Aromatic acetylene derivative, preparation method and medical application thereof

Abstract

The invention relates to an aromatic acetylene derivative, a preparation method thereof and application of a pharmaceutical composition containing the derivative in medicine. Specifically, the present invention relates to an aromatic acetylene derivative represented by general formula (I), a preparation method and a pharmaceutically acceptable salt thereof, and uses of the aromatic acetylene derivative and the pharmaceutically acceptable salt thereof as therapeutic agents, especially LPXC inhibitors, and definitions of substituents in the general formula (I) are the same as those in the specification. # imgabs0 #

Description

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

[0001] The present invention relates to an aromatic acetylene derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, in particular as an LPXC inhibitor. Background Art

[0002] The 1930s to 1960s marked the golden age of antibiotic development. Since then, antibiotics have been widely used worldwide, but bacterial resistance has also emerged, and 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 severe shortage of clinical drugs to treat multidrug-resistant Gram-negative infections, and highly toxic drugs are still used. Although bacterial resistance has been a hot topic in the international medical community in recent years, research and development has been slow, and few compounds have entered clinical research at home and abroad. Therefore, finding a new antibacterial drug for Gram-negative bacteria is an important issue that needs to be addressed urgently.

[0003] UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LPXC) is a Zn-dependent + LPXC is a metalloenzyme that is the first, rate-limiting enzyme in the synthesis of lipid A. Lipid A is a key component of the outer membrane of Gram-negative bacteria, anchoring lipopolysaccharide to the outer membrane and maintaining the integrity of the cell. It also acts as a hydrophobic barrier, preventing external factors such as antibiotics from entering the cell, protecting the bacteria from damage. Furthermore, lipid A is also the active ingredient of bacterial endotoxins, which enter the bloodstream through the intestinal mucosa, activating the body's immune response and even causing severe septic shock, which contributes to the pathogenicity of Gram-negative bacteria. Therefore, by inhibiting LPXC, the biosynthesis of lipid A in Gram-negative bacteria can be inhibited, effectively controlling Gram-negative infections.

[0004] To date, much of the knowledge regarding the structure and properties of LPXC has been gained through the isolation, purification, and characterization of LPXC crystals from Escherichia coli, Pseudomonas aeruginosa, and thermophilic bacteria. These three different sources of LPXC exhibit highly similar structures, each containing two domains with the active region located at their junction. Each domain comprises an α-helix and a β-sheet, with the β-sheet enclosing the α-helix to form a "β-α-α-β" sandwich structure. Although the amino acid sequences of these two domains differ slightly, they share a common spatial structure. Furthermore, each domain has a corresponding insertion region composed of β-sheets, forming distinct functional domains. Studies have shown that LPXC shares a high degree of homology among Gram-negative bacteria and shares no common sequences with various mammalian enzymes. From a biological perspective, due to its unique advantages of broad spectrum and low toxicity, inhibiting LPXC would be an ideal target for antibacterial drug development.

[0005] Currently, no new LPXC inhibitors have been marketed. The small molecule compound RC-01, developed by Toyama Chemical Co., Ltd., has entered Phase I clinical trials. Other pharmaceutical companies, such as Novartis and Taiwan's Taisho Pharmaceutical, are still in the preclinical stage. While the research and application of LPXC inhibitors have made some progress, significant room for improvement remains, and continued research and development of new LPXC inhibitors is necessary.

[0006] Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides a compound represented by the general formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0008] in:

[0009] Ring A is selected from a 5-membered heteroaryl group or a 5- to 6-membered heterocyclic group;

[0010] Ring B is selected from 5- to 6-membered heteroaryl groups;

[0011] R a are the same or different, each independently selected from hydroxy, cyano, halogen, alkyl or alkoxy;

[0012] R b are the same or different, each independently selected from cyano, halogen, hydroxy, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted with one or more substituents selected from hydroxy, cyano, halogen, alkyl or alkoxy;

[0013] X, Y, Z, 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;

[0014] R 2 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;

[0015] L is selected from C1-C3 alkylene, C2-C3 alkenylene or C2-C4 alkynylene, wherein the alkylene, alkenylene or alkynylene is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, amino or alkoxy;

[0016] R 1 Selected from hydrogen atom, cyano group, halogen, alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, 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, heterocyclyl, aryl, heteroaryl or fused ring is optionally further substituted by one or more R 3 replaced by;

[0017] R 3 are 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 、-CH2NHC(O)OR 4 、-CH2NR 5 R 6 or -S(O) r R 4 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, 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 、-SO2NR 8 R 9 or -NR 8 C(O)R 9 substituted by a substituent;

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

[0019] R 4 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =O, -C(O)R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO2NR 8 R 9 or -NR 8 C(O)R 9 substituted by a substituent;

[0020] R 5 and R 6 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, 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 、-SO2NR 8 R 9 or -NR 8 C(O)R 9 substituted by a substituent;

[0021] Or, R 5 and R 6 Together with the atoms to which they are attached, they 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)R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO2NR 8 R 9 or -NR 8 C(O)R 9 substituted by a substituent;

[0022] R 7 、R 8 and R 9 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

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

[0024] n is 0, 1, 2, 3 or 4; and

[0025] r is independently 0, 1 or 2.

[0026] 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:

[0027] Where: X, Y, Z, Q, R 1 and L are as defined in Formula (AI).

[0028] A preferred embodiment of the present invention is a compound of formula (AI) or (I) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0029] in:

[0030] Q is selected from CH or N atoms;

[0031] R 1 and L are as defined in Formula (AI).

[0032] A preferred embodiment of the present invention is a compound of formula (AI), (I) or (II) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof:

[0033] in:

[0034] 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 nitrogen atom;

[0035] p is selected from 0, 1, 2, 3, 4 or 5;

[0036] Q is selected from CH or N atoms;

[0037] R 3 and L are as defined in Formula (AI).

[0038] A preferred embodiment of the present invention is a compound of formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of formula (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0039] Where: R 1 and L are as defined in Formula (AI).

[0040] A preferred embodiment of the present invention is a compound of formula (AI), (I), (II), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:

[0041] R 1 Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic group, heteroaryl, fused ring, 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 6wherein the alkyl, cycloalkyl, heterocyclyl, heteroaryl or fused ring is optionally further substituted by one or more R 3 replaced by;

[0042] R 3 Each is independently selected from halogen, cyano, alkyl, hydroxy, heterocyclic, -C(O)R 4 、-C(O)OR 4 、-NR 5 R 6 or -C(O)NR 5 R 6 wherein the alkyl or heterocyclic group is optionally further substituted by one or more halogen, cyano, amino, hydroxyl, heteroaryl or -C(O)NR 8 R 9 substituted by a substituent;

[0043] Or, two R 3 Form a -C(=O) with the same carbon atom to which it is attached;

[0044] 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 a hydroxyl group, a cyano group or an alkoxy group;

[0045] R 5 and R 6 Each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more selected from hydroxyl, cyano, heteroaryl, -C(O)OR 7 or -C(O)NR 8 R 9 substituted by a substituent;

[0046] R 7 、R 8 、R 9 are each independently selected from a hydrogen atom or an alkyl group.

[0047] A preferred embodiment of the present invention is a compound of formula (AI), (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:

[0048] L is selected from methylene, ethylene, propylene, vinylidene, ethynylene, propynylene or butynylene; wherein the methylene, ethylene, propylene, vinylidene, ethynylene, propynylene or butynylene is optionally further substituted with one or more halogen, cyano or amino groups.

[0049] A preferred embodiment of the present invention is a compound of formula (AI), (I), (II), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:

[0050] L is selected from -CH2-, -(CH2)2-, -(CH2)3-, -CH=CH-, -C≡C-, -CH2C≡C- or -(CH2)2C≡C-;

[0051] R 1 Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic group, heteroaryl, fused ring, 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 by one or more R 3 replaced by;

[0052] R 3 Each is independently selected from halogen, cyano, alkyl, hydroxy, heterocyclic, -C(O)R 4 、-C(O)OR 4 、-NR 5 R 6 or -C(O)NR 5 R 6 wherein the alkyl or heterocyclic group is optionally further substituted by one or more halogen, cyano, amino, hydroxyl, heteroaryl or -C(O)NR 8 R 9 substituted by a substituent;

[0053] Or, two R 3 Form a -C(=O) with the same carbon atom to which it is attached;

[0054] 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 a hydroxyl group, a cyano group or an alkoxy group;

[0055] R 5 and R 6 Each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more selected from hydroxyl, cyano, heteroaryl, -C(O)OR 7 or -C(O)NR8 R 9 substituted by a substituent;

[0056] R 7 、R 8 、R 9 are each independently selected from a hydrogen atom or an alkyl group.

[0057] In a preferred embodiment of the present invention, the compound described by general formula (A-1) is selected from:

[0058] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0059] 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.

[0060] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (AI), (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0061] The present invention provides a compound of formula (AI), (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing an LPXC inhibitor.

[0062] The present invention also provides a use of a compound of formula (AI), (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or 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.

[0063] The present invention further provides a compound of the general formula (AI), (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.

[0064] The present invention provides a compound of the general formula (AI), (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preparing a drug for treating 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.

[0065] Detailed Description of the Invention

[0066] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0067] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0068] "Alkylene" refers to a saturated C1-C 20 A 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, preferably C1-C 10 Alkylene, more preferably C1-C6 alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. Alkylene can be substituted or unsubstituted.

[0069] "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 of which 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.

[0070] "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 can be optionally substituted or unsubstituted.

[0071] "Alkynylene" 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 alkynylene groups include -CH≡CH-, -CH2CH≡CH-, -CH2CH≡CHCH2-, -CH≡CH-CH≡CH-, -(CH2)2CH≡CH-, and the like. Alkynylene groups can be optionally substituted or unsubstituted.

[0072] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the ring atoms is a carbon atom, including monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably having a 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.

[0073] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing 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, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into single spiro, double spiro or multiple spiroalkyl groups, preferably single spiro and double spiroalkyl groups, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0074] "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. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl group, preferably a bicyclic or tricyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. 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 tetradecahydrophenanthrenyl.

[0075] "Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures that share two non-directly connected carbon atoms. One or more rings may contain one or more double bonds, but none of the rings have completely conjugated π electrons. It is preferably an aromatic system with 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and 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)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r,5r)-bicyclo[3.3.2]decyl.

[0076] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more ring atoms are selected from nitrogen, oxygen, or S(O) r (wherein r is selected from 0, 1 or 2) heteroatom, the remaining ring atoms are carbon, including monocyclic, polycyclic, condensed, bridged and spirocyclic rings, and the heterocyclic group can be substituted or unsubstituted.

[0077] 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,

[0078] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the 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 spiro atoms between rings, spiroalkyl is divided into monospiro heterocyclic group, bispiro heterocyclic group or polyspiro heterocyclic group, preferably monospiro heterocyclic group and bispiro heterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0079] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, 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) heteroatom, 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]dioxin.

