Aromatic amide derivative as well as preparation method and application thereof

Abstract

The invention relates to an aromatic amide derivative, a preparation method of the aromatic amide derivative and application of a pharmaceutical composition containing the aromatic amide derivative in medicine. Specifically, the present invention relates to an aromatic amide derivative represented by general formula (I), a preparation method and a pharmaceutically acceptable salt thereof, and uses of the aromatic amide derivative and the pharmaceutically acceptable salt thereof as a therapeutic agent, especially a KIF18A inhibitor, in which the definition of each substituent in the general formula (I) is the same as the definition 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 C3-C6 cycloalkyl, a 5- to 7-membered aryl, or a 5- to 7-membered heteroaryl;

[0010] X1, X2, and X3 are each independently selected from CR aor N atoms, and at most two atoms among X1, X2, and X3 are N atoms at the same time;

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

[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; the "one or more methylene groups" mentioned therein include any one, multiple or all of the methylene groups in the C1-C6 alkylene group.

[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 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0016] R 2 are the same or different, each independently selected from halogen, hydroxy, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

[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; R3 Preferably a hydrogen atom;

[0018] R 4 The same or different, each independently selected from cyano, halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more groups selected from R A substituted by a substituent;

[0019] R A Selected from hydroxy, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, OR 8 、-C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more alkyl radicals selected from cyano, halogen, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0020] Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached;

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

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

[0023] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

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

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

[0026] n is 0, 1, 2, 3 or 4; and

[0027] r is independently 0, 1 or 2.

[0028] 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:

[0029] Ring A, R 1 、R 3 、R 4 , L1 and n are as defined in the general formula (I).

[0030] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from:

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

[0032] 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 NRb replaced by;

[0033] r is 2;

[0034] R b is selected from a hydrogen atom or a methyl group.

[0035] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -NHSO2CH2CH2-, -NHSO2CH2CH2O-, -NHSO2CH2CH2NH-, -SO2NHCH2CH2-, -SO2-, -CH2SO2-, -NHSO2-, -SO2NH-, -NHC(CH3)2CH2-, -C(O)NHCH2CH2-, -C(O)NHC(CH3)2CH2-, -C(O)N(CH3)CH2CH2-, -C(CH3)(OH)CH2-, -NHSO2CH(CH3)CH2-, -SO2NHC(CH3)2CH2-, -C(O)NH-, -NHCH2CH2 or -CH2SO2CH2CH2-.

[0036] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 1 is selected from hydrogen atom, hydroxyl, alkyl, heterocyclic, cycloalkyl or heteroaryl, wherein the alkyl, heterocyclic, cycloalkyl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl or alkyl.

[0037] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein Selected from

[0038] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 3 A hydrogen atom.

[0039] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 4 The same or different, each independently selected from halogen, alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 or -NR6 R 7 wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R A replace;

[0040] Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached.

[0041] R A Selected from halogen, cyano, alkyl, cycloalkyl, heterocyclic, -OR 8 、-NR 9 R 10 wherein the alkyl, cycloalkyl, and heterocyclic group are optionally further substituted by one or more substituents selected from halogen and haloalkyl;

[0042] R 5 are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group or a haloheterocyclic group;

[0043] R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group,

[0044] R 8 are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group or a haloheterocyclic group;

[0045] R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, and a halogenated alkyl group.

[0046] A preferred embodiment of the present invention is a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, wherein R 4 Selected from methyl, difluoromethyl, cyclopropyl,

[0047] Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached.

[0048] In a preferred embodiment of the present invention, the compound described by the general formula is selected from:

[0049] or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

[0050] 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.

[0051] Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of formula (I), (II) or (III) or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

[0052] The present invention provides a use of a compound of general formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a KIF18A inhibitor.

[0053] The present invention also provides a use of a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, 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.

[0054] The present invention further provides a use of a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts, or a pharmaceutical composition thereof in the preparation of a drug for treating cancer.

[0055] The present invention provides a compound of general formula (I), (II) or (III) 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.

[0056] Detailed Description of the Invention

[0057] Unless otherwise stated, some of the terms used in the specification and claims of the present invention are defined as follows:

[0058] "Alkyl" when used as a group or a part of a group refers to a group comprising C1-C 20 A straight chain or branched aliphatic hydrocarbon group. Preferably C1-C 10 Alkyl, more preferably C1-C6 alkyl. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl can be substituted or unsubstituted.

[0059] "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.

[0060] "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.

[0061] "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.

[0062] "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.

[0063] "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.

[0064] "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,

[0065] The heterocyclic group may be substituted or unsubstituted.

[0066] "Spiro heterocyclyl" refers to a polycyclic group with 5 to 18 members, two or more ring structures, and one atom shared between the rings, containing one or more double bonds in the ring, but no ring has a completely conjugated π electron aromatic system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) t (wherein t is selected from 0, 1 or 2) heteroatoms, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiro atoms between rings, spiroalkyl is divided into monospiro heterocyclic group, bispiro heterocyclic group or polyspiro heterocyclic group, preferably monospiro heterocyclic group and bispiro heterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of "spiro heterocyclic group" include but are not limited to: 1,7-dioxaspiro[4.5]decyl, 2-oxa-7-azaspiro[4.4]nonyl, 7-oxaspiro[3.5]nonyl, 5-oxaspiro[2.4]heptyl,

[0067] "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) heteroatoms, and the remaining ring atoms are carbon. Preferably it is 6 to 14 members, more preferably 7 to 10 members. According to the number of 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.

[0068] "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.

[0069] "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.

[0070] "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.

[0071] "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.

[0072] "Nitro" refers to a -NO2 group.

[0073] "Hydroxy" refers to an -OH group.

[0074] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0075] "Amino" refers to -NH2.

[0076] "Cyano" refers to -CN.

[0077] "Benzyl" refers to -CH2-phenyl.

[0078] "Carboxyl" refers to -C(O)OH.

[0079] "Carboxylate" refers to a -C(O)O-alkyl group or a -C(O)O-cycloalkyl group, wherein alkyl and cycloalkyl are as defined above.

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

[0081] "Aminoalkyl" refers to an alkyl group substituted with an amino group, wherein alkyl is as defined above.

[0082] "Haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0083] "Haloalkoxy" refers to an alkoxy group substituted with a halogen group, wherein alkoxy is as defined above.

[0084] "DMSO" refers to dimethyl sulfoxide.

[0085] "BOC" refers to tert-butoxycarbonyl.

[0086] "Bn" refers to benzyl.

[0087] "THP" refers to 2-tetrahydropyranyl.

[0088] "TFA" refers to trifluoroacetic acid.

[0089] "Ts" refers to p-toluenesulfonyl.

[0090] "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.

[0091] "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.

[0092] 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 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 substituted by a substituent;

[0093] R 5Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =O, -C(O)R 8 、 -C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0094] R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0095] Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR9 R 10 or -NR 9 C(O)R 10 substituted by a substituent;

[0096] R 8 、R 9 and R 10 Each is independently selected from hydrogen, alkyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxyl or carboxylate; r is selected from 0, 1 or 2;

[0097] 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.

[0098] 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.

[0099] "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.

[0100] 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.

[0101] Synthesis method of the compound of the present invention

[0102] In order to achieve the purpose of the present invention, the present invention adopts the following technical solutions:

[0103] 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:

[0104] 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)

[0105] in:

[0106] L2 is selected from

[0107] Y is selected from hydroxy or chlorine;

[0108] Ring A, X1, X2, X3, L1, R 1 ~R 2 , m and n are as defined in the general formula (I). DETAILED DESCRIPTION

[0109] 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.

[0110] Example

[0111] 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.

[0112] Mass spectra were obtained using LC / MS, and the ionization method could be ESI or APCI.

[0113] 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.

[0114] Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.

[0115] 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.

[0116] CD3OD: deuterated methanol.

[0117] CDCl3: deuterated chloroform.

[0118] DMSO-d6: deuterated dimethyl sulfoxide.

[0119] Argon atmosphere means that the reaction bottle is connected to an argon balloon with a capacity of about 1 L.

[0120] Unless otherwise specified in the examples, the solution in the reaction refers to an aqueous solution.

[0121] 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.

[0122] Example 1

[0123] 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)benzamide

[0124] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)benzamide

[0125] first step

[0126] 6-nitro-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole

[0127] 6-Nitro-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole

[0128] To a solution of 5-nitro-1H-benzimidazole 1a (2.50 g, 15.3 mmol, commercially available) in N,N-dimethylformamide (30 mL) was added cesium carbonate (9.99 g, 30.7 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate 1b (5.34 g, 23.0 mmol) at 25°C. The reaction was allowed to proceed at 25°C for 2 hours. The mixture was poured into water (300 mL) and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a mixture of 6-nitro-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole 1c-1 and 5-nitro-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole 1c-2 (3.30 g) in 88% yield.

[0129] MS m / z(ESI):246.0[M+1]

[0130] Step 2

[0131] 1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-amine

[0132] 1-(2,2,2-Trifluoroethyl)-1H-benzo[d]imidazol-6-amine

[0133] To a solution of a mixture of 6-nitro-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole 1c-1 and 5-nitro-1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazole 1c-2 (3.30 g, 13.5 mmol) in ethanol (30 mL) was added 10% palladium on carbon (1.50 g, 14.1 mmol) at room temperature. The atmosphere was replaced with hydrogen three times and the reaction was carried out at 25°C for 18 h. The mixture was filtered and concentrated under reduced pressure to give a crude product, which was separated by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH 4 HCO 3 + H 2 O, mobile phase B: CH 3 CN) to give 1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-amine 1d-1 (600 mg) in a yield of 21%; and 1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-amine 1d-2 (1.00 g) in a yield of 35%.

