (1 mL), cooled to 0°C, and boron tribromide (268.48 mg, 1.07 mmol) was slowly added dropwise. The mixture was slowly brought to room temperature and reacted for 2 hours. The reaction mixture was quenched with ice water and concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 3,4-dichloro-2-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-7-yl)phenol 14 (35 mg) in a yield of 17.99%.

[0379] MS m / z(ESI):359.1[M+1]

[0380] 1 H NMR (400MHz, DMSO-d6) δ10.41(s,1H),8.76(d,J=6.9Hz,1H),8.33(s,1H),8.26(s,1H),7.98(s,1H) ,7.69(s,1H),7.53(d,J=8.9Hz,1H),7.14(d,J=6.9Hz,1H),7.01(d,J=8.9Hz,1H),3.93(s,3H)ppm.

[0381] Example 15

[0382] (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperazin-1-yl)methanone

[0383] (7-(2,3-Dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperazin-1-yl)methanone

[0384] first step

[0385] ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate

[0386] Ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate

[0387] 4-Bromopyridin-2-amine 4a (1 g, 5.78 mmol), ethyl 3-bromo-2-oxopropionate 15a (5.64 g, 28.90 mmol, 3.63 mL, commercially available), and sodium carbonate (1.84 g, 17.34 mmol) were added to ethanol (10 mL), sealed, and stirred at 80°C for 4 hours. Water (30 mL) was added to the reaction solution, and extraction with ethyl acetate (30 mL x 3) was performed. The combined organic phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate 15b (700 mg) in a 45.01% yield.

[0388] MS m / z(ESI):268.9[M+1]

[0389] Step 2

[0390] 7-bromoimidazo[1,2-a]pyridine-2-carboxylic acid

[0391] 7-Bromoimidazo[1,2-a]pyridine-2-carboxylic acid

[0392] Ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate 15b (420 mg, 1.56 mmol) was dissolved in methanol (10 mL), and lithium hydroxide monohydrate (654.91 mg, 15.61 mmol) and water (2 mL) were added. The mixture was allowed to react at room temperature for 3 hours. The reaction mixture was concentrated, acidified with dilute hydrochloric acid, and then concentrated. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 7-bromoimidazo[1,2-a]pyridine-2-carboxylic acid 15c (376 mg) in a 99.94% yield.

[0393] MS m / z(ESI):240.9[M+1]

[0394] Step 3

[0395] tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate

[0396] tert-Butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate

[0397] 7-Bromoimidazo[1,2-a]pyridine-2-carboxylic acid 15c (170 mg, 705.27 μmol), tert-butyl piperazine-1-carboxylate 15d (144.49 mg, 775.80 μmol, commercially available) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (536.33 mg, 1.41 mmol) were dissolved in N,N-dimethylformamide (3 mL) and N,N-diisopropylethylamine (273.45 mg, 2.12 mmol, 368.53 μL) was added, and the mixture was reacted at room temperature for 0.5 h. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate 15e (280 mg) in a yield of 97.00%.

[0398] MS m / z(ESI):408.9[M+1]

[0399] Step 4

[0400] tert-butyl

[0401] 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate

[0402] tert-Butyl 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate

[0403] To the mixture of (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (120 mg, 543.37 μmol), tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate 15e (222.39 mg, 543.37 μmol), potassium carbonate (225.30 mg, 1.63 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (39.76 mg, 54.34 μmol) were added 1,4-dioxane (10 mL) and water (1 mL). The mixture was purged with argon at 110°C and heated for 4 h. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate 15f (220 mg) in a yield of 80.11%.

[0404] MS m / z(ESI):505.1[M+1]

[0405] Step 5

[0406] (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperazin-1-yl)methanone

[0407] (7-(2,3-Dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperazin-1-yl)methanone

[0408] Tert-butyl 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate 15f (50 mg, 98.93 μmol) was dissolved in dichloromethane (5 mL) and boron tribromide (247.85 mg, 989.33 μmol) was added and reacted at room temperature for 18 hours. The reaction was quenched with methanol in an ice-water bath and concentrated under reduced pressure. The residue was separated and purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperazin-1-yl)methanone 15 (30 mg) in a yield of 59.41%.

[0409] MS m / z(ESI):390.8[M+1]

[0410] 1 H NMR(400MHz, DMSO-d6)δ10.32(s,1H),8.86(brs,2H),8.63(d,J=7.0Hz,1H),8.46(s,1H),7.55–7.46( m,2H),7.03–6.95(m,1H),6.90(dd,J=7.0,1.6Hz,1H),4.53(brs,2H),3.85(brs,2H),3.22(s,4H)ppm.

[0411] Example 16

[0412] 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0413] 3,4-Dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0414] first step

[0415] 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol

[0416] 2-(7-Bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol

[0417] Ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate 15b (1 g, 3.72 mmol) was added to tetrahydrofuran (10 mL). Methylmagnesium bromide (3 M, 2.48 mL) was added dropwise under ice-cooling, and the mixture was warmed to room temperature and stirred for 2 hours. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol 16a (238 mg) in a 25.10% yield.

[0418] MS m / z(ESI):255.0[M+1]

[0419] Step 2

[0420] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)propan-2-ol

[0421] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)propan-2-ol

[0422] (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (103.88 mg, 470.38 μmol), 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol 16a (100 mg, 391.99 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (57.36 mg, 78.40 μmol), and cesium carbonate (383.15 mg, 1.18 mmol) were added to 1,4-dioxane (2 mL) and water (0.3 mL). The air was replaced with nitrogen, and the reaction was stirred at 80°C for 5 hours. After the reaction was complete, the sample was directly mixed and purified by silica gel column chromatography (eluent: System A) to give 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)propan-2-ol 16b (120 mg) in a yield of 87.16%.

[0423] MS m / z(ESI):351.0[M+1]

[0424] Step 3

[0425] 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0426] 3,4-Dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0427] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)propan-2-ol 16b (120 mg, 341.66 μmol) was added to dichloromethane (4 mL). Boron tribromide (341.66 mg, 1.37 mmol) was added dropwise under ice-cooling and stirred for 3 hours. The mixture was quenched with water (1 mL) and concentrated under reduced pressure. The resulting residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to afford 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol 16 (71.4 mg) in a 58.84% yield.

[0428] MS m / z(ESI):337.0[M+1]

[0429] 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.86(s,1H),8.20(s,1H),7.76(s,1H) ,7.57(d,J=8.9Hz,1H),7.38(s,1H),7.02(d,J=8.9Hz,1H),1.59(s,6H)ppm.

[0430] Example 17

[0431] 3,4-dichloro-2-(2-(2-hydroxyethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol

[0432] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol

[0433] first step

[0434] methyl 4-bromo-3-oxopentanoate

[0435] Methyl 4-bromo-3-oxopentanoate

[0436] To a stirred solution of methyl 3-oxopentanoate 17a (500 mg, 3.84 mmol, 482.16 μL, commercially available) in dichloromethane (10 mL) at 0°C under a nitrogen atmosphere was added dropwise bromine (920.97 mg, 5.76 mmol, 295.18 μL). The resulting mixture was stirred at 25°C under a nitrogen atmosphere for 15 hours. The reaction was quenched with aqueous sodium carbonate solution, and the mixture was stirred at 25°C for 15 minutes and extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with saturated sodium chloride solution (1 × 50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 4-bromo-3-oxopentanoate 17b (240 mg) in a 29.88% yield.

[0437] MS m / z(ESI):208.8[M+1]

[0438] Step 2

[0439] methyl 2-(7-bromo-3-methylimidazo[1,2-a]pyridin-2-yl)acetate

[0440] Methyl 2-(7-bromo-3-methylimidazo[1,2-a]pyridin-2-yl)acetate

[0441] To a solution of 4-bromopyridin-2-amine 4a (500 mg, 2.89 mmol) in tert-butyl alcohol (25 mL) was added methyl 4-bromo-3-oxopentanoate 17b (1.81 g, 8.67 mmol). The resulting mixture was heated to 80°C in a microwave oven under a nitrogen atmosphere for 1 hour. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 2-(7-bromo-3-methylimidazo[1,2-a]pyridin-2-yl)acetate 17c (358 mg) in a 43.75% yield.

[0442] MS m / z(ESI):282.8[M+1]

[0443] Step 3

[0444] methyl 2-(7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetate

[0445] Methyl 2-(7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetate

[0446] Methyl 2-(7-bromo-3-methylimidazo[1,2-a]pyridin-2-yl)acetate 17c (348 mg, 1.23 mmol) and (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (271.45 mg, 1.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (79.37 mg, 122.92 μmol), and potassium phosphate (782.74 mg, 3.69 mmol) were dissolved in 1,4-dioxane (15 mL) and water (3 mL) and stirred at 80°C under a nitrogen atmosphere for 3 hours. The mixture was cooled to room temperature and diluted with water. The resulting mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel column chromatography (eluent: System A) to give methyl 2-(7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetate 17d (246 mg) in a yield of 52.77%.

[0447] MS m / z(ESI):378.8[M+1]

[0448] Step 4

[0449] 2-(7-(2,3-dichloro-6-hydroxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetic acid

[0450] 2-(7-(2,3-dichloro-6-hydroxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetic acid

[0451] Methyl 2-(7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetate 17d (216.00 mg, 569.57 μmol) was dissolved in an aqueous solution of hydrogen bromide (48%, 20 mL) and stirred at 100°C for 12 hours. The mixture was concentrated in vacuo to afford 2-(7-(2,3-dichloro-6-hydroxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetic acid 17e (200 mg), which was used directly in the next step.

[0452] MS m / z(ESI):351.0[M+1]

[0453] Step 5

[0454] 3,4-dichloro-2-(2-(2-hydroxyethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol

[0455] 3,4-Dichloro-2-(2-(2-hydroxyethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol

[0456] To a stirred solution of 2-(7-(2,3-dichloro-6-hydroxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)acetic acid 17e (240 mg, 683.40 μmol) in tetrahydrofuran (10 mL) was added dropwise borane tetrahydrofuran complex (1 M, 587.32 mg, 6.83 mmol, 5 mL) at 0°C, and the resulting mixture was stirred at 70°C for 5 hours. The mixture was quenched with methanol at 0°C and concentrated under reduced pressure. The resulting residue was separated and purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H₂O, mobile phase B: CH₃CN) to afford 3,4-dichloro-2-(2-(2-hydroxyethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol 17 (85 mg) in a 34.57% yield. MS m / z (ESI): 337.0 [M+1].

[0457] 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),8.86(s,1H),8.20(s,1H),7.76(s,1H) ,7.57(d,J=8.9Hz,1H),7.38(s,1H),7.02(d,J=8.9Hz,1H),1.59(s,6H)ppm.

[0458] Example 18

[0459] 2-(2-(azetidin-3-ylmethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0460] 2-(2-(azetidin-3-ylmethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0461] first step

[0462] tert-butyl 3-(3-(dimethyl(oxo)-λ 6-sulfaneylidene)-2-oxopropyl)azetidine-1-carboxylate

[0463] 3-(3-(dimethyl(oxo)-λ 6 tert-Butyl (sulfamethoxy)-2-oxopropyl)azetidine-1-carboxylate

[0464] To a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid 18a (2 g, 9.29 mmol) in tetrahydrofuran (20 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (5.30 g, 13.94 mmol) and triethylamine (2.82 g, 27.88 mmol) at room temperature, and the mixture was stirred at 25°C for 16 hours. To a solution of trimethylsulfoxide chloride (3.59 g, 27.88 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1 M, 27.88 mL) at room temperature, and the reaction mixture was stirred at 60°C for 2 hours. After the reaction was complete, the mixture was cooled to 0°C, and the active ester solution obtained above was added dropwise. After the addition was complete, the reaction mixture was stirred at 25°C for 1 hour. After the reaction was completed, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL × 3), and the combined organic phase was washed with saturated sodium chloride solution (150 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: A system) to obtain 3-(3-(dimethyl(oxo)-λ 6 tert-Butyl (2-(2-(2-(2-((2-((2-((2-sulfamidesulfoxide)-2-oxopropyl)azetidine-1-carboxylate) 18b) (1 g)) was added in a 37.19% yield.

[0465] MS m / z(ESI):290.2[M+1]

[0466] Step 2

[0467] tert-butyl 3-(3-bromo-2-oxopropyl)azetidine-1-carboxylate

[0468] tert-Butyl 3-(3-bromo-2-oxopropyl)azetidine-1-carboxylate

[0469] At 0 ° C, 3-(3-(dimethyl(oxy)-λ 6To a solution of tert-butyl 3-(3-bromo-2-oxopropyl)azetidine-1-carboxylate 18b (700 mg, 2.42 mmol) in tetrahydrofuran (10 mL) was added lithium bromide (252.10 mg, 2.90 mmol), and the mixture was stirred at 0°C for 30 minutes. Methanesulfonic acid (255.73 mg, 2.66 mmol) was then added dropwise to the mixture, and the reaction mixture was stirred at 50°C for 16 hours. After completion of the reaction, the reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent: System B) to afford tert-butyl 3-(3-bromo-2-oxopropyl)azetidine-1-carboxylate 18c (150 mg) in a yield of 21.22%.

[0470] MS m / z(ESI):236.0[M-55]

[0471] Step 3

[0472] tert-butyl 3-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylate

[0473] tert-Butyl 3-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylate

[0474] To a solution of tert-butyl 3-(3-bromo-2-oxopropyl)azetidine-1-carboxylate 18c (150 mg, 513.40 μmol) in ethanol (5 mL) were added 4-bromopyridin-2-amine 4a (88.82 mg, 513.40 μmol) and sodium bicarbonate (86.26 mg, 1.03 mmol), and the reaction mixture was stirred at 80°C for 16 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the resulting residue was purified by column chromatography (eluent: System B) to afford tert-butyl 3-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylate 18d (100 mg) in a yield of 53.18%.

[0475] MS m / z(ESI):366.0[M+1]

[0476] Step 4

[0477] tert-butyl

[0478] 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylate

[0479] tert-Butyl 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylate

[0480] Tert-butyl 3-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylate 18d (70 mg, 191.13 μmol) was dissolved in 1,4-dioxane (4 mL) and water (0.4 mL). Bistriphenylphosphine palladium dichloride (13.98 mg, 19.11 μmol), cesium carbonate (124.54 mg, 382.25 μmol) and (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (63.31 mg, 286.69 μmol) were added, and the reaction mixture was stirred at 110 °C under nitrogen for 2 h. After the reaction was complete, the solvent was removed under reduced pressure, and the resulting residue was separated and purified by column chromatography (eluent: System B) to give tert-butyl 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylate 18e (100 mg) in a yield of 75.44%.

[0481] MS m / z(ESI):462.0[M+1]

[0482] Step 5

[0483] 2-(2-(azetidin-3-ylmethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0484] 2-(2-(azetidin-3-ylmethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0485] Tert-butyl 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylate 18e (80 mg, 173.02 μmol) was dissolved in dichloromethane (2 mL), cooled to -78°C, and boron tribromide (0.4 mL) was added dropwise. After the addition was completed, the mixture was heated to 0°C and reacted for 10 minutes. After the reaction was completed, the reaction solution was quenched with methanol (2 mL) at -78°C, and aqueous ammonia was added to adjust the pH to 8-9. The solvent was removed under reduced pressure, and the excess salt was removed by beating with dichloromethane. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.1% formic acid + water, mobile phase B: acetonitrile) to obtain 2-(2-(azetidin-3-ylmethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 18 (25 mg) with a yield of 41.49%.

[0486] MS m / z(ESI):348.0[M+1]

[0487] 1 H NMR (400MHz, DMSO-d6) δ8.49(d,J=6.8Hz,1H),8.42(s,1H),7.77(s,1H),7.45(d,J =8.9Hz,1H),7.31(s,1H),6.99(d,J=8.9Hz,1H),6.72(dd,J=6.9,1.6Hz,1H),3.91 (t,J=8.7Hz,2H),3.74–3.65(m,2H),3.21–3.07(m,1H),3.00(d,J=7.5Hz,2H)ppm.

[0488] Example 19

[0489] 3,4-dichloro-2-(2-(2,5-dihydro-1H-pyrrol-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0490] 3,4-Dichloro-2-(2-(2,5-dihydro-1H-pyrrol-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0491] first step

[0492] ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate

[0493] Ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate

[0494] Ethyl 2-bromoacetate (16.68 g, 99.88 mmol, 11.08 mL) and 4-bromopyridin-2-amine 4a (2.88 g, 16.65 mmol) were mixed and reacted at room temperature for 8 hours. The mixture was filtered and washed with isopropyl ether to obtain ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate 19a (4.31 g), which was used in the next step without further purification.

[0495] MS m / z(ESI):259.0[M+1]

[0496] Step 2

[0497] 2,7-dibromoimidazo[1,2-a]pyridine

[0498] 2,7-Dibromoimidazo[1,2-a]pyridine

[0499] Ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate 19a (4.31 g, 16.63 mmol) and phosphorus oxybromide (23.84 g, 83.17 mmol) were mixed and reacted at 120°C for 3 hours. The mixture was cooled to room temperature, ice water (20 mL) was added, and the pH of the reaction mixture was adjusted to 7-8 with aqueous ammonia at 0°C. The mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent: System B) to afford 2,7-dibromoimidazo[1,2-a]pyridine 19b (850 mg) in an 18.52% yield.

[0500] MS m / z(ESI):274.9[M+1]

[0501] Step 3

[0502] 2-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[0503] 2-Bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[0504] (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (400.19 mg, 1.81 mmol), 2,7-dibromoimidazo[1,2-a]pyridine 19b (500 mg, 1.81 mmol), potassium carbonate (751.34 mg, 5.44 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (132.59 mg, 181.21 μmol) were mixed, and dioxane (50 mL) and water (5 mL) were added. After argon replacement at 100°C, the mixture was heated in a modular manner for 18 hours. The reaction solution was directly concentrated, and the resulting residue was separated and purified by column chromatography (eluent: System B) to give 2-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 19c (350 mg) in a yield of 51.92%. MS m / z(ESI):371.9[M+3]

[0505] Step 4

[0506] tert-butyl

[0507] 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0508] tert-Butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate

[0509] 2-Bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 19c (150 mg, 403.18 μmol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 19d (119.01 mg, 403.18 μmol, commercially available), and sodium carbonate (128.20 mg, 1.21 mmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (32.68 mg, 40.32 μmol) was added under nitrogen, and the atmosphere was purged with nitrogen three times. The reaction mixture was stirred at 110°C under nitrogen for 18 hours. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by column chromatography (eluent: System A) to give tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 19e (70 mg) in a yield of 37.71%.

