WO2025077671A1 - Polysubstituted aryl derivative and preparation method therefor and use thereof - Google Patents

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

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

Background Art

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

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

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

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

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

Summary of the invention

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

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;

^R1 is selected from a hydrogen atom or an alkyl group;

^R4 is selected from a hydrogen atom, a deuterium atom, an alkyl group or a halogen;

X ₁ , X ₂ , and X ₃ 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 a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -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 group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more ^RA ;

R and ^A are the same or different and are 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 , -SO ₂ NR 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 with one or more substituents selected from ＝O, -C _1-6 alkylene- ^RB , halogen, hydroxy, cyano, -NR ⁹ R ¹⁰ , alkoxy, aryl or heteroaryl;

^RB is selected ^from hydrogen, halogen, hydroxy, cyano, amino, alkoxy, -S(=O) _rR8 or -S(=O)(=NH) ^R8 ; ^R3 are the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, alkyl or alkoxy;

Alternatively, two R ³ together with the same carbon atom to which they are attached form a -C(=O)-;

R ⁵ is each 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 substituents 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 , -SO ₂ NR ⁹ R ¹⁰ , -NR ⁹ C(=O)R ¹⁰ or -NR ⁹ C(=O)OR ¹⁰ ;

^R6 and ^R7 are each 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 substituents selected from hydroxyl group, halogen, nitro group, cyano group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, ^heteroaryl group, = ^O , -C(=O) ^R8 , -C(=O) ^OR8 , ^-OC ₍ = ^O ) ^R8 , ^-NR9R10 , ^{-C(=O)NR9R10 ,} -SO2NR9R10, -NR9C(=O) ^R10 or ^-NR9C (=O) ^OR10 ;

Alternatively, ^R6 and ^R7 together with the atoms to which they are attached 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 substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O) ^R8 , ^-C (=O) ^OR8 , ^-OC (= ^O ₎ ^R8 , ^-NR9R10 , ^-C (=O) ^NR9R10 , ^-SO2NR9R10 , -NR9C(=O) ^R10 or ^-NR9C (=O) ^OR10 ;

R ⁸ , R ⁹ and R ¹⁰ are each 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, two R ³ and the same carbon atom to which they are attached do not form -C(=O)-: Wherein, Ring B is selected from a 5-6 membered heterocyclic group, and n ₁ , n ₂ , and n ₃ are each independently 0, 1 or 2.

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

A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein X ₁ , X ₂ and X ₃ are each independently selected from hydrogen atom or halogen.

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 connected form a phenyl group.

A preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of general formula (IIA), (IIB) or (IIC) or its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

Wherein: X ₃ is selected from hydrogen atom or halogen;

^R4 is selected from a hydrogen atom, a deuterium atom or a halogen;

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

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

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

wherein: Ring A, R ² , R ³ and n are as defined in the general formula (I).

A preferred embodiment of the present invention is a compound of the general formula (I), (II), (IIA), (IIB) or (IIC) or a stereoisomer, a 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.

In a preferred embodiment of the present invention, a compound of formula (I), (II), (IIA), (IIB) or (IIC) or a stereoisomer thereof isomer, 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); It represents the connection site between ring A and ^R2 in the general formula (I), (II), (IIA), (IIB) or (IIC).

A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB) or (IIC) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein ring A is selected from 8-10 membered bicyclic heteroaryl groups.

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:

in represents the connection site between ring A and the benzene ring in general formula (I), (II), (IIA), (IIB) or (IIC); It represents the connection site between ring A and ^R2 in the general formula (I), (II), (IIA), (IIB) or (IIC).

A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB) or (IIC) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein ring A is selected from a 8- to 10-membered bicyclic fused ring.

In a preferred embodiment of the present invention, a compound of formula (I), (II), (IIA), (IIB) or (IIC) or a stereoisomer thereof isomer, 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); It represents the connection site between ring A and ^R2 in the general formula (I), (II), (IIA), (IIB) or (IIC).

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), (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

Wherein X ₃ is selected from hydrogen atom or chlorine;

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

^R2 and ^R3 are as defined in claim 1.

A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R ² is selected from a 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 is optionally further substituted by one or more ^RA ;

^RA are the same or different and are each independently selected from -C(=O) ^R8 , -C(=O ^{) NR9R10} , =O, hydroxy, halogen, cyano, amino, _C1-6 alkyl, _C1-6 alkoxy, 3-10 membered heterocyclyl or 3-6 membered cycloalkyl, wherein said _C1-6 alkyl, _C1-6 alkoxy, 3-10 membered heterocyclyl or 3-6 membered cycloalkyl is optionally further substituted with one or more substituents selected from =O, halogen, ^-NR9R10 , ^hydroxy , cyano, _-C1-6 alkylene- ^RB , _C1-6 alkoxy or phenyl;

^RB is selected ^from hydrogen, halogen, hydroxy, cyano, amino, alkoxy, -S(=O) _rR8 or -S(=O)(=NH) ^R8 ;

m is 1, 2 or 3;

r is 0, 1 or 2;

R ⁵ is independently selected from hydrogen atom, C _1-6 alkyl or 3-10 membered heterocyclic group, wherein the C _1-6 alkyl or 3-10 membered heterocyclic group is optionally further substituted by one or more selected from =O, halogen, hydroxyl, cyano, amino, C _1-6 alkyl or C _1-6 alkane The oxy group is substituted by a substituent.

R ⁶ are each independently selected from a hydrogen atom;

R ⁷ is independently selected from hydrogen atom, C _1-6 alkyl or 3-10 membered heterocyclic group, wherein the C _1-6 alkyl or 3-10 membered heterocyclic group is optionally further substituted by one or more substituents selected from =0, halogen, hydroxyl, cyano, amino or 3-10 membered heterocyclic group.

R ⁸ is selected from C _1-6 alkyl or 3-10 membered heterocyclyl, wherein the C _1-6 alkyl or 3-10 membered heterocyclyl is optionally further substituted by one or more substituents selected from =0, halogen, hydroxy, cyano, amino or 3-10 membered heterocyclyl.

R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom or a methyl group.

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 is selected from the following groups:

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

A preferred embodiment of the present invention is a compound of formula (I), (II), (IIA), (IIB), (IIC), (IIIA), (IIIB) or (IIIC). A compound or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, a C _1-6 alkyl group or a C _3-6 cycloalkyl group; wherein the C _1-6 alkyl group or the C _3-6 cycloalkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or amino.

Alternatively, two R ³ together with the same carbon atom to which they are attached form a -C(=O)-.

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

Alternatively, two R ³ together with the same carbon atom to which they are attached form a -C(=O)-.

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

or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

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.

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

The present invention provides a compound of general 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.

The present invention also provides a use of 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 in the preparation of a medicament for treating a disease mediated by Kv1.3, wherein the disease mediated by Kv1.3 is preferably an autoimmune disease; wherein the 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.

The present invention further provides a use of 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 in the preparation of a drug for treating cancer.

The present invention provides a compound of general 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 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.

Detailed description of the invention

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

"Alkyl" when used as a group or a part of a group refers to a straight or branched aliphatic hydrocarbon group including _C1 - _C20 . Preferably, it is _C1 - _C10 alkyl, and 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.

"Alkylene" refers to a saturated C ₁ -C ₂₀ 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 C ₁ -C ₁₀ alkylene, more preferably C ₁ -C ₆ 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 may be substituted or unsubstituted. "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the atoms forming the ring are carbon atoms, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings, preferably having a 3- to 7-membered monocyclic or 4- to 18-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl may be substituted or unsubstituted.

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

"Fused cycloalkyl" refers to a 4- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share a pair of carbon atoms, one or more rings may contain 0, 1 or more double bonds, but none of the rings has a completely conjugated π The aromatic system of the electron is 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 condensed cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic condensed cycloalkyl. Non-limiting examples of "condensed 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,

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

"Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and all refer to non-aromatic heterocyclic groups, wherein one or more of the atoms forming the ring are selected from nitrogen, oxygen or S(O) _r (wherein r is selected from 0, 1 or 2) heteroatoms, including monocyclic, polycyclic, fused, bridged and spirocyclic rings, preferably having 3 to 7 membered monocyclic rings 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,

The heterocyclic group may be substituted or unsubstituted.

"Spiro heterocyclic group" refers to a polycyclic group of 5 to 18 yuan, two or more cyclic structures, and one atom is shared between the monocyclic rings, and the ring 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, it is 6 to 14 yuan, and more preferably 7 to 10 yuan. According to the number of shared spiral atoms between the rings, the spiro alkyl is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group, more preferably a 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 single spiral heterocyclic group. Non-limiting examples of "spiroheterocyclyl" 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,

"Fused heterocyclic group" refers to a polycyclic group containing two or more cyclic structures that share a pair of 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, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) _r (wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon, preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic 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]dioxine,

"Bridged heterocyclic group" refers to a 5 to 18-membered polycyclic group containing two or more cyclic structures, which share 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, and 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[2.2.1]heptyl, Cyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl,

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is a C ₆ -C ₁₀ aromatic group, more preferably, the aryl group is phenyl and naphthyl, and most preferably, it is naphthyl. The aryl group may be substituted or unsubstituted.

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

A heteroaryl group can be substituted or unsubstituted.

"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 heteroatoms selected from nitrogen, oxygen or S(O) _r (wherein r is selected from 0, 1 or 2), and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl and a monocyclic heterocyclic group or a monocyclic cycloalkyl, preferably 6 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include, but are not limited to:

"Alkoxy" refers to a group of (alkyl-O-), wherein alkyl is as defined herein. C ₁ -C ₆ alkoxy is preferred, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

"Nitro" refers to a _-NO2 radical.

"Hydroxy" refers to an -OH group.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Benzyl" refers to _-CH2 -phenyl.

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

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

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

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

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

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

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to tert-butoxycarbonyl.

"Bn" refers to benzyl.

"THP" refers to 2-tetrahydropyranyl.

"TFA" refers to trifluoroacetic acid.

“FA” stands for formic acid.

"Ts" refers to p-toluenesulfonyl.

"Bn" refers to benzyl.

"SEM" refers to (trimethylsilyl)ethoxymethyl.

"Leaving group", or leaving group, is an atom or functional group that leaves a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called 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 are easy to accept electrons and have strong negative charge tolerance 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 leave other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to combine with other atoms, and the tendency to exist as an anion (or electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, mesyl, -OTs or -OH.

"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 the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds. The term “substituted” or “substituted” as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, halocycloalkyl, haloalkoxy, hydroxyalkyl, carboxyl, carboxylate, =O, ^OR5 , OC(=O) ^R5 , -C(=O) ^R5 , -C(=O) ^OR5 , ^-NR6C (=O) ^R7 , ^-NR6C (=O) ^OR7 , ^-NR6R7 , ^-C (=O) ^NR6R7 , _-S (= ^{O ) rNR6R7} or -S(=O) _r R ⁵ ;

R ⁵ is each 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 substituents 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 , -SO ₂ NR ⁹ R ¹⁰ , -NR ⁹ C(=O)R ¹⁰ or -NR ⁹ C(=O)OR ¹⁰ ; R ⁶ and R ⁷ are each 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 substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl ^, heteroaryl, =O, -C(=O) ^R8 , -C(=O) ^OR8 , ^{-OC(=O)R8 , -NR9R10} , ^-C ( ⁼ O ₎ ^NR9R10 , -SO2NR9R10, -NR9C(=O) ^R10 or ^-NR9C (=O) ^{OR10 ;}

Alternatively, ^R6 and ^R7 together with the atoms to which they are attached 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 substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O) ^R8 , ^-C (=O) ^OR8 , ^-OC (= ^O ₎ ^R8 , ^-NR9R10 , ^-C (=O) ^NR9R10 , ^-SO2NR9R10 , -NR9C(=O) ^R10 or ^-NR9C (=O) ^OR10 ;

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 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;

r is independently 0, 1 or 2.

