Aromatic amide derivatives, methods for producing the same, and uses thereof

Abstract

The present invention relates to aromatic amide derivatives, methods for producing the same, and the medical use of pharmaceutical compositions containing the derivatives. Specifically, the present invention relates to aromatic amide derivatives represented by general formula (I), methods for producing the same, pharmaceutically acceptable salts thereof, and their use as therapeutic agents, particularly as KIF18A inhibitors. The definitions of each substituent in general formula (I) are the same as those defined herein. [Formula 1] JPEG2026509288000061.jpg35169

Description

Detailed description of the invention

[0001] [Technical Field] The present invention relates to aromatic amide derivatives, methods for producing the same, pharmaceutical compositions containing the derivative, and their use as therapeutic agents, particularly as KIF18A inhibitors.

[0002] 〔background〕 Kinesin molecules are motor proteins that use microtubules as orbitals and play crucial roles in organelle migration, tissue and organ development, signal transduction, mitosis, meiosis, and other processes. Several microtubule-associated proteins (MAPs) of the kinesin-8 family play a role in regulating microtubule dynamic instability by influencing microtubule polymerization and depolymerization. KIF18A belongs to the kinesin-8 family, can move toward the positive electrode using microtubules as orbitals, and tends to bind to longer microtubules. Its activity is length-dependent and can ensure the timely and smooth completion of sister chromosome sequences by influencing spindle length. KIF18A has very similar functions across different species and is therefore conserved.

[0003] KIF18A is a molecular motor protein that moves to the positive pole of microtubules using microtubules as its orbital. It regulates chromosome assembly by influencing the dynamic instability of the microtubule ends and plays a role in mitosis. In anaphase, this protein is ubiquitinated and degraded. This ensures accurate chromosome segregation during mitosis and promotes the smooth completion of mitosis and cytokinesis. In prophase, the position of KIF18A at the positive pole of microtubules near the kinetochore is a necessary condition for it to exert its function, and its localization depends not only on the motor activity of its N-terminus but also on the tail structure domain that has microtubule-binding ability. KIF18A can also be modified by reversible phosphorylation / dephosphorylation of the protein, but systematic studies on how this post-translational modification modifies KIF18A function remain lacking. The estrogen receptor ERα may bind to KIF18A and promote its transcription, but it remains unclear whether KIF18A is regulated by other transcription factors. Therefore, further research is needed on the gene transcription regulatory mechanism of KIF18A. During meiosis, cells lacking KIF18A cannot complete meiosis, leading to spermatogenesis abnormalities and testicular malformations in male animals.

[0004] Studies have shown that the KIF18A protein is highly expressed in many cancers (including, but not limited to, hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, head cancer, cervical cancer, uterine cancer, ovarian cancer, synovial sarcoma, and rhabdomyosarcoma), indicating that KIF18A is closely related to tumor development and progression and may be a target for molecular diagnosis and treatment of various tumors. KIF18A expression is clinically associated with the progression of colorectal cancer. Studies have shown that KIF18A can induce Akt phosphorylation, and knocking out KIF18A in mice significantly promotes cell apoptosis. It is thought that KIF18A may promote the development 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 the classification, metastasis, and prognosis of breast tumors. Studies in breast cancer have shown that the aforementioned overexpression of KIF18A may lead to the generation of multinucleated cells. On the other hand, low expression of KIF18A can significantly weaken cell proliferation in vitro and in vivo, due to apoptosis induced by microtubule stabilization at microtubule terminals via KIF18A, and inactivation of the PI3K-Akt signaling pathway. In addition, KIF18A is upregulated at the transcriptional and translational levels in lung adenocarcinoma, and abnormal expression of KIF18A is associated with clinicopathological malignancy. KIF18 gene mutations can be observed in lung adenocarcinoma, and its expression is also regulated by DNA copy number. KIF18A gene knockout can suppress the proliferation of lung adenocarcinoma cells in vivo and in vitro, thus inducing cell apoptosis and G2 / M phase arrest. All genes that are highly expressed together with KIF18A are concentrated in cell cycle signaling pathways, making further study of the mechanism of action of KIF18A in tumors clinically extremely important.

[0005] There are currently no new KIF18A-targeting inhibitors on the market, and only Amgen's AMG-650 is in Phase I clinical trials. As a relatively advanced research direction, there is still enormous room for exploration in correlational research on KIF18A targets, and it is extremely important to continue studying its mechanism of action and develop new inhibitors.

[0006] 〔overview〕 To solve the above technical problems, the present invention provides an aromatic amide derivative represented by general formula (I), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

[0007] [ka]

[0008] In general formula (I), Ring A is selected from a 5- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl; G is

[0009] [ka]

[0010] Selected from; X1 and X2 are independent of each other, CR a or selected from N atoms; Y1, Y2, and Y3 are each independent of CR b Alternatively, there may be at most two atoms selected from N atoms, and Y1, Y2, and Y3 may simultaneously be N atoms; R a and R 6 Each of these is independently selected from a hydrogen atom, halogen, hydroxyl, cyano, alkyl, or alkoxy, and the alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxyl, cyano, alkyl, or alkoxy; RA are the same or different and each independently selected from a hydrogen atom, halogen, hydroxyl, cyano, alkyl, or alkoxy, wherein the alkyl or the alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl, or alkoxy; or, two Rs A are, together with the same carbon atom to which the two Rs A are attached, forming C(O); L1 is selected from a bond or C1-C6 alkylene, wherein the alkylene is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, or alkoxy, and one or more methylene groups of the alkylene are optionally substituted by one or more of O, S(O) r , C(O), or NR C ; R C is selected from a hydrogen atom or alkyl; L2 is

[0011]

Chemical formula

[0012] selected from; R 3 are each independently selected from a hydrogen atom or alkyl, wherein the alkyl is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, or alkoxy; R 3 is preferably a hydrogen atom; R 1The element is selected from hydrogen, cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated 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 It is optionally further substituted by one or more substituents selected from; R 4 cyano, halogen, alkyl, alkenyl, alkynyl, 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 Selected from, the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 8 , -C(O)OR 8 -OC(O)R 8 , -NR9 R 10 -C(O)NR 9 R 10 -SO2NR 9 R 10 , or -NR 9 C(O)R 10 It is optionally further substituted by one or more substituents selected from; R 5 Each is independently selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated 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 It is optionally further substituted by one or more substituents selected from; R 6 and R 7 Each is independently selected from a hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydroxyl, 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 -SO2NR9 R 10 or -NR 9 C(O)R 10 and is optionally further substituted by one or more substituents selected from; or R 6 and R 7 form a 4- to 8-membered heterocyclyl together with the atom to which the R 6 and the R 7 is attached, said 4- to 8-membered heterocyclyl containing one or more N, O, or S(O) r and said 4- to 8-membered heterocyclyl being optionally further substituted by one or more substituents selected from hydroxyl, 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 ; R 8 R 9 and R 10 are each independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, said alkyl, said cycloalkyl, said heterocyclyl, said aryl, or said heteroaryl being optionally further substituted by one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate group.

[0013] n is 0, 1, 2, 3 or 4; r is each independently 0, 1 or 2.

[0014] A preferred solution of the present invention provides a compound represented by the general formula (I), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, which is a compound represented by the general formula (II) or (III), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof;

[0015]

Chemical formula

[0016] In the general formula (II) or (III), ring A, X1, X2, R A 、R 1 、R 4 、L1, and n are as described in the general formula (I).

[0017] A preferred solution of the present invention provides a compound represented by the general formula (I), (II) or (III), or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond or C1-C6 alkylene, which alkylene is optionally further substituted by one or more hydroxyl groups, and one or more methylene groups of the alkylene are optionally substituted by one or more O, S(O) r 、C(O), or NR C ; r is 2; and R C is selected from a hydrogen atom or methyl.

[0018] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, where L1 is selected from the following: -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-.

[0019] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, where R 1 This is selected from a hydrogen atom, hydroxyl, alkyl, heterocyclyl, cycloalkyl, or heteroaryl, and the alkyl, heterocyclyl, cycloalkyl, or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl or alkyl.

[0020] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0021] [ka]

[0022] teeth,

[0023] [ka]

[0024] That is the case.

[0025] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein

[0026] [ka]

[0027] teeth,

[0028] [ka]

[0029] That is the case.

[0030] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, where X1 and X2 are each independently selected from CH.

[0031] A preferred solution of the present invention provides compounds represented by general formula (I), (II), or (III), or stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts thereof, where ring A is one of the following compounds:

[0032] [ka]

[0033] Selected from.

[0034] A preferred solution of the present invention provides compounds represented by general formula (I), (II), or (III), or stereoisomers thereof, tautomers thereof, or pharmaceutically acceptable salts thereof, where ring A is one of the following compounds:

[0035] [ka]

[0036] Selected from.

[0037] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R A Each is independently selected from a hydrogen atom or a methyl atom; Or, two R's A These are the two R's A Together with the same carbon atom to which it is bonded, it forms C(O).

[0038] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 These are, independently, 3-10 member heterocyclines, or C3-C 10 Selected from cycloalkyl groups, The heterocyclyl or cycloalkyl group may be optionally further substituted with one or more hydroxyl groups or halogens.

[0039] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 Each of these is independently selected from C2-C6 alkenyl or C1-C6 alkyl groups. The alkenyl or alkyl group may optionally be further substituted with one or more hydroxyl groups or halogens.

[0040] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 teeth,

[0041] [ka]

[0042] That is the case.

[0043] A preferred solution of the present invention provides a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, where R 4 The following compounds:

[0044] [ka]

[0045] That is the case.

[0046] In a preferred solution of the present invention, the compound represented by general formula (I), (II), or (III) is the following compound:

[0047] [ka] JPEG2026509288000015.jpg226169

[0048] Selected from.

[0049] In a more preferred solution of the present invention, the compound represented by general formula (I), (II), or (III) is the following compound:

[0050] [Table 1] JPEG2026509288000017.jpg241169JPEG2026509288000018.jpg241169JPEG2026509288000019.jpg151169

[0051] Alternatively, a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof may be selected.

[0052] Note: If there is a discrepancy between the depicted structure and the name assigned to it, the depicted structure takes precedence.

[0053] Furthermore, the present invention provides a pharmaceutical composition comprising an effective amount of a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

[0054] The present invention provides for the use of compounds represented by general formula (I), (II), or (III), or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or their pharmaceutically acceptable compositions (such as the pharmaceutically acceptable compositions described in the above technical solutions), as pharmaceuticals (such as therapeutics).

[0055] The present invention provides for the use of compounds represented by general formula (I), (II), or (III), or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or their pharmaceutically acceptable compositions (such as the pharmaceutically acceptable compositions described in the above technical solutions) in the production of KIF18A inhibitors.

