WO2024083177A1 - Aromatic acetylene derivative, preparation method therefor and medical use thereof - Google Patents

Abstract

The present invention relates to an aromatic acetylene derivative, a preparation method therefor, and a medical use of a pharmaceutical composition containing the derivative. Specifically, the present invention relates to an aromatic acetylene derivative represented by a general formula (I), a preparation method therefor, a pharmaceutically acceptable salt thereof, and a use thereof as a therapeutic agent, particularly an LPXC inhibitor; the definitions of the substituents in the general formula (I) are the same as in the description.

Description

Aromatic acetylene derivatives, preparation methods and medical uses thereof Technical Field

The present invention relates to an aromatic acetylene derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and the use of the aromatic acetylene derivative as a therapeutic agent, in particular as an LPXC inhibitor.

Background technique

The 1930s to 1960s were the golden age of antibiotic development. Since then, antibiotics have been widely used worldwide, but bacterial resistance has also emerged. Drug-resistant bacteria have become a major threat to human health. Multidrug-resistant Gram-negative bacteria are one of the main pathogens of infection. Currently, there is a serious shortage of drugs used in clinical treatment of multidrug-resistant Gram-negative bacterial infections, and drugs with high toxicity are still used. In recent years, although bacterial resistance has been a hot topic in the international medical community, the pace of research and development has been slow, and there are very few compounds entering clinical research at home and abroad. Therefore, finding a new type of Gram-negative antibacterial drug is an important issue that needs to be solved urgently.

UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LPXC) is a Zn ⁺ -dependent metalloenzyme. It is the first rate-limiting enzyme in the synthesis of lipid A, which is an important component of the outer membrane of Gram-negative bacteria. It can anchor lipopolysaccharide on the outer membrane of the cell to maintain the integrity of its own cells. At the same time, as a hydrophobic external barrier, it hinders external factors such as antibiotics from entering the cell and protects bacteria from being invaded. In addition, lipid A is also the active ingredient of bacterial endotoxins, which enters the blood through the intestinal mucosa, activates the human immune response, and even causes severe septic shock, which is also the reason why Gram-negative bacteria have pathogenic infections. Therefore, by inhibiting LPXC, the biosynthesis of Gram-negative lipid A can be inhibited, thereby effectively controlling the infection of Gram-negative bacteria.

At present, further understanding of the structure and characteristics of LPXC is mostly obtained through the separation, purification and analytical identification of LPXC crystals from Escherichia coli, Pseudomonas aeruginosa and hyperthermophilic bacteria. The structures of LPXC from these three different sources are highly similar, all containing two domains, and the active region is located at the junction of the two domains. Each domain contains an α-helix and a β-fold, and the β-fold sandwiches the α-helix to form a "β-α-α-β" sandwich structure. Although the amino acid sequences of the two domains are slightly different, they have the same spatial structure. In addition, each domain has a corresponding insertion region composed of β-folds to form different functional regions. Studies have shown that LPXC has a high homology in Gram-negative bacteria and has no common sequences with various enzyme systems in mammals. From a biological point of view, due to its unique advantages of broad spectrum and low toxicity, inhibiting LPXC as a target will be an ideal direction for studying antibacterial drugs.

Currently, there are no new LPXC inhibitors on the market. The small molecule compound developed by Toyama Chemical Co., Ltd. RC-01 has entered Phase I clinical trials, and other pharmaceutical companies such as Novartis and Taiwan Taisho Pharmaceutical are still in the preclinical stage for LPXC research. Therefore, the research and application of LPXC inhibitors have made some progress, but there is still huge room for improvement, and it is still necessary to continue researching and developing new LPXC inhibitors.

Summary of the invention

In view of the above technical problems, the present invention provides a compound represented by the general formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

in:

Ring A is selected from a 5-membered heteroaryl group or a 5- to 6-membered heterocyclic group;

Ring B is selected from 5-6 membered heteroaryl groups;

R ^a are the same or different and are independently selected from hydroxy, cyano, halogen, alkyl or alkoxy;

R ^b are the same or different and are independently selected from cyano, halogen, hydroxyl, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted with one or more substituents selected from hydroxyl, cyano, halogen, alkyl or alkoxy;

X, Y, Z, and Q are each independently selected from CR ² or N atoms, and at most two atoms among X, Y, Z, and Q are N atoms at the same time;

^R2 is selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

L is selected from C ₁ -C ₃ alkylene, C ₂ -C ₃ alkenylene or C ₂ -C ₄ alkynylene, wherein the alkylene, alkenylene or alkynylene is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, amino or alkoxy;

R ¹ is selected from hydrogen atom, cyano, halogen, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, fused ring, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O)NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(O)NR ⁵ R ⁶ or -S(O) _r R ⁴ ; wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl or fused ring is optionally further substituted by one or more R ³ ;

R ³ is each independently selected from cyano, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NR ⁵ R ⁶ , -C(O)NR ⁵ R ⁶ , -CH ₂ NHC(O)OR ⁴ , -CH ₂ NR ⁵ R ⁶ or -S(O) _r R ⁴ ; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R ⁷ , -C(O)OR ⁷ , -OC(O)R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ 、-SO ₂ NR ⁸ R ⁹ or -NR ⁸ C(O)R ⁹ is substituted by a substituent;

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

R ⁴ 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 ⁷ , -C(O)OR ⁷ , -OC(O)R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -SO ₂ NR ⁸ R ⁹ or -NR ⁸ C(O)R ⁹ ;

R ⁵ and R ⁶ are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, 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 with one or more substituents selected from hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O)R ⁷ , -C(O)OR ⁷ , -OC(O)R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -SO ₂ NR ⁸ R ⁹ or -NR ⁸ C(O)R ⁹ ;

Alternatively, R ⁵ and R ⁶ together with the atoms to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O)r, and the 4- to 8-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)R ⁷ , -C(O)OR ⁷ , -OC(O)R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -SO ₂ NR ⁸ R ⁹ or -NR ⁸ C(O)R ⁹ ;

R ⁷ , R ⁸ and R ⁹ 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;

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2, 3 or 4; and

r is independently 0, 1 or 2.

A preferred embodiment of the present invention is a compound of general formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

wherein: X, Y, Z, Q, ^R1 and L are as defined in the general formula (AI).

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

in:

Q is selected from CH or N atoms;

^R1 and L are as defined in Formula (AI).

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

in:

Ring C is selected from a heteroaryl group, a heterocyclic group or a fused ring, wherein the heteroaryl group, the heterocyclic group or the fused ring contains at least one N atom;

p is selected from 0, 1, 2, 3, 4 or 5;

Q is selected from CH or N atoms;

^R3 and L are as defined in Formula (AI).

A preferred embodiment of the present invention is a compound of general formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of general formula (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

Wherein: ^R1 and L are as defined in the general formula (AI).

A preferred embodiment of the present invention is a compound of general formula (A-I), (I), (II), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

R ¹ is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, a heteroaryl group, a condensed ring, a cyano group, -OR ⁴ , -C(O)OR ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NR ⁵ R ⁶ , -NHC(O)NR ⁵ R ⁶ or -C(O)NR ⁵ R ⁶ , wherein the alkyl, cycloalkyl, heterocyclyl, heteroaryl or fused ring is optionally further substituted with one or more R ³ ;

R ³ is each independently selected from halogen, cyano, alkyl, hydroxyl, heterocyclyl, -C(O)R ⁴ , -C(O)OR ⁴ , -NR ⁵ R ⁶ or -C(O)NR ⁵ R ⁶ , wherein the alkyl or heterocyclyl is optionally further substituted with one or more substituents selected from halogen, cyano, amino, hydroxyl, heteroaryl or -C(O)NR ⁸ R ⁹ ;

Alternatively, two R ^3's and the same carbon atom to which they are attached form a -C(=O);

R ⁴ is selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from hydroxyl, cyano or alkoxy;

R ⁵ and R ⁶ are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from hydroxyl, cyano, heteroaryl, -C(O)OR ⁷ or -C(O)NR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom or an alkyl group.

A preferred embodiment of the present invention is a compound of general formula (A-I), (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

L is selected from methylene, ethylene, propylene, vinylene, ethynylene, propynylene or butynylene; wherein the methylene, ethylene, propylene, vinylene, ethynylene, propynylene or butynylene is optionally further substituted by one or more halogen, cyano or amino.

A preferred embodiment of the present invention is a compound of general formula (A-I), (I), (II), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein:

L is selected from _-CH2- , -( _CH2 ) _2- , -( _CH2 ) _3- , -CH=CH-, -C≡C-, _-CH2C≡C- or -( _CH2 ) _2C≡C- ;

R ¹ is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, a heteroaryl group, a fused ring, a cyano group, -OR ⁴ , -C(O)OR ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NR ⁵ R ⁶ , -NHC(O)NR ⁵ R ⁶ or -C(O)NR ⁵ R ⁶ , wherein the alkyl group, cycloalkyl group, heterocyclic group, heteroaryl group or fused ring is optionally further substituted by one or more R ³ ;

R ³ is each independently selected from halogen, cyano, alkyl, hydroxyl, heterocyclyl, -C(O)R ⁴ , -C(O)OR ⁴ , -NR ⁵ R ⁶ or -C(O)NR ⁵ R ⁶ , wherein the alkyl or heterocyclyl is optionally further substituted with one or more substituents selected from halogen, cyano, amino, hydroxyl, heteroaryl or -C(O)NR ⁸ R ⁹ ;

Alternatively, two R ^3's and the same carbon atom to which they are attached form a -C(=O);

R ⁴ is selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from hydroxyl, cyano or alkoxy;

R ⁵ and R ⁶ are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from hydroxyl, cyano, heteroaryl, -C(O)OR ⁷ or -C(O)NR ⁸ R ⁹ ;

R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom or an alkyl group.

In a preferred embodiment of the present invention, the compound described by general formula (A-1) 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 (A-I), (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

The present invention provides a use of a compound of general formula (A-I), (I), (II), (III), (IV) or (V) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of an LPXC inhibitor.

The present invention also provides a use of a compound of formula (A-I), (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by LPXC, wherein the disease mediated by LPXC is preferably a bacterial infection caused by Gram-negative bacteria; wherein the disease mediated by LPXC is selected from bacterial infections caused by Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella dysenteriae, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella, Vibrio cholerae, and Neisseria meningitidis.

The present invention further provides a compound of general formula (A-I), (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof for use in the preparation of a medicament for treating bacterial infections caused by Gram-negative bacteria.

The present invention provides a compound described in general formula (A-I), (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing a drug for preventing bacterial infection caused by Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella dysenteriae, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella, Vibrio cholerae, and Neisseria meningitidis.

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 _C1 - _C20 straight chain or branched aliphatic hydrocarbon group. Preferably, it is a _C1 - _C10 alkyl group, and more preferably a _C1 - _C6 alkyl group. 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. The alkyl group may be substituted or unsubstituted.

"Alkylene" refers to a saturated C ₁ -C ₂₀ straight chain or branched aliphatic hydrocarbon group having two residues 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 can be substituted or unsubstituted.

"Alkenyl" refers to an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, representative examples include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. Alkenyl groups may be optionally substituted or unsubstituted.

"Alkenylene" refers to an alkylene group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a _C2 - _C6 alkenyl group. Examples of alkenylene groups include _-CH2 =CH2-, -CH2CH= _CHCH2- , -CH2=CH _- CH= _CH2- , -( _CH2 ) _2CH =CH( _CH2 ) _3- , and the like. Alkenylene groups may be optionally substituted _{or unsubstituted} .

"Alkyne" refers to an alkylene group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a _C2 - _C6 alkynyl group. Examples of alkynyl groups include -CH≡CH-, _-CH2CH≡CH- , -CH2CH≡CHCH2-, -CH≡CH-CH≡CH-, -( _CH2 ) _{2CH≡CH- ,} and the like. Alkyne groups may be optionally 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 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.

"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 one 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 4/5 members, 4/6 members, 5/5 members or 5/6 members. 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 5 to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl or tetradecahydrophenanthryl.

"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 one or more double bonds, but no ring has a completely conjugated π electron aromatic system, preferably 6-12 members, more preferably 7-10 members. Preferably 6-14 members, More preferably, it is 7 to 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 refer to non-aromatic heterocyclic groups, 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, including monocyclic, polycyclic, fused, bridged and spirocyclic rings, and the heterocyclic group can be substituted or unsubstituted.

Examples of "monocyclic heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, azetidinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, piperazinyl, hexahydropyrimidinyl,

"Spiro heterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one atom shared between the monocyclic rings, containing one or more double bonds in the ring, 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 shared spiral atoms between the rings, the spiro alkyl group 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, it is a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member 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 an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, one or more rings 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 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 5-14-membered, 5-18-membered, polycyclic group containing two or more cyclic structures, sharing two atoms that are not directly connected to each other, one or more rings 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 6-14 members, more preferably 7-10 members. According to The number of constituent rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

"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, 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, pyridyl, 2-oxo-1,2-dihydropyridyl, 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, pyridyl, pyrimidinyl, pyrazin-2(1H)-onyl, pyrimidin-4(3H)-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 one 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, one 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, it is 7 to 14 yuan, and more preferably 8 to 10 yuan. 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.

"Carboxylate" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, wherein alkyl and cycloalkyl 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.

"Ts" refers to p-toluenesulfonyl.

"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 a strong ability to bear negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to 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, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -OR ⁶ , -C(O)R ⁶ , -C(O)OR ⁶ , -NHC(O)R ⁶ , -NHC(O)OR ⁶ , -NR ⁷ R ⁸ , -C(O)NR ⁷ R ⁸ , -CH ₂ NHC(O)OR ⁶ , -CH ₂ NR ⁷ R ⁸ or -S(O)rR ⁶ ;

R ⁶ is 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 ⁹ , -C(O)OR ⁹ , -OC(O)R ⁹ , -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ or -NR ¹⁰ C(O)R ¹¹ ;

R ⁷ and R ⁸ are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, 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, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O)R ⁹ , -C(O)OR ⁹ , -OC(O)R ⁹ , -NR ¹⁰ R ¹¹ , -C(O)NR ¹⁰ R ¹¹ , -SO ₂ NR ¹⁰ R ¹¹ or -NR ¹⁰ C(O)R ¹¹ ;

Alternatively, ^R7 and ^R8 together with the atoms to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O)r, and the ^4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy ^, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R9, -C(O) ^OR9 , -OC(O) ^{R9 , -NR10R11 ,} _-C (O) ^NR10R11 , ^-SO2NR10R11 or ^-NR10C (O) ^{R11 .} substituted by a substituent;

^R9 , ^R10 and ^R11 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 selected from 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 solution:

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

The compound of general formula (I-a) and the compound of (I-b) undergo coupling reaction under the action of a catalyst, and optionally further undergo deprotection and substitution reaction to obtain a compound of general formula (A-I)

in:

_X1 is selected from halogen;

Ring A, Ring B, ^Ra , ^Rb , m, n, X, Y, Z, Q, L and ^R1 are as described in the general formula (I).

Detailed ways

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, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification. Unless otherwise specified, 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 using a silica gel column chromatography eluent system and thin layer chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; wherein 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, may also be added for adjustment.

Example 1

(S)-1-(1-((5-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

Ethyl 4-(4-iodophenyl)-2,4-dioxobutanoate

Sodium hydride (1.63 g, 40.64 mmol, 60% oil dispersion) was added to toluene (20 mL), 1-(4-iodophenyl)ethan-1-one 1a (5 g, 20.32 mmol, commercially available) was added, and the mixture was heated to 50°C. A toluene solution (20 mL) of diethyl oxalate 1b (4.45 g, 30.48 mmol) was added dropwise, and the mixture was heated to 50°C for 2 hours. The mixture was cooled, poured into ice water, and acidified with 1M hydrochloric acid. The mixture was extracted with ethyl acetate (100 mL × 2), and the combined organic phase was washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain ethyl 4-(4-iodophenyl)-2,4-dioxobutanoate 1c (2.8 g) with a yield of 39.81%.

