Aromatic acetylene derivatives, processes for their preparation and uses thereof

Abstract

The present application relates to a kind of aromatic acetylene derivatives, its preparation method and the medical use of pharmaceutical composition containing the derivative. Specifically, the present application relates to a kind of aromatic acetylene derivatives shown in general formula (I), its preparation method and its pharmaceutically acceptable salt, and they are used as therapeutic agent, especially the use of LPXC inhibitor, wherein the definition of each substituent in general formula (I) is the same as the definition in the specification.

Description

[0001] This application claims priority to the following Chinese patent applications: 1) Chinese patent application No. 202110893756.3, filed with the China National Intellectual Property Administration on August 5, 2021, entitled "Aromatic Acetylene Derivatives and Their Preparation Methods and Uses"; 2) Chinese patent application No. 202210596714.8, filed with the China National Intellectual Property Administration on May 30, 2022, entitled "Aromatic Acetylene Derivatives and Their Preparation Methods and Uses"; 3) Chinese patent application No. 202210756227.3, filed with the China National Intellectual Property Administration on June 29, 2022, entitled "Aromatic Acetylene Derivatives and Their Preparation Methods and Uses". The entire contents of the foregoing Chinese patent applications are incorporated herein by reference. Technical Field

[0002] This invention relates to an aromatic acetylene derivative, its preparation method, a pharmaceutical composition containing the derivative, and the use of the aromatic acetylene derivative or pharmaceutical composition as a therapeutic agent, particularly as an LPXC inhibitor. Background Technology

[0003] The 1930s to 1960s were the golden age of antibiotic development, after which antibiotics were widely used worldwide. However, bacterial resistance also emerged, and drug-resistant bacteria have become a major threat to human health. Multidrug-resistant Gram-negative bacteria are among the main pathogens causing infections, and currently, there is a severe shortage of drugs available for treating multidrug-resistant Gram-negative bacterial infections, with the continued use of highly toxic drugs. Although bacterial resistance has been a hot topic in the international pharmaceutical community in recent years, research and development have progressed slowly, with very few compounds entering clinical trials both domestically and internationally. Therefore, finding a novel antibacterial drug for Gram-negative bacteria is a crucial problem that urgently needs to be solved.

[0004] UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LPXC) is a Zn-dependent enzyme. 2+ Lipopolysaccharide (LPXC) is a metalloenzyme that is the rate-limiting enzyme in the first step of lipid A synthesis. Lipopolysaccharide is an important component of the outer membrane of Gram-negative bacteria, anchoring lipopolysaccharide to the outer membrane and maintaining cellular integrity. It also acts as a hydrophobic external barrier, preventing external factors such as antibiotics from entering the cell and protecting bacteria from infection. Furthermore, lipid A is also an active component of bacterial endotoxins, entering the bloodstream through the intestinal mucosa and activating the body's immune response, even causing severe septic shock. This is also the reason why Gram-negative bacteria cause pathogenic infections. Therefore, inhibiting LPXC can suppress the biosynthesis of lipid A in Gram-negative bacteria, thereby effectively controlling Gram-negative bacterial infections.

[0005] Current understanding of the structure and properties of LPXC is largely based on the isolation, purification, and analysis of LPXC crystals from *Escherichia coli*, *Pseudomonas aeruginosa*, and hyperthermophiles. These three different sources of LPXC exhibit highly similar structures, each containing two domains with the active region located at the junction of these two domains. Each domain comprises an α-helix and a β-sheet, with the β-sheet enclosing the α-helix, forming a "β-α-α-β" sandwich structure. Although the amino acid sequences of these two domains differ slightly, they share the same spatial structure. Furthermore, each domain has a corresponding insertion region composed of β-sheets, forming different functional regions. Studies have shown that LPXC exhibits high homology in Gram-negative bacteria and does not share sequences with various mammalian enzyme systems. From a biological perspective, due to its unique advantages of broad spectrum and low toxicity, inhibiting LPXC would be an ideal direction for researching antibacterial drugs.

[0006] Currently, there are no marketed inhibitors of LPXC. 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 lot of room for improvement. It is still necessary to continue to research and develop new LPXC inhibitors. Summary of the Invention

[0007] To address the aforementioned technical problems, the present invention provides an aromatic acetylene derivative or its stereoisomer, tautomer, or pharmaceutically usable salt thereof, represented by general formula (I):

[0008]

[0009] in:

[0010] X and Y are each independently selected from C or N, and X and Y are not both N at the same time;

[0011] Ring A is selected from 4-6-membered heteroaryl or 4-6-membered heterocyclic group, preferably 5-membered heteroaryl or 5-membered heterocyclic group;

[0012] L1 is selected from a single bond or -CH2-;

[0013] Whether R1 is the same or different, each is independently selected from -G1-R4;

[0014] G1 is selected from single bonds, -CH2-, or -C(=O)-;

[0015] R2 may be the same or different, each independently selected from hydroxyl, cyano, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy;

[0016] R3 may be the same or different, each independently selected from hydroxyl, cyano, halogen, alkyl, cycloalkyl, heterocyclic, alkoxy or -C(O)R5, wherein the alkyl, cycloalkyl, heterocyclic or alkoxy may optionally be further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkoxy, -C(O)OR5 or -C(O)NR6R7;

[0017] R4 is selected from cyano, halogen, alkyl, hydroxy, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R5, -C(O)OR5, -OC(O)R5, -NR6R7, -C(O)NR6R7, -SO2NR6R7 or -NR6C(O)R7, wherein the alkoxy, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further influenced by one or more R4 groups. A Replaced;

[0018] R A The group is selected from halogen, hydroxyl, amino, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R5, -C(O)OR5, -OC(O)R5, -NR6R7, -C(O)NR6R7, -SO2NR6R7 or -NR6C(O)R7, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, amino, haloalkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -C(O)R5, -C(O)OR5, -OC(O)R5, -NR6R7, -C(O)NR6R7, -SO2NR6R7 or -NR6C(O)R7;

[0019] R5 is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R 10 -C(O)NR9R 10 -SO2NR9R 10 or -NR9C(O)R 10 The substituents are replaced by;

[0020] R6 and R7 are each independently selected from hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R 10 -C(O)NR9R 10 -SO2NR9R 10 or -NR9C(O)R 10 The substituents are replaced by;

[0021] Or, R 6 and R 7 Together with the atoms to which it is attached, it forms a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, S or SO2, and the 4- to 8-membered heterocyclic group is optionally further composed of one or more elements selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R 10 -C(O)NR9R 10 -SO2NR9R 10 or -NR9C(O)R 10 The substituents are replaced by;

[0022] R8, R9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic acid ester group;

[0023] m can be 0, 1, 2, or 3;

[0024] n can be 0, 1, or 2, with n preferably being 0; and

[0025] p is 0, 1, or 2.

[0026] According to a preferred embodiment of the present invention, a compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is provided, which is a compound of general formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0027]

[0028] Wherein: the definitions of rings A, R1~R3, L1, m, n and p are as described in general formula (I).

[0029] According to a preferred embodiment of the present invention, a compound of general formula (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is provided, which is a compound of general formula (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof:

[0030]

[0031] in:

[0032] R A The group is selected from halogenated alkyl, hydroxyalkyl, alkoxy, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, and carboxyl groups, wherein the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups are optionally further substituted with a carboxyl group;

[0033] q is 0, 1, or 2;

[0034] The rings A, G1, R2, R3, L1, n and p are defined as described in general formula (I).

[0035] According to a preferred embodiment of the present invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is provided, wherein ring A is selected from:

[0036]

[0037] According to a preferred embodiment of the present invention, a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is provided, wherein...

[0038] Selected from:

[0039]

[0040] According to a preferred embodiment of the present invention, a compound of general formula (I) or (II) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof is provided, wherein...

[0041] Selected from:

[0042]

[0043]

[0044] According to a preferred embodiment of the present invention, a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is provided, wherein n is selected from 0.

[0045] According to a preferred embodiment of the present invention, a compound of general formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is provided, wherein L1 is selected from -CH2-.

[0046] In a preferred embodiment of the present invention, the compound of general formula (I) is selected from:

[0047]

[0048]

[0049]

[0050]

[0051]

[0052]

[0053]

[0054]

[0055]

[0056]

[0057]

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070] Or its stereoisomers, tautomers, or medicinal salts.

[0071] Note: If there is a difference between the drawn structure and the given name of the structure, the drawn structure will be given greater weight.

[0072] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0073] The present invention provides the use of a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of an LPXC inhibitor.

[0074] The present invention also provides the use of a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating LPXC-mediated diseases, wherein the LPXC-mediated diseases are preferably bacterial infections caused by Gram-negative bacteria; wherein the LPXC-mediated diseases are selected from bacterial infections caused by Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter spp., Yersinia spp., Legionella pneumophila, Bordetella pertussis, Shigella spp., Pasteurella spp., Vibrio cholerae, Neisseria meningitidis, etc.

[0075] The present invention further provides the use of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating bacterial infections caused by Gram-negative bacteria.

[0076] This invention provides the use of a compound of general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically usable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for bacterial infections caused by Gram-negative bacteria such as Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter spp., Yersinia spp., Legionella pneumophila, Bordetella pertussis, Shigella spp., Pasteurella spp., Vibrio cholerae, and Neisseria meningitidis.

[0077] The present invention also provides a method for treating LPXC-mediated diseases, comprising administering to a subject in need a compound of formula (I), (II), or (III) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Preferably, the LPXC-mediated disease is a bacterial infection caused by Gram-negative bacteria; more preferably, the Gram-negative bacteria are selected from Escherichia coli, Pseudomonas aeruginosa, Proteus, Shigella, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter spp., Yersinia spp., Legionella pneumophila, Bordetella pertussis, Shigella spp., Pasteurella spp., Vibrio cholerae, and Neisseria meningitidis.

[0078] Detailed description of the invention

[0079] Unless otherwise stated, some terms used in this specification and claims are defined as follows:

[0080] When "alkyl" is used as a group or part of a group, it refers to a group consisting of C1-C2. 20 Straight-chain or branched aliphatic hydrocarbon groups. Preferably C1-C. 10 Alkyl groups, more preferably C1-C6 or C1-C4 alkyl groups. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted.

[0081] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more cyclic atoms are carbon atoms, including monocyclic, polycyclic, fused, bridged, and spirocyclic groups, preferably having a 3- to 7-membered monocyclic or a 7- to 10-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups can be substituted or unsubstituted. C3-C7, C3-C6, or C5-C7 cycloalkyl groups are preferred.

[0082] "Spirocycloalkyl" refers to a polycyclic aromatic system with 5 to 18 quinones, two or more cyclic structures, where the monocyclic rings share a carbon atom (called a spiro atom) with each other, and containing one or more double bonds within the rings, but none of the rings has fully conjugated π electrons. Preferably, it is 6 to 14 quinones, more preferably 7 to 10 quinones. Based on the number of spiro atoms shared between the rings, spirocycloalkyl is classified into monospiro, bispiro, or polyspirocycloalkyl, preferably monospiro and bispirocycloalkyl, and preferably 4 / 5, 4 / 6, 5 / 5, or 5 / 6 quinones. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, and spiro[2.4]heptyl.

[0083] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more ring structures sharing a pair of carbon atoms, wherein one or more rings may contain one or more double bonds, but none of the rings have fully conjugated π electrons, preferably a 6- to 12-membered aromatic system, more preferably a 7- to 10-membered system. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting examples of "fused cycloalkyl" include, but are not limited to: bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, or tetradecahydrophenanthrene.

[0084] "Bridged cycloalkyl" refers to an aromatic system consisting of 5 to 18 quintiles, containing two or more cyclic structures sharing two non-directly connected carbon atoms, and one or more rings may contain one or more double bonds, but none of the rings has fully conjugated π electrons. Preferably, it consists of 6 to 12 quintiles, more preferably 7 to 10 quintiles. More preferably, it consists of 6 to 14 quintiles, more preferably 7 to 10 quintiles. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s, 5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r, 5r)-bicyclo[3.3.2]decyl.

[0085] The terms “heterocyclic group,” “heterocyclic alkyl group,” “heterocyclic,” or “heterocyclic” are used interchangeably in this application and all refer to a non-aromatic heterocyclic group in which one or more cyclic atoms are heteroatoms, such as oxygen, nitrogen, or S(O). r(where r is selected from 0, 1, or 2), etc., and the ring atoms optionally include -C(=O)-, including monocyclic, polycyclic, fused ring, bridged ring, and spirocyclic rings. Preferably, it has a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring, which may contain 1, 2, or 3 atoms selected from nitrogen, oxygen, and / or S(O). r (where r is selected from 0, 1, or 2) atoms. Examples of "heterocyclic groups" include, but are not limited to, morpholino, oxetane, thiomorpholino, tetrahydrofurano, tetrahydropyrano, 1,1-dioxo-thiomorpholino, piperidino, 2-oxo-piperidino, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazine, hexahydropyrimidine,

[0086]

[0087]

[0088] The heterocyclic group can be substituted or unsubstituted.

[0089] "Spirocyclone" refers to a polycyclic aromatic system with 5 to 18 members, two or more ring structures, where the monocyclic rings share an atom with each other, and the rings contain one or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, C (=O) or S (O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 membered, more preferably 7 to 10 membered. Spirocycloalkyl groups are classified into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl groups according to the number of shared spiroatoms between rings, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monospirocycloalkyl. Non-limiting examples of "spirocycloalkyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl.

[0090] "Dense cyclic group" refers to a polycyclic group containing two or more ring structures that share a pair of atoms. One or more rings may contain one or more double bonds, but none of the rings have fully conjugated π electrons. The one or more ring atoms are selected from nitrogen, oxygen, C (=O) or S (O). r(where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclic group" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrol, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin,

[0091] "Bridged heterocyclic group" refers to a polycyclic group with 5 to 14 members or 5 to 18 members, containing two or more ring structures that share two atoms that are not directly connected. One or more rings may contain one or more double bonds, but none of the rings have fully conjugated π electrons. One or more ring atoms are selected from nitrogen, oxygen, C (=O) or S (O). r (where r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably, it is 6 to 14-membered, more preferably 7 to 10-membered. Depending on the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting embodiments of "bridged heterocyclic groups" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

[0092] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is C6-C. 10 Aryl, more preferably phenyl and naphthyl, most preferably naphthyl. The aryl group can be substituted or unsubstituted.

[0093] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring, which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Preferred heteroaryl groups are C6-C. 10Heteroaryl groups, comprising 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiopheneyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrroleyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo[m]dioxacyclopentenyl, benzo[thiophene], benzimidazolyl, indoleyl, isoyindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indoleyl, benzo[isothiazolyl], benzo[oxazolyl], benzo[isothiazolyl], isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl. - Triazolyl, pyridyl, pyrimidinyl, pyrazin-2(1H)-keto, pyrimidin-4(3H)-keto, pyridazin-3(2H)-keto, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridyl, 3H-imidazo[4,5-c]pyridyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furan[3,2-b]pyridyl, furan[2,3-c]pyridyl, thieno[2,3-c]pyridyl, benzofuranyl, benzo[b]thienoyl, 1H-pyrrolo[3,2-b]pyridyl, 2H-pyrrolo[3,4-c]pyridyl. Heteroaryl groups can be substituted or unsubstituted.

[0094] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined in the relevant section of this document. C1-C6 or C1-C4 alkoxy groups are preferred. Examples include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, etc.

[0095] "Nitro" refers to the -NO2 group.

[0096] "Hydroxy" refers to the -OH group.

[0097] "Halogens" refers to fluorine, chlorine, bromine, and iodine.

[0098] "Amino" refers to -NH2.

[0099] “Cyano” refers to -CN.

[0100] "Benzyl" refers to -CH2-phenyl.

[0101] "Carboxyl group" refers to -C(O)OH.

[0102] "Carboxylic acid ester group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, where the definitions of alkyl and cycloalkyl are as described above.

[0103] “Hydroxyalkyl” refers to an alkyl group substituted with a hydroxyl group, where the definition of alkyl is as described above.

[0104] "Aminoalkyl" refers to an amino-substituted alkyl group, where the definition of alkyl is as described above.

[0105] "Halogenated alkyl" refers to halogen-substituted alkyl groups, where the definition of alkyl is as described above.

[0106] "Haloalkoxy" refers to halogen-substituted alkoxy groups, where the definition of alkoxy groups is as described above.

[0107] "DMSO" refers to dimethyl sulfoxide.

[0108] “BOC” refers to tert-butoxycarbonyl.

[0109] “Bn” refers to benzyl.

[0110] "THP" refers to 2-tetrahydropyranyl.

[0111] "TFA" refers to trifluoroacetic acid.

[0112] “Ts” refers to p-toluenesulfonyl group.

[0113] A "leaving group," or simply a group, is an atom or functional group that breaks off from a larger molecule in a chemical reaction. It's a term used in nucleophilic substitution and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks off with a pair of electrons from the substrate molecule is called the leaving group. Groups that readily accept electrons and have a strong ability to accept negative charges are desirable leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break off from other molecules. This is because a smaller pKa means the leaving group doesn't need to bond with other atoms and has a stronger tendency to exist as an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyl groups, -OTs, or -OH.