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

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

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

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

Synthesis method of the compound of the present invention

In order to achieve the purpose of the present invention, the present invention adopts the following technical scheme:

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

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

in:

Y is selected from halogen;

W is selected from boric acid or

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

^R1 is selected from a hydrogen atom;

X ₁ , X ₂ , X ₃ , R ² , R ³ , R ⁴ and n are as defined in the general formula (I).

DETAILED DESCRIPTION

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

Example

The examples give the preparation of representative compounds represented by formula (I) and the relevant 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. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR representation method: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplet. If coupling constants are provided, their units are Hz.

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

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

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

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

CD ₃ OD: deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

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

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

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

Example 1

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

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

first step

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

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

4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidin-2-one 1a (300 mg, 797.13 μmol, prepared according to the patent WO2021183994) was added to dichloromethane (3 mL), and trimethyloxonium tetrafluoroborate (117.90 mg, 797.13 μmol) was added under ice bath conditions, and stirred at room temperature for 3 hours. The mixture was quenched with saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate. The mixture was filtered and concentrated under reduced pressure to give 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 step.

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

Step 2

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

4-(2,3-Dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidine-2-imine

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, concentrated under reduced pressure, and 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+H ₂ O, mobile phase B: CH ₃ CN) to obtain 4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)pyrrolidine-2-imine 1c (130 mg), yield: 67.6%.

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

Step 3

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

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

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)pyrrolidine-2-imine 1c (130 mg, 346.33 μmol) were added, and the mixture was heated to 60°C for 6 hours. After the reaction was completed after mass spectrometry detection, the product was filtered and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column: Waters 3767 Column: SunFire Sunfire C18, 19*250 mm, 10 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 1-(4-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-2-iminopyrrolidin-1-yl)-4-hydroxybutan-2-one 1e (20 mg) with a yield of 12.5%.

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

Step 4

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

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

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 directly used in the next reaction.

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

Step 5

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

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

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, and 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+H ₂ O, mobile phase B: CH 3 CN) 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), with a yield of 57.1%.

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

Example 2 and Example 3

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

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

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

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

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 separated 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.

Single configuration compound (short retention time):

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

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

¹ H NMR (400MHz, DMSO-d ₆ )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).

Single configuration compound (longer retention time):

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

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

¹ H NMR (400MHz, DMSO-d ₆ )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).

Example 4

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

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

first step

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

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

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 solution was filtered and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (eluent: B system) to obtain 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4b (380 mg), with a yield of 54.54%.

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

Step 2

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

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

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(diphenyl) [7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4d (230 mg) was obtained. The yield was 45.68%.

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

Step 3

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

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

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), and then platinum dioxide (80.78 mg, 355.87 μmol) was added. The reaction solution was stirred at room temperature for 12 hours under a hydrogen atmosphere. The reaction solution was filtered and concentrated under reduced pressure to obtain 2-(7-(2,3-dichloro-6-methoxyphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 4e (100 mg) with a yield of 82.35%.

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

Step 4

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

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

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) was dissolved in dichloromethane (1 mL), cooled to -78°C, and then added with boron tribromide (2 mL). The reaction was carried out 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 residue was separated 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+H ₂ O, mobile phase B: CH ₃ CN) 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%.

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

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).

Example 5

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

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

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 added with boron tribromide (2 mL). The reaction mixture was reacted for 1 hour in an ice bath. Methanol (2 mL) was added to the reaction mixture to quench the reaction mixture, and the reaction mixture 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+H ₂ O, mobile phase B: CH ₃ CN) to obtain 3,4-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 5 (20.15 mg) with a yield of 30.04%.

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

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).

Example 6

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

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

first step

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

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

5-Bromopyridin-2-amine 6a (1.0 g, 5.78 mmol) was dissolved in ethanol (10 mL) and 1-bromo-4-hydroxybutan-2-one was added. 1d (1.45 g, 8.67 mmol) and sodium bicarbonate (971.16 mg, 11.56 mmol), the mixture was stirred at 80 ° C for 12 hours. The reaction solution was concentrated under reduced pressure, 10% sodium bicarbonate aqueous solution was added to adjust the pH to 8-9, extracted with n-butanol (10 mL × 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 obtain 2-(6-bromoimidazo[1,2-a]pyridin-2-yl)ethan-1-ol 6b (717 mg), with a yield of 51.45%.

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

Step 2

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

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

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, and nitrogen was replaced 3 to 5 times. 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%.

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

Step 3

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

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

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 obtained 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+H ₂ O, mobile phase B: CH ₃ CN) to obtain 3,4-dichloro-2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-6-yl)phenol 6 (21.3 mg) with a yield of 44.45%.

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

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).

Example 7

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

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

first step

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

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

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

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

Step 2

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

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

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, 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)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)phenol 7 (5.02 mg) with a yield of 8.73%.

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

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).

Example 8

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

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

first step

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

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

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), and then sodium bicarbonate (482.82 mg, 5.75 mmol) was added and stirred at 80° C. for 12 hours. The reaction solution was filtered and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (eluent: B system) to obtain 2-(6-bromoimidazo[1,2-b]pyridazin-2-yl)ethan-1-ol 8b (500 mg) with a yield of 77.18%.

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

Step 2

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

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

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 solution 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%.

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

Step 3

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

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

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 added with boron tribromide (2 mL). The reaction was carried out in an ice bath for 1 hour. The reaction solution was quenched with methanol (2 mL) at -78°C and 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+H ₂ O, mobile phase B: CH ₃ CN) to obtain 3,4-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-b]pyridazin-6-yl)phenol 8 (5.1 mg), yield: 8.79%.

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

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).

Example 9

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

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

first step

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

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

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), protected by nitrogen, sealed with a tube, heated to 100 °C and stirred overnight. The reaction solution was concentrated under reduced pressure, water (20 mL) was added, 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) with a yield of 42.60%.

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

Step 2

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

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

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 reaction mixture was stirred for 1 hour. The reaction solution was quenched with methanol (2 mL) at -78°C and 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+H ₂ O, mobile phase B: CH ₃ CN) to give chloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 9 (7.03 mg) with a yield of 14.74%.

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

¹ H 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).

Example 10

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

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

first step

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

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

(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), and 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, extracted with ethyl acetate (15 mL×3), the combined organic phase was washed with saturated sodium chloride solution (15 mL×3), and dried over anhydrous sodium sulfate. The 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) with a yield of 78.59%.

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

Step 2

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

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

7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 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, and the mixture was slowly reacted at room temperature for 18 hours. Water (15 mL) was added to the reaction solution, and ethyl acetate was extracted (15 mL×3). The combined organic phase was washed with saturated sodium chloride solution (15 mL×3), dried over anhydrous sodium sulfate, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 10 (20 mg), with a yield of 9.34%.

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

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＝8.9 Hz,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.

Embodiment 11

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

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

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 was completed, 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+H ₂ O, mobile phase B: CH ₃ CN) 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%.

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

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＝8.9 Hz,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.

Example 12

phenol

phenol

first step

benzyl 3-(chlorocarbonyl)pyrrolidine-1-carboxylate

Benzyl 3-(Chlorocarbonyl)pyrrolidine-1-carboxylate

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

Step 2

benzyl 3-(2-diazoacetyl)pyrrolidine-1-carboxylate

Benzyl 3-(2-diazoacetyl)pyrrolidine-1-carboxylate

3-(Chlorocarbonyl)pyrrolidine-1-carboxylic acid benzyl ester 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, and the mixture was stirred at -10°C for 2 hours to obtain 3-(2-diazoacetyl)pyrrolidine-1-carboxylic acid benzyl ester 12c, which was directly used in the next step reaction.

Step 3

benzyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate

Benzyl 3-(2-bromoacetyl)pyrrolidine-1-carboxylate

To a mixed solution of 3-(2-diazoacetyl)pyrrolidine-1-carboxylic acid benzyl ester 12c (1.62 g, 5.93 mmol) in tetrahydrofuran (10 mL) and acetonitrile (10 mL) was added a 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 ethyl acetate was extracted (50 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain 3-(2-bromoacetyl)pyrrolidine-1-carboxylic acid benzyl ester 12d (1.42 g) with a yield of 73.44%.

Step 4

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

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

4-Bromopyridin-2-amine 4a (500 mg, 2.89 mmol), 3-(2-bromoacetyl)pyrrolidine-1-carboxylic acid benzyl ester 12d (1.13 g, 3.47 mmol), 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 completed, the reaction solution was filtered to remove the insoluble matter, and purified by silica gel column chromatography (eluent: A system) to obtain 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylic acid benzyl ester 12e (506 mg) with a yield of 43.74%. MS m/z (ESI): 399.8 [M+1]

Step 5

benzyl

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

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

(2,3-Dichloro-6-methoxy-phenyl)boronic acid 4c (150 mg, 679.21 μmol), 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidine-1-carboxylic acid benzyl ester 12e (271.87 mg, 679.21 μmol), cesium carbonate (442.60 mg, 1.36 mmol), [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 by nitrogen, and the reaction was stirred at 80°C for 18 hours. The insoluble matter was removed by filtration and 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%.

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

Step 6

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

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

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 bath, and the temperature was slowly raised to room temperature and stirred for 6 hours. After the reaction was completed, 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 I.D.; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain 3,4-dichloro-2-(2-(pyrrolidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol 12 (84 mg) with a yield of 34.61%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 13

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

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

first step

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

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

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 then 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 phase was 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) with a yield of 98.60%.

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

Step 2

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

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

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, and 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×3). The combined organic phase was 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 2-(2-azidoethyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 13b (65 mg) with a yield of 82.81%.

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

Step 3

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

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

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 and heated to 60°C for 6 hours. The reaction solution was directly concentrated and the residue was purified by silica gel column chromatography (eluent: A system) to obtain 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethane-1-amine 13c (25 mg) with a yield of 41.44%.

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

Step 4

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

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

2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethane-1-amine 13c (25 mg, 74.36 μmol) was dissolved in dichloromethane (5 mL) and then added with boron tribromide (186.28 mg, 743.57 μmol) and reacted at room temperature for 18 hours. The reaction solution was quenched by adding methanol and concentrated. The obtained 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 obtain 2-(2-(2-aminoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 13 (10 mg) with a yield of 30.21%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Embodiment 14

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

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

first step

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

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

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, saturated sodium bisulfite solution was added to quench. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: A system) to obtain 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one 14b (1.05 g, 5.17 mmol) with a yield of 64.20%.

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

Step 2

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

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

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), and 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 × 3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography (washing The product was purified by degassing with the solvent (system A) to give 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridine 14c (1.5 g, 5.41 mmol) in a yield of 57.26%.

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

Step 3

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

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

(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]palladium dichloride (48.18 mg, 65.84 μmol) were added, and the mixture was heated to 100 °C under argon protection 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 phase was 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) with a yield of 81.38%.

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

Step 4

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

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

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, boron tribromide (268.48 mg, 1.07 mmol) was slowly added dropwise, and the mixture was slowly transferred to room temperature for reaction 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+H ₂ O, mobile phase B: CH 3 CN) to give 3,4-dichloro-2-(2-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyridin-7-yl)phenol 14 (35 mg) with a yield of 17.99%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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,1 H),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.

Embodiment 15

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

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

first step

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

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

4-Bromopyridin-2-amine 4a (1g, 5.78mmol), 3-bromo-2-oxo-propionic acid ethyl ester 15a (5.64g, 28.90mmol, 3.63mL, commercially available), sodium carbonate (1.84g, 17.34mmol) were added to ethanol (10mL), sealed and stirred at 80°C for 4 hours. Water (30mL) was added to the reaction solution, extracted with ethyl acetate (30mL×3), the combined organic phase was washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 7-bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 15b (700mg), with a yield of 45.01%.

