Aromatic acetylene derivatives, production methods thereof, and uses thereof

Abstract

The present invention relates to an aromatic acetylenic derivative, a method for producing the same, a pharmaceutical composition containing the same, and a medical use of the aromatic acetylenic derivative or the pharmaceutical composition. Specifically, the present invention relates to an aromatic acetylenic derivative represented by general formula (AI), a method for producing the same and a pharma- ceutical acceptable salt thereof, and their use as a therapeutic agent, particularly as an LPXC inhibitor. However, the definition of each substituent in general formula (AI) is the same as that in the specification. TIFF2024528245000254.tif3684

Description

Technical Field

[0001] Cross-reference This application claims the priority of Chinese patent applications filed with the China National Patent Office on August 5, 2021, with application number 202110893728.1, title of the invention "Aromatic acetylene derivatives and their production methods and uses", and on March 22, 2022, with application number 202210285860.9, title of the invention "Aromatic acetylene derivatives and their production methods and uses", and the entire contents thereof are incorporated herein by reference.

[0002] Technical field The present invention relates to aromatic acetylene derivatives, methods for producing the same, pharmaceutical compositions containing the derivatives, and uses of the aromatic acetylene derivatives or pharmaceutical compositions as therapeutic agents, particularly as LPXC inhibitors.

Background Art

[0003] The development of antibiotics reached its golden age from the 1930s to the 1960s, and since then antibiotic drugs have been widely used around the world. However, the problem of bacterial resistance has also emerged one after another, and resistant bacteria have become a major problem threatening human health. However, for multidrug-resistant Gram-negative bacteria, which are one of the main pathogens of infectious diseases, the lack of drugs clinically used for treatment has become serious, and highly toxic drugs are still being adopted. In recent years, bacterial resistance has always been a focus in the international pharmaceutical industry. However, the progress of research and development has been slow, and there are only a few compounds entering clinical research at home and abroad. Therefore, the discovery of new antibacterial drugs against Gram-negative bacteria has become an important issue that needs to be solved urgently.

[0004] UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LPXC) is Zn 2+It is a dependent metal enzyme and the first rate-limiting enzyme for the synthesis of lipid A, which is an important component of the outer membrane of Gram-negative bacteria and fixes lipopolysaccharide to the outer membrane to maintain the integrity of its own cells. Lipid A also serves as a hydrophobic outer barrier to prevent external factors such as antibiotics from invading the cell and protects the bacteria from infection. Furthermore, lipid A is also an active ingredient of bacterial endotoxin, which can enter the bloodstream through the intestinal mucosa, activate the body's immune response, and may cause severe septic shock, which is also the cause of pathogenic infections caused by Gram-negative bacteria. Therefore, by inhibiting LPXC, the biosynthesis of lipid A in Gram-negative bacteria can be inhibited, and infections caused by Gram-negative bacteria can be effectively controlled.

[0005] Currently, a further understanding of the structure and properties of LPXC is often obtained by the isolation, purification, analysis, and identification of LPXC crystals from Escherichia coli, Pseudomonas aeruginosa, and hyperthermophilic bacteria. LPXC from these three different sources has a very similar structure, all containing two domains, and the active region is located at the boundary of the two domains. Each domain contains an α-helix and a β-sheet incorporating the α-helix, forming a "β-α-α-β" sandwich structure. These two domains have slightly different amino acid sequences but the same spatial structure. Also, each domain has a corresponding insertion region, which is composed of β-sheets and forms different functional regions. Studies have shown that LPXC has high homology with Gram-negative bacteria and does not have a common sequence with various enzyme systems in mammals. From a biological perspective, due to its unique advantages of broad spectrum and low toxicity, targeting and inhibiting LPXC would be an ideal direction for antibacterial drug research.

[0006] Currently, there are no commercially available drugs as LPXC inhibitors. Although some progress has been made in the research and application of LPXC inhibitors, they are still far from meeting people's treatment needs, and there is still a large room for improvement. Therefore, it is necessary to continue the research and development of new LPXC inhibitors.

Summary of the Invention

[0007] In view of the above technical problems, the present invention provides a compound represented by the following general formula (A-I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Chemical formula

[0008] Q is C or N. X, Y, Z, and V are each independently C or N, and X and Y are not N simultaneously, and Z and Y are not N simultaneously. R1 is the same or different and is each independently selected from the group consisting of -G1-R5. G1 is selected from the group consisting of a single bond, -O-, -CH2-, and -C(=O)-. L1 is -(CH2) s -, preferably -CH2-.

[0009] R2 is the same or different and is each independently selected from the group consisting of a hydroxy group, a cyano group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, provided that the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a halogen, a hydroxy group, a cyano group, and an alkoxy group.

[0010] R3 is the same or different and is each independently selected from the group consisting of a hydroxy group, a cyano group, a halogen, an alkyl group, and an alkoxy group. Alternatively, two R3s together with the C atom to which they are attached form -C(=O)-.

[0011] R4 is the same or different and each independently selected from the group consisting of a hydroxy group, a cyano group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, a heteroaryl group, -C(O)R6, -C(O)OR6, -OC(O)R6, -NR7R8, -C(O)NR7R8, -SO2NR7R8 and -NR7C(O)R8, provided that the alkyl group, cycloalkyl group, heterocyclyl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a halogen, a hydroxy group, a cyano group, an alkoxy group, and an amino group.

[0012] R5 is selected from the group consisting of a cyano group, a halogen, an alkyl group, a hydroxy group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -C(O)R6, -C(O)OR6, -OC(O)R6, -NR 12 R 13 、-C(O)NR 12 R 13 、-SO2R6、-SO2NR 12 R 13 and -NR 12 C(O)R 13 selected from the group consisting of, provided that the alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more R A s.

[0013] R Ais selected from the group consisting of halogen, hydroxy group, cyano group, hydroxyalkyl group, alkoxy group, alkyl group, alkenyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -C(O)R6, -C(O)OR6, -OC(O)R6, -NR7R8, -C(O)NR7R8, -SO2NR7R8 and -NR7C(O)R8, provided that the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group are optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy group, cyano group, amino group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -C(O)R6, -C(O)OR6, -OC(O)R6, -NR7R8, -C(O)NR7R8, -SO2NR7R8 and -NR7C(O)R8, or, two Rs A together form -C(O)- with the same carbon atom to which they are attached,

[0014] R6 is selected from the group consisting of a hydrogen atom, alkyl group, cycloalkyl group, heterocyclyl group, aryl group and heteroaryl group, provided that the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxy group, halogen, nitro group, cyano group, alkyl group, alkoxy group, haloalkyl group, haloalkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 , -C(O)NR 10 R 11 , -SO2NR 10 R 11 and -NR 10 C(O)R 11 and is optionally further substituted with one or more substituents selected from the group consisting of,

[0015] R7, R8, R 12 and R 13is independently selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, provided that the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 ,-C(O)NR 10 R 11 ,-SO2R9, -SO2NR 10 R 11 and -NR 10 C(O)R 11 selected from the group consisting of one or more substituents, and

[0016] alternatively, R7 and R8 together with the atoms to which they are attached form a 4- to 8-membered heterocyclyl group, provided that the 4- to 8-membered heterocyclyl group contains one or more of N, O, S or SO2, and the 4- to 8-membered heterocyclyl group is a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 ,-C(O)NR 10 R 11 ,-SO2NR 10 R 11 and -NR 10 C(O)R 11 selected from the group consisting of one or more substituents, and

[0017] alternatively, R 12 and R 13forms a 4- to 8-membered heterocyclyl group together with the atoms to which they are attached, provided that the 4- to 8-membered heterocyclyl group contains one or more of N, O, S or SO2, and the 4- to 8-membered heterocyclyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 and -NR 10 C(O)R 11 and is optionally further substituted with one or more substituents selected from the group consisting of

[0018] R9, R 10 and R 11 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, provided that the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxy group and a carboxylic acid ester group,

[0019] m is 0, 1, 2 or 3, n is 0, 1 or 2, n is preferably 0, p is 0, 1 or 2, s is 1 or 2, q is 1, 2 or 3.

[0020] According to a preferred embodiment of the present invention, the present invention provides a compound represented by the following general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, a compound represented by general formula (A-I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. [Chemical formula] In the formula, ring A is a 5- to 6-membered heteroaryl group or a 5- to 6-membered heterocyclyl group, preferably a 5-membered heteroaryl group or a 5-membered heterocyclyl group. Ring B is a 5- to 10-membered heteroaryl group.

[0021] X and Y are each independently C or N, and X and Y are not N at the same time. R1 is the same or different and is each independently selected from the group consisting of -G1-R5. G1 is selected from the group consisting of a single bond, -CH2- and -C(=O)-. L1 is -(CH2) s -, preferably -CH2-.

[0022] R2 is the same or different and is each independently selected from the group consisting of a hydroxy group, a cyano group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, provided that the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a halogen, a hydroxy group, a cyano group and an alkoxy group.

[0023] R3 is the same or different and is each independently selected from the group consisting of a hydroxy group, a cyano group, a halogen, an alkyl group and an alkoxy group. Alternatively, two R3s together with the C atom to which they are attached form -C(=O)-.

[0024] R4 are the same or different and each independently selected from the group consisting of hydroxy, cyano, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, -C(O)R6, -C(O)OR6, -OC(O)R6, -NR7R8, -C(O)NR7R8, -SON2NR7R8 and -NR7C(O)R8, wherein the alkyl, cycloalkyl, heterocyclyl or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, cyano, alkoxy and amino;

[0025] R5 is a cyano group, a halogen, an alkyl group, a hydroxyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -C(O)R6, -C(O)OR6, -OC(O)R6, -NR 12 R 13 , -C(O)NR 12 R 13 , -SO2NR 12 R 13 and -NR 12 C(O)R 13 wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group is selected from the group consisting of one or more R A and optionally further substituted with

[0026] R Ais selected from the group consisting of halogen, hydroxy, cyano, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -OC(O)R, -NR, -C(O)NR, -SONR and -NRC(O)R, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)R, -C(O)OR, -OC(O)R, -NR, -C(O)NR, -SONR and -NRC(O)R;

[0027] R6 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, provided that the alkyl group, the cycloalkyl group, the heterocyclyl group, the aryl group, or the heteroaryl group is not selected from the group consisting of a hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 , -C(O)NR 10 R 11 , -SO2NR 10 R 11 and -NR 10 C(O)R 11 and optionally further substituted with one or more substituents selected from the group consisting of:

[0028] R7, R8, R 12 and R 13is independently selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, provided that the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 、 -C(O)NR 10 R 11 、 -SO2NR 10 R 11 and -NR 10 C(O)R 11 and is optionally further substituted with one or more substituents selected from the group consisting of

[0029] or R7 and R8 together with the atoms to which they are attached form a 4- to 8-membered heterocyclyl group, provided that the 4- to 8-membered heterocyclyl group contains one or more of N, O, S or SO2, and the 4- to 8-membered heterocyclyl group is a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 、 -C(O)NR 10 R 11 、 -SO2NR 10 R 11 and -NR 10 C(O)R 11 and is optionally further substituted with one or more substituents selected from the group consisting of

[0030] or R 12 and R 13forms a 4- to 8-membered heterocyclyl group together with the atoms to which they are attached, provided that the 4- to 8-membered heterocyclyl group contains one or more of N, O, S or SO2, and the 4- to 8-membered heterocyclyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 and -NR 10 C(O)R 11 and is optionally further substituted with one or more substituents selected from the group consisting of

[0031] R9, R 10 and R 11 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group, provided that the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a carboxy group and a carboxylic acid ester group,

[0032] m is 0, 1, 2 or 3, n is 0, 1 or 2, and n is preferably 0, p is 0, 1 or 2, s is 1 or 2, q is 1, 2 or 3.

[0033] According to a preferred embodiment of the present invention, the present invention provides a compound represented by the following general formula (II-1), (II-2), (II-3), (II-4) or (II-5), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, a compound represented by general formula (A-I), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Chemical formula

[0034] According to a preferred embodiment of the present invention, the present invention provides a compound represented by general formula (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, a compound represented by general formula (A-I), (I) or (II-3), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

Chemical formula

Chemical formula

[0035] R A are the same or different and are each independently selected from the group consisting of a haloalkyl group, a hydroxyalkyl group, an alkoxy group, an alkyl group, an alkenyl group, a hydroxy group, a halogen, a cyano group, -C(O)NH2, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, and a carboxy group, provided that the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with a hydroxy group, a cyano group, a carboxy group, or an ester group. Alternatively, two R Aform -C(O)- with the same carbon atom to which they are attached, and t is 0, 1, 2 or 3,

[0036] Ring A, Ring B, R2 - R4, G1, L1, n, p and q are defined as described in general formula (A - I).

[0037] According to a preferred embodiment of the present invention, the present invention provides a compound represented by general formula (A - I), (I), (II - 1), (II - 2), (II - 3), (II - 4), (II - 5), (III - 1) or (III - 2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Ring A is

Chemical formula

[0038] According to a preferred embodiment of the present invention, the present invention provides a compound represented by general formula (A - I), (I), (II - 1), (II - 2), (II - 3), (II - 4), (II - 5), (III - 1) or (III - 2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Ring B is

Chemical formula

[0039] According to a preferred embodiment of the present invention, the present invention provides a compound represented by general formula (A - I), (I), (II - 1), (II - 2), (II - 3), (II - 4), (II - 5), (III - 1) or (III - 2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Ring C is

Chemical formula

[0040] According to a preferred embodiment of the present invention, the present invention provides a compound represented by general formula (A-I), (I), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein, R4 is selected from the group consisting of an alkyl group, -C(O)R6, -C(O)OR6 and -C(O)NR7R8, provided that the alkyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group and a halogen, R6 is selected from the group consisting of a hydrogen atom, a hydroxy group, an alkyl group and an alkoxy group, R7 and R8 are each independently selected from the group consisting of a hydrogen atom and an alkyl group.

[0041] According to a preferred embodiment of the present invention, the present invention provides a compound represented by general formula (A-I), (I), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R4 is

Chemical formula

[0042] In a preferred embodiment of the present invention, the compound represented by general formula (A-I) is selected from the group consisting of the compounds described in the following table and their stereoisomers, tautomers or pharmaceutically acceptable salts thereof.

Table 1

[0043] Furthermore, the present invention provides a pharmaceutical composition comprising an effective amount of a compound represented by general formula (A-I), (I), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0044] The present invention provides the use of a compound represented by general formula (A-I), (I), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of an LPXC inhibitor.

[0045] The present invention also provides the use of a compound represented by general formula (A-I), (I), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a disease mediated by LPXC. Here, the disease mediated by LPXC is preferably a bacterial infection caused by Gram-negative bacteria. The disease mediated by LPXC is more preferably selected from the group consisting of bacterial infections caused by Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Proteus spp., Shigella dysenteriae, Klebsiella pneumoniae, Brucella spp., Salmonella spp., Acinetobacter spp., Yersinia spp., Legionella pneumophila, Bordetella pertussis, Shigella spp., Pasteurella spp., Vibrio cholerae, Neisseria meningitidis, etc.

[0046] The present invention further provides the use of a compound represented by general formula (A-I), (I), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating a bacterial infection caused by Gram-negative bacteria.

[0047] The present invention provides the use of a compound represented by general formula (A-I), (I), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for bacterial infections caused by Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Proteus spp., Shigella dysenteriae, Klebsiella pneumoniae, Brucella spp., Salmonella spp., Acinetobacter spp., Yersinia spp., Legionella pneumophila, Bordetella pertussis, Shigella spp., Pasteurella spp., Vibrio cholerae, Neisseria meningitidis, etc.

[0048] The present invention also provides a method for treating a disease mediated by LPXC. The method includes administering to a subject in need thereof a compound represented by general formula (A-I), (I), (II-1), (II-2), (II-3), (II-4), (II-5), (III-1) or (III-2), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Preferably, the disease mediated by LPXC is a bacterial infection caused by Gram-negative bacteria. More preferably, the Gram-negative bacteria are selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Proteus spp., Shigella dysenteriae, Klebsiella pneumoniae, Brucella spp., Salmonella spp., Acinetobacter spp., Yersinia spp., Legionella pneumophila, Bordetella pertussis, Shigella spp., Pasteurella spp., Vibrio cholerae, and Neisseria meningitidis. Detailed description of the invention

[0049] Unless otherwise indicated, several terms used in the present invention in the specification and claims are defined as follows.

[0050] The term "alkyl group", when used as a group or part of a group, refers to an aliphatic hydrocarbon group including a straight-chain or branched-chain of C1 to C 20 Preferably, as the alkyl group, it is C1 to C 10is an alkyl group, more preferably a C1-C6 alkyl group or a C1-C4 alkyl group. Examples of the alkyl group include, but are not limited to, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group, s-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-methylbutyl group, 3-methylbutyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, etc. The alkyl group may be substituted or unsubstituted.

[0051] The "alkenyl group" refers to the alkyl group defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond. Representative examples include, but are not limited to, ethenyl group, 1-propenyl group, 2-propenyl group, 1-, 2- or 3-butenyl group, etc. Preferably it is a C2-C4 alkenyl group. The alkenyl group may be optionally substituted or unsubstituted.

[0052] The "cycloalkyl group" refers to non-aromatic cyclic alkyl groups such as monocyclic, polycyclic, fused polycyclic, bridged ring and spiro ring, preferably having a 5-7 membered monocyclic ring or a 7-10 membered bicyclic or tricyclic ring. Examples of the "cycloalkyl group" include, but are not limited to, cyclopropyl group, cyclopentyl group, cyclobutyl group, cyclohexane. The cycloalkyl group may be substituted or unsubstituted. Preferably it is a C3-C7 cycloalkyl group, a C3-C6 cycloalkyl group or a C5-C7 cycloalkyl group.

[0053] The "spirocycloalkyl group" is a fully carbon polycyclic group having 5 to 18 members that contains two or more cyclic structures and shares one carbon atom (referred to as a spiro atom) between monocyclic rings, and may contain one or more double bonds within the rings, but refers to a group having no ring with a completely conjugated π-electron aromatic system. Preferably it is 6 to 14 members, more preferably 7 to 10 members. Based on the number of spiro atoms shared between the rings, the spirocycloalkyl group is classified into monospiro, dispiro, and polyspirocycloalkyl groups, preferably monospiro and dispirocycloalkyl groups, and more preferably 4-member / 5-member, 4-member / 6-member, 5-member / 5-member, or 5-member / 6-member. Non-limiting examples of the "spirocycloalkyl group" include, but are not limited to, spiro[4.5]decyl group, spiro[4.4]nonyl group, spiro[3.5]nonyl group, spiro[2.4]heptyl group.

[0054] The "condensed cycloalkyl group" is a fully carbon polycyclic group having 5 to 18 members that contains two or more cyclic structures and shares a pair of carbon atoms between them, and one or more rings may contain one or more double bonds, but refers to a group having no ring with a completely conjugated π-electron aromatic system. Preferably it is 6 to 12 members, more preferably 7 to 10 members. Based on the number of constituent rings, it is classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, and more preferably a 5-member / 5-member or 5-member / 6-member bicyclic alkyl group. Non-limiting examples of the "condensed cycloalkyl group" include, but are not limited to, dicyclo[3.1.0]hexyl group, dicyclo[3.2.0]hept-1-enyl group, dicyclo[3.2.0]heptyl group, decahydronaphthyl group, and tetradecahydrophenanthrenyl group.

[0055] The "bridged cycloalkyl group" refers to a 5- to 18-membered all-carbon polycyclic group that contains two or more cyclic structures and shares two carbon atoms that are not directly linked to each other, and one or more rings may contain one or more double bonds, but none of the rings have a completely conjugated π-electron aromatic system. Preferably, it is 6 to 12 members, more preferably 7 to 10 members. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Based on the number of constituent rings, it is classified into bicyclic, tricyclic, tetracyclic, and polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of the "bridged cycloalkyl group" include (1s,4s)-dicyclo[2.2.1]heptyl group, dicyclo[3.2.1]octyl group, (1s,5s)-dicyclo[3.3.1]nonyl group, dicyclo[2.2.2]octyl group, (1r,5r)-dicyclo[3.3.2]decyl group, but are not limited thereto.

[0056] The "heterocyclyl group", "heterocycloalkyl group", "heterocyclic ring", and "heterocyclic" can be used interchangeably in this application and refer to a non-aromatic heterocyclyl group in which one or more ring atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and S(O) r (where r is 0, 1 or 2), and includes monocyclic, polycyclic, fused polycyclic, bridged ring and spiro ring. It preferably has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring, and may contain 1, 2 or 3 nitrogen, oxygen and / or sulfur atoms. Examples of the "heterocyclyl group" include morpholinyl group, oxetanyl group, azetidinyl group, thiomorpholinyl group, tetrahydrofuran group, tetrahydropyranyl group, 1,1-dioxo-thiomorpholinyl group, piperidinyl group, 2-oxo-piperidinyl group, pyrrolidinyl group, 2-oxo-pyrrolidinyl group, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl group, piperazinyl group, hexahydropyrimidine, [Chemical formula] but are not limited thereto. The heterocyclic group may be substituted or unsubstituted.

[0057] The "spiroheterocyclic group" is a polycyclic group having 5 to 18 members containing two or more cyclic structures and sharing one atom between monocyclic rings, and one or more double bonds may be contained in the ring, but it refers to a group having no ring with a completely conjugated π-electron aromatic system. One or more of the ring atoms therein are heteroatoms selected from the group consisting of nitrogen, oxygen and S(O) r (where r is 0, 1 or 2), and the other ring atoms are carbon. Preferably, it has 6 to 14 members, more preferably 7 to 10 members. Based on the number of spiro atoms shared between the rings, the spirocycloalkyl group is divided into a monospiroheterocyclic group, a double spiroheterocyclic group and a polyspiroheterocyclic group, and preferably a monospiroheterocyclic group or a double spiroheterocyclic group. More preferably, it is a monospiroheterocyclic group of 4-member / 4-member, 4-member / 5-member, 4-member / 6-member, 5-member / 5-member or 5-member / 6-member. Non-limiting examples of the "spiroheterocyclic group" include, but are not limited to, 1,7-dioxaspiro[4.5]decyl group, 2-oxa-7-azaspiro[4.4]nonyl group, 7-oxaspiro[3.5]nonyl group, 5-oxaspiro[2.4]heptyl group.