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

Step 2

Ethyl 5-(4-iodophenyl)isoxazole-3-carboxylate

Ethyl 4-(4-iodophenyl)-2,4-dioxobutanoate 1c (2.8 g, 8.09 mmol) and hydroxylamine hydrochloride (1.69 g, 24.27 mmol) were added to ethanol (25 mL) and heated under reflux for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure and ethyl acetate (100 mL) was added to dissolve the mixture. The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give ethyl 5-(4-iodophenyl)isoxazole-3-carboxylate 1d (2.3 g) with a yield of 82.86%.

MS m/z(ESI):343.8[M+1]

third step

(5-(4-iodophenyl)isoxazol-3-yl)methanol

Ethyl 5-(4-iodophenyl)isoxazole-3-carboxylate 1d (1.20 g, 3.50 mmol) was added to methanol (25 mL), sodium borohydride (198.46 mg, 5.25 mmol) was added in batches, the temperature was raised to 80°C, and the reaction was continued for 4 hours. After the reaction was completed, ice water was added to quench the reaction, and the reaction was extracted with ethyl acetate (50 mL×2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain (5-(4-iodophenyl)isoxazol-3-yl)methanol 1e (0.36 g), with a yield of 34.19%.

MS m/z(ESI):302.0[M+1]

the fourth step

(5-(4-iodophenyl)isoxazol-3-yl)methanesulfonate

(5-(4-iodophenyl)isoxazol-3-yl)methanol 1e (0.36 g, 1.20 mmol) and triethylamine (241.99 mg, 2.39 mmol, 333.31 μL) were added to dichloromethane (5 mL), cooled to 0°C, and methanesulfonyl chloride 1f (205.45 mg, 1.79 mmol) was added dropwise, and the mixture was heated to room temperature for 4 hours. After the reaction was completed, water was added to quench the reaction, and dichloromethane (50 mL×3) was used for extraction. The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to obtain (5-(4-iodophenyl)isoxazol-3-yl)methanesulfonic acid methyl ester 1g (0.45 g), with a yield of 99.26%.

MS m/z(ESI):379.8[M+1]

the fifth step

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole 1h (100 mg, 509.57 μmol) was added to N,N-dimethylformamide (2 mL), cooled to 0°C, sodium hydride (50.96 mg, 764.35 μmol, 60% oil dispersion) was added in batches, the temperature was raised to room temperature for reaction for 1 hour, (5-(4-iodophenyl)isoxazol-3-yl)methanesulfonic acid methyl ester 1g (193.21 mg, 509.57 μmol) was added, and the reaction was continued at room temperature for 4 hours. After the reaction was completed, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (0.12 g), yield: 49.13%.

MS m/z(ESI):480.1[M+1]

Step 6

4-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)morpholine

4-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)morpholine

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), 4-(prop-2-yn-1-yl)morpholine 1j (15.67 mg, 125.18 μmol, commercially available), palladium dichloride (1.85 mg, 10.43 μmol), triphenylphosphine (2.74 mg, 10.43 μmol), cuprous iodide (198.67 μg, 1.04 μmol) and triethylamine (21.11 mg, 208.63 μmol, 29.00 μL) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. Stir at 60°C for 16 hours. After the reaction was complete, the product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: B system) to obtain To 4-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)morpholine 1k (42 mg), yield: 84.48%.

MS m/z(ESI):477.0[M+1]

Step 7

(S)-1-(1-((5-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

4-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)morpholine 1k (50 mg, 104.92 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (35.89 mg, 314.75 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 6 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 1 (25.3 mg) in a yield of 42.85%.

MS m/z(ESI):393.1[M+1]

Example 2

(S)-1-(1-((5-(4-(4-morpholinobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-morpholinobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

4-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol- 5-yl)phenyl)but-3-yn-1-yl)morpholine

4-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)morpholine

4-(But-3-yn-1-yl)morpholine 2a (43.56 mg, 312.95 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), tetrakis(triphenylphosphine)palladium (24.11 mg, 20.86 μmol), cuprous iodide (2.78 mg, 14.60 μmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (95.29 mg, 625.90 μmol, 93.42 μL) were added to tetrahydrofuran (1 mL) in sequence, and argon was replaced three times. The mixture was stirred at 90°C 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 give 4-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)morpholine 2b (20 mg) in a yield of 39.08%.

MS m/z(ESI):491.0[M+1]

Step 2

(S)-1-(1-((5-(4-(4-morpholinobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-morpholinobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

4-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)morpholine 2b (20 mg, 40.77 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (13.95 mg, 122.30 μmol) was slowly added dropwise, and then stirred at 25°C for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(4-morpholinobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 2 (5 mg) in a yield of 23.33%.

MS m/z(ESI):407.1[M+1]

Example 3

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

first step

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), pent-4-yn-1-ol 3a (10.53 mg, 125.18 μmol, 11.65 μL, commercially available), tetrakis(triphenylphosphine)palladium (12.05 mg, 10.43 μmol), cuprous iodide (1.39 mg, 7.30 μmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (31.76 mg, 208.63 μmol, 31.14 μL) were added to tetrahydrofuran (1 mL) in sequence, and argon was replaced three times. Stir at 50°C 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 give 5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol 3b (20 mg) in a yield of 44.02%.

MS m/z(ESI):436.0[M+1]

Step 2

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol 3b (20 mg, 45.92 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (10.47 mg, 91.85 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 6 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol 3 (4 mg) with a yield of 24.54%.

MS m/z(ESI):352.2[M+1]

Example 4

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid

first step

methyl 5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoate

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid methyl ester

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), pent-4-ynoic acid methyl ester 4a (14.04 mg, 125.18 μmol, 14.38 μL, commercially available), tetrakis(triphenylphosphine)palladium (12.05 mg, 10.43 μmol), cuprous iodide (1.39 mg, 7.30 μmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (31.76 mg, 208.63 μmol, 31.14 μL) were added sequentially to tetrahydrofuran (0.5 mL), argon was replaced three times, and the mixture was stirred at 50°C 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 A) to give 5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid methyl ester 4b (40 mg) in a yield of 82.72%.

MS m/z(ESI):464.2[M+1]

Step 2

methyl(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoate

(S)-methyl 5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoate

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid methyl ester 4b (20 mg, 43.15 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (9.84 mg, 86.30 μmol) was slowly added dropwise, and stirred at 25 ° C for 4 hours. After the reaction was completed, it was neutralized with saturated sodium carbonate solution, and the organic phase was separated. The phase was concentrated under reduced pressure and the residue was used directly in the next step to give (S)-methyl 5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoate 4c (8 mg) in a yield of 48.87%.

MS m/z(ESI):380.3[M+1]

third step

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid methyl ester 4c (20 mg, 52.71 μmol) and lithium hydroxide monohydrate (4.42 mg, 105.43 μmol) were added to tetrahydrofuran (1 mL) and water (0.2 mL) in sequence and stirred at 25 °C for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid 4 (8 mg) with a yield of 30.07%.

MS m/z(ESI):366.1[M+1]

Example 5

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide

first step

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) Pent-4-ynamide

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid methyl ester 4b (50 mg, 107.87 μmol) and aqueous ammonia (3.78 mg, 107.87 μmol) were added to acetonitrile (0.5 mL) in sequence and stirred at 25°C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was directly subjected to the next step to give 5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid amide 5a (20 mg) in a yield of 41.34%.

MS m/z(ESI):449.0[M+1]

Step 2

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide

(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide 5a (20 mg, 44.59 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (5.08 mg, 44.59 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide 5 (10 mg) with a yield of 60.93%.

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

Example 6

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)piperidin-4-ol

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)piperidin-4-ol

first step

4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-ol

4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-ol

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), but-3-yn-1-ol 6a (8.77 mg, 125.18 μmol, 9.47 μL, commercially available), tetrakis(triphenylphosphine)palladium (12.05 mg, 10.43 μmol), cuprous iodide (1.39 mg, 7.30 μmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (31.76 mg, 208.63 μmol, 31.14 μL) were added to tetrahydrofuran (1 mL) in sequence, and argon was replaced three times. Stir at 50°C 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 give 4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-ol 6b (30 mg) in a yield of 68.23%.

MS m/z(ESI):422.0[M+1]

Step 2

4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl methanesulfonate

4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl methanesulfonate

4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-ol 6b (30 mg, 71.18 μmol) and triethylamine (14.40 mg, 142.35 μmol, 19.79 μL) were added to dichloromethane (0.5 mL) in sequence, and argon was replaced three times. Methanesulfonyl chloride (12.23 mg, 106.76 μmol, 8.26 μL) was slowly added dropwise under ice-water cooling, and then stirred at 25°C for 6 hours. After the reaction was completed, dichloromethane (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted twice with dichloromethane (30 mL×2), the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl methanesulfonate 6c (30 mg), yield: 84.37%.

MS m/z(ESI):500.0[M+1]

third step

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)piperidin-4-ol

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)piperidin-4-ol

4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl methanesulfonate 6c (20 mg, 40.03 μmol), piperidin-4-ol 6d (4.05 mg, 40.03 μmol, 4.09 μL, commercially available) and potassium carbonate (11.07 mg, 80.07 μmol) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. Stir at 50°C 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 give 1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)piperidin-4-ol 6e (10 mg) in a yield of 49.50%.

MS m/z(ESI):505.0[M+1]

the fourth step

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)piperidin-4-ol

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)piperidin-4-ol

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)piperidin-4-ol 6e (10 mg, 19.82 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (4.52 mg, 39.63 μmol, 3.04 μL) was slowly added dropwise, and the mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)piperidin-4-ol 6 (8 mg) in a yield of 74.77%.

MS m/z(ESI):421.1[M+1]

Example 7

(S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid

(S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid

first step

methyl 6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoate

6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid methyl ester

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50.00 mg, 104.32 μmol), methyl hex-5-ynoate 7a (15.79 mg, 125.18 μmol, 16.45 μL, commercially available), allylpalladium(II) chloride dimer (3.82 mg, 10.43 μmol), tri-tert-butylphosphine (2.11 mg, 10.43 μmol) and triethylene glycol were added. The diamine (35.10 mg, 312.95 μmol) was added to acetonitrile (0.5 mL) in sequence, and the argon was replaced three times. The mixture was stirred at 25°C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain 6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid methyl ester 7b (27 mg), yield: 54.20%.

MS m/z(ESI):478.3[M+1]

Step 2

6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid

6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid

6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid methyl ester 7b (20 mg, 41.88 μmol) and lithium hydroxide monohydrate (1.76 mg, 41.88 μmol) were added to tetrahydrofuran (0.5 mL) in sequence and stirred at 25° C. for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and the residue was directly subjected to the next step to give 6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid 7c (15 mg) in a yield of 77.27%.

MS m/z(ESI):464.0[M+1]

third step

(S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid

(S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid

6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid 7c (15 mg, 32.36 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (7.38 mg, 64.72 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid 7 (8 mg) with a yield of 61.90%.

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

Example 8

(S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

(S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

first step

6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide 7c (20 mg, 41.88 μmol) and aqueous ammonia (4.40 mg, 125.64 μmol) were added to acetonitrile (1 mL) in sequence and stirred at 25° C. for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was directly subjected to the next step to give 6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide 8a (19 mg) in a yield of 98.08%.

MS m/z(ESI):463.0[M+1]

Step 2

(S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

(S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide 8a (20 mg, 43.24 μmol) was added to acetonitrile (1 mL), and trifluoroacetic acid (7.40 mg, 64.86 μmol) was added dropwise. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide 8 (5 mg, 13.08 μmol) with a yield of 30.25%.

Example 9

(S)-1-(1-((5-(4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

5-(4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl methanesulfonate 6c (50 mg, 100.08 μmol), 1-methylpiperazine 9a (40.10 mg, 400.34 μmol, 44.41 μL) and potassium carbonate (82.99 mg, 600.51 μmol) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. Then, the mixture was stirred at 60°C for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, dissolved and filtered with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System B) to give 5-(4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 9b (25 mg), yield: 49.60%; 5-(4-(but-3-ene-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 9c (10 mg), yield: 24.76%.

MS m/z(ESI):504.0[M+1]

Step 2

(S)-1-(1-((5-(4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

5-(4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 9b (50 mg, 99.28 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (22.64 mg, 198.56 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was 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 (S)-1-(1-((5-(4-(4-(4-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 9b (50 mg, 99.28 μmol) was added to dichloromethane ( _{1 mL} ), trifluoroacetic acid (22.64 mg, 198.56 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was 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: -1-alkyne-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 9 (20 mg), yield: 43.22%.

MS m/z(ESI):420.1[M+1]

Example 10

(S)-1-(1-((5-(4-(but-3-en-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(but-3-en-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

5-(4-(But-3-en-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 9c (10 mg, 24.78 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (5.65 mg, 49.57 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was 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 (S)-1-(1-((5-(4-(but-3-en-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 10 (4.8 mg), yield: 40.22%.

MS m/z(ESI):320.0[M+1]

Embodiment 11

(S)-1-(1-((5-(4-(5-morpholinopent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-morpholinopent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5- yl)phenyl)pent-4-yn-1-yl methanesulfonate

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl methanesulfonate

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol 3b (900 mg, 2.07 mmol) and triethylamine (418.22 mg, 4.13 mmol, 574.48 μL) were added to dichloromethane (2 mL) in sequence, and argon was replaced three times. Methanesulfonyl chloride (355.08 mg, 3.10 mmol, 239.92 μL) was slowly added dropwise under ice-water cooling, and then stirred at room temperature 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 give 5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl methanesulfonate 11a (600 mg) in a yield of 56.53%.

MS m/z(ESI):513.9[M+1]

Step 2

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholine

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholine

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl methanesulfonate 11a (50 mg, 97.35 μmol), morpholine 11b (12.72 mg, 146.03 μmol, 12.77 mL, commercially available) and potassium carbonate (26.91 mg, 194.70 μmol) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. Stir at 50°C 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 give 4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholine 11c (49 mg) in a yield of 99.75%.

MS m/z(ESI):505.0[M+1]

third step

(S)-1-(1-((5-(4-(5-morpholinopent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-morpholinopent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholine 11c (49 mg, 97.10 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (11.07 mg, 97.10 μmol) was slowly added dropwise. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was 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 (S)-1-(1-((5-(4-(5-morpholinopent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 11 (5 mg), yield: 16.38%.

MS m/z(ESI):421.3[M+1]

Example 12

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile

first step

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile

4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl methanesulfonate 6c (50 mg, 100.08 μmol), azetidine-3-carbonitrile 12a (32.87 mg, 400.34 μmol, commercially available) and potassium carbonate (110.66 mg, 800.68 μmol) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. Stir at 80°C 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 give 1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile 12b (16 mg) in a yield of 32.92%.

MS m/z(ESI):486.3[M+1]

Step 2

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole-5-yl 1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile 12b (16 mg, 32.95 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (7.51 mg, 65.90 μmol) was slowly added dropwise, and stirred at 25°C for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was 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 (S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile 12 (8 mg), yield: 40.03%.

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

Example 13

(S)-1-(1-((5-(4-(5-(4-methylpiperazin-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-(4-methylpiperazin-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

5-(4-(5-(4-methylpiperazin-1-yl)pent-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(5-(4-methylpiperazin-1-yl)pent-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl methanesulfonate 11a (50 mg, 97.35 μmol), 1-methylpiperazine 9a (48.75 mg, 486.76 μmol, 53.99 μL) and potassium carbonate (26.91 mg, 194.70 μmol) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. Stir at 60°C for 16 hours. After the reaction was complete, the product was evaporated under reduced pressure to give 5-(4-(5-(4-methylpiperazin-1-yl)pent-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 13a (50 mg). Yield: 99.22%.

