Aromatic amide derivative as well as preparation method and application thereof

Abstract

Provided are an aromatic amide derivative, a preparation method thereof, and an application of a pharmaceutical composition containing the derivative in medicine. Specifically, the invention provides an aromatic amide derivative as shown in a general formula (I), a preparation method and medicinal salts thereof, and application of the aromatic amide derivative and the medicinal salts thereof as therapeutic agents, especially KIF18A inhibitors, and definitions of substituent groups in the general formula (I) are the same as those in the specification. # imgabs0 #

Description

Aromatic amide derivatives and their preparation method and use Technical Field

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

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

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

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

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

[0006] Summary of the Invention

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

[0008] in:

[0009] Ring A is selected from a 5- to 7-membered heterocyclyl, a C4-C7 cycloalkyl, a 5- to 7-membered aryl, or a 5- to 7-membered heteroaryl;

[0010] X1, X2, X3, X4, X5 and X6 are each independently selected from CR a or N atoms;

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

[0012] 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, hydroxy, cyano or alkoxy, and wherein the one or more methylene groups of the alkylene are optionally replaced by one or more O, S(O) r , C(O) or NR b replaced by;

[0013] L2 is selected from

[0014] R b is selected from a hydrogen atom or an alkyl group;

[0015] R 1 is selected from hydrogen, cyano, halogen, alkyl, hydroxy, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0016] R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; wherein the alkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group;

[0017] R 3 are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy; R 3 Preferably a hydrogen atom;

[0018] R 4is selected from hydrogen atom, deuterated alkyl, haloalkyl, alkyl, alkoxy, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more deuterium atoms, hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0019] The condition is that when X1, X2, X3, X4, X5 and X6 are simultaneously selected from CR a When R 4 not selected from hydrogen atoms;

[0020] R 5 Selected from hydrogen, cyano, halogen, alkyl, hydroxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -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 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0021] Or, two R 5 It forms a -C(O)- with the same carbon atom to which it is attached;

[0022] R 6 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0023] R 7 and R 8 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0024] Or, R 7 and R 8Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0025] R 9 、R 10 and R 11 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0026] m is 0, 1 or 2; m is preferably 0;

[0027] n is 0, 1, 2, 3 or 4; and

[0028] r is independently 0, 1 or 2.

[0029] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of formula (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0030] Ring A, R 1 、R 3 、R 4 、R 5 , L1 and n are as defined in the general formula (I).

[0031] A preferred embodiment of the present invention is a compound of formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, which is a compound of formula (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts:

[0032] Among them, R a Selected from C 1-6 Alkoxy or 5- to 6-membered heteroaryl;

[0033] R 4 is selected from alkyl, alkoxy, haloalkyl, deuterated alkyl or cycloalkyl, wherein the cycloalkyl is optionally further substituted with one or more deuterium atoms or halogen;

[0034] Ring A, R 1 、R 3 、R 5 , L1 and n are as defined in the general formula (I).

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

[0036] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein:

[0037] L1 is selected from a bond or a C1-C6 alkylene group, wherein the alkylene group is optionally further substituted with one or more hydroxyl groups, and wherein the one or more methylene groups of the alkylene group are optionally replaced with one or more O, S(O) r , C(O) or NR b replaced by;

[0038] r is 2;

[0039] R b is selected from a hydrogen atom or a methyl group.

[0040] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -NHSO2CH2CH2-, -SO2NHCH2CH2-, -SO2-, -CH2SO2-, -NHSO2-, -SO2NH-, -NHC(CH3)2CH2-, -C(O)NHCH2CH2-, -C(O)NHC(CH3)2CH2-, -C(O)N(CH3)CH2CH2-, -CH(CH3)(OH)CH2-, -NHSO2CH(CH3)CH2-, -SO2NHC(CH3)2CH2-, -C(O)NH-, -NHCH2CH2 or -CH2SO2CH2CH2-.

[0041] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 is selected from hydroxy, alkyl, heterocyclyl, cycloalkyl or heteroaryl, wherein the alkyl, heterocyclyl, cycloalkyl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxy or alkyl.

[0042] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein for

[0043] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 3 A hydrogen atom.

[0044] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 4 is selected from methyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, methoxy, isopropyl, deuterated methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl,

[0045] A preferred embodiment of the present invention is a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 5 are selected from hydrogen, halogen, alkyl, cycloalkyl or heterocyclic groups; wherein the alkyl, cycloalkyl or heterocyclic group is optionally further substituted by one or more halogens; or, two R 5 It forms a -C(O)- with the same carbon atom to which it is attached.

[0046] In a preferred embodiment of the present invention, the compound described by the general formula is selected from:

[0047] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0048] Note: If there is a discrepancy between a drawn structure and the name given for that structure, the drawn structure will be given greater weight.

[0049] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0050] The present invention provides a use of a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a KIF18A inhibitor.

[0051] The present invention also provides a use of a compound of formula (I), (II), (III) or (IV) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating a disease mediated by KIF18A, wherein the disease mediated by KIF18A is preferably cancer; wherein the disease mediated by KIF18A is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.

[0052] The present invention further provides a use of a compound of formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug for treating cancer.

[0053] The present invention provides a compound of general formula (I), (II), (III) or (IV) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof, for use in preparing a medicament for treating hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.

[0054] Detailed Description of the Invention

[0055] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0056] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0057] "Alkylene" refers to a saturated C1-C 20 A straight-chain or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane, preferably C1-C 10 Alkylene, more preferably C1-C6 alkylene. Examples of alkylene groups include, but are not limited to, methylene, 1,1-ethylene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,4-butylene, etc. The alkylene group may be substituted or unsubstituted.

[0058] "Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the ring atoms is a carbon atom, including monocyclic, polycyclic, fused, bridged, and spirocyclic rings, preferably having a 5- to 7-membered monocyclic ring or a 7- to 10-membered bicyclic or tricyclic ring. Examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclopentyl, and cyclobutyl. Cycloalkyl groups may be substituted or unsubstituted.

[0059] "Spiroalkyl" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one carbon atom (called spiro atom) shared between the monocyclic rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into single spiro, double spiro or multiple spiroalkyl groups, preferably single spiro and double spiroalkyl groups, preferably 4 / 5 members, 4 / 6 members, 5 / 5 members or 5 / 6 members. Non-limiting examples of "spiroalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

[0060] "Fused cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms. One or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron aromatic system. It is preferably 6- to 12-membered, and more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic, or polycyclic fused cycloalkyl group, preferably a bicyclic or tricyclic group, and more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl group. Non-limiting examples of "fused cycloalkyl" include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, decahydronaphthyl, or tetradecahydrophenanthrenyl.

[0061] "Bridged cycloalkyl" refers to an all-carbon polycyclic group with 5 to 18 members, containing two or more cyclic structures that share two non-directly connected carbon atoms. One or more rings may contain one or more double bonds, but none of the rings have completely conjugated π electrons. It is an aromatic system with preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, bridged cycloalkyl groups can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic, preferably bicyclic, tricyclic, or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to: (1s,4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-bicyclo[3.3.1]nonyl, bicyclo[2.2.2]octyl, and (1r,5r)-bicyclo[3.3.2]decyl.

[0062] "Heterocyclyl," "heterocycloalkyl," "heterocycle," or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring atoms is selected from nitrogen, oxygen, or S(O) t (wherein t is selected from 0,1 or 2) heteroatoms, including monocycles, polycycles, condensed rings, bridged rings and spirocycles. Preferably there are 5 to 7 membered monocycles or 7 to 10 membered bicyclic or tricyclic rings, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and / or sulphur. The example of "heterocyclic radical" includes but is not limited to morpholinyl, oxetanes, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazine-2-one, 8-oxa-3-aza-bicyclo [3.2.1] octyl, piperazinyl, hexahydropyrimidine,

[0063] The heterocyclic group may be substituted or unsubstituted.

[0064] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spirocycloalkyl is divided into single spiro heterocyclyl, double spiro heterocyclyl or multiple spiro heterocyclyl, preferably single spiro heterocyclyl and double spiro heterocyclyl. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered single spiro heterocyclyl. Non-limiting examples of "spiro heterocyclyl" include, but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl.

[0065] "Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures sharing a pair of atoms, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatom, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of "fused heterocyclic groups" include, but are not limited to: octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo[3.1.0]hexyl, octahydrobenzo[b][1,4]dioxin.

[0066] "Bridged heterocyclic group" refers to a 5- to 14-membered, 5- to 18-membered polycyclic group containing two or more ring structures that share two atoms that are not directly connected to each other, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π-electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic groups" include but are not limited to: 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 2-azabicyclo [3.3.2] decyl.

[0067] "Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be joined together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably, aryl is C6-C 10 The aryl group is more preferably phenyl and naphthyl, and most preferably naphthyl. The aryl group may be substituted or unsubstituted.

[0068] "Heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or 8- to 10-membered bicyclic ring which may contain 1 to 4 atoms selected from nitrogen, oxygen, and / or sulfur. Examples of "heteroaryl" include, but are not limited to, furanyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1,3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, isothiazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4 -triazolyl, pyridyl, pyrimidinyl, pyrazin-2(1H)-onyl, pyrimidin-4(3H)-onyl, pyridazin-3(2H)-onyl, 1H-indolyl, 1H-benzo[d]imidazolyl, 1H-pyrrolo[2,3-c]pyridinyl, 3H-imidazo[4,5-c]pyridinyl, isoquinolinyl, quinazolinyl, 2H-isoindolyl, furo[3,2-b]pyridinyl, furo[2,3-c]pyridinyl, thieno[2,3-c]pyridinyl, benzofuranyl, benzo[b]thienyl, 1H-pyrrolo[3,2-b]pyridinyl, 2H-pyrrolo[3,4-c]pyridinyl, Heteroaryl groups can be substituted or unsubstituted.

[0069] "Alkoxy" refers to a group (alkyl-O-). Alkyl is defined herein. C1-C6 alkoxy groups are preferred. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy.

[0070] "Nitro" refers to a -NO2 group.

[0071] "Hydroxy" refers to an -OH group.

[0072] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0073] "Amino" refers to -NH2.

[0074] "Cyano" refers to -CN.

[0075] "Benzyl" refers to -CH2-phenyl.

[0076] "Carboxyl" refers to -C(O)OH.

[0077] "Carboxylate" refers to a -C(O)O-alkyl group or a -C(O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

[0078] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0079] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0080] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0081] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0082] "DMSO" refers to dimethyl sulfoxide.

[0083] "BOC" refers to tert-butoxycarbonyl.

[0084] "Bn" refers to benzyl.

[0085] "THP" refers to 2-tetrahydropyranyl.

[0086] "TFA" refers to trifluoroacetic acid.

[0087] "Ts" refers to p-toluenesulfonyl.

[0088] "Leaving group", or leaving group, is an atom or functional group that breaks away from a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In a nucleophilic substitution reaction, the reactant attacked by the nucleophile is called the substrate, and the atom or group of atoms that breaks away from the substrate molecule with a pair of electrons is called the leaving group. Groups that easily accept electrons and have a strong ability to withstand negative charges are good leaving groups. The smaller the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to break away from other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to bind to other atoms, and the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, methylsulfonyl, -OTs or -OH.

[0089] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0090] As used herein, "substituted" or "substituted", unless otherwise specified, means that a group may be substituted by one or more groups selected from the following groups: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate, =O, -OR 6 、-C(O)R 6 、-C(O)OR 6 、-NHC(O)R 6 、-NHC(O)OR 6 、-NR 7 R 8 、-C(O)NR 7 R 8 、-CH2NHC(O)OR 6 、-CH2NR 7 R 8 or -S(O)rR 6 substituted by a substituent;

[0091] R 6 is selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0092] R 7 and R 8Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0093] Or, R 7 and R 8 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent;

[0094] R 9 、R 10 and R 11 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;

[0095] r is selected from 0, 1 or 2;

[0096] The compounds of the present invention may contain asymmetric centers or chiral centers and therefore exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers and atropisomers and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

[0097] Unless otherwise indicated, structures depicted herein also encompass all isomers (e.g., diastereoisomers, enantiomers, and atropisomers, and geometric (conformational) isomeric forms of such structures; for example, R and S configurations at various asymmetric centers, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, individual stereoisomers as well as enantiomeric mixtures, diastereomeric mixtures, and geometric (conformational) isomeric mixtures of the present compounds are within the scope of the invention.

[0098] "Pharmaceutically acceptable salts" refer to salts of the above compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of the compounds represented by general formula (I) may be metal salts or amine salts formed with suitable acids.

[0099] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0100] Synthesis method of the compound of the present invention

[0101] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0102] The present invention provides a method for preparing a compound of general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts, the method comprising:

[0103] The compound of formula (IA) undergoes a condensation reaction with the compound (IB), and optionally further undergoes a substitution reaction to obtain the compound of formula (I)

[0104] in:

[0105] L2 is selected from

[0106] Y is selected from hydroxy or chlorine;

[0107] Ring A, X1 to X6, L1, R 1 ~R 5 , m and n are as defined in the general formula (I). DETAILED DESCRIPTION

[0108] The present invention is further described below with reference to the following examples, but these examples are not intended to limit the scope of the present invention.

[0109] Example

[0110] The examples provide the preparation of representative compounds represented by formula (I) and related structural identification data. It must be noted that the following examples are used to illustrate the present invention rather than to limit the present invention. 1 H NMR spectra were obtained using a Bruker instrument (400 MHz), and chemical shifts are expressed in ppm using tetramethylsilane as an internal standard (0.00 ppm). 1 H NMR notation: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of a doublet, dt = doublet of a triplet. Coupling constants, when given, are given in Hz.