[0510] MS m / z(ESI):460.1[M+1]

[0511] Step 5

[0512] 3,4-dichloro-2-(2-(2,5-dihydro-1H-pyrrol-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0513] 3,4-Dichloro-2-(2-(2,5-dihydro-1H-pyrrol-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0514] Tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 19e (60 mg, 130.34 μmol) was dissolved in dichloromethane (1.5 mL). Boron tribromide (0.3 mL) was then added dropwise at -78°C. After the addition was complete, the reaction mixture was stirred at 0°C for 30 minutes. After the reaction was complete, methanol was added at -78°C to quench the reaction, and the pH was adjusted to 8 with aqueous ammonia. 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 separation (Separation column Sunfire C18; 19*250mm, 10um, 20ml / min; mobile phase A: 10mmol / LA:0.1% formic acid / water, mobile phase B: acetonitrile) to obtain 3,4-dichloro-2-(2-(2,5-dihydro-1H-pyrrol-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol 19 (13.07mg) with a yield of 28.97%.

[0515] MS m / z(ESI):346.1[M+1]

[0516] 1 H NMR (400MHz, DMSO-d6)δ8.52 (dd, J=7.0, 1.0Hz, 1H), 8.31 (s, 1H), 8.06 (s, 1H), 7.47 (d, J=8.8Hz, 1H), 7. 39(s,1H), 6.98(d,J=8.9Hz,1H), 6.76(dd,J=7.0,1.7Hz,1H), 6.39(s,1H), 4.11(s,2H), 3.93(s,2H) ppm.

[0517] According to the synthesis method of Example 19 of the present invention, Examples 22, 28, 31, 68 and 84 were synthesized, and their structures and characterization data are shown in the following table:

[0518] Example 20

[0519] 1-((7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperazin-2-one

[0520] 1-((7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperazin-2-one

[0521] first step

[0522] (7-bromoimidazo[1,2-a]pyridin-2-yl)methanol

[0523] (7-Bromoimidazo[1,2-a]pyridin-2-yl)methanol

[0524] Ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate 15b (500 mg, 1.86 mmol) was added to tetrahydrofuran (4 mL), and lithium borohydride (121.41 mg, 5.57 mmol) was added dropwise at 0°C. The reaction was allowed to react for 3 hours. The mixture was diluted with methanol and purified by column chromatography (eluent: System B) to afford (7-bromoimidazo[1,2-a]pyridin-2-yl)methanol 20a (360 mg) in an 85.33% yield. MS m / z (ESI): 227.0 [M+1].

[0525] Step 2

[0526] 7-bromo-2-(bromomethyl)imidazo[1,2-a]pyridine

[0527] 7-Bromo-2-(bromomethyl)imidazo[1,2-a]pyridine

[0528] (7-Bromoimidazo[1,2-a]pyridin-2-yl)methanol 20a (360 mg, 1.59 mmol) was added to dichloromethane (5 mL), and phosphorus tribromide (1.29 g, 4.76 mmol, 447.06 μL) was added dropwise. The mixture was allowed to react at 0°C for 3 hours. The reaction was quenched with water and extracted with dichloromethane / isopropanol (3:1) (30 mL x 3). The combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and dried to dryness. The residue was purified by silica gel column chromatography (eluent: System B) to afford 7-bromo-2-(bromomethyl)imidazo[1,2-a]pyridine 20b (250 mg) in a 54.38% yield.

[0529] MS m / z(ESI):288.8[M+1]

[0530] Step 3

[0531] tert-butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylate

[0532] tert-Butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylate

[0533] tert-Butyl 3-oxopiperazine-1-carboxylate 20c (124.30 mg, 620.79 μmol) was added to tetrahydrofuran (1 mL), and sodium hydride (31.04 mg, 775.98 μmol, 60% purity) was added. The mixture was reacted in an ice bath for 30 min. 7-Bromo-2-(bromomethyl)imidazo[1,2-a]pyridine 20b (150 mg, 517.32 μmol) was added and the mixture was heated to 70 °C for 18 h. The mixture was quenched with ice water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylate 20d (140 mg) in a yield of 66.12%.

[0534] MS m / z(ESI):409.1[M+1]

[0535] Step 4

[0536] tert-butyl

[0537] 4-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylate

[0538] tert-Butyl 4-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylate

[0539] Tert-butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylate 20d (40 mg, 97.73 μmol) was added to water (0.5 mL) and 1,4-dioxane (2 mL), followed by (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (21.58 mg, 97.73 μmol), potassium phosphate (62.24 mg, 293.20 μmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.94 mg, 9.77 μmol). The mixture was heated to 80 °C and reacted for 6 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylate 20e (30 mg) in a 60.74% yield. MS m / z (ESI): 505.2 [M+1].

[0540] Step 5

[0541] 1-((7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperazin-2-one

[0542] 1-((7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperazin-2-one

[0543] Tert-butyl 4-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylate 20e (20 mg, 39.57 μmol) was added to dichloromethane (0.5 mL), and a 1 M solution of boron tribromide in dichloromethane (0.5 mL) was added dropwise. The mixture was allowed to react at room temperature for 2 hours. The reaction was quenched with methanol, and the residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.1% formic acid in water, mobile phase B: acetonitrile) to afford 1-((7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperazin-2-one 20 (10 mg) in a 48.21% yield.

[0544] MS m / z(ESI):391.1[M+1]

[0545] 1 H NMR (400MHz, DMSO-d6) δ10.50(brs,1H),9.33(brs,2H),8.79(d,J=7.0Hz,1H),8.20(s,1H),7.73(s,1H),7.54(d,J=8. 9Hz,1H),7.26–7.15(m,1H),7.01(d,J=8.9Hz,1H),4.79(s,2H),3.82(s,2H),3.68–3.57(m,2H),3.49–3.37(m,2H)ppm.

[0546] According to the synthesis method of Example 20 of the present invention, Examples 32, 63, 77, 81, 82, 83 and 87 were synthesized, and their structures and characterization data are shown in the following table:

[0547] Example 23

[0548] 3,4-dichloro-2-(2-(octahydrocyclopenta[c]pyrrol-5-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0549] 3,4-Dichloro-2-(2-(octahydrocyclopenta[c]pyrrol-5-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0550] first step

[0551] tert-butyl

[0552] 5-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0553] tert-Butyl 5-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0554] 2-Bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 19c (200 mg, 537.57 μmol) and tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 23a (180.22 mg, 537.57 μmol, prepared according to patent publication WO2013021054) were dissolved in 1,4-dioxane (10 mL) and water (2 mL). [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10 mg, 537.57 μmol) and sodium carbonate (170.93 mg, 1.61 mmol) were added, and the reaction mixture was stirred at 110 °C under nitrogen for 2 h. After completion of the reaction, the product was concentrated, and the resulting residue was purified by column chromatography (eluent: System A) to afford tert-butyl 5-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 23b (120 mg) in a 44.61% yield. MS m / z (ESI): 500.1 [M+1].

[0555] Step 2

[0556] tert-butyl

[0557] 5-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)hexahydrocyclopenta[c]pyrrole- 2(1H)-carboxylate

[0558] tert-Butyl 5-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate

[0559] To a solution of tert-butyl 5-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 23b (82 mg, 163.86 μmol) in ethanol (3 mL) was added platinum dioxide (30 mg, 163.86 μmol). The reaction was stirred under hydrogen (30 psi) at room temperature for 18 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with ethanol, and the combined filtrates were concentrated under reduced pressure to afford tert-butyl 5-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 23c (73 mg) in 89.64% yield, which was used directly in the next step. MS m / z(ESI):502.1[M+1]

[0560] Step 3

[0561] 3,4-dichloro-2-(2-(octahydrocyclopenta[c]pyrrol-5-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0562] 3,4-Dichloro-2-(2-(octahydrocyclopenta[c]pyrrol-5-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0563] To a solution of tert-butyl 5-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 23c (70 mg, 139.32 μmol) in dichloromethane (2 mL) at -78°C was added boron tribromide (100 mg, 0.4 mmol). The reaction mixture was then stirred at 0°C for 10 minutes. Upon completion of the reaction, methanol was added at -78°C to quench the reaction, 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 resulting residue was purified by preparative liquid separation (Waters 2767 / Qda column: SunFire C18[UNK]19×250mm[UNK]10um mobile phase A: 0.1% formic acid / water, B: acetonitrile; flow rate: 20 mL / min) to obtain 3,4-dichloro-2-(2-(octahydrocyclopenta[c]pyrrol-5-yl)imidazo[1,2-a]pyridin-7-yl)phenol 23 (21.47 mg) in a yield of 39.69%.

[0564] MS m / z(ESI):388.1[M+1]

[0565] 1H NMR (400MHz, DMSO-d6) δ9.65(brs,1H),8.52(d,J=7.0Hz,1H),8.19(s,1H),7.76(s,1H),7.48(d,J=8.9Hz,1H),7.33(s,1H),6.98(d,J=8. 9Hz,1H),6.72(dd,J=6.9,1.5Hz,1H),3.29–3.18(m,4H),3.18–3.10(m,2H),2.98–2.85(m,3H),2.37–2.24(m,3H),1.79–1.65(m,2H)ppm.

[0566] Example 25

[0567] 3,4-dichloro-2-(2-(piperidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0568] 3,4-Dichloro-2-(2-(piperidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0569] first step

[0570] tert-butyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate

[0571] tert-Butyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate

[0572] 4-Bromopyridin-2-amine 4a (160 mg, 24.80 μmol) was added to isopropanol (3 mL), followed by tert-butyl 3-(2-bromoacetyl)piperidine-1-carboxylate 25a (424.75 mg, 1.39 mmol, prepared according to patent publication WO2011025690). The mixture was heated to 100°C for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: System B) to afford tert-butyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate 25b (200 mg) in a 56.87% yield.

[0573] MS m / z(ESI):380.1[M+1]

[0574] Step 2

[0575] tert-butyl

[0576] 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate

[0577] tert-Butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate

[0578] Tert-butyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate 25b (40 mg, 105.19 μmol) was added to a mixed solution of 1,4-dioxane (2 mL) and water (0.5 mL), and (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (25.55 mg, 115.70 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (8.54 mg, 10.52 μmol), and potassium phosphate (66.98 mg, 315.56 μmol) were added, and the mixture was heated to 80 °C for 2 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: System B) to give tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate 25c (30 mg) in a yield of 59.87%.

[0579] MS m / z(ESI):476.1[M+1]

[0580] Step 3

[0581] 3,4-dichloro-2-(2-(piperidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0582] 3,4-Dichloro-2-(2-(piperidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[0583] To a solution of tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate 25c (30 mg, 62.97 μmol) in dichloromethane (0.5 mL) was added boron tribromide in dichloromethane (0.5 mL) and allowed to react at room temperature for 2 hours. The mixture was quenched with methanol and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (Waters 3767 / QDA column: SunFire C18, 19*250 mm, 10 μm; mobile phase A: 10 mmol / L A: 0.1% formic acid / water, mobile phase B: acetonitrile; flow rate: 20 mL / min) to afford 3,4-dichloro-2-(2-(piperidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol 25 (10 mg) in a 31.01% yield.

[0584] MS m / z(ESI):362.1[M+1]

[0585] 1 H NMR(400MHz,DMSO-d6)δ10.49(s,1H),9.11–8.56(m,3H),8.26–8.04(m,1H), 7.86–7.62(m,1H),7.54(dd,J=8.9,1.6Hz,1H),7.29–7.05(m,1H),7.01(dd,J =8.9,2.0Hz,1H),3.66–3.50(m,1H),3.44–3.23(m,2H),3.22–3.07(m,1H),3. 05–2.86(m,1H),2.25–2.04(m,1H),2.03–1.87(m,1H),1.87–1.71(m,2H)ppm.

[0586] According to the synthesis method of Example 25 of the present invention, Example 27, Example 93 and Example 94 were synthesized, and their structures and characterization data are shown in the following table:

[0587] Example 26

[0588] (3,8-diazabicyclo[3.2.1]octan-3-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone

[0589] (3,8-Diazabicyclo[3.2.1]octan-3-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone

[0590] first step

[0591] tert-butyl

[0592] 3-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0593] tert-Butyl 3-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0594] To the mixture of tert-butyl 3-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 15c (50 mg, 207.43 μmol), tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate 26a (44.04 mg, 207.43 μmol, commercially available), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (236.62 mg, 622.30 μmol) were added N,N-dimethylformamide (4.82 mL) and N,N-diisopropylethylamine (134.04 mg, 1.04 mmol, 180.65 μL), and the mixture was reacted at room temperature for 18 h. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 3), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: System B) to give tert-butyl 3-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 26b (62 mg) in a yield of 68.66%.

[0595] MS m / z(ESI):434.7[M+1]

[0596] Step 2

[0597] tert-butyl

[0598] 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0599] tert-Butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

[0600] To the mixture of tert-butyl 3-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 26b (62 mg, 142.43 μmol), (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (31.45 mg, 142.43 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (10.42 mg, 14.24 μmol) and potassium carbonate (59.05 mg, 427.28 μmol) were added 1,4-dioxane (10 mL) and water (1 mL). After argon replacement, the mixture was heated in an oil bath at 100°C for 4 h. The reaction solution was directly concentrated and separated by silica gel column chromatography (eluent: System B) to give tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 26c (60 mg) in a yield of 79.27%.

[0601] MS m / z(ESI):530.7[M+1]

[0602] Step 3 (3,8-diazabicyclo[3.2.1]octan-3-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone

[0603] (3,8-Diazabicyclo[3.2.1]octan-3-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone

[0604] Tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate 26c (60 mg, 112.90 μmol) was dissolved in dichloromethane (10 mL) and boron tribromide (1 M, 1.13 mL) was added, and the mixture was reacted at room temperature for 18 hours. The reaction solution was quenched with methanol and concentrated under reduced pressure. The residue was purified by preparative liquid separation (Waters 3767 / QDA column: SunFire C18, 19*250 mm, 10 um; mobile phase A: 10 mmol / LA:0.1% formic acid / water, B: acetonitrile; flow rate: 20 ml / min) to give (3,8-diazabicyclo[3.2.1]octan-3-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone 26 (35 mg) in a yield of 58.35%.

[0605] MS m / z(ESI):416.7[M+1]

[0606] 1 H NMR (400MHz, DMSO-d6) δ10.35(s,1H),9.26–9.10(m,1H),9.03(s,1H),8.63(d,J=7.0Hz,1H),8.47(s,1H),7.57–7.43(m,2H),6.99(d,J=8.8Hz,1 H),6.91(dd,J=7.0,1.7Hz,1H),5.35–5.11(m,1H),4.59–4.34(m,1H),4 .13(s,2H),3.71–3.51(m,1H),3.31–3.13(m,1H),2.05–1.69(m,4H)ppm.

[0607] Example 29

[0608] (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperidin-4-yl)methanone

[0609] (7-(2,3-Dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperidin-4-yl)methanone

[0610] first step

[0611] tert-butyl 4-(2-tosylhydrazineylidene)piperidine-1-carboxylate

[0612] tert-Butyl 4-(2-toluenesulfonylhydrazide)piperidine-1-carboxylate

[0613] Dissolve tert-butyl 4-oxopiperidine-1-carboxylate 29a (1.0 g, 5.02 mmol, commercially available) and p-toluenesulfonylhydrazide (934.68 mg, 5.02 mmol) in methanol (50 mL) and allow to react at room temperature for 18 hours. The reaction mixture was concentrated to afford tert-butyl 4-(2-toluenesulfonylhydrazide)piperidine-1-carboxylate 29b (1.84 g), which was used directly in the next step.

[0614] MS m / z(ESI):368.2[M+1]

[0615] Step 2

[0616] tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate

[0617] tert-Butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate

[0618] 7-Bromoimidazo[1,2-a]pyridine-2-carboxaldehyde 29c (779 mg, 3.46 mmol, prepared by the known method "Organic Chemistry Frontiers (2019), 6(13), 2234-2239"), tert-butyl 4-(2-toluenesulfonylhydrazide)piperidine-1-carboxylate 29b (1.27 g, 3.46 mmol) and cesium carbonate (3.38 g, 10.38 mmol) were mixed and dimethyl sulfoxide (5 mL) was added, and the mixture was reacted at 110°C for 2 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: System B) to obtain tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate 29d (583 mg) in a yield of 41.25%. MS m / z (ESI): 408.1 [M+1].

[0619] Step 3

[0620] tert-butyl

[0621] 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate

[0622] tert-Butyl 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate

[0623] To a mixture of (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (54.09 mg, 244.92 μmol), tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate 29d (100 mg, 244.92 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (17.92 mg, 24.49 μmol) and potassium carbonate (101.55 mg, 734.77 μmol) was added 1,4-dioxane (10 mL) and water (1 mL). After argon replacement, the reaction was carried out at 100°C for 4 hours. The reaction solution was directly concentrated, and the residue was separated by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate 29e (80 mg) in a yield of 64.76%.

[0624] MS m / z(ESI):504.2[M+1]

[0625] Step 4

[0626] (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperidin-4-yl)methanone

[0627] (7-(2,3-Dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperidin-4-yl)methanone

[0628] Tert-butyl 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate 29e (80 mg, 158.60 μmol) was dissolved in dichloromethane (10 mL) and added with boron tribromide (1 M, 1.59 mL) under ice-water cooling. The mixture was allowed to react at room temperature for 18 hours. After completion, the reaction was quenched with methanol and concentrated to afford (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperidin-4-yl)methanone 29 (55 mg) in a 67.39% yield.

[0629] MS m / z(ESI):390.0[M+1]

[0630] 1 H NMR (400MHz, DMSO-d6) δ10.38(s,1H),8.68(brs,1H),8.63(d,J=7.1Hz,1H),8.60(s,1H),8.39(brs,1H),7.55(s,1H),7.50(d,J=8.8Hz,1H),7.00 (d,J=8.9Hz,1H),6.92(dd,J=7.0,1.7Hz,1H),3.94–3.81(m,1H),3.43–3 .32(m,2H),3.20–3.01(m,2H),2.17–2.02(m,2H),1.89–1.71(m,2H)ppm.