[0056] The present invention further provides the use of compounds represented by general formula (I), (II), or (III), or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof (such as the pharmaceutically acceptable compositions described in the above technical solutions) in the manufacture of pharmaceuticals for the treatment of KIF18A-mediated diseases. Herein, the KIF18A-mediated disease is preferably cancer; more preferably, the KIF18A-mediated disease is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, head cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer, and lung adenocarcinoma.

[0057] The present invention provides for the use of compounds represented by general formula (I), (II), or (III), or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or their pharmaceutically acceptable compositions (such as the pharmaceutically acceptable compositions described in the above technical solutions) in the manufacture of pharmaceuticals for the treatment of cancer.

[0058] The present invention provides for the use of compounds represented by general formula (I), (II), or (III), or their stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof (such as the pharmaceutically acceptable compositions described in the above technical solutions), in the manufacture of pharmaceuticals for the treatment of hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, head cancer, cervical cancer, uterine cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer, and lung adenocarcinoma.

[0059] The present invention further provides a method for preventing and / or treating KIF18A-mediated diseases. The method comprises administering to a patient an effective amount of a compound represented by general formula (I), (II), or (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof (such as the pharmaceutically acceptable compositions described in the technical solutions above). Herein, the KIF18A-mediated disease is preferably cancer; more preferably, the KIF18A-mediated disease is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, head cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer, and lung adenocarcinoma.

[0060] The present invention further provides a method for preventing and / or treating cancer. The method comprises administering to a patient an effective amount of a compound represented by general formula (I), (II), or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof (such as the pharmaceutically acceptable compositions described in the technical solutions above).

[0061] The present invention further provides a method for preventing and / or treating hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, head cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer, or lung adenocarcinoma. The method comprises administering to a patient an effective amount of a compound represented by general formula (I), (II), or (III), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition thereof (such as the pharmaceutically acceptable compositions described in the above technical solutions).

[0062] [Detailed explanation] Unless otherwise stated, several terms used in the specification and claims of this invention are defined as follows:

[0063] "Bond" refers to a bond formed by the direct bonding of the two terminal portions of a substituent, where no labeled substituent is present.

[0064] "Alkyl" refers to a group that is C1-C when viewed as a single group or as part of a single group. 20 This refers to aliphatic hydrocarbon groups, including linear or branched chains. Preferably, alkyl groups are C1-C1 10 The alkyl group is alkyl, and more preferably C1-C6 alkyl. Embodiments of the alkyl group 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. The alkyl group may be substituted or unsubstituted.

[0065] "Alkenyl" refers to the alkyl group defined above, consisting of at least two carbon atoms and at least one carbon-carbon double bond. Typical examples include vinyl, 1-propenyl, 2-propenyl, 1-,2- or 3-butenyl.

[0066] [ka]

[0067] This includes, but is not limited to, the following. Preferably, the alkenyl is a C2-C4 alkenyl. The alkenyl may or may not be substituted.

[0068] "Alkynyl" refers to an aliphatic hydrocarbon group containing one carbon-carbon triple bond, which may be linear or branched. Preferably, the alkynyl is C2-C 10The alkynyl group is more preferably a C2-C6 alkynyl, and most preferably a C2-C4 alkynyl. Embodiments of the alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2-, or 3-butynyl. The alkynyl may or may not be substituted.

[0069] "Alkylene" is a saturated C1-C molecule with two residues, obtained by removing two hydrogen atoms from the same carbon or two different carbon atoms of a parent alkane. 20 This refers to a linear or branched aliphatic hydrocarbon group, preferably C1-C1. 10 The alkylene is an alkylene, more preferably a C1-C6 alkylene. Embodiments of the alkylene group include, but are not limited to, methylene, 1,1-ethylidene, 1,2-ethylidene, 1,1-propyridene, 1,2-propyridene, 1,3-propyridene, 1,4-butylidene, etc. The alkylene may or may not be substituted.

[0070] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more atoms forming the ring are carbon atoms. "Cycloalkyl" includes monocyclic rings, polycyclic rings, fused rings, bridged rings, and spirocyclic rings, and preferably includes 5-7 membered monocyclic rings or 7-10 membered bicyclic or tricyclic rings. Embodiments of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl may or may not be substituted.

[0071] "Spiroalkyl" refers to a 5- to 18-membered polycyclic group having two or more cyclic structures, where the monocyclic rings share one carbon atom (called a spiro atom) with each other, and the rings contain one or more double bonds but do not have a fully conjugated π-electron aromatic system. Preferably, spiroalkyls are 6- to 14-membered groups, and more preferably, 7- to 10-membered groups. Depending on the number of shared spiro atoms between the rings, spiroalkyls are classified as mono-, di-, or multi-spiroalkyls, preferably mono- and di-spiroalkyls, and preferably 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered, or 5-membered / 6-membered. Non-limiting embodiments of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl, etc.

[0072] A "condensed cycloalkyl" refers to a 5- to 18-membered all-carbon polycyclic group having two or more cyclic structures sharing one pair of carbon atoms with each other, where one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron aromatic system. Preferably, a condensed cycloalkyl is a 6- to 12-membered group, and more preferably, a 7- to 10-membered group. Condensed cycloalkyls can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed cycloalkyls depending on the number of rings they comprise. Preferably, a condensed cycloalkyl is a bicyclic or tricyclic condensed cycloalkyl, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl. Non-limiting embodiments of a "condensed cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl-1-alkenyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, tetrahydrophenyl, and the like.

[0073] A "crosslinked cycloalkyl" refers to a 5-18 membered all-carbon polycyclic group having two or more cyclic structures that share two carbon atoms that are not directly bonded to each other, where one or more rings may contain one or more double bonds, but do not have a fully conjugated π-electron aromatic system. Preferably, the crosslinked cycloalkyl is a 6-12 membered group, and more preferably, a 7-10 membered group. Preferably, the crosslinked cycloalkyl is a 6-14 membered group, and more preferably, a 7-10 membered group. Crosslinked cycloalkyls can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic crosslinked cycloalkyls depending on the number of rings they comprise. Preferably, the crosslinked cycloalkyl is a bicyclic, tricyclic, or tetracyclic crosslinked cycloalkyl, and more preferably, a bicyclic or tricyclic crosslinked cycloalkyl. Non-limiting embodiments of "crosslinked 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.

[0074] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" may be used interchangeably in this application, each referring to a non-aromatic heterocycline, where one or more ring-forming atoms are heteroatoms (nitrogen, oxygen, or S(O)). t(where t is selected from 0, 1 or 2)). Heterocyclyls include monocyclic rings, polycyclic rings, fused rings, bridging rings and spirocyclic rings. Preferably, heterocyclyls are 5-7 membered monocyclic rings or 7-10 membered bicyclic or tricyclic rings and may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and / or sulfur. Embodiments of "heterocyclyl" include morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuryl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-azabicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine,

[0075] [ka]

[0076] This includes, but is not limited to, the following.

[0077] Heterocyclines may or may not be substituted.

[0078] A "spiro-heterocyclyl" refers to a 5-18 member polycyclic group having two or more cyclic structures, where each ring shares one atom with the others, and the ring contains one or more double bonds but does not have a fully conjugated π-electron aromatic system. Here, one or more ring atoms are heteroatoms (nitrogen, oxygen, or S(O)). t (Here, t is selected from 0, 1, or 2) The remaining ring atoms are carbon. Preferably, the spiro-heterocyclyl is a 6- to 14-membered group, and more preferably, the spiro-heterocyclyl is a 7- to 10-membered group. Spiro-heterocyclyls are divided into mono-, di-, or multi-spiro-heterocyclyls depending on the number of covalent spiro atoms between the rings. Spiro-heterocyclyls are preferably mono- and di-spiro-heterocyclyls, and more preferably mono-spiro-heterocyclyls having 4-member / 4-member, 4-member / 5-member, 3-member / 5-member, 3-member / 6-member, 4-member / 6-member, 5-member / 5-member or 5-member / 6-member. Non-limiting embodiments of "spiro-heterocyclyl" include 1,7-dioxane[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0079] [ka]

[0080] This includes, but is not limited to, the following.

[0081] A "condensed heterocyclyl" refers to a polycyclic all-carbon group having two or more cyclic structures sharing a pair of atoms, where one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated π-electron aromatic system. Here, one or more ring atoms are heteroatoms (nitrogen, oxygen, or S(O)). t(where t is selected from 0, 1, or 2), and the remaining ring atoms are carbon. Preferably, the condensed heterocyclyl is a 6- to 14-membered group, and more preferably, the condensed heterocyclyl is a 7- to 10-membered group. Depending on the number of rings it comprises, the condensed heterocyclyl can be classified into bicyclic, tricyclic, tetracyclic, or polycyclic condensed heterocyclyl. The condensed heterocyclyl is preferably a bicyclic or tricyclic condensed heterocyclyl, and more preferably a bicyclic condensed heterocyclyl having 5 / 5 or 5 / 6 members. Non-limiting embodiments of "condensed heterocyclyl" 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, etc.

[0082] A "bridged heterocyclyl" refers to a 5-18 membered polycyclic group having two or more cyclic structures that share two atoms that are not directly bonded to each other, where one or more rings may contain one or more double bonds, but do not have a fully conjugated π-electron aromatic system. Here, one or more ring atoms are heteroatoms (nitrogen, oxygen, or S(O)). t (where t is selected from 0, 1, or 2), and the remaining ring atoms are carbon. Preferably, the bridging heterocyclyl is a 6- to 14-membered group, and more preferably, the bridging heterocyclyl is a 7- to 10-membered group. Depending on the number of rings it comprises, the bridging heterocyclyl can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic bridging heterocyclyls. The bridging heterocyclyl is preferably a bicyclic, tricyclic, or tetracyclic bridging heterocyclyl, and more preferably a bicyclic or tricyclic bridging heterocyclyl. Non-limiting embodiments of "bridging heterocyclyl" include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl, etc.

[0083] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, which may be linked together by condensation. The term "aryl" includes monocyclic or bicyclic aryls (such as the aromatic groups of phenyl, naphthyl, and tetrahydronaphthyl). Preferably, the aryl is C6-C6 10 The aryl is aryl, more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl may or may not be substituted.

[0084] "Heteroaryl" refers to a 5-6 membered aromatic monocyclic ring or an 8-10 membered aromatic bicyclic ring that may contain 1-4 atoms selected from nitrogen, oxygen, and / or sulfur. Embodiments of "heteroaryl" include furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridadinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothiophenyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolyl, indazolyl, benzoisothiazolyl, benzoxazolyl, benzoisoxazolyl, isothiazolyl, 1H- 1,2,4-Triazolyl, 4H-1,2,4-Triazolyl, Pyridyl, Pyrimidinyl, Pyrazine-2(1H)-Keto, Pyrimidine-4(3H)-Keto, Pyridazine-3(2H)-Keto, 1H-Indolyl, 1H-Benzo[d]Imidazolyl, 1H-Pyrrolo[2,3-c]Pyridyl, 3H-Imidazolyl[4,5-c]Pyridyl, Isoquinolinyl, Quinazolinyl, 2H-Isoindolyl, Furan[3,2-b]Pyridyl, Furan[2,3-b]Pyridyl, Thieno[2,3-c]Pyridyl, Benzofuryl, Benzo[b]Tienyl, 1H-Pyrrolo[3,2-b]Pyridyl, 2H-Pyrrolo[3,4-c]Pyridyl,

[0085] [ka]

[0086] This includes, but is not limited to, the following.