[0134] MS m / z(ESI):216.1[M+1]

[0135] Step 3

[0136] 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)benzamide

[0137] 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)benzamide

[0138] At room temperature, 1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-amine 1d-1 (100 mg, 0.460 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (216 mg, 0.700 mmol, prepared using the known method of "Patent WO-2020132648") were dissolved in N,N-dimethylformamide (5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (134 mg, 0.700 mmol), N-methylmorpholine (70.5 mg, 0.700 mmol), and 1-hydroxybenzotriazole (94.2 mg, 0.700 mmol) were added to the reaction solution and reacted at 25°C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (10 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-(6-azaspiro[2.5]octane-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)benzamide 1f (120 mg) in a yield of 51%.

[0139] MS m / z(ESI):507.0 / 509.0[M+1]

[0140] Step 4

[0141] 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)benzamide

[0142] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)benzamide

[0143] At room temperature, 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)benzamide 1f (120 mg, 0.240 mmol) and 2-hydroxyethane-1-sulfonamide 1g (59.2 mg, 0.470 mmol) were added to N,N-dimethylformamide (2 mL). Potassium phosphate (100 mg, 0.473 mmol), cuprous iodide (52.5 mg, 0.240 mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (16.8 mg, 0.120 mmol) were added to the reaction mixture. The atmosphere was replaced with nitrogen three times and the reaction was continued at 90°C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-yl)benzamide 1 (37.0 mg), yield: 28%.

[0144] MS m / z(ESI):550.2[M-1]

[0145] 1H NMR (400MHz, DMSO-d6) δ11.64(s,1H),8.25(d,J=1.8Hz,1H),8.09(s,1H),7.72(d,J=8.6Hz,1H),7.56(d,J=8.6Hz,1H),7.27(dd,J=8.6,1. 8Hz,1H),7.03(d,J=2.0Hz,1H),6.89(dd,J=8.6,2.0Hz,1H),5.19(m,2H),3.62(m,2H),3.18(s,2H),2.85(m,4H),1.39(m,4H),0.20(s,4H)

[0146] Example 2

[0147] 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)benzamide

[0148] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)benzamide

[0149] first step

[0150] 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)benzamide

[0151] 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)benzamide

[0152] At room temperature, 1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-amine 1d-2 (100 mg, 0.460 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (216.2 mg, 0.700 mmol) were added to N,N-dimethylformamide (5 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (134 mg, 0.700 mmol), N-methylmorpholine (70.5 mg, 0.700 mmol), and 1-hydroxybenzotriazole (94.2 mg, 0.700 mmol) were added to the reaction mixture. The mixture was reacted at 25°C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 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-(6-azaspiro[2.5]octane-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)benzamide 2a (120 mg) in a yield of 51%.

[0153] MS m / z(ESI):507.0 / 509.0[M+1]

[0154] Step 2

[0155] 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)benzamide

[0156] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)benzamide

[0157] At room temperature, 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)benzamide 2a (120 mg, 0.240 mmol) and 2-hydroxyethane-1-sulfonamide (1 g, 59.2 mg, 0.470 mmol) were added to N,N-dimethylformamide (2 mL). Potassium phosphate (100 mg, 0.473 mmol), cuprous iodide (52.5 mg, 0.240 mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (16.8 mg, 0.120 mmol) were added to the reaction mixture. The atmosphere was replaced with nitrogen three times and the reaction was continued at 90°C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (60 mL). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-yl)benzamide 2 (39 mg), yield: 30%.

[0158] MS m / z(ESI):552.0[M+1]

[0159] 1H NMR (400MHz, DMSO-d6) δ11.57(s,1H),8.29(s,1H),8.24(d,J=2.0Hz,1H),7.84(d,J=8.6Hz,1H),7.72(d,J=8.6Hz,1H),7.62(dd,J=8.6,2. 0Hz,1H),7.16(d,J=2.0Hz,1H),7.02(dd,J=8.6,2.0Hz,1H),5.35(m,2H),3.76(m,2H),3.33(m,2H),3.00(m,4H),1.53(m,4H),0.35(s,4H).

[0160] Example 3

[0161] 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide

[0162] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide

[0163] first step

[0164] methyl 2-(bromomethyl)-4-nitrobenzoate

[0165] Methyl 2-(bromomethyl)-4-nitrobenzoate

[0166] Methyl 2-methyl-4-nitrobenzoate 3a (2.0 g, 10.25 mmol) was dissolved in 1,2-dichloroethane (10 mL), and N-bromosuccinimide (2.19 g, 12.30 mmol) and benzoyl peroxide (248.22 mg, 1.02 mmol) were added. The mixture was stirred at 100°C for 20 hours. The reaction mixture was cooled to room temperature and concentrated. Ethyl acetate (5 mL) and petroleum ether (15 mL) were added, and the precipitated solid was filtered and dried to obtain methyl 2-(bromomethyl)-4-nitrobenzoate 3b (2.6 g) in a yield of 92.58%.

[0167] MS m / z(ESI):273.9[M+1]

[0168] Step 2

[0169] 5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

[0170] 5-Nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

[0171] Methyl 2-(bromomethyl)-4-nitrobenzoate 3b (4.10 g, 14.9 mmol) was dissolved in methanol (50 mL) at room temperature. Triethylamine (6.06 g, 59.8 mmol) and commercially available 2,2,2-trifluoroethylamine 3c (1.78 g, 17.9 mmol) were added sequentially. The reaction mixture was stirred in a sealed container at 80°C for 18 hours to yield a brown solution. The cooled reaction solution was spun dry, poured into water (80 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 under reduced pressure to afford 5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one 3d (3.80 g) in a 97% yield. The crude product was used directly in the next reaction.

[0172] MS m / z(ESI):261.1[M+1]

[0173] Step 3

[0174] 5-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one

[0175] 5-Amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one

[0176] 5-Nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one 3d (3.80 g, 14.6 mmol) was dissolved in ethanol (50 mL) and water (10 mL) at room temperature. Iron powder (3.26 g, 58.4 mmol) and ammonium chloride (3.18 g, 58.4 mmol) were added sequentially. The mixture was reacted at 84°C for 3 hours to yield a black solution. LCMS analysis confirmed complete reaction of the starting material and the formation of the product. The cooled reaction solution was adjusted to pH 9 with saturated sodium bicarbonate solution and filtered. The filter cake was washed with ethyl acetate (50 mL). The combined filtrates were diluted with water (100 mL) and extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (60 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (eluent: System A) to give 5-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 3e (1.00 g) in a yield of 29%.

[0177] MS m / z(ESI):231.0[M+1]

[0178] Step 4

[0179] 2-(2,2,2-trifluoroethyl)isoindolin-5-amine

[0180] 2-(2,2,2-Trifluoroethyl)isoindolin-5-amine

[0181] To a solution of 5-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 3e (250 mg, 1.09 mmol) in tetrahydrofuran (10 mL) was added dropwise a 1 M solution of borane in tetrahydrofuran (5.43 mmol, 5.43 mL) at 0°C. The mixture was reacted at 65°C for 18 hours. The mixture was concentrated under reduced pressure to obtain a crude product, which was dissolved in ethanol (10 mL). After stirring at 85°C for 2 hours, the mixture was concentrated under reduced pressure to afford 2-(2,2,2-trifluoroethyl)isoindolin-5-amine 3f (200 mg) in an 85% yield.

[0182] MS m / z(ESI):217.1[M+1]

[0183] Step 5

[0184] 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide

[0185] 4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide

[0186] At 25°C, 2-(2,2,2-trifluoroethyl)isoindolin-5-amine 3f (200 mg, 0.925 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (430 mg, 1.39 mmol) were added to N,N-dimethylformamide (5 mL). (7-Azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (724 mg, 1.39 mmol) and N,N-diisopropylethylamine (478 mg, 3.70 mmol) were added to the reaction solution. The mixture was reacted at 65°C for 18 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 3 g (180 mg) of 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindoline-5-yl)benzamide in a yield of 38%.

[0187] MS m / z(ESI):508.0 / 510.0[M+1]

[0188] Step 6

[0189] 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide

[0190] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide

[0191] At room temperature, 3 g (180 mg, 0.354 mmol) of 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide and 1 g (88.6 mg, 0.708 mmol) of 2-hydroxyethane-1-sulfonamide were added to N,N-dimethylformamide (5 mL). Potassium phosphate (150 mg, 0.708 mmol), cuprous iodide (78.6 mg, 0.354 mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (25.2 mg, 0.177 mmol) were added to the reaction mixture. The atmosphere was replaced with nitrogen three times and the reaction was continued 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 saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide 3 (125 mg) in a yield of 64%.

[0192] MS m / z(ESI):553.2[M+1]

[0193] 1 H NMR(400MHz,DMSO-d6)δ11.42(s,1H),10.08(s,1H),7.85(m,2H),7.46(m,1H ),7.26(d,J=8.0Hz,1H),7.15(d,J=2.0Hz,1H),7.02(dd,J=8.0,2.0Hz,1H), 4.96(s,1H),4.09(d,J=17.0Hz,4H),3.76(t,J=6.6Hz,2H),3.56(m,2H),3.3 2(t,J=6.6Hz,2H),2.97(t,J=5.4Hz,4H),1.51(t,J=5.4Hz,4H),0.35(s,4H).

[0194] Example 4

[0195] 4-((2-hydroxyethyl)sulfonamido)-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0196] 4-((2-Hydroxyethyl)sulfonamido)-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0197] first step

[0198] 4-bromo-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0199] 4-Bromo-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0200] At room temperature, 5-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 3e (200 mg, 0.869 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (296 mg, 0.956 mmol) were added to N,N-dimethylformamide (5 mL). (7-Azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (907 mg, 1.74 mmol) and N,N-diisopropylethylamine (449 mg, 3.48 mmol) were added to the reaction solution. The mixture was reacted at 65°C for 18 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 4a (230 mg) in a yield of 51%.

