MDM2 / MDMX dual target inhibitor compounds, prodrugs, pharmaceutical compositions, and methods for preparing and using the same

Abstract

The present invention provides compounds represented by formula (I) and prodrugs thereof, which have good MDM2 and / or MDMX inhibitory activity and can treat symptoms and / or diseases mediated by MDM2 and / or MDMX, such as tumor diseases and / or idiopathic pulmonary fibrosis, and can be used to prepare medicaments for such symptoms or diseases. In particular, compounds containing a phosphate (ester) structure have higher solubility and can release highly active MDM2 and / or MDMX dual-targeted inhibitor compounds in animal bodies as prodrugs, thereby solving the difficult problem of such dual-targeted inhibitors being difficult to synthesize as pharmaceuticals. TIFF2025535028000167.tif42170

Description

[Technical Field]

[0001] The present invention claims priority to a prior application bearing patent application number 202211419976.3 and entitled "MDM2 / MDMX dual-targeted inhibitor compounds, prodrugs, pharmaceutical compositions, and preparation methods and applications thereof," filed with the State Intellectual Property Office of China on November 14, 2022, the entire text of which is incorporated herein by reference.

[0002] The present invention relates to the pharmaceutical field, specifically to MDM2 / MDMX dual-target inhibitor compounds, prodrugs, pharmaceutical compositions, and their preparation methods and applications. [Background technology]

[0003] MDM2 and MDMX, members of the murine double minute (MDM) family, are genes closely related to the development and progression of malignant tumors and are major negative regulators of p53. MDM2, a member of the MDM family, is one of the most potent apoptosis inhibitors discovered to date. It is a ubiquitin-protein ligase that mediates the labeling of target proteins with ubiquitin, leading to their subsequent degradation by the proteasome. The protein it encodes can bind to p53, degrading it through ubiquitination and reducing its activity. p53 then binds to the promoter sequence of the gene, inhibiting its transcriptional activity and reducing MDM2 expression, forming a negative feedback loop that enhances cell transformation, proliferation, and malignant potential. MDMX, an MDM2 homolog, is another important binding factor for p53. Its inhibitory function is similar to that of MDM2, but it lacks E3 ligase activity.

[0004] p53 is divided into two types: wild-type p53 and mutant p53. Wild-type p53 is currently the most studied tumor inhibitor gene, capable of rapidly inducing cell apoptosis and effectively inhibiting tumor growth by preventing the development of potentially cancerous cells. Wild-type p53 accounts for approximately 50% of all cancers, and overexpression of MDM2 / X protein is often observed in these cancers. Analysis of approximately 4,000 tumor specimens from 28 different tumor types revealed that the MDM2 gene was amplified in approximately 7% of tumor specimens on average, with amplification ranging from 2-10 fold. Furthermore, overexpression of the MDM2 gene and protein was observed in over 80% of liposarcomas. Furthermore, MDM2 overexpression is commonly observed in osteosarcoma, esophageal cancer, and breast cancer. MDMX is overexpressed in many human cancers, including glioma, soft tissue sarcoma, melanoma, retinoblastoma, breast cancer, and hematological malignancies. Comparative studies of data published in The Cancer Genome Atlas (TCGA) have allowed scientists to identify MDMX expression in patients with different types of cancer. It is noteworthy that in AML patients, MDMX expression is much higher than that found in many other tumor types. It is also noteworthy that high levels of MDMX expression are found in hematological malignancies compared to other tumor cells.

[0005] Studies have shown that MDMX is overexpressed in fibrotic lesions of human idiopathic pulmonary fibrosis (IPF) and in animal models of lung fibrosis in aged mice. MDMX is an endogenous p53 inhibitor that regulates matrix stiffness. Reducing matrix stiffness reduces MDMX expression, thereby activating p53 in primary lung myofibroblasts isolated from IPF patients. Increasing p53 function activates a genetic program that sensitizes lung myofibroblasts to the apoptotic process and promotes their removal by macrophages. Removal of MDMX from the fibrotic lung matrix by targeted nonenzymatic crosslinking or gene knockout methods activates the MDMX-p53 pathway, thereby eliminating age-related lung fibrosis in mice. These findings suggest that mechanosensitive MDMX is a potential therapeutic molecular target for combating persistent age-related pulmonary fibrosis.

[0006] Currently, small molecule inhibitors of the MDM2-p53 protein interaction under clinical investigation include Catos Pharmaceutical's AMG232 (KRT-232), Yasun Pharmaceutical's APG-115, and Daiichi Sankyo Co., Ltd.'s DS-3032b, all of which are in various stages of clinical research. These compounds have very low affinity for MDMX and only inhibit the MDM2-p53 protein interaction. Because MDMX has a compensatory effect on MDM2, when p53 is activated with an MDM2-selective inhibitor, the MDMX-p53 interaction reduces the p53 activation effect of MDM2 inhibition. This phenomenon may be one reason why the clinical therapeutic efficacy of MDM2-selective inhibitors is not significant. To date, no highly active MDMX-selective inhibitors have been developed. ALRN-6924 is the only p53-MDM2 / MDMX dual inhibitor in clinical development. It is a "stapled peptide" that can inhibit the interactions between p53 and MDM2 and MDMX. Clinical studies have shown that its safety profile is superior to that of MDM2-selective inhibitors, but its micromolar-level cellular activity limits its widespread clinical application. Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt, or prodrug compound thereof. TIFF2025535028000002.tif48170 where, R1 is H, halogen elements, CN, C 1-6 Alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 1-6 Alkoxy group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, R2 is H, C 1-6 Alkyl groups, halogen elements, C 1-6 Alkoxy group, C 1-6 Alkylthio group, halogenated C 1-6 Alkyl groups, halogenated C 1-6 alkoxy groups, R3 is H, R 3a -OC 1-6 Alkyl group, -CH(=O), -C(=O)-NH-R 3b Selected from R 3a is H or -P(=O)(OR 31 )(OR 32 ) and R 3b is unsubstituted or optionally contains one, two, three or more R 3c C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl group-C 1-6 alkyl groups, and R 3c OH, C 1-6 Alkyl group -NH-, (C 1-6 alkyl group)2-N-, -OP(=O)(OR 31 )(OR 32 ) and R 31 , R 32 may be the same or different, or each independently represents H, C1-6 alkyl groups, R4 is H, -P(=O)(OR 41 )(OR 42 ) and R 41 , R 42 may be the same or different, or each independently represents H, C 1-6 alkyl groups, R5 is H, -P(=O)(OR 51 )(OR 52 ) and R 51 , R 52 may be the same or different, or each independently represents H, C 1-6 alkyl groups, Y is O or OR6, and R6 is H, -P(=O)(OR 61 )(OR 62 ) and R 61 , R 62 may be the same or different, or each independently represents H, C 1-6 alkyl groups, TIFF2025535028000003.tif5170 is selected from a single bond or a double bond, m is selected from 0, 1, 2, 3, 4, or 5; n is selected from 0, 1, 2, 3 or 4.

[0008] According to an embodiment of the present invention, R1 is selected from the group consisting of H, halogen atoms, CN, C 1-3 Alkyl group, C 2-3 Alkynyl group, C 1-3 Alkoxy group, halogenated C 1-3 Alkyl groups, halogenated C 1-3 alkoxy groups, According to an embodiment of the present invention, R1 is selected from H, F, Cl, CN, ethynyl, methyl, ethyl, and propyl groups.

[0009] According to an embodiment of the present invention, R2 is selected from the group consisting of H, C 1-3 Alkyl groups, halogen elements, C 1-3 Alkoxy group, C 1-3 Alkylthio group, halogenated C1-3 alkoxy groups, According to an embodiment of the present invention, R2 is selected from H, F, Cl, Br, methyl, methoxy, fluoromethoxy, methylthio groups.

[0010] According to an embodiment of the present invention, R3 is H, R 3a -OC 1-3 Alkyl group, -CH(=O), -C(=O)-NH-R 3b Selected from R 3a is selected from H or -P(=O)(OH)(OH), and R 3b is unsubstituted or optionally contains one, two or more R 3c C replaced by 1-3 Alkyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl group-C 1-3 alkyl groups, and R 3c OH, C 1-3 Alkyl group -NH-, (C 1-3 alkyl group)2-N-, -OP(=O)(OH)(OH).

[0011] According to an embodiment of the present invention, R3 is selected from the group consisting of H, methyl group, Selected from TIFF2025535028000004.tif136170, for example, Selected from TIFF2025535028000005.tif18170.

[0012] According to an embodiment of the present invention, R4 is selected from the group consisting of H, -P(=O)(OR 41 )(OR 42 ) and R 41 , R 42 may be the same or different, or each independently represents H, C 1-3 alkyl groups, According to an embodiment of the present invention, R4 is selected from H, —P(═O)(OH)(OH), According to an embodiment of the present invention, R5 is selected from H, -P(=O)(OR 51 )(OR 52) and R 51 , R 52 may be the same or different, or each independently represents H, C 1-3 alkyl groups, According to an embodiment of the present invention, R5 is selected from H, —P(═O)(OH)(OH), According to an embodiment of the present invention, Y is O or OR6, and R6 is H, -P(=O)(OR 61 )(OR 62 ) and R 61 , R 62 may be the same or different, or each independently represents H, C 1-3 alkyl groups, According to an embodiment of the present invention, R6 is selected from H, —P(═O)(OH)(OH), According to an embodiment of the present invention, m is selected from 1, 2 or 3.

[0013] According to an embodiment of the present invention, n is selected from 1 or 2.

[0014] According to an embodiment of the present invention, the prodrug of the compound of formula (I) has the structure shown in formula (II): TIFF2025535028000006.tif48170 where R1, R2, m and n independently have the definitions set forth above; R3' has the definition of R3, R4' is H, -P(=O)(OR 41 ')(OR 42 ') and R 41 ', R 42 ' may be the same or different, or each independently represents H, C 1-6 alkyl groups, R5' is H, -P(=O)(OR 51 ')(OR 52 ') and R 51 ', R 52 ' may be the same or different, or each independently represents H, C 1-6 alkyl groups, Y' is O or OR6', and R6' is H, -P(=O)(OR 61 ')(OR 62 ') and R 61 ', R 62 ' may be the same or different, or each independently represents H, C 1-6 alkyl groups, TIFF2025535028000007.tif5170 is selected from a single bond or a double bond.

[0015] According to the technical solution of the present invention, R3' can be, for example, H, R 3a -OC 1-6 Alkyl group, -CH(=O), -C(=O)-NH-R 3b Selected from R 3a is selected from H or -P(=O)(OH)(OH), and R 3b is unsubstituted or optionally contains one, two, three or more R 3c C replaced by 1-6 Alkyl group, C 3-8 Cycloalkyl groups, C 3-8 Cycloalkyl group-C 1-6 alkyl groups, and R 3c OH, C 1-6 Alkyl group -NH-, (C 1-6 alkyl group)2-N-, -OP(=O)(OH)(OH), R4' is H, -P(=O)(OR 41 ')(OR 42 ') and R 41 ', R 42 ' may be the same or different, or each independently represents H, C 1-3 alkyl groups, preferably R4' is selected from H, -P(=O)(OH)(OH); R5' is H, -P(=O)(OR 51 ')(OR 52 ') and R 51 ', R 52 ' may be the same or different, or each independently represents H, C 1-3alkyl groups, preferably R5' is selected from H, -P(=O)(OH)(OH); Y' is O or OR6', and R6' is H, -P(=O)(OR 61 ')(OR 62 ') and R 61 ', R 62 ' may be the same or different, or each independently represents H, C 1-3 alkyl groups, preferably R6' is selected from H, -P(=O)(OH)(OH); TIFF2025535028000008.tif5170 is selected from a single bond or a double bond, And R4', R5', R6', R 3a , R 3c At least one of the groups is —P(═O)(OH)(OH).

[0016] According to an embodiment of the present invention, the compound is selected from the following structures: TIFF2025535028000009.tif246170TIFF2025535028000010.tif245170TIFF202 5535028000011.tif228170TIFF2025535028000012.tif239170TIFF2025535028 000013.tif244170TIFF2025535028000014.tif234170TIFF2025535028000015. tif251170TIFF2025535028000016.tif239170TIFF2025535028000017.tif57170

[0017] The present invention further provides a method for preparing a compound represented by formula (I), which comprises the following method 1 and / or method 2: In Method 1, compound a is reacted with compound b to give a compound of formula (I): TIFF2025535028000018.tif29170 wherein R1, R2, R3, R4, R5, Y, m, and n independently have the definitions set forth above; In method 2, compound c is R 3b-NH2 to give a compound of formula (I), TIFF2025535028000019.tif42170 where R1, R2, R3, R4, R5, R 3b , Y, m, n independently have the definitions set forth above.

[0018] The present invention further provides pharmaceutical compositions comprising a therapeutically effective amount of at least one of a compound of formula (I), its racemate, stereoisomer, tautomer, isotopically labeled material, solvate, polycrystalline material, pharmaceutically acceptable salt, or prodrug compound thereof.

[0019] According to an embodiment of the invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable auxiliary materials.

[0020] According to embodiments of the present invention, the pharmaceutical composition may further comprise one or more additional therapeutic agents.

[0021] The present invention further provides a method for treating tumor diseases and / or idiopathic pulmonary fibrosis, comprising administering to a patient a prophylactically or therapeutically effective amount of at least one of a compound represented by formula (I), its racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt, or prodrug compound thereof.

[0022] The present invention further provides a method for treating tumor diseases and / or idiopathic pulmonary fibrosis, which comprises administering to a patient a prophylactically or therapeutically effective amount of the pharmaceutical composition described above.

[0023] According to an embodiment of the present invention, the tumor disease may be a tumor disease caused by overexpression of MDM2 and MDMX.

[0024] According to an embodiment of the present invention, the neoplastic disease comprises at least one of leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphocytic leukemia, hairy cell leukemia, lymphoblastic T-cell leukemia, lymphoma, B-cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, chondrosarcoma, fibrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, small cell lung cancer, non-small cell lung cancer, myeloma, glioma, prostate cancer, breast cancer, bone cancer, neuroblastoma, gastric cancer, ovarian cancer, colorectal cancer, kidney cancer, medulloblastoma, pancreatic cancer, thyroid cancer, mesothelioma, cervical cancer, bladder cancer, liver cancer, skin cancer, and tumors of the central or peripheral nervous system.

[0025] In some embodiments, the patient comprises a mammal, preferably a human.

[0026] The present invention further provides at least one of the compounds represented by formula (I), their racemates, stereoisomers, tautomers, isotopically labeled substances, solvates, polycrystalline substances, pharmaceutically acceptable salts or prodrug compounds thereof, or pharmaceutical compositions thereof, for treating tumor diseases and / or idiopathic pulmonary fibrosis.

[0027] The present invention further provides the use of at least one of the compounds of formula (I), their racemates, stereoisomers, tautomers, isotopically labeled substances, solvates, polycrystalline substances, pharmaceutically acceptable salts or prodrug compounds thereof in the preparation of a medicament.

[0028] According to an embodiment of the present invention, the use may be in the preparation of a medicament for treating a condition and / or disease mediated by MDM2 and / or MDMX, for example in the preparation of an MDM2 and / or MDMX inhibitor.

[0029] According to an embodiment of the present invention, the use may be in the preparation of a medicament for treating idiopathic pulmonary fibrosis.

[0030] According to an embodiment of the present invention, the disease is, for example, a tumor disease, and the tumor disease includes at least one of leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphocytic leukemia, hairy cell leukemia, lymphoblastic T-cell leukemia, lymphoma, B-cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, chondrosarcoma, fibrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, small cell lung cancer, non-small cell lung cancer, myeloma, glioma, prostate cancer, breast cancer, bone cancer, neuroblastoma, gastric cancer, ovarian cancer, colorectal cancer, kidney cancer, medulloblastoma, pancreatic cancer, thyroid cancer, mesothelioma, cervical cancer, bladder cancer, liver cancer, skin cancer, and tumors of the central or peripheral nervous system. [Effects of the Invention]

[0031] The compounds of the present invention have good MDM2 and / or MDMX inhibitory activity and can treat symptoms and / or diseases mediated by MDM2 and / or MDMX, such as tumor diseases and / or idiopathic pulmonary fibrosis, and can be used to prepare medicaments for such symptoms or diseases. In particular, compounds containing a phosphate (ester) structure have higher solubility and can release highly active MDM2 and / or MDMX dual-target inhibitor compounds in animal bodies as prodrugs. In addition, preferred compounds of the present invention also have favorable pk activity. Such dual-target inhibitors solve the difficult problem of pharmaceutical synthesis. Definition and Explanation of Terms

[0032] Unless otherwise specified, the definitions of groups and terms set forth in the specification and claims of this application, including illustrative definitions, exemplary definitions, preferred definitions, definitions set forth in the tables, definitions of specific compounds in the examples, etc., can be combined or linked in any manner, and all such combined or linked group definitions and compound structures are to be understood as falling within the scope of the specification and / or claims of this application.

[0033] Unless otherwise specified, the numerical ranges described in this specification and claims are equivalent to describing at least each specific integer value therein. For example, the numerical range "1 to 8" is equivalent to describing each integer value in the numerical range "1 to 8," i.e., 1, 2, 3, 4, 5, 6, 7, or 8.

[0034] The term "optional" (or "optionally" or "optionally") defined in the general formula of the present application means that the group is substituted with zero, one, or more substituents. For example, "optionally substituted with one, two, or more R" means that the group may not be substituted with R (unsubstituted), or may be substituted with one, two, or more R.

[0035] "Plurality" refers to three or more than two.

[0036] The term “C 1-6 The term "alkyl group" should be understood to denote straight-chain and branched alkyl groups having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like, or isomers thereof.

[0037] The term “C 2-6 "Alkenyl group" refers to a linear or branched monovalent hydrocarbon group containing one or more double bonds and having from 2 to 6 carbon atoms, for example, 2 or 3 carbon atoms (i.e., C 2-3It should be understood that when the alkenyl group contains one or more double bonds, the double bonds may be separated or conjugated. The alkenyl group may be, for example, a vinyl group, an allyl group, an (E)-2-methylvinyl group, a (Z)-2-methylvinyl group, an (E)-but-2-enyl group, a (Z)-but-2-enyl group, an (E)-but-1-enyl group, a (Z)-but-1-enyl group, a pent-4-enyl group, a (E)-pent-4-enyl group, a (Z)-pent-3-enyl group, an (E)-pent-2-enyl group, a (Z)-pent-2-enyl group, a (E)-pent- 1-enyl group, (Z)-pent-1-enyl group, hex-5-enyl group, (E)-hex-4-enyl group, (Z)-hex-4-enyl group, (E)-hex-3-enyl group, (Z)-hex-3-enyl group, (E)-hex-2-enyl group, (Z)-hex-2-enyl group, (E)-hex-1-enyl group, (Z)-hex-1-enyl group, isopropenyl group, 2-methylprop-2-enyl group, 1-methylprop- 2-enyl group, 2-methylprop-1-enyl group, (E)-1-methylprop-1-enyl group, (Z)-1-methylprop-1-enyl group, 3-methylbut-3-enyl group, 2-methylbut-3-enyl group, 1-methylbut-3-enyl group, 3-methylbut-2-enyl group, (E)-2-methylbut-2-enyl group, (Z)-2-methylbut-2-enyl group, (E)-1-methylbut-2-enyl group, (Z)-1-methylbut-2-enyl group 1-ethylbut-2-enyl group, (E)-3-methylbut-1-enyl group, (Z)-3-methylbut-1-enyl group, (E)-2-methylbut-1-enyl group, (Z)-2-methylbut-1-enyl group, (E)-1-methylbut-1-enyl group, (Z)-1-methylbut-1-enyl group, 1,1-dimethylprop-2-enyl group, 1-ethylprop-1-enyl group, 1-propylvinyl group, and 1-isopropylvinyl group.

[0038] The term “C 2-6 An "alkynyl group" refers to a linear or branched monovalent hydrocarbon group containing one or more triple bonds and having from 2 to 6 carbon atoms, e.g., 2 or 3 carbon atoms ("C 2-3The alkynyl group includes, for example, an ethynyl group, a prop-1-ynyl group, a prop-2-ynyl group, a but-1-ynyl group, a but-2-ynyl group, a but-3-ynyl group, a pent-1-ynyl group, a pent-2-ynyl group, a pent-3-ynyl group, a pent-4-ynyl group, a hex-1-ynyl group, a hex-2-ynyl group, a hex-3-ynyl group, a hex-4-ynyl group, a hex-5-ynyl group, a 1-methylprop-2-ynyl group, a 2-methylbut-3-ynyl group, a 1-methylbut-3-ynyl group, a 1-methylbut-2-ynyl group, a 3-methylbut-1-ynyl group, a 1-ethylprop-2-ynyl group, a 3-methylpent-4-ynyl group, a 2-methylprop-2-ynyl group, a 2-methylbut-3-ynyl group, a 1-methylbut-2-ynyl group, a 3-methylbut-1-ynyl group, a 1-ethylprop-2-ynyl group, a 3-methylpent-4-ynyl group, a 2-methylbut-5-ynyl group, a 2-methylbut-6-ynyl group, a 2-methylbut-7-ynyl group, a 2-methylbut-8-ynyl group, a 2-methylbut-9-ynyl group, a 2-methylbut-10-ynyl group, a 2-methylbut-11-ynyl group, a 2-methylbut-12-ynyl group, a 2-methylbut-13-ynyl group, a 2-methylbut-14-ynyl group, a 2-methylbut-15-ynyl group, a 2-methylbut-16-ynyl group, a 2-methylbut-17-ynyl group, a 2-methylbut-18-ynyl and 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, 3,3-dimethylbut-1-ynyl, 2-ethylbut-3-ynyl, 1-ethylbut-3-ynyl, 1-ethylbut-2-ynyl, 1-propylprop-2-ynyl, 1-isopropylprop-2-ynyl, 2,2-dimethylbut-3-ynyl, 1,1-dimethylbut-3-ynyl, 1,1-dimethylbut-2-ynyl, or 3,3-dimethylbut-1-ynyl.

[0039] The term “C 3-8 A "cycloalkyl group" should be understood to refer to a saturated, monovalent, monocyclic, bicyclic (e.g., fused, bridged, spiro) hydrocarbon ring or tricycloalkane having 3 to 8 carbon atoms. 3-8The cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, or a cyclooctyl group, or may be a bridged cyclic hydrocarbon group such as a bicyclo[2.1.1]hexyl group, a bicyclo[2.1.1]heptyl group, a bicyclo[2.2.1]heptenyl group, a 6,6-dimethylbicyclo[3.1.1]heptyl group, a 2,6,6-trimethylbicyclo[3.1.1]heptyl group, a bicyclo[2.2.2]octyl group, a 2,7-diazaspiro[3,5]nonanyl group, or a 2,6-diazaspiro[3,4]octanyl group.