MS m/z(ESI):518.0[M+1]

Step 2

(S)-1-(1-((5-(4-(5-(4-methylpiperazin-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-(4-methylpiperazin-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

5-(4-(5-(4-methylpiperazin-1-yl)pent-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 13a (50 mg, 96.59 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (22.03 mg, 193.18 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(5-(4-methylpiperazin-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 13 (5 mg) in a yield of 8.51%.

MS m/z(ESI):434.3[M+1]

Embodiment 14

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholin-3-one

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholin-3-one

first step

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholin-3-one

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholin-3-one

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl methanesulfonate 11a (50 mg, 97.35 μmol), morpholin-3-one 14a (49.21 mg, 486.76 μmol, 43.86 μL, commercially available) and potassium carbonate (26.91 mg, 194.70 μmol) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. Stir at 100°C for 16 hours. After the reaction was completed, the product was evaporated under reduced pressure to give 4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholin-3-one 14b (50 mg) with a yield of 99.04%.

MS m/z(ESI):519.3[M+1]

Step 2

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholin-3-one

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholin-3-one

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholin-3-one 14b (50 mg, 96.41 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (21.99 mg, 192.83 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)morpholin-3-one 14 (5 mg) in a yield of 10.74%.

MS m/z(ESI):435.2[M+1]

Embodiment 15

(S)-1-(1-((5-(4-(5-(1H-imidazol-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-(1H-imidazol-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

5-(4-(5-(1H-imidazol-1-yl)pent-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(5-(1H-imidazol-1-yl)pent-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl methanesulfonate 11a (50 mg, 97.35 μmol), imidazole 15a (33.14 mg, 486.76 μmol, 32.81 μL, commercially available) and potassium carbonate (26.91 mg, 194.70 μmol) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. The mixture was stirred at 100°C for 16 hours. After the reaction was completed, the reaction was evaporated under reduced pressure to give crude 5-(4-(5-(1H-imidazol-1-yl)pent-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 15b (47 mg) in a yield of 99.43%.

MS m/z(ESI):486.1[M+1]

Step 2

(S)-1-(1-((5-(4-(5-(1H-imidazol-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-(1H-imidazol-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

5-(4-(5-(1H-imidazol-1-yl)pent-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 15b (47 mg, 96.79 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (11.04 mg, 96.79 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(5-(1H-imidazol-1-yl)pent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 15 (5 mg) in a yield of 9.02%.

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

Example 16

(S)-2-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

(S)-2-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

first step

2-((5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

2-((5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl methanesulfonate 11a (20 mg, 38.94 μmol), 2-aminoacetamide 16a (28.85 mg, 389.40 μmol, commercially available) and potassium carbonate (10.76 mg, 77.88 μmol) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. The mixture was stirred at 100°C for 6 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give 2-((5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide 16b (19 mg) with a yield of 99.26%.

MS m/z(ESI):492.3[M+1]

Step 2

(S)-2-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

(S)-2-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

2-((5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide 16b (19 mg, 38.65 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (8.81 mg, 77.30 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-2-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide 16 (5 mg) in a yield of 22.82%.

MS m/z(ESI):408.2[M+1]

Embodiment 17

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carboxamide

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carboxamide

first step

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carboxamide

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carboxamide

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carbonitrile 12b (20 mg, 41.19 μmol) and sodium hydroxide (3.29 mg, 82.38 μmol) were added successively to dimethyl sulfoxide (0.5 mL), hydrogen peroxide (0.5 mL) was slowly added dropwise under water bath cooling, and then stirred at room temperature for 16 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted twice with ethyl acetate (30 mL×2), the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carboxamide 17a (20 mg), yield: 96.42%.

MS m/z(ESI):504.0[M+1]

Step 2

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carboxamide

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carboxamide

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carboxamide 17a (20 mg, 39.71 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (9.06 mg, 79.43 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 6 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)azetidine-3-carboxamide 17 (1.15 mg) in a yield of 4.88%.

MS m/z(ESI):420.0[M+1]

Embodiment 18

(S)-3-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propanenitrile

(S)-3-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propionitrile

first step

3-((5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propanenitrile

3-((5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propionitrile

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl methanesulfonate 11a (50 mg, 97.35 μmol), 3-aminopropionitrile 18a (68.24 mg, 973.51 μmol, 71.20 μL, commercially available) and potassium carbonate (26.91 mg, 194.70 μmol) were added to acetonitrile (1 mL) in sequence, and the argon atmosphere was replaced. 100 °C The mixture was stirred for 4 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give 3-((5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propionitrile 18b (47 mg) in a yield of 99.01%.

MS m/z(ESI):488.3[M+1]

Step 2

(S)-3-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propanenitrile

(S)-3-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propionitrile

3-((5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propionitrile 18b (47 mg, 96.39 μmol) was added to dichloromethane (1 mL), trifluoroacetic acid (21.98 mg, 192.78 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-3-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propionitrile 18 (5 mg) in a yield of 9.02%.

MS m/z(ESI):404.3[M+1]

Embodiment 19

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)piperazin-2-one

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)piperazin-2-one

first step

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol- 5-yl)phenyl)pent-4-yn-1-yl)piperazin-2-one

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)piperazin-2-one

5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl methanesulfonate 11a (50 mg, 97.35 μmol), piperazin-2-one 19a (97.47 mg, 973.51 μmol, 92.56 μL, commercially available) and potassium carbonate (26.91 mg, 194.70 μmol) were added to acetonitrile (1 mL) in sequence, and argon was replaced three times. The mixture was stirred at 100°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to give 4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)piperazin-2-one 19b (50 mg) with a yield of 99.22%.

MS m/z(ESI):518.3[M+1]

Step 2

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)piperazin-2-one

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)piperazin-2-one

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)piperazin-2-one 19b (50 mg, 96.60 μmol) was added to dichloromethane (1 mL), argon was replaced three times, trifluoroacetic acid (11.01 mg, 96.60 μmol) was slowly added dropwise, and stirred at 25 °C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)piperazin-2-one 19 (5 mg). Yield: 8.51%.

MS m/z(ESI):434.3[M+1]

Embodiment 20

(S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

tert-butyl(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)carbamate

tert-Butyl (4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)carbamate

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (30 mg, 62.59 μmol), tert-butyl N-but-3-ynylcarbamate 20a (15.89 mg, 93.88 μmol), bis(triphenylphosphine)palladium(II) chloride (4.87 mg, 6.26 μmol) and cuprous iodide (1.19 mg, 6.26 μmol) were added to N,N-dimethylformamide (0.5 mL) in sequence, and argon was replaced three times. The mixture was stirred at room temperature for 1 hour, and then triethylamine (38.00 mg, 375.54 μmol, 48.72 μL) was slowly added dropwise, and then stirred at room temperature for 16 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted twice with ethyl acetate (30 mL×2), the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give tert-butyl (4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)carbamate 20b (20 mg), yield: 61.38%.

MS m/z(ESI):520.8[M+1]

Step 2

(S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Tert-butyl (4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)carbamate 20b (40 mg, 76.83 μmol) was added to dichloromethane (0.5 mL) and methanol (0.5 mL) and stirred at room temperature for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 20 (8 mg). Yield: 21.50%.

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

Embodiment 21

(S)-N-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)formamide

(S)-N-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)formamide

(S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 20 (20 mg, 59.46 μmol) and triethylamine (60.16 mg, 594.55 μmol) were added to formamide (2 mL) in sequence and stirred at room temperature for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-N-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)formamide 21 (8 mg) in a yield of 27.00%.

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

Embodiment 22

methyl(S)-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)glycinate

(S)-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)glycine methyl ester

(S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 20 (30 mg, 89.18 μmol), ethyl 2-bromoacetate 22a (11.91 mg, 71.35 μmol, 7.91 μL) and N,N-diisopropylethylamine (34.58 mg, 267.55 μmol) were added to methanol (0.2 mL) in sequence and stirred at 25 °C for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)glycine methyl ester 22 (5 mg) in a yield of 10.41%.

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

Embodiment 23

(S)-1-(1-((5-(4-(4-(1H-imidazol-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-(1H-imidazol-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

1-(but-3-yn-1-yl)-1H-imidazole

1-(But-3-yn-1-yl)-1H-imidazole

Imidazole 15a (255.96 mg, 3.76 mmol, commercially available) was added to tetrahydrofuran (0.5 mL) and argon was replaced three times. Sodium hydride (195.61 mg, 7.52 mmol) was slowly added, and then stirred at 85°C for 1 hour. After returning to room temperature, 4-bromobut-1-yne 23a (500 mg, 3.76 mmol, 352.86 μL, commercially available) was added, and stirred at 85°C for 3 hours. After the reaction was complete, it was concentrated under reduced pressure, and dichloromethane (5 mL) was added and filtered to obtain 1-(but-3-yne-1-yl)-1H-imidazole 23b (380 mg), with a yield of 84.12%.

MS m/z(ESI):121.2[M+1]

Step 2

5-(4-(4-(1H-imidazol-1-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(4-(1H-imidazol-1-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), 1-(but-3-yn-1-yl)-1H-imidazole 23b (18.80 mg, 156.47 μmol), triethylamine (10.56 mg, 104.32 μmol, 14.50 μL), bis(triphenylphosphine)palladium(II) dichloride (8.12 mg, 10.43 μmol) and cuprous iodide (3.97 mg, 20.86 μmol) were added to ethylene glycol dimethyl ether (0.5 mL) in sequence, argon was replaced, and the mixture was stirred at 65° C. for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure to give 5-(4-(4-(1H-imidazol-1-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 23c (20 mg), yield: 40.66%.

MS m/z(ESI):472.0[M+1]

third step

(S)-1-(1-((5-(4-(4-(1H-imidazol-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-(1H-imidazol-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

5-(4-(4-(1H-imidazol-1-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 23c (20 mg, 42.41 μmol) was added to dichloromethane (0.3 mL), trifluoroacetic acid (9.67 mg, 84.83 μmol) was slowly added dropwise, and then stirred at 25°C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(4-(1H-imidazol-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 23 (5 mg) in a yield of 22.33%.

MS m/z(ESI):388.0[M+1]

Embodiment 24

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile

first step

1-(prop-2-yn-1-yl)azetidine-3-carbonitrile

1-(Propan-2-yn-1-yl)azetidine-3-carbonitrile

Azetidine-3-carbonitrile 12a (498.34 mg, 4.20 mmol) was added to tetrahydrofuran (2 mL), argon was replaced three times, sodium hydride (437.29 mg, 16.81 mmol) was slowly added under ice-water cooling, and then stirred at room temperature for 0.5 hours, and then 3-bromoprop-1-yne 24a (500 mg, 4.20 mmol, 362.32 μL, commercially available) was added, and the reaction was carried out at 85°C for 24 hours. After the reaction was complete, water (20 mL) was added to quench the reaction, and the reaction was concentrated under reduced pressure, extracted with dichloromethane (30 mL×3), and concentrated under reduced pressure to obtain 1-(prop-2-yn-1-yl)azetidine-3-carbonitrile 24b (200 mg), with a yield of 39.60%.

MS m/z(ESI):121.2[M+1]

Step 2

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), 1-(prop-2-yn-1-yl)azetidine-3-carbonitrile 24b (37.60 mg, 312.95 μmol), triethylamine (10.56 mg, 104.32 μmol), bis(triphenylphosphine)palladium(II) dichloride (8.12 mg, 10.43 μmol) and cuprous iodide (3.97 mg, 20.86 μmol) were added sequentially to ethylene glycol dimethyl ether (0.5 mL), argon was replaced, and the mixture was stirred at 65° C. for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure and the next step was carried out directly to give 1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile 24c (20 mg) in a yield of 40.66%.

MS m/z(ESI):472.4[M+1]

third step

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile 24c (20 mg, 42.41 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (9.67 mg, 84.83 μmol) was slowly added dropwise, and then stirred at 25°C for 4 hours. After the reaction was complete, it was concentrated under reduced pressure. The residue was 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 (S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile 24 (3.2 mg). Yield: 14.59%.

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

Embodiment 25

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxamide

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxamide

first step

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxamide

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxamide

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile 24c (20 mg, 42.41 μmol) and sodium hydroxide (3.39 mg, 84.83 μmol) were added to dimethyl sulfoxide (0.5 mL) in sequence. Under water bath cooling, hydrogen peroxide solution (0.3 mL) was slowly added dropwise and stirred at 25 °C for 2 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxamide 25a (10 mg), yield: 48.16%.

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

Step 2

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxamide

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxamide

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxamide 25a (10 mg, 20.43 μmol) was added to dichloromethane (0.2 mL), trifluoroacetic acid (4.66 mg, 40.85 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxamide 25 (1.44 mg) in a yield of 13.16%.

MS m/z(ESI):406.2[M+1]

Embodiment 26

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxylic acid

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxylic acid

first step

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxylic acid

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxylic acid

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole-5-yl 1-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carbonitrile 24c (20 mg, 42.41 μmol) and sodium hydroxide (3.39 mg, 84.83 μmol) were added to dimethyl sulfoxide (0.3 mL) in sequence, and hydrogen peroxide (0.2 mL) was slowly added dropwise, followed by stirring at room temperature for 3 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxylic acid 26a (10 mg), yield: 48.06%.

MS m/z(ESI):491.1[M+1]

Step 2

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxylic acid

(S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxylic acid

1-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxylic acid 26a (10 mg, 20.39 μmol) was added to dichloromethane (0.2 mL), trifluoroacetic acid (4.65 mg, 40.77 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)azetidine-3-carboxylic acid 26 (0.49 mg) in a yield of 5.38%.

MS m/z(ESI):407.1[M+1]

Embodiment 27

(S)-4-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)piperazin-2-one

(S)-4-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)piperazin-2-one

first step

4-(prop-2-yn-1-yl)piperazin-2-one

4-(Propan-2-yn-1-yl)piperazin-2-one

3-Bromoprop-1-yne 24a (500 mg, 4.20 mmol, 362.32 μL) and piperazin-2-one 19a (420.81 mg, 4.20 mmol, 399.63 μL) were added to N,N-dimethylformamide (2 mL) in sequence, and the argon gas was replaced three times. Under ice-water cooling, sodium hydride (437.29 mg, 16.81 mmol) was slowly added, and then stirred at 85°C for 24 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added, and the liquids were separated. The aqueous phase was extracted with ethyl acetate (30 mL×2), and the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 4-(prop-2-yn-1-yl)piperazin-2-one 27a (200 mg), with a yield of 34.44%.

MS m/z(ESI):139.2[M+1]

Step 2

4-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)piperazin-2-one

4-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)piperazin-2-one

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), 4-(prop-2-yn-1-yl)piperazin-2-one 27a (144.13 mg, 1.04 mmol), triethylamine (10.56 mg, 104.32 μmol), bis(triphenylphosphine)palladium(II) dichloride (8.12 mg, 10.43 μmol) and cuprous iodide (3.97 mg, 20.86 μmol) were added sequentially to ethylene glycol dimethyl ether (0.5 mL), argon was replaced, and the mixture was stirred at 65° C. for 16 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted twice with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and filtered to give 4-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)piperazin-2-one 27b (20 mg), yield: 39.16%.

MS m/z(ESI):490.3[M+1]

third step

(S)-4-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)piperazin-2-one

(S)-4-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)piperazin-2-one

4-(3-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)piperazin-2-one 27b (20 mg, 40.85 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (13.97 mg, 122.56 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-4-(3-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)prop-2-yn-1-yl)piperazin-2-one 27 (6.02 mg) in a yield of 26.95%.

