Aromatic amide derivative as well as preparation method and application thereof

Abstract

The invention provides an aromatic amide derivative, a preparation method thereof and application of a pharmaceutical composition containing the aromatic amide derivative in medicine. Specifically, the invention provides an aromatic amide derivative as shown in a general formula (I), a preparation method and a medicinal salt thereof, and application of the aromatic amide derivative and the medicinal salt as a therapeutic agent, especially a KIF18A inhibitor, and definition of each substituent in the general formula (I) is the same as that in the specification.

Description

Aromatic amide derivatives and their preparation method and use Technical Field

[0001] The present invention relates to an aromatic amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative, and use of the derivative as a therapeutic agent, in particular as a KIF18A inhibitor. Background Art

[0002] Kinesin molecules are motor proteins that use microtubules as tracks and play an important role in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis, and other processes. Various microtubule-associated proteins (MAPs) in the kinesin-8 family regulate microtubule dynamic instability by affecting microtubule polymerization and depolymerization. KIF18A, a member of the kinesin-8 family, can move toward the positive pole using microtubules as tracks and prefers to bind to longer microtubules. Its activity is length-dependent and affects the length of the spindle, ensuring the timely and smooth alignment of sister chromosomes. Its functions are very similar and conserved across species.

[0003] KIF18A is a molecular motor protein that moves along microtubules toward the plus-end of microtubules. It regulates chromosome midplate assembly by influencing the dynamic instability of microtubule ends, thus functioning during mitosis. During anaphase, the protein is ubiquitinated and degraded, ensuring precise chromosome segregation during mitosis and enabling the successful completion of mitosis and cytokinesis. During early mitosis, KIF18A localization to the plus-end of microtubules near the kinetochore is essential for its function. This localization depends not only on the motor activity of its N-terminus but also on the microtubule-binding tail domain. KIF18A is also subject to reversible phosphorylation / dephosphorylation, but how these post-translational modifications regulate KIF18A function remains understudied. The estrogen receptor ERɑ binds to KIF18A and promotes its transcription, but whether KIF18A is regulated by other transcription factors remains unclear. Therefore, further research is needed into the mechanisms regulating KIF18A's gene transcription. During meiosis, cells lacking KIF18A will be unable to complete meiosis, which will lead to sperm formation disorders and testicular dysplasia in male animals.

[0004] Studies have found that KIF18A protein is highly expressed in a variety of cancers, including but not limited to hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, and rhabdomyosarcoma. This suggests that KIF18A is closely associated with the occurrence and progression of tumors and could serve as a target for molecular diagnosis and treatment of various tumors. KIF18A expression is associated with the progression of clinical colorectal cancer. Studies have shown that KIF18A can induce Akt phosphorylation, and knocking out KIF18A in mice significantly promotes cell apoptosis. It is speculated that KIF18A promotes the occurrence and progression of colorectal cancer by activating the PI3K-Akt signaling pathway. KIF18A is also highly expressed in human breast cancer cells, and its overexpression is associated with breast tumor grade, migration, and prognosis. Studies in breast cancer cells have revealed that overexpression of KIF18A leads to the formation of multinucleated cells, while low expression significantly reduces cell proliferation both in vitro and in vivo. This is attributed to KIF18A stabilizing microtubules at their ends and inactivating the PI3K-Akt signaling pathway, leading to apoptosis. Furthermore, KIF18A is upregulated at both the transcriptional and translational levels in lung adenocarcinoma, and abnormal KIF18A expression correlates with clinical and pathological malignancy. KIF18 gene mutations have been observed in lung adenocarcinoma, and its expression is also regulated by DNA copy number. KIF18A knockout inhibits lung adenocarcinoma cell proliferation in vitro and in vivo, inducing apoptosis and G2 / M arrest. Genes that are overexpressed alongside KIF18A are concentrated in cell cycle signaling pathways, thus further investigation of the mechanisms of action of KIF18A in tumors is of great clinical significance.

[0005] No new KIF18A inhibitors have been marketed, and currently only Amgen's AMG-650 has entered Phase I clinical trials. As a cutting-edge research area, KIF18A remains a promising target for further investigation, necessitating continued study of its mechanism of action and the development of new inhibitors.

[0006] Summary of the Invention

[0007] In order to solve the above technical problems, the present invention provides an aromatic amide derivative represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0008] in:

[0009] Ring A is selected from a 5- to 10-membered aryl group or a 5- to 6-membered heteroaryl group;

[0010] Y1, Y2 and Y3 are each independently selected from CR d or N atoms, and at most two atoms among Y1, Y2, and Y3 are N atoms at the same time;

[0011] R d is selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy, wherein the alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

[0012] G is selected from 5-10 membered aryl, 5-10 membered heteroaryl or 6-14 membered fused ring, wherein the aryl, heteroaryl or fused ring is optionally further replaced by one or more R 4 replace;

[0013] R 4 The same or different, each independently selected from cyano, halogen, alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0014] Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached;

[0015] L1 is selected from a bond, -C 1-6 Alkylene-, -C 0-4 Alkylene-NR c S(=O)(=NH)-C 0-4Alkylene-, -C 0-4 Alkylene-SC 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)-C 0-4 Alkylene-, -C 0-4 Alkylene-SO2-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)(=NH)-C 0-4 Alkylene-, -C 0-4 Alkylene-NR c SO2-C 0-4 Alkylene-, -C 0-4 Alkylene-SO2NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-OC 0-4 Alkylene-, -C 0-4 Alkylene-NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-NR c SO2NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-NR c C(O)NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-C(O)NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-NR c C(O)-C 0-4 Alkylene-, -C 0-4 Alkylene-PC 0-4 Alkylene-, -C 0-4 Alkylene-P(=O)2-C 0-4 Alkylene, -C 0-4 Alkylene-C(=O)-C 0-4 Alkylene- or -C 0-4 Alkylene-C(=N(OH))-C 0-4 Alkylene-, wherein the -C 1-6 Alkylene- or -C 0-4 Alkylene - optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, cycloalkyl or alkoxy;

[0016] R c is selected from a hydrogen atom or an alkyl group;

[0017] R 1Selected from hydrogen, cyano, halogen, alkyl, hydroxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0018] R 2 are the same or different and are each independently selected from halogen, hydroxy, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

[0019] L2 is selected from in represents the connection site between the group and G in the general formula (I); Indicates that the group and the general formula (I) The attachment site;

[0020] R 3 are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy; R 3 Preferably a hydrogen atom;

[0021] R 5Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0022] R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0023] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0024] R 8 、R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0025] m is 0, 1 or 2; and

[0026] r is independently 0, 1 or 2.

[0027] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0028] Wherein, X1, X2, X3, and X4 are each independently selected from CR a 、C(O)、NR b or N atoms;

[0029] X5 is selected from a C atom or a N atom; and at most three atoms among X1, X2, X3, X4, and X5 are N atoms at the same time;

[0030] R a Each is independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; wherein the alkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group;

[0031] R b are each independently selected from a hydrogen atom or an alkyl group;

[0032] Ring A, Y1, Y2, Y3, L1, L2, R 1 、R 2 、R 4 and m are as defined in the general formula (I).

[0033] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of formula (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0034] wherein Ring B is independently selected from a 3- to 10-membered heterocyclyl, a 3- to 10-membered cycloalkyl, a 5- to 6-membered aryl, or a 5- to 6-membered heteroaryl;

[0035] X6 and X7 are each independently selected from CR a 、C(O)、NR b or N atoms;

[0036] X8, X9, X 10 Each independently selected from CR a 、C(O)、NR b or N atom, and X8, X9, X 10 At most two atoms in the molecule are N atoms at the same time;

[0037] X 11 、X 12 、X 13 Each independently selected from CR a 、C(O)、NR b or N atoms, and X 11 、X 12 、X 13 At most two atoms in the molecule are N atoms at the same time;

[0038] R a Each is independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; wherein the alkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group;

[0039] R b are each independently selected from a hydrogen atom or an alkyl group;

[0040] n is each independently selected from 0, 1, 2, 3 or 4;

[0041] Ring A, Y1, Y2, Y3, L1, L2, R 1 、R 2 、R 4 and m are as defined in the general formula (I).

[0042] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein Y1, Y2 and Y3 are each independently selected to be CH.