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

Step 2

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

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

7-Bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 15b (420 mg, 1.56 mmol) was dissolved in methanol (10 mL) and then lithium hydroxide monohydrate (654.91 mg, 15.61 mmol) and water (2 mL) were added and reacted at room temperature for 3 hours. The reaction solution was concentrated, acidified by adding dilute hydrochloric acid and then concentrated. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 7-bromoimidazo[1,2-a]pyridine-2-carboxylic acid 15c (376 mg) with a yield of 99.94%.

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

Step 3

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

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

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 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 phase was washed with a 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 obtain tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate. 15e (280 mg), yield 97.00%.

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

Step 4

tert-butyl

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

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

(2,3-Dichloro-6-methoxy-phenyl)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), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (39.76 mg, 54.34 μmol) were mixed, 1,4-dioxane (10 mL) and water (1 mL) were added, and the mixture was heated at 110°C for 4 hours after argon replacement. Water (30 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the combined organic phase was washed with saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)piperazine-1-carboxylate 15f (220 mg) with a yield of 80.11%.

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

Step 5

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

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

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 then added with boron tribromide (247.85 mg, 989.33 μmol) and reacted at room temperature for 18 hours. The reaction was quenched by adding methanol under 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+H ₂ O, mobile phase B: CH ₃ CN) to give (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperazine-1-yl)methanone 15 (30 mg) with a yield of 59.41%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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),7.0 3–6.95(m,1H),6.90(dd,J＝7.0,1.6Hz,1H),4.53(brs,2H),3.85(brs,2H),3.22(s,4H)ppm.

Example 16

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

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

first step

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

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

7-Bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 15b (1 g, 3.72 mmol) was added to tetrahydrofuran (10 mL), methylmagnesium bromide (3M, 2.48 mL) was added dropwise under ice bath, and the mixture was heated to room temperature and stirred for 2 hours. Water (30 mL) was added to the reaction solution, and ethyl acetate was used for extraction (30 mL×3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol 16a (238 mg) with a yield of 25.10%.

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

Step 2

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

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

(2,3-Dichloro-6-methoxy-phenyl)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]palladium dichloride (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), and the air was replaced by nitrogen. 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 obtain 2-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)propan-2-ol 16b (120 mg) with a yield of 87.16%.

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

Step 3

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

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

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), and boron tribromide (341.66 mg, 1.37 mmol) was added dropwise under ice bath, and stirred for 3 hours. Water (1 mL) was added to quench the reaction and the mixture 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+H ₂ O, mobile phase B: CH ₃ CN) to give 3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol 16 (71.4 mg) with a yield of 58.84%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Embodiment 17

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

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

first step

methyl 4-bromo-3-oxopentanoate

Methyl 4-bromo-3-oxopentanoate

Bromine (920.97 mg, 5.76 mmol, 295.18 μL) was added dropwise 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 nitrogen atmosphere. The resulting mixture was stirred at 25°C for 15 hours under nitrogen atmosphere. 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 layer was 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: A system) to obtain methyl 4-bromo-3-oxopentanoate 17b (240 mg) with a yield of 29.88%.

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

Step 2

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

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

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 by microwave under nitrogen atmosphere and reacted for 1 hour. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: A system) to give methyl 2-(7-bromo-3-methylimidazo[1,2-a]pyridin-2-yl)acetate 17c (358 mg) in a yield of 43.75%.

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

Step 3

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

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

Methyl 2-(7-bromo-3-methylimidazo[1,2-a]pyridin-2-yl)acetate 17c (348 mg, 1.23 mmol) and (2,3-dichloro-6-methoxy-phenyl)boronic acid 4c (271.45 mg, 1.23 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (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 for 3 hours under nitrogen atmosphere. The mixture was cooled to room temperature and the resulting mixture was diluted with water. The resulting mixture was extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure and 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) with a yield of 52.77%.

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

Step 4

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

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

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 aqueous hydrogen bromide (48%, 20 mL) and stirred at 100°C for 12 hours. The mixture was concentrated in vacuo to give 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.

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

Step 5

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

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

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 obtained 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 obtain 3,4-dichloro-2-(2-(2-hydroxyethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol 17 (85 mg) with a yield of 34.57%. MS m/z (ESI): 337.0 [M+1]

¹ H NMR (400MHz, DMSO-d ₆ )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.

Embodiment 18

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

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

first step

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

tert-Butyl 3-(3-(dimethyl(oxo)-λ ^6sulfonamide sulfoxide)-2-oxopropyl)azetidine-1-carboxylate

At room temperature, 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) were added to a solution of 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid 18a (2 g, 9.29 mmol) in tetrahydrofuran (20 mL), and the mixture was stirred at 25°C for 16 hours. At room temperature, potassium tert-butoxide (1 M, 27.88 mL) was added to a solution of trimethyl sulfoxide chloride (3.59 g, 27.88 mmol) in tetrahydrofuran (20 mL), 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: System A) to give tert-butyl 3-(3-(dimethyl(oxo)-λ ^6sulfonamide sulfoxide)-2-oxopropyl)azetidine-1-carboxylate 18b (1 g) with a yield of 37.19%.

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

Step 2

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

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

At 0°C, lithium bromide (252.10 mg, 2.90 mmol) was added to a solution of tert-butyl 3-(3-(dimethyl(oxo)-λ ^6sulfonamide sulfoxide)-2-oxopropyl)azetidine-1-carboxylate 18b (700 mg, 2.42 mmol) in tetrahydrofuran (10 mL), 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 the reaction was completed, water (20 mL) was added to dilute the reaction solution, extracted with ethyl acetate (20 mL×3), and 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 to obtain The residue was separated and purified by column chromatography (eluent: System B) to give tert-butyl 3-(3-bromo-2-oxopropyl)azetidine-1-carboxylate 18c (150 mg) in a yield of 21.22%.

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

Step 3

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

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

4-Bromopyridin-2-amine 4a (88.82 mg, 513.40 μmol) and sodium bicarbonate (86.26 mg, 1.03 mmol) were added to a solution of tert-butyl 3-(3-bromo-2-oxopropyl)azetidine-1-carboxylate 18c (150 mg, 513.40 μmol) in ethanol (5 mL), 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 obtained residue was separated and purified by column chromatography (eluent: B system) to obtain tert-butyl 3-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylate 18d (100 mg) with a yield of 53.18%.

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

Step 4

tert-butyl

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

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

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), and 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 protection for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the 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) with a yield of 75.44%.

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

Step 5

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

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

3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)azetidine-1-carboxylic acid tert-butyl ester 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 excess salt was removed by beating with dichloromethane. The product 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 I.D.; 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%.

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

¹ H NMR (400MHz, DMSO-d ₆ ) δ8.49 (d, J = 6.8 Hz, 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.

Embodiment 19

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

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

first step

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

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

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, washed with isopropyl ether, and the solid was collected to obtain ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate 19a (4.31 g), which was directly used for the next step without further purification.

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

Step 2

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

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

2-(4-bromo-2-iminopyridin-1(2H)-yl)acetic acid ethyl ester 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. After cooling to room temperature, ice water (20 mL) was added, and the pH of the reaction solution was adjusted to 7-8 with aqueous ammonia at 0°C, extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (eluent: B system) to obtain 2,7-dibromoimidazo[1,2-a]pyridine 19b (850 mg) with a yield of 18.52%.

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

Step 3

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

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

(2,3-Dichloro-6-methoxy-phenyl)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), [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 module was heated for 18 hours. The reaction solution was directly concentrated, and the obtained residue was separated and purified by column chromatography (eluent: B system) to obtain 2-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 19c (350 mg) with a yield of 51.92%. MS m/z(ESI):371.9[M+3]

Step 4

tert-butyl

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

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

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), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (32.68 mg, 40.32 μmol) was added under nitrogen, and the system was replaced with nitrogen three times. The reaction mixture was stirred at 110°C under nitrogen protection for 18 hours. After the reaction was completed, 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 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) with a yield of 37.71%.

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

Step 5

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

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

3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2,5-dihydro-1H-pyrrole-1-carboxylic acid tert-butyl ester 19e (60 mg, 130.34 μmol) was dissolved in dichloromethane (1.5 mL), and then boron tribromide (0.3 mL) was added dropwise at -78 °C. After the addition, 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/L A: 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%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

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

Embodiment 20

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

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

first step

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

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

7-Bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 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 and reacted for 3 hours. Methanol was added for dilution and purification by column chromatography (eluent: B system) to obtain (7-bromoimidazo[1,2-a]pyridin-2-yl)methanol 20a (360 mg) with a yield of 85.33%. MS m/z (ESI): 227.0 [M+1]

Step 2

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

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

(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, and the mixture was reacted at 0°C for 3 hours. The mixture was quenched with water, extracted with dichloromethane/isopropanol (3:1) (30 mL×3), and the combined organic phase was washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered and dried, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain 7-bromo-2-(bromomethyl)imidazo[1,2-a]pyridine 20b (250 mg) with a yield of 54.38%.

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

Step 3

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

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

3-Oxopiperazine-1-carboxylic acid tert-butyl ester 20c (124.30 mg, 620.79 μmol) was added to tetrahydrofuran (1 mL), sodium hydride (31.04 mg, 775.98 μmol, 60% purity) was added, and the mixture was reacted in an ice bath for 30 minutes. 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 hours. The mixture was quenched with ice water (10 mL), extracted with ethyl acetate (30 mL×3), and 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) with a yield of 66.12%.

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

Step 4

tert-butyl

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

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

4-((7-bromoimidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylic acid tert-butyl ester 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-methoxy-phenyl)boronic acid 4c (21.58 mg, 97.73 μmol), potassium phosphate (62.24 mg, 293.20 μmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (7.94 mg, 9.77 μmol), and heated to 80 °C 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 phase was washed with a 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: B system) to obtain tert-butyl 4-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3-oxopiperazine-1-carboxylate 20e (30 mg), with a yield of 60.74%. MS m/z (ESI): 505.2 [M+1].

Step 5

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

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

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

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

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

Embodiment 23

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

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

first step

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

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

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 WO2013021054) were dissolved in 1,4-dioxane (10 mL) and water (2 mL), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (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 protection for 2 hours. After the reaction was completed, the residue was concentrated and purified by column chromatography (eluent: System A) to give 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) with a yield of 44.61%. MS m/z(ESI):500.1[M+1].

Step 2

tert-butyl

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

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

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

Step 3

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

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

Boron tribromide (100 mg, 0.4 mmol) was added to 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. The reaction mixture was then stirred at 0 °C for 10 minutes. After the reaction was complete, methanol was added at -78 °C to quench the reaction and the pH was adjusted to 8 with saturated sodium bicarbonate solution. The 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 (Waters 2767/Qda column: SunFire C18[UNK]19×250mm[UNK]10um mobile phase A: 0.1% formic acid/water, B: acetonitrile; flow rate: 20mL/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) with a yield of 39.69%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Embodiment 25

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

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

first step

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

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

4-Bromopyridin-2-amine 4a (160 mg, 24.80 μmol) was added to isopropanol (3 mL), and tert-butyl 3-(2-bromoacetyl)piperidine-1-carboxylate 25a (424.75 mg, 1.39 mmol, prepared according to the patent publication "WO2011025690") was added, and heated to 100 °C for 2 hours. Water (20 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (30 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 residue was separated by silica gel column chromatography (eluent: B system) to obtain tert-butyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylate 25b (200 mg), with a yield of 56.87%.

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

Step 2

tert-butyl

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

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

3-(7-bromoimidazo[1,2-a]pyridin-2-yl)piperidine-1-carboxylic acid tert-butyl ester 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]dichloropalladium (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 hours. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was 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) with a yield of 59.87%.