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

Embodiment 28

(S)-4-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

(S)-4-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

first step

4-(but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-(But-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-Bromobut-1-yne 23a (1.75 g, 13.16 mmol, 1.24 mL), 2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one 28a (846.71 mg, 5.64 mmol) and cesium carbonate (3.68 g, 11.28 mmol) were added to N,N-dimethylformamide (3 mL) in sequence. The argon atmosphere was replaced three times. The mixture was stirred at 70°C for 24 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to give 4-(but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazine-3(4H)-one 28b (150 mg) in a yield of 19.73%.

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

Step 2

4-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), 4-(but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one 28b (25.31 mg, 125.18 μmol), triethylamine (31.67 mg, 312.95 μmol, 43.50 μL), bis(triphenylphosphine)palladium(II) dichloride (8.12 mg, 10.43 μmol) and cuprous iodide (3.97 mg, 20.86 μmol) were added sequentially to ethylene glycol dimethyl ether (0.5 mL), argon was replaced, and the mixture was stirred at 65°C for 16 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted twice with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and filtered to give 4-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one 28c (50 mg), yield: 86.58%.

MS m/z(ESI):554.2[M+1]

third step

(S)-4-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

(S)-4-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

4-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one 28c (50 mg, 90.32 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (20.60 mg, 180.63 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-4-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one 28 (3.74 mg) in a yield of 6.74%.

MS m/z(ESI):470.2[M+1]

Embodiment 29

(S)-3-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1- yl)imidazolidine-2,4-dione

(S)-3-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)imidazolidine-2,4-dione

first step

3-(but-3-yn-1-yl)imidazolidine-2,4-dione

3-(But-3-yn-1-yl)imidazolidine-2,4-dione

4-Bromobut-1-yne 23a (500 mg, 3.76 mmol, 352.86 μL), imidazolidine-2,4-dione 29a (451.52 mg, 4.51 mmol), potassium carbonate (519.62 mg, 3.76 mmol) and tetrabutylammonium bromide (242.41 mg, 751.96 μmol) were added to tetrahydrofuran (4 mL) in sequence, argon was replaced three times, and stirred at 70°C for 24 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added, the liquid was separated, the aqueous phase was extracted with ethyl acetate (30 mL×2), the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 3-(but-3-yn-1-yl)imidazolidine-2,4-dione 29b (120 mg), with a yield of 20.98%.

MS m/z(ESI):153.1[M+1]

Step 2

3-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)imidazolidine-2,4-dione

3-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)imidazolidine-2,4-dione

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), 3-(but-3-yn-1-yl)imidazolidine-2,4-dione 29b (19.05 mg, 125.18 μmol), triethylamine (31.67 mg, 312.95 μmol, 43.50 μL), bis(triphenylphosphine)palladium(II) dichloride (8.12 mg, 10.43 μmol) and Cuprous iodide (3.97 mg, 20.86 μmol) was added to ethylene glycol dimethyl ether (0.5 mL) in sequence, argon was replaced, and the mixture was stirred at 65°C for 16 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added, and the mixture was separated. The aqueous phase was extracted with ethyl acetate twice (30 mL×2). The combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and filtered to give 3-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)imidazolidine-2,4-dione 29c (50 mg) in a yield of 95.19%.

MS m/z(ESI):504.1[M+1]

third step

(S)-3-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)imidazolidine-2,4-dione

(S)-3-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)imidazolidine-2,4-dione

3-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)imidazolidine-2,4-dione 29c (50 mg, 99.30 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (22.64 mg, 198.59 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-3-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)imidazolidine-2,4-dione 29 (7.45 mg) in a yield of 13.36%.

MS m/z(ESI):420.1[M+1]

Embodiment 30

(S)-1-(1-((5-(4-(4-(7H-purin-7-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-(7H-purin-7-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

7-(but-3-yn-1-yl)-7H-purine

7-(But-3-yn-1-yl)-7H-purine

4-Bromobut-1-yne 23a (830.39 mg, 6.24 mmol, 586.02 μL), 7H-purine 30a (500 mg, 4.16 mmol) and potassium carbonate (1.15 g, 8.33 mmol) were added to N,N-dimethylformamide (3 mL) in sequence, and argon was replaced three times. Stir at 70°C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain 7-(but-3-yn-1-yl)-7H-purine 30b (200 mg) with a yield of 27.90%.

MS m/z(ESI):173.1[M+1]

Step 2

5-(4-(4-(7H-purin-7-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(4-(7H-purin-7-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), 7-(but-3-yn-1-yl)-7H-purine 30b (26.94 mg, 156.47 μmol), triethylamine (31.67 mg, 312.95 μmol, 43.50 μL), bis(triphenylphosphine)palladium(II) dichloride (8.12 mg, 10.43 μmol) and cuprous iodide (3.97 mg, 20.86 μmol) were added to ethylene glycol dimethyl ether (0.5 mL) in sequence, and argon was replaced. The mixture was stirred at 65°C for 16 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted twice with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and filtered to give 5-(4-(4-(7H-purin-7-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 30c (50 mg), yield: 91.54%.

MS m/z(ESI):524.3[M+1]

third step

(S)-1-(1-((5-(4-(4-(7H-purin-7-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-(7H-purin-7-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)eth-1- alcohol

5-(4-(4-(7H-purin-7-yl)but-1-yn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 30c (25 mg, 47.75 μmol) was added to N,N-dimethylformamide (0.5 mL), trifluoroacetic acid (10.89 mg, 95.50 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(4-(7H-purin-7-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 30 (4.8 mg) in a yield of 17.62%.

MS m/z(ESI):440.0[M+1]

Embodiment 31

(S)-1-(1-((5-(4-(4-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

(S)-(1-(but-3-yn-1-yl)pyrrolidin-2-yl)methanol

(S)-(1-(But-3-yn-1-yl)pyrrolidin-2-yl)methanol

4-Bromobut-1-yne 23a (788.87 mg, 5.93 mmol, 556.72 μL), (S)-pyrrolidin-2-ylmethanol 31a (500 mg, 4.94 mmol) and potassium carbonate (2.05 g, 14.83 mmol) were added to toluene (0.2 mL) in sequence, and argon was replaced three times. Stir at 110°C for 24 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain (S)-(1-(but-3-yn-1-yl)pyrrolidin-2-yl)methanol 31b (280 mg) with a yield of 36.97%.

MS m/z(ESI):154.2[M+1]

Step 2

((2S)-1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyrrolidin-2-yl)methanol

((2S)-1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyrrolidin-2-yl)methanol

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), (S)-(1-(but-3-yn-1-yl)pyrrolidin-2-yl)methanol 31b (15.98 mg, 104.32 μmol), triethylamine (31.67 mg, 312.95 μmol, 43.50 μL), bis(triphenylphosphine)palladium(II) dichloride (8.12 mg, 10.43 μmol) and cuprous iodide (3.97 mg, 20.86 μmol) were added sequentially to ethylene glycol dimethyl ether (0.5 mL), argon was replaced, and the mixture was stirred at 65° C. for 16 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted twice with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and filtered to give ((2S)-1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyrrolidin-2-yl)methanol 31c (20 mg), yield: 37.99%.

MS m/z(ESI):505.0[M+1]

third step

(S)-1-(1-((5-(4-(4-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(4-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

((2S)-1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyrrolidin-2-yl)methanol 31c (20 mg, 39.63 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (4.52 mg, 39.63 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(4-((S)-2-(hydroxymethyl)pyrrolidin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 31 (4.22 mg) in a yield of 19.72%.

MS m/z(ESI):421.1[M+1]

Embodiment 32

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyridin-2(1H)-one

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyridin-2(1H)-one

first step

1-(but-3-yn-1-yl)pyridin-2(1H)-one

1-(But-3-yn-1-yl)pyridin-2(1H)-one

1H-pyridin-2-one 32a (500.00 mg, 5.26 mmol), 4-bromobut-1-yne 23a (4.89 g, 36.80 mmol, 3.45 mL) and cesium carbonate (2.57 g, 7.89 mmol) were added to acetonitrile (0.5 mL) in sequence, and argon was replaced three times. Stir at 70°C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain 1-(but-3-yn-1-yl)pyridin-2(1H)-one 32b (150 mg) with a yield of 19.39%.

MS m/z(ESI):148.1[M+1]

Step 2

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyridin-2(1H)-one

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyridin-2(1H)-one

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), 1-(but-3-yn-1-yl)pyridin-2(1H)-one 32b (23.03 mg, 156.47 μmol), triethylamine (31.67 mg, 312.95 μmol, 43.50 μL), bis(triphenylphosphine)palladium(II) dichloride (8.12 mg, 10.43 μmol) and cuprous iodide (3.97 mg, 20.86 μmol) were added sequentially to ethylene glycol dimethyl ether (0.5 mL), argon was replaced three times, and the mixture was stirred at 65°C for 16 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, the liquids were separated, the aqueous phase was extracted twice with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, and filtered to give 1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyridine-2(1H)-one 32c (50 mg), yield: 96.14%.

MS m/z(ESI):499.0[M+1]

third step

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyridin-2(1H)-one

(S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyridin-2(1H)-one

1-(4-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyridin-2(1H)-one 32c (50 mg, 100.29 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (22.87 mg, 200.57 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)pyridin-2(1H)-one 32 (20 mg) in a yield of 33.96%.

MS m/z(ESI):415.1[M+1]

Embodiment 33

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)piperazin-2-one

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperazin-2-one

first step

3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole

3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (8 g, 16.69 mmol), ethynyltrimethylsilane 33a (3.28 g, 33.38 mmol, 4.72 mL, commercially available), allylpalladium(II) chloride dimer (609.21 mg, 1.67 mmol) and triethylenediamine (3.74 g, 33.38 mmol) and tri-tert-butylphosphine (10% toluene solution) (3.38 g, 1.67 mmol) were added to acetonitrile (20 mL) in sequence, argon was replaced 3 times, and stirring was continued at room temperature for 12 hours. The system was concentrated to dryness under reduced pressure, water (50 mL) was added, and extraction was carried out with ethyl acetate (50 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole 33b (7.5 g), yield: 99.94%.

MS m/z(ESI):450.3[M+1]

Step 2

5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole 33b (7.5 g, 16.68 mmol) and potassium fluoride (1.94 g, 33.36 mmol) were added to methanol (50 mL) in sequence. The reaction was completed after continuous stirring at room temperature for 5 hours. Water was added to obtain the mixture. The residue was purified by silica gel column chromatography (eluent: system A) to give 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (5.8 g), yield: 92.21%.

MS m/z(ESI):378.2[M+1]

third step

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)piperazin-2-one

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperazin-2-one

4-(Propan-2-yn-1-yl)piperazin-2-one 27a (24.16 mg, 174.86 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (55 mg, 145.72 μmol), N,N,N',N'-tetramethylethylenediamine (5.08 mg, 43.72 μmol) and cuprous iodide (8.33 mg, 43.72 μmol) were added to acetone (2 mL) in sequence, and the atmosphere was replaced with argon three times. The reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperazin-2-one 33d (50 mg) in a yield of 66.81%.

MS m/z(ESI):514.3[M+1]

the fourth step

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4- diyn-1-yl)piperazin-2-one

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperazin-2-one

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperazin-2-one 33d (50 mg, 97.35 μmol) was dissolved in dichloromethane (1.5 mL), and trifluoroacetic acid (0.5 mL) was added dropwise, and the mixture was stirred at 25° C. for 2 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperazin-2-one 33 (11.69 mg) in a yield of 20.11%.

MS m/z(ESI):430.1[M+1]

Embodiment 34

(1r,3r)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1r,3r)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

first step

5-(4-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

Tert-butyl((1r,3r)-3-ethynylcyclobutyloxy)dimethylsilane 34a (50.67 mg, 240.86 μmol, commercially available), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (100 mg, 264.95 μmol), N,N,N',N'-tetramethylethylenediamine (4.20 mg, 36.13 μmol), and cuprous iodide (13.76 mg, 72.26 μmol) were added to acetone (2 mL) in sequence. After argon replacement three times, the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to obtain 5-(4-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro- (2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 34b (80 mg), yield: 56.70%.

MS m/z(ESI):586.2[M+1]

Step 2

(1r,3r)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1r,3r)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

5-(4-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)but-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 34b (80 mg, 136.56 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued for half an hour at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (1r,3r)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)cyclobutan-1-ol 34 (11.62 mg) in a yield of 14.78%.

MS m/z(ESI):388.0[M+1]

Embodiment 35

(S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetonitrile

(S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetonitrile

first step

3-ethynylazetidine

3-Ethynylazetidine

Under ice bath, tert-butyl 3-ethynylazetidine-1-carboxylate 35a (100 mg, 551.78 μmol, commercially available) was added to ethyl acetate solution of hydrogen chloride (4M) (1.5 mL), and then stirred continuously to gradually warm to room temperature, and continued to stir for 1 hour. After the reaction was complete, a white suspension was obtained, and the reaction solution was directly dried to obtain 3-ethynylazetidine 35b (65 mg, hydrochloride), which was directly used for the next step reaction.

Step 2

2-(3-ethynylazetidin-1-yl)acetonitrile

2-(3-ethynylazetidin-1-yl)acetonitrile

2-iodoacetonitrile 35c (308.72 mg, 1.85 mmol, commercially available), 3-ethynylazetidine 35b (100 mg, 1.23 mmol), and cesium carbonate (803.35 mg, 2.47 mmol) were added to acetonitrile (2 mL) in sequence, and then the temperature was raised to 70°C and stirred for 3 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the organic solvent, water (20 mL) was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product of 2-(3-ethynylazetidine-1-yl)acetonitrile 35d, which was directly used in the next step.

MS m/z(ESI):121.2[M+1]

third step

2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetonitrile

2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetonitrile

Under argon atmosphere, 2-(3-ethynylazetidin-1-yl)acetonitrile 35d (76.40 mg, 635.87 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (80 mg, 211.96 μmol), cuprous iodide (12.11 mg, 63.59 μmol), and N,N,N',N'-tetramethylethylenediamine (7.39 mg, 63.59 μmol) were added to acetone (1 mL) in sequence, and the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidine-1-yl)acetonitrile 35e (40 mg) in a yield of 38.08%.

MS m/z(ESI):496.1[M+1]

the fourth step

(S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetonitrile

(S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetonitrile

2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidin-1-yl)acetonitrile 35e (40.00 mg, 80.71 μmol) was added to dichloromethane 1-Hydroxy-1-nitropropane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and continued stirring at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was 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 (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidin-1-yl)acetonitrile 35 (2.12 mg), yield: 4.89%.

MS m/z(ESI):412.0[M+1]

Embodiment 36

(S)-1-(1-((5-(4-(pyrimidin-5-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(pyrimidin-5-ylbutyl-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

5-(4-(pyrimidin-5-ylbuta-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(Pyrimidin-5-ylbut-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

Under argon atmosphere, 5-ethynylpyrimidine 36a (27.58 mg, 264.95 μmol, commercially available), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (50 mg, 132.47 μmol), cuprous iodide (7.57 mg, 39.74 μmol), and N,N,N’,N’-tetramethylethylenediamine (4.62 mg, 39.74 μmol) were added to acetone (1 mL) in sequence, and the reaction was completed after continuous stirring for 12 hours at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 5-(4-(pyrimidin-5-ylbut-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 36b (45 mg) in a yield of 70.84%.

MS m/z(ESI):480.3[M+1]

Step 2

(S)-1-(1-((5-(4-(pyrimidin-5-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(pyrimidin-5-ylbutyl-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

5-(4-(pyrimidin-5-ylbut-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl 1-((5-(4-(pyrimidin-5-ylbutyl-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 36b (45 mg, 93.84 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and continued stirring at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was 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 (S)-1-(1-((5-(4-(pyrimidin-5-ylbutyl-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 36 (9.9 mg), yield: 19.88%.