[0111] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0112] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0113] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0114] In the following examples, unless otherwise indicated, all temperatures are in degrees Celsius. Unless otherwise indicated, various starting materials and reagents are commercially available or synthesized according to known methods. Commercially available raw materials and reagents are used directly without further purification, unless otherwise indicated. Commercial manufacturers include but are not limited to Aldrich Chemical Company, ABCR GmbH & Co.KG, Acros Organics, Guangzan Chemical Technology Co., Ltd. and Jingyan Chemical Technology Co., Ltd.

[0115] CD3OD: deuterated methanol.

[0116] CDCl3: deuterated chloroform.

[0117] DMSO-d6: deuterated dimethyl sulfoxide.

[0118] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1 L.

[0119] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0120] The compound was purified using silica gel column chromatography and reverse phase column chromatography, with the eluent system selected from: A: petroleum ether and ethyl acetate; B: dichloromethane and methanol; C: dichloromethane: ethyl acetate; and D: aqueous trifluoroacetic acid and acetonitrile. The volume ratio of the solvents varied depending on the polarity of the compound and could be adjusted by adding a small amount of an acidic or alkaline reagent, such as acetic acid or triethylamine.

[0121] Example 1

[0122] N-(2-(3,3-difluorocyclobutyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0123] N-(2-(3,3-difluorocyclobutyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0124] first step

[0125] 2-(3,3-difluorocyclobutyl)-7-nitroisoindolin-1-one

[0126] 2-(3,3-Difluorocyclobutyl)-7-nitroisoindolin-1-one

[0127] At room temperature, methyl 2-(bromomethyl)-6-nitrobenzoate 1a (300 mg, 1.09 mmol, prepared using the known method "Patent WO2021126973A1") was added to methanol (8 mL). Triethylamine (443 mg, 4.38 mmol) and 3,3-difluorocyclobutan-1-amine 1b (314 mg, 2.19 mmol, commercially available) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was continued at 70°C for 18 hours. The mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 2-(3,3-difluorocyclobutyl)-7-nitroisoindolin-1-one 1c (250 mg) in a 95.87% yield.

[0128] MS m / z(ESI):269.0[M+1]

[0129] Step 2

[0130] 7-amino-2-(3,3-difluorocyclobutyl)isoindolin-1-one

[0131] 7-Amino-2-(3,3-difluorocyclobutyl)isoindolin-1-one

[0132] 2-(3,3-difluorocyclobutyl)-7-nitroisoindolin-1-one 1c (250 mg, 0.932 mmol) was added to methanol (5 mL) at room temperature. 10% palladium on carbon (49.6 mg, 0.466 mmol) was added to the reaction mixture, and the atmosphere was replaced with hydrogen three times. The reaction was continued at 25°C for 18 hours. The reaction mixture was filtered and rinsed with methanol (20 mL x 3). The organic phase was collected and concentrated to dryness under reduced pressure to provide 7-amino-2-(3,3-difluorocyclobutyl)isoindolin-1-one 1d (200 mg) in a 90% yield.

[0133] MS m / z(ESI):239.0[M+1]

[0134] Step 3

[0135] 4-bromo-N-(2-(3,3-difluorocyclobutyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0136] 4-Bromo-N-(2-(3,3-difluorocyclobutyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0137] At room temperature, 7-amino-2-(3,3-difluorocyclobutyl)isoindolin-1-one 1d (150 mg, 0.630 mmol) and 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)benzoyl chloride 1e (207 mg, 0.630 mmol, prepared by the known method "Patent WO-2020132648") were added to pyridine (5 mL), and 4-dimethylaminopyridine (38.5 mg, 0.315 mmol) was added to the above reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90 ° C for 18 hours. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(2-(3,3-difluorocyclobutyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 1f (70.0 mg) in a yield of 21%.

[0138] MS m / z(ESI):530.2[M+1]

[0139] Step 4

[0140] N-(2-(3,3-difluorocyclobutyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0141] N-(2-(3,3-difluorocyclobutyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0142] At room temperature, 4-bromo-N-(2-(3,3-difluorocyclobutyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 1f (50 mg, 0.0943 mmol) and 2-hydroxyethane-1-sulfonamide 1g (13.0 mg, 103.69 mmol) were added to N,N-dimethylformamide (5 mL). Cuprous iodide (20.9 mg, 0.0943 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (6.70 mg, 0.0471 mmol) and potassium phosphate (40.0 mg, 0.189 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 18 hours. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(2-(3,3-difluorocyclobutyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 1 (20 mg) with a yield of 37%.

[0143] MS m / z(ESI):575.2[M+1]

[0144] 1 H NMR (400MHz, DMSO-d6) δ11.76(s,1H),8.57(d,J=8.4Hz,1H),7.67(d,J=8.4Hz ,1H),7.59(t,J=8.0Hz,1H),7.27(d,J=7.2Hz,1H),7.05(d,J=2.0Hz,1H),6.9 5-6.89(m,1H),4.66(s,2H),4.59-4.50(m,1H),3.75(t,J=6.8Hz,2H),3.32-3 .29(m,2H),3.17-3.07(m,2H),3.00-2.90(m,6H),1.43(brs,4H),0.24(s,4H).

[0145] Example 2

[0146] N-(2-(cyclopropylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0147] N-(2-(Cyclopropylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0148] first step

[0149] 2-(cyclopropylmethyl)-7-nitroisoindolin-1-one

[0150] 2-(Cyclopropylmethyl)-7-nitroisoindolin-1-one

[0151] To a solution of methyl 2-(bromomethyl)-6-nitrobenzoate 1a (500 mg, 1.82 mmol) in methanol (10 mL) were added cyclopropylmethylamine 2a (194 mg, 2.73 mmol, commercially available) and triethylamine (551 mg, 5.46 mmol) at 25°C. The mixture was reacted at 65°C for 18 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to afford 2-(cyclopropylmethyl)-7-nitroisoindolin-1-one 2b (350 mg) in 83% yield.

[0152] MS m / z(ESI):233.0[M+1]

[0153] Step 2

[0154] 7-amino-2-(cyclopropylmethyl)isoindolin-1-one

[0155] 7-Amino-2-(cyclopropylmethyl)isoindolin-1-one

[0156] To a solution of 2-(cyclopropylmethyl)-7-nitroisoindolin-1-one 2b (300 mg, 1.29 mmol) in methanol (5 mL) was added zinc powder (845 mg, 12.9 mmol) and ammonium chloride (346 mg, 6.46 mmol) at 25°C, and the mixture was reacted at 65°C for 6 hours. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 7-amino-2-(cyclopropylmethyl)isoindolin-1-one 2c (150 mg) in a 57% yield.

[0157] MS m / z(ESI):203.0[M+1]

[0158] Step 3

[0159] 4-bromo-N-(2-(cyclopropylmethyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0160] 4-Bromo-N-(2-(cyclopropylmethyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0161] To a solution of 7-amino-2-(cyclopropylmethyl)isoindolin-1-one 2c (100 mg, 0.494 mmol) in pyridine (10 mL) were added 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride 1e (195 mg, 0.593 mmol) and 4-dimethylaminopyridine (18.1 mg, 0.148 mmol) at 25°C. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 18 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(2-(cyclopropylmethyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 2d (50 mg) in a yield of 20%.

[0162] MS m / z(ESI):496.1[M+1]

[0163] Step 4

[0164] N-(2-(cyclopropylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0165] N-(2-(Cyclopropylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0166] At 25°C, 4-bromo-N-(2-(cyclopropylmethyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 2d (50 mg, 0.101 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (25.3 mg, 0.202 mmol) were added to N,N-dimethylformamide (3 mL). Potassium phosphate (42.9 mg, 0.202 mmol), cuprous iodide (22.46 mg, 0.101 mmol) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (7.19 mg, 0.0505 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (60 mL). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(2-(cyclopropylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 2 (16 mg) in a yield of 29%.

[0167] MS m / z(ESI):539.2[M+1]

[0168] 1 H NMR (400MHz, DMSO-d6) δ11.82(s,1H),8.58(d,J=8.4Hz,1H),7.66(d,J=8.4Hz,1H),7.5 6(t,J=8.0Hz,1H),7.26(d,J=7.4Hz,1H),7.04(d,J=2.0Hz,1H),6.92(dd,J=8.4,2.0Hz ,1H),4.59(s,2H),3.76(t,J=6.6Hz,2H),3.36(d,J=7.0Hz,2H),3.31(t,J=6.6Hz,2H), 2.96(t,J=5.4Hz,4H),1.44(s,4H),1.02(m,1H),0.49(m,2H),0.31(m,2H),0.23(s,4H).

[0169] Example 3

[0170] N-(2-(cyclobutylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0171] N-(2-(Cyclobutylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0172] first step

[0173] 2-(cyclobutylmethyl)-7-nitroisoindolin-1-one

[0174] 2-(Cyclobutylmethyl)-7-nitroisoindolin-1-one

[0175] Methyl 2-(bromomethyl)-6-nitrobenzoate 1a (500 mg, 1.80 mmol) was added to methanol (5 mL) at room temperature. Triethylamine (0.76 mL, 5.45 mmol) and cyclobutylmethylamine 3a (0.35 mL, 3.65 mmol) were added to the reaction mixture. The atmosphere was replaced with nitrogen three times and the reaction was continued at 70°C for 18 hours. The mixture was filtered and concentrated to dryness under reduced pressure to provide 2-(cyclobutylmethyl)-7-nitroisoindolin-1-one 3b (320 mg) in a 71% yield.

[0176] MS m / z(ESI):247.0[M+1]

[0177] Step 2

[0178] 7-amino-2-(cyclobutylmethyl)isoindolin-1-one

[0179] 7-Amino-2-(cyclobutylmethyl)isoindolin-1-one

[0180] 2-(Cyclobutylmethyl)-7-nitroisoindolin-1-one 3b (320 mg, 1.30 mmol) was added to methanol (5 mL) at room temperature. 10% palladium on carbon (41.5 mg, 0.39 mmol) was added to the reaction mixture, and the atmosphere was replaced with hydrogen three times. The reaction was allowed to proceed at 25°C for 2 hours. The reaction mixture was filtered and rinsed with methanol (20 mL x 3). The organic phase was collected and concentrated to dryness under reduced pressure to provide 7-amino-2-(cyclobutylmethyl)isoindolin-1-one 3c (270 mg) in a 96% yield.

[0181] MS m / z(ESI):217.1[M+1]

[0182] Step 3

[0183] 4-bromo-N-(2-(cyclobutylmethyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0184] 4-Bromo-N-(2-(cyclobutylmethyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0185] 7-Amino-2-(cyclobutylmethyl)isoindolin-1-one 3c (200 mg, 0.92 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride 1e (320 mg, 1.02 mmol) were added to N,N-dimethylformamide (7 mL) at room temperature. (7-Azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (960 mg, 1.85 mmol) and N,N-diisopropylethylamine (360 mg, 2.77 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 70°C for 18 h. The reaction solution was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(2-(cyclobutylmethyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 3d (210 mg) in a yield of 45%.

[0186] MS m / z(ESI):508.2[M+1]

[0187] Step 4

[0188] N-(2-(cyclobutylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0189] N-(2-(Cyclobutylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0190] At room temperature, 4-bromo-N-(2-(cyclobutylmethyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 3d (50 mg, 0.100 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (13 mg, 0.110 mmol) were added to N,N-dimethylformamide (2 mL). Cuprous iodide (20 mg, 0.10 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (7 mg, 0.05 mmol) and potassium phosphate (80 mg, 0.39 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 18 hours. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(2-(cyclobutylmethyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 3 (40 mg) with a yield of 64%.

[0191] MS m / z(ESI):553.2[M+1]

[0192] 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),8.58(d,J=8.4Hz,1H),7.67(d,J=8.4Hz,1H),7.54(t,J= 8.0Hz,1H),7.22(d,J=7.6Hz,1H),7.05(d,J=2.0Hz,1H),6.94-6.91(m,1H),4.46(s,2H),3.75 (t,J=6.4Hz,2H),3.53(d,J=7.6Hz,2H),3.33(d,J=6.8Hz,2H),2.96(t,J=5.2Hz,4H),2.78-2. 73(m,1H),2.03-1.98(m,2H),1.89-1.81(m,2H),1.78-1.72(m,2H),1.43(s,4H),0.20(s,4H).

[0193] Example 4

[0194] N-(2-((3,3-difluorocyclobutyl)methyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0195] N-(2-((3,3-difluorocyclobutyl)methyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0196] first step

[0197] 2-((3,3-difluorocyclobutyl)methyl)-7-nitroisoindolin-1-one

[0198] 2-((3,3-difluorocyclobutyl)methyl)-7-nitroisoindol-1-one

[0199] Methyl 2-(bromomethyl)-6-nitrobenzoate 1a (500 mg, 1.82 mmol) was added to methanol (10 mL) at room temperature. Triethylamine (554 mg, 5.47 mmol) and (3,3-difluorocyclobutyl)methylamine hydrochloride 4a (332 mg, 2.74 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was continued at 70°C for 18 hours. The mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give 2-((3,3-difluorocyclobutyl)methyl)-7-nitroisoindolyl-1-one 4b (400 mg) in a 78% yield.

[0200] MS m / z(ESI):283.4[M+1]

[0201] Step 2

[0202] 7-amino-2-((3,3-difluorocyclobutyl)methyl)isoindolin-1-one

[0203] 7-Amino-2-((3,3-difluorocyclobutyl)methyl)isoindolin-1-one

[0204] 2-((3,3-difluorocyclobutyl)methyl)-7-nitroisoindolyl-1-one 4b (400 mg, 1.42 mmol) was added to methanol (5 mL) at room temperature. 10% palladium on carbon (75.4 mg, 0.709 mmol) was added to the reaction mixture, and the atmosphere was replaced with hydrogen three times. The reaction was continued at 25°C for 18 hours. The reaction mixture was filtered and washed with anhydrous methanol (20 mL x 3). The organic phase was collected and concentrated to dryness under reduced pressure to provide 7-amino-2-((3,3-difluorocyclobutyl)methyl)isoindolin-1-one 4c (250 mg) in a 70% yield.