[0040] It will be understood by those skilled in the art that the compounds of formula (I) can exist in the form of various pharmaceutically acceptable salts. These compounds may form acid addition salts if they contain a basic center, base addition salts if they contain an acidic center, and may also form inner salts if they contain not only an acidic center (e.g., a carboxy group) but also a basic center (e.g., an amino group).

[0041] The compounds of the present invention can exist in the form of solvates (e.g., hydrates), in which the compounds of the present invention contain polar solvents, particularly water, methanol, or ethanol, which are structural elements of the compound's crystal lattice. The amount of polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric proportions.

[0042] Based on their molecular structure, the compounds of the present invention may be chiral and therefore may exist in various enantiomeric forms. Therefore, these compounds may exist in racemic or optically active forms. The compounds of the present invention include isomers in which each chiral carbon is in the R or S configuration, or mixtures thereof, such as racemates. The compounds of the present invention or their intermediates can be separated into enantiomeric compounds by chemical or physical methods well known to those skilled in the art, or may be used in synthesis in this form. In the case of racemic amines, diastereomers can be obtained from the mixture by reaction with an optically active resolving agent. Examples of suitable resolving agents are optically active acids, such as the R and S forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, suitable N-protected amino acids (e.g., N-benzoylproline or N-phenylsulfonylproline), or various optically active camphorsulfonic acids. Chromatographic resolution of enantiomers can also be advantageously achieved by optically active resolving agents (e.g., dinitrobenzoylphenylglycine immobilized on silicone rubber, cellulose triacetate or other carbohydrate derivatives or chirally derivatized methacrylate polymers). Suitable eluents for this purpose are water or alcohol-containing solvent mixtures, e.g., hexane / isopropanol / acetonitrile.

[0043] The corresponding stable isomers can be separated according to known methods, such as extraction, filtration or column chromatography.

[0044] The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0045] The term "therapeutically effective amount" refers to an amount of an active compound or agent that elicits the biological or medical response a researcher, veterinarian, physician, or other clinician is looking for in a tissue, system, animal, individual, or human, and includes one or more of the following: (1) disease prevention: e.g., preventing a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who has not yet experienced or developed the pathology or symptoms of the disease; (2) disease inhibition: e.g., inhibiting a disease, disorder, or condition (i.e., preventing further progression of the pathology and / or symptoms) in an individual who has experienced or developed the pathology or symptoms of the disease, disorder, or condition; and (3) disease mitigation: e.g., alleviating a disease, disorder, or condition (i.e., reversing the pathology and / or symptoms) in an individual who has experienced or developed the pathology or symptoms of the disease, disorder, or condition. DETAILED DESCRIPTION OF THE INVENTION

[0046] The technical solutions of the present invention will be described in more detail below with reference to specific examples. It should be understood that the following examples are merely for illustrative purposes and should not be construed as limiting the scope of the claims of the present invention. Any technology realized based on the above content of the present invention is included in the scope of the claims of the present invention.

[0047] Unless otherwise specified, all materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0048] Intermediates Intermediate I-1: Synthesis of 3-(3,4-difluorobenzyl)imidazolidine-2,4-dione TIFF2025535028000020.tif26170 4-(Bromomethyl)-1,2-difluorobenzene (2 g, 9.178 mmol) and potassium carbonate (3.17 g, 22.945 mmol) were dissolved in N,N-dimethylformamide (20 mL) at room temperature. Hydantoin (1.35 g, 12.849 mmol) was added portionwise to the mixture while stirring. The mixture was stirred at room temperature for 16 h, then poured into water (30 mL) and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give crude intermediate I-1 (1 g, 41.72%) as a white solid. This crude product was used directly in the next reaction without further purification. LC-MS m / z(ESI):227.15[M+H] + .

[0049] Intermediate I-2: Synthesis of 3-(4-chlorobenzyl)imidazolidine-2,4-dione Using the method for TIFF2025535028000021.tif32170 Intermediate I-1, 1-(bromomethyl)-4-chlorobenzene and hydantoin was used to obtain crude intermediate I-2 (500 mg, 92.78%) as a white solid, which was used directly in the next reaction without further purification.

[0050] Intermediate I-3: Synthesis of 4-((2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile Using the method described in TIFF2025535028000022.tif30170 Intermediate I-1, 4-(bromomethyl)benzonitrile and hydantoin were used to obtain crude intermediate I-3 (2.26 g, 84%) as a white solid, which was used directly in the next reaction without further purification.

[0051] Intermediate I-4: Synthesis of 4-((2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile Using the method described in TIFF2025535028000023.tif29170 Intermediate I-1, 1-(bromomethyl)-4-chlorobenzene and hydantoin was used to obtain crude intermediate I-4 (500 mg, 81%) as a white solid, which was used directly in the next reaction without further purification. LC-MS m / z(ESI):232.00[MH] - .

[0052] Intermediate I-5: Synthesis of 6-chloro-7-methoxy-1H-indole-3-carbaldehyde TIFF2025535028000024.tif23170

[0053] Intermediate I-5-1: 6-chloro-7-methoxy-1H-indole At -20°C, a solution of 1-chloro-2-methoxy-3-nitrobenzene (10 g, 53.31 mmol) in tetrahydrofuran (200 mL) was slowly added dropwise to a solution of vinylmagnesium bromide in tetrahydrofuran (1N, 160 mL). The mixture was stirred at room temperature for 3 hours, poured into ice-water (200 mL), and extracted twice with ethyl acetate (500 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was purified by high-performance chromatography to give I-5-1 (2.1 g, 19.52%) as a white solid. LC-MS m / z (ESI): 182.1 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.30 (dd, J= 8.4, 0.5 Hz, 1H), 7.19 (dd, J = 3.1, 2.5 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.53 (dd, J = 3.1, 2.2 Hz, 1H), 4.02 (s, 3H).

[0054] I-5: 6-chloro-7-methoxy-1H-indole-3-carbaldehyde Phosphorus oxychloride (2.12 g, 13.87 mmol) was added to dimethylformamide (20 mL) at 0 °C. The mixture was stirred for 10 min at 0 °C. Then, a solution of 6-chloro-7-methoxy-1H-indole (2.1 g, 11.56 mmol) in dichloromethane (5 mL) was added. The mixture was stirred at room temperature for 1 h, and sodium hydroxide (1N, 30 mL) was added to the mixture and stirred for 30 min. The mixture was extracted three times with ethyl acetate (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was purified by high-performance chromatography to give I-5 (0.9 g, 37.1%) as a white solid. LC-MS m / z (ESI): 210.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.94 (s, 1H), 8.35 (s, 1H), 7.82 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 3.94 (s, 3H).

[0055] Intermediate I-6: Synthesis of 3-[(4-ethynylphenyl)methyl]imidazolidine-2,4-dione TIFF2025535028000025.tif19170 Using the method for intermediate I-1, 1-(bromomethyl)-4-ethynylbenzene and hydantoin were used to obtain intermediate I-6 (122 mg, 26%) as a white solid. LC-MS m / z(ESI):215.1[M+H] + .

[0056] Intermediate I-7: Synthesis of 3-[4-(8-aminooctyl)-1-oxo-3H-isoindol-2-yl]piperidine-2,6-dione Using the method for TIFF2025535028000026.tif26170 Intermediate I-1, 3-(bromomethyl)benzonitrile and hydantoin were used to obtain intermediate I-7 (129 mg, 29%) as a brown solid. LC-MS m / z(ESI):214.0[MH] -.

[0057] Intermediate I-8: Synthesis of 6-chloro-7-methyl-1H-indole-3-carbaldehyde TIFF2025535028000027.tif19170

[0058] I-8-1: 6-chloro-7-methyl-1H-indole Under a nitrogen atmosphere, 1-chloro-2-methyl-3-nitrobenzene (2.0 g, 11.656 mmol) was dissolved in tetrahydrofuran (20 mL). The solution was cooled to -78 °C, and vinylmagnesium bromide (1N, 46.6 mL, 46.626 mmol) was slowly added dropwise. Stirring was continued for 2 hours. Saturated ammonium chloride (100 mL) solution was slowly added to the mixture, maintaining the reaction temperature below -60 °C. The reaction mixture was allowed to warm to room temperature, and the mixture was extracted three times with ethyl acetate (100 mL). The combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give I-8-1 (1.08 g, 56%) as a brown oil. LC-MS m / z(ESI):166.2[M+H] + .

[0059] I-8: 6-chloro-7-methyl-1H-indole-3-carbaldehyde Phosphorus oxychloride (2.4 g, 16.094 mol) was added dropwise to a solution of dimethylformamide (2.5 mL) at 0 °C. The resulting mixture was stirred under a nitrogen atmosphere for 30 minutes and maintained at 0 °C. A solution of 6-chloro-7-methyl-1H-indole (540 mg, 3.260 mmol) in dimethylformamide (2.5 mL) was added to the above solution. The mixture was stirred at 40 °C for 1 hour, cooled to room temperature, and quenched by adding water (20 mL). The pH of the reaction mixture was adjusted to 8 with a solution of sodium hydroxide (30%). The resulting mixture was extracted three times with ethyl acetate (50 mL). The combined organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:1) to give I-8 (623 mg, 96%) as a brown oil. LC-MS m / z(ESI):194.1[M+H] + .

[0060] Intermediate I-9: Synthesis of 6-chloro-7-(methylsulfonyl)-1H-indole-3-carbaldehyde TIFF2025535028000028.tif25170

[0061] I-9-1: 1-chloro-2-methylthio-3-nitrobenzene At room temperature under a nitrogen atmosphere, 1-chloro-2-fluoro-3-nitrobenzene (2 g, 10.824 mmol) was dissolved in DMF (40 mL). Sodium thiomethoxide (0.88 g, 11.906 mmol) was added to the solution and stirring was continued. The mixture was heated to 120 °C and stirred for 12 hours. After the reaction was completed, the mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with ethyl acetate / petroleum ether (5 / 95) to give I-9-1 (770 mg, 29%) as a reddish-brown oil. 1H NMR (300 MHz, CDCl3) δ 7.68-7.60 (m, 1H), 7.55-7.47 (m, 1H), 7.41-7.38 (m, 1H), 2.46 (s, 3H).

[0062] I-9-2: 6-chloro-7-(methylsulfonyl)-1H-indole Under a nitrogen atmosphere, 1-chloro-2-methylthio-3-nitrobenzene (230 mg, 0.932 mol) was dissolved in tetrahydrofuran (5 mL). The solution was cooled to -78 °C, and vinylmagnesium bromide (1N, 3.7 mL, 3.7 mmol) was slowly added dropwise. Stirring was continued for 3 hours. Saturated ammonium chloride (50 mL) was slowly added to the mixture, and the reaction temperature was maintained below -60 °C. The reaction mixture was allowed to warm to room temperature, and the mixture was extracted twice with ethyl acetate (50 mL). The combined organic phase was washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative high-performance liquid chromatography to give I-9-2 (180 mg, 81%) as a brown oil. LC-MS m / z(ESI):198.1[M+H] + .

[0063] I-9: 6-chloro-7-(methylthio)-1H-indole-3-carbaldehyde Phosphorus oxychloride (0.178 g, 1.115 mol) was added dropwise to a solution of dimethylformamide (1.5 mL) at 0 °C. The resulting mixture was stirred under a nitrogen atmosphere for 30 minutes and maintained at 0 °C. A solution of 6-chloro-7-(methylsulfonyl)-1H-indole (180 mg, 0.76 mmol) in dimethylformamide (1.5 mL) was added to the above solution. The mixture was stirred at 40 °C for 1 hour, cooled to room temperature, and quenched by adding water (5 mL). The pH of the reaction mixture was adjusted to 8 with a solution of sodium hydroxide (30%). The resulting mixture was extracted three times with ethyl acetate (20 mL). The combined organic phase was washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give I-9 (160 mg, 89%) as a pale yellow solid. The crude product was used directly in the next step without further purification. LC-MS m / z(ESI):226.0[M+H] + .

[0064] Intermediate I-10: Synthesis of 6-chloro-7-fluoro-1H-indole-3-carbaldehyde Phosphorus oxychloride (0.18 ml, 1.117 mol) was added dropwise to a solution of dimethylformamide (1.5 ml) at 700 °C. The resulting mixture was stirred under a nitrogen atmosphere for 30 minutes and maintained at 0 °C. A solution of 6-chloro-7-fluoro-1H-indole (75 mg, 0.44 mmol) in dimethylformamide (1.5 ml) was added to the above solution. The mixture was stirred at 40 °C for 1 hour, cooled to room temperature, and quenched by adding water (5 ml). The pH of the reaction mixture was adjusted to 8 with a solution of sodium hydroxide (30%). The resulting mixture was extracted three times with ethyl acetate (50 ml), and the combined organic phase was washed with saturated brine (30 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give I-10 (75 mg, 44.07%) as an off-white solid. The crude product was carried directly to the next step without further purification.

[0065] Intermediate I-11: Synthesis of 6-chloro-7-(fluoromethoxy)-1H-indole-3-carbaldehyde TIFF2025535028000030.tif24170

[0066] I-11-1: 1-chloro-2-(fluoromethoxy)-3-nitrobenzene At room temperature, 6-chloro-2-nitrophenol (1 g, 5.474 mmol) and potassium carbonate (1.59 g, 10.929 mmol) were added to a solution of dimethylformamide (15 mL) and stirring was continued. Bromofluoromethane (6.51 g, 54.764 mmol) was then added to the mixture. The mixture was stirred overnight at room temperature under a nitrogen atmosphere. After the reaction was complete, the mixture was added to water (50 mL). The resulting mixture was extracted three times with ethyl acetate (30 mL), washed with saturated brine (20 mL), and the combined organic phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give I-11-1 (430 mg, 38.14%) as a yellow oil. 1 H NMR (300 MHz, DMSO-d6) δ 8.02-7.95 (m, 2H), 7.52 (d, J = 8.1 Hz, 1H), 5.87 (s, 1H), 5.70 (s, 1H).

[0067] I-11-2: 6-chloro-7-(fluoromethoxy)-1H-indole Under a nitrogen atmosphere, 1-chloro-2-(fluoromethoxy)-3-nitrobenzene (590 mg, 2.864 mol) was dissolved in tetrahydrofuran (8 mL). The solution was cooled to -78 °C, and vinylmagnesium bromide (1N, 8 mL, 8 mmol) was slowly added dropwise. Stirring was continued for 3 hours. Saturated ammonium chloride (50 mL) was slowly added to the mixture, maintaining the reaction temperature below -60 °C. The reaction was allowed to warm to room temperature, and the mixture was extracted twice with ethyl acetate (50 mL). The organic phases were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by preparative high-performance liquid chromatography to give I-11-2 (690 mg, 81%) as a gray oil. LC-MS m / z(ESI):198.0[MH] - .

[0068] I-11: 6-chloro-7-(fluoromethoxy)-1H-indole-3-carbaldehyde Phosphorus oxychloride (1.25 g, 7.848 mol) was added dropwise to a solution of dimethylformamide (13 mL) at 0 °C. The resulting mixture was stirred under a nitrogen atmosphere for 30 minutes and maintained at 0 °C. A solution of 6-chloro-7-(fluoromethoxy)-1H-indole (640 mg, 3.2 mmol) in dimethylformamide (13 mL) was added to the above solution. The mixture was stirred at 40 °C for 1 hour, cooled to room temperature, and quenched by adding water (4 mL). The pH of the reaction mixture was adjusted to 8 with a solution of sodium hydroxide (30%). The resulting mixture was extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo to give I-11 (380 mg, 51.56%) as a brown oil. The crude product was used directly in the next step without further purification. LC-MS m / z(ESI):228.2[M+H] + .

[0069] Intermediate I-12: Synthesis of 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetic acid TIFF2025535028000031.tif22170

[0070] I-12-1: 2-Bromo-2-(4-chlorophenyl)acetate methyl ester Methyl 2-(4-chlorophenyl)acetate (2 g, 10.83 mmol) was dissolved in carbon tetrachloride (20 mL) and N-bromosuccinimide (1.93 g, 10.83 mmol) and azobisisobutyronitrile (1.78 g, 10.83 mmol) were added. The mixture was stirred at 80 °C for 5 h. The resulting product was dried in vacuo to give I-12-1 (1.7 g, 56%) as a yellow oil. 1 H NMR (300 MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.36-7.33 (m, 2H), 5.32 (s, 1H), 3.79 (s, 3H).

[0071] I-12-2: 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate methyl ester To a solution of methyl 2-bromo-2-(4-chlorophenyl)acetate (1.56 g, 5.9 mmol) in dimethylformamide (20 mL) was added hydantoin (0.89 g, 8.55 mmol) and potassium carbonate (1.63 g, 11.8 mmol) at room temperature. The mixture was stirred at 25 °C for 16 h. After the reaction was completed, the mixture was diluted with water and extracted three times with ethyl acetate (50 mL). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by liquid chromatography afforded I-12-2 (1.85 g, 88%) as a yellow oil. 1 H NMR (300 MHz, CDCl3) δ 7.45 (d, J= 8.5 Hz, 2H), 7.34-7.26 (m, 2H), 5.75 (s, 1H), 5.71 (s, 1H), 4.01 (s, 2H), 3.80 (s, 3H).

[0072] I-12: (4-chlorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid Methyl 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (1.17 g, 4.139 mmol) was added to 2.5 mL of concentrated hydrochloric acid at room temperature. Stirring was continued, and acetic acid (7.5 mL) was added dropwise to the mixture. The resulting mixture was heated to 120 °C and stirred for an additional 3 h. After the reaction was complete, the reaction solution was cooled to room temperature. The resulting mixture was concentrated under reduced pressure to give crude product I-12 (1.1 g, 86.7%) as a white solid. The purified crude product was used in the next step. LC-MS m / z (ESI): 269.0 [M+H] + .

[0073] Intermediate I-13: Synthesis of (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetic acid TIFF2025535028000032.tif27170 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)methyl acetate (1.56 g, 5.5 mmol) was added to a solution of ethyl acetate (10 mL), followed by the addition of concentrated hydrochloric acid (3 mL). The resulting mixture was refluxed until complete dissolution. The mixture was concentrated to give the intermediate. The intermediate was dissolved in ethyl acetate (15 mL) and piperidine (2 mL), and then refluxed for 2 hours. After that, 6-chloro-1H-indole-3-carbaldehyde (0.99 g, 5.5 mmol) was added. The mixture was stirred and refluxed for 16 hours. After the reaction was complete, the reaction solution was cooled to room temperature, filtered, and the yellow precipitate was collected to give the crude product in the form of the piperidine salt. Liberation with hydrochloric acid gave I-13 (0.56 g, 21.82%). The purified crude product is used in the next step. LC-MS m / z (ESI): 429.9 [M+H] + .

[0074] Intermediate I-14: Synthesis of (4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-chlorophenyl)acetic acid TIFF2025535028000033.tif57170

[0075] I-14-1: 2-Bromo-2-(4-chlorophenyl)acetate methyl ester To a stirred solution of methyl 2-(4-chlorophenyl)acetate (5 g, 27.083 mmol) and NBS (6.27 g, 35.208 mmol) in DCE (50 mL) at room temperature, a solution of hydrobromic acid in acetic acid (7.04 g, 35.208 mmol) was added dropwise. The resulting mixture was stirred at 85 °C for an additional 12 h. After cooling to room temperature, the resulting mixture was concentrated in vacuo to give crude product I-14-1 (8 g) as a white solid, which was used directly in the next step without further purification.

[0076] I-14-2: 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate methyl ester Methyl 2-bromo-2-(4-chlorophenyl)acetate (2 g) and potassium carbonate (13.1 g, 9.488 mmol) were added to a DMF (15 mL) solution at room temperature, followed by hydantoin (570 mg, 5.692 mmol). The resulting mixture was stirred at room temperature for an additional 12 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (5:1) to give I-14-2 (1.17 g, 93.45%) as a white solid. LC-MS m / z(ESI):283.1[M+H] + .

[0077] I-14-3: (4-chlorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid At room temperature, 2-(4-chlorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)methyl acetate (1.17 g, 4.139 mmol) was added to 2.5 mL of concentrated hydrochloric acid and stirring was continued. Then, acetic acid (7.5 mL) was added dropwise to the mixture. The resulting mixture was heated to 120 °C and stirred for an additional 3 h. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo to give crude product I-14-3 (1.1 g) as a white solid, which was used directly in the next step without further purification. LC-MS m / z(ESI):269[M+H] + .

[0078] I-14: (4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-chlorophenyl)acetic acid (4-Chlorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (400 mg, 1.487 mmol) and 6-chloro-7-fluoro-1H-indole-3-carbaldehyde (294 mg, 1.489 mmol) were added to ethanol (6 mL) at room temperature, followed by the addition of piperidine (0.54 mL). The resulting mixture was heated to 100 °C and stirred for 12 h. The reaction mixture was cooled to room temperature. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (2:1) to give I-14 (196 mg, 31%) as a yellow solid. LC-MS m / z(ESI):446.0[MH] - .

[0079] Intermediate I-15: Synthesis of (4-cyanophenyl)(2,5-dioxopyrimidin-1-yl)acetic acid TIFF2025535028000034.tif19170

[0080] I-15-1: 2-Bromo-2-(4-cyanophenyl)acetate methyl ester Methyl 2-(4-cyanophenyl)acetate (1200 mg, 6.507 mmol) and NBS (1552 mg, 8.719 mmol) were added to a DCE (12 mL) solution at room temperature. Then, hydrogen bromide in acetic acid (0.27 mL, 8.784 mmol) was added dropwise to the reaction mixture and stirring was continued. The resulting mixture was heated to 85 °C and stirred for 12 h. After that, the reaction mixture was cooled to room temperature. The resulting mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL). It was washed three times with saturated brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give crude product I-15-1 (1.46 g) as a pale yellow oil, which was used in the next step without further purification.