[0114] "Substituted" refers to one or more hydrogen atoms in a group, preferably up to five, and more preferably one to three hydrogen atoms, which are independently substituted by the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated bond (such as an alkene).

[0115] Unless otherwise specified, “substitution” or “substituted” as used in this specification means that a group may be substituted by one or more groups selected from the following: alkyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylic acid ester, =O, -C(O)R5, -C(O)OR5, -OC(O)R5, -NR6R7, -C(O)NR6R7, -SO2NR6R7 or -NR6C(O)R7;

[0116] R5 is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R 10 -C(O)NR9R 10 -SO2NR9R 10 or -NR9C(O)R 10 The substituents are replaced by;

[0117] R6 and R7 are each independently selected from hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further selected from one or more of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R 10 -C(O)NR9R 10 -SO2NR9R 10 or -NR9C(O)R 10 The substituents are replaced by;

[0118] Or, R 6 and R 7 Together with the atoms to which it is attached, it forms a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, S or SO2, and the 4- to 8-membered heterocyclic group is optionally further composed of one or more elements selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R8, -C(O)OR8, -OC(O)R8, -NR9R 10 -C(O)NR9R 10 -SO2NR9R 10 or -NR9C(O)R10 The substituents are replaced by;

[0119] R8, R9 and R 10 Each is independently selected from hydrogen atoms, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylic ester group.

[0120] "Medicinal salts" refer to certain salts of the above-mentioned compounds that retain their original biological activity and are suitable for medicinal use. Medicinal salts of compounds represented by general formula (I) can be metal salts or amine salts formed with suitable acids.

[0121] "Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs, along with other chemical components, such as a physiologically pharmaceutically acceptable carrier. The purpose of a pharmaceutical composition is to facilitate administration to a living organism, thereby promoting the absorption of the active ingredient and the exertment of its biological activity.

[0122] Method for synthesizing the compounds of the present invention

[0123] To achieve the objectives of this invention, the following technical solution is adopted:

[0124] This invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, the method comprising:

[0125]

[0126] Compounds of general formula (Ia) and (Ib) undergo a coupling reaction in the presence of a catalyst, and optionally further deprotection of the protecting group yields compound of general formula (I).

[0127] in:

[0128] X1 is selected from halogens;

[0129] The rings A, X, Y, R1 to R3, L1, n, m and p are defined as described in general formula (I). Detailed Implementation

[0130] The following embodiments are used to further describe the present invention, but these embodiments are not intended to limit the scope of the present invention.

[0131] Example

[0132] The examples provide preparation and structural identification data for representative compounds represented by formula (I). It must be noted that the following examples are illustrative of the invention and not intended to limit it. 1 The 1H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm. Tetramethylsilane internal standard (0.00 ppm) was used. 1 H NMR representation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublet, dt = doublet of triplet. If the coupling constant is provided, the unit is Hz.

[0133] Mass spectrometry is performed using an LC / MS instrument, and the ionization method can be ESI or APCI.

[0134] Thin-layer chromatography silica gel plates are Yantai Huanghai HSGF254 or Qingdao GF254. The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15 mm to 0.2 mm, and the diameter of the silica gel plates used for thin-layer chromatography separation and purification products is 0.4 mm to 0.5 mm.

[0135] Column chromatography typically uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.

[0136] In the following examples, all temperatures are in Celsius unless otherwise specified. Unless otherwise specified, all starting materials and reagents are commercially available or synthesized according to known methods. Commercially available materials and reagents are used directly without further purification. Unless otherwise specified, they are purchased from manufacturers including but not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd., and Jingyan Chemical Technology Co., Ltd.

[0137] CD3OD: Deuterated methanol.

[0138] CDCl3: Deuterated chloroform.

[0139] DMSO-d6: Deuterated dimethyl sulfoxide.

[0140] Argon atmosphere refers to a reaction flask connected to an argon gas balloon with a volume of approximately 1L.

[0141] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0142] The compound was purified using silica gel column chromatography eluent system and thin-layer chromatography. The eluent system was selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane and ethyl acetate system. The volume ratio of the solvent varied depending on the polarity of the compound, and a small amount of acidic or basic reagent, such as acetic acid or triethylamine, could be added for adjustment.

[0143] Example 1

[0144] 5-Hydroxy-6-(3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazo-5-yl)pyrimidin-4(3H)-one

[0145]

[0146] first step

[0147] (E)-4-iodobenzaldehyde oxime

[0148] Hydroxylamine hydrochloride (5.99 g, 86.20 mmol), potassium carbonate (11.9 g, 86.20 mmol), 4-iodobenzaldehyde 1a (10 g, 43.10 mmol), and water (80 mL) were added sequentially to ethanol (80 mL), and the mixture was reacted overnight at room temperature. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (E)-4-iodobenzaldehyde oxime 1b (8 g), yield: 75.14%.

[0149] MS m / z (ESI): 247.8 [M+1] +

[0150] Step 2

[0151] (Z)-N-hydroxy-4-iodobenzoimine chloride

[0152] (E)-4-iodobenzaldehyde oxime 1b (1 g, 4.05 mmol) was dissolved in N,N-dimethylformamide (10 mL), and chlorosuccinimide (594.59 mg, 4.45 mmol) was slowly added. The mixture was stirred overnight at room temperature. After the reaction was complete, (Z)-N-hydroxy-4-iodobenzoimide chloride 1c was obtained. The reaction solution was used directly in the next step without purification.

[0153] Step 3

[0154] 5-(5,6-bis(benzyloxy)pyrimidin-4-yl)-3-(4-iodophenyl)-4,5-dihydroisoxazole

[0155] 4,5-bis(benzyloxy)-6-vinylpyrimidine 1d (1.1 g, 3.46 mmol, prepared according to patent WO2020061375) and triethylamine (699.25 mg, 6.91 mmol, 957.87 μL) were dissolved in N,N-dimethylformamide (14.04 mL), and (Z)-N-hydroxy-4-iodobenzoimine chloride 1c (972.54 mg, 3.46 mmol) in N,N-dimethylformamide solution (10 mL) were slowly added dropwise. The reaction was carried out at room temperature for 6 hours. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 5-(5,6-bis(benzyloxy)pyrimidin-4-yl)-3-(4-iodophenyl)-4,5-dihydroisoxazole 1e (1.4 g), yield: 71.92%.

[0156] MS m / z (ESI): 563.8 [M+1] +

[0157] Step 4

[0158] 4-(4-((4-(5-(5,6-bis(benzyloxy))pyrimidin-4-yl)-4,5-dihydroisoxazo-3-yl)phenyl)ethynyl)benzyl)morpholine

[0159] 5-(5,6-bis(benzyloxy)pyrimidin-4-yl)-3-(4-iodophenyl)-4,5-dihydroisoxazole 1e (0.8 g, 1.42 mmol), 4-(4-ethynylbenzyl)morpholine 1f (285.79 mg, 1.42 mmol), bis(triphenylphosphine)palladium dichloride (199.34 mg, 284.00 μmol), cuprous iodide (54.09 mg, 284.00 μmol), and triethylamine (431.07 mg, 4.26 mmol) were dissolved in N,N-dimethylformamide (6 mL), purged with argon three times, and stirred overnight at room temperature. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate (20 ml × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1 g (0.85 g) of 4-(4-((4-(5-(5,6-bis(benzyloxy))pyrimidin-4-yl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine, yield: 94.01%.

[0160] MS m / z (ESI): 637.0 [M+1] +

[0161] Step 5

[0162] 5-Hydroxy-6-(3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazo-5-yl)pyrimidin-4(3H)-one

[0163] 1 g (0.2 g, 314.10 μmol) of 4-(4-((4-(5-(5,6-bis(benzyloxy))pyrimidin-4-yl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine was dissolved in 2 mL of dichloromethane, and boron trichloride (1.84 g, 15.71 mmol, 5 mL) was slowly added dropwise. The mixture was heated to 30 °C and reacted for 6 hours. After the reaction was completed, the mixture was quenched with an appropriate amount of methanol in an ice bath. Reduced pressure filtration and preparative liquid chromatography (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) yielded 1 (25 mg) of 5-hydroxy-6-(3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)pyrimidin-4(3H)-one, yield: 13.67%.

[0164] MS m / z (ESI): 457.2 [M+1] +

[0165] Example 2

[0166] 3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)oxazolidin-2-one 2

[0167]

[0168] first step

[0169] 2-Amino-1-(4-bromophenyl)ethyl-1-ol

[0170] Sodium borohydride (1.98 g, 52.27 mmol) was added to a tetrahydrofuran (100 mL) solution of 2-amino-1-(4-bromophenyl)ethyl-1-one hydrochloride 2a (5 g, 17.42 mmol), followed by ethanol (50 mL). The reaction was carried out at room temperature for 2 hours. After the reaction was completed, 30 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (40 mL × 3). The mixture was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 2-amino-1-(4-bromophenyl)ethyl-1-ol 2b (3.76 g) in 100% yield. The product was carried out directly in the next step without purification.

[0171] MS m / z (ESI): 216.0 [M+1]+

[0172] Step 2

[0173] 5-(4-Bromophenyl)oxazolidin-2-one

[0174] At -78°C, bis(trichloromethyl) carbonate (2.58 g, 8.70 mmol) was added to a solution of 2-amino-1-(4-bromophenyl)ethane-1-ol 2b (3.76 g, 17.40 mmol) and triethylamine (3.52 g, 34.80 mmol, 4.84 mL) in 80 mL of dichloromethane. The reaction mixture was allowed to react at low temperature for 20 minutes, then allowed to rise to room temperature and react overnight. 20 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (60 mL × 3). The extract was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 5-(4-bromophenyl)oxazolidin-2-one 2c (2.62 g), yield: 62.2%.

[0175] MS m / z (ESI): 242.0 [M+1] +

[0176] Step 3

[0177] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-bromophenyl)oxazolidin-2-one

[0178] Potassium carbonate (856.43 mg, 6.20 mmol) was added to acetonitrile (40 mL) containing 5-(4-bromophenyl)oxazolidine-2-one 2c (500 mg, 2.07 mmol) and 4,5-bis(benzyloxy)-6-(iodomethyl)pyrimidine 2d (892.83 mg, 2.07 mmol, prepared according to patent WO2020061375). The mixture was heated to reflux and reacted for 6 hours. After the reaction was completed, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The solution was washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 3-((5,6-bis(benzyloxy)pyrimidine-4-yl)methyl)-5-(4-bromophenyl)oxazolidine-2-one 2e (0.94 g), yield: 83.29%.

[0179] MS m / z (ESI): 546.1 [M+1] +

[0180] Step 4

[0181] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)oxazolidin-2-one

[0182] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-bromophenyl)oxazolidin-2-one 2e (910 mg, 1.67 mmol), 4-(4-ethynylbenzyl)morpholine 1f (435.74 mg, 2.17 mmol), bis(triphenylphosphine)palladium dichloride (58.45 mg, 83.27 μmol), tetrabutylammonium bromide (536.88 mg, 1.67 mmol), and piperidine (425.43 mg, 5.00 mmol) were added to water (20 mL), purged three times with argon, heated to 85 °C, and reacted for 4 hours. After the reaction was completed, ethyl acetate (30 mL × 3) was added to the reaction solution for extraction, followed by washing with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)oxazolidin-2-one 2f (0.835 g), yield: 75.2%.

[0183] MS m / z (ESI): 667.3 [M+1] +

[0184] Step 5

[0185] 3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)oxazolidin-2-one

[0186] Under ice-water bath conditions, boron trichloride (8 mL) was added to 3 mL of dichloromethane containing 2f (860 mg, 1.29 mmol) of 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)oxazolidin-2-one 2f) and the mixture was slowly heated to 35 °C and reacted for 5 hours. After the reaction was completed, the reaction was quenched with methanol, and the reaction solution was concentrated under reduced pressure to prepare a liquid phase separator (AKZONOBEL Kromasil column; 250 × 21.2 mm). ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), yielded 3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)oxazolidin-2-one 2 (100 mg), yield: 12.34%.

[0187] MS m / z (ESI): 487.2 [M+1] +

[0188] 1 H NMR (400MHz, DMSO-d6) δ10.17 (s, 1H), 9.66 (s, 1H), 7.80 (s, 1H), 7.68 (d, J= 7.9Hz, 2H), 7.63 (d, J=8.2Hz, 2H), 7.57 (d, J=7.9Hz, 2H), 7.52 (d, J=8.1Hz, 2H), 5.62 (dd, J=8.8, 7.0Hz, 1H), 4.38 (s, 2H), 4.32 (s, 2H), 3.99 (t, J=8.9H z, 3H), 3.65 (s, 2H), 3.43 (dd, J=8.8, 7.0Hz, 1H), 3.26 (s, 2H), 3.13 (s, 2H).

[0189] Example 3

[0190] 3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)oxazoline-2-one

[0191]

[0192] first step

[0193] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-(((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)oxazolidin-2-one

[0194] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-bromophenyl)oxazolidin-2-one 2e (130 mg, 237.92 μmol), (4-ethynylphenyl)(morpholino) methyl ketone 3a (51.21 mg, 237.92 μmol), bis(triphenylphosphine)palladium dichloride (8.35 mg, 11.90 μmol), tetrabutylammonium bromide (76.70 mg, 237.92 μmol), and piperidine (60.78 mg, 713.75 μmol) were added to water (3 mL), purged three times with argon, heated to 85 °C, and reacted for 4 hours. After the reaction was completed, ethyl acetate (20 mL × 3) was added to the reaction solution for extraction, followed by washing with saturated sodium chloride solution (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-(((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)oxazolidin-2-one 3b (130 mg), yield: 80.27%.

[0195] MS m / z (ESI): 681.3 [M+1] +

[0196] Step 2

[0197] 3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)oxazoline-2-one

[0198] Under ice-water bath conditions, boron trichloride (1.5 mL) was added dropwise to 2 mL of dichloromethane containing 130 mg (190.97 μmol) of 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-(((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)oxazolidin-2-one 3b). The mixture was heated to 35 °C and reacted for 5 hours. After the reaction was completed, the reaction was quenched with methanol, and the reaction solution was concentrated under reduced pressure to prepare a liquid phase separator (AKZONOBEL Kromasil column; 250 × 21.2 mm). ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), yielded 3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)oxazoline-2-one 3 (11.97 mg), yield: 9.96%.

[0199] MS m / z (ESI): 501.2 [M+1] +

[0200] 1 H NMR (400MHz, DMSO-d6) δ9.14-9.51 (m, 4H), 8.44 (dd, J=5.2, 1.7Hz, 1H), 8.14 (s, 4H), 7. 20 (dd, J=16.8, 11.0Hz, 1H), 6.62 (dd, J=16.9, 1.7Hz, 1H), 5.92 (dd, J=10.8, 1.8Hz, 1H), 5.09 (d, J=7.5Hz, 2H), 4.95 (t, J=7.5Hz, 2H), 4.88 (t, J=7.6Hz, 1H), 3.91 (t, J=6.7Hz, 1 H), 3.64 (s, 1H), 3.52 (d, J = 6.1Hz, 1H), 3.45 (s, 1H), 3.32 (s, 1H), 3.29 (d, J = 7.3Hz, 2H).

[0201] Example 4

[0202] 5-Hydroxy-6-((4-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0203]

[0204] first step

[0205] (E)-3-(4-iodophenyl)acrylic acid

[0206] 10 g (43.10 mmol) of 4-iodobenzaldehyde 1a, 5.38 g (51.72 mmol) of malonic acid, and 6.64 g (86.20 mmol) of ammonium acetate were added to 10 mL of ethanol and refluxed for 6 hours. After cooling to room temperature, the mixture was filtered, and the filter cake was washed once with 40 mL of ethanol and once with 40 mL of n-hexane. The filter cake was dried to give (E)-3-(4-iodophenyl)acrylic acid 4a (9.8 g), with a yield of 82.97%.

[0207] MS m / z (ESI): 275.0 [M+1] +

[0208] Step 2

[0209] 3-Amino-3-(4-iodophenyl)propionic acid

[0210] (E)-3-(4-iodophenyl)propionic acid 4a (6 g, 21.89 mmol), ammonium acetate (5.06 g, 65.68 mmol), and ethanol (50 mL) were added to a pressure tube and heated to reflux for 6 hours. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed once with ethanol and once with 40 mL of n-hexane. The filter cake was dried to give 3-amino-3-(4-iodophenyl)propionic acid 4b (5 g), yield: 78.16%. MS m / z (ESI): 292.0 [M+1] +

[0211] Step 3

[0212] 3-((tert-Butoxycarbonyl)amino)-3-(4-iodophenyl)propionic acid

[0213] Di-tert-butyl dicarbonate (5.51 g, 25.25 mmol) was added to 50 mL of dioxane containing 4.9 g (16.83 mmol) of 3-amino-3-(4-iodophenyl)propionic acid 4b, followed by 50 mL of saturated sodium bicarbonate solution. The mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was filtered, and the filter cake was washed twice with 50 mL of n-hexane. The filtrate was acidified with citric acid solution, extracted with ethyl acetate (40 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-((tert-butyloxycarbonyl)amino)-3-(4-iodophenyl)propionic acid 4c (4.85 g), yield: 73.65%. This product was used directly in the next reaction without purification.