[0043] A preferred embodiment of the present invention is a compound of formula (II) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein Selected from the following groups:

[0044] in, Indicates that the group and R in the general formula (II) 4 The attachment site; Represents the connection site between the group and L2 in the general formula (II);

[0045] R aa 、R bb 、R cc 、R dd 、R ee 、R ff 、R gg 、R hh 、R ii 、R jj 、R kk 、R mm 、R nn 、R oo 、R pp 、R qq 、 R rr are the same or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, a cyano group, a methyl group or a methoxy group;

[0046] R aaa is selected from a hydrogen atom or a methyl group.

[0047] A preferred embodiment of the present invention is a compound of formula (III), (IV) or (V) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein X6, X7, X8, X9, X 10 、X 11 、X 12 and X 13 Each is independently selected as CH.

[0048] A preferred embodiment of the present invention is a compound of formula (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein Ring B is independently selected from the following groups:

[0049] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein ring A is phenyl.

[0050] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 2 are the same or different, and are each independently selected from halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or methoxy.

[0051] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:

[0052] L1 is selected from a bond, -NR c -C 0-4 Alkylene-, -NR c SO2-C 0-4 Alkylene-, -SO2NR c -C 0-4 Alkylene-, -NR c SO2NR c -, -S(=O)(=NH)-, -NR c S(=O)(=NH)-, -C 1-4 Alkylene-, -S(=O)-, -O-, -C(=O)-, -C(=O)NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-SO2-C 0-4 Alkylene-, -C=N(OH)- or -NR c -C(=O)-, wherein the -C 0-4 Alkylene- or -C 1-4 Alkylene - optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, cyclopropyl or methoxy;

[0053] R c are each independently selected from a hydrogen atom or a methyl group.

[0054] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -NHSO2CH2CH2-, -SO2NHCH2CH2-, -SO2-, -CH2SO2-, -NHSO2-, -SO2NH-, -NHC(CH3)2CH2-, -C(O)NHCH2CH2-, -C(O)NHC(CH3)2CH2-, -C(O)N(CH3)CH2CH2-, -CH(CH3)(OH)CH2-, -NHSO2CH(CH3)CH2-, -SO2NHC(CH3)2CH2-, -C(O)NH-, -NHCH2CH2 or -CH2SO2CH2CH2-.

[0055] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen atom, hydroxyl, alkyl, heterocyclic, cycloalkyl or heteroaryl, wherein the alkyl, heterocyclic, cycloalkyl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl or alkyl.

[0056] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein for

[0057] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein L2 is selected from in represents the connection site of the group to G in the general formula (I); The group represented by the general formula (I) The attachment site;

[0058] R 3 A hydrogen atom.

[0059] A preferred embodiment of the present invention is a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from halogen, alkyl, alkoxy, cycloalkyl or heterocyclyl; wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more halogen;

[0060] Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached.

[0061] In a preferred embodiment of the present invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, R 4 is halogen, methyl, difluoromethyl, trifluoromethyl, methoxy,

[0062] Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached.

[0063] In a preferred embodiment of the present invention, the compound described by the general formula is selected from:

[0064] or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof. Note: If there is a discrepancy between the drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0065] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0066] The present invention provides a use of a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a KIF18A inhibitor.

[0067] The present invention also provides a use of a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by KIF18A, wherein the disease mediated by KIF18A is preferably cancer; wherein the disease mediated by KIF18A is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.

[0068] The present invention further provides a use of a compound of formula (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug for treating cancer.

[0069] The present invention provides a compound of general formula (III), (IV) or (V) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing a medicament for treating hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.

[0070] Detailed Description of the Invention

[0071] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0072] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0073] “C α-β "Alkylene" refers to an aliphatic hydrocarbon group containing a minimum of α and a maximum of β carbon atoms in a branched or linear relationship, having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, wherein α and β represent integers, the designation of C0 alkylene represents a direct bond, and C 1-6 Examples of alkylene include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, and the like. α-β The alkylene group may be substituted or unsubstituted.

[0074] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the ring atoms is a carbon atom, including monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably having a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.

[0075] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into single spiro, double spiro or multiple spiroalkyl groups, preferably single spiro and double spiroalkyl groups, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0076] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl group, preferably a bicyclic or tricyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. Non-limiting examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, or tetradecahydrophenanthrenyl.

[0077] "Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures that share two non-directly connected carbon atoms. One or more rings may contain one or more double bonds, but none of the rings have completely conjugated π electrons. It is an aromatic system with preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r,5r)-bicyclo[3.3.2]decyl.

[0078] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring atoms is selected from nitrogen, oxygen, or S(O) t (wherein t is selected from 0,1 or 2) heteroatoms, including monocycles, polycycles, condensed rings, bridged rings and spirocycles. Preferably there are 5 to 7 membered monocycles or 7 to 10 membered bicyclic or tricyclic rings, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and / or sulphur. The example of "heterocyclic radical" includes but is not limited to morpholinyl, oxetanes, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, piperazinyl, hexahydropyrimidine,

[0079] The heterocyclic group may be substituted or unsubstituted.

[0080] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spiroalkyl is divided into monospiro heterocyclic group, bispiro heterocyclic group or polyspiro heterocyclic group, preferably monospiro heterocyclic group and bispiro heterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0081] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin.

[0082] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more ring structures that share two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 2-azabicyclo [3.3.2] decyl.

[0083] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0084] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridinyl, 2-oxo-1,2-dihydropyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, pyridinyl, pyridinyl- 2(1H)-one, pyrimidinyl, pyrazin-2(1H)-one, pyrimidin-4(3H)-one, pyrimidin-2(1H)-one, pyridazin-3(2H)-one, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furo[3,2-b]pyridinyl, furo[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl,

[0085] Heteroaryl groups can be substituted or unsubstituted.

[0086] "Fused ring" refers to a polycyclic group in which two or more cyclic structures share a pair of atoms, wherein at least one ring has a completely conjugated π-electron aromatic system, and at least one ring may contain one or more double bonds, but at least one ring does not have a completely conjugated π-electron aromatic system, wherein the ring atoms are selected from 0, one or more selected from nitrogen, oxygen or S(O) r(wherein r is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. The fused ring preferably includes a bicyclic or tricyclic fused ring, wherein the bicyclic fused ring is preferably a fused ring of an aryl or heteroaryl group and a monocyclic heterocyclyl or monocyclic cycloalkyl group. Preferably, it includes 6 to 14 members, more preferably 8 to 10 members. Examples of "fused rings" include but are not limited to:

[0087] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0088] "Nitro" refers to a -NO2 group.

[0089] "Hydroxy" refers to an -OH group.

[0090] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0091] "Amino" refers to -NH2.

[0092] "Cyano" refers to -CN.

[0093] "Benzyl" refers to -CH2-phenyl.

[0094] "Carboxyl" refers to -C(O)OH.

[0095] "Carboxylate" refers to a -C(O)O-alkyl group or a -C(O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0096] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0097] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0098] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0099] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0100] "DMSO" refers to dimethyl sulfoxide.

[0101] "BOC" refers to tert-butoxycarbonyl.

[0102] "Bn" refers to benzyl.

[0103] "THP" refers to 2-tetrahydropyranyl.

[0104] "TFA" refers to trifluoroacetic acid.

[0105] "Ts" refers to p-toluenesulfonyl.

[0106] "Leaving group", or leaving group, is an atom or functional group that breaks away from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that easily accept electrons and have a strong ability to withstand negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break away from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to bind to other atoms, and the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, methylsulfonyl, -OTs or -OH.

[0107] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0108] As used herein, "substituted" or "substituted", unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -OR 6 、-C(O)R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH2NHC(O)OR 6 、-CH2NR 7 R 8 or -S(O)rR 6 substituted by a substituent;

[0109] R6 is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0110] R 7 and R 8 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0111] Or, R 7 and R 8 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0112] R 9 、R 10 and R 11 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0113] r is selected from 0, 1 or 2;

[0114] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0115] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0116] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0117] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0118] Synthesis method of the compound of the present invention

[0119] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0120] The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, the method comprising:

[0121] Method 1:

[0122] Compound (IA) reacts with compound (IB) to obtain compound (IC), and compound (IC) reacts with compound (ID) to produce compound (I).

[0123] Where: L2 is selected from R 3 is a hydrogen atom;

[0124] Y represents hydroxyl or chlorine;

[0125] W1 represents fluorine, chlorine, bromine or iodine;

[0126] Ring A, G, Y1, Y2, Y3, L1, R 1 、R 2 、R 4 and m are as defined in the general formula (I).