[0201] MS m / z(ESI):552.0 / 524.0[M+1]

[0202] Step 2

[0203] 4-((2-hydroxyethyl)sulfonamido)-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0204] 4-((2-Hydroxyethyl)sulfonamido)-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0205] At room temperature, 4-bromo-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 4a (100 mg, 0.190 mmol) and 1 g of 2-hydroxyethane-1-sulfonamide (47.9 mg, 0.383 mmol) were added to N,N-dimethylformamide (4 mL). Potassium phosphate (81.3 mg, 0.383 mmol), cuprous iodide (42.5 mg, 0.191 mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (13.6 mg, 0.0957 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 saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-((2-hydroxyethyl)sulfonamido)-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 4 (40.0 mg), yield: 37%.

[0206] MS m / z(ESI):567.2[M+1]

[0207] 1H NMR (400MHz, DMSO-d6) δ11.66(s,1H),10.12(s,1H),8.26(s,1H),7.78(m,2H),7.70(m,1H),7.15(d,J=2.2Hz,1H),7.02(m,1H ),4.99(s,1H),4.64(s,2H),4.37(q,J=9.8Hz,2H),3.76(m,2H),3.32(s,2H),2.99(t,J=5.6Hz,4H),1.50(s,4H),0.34(s,4H)

[0208] Example 5

[0209] 4-((2-hydroxyethyl)sulfonamido)-N-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0210] 4-((2-Hydroxyethyl)sulfonamido)-N-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0211] first step

[0212] methyl 2-(bromomethyl)-5-nitrobenzoate

[0213] Methyl 2-(bromomethyl)-5-nitrobenzoate

[0214] At room temperature, methyl 2-methyl-5-nitrobenzoate 5a (2.00 g, 10.3 mmol) was added to carbon tetrachloride (20 mL). N-bromosuccinimide (2.74 g, 15.4 mmol) and azobisisobutyronitrile (168 mg, 1.02 mmol) were added to the reaction mixture. The atmosphere was purged with nitrogen three times and the reaction was continued at 80°C for 18 hours. The reaction mixture was filtered and concentrated to dryness under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give methyl 2-(bromomethyl)-5-nitrobenzoate 5b (1.80 g) in a 64% yield. MS m / z (ESI): 274.2 [M+1].

[0215] Step 2

[0216] 6-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

[0217] 6-Nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

[0218] Methyl 2-(bromomethyl)-5-nitrobenzoate 5b (1.80 g, 6.57 mmol) was added to anhydrous methanol (20 mL) at room temperature. Triethylamine (1.99 g, 19.7 mmol) and 2,2,2-trifluoroethylamine 3c (1.95 g, 19.7 mmol) were also added. The atmosphere was replaced with nitrogen three times and the reaction was continued at 70°C for 18 hours. 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 6-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5c (500 mg) in a 29% yield.

[0219] MS m / z(ESI):261.0[M+1]

[0220] Step 3

[0221] 6-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one

[0222] 6-Amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one

[0223] 6-Nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5c (500 mg, 1.92 mmol) was added to anhydrous methanol (10 mL) at room temperature. 10% palladium on carbon (102 mg, 0.961 mmol) was added to the reaction solution, and the atmosphere was replaced with hydrogen three times. The reaction was continued at 25°C for 2 hours. The reaction solution was filtered, and the filter cake was washed with anhydrous methanol (3 mL x 3). The filtrate was collected and concentrated under reduced pressure to give 6-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5d (400 mg) in a 90.4% yield.

[0224] MS m / z(ESI):231.0[M+1]

[0225] Step 4

[0226] 4-bromo-N-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0227] 4-Bromo-N-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0228] At room temperature, 6-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5d (200 mg, 0.869 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (296 mg, 0.956 mmol) were added to N,N-dimethylformamide (5 mL). 1-Hydroxybenzotriazole (176 mg, 1.30 mmol), N-methylmorphine (132 mg, 1.30 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (250 mg, 1.30 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 60°C for 18 hours. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (20 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 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-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 5e (210 mg) in a yield of 46.3%.

[0229] MS m / z(ESI):522.2[M+1]

[0230] Step 5

[0231] 4-((2-hydroxyethyl)sulfonamido)-N-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0232] 4-((2-Hydroxyethyl)sulfonamido)-N-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0233] 4-Bromo-N-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 5e (100 mg, 0.191 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (43.0 mg, 0.191 mmol) were added to N,N-dimethylformamide (5 mL) at room temperature. Cuprous iodide (48.0 mg, 0.383 μmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (14 mg, 0.096 mmol) and potassium phosphate (81.0 mg, 0.383 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 (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was separated by preparative liquid phase (separation 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 give 4-((2-hydroxyethyl)sulfonamido)-N-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 5 (30.0 mg) in a yield of 27.7%.

[0234] MS m / z(ESI):567.2[M+1]

[0235] 1 H NMR (400MHz, DMSO-d6) δ11.54(s,1H),8.32(d,J=2.0Hz,1H),7.90-7.83(m,1H),7.77(d,J=8.4Hz,1H),7.64(d,J=8.0Hz,1H),7.14-7.08(m,1 H),7.03-6.96(m,1H),4.59(s,2H),4.45-4.35(m,2H),3.75(t,J=6.4H z,2H),3.32-3.28(m,2H),3.02-2.93(m,4H),1.48(s,4H),0.33(s,4H).

[0236] Example 6

[0237] N-(3-(4,4-difluoropiperidin-1-yl)benzo[d]isoxazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0238] N-(3-(4,4-difluoropiperidin-1-yl)benzo[d]isoxazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0239] first step

[0240] 2-hydroxy-5-nitrobenzoic acid

[0241] 2-Hydroxy-5-nitrobenzoic acid

[0242] To a solution of methyl 2-hydroxy-5-nitrobenzoate 6a (5.50 g, 27.9 mmol) in water (15 mL), tetrahydrofuran (15 mL), and methanol (15 mL) was added lithium hydroxide (1.34 g, 55.8 mmol), and the mixture was stirred at 30°C for 4 hours. A colorless solution formed. The mixture was concentrated to dryness under reduced pressure to remove methanol and tetrahydrofuran. The solution was adjusted to pH 2 with hydrochloric acid (4 M) and filtered. The filter cake was washed with water (20 mL x 3), and the filtrate was concentrated to dryness under reduced pressure to give 2-hydroxy-5-nitrobenzoic acid 6b (4.20 g) in 82% yield. The crude product was used directly in the next step.

[0243] MS m / z(ESI):182.0(M+1)

[0244] Step 2

[0245] 2-hydroxy-5-nitrobenzoyl chloride

[0246] 2-Hydroxy-5-nitrobenzoyl chloride

[0247] To a solution of 2-hydroxy-5-nitrobenzoic acid 6b (4.00 g, 21.8 mmol) in dichloromethane (40 mL) was added oxalyl chloride (13.9 g, 109 mmol) and N,N-dimethylformamide (159.66 mg, 2.18 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour to obtain a colorless solution. The mixture was concentrated to dryness under reduced pressure to obtain 2-hydroxy-5-nitrobenzoyl chloride 6c (4.40 g) in a 99% yield. The crude product was used directly in the next step without further purification.

[0248] Step 3

[0249] N,2-dihydroxy-5-nitrobenzamide

[0250] N,2-Dihydroxy-5-nitrobenzamide

[0251] To an aqueous solution of hydroxylamine (42.8 g, 648 mmol, 50% purity) at 0°C was added a solution of 2-hydroxy-5-nitrobenzoyl chloride 6c (4.40 g, 21.8 mmol) in dichloromethane (40 mL). The reaction was stirred at 30°C for 1 hour to form a yellow suspension. The crude product obtained by filtration was slurried with tetrahydrofuran (30 mL) and filtered. The filter cake was washed with ethyl acetate (30 mL) and then dried under reduced pressure to provide N,2-dihydroxy-5-nitrobenzamide 6d (4.70 g) in an 85% yield.

[0252] MS m / z(ESI):197.0(M-1)

[0253] Step 4

[0254] 5-nitrobenzo[d]isoxazol-3(2H)-one

[0255] 5-Nitrobenzo[d]isoxazol-3(2H)-one

[0256] To a solution of N,2-dihydroxy-5-nitrobenzamide 6d (4.70 g, 23.7 mmol) in tetrahydrofuran (45 mL) was added N,N'-carbonyldiimidazole (7.79 g, 94.9 mmol). The mixture was stirred at 65°C for 1 hour to yield a yellow suspension. The reaction mixture was adjusted to pH 5 with hydrochloric acid (1 M) 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 under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to afford 5-nitrobenz[d]isoxazol-3(2H)-one 6e (2.50 g) in 58% yield.

[0257] MS m / z(ESI):179.0(M-1)

[0258] Step 5

[0259] 3-(4,4-difluoropiperidin-1-yl)-5-nitrobenzo[d]isoxazole

[0260] 3-(4,4-Difluoropiperidin-1-yl)-5-nitrobenzo[d]isoxazole

[0261] To a solution of 5-nitrobenzo[d]isoxazol-3(2H)-one 6e (500 mg, 2.78 mmol) and 4,4-difluoropiperidine hydrochloride 6f (370 mg, 3.05 mmol, commercially available) in tetrahydrofuran (30 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.69 g, 11.1 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.84 g, 4.16 mmol). The reaction mixture was stirred at 30°C for 16 hours to form a brown suspension. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluent: System A) to give 6 g (490 mg) of 3-(4,4-difluoropiperidin-1-yl)-5-nitrobenzo[d]isoxazole in a yield of 61.88%.