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

Step 3

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

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

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 a dichloromethane solution of boron tribromide (0.5 mL) and reacted at room temperature for 2 hours. Methanol was added to quench the mixture and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid phase separation (Waters 3767/QDA column: SunFire C18, 19*250mm, 10um; mobile phase A: 10mmol/L A: 0.1% formic acid/water, B: acetonitrile; flow rate: 20ml/min) to obtain 3,4-dichloro-2-(2-(piperidin-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol 25 (10 mg) with a yield of 31.01%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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＝8.9,2.0H z,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.

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

Embodiment 26

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

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

first step

tert-butyl

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

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

3-(7-Bromoimidazo[1,2-a]pyridine-2-carbonyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 15c (50 mg, 207.43 μmol), 3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester 26a (44.04 mg, 207.43 μmol, commercially available), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (236.62 mg, 622.30 μmol) were mixed, and N,N-dimethylformamide (4.82 mL) and N,N-diisopropylethylamine (134.04 mg, 1.04 mmol, 180.65 μL) were added, and the mixture was reacted at room temperature for 18 hours. Water (20 mL) was added to the reaction mixture, 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) with a yield of 68.66%.

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

Step 2

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

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

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 mixed, 1,4-dioxane (10 mL) and water (1 mL) were added, and the atmosphere was replaced with argon and heated in an oil bath at 100°C for 4 hours. 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) with a yield of 79.27%.

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

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

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

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 then boron tribromide (1 M, 1.13 mL) was added and 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/L A: 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) with a yield of 58.35%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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,1H),6.91(d d,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.

Embodiment 29

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

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

first step

tert-butyl 4-(2-tosylhydrazineylidene)piperidine-1-carboxylate

tert-Butyl 4-(2-toluenesulfonylhydrazide)piperidine-1-carboxylate

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

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

Step 2

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

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

7-Bromoimidazo[1,2-a]pyridine-2-carbaldehyde 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, extracted with ethyl acetate (30 mL×3), washed with saturated ammonium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: B system) to obtain tert-butyl 4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylate 29d (583 mg), with a yield of 41.25%. MS m/z(ESI):408.1[M+1]

Step 3

tert-butyl

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

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

(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) were mixed, 1,4-dioxane (10 mL) and water (1 mL) were added, and the mixture was replaced with argon and reacted 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) with a yield of 64.76%.

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

Step 4

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

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

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 then added with boron tribromide (1M, 1.59 mL) under ice-water bath and reacted at room temperature for 18 hours. After the reaction was completed, methanol was quenched and concentrated to obtain (7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperidin-4-yl)methanone 29 (55 mg) with a yield of 67.39%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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＝8.9H z,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.

Embodiment 30

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

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

first step

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

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

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 pH ≤ 5. The reaction solution was concentrated under reduced pressure to give 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)acetic acid 30a (1.5 g), which was used directly in the next step.

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

Step 2

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

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

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) with 1-hydroxybenzotriazole (635.69 mg, 4.70 mmol) and 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) and stirred at room temperature for 18 hours under nitrogen atmosphere. The resulting mixture was acidified with aqueous hydrochloric acid solution (1 M) to pH ≤ 7. Diluted with water (30 mL) and extracted with dichloromethane (3×30 mL). The combined organic layer was washed with aqueous sodium bicarbonate solution (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 a yield of 11.30%.

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

Step 3

tert-butyl

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

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

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]dichloropalladium (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 nitrogen atmosphere for 1 hour. Cool to room temperature, dilute with water (30 mL), and extract with dichloromethane (3×20 mL). The combined organic phase was 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%.

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

Step 4

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

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

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 a solution of boron tribromide (1M, 5 mL) in dichloromethane at 0°C. 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 phase separation (mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 40 mL/min) to give 2-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-(piperazin-1-yl)ethane-1-one 30 (15 mg) in a yield of 15.51%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Example 69 was synthesized according to the synthesis method of Example 30 of the present invention, and the structure and characterization data are shown in the following table:

Embodiment 33

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

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

first step

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

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

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

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

Step 2

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

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

7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 33a (2.25 g, 6.16 mmol) was dissolved in Methanol (50 mL) was followed by the addition of lithium hydroxide monohydrate (775.53 mg, 18.48 mmol) and water (5 mL), and the reaction was carried out at room temperature for 18 hours. The reaction solution was concentrated, water (50 mL) was added, and hydrochloric acid was adjusted to weak acidity, and extracted with ethyl acetate (3×30 mL). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 33b (1.6 g) with a yield of 77.03%.

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

Step 3

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

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

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)urea 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, and 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 phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: System A) to obtain 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) with a yield of 91.23%.

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

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

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

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) and reacted at room temperature for 18 hours. The reaction solution was quenched with methanol and concentrated. The (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) was obtained by preparative liquid separation (mobile phase A: water (0.05% trifluoroacetic acid), mobile phase B: acetonitrile; flow rate: 40 mL/min) with a yield of 14.26%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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,1 H),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.

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

Embodiment 35

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

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

first step

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

1-(7-Bromoimidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylic acid ethyl ester

4-Bromopyridin-2-amine 4a (220.79 mg, 1.28 mmol) and 1-(2-bromoacetyl)cyclopropanecarboxylic acid ethyl ester 36a (300 mg, 1.28 mmol) were dissolved in a mixed solvent 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 it was extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: B system) to obtain 1-(7-bromoimidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylic acid ethyl ester 36b (120 mg) with a yield of 30.41%. MS m/z (ESI): 309.1 [M+1]

Step 2

ethyl

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

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

(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), and 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×3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (eluent: B system) to give 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)cyclopropane-1-carboxylic acid ethyl ester 36c (120 mg) with a yield of 45.77%. MS m/z(ESI):405.1[M+1]

Step 3

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

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

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, and the mixture was slowly transferred to room temperature for 1 hour. After quenching with ice water (20 mL), the mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was 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%.

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

Step 4

109.82μmol) was dissolved in dichloromethane (2mL) and cooled to -78℃. Boron tribromide (0.2mL) was added dropwise at -78℃. After the addition was completed, the mixture was heated to 0℃ for 10 minutes. After the reaction was completed, the reaction solution was quenched with methanol (2mL) at -78℃, 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 slurrying with dichloromethane. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×19mm I.D.; 10μm, 20mL/min; mobile phase A: 10mmol/L ammonium bicarbonate + water, mobile phase B: acetonitrile) to obtain 1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)azetidine-3-ol 37 (8mg) with a yield of 20.80%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Embodiment 38

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

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

first step

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

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

1-(tert-Butyloxycarbonyl)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), and 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 by adding water (15 mL), extracted with ethyl acetate (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate 38c (1.1 g) with a yield of 91.7%. MS m/z (ESI): 203.0 [M-55]

Step 2

tert-butyl

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

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

Under nitrogen protection at -78°C, n-butyl lithium (2.5M n-hexane solution) (22.38 mg, 349.42 μmol) was added 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). The reaction mixture was then stirred at -78°C for 30 minutes, followed by a solution of tert-butyl 3-(methoxy(methyl)carbamoyl)pyrrolidine-1-carboxylate 38c (90.26 mg, 349.42 μmol) in tetrahydrofuran (2 mL) which was then slowly added dropwise, and then warmed to room temperature and stirred under nitrogen protection for 2 hours. After the reaction was completed, saturated ammonium chloride (10 mL) was added to the reaction mixture, extracted with ethyl acetate (10 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl 3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)pyrrolidine-1-carboxylate 38d (50 mg) with a yield of 37.9%.

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

Step 3

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

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

Boron tribromide (0.2 mL) was added 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) 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 filtrate was decompressed to remove the solvent, and the residue was purified by preparative liquid separation (separation column Waters 3767/QDA SunFire C18*19*250mm*10um mobile phase A: 10mmol/L A: +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%.

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

¹ H NMR (400MHz, DMSO-d ₆ )δ9.04(s,1H),8.29(s,1H),8.04(s,1H),7.94(s,1H),7.87(s,1H),7.53(d,J＝8.9Hz,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.

Embodiment 39

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

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

first step

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

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

2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-7-azaspiro[3.5]non-1-ene-7-carboxylic acid tert-butyl ester 39a (150 mg, 429.47 μmol, prepared according to the patent publication 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%.

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

Step 2

tert-butyl

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

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

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

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

Step 3

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

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

2-(7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-7-azaspiro[3.5]nonane-7-carboxylic acid tert-butyl ester 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 product 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 I.D.; 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]non-2-yl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 39 (12 mg) with a yield of 38.51%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Embodiment 40

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

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

first step

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

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

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-dicyclohexylphosphine)-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, and then the reaction mixture was stirred at 100 ° C under nitrogen protection for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System B) to obtain tert-butyl (7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)carbamate 40a (50 mg) with a yield of 91.1%.

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

Step 2

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

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

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) solution, and then boron tribromide (0.2 mL) was added at -78 °C. The reaction 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 filtrate was decompressed to remove the solvent and the residue was purified by preparative liquid separation (Waters 2767/QDA column: SunFire C18, 19*250mm, 10um; mobile phase A: 10mmol/L A: 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%.

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

¹ H NMR (400MHz, DMSO-d ₆ ) 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.

Embodiment 45

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

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

first step

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

2-((3-(Benzyloxy)cyclobutylene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

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 was then cooled to -78°C, and a solution of bis[(pinacol)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, and a solution of 3-(benzyloxy)cyclobutane-1-one 45a (500 mg, 2.84 mmol) in tetrahydrofuran (5 mL) was slowly added dropwise. The reaction mixture was then warmed to room temperature and stirred for another 12 hours. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to the reaction mixture, extracted with ethyl acetate (20 mL×3), and the combined organic phase was 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)cyclobutylene)methyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 45b (500 mg) with a yield of 58.7%.

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

Step 2

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

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

2-Bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 19c (150 mg, 403.18 μmol) and 2-((3-(benzyloxy)cyclobutylene)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), and then [1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (30 mg, 40.32 μmol) and potassium carbonate (167.17 mg, 1.21 μmol) were added. The mixture was stirred at 110 °C under nitrogen protection for 2 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the obtained residue was separated and purified by reverse phase column chromatography (eluent: System A) to obtain 2-((3-(benzyloxy)cyclobutylene)methyl)-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine 45c (183 mg) in a yield of 97.5%.

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

Step 3

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

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

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

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

Step 4

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

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

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 system was filtered and the filter cake was washed with dichloromethane. The filtrate was decompressed to remove the solvent, 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-(2-(3-hydroxycyclobutyl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol 45 (0.87mg) with a yield of 5.6%.

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

¹ H NMR (400MHz, Methanol-d ₄ )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.

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

Embodiment 46

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

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

first step

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

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

7-Bromoimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester 46a (300 mg, 1.11 mmol, commercially available) was dissolved in 1,4-dioxane (6 mL) and water (0.6 mL), and 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, and the reaction mixture was stirred at 110°C under nitrogen protection for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to obtain 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester 46b (300 mg) with a yield of 73.68%.

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

Step 2

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

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

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

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

Step 3

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

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

(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 excess salt was removed by beating with dichloromethane. The product 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 I.D.; 10 μm, 20 mL/min; mobile phase A: 0.1% formic acid + water, mobile phase B: acetonitrile) to obtain 2-(3-(aminomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 46 (6 mg) with a yield of 10.49%.

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

¹ H NMR (400MHz, DMSO-d ₆ )δ8.55(d,J＝7.0Hz,1H),8.31(brs,1H),7.56(s,1H),7.47(d,J＝8.9Hz,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.