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

Embodiment 37

(S)-1-(1-((5-(4-(pyridin-3-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(pyridin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

5-(4-(pyridin-3-ylbuta-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(pyridin-3-ylbut-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

Under argon atmosphere, 3-ethynylpyridine 37a (27.32 mg, 264.95 μmol, commercially available), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (50 mg, 132.47 μmol), cuprous iodide (7.57 mg, 39.74 μmol), and N,N,N’,N’-tetramethylethylenediamine (4.62 mg, 39.74 μmol) were added to acetone (1 mL) in sequence, and the reaction was completed after continuous stirring for 12 hours at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 5-(4-(pyridin-3-ylbut-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 37b (40 mg) in a yield of 63.10%.

MS m/z(ESI):479.3[M+1]

Step 2

(S)-1-(1-((5-(4-(pyridin-3-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(pyridin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

5-(4-(pyridin-3-ylbut-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl 1-((5-(4-(pyridin-3-ylbutan-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 37b (40 mg, 83.59 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid and continued stirring at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(pyridin-3-ylbutan-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 37 (31 mg) in a yield of 69.29%.

MS m/z(ESI):395.2[M+1]

Embodiment 38

(S)-1-(1-((5-(4-(5-morpholinopenta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-morpholino-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

4-(5-(trimethylsilyl)penta-2,4-diyn-1-yl)morpholine

4-(5-(Trimethylsilyl)penta-2,4-diyn-1-yl)morpholine

Under argon atmosphere, 4-(prop-2-yn-1-yl)morpholine 1j (50 mg, 399.46 μmol, commercially available), (iodoethynyl)trimethylsilane 38b (179.05 mg, 798.93 μmol, commercially available), triethylamine (80.84 mg, 798.93 μmol), cuprous iodide (15.22 mg, 79.89 μmol), bistriphenylphosphine palladium dichloride (56.08 mg, 79.89 μmol) were added to N,N-dimethylformamide (1 mL) in sequence, and stirred for 16 hours at 60°C. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4-(5-(trimethylsilyl)penta-2,4-diyn-1-yl)morpholine 38c, which was used directly in the next step.

MS m/z(ESI):222.3[M+1]

Step 2

4-(penta-2,4-diyn-1-yl)morpholine

4-(Penta-2,4-diyn-1-yl)morpholine

4-(5-(Trimethylsilyl)penta-2,4-diyn-1-yl)morpholine 38c (250 mg, 1.13 mmol) and potassium fluoride (131.23 mg, 2.26 mmol) were added to methanol (3 mL) in sequence and stirred for 5 hours at room temperature. Water (50 mL) was added and extracted with ethyl acetate (50 mL×3). The combined organic phase was dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to obtain 4-(penta-2,4-diyn-1-yl)morpholine 38d (150 mg) with a yield of 89.03%.

MS m/z(ESI):150.1[M+1]

third step

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)morpholine

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)morpholine

5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 1i (50 mg, 104.32 μmol), 4-(pentan-2,4-diyn-1-yl)morpholine 38d (31.13 mg, 208.63 μmol), allylpalladium(II) chloride dimer (7.62 mg, 20.86 μmol), triethylenediamine (23.40 mg, 208.63 μmol), and tri-tert-butylphosphine (10% in toluene solution) (4.22 mg, 20.86 μmol) were added to acetonitrile (2 mL) in sequence and stirred at room temperature for 12 hours under argon atmosphere. The system was concentrated to dryness under reduced pressure, water (50 mL) was added, and extraction was carried out with ethyl acetate (50 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and then distilled under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)morpholine 38e (43 mg) in a yield of 82.33%.

MS m/z(ESI):501.1[M+1]

the fourth step

(S)-1-(1-((5-(4-(5-morpholinopenta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-morpholino-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)morpholine 38e (43 mg, 85.90 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(5-morpholino-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 38 (30 mg) in a yield of 62.54%.

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

Embodiment 39

(S)-1-(1-((5-(4-(azetidin-3-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(azetidin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethyl -1-ol

first step

tert-butyl 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidine-1-carboxylate

tert-Butyl 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidine-1-carboxylate

Under argon atmosphere, tert-butyl 3-ethynylazetidine-1-carboxylate 35a (28.81 mg, 158.97 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (30 mg, 79.48 μmol), cuprous iodide (15.14 mg, 79.48 μmol), and N,N,N’,N’-tetramethylethylenediamine (18.47 mg, 158.97 μmol) were added to acetone (2 mL) in sequence, and the reaction was completed after continuous stirring for 12 hours at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidine-1-carboxylate 39a (27 mg) in a yield of 61%.

MS m/z(ESI):557.3[M+1]

Step 2

(S)-1-(1-((5-(4-(azetidin-3-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(azetidin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidine-1-carboxylic acid tert-butyl ester 39a (27 mg, 48.50 μmol) was added to dichloromethane (1 mL), and then trifluoroacetic acid (0.3 mL) was added dropwise to the mixed solution and stirred for 1 hour at room temperature. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(azetidin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 39 (11.51 mg) in a yield of 48.29%.

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

Embodiment 40

(S)-3-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)-3-oxopropanenitrile

(S)-3-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)-3-oxopropionitrile

2-Cyanoacetic acid 40a (25.12 mg, 295.37 μmol, commercially available), (S)-1-(1-((5-(4-(azetidin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 39 (55 mg, 147.68 μmol), N-methylmorpholine (44.81 mg, 443.05 μmol), 1-hydroxybenzotriazole (39.91 mg, 295.37 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56.62 mg, 295.37 μmol) were added to dichloromethane (2 mL) in sequence and stirred at room temperature for 16 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-3-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidin-1-yl)-3-oxopropionitrile 40 (5.01 mg) in a yield of 5.95%.

MS m/z(ESI):440.1[M+1]

Embodiment 41

(S)-2-hydroxy-1-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)ethan-1-one

(S)-2-Hydroxy-1-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)ethan-1-one

2-Hydroxyacetic acid 41a (22.46 mg, 295.37 μmol, commercially available), (S)-1-(1-((5-(4-(azetidin-3-ylbutane- 1,3-Diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 39 (55 mg, 147.68 μmol), N-methylmorpholine (44.81 mg, 443.05 μmol), 1-hydroxybenzotriazole (39.91 mg, 295.37 μmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (56.62 mg, 295.37 μmol) were added to dichloromethane (2 mL) in sequence and stirred at room temperature for 16 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-2-hydroxy-1-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidin-1-yl)ethan-1-one 41 (7.05 mg) in a yield of 8.33%.

MS m/z(ESI):431.1[M+1]

Embodiment 42

(S)-3-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)propanenitrile

(S)-3-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)propionitrile

Acrylonitrile 42a (5.70 mg, 107.41 μmol, commercially available), (S)-1-(1-((5-(4-(azetidin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 39 (20 mg, 53.70 mol) and potassium carbonate (14.84 mg, 107.41 μmol) were added sequentially to a mixed solution of acetonitrile (0.8 mL) and water (0.4 mL), and stirring was continued for 16 hours at room temperature. After the reaction was completed, the product was filtered and the filtrate was 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 (S)-3-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidin-1-yl)propionitrile 42 (6.23 mg) in a yield of 20.21%.

MS m/z(ESI):426.2[M+1]

Embodiment 43

(S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetamide

(S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetamide

first step

2-(3-ethynylazetidin-1-yl)acetamide

2-(3-ethynylazetidin-1-yl)acetamide

2-iodoacetamide 43a (150.50 mg, 813.65 μmol, commercially available), 3-ethynylazetidine 35b (44 mg, 542.44 μmol), and cesium carbonate (353.47 mg, 1.08 mmol) were added to acetonitrile (2 mL) in sequence, and then the temperature was raised to 70°C for continuous reaction for 3 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the organic solvent, water (20 mL) was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 2-(3-ethynylazetidine-1-yl)acetamide 43b, and the crude product was directly used in the next step.

MS m/z(ESI):139.1[M+1]

Step 2

2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetamide

2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidin-1-yl)acetamide

Under argon atmosphere, 2-(3-ethynylazetidin-1-yl)acetamide 43b (36.61 mg, 264.95 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (50 mg, 132.47 μmol), cuprous iodide (2.52 mg, 13.25 μmol), and N,N,N’,N’-tetramethylethylenediamine (4.62 mg, 39.74 μmol) were added sequentially to acetone (1 mL) and the reaction was completed after continuous stirring for 12 hours at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidine-1-yl)acetamide 43c (50 mg) in a yield of 73.49%.

MS m/z(ESI):514.3[M+1]

third step

(S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetamide

(S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)azetidin-1-yl)acetamide

2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-1,3-diyn-1-yl)azetidin-1-yl)acetamide 43c (50 mg, 97.35 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)azetidin-1-yl)acetamide 43 (3.87 mg) in a yield of 7.09%.

MS m/z(ESI):430.0[M+1]

Embodiment 44

(S)-1-(1-((5-(4-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)penta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-(2-oxa-6-azaspiro[3.3]heptane-6-yl)penta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

6-(prop-2-yn-1-yl)-2-oxa-6-azaspiro[3.3]heptane

6-(Prop-2-yn-1-yl)-2-oxa-6-azaspiro[3.3]heptane

2-Oxa-6-azaspiro[3.3]heptane 44a (500 mg, 5.04 mmol, commercially available) and 3-bromoprop-1-yne 24a (900.02 mg, 6.05 mmol) were added to potassium carbonate (836.53 mg, 6.05 mmol) in acetonitrile (15 mL) in sequence and the mixture was stirred at room temperature. The reaction was continued for 3 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the organic solvent, water (20 mL) was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 6-(prop-2-yn-1-yl)-2-oxa-6-azaspiro[3.3]heptane 44b (620 mg) with a yield of 89.61%.

MS m/z(ESI):138.2[M+1]

Step 2

6-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-2-oxa-6-azaspiro[3.3]heptane

6-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-2-oxa-6-azaspiro[3.3]heptane

6-(Propan-2-yn-1-yl)-2-oxa-6-azaspiro[3.3]heptane 44b (72.69 mg, 529.89 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (100 mg, 264.95 μmol), cuprous iodide (50.46 mg, 264.95 μmol), and N,N,N’,N’-tetramethylethylenediamine (30.79 mg, 264.95 μmol) were added to acetone (2 mL) in sequence, and the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 6-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)-2-oxa-6-azaspiro[3.3]heptane 44c (500 mg) in a yield of 36.82%.

third step

(S)-1-(1-((5-(4-(5-(2-oxa-6-azaspiro[3.3]heptan-6-yl)penta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-(2-oxa-6-azaspiro[3.3]heptane-6-yl)penta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

6-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-2-oxa-6-azaspiro[3.3]heptane 44c (50 mg, 97.54 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, it was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(5-(2-oxa-6-azaspiro[3.3]heptane-6-yl)penta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 44 (4.00 mg), 7.03%.

MS m/z(ESI):429.1[M+1]

Embodiment 45

(S)-1-(1-((5-(4-(5-((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)penta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)pentan-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

tert-butyl(2-(1H-1,2,3-triazol-1-yl)ethyl)carbamate

tert-Butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)aminocarboxylate

2-(1H-1,2,3-triazol-1-yl)ethylamine 45a (100 mg, 891.80 μmol, commercially available), triethylamine (180.48 mg, 1.78 mmol), di-tert-butyl dicarbonate (389.27 mg, 1.78 mmol) were added to dichloromethane (1 mL) in sequence, and the reaction was continued for 3 hours at room temperature. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the organic solvent, water (20 mL) was added, and ethyl acetate was extracted (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain tert-butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)aminocarboxylate 45b (180 mg), with a yield of 95.10%.

MS m/z(ESI):213.2[M+1]

Step 2

tert-butyl(2-(1H-1,2,3-triazol-1-yl)ethyl)(prop-2-yn-1-yl)carbamate

tert-Butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)(prop-2-yn-1-yl)aminocarboxylate

Under ice bath, tert-butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)aminocarboxylate 45b (160 mg, 753.83 μmol) was added to N,N-dimethylformamide (1 mL) in sequence, and then sodium hydride (39.21 mg, 1.51 mmol) was added to the above mixed solution, stirred for 15 min, and then 3-bromoprop-1-yne 24a (112.09 mg, 753.83 μmol) was added to the above mixed solution, and the temperature was gradually raised to room temperature and the reaction was continued for 5 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the organic solvent, water (20 mL) was added, and ethyl acetate (20 mL×3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give (2-(1H-1,2,3-triazol-1-yl)ethyl)(prop-2-yn-1-yl)aminocarboxylic acid tert-butyl ester 45c (180 mg) in a yield of 95.40%.

MS m/z(ESI):251.2[M+1]

third step

tert-butyl(2-(1H-1,2,3-triazol-1-yl)ethyl)(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)carbamate

tert-Butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)aminocarboxylate

Tert-butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)(prop-2-yn-1-yl)aminocarboxylate 45c (132.63 mg, 529.89 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (100 mg, 264.95 μmol), cuprous iodide (50.46 mg, 264.95 μmol), and N,N,N’,N’-tetramethylethylenediamine (30.79 mg, 264.95 μmol) were added to acetone (2 mL) in sequence, and the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)aminocarboxylate 45d (40 mg) in a yield of 24.13%.

MS m/z(ESI):626.2[M+1]

the fourth step

(S)-1-(1-((5-(4-(5-((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)penta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(5-((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)pentan-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Tert-butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)aminocarboxylate 45d (40 mg, 63.93 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(5-((2-(1H-1,2,3-triazol-1-yl)ethyl)amino)pentan-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 45 (6.93 mg), yield: 15.03%.

MS m/z(ESI):442.2[M+1]

Embodiment 46

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

first step

4-(prop-2-yn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

4-(Propan-2-yn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

3-Bromoprop-1-yne 24a (869.36 mg, 5.85 mmol) and 4H-1,2,4-triazole-3-carbonitrile 46a (500 mg, 5.31 mmol, commercially available) were added to acetonitrile (3 mL) in sequence and reacted at room temperature for 4 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the organic solvent, water (50 mL) was added, and ethyl acetate was extracted (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to obtain 4-(prop-2-yn-1-yl)-4H-1,2,4-triazole-3-carbonitrile 46b (700 mg) with a yield of 99.68%.

MS m/z(ESI):133.2[M+1]

Step 2

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

4-(Propan-2-yn-1-yl)-4H-1,2,4-triazole-3-carbonitrile 46b (70.01 mg, 529.89 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (100 mg, 264.95 μmol), cuprous iodide (50.46 mg, 264.95 μmol), and N,N,N’,N’-tetramethylethylenediamine (30.79 mg, 264.95 μmol) were added to acetone (2 mL) in sequence, and the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile 46c (90 mg) in a yield of 66.93%.

MS m/z(ESI):508.3[M+1]

third step

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile 46c (90 mg, 177.33 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile 46 (28.75 mg) in a yield of 28.63%.

MS m/z(ESI):424.3[M+1]

Embodiment 47

(S)-4-(6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hexa-3,5-diyn-1-yl)piperazin-2-one

(S)-4-(6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hexane-3,5-diyn-1-yl)piperazin-2-one

first step

4-(but-3-yn-1-yl)piperazin-2-one

4-(But-3-yn-1-yl)piperazin-2-one

4-Bromobutyne 47a (996.21 mg, 5.99 mmol, commercially available), piperazin-2-one 19a (600 mg, 5.99 mmol, 569.80 μL), and potassium carbonate (1.66 g, 11.99 mmol) were added to acetonitrile (3 mL) in sequence, and the reaction was completed after continuous stirring for 12 hours at room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain 4-(but-3-yn-1-yl)piperazin-2-one 47b (410 mg), with a yield of 44.95%.