[0631] Example 30

[0632] 2-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-(piperazin-1-yl)ethan-1-one

[0633] 2-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-(piperazin-1-yl)ethan-1-one

[0634] first step

[0635] 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)acetic acid

[0636] 2-(7-Bromoimidazo[1,2-a]pyridin-2-yl)acetic acid

[0637] To a stirred solution of ethyl 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)acetate 13b (1 g, 3.53 mmol) in methanol (20 mL) was added lithium hydroxide monohydrate (741.03 mg, 17.66 mmol) at 0°C. The resulting mixture was stirred at 25°C for 1 hour. The resulting mixture was acidified with aqueous hydrochloric acid (1 M) to a pH ≤ 5. The reaction solution was concentrated under reduced pressure to afford ethyl 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)acetate 30a (1.5 g), which was used directly in the next step.

[0638] MS m / z(ESI):254.8[M+1]

[0639] Step 2

[0640] tert-butyl 4-(2-(7-bromoimidazo[1,2-a]pyridin-2-yl)acetyl)piperazine-1-carboxylate

[0641] tert-Butyl 4-(2-(7-bromoimidazo[1,2-a]pyridin-2-yl)acetyl)piperazine-1-carboxylate

[0642] 2-(7-Bromoimidazo[1,2-a]pyridin-2-yl)acetic acid 30a (800 mg, 3.14 mmol) and tert-butyl piperazine-1-carboxylate 15d (1.17 g, 6.27 mmol) were added to dichloromethane (20 mL) along with 1-hydroxybenzotriazole (635.69 mg, 4.70 mmol), N,N-diisopropylethylamine (1.22 g, 9.41 mmol, 1.64 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (901.88 mg, 4.70 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 18 hours. The resulting mixture was acidified with aqueous hydrochloric acid (1 M) to pH ≤ 7. The mixture was diluted with water (30 mL) and extracted with dichloromethane (3 × 30 mL). The combined organic layers were washed with aqueous sodium bicarbonate (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 4-(2-(7-bromoimidazo[1,2-a]pyridin-2-yl)acetyl)piperazine-1-carboxylate 30b (150 mg) in an 11.30% yield.

[0643] MS m / z(ESI):423.1[M+1]

[0644] Step 3

[0645] tert-butyl

[0646] 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)acetyl)piperazine-1-carboxylate

[0647] tert-Butyl 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)acetyl)piperazine-1-carboxylate

[0648] Tert-butyl 4-(2-(7-bromoimidazo[1,2-a]pyridin-2-yl)acetyl)piperazine-1-carboxylate 30b (110 mg, 259.86 μmol), (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (64.49 mg, 311.83 μmol), [1,1'-bis(di-tert-butylphosphino)ferrocene]palladium dichloride (16.78 mg, 25.99 μmol), and potassium phosphate (165.48 mg, 779.58 μmol) were dissolved in 1,4-dioxane (5 mL) / water (1 mL) and stirred at 100°C under a nitrogen atmosphere for 1 hour. The mixture was cooled to room temperature, diluted with water (30 mL), and extracted with dichloromethane (3 × 20 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)acetyl)piperazine-1-carboxylate 30c (104 mg) in a yield of 46.23%.

[0649] MS m / z(ESI):519.2[M+1]

[0650] Step 4

[0651] 2-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-(piperazin-1-yl)ethan-1-one

[0652] 2-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-(piperazin-1-yl)ethan-1-one

[0653] To a stirred solution of tert-butyl 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)acetyl)piperazine-1-carboxylate 30c (94 mg, 180.97 μmol) in dichloromethane (5 mL) was added dropwise a 1 M dichloromethane solution of boron tribromide (5 mL). The reaction was stirred at room temperature for 2 hours. The mixture was quenched with methanol at 0°C and concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography (mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 40 mL / min) to afford 2-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-(piperazin-1-yl)ethan-1-one 30 (15 mg) in a 15.51% yield.

[0654] MS m / z(ESI):405.0[M+1]

[0655] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),9.02–8.80(m,3H),8.14(s,1H),7.95(d,J=9.1Hz,1H),7.75(brs,1H),7.57(d,J=8 .9Hz,1H),7.03(d,J=8.9Hz,1H),4.17(s,2H),3.80(t,J=5.2Hz,2H),3.70(t,J=5.3Hz,2H),3.22(s,2H),3.11(s,2H)ppm.

[0656] Example 69 was synthesized according to the synthesis method of Example 30 of the present invention. The structure and characterization data are shown in the following table:

[0657] Example 33

[0658] (3,6-diazabicyclo[3.1.1]heptan-6-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone

[0659] (3,6-diazabicyclo[3.1.1]heptane-6-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone

[0660] first step

[0661] ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[0662] Ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[0663] (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (2.46 g, 11.15 mmol), ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate 15b (3 g, 11.15 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (815.74 mg, 1.11 mmol), and potassium carbonate (4.62 g, 33.45 mmol) were added to 1,4-dioxane (50 mL) and water (5 mL). After argon replacement at 100°C, the mixture was heated and reacted for 6 hours. The reaction solution was directly concentrated and purified by silica gel column chromatography (eluent: System A) to give ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 33a (2.25 g) in a 55.26% yield.

[0664] MS m / z(ESI):365.0[M+1]

[0665] Step 2

[0666] 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid

[0667] 7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid

[0668] Ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 33a (2.25 g, 6.16 mmol) was dissolved in methanol (50 mL) and lithium hydroxide monohydrate (775.53 mg, 18.48 mmol) and water (5 mL) were added. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was concentrated, water (50 mL) was added, and the mixture was adjusted to a weak acidic state with hydrochloric acid. The mixture was extracted with ethyl acetate (3 × 30 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 33b (1.6 g) in a yield of 77.03%.

[0669] MS m / z(ESI):337.0[M+1]

[0670] Step 3

[0671] tert-butyl

[0672] 6-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0673] tert-Butyl 6-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate

[0674] 7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 33b (50 mg, 148.30 μmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate 33c (44.10 mg, 222.45 μmol, commercially available), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (112.78 mg, 296.60 μmol) were mixed, and N,N-dimethylformamide (5 mL) and N,N-diisopropylethylamine (95.83 mg, 741.49 μmol, 129.15 μL) were added. The mixture was reacted at room temperature for 2 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (3×20 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System A) to give tert-butyl 6-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate 33d (70 mg) in a yield of 91.23%.

[0675] MS m / z(ESI):517.1[M+1]

[0676] Step 4(3,6-diazabicyclo[3.1.1]heptan-6-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone

[0677] (3,6-diazabicyclo[3.1.1]heptane-6-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone

[0678] Tert-butyl 6-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate 33d (70 mg, 135.29 μmol) was dissolved in dichloromethane (10 mL) and then added with boron tribromide (1 M, 1.35 mL). The reaction was allowed to react at room temperature for 18 hours. The reaction solution was quenched with methanol and concentrated. Preparative liquid phase separation (mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 40 mL / min) afforded (3,6-diazabicyclo[3.1.1]heptane-6-yl)(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanone 33 (10 mg) in a 14.26% yield.

[0679] MS m / z(ESI):403.1[M+1]

[0680] 1 H NMR(400MHz,DMSO-d6)δ10.39(s,1H),9.31(brs,2H),8.64(d,J=7.0Hz,1H),8 .53(s,1H),7.50(d,J=8.9Hz,1H),7.47(s,1H),7.00(d,J=8.8Hz,1H),6.91(d, J=7.0Hz,1H),5.31(s,1H),4.53(s,1H),3.71(d,J=12.4Hz,1H),3.59(s,2H), 3.47(d,J=12.4Hz,1H), 2.87(dt,J=9.4,6.4Hz,1H), 1.90(d,J=9.6Hz,1H)ppm.

[0681] According to the synthesis method of Example 33 of the present invention, Examples 34, 41, 42, 43, 44, 48, 49, 51, 52, 56, 58, 59, 65, 66 and 73 were synthesized, and their structures and characterization data are shown in the following table:

[0682] Example 35

[0683] 3,4-dichloro-2-(2-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0684] 3,4-Dichloro-2-(2-(2-hydroxy-2-methylpropyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0685] first step

[0686] ethyl 1-(7-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylate

[0687] Ethyl 1-(7-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylate

[0688] 4-Bromopyridin-2-amine 4a (220.79 mg, 1.28 mmol) and ethyl 1-(2-bromoacetyl)cyclopropanecarboxylate 36a (300 mg, 1.28 mmol) were dissolved in a mixture of acetonitrile (2.5 mL) and toluene (2.5 mL) and heated to 85°C for 18 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: System B) to afford ethyl 1-(7-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylate 36b (120 mg) in a 30.41% yield. MS m / z (ESI): 309.1 [M+1].

[0689] Step 2

[0690] ethyl

[0691] 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylate

[0692] Ethyl 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylate

[0693] (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (142.87 mg, 646.92 μmol) and ethyl 1-(7-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylate 36b (200 mg, 646.92 μmol) were dissolved in 1,4-dioxane (3 mL) and water (3 mL). Cesium carbonate (421.56 mg, 1.29 mmol) was added and the mixture was heated to 100°C for 18 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: System B) to give ethyl 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylate 36c (120 mg) in a 45.77% yield. MS m / z (ESI): 405.1 [M+1].

[0694] Step 3

[0695] (1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropyl)methanol

[0696] (1-(7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropyl)methanol

[0697] Ethyl 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylate 36c (120 mg, 296.10 μmol) was added to anhydrous tetrahydrofuran (5 mL), cooled to 0°C, and then lithium borohydride (296.10 μL, 592.2 μmol, 2 M) was slowly added. The mixture was slowly brought to room temperature and reacted for 1 hour. After quenching with ice water (20 mL), the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: System B) to give (1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropyl)methanol 36d (85 mg) in a yield of 79.03%.

[0698] MS m / z(ESI):362.1[M+1]

[0699] Step 4

[0700] The 109.82 μmol of 2-hydroxy-6-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)azetidin-3-ol (109.82 μmol) was dissolved in dichloromethane (2 mL) and cooled to -78°C. Boron tribromide (0.2 mL) was added dropwise at -78°C. After the addition was complete, the mixture was warmed to 0°C and reacted for 10 minutes. After completion of the reaction, the reaction solution was quenched with methanol (2 mL) at -78°C and adjusted to pH 8-9 by adding aqueous ammonia. The solvent was removed under reduced pressure, and the mixture was slurried with dichloromethane to remove excess salts. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (AKZONOBEL Kromasil column; 250 × 19 mm ID; 10 μm, 20 mL / min; mobile phase A: 10 mmol / L ammonium bicarbonate + water, mobile phase B: acetonitrile) to afford 1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)azetidin-3-ol 37 (8 mg) in a 20.80% yield.

[0701] MS m / z(ESI):350.0[M+1]

[0702] 1 H NMR (400MHz, DMSO-d6) δ10.13(s,1H),8.36(d,J=6.8Hz,1H),7.45(d,J=8.9Hz,1H),7.16–7.10(m,2H),6.95(d,J=8.9Hz,1H), 6.63(dd,J=6.8,1.7Hz,1H),5.59(d,J=5.8Hz,1H),4.57(d,J=5.6Hz,1H),4.11–4.02(m,2H),3.56(dd,J=8.1,5.4Hz,2H)ppm.

[0703] Example 38

[0704] (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(pyrrolidin-3-yl)methanone

[0705] (7-(2,3-Dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(pyrrolidin-3-yl)methanone

[0706] first step

[0707] tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

[0708] tert-Butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate

[0709] 1-(tert-Butoxycarbonyl)pyrrolidine-3-carboxylic acid 38a (1.0 g, 4.65 mmol) and carbonyldiimidazole (753.33 mg, 4.65 mmol) were dissolved in dichloromethane (20 mL). N-methoxymethylamine hydrochloride 38b (793.05 mg, 8.13 mmol, commercially available) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water (15 mL), extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate 38c (1.1 g) in a 91.7% yield. MS m / z (ESI): 203.0 [M-55].

[0710] Step 2

[0711] tert-butyl

[0712] 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidine-1-carboxylate

[0713] tert-Butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidine-1-carboxylate

[0714] To a solution of 2-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 19c (100 mg, 268.79 μmol) in tetrahydrofuran (3 mL) was added n-butyllithium (2.5 M in n-hexane) (22.38 mg, 349.42 μmol) at -78°C under nitrogen. The reaction mixture was then stirred at -78°C for 30 minutes, followed by the dropwise addition of a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate 38c (90.26 mg, 349.42 μmol) in tetrahydrofuran (2 mL). The mixture was then allowed to warm to room temperature and stirred under nitrogen for 2 hours. After the reaction was complete, saturated ammonium chloride (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidine-1-carboxylate 38d (50 mg) in a yield of 37.9%.

[0715] MS m / z(ESI):490.2[M+1]

[0716] Step 3

[0717] (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(pyrrolidin-3-yl)methanone

[0718] (7-(2,3-Dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(pyrrolidin-3-yl)methanone

[0719] To a solution of tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidine-1-carboxylate 38d (50 mg, 101.96 μmol) in dichloromethane (1 mL) was added boron tribromide (0.2 mL) at -78°C. The mixture was 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 system was filtered and the filter cake was washed with dichloromethane. The solvent was removed from the filtrate under reduced pressure, and the residue was purified by preparative liquid separation (separation column Waters 3767 / QDASunFire C18*19*250mm*10um mobile phase A: 10mmol / LA:+0.1% formic acid / water, B: acetonitrile; flow rate: 20ml / min) to obtain (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(pyrrolidin-3-yl)methanone 38 (6.8mg) with a yield of 17.7%.

[0720] MS m / z(ESI):376.0[M+1]

[0721] 1 H NMR (400MHz, DMSO-d6) δ9.04(s,1H),8.29(s,1H),8.04(s,1H),7.94(s,1H),7.87(s,1H),7.53(d,J=8.9 Hz,1H),7.03(d,J=8.9Hz,1H),4.30–4.16(m,1H),3.36–3.10(m,2H),3.01(s,2H),2.19–1.98(m,2H)ppm.

[0722] Example 39

[0723] 2-(2-(7-azaspiro[3.5]nonan-2-yl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0724] 2-(2-(7-azaspiro[3.5]nonan-2-yl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0725] first step

[0726] tert-butyl

[0727] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate

[0728] tert-Butyl 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate

[0729] Tert-butyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate 39a (150 mg, 429.47 μmol, prepared according to patent WO2018134695) was dissolved in 1,4-dioxane (4 mL) and water (0.4 mL), and bistriphenylphosphine palladium dichloride (31.42 mg, 42.95 μmol), sodium carbonate (136.56 mg, 1.29 mmol) and 2-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 19c (159.78 mg, 429.47 μmol) were added, and the reaction was stirred at 110 °C under nitrogen protection for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate 39b (50 mg) in a yield of 22.63%.

[0730] MS m / z(ESI):514.1[M+1]

[0731] Step 2

[0732] tert-butyl

[0733] 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0734] tert-Butyl 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate

[0735] Tert-butyl 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylate 39b (40 mg, 77.75 μmol) was dissolved in ethanol (3 mL). Platinum dioxide (17.66 mg, 35.31 mmol) was added to displace the hydrogen atmosphere. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (30 psi) for 2 hours. After completion of the reaction, the mixture was filtered, and the solvent was removed from the filtrate under reduced pressure to afford tert-butyl 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate 39c (40 mg) in a 99.61% yield.

[0736] MS m / z(ESI):516.2[M+1]

[0737] Step 3

[0738] 2-(2-(7-azaspiro[3.5]nonan-2-yl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0739] 2-(2-(7-azaspiro[3.5]nonan-2-yl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0740] Tert-butyl 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylate 39c (40 mg, 77.45 μmol) was dissolved in dichloromethane (2 mL), cooled to -78°C, and boron tribromide (0.4 mL) was added dropwise. After the addition was completed, the mixture was heated to 0°C and reacted for 10 minutes. After the reaction was completed, the reaction solution was quenched with methanol (2 mL) at -78°C, and ammonia water was added to adjust the pH to 8-9. The solvent was removed under reduced pressure, and the excess salt was removed by beating with dichloromethane. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid separation (AKZONOBEL Kromasil column; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.1% formic acid + water, mobile phase B: acetonitrile) to obtain 2-(2-(7-azaspiro[3.5]nonan-2-yl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 39 (12 mg) in a yield of 38.51%.

[0741] MS m / z(ESI):402.2[M+1]

[0742] 1 H NMR(400MHz, DMSO-d6)δ8.46(d,J=7.0Hz,1H),8.32(brs,1H),7.76(s,1H),7.46(d,J= 8.8Hz,1H),7.32(s,1H),6.98(d,J=8.9Hz,1H),6.70(dd,J=6.9,1.6Hz,1H),3.65–3.53 (m,1H),3.03–2.95(m,2H),2.94–2.84(m,2H),2.24(t,J=10.5Hz,2H),2.12–2.01(m,2H),1.87–1.76(m,2H),1.76–1.65(m,2H)ppm.

[0743] Example 40

[0744] 2-(2-aminoimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0745] 2-(2-aminoimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0746] first step

[0747] tert-butyl(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)carbamate

[0748] tert-Butyl (7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)carbamate

[0749] To a solution of 2-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 19c (50 mg, 134.39 μmol) and tert-butylcarbamate (15.74 mg, 134.39 μmol) in 1,4-dioxane (2 mL) were added methanesulfonic acid (2-dicyclohexylphosphino)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (12.20 mg, 13.44 μmol, 95%) and cesium carbonate (131.36 mg, 403.18 μmol), respectively. The reaction mixture was then stirred at 100 °C under nitrogen for 16 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl (7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)carbamate 40a (50 mg) in a yield of 91.1%.

[0750] MS m / z(ESI):408.1[M+1]

[0751] Step 2

[0752] 2-(2-aminoimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0753] 2-(2-aminoimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0754] Tert-butyl (7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)carbamate 40a (50 mg, 122.47 μmol) was dissolved in dichloromethane (3 mL), and then boron tribromide (0.2 mL) was added at -78°C. The reaction mixture was stirred at 0°C for 10 minutes. After completion of the reaction, methanol was added at -78°C to quench the reaction, 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 solvent was removed from the filtrate under reduced pressure, and the residue was purified by preparative liquid separation (Waters 2767 / QDA column: SunFire C18, 19*250mm, 10um; mobile phase A: 10mmol / LA:0.1% formic acid / water, B: acetonitrile; flow rate: 20ml / min) to obtain 2-(2-aminoimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 40 (5.87mg) with a yield of 16.3%.

[0755] MS m / z(ESI):294.1[M+1]

[0756] 1 H NMR (400MHz, DMSO-d6) δ10.10(brs,1H),8.29(d,J=6.8Hz,1H),7.44(d,J=8.8Hz,1H),7.05–6.98(m,2H),6.94(d,J=8.8Hz,2H),5.07(brs,2H)ppm.