Embodiment 47

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

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

first step

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

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

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 protection for 30 minutes. Then, iodomethane (94.71 mg, 667.26 μmol) was added and stirred at room temperature for 2 hours. After the reaction was completed, water (30 mL) was added to the reaction mixture, extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 7-(2,3-dichloro-6-methoxyphenyl)-2-(2-methoxyethyl)imidazo[1,2-a]pyridine 47a (103 mg) with a yield of 65.92%.

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

Step 2

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

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

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, and 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 (separation column Sunfire C18; 19*250mm, 10um, 20ml/min; mobile phase A: 10mmol/L A: 0.1% formic acid/water, mobile phase B: acetonitrile) to obtain 3,4-dichloro-2-(2-(2-methoxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 47 (13.32mg) with a yield of 19.01%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Embodiment 50

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

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

first step

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

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

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]dichloropalladium (30.32 mg, 41.48 μmol) were added at room temperature. The reaction mixture was stirred at 90°C under nitrogen protection for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-(7-(2-methoxynaphthalen-1-yl)imidazo[1,2-a]pyridin-2-yl)ethanol-1-ol 50b (80 mg) with a yield of 60.6%.

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

Step 2

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

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

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) solution, 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 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 filtrate was decompressed to remove the solvent, 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 1-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)naphthalen-2-ol 50 (16.89mg), with a yield of 58.9%. MS m/z(ESI):305.1[M+1]

¹ H NMR (400MHz, DMSO-d ₆ )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.

Embodiment 55

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

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

first step

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

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

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 solution was concentrated, water (30 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated ammonium 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: B system) to obtain ethyl 7-bromo-3-methylimidazo[1,2-a]pyridine-2-carboxylate 55b (800 mg) with a yield of 97.77%.

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

Step 2

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

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

(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), and the mixture was heated at 100°C for 4 hours after argon replacement. The reaction solution was directly concentrated, 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%.

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

Step 3

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

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

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 and reacted at room temperature for 2 hours. The mixture was quenched with saturated ammonium chloride (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to obtain (7-(2,3-dichloro-6-methoxyphenyl)-3-methylimidazo[1,2-a]pyridin-2-yl)methanol 55d (40 mg) in a yield of 24.99%.

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

Step 4

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

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

(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 then added with boron tribromide (148.59 mg, 593.12 μmol) and reacted at room temperature for 18 hours. The reaction solution was quenched with methanol, then concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: B system) to obtain 2-(2-(bromomethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 55e (45 mg) with a yield of 98.26%.

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

Step 5

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

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

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 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-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-7-yl)phenol 55 (24 mg) with a yield of 63.71%.

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

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, 1H),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.

Embodiment 57

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

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

first step

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

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

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

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

Step 2

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

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

Under nitrogen protection, 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) were added diboric acid pinacol ester (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). The mixture was then stirred at 100°C under nitrogen protection for 12 hours. After the reaction was completed, the reaction solution was filtered, 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 obtain (2-(2-(benzyloxy)ethyl)imidazo[1,2-a]pyridin-7-yl)boronic acid 57c (1.55 g) with a yield of 75.4%.

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

Step 3

3,4,5-trichlorophenol

3,4,5-Trichlorophenol

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

Step 4

2-bromo-3,4,5-trichlorophenol

2-Bromo-3,4,5-trichlorophenol

3,4,5-Trichlorophenol 57e (770 mg, 3.90 mmol) was dissolved in acetic acid (10 mL) and then bromine (623.23 mg, 3.90 mmol) was added and reacted at room temperature for 18 hours. Saturated sodium sulfite solution (20 mL) was added to the reaction solution for quenching, and ethyl acetate was extracted (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: B system) to obtain 2-bromo-3,4,5-trichlorophenol 57f (1.0 g) with a yield of 92.79%.

Step 5

2-bromo-3,4,5-trichloro-1-methoxybenzene

2-Bromo-3,4,5-trichloro-1-methoxybenzene

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, and the mixture was reacted at 50°C for 2 hours. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-bromo-3,4,5-trichloro-1-methoxybenzene 57 g (400 mg) with a yield of 38.07%.

Step 6

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

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

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

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

Step 7

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

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

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 then added with boron tribromide (151.91 mg, 606.37 μmol) and reacted at room temperature for 18 hours. Methanol was added to the reaction solution to quench it, and then it was directly concentrated. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-(2-(2-bromoethyl)imidazo[1,2-a]pyridin-7-yl)-3,4,5-trichlorophenol 57i (50 mg) with a yield of 9.80%. MS m/z(ESI):419.0[M+1]

Step 8

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

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

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 separation (chromatographic column: SunFire C ₁₈ ,19*250mm,10um, mobile phase A: 0.1% formic acid/water, B: acetonitrile; flow rate: 20 ml/min) to obtain 3,4,5-trichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 57 (1.5 mg) with a yield of 21.61%.

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

¹ H NMR (400MHz, Methanol-d ₄ )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.

Embodiment 60

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

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

first step

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

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

(2-((2-bromo-4,5-dichlorophenoxy)methoxy)ethyl)trimethylsilane 60a (30 mg, 80.61 μmol, prepared according to patent 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 the reaction was stirred at 80°C for 16 hours. After the reaction was completed, 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%.

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

Step 2

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

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

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 the mixture was stirred at 70°C for 18 hours. The reaction solution was directly 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: 20 mL/min) to obtain 4,5-dichloro-2-(2-(2-hydroxyethyl)imidazo[1,2-a]pyridin-7-yl)phenol 60 (8 mg) with a yield of 33.12%.

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

Embodiment 61

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

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

first step

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

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

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 and reacted at room temperature for 3 hours. After the reaction was completed, saturated sodium bisulfite was added to quench (20 mL), and ethyl acetate was used for extraction (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 separated by silica gel column chromatography.

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

Step 2

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

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

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), and 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 3-bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 61b (125 mg) with a yield of 34.24%.

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

Step 3

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

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

3-Bromo-7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 61b (200 mg, 493.49 μmol) was added to dichloromethane (1 mL), cooled to 0°C, and boron tribromide (618.15 mg, 2.47 mmol) was slowly added dropwise, and the mixture was slowly transferred to room temperature for reaction for 18 hours. Water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (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: B system) to obtain 3-cyclopropyl-7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 61c (120 mg) with a yield of 66.95%.

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

Step 4

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

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

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, and the reaction was carried out at room temperature for 2 hours. The mixture was 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: 20 mL/min) to obtain 3,4-dichloro-2-(3-cyclopropyl-2-(hydroxymethyl)imidazo[1,2-a]pyridin-7-yl)phenol 61 (3.28 mg) with a yield of 3.24%.

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

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.

Embodiment 67

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

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

(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)(piperidin-4-yl)methanone 29 (5 mg, 12.81 μmol) was dissolved in ethanol (1 mL), cooled to 0°C, and sodium borohydride (727.01 μg, 19.22 μmol) was slowly added. The mixture was reacted at this temperature for 1 hour. The mixture was quenched with ice water, filtered and 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: 20 mL/min) to obtain 3,4-dichloro-2-(2-(hydroxy(piperidin-4-yl)methyl)imidazo[1,2-a]pyridin-7-yl)phenol 67 (1.26 mg) with a yield of 18.38%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

Embodiment 70

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

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

first step

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

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

At 0°C, 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) and reacted at 0°C for half an hour. 7-Bromoimidazo[1,2-a]pyridine-2-carboxaldehyde 29c (300 mg, 1.33 mmol) was slowly heated to room temperature and reacted overnight. The reaction solution was quenched with saturated ammonium chloride (20 mL), extracted with ethyl acetate (20 mL × 3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain (E)-3-(7-bromoimidazo[1,2-a]pyridin-2-yl) ethyl acrylate 70a (380 mg) with a yield of 96.59%. MS m/z (ESI): 294.9 [M+1]

Step 2

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

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

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, and 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: B system) to obtain ethyl 3-(7-bromoimidazo[1,2-a]pyridin-2-yl)-4-nitrobutyrate 70b (312 mg) with a yield of 86.18%.

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

Step 3

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

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

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: B system) to obtain ethyl 4-amino-3-(7-bromoimidazo[1,2-a]pyridin-2-yl)butyrate 70c (40 mg) with a yield of 87.35%.

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

Step 4

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

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

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. The residue was purified by silica gel column chromatography (eluent: B system) to give 4-(7-bromoimidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one 70d (30 mg) with a yield of 87.33%.

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

Step 5

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

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

(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]palladium dichloride (7.94 mg, 10.71 μmol) and potassium carbonate (44.41 mg, 321.29 μmol) were mixed, and 1,4-dioxane (5 mL) and water (1 mL) were added. Argon After gas replacement, the mixture was reacted at 100°C for 4 hours. After the reaction solution was concentrated, 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 4-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one 70d (24mg) with a yield of 59.56%.

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

Step 6

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

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

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 and reacted at room temperature for 2 hours. After the reaction solution was quenched with methanol, the residue was 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: 20 mL/min) to obtain 4-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)pyrrolidin-2-one 70 (10 mg) with a yield of 42.41%.

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

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,1 H),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.

Embodiment 71

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

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

first step

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

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

7-(2,3-Dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 33b (50 mg, 148.30 μmol) and 6-(tert-butyloxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane 71a (44.10 mg, 222.45 μmol) were dissolved in N,N-dimethylformamide. (4.87 mL), added 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), and 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 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 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) with a yield of 75.59%.

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

Step 2

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

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

3-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carbonyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester 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, and the mixture was heated to 50°C for 8 hours. Methanol was added to quench the mixture at 0°C, and the mixture was concentrated under reduced pressure to obtain 3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester 71c, which was directly used in the next step.

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

Step 3

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

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

3-((7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylic acid tert-butyl ester 71c (46.00 mg, 91.38 μmol) was dissolved in dichloromethane (1 mL), cooled to 0°C, boron tribromide (45.78 mg, 182.75 μmol) was slowly added, and the mixture was slowly transferred to room temperature for reaction for 18 hours. The mixture was quenched with ice water and concentrated under reduced pressure. 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 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) with a yield of 43.77%.

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

¹ H NMR (400MHz, DMSO-d ₆ )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.

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

Embodiment 72

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

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

first step

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

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

Under nitrogen protection, 7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid 33b (1.2 g, 3.56 mmol) and O-(7-azabenzotriazole-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 protection for 16 hours. In another reaction bottle, trimethyl sulfoxide chloride (1.37 g, 10.68 mmol) and potassium tert-butoxide (1.20 g, 10.68 mmol) were added to the reaction bottle under nitrogen protection, and stirred at 60°C for 2 hours. The reaction solution was cooled to 0°C, and then the above-prepared active ester was slowly added to the reaction solution. 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) with a yield of 51.23%.

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

Step 2

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

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

To a solution of 1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-2-(dimethyl(oxo)-λ ⁶ -sulfonamido)ethan-1-one 72a (200 mg, 486.26 μmol) in tetrahydrofuran (10 mL) was added lithium bromide (42.23 mg, 486.2 μmol) at 0° C., followed by methanesulfonic acid (46.68 mg, 486.26 μmol) at 0° C. The reaction mixture was heated to 65° C. and stirred for 2 hours under nitrogen protection. After the reaction was completed, the temperature was lowered to 0°C, 1 M sodium carbonate solution was added to adjust the pH to 7-9, and the product was extracted with ethyl acetate (15 mL × 2), washed with saturated sodium chloride (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 give 2-bromo-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72b (132 mg) with a yield of 65.56%.

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

Step 3

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

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

Under nitrogen protection, 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). Then, concentrated hydrochloric acid (1 drop) was added and 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 preparation (C18) (eluent: D system) to give 2-amino-1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72c (30 mg) with a yield of 70.94%.