[0205] MS m / z(ESI):253.5[M+1]

[0206] Step 3

[0207] 4-bromo-N-(2-((3,3-difluorocyclobutyl)methyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6 -yl)benzamide

[0208] 4-Bromo-N-(2-((3,3-difluorocyclobutyl)methyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0209] 7-Amino-2-((3,3-difluorocyclobutyl)methyl)isoindolin-1-one 4c (100 mg, 0.396 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride 1e (135 mg, 0.436 mmol) were added to N,N-dimethylformamide (5 mL) at room temperature. (7-Azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (413 mg, 0.793 mmol) and N,N-diisopropylethylamine (154 mg, 1.19 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 70°C for 18 h. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(2-((3,3-difluorocyclobutyl)methyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 4d (60 mg) in a yield of 28%.

[0210] MS m / z(ESI):544.1[M+1]

[0211] Step 4

[0212] N-(2-((3,3-difluorocyclobutyl)methyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0213] N-(2-((3,3-difluorocyclobutyl)methyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0214] At room temperature, 4-bromo-N-(2-((3,3-difluorocyclobutyl)methyl)-3-oxoisoindolin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 4d (50.0 mg, 0.0918 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (13 mg, 0.101 mmol) were added to N,N-dimethylformamide (5 mL). Cuprous iodide (17.5 mg, 0.0918 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (6.5 mg, 0.046 mmol) and potassium phosphate (39.0 mg, 0.184 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 18 hours. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(2-((3,3-difluorocyclobutyl)methyl)-3-oxoisoindolin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 4 (10 mg) with a yield of 19%.

[0215] MS m / z(ESI):589.2[M+1]

[0216] 1H NMR (400MHz, DMSO-d6) δ11.82(s,1H),8.60(d,J=8.0Hz,1H),7.66(d,J=8.4Hz,1H), 7.56(t,J=8.0Hz,1H),7.24(d,J=7.6Hz,1H),7.01(d,J=2.4Hz,1H),6.92-6.86(m,1 H),4.53(s,2H),3.75(t,J=6.8Hz,2H),3.65(d,J=7.2Hz,2H),3.29-3.26(m,3H),3. 00-2.91(m,4H),2.72-2.62(m,2H),2.45-2.35(m,2H),1.45(brs,4H),0.22(s,4H).

[0217] Example 5

[0218] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0219] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0220] first step

[0221] 3-bromo-1-methyl-7-nitro-1H-indazole

[0222] 3-Bromo-1-methyl-7-nitro-1H-indazole

[0223] Potassium hydroxide (301 mg, 5.37 mmol) was added to a solution of 3-bromo-7-nitro-1H-indazole 5a (1 g, 4.13 mmol, commercially available) and iodomethane (1.17 g, 8.26 mmol) in acetone (20 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 3-bromo-1-methyl-7-nitro-1H-indazole 5b (770 mg) in a 73% yield.

[0224] MS m / z(ESI):255.8[M+1]

[0225] 1 H NMR (400MHz, DMSO-d6) δ8.33–8.27(m,1H),8.04(d,J=8.0Hz,1H),7.43(t,J=8.0Hz,1H),4.14(s,3H).

[0226] Step 2

[0227] 3-(4,4-difluoropiperidin-1-yl)-1-methyl-7-nitro-1H-indazole

[0228] 3-(4,4-difluoropiperidin-1-yl)-1-methyl-7-nitro-1H-indazole

[0229] Palladium acetate (52.6 mg, 0.23 mmol), R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (146 mg, 0.23 mmol), and cesium carbonate (2.29 g, 7.03 mmol) were added to a toluene (5 mL) solution of 3-bromo-1-methyl-7-nitro-1H-indazole 5b (600 mg, 2.34 mmol) and 4,4-difluoropiperidine (426 mg, 3.51 mmol). The atmosphere was purged with nitrogen three times and the mixture was reacted at 100°C for 16 hours. The mixture was filtered, the filter cake was rinsed with ethyl acetate (300 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 3-(4,4-difluoropiperidin-1-yl)-1-methyl-7-nitro-1H-indazole 5c (280 mg) in a 40% yield.

[0230] MS m / z(ESI):297.2[M+1]

[0231] Step 3

[0232] 3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-amine

[0233] 3-(4,4-Difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-amine

[0234] At room temperature, 10% palladium on carbon (50.00 mg) was added to a solution of 3-(4,4-difluoropiperidin-1-yl)-1-methyl-7-nitro-1H-indazole 5c (280 mg, 0.95 mmol) in methanol (10 mL). The hydrogen atmosphere was replaced three times and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was filtered, the filter cake was rinsed with methanol (200 mL), and the filtrate was concentrated under reduced pressure to afford 3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-amine 5d (210 mg) in an 83% yield.

[0235] MS m / z(ESI):267.2[M+1]

[0236] Step 4

[0237] 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0238] 4-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0239] At room temperature, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (450 mg, 1.18 mmol) and N,N-diisopropylethylamine (204 mg, 1.58 mmol) were added to a solution of 3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-amine 5d (210 mg, 0.78 mmol) and 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid 5e (318 mg, 1.03 mmol, prepared in-house using the known method "WO2020132648") in N,N-dimethylformamide (5 mL), and the reaction mixture was reacted at 60 ° C for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate (50 mL×3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 5f (180 mg) in a yield of 41%.

[0240] MS m / z(ESI):558.2[M+1]

[0241] Step 5

[0242] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0243] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0244] To a solution of 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 5f (180 mg, 0.32 mmol) in N,N-dimethylformamide (5 mL) was added 2-hydroxyethane-1-sulfonamide (80.7 mg, 0.64 mmol), cuprous iodide (61.4 mg, 0.32 mmol), potassium phosphate (137 mg, 0.64 mmol) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (22.9 mg, 0.16 mmol) at room temperature. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (50 mL×3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified sequentially by silica gel column chromatography (eluent: System A) and preparative high performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to obtain N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 5 (67.1 mg) in a yield of 35%.

[0245] MS m / z(ESI):603.2[M+1]

[0246] 1H NMR (400MHz, DMSO-d6) δ11.47(s,1H),10.11(s,1H),7.88(d,J=8.4Hz,1H),7.71 (d,J=8.0Hz,1H),7.28(d,J=7.2Hz,1H),7.23(d,J=2.0Hz,1H),7.10–7.02(m,2H) ,4.96(t,J=5.6Hz,1H),3.86(s,3H),3.81–3.72(m,2H),3.51–3.40(m,4H),3.35( t,J=6.4Hz,2H),3.13–2.98(m,4H),2.23–2.08(m,4H),1.52(s,4H),0.34(s,4H).

[0247] Example 6

[0248] N-(2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0249] N-(2-(3,3-Difluoroazetidin-1-yl)quinazolin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0250] first step

[0251] 5-bromo-2-(3,3-difluoroazetidin-1-yl)quinazoline

[0252] 5-Bromo-2-(3,3-difluoroazetidin-1-yl)quinazoline

[0253] To a solution of 5-bromo-2-chloro-quinazoline 6a (300 mg, 1.23 mmol) in dimethyl sulfoxide (10 mL) at 25°C were added 3,3-difluoroazetidine hydrochloride (319 mg, 2.46 mmol) and cesium carbonate (1.20 g, 3.70 mmol). The mixture was reacted at 100°C for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 5-bromo-2-(3,3-difluoroazetidin-1-yl)quinazoline 6b (330 mg) in an 89% yield.

[0254] MS m / z(ESI):300.0 / 302.0[M+1]

[0255] Step 2

[0256] tert-butyl(2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)carbamate

[0257] tert-Butyl (2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)carbamate

[0258] To a solution of 5-bromo-2-(3,3-difluoroazetidin-1-yl)quinazoline 6b (280 mg, 0.933 mmol) in 1,4-dioxane (5 mL) were added tert-butyl carbamate (219 mg, 1.87 mmol), cesium carbonate (912 mg, 2.80 mmol), tris(dibenzylideneacetone)dipalladium (256 mg, 0.278 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (445 mg, 0.933 mmol) at 25°C. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 2 hours. The mixture was filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)carbamate 6c (300 mg) in a yield of 96%.

[0259] MS m / z(ESI):337.2[M+1]

[0260] Step 3

[0261] 2-(3,3-difluoroazetidin-1-yl)quinazolin-5-amine

[0262] 2-(3,3-Difluoroazetidin-1-yl)quinazolin-5-amine

[0263] To a solution of tert-butyl (2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)carbamate 6c (200 mg, 0.595 mmol) in dichloromethane (2 mL) was added a 1,4-dioxane solution of hydrogen chloride (4 M, 2 mL) at 25°C. The mixture was reacted at 25°C for 18 hours. The mixture was concentrated under reduced pressure to give 2-(3,3-difluoroazetidin-1-yl)quinazolin-5-amine 6d (200 mg).

[0264] MS m / z(ESI):237.0[M+1]

[0265] Step 4

[0266] 4-bromo-N-(2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0267] 4-Bromo-N-(2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0268] To a solution of 2-(3,3-difluoroazetidin-1-yl)quinazolin-5-amine 6d (200 mg, 0.846 mmol) in N,N-dimethylformamide (10 mL) were added 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (394 mg, 1.27 mmol), (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (663 mg, 1.27 mmol) and N,N-diisopropylethylamine (438 mg, 3.39 mmol) at 25°C and reacted at 65°C for 3 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 6e (100 mg) in a yield of 22%.

[0269] MS m / z(ESI):528.2 / 530.2[M+1]

[0270] Step 5

[0271] N-(2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0272] N-(2-(3,3-Difluoroazetidin-1-yl)quinazolin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0273] 4-Bromo-N-(2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 6e (100 mg, 0.189 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (47.4 mg, 0.379 mmol) were added to N,N-dimethylformamide (10 mL) at 25°C. Potassium phosphate (80.3 mg, 0.379 mmol), cuprous iodide (42.0 mg, 0.189 mmol) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (13.5 mg, 0.0946 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 18 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(2-(3,3-difluoroazetidin-1-yl)quinazolin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 6 (22 mg) with a yield of 20%.

[0274] MS m / z(ESI):573.2[M+1]

[0275] 1 H NMR (400MHz, DMSO-d6) δ11.83(s,1H),9.54(s,1H),7.93(d,J=7.8Hz,1H),7.88–7.78(m,2H),7.42(d,J=8.4Hz,1H),7.22(d,J=2.0Hz,1H),7.06(dd ,J=8.4,2.0Hz,1H),4.59(t,J=12.4Hz,4H),3.78(t,J=6.6Hz,2H),3.35(t ,J=6.6Hz,2H),3.04(t,J=5.2Hz,4H),1.41(t,J=5.2Hz,4H),0.28(s,4H).

[0276] Example 7

[0277] N-(2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0278] N-(2-(3,3-Difluoroazetidin-1-yl)quinoxalin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0279] first step

[0280] 5-bromoquinoxalin-2(1H)-one

[0281] 5-Bromoquinoxalin-2(1H)-one

[0282] To a solution of 3-bromobenzene-1,2-diamine 7a (2.00 g, 10.69 mmol) in ethanol (20 mL) was added ethyl glyoxylate (1.64 g, 16.0 mmol) at 25°C, and the mixture was allowed to react at 80°C for 18 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 5-bromoquinoxalin-2(1H)-one 7b (2.20 g) in a 91% yield.

[0283] MS m / z(ESI):225.0 / 227.0[M+1]

[0284] Step 2

[0285] 5-bromo-2-chloroquinoxaline

[0286] 5-Bromo-2-chloroquinoxaline

[0287] Phosphorus oxychloride (8.18 g, 53.3 mmol) was added to a solution of 5-bromoquinoxaline-2(1H)-one 7b (2.00 g, 8.89 mmol) in acetonitrile (20 mL) at 25°C, and the mixture was reacted at 90°C for 3 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 5-bromo-2-chloroquinoxaline 7c (260 mg) in a 12% yield.

[0288] MS m / z(ESI):242.9 / 244.9[M+1]

[0289] 1 H NMR (400MHz, DMSO-d6) δ9.10(s,1H),8.26(dd,J=7.6,1.2Hz,1H),8.07(dd,J=8.4,1.2Hz,1H),7.84(dd,J=8.4,7.6Hz,1H).

[0290] Step 3

[0291] 5-bromo-2-(3,3-difluoroazetidin-1-yl)quinoxaline

[0292] 5-Bromo-2-(3,3-difluoroazetidin-1-yl)quinoxaline

[0293] To a solution of 5-bromo-2-chloroquinoxaline 7c (230 mg, 0.945 mmol) in dimethyl sulfoxide (5 mL) was added 3,3-difluoroazetidine hydrochloride (245 mg, 1.89 mmol) and cesium carbonate (392 mg, 2.83 mmol) at 25°C. The mixture was reacted at 65°C for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 5-bromo-2-(3,3-difluoroazetidin-1-yl)quinoxaline 7d (260 mg) in a 92% yield.

[0294] MS m / z(ESI):300.0 / 302.0[M+1]

[0295] Step 4

[0296] tert-butyl(2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)carbamate

[0297] tert-Butyl (2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)carbamate

[0298] To a solution of 5-bromo-2-(3,3-difluoroazetidin-1-yl)quinoxaline 7d (200 mg, 0.666 mmol) in 1,4-dioxane (10 mL) were added tert-butyl carbamate (156 mg, 1.33 mmol), cesium carbonate (651 mg, 2.00 mmol), tris(dibenzylideneacetone)dipalladium (183 mg, 0.200 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (318 mg, 0.666 mmol) at 25°C. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 2 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)carbamate 7e (200 mg) in a yield of 89%.