[0087] Heteroaryls may or may not be substituted.

[0088] "Alkoxy" refers to an (alkyl-O-) group. Alkyl is defined herein. C1-C6 alkoxys are preferred. Embodiments of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

[0089] "Nitro" refers to the -NO2 group.

[0090] "Hydroxyl" refers to the -OH group.

[0091] "Halogens" refer to fluorine, chlorine, bromine, and iodine.

[0092] "Amino" refers to -NH2.

[0093] "Cyano" refers to -CN.

[0094] "Benzyl" refers to -CH2-phenyl.

[0095] "Carboxyl" refers to -C(O)OH.

[0096] The term "carboxylate group" refers to -C(O)O-alkyl or -C(O)O-cycloalkyl, where alkyl and cycloalkyl are defined as described above.

[0097] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxyl group, where alkyl is defined as described above.

[0098] "Aminoalkyl" refers to an alkyl group substituted with an amino, where alkyl is defined as described above.

[0099] "Alkyl halogenated compounds" refer to alkyl groups substituted with halogens, where alkyl is defined as described above.

[0100] "Halogenated alkoxy" refers to an alkoxy compound substituted with a halogen, where alkoxy is defined as described above.

[0101] "DMSO" refers to dimethyl sulfoxide.

[0102] "BOC" refers to tert-butoxycarbonyl.

[0103] "Bn" refers to benzyl.

[0104] "THP" refers to 2-tetrahydropyranyl.

[0105] "TFA" refers to trifluoroacetic acid.

[0106] "Ts" refers to p-toluenesulfonyl.

[0107] A "leaving group" is an atom or functional group that is separated from a larger molecule in a chemical reaction, and is a term used in nucleophilic substitution and elimination reactions. In the aforementioned nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that is separated from the substrate molecule along with its electron pair is called the leaving group. Groups that readily accept electrons and carry a strong negative charge are excellent leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to separate from other molecules. This is because when the pKa of the conjugate acid is small, the corresponding leaving group does not need to bond with other atoms and is more likely to exist in the form of an anion (or an electrically neutral leaving group). Common leaving groups include, but are not limited to, halogens, methanesulfonyls, -OTs, or -OH.

[0108] "Substitutable" means that one or more hydrogen atoms in the group, preferably up to five, more preferably one to three, are independently substituted by a corresponding number of substituents. It goes without saying that substituents exist only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) whether a substitution is possible or impossible without excessive trial and error. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated (such as olefinic) bond.

[0109] In this specification, "substituted" or "substituted" means, unless otherwise specified, a group having the following substituents: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthiol, heterocycloalkylthiol, amino, alkyl halogen, hydroxyalkyl, carboxyl, carboxylate group, =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) r R 6 ; indicates that it may be substituted by one or more elements selected from the list.

[0110] R 6is selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated 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 It is optionally further substituted by one or more substituents selected from; R 7 and R 8 Each is independently selected from a hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, where the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl are hydroxyl, 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 It is optionally further substituted by one or more substituents selected from; Or, R 7 and R 8 R 7 and the R 8Together with the atom to which it bonds, it forms a 4-8 membered heterocycline, and this 4-8 membered heterocycline contains one or more N, O, or S(O) r It contains, and the 4-8 membered heterocyclyl is hydroxyl, 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 It is optionally further substituted by one or more substituents selected from; R 9 , R 10 and R 11 Each of these is independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate groups.

[0111] r is selected from 0, 1, or 2.

[0112] The compounds of the present invention may contain chiral centers or other centers and may therefore exist in various stereoisomeric forms. All stereoisomers of the compounds of the present invention include, but are not limited to, diastereomers, enantiomers, atropisomers and geometric (conformational)isomers, and mixtures thereof such as racemic mixtures, and are all within the scope of the present invention.

[0113] Unless otherwise specified, the structures described in this invention further include all isomers of this structure (e.g., diastereomers, enantiomers, and atropisomers and geometric (conformational) isomers; for example, R-coordination and S-coordination of the chiral center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers). Therefore, single stereoisomers of the compounds of this invention, as well as enantiomer mixtures, diastereomer mixtures, and geometric (conformational) isomer mixtures, are all within the scope of this invention.

[0114] "Pharmacologically acceptable salts" refer to some of the above compounds that are suitable for medical use and can maintain their original biological activity. A pharmaceutically acceptable salt of a compound represented by general formula (I) may be a metal salt or amine salt formed using a suitable acid.

[0115] "Pharmaceutical composition" means a mixture comprising one or more compounds described herein, or a pharmaceutically acceptable salt or prodrug thereof, other chemical components, and other components (such as physiologically acceptable carriers and excipients). The purpose of the pharmaceutical composition is to facilitate administration to a living organism, which is beneficial for the absorption of the active ingredient and thus exerts biological activity.

[0116] [Method for synthesizing the compound of the present invention] To achieve the objectives of the present invention, the following technical solutions are used in the present invention.

[0117] The present invention provides a method for producing a compound represented by general formula (I), or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof. The method is as follows:

[0118] [ka]

[0119] The process includes a step of carrying out a condensation reaction of a compound represented by general formula (IA) and a compound represented by general formula (IB), and optionally a further step of carrying out a substitution reaction to obtain a compound represented by general formula (I).

[0120] Here, L2 is,

[0121] [ka]

[0122] Selected from; Y is selected from hydroxyl or chlorine; and, Ring A, X1, X2, Y1, Y2, Y3, L1, G, R 1 , R 3 , R 4 , R A , and n are as explained in general formula (I).

[0123] [Embodiment] The present invention will be further described in combination with the following embodiments, but these embodiments will not limit the scope of the present invention.

[0124] [Examples] The examples show the preparation of a representative compound represented by formula (I) and related structural identification data. It should be noted that the following embodiments are for illustrative purposes only and do not limit the present invention. 1 The 1H NMR spectrum was measured using a Bruker instrument (400 MHz), and the chemical shift was expressed in ppm. Tetramethylsilane was used as an internal standard (0.00 ppm). 1 1H NMR spectrum is represented as follows: s = single peak, d = double peak, t = triple peak, m = multiple peaks, br = spread peak, dd = double peak of a double peak, and dt = double peak of a triple peak. When a coupling constant is given, its unit is Hz.

[0125] The mass spectrum is measured using an LC / MS instrument, and the ionization mode may be ESI or APCI.

[0126] The silica gel plates used for thin-layer chromatography were Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The silica gel plates used for thin-layer chromatography (TLC) were of a size of 0.15 mm to 0.2 mm, and the plates used for the separated and purified products were of a size of 0.4 mm to 0.5 mm.

[0127] Yantai Huanghai silica gel with a mesh size of 200-300 is commonly used as a support in column chromatography.

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

[0129] CD3OD: Deuterated methanol: CDCl3: Deuterated chloroform: DMSO-d6: Deuterated dimethyl sulfoxide.

[0130] An argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of approximately 1 liter.

[0131] In embodiments, unless otherwise specified, the solution during the reaction refers to an aqueous solution.

[0132] The compounds were purified by silica gel column chromatography and reversed-phase column chromatography, where the eluent systems were selected from: System A: petroleum ether and ethyl acetate system; System B: dichloromethane and methanol system; System C: dichloromethane and ethyl acetate system; and System D: aqueous trifluoroacetic acid and acetonitrile system. The volume ratio of the solvents varied depending on the polarity of the compound and could also be adjusted by adding small amounts of acidic or basic reagents (e.g., acetic acid or triethylamine).

[0133] [Example 1] N-(7-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0134] [ka]

[0135] Process 1 7-Bromo-5-nitro-2,3-dihydrobenzofuran Nitric acid (1.5 mL) was added dropwise to a solution of 7-bromo-2,3-dihydrobenzofuran 1a (700 mg, 3.52 mmol, commercially available) in trifluoroacetic acid (3 mL), and the mixture was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was slowly added dropwise to water (50 mL) to precipitate a pale yellow solid. After filtration, the filter cake was dried under vacuum to obtain 7-bromo-5-nitro-2,3-dihydrobenzofuran 1b (750 mg) in yield 87.39%. MS m / z(ESI):244.0[M+1].

[0136] Process 2 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine 7-Bromo-5-nitro-2,3-dihydrobenzofuran 1b (650 mg, 2.66 mmol) and 4,4-difluoropiperidine 1c (645.24 mg, 5.33 mmol) were dissolved in toluene (20 mL), and then palladium acetate (59.80 mg, 266.35 μmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (497.54 mg, 799.04 μmol), and cesium carbonate (2.60 g, 7.99 mmol) were added. The mixture was subjected to three argon substitutions, heated to 100°C, and stirred for 16 hours. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 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 obtain 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine 1d (610 mg) in yield 80.57%. MS m / z(ESI):285.1[M+1].

[0137] Process 3 7-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzofuran-5-amine Ammonium chloride (559.35 mg, 10.55 mmol) and iron powder (589.38 mg, 10.55 mmol) were added to a mixed solution of 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine 1d (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 solution was filtered and extracted with ethyl acetate (30 mL). The aqueous phase was further extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 7-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzofuran-5-amine 1e (220 mg) in 81.98% yield. MS m / z(ESI):255.1[M+1].

[0138] Process 4 N-(7-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 7-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzofuran-5-amine 1e (68.34 mg, 268.77 μmol), 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid 1f (80 mg, 223.97 μmol, prepared according to the method of published patent WO2020132648), and 1-methylimidazole (55.84 mg, 671.92 μmol) were added to N,N-dimethylformamide (2 mL) and stirred at room temperature for 30 minutes. Then, (chloro(dimethylamino)methylene)-dimethylammonium hexafluorophosphate (188.53 mg, 671.92 μmol) was added to the mixture and stirred at room temperature for 2 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure. The aforementioned residue was purified by silica gel column chromatography (eluent: system A) to obtain 1 g (92 mg) of N-(7-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide in a yield of 69.22%. MS m / z(ESI): 594.4[M+1].

[0139] Process 5 N-(7-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide N-(7-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 1 g (80 mg, 134.81 μmol), ethylsulfonamide 1 h (22.07 mg, 202.21 μmol, commercially available), 2-(methylamino)acetic acid (18.01 mg, 202.21 μmol), cuprous iodide (7.70 mg, 40.44 μmol), and potassium phosphate trihydrate (179.50 mg, 674.03 μmol) were added to N,N-dimethylformamide (2 mL). The mixture was purged with argon, heated to 100°C, and stirred for 6 hours. After the reaction was completed, the mixture was filtered, and the filtrate was purified using a prepared liquid phase (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm inner diameter; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain N-(7-(4,4-difluoropiperidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 1 (31 mg) in yield of 40.02%. MS m / z(ESI): 575.3[M+1].