[0058] The "fused heterocyclic group" is a polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, and one or more rings may contain one or more double bonds, but it refers to a group having no ring with a completely conjugated π-electron aromatic system. One or more of the ring atoms therein are heteroatoms selected from the group consisting of nitrogen, oxygen and S(O) r(However, r is a heteroatom selected from the group consisting of 0, 1, or 2, and the other ring atoms are carbon. Preferably, it is a 6- to 14-membered ring, more preferably a 7- to 10-membered ring. Based on the number of constituent rings, it is classified into bicyclic, tricyclic, tetracyclic, and polycyclic fused heterocyclyl groups, preferably bicyclic or tricyclic, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl group. Non-limiting examples of the "fused heterocyclyl group" include octahydropyrrolo[3,4-c]pyrrolyl group, octahydro-1H-isoindolyl group, 3-azabicyclo[3.1.0]hexyl group, octahydrobenzene[b][1,4]dioxine, but are not limited thereto.)

[0059] The "bridged heterocyclyl group" is a 5- to 14-membered or 5- to 18-membered polycyclic group containing two or more cyclic structures and sharing two atoms that are not directly connected to each other, and one or more rings may contain one or more double bonds, but it refers to a group having no ring with a completely conjugated π-electron aromatic system. One or more of the ring atoms therein are nitrogen, oxygen, and S(O) r (However, r is a heteroatom selected from the group consisting of 0, 1, or 2, and the other ring atoms are carbon. Preferably, it is a 6- to 14-membered ring, more preferably a 7- to 10-membered ring. Based on the number of constituent rings, it is classified into bicyclic, tricyclic, tetracyclic, and polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of the "bridged heterocyclyl group" include 2-azabicyclo[2.2.1]heptyl group, 2-azabicyclo[2.2.2]octyl group, 2-azabicyclo[3.3.2]decyl group, but are not limited thereto.)

[0060] The "aryl group" refers to a carbocyclic aromatic system containing one or two rings that can be linked by condensation. The term "aryl group" includes monocyclic or bicyclic aryl groups such as phenyl group, naphthyl group, and aromatic groups of tetrahydronaphthyl group. Preferably, the aryl group is C6~C 10is an aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a naphthyl group. The aryl group may be substituted or unsubstituted.

[0061] The "heteroaryl group" refers to an aromatic 5- to 6-membered monocyclic ring or 8- to 10-membered bicyclic ring that may contain 1 to 4 nitrogen, oxygen, and / or sulfur atoms. Preferred heteroaryl groups are C6-C 10 heteroaryl groups containing 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Examples of the "heteroaryl group" include, but are not limited to, furanyl group, pyridyl group, 2-oxo-1,2-dihydropyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, thienyl group, isoxazolyl group, oxazolyl group, oxadiazolyl group, imidazolyl group, pyrrolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, thiazolyl group, isothiazolyl group, 1,2,3-thiadiazolyl group, benzodioxolyl group, benzothienyl group, benzimidazolyl group, indolyl group, isoindolyl group, 1,3-dioxo-isoindolyl group, quinolinyl group, indazolyl group, benzoisothiazolyl group, benzoxazolyl group, benzisoxazolyl group, isothiazolyl group, 1H-1,2,4-triazolyl group, 4H-1,2,4-triazolyl group, pyridyl group, pyrimidinyl group, pyrazin-2(1H)-one group, pyrimidin-4(3H)-one group, pyridazin-3(2H)-one group, 1H-indolyl group, 1H-benzo[d]imidazolyl group, 1H-pyrrolo[2,3-c]pyridyl group, 3H-imidazo[4,5-c]pyridyl group, isoquinolinyl group, quinazolinyl group, 2H-isoindolyl group, furan[3,2-b]pyridyl group, furan[2,3-c]pyridyl group, thieno[2,3-c]pyridyl group, benzofuranyl group, benzo[b]thienyl group, 1H-pyrrolo[3,2-b]pyridyl group, 2H-pyrrolo[3,4-c]pyridyl group. The heteroaryl group may be substituted or unsubstituted.

[0062] "Alkoxy group" refers to a group of (alkyl group - O-). The alkyl group is as defined in this specification. Preferably, it is a C1-C6 or C1-C4 alkoxy group. Examples thereof include, but are not limited to, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, t-butoxy group, etc.

[0063] "Nitro group" refers to a -NO2 group. "Hydroxy group" refers to a -OH group. "Halogen" refers to fluorine, chlorine, bromine and iodine. "Amino group" refers to -NH2. "Cyano group" refers to -CN. "Benzyl group" refers to a -CH2-phenyl group. "Carboxy group" refers to -C(O)OH.

[0064] "Carboxylic acid ester group" refers to a -C(O)O-alkyl group or a -C(O)O-cycloalkyl group. However, the definitions of the alkyl group and the cycloalkyl group are as described above.

[0065] "Hydroxyalkyl group" refers to an alkyl group substituted with a hydroxy group. However, the definition of the alkyl group is as described above.

[0066] "Aminoalkyl group" refers to an alkyl group substituted with an amino group. However, the definition of the alkyl group is as described above.

[0067] "Haloalkyl group" refers to an alkyl group substituted with a halogen. However, the definition of the alkyl group is as described above.

[0068] "Haloalkoxy group" refers to an alkoxy group substituted with a halogen. However, the definition of the alkoxy group is as described above.

[0069] "DMSO" refers to dimethyl sulfoxide. "BOC" refers to the tert-butoxycarbonyl group. "Bn" refers to the benzyl group. "THP" refers to the 2-tetrahydropyranyl group. "TFA" refers to trifluoroacetic acid. "Ts" refers to p-toluenesulfonyl.

[0070] "Leaving group" is an atom or functional group that detaches from a larger molecule in a chemical reaction and 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 atomic group with a pair of electrons cleaved from the substrate molecule is called the leaving group. A group that is prone to accepting electrons and has a high ability to accept a negative charge is a good leaving group. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to detach from other molecules. The reason is that the smaller the pKa of the conjugate acid, the less the corresponding leaving group needs to bind to other atoms, and the tendency to exist as an anion (or an electrically neutral leaving group) increases. Common leaving groups include, but are not limited to, halogen, methanesulfonyl group, -OTs, and -OH.

[0071] "Substituted" means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are each independently substituted with the corresponding number of substituents. Needless to say, the substituents are only at their possible chemical positions, and whether the substitution is possible or not can be determined (by experiment or theory) by those skilled in the art without undue effort. For example, an amino group or a hydroxy group having free hydrogen may become unstable when bonded to a carbon atom having an unsaturated (e.g., olefinic) bond.

[0072] As used herein, "substituted" or "substitution", unless otherwise specified, means that a group can be substituted with one or more groups selected from the group consisting of an alkyl group, an alkoxy group, an alkylthio group, an alkylamino group, a halogen, a mercapto group, a hydroxy group, a nitro group, a cyano group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, a cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, an amino group, a haloalkyl group, a hydroxyalkyl group, a carboxy group, a carboxylic acid ester group, -C(O)R6, -C(O)OR6, -OC(O)R6, -NR7R8, -C(O)NR7R8, -SO2NR7R8, -SO2R6, -NR7C(O)R8, -NR 12 R 13 ,-C(O)NR 12 R 13 ,-SO2NR 12 R 13 and -NR 12 C(O)R 13 selected from the group consisting of one or more groups.

[0073] R6 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. However, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 ,-C(O)NR 10 R 11 ,-SO2NR 10 R 11 and -NR 10 C(O)R 11 optionally further substituted with one or more substituents selected from the group consisting of.

[0074] R7, R8, R 12 and R 13is independently selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group. However, the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 ,-C(O)NR 10 R 11 , -SO2R9, -SO2NR 10 R 11 and -NR 10 C(O)R 11 optionally further substituted with one or more substituents selected from the group consisting of.

[0075] Alternatively, R 7 and R 8 together with the atoms to which they are attached form a 4- to 8-membered heterocyclyl group. However, the 4- to 8-membered heterocyclyl group contains one or more of N, O, S, or SO2, and the 4- to 8-membered heterocyclyl group is a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 , -C(O)NR 10 R 11 , -SO2NR 10 R 11 and -NR 10 C(O)R 11 optionally further substituted with one or more substituents selected from the group consisting of.

[0076] Alternatively, R 12 and R 13Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclyl group. However, the 4- to 8-membered heterocyclyl group contains one or more of N, O, S or SO2, and the 4- to 8-membered heterocyclyl group is a hydroxy group, halogen, nitro group, cyano group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, =O, -C(O)R9, -C(O)OR9, -OC(O)R9, -NR 10 R 11 , -C(O)NR 10 R 11 , -SO2NR 10 R 11 and -NR 10 C(O)R 11 optionally further substituted with one or more substituents selected from the group consisting of.

[0077] R9, R 10 and R 11 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclyl group, an aryl group and a heteroaryl group. However, the alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, halogen, nitro group, amino group, cyano group, alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, carboxy group and carboxylic acid ester group.

[0078] "Pharmaceutically acceptable salts" refers to specific salts suitable for pharmaceutical use while retaining the original biological activity of the above compounds. The pharmaceutically acceptable salts of the compounds represented by the general formula (A-I) may be metal salts or amine salts formed with appropriate acids.

[0079] The term "pharmaceutical composition" means a mixture of one or more compounds described in this specification or their physiologically and pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as a physiologically and pharmaceutically acceptable carrier. The pharmaceutical composition is intended to facilitate administration to a living body and to promote the absorption of the active ingredient and thus the exertion of biological activity. Synthesis method of the compound according to the present invention

[0080] To achieve the object of the present invention, the present invention adopts the following technical solutions.

[0081] The present invention provides a method for producing a compound represented by the general formula (A-I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, which comprises any of the following methods.

[0082] Method 1:

Chemical formula

[0083] Method 2:

Chemical formula

[0084] Method Three:

Chemical Formula

Brief Description of the Drawings

[0085]

Figure 1

Figure 2

Modes for Carrying Out the Invention

[0086] Hereinafter, the present invention will be further described in conjunction with examples, but these examples do not limit the scope of the present invention.

Examples

[0087] In the examples, the production of representative compounds represented by the formula (A-I) and related structure identification data are described. Note that the following examples do not limit the present invention, but are used to explain the present invention. 11H NMR spectra were measured on a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane was used as an internal standard (0.00 ppm). 1 1H NMR display method: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad, dd = doublet of doublets, dt = doublet of triplets. When coupling constants are provided, their units are Hz.

[0088] Mass spectra were measured on an LC / MS instrument, and the ionization mode was ESI or APCI.

[0089] For silica gel plates for thin-layer chromatography, Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates were used. The specification of the silica gel plates used for thin-layer chromatography (TLC) was 0.15 mm - 0.2 mm, and the specification of the thin-layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0090] For column chromatography, generally, silica gel with a mesh size of 200 - 300 from Yantai Huanghai was used as the carrier.

[0091] In the following examples, unless otherwise specified, all temperatures are in degrees Celsius. Unless otherwise specified, various starting materials and reagents are either commercially available or synthesized according to known methods. Commercially available raw materials and reagents were used as they were without further purification. Unless otherwise specified, commercially available manufacturers include, but are not limited to, Aldrich Chemical Company, ABCR GmbH & Co.KG, Across Organics, Guangzan Chemical Industry Technology Co., Ltd., and Jingyan Chemical Industry Technology Co., Ltd.

[0092] CD3OD: Deuterated methanol. CDCl3: Deuterated chloroform. DMSO-d6: Deuterated dimethyl sulfoxide.

[0093] An argon atmosphere means that the flask is connected to an argon gas balloon of about 1 L.

[0094] Unless otherwise specified, in the examples, the reaction solution refers to an aqueous solution.

[0095] The compound was purified by silica gel column chromatography eluent system or thin layer chromatography, selecting eluent system A of petroleum ether and ethyl acetate, eluent system B of dichloromethane and methanol, or eluent system C of dichloromethane and ethyl acetate as the eluent system. However, the volume ratio of the solvents in the eluent system varies depending on the polarity of the compound, and a small amount of an acidic reagent such as acetic acid or a basic reagent such as triethylamine may be added for adjustment. Example 1

[0096] (S)-1-(1-((2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)oxazol-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0097] Step 1 (4-Iodobenzoyl)serine methyl ester

[0098] Serine methyl ester hydrochloride 1b (10.6 g, 68.13 mmol) and triethylamine (34.47 g, 340.66 mmol) were added to dichloromethane (230 mL), and 4-iodobenzoyl chloride 1a (19.97 g, 74.95 mmol) was added at 0 °C. The temperature was raised to room temperature and the reaction was carried out for 3 hours. Water was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 2). The aqueous layer was separated and discarded. The combined organic phases were successively washed with an aqueous sodium bicarbonate solution and a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (4-iodobenzoyl)serine methyl ester 1c (14 g) in a yield of 58.86%.

[0099] MS m / z(ESI): 350.0 [M+1]

[0100] Step 2 Methyl 2-(4-iodophenyl)-4,5-dihydrooxazole-4-carboxylate

[0101] (4-Iodobenzoyl)serine methyl ester 1c (7 g, 20.05 mmol) and triethylammonium (methoxycarbonylsulfamoyl)hydroxide (5.26 g, 22.06 mmol) were added to tetrahydrofuran (65 mL), and the mixture was heated until refluxing and reacted for 5 hours. After completion of the reaction, the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 2-(4-iodophenyl)-4,5-dihydrooxazole-4-carboxylate 1d (5.75 g) in a yield of 86.61%.

[0102] MS m / z(ESI): 332.0 [M+1]

[0103] Step 3 Methyl 2-(4-iodophenyl)oxazole-4-carboxylate

[0104] Methyl 2-(4-iodophenyl)-4,5-dihydrooxazole-4-carboxylate 1d (2 g, 6.04 mmol), 70% aqueous tert-butyl hydroperoxide (2.33 g, 18.12 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (1.84 g, 12.08 mmol) and iodine (153.30 mg, 604.04 μmol) were added to tetrahydrofuran (50 mL), heated to 60 °C and reacted for 4 hours. An aqueous sodium thiosulfate solution was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The aqueous layer was separated and discarded. The combined organic phases were successively washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 2-(4-iodophenyl)oxazole-4-carboxylate 1e (550 mg) in a yield of 27.67%.

[0105] MS m / z(ESI):330.0 [M+1]

[0106] Step 4 (2-(4-Iodophenyl)oxazol-4-yl)methanol

[0107] Methyl 2-(4-iodophenyl)oxazole-4-carboxylate 1e (850 mg, 2.58 mmol) was added to tetrahydrofuran (15 mL), and diisobutylaluminum hydride (1.0 M, 7.75 mL) was added dropwise at 0 °C. The reaction was continued at 0 °C for 2 hours. An aqueous potassium sodium tartrate solution was added, ethyl acetate was added, and the mixture was vigorously stirred at room temperature for 3 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2). The aqueous layer was separated and discarded. The combined organic phases were successively washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system A) to obtain (2-(4-iodophenyl)oxazol-4-yl)methanol 1f (650 mg) in a yield of 83.58%.

[0108] MS m / z(ESI):302.0 [M+1] 1 1H NMR (400 MHz, Chloroform-d) δ 7.75 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.5 Hz, 2H), 7.59 (s, 1H), 4.62 (s, 2H).

[0109] Step 5 4-(Chloromethyl)-2-(4-iodophenyl)oxazole

[0110] At 0 °C, (2-(4-iodophenyl)oxazol-4-yl)methanol 1f (660 mg, 2.19 mmol) was added to dichloromethane (10 mL), triethylamine (332.73 mg, 3.29 mmol, 457.05 μL) was added, and then methanesulfonyl chloride (251.11 mg, 2.19 mmol) was slowly added dropwise, and the reaction was carried out overnight at room temperature. After completion of the reaction, extraction was performed with dichloromethane, and concentration was carried out under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: System A) to obtain 4-(chloromethyl)-2-(4-iodophenyl)oxazole 1g (330 mg) in a yield of 47.11%.

[0111] MS m / z (ESI): 319.8 [M+1]

[0112] Step 6 2-(4-Iodophenyl)-4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazole

[0113] 2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole 1h (61.42 mg, 312.96 μmol, prepared by the inventors themselves according to JP-A WO2018216822) was added to acetonitrile (10 mL), and then cesium carbonate (611.82 mg, 1.88 mmol) and 4-(chloromethyl)-2-(4-iodophenyl)oxazole 1g (100 mg, 312.96 μmol) were added. The mixture was heated to 100 °C and reacted for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated and discarded, the combined organic phases were successively washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System A) to obtain 2-(4-iodophenyl)-4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazole 1i (140 mg) in a yield of 93.2%.

[0114] MS m / z(ESI):480.1 [M+1] 1 H NMR(400 MHz, Chloroform-d) δ7.74(dd,J= 8.6,2.0 Hz,2H),7.66(dd,J= 8.5,1.7 Hz,2H),7.44(d,J=37.7 Hz,1H),7.01(d,J=1.3 Hz,2H), 5.06-5.37(m,3H),4.36-4.73(m,1H),3.71-3.90(m,1H),3.42(tdd,J=15.4,6.6,3.1 Hz,1H),1.68-1.89(m,2H),1.59(dd,J=6.7, 5.1 Hz,3H),1.36-1.50(m,4H).

[0115] Step 7 4-(4-((4-(4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)morpholine

[0116] At room temperature, 2-(4-iodophenyl)-4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazole 1i (75 mg, 156.47 μmol), 4-(4-ethynylbenzyl)morpholine 1j (31.49 mg, 156.47 μmol, prepared by the inventors themselves according to JP-A WO2018208987), bis(triphenylphosphine)palladium(II) dichloride (4.39 mg, 6.26 μmol), tetrabutylammonium bromide (50.44 mg, 156.47 μmol) and piperidine (39.97 mg, 469.42 μmol) were added to 1.5 mL of water. The mixture was heated to 70 °C and reacted for 14 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated and discarded, the combined organic phases were successively washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to obtain 4-(4-((4-(4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)morpholine 1k (66 mg) in a yield of 76.32%.

[0117] MS m / z (ESI): 553.3 [M+1]

[0118] Step 8 (S)-1-(1-((2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)oxazol-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0119] 4-(4-((4-(4-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)morpholine 1k (66 mg, 119.42 μmol) and trifluoroacetic acid (0.1 mL) were added to dichloromethane (2 mL), and the mixture was reacted at room temperature for 30 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), and (S)-1-(1-((2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)oxazol-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 1 (10 mg) was obtained in a yield of 12.85%.

[0120] MS m / z(ESI): 469.2 [M+1] 1 H NMR(400 MHz, DMSO-d6) δ 8.39(s,1H), 8.00(d,J = 8.1 Hz,2H),7.71(dd,J = 16.6, 8.1 Hz, 5H),7.64(s,1H),7.56(d,J = 7.9 Hz,2H),6.33 - 6.43(m,1H), 5.76(s,2H), 5.49(s,2H), 5.35(dd,J = 14.5,6.6 Hz,1H),3.14(d,J = 19.2 Hz,4H),2.42(m,4H),1.56(d,J = 6.6 Hz,3H). Example 2

[0121] (S)-1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0122] Step 1 Ethyl 4-(4-iodophenyl)-2,4-dioxobutyrate

[0123] Sodium hydride (1.63 g, 40.64 mmol, purity 60%) was added to toluene (20 mL), 1-(4-iodophenyl)ethan-1-one 2a (5 g, 20.32 mmol) was added, and the mixture was heated to 50 °C. A toluene solution of diethyl oxalate 2b (4.45 g, 30.48 mmol) was added dropwise, and the mixture was heated at 50 °C and reacted for 2 hours. After cooling, it was poured into ice water, adjusted to acidic with 1 M hydrochloric acid, extracted with ethyl acetate (100 mL × 2), the combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System A) to obtain ethyl 4-(4-iodophenyl)-2,4-dioxobutyrate 2c (2.8 g) in a yield of 39.81%.

[0124] MS m / z (ESI): 347.0 [M+1]

[0125] Step 2 Ethyl 5-(4-iodophenyl)isoxazole-3-carboxylate

[0126] Ethyl 4-(4-iodophenyl)-2,4-dioxobutyrate 2c (2.8 g, 8.09 mmol) and hydroxylamine hydrochloride (1.69 g, 24.27 mmol) were added to ethanol (25 mL), and the mixture was heated under reflux for 1 hour. After completion of the reaction, it was concentrated under reduced pressure, ethyl acetate (100 mL) was added to dissolve it, the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System A) to obtain ethyl 5-(4-iodophenyl)isoxazole-3-carboxylate 2d (2.3 g) in a yield of 82.86%.

[0127] MS m / z (ESI): 343.8 [M+1]

[0128] Step 3 (5-(4-Iodophenyl)isoxazol-3-yl)methanol

[0129] Ethyl 5-(4-iodophenyl)isoxazole-3-carboxylate 2d (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 carried out 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 × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and (5-(4-iodophenyl)isoxazol-3-yl)methanol 2e (0.36 g) was obtained in a yield of 34.19%.

[0130] MS m / z(ESI): 302.0 [M+1]

[0131] Step 4 (5-(4-Iodophenyl)isoxazol-3-yl)methyl methanesulfonate

[0132] (5-(4-Iodophenyl)isoxazol-3-yl)methanol 2e (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 (205.45 mg, 1.79 mmol) was added dropwise. The temperature was raised to room temperature and the reaction was carried out for 4 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to give (5-(4-iodophenyl)isoxazol-3-yl)methyl methanesulfonate 2f (0.45 g) in a yield of 99.26%.

[0133] MS m / z(ESI): 379.8 [M+1]

[0134] Step 5 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0135] 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, and sodium hydride (50.96 mg, 764.35 μmol, purity 60%) was added portionwise in several times. The temperature was raised to room temperature and reacted for 1 hour. Methyl (5-(4-iodophenyl)isoxazol-3-yl)methanesulfonate 2f (193.21 mg, 509.57 μmol) was added, and the reaction was continued at room temperature for 4 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated under reduced pressure. The obtained 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 2g (0.12 g) in a yield of 49.13%.

[0136] MS m / z (ESI): 480.1 [M+1]

[0137] Step 6 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine

[0138] 4-(4-Ethynylbenzyl)morpholine 1j (60 mg, 298.12 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (142.89 mg, 298.12 μmol), triethylamine (90.50 mg, 894.35 μmol), bis(triphenylphosphine)palladium(II) dichloride (68.86 mg, 59.62 μmol), and cuprous iodide (11.39 mg, 59.62 μmol) were added to N,N-dimethylformamide (2 mL), purged with argon, and reacted at room temperature for 3 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine 2h (75 mg) in a yield of 45.52%.

[0139] MS m / z(ESI):553.3 [M+1]

[0140] Step 7 (S)-1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0141] 4-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine 2h (70 mg, 126.66 μmol) was dissolved in dioxane (2 mL), 1 mL of 4M hydrochloric acid dioxane solution was added, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 2 (5 mg) in a yield of 6.16%.