[0757] Example 45

[0758] 3,4-dichloro-2-(2-((3-hydroxycyclobutyl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0759] 3,4-Dichloro-2-(2-(3-hydroxycyclobutyl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0760] first step

[0761] 2-((3-(benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0762] 2-((3-(Benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0763] To a solution of 2,2,6,6-tetramethylpiperidine (480.97 mg, 3.41 mmol) in tetrahydrofuran (4 mL) was added n-butyllithium (2.5 M in n-hexane) (218.09 mg, 3.41 mmol) dropwise under nitrogen at -30°C, and the mixture was stirred at -30°C for 30 minutes. The reaction mixture was then cooled to -78°C, and a solution of bis[(pinacolato)boryl]methane (760.35 mg, 2.84 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise. The reaction mixture was stirred at -78°C for 0.5 hours, followed by the slow addition of a solution of 3-(benzyloxy)cyclobutan-1-one 45a (500 mg, 2.84 mmol) in tetrahydrofuran (5 mL). The reaction mixture was then allowed to warm to room temperature and stirred for an additional 12 hours. After the reaction was complete, saturated ammonium chloride solution (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-((3-(benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 45b (500 mg) in a yield of 58.7%.

[0764] MS m / z(ESI):301.2[M+1]

[0765] Step 2

[0766] 2-((3-(benzyloxy)cyclobutylidene)methyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[0767] 2-((3-(Benzyloxy)cyclobutylidene)methyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[0768] 2-Bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 19c (150 mg, 403.18 μmol) and 2-((3-(benzyloxy)cyclobutylidene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 45b (242.07 mg, 806.36 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.2 mL). [1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (30 mg, 40.32 μmol) and potassium carbonate (167.17 mg, 1.21 μmol) were then added. The mixture was stirred at 110°C under nitrogen for 2 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure, and the residue was separated and purified by reverse phase column chromatography (eluent: System A) to give 2-((3-(benzyloxy)cyclobutylidene)methyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 45c (183 mg) in a yield of 97.5%.

[0769] MS m / z(ESI):465.0[M+1]

[0770] Step 3

[0771] 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)cyclobutan-1-ol

[0772] 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)cyclobutan-1-ol

[0773] 2-((3-(Benzyloxy)cyclobutylidene)methyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 45c (70 mg, 150.42 μmol) was dissolved in ethanol (3 mL), followed by the addition of platinum dioxide (30 mg, 150.42 μmol). The mixture was stirred at room temperature under a hydrogen atmosphere (30 psi) for 2 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to afford 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)cyclobutan-1-ol 45d (60 mg) in an 85.3% yield.

[0774] MS m / z(ESI):376.9[M+1]

[0775] Step 4

[0776] 3,4-dichloro-2-(2-((3-hydroxycyclobutyl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0777] 3,4-Dichloro-2-(2-(3-hydroxycyclobutyl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0778] To a solution of 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)cyclobutan-1-ol 45d (20 mg, 42,79 μmol) in dichloromethane (1 mL) was added boron tribromide (30 mg, 85.68 μmol) at -78°C. The mixture was 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 and the filter cake was washed with dichloromethane. The solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (SunFire C 18 ,19*250mm,10um; mobile phase A: 0.1% formic acid / water, B: acetonitrile; flow rate: 20mL / min) to obtain 3,4-dichloro-2-(2-(3-hydroxycyclobutyl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol 45 (0.87mg) with a yield of 5.6%.

[0779] MS m / z(ESI):363.0[M+1]

[0780] 1 H NMR (400MHz, Methanol-d4) δ8.39(d,J=6.8Hz,1H),7.66(s,1H),7.38(d,J=8.8Hz,1H),7.34(s,1H),6.88(d,J=8.8Hz,1H),6.79(d, J=7.0Hz,1H),4.78–4.64(m,1H),4.12–4.00(m,1H),2.93–2.82(m,2H),2.50–2.40(m,1H),2.26–2.05(m,2H),1.73–1.61(m,1H)ppm.

[0781] According to the synthesis method of Example 45 of the present invention, Examples 53, 54 and 64 were synthesized, and their structures and characterization data are shown in the following table:

[0782] Example 46

[0783] 2-(3-(aminomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0784] 2-(3-(Aminomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0785] first step

[0786] ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-3-carboxylate

[0787] Ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-3-carboxylate

[0788] Ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate 46a (300 mg, 1.11 mmol, commercially available) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL). Bistriphenylphosphine palladium dichloride (81.57 mg, 111.49 μmol), cesium carbonate (726.48 mg, 2.23 mmol), and (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (369.31 mg, 1.67 mmol) were added. The reaction mixture was stirred at 110°C under nitrogen for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to afford ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-3-carboxylate 46b (300 mg) in a 73.68% yield.

[0789] MS m / z(ESI):365.0[M+1]

[0790] Step 2

[0791] (7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methanol

[0792] (7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methanol

[0793] Ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-3-carboxylate 46b (300 mg, 821.45 μmol) was dissolved in tetrahydrofuran (4 mL), and lithium aluminum hydride (1 M, 985.73 μL) was added dropwise at 0°C. After the addition was complete, the mixture was allowed to react at 0°C for 1 hour. After completion of the reaction, the reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford (7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methanol 46c (60 mg) in a yield of 22.60%.

[0794] MS m / z(ESI):323.0[M+1]

[0795] Step 3

[0796] 2-(3-(aminomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0797] 2-(3-(Aminomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0798] (7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)methanol 46c (60 mg, 185.66 μmol) was dissolved in dichloromethane (2 mL), cooled to -78°C, and boron tribromide (0.4 mL) was added dropwise. After the addition was completed, the mixture was heated to 0°C and reacted for 10 minutes. After the reaction was completed, the reaction solution was quenched with methanol (4 mL) at -78°C, and aqueous ammonia was added to adjust the pH to 8-9. The solvent was removed under reduced pressure, and the excess salt was removed by beating with dichloromethane. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.1% formic acid + water, mobile phase B: acetonitrile) to give 2-(3-(aminomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 46 (6 mg) in a yield of 10.49%.

[0799] MS m / z(ESI):308.0[M+1]

[0800] 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=7.0Hz,1H),8.31(brs,1H),7.56(s,1H),7.47(d,J=8.9 Hz,1H),7.42(s,1H),6.99(d,J=8.9Hz,1H),6.83(dd,J=7.0,1.3Hz,1H),4.22(s,2H)ppm.

[0801] Example 47

[0802] 3,4-dichloro-2-(2-(2-methoxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0803] 3,4-Dichloro-2-(2-(2-methoxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0804] first step

[0805] 7-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyethyl)imidazo[1,2-a]pyridine

[0806] 7-(2,3-Dichloro-6-methoxyphenyl)-2-(2-methoxyethyl)imidazo[1,2-a]pyridine

[0807] To a solution of 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethanol-1-ol 4d (150 mg, 444.84 μmol) in N,N-dimethylformamide (5 mL) was added sodium hydride 60% (13.88 mg, 578.29 μmol), and the mixture was stirred at 0°C under nitrogen for 30 minutes. Then, iodomethane (94.71 mg, 667.26 μmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System B) to give 7-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyethyl)imidazo[1,2-a]pyridine 47a (103 mg) in a yield of 65.92%.

[0808] MS m / z(ESI):351.0[M+1]

[0809] Step 2

[0810] 3,4-dichloro-2-(2-(2-methoxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0811] 3,4-Dichloro-2-(2-(2-methoxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0812] 7-(2,3-Dichloro-6-methoxyphenyl)-2-(2-methoxyethyl)imidazo[1,2-a]pyridine 47a (73 mg, 207.84 μmol) was dissolved in dichloromethane (3 mL), and then boron tribromide (260.35 mg, 1.04 mmol) was added dropwise at -20°C. The reaction mixture was stirred at -20°C for 3 hours. After the reaction was complete, methanol was added at -78°C to quench the reaction, and the pH was adjusted to 8 with aqueous ammonia. The system was filtered and the filter cake was washed with dichloromethane. The solvent was removed from the filtrate under reduced pressure, and the residue was purified by preparative liquid separation (Sunfire C18 column; 19*250 mm, 10 μm, 20 ml / min; mobile phase A: 10 mmol / LA:0.1% formic acid / water, mobile phase B: acetonitrile) to give 3,4-dichloro-2-(2-(2-methoxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 47 (13.32 mg) in a yield of 19.01%.

[0813] MS m / z(ESI):337.0[M+1]

[0814] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),8.49(dd,J=7.0,0.8Hz,1H),7.76(s,1H),7.47(d,J=8.9Hz,1H),7.31(s,1H) ,6.96(d,J=8.9Hz,1H),6.70(dd,J=6.9,1.6Hz,1H),3.67(t,J=6.8Hz,2H),3.27(s,3H),2.93(t,J=6.8Hz,2H)ppm.

[0815] Example 50

[0816] 1-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)naphthalen-2-ol

[0817] 1-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)naphthalen-2-ol

[0818] first step

[0819] 2-(7-(2-methoxynaphthalen-1-yl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol

[0820] 2-(7-(2-methoxynaphthalen-1-yl)imidazo[1,2-a]pyridin-2-yl)ethanol-1-ol

[0821] Compound 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)ethanol-1-ol 4b (100 mg, 414.79 μmol) and 2-methoxy-1-naphthoboronic acid pinacol ester 50a (176.80 mg, 622.19 μmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL). Potassium carbonate (171.99 mg, 1.24 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (30.32 mg, 41.48 μmol) were added at room temperature. The reaction mixture was stirred at 90°C under nitrogen for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to give 2-(7-(2-methoxynaphthalen-1-yl)imidazo[1,2-a]pyridin-2-yl)ethanol-1-ol 50b (80 mg) in a yield of 60.6%.

[0822] MS m / z(ESI):319.2[M+1]

[0823] Step 2

[0824] 1-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)naphthalen-2-ol

[0825] 1-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)naphthalen-2-ol

[0826] 2-(7-(2-Methoxynaphthalen-1-yl)imidazo[1,2-a]pyridin-2-yl)ethanol-1-ol 50b (30 mg, 94.23 μmol) was dissolved in dichloromethane (3 mL), and then boron tribromide (118.26 mg, 471.15 μmol) was added at -78°C. The reaction mixture was stirred at 0°C for 10 minutes. After completion, 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, and the filter cake was washed with dichloromethane. The solvent was removed from the filtrate under reduced pressure, and the resulting residue was purified by preparative liquid chromatography (SunFire C column). 18,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20mL / min) to obtain 1-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)naphthalen-2-ol 50 (16.89mg),yield:58.9%.MS m / z(ESI):305.1[M+1]

[0827] 1 H NMR (400MHz, DMSO-d6) δ9.87(s,1H),8.76(d,J=6.9Hz,1H),8.03(s,1H),7.88(dd,J=8.3,3.1Hz,2H),7.62(s,1H),7.45(d ,J=8.3Hz,1H),7.41–7.28(m,3H),7.14(d,J=6.5Hz,1H),4.88(brs,1H),3.78(t,J=6.4Hz,2H),2.95(t,J=6.4Hz,2H)ppm.

[0828] Example 55

[0829] 3,4-dichloro-2-(2-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol

[0830] 3,4-Dichloro-2-(2-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol

[0831] first step

[0832] ethyl 7-bromo-3-methylimidazo[1,2-a]pyridine-2-carboxylate

[0833] 7-Bromo-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

[0834] 4-Bromo-1,2-dihydropyridin-2-amine 4a (500 mg, 2.89 mmol), ethyl 3-bromo-2-oxobutanoate 55a (3.02 g, 14.45 mmol, 2.05 mL), and sodium carbonate (918.92 mg, 8.67 mmol) were added to ethanol (20 mL) and stirred at 80°C for 3 hours. The reaction mixture was concentrated, and water (30 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated ammonium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System B) to afford ethyl 7-bromo-3-methylimidazo[1,2-a]pyridine-2-carboxylate 55b (800 mg) in a 97.77% yield.

[0835] MS m / z(ESI):283.0[M+1]

[0836] Step 2

[0837] ethyl 7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridine-2-carboxylate

[0838] 7-(2,3-Dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

[0839] (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (124.81 mg, 565.13 μmol), ethyl 7-bromo-3-methylimidazo[1,2-a]pyridine-2-carboxylate 55b (160 mg, 565.13 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (41.35 mg, 56.51 μmol), and potassium carbonate (234.32 mg, 1.70 mmol) were added to 1,4-dioxane (10 mL) and water (1 mL). After argon replacement at 100°C, the reaction was heated for 4 hours. The reaction mixture was concentrated directly, and the residue was purified by silica gel column chromatography (eluent: System B) to give ethyl 7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridine-2-carboxylate 55c (200 mg) in a yield of 93.32%.

[0840] MS m / z(ESI):379.0[M+1]

[0841] Step 3

[0842] (7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)methanol

[0843] (7-(2,3-Dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)methanol

[0844] Ethyl 7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridine-2-carboxylate 55c (180 mg, 474.64 μmol) was dissolved in tetrahydrofuran (20 mL) and lithium aluminum hydride (90.07 mg, 2.37 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction solution was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford (7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)methanol 55d (40 mg) in a yield of 24.99%.

[0845] MS m / z(ESI):337.1[M+1]

[0846] Step 4

[0847] 2-(2-(bromomethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0848] 2-(2-(Bromomethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0849] (7-(2,3-Dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)methanol 55d (40 mg, 118.62 μmol) was dissolved in dichloromethane (10 mL) and boron tribromide (148.59 mg, 593.12 μmol) was added. The mixture was allowed to react at room temperature for 18 hours. The reaction solution was quenched with methanol, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System B) to afford 2-(2-(bromomethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 55e (45 mg) in a 98.26% yield.

[0850] MS m / z(ESI):385.0[M+3]

[0851] Step 5

[0852] 3,4-dichloro-2-(2-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol

[0853] 3,4-Dichloro-2-(2-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol

[0854] 2-(2-(Bromomethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 55e (45 mg, 116.56 μmol) was dissolved in dimethyl sulfoxide (2 mL) and water (2 mL) and reacted at 110°C for 3 hours. The reaction solution was directly concentrated and the residue was purified by preparative liquid chromatography (Chromatographic column: SunFire C 18 ,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20ml / min),to obtain 3,4-dichloro-2-(2-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol 55 (24mg),yield 63.71%.

[0855] MS m / z(ESI):323.0[M+1]

[0856] 1H NMR (400MHz, DMSO-d6) δ10.63(s,1H),8.76(d,J=6.9Hz,1H),7.82(s,1H),7.57(d,J=8.9Hz,1 H),7.45(d,J=7.0Hz,1H),7.04(d,J=8.9Hz,1H),5.77(brs,1H),4.76(s,2H),2.59(s,3H)ppm.

[0857] Example 57

[0858] 3,4,5-trichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0859] 3,4,5-Trichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0860] first step

[0861] 2-(2-(benzyloxy)ethyl)-7-bromoimidazo[1,2-a]pyridine

[0862] 2-(2-(Benzyloxy)ethyl)-7-bromoimidazo[1,2-a]pyridine

[0863] 4-Bromopyridin-2-amine 4a (2 g, 11.56 mmol) was dissolved in ethanol (60 mL). 4-(Benzyloxy)-1-bromobutan-2-one 57a (3.86 g, 15.03 mmol, prepared according to patent publication WO2017009651) and sodium bicarbonate (1.94 g, 23.12 mmol) were then added at room temperature. After the addition was complete, the mixture was stirred at 80°C for 10 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to afford 2-(2-(Benzyloxy)ethyl)-7-bromoimidazo[1,2-a]pyridine 57b (2.30 g) in a 60.1% yield.

[0864] MS m / z(ESI):331.0[M+1]

[0865] Step 2

[0866] (2-(2-(benzyloxy)ethyl)imidazo[1,2-a]pyridin-7-yl)boronic acid

[0867] (2-(2-(Benzyloxy)ethyl)imidazo[1,2-a]pyridin-7-yl)boronic acid

[0868] To a solution of 2-(2-(benzyloxy)ethyl)-7-bromoimidazo[1,2-a]pyridine 57b (2.3 g, 6.94 mmol) in 1,4-dioxane (30 mL) was added pinacol diboronate (2.29 g, 9.03 mmol), potassium acetate (2.04 g, 20.83 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (562.90 mg, 694.43 μmol) under nitrogen. The mixture was then stirred at 100°C under nitrogen for 12 hours. After completion of the reaction, the reaction solution was filtered, and the filter residue was washed with dichloromethane. The filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by reverse phase chromatography (C18) (eluent: D system) to give (2-(2-(benzyloxy)ethyl)imidazo[1,2-a]pyridin-7-yl)boronic acid 57c (1.55 g) in a yield of 75.4%.

[0869] MS m / z(ESI):297.1[M+1]

[0870] Step 3

[0871] 3,4,5-trichlorophenol

[0872] 3,4,5-Trichlorophenol

[0873] (3,4,5-Trichlorophenyl)boronic acid 57d (1 g, 4.44 mmol, commercially available) was dissolved in tetrahydrofuran (10 mL), followed by the addition of hydrogen peroxide (1.01 g, 8.88 mmol, 30% purity) and sodium hydroxide (355.14 mg, 8.88 mmol). The reaction was allowed to react at room temperature for 18 hours. The reaction mixture was quenched with water (20 mL), adjusted to pH 3 with dilute hydrochloric acid, and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford 3,4,5-trichlorophenol 57e (700 mg) in a yield of 79.86%.

[0874] Step 4

[0875] 2-bromo-3,4,5-trichlorophenol

[0876] 2-Bromo-3,4,5-trichlorophenol

[0877] 3,4,5-Trichlorophenol 57e (770 mg, 3.90 mmol) was dissolved in acetic acid (10 mL) and bromine (623.23 mg, 3.90 mmol) was added. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was quenched with saturated sodium sulfite solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford 2-bromo-3,4,5-trichlorophenol 57f (1.0 g) in a 92.79% yield.

[0878] Step 5

[0879] 2-bromo-3,4,5-trichloro-1-methoxybenzene

[0880] 2-Bromo-3,4,5-trichloro-1-methoxybenzene

[0881] 2-Bromo-3,4,5-trichlorophenol 57f (1.0 g, 3.62 mmol) and potassium carbonate (1.00 g, 7.24 mmol) were dissolved in N,N-dimethylformamide (5 mL), and iodomethane (1.54 g, 10.86 mmol, 675.84 μL) was added. The mixture was allowed to react at 50°C for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford 57 g (400 mg) of 2-bromo-3,4,5-trichloro-1-methoxybenzene in a 38.07% yield.