[0299] MS m / z(ESI):337.2[M+1]

[0300] Step 5

[0301] 2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-amine

[0302] 2-(3,3-Difluoroazetidin-1-yl)quinoxalin-5-amine

[0303] To a solution of tert-butyl (2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)carbamate 7e (200 mg, 0.595 mmol) in dichloromethane (2 mL) was added a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) at 25°C, and the mixture was reacted for 2 hours at 25°C. The mixture was concentrated under reduced pressure to afford 2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-amine 7f (200 mg).

[0304] MS m / z(ESI):237.2[M+1]

[0305] Step 6

[0306] 4-bromo-N-(2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0307] 4-Bromo-N-(2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0308] To a solution of 2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-amine 7f (200 mg, 0.846 mmol) in N,N-dimethylformamide (10 mL) were added 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (394 mg, 1.27 mmol), (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (663 mg, 1.27 mmol) and N,N-diisopropylethylamine (438 mg, 3.39 mmol) at 25°C and the reaction was carried out at 65°C for 18 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The aqueous phase was extracted with dichloromethane (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 7 g (300 mg) of 4-bromo-N-(2-(3,3-difluoroazetidin-1-yl)quinoxaline-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide. Yield: 67%.

[0309] MS m / z(ESI):528.2 / 530.2[M+1]

[0310] Step 7

[0311] N-(2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro [2.5]octan-6-yl)benzamide

[0312] N-(2-(3,3-Difluoroazetidin-1-yl)quinoxalin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0313] At 25°C, 7 g (200 mg, 0.379 mmol) of 4-bromo-N-(2-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide and 1 g (94.7 mg, 0.757 mmol) of 2-hydroxyethane-1-sulfonamide were added to N,N-dimethylformamide (10 mL). Potassium phosphate (161 mg, 0.757 mmol), cuprous iodide (84.1 mg, 0.379 mmol) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (26.9 mg, 0.189 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The extracts were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(2-(3,3-difluoroazetidin-1-yl)quinoxaline-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 7 (26.0 mg) in a yield of 12%.

[0314] MS m / z(ESI):573.2[M+1]

[0315] 1 H NMR (400MHz, DMSO-d6) δ12.57 (s, 1H), 8.69 (dd, J = 8.0, 1.2Hz, 1H), 8.38 (s, 1H), 7.97(d,J=8.4Hz,1H),7.66(t,J=8.0Hz,1H),7.40(dd,J=8.4,1.2Hz,1H),7.23(d ,J=2.0Hz,1H),7.05(dd,J=8.4,2.0Hz,1H),4.70(t,J=12.4Hz,4H),3.77(t,J=6. 4Hz, 2H), 3.35 (t, J = 6.4Hz, 2H), 3.02 (t, J = 5.2Hz, 4H), 1.59 (s, 4H), 0.30 (s, 4H).

[0316] Example 8

[0317] N-(3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0318] N-(3-(3,3-Difluoroazetidin-1-yl)quinoxalin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0319] first step

[0320] 8-bromo-2-(3,3-difluoroazetidin-1-yl)quinoxaline

[0321] 8-Bromo-2-(3,3-difluoroazetidin-1-yl)quinoxaline

[0322] At room temperature, 8-bromo-2-chloroquinoxaline 8a (300 mg, 1.23 mmol, prepared in-house using the known method described in WO2013130660A1) was added to dimethyl sulfoxide (8 mL). 3,3-Difluoroazetidine hydrochloride (160 mg, 1.23 mmol) and potassium carbonate (341 mg, 2.46 mmol) were added to the reaction solution. The atmosphere was purged with nitrogen three times and the reaction was continued at 65°C for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain 8-bromo-2-(3,3-difluoroazetidin-1-yl)quinoxaline 8b (300 mg) in an 81.14% yield.

[0323] MS m / z(ESI):300.0 / 302.0[M+1]

[0324] Step 2

[0325] tert-butyl(3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)carbamate

[0326] tert-Butyl (3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)carbamate

[0327] At room temperature, 8-bromo-2-(3,3-difluoroazetidin-1-yl)quinoxaline 8b (300 mg, 1.00 mmol) and tert-butyl carbamate (129 mg, 1.10 mmol) were added to 1,4-dioxane (5 mL). 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (71.5 mg, 0.150 mmol), triphenylphosphine (129 mg, 1.10 mmol), and cesium carbonate (977 mg, 3.00 mmol) were then added to the reaction mixture. The atmosphere was purged with nitrogen three times and the reaction was continued at 90°C for 18 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)carbamate 8c (220 mg) in a 65.43% yield.

[0328] MS m / z(ESI):337.0[M+1]

[0329] Step 3

[0330] 3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-amine

[0331] 3-(3,3-Difluoroazetidin-1-yl)quinoxalin-5-amine

[0332] Tert-butyl (3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)carbamate 8c (100 mg, 0.297 mmol) was added to dichloromethane (2 mL) at room temperature. A 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) was added to the reaction mixture, and the mixture was reacted at 25°C for 18 hours. The mixture was concentrated under reduced pressure to provide 3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-amine 8d (60 mg, 0.254 mmol, 85.43% yield).

[0333] MS m / z(ESI):237.0[M+1]

[0334] Step 4

[0335] 4-bromo-N-(3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0336] 4-Bromo-N-(3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0337] At room temperature, 3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-amine 8d (50.0 mg, 0.212 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoyl chloride 1e (69.6 mg, 0.212 mmol) were added to pyridine (5 mL). 4-Dimethylaminopyridine (12.9 mg, 0.106 mmol) was added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 18 hours. The mixture was poured into water (10 mL), extracted with ethyl acetate (10 mL×3), washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(3-(3,3-difluoroazetidin-1-yl)quinoxaline-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 8e (60.0 mg) in a yield of 53.65%.

[0338] MS m / z(ESI):528.2 / 530.2[M+1]

[0339] Step 5

[0340] N-(3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0341] N-(3-(3,3-Difluoroazetidin-1-yl)quinoxalin-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0342] At room temperature, 4-bromo-N-(3-(3,3-difluoroazetidin-1-yl)quinoxalin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8e (80.0 mg, 0.189 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (26.1 mg, 0.208 mmol) were added to N,N-dimethylformamide (5 mL). Cuprous iodide (36.0 mg, 0.189 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (13.5 mg, 0.0946 mmol) and potassium phosphate (80.3 mg, 0.379 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 100°C for 18 h. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(3-(3,3-difluoroazetidin-1-yl)quinoxaline-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 8 (25.0 mg) in a yield of 23.07%.

[0343] MS m / z(ESI):573.0[M+1]

[0344] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.15(s,1H),8.76-8.70(m,1H),8.54(s,1H),7.79(d,J=8.4Hz,1H),7.67–7.62(m,1H),7.50(t,J=8.0 Hz,1H),7.16(d,J=2.4Hz,1H),7.03-6.99(m,1H),4.72-4.62(m,4H),3.78(t,J=6.4Hz,2H),3.38(t,J=6.8Hz,2H),3.05–2.97(m,4H),1.31(br s,4H),0.21(s,4H).

[0345] Example 9

[0346] N-(2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0347] N-(2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0348] first step

[0349] 2-(4,4-difluoropiperidin-1-yl)-4-nitro-1H-benzo[d]imidazole

[0350] 2-(4,4-difluoropiperidin-1-yl)-4-nitro-1H-benzo[d]imidazole

[0351] 2-Chloro-4-nitro-1H-benzo[d]imidazole 9a (40.0 mg, 0.202 mmol, prepared in-house using the known method "WO2013104577A1") and 4,4-difluoropiperidine (245 mg, 2.02 mmol) were mixed at 25°C and reacted at 100°C for 18 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 2-(4,4-difluoropiperidin-1-yl)-4-nitro-1H-benzo[d]imidazole 9b (40 mg) in a 70% yield.

[0352] MS m / z(ESI):283.0[M+1]

[0353] Step 2

[0354] 2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-amine

[0355] 2-(4,4-Difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-amine

[0356] 2-(4,4-difluoropiperidin-1-yl)-4-nitro-1H-benzo[d]imidazole 9b (40.0 mg, 0.142 mmol) was added to methanol (3 mL) at 25°C. 10% palladium on carbon (20 mg, 0.188 mmol) was added to the reaction mixture, and the atmosphere was replaced with hydrogen three times. The reaction was continued at 25°C for 4 hours. The mixture was filtered and concentrated under reduced pressure to afford 2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole-4-amine 9c (40.0 mg) in a 95% yield.

[0357] MS m / z(ESI):253.2[M+1]

[0358] Step 3

[0359] 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0360] 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0361] To a solution of 2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-amine 9c (40.0 mg, 0.159 mmol) in N,N-dimethylformamide (3 mL) were added 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (73.8 mg, 0.238 mmol), (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (124 mg, 0.238 mmol) and N,N-diisopropylethylamine (82.0 mg, 0.634 mmol) at 25°C and reacted at 65°C for 2 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 9d (40.0 mg) in a yield of 46%.

[0362] MS m / z(ESI):544.3 / 546.3[M+1]

[0363] Step 4

[0364] N-(2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0365] N-(2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0366] 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 9d (40.0 mg, 0.0735 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (18.4 mg, 0.147 mmol) were added to N,N-dimethylformamide (3 mL) at 25°C. Potassium phosphate (31.2 mg, 0.147 mmol), cuprous iodide (16.3 mg, 0.0735 mmol) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (5.23 mg, 0.0367 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 2 h. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H 2 O, mobile phase B: CH 3 CN) to give N-(2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 9 (10.7 mg) in a yield of 25%.

[0367] MS m / z(ESI):589.4[M+1]

[0368] 1H NMR (400MHz, DMSO-d6) δ11.65 (s, 1H), 11.50 (s, 1H), 8.22 (d, J = 8.4Hz, 1H), 7. 96(d,J=8.4Hz,1H),7.21(d,J=2.0Hz,1H),7.04(dd,J=8.4,2.0Hz,1H),6.96(d ,J=7.6Hz,1H),6.91(t,J=7.6Hz,1H),3.77(m,2H),3.74(m,4H),3.34(m,2H), 3.01(t,J=5.2Hz,4H),2.09(tt,J=14.0,5.6Hz,4H),1.68(s,4H),0.30(s,4H).

[0369] Example 10

[0370] N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0371] N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0372] first step

[0373] 4-bromo-2-chloro-1H-benzo[d]imidazole

[0374] 4-Bromo-2-chloro-1H-benzo[d]imidazole

[0375] Phosphorus oxychloride (10 mL) was added to 4-bromo-1,3-dihydro-2H-benzo[d]imidazol-2-one 10a (1.00 g, 4.69 mmol, prepared in-house using the known method "WO2009111260A1"). After nitrogen displacement three times, the reaction was allowed to proceed at 90°C for 3 hours. The phosphorus oxychloride was removed under reduced pressure and slowly added dropwise to water (50 mL) with stirring to quench the product. The resulting product was poured into water (50 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-bromo-2-chloro-1H-benzo[d]imidazol-2-one 10b (1.00 g) in a 92.03% yield.

[0376] MS m / z(ESI):231.0 / 233.0[M+1]

[0377] Step 2

[0378] 4-bromo-2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole

[0379] 4-Bromo-2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole

[0380] 4,4-Difluoropiperidine (5.23 g, 43.20 mmol) and 4-bromo-2-chloro-1H-benzo[d]imidazole 10b (1.00 g, 4.32 mmol) were mixed at room temperature and reacted at 100°C overnight to yield a pale yellow solution. The mixture was poured into water (150 mL), adjusted to pH 10 with 1N sodium hydroxide solution, and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4-bromo-2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole 10c (1.20 g) in 87.86% yield.

[0381] MS m / z(ESI):316.0 / 318.0[M+1]

[0382] Step 3

[0383] 4-bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole

[0384] 4-Bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole 10d

[0385] 7-bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole

[0386] 7-Bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole 10e

[0387] 4-Bromo-2-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazole 10c (1.20 g, 3.80 mmol) was dissolved in N,N-dimethylformamide (10 mL). Sodium hydride (197.48 mg, 7.59 mmol) was added under ice-cooling and stirring was continued for 0.5 h. Then, iodomethane (1.08 g, 7.59 mmol) was added under ice-cooling and the reaction solution was returned to room temperature for 1 h. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL×2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole 10d (520.00 mg) in a yield of 41.49%; 7-bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole 10e (400.00 mg) in a yield of 31.92%.

[0388] 10d:MS m / z(ESI):330.0 / 332.0[M+1]

[0389] 1 H NMR (400MHz, DMSO-d6) δ7.39(d,J=7.8Hz,1H),7.36–7.27(m,1H),7.05(t,J=7.8Hz,1H),3.65(s,3H),3.44–3.42(m,4H),2.22–2.16(m,4H).

[0390] 10e:MS m / z(ESI):330.0 / 332.0[M+1]

[0391] 1 H NMR (400MHz, DMSO-d6) δ7.43(d,J=7.4Hz,1H),7.27(d,J=7.8Hz,1H),7.03(t ,J=7.8Hz,1H),3.83(s,3H),3.40–3.36(d,J=5.6Hz,4H),2.22–2.16(m,4H).

[0392] Step 4

[0393] tert-butyl(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)carbamate

[0394] tert-Butyl (2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)carbamate

[0395] 4-Bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole 10d (520 mg, 1.57 mmol) was dissolved in dioxane (8 mL), and cesium carbonate (1.03 g, 3.15 mmol), tert-butyl carbamate (184 mg, 1.57 mmol), dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (144 mg, 158 μmol) and tris(dibenzylideneacetone)dipalladium (150 mg, 315 μmol) were added in sequence and the reaction was carried out at 100 °C for 18 hours. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (40 mL×2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)carbamate 10f (480 mg) in a yield of 83%.