[0081] I-15-2: 2-(4-cyanophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetic acid methyl ester Methyl 2-bromo-2-(4-cyanophenyl)acetate (1.46 g) and hydantoin (1.52 g, 14.429 mmol) were added to a solution of dimethylformamide (20 mL) at room temperature, followed by the addition of potassium carbonate (2.10 g, 14.471 mmol). The mixture was stirred at room temperature under a nitrogen atmosphere for 12 hours, and the reaction mixture was added to saturated ammonium chloride solution (150 mL). The mixture was extracted three times with ethyl acetate (100 mL). The combined organic phases were washed twice with saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse chromatography to give I-15-2 (400 mg, 24.3%) as a pale yellow solid. LC-MS m / z(ESI):274.2[M+H] + .

[0082] I-15: (4-cyanophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid Methyl 2-(4-cyanophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (400 mg, 1.421 mmol) was dissolved in a mixture of tetrahydrofuran (15 mL) and water (15 mL), and aqueous lithium hydroxide (2.1 mL, 2.100 mmol) was added dropwise to the solution. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 0.5 h. The residue was acidified with hydrochloric acid to a pH of 5. The resulting mixture was concentrated in vacuo. The residue was purified by reverse chromatography to give I-15 (380 mg, 42%) as a white solid. LC-MS m / z(ESI):260.1[M+H] + .

[0083] Intermediate I-16: Synthesis of (4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-cyanophenyl)acetic acid TIFF2025535028000035.tif32170 (4-Cyanophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (200 mg, 0.734 mmol) was added to ethanol (4 mL) at room temperature, followed by the addition of piperidine (263 mg, 2.936 mmol). The resulting mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 0.5 h. The reaction mixture was cooled to room temperature, and 6-chloro-7-fluoro-1H-indole-3-carbaldehyde (137 mg, 0.661 mmol) was added in portions to the above mixture. The resulting mixture was heated to 80 °C and stirred for an additional 12 h. The mixture was concentrated under reduced pressure. The residue was purified by reverse chromatography to give I-16 (60 mg, 24%) as a yellow solid. LC-MS m / z(ESI):439.1[M+H] + .

[0084] Intermediate I-17: Synthesis of (4Z)-4-[(6-chloro-7-methyl-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](3,4-difluorophenyl)acetic acid TIFF2025535028000036.tif57170

[0085] I-17-1: 2-(3,4-difluorophenyl) methyl acetate (3,4-Difluorophenyl)acetic acid (10 g, 58 mmol) was added to a solution of methanol (100 mL), and sulfuric acid (10 mL) was slowly added dropwise to the mixture. The reaction mixture was refluxed overnight, cooled to room temperature, and then added to ice water (100 mL). The mixture was extracted three times with ethyl acetate (100 ml). The organic phases were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate) to give I-17-1 (10 g, 88%) as a yellow oil. LC-MS m / z(ESI):187.0[M+H] + .

[0086] I-17-2: 2-bromo-2-(3,4-difluorophenyl)acetic acid methyl ester Methyl 2-(3,4-difluorophenyl)acetate (3.0 g, 16 mmol) was added to a solution of carbon tetrachloride (30 mL), and NBS (2.6 g, 14 mmol) and 12 drops of hydrobromic acid / acetic acid solution were added to the above mixture. The reaction mixture was heated to 70 °C and stirred for 10 min. The reaction mixture was then heated to 85 °C and stirred for 2.5 h, until complete consumption of the starting material was confirmed by thin-layer chromatography. After cooling to room temperature, the mixture was concentrated in vacuo to give the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate) to give I-17-2 (1.1 g, 72%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.49-7.44 (m, 1H), 7.28-7.24 (m, 1H), 7.18-7.11 (m, 1H), 5.31 (s, 1H), 3.80 (s, 3H).

[0087] I-17-3: 2-(3,4-difluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetic acid methyl ester To a solution of methyl 2-bromo-2-(3,4-difluorophenyl)acetate (3.8 g, 14 mmol) in dimethylformamide (37 mL) was added imidazolidine-2,4-dione (1.71 g, 17 mmol) and potassium carbonate (3.93 g, 28.4 mmol). The reaction mixture was stirred at room temperature for 14 h. After the reaction was complete, the reaction mixture was diluted with water (100 mL) and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 2:1) to give I-17-3 (1.6 g, 37%) as a brown solid. LC-MS m / z(ESI):285.0[M+H] + .

[0088] I-17-4: 2-(3,4-difluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetic acid Methyl 2-(3,4-difluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (0.85 g, 3.0 mmol) was added to a mixture of concentrated hydrochloric acid (26 mL) and ethyl acetate (85 mL), heated to 120° C., and stirred for 1 h. The mixture was concentrated in vacuo to give crude product I-17-4 (0.80 g, 94%) as a yellow oil, which was used directly in the next step without further purification. LC-MS m / z(ESI):271.0[M+H] + .

[0089] I-17: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetic acid 2-(3,4-Difluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetic acid (0.60 g, 2.2 mmol) was added to ethanol (20 mL), and piperidine (1.9 g, 22 mmol) was added to the reaction mixture. The mixture was heated to reflux for 2 hours, and then 6-chloro-7-methyl-1H-indole-3-carbaldehyde (0.43 g, 2.2 mmol) was added. The mixture was stirred at reflux for 24 hours. The mixture was filtered and washed with ethyl acetate (2 mL). The solid was dried in vacuo to give I-17 (0.7 g, 71%) as a yellow solid, which was used directly in the next step without further purification. LC-MS m / z (ESI): 446.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (brs, 1H), 8.75 (brs, 1H), 8.16 (brs, 1H), 7.62-7.58 (m, 2H), 7.33-7.19 (m, 2H), 7.14 (d, J = 8.4 Hz, 1H), 6.74 (s, 1H), 6.67 (s, 1H), 5.31 (s, 1H), 2.49 (s, 3H).

[0090] Intermediate I-18: Synthesis of [(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-cyanophenyl)acetic acid TIFF2025535028000037.tif32170 (4-Cyanophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (200 mg, 0.772 mmol) and piperazine (279.82 mg, 3.088 mmol) were added to a solution of ethanol (3 mL) at room temperature. The resulting mixture was heated to 65 °C and stirred for 20 min. 6-Chloro-1H-indole-3-carbaldehyde (102 mg, 0.540 mmol) was added in portions to the mixture. The mixture was stirred at 65 °C for an additional 12 h. After concentration in vacuo, the residue was purified by reverse chromatography to give I-18 (102 mg, 31%) as a yellow solid. LC-MS m / z(ESI):419.0[MH]- .

[0091] Intermediate I-19: Synthesis of [(4Z)-4-[(6-chloro-7-methyl-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-cyanophenyl)acetic acid (4-Cyanophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (300 mg, 1.157 mmol) and piperazine (420 mg, 4.628 mmol) were added to a solution of ethanol (3 mL) at room temperature, and the mixture was heated to 65 °C and stirred for 20 min. After cooling to room temperature, 6-chloro-7-methyl-1H-indole-3-carbaldehyde (157 mg, 0.810 mmol) was added in portions, and the resulting mixture was heated to 65 °C and stirred for an additional 12 h. After concentration in vacuo, the residue was purified by reverse chromatography to give I-19 (270 mg, 59%) as a yellow solid. LC-MS m / z(ESI):433.0[MH] - .

[0092] I-20: Synthesis of (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetic acid Using the method described in TIFF2025535028000039.tif25170I-19, I-17-4 and the corresponding aldehyde were used to give I-20 (1.5 g, 84.77%) as a red solid. LC-MS m / z(ESI):432.1[M+H] + .

[0093] I-21: Synthesis of 2-(4-cyano-3-fluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetic acid TIFF2025535028000040.tif43170

[0094] I-21-1: 2-Bromo-2-(4-bromo-3-fluorophenyl)acetate methyl ester A solution of methyl 2-(4-bromo-3-fluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate (3 g, 11.536 mmol) and NBS (2.81 g, 14.997 mmol) in DCE (30 mL) was added to a solution of HBr in AcOH (2.3 mL, 16.261 mmol) at room temperature, and the resulting mixture was stirred at 85 °C for 12 h. The mixture was concentrated in vacuo, and the residue was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (100 mL × 3), and the combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with PE / EA (8:1) to give I-21-1 (3.2 g, 77%) as a yellow oil.

[0095] I-21-2: 2-(4-bromo-3-fluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate methyl ester To a stirred solution of 2-bromo-2-(4-bromo-3-fluorophenyl)methyl acetate (10 g, 27.611 mmol) and potassium carbonate (8.03 g, 55.222 mmol) in DMF (100 mL) was added hydantoin (4.36 g, 41.388 mmol) in portions at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 12 h. The resulting mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated in vacuo. The residue was purified by reverse-phase high-performance chromatography to give I-21-2 (3.9 g, 36.38%) as a white solid. LC-MS m / z(ESI):344.9[M+H] + .

[0096] I-21-3: 2-(4-cyano-3-fluorophenyl)-2-(2,5-dioxoimidazolidin-1-yl)acetate methyl ester To a solution of 2-(4-bromo-3-fluorophenyl)-2-(2,5-dioxoimidazol-1-yl)methyl acetate (1000 mg, 2.576 mmol) and tetrakis(triphenylphosphine)palladium (313 mg, 0.258 mmol) in DMF (10 mL) stirred at room temperature, zinc cyanide (318 mg, 2.576 mmol) was added in portions, and the resulting mixture was stirred at 120 °C under a nitrogen atmosphere for 16 h. The resulting mixture was concentrated in vacuo, and the residue was purified by reverse-phase high-performance chromatography to give I-21-3 (600 mg, 79%) as a yellow solid. LC-MS m / z(ESI):290.0[MH] - .

[0097] I-21: (4-cyano-3-fluorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid To a solution of 2-(4-cyano-3-fluorophenyl)-2-(2,5-dioxoimidazol-1-yl)methyl acetate (800 mg, 2.747 mmol) in AcOH (6 mL) was added HCl (2 mL, 4N) in portions at room temperature, and the resulting mixture was stirred at 100 °C under a nitrogen atmosphere for 1 h. The reaction mixture was concentrated to give I-21 (700 mg, 92%) as a white solid. The crude product was used directly in the next step without further purification. LC-MS m / z(ESI):278.1[M+H] + . [Example]

[0098] Example 1 Compound 1: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione TIFF2025535028000041.tif35170 Intermediate I-1 (119 mg, 0.505 mmol) and 6-chloro-1H-indole-3-carbaldehyde (90 mg, 0.476 mmol) were dissolved in ethanol (5 mL) at room temperature. To the mixture, acetic acid (150 mg, 2.370 mmol) and piperidine (0.5 mL) were slowly added with stirring. The reaction mixture was heated to 100 °C under a nitrogen atmosphere and stirred for 2 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative liquid chromatography to give compound 1 (33.5 mg, 17.61%) as a yellow solid. LC-MS m / z (ESI): 385.75 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (brs, 1H), 10.51 (brs, 1H), 8.19 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.45-7.35 (m, 2H), 7.19-7.11 (m, 2H), 6.88 (s, 1H), 4.68 (s, 2H).

[0099] Example 2 Compound 2: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione TIFF2025535028000042.tif27170 Using the method described in Example 1, I-2 and the corresponding aldehyde were used to give compound 2 (104.6 mg, 32.42%) as a yellow solid. LC-MS m / z (ESI): 386.60 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 10.54-10.30 (m, 1H), 8.16 (d, J = 1.9 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.45 (d, J = 1.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.32-7.27 (m, 2H), 7.10 (dd, J = 8.5, 1.9 Hz, 1H), 6.85-6.83 (m, 1H), 4.64 (s, 2H).

[0100] Example 3 Compound 3: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(4-fluorobenzyl)imidazolidine-2,4-dione TIFF2025535028000043.tif27170 Using the method described in Example 1, 3-(4-fluorobenzyl)imidazolidine-2,4-dione and the corresponding aldehyde were used to give compound 3 (75.8 mg, 14.24%) as a yellow solid. LC-MS m / z (ESI): 369.70 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.50 (s, 1H), 8.19 (s, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.48 (d, J= 1.7 Hz, 1H), 7.36 (dd, J = 8.6, 5.6 Hz, 2H), 7.24-7.10 (m, 3H), 6.87 (s, 1H), 4.67 (s, 2H).

[0101] Example 4 Compound 4: (Z)-4-((4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile TIFF2025535028000044.tif25170 Using the method described in Example 1, I-3 and the corresponding aldehyde were used to give compound 4 (12.3 mg, 2.34%) as a white solid. LC-MS m / z (ESI): 376.70 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.56 (s, 1H), 8.21 (d, J = 2.5 Hz, 1H), 7.84 (dd, J= 8.3, 1.6 Hz, 3H), 7.50 (d, J = 8.2 Hz, 3H), 7.14 (dd, J = 8.5, 1.8 Hz, 1H), 6.90 (s, 1H), 4.78 (s, 2H).

[0102] Example 5 Compound 5: (Z)-5-((6-bromo-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione TIFF2025535028000045.tif27170 Using the method described in Example 1, I-2 and the corresponding aldehyde were used to give compound 5 (15.6 mg, 6.73%) as a yellow solid. LC-MS m / z (ESI): 430.50 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.45 (s, 1H), 8.18 (s, 1H), 7.78 (d, J = 8.5 Hz, 1H), 7.62 (d, J= 1.3 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 7.28-7.23 (m, 1H), 6.87 (s, 1H), 4.68 (s, 2H).

[0103] Example 6 Compound 6: (Z)-5-((6-chloro-7-(fluoromethoxy)-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione TIFF2025535028000046.tif27170 Using the method described in Example 1, I-1 and the corresponding aldehyde were used to give compound 6 (32.5 mg, 34.43%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 10.57 (s, 1H), 8.22 (s, 1H), 7.70 (m, 1H), 7.45-7.37 (m, 2H), 7.21 (d, J= 8.5 Hz, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 5.90 (s, 1H), 5.77 (s, 1H), 4.68 (s, 2H).

[0104] Example 7 Compound 7: (Z)-5-((6,7-dichloro-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione TIFF2025535028000047.tif29170 Using the method described in Example 1, compound I-1 and the corresponding aldehyde were used to give compound 7 (21.6 mg, 4.95%) as a yellow solid. LC-MS m / z (ESI): 420.05 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 12.36 (s, 1H), 10.62 (s, 1H), 8.27 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.41 (ddd, J = 13.5, 10.0, 6.9 Hz, 2H), 7.31 (d, J = 8.5 Hz, 1H), 7.16 (s, 1H), 6.86 (s, 1H), 4.68 (s, 2H).

[0105] Example 8 Compound 8: (Z)-5-((6-chloro-7-methoxy-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione TIFF2025535028000048.tif32170 Using the method described in Example 1, intermediates I-5 and I-1 were used to give compound 8 (40 mg, 16.56%) as a yellow solid. LC-MS m / z (ESI): 417.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.19 (d, J = 2.4 Hz, 1H), 10.53 (s, 1H), 8.17 (d, J = 2.6 Hz, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.37 (ddt, J = 10.0, 8.1, 5.3 Hz, 2H), 7.14-7.08 (m, 2H), 6.81 (s, 1H), 4.64 (s, 2H), 3.89 (s, 3H).

[0106] Example 9 Compound 9: (Z)-5-((6-chloro-7-(methylthio)-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione TIFF2025535028000049.tif35170 Using the method described in Example 1, intermediates I-9 and I-1 were used to give compound 9 (12.7 mg, 33.28%) as a yellow solid. LC-MS m / z (ESI): 433.9 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) 12.06 (s, 1H), 10.63 (s, 1H), 8.25 (s, 1H), 7.86-7.83 (m, 1H), 7.44-7.29 (m, 3H), 7.26-7.16 (m, 1H), 6.86 (s, 1H), 4.68 (s, 2H), 2.43 (s, 3H).

[0107] Example 10 Compound 10: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione TIFF2025535028000050.tif30170 Using the method described in Example 1, intermediates I-10 and I-1 were used to give compound 10 (19.5 mg, 13.35%) as a yellow solid. LC-MS m / z (ESI): 403.8 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.57 (s, 1H), 8.25 (s, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.46-7.36 (m, 2H), 7.23-7.18 (m, 2H), 6.86 (s, 1H), 4.68 (s, 2H).

[0108] Example 11 Compound 11: (Z)-4-((4-((6-chloro-7-(fluoromethoxy)-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile TIFF2025535028000051.tif29170 Using the method described in Example 1, intermediates I-11 and I-4 were used to give compound 11 (9.8 mg, 2.2%) as a yellow solid. LC-MS m / z (ESI): 443.1 [M+H] + .1H NMR (300 MHz, DMSO-d6) δ 12.21 (s, 1H), 10.63 (s, 1H), 8.24 (s, 1H), 7.94-7.89 (m, 1H), 7.73-7.70 (m, 1H), 7.52-7.48 (m, 1H), 7.35-7.33 (m, 1H), 7.23-7.20 (m, 1H), 6.88 (s, 1H), 5.93 (s, 1H), 5.75 (s, 1H), 4.80 (s, 2H).

[0109] Example 12 Compound 12: (Z)-5-((6-chloro-7-(fluoromethoxy)-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione TIFF2025535028000052.tif34170 Using the method described in Example 1, intermediates I-11 and I-2 were used to give compound 12 (8.9 mg, 5.18%) as a yellow solid. LC-MS m / z (ESI): 431.8 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 10.58 (s, 1H), 8.22 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.44-7.40 (m, 2H), 7.35-7.22 (m, 2H), 7.17-7.27 (m, 1H), 6.86 (s, 1H), 5.93 (s, 1H), 5.75 (s, 1H), 4.68 (s, 2H).

[0110] Example 13 Compound 13: (Z)-4-((4-((6-chloro-7-(fluoromethoxy)-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile TIFF2025535028000053.tif29170 Using the method described in Example 1, intermediates I-11 and I-3 were used to give compound 13 (8.1 mg, 4.68%) as a yellow solid. LC-MS m / z (ESI): 422.8 [MH] - . 1 H NMR (300 MHz, DMSO- d6) δ 12.21 (s, 1H), 10.62 (s, 1H), 8.23 ​​(m, 1H), 7.85-7.82 (m, 2H), 7.72-7.69 (m, 1H), 7.51-7.48 (m, 2H), 7.22-7.20 (m, 1H), 6.87 (s, 1H), 5.93 (s, 1H), 5.75 (s, 1H), 4.78 (s, 2H).

[0111] Example 14 Compound 14: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile TIFF2025535028000054.tif32170 Using the method described in Example 1, intermediates I-10 and I-4 were used to give compound 14 (6.6 mg, 4.89%) as a yellow solid. LC-MS m / z (ESI): 410.9 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.63 (s, 1H), 8.28 (s, 1H), 7.95-7.90 (m, 1H), 7.71-7.68 (m, 1H), 7.52-7.48 (m, 1H), 7.35-7.32 (m, 1H), 7.24-7.19 (m, 1H), 6.87 (s, 1H), 4.80 (s, 2H).

[0112] Example 15 Compound 15: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione TIFF2025535028000055.tif34170 Using the method described in Example 1, intermediates I-10 and I-2 were used to give compound 15 (9.4 mg, 7.51%) as a yellow solid. LC-MS m / z (ESI): 401.70 [MH] - . 1 H NMR (400 MHz, DMSO- d6) 12.53 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.43-7.33 (m, 4H), 7.22-7.19 (m, 1H), 6.85 (s, 1H), 4.68 (s, 2H).

[0113] Example 16 Compound 16: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile TIFF2025535028000056.tif29170 Using the method described in Example 1, intermediates I-10 and I-3 were used to give compound 16 (25.9 mg, 12.16%) as a yellow solid. LC-MS m / z (ESI): 392.8 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.60 (s, 1H), 8.26 (s, 1H), 7.83 (d, J = 8.0 Hz 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 2H), 7.21 (t, J = 6.8 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H).

[0114] Example 17 Compound 17: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(4-ethynylbenzyl)imidazolidine-2,4-dione TIFF2025535028000057.tif30170 Using the method described in Example 1, intermediates I-10 and I-6 were used to give compound 17 (23.1 mg, 22.88%) as a yellow solid. LC-MS m / z (ESI): 391.9 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.56 (s, 1H), 10.59 (s, 1H), 8.26 (d, J = 2.8 Hz, 1H), 7.67 (d, J= 8.6 Hz, 1H), 7.50-7.43 (m, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.20 (dd, J= 8.5, 6.5 Hz, 1H), 6.85 (s, 1H), 4.70 (s, 2H), 4.18 (s, 1H).

[0115] Example 18 Compound 18: (Z)-3-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile TIFF2025535028000058.tif32170 Using the method described in Example 1, intermediates I-10 and I-7 were used to give compound 18 (12.8 mg, 14.52%) as a yellow solid. LC-MS m / z (ESI): 392.8 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.60-12.39 (m, 1H), 10.58 (s, 1H), 8.82-8.21 (m, 1H), 7.82-7.73 (m, 2H), 7.72-7.57 (m, 3H), 7.33-7.10 (m, 1H), 6.80 (s, 1H), 4.75 (s, 2H).

[0116] Example 19 Compound 19: (Z)-4-((4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile TIFF2025535028000059.tif27170 Using the method described in Example 1, intermediates I-3 and I-8 were used to give compound 19 (47 mg, 23%) as a yellow solid. LC-MS m / z (ESI): 388.8 [MH] - . 1H NMR (300 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.55 (s, 1H), 8.21 (d, J = 2.5 Hz, 1H), 7.84-7.78 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.54-7.45 (m, 2H), 7.14 (d, J = 8.5 Hz, 1H), 6.87 (d, J = 0.6 Hz, 1H), 4.78 (s, 2H), 2.52 (s, 3H).

[0117] Example 20 Compound 20: (Z)-4-((4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile TIFF2025535028000060.tif31170 Using the method described in Example 1, intermediate I-4 and the corresponding aldehyde were used to give compound 20 (27 mg, 12%) as a yellow solid. LC-MS m / z (ESI): 393.0 [M+H] - . 1 H NMR (400 MHz, DMSO-d6) δ 12.01-11.75 (m, 1H), 10.53 (m, 1H), 8.48 (m, 1H), 7.91 (t, J= 7.5 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.67-7.45 (m, 2H), 7.33 (d, J= 8.1 Hz, 1H), 7.15 (m, 1H), 6.84 (m, 1H), 4.79 (s, 2H).

[0118] Example 21 Compound 21: (Z)-4-((4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2-fluorobenzonitrile TIFF2025535028000061.tif29170 Using the method described in Example 1, intermediates I-4 and I-8 were used to give compound 21 (42 mg, 18%) as a yellow solid. LC-MS m / z (ESI): 407.1 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 10.57 (s, 1H), 8.22 (d, J = 2.9 Hz, 1H), 7.91 (t, J= 7.4 Hz, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.54-7.44 (m, 1H), 7.33 (dd, J= 8.1, 1.6 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.88 (s, 1H), 4.80 (s, 2H), 2.52 (s, 3H).