[0882] Step 6

[0883] 2-(2-(benzyloxy)ethyl)-7-(2,3,4-trichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[0884] 2-(2-(Benzyloxy)ethyl)-7-(2,3,4-trichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[0885] 2-Bromo-3,4,5-trichloro-1-methoxybenzene 57g (49.03 mg, 168.85 μmol), (2-(2-(benzyloxy)ethyl)imidazo[1,2-a]pyridin-7-yl)boronic acid 57c (50 mg, 168.85 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (12.35 mg, 16.88 μmol) and cesium carbonate (165.04 mg, 506.54 μmol) were mixed, 1,4-dioxane (2 mL) and water (0.2 mL) were added, and the atmosphere was replaced with argon and reacted at 100°C for 15 hours. The reaction solution was quenched with water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 2-(2-(benzyloxy)ethyl)-7-(2,3,4-trichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 57h (70 mg) in a yield of 71.82%.

[0886] MS m / z(ESI):461.0[M+1]

[0887] Step 7

[0888] 2-(2-(2-bromoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4,5-trichlorophenol

[0889] 2-(2-(2-bromoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4,5-trichlorophenol

[0890] 2-(2-(Benzyloxy)ethyl)-7-(2,3,4-trichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 57h (70 mg, 121.27 μmol) was dissolved in dichloromethane (10 mL) and boron tribromide (151.91 mg, 606.37 μmol) was added. The mixture was allowed to react at room temperature for 18 hours. Methanol was added to quench the reaction solution, which was then concentrated directly. The residue was purified by silica gel column chromatography (eluent: System B) to afford 2-(2-(2-bromoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4,5-trichlorophenol 57i (50 mg) in a 9.80% yield. MS m / z (ESI): 419.0 [M+1].

[0891] Step 8

[0892] 3,4,5-trichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0893] 3,4,5-Trichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0894] 2-(2-(2-Bromoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4,5-trichlorophenol 57i (8 mg, 19.02 μmol) was dissolved in dimethyl sulfoxide (2 mL) and water (2 mL) and heated at 100°C for 18 hours. The reaction solution was directly concentrated and the residue was purified by preparative liquid chromatography (HPLC column: SunFire C 18 ,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20ml / min),to obtain 3,4,5-trichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 57 (1.5mg),yield 21.61%.

[0895] MS m / z(ESI):357.0[M+1]

[0896] 1H NMR(400MHz, Methanol-d4)δ8.79(d,J=7.0Hz,1H),8.09(s,1H),7.83(s,1H),7.40( dd,J=7.0,1.6Hz,1H),7.16(s,1H),3.95(t,J=5.9Hz,2H),3.11(t,J=5.9Hz,2H)ppm.

[0897] Example 60

[0898] 4,5-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0899] 4,5-Dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0900] first step

[0901] 2-(2-(benzyloxy)ethyl)-7-(4,5-dichloro-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)imidazo[1,2-a]pyridine

[0902] 2-(2-(Benzyloxy)ethyl)-7-(4,5-dichloro-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)imidazo[1,2-a]pyridine

[0903] (2-((2-bromo-4,5-dichlorophenoxy)methoxy)ethyl)trimethylsilane 60a (30 mg, 80.61 μmol, prepared according to patent publication WO2021071802), (2-(2-(benzyloxy)ethyl)imidazo[1,2-a]pyridin-7-yl)boronic acid 57c (28.65 mg, 96.73 μmol), cesium carbonate (78.79 mg, 241.83 μmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (5.90 mg, 8.06 μmol) were added to 1,4-dioxane (1 mL) and stirred at 80 °C for 16 hours. After the reaction was complete, the product was filtered under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System B) to give 2-(2-(benzyloxy)ethyl)-7-(4,5-dichloro-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)imidazo[1,2-a]pyridine 60b (42 mg) in a yield of 95.85%.

[0904] MS m / z(ESI):543.2[M+1]

[0905] Step 2

[0906] 4,5-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0907] 4,5-Dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0908] 2-(2-(Benzyloxy)ethyl)-7-(4,5-dichloro-2-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)imidazo[1,2-a]pyridine 60b (40 mg, 73.59 μmol) was added to trifluoroacetic acid (2 mL) and stirred at 70°C for 18 hours. The reaction solution was directly concentrated and the residue was purified by preparative liquid phase separation (Chromatographic column: SunFire C 18 ,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20mL / min),to obtain 4,5-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 60 (8mg),yield 33.12%.

[0909] MS m / z(ESI):323.0[M+1]

[0910] Example 61

[0911] 3,4-dichloro-2-(3-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0912] 3,4-Dichloro-2-(3-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0913] first step

[0914] ethyl 3-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[0915] Ethyl 3-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[0916] 7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 33b (20.80 mg, 56.95 μmol) was dissolved in acetonitrile (1 mL) and N-bromosuccinimide (12.16 mg, 68.34 μmol) was added. The mixture was allowed to react at room temperature for 3 hours. After completion of the reaction, the mixture was quenched with saturated sodium bisulfite (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was then separated by silica gel column chromatography.

[0917] MS m / z(ESI):443.1[M+1]

[0918] Step 2

[0919] ethyl 3-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[0920] Ethyl 3-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[0921] 3-Bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 61a (180 mg, 405.31 μmol) and cyclopropylboronic acid (348.15 mg, 4.05 mmol) were added to 1,4-dioxane (1 mL) and water (0.2 mL). Sodium carbonate (85.92 mg, 810.62 μmol) and palladium acetate (9.18 mg, 40.53 μmol) were added, and the mixture was heated to 120 °C for 4 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give ethyl 3-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 61b (125 mg) in a yield of 34.24%.

[0922] MS m / z(ESI):405.1[M+1]

[0923] Step 3

[0924] 3-cyclopropyl-7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid

[0925] 3-Cyclopropyl-7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid

[0926] Ethyl 3-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 61b (200 mg, 493.49 μmol) was added to dichloromethane (1 mL). The temperature was cooled to 0°C, and boron tribromide (618.15 mg, 2.47 mmol) was slowly added dropwise. The mixture was then allowed to react at room temperature for 18 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford 3-cyclopropyl-7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 61c (120 mg) in a 66.95% yield.

[0927] MS m / z(ESI):363.1[M+1]

[0928] Step 4

[0929] 3,4-dichloro-2-(3-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0930] 3,4-Dichloro-2-(3-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0931] 3-Cyclopropyl-7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 61c (100 mg, 275.33 μmol) was added to tetrahydrofuran (1 mL), and borane tetrahydrofuran complex (70.99 mg, 826.00 μmol, 1 M in THF) was added. The mixture was reacted at room temperature for 2 hours, quenched with ice water, filtered and concentrated, and the residue was purified by preparative liquid separation (chromatographic column: SunFire C 18 ,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20mL / min),to obtain 3,4-dichloro-2-(3-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-7-yl)phenol 61 (3.28mg),yield 3.24%.

[0932] MS m / z(ESI):349.0[M+1]

[0933] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),8.92–8.81(m,1H),7.78(s,1H),7.57(d,J=8.9Hz,1H),7.46(s, 1H),7.03(d,J=8.7Hz,1H),4.77(s,2H),2.05–1.95(m,1H),1.24–1.11(m,2H),0.91–0.79(m,2H)ppm.

[0934] Example 67

[0935] 3,4-dichloro-2-(2-(hydroxy(piperidin-4-yl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0936] 3,4-Dichloro-2-(2-(hydroxy(piperidin-4-yl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol

[0937] Dissolve (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperidin-4-yl)methanone 29 (5 mg, 12.81 μmol) in ethanol (1 mL), cool to 0°C, slowly add sodium borohydride (727.01 μg, 19.22 μmol), and react at this temperature for 1 hour. Quench with ice water, filter, and concentrate. The residue is purified by preparative liquid chromatography (HPLC column: SunFire C 18 ,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20mL / min),to obtain 3,4-dichloro-2-(2-(hydroxy(piperidin-4-yl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol 67 (1.26mg),yield 18.38%.

[0938] MS m / z(ESI):392.0[M+1]

[0939] 1H NMR (400MHz, DMSO-d6) δ8.31(d,J=6.9Hz,1H),7.64(s,1H),7.20(s,1H),6.89(d,J=9.0Hz,1H),6.67(dd,J=7.0,1.7Hz,1H),6.23(d,J=8.9Hz, 1H),4.71–4.25(m,4H),2.95–2.78(m,2H),2.43–2.28(m,2H),1.86–1. 67(m,1H),1.62–1.51(m,1H),1.40–1.30(m,1H),1.27–1.12(m,1H)ppm.

[0940] Example 70

[0941] 4-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one

[0942] 4-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one

[0943] first step

[0944] ethyl(E)-3-(7-bromoimidazo[1,2-a]pyridin-2-yl)acrylate

[0945] Ethyl (E)-3-(7-bromoimidazo[1,2-a]pyridin-2-yl)acrylate

[0946] Sodium hydride (69.32 mg, 1.73 mmol, 60% purity) and triethylphosphonoacetate (777.05 mg, 3.47 mmol, 687.65 μL) were added to tetrahydrofuran (9.54 mL) at 0°C and reacted for half an hour at 0°C. 7-Bromoimidazo[1,2-a]pyridine-2-carbaldehyde 29c (300 mg, 1.33 mmol) was added at the same temperature, and the mixture was slowly warmed to room temperature and allowed to react overnight. The reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to obtain ethyl (E)-3-(7-bromoimidazo[1,2-a]pyridin-2-yl)acrylate 70a (380 mg) in a 96.59% yield. MS m / z (ESI): 294.9 [M+1].

[0947] Step 2

[0948] ethyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)-4-nitrobutanoate

[0949] Ethyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)-4-nitrobutyrate

[0950] Ethyl (E)-3-(7-bromoimidazo[1,2-a]pyridin-2-yl)acrylate 70a (300 mg, 1.02 mmol) was dissolved in nitromethane (10 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (309.50 mg, 2.03 mmol, 303.73 μL) was added. The mixture was heated to 70°C for 2 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: System B) to afford ethyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)-4-nitrobutyrate 70b (312 mg) in an 86.18% yield.

[0951] MS m / z(ESI):356.0[M+1]

[0952] Step 3

[0953] ethyl 4-amino-3-(7-bromoimidazo[1,2-a]pyridin-2-yl)butanoate

[0954] Ethyl 4-amino-3-(7-bromoimidazo[1,2-a]pyridin-2-yl)butanoate

[0955] Ethyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)-4-nitrobutyrate 70b (50 mg, 140.38 μmol), reduced iron powder (39.20 mg, 701.91 μmol), and ammonium chloride (37.55 mg, 701.91 μmol) were added to methanol (2 mL) and water (1 mL) and heated to 80°C for 3 hours. After filtration and concentration, the residue was purified by silica gel column chromatography (eluent: System B) to afford ethyl 4-amino-3-(7-bromoimidazo[1,2-a]pyridin-2-yl)butyrate 70c (40 mg) in an 87.35% yield.

[0956] MS m / z(ESI):326.0[M+1]

[0957] Step 4

[0958] 4-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one

[0959] 4-(7-Bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one

[0960] Ethyl 4-amino-3-(7-bromoimidazo[1,2-a]pyridin-2-yl)butanoate 70c (40.00 mg, 122.63 μmol) was dissolved in methanol (5 mL) and potassium carbonate (84.74 mg, 613.14 μmol) was added. The mixture was heated to 80°C for 3 hours, filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: System B) to give 4-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one 70d (30 mg) in a yield of 87.33%.

[0961] MS m / z(ESI):280.0[M+1]

[0962] Step 5

[0963] 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one

[0964] 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one

[0965] (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (47.30 mg, 214.19 μmol), 4-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one 70d (30 mg, 107.10 μmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (7.94 mg, 10.71 μmol) and potassium carbonate (44.41 mg, 321.29 μmol) were mixed, 1,4-dioxane (5 mL) and water (1 mL) were added, and the mixture was purged with argon and reacted at 100°C for 4 hours. The reaction solution was concentrated and the residue was purified by preparative liquid phase separation (Chromatographic column: SunFire C 18 ,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20ml / min),to obtain 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one 70d (24mg),yield 59.56%.

[0966] MS m / z(ESI):376.1[M+1]

[0967] Step 6

[0968] 4-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one

[0969] 4-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one

[0970] 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one 70d (24 mg, 63.79 μmol) was dissolved in dichloromethane (5 mL) and boron tribromide (159.81 mg, 637.90 μmol) was added. The mixture was allowed to react at room temperature for 2 hours. The reaction was quenched with methanol, and the residue was purified by preparative liquid chromatography (SunFire C18 column, 19*250 mm, 10 μm, mobile phase A: 0.1% formic acid / water, mobile phase B: acetonitrile; flow rate: 20 mL / min) to afford 4-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one 70 (10 mg) in a 42.41% yield.

[0971] MS m / z(ESI):362.0[M+1]

[0972] 1H NMR(400MHz,DMSO-d6)δ10.49(s,1H),8.90(d,J=6.9Hz,1H),8.31(s,1H),7 .92(s,1H),7.86(s,1H),7.57(d,J=8.9Hz,1H),7.42(dd,J=6.9,1.6Hz,1H) ,7.04(d,J=8.9Hz,1H),4.00(p,J=8.0Hz,1H),3.72(t,J=8.9Hz,1H),3.44( dd,J=9.7,6.6Hz,1H),2.68(dd,J=16.5,9.1Hz,1H),2.55–2.44(m,1H)ppm.

[0973] Example 71

[0974] 2-(2-((3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0975] 2-(2-((3,6-diazabicyclo[3.1.1]hept-3-yl)methyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0976] first step

[0977] tert-butyl

[0978] 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0979] tert-Butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0980] 7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 33b (50 mg, 148.30 μmol) and 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane 71a (44.10 mg, 222.45 μmol) were dissolved in N,N-dimethylformamide (4.87 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (112.78 mg, 296.60 μmol) and N,N-diisopropylethylamine (95.83 mg, 741.49 μmol, 129.15 μL) were added, and the mixture was reacted at room temperature for 18 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 71b (58 mg) in a yield of 75.59%.

[0981] MS m / z(ESI):517.0[M+1]

[0982] Step 2

[0983] tert-butyl

[0984] 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0985] tert-Butyl 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate

[0986] tert-Butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 71b (48.00 mg, 92.77 μmol) was dissolved in tetrahydrofuran (1 mL), and borane tetrahydrofuran complex (15.95 mg, 185.54 μmol, 1 M in THF) was added. The mixture was heated to 50°C for 8 hours. The reaction was quenched with methanol at 0°C and concentrated under reduced pressure to afford tert-butyl 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 71c, which was used directly in the next reaction.

[0987] MS m / z(ESI):503.2[M+1]

[0988] Step 3

[0989] 2-(2-((3,6-diazabicyclo[3.1.1]heptan-3-yl)methyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0990] 2-(2-((3,6-diazabicyclo[3.1.1]hept-3-yl)methyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[0991] Dissolve tert-butyl 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate 71c (46.00 mg, 91.38 μmol) in dichloromethane (1 mL), cool to 0°C, slowly add boron tribromide (45.78 mg, 182.75 μmol), and slowly return to room temperature for 18 hours. Quench with ice water, concentrate under reduced pressure, and the residue is purified by preparative liquid phase separation (Chromatographic column: SunFire C18 ,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20mL / min),to obtain 2-(2-((3,6-diazabicyclo[3.1.1]hept-3-yl)methyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 71 (16.32mg),yield 43.77%.

[0992] MS m / z(ESI):389.2[M+1]

[0993] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),8.67(d,J=6.9Hz,1H),8.16–8.08(m,1H),7.53–7.45(m,2H),6.99(d,J=8.9Hz,1H ),6.95–6.85(m,1H),4.58–4.35(m,2H),4.31–4.17(m,2H),3.88–3.78(m,2H),3.12–2.87(m,2H),2.36–2.00(m,2H)ppm.

[0994] According to the synthesis method of Example 71 of the present invention, Examples 74, 75 and 80 were synthesized, and their structures and characterization data are shown in the following table:

[0995] Example 72

[0996] 2-amino-1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[0997] 2-Amino-1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[0998] first step

[0999] 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-(dimethyl(oxo)-λ 6 -sulfaneylidene)ethan-1-one

[1000] 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-(dimethyl(oxo)-λ6 -sulfonamido)ethan-1-one

[1001] Under nitrogen, 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 33b (1.2 g, 3.56 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.06 g, 10.68 mmol) were dissolved in tetrahydrofuran (50 mL). Triethylamine (1.08 g, 10.68 mmol) was added at room temperature, and the mixture was stirred at room temperature under nitrogen for 16 hours. In a separate reaction flask, trimethylsulfoxide chloride (1.37 g, 10.68 mmol) and potassium tert-butoxide (1.20 g, 10.68 mmol) were added to the reaction flask under nitrogen, and the mixture was stirred at 60°C for 2 hours. The reaction mixture was cooled to 0°C, and the prepared active ester was then slowly added to the reaction mixture. The mixture was stirred at room temperature under nitrogen for 2 hours. After the reaction was complete, water (15 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to obtain 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-(dimethyl(oxo)-λ 6 -sulfonamido)ethan-1-one 72a (750 mg), yield 51.23%.

[1002] MS m / z(ESI):410.9[M+1]

[1003] Step 2

[1004] 2-bromo-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[1005] 2-Bromo-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[1006] At 0 ° C, 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-(dimethyl(oxo)-λ 6To a solution of 2-bromo-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72a (200 mg, 486.26 μmol) in tetrahydrofuran (10 mL) was added lithium bromide (42.23 mg, 486.2 μmol), followed by the addition of methanesulfonic acid (46.68 mg, 486.26 μmol) at 0°C. The reaction mixture was heated to 65°C and stirred under nitrogen for 2 hours. After completion, the reaction was cooled to 0°C and a 1M sodium carbonate solution was added to adjust the pH to 7-9. The product was extracted with ethyl acetate (15 mL x 2), washed with saturated sodium chloride (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to afford 2-bromo-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72b (132 mg) in a yield of 65.56%.

[1007] MS m / z(ESI):412.9[M+1]

[1008] Step 3

[1009] 2-amino-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[1010] 2-Amino-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[1011] Under nitrogen, a solution of 2-bromo-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72b (50 mg, 120.75 μmol) and sodium diformamide (23 mg, 241.5 μmol) in acetonitrile (2 mL) was heated to 55°C and stirred for 16 hours. The reaction was concentrated under reduced pressure, and the residue was dissolved in ethanol (2 mL). Concentrated hydrochloric acid (1 drop) was then added, and the mixture was stirred at 80°C under nitrogen for 2 hours. After the reaction was complete, the mixture was cooled to room temperature and purified by atmospheric pressure reverse phase preparative chromatography (C18) (eluent: System D) to afford 2-amino-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72c (30 mg) in a 70.94% yield.