[0214] MS m / z (ESI): 414.0 [M+23] +

[0215] Step 4

[0216] 5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester

[0217] 3-((tert-Butoxycarbonyl)amino)-3-(4-iodophenyl)propionic acid 4c (1 g, 2.56 mmol), diphenyl azide phosphate (844.17 mg, 3.07 mmol), and triethylamine (646.66 mg, 6.39 mmol) were added to toluene (25 mL) and stirred at room temperature for 30 minutes. The mixture was then heated to 80 °C and reacted for 4 hours. After the reaction was complete, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The extract was washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and yielded tert-butyl 5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylate 4d (992 mg), yield: 99.97%. This product was used directly in the next reaction without purification.

[0218] MS m / z (ESI): 333.0 [M-55] +

[0219] Step 5

[0220] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester

[0221] 4d (800 mg, 2.06 mmol) of 5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester, 4d, 4,5-bis(benzyloxy)-6-(iodomethyl)pyrimidine 2d (890.79 mg, 2.06 mmol), and potassium carbonate (854.47 mg, 6.18 mmol) were added to acetonitrile (5 mL). The mixture was heated to 90 °C and reacted for 10 hours. After the reaction was completed, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The solution was washed with saturated sodium chloride solution (20 mL), and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4e (510 mg) of 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester, yield: 35.73%.

[0222] MS m / z (ESI): 637.1 [M-55] +

[0223] Step 6

[0224] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester

[0225] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 4e (100 mg, 154.91 μmol), (4-ethynylphenyl)(morpholino) methyl ketone 3a (33.34 mg, 154.91 μmol), bis(triphenylphosphine)palladium dichloride (5.44 mg, 7.75 μmol), tetrabutylammonium bromide (49.94 mg, 154.91 μmol), and piperidine (39.57 mg, 464.73 μmol) were added to water (2 mL) and argon gas was introduced. The mixture was replaced three times, heated to 85°C, and reacted for 4 hours. After the reaction was completed, 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The solution was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4f (60 mg) of tert-butyl 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholino-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid, with a yield of 49.66%.

[0226] MS m / z (ESI): 780.5 [M+1] +

[0227] Step 7

[0228] 5-Hydroxy-6-((4-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0229] Boron trichloride (1 mL) was added to 1 mL of dichloromethane containing 4f (60 mg, 76.94 μmol) of 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester (4f). The mixture was heated to 35 °C and reacted for 6 hours. After the reaction was completed, the reaction was quenched with methanol, and the reaction solution was concentrated under reduced pressure to prepare a liquid phase separator (AKZONOBEL Kromasil column; 250 × 21.2 mm). ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), yielded 5-hydroxy-6-((4-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one 4 (8.58 mg), yield: 17.78%.

[0230] MS m / z (ESI): 500.2 [M+1] +

[0231] 1 H NMR (400MHz, DMSO-d6) δ12.65 (s, 1H), 9.31-9.76 (m, 1H), 7.78 (s, 1H), 7.59 (dd, J=18.8, 8.0Hz, 4H), 7.45 (dd, J=12.0, 8 .0Hz, 4H), 7.10 (d, J=14.3Hz, 1H), 4.72 (t, J=8.1Hz, 1H), 4.19 (d, J=6.7Hz, 2H), 3.80 (s, 1H), 3.63 (s, 8H), 3.09 (s, 1H).

[0232] Example 5

[0233] 5-Hydroxy-6-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazo-5-yl)methyl)pyrimidin-4(3H)-one

[0234] Example 6

[0235] 5-Hydroxy-6-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazo-4-yl)methyl)pyrimidin-4(3H)-one

[0236]

[0237] first step

[0238] 4-Allyl-5,6-bis(benzyloxy)pyrimidine

[0239] Potassium phosphate (6.50 g, 30.60 mmol), bis(triphenylphosphine)palladium dichloride (859.18 mg, 1.22 mmol), 4,5-dibenzyloxy-6-chloropyrimidine 5a (2.0 g, 6.12 mmol, prepared according to patent WO2020102572) and 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxorane (4.11 g, 24.48 mmol) were added sequentially to a mixed solution of tetrahydrofuran (20 mL) and water (4 mL), purged with argon three times, heated to 90 °C, and reacted for 20 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-allyl-5,6-bis(benzyloxy)pyrimidine 5b (250 mg), yield: 21.6%.

[0240] MS m / z (ESI): 333.1 [M+1] +

[0241] Step 2

[0242] 5-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-4,5-dihydroisoxazole 5c

[0243] 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-4,5-dihydroisoxazole 5d

[0244] Pyridine (24.02 mg, 303.60 μmol), (E)-4-iodobenzaldehyde oxime 1b (250 mg, 1.01 mmol), and 4-allyl-5,6-bis(benzyloxy)pyrimidine 5b (504.58 mg, 1.52 mmol) were added sequentially to a chloroform (5 mL) solution. Sodium hypochlorite solution (1.61 g, 3.04 mmol) was slowly added dropwise under ice-water bath cooling. The mixture was then heated to room temperature and stirred for 3 hours. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give a mixture (470 mg) of 5-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-4,5-dihydroisoxazole 5c and 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-4,5-dihydroisoxazole 5d, yield: 80.4%.

[0245] MS m / z (ESI): 578.1 [M+1] +

[0246] Step 3

[0247] 4-(4-((4-(5-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4,5-dihydroisoxazo-3-yl)phenyl)ethynyl)benzyl)morpholine 5e

[0248] 4-(4-((4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine 5f

[0249] A mixture of the above-mentioned 5-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-4,5-dihydroisoxazole 5c and 4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(4-iodophenyl)-4,5-dihydroisoxazole 5d (470 mg, 813.98 μmol), 4-(4-ethynylbenzyl)morpholine 1f (163.82 mg, 813.98 μmol), allyl palladium chloride dimer (29.78 mg, 81.40 μmol), 1,4-diazabicyclooctane (182.61 mg, 1.63 mmol), and tri-tert-butylphosphine (16.47 mg, 81.40 μmol) was added to an acetonitrile (10 mL) solution, purged with argon gas three times, and reacted at room temperature for 20 hours. After the reaction was complete, water (10 mL) was added. Extracted with ethyl acetate (10 mL × 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-(4-((4-(5-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine 5e (210 mg) and 4-(4-((4-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine 5f (110 mg), with yields of 39.6% and 20.8%, respectively.

[0250] MS m / z (ESI): 651.2 [M+1] +

[0251] MS m / z (ESI): 651.0 [M+1] +

[0252] Step 4

[0253] 5-Hydroxy-6-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazo-5-yl)methyl)pyrimidin-4(3H)-one

[0254] 4-(4-((4-(5-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine 5e (100 mg, 153.67 μmol) was dissolved in dichloromethane (2 mL). Under ice-water bath cooling, 1 M boron trichloride dichloromethane solution (2 mL) was slowly added dropwise, and then the mixture was brought to room temperature and stirred for 20 hours. After the reaction was complete, methanol (2 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. Liquid phase separation was then performed (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-hydroxy-6-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazol-5-yl)methyl)pyrimidin-4(3H)-one 5 (6.7 mg), yield: 18.5%.

[0255] MS m / z (ESI): 470.8 [M+1] +

[0256] Step 5

[0257] 5-Hydroxy-6-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazo-4-yl)methyl)pyrimidin-4(3H)-one

[0258] 4-(4-((4-(((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4,5-dihydroisoxazol-3-yl)phenyl)ethynyl)benzyl)morpholine 5f (110 mg, 169 μmol) was added to a dichloromethane (2 mL) solution. Under ice-water bath cooling, a 1 M boron trichloride dichloromethane solution (2 mL) was slowly added dropwise. Then the mixture was brought to room temperature and stirred for 20 hours. After the reaction was complete, methanol (2 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. Liquid phase separation was then performed (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 5-hydroxy-6-((3-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-4,5-dihydroisoxazol-4-yl)methyl)pyrimidin-4(3H)-one 6 (27 mg), yield: 27.2%.

[0259] MS m / z (ESI): 471.1 [M+1] +

[0260] Example 7

[0261] 5-Hydroxy-6-((4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidone-1-yl)methyl)pyrimidin-4(3H)-one

[0262]

[0263]

[0264] first step

[0265] (E)-3-(4-iodophenyl)methyl acrylate

[0266] Under an argon atmosphere at 0°C, methyl 2-(ethoxy(propyl)phosphonyl)acetate 7a (5.43 g, 25.86 mmol) was slowly added dropwise to a tetrahydrofuran solution of potassium tert-butoxide (2.90 g, 25.86 mmol) in 50 mL. After reacting for 30 minutes, a tetrahydrofuran solution of 4-iodobenzaldehyde 1a (5 g, 21.55 mmol) in 10 mL was added. The mixture was brought to room temperature and stirred for 3 hours. After the reaction was complete, the reaction was quenched with water (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give methyl (E)-3-(4-iodophenyl)acrylate 7b (6 g), yield: 96.65%. This methyl acrylate was used directly in the next reaction without purification.

[0267] MS m / z (ESI): 288.6 [M+1] +

[0268] Step 2

[0269] Methyl 3-(4-iodophenyl)-4-nitrobutyrate

[0270] At -10°C, 1,8-diazabicyclo[5.4.0]undec-7-ene (1.59 g, 10.41 mmol) was added to nitromethane (15 mL), followed by (E)-3-(4-iodophenyl)acrylate methyl 7b (3 g, 10.41 mmol). The mixture was stirred for 1 hour, then slowly brought to room temperature and stirred for 5 hours. After the reaction was complete, the reaction was quenched with water (10 mL), the system was acidified with dilute hydrochloric acid solution, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl 3-(4-iodophenyl)-4-nitrobutyrate methyl 7c (3.1 g), yield: 85.27%.

[0271] 1H NMR (400MHz, DMSO-d6) δ7.62-7.72 (m, 2H), 7.12-7.19 (m, 2H), 4.96 (dd, J=13.3, 5.9Hz, 1H), 4.85 (dd, J=13.3, 9.5H z, 1H), 3.77 (ddd, J=9.1, 6.0, 3.0Hz, 1H), 3.52 (s, 3H), 2.82 (dd, J=16.3, 6.3Hz, 1H), 2.71 (dd, J=16.3, 8.6Hz, 1H).

[0272] Step 3

[0273] 4-(4-iodophenyl)pyrrolidone-2-one

[0274] Methyl 3-(4-iodophenyl)-4-nitrobutyrate 7c (500 mg, 1.43 mmol) was added to methanol (10 mL), followed by nickel chloride (92.80 mg, 716.08 μmol). After reacting for 5 minutes, sodium borohydride (108.36 mg, 2.86 mmol) was added, and the reaction was allowed to proceed overnight at room temperature. A saturated aqueous solution of ammonium chloride was added at 0°C, followed by extraction with ethyl acetate (30 mL × 2). The aqueous layer was separated, and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 4-(4-iodophenyl)pyrrolidone-2-one 7d (200 mg), yield: 48.64%.

[0275] MS m / z (ESI): 287.9 ​​[M+1] +

[0276] Step 4

[0277] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)pyrrolidine-2-one

[0278] 4-(4-iodophenyl)pyrrolidone-2-one 7d (184 mg, 640.90 μmol) and 4,5-bis(benzyloxy)-6-(iodomethyl)pyrimidine 2d (277.03 mg, 640.90 μmol) were added to acetonitrile (5 mL), followed by cesium carbonate (835.27 mg, 2.56 mmol). 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 the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)pyrrolidone-2-one 7e (110 mg), yield: 29.02%.

[0279] MS m / z (ESI): 591.8 [M+1] +

[0280] Step 5

[0281] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)pyrrolidine-2-one

[0282] At room temperature, bis(triphenylphosphine)palladium dichloride (4.75 mg, 6.76 μmol), tetrabutylammonium bromide (54.51 mg, 169.08 μmol), and piperidine (43.19 mg, 507.24 μmol) were added to 2 mL of an aqueous solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)pyrrolidine-2-one 7e (100 mg, 169.08 μmol). The reaction was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)pyrrolidine-2-one 7f (60 mg), yield: 53.38%.

[0283] MS m / z (ESI): 665.0 [M+1] +

[0284] Step 6

[0285] 5-Hydroxy-6-((4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidone-1-yl)methyl)pyrimidin-4(3H)-one

[0286] Under ice-water bath conditions, boron trichloride (1 mL) was added dropwise to 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)pyrrolidine-2-one 7f (60 mg, 90.25 μmol) in dichloromethane (2 mL). The reaction was carried out at room temperature for 2 hours. After the reaction was completed, methanol (2 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure to prepare a liquid phase separator (AKZONOBEL Kromasil column; 250 × 21.2 mm). ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), yielded 7 (13 mg) of 5-hydroxy-6-((4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidone-1-yl)methyl)pyrimidin-4(3H)-one, yield: 22.47%.

[0287] MS m / z (ESI): 485.2 [M+1] +

[0288] 1 H NMR (400MHz, DMSO-d6) δ10.22 (s, 1H), 9.57 (s, 1H), 7.77 (s, 1H), 7.66 (d, J=7.9H z, 2H), 7.54 (dd, J=14.6, 8.0Hz, 4H), 7.39 (d, J=8.0Hz, 2H), 4.37 (q, J=9.0, 8.6H z, 4H), 3.96 (s, 2H), 3.74 (t, J=8.8Hz, 2H), 3.60-3.65 (m, 2H), 3.29-3.33 (m, 1H) , 3.06-3.26 (m, 4H), 2.75 (dd, J=16.5, 9.0Hz, 1H), 2.38 (dd, J=16.5, 8.1Hz, 1H).

[0289] Example 8

[0290] 5-Hydroxy-6-((4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0291]

[0292] first step

[0293] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester

[0294] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 4e (1 g, 1.44 mmol), 4-(4-ethynylbenzyl)morpholine 1f (311.77 mg, 1.55 mmol), bis(triphenylphosphine)palladium dichloride (54.37 mg, 77.45 μmol), tetrabutylammonium bromide (499.38 mg, 1.55 mmol), and piperidine (395.71 mg, 4.65 mmol) were added to water (2 mL) and argon atmosphere was introduced. The reaction mixture was changed three times, heated to 85°C, and reacted for 4 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The solution was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give tert-butyl 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid 8a (660 mg), yield: 55.63%.

[0295] MS m / z (ESI): 766.4 [M+1] +

[0296] Step 2

[0297] 5-Hydroxy-6-((4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0298] Under ice-water bath conditions, boron trichloride (0.5 mL) and a solution of 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 8a (60 mg, 78.34 μmol) in dichloromethane (1 mL) were slowly heated to room temperature and reacted overnight. After the reaction was complete, methanol (2 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. Liquid phase separation was then performed (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 5-hydroxy-6-((4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one 8 (11.54 mg), yield: 23.78%.

[0299] MS m / z (ESI): 486.2 [M+1] +

[0300] 1 H NMR (400MHz, DMSO-d6) δ10.64 (s, 1H), 9.57 (s, 1H), 7.83 (s, 1H), 7.71 (d, J=8.0Hz, 2H), 7.57-7.69 (m, 4H), 7.49 (d, J=8.1Hz, 2H), 7.1 4 (s, 1H), 4.79 (t, J=8.1Hz, 1H), 4.44 (s, 2H), 4.25 (d, J=9.6Hz, 2H), 3.86 (s, 2H), 3.77 (s, 2H), 3.23-3.44 (m, 3H), 3.04-3.24 (m, 3H).

[0301] Example 9

[0302] 5-Hydroxy-6-((3-(2-fluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0303]

[0304] first step

[0305] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0306] Hydrochloric acid (457.00 mg, 12.53 mmol) was added to a solution of tert-butyl 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 8a (480 mg, 626.72 μmol) in ethyl acetate (4 mL). The mixture was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and 20 mL of saturated sodium bicarbonate was added. The solution was extracted with ethyl acetate (20 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 9a (200 mg), yield: 47.93%.

[0307] MS m / z (ESI): 666.3 [M+1] +

[0308] Step 2

[0309] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-fluoroethyl)-4-(4-(((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0310] Under ice-water bath conditions, sodium hydride (6.25 mg, 144.19 μmol, 60% purity) was added to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 9a (80 mg, 120.16 μmol) in N,N-dimethylformamide (2 mL). The mixture was stirred for 20 minutes, and then 1-fluoro-2-iodoethane (25.08 mg, 144.19 μmol) was added. The mixture was stirred at room temperature. After stirring for 2 hours, the reaction solution was quenched with 20 mL of ice water. It was extracted with ethyl acetate (20 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-fluoroethyl)-4-(4-(((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazoline-2-one 9b (85 mg), yield: 99.38%. It was directly used for the next reaction without purification.

[0311] MS m / z (ESI): 712.3 [M+1] +

[0312] Step 3

[0313] 5-Hydroxy-6-((3-(2-fluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0314] Under ice-water bath conditions, boron trichloride (1 mL) was added to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(2-fluoroethyl)-4-(4-(((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazoline-2-one 9b (85 mg, 119.41 μmol) in dichloromethane (1 mL). The reaction was carried out at room temperature for 5 hours. After the reaction was complete, methanol (2 mL) was added to quench the reaction, and the solution was concentrated under reduced pressure to prepare a liquid phase separator (AKZONOBEL Kromasil column; 250 × 21.2 mm). ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), yielded 9 (4.4 mg) of 5-hydroxy-6-((3-(2-fluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one, yield: 5.51%.