[0119] Example 22 Compound 22: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide TIFF2025535028000062.tif33170 Intermediate I-13 (150 mg, 0.35 mmol), HATU (199 mg, 0.52 mmol), and N,N-diisopropylethylamine (90 mg, 0.7 mmol) were added to a solution of dimethylformamide (5 mL). The mixture was stirred at 25 °C for 10 min, and then 2-aminopropane-1,3-diol (47 mg, 0.52 mmol) was added to the mixture. The reaction mixture was stirred at 25 °C for 2 h. The mixture was concentrated in vacuo and purified by preparative thin-layer chromatography to give compound 22 (160 mg, 90%) as a yellow solid. LC-MS m / z (ESI): 502.9 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.98 (d, J = 2.0 Hz, 1H), 10.53 (s, 1H), 8.19 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.75 (d, J = 8.2 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H),7.46-7.39 (m, 4H), 7.13 (dd, J = 8.5, 1.9 Hz, 1H), 6.83 (s, 1H), 5.77 (s, 1H), 4.63 (t, J = 5.5 Hz, 1H), 4.49 (t, J= 5.7 Hz, 1H), 3.85-3.77 (m, 1H), 3.47-3.35 (m, 4H).

[0120] Example 23 Compound 23: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-(diethylamino)ethyl)acetamide TIFF2025535028000063.tif36170 Using the method described in Example 22, intermediate I-13 and N,N-divinylethane-1,2-diamine were used to give compound 23 (180 mg, 58.61%) as a yellow solid. LC-MS m / z (ESI): 527.9 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.08 (s, 1H), 10.68 (s, 1H), 8.26 (d, J = 2.7 Hz, 2H), 7.87 (d, J = 8.6 Hz, 1H), 7.54 (d, J = 1.8 Hz, 1H), 7.51 (s, 4H), 7.20 (dd, J = 8.5, 1.9 Hz, 1H), 6.93 (s, 1H), 5.86 (s, 1H), 3.51 (m, 2H), 3.27-3.15 (m, 6H), 1.24 (t, J = 7.1 Hz, 6H).

[0121] Example 24 Compound 24: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide TIFF2025535028000064.tif33170 Using the method described in Example 22, intermediate I-20 and 2-aminopropane-1,3-diol were used to give compound 24 (30 mg, 24.98%) as a yellow solid. LC-MS m / z (ESI): 502.9 [MH] - . 1 HNMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.53 (s, 1H), 8.19 (s, 1H), 7.87-7.77 (m, 2H), 7.55-7.36 (m, 3H), 7.30-7.28 (m, 1H), 7.18-7.10 (m, 1H), 6.84 (s, 1H), 5.79 (s, 1H), 4.64-4.61 (m, 1H), 4.50-4.47 (m, 1H), 3.85-3.80 (m, 1H), 3.52-3.43 (m, 4H).

[0122] Example 25 Compound 25: (Z)-5-((6-chloro-7-methoxy-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)ethyl)imidazolidine-2,4-dione TIFF2025535028000065.tif24170 Using the method described in Example 1, compound 25 (7.3 mg, 0.76%) was obtained as a yellow solid. LC-MS m / z (ESI): 432.0 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 12.19 (s, 1H), 10.51 (s, 1H), 8.18 (d, J = 2.5 Hz, 1H), 7.55 (d, J = 8.6 Hz, 1H), 7.52-7.36 (m, 2H), 7.23 (s, 1H), 7.14 (d, J = 8.6 Hz, 1H), 6.79 (s, 1H), 5.41-5.29 (m, 1H), 3.93 (s, 3H), 1.78 (d, J = 7.2 Hz, 3H).

[0123] Example 26 Compound 26: 6-chloro-3-{[(4Z)-1-[1-(3,4-difluorophenyl)-2-hydroxyethyl]-2,5-dioxoimidazolidine-4-methylene]methyl}indole-1-carboxylic acid ester TIFF2025535028000066.tif63170

[0124] 26-1: 2-Bromo-1-(3,4-difluorophenyl)ethanone Bromine (2 g, 11.889 mmol) was slowly added to a solution of 1-(3,4-difluorophenyl)ethanone (2 g, 12.169 mmol) in dichloromethane (20 mL) at 0 °C. After the reaction was completed, the mixture was poured into ice water. The resulting mixture was extracted three times with dichloromethane (40 mL). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with DCM / PE (1:20) to give 26-1 (1.68 g, 58%) as a white solid. 1 H NMR (300 MHz, DMSO-d6) δ 8.15-8.05 (m, 1H), 7.98-7.86 (m, 1H), 7.70-7.60 (m, 1H), 4.95 (s, 2H).

[0125] 26-2: 1-(3,4-difluorophenyl)-2-hydroxyethanone 2-Bromo-1-(3,4-difluorophenyl)ethanone (2 g, 8.399 mmol), sodium formate (6.97 g, 97.365 mmol), and sodium bicarbonate (800 mg, 9.047 mmol) were added to a mixture of acetonitrile (8 mL) and water (4 mL) at room temperature. The resulting mixture was heated to 65 °C under a nitrogen atmosphere and stirred for 18 h. After the reaction was completed, the mixture was cooled to room temperature. The resulting mixture was added to water (5 mL). The resulting mixture was extracted three times with ethyl acetate (20 mL). The combined organic phases were washed three times with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (2:1) to give 26-2 (610 mg, 39%) as a yellow solid. 1 HNMR (300 MHz, DMSO-d6) δ 8.05-7.95 (m, 1H), 7.90-7.80 (m, 1H), 7.75-7.62 (m, 1H), 5.26-5.18 (m, 1H), 4.82-4.74 (m, 2H).

[0126] 26-3: 2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethanone At room temperature, 1-(3,4-difluorophenyl)-2-hydroxyethanone (2.1 g, 11.346 mmol) and triethylamine (1.48 g, 13.894 mmol) were added to a solution of dichloromethane (20 mL), and tert-butyldimethylchlorosilane (2.76 g, 17.396 mmol) was added to the above solution while stirring. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 h. The mixture was poured into ice water and extracted three times with ethyl acetate (80 mL). The combined organic phases were washed three times with saturated brine (50 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with DCM / PE (1:2) to give compound 26-3 (2.48 g, 69%) as a yellow oil. LC-MS m / z(ESI):285.0[MH] -.

[0127] 26-4: 2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethanol Under a nitrogen atmosphere, 2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethanone (2.0 g, 6.299 mmol) was added to a solution of methanol (25 mL), and sodium borohydride (800 mg, 20.090 mmol) was added in portions at 0 °C. The resulting mixture was stirred at room temperature for 0.5 h, then poured into ice water and extracted three times with ethyl acetate (10 mL). The combined organic phases were washed three times with saturated brine (5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with petroleum ether / ethyl acetate (1:20) to give compound 26-4 (1.56 g, 86%) as a brown oil. 1 HNMR (400 MHz, DMSO-d6) δ 7.45-7.35 (m, 2H), 7.30-7.20 (m, 1H), 5.56-5.50 (m, 1H), 4.70-4.60 (m, 1H), 3.80-3.70 (m, 1H), 3.65-3.55 (m, 1H) 0.86 (s, 9H), 0.07 (s, 6H).

[0128] 26-5: 3-{2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethyl}imidazolidine-2,4-dione At 0 °C, 2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethanol (1.56 g, 5.404 mmol) and triphenylphosphine (2.84 g, 10.286 mmol) were added to a solution of THF (20 mL), and diethyl azodicarboxylate (1.88 g, 10.255 mmol) was added to the mixture under a nitrogen atmosphere. The resulting mixture was heated to 40 °C and stirred for 16 h. After cooling to room temperature, the resulting mixture was concentrated in vacuo. The residue was purified by reverse chromatography to give compound 26-5 (640 mg, 25%) as a brown oil. LC-MS m / z(ESI):371.2[M+H] + .

[0129] 26-6: (5Z)-3-{2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethyl}-5-[(6-chloro-1H-indol-3-yl)methylene]imidazolidine-2,4-dione At room temperature, 3-{2-[(tert-butyldimethylsilyl)oxy]-1-(3,4-difluorophenyl)ethyl}imidazolidine-2,4-dione (440 mg, 0.927 mmol) and 6-chloro-1H-indole-3-carbaldehyde (236 mg, 1.25 mmol) were added to a solution of ethanol (5 mL), and piperidine (0.5 mL) was added dropwise to the reaction mixture while maintaining the temperature at room temperature. The resulting mixture was heated to 100 °C and stirred for 4 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by reverse chromatography to give compound 26-6 (325 mg, 37%) as a yellow solid. LC-MS m / z(ESI):532.3[M+H] + .

[0130] Compound 26: 6-chloro-3-{[(4Z)-1-[1-(3,4-difluorophenyl)-2-hydroxyethyl]-2,5-dioxoimidazolidine-4-methylene]methyl}indole-1-carboxylic acid ester (Z)-3-(2-(tert-butyldimethylsilyl)-1-(3,4-difluorophenyl)ethyl)-5-((6-chloro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione (263 mg, 0.457 mmol) was added to a solution of tetrahydrofuran (6 mL) at room temperature, and tetramethylammonium fluoride (3.66 mL, 3.66 mmol, 1N) was added dropwise to the solution. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The residue was purified by preparative high-performance liquid chromatography to give compound 26 (2.4 mg, 29.66%) as a yellow solid. LC-MS m / z (ESI): 416.1 [MH] - . 1 HNMR (300 MHz, DMSO-d6) δ 12.03-11.73 (m, 1H), 10.50 (s, 1H), 8.79-8.14 (m, 1H), 7.86-7.61 (m, 1H), 7.56-7.36 (m, 3H), 7.27 (dd, J = 5.2, 3.0 Hz, 1H), 7.18-7.10 (m, 1H), 6.84 (s, 1H), 5.20 (dt, J = 10.7, 5.7 Hz, 2H), 4.31 (td, J = 10.3, 5.4 Hz, 1H), 3.94 (dt, J = 11.2, 5.8 Hz, 1H).

[0131] Example 27 Compound 27: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide TIFF2025535028000067.tif28170

[0132] 27-1: 2-(4-cyano-3-fluorophenyl)-N-(1,3-dihydroxypropan-2-yl)-2-(2,5-dioxoimidazolidin-1-yl)acetamide 2-Aminopropane-1,3-diol (62 mg, 0.686 mmol) and HATU (261 mg, 0.686 mmol) were added to dimethylformamide (1 mL) at room temperature. To the solution was added (4-cyano-3-fluorophenyl)(2,5-dioxoimidazolidin-1-yl)acetic acid (100 mg, 0.343 mmol) and diisopropylethylamine (74 mg, 0.686 mmol) in portions. Under a nitrogen atmosphere, the resulting mixture was heated to 40 °C and stirred for 12 h. After concentration in vacuo, the residue was purified by reverse chromatography to give compound 27-1 (60 mg, 50%) as a yellow solid. LC-MS m / z(ESI):349.0[MH] - .

[0133] Compound 27: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide To the mixture of 2-(4-cyano-3-fluorophenyl)-N-(1,3-dihydroxypropan-2-yl)-2-(2,5-dioxoimidazolidin-1-yl)acetamide (20 mg, 0.051 mmol) in ethyl acetate (1 mL) was added piperidine (18.42 mg, 0.204 mmol) in portions at room temperature, and the resulting mixture was refluxed for 20 min. After cooling to room temperature, 6-chloro-7-fluoro-1H-indole-3-carbaldehyde (8 mg, 0.036 mmol) was added in portions. The resulting mixture was refluxed for an additional 12 h. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was purified by preparative HPLC to give compound 27 (4.3 mg, 15.35%) as a yellow solid. LC-MS m / z (ESI): 528.1 [MH] - . 1H NMR (400 MHz, DMSO-d6) δ 12.55 (d, J = 3.0 Hz, 1H), 10.63 (s, 1H), 8.71-8.20 (m, 1H), 8.04 (d, J= 8.2 Hz, 1H), 7.96-7.80 (m, 1H), 7.76-7.55 (m, 2H), 7.43 (d, J = 8.1 Hz, 1H), 7.25-7.16 (m, 1H), 6.83 (s, 1H), 5.91 (s, 1H), 4.58 (dt, J = 57.7, 5.7 Hz, 2H), 4.10-3.77 (m, 1H), 3.56-3.35 (m, 4H).

[0134] Example 28 Compound 28: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide TIFF2025535028000068.tif35170 Using the method described in Example 22, intermediate I-14 and 2-aminopropane-1,3-diol were used to give compound 28 (54.1 mg, 29%) as a yellow solid. LC-MS m / z (ESI): 521.1 [M+H] + . 1 HNMR (300 MHz, DMSO-d6) δ 12.52 (s, 1H), 10.57 (s, 1H), 8.24 (d, J = 2.8 Hz, 1H), 7.69 (dd, J= 17.6, 8.4 Hz, 2H), 7.42 (d, J = 1.2 Hz, 5H), 7.20 (dd, J = 8.6, 6.5 Hz, 1H), 6.81 (s, 1H), 5.77 (s, 1H), 4.60-4.30 (m, 1H), 3.86-3.75 (m, 1H), 3.48-3.33 (m, 5H).

[0135] Example 29 Compound 29: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide TIFF2025535028000069.tif37170 Using the method described in Example 22, intermediate I-16 and 2-aminopropane-1,3-diol were used to give compound 29 (34 mg, 21%) as a yellow solid. LC-MS m / z (ESI): 510.1 [MH] - . 1 HNMR (400 MHz, DMSO-d6) δ 12.59-12.37 (m, 1H), 10.62 (s, 1H), 8.25 (d, J = 2.8 Hz, 1H), 7.94 (d, J= 8.2 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.67 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.20 (dd, J = 8.5, 6.4 Hz, 1H), 6.82 (s, 1H), 5.87 (s, 1H), 3.82 (q, J = 6.5 Hz, 2H), 3.53-3.31 (m, 5H).

[0136] Example 30 Compound 30: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)acetamide TIFF2025535028000070.tif37170 Using the method described in Example 22, intermediate I-17 and 2-amino-2-(hydroxymethyl)propane-1,3-diol were used to give compound 30 (4.4 mg, 4.57%) as a yellow solid. LC-MS m / z (ESI): 549.1 [M+H] + . 1HNMR (300 MHz, DMSO-d6) δ 12.07 (s, 1H), 10.64 (s, 1H), 8.24 (s, 1H), 7.69-7.31 (m, 4H), 7.19-7.14 (m, 2H), 6.86 (s, 1H), 5.86 (s, 1H), 4.54 (br, 2H), 3.70-3.40 (m, 7H).

[0137] Example 31 Compound 31: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide TIFF2025535028000071.tif32170 Using the method described in Example 22, intermediate I-18 and 2-aminopropane-1,3-diol were used to give compound 31 (6.4 mg, 4.28%) as a yellow solid. LC-MS m / z (ESI): 494.1 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.07 (d, J = 2.8 Hz, 1H), 10.76 (s, 1H), 8.24 (d, J = 2.5 Hz, 1H), 8.00 (s, 3H), 7.86 (dd, J = 21.8, 8.3 Hz, 3H), 7.64 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 1.9 Hz, 1H), 7.15 (dd, J = 8.5, 1.9 Hz, 1H), 6.95 (s, 1H), 6.24 (s, 1H), 5.40 (s, 1H), 4.31 (q, J = 6.9, 6.0 Hz, 2H), 3.62-3.53 (m, 1H), 3.51-3.45 (m, 1H).

[0138] Example 32 Compound 32: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide TIFF2025535028000072.tif37170 Using the method described in Example 22, intermediate I-19 and 2-aminopropane-1,3-diol were used to give compound 32 (58 mg, 21%) as a yellow solid. LC-MS m / z (ESI): 508.0 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 12.01 (d, J = 3.0 Hz, 1H), 10.57 (s, 1H), 8.21 (d, J = 2.9 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 5.87 (s, 1H), 4.18-3.65 (m, 3H), 3.53-3.31 (m, 4H), 2.51 (s, 3H).

[0139] Example 33 Compound 33: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-oxoethyl)-2-fluorobenzonitrile TIFF2025535028000073.tif35170-78°C under a nitrogen atmosphere, a solution of compound 14 (400 mg, 0.958 mmol, 1 equiv, 98.9%) in tetrahydrofuran (24.5 mL) was added with Li MDS (4.8 mL, 4.8 mmol, 5 equiv, 1 N) and stirred at -78°C for 1 h. Formylmorpholine (1.4 g, 11.552 mmol, 12.05 equiv, 95%) was then added and stirred at -80°C for 4 h. A solution of HOAc (1 mL) in THF (3 mL) was added at -80°C to quench the reaction. The mixture was heated to -20°C and water (100 mL) was added to the reaction mixture. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (100 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase HPLC to give compound 33 (14.2 mg, 3.3%) as a yellow solid. LC-MS m / z (ESI): 439.0 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.55 (s, 1H), 11.08 (s, 1H), 10.62 (s, 1H), 8.30 (s, 1H), 7.93 (s, 1H), 7.87-7.62 (m, 2H), 7.58-7.48 (m, 1H), 7.44-7.16 (m, 2H), 6.87 (s, 1H).

[0140] Example 34 Compound 34: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2,3-difluorobenzonitrile TIFF2025535028000074.tif25170

[0141] 34-1: 4-(Bromomethyl)-2,3-difluorobenzonitrile AIBN (180 mg, 1.061 mmol, 1.0 equiv, 95%) was added in portions to a solution of 2,3-difluoro-4-methylbenzonitrile (2 g, 11.787 mmol, 1.0 equiv, 95%) and NBS (3 g, 16.738 mmol, 1.4 equiv, 95%) in CHCl3 (95 mL) at room temperature, and the resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 8 h. The mixture was cooled to room temperature, and water was added to quench the reaction. The resulting mixture was extracted with EtOAc (3 × 200 mL), and the combined organic layer was washed with brine (3 × 200 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 34-1 (1.7 g, 67.5%) as a yellow oil. LC-MS m / z(ESI):299.8[MH] - .

[0142] 34-2: 4-[(2,5-dioxoimidazolidin-1-yl)methyl]-2,3-difluorobenzonitrile Hydantoin (1.0 g, 9.398 mmol, 1.3 equiv, 95%) was added to a solution of 34-1 (1.7 g, 7.241 mmol, 1.0 equiv, 99%) and potassium carbonate (2.0 g, 13.748 mmol, 1.9 equiv, 95%) in DMF (15 mL) at room temperature, and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 12 h. Water was added to quench the reaction, and the resulting mixture was extracted with EtOAc (3 × 110 mL). The combined organic layers were washed with brine (3 × 60 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 34-2 (1.2 g, 67%) as a white solid. LC-MS (MH) - =250.0

[0143] Compound 34: 4-{[(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]methyl}-2,3-difluorobenzonitrile Using the method described in Example 1, 34-2 and I-10 were used to give compound 34 (31.7 mg, 14.6%) as a yellow solid. LC-MS (MH) - = 428.8. 1 H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 10.64 (s, 1H), 8.26 (s, 1H), 7.79-7.62 (m, 2H), 7.41-7.31 (m, 1H), 7.27-7.16 (m, 1H), 6.86 (s, 1H), 4.84 (s, 2H).

[0144] Example 35 Compound 35: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2,6-difluorobenzonitrile TIFF2025535028000075.tif51170

[0145] 35-1: 2,6-difluoro-4-(hydroxymethyl)benzonitrile Sodium borohydride (257 mg, 6.458 mmol, 1.00 equiv) was added in portions to a solution of 2,6-difluoro-4-formylbenzonitrile (11.40 g, 6.458 mmol, 1.00 equiv) in methanol (25 mL) at 0 °C under a nitrogen atmosphere, and the resulting mixture was stirred at 0 °C for 1 h. Water was added to quench the reaction, and the resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CHCl / EA (5:1) to give 35-1 (936 mg, 3.682 mmol, 84.7%) as a yellow solid. LC-MS m / z(ESI):168.0[MH] -

[0146] 35-2: 4-(Bromomethyl)-2,6-difluorobenzonitrile To a solution of 35-1 (936 mg, 5.534 mmol, 1.00 equiv) and PPI (1.33 g, 6.032 mmol, 1.10 equiv) in THF (33.0 mL) was added carbon tetrabromide (2.30 g, 6.917 mmol, 1.30 equiv) in portions at 0 °C under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 20 h. The reaction mixture was filtered and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (5:1) to give 35-2 (218 mg, 0.930 mmol, 16.8%) as a yellow oil. LC-MS m / z(ESI):247.9[M-H+18] -

[0147] 35-3: Synthesis of 4-[(2,5-dioxoimidazolidin-1-yl)methyl]-2,6-difluorobenzonitrile Using the method described in 34-2, 35-2 was used to give compound 35-3 (164 mg, 0.648 mmol, 75.9%) as a white solid. LC-MS m / z(ESI):250.0[MH] -

[0148] Compound 35: 4-{[(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]methyl}-2,6-difluorobenzonitrile Using the method described in Example 1, 35-3 and I-10 were used to give compound 35 (5.1 mg, 0.011 mmol, 2.95%) as a yellow solid. LC-MS m / z (ESI): 428.8[MH] - . 1H NMR: (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.62 (s, 1H), 8.27 (s, 1H), 7.73-7.63 (m, 1H), 7.55-7.35 (m, 2H), 7.27-7.17 (m, 1H), 6.87 (s, 1H), 4.80 (s, 2H).