[0142] MS m / z(ESI): 469.0 [M+1] Example 3

[0143] (S)-1-(1-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-5-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0144] Step 1 (E)-4-Iodobenzaldoxime

[0145] Hydroxylamine hydrochloride (5.99 g, 86.20 mmol), potassium carbonate (11.9 g, 86.20 mmol), 4-iodobenzaldehyde 3a (10 g, 43.10 mmol) and water (80 mL) were sequentially added to ethanol (80 mL), and the mixture was reacted overnight at room temperature. After completion of the reaction, the mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain (E)-4-iodobenzaldehyde oxime 3b (8 g) in a yield of 75.14%.

[0146] MS m / z(ESI):247.8 [M+1]

[0147] Step 2 5-(Bromomethyl)-3-(4-iodophenyl)isoxazole

[0148] (E)-4-iodobenzaldehyde oxime 3b (0.5 g, 2.02 mmol), 3-bromoprop-1-yne 3c (288.93 mg, 2.43 mmol) and triethylamine (204.81 mg, 2.02 mmol, 0.3 mL) were dissolved in dichloromethane (6 mL), and a sodium hypochlorite solution (7.5 mL) was slowly added dropwise under an ice bath, followed by stirring at room temperature for 12 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-(bromomethyl)-3-(4-iodophenyl)isoxazole 3d (220 mg) in a yield of 29.86%.

[0149] MS m / z(ESI):363.7 [M+1]

[0150] Step 3 3-(4-Iodophenyl)-5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0151] 2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole 1h (120 mg, 611.48 μmol), potassium carbonate (211.28 mg, 1.53 mmol), and 5-(bromomethyl)-3-(4-iodophenyl)isoxazole 3d (222.56 mg, 611.48 μmol) were added to acetonitrile (3 mL), the temperature was raised to 70 °C, and the mixture was reacted for 7 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 3-(4-iodophenyl)-5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 3e (0.2 g) in a yield of 68.24%.

[0152] MS m / z(ESI):480.1 [M+1]

[0153] Step 4 4-(4-((4-(5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine

[0154] 4-(4-Ethynylbenzyl)morpholine 1j (80 mg, 397.49 μmol), 3-(4-iodophenyl)-5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 3e (0.2 g, 417.27 μmol), triethylamine (120.67 mg, 1.19 mmol), bis(triphenylphosphine)palladium(II) dichloride (91.82 mg, 79.50 μmol), and cuprous iodide (15.18 mg, 79.50 μmol) were sequentially added to N,N-dimethylformamide (2 mL). After performing argon substitution three times, the reaction was carried out overnight at room temperature. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 4-(4-((4-(5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine 3f (60 mg) in a yield of 27.31%.

[0155] MS m / z(ESI):553.3 [M+1]

[0156] Step 5 (S)-1-(1-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-5-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0157] 4-(4-((4-(5-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine 3f (60 mg, 108.57 μmol) was dissolved in dioxane (2 mL), 0.5 mL of 4 M hydrochloric acid dioxane solution was added, and the mixture was reacted for 4 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-5-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 3 (15 mg) in a yield of 23.18%.

[0158] MS m / z(ESI): 469.0 [M+1] Example 4

[0159] (S)-1-(1-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chem.

Chem.

[0160] Step 1 1-Allyl-2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole

[0161] 2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole 1h (300 mg, 1.53 mmol) was added to tetrahydrofuran (5 mL), cooled to 0 °C, sodium hydride (67.26 mg, 1.68 mmol) was added in several portions, reacted at room temperature for 1 hour, 3-bromoprop-1-ene (203.43 mg, 1.68 mmol) was added, and reacted at room temperature for 4 hours. After completion of the reaction, water was added to quench the reaction, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, concentrated under reduced pressure, and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 1-allyl-2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole 4a (0.25 g) in a yield of 69.21%.

[0162] MS m / z(ESI): 237.1 [M+1]

[0163] Step 2 (Z)-N-Hydroxy-4-iodobenzimidoyl chloride

[0164] (E)-4-Iodobenzaldoxime 3b (200 mg, 809.61 μmol) was dissolved in N,N-dimethylformamide (2 mL), chlorosuccinimide (118.92 mg, 890.57 μmol) was slowly added, and stirred at room temperature overnight. After completion of the reaction, (Z)-N-hydroxy-4-iodobenzimidoyl chloride 4b was obtained and used directly in the next reaction without purification of the reaction solution.

[0165] Step 3 3-(4-Iodophenyl)-5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydroisoxazole

[0166] 1-Allyl-2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole 4a (167.91 mg, 710.54 μmol) and triethylamine (143.80 mg, 1.42 mmol, 0.2 mL) were sequentially added to N,N-dimethylformamide (4 mL), and the above reaction solution of (Z)-N-hydroxy-4-iodobenzimidoyl chloride 4b was added dropwise, and the reaction was carried out at room temperature for 4 hours. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: System A) to obtain 3-(4-iodophenyl)-5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydroisoxazole 4c (120 mg) in a yield of 35.09%.

[0167] MS m / z (ESI): 481.8 [M+1]

[0168] Step 4 4-(4-((4-(5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine

[0169] 4-(4-Ethynylbenzyl)morpholine 1j (50 mg, 248.43 μmol), 3-(4-iodophenyl)-5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydroisoxazole 4c (120 mg, 249.31 μmol), triethylamine (75.42 mg, 745.29 μmol), bis(triphenylphosphine)palladium(II) dichloride (57.39 mg, 49.69 μmol), and cuprous iodide (9.49 mg, 49.69 μmol) were successively added to N,N-dimethylformamide (1 mL). The mixture was purged with argon three times and reacted overnight at room temperature. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 4-(4-((4-(5-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine 4d (30 mg) in a yield of 21.77%.

[0170] MS m / z(ESI):555.0 [M+1]

[0171] Step 5 (S)-1-(1-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0172] 4-(4-((4-(5-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine 4d (30 mg, 54.09 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (6.17 mg, 54.09 μmol, 0.3 mL) was added, and the mixture was reacted at room temperature for 4 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 4 (10 mg) in a yield of 26.88%.

[0173] MS m / z(ESI):471.0 [M+1] Example 5

[0174] (S)-1-(1-((5-(4-((4-morpholinophenyl))ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0175] Step 1 4-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)morpholine

[0176] 4-(4-Ethynylphenyl)morpholine 5a (10 mg, 53.41 μmol), 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (25.60 mg, 53.41 μmol), cuprous iodide (1.02 mg, 5.34 μmol), bis(triphenylphosphine)palladium(II) dichloride (6.17 mg, 5.34 μmol) and triethylamine (16.21 mg, 160.22 μmol) were sequentially added to N,N-dimethylformamide (1 mL). The mixture was purged with argon three times and stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered under reduced pressure, and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)morpholine 5b (15 mg) in a yield of 52.14%.

[0177] MS m / z(ESI):539.0 [M+1]

[0178] Step 2 (S)-1-(1-((5-(4-((4-Morpholinophenyl))ethynyl)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)ethynyl)phenyl)morpholine 5b (10 mg, 18.57 μmol) was added to a mixed solution of dichloromethane (4 mL) and trifluoroacetic acid (1 mL), and stirring was continued at room temperature for 3 hours. It was filtered under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-morpholinophenyl))ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 5 (4.4 mg) in a yield of 39.6%.

[0180] MS m / z(ESI): 455.0 [M+1] Example 6

[0181] (S)-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)(morpholino)methanone

Chemical formula

Chemical formula

[0182] Step 1 Morpholino(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanone

[0183] (4-Ethynylphenyl)(morpholino)methanone 6a (85.56 mg, 397.49 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (190.52 mg, 397.49 μmol), triethylamine (120.67 mg, 1.19 mmol), bis(triphenylphosphine)palladium(II) dichloride (91.82 mg, 79.50 μmol) and cuprous iodide (15.18 mg, 79.50 μmol) were dissolved in N,N-dimethylformamide (2.5 mL). After performing three argon replacements, the reaction was carried out overnight at room temperature. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain morpholino(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanone 6b (100 mg) in a yield of 44.4%.

[0184] MS m / z(ESI):567.3 [M+1]

[0185] Step 2 (S)-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)(morpholino)methanone

[0186] Morpholino(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanone 6b (100 mg, 176.48 μmol) was dissolved in dioxane (2 mL), and 0.5 mL of 4 M hydrochloric acid dioxane solution was slowly added, and the reaction was carried out at room temperature for 4 hours. After the reaction was completed, it was filtered under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)(morpholino)methanone 6 (15 mg) in a yield of 13.81%.

[0187] MS m / z(ESI):483.2 [M+1] Example 7

[0188] (S)-1-(1-((5-(4-(phenylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0189] Step 1 5-(4-(phenylethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0190] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (234.65 mg, 489.56 μmol), phenylacetylene 7a (50 mg, 489.56 μmol), allylpalladium(II) chloride dimer (17.91 mg, 48.96 μmol), tri-tert-butylphosphine (99.05 mg, 48.96 μmol, purity 10%) and triethylenediamine (164.74 mg, 1.47 mmol) were sequentially added to acetonitrile (4 mL). The mixture was purged with argon three times and stirred at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: B system) to obtain 5-(4-(phenylethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 7b (100 mg) in a yield of 45.04%.

[0191] MS m / z (ESI): 454.2 [M+1]

[0192] Step 2 (S)-1-(1-((5-(4-(phenylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0193] 5-(4-(phenylethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 7b (100 mg, 220.49 μmol) was successively added to a mixed solvent of dichloromethane (3 mL) and trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 3 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-(phenylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 7 (70 mg) in a yield of 62.91%.

[0194] MS m / z(ESI): 370.1 [M+1] 1 H NMR(400 MHz, DMSO-d6) δ7.92(d,J=8.4 Hz,2H), 7.77(d,J=1.6 Hz,1H), 7.73(d,J=8.4 Hz,2H), 7.67(d,J=1.6 Hz,1H), 7.61 -7.57(m,2H), 7.50 -7.42(m,3H), 7.19(s,1H), 6.39(br,1H), 5.72(s,2H), 5.24(q,J=6.8 Hz,1H), 1.50(d,J=6.4 Hz,3H). Example 8

[0195] (S)-1-(1-((5-(4-((3-(2-methoxyethoxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0196] Step 1 1-Ethynyl-3-(2-methoxyethoxy)benzene

[0197] 3-Ethynylphenol 8a (500 mg, 4.23 mmol), 1-bromo-2-methoxyethane 8b (705.94 mg, 5.08 mmol), and potassium carbonate (701.95 mg, 5.08 mmol) were sequentially added to acetone (2 mL). The mixture was purged with argon and subjected to microwave reaction. It was heated to 110 °C and reacted for 2 hours. After completion of the reaction, water (20 mL) was added to quench the reaction. The mixture was extracted with dichloromethane (10 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-ethynyl-3-(2-methoxyethoxy)benzene 8c (380 mg) in a yield of 50.95%.

[0198] MS m / z (ESI): 177.0 [M+1]

[0199] Step 2 5-(4-((3-(2-Methoxyethoxy)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0200] 1-Ethynyl-3-(2-methoxyethoxy)benzene 8c (50 mg, 283.75 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (136.00 mg, 283.75 μmol), cuprous iodide (5.42 mg, 28.38 μmol), bis(triphenylphosphine)palladium(II) dichloride (32.77 mg, 28.38 μmol) and triethylamine (143.56 mg, 1.42 mmol) were sequentially added to N,N-dimethylformamide (2 mL), and argon substitution was carried out 3 times. The mixture was stirred at room temperature for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to obtain 5-(4-((3-(2-methoxyethoxy)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 8d (30 mg) in a yield of 20.04%.

[0201] MS m / z(ESI):527.9 [M+1]

[0202] Step 3 (S)-1-(1-((5-(4-((3-(2-methoxyethoxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0203] 5-(4-((3-(2-Methoxyethoxy)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 8d (60 mg, 113.72 μmol) and trifluoroacetic acid (12.97 mg, 113.72 μmol, 0.5 mL) were sequentially added to dichloromethane (1 mL), and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((3-(2-methoxyethoxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 8 (3.8 mg, 6.13 μmol) in a yield of 5.39%.

[0204] MS m / z(ESI): 444.2 [M+1] Example 9

[0205] (S)-1-(1-((5-(4-(Pyridin-3-ylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0206] Step 1 5-(4-(Pyridin-3-ylethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0207] 3-Ethynylpyridine 9a (20 mg, 193.95 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2 g (92.96 mg, 193.95 μmol), allylpalladium(II) chloride dimer (7.08 mg, 19.39 μmol), triethylenediamine (43.51 mg, 387.89 μmol) and tri-tert-butylphosphine (3.92 mg, 19.39 μmol, 10% toluene solution) were sequentially added to acetonitrile (2 mL). After three argon purges, the reaction was carried out at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to obtain 5-(4-(pyridin-3-ylethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 9b (60 mg) in a yield of 68.06%.

[0208] MS m / z(ESI):455.2 [M+1]

[0209] Step 2 (S)-1-(1-((5-(4-(pyridin-3-ylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0210] 5-(4-(Pyridin-3-yl ethynyl)phenyl)-3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 9b (60 mg, 132.01 μmol) was dissolved in 4 M hydrochloric acid dioxane (3 mL) and stirred at room temperature for 4 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-(Pyridin-3-yl ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 9 (20 mg) in a yield of 31.12%.

[0211] MS m / z(ESI): 371.2 [M+1] Example 10

[0212] (S)-1-(1-((5-(4-(Pyridin-4-yl ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol [Chemical formula] [Chemical formula]

[0213] Step 1 5-(4-(Pyridin-4-yl ethynyl)phenyl)-3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0214] 4-Ethynylpyridine 10a (20 mg, 193.95 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (92.96 mg, 193.95 μmol), allylpalladium(II) chloride dimer (7.08 mg, 19.39 μmol), triethylenediamine (43.51 mg, 387.89 μmol) and tri-tert-butylphosphine (3.92 mg, 19.39 μmol) were sequentially added to acetonitrile (2 mL), and the argon substitution was carried out 3 times, followed by reaction at room temperature for 12 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to obtain 5-(4-(pyridin-4-ylethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 10b (80 mg) in a yield of 90.75%.

[0215] MS m / z(ESI): 455.1 [M+1]

[0216] Step 2 (S)-1-(1-((5-(4-(pyridin-4-ylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0217] 5-(4-(Pyridin-4-ylethynyl)phenyl)-3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 10b (80 mg, 176.01 μmol) was dissolved in dioxane (2 mL), and 4 M hydrochloric acid in dioxane (1 mL) was added dropwise. The reaction was carried out at room temperature for 4 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-(pyridin-4-ylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 10 (20 mg) in a yield of 21.77%.

[0218] MS m / z(ESI): 371.1 [M+1] Example 11

[0219] 1-((5-(4-((4-(Morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carboxamide

Chemical formula

Chemical formula

[0220] Step 1 3-(Chloromethyl)-5-(4-iodophenyl)isoxazole

[0221] (5-(4-Iodophenyl)isoxazol-3-yl)methanol 2e (1.0 g, 3.32 mmol) and triethylamine (840.23 mg, 8.30 mmol) were sequentially added to dichloromethane (20 mL). Under ice bath conditions, methanesulfonyl chloride (684.84 mg, 5.98 mmol) was added, and stirring was continued at room temperature for 12 hours. Dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 3-(chloromethyl)-5-(4-iodophenyl)isoxazole 11a (800 mg) in a yield of 75.38%.

[0222] MS m / z(ESI): 320.0 [M+1]

[0223] Step 2 1-((5-(4-Iodophenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carbonitrile

[0224] 1H-Imidazole-2-carbonitrile 11b (150 mg, 1.61 mmol), 3-(chloromethyl)-5-(4-iodophenyl)isoxazole 11a (514.88 mg, 1.61 mmol), and sodium hydride (83.83 mg, 2.10 mmol, purity 60%) were sequentially added to N,N-dimethylformamide (3 mL). The mixture was purged with argon three times and stirred at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 1-((5-(4-iodophenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carbonitrile 11c (600 mg) in a yield of 98.99%.

[0225] MS m / z (ESI): 377.0 [M+1]

[0226] Step 3 1-((5-(4-((4-(Morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carbonitrile

[0227] 1-((5-(4-Iodophenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carbonitrile 11c (50 mg, 132.93 μmol), 4-(4-Ethynylbenzyl)morpholine 1j (26.75 mg, 132.93 μmol), cuprous iodide (5.08 mg, 26.59 μmol), bis(triphenylphosphine)palladium(II) dichloride (30.71 mg, 26.59 μmol) and triethylamine (40.35 mg, 398.78 μmol) were successively added to N,N-dimethylformamide (1 mL), and argon substitution was performed three times, followed by stirring at room temperature for 1 hour. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carbonitrile 11d (40 mg) in a yield of 66.95%.

[0228] MS m / z (ESI): 450.2 [M+1]

[0229] Step 4 1-((5-(4-((4-(Morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carboxamide

[0230] 1 - ((5 - (4 - ((4 - (morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol - 3 - yl)methyl)-1H - imidazole - 2 - carbonitrile 11d (30 mg, 66.74 μmol) was dissolved in dimethyl sulfoxide (1 mL), and 5 M aqueous sodium hydroxide solution (1 mL) and hydrogen peroxide (0.5 mL) were sequentially added slowly, followed by continuous stirring at room temperature for 1 hour. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 1 - ((5 - (4 - ((4 - (morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol - 3 - yl)methyl)-1H - imidazole - 2 - carboxamide 11 (8.0 mg) in a yield of 19.68%.

[0231] MS m / z(ESI): 468.1 [M + 1] Example 12

[0232] 1 - ((5 - (4 - ((4 - (morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol - 3 - yl)methyl)-1H - imidazole - 2 - carboxylic acid

Chemical Structure

Chemical Structure

[0233] Step 1 1 - ((5 - (4 - ((4 - (morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol - 3 - yl)methyl)-1H - imidazole - 2 - carboxylic acid

[0234] 1-((5-(4-((4-(Morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carbonitrile 11d (50 mg, 111.23 μmol) was dissolved in dioxane (0.5 mL), and water (0.5 mL) and concentrated sulfuric acid (1 mL) were sequentially added slowly. It was heated to 100 °C and stirring was continued for 2 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and liquid separation was performed. 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, concentrated under reduced pressure, and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carboxylic acid 12 (3.2 mg) in a yield of 5.51%.

[0235] MS m / z(ESI):486.2 [M+18] Example 13

[0236] Ethyl 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carboxylate

Chemical formula

Chemical formula

[0237] Step 1 Ethyl 1-((5-(4-iodophenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carboxylate

[0238] Ethyl 1H-imidazole-2-carboxylate 13a (100 mg, 713.57 μmol), methyl (5-(4-iodophenyl)isoxazol-3-yl)methanesulfonate 2f (270.57 mg, 713.57 μmol), and sodium hydride (37.12 mg, 928.00 μmol, 60% purity) were sequentially added to N,N-dimethylformamide (3 mL). The mixture was purged with argon three times and stirred at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain ethyl 1-((5-(4-iodophenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carboxylate 13b (70 mg) in a yield of 23.18%.

[0239] MS m / z (ESI): 424.0 [M+1]

[0240] Step 2 Ethyl 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carboxylate

[0241] Ethyl 1-((5-(4-iodophenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carboxylate 13b (70 mg, 165.40 μmol), 4-(4-ethynylbenzyl)morpholine 1j (33.29 mg, 165.40 μmol), cuprous iodide (6.32 mg, 33.08 μmol), bis(triphenylphosphine)palladium(II) dichloride (38.21 mg, 33.08 μmol) and triethylamine (50.21 mg, 496.21 μmol) were successively added to N,N-dimethylformamide (2 mL). The mixture was purged with argon three times and stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain ethyl 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazole-2-carboxylate 13 (3.2 mg) in a yield of 3.07%.

[0242] MS m / z(ESI):497.2 [M+1] Example 14

[0243] 1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazol-5-yl)ethan-1-one

Chemical formula

Chemical formula

[0244] Step 1 1-((5-(4-Iodophenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carbonitrile

[0245] 1H-1,2,4-Triazole-5-carbonitrile 14a (100 mg, 1.06 mmol), methyl (5-(4-iodophenyl)isoxazol-3-yl)methanesulfonate 2f (403.05 mg, 1.06 mmol), and potassium carbonate (293.83 mg, 2.13 mmol) were sequentially added to acetonitrile (5 mL), and stirring was continued at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: System A) to give 1-((5-(4-iodophenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carbonitrile 14b (200 mg) in a yield of 49.89%.

[0246] MS m / z (ESI): 378.0 [M+1]

[0247] Step 2 1-((5-(4-((4-(Morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carbonitrile

[0248] 1-((5-(4-Iodophenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carbonitrile 14b (100.00 mg, 265.15 μmol), 4-(4-Ethynylbenzyl)morpholine 1j (53.37 mg, 265.15 μmol), cuprous iodide (10.13 mg, 53.03 μmol), bis(triphenylphosphine)palladium(II) dichloride (61.25 mg, 53.03 μmol) and triethylamine (80.49 mg, 795.46 μmol) were successively added to N,N-dimethylformamide (1 mL), and argon substitution was carried out three times, followed by stirring at room temperature for 1 hour. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and liquid separation was performed. 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, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carbonitrile 14c (80 mg) in a yield of 66.97%.

[0249] MS m / z(ESI):451.0 [M+1]

[0250] Step 3 1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazol-5-yl)ethan-1-one

[0251] Under nitrogen protection, 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carbonitrile 14c (20 mg, 44.40 μmol) was added to tetrahydrofuran (1 mL), and methylmagnesium bromide (3 M, 29.60 μL) was added dropwise under ice bath conditions, followed by continuous stirring for 3 hours. After completion of the reaction, 2 M dilute hydrochloric acid (10 mL) was added, and the mixture was stirred at room temperature for 1 hour. Ethyl acetate (30 mL × 2) was added for extraction, and the combined organic phases were successively washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazol-5-yl)ethan-1-one 14 (2.8 mg) in a yield of 9.76%.

[0252] MS m / z(ESI):468.2 [M+1] Example 15

[0253] (S)-1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0254] Step 1 (S)-1-(1H-benzo[d]imidazol-2-yl)ethan-1-ol

[0255] 1,2 - Diaminobenzene 15a (50 mg, 462.36 μmol) and (S)-2 - hydroxypropionic acid 15b (124.95 mg, 1.39 mmol) were sequentially added to 6 M hydrochloric acid (1 mL), heated to 110 °C, and stirring was continued for 4 hours. After completion of the reaction, it was neutralized to pH = 8 with sodium hydroxide solution, suction filtered, and dried under vacuum to obtain (S)-1-(1H - benzimidazol - 2 - yl)ethan - 1 - ol 15c (60 mg) in a yield of 80.01%.