[0315] MS m / z (ESI): 532.2 [M+1] +

[0316] 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 9.51 (s, 1H), 7.78 (s, 1H), 7.66 (d, J=7. 9Hz, 2H), 7.52-7.63 (m, 4H), 7.46 (d, J=8.0Hz, 2H), 4.77 (dd, J=9.1, 7.0Hz, 1H ), 4.21-4.50(m, 6H), 3.95(s, 2H), 3.77(t, J=9.0Hz, 2H), 3.67(s, 2H), 3.22(s , 2H), 3.13 (dd, J=8.9, 6.9Hz, 3H), 2.91 (dddd, J=25.0, 15.0, 6.4, 3.5Hz, 1H).

[0317] Example 10

[0318] 5-Hydroxy-6-((3-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0319]

[0320] first step

[0321] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0322] Under ice-water bath conditions, sodium hydride (6.25 mg, 144.19 μmol, 60% purity) was added to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 9a (80 mg, 120.16 μmol) in N,N-dimethylformamide (2 mL). The mixture was stirred for 20 minutes, then iodomethane (20.47 mg, 144.19 μmol) was added, and the mixture was stirred at room temperature. After stirring for 2 hours, the reaction solution was quenched with 20 mL of ice water. It was extracted with ethyl acetate (20 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 10a (81 mg), yield: 99.16%. It was directly used for the next reaction without purification.

[0323] MS m / z (ESI): 680.3 [M+1] +

[0324] Step 2

[0325] 5-Hydroxy-6-((3-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0326] Under ice-water bath conditions, boron trichloride (1 mL) was added to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 10a (81 mg, 119.15 μmol) in dichloromethane (1 mL), and the reaction was carried out overnight at room temperature. After the reaction was complete, methanol (2 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure. Liquid phase separation was then performed (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 10 (4.38 mg) of 5-hydroxy-6-((3-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one, yield: 5.87%.

[0327] MS m / z (ESI): 500.2 [M+1] +

[0328] 1 H NMR (400MHz, DMSO-d6) δ10.52 (s, 1H), 9.51 (s, 1H), 7.79 (s, 1H), 7.66 (d, J=8.0Hz, 2H), 7.60 (p, J=4.9, 4.4Hz, 4H), 7.44 (d, J=8.0Hz, 2H), 4 .53 (t, J=8.4Hz, 1H), 4.39 (s, 2H), 4.25 (s, 2H), 3.83-4.15 (m, 4H), 3.72 (s, 1H), 3.70 (s, 3H), 3.20 (d, J=23.5Hz, 4H), 3.06 (t, J=8.3Hz, 1H).

[0329] Example 11

[0330] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0331]

[0332] first step

[0333] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0334] Under ice-water bath conditions, sodium hydride (5.47 mg, 126.17 μmol, 60% purity) was added to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 9a (70 mg, 105.14 μmol) in N,N-dimethylformamide (2 mL). The mixture was stirred in an ice bath for 20 minutes, and then 2-iodopropane (19.66 mg, 115.65 μmol) was added. The mixture was then incubated at room temperature. After stirring for 2 hours, the reaction was quenched with 20 mL of ice water. The mixture was extracted with ethyl acetate (20 mL × 3), washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 11a (74 mg), yield: 99.43%. It was directly used for the next reaction without purification.

[0335] MS m / z (ESI): 708.3 [M+1] +

[0336] Step 2

[0337] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0338] Under ice-water bath conditions, boron trichloride (1.5 mL) was added to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 11a (74 mg, 104.54 μmol) in dichloromethane (1 mL). The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, methanol (2 mL) was added to quench the reaction, and the solution was concentrated under reduced pressure. Liquid chromatography was then performed (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm). ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), yielded 11 (1.36 mg) of 5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one, yield: 1.95%.

[0339] MS m / z (ESI): 528.2 [M+1] +

[0340] 1 H NMR (400MHz, Methanol-d4) δ7.79 (s, 1H), 7.65 (d, J=8.0Hz, 2H), 7.52-7.59 (m, 4H), 7 .49 (d, J=8.3Hz, 2H), 4.93-4.94 (m, 1H), 4.79 (q, J=2.3Hz, 1H), 4.35-4.43 (m, 3H), 4. 05 (s, 2H), 3.77-3.89 (m, 2H), 3.75 (d, J = 14.2Hz, 2H), 3.36 (d, J = 9.6Hz, 2H), 3.24 (dd , J=15.7, 6.0Hz, 2H), 3.17-3.21 (m, 1H), 1.23 (d, J=6.8Hz, 3H), 0.89 (d, J=6.8Hz, 3H).

[0341] Example 12

[0342] 5-Hydroxy-6-((3-(2-hydroxyethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0343]

[0344]

[0345] first step

[0346] 1-((5-(benzyloxy)-6-hydroxypyrimidin-4-yl)methyl)-3-(2-hydroxyethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0347] Cesium carbonate (101.0 mg, 310.0 μmol) and 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 9a (70 mg, 105.14 μmol) were added to N,N-dimethylformamide (2 mL), followed by 2-iodoethanol (19.89 mg, 115.65 μmol). The mixture was heated to 120 °C and reacted for 3 hours. After the reaction was completed, the solution was... Extracted with ethyl acetate (20 mL × 3), washed with water (20 mL) and saturated sodium chloride solution (20 mL), respectively. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-((5-(benzyloxy)-6-hydroxypyrimidin-4-yl)methyl)-3-(2-hydroxyethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 12a (65 mg), yield: 99.76%. It was directly used for the next reaction without purification.

[0348] MS m / z (ESI): 620.3 [M+1] +

[0349] Step 2

[0350] 5-Hydroxy-6-((3-(2-hydroxyethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0351] Under ice-water bath conditions, boron trichloride (1.5 mL) was added to 1-((5-(benzyloxy)-6-hydroxypyrimidin-4-yl)methyl)-3-(2-hydroxyethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazoline-2-one 12a (20 mg, 32.27 μmol) in dichloromethane (1 mL). The reaction was carried out at room temperature for 5 hours. After the reaction was complete, methanol (2 mL) was added to quench the reaction, and the mixture was concentrated under reduced pressure to prepare a liquid phase separator (AKZONOBEL Kromasil column; 250 × 21.2 mm). ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN), yielded 12 (9.53 mg) of 5-hydroxy-6-((3-(2-hydroxyethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one, yield: 43.49%.

[0352] MS m / z (ESI): 530.2 [M+1] +

[0353] 1 H NMR (400MHz, Methanol-d4) δ7.76 (s, 1H), 7.65 (d, J=7.9Hz, 2H), 7.54 (dd, J=8.2, 3.7Hz, 4H), 7.41-7.47 (m, 2H), 4.95-4.92 (m, 2H), 4.39 (d, J=2.4Hz, 4H), 3.99-4.15 (m, 3H), 3.92 (t, J=9.1Hz, 2H), 3.66-3.82 (m, 3H), 3.37 (s, 2H), 3.20-3.29 (m, 3H).

[0354] Examples 13 and 14

[0355] (R)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one 13

[0356] (R)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one 13

[0357] (S)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one 14

[0358] (S)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one 14

[0359]

[0360] first step

[0361] 11 mg (412 mg) of 5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one was purified by preparative supercritical fluid chromatography (model: MG II preparative SFC (SFC-14), column: ChiralCel OX (250×30mm ID, 10μm), mobile phase: phase A: CO2, phase B: Ethanol (0.1% NH3H2O), gradient: phase B 40%, flow rate: 80 mL / min, back pressure: 100 bar, column temperature: 38℃). The separated fraction was purified by removing the solvent using a rotary evaporator at a bath temperature of 40℃ to obtain (R)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one. (S)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one 13 (114 mg, 215 μmol, 27.6% yield) and (S)-5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one 14 (122 mg, 28.6% yield).

[0362] 13 MS m / z (ESI): 528.0 [M+1] +

[0363] 1H NMR (400MHz, DMSO-d6) δ7.78 (s, 1H), 7.64-7.41 (m, 6H), 7.36 (d, J=8.0Hz, 2H), 4.70 (dd, J=9.2, 7.2Hz, 1H), 4.26 (d, J=15.6Hz, 1H), 4.19 (d, J=15.2H z, 1H), 3.74-3.66 (m, 2H), 3.59-3.57 (m, 4H), 3.49 (s, 2H), 3.04 (t, J=8.0H z, 1H), 2.35 (t, J=4.7Hz, 4H), 1.13 (d, J=6.8Hz, 3H), 0.77 (d, J=7.2Hz, 3H).

[0364] 14 MS m / z (ESI): 528.0 [M+1] +

[0365] Example 15

[0366] 5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0367] 5-Hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0368]

[0369] first step

[0370] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0371] 1-((5,6-di(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0372] 4-((4-(1-((5,6-di(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde 4e (50 mg, 78.53 μmol) and tetrahydrofuran-3-amine 15b (13.68 mg, 157.05 μmol) were dissolved in 1,2-dichloroethane (5 mL), and then acetic acid (0.2 mL) was added. The mixture was stirred for 30 minutes, and then sodium borohydride acetate (49.93 mg, 235.58 μmol) was added. The mixture was stirred continuously at room temperature for 12 hours. Quenching was performed by adding 15 mL of saturated sodium bicarbonate aqueous solution, followed by the addition of dichloromethane (30 mL) and water (15 mL). The mixture was separated, and 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 to dryness under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 1-((5,6-di(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolin-2-one 15c (40 mg, 71.96% yield).

[0373] MS m / z (ESI): 708.0 [M+1] +

[0374] Step 2

[0375] 5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0376] 5-Hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-(((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0377] Under ice bath conditions, boron trichloride (0.4 mL) was added dropwise to a solution of 1-((5,6-di(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolin-2-one 15c (40 mg, 56.51 μmol) in dichloromethane (1 mL). The reaction was carried out at room temperature for 2 hours, and the reaction was quenched with methanol. The solution was purified by preparative liquid chromatography to obtain 5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((((tetrahydrofuran-3-yl)amino)methyl)phenyl)ethynyl)phenyl)imidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one 15c (6 mg, 15.14% yield, 91.5% purity).

[0378] MS m / z (ESI): 528.0 [M+1] +

[0379] Example 16

[0380] 5-hydroxy-6-((3-isopropyl-4-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0381] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(((3-methoxyacryl-1-yl)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidinyl4(3H)-one

[0382]

[0383] first step

[0384] 3-methoxy-1-(4-((trimethylsilyl)ethynyl)benzyl)azetidine

[0385] 3-Methoxy-1-(4-((trimethylsilyl)ethynyl)benzyl)acetidine

[0386] 4-(2-trimethylsilylethynyl)benzaldehyde 16a (400 mg, 1.98 mmol) was dissolved in 1,2-dichloroethane (10 mL), followed by the addition of 3-methoxyacridine hydrochloride 16b (488.65 mg, 3.95 mmol) and acetic acid (1.2 mL). The reaction was carried out at room temperature for 30 minutes, followed by the addition of sodium triacetoxyborohydride (1.26 g, 5.93 mmol) at 0 °C, and the reaction was carried out at room temperature for 2 hours. The reaction solution was then extracted with 50 mL of saturated sodium bicarbonate solution and 100 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: system A) to give 3-methoxy-1-(4-((trimethylsilyl)ethynyl)benzyl)acridine 16c (400 mg, 73.99% yield).

[0387] MS m / z (ESI): 274.0 [M+1] +

[0388] Step 2

[0389] 1-(4-ethynylbenzyl)-3-methoxyazetidine

[0390] 1-(4-ethynylbenzyl)-3-methoxyacridine

[0391] 3-Methoxy-1-(4-((trimethylsilyl)ethynyl)benzyl)acetidine 16c (400 mg, 1.46 mmol) was added to methanol (10 mL), followed by potassium fluoride (339.96 mg, 5.85 mmol). The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-(4-ethynylbenzyl)-3-3-methoxyacetidine 16d (280 mg, 95.10% yield).

[0392] MS m / z (ESI): 202.0 [M+1] +

[0393] Step 3

[0394] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0395] 1-((5,6-di(benzyloxy)pyrimidinyl-4-yl)methyl)-3-isopropyl-4-(4-((4-((3-methoxyacrylidinyl-1-yl)methyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0396] At room temperature, bis(triphenylphosphine)palladium chloride (2.43 mg, 3.47 μmol), tetrabutylammonium bromide (27.94 mg, 86.68 μmol), and piperidine (22.14 mg, 260.04 μmol) were added sequentially to an aqueous solution of 1-((5,6-di(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolium-2-one 16e (55 mg, 86.68 μmol) and 1-(4-ethynylbenzyl)-3-3-methoxyacridine 16d (34.9 mg, 173 μmol) in 1 mL, and the mixture was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 ml x 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 ml x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-di(benzyloxy)pyrimidinyl-4-yl)methyl)-3-isopropyl-4-(4-((4-((3-methoxyacrylidinyl-1-yl)methyl)phenyl)ethynyl)phenyl)imidazolin-2-one 16f (29 mg, 47.26% yield).

[0397] MS m / z (ESI): 708.4 [M+1] +

[0398] Step 4

[0399] 5-hydroxy-6-((3-isopropyl-4-(4-((4-((3-methoxyazetidin-1-yl)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0400] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(((3-methoxyacryl-1-yl)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidinyl4(3H)-one

[0401] Under ice bath conditions, boron trichloride (0.8 mL) was added dropwise to a solution of 1-((5,6-di(benzyloxy)pyrimidinyl-4-yl)methyl)-3-isopropyl-4-(4-((4-(((3-methoxyacinyl-1-yl)methyl)phenyl)ethynyl)phenyl)imidazolin-2-one 16f (29 mg, 40.97 μmol) in dichloromethane (2 mL). The reaction was carried out at room temperature for 2 hours, quenched with methanol, and purified by preparative liquid chromatography to obtain 5-hydroxy-6-((3-isopropyl-4-(4-((4-(((3-methoxyacinyl-1-yl)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidinyl4(3H)-one 16 (2 mg, 7.55% yield, 99.26% purity).

[0402] MS m / z (ESI): 528.3 [M+1] +

[0403] Example 17

[0404] 5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0405] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(morpholino-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidinyl4(3H)-one

[0406]

[0407] first step

[0408] (4-ethynylphenyl)(morpholino)methanone

[0409] (4-ethynylphenyl)(morpholino)methyl ketone

[0410] 4-Ethynylbenzoic acid 17a (1 g, 6.84 mmol) and morpholine 17b (3.58 g, 41.06 mmol) were added to 5 mL of dichloromethane, followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.10 g, 10.95 mmol). The reaction was allowed to proceed overnight at room temperature. After the reaction was complete, the reaction mixture was extracted with dichloromethane (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give (4-ethynylphenyl)(morpholine) methyl ketone 17c (600 mg, 40.74% yield).

[0411] MS m / z (ESI): 216.2 [M+1] +

[0412] Step 2

[0413] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(morpholine-4-carbonyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0414] 1-((5,6-di(benzyloxy)pyrimidinyl-4-yl)methyl)-3-isopropyl-4-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0415] At room temperature, bis(triphenylphosphine)palladium chloride (4.42 mg, 6.30 μmol), tetrabutylammonium bromide (50.81 mg, 157.60 μmol), and piperidine (40.26 mg, 472.81 μmol) were added to 1.5 mL of an aqueous solution of 1-((5,6-di(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolium-2-one 17d and (4-ethynylphenyl)(morpholino)methyl ketone 17c (67.85 mg, 315.21 μmol), and the reaction was heated to 70 °C and stirred for 5 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30 mL x 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-di(benzyloxy)pyrimidinyl-4-yl)methyl)-3-isopropyl-4-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one 17e (100 mg, 87.90% yield).

[0416] MS m / z (ESI): 722.0 [M+1] +

[0417] Step 3

[0418] 5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0419] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidinyl4(3H)-one

[0420] 1-((5,6-di(benzyloxy)pyrimidinyl-4-yl)methyl)-3-isopropyl-4-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one 17e (99.86 mg, 138.35 μmol) was added to dichloromethane (5 mL), followed by boron trichloride (2 mL), and reacted at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure and purified by preparative liquid chromatography to obtain 5-hydroxy-6-((3-isopropyl-4-(4-((4-(morpholin-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidinyl 4(3H)-one 17 (23 mg, 24.57% yield, 96.88% purity).