[0140] 1 H NMR (400MHz, DMSO-d6):δ 11.50(s, 1H), 10.14(s, 1H), 7.82(d, J=8.5Hz, 1H), 7.42(d, J=1.8Hz, 1H), 7.17(d, J=2.1Hz, 1H), 7.07~7.01(m, 2H), 4.54(d, J=8.7Hz, 2H), 3. 19(qd, J=8.7, 7.2, 4.1Hz, 8H), 2.97(t, J=5.2Hz, 4H), 2.09(tt, J=13.8, 5.3Hz, 4H), 1.55(t, J=5.1Hz, 4H), 1.20(t, J=7.3Hz, 3H), 0.35(s, 4H).

[0141] [Example 2] N-(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindorin-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0142] [ka]

[0143] Process 1 Methyl 4-bromo-2-fluoro-6-methylbenzoate 4-Bromo-2-fluoro-6-methylbenzoic acid 2a (1.0 g, 4.29 mmol, commercially available) and potassium carbonate (1.19 g, 8.58 mmol) were dissolved in N,N-dimethylformamide (10 mL). Methyl iodide (913.63 mg, 6.44 mmol) was added dropwise at room temperature, and the mixture was stirred for 2 hours. After the reaction was complete, water (20 mL) was added dropwise to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 4-bromo-2-fluoro-6-methylbenzoate 2b (1.03 g) in 97.15% yield. MS m / z(ESI):247.0[M+1].

[0144] 1 H NMR (400MHz, DMSO-d6): δ 7.54 (dd, J=9.5, 1.8Hz, 1H), 7.46 (d, J=1.8Hz, 1H), 3.87 (s, 3H), 2.33 (s, 3H).

[0145] Process 2 Methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate Methyl 4-bromo-2-fluoro-6-methylbenzoate 2b (500 mg, 2.02 mmol) and azobisisobutyronitrile (33.23 mg, 202.38 μmol) were dissolved in acetonitrile (10 mL), and then N-bromosuccinimide (468.26 mg, 2.63 mmol) was added at room temperature. The resulting mixture was heated to 90°C and stirred for 2 hours. After the reaction was complete, water (20 mL) was added dropwise to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate 2c (0.53 g) in 80.34% yield. MS m / z(ESI):326.9[M+1].

[0146] Process 3 5-Bromo-7-fluoro-2-methylisoindoline-1-one Methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate 2c (500 mg, 1.53 mmol) was dissolved in methylamine-dioxane solution (4 M, 3.83 mL), heated to 40°C, and stirred for 2 hours. After the reaction was complete, water (20 mL) was added dropwise to the reaction mixture, and the resulting system was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo-7-fluoro-2-methylisoindorin-1-one 2d (130 mg) in a yield of 34.72%. MS m / z(ESI):244.0[M+1].

[0147] Process 4 5-Bromo-7-(4,4-difluoropiperidine-1-yl)-2-methylisoindorin-1-one 5-Bromo-7-fluoro-2-methylisoindorin-1-one 2d (120 mg, 491.68 μmol) and 4,4-difluoropiperidine 1c (9.93 mg, 81.95 μmol) were dissolved in dimethyl sulfoxide (5 mL), then N,N-diisopropylethylamine (158.87 mg, 1.23 mmol) was added, and the mixture was heated to 150°C and stirred for 8 hours. After the reaction was complete, water (20 mL) was added dropwise to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The aforementioned residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo-7-(4,4-difluoropiperidine-1-yl)-2-methylisoindorin-1-one 2e (150 mg) in yield 88.38%. MS m / z(ESI):344.8[M+1].

[0148] Process 5 tert-butyl(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindorin-5-yl)carbamate 5-Bromo-7-(4,4-difluoropiperidine-1-yl)-2-methylisoindorin-1-one 2e (140 mg, 405.58 μmol) and tert-butylcarbamate (95.02 mg, 811.17 μmol) were dissolved in 1,4-dioxane (10 mL), and then palladium acetate (9.11 mg, 40.56 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (46.94 mg, 81.12 μmol), and cesium carbonate (396.44 mg, 1.22 mmol) were added. The mixture was sparged with argon gas for 5 minutes, heated to 100°C, and stirred for 18 hours. After the reaction was complete, water (20 mL) was added dropwise to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindorin-5-yl)carbamate 2f (150 mg) in 96.96% yield. MS m / z(ESI):382.0[M+1].

[0149] Process 6 5-amino-7-(4,4-difluoropiperidine-1-yl)-2-methylisoindorin-1-one 150 mg (393.27 μmol) of tert-butyl(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindorin-5-yl)carbamate was dissolved in hydrochloric acid (4 M, 983.18 μL) and heated to 60°C, stirring for 16 hours. After the reaction was complete, 20 mL of water and 20 mL of ethyl acetate were sequentially added to the reaction mixture. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 2 g (110 mg) of 5-amino-7-(4,4-difluoropiperidine-1-yl)-2-methylisoindorin-1-one in 99.43% yield. MS m / z (ESI): 281.9 [M+1].

[0150] Process 7 N-(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindorin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 1 f (130 mg, 363.96 μmol) of 2-(6-azaspiro[2,5]octan-6-yl)-4-iodobenzoic acid was dissolved in acetonitrile (10 mL), then 1-methylimidazole (60.50 mg, 727.91 μmol) and tetramethylchloroformamidinium-hexafluorophosphate (204.24 mg, 727.91 μmol) were added, and the mixture was stirred at room temperature for 1 hour. 2 g (112.62 mg, 400.35 μmol) of 5-amino-7-(4,4-difluoropiperidine-1-yl)-2-methylisoindorin-1-one was added, and the resulting mixture was heated to 60°C and stirred for 4 hours. After the reaction was complete, the reaction mixture was concentrated under reduced pressure. The aforementioned residue was purified by silica gel column chromatography (eluent: system A) to obtain N-(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindorin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 2h (180 mg) in yield 79.71%. MS m / z (ESI): 620.8 [M+1].

[0151] Process 8 N-(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindorin-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide N-(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindorin-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 2h (100 mg, 161.17 μmol) and ethylsulfonamide 1h (35.18 mg, 322.34 μmol) were dissolved in N,N-dimethylformamide (10 mL), and then cuprous iodide (17.89 mg, 80.58 μmol), 2-(methylamino)acetic acid (14.36 mg, 161.17 μmol), and potassium phosphate trihydrate (214.60 mg, 805.84 μmol) were added. The mixture was sparged with argon gas for 5 minutes, heated to 100°C, and stirred for 18 hours. After the reaction was completed, water (20 mL) was added dropwise to the reaction mixture, and the resulting system was extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified using a prepared liquid phase (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm inner diameter; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain N-(7-(4,4-difluoropiperidine-1-yl)-2-methyl-1-oxoisoindorin-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 2 (45.3 mg) in yield of 45.92%. MS m / z(ESI):602.3[M+1].

[0152] 1H NMR (400MHz, DMSO-d6):δ 11.87(s, 1H), 10.18(s, 1H), 7.82(d, J=8.5Hz, 1H), 7.74(s, 1H), 7.17(d, J=2 .1Hz, 1H), 7.11(s, 1H), 7.05(dd, J=8.5, 2.1Hz, 1H), 4.37(s, 1H), 3.20(q, J=7 .3Hz, 2H), 3.30(m, 4H), 3.00(s, 3H), 2.97(t, J=5.3Hz, 4H), 2.15(ddt, J=25.7 , 18.1, 8.9Hz, 4H), 1.55(t, J=5.3Hz, 4H), 1.21(t, J=7.3Hz, 3H), 0.34(s, 4H).

[0153] [Example 3] 4-(ethylsulfonamide)-N-(7-(piperidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0154] [ka]

[0155] Process 1 4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 2-(6-azaspiro[2,5]octan-6-yl)-4-iodobenzoic acid 1f (1.0 g, 2.80 mmol) and ethyl sulfonamide 1h (458.36 mg, 4.20 mmol) were dissolved in N,N-dimethylformamide (10 mL), and then cuprous iodide (266.60 mg, 1.40 mmol), sarcosine (249.43 mg, 2.80 mmol), and potassium phosphate (3.73 g, 14.00 mmol) were added. The mixture was purged with argon, heated to 110°C, and stirred for 6 hours. After cooling to room temperature, the reaction mixture was poured into ice water (200 mL) and the pH was adjusted to 6 with dilute hydrochloric acid (2 M). The mixture was extracted with dichloromethane (200 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 3a (0.75 g) in yield 79.16%. MS m / z(ESI):339.4[M+1].

[0156] Process 2 1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine At room temperature, 7-bromo-5-nitro-2,3-dihydrobenzofuran 1b (488 mg, 2.00 mmol) and piperidine (340.53 mg, 4.00 mmol) were dissolved in toluene (20 mL), and then palladium acetate (44.89 mg, 199.97 μmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (373.54 mg, 599.90 μmol), and cesium carbonate (1.95 g, 6.00 mmol) were added. The mixture was purged three times with argon, then heated to 100°C and stirred for 16 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The aforementioned residue was purified by silica gel column chromatography (eluent: system A) to obtain 310 mg of 1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine in 62% yield. MS m / z(ESI):249.1[M+1].

[0157] Process 3 7-(piperidine-1-yl)-2,3-dihydrobenzofuran-5-amine At room temperature, 100 mg (805.55 μmol, 10%) of carbon-supported palladium was added to a solution of 1-(5-nitro-2,3-dihydrobenzofuran-7-yl)piperidine 3b (0.2 g, 805.55 μmol) in methanol (20 mL). The mixture was purged with hydrogen and then heated to 50°C and stirred for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 7-(piperidine-1-yl)-2,3-dihydrobenzofuran-5-amine 3c (152 mg) in 86% yield. The crude product was used directly in the following reaction. MS m / z(ESI):219.0[M+1].

[0158] Process 4 4-(ethylsulfonamide)-N-(7-(piperidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide At room temperature, tetramethylchloroformamidinium-hexafluorophosphate (345.98 mg, 664.85 μmol), 4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 3a (150 mg, 443.23 μmol), and N,N-diisopropylethylamine (171.85 mg, 1.33 mmol) were added to N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 10 minutes. Then, 7-(piperidine-1-yl)-2,3-dihydrobenzofuran-5-amine 3c (116.11 mg, 531.88 μmol) was added to the mixture, and the mixture was heated to 65°C and stirred for 2 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated using a prepared liquid phase (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm inner diameter; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 4-(ethylsulfonamide)-N-(7-(piperidine-1-yl)-2,3-dihydrobenzofuran-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 3 (38 mg) in 16% yield. MS m / z(ESI): 539.3[M+1].