[0256] MS m / z(ESI): 163.0 [M + 1]

[0257] Step 2 (S)-Ethyl 1-(1H - benzimidazol - 2 - yl)acetate

[0258] (S)-1-(1H - benzimidazol - 2 - yl)ethan - 1 - ol 15c (50 mg, 308.28 μmol) was added to acetic anhydride (0.5 mL), heated to 130 °C, and stirring was continued for 2 hours. After completion of the reaction, water was added to quench the reaction, extracted with dichloromethane (2 mL × 3), dried over anhydrous sodium sulfate, and (S)-ethyl 1-(1H - benzimidazol - 2 - yl)acetate 15d (50 mg) was obtained in a yield of 79.42% and used directly in the next reaction without purification.

[0259] MS m / z(ESI): 205.0 [M + 1]

[0260] Step 3 (S)-Ethyl 1-(1 - ((5-(4 - iodophenyl))isoxazol - 3 - yl)methyl)-1H - benzimidazol - 2 - yl)acetate

[0261] (S)-Ethyl 1-(1H-benzo[d]imidazol-2-yl)acetate 15d (600 mg, 2.94 mmol), methyl (5-(4-iodophenyl)isoxazol-3-yl)methanesulfonate 2f (1.67 g, 4.41 mmol), and potassium carbonate (2.03 g, 14.69 mmol) were sequentially added to N,N-dimethylformamide (1 mL), heated to 65 °C, and stirring was continued for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure, water and dichloromethane were added, and the layers were separated. The aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain ethyl (S)-1-(1-((5-(4-iodophenyl)isoxazol-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)acetate 15e (80 mg) in a yield of 5.59%.

[0262] MS m / z(ESI):487.8 [M+1]

[0263] Step 4 (S)-Ethyl 1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)acetate

[0264] (S)-Ethyl 1-(1-((5-(4-iodophenyl)isoxazol-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)acetate 15e (20 mg, 41.04 μmol), 4-(4-ethynylbenzyl)morpholine 1j (8.26 mg, 41.04 μmol), allylpalladium(II) chloride dimer (375.43 μg, 1.03 μmol), tri-tert-butylphosphine (830.39 μg, 4.10 μmol) and triethylenediamine (9.21 mg, 82.09 μmol) were successively added to acetonitrile (1 mL), and stirring was continued at room temperature for 16 h. After completion of the reaction, it was concentrated under reduced pressure, 6 mL of ethyl acetate was added, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to give (S)-ethyl 1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)acetate 15f (15 mg) in a yield of 65.19%.

[0265] MS m / z(ESI):561.0 [M+1]

[0266] Step 5 (S)-1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethan-1-ol

[0267] (S)-Ethyl 1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)acetate 15f (100 mg, 178.37 μmol) and potassium carbonate (29.58 mg, 214.04 μmol) were sequentially added to methanol, and stirring was continued at room temperature for 16 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-benzo[d]imidazol-2-yl)ethan-1-ol 15 (10 mg) in a yield of 7.98%.

[0268] MS m / z(ESI): 519.0 [M+1] Example 16

[0269] 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carboxamide

Chemical formula

Chemical formula

[0270] Step 1 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carboxamide

[0271] 1-((5-(4-((4-(Morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carbonitrile 14c (20 mg, 44.40 μmol) was dissolved in dimethyl sulfoxide (1 mL), and 5 M aqueous sodium hydroxide solution (1 mL) and hydrogen peroxide (0.5 mL) were sequentially added slowly, followed by stirring at room temperature for 1 hour. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 1-((5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-1,2,4-triazole-5-carboxamide 16 (1.9 mg) in a yield of 6.61%.

[0272] MS m / z(ESI):469.1 [M+1] Example 17

[0273] (S)-1-(4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidine-4-carboxylic acid

Chemical formula

Chemical formula

[0274] Step 1 Methyl 1-(4-((trimethylsilyl)ethynyl)benzyl)piperidine-4-carboxylate

[0275] 4-((Trimethylsilyl)ethynyl)benzaldehyde 17a (200 mg, 988.51 μmol), methyl piperidine-4-carboxylate 17b (283.08 mg, 1.98 mmol) and acetic acid (0.4 mL) were dissolved in 1,2-dichloroethane (4 mL), stirred for 30 minutes, sodium triacetoxyborohydride (628.52 mg, 2.97 mmol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, the layers were separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 1-(4-((trimethylsilyl)ethynyl)benzyl)piperidine-4-carboxylate 17c (250 mg) in a yield of 76.75%.

[0276] MS m / z(ESI): 330.0 [M+1]

[0277] Step 2 Methyl 1-(4-ethynylbenzyl)piperidine-4-carboxylate

[0278] Methyl 1-(4-((trimethylsilyl)ethynyl)benzyl)piperidine-4-carboxylate 17c (125 mg, 379.35 μmol) was dissolved in methanol (5 mL), potassium fluoride (44.08 mg, 758.71 μmol) was added. Stirring was continued at room temperature for 4 hours. After completion of the reaction, it was concentrated and dried under reduced pressure. Ethyl acetate (30 mL) and water (15 mL) were added to the residue, the layers were separated, the aqueous phase was extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain methyl 1-(4-ethynylbenzyl)piperidine-4-carboxylate 17d (90 mg) in a yield of 92.2%, and used directly in the next reaction without purification.

[0279] MS m / z (ESI): 258.0 [M+1]

[0280] Step 3 Methyl 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidine-4-carboxylate

[0281] Methyl 1-(4-ethynylbenzyl)piperidine-4-carboxylate 17d (90 mg, 349.75 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (167.64 mg, 349.75 μmol), cuprous iodide (6.68 mg, 34.97 μmol), bis(triphenylphosphine)palladium(II) dichloride (40.40 mg, 34.97 μmol) and triethylamine (176.96 mg, 1.75 mmol) were successively added to N,N-dimethylformamide (4 mL). The mixture was purged with argon three times and stirred at room temperature for 1 hour. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain methyl 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidine-4-carboxylate 17e (60 mg) in a yield of 28.18%.

[0282] MS m / z (ESI): 609.0 [M+1]

[0283] Step 4 1-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidine-4-carboxylic acid

[0284] Methyl 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidine-4-carboxylate (50 mg, 82.14 μmol) and lithium hydroxide monohydrate (10.34 mg, 246.42 μmol) were successively added to a mixed solvent of tetrahydrofuran (1 mL) and water (0.2 mL), heated to 60 °C, and reacted for 4 hours. After completion of the reaction, 2 M hydrochloric acid was added to adjust the acidity, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System A) to obtain 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidine-4-carboxylic acid 17f (40 mg) in a yield of 81.89%.

[0285] MS m / z (ESI): 595.1 [M+1]

[0286] Step 5 (S)-1-(4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidine-4-carboxylic acid

[0287] 1-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidine-4-carboxylic acid 17f (40 mg, 67.26 μmol) was sequentially added to a mixed solvent of dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL), and stirring was continued at room temperature for 3 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidine-4-carboxylic acid 17 (10 mg) in a yield of 23.8%.

[0288] MS m / z(ESI): 511.1 [M+1] 1 H NMR(400 MHz, DMSO-d6) δ12.13(br,1H), 7.89(d,J = 8.0 Hz,2H), 7.69(d,J = 8.4 Hz,2H), 7.54(d,J = 8.4 Hz,2H), 7.37(d,J = 8.0 Hz,2H), 7.19(s,1H), 7.01(s,1H), 6.84(s1H), 5.51 -5.42(m,3H), 4.89(penta,J = 6.0 Hz,1H), 3.50(br,2H), 2.75(d,J = 8.0 Hz,2H), 2.21(br,1H), 2.01(br,2H), 1.79(d,J = 11.2 Hz,2H), 1.63 -1.50(m,2H), 1.48(d,J = 6.4 Hz,3H). Example 18

[0289] (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-ol

Chemical formula

Chem.

[0290] Step 1 1-(4-((Trimethylsilyl)ethynyl)benzyl)piperidin-4-ol

[0291] 4-((Trimethylsilyl)ethynyl)benzaldehyde 17a (200 mg, 988.51 μmol), piperidin-4-ol 18a (149.98 mg, 1.48 mmol) and acetic acid (0.5 mL) were dissolved in dichloroethane (5 mL), stirred for 30 minutes, sodium triacetoxyborohydride (628.52 mg, 2.97 mmol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 1-(4-((trimethylsilyl)ethynyl)benzyl)piperidin-4-ol 18b (90 mg) in a yield of 31.67%.

[0292] MS m / z (ESI): 287.9 [M+1]

[0293] Step 2 1-(4-Ethynylbenzyl)piperidin-4-ol

[0294] 1-(4-((Trimethylsilyl)ethynyl)benzyl)piperidin-4-ol 18b (90 mg, 313.08 μmol) was dissolved in methanol (2 mL), and potassium fluoride (72.76 mg, 1.25 mmol) was added. Stirring was continued at room temperature for 4 hours. After completion of the reaction, it was concentrated to dryness under reduced pressure. Ethyl acetate (30 mL) and water (15 mL) were added to the residue, and liquid separation was performed. 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, concentrated under reduced pressure, and 1-(4-ethynylbenzyl)piperidin-4-ol 18c (50 mg) was obtained in a yield of 74.18% and used directly in the next reaction without purification.

[0295] MS m / z(ESI):216.0 [M+1]

[0296] Step 3 1-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-ol

[0297] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (100 mg, 208.63 μmol), 1-(4-ethynylbenzyl)piperidin-4-ol 18c (35.93 mg, 166.91 μmol), allylpalladium(II) chloride dimer (7.63 mg, 20.86 μmol), tri-tert-butylphosphine (42.21 mg, 20.86 μmol) and triethylenediamine (70.21 mg, 625.90 μmol) were successively added to acetonitrile (2 mL), and the argon substitution was carried out 3 times, followed by stirring at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and liquid separation was performed. 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, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-ol 18d (40 mg) in a yield of 33.83%.

[0298] MS m / z(ESI): 567.0 [M+1]

[0299] Step 4 (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-ol

[0300] 1-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-ol 18d (40 mg, 70.59 μmol) was added to a mixed solvent of dichloromethane (3 mL) and trifluoroacetic acid (1 mL), and stirring was continued at room temperature for 4 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-ol 18 (15.0 mg) in a yield of 35.09%.

[0301] MS m / z(ESI): 483.3 [M+1] Example 19

[0302] (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile

Chemical formula

Chemical formula

[0303] Step 1 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile

[0304] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (376.99 mg, 786.52 μmol), 4-ethynylbenzonitrile 19a (100 mg, 786.52 μmol), allylpalladium(II) chloride dimer (28.78 mg, 78.65 μmol), tri-tert-butylphosphine (159.13 mg, 78.65 μmol) and triethylenediamine (264.67 mg, 2.36 mmol) were sequentially added to acetonitrile (5.0 mL). The mixture was purged with argon three times and stirred at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile 19b (320 mg) in a yield of 85.02%.

[0305] MS m / z (ESI): 478.9 [M+1]

[0306] Step 2 (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile

[0307] 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile 19b (30 mg, 62.69 μmol) was added to a mixed solvent of trifluoroacetic acid (0.5 mL) and dichloromethane (3 mL), stirred at room temperature for 3 hours, concentrated under reduced pressure, and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile 19 (1.87 mg) in a yield of 5.67%.

[0308] MS m / z(ESI): 395.0 [M+1] Example 20

[0309] 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-3-carboxylic acid

Chem.

Chem.

[0310] Step 1 Methyl 4-(4-((trimethylsilyl)ethynyl)benzyl)morpholine-3-carboxylate

[0311] 4-((Trimethylsilyl)ethynyl)benzaldehyde 17a (1 g, 4.94 mmol), methyl morpholine-3-carboxylate 20a (1.08 g, 5.93 mmol), and acetic acid (0.6 g, 24.71 mmol, 0.5 mL) were dissolved in dichloroethane (12 mL), stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (3.14 g, 14.83 mmol) was slowly added. The reaction was carried out overnight at room temperature. After completion of the reaction, water was added to quench the reaction, and the mixture was extracted with dichloromethane (50 mL × 3). The combined organic phases were concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 4-(4-((trimethylsilyl)ethynyl)benzyl)morpholine-3-carboxylate 20b (0.9 g) in a yield of 54.93%.

[0312] MS m / z(ESI): 332.2 [M+1]

[0313] Step 2 Methyl 4-(4-ethynylbenzyl)morpholine-3-carboxylate

[0314] Methyl 4-(4-((trimethylsilyl)ethynyl)benzyl)morpholine-3-carboxylate 20b (0.9 g, 2.72 mmol) and tetrabutylammonium fluoride (851.87 mg, 3.26 mmol, 6 mL) were dissolved in tetrahydrofuran (10 mL) and reacted at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 4-(4-ethynylbenzyl)morpholine-3-carboxylate 20c (0.45 g) in a yield of 63.92%.

[0315] MS m / z(ESI): 260.1 [M+1]

[0316] Step 3 Methyl 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-3-carboxylate

[0317] Methyl 4-(4-ethynylbenzyl)morpholine-3-carboxylate 20c (80 mg, 308.52 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (147.88 mg, 308.52 μmol), allylpalladium(II) chloride dimer (11.26 mg, 30.85 μmol), triethylenediamine (69.21 mg, 617.05 μmol) and tri-tert-butylphosphine (6.24 mg, 30.85 μmol) were sequentially added to acetonitrile (2 mL), and the mixture was purged with argon three times and reacted at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain methyl 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-3-carboxylate 20d (110 mg) in a yield of 58.38%.

[0318] MS m / z (ESI): 611.0 [M+1]

[0319] Step 4 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-3-carboxylic acid

[0320] Methyl 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-3-carboxylate 20d (105 mg, 171.93 μmol) was dissolved in a mixed solvent of tetrahydrofuran (2 ml) and water (0.5 mL), lithium hydroxide monohydrate (72.14 mg, 1.72 mmol) was added, and the mixture was heated to 70 °C and reacted overnight. After completion of the reaction, an appropriate amount of 2 M hydrochloric acid was added to adjust the pH to 3, and the mixture was washed with ethyl acetate (50 mL × 3) and concentrated under reduced pressure. It was isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-3-carboxylic acid 20e (90 mg) in a yield of 87.73%.

[0321] MS m / z(ESI):597.3 [M+1]

[0322] Step 5 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-3-carboxylic acid

[0323] 4-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-3-carboxylic acid 20e (90 mg, 150.84 μmol) was dissolved in dioxane (2 mL), and 4 M hydrochloric acid dioxane solution (1 mL) was added dropwise, followed by reaction at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-3-carboxylic acid 20 (20 mg) in a yield of 20.42%.

[0324] MS m / z(ESI): 513.2 [M+1] Example 21

[0325] (1S)-1-(1-((2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydrooxazol-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (1S)-1-(1-((2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydrooxazol-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0326] Step 1 (2-(4-iodophenyl)-4,5-dihydrooxazol-4-yl)methanol (2-(4-Iodophenyl)-4,5-dihydrooxazol-4-yl)methanol

[0327] Methyl 2-(4-iodophenyl)-4,5-dihydrooxazole-4-carboxylate 1d (3.5 g, 10.57 mmol) was added to tetrahydrofuran (80 mL), and diisobutylaluminum hydride (1.0 M, 31.71 mL) was added dropwise at 0 °C. Stirring was continued at 0 °C for 2 hours. A sodium potassium tartrate solution (50 mL) and ethyl acetate (50 mL) were added, and the mixture was vigorously stirred at room temperature for 3 hours. The reaction mixture was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated and discarded, the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain (2-(4-iodophenyl)-4,5-dihydrooxazol-4-yl)methanol 21a (2.5 g) in a yield of 78.03%.

[0328] MS m / z (ESI): 303.8 [M+1]

[0329] Step 2 (2-(4-Iodophenyl)-4,5-dihydrooxazol-4-yl)methyl 4-methylbenzenesulfonate (2-(4-Iodophenyl)-4,5-dihydrooxazol-4-yl)methyl 4-methylbenzenesulfonate

[0330] (2-(4-Iodophenyl)-4,5-dihydrooxazol-4-yl)methanol 21a (2.4 g, 7.92 mmol) was added to dichloromethane (60 mL), and triethylamine (2.40 g, 23.75 mmol, 3.30 mL) was slowly added dropwise at 0 °C, followed by reaction overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl (2-(4-iodophenyl)-4,5-dihydrooxazol-4-yl)4-methylbenzenesulfonate 21b (2.4 g) in a yield of 66.28%.

[0331] MS m / z(ESI):457.7 [M+1]

[0332] Step 3 2-(4-iodophenyl)-4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydrooxazole 2-(4-Iodophenyl)-4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydrooxazole

[0333] 2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole 1h (257.49 mg, 1.31 mmol) was added to N,N-dimethylformamide (10 mL), and then sodium hydride (56.88 mg, 1.31 mmol, dispersed in 60% oily liquid) was added. Methyl 2-(4-iodophenyl)-4,5-dihydrooxazole-4-yl)4-methylbenzenesulfonate 21b (300 mg, 656.05 μmol) was added, and the reaction mixture was heated to 70 °C and reacted for 10 minutes. The reaction mixture was cooled to 0 °C, water (50 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The aqueous layer was separated and discarded. The organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 2-(4-iodophenyl)-4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydrooxazole 21c (130 mg) in a yield of 41.17%.

[0334] MS m / z(ESI):481.8 [M+1]

[0335] Step 4 4-(4-((4-(4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydrooxazol-2-yl)phenyl)ethynyl)benzyl)morpholine 4-(4-((4-(4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydrooxazol-2-yl)phenyl)ethynyl)benzyl)morpholine

[0336] At room temperature, to a mixture of 2-(4-iodophenyl)-4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydrooxazole 21c (100 mg, 207.76 μmol) and 4-(4-ethynylbenzyl)morpholine 1j (41.81 mg, 207.76 μmol) were sequentially added bis(dichloride)(triphenylphosphino)palladium(II) (5.83 mg, 8.31 μmol), tetrabutylammonium bromide (66.97 mg, 207.76 μmol) and piperidine (53.07 mg, 623.28 μmol). The reaction solution was heated to 70 °C and stirred for 4 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated and discarded, the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 4-(4-((4-(4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydrooxazol-2-yl)phenyl)ethynyl)benzyl)morpholine 21d (100 mg) was obtained in a yield of 86.78%.

[0337] MS m / z(ESI):555.3 [M+1]

[0338] Step 5 (1S)-1-(1-((2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydrooxazol-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (1S)-1-(1-((2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydrooxazol-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0339] 4-(4-((4-(4-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-4,5-dihydrooxazol-2-yl)phenyl)ethynyl)benzyl)morpholine 21d (100 mg, 180.28 μmol) was added to dichloromethane (2 mL), trifluoroacetic acid (0.1 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was cooled to 0 °C, 1N sodium hydroxide solution was added to adjust the pH to neutral, extracted with dichloromethane (30 mL × 3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and (1S)-1-(1-((2-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydrooxazol-4-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 21 (4 mg) was obtained in a yield of 4.15%.

[0340] MS m / z(ESI): 471.0 [M+1] Example 22

[0341] (S)-1-(4-((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl) ethynyl)benzyl)piperidin-4-ol (S)-1-(4-((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)piperidin-4-ol

Chemical formula

Chemical formula

[0342] Step 1 1-(4-((4-(4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)piperidin-4-ol 1-(4-((4-(4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)piperidin-4-ol

[0343] At room temperature, to an aqueous solution (1 mL) of 2-(4-iodophenyl)-4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazole 1i (60 mg, 125.18 μmol) and 1-(4-ethynylbenzyl)piperidin-4-ol 18c (26.95 mg, 125.18 μmol), bis(dichloride)(triphenylphosphino)palladium(II) (3.51 mg, 5.01 μmol), tetrabutylammonium bromide (40.35 mg, 125.18 μmol) and piperidine (31.98 mg, 375.54 μmol) were added, the temperature was raised to 70 °C and stirred for 5 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated and discarded, the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-(4-((4-(4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)piperidin-4-ol 22a (60 mg) in a yield of 84.58%.

[0344] MS m / z(ESI):567.0 [M+1]

[0345] Step 2 (S)-1-(4-((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)piperidin-4-ol (S)-1-(4-((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)piperidin-4-ol

[0346] 1-(4-((4-(4-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)piperidin-4-ol 22a (60 mg, 105.88 μmol) was added to dichloromethane (2 mL), and then trifluoroacetic acid (0.1 mL) was added, and the reaction was carried out at room temperature for 30 minutes. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(4-((4-(4-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)oxazol-2-yl)phenyl)ethynyl)benzyl)piperidin-4-ol 22 (13 mg) in a yield of 20.07%.

[0347] MS m / z(ESI): 483.0 [M+1] Example 23

[0348] (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide [Chemical formula]

Chem.

[0349] Step 1 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide

[0350] 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile 19b (230 mg, 480.63 μmol) was added to dimethyl sulfoxide (5 mL), and 5N aqueous sodium hydroxide solution (2 mL) was added to the mixture. Hydrogen peroxide (1 mL) was added dropwise under an ice bath, and the temperature was raised to room temperature and stirring was continued for 1 hour. Ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 23a (200 mg) was obtained and used directly in the next reaction.

[0351] MS m / z (ESI): 496.9 [M+1]

[0352] Step 2 (S)-4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide (S)-4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide

[0353] 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 23a (180 mg, 362.50 μmol) was added to dichloromethane (10 mL), trifluoroacetic acid (1 mL) was added, and stirring was continued at room temperature for 2 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 23 (89.96 mg) in a yield of 58.31%.

[0354] MS m / z (ESI): 413.0 [M+1] 1 H NMR (400 MHz, DMSO-d6) δ8.10 (s, 1H), 7.94 (d, J = 8.4 Hz, 4H), 7.80 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 2.0 Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 7.51 (s, 1H), 7.21 (s, 1H), 6.44 (br, 1H), 5.73 (s, 2H), 5.26 (q, J = 6.8 Hz, 1H), 1.50 (d, J = 6.4 Hz, 3H). Example 24

[0355] (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)benzoic acid (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)benzoic acid

Chem.

Chem.

[0356] Step 1 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl) isoxazol-5-yl)phenyl)ethynyl)benzoic acid 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl) isoxazol-5-yl)phenyl)ethynyl)benzoic acid

[0357] 4-Ethynylbenzoic acid 24a (25 mg, 171.07 μmol, commercially available), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (82.0 mg, 171.07 μmol), allylpalladium chloride (II) dimer (6.24 mg, 17.11 μmol), triethylenediamine (38.4 mg, 342.13 μmol), tri-tert-butylphosphine (10% toluene solution) (3.46 mg, 17.11 μmol) were sequentially added to acetonitrile (2 mL). After performing argon substitution three times, the reaction was carried out at room temperature for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to obtain 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzoic acid 24b (50 mg) in a yield of 58.75%.