[0421] MS m / z (ESI): 542.3 [M+1] +

[0422] Example 20

[0423] 5-hydroxy-6-((4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0424] 5-Hydroxy-6-((4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidone-1-yl)methyl)pyrimidinyl-4(3H)-one

[0425]

[0426]

[0427] first step

[0428] methyl(E)-3-(4-iodophenyl)but-2-enoate

[0429] Methyl (E)-3-(4-iodophenyl)but-2-enoate

[0430] At 0 °C, methyl 2-(ethoxyphosphoryl)acetate 20b (6.11 g, 33.53 mmol) was slowly added dropwise to a tetrahydrofuran (60 mL) solution of sodium hydride (1.32 g, 30.48 mmol, 60% purity). The mixture was brought to room temperature, and a tetrahydrofuran (20 mL) solution of 1-(4-iodophenyl)ethyl ketone 20a (5 g, 20.32 mmol) was added dropwise. The reaction was allowed to proceed for 16 hours at room temperature, and LC-MS was used to confirm the completeness of the reaction. The reaction solution was quenched with 60 mL of water, extracted with ethyl acetate (30 mL × 3), and the combined organic phases were washed sequentially with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give methyl (E)-3-(4-iodophenyl)but-2-enoate 20c (2.8 g, 9.27 mmol, 45.61% yield). MS m / z (ESI): 303.0 [M+1] +

[0431] Step 2

[0432] methyl 3-(4-iodophenyl)-3-methyl-4-nitrobutanoate

[0433] methyl 3-(4-iodophenyl)-3-methyl-4-nitrobutyrate

[0434] To methyl (E)-3-(4-iodophenyl)but-2-enoate 20c (1.7 g, 5.63 mmol) in nitromethane (20 mL), tetrabutylammonium fluoride (1 M, 5.63 mL) was added dropwise, and the reaction was carried out overnight at 100 °C. The reaction was confirmed to be complete by LC-MS. The reaction solution was concentrated under reduced pressure, and 12 mL of ethyl acetate was added. The system was acidified with 1 M hydrochloric acid solution. Extraction was performed with ethyl acetate (30 mL × 3). The combined organic phases were washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and the residue was further purified by silica gel column chromatography (eluent: system A) to give methyl 3-(4-iodophenyl)-3-methyl-4-nitrobutyrate 20d (800 mg, 2.20 mmol, 39.15% yield).

[0435] MS m / z (ESI): 361.8 [M-1] +

[0436] Step 3

[0437] 4-(4-iodophenyl)-4-methylpyrrolidin-2-one

[0438] 4-(4-iodophenyl)-4-methylpyrrolidone-2-one

[0439] 20d of methyl 3-(4-iodophenyl)-3-methyl-4-nitrobutyrate (100 mg, 275.37 μmol) was added to 1 mL of methanol, followed by nickel(II) hexahydrate (17.84 mg, 137.69 μmol). After reacting for 5 minutes, sodium borohydride (20.83 mg, 550.74 μmol) was added at 0 °C, and the reaction was allowed to proceed overnight at room temperature. A saturated ammonium chloride solution was added at 0 °C, followed by extraction with dichloromethane (30 mL x 2). The aqueous layer was separated, and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 20e of 4-(4-iodophenyl)-4-methylpyrrolidone-2-one (40 mg, 132.84 μmol, 48.24% yield).

[0440] MS m / z (ESI): 301.8 [M+1] +

[0441] Step 4

[0442] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-4-methylpyrrolidin-2-one

[0443] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-4-methylpyrrolidone-2-one

[0444] 4-(4-iodophenyl)-4-methylpyrrolidone-2-one 20e (137 mg, 454.96 μmol) was added to 5 mL of acetonitrile, followed by the addition of 4,5-dibenzyloxy-6-(iodomethyl)pyrimidine 20f (196.66 mg, 454.96 μmol) and cesium carbonate (370.59 mg, 1.14 mmol). The reaction solution was heated to 90 °C and reacted for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A and system B) to give 20 g (130 mg, 214.71 μmol, 47.19% yield) of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-4-methylpyrrolidone-2-one.

[0445] MS m / z (ESI): 606.1 [M+1] +

[0446] Step 5

[0447] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)pyrrolidin-2-one

[0448] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)pyrrolidine-2-one

[0449] At room temperature, to 1 mL of an aqueous solution containing 20 g (80 mg, 132.13 μmol) of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-4-methylpyrrolidone (20 h, 26.6 mg, 132 μmol), tetrabutylammonium bromide (42.59 mg, 132.13 μmol), and piperidine (33.75 mg, 396.39 μmol) were added sequentially. The reaction mixture was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)pyrrolidine-2-one 20j (50 mg, 73.66 μmol, 55.75% yield).

[0450] MS m / z (ESI): 679.0 [M+1] +

[0451] Step 6

[0452] 5-hydroxy-6-((4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0453] 5-Hydroxy-6-((4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidone-1-yl)methyl)pyrimidinyl-4(3H)-one

[0454] Under ice bath conditions, boron trichloride (0.8 mL) was added dropwise to 2 mL of dichloromethane solution containing 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)pyrrolidine-2-one 20j (50 mg, 73.66 μmol). The reaction was carried out at room temperature for 2 hours, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 5-hydroxy-6-((4-methyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxopyrrolidine-1-yl)methyl)pyrimidinyl-4(3H)-one 20 (10 mg, 15.12 μmol, 20.52% yield, 92.6%).

[0455] MS m / z (ESI): 499.2 [M+1] +

[0456] Example 21

[0457] 6-((4-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one

[0458] 6-((4-((4-(((1,1-tetrahydrothiophene-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one

[0459]

[0460] first step

[0461] tert-butyl

[0462] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazolidine-1-carboxylate

[0463] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester

[0464] 5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 21a (4.2 g, 10.82 mmol), 4,5-dibenzyloxy-6-(iodomethyl)pyrimidine 21b (4.68 g, 10.82 mmol), and potassium carbonate (4.49 g, 32.46 mmol) were added to 70 mL of acetonitrile. The reaction solution was heated to 98 °C and refluxed overnight. The reaction was monitored to ensure complete reaction. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed successively with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give tert-butyl 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid 21c (3 g, 4.33 mmol, 40.04% yield).

[0465] MS m / z (ESI): 592.8 [M-100+H]

[0466] Step 2

[0467] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)imidazolidin-2-one

[0468] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)imidazolin-2-one

[0469] Under ice bath conditions, a 1,4-dioxane hydrochloric acid solution (4M, 10.83 mL) was added dropwise to a 1,4-dioxane (20 mL) solution of 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-iodophenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 21c (1.5 g, 2.17 mmol). The ice bath was removed, and the reaction was allowed to proceed at room temperature for 1 hour. The reaction was monitored for completeness. The reaction solution was concentrated under reduced pressure. 30 mL of saturated sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed successively with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)imidazolin-2-one 21d (1 g, 1.69 mmol, 77.93% yield).

[0470] MS m / z (ESI): 592.8 [M+1] +

[0471] Step 3

[0472] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolidin-2-one

[0473] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one

[0474] Under an argon atmosphere and in an ice bath, sodium hydride (146.35 mg, 3.38 mmol, 60% purity) was added to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)imidazolin-2-one 21d (1 g, 1.69 mmol) in N,N-dimethylformamide (30 mL). After stirring in an ice bath for 20 minutes, 2-iodopropane (573.88 mg, 3.38 mmol, 336.98 μL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction was monitored for completeness. The reaction solution was quenched with 20 mL of ice water, extracted with ethyl acetate (20 mL × 3), and the combined organic phases were washed successively with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one 21e (450 mg, 709.21 μmol, 42.02% yield).

[0475] MS m / z (ESI): 634.8 [M+1]

[0476] Step 4

[0477] 3-((4-((trimethylsilyl)ethynyl)benzyl)amino)tetrahydrothiophene 1,1-dioxide

[0478] 3-((4-((trimethylsilyl)ethynyl)phenyl)amino)tetrahydrothiophene 1,1-dioxide

[0479] 21f of 4-(2-trimethylsilylethynyl)benzaldehyde (400 mg, 1.98 mmol) was dissolved in 20 L of 1,2-dichloroethane, and then 21 g of 1,1-dioxotetrahydrothiophene-3-amine hydrochloride (678.70 mg, 3.95 mmol) and acetic acid (1.25 mL) were added. After reacting at room temperature for 30 minutes, sodium triacetoxyborohydride (1.26 g, 5.93 mmol) was added at 0 °C, and the reaction was carried out at room temperature for 2 hours. The reaction solution was added to 50 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (100 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 3-((4-((trimethylsilyl)ethynyl)phenyl)amino)tetrahydrothiophene 1,1-dioxide 21h (290 mg, 902.00 μmol, 45.62% yield).

[0480] MS m / z (ESI): 321.9 [M+1] +

[0481] Step 5

[0482] 3-((4-ethynylbenzyl)amino)tetrahydrothiophene 1,1-dioxide

[0483] 3-((4-ethynylbenzyl)amino)tetrahydrothiophene 1,1-dioxide

[0484] Potassium fluoride (202.40 mg, 3.48 mmol) was added to a 30 mL methanol solution of 3-((4-((trimethylsilyl)ethynyl)phenyl)amino)tetrahydrothiophene 1,1-dioxide 21h (280 mg, 870.89 μmol), and the reaction was carried out at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 3-((4-ethynylbenzyl)amino)tetrahydrothiophene 1,1-dioxide 21j (180 mg, 721.94 μmol, 82.90% yield).

[0485] MS m / z (ESI): 250.0 [M+1] +

[0486] Step 6

[0487] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one

[0488] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((1,1-dioxotetrahydrothiophene-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one

[0489] At room temperature, 1 mL of an aqueous solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one 21e (45 mg, 70.92 μmol) and 3-((4-ethynylbenzyl)amino)tetrahydrothiophene 1,1-dioxide 21j (21.22 mg, 85.11 μmol) was added sequentially with bis(triphenylphosphine)palladium dichloride (1.99 mg, 2.84 μmol), tetrabutylammonium bromide (22.86 mg, 70.92 μmol), and piperidine (18.12 mg, 212.76 μmol). The reaction was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((1,1-dioxotetrahydrothiophene-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolium-2-one 21k (50 mg, 66.14 μmol, 93.26% yield).

[0490] MS m / z (ESI): 755.9 [M+1] +

[0491] Step 7

[0492] 6-((4-(4-((4-(((1,1-dioxidotetrahydrothiophen-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one

[0493] 6-((4-((4-(((1,1-tetrahydrothiophene-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one

[0494] Under ice bath conditions, boron trichloride (0.8 mL) was added dropwise to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((((1,1-dioxotetrahydrothiophene-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolium-2-one 21k (60 mg, 79.37 μmol) in dichloromethane (2 mL). The reaction was carried out at room temperature for 2 hours, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 6-((4-(4-((4-((((1,1-dioxotetrahydrothiophene-3-yl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolium-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one 21 (2 mg, 2.81 μmol, 3.54% yield).

[0495] MS m / z (ESI): 575.9 [M+1] +

[0496] Example 22

[0497] 6-((4-(4-((4-((1,1-dioxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one

[0498] 6-((4-((4-(((1,1-thiomorpholine)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazoline-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one

[0499]

[0500] first step

[0501] 4-(4-((trimethylsilyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide

[0502] 4-(4-((trimethylsilyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide

[0503] 4-(2-Trimethylsilylethynyl)benzaldehyde 22a (400 mg, 1.98 mmol) was dissolved in 1,2-dichloroethane (15 mL), followed by the sequential addition of thiomorpholine 1,1-dioxide 22b (534.53 mg, 3.95 mmol) and acetic acid (1.25 mL). After reacting at room temperature for 30 minutes, sodium triacetoxyborohydride (1.26 g, 5.93 mmol) was added at 0 °C, and the reaction was continued at room temperature for two hours. The reaction solution was then extracted with 50 mL of saturated sodium bicarbonate solution and 100 mL of dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: system A) to obtain 4-(4-((trimethylsilyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide 22c (157 mg, 488.32 μmol, 24.70% yield).

[0504] MS m / z (ESI): 321.9 [M+1] +

[0505] Step 2

[0506] 4-(4-ethynylbenzyl)thiomorpholine 1,1-dioxide

[0507] 4-(4-ethynylbenzyl)thiomorpholine 1,1-dioxide

[0508] 4-(4-((trimethylsilyl)ethynyl)benzyl)thiomorpholine 1,1-dioxide 22c (157 mg, 488.32 μmol) was added to methanol (5 mL), followed by potassium fluoride (113.49 mg, 1.95 mmol). The reaction was carried out at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: eluent: system A) to give 4-(4-ethynylbenzyl)thiomorpholine 1,1-dioxide 22d (90 mg, 360.97 μmol, 73.92% yield).

[0509] MS m / z (ESI): 249.9 [M+1] +

[0510] Step 3

[0511] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((1,1-dioxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one

[0512] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((1,1-thiomorpholine)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one

[0513] At room temperature, a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one 21e (45 mg, 70.92 μmol) and 4-(4-ethynylbenzyl)thiomorpholine 1,1-dioxide 22d (21.22 mg, 85.11 μmol) in water (1 mL) was successively added with bis(triphenylphosphine)palladium dichloride (1.99 mg, 2.84 μmol), tetrabutylammonium bromide (22.86 mg, 70.92 μmol), and piperidine (18.12 mg, 212.76 μmol), and the mixture was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((1,1-thiomorpholine)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazoline-2-one 22e (26 mg, 34.40 μmol, 48.50% yield).

[0514] MS m / z (ESI): 755.9 [M+1] +

[0515] Step 4

[0516] 6-((4-(4-((4-((1,1-dioxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one

[0517] 6-((4-((4-(((1,1-thiomorpholine)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazoline-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one

[0518] Under ice bath conditions, boron trichloride (0.4 mL) was added dropwise to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((1,1-thiomorpholinedioxide)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolium-2-one 22e (26 mg, 34.40 μmol) in dichloromethane (1 mL). The reaction was carried out at room temperature for 2 hours, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 6-((4-(4-((4-((1,1-thiomorpholinedioxide)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolium-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one 22 (3 mg, 4.11 μmol, 11.96% yield).

[0519] MS m / z (ESI): 575.9 [M+1] +

[0520] Example 23

[0521] 5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0522] 5-Hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((tetrahydro-1H-furan[3,4-c]pyrrole-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0523]

[0524] first step

[0525] 5-(4-((trimethylsilyl)ethynyl)benzyl)hexahydro-1H-furo[3,4-c]pyrrole

[0526] 5-(4-((trimethylsilyl)ethynyl)benzyl)hexahydro-1H-furano[3,4-c]pyrrole

[0527] 4-(2-trimethylsilylethynyl)benzaldehyde 22a (400 mg, 1.98 mmol) was dissolved in 1,2-dichloroethane (20 mL), followed by the addition of hexahydro-1H-furano[3,4-c]pyrrole 23a (335.57 mg, 2.97 mmol) and acetic acid (1.25 mL). After reacting at room temperature for 2 hours, sodium triacetoxyborohydride (1.26 g, 5.93 mmol) was added, and the reaction was continued at room temperature for 2 hours. The reaction solution was added to 50 mL of saturated sodium bicarbonate solution and extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further separated and purified by silica gel column chromatography (eluent: system B) to obtain 5-(4-((trimethylsilyl)ethynyl)benzyl)hexahydro-1H-furano[3,4-c]pyrrole 23b (460 mg, 1.54 mmol, 77.69% yield).

[0528] MS n / z (ESI): 300.0 [M+1] +

[0529] Step 2

[0530] 5-(4-ethynylbenzyl)hexahydro-1H-furo[3,4-c]pyrrole

[0531] 5-(4-ethynylbenzyl)hexahydro-1H-furano[3,4-c]pyrrole

[0532] Potassium fluoride (356.96 mg, 6.14 mmol) was added to a methanol (20 mL) solution of 5-(4-((trimethylsilyl)ethynyl)benzyl)hexahydro-1H-furano[3,4-c]pyrrole 23b (460 mg, 1.54 mmol) and reacted at room temperature for 4 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 5-(4-ethynylbenzyl)hexahydro-1H-furano[3,4-c]pyrrole 23c (311 mg, 1.37 mmol, 89.08% yield).

[0533] MS m / z (ESI): 228.0 [M+1] +

[0534] Step 3

[0535] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0536] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((tetrahydro-1H-furano[3,4-c]pyrrolo-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0537] At room temperature, a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one 21e (45.81 mg, 72.20 μmol) and 5-(4-ethynylbenzyl)hexahydro-1H-furano[3,4-c]pyrrole 23c (19.7 mg, 87 μmol) in water (1 mL) was successively added with bis(triphenylphosphine)palladium dichloride (2.03 mg, 2.89 μmol), tetrabutylammonium bromide (23.27 mg, 72.20 μmol), and piperidine (18.44 mg, 216.59 μmol). The reaction was heated to 70 °C and stirred for 5 hours. The reaction mixture was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((tetrahydro-1H-furano[3,4-c]pyrrolo-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolin-2-one 23d (45 mg, 61.32 μmol, 84.93% yield). MS m / z (ESI): 734.0 [M+1] +

[0538] Step 4

[0539] 5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0540] 5-Hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((tetrahydro-1H-furan[3,4-c]pyrrole-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0541] Under ice bath conditions, 0.4 mL of boron trichloride was added dropwise to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((tetrahydro-1H-furano[3,4-c]pyrrolo-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazolin-2-one 23d (45 mg, 61.32 μmol) in dichloromethane. The reaction was carried out at room temperature for 2 hours. The residue was quenched with methanol, concentrated under reduced pressure, and purified by preparative liquid chromatography to obtain 5-hydroxy-6-((3-isopropyl-2-oxo-4-(4-((4-((tetrahydro-1H-furan[3,4-c]pyrrole-5(3H)-yl)methyl)phenyl)ethynyl)phenyl)imidazoline-1-yl)methyl)pyrimidinyl-4(3H)-one 23 (5 mg, 7.38 μmol, 12.04% yield).