[0159] 1 1H NMR (400 MHz, DMSO-d6):δ 11.62(s, 1H), 10.11(s, 1H), 7.84(d, J=8.5Hz, 1H), 7.40(s, 1H), 7.17(d, J =2.1Hz, 1H), 7.04(dd, J=8.4, 2.1Hz, 1H), 6.94(d, J=2.0Hz, 1H), 4.50(t, J =8.7Hz, 2H), 3.23~3.11(m, 4H), 3.10~3.0(m, 4H), 3.0~2.90(m, 4H), 1.67~ 1.59(m, 4H), 1.59~1.46(m, 6H), 1.20(t, J=7.3Hz, 3H), 0.40~0.28(m, 4H).

[0160] Examples 4 to 7 were synthesized according to the synthesis methods described in Examples 1 to 3 of the present invention. The structures and property evaluation data of Examples 4 to 7 are shown in the following table.

[0161]

Table 2

[0162] 〔Example 8〕 N-(7-Cyclopropyl-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0163]

Chemical formula

[0164] Step 1 7-Cyclopropyl-5-nitro-2,3-dihydrobenzofuran At room temperature, 7-bromo-5-nitro-2,3-dihydrobenzofuran 1b (0.5 g, 2.05 mmol), cyclopropylboronic acid (351.98 mg, 4.10 mmol), potassium phosphate trihydrate (1.64 g, 6.15 mmol), and tetrakis(triphenylphosphine)palladium (236.75 mg, 204.88 μmol) were added to a mixed solvent of ethanol (2 mL), water (2 mL) and toluene (10 mL). After purging the mixture with argon three times, it was heated to 100 °C and stirred for 16 hours. Water (20 mL) was added and extracted with ethyl acetate (20 mL × 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 residue was purified by silica gel column chromatography (eluent: System A) to obtain 7-cyclopropyl-5-nitro-2,3-dihydrobenzofuran 8a (255 mg) in a yield of 61%. MS m / z (ESI): 205.9 [M+1].

[0165] Step 2 7-Cyclopropyl-2,3-dihydrobenzofuran-5-amine At room temperature, palladium on carbon (20 mg, 1.24 mmol, 10%) was added to a solution of 7-cyclopropyl-5-nitro-2,3-dihydrobenzofuran 8a (255 mg, 1.24 mmol) in methanol (5 mL). After purging the mixture with hydrogen, it was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 7-cyclopropyl-2,3-dihydrobenzofuran-5-amine 8b (195 mg) in a yield of 90%. The crude product was used directly in the next reaction. MS m / z (ESI): 176.1 [M+1].

[0166] Step 3 N-(Tricyclo[3.3.1.13,7]dec-1-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide A solution of 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid 1f (0.1 g, 279.97 μmol) and N,N-dimethylformamide (0.1 mL) in dichloromethane (3 mL) was cooled in an ice bath, and oxalyl chloride (71.07 mg, 559.93 μmol) was slowly added dropwise. The resulting mixture was stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure. The residue was added to a solution of 7-cyclopropyl-2,3-dihydrobenzofuran-5-amine 8b (53.96 mg, 307.96 μmol) and triethylamine (84.99 mg, 839.90 μmol) in dichloromethane (3 mL), and the resulting mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and the mixture was 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 residue was purified by silica gel column chromatography (eluent: System A) to obtain N-(7-cyclopropyl-2,3-dihydrobenzofuran-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8c (121 mg) in a yield of 84%. MS m / z (ESI): 514.8 [M+1].

[0167] Process 4 N-(7-cyclopropyl-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide At room temperature, N-(7-cyclopropyl-2,3-dihydrobenzofuran-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8c (150 mg, 291.60 μmol), ethylsulfonamide 1h (47.74 mg, 437.41 μmol), 2-(methylamino)acetic acid (38.97 mg, 437.41 μmol), cuprous iodide (16.66 mg, 87.48 μmol), and potassium phosphate trihydrate (232.97 mg, 874.81 μmol) were added to N,N-dimethylformamide (2 mL). The mixture was purged with argon, heated to 100°C, and stirred for 6 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified using a prepared liquid phase (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm inner diameter; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4CO3 + H2O, mobile phase B: CH3CN) to obtain N-(7-cyclopropyl-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8 (18 mg) in 12% yield. MS m / z(ESI):495.9[M+1].

[0168] 1H NMR (400MHz, DMSO-d6):δ 11.39(s, 1H), 10.09(s, 1H), 7.80(d, J=8.5Hz, 1H), 7.57(d, J=2.0Hz, 1H), 7.15(d, J =2.1Hz, 1H), 7.02(dd, J=8.5, 2.1Hz, 1H), 6.89(d, J=2.1Hz, 1H), 4.52(t, J=8.6Hz, 2 H), 3.23~3.09(m, 4H), 3.0~2.90(m, 4H), 1.91(tt, J=8.4, 5.2Hz, 1H), 1.55~1.48(m, 4H), 1.20(t, J=7.3Hz, 3H), 0.97~0.87(m, 2H), 0.69~0.61(m, 2H), 0.37~0.31(m, 4H).

[0169] Example 9 was synthesized according to the synthesis method described in Example 8 of the present invention. The structure and characterization data for Example 9 are shown in the table below.

[0170] [Table 3]

[0171] [Example 10] 4-(ethylsulfonamide)-N-(7-isobutyl-2,3-dihydrobenzofuran-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0172] [ka]

[0173] At room temperature, 4-(ethylsulfonamide)-N-(7-(2-methylprop-1-en-1-yl)-2,3-dihydrobenzofuran-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 9 (50 mg, 98.10 μmol) and 10% carbon-supported palladium hydrogenation catalyst (10 mg, 98.10 μmol) were added to methanol (3 mL). The mixture was purged three times with hydrogen and then stirred at room temperature for 4 hours. The reaction mixture was filtered, the filter cake was washed with methanol (10 mL), and the filtrate was concentrated under reduced pressure. The aforementioned residue was purified using a prepared liquid phase (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm inner diameter; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain 10 (2.5 mg) of 4-(ethylsulfonamide)-N-(7-isobutyl-2,3-dihydrobenzofuran-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide in 5% yield. MS m / z(ESI): 512.3[M+1].

[0174] 1 1H NMR (400 MHz, DMSO-d6):δ 11.36(s, 1H), 10.12(s, 1H), 7.83(d, J=8.5Hz, 1H), 7.68(d, J=2.0Hz, 1H), 7 .18(d, J=2.1Hz, 1H), 7.12~7.00(m, 2H), 4.49(t, J=8.6Hz, 2H), 3.24~3.1(m , 4H), 3.03~2.94(m, 4H), 2.37(d, J=7.1Hz, 2H), 1.95~1.80(m, 1H), 1.57~1. 49(m, 4H), 1.21(t, J=7.3Hz, 3H), 0.89(d, J=6.6Hz, 6H), 0.37~0.31(m, 4H).

[0175] [Example 11] N-(7-(4,4-difluoro-1-hydroxycyclohexyl)-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0176] [Chemical]

[0177] Project 1 1-(2,3-Dihydrobenzofuran-7-yl)-4,4-difluorocyclohexan-1-ol At -78 °C, n-butyllithium (965.44 mg, 15.07 mmol, 2.5 M) was added dropwise to a solution of 7-bromo-2,3-dihydrobenzofuran 1a (2 g, 10.05 mmol) in tetrahydrofuran (50 mL), and after stirring at -78 °C for 0.5 h, 4,4-difluorocyclohexanone 11a (1.48 g, 11.05 mmol) was added dropwise to the reaction mixture. The resulting mixture was stirred at -78 °C for 0.5 h, then slowly warmed to room temperature and stirred for 2 h. The mixture was quenched with saturated aqueous ammonium chloride solution (20 mL), and ethyl acetate (30 mL × 2) was added for extraction. The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to obtain 1-(2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexan-1-ol 11b (1.6 g) in a yield of 63%. MS m / z (ESI): 237.1 [M+1].

[0178] 1 H NMR (400 MHz, DMSO-d6): δ 7.34 (dd, J = 7.8, 1.4 Hz, 1H), 7.11 (dd, J = 7.3, 1.3 Hz, 1H), 6.82 (t, J = 7.5 Hz, 1H), 5.11 (s, 1H), 4.50 (t, J = 8.7 Hz, 2H), 3.13 (t, J = 8.7 Hz, 2H), 2.45 - 2.30 (m, 2H), 2.30 - 2.04 (m, 2H), 1.96 - 1.80 (m, 2H), 1.60 - 1.50 (m, 2H). <​​​​At room temperature, 2 mL of nitric acid was added to a solution of 1-(2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexane-1-ol 11b (500 mg, 1.97 mmol) in acetic acid (5 mL), and the mixture was stirred for 4 hours. 20 mL of water was slowly added dropwise, and the resulting mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)cyclohexane-1-ol 11c (274 mg) in 46% yield. MS m / z (ESI): 300.1 [M+1].

[0180] 1 H NMR (400MHz, DMSO-d6):δ 8.34(d, J=2.6Hz, 1H), 8.16~7.88(m, 1H), 4.75(t, J=8.9Hz, 2H), 3.28(t, J=8.8Hz, 2H), 2.40(td, J=13.7, 4.2Hz, 2H), 2.29~2.07(m, 2H), 2.00~1.85(m, 2H), 1.63~1.49(m, 2H).

[0181] Process 3 1-(5-amino-2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexane-1-ol At room temperature, a solution of 4,4-difluoro-1-(5-nitro-2,3-dihydrobenzofuran-7-yl)cyclohexane-1-ol 11c (55 mg, 183.78 μmol) in methanol (5 mL) was mixed with a carbon-supported palladium hydrogenation catalyst (20 mg, 183.78 μmol, 10%). The mixture was purged with hydrogen and stirred at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1-(5-amino-2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexane-1-ol 11d (41 mg) in 83% yield. MS m / z(ESI):270.1[M+1].

[0182] Process 4 N-(7-(4,4-difluoro-1-hydroxycyclohexyl)-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide At room temperature, tetramethylchloroformamidinium-hexafluorophosphate (92.26 mg, 177.29 μmol), 4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 3a (40 mg, 118.20 μmol), and N,N-diisopropylethylamine (45.83 mg, 354.59 μmol) were added to N,N-dimethylformamide (3 mL), and the mixture was stirred at room temperature for 10 minutes. Then, 1-(5-amino-2,3-dihydrobenzofuran-7-yl)-4,4-difluorocyclohexane-1-ol 11d (35.01 mg, 130.02 μmol) was added to the mixture, and the resulting mixture was heated to 65°C and stirred for 2 hours. Water (10 mL) was added, and the resulting mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated using a prepared liquid phase (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm inner diameter; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to obtain N-(7-(4,4-difluoro-1-hydroxycyclohexyl)-2,3-dihydrobenzofuran-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11 (31 mg) in yield 41%. MS m / z(ESI): 590.3[M+1].