[0149] Example 36 Compound 36: (Z)-4-((4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)-2,5-difluorobenzonitrile TIFF2025535028000076.tif51170

[0150] 36-1: Synthesis of 2,5-difluoro-4-(hydroxymethyl)benzonitrile Using the method described in 35-1, 2,5-difluoro-4-formylbenzonitrile was used to obtain compound 36-1 (950 mg, 5.611 mmol, 96.6%) as a white solid. LC-MS m / z(ESI):168.0[MH] -

[0151] 36-2: 4-(bromomethyl)-2,5-difluorobenzonitrile Phosphorus tribromide (1.55 g, 5.804 mmol, 1.10 equiv) was added dropwise to a solution of 2,5-difluoro-4-(hydroxymethyl)benzonitrile (920 mg, 5.276 mmol, 1.00 equiv) in DCM (5 mL) at 0 °C under a nitrogen atmosphere, and the resulting mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (50 mL) and extracted with sodium bicarbonate (3 × 70 mL). The organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 36-2 (545 mg, 1.966 mmol, 40.3%) as a white solid. LC-MS m / z(ESI):232.00[M+H] +

[0152] 36-3: 4-[(2,5-dioxoimidazol-1-yl)methyl]-2,5-difluorobenzonitrile Using the method described in 34-2, compound 36-2 was used to give compound 36-3 (183 mg, 0.626 mmol, 29.1%) as a yellow solid. LC-MS m / z(ESI):250.0[MH] -

[0153] Compound 36: 4-{[(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]methyl}-2,5-difluorobenzonitrile Using the method described in Example 1, 36-3 and the corresponding aldehyde were used to give compound 36 (18.6 mg, 0.041 mmol, 13.6%) as a yellow solid. LC-MS m / z (ESI): 428.8 [MH] - . 1 H NMR: (400 MHz, CDCl3) δ12.55 (s, 1H), 10.61 (s, 1H), 8.27 (s, 1H), 8.07-7.97(m, 1H), 7.78-7.68 (m, 1H), 7.65-7.45 (m, 1H), 7.28-7.18 (m, 1H), 6.86 (s, 1H), 4.79 (s, 2H).

[0154] Example 37 Compound 37: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)-2-fluorobenzonitrile To a solution of 4-{1-[(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-oxoethyl}-2-fluorobenzonitrile (30 mg, 0.066 mmol, 1 equiv) and AcOH (10 mg, 0.153 mmol, 2.32 equiv) in DCE (1 mL) was added STAB (38 mg, 0.174 mmol, 2.63 equiv) in portions, and the resulting mixture was stirred at 40 °C for 1 h. The mixture was cooled to room temperature and concentrated in vacuo. The crude product was purified by preparative HPLC to give compound 37 (6.9 mg, 0.012 mmol, 18.8%) as a yellow solid. LC-MS m / z (ESI): 440.9 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.61 (s, 1H), 8.31-8.21 (m, 1H), 7.98-7.88 (m, 1H), 7.73-7.63 (m, 1H), 7.65-7.55 (m, 1H), 7.50-7.40 (m, 1H), 7.27-7.17 (m, 1H), 6.84 (s, 1H), 5.35-5.25 (m, 2H), 4.33-4.23 (m, 1H), 4.09-3.99 (m, 1H).

[0155] Example 38 Compound 38: (Z)-4-(1-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile TIFF2025535028000078.tif24170

[0156] 38-1: 4-{1-[(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-oxoethyl}benzonitrile Using the method described in Example 33, compound 4 was used to give 38-1 (220 mg, 0.327 mmol, 9.7%) as a yellow solid. LC-MS m / z(ESI):403.1[MH] -

[0157] Compound 38: (Z)-4-(1-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile Using the method described in Example 37 and employing 38-1, compound 38 (13.6 mg, 0.032 mmol, 40%) was obtained as a yellow solid. LC-MS m / z (ESI): 407.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.51 (brs, 1H), 8.19 (s, 1H), 7.88-7.68 (m, 3H), 7.66-7.56 (m, 2H), 7.55-7.45 (m, 1H), 7.21-7.09 (m, 1H), 6.85 (s, 1H), 5.33-5.17 (m, 2H), 4.37-4.27 (m, 1H), 4.07-3.97 (m, 1H).

[0158] Example 39 Compound 39: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione TIFF2025535028000079.tif23170

[0159] 39-1: 2-[(4Z)-4-[(6-chloro-7-methyl-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-(3,4-difluorophenyl)acetaldehyde Using the procedure described in Example 33, (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(3,4-difluorobenzyl)imidazolidine-2,4-dione, 39-1 (80 mg, 0.219 mmol, 12.7%) was obtained as a yellow solid. LC-MS m / z(ESI):430.0[M+H] +

[0160] Compound 39: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione Using the method described in Example 37 and employing 39-1, compound 39 (8.5 mg, 0.019 mmol, 9.5%) was obtained as a yellow solid. LC-MS m / z (ESI): 430.0 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.51 (s, 1H), 8.21 (s, 1H), 7.69-7.59 (m, 1H), 7.58-7.35 (m, 2H), 7.33-7.10 (m, 2H), 6.83 (s, 1H), 5.26-5.15 (m, 2H), 4.37-4.27 (m, 1H), 4.00-3.90 (m, 1H). 2.45 (s, 3H).

[0161] Example 40 Compound 40: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)ethyl dihydrogen phosphate TIFF2025535028000080.tif57170

[0162] 40-1: 3-{[(4Z)-3-(tert-butoxycarbonyl)-1-[1-(4-cyanophenyl)-2-hydroxyethyl]-2,5-dioxoimidazolidin-4-ylidene]methyl}-6-chloroindole-1-carboxylic acid tert-butyl ester To a solution of 4-{1-[(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-hydroxyethyl}benzonitrile (155 mg, 0.360 mmol, 1 equiv), DMAP (9 mg, 0.068 mmol, 0.19 equiv), and BocO (243 mg, 1.058 mmol, 2.94 equiv) in DMF (3 mL) was added DIEA (104 mg, 0.763 mmol, 2.12 equiv) and stirred at room temperature under a nitrogen atmosphere at 40 °C for 2 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by reverse-phase high-performance chromatography to give 40-1 (20 mg, 0.033 mmol, 9.13%) as a yellow solid. LC-MS m / z(ESI):505.1[MH-100] -

[0163] 40-2: 2-[(4Z)-3-(tert-butoxycarbonyl)-4-{[1-(tert-butoxycarbonyl)-6-chloroindol-3-yl]methylene}-2,5-dioxoimidazolidin-1-yl]-2-(4-cyanophenyl)ethoxyphosphonic acid To a solution of tert-butyl 3-{[(4Z)-3-(tert-butoxycarbonyl)-1-[1-(4-cyanophenyl)-2-hydroxyethyl]-2,5-dioxoimidazolidin-4-ylidene]methyl}-6-chloroindole-1-carboxylate (25 mg, 0.041 mmol, 1 equiv) and TEA (150 mg, 1.403 mmol, 0.20 mL, 34.23 equiv) in THF (1 mL) was added phosphorus oxychloride (125 mg, 0.772 mmol, 0.16 mL, 18.83 equiv) and the resulting mixture was stirred at room temperature for 18 hours. Water (0.5 mL) was then added to the reaction mixture at 0 °C and the resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give 40-2 (40 mg, crude product) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS m / z(ESI):685.1[MH] -

[0164] Compound 40: 2-[(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-(4-cyanophenyl)ethoxyphosphonic acid A solution of HCl in 1,4-dioxane (1 mL, 4.000 mmol, 4N) was added to 2-[(4Z)-3-(tert-butoxycarbonyl)-4-{[1-(tert-butoxycarbonyl)-6-chloroindol-3-yl]methylene}-2,5-dioxoimidazol-1-yl]-2-(4-cyanophenyl)ethoxyphosphonic acid (40 mg, crude product), and the resulting mixture was stirred at room temperature for 12 h. The resulting mixture was concentrated in vacuo, and the crude product was purified by reverse-phase HPLC to give compound 40 (2.2 mg, 0.004 mmol, 29.11%) as a white solid. LC-MS m / z (ESI): 484.9 [MH] - . 1H NMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.85-7.75 (m, 3H), 7.71-7.57 (m, 2H), 7.54-7.44 (m, 1H), 7.13 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 5.47-5.37 (m, 1H), 4.46-4.36 (m, 2H).

[0165] Example 41 Compound 41: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(2-hydroxyethyl)acetamide TIFF2025535028000081.tif35170

[0166] 41-1: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)acetic acid To a solution of 2-(4-cyano-3-fluorophenyl)-2-(2,5-dioxoimidazol-1-yl)methyl acetate (300 mg, 1.020 mmol, 1.0 equiv, 99%) and 6-chloro-7-fluoro-1H-indole-3-carbaldehyde (409 mg, 2.050 mmol, 2.0 equiv, 99%) in ethanol (5 mL) was added pyridine (341 mg, 4.100 mmol, 4.0 equiv, 95%) in portions at room temperature, and the resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 4 h. The residue was purified by reverse-phase high-performance chromatography to give compound 41-1 (120 mg, 23%) as a yellow solid. LC-MS (MH) - =455.0.

[0167] Compound 41: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazol-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(2-hydroxyethyl)acetamide To a solution of [(4Z)-4-[(6-chloro-7-fluoro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](4-cyano-3-fluorophenyl)acetic acid (20 mg, 0.043 mmol, 1 equiv), HATU (30 mg, 0.075 mmol, 1.75 equiv), and DIEA (27 mg, 0.198 mmol, 4.63 equiv) in DMF (0.5 mL) was added dropwise at room temperature, and the resulting mixture was stirred at 40 °C under a nitrogen atmosphere for 12 h. The mixture was cooled to room temperature and purified by prep-HPLC to give compound 41 (1.6 mg, 0.003 mmol, 7.55%) as a yellow solid. LC-MS m / z (ESI): 500.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 10.64 (s, 1H), 8.29-8.18 (m, 2H), 7.97-7.89 (m, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 10.6 Hz, 1H), 7.47 (d, J = 8.6 Hz, 1H), 7.28-7.17 (m, 1H), 6.84 (s, 1H), 5.89 (s, 1H), 4.67-4.60 (m, 1H), 3.46-3.39 (m, 2H), 3.26-3.19 (m, 1H), 3.18-3.09 (m, 1H).

[0168] Example 42 Compound 42: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)ethyl dihydrogen phosphate TIFF2025535028000082.tif291700°C. To a stirred solution of (5Z)-5-[(6-chloro-1H-indol-3-yl)methylene]-3-[1-(3,4-difluorophenyl)-2-hydroxyethyl]imidazolidine-2,4-dione (15 mg, 0.036 mmol, 1 eq) in ACN (1 mL) was added dichlorophosphoric anhydride (35 mg, 0.14 mmol, 3.91 eq) dropwise at 700°C. The resulting mixture was stirred for an additional 3 h at 0°C. The mixture was alkalized to pH = 8-9 with sodium bicarbonate (1 M) at 0°C. The resulting mixture was stirred for 30 min at 0°C. The mixture was then acidified to pH = 1 with HCl (12 M) and stirred for 1.5 h at 0°C. The resulting mixture was extracted with EtOAc (3 x 25 mL), and the combined organic layers were washed with brine (1 x 25 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by prep-HPLC to give compound 42 (4.4 mg, 23.0%) as a yellow solid. LC-MS m / z (ESI): 496.0 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.20 (s,1H), 7.79 (d, J = 8.5 Hz,1H), 7.60-7.20 (m, 4H), 7.19-7.05 (m, 1H), 6.84 (s, 1H), 5.42-5.28 (m, 1H), 4.60-4.30 (m,2H).

[0169] Example 43 Compound 43: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)ethyl dihydrogen phosphate TIFF2025535028000083.tif29170 Using the method described in Example 42, compound 39 was used to give compound 43 (10.9 mg, 17.4%) as a yellow solid. LC-MS m / z (ESI): 510.1 [MH] -. 1 H NMR (300 MHz, DMSO-d6) δ 12.09 (s, 1H), 8.21 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.57- 7.32 (m, 2H), 7.30-7.21 (m,1H), 7.14 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 5.40-5.29 (m,1H), 4.56-4.25 (m, 2H), 2.54 (s, 3H).

[0170] Example 44 Compound 44: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)ethyl dihydrogen phosphate TIFF2025535028000084.tif27170

[0171] 44-1: 2,5-dioxopyrrolidin-1-yl (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetate To a solution of (4Z)-4-[(6-chloro-7-methyl-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl](3,4-difluorophenyl)acetic acid (60 mg, 0.128 mmol, 1 equiv) and N-hydroxysuccinimide (16 mg, 0.132 mmol, 1.03 equiv, 95%) in DCM (2 mL) was added DCC (30 mg, 0.138 mmol), and the resulting mixture was stirred at room temperature for 12 h under a nitrogen atmosphere at 0 °C. The reaction was quenched with ice water and the resulting mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (3 × 5 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give 44-1 (100 mg, 99.12%) as a yellow solid. The crude product was used directly in the next step without further purification. LC-MS m / z(ESI):541.0[MH] - .

[0172] Compound 44: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)ethyl dihydrogen phosphate To a solution of 2,5-dioxopyrrolidin-1-yl-2-[(4Z)-4-[(6-chloro-1H-indol-3-yl)methylene]-2,5-dioxoimidazolidin-1-yl]-2-(3,4-difluorophenyl)acetate (100 mg, 0.130 mmol, 1 equiv) and ethanolamine phosphate (33 mg, 0.221 mmol, 1.70 equiv) in DMF (3 mL) and water (2 mL) was added TEA (33 mg, 0.308 mmol, 2.37 equiv) and stirred at 0 °C under nitrogen atmosphere for 16 h. The mixture was concentrated in vacuo, and the crude product was purified by prep-HPLC to give compound 44 (17.3 mg, 19.85%) as a yellow solid. LC-MS m / z (ESI): 569.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.52-8.46 (m, 1H), 8.21 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.55-7.21 (m, 3H), 7.14 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 5.75 (s, 1H), 3.75-3.69 (m, 2H), 3.27-3.08 (m, 2H), 2.51 (s, 3H).

[0173] Example 45 Compound 45: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione TIFF2025535028000085.tif24170

[0174] 45-1: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetaldehyde Using the method described for Compound 33, Compound 2 was used to give Compound 45-1 (205 mg, 38.2%) as a yellow solid. LC-MS m / z(ESI):411.9[MH] - .

[0175] Compound 45: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione Using the method described for Compound 37 and Compound 45-1, Compound 45 (8.9 mg, 40.3%) was obtained as a yellow solid. LC-MS m / z (ESI): 413.9 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 11.96 (s, 1H), 10.47 (s, 1H), 8.18 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.54-7.40 (m, 5H), 7.13 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 5.24-5.13 (m, 2H), 4.42-4.28 (m, 1H), 4.01-3.87 (m, 1H).

[0176] Example 46 Compound 46: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)ethyl dihydrogen phosphate TIFF2025535028000086.tif27170 Using the method described for Compound 42, Compound 45 was used to give Compound 46 (13.3 mg, 31.6%) as a yellow solid. LC-MS m / z (ESI): 496.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.21 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.51-7.37 (m, 5H), 7.13 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 5.40-5.30 (m, 1H), 4.56-4.47 (m, 1H), 4.39-4.27 (m, 1H).

[0177] Example 47 Compound 47: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)ethyl dihydrogen phosphate TIFF2025535028000087.tif31170

[0178] 47-1: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)-2-fluorobenzonitrile Using the method described for Compound 37, Compound 33 was used to give Compound 47-1 (19 mg, 39.4%) as a yellow solid. LC-MS m / z(ESI):441.0[MH] -

[0179] Compound 47: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)ethyl dihydrogen phosphate Using the method described for Compound 42, Compound 47-1 was used to give Compound 44 (2.8 mg, 17.8%) as a yellow solid. LC-MS m / z (ESI): 521.0 [MH] - . 1HNMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 10.67 (s, 1H), 8.26 (s, 1H),7.98-7.90 (m, 1H), 7.69-7.55 (m,2H), 7.53-7.40 (m, 1H), 7.25-7.17 (m, 1H), 6.84 (s, 1H), 5.57-5.45 (m, 1H), 4.65-4.46 (m, 2H), 3.40-3.30 (s, 2H).

[0180] Example 48 Compound 48: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-hydroxyethyl)acetamide TIFF2025535028000088.tif32170

[0181] 48-1: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetic acid Using the method described in I-19, I-14-3 and I-8 gave 48-1 (16 g, 52%) as a yellow solid. LC-MS m / z(ESI):442.1.0[MH] - .

[0182] Compound 48: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-hydroxyethyl)acetamide Using the method described for compound 41, 48-1 was used to give 48 (10 g, 57%) as a yellow solid. LC-MS m / z (ESI): 485.1 [MH] - . 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.52 (s, 1H), 8.20 (s, 1H), 8.07-8.02 (m, 1H), 7.64-7.62 (m, 1H), 7.48-7.40 (m, 4H), 7.20-7.13 (m, 1H), 6.82 (s, 1H), 5.76-5.73 (m, 1H), 4.63-4.55 (m, 1H), 3.44-3.30 (m, 3H), 3.25-3.12 (m, 3H).

[0183] Example 49 Compound 49: (R,Z)-4-(1-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile TIFF2025535028000089.tif30170 Compound 38 was resolved by chiral SFC according to the following conditions to obtain compound 49, column: CHIRALPAK ID-3 4.6 x 50 mm 3 um, mobile phase: Hex (0.1% DEA): EtOH = 50:50, 20 min, detection: UV 254 nm. LC-MS m / z (ESI): 404.8 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 11.98 (s, 1H), 10.53 (s, 1H), 8.20 (s, 1H), 7.88-7.79 (m, 3H), 7.64-7.58 (m, 2H), 7.52-7.47 (m, 1H), 7.20-7.11 (m, 1H), 6.85 (s, 1H), 5.32-5.23 (m, 2H), 4.38-4.28 (m, 1H), 4.07-3.97 (m, 1H).

[0184] Example 50 Compound 50: (S,Z)-4-(1-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile TIFF2025535028000090.tif29170 Compound 38 was resolved by chiral SFC according to the following conditions to obtain compound 50, column: CHIRALPAK ID-3 4.6 x 50 mm 3 um, mobile phase: Hex (0.1% DEA): EtOH = 50:50, 20 min, detection: UV 254 nm. LC-MS m / z (ESI): 404.8 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.53 (s, 1H), 8.20 (s, 1H), 7.89-7.79 (m, 3H), 7.63-7.59 (m, 2H), 7.50-7.46 (m, 1H), 7.22-7.11 (m, 1H), 6.86 (s, 1H), 5.32-5.24 (m, 2H), 4.39-4.28 (m, 1H), 4.07-3.98 (m, 1H).

[0185] Example 51 Compound 51: (R,Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)ethyl dihydrogen phosphate Using the method described for Compound 42, Compound 49 was used to give Compound 51 (17.3 mg, 53.0%) as a yellow solid. LC-MS m / z (ESI): 484.9 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.20 (s, 1H), 8.21 (s, 1H), 7.85-7.75 (m, 3H), 7.72-7.57 (m, 2H), 7.54-7.46 (m, 1H), 7.17-7.08 (m, 1H), 6.84 (s, 1H), 5.49-5.38 (m, 1H), 4.59-4.33 (m, 2H).

[0186] Example 52 Compound 52: (S,Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)ethyl dihydrogen phosphate Using the method described for Compound 42, Compound 50 was used to give Compound 52 (17.9 mg, 59.1%) as a yellow solid. LC-MS m / z (ESI): 487.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 12.19 (s, 1H), 8.21 (s, 1H), 7.85-7.75 (m, 3H), 7.72-7.57 (m, 2H), 7.54-7.46 (m, 1H), 7.17-7.07 (m, 1H), 6.84 (s, 1H), 5.49-5.38 (m, 1H), 4.52-4.34 (m, 2H).

[0187] Example 53 Compound 53: (S,Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione TIFF2025535028000093.tif27170 Compound 26 was resolved by chiral HPLC according to the following conditions to obtain compound 53, column: CHIRALPAK IG, 2 x 25 cm, mobile phase: Hex (0.5% 2M NH3-MeOH) in MeOH, 50% isocratic in 15 minutes, detection: UV 254 nm. LC-MS m / z (ESI): 415.8 [MH] - . 1 H NMR (400 MHz, DMSO-d 6)δ 11.96 (s, 1H), 10.49 (s, 1H), 8.19 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.57-7.47 (m, 2H), 7.47-7.37 (m, 1H), 7.33-7.23 (m, 1H), 7.19-7.09 (m, 1H), 6.83 (s, 1H), 5.25-5.15 (m, 2H), 4.36-4.26 (m, 1H), 3.99-3.89 (m, 1H).

[0188] Example 54 Compound 54: (R,Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione TIFF2025535028000094.tif27170 Compound 26 was resolved by chiral HPLC according to the following conditions to obtain compound 54, column: CHIRALPAK IG, 2 x 25 cm, mobile phase: Hex (0.5% 2M NH3-MeOH) in MeOH, 50% isocratic for 15 minutes, detection: UV 254 nm. LC-MS m / z (ESI): 415.8 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 11.96 (s, 1H), 10.49 (s, 1H), 8.19 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.57-7.37 (m, 3H), 7.33-7.23 (m, 1H), 7.19-7.09 (m, 1H), 6.83 (s, 1H), 5.25-5.15 (m, 2H), 4.36-4.26 (m, 1H), 3.99-3.89 (m, 1H).

[0189] Example 55 Compound 55: (Z)-(6-chloro-3-((1-(3,4-difluorobenzyl)-2,5-dioxoimidazolidin-4-ylidene)methyl)-1H-indol-1-yl)phosphonic acid TIFF2025535028000095.tif32170 To a solution of compound 1 (500 mg, 1.29 mmol, 1.00 eq) in THF (10 mL) and DCM (20 mL) was added NaH (68 mg, 2.84 mmol, 2.20 eq) and stirred at room temperature under argon for 15 min. Phosphorus oxychloride (988 mg, 6.44 mmol, 5.00 eq) was added dropwise to the mixture at 0 °C and stirred at 0 °C under argon for 3 h. The resulting mixture was concentrated under reduced pressure, and the residue was dissolved in acetonitrile (10 mL). The mixture was alkalized to pH 8 with cold saturated sodium bicarbonate and stirred at 0 °C for 30 min. The mixture was acidified with concentrated hydrochloric acid to pH 1 and stirred at 0°C for 30 min. The mixture was extracted with EtOAc (3 x 30 mL) and the combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the crude product was purified by prep-HPLC to give compound 55 (20.1 mg, 3.10%) as a yellow solid. LC-MS m / z (ESI): 466.0[MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.01 (s, 1H), 7.75-7.55 (m, 1H), 7.54-7.29 (m, 2H), 7.28-7.00 (m, 2H), 6.72 (s, 1H), 4.70 (s, 2H).