[0080] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more ring structures that share 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 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 2-azabicyclo [3.3.2] decyl.

[0081] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0082] "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, quinolinyl, 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, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furo[3,2-b]pyridinyl, furo[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl, Heteroaryl groups can be substituted or unsubstituted.

[0083] "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 least one ring 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 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. 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 heterocyclyl or monocyclic cycloalkyl. Preferably, it includes 7 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include but are not limited to:

[0084] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0085] "Nitro" refers to a -NO2 group.

[0086] "Hydroxy" refers to an -OH group.

[0087] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0088] "Amino" refers to -NH2.

[0089] "Cyano" refers to -CN.

[0090] "Benzyl" refers to -CH2-phenyl.

[0091] "Carboxyl" refers to -C(O)OH.

[0092] "Carboxylate" refers to a -C(O)O-alkyl group or a -C(O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0093] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0094] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0095] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0096] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0097] "DMSO" refers to dimethyl sulfoxide.

[0098] "BOC" refers to tert-butoxycarbonyl.

[0099] "Bn" refers to benzyl.

[0100] "THP" refers to 2-tetrahydropyranyl.

[0101] "TFA" refers to trifluoroacetic acid.

[0102] "Ts" refers to p-toluenesulfonyl.

[0103] "Leaving group", or leaving group, is an atom or functional group that breaks away from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that easily accept electrons and have a strong ability to withstand negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break away from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to bind to other atoms, and the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, methylsulfonyl, -OTs or -OH.

[0104] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0105] As used herein, "substituted" or "substituted", unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, 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、-CH2NHC(O)OR 6 、-CH2NR 7 R 8 or -S(O)rR 6 substituted by a substituent;

[0106] R 6 is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0107] R 7 and R 8 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0108] Or, R 7 and R 8 Together with the atoms to which they are attached, they 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)R 9、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0109] R 9 、R 10 and R 11 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0110] r is selected from 0, 1 or 2;

[0111] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0112] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0113] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0114] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0115] Synthesis method of the compound of the present invention

[0116] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0117] The present invention provides a method for preparing a compound of formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts, the method comprising:

[0118] The compound of formula (Ia) and the compound of formula (Ib) undergo coupling reaction under the action of a catalyst, and optionally further undergo deprotection and substitution reaction to obtain the compound of formula (AI)

[0119] in:

[0120] X1 is selected from halogen;

[0121] Ring A, Ring B, R a 、R b ,m,n,X,Y,Z,Q,L and R 1 As described in general formula (I). DETAILED DESCRIPTION

[0122] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0123] Example

[0124] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0125] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0126] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0127] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0128] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise indicated. Commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0129] CD3OD: deuterated methanol.

[0130] CDCl3: deuterated chloroform.

[0131] DMSO-d6: deuterated dimethyl sulfoxide.

[0132] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1 L.

[0133] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0134] 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; the volume ratio of the solvent varies according to the polarity of the compound and can also be adjusted by adding a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine.

[0135] Example 1

[0136] (S)-1-(1-((5-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0137] (S)-1-(1-((5-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0138] first step

[0139] Ethyl 4-(4-iodophenyl)-2,4-dioxobutanoate

[0140] Sodium hydride (1.63 g, 40.64 mmol, 60% oil dispersion) was added to toluene (20 mL), followed by 1-(4-iodophenyl)ethan-1-one 1a (5 g, 20.32 mmol, commercially available). The mixture was heated to 50°C, and a toluene solution (20 mL) of diethyl oxalate 1b (4.45 g, 30.48 mmol) was added dropwise. The mixture was heated to 50°C and allowed to react 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 x 2). The combined organic phases were washed with saturated brine (100 mL x 3), 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 4-(4-iodophenyl)-2,4-dioxobutanoate 1c (2.8 g) in a yield of 39.81%.

[0141] MS m / z(ESI):347.0[M+1]

[0142] Step 2

[0143] Ethyl 5-(4-iodophenyl)isoxazole-3-carboxylate

[0144] 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 completion of the reaction, the mixture was concentrated under reduced pressure and dissolved in ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to give ethyl 5-(4-iodophenyl)isoxazole-3-carboxylate 1d (2.3 g) in a yield of 82.86%.

[0145] MS m / z(ESI):343.8[M+1]

[0146] Step 3

[0147] (5-(4-iodophenyl)isoxazol-3-yl)methanol

[0148] Ethyl 5-(4-iodophenyl)isoxazole-3-carboxylate 1d (1.20 g, 3.50 mmol) was added to methanol (25 mL), and sodium borohydride (198.46 mg, 5.25 mmol) was added portionwise. The temperature was raised to 80°C and the reaction was allowed to react for 4 hours. After completion of the reaction, ice water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide (5-(4-iodophenyl)isoxazol-3-yl)methanol 1e (0.36 g) in a yield of 34.19%.

[0149] MS m / z(ESI):302.0[M+1]

[0150] Step 4

[0151] Methyl (5-(4-iodophenyl)isoxazol-3-yl)methanesulfonate

[0152] (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). The mixture was cooled to 0°C, and methanesulfonyl chloride 1f (205.45 mg, 1.79 mmol) was added dropwise. The mixture was allowed to warm to room temperature and allowed to react for 4 hours. After completion, the reaction was quenched with water and extracted with dichloromethane (50 mL x 3). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl (5-(4-iodophenyl)isoxazol-3-yl)methanesulfonate 1g (0.45 g) in a yield of 99.26%.

[0153] MS m / z(ESI):379.8[M+1]

[0154] Step 5

[0155] 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0156] 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 portionwise, and the mixture was heated to room temperature for 1 hour. 1 g (193.21 mg, 509.57 μmol) of methyl (5-(4-iodophenyl)isoxazol-3-yl)methanesulfonate 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 product 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) in a yield of 49.13%.

[0157] MS m / z(ESI):480.1[M+1]

[0158] Step 6

[0159] 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

[0160] 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

[0161] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon three times. The mixture was stirred at 60°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-(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) in a yield of 84.48%.

[0162] MS m / z(ESI):477.0[M+1]

[0163] Step 7

[0164] (S)-1-(1-((5-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0165] (S)-1-(1-((5-(4-(3-morpholinoprop-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0166] 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), and 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 reaction 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%.

[0167] MS m / z(ESI):393.1[M+1]

[0168] Example 2

[0169] (S)-1-(1-((5-(4-(4-morpholinobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0170] (S)-1-(1-((5-(4-(4-morpholinobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0171] first step

[0172] 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

[0173] 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

[0174] 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 sequentially to tetrahydrofuran (1 mL), and the atmosphere was replaced with argon 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%.

[0175] MS m / z(ESI):491.0[M+1]

[0176] Step 2

[0177] (S)-1-(1-((5-(4-(4-morpholinobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0178] (S)-1-(1-((5-(4-(4-morpholinobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0179] 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), and trifluoroacetic acid (13.95 mg, 122.30 μmol) was slowly added dropwise, followed by stirring 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%.

[0180] MS m / z(ESI):407.1[M+1]

[0181] Example 3

[0182] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

[0183] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

[0184] first step

[0185] 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

[0186] 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

[0187] 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 sequentially to tetrahydrofuran (1 mL), and the atmosphere was replaced with argon three times. 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 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%.

[0188] MS m / z(ESI):436.0[M+1]

[0189] Step 2

[0190] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

[0191] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol

[0192] 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), and 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 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)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-ol 3 (4 mg) in a yield of 24.54%.

[0193] MS m / z(ESI):352.2[M+1]

[0194] Example 4

[0195] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid

[0196] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid

[0197] first step

[0198] 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

[0199] 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

[0200] 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 product was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: System A) to give 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 4b (40 mg) in a yield of 82.72%.

[0201] MS m / z(ESI):464.2[M+1]

[0202] Step 2

[0203] methyl(S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoate

[0204] (S)-methyl 5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoate

[0205] 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 4b (20 mg, 43.15 μmol) was added to dichloromethane (0.5 mL), and trifluoroacetic acid (9.84 mg, 86.30 μmol) was slowly added dropwise. The mixture was stirred at 25°C for 4 hours. After the reaction was complete, the mixture was neutralized with saturated sodium carbonate solution. The organic phase was separated and concentrated under reduced pressure. The residue was used directly in the next step to afford methyl (S)-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%.

[0206] MS m / z(ESI):380.3[M+1]

[0207] Step 3

[0208] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoicacid

[0209] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid

[0210] Methyl (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoate 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 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)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynoic acid 4 (8 mg) in a yield of 30.07%.

[0211] MS m / z(ESI):366.1[M+1]

[0212] Example 5

[0213] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide

[0214] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide

[0215] first step

[0216] 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

[0217] 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

[0218] 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-ynamide 4b (50 mg, 107.87 μmol) and aqueous ammonia (3.78 mg, 107.87 μmol) were added sequentially to acetonitrile (0.5 mL) and stirred at 25°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was directly subjected to the next step to afford 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) in a yield of 41.34%.

[0219] MS m / z(ESI):449.0[M+1]

[0220] Step 2

[0221] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide

[0222] (S)-5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-ynamide

[0223] 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), and 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 complete, 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) in a yield of 60.93%.

[0224] MS m / z(ESI):365.1[M+1]

[0225] Example 6

[0226] (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

[0227] (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

[0228] first step

[0229] 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

[0230] 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

[0231] 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 sequentially to tetrahydrofuran (1 mL), and the atmosphere was replaced with argon three times. The mixture was stirred at 50°C for 16 hours. After completion of the reaction, the product 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%.

[0232] MS m / z(ESI):422.0[M+1]

[0233] Step 2

[0234] 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

[0235] 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

[0236] 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 sequentially to dichloromethane (0.5 mL), and the argon atmosphere was replaced three times. Methanesulfonyl chloride (12.23 mg, 106.76 μmol, 8.26 μL) was slowly added dropwise under ice-water cooling, and the mixture was stirred at 25°C for 6 hours. After the reaction was complete, dichloromethane (30 mL) and water (15 mL) were added, the liquid was separated, and 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) in a yield of 84.37%.

[0237] MS m / z(ESI):500.0[M+1]

[0238] Step 3

[0239] 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

[0240] 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

[0241] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon three times. The mixture was stirred at 50°C for 16 hours. After the reaction was completed, the product 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%.

[0242] MS m / z(ESI):505.0[M+1]

[0243] Step 4

[0244] (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

[0245] (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

[0246] 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), and 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 completion of the reaction, 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-(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%.

[0247] MS m / z(ESI):421.1[M+1]

[0248] Example 7

[0249] (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoicacid

[0250] (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid

[0251] first step

[0252] 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

[0253] 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

[0254] 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 triethylenediamine (35.10 mg, 312.95 μmol) were added sequentially to acetonitrile (0.5 mL), and 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: System B) to give 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 7b (27 mg) in a yield of 54.20%.