[0127] Method 2:

[0128] Compound (IA) undergoes a condensation reaction with compound (IIA) to obtain a compound of formula (IIB), which then undergoes a coupling reaction with compound (IIC) to obtain a compound of formula (IC), which then reacts with compound (ID) to produce compound (I).

[0129] Where: L2 is selected from R 3 is a hydrogen atom;

[0130] Y represents hydroxyl or chlorine;

[0131] W1 represents fluorine, chlorine, bromine or iodine;

[0132] W2 represents bromine or iodine;

[0133] Ring A, G, Y1, Y2, Y3, L1, R 1 、R 2 、R 4 and m are as defined in the general formula (I). DETAILED DESCRIPTION

[0134] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0135] Example

[0136] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0137] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0138] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0139] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0140] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise indicated. Commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co. KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0141] CD3OD: deuterated methanol.

[0142] CDCl3: deuterated chloroform.

[0143] DMSO-d6: deuterated dimethyl sulfoxide.

[0144] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1 L.

[0145] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0146] The compound was purified using silica gel column chromatography and reverse phase column chromatography, with the eluent system selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; and D: aqueous trifluoroacetic acid and acetonitrile. The volume ratio of the solvents varied depending on the polarity of the compound and could be adjusted by adding a small amount of an acidic or alkaline reagent, such as acetic acid or triethylamine.

[0147] Example 1

[0148] 4'-cyclopropyl-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0149] 4'-Cyclopropyl-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamide)-[1,1'-biphenyl]-2-carboxamide

[0150] first step

[0151] 2-(4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0152] 2-(4-Cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0153] 1-Bromo-4-cyclopropylbenzene 1a (3.00 g, 15.22 mmol, commercially available) was dissolved in dioxane (30 mL). Potassium acetate (4.48 g, 45.67 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborolane) 1b (5.03 g, 19.79 mmol, commercially available), and 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (1.10 g, 1.52 mmol) were added to the mixture. After nitrogen substitution three times, the mixture was heated to 100°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting materials and the formation of the product. The reaction solution was concentrated to dryness under reduced pressure to give 2-(4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1c (13.00 g), which was used directly in the next reaction.

[0154] Step 2

[0155] methyl 5-bromo-4'-cyclopropyl-[1,1'-biphenyl]-2-carboxylate

[0156] 5-Bromo-4'-cyclopropyl-[1,1'-biphenyl]-2-carboxylic acid methyl ester

[0157] 2-(4-Cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1c (13.00 g, 53.27 mmol) and methyl 4-bromo-2-iodobenzoate 1d (4.2 g, 12.32 mmol, commercially available) were dissolved in a mixture of dioxane (30 mL) and water (6 mL). Potassium carbonate (5.10 g, 36.86 mmol) and tetrakis(triphenylphosphine)palladium (1.42 g, 1.23 mmol) were added sequentially. The mixture was reacted at 90°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting materials and the formation of the product. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give methyl 5-bromo-4'-cyclopropyl-[1,1'-biphenyl]-2-carboxylate 1e (3.30 g) in a yield of 81.08%.

[0158] MS m / z(ESI):331.0 / 333.0[M+1].

[0159] Step 3

[0160] 5-bromo-4'-cyclopropyl-[1,1'-biphenyl]-2-carboxylic acid

[0161] 5-Bromo-4'-cyclopropyl-[1,1'-biphenyl]-2-carboxylic acid

[0162] Methyl 5-bromo-4'-cyclopropyl-[1,1'-biphenyl]-2-carboxylate 1e (1.00 g, 3.02 mmol) was dissolved in a 2:1:1 mixture of tetrahydrofuran:methanol:water (12 mL) at room temperature. Lithium hydroxide monohydrate (1.27 g, 30.19 mmol) was added and the mixture was heated to 60°C for 4 hours. Mass spectrometry confirmed the complete reaction of the starting material and the formation of the product. The mixture was poured into water (100 mL), adjusted to pH 4 with hydrochloric acid (2 M), and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-bromo-4'-cyclopropyl-[1,1'-biphenyl]-2-carboxylic acid 1f (950 mg), which was used directly in the next reaction.

[0163] MS m / z(ESI):317.0 / 319.0[M+1].

[0164] Step 4

[0165] 5-bromo-4'-cyclopropyl-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-[1,1'-biphenyl]-2-carboxamide

[0166] 5-Bromo-4'-cyclopropyl-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-[1,1'-biphenyl]-2-carboxamide

[0167] At room temperature, 5-bromo-4'-cyclopropyl-[1,1'-biphenyl]-2-carboxylic acid 1f (200.00 mg, 0.63 mmol) was dissolved in N,N-dimethylformamide (2 mL). 3-(4,4-difluoropiperidin-1-yl)aniline 1g (160.60 mg, 0.76 mmol, prepared according to patent WO2018209030 A1), N,N-diisopropylethylamine (325.98 mg, 2.52 mmol), and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (493.14 mg, 0.95 mmol) were added sequentially. After nitrogen substitution three times, the reaction was continued at 20°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting materials. The mixture was poured into water (60 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with a saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-4'-cyclopropyl-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-[1,1'-biphenyl]-2-carboxamide 1h (250.00 mg) in a yield of 77.53%.

[0168] MS m / z(ESI):511.2 / 513.2[M+1]

[0169] Step 5

[0170] 4'-cyclopropyl-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0171] 4'-Cyclopropyl-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamide)-[1,1'-biphenyl]-2-carboxamide

[0172] At room temperature, 5-bromo-4'-cyclopropyl-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-[1,1'-biphenyl]-2-carboxamide 1h (50.00 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1 mL), and potassium phosphate (41.51 mg, 0.20 mmol), 2-hydroxyethane-1-sulfonamide 1i (13.46 mg, 0.11 mmol, commercially available), trans-N,N'-dimethyl-1,2-cyclohexanediamine (6.95 mg, 0.05 mmol) and cuprous iodide (18.62 mg, 0.10 mmol) were added sequentially. After nitrogen substitution three times, the reaction was incubated at 100°C for 18 h. The mixture was poured into water (60 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% FA+H2O, mobile phase B: CH3CN) to give 4'-cyclopropyl-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamide)-[1,1'-biphenyl]-2-carboxamide 1 (23.00 mg) with a yield of 42.34%.

[0173] MS m / z(ESI):556.2[M+1]

[0174] 1 H NMR(400MHz,DMSO)δ9.98(s,1H),7.51(d,J=8.4Hz,1H),7.27(d,J=8.0Hz,3H),7 .21(s,1H),7.16(s,1H),7.09(dd,J=8.0,6.1Hz,3H),6.97(d,J=8.0Hz,1H),6.7 0(dd,J=8.4,2.0Hz,1H),3.77(t,J=6.4Hz,2H),3.30(d,J=6.8Hz,4H),3.25(s,2 H),2.08–1.98(m,4H),1.93–1.87(m,1H),0.96–0.91(m,2H),0.68–0.63(m,2H).

[0175] Example 2

[0176] 4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0177] 4'-(Difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0178] first step

[0179] methyl 5-bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylate

[0180] 5-Bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid methyl ester

[0181] Methyl 4-bromo-2-iodobenzoate 1d (500 mg, 1.47 mmol) and (4-(difluoromethyl)phenyl)boronic acid 2a (252 mg, 1.47 mmol, commercially available) were added to 1,4-dioxane (10 mL) and water (4 mL) at room temperature. Potassium carbonate (405 mg, 2.93 mmol) and tetrakis(triphenylphosphine)palladium (169 mg, 0.147 mmol) were then added. The atmosphere was purged with nitrogen three times and the reaction was continued at 50°C for 18 hours. The mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford methyl 5-bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylate 2b (70.0 mg) in a 13.99% yield.

[0182] MS m / z(ESI):341.0 / 343.0[M+1]

[0183] Step 2

[0184] 5-bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid

[0185] 5-Bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid

[0186] Methyl 5-bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylate 2b (70.0 mg, 0.205 mmol) was added to a mixture of tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL) at room temperature, followed by lithium hydroxide monohydrate (17.2 mg, 0.410 mmol). The mixture was reacted at 60°C for 18 hours. The mixture was concentrated to dryness under reduced pressure to afford 5-bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid 2c (50 mg) in a 74.49% yield.