[0190] Example 56 Compound 56: (Z)-(6-chloro-3-((1-(1-(4-cyano-3-fluorophenyl)-2-((2-hydroxyethyl)amino)-2-oxyethyl)-2,5-dioxoimidazolidin-4-ylidene)methyl)-7-fluoro-1H-indol-1-yl)phosphonic acid Using the method described in TIFF2025535028000096.tif38170 for Compound 42, Compound 41 was used to give Compound 56 (6.1 mg, 15.6%) as a yellow solid. LC-MS m / z (ESI): 578.2 [MH] - . 1H NMR (300 MHz, DMSO-d6)δ 8.19 (s, 1H), 7.85-7.75 (m, 1H), 7.59 (d, J = 8.6 Hz, 1H), 7.49 (d, J = 10.4 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 7.20-7.09 (m, 1H), 6.76 (s, 1H), 4.50 (s, 1H), 3.70-3.61 (m, 2H), 3.36-3.17 (m, 2H).

[0191] Example 57 Compound 57: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(3-hydroxybicyclo[1.1.1]pent-1-yl)acetamide Using the method described in TIFF2025535028000097.tif41170 for compound 41, I-17 was used to give compound 57 (12.4 mg, 34.5%) as a yellow solid. LC-MS m / z (ESI): 527.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.51 (s, 1H), 8.68 (s, 1H), 8.20-8.19 (m, 1H), 7.67-7.64 (d, J = 8.5 Hz, 1H), 7.50-7.35 (m, 2H), 7.22-7.13 (m, 2H), 6.82 (s, 1H), 6.18 (s, 1H), 5.68 (s, 1H), 2.54 (s, 3H), 2.02 (s, 6H).

[0192] Example 58 Compound 58: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(2-hydroxyethyl)acetamide Using the method described in TIFF2025535028000098.tif38170 for compound 41, I-16 was used to give compound 58 (11.2 mg, 29.9%) as a yellow solid. LC-MS m / z (ESI): 480.0 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.61 (s, 1H), 8.30-8.14 (m, 2H), 7.83 (d, J = 7.9 Hz, 2H), 7.72-7.52 (m, 3H), 7.32-7.15 (m, 1H), 6.82 (s, 1H), 5.84 (s, 1H), 4.66-4.56 (m, 1H), 3.53-3.15 (m, 4H).

[0193] Example 59 Compound 59: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-hydroxyethyl)acetamide Using the method described in TIFF2025535028000099.tif37170 for compound 41, I-14 was used to give compound 59 (6.2 mg, 17.0%) as a yellow solid. LC-MS m / z (ESI): 491.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.59 (s, 1H), 8.25 (s, 1H), 8.09-8.00 (m, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.52-7.38 (m, 4H), 7.25-7.17 (m, 1H), 6.82 (s, 1H), 5.74 (s, 1H), 4.65-4.58 (m, 1H), 3.46-3.39 (m, 2H), 3.28-3.10 (m, 2H).

[0194] Example 60 Compound 60: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(2-hydroxyethyl)acetamide Using the method described in TIFF2025535028000100.tif30170 for compound 41, I-19 was used to give compound 60 (12 mg, 42.1%) as a yellow solid. LC-MS m / z (ESI): 476.1 [MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.54 (s, 1H), 8.24-8.13 (m, 2H), 7.87-7.78 (m, 2H), 7.68-7.55 (m, 3H), 7.15 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 5.84 (s, 1H), 4.65-4.55 (m, 1H), 3.49-3.36 (m, 2H), 3.27-3.08 (m, 2H),2.50 (s, 3H).

[0195] Example 61 Compound 61: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)-N-(2-hydroxyethyl)acetamide Using the method described for compound 41, I-18 was used to give compound 61 (14.1 mg, 29.9%) as a yellow solid. LC-MS m / z (ESI): 464.1 [M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.54 (s, 1H), 8.23-8.13 (m, 2H), 7.87-7.77 (m, 3H), 7.65-7.55 (m, 2H), 7.53-7.43 (m, 1H), 7.19-7.09 (m, 1H), 6.85 (s, 1H), 5.84 (s, 1H), 4.70-4.56 (m, 1H), 3.48-3.37 (m, 2H), 3.29-3.08 (m, 2H).

[0196] Example 62 Compound 62: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)-N-(2-hydroxyethyl)acetamide Using the method described in TIFF2025535028000102.tif34170 for compound 41, I-13 was used to give compound 62 (12.1 mg, 38.5%) as a yellow solid. LC-MS m / z (ESI): 473.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 10.50 (s, 1H), 8.18 (s, 1H), 8.05-8.03 (m, 1H), 7.82 (d, J = 8.5Hz, 1H), 7.48-7.39 (m, 5H), 7.13 (d, J = 8.5Hz, 1H), 6.83 (s, 1H), 5.73 (s, 1H), 4.61-4.57 (m, 1H), 3.44-3.39 (m, 2H), 3.25-3.13 (m, 2H).

[0197] Example 63 Compound 63: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(2-hydroxyethyl)acetamide Using the method described for compound 41, I-20 was used to give compound 63 (11 mg, 14.5%) as a yellow solid. LC-MS m / z (ESI): 475.0 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.52 (s, 1H), 8.19 (s, 1H), 8.11-8.00 (m, 1H), 7.82 (d, J = 8.6 Hz, 1H), 7.58-7.34 (m, 3H), 7.32-7.21 (m, 1H), 7.14 (d, J = 8.6, 1H), 6.85 (s, 1H), 5.75 (s, 1H), 3.48-3.35 (m, 2H), 3.31-3.05 (m, 2H).

[0198] Example 64 Compound 64: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-((4-hydroxybicyclo[2.2.2]octan-1-yl)methyl)acetamide Using the method described in TIFF2025535028000104.tif47170 for compound 41, I-17 was used to give compound 64 (19.1 mg, 47.0%) as a yellow solid. LC-MS m / z (ESI): 581.0 [MH] - . 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.53 (s, 1H), 8.28 (s, 1H), 7.97-7.94 (m, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.51-7.26 (m, 2H), 7.30-7.22 (m, 1H), 7.15 (d, J = 8.4 Hz, 1H), 6.82 (s, 1H), 5.74 (s, 1H), 4.22-4.12 (m, 1H), 2.89-2.78 (m, 2H), 2.51 (s, 3H), 1.43-1.42 (m, 12H).

[0199] Example 65 Compound 65: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)-3-hydroxypropyl dihydrogen phosphate TIFF2025535028000105.tif38170

[0200] 65-1: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(1,3-dihydroxypropan-2-yl)acetamide Using the method described for compound 41, I-17 was used to give compound 65-1 (23.4 mg, 41%) as a yellow solid. LC-MS m / z(ESI):519.05[M+H] + .

[0201] Compound 65: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)-3-hydroxypropyl dihydrogen phosphate Dichlorophosphoric anhydride (243 mg, 0.96 mmol, 5.00 eq) was added to a solution of compound 65-1 (100 mg, 0.19 mmol, 1.00 eq) in ACN (5 mL) and THF (2.5 mL) stirred at 0 °C under argon atmosphere. The resulting mixture was stirred at 0 °C for 3 h. Ice water (3 mL) was added to quench the reaction, and the mixture was neutralized to pH = 8 with saturated sodium bicarbonate. The resulting mixture was stirred at 0 °C under argon atmosphere for 30 min. The mixture was acidified to pH = 1 with concentrated hydrochloric acid. The resulting mixture was stirred at 0 °C under argon atmosphere for 1.5 h. The resulting mixture was extracted with EtOAc (3 × 30 mL), and the combined organic layer was washed with brine (30 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC to give compound 65 (4.9 mg, 4.16%) as a yellow solid. LC-MS m / z (ESI): 597.1[MH] - . 1 HNMR (300 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.57-7.32 (m, 2H), 7.31-7.11 (m, 2H), 6.82 (s, 1H), 5.78 (s, 1H), 3.88-3.83 (m, 1H), 3.82-3.65 (m, 2H), 3.46-3.30 (m, 2H), 2.57 (s, 3H).

[0202] Example 66 Compound 66: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(4-hydroxybicyclo[2.2.2]octan-1-yl)acetamide Using the method described in TIFF2025535028000106.tif42170 for compound 41, I-17 was used to give compound 66 (2.2 mg, 4.95%) as a yellow solid. LC-MS m / z (ESI): 566.9 [MH] - . 1H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.04 (s, 1H), 8.18 (s, 1H), 7.64-7.61 (m, 2H), 7.48-7.35 (m, 2H), 7.18-7.12 (m, 2H), 6.77 (s, 1H), 5.64 (s, 1H), 4.27 (s, 1H), 2.45 (s, 3H), 1.92-1.87 (m, 6H), 1.59-1.53 ​​(m, 6H).

[0203] Example 67 Compound 67: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(2-hydroxyethyl)acetamide TIFF2025535028000107.tif26170

[0204] 67-1: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)acetic acid To a solution of compound 21 (80 mg, 0.186 mmol, 1.0 equiv) in THF (3 mL) was added LiHMDS (1 mL, 1.000 mmol, 5.4 equiv) and stirred at −78 °C under a nitrogen atmosphere. The resulting mixture was stirred at −78 °C for 1 h. The mixture was then stirred for 15 min under a CO atmosphere. The resulting mixture was then stirred at −65 °C under a nitrogen atmosphere for 30 min. The reaction was quenched with a solution of HOAc (2 mL) in THF (1 mL) at −65 °C, and the reaction mixture was then added to 50 mL of cold water. The resulting mixture was extracted with EtOAc (3 × 30 mL), and the combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase high-performance chromatography to give compound 67-1 (23 mg, 27.3%) as a yellow solid.

[0205] Compound 67: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyano-3-fluorophenyl)-N-(2-hydroxyethyl)acetamide Using the method described for Compound 41, 67-1 was used to give Compound 67 (3.7 mg, 13.0%) as a yellow solid. LC-MS m / z (ESI): 496.1 [M+H] + . 1 H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1H), 10.59 (s, 1H), 8.29-8.19 (m, 2H), 7.98-7.87 (m, 1H), 7.67-7.57 (m, 2H), 7.53-7.40 (m, 1H), 7.20-7.05 (m, 1H), 6.85 (s, 1H), 5.88 (s, 1H), 3.48-3.40 (m, 2H), 3.30-3.06 (m, 2H), 2.50 (s, 3H).

[0206] Example 68 Compound 68: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-((3-hydroxybicyclo[1.1.1]pentan-1-yl)methyl)acetamide Using the method described in TIFF2025535028000108.tif46170 for compound 41, I-17 was used to give compound 68 (5.1 mg, 24.44%) as a yellow solid. LC-MS m / z (ESI): 541.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.53 (s, 1H), 8.20 (s, 1H), 8.15-8.05 (m, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.55-7.37 (m, 2H), 7.40-7.30 (m, 1H), 7.26 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 5.73 (s, 1H), 3.35-3.30 (m, 2H), 2.51 (s, 3H), 1.65 (s, 6H).

[0207] Example 69 Compound 69: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione TIFF2025535028000109.tif24170

[0208] 69-1: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetaldehyde Using the method described for Compound 33, Compound 15 was used to give Compound 69-1 (80 mg, 53.3%) as a white solid. LC-MS m / z(ESI):430.0[MH] -

[0209] Compound 69: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione Using the method described for Compound 37, Compound 69-1 was used to give Compound 69 (12.3 mg, 20.4%) as a yellow solid. LC-MS m / z (ESI): 434.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.55 (s, 1H), 8.25 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.49-7.39 (m, 4H), 7.26-7.16 (m, 1H), 6.81 (s, 1H), 5.25-5.15 (m, 2H), 4.40-4.31 (m, 1H), 3.98-3.92 (m, 1H).

[0210] Example 70 Compound 70: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione TIFF2025535028000110.tif57170

[0211] 70-1: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(4-chlorobenzyl)imidazolidine-2,4-dione Using the method described in Example 1, intermediates I-2 and I-8 were used to give compound 70-1 (800 mg, 62%) as a yellow solid.

[0212] 70-2: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)acetaldehyde Using the method described for Compound 33, Compound 70-1 was used to give Compound 70-2 (140 mg, 21.2%) as a white solid.

[0213] Compound 70: (Z)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione Using the method described for Compound 37, Compound 70-2 was used to give Compound 70 (20 mg, 30.5%) as a yellow solid. LC-MS m / z (ESI): 428.0 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 11.99 (s, 1H), 10.50 (s, 1H), 8.20 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.46-7.41 (m, 4H), 7.15 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 5.26-5.14 (m, 2H), 4.41-4.30 (m, 1H), 4.00-3.90 (m, 1H), 2.52 (s, 3H).

[0214] Example 71 Compound 71: (Z)-(6-chloro-3-((1-(4-cyano-3-fluorobenzyl)-2,5-dioxoimidazolidin-4-ylidene)methyl)-7-fluoro-1H-indol-1-yl)phosphonic acid TIFF2025535028000111.tif291700 °C, under an argon atmosphere, a solution of compound 14 (100 mg, 0.24 mmol, 1.00 eq) in THF (1 mL) was added to the stirred solution. A solution of triethyl ether (TEA) (278 mg, 2.74 mmol, 11.32 eq) in THF (1 mL) was added dropwise to the mixture at 0 °C, and the resulting mixture was stirred for an additional 2 h at 0 °C. The mixture was alkalized to pH = 8 with saturated sodium bicarbonate, and the resulting mixture was stirred for 30 min at 0 °C. The mixture was acidified to pH = 1 with concentrated hydrochloric acid, diluted with water (20 mL), and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by prep-HPLC to give Compound 71 (13.1 mg, 0.018 mmol 7.4%) as a yellow solid. LC-MS m / z (ESI): 491.0[MH] - . 1H NMR (300 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.91-7.79 (m, 1H), 7.47-7.36 (m, 1H), 7.32-7.19 (m, 2H), 7.07-6.97 (m, 1H), 6.27 (s, 1H), 4.70 (s, 2H).

[0215] Example 72 Compound 72: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(2-hydroxyethyl)acetamide TIFF2025535028000112.tif24170

[0216] 72-1: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetic acid Using the method described for compound 67-1, 10 was used to give compound 72-1 (23 mg, 47%) as a yellow solid. LC-MS m / z(ESI):448.01[MH] - . 1 H NMR (400 MHz, DMSO-d6) δ

[0217] Compound 72: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)-N-(2-hydroxyethyl)acetamide Using the method described for compound 41 and 72-1, compound 72 (10.6 mg, 45.6%) was obtained as a yellow solid. LC-MS m / z (ESI): 493.15 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 12.54 (d, J = 2.8 Hz, 1H), 10.60 (s, 1H), 8.25 (d, J = 2.8 Hz, 1H), 8.08 (t, J = 5.7 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.54-7.48 (m, 1H), 7.46-7.38 (m, 1H), 7.29-7.18 (m, 2H), 6.83 (s, 1H), 5.76 (s, 1H), 4.61 (s, 1H), 3.43-3.40 (m, 2H), 3.26-3.12 (m, 2H).

[0218] Example 73 Compound 73: (Z)-3-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)bicyclo[1.1.1]pentan-1-yl dihydrogen phosphate TIFF2025535028000113.tif51170 Using the method described for Compound 42, Compound 57 was used to give Compound 73 (6.1 mg, 16.69%) as a yellow solid. LC-MS m / z (ESI): 607.01 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.72 (s, 1H), 8.12 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.48-7.34 (m, 2H), 7.26-7.18 (s, 1H), 7.15 (d, J = 8.5 Hz, 1H), 6.82 (s, 1H), 5.69 (s, 1H), 3.60-3.50 (m, 5 H), 2.49 (s, 3H), 2.27-2.16 (m, 6H).

[0219] Example 74 Compound 74: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)propane-1,3-diyl bis(dihydrogen phosphate) TIFF2025535028000114.tif32170

[0220] 74-1: (Z)-tetra-tert-butyl(2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)propane-1,3-diyl)bis(phosphate) Under an argon atmosphere, a solution of 65-1 (240 mg, 0.46 mmol, 1.00 eq) in THF (24 mL) was added with a solution of 1H-1,2,3,4-tetrazole (259 mg, 3.70 mmol, 8.00 eq) in MeCN (9.5 mL) and [bis(tert-butoxy)phosphonyl]diethylamine (464 mg, 1.86 mmol, 4.02 eq). The resulting mixture was stirred at room temperature under an argon atmosphere for 12 h. A solution of metachloroperbenzoic acid (563 mg, 2.78 mmol, 6.00 eq, 85%) in DCM (24 mL) was added to the mixture at 0 °C, and the resulting mixture was stirred for an additional 1.5 h at 4 °C. The resulting mixture was diluted with DCM (50 mL) and washed successively with 10% NaSO, sodium bicarbonate, and brine, respectively. The organic phase was concentrated, and the residue was purified by reversed-phase high performance chromatography to give compound 74-1 (120 mg, 26.5%) as a light brown syrup. LC-MS m / z(ESI):901.3[MH] - .

[0221] Compound 74: (Z)-2-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)propane-1,3-diyl bis(dihydrogen phosphate) To a solution of 74-1 (50 mg, 0.05 mmol, 1.00 eq) in DCM (10 mL) was added TFA (5 mL, 1283 eq) dropwise at 0° C., and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo, and the crude product was purified by prep-HPLC to give compound 74 (3.8 mg, 11.2%) as a yellow solid. LC-MS m / z (ESI): 677.0[MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 11.99 (s, 1H), 8.19 (s, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.48-7.34 (m, 3H), 7.29-7.20(m,1H), 7.17-7.12 (m,1H), 6.81 (s, 1H),4.80 (s, 1H), 4.02-3.94 (m, 1H), 3.93-3.85 (m, 2H), 3.84-3.66 (m,2H), 2.52 (s, 3H).

[0222] Example 75 Compound 75: (Z)-4-(2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)bicyclo[2.2.2]octan-1-yl dihydrogen phosphate TIFF2025535028000115.tif57170 Using the method described for Compound 42, Compound 66 was used to give Compound 75 (15.2 mg, 33.7%) as a yellow solid. LC-MS m / z (ESI): 647.05 [MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.12 (s, 1H), 7.67-7.61 (m, 2H), 7.46-7.35 (m, 2H), 7.19-7.12 (m, 2H), 6.78 (s, 1H), 5.64 (s, 1H), 2.49 (s, 3H), 1.91 (s, 12H).

[0223] Example 76 Compound 76: (Z)-4-((2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetamido)methyl)bicyclo[2.2.2]octan-1-yl dihydrogen phosphate TIFF2025535028000116.tif57170 Using the method described for Compound 42, Compound 64 was used to give Compound 76 (24.7 mg, 37.6%) as a yellow solid. LC-MS m / z (ESI): 663.01 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.93 (s, 1H), 8.13-8.11 (m, 1H), 7.53-7.45 (m, 1H), 7.57-7.59 (d, J = 8.5 Hz, 1H), 7.42-7.29 (m, 2H), 7.22-7.14 (m, 1H), 7.07-7.05 (d, J = 8.5 Hz, 1H), 6.75 (s, 1H), 5.67 (s, 1H), 2.82-2.60 (m, 2H), 2.44 (s, 3H), 1.79-1.69 (m, 6H), 1.41-1.31 (m, 6H).

[0224] Example 77 Compound 77: (Z)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000117.tif73170

[0225] 77-1: 3-(4-chloro-3-fluorobenzyl)imidazolidine-2,4-dione Using the method described for compound I-1, hydantoin and 4-(bromomethyl)-1-chloro-2-fluorobenzene were used to give compound 77-1 (10 g, 88.4%) as an off-white solid. LC-MS m / z(ESI):241.0[MH] - .

[0226] 77-2: (Z)-3-(4-chloro-3-fluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 1, Compound 77-1 and I-10 were used to give Compound 77-2 (2.0 g, 91.5%) as a yellow solid. LC-MS m / z(ESI):420.0[MH] - .

[0227] 77-3: (Z)-2-(4-chloro-3-fluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde Using the method described for Compound 33, Compound 77-2 was used to give Compound 77-3 (50 mg, 8.3%) as a yellow solid. LC-MS m / z(ESI):450.0[M+H] + .

[0228] Compound 77: (Z)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 37, Compound 77-3 was used to give Compound 77 (22.4 mg, 53.1%) as a yellow solid. LC-MS m / z (ESI): 451.9[M+H] + . 1H NMR (300 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.72-7.64 (m, 1H), 7.63-7.55 (m, 1H), 7.49 (d, J = 10.6,1H), 7.32- 7.16 (m, 2H), 6.82 (s, 1H), 5.30-5.15 (m, 2H), 4.40-4.20 (m, 1H), 4.10-3.90 (m, 1H).

[0229] Example 78 Compound 78: (Z)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000118.tif71170

[0230] 78-1: (Z)-5-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-3-(4-chloro-3-fluorobenzyl)imidazolidine-2,4-dione Using the method described for Compound 1, compound 77-1 and 7-bromo-6-chloro-1H-indole-3-carbaldehyde were used to give compound 78-1 (1.9 g, 97.6%) as a yellow solid. LC-MS m / z(ESI):481.9[M+H] + .

[0231] 78-2: (Z)-2-(4-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chloro-3-fluorophenyl)acetaldehyde Using the method described for Compound 33, Compound 78-1 was used to give Compound 78-2 (110 mg, 13.5%) as a yellow solid. LC-MS m / z(ESI):509.9[M+H] + .

[0232] 78-3: (Z)-5-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione Using the method described for Compound 37, Compound 78-2 was used to give Compound 78-3 (66 mg, 57.5%) as a yellow solid. LC-MS m / z (ESI): 510.0[MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.18 (s, 1H), 10.64 (s, 1H), 8.26 (s, 1H), 7.86 (d, J = 8.5 Hz, 1H), 7.60-7.58 (m, 1H), 7.48 (d, J = 10.6, 1H), 7.34-7.20 (m, 2H), 6.81 (s, 1H), 5.30-5.10 (m, 2H), 4.40-4.20 (m, 1H), 4.05-3.90 (m, 1H).

[0233] Compound 78: (Z)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-methyl-1H-indol-3-yl)methylene)imidazolidine-2,4-dione To a stirred mixture of compound 78-3 (32 mg, 0.062 mmol, 1.00 eq) and Pd(dppf)Cl2 (8 mg, 0.01 mmol, 0.18 eq) in dioxane (3 mL) and HO (0.3 mL) was added trimethyl-1,3,5,2,4,6-trioxatripyridinone (350 μL, 1.23 mmol, 19.64 eq) and potassium carbonate (51 mg, 0.5 mg). The mixture was stirred at 120 °C under argon for 12 h. The mixture was cooled to room temperature and diluted with EtOAc (50 mL). The mixture was washed with brine (5 × 30 mL) and dried over anhydrous Na2SO4. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC to give compound 78 (3.1 mg, 9.9%) as a yellow solid. LC-MS m / z (ESI): 448.2[M+H] + .1 H NMR (300 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.53 (s, 1H), 8.21 (s,1H), 7.72-7.40 (m, 3H), 7.27 (d, J = 8.3,1H), 7.16 (d, J = 8.4 Hz, 1H), 6.84 (s, 1H), 5.30-5.16 (m, 2H), 4.48-4.23 (m, 1H), 4.10-3.90 (m, 1H), 2.45 (s, 3H).