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

Step 4

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

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

Boron tribromide (57 mg, 228.44 μmol) was added 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) under nitrogen protection at -78°C. The mixture was slowly heated to 0°C and then stirred under nitrogen protection for 30 minutes. After the reaction was completed, the reaction was quenched with methanol (3 mL), and the mixture was directly purified by reverse phase preparation (Waters 2767/Qda, column: SunFire SunFire C ₁₈ , 19*250 mm, 10 um; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 mL/min; gradient: 20% to 25%) to obtain 2-amino-1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)ethan-1-one 72 (5.6 mg) with a yield of 29.17%. MS m/z (ESI): 336.0 [M+1]

¹ H NMR (400MHz, Methanol-d ₄ )δ8.76(s,1H),8.65(d,J＝7.1Hz,1H),7.63(s,1H),7.45(d,J＝8.9Hz,1H),7.13(d,J＝7.2Hz,1H),6.93(d,J＝8.9Hz,1H),4.64(s,2H)ppm.

Embodiment 76

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

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

first step

tert-butyl

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

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

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 piperazine-1-carboxylic acid tert-butyl ester 15d (50 mg, 265.6 μmol) in acetonitrile (3 mL) was added potassium carbonate (74 mg, 531.30 μmol), and the reaction was stirred at room temperature under nitrogen protection for 24 hours. 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 phase was 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%.

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

Step 2

tert-butyl

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

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

Under nitrogen protection at 0°C, sodium borohydride (11 mg, 269.53 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-oxoethyl)piperazine-1-carboxylate 76a (70 mg, 134.77 μmol) in methanol (2 mL) and tetrahydrofuran (0.5 mL), and the reaction mixture was warmed to room temperature and stirred for 2 hours. After the reaction was completed, the temperature was lowered to 0°C, saturated ammonium chloride (8 mL) was added to quench, and ethyl acetate (10 mL × 3) was used for extraction. The combined organic phase was washed with saturated sodium chloride solution (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 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) with a yield of 71%. It was used directly in the next step.

MS m/z(ESI):521.0[M+1]

Step 3

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

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

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), and 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*250 mm, 10 um; mobile phase A: 0.1% FA/H ₂ O, B: ACN; flow rate: 20 ml/min) to give 3,4-dichloro-2-(2-(1-hydroxy-2-(piperazin-1-yl)ethyl)imidazo[1,2-a]pyridin-7-yl)phenol 76 (8.85 mg) with a yield of 22.66%.

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

¹ H NMR (400MHz, Methanol-d ₄ ) 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.

Embodiment 78

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

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

first step

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

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

At 0°C, 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 while adding a solution of lithium borohydride in tetrahydrofuran (2M, 3.61 mL). The mixture was heated to room temperature and stirred for 12 hours. The reaction was quenched with ice water at 0°C and diluted with water (30 mL), and then extracted with dichloromethane/methanol (10/1) (3×50 mL). The combined organic phases were washed with a 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) with a yield of 62.43%. MS m/z (ESI): 322.9 [M+1]

Step 2

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

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

At 0°C, a dichloromethane solution (1M, 15 mL) of boron tribromide was added dropwise 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) and the mixture was heated to room temperature and stirred for 2 hours. The reaction was quenched with ice water at 0°C, the precipitated solid was collected by filtration and washed with water to give 22-(2-(bromomethyl)imidazo[1,2-a]pyridin-7-yl)-3,4-dichlorophenol 78b (370 mg) with a yield of 89.28%. MS m/z(ESI):372.9[M+3]

Step 3

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

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

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) was added piperidin-4-ol 78c (16.31 mg, 161.27 μmol, Commercially available) and potassium carbonate (37.15 mg, 268.79 μmol), warm to room temperature and stir for 2 hours. Filter under reduced pressure, separate and purify by preparative liquid phase (chromatographic column: SunFire C ₁₈ ,19*250mm,10um, mobile phase A: 0.1% formic acid/water, B: acetonitrile; flow rate: 20mL/min), and obtain 1-(7-(2,3-dichloro-6-hydroxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidin-4-ol 78 (7 mg), with a yield of 25.72%.

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

According to the synthesis method of Example 78 of the present invention, Example 85, Example 88, Example 89, Example 90, Example 95 and Example 96 were synthesized, and the structures and characterization data are shown in the following table:

Embodiment 79

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

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

first step

tert-butyl 4-(1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate

tert-Butyl 4-(1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate

4-(7-bromoimidazo[1,2-a]pyridine-2-carbonyl)piperidine-1-carboxylic acid tert-butyl ester 29d (100 mg, 244.92 μmol) was dissolved in tetrahydrofuran (10 mL) and methylmagnesium bromide (163.28 μL, 3.0 M 2-methyltetrahydrofuran solution) was added and reacted at room temperature for 18 hours. The reaction solution was quenched with saturated ammonium chloride (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 4-(1-(7-bromoimidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylic acid tert-butyl ester 79a (97 mg) with a yield of 93.33%.

MS m/z(ESI):424.0[M+1]

Step 2

tert-butyl

4-(1-(7-(2,3-dichloro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)-1-hydroxyethyl)piperidine-1-carboxylate

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

(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]dichloropalladium (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 mixture 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) with a yield of 87.67%.

MS m/z(ESI):520.1[M+1]

Step 3

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

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

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 boron tribromide (481.36 mg, 1.92 mmol) was added and 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 (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) with a yield of 45.51%.

MS m/z(ESI):406.1[M+1]

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＝8.9H z,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.

Embodiment 86

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

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

first step

(2,3-dichloro-6-hydroxyphenyl)boronic acid

(2,3-Dichloro-6-hydroxyphenyl)boronic acid

At 0°C, (2,3-dichloro-6-methoxyphenyl)boronic acid 4c (2 g, 9.06 mmol) was dissolved in dichloromethane (1 mL), and boron tribromide (11.34 g, 45.28 mmol) was slowly added, and the mixture was slowly transferred to room temperature for 4 hours. Ice water (30 mL) was slowly added, and after stirring for 30 minutes, solids precipitated, which were filtered and dried to obtain (2,3-dichloro-6-hydroxyphenyl)boronic acid 86a (1.85 g), with a yield of 98.77%.

Step 2

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

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

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 the reaction was completed, methyl tert-butyl ether was added and stirred, filtered, and the filter residue was dried under reduced pressure to obtain ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate 86b (1.5 g) with a yield of 99.7%.

MS m/z(ESI):259.1[M+1]

Step 3

7-bromoimidazo[1,2-a]pyridin-2-ol

7-Bromoimidazo[1,2-a]pyridin-2-ol

Ethyl 2-(4-bromo-2-iminopyridin-1(2H)-yl)acetate 86b (2 g, 7.69 mmol) was dissolved in methanol (20 mL), potassium carbonate (531 mg, 3.84 mmol) was added, and the mixture was reacted at 25° C. for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 7-bromoimidazo[1,2-a]pyridine-2-ol 86c (900 mg) with a yield of 54.9%.

MS m/z(ESI):213.0[M+1]

Step 4

tert-butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)oxy)piperidine-1-carboxylate

tert-Butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)oxy)piperidine-1-carboxylate

Under nitrogen protection at room temperature, tert-butyl 4-bromopiperidine-1-carboxylate 86d (1.24 g, 4.69 mmol) was added 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). The mixture was stirred at 80°C for 2 hours. After the reaction was completed, the filtrate was filtered, and the filtrate was concentrated under reduced pressure. The residue was directly purified by atmospheric pressure reverse phase preparation (C18) (eluent: D system) to obtain tert-butyl 4-((7-bromoimidazo[1,2-a]pyridin-2-yl)oxy)piperidine-1-carboxylate 86e (158 mg) with a yield of 17.0%.

MS m/z(ESI):396.2[M+1]

Step 5

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

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

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) at room temperature, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 37.85 μmol) and cesium carbonate (370 mg, 1.14 mmol) were added. The mixture was stirred at 110°C for 2 hours under nitrogen protection. After the reaction was completed, the temperature was lowered 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/H ₂ O, 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%.

MS m/z(ESI):278.2[M+1]

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,1 H),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.

Embodiment 91

3,4,6-trichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

3,4,6-Trichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

first step

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

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

7-Bromoimidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 10a (2g, 7.43mmol) was dissolved in tetrahydrofuran (20mL), cooled to 0°C, methylmagnesium bromide (3M, 4.95mL) was added dropwise, and the mixture was heated to room temperature and stirred for 6 hours. After the reaction was complete, water was added to quench the reaction (20mL), and ethyl acetate was used for extraction (20mL×3). The combined organic phase was washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-(7-bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol 91a (1g, 3.92mmol) with a yield of 52.74%.

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

Step 2

(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)boronic acid

(2-(2-Hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)boronic acid

2-(7-bromoimidazo[1,2-a]pyridin-2-yl)propan-2-ol 91a (1 g, 3.92 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (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 purified by atmospheric pressure reverse phase preparation (C ₁₈ ) (eluent: D system) to obtain (2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)boronic acid 91b (650 mg) with a yield of 75.36%. MS m/z(ESI):221.1[M+1]

Step 3

3,4,6-trichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

3,4,6-Trichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

(2-(2-Hydroxypropan-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), heated to 100°C and stirred for 16 hours. After the reaction was complete, the product was concentrated under reduced pressure, and the residue was purified by reverse phase preparation (Waters 3767/QDA) column (SunFire C18, 19*250 mm, 10 um mobile phase A: 0.1% FA/H ₂ O, 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) with a yield of 22.98%.

MS m/z(ESI):371.0[M+1]

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.

Example 92 was synthesized according to the synthesis method of Example 91 of the present invention, and the structure and characterization data are shown in the following table:

Embodiment 97

3,4-dichloro-6-fluoro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

first step

2-bromo-3,4-dichloro-6-fluorophenol

2-Bromo-3,4-dichloro-6-fluorophenol

4,5-dichloro-2-fluorophenol 97a (800 mg, 4.42 mmol, prepared according to the patent publication "WO2024088343") was dissolved in dichloromethane (8 mL), cooled to 0 ° C, and then liquid bromine (3.53 g, 22.10 mmol) was added, and the temperature was slowly raised to room temperature for 12 hours. After the reaction was completed, it was quenched with saturated sodium sulfite (20 mL), extracted with dichloromethane (20 mL × 3), and the combined 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: A system) to obtain 2-bromo-3,4-dichloro-6-fluorophenol 97b (509 mg) with a yield of 44.31%.

Step 2

ethyl 7-(2,3-dichloro-5-fluoro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate

7-(2,3-Dichloro-5-fluoro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester

2-Bromo-3,4-dichloro-6-fluorophenol 97b (509 mg, 1.96 mmol) was added to 1,4-dioxane (10 mL), and then (2-(ethoxycarbonyl)imidazo[1,2-a]pyridin-7-yl)boronic acid 97c (504.16 mg, 2.15 mmol, prepared according to the patent publication "WO2022017338"), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (145.28 mg, 195.85 μmol) and potassium carbonate (812.04 mg, 5.88 mmol) were added to the system. The reaction was carried out at 90°C under nitrogen protection 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 obtain ethyl 7-(2,3-dichloro-5-fluoro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate 97d (112 mg) with a yield of 15.49%.

MS m/z(ESI):369.1[M+1]

Step 3

3,4-dichloro-6-fluoro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

3,4-Dichloro-6-fluoro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol

7-(2,3-dichloro-5-fluoro-6-hydroxyphenyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester 97d (194 mg, 525.50 μmol) was added to tetrahydrofuran (10 mL), and methylmagnesium bromide (3M, 2.63 mL) was added dropwise at -78°C under nitrogen protection. After the addition was completed, the temperature was raised to 50°C for reaction for 3 hours. The reaction solution was quenched with water (100 mL), 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 residue was purified by preparative liquid separation (separation column SunFire Sunfire C ₁₈ ; 19*250 mm, 10 um, 20 mL/min; mobile phase A: 0.1% FA/H ₂ O, mobile phase B: CH ₃ CN) to give 3,4-dichloro-6-fluoro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phenol 97 (82.4 mg) with a yield of 44.15%.