[0183] 1H NMR (400MHz, DMSO-d6):δ 11.37(s, 1H), 10.19(s, 1H), 7.89(d, J=8.5Hz, 1H), 7.70(s, 1H), 7.56(s, 1H) , 7.25(s, 1H), 7.09(d, J=8.5, 2.0Hz, 1H), 4.53(t, J=8.7Hz, 2H), 3.30~3.13( m, 4H), 3.13~3.0(m, 4H), 2.39(td, J=13.7, 4.2Hz, 2H), 2.31~2.07(m, 2H), 1. 98~1.83(m, 2H), 1.67~1.52(m, 6H), 1.21(t, J=7.3Hz, 3H), 0.37~0.31(m, 4H).

[0184] Examples 12 to 21 were synthesized according to the synthesis methods described in Examples 1 and 11 of the present invention. The structure and characterization data for Examples 12 to 21 are shown in the table below.

[0185] [Table 4] JPEG2026509288000035.jpg225169

[0186] [Example 22] N-(7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0187] [ka]

[0188] Process 1 Methyl 3-amino-5-bromo-4-hydroxybenzoate At room temperature, methyl 3-bromo-4-hydroxy-5-nitrobenzoate 22a (1.0 g, 3.62 mmol, commercially available) was dissolved in N,N-dimethylformamide (5 mL), and stannous chloride (2.40 g, 12.68 mmol) was added. The mixture was purged three times with argon and then stirred at room temperature for 3 hours. The mass spectrum indicated that the reaction was complete. Water (30 mL) was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 3-amino-5-bromo-4-hydroxybenzoate 22b (0.85 g) in 95.36% yield. MS m / z(ESI):246.0[M+1].

[0189] Process 2 Methyl 7-bromo-2-methylbenzo[d]oxazole-5-carboxylate At room temperature, methyl 3-amino-5-bromo-4-hydroxybenzoate 22b (850 mg, 3.45 mmol) was dissolved in 1,1,1-triethoxyethane (8.85 g, 54.55 mmol, 10 mL), and 4-methylbenzenesulfonic acid (59.49 mg, 345.45 μmol) was added. The mixture was purged three times with argon, then heated to 80°C and stirred for 1 hour. The mass spectrum indicated that the reaction was complete. The reaction solution was concentrated and dried. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 7-bromo-2-methylbenzo[d]oxazole-5-carboxylate 22c (0.75 g) in yield 80.39%. MS m / z(ESI):270.0[M+1].

[0190] Process 3 Methyl 7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-carboxylate At room temperature, methyl 7-bromo-2-methylbenzo[d]oxazole-5-carboxylate 22c (750 mg, 2.78 mmol) and 4,4-difluoropiperidine (504.55 mg, 4.17 mmol) were dissolved in toluene (20 mL), and tri(dibenzylideneacetone)palladium (127.15 mg, 138.85 μmol), R-(+)-1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (172.91 mg, 277.70 μmol), and cesium carbonate (2.71 g, 8.33 mmol) were added. The mixture was purged with argon and heated to 100 °C, and stirred for 18 hours. The mass spectrum indicated that the reaction was complete. Water (20 mL) was added, and the resulting mixture was stirred to separate layers and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain methyl 7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-carboxylate 22d (0.65 g) in 75.43% yield. MS m / z(ESI):311.1[M+1].

[0191] Process 4 7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-carboxylic acid At room temperature, methyl 7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-carboxylate 22d (600 mg, 1.93 mmol) was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL), and lithium hydroxide solution (2 M, 4.83 mL) was added. The resulting mixture was stirred at room temperature for 4 hours. The mass spectrum indicated that the reaction was complete. After concentrating the reaction mixture, water (20 mL) was added, and the pH was adjusted to 3-4 with hydrochloric acid solution (1 M). The resulting mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-carboxylic acid 22e (0.53 g) in 92.52% yield. MS m / z(ESI):297.1[M+1].

[0192] Process 5 tert-butyl(7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-yl)carbamate At room temperature, 7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-carboxylic acid 22e (200 mg, 675.06 μmol) was dissolved in tetrahydrofuran (10 mL), and triethylamine (102.46 mg, 1.01 mmol) and diphenyl phosphoryl azide (278.67 mg, 1.01 mmol) were added. The mixture was stirred at room temperature for 3 hours. The mass spectrum indicated that the reaction was complete. Tert-butanol (50 mL) was added to the reaction mixture, and the resulting mixture was heated to 80°C and stirred for 20 hours. The reaction mixture was concentrated under reduced pressure and dried. The aforementioned residue was purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl(7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-yl)carbamate 22f (100 mg) in a yield of 40.32%. MS m / z(ESI):368.1[M+1].

[0193] Process 6 7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-amine At room temperature, tert-butyl(7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-yl)carbamate 22f (90 mg, 244.97 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (55.86 mg, 489.94 μmol, 5 mL) was added dropwise. The resulting mixture was stirred at room temperature for 1 hour. The mass spectrum indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure, dried, and water (10 mL) was added. The pH was adjusted to 7-8 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-amine 22 g (50 mg) in yield 76.37%. MS m / z(ESI):268.1[M+1].

[0194] Process 7 N-(7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide At room temperature, 4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 3a (50 mg, 147.74 μmol) was dissolved in acetonitrile (5 mL), and 1-methylimidazole (36.39 mg, 443.23 μmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (124.36 mg, 443.23 μmol) were added, and the mixture was stirred at room temperature for 1 hour. 7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-amine 22 g (51.33 mg, 192.07 μmol) was added, and the mixture was heated to 60°C and stirred for 1 hour. The mass spectrum indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure, dried, and ethyl acetate (30 mL) was added. The resulting mixture was washed with saturated sodium bicarbonate solution (10 mL x 2) and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified using a prepared liquid phase (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm inner diameter; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4CO3 + H2O, mobile phase B: CH3CN), lyophilized, and obtained N-(7-(4,4-difluoropiperidine-1-yl)-2-methylbenzo[d]oxazole-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22 (5.7 mg) in yield 5.2%. MS m / z(ESI): 588.3[M+1].

[0195] 1 H NMR (400MHz, DMSO-d6):δ 11.70(s, 1H), 10.15(s, 1H), 7.84(d, J=8.5Hz, 1H), 7.75(d, J=1.7Hz, 1H), 7.18(s, 2H), 7.04(dd, J=8.5, 2.1Hz, 1H), 3.49(t, J=5.7Hz, 4H), 3.20(q, J=7.3Hz, 2H), 3.04~2.92(m, 4H), 2.60(s, 3H), 2.22~2.10(m, 4H), 1.66~1.43(m, 4H), 1.21(t, J=7.3Hz, 3H), 0.35(s, 4H).

[0196] Example 23 N-(7-(4,4-difluoropiperidine-1-yl)-1-oxoisoindorin-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0197] [ka]

[0198] Process 1 5-Bromo-7-fluoro-2-(4-methoxybenzyl)isoindorin-1-one At room temperature, methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate 2c (1.0 g, 3.07 mmol) and (4-methoxyphenyl)methylamine (631.27 mg, 4.60 mmol) were dissolved in N,N-dimethylformamide (10 mL), and N,N-diisopropylethylamine (793.00 mg, 6.14 mmol) was added. The resulting mixture was heated to 40°C and stirred for 10 hours. Water (30 mL) was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo-7-fluoro-2-(4-methoxybenzyl)isoindorin-1-one 23a (0.79 g) in 73.53% yield. MS m / z(ESI):349.8[M+1].

[0199] Process 2 5-Bromo-7-(4,4-difluoropiperidine-1-yl)-2-(4-methoxybenzyl)isoindorin-1-one At room temperature, 5-bromo-7-fluoro-2-(4-methoxybenzyl)isoindorin-1-one 23a (450 mg, 1.29 mmol) and 4,4-difluoropiperidine (233.48 mg, 1.93 mmol) were dissolved in dimethyl sulfoxide (10 mL), and N,N-diisopropylethylamine (332.17 mg, 2.57 mmol) was added. The resulting mixture was heated to 150°C and stirred for 6 hours. The mass spectrum indicated that the reaction was complete. Water (20 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated. The aforementioned residue was purified by silica gel column chromatography (eluent: system A) to obtain 5-bromo-7-(4,4-difluoropiperidine-1-yl)-2-(4-methoxybenzyl)isoindorin-1-one 23b (0.44 g) in yield 75.8%. MS m / z (ESI): 450.8 [M+1].

[0200] Process 3 tert-butyl(7-(4,4-difluoropiperidine-1-yl)-2-(4-methoxybenzyl)-1-oxoisoindorin-5-yl)carbamate At room temperature, 5-bromo-7-(4,4-difluoropiperidine-1-yl)-2-(4-methoxybenzyl)isoindorin-1-one 23b (400 mg, 886.32 μmol) and tert-butylcarbamate (207.66 mg, 1.77 mmol) were dissolved in 1,4-dioxane (10 mL), and palladium acetate (19.90 mg, 88.63 μmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (102.57 mg, 177.26 μmol), and cesium carbonate (866.34 mg, 2.66 mmol) were added. The mixture was purged with argon for 5 minutes, then heated to 100°C and stirred for 18 hours. The mass spectrum indicated that the reaction was complete. Water (20 mL) was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: system A) to obtain tert-butyl(7-(4,4-difluoropiperidine-1-yl)-2-(4-methoxybenzyl)-1-oxoisoindorin-5-yl)carbamate 23c (0.4 g) in yield 92.57%. MS m / z(ESI):488.0[M+1].

[0201] Process 4 5-amino-7-(4,4-difluoropiperidine-1-yl)isoindorin-1-one At room temperature, tert-butyl(7-(4,4-difluoropiperidine-1-yl)-2-(4-methoxybenzyl)-1-oxoisoindorin-5-yl)carbamate 23c (400 mg, 820.45 μmol) was dissolved in trifluoroacetic acid (4 mL) and stirred at room temperature for 18 hours. Methanesulfonic acid (2 mL) was added, and the mixture was heated to 60°C and stirred for 3 hours. The mass spectrum indicated that the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated and dried. Water (20 mL) was added to the residue, the pH was adjusted to 8-9 with saturated sodium carbonate solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-amino-7-(4,4-difluoropiperidine-1-yl)isoindorin-1-one 23d (0.2 g) in 91.21% yield. MS m / z(ESI):268.1[M+1].