[0187] MS m / z(ESI):327.1 / 329.1[M+1]

[0188] Step 3

[0189] 5-bromo-4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-[1,1'-biphenyl]-2-carboxamide

[0190] 5-Bromo-4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-[1,1'-biphenyl]-2-carboxamide

[0191] At room temperature, 5-bromo-4'-(difluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid 2c (50.0 mg, 0.153 mmol) and 1 g of 3-(4,4-difluoropiperidin-1-yl)aniline (35.7 mg, 0.168 mmol) were added to N,N-dimethylformamide (1 mL). (7-Azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (159 mg, 0.305 mmol) and N,N-diisopropylethylamine (59.3 mg, 0.459 mmol) were then added. The atmosphere was purged with nitrogen three times and the reaction was continued at 70°C for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-[1,1'-biphenyl]-2-carboxamide 2d (70.0 mg) in a yield of 87.84%.

[0192] MS m / z(ESI):521.2 / 523.2[M+1]

[0193] Step 4

[0194] 4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0195] 4'-(Difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0196] At room temperature, 5-bromo-4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-[1,1'-biphenyl]-2-carboxamide 2d (70.0 mg, 0.134 mmol) and 2-hydroxyethane-1-sulfonamide 1i (18.5 mg, 0.148 mmol) were added to N,N-dimethylformamide (5 mL). Subsequently, cuprous iodide (25.6 mg, 0.134 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (9.6 mg, 0.067 mmol), and potassium phosphate (57.0 mg, 0.269 mmol) were added. The atmosphere was purged with nitrogen three times and the reaction was continued at 90°C for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% FA+H2O, mobile phase B: CH3CN) to give 4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)phenyl)-5-((2-hydroxyethyl)sulfonamido)-[1,1'-biphenyl]-2-carboxamide 2 (25.0 mg) with a yield of 32.92%.

[0197] MS m / z(ESI):566.2[M+1]

[0198] 1H NMR(400MHz, DMSO-d6)δ10.08(s,1H),7.66–7.54(m,3H),7.53–7.48(m,2H),7.35–7.29(m,1H),7.24(d,J=2.0Hz,1H),7.18–7.16(m,1H),7 .10(t,J=8.4Hz,1H),7.07–6.83(m,2H),6.73–6.66(m,1H),3.78(t,J=6.8Hz,2H),3.36–3.33(m,2H),3.26–3.22(m,4H),2.07–1.97(m,4H).

[0199] Example 3

[0200] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-4'-fluoro-[1,1'-biphenyl]-2-carboxamide

[0201] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-4'-fluoro-[1,1'-biphenyl]-2-carboxamide

[0202] first step

[0203] 4,4-difluoro-1-(2-methoxy-5-nitrophenyl)piperidine

[0204] 4,4-Difluoro-1-(2-methoxy-5-nitrophenyl)piperidine

[0205] 2-Iodo-1-methoxy-4-nitrobenzene 3a (5.00 g, 17.92 mmol, commercially available) was dissolved in 1,4-dioxane (50 mL). Cesium carbonate (11.68 g, 35.84 mmol), 4,4-difluoropiperidine hydrochloride 3b (3.39 g, 21.50 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (1.71 g, 3.58 mmol), and palladium acetate (402.30 mg, 1.79 mmol) were added sequentially. After nitrogen substitution three times, the reaction was continued at 100°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting materials and the formation of the product. The reaction solution was diluted with water (250 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 4,4-difluoro-1-(2-methoxy-5-nitrophenyl)piperidine 3c (4.60 g) in a yield of 94.3%.

[0206] MS m / z(ESI):273.2[M+1]

[0207] Step 2

[0208] 3-(4,4-difluoropiperidin-1-yl)-4-methoxyaniline

[0209] 3-(4,4-difluoropiperidin-1-yl)-4-methoxyaniline

[0210] 4,4-Difluoro-1-(2-methoxy-5-nitrophenyl)piperidine 3c (4.60 g, 16.90 mmol) was dissolved in methanol (50 mL) at room temperature. Palladium on carbon (179.81 mg, 1.69 mmol, 10%) was added and the atmosphere was purged with hydrogen three times. The reaction was allowed to proceed under a hydrogen atmosphere for 18 hours at room temperature. Formic acid (155.53 mg, 3.38 mmol) was then added and the atmosphere was purged with hydrogen three times. The reaction was allowed to proceed under a hydrogen atmosphere for 6 hours at room temperature. The reaction solution was concentrated to dryness under reduced pressure and the mixture was dissolved in a mixture of methanol (40 mL) and hydrochloric acid (8 mL). The mixture was stirred at room temperature for 1 hour and then concentrated to dryness under reduced pressure to yield 3-(4,4-difluoropiperidin-1-yl)-4-methoxyaniline 3d (4.80 g), which was used directly in the next step.

[0211] MS m / z(ESI):243.2[M+1]

[0212] Step 3

[0213] 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-2-iodobenzamide

[0214] 4-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-2-iodobenzamide

[0215] 3-(4,4-Difluoropiperidin-1-yl)-4-methoxyaniline 3d (1.00 g, 4.13 mmol) was dissolved in N,N-dimethylformamide (10 mL). N,N-diisopropylethylamine (2.67 g, 20.64 mmol), 4-bromo-2-iodobenzoic acid 3e (1.35 g, 4.13 mmol, commercially available), and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (3.23 g, 6.19 mmol) were added sequentially. The atmosphere was purged with nitrogen three times. The reaction was allowed to proceed at 25°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was poured into water (150 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-2-iodobenzamide 3f (1.25 g) in a 54.94% yield. MS m / z (ESI): 551.0 / 553.0 [M+1].

[0216] Step 4

[0217] 5-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4'-fluoro-[1,1'-biphenyl]-2-carboxamide

[0218] 5-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4'-fluoro-[1,1'-biphenyl]-2-carboxamide

[0219] 4-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-2-iodobenzamide 3f (100.00 mg, 0.18 mmol) was dissolved in a mixture of 1.4-dioxane (1 mL) and water (0.2 mL). Cesium carbonate (177.34 mg, 0.54 mmol), 4-fluorophenylboronic acid (3 g, 25.33 mg, 0.18 mmol, commercially available), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (26.33 mg, 0.04 mmol) were added sequentially. The atmosphere was purged with nitrogen three times. The reaction was incubated at 100°C for 3 hours. Mass spectrometry confirmed the complete reaction. The reaction mixture was poured into water (80 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with a saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4'-fluoro-[1,1'-biphenyl]-2-carboxamide 3h (35.00 mg) in a yield of 37.14%.

[0220] MS m / z(ESI):519.1 / 521.1[M+1]

[0221] Step 5

[0222] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-4'-fluoro-[1,1'-biphen

[0223] yl]-2-carboxamide

[0224] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-4'-fluoro-[1,1'-biphenyl]-2-carboxamide

[0225] At room temperature, 5-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4'-fluoro-[1,1'-biphenyl]-2-carboxamide 3h (35.00 mg, 0.07 mmol) was dissolved in N,N-dimethylformamide (1 mL), and potassium phosphate (28.61 mg, 0.13 mmol), ethylsulfonic acid amide 3i (7.36 mg, 0.07 mmol, commercially available), N 1 ,N 2-dimethylcyclohexane-1,2-diamine (4.79 mg, 0.03 mmol) and cuprous iodide (12.83 mg, 0.07 mmol) were added, and the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 100°C for 4 hours. The mixture was poured into water (60 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% FA+H2O, mobile phase B: CH3CN) to give N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonyl)-4'-fluoro-[1,1'-biphenyl]-2-carboxamide 3 (6.75 mg) with a yield of 18.29%.

[0226] MS m / z(ESI):548.2[M+1]

[0227] 1H NMR(400MHz, DMSO-d6)δ9.92(s,1H),7.53(d,J=8.4Hz,1H),7.42–7.40(m,2H),7.30–7.21(m,4H),7.15–7.11(m,1H),7.08(d, J=2.4Hz,1H),6.85(d,J=8.8Hz,1H),3.75(s,3H),3.22–3.16(m,2H),3.02–3.01(m,4H),2.11–1.99(m,4H),1.24–1.21(m,3H).