[0542] MS m / z (ESI): 554.0 [M+1] +

[0543] Example 24

[0544] 5-hydroxy-6-((4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0545] 5-Hydroxy-6-((4-(4-((4-(((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0546]

[0547] first step

[0548] 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzaldehyde

[0549] 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde

[0550] At room temperature, bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)imidazolin-2-one 21d (300 mg, 472.81 μmol) and 4-ethynylbenzaldehyde 24a (73.8 mg, 567 μmol) were added sequentially to an aqueous solution (1 mL) of bis(triphenylphosphine)palladium dichloride (13.27 mg, 18.91 μmol), tetrabutylammonium bromide (152.42 mg, 472.81 μmol), and piperidine (120.78 mg, 1.42 mmol). The reaction was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde 24b (230 mg, 361.22 μmol, 76.40% yield).

[0551] MS m / z (ESI): 637.3 [M+1] +

[0552] Step 2

[0553] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one

[0554] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one

[0555] 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde 24b (50 mg, 78.53 μmol) and piperin-4-ol (15.89 mg, 157.05 μmol) were dissolved in 5 mL of 1,2-dichloroethane. Acetic acid (0.2 mL) was added, and the mixture was stirred for 30 minutes. Sodium borohydride acetate (49.93 mg, 235.58 μmol) was added, and the mixture was stirred continuously at room temperature for 12 hours. The solution was quenched with 15 mL of saturated sodium bicarbonate aqueous solution, followed by the addition of dichloromethane (30 mL) and water.

[0556] (15 mL), 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 silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((4-hydroxypiperidinyl-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolium-2-one 24c (20 mg, 27.71 μmol, 35.28% yield).

[0557] MS m / z (ESI): 722.0 [M+1] +

[0558] Step 3

[0559] 5-hydroxy-6-((4-(4-((4-((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0560] 5-Hydroxy-6-((4-(4-((4-(((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0561] In an ice bath, 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-(((4-(((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolium-2-one 24c (20 mg, 27.71 μmol) was added dropwise to a dichloromethane solution (2 mL), and boron trichloride (0.8 mL) was added. The reaction was carried out at room temperature for 2 hours, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 5-hydroxy-6-((4-(4-((4-(((4-hydroxypiperidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolium-1-yl)methyl)pyrimidinium-4(3H)-one 24 (1 mg, 1.41 μmol, 5.08% yield).

[0562] MS m / z (ESI): 542.0 [M+1] +

[0563] Example 25

[0564] 5-hydroxy-6-((3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0565] 5-Hydroxy-6-((3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0566]

[0567]

[0568] first step

[0569] 4-((5-ethynylpyridin-2-yl)methyl)morpholine

[0570] 4-((5-ethynylpyridin-2-yl)methyl)morpholine

[0571] 5-Ethynylpyridin-2-carboxaldehyde 25a (200 mg, 1.53 mmol) was dissolved in 1,2-dichloroethane (3 mL), followed by the addition of morpholine 25b (398.62 mg, 4.58 mmol), acetic acid (0.2 mL), and sodium borohydride acetate (969.75 mg, 4.58 mmol). The reaction was carried out at room temperature for 4 hours. The reaction was quenched with water at 0 °C, and the mixture was extracted with dichloromethane (30 mL × 2). The aqueous layer was separated, and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 4-((5-ethynylpyridin-2-yl)methyl)morpholine 25c (170 mg, 840.54 μmol, 55.11% yield).

[0572] MS m / z (ESI): 203.1 [M+1] +

[0573] Step 2

[0574] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)imidazolidin-2-one

[0575] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)imidazolin-2-one

[0576] At room temperature, a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one 21e (50 mg, 78.80 μmol) and 4-((5-ethynylpyridin-2-yl)methyl)morpholine 25c (19.13 mg, 94.56 μmol) in water (1 mL) was successively added with bis(triphenylphosphine)palladium dichloride (2.21 mg, 3.15 μmol), tetrabutylammonium bromide (25.40 mg, 78.80 μmol), and piperidine (20.13 mg, 236.40 μmol). The reaction was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)imidazoline-2-one 25d (55 mg, 77.59 μmol, 98.46% yield).

[0577] MS m / z (ESI): 709.3 [M+1] +

[0578] Step 3

[0579] 5-hydroxy-6-((3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0580] 5-Hydroxy-6-((3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0581] Under ice bath conditions, boron trichloride (0.8 mL) was added dropwise to a 2 mL solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-(((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)imidazolin-2-one 25d (50 mg, 70.54 μmol) in dichloromethane. The reaction was carried out at room temperature for 2 hours, quenched with methanol, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 5-hydroxy-6-((3-isopropyl-4-(4-((6-(morpholinomethyl)pyridin-3-yl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one 25 (10 mg, 14.83 μmol, 21.03% yield).

[0582] MS m / z (ESI): 529.0 [M+1] +

[0583] Example 26

[0584] 6-((3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one

[0585] 6-((3-Cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one

[0586]

[0587] first step

[0588] tert-butyl

[0589] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidine-1-carboxylate

[0590] 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester

[0591] Under an argon atmosphere, tert-butyl ester 21c (4 g, 5.78 mmol), 4-(4-ethynylbenzyl)morpholine 26a (1.39 g, 6.93 mmol), palladium dichloride bis(triphenylphosphine) chloride (203 mg, 289 μmol), tetrabutylammonium bromide (1.86 g, 5.78 mmol), and piperidine (1.48 g, 17.33 mmol) were added to 50 mL of water, and the mixture was heated to 75 °C and reacted for 5 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed successively with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 26b (3 g, 3.92 mmol, 67.8% yield).

[0592] MS m / z (ESI): 766.5 [M+1] +

[0593] Step 2

[0594] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0595] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0596] Under ice bath conditions, concentrated hydrochloric acid (3.0 mL) was added to 30 mL of 1,4-dioxane solution of 3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-carboxylic acid tert-butyl ester 26b (3 g, 3.92 mmol) and reacted at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to make it alkaline, and the organic solvent was removed by concentration under reduced pressure. The mixture was extracted with ethyl acetate (40 mL × 3), and the organic residues were combined and washed successively with saturated sodium chloride solution (20 mL). The residues were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residues were purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazoline-2-one 26c (2.34 g, 3.51 mmol, 89.7% yield).

[0597] MS m / z (ESI): 666.3 [M+1] +

[0598] Step 3

[0599] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0600] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0601] A solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 26c (200 mg, 300 μmol) in tetrahydrofuran (1.5 mL) was mixed with cyclopropylboronic acid (77.4 mg, 901 μmol) and copper acetate (164 mg, 901 μmol), and the mixture was heated to 80 °C and reacted overnight. After the reaction was complete, ethyl acetate (50 mL) was added, filtered, and the filtrate was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazoline-2-one 26d (40 mg, 56.7 μmol, 18.9% yield).

[0602] MS m / z (ESI): 706.3 [M+1] +

[0603] Step 4

[0604] 6-((3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one

[0605] 6-((3-Cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one

[0606] In an ice bath, boron trichloride (2.5 mL) was added dropwise to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 26d (60 mg, 85 μmol) in dichloromethane (1.2 mL), and the reaction was carried out at room temperature for 5 hours. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 6-((3-cyclopropyl-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one 26 (11.7 mg, 18.3 μmol, 21.5% yield).

[0607] MS m / z (ESI): 526.2 [M+1] +

[0608] Example 27

[0609] 2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetonitrile

[0610] 2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)acetonitrile

[0611]

[0612] first step

[0613] 2-(3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetonitrile

[0614] 2-(3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)acetonitrile

[0615] Under an ice bath and argon atmosphere, sodium hydride (121 mg, 2.79 mmol, 60% purity) was added to 10 mL of a N,N-dimethylformamide solution containing 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one (620 mg, 931 μmol) for 26 h. The reaction was then brought to room temperature and reacted for 20 min. 2-Chloroacetonitrile (211 mg, 2.79 mmol) was added, and the reaction was continued for 3 h. After the reaction was complete, water (20 mL) was added to quench the reaction. Extracted with ethyl acetate (30 mL × 3), the combined organic phases were washed successively with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 2-(3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-yl)acetonitrile 27a (270 mg, 383 μmol, 41.1% yield).

[0616] MS m / z (ESI): 705.3 [M+1] +

[0617] Step 2

[0618] 2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetonitrile

[0619] 2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)acetonitrile

[0620] At room temperature, boron trichloride (3 mL) was added to 1.2 mL of a dichloromethane solution containing 2-(3-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-yl)acetonitrile 27a (130 mg, 184 μmol), and the mixture was stirred for 5 hours. After the reaction was complete, a small amount of ice water was added to quench the reaction, and the mixture was concentrated. The residue was purified by preparative liquid chromatography to obtain 2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-yl)acetonitrile 27a (31.5 mg, 49.0 μmol, 26.6% yield).

[0621] MS m / z (ESI): 525.3 [M+1] +

[0622] Example 28

[0623] 2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)acetamide

[0624] 2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)acetamide

[0625]

[0626] Under ice bath conditions, potassium hydroxide (3.21 mg, 57.2 μmol) was added to a solution of 2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)acetonitrile 27 (15 mg, 28.6 μmol) in dimethyl sulfoxide (1 mL), and hydrogen peroxide (30%, 0.5 mL) was added dropwise. The mixture was then brought to room temperature and reacted for 1 hour. After the reaction was complete, the solution was adjusted to neutral with 1M hydrochloric acid, concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 2-(3-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-5-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)acetamide 28 (13.0 mg, 19.0 μmol, 66.5% yield).

[0627] MS m / z (ESI): 543.2 [M+1] +

[0628] Example 29

[0629] 6-((3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one

[0630] 6-((3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one

[0631]

[0632] first step

[0633] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0634] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0635] Under an ice bath and argon atmosphere, sodium hydride (7.81 mg, 180 μmol, 60% purity) was added to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazoline-2-one 26h (80 mg, 120 μmol) in N,N-dimethylformamide (2 mL). After stirring for 10 minutes, trifluoromethanesulfonic acid (2,2-difluoroethyl ester) (515 mg, 240 μmol) was added, and the reaction was continued for 2 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 29a (80 mg, 110 μmol, 91.2% yield).

[0636] MS m / z (ESI): 730.3 [M+1] +

[0637] Step 2

[0638] 6-((3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)-5-hydroxypyrimidin-4(3H)-one

[0639] 6-((3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one

[0640] Boron trichloride (3 mL) was added to 1.5 mL of a dichloromethane solution containing 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)imidazolin-2-one 29a (100 mg, 137 μmol), and the reaction was carried out overnight at room temperature. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 6-((3-(2,2-difluoroethyl)-4-(4-((4-(morpholinomethyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)-5-hydroxypyrimidinyl-4(3H)-one 29a (34.8 mg, 50.3 μmol, 36.7% yield). MS m / z (ESI): 550.3 [M+1] +

[0641] Example 30

[0642] 5-hydroxy-6-((4-(4-((4-(((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0643] 5-Hydroxy-6-((4-(4-((((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0644]

[0645] first step

[0646] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one

[0647] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one

[0648] 24 g (62 mg, 97.37 μmol) of 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde and 30a (11.90 mg, 194.74 μmol) of 2-aminoethanol were dissolved in 3 mL of 1,2-dichloroethane. Acetic acid (1 mL) was added, and the mixture was stirred at room temperature for 30 minutes. Then, sodium triacetylborohydride (41.27 mg, 194.74 μmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was complete, 15 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. The mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed sequentially 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 (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one 30b (25 mg, 36.67 μmol, 37.66% yield).

[0649] MS m / z (ESI): 682.0 [M+1] +

[0650] Step 2

[0651] 5-hydroxy-6-((4-(4-((4-(((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0652] 5-Hydroxy-6-((4-(4-((((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0653] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazol-2-one 30b (25 mg, 36.67 μmol) was added to 2 mL of dichloromethane, and boron trichloride (0.8 mL) was added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 5-hydroxy-6-((4-(4-((4-((((2-hydroxyethyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazol-1-yl)methyl)pyrimidinyl-4(3H)-one 30 (7 mg, 10.81 μmol, 29.48% yield).

[0654] MS m / z (ESI): 502.0 [M+1] +

[0655] Example 31

[0656] 2-((4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)amino)acetamide

[0657] 2-((4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)amino)acetamide

[0658]

[0659]

[0660] first step

[0661] 2-((4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)amino)acetamide

[0662] 2-((4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)amino)acetamide

[0663] 24 g (73 mg, 114.65 μmol) of 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde and 2-aminoacetamide 31a (16.99 mg, 229.29 μmol) were dissolved in 2 mL of 1,2-dichloroethane, and then 0.5 mL of acetic acid was added. The mixture was stirred at room temperature for 30 minutes, and then sodium triacetylborohydride (48.60 mg, 229.29 μmol) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, 15 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, followed by the addition of dichloromethane (30 mL) and water (15 mL). The mixture was separated, and 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 (eluent: system B) to obtain 2-((4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)amino)acetamide 31b (50 mg, 71.96 μmol, 62.77% yield).

[0664] MS m / z (ESI): 695.4 [M+1] +

[0665] Step 2

[0666] 2-((4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)amino)acetamide

[0667] 2-((4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)amino)acetamide

[0668] 2-((4-((4-(1-((5,6-)bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)amino)acetamide 31b (50 mg, 71.96 μmol) was added to 2 mL of dichloromethane, followed by 0.8 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 2-((4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)amino)acetamide 31 (16 mg, 24.53 μmol, 34.09% yield).

[0669] MS m / z (ESI): 515.0 [M+1] +

[0670] Example 32

[0671] 5-hydroxy-6-((4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0672] 5-Hydroxy-6-((4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0673]

[0674] first step

[0675] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one

[0676] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((3-hydroxypyrrolidone-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one

[0677] 24 g (50 mg, 78.53 μmol) of 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde and pyrrolidine-3-ol 32a (13.68 mg, 157.05 μmol) were dissolved in 1 mL of 1,2-dichloroethane, and then 0.2 mL of acetic acid was added. The mixture was stirred for 30 minutes, and then sodium triacetylborohydride (33.29 mg, 157.05 μmol) was added. The mixture was stirred continuously at room temperature for 12 hours. After the reaction was complete, 15 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, followed by the addition of dichloromethane (30 mL) and water (15 mL). The mixture was separated, and 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 (eluent: system A) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((3-hydroxypyrrolidone-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolium-2-one 32b (40 mg, 56.51 μmol, 71.96% yield). MS m / z (ESI): 708.5 [M+1] +

[0678] Step 2

[0679] 5-hydroxy-6-((4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0680] 5-Hydroxy-6-((4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0681] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolium-2-one 32b (40 mg, 56.51 μmol) was added to 2 mL of dichloromethane, followed by 0.8 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 5-hydroxy-6-((4-(4-((4-((3-hydroxypyrrolidin-1-yl)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolium-1-yl)methyl)pyrimidin-4(3H)-one 32 (9.78 mg, 15.20 μmol, 26.91% yield).

[0682] MS m / z (ESI): 528.0 [M+1] +

[0683] Example 33

[0684] 5-hydroxy-6-((4-(4-((4-(((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0685] 5-Hydroxy-6-((4-(4-((4-((((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0686]

[0687] first step

[0688] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one

[0689] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one

[0690] 24 g (50 mg, 78.53 μmol) of 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde and 3-aminocyclobutane-1-ol hydrochloride 33a (19.41 mg, 157.05 μmol) were dissolved in 1 mL of 1,2-dichloroethane. Acetic acid (0.2 mL) was added, and the mixture was stirred for 30 minutes. Then, sodium triacetylborohydride (33.29 mg, 157.05 μmol) was added, and the mixture was stirred continuously at room temperature for 12 hours. After the reaction was complete, 15 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. Then, 30 mL of dichloromethane and 15 mL of water were added. The mixture was separated, and 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 (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one 33b (20 mg, 28.25 μmol, 35.98% yield).

[0691] MS m / z (ESI): 708.0 [M+1] +

[0692] Step 2

[0693] 5-hydroxy-6-((4-(4-((4-(((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0694] 5-Hydroxy-6-((4-(4-((4-((((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidinyl-4(3H)-one

[0695] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-((((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolium-2-one 33b (20 mg, 28.25 μmol) was added to 2 mL of dichloromethane, followed by 0.8 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, the mixture was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography to obtain 5-hydroxy-6-((4-(4-((4-((((3-hydroxycyclobutyl)amino)methyl)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolium-1-yl)methyl)pyrimidinyl-4(3H)-one 33 (11 mg, 17.08 μmol, 60.45% yield).