[0255] MS m / z(ESI):478.3[M+1]

[0256] Step 2

[0257] 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

[0258] 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

[0259] 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 7b (20 mg, 41.88 μmol) and lithium hydroxide monohydrate (1.76 mg, 41.88 μmol) were added sequentially to tetrahydrofuran (0.5 mL) 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 afford 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%.

[0260] MS m / z(ESI):464.0[M+1]

[0261] Step 3

[0262] (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoicacid

[0263] (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid

[0264] 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), and trifluoroacetic acid (7.38 mg, 64.72 μmol) was slowly added dropwise. The mixture was stirred at 25 °C for 4 h. After completion of the reaction, 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)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynoic acid 7 (8 mg) in a yield of 61.90%.

[0265] MS m / z(ESI):380.1[M+1]

[0266] Example 8

[0267] (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

[0268] (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

[0269] first step

[0270] 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

[0271] 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

[0272] 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 sequentially to acetonitrile (1 mL) 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 afford 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%.

[0273] MS m / z(ESI):463.0[M+1]

[0274] Step 2

[0275] (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

[0276] (S)-6-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)hex-5-ynamide

[0277] 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 completion of the reaction, 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) in a yield of 30.25%.

[0278] Example 9

[0279] (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

[0280] (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

[0281] first step

[0282] 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

[0283] 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

[0284] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon three times. The mixture was then stirred at 60°C for 6 hours. After the reaction was completed, the product was concentrated under reduced pressure, dissolved in dichloromethane and filtered, 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) in a yield of 49.60%; and 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) in a yield of 24.76%.

[0285] MS m / z(ESI):504.0[M+1]

[0286] Step 2

[0287] (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

[0288] (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

[0289] 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), and trifluoroacetic acid (22.64 mg, 198.56 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 6 hours. After completion of the reaction, 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-methylpiperazin-1-yl)but-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 9 (20 mg) in a yield of 43.22%.

[0290] MS m / z(ESI):420.1[M+1]

[0291] Example 10

[0292] (S)-1-(1-((5-(4-(but-3-en-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0293] (S)-1-(1-((5-(4-(but-3-en-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0294] 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), and trifluoroacetic acid (5.65 mg, 49.57 μmol) was slowly added dropwise. The mixture was stirred at 25°C for 6 hours. 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+H2O, mobile phase B: CH3CN), to obtain (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%.

[0295] MS m / z(ESI):320.0[M+1]

[0296] Example 11

[0297] (S)-1-(1-((5-(4-(5-morpholinopent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0298] (S)-1-(1-((5-(4-(5-morpholinopent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0299] first step

[0300] 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

[0301] 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

[0302] 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 sequentially to dichloromethane (2 mL), and the argon atmosphere was replaced three times. Methanesulfonyl chloride (355.08 mg, 3.10 mmol, 239.92 μL) was slowly added dropwise under ice-water cooling, and the mixture was 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%.

[0303] MS m / z(ESI):513.9[M+1]

[0304] Step 2

[0305] 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

[0306] 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

[0307] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon three times. 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 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%.

[0308] MS m / z(ESI):505.0[M+1]

[0309] Step 3

[0310] (S)-1-(1-((5-(4-(5-morpholinopent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0311] (S)-1-(1-((5-(4-(5-morpholinopent-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0312] 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 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+H2O, mobile phase B: CH3CN), 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%.

[0313] MS m / z(ESI):421.3[M+1]

[0314] Example 12

[0315] (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

[0316] (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

[0317] first step

[0318] 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

[0319] 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

[0320] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon three times. The mixture was stirred 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%.

[0321] MS m / z(ESI):486.3[M+1]

[0322] Step 2

[0323] (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

[0324] (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

[0325] 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, 32.95 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (7.51 mg, 65.90 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 6 hours. After the reaction was completed, the reaction 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-carbonitrile 12 (8 mg) in a yield of 40.03%.

[0326] MS m / z(ESI):402.0[M+1]

[0327] Example 13

[0328] (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

[0329] (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

[0330] first step

[0331] 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

[0332] 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

[0333] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon three times. The mixture was stirred at 60°C for 16 hours. After the reaction was completed, 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) in a yield of 99.22%.

[0334] MS m / z(ESI):518.0[M+1]

[0335] Step 2

[0336] (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

[0337] (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

[0338] 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), and trifluoroacetic acid (22.03 mg, 193.18 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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%.

[0339] MS m / z(ESI):434.3[M+1]

[0340] Example 14

[0341] (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

[0342] (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

[0343] first step

[0344] 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

[0345] 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

[0346] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon three times. The mixture was stirred at 100°C for 16 hours. After the reaction was complete, 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) in a yield of 99.04%.

[0347] MS m / z(ESI):519.3[M+1]

[0348] Step 2

[0349] (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

[0350] (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

[0351] 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), and 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%.

[0352] MS m / z(ESI):435.2[M+1]

[0353] Example 15

[0354] (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

[0355] (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

[0356] first step

[0357] 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

[0358] 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

[0359] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon three times. The mixture was stirred at 100°C for 16 hours. After the reaction was complete, the product 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%.

[0360] MS m / z(ESI):486.1[M+1]

[0361] Step 2

[0362] (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

[0363] (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

[0364] 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), and trifluoroacetic acid (11.04 mg, 96.79 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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%.

[0365] MS m / z(ESI):402.2[M+1]

[0366] Example 16

[0367] (S)-2-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

[0368] (S)-2-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

[0369] first step

[0370] 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

[0371] 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

[0372] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon 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) in a yield of 99.26%.

[0373] MS m / z(ESI):492.3[M+1]

[0374] Step 2

[0375] (S)-2-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

[0376] (S)-2-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)acetamide

[0377] 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), and trifluoroacetic acid (8.81 mg, 77.30 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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%.

[0378] MS m / z(ESI):408.2[M+1]

[0379] Example 17

[0380] (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

[0381] (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

[0382] first step

[0383] 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

[0384] 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

[0385] 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 sequentially to dimethyl sulfoxide (0.5 mL). Under water bath cooling, hydrogen peroxide (0.5 mL) 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 liquid was separated, the aqueous phase was extracted twice 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 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) in a yield of 96.42%.

[0386] MS m / z(ESI):504.0[M+1]

[0387] Step 2

[0388] (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

[0389] (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

[0390] 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), and 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 reaction 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%.

[0391] MS m / z(ESI):420.0[M+1]

[0392] Example 18

[0393] (S)-3-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propanenitrile

[0394] (S)-3-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propionitrile

[0395] first step

[0396] 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

[0397] 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

[0398] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon. The mixture was stirred at 100°C for 4 hours. After the reaction was completed, the reaction 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%.

[0399] MS m / z(ESI):488.3[M+1]

[0400] Step 2

[0401] (S)-3-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propanenitrile

[0402] (S)-3-((5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pent-4-yn-1-yl)amino)propionitrile

[0403] 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), and trifluoroacetic acid (21.98 mg, 192.78 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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)-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%.

[0404] MS m / z(ESI):404.3[M+1]

[0405] Example 19

[0406] (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

[0407] (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

[0408] first step

[0409] 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

[0410] 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

[0411] 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 sequentially to acetonitrile (1 mL), and the atmosphere was replaced with argon 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) in a yield of 99.22%.

[0412] MS m / z(ESI):518.3[M+1]

[0413] Step 2

[0414] (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

[0415] (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

[0416] 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), and the argon atmosphere was replaced three times. Trifluoroacetic acid (11.01 mg, 96.60 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After the reaction was complete, 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) in a yield of 8.51%.

[0417] MS m / z(ESI):434.3[M+1]

[0418] Example 20

[0419] (S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0420] (S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0421] first step

[0422] 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

[0423] 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

[0424] 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) dichloride (4.87 mg, 6.26 μmol), and cuprous iodide (1.19 mg, 6.26 μmol) were added sequentially to N,N-dimethylformamide (0.5 mL), and the argon atmosphere 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, followed by stirring at room temperature for 16 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added, the layers were separated, and 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, 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) in a yield of 61.38%.

[0425] MS m / z(ESI):520.8[M+1]

[0426] Step 2

[0427] (S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0428] (S)-1-(1-((5-(4-(4-aminobut-1-yn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0429] 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 completion of the reaction, 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) in a yield of 21.50%.

[0430] MS m / z(ESI):337.1[M+1]

[0431] Example 21

[0432] (S)-N-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)formamide

[0433] (S)-N-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)formamide

[0434] (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 sequentially to formamide (2 mL) and stirred at room temperature for 16 hours. After completion of the reaction, 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%.

[0435] MS m / z(ESI):365.1[M+1]

[0436] Example 22

[0437] methyl(S)-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)glycinate

[0438] (S)-(4-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-3-yn-1-yl)glycine methyl ester

[0439] (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 sequentially to methanol (0.2 mL) 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%.

[0440] MS m / z(ESI):409.1[M+1]

[0441] Example 23

[0442] (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

[0443] (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

[0444] first step

[0445] 1-(but-3-yn-1-yl)-1H-imidazole

[0446] 1-(But-3-yn-1-yl)-1H-imidazole

[0447] Imidazole 15a (255.96 mg, 3.76 mmol, commercially available) was added to tetrahydrofuran (0.5 mL), and the argon atmosphere was replaced three times. Sodium hydride (195.61 mg, 7.52 mmol) was slowly added, and the mixture was 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, the mixture was concentrated under reduced pressure, added with dichloromethane (5 mL), and filtered to afford 1-(but-3-yn-1-yl)-1H-imidazole 23b (380 mg) in an 84.12% yield.

[0448] MS m / z(ESI):121.2[M+1]

[0449] Step 2

[0450] 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

[0451] 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

[0452] 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 sequentially to ethylene glycol dimethyl ether (0.5 mL), the atmosphere was replaced with argon, and the mixture was stirred at 65°C for 16 hours. After the reaction was completed, the reaction 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) in a yield of 40.66%.

[0453] MS m / z(ESI):472.0[M+1]

[0454] Step 3

[0455] (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

[0456] (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

[0457] 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), and trifluoroacetic acid (9.67 mg, 84.83 μmol) was slowly added dropwise, followed by stirring at 25 ° C for 4 hours. After completion of the reaction, 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%.