[0228] Example 4

[0229] 4'-chloro-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0230] 4'-Chloro-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0231] first step

[0232] 5-bromo-4'-chloro-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide

[0233] 5-Bromo-4'-chloro-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide

[0234] 4-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-2-iodobenzamide 3f (200.00 mg, 0.36 mmol) was dissolved in a mixture of 1.4-dioxane (1 mL) and water (0.2 mL). Cesium carbonate (354.69 mg, 1.09 mmol), 4-chlorophenylboronic acid 4a (56.74 mg, 0.36 mmol, commercially available), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (52.66 mg, 0.07 mmol) were then added. The atmosphere was purged with nitrogen three times. The reaction was continued at 100°C for 3 hours to obtain a black suspension. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-4'-chloro-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide 4b (55.00 mg) in a yield of 28.29%.

[0235] MS m / z(ESI):535.2 / 537.2[M+1]

[0236] Step 2

[0237] 4'-chloro-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0238] 4'-Chloro-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0239] At room temperature, 5-bromo-4'-chloro-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide 4b (55.00 mg, 0.10 mmol) was dissolved in N,N-dimethylformamide (1 mL), and potassium phosphate (65.37 mg, 0.13 mmol), ethylsulfonic acid amide 3i (12.32 mg, 0.11 mmol), N 1 ,N 2 -dimethylcyclohexane-1,2-diamine (7.30 mg, 0.05 mmol) and cuprous iodide (19.55 mg, 0.10 mmol) were added, and the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 100°C for 4 hours. The mixture was poured into water (80 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% FA+H2O, mobile phase B: CH3CN) to give 4'-chloro-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonyl)-[1,1'-biphenyl]-2-carboxamide 4 (7.60 mg) with a yield of 13.13%.

[0240] MS m / z(ESI):564.0[M+1]

[0241] 1H NMR(400MHz,DMSO-d6)δ10.17(br s,1H),9.90(s,1H),7.54(d,J=8.4Hz,1H),7.46(d,J=8.4Hz,2H),7.38(d,J= 8.4Hz,2H),7.30(dd,J=8.4,2.0Hz,1H),7.22(d,J=2.0Hz,1H),7.14(dd,J=8 .7,2.2Hz,1H),7.03(d,J=2.4Hz,1H),6.85(d,J=8.8Hz,1H),3.75(s,3H),3. 22–3.16(m,2H),3.03–3.01(m,4H),2.10–2.04(m,4H),1.23(t,J=7.2Hz,3H).

[0242] Example 5

[0243] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0244] first step

[0245] 5-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0246] 5-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0247] To a mixture of 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-2-iodobenzamide 3f (100 mg, 0.181 mmol) and 4-trifluoromethylphenylboronic acid pinacol ester 5a (49.2 mg, 0.181 mmol, commercially available) in 1,4-dioxane (5 mL) and water (1 mL) was added tetrakistriphenylphosphine palladium (21.0 mg, 0.0181 mmol) and potassium carbonate (75.2 mg, 0.544 mmol) at room temperature. The reaction mixture was heated to 90°C and stirred for 18 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide 5b (30.0 mg) in a yield of 29%.

[0248] MS m / z(ESI):569.2 / 571.2[M+1]

[0249] Step 2

[0250] N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0251] At room temperature, 5-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide 5b (30.0 mg, 0.0527 mol) and ethylsulfonamide 3i (11.5 mg, 0.105 mmol) were added to N,N-dimethylformamide (3 mL). Potassium phosphate (22.4 mg, 0.105 mmol), cuprous iodide (11.7 mg, 0.0527 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (3.75 mg, 0.0264 mmol) were then added. The atmosphere was purged with nitrogen three times and the reaction was continued at 90°C for 3 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% FA+H2O, mobile phase B: CH3CN) to give N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonyl)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide 5 (3.00 mg) with a yield of 10%.

[0252] MS m / z(ESI):598.2[M+1]

[0253] 1H NMR (400MHz, DMSO-d6) δ9.95 (s, 1H), 7.77 (d, J = 8.0Hz, 2H), 7.58 (d, J = 8.0Hz ,3H),7.32(dd,J=8.4,2.4Hz,1H),7.24(d,J=2.4Hz,1H),7.14(dd,J=8.8,2.4 Hz,1H),7.00(d,J=2.4Hz,1H),6.84(d,J=8.8Hz,1H),3.75(s,3H),3.19(q,J =7.2Hz,2H),3.00(t,J=5.6Hz,4H),2.10-2.03(m,4H),1.23(t,J=7.2Hz,3H).

[0254] Example 6

[0255] 4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0256] first step

[0257] 5-bromo-4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide

[0258] 5-Bromo-4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide

[0259] To a mixture of 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-2-iodobenzamide 3f (100 mg, 0.181 mmol) and 4-difluoromethylphenylboronic acid 6a (25.0 mg, 0.145 mmol, commercially available) in 1,4-dioxane (5 mL) and water (1 mL) was added tetrakistriphenylphosphine palladium (21.0 mg, 0.0181 mmol) and potassium carbonate (75.2 mg, 0.544 mmol) at room temperature. The mixture was heated to 90°C and reacted for 18 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide 6b (30.0 mg) in a 30% yield.

[0260] MS m / z(ESI):551.0 / 553.0[M+1]

[0261] Step 2

[0262] 4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0263] At room temperature, 5-bromo-4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide 6b (30.0 mg, 0.0544 mol) and ethylsulfonamide 3i (11.9 mg, 0.109 mmol) were added to N,N-dimethylformamide (3 mL), followed by potassium phosphate (23.1 mg, 0.109 mmol), cuprous iodide (12.1 mg, 0.0544 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (3.87 mg, 0.0272 mmol). The atmosphere was purged with nitrogen three times and the reaction was continued at 90°C for 3 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% FA+H2O, mobile phase B: CH3CN) to give 4'-(difluoromethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonyl)-[1,1'-biphenyl]-2-carboxamide 6 (1.00 mg) with a yield of 3%.

[0264] MS m / z(ESI):580.2[M+1]

[0265] 1H NMR (400MHz, DMSO-d6) δ9.94(s,1H),7.66–7.45(m,5H),7.32(dd,J=8.4,2.4Hz,1H),7.24(d,J=2.4Hz,1H),7.19–6.89(m,3H ),6.84(d,J=8.8Hz,1H),3.75(s,3H),3.20(q,J=7.2Hz,2H),2.99(t,J=6.4Hz,4H),2.16–1.96(m,4H),1.23(t,J=7.2Hz,3H).

[0266] Example 7

[0267] 4'-(1,1-difluoroethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0268] 4'-(1,1-difluoroethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0269] first step

[0270] 2-(4-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0271] 2-(4-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0272] To a solution of 1-bromo-4-(1,1-difluoroethyl)benzene 7a (500 mg, 2.26 mmol, commercially available) and pinacol diboron (747 mg, 2.94 mmol) in 1,4-dioxane (10 mL) was added 1,1-bis(diphenylphosphino)ferrocenepalladium dichloride (164 mg, 0.226 mmol) and potassium acetate (666 mg, 6.79 mmol) at room temperature. The mixture was allowed to react at 90°C for 18 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 2-(4-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7b (300 mg) in a 49% yield.

[0273] MS m / z(ESI):269.2[M+1]

[0274] Step 2

[0275] 5-bromo-4'-(1,1-difluoroethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide

[0276] 5-Bromo-4'-(1,1-difluoroethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide

[0277] At room temperature, 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-2-iodobenzamide 3f (200 mg, 0.363 mmol) and 2-(4-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 7b (87.6 mg, 0.327 mmol) were added to a mixture of 1,4-dioxane (5 mL) and water (1 mL). Tetrakistriphenylphosphine palladium (41.9 mg, 0.0363 mmol) and potassium carbonate (150 mg, 1.09 mmol) were then added. The mixture was heated to 90°C and reacted for 18 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent: System A) to give 5-bromo-4'-(1,1-difluoroethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide 7c (60.0 mg) in a 30% yield.