[0234] Example 79 Compound 79: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione TIFF2025535028000119.tif71170

[0235] 79-1: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(4-chloro-3-fluorobenzyl)imidazolidine-2,4-dione Using the method described for Compound 1, Compound 77-1 and 6-chloro-1H-indole-3-carbaldehyde were used to give Compound 79-1 (2.1 g, 90.3%) as a yellow solid. LC-MS m / z(ESI):402.0[MH] - .

[0236] 79-2: (Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chloro-3-fluorophenyl)acetaldehyde Using the method described for Compound 33, Compound 79-1 was used to give Compound 79-2 (210 mg, 36.1%) as a yellow solid. LC-MS m / z(ESI):432.0[M+H] + .

[0237] 79: (Z)-5-((6-chloro-1H-indol-3-yl)methylene)-3-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione Using the method described for Compound 37 and Compound 79-2, Compound 79 (40.2 mg, 39.2%) was obtained as a yellow solid. LC-MS m / z (ESI): 431.8[MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 11.97 (s, 1H), 10.50 (s, 1H), 8.19 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.65-7.55 (m, 1H), 7.54-7.45 (m, 2H), 7.27 (d, J = 8.3, 1H), 7.14 (d, J = 8.5, 1H), 6.85 (s, 1H), 5.30-5.15 (m, 2H), 4.40-4.18 (m, 1H), 4.10-3.90 (m, 1H).

[0238] Example 84 Compound 84: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione TIFF2025535028000120.tif69170

[0239] 84-1: 3-(4-fluorobenzyl)imidazolidine-2,4-dione Using the method described for compound I-1, hydantoin and 4-(bromomethyl)-1,2-difluorobenzene were used to give compound 84-1 (4.12 g, 77.9%) as a white solid. LC-MS m / z(ESI):207.0[MH] - .

[0240] 84-2: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(4-fluorobenzyl)imidazolidine-2,4-dione Using the method described for Compound 1, Compound 84-1 and I-10 were used to give Compound 84-2 (1.1 g, 79.7%) as a yellow solid. LC-MS m / z(ESI):386.0[MH] - .

[0241] 84-3: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-fluorophenyl)acetaldehyde Using the method described for Compound 33, Compound 84-2 was used to give Compound 84-3 (340 mg, 61.45%) as a yellow solid. LC-MS m / z(ESI):414.0[MH] - .

[0242] Compound 84: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-fluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione Using the method described for Compound 37, Compound 84-3 was used to give Compound 84 (28.0 mg, 28.2%) as a yellow solid. LC-MS m / z (ESI): 418.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.71-7.61 (m, 1H), 7.60-7.35 (m, 2H), 7.34-7.10 (m, 3H), 6.81 (s, 1H), 5.25-5.15 (m, 2H), 4.50-4.30 (m, 1H), 3.97- 3.88 (m, 1H).

[0243] Example 85 Compound 85: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile TIFF2025535028000121.tif25170

[0244] 85-1: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-oxoethyl)benzonitrile Using the method described for Compound 33, Compound 16 was used to give Compound 85-1 (120 mg, 23.0%) as a brown solid. LC-MS m / z(ESI):423.1[M+H] + .

[0245] Compound 85: (Z)-4-(1-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile Using the method described for Compound 37 and Compound 85-1, Compound 85 (38.1 mg, 31.1%) was obtained as a yellow solid. LC-MS m / z (ESI): 423.1[MH] - . 1 H NMR (300 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.59 (s, 1H), 8.26 (s, 1H), 7.89-7.79 (m,2H), 7.71- 7.61 (m, 3H), 7.24-7.19 (m, 1H), 6.83 (s, 1H), 5.31-5.24 (m,2H), 4.37-4.29 (m, 1H), 4.06-3.99 (m,1H).

[0246] Example 86 Compound 86: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione TIFF2025535028000122.tif25170

[0247] 86-1: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)acetaldehyde Using the method described for Compound 33, Compound 10 was used to give Compound 86-1 (240 mg, 33.5%) as a brown solid. LC-MS m / z(ESI):434.0[M+H] + .

[0248] Compound 86: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(3,4-difluorophenyl)-2-hydroxyethyl)imidazolidine-2,4-dione Using the method described for Compound 37 and Compound 86-1, Compound 86 (90 mg, 46.4%) was obtained as a yellow solid. LC-MS m / z (ESI): 434.1[MH] - . 1 H NMR (400 MHz, DMSO-d6) δ12.52 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.57-7.38 (m, 2H), 7.30-7.17 (m, 2H), 6.82 (s, 1H), 5.25- 5.16 (m, 2H), 4.40-4.25 (m, 1H), 4.00-3.90 (m, 1H).

[0249] Example 88 Compound 88: (Z)-4-(1-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile TIFF2025535028000123.tif43170

[0250] 88-1: 7-Bromo-6-chloro-1H-indole-3-carbaldehyde Using the method described for compound I-10, 7-bromo-6-chloro-1H-indole was used to give compound 88-1 (4.45 g, 68.9%) as a light brown solid. LC-MS m / z(ESI):257.9[M+H] + .

[0251] 88-2: (Z)-4-((4-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl)benzonitrile Using the method described for Compound 1, Compound 88-1 was used to give Compound 88-2 (5.0 g, 96.9%) as a yellow solid. LC-MS m / z(ESI):454.9[M+H] + .

[0252] 88-3: (Z)-4-(1-(4-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-oxoethyl)benzonitrile Using the method described for Compound 33, Compound 88-2 was used to give Compound 88-3 (320 mg, 14.9%) as a brown solid. LC-MS m / z(ESI):482.9[M+H] + .

[0253] 88-4: (Z)-4-(1-(4-((7-bromo-6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile Using the method described for Compound 37, Compound 88-3 was used to give Compound 88-4 (120 mg, 46.7%) as a yellow solid. LC-MS m / z(ESI):485.0[M+H] + .

[0254] Compound 88: (Z)-4-(1-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile To a stirred mixture of compound 88-4 (120 mg, 0.25 mmol, 1.00 eq) and trimethyl-1,3,5,2,4,6-trioxatriphenyl (186 mg, 1.48 mmol, 6.00 eq) in 1,4-dioxane (12 mL) and water (0.3 mL) was added Pd(dppf)Cl2 (18.1 mg, 0.025 mmol, 0.10 eq) and K2CO3 (204 mg, 1.48 mmol, 6.00 eq). The resulting mixture was stirred at 120 °C under argon for 6 h. The mixture was cooled to room temperature and quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with brine (3 × 30 mL) and dried over anhydrous Na2SO4. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give compound 88 (19.3 mg, 18.2%) as a yellow solid. LC-MS m / z (ESI): 421.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.55 (s, 1H), 8.21 (s, 1H), 7.85-7.83 (m, 2H), 7.65-7.60 (m,3H), 7.15 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 5.30- 5.26 (m, 1H), 4.35-4.30 (m,1H), 4.04-3.99 (m,1H), 2.50 (s, 3H).

[0255] Example 92 Compound 92: (Z)-2-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-cyanophenyl)ethyl dihydrogen phosphate TIFF2025535028000124.tif35170 Using the method described for Compound 42, Compound 88 was used to give Compound 92 (44.7 mg, 24.6%) as a yellow solid. LC-MS m / z (ESI): 499.1[MH] - . 1H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H),8.23 (s, 1H), 7.85-7.75 (m, 2H), 7.69-7.56 (m,3 H), 7.13 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 5.55-5.39 (m, 1H), 4.54-4.36 (m, 2H), 2.52 (s, 3H).

[0256] Example 93 Compound 93: (Z)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(4-chlorophenyl)ethyl dihydrogen phosphate TIFF2025535028000125.tif42170 Using the method described for Compound 42, Compound 69 was used to give Compound 93 (232.5 mg, 45.0%) as a yellow solid. LC-MS m / z (ESI): 511.9[MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.63 (s, 1H), 8.26 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.52-7.38 (m, 4H), 7.30-7.15 (m, 1H), 6.84 (s, 1H),5.50- 5.32 (m, 1H), 4.90-4.67 (m,1H), 4.55-4.36 (m, 1H).

[0257] Example 94 Compound 94: (S,Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)ethyl dihydrogen phosphate TIFF2025535028000126.tif26170 Using the method described for Compound 42, Compound 53 was used to give Compound 94 (16.4 mg, 0.032 mmol) as a yellow solid. LC-MS m / z (ESI): 498.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.19 (s, 1H), 7.83-7.77 (d, J = 8.4 Hz, 1H), 7.52-7.47 (m, 2H), 7.54 -7.45 (m, 1H), 7.29-7.25 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.86 (s, 1H), 5.40-5.31 (m, 1H), 4.52-4.47 (m, 2H).

[0258] Example 95 Compound 95: (R,Z)-2-(4-((6-chloro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-(3,4-difluorophenyl)ethyl dihydrogen phosphate TIFF2025535028000127.tif29170 Using the method described for Compound 42, Compound 54 was used to give Compound 95 (21.2 mg, 0.042 mmol) as a yellow solid. LC-MS m / z (ESI): 498.1 [M+H] + . 1 H NMR (400 MHz, DMSO- d6) δ 12.04 (s, 1H), 8.19 (s, 1H), 7.83-7.77 (d, J = 8.4 Hz, 1H), 7.52-7.47 (m, 2H), 7.54 -7.45 (m, 1H), 7.29-7.25 (m, 1H), 7.13 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 5.40 - 5.31 (m, 1H), 4.52-4.47 (m, 2H).

[0259] Example 96 Compound 96: (R,Z)-4-(1-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile Compound 88 (60 mg, 0.14 mmol, 1.0 equiv) was separated using a chiral column, CHIRALPAKIG-34.6*50 mm3 um, mobile phase A: MtBE (0.1% DEA): EtOH = 93:7, flow rate: 1.0 mL / min mL / min, gradient: isocratic, injection volume: 1.0 mL. Finally, compound 96 (17.0 mg, 29.1%) was obtained as a yellow solid. LC-MS m / z (ESI): 419.1[MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.55 (s, 1H), 8.24-8.19 (m, 1H), 7.88-7.81 (m, 2H), 7.67-7.58 (m, 3H), 7.19-7.12 (m, 1H), 6.84 (s, 1H), 5.32-5.22 (m, 2H), 4.39-4.28 (m, 1H), 4.07-3.97 (m, 1H), 2.52 (s, 3H).

[0260] Example 97 Compound 97: (S,Z)-4-(1-(4-((6-chloro-7-methyl-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-2-hydroxyethyl)benzonitrile Compound 88 (60 mg, 0.14 mmol, 1.0 equiv) was separated using a chiral column, CHIRALPAKIG-34.6*50 mm3 um, mobile phase A: MtBE (0.1% DEA): EtOH = 93:7, flow rate: 1.0 mL / min mL / min, gradient: isocratic, injection volume: 1.0 mL. Finally, compound 97 (23.3 mg, 39.8%) was obtained as a yellow solid. LC-MS m / z (ESI): 419.1[MH] - . 1H NMR (400 MHz, DMSO-d6) δ 12.00 (s, 1H), 10.55 (s, 1H), 8.24-8.19 (m, 1H), 7.88-7.81 (m, 2H), 7.67-7.58 (m, 3H), 7.19-7.12 (m, 1H), 6.84 (s, 1H), 5.32-5.22 (m, 2H), 4.39-4.28 (m, 1H), 4.07-3.97 (m, 1H), 2.52 (s, 3H).

[0261] Example 98 Compound 98: (Z)-3-(4-chloro-2-fluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000130.tif35170

[0262] 98-1: 3-(4-chloro-2-fluorobenzyl)imidazolidine-2,4-dione Using the method described for compound I-1, 1-(bromomethyl)-4-chloro-2-fluorobenzene and hydantoin was used to give compound 98-1 (2.2 g, 66.1%) as an off-white solid. LC-MS m / z(ESI):241.0[MH] - .

[0263] Compound 98: (Z)-3-(4-chloro-2-fluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 1, 98-1 and I-10 were used to give Compound 98 (36.3 mg, 16.2%) as a pale yellow solid. LC-MS m / z (ESI): 420.1[MH] - . 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.60 (s, 1H), 8.26 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.47-7.44 (m, 1H), 7.36-7.34 (m, 1H),7.30-7.27 (m, 1H), 7.25-7.20(m,1H), 6.85 (s, 1H), 4.72 (s, 2H).

[0264] Example 99 Compound 99: (Z)-3-(1-(4-chloro-2-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000131.tif29170

[0265] 99-1: (Z)-2-(4-chloro-2-fluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde Using the method described for Compound 33, Compound 98 was used to give Compound 99-1 (120 mg, 33.1%) as a brown solid. LC-MS m / z(ESI):450.0[M+H] + .

[0266] Compound 99: (Z)-3-(1-(4-chloro-2-fluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 37 and Compound 99-1, Compound 99 (32.5 mg, 30.8%) was obtained as a yellow solid. LC-MS m / z (ESI): 450.1[MH] - . 1H NMR (400 MHz, DMSO-d6) δ 12.53 (s, 1H), 10.55 (s, 1H), 8.24 (s, 1H), 7.67-7.62 (m,2H), 7.46-7.44 (m,1H), 7.34-7.32 (m, 1H), 7.23-7.21 (m, 1H), 6.80 (s, 1H),5.45- 5.41 (m, 1H),5.30- 5.27 (m, 1H),4.40- 4.20 (m, 1H), 3.99-3.81 (m, 1H).

[0267] Example 100 Compound 100: (Z)-3-(4-chloro-2,5-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000132.tif37170

[0268] 100-1: 3-(4-chloro-2,5-difluorobenzyl)imidazolidine-2,4-dione Using the method described for compound I-1, hydantoin and 1-(bromomethyl)-4-chloro-2,5-difluorobenzene were used to give compound 100-1 (1.8 g, 78.5%) as a pale yellow solid. LC-MS m / z(ESI):259.0[MH] - .

[0269] Compound 100: (Z)-3-(4-chloro-2,5-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 1, Compound 100-1 and I-10 were used to give Compound 100 (45.6 mg, 19.5%) as a pale yellow solid. LC-MS m / z (ESI): 438.0[MH] - . 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.60 (s, 1H), 8.26 (s, 1H), 7.69-7.66 (m, 2H), 7.50-7.42 (m, 1H), 7.28-7.17 (m, 1H), 6.85 (s, 1H), 4.72 (s, 2H).

[0270] Example 101 Compound 101: (Z)-3-(1-(4-chloro-2,5-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000133.tif30170

[0271] 101-1: (Z)-2-(4-chloro-2,5-difluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde Using the method described for Compound 33, Compound 100 was used to give Compound 101-1 (200 mg, 56.0%) as a brown solid. LC-MS m / z(ESI):466.0[MH] - .

[0272] Compound 101: (Z)-3-(1-(4-chloro-2,5-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 37 and Compound 101-1, Compound 101 (24.3 mg, 14.2%) was obtained as a yellow solid. LC-MS m / z (ESI): 468.1[MH] - . 1H NMR (300 MHz, DMSO-d6) δ12.55 (s, 1H), 10.56 (s, 1H),δ 8.24 (s, 1H), 7.70-7.63 (m, 3H), 7.23-7.18 (m, 1H), 6.81 (s, 1H), 5.44-5.39 (m,1H), 5.34-5.20 (m, 1H), 4.28-4.19 (m, 1H), 3.96-3.85 (m, 1H).

[0273] Example 102 Compound 102: (Z)-3-(4-chloro-2,6-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000134.tif32170

[0274] 102-1: 3-(4-chloro-2,6-difluorobenzyl)imidazolidine-2,4-dione Using the method described for compound I-1, compound 102-1 (1.3 g, 56.9%) was obtained as a white solid using hydantoin and 2-(bromomethyl)-5-chloro-1,3-difluorobenzene. LC-MS m / z(ESI):259.0[MH] - .

[0275] Compound 102: (Z)-3-(4-chloro-2,6-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 1, Compound 102-1 and I-10 were used to give Compound 102 (41.4 mg, 18.3%) as a pale yellow solid. LC-MS m / z (ESI): 438.0[MH] - . 1H NMR (400 MHz, DMSO-d6) 12.52 (s, 1H), 10.50 (s, 1H), 8.23 ​​(s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 7.42-7.32 (m, 2H), 7.22-7.18 (m, 1H), 6.80 (s, 1H), 4.76 (s, 2H).

[0276] (Example 103) Compound 103: (Z)-3-(1-(4-chloro-2,6-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000135.tif29170

[0277] 103-1: (Z)-2-(4-chloro-2,6-difluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde Using the method described for Compound 33, Compound 102 was used to give Compound 103-1 (160 mg, 36.8%) as a brown solid. LC-MS m / z(ESI):468.2[M+H] + .

[0278] Compound 103: (Z)-3-(1-(4-chloro-2,6-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 37 and Compound 103-1, Compound 103 (23.3 mg, 12.48%) was obtained as a pale yellow solid. LC-MS m / z (ESI): 468.1[MH] - . 1H NMR (300 MHz, DMSO-d6) δ 12.51 (s, 1H), 10.48 (s, 1H), 8.22 (s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.42 -7.29 (m, 2H), 7.23-7.10 (m,1H), 6.77 (s, 1H), 5.50 -5.30(m, 1H), 5.28-5.10 (m, 1H), 4.50-4.15 (m, 1H), 4.10-3.90 (m, 1H)

[0279] Example 104 Compound 104: (Z)-3-(4-chloro-2,3-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000136.tif35170

[0280] 104-1: 3-(4-chloro-2,3-difluorobenzyl)imidazolidine-2,4-dione Using the method described for compound I-1, compound 104-1 (0.9 g, 3.3 mmol, 79.0%) was obtained as a white solid using hydantoin and 1-(bromomethyl)-4-chloro-2,3-difluorobenzene. LC-MS m / z(ESI):259.0[MH] - .

[0281] Compound 104: (Z)-3-(4-chloro-2,3-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 1, Compound 104-1 and I-10 were used to give Compound 104 (41.6 mg, 16.2%) as a yellow solid. LC-MS m / z (ESI): 438.0[MH] - . 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.59 (s, 1H), 8.25 (s, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.52 -7.38 (m, 1H), 7.28-7.16 (m, 2H), 6.86 (s, 1H), 4.77 (s, 2H)

[0282] Example 105 Compound 105: (Z)-3-(1-(4-chloro-2,3-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000137.tif24170

[0283] 105-1: (Z)-2-(4-chloro-2,3-difluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde Using the method described for Compound 33, Compound 104 was used to give Compound 105-1 (257 mg, 55.3%) as a brown solid. LC-MS m / z(ESI):468.0[M+H] + .

[0284] Compound 105: (Z)-3-(1-(4-chloro-2,3-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 37 and Compound 105-1, Compound 105 (20.5 mg, 22.8%) was obtained as a pale yellow solid. LC-MS m / z (ESI): 468.1[MH] - . 1H NMR (400 MHz, DMSO-d6) δ12.54 (s, 1H), 10.58 (s, 1H), 8.24 (s, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.55-7.36 (m,2H), 7.34-7.11 (m,1H), 6.81 (s, 1H), 5.61-5.40 (m, 1H), 5.39-5.20 (m,1H), 4.50-4.20 (m, 1H),4.05- 3.85 (m,1H).

[0285] Example 106 Compound 106: (Z)-3-(4-chloro-3,5-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000138.tif33170

[0286] 106-1: 3-(4-chloro-3,5-difluorobenzyl)imidazolidine-2,4-dione Using the method described for compound I-1, compound 106-1 (1.82 g, 83.2%) was obtained as a white solid using hydantoin and 5-(bromomethyl)-2-chloro-1,3-difluorobenzene. LC-MS m / z(ESI):259.0[MH] - .

[0287] Compound 106: (Z)-3-(4-chloro-3,5-difluorobenzyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 1, Compound 106-1 and I-10 were used to give Compound 106 (38.0 mg, 16.5%) as a gray solid. LC-MS m / z (ESI): 438.0[MH] - . 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H), 10.59 (s, 1H), 8.27 (s, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.40-7.29 (m, 2H), 7.28-7.10 (m,1 H), 6.86 (s, 1H), 4.72 (s, 2H).

[0288] (Example 107) Compound 107: (Z)-3-(1-(4-chloro-3,5-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione TIFF2025535028000139.tif26170

[0289] 107-1: (Z)-2-(4-chloro-3,5-difluorophenyl)-2-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)acetaldehyde Using the method described for Compound 33, Compound 106 was used to give Compound 107-1 (180 mg, 34.02%) as a brown solid. LC-MS m / z(ESI):466.0[MH] - .

[0290] Compound 107: (Z)-3-(1-(4-chloro-3,5-difluorophenyl)-2-hydroxyethyl)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)imidazolidine-2,4-dione Using the method described for Compound 37 and Compound 107-1, Compound 107 (31.1 mg, 24.7%) was obtained as a yellow solid. LC-MS m / z (ESI): 468.1[MH] - . 1H NMR (300 MHz, DMSO-d6) δ11.90-10.50 (br, 1H), 8.26 (s, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.45-7.35 (m, 2H), 7.30-7.16 (m, 1H), 6.82 (s, 1H), 5.45- 5.17 (m, 2H), 4.4- 4.12 (m, 1H), 4.10-3.85 (m, 1H).

[0291] Example 108 Compound 108: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-3-hydroxypropyl)imidazolidine-2,4-dione TIFF2025535028000140.tif25170

[0292] 108-1: tert-butyl(3-(4-chlorophenyl)propoxy)dimethylsilane To a solution of 3-(4-chlorophenyl)propan-1-ol (5 g, 29.30 mmol, 1.00 eq) and DMAP (0.36 g, 2.95 mmol, 0.10 eq) in DCM (50 mL) was added TEA (8.9 g, 87.95 mmol, 3.00 eq) in portions, and the mixture was stirred at room temperature under nitrogen for 16 h. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EA (10:1) to give compound 108-1 (6.6 g, 78.5%) as a colorless liquid.