[0458] MS m / z(ESI):388.0[M+1]

[0459] Example 24

[0460] (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

[0461] (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

[0462] first step

[0463] 1-(prop-2-yn-1-yl)azetidine-3-carbonitrile

[0464] 1-(Propan-2-yn-1-yl)azetidine-3-carbonitrile

[0465] Azetidine-3-carbonitrile 12a (498.34 mg, 4.20 mmol) was added to tetrahydrofuran (2 mL), and the argon atmosphere was replaced three times. Sodium hydride (437.29 mg, 16.81 mmol) was slowly added under ice-water cooling. The mixture was then stirred at room temperature for 0.5 hours. 3-Bromoprop-1-yne 24a (500 mg, 4.20 mmol, 362.32 μL, commercially available) was then added and allowed to react at 85°C for 24 hours. After completion of the reaction, the mixture was quenched with water (20 mL), concentrated under reduced pressure, and extracted with dichloromethane (30 mL × 3). The mixture was then concentrated under reduced pressure to afford 1-(prop-2-yn-1-yl)azetidine-3-carbonitrile 24b (200 mg) in a 39.60% yield.

[0466] MS m / z(ESI):121.2[M+1]

[0467] Step 2

[0468] 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

[0469] 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

[0470] 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), the atmosphere was replaced with argon, and the mixture was stirred at 65°C for 16 hours. After the reaction was complete, 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%.

[0471] MS m / z(ESI):472.4[M+1]

[0472] Step 3

[0473] (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

[0474] (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

[0475] 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), and trifluoroacetic acid (9.67 mg, 84.83 μmol) was slowly added dropwise, followed by stirring at 25 °C for 4 hours. After completion of the reaction, 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-(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) in a yield of 14.59%.

[0476] MS m / z(ESI):388.1[M+1]

[0477] Example 25

[0478] (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

[0479] (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

[0480] first step

[0481] 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

[0482] 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

[0483] 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 sequentially to dimethyl sulfoxide (0.5 mL). Under water bath cooling, hydrogen peroxide solution (0.3 mL) was slowly added dropwise, and the mixture was 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), and 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) in a yield of 48.16%.

[0484] MS m / z(ESI):490.2[M+1]

[0485] Step 2

[0486] (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

[0487] (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

[0488] 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), and trifluoroacetic acid (4.66 mg, 40.85 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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-(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%.

[0489] MS m / z(ESI):406.2[M+1]

[0490] Example 26

[0491] (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

[0492] (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

[0493] first step

[0494] 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

[0495] 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

[0496] 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 sequentially to dimethyl sulfoxide (0.3 mL), and hydrogen peroxide (0.2 mL) was slowly added dropwise, followed by stirring at room temperature for 3 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), 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 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) in a yield of 48.06%.

[0497] MS m / z(ESI):491.1[M+1]

[0498] Step 2

[0499] (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

[0500] (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

[0501] 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), and trifluoroacetic acid (4.65 mg, 40.77 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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-(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%.

[0502] MS m / z(ESI):407.1[M+1]

[0503] Example 27

[0504] (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

[0505] (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

[0506] first step

[0507] 4-(prop-2-yn-1-yl)piperazin-2-one

[0508] 4-(Propan-2-yn-1-yl)piperazin-2-one

[0509] 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 sequentially to N,N-dimethylformamide (2 mL), and the argon atmosphere was replaced three times. Sodium hydride (437.29 mg, 16.81 mmol) was slowly added under ice-water cooling, and the mixture was stirred at 85°C for 24 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added. The mixture was separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to afford 4-(prop-2-yn-1-yl)piperazin-2-one 27a (200 mg) in a 34.44% yield.

[0510] MS m / z(ESI):139.2[M+1]

[0511] Step 2

[0512] 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

[0513] 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

[0514] 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 complete, ethyl acetate (30 mL) and water (15 mL) were added, the layers were separated, and 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) in a yield of 39.16%.

[0515] MS m / z(ESI):490.3[M+1]

[0516] Step 3

[0517] (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

[0518] (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

[0519] 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), and trifluoroacetic acid (13.97 mg, 122.56 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 4 hours. After completion of the reaction, 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%.

[0520] MS m / z(ESI):406.1[M+1]

[0521] Example 28

[0522] (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

[0523] (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

[0524] first step

[0525] 4-(but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

[0526] 4-(But-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one

[0527] 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 sequentially to N,N-dimethylformamide (3 mL). The atmosphere was replaced with argon three times. The mixture was stirred at 70°C for 24 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 4-(but-3-yn-1-yl)-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one 28b (150 mg) in a yield of 19.73%.

[0528] MS m / z(ESI):203.1[M+1]

[0529] Step 2

[0530] 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

[0531] 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

[0532] 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), the atmosphere was replaced with argon, 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, the layers were separated, and 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) in a yield of 86.58%.

[0533] MS m / z(ESI):554.2[M+1]

[0534] Step 3

[0535] (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

[0536] (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

[0537] 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), and trifluoroacetic acid (20.60 mg, 180.63 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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-(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%.

[0538] MS m / z(ESI):470.2[M+1]

[0539] Example 29

[0540] (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

[0541] (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

[0542] first step

[0543] 3-(but-3-yn-1-yl)imidazolidine-2,4-dione

[0544] 3-(But-3-yn-1-yl)imidazolidine-2,4-dione

[0545] 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 sequentially to tetrahydrofuran (4 mL). The argon atmosphere was replaced three times, and the mixture was stirred at 70°C for 24 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added. The mixture was separated, and 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 afford 3-(but-3-yn-1-yl)imidazolidine-2,4-dione 29b (120 mg) in a yield of 20.98%.

[0546] MS m / z(ESI):153.1[M+1]

[0547] Step 2

[0548] 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

[0549] 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

[0550] 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) 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 complete, ethyl acetate (30 mL) and water (15 mL) were added, the layers were separated, and 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 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%.

[0551] MS m / z(ESI):504.1[M+1]

[0552] Step 3

[0553] (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

[0554] (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

[0555] 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), and 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 complete, 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%.

[0556] MS m / z(ESI):420.1[M+1]

[0557] Example 30

[0558] (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

[0559] (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

[0560] first step

[0561] 7-(but-3-yn-1-yl)-7H-purine

[0562] 7-(But-3-yn-1-yl)-7H-purine

[0563] 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 sequentially to N,N-dimethylformamide (3 mL). The argon atmosphere was replaced three times. The mixture was stirred at 70°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 7-(but-3-yn-1-yl)-7H-purine 30b (200 mg) in a 27.90% yield.

[0564] MS m / z(ESI):173.1[M+1]

[0565] Step 2

[0566] 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

[0567] 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

[0568] 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 sequentially to ethylene glycol dimethyl ether (0.5 mL), and the atmosphere was replaced with argon. 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, the layers were separated, and 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) in a yield of 91.54%.

[0569] MS m / z(ESI):524.3[M+1]

[0570] Step 3

[0571] (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

[0572] (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

[0573] 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), and trifluoroacetic acid (10.89 mg, 95.50 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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%.

[0574] MS m / z(ESI):440.0[M+1]

[0575] Example 31

[0576] (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

[0577] (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

[0578] first step

[0579] (S)-(1-(but-3-yn-1-yl)pyrrolidin-2-yl)methanol

[0580] (S)-(1-(But-3-yn-1-yl)pyrrolidin-2-yl)methanol

[0581] 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 sequentially to toluene (0.2 mL), and the argon atmosphere was replaced three times. The mixture was stirred at 110°C for 24 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford (S)-(1-(but-3-yn-1-yl)pyrrolidin-2-yl)methanol 31b (280 mg) in a 36.97% yield.

[0582] MS m / z(ESI):154.2[M+1]

[0583] Step 2

[0584] ((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

[0585] ((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

[0586] 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), the atmosphere was replaced with argon, 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, the layers were separated, and 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) in a yield of 37.99%.

[0587] MS m / z(ESI):505.0[M+1]

[0588] Step 3

[0589] (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

[0590] (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

[0591] ((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), and trifluoroacetic acid (4.52 mg, 39.63 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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-((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%.

[0592] MS m / z(ESI):421.1[M+1]

[0593] Example 32

[0594] (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

[0595] (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

[0596] first step

[0597] 1-(but-3-yn-1-yl)pyridin-2(1H)-one

[0598] 1-(But-3-yn-1-yl)pyridin-2(1H)-one

[0599] 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 sequentially to acetonitrile (0.5 mL), and the argon atmosphere was replaced three times. The mixture was stirred at 70°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 1-(but-3-yn-1-yl)pyridin-2(1H)-one 32b (150 mg) in a 19.39% yield.

[0600] MS m / z(ESI):148.1[M+1]

[0601] Step 2

[0602] 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

[0603] 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

[0604] 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 complete, ethyl acetate (30 mL) and water (15 mL) were added, the layers were separated, and 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)pyridin-2(1H)-one 32c (50 mg) in a yield of 96.14%.

[0605] MS m / z(ESI):499.0[M+1]

[0606] Step 3

[0607] (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

[0608] (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

[0609] 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), and trifluoroacetic acid (22.87 mg, 200.57 μmol) was slowly added dropwise, and the mixture was stirred at 25°C for 4 hours. After completion of the reaction, 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%.

[0610] MS m / z(ESI):415.1[M+1]

[0611] Example 33

[0612] (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

[0613] (S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperazin-2-one

[0614] first step

[0615] 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole

[0616] 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole

[0617] 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), 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, and the argon atmosphere was replaced three times. The mixture was stirred at room temperature for 12 hours. The system was concentrated to dryness under reduced pressure, water (50 mL) was added, and the mixture was extracted 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 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) in a yield of 99.94%.

[0618] MS m / z(ESI):450.3[M+1]

[0619] Step 2

[0620] 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0621] 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0622] 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 product was stirred for 2 hours at room temperature for 1 h (50 mL), extracted with ethyl acetate (50 mL × 3), and 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 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33c (5.8 g) in a yield of 92.21%.

[0623] MS m / z(ESI):378.2[M+1]

[0624] Step 3

[0625] 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

[0626] 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

[0627] 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 sequentially to acetone (2 mL), and the atmosphere was replaced with argon three times. The reaction was completed after continuous stirring at room temperature for 12 h. 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)pentan-2,4-diyn-1-yl)piperazin-2-one 33d (50 mg) in a yield of 66.81%.

[0628] MS m / z(ESI):514.3[M+1]

[0629] Step 4

[0630] (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

[0631] (S)-4-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperazin-2-one

[0632] 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 complete, 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-2,4-diyn-1-yl)piperazin-2-one 33 (11.69 mg) in a yield of 20.11%.

[0633] MS m / z(ESI):430.1[M+1]

[0634] Example 34

[0635] (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

[0636] (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

[0637] first step

[0638] 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

[0639] 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

[0640] 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 sequentially to acetone (2 mL). After argon replacement three times, the reaction was completed after continuous stirring at room temperature for 12 h. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to give 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) in a yield of 56.70%.

[0641] MS m / z(ESI):586.2[M+1]

[0642] Step 2

[0643] (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

[0644] (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

[0645] 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 continuous stirring at room temperature for half an hour. After the reaction was complete, 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 (1r,3r)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-1,3-diyn-1-yl)cyclobutan-1-ol 34 (11.62 mg) in a yield of 14.78%.