[0696] MS m / z (ESI): 528.0 [M+1] +

[0697] Example 34

[0698] 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile

[0699] 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)azacyclobutane-3-nitrile

[0700]

[0701] first step

[0702] 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile

[0703] 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)azacyclobutane-3-nitrile

[0704] 24 g (43 mg, 67.53 μmol) of 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde and 34a (12.01 mg, 101.30 μmol) of aziridine-3-nitrile hydrochloride were dissolved in 1,2-dichloroethane (999.73 μL), acetic acid (4.06 mg, 67.53 μmol, 3.86 μL) was added, and the mixture was stirred for 30 minutes. Then, sodium triacetylborohydride (28.63 mg, 135.06 μmol) was added, and the mixture was stirred continuously at room temperature for 12 hours. After the reaction was complete, 15 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, followed by the addition of dichloromethane (30 mL) and water (15 mL). The mixture was separated, and 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 (eluent: system B) to give 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)azacyclobutane-3-nitrile 34b (26 mg, 36.99 μmol, 54.78% yield).

[0705] MS m / z (ESI): 703.3 [M+1] +

[0706] Step 2

[0707] 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carbonitrile

[0708] 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)azacyclobutane-3-nitrile

[0709] 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)azacyclobutane-3-nitrile 34b (26 mg, 36.99 μmol) was added to 2.5 mL of dichloromethane, followed by 0.1 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)azacyclobutane-3-nitrile 34 (6.8 mg, 10.62 μmol, 28.70% yield).

[0710] MS m / z (ESI): 523.4 [M+1] +

[0711] Example 35

[0712] 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile

[0713] 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-nitrile

[0714]

[0715]

[0716] first step

[0717] 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile

[0718] 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-nitrile

[0719] 24 g (40 mg, 62.82 μmol) of 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde and 35a (9.06 mg, 68.32 μmol) of pyrrolidine-3-nitrile hydrochloride were dissolved in 1 mL of 1,2-dichloroethane. Acetic acid (3.77 mg, 62.82 μmol, 3.59 μL) was added, and the mixture was stirred for 30 minutes. Then, sodium triacetylborohydride (26.63 mg, 125.64 μmol) was added, and the mixture was stirred continuously at room temperature for 12 hours. After the reaction was complete, 15 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction, followed by the addition of dichloromethane (30 mL) and water (15 mL). The mixture was separated, and 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 (eluent: system B) to give 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-onitrile 35b (40 mg, 55.80 μmol, 88.82% yield).

[0720] MS m / z (ESI): 717.4 [M+1] +

[0721] Step 2

[0722] 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-carbonitrile

[0723] 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-nitrile

[0724] 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-onitrile 35b (40 mg, 55.80 μmol) was added to 2 mL of dichloromethane, followed by 0.5 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 1-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)pyrrolidine-3-onitrile 35 (8 mg, 12.10 μmol, 21.69% yield).

[0725] MS m / z (ESI): 537.0 [M+1] +

[0726] Example 36

[0727] 5-hydroxy-6-((3-isopropyl-4-(4-((4-((1-oxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0728] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-((1-oxomorpholine)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-yl)methyl)pyrimidinyl-4(3H)-one

[0729]

[0730] first step

[0731] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((1-oxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0732] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((1-thiomorpholine)methyl)phenyl)ethynyl)phenyl)imidazoline-2-one

[0733] 24 g (40 mg, 62.82 μmol) of 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzaldehyde and 1-thiomorpholine 1-oxide 36a (14.67 mg, 94.23 μmol) were dissolved in 1 mL of 1,2-dichloroethane. Acetic acid (3.77 mg, 62.82 μmol, 3.59 μL) was added, and the mixture was stirred for 30 minutes. Then, sodium triacetylborohydride (26.63 mg, 125.64 μmol) was added, and the mixture was stirred continuously at room temperature for 12 hours. After the reaction was complete, 15 mL of saturated sodium bicarbonate aqueous solution was added to quench the reaction. Then, 30 mL of dichloromethane and 15 mL of water were added. The mixture was separated, and 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 (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-((1-oxomorpholine)methyl)phenyl)ethynyl)phenyl)imidazoline-2-one 36b (20 mg, 27.03 μmol, 43.03% yield).

[0734] MS m / z (ESI): 740.0 [M+1] +

[0735] Step 2

[0736] 5-hydroxy-6-((3-isopropyl-4-(4-((4-((1-oxidothiomorpholino)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0737] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-((1-oxomorpholine)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-yl)methyl)pyrimidinyl-4(3H)-one

[0738] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(((1-oxomorpholine)methyl)phenyl)ethynyl)phenyl)imidazoline-2-one 36b (20 mg, 27.03 μmol) was added to 2 mL of dichloromethane, followed by 0.5 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to obtain 5-hydroxy-6-((3-isopropyl-4-(4-((4-(((1-oxomorpholine)methyl)phenyl)ethynyl)phenyl)-2-oxoimidazoline-1-yl)methyl)pyrimidinyl-4(3H)-one 36 (4 mg, 5.90 μmol, 21.83% yield).

[0739] MS m / z (ESI): 560.0 [M+1] +

[0740] According to the synthesis methods of Examples 1-36, the following compounds were prepared, including:

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747] Example 88

[0748] 1-((5-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxamide

[0749] 1-((5-((4-(1-((5-hydroxy-6-oxo-1,6-dihydroxypyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azacyclobutane-3-carboxamide

[0750]

[0751] first step

[0752] 1-(4-ethynylbenzyl)azetidine-3-carboxamide

[0753] 1-(4-ethynylphenyl)azacyclobutane-3-carboxamide

[0754] 4-ethynylbenzaldehyde 88a (200 mg, 1.54 mmol) and aziridine-3-carboxamide hydrochloride 88b (307.72 mg, 2.25 mmol) were dissolved in 1,2-dichloroethane (2.00 mL), acetic acid (92.28 mg, 1.54 mmol, 87.89 μL) was added, and the mixture was stirred for 30 minutes. Then, sodium triacetylborohydride (651.41 mg, 3.07 mmol) was added, and the mixture was stirred continuously at room temperature for 12 hours. After the reaction was complete, 15 mL of saturated sodium bicarbonate aqueous solution was added to the reaction solution to quench the reaction, followed by the addition of dichloromethane (30 mL) and water (15 mL). The mixture was separated, and 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 to dryness under reduced pressure. The residue was purified by preparative liquid chromatography (eluent: system B) to obtain 1-(4-ethynylphenyl)azacyclobutane-3-carboxamide 88c (100 mg, 466.72 μmol, 30.37% yield).

[0755] MS m / z (ESI): 214.9 [M+1]

[0756] Step 2

[0757] 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)azetidine-3-carboxamide

[0758] 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)methyl)ethynyl)benzyl)azacyclobutane-3-carboxamide

[0759] At room temperature, bis(triphenylphosphine)palladium dichloride (2.21 mg, 3.15 μmol), tetrabutylammonium bromide (25.40 mg, 78.80 μmol) and piperidine (20.13 mg, 236.40 μmol) were added to an aqueous solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolium-2-one 21e (50 mg, 78.80 μmol) and 1-(4-ethynylphenyl)azacyclobutane-3-carboxamide 88c (33.77 mg, 157.60 μmol) in 2 mL. The reaction was heated to 70℃ and stirred for 5 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)methyl)ethynyl)benzyl)azacyclobutane-3-carboxamide 88d (30 mg, 41.62 μmol, 52.81% yield).

[0760] MS m / z (ESI): 721.0 [M+1]

[0761] Step 3

[0762] 1-((5-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azetidine-3-carboxamide

[0763] 1-((5-((4-(1-((5-hydroxy-6-oxo-1,6-dihydroxypyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azacyclobutane-3-carboxamide

[0764] 1-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)methyl)ethynyl)benzyl)azacyclobutane-3-carboxamide 88 (30 mg, 41.62 μmol) was added to 2 mL of dichloromethane, followed by the addition of boron trichloride (0.8 mL), and the reaction was carried out at room temperature for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by preparative liquid chromatography to obtain 1-((5-((4-(1-((5-hydroxy-6-oxo-1,6-dihydroxypyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)pyridin-2-yl)methyl)azacyclobutane-3-carboxamide 88 (7 mg, 9.88 μmol, 23.75% yield).

[0765] MS m / z (ESI): 541.3 [M+1]

[0766] Example 89

[0767] 5-hydroxy-6-((4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0768] 5-Hydroxy-6-((4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0769]

[0770]

[0771] first step

[0772] 2-(4-((trimethylsilyl)ethynyl)phenoxy)ethan-1-ol

[0773] 2-(4-((trimethylsilyl)ethynyl)phenoxy)eth-1-ol

[0774] At room temperature, cuprous iodide (52.64 mg, 276.42 μmol) and palladium dichloride dichloride (194.02 mg, 276.42 μmol) were added to a triethylamine (10.29 mL) solution of 2-(4-bromophenoxy)ethanol 89a (600 mg, 2.76 mmol) and ethynyl(trimethyl)silane 89b (298.65 mg, 3.04 mmol, 429.71 μL). The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 2-(4-((trimethylsilyl)ethynyl)phenoxy)ethanol-1-ol 89c (250 mg, 1.07 mmol, 38.59% yield).

[0775] MS m / z (ESI): 235.1 [M+1]

[0776] Step 2

[0777] 2-(4-ethynylphenoxy)ethan-1-ol

[0778] 2-(4-ethynylphenoxy)ethane-1-ol

[0779] 2-(4-((trimethylsilyl)ethynyl)phenoxy)ethanol-1-ol 89c (236 mg, 1.01 mmol) was added to methanol, followed by potassium carbonate (417.52 mg, 3.02 mmol). The reaction was carried out at room temperature for 1 hour. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system A) to give 2-(4-ethynylphenoxy)ethanol-1-ol 89d (120 mg, 739.90 μmol, 73.48% yield).

[0780] MS m / z (ESI): 163.0 [M+1]

[0781] Step 3

[0782] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropylimidazolidin-2-one

[0783] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(2-hydroxyethyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one

[0784] At room temperature, bis(triphenylphosphine)palladium dichloride (2.65 mg, 3.78 μmol), tetrabutylammonium bromide (30.48 mg, 94.56 μmol), and piperidine (24.16 mg, 283.69 μmol) were added to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazol-2-one 21e (60 mg, 94.56 μmol) and 2-(4-ethynylphenoxy)eth-1-ol 89d (30.67 mg, 189.12 μmol) in water (2 mL). The reaction was heated to 70℃ and stirred for 5 hours. After the reaction was complete, the reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(2-hydroxyethyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one 89e (30 mg, 44.86 μmol, 47.44% yield).

[0785] MS m / z (ESI): 669.3 [M+1]

[0786] Step 4

[0787] 5-hydroxy-6-((4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0788] 5-Hydroxy-6-((4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0789] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-((4-(2-hydroxyethyl)phenyl)ethynyl)phenyl)-3-isopropylimidazolin-2-one 89e (30 mg, 44.86 μmol) was added to 2 mL of dichloromethane, followed by 0.5 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was further purified by preparative liquid chromatography to obtain 5-hydroxy-6-((4-(4-((4-(2-hydroxyethoxy)phenyl)ethynyl)phenyl)-3-isopropyl-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one 89 (4 mg, 6.48 μmol, 14.44% yield).

[0790] MS m / z (ESI): 488.9 [M+1]

[0791] 1 H NMR (400MHz, DMSO) δ12.60 (s, 1H), 9.48 (s, 1H), 7.79 (s, 1H), 7.60-7.40 (m, 6H), 6.99 (d, J=8.4Hz, 2H), 4.69 (t, J=8.2Hz, 1H), 4.26 (d, J=15.6 Hz, 1H), 4.19 (d, J=15.6Hz, 1H), 4.02 (t, J=4.8Hz, 2H), 3.73-3.67 (m, 4H), 3.04 (t, J=8.0Hz, 1H), 1.13 (d, J=6.8Hz, 3H), 0.77 (d, J=6.4Hz, 3H).

[0792] Example 90

[0793] 5-hydroxy-6-((3-isopropyl-4-(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0794] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(3-methoxyaziridine-1-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0795]

[0796]

[0797] first step

[0798] (4-ethynylphenyl)(3-methoxyazetidin-1-yl)methanone

[0799] (4-ethynylphenyl)(3-methoxyazacyclobut-1-yl)methyl ketone

[0800] 4-Ethynylbenzoic acid 90a (500 mg, 3.42 mmol) and 3-methoxyazinon hydrochloride 90b (845.62 mg, 6.84 mmol) were added to 5 mL of dichloromethane, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.05 g, 5.47 mmol) and 4-dimethylaminopyridine (41.80 mg, 342.13 μmol). The mixture was reacted overnight at room temperature. The reaction solution was extracted with dichloromethane (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: system C) to give (4-ethynylphenyl)(3-methoxyazacyclobut-1-yl) ketone 90c (500 mg, 2.32 mmol, 67.90% yield). MS m / z (ESI): 216.2 [M+1] +

[0801] Step 2

[0802] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0803] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(3-methoxyazine-1-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0804] At room temperature, to a water solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one 21e (60 mg, 94.56 μmol) and (4-ethynylphenyl)(3-methoxyazacyclobut-1-yl) methyl ketone 90c (40.71 mg, 189.12 μmol), bis(triphenylphosphine)palladium dichloride (2.65 mg, 3.78 μmol), tetrabutylammonium bromide (30.48 mg, 94.56 μmol) and piperidine (24.16 mg, 283.69 μmol) were added sequentially, and the reaction was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(3-methoxyazine-1-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one 90d (35 mg, 48.49 μmol, 51.28% yield).

[0805] MS m / z (ESI): 722.0 [M+1] +

[0806] Step 3

[0807] 5-hydroxy-6-((3-isopropyl-4-(4-((4-(3-methoxyazetidine-1-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0808] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(3-methoxyaziridine-1-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0809] 90 d (35 mg, 48.49 μmol) of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(3-methoxyaziridine-1-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one was added to 2 mL of dichloromethane, followed by 0.5 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was further separated and purified by preparative liquid chromatography to obtain 90 d (6 mg, 8.40 μmol, 17.33% yield) of 5-hydroxy-6-((3-isopropyl-4-(4-((4-(3-methoxyaziridine-1-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one.

[0810] MS m / z (ESI): 542.3 [M+1] +

[0811] 1 H NMR (400MHz, DMSO) δ12.59 (br, 1H), 9.50 (s, 1H), 7.79 (s, 1H), 7.68 (d, J=8.3Hz, 2H), 7. 61 (d, J=8.4Hz, 2H), 7.58 (d, J=8.4Hz, 2H), 7.52 (d, J=8.4Hz, 2H), 4.71 (dd, J=9.2, 7.2Hz , 1H), 4.45 (dt, J=6.4, 3.3Hz, 1H), 4.29-4.12 (m, 5H), 3.85 (q, J=7.1Hz, 1H), 3.74-3.67 ( m, 2H), 3.22 (s, 3H), 3.04 (t, J=8.0Hz, 1H), 1.13 (d, J=6.8Hz, 3H), 0.78 (d, J=6.8Hz, 3H).

[0812] Example 91

[0813] 5-hydroxy-6-((3-isopropyl-4-(4-((4-(1-oxidothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0814] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(1-oxomorpholino-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0815]

[0816] first step

[0817] (4-ethynylphenyl)(1-oxidothiomorpholino)methanone

[0818] (4-ethynylphenyl)(1-thiomorpholine) methyl ketone

[0819] 4-ethynylbenzoic acid 90a (150 mg, 1.03 mmol) and thiomorpholine 1-oxide hydrochloride 36a (255.61 mg, 1.64 mmol) were added to 1 mL of dichloromethane, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (314.82 mg, 1.64 mmol) and 4-dimethylaminopyridine (12.54 mg, 102.64 μmol). The mixture was reacted overnight at room temperature. The reaction solution was extracted with dichloromethane (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: system A) to obtain (4-ethynylphenyl)(1-thiomorpholine) methyl ketone 91a (100 mg, 404.35 μmol, 39.39% yield).

[0820] MS m / z (ESI): 247.9 [M+1] +

[0821] Step 2

[0822] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(1-oxidothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)imidazolidin-2-one

[0823] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(1-oxomorpholino-4-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one

[0824] At room temperature, a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one 21e (50 mg, 78.80 μmol) and (4-ethynylphenyl)(1-thiomorpholine) methyl ketone 91a (38.98 mg, 157.60 μmol) in water (1.5 mL) was successively supplemented with bis(triphenylphosphine)palladium dichloride (2.21 mg, 3.15 μmol), tetrabutylammonium bromide (25.40 mg, 78.80 μmol), and piperidine (20.13 mg, 236.40 μmol). The reaction was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: system B) to obtain 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(1-oxomorpholino-4-carbonyl)phenyl)ethynyl)phenyl)imidazoline-2-one 91b (30 mg, 39.79 μmol, 50.50% yield).

[0825] MS m / z (ESI): 754.9 [M+1] +

[0826] Step 3

[0827] 5-hydroxy-6-((3-isopropyl-4-(4-((4-(1-oxidothiomorpholine-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolidin-1-yl)methyl)pyrimidin-4(3H)-one

[0828] 5-Hydroxy-6-((3-isopropyl-4-(4-((4-(1-oxomorpholino-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one

[0829] 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-4-(4-((4-(1-oxomorpholin-4-carbonyl)phenyl)ethynyl)phenyl)imidazolin-2-one 91b (30 mg, 39.79 μmol) was added to 2 mL of dichloromethane, followed by 0.8 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was further purified by preparative liquid chromatography to obtain 5-hydroxy-6-((3-isopropyl-4-(4-((4-(1-oxomorpholin-4-carbonyl)phenyl)ethynyl)phenyl)-2-oxoimidazolin-1-yl)methyl)pyrimidin-4(3H)-one 91 (8 mg, 11.57 μmol, 29.08% yield).