[0278] MS m / z(ESI):565.0 / 567.0[M+1]

[0279] Step 3

[0280] 4'-(1,1-difluoroethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0281] 4'-(1,1-difluoroethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0282] At room temperature, 5-bromo-4'-(1,1-difluoroethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-[1,1'-biphenyl]-2-carboxamide 7c (60.0 mg, 0.106 mmol) and ethylsulfonamide 3i (23.2 mg, 0.212 mmol) were added to N,N-dimethylformamide (3 mL). Potassium phosphate (45.1 mg, 0.212 mmol), cuprous iodide (23.6 mg, 0.106 mmol), and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (7.55 mg, 0.0531 mmol) were then added. The atmosphere was purged with nitrogen three times, and the temperature was raised to 90°C for 3 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% FA+H2O, mobile phase B: CH3CN) to give 4'-(1,1-difluoroethyl)-N-(3-(4,4-difluoropiperidin-1-yl)-4-methoxyphenyl)-5-(ethylsulfonyl)-[1,1'-biphenyl]-2-carboxamide 7 (3.00 mg) with a yield of 5%.

[0283] MS m / z(ESI):594.4[M+1]

[0284] 1H NMR (400MHz, DMSO-d6) δ9.94 (s, 1H), 7.60-7.54 (m, 3H), 7.48 (d, J = 8.0Hz, 2H), 7. 30(dd,J=8.4,2.4Hz,1H),7.23(d,J=2.4Hz,1H),7.14(dd,J=8.8,2.4Hz,1H),7.04 (d,J=2.4Hz,1H),6.85(d,J=8.8Hz,1H),3.75(s,3H),3.18(q,J=7.2Hz,2H),3.00( t,J=5.6Hz,4H),2.14–2.02(m,4H),1.97(t,J=18.8Hz,3H),1.22(t,J=7.2Hz,3H).

[0285] Example 8

[0286] N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-5-(ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0287] N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-5-(ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0288] first step

[0289] 7-bromo-5-nitro-2,3-dihydrobenzofuran

[0290] 7-Bromo-5-nitro-2,3-dihydrobenzofuran

[0291] Nitric acid (1.5 mL) was added dropwise to a solution of 7-bromo-2,3-dihydrobenzofuran 8a (700 mg, 3.52 mmol, commercially available) in trifluoroacetic acid (3 mL) and stirred at room temperature for 2 hours. Mass spectrometry indicated completion of the reaction. The reaction solution was then slowly added dropwise to water (50 mL), resulting in the precipitation of a solid. This solid was filtered under reduced pressure, and the filter cake was dried under vacuum to afford 7-bromo-5-nitro-2,3-dihydrobenzofuran 8b (750 mg) in an 87.39% yield.

[0292] MS m / z(ESI):244.0[M+1]

[0293] Step 2

[0294] 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine

[0295] 4,4-Difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine

[0296] 7-Bromo-5-nitro-2,3-dihydrobenzofuran 8b (650 mg, 2.66 mmol) and 4,4-difluoropiperidine 3b (645.24 mg, 5.33 mmol) were dissolved in toluene (20 mL), and palladium acetate (59.80 mg, 266.35 μmol), R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (497.54 mg, 799.04 μmol) and cesium carbonate (2.60 g, 7.99 mmol) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 100°C and stirred for 16 hours. After the reaction was complete, water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (20 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine 8c (610 mg) in a yield of 80.57%.

[0297] MS m / z(ESI):285.1[M+1]

[0298] Step 3

[0299] 7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-amine

[0300] 7-(4,4-Difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-amine

[0301] Ammonium chloride (559.35 mg, 10.55 mmol) and iron powder (589.38 mg, 10.55 mmol) were added to a mixture of 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine 8c (300 mg, 1.06 mmol) in water (20 mL) and ethanol (20 mL). The mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, the mixture was filtered, and ethyl acetate (30 mL) was added to the filtrate. The layers were separated, and the aqueous phase was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-amine 8d (220 mg) in an 81.98% yield.

[0302] MS m / z(ESI):255.1[M+1]

[0303] Step 4

[0304] methyl 2-bromo-4-(ethylsulfonamido)benzoate

[0305] Methyl 2-bromo-4-(ethylsulfonamido)benzoate

[0306] Ethylsulfonyl chloride 8f (1.34 g, 10.43 mmol, commercially available), methyl 4-amino-2-bromobenzoate 8e (2 g, 8.69 mmol, commercially available), and triethylamine (2.64 g, 26.08 mmol) were added to dichloromethane (30 mL) at room temperature and stirred for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to obtain methyl 2-bromo-4-(ethylsulfonamido)benzoate (8 g (710 mg) in a 25.37% yield).

[0307] MS m / z(ESI):322.0[M+1]

[0308] Step 5

[0309] methyl 5-(ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylate

[0310] 5-(Ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0311] At room temperature, methyl 2-bromo-4-(ethylsulfonylamino)benzoate (8g, 600mg, 1.86mmol), 4-trifluoromethylphenylboronic acid (8h, 530mg, 2.79mmol), tetrakis(triphenylphosphine)palladium (215mg, 0.186mmol), and potassium carbonate (772mg, 5.59mmol) were added to a mixture of water (2mL) and 1,4-dioxane (10mL). After argon replacement, the mixture was heated at 100°C and stirred for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (20mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to give 5-(ethylsulfonylamino)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide (8i, 660mg) in a 91.69% yield.

[0312] MS m / z(ESI):388.1[M+1]

[0313] Step 6

[0314] 5-(ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid

[0315] 5-(Ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid

[0316] At room temperature, a solution of sodium hydroxide (826 mg, 20.65 mmol) in water (20 mL) was added to a mixture of 5-(ethylsulfonylamino)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide 8i (660 mg, 1.71 mmol) in tetrahydrofuran (20 mL) and methanol (20 mL). The mixture was heated at 50°C and stirred for 16 hours. After completion of the reaction, the solvent was removed by concentration under reduced pressure. The remaining solution was adjusted to pH 3-4 with dilute hydrochloric acid (1 M) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 5-(ethylsulfonylamino)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid 8j (580 mg) in a 90.93% yield. The crude product was used directly in the next reaction.

[0317] MS m / z(ESI):374.0[M+1]

[0318] Step 7

[0319] N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-5-(ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0320] N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-5-(ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxamide

[0321] Benzotriazol-1-yloxytripyrrolidinylphosphine hexafluorophosphate (418 mg, 803.54 μmol), 5-(ethylsulfonamido)-4'-(trifluoromethyl)-[1,1'-biphenyl]-2-carboxylic acid 8j (200 mg, 0.54 mmol), and N,N-diisopropylethylamine (207 mg, 1.61 mmol) were added to N,N-dimethylformamide (3 mL) at room temperature and stirred at room temperature for 10 minutes. 7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-amine 8d (163 mg, 0.64 mmol) was then added, and the mixture was heated to 65°C and stirred for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4CO3+H2O, mobile phase B: CH3CN) to give N-(7-(4,4-difluoropiperidin-1-yl)-2,3-dihydrobenzofuran-5-yl)-5-(ethylsulfonyl)-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxamide 8 (142 mg) with a yield of 43.18%.

[0322] MS m / z(ESI):610.2[M+1]

[0323] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),9.95(s,1H),7.79(d,J=7.9Hz,2H),7.60(d,J=7.9Hz,3H),7.36(d,J=8.5Hz,1H),7.27(s,1 H),7.09(s,1H),6.75(s,1H),4.49(d,J=9.5Hz,2H),3.26-3.19(m,2H),3.15-3.06(m,5H),2.13-1.96(m,4H),1.42–1.14(m,4H).

[0324] Example 9

[0325] 4'-(difluoromethyl)-N-(2-(difluoromethyl)-1H-benzo[d]imidazol-4-yl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0326] 4'-(Difluoromethyl)-N-(2-(difluoromethyl)-1H-benzo[d]imidazol-4-yl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0327] first step

[0328] 2-(difluoromethyl)-4-nitro-1H-benzo[d]imidazole

[0329] 2-(Difluoromethyl)-4-nitro-1H-benzo[d]imidazole

[0330] To 3-nitrobenzene-1,2-diamine 9a (200.00 mg, 1.31 mmol, commercially available) was added aqueous hydrochloric acid (4 M, 0.33 mL), followed by 2,2-difluoroacetic acid 9b (125.42 mg, 1.31 mmol, commercially available). After nitrogen substitution three times, the reaction was allowed to proceed at 100°C for 16 hours. Mass spectrometry confirmed the complete reaction of the starting material. The reaction mixture was cooled, adjusted to pH 7 with saturated sodium bicarbonate, diluted with water (100 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to afford 2-(difluoromethyl)-4-nitro-1H-benzo[d]imidazole 9c (271 mg) in a 97.35% yield.