[0646] MS m / z(ESI):388.0[M+1]

[0647] Example 35

[0648] (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

[0649] (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

[0650] first step

[0651] 3-ethynylazetidine

[0652] 3-Ethynylazetidine

[0653] Under ice, tert-butyl 3-ethynylazetidine-1-carboxylate 35a (100 mg, 551.78 μmol, commercially available) was added to a 4 M solution of hydrogen chloride in ethyl acetate (1.5 mL). The mixture was then stirred and gradually warmed to room temperature. Stirring was continued for 1 hour. Upon completion of the reaction, a white suspension was obtained. The reaction solution was directly drained to afford 3-ethynylazetidine 35b (65 mg, hydrochloride salt), which was used directly in the next reaction.

[0654] Step 2

[0655] 2-(3-ethynylazetidin-1-yl)acetonitrile

[0656] 2-(3-ethynylazetidin-1-yl)acetonitrile

[0657] 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 sequentially to acetonitrile (2 mL), then heated 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, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude 2-(3-ethynylazetidin-1-yl)acetonitrile 35d, which was used directly in the next reaction.

[0658] MS m / z(ESI):121.2[M+1]

[0659] Step 3

[0660] 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

[0661] 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

[0662] 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 sequentially to acetone (1 mL). The reaction was completed after continuous stirring at room temperature for 12 h. 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)azetidin-1-yl)acetonitrile 35e (40 mg) in a yield of 38.08%.

[0663] MS m / z(ESI):496.1[M+1]

[0664] Step 4

[0665] (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

[0666] (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

[0667] 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)acetonitrile 35e (40.00 mg, 80.71 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 completion of the reaction, 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-(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) in a yield of 4.89%.

[0668] MS m / z(ESI):412.0[M+1]

[0669] Example 36

[0670] (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

[0671] (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

[0672] first step

[0673] 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

[0674] 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

[0675] 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 sequentially to acetone (1 mL). The reaction was completed after continuous stirring at room temperature for 12 h. 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%.

[0676] MS m / z(ESI):480.3[M+1]

[0677] Step 2

[0678] (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

[0679] (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

[0680] 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, 93.84 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 complete, 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-(pyrimidin-5-ylbutyl-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 36 (9.9 mg) in a yield of 19.88%.

[0681] MS m / z(ESI):396.2[M+1]

[0682] Example 37

[0683] (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

[0684] (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

[0685] first step

[0686] 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

[0687] 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

[0688] 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 sequentially to acetone (1 mL). The reaction was completed after continuous stirring at room temperature for 12 h. 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%.

[0689] MS m / z(ESI):479.3[M+1]

[0690] Step 2

[0691] (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

[0692] (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

[0693] 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, 83.59 μmol) was added to dichloromethane (1.5 mL), followed by dropwise addition of trifluoroacetic acid, and stirring was continued at room temperature for 1 hour. After completion of the reaction, 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-(pyridin-3-ylbut-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%.

[0694] MS m / z(ESI):395.2[M+1]

[0695] Example 38

[0696] (S)-1-(1-((5-(4-(5-morpholinopenta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0697] (S)-1-(1-((5-(4-(5-morpholino-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0698] first step

[0699] 4-(5-(trimethylsilyl)penta-2,4-diyn-1-yl)morpholine

[0700] 4-(5-(Trimethylsilyl)penta-2,4-diyn-1-yl)morpholine

[0701] Under argon, 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), and bistriphenylphosphine palladium dichloride (56.08 mg, 79.89 μmol) were added sequentially to N,N-dimethylformamide (1 mL) and stirred at 60°C for 16 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 4-(5-(trimethylsilyl)penta-2,4-diyn-1-yl)morpholine 38c, which was used directly in the next reaction.

[0702] MS m / z(ESI):222.3[M+1]

[0703] Step 2

[0704] 4-(penta-2,4-diyn-1-yl)morpholine

[0705] 4-(Penta-2,4-diyn-1-yl)morpholine

[0706] 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 sequentially to methanol (3 mL) and stirred at room temperature for 5 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to provide 4-(penta-2,4-diyn-1-yl)morpholine 38d (150 mg) in an 89.03% yield.

[0707] MS m / z(ESI):150.1[M+1]

[0708] Step 3

[0709] 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

[0710] 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

[0711] 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-(penta-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 sequentially to acetonitrile (2 mL) and stirred at room temperature under argon atmosphere 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 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)penta-2,4-diyn-1-yl)morpholine 38e (43 mg) in a yield of 82.33%.

[0712] MS m / z(ESI):501.1[M+1]

[0713] Step 4

[0714] (S)-1-(1-((5-(4-(5-morpholinopenta-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0715] (S)-1-(1-((5-(4-(5-morpholino-1,3-diyn-1-yl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0716] 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 38e (43 mg, 85.90 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 complete, 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%.

[0717] MS m / z(ESI):417.0[M+1]

[0718] Example 39

[0719] (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

[0720] (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

[0721] first step

[0722] 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

[0723] 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

[0724] 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 sequentially to acetone (2 mL) and stirred at room temperature for 12 h until the reaction was complete. 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 61% yield.

[0725] MS m / z(ESI):557.3[M+1]

[0726] Step 2

[0727] (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

[0728] (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

[0729] Tert-butyl 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)azetidine-1-carboxylate 39a (27 mg, 48.50 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (0.3 mL) was added dropwise to the mixed solution and stirred at room temperature for 1 hour. After the reaction was complete, 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-(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%.

[0730] MS m / z(ESI):373.1[M+1]

[0731] Example 40

[0732] (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

[0733] (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

[0734] 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 sequentially to dichloromethane (2 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)-3-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-1,3-diyn-1-yl)azetidin-1-yl)-3-oxopropionitrile 40 (5.01 mg) in a yield of 5.95%.

[0735] MS m / z(ESI):440.1[M+1]

[0736] Example 41

[0737] (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

[0738] (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

[0739] 2-Hydroxyacetic acid 41a (22.46 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 sequentially to dichloromethane (2 mL) and stirred at room temperature for 16 hours. After the reaction was complete, 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%.

[0740] MS m / z(ESI):431.1[M+1]

[0741] Example 42

[0742] (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

[0743] (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

[0744] 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 at room temperature for 16 hours. After the reaction was complete, 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+H2O, mobile phase B: CH3CN) 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%.

[0745] MS m / z(ESI):426.2[M+1]

[0746] Example 43

[0747] (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

[0748] (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

[0749] first step

[0750] 2-(3-ethynylazetidin-1-yl)acetamide

[0751] 2-(3-ethynylazetidin-1-yl)acetamide

[0752] 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 sequentially to acetonitrile (2 mL), and the reaction was continued at 70°C for 3 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove the organic solvent, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 2-(3-ethynylazetidin-1-yl)acetamide 43b, which was used directly in the next reaction.

[0753] MS m / z(ESI):139.1[M+1]

[0754] Step 2

[0755] 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

[0756] 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

[0757] 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 stirred at room temperature for 12 h, and the reaction was complete. 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)azetidin-1-yl)acetamide 43c (50 mg) in a yield of 73.49%.

[0758] MS m / z(ESI):514.3[M+1]

[0759] Step 3

[0760] (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

[0761] (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

[0762] 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 the dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After completion of the reaction, 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-(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%.

[0763] MS m / z(ESI):430.0[M+1]

[0764] Example 44

[0765] (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

[0766] (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

[0767] first step

[0768] 6-(prop-2-yn-1-yl)-2-oxa-6-azaspiro[3.3]heptane

[0769] 6-(Prop-2-yn-1-yl)-2-oxa-6-azaspiro[3.3]heptane

[0770] 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 sequentially to potassium carbonate (836.53 mg, 6.05 mmol) in acetonitrile (15 mL) and the reaction was continued at room temperature for 3 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the organic solvent, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 6-(prop-2-yn-1-yl)-2-oxa-6-azaspiro[3.3]heptane 44b (620 mg) in a yield of 89.61%.

[0771] MS m / z(ESI):138.2[M+1]

[0772] Step 2

[0773] 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

[0774] 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

[0775] 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 sequentially to acetone (2 mL) and stirred at room temperature for 12 h before the reaction was complete. 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)pent-2,4-diyn-1-yl)-2-oxa-6-azaspiro[3.3]heptane 44c (500 mg) in a yield of 36.82%.

[0776] Step 3

[0777] (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

[0778] (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

[0779] 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 the dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After completion of the reaction, 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-(2-oxa-6-azaspiro[3.3]hept-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%.

[0780] MS m / z(ESI):429.1[M+1]

[0781] Example 45

[0782] (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

[0783] (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

[0784] first step

[0785] tert-butyl(2-(1H-1,2,3-triazol-1-yl)ethyl)carbamate

[0786] tert-Butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)aminocarboxylate

[0787] 2-(1H-1,2,3-triazol-1-yl)ethanamine 45a (100 mg, 891.80 μmol, commercially available), triethylamine (180.48 mg, 1.78 mmol), and di-tert-butyl dicarbonate (389.27 mg, 1.78 mmol) were added sequentially to dichloromethane (1 mL) and the reaction was continued at room temperature for 3 hours. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the organic solvent, and water (20 mL) was added. The mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide tert-butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)aminocarboxylate 45b (180 mg) in a yield of 95.10%.

[0788] MS m / z(ESI):213.2[M+1]

[0789] Step 2

[0790] tert-butyl(2-(1H-1,2,3-triazol-1-yl)ethyl)(prop-2-yn-1-yl)carbamate

[0791] tert-Butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)(prop-2-yn-1-yl)aminocarboxylate

[0792] 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, followed by sodium hydride (39.21 mg, 1.51 mmol) and stirring for 15 min. Then, 3-bromoprop-1-yne 24a (112.09 mg, 753.83 μmol) was added to the mixed solution, and the temperature was gradually raised to room temperature and the reaction was continued for 5 h. After the reaction was complete, the reaction solution was distilled under reduced pressure to remove the organic solvent, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 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 A) to give tert-butyl (2-(1H-1,2,3-triazol-1-yl)ethyl)(prop-2-yn-1-yl)aminocarboxylate 45c (180 mg) in a yield of 95.40%.

[0793] MS m / z(ESI):251.2[M+1]

[0794] Step 3

[0795] 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

[0796] 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

[0797] 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 sequentially to acetone (2 mL). The reaction was completed after continuous stirring at room temperature for 12 h. 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-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)aminocarboxylate 45d (40 mg) in a yield of 24.13%.

[0798] MS m / z(ESI):626.2[M+1]

[0799] Step 4

[0800] (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

[0801] (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

[0802] 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 45d (40 mg, 63.93 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 completion of the reaction, 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+H2O, mobile phase B: CH3CN) to give (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 45 (6.93 mg) in a yield of 15.03%.