[0396] MS m / z(ESI):367.2[M+1]

[0397] Step 5

[0398] 2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-amine

[0399] 2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-amine

[0400] Dissolve tert-butyl (2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)carbamate 10f (480 mg, 1.31 mmol) in dioxane (5 mL). Add 4M hydrogen chloride in dioxane (1 mL) dropwise and allow to react at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure to afford 10 g (400 mg) of 2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-amine in an 85% yield.

[0401] MS m / z(ESI):267.2[M+1]

[0402] Step 6

[0403] 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0404] 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0405] At room temperature, 10 g (100 mg, 0.38 mmol) of 2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-amine was dissolved in N,N-dimethylformamide (1 mL). 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (116 mg, 0.38 mmol), N,N-diisopropylethylamine (194 mg, 1.50 mmol) and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (293.69 mg, 0.56 mmol) were added sequentially. The atmosphere was replaced with nitrogen three times and the mixture was reacted at 60°C for 6 h. The mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 10h (200 mg) in a yield of 95%.

[0406] MS m / z(ESI):558.2 / 560.2[M+1]

[0407] Step 7

[0408] N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0409] N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0410] At room temperature, 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 10h (50 mg, 0.09 mmol) was dissolved in N,N-dimethylformamide (1 mL). 2-Hydroxyethane-1-sulfonamide 1g (12 mg, 0.10 mmol), potassium phosphate (38 mg, 179.06 mmol), cuprous iodide (17 mg, 0.09 mmol) and trans-N,N'-dimethyl-1,2-cyclohexanediamine (6.37 mg, 0.05 mmol) were added in sequence. After nitrogen substitution three times, the reaction was incubated at 100°C for 18 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 10 (23 mg) in a yield of 46%.

[0411] MS m / z(ESI):603.4[M+1]

[0412] 1 H NMR (400MHz, DMSO-d6) δ11.79(s,1H),8.39(dd,J=5.8,3.4Hz,1H),7.98(d,J=8.6Hz,1H),7.20(d,J=1.8Hz,1H),7.15–7.10(m,2H),7.03(dd,J= 8.6,1.8Hz,1H),3.76(t,J=6.6Hz,2H),3.67(s,3H),3.40–3.37(m,4H), 3.32(s,2H),3.00(s,4H),2.27–2.16(m,4H),1.73(s,4H),0.30(s,4H).

[0413] Example 11

[0414] N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0415] N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0416] first step

[0417] tert-butyl(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)carbamate

[0418] tert-Butyl (2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)carbamate

[0419] 7-Bromo-2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazole 10e (400 mg, 1.21 mmol) was dissolved in dioxane (8 mL), and cesium carbonate (789 mg, 2.42 mmol), tert-butyl carbamate (170 mg, 1.45 mmol), dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (115.51 mg, 0.24 mmol) and tris(dibenzylideneacetone)dipalladium (111 mg, 0.12 mmol) were added in sequence and the reaction was carried out at 100 °C for 18 hours. The reaction solution was diluted with water (40 mL) and extracted with ethyl acetate (40 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)carbamate 11a (280 mg) in a yield of 63%.

[0420] MS m / z(ESI):367.2[M+1]

[0421] Step 2

[0422] 2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-amine

[0423] 2-(4,4-Difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-amine

[0424] Tert-butyl (2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)carbamate 11a (280.00 mg, 0.833 mmol) was dissolved in dioxane (5 mL). A 4M solution of hydrogen chloride in dioxane (1 mL) was added dropwise and allowed to react at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to afford 2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-amine 11b (200.00 mg) in a 90.26% yield.

[0425] MS m / z(ESI):267.2[M+1]

[0426] Step 3

[0427] 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0428] 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0429] 2-(4,4-Difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-amine 11b (100 mg, 0.38 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature. 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (116.48 mg, 0.38 mmol), N,N-diisopropylethylamine (194.14 mg, 1.50 mmol) and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (293.69 mg, 0.56 mmol) were added sequentially. The atmosphere was replaced with nitrogen three times and the mixture was reacted at room temperature for 6 h. The mixture was poured into water (100 mL) and extracted with ethyl acetate (60 mL×2). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 11c (60 mg) in a yield of 29%.

[0430] MS m / z(ESI):558.2 / 560.2[M+1]

[0431] Step 4

[0432] N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0433] N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0434] 4-Bromo-N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11c (60 mg, 0.11 mmol) was dissolved in N,N-dimethylformamide (1 mL) at room temperature. 2-Hydroxyethane-1-sulfonamide 1 g (13 mg, 0.11 mmol), potassium phosphate (45 mg, 0.22 mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (7.6 mg, 0.05 mmol) and cuprous iodide (20 mg, 0.11 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was incubated at 100°C for 18 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H 2 O, mobile phase B: CH 3 CN) to give N-(2-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-benzo[d]imidazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 11 (12 mg) in a yield of 19%.

[0435] MS m / z(ESI):603.4[M+1]

[0436] 1 H NMR (400MHz, DMSO-d6) δ11.45(s,1H),7.88(d,J=8.6Hz,1H),7.36(d,J=7.6Hz,1H),7.19(d,J=1.8Hz,1H),7.10(d,J=7.8Hz,1H),7.06–7.00 (m,2H),3.77(t,J=6.6Hz,2H),3.59(s,3H),3.37–3.34(m,4H),3.31(s ,2H),3.07–3.00(m,4H),2.23–2.13(m,4H),1.53(s,4H),0.35(s,4H).

[0437] Example 12

[0438] N-(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0439] N-(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl 1-)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0440] first step

[0441] 3-bromo-N-cyclopropyl-2-nitroaniline

[0442] 3-Bromo-N-cyclopropyl-2-nitroaniline

[0443] 1-Bromo-3-fluoro-2-nitrobenzene 12a (5.00 g, 22.7 mmol, commercially available) was added to 1,2-dichloroethane (50 mL) at room temperature. Cyclopropylamine (3.89 g, 68.2 mmol) was added to the reaction mixture, and the atmosphere was replaced with nitrogen three times. The reaction was continued at 80°C for 18 hours. The mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to obtain 3-bromo-N-cyclopropyl-2-nitroaniline 12b (5.50 g) in a 94.13% yield.

[0444] MS m / z(ESI):257.0[M+1]

[0445] Step 2

[0446] 3-bromo-N1-cyclopropylbenzene-1,2-diamine

[0447] 3-Bromo-N1-cyclopropylbenzene-1,2-diamine

[0448] At room temperature, 3-bromo-N-cyclopropyl-2-nitroaniline 12b (5.50 g, 21.4 mmol) was added to a mixture of ethanol (30 mL), tetrahydrofuran (30 mL), and water (15 mL). Iron powder (7.17 g, 128 mmol) and ammonium chloride (11.4 g, 214 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was continued at 60°C for 2 hours. After the mixture was cooled to room temperature, ethyl acetate (30 mL) and celite (10 g) were added to the solution and stirred for 1 hour. The solid was filtered, and the filtrate was concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain 3-bromo-N1-cyclopropylbenzene-1,2-diamine 12c (3 g) in a yield of 61.75%.

[0449] MS m / z(ESI):227.9[M+1]

[0450] Step 3

[0451] 4-bromo-1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0452] 4-Bromo-1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0453] To a solution of 3-bromo-N1-cyclopropylbenzene-1,2-diamine 12c (300 mg, 1.32 mmol), pyridine (418 mg, 5.28 mmol), and 4-dimethylaminopyridine (32.3 mg, 0.264 mmol) in tetrahydrofuran (3 mL) was added trifluoroacetic anhydride (277.45 mg, 1.32 mmol). The mixture was stirred at 70°C for 2 hours to form a yellow solution. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazole 12d (366 mg) in a 54% yield.

[0454] MS m / z(ESI):305.0[M+1]

[0455] Step 4

[0456] tert-butyl(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)carbamate

[0457] tert-Butyl (1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)carbamate

[0458] To a solution of 4-bromo-1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazole 12d (370 mg, 1.21 mmol), tert-butyl carbamate (185 mg, 1.58 mmol) and potassium carbonate (335 mg, 2.43 mmol) in dioxane (15 mL) were added dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (116 mg, 0.243 mmol) and tris(dibenzylideneacetone)dipalladium (111 mg, 0.121 mmol). The reaction mixture was stirred at 100 °C under nitrogen for 16 hours. The mixture was poured into water (40 mL) and extracted with ethyl acetate (50 mL×2). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)carbamate 12e (350 mg) in a yield of 84%.

[0459] MS m / z(ESI):342.2[M+1]

[0460] Step 5

[0461] 1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine

[0462] 1-Cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine

[0463] Tert-butyl (1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)carbamate 12e (200 mg, 0.586 mmol) was stirred in a solution of hydrogen chloride in dioxane (4 M, 4 mL) at 25° C. for 16 hours. The mixture was concentrated to dryness under reduced pressure to afford 1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine 12f (141 mg) in 99% yield.

[0464] MS m / z(ESI):242.1[M+1]

[0465] Step 6

[0466] 4-bromo-N-(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0467] 4-Bromo-N-(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0468] To a solution of 1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine 12f (141 mg, 0.585 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (199 mg, 0.643 mmol) and N,N-diisopropylethylamine (378 mg, 2.92 mmol) in N,N-dimethylformamide (2.5 mL) was added (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (457 mg, 0.877 mmol) and the reaction mixture was stirred at 25 °C for 16 h. The mixture was poured into water (40 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 12 g (183 mg) of 4-bromo-N-(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide, yield: 58%.

[0469] MS m / z(ESI):535.1[M+1]

[0470] Step 7

[0471] N-(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0472] N-(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl 1-)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0473] To a solution of 12 g (50 mg, 0.094 mmol) of 4-bromo-N-(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide, 1 g (14.1 mg, 0.112 mmol) of 2-hydroxyethane-1-sulfonamide and potassium phosphate (59.7 mg, 0.281 mmol) in N,N-dimethylformamide (1 mL) were added trans-N,N'-dimethyl-1,2-cyclohexanediamine (6.67 mg, 0.047 mmol) and cuprous iodide (17.9 mg, 0.093 mmol), and the reaction mixture was stirred at 100 ° C under nitrogen for 16 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(1-cyclopropyl-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl 1)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 12 (26.4 mg) in a yield of 48%.

[0474] MS m / z(ESI):578.2[M+1]

[0475] 1 H NMR (400MHz, DMSO-d6) δ12.48(s,1H),8.55(t,J=4.4Hz,1H),8.04(d,J=8.8Hz,1H),7.47(d,J=4.4Hz,2H),7.26(d,J=2.0Hz,1H),7.08(dd,J= 8.4,2.0Hz,1H),3.76(t,J=6.4Hz,2H),3.70–3.61(m,1H),3.37–3.33( m,2H),2.99(s,4H),1.99–1.45m,4H),1.31–1.13(m,4H),0.29(s,4H).

[0476] Example 13

[0477] N-(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0478] N-(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0479] first step

[0480] N-(2-bromo-6-(cyclopropylamino)phenyl)-3,3,3-trifluoropropanamide

[0481] N-(2-Bromo-6-(cyclopropylamino)phenyl)-3,3,3-trifluoropropionamide

[0482] 3-Bromo-N1-cyclopropylbenzene-1,2-diamine 12c (2.00 g, 8.81 mmol) and 3,3,3-trifluoropropionic acid (1.35 g, 10.6 mmol) were added to N,N-dimethylformamide (20 mL) at room temperature. (7-Azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (6.89 g, 13.2 mmol) and N,N-diisopropylethylamine (3.41 g, 26.4 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 70°C for 18 h. The mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give N-(2-bromo-6-(cyclopropylamino)phenyl)-3,3,3-trifluoropropionamide 13a (1.30 g) in a yield of 43.79%.

[0483] MS m / z(ESI):338.9[M+1]

[0484] Step 2

[0485] 4-bromo-1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole

[0486] 4-Bromo-1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole

[0487] N-(2-Bromo-6-(cyclopropylamino)phenyl)-3,3,3-trifluoropropionamide 13a (1.3 g, 3.86 mmol) was added to acetic acid (5 mL) at room temperature, and the atmosphere was replaced with nitrogen three times. The reaction was continued at 65°C for 18 hours. The mixture was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 4-bromo-1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole 13b (1.0 g) in an 81.27% yield.

[0488] MS m / z(ESI):321.0[M+1]

[0489] Step 3

[0490] tert-butyl(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)carbamate

[0491] tert-Butyl (1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)carbamate

[0492] At room temperature, 4-bromo-1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole 13b (1.00 g, 3.13 mmol) and tert-butyl carbamate (404 mg, 3.45 mmol) were added to 1,4-dioxane (15 mL). Tris(dibenzylideneacetone)dipalladium (287 mg, 0.313 mmol), cesium carbonate (3.06 g, 9.40 mmol) and dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (224 mg, 0.470 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 18 hours. The mixture was concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)carbamate 13c (350 mg) in a yield of 31.43%.

[0493] MS m / z(ESI):356.1[M+1]

[0494] Step 4

[0495] 1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-amine

[0496] 1-Cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-amine

[0497] Tert-butyl (1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)carbamate 13c (350 mg, 0.985 mmol) was added to dichloromethane (5 mL) at room temperature. A 4 M solution of hydrogen chloride in dioxane (2.5 mL) was added to the reaction mixture and allowed to react at 25°C for 18 hours. The mixture was concentrated to dryness under reduced pressure to afford 1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-amine 13d (250 mg) in a 99.45% yield.

[0498] MS m / z(ESI):256.0[M+1]

[0499] Step 5

[0500] 4-bromo-N-(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0501] 4-Bromo-N-(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0502] 1-Cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-amine 13d (250 mg, 0.979 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (334 mg, 1.08 mmol) were added to N,N-dimethylformamide (5 mL) at room temperature. (7-Azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (1.02 g, 1.96 mmol) and N,N-diisopropylethylamine (380 mg, 2.94 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 70°C for 18 h. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 13e (200 mg) in a yield of 37.30%.