[1012] MS m / z(ESI):350.0[M+1]

[1013] Step 4

[1014] 2-amino-1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[1015] 2-Amino-1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one

[1016] To a solution of 2-amino-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72c (20 mg, 57.11 μmol) in dichloromethane (3 mL) was added boron tribromide (57 mg, 228.44 μmol) under nitrogen at -78°C. The mixture was slowly heated to 0°C and then stirred under nitrogen for 30 minutes. After completion of the reaction, the reaction was quenched with methanol (3 mL) and the mixture was directly prepared by reverse phase chromatography (Waters 2767 / Qda, column: SunFire SunFire C 18 Purification was performed using a 19*250mm filter, 10 μm column; mobile phase A: 0.1% FA / H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 20% to 25%) to afford 2-amino-1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72 (5.6 mg) in a 29.17% yield. MS m / z (ESI): 336.0 [M+1].

[1017] 1 H NMR (400MHz, Methanol-d4) δ8.76 (s, 1H), 8.65 (d, J = 7.1Hz, 1H), 7.63 (s, 1H), 7.4 5(d,J=8.9Hz,1H),7.13(d,J=7.2Hz,1H),6.93(d,J=8.9Hz,1H),4.64(s,2H)ppm.

[1018] Example 76

[1019] 3,4-dichloro-2-(2-(1-hydroxy-2-(piperazin-1-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1020] 3,4-Dichloro-2-(2-(1-hydroxy-2-(piperazin-1-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1021] first step

[1022] tert-butyl

[1023] 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-oxoethyl)piperazine-1-carboxylate

[1024] tert-Butyl 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-oxoethyl)piperazine-1-carboxylate

[1025] To a solution of 2-bromo-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72b (110 mg, 265.65 μmol) and tert-butyl piperazine-1-carboxylate 15d (50 mg, 265.6 μmol) in acetonitrile (3 mL) was added potassium carbonate (74 mg, 531.30 μmol), and the mixture was stirred at room temperature under nitrogen for 24 h. After the reaction was completed, water (8 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give tert-butyl 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-oxoethyl)piperazine-1-carboxylate 76a (70 mg) with a yield of 51%.

[1026] MS m / z(ESI):519.2[M+1].

[1027] Step 2

[1028] tert-butyl

[1029] 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-hydroxyethyl)piperazine-1-carboxylate

[1030] tert-Butyl 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-hydroxyethyl)piperazine-1-carboxylate

[1031] To a solution of tert-butyl 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-oxoethyl)piperazine-1-carboxylate 76a (70 mg, 134.77 μmol) in methanol (2 mL) and tetrahydrofuran (0.5 mL) was added sodium borohydride (11 mg, 269.53 μmol) at 0°C under nitrogen protection, and the reaction mixture was warmed to room temperature and stirred for 2 hours. After completion of the reaction, the temperature was lowered to 0°C and quenched by the addition of saturated ammonium chloride (8 mL). The mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-hydroxyethyl)piperazine-1-carboxylate 76b (50 mg) in a 71% yield. This was used directly in the next step.

[1032] MS m / z(ESI):521.0[M+1]

[1033] Step 3

[1034] 3,4-dichloro-2-(2-(1-hydroxy-2-(piperazin-1-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1035] 3,4-Dichloro-2-(2-(1-hydroxy-2-(piperazin-1-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1036] Under nitrogen protection at -78 ° C, boron tribromide (95 mg, 383.56 μmol) was added to a solution of tert-butyl 4-(2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-hydroxyethyl)piperazine-1-carboxylate 76b (50 mg, 95.89 μmol) in dichloromethane (3 mL). The reaction mixture was slowly heated to 0 ° C and stirred for 1 hour. After the reaction was completed, the temperature was lowered to 0 ° C, the reaction was quenched with methanol (3 mL), and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (Waters 3767 / Qda column: SunFire C 18 ,19*250mm, 10um; mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20ml / min) to obtain 3,4-dichloro-2-(2-(1-hydroxy-2-(piperazin-1-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol 76 (8.85mg) with a yield of 22.66%.

[1037] MS m / z(ESI):407.0[M+1]

[1038] 1 H NMR (400MHz, Methanol-d4) δ8.45 (d, J=7.0Hz, 1H), 7.86 (s, 1H), 7.42–7.35 (m, 2H), 6.89(d,J=8.9Hz,1H),6.83(dd,J=7.0,1.5Hz,1H),5.09–5.01(m,1H),3.27–3.21(m,6H),2.88(dd,J=22.4,12.9,10.3,4.3Hz,6H)ppm.

[1039] Example 78

[1040] 1-((7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidin-4-ol

[1041] 1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidin-4-ol

[1042] first step

[1043] (7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanol

[1044] (7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanol

[1045] To a solution of ethyl 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 33a (880 mg, 2.41 mmol) in dichloromethane (20 mL) was added dropwise with stirring at 0°C. The mixture was allowed to warm to room temperature and stirred for 12 hours. The reaction was quenched with ice water at 0°C and diluted with water (30 mL). The mixture was then extracted with dichloromethane / methanol (10 / 1) (3 x 50 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give (7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanol 78a (657 mg) in a 62.43% yield. MS m / z (ESI): 322.9 [M+1].

[1046] Step 2

[1047] 2-(2-(bromomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[1048] 2-(2-(Bromomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol

[1049] To a stirred solution of (7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methanol 78a (360 mg, 1.11 mmol) in dichloromethane (15 mL) was added dropwise a 1 M solution of boron tribromide in dichloromethane (15 mL) at 0°C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with ice water at 0°C, and the precipitated solid was collected by filtration and washed with water to afford 22-(2-(bromomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 78b (370 mg) in an 89.28% yield. MS m / z (ESI): 372.9 [M+3].

[1050] Step 3

[1051] 1-((7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidin-4-ol

[1052] 1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidin-4-ol

[1053] To a stirred solution of 2-(2-(bromomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 78b (20 mg, 53.76 μmol) in N,N-dimethylformamide (0.5 mL) at 0°C, piperidin-4-ol 78c (16.31 mg, 161.27 μmol, commercially available) and potassium carbonate (37.15 mg, 268.79 μmol) were added. The mixture was stirred at room temperature for 2 hours. The mixture was filtered under reduced pressure and purified by preparative liquid chromatography (Chromatographic column: SunFire C 18 ,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20mL / min),to obtain 1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidin-4-ol 78 (7 mg),yield 25.72%.

[1054] MS m / z(ESI):392.0[M+1]

[1055] According to the synthesis method of Example 78 of the present invention, Examples 85, 88, 89, 90, 95 and 96 were synthesized, and their structures and characterization data are shown in the following table:

[1056] Example 79

[1057] 3,4-dichloro-2-(2-(1-hydroxy-1-(piperidin-4-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1058] 3,4-Dichloro-2-(2-(1-hydroxy-1-(piperidin-4-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1059] first step

[1060] tert-butyl 4-(1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate

[1061] tert-Butyl 4-(1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate

[1062] Tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate 29d (100 mg, 244.92 μmol) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (163.28 μL, 3.0 M solution in 2-methyltetrahydrofuran) was added. The mixture was allowed to react at room temperature for 18 hours. The reaction mixture was quenched with saturated ammonium chloride (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 4-(1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate 79a (97 mg) in a 93.33% yield.

[1063] MS m / z(ESI):424.0[M+1]

[1064] Step 2

[1065] tert-butyl

[1066] 4-(1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate

[1067] tert-Butyl 4-(1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate

[1068] (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (48.40 mg, 219.17 μmol), tert-butyl 4-(1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate 79a (93 mg, 219.17 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16.04 mg, 21.92 μmol) and potassium carbonate (90.87 mg, 657.51 μmol) were mixed, 1,4-dioxane (10 mL) and water (1 mL) were added, and the atmosphere was replaced with argon and reacted at 100°C for 4 hours. The reaction solution was concentrated and purified by silica gel column chromatography (eluent: System B) to give tert-butyl 4-(1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate 79b (100 mg) in a yield of 87.67%.

[1069] MS m / z(ESI):520.1[M+1]

[1070] Step 3

[1071] 3,4-dichloro-2-(2-(1-hydroxy-1-(piperidin-4-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1072] 3,4-Dichloro-2-(2-(1-hydroxy-1-(piperidin-4-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1073] Tert-butyl 4-(1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate 79b (100 mg, 192.14 μmol) was dissolved in dichloromethane (10 mL) and then added with boron tribromide (481.36 mg, 1.92 mmol). The mixture was reacted at room temperature for 18 hours. The reaction solution was quenched with methanol and concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (Chromatographic column: SunFire C 18 ,19*250mm,10um,mobile phase A:0.1% formic acid / water,B:acetonitrile;flow rate:20mL / min),to obtain 3,4-dichloro-2-(2-(1-hydroxy-1-(piperidin-4-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol 79 (50mg),yield 45.51%.

[1074] MS m / z(ESI):406.1[M+1]

[1075] 1H NMR (400MHz, DMSO-d6) δ10.76(brs,1H),8.85(d,J=6.9Hz,1H),8.80–8.63(m,1H),8.38–8.20(m,1H),8.18(s,1H),7.74(s,1H),7.55(d,J=8.9Hz, 1H),7.30(d,J=7.0Hz,1H),7.04(d,J=8.8Hz,1H),5.87(brs,1H),3.37–3 .21(m,2H),2.91–2.71(m,2H),2.05–1.84(m,2H),1.77–1.33(m,6H)ppm.

[1076] Example 86

[1077] 3,4-dichloro-2-(2-(piperidin-4-yloxy)imidazo[1,2-a]pyridin-7-yl)phenol

[1078] 3,4-Dichloro-2-(2-(piperidin-4-yloxy)imidazo[1,2-a]pyridin-7-yl)phenol

[1079] first step

[1080] (2,3-dichloro-6-hydroxyphenyl)boronic acid

[1081] (2,3-Dichloro-6-hydroxyphenyl)boronic acid

[1082] (2,3-Dichloro-6-methoxyphenyl)boronic acid 4c (2 g, 9.06 mmol) was dissolved in dichloromethane (1 mL) at 0°C. Boron tribromide (11.34 g, 45.28 mmol) was slowly added and the mixture was allowed to react at room temperature for 4 hours. Ice water (30 mL) was slowly added and stirred for 30 minutes. A solid precipitated and was filtered and dried to afford (2,3-dichloro-6-hydroxyphenyl)boronic acid 86a (1.85 g) in a 98.77% yield.

[1083] Step 2

[1084] ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate

[1085] Ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate

[1086] 4-Bromopyridin-2-amine 4a (1 g, 5.78 mmol) was dissolved in ethyl 2-bromoacetate, and the mixture was reacted at 25°C under a nitrogen atmosphere for 16 hours. After completion of the reaction, methyl tert-butyl ether was added, stirred, filtered, and the filter residue was dried under reduced pressure to provide ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate 86b (1.5 g) in a 99.7% yield.

[1087] MS m / z(ESI):259.1[M+1]

[1088] Step 3

[1089] 7-bromoimidazo[1,2-a]pyridin-2-ol

[1090] 7-Bromoimidazo[1,2-a]pyridin-2-ol

[1091] Ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate 86b (2 g, 7.69 mmol) was dissolved in methanol (20 mL), and potassium carbonate (531 mg, 3.84 mmol) was added. The mixture was reacted at 25°C under nitrogen for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to afford 7-bromoimidazo[1,2-a]pyridin-2-ol 86c (900 mg) in a 54.9% yield.

[1092] MS m / z(ESI):213.0[M+1]

[1093] Step 4

[1094] tert-butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)oxy)piperidine-1-carboxylate

[1095] tert-Butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)oxy)piperidine-1-carboxylate

[1096] To a solution of 7-bromoimidazo[1,2-a]pyridin-2-ol 86c (500 mg, 2.35 mmol) and cesium carbonate (2.30 g, 7.04 mmol) in N,N-dimethylformamide (8 mL) at room temperature under nitrogen was added tert-butyl 4-bromopiperidine-1-carboxylate 86d (1.24 g, 4.69 mmol). The mixture was stirred at 80°C for 2 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was directly purified by atmospheric pressure reverse phase preparative (C18) (eluent: System D) to afford tert-butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)oxy)piperidine-1-carboxylate 86e (158 mg) in a 17.0% yield.

[1097] MS m / z(ESI):396.2[M+1]

[1098] Step 5

[1099] 3,4-dichloro-2-(2-(piperidin-4-yloxy)imidazo[1,2-a]pyridin-7-yl)phenol

[1100] 3,4-Dichloro-2-(2-(piperidin-4-yloxy)imidazo[1,2-a]pyridin-7-yl)phenol

[1101] To a mixed solution of tert-butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)oxy)piperidine-1-carboxylate 86e (150 mg, 378.52 μmol) and (2,3-dichloro-6-hydroxyphenyl)boronic acid 86a (156 mg, 757.04 μmol) in 1,4-dioxane (1 mL) and water (0.1 mL) was added [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 37.85 μmol) and cesium carbonate (370 mg, 1.14 mmol) at room temperature. The mixture was stirred at 110°C for 2 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase preparative (Waters 3767 / QDA) column (SunFire C 18 ,19*250mm, 10um mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20mL / min), to obtain 3,4-dichloro-2-(2-(piperidin-4-yloxy)imidazo[1,2-a]pyridin-7-yl)phenol 86 (8.5mg), with a yield of 5.9%.

[1102] MS m / z(ESI):278.2[M+1]

[1103] 1H NMR (400MHz, DMSO-d6) δ8.42(d,J=6.9Hz,1H),8.26(s,1H),7.47(d,J=8.9Hz,1H),7.43(s,1H),7.24(s,1H),6.96(d,J=8.9Hz,1H ),6.74(dd,J=6.9,1.7Hz,1H),4.83–4.72(m,1H),3.18–3.06(m,2H),2.91–2.78(m,2H),2.14–2.00(m,2H),1.77–1.63(m,2H)ppm.

[1104] Example 91

[1105] 3,4,6-trichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1106] 3,4,6-Trichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1107] first step

[1108] 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol

[1109] 2-(7-Bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol

[1110] Ethyl 7-bromoimidazo[1,2-a]pyridine-2-carboxylate 10a (2 g, 7.43 mmol) was dissolved in tetrahydrofuran (20 mL), cooled to 0°C, and methylmagnesium bromide (3 M, 4.95 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred for 6 hours. After completion, the reaction was quenched with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to afford 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol 91a (1 g, 3.92 mmol) in a 52.74% yield.

[1111] MS m / z(ESI):255.0[M+1]

[1112] Step 2

[1113] (2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)boronic acid

[1114] (2-(2-Hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-7-yl)boronic acid

[1115] 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol 91a (1 g, 3.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (290.77 mg, 391.99 μmol), potassium acetate (769.39 mg, 7.84 mmol), and biboronic acid pinacol ester (1.99 g, 7.84 mmol) were added to 1,4-dioxane (30 mL), and the air was replaced by nitrogen. The temperature was raised to 100°C and stirred for 18 hours. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure. The residue was directly prepared by normal pressure reverse phase (C 18 Purification with 5% (2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)boronic acid 91b (650 mg) (eluent: System D) gave 75.36% yield. MS m / z (ESI): 221.1 [M+1]

[1116] Step 3

[1117] 3,4,6-trichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1118] 3,4,6-Trichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1119] (2-(2-Hydroxyprop-2-yl)imidazo[1,2-a]pyridin-7-yl)boronic acid 91b (50 mg, 227.24 μmol), 6-bromo-2,4,5-trichlorophenol 91c (62.80 mg, 227.24 μmol, commercially available), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16.86 mg, 22.72 μmol) and potassium carbonate (94.22 mg, 681.72 μmol) were mixed and added to 1,4-dioxane (5 mL) and water (0.5 mL). The mixture was heated to 100°C and stirred for 16 hours. After completion of the reaction, the product was concentrated under reduced pressure, and the residue was purified by reverse phase preparative (Waters 3767 / QDA) column (SunFire C18, 19*250 mm, 10 μm mobile phase A: 0.1% FA / H2O, B: ACN; flow rate: 20 ml / min) to give 3,4,6-trichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol 91 (20 mg) in a yield of 22.98%.

[1120] MS m / z(ESI):371.0[M+1]

[1121] 1H NMR (400MHz, Methanol-d4) δ8.78(d,J=7.0Hz,1H),8.12(s,1H),7.78(s,1H),7.73(s,1H),7.38(dd,J=7.0,1.5Hz,1H),1.71(s,6H)ppm.

[1122] Example 92 was synthesized according to the synthesis method of Example 91 of the present invention. The structure and characterization data are shown in the following table:

[1123] Example 97

[1124] 3,4-dichloro-6-fluoro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1125] first step

[1126] 2-bromo-3,4-dichloro-6-fluorophenol

[1127] 2-Bromo-3,4-dichloro-6-fluorophenol

[1128] 4,5-Dichloro-2-fluorophenol 97a (800 mg, 4.42 mmol, prepared according to patent publication "WO2024088343") was dissolved in dichloromethane (8 mL), cooled to 0°C, and liquid bromine (3.53 g, 22.10 mmol) was added. The temperature was slowly raised to room temperature and allowed to react for 12 hours. After completion, the reaction was quenched with saturated sodium sulfite (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (eluent: System A) to obtain 2-bromo-3,4-dichloro-6-fluorophenol 97b (509 mg) in a 44.31% yield.

[1129] Step 2

[1130] ethyl 7-(2,3-dichloro-5-fluoro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[1131] Ethyl 7-(2,3-dichloro-5-fluoro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

[1132] 2-Bromo-3,4-dichloro-6-fluorophenol 97b (509 mg, 1.96 mmol) was added to 1,4-dioxane (10 mL). (2-(Ethoxycarbonyl)imidazo[1,2-a]pyridin-7-yl)boronic acid 97c (504.16 mg, 2.15 mmol, prepared according to patent publication WO2022017338), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (145.28 mg, 195.85 μmol), and potassium carbonate (812.04 mg, 5.88 mmol) were then added. The reaction was stirred at 90°C under nitrogen for 12 hours. After the reaction was completed, water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: System A) to give ethyl 7-(2,3-dichloro-5-fluoro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 97d (112 mg) in a yield of 15.49%.