[0202] Process 5 N-(7-(4,4-difluoropiperidine-1-yl)-1-oxoisoindorin-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide At room temperature, 4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 3a (150 mg, 443.23 μmol) was dissolved in acetonitrile (10 mL), and 1-methylimidazole (110.51 mg, 1.33 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (373.09 mg, 1.33 mmol) were added. The resulting mixture was stirred at room temperature for 1 hour. 5-amino-7-(4,4-difluoropiperidine-1-yl)isoindorin-1-one 23d (130.31 mg, 487.56 μmol) was added, and the mixture was heated to 60°C and stirred for 2 hours. The mass spectrum indicated that the reaction was complete. The reaction solution was purified using a prepared liquid phase (separation column: AKZONOBEL Kromasil; 250 × 21.2 mm inner diameter; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4CO3 + H2O, mobile phase B: CH3CN) to obtain N-(7-(4,4-difluoropiperidine-1-yl)-1-oxoisoindorin-5-yl)-4-(ethylsulfonamide)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 23 (43.0 mg) in yield of 15.75%. MS m / z(ESI): 588.3[M+1].

[0203] 1 1H NMR (400 MHz, DMSO-d6):δ 11.88(s, 1H), 9.82(s, 1H), 8.18(s, 1H), 7.82(d, J=8.4Hz, 1H), 7.74(s, 1 H), 7.17(d, J=2.1Hz, 1H), 7.08(s, 1H), 7.05(dd, J=8.5, 2.1Hz, 1H), 4.28 (s, 2H), 3.44~3.22(m, 4H), 3.20(q, J=7.3Hz, 2H), 2.97(t, J=5.2Hz, 4H), 2.23~2.09(m, 4H), 1.61~1.50(m, 4H), 1.21(t, J=7.3Hz, 3H), 0.35(s, 4H).

[0204] Examples 24-26 were synthesized according to the synthesis methods described in Examples 1 and 11 of the present invention. The structure and characterization data for Examples 24-26 are shown in the table below.

[0205] [Table 5]

[0206] Examples 27-28 were synthesized according to the synthesis method described in Example 2 of the present invention. The structure and characterization data for Examples 27-28 are shown in the table below.

[0207] [Table 6]

[0208] Example 29 was synthesized according to the synthesis method described in Example 1 of the present invention. The structure and characterization data of Example 29 are shown in the table below.

[0209] [Table 7]

[0210] [Biological evaluation] [Test Example 1: Measurement of inhibition of OVCAR-3 cell proliferation by the compound of the present invention] The effect of the compound of the present invention on the proliferation of OVCAR-3 cells was measured by the following method. OVCAR-3 cells (containing the TP53 R248Q mutation) were purchased from the Cell Bank of Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, and cultured in RPMI 1640 culture medium (containing 10% fetal bovine serum, 100U penicillin, and 100μg / mL streptomycin). Cell viability was measured using the CellTiter-Glo® luminescent cell viability assay kit (Promega, catalog number G7573).

[0211] The experimental procedure was carried out according to the instructions of the kit, and the outline is as follows: First, the test compound was dissolved in DMSO to prepare a 10 mM stock solution. Next, the stock solution was diluted with the RPMI 1640 culture medium to prepare the test sample. The final concentration of the compound was in the range of 1000 nM to 0.015 nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate (density: 1000 cells / well) and cultured overnight in a 5% CO2 incubator at 37°C. After that, the test compound was added and cultured continuously for 72 hours. After the culture was completed, CellTiter-Glo detection solution (50 μL) was added to each well. The plate was shaken for 5 minutes and then allowed to stand for 10 minutes. After that, the luminescence value of the sample in each well was read using the luminescence mode of a microplate reader. The inhibition rate (%) of the compound at each concentration was calculated by comparing it with the values ​​of the control group (0.3% DMSO). Subsequently, GraphPad Prism 5 software was used to perform a nonlinear regression analysis based on the logarithm of the concentration and the inhibition rate of the compound, thereby determining the IC of the compound in inhibiting cell proliferation. 50 Values ​​were obtained. The results are shown in Table 1.

[0212] [Table 8]

[0213] Conclusion: The compounds of the present invention show a relatively good inhibitory effect on the proliferation of OVCAR-3 cells, and IC 50 The value was <50 nM.

[0214] Note: The structure of the AMG 650 (manufactured according to Example 4 of published patent WO2020132648A1) was as follows:

[0215] [ka]

[0216] [Test Example 2: Measurement of the inhibitory effect of the compound of the present invention on the proliferation of HT-29 cells] The effect of the compound of the present invention on the proliferation of HT-29 cells was measured by the following method. HT-29 cells (containing the TP53 R273H mutation) were purchased from the Cell Bank of Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, and cultured in McCoy's 5A culture medium (containing 10% fetal bovine serum, 100U penicillin, and 100μg / mL streptomycin). Cell viability was measured using the CellTiter-Glo® luminescent cell viability assay kit (Promega, catalog number G7573).

[0217] The experimental procedure was carried out according to the instructions of the kit, and the outline is as follows: First, the test compound was dissolved in DMSO to prepare a 10 mM stock solution. Next, the stock solution was diluted with McCoy's 5A culture medium to prepare the test sample. The final concentration of the compound was in the range of 1000 nM to 0.015 nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate (density: 1000 cells / well) and cultured overnight in a 5% CO2 incubator at 37°C. After that, the test compound was added and cultured continuously for 120 hours. After the culture was completed, CellTiter-Glo detection solution (50 μL) was added to each well. The plate was shaken for 5 minutes and then allowed to stand for 10 minutes. After that, the luminescence value of the sample in each well was read using the luminescence mode of a microplate reader. The inhibition rate (%) of the compound at each concentration was calculated by comparing it with the values ​​of the control group (0.3% DMSO). Subsequently, GraphPad Prism 5 software was used to perform a nonlinear regression analysis based on the logarithm of the concentration and the inhibition rate of the compound, thereby determining the IC of the compound in inhibiting cell proliferation. 50 Values ​​were obtained. The results are shown in Table 2.

[0218] [Table 9]

[0219] Conclusion: The compounds of the present invention show a relatively good inhibitory effect on the proliferation of HT-29 cells, and IC 50 The value was <50 nM.

[0220] [Test Example 3: Test of the inhibitory effect of the compound of the present invention on the activity of the KIF18A enzyme] The degree of inhibition of the compound of the present invention against the activity of recombinant human KIF18A enzyme in vitro was measured by the following method. The ADP-Glo® kinase assay kit (Promega Company, catalog number V9102) was used for this method. For detailed experimental procedures, please refer to the instructions included with the kit.

[0221] The experimental flow was outlined as follows: First, the test compound was dissolved in DMSO to prepare a stock solution. Next, the stock solution was serially diluted with reaction buffer A (15 mM Tris, pH 7.5, 10 mM MgCl2, 0.01% Pluronic F-68). The final concentration of the test compound in the reaction system was in the range of 10,000 nM to 0.15 nM; the KIF18A protein and ATP working solution were prepared using reaction buffer B (15 mM Tris, pH 7.5, 10 mM MgCl2, 0.01% Pluronic F-68, 37.5 μg / ml tubulin, 1.25 μM paclitaxel). The reaction was carried out in a 384-well microplate. The test compound and the recombinant human KIF18A protein (final concentration 100 nM, expression commissioned to GenScript) were added to the wells and incubated at room temperature for 20 minutes. Subsequently, ATP solution (component V915A of the ADP-Glo(trademark) kinase assay kit, final concentration 60 μM) was added to the reaction solution, and the resulting system was incubated at room temperature for 20 minutes. Then, 5 μL of ADP-Glo ​​reagent was added to the reaction system, and the resulting system was incubated at room temperature for 50 minutes. Next, 10 μL of kinase detection reagent was added to the reaction system, and the resulting system was incubated at room temperature for 30 minutes. After incubation, the chemiluminescence intensity of each well was measured using the luminescence mode of a microplate reader. By comparing the luminescence intensity of the control group (0.1% DMSO), the inhibition rate (%) of the compound at each concentration was calculated, and nonlinear regression analysis based on the logarithm of the concentration and the inhibition rate of the compound was performed using GraphPad Prism 5 software to determine the IC of the compound. 50 Values ​​were obtained. The results are shown in Table 3.

[0222] [Table 10]

[0223] Conclusion: The compounds of the present invention show a significant inhibitory effect on the activity of the KIF18A enzyme, and IC 50 The value was <500 nM.

[0224] [Test Example 4: Pharmacokinetic study of the compound of the present invention in mice] [1. Experimental Objectives] ICR mice were used as test animals and administered the control compound AMG650 and compounds 1, 18, and 29 of the present invention intragastricly. Subsequently, drug concentrations in plasma were measured at different time points by LC / MS / MS to investigate the pharmacokinetic properties of the compounds of the present invention in mice.

[0225] [2. Experimental Scheme] (2.1: Experimental drugs and animals) Control compound AMG650 and compounds 1, 18, and 29.

[0226] ICR mice, male, 27.3-30.3g (purchased from Vital River Laboratory Animal Technology Co., Ltd).

[0227] (2.2: Drug manufacturing) An appropriate amount of the test compound was weighed, and appropriate amounts of DMA (N,N-dimethylacetamide), CrEL (polyoxyethylene 35 castor oil), and 5% GS (5% glucose injection) were added sequentially. The resulting system was homogeneously mixed using an ultrasonic vortex to produce a 1 mg / mL formulation. Here, the volume ratio of DMA, CrEL, and 5% GS was 10:10:80.

[0228] (2.3: Administration) ICR mice (9 mice per group) in each group of test compound injections were fasted overnight, then administered the compound intragastricly (PO: oral administration, dose of the compound was 10 mg / kg, volume of the compound was 10 mL / kg), and fed 4 hours after administration.

[0229] [3.Operation] Approximately 0.1 μL of blood was collected from the orbit at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours, and 24 hours before and after administration, and the whole blood samples were placed in EDTA-K2-containing anticoagulant tubes. The collected blood samples were placed on ice, and the plasma was centrifuged (centrifugation conditions: 1500 g, 10 minutes). Before analysis, the recovered plasma was stored at -40 to -20°C.

[0230] The content of the test compound in mouse plasma after intragastric administration was measured by LC-MS / MS.

[0231] [4. Results of pharmacokinetic parameters] The pharmacokinetic parameters of the test compounds are shown in Table 4 below.

[0232] [Table 11]

[0233] Conclusion: Compounds 1, 18, and 29 of the present invention exhibit good pharmacokinetic properties, possessing both high plasma concentrations and a large area under the curve.

[0234] [Test Example 5: Pharmacokinetic study of Compound 1 of the present invention in mice] [1. Experimental Objectives] The antitumor effect of compound 1 of the present invention was evaluated in a BALB / c nude mouse xenograft animal model containing subcutaneous OVCAR-3 human ovarian adenocarcinoma tumor fragments.

[0235] [2. Laboratory Animals] BALB / c nude mouse, female, 6-7 weeks old (purchased from Jiangsu Gempharmatech Biotechnology Co., Ltd).

[0236] [3. Preparation of test compounds] The solvent control group of mice was administered DMA:CrEL:5%GS = 10:10:80 (volume ratio).

[0237] AMG650: An appropriate amount of AMG-650 was weighed, and appropriate amounts of DMA, CrEL, and 5% GS were added sequentially. The resulting system was homogeneously mixed using an ultrasonic vortex to produce formulations of 0.8 mg / mL and 0.4 mg / mL, respectively. Here, the volume ratio of DMA, CrEL, and 5% GS was 10:10:80.