MS m/z(ESI):153.2[M+1]

Step 2

4-(6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hexa-3,5-diyn-1-yl)piperazin-2-one

4-(6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hexane-3,5-diyn-1-yl)piperazin-2-one

4-(But-3-yn-1-yl)piperazin-2-one 47b (24.19 mg, 158.97 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (50 mg, 132.47 μmol), N,N,N’,N’-tetramethylethylenediamine (4.62 mg, 39.74 μmol), and cuprous iodide (7.57 mg, 39.74 μmol) were added to acetone (2 mL) in sequence. After argon replacement three times, the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 4-(6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-3,5-diyn-1-yl)piperazin-2-one 47c (40 mg) in a yield of 57.23%.

MS m/z(ESI):528.3[M+1]

third step

(S)-4-(6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hexa-3,5-diyn-1-yl)piperazin-2-one

(S)-4-(6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hexane-3,5-diyn-1-yl)piperazin-2-one

4-(6-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-3,5-diyn-1-yl)piperazin-2-one 47c (40 mg, 75.81 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-4-(6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-3,5-diyn-1-yl)piperazin-2-one 47 (11.28 mg) in a yield of 25.62%.

MS m/z(ESI):444.3[M+1]

Embodiment 48

(S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)piperidine-4-carbonitrile

(S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidine-4-carbonitrile

first step

1-(prop-2-yn-1-yl)piperidine-4-carbonitrile

1-(Propan-2-yn-1-yl)piperidine-4-carbonitrile

Piperidine-4-carbonitrile 48a (500 mg, 4.54 mmol, commercially available), 3-bromoprop-1-yne 24a (593.95 mg, 4.99 mmol), potassium carbonate (1.25 g, 9.08 mmol) were added to acetonitrile (3 mL) in sequence, and the reaction was continued at room temperature for 16 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the organic solvent, water (50 mL) was added, and ethyl acetate was extracted (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to obtain 1-(prop-2-yn-1-yl)piperidine-4-carbonitrile 48b (550 mg) with a yield of 81%.

MS m/z(ESI):149.2[M+1]

Step 2

1-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)piperidine-4-carbonitrile

1-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidine-4-carbonitrile

1-(Propan-2-yn-1-yl)piperidine-4-carbonitrile 48b (129.58 mg, 874.32 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (300 mg, 794.84 μmol), N,N,N',N'-tetramethylethylenediamine (92.36 mg, 794.84 μmol), and cuprous iodide (151.38 mg, 794.84 μmol) were added to acetone (2 mL) in sequence, and the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 1-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidine-4-carbonitrile 48c (370 mg) in a yield of 88.90%.

MS m/z(ESI):524.3[M+1]

third step

(S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)piperidine-4-carbonitrile

(S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidin- 4-Nitrile

1-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperidine-4-carbonitrile 48c (180 mg, 706.61 μmol) was added successively to dichloromethane (1.5 mL), and then trifluoroacetic acid (0.5 mL) was added dropwise, and stirring was continued at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidine-4-carbonitrile 48 (32.11 mg) in a yield of 8.13%.

MS m/z(ESI):440.3[M+1]

Embodiment 49

(S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)piperidine-4-carboxamide

(S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidine-4-carboxamide

first step

1-(prop-2-yn-1-yl)piperidine-4-carboxamide

1-(Propan-2-yn-1-yl)piperidine-4-carboxamide

3-Bromoprop-1-yne 24a (306.28 mg, 2.57 mmol), piperidine-4-carboxamide 49a (300 mg, 2.34 mmol, commercially available), and potassium carbonate (388.19 mg, 2.81 mmol) were added to acetonitrile (1 mL) in sequence and stirred for 12 h at room temperature. The reaction was complete. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 1-(prop-2-yn-1-yl)piperidine-4-carboxamide 49b (290 mg) in a yield of 74.54%.

MS m/z(ESI):167.2[M+1]

Step 2

1-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)piperidine-4-carboxamide

1-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidine-4-carboxamide

1-(Propan-2-yn-1-yl)piperidine-4-carboxamide 49b (88.08 mg, 529.89 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (100 mg, 264.95 μmol), N,N,N',N'-tetramethylethylenediamine (30.79 mg, 264.95 μmol), and cuprous iodide (50.46 mg, 264.95 μmol) were added to acetone (2 mL) in sequence, and the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 1-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidine-4-carboxamide 49c (80 mg) in a yield of 55.75%.

MS m/z(ESI):542.3[M+1]

third step

(S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)piperidine-4-carboxamide

(S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidine-4-carboxamide

1-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperidine-4-carboxamide 49c (80 mg, 147.70 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperidine-4-carboxamide 49 (14.32 mg) in a yield of 16.62%.

MS m/z(ESI):458.3[M+1]

Embodiment 50

(1S)-1-(1-((5-(4-(pyrrolidin-3-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(1S)-1-(1-((5-(4-(pyrrolidin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

tert-butyl 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)pyrrolidine-1-carboxylate

tert-Butyl 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)pyrrolidine-1-carboxylate

Under argon atmosphere, tert-butyl 3-ethynylpyrrolidine-1-carboxylate 50a (51.73 mg, 264.95 μmol, commercially available), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (50 mg, 132.47 μmol), cuprous iodide (25.23 mg, 132.47 μmol), and N,N,N',N'-tetramethylethylenediamine (30.79 mg, 264.95 μmol) were added to acetone (2 mL) in sequence, and the reaction was completed after continuous stirring for 12 hours at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)pyrrolidine-1-carboxylate 50b (28 mg) in a yield of 37.04%.

MS m/z(ESI):571.2[M+1]

Step 2

(1S)-1-(1-((5-(4-(pyrrolidin-3-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(1S)-1-(1-((5-(4-(pyrrolidin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 50b (28 mg, 49.06 μmol) and trifluoroacetic acid (0.3 mL) were added to dichloromethane (1 mL) in sequence, and stirring was continued at room temperature for 1 hour. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (1S)-1-(1-((5-(4-(pyrrolidin-3-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 50 (8.70 mg) in a yield of 34.37%.

MS m/z(ESI):387.0[M+1]

Embodiment 51

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-1-methylpiperazin-2-one

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)-1-methylpiperazin-2-one

first step

1-methyl-4-(prop-2-yn-1-yl)piperazin-2-one

1-Methyl-4-(prop-2-yn-1-yl)piperazin-2-one

3-Bromoprop-1-yne 24a (625.31 mg, 5.26 mmol), 1-methylpiperazine-2-one 51a (500 mg, 4.38 mmol, commercially available), potassium carbonate (1.21 g, 8.76 mmol) were added to acetonitrile (3 mL) in sequence, and the reaction was completed after continuous stirring for 12 hours at room temperature. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain 1-methyl-4-(prop-2-yn-1-yl)piperazine-2-one 51b (430 mg), with a yield of 64.50%.

MS m/z(ESI):153.2[M+1]

Step 2

1-methyl-4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)piperazin-2-one

1-Methyl-4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperazin-2-one

1-Methyl-4-(prop-2-yn-1-yl)piperazin-2-one 51b (48.39 mg, 317.94 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (100 mg, 264.95 μmol), N,N,N',N'-tetramethylethylenediamine (9.24 mg, 79.48 μmol), cuprous iodide (15.14 mg, 79.48 μmol) were added to acetone (2 mL) in sequence, and the gas was replaced with argon three times. After continuous stirring at room temperature for 12 hours, the reaction was complete. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 1-methyl-4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperazin-2-one 51c (70 mg) in a yield of 50.08%.

MS m/z(ESI):528.3[M+1]

third step

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)penta-2,4-diyn-1-yl)-1-methylpiperazin-2-one

(S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)-1-methylpiperazin-2-one

1-Methyl-4-(5-(4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)piperazin-2-one 51c (70 mg, 132.67 μmol) was added to dichloromethane (1.5 mL), followed by the dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentane-2,4-diyn-1-yl)-1-methylpiperazin-2-one 51 (24.49 mg) in a yield of 31.78%.

MS m/z(ESI):444.3[M+1]

Embodiment 52

(S)-1-(1-((5-(4-(piperidin-4-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(piperidin-4-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

tert-butyl 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)piperidine-1-carboxylate

tert-Butyl 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)piperidine-1-carboxylate

Under argon atmosphere, tert-butyl 4-ethynylpiperidine-1-carboxylate 52a (55.45 mg, 264.95 μmol, commercially available), 5- (4-Ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (50 mg, 132.47 μmol), cuprous iodide (25.23 mg, 132.47 μmol), and N,N,N',N'-tetramethylethylenediamine (30.79 mg, 264.95 μmol) were added to acetone (2 mL) in sequence, and the reaction was completed after continuous stirring for 12 hours at room temperature. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)piperidine-1-carboxylate 52b (42 mg) in a yield of 54.22%.

MS m/z(ESI):585.3[M+1]

Step 2

(S)-1-(1-((5-(4-(piperidin-4-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(piperidin-4-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

tert-Butyl 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)piperidine-1-carboxylate 52b (42 mg, 71.83 μmol) and trifluoroacetic acid (0.3 mL) were added sequentially to dichloromethane (1 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(piperidin-4-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 52 (23.18 mg) in a yield of 62.03%.

MS m/z(ESI):401.0[M+1]

Embodiment 53

(S)-1-(1-((5-(4-(pyridin-4-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(pyridin-4-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

5-(4-(pyridin-4-ylbuta-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(pyridin-4-ylbut-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

Under argon atmosphere, 4-ethynylpyridine 53a (27.32 mg, 264.95 μmol), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (50 mg, 132.47 μmol), cuprous iodide (7.57 mg, 39.74 μmol), and N,N,N’,N’-tetramethylethylenediamine (4.62 mg, 39.74 μmol) were added to acetone (1 mL) in sequence, and the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 5-(4-(pyridin-4-ylbut-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 53b (42 mg) in a yield of 66.25%.

MS m/z(ESI):479.3[M+1]

Step 2

(S)-1-(1-((5-(4-(pyridin-4-ylbuta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(4-(pyridin-4-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

5-(4-(Pyridin-4-ylbut-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 53b (42 mg, 87.77 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(4-(pyridin-4-ylbut-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 53 (15.1 mg) in a yield of 32.79%.

MS m/z(ESI):395.2[M+1]

Embodiment 54

(1s,3s)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1s,3s)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

first step

5-(4-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(4-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

Tert-butyl((1s,3s)-3-ethynylcyclobutyloxy)dimethylsilane 54a (50.67 mg, 240.86 μmol, commercially available), 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (100 mg, 264.95 μmol), N,N,N',N'-tetramethylethylenediamine (4.20 mg, 36.13 μmol), and cuprous iodide (13.76 mg, 72.26 μmol) were added to acetone (2 mL) in sequence. After argon replacement three times, the reaction was completed after continuous stirring at room temperature for 12 hours. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (eluent: System A) to give 5-(4-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)but-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 54b (70 mg) in a yield of 49.61%.

MS m/z(ESI):586.3[M+1]

Step 2

(1s,3s)-3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1s,3s)-3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)butane-1,3-diyn-1-yl)cyclobutan-1-ol

5-(4-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)but-1,3-diyn-1-yl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 54b (70 mg, 119.49 μmol) and tetrabutylammonium fluoride (62.49 mg, 238.99 μmol) were added to tetrahydrofuran (1.5 mL) in sequence, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the organic solvent, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system B) to give (1s, 3s)-3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-1,3-diyn-1-yl)cyclobutan-1-ol 54c (56 mg) in a yield of 99%.

MS m/z(ESI):472.2[M+1]

third step

(1s,3s)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1s,3s)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1s,3s)-3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-1,3-diyn-1-yl)cyclobutan-1-ol 54c (56 mg, 118.76 μmol) was added to dichloromethane (1 mL), followed by dropwise addition of trifluoroacetic acid (0.3 mL), and stirring was continued for 1 hour at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was 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 (1s,3s)-3-((4-(3-((2-((S)-1- (4-(2-(4-(2-((4-((2-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)buta-1,3-diyn-1-yl)cyclobutan-1-ol 54 (21.42 mg), yield: 34.61%.

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

Embodiment 55

(S)-1-(1-((5-(5-(5-morpholinopenta-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(5-(5-morpholinopenta-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

ethyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate

Ethyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate

1-(5-bromopyridin-2-yl)ethan-1-one 55a (2 g, 10.00 mmol, commercially available) and diethyl oxalate 1b (1.46 g, 10.00 mmol, 1.36 mL, commercially available) were added to toluene (6 mL) in sequence, and the argon gas was replaced three times. Potassium tert-butoxide (1.12 g, 10.00 mmol) was slowly added and stirred at 25°C for 12 hours. After the reaction was complete, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: B system) to obtain ethyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate 55c (2.58 g) with a yield of 85.98%.

MS m/z(ESI):299.9[M+1]

Step 2

ethyl(E)-4-(5-bromopyridin-2-yl)-2-(hydroxyimino)-4-oxobutanoate

(E)-4-(5-bromopyridin-2-yl)-2-(hydroxyimino)-4-oxobutanoic acid ethyl ester

Ethyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate 55c (1 g, 3.33 mmol) and hydroxylamine hydrochloride (231.55 mg, 3.33 mmol) were added to ethanol (5 mL) in sequence, and argon was replaced three times. The reaction was heated to 80 ° C and stirred for 1 hour. After the reaction was complete, it was concentrated under reduced pressure to obtain ethyl (E)-4-(5-bromopyridin-2-yl)-2-(hydroxyimino)-4-oxobutanoate 55d (1 g) with a yield of 95.24%. The crude product was directly used for the next step reaction.

MS m/z(ESI):314.8[M+1]

third step

ethyl 5-(5-bromopyridin-2-yl)isoxazole-3-carboxylate

Ethyl 5-(5-bromopyridin-2-yl)isoxazole-3-carboxylate

(E)-4-(5-bromopyridin-2-yl)-2-(hydroxyimino)-4-oxobutanoic acid ethyl ester 55d (1 g, 3.17 mmol) was added to acetic acid (3 mL) and argon was replaced three times. The mixture was stirred at 100°C for 16 hours. After the reaction was complete, the mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System A) to give 5-(5-bromopyridin-2-yl)isoxazole-3-carboxylic acid ethyl ester 55e (0.5 g) in a yield of 53.03%.

MS m/z(ESI):296.9[M+1]

the fourth step

(5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanol

(5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanol

5-(5-bromopyridin-2-yl)isoxazole-3-carboxylic acid ethyl ester 55e (50.00 mg, 168.29 μmol) was added to methanol (0.5 mL) and argon was replaced three times. Sodium borohydride (9.55 mg, 252.44 μmol) was slowly added under ice-water cooling, and then stirred at 80°C for 16 hours. After the reaction was complete, it was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain (5-(5-bromopyridin-2-yl)isoxazole-3-yl)methanol 55f (30 mg), yield: 69.89%.

MS m/z(ESI):254.9[M+1]

the fifth step

(5-(5-bromopyridin-2-yl)isoxazol-3-yl)methyl methanesulfonate

(5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanesulfonate

(5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanol 55f (30.00 mg, 117.62 μmol) and triethylamine (23.80 mg, 235.23 μmol, 32.70 μL) were added to dichloromethane (453.65 μL) in sequence, and the argon gas was replaced three times. Methanesulfonyl chloride (20.21 mg, 176.42 μmol, 13.66 μL) was slowly added dropwise under ice-water cooling, and then stirred at room temperature for 16 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL×2), the combined organic phases were washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain 55 g (30 mg) of methyl (5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanesulfonate, with a yield of 76.56%.