[0262] MS m / z(ESI):284.0(M+1)

[0263] Step 6

[0264] 3-(4,4-difluoropiperidin-1-yl)benzo[d]isoxazol-5-amine

[0265] 3-(4,4-Difluoropiperidin-1-yl)benzo[d]isoxazol-5-amine

[0266] To a solution of 6 g (490 mg, 1.72 mmol) of 3-(4,4-difluoropiperidin-1-yl)-5-nitrobenzo[d]isoxazole in tetrahydrofuran (10 mL) and methanol (40 mL) was added 10% palladium on carbon (91.40 mg, 85.89 μmol). The resulting reaction solution was replaced with hydrogen three times and stirred at 30°C under a hydrogen atmosphere for 16 hours to form a black suspension. The mixture was filtered and the solid was washed with methanol (100 mL). The filtrate was concentrated to dryness under reduced pressure to afford 3-(4,4-difluoropiperidin-1-yl)benzo[d]isoxazol-5-amine 6h (420 mg) in a 95% yield.

[0267] MS m / z(ESI):254.1(M+1)

[0268] Step 7

[0269] N-(3-(4,4-difluoropiperidin-1-yl)benzo[d]isoxazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0270] N-(3-(4,4-difluoropiperidin-1-yl)benzo[d]isoxazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0271] To a solution of 3-(4,4-difluoropiperidin-1-yl)benzo[d]isoxazol-5-amine 6h (130 mg, 0.513 mmol), 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 6i (191 mg, 0.539 mmol, prepared using the known method "Patent WO-2020132648"), and N,N-diisopropylethylamine (1329 mg, 1.03 mmol) in N,N-dimethylformamide (1 mL) was added 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.78 mg, 0.770 mmol). The mixture was stirred at 30°C for 16 hours to form a brown suspension. The mixture was poured into water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-(4,4-difluoropiperidin-1-yl)benzo[d]isoxazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 6 (29.3 mg), yield: 9%.

[0272] MS m / z(ESI):590.2[M+1]

[0273] 1H NMR (400MHz, DMSO-d6) δ11.64(s,1H),10.10(s,1H),8.50(d,J=1.76Hz,1H), 7.85–7.77m,2H),7.66(d,J=9.2Hz,1H),7.16(d,J=2.0Hz,1H),7.02(dd,J=8 .4,2.0Hz,1H),4.98(s,1H),3.76(t,J=6.4Hz,2H),3.68–3.56(m,4H),3.33- 3.29(m,2H),3.05–2.93(m,4H),2.26-2.11(m,4H),1.51(s,4H),0.34(s,4H).

[0274] Example 7

[0275] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0276] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0277] first step

[0278] 3-bromo-1-methyl-5-nitro-1H-indazole

[0279] 3-Bromo-1-methyl-5-nitro-1H-indazole

[0280] Sodium hydride (717 mg, 16.5 mmol, 60% purity) was added to a solution of 3-bromo-5-nitroindazole 7a (2.00 g, 8.26 mmol, commercially available) in N,N-dimethylformamide (20 mL) under ice. The reaction was stirred under ice for half an hour, and then iodomethane (1.76 g, 12.4 mmol) was added. The reaction was allowed to react at room temperature for 4 hours. The reaction was quenched with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (200 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was slurried with ethyl acetate (30 mL) to give 3-bromo-1-methyl-5-nitro-1H-indazole 7b (2.00 g) in a 95% yield.

[0281] MS m / z(ESI):255.8[M+1]

[0282] 1H NMR (400MHz, DMSO-d6) δ8.46(d,J=1.8Hz,1H),8.34–8.27(m,1H),7.96(d,J=9.2Hz,1H),4.12(s,3H)

[0283] Step 2

[0284] 3-(4,4-difluoropiperidin-1-yl)-1-methyl-5-nitro-1H-indazole

[0285] 3-(4,4-difluoropiperidin-1-yl)-1-methyl-5-nitro-1H-indazole

[0286] Palladium acetate (158 mg, 0.70 mmol), R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (438 mg, 0.70 mmol), and cesium carbonate (6.87 g, 21.1 mmol) were added to a toluene (30 mL) solution of 3-bromo-1-methyl-5-nitro-1H-indazole 7b (1.8 g, 7.03 mmol) and 4,4-difluoropiperidine hydrochloride 6f (1.28 g, 10.5 mmol) at room temperature. 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 rinsed with ethyl acetate (1500 mL), and the filtrate concentrated under reduced pressure. The crude product was slurried with ethyl acetate (30 mL) to afford 3-(4,4-difluoropiperidin-1-yl)-1-methyl-5-nitro-1H-indazole 7c (1.10 g) in a 53% yield.

[0287] MS m / z(ESI):297.0[M+1]

[0288] Step 3

[0289] 3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-amine

[0290] 3-(4,4-Difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-amine

[0291] Palladium on carbon (100.00 mg, 10%) was added to a solution of 3-(4,4-difluoropiperidin-1-yl)-1-methyl-5-nitro-1H-indazole 7c (1 g, 3.38 mmol) in methanol (50 mL) at room temperature. The mixture was purged with a hydrogen balloon three times and allowed to react at room temperature for 4 hours. The reaction mixture was filtered, the filter cake rinsed with methanol (300 mL), and the filtrate concentrated under reduced pressure. The crude product was used directly in the next step without further treatment. 3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-amine 7d (850 mg) was obtained in a 95% yield. MS m / z (ESI): 267.0 [M+1]

[0292] Step 4

[0293] 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0294] 4-Bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0295] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (857 mg, 2.25 mmol) and N,N-diisopropylethylamine (388 mg, 3.00 mmol) were added to a solution of 3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-amine 7d (400 mg, 1.50 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (699 mg, 2.25 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The reaction mixture was allowed to react at 65°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to afford 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 7f (650 mg) in a 77% yield. MS m / z (ESI): 560.2 [M+1].

[0296] Step 5

[0297] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0298] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0299] To a solution of 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 7f (200 mg, 0.36 mmol) in N,N-dimethylformamide (5 mL) was added 2-hydroxyethane-1-sulfonamide (1 g, 89.6 mg, 0.72 mmol), cuprous iodide (68.2 mg, 0.36 mmol), potassium phosphate (152 mg, 0.72 mmol), and trans-N,N'-dimethyl-1,2-cyclohexanediamine (25.5 mg, 0.18 mmol) at room temperature. The atmosphere was replaced with nitrogen three times, and the reaction was carried out at 90°C for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 7 (84 mg) in a yield of 39%.

[0300] MS m / z(ESI):603.2[M+1]

[0301] 1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),10.08(br s,1H),8.32(s,1H),7.84(d,J=8.4Hz,1H),7.65–7.57(m,1H),7.52(d,J=9.2Hz,1H),7.16(d,J=2.0Hz,1H),7.07–6.98(m,1H),4.96(s,1H) ,3.84(s,3H),3.76(t,J=6.4Hz,2H),3.52–3.40(m,4H),3.31-3.32(m ,2H),3.06–2.90(m,4H),2.24–2.08(m,4H),1.52(s,4H),0.36(s,4H).

[0302] Example 8

[0303] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0304] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0305] first step

[0306] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0307] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0308] 3-(4,4-Difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-amine 7d (615.05 mg, 2.31 mmol) and 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (750 mg, 2.10 mmol, prepared by the known method "Patent WO-2020132648") were dissolved in acetonitrile (2 mL), and 1-methylimidazole (517.19 To the reaction mixture of 4-nitro-1-nitro-2-nitro-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8b (0.74 g) was obtained. The product was added with 4-nitro-1-nitro-2-nitro-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8b (0.74 g) in a yield of 58.21%.

[0309] MS m / z(ESI):605.2.2[M+1]

[0310] Step 2

[0311] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0312] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0313] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8b (100 mg, 165.16 μmol) and ethanesulfonamide 8c (36.05 mg, 330.33 μmol) were dissolved in N,N-dimethylformamide (5 mL), and 2-(methylamino)acetic acid (14.7 mg, 165.16 μmol) was added. 16μmol), tripotassium phosphate trihydrate (219.93mg, 825.82μmol) and cuprous iodide (15.73mg, 82.58μmol), argon replacement, heating to 110℃, stirring for 6 hours, mass spectrometry showed that the reaction was complete, water (20mL) was added to the reaction solution, and ethyl acetate was extracted (50mL×2), the combined organic phase was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to obtain N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 8 (65.7 mg) with a yield of 67.53%.

[0314] MS m / z(ESI):587.3[M+1]

[0315] 1H NMR (400MHz, DMSO-d6) δ11.56(s,1H),10.09(s,1H),8.31(d,J=1.7Hz,1H),7.83(d,J=8.5H z,1H),7.61(dd,J=9.0,1.8Hz,1H),7.54(d,J=8.9Hz,1H),7.17(d,J=2.1Hz,1H),7.03(dd,J =8.5,2.0Hz,1H),3.86(s,3H),3.46(t,J=5.7Hz,4H),3.19(q,J=7.3Hz,2H),2.98(t,J=5.3H z,4H),2.16(tt,J=13.7,5.5Hz,4H),1.61–1.45(m,4H),1.21(t,J=7.3Hz,3H),0.34(s,4H).

[0316] Example 9

[0317] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-methoxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0318] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-methoxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0319] first step

[0320] tert-butyl

[0321] (4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)carbamate

[0322] tert-Butyl 4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)carbamate

[0323] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8b (300 mg, 495.49 μmol) and tert-butyl carbamate 9a (116.09 mg, 990.98 μmol) were dissolved in toluene (10 mL), and dicyclohexyl(2,4,6-tri(1-methylethyl)phenyl)phosphine (47.24 mg, 99 The reaction mixture was stirred for 16 hours at 100°C for 16 hours. Mass spectrometry indicated the reaction was complete. The mixture was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (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 tert-butyl 4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)carbamate 9b (230.4 mg) in a yield of 77.02%.