[0238] Compound 1: An appropriate amount of Compound 1 was weighed, and appropriate amounts of DMA, CrEL, and 5% GS were added sequentially. The resulting system was homogeneously mixed using an ultrasonic vortex to produce formulations of 0.8 mg / mL and 0.4 mg / mL, respectively. Here, the volume ratio of DMA, CrEL, and 5% GS was 10:10:80.

[0239] [4. Collection of tumor tissue for inoculation] Appropriate OVCAR-3 tumor-carrying animals were selected, and 1 mm × 1 mm × 1 mm OVCAR-3 tumor fragments were aseptically collected and placed in physiological saline for later use. These tumor fragments were then subcutaneously inoculated into the right dorsal region of BALB / c nude mice.

[0240] [5. Inoculation and grouping of animals] Female BALB / c nude mice were subcutaneously inoculated with 1mm x 1mm x 1mm OVCAR-3 tumor fragments into the right dorsal region. The average tumor volume was approximately 100-250mm². 3 Once the tumor size was reached, the mice were randomly divided into groups of 6 based on the size of the tumor.

[0241] [6. Administration to animals and observation] Each group of animals was orally administered (PO) with the test compound once a day at a fixed time, according to the animal's body weight. Administration of the test compound began on the day of group assignment and continued for 22 consecutive days. The animals' body weight was recorded daily.

[0242] Group 1 (G1) is the solvent control group; Group 2 (G2) and Group 3 (G3) were administered (QD)AMG-650 orally once daily at doses of 8 mg / kg and 4 mg / kg, respectively; and Groups 4 (G4) and 5 (G5) received compound 1 (QD) orally once daily at doses of 8 mg / kg and 4 mg / kg, respectively.

[0243] Tumor formation at the inoculation site was observed in each group of animals, and tumor volume was measured twice a week and calculated according to the following formula: Tumor volume (TV), relative tumor volume (RTV), relative tumor growth rate (T / C), and relative tumor suppression rate (TGI) were calculated according to the following formulas: (1) TV (tumor volume) = 1 / 2 × a × b 2 Here, a and b represent the length and width of the tumor, respectively; (2) RTV (Relative Tumor Volume) = V t / V0, where V0 is the tumor volume measured at the time of group assignment, and V t This represents the tumor volume at each measurement; (3) T / C(%) = T RTV / C RTV It is ×100%, and here, T RTV This refers to the RTV and C values ​​of the treatment group. RTV This is the RTV of the solvent control group; (4) TGI% = (1 - T / C) × 100%, where T and C are the relative tumor volumes of the treatment group and the solvent control group at a specific time point, respectively.

[0244] [7. Results]

[0245] [Table 12]

[0246] Note: Data is expressed as "mean ± standard error".

[0247] Conclusion: In a BALB / c nude mouse xenograft model containing OVCAR-3 human ovarian adenocarcinoma tumor fragments under the experimental conditions specified in this study, compound 1 of the present invention showed significantly enhanced tumor growth inhibition at both 8 mg / kg and 4 mg / kg doses compared to the solvent control and AMG650.

[0248] Unless otherwise defined, all terms used in this invention have the meanings generally understood by those skilled in the art.

[0249] The embodiments described in this invention are for illustrative purposes only and are not intended to limit the scope of protection of the invention. Those skilled in the art can make various other substitutions, modifications, and improvements within the scope of the invention. Therefore, the invention is not limited to the embodiments described above, but is limited only by the claims.

Claims

1. A compound represented by general formula (I), or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof: 【Chemistry 1】 In general formula (I), Ring A is selected from a 5- to 7-membered heterocyclyl or a 5- to 7-membered heteroaryl; G is, 【Chemistry 2】 Selected from; X １ and X ２ Each of them operates independently, CR ａ or selected from N atoms; Y １ 、 Y ２ 、 and, Y ３ are each independently selected from CR ｂ or N atoms, and Y １ 、 Y ２ 、 and, Y ３ that are simultaneously N atoms among them are at most two; R ａ and R ６ Each of these is independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano, an alkyl, or an alkoxy, and the alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogens, hydroxyl, cyano, alkyl, or alkoxy; R Ａ These are either identical or different, and each is independently selected from a hydrogen atom, halogen, hydroxyl, cyano, alkyl, or alkoxy, and the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl, or alkoxy; Or, two R's Ａ These are the two R's Ａ It forms C(O) with the same carbon atom to which it is bonded; L １ is a combination or C １ ~C ６ Selected from alkylenes, the alkylene is optionally further substituted with one or more substituents selected from halogens, hydroxyls, cyanos, or alkoxys, and one or more methylene groups of the alkylene are one or more O,S(O) ｒ , C(O), or NR Ｃ It is arbitrarily replaced by; R Ｃ is selected from a hydrogen atom or an alkyl group; L ２ teeth, 【Transformation 3】 Selected from; R ３ Each is independently selected from a hydrogen atom or an alkyl group, and the alkyl group is optionally further substituted with one or more substituents selected from halogens, hydroxyls, cyanos, or alkoxy groups; R ３ is preferably a hydrogen atom; R １ The element is selected from hydrogen, cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated 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 , -SO ２ NR ９ R １０ , or -NR ９ C(O)R １０ It is optionally further substituted by one or more substituents selected from; R ４ cyano, halogen, alkyl, alkenyl, alkynyl, 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 ien-CH ２ NHC(O)OR ５ ien-CH ２ NR ６ R ７ , or -S(O) ｒ R ５ Selected from, the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated 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 , -SO ２ NR ９ R １０ , or -NR ９ C(O)R １０ It is optionally further substituted by one or more substituents selected from; R ５ Each is independently selected from a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, halogenated alkyl, halogenated 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 , -SO ２ NR ９ R １０ , or -NR ９ C(O)R １０ It is optionally further substituted by one or more substituents selected from; R ６ and R ７ are each independently selected from a hydrogen atom, hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the alkyl, the alkoxy, the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl is substituted with one or more substituents selected from hydroxyl, 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 , -SO ２ NR ９ R １０ , or -NR ９ C(O)R １０ )]]and is optionally further substituted by one or more substituents selected from; or R ６ and R ７ together with the atom to which the R ６ and the R ７ is bonded form a 4- to 8-membered heterocyclyl, and the 4- to 8-membered heterocyclyl contains one or more N, O, or S(O) ｒ and the 4- to 8-membered heterocyclyl is optionally further substituted by one or more substituents selected from hydroxyl, 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 , -SO ２ NR ９ R １０ , or -NR ９ C(O)R １０ ; R ８ , R ９ and R １０ Each of these is independently selected from a hydrogen atom, alkyl, amino, cycloalkyl, heterocyclyl, aryl, or heteroaryl, and the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from hydroxyl, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl, or carboxylate groups; n is 0, 1, 2, 3, or 4; r is independently 0, 1, or 2. A compound, or its stereoisomer, its tautomer, or its pharmaceutically acceptable salt.

2. The compound according to claim 1, which is a compound represented by general formula (II) or (III), or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof: 【Chemistry 4】 In general formula (II) or (III), Ring A, X １ , X ２ , R Ａ , R １ , R ４ , L １ The definition of n is as described in claim 1.

3. L １ However, bond or C １ ~C ６ Selected from alkylenes, the alkylene is optionally further substituted with one or more hydroxyl groups, and one or more methylene groups of the alkylene are one or more O,S(O) ｒ , C(O), or NR Ｃ It is arbitrarily replaced by; r is 2; and, R Ｃ is selected from hydrogen atoms or methyl atoms. A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

4. L １ is a bond, -NHSO ２ CH ２ CH ２ -, -SO ２ NHCH ２ CH ２ -, -SO ２ -, -CH ２ SO ２ -, -NHSO ２ -, -SO ２ NH-, -NHC(CH ３ ) ２ CH ２ -, -C(O)NHCH ２ CH ２ -, -C(O)NHC(CH ３ ) ２ CH ２ -, -C(O)N(CH ３ )CH ２ CH ２ -, -CH(CH ３ )(OH)CH ２ -, -NHSO ２ CH(CH ３ )CH ２ -, -SO ２ NH C(CH ３ ) ２ CH ２ -, -C(O)NH-, -NHCH ２ CH ２ -, or, -CH ２ SO ２ CH ２ CH ２ selected from - The compound according to claim 3, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

5. R １ However, selected from a hydrogen atom, hydroxyl, alkyl, heterocyclyl, cycloalkyl, or heteroaryl, the alkyl, heterocyclyl, cycloalkyl, or heteroaryl may be further optionally substituted with one or more substituents selected from hydroxyl or alkyl. A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof. 【Request Item 6】 【Chemistry 5】 but, 【Transformation 6】 That is, A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof. 【Request Item 7】 【Chemistry 7】 but, 【Transformation 8】 That is, A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

8. X １ and X ２ However, each is independently selected from CH, A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

9. Ring A is found in the following compounds: 【Chemistry 9】 Selected from, A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

10. Ring A is found in the following compounds: 【Chemistry 10】 Selected from, A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

11. R Ａ However, each is independently selected from a hydrogen atom or a methyl atom; Or, two R's Ａ These are the two R's Ａ Together with the same carbon atom to which it is bonded, it forms C(O). A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

12. R ４ However, each is independently a 3-10 member heterocycline, or C ３ ~C １０ Selected from cycloalkyls, the heterocyclyl or cycloalkyl is optionally further substituted with one or more hydroxyl groups or halogens. A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

13. R ４ However, each is independent of C ２ ~C ６ Alkenyl, or C １ ~C ６ Selected from alkyl groups, the alkenyl or alkyl group is optionally further substituted with one or more hydroxyl groups or halogens. A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

14. R ４ but, 【Chemistry 11】 That is, The compound according to claim 12, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

15. R ４ However, the following compounds: 【Chemistry 12】 That is, A compound according to claim 1 or 2, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

16. The aforementioned compound is the following compound: 【Chemistry 13】 【change】 That is, A compound according to any one of claims 1 to 15, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising any one of claims 1 to 16, or an effective amount of a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

18. Using a compound according to any one of claims 1 to 16, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to claim 17, in the production of a KIF18A inhibitor.

19. Use of a compound according to any one of claims 1 to 16, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable composition according to claim 17, in the manufacture of a pharmaceutical product for the treatment of a KIF18A-mediated disease, wherein the KIF18A-mediated disease is preferably cancer.

20. The use according to claim 19, 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, cervical cancer, uterine cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer, or lung adenocarcinoma.

21. The use of a compound according to any one of claims 1 to 16, or a stereoisomer thereof, a tautomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 17, in the manufacture of a pharmaceutical for the treatment of cancer.

22. The use according to claim 21, 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, cervical cancer, uterine cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer, or lung adenocarcinoma.

Images