MS m/z(ESI):332.8[M+1]

Step 6

5-(5-bromopyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(5-bromopyridin-2-yl)-3-((2-((1S)-1-((tetrahydro 2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)iso Oxazole

55 g (140.00 mg, 420.22 μmol) of methyl (5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanesulfonate and 2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole 1h (82.47 mg, 420.22 μmol) were added to N,N-dimethylformamide (1 mL) in sequence, and argon was replaced three times. Sodium hydride (16.40 mg, 630.33 μmol) was slowly added under ice-water cooling, and then stirred at room temperature for 4 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL×2), the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 5-(5-bromopyridin-2-yl)-3-((2-((1S)-1-((tetrahydro 2H-pyran-2-yl)oxy)ethyl)-1H-imidazole-1-yl)methyl)isoxazole 55h (156 mg), yield: 85.68%.

MS m/z(ESI):432.9[M+1]

Step 7

4-(5-(6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)penta-2,4-diyn-1-yl)morpholine

4-(5-(6-(3-((2-((1S)-1-((tetrahydro2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)pentan-2,4-diyn-1-yl)morpholine

5-(5-Bromopyridin-2-yl)-3-((2-((1S)-1-((tetrahydro 2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 55h (25 mg, 57.70 μmol), 4-(pentan-2,4-diyn-1-yl)morpholine 38d (15.49 mg, 103.85 μmol), bis(triphenylphosphine)palladium(II) dichloride (4.04 mg, 5.77 μmol), cuprous iodide (1.10 mg, 5.77 μmol), and triethylamine (17.52 mg, 173.09 μmol) were added to N,N-dimethylformamide (0.5 mL) in sequence. After replacing argon three times, the temperature was raised to 75°C and the reaction was carried out for 8 hours. After the reaction was completed, ethyl acetate (30 mL) and water (15 mL) were added, the organic phase was separated, the aqueous phase was extracted with ethyl acetate (30 mL×2), the combined organic phase was washed with saturated sodium chloride solution (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 4-(5-(6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)pentane-2,4-diyn-1-yl)morpholine 55i (15 mg), yield: 34.55%.

MS m/z(ESI):502.3[M+1]

Step 8

(S)-1-(1-((5-(5-(5-morpholinopenta-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(5-(5-morpholinopenta-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

4-(5-(6-(3-((2-((1S)-1-((tetrahydro2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)pentan-2,4-diyn-1-yl)morpholine 55i (15 mg, 29.91 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.1 mL) was added, and stirring was continued at room temperature for 4 hours. After the reaction was completed, the product was concentrated under reduced pressure and the residue was 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 (S)-1-(1-((5-(5-(5-morpholinopenta-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 55 (8.0 mg) in a yield of 45.30%.

MS m/z(ESI):418.0[M+1]

Embodiment 56

(S)-1-(1-((5-(5-(azetidin-3-ylbuta-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(5-(azetidin-3-ylbut-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

first step

3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)isoxazole

3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)isoxazole

5-(5-bromopyridin-2-yl)-3-((2-((1S)-1-((tetrahydro 2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 55h (1 g, 2.31 mmol), cuprous iodide (43.95 mg, 230.79 μmol), bistriphenylphosphine palladium (II) dichloride (323.98 mg, 461.58 μmol), and triethylamine (4 mL) were added to N,N-dimethylformamide (12 mL), and the atmosphere was replaced with argon three times. Ethylenetrimethylsilane 33a (340.01 mg, 3.46 mmol, 489.23 μL) was added, and the atmosphere was replaced with argon twice. The temperature was raised to 60°C for 4 hours, and the reaction was monitored to be complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, 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 A) to give 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)isoxazole 56a (1.04 g).

MS m/z(ESI):451.2[M+1]

Step 2

5-(5-ethynylpyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H- imidazol-1-yl)methyl)isoxazole

5-(5-ethynylpyridin-2-yl)-3-((2-((1S)-1-((tetrahydro 2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

Tetrabutylammonium fluoride (784.49 mg, 3.00 mmol) was added to a solution of 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)isoxazole 56a (1.04 g, 2.31 mmol) in tetrahydrofuran (12 mL) at room temperature and reacted for 1 hour at room temperature. The reaction was monitored for completion. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, 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 A) to give 5-(5-ethynylpyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 56b (380 mg) in a yield of 43.51%.

MS m/z(ESI):379.1[M+1]

third step

tert-butyl 3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)buta-1,3-diyn-1-yl)azetidine-1-carboxylate

tert-Butyl 3-((6-(3-((2-((1S)-1-((tetrahydro2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)azetidine-1-carboxylate

5-(5-ethynylpyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 56b (80 mg, 211.40 μmol), tert-butyl 3-ethynylazetidine-1-carboxylate 35a (76.63 mg, 422.81 μmol), cuprous iodide (40.26 mg, 211.40 μmol), N,N,N',N'-tetramethylethylenediamine (4 9.13 mg, 422.81 μmol) were added to acetone (2 mL) in turn and stirred at room temperature for 16 h. After the reaction was complete, the mixture was filtered and concentrated to give tert-butyl 3-((6-(3-((2-((1S)-1-((tetrahydro 2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)azetidine-1-carboxylate 56c (117 mg). The crude product was used directly in the next step.

MS m/z(ESI):558.3[M+1]

the fourth step

(S)-1-(1-((5-(5-(azetidin-3-ylbuta-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

(S)-1-(1-((5-(5-(azetidin-3-ylbut-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Trifluoroacetic acid (1.5 mL) was added to a solution of tert-butyl 3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)azetidine-1-carboxylate 56c (117 mg, 209.81 μmol) in dichloromethane (6 mL), and the mixture was reacted at room temperature for 40 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was 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 (S)-1-(1-((5-(5-(azetidin-3-ylbut-1,3-diyn-1-yl)pyridin-2-yl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 56 (33.13 mg), yield: 32.04%.

MS m/z(ESI):374.2[M+1]

Embodiment 57

(1s,3s)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1s,3s)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)cyclobutan-1-ol

first step

5-(5-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)pyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(5-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)pyridin-2-yl)-3-((2-((1S)-1-((tetrahydro2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

At room temperature, 5-(5-ethynylpyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 56b (70 mg, 184.98 μmol), tert-butyl((1s,3s)-3-ethynylcyclobutyloxy)dimethylsilane 54a (97.29 mg, 462.44 μmol), N,N,N’,N’-tetramethylethylenediamine (42.99 mg, 369.96 μmol), and cuprous iodide (35.23 mg, 184.98 μmol) were added to acetone (2 mL) in sequence. After argon replacement three times, the reaction was continued at room temperature for 16 hours. After the reaction was completed, the reaction solution was distilled under reduced pressure to remove the organic solvent to give 5-(5-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)but-1,3-diyn-1-yl)pyridin-2-yl)-3-((2-((1S)-1-((tetrahydro 2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 57a (108 mg), and the crude product was used directly in the next step.

MS m/z(ESI):587.4[M+1]

Step 2

(1s,3s)-3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1- yl)methyl)isoxazol-5-yl)pyridin-3-yl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1s,3s)-3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)cyclobutane-1-ol

Tetrabutylammonium fluoride (62.56 mg, 239.27 μmol) was added to a solution of 5-(5-(((1s,3s)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)but-1,3-diyn-1-yl)pyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 57a (108 mg, 184.05 μmol) in tetrahydrofuran (3 mL) at room temperature and reacted for 1 hour at room temperature. The reaction was monitored for completion. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1s, 3s)-3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)cyclobutane-1-ol 57b (86 mg), and the crude product was used directly in the next step.

third step

(1s,3s)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1s,3s)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)cyclobutan-1-ol

Trifluoroacetic acid (1 mL) was added to a solution of (1s,3s)-3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)but-1,3-diyn-1-yl)cyclobutane-1-ol 57b (86 mg, 182.00 μmol) in dichloromethane (4 mL) at room temperature and reacted for 40 minutes at room temperature. After the reaction was complete, the mixture was concentrated under reduced pressure and the residue was 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 (1s,3s)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)but-1,3-diyn-1-yl)cyclobutan-1-ol 57 (11.84 mg), yield: 12.62% yield.

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

Embodiment 58

(1r,3r)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1r,3r)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)cyclobutan-1-ol

first step

5-(5-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)pyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

5-(5-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)pyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

At room temperature, 5-(5-ethynylpyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 56b (80 mg, 211.40 μmol), tert-butyl((1r,3r)-3-ethynylcyclobutyloxy)dimethylsilane 34a (88.95 mg, 422.81 μmol), N,N,N',N'-tetramethylethylenediamine (49.13 mg, 422.81 μmol), cuprous iodide (4 The reaction mixture was added with 4% paraformaldehyde (0.26 mg, 211.40 μmol) in acetone (3 mL) and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered and concentrated to give 5-(5-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)but-1,3-diyn-1-yl)pyridin-2-yl)-3-((2-((1S)-1-((tetrahydro 2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 58a (124 mg). The crude product was used directly in the next step.

MS m/z(ESI):587.4[M+1]

Step 2

(1r,3r)-3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1r,3r)-3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)cyclobutane-1-ol

At room temperature, tetrabutylammonium fluoride (71.83 mg, 274.71 μmol) was added to a solution of 5-(5-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)but-1,3-diyn-1-yl)pyridin-2-yl)-3-((2-((1S)-1-((tetrahydro 2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 58a (124 mg, 211.32 μmol) in tetrahydrofuran (2 mL) and reacted at room temperature for 1.5 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (1r,3r)-3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)cyclobutane-1-ol 58b (99 mg), which was used directly in the next step.

MS m/z(ESI):473.4[M+1]

third step

(1r,3r)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)buta-1,3-diyn-1-yl)cyclobutan-1-ol

(1r,3r)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)butane-1,3-diyn-1-yl)cyclobutan-1-ol

At room temperature, trifluoroacetic acid (1 mL) was added to a solution of (1r,3r)-3-((6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)but-1,3-diyn-1-yl)cyclobutane-1-ol 58b (99 mg, 209.51 μmol) in dichloromethane (4 mL), and the mixture was reacted at room temperature for 40 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was 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 (1r,3r)-3-((6-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)but-1,3-diyn-1-yl)cyclobutan-1-ol 58 (14.27 mg), yield: 13.03%.

MS m/z(ESI):389.1[M+1]

Embodiment 59

(S)-4-(5-(6-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)penta-2,4-diyn-1-yl)piperazin-2-one

(S)-4-(5-(6-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)pentan-2,4-diyn-1-yl)piperazin-2-one

first step

4-(5-(6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)penta-2,4-diyn-1-yl)piperazin-2-one

4-(5-(6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)pentan-2,4-diyn-1-yl)piperazin-2-one

At room temperature, 5-(5-ethynylpyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 56b (70 mg, 184.98 μmol), 4-(prop-2-yn-1-yl)piperazin-2-one 27a (51.12 mg, 369.96 μmol), N,N,N’,N’-tetramethylethylenediamine (42.99 mg, 369.96 μmol) and cuprous iodide (35.23 mg, 184.98 μmol) were added sequentially to acetone (3 mL) and stirred at room temperature for 16 hours. After the reaction was completed, the mixture was filtered and concentrated to give 4-(5-(6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)pentan-2,4-diyn-1-yl)piperazin-2-one 59a (95 mg), and the crude product was used directly in the next step.

MS m/z(ESI):515.2[M+1]

Step 2

(S)-4-(5-(6-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)penta-2,4-diyn-1-yl)piperazin-2-one

(S)-4-(5-(6-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)pentan-2,4-diyn-1-yl)piperazin-2-one

At room temperature, trifluoroacetic acid (1 mL) was added to a solution of 4-(5-(6-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)pentan-2,4-diyn-1-yl)piperazin-2-one 59a (95 mg, 184.62 μmol) in dichloromethane (4 mL), and the mixture was reacted at room temperature for 40 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was 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 (S)-4-(5-(6-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)pentan-2,4-diyn-1-yl)piperazin-2-one 59 (14.83 mg), yield: 14.47%.

MS m/z(ESI):431.2[M+1]

Embodiment 60

5-hydroxy-6-((4-(4-(((1r,3r)-3-hydroxycyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

5-Hydroxy-6-((4-(4-(((1r,3r)-3-hydroxycyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

first step

methyl 2-bromo-2-(4-iodophenyl)acetate

Methyl 2-bromo-2-(4-iodophenyl)acetate

2-(4-iodophenyl)acetic acid methyl ester 60a (1.5 g, 5.43 mmol, commercially available), N-bromosuccinimide (1.06 g, 5.98 mmol), 4-chlorobenzoic acid (131.61 mg, 543.34 μmol), carbon tetrachloride (12 mL) were added to a 20 ml microwave tube, sealed and heated to 85 ° C for 8 hours. The solid was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain 2-bromo-2-(4-iodophenyl)acetic acid methyl ester 60b (1.6 g), with a yield of 82.96%.

¹ H NMR (400 MHz, Chloroform-d) δ7.71 (d, J＝8.4 Hz, 2H), 7.32–7.27 (m, 2H), 5.28 (s, 1H), 3.79 (s, 3H).

Step 2

3-(4-iodophenyl)piperazin-2-one

3-(4-Iodophenyl)piperazin-2-one

At room temperature and argon, methyl 2-bromo-2-(4-iodophenyl)acetate 60b (1.4 g, 3.94 mmol) and propane-1,3-diamine 60c (584.70 mg, 7.89 mmol) were added to methanol (25 mL), stirred at room temperature for 20 min, and then sodium methoxide (234.36 mg, 4.34 mmol) was added, and the temperature was raised to 86 ° C for 4 hours, and then stirred at room temperature overnight. Concentrated under reduced pressure, water (20 mL) was added, and dichloromethane (30 mL) was extracted. 2M HCl was added to the aqueous phase to adjust the pH to 7.5, and dichloromethane (20 mL×3) was extracted. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-(4-iodophenyl)piperazine-2-one 60d (1.03 g) with a yield of 86.44%.

MS m/z(ESI):303.1[M+1]

third step

4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)piperazin-2-one

4-((5,6-Bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)piperazin-2-one

3-(4-iodophenyl)piperazine-2-one 60d (400 mg, 1.32 mmol), 4,5-dibenzyloxy-6-(iodomethyl)pyrimidine 60e (600.93 mg, 1.39 mmol), potassium carbonate (548.98 mg, 3.97 mmol) were dissolved in acetonitrile (7 mL), heated to 75 °C for 3 hours, and the reaction was monitored to be complete. Water (30 mL) was added to the reaction solution, and ethyl acetate (30 mL × 3) was extracted. Saturated sodium chloride solution was added. The organic phase was 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 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)piperazin-2-one 60f (600 mg) in a yield of 74.72%.

MS m/z(ESI):607.1[M+1]

the fourth step

4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-1-isopropylpiperazin-2-one

4-((5,6-Bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-1-isopropylpiperazin-2-one

In an ice bath, sodium hydride (14.30 mg, 329.79 μmol, 60% purity) was added to a solution of 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)piperazin-2-one 60f (100 mg, 164.89 μmol) in N,N-dimethylformamide (2 mL), and the mixture was reacted at this temperature for 20 minutes. Then, 2-iodopropane 60 g (42.05 mg, 247.34 μmol, commercially available) was added, and the mixture was reacted at room temperature for 2 hours. A small amount of water was added to quench the mixture, and the mixture was dissolved in methanol. The mixture was 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 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-1-isopropylpiperazin-2-one 60h (40 mg), yield: 37.40%.