[0830] MS m / z (ESI): 574.2 [M+1] +

[0831] Example 92

[0832] 2-hydroxy-N-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)acetamide

[0833] 2-Hydroxy-N-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)acetamide

[0834] first step

[0835] N-(4-ethynylbenzyl)-2-hydroxyacetamide

[0836] N-(4-ethynylbenzyl)-2-hydroxyacetamide

[0837] (4-ethynylphenyl)methylamine 92a (600 mg, 3.58 mmol, SO2) and 2-hydroxyacetic acid 92b (326.64 mg, 4.30 mmol) were added to 2 mL of dichloromethane, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.10 g, 5.73 mmol) and 4-dimethylaminopyridine (43.73 mg, 357.92 μmol). The mixture was reacted overnight at room temperature. After the reaction was complete, the reaction solution was extracted with dichloromethane (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: system C) to obtain N-(4-ethynylbenzyl)-2-hydroxyacetamide 92c (300 mg, 1.59 mmol, 44.30% yield).

[0838] MS m / z (ESI): 190.2 [M+1] +

[0839] Step 2

[0840] N-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)-2-hydroxyacetamide

[0841] N-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)-2-hydroxyacetamide

[0842] At room temperature, to a solution of 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one 21e (60 mg, 94.56 μmol) and N-(4-ethynylbenzyl)-2-hydroxyacetamide 92c (35.78 mg, 189.12 μmol) in water (1 mL), bis(triphenylphosphine)palladium dichloride (2.65 mg, 3.78 μmol), tetrabutylammonium bromide (30.48 mg, 94.56 μmol) and piperidine (24.16 mg, 283.69 μmol) were added sequentially, and the reaction was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed sequentially with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: system B) to obtain N-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)-2-hydroxyacetamide 92d (30 mg, 43.12 μmol, 45.60% yield).

[0843] MS m / z (ESI): 696.3 [M+1] +

[0844] Step 3

[0845] 2-hydroxy-N-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)benzyl)acetamide

[0846] 2-Hydroxy-N-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)acetamide

[0847] N-(4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)-2-hydroxyacetamide 92 (20 mg, 28.74 μmol) was added to 1.5 mL of dichloromethane, followed by 0.8 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was further purified by preparative liquid chromatography to obtain 2-hydroxy-N-(4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)benzyl)acetamide 92 (8 mg, 12.03 μmol, 41.86% yield).

[0848] MS m / z (ESI): 516.0 [M+1] +

[0849] 1 H NMR (400MHz, DMSO) δ12.57 (br, 1H), 9.48 (s, 1H), 8.37 (t, J=6.4Hz, 1H), 7.79 (s, 1 H), 7.59-7.45 (m, 6H), 7.31 (d, J=8.4Hz, 2H), 4.70 (dd, J=9.2, 7.2Hz, 1H), 4.33 (d , J=6.3Hz, 2H), 4.26 (d, J=15.6Hz, 1H), 4.18 (d, J=15.6Hz, 1H), 3.87 (s, 2H), 3.74 -3.67 (m, 4H), 3.04 (t, J = 8.0Hz, 1H), 1.13 (d, J = 6.8Hz, 3H), 0.77 (d, J = 6.8Hz, 3H).

[0850] Example 93

[0851] 4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide

[0852] 4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide

[0853]

[0854]

[0855] first step

[0856] 4-ethynyl-N-(2-methoxyethyl)benzamide

[0857] 4-Ethynyl-N-(2-methoxyethyl)benzamide

[0858] 4-Ethynylbenzoic acid 90a (500 mg, 3.42 mmol) and methoxyethylamine 93a (513.95 mg, 6.84 mmol) were added to 2 mL of dichloromethane, followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (655.87 mg, 3.42 mmol) and 4-dimethylaminopyridine (41.80 mg, 342.13 μmol). The reaction mixture was allowed to react overnight at room temperature. The reaction solution was extracted with dichloromethane (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was further purified by silica gel column chromatography (eluent: system A) to obtain 4-ethynyl-N-(2-methoxyethyl)benzamide 93b (360 mg, 1.77 mmol, 51.77% yield).

[0859] MS m / z (ESI): 204.2 [M+1] +

[0860] Step 2

[0861] 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide

[0862] 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide

[0863] At room temperature, 1 mL of water containing 1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-4-(4-iodophenyl)-3-isopropylimidazolin-2-one 21e (60 mg, 94.56 μmol) and 4-ethynyl-N-(2-methoxyethyl)benzamide 93b (38.44 mg, 189.12 μmol) was added sequentially with bis(triphenylphosphine)palladium dichloride (2.65 mg, 3.78 μmol), tetrabutylammonium bromide (30.48 mg, 94.56 μmol), and piperidine (24.16 mg, 283.69 μmol). The reaction was heated to 70 °C and stirred for 5 hours. The reaction solution was extracted with ethyl acetate (30 mL × 2), the aqueous layer was separated, and the combined organic phases were washed successively with saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: system B) to give 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide 93d (40 mg, 56.35 μmol, 59.59% yield).

[0864] MS m / z (ESI): 710.3 [M+1] +

[0865] Step 3

[0866] 4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazolidin-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide

[0867] 4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide

[0868] 4-((4-(1-((5,6-bis(benzyloxy)pyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide 93 (40 mg, 56.35 μmol) was added to 2 mL of dichloromethane, followed by 0.8 mL of boron trichloride. The reaction was carried out at room temperature for 1 hour. After the reaction was complete, methanol was added to quench the reaction, and the mixture was concentrated under reduced pressure. The residue was further purified by preparative liquid chromatography to obtain 4-((4-(1-((5-hydroxy-6-oxo-1,6-dihydropyrimidin-4-yl)methyl)-3-isopropyl-2-oxoimidazoline-4-yl)phenyl)ethynyl)-N-(2-methoxyethyl)benzamide 93 (1.82 mg, 2.68 μmol, 4.75% yield).

[0869] MS m / z (ESI): 530.2 [M+1] +

[0870] 1H NMR (400MHz, DMSO) δ9.61 (br, 1H), 8.65 (s, 1H), 7.92-7.89 (m, 3H), 7.64 (d, J=8. 0, 2H), 7.58 (d, J=8.0Hz, 2H), 7.52 (d, J=8.0Hz, 2H), 4.71 (t, J=8.0, 1H), 4.24 (d, J=15.6Hz,,1H), 4.22(d, J=15.6Hz,,1H), 3.72-3.67(m, 2H), 3.47-3.42(m, 4H), 3.27 (s, 3H), 3.05 (t, J=8.0Hz, 1H), 1.13 (d, J=6.8Hz, 3H), 0.78 (d, J=6.4Hz, 3H).

[0871] According to the synthesis methods of Examples 1-93, the following compounds were prepared, including:

[0872]

[0873] Biological evaluation

[0874] Test Example 1: Determination of the inhibitory effect of the compound of the present invention on LpxC enzymatic activity.

[0875] The following method was used to determine the degree of inhibition of the enzymatic activity of recombinant Pseudomonas aeruginosa LpxC by the compounds of the present invention under in vitro conditions.

[0876] The experimental procedure is briefly described as follows: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution. The reaction was carried out in a 96-well microplate. First, 20 μL of recombinant Pseudomonas aeruginosa LpxC (purchased from Signalway Antibody, catalog number AP74647-2) was added to the wells, with a final concentration of 5 nM; 5 μL of the test compound was added, and the compound was diluted 4-fold to 8 concentration points, with a concentration range of 0.61-10000 nM; 5 μL of the LpxC substrate UDP-3-O-(R-3-hydroxydecanoyl)-GlcNAc (purchased from Biosynth Carbosynth, catalog number mu75071) was added, with a final substrate concentration of 10 μM, and incubated at 25 °C for 120 minutes. Subsequently, 20 μL of 2.0 mg / mL fluorescamine (purchased from Sigma-Aldrich, catalog number F9015, solvent: 1:1 dimethylformamide / acetonitrile) was added to the reaction system, mixed well, and reacted for 10 minutes. Finally, 50 μL of 200 mM sodium phosphate buffer (pH 8.0) was added to terminate the reaction. The excitation and emission wavelengths were measured using a microplate reader (BMG) at 390 nm and 495 nm, respectively. The percentage inhibition rate of the compound at each concentration was calculated by comparing the fluorescence intensity ratio with that of the control group (0.1% DMSO). The IC50 of the compound was obtained by nonlinear regression analysis using GraphPad Prism 5 software with the compound concentration as the logarithm of the inhibition rate. 50 The values ​​are shown in Table 1 below.

[0877] Table 1. Results of the inhibitory effect of the compounds of the present invention on LpxC enzyme activity.

[0878]

[0879]

[0880] Conclusion: The IC50 of the compound of this invention inhibits the activity of recombinant Pseudomonas aeruginosa LpxC enzyme. 50 All values ​​are less than 100 nM, and they have a significant inhibitory effect on LpxC enzyme activity.

[0881] Test Example 2: Evaluation of the antibacterial activity of the compounds of this invention

[0882] The minimum inhibitory concentration (MIC) was determined in vitro according to the CLSI guidelines, using the microbroth dilution method.

[0883] The experimental procedure is briefly described as follows: The test compound was dissolved in DMSO to prepare a 12.8 mg / mL stock solution, and then 11 two-fold diluted 100× high-concentration working solutions were prepared using DMSO (final system concentration: 64 μg / mL - 0.06 μg / mL). The strains (K. Pneumoniae ATCC13883 and E. coli ATCC 25922) frozen in glycerol at -80℃ were inoculated into solid agar medium and incubated at 35℃ for 18–24 h to complete the strain preparation. Then, an appropriate amount of solid agar culture was collected and resuspended in physiological saline, mixed well, and the turbidity of the bacterial suspension was adjusted to a suitable level using a turbidimeter, approximately 1 × 10⁻⁶ mg / mL. 8 The bacterial suspension was then diluted with test medium to a bacterial concentration of 5 × 10⁻⁶ CFU / mL. 5 The inoculum concentration was determined to be cfu / ml. 198 μL of the inoculum was inoculated into a 96-well plate, followed by the addition of 2 μL of a 100× high-concentration working solution of the compound. The 96-well plate was then incubated at 35°C for 18–24 h. After incubation, the lowest drug concentration that completely inhibited bacterial growth was determined by visual observation of the test plate. This was defined as the minimum inhibitory concentration (MIC) of the compound, as shown in Table 2 below.

[0884] Table 2. Results of antibacterial activity tests of the compounds of this invention.

[0885]

[0886]

[0887] Conclusion: The compounds of this invention have good inhibitory effects on both Klebsiella pneumoniae (K. Pneumoniae ATCC13883) and Escherichia coli (E. coli ATCC 25922).

[0888] Note: ND indicates not measured.

[0889] Test Example 3: Pharmacokinetic Study of the Compound ICR in Mice

[0890] 1. Experimental Objective

[0891] Using ICR mice as test animals, the pharmacokinetic characteristics of the compound 13 of the present invention were studied in mice by intravenous injection or gavage using LC / MS / MS.

[0892] 2. Experimental Design

[0893] 2.1 Experimental drugs and animals;

[0894] Example 13 Compound;

[0895] Male ICR mice, 29.0–33.8 g, were purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd.

[0896] 2.2 Drug Preparation

[0897] Intravenous injection group: Weigh an appropriate amount of drug, add 10% HP-β-CD aqueous solution, vortex, and sonicate for 60 minutes. Add 10 μL of 1M HCl, vortex, mix well, adjust pH to 3.5-4.0, filter using (Rephile, Nylon, 0.45 μm) to obtain a colorless solution, and prepare a final concentration of 0.2 mg / mL;

[0898] Oral gavage group: Weigh an appropriate amount of drug, add 10% Solutol HS15-20% HP-β-CD, vortex, sonicate for 30 minutes to obtain a colorless solution, and prepare a final concentration of 0.5 mg / kg.

[0899] 2.3 Administration

[0900] ICR mice were divided into an intravenous injection group (n=9 per group) and a gavage group (n=9 per group) for each test compound. After fasting overnight, the mice were administered the compound via intraorbital injection (dose 1 mg / kg, volume 5 mL / kg) and gavage (dose 5 mg / kg, volume 10 mL / kg), respectively. The mice were fed 4 hours after administration.

[0901] 3. Operation

[0902] Approximately 0.1 mL of blood was collected via the neck and orbital region before administration and at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. Whole blood samples were placed in anticoagulant tubes containing EDTA-K2. After collection, blood samples were placed on ice and centrifuged to separate the plasma (centrifugation conditions: 1500 g, 10 min). Collected plasma was stored at -40 to -20°C before analysis.

[0903] The levels of different compounds in mouse plasma after intravenous injection and gavage administration were determined by LC-MS / MS.

[0904] 4. Pharmacokinetic Parameter Results

[0905] The pharmacokinetic parameters of the compounds of this invention are shown in Table 3.

[0906] Table 3. Pharmacokinetic parameters of the compounds of this invention.

[0907]

[0908]

[0909] Conclusion: The compound in Example 13 of this invention has high blood drug concentration and area under the curve, as well as high bioavailability and good pharmacokinetic properties.

Claims

1. A compound of general formula (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: X and Y are each independently selected from C or N, and X and Y are not both N at the same time; Ring A is selected from , , or ; L1 is selected from a single bond or -CH2-; Whether R1 is the same or different, each is independently selected from -G1-R4; G1 is selected from single bonds, -CH2-, or -C(=O)-; R2 may be the same or different, and each is independently selected from halogen or C. 1-6 alkyl; R3 may be the same or different, and each is independently selected from C. 1-6 Alkyl or C 3-7 cycloalkyl, wherein the C 1-6 Alkyl or C 3-7 The cycloalkyl group may optionally be further substituted by one or more substituents selected from halogen cyano or -C(O)NR6R7; R4 is selected from cyano, halogen, and C. 1-6 Alkyl, 5-7 membered heterocyclic or -NR6R7, wherein the C 1-6 Alkyl or 5-7 membered heterocyclic groups optionally further surrounded by one or more R A Replaced; R A Selected from halogens, hydroxyl groups, C 1-6 Substituted with alkoxy, -C(O)NR6R7 or -NR6C(O)R7 substituents; R6 and R7 are each independently selected from hydrogen atoms, C atoms, and C atoms. 1-6 Alkyl, C 3-7 Cycloalkyl or 5-7 membered heterocyclic group, wherein the C 1-6 Alkyl, C 3-7 Cycloalkyl or 5-7 membered heterocyclic groups may optionally be further selected from one or more hydroxyl, C 1-6 Alkyl group, -C(O)NR9R 10 The substituents are replaced by; R9 and R 10 Each atom is independently selected from hydrogen atoms; The 5-7 membered heterocyclic group contains 1, 2 or 3 atoms selected from nitrogen, oxygen and / or S(O)r, where r is selected from 0, 1 or 2; The heterocyclic groups mentioned refer to non-aromatic heterocyclic groups; m is 1; n is 0 or 1; and p is 0, 1, or 2; Or the above Selected from , , , or .

2. The compound according to claim 1, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein it is the compound according to general formula (II), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: The definitions of rings A, R1~R3, L1, m, n and p are as described in claim 1.

3. The compound according to claim 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein it is the compound according to general formula (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: in: R A Selected from C 1-6 alkyl; q is 0; The definitions of rings A, G1, R2, R3, L1, n, and p are as described in claim 1.

4. The compound according to any one of claims 1 to 3, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein ring A is selected from: , or .

5. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein... Selected from: , , , , , , , , , or .

6. The compound according to any one of claims 1 to 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein... Selected from: , , , , , , , , , , , ,or .

7. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein n is selected from 0.

8. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L1 is selected from -CH2-.

9. The compound described below, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein the compound is: 。 10. A method for preparing a compound of general formula (I) or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, the method comprising: Compounds of general formula (Ia) and (Ib) undergo a coupling reaction in the presence of a catalyst to give compound of general formula (I); in: X1 is selected from halogens; The definitions of rings A, X, Y, R1~R3, L1, n, m and p are as described in claim 1.

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

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

13. Use of the compound or stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, or the pharmaceutical composition according to claim 11, in the preparation of a medicament for treating LPXC-mediated diseases, wherein the LPXC-mediated diseases are selected from bacterial infections caused by Gram-negative bacteria.

14. The use according to claim 13, wherein the Gram-negative bacteria are selected from Escherichia coli, Pseudomonas aeruginosa, Proteus, Klebsiella pneumoniae, Brucella, Salmonella typhi, Acinetobacter spp., Yersinia spp., Legionella pneumophila, Bordetella pertussis, Shigella spp., Pasteurella spp., Vibrio cholerae, and Neisseria meningitidis.

15. The use according to claim 13, wherein the Gram-negative bacterium is selected from Shigella bacteria.

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