MS m/z(ESI):355.1[M+1]

1H NMR(400MHz,DMSO-d6)δ8.55(d,J＝6.9Hz,1H),7.80(s,1H),7.70(d,J＝10.5 Hz,1H),7.38(s,1H),6.72(dd,J＝6.9,1.6Hz,1H),5.05(s,1H),1.50(s,6H)ppm.

Embodiment 99

3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phen-6-d-ol

3,4-Dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)benzene-6-d-ol

first step

(2-((3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane

(2-((3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane

Dissolve (2-((2-bromo-4,5-dichlorophenoxy)methoxy)ethyl)trimethylsilane 99a (400 mg, 1.07 mmol, prepared according to the patent publication "WO2021071802") in tetrahydrofuran (3 mL), cool to -78 ° C, add n-butyl lithium (2.5 M, 644.89 μL) dropwise under nitrogen protection, stir for 1 hour, add heavy water (215.29 mg, 10.75 mmol, 194.48 μL) dropwise, and heat to room temperature and stir for 18 hours. After the starting material disappeared, water (30 mL) was added, 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) with a yield of 99.91%.

Step 2

(2-((2-bromo-3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane

(2-((2-Bromo-3,4-dichlorophenoxy-6-d)methoxy)ethyl)trimethylsilane

(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.

Step 3

2-(7-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl-5-d)imidazo[1,2-a]pyridin-2-yl)propan-2-ol

2-(7-(2,3-dichloro-6-((2-(trimethylsilyl)ethoxy)methoxy)phenyl-5-d)imidazo[1,2-a]pyridin-2-yl)propan-2-ol

(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), [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 by nitrogen, and the reaction was stirred at 70°C. After the reaction was complete, the mixture was filtered and reduced. The residue was directly purified by reverse phase preparation (C18) (eluent: D system) at normal 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%.

MS m/z(ESI):468.1[M+1]

Step 4

3,4-dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)phen-6-d-ol

3,4-Dichloro-2-(2-(2-hydroxypropan-2-yl)imidazo[1,2-a]pyridin-7-yl)benzene-6-d-ol

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), trifluoroacetic acid (29.21 mg, 256.16 μmol) was added dropwise, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column SunFire Sunfire C ₁₈ ; 19*250 mm, 10 um, 20 mL/min; mobile phase A: 0.1% FA/H ₂ O, mobile phase B: CH ₃ CN) 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) with a yield of 61.40%.

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

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.

Embodiment 100

1-((7-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methylpiperidin-4-ol

1-((7-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methylpiperidin-4-ol

first step

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

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

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, and the mixture was heated to 100°C and stirred for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to obtain diethyl 7-bromoimidazo[1,2-a]pyridine-2,3-dicarboxylate 100b (6 g) with a yield of 60.86%.

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

Step 2

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

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

7-Bromoimidazo[1,2-a]pyridine-2,3-dicarboxylic acid diethyl ester 100b (6 g, 17.59 mmol) was dissolved in tetrahydrofuran (60 mL), cooled to 0°C, and then lithium borohydride (2M, 13.19 mL) was added, and the temperature was slowly raised to room temperature for 16 hours. Water (100 mL) was added to quench the reaction, and ethyl acetate (100 mL×3) was used for extraction. The organic phases were combined and 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: A system) to obtain 7-bromo-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester 100c (2.5 g) with a yield of 47.52%.

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

Step 3

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

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

7-Bromo-2-(hydroxymethyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester 100c (100 mg, 0.35 mmol) was added to dichloromethane (3 mL), and manganese dioxide (152 mg, 1.75 mmol) was added, and the reaction mixture was reacted at 25°C for 16 hours. After the reaction was completed, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (eluent: A system) to obtain 7-bromo-2-formylimidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester 100d (50 mg), with a yield of 50.3%. MS m/z (ESI): 297.0 [M+1]

Step 4

ethyl

7-bromo-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylate

7-Bromo-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

7-Bromo-2-formyl imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester 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 the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated sodium chloride solution (10 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 7-bromo-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester 100e (25 mg) with a yield of 37.0%. MS m/z(ESI):397.1[M+1]

Step 5

ethyl

7-(2,3-dichloro-6-hydroxyphenyl)-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylate

7-(2,3-Dichloro-6-hydroxyphenyl)-2-((4-hydroxy-4-methylpiperidin-1-yl)methyl)imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester

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), 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 residue was separated and purified by silica gel column chromatography (eluent: B system) to obtain 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 (110 mg) with a yield of 50.3%.

MS m/z(ESI):478.1[M+1]

Step 6

1-((7-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methylpiperidin-4-ol

1-((7-(2,3-dichloro-6-hydroxyphenyl)-3-(hydroxymethyl)imidazo[1,2-a]pyridin-2-yl)methyl)-4-methylpiperidin-4-ol

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, lithium aluminum hydride (1 M, 77 μL) was added, and the reaction was carried out at 0°C for 1 hour. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated sodium chloride solution (15 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid separation (separation column SunFire _C18 ; 250×19 mm ID; 10 μm, 20 mL/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%.

MS m/z(ESI):436.1[M+1].

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.

Embodiment 102

3,4-dichloro-6-fluoro-2-(2-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenol

3,4-Dichloro-6-fluoro-2-(2-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenol

first step

3-bromo-1,2-dichloro-5-fluoro-4-methoxybenzene

3-Bromo-1,2-dichloro-5-fluoro-4-methoxybenzene

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 mixture was reacted at room temperature for 18 hours. The reaction solution was diluted with water (100 mL), extracted with ethyl acetate (100 mL×3), and the organic phase was washed with saturated sodium chloride solution (100 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and then purified by silica gel column chromatography (eluent: system A) to obtain 3-bromo-1,2-dichloro-5-fluoro-4-methoxybenzene 102a (1.95 g) with a yield of 80.44%.

Step 2

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

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

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 biboronic acid pinacol ester (920.31 mg, 3.62 mmol) were added to 1,4-dioxane (20 mL), the air was replaced by nitrogen, and the reaction was stirred at 100°C for 18 hours. After the reaction was complete, the mixture was filtered off with suction, diluted with water (30 mL), extracted with ethyl acetate (30 mL × 3), and 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 obtain (2-bromoimidazo[1,2-a]pyridin-7-yl)boronic acid 102b (375 mg) with a yield of 85.92%.

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

Step 3

2-bromo-7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridine

2-Bromo-7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridine

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, 78.47μmol), potassium carbonate (325.37mg, 2.35mmol) were mixed and then 1,4-dioxane (5mL) was added. After argon replacement, the mixture was reacted at 100°C for 5 hours. The reaction solution was directly concentrated and purified by silica gel column chromatography (eluent: B system) to obtain 2-bromo-7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridine 102c (83mg) with a yield of 27.12%.

MS m/z(ESI):388.9[M+1]

Step 4

tert-butyl

4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methylene)piperidine-1-carboxylate

tert-Butyl 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methylene)piperidine-1-carboxylate

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 solution was directly concentrated and purified by silica gel column chromatography (eluent: B system) to obtain 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) with a yield of 52.89%. MS m/z (ESI): 506.1 [M+1]

Step 5

tert-butyl

4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidine-1-carboxylate

tert-Butyl 4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methyl)piperidine-1-carboxylate

4-((7-(2,3-dichloro-5-fluoro-6-methoxyphenyl)imidazo[1,2-a]pyridin-2-yl)methylene)piperidine-1-carboxylic acid tert-butyl ester 102e (57 mg, 112.56 μmol) was dissolved in methanol (10 mL) and palladium carbon (23.96 mg, 225.12 μmol, 10%) was added. After replacement with a hydrogen balloon, the mixture was reacted at room temperature for 3 hours. The reaction solution was filtered, concentrated, and purified by silica gel column chromatography (eluent: B system) to obtain 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) with a yield of 69.90%.

MS m/z(ESI):508.1[M+1]

Step 6

3,4-dichloro-6-fluoro-2-(2-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenol

3,4-Dichloro-6-fluoro-2-(2-(piperidin-4-ylmethyl)imidazo[1,2-a]pyridin-7-yl)phenol

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, 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 separation (Separation column SunFire C ₁₈ ; 250×19 mm ID; 10 μm, 20 mL/min; Mobile phase A: 0.1% FA+H ₂ O, Mobile phase B: CH ₃ CN) 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%.

MS m/z(ESI):394.1[M+1]

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. 47–3.38(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.

Embodiment 103

3,4-dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

3,4-Dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

first step

2-(2-bromoimidazo[1,2-a]pyridin-7-yl)-3,4-dichloro-6-fluorophenol

2-(2-Bromoimidazo[1,2-a]pyridin-7-yl)-3,4-dichloro-6-fluorophenol

(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 by nitrogen, and the reaction was stirred at 80°C. After the reaction was complete, the mixture was filtered and concentrated, and then purified by silica gel column chromatography (eluent: system A) to obtain 2-(2-bromoimidazo[1,2-a]pyridin-7-yl)-3,4-dichloro-6-fluorophenol 103a (35 mg) with a yield of 20.54%. MS m/z (ESI): 374.9 [M+1]

Step 2

3,4-dichloro-2-(2-(2,5-dihydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)-6-fluorophenol

3,4-Dichloro-2-(2-(2,5-dihydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)-6-fluorophenol

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), [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 reaction for 1 hour. After the reaction was completed, water was added to dilute (30 mL), 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: A system) to obtain 3,4-dichloro-2-(2-(2,5-dihydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)-6-fluorophenol 103c (15.32 mg) with a yield of 11.18%.

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

Step 3

3,4-dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

3,4-Dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol

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 and the reaction was carried out at room temperature for 18 hours. After the reaction was complete, the product was filtered, the filtrate was collected and concentrated, and then purified by preparative liquid separation (separation column SunFire C ₁₈ ; 250×19 mm ID; 10 μm, 20 mL/min; mobile phase A: 0.1% FA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 3,4-dichloro-6-fluoro-2-(2-(tetrahydrofuran-3-yl)imidazo[1,2-a]pyridin-7-yl)phenol 103 (2.21 mg) with a yield of 4.21%. MS m/z (ESI): 367.0 [M+1]

Biological evaluation

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)

1.1. Purpose of the experiment:

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 on hKv1.3 current at different concentrations and their dose-effect relationship.

1.2 Experimental methods

Cell culture

The CHO cells stably expressing hKv1.3 potassium ion channels used in the experiment were obtained from Shanghai WuXi AppTec Pharmaceuticals 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.

Table 1. CHO hKv1.3 culture medium

1.2.2. Preliminary preparation of cells

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, the cells were digested with TrypLE (source: Thermo Fisher Scientific), and then resuspended and collected with extracellular fluid.

1.2.3. Preparation of intracellular and extracellular fluids

1) Extracellular fluid: 145 mM NaCl, 4 mM KCl, 2 mM CaCl, 1 mM MgCl, 10 mM glucose and 10 mM HEPES (pH adjusted to 7.4 with NaOH).

2) Intracellular solution: 10 mM EGTA, 10 mM HEPES, 2 mM magnesium chloride, 145 mM potassium fluoride (using hydrogen The pH was adjusted to 7.2 with potassium hydroxide).

Note: The osmotic pressure of the solution should be controlled between 280 and 320 mOsmol/kg. The solution needs to be filtered and stored at 4°C before use.

The extracellular solution was prepared at least once a month, filtered and stored in a refrigerator at 4°C. The intracellular solution was prepared once every three months, filtered and stored in aliquots at -20°C.