[0331] MS m / z(ESI):241.0[M+1]

[0332] Step 2

[0333] 2-(difluoromethyl)-1H-benzo[d]imidazol-4-amine

[0334] 2-(Difluoromethyl)-1H-benzo[d]imidazol-4-amine

[0335] 2-(Difluoromethyl)-4-nitro-1H-benzo[d]imidazole 9c (271.00 mg, 1.27 mmol) was dissolved in ethanol (3 mL) at room temperature. Palladium on carbon (27.06 mg, 0.25 mmol) was added, and the atmosphere was replaced with hydrogen three times. The reaction was stirred at 25°C for 6 hours. Mass spectrometry confirmed the complete reaction. The reaction solution was concentrated to dryness under reduced pressure to afford 2-(difluoromethyl)-1H-benzo[d]imidazole-4-amine 9d (218.00 mg) in a 96.61% yield. The crude product was used directly in the next step.

[0336] MS m / z(ESI):184.0[M+1]

[0337] Step 3

[0338] methyl 4'-(difluoromethyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxylate

[0339] 4'-(Difluoromethyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxylic acid methyl ester

[0340] Dissolve 8 g (300 mg, 0.93 mmol) of methyl 2-bromo-4-(ethylsulfonylamino)benzoate in 1,4-dioxane (3 mL) and water (1 mL). Cesium carbonate (908 mg, 2.79 mmol), 4-difluoromethylphenylboronic acid 6a (160.10 mg, 0.93 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (67 mg, 0.01 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was incubated at 100°C for 3 hours. Mass spectrometry confirmed the complete reaction of the starting material. After cooling, the reaction solution was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to give methyl 4'-(difluoromethyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxylate 9e (412 mg) in a yield of 89.83%.

[0341] Step 4

[0342] 4'-(difluoromethyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxylic acid

[0343] 4'-(Difluoromethyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxylic acid

[0344] Methyl 4'-(difluoromethyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxylate 9e (150 mg, 0.40 mmol) was dissolved in a mixture of methanol (1 mL), tetrahydrofuran (0.5 mL), and water (0.5 mL) at room temperature, and lithium hydroxide monohydrate (17 mg, 0.40 mmol) was added. The reaction was stirred at room temperature for 3 hours. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was poured into water (80 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4'-(difluoromethyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxylic acid 9f (128 mg) in an 88.70% yield. The crude product was used directly in the next reaction.

[0345] MS m / z(ESI):356.0[M+1]

[0346] Step 5

[0347] 4'-(difluoromethyl)-N-(2-(difluoromethyl)-1H-benzo[d]imidazol-4-yl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0348] 4'-(Difluoromethyl)-N-(2-(difluoromethyl)-1H-benzo[d]imidazol-4-yl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxamide

[0349] 4'-(Difluoromethyl)-5-(ethylsulfonamido)-[1,1'-biphenyl]-2-carboxylic acid 9f (128 mg, 0.36 mmol) was dissolved in dichloromethane (1 mL) at room temperature. A catalytic amount of N,N-dimethylformamide was added dropwise. Oxalyl chloride (46 mg, 0.36 mmol) was added dropwise at 0°C and stirred for half an hour. TLC analysis showed complete reaction with the formation of new spots. The reaction solution was concentrated to dryness under reduced pressure. 2-(Difluoromethyl)-1H-benzo[d]imidazol-4-amine 9d (66 mg, 0.36 mmol) was dissolved in dichloromethane (1 mL) and the resulting concentrate was added to the system at 0°C. After nitrogen substitution three times, the reaction was allowed to proceed at 25°C for 1 hour. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was poured into water (80 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4CO3+H2O, mobile phase B: CH3CN) to give 4'-(difluoromethyl)-N-(2-(difluoromethyl)-1H-benzo[d]imidazol-4-yl)-5-(ethylsulfonyl)-[1,1'-biphenyl]-2-carboxamide 9 (33 mg) with a yield of 17.91%.

[0350] MS m / z(ESI):521.2[M+1]

[0351] 1 H NMR(400MHz,DMSO-d6)δ12.84(s,1H),10.03(s,1H),7.80–7.63(m,2H),7.58(s,4H),7.42–7.34 (m,2H),7.29–7.15(m,3H),7.01(t,J=52.0Hz,1H),3.23(q,J=7.2Hz,2H),1.24(t,J=7.3Hz,3H).

[0352] According to the preparation method of Example 9 of the present invention, Example 10 was prepared, and the specific structure and structural characterization are as follows:

[0353] Biological evaluation

[0354] Test Example 1: Determination of the Inhibitory Effect of the Compounds of the Invention on OVCAR-3 Cell Proliferation

[0355] The following method was used to determine the effect of the compounds of the present invention on the proliferation of OVCAR-3 cells. OVCAR-3 cells (containing the TP53 R248Q mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).

[0356] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well and cultured overnight in a 37°C, 5% CO2 incubator. The test compound was then added and cultured for another 72 hours. After the culture was completed, 50uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and then allowed to stand for 10 minutes. The luminescence value of each sample well was then read on a microplate reader using the Luminescence mode. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO). Nonlinear regression analysis was then performed in GraphPad Prism 5 software using the logarithm of the compound concentration-inhibition rate to obtain the IC value of the compound for inhibiting cell proliferation. 50 Values ​​are shown in Table 1.

[0357] Table 1 IC of the compounds of the present invention on the inhibition of OVCAR-3 cell proliferation 50 data

[0358] Conclusion: The compounds of the present invention have an IC inhibitory effect on the proliferation of OVCAR-3 cells. 50 <100nM, with good inhibitory effect.

[0359] Note: The structure of AMG 650 (prepared according to Example 4 of patent publication WO2020132648A1) is as follows:

[0360] Test Example 2: Determination of the Inhibitory Effect of the Compounds of the Invention on HT-29 Cell Proliferation

[0361] The following method was used to determine the effect of the compounds of the present invention on HT-29 cell proliferation. HT-29 cells (containing the TP53R273H mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in McCoy's 5A medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).

[0362] The experimental method was performed according to the kit instructions and is briefly described as follows: The test compound was first dissolved in DMSO to prepare a 10 mM stock solution. The solution was then diluted with McCoy's 5A medium as described above to prepare the test sample. The final compound concentration ranged from 1000 nM to 0.015 nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well and incubated overnight at 37°C in a 5% CO2 incubator. The test compound was then added and cultured for an additional 120 hours. After incubation, 50 μL of CellTiter-Glo assay solution was added to each well. The cells were shaken for 5 minutes and allowed to stand for 10 minutes. Luminescence was then read on a microplate reader using the luminescence mode. The percent inhibition rate of the compound at each concentration was calculated by comparison with the control (0.3% DMSO). Nonlinear regression analysis was then performed in GraphPad Prism 5 software using the logarithm of compound concentration versus inhibition rate to obtain the IC value for the compound's inhibition of cell proliferation. 50 Values ​​are shown in Table 2.

[0363] Table 2 IC of the compounds of the present invention on the inhibition of HT-29 cell proliferation 50 data

[0364] Conclusion: The compounds of the present invention have an inhibitory effect on the proliferation of HT-29 cells. 50 <100nM, with good inhibitory effect.

[0365] Test Example 3: Test of the Inhibition of KIF18A Enzyme Activity by the Compounds of the Invention

[0366] The following method is used to determine the degree of inhibition of the compound of the present invention on the activity of recombinant human KIF18A enzyme under in vitro conditions. This method uses Promega's ADP-Glo TM Kinase Assay Kit (Cat. No. V9102). Detailed experimental procedures can be found in the kit instructions.