[0358] MS m / z(ESI):498.1 [M+1]

[0359] Step 2 (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)benzoic acid (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzoic acid

[0360] 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzoic acid 24b (10 mg, 20.10 μmol) was dissolved in 4N hydrogen chloride dioxane solution (0.5 mL) and reacted at room temperature for 4 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzoic acid 24 (4 mg) in a yield of 36.34%.

[0361] MS m / z(ESI): 414.1[M+1] Example 25

[0362] (S)-N-(2-hydroxyethyl)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide (S)-N-(2-hydroxyethyl)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide [Chemical formula] [Chemical formula]

[0363] Step 1 N-(2-hydroxyethyl)-4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide N-(2-hydroxyethyl)-4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide

[0364] 2-Aminoethanol (6.14 mg, 100.49 μmol), 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzoic acid 24b (50 mg, 100.49 μmol), triethylamine (10.2 mg, 100.49 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.9 mg, 150.74 μmol) and 1-hydroxybenzotriazole (20.4 mg, 150.74 μmol) were sequentially added to N,N-dimethylformamide (2 mL) and reacted overnight at room temperature. After completion of the reaction, ethyl acetate was added for extraction (50 mL × 3), the organic phases were combined and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain N-(2-hydroxyethyl)-4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 25a (40 mg) in a yield of 73.63%.

[0365] MS m / z(ESI):541.1[M+1]

[0366] Step 2 (S)-N-(2-hydroxyethyl)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide (S)-N-(2-hydroxyethyl)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide

[0367] N-(2-hydroxyethyl)-4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 25a (40 mg, 73.99 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added dropwise, and the reaction was carried out at room temperature for 4 hours. After completion of the reaction, it was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-N-(2-hydroxyethyl)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 25 (5 mg) in a yield of 10.84%.

[0368] MS m / z(ESI):457.3[M+1] Example 26

[0369] (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)ethan-1-one (S)-1-(4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethan-1-one

Chem.

Chem.

[0370] Step 1 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethan-1-one 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethan-1-one

[0371] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (166 mg, 346.81 μmol), 1-(4-ethynylphenyl)ethan-1-one 26a (50 mg, 346.81 μmol, commercially available), allylpalladium chloride (II) dimer (12.7 mg, 34.68 μmol), triethylenediamine (77.8 mg, 693.63 μmol) and tri-tert-butylphosphine (10% toluene solution) (7.02 mg, 34.68 μmol) were sequentially added to acetonitrile (2 mL), and argon substitution was performed three times, followed by reaction at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethan-1-one 26b (50 mg) in a yield of 29.09%.

[0372] MS m / z(ESI):496.3 [M+1]

[0373] Step 2 (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)ethan-1-one (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl) phenyl)ethynyl)phenyl)ethan-1-one

[0374] 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethan-1-one 26b (30 mg, 60.54 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.2 mL) was added dropwise, and the mixture was reacted at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethan-1-one 26 (10 mg) in a yield of 29.68%.

[0375] MS m / z(ESI): 412.1 [M+1] Example 27

[0376] (S)-3-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)propanoic acid (S)-3-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)propanoic acid

Chem.

Chem.

[0377] Step 1 methyl 3-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)propanoate methyl 3-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)propionate

[0378] 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2 g (50 mg, 104.32 μmol), methyl 3-(4-ethynylphenyl)propionate 27a (39.27 mg, 208.63 μmol, prepared according to JP-A WO2010012650A), allyl palladium chloride (II) dimer (12.7 mg, 34.68 μmol), triethylenediamine (35.10 mg, 312.95 μmol) and tri-tert-butylphosphine (10% toluene solution) (42.21 mg, 20.86 μmol) were successively added to acetonitrile (5 mL), and the argon substitution was carried out 3 times, and stirring was continued at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added to the reaction solution, and liquid separation was carried out. 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, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain methyl 3-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)propionate 27b (25 mg) in a yield of 44.41%.

[0379] MS m / z (ESI): 540.0 [M+1]

[0380] Step 2 methyl(S)-3-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)propanoate (S)-3-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)propanoic acid methyl ester

[0381] Methyl 3-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)propionate 27b (25 mg, 46.33 μmol) was added to dichloromethane (3 mL), trifluoroacetic acid (1 mL) was added, and stirring was continued at room temperature for 2 hours. After completion of the reaction, it was concentrated under reduced pressure to obtain methyl (S)-3-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)propionate 27c (20 mg), which was used directly in the next reaction.

[0382] MS m / z(ESI):456.0 [M+1]

[0383] Step 3 (S)-3-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)propanoic acid (S)-3-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)propanoic acid

[0384] (S)-Methyl 3-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)propionate 27c (20 mg, 43.91 μmol) was added to a mixed solution of 2.5 N aqueous sodium hydroxide and tetrahydrofuran (4 mL, V:V = 1:3), and the temperature was raised to 75 °C and stirring was continued for 3 hours. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated under reduced pressure, and isolated by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-3-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)propionic acid 27 (1.4 mg) in a yield of 6.50%.

[0385] MS m / z(ESI):442.0 [M+1] Example 28

[0386] (S)-5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)picolinamide (S)-5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinamide

Chem.

Chem.

[0387] Step 1 methyl 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinate 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinate methyl ester

[0388] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2 g (50 mg, 104.32 μmol), methyl 5-ethynylpicolinate 28a (33.62 mg, 208.63 μmol, commercially available), allylpalladium chloride (II) dimer (3.82 mg, 10.43 μmol), tri-tert-butylphosphine (10% toluene solution) (2.11 mg, 10.43 μmol) and triethylenediamine (35.10 mg, 312.95 μmol) were sequentially added to acetonitrile (0.5 mL), and the mixture was purged with argon three times. The reaction solution was heated to 100 °C and stirred for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to obtain methyl 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinate 28b (13 mg) in a yield of 24.31%.

[0389] MS m / z (ESI): 512.9 [M+1]

[0390] Step 2 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinamide 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinamide

[0391] Methyl 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinate (20 mg, 39.02 μmol) was added to a mixed solvent of aqueous ammonia (1 mL) and methanol (1 mL), and the mixture was stirred at 25 °C for 16 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 I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinamide 28c (12.5 mg) in a yield of 64.39%.

[0392] MS m / z(ESI):498.2 [M+1]

[0393] Step 3 (S)-5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)picolinamide (S)-5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinamide

[0394] 5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinamide 28c (20 mg, 40.20 μmol) and aqueous ammonia (2.82 mg, 80.39 μmol) were successively added to methanol (0.5 mL), and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinamide 28 (8 mg) in a yield of 35.85%.

[0395] MS m / z(ESI): 414.1 [M+1] Example 29

[0396] (S)-1-(1-((5-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0397] Step 1 (5-(4-((4-bromophenyl)ethynyl)phenyl)isoxazol-3-yl)methanol (5-(4-((4-bromophenyl)ethynyl)phenyl)isoxazol-3-yl)methanol

[0398] (5-(4-iodophenyl)isoxazol-3-yl)methanol 2e (2g, 6.64 mmol), 1-bromo-4-ethynylbenzene 29a (1.32g, 7.31 mmol), cuprous iodide (25.30 mg, 132.86 μmol), bis dichloride (triphenylphosphino)palladium(II) (46.63 mg, 66.43 μmol) and triethylamine (2.08g, 20.59 mmol, 2.86 mL) were sequentially added to tetrahydrofuran (5 mL), and the argon substitution was carried out three times, followed by stirring at room temperature for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to obtain (5-(4-((4-bromophenyl)ethynyl)phenyl)isoxazol-3-yl)methanol 29b (1.6g) in a yield of 68.0%.

[0399] MS m / z(ESI):353.8 [M+1]

[0400] Step 2 5-(4-((4-bromophenyl)ethynyl)phenyl)-3-(chloromethyl)isoxazole 5-(4-((4-bromophenyl)ethynyl)phenyl)-3-(chloromethyl)isoxazole

[0401] (5-(4-((4-Bromophenyl)ethynyl)phenyl)isoxazol-3-yl)methanol 29b (1.25 g, 3.53 mmol) and triethylamine (714.22 mg, 7.06 mmol, 983.78 μL) were successively added to a mixed solvent of dichloromethane (4 mL) and N,N-dimethylformamide (1 mL). The mixture was purged with argon three times and cooled in an ice-water bath. Methanesulfonyl chloride (4.04 g, 35.29 mmol, 2.73 mL) was slowly added dropwise, and the reaction mixture was heated to 65 °C and stirred for 16 h. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 5-(4-((4-bromophenyl)ethynyl)phenyl)-3-(chloromethyl)isoxazole 29c (1.2 g) in a yield of 91.25%.

[0402] MS m / z(ESI):371.8 [M+1]

[0403] Step 3 5-(4-((4-bromophenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 5-(4-((4-Bromophenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0404] 2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole 1h (347.58 mg, 1.77 mmol) and sodium hydride (50.26 mg, 1.93 mmol) were sequentially added to N,N-dimethylformamide (2 mL). The mixture was purged with argon three times, stirred at 0 °C for 0.5 h, and then 5-(4-((4-bromophenyl)ethynyl)phenyl)-3-(chloromethyl)isoxazole 29c (600 mg, 1.61 mmol) was slowly added dropwise under an ice-water bath. The reaction mixture was warmed to 25 °C and stirred for 16 h. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was suction filtered. The solid was collected and dried under vacuum to obtain 5-(4-((4-bromophenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 29d (700 mg) in a yield of 81.65%.

[0405] MS m / z(ESI):531.8 [M+1]

[0406] Step 4 2-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)ethan-1-ol 2-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)ethan-1-ol

[0407] 5-(4-((4-Bromophenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 29d (300 mg, 563.46 μmol), ethylene glycol (104.92 mg, 1.69 mmol, 94.27 μL), 5-di-tert-butylphosphine-1’,3’,5’-triphenyl-1’H-[1,4’]dipyrazole (114.18 mg, 225.38 μmol), and cesium carbonate (550.76 mg, 1.69 mmol) were sequentially added to toluene (2 mL). The mixture was purged with argon three times, and tris(dibenzylideneacetone)dipalladium (50.39 mg, 112.69 μmol) was slowly added dropwise. The mixture was stirred at 25 °C for 16 h. After completion of the reaction, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and 2-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)ethan-1-ol 29e (30 mg) was obtained in a yield of 10.37%.

[0408] MS m / z(ESI):513.7 [M+1]

[0409] Step 5 (S)-1-(1-((5-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0410] 2-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethoxy)ethanol 29e (30 mg, 58.41 μmol) and trifluoroacetic acid (6.66 mg, 58.41 μmol) were sequentially added to dichloromethane (2 mL), and the mixture was stirred at 25 °C for 4 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by thin-layer chromatography (developer: System B) to obtain (S)-1-(1-((5-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethanol 29 (10 mg) in a yield of 37.47%.

[0411] MS m / z(ESI):429.9 [M+1] Example 30

[0412] 1-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)ethane-1,2-diol 1-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethane-1,2-diol

Chem.

Chem.

[0413] Step 1 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethane-1,2-diol 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethane-1,2-diol

[0414] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (50 mg, 104.32 μmol), 1-(4-Ethynylphenyl)ethane-1,2-diol 30a (33.84 mg, 208.63 μmol, prepared according to JP-A WO2014142298A1), allyl palladium chloride (II) dimer (5.71 mg, 15.65 μmol), triethylenediamine (35.10 mg, 312.95 μmol) and tri-tert-butylphosphine (10% toluene solution) (42.21 mg, 20.86 μmol) were successively added to acetonitrile (5 mL), purged with argon three times, and stirred at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)ethane-1,2-diol 30b (40 mg) in a yield of 74.66%.

[0415] MS m / z(ESI):514.2 [M+1]

[0416] Step 2 1-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)ethane-1,2-diol 1-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)ethane-1,2-diol

[0417] 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)ethane-1,2-diol 30b (40 mg, 77.88 μmol) and trifluoroacetic acid (0.5 mL) were successively added to dichloromethane (5 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, methanol (5 mL) was added to the obtained residue to dissolve it, 2N aqueous sodium hydroxide solution (1 mL) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), and 1-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)ethane-1,2-diol 30 (20 mg) was obtained in a yield of 57.75%.

[0418] MS m / z (ESI): 430.1 [M+1] Example 31

[0419] 3-((4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1-dioxide 3-((4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1-dioxide

Chem.

Chem.

[0420] Step 1 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde

[0421] 4-Ethynylbenzaldehyde 31a (40 mg, 307.35 μmol, commercially available), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (147 mg, 307.35 μmol), allylpalladium chloride (II) dimer (11.2 mg, 30.74 μmol), triethylenediamine (69.0 mg, 614.71 μmol) and tri-tert-butylphosphine (10% toluene solution) (6.22 mg, 30.74 μmol) were dissolved in acetonitrile (2 mL), purged with argon three times, and reacted at room temperature for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: B system) to obtain 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (80 mg) in a yield of 54.05%.

[0422] MS m / z (ESI): 482.1 [M+1]

[0423] Step 2 3-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1-dioxide 3-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1-dioxide

[0424] 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (50 mg, 103.83 μmol), 3-aminotetrahydrothiophene 1,1-dioxide 31c (21.39 mg, 124.60 μmol, commercially available) were dissolved in 1,2-dichloroethane (2 mL), acetic acid (0.2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (66.02 mg, 311.50 μmol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 3-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1-dioxide 31d (50 mg) in a yield of 80.16%.

[0425] MS m / z(ESI):601.4 [M+1]

[0426] Step 3 3-((4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)benzyl)amino)tetrahydrothiophene1,1-dioxide 3-((4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1-dioxide

[0427] 3 - ((4 - ((4 - (3 - ((2 - ((1S)-1 - ((tetrahydro - 2H - pyran - 2 - yl)oxy)ethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1 - dioxide 31d (50 mg, 83.23 μmol) was added to dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and stirring was continued at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 3 - ((4 - ((4 - (3 - ((2 - ((S)-1 - hydroxyethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1 - dioxide 31 (43.2 mg) in a yield of 79.42%.

[0428] MS m / z(ESI): 517.2 [M + 1] Example 32

[0429] (S)-2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)benzyl)azetidin-3-yl)acetic acid (S)-2-(1-(4-((4-(3-((2-(1 - hydroxyethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)benzyl)azetidin - 3 - yl)acetic acid

Chemical Structure

Chemical Structure

[0430] Step 1 methyl 2-(1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate methyl 2-(1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate

[0431] 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (70 mg, 145.37 μmol), methyl 2-(azetidin-3-yl)acetate 32a (37.55 mg, 154.41 μmol, commercially available) were dissolved in 1,2-dichloroethane (5 mL), acetic acid (0.5 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (92.43 mg, 436.10 μmol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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 obtain methyl 2-(1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate 32b (80 mg), which was used directly in the next reaction.

[0432] MS m / z (ESI): 595.0 [M+1]

[0433] Step 2 (S)-2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)methyl acetate (S)-2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)methyl acetate

[0434] Methyl 2-(1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate 32b (80 mg, 134.52 μmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. Stirring was continued at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain methyl (S)-2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate 32c (60 mg), which was used directly in the next reaction.

[0435] MS m / z (ESI): 511.2 [M+1]

[0436] Step 3 (S)-2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetic acid (S)-2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetic acid

[0437] (S)-Methyl 2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate 32c (60.0 mg, 117.51 μmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and methanol (2 mL), 2.5 N aqueous sodium hydroxide solution (1 mL) was added, and stirring was continued at room temperature for 4 hours. 1 N dilute hydrochloric acid was added to adjust the pH to 6, and the mixture was concentrated under reduced pressure to dryness. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetic acid 32 (50.0 mg) in a yield of 68.29%.

[0438] MS m / z (ESI): 497.2 [M+1] 1 H NMR (400 MHz, CD3OD) δ 7.78 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.16 (s, 1H), 6.94 (s, 1H), 6.75 (s, 1H), 5.53 (d, J = 16.0 Hz, 1H), 5.06 (q, J = 6.8 Hz, 1H), 4.43 (t, J = 8.0 Hz, 1H), 4.08 (dd, J = 9.2, 6.6 Hz, 1H), 3.78 (s, 2H), 3.31 (br, 1H), 2.79 - 2.61 (m, 4H), 2.33 (dd, J = 17.4, 6.6 Hz, 1H), 1.61 (d, J = 6.4 Hz, 3H). Example 33

[0439] (S)-1-(1-((5-(4-((4-((1H-pyrazol-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((1H-pyrazol-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol [Chemical formula] [Chemical formula]

[0440] Step 1 4-((trimethylsilyl)ethynyl)benzyl methanesulfonate 4-((trimethylsilyl)ethynyl)benzyl methanesulfonate

[0441] (4-((trimethylsilyl)ethynyl)phenyl)methanol 33a (500 mg, 2.45 mmol, commercially available) and triethylamine (742.81 mg, 7.34 mmol, 1.02 mL) were sequentially added to dichloromethane (10 mL). Under ice bath conditions, methylsulfonyl chloride (560.59 mg, 4.89 mmol, 378.77 μL) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The obtained residue was purified by silica gel column chromatography (eluent: System B) to obtain 4-((trimethylsilyl)ethynyl)benzyl methanesulfonate 33b (600 mg) in a yield of 60.77%.

[0442] Step 2 1-(4-((Trimethylsilyl)ethynyl)benzyl)-1H-pyrazole 1-(4-((Trimethylsilyl)ethynyl)benzyl)-1H-pyrazole

[0443] 4-((Trimethylsilyl)ethynyl)benzyl methanesulfonate 33b (100 mg, 354.07 μmol), 1H-pyrazole 33c (48.21 mg, 708.14 μmol, commercially available), and potassium carbonate (146.81 mg, 1.06 mmol) were sequentially added to N,N-dimethylformamide (2 mL), and stirring was continued at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-(4-((trimethylsilyl)ethynyl)benzyl)-1H-pyrazole 33d (80 mg) in a yield of 88.81%.

[0444] MS m / z(ESI): 255.0 [M+1]

[0445] Step 3 1-(4-ethynylbenzyl)-1H-pyrazole 1-(4-Ethynylbenzyl)-1H-pyrazole

[0446] 1-(4-((Trimethylsilyl)ethynyl)benzyl)-1H-pyrazole 33d (80 mg, 314.46 μmol) and potassium fluoride (18.27 mg, 314.46 μmol) were sequentially added to methanol (2 mL), and stirring was continued at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-(4-ethynylbenzyl)-1H-pyrazole 33e (30 mg) in a yield of 52.35%.

[0447] MS m / z(ESI): 183.0 [M+1]

[0448] Step 4 5-(4-((4-((1H-pyrazol-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 5-(4-((4-((1H-pyrazol-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0449] 1-(4-Ethynylbenzyl)-1H-pyrazole 33e (30.0 mg, 164.64 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (71.02 mg, 148.17 μmol), allylpalladium chloride (II) dimer (12.02 mg, 32.93 μmol), triethylenediamine (55.40 mg, 493.91 μmol) and tri-tert-butylphosphine (10% toluene solution) (66.62 mg, 32.93 μmol) were successively added to acetonitrile (2 mL). The mixture was purged with argon three times and stirred at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 5-(4-((4-((1H-pyrazol-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33f (50 mg) in a yield of 56.91%.

[0450] MS m / z (ESI): 534.2 [M+1]

[0451] Step 5 (S)-1-(1-((5-(4-((4-((1H-pyrazol-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((1H-pyrazol-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0452] 5-(4-((4-((1H-pyrazol-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 33f (50 mg, 93.70 μmol) was added to dichloromethane (5 mL), and trifluoroacetic acid (0.5 mL) was added. Stirring was continued at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-((1H-pyrazol-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 33 (22.9 mg) in a yield of 41.55%.

[0453] MS m / z (ESI): 450.1 [M+1] Example 34

[0454] (S)-2-((4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethan-1-ol (S)-2-((4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethan-1-ol

Chem.

Chem.

[0455] Step 1 2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethan-1-ol 2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethan-1-ol

[0456] 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (100 mg, 207.67 μmol), 2-aminoethanol (25.37 mg, 415.33 μmol) were dissolved in 1,2-dichloroethane (5 mL), acetic acid (0.5 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (132.04 mg, 623.00 μmol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethan-1-ol 34a (50 mg) in a yield of 45.72%.

[0457] MS m / z(ESI):527.3 [M+1]

[0458] Step 2 (S)-2-((4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)benzyl)amino)ethan-1-ol (S)-2-((4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethan-1-ol

[0459] 2 - ((4 - ((4 - (3 - ((2 - ((1S)-1 - ((tetrahydro - 2H - pyran - 2 - yl)oxy)ethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)benzyl)amino)ethan - 1 - ol 34a (50 mg, 94.94 μmol) was added to dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and stirring was continued at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-2 - ((4 - ((4 - (3 - ((2 - (1 - hydroxyethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)benzyl)amino)ethan - 1 - ol 34 (40.0 mg) in a yield of 66.47%.

[0460] MS m / z(ESI): 443.2 [M + 1] Example 35

[0461] (S)-2 - ((4 - ((4 - (3 - ((2 - (1 - hydroxyethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)benzyl)amino)acetamide (S)-2 - ((4 - ((4 - (3 - ((2 - (1 - hydroxyethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)benzyl)amino)acetamide

Chemical formula

Chemical formula

[0462] Step 1 methyl(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)glycinate (4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)glycine methyl ester

[0463] 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (200 mg, 415.33 μmol) and glycine methyl ester (104.29 mg, 830.67 μmol) were dissolved in 1,2-dichloroethane (20 mL), acetic acid (0.5 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (264.08 mg, 1.25 mmol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain (4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)glycine methyl ester 35a (200 mg) in a yield of 86.82%.

[0464] MS m / z(ESI):555.0 [M+1]

[0465] Step 2 2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)acetamide 2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)acetamide

[0466] (4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)glycine methyl ester 35a (50 mg, 90.15 μmol) and aqueous ammonia (3 mL) were successively added to ethanol (3 mL), and stirring was continued at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)acetamide 35b (40 mg), which was used directly in the next reaction.

[0467] MS m / z(ESI):540.0 [M+1]

[0468] Step 3 (S)-2-((4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)acetamide (S)-2-((4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)acetamide

[0469] 2-((4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)acetamide 35b (40 mg, 74.13 μmol) and trifluoroacetic acid (0.5 mL) were successively added to dichloromethane (2 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-2-((4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)acetamide 35 (10.4 mg) in a yield of 22.42%.