[0803] MS m / z(ESI):442.2[M+1]

[0804] Example 46

[0805] (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

[0806] (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

[0807] first step

[0808] 4-(prop-2-yn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

[0809] 4-(Propan-2-yn-1-yl)-4H-1,2,4-triazole-3-carbonitrile

[0810] 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 sequentially to acetonitrile (3 mL) and allowed to react at room temperature for 4 hours. After completion of the reaction, the organic solvent was removed by distillation under reduced pressure. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 4-(prop-2-yn-1-yl)-4H-1,2,4-triazole-3-carbonitrile 46b (700 mg) in a yield of 99.68%.

[0811] MS m / z(ESI):133.2[M+1]

[0812] Step 2

[0813] 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

[0814] 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

[0815] 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 sequentially to acetone (2 mL) and the reaction was completed after continuous stirring at room temperature for 12 h. 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)pentan-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile 46c (90 mg) in a yield of 66.93%.

[0816] MS m / z(ESI):508.3[M+1]

[0817] Step 3

[0818] (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

[0819] (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

[0820] 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 46c (90 mg, 177.33 μmol) was added to dichloromethane (1.5 mL), followed by the dropwise addition of trifluoroacetic acid (0.5 mL) and continued stirring 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)penta-2,4-diyn-1-yl)-4H-1,2,4-triazole-3-carbonitrile 46 (28.75 mg) in a yield of 28.63%.

[0821] MS m / z(ESI):424.3[M+1]

[0822] Example 47

[0823] (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

[0824] (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

[0825] first step

[0826] 4-(but-3-yn-1-yl)piperazin-2-one

[0827] 4-(But-3-yn-1-yl)piperazin-2-one

[0828] 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 sequentially to acetonitrile (3 mL). The reaction was stirred at room temperature for 12 hours until completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 4-(but-3-yn-1-yl)piperazin-2-one 47b (410 mg) in a 44.95% yield.

[0829] MS m / z(ESI):153.2[M+1]

[0830] Step 2

[0831] 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

[0832] 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

[0833] 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 sequentially to acetone (2 mL). 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)hexane-3,5-diyn-1-yl)piperazin-2-one 47c (40 mg) in a yield of 57.23%.

[0834] MS m / z(ESI):528.3[M+1]

[0835] Step 3

[0836] (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

[0837] (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

[0838] 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 47c (40 mg, 75.81 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 completion of the reaction, 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)hexane-3,5-diyn-1-yl)piperazin-2-one 47 (11.28 mg) in a yield of 25.62%.

[0839] MS m / z(ESI):444.3[M+1]

[0840] Example 48

[0841] (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

[0842] (S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperidine-4-carbonitrile

[0843] first step

[0844] 1-(prop-2-yn-1-yl)piperidine-4-carbonitrile

[0845] 1-(Propan-2-yn-1-yl)piperidine-4-carbonitrile

[0846] Piperidine-4-carbonitrile 48a (500 mg, 4.54 mmol, commercially available), 3-bromoprop-1-yne 24a (593.95 mg, 4.99 mmol), and potassium carbonate (1.25 g, 9.08 mmol) were added sequentially to acetonitrile (3 mL) and allowed to react at room temperature for 16 hours. After completion of the reaction, the organic solvent was removed by distillation under reduced pressure, water (50 mL) was added, and extraction with ethyl acetate (50 mL x 3) was performed. The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 1-(prop-2-yn-1-yl)piperidine-4-carbonitrile 48b (550 mg) in an 81% yield.

[0847] MS m / z(ESI):149.2[M+1]

[0848] Step 2

[0849] 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

[0850] 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

[0851] 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 sequentially to acetone (2 mL) and stirred at room temperature for 12 h until 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-(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 (370 mg) in a yield of 88.90%.

[0852] MS m / z(ESI):524.3[M+1]

[0853] Step 3

[0854] (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

[0855] (S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperidine-4-carbonitrile

[0856] 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 sequentially 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-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperidine-4-carbonitrile 48 (32.11 mg) in a yield of 8.13%.

[0857] MS m / z(ESI):440.3[M+1]

[0858] Example 49

[0859] (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

[0860] (S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperidine-4-carboxamide

[0861] first step

[0862] 1-(prop-2-yn-1-yl)piperidine-4-carboxamide

[0863] 1-(Propan-2-yn-1-yl)piperidine-4-carboxamide

[0864] 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 sequentially to acetonitrile (1 mL). The reaction was stirred at room temperature for 12 hours until completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 1-(prop-2-yn-1-yl)piperidine-4-carboxamide 49b (290 mg) in a 74.54% yield.

[0865] MS m / z(ESI):167.2[M+1]

[0866] Step 2

[0867] 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

[0868] 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

[0869] 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 sequentially to acetone (2 mL) and stirred at room temperature for 12 h, resulting in complete reaction. 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)pentan-2,4-diyn-1-yl)piperidine-4-carboxamide 49c (80 mg) in a yield of 55.75%.

[0870] MS m / z(ESI):542.3[M+1]

[0871] Step 3

[0872] (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

[0873] (S)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperidine-4-carboxamide

[0874] 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 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)-1-(5-(4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)pentan-2,4-diyn-1-yl)piperidine-4-carboxamide 49 (14.32 mg) in a yield of 16.62%.

[0875] MS m / z(ESI):458.3[M+1]

[0876] Example 50

[0877] (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

[0878] (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

[0879] first step

[0880] 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

[0881] 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

[0882] 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 sequentially to acetone (2 mL) and stirred at room temperature for 12 h until the reaction was complete. 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%.

[0883] MS m / z(ESI):571.2[M+1]

[0884] Step 2

[0885] (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

[0886] (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

[0887] Tert-butyl 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)pyrrolidine-1-carboxylate 50b (28 mg, 49.06 μmol) and trifluoroacetic acid (0.3 mL) were added sequentially to dichloromethane (1 mL) and stirred at room temperature for 1 hour. After the reaction was complete, 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%.

[0888] MS m / z(ESI):387.0[M+1]

[0889] Example 51

[0890] (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

[0891] (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

[0892] first step

[0893] 1-methyl-4-(prop-2-yn-1-yl)piperazin-2-one

[0894] 1-Methyl-4-(prop-2-yn-1-yl)piperazin-2-one

[0895] 3-Bromoprop-1-yne 24a (625.31 mg, 5.26 mmol), 1-methylpiperazin-2-one 51a (500 mg, 4.38 mmol, commercially available), and potassium carbonate (1.21 g, 8.76 mmol) were added sequentially to acetonitrile (3 mL). The reaction was stirred at room temperature for 12 hours until completion. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 1-methyl-4-(prop-2-yn-1-yl)piperazin-2-one 51b (430 mg) in a 64.50% yield.

[0896] MS m / z(ESI):153.2[M+1]

[0897] Step 2

[0898] 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

[0899] 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

[0900] 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), and cuprous iodide (15.14 mg, 79.48 μmol) were added sequentially to acetone (2 mL). 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 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)pentan-2,4-diyn-1-yl)piperazin-2-one 51c (70 mg) in a yield of 50.08%.

[0901] MS m / z(ESI):528.3[M+1]

[0902] Step 3

[0903] (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

[0904] (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

[0905] 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)pentan-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)penta-2,4-diyn-1-yl)-1-methylpiperazin-2-one 51 (24.49 mg) in a yield of 31.78%.

[0906] MS m / z(ESI):444.3[M+1]

[0907] Example 52

[0908] (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

[0909] (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

[0910] first step

[0911] 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

[0912] 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

[0913] 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 sequentially to acetone (2 mL) and stirred at room temperature for 12 h until the reaction was complete. 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%.

[0914] MS m / z(ESI):585.3[M+1]

[0915] Step 2

[0916] (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

[0917] (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

[0918] 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 stirred at room temperature for 1 hour. After the reaction was complete, 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-(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%.

[0919] MS m / z(ESI):401.0[M+1]

[0920] Example 53

[0921] (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

[0922] (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

[0923] first step

[0924] 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

[0925] 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

[0926] 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 sequentially to acetone (1 mL) and stirred at room temperature for 12 h, and the reaction was complete. 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%.

[0927] MS m / z(ESI):479.3[M+1]

[0928] Step 2

[0929] (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

[0930] (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

[0931] 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 the dropwise addition of trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 1 hour. After the reaction was complete, 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-(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%.

[0932] MS m / z(ESI):395.2[M+1]

[0933] Example 54

[0934] (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

[0935] (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

[0936] first step

[0937] 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

[0938] 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

[0939] 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 sequentially to acetone (2 mL). After argon replacement three times, the reaction was completed after continuous stirring at room temperature for 12 h. 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%.

[0940] MS m / z(ESI):586.3[M+1]

[0941] Step 2

[0942] (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

[0943] (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

[0944] 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 sequentially to tetrahydrofuran (1.5 mL), 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%.

[0945] MS m / z(ESI):472.2[M+1]

[0946] Step 3

[0947] (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

[0948] (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

[0949] (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 the dropwise addition of trifluoroacetic acid (0.3 mL) and continued stirring at room temperature for 1 hour. After completion of the reaction, the product was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H 2 O, mobile phase B: CH 3 CN) to give (1s,3s)-3-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)but-1,3-diyn-1-yl)cyclobutan-1-ol 54 (21.42 mg) in a yield of 34.61%.

[0950] MS m / z(ESI):388.1[M+1]

[0951] Example 55

[0952] (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

[0953] (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

[0954] first step

[0955] ethyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate

[0956] Ethyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate

[0957] 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 sequentially to toluene (6 mL), and the argon atmosphere was replaced three times. Potassium tert-butoxide (1.12 g, 10.00 mmol) was slowly added, and the mixture was stirred at 25°C for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System B) to afford ethyl 4-(5-bromopyridin-2-yl)-2,4-dioxobutanoate 55c (2.58 g) in an 85.98% yield.

[0958] MS m / z(ESI):299.9[M+1]

[0959] Step 2

[0960] ethyl(E)-4-(5-bromopyridin-2-yl)-2-(hydroxyimino)-4-oxobutanoate

[0961] (E)-4-(5-bromopyridin-2-yl)-2-(hydroxyimino)-4-oxobutanoic acid ethyl ester

[0962] 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 sequentially to ethanol (5 mL), and the argon atmosphere was replaced three times. The reaction mixture was heated to 80°C and stirred for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure to afford ethyl (E)-4-(5-bromopyridin-2-yl)-2-(hydroxyimino)-4-oxobutanoate 55d (1 g) in a 95.24% yield. The crude product was used directly in the next reaction.

[0963] MS m / z(ESI):314.8[M+1]

[0964] Step 3

[0965] ethyl 5-(5-bromopyridin-2-yl)isoxazole-3-carboxylate

[0966] Ethyl 5-(5-bromopyridin-2-yl)isoxazole-3-carboxylate

[0967] Ethyl (E)-4-(5-bromopyridin-2-yl)-2-(hydroxyimino)-4-oxobutanoate 55d (1 g, 3.17 mmol) was added to acetic acid (3 mL), and the argon atmosphere was replaced three times. The mixture was stirred at 100°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford ethyl 5-(5-bromopyridin-2-yl)isoxazole-3-carboxylate 55e (0.5 g) in a 53.03% yield.