[0324] MS m / z(ESI):595.4[M+1]

[0325] 1H NMR(400MHz,DMSO-d6)δ12.00(s,1H),9.66(s,1H),8.30(d,J=1.6Hz,1H),7.86 (d,J=8.6Hz,1H),7.66(s,1H),7.62(dd,J=9.1,1.7Hz,1H),7.54(d,J=9.0Hz,1 H),7.25(d,J=8.6Hz,1H),3.86(s,3H),3.46(t,J=5.6Hz,4H),2.98(t,J=5.3Hz ,4H),2.15(dq,J=13.6,6.7,5.3Hz,4H),1.56(s,4H),1.50(s,9H),0.37(s,4H).

[0326] Step 2

[0327] 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0328] 4-Amino-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0329] Tert-butyl 4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)carbamate 9b (220 mg, 369.94 μmol) was dissolved in trifluoroacetic acid (8.89 g, 77.94 mmol, 5.79 mL) and stirred at room temperature for 1 hour. Mass spectrometry showed that the reaction was complete. The reaction solution was concentrated. Water (20 mL) and ethyl acetate (30 mL) were then added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. The organic phase was separated, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give 4-amino-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 9c (220 mg) in a yield of 96.25%.

[0330] MS m / z(ESI):495.3[M+1]

[0331] 1H NMR (400MHz, DMSO-d6) δ8.15(s,1H),7.86(d,J=8.4Hz,1H),7.62(d,J=9.0Hz,1H),7.53(d,J=8.9Hz,1H),6.76(s,1H), 6.55(s,1H),3.86(s,3H),3.46(t,J=5.7Hz,4H),3.16(s,4H),2.16(tt,J=13.7,5.5Hz,4H),1.62(s,4H),0.42(s,4H).

[0332] Step 3

[0333] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-methoxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0334] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-methoxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0335] 4-Amino-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 9c (34 mg, 68.75 μmol) was dissolved in dichloromethane (5 mL), triethylamine (13.91 mg, 137.49 μmol) was added, and 2-methoxyethylsulfonyl chloride 9d (26.16 mg, 185.0 μmol) was added dropwise. The mixture was stirred at room temperature for 18 hours. Mass spectrometry showed that the reaction was complete. Water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL×2). The organic phases were combined, concentrated, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-methoxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 9 (5.1 mg) with a yield of 11.97%.

[0336] MS m / z(ESI):617.3[M+1]

[0337] 1H NMR (400MHz, DMSO-d6) δ11.59(s,1H),10.14(s,1H),8.30(s,1H),7.84(d,J=8.4 Hz,1H),7.62(d,J=9.1Hz,1H),7.54(d,J=8.9Hz,1H),7.16(s,1H),7.03(d,J=8. 6Hz,1H),3.86(s,3H),3.68(t,J=5.9Hz,2H),3.45(m,6H),3.18(s,3H),2.99(t, J=5.2Hz,4H),2.16(tt,J=13.8,5.4Hz,4H),1.53(t,J=5.2Hz,4H),0.34(s,4H).

[0338] Example 10

[0339] 4-((2-aminoethyl)sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0340] 4-((2-aminoethyl)sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0341] first step

[0342] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)-4-(vinylsulfonamido)benzamide

[0343] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)-4-(vinylsulfonamido)benzamide

[0344] 4-Amino-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 9c (800 mg, 1.62 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (327.35 mg, 3.24 mmol) was added. 2-Chloroethylsulfonyl chloride 10a (316.44 mg, 1.94 mmol, commercially available) was added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. Mass spectrometry showed that the reaction was complete. Water (30 mL) was added to the reaction solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, washed sequentially with saturated sodium bicarbonate and saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)-4-(vinylsulfonamido)benzamide 10a (872 mg) in a yield of 92.20%.

[0345] MS m / z(ESI):585.3[M+1]

[0346] Step 2

[0347] 4-((2-aminoethyl)sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0348] 4-((2-aminoethyl)sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0349] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)-4-(vinylsulfonamido)benzamide 10a (100 mg, 171.03 μmol) was dissolved in aqueous ammonia (0.4 M, 10 mL), heated to 60°C, and stirred for 18 hours. The reaction was complete after mass spectrometry. The reaction solution was concentrated under reduced pressure, and the residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5μm, 20mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN), to obtain 4-((2-aminoethyl)sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 10 (15.0 mg), yield: 10.61%.

[0350] MS m / z(ESI):602.3[M+1]

[0351] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.46(s,1H),8.31(s,1H),7.87(d,J=8 .0Hz,3H),7.61(d,J=9.0Hz,1H),7.54(d,J=9.0Hz,1H),7.15(s,1H),7.06(d,J =8.5Hz,1H),3.86(s,3H),3.47(t,J=9.8Hz,6H),3.23–3.10(m,2H),2.99(d,J =5.5Hz,4H),2.16(tt,J=13.8,5.4Hz,4H),1.53(d,J=5.7Hz,4H),0.35(s,4H).

[0352] Example 11

[0353] 4-(azetidine-3-sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0354] 4-(Azetidine-3-sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0355] first step

[0356] tert-butyl 3-(acetylthio)azetidine-1-carboxylate

[0357] tert-Butyl 3-(acetylthio)azetidine-1-carboxylate

[0358] tert-Butyl 3-iodoazetidine-1-carboxylate 11a (0.5 g, 1.77 mmol) and cesium carbonate (1.15 g, 3.53 mmol) were dissolved in N,N-dimethylformamide (5 mL). Ethylthiosulfate 11b (268.87 mg, 3.53 mmol) was added, and the mixture was heated to 70°C and stirred for 2 hours. Mass spectrometry indicated the reaction was complete. Water (20 mL) was added to the reaction solution, and extraction was performed with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (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 tert-butyl 3-(acetylthio)azetidine-1-carboxylate 11c (0.27 g) in a yield of 66.09%.

[0359] MS m / z(ESI):254.1[M+1]

[0360] 1H NMR (400MHz, Chloroform-d) δ4.36 (t, J = 8.7 Hz, 2H), 4.21–4.09 (m, 1H), 3.81 (dd, J = 9.3, 5.5 Hz, 2H), 2.33 (s, 3H), 1.43 (s, 9H).

[0361] Step 2

[0362] tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate

[0363] tert-Butyl 3-(chlorosulfonyl)azetidine-1-carboxylate

[0364] Dissolve tert-butyl 3-(acetylthio)azetidine-1-carboxylate 11c (260 mg, 1.12 mmol) in water (1 mL) and acetic acid (10 mL). Add N-chlorosuccinimide (450.27 mg, 3.37 mmol) and stir at room temperature for 1 hour. Mass spectrometry shows the reaction is complete. Add water (20 mL) and extract with dichloromethane (30 mL x 2). The organic phases are combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate used directly in the next step.

[0365] Step 3

[0366] tert-butyl 3-sulfamoylazetidine-1-carboxylate

[0367] tert-Butyl 3-sulfamopyridine-1-carboxylate

[0368] The above solution was added dropwise to aqueous ammonia (7.0 M, 8.03 mL), stirred at room temperature for 1 hour, concentrated under reduced pressure, added with dichloromethane (20 mL), stirred for 30 minutes, filtered, and the filtrate was concentrated. The crude product was dissolved in ethyl acetate (50 mL) and water (20 mL), and the pH was adjusted to 9-10 with 2 M sodium hydroxide solution. The layers were separated, and the aqueous phase was extracted with ethyl acetate (20 mL). The organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl 3-sulfamopyridine-1-carboxylate 11e (36 mg) with a yield of 13.55%.

[0369] 1H NMR (400MHz, Chloroform-d) δ4.27-4.10 (m, 4H), 4.00 (ddd, J = 8.3, 5.3, 3.1Hz, 1H), 1.45 (s, 9H).

[0370] Step 4

[0371] tert-butyl

[0372] 3-(N-(4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)azetidine-1-carboxylate

[0373] tert-Butyl 3-(N-(4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]oct-6-yl)phenyl)sulfamoyl)azetidine-1-carboxylate

[0374] N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8b (40 mg, 66.07 μmol) and tert-butyl 3-sulfamopyridine-1-carboxylate 11e (31.22 mg, 132.13 μmol) were dissolved in N,N-dimethylformamide (2 mL). 2-(Methylamino)acetic acid (5.89 mg, 66.07 μmol), tripotassium phosphate trihydrate (87.97 mg, 330.33 μmol) and cuprous iodide (6.29 mg, 33.03 μmol) were added. The atmosphere was replaced with argon for 5 minutes, the temperature was raised to 100°C, and the mixture was stirred for 18 hours. Mass spectrometry showed that the reaction was complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl 3-(N-(4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)azetidine-1-carboxylate 11f (45 mg) with a yield of 95.42%.

[0375] MS m / z(ESI):714.4[M+1]

[0376] Step 5

[0377] 4-(azetidine-3-sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0378] 4-(Azetidine-3-sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0379] Tert-butyl 3-(N-(4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfamoyl)azetidine-1-carboxylate 11f (45 mg, 63.04 μmol) was dissolved in methanol (5 mL), followed by addition of hydrochloric acid (4.0 M, 157.60 μL), heating to 60°C, and stirring for 10 hours. Mass spectrometry showed that the reaction was complete. The product was concentrated and separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-(azetidine-3-sulfonamido)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 11 (10.8 mg) with a yield of 23.54%.

[0380] MS m / z(ESI):614.3[M+1]

[0381] 1H NMR (400MHz, DMSO-d6) δ11.49(s,1H),10.57(s,1H),9.22(d,J=60.2Hz,1H),8.30(d,J=1.8Hz,1H) ,7.85(d,J=8.4Hz,1H),7.61(dd,J=9.0,1.8Hz,1H),7.54(d,J=9.0Hz,1H),7.15–7.07(m,1H),7.02 (dd,J=8.5,2.0Hz,1H),4.51(p,J=7.4Hz,1H),4.32(m,2H),4.13(m,2H),3.86(s,3H),3.46(t,J=5 .6Hz,4H),2.99(t,J=5.2Hz,4H),2.16(tt,J=13.8,5.4Hz,4H),1.53(t,J=5.2Hz,4H),0.34(s,4H).