[0470] MS m / z (ESI): 456.2 [M+1] Example 36

[0471] (S)-1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperidin-4-ol (S)-1-((5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperidin-4-ol [Chemical formula] [Chemical formula]

[0472] Step 1 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde

[0473] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2 g (200 mg, 417.27 μmol), 5-ethynylpicolinaldehyde 36a (109.43 mg, 834.53 μmol), allylpalladium chloride (II) dimer (30.46 mg, 83.45 μmol), triethylenediamine (140.41 mg, 1.25 mmol) and tri-tert-butylphosphine (10% toluene solution) (168.84 mg, 83.45 μmol) were sequentially added to acetonitrile (2 mL). The mixture was purged with argon three times and stirred at room temperature for 12 hours. After completion of the reaction, ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (108 mg) in a yield of 53.64%.

[0474] MS m / z (ESI): 483.3 [M+1]

[0475] Step 2 1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperidin-4-ol 1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperidin-4-ol

[0476] 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (50 mg, 103.62 μmol) and piperidin-4-ol 36c (15.72 mg, 155.43 μmol) were dissolved in dichloromethane (0.5 mL), stirred for 30 minutes, sodium triacetoxyborohydride (43.92 mg, 207.24 μmol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, the layers were separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperidin-4-ol 36d (20 mg) in a yield of 34.00%.

[0477] MS m / z (ESI): 568.4 [M+1]

[0478] Step 3 (S)-1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)piperidin-4-ol (S)-1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)piperidin-4-ol

[0479] 1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)piperidin-4-ol 36d (20 mg, 35.23 μmol) and trifluoroacetic acid (12.05 mg, 105.69 μmol) were successively added to dichloromethane (2 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)piperidin-4-ol 36 (10 mg) in a yield of 47.36%.

[0480] MS m / z (ESI): 484.3 [M+1] Example 37

[0481] (S)-1-(1-((5-(4-((6-(hydroxymethyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((6-(ヒドロキシメチル)ピリジン-3-イル)エチニル)フェニル)イソオキサゾール-3-イル)メチル)-1H-イミダゾール-2-イル)エタン-1-オール

Chem.

Chem.

[0482] Step 1 (5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl) methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methanol (5-((4-(3-((2-((1S)- 1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methanol

[0483] 5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (50 mg, 103.62 μmol) was dissolved in dichloromethane (0.5 mL), sodium triacetoxyborohydride (39.53 mg, 186.52 μmol) was added, and stirring was continued at room temperature for 12 hours. After completion of the reaction, saturated aqueous sodium bicarbonate solution (15 mL) was added to quench, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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 obtain (5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methanol 37a (20 mg), which was used directly in the next reaction.

[0484] MS m / z(ESI):485.0 [M+1]

[0485] Step 2 (S)-1-(1-((5-(4-((6-(hydroxymethyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((6-(hydroxymethyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0486] (5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methanol 37a (10 mg, 20.64 μmol) and trifluoroacetic acid (4.71 mg, 41.28 μmol) were sequentially added to dichloromethane (2 mL), and stirring was continued at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((6-(hydroxymethyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 37 (4.90 mg) in a yield of 44.77%.

[0487] MS m / z(ESI): 401.3 [M+1] Example 38

[0488] (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile

Chemical formula

Chemical formula

[0489] Step 1 2-(3-((trimethylsilyl)ethynyl)phenoxy)acetonitrile 2-(3-((Trimethylsilyl)ethynyl)phenoxy)acetonitrile

[0490] 2-(3-Bromophenoxy)acetonitrile 38a (50 mg, 235.80 μmol, produced according to JP-A-2000-34258A2), (trimethylsilyl)acetylene (27.79 mg, 282.96 μmol, 39.99 μL), allylpalladium chloride (II) dimer (8.63 mg, 23.58 μmol), tri-tert-butylphosphine (10% toluene solution) (4.77 mg, 23.58 μmol) and triethylenediamine (79.35 mg, 707.40 μmol) were successively added to acetonitrile (1 mL), purged with argon three times, the reaction solution was heated to 100 °C and stirred for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to obtain 2-(3-((trimethylsilyl)ethynyl)phenoxy)acetonitrile 38b (35 mg) in a yield of 64.72%.

[0491] MS m / z (ESI): 229.9 [M+1]

[0492] Step 2 2-(3-ethynylphenoxy)acetonitrile 2-(3-Ethynylphenoxy)acetonitrile

[0493] 2-(3-((Trimethylsilyl)ethynyl)phenoxy)acetonitrile 38b (70 mg, 305.21 μmol) and potassium fluoride (53.20 mg, 915.63 μmol) were successively added to methanol (1 mL), and stirring was continued at 25 °C for 16 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain 2-(3-ethynylphenoxy)acetonitrile 38c (47 mg), which was used as it was in the next reaction.

[0494] MS m / z (ESI): 157.9 [M+1]

[0495] Step 3 2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile 2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile

[0496] 2-(3-Ethynylphenoxy)acetonitrile 38c (50 mg, 318.13 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2 g (76.24 mg, 159.07 μmol), allylpalladium chloride (II) dimer (11.64 mg, 31.81 μmol), tri-tert-butylphosphine (10% toluene solution) (6.44 mg, 31.81 μmol) and triethylenediamine (107.06 mg, 954.39 μmol) were successively added to acetonitrile (1 mL), and argon substitution was carried out 3 times. Stirring was continued at 25 °C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile 38d (10 mg) in a yield of 6.18%.

[0497] MS m / z(ESI):509.0 [M+1]

[0498] Step 4 (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile

[0499] Trifluoroacetic acid (6.73 mg, 58.99 μmol) was slowly added dropwise to a dichloromethane solution (0.5 mL) of 2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile 38d (10 mg, 19.66 μmol), and stirring was continued at 25 °C for 16 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 I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile 38 (5.4 mg) in a yield of 51%.

[0500] MS m / z(ESI): 424.9 [M+1] Example 39

[0501] (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetic acid (S)-2-(5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetic acid

Chem.

Chem.

[0502] Step 1 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole

[0503] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2 g (250 mg, 521.58 μmol), (trimethylsilyl)acetylene (204.92 mg, 2.09 mmol, 294.84 μL), allylpalladium chloride (II) dimer (28.56 mg, 78.24 μmol), triethylenediamine (117.01 mg, 1.04 mmol) and tri-tert-butylphosphine (10% toluene solution) (211.05 mg, 104.32 μmol) were sequentially added to acetonitrile (4.75 mL). The mixture was purged with argon three times and stirred at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain 3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole 39a (200 mg) in a yield of 85.28%.

[0504] MS m / z(ESI):450.3 [M+1]

[0505] Step 2 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 5-(4-Ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0506] 3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)-5-(4-((trimethylsilyl)ethynyl)phenyl)isoxazole 39a (200 mg, 444.82 μmol) and potassium fluoride (77.53 mg, 1.33 mmol) were sequentially added to methanol (5 mL), and stirring was continued at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to obtain 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 39b (150 mg) in a yield of 89.34%.

[0507] MS m / z(ESI):378.2 [M+1]

[0508] Step 3 methyl 2-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetate methyl 2-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetate

[0509] 5-(4-Ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 39b (100 mg, 264.95 μmol), methyl 2-(5-bromopyridin-2-yl)acetate 39c (30.48 mg, 132.47 μmol, commercially available), allylpalladium chloride (II) dimer (19.34 mg, 52.99 μmol), triethylenediamine (89.16 mg, 794.84 μmol) and tri-tert-butylphosphine (10% toluene solution) (107.21 mg, 52.99 μmol, purity 10%) were sequentially added to acetonitrile (2 mL). The mixture was purged with argon three times and stirred at room temperature for 12 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: system B) to obtain methyl 2-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetate 39d (12 mg) in a yield of 8.60%.

[0510] MS m / z(ESI):527.3 [M+1]

[0511] Step 4 methyl(S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetate (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl acetate

[0512] Methyl (S)-2-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetate 39d (12 mg, 22.79 μmol) and trifluoroacetic acid (5.20 mg, 45.58 μmol) were successively added to dichloromethane (1 mL), and stirring was continued at room temperature for 12 hours. After completion of the reaction, it was concentrated under reduced pressure to obtain methyl (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetate 39e (10 mg), which was used directly in the next reaction.

[0513] MS m / z(ESI):443.3 [M+1]

[0514] Step 5 (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)acetic acid (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetic acid

[0515] (S)-Methyl 2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetate 39e (10 mg, 22.60 μmol) was added to a mixed solvent of methanol (2 mL) and tetrahydrofuran (2 mL), and 2.5 N aqueous sodium hydroxide solution (1 mL) was added to the mixture. Stirring was continued at room temperature for 12 hours. 1 N dilute hydrochloric acid was added to adjust the pH to 5, and the reaction solution was concentrated under reduced pressure. Ethyl acetate (30 mL) and water (15 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetic acid 39 (1.8 mg) in a yield of 13.21%.

[0516] MS m / z(ESI): 429.0 [M+1] 1 H NMR(400 MHz, DMSO-d6) δ8.72(br,1H), 8.03 -7.94(m,3H), 7.82 -7.73(m,4H), 7.44(dd,J=26.4,8.0 Hz,1H), 7.22(s,1H), 5.76(s,2H), 5.29(q,J=6.4 Hz,1H), 3.84(s,1H), 2.55(d,J=6.4 Hz,2H), 1.52(d,J=6.4 Hz,3H). Example 40

[0517] (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propanamide (S)-3-(5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionamide

Chem.

Chem.

[0518] Step 1 ethyl 3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)propanoate Ethyl 3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)propionate

[0519] Ethyl 3-(5-bromopyridin-2-yl)propionate 40a (200 mg, 774.86 μmol, commercially available), (trimethylsilyl)acetylene (456.63 mg, 4.65 mmol, 657.02 μL), allylpalladium chloride (II) dimer (56.56 mg, 154.97 μmol), triethylenediamine (260.75 mg, 2.32 mmol) and tri-tert-butylphosphine (10% toluene solution) (313.54 mg, 154.97 μmol) were sequentially added to acetonitrile (2.53 mL). The reaction mixture was purged with argon three times, heated to 100 °C and stirred for 6 hours. Ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, dried, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain ethyl 3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)propionate 40b (180 mg) in a yield of 84.34%.

[0520] MS m / z (ESI): 276.2 [M+1]

[0521] Step 2 ethyl 3-(5-ethynylpyridin-2-yl)propanoate Ethyl 3-(5-ethynylpyridin-2-yl)propionate

[0522] Ethyl 3-(5-((trimethylsilyl)ethynyl)pyridin-2-yl)propionate 40b (180 mg, 653.55 μmol) and potassium fluoride (75.94 mg, 1.31 mmol) were successively added to methanol (2 mL), and stirring was continued at room temperature for 12 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to obtain ethyl 3-(5-ethynylpyridin-2-yl)propionate 40c (108 mg) in a yield of 81.31%.

[0523] MS m / z (ESI): 204.2 [M+1]

[0524] Step 3 ethyl 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propanoate Ethyl 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionate

[0525] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (170 mg, 354.68 μmol), ethyl 3-(5-ethynylpyridin-2-yl)propionate 40c (108.13 mg, 532.01 μmol), allylpalladium chloride (II) dimer (25.89 mg, 70.94 μmol), triethylenediamine (119.35 mg, 1.06 mmol) and tri-tert-butylphosphine (10% toluene solution) (143.52 mg, 70.94 μmol) were sequentially added to acetonitrile (2 mL), and the argon replacement was carried out 3 times, followed by stirring at room temperature for 12 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: system B) to obtain ethyl 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionate 40d (30 mg) in a yield of 15.25%.

[0526] MS m / z(ESI): 555.0 [M+1]

[0527] Step 4 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propanamide 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionamide

[0528] Ethyl 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionate 40d (30 mg, 54.09 μmol) and aqueous ammonia (18.96 mg, 540.90 μmol) were successively added to ethanol (0.5 mL), and stirring was continued at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propanamide 40e (20 mg), which was used directly in the next reaction.

[0529] MS m / z(ESI):526.3 [M+1]

[0530] Step 5 (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)propanamide (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propanamide

[0531] 3-(5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionamide 40e (20 mg, 38.05 μmol) and trifluoroacetic acid (13.02 mg, 114.16 μmol) were successively added to dichloromethane (2 mL), and stirring was continued at room temperature for 12 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionamide 40 (4.20 mg) in a yield of 19.45%.

[0532] MS m / z(ESI): 442.2 [M+1] Example 41

[0533] (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)piperidin-4-ol (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)piperidin-4-ol

Chem.

Chem.

[0534] Step 1 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)piperidin-4-ol 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole-1-yl)methyl)isoxazole-5-yl)phenyl)ethynyl)phenyl)piperidin-4-ol

[0535] 5-(4-((4-bromophenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole-1-yl)methyl)isoxazole 29d (50 mg, 281.73 μmol), 4-hydroxypiperidine 41a (28.50 mg, 9.39 μmol, commercially available), sodium tert-butoxide (27.07 mg, 281.73 μmol) and methanesulfonic acid (2-dicyclohexylphosphino-2’,6’-diisopropoxy-1,1’-biphenyl)(2-amino-1,1’-biphenyl-2-yl)palladium(II) (7.86 mg, 9.39 μmol) were sequentially added to 1,4-dioxane (1 mL), the argon substitution was carried out 3 times, the temperature was raised to 100 °C and stirred for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to obtain 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazole-1-yl)methyl)isoxazole-5-yl)phenyl)ethynyl)phenyl)piperidin-4-ol 41b (10 mg) in a yield of 19.27%.

[0536] MS m / z(ESI):553.0 [M+1]

[0537] Step 2 (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)piperidin-4-ol (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)piperidin-4-ol

[0538] 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)piperidin-4-ol 41b (10 mg, 18.09 μmol) was added to dichloromethane (0.5 mL), trifluoroacetic acid (2.06 mg, 18.09 μmol) was slowly added dropwise, and the mixture was stirred at 25 °C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)piperidin-4-ol 41 (7 mg) in a yield of 63.88%.

[0539] MS m / z(ESI): 469.0 [M+1] Example 42

[0540] (S)-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)(4-methylpiperazin-1-yl)methanone (S)-(4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)(4-methylpiperazin-1-yl)methanone

Chem.

Chem.

[0541] Step 1 (4-methylpiperazin-1-yl)(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanone (4-Methylpiperazin-1-yl)(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanone

[0542] 1-Methylpiperazine 42a (10 mg, 99.84 μmol, commercially available), 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzoic acid 24b (49.7 mg, 99.84 μmol), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (75.9 mg, 199.68 μmol) and N,N-diisopropylethylamine (38.7 mg, 299.52 μmol) were sequentially added to dimethyl sulfoxide (2 mL), and reacted at room temperature for 4 hours. After completion of the reaction, water (50 mL) was added to quench the reaction, ethyl acetate was added for extraction (50 mL × 3), the organic phases were combined and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: B system) to obtain (4-methylpiperazin-1-yl)(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanone 42b (40 mg) in a yield of 69.11%.

[0543] MS m / z(ESI):580.1 [M+1]

[0544] Step 2 (S)-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenyl)(4-methylpiperazin-1-yl)methanone (S)-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)(4-methylpiperazin-1-yl)methanone

[0545] (4-Methylpiperazin-1-yl)(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanone 42b (40 mg, 69.00 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.2 mL) was added dropwise, and the mixture was reacted at room temperature for 3 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 I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)(4-methylpiperazin-1-yl)methanone 42 (10 mg) in a yield of 22.58%.

[0546] MS m / z(ESI): 496.1[M+1] Example 43

[0547] (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)-N-methylbenzamide (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)-N-methylbenzamide

Chemical formula

Chemical formula

[0548] Step 1 N-methyl-4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide N-methyl-4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide

[0549] Methylamine gas was poured into a solution of 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzoic acid 24b (50 mg, 100.49 μmol), triethylamine (30.5 mg, 301.48 μmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (28.9 mg, 150.74 μmol) and 1-hydroxybenzotriazole (20.4 mg, 150.74 μmol) in N,N-dimethylformamide (5 mL), and the mixture was reacted at room temperature for 24 hours. After completion of the reaction, water (50 mL) was added to quench the reaction, and ethyl acetate was added for extraction (50 mL × 3). The organic phases were combined and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain N-methyl-4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 43a (10 mg) in a yield of 19.49%.

[0550] MS m / z(ESI):511.3 [M+1]

[0551] Step 2 (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)-N-methylbenzamide (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)-N-methylbenzamide

[0552] N-methyl-4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)benzamide 43a (10 mg, 19.59 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.2 mL) was added, and the reaction was carried out at room temperature for 4 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)-N-methylbenzamide 43 (840.00 μg) in a yield of 7.54%.

[0553] MS m / z(ESI):427.3[M+1] Example 44

[0554] (S)-1-(1-((5-(4-((4-((1-methylpiperidin-4-yl)oxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((1-methylpiperidin-4-yl)oxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol [Chemistry] [Chemistry]

[0555] Step 1 5-(4-((4-((1-methylpiperidin-4-yl)oxy)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 5-(4-((4-((1-methylpiperidin-4-yl)oxy)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0556] 5-(4-((4-Bromophenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 29d (50 mg, 93.91 μmol), 1-methylpiperidin-4-ol 44a (32.45 mg, 281.73 μmol, 33.11 μL), tris(dibenzylideneacetone)dipalladium (8.40 mg, 18.78 μmol), 5-di-tert-butylphosphine-1’,3’,5’-triphenyl-1’H-[1,4’]dipyrazole (19.03 mg, 37.56 μmol) and cesium carbonate (91.79 mg, 281.73 μmol) were sequentially added to toluene (0.5 mL), and argon substitution was performed three times. The temperature was raised to 100 °C and stirred for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: System B) to obtain 5-(4-((4-((1-methylpiperidin-4-yl)oxy)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 44b (20 mg) in a yield of 37.58%.

[0557] MS m / z(ESI):567.0 [M+1]

[0558] Step 2 (S)-1-(1-((5-(4-((4-((1-methylpiperidin-4-yl)oxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((1-methylpiperidin-4-yl)oxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0559] 5-(4-((4-((1-Methylpiperidin-4-yl)oxy)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 44b (20 mg, 35.29 μmol) was added to dichloromethane (0.5 mL), and trifluoroacetic acid (12.07 mg, 105.88 μmol) was slowly added dropwise, followed by stirring at 25 °C for 16 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 I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-((1-methylpiperidin-4-yl)oxy)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 44 (10 mg) in a yield of 55.49%.

[0560] MS m / z(ESI): 484.0 [M+1] Example 45

[0561] (S)-1-(1-((5-(4-(pyridin-2-ylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-(pyridin-2-ylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0562] Step 1 5-(4-(Pyridin-2-ylethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 5-(4-(Pyridin-2-ylethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0563] 2-Ethynylpyridine 45a (150.00 mg, 1.45 mmol, 146.91 μL), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2 g (464.80 mg, 969.73 μmol), allylpalladium chloride (II) dimer (35.48 mg, 96.97 μmol), tri-tert-butylphosphine (19.62 mg, 96.97 μmol) and triethylenediamine (326.33 mg, 2.91 mmol) were sequentially added to acetonitrile (1 mL), the argon substitution was carried out 3 times, and the mixture was stirred at 25 °C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent: A system) to obtain 5-(4-(pyridin-2-ylethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 45b (320 mg) in a yield of 72.60%.

[0564] MS m / z (ESI): 455.0 [M+1]

[0565] Step 2 (S)-1-(1-((5-(4-(pyridin-2-ylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-(Pyridin-2-ylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0566] 5-(4-(Pyridin-2-ylethynyl)phenyl)-3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 45b (320 mg, 704.04 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (80.28 mg, 704.04 μmol, 2 mL) was slowly added dropwise. The mixture was stirred at 25 °C for 4 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-(Pyridin-2-ylethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 45 (10 mg) in a yield of 2.58%.

[0567] MS m / z (ESI): 371.0 [M+1] Example 46

[0568] (S)-1-(1-((5-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-(Hydroxymethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0569] Step 1 (4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanol (4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanol

[0570] 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (20 mg, 41.53 μmol) was added to 1,2-dichloroethane (3 mL), stirred for 30 minutes, sodium cyanoborohydride (2.61 mg, 41.53 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench, dichloromethane (30 mL) and water (15 mL) were added, the layers were separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the organic phases were combined, washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain (4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanol 46a (10 mg) in a yield of 48.55%.

[0571] MS m / z(ESI): 484.0 [M+1]

[0572] Step 2 (S)-1-(1-((5-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0573] (4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenyl)methanol 46a (10 mg, 20.68 μmol) and trifluoroacetic acid (0.2 mL) were successively added to dichloromethane (5 mL), and stirring was continued at room temperature for 12 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-(hydroxymethyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 46 (2.0 mg) in a yield of 21.79%.

[0574] MS m / z(ESI):400.1 [M+1] Example 47

[0575] 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylic acid 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylic acid [Chemical] [Chemical]

[0576] Step 1 methyl 4-(4-((trimethylsilyl)ethynyl)benzyl)morpholine-2-carboxylate methyl 4-(4-((trimethylsilyl)ethynyl)benzyl)morpholine-2-carboxylate

[0577] 4-((trimethylsilyl)ethynyl)benzaldehyde 17a (200 mg, 988.51 μmol), methyl morpholine-2-carboxylate 47a (269.30 mg, 1.48 mmol) were dissolved in 1,2-dichloroethane (5 mL), (0.4 mL) was added, stirred for 30 minutes, sodium acetoxyborohydride (628.52 mg, 2.97 mmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench, dichloromethane (30 mL) and water (15 mL) were added, separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 4-(4-((trimethylsilyl)ethynyl)benzyl)morpholine-2-carboxylate 47b (120 mg) in a yield of 36.62%.

[0578] MS m / z(ESI): 331.2 [M+1]

[0579] Step 2 methyl 4-(4-ethynylbenzyl)morpholine-2-carboxylate methyl 4-(4-ethynylbenzyl)morpholine-2-carboxylate

[0580] Methyl 4-(4-((trimethylsilyl)ethynyl)benzyl)morpholine-2-carboxylate 47b (120 mg, 362.01 μmol) and potassium fluoride (105.16 mg, 1.81 mmol) were sequentially added to methanol (3 mL), and stirring was continued at room temperature for 12 hours. The system was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain methyl 4-(4-ethynylbenzyl)morpholine-2-carboxylate 47c (90 mg) in a yield of 95.88%.

[0581] MS m / z (ESI): 260.1 [M+1]

[0582] Step 3 methyl4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylate Methyl 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylate

[0583] Methyl 4-(4-ethynylbenzyl)morpholine-2-carboxylate 47c (50 mg, 192.83 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (101.67 mg, 212.11 μmol), allylpalladium(II) chloride dimer (7.06 mg, 19.28 μmol), tri-tert-butylphosphine (39.01 mg, 19.28 μmol, 10% toluene solution), and triethylenediamine (64.89 mg, 578.48 μmol) were sequentially added to acetonitrile (2 mL). The mixture was purged with argon three times and stirred at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: B system) to obtain methyl 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylate 47d (60 mg) in a yield of 50.95%.