[0367] The experimental process is briefly described as follows: the test compound is first dissolved in DMSO to prepare a stock solution, and then serially diluted using reaction buffer A (15mM Tris, pH 7.5, 10mM MgCl2, 0.01% Pluronic F-68). The final concentration of the test compound in the reaction system ranges from 10000nM to 0.15nM; KIF18A protein and ATP working solution are prepared using reaction buffer B (15mM Tris, pH7.5, 10mM MgCl2, 0.01% Pluronic F-68, 37.5μg / ml tubulin, 1.25μM paclitaxel). The reaction is carried out in a 384-well microplate. First, the test compound and recombinant human KIF18A protein (final concentration 100nM, expressed by GenScript) are added to the wells and incubated at room temperature for 20 minutes. Then, ATP solution (from ADP-Glo) is added to the reaction solution. TM Kinase Assay kit component V915A, final concentration 60 μM) and incubate at room temperature for 20 minutes. Subsequently, 5 μL ADP-Glo ​​Reagent was added to the reaction system and incubated at room temperature for 50 minutes. Thereafter, 10 μL Kinase Detection Reagent was added to the reaction system and incubated at room temperature for 30 minutes. After the incubation, the chemiluminescence intensity value of each well was measured in the luminescence mode on the microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing with the luminescence intensity value of the control group (0.1% DMSO), and the nonlinear regression analysis of the compound concentration-inhibition rate was performed using GraphPad Prism 5 software to obtain the IC value of the compound. 50 Values ​​are shown in Table 3.

[0368] Table 3 IC values ​​of the compounds of the present invention for inhibiting KIF18A enzyme activity 50 data

[0369] Conclusion: The compounds of the present invention have an IC inhibitory effect on KIF18A enzyme activity. 50 <200nM, with significant inhibitory effect.

Claims

1. A compound represented by general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt: in: Ring A is selected from 5- to 10-membered aryl or 5- to 6-membered heteroaryl; Y1, Y2 and Y3 are each independently selected from CR d or N atoms, and at most two atoms among Y1, Y2, and Y3 are N atoms at the same time; R d is selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy, wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; G is selected from 5-10 membered aryl, 5-10 membered heteroaryl or 6-14 membered fused ring, wherein the aryl, heteroaryl or fused ring is optionally further substituted by one or more R 4 replace; R 4 are the same or different and are each independently selected from cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached; L1 is selected from a bond, -C 1-6 Alkylene-, -C 0-4 Alkylene-NR c S(=O)(=NH)-C 0-4 Alkylene-, -C 0-4 Alkylene-SC 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)-C 0-4 Alkylene-, -C 0-4 Alkylene-SO2-C 0-4 Alkylene-, -C 0-4 Alkylene-S(=O)(=NH)-C 0-4 Alkylene-, -C 0-4 Alkylene-NR c SO2-C 0-4 Alkylene-, -C 0-4 Alkylene-SO2NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-OC 0-4 Alkylene-, -C 0-4 Alkylene-NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-NR c SO2NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-NR c C(O)NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-C(O)NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-NR c C(O)-C 0-4 Alkylene-, -C 0-4 Alkylene-PC 0-4 Alkylene-, -C 0-4 Alkylene-P(=O)2-C 0-4 Alkylene, -C 0-4 Alkylene-C(=O)-C 0-4 Alkylene- or -C 0-4 Alkylene-C(=N(OH))-C 0-4 Alkylene-, wherein the -C 1-6 Alkylene- or -C 0-4 Alkylene - optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, cycloalkyl or alkoxy; R c is selected from a hydrogen atom or an alkyl group; R 1 is selected from hydrogen, cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 , -CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; R 2 are the same or different and are independently selected from halogen, hydroxy, cyano, alkyl, cycloalkyl or alkoxy; wherein the alkyl, cycloalkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; L2 is selected from in represents the connection site between the group and G in the general formula (I); Indicates that the group and the general formula (I) The attachment site of R 3 are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy; R 3 Preferably a hydrogen atom; R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; R 8 , R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; m is 0, 1 or 2; and r is independently 0, 1 or 2.

2. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof described by general formula (II): in, X1, X2, X3, and X4 are each independently selected from CR a 、C(O)、NR b or N atoms; X5 is selected from C atoms or N atoms; and at most three atoms among X1, X2, X3, X4, and X5 are N atoms at the same time; R a Each is independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; wherein the alkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; R b are each independently selected from a hydrogen atom or an alkyl group; Ring A, Y1, Y2, Y3, L1, L2, R 1 , R 2 , R 4 and m are as defined in claim 1.

3. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof according to general formula (III), (IV) or (V): in, Ring B is independently selected from a 3- to 10-membered heterocyclyl, a 3- to 10-membered cycloalkyl, a 5- to 6-membered aryl or a 5- to 6-membered heteroaryl; X6 and X7 are each independently selected from CR a 、C(O)、NR b or N atoms; X8, X9, X 10 Each independently selected from CR a 、C(O)、NR b or N atom, and X8, X9, X 10 At most two atoms in the molecule are N atoms at the same time; X 11 , X 12 , X 13 Each independently selected from CR a 、C(O)、NR b or N atoms, and X 11 , X 12 , X 13 At most two atoms in the molecule are N atoms at the same time; R a Each is independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; wherein the alkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; R b are each independently selected from a hydrogen atom or an alkyl group; n is each independently selected from 0, 1, 2, 3 or 4; Ring A, Y1, Y2, Y3, L1, L2, R 1 , R 2 , R 4 and m are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein Y1, Y2 and Y3 are each independently selected to be CH.

5. The compound according to claim 2 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Selected from the following groups: in, Indicates that the group and R in the general formula (II) 4 The attachment site of represents the connection site between the group and L2 in the general formula (II); R aa , R bb , R cc , R dd , R ee , R ff , R gg , R hh , R ii , R jj , R kk , R mm , R nn , R oo , R pp , R qq , R rr are the same or different and are each independently selected from hydrogen, halogen, hydroxy, cyano, methyl or methoxy; R aaa is selected from a hydrogen atom or a methyl group.

6. The compound according to claim 3 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein X6, X7, X8, X9, X 10 , X 11 , X 12 and X 13 Each is independently selected as CH.

7. The compound according to claim 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Ring B is each independently selected from the following groups: 8 . The compound according to claim 1 , or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

9. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein R 2 are the same or different and are each independently selected from halogen, hydroxy, cyano, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl or methoxy.

10. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: L1 is selected from a bond, -NR c -C 0-4 Alkylene-, -NR c SO2-C 0-4 Alkylene-, -SO2NR c -C 0-4 Alkylene-, -NR c SO2NR c -, -S(=O)(=NH)-, -NR c S(=O)(=NH)-、-C 1-4 Alkylene-, -S(=O)-, -O-, -C(=O)-, -C(=O)NR c -C 0-4 Alkylene-, -C 0-4 Alkylene-SO2-C 0-4 Alkylene-, -C=N(OH)- or -NR c -C(=O)-, wherein the -C 0-4 Alkylene- or -C 1-4 Alkylene - optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, cyclopropyl or methoxy; R c Each is independently selected from a hydrogen atom or a methyl group.

11. A compound according to claim 10, or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -NHSO2CH2CH2-, -SO2NHCH2CH2-, -SO2-, -CH2SO2-, -NHSO2-, -SO2NH-, -NHC(CH3)2CH2-, -C(O)NHCH2CH2-, -C(O)NHC(CH3)2CH2-, -C(O)N(CH3)CH2CH2-, -CH(CH3)(OH)CH2-, -NHSO2CH(CH3)CH2-, -SO2NHC(CH3)2CH2-, -C(O)NH-, -NHCH2CH2 or -CH2SO2CH2CH2-.

12. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein R 1 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, a heterocyclic group, a cycloalkyl group or a heteroaryl group, wherein the alkyl group, the heterocyclic group, the cycloalkyl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group or an alkyl group.

13. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein for 14. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein L2 is selected from in represents the connection site of the group to G in the general formula (I); The group represented by The attachment site of R 3 A hydrogen atom.

15. The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein R 4 Selected from halogen, alkyl, alkoxy, cycloalkyl or heterocyclyl; wherein the alkyl, alkoxy, cycloalkyl or heterocyclyl is optionally further substituted with one or more halogen; Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached.

16. The compound according to claim 15 or its stereoisomer, tautomer or pharmaceutically acceptable salt, wherein R 4 is halogen, methyl, difluoromethyl, trifluoromethyl, methoxy, Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached.

17. The compound according to any one of claims 1 to 16, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein the compound is:

18. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 17 or its stereoisomer, tautomer or pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

19. Use of the compound according to any one of claims 1 to 17 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a KIF18A inhibitor.

20. Use of the compound according to any one of claims 1 to 17 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for treating a disease mediated by KIF18A; preferably, the disease mediated by KIF18A is cancer.

21. The method of claim 20, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.

22. Use of the compound according to any one of claims 1 to 17 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a drug for treating cancer.

23. The use according to claim 22, wherein the cancer is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.

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