[1133] MS m / z(ESI):369.1[M+1]

[1134] Step 3

[1135] 3,4-dichloro-6-fluoro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1136] 3,4-Dichloro-6-fluoro-2-(2-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1137] Ethyl 7-(2,3-dichloro-5-fluoro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 97d (194 mg, 525.50 μmol) was added to tetrahydrofuran (10 mL) under nitrogen protection. Methylmagnesium bromide (3M, 2.63 mL) was added dropwise at -78°C. After the addition was complete, the temperature was raised to 50°C and the reaction was allowed to proceed for 3 hours. The reaction solution was quenched by adding water (100 mL) and extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (Separation column SunFire Sunfire C 18 ; 19*250mm, 10um, 20mL / min; mobile phase A: 0.1% FA / H2O, mobile phase B: CH3CN), to obtain 3,4-dichloro-6-fluoro-2-(2-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol 97 (82.4 mg), with a yield of 44.15%.

[1138] MS m / z(ESI):355.1[M+1]

[1139] 1H NMR (400MHz, DMSO-d6) δ8.55(d,J=6.9Hz,1H),7.80(s,1H),7.70(d,J=10.5Hz ,1H),7.38(s,1H),6.72(dd,J=6.9,1.6Hz,1H),5.05(s,1H),1.50(s,6H)ppm.

[1140] Example 99

[1141] 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phen-6-d-ol

[1142] 3,4-Dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)benzene-6-d-ol

[1143] first step

[1144] (2-((3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane

[1145] (2-((3,4-Dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane

[1146] (2-((2-bromo-4,5-dichlorophenoxy)methoxy)ethyl)trimethylsilane 99a (400 mg, 1.07 mmol, prepared according to the patent publication "WO2021071802") was dissolved in tetrahydrofuran (3 mL), cooled to -78 °C, and under nitrogen protection, n-butyl lithium (2.5 M, 644.89 μL) was added dropwise. After stirring for 1 hour, heavy water (215.29 mg, 10.75 mmol, 194.48 μL) was added dropwise. The temperature was raised to room temperature and stirred for 18 hours. After the starting material disappeared, water (30 mL) was added and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: System A) to give (2-((3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane 99b (316 mg) in a yield of 99.91%.

[1147] Step 2

[1148] (2-((2-bromo-3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane

[1149] (2-((2-Bromo-3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane

[1150] (2-((3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane 99b (316 mg, 1.07 mmol) was dissolved in dichloromethane (10 mL), and bromine (188.76 mg, 1.18 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain (2-((2-bromo-3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane 99c, which was used directly in the next step.

[1151] Step 3

[1152] 2-(7-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl-5-d)imidazo[1,2-a]pyridin-2-yl)propan-2-ol

[1153] 2-(7-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl-5-d)imidazo[1,2-a]pyridin-2-yl)propan-2-ol

[1154] (2-((2-bromo-3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane 99c (160 mg, 428.77 μmol), (2-(2-hydroxypropyl-2-yl)imidazo[1,2-a]pyridin-7-yl)boronic acid 91b (141.51 mg, 643.15 μmol), cesium carbonate (419.10 mg, 1.29 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (63.61 mg, 85.75 μmol) were added to 1,4-dioxane (4 mL) and water (1 mL). The air was replaced with nitrogen and the reaction was stirred at 70°C. After the reaction was complete, the product was filtered and concentrated under reduced pressure. The residue was directly purified by reverse phase preparative (C18) (eluent: System D) at atmospheric pressure to give 2-(7-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl-5-d)imidazo[1,2-a]pyridin-2-yl)propan-2-ol 99d (40 mg) in a yield of 19.91%.

[1155] MS m / z(ESI):468.1[M+1]

[1156] Step 4

[1157] 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phen-6-d-ol

[1158] 3,4-Dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)benzene-6-d-ol

[1159] 2-(7-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl-5-d)imidazo[1,2-a]pyridin-2-yl)propan-2-ol 99d (40 mg, 85.39 μmol) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (29.21 mg, 256.16 μmol) was added dropwise. The mixture was stirred at room temperature for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative liquid phase separation (Separation column SunFire Sunfire C 18 ; 19*250mm, 10um, 20mL / min; mobile phase A: 0.1% FA / H2O, mobile phase B: CH3CN), to obtain 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)benzene-6-d-ol 99 (18 mg), yield 61.40%.

[1160] MS m / z(ESI):338.0[M+1]

[1161] 1H NMR (400MHz, DMSO-d6) δ8.48(d,J=7.1Hz,1H),7.95(s,1H),7.75(s,1H),7.68(s,1H),7.62(s,1H),7.06(dd,J=7.2,1.8Hz,1H),1.49(s,6H)ppm.

[1162] Example 100

[1163] 1-((7-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methylpiperidin-4-ol

[1164] 1-((7-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methylpiperidin-4-ol

[1165] first step

[1166] diethyl 7-bromoimidazo[1,2-a]pyridine-2,3-dicarboxylate

[1167] Diethyl 7-bromoimidazo[1,2-a]pyridine-2,3-dicarboxylate

[1168] 4-Bromopyridin-2-amine 4a (5 g, 28.90 mmol) was dissolved in ethanol (50 mL), and diethyl α-chlorooxaloacetate 100a (6.43 g, 28.90 mmol, commercially available) was added. The mixture was heated to 100°C and stirred for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to afford the crude product, which was purified by silica gel column chromatography (eluent: System A) to afford diethyl 7-bromoimidazo[1,2-a]pyridine-2,3-dicarboxylate 100b (6 g) in a 60.86% yield.

[1169] MS m / z(ESI):341.1[M+1]

[1170] Step 2

[1171] ethyl 7-bromo-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate

[1172] Ethyl 7-bromo-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate

[1173] Diethyl 7-bromoimidazo[1,2-a]pyridine-2,3-dicarboxylate 100b (6 g, 17.59 mmol) was dissolved in tetrahydrofuran (60 mL) and cooled to 0°C. Lithium borohydride (2 M, 13.19 mL) was added and the temperature was slowly warmed to room temperature for 16 hours. The reaction was quenched by the addition of water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: System A) to afford ethyl 7-bromo-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate 100c (2.5 g) in a 47.52% yield.

[1174] MS m / z(ESI):299.1[M+1]

[1175] Step 3

[1176] ethyl 7-bromo-2-formylimidazo[1,2-a]pyridine-3-carboxylate

[1177] Ethyl 7-bromo-2-formylimidazo[1,2-a]pyridine-3-carboxylate

[1178] Ethyl 7-bromo-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylate 100c (100 mg, 0.35 mmol) was added to dichloromethane (3 mL), followed by manganese dioxide (152 mg, 1.75 mmol). The reaction mixture was allowed to react at 25°C for 16 hours. After completion, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (eluent: System A) to afford ethyl 7-bromo-2-formylimidazo[1,2-a]pyridine-3-carboxylate 100d (50 mg) in a 50.3% yield. MS m / z (ESI): 297.0 [M+1]

[1179] Step 4

[1180] ethyl

[1181] 7-bromo-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylate

[1182] Ethyl 7-bromo-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylate

[1183] Ethyl 7-bromo-2-formylimidazo[1,2-a]pyridine-3-carboxylate 100d (40 mg, 0.35 mmol) and 4-methyl-4-hydroxypiperidine 81a (40 mg, 0.35 mmol) were dissolved in methanol (2 mL). Sodium cyanoborohydride (13 mg, 0.21 mmol) was added at 0°C, and the reaction mixture was heated to 70°C for 1 hour. After completion of the reaction, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phase was washed with saturated sodium chloride solution (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was isolated and purified by silica gel column chromatography (eluent: System B) to obtain ethyl 7-bromo-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylate 100e (25 mg) in a 37.0% yield. MS m / z(ESI):397.1[M+1]

[1184] Step 5

[1185] ethyl

[1186] 7-(2,3-dichloro-6-hydroxyphenyl)-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylate

[1187] Ethyl 7-(2,3-dichloro-6-hydroxyphenyl)-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylate

[1188] 7-Bromo-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester 100e (180 mg, 0.47 mmol) and (2,3-dichloro-6-hydroxyphenyl)boronic acid 86a (146 mg, 0.70 mmol), cesium carbonate (130 mg, 0.94 mmol) and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (34.4 mg, 0.05 mmol) were added sequentially to a mixed solvent of 1,4-dioxane (2 mL) and water (0.2 mL), protected by nitrogen, and heated to 110 °C for 2 hours. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was washed with saturated sodium chloride solution (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was separated and purified by silica gel column chromatography (eluent: System B) to give ethyl 7-(2,3-dichloro-6-hydroxyphenyl)-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylate 100f (110 mg) in a yield of 50.3%.

[1189] MS m / z(ESI):478.1[M+1]

[1190] Step 6

[1191] 1-((7-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methylpiperidin-4-ol

[1192] 1-((7-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methylpiperidin-4-ol

[1193] 7-(2,3-dichloro-6-hydroxyphenyl)-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester 100f (30 mg, 0.06 mmol) was added to tetrahydrofuran (2 mL), cooled to 0°C, and lithium aluminum hydride (1 M, 77 μL) was added. The reaction mixture was reacted at 0°C for 1 hour. The reaction solution was diluted with water (10 mL) and 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, and concentrated under reduced pressure. The resulting residue was purified by preparative liquid phase separation (Separation column SunFire C 18 ; 250×19mm ID; 10μm, 20mL / min; mobile phase A: 0.1% FA+H2O, mobile phase B: CH3CN), to obtain 1-((7-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methylpiperidin-4-ol 100 (5 mg), with a yield of 17.7%.

[1194] MS m / z(ESI):436.1[M+1].

[1195] 1H NMR (400MHz, Methanol-d4) δ8.51(s,1H),8.48(d,J=7.1Hz,1H),7.47(s,1H),7.40(d,J=8.9Hz,1H),6.95(dd,J=7.1 ,1.5Hz,1H),6.90(d,J=8.9Hz,1H),5.05(s,2H),4.21(s,2H),3.18–3.02(m,4H),1.82–1.69(m,4H),1.26(s,3H)ppm.

[1196] Example 102

[1197] 3,4-dichloro-6-fluoro-2-(2-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1198] 3,4-Dichloro-6-fluoro-2-(2-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1199] first step

[1200] 3-bromo-1,2-dichloro-5-fluoro-4-methoxybenzene

[1201] 3-Bromo-1,2-dichloro-5-fluoro-4-methoxybenzene

[1202] 2-Bromo-3,4-dichloro-6-fluorophenol 97b (2.3 g, 8.85 mmol) and potassium carbonate (3.67 g, 26.55 mmol) were added to N,N-dimethylformamide (10 mL), and iodomethane (2.51 g, 17.70 mmol, 1.10 mL) was added. The reaction was allowed to react at room temperature for 18 hours. The reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (100 mL × 3). The organic phase was washed with saturated sodium chloride solution (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. It was then purified by silica gel column chromatography (eluent: System A) to give 3-bromo-1,2-dichloro-5-fluoro-4-methoxybenzene 102a (1.95 g) in a yield of 80.44%.

[1203] Step 2

[1204] (2-bromoimidazo[1,2-a]pyridin-7-yl)boronic acid

[1205] (2-Bromoimidazo[1,2-a]pyridin-7-yl)boronic acid

[1206] 2,7-Dibromoimidazo[1,2-a]pyridine 19b (500 mg, 1.81 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (134.42 mg, 181.21 μmol), potassium acetate (533.51 mg, 5.44 mmol), and pinacol diboron (920.31 mg, 3.62 mmol) were added to 1,4-dioxane (20 mL). The air was replaced with nitrogen, and the reaction was stirred at 100°C for 18 hours. After the reaction was complete, the mixture was filtered and diluted with water (30 mL). The mixture was extracted with ethyl acetate (30 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 then purified by silica gel column chromatography (eluent: System A) to give (2-bromoimidazo[1,2-a]pyridin-7-yl)boronic acid 102b (375 mg) in a yield of 85.92%.

[1207] MS m / z(ESI):240.9[M+1]

[1208] Step 3

[1209] 2-bromo-7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[1210] 2-Bromo-7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridine

[1211] 3-Bromo-1,2-dichloro-5-fluoro-4-methoxybenzene 102a (214.95 mg, 784.72 μmol), (2-bromoimidazo[1,2-a]pyridin-7-yl)boronic acid 102b (189 mg, 784.72 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (58.21 mg, 78.47 μmol), and potassium carbonate (325.37 mg, 2.35 mmol) were mixed, 1,4-dioxane (5 mL) was added, and the atmosphere was replaced with argon at 100°C for 5 hours. The reaction mixture was directly concentrated and purified by silica gel column chromatography (eluent: System B) to give 2-bromo-7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridine 102c (83 mg) in a yield of 27.12%.

[1212] MS m / z(ESI):388.9[M+1]

[1213] Step 4

[1214] tert-butyl

[1215] 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methylene)piperidine-1-carboxylate

[1216] tert-Butyl 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methylene)piperidine-1-carboxylate

[1217] 2-Bromo-7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridine 102c (83 mg, 212.80 μmol) and tert-butyl 4-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]piperidine-1-carboxylate 102d (68.78 mg, 212.80 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (15.79 mg, 21.28 μmol) and potassium carbonate (88.23 mg, 638.41 μmol) were mixed, and dioxane (5 mL) and water (0.5 mL) were added. After argon replacement, the reaction was carried out at 100°C for 5 hours. The reaction mixture was concentrated and purified by silica gel column chromatography (eluent: System B) to afford tert-butyl 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methylene)piperidine-1-carboxylate 102e (57 mg) in a 52.89% yield. MS m / z (ESI): 506.1 [M+1].

[1218] Step 5

[1219] tert-butyl

[1220] 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidine-1-carboxylate

[1221] tert-Butyl 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidine-1-carboxylate

[1222] tert-Butyl 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methylene)piperidine-1-carboxylate 102e (57 mg, 112.56 μmol) was dissolved in methanol (10 mL) and palladium on carbon (23.96 mg, 225.12 μmol, 10%) was added. The mixture was purged with a hydrogen balloon and allowed to react at room temperature for 3 hours. The reaction mixture was filtered, concentrated, and purified by silica gel column chromatography (eluent: System B) to afford tert-Butyl 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidine-1-carboxylate 102f (40 mg) in a 69.90% yield.

[1223] MS m / z(ESI):508.1[M+1]

[1224] Step 6

[1225] 3,4-dichloro-6-fluoro-2-(2-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1226] 3,4-Dichloro-6-fluoro-2-(2-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenol

[1227] 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester 102f (40 mg, 78.68 μmol) was dissolved in dichloromethane (5 mL) and then added with boron tribromide (197.10 mg, 786.76 μmol) and reacted at room temperature for 3 hours. The reaction solution was quenched with methanol and purified by preparative liquid phase separation (Separation column SunFire C 18 ; 250×19mm ID; 10μm, 20mL / min; mobile phase A: 0.1% FA+H2O, mobile phase B: CH3CN), to obtain 3,4-dichloro-6-fluoro-2-(2-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenol 102 (6.0 mg), with a yield of 14.67%.

[1228] MS m / z(ESI):394.1[M+1]

[1229] 1H NMR (400MHz, Methanol-d4) δ8.67(d,J=7.0Hz,1H),7.98(s,1H),7.69(s,1H),7.50(d,J=10.3Hz,1H),7.20(dd,J=6.9,1.5Hz,1H),3.4 7–3.38(m,2H),3.08–2.95(m,2H),2.90(d,J=7.0Hz,2H),2.23–2.08(m,1H),2.07–1.94(m,2H),1.55(qd,J=14.4,13.6,4.2Hz,2H)ppm.

[1230] Example 103

[1231] 3,4-dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1232] 3,4-Dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1233] first step

[1234] 2-(2-bromoimidazo[1,2-a]pyridin-7-yl)-3,4-dichloro-6-fluorophenol

[1235] 2-(2-Bromoimidazo[1,2-a]pyridin-7-yl)-3,4-dichloro-6-fluorophenol

[1236] (2-Bromoimidazo[1,2-a]pyridin-7-yl)boronic acid 102b (125.50 mg, 521.09 μmol), 2-bromo-3,4-dichloro-6-fluorophenol 97b (120 mg, 416.75 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (64.42 mg, 86.85 μmol) and cesium carbonate (424.46 mg, 1.30 mmol) were added to 1,4-dioxane (1 mL) and water (0.2 mL). The air was replaced with nitrogen and the reaction was stirred at 80°C. After the reaction was complete, the product was filtered, concentrated, and purified by silica gel column chromatography (eluent: System A) to afford 2-(2-bromoimidazo[1,2-a]pyridin-7-yl)-3,4-dichloro-6-fluorophenol 103a (35 mg) in a 20.54% yield. MS m / z (ESI): 374.9 [M+1].

[1237] Step 2

[1238] 3,4-dichloro-2-(2-(2,5-dihydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)-6-fluorophenol

[1239] 3,4-Dichloro-2-(2-(2,5-dihydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)-6-fluorophenol

[1240] 2-(2-Bromoimidazo[1,2-a]pyridin-7-yl)-3,4-dichloro-6-fluorophenol 103a (120 mg, 319.14 μmol), 2,5-dihydrofuran-3-naphthalene borate 103b (68.82 mg, 351.06 μmol), cesium carbonate (103.98 mg, 319.14 μmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (236.73 mg, 319.14 μmol) were added to 1,4-dioxane (5 mL) and water (1 mL) and heated to 80°C for 1 h. After the reaction was complete, water was added to dilute the mixture (30 mL), and the mixture was extracted with ethyl acetate (30 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 then purified by silica gel column chromatography (eluent: System A) to give 3,4-dichloro-2-(2-(2,5-dihydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)-6-fluorophenol 103c (15.32 mg) in a yield of 11.18%.

[1241] MS m / z(ESI):365.0[M+1]

[1242] Step 3

[1243] 3,4-dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1244] 3,4-Dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

[1245] 3,4-Dichloro-2-(2-(2,5-dihydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)-6-fluorophenol 103c (35 mg, 95.84 μmol) was dissolved in methanol (1 mL), and Raney nickel (10.50 mg, 178.91 μmol) was added. Hydrogen was passed through the mixture and the mixture was allowed to react at room temperature for 18 hours. After the reaction was complete, the mixture was filtered, the filtrate was collected, concentrated, and purified by preparative liquid phase separation (SunFire C column). 18 ; 250×19 mm ID; 10 μm, 20 mL / min; mobile phase A: 0.1% FA + H2O, mobile phase B: CH3CN) to afford 3,4-dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol 103 (2.21 mg) in a 4.21% yield. MS m / z (ESI): 367.0 [M+1]

[1246] Biological evaluation

[1247] Test Example 1: Manual patch clamp method to detect the effect of the compound of the present invention on hKv1.3 potassium ion channel (CHO cells)

[1248] 1.1. Experimental Purpose:

[1249] Using CHO cells stably expressing hKv1.3 potassium ion channels, the manual patch clamp method was used to study the effects of the compounds of the present invention at different concentrations on hKv1.3 currents and their dose-effect relationships.