[0584] MS m / z(ESI):611.3 [M+1]

[0585] Step 4 methyl4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylate Methyl 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylate

[0586] Methyl 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylate 47d (50 mg, 81.87 μmol) was added to dichloromethane (3 mL) and stirred, and trifluoroacetic acid (0.5 mL) was added thereto, followed by continued stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain methyl 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylate 47e (30 mg), which was used directly in the next reaction.

[0587] MS m / z(ESI):527.2 [M+1]

[0588] Step 5 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylic acid 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylic acid

[0589] Methyl 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylate 47e (30 mg, 56.97 μmol) and lithium hydroxide monohydrate (7.17 mg, 170.91 μmol) were successively added to tetrahydrofuran (3 mL), and stirring was continued at room temperature for 12 hours. The system was adjusted to pH 5 with 2N dilute hydrochloric acid and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 4-(4-((4-(3-((2-((S)-1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)morpholine-2-carboxylic acid 47 (20 mg) in a yield of 56.03%.

[0590] MS m / z(ESI): 512.9 [M+1] Example 48

[0591] (S)-1-(1-((5-(4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0592] Step 1 5-(4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 5-(4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole

[0593] 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (25 mg, 51.92 μmol) and 1-methylpiperazine 48a (7.80 mg, 77.87 μmol, commercially available) were dissolved in methanol (2 mL), acetic acid (0.2 mL) was added, and the mixture was stirred for 30 minutes. Sodium cyanoborohydride (9.79 mg, 155.75 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 5-(4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 48b (25 mg) in a yield of 85.12%.

[0594] MS m / z (ESI): 566.7 [M+1]

[0595] Step 2 (S)-1-(1-((5-(4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethanol

[0596] 5-(4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 48b (25 mg, 44.19 μmol) was added to dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and stirring was continued at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 48 (18.0 mg) in a yield of 67.29%.

[0597] MS m / z(ESI):482.0 [M+1] Example 49

[0598] (S)-1-(1-((5-(4-((4-(((2-(methylsulfonyl)ethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-(((2-(methylsulfonyl)ethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chem.

Chem.

[0599] Step 1 2-(methylsulfonyl)-N-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)ethan-1-amine 2-(methylsulfonyl)-N-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)ethan-1-amine

[0600] 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (25 mg, 51.92 μmol) and 2-(methylsulfonyl)ethan-1-amine 49a (7.67 mg, 62.30 μmol, commercially available) were dissolved in 1,2-dichloroethane (2 mL), acetic acid (0.2 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (33.01 mg, 155.75 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 2-(methylsulfonyl)-N-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)ethan-1-amine 49b (25 mg) in a yield of 81.80%.

[0601] MS m / z(ESI):589.2 [M+1]

[0602] Step 2 (S)-1-(1-((5-(4-((4-(((2-(methylsulfonyl)ethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-(((2-(methylsulfonyl)ethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0603] 2-(Methylsulfonyl)-N-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)ethane-1-amine 49b (25 mg, 42.47 μmol) was added to dichloromethane (3 mL), trifluoroacetic acid (0.3 mL) was added, and stirring was continued at room temperature for 4 hours. It was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-(((2-(Methylsulfonyl)ethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethane-1-ol 49 (19 mg) in a yield of 68.85%.

[0604] MS m / z (ESI): 505.2 [M+1] Example 50

[0605] (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide

Chemical formula

Chemical formula

[0606] Step 1 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide

[0607] 5-(4-Iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2g (30 mg, 62.59 μmol), 4-(4-Ethynylbenzyl)thiomorpholine 1,1-dioxide 50a (23.41 mg, 93.88 μmol, prepared by the inventors themselves according to JP-A WO2017093544), allyl palladium chloride (II) dimer (2.29 mg, 6.26 μmol), tri-tert-butylphosphine (12.66 mg, 6.26 μmol, 10% toluene solution) and triethylenediamine (21.06 mg, 187.77 μmol) were successively added to acetonitrile (5 mL), purged with argon three times, and stirred at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide 50b (30 mg) in a yield of 79.79%.

[0608] MS m / z (ESI): 601.4 [M+1]

[0609] Step 2 (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide

[0610] 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide 50b (30 mg, 49.94 μmol) was added to dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and stirring was continued at room temperature for 4 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide 50 (3.3 mg) in a yield of 9.95%.

[0611] MS m / z (ESI): 517.0 [M+1] Example 51

[0612] (S)-1-(1-((5-(4-((4-((4-morpholinopiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((4-Morpholinopiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chem.

Chem.

[0613] Step 1 4-(1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)morpholine 4-(1-(4-((4-(3-((2-((1S)-1-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)morpholine

[0614] 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (50 mg, 103.83 μmol) and 4-(piperidin-4-yl)morpholine 51a (35.36 mg, 207.67 μmol, commercially available) were dissolved in 1,2-dichloroethane (5 mL), acetic acid (0.2 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (66.02 mg, 311.50 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 4-(1-(4-((4-(3-((2-((1S)-1-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)morpholine 51b (50 mg) in a yield of 75.74%.

[0615] MS m / z(ESI):636.4 [M+1]

[0616] Step 2 (S)-1-(1-((5-(4-((4-((4-morpholinopiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((4-morpholinopiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0617] 4-(1-(4-((4-(3-((2-((1S)-1-(tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)morpholine 51b (50 mg, 78.64 μmol) was added to dichloromethane (5 mL), trifluoroacetic acid (0.2 mL) was added, and stirring was continued at room temperature for 2 hours. It was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-((4-morpholinopiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 51 (50.0 mg) in a yield of 76.79%.

[0618] MS m / z(ESI): 552.3 [M+1] Example 52

[0619] (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile

Chemical Structure

Chemical Structure

[0620] Step 1 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile

[0621] 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (50 mg, 103.83 μmol) and azetidine-3-carbonitrile 52a (24.62 mg, 207.67 μmol, commercially available) were dissolved in 1,2-dichloroethane (5 mL), acetic acid (0.2 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (66.02 mg, 311.50 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile 52b (50 mg) in a yield of 87.93%.

[0622] MS m / z(ESI):548.3 [M+1]

[0623] Step 2 (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile

[0624] 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile 52b (50 mg, 91.30 μmol) was added to dichloromethane (5 mL), trifluoroacetic acid (0.2 mL) was added, and stirring was continued at room temperature for 2 hours. It was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile 52 (50.1 mg) in a yield of 87.13%.

[0625] MS m / z(ESI): 464.0 [M+1] Example 53

[0626] (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide (S)-1-(4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide

Chem.

Chem.

[0627] Step 1 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide

[0628] 1-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile 52b (50 mg, 91.30 μmol) was added to dimethyl sulfoxide (1 mL), and 2.5 M aqueous sodium hydroxide solution (1 mL) and hydrogen peroxide (0.3 mL) were sequentially added under an ice bath, and stirring was continued at room temperature for 0.5 hour. Ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to dryness, and 1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide 53a (40 mg) was obtained and used directly in the next reaction.

[0629] MS m / z(ESI):566.3 [M+1]

[0630] Step 2 (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide

[0631] 1-(4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide 53a (40 mg, 70.71 μmol) was added to dichloromethane (5 mL), trifluoroacetic acid (0.2 mL) was added, and stirring was continued at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide 53 (25.9 mg) in a yield of 55.35%.

[0632] MS m / z(ESI): 482.2 [M+1] Example 54

[0633] (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperazin-2-one (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperazin-2-one

Chem.

Chem.

[0634] Step 1 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperazin-2-one 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperazin-2-one

[0635] 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (50 mg, 103.83 μmol) and piperazin-2-one 54a (15.59 mg, 155.75 μmol, commercially available) were dissolved in 1,2-dichloroethane (5 mL), acetic acid (0.2 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (66.02 mg, 311.50 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperazin-2-one 54b (50 mg) in a yield of 85.13%.

[0636] MS m / z(ESI):566.3 [M+1]

[0637] Step 2 (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperazin-2-one (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperazin-2-one

[0638] 4-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperazin2-one 54b (50 mg, 88.39 μmol) was added to dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and stirring was continued at room temperature for 2 hours. It was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-4-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperazin-2-one 54 (26.1 mg) in a yield of 47.15%.

[0639] MS m / z(ESI):482.2 [M+1] Example 55

[0640] (S)-3-((4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)propanoic acid (S)-3-((4-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)propanoic acid

Chem.

Chem.

[0641] Step 1 3-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)propanoic acid 3-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)propanoic acid

[0642] 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (50 mg, 103.83 μmol) and 3-aminopropionic acid 55a (13.88 mg, 155.75 μmol) were dissolved in 1,2-dichloroethane (5 mL), acetic acid (0.2 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (66.02 mg, 311.50 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain 3-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)propanoic acid 55b (50 mg) in a yield of 86.82%.

[0643] MS m / z(ESI):555.3 [M+1]

[0644] Step 2 (S)-3-((4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)benzyl)amino)propanoic acid (S)-3-((4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)propanoic acid

[0645] 3-((4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)propanoic acid 55b (50 mg, 90.15 μmol) was added to dichloromethane (5 mL), trifluoroacetic acid (0.5 mL) was added, and stirring was continued at room temperature for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-3-((4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)propanoic acid 55 (23.0 mg) in a yield of 39.28%.

[0646] MS m / z(ESI): 471.0 [M+1] Example 56

[0647] (S)-1-(1-((5-(4-((4-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0648] Step 1 (1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)methanol (1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)methanol

[0649] 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (75 mg, 155.75 μmol) and piperidin-4-ylmethanol 56a (42.84 mg, 186.90 μmol, commercially available) were dissolved in 1,2-dichloroethane (5 mL), acetic acid (0.5 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (99.03 mg, 467.25 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain (1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)methanol 56b (65 mg) in a yield of 71.87%.

[0650] MS m / z(ESI):581.3 [M+1]

[0651] Step 2 (S)-1-(1-((5-(4-((4-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0652] (1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)piperidin-4-yl)methanol 56b (65 mg, 111.93 μmol) and trifluoroacetic acid (0.5 mL) were sequentially added to dichloromethane (5 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, the obtained residue was added to methanol (2 mL), 5M aqueous sodium hydroxide solution (2 mL) was added, and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-((4-(hydroxymethyl)piperidin-1-yl)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 56 (20.5 mg) in a yield of 28.49%.

[0653] MS m / z(ESI):497.0 [M+1] Example 57

[0654] (S)-1-(1-((5-(4-((4-(((2-aminoethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl) methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-(((2-aminoethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol [ka] [ka]

[0655] Step 1 tert-butyl(2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethyl)carbamate tert-Butyl (2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethyl)carbamate

[0656] 4-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (65 mg, 134.98 μmol) and tert-butyl (2-aminoethyl)carbamate 57a (32.44 mg, 202.47 μmol, commercially available) were dissolved in 1,2-dichloroethane (20 mL), acetic acid (0.5 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (85.83 mg, 404.95 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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. The resulting residue was purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl (2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethyl)carbamate 57b (65 mg) in a yield of 76.95%.

[0657] MS m / z(ESI):626.0 [M+1]

[0658] Step 2 (S)-1-(1-((5-(4-((4-(((2-aminoethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((4-(((2-aminoethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0659] (2-((4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)amino)ethyl)carbamic acid tert-butyl 57b (65.00 mg, 103.87 μmol) and trifluoroacetic acid (1 mL) were successively added to dichloromethane (3 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((4-(((2-aminoethyl)amino)methyl)phenyl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 57 (20 mg) in a yield of 31.95%.

[0660] MS m / z(ESI): 442.3 [M+1] Example 58

[0661] (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)propanoic acid (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propanoic acid

Chemical formula

Chemical formula

[0662] Step 1 ethyl 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propanoate ethyl 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionate

[0663] 5-(4-ethynylphenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 39b (100 mg, 264.95 μmol), ethyl 3-(5-bromopyridin-2-yl)propionate 58a (34.19 mg, 132.47 μmol, prepared by the inventors themselves according to JP-A WO2017221100), allyl palladium chloride (II) dimer (19.34 mg, 52.99 μmol), triethylenediamine (89.16 mg, 794.84 μmol) and tri-tert-butylphosphine (107.21 mg, 52.99 μmol, 10% toluene solution) were successively added to acetonitrile (2 mL), purged with argon three times, and stirred at room temperature for 12 hours. After completion of the reaction, it was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System B) to obtain ethyl 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionate 58b (20 mg) in a yield of 13.61%.

[0664] MS m / z (ESI): 555.4 [M+1]

[0665] Step 2 ethyl (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propanoate (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)ethyl propionate

[0666] Ethyl 3-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionate (20 mg, 36.06 μmol) and trifluoroacetic acid (8.22 mg, 72.12 μmol) were successively added to dichloromethane (1 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain ethyl (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionate 58c (10 mg) in a yield of 58.94%.

[0667] MS m / z (ESI): 471.3 [M+1]

[0668] Step 3 (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propanoic acid (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionic acid

[0669] (S)-Ethyl 3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionate 58c (10 mg, 21.25 μmol) was added to a mixed solution of methanol (2 mL) and tetrahydrofuran (2 mL), and 2.5 M aqueous sodium hydroxide solution (1 mL) was added to the mixture. The mixture was stirred at room temperature for 12 hours. 1 M dilute hydrochloric acid was added to adjust the pH to 5, and the reaction solution was concentrated under reduced pressure. Ethyl acetate (30 mL) and water (15 mL) were added to the residue, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-3-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)propionic acid 58 (2.5 mg) in a yield of 18.18%.

[0670] MS m / z(ESI):443.2 [M+1] Example 59

[0671] (S)-1-(1-((5-(4-((6-(((2-(methylsulfonyl)ethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((6-(((2-(methylsulfonyl)ethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical Structure

[0672] Step 1 2-(methylsulfonyl)-N-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)ethan-1-amine 2-(methylsulfonyl)-N-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)ethan-1-amine

[0673] 5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (50 mg, 103.62 μmol), 2-(methylsulfonyl)ethan-1-amine 59a (19.15 mg, 155.43 μmol, commercially available) were dissolved in dichloromethane (0.5 mL), stirred for 30 minutes, sodium triacetoxyborohydride (43.92 mg, 207.24 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench, dichloromethane (30 mL) and water (15 mL) were added, the layers were separated, the aqueous phase was extracted with dichloromethane (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 obtain (S)-1-(1-((5-(4-((6-(((2-(methylsulfonyl)ethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 59b (20 mg), which was used directly in the next reaction.

[0674] MS m / z(ESI):590.3 [M+1]

[0675] Step 2 (S)-1-(1-((5-(4-((6-(((2-(methylsulfonyl)ethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((6-(((2-(methylsulfonyl)ethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0676] (S)-1-(1-((5-(4-((6-(((2-(Methylsulfonyl)ethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 59b (20 mg, 33.92 μmol) was added to dichloromethane (2 mL), and then trifluoroacetic acid (0.5 mL) was added. Stirring was continued at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((6-(((2-(Methylsulfonyl)ethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 59 (12 mg) in a yield of 52.94%.

[0677] MS m / z(ESI): 505.9 [M+1] Example 60

[0678] (S)-2-(((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)ethan-1-ol (S)-2-(((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)ethan-1-ol

Chemical formula

Chemical formula

[0679] Step 1 2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)ethan-1-ol 2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)ethan-1-ol

[0680] 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (50 mg, 103.62 μmol), 2-aminoethan-1-ol 60a (9.49 mg, 155.43 μmol, commercially available) were dissolved in dichloromethane (0.5 mL), stirred for 30 minutes, sodium triacetoxyborohydride (65.88 mg, 310.86 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench, dichloromethane (30 mL) and water (15 mL) were added, the layers were separated, the aqueous phase was extracted with dichloromethane (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 obtain 2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)ethan-1-ol 60b (20 mg), which was used directly in the next reaction.

[0681] MS m / z(ESI):528.3 [M+1]

[0682] Step 2 (S)-2-(((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)amino)ethan-1-ol (S)-2-(((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)amino)ethan-1-ol

[0683] 2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)amino)ethan-1-ol 60b (20 mg, 37.91 μmol) and trifluoroacetic acid (8.64 mg, 75.81 μmol) were successively added to dichloromethane (2 mL), and stirring was continued at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), and (S)-2-(((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)amino)ethan-1-ol 60 (12.75 mg) was obtained in a yield of 57.31%.

[0684] MS m / z(ESI):444.3 [M+1] Example 61

[0685] (S)-2-(((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)amino)acetamide (S)-2-(((5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)acetamide

Chem.

Chem.

[0686] Step 1 2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)acetamide 2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)acetamide

[0687] 5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (50 mg, 103.62 μmol), 2-aminoacetamide 61a (11.51 mg, 155.43 μmol) were dissolved in dichloromethane (0.5 mL), stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (39.53 mg, 186.52 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench, dichloromethane (30 mL) and water (15 mL) were added, separated, the aqueous phase was extracted with dichloromethane (30 mL × 2), the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to obtain 2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)acetamide 61b (20 mg), which was used directly in the next reaction.

[0688] MS m / z(ESI):541.0 [M+1]

[0689] Step 2 (S)-2-(((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)amino)acetamide (S)-2-(((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)acetamide

[0690] 2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)acetamide 61b (20 mg, 37.00 μmol) and trifluoroacetic acid (8.44 mg, 73.99 μmol) were successively added to dichloromethane (2 mL), and stirring was continued at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-2-(((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)acetamide 61 (5.50 mg) in a yield of 3.45%.

[0691] MS m / z(ESI): 457.3 [M+1] Example 62

[0692] (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)acetamide (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetamide

Chemical Structure

Chemical Structure

[0693] Step 1 2-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetamide 2-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetamide

[0694] Methyl 2-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetate (45 mg, 85.46 μmol) and aqueous ammonia (29.95 mg, 854.57 μmol) were successively added to ethanol (1 mL), and stirring was continued at room temperature for 12 hours. Ethyl acetate (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2-(5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetamide 62a (40 mg), which was used directly in the next reaction.

[0695] MS m / z(ESI):512.0 [M+1]

[0696] Step 2 (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)acetamide (S)-2-(5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetamide

[0697] 2-(5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetamide 62a (40 mg, 78.19 μmol) and trifluoroacetic acid (8.92 mg, 78.19 μmol) were successively added to dichloromethane (1 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-2-(5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)acetamide 62 (19.0 mg) in a yield of 44.43%.

[0698] MS m / z(ESI): 428.1 [M+1] Example 63

[0699] (S)-3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide (S)-3-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide [Chemical Structure] [Chemical Structure]

[0700] Step 1 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile

[0701] 3-Ethylbenzonitrile 63a (50 mg, 393.26 μmol), 5-(4-iodophenyl)-3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazole 2 g (94.25 mg, 196.63 μmol), allylpalladium chloride (II) dimer (14.39 mg, 39.33 μmol), tri-tert-butylphosphine (7.96 mg, 39.33 μmol, 10% toluene solution) and triethylenediamine (132.34 mg, 1.18 mmol) were sequentially added to acetonitrile (0.5 mL), and argon substitution was performed three times. The mixture was stirred at 25 °C for 16 hours. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent: System B) to obtain 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile 63b (40 mg) in a yield of 21.26%.

[0702] MS m / z (ESI): 479.0 [M+1]

[0703] Step 2 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide

[0704] 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzonitrile 63b (20 mg, 41.79 μmol) and sodium hydroxide (2.01 mg, 50.15 μmol) were successively added to dimethyl sulfoxide (0.5 mL). While cooling in a water bath, hydrogen peroxide (0.5 mL) was slowly added dropwise, and then the temperature was raised to 25 °C and stirred for 0.5 h. After completion of the reaction, it was concentrated under reduced pressure to obtain 3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 63c (20 mg), which was used directly in the next reaction.

[0705] MS m / z(ESI):497.0 [M+1]

[0706] Step 3 (S)-3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)benzamide (S)-3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide

[0707] 3-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 63c (20 mg, 40.28 μmol) was added to dichloromethane (0.5 mL), and trifluoroacetic acid (13.78 mg, 120.83 μmol) was slowly added dropwise. The mixture was stirred at 25 °C for 16 h. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzamide 63 (6 mg) in a yield of 26.82%.

[0708] MS m / z(ESI): 413.0 [M+1] Example 64

[0709] (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenoxy)acetamide (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenoxy)acetamide

Chemical Structure

Chemical Structure

[0710] Step 1 2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetamide 2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetamide

[0711] 2-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetonitrile 38d (50 mg, 98.32 μmol) and sodium hydroxide (11.80 mg, 294.95 μmol) were sequentially added to dimethyl sulfoxide (0.5 mL). While cooling in a water bath, hydrogen peroxide (0.5 mL) was slowly added dropwise, and then the temperature was raised to room temperature and stirred for 2 hours. After completion of the reaction, it was concentrated under reduced pressure to obtain 2-(3-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetamide 64a (51 mg), which was used directly in the next reaction.

[0712] MS m / z(ESI):527.9 [M+1]

[0713] Step 2 (S)-2-(3-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)phenoxy)acetamide (S)-2-(3-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetamide

[0714] 2-(3-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetamide 64a (50 mg, 94.95 μmol) was added to dichloromethane (1 mL), and trifluoroacetic acid (32.48 mg, 284.86 μmol) was slowly added dropwise, followed by stirring at 25 °C for 16 h. After completion of the reaction, it was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-2-(3-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)phenoxy)acetamide 64 (9.4 mg) in a yield of 16.01%.

[0715] MS m / z (ESI): 442.9 [M+1]

[0716] Examples 65 to 110 were synthesized according to the synthesis methods of Examples 1 to 64 of the present invention, and the structures and characterization data are shown in the following table.

Table 2

[0717] ethyl (S)-2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate (S)-2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)ethyl acetate

Chemical formula

Chemical formula

[0718] Step 1 ethyl 2-(1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate Ethyl 2-(1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate

[0719] 4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzaldehyde 31b (100 mg, 207.67 μmol) and ethyl 2-(azetidin-3-yl)acetate 111a (133.53 mg, 519.17 μmol, commercially available) were dissolved in dichloromethane (2 mL), acetic acid (12.47 mg, 207.67 μmol, 11.88 μL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (70.42 mg, 332.27 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250 × 21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain ethyl 2-(1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate 111b (60 mg) in a yield of 47.46%.