[0968] MS m / z(ESI):296.9[M+1]

[0969] Step 4

[0970] (5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanol

[0971] (5-(5-Bromopyridin-2-yl)isoxazol-3-yl)methanol

[0972] Ethyl 5-(5-bromopyridin-2-yl)isoxazole-3-carboxylate 55e (50.00 mg, 168.29 μmol) was added to methanol (0.5 mL), and the argon atmosphere was replaced three times. Sodium borohydride (9.55 mg, 252.44 μmol) was slowly added under ice-water cooling, and the mixture was stirred at 80°C for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford (5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanol 55f (30 mg) in a 69.89% yield.

[0973] MS m / z(ESI):254.9[M+1]

[0974] Step 5

[0975] (5-(5-bromopyridin-2-yl)isoxazol-3-yl)methyl methanesulfonate

[0976] Methyl (5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanesulfonate

[0977] (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 sequentially to dichloromethane (453.65 μL), and the argon atmosphere was replaced three times. Methanesulfonyl chloride (20.21 mg, 176.42 μmol, 13.66 μL) was slowly added dropwise under ice-water cooling, and the mixture was 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), and 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 in a yield of 76.56%.

[0978] MS m / z(ESI):332.8[M+1]

[0979] Step 6

[0980] 5-(5-bromopyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0981] 5-(5-bromopyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0982] 55 g (140.00 mg, 420.22 μmol) of methyl (5-(5-bromopyridin-2-yl)isoxazol-3-yl)methanesulfonate and 1 h (82.47 mg, 420.22 μmol) of 2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole) were added sequentially to N,N-dimethylformamide (1 mL). The argon atmosphere was replaced three times. Sodium hydride (16.40 mg, 630.33 μmol) was slowly added under ice-water cooling, and the mixture was stirred at room temperature for 4 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), and 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 5-(5-bromopyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 55h (156 mg) in a yield of 85.68%.

[0983] MS m / z(ESI):432.9[M+1]

[0984] Step 7

[0985] 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

[0986] 4-(5-(6-(3-((2-((1S)-1-((tetrahydro2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)penta-2,4-diyn-1-yl)morpholine

[0987] 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-(penta-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 sequentially to N,N-dimethylformamide (0.5 mL). After replacing argon three times, the mixture was heated to 75°C and reacted for 8 hours. After the reaction was complete, ethyl acetate (30 mL) and water (15 mL) were added, the organic phase was separated, and 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. 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)penta-2,4-diyn-1-yl)morpholine 55i (15 mg) in a yield of 34.55%.

[0988] MS m / z(ESI):502.3[M+1]

[0989] Step 8

[0990] (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

[0991] (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

[0992] 4-(5-(6-(3-((2-((1S)-1-((tetrahydro2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)pyridin-3-yl)penta-2,4-diyn-1-yl)morpholine 55i (15 mg, 29.91 μmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.1 mL) was added. 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+H2O, mobile phase B: CH3CN) 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%.

[0993] MS m / z(ESI):418.0[M+1]

[0994] Example 56

[0995] (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

[0996] (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

[0997] first step

[0998] 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)isoxazole

[0999] 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)isoxazole

[1000] 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. Ethynyltrimethylsilane 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 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 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).

[1001] MS m / z(ESI):451.2[M+1]

[1002] Step 2

[1003] 5-(5-ethynylpyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H- imidazol-1-yl)methyl)isoxazole

[1004] 5-(5-ethynylpyridin-2-yl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[1005] 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. 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%.

[1006] MS m / z(ESI):379.1[M+1]

[1007] Step 3

[1008] 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

[1009] 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

[1010] 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 To the reaction mixture of the reaction mixture and the organic phase was stirred at room temperature for 16 h, and 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.

[1011] MS m / z(ESI):558.3[M+1]

[1012] Step 4

[1013] (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

[1014] (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

[1015] 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)but-1,3-diyn-1-yl)azetidine-1-carboxylate 56c (117 mg, 209.81 μmol) in dichloromethane (6 mL). The mixture was reacted at room temperature for 40 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm column). ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain (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%.

[1016] MS m / z(ESI):374.2[M+1]

[1017] Example 57

[1018] (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

[1019] (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

[1020] first step

[1021] 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

[1022] 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

[1023] 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 sequentially to acetone (2 mL). The atmosphere was replaced with argon three times and the reaction mixture was stirred 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.

[1024] MS m / z(ESI):587.4[M+1]

[1025] Step 2

[1026] (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

[1027] (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)cyclobutan-1-ol

[1028] To the solution of tetrabutylammonium fluoride (62.56 mg, 239.27 μmol) in tetrahydrofuran (3 mL) was added 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) at room temperature. The mixture was reacted for 1 hour and 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)but-1,3-diyn-1-yl)cyclobutane-1-ol 57b (86 mg), which was used directly in the next step.

[1029] Step 3

[1030] (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

[1031] (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

[1032] 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 allowed to react for 40 minutes. After the reaction was complete, the mixture was concentrated under reduced pressure and the residue was purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm column). ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), 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.

[1033] MS m / z(ESI):389.2[M+1]

[1034] Example 58

[1035] (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

[1036] (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

[1037] first step

[1038] 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

[1039] 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

[1040] 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 To the reaction mixture of 5-[[(tert-butyldimethylsilyl)oxy]cyclobutyl]butane-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) was added successively to acetone (3 mL) and stirred at room temperature for 16 h. After the reaction was complete, the mixture was filtered and concentrated to give 5-(5-((1r,3r)-3-((tert-butyldimethylsilyl)oxy)cyclobutyl)butane-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.

[1041] MS m / z(ESI):587.4[M+1]

[1042] Step 2

[1043] (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

[1044] (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)cyclobutan-1-ol

[1045] Tetrabutylammonium fluoride (71.83 mg, 274.71 μmol) was added to a solution of 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 58a (124 mg, 211.32 μmol) in tetrahydrofuran (2 mL) at room temperature 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)but-1,3-diyn-1-yl)cyclobutane-1-ol 58b (99 mg), which was used directly in the next step.

[1046] MS m / z(ESI):473.4[M+1]

[1047] Step 3

[1048] (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

[1049] (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

[1050] 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). 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 (AKZONOBEL Kromasil column; 250 × 21.2 mm column). ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain (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%.

[1051] MS m / z(ESI):389.1[M+1]

[1052] Example 59

[1053] (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

[1054] (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

[1055] first step

[1056] 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

[1057] 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

[1058] 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) at room temperature and stirred at room temperature for 16 hours. After the reaction was complete, 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), which was used directly in the next step.

[1059] MS m / z(ESI):515.2[M+1]

[1060] Step 2

[1061] (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

[1062] (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

[1063] 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)penta-2,4-diyn-1-yl)piperazin-2-one 59a (95 mg, 184.62 μmol) in dichloromethane (4 mL) at room temperature and 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 (AKZONOBEL Kromasil column; 250×21.2 mm column). ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain (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%.

[1064] MS m / z(ESI):431.2[M+1]

[1065] Example 60

[1066] 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

[1067] 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

[1068] first step

[1069] methyl 2-bromo-2-(4-iodophenyl)acetate

[1070] Methyl 2-bromo-2-(4-iodophenyl)acetate

[1071] Methyl 2-(4-iodophenyl)acetate 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), and carbon tetrachloride (12 mL) were placed in a 20 mL microwave tube, sealed, and heated to 85°C on a heat block for 8 hours. The solid was removed by filtration, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 2-bromo-2-(4-iodophenyl)acetate 60b (1.6 g) in an 82.96% yield.

[1072] 1 H NMR (400MHz, Chloroform-d) δ7.71 (d, J = 8.4Hz, 2H), 7.32–7.27 (m, 2H), 5.28 (s, 1H), 3.79 (s, 3H).

[1073] Step 2

[1074] 3-(4-iodophenyl)piperazin-2-one

[1075] 3-(4-iodophenyl)piperazin-2-one

[1076] At room temperature under 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) and stirred at room temperature for 20 min. Sodium methoxide (234.36 mg, 4.34 mmol) was then added and the temperature was raised to 86°C for 4 hours, followed by overnight stirring at room temperature. The mixture was concentrated under reduced pressure, water (20 mL) was added, and the mixture was extracted with dichloromethane (30 mL). The aqueous phase was adjusted to pH 7.5 with 2M HCl and extracted with dichloromethane (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-(4-iodophenyl)piperazin-2-one 60d (1.03 g) in an 86.44% yield.

[1077] MS m / z(ESI):303.1[M+1]

[1078] Step 3

[1079] 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)piperazin-2-one

[1080] 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)piperazin-2-one

[1081] 3-(4-Iodophenyl)piperazin-2-one 60d (400 mg, 1.32 mmol), 4,5-dibenzyloxy-6-(iodomethyl)pyrimidine 60e (600.93 mg, 1.39 mmol), and potassium carbonate (548.98 mg, 3.97 mmol) were dissolved in acetonitrile (7 mL) and the temperature was raised to 75°C for 3 hours. The reaction was monitored for completion. Water (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The mixture was washed with saturated sodium chloride solution (20 mL). 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 afford 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)piperazin-2-one 60f (600 mg) in a yield of 74.72%.

[1082] MS m / z(ESI):607.1[M+1]

[1083] Step 4

[1084] 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-1-isopropylpiperazin-2-one

[1085] 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-1-isopropylpiperazin-2-one

[1086] 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). The reaction was allowed to proceed at this temperature for 20 minutes. 2-Iodopropane 60 g (42.05 mg, 247.34 μmol, commercially available) was then added and the reaction was allowed to proceed at room temperature for 2 hours. A small amount of water was added to quench the reaction, the product was dissolved in methanol, and purified by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-1-isopropylpiperazine-2-one 60h (40 mg), yield: 37.40%.

[1087] MS m / z(ESI):649.2[M+1]

[1088] Step 5

[1089] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((trimethylsilyl)ethynyl)phenyl)imidazolidin-2-one

[1090] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((trimethylsilyl)ethynyl)phenyl)imidazolidin-2-one

[1091] 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 the reaction was allowed to react at room temperature for 16 hours. After the reaction was complete, water (20 mL) was added and the reaction solution was extracted with ethyl acetate (30 ml x 2). The aqueous layer was separated and the combined organic phases were washed sequentially 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: System A) 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%.

[1092] MS m / z(ESI):605.2[M+1]

[1093] Step 6

[1094] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-ethynylphenyl)-3-isopropylimidazolidin-2-one

[1095] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-ethynylphenyl)-3-isopropylimidazolidin-2-one

[1096] 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, and the mixture was reacted at room temperature for 4 hours. 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 sequentially 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 B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-ethynylphenyl)-3-isopropylimidazolidin-2-one 60j (160 mg) in a yield of 84.11%.