[0382] Example 12

[0383] 4-(azetidin-3-ylsulfonyl)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0384] 4-(azetidin-3-ylsulfonyl)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0385] first step

[0386] methyl 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoate

[0387] Methyl 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoate

[0388] 2-(6-Azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid 8a (500 mg, 1.40 mmol) was dissolved in dichloromethane (10 mL). N,N-dimethylformamide (10.23 mg, 139.98 μmol) was added, and oxalyl chloride (266.52 mg, 2.10 mmol) was added dropwise at room temperature and stirred for 1 hour. The reaction solution was added dropwise to methanol (20 mL) and stirred for 30 minutes. Mass spectrometry indicated that the reaction was complete. The reaction solution was concentrated under reduced pressure, water (20 mL) was added, and the pH was adjusted to 7-8 with sodium bicarbonate solution. The solution was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to afford methyl 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoate 12a (0.5 g) in a yield of 96.22%.

[0389] MS m / z(ESI):372.0[M+1]

[0390] Step 2

[0391] tert-butyl

[0392] 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylate

[0393] tert-Butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylate

[0394] Methyl 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoate 12a (500 mg, 1.35 mmol) and tert-butyl 3-sulfanylazetidine-1-carboxylate 12b (509.88 mg, 2.69 mmol) were dissolved in 1,4-dioxane (2 mL). Tris(dibenzylideneacetone)dipalladium (123.34 mg, 134.69 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (77.94 mg, 134.69 μmol) and N,N-diisopropylethylamine (522.24 mg, 4.04 mmol) were added. The atmosphere was replaced with argon three times, the temperature was raised to 100°C, and the mixture was stirred for 18 hours. Mass spectrometry showed that the reaction was complete. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (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 tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylate 12c (464 mg) in a yield of 79.64%.

[0395] MS m / z(ESI):433.2[M+1]

[0396] Step 3

[0397] tert-butyl

[0398] 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate

[0399] tert-Butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate

[0400] Tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylate 12c (410 mg, 947.81 μmol) was dissolved in 1,4-dioxane (5 mL). A solution of potassium peroxymonosulfate (1.17 g, 1.90 mmol) in water (2.5 mL) was added. The mixture was stirred at room temperature for 18 hours. Mass spectrometry indicated the reaction was complete. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (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 tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate 12d (264 mg) in a yield of 59.96%.

[0401] MS m / z(ESI):465.2[M+1]

[0402] Step 4

[0403] 4-((1-(tert-butoxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0404] 4-((1-(tert-Butyloxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0405] Tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate 12d (264 mg, 568.26 μmol) was dissolved in tetrahydrofuran (2 mL) and methanol (2 mL), and a solution of lithium; hydroxide; hydrate (238.46 mg, 5.68 mmol) in water (2 mL) was added. The mixture was stirred at room temperature for 18 hours. Mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and water (15 mL) was added. The pH was adjusted to 3 with 2N hydrochloric acid solution and extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. 4-((1-(tert-Butyloxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 12e (242 mg) was obtained with a yield of 94.52%.

[0406] MS m / z(ESI):451.3[M+1]

[0407] Step 5

[0408] tert-butyl

[0409] 3-((4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate

[0410] tert-Butyl 3-((4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate

[0411] 3-(4,4-Difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-amine 7d (106.39 mg, 399.51 μmol) and 4-((1-(tert-butyloxycarbonyl)azetidin-3-yl)sulfonyl)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 12e (150 mg, 332.93 μmol) were dissolved in acetonitrile (2 mL). 1-Methylimidazole (54.67 mg, 665.86 μmol) and [chloro(dimethylamino)methylene]-dimethyl-ammonium;hexafluorophosphate (186.83 mg, 665.86 μmol) were added. The mixture was stirred at room temperature for 1 hour. Mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl 3-((4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate 12f (200 mg) in a yield of 85.96%.

[0412] MS m / z(ESI):699.4[M+1]

[0413] Step 6

[0414] 4-(azetidin-3-ylsulfonyl)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0415] 4-(azetidin-3-ylsulfonyl)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0416] Tert-butyl 3-((4-((3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)sulfonyl)azetidine-1-carboxylate 12f (200 mg, 286.20 μmol) was dissolved in methanol (5 mL), and hydrochloric acid (4 M, 715.49 μL) was added. The temperature was raised to 60°C and stirred for 5 hours. Mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-(azetidin-3-ylsulfonyl)-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 12 (147.9 mg) in a yield of 71.78%.

[0417] MS m / z(ESI):599.4[M+1]

[0418] 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.37(d,J=29.3Hz,1H),8.26(d,J=1.8Hz,1 H),7.88(d,J=7.9Hz,1H),7.66-7.58(m,3H),7.53(d,J=9.0Hz,1H),4.83(qd,J=8. 3,7.6,4.3Hz,1H),4.36-4.16(m,4H),3.86(s,3H),3.46(dd,J=7.0,4.4Hz,4H),3. 19-3.08(m,4H),2.16(tt,J=13.9,5.6Hz,4H),1.45(t,J=5.2Hz,4H),0.30(s,4H).

[0419] Example 13

[0420] N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0421] N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0422] first step

[0423] 3-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0424] 3-Bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0425] 3-Bromo-5-nitroindazole 7a (500 mg, 2.07 mmol) and 4-methylbenzenesulfonic acid (35.57 mg, 206.59 μmol) were dissolved in dichloromethane (10 mL). 3,4-Dihydro-2H-pyran (208.53 mg, 2.48 mmol) was added dropwise, and the mixture was stirred at room temperature for 4 hours. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was isolated and purified by silica gel column chromatography (eluent: System A) to give 3-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 13a (0.62 g) in a yield of 92.02%.

[0426] 1H NMR (400MHz, DMSO-d6) δ8.50(d,J=2.1Hz,1H),8.36(dd,J=9.3,2.2Hz,1H),8.05(d,J=9.3Hz,1H),6.00(dd,J=9.5,2.2Hz,1H), 3.93–3.74(m,2H),2.32(tdd,J=12.6,8.3,3.1Hz,1H),2.08–1.97(m,2H),1.80–1.70(m,1H),1.60(dq,J=9.4,5.1,4.3Hz,2H).

[0427] Step 2

[0428] 3-(4,4-difluoropiperidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0429] 3-(4,4-difluoropiperidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0430] 3-Bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 13a (300 mg, 919.83 μmol) and 4,4-difluoropiperidine (122.56 mg, 1.01 mmol) were dissolved in toluene (20 mL). Palladium acetate (20.65 mg, 91.98 μmol), R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (114.55 mg, 183.97 μmol), and sodium tert-butoxide (265.19 mg, 2.76 mmol) were added. The atmosphere was replaced with argon, the temperature was raised to 100°C, and the mixture was stirred for 18 hours. Mass spectrometry indicated the reaction was complete. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (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 3-(4,4-difluoropiperidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 13b (300 mg) in a yield of 89.02%.

[0431] MS m / z(ESI):367.1[M+1]

[0432] Step 3

[0433] 3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazole

[0434] 3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazole

[0435] 3-(4,4-difluoropiperidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 13b (300 mg, 818.86 μmol) was dissolved in methanol (10 mL). Hydrochloric acid (4 M, 818.86 μL) was added dropwise. The temperature was raised to 60°C and stirred for 6 hours. Mass spectrometry indicated the reaction was complete. The reaction solution was concentrated under reduced pressure, ethyl acetate (30 mL) was added, and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazole 13c (230 mg) in a yield of 99.52%.

[0436] MS m / z(ESI):283.1[M+1]

[0437] Step 4

[0438] 1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazole

[0439] 1-Cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazole

[0440] 3-(4,4-Difluoropiperidin-1-yl)-5-nitro-1H-indazole 13c (250 mg, 885.75 μmol) and cyclopropylboronic acid (152.17 mg, 1.77 mmol) were dissolved in 1,2-dichloroethane (5 mL). Anhydrous copper acetate (160.88 mg, 885.75 μmol), 2,2'-bipyridine (138.34 mg, 885.75 μmol) and sodium carbonate (281.64 mg, 2.66 mmol) were added. The temperature was raised to 80°C and stirred for 18 hours. Mass spectrometry showed that the reaction was complete. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 2). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-5-nitro1H-indazole 13d (160 mg) in a yield of 56.04%.

[0441] MS m / z(ESI):323.2[M+1]

[0442] Step 5

[0443] 1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-amine

[0444] 1-Cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-amine

[0445] 1-Cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazole 13d (160 mg, 496.42 μmol) was dissolved in ethanol (3 mL). A solution of ammonium chloride (185.88 mg, 3.47 mmol) in water (1 mL) was added, followed by zinc powder (162.30 mg, 2.48 mmol). The atmosphere was replaced with argon three times, and the temperature was raised to 80°C. The mixture was stirred for 2 hours, and mass spectrometry indicated the reaction was complete. The reaction mixture was filtered, concentrated under reduced pressure, and water (20 mL) was added. The pH was adjusted to 8-9 with saturated sodium bicarbonate. The mixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (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 1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-amine 13e (60 mg) in a yield of 41.35%.

[0446] MS m / z(ESI):293.2[M+1]

[0447] Step 6

[0448] N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0449] N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0450] 1-Cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-amine 13e (58.52 mg, 200.18 μmol) and 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (65 mg, 181.98 μmol) were dissolved in acetonitrile (5 mL). 1-Methylimidazole (45.37 mg, 545.93 μmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (153.18 mg, 545.93 μmol) were added. The mixture was stirred at room temperature for 1 hour. Mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 13f (100 mg) in a yield of 87.02%.