[0720] MS m / z (ESI): 609.4 [M+1]

[0721] Step 2 (S)-ethyl 2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate (S)-ethyl 2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate

[0722] (S)-ethyl 2-(1-(4-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate (120 mg, 197.13 μmol) and trifluoroacetic acid (0.2 mL) were successively added to dichloromethane (6 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-ethyl 2-(1-(4-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)benzyl)azetidin-3-yl)acetate (90 mg) in a yield of 78.44%.

[0723] MS m / z (ESI): 525.3 [M+1] Example 112

[0724] (S)-1-(1-((5-(4-((6-(((2-aminoethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((6-(((2-Aminoethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethanol

Chem.

Chem.

[0725] Step 1 tert-butyl(2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)ethyl)carbamate (2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)ethyl)carbamic acid tert-butyl

[0726] 5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (50 mg, 103.62 μmol) and tert-butyl (2-aminoethyl)carbamate 112a (24.90 mg, 155.43 μmol, commercially available) were dissolved in dichloromethane (2 mL), acetic acid (0.5 mL) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (35.14 mg, 165.79 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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 obtain tert-butyl (2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)ethyl)carbamate 112b (50 mg) in a yield of 76.99% and used directly in the next reaction.

[0727] MS m / z(ESI):627.4 [M+1]

[0728] Step 2 (S)-1-(1-((5-(4-((6-(((2-aminoethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((6-(((2-aminoethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0729] (2-(((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)amino)ethyl)carbamic acid tert-butyl 112b (50 mg, 79.78 μmol) and trifluoroacetic acid (0.2 mL) were successively added to dichloromethane (2 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((6-(((2-aminoethyl)amino)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 112 (3.30 mg) in a yield of 6.81%.

[0730] MS m / z(ESI):443.2 [M+1] Example 113

[0731] (S)-1-(1-((5-(4-((6-((3-(hydroxymethyl)azetidin-1-yl)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((6-((3-(hydroxymethyl)azetidin-1-yl)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

Chemical formula

Chemical formula

[0732] Step 1 (1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)methanol (1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)methanol

[0733] 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (100 mg, 207.24 μmol), azetidin-3-ylmethanol 113a (51.22 mg, 414.48 μmol, commercially available) were dissolved in dichloromethane (1 mL), stirred for 30 minutes, sodium triacetoxyborohydride (65.88 mg, 310.86 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench, dichloromethane (30 mL) and water (15 mL) were added, the layers were separated, the aqueous phase was extracted with dichloromethane (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 obtain (1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)methanol 113b (80 mg) in a yield of 69.72% and used directly in the next reaction.

[0734] MS m / z(ESI):554.3 [M+1]

[0735] Step 2 (S)-1-(1-((5-(4-((6-((3-(hydroxymethyl)azetidin-1-yl)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol (S)-1-(1-((5-(4-((6-((3-(hydroxymethyl)azetidin-1-yl)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol

[0736] (1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)methanol 113b (80 mg, 144.50 μmol) and trifluoroacetic acid (0.5 mL) were successively added to dichloromethane (2 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-1-(1-((5-(4-((6-((3-(hydroxymethyl)azetidin-1-yl)methyl)pyridin-3-yl)ethynyl)phenyl)isoxazol-3-yl)methyl)-1H-imidazol-2-yl)ethan-1-ol 113 (6.50 mg) in a yield of 7.40%.

[0737] MS m / z(ESI):470.2 [M+1] Example 114

[0738] (S)-4-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperazin-2-one (S)-4-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperazin-2-one [Chemical formula] [Chemical formula]

[0739] Step 1 4-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperazin-2-one 4-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperazin-2-one

[0740] 5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (50 mg, 103.62 μmol) and piperazin-2-one 114a (15.56 mg, 155.43 μmol, commercially available) were dissolved in dichloromethane (1 mL), acetic acid (6.22 mg, 103.62 μmol) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (32.94 mg, 155.43 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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 obtain 4-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperazin-2-one 114b (40 mg) in a yield of 68.12% and used directly in the next reaction.

[0741] MS m / z(ESI):567.3 [M+1]

[0742] Step 2 (S)-4-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperazin-2-one (S)-4-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperazin-2-one

[0743] 4-((5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperazin-2-one 114b (50 mg, 88.24 μmol) and trifluoroacetic acid (0.5 mL) were sequentially added to dichloromethane (1 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-4-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)piperazin-2-one 114 (30 mg) in a yield of 55.34%.

[0744] MS m / z(ESI): 483.2 [M+1] Example 115

[0745] (S)-2-(1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetic acid (S)-2-(1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetic acid

Chemical formula

Chemical formula

[0746] Step 1 methyl 2-(1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetate methyl 2-(1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetate

[0747] 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (50 mg, 103.62 μmol) and methyl 2-(azetidin-3-yl)acetate 115a (63.00 mg, 259.05 μmol, commercially available) were dissolved in dichloromethane (1 mL), acetic acid (6.22 mg, 103.62 μmol) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (32.94 mg, 155.43 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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 obtain methyl 2-(1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetate 115b (50 mg) in a yield of 81.00% and used directly in the next reaction.

[0748] MS m / z (ESI): 627.4 [M+1]

[0749] Step 2 methyl(S)-2-(1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetate (S)-2-(1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetic acid methyl ester

[0750] Methyl 2-(1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetate 115b (50 mg, 83.94 μmol) and trifluoroacetic acid (0.5 mL) were successively added to dichloromethane (1 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain methyl (S)-2-(1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetate 115c (40 mg) in a yield of 93.15% and used directly in the next reaction.

[0751] MS m / z(ESI):512.0 [M+1]

[0752] Step 3 (S)-2-(1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetic acid (S)-2-(1-((5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetic acid

[0753] (S)-2-(1-((5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetic acid methyl 115c (40 mg, 78.19 μmol) and 2.5 N aqueous sodium hydroxide solution (1 mL) were successively added to methanol (3 mL), and stirring was continued at room temperature for 12 hours. 2 N dilute hydrochloric acid was added to adjust the pH to 3, and the system was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-2-(1-((5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidin-3-yl)acetic acid 115 (10 mg) in a yield of 17.98%.

[0754] MS m / z(ESI):498.2 [M+1] Example 116

[0755] (S)-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl) ethynyl)pyridin-2-yl)methyl)glycine (S)-((5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)glycine [Chemical formula] [ka]

[0756] Step 1 methyl((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl) methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)glycinate ((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)glycine methyl ester

[0757] 5-((4-(3-((2-((1S)-1-((Tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (50 mg, 103.62 μmol) and glycine methyl ester 116a (15.61 mg, 124.34 μmol) were dissolved in dichloromethane (1 mL), acetic acid (6.22 mg, 103.62 μmol) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (24.16 mg, 113.98 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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 obtain ((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)glycine methyl ester 116b (50 mg) in a yield of 86.84% and used directly in the next reaction.

[0758] MS m / z(ESI):556.3 [M+1]

[0759] Step 2 methyl(S)-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)glycinate (S)-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)glycine methyl ester

[0760] ((5 - ((4 - (3 - ((2 - ((1S)-1 - ((tetrahydro - 2H - pyran - 2 - yl)oxy)ethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)pyridin - 2 - yl)methyl)glycine methyl ester 116b (50 mg, 89.99 μmol) and trifluoroacetic acid (0.5 mL) were successively added to dichloromethane (1.5 mL), and stirring was continued at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain (S)-((5 - ((4 - (3 - ((2 - (1 - hydroxyethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)pyridin - 2 - yl)methyl)glycine methyl ester 116c (40 mg) in a yield of 94.27% and used directly in the next reaction.

[0761] MS m / z(ESI):472.2 [M + 1]

[0762] Step 3 (S)-((5 - ((4 - (3 - ((2 - (1 - hydroxyethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)pyridin - 2 - yl)methyl)glycine (S)-((5 - ((4 - (3 - ((2 - (1 - hydroxyethyl)-1H - imidazol - 1 - yl)methyl)isoxazol - 5 - yl)phenyl)ethynyl)pyridin - 2 - yl)methyl)glycine

[0763] (S)-((5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)glycine methyl ester 116c (40 mg, 84.83 μmol) and 2.5 N aqueous sodium hydroxide solution (0.5 mL) were successively added to methanol (1 mL), and stirring was continued at room temperature for 12 hours. 2 N dilute hydrochloric acid was added to adjust the pH to 3, and the system was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm I.D.; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain (S)-((5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)glycine 116 (15 mg) in a yield of 28.46%.

[0764] MS m / z(ESI): 458.1 [M+1] Example 117

[0765] (S)-1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxylic acid (S)-1-((5-((4-(3-((2-(1-Hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxylic acid

Chemical formula

Chemical formula

[0766] Step 1 methyl 1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxylate methyl 1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxylate

[0767] 5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)picolinaldehyde 36b (100 mg, 207.24 μmol) and methyl azetidine-3-carboxylate 117a (37.70 mg, 248.69 μmol, commercially available) were dissolved in dichloromethane (1.5 mL), acetic acid (12.44 mg, 207.24 μmol) was added, and the mixture was stirred for 30 minutes. Sodium triacetoxyborohydride (43.92 mg, 207.24 μmol) was added, and stirring was continued at room temperature for 12 hours. Saturated aqueous sodium bicarbonate solution (15 mL) was added to quench the reaction, dichloromethane (30 mL) and water (15 mL) were added, and the layers were separated. The aqueous phase was extracted with dichloromethane (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 obtain methyl 1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxylate 117b (100 mg) in a yield of 82.96% and used directly in the next reaction.

[0768] MS m / z(ESI):582.3 [M+1]

[0769] Step 2 methyl(S)-1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxylate (S)-1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxylic acid methyl ester

[0770] Methyl 1-((5-((4-(3-((2-((1S)-1-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxylate (100 mg, 171.92 μmol) and trifluoroacetic acid (0.5 mL) were successively added to dichloromethane (2 mL), and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure to obtain methyl (S)-1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol-1-yl)methyl)isoxazol-5-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxylate 117c (60 mg) in a yield of 70.14% and used directly in the next reaction.

[0771] MS m / z(ESI):498.3 [M+1]

[0772] Step 3 (S)-1-((5-((4-(3-((2-(1-hydroxyethyl)-1H-imidazol...

Claims

1. A compound represented by the following general formula (A-I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 【Chemical 1】 (In the formula, Ring A is 【Chemical 2】 selected from the group consisting of Ring B is 【Chemical Formula 3】 selected from the group consisting of Q is C or N, X, Y, Z, V are each independently C or N, and X and Y are not N simultaneously, and Z and Y are not N simultaneously, R １ is the same or different and each independently is -G １ -R ５ wherein G １ is selected from the group consisting of a single bond, -O-, CH ２ -, and -C(=O)-), and is selected from the group consisting of L １ is -CH ２ -. R ２ is the same or different and each independently selected from the group consisting of a hydroxy group, a cyano group, a halogen, an alkyl group, and an alkoxy group, provided that the alkyl group is optionally further substituted with one or more substituents selected from the group consisting of a halogen, a hydroxy group, a cyano group, and an alkoxy group, R ３ which is the same or different and each independently selected from the group consisting of a hydroxy group, a halogen, an alkyl group, and an alkoxy group, Alternatively, the two Rs ３ together with the C atom to which they are attached form -C(=O)-, R ４ is, independently of each other and identically or differently, a hydroxy group, a cyano group, a halogen, an alkyl group, an alkoxy group, -C(O)R ６ , -C(O)OR ６ , -OC(O)R ６ , -NR ７ R ８ and -C(O)NR7R8, provided that the alkyl group is optionally further substituted with one or more substituents selected from the group consisting of a halogen, a hydroxy group, a cyano group, an alkoxy group, and an amino group R ５ is selected from the group consisting of a cyano group, a halogen, an alkyl group, a hydroxy group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -C(O)R ６ , -C(O)OR ６ , -OC(O)R ６ , -NR １２ R １３ , -C(O)NR １２ R １３ , -SO ２ R ６ , -SO ２ NR １２ R １３ and -NR １２ C(O)R １３ wherein the alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more R Ａ ; R Ａ is selected from the group consisting of halogen, hydroxy group, cyano group, hydroxyalkyl group, alkoxy group, alkyl group, alkenyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -C(O)R ６ , -C(O)OR ６ , -OC(O)R ６ , -NR ７ R ８ , -C(O)NR ７ R ８ , -SO ２ NR ７ R ８ and -NR ７ C(O)R ８ and is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy group, cyano group, amino group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -C(O)R ６ , -C(O)OR ６ , -OC(O)R ６ , -NR ７ R ８ , -C(O)NR ７ R ８ , -SO ２ NR ７ R ８ and -NR ７ C(O)R ８ ; Alternatively, the two Rs Ａ form -C(O)- with the same carbon atom to which they are attached, R ６ is selected from the group consisting of a hydrogen atom, an alkyl group, or a heterocyclyl group, provided that the alkyl group or heterocyclyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a haloalkyl group, a haloalkoxy group, -C(O)R ９ , -C(O)OR ９ , -OC(O)R ９ , -NR １０ R １１ and -C(O)NR １０ R11, R ７ 、R ８ 、R １２ and R １３ are each independently selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, provided that the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R ９ 、-C(O)OR ９ 、-OC(O)R ９ 、-NR １０ R １１ 、-C(O)NR １０ R １１ 、-SO ２ R ９ 、-SO ２ NR １０ R １１ and -NR １０ C(O)R １１ and is optionally further substituted with one or more substituents selected from the group consisting of Alternatively, R ７ and R ８ together with the atoms to which they are attached form a 4- to 8-membered heterocyclyl group, provided that the 4- to 8-membered heterocyclyl group contains one or more of N, O, S or SO ２ and the 4- to 8-membered heterocyclyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R ９ , -C(O)OR ９ , -OC(O)R ９ , -NR １０ R １１ , -C(O)NR １０ R １１ , -SO ２ NR １０ R １１ and -NR １０ C(O)R １１ and is optionally further substituted with one or more substituents selected from the group consisting of: Alternatively, R １２ and R １３ together with the atoms to which they are attached form a 4- to 8-membered heterocyclyl group, provided that the 4- to 8-membered heterocyclyl group contains one or more of N, O, S or SO ２ and the 4- to 8-membered heterocyclyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R ９ , -C(O)OR ９ , -OC(O)R ９ , -NR １０ R １１ , -C(O)NR １０ R １１ , -SO ２ NR １０ R １１ and -NR １０ C(O)R １１ and is optionally further substituted with one or more substituents selected from the group consisting of R ９ 、R １０ and R １１ is each independently optionally further substituted with one or more substituents selected from the group consisting of a hydrogen atom and an alkyl group, m is 0 or 1, n is 0 or 1, p is 0, 1 or 2, and q is 1.)

2. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to Claim 1, wherein n is 0.

3. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to Claim 1, which is a compound represented by the following general formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 【Chemical 4】 (In the formula, X and Y are each independently C or N, and X and Y are not N simultaneously, R １ is, independently of each other and identically or differently, selected from the group consisting of -G １ -R ５ and is selected from the group consisting of; G １ is a single bond, -CH ２ - and -C(=O) selected from the group consisting of - R ５ is selected from the group consisting of a cyano group, a halogen, an alkyl group, a hydroxy group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, -C(O)R ６ , -C(O)OR ６ , -OC(O)R ６ , -NR １２ R １３ , -C(O)NR １２ R １３ , -SO ２ NR １２ R １３ and -NR １２ C(O)R １３ provided that the alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more R Ａ ; R Ａ is selected from the group consisting of halogen, hydroxy group, cyano group, hydroxyalkyl group, alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -C(O)R ６ , -C(O)OR ６ , -OC(O)R ６ , -NR ７ R ８ , -C(O)NR ７ R ８ , -SO ２ NR ７ R ８ and -NR ７ C(O)R ８ and is optionally further substituted with one or more substituents selected from the group consisting of halogen, hydroxy group, amino group, haloalkyl group, hydroxyalkyl group, alkoxy group, alkyl group, cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group, -C(O)R ６ , -C(O)OR ６ , -OC(O)R ６ , -NR ７ R ８ , -C(O)NR ７ R ８ , -SO ２ NR ７ R ８ and -NR ７ C(O)R ８ ; R ７ 、R ８ 、R １２ and R １３ are each independently selected from the group consisting of a hydrogen atom, a hydroxy group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, and a heteroaryl group, provided that the alkyl group, alkoxy group, cycloalkyl group, heterocyclyl group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R ９ 、-C(O)OR ９ 、-OC(O)R ９ 、-NR １０ R １１ 、-C(O)NR １０ R １１ 、-SO ２ NR １０ R １１ and -NR １０ C(O)R １１ and is optionally further substituted with one or more substituents selected from the group consisting of Alternatively, R ７ and R ８ together with the atoms to which they are attached form a 4- to 8-membered heterocyclyl group, provided that the 4- to 8-membered heterocyclyl group contains one or more of N, O, S or SO ２ and the 4- to 8-membered heterocyclyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R ９ , -C(O)OR ９ , -OC(O)R ９ , -NR １０ R １１ , -C(O)NR １０ R １１ , -SO ２ NR １０ R １１ and -NR １０ C(O)R １１ and is optionally further substituted with one or more substituents selected from the group consisting of Alternatively, R １２ and R １３ together with the atoms to which they are attached form a 4- to 8-membered heterocyclyl group, provided that the 4- to 8-membered heterocyclyl group contains one or more of N, O, S or SO ２ and the 4- to 8-membered heterocyclyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclyl group, an aryl group, a heteroaryl group, =O, -C(O)R ９ , -C(O)OR ９ , -OC(O)R ９ , -NR １０ R １１ , -C(O)NR １０ R １１ , -SO ２ NR １０ R １１ and -NR １０ C(O)R １１ and is optionally further substituted with one or more substituents selected from the group consisting of Ring A, Ring B, R ２ ~R ４ , R ６ , R ９ ~R １１ , L １ , m, n, p and q are defined as described in claim 1.)

4. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to Claim 1, which is a compound represented by the following general formula (II-1), (II-2), (II-3), (II-4) or (II-5) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. [Chemical Formula 5] (wherein ring A, ring B, R １ ~R ４ , L １ , m, n, p and q are defined as described in claim 1.)

5. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of Claims 1 to 4, which is a compound represented by general formula (III-1) or (III-2) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. 【Chemical Formula 6】 [Chemical Formula 7] (In the formula, Ring C is C ４ to C ８ selected from the group consisting of a cycloalkyl group of C R Ａ is, independently of one another and being the same or different, each a haloalkyl group, hydroxyalkyl group, alkoxy group, alkyl group, alkenyl group, hydroxy group, halogen, cyano group, -C(O)NH ２ , cycloalkyl group, heterocyclyl group, aryl group, heteroaryl group or carboxy group, provided that the alkyl group, cycloalkyl group, heterocyclyl group, aryl group or heteroaryl group is optionally further substituted with a hydroxy group, cyano group, carboxy group or ester group, Alternatively, two Rs Ａ form -C(O)- with the same carbon atom to which they are attached, and t is 0, 1, 2 or 3, Ring A, Ring B, R ２ ~R ４ , G １ , L １ , n, p, and q are defined as described in claim 1.)

6. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to Claim 5, wherein ring C is 【Chemical 8】 selected from the group consisting of

7. R ４ is selected from the group consisting of an alkyl group, -C(O)R ６ , -C(O)OR ６ and -C(O)NR ７ R ８ wherein the alkyl group is optionally further substituted with one or more substituents selected from the group consisting of a hydroxy group and a halogen, R ６ is selected from the group consisting of a hydrogen atom and an alkyl group, R ７ and R ８ is each independently selected from the group consisting of a hydrogen atom and an alkyl group, the compound according to any one of claims 1 to 4, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

8. R ４ is 【Chemical Formula 9】 selected from the group consisting of, the compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of Claims 1 to 4.

9. The compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of Claims 1 to 4, wherein the compound is 【Chemical 10】 【Chemical 11】 【Chemical 12】 【Chemical 13】 【Chemical 14】 【Chemical Formula 15】 【Chemical Formula 16】 【Chemical 17】 【Chemical 18】 【Chemical Formula 19】 【Chemical 20】 【Chemical 21】 【Chemical 22】 【Chemical 23】 【Chemical formula 24】 【Chemical 25】 【Chemical 26】 【Chemical 27】 【Chemical 28】 【Chemical Formula 29】 【Chemical 30】 【Chemical 31】 【Chemical 32】 【Chemical Formula 33】 【Chemical 34】 【Chemical Formula 35】 【Chemical 36】 【Chemical 37】 【Chemical 38】 【Chemical Formula 39】 【Chemical Formula 40】

10. 【Fig. 41】 The compound represented by the above general formula (I-a) and the compound represented by general formula (I-b) undergo a coupling reaction under the action of a catalyst, and optionally further undergo one or more steps of deprotection, hydrolysis, reduction, reductive amination or acid-amine condensation reaction to obtain a compound represented by general formula (A-I) (wherein X １ is a halogen, and ring A, ring B, X, Y, Z, V, Q, R １ to R ４ , L １ , n, m, p, q are as described in claim 1.). A process for producing a compound represented by general formula (A-I) according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

11. 【Chemical Formula 42】 The compound represented by the above general formula (I-c) and the compound represented by (I-d) undergo a coupling reaction under the action of a catalyst, and optionally further undergo one or more steps of deprotection, hydrolysis, reduction, reductive amination or acid-amine condensation reaction to obtain a compound represented by the general formula (A-I) (wherein X ２ is a halogen, and ring A, ring B, X, Y, Z, V, Q, R １ to R ４ , L １ , n, m, p, q are as described in claim 1.). A process for producing a compound represented by the general formula (A-I) according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

12. 【Fig. 43】 A step in which the compound represented by the above general formula (I-e) and the compound represented by (I-f) undergo a substitution reaction under the action of a basic reagent and optionally further undergo a deprotection reaction to obtain a compound represented by the general formula (A-I) (wherein X ３ is a halogen, and ring A, ring B, X, Y, Z, V, Q, R １ to R ４ , L １ , n, m, p, q are as described in claim 1). A process for producing a compound represented by the general formula (A-I) according to claim 1 or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition comprising the compound or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of Claims 1 to 4 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 13, which is used for inhibiting LPXC.

15. The pharmaceutical composition according to claim 13, which is used for treating a disease mediated by LPXC, which is a bacterial infectious disease caused by Gram-negative bacteria.

16. The pharmaceutical composition according to claim 15, wherein the Gram-negative bacteria are selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Proteus spp., Shigella dysenteriae, Klebsiella pneumoniae, Brucella spp., Salmonella spp., Acinetobacter spp., Yersinia spp., Legionella pneumophila, Bordetella pertussis, Shigella spp., Pasteurella spp., Vibrio cholerae, and Neisseria meningitidis.

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