[0503] MS m / z(ESI):547.1[M+1]

[0504] Step 6

[0505] N-(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0506] N-(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0507] 4-Bromo-N-(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 13e (100 mg, 0.183 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (25.2 mg, 0.201 mmol) were added to N,N-dimethylformamide (5 mL) at room temperature. Cuprous iodide (34.8 mg, 0.183 mmol), trans-N,N′-dimethyl-1,2-cyclohexanediamine (2.60 mg, 0.0180 mmol) and potassium phosphate (77.6 mg, 0.365 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90°C for 18 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×2). The organic phase was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give N-(1-cyclopropyl-2-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 13 (10.0 mg) in a yield of 9.25%.

[0508] MS m / z(ESI):592.2[M+1]

[0509] 1 H NMR(400MHz,DMSO-d6)δ12.34(s,1H),8.45–8.37(m,1H),8.02(d,J=8.4Hz, 1H),7.36–7.32(m,1H),7.30–7.24(m,2H),7.08–7.04(m,1H),4.22–4.07(m, 2H),3.75(t,J=6.4Hz,2H),3.42–3.35(m,2H),3.34–3.33(m,1H),3.02–2.9 6(m,4H),1.76(brs,4H),1.28–1.23(m,2H),1.15–1.10(m,2H),0.31(s,4H).

[0510] Example 14 was synthesized according to the synthesis method of Example 12 of the present invention. The structure and characterization data of Example 14 are shown in the following table:

[0511] Example 15

[0512] N-(2-cyclopropyl-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0513] N-(2-Cyclopropyl-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0514] first step

[0515] 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0516] 4-(Ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0517] 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 15a (1.0 g, 2.80 mmol, prepared according to the patent publication "WO2021211549A1") and ethanesulfonamide 15b (458.36 mg, 4.20 mmol, commercially available) were dissolved in N,N-dimethylformamide (10 mL), and 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 atmosphere was replaced with argon, the temperature was raised to 110 °C, and the mixture was stirred for 6 hours. The reaction mixture was cooled to room temperature and poured into 200 mL of ice water. The pH was adjusted to 6 with 2 M dilute hydrochloric acid and extracted with dichloromethane (200 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 15c (0.75 g). Yield: 79.16%.

[0518] MS m / z(ESI):339.4[M+1]

[0519] Step 2

[0520] N-(2-amino-3-nitrophenyl)cyclopropanecarboxamide

[0521] N-(2-Amino-3-nitrophenyl)cyclopropanecarboxamide

[0522] 3-Nitrophenyl-1,2-diamine 15d (2.00 g, 13.1 mmol, commercially available) and triethylamine (1.35 g, 13.32 mmol) were added to acetonitrile (20 mL), followed by cyclopropylcarbonyl chloride (1.37 g, 13.1 mmol), and the reaction mixture was stirred at 25°C for 2 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (80 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford N-(2-amino-3-nitrophenyl)cyclopropanecarboxamide 15e (2.80 g). Yield: 96%.

[0523] MS m / z(ESI):222.0[M+1]

[0524] Step 3

[0525] 2-cyclopropyl-4-nitro-1H-benzo[d]imidazole

[0526] 2-Cyclopropyl-4-nitro-1H-benzo[d]imidazole

[0527] N-(2-Amino-3-nitrophenyl)cyclopropanecarboxamide 15e (500 mg, 2.26 mmol) was dissolved in acetic acid (5 mL) and stirred at 100°C for 1 hour. The mixture was concentrated under reduced pressure to afford 2-cyclopropyl-4-nitro-1H-benzo[d]imidazole 15f (450 mg, 97% yield).

[0528] MS m / z(ESI):204.0[M+1]

[0529] Step 4

[0530] 2-cyclopropyl-1H-benzo[d]imidazol-4-amine

[0531] 2-Cyclopropyl-1H-benzo[d]imidazol-4-amine

[0532] 2-Cyclopropyl-4-nitro-1H-benzo[d]imidazole 15f (450 mg, 2.21 mmol) was added to methanol (20 mL), followed by the addition of 10% palladium on carbon (117 mg, 0.111 mmol). The mixture was replaced with hydrogen three times and stirred at 25°C under a hydrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filter cake was washed with ethyl acetate (30 mL x 2). The filtrate was concentrated to dryness under reduced pressure to afford 2-cyclopropyl-1H-benzo[d]imidazole-4-amine 15g (350 mg). Yield: 91%.

[0533] MS m / z(ESI):171.4[M+1]

[0534] Step 5

[0535] N-(2-cyclopropyl-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0536] N-(2-Cyclopropyl-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0537] 2-Cyclopropyl-1H-benzo[d]imidazol-4-amine 15g (40 mg, 0.231 mmol), 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 15c (85.97 mg, 254.02 μmol) and N,N-diisopropylethylamine (90 mg, 0.693 mmol) were added to N,N-dimethylformamide (1 mL), and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (181 mg, 30.46 mmol) was added. The resulting mixture was stirred at 50 °C for 6 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by preparative HPLC (AKZONOBEL Kromasil column; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% ammonium bicarbonate + H₂O, mobile phase B: CH₃CN) to afford N-(2-cyclopropyl-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 15 (38.3 mg). Yield: 33%.

[0538] MS m / z(ESI):494.2[M+1]

[0539] 1H NMR (400MHz, DMSO-d6) δ12.34(s,1H),11.92(s,1H),10.16(s,1H),8.30(d,J=7.6Hz,1H),7.99(d,J=8.8Hz,1H),7.24(s,1H),7.13-7.00(m, 3H),3.21(dd,J=14.4,7.1Hz,2H),3.00(s,4H),2.18–2.10(s,1H),1.88–1.58(s,4H),1.21(t,J=7.2Hz,3H),1.15–1.03(m,4H),0.32(s,4H).

[0540] Examples 16-21 were synthesized according to the synthesis method of Example 15 of the present invention. The structures and characterization data of Examples 16-21 are shown in the following table:

[0541] Example 22

[0542] 4-(ethylsulfonamido)-N-(7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0543] 4-(Ethylsulfonamido)-N-(7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0544] first step

[0545] 7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0546] 7-Methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0547] 3-Methoxybenzene-1,2-diamine 22a (850 mg, 6.15 mmol, commercially available) was dissolved in trifluoroacetic acid (7.01 g, 61.5 mmol) at 0°C, replaced with nitrogen three times, and heated to 70°C with stirring under nitrogen for 5 hours. The cooled reaction solution was poured into 100 mL of water and extracted with ethyl acetate (50 mL x 2). The mixture was washed with saturated sodium chloride solution (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazole 22b (1.15 g). Yield: 86%.

[0548] MS m / z(ESI):271.1[M+1]

[0549] Step 2

[0550] 7-methoxy-4-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0551] 7-Methoxy-4-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole

[0552] 7-Methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazole 22b (600 mg, 2.78 mmol) was added to trifluoroacetic acid (3 mL), and nitric acid (1.50 g, 1 mL) was slowly added. The mixture was heated to 70°C and stirred for 1 hour. The reaction mixture was diluted with cold water (200 mL), and the aqueous layer was extracted with ethyl acetate (150 mL × 3). The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC (AKZONOBEL Kromasil column; 250 × 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H2O, mobile phase B: CH3CN) to give 7-methoxy-4-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole 22c (380 mg). Yield: 52.42%.

[0553] MS m / z(ESI):262.1[M+1]

[0554] Step 3

[0555] 7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine

[0556] 7-Methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine

[0557] 7-Methoxy-4-nitro-2-(trifluoromethyl)-1H-benzo[d]imidazole 22c (150 mg, 0.574 mmol) was added to methanol (10 mL), and 10% palladium on carbon (611 mg, 0.574 mmol) was added. The mixture was replaced with hydrogen three times and stirred under a hydrogen atmosphere at 25°C for 16 hours. The mixture was filtered, the filter cake was washed with methanol (30 mL x 3), and the filtrate was concentrated to dryness under reduced pressure to provide 7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazole-4-amine 22d (120 mg). Yield: 90%.

[0558] MS m / z(ESI):232.1[M+1]

[0559] Step 4

[0560] 4-bromo-N-(7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0561] 4-Bromo-N-(7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0562] 7-Methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-amine 22d (60 mg, 0.260 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (80.5 mg, 0.260 mmol) were added to a solution of N,N-dimethylformamide (3 mL), (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (176 mg, 0.337 mmol) and N,N-diisopropylethylamine (101 mg, 0.779 mmol) were added, and the reaction mixture was stirred at 25 °C for 16 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22e (2.00 g). Yield: 86%.

[0563] MS m / z(ESI):525.2[M+1]

[0564] Step 5

[0565] 4-(ethylsulfonamido)-N-(7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0566] 4-(Ethylsulfonamido)-N-(7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0567] 4-Bromo-N-(7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22e (50 mg, 95.54 μmol), ethanesulfonamide 15b (12.51 mg, 114.65 μmol), and potassium phosphate (60.84 mg, 286.62 μmol) were added to N,N-dimethylformamide (1.5 mL). Trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (6.79 mg, 47.77 μmol) and cuprous iodide (18.20 mg, 95.54 μmol) were also added. The mixture was stirred at 100°C under nitrogen for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H₂O, mobile phase B: CH₃CN) to afford 4-(ethylsulfonamido)-N-(7-methoxy-2-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22 (0.66 mg). Yield: 1.3%.

[0568] MS m / z(ESI):552.3[M+1]

[0569] 1H NMR (400MHz, DMSO-d6) δ14.77–13.77(m,1H),12.31(s,1H),10.19(s,1H),8.35(s,1H),8.03(d,J=8.8Hz,1H),7.28(d,J=2.0Hz,1H),7.09(dd ,J=8.8,2.0Hz,1H),6.87(d,J=7.6Hz,1H),3.96(s,3H),3.22(q,J=7.2Hz,2H),2.98(s,4H),1.73(s,4H),1.21(t,J=7.2Hz,3H),0.27(s,4H).

[0570] Examples 23-32 were synthesized according to the synthesis method of Example 22 of the present invention. The structures and characterization data of Examples 23-32 are shown in the following table:

[0571] Example 33

[0572] N-(2,7-dimethoxy-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0573] N-(2,7-Dimethoxy-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0574] first step

[0575] 2,7-dimethoxy-4-nitro-1H-benzo[d]imidazole

[0576] 2,7-Dimethoxy-4-nitro-1H-benzo[d]imidazole

[0577] Tetramethyl orthocarbonate (223 mg, 1.64 mmol) was added to a mixture of 3-methoxy-6-nitrobenzene-1,2-diamine 33a (150 mg, 0.82 mmol) and acetic acid (1 mL) at room temperature. The reaction mixture was allowed to react at 25°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (5 mL x 3). The combined extracts were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 2,7-dimethoxy-4-nitro-1H-benzo[d]imidazole 33b (150 mg). Yield: 82%.

[0578] MS m / z(ESI):224.0[M+1]

[0579] Step 2

[0580] 2,7-dimethoxy-1H-benzo[d]imidazol-4-amine

[0581] 2,7-Dimethoxy-1H-benzo[d]imidazol-4-amine

[0582] 10% palladium on carbon (40.0 mg) was added to a solution of 2,7-dimethoxy-4-nitro-1H-benzo[d]imidazole 33b (150 mg, 0.67 mmol) in methanol (10 mL) at room temperature. The mixture was replaced with hydrogen three times and then reacted at room temperature for 2 hours. The reaction mixture was filtered, the filter cake was rinsed with methanol (30 mL), and the filtrate was concentrated under reduced pressure to afford 2,7-dimethoxy-1H-benzo[d]imidazole-4-amine 33c (120 mg). Yield: 92%.

[0583] MS m / z(ESI):194.0[M+1]

[0584] Step 3

[0585] N-(2,7-dimethoxy-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0586] N-(2,7-Dimethoxy-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0587] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (66.4 mg, 0.17 mmol) and N,N-diisopropylethylamine (26 mg, 0.2 mmol) were added to a solution of 2,7-dimethoxy-1H-benzo[d]imidazol-4-amine 33c (28.5 mg, 0.15 mmol) and 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 15c (50 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction was incubated at 25°C for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate (1 mL x 3). The combined extracts were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (AKZONOBEL Kromasil column; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% ammonium bicarbonate + H₂O, mobile phase B: CH₃CN) to obtain N-(2,7-dimethoxy-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 33 (16.4 mg). Yield: 24%.

[0588] MS m / z(ESI):514.2[M+1]

[0589] 1 H NMR (400MHz, DMSO-d6) δ12.22(s,1H),11.66(s,1H),10.26(s,1H),8.24(d,J=8.8Hz,1H),8.00(d,J=8.4Hz,1H),7.24(s,1H),7.06(d,J=8.4,1.9 Hz,1H),6.66(d,J=8.8Hz,1H),4.11(s,3H),3.87(s,3H),3.26–3.14(m, 2H),3.10–2.84(m,4H),1.76(s,4H),1.21(t,J=7.2Hz,3H),0.31(s,4H).

[0590] Example 34

[0591] N-(2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0592] N-(2-(2,2-Difluorocyclopropyl)benzo[d]oxazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0593] first step

[0594] 7-bromo-2-(2,2-difluorocyclopropyl)benzo[d]oxazole

[0595] 7-Bromo-2-(2,2-difluorocyclopropyl)benzo[d]oxazole

[0596] 2-Amino-6-bromophenol 34a (1.00 g, 5.32 mmol) and 2,2-difluorocyclopropane-1-carboxylic acid (844 mg, 6.91 mmol) were added to carbon tetrachloride (20 mL). Triethylamine (1.61 g, 16.0 mmol) and triphenylphosphine (4.86 g, 16.0 mmol) were added, and the resulting mixture was stirred at 80°C under nitrogen for 16 hours. The mixture was poured into water (80 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 7-bromo-2-(2,2-difluorocyclopropyl)benzo[d]oxazole 34b (795 mg). Yield: 54%.