[1097] MS m / z(ESI):533.0[M+1]

[1098] Step 7

[1099] 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

[1100] 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

[1101] 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 complete, 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 sequentially 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%.

[1102] Step 8

[1103] 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

[1104] 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

[1105] 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 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)but-1,3-diyn-1-yl)phenyl)-3-isopropylimidazolidin-2-one 601 (10 mg) in a yield of 47.29%.

[1106] MS m / z(ESI):627.0[M+1]

[1107] Step 9

[1108] 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

[1109] 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

[1110] 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 complete, methanol was added to quench the reaction, and the product 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+H2O, mobile phase B: CH3CN) 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) in a yield of 4.66%.

[1111] MS m / z(ESI):447.2[M+1]

[1112] Examples 61-85 were synthesized according to the synthesis method of Examples 1-60 of the present invention, and their structures and characterization data are shown in the following table:

[1113] Biological evaluation

[1114] Test Example 1: Determination of the Inhibition of LpxC Enzyme Activity by the Compounds of the Invention

[1115] 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 in vitro.

[1116] The experimental procedure is briefly summarized as follows: Test compounds were first dissolved in DMSO to a 10 mM stock solution. Reactions were performed in a 96-well microplate. First, 20 μL of recombinant Pseudomonas aeruginosa LpxC (purchased from Signalway Antibody, Catalog No. AP74647-2) was added to each well to a final concentration of 5 nM. Then, 5 μL of the test compound was added, and the compound was diluted fourfold to eight concentration points, ranging from 0.61 to 10,000 nM. Then, 5 μL of the LpxC substrate UDP-3-O-(R-3-hydroxydecanoyl)-GlcNAc (purchased from Biosynth Carbosynth, Catalog No. mu75071) was added to a final concentration of 10 μM. The cells were incubated at 25°C for 120 minutes. Then, 20 μL of 2.0 mg / mL fluorescamine (purchased from Sigma-Aldrich, product number F9015, solvent is 1:1 dimethylformamide / acetonitrile) was added to the reaction system, mixed, and reacted for 10 minutes; finally, 50 μL of 200 mM sodium phosphate buffer (pH 8.0) was added to terminate the reaction, and the plate was read using a microplate reader (BMG) with excitation and emission wavelengths of 390 and 495 nm, 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 nonlinear regression analysis of the compound concentration-inhibition rate was performed using GraphPad Prism 5 software to obtain the compound's IC 50 The specific values ​​are shown in Table 1 below.

[1117] Table 1 Inhibition results of the compounds of the present invention on LpxC enzymatic activity

[1118] Conclusion: The IC values ​​of the preferred compounds of the present invention for inhibition of recombinant Pseudomonas aeruginosa LpxC enzyme activity are 50 <100nM, has a significant inhibitory effect on LpxC enzyme activity.

[1119] Test Example 2: Evaluation of the antibacterial activity of the compounds of the present invention

[1120] The in vitro minimum inhibitory concentration (MIC) determination was performed according to the CLSI guidelines using the broth microdilution method.

[1121] 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 11 two-fold dilutions of 100× high-concentration working solutions are prepared using DMSO (the final concentration of the system is 64 μg / mL-0.06 μg / mL). The strains (K. Pneumoniae ATCC13883, K. Pneumoniae ATCC51504, and E. coli ATCC 25922) frozen in glycerol at -80°C are inoculated onto solid agar medium and placed in an incubator at 35°C for 18-24 hours to complete the strain preparation. Then, an appropriate amount of the solid plate culture is collected and resuspended in physiological saline, mixed, and the turbidity of the bacterial suspension is adjusted to an appropriate turbidity using a turbidimeter, containing approximately 1×10 8 cfu / mL bacteria, and then dilute the bacterial suspension with the test medium to a bacterial concentration of 5×10 5 cfu / ml to complete the inoculum preparation. 198 μL of the inoculum was inoculated into a 96-well plate, followed by the addition of 2 μL of a 100× high-concentration working solution of the compound. The 96-well plate was then incubated at 35°C for 18–24 hours. After incubation, the test plate was visually inspected. The lowest drug concentration that completely inhibited bacterial growth was the minimum inhibitory concentration (MIC) of the compound, as shown in Table 2.

[1122] Table 2 Antibacterial activity test results of the compounds of the present invention

[1123] 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 E. coli ATCC 25922; they have good inhibitory effects on both K. pneumoniae and E. coli.

[1124] Test Example 3: Pharmacokinetic Study of the Compounds of the Invention in Mice

[1125] 1. Experimental Purpose

[1126] ICR mice were used as test animals, and the pharmacokinetic characteristics of the compounds of the present invention in mice were studied by LC / MS / MS method to determine the drug concentrations in plasma at different times after injection of the compounds of the present invention Examples 33 and 41.

[1127] 2. Experimental plan

[1128] 2.1 Experimental drugs and animals;

[1129] Examples 33 and 41;

[1130] ICR mice, male, 27.8-38 g, were purchased from Weitonglihua Laboratory Animal Technology Co., Ltd.

[1131] 2.2 Drug preparation

[1132] Intravenous injection group: Weigh an appropriate amount of drug and add DMSO:30% HS-15:Saline = 10:10:80 (v / v / v) to prepare a complete solution of appropriate concentration;

[1133] Oral gavage group: weigh an appropriate amount of drug, add DMSO:30% HS-15:Saline=10:10:80 (v / v / v) to prepare a complete solution of appropriate concentration;

[1134] 2.3 Administration

[1135] Thirty-six ICR mice were included in four groups, with nine mice in each group. After overnight fasting, the mice were intravenously injected and orally administered with drugs, and were fed 4 hours after administration.

[1136] The dosage of each compound is as follows:

[1137] 3. Operation

[1138] Blood samples (100 μL) were collected retro-orbitally before dosing and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after dosing. The samples were anticoagulated with EDTA-K2. After collection, the blood samples were placed on ice and centrifuged within 30 minutes to separate plasma (1500 g for 10 minutes). The collected plasma was stored at –40 to –20°C until analysis.

[1139] The levels of the test compounds in mouse plasma after intravenous and oral administration of different compounds were determined by LC-MS / MS.

[1140] 4. Pharmacokinetic parameter results

[1141] The pharmacokinetic parameters of the compounds of the present invention in mice are shown in the table below.

[1142] Note: N / A means no relevant results

[1143] Conclusion: Compounds Examples 33 and 41 of the present invention have good pharmacokinetic absorption, high bioavailability, and good pharmacokinetic properties.

Claims

1. A compound represented by the general formula (AI) or its stereoisomers, tautomers or pharmaceutically acceptable salts: 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- to 6-membered heteroaryl groups; R a are the same or different, each independently selected from hydroxy, cyano, halogen, alkyl or alkoxy; R b are the same or different and are each independently selected from cyano, halogen, hydroxy, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted with one or more substituents selected from hydroxy, cyano, halogen, alkyl or alkoxy; X, Y, Z, 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; R 2 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 C1-C3 alkylene, C2-C3 alkenylene or C2-C4 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 Selected from hydrogen atom, cyano group, halogen, alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group, 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, heterocyclyl, aryl, heteroaryl or fused ring is optionally further substituted by one or more R 3 replaced by; R 3 Each is 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 、-CH2NHC(O)OR 4 、-CH2NR 5 R 6 or -S(O) r R 4 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, 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 、-SO2NR 8 R 9 or -NR 8 C(O)R 9 substituted by a substituent; Or, two R 3 Form a -C(=O)- with the same carbon atom to which it is attached; R 4 Each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, Aryl, =O, -C(O)R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO2NR 8 R 9 or -NR 8 C(O)R 9 substituted by a substituent; R 5 and R 6 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, 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 、-SO2NR 8 R 9 or -NR 8 C(O)R 9 substituted by a substituent; Or, R 5 and R 6 Together with the atoms to which they are attached, they 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)R 7 、-C(O)OR 7 、-OC(O)R 7 、-NR 8 R 9 、-C(O)NR 8 R 9 、-SO2NR 8 R 9 or -NR 8 C(O)R 9 substituted by a substituent; R 7 、R 8 and R 9 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; m is 0, 1, 2, 3 or 4; n is 0, 1, 2, 3 or 4; and r is independently 0, 1 or 2.

2. The compound according to claim 1, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound according to general formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt: in: X, Y, Z, Q, R 1 and L are as defined in claim 1.

3. The compound according to claim 1 or 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound according to general formula (II), or its stereoisomer, tautomer, or pharmaceutically acceptable salt: in: Q is selected from CH or N atoms; R 1 and L are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, which is a compound according to general formula (III), or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof: 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 nitrogen atom; p is selected from 0, 1, 2, 3, 4 or 5; Q is selected from CH or N atoms; R 3 and L are as defined in claim 1.

5. 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 represented by general formula (IV) or (V): in: R 1 and L are as defined in claim 1.

6. 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 Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic group, heteroaryl, fused ring, 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 by one or more R 3 replaced by; R 3 Each is independently selected from halogen, cyano, alkyl, hydroxy, heterocyclic, -C(O)R 4 、-C(O)OR 4 、-NR 5 R 6 or -C(O)NR 5 R 6 wherein the alkyl or heterocyclic group is optionally further substituted by one or more halogen, cyano, amino, hydroxyl, heteroaryl or -C(O)NR 8 R 9 substituted by a substituent; Or, two R 3 Form a -C(=O) with the same carbon atom to which it is attached; 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 a hydroxyl group, a cyano group or an alkoxy group; R 5 and R 6 Each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more selected from hydroxyl, cyano, heteroaryl, -C(O)OR 7 or -C(O)NR 8 R 9 substituted by a substituent; R 7 、R 8 、R 9 are each independently selected from a hydrogen atom or an alkyl group.

7. The compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: L is selected from methylene, ethylene, propylene, vinylidene, ethynylene, propynylene or butynylene; wherein the methylene, ethylene, propylene, vinylidene, ethynylene, propynylene or butynylene is optionally further substituted with one or more halogen, cyano or amino groups.

8. The compound according to claim 7, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L is selected from -CH2-, -(CH2)2-, -(CH2)3-, -CH=CH-, -C≡C-, -CH2C≡C- or -(CH2)2C≡C-.

9. The compound according to any one of claims 1 to 8, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is:

10. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 9, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

11. Use of the compound according to any one of claims 1 to 9, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 10, in the preparation of an LPXC inhibitor.

12. Use of the compound according to any one of claims 1 to 9, or its stereoisomers, tautomers or pharmaceutically acceptable salts 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.

13. The method according to claim 12, wherein the Gram-negative bacteria is selected from the group consisting of 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.

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