[0451] MS m / z(ESI):316.7[M / 2+1]

[0452] Step 7

[0453] N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0454] N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0455] N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 13f (100 mg, 158.35 μmol) and 2-hydroxyethane-1-sulfonamide 1 g (39.64 mg, 316.71 μmol) were dissolved in N,N-dimethylformamide (5 mL). 2-(Methylamino)acetic acid (14.11 mg, 158.35 μmol), tripotassium phosphate trihydrate (210.86 mg, 791.77 μmol) and cuprous iodide (15.08 mg, 79.18 μmol) were added. The atmosphere was replaced with argon, the temperature was raised to 110°C, and the mixture was stirred for 6 h. Mass spectrometry showed that the reaction was complete. The reaction solution was concentrated under reduced pressure and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(1-cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 13 (48.2 mg) in a yield of 47.40%.

[0456] MS m / z(ESI):629.3[M+1]

[0457] 1H NMR (400MHz, DMSO-d6) δ11.59(s,1H),10.07(s,1H),8.29(s,1H),7.84(d,J=8.4Hz,1H), 7.65(d,J=9.0Hz,1H),7.59(d,J=8.9Hz,1H),7.17(d,J=2.1Hz,1H),7.06–7.00(m,1H),4 .97(s,1H),3.76(t,J=6.6Hz,2H),3.47(m,5H),3.35(s,2H),2.99(t,J=5.3Hz,4H),2.16 (td,J=14.4,13.8,6.7Hz,4H),1.53(t,J=5.3Hz,4H),1.05(d,J=5.2Hz,4H),0.34(s,4H).

[0458] Example 14

[0459] N-(3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0460] N-(3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0461] first step

[0462] 3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

[0463] 3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine

[0464] To a solution of 3-(4,4-difluoropiperidin-1-yl)-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 13b (100 mg, 272.95 μmol) in ethanol (2 mL) and water (1 mL) were added zinc powder (35.70 mg, 545.91 μmol) and ammonium chloride (14.60 mg, 272.95 μmol) at room temperature. The mixture was stirred at 78°C for 1 hour. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (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 3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine 14a (60 mg) in a yield of 65.35%.

[0465] MS m / z(ESI):337.3[M+1]

[0466] Step 2

[0467] N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0468] N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0469] 2-(6-Azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (60 mg, 167.98 μmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (47.13 mg, 167.98 μmol) were added to a solution of N-methylimidazole (27.58 mg, 335.96 μmol) in N,N-dimethylformamide (0.5 mL) at room temperature. The mixture was stirred at room temperature for 30 min, and then 3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine 14a (56.50 mg, 167.98 μmol) was added. Stirring was continued for 16 h until the reaction was complete. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (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 N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14b (40 mg) in a yield of 35.25%.

[0470] MS m / z(ESI):676.5[M+1]

[0471] Step 3

[0472] N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0473] N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0474] N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14b (40 mg, 59.21 μmol) and ethanesulfonamide 8c (6.46 mg, 59.21 μmol) were added to cuprous iodide (5.64 mg, 29.61 μmol) at room temperature. Sarcosine (5.28 mg, 59.21 μmol) and potassium phosphate (62.84 mg, 296.06 μmol) in N,N-dimethylformamide (1 mL) were stirred at 100°C for 16 hours under a nitrogen atmosphere. After completion of the reaction, the reaction solution was poured into water and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14c (30 mg) in a yield of 77.14%.

[0475] MS m / z(ESI):657.7[M+1]

[0476] Step 4

[0477] N-(3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0478] N-(3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0479] N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14c (30 mg, 45.68 μmol) was added to a solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) at room temperature and stirred for 1 hour. The reaction was complete. 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% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 14 (2 mg) with a yield of 6.66%.

[0480] MS m / z(ESI):573.3[M+1]

[0481] Example 15

[0482] 4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0483] 4-((2-Hydroxyethyl)sulfonamido)-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0484] first step

[0485] 1-methyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine

[0486] 1-Methyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine

[0487] 3-Bromo-1-methyl-5-nitro-1H-indazole 7b (300 mg, 1.17 mmol) and 2,2,2-trifluoroethylamine 15a (232.11 mg, 2.34 mmol, commercially available) were dissolved in toluene (5 mL). Palladium acetate (26.30 mg, 117.16 μmol), R-(+)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine (145.91 mg, 234.32 μmol), and cesium carbonate (1.15 g, 3.51 mmol) were added. The atmosphere was replaced with argon three times, and the temperature was raised to 100°C. The mixture was stirred for 20 hours. Mass spectrometry indicated the reaction was complete. The reaction mixture was poured into water (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 1-methyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine 15b (235 mg) in a yield of 73.15%.

[0488] MS m / z(ESI):275.1[M+1]

[0489] Step 2

[0490] N,1-dimethyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine

[0491] N,1-Dimethyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine

[0492] 1-Methyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine 15b (215 mg, 784.10 μmol) was dissolved in N,N-dimethylformamide (10 mL), cooled to 0°C, and sodium hydride (62.72 mg, 1.57 mmol, 60% purity) was added. The mixture was stirred at 0°C for 30 minutes. Iodomethane (166.94 mg, 1.18 mmol) was added and stirred at 0°C for 1 hour. Mass spectrometry showed that the reaction was complete. The reaction solution was poured into water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give N,1-dimethyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine 15c (220 mg) in a yield of 97.35%.

[0493] MS m / z(ESI):289.1[M+1]

[0494] Step 3

[0495] N3,1-dimethyl-N3-(2,2,2-trifluoroethyl)-1H-indazole-3,5-diamine

[0496] N3,1-Dimethyl-N3-(2,2,2-trifluoroethyl)-1H-indazole-3,5-diamine

[0497] N,1-Dimethyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine 15c (120 mg, 416.34 μmol) was dissolved in methanol (10 mL). Palladium on carbon (10%) (4.43 mg, 41.63 μmol) was added and stirred at room temperature for 4 hours. Mass spectrometry indicated the reaction was complete. The mixture was filtered and concentrated under reduced pressure to afford N3,1-dimethyl-N3-(2,2,2-trifluoroethyl)-1H-indazole-3,5-diamine 15d (100 mg) in a 93.01% yield.

[0498] MS m / z(ESI):259.1[M+1]

[0499] Step 4

[0500] 4-iodo-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0501] 4-Iodo-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0502] N3,1-Dimethyl-N3-(2,2,2-trifluoroethyl)-1H-indazole-3,5-diamine 15d (99.41 mg, 384.95 μmol) and 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (125.00 mg, 349.96 μmol) were dissolved in acetonitrile (5 mL). 1-Methylimidazole (87.26 mg, 1.05 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (294.57 mg, 1.05 mmol) were added. The mixture was stirred at room temperature for 1 hour. Mass spectrometry showed that the reaction was complete. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: System A) to give 4-iodo-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 15e (160 mg) in a yield of 76.53%.

[0503] MS m / z(ESI):598.2[M+1]

[0504] Step 5

[0505] 4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0506] 4-((2-Hydroxyethyl)sulfonamido)-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0507] 4-Iodo-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 15e (160 mg, 267.82 μmol) and 2-hydroxyethane-1-sulfonamide 1 g (67.03 mg, 535.64 μmol) were dissolved in N,N-dimethylformamide (5 mL). Sarcosine (23.86 mg, 267.82 μmol), tripotassium phosphate trihydrate (356.62 mg, 1.34 mmol) and cuprous iodide (25.50 mg, 133.91 μmol) were added. The atmosphere was replaced with argon, the temperature was raised to 110°C, and the mixture was stirred for 6 hours. Mass spectrometry showed that the reaction was complete. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 15 (58.0 mg) in a yield of 36.27%.

[0508] MS m / z(ESI):595.3[M+1]

[0509] 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.08(s,1H),8.32(d,J=1.8Hz,1H),7.83(d,J= 8.5Hz,1H),7.69(dd,J=9.1,1.8Hz,1H),7.51(d,J=9.1Hz,1H),7.16(d,J=2.1Hz,1H), 7.02(dd,J=8.5,2.1Hz,1H),4.96(s,1H),4.25(q,J=9.6Hz,2H),3.83(s,3H),3.79 -3.72(m,2H),3.35-3.29(m,2H),3.19(s,3H),2.98(t,J=5.3Hz,4H),1.57-1.44(m 4H),0.33(s,4H).

[0510] Example 16

[0511] 4-(ethylsulfonamido)-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0512] 4-(Ethylsulfonamido)-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0513] 4-Iodo-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 15e (160 mg, 267.82 μmol) and ethanesulfonamide 8c (67.03 mg, 535.64 μmol) were dissolved in N,N-dichloromethane (5 mL). Sarcosine (23.86 mg, 267.82 μmol), tripotassium phosphate trihydrate (356.62 mg, 1.34 mmol) and cuprous iodide (25.50 mg, 133.91 μmol) were added. The atmosphere was replaced with argon, the temperature was raised to 110°C, and the mixture was stirred for 6 hours. Mass spectrometry showed that the reaction was complete. After the reaction was complete, the reaction solution was poured into water and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by preparative liquid chromatography (AKZONOBEL Kromasil column; 250 x 21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA + H2O, mobile phase B: CH3CN) to give 4-(ethylsulfonylamino)-N-(1-methyl-3-(methyl(2,2,2-trifluoroethyl)amino)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 16 (21 mg) in a yield of 13.56%.

[0514] MS m / z(ESI):579.3[M+1]

[0515] 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.10(s,1H),8.31(d,J=1.8Hz,1H),7.84(d,J= 8.5Hz,1H),7.69(dd,J=9.1,1.8Hz,1H),7.50(d,J=9.0Hz,1H),7.17(d,J=2.2Hz,1H),7 .03(dd,J=8.4,2.1Hz,1H),4.25(q,J=9.6Hz,2H),3.83(s,3H),3.23-319(m,3H),3.19- 3.12(m,2H),3.03-2.94(m,4H),1.59-1.46(m,4H),1.21(t,J=7.3Hz,3H),0.33(s,4H).