[0597] MS m / z(ESI):276.0[M+1]

[0598] Step 2

[0599] tert-butyl(2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)carbamate

[0600] tert-Butyl (2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)carboxylate

[0601] 7-Bromo-2-(2,2-difluorocyclopropyl)benzo[d]oxazole 34b (495 mg, 1.81 mmol), cesium carbonate (1.47 g, 4.52 mmol), and tert-butyl carbamate (254 mg, 2.17 mmol) were added to dioxane (3 mL). Tris(dibenzylideneacetone)dipalladium (165 mg, 0.181 mmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (172 mg, 0.361 mmol) were also added. The reaction mixture was stirred at 100°C under nitrogen for 16 hours. The mixture was concentrated to dryness under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)carboxylate 34c (400 mg). Yield: 71%.

[0602] MS m / z(ESI):311.1[M+1]

[0603] Step 3

[0604] 2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-amine

[0605] 2-(2,2-Difluorocyclopropyl)benzo[d]oxazol-7-amine

[0606] Tert-butyl (2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)carboxylate 34c (180 mg, 0.580 mmol) was added to dichloromethane (5 mL) and trifluoroacetic acid (1 mL). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to afford 2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-amine 34d (120 mg). Yield: 98%.

[0607] MS m / z(ESI):211.2[M+1]

[0608] Step 4

[0609] 4-bromo-N-(2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0610] 4-Bromo-N-(2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0611] 2-(2,2-Difluorocyclopropyl)benzo[d]oxazol-7-amine 34d (120 mg, 0.571 mmol), N,N-diisopropylethylamine (369 mg, 2.85 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 5e (177 mg, 0.571 mmol) were added to N,N-dimethylformamide (3 mL), and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (447 mg, 0.856 mmol) was added. The reaction mixture was stirred at 25 °C for 16 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (80 mL), filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 34e (188 mg). Yield: 65%.

[0612] Step 5

[0613] N-(2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0614] N-(2-(2,2-Difluorocyclopropyl)benzo[d]oxazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0615] 4-Bromo-N-(2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 34e (90 mg, 0.179 mmol), potassium phosphate (114 mg, 0.537 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (27.0 mg, 0.089 mmol) were added to N,N-dimethylformamide (1.5 mL), and trans-(1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (13 mg, 0.090 mmol) and cuprous iodide (40 mg, 0.179 mmol) were added. The reaction mixture was stirred at 100 °C under nitrogen for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC (AKZONOBEL Kromasil column; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% ammonium bicarbonate + H₂O, mobile phase B: CH₃CN) to afford N-(2-(2,2-difluorocyclopropyl)benzo[d]oxazol-7-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 34 (16.8 mg). Yield: 17%.

[0616] MS m / z(ESI):547.2[M+1]

[0617] 1 H NMR (400MHz, DMSO-d6) δ12.66(s,1H),10.20(s,1H),8.42(d,J=8.0Hz,1H),8.06(d,J= 8.8Hz,1H),7.47(d,J=8.0Hz,1H),7.38(t,J=8.0Hz,1H),7.33(d,J=2.0Hz,1H),7.14( dd,J=8.8,2.0Hz,1H),4.95(s,1H),3.77(t,J=6.5Hz,2H),3.43(m,1H),3.36(t,J=6.4 Hz,2H),3.03(d,J=4.8Hz,4H),2.43-2.34(m,2H),1.67(s,4H),0.39(d,J=3.6Hz,4H).

[0618] Examples 35-48 were synthesized according to the synthesis method of Example 34 of the present invention. The structures and characterization data of Examples 35-48 are shown in the following table:

[0619] Example 49

[0620] N-(2-cyclopropyl-7-(oxazol-2-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0621] N-(2-cyclopropyl-7-(oxazol-2-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0622] first step

[0623] 3-bromo-6-nitrobenzene-1,2-diamine

[0624] 3-Bromo-6-nitrobenzene-1,2-diamine

[0625] 2-Bromo-5-nitroaniline 49a (2.00 g, 9.22 mmol) and sodium tert-amyl alcohol (3.04 g, 27.65 mmol) were added to dimethyl sulfoxide (100 mL), followed by 1,1,1-trimethylhydrazine iodide (1.86 g, 9.22 mmol). The atmosphere was replaced with nitrogen three times and stirred at 25°C under nitrogen for 16 hours. The reaction mixture was poured into ice water (500 mL), adjusted to pH 3 with 10% hydrochloric acid, and extracted with dichloromethane (500 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 3-bromo-6-nitrobenzene-1,2-diamine 49b (900 mg). Yield: 42%.

[0626] MS m / z(ESI):233.8[M+1]

[0627] Step 2

[0628] N-(2-amino-6-bromo-3-nitrophenyl)cyclopropanecarboxamide

[0629] N-(2-Amino-6-bromo-3-nitrobenzene)cyclopropanecarboxamide

[0630] 3-Bromo-6-nitrobenzene-1,2-diamine 49b (700 mg, 3.02 mmol) and cyclopropylcarbonyl chloride (473 mg, 4.53 mmol) were added to acetonitrile (8 mL) at 0°C. Triethylamine (305.27 mg, 3.02 mmol) was added, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to provide N-(2-amino-6-bromo-3-nitrobenzene)cyclopropanecarboxamide 49c (900 mg). Yield: 99%.

[0631] MS m / z(ESI):302.0[M+1]

[0632] Step 3

[0633] 7-bromo-2-cyclopropyl-4-nitro-1H-benzo[d]imidazole

[0634] 7-Bromo-2-cyclopropyl-4-nitro-1H-benzo[d]imidazole

[0635] N-(2-Amino-6-bromo-3-nitrobenzene)cyclopropanecarboxamide 49c (900 mg, 3.00 mmol) was dissolved in acetic acid (13 mL) and stirred at 100°C for 6 hours. The reaction mixture was concentrated to dryness under reduced pressure. The crude product was added to ethyl acetate (100 mL), washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 7-bromo-2-cyclopropyl-4-nitro-1H-benzo[d]imidazole 49d (465 mg). Yield: 54%.

[0636] MS m / z(ESI):284.0[M+1]

[0637] Step 4

[0638] 2-(2-cyclopropyl-4-nitro-1H-benzo[d]imidazol-7-yl)oxazole

[0639] 2-(2-cyclopropyl-4-nitro-1H-benzo[d]imidazol-7-yl)oxazole

[0640] 7-Bromo-2-cyclopropyl-4-nitro-1H-benzo[d]imidazole 49d (200 mg, 0.709 mmol), tetrakis(triphenylphosphine)palladium (82 mg, 0.071 mmol), and cuprous iodide (14 mg, 0.071 mmol) were added to N,N-dimethylformamide (2 mL), and 2-(tri-n-butyltinyl)oxazole (381 mg, 1.06 mmol) was added. The resulting mixture was stirred at 100°C for 4 hours. The mixture was dissolved in water (30 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 2-(2-cyclopropyl-4-nitro-1H-benzo[d]imidazol-7-yl)oxazole 49e (136 mg). Yield: 70%. MS m / z (ESI): 271.1 [M+1]

[0641] Step 5

[0642] 2-cyclopropyl-7-(oxazol-2-yl)-1H-benzo[d]imidazol-4-amine

[0643] 2-Cyclopropyl-7-(oxazol-2-yl)-1H-benzo[d]imidazol-4-amine

[0644] 2-(2-Cyclopropyl-4-nitro-1H-benzo[d]imidazol-7-yl)oxazole 49e (136 mg, 0.503 mmol) was dissolved in acetic acid (3 mL) and iron powder (281 mg, 5.03 mmol) was added. The resulting mixture was stirred at 100°C for 2 hours. The mixture was filtered and the solid was washed with ethyl acetate (20 mL x 3). The filtrate was concentrated to dryness under reduced pressure. The resulting residue was added to saturated sodium bicarbonate solution (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to afford 2-cyclopropyl-7-(oxazol-2-yl)-1H-benzo[d]imidazol-4-amine 49f (60 mg). Yield: 49%.

[0645] MS m / z(ESI):241.2[M+1]

[0646] Step 6

[0647] N-(2-cyclopropyl-7-(oxazol-2-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0648] N-(2-cyclopropyl-7-(oxazol-2-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0649] 2-Cyclopropyl-7-(oxazol-2-yl)-1H-benzo[d]imidazol-4-amine 49f (60 mg, 0.150 mmol), N,N-diisopropylethylamine (48 mg, 0.375 mmol) and 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 15c (46 mg, 0.135 mmol) were added to N,N-dimethylformamide (1 mL), and O-(7-azabenzene) was added. The mixture was stirred at 60 ° C for 16 hours. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by preparative high performance liquid chromatography (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H₂O, mobile phase B: CH₃CN) to afford N-(2-cyclopropyl-7-(oxazol-2-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 49 (16.3 mg). Yield: 19%.

[0650] MS m / z(ESI):561.4[M+1]

[0651] 1H NMR (400MHz, DMSO-d6) δ12.57(s,1H),11.95(s,1H),10.28(s,1H),8.51(d,J=8.8Hz, 1H),8.27(s,1H),8.00(d,J=8.4Hz,1H),7.72(d,J=8.8Hz,1H),7.50(s,1H),7.25(d,J=2.0Hz,1H),7.07(dd,J=8.4,2.0Hz, 1H),3.23(q,J=7.2Hz,2H),3.02(s,4H),2.60–2.53(m,1H),1.68(s,4H),1.24–1.18(m,5H),1.14–1.06(m,2H),0.34(s,4H).

[0652] Example 50

[0653] N-(2-cyclopropyl-7-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0654] N-(2-Cyclopropyl-7-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0655] first step

[0656] N-(2-amino-3-fluorophenyl)cyclopropanecarboxamide

[0657] N-(2-amino-3-fluorophenyl)cyclopropanecarboxamido

[0658] 3-Fluorophenyl-1,2-diamine 50a (500 mg, 3.96 mmol), cyclopropanecarboxylic acid (341 mg, 3.96 mmol), and N,N-diisopropylethylamine (1.54 g, 11.89 mmol) were added to N,N-dimethylformamide, followed by O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.96 g, 5.15 mmol). The mixture was stirred at 25°C for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure to afford N-(2-amino-3-fluorophenyl)cyclopropanecarboxamido 50b (769 mg). Yield: 99%.

[0659] MS m / z(ESI):195.0[M+1]

[0660] Step 2

[0661] 2-cyclopropyl-7-fluoro-1H-benzo[d]imidazole

[0662] 2-Cyclopropyl-7-fluoro-1H-benzo[d]imidazole

[0663] N-(2-Amino-3-fluorophenyl)cyclopropanecarboxamido 50b (769 mg, 3.96 mmol) was dissolved in acetic acid (20 mL) and stirred at 100°C for 2 hours. The reaction solution was concentrated to dryness and poured into saturated sodium bicarbonate solution (70 mL). The mixture was extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 2-cyclopropyl-7-fluoro-1H-benzo[d]imidazole 50c (583 mg). Yield: 83%.

[0664] MS m / z(ESI):177.0[M+1]

[0665] Step 3

[0666] 2-cyclopropyl-7-fluoro-4-nitro-1H-benzo[d]imidazole

[0667] 2-Cyclopropyl-7-fluoro-4-nitro-1H-benzo[d]imidazole

[0668] 2-Cyclopropyl-7-fluoro-1H-benzo[d]imidazole 50c (200 mg, 1.14 mmol) was added to concentrated sulfuric acid (2 mL) at 0°C. Nitric acid (358 mg, 3.41 mmol, 60-63% purity) was added dropwise, and the resulting mixture was stirred at 0°C for 0.5 hours. The pH of the reaction mixture was adjusted to 7 with saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 2-cyclopropyl-7-fluoro-4-nitro-1H-benzo[d]imidazole 50d (70 mg). Yield: 27%.

[0669] MS m / z(ESI):222.0[M+1]

[0670] Step 4

[0671] 2-cyclopropyl-7-(1H-imidazol-1-yl)-4-nitro-1H-benzo[d]imidazole

[0672] 2-Cyclopropyl-7-(1H-imidazol-1-yl)-4-nitro-1H-benzo[d]imidazole

[0673] 2-Cyclopropyl-7-fluoro-4-nitro-1H-benzo[d]imidazole 50d (68 mg, 0.307 mmol) and imidazole (105 mg, 1.54 mmol) were added to N,N-dimethylformamide (2 mL), followed by cesium carbonate (130 mg, 0.400 mmol). The resulting mixture was stirred at 80°C for 18 hours. The reaction mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: System A) to afford 2-cyclopropyl-7-(1H-imidazol-1-yl)-4-nitro-1H-benzo[d]imidazole 50e (40 mg). Yield: 48%.

[0674] MS m / z(ESI):270.0[M+1]

[0675] Step 5

[0676] 2-cyclopropyl-7-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-4-amine

[0677] 2-Cyclopropyl-7-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-4-amine

[0678] 2-Cyclopropyl-7-(1H-imidazol-1-yl)-4-nitro-1H-benzo[d]imidazole 50e (40 mg, 148.56 μmol) was added to methanol (10 mL), and 10% palladium on carbon (16 mg, 0.015 mmol) and hydrochloric acid (4 M, 0.5 mL) were added. The mixture was replaced with hydrogen three times and stirred under a hydrogen atmosphere at 25° C. for 16 hours. The reaction mixture was concentrated to dryness under reduced pressure to afford 2-cyclopropyl-7-(1H-imidazol-1-yl)-1H-benzo[d]imidazole-4-amine 50f (40 mg). Yield: 97%.