MS m/z(ESI):649.2[M+1]

the fifth step

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((trimethylsilyl)ethynyl)phenyl)imidazolidin-2-one

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((trimethylsilyl)ethynyl)phenyl)imidazolidin-2-one

4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-1-isopropylpiperazin-2-one 60h (300 mg, 472.81 μmol) was dissolved in acetonitrile (5 mL), followed by the addition of allylpalladium dichloride (17.30 mg, 47.28 μmol), tri-tert-butylphosphine (9.57 mg, 47.28 μmol), and triethylenediamine (106.07 mg, 945.62 μmol). After 5 minutes, ethynyltrimethylsilane 33a (55.73 mg, 567.37 μmol, 80.18 μL) was added and reacted at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added, and the reaction solution was extracted with ethyl acetate (30 ml x 2). The water layer was separated and the combined organic phase was washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: A system) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((trimethylsilyl)ethynyl)phenyl)imidazolidin-2-one 60i (216 mg) in a yield of 75.53%.

MS m/z(ESI):605.2[M+1]

Step 6

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-ethynylphenyl)-3-isopropylimidazolidin-2-one

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-ethynylphenyl)-3-isopropylimidazolidin-2-one

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((trimethylsilyl)ethynyl)phenyl)imidazolidin-2-one 60i (216 mg, 357.14 μmol) was dissolved in methanol (5 mL), potassium fluoride (62.25 mg, 1.07 mmol) was added, The reaction was carried out at room temperature for 4 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 2), the water layer was separated, and the combined organic phase was washed with saturated sodium chloride solution (30 mL × 2) in turn, 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 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-ethynylphenyl)-3-isopropylimidazolidin-2-one 60j (160 mg), with a yield of 84.11%.

MS m/z(ESI):533.0[M+1]

Step 7

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-isopropylimidazolidin-2-one

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-isopropylimidazolidin-2-one

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-ethynylphenyl)-3-isopropylimidazolidin-2-one 60j (30 mg, 56.32 μmol) and tert-butyl((1r,3r)-3-ethynylcyclobutyloxy)dimethylsilane 34a (11.85 mg, 56.32 μmol) were added to acetone (1 mL), followed by cuprous iodide (1.61 mg, 8.45 μmol) and N,N,N’,N’-tetramethylethylenediamine (1.96 mg, 16.90 μmol), and the reaction was carried out at room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL×2). The aqueous layer was separated and the combined organic phases were 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 silica gel column chromatography (eluent: System A) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)but-1,3-diyn-1-yl)phenyl)-3-isopropylimidazolidin-2-one 60k (25 mg) in a yield of 59.90%.

Step 8

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(((1r,3r)-3-hydroxycyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-isopropylimidazolidin-2-one

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(((1r,3r)-3-hydroxycyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-isopropylimidazolidin-2-one

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)but-1,3-diyn-1-yl)phenyl)-3-isopropylimidazolidin-2-one 60k (25 mg, 33.74 μmol) was added to tetrahydrofuran (966.21 μL), and tetrabutylammonium fluoride (1 M, 33.74 μL) was added at 0°C, and the temperature was raised to room temperature for reaction for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System A) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(((1r,3r)-3-hydroxycyclobutyl)butane-1,3-diyn-1-yl)phenyl)-3-isopropylimidazolidin-2-one 601 (10 mg) in a yield of 47.29%.

MS m/z(ESI):627.0[M+1]

Step 9

5-hydroxy-6-((4-(4-(((1r,3r)-3-hydroxycyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

5-Hydroxy-6-((4-(4-(((1r,3r)-3-hydroxycyclobutyl)buta-1,3-diyn-1-yl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(((1r,3r)-3-hydroxycyclobutyl)but-1,3-diyn-1-yl)phenyl)-3-isopropylimidazolidin-2-one 60l (10 mg, 15.96 μmol) was added to dichloromethane (2 mL), followed by boron trichloride (0.6 mL, 1 M in THF) and reacted at room temperature for 1 hour. After the reaction was completed, methanol was added to quench the reaction, and the reaction mixture was concentrated under reduced pressure. The residue was 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 5-hydroxy-6-((4-(4-(((1r,3r)-3-hydroxycyclobutyl)but-1,3-diyn-1-yl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one 60 (480.00 μg), yield: 4.66% yield.

MS m/z(ESI):447.2[M+1]

According to the synthesis method of Examples 1-60 of the present invention, Examples 61-85 were synthesized, and the structures and characterization data are shown in the following table:

Biological evaluation

Test Example 1: Determination of the Inhibition of LpxC Enzyme Activity by the Compounds of the Invention

The following method is used to determine the degree of inhibition of the compounds of the present invention on the enzymatic activity of recombinant Pseudomonas aeruginosa LpxC under in vitro conditions.

The experimental process is briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution. The reaction was carried out in a 96-well microplate. First, 20μL of recombinant Pseudomonas aeruginosa LpxC (purchased from Signalway Antibody, catalog number AP74647-2) was added to the wells, with a final concentration of 5nM; 5μL of the test compound was added, and the compound was subjected to 4-fold incubation. Dilution, 8 concentration points, the concentration range is 0.61-10000nM; add 5μL LpxC substrate UDP-3-O-(R-3-hydroxydecanoyl)-GlcNAc (purchased from Biosynth Carbosynth, product number mu75071), the final concentration of the substrate is 10μM, and incubate at 25℃ for 120 minutes. Then add 20μL of 2.0mg/mL fluorescamine (purchased from Sigmaaldrich, product number F9015, solvent is 1:1 dimethylformamide/acetonitrile) to the reaction system, mix well, and react for 10 minutes; finally, add 50μL of 200mM sodium phosphate buffer (pH 8.0) to terminate the reaction, and read using a microplate reader (BMG), with excitation wavelength and emission wavelength of 390 and 495nm, respectively. The percentage inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio with that of the control group (0.1% DMSO), and the _IC50 value of the compound was obtained by nonlinear regression analysis using the compound concentration logarithm-inhibition rate using GraphPad Prism 5 software, as shown in Table 1 below.

Table 1 Inhibition results of the compounds of the present invention on the enzymatic activity of LpxC

Conclusion: The preferred compounds of the present invention have an IC ₅₀ <100 nM for inhibiting the activity of the recombinant Pseudomonas aeruginosa LpxC enzyme, and have a significant inhibitory effect on the activity of the LpxC enzyme.

Test Example 2: Evaluation of Antibacterial Activity of the Compounds of the Invention

In vitro minimum inhibitory concentration (MIC) determination was performed according to the CLSI guidelines using the broth microdilution method.

The experimental process is briefly described as follows: the test compound is dissolved in DMSO to prepare a 12.8 mg/mL stock solution, and then DMSO is used to prepare 11 two-fold dilutions of 100× high concentration working solutions (the final concentration of the system is 64μg/mL-0.06μg/mL). The strains (K.Pneumoniae ATCC13883, K.PneumoniaeATCC51504 and E.coli ATCC 25922) frozen in -80℃ glycerol are inoculated on solid agar medium and placed in an incubator at 35℃ for 18-24h to complete the strain preparation work, and then an appropriate amount of solid plate culture is collected and resuspended in physiological saline, mixed, and the turbidity of the bacterial suspension is adjusted to an appropriate turbidity with a turbidity meter, containing about 1×10 ⁸ cfu/mL of bacteria, and then the bacterial suspension with adjusted turbidity is diluted with the test medium to a bacterial concentration of 5×10 ⁵ cfu/ml to complete the inoculum preparation. 198 μL of the inoculum solution was inoculated into a 96-well plate, followed by the addition of 2 μL of a 100× high concentration working solution of the compound, and then the 96-well plate was cultured at 35° C. for 18 to 24 h. After culture, the test plate was observed by naked eye, and the minimum drug concentration that completely inhibited bacterial growth was the minimum inhibitory concentration (MIC) of the compound, as shown in Table 2.

Table 2 Antibacterial activity test results of the compounds of the present invention

Conclusion: The preferred compounds of the present invention have an in vitro minimum inhibitory degree of less than 50 μg/mL against K. Pneumoniae ATCC13883, K. Pneumoniae ATCC51504 and Escherichia coli ATCC 25922; they have good inhibitory effects on K. Pneumoniae and Escherichia coli.

Test Example 3: Pharmacokinetic study of the compounds of the present invention in mice

1. Experimental purpose

Using ICR mice as test animals, the LC/MS/MS method was used to determine the drug concentrations in plasma at different times after injection of the compounds of Examples 33 and 41 of the present invention, and to study the pharmacokinetic characteristics of the compounds of the present invention in mice.

2. Experimental plan

2.1 Experimental drugs and animals;

Examples 33 and 41;

ICR mice, male, 27.8-38 g, were purchased from Weitonglihua Laboratory Animal Technology Co., Ltd.

2.2 Drug preparation

Intravenous injection group: weigh an appropriate amount of drug, add DMSO: 30% HS-15: Saline = 10: 10: 80 (v/v/v), and prepare a complete solution of appropriate concentration;

Oral gavage group: weigh an appropriate amount of drug, add DMSO: 30% HS-15: Saline = 10: 10: 80 (v/v/v), and prepare a complete solution of appropriate concentration;

2.3 Administration

Thirty-six ICR mice were included in four groups, nine in each group. After overnight fasting, the mice were intravenously injected and intragastrically gavaged and fed 4 hours after the administration.

The dosage of each compound is as follows:

3. Operation

100 μL of blood was collected from the eye socket before administration and at 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and 24 hours after administration, and anticoagulated with EDTA-K2. After blood collection, the samples were placed on ice and centrifuged within 30 minutes to separate plasma (centrifugation conditions: 1500g, 10 minutes). The collected plasma was stored at -40 to -20°C before analysis.

LC-MS/MS was used to determine the content of the test compound in mouse plasma after intravenous injection and oral administration of different compounds.

4. Pharmacokinetic parameter results

The mouse pharmacokinetic parameters of the compounds of the present invention are shown in the following table.

Note: N/A means no relevant results

Conclusion: Compound Examples 33 and 41 of the present invention have good pharmacokinetic absorption, high bioavailability and good pharmacokinetic properties.

Claims (13)

A compound represented by the general formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
in: Ring A is selected from a 5-membered heteroaryl group or a 5- to 6-membered heterocyclic group; Ring B is selected from 5-6 membered heteroaryl groups; R ^a are the same or different and are independently selected from hydroxy, cyano, halogen, alkyl or alkoxy; R ^b are the same or different and are independently selected from cyano, halogen, hydroxyl, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted with one or more substituents selected from hydroxyl, cyano, halogen, alkyl or alkoxy; X, Y, Z, and Q are each independently selected from CR ² or N atoms, and at most two atoms among X, Y, Z, and Q are N atoms at the same time; ^R2 is selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; L is selected from C ₁ -C ₃ alkylene, C ₂ -C ₃ alkenylene or C ₂ -C ₄ alkynylene, wherein the alkylene, alkenylene or alkynylene is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, amino or alkoxy; R ¹ is selected from hydrogen atom, cyano, halogen, alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl, fused ring, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NHC(O)NR ⁵ R ⁶ , -NR ⁵ R ⁶ , -C(O)NR ⁵ R ⁶ or -S(O) _r R ⁴ ; wherein the alkyl, cycloalkyl, heterocyclic group, aryl, heteroaryl or fused ring is optionally further substituted by one or more R ³ ; R ³ is each independently selected from cyano, halogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ⁴ , -C(O)R ⁴ , -C(O)OR ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NR ⁵ R ⁶ , -C(O)NR ⁵ R ⁶ , -CH ₂ NHC(O)OR ⁴ , -CH ₂ NR ⁵ R ⁶ or -S(O) _r R ⁴ ; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R ⁷ , -C(O)OR ⁷ , -OC(O)R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -SO ₂ NR ⁸ R ⁹ or -NR ⁸ C(O)R ⁹ ; Alternatively, two R ³ and the same carbon atom to which they are attached form a -C(=O)-; ^R4 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 with one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, substituted by a substituent selected from aryl, =O, -C(O)R ⁷ , -C(O)OR ⁷ , -OC(O)R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -SO ₂ NR ⁸ R ⁹ or -NR ⁸ C(O)R ⁹ ; R ⁵ and R ⁶ are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, 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 with one or more substituents selected from hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O)R ⁷ , -C(O)OR ⁷ , -OC(O)R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -SO ₂ NR ⁸ R ⁹ or -NR ⁸ C(O)R ⁹ ; Alternatively, R ⁵ and R ⁶ together with the atoms to which they are attached form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O)r, and the 4- to 8-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)R ⁷ , -C(O)OR ⁷ , -OC(O)R ⁷ , -NR ⁸ R ⁹ , -C(O)NR ⁸ R ⁹ , -SO ₂ NR ⁸ R ⁹ or -NR ⁸ C(O)R ⁹ ; R ⁷ , R ⁸ and R ⁹ 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; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; and r is independently 0, 1 or 2. The compound according to claim 1 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 (I):
Wherein: X, Y, Z, Q, ^R1 and L are as defined in claim 1. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt described by general formula (II):
in: Q is selected from CH or N atoms; ^R1 and L are as defined in claim 1. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt described by general formula (III):
in: Ring C is selected from a heteroaryl group, a heterocyclic group or a fused ring, wherein the heteroaryl group, the heterocyclic group or the fused ring contains at least one N atom; p is selected from 0, 1, 2, 3, 4 or 5; Q is selected from CH or N atoms; ^R3 and L are as defined in claim 1. The compound according to claim 1, 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 (IV) or (V):
Wherein: ^R1 and L are as defined in claim 1. The compound according to any one of claims 1, 2, 3 or 5, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein: R ¹ is selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, a heteroaryl group, a fused ring, a cyano group, -OR ⁴ , -C(O)OR ⁴ , -NHC(O)R ⁴ , -NHC(O)OR ⁴ , -NR ⁵ R ⁶ , -NHC(O)NR ⁵ R ⁶ or -C(O)NR ⁵ R ⁶ , wherein the alkyl group, cycloalkyl group, heterocyclic group, heteroaryl group or fused ring is optionally further substituted by one or more R ³ ; R ³ is each independently selected from halogen, cyano, alkyl, hydroxyl, heterocyclyl, -C(O)R ⁴ , -C(O)OR ⁴ , -NR ⁵ R ⁶ or -C(O)NR ⁵ R ⁶ , wherein the alkyl or heterocyclyl is optionally further substituted with one or more substituents selected from halogen, cyano, amino, hydroxyl, heteroaryl or -C(O)NR ⁸ R ⁹ ; Alternatively, two R ^3's and the same carbon atom to which they are attached form a -C(=O); R ⁴ is selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from hydroxyl, cyano or alkoxy; R ⁵ and R ⁶ are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from hydroxyl, cyano, heteroaryl, -C(O)OR ⁷ or -C(O)NR ⁸ R ⁹ ; R ⁷ , R ⁸ and R ⁹ are each independently selected from a hydrogen atom or an alkyl group. The compound according to any one of claims 1 to 5, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: L is selected from methylene, ethylene, propylene, vinylene, ethynylene, propynylene or butynylene; wherein the methylene, ethylene, propylene, vinylene, ethynylene, propynylene or butynylene is optionally further substituted by one or more halogen, cyano or amino. The compound or its stereoisomer, tautomer or pharmaceutically acceptable salt according to claim 7, wherein L is selected from _-CH2- , -( _CH2 ) _2- , -( _CH2 ) _3- , -CH=CH-, -C≡C-, _-CH2C≡C- or -( _CH2 ) _2C≡C- . The compound according to any one of claims 1 to 8 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is:






A pharmaceutical composition comprising an effective dose of a compound according to any one of claims 1 to 9 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 9 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10 in the preparation of an LPXC inhibitor. Use of the compound according to any one of claims 1 to 9 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 10 in the preparation of a medicament for treating a disease mediated by LPXC, wherein the disease mediated by LPXC is selected from bacterial infections caused by Gram-negative bacteria. The use according to claim 12, wherein the Gram-negative bacteria are selected from Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella dysenteriae, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter, Yersinia, Legionella pneumophila, Bordetella pertussis, Shigella, Pasteurella, Vibrio cholerae, and Neisseria meningitidis.