[0293] 108-2: (3-bromo-3-(4-chlorophenyl)propoxy)(tert-butyl)dimethylsilane To a stirred mixture of 108-1 (6.6 g, 23.17 mmol, 1.00 eq) and NBS (4.12 g, 23.15 mmol, 1.00 eq) in CCl4 (120 mL) was added benzoyl peroxide (168 mg, 0.70 mmol, 0.03 eq) at room temperature, and the resulting mixture was stirred for 3 h. The mixture was cooled to room temperature. The resulting mixture was filtered, and the filter cake was washed with CCl4 (2 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (15:1) to give compound 108-2 (2.7 g, 25.8%) as a light brown liquid.

[0294] 108-3: 3-(3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorophenyl)propyl)imidazolidine-2,4-dione To a mixture of hydantoin (2.23 g, 22.28 mmol, 3.00 eq) and K2CO3 (1.54 g, 11.13 mmol, 1.50 eq) in DMF (54 mL) was added 108-2 (2.7 g, 7.42 mmol, 1.00 eq) at room temperature. The resulting mixture was stirred at 60 °C under a nitrogen atmosphere for 16 h. The mixture was cooled to room temperature and quenched by the addition of cold saturated aqueous ammonium chloride solution (200 mL). The resulting mixture was extracted with ethyl acetate (3 × 150 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase high-performance chromatography to give compound 108-3 (1.5 g, 47.0%) as a pale yellow syrup. LC-MS m / z(ESI):383.1[M+H] + .

[0295] Compound 108: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-3-hydroxypropyl)imidazolidine-2,4-dione To a stirred solution of 108-3 (186 mg, 0.49 mmol, 1.20 eq) and 6-chloro-7-fluoro-1H-indole-3-carbaldehyde (80 mg, 0.41 mmol, 1.00 eq) in ethanol (10 mL) at room temperature, HOAc (122 mg, 2.03 mmol, 5.00 eq) was added dropwise. The resulting mixture was stirred at 100 °C under an argon atmosphere for 16 min, and then cooled to room temperature. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to obtain a brown syrup-like crude product. The residue was dissolved in methanol (2 mL). To the above mixture was added dropwise a solution of HCl (g) in methanol (0.51 mL, 2.04 mmol, 5.04 eq) at room temperature. The resulting mixture was stirred for an additional 2 h at room temperature, and then concentrated in vacuo. The crude product (50 mg) was purified by HPLC to give compound 108 (12.5 mg, 6.11%) as a yellow solid. LC-MS m / z (ESI): 446.0[MH] - . 1 H NMR (400 MHz, DMSO-d6) δ 8.23 ​​(s, 1H), 7.65 (d, J = 8.6 Hz, 1H), 7.51-7.40 (m, 4H), 7.30-7.16 (m, 1H), 6.79 (s, 1H), 5.50-5.22 (m, J = 9.4, 6.4 Hz, 1H), 4.64 (s, 1H), 3.46-3.42 (m, 2H), 2.71- 2.56 (m, 1H), 2.34-2.22(m, 1H).

[0296] Example 109 Compound 109: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-4-hydroxybutyl)imidazolidine-2,4-dione TIFF2025535028000141.tif64170

[0297] 109-1: (Z)-4-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-4-(4-chlorophenyl)butyric acid tert-butyl ester To a stirred solution of compound 15 (420 mg, 1.04 mmol, 1.00 eq) and acrylic acid tert-butyl ester (2.66 g, 20.78 mmol, 20.00 eq) in THF (140 mL) was added n-BuLi (4.2 mL, 10.50 mmol, 10.11 eq) dropwise at −78 °C under argon. The resulting mixture was stirred at −78 °C under argon for 1 h. The reaction was quenched with a solution of acetic acid in THF at −82 °C. The mixture was warmed to −30 °C and added to 300 mL of water. The resulting mixture was extracted with ethyl acetate (1 × 300 mL). The combined organic layer was washed with brine (2 × 150 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase high-performance chromatography to give compound 109-1 (305 mg, 53.2%) as a pale yellow solid. LC-MS m / z(ESI):530.2[MH] - .

[0298] 109-2: (Z)-4-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-4-(4-chlorophenyl)butyric acid To a stirred solution of 109-1 (300 mg, 0.56 mmol, 1.00 eq) in DCM (20 mL) was added TFA (3 mL) dropwise at room temperature, and the resulting mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo, and the residue was purified by reverse-phase high-performance chromatography to give compound 109-2 (135 mg, 49.8%) as a yellow solid. LC-MS m / z(ESI):476.1[M+H] + .

[0299] Example 109 Compound 109: (Z)-5-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-3-(1-(4-chlorophenyl)-4-hydroxybutyl)imidazolidine-2,4-dione To a mixture of 109-2 (105 mg, 0.22 mmol, 1.00 eq) and amine borane (13.7 mg, 0.44 mmol, 2.01 eq) in diethyl ether (2.8 mL) was added TiCl4 (8.4 mg, 0.04 mmol, 0.20 eq) dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The reaction was quenched by the addition of saturated ammonium chloride solution (20 mL) at room temperature. The resulting mixture was extracted with ethyl acetate (4 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by HPLC to give compound 109 (50.6 mg, 48.9%) as a yellow solid. LC-MS m / z (ESI): 460.0[MH] - . 1 H NMR (400 MHz, DMSO-d6) δ12.04 br, 1H), 10.63 (br,1H), 8.24 (s, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.55-7.35 (m, 4H), 7.30-7.10 (m, 1H), 6.81 (s, 1H), 5.22-5.10 (m, 1H), 4.55-4.31 (m, 1H), 3.5-3.41 (m, 2H), 2.49-2.37 (m, 1H),2.30- 2.10 (m, 1H), 1.51-1.30 (m, 2H)

[0300] Compound 110: (Z)-3-(4-((6-chloro-7-fluoro-1H-indol-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)-3-(4-chlorophenyl)propyl dihydrogen phosphate TIFF2025535028000142.tif411700 °C under nitrogen atmosphere, a solution of compound 108 (150 mg, 0.34 mmol, 1.00 eq) in THF (9 mL) was stirred and added with phosphoric acid chloride (513 mg, 3.35 mmol, 10.00 eq). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 7 h. The reaction was quenched with saturated NaHCO3 solution at room temperature, and the resulting mixture was stirred for 30 min. The mixture was acidified to pH = 2 with HCl (aq), extracted with EtOAc (3 x 50 mL), and the combined organic layers were washed with brine (2 x 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by reverse-phase high-performance chromatography to give compound 110 (39.2 mg, 21.9%) as a yellow solid. LC-MS m / z (ESI): 528.0[M+H] + . 1 H NMR (300 MHz, DMSO-d6)) δ 8.24 (s, 1H), 7.63 (d, J = 8.6 Hz, 1H), 7.51-7.35 (m, 4H), 7.25-7.11 (m, 1H), 6.79 (s, 1H), 5.45-5.21 (m, 1H), 3.70-3.60(m,2H),2.70 - 2.51 (m,1H),2.45-2.40(m,1H).

[0301] Test example 1: Compound activity measurement CellTiter Glo is used to test cell growth inhibition by candidate compounds. Candidate compounds were dissolved in DMSO to an initial concentration of 50 mM, diluted three-fold, and transferred to a 384-well storage plate. Using an Echo 520 instrument, the compounds in the storage plate were dropped into a 96-well cell culture plate (Corning 3610) at a volume of 100 nL per well, diluted three-fold, and replicated in duplicate. Hematologic tumor cells RS4;11 were seeded into a 96-well cell culture plate using a Multidrop at a density of 3,000 cells per well in a volume of 100 μL. The final compound concentrations ranged from 50 μM to 0.01 μM, with nine concentration gradients, and the final DMSO concentration was 0.1%. The cells and compounds were incubated in a cell culture incubator at 37°C for 72 hours, after which 100 μL of CellTiter-Glo Luminescent Cell Viability Assay reagent was added per well, mixed thoroughly, and incubated at room temperature for 10 minutes. Data were then read using an Envision scanner. The positive control was a sample treated with 50 μM of a positive compound, and the negative control was a sample treated with 100 nL of DMSO. The calculation formula was (sample reading - positive control reading) / (negative control reading - positive control reading) * 100%, using a four-parameter equation to calculate IC 50 Calculate the compound cellular activity IC 50 The interval is A≦1μM, 1<B≦10μM、C> It is 10 μM.

[0302] HTRF experiment: An experiment to detect whether candidate compounds inhibit the binding of MDM2-p53 and MDMX-p53 proteins, respectively. Candidate compounds were dissolved in DMSO to an initial concentration of 50 mM, diluted 3-fold, and transferred to a 384-well storage plate. Using an Echo 520 instrument, compounds from the storage plate were added dropwise to a 384-well plate (PE 6008280) at 100 nL per well, diluted 3-fold, and replicated in duplicate. Proteins and / or polypeptides were diluted with HTRF buffer (1X PBS pH 7.4, 0.1% BSA, and 1 mM DTT) as follows: The MDM2-p53 reaction system contained 10 nM purified GST-MDM2 (2-138 aa) protein and 5 nM HIS-p53 (2-312 aa) protein. The MDMX reaction system contained 5 nM purified GST-MDMX (2-134 aa) protein and 100 nM WT HIS-p53 peptide fragment (Rui Biotech). The negative control proteins for the MDM2-p53 binding inhibition experiment were 10 nM GST protein and 5 nM HIS-p53 (2-312 aa) protein, and the negative control proteins for the MDMX-p53 binding inhibition experiment were 10 nM GST protein and 100 nM WT HIS-p53 peptide fragment. The positive controls for both binding experiments were DMSO-treated. Using a multidrop filter, 10 μL of each of the above protein and / or polypeptide reaction mixtures was added to a 384-well plate containing the compounds, with final compound concentrations ranging from 250 μM to 0.05 nM. The compounds were diluted 3-fold to 15 concentrations, replicated in duplicate, with a final DMSO concentration of 1%. The mixture was incubated at room temperature for 1 hour. Add 400-fold diluted Anti 6HIS-Tb cryptate Gold (Cisbio 61HI2TLF) and Anti GST-XL665 (Cisbio 61GSTXLF) to the buffer solution and mix thoroughly. Add 10 μL of the antibody mixture to a 384-well plate using a multidrop filter. Incubate at room temperature for 1 hour. Read data using an Envision scanner. Laser excitation wavelength: 340 nM, emission wavelength: 665 nM, emission wavelength: 615 nM. The 665 / 615 ratio was calculated. Siremadlin (NVP-HDM201; MCE HY-18658), a known MDM2-p53 binding inhibitor, was used as a positive control.100nL DMSO treatment is the negative control. The formula is (analyte reading - positive control reading) / (negative control reading - positive control reading)*100%, and the IC50 is calculated using a four-parameter formula. Compound protein binding IC. 50 The interval is A ≤ 10 nM, 10<B≦100nM、C> It is 100nM. TIFF2025535028000143.tif252170TIFF2025535028000144.tif246170TIFF2025535028000145.tif246170TIFF2025535028000146.tif27170

[0303] Test example 2: Solubility test 1) Preparation of stock solutions Test substances and the control drug progesterone are prepared as 10 mM stock solutions in DMSO.

[0304] 2) Solubility measurement 30 μL of 10 mM test substance and control progesterone stock solutions were added to the corresponding vials in a 96-well sample plate in the specified order. Then, 970 μL of pH 7.4 phosphate buffer was added to the corresponding vials in the sample plate. Two parallel experiments were performed. Each vial was fitted with a stir bar and capped with a polytetrafluoroethylene / silicone stopper. The sample tray was then placed in an Eppendorf Comfort Thermomixer and shaken at 1100 rpm for 2 hours at 25°C. After 2 hours, the stoppers were removed, the stir bars were pulled with a large magnet, and the samples were then transferred from the sample plate to a filter plate. Negative pressure was generated using a vacuum pump to filter the samples. 5 μL of the filtrate was transferred to a new sample plate, followed by the addition of 5 μL of DMSO and 490 μL of acetonitrile / water (1:1 in v / v). The dilution ratio may be adjusted depending on the solubility of the test substance or the strength of the response signal in the liquid analysis method.

[0305] 3) Preparation of standard solutions 15 μL of the 10 mM DMSO stock solution was transferred to an empty plate, and 485 μL of DMSO was added to obtain a 300 μM standard solution. 5 μL of the 300 μM standard solution was transferred to another empty plate, and 5 μL of pH 7.4 phosphate buffer and 490 μL of acetonitrile / water (1:1 in v / v) were added to obtain a 3 μM standard solution. The concentration of the standard solution may be adjusted to adjust the intensity of the response signal in the liquid analysis method.

[0306] 4) Sample analysis The sample plate is placed in the sample tray of the autosampler and the samples are evaluated by liquid analysis.

[0307] 5) Data analysis All calculations are performed using Microsoft Excel.

[0308] Analysis and quantification of the sample filtrate is achieved by using a liquid analysis method to qualify and quantify the peaks of known concentrations of standards. The formula for calculating the solubility values ​​of the control and test substances is: TIFF2025535028000147.tif75170TIFF2025535028000148.tif35170

[0309] The above is an illustrative description of the embodiments of the technical solutions of the present invention. It should be understood that the scope of the claims of the present invention is not limited to the above embodiments. Any modifications, equivalent changes, improvements, etc. made by those skilled in the art without departing from the spirit and principle of the present invention should be included in the scope of the claims.

Claims

1. A compound of formula (I), its racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt or prodrug compound thereof, R １ is H, halogen elements, CN, C １－６ Alkyl group, C ２－６ Alkenyl group, C ２－６ Alkynyl group, C １－６ Alkoxy group, halogenated C １－６ Alkyl group, halogenated C １－６ alkoxy groups, R ２ is H, C １－６ Alkyl group, halogen element, C １－６ Alkoxy group, C １－６ Alkylthio group, halogenated C １－６ Alkyl group, halogenated C １－６ alkoxy groups, R ３ is H, R ３ａ -O-C １－６ Alkyl group, —CH(═O), —C(═O)—NH—R ３ｂ and R ３ａ is H or -P(=O)(OR ３１ ) (OR ３２ ) and R ３ｂ is unsubstituted or optionally contains one, two, three or more R ３ｃ C substituted by １－６ Alkyl group, C ３－８ Cycloalkyl group, C ３－８ Cycloalkyl group -C １－６ alkyl groups, R ３ｃ OH, C １－６ Alkyl group -NH-, (C １－６ alkyl group) ２ -N-, -O-P (=O) (OR ３１ ) (OR ３２ ) and R ３１ , R ３２ may be the same or different, or each independently represents H, C １－６ alkyl groups, R ４ is H, -P(=O)(OR ４１ ) (OR ４２ ) and R ４１ , R ４２ may be the same or different, or each independently represents H, C １－６ alkyl groups, R ５ is H, -P(=O)(OR ５１ ) (OR ５２ ) and R ５１ , R ５２ may be the same or different, or each independently represents H, C １－６ alkyl groups, Y is O or OR ６ and R ６ is H, -P(=O)(OR ６１ ) (OR ６２ ) and R ６１ , R ６２ may be the same or different, or each independently represents H, C １－６ alkyl groups, is selected from a single bond or a double bond; m is selected from 0, 1, 2, 3, 4 or 5; A compound of formula (I), wherein n is selected from 0, 1, 2, 3, or 4, or a racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt, or prodrug compound thereof.

2. R １ is H, halogen elements, CN, C １－３ Alkyl group, C ２－３ Alkynyl group, C １－３ Alkoxy group, halogenated C １－３ Alkyl group, halogenated C １－３ alkoxy groups, Preferably, R １ is selected from H, F, Cl, CN, an ethynyl group, a methyl group, an ethyl group, and a propyl group; Preferably, R ２ is H, C １－３ Alkyl group, halogen element, C １－３ Alkoxy group, C １－３ Alkylthio group, halogenated C １－３ alkoxy groups, Preferably, R ２ is selected from H, F, Cl, Br, a methyl group, a methoxy group, a fluoromethoxy group, and a methylthio group, or a racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt, or prodrug compound thereof according to claim 1.

3. R ３ is H, R ３ａ -O-C １－３ Alkyl group, —CH(═O), —C(═O)—NH—R ３ｂ and R ３ａ is selected from H or —P(═O)(OH)(OH), and R ３ｂ is unsubstituted or optionally contains one, two or more R ３ｃ C substituted by １－３ Alkyl group, C ３－８ Cycloalkyl group, C ３－８ Cycloalkyl group -C １－３ alkyl groups, R ３ｃ OH, C １－３ Alkyl group -NH-, (C １－３ alkyl group) ２ -N-, -O-P(=O)(OH)(OH), Preferably, R ３ is H, a methyl group, is selected from, for example, The compound according to claim 1 or 2, or a racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt, or prodrug compound thereof, selected from the group consisting of:

4. R ４ is H, -P(=O)(OR ４１ ) (OR ４２ ) and R ４１ , R ４２ may be the same or different, or each independently represents H, C １－３ alkyl groups, Preferably, R ４ is selected from H, —P(═O)(OH)(OH), Preferably, R ５ is H, -P(=O)(OR ５１ ) (OR ５２ ) and R ５１ , R ５２ may be the same or different, or each independently represents H, C １－３ alkyl groups, Preferably, R ５ is selected from H, —P(═O)(OH)(OH), Preferably, Y is O or OR ６ and R ６ is H, -P(=O)(OR ６１ ) (OR ６２ ) and R ６１ , R ６２ may be the same or different, or each independently represents H, C １－３ alkyl groups, Preferably, R ６ is selected from H, —P(═O)(OH)(OH), Preferably, m is selected from 1, 2 or 3; Preferably, n is selected from 1 or 2. The compound according to any one of claims 1 to 3, its racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt or prodrug compound thereof.

5. The prodrug compound has the structure shown in formula (II): Here, R １ , R ２ , m and n independently have the definitions set forth in any one of claims 1 to 4; R ３ ' is R according to any one of claims 1 to 4 ３ has the definition of R ４ ' is H, -P(=O)(OR ４１ ') (OR ４２ '), and R ４１ ', R ４２ ' may be the same or different, and each independently represents H, C １－３ alkyl groups, preferably R ４ ' is H, -P(=O)(OR ４１ ') (OR ４２ '), and R ４１ ', R ４２ ' may be the same or different, and each independently represents H, C １－６ alkyl groups, R ５ ' is H, -P(=O)(OR ５１ ') (OR ５２ '), and R ５１ ', R ５２ ' may be the same or different, and each independently represents H, C １－３ alkyl groups, preferably R ５ ' is H, -P(=O)(OR ５１ ') (OR ５２ '), and R ５１ ', R ５２ ' may be the same or different, and each independently represents H, C １－６ alkyl groups, Y' is O or OR ６ ' and R ６ ' is H, -P(=O)(OR ６１ ') (OR ６２ '), and R ６１ ', R ６２ ' may be the same or different, and each independently represents H, C １－３ alkyl groups, preferably R ６ ' is H, -P(=O)(OR ６１ ') (OR ６２ '), and R ６１ ', R ６２ ' may be the same or different, and each independently represents H, C １－６ alkyl groups, is selected from a single bond or a double bond; Preferably, R ３ ' is H, R ３ａ -O-C １－６ Alkyl group, —CH(═O), —C(═O)—NH—R ３ｂ and R ３ａ is selected from H or —P(═O)(OH)(OH), and R ３ｂ is unsubstituted or optionally contains one, two, three or more R ３ｃ C substituted by １－６ Alkyl group, C ３－８ Cycloalkyl group, C ３－８ Cycloalkyl group -C １－６ alkyl groups, R ３ｃ OH, C １－６ Alkyl group -NH-, (C １－６ alkyl group) ２ -N-, -O-P(=O)(OH)(OH), Preferably, R ４ ' is selected from H, -P(=O)(OH)(OH), Preferably, R ５ ' is selected from H, -P(=O)(OH)(OH), Preferably, Y' is O or OR ６ ' and R ６ ' is selected from H, -P(=O)(OH)(OH), is selected from a single bond or a double bond; And R ４ ', R ５ ', R ６ ', R ３ａ , R ３ｃ The compound according to any one of claims 1 to 4, characterized in that at least one of -P(=O)(OH)(OH) is -P(=O)(OH), or a racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt, or prodrug compound thereof.

6. The compound is selected from the following structures: The compound according to any one of claims 1 to 5, its racemate, stereoisomer, tautomer, isotope-labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt or prodrug compound thereof.

7. The method includes the following method 1 and / or method 2: In Method 1, compound a is reacted with compound b to give a compound of formula (I): Here, R １ , R ２ , R ３ , R ４ , R ５ , Y, m, n independently have the definitions according to any one of claims 1 to 6; In method 2, compound c is R ３ｂ -NH ２ to give a compound of formula (I), Here, R １ , R ２ , R ３ , R ４ , R ５ , R ３ｂ 7. A process for preparing a compound according to any one of claims 1 to 6, wherein Y, m, n independently have the definitions according to any one of claims 1 to 6.

8. A pharmaceutical composition comprising a therapeutically effective amount of at least one of the compounds of any one of claims 1 to 6, their racemates, stereoisomers, tautomers, isotopically labeled substances, solvates, polycrystalline substances, pharmaceutically acceptable salts, or prodrug compounds thereof.

9. Use of at least one of the compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a medicament, comprising: Preferably, the use may be in the preparation of a medicament for the treatment of a condition and / or disease mediated by MDM2 and / or MDMX, such as in the preparation of an MDM2 and / or MDMX inhibitor; The use of at least one of the compound according to any one of claims 1 to 6, its racemate, stereoisomer, tautomer, isotopically labeled substance, solvate, polycrystalline substance, pharmaceutically acceptable salt or prodrug compound thereof in the preparation of a medicament for treating idiopathic pulmonary fibrosis, preferably, the use may be in the preparation of a medicament for treating idiopathic pulmonary fibrosis.

10. 10. The use of claim 9, wherein the disease is a tumor disease, and the tumor disease comprises at least one of leukemia, chronic myeloid leukemia, acute myeloid leukemia, lymphocytic leukemia, hairy cell leukemia, lymphoblastic T-cell leukemia, lymphoma, B-cell lymphoma, Burkitt's lymphoma, Hodgkin's lymphoma, chondrosarcoma, fibrosarcoma, Ewing's sarcoma, rhabdomyosarcoma, small cell lung cancer, non-small cell lung cancer, myeloma, glioma, prostate cancer, breast cancer, bone cancer, neuroblastoma, gastric cancer, ovarian cancer, colorectal cancer, kidney cancer, medulloblastoma, pancreatic cancer, thyroid cancer, mesothelioma, cervical cancer, bladder cancer, liver cancer, skin cancer, and tumors involving the central or peripheral nervous system.

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