[0679] MS m / z(ESI):240.1[M+1]

[0680] Step 6

[0681] N-(2-cyclopropyl-7-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0682] N-(2-Cyclopropyl-7-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0683] 2-Cyclopropyl-7-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-4-amine 50f (40 mg, 0.167 mmol), 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 15c (57 mg, 0.167.17 mmol) and N,N-diisopropylethylamine (108.0 mg, 0.836 mmol) were added to N,N-dimethylformamide (1 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (95 mg, 0.251 mmol) was added, and the mixture was stirred at 50 °C for 16 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The crude product was purified by preparative HPLC (AKZONOBEL Kromasil column; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% formic acid + H₂O, mobile phase B: CH₃CN) to afford N-(2-cyclopropyl-7-(1H-imidazol-1-yl)-1H-benzo[d]imidazol-4-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 50 (21.86 mg). Yield: 23%.

[0684] MS m / z(ESI):560.2[M+1]

[0685] 1H NMR(400MHz,DMSO-d6)δ11.87(s,1H),10.65(s,1H),9.77(s,1H),8.41–8.28 (s,1H),8.24(s,1H),8.02–7.93(m,2H),7.70(d,J=8.4Hz,1H),7.56(s,1H), 7.31(d,J=8.8Hz,1H),3.44(s,4H),3.31(q,J=7.2Hz,2H),2.53(s,1H),1.70 (s,4H),1.51(s,2H),1.42–1.35(m,2H),1.25(t,J=7.2Hz,3H),0.42(s,4H).

[0686] Biological evaluation

[0687] Test Example 1: Determination of the Inhibitory Effect of the Compounds of the Invention on OVCAR-3 Cell Proliferation

[0688] The following method was used to determine the effect of the compounds of the present invention on the proliferation of OVCAR-3 cells. OVCAR-3 cells (containing the TP53 R248Q mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).

[0689] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and cultured for 72 hours. After the culture was completed, 50uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes and then allowed to stand for 10 minutes. The luminescence value of each sample well was then read on the microplate reader using the Luminescence mode. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO). The nonlinear regression analysis of the compound concentration logarithm-inhibition rate was then performed in GraphPad Prism 5 software to obtain the IC value of the compound for inhibiting cell proliferation. 50 Values ​​are shown in Table 1.

[0690] Table 1 IC of the compounds of the present invention on the inhibition of OVCAR-3 cell proliferation 50 data

[0691] Conclusion: The compounds of the present invention have an IC inhibitory effect on the proliferation of OVCAR-3 cells. 50 <50nM, showing good inhibitory effect.

[0692] Note: The structure of AMG 650 (prepared according to Example 4 of patent publication WO2020132648A1) is as follows:

[0693] Test Example 2: Determination of the Inhibitory Effect of the Compounds of the Invention on HT-29 Cell Proliferation

[0694] The following method was used to determine the effect of the compounds of the present invention on HT-29 cell proliferation. HT-29 cells (containing the TP53R273H mutation) were purchased from the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and cultured in McCoy's 5A medium containing 10% fetal bovine serum, 100 U penicillin, and 100 μg / mL streptomycin. Cell viability was measured by The assay was performed using the Luminescent Cell Viability Assay Kit (Promega, Cat. No. G7573).

[0695] The experimental method was performed according to the steps in the kit instructions, which are briefly described as follows: the test compound was first dissolved in DMSO to prepare a 10mM stock solution, and then diluted with culture medium to prepare the test sample. The final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded into 96-well cell culture plates at a density of 1000 cells per well, cultured overnight in a 37°C, 5% CO2 incubator, and then the test compound was added and cultured for 120 hours. After the culture was completed, 50uL of CellTiter-Glo detection solution was added to each well, shaken for 5 minutes, and then allowed to stand for 10 minutes. The luminescence value of each sample well was then read using the Luminescence mode on the microplate reader. The percentage inhibition rate of the compound at each concentration point was calculated by comparing it with the value of the control group (0.3% DMSO). The nonlinear regression analysis of the compound concentration logarithm-inhibition rate was then performed in GraphPad Prism 5 software to obtain the IC value of the compound for inhibiting cell proliferation. 50 Values ​​are shown in Table 2.

[0696] Table 2 IC of the compounds of the present invention on the inhibition of HT-29 cell proliferation 50 data

[0697] Conclusion: The compounds of the present invention have an inhibitory effect on the proliferation of HT-29 cells. 50 <50nM, showing good inhibitory effect.

[0698] Test Example 3: Test of the Inhibition of KIF18A Enzyme Activity by the Compounds of the Invention

[0699] The following method is used to determine the degree of inhibition of the compound of the present invention on the activity of recombinant human KIF18A enzyme under in vitro conditions. This method uses Promega's ADP-Glo TM Kinase Assay Kit (Cat. No. V9102). Detailed experimental procedures can be found in the kit instructions.

[0700] The experimental process is briefly described as follows: the test compound is first dissolved in DMSO to prepare a stock solution, and then serially diluted using reaction buffer A (15mM Tris, pH 7.5, 10mM MgCl2, 0.01% Pluronic F-68). The final concentration of the test compound in the reaction system ranges from 10000nM to 0.15nM; KIF18A protein and ATP working solution are prepared using reaction buffer B (15mM Tris, pH 7.5, 10mM MgCl2, 0.01% Pluronic F-68, 37.5ug / ml tubulin, 1.25uM paclitaxel). The reaction is performed in a 384-well microplate. First, the compound and recombinant human KIF18A protein (final concentration 100nM, expressed by GenScript) are added to the wells and incubated at room temperature for 20 minutes. Then, ATP solution (from ADP-Glo) is added to the reaction solution. TM Kinase Assay kit component V915A, final concentration 60uM) and incubate at room temperature for 20 minutes. Subsequently, 5μL ADP-Glo ​​Reagent was added to the reaction system and incubated at room temperature for 50 minutes. Thereafter, 10μL Kinase Detection Reagent was added to the reaction system and incubated at room temperature for 30 minutes. After the incubation, the chemiluminescence intensity value of each well was measured in the luminescence mode on the microplate reader. The percentage inhibition rate of the compound at each concentration was calculated by comparing it with the luminescence intensity ratio of the control group (0.1% DMSO), and the nonlinear regression analysis of the compound concentration-inhibition rate was performed using GraphPad Prism 5 software to obtain the IC value of the compound. 50 Values ​​are shown in Table 3.

[0701] Table 3 IC values ​​of the compounds of the present invention for inhibiting KIF18A enzyme activity 50 data

[0702] Conclusion: The compounds of the present invention have an inhibitory effect on KIF18A enzyme activity. 50 <200nM, with significant inhibitory effect.

[0703] Test Example 4: Pharmacokinetics of the Compounds of the Invention in Mice

[0704] 1. Experimental Purpose

[0705] ICR mice were used as test animals. After oral administration of the control compound AMG650 and the present compound 22, the drug concentrations in plasma at different times were determined by LC / MS / MS to study the pharmacokinetic characteristics of the present compound in mice.

[0706] 2. Experimental plan

[0707] 2.1 Experimental drugs and animals;

[0708] control compounds AMG650 and compound 22;

[0709] ICR mice, male, 27.2-30.5 g, were purchased from Weitonglihua Laboratory Animal Technology Co., Ltd.

[0710] 2.2 Drug preparation

[0711] An appropriate amount of drug compound was weighed, and appropriate amounts of DMA, CrEL, and 5% GS were added in sequence, and the mixture was mixed by ultrasonic vortexing to prepare a 1 mg / mL dosing formulation, wherein DMA, CrEL, and 5% GS were in a ratio of 10:10:80 (v:v:v).

[0712] 2.3 Administration

[0713] ICR mice were fasted overnight and then given the compound by gavage (PO, compound dosage: 10 mg / kg, administration volume: 10 mL / kg) for each test compound injection group (9 mice per group). The mice were fed 4 hours after administration.

[0714] 3. Operation

[0715] Approximately 0.1 mL of blood was collected intraorbitally before dosing and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours after dosing. Whole blood samples were placed in tubes containing EDTA-K2 for anticoagulant treatment. After collection, the blood samples were placed on ice and centrifuged at 1500 g for 10 minutes to separate the plasma. The collected plasma was stored at –40 to –20°C until analysis.

[0716] The levels of the test compounds in mouse plasma after oral administration were determined by LC-MS / MS.

[0717] 4. Pharmacokinetic parameter results

[0718] The pharmacokinetic parameters of the compounds of the present invention are shown in Table 4 below.

[0719] Table 4 Pharmacokinetic parameters of the compounds of the present invention in mice

[0720] Conclusion: The plasma concentration and area under the curve of compound 22 of the present invention are both high, and it has good pharmacokinetic properties.

Claims

1. A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts: in: Ring A is selected from a 5- to 7-membered heterocyclyl, a C4-C7 cycloalkyl, a 5- to 7-membered aryl, or a 5- to 7-membered heteroaryl; X1, X2, X3, X4, X5 and X6 are each independently selected from CR a or N atoms; R a is selected from hydrogen, halogen, hydroxy, cyano, alkyl, alkoxy or heteroaryl; wherein the alkyl, alkoxy or heteroaryl is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; 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, hydroxy, cyano or alkoxy, and wherein the one or more methylene groups of the alkylene are optionally replaced by one or more O, S(O) r , C(O) or NR b replaced by; L2 is selected from R b is selected from a hydrogen atom or an alkyl group; R 1 is selected from hydrogen, cyano, halogen, alkyl, hydroxy, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent; R 2 are the same or different and are each independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; wherein the alkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; R 3 are each independently selected from a hydrogen atom or an alkyl group, wherein the alkyl group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy; R 3 Preferably a hydrogen atom; R 4 is selected from hydrogen atom, deuterated alkyl, haloalkyl, alkyl, alkoxy, cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein said cycloalkylalkyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more deuterium atoms, hydroxyl, halogen, nitrile alkyl, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent; The condition is that when X1, X2, X3, X4, X5 and X6 are simultaneously selected from CR a When R 4 not selected from hydrogen atoms; R 5 Selected from hydrogen, cyano, halogen, alkyl, hydroxy, cycloalkyl, heterocyclic, aryl, heteroaryl, -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 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent; Or, two R 5 It forms a -C(O)- with the same carbon atom to which it is attached; R 6 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent; R 7 and R 8 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent; Or, R 7 and R 8 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 9 、-C(O)OR 9 、-OC(O)R 9 、-NR 10 R 11 、-C(O)NR 10 R 11 、-SO2NR 10 R 11 or -NR 10 C(O)R 11 substituted by a substituent; R 9 、R 10 and R 11 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted with one or more substituents selected from a hydroxyl group, a halogen group, a nitro group, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group; m is 0, 1 or 2; m is preferably 0; n is 0, 1, 2, 3 or 4; and r is independently 0, 1 or 2.

2. The compound according to claim 1, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt according to general formula (II) or (III): Ring A, R 1 、R 3 、R 4 、R 5 , L1 and n are as defined in claim 1.

3. The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt described by general formula (IV): in, R a Selected from C 1-6 Alkoxy or 5- to 6-membered heteroaryl; R 4 is selected from alkyl, alkoxy, haloalkyl, deuterated alkyl or cycloalkyl, wherein the cycloalkyl is optionally further substituted with one or more deuterium atoms or halogen; Ring A, R 1 、R 3 、R 5 , L1 and n are as defined in claim 1.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

5. The compound according to any one of claims 1 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein: L1 is selected from a bond or a C1-C6 alkylene group, wherein the alkylene group is optionally further replaced by one or more hydroxyl groups. substituted, and wherein the one or more methylene groups of the alkylene group are optionally replaced by one or more O, S(O) r , C(O) or NR b replaced by; r is 2; R b is selected from a hydrogen atom or a methyl group.

6. The compound according to claim 5, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -NHSO2CH2CH2-, -SO2NHCH2CH2-, -SO2-, -CH2SO2-, -NHSO2-, -SO2NH-, -NHC(CH3)2CH2-, -C(O)NHCH2CH2-, -C(O)NHC(CH3)2CH2-, -C(O)N(CH3)CH2CH2-, -CH(CH3)(OH)CH2-, -NHSO2CH(CH3)CH2-, -SO2NHC(CH3)2CH2-, -C(O)NH-, -NHCH2CH2, or -CH2SO2CH2CH2-.

7. The compound according to any one of claims 1 to 6, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydroxy, alkyl, heterocyclyl, cycloalkyl or heteroaryl, wherein the alkyl, heterocyclyl, cycloalkyl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxy or alkyl.

8. The compound according to any one of claims 6 to 7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein for 9. The compound according to any one of claims 1 to 8, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom.

10. The compound according to claim 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from methyl, trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, methoxy, isopropyl, deuterated methyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, piperazinyl, morpholinyl, 11. The compound according to claim 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from hydrogen, halogen, alkyl, cycloalkyl or heterocyclic group; wherein the alkyl, cycloalkyl or heterocyclic group is optionally further substituted by one or more halogen; Or, two R 5 It forms a -C(O)- with the same carbon atom to which it is attached.

12. The compound according to claim 3, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R a is selected from methoxy or 5-membered heteroaryl.

13. The compound according to any one of claims 1 to 12, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is:

14. A pharmaceutical composition comprising an effective dose of the compound according to any one of claims 1 to 13, or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient, or a combination thereof.

15. Use of the compound according to any one of claims 1 to 13, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 14, in the preparation of a KIF18A inhibitor.

16. Use of the compound according to any one of claims 1 to 13, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 14, in the preparation of a medicament for treating a disease mediated by KIF18A, wherein the disease mediated by KIF18A is preferably cancer.

17. The method of claim 15, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer, and lung adenocarcinoma.

18. Use of the compound according to any one of claims 1 to 13, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 14, in the preparation of a drug for treating cancer.

19. The use according to claim 18, wherein the cancer is selected from the group consisting of hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.

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