1.2.4. Preparation of compounds

The compounds of the invention were dissolved in 100% DMSO to prepare a 10 mM stock solution. The stock solution was then further diluted into the extracellular fluid to obtain the final concentration required for testing. The precipitate was visually inspected before testing. The final DMSO external solution concentration of the test compound was no greater than 0.30%.

1.2.5. Voltage stimulation protocol

The voltage stimulation scheme is as shown in Table 2. The clamping potential is maintained at -80 mv for 50 ms. Then the voltage stimulation is depolarized to +40 mv for 200 ms to open the hKv1.3 channel. Finally, the voltage is restored to the clamping potential of -80 mv. The above voltage stimulation is repeated every 30,000 ms.

Table 2. Voltage stimulation protocol

1.2.6. Manual whole-cell patch clamp recording

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, U.S.A.), data were acquired using a DigiData 1440 A/D-D/A board (Molecular Devices, U.S.A.), and currents were observed and recorded using Clampex 10 software.

Glass microelectrodes were made by pulling borosilicate glass capillaries (GC150tF-10, Harvard Apparatus Co. UK) on a programmed microelectrode puller (NARISHIGE PC-10 Puller, Japan). The electrode tip resistance was 2-5MΩ.

Before the experiment, the cell suspension was added to a 35 mm culture dish and placed on the stage of an inverted microscope (Nikon ECLIPSE Ti, Japan). After the cells adhered to the wall, they were perfused with extracellular fluid at a flow rate of 1-2 mL/min. The perfusion was completed by a perfusion system (Warner Instrument Corporation, VC-6-PINCH) installed on the platform of the inverted microscope. Two cells were repeated for each concentration.

Data analysis

Clampfit 10, EXCEL and GraphPad Prism were used for further data analysis and curve fitting. All data are expressed as mean ± standard deviation.

For each cell, the average of the last five current peaks during the monitoring period (no test compound was given) was used as the current peak of the blank control. When each concentration was detected, the average of the last five current peaks was used as the current peak under the action of that concentration for data analysis statistics. The inhibition percentage of hKv1.3 current at each detection concentration was calculated by the following formula:

(1 – peak current value recorded after compound perfusion / peak current value recorded before compound perfusion) × 100%

The final half inhibition concentration _IC50 value was obtained by fitting the Hill equation:

Wherein y = I/I _control ; max = 100%; min = 0%; [drug] = concentration of the test compound; nH = Hill coefficient; IC ₅₀ = half maximal inhibitory concentration of the test substance.

1.3 Experimental results

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

Table 3 IC ₅₀ of the inhibitory activity of the compounds of the present invention on hKv1.3 potassium ion channel

Conclusion: The compounds of the present invention have a good inhibitory effect on hKv1.3 potassium channel with an IC ₅₀ of <0.1 μM. use.

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)

2.1 Cells

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

2.2 Experimental solution

1) Extracellular fluid: 132 mM NaCl, 4 mM KCl, 3 mM CaCl, 0.5 mM MgCl, 11.1 mM glucose, and 10 mM HEPES (pH adjusted to 7.35 with NaOH).

2) Intracellular fluid: 10 mM EGTA, 10 mM HEPES, 10 mM KCl, 10 mM NaCl, 110 mM KF (pH adjusted to 7.2 with KOH).

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

2.3 Test compound solution

The compound to be tested was dissolved in DMSO and prepared into a stock solution with a final concentration of 10 mM. The stock solution was then diluted in a gradient manner and further diluted into the extracellular fluid to obtain the test solutions with the required two final concentrations, which were (μM): 1 and 0.01 or 0.1 and 10. The content of DMSO in the test solution was 0.1-0.3% (volume ratio). 2.4 Experimental steps

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

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

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

2.5 Data Analysis

Note: Data is output by PatchMaster software.

1) After perfusing the blank solvent or compound gradient solution, the average of the five consecutive current values obtained was calculated. Don't use as "current size _blank " and "current size _compound ".

The current suppression percentage is calculated by the following formula.

2) The dose-effect curve was fitted using Graphpad Prism 8.0 software.

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

2.6 Experimental Results

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.

Table 4 Inhibitory activity of the compounds of the present invention on hKv1.3 potassium channel (two concentration points, 0.1 μM/10 μM)

Table 5 Inhibitory activity of the compounds of the present invention on hKv1.3 potassium channel (two concentration points, 0.01 μM/1 μM)

The compound of the present invention has a good inhibitory effect on hKv1.3 potassium ion channel.

Claims (26)

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; ^R1 is selected from a hydrogen atom or an alkyl group; ^R4 is selected from a hydrogen atom, a deuterium atom, an alkyl group or a halogen; X ₁ , X ₂ , and X ₃ 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 a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, -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 group, alkenyl group, alkynyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is optionally further substituted by one or more ^RA ; ^RA are the same or different and are each independently selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, ^-OR8 , =O ^{, -C(=O)R8, -C(=O)OR8, -OC(=O)R8, -NR9R10, -C(=O)NR9R10, -SO2NR9R10 , -NR9C ( =} _O ^{) R10 or -NR9C (} =O) ^{OR10 ;} wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl ^, aryl or heteroaryl is optionally further substituted with one or more substituents selected from =O, _{-C1-6alkylene} - ^RB , halogen, hydroxy, cyano, ^-NR9R10 , alkoxy, ^aryl or heteroaryl; ^RB is selected ^from hydrogen, halogen, hydroxy, cyano, amino, alkoxy, -S(=O) _rR8 or -S(=O)(=NH) ^R8 ; ^R3 are the same or different and are independently selected from hydrogen, halogen, hydroxy, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, amino, alkyl or alkoxy; Alternatively, two R ³ together with the same carbon atom to which they are attached form a -C(=O)-; R ⁵ is each 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 substituents 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 , -SO ₂ NR ⁹ R ¹⁰ , -NR ⁹ C(=O)R ¹⁰ or -NR ⁹ C(=O)OR ¹⁰ ; ^R6 and ^R7 are each 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 substituents selected from hydroxyl group, halogen, nitro group, cyano group, alkyl group ^{, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, =O, -C(=O)R8, -C(=O)OR8, -OC(=O)R8 , -NR9R10 , -C (} ₌ ^{O ) NR9R10 ,} -SO2NR9R10, -NR9C(=O) ^R10 or ^-NR9C (=O) ^OR10 ; Alternatively, ^R6 and ^R7 together with the atoms to which they are attached 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 substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(=O) ^R8 , ^-C (=O) ^OR8 , ^-OC (= ^O ₎ ^R8 , ^-NR9R10 , ^-C (=O) ^NR9R10 , ^-SO2NR9R10 , -NR9C(=O) ^R10 or ^-NR9C (=O) ^OR10 ; R ⁸ , R ⁹ and R ¹⁰ are each 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, two R ³ and the same carbon atom to which they are attached do not form -C(=O)-:
Wherein, Ring B is selected from a 5-6 membered heterocyclic group, and n ₁ , n ₂ , and n ₃ are each independently 0, 1 or 2. The compound according to claim 1, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹ is a hydrogen atom. The compound according to claim 1 or 2, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X ₁ , X ₂ and X ₃ are each independently selected from a hydrogen atom or a halogen. 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. The compound according to any one of claims 1 to 4, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to general formula (IIA), (IIB) or (IIC):
Wherein: X ₃ is selected from hydrogen atom or halogen; ^R4 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 . The compound according to any one of claims 1 to 5, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ⁴ is a hydrogen atom. 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):
wherein: Ring A, R ² , R ³ and n are as defined in claim 1. 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 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. The compound according to claim 8 or its stereoisomer, tautomer or pharmaceutically acceptable salt, 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); It represents the connection site between ring A and ^R2 in the general formula (I), (II), (IIA), (IIB) or (IIC). The compound according to any one of claims 1 to 7, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from 8-10 membered bicyclic heteroaryl groups. 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); It represents the connection site between ring A and ^R2 in the general formula (I), (II), (IIA), (IIB) or (IIC). The compound according to any one of claims 1 to 7, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring A is selected from an 8- to 10-membered bicyclic condensed ring. 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); It represents the connection site between ring A and ^R2 in the general formula (I), (II), (IIA), (IIB) or (IIC). The compound according to any one of claims 1 to 5 or its stereoisomers, tautomers or A pharmaceutically acceptable salt, which is a compound of general formula (IIIA), (IIIB) or (IIIC) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:
Wherein X ₃ is selected from hydrogen atom or chlorine; R ⁴ is selected from hydrogen atom, deuterium atom, fluorine or chlorine; preferably hydrogen atom; ^R2 and ^R3 are as defined in claim 1. 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 is selected from a hydrogen atom, -OR ⁵ , -C(=O)OR ⁵ , -C(=O)R ⁵ , -NR ⁶ R ⁷ , -C(=O)NR ⁶ R ⁷ , a C _1-6 alkyl group, a 3-10 membered heterocyclic group, a 3-6 membered cycloalkyl group, or a 5-6 membered heteroaryl group, wherein the C _1-6 alkyl group, the 3-6 membered cycloalkyl group, the 3-10 membered heterocyclic group, or the 5-6 membered heteroaryl group is optionally further substituted by one or more ^RAs ; ^RA are the same or different and are each independently selected from -C(=O) ^R8 , -C(=O ^{) NR9R10} , =O, hydroxy, halogen, cyano, amino, _C1-6 alkyl, _C1-6 alkoxy, 3-10 membered heterocyclyl or 3-6 membered cycloalkyl, wherein said _C1-6 alkyl, _C1-6 alkoxy, 3-10 membered heterocyclyl or 3-6 membered cycloalkyl is optionally further substituted with one or more substituents selected from =O, halogen, ^-NR9R10 , ^hydroxy , cyano, _-C1-6 alkylene- ^RB , _C1-6 alkoxy or phenyl; ^RB is selected ^from hydrogen, halogen, hydroxy, cyano, amino, alkoxy, -S(=O) _rR8 or -S(=O)(=NH) ^R8 ; m is 1, 2 or 3; r is 0, 1 or 2; R ⁵ is independently selected from a hydrogen atom, a C _1-6 alkyl group or a 3-10 membered heterocyclic group, wherein the C _1-6 alkyl group or the 3-10 membered heterocyclic group is optionally further substituted by one or more substituents selected from =O, halogen, hydroxyl, cyano, amino, C _1-6 alkyl or C _1-6 alkoxy. R ⁶ are each independently selected from a hydrogen atom; R ⁷ is independently selected from hydrogen atom, C _1-6 alkyl or 3-10 membered heterocyclic group, wherein the C _1-6 alkyl or 3-10 membered heterocyclic group is optionally further substituted by one or more substituents selected from =0, halogen, hydroxyl, cyano, amino or 3-10 membered heterocyclic group. R ⁸ is selected from C _1-6 alkyl or 3-10 membered heterocyclyl, wherein the C _1-6 alkyl or 3-10 membered heterocyclyl is optionally further substituted by one or more substituents selected from =0, halogen, hydroxy, cyano, amino or 3-10 membered heterocyclyl. R ⁹ and R ¹⁰ are each independently selected from a hydrogen atom or a methyl group. The compound according to claim 15 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof A salt wherein R ² is selected from the following groups:
The compound according to claim 15 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein R ² is selected from the following groups: hydrogen atom, carboxyl group, amino group, The compound according to any one of claims 1 to 17, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, a C _1-6 alkyl group, or a C _3-6 cycloalkyl group; wherein the C _1-6 alkyl group or the C _3-6 cycloalkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, or amino. Alternatively, two R ³ together with the same carbon atom to which they are attached form a -C(=O)-. The compound according to claim 18, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom, a methyl group, a cyclopropyl group, Alternatively, two R ³ together with the same carbon atom to which they are attached form a -C(=O)-. The compound according to any one of claims 1 to 19 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is:



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, and a pharmaceutically acceptable carrier, excipient or a combination thereof. 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. 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. 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. 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. 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.