[1250] Experimental methods

[1251] Cell culture

[1252] The CHO cells stably expressing the hKv1.3 potassium channel used in the experiment were obtained from Shanghai WuXi AppTec Pharmaceutical Development Co., Ltd. The cells were cultured in an incubator at 37°C and 5% carbon dioxide. The reagent conditions in the CHO hKv1.3 culture medium used are shown in Table 1.

[1253] Table 1. CHO hKv1.3 culture medium

[1254] 1.2.2. Preliminary preparation of cells

[1255] The CHO-hKv1.3 cells prepared for the experiment were cultured for at least two days and the cell density reached more than 75%. Before the experiment began, the cells were digested with TrypLE (source: Thermo Fisher Scientific) and then resuspended in extracellular solution to collect the cells.

[1256] 1.2.3. Preparation of intracellular and extracellular fluids

[1257] 1) Extracellular solution: 145 mM sodium chloride, 4 mM potassium chloride, 2 mM calcium chloride, 1 mM magnesium chloride, 10 mM glucose and 10 mM HEPES (pH adjusted to 7.4 with sodium hydroxide).

[1258] 2) Intracellular solution: 10 mM EGTA, 10 mM HEPES, 2 mM magnesium chloride, 145 mM potassium fluoride (pH adjusted to 7.2 with potassium hydroxide).

[1259] Note: The osmotic pressure of the solution should be controlled between 280 and 320 mOsmol / kg. The solution should be filtered and stored at 4°C before use.

[1260] The extracellular solution was prepared at least once a month, filtered, and stored in a refrigerator at 4°C. The intracellular solution was prepared every three months, filtered, aliquoted, and stored in a refrigerator at -20°C.

[1261] 1.2.4. Preparation of compounds

[1262] Dissolve the compound of the invention in 100% DMSO to prepare a 10 mM stock solution. The stock solution is then further diluted into the extracellular fluid to obtain the desired final concentration. Visually inspect the precipitate before testing. The final DMSO external solution concentration of the test compound is no greater than 0.30%.

[1263] 1.2.5. Voltage stimulation protocol

[1264] The voltage stimulation protocol is as shown in Table 2. Maintain the holding potential at -80 mV for 50 ms. Then, depolarize to +40 mV for 200 ms to open hKv1.3 channels. Finally, return the voltage to the holding potential of -80 mV. Repeat this voltage stimulation cycle every 30,000 ms.

[1265] Table 2. Voltage stimulation protocol

[1266] 1.2.6. Manual whole-cell patch clamp recording

[1267] Whole-cell currents were recorded at room temperature using a manual whole-cell patch-clamp technique in cells stably expressing hKv1.3 channels. Signals were amplified using a Multiclamp 700B (Molecular Devices, USA), data were acquired using a DigiData 1440 A / DD / A board (Molecular Devices, USA), and currents were observed and recorded using Clampex 10 software.

[1268] Glass microelectrodes were made from borosilicate glass capillaries (GC150tF-10, Harvard Apparatus Co., UK) using a programmed microelectrode puller (NARISHIGE PC-10 Puller, Japan). The electrode tip resistance was 2–5 MΩ.

[1269] Before the experiment began, the cell suspension was placed in a 35 mm culture dish and placed on the stage of an inverted microscope (Nikon ECLIPSE Ti, Japan). After the cells adhered, they were perfused with extracellular solution at a flow rate of 1-2 mL / min. Perfusion was performed using a perfusion system (Warner Instrument Corporation, VC-6-PINCH) mounted on the inverted microscope stage. Two cells were cultured at each concentration.

[1270] Data analysis

[1271] Further data analysis and curve fitting were performed using Clampfit 10, Excel, and GraphPad Prism. Data are presented as mean ± standard deviation.

[1272] For each cell, the average of the last five current peaks during the monitoring period (no test compound was administered) was used as the peak current for the blank control. At each concentration tested, the average of the last five current peaks was used as the peak current for that concentration for statistical analysis. The percentage inhibition of hKv1.3 current at each tested concentration was calculated using the following formula:

[1273] (1-peak current recorded after compound perfusion / peak current recorded before compound perfusion) × 100%

[1274] Final inhibitory concentration (IC50) 50 The value is obtained by fitting the Hill equation:

[1275] where y=I / I control ; max = 100%; min = 0%; [drug] = concentration of test compound; nH = Hill coefficient; IC 50 = half-maximal inhibitory concentration of the test substance.

[1276] 1.3 Experimental results

[1277] The IC50 results of the inhibitory activity of the compounds of the present invention on hKv1.3 potassium ion channel are shown in Table 3

[1278] Table 3 IC inhibitory activity of the compounds of the present invention on hKv1.3 potassium channel 50

[1279] Conclusion: The compounds of the present invention have inhibitory activity against hKv1.3 potassium channel IC 50 <0.1μM, with good inhibitory effect.

[1280] Test Example 2: Manual patch clamp method to detect the effect of the compound of the present invention on hKv1.3 potassium ion channel (HEK293 cells)

[1281] 2.1 Cells

[1282] The HEK293 cell line stably expressing the hKv1.3 ion channel used in this experiment was constructed by Kanglong Chemical. The cell line was cultured in a medium containing 90% DMEM (source: Thermo Fisher Scientific), 10% fetal bovine serum, 100 U / mL penicillin-streptomycin solution (source: Thermo Fisher Scientific), and 6 μg / mL puromycin (source: Sigma). Before the experiment, the cells were digested and the cells were plated at 5×10 5 The cells were seeded at a density of 100 μg / mL in a 3.5 cm culture dish containing a coverslip for subsequent manual patch clamp experiments.

[1283] 2.2 Experimental solution

[1284] 1) Extracellular solution: 132 mM sodium chloride, 4 mM potassium chloride, 3 mM calcium chloride, 0.5 mM magnesium chloride, 11.1 mM glucose and 10 mM HEPES (pH adjusted to 7.35 with sodium hydroxide).

[1285] 2) Intracellular solution: 10 mM EGTA, 10 mM HEPES, 10 mM potassium chloride, 10 mM sodium chloride, 110 mM potassium fluoride (pH adjusted to 7.2 with potassium hydroxide).

[1286] Note: The osmotic pressure of the solution should be controlled between 280 and 300 mOsmol / kg. The solution should be filtered and stored at 4°C before use.

[1287] 2.3 Test compound solution

[1288] The test compound was dissolved in DMSO and prepared into a stock solution with a final concentration of 10 mM. The stock solution was then diluted in a gradient and further diluted into the extracellular fluid to obtain the desired two final concentrations of the test solution, which were (μM): 1 and 0.01 or 0.1 and 10. The DMSO content in the test solution was 0.1-0.3% (volume ratio). 2.4 Experimental Procedure

[1289] 1) The hKv1.3 current measurement method is as follows: Apply a 2-second depolarization command voltage to depolarize the membrane potential from -80 mV to +50 mV, thereby observing the hKv1.3 current. The peak current is the magnitude of the hKv1.3 current.

[1290] 2) The hKv1.3 current used to detect the test compound was recorded continuously for 120 seconds before administration to assess the stability of the hKv1.3 current generated by the test cells. Only cells that were stable within the acceptable range of the evaluation criteria were allowed to proceed to the subsequent compound testing.

[1291] 3) Testing the inhibitory effect of the test compound on hKv1.3 current: First, the hKv1.3 current measured in extracellular fluid containing 0.1% DMSO is used as the detection baseline. After the hKv1.3 current remains stable for at least 5 minutes, solutions containing the test compound are perfused around the cells in order from low concentration to high concentration. After each perfusion, wait for approximately 5 minutes to allow the compound to fully act on the cells and simultaneously record the hKv1.3 current. After the recorded current stabilizes, record the last 5 hKv1.3 current values ​​and take the average as the final current value at the specific concentration. After testing the compound, add 100 μM carvedilol to the same cell to completely inhibit its current and serve as a positive control for the cell.

[1292] 2.5 Data Analysis

[1293] Note: Data is output by PatchMaster software.

[1294] 1) After perfusing the blank solvent or compound gradient solution, the average value of the 5 consecutive current values ​​obtained was calculated and used as the "current magnitude" 空白 ” and “current magnitude 化合物 ”.

[1295] The current suppression percentage is calculated using the following formula.

[1296] 2) The dose-effect curves were fitted using Graphpad Prism 8.0 software.

[1297] 3) The standard deviation of the three sets of data is less than 15 (SD<15)

[1298] 2.6 Experimental Results

[1299] This experiment used manual patch clamp technology to evaluate whether the test compound has a potential inhibitory effect on the voltage-gated potassium channel hKv1.3. The results are shown in Tables 4 and 5.

[1300] Table 4 Inhibitory activity of the compounds of the present invention on hKv1.3 potassium channel (two concentration points, 0.1 μM / 10 μM)

[1301] Table 5 Inhibitory activity of the compounds of the present invention on hKv1.3 potassium channel (two concentration points, 0.01 μM / 1 μM)

[1302] The compound of the present invention has a good inhibitory effect on hKv1.3 potassium ion channel.

Claims

1. A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof: in: Ring A is selected from a 6- to 14-membered fused heterocyclic group, a 6- to 14-membered fused cycloalkyl group, a 6- to 10-membered heteroaryl group, or a 6- to 14-membered fused ring; R 1 is selected from a hydrogen atom or an alkyl group; R 4 is selected from a hydrogen atom, a deuterium atom, an alkyl group or a halogen; X1, X2, X3 are each independently selected from a hydrogen atom, a halogen, a cyano group, an alkyl group, a cycloalkyl group, a halogenated cycloalkyl group or a halogenated alkyl group; Alternatively, X1 and X2, X2 and X3 independently form together with the carbon atoms to which they are attached a 5-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered cycloalkyl or 4-10 membered heterocyclic group, wherein the aryl, heteroaryl, cycloalkyl or heterocyclic group is optionally further substituted with one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy; R 2 is selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5 、-OC(=O)R 5 、-C(=O)OR 5 、-C(=O)R 5 、-NR 6 C(=O)R 7 、-NR 6 C(=O)OR 7 、-NR 6 R 7 、-C(=O)NR 6 R 7 、-S(=O) r NR 6 R 7 or -S(=O) r R 5 wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R A replaced by; R A are the same or different and are each independently selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 ,=O,-C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from =O, -C 1-6 Alkylene-R B , halogen, hydroxyl, cyano, -NR 9 R 10 , alkoxy, aryl or heteroaryl substituents; R B is selected from hydrogen, halogen, hydroxy, cyano, amino, alkoxy, -S(=O) r R 8 or -S(=O)(=NH)R 8 ; R 3 are the same or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group, a cycloalkyl group or an alkoxy group; wherein the alkyl group, the cycloalkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an amino group, an alkyl group or an alkoxy group; Or, two R 3 Together with the same carbon atom to which it is attached, it forms a -C(=O)-; R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent; R 6 and R 7 Each is independently selected from a hydrogen atom, a hydroxyl group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent; Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 3-12 membered heterocyclic group, wherein the 3-12 membered heterocyclic group contains one or more N, O or S(O)r, and the 3-12 membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O)R 8 、-C(=O)OR 8 、-OC(=O)R 8 、-NR 9 R 10 、-C(=O)NR 9 R 10 、-SO2NR 9 R 10 、-NR 9 C(=O)R 10 or -NR 9 C(=O)OR 10 substituted by a substituent; R 8 , R 9 and R 10 Each is independently selected from hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from =O, hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate; n is 0, 1, 2, 3 or 4; and r is each independently 0, 1 or 2; Provided that: when ring A is selected from the following structures, the two R 3 The same carbon atom to which it is attached does not form -C(=O)-: Wherein, ring B is selected from a 5-6 membered heterocyclic group, and n1, n2, and n3 are each independently 0, 1 or 2.

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

3. The compound according to claim 1 or 2, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein X1, X2, and X3 are each independently selected from a hydrogen atom or a halogen.

4. The compound according to claim 1 or 2, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein X1 is selected from a hydrogen atom, and X2 and X3 together with the carbon atom to which they are attached form a phenyl group.

5. The compound according to any one of claims 1 to 4, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound according to general formula (IIA), (IIB) or (IIC), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: X3 is selected from a hydrogen atom or a halogen; R 4 is selected from a hydrogen atom, a deuterium atom or a halogen; Ring A, R 2 , R 3 and n are as defined in claim 1.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 4 A hydrogen atom.

7. The compound according to any one of claims 1 to 6, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt described by general formula (II): in: Ring A, R 2 , R 3 and n are as defined in claim 1.

8. The compound according to any one of claims 1 to 7, or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from a 5-membered / 5-membered bicyclic fused heterocyclic group, a 5-membered / 6-membered bicyclic fused heterocyclic group, a 5-membered / 5-membered bicyclic fused cycloalkyl group or a 5-membered / 6-membered bicyclic fused cycloalkyl group.

9. The compound according to claim 8, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups: in represents the connection site between ring A and the benzene ring in general formula (I), (II), (IIA), (IIB) or (IIC); represents the ring A and R in the general formula (I), (II), (IIA), (IIB) or (IIC) 2 connection site.

10. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 8- to 10-membered bicyclic heteroaryl groups.

11. The compound according to claim 10 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups: in represents the connection site between ring A and the benzene ring in general formula (I), (II), (IIA), (IIB) or (IIC); represents the ring A and R in the general formula (I), (II), (IIA), (IIB) or (IIC) 2 connection site.

12. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from an 8- to 10-membered bicyclic condensed ring.

13. The compound according to claim 12 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from the following groups: in represents the connection site between ring A and the benzene ring in general formula (I), (II), (IIA), (IIB) or (IIC); represents the ring A and R in the general formula (I), (II), (IIA), (IIB) or (IIC) 2 connection site.

14. The compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof according to general formula (IIIA), (IIIB) or (IIIC): Wherein X3 is selected from hydrogen atom or chlorine; R 4 is selected from a hydrogen atom, a deuterium atom, a fluorine atom or a chlorine atom; preferably a hydrogen atom; R 2 and R 3 The definition is as stated in claim 1.

15. The compound according to any one of claims 1 to 14, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from hydrogen atoms, -OR 5 、-C(=O)OR 5 、-C(=O)R 5 、-NR 6 R 7 、-C(=O)NR 6 R 7 , C 1-6 alkyl, 3-10 membered heterocyclic group, 3-6 membered cycloalkyl or 5-6 membered heteroaryl, wherein the C 1-6 The alkyl, 3-6 membered cycloalkyl, 3-10 membered heterocyclic group or 5-6 membered heteroaryl group may be further substituted with one or more R A replaced by; R A the same or different, each independently selected from -C(=O)R 8 、-C(=O)NR 9 R 10 , =O, hydroxyl, halogen, cyano, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered heterocyclic group or 3-6 membered cycloalkyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, 3-10 membered heterocyclyl or 3-6 membered cycloalkyl may be further substituted with one or more selected from =O, halogen, -NR 9 R 10 , hydroxyl, cyano, -C 1-6 Alkylene-R B , C 1-6 substituted by an alkoxy or phenyl substituent; R B is selected from hydrogen, halogen, hydroxy, cyano, amino, alkoxy, -S(=O) r R 8 or -S(=O)(=NH)R 8 ; m is 1, 2 or 3; r is 0, 1 or 2; R 5 are independently selected from hydrogen atoms, C 1-6 alkyl or 3-10 membered heterocyclic group, wherein the C 1-6 The alkyl or 3-10 membered heterocyclic group is optionally further substituted by one or more selected from =O, halogen, hydroxy, cyano, amino, C 1-6 Alkyl or C 1-6 The alkoxy group is substituted with an alkoxy substituent. R 6 are each independently selected from a hydrogen atom; R 7 are independently selected from hydrogen atoms, C 1-6 alkyl or 3-10 membered heterocyclic group, wherein the C 1-6 The alkyl or 3-10 membered heterocyclyl is optionally further substituted with one or more substituents selected from =0, halogen, hydroxy, cyano, amino or 3-10 membered heterocyclyl. R 8 Selected from C 1-6 alkyl or 3-10 membered heterocyclic group, wherein the C 1-6 The alkyl or 3-10 membered heterocyclyl is optionally further substituted with one or more substituents selected from =0, halogen, hydroxy, cyano, amino or 3-10 membered heterocyclyl. R 9 , R 10 Each is independently selected from a hydrogen atom or a methyl group.

16. The compound according to claim 15 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein R 2 Selected from the following groups:

17. The compound according to claim 15 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein R 2 Selected from the following groups: hydrogen atom, carboxyl group, amino group, 18. The compound according to any one of claims 1 to 17, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 3 For hydrogen atoms, C 1-6 Alkyl or C 3-6 Cycloalkyl; wherein the C 1-6 Alkyl or C 3-6 The cycloalkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or amino. Or, two R 3 Together with the carbon atom to which it is attached, it forms a -C(=O)-.

19. The compound according to claim 18, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 3 is a hydrogen atom, a methyl group, a cyclopropyl group, Or, two R 3 Together with the carbon atom to which it is attached, it forms a -C(=O)-.

20. The compound according to any one of claims 1 to 19, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:

21. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 20 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

22. Use of the compound according to any one of claims 1 to 20 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 21 in the preparation of a Kv1.3 potassium channel inhibitor.

23. Use of the compound according to any one of claims 1 to 20 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof or the pharmaceutical composition according to claim 21 in the preparation of a medicament for treating a disease mediated by Kv1.3 potassium channel; preferably, the disease mediated by Kv1.3 potassium channel is an autoimmune disease.

24. The use according to claim 23, wherein the autoimmune disease is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis or chronic kidney disease.

25. Use of the compound according to any one of claims 1 to 20 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 21 in the preparation of a medicament for treating an autoimmune disease.

26. The use according to claim 25, wherein the autoimmune disease is selected from rheumatoid arthritis, psoriasis, systemic lupus erythematosus, atopic dermatitis, ulcerative colitis, Crohn's disease, type I diabetes, obesity, hypertension, transplant rejection, multiple sclerosis, periodontitis or chronic kidney disease.

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