[0516] Example 17

[0517] 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)benzamide

[0518] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)benzamide

[0519] first step

[0520] 6-nitro-1-(2,2,2-trifluoroethyl)-1H-indazole

[0521] 6-Nitro-1-(2,2,2-trifluoroethyl)-1H-indazole

[0522] At room temperature, 6-nitro-1H-indazole 17a (500 mg, 3.06 mmol, commercially available) was added to N,N-dimethylformamide (10 mL). Cesium carbonate (2.00 g, 6.13 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate 1b (1.07 g, 4.60 mmol, commercially available) were added to the reaction mixture. The atmosphere was purged with nitrogen three times and the reaction was allowed to proceed at 25°C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with brine (30 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 6-nitro-1-(2,2,2-trifluoroethyl)-1H-indazole 17b (200 mg) in a yield of 26.62%.

[0523] MS m / z(ESI):246.0[M+1]

[0524] 1H NMR (400MHz, DMSO-d6) δ9.00 (s, 1H), 8.47 (d, J = 1.2Hz, 1H), 8.11-7.99 (m, 2H), 5.73-5.64 (m, 2H).

[0525] Step 2

[0526] 1-(2,2,2-trifluoroethyl)-1H-indazol-6-amine

[0527] 1-(2,2,2-Trifluoroethyl)-1H-indazol-6-amine

[0528] 6-Nitro-1-(2,2,2-trifluoroethyl)-1H-indazole 17b (200 mg, 0.816 mmol) was added to anhydrous methanol (5 mL) at room temperature, followed by palladium on carbon (10%) (43.4 mg, 0.408 mmol). The atmosphere was replaced with hydrogen three times, and the reaction was continued at 30°C for 2 hours. The reaction mixture was filtered, and the filter cake was washed with anhydrous methanol (5 mL x 3). The organic phase was collected and concentrated to dryness under reduced pressure to provide 1-(2,2,2-trifluoroethyl)-1H-indazol-6-amine 17c (170 mg) in a yield of 96.84%.

[0529] MS m / z(ESI):216.0[M+1]

[0530] Step 3

[0531] 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)benzamide

[0532] 4-((2-Hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)benzamide

[0533] At room temperature, 1-(2,2,2-trifluoroethyl)-1H-indazol-6-amine 17c (100 mg, 0.465 mmol) and 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 6i (164.71 mg, 0.465 mmol) were added to N,N-dimethylformamide (5 mL), followed by O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (353 mg, 0.929 mmol) and N,N-diisopropylethylamine (180 mg, 1.39 mmol). The atmosphere was replaced with nitrogen three times and the reaction was continued at 70°C for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)benzamide 17 (50 mg) in a yield of 19.51%.

[0534] MS m / z(ESI):552.2[M+1]

[0535] 1H NMR (400MHz, DMSO-d6) δ11.79(s,1H),10.13(s,1H),8.45(s,1H),8.13(d,J=1.2Hz,1H),7.88-7.79(m,2H),7.36-7.30(m,1H),7.21-7.17( m,1H),7.07-7.03(m,1H),5.43-5.34(m,2H),3.76(t,J=6.4Hz,2H),3.35-3.32(m,2H),3.04-2.96(m,4H),1.60-1.47(m,4H),0.34(s,4H).

[0536] Example 18

[0537] N-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0538] N-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0539] first step

[0540] 6-bromo-1-(4,4-difluorocyclohexyl)-1H-indazole

[0541] 6-Bromo-1-(4,4-difluorocyclohexyl)-1H-indazole

[0542] 6-Bromo-1H-indazole 18a (1.00 g, 5.08 mmol, commercially available) and 4,4-difluorocyclohexan-1-ol 18b (760 mg, 5.58 mmol, commercially available) were added to tetrahydrofuran (10 mL) at 0°C, followed by diisopropyl azodicarboxylate (1.54 g, 7.61 mmol) and triphenylphosphine (2.00 g, 7.61 mmol). The atmosphere was purged with nitrogen three times and the reaction was continued at 25°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 6-bromo-1-(4,4-difluorocyclohexyl)-1H-indazole 18c (500 mg) in a 31.26% yield.

[0543] MS m / z(ESI):315.0[M+1]

[0544] Step 2

[0545] tert-butyl(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)carbamate

[0546] tert-Butyl (1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)carbamate

[0547] At room temperature, 6-bromo-1-(4,4-difluorocyclohexyl)-1H-indazole 18c (300 mg, 0.952 mmol) and tert-butyl carbamate (123 mg, 1.05 mmol) were added to 1,4-dioxane (8 mL), followed by tris(dibenzylideneacetone)dipalladium (87.2 mg, 0.0952 mmol), cesium carbonate (930 mg, 2.86 mmol) and 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (68.1 mg, 0.143 mmol). The atmosphere was replaced with nitrogen three times and the reaction was carried out at 90 °C for 18 h. 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 (1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)carbamate 18d (330 mg) in a yield of 98.66%.

[0548] MS m / z(ESI):352.2[M+1]

[0549] Step 3

[0550] 1-(4,4-difluorocyclohexyl)-1H-indazol-6-amine

[0551] 1-(4,4-Difluorocyclohexyl)-1H-indazol-6-amine

[0552] Tert-butyl (1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)carbamate 18d (200 mg, 569.17 μmol) was added to dichloromethane (5 mL) at room temperature, followed by hydrochloric acid (4 M in 1,4-dioxane) (2.5 mL). The mixture was reacted at 25°C for 18 hours. The mixture was concentrated under reduced pressure to afford 1-(4,4-difluorocyclohexyl)-1H-indazol-6-amine 18e (140 mg) in a 97.89% yield.

[0553] MS m / z(ESI):252.0[M+1]

[0554] Step 4

[0555] 4-bromo-N-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0556] 4-Bromo-N-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0557] At room temperature, 1-(4,4-difluorocyclohexyl)-1H-indazol-6-amine 18e (180 mg, 716.35 μmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (244.42 mg, 787.98 μmol) were added to N,N-dimethylformamide (5 mL), followed by (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (746.98 mg, 1.43 mmol) and N,N-diisopropylethylamine (277.74 mg, 2.15 mmol). The atmosphere was purged with nitrogen three times and the reaction was continued at 70°C for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (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-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 18f (150 mg) in a yield of 38.53%.

[0558] MS m / z(ESI):543.2[M+1]

[0559] Step 5

[0560] N-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0561] N-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0562] At room temperature, 4-bromo-N-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 18f (100 mg, 184.01 μmol) and 2-hydroxyethane-1-sulfonamide 1 g (25.33 mg, 202.41 μmol) were added to N,N-dimethylformamide (5 mL). Subsequently, cuprous iodide (35.04 mg, 184.01 μmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (2.62 mg, 18.40 μmol), and potassium phosphate (78.12 mg, 368.02 μmol) were added. The atmosphere was purged with nitrogen three times and the reaction was continued at 90°C for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 18 (30 mg) in a yield of 27.74%.

[0563] MS m / z(ESI):588.2[M+1]

[0564] 1H NMR (400MHz, DMSO-d6) δ11.76(s,1H),8.49(s,1H),8.01(s,1H),7.85(d,J=8.4 Hz,1H),7.76(d,J=8.4Hz,1H),7.20–7.13(m,2H),7.06–7.01(m,1H),4.85–4.73 (m,1H),3.76(t,J=6.4Hz,2H),3.35–3.33(m,2H),3.04–2.94(m,4H),2.25–2.2 0(m,2H),2.19–2.11(m,4H),2.06–1.99(m,2H),1.61–1.48(m,4H),0.35(s,4H).

[0565] Example 19 was synthesized according to the synthesis method of Example 18 of the present invention. The spectrum parameters of Example 19 are shown in the following table:

[0566] Example 20

[0567] N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0568] N-(3-(Difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0569] first step

[0570] 5-bromo-3-(difluoromethyl)-1H-indazole

[0571] 5-Bromo-3-(difluoromethyl)-1H-indazole

[0572] Diethylaminosulfur trifluoride (1.97 g, 12.22 mmol) was added dropwise to a solution of 5-bromo-1H-indazole-3-carbaldehyde 20a (1.1 g, 4.89 mmol) in dichloromethane (20 mL) under ice-cooling and stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated aqueous sodium carbonate (20 mL) and extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 5-bromo-3-(difluoromethyl)-1H-indazole 20b (0.8 g) in a 66% yield.

[0573] MS m / z(ESI):249.0[M+1]

[0574] Step 2

[0575] 5-bromo-3-(difluoromethyl)-1-methyl-1H-indazole

[0576] 5-Bromo-3-(difluoromethyl)-1-methyl-1H-indazole

[0577] Under ice-cooling, sodium hydride (259.07 mg, 6.48 mmol, 60% purity) was added to a solution of 5-bromo-3-(difluoromethyl)-1H-indazole 20b (0.8 g, 3.24 mmol) in N,N-dimethylformamide (20 mL). The mixture was stirred under ice-cooling for 30 minutes, followed by the addition of iodomethane (919.29 mg, 6.48 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 5-bromo-3-(difluoromethyl)-1-methyl-1H-indazole 20c (632 mg) in a 75% yield.

[0578] MS m / z(ESI):263.0[M+1]

[0579] Step 3

[0580] tert-butyl(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)carbamate

[0581] tert-Butyl (3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)carbamate

[0582] 5-Bromo-3-(difluoromethyl)-1-methyl-1H-indazole 20c (158 mg, 605.21 μmol), tert-butyl carbamate (158 mg, 605.21 μmol), cuprous iodide (57.63 mg, 302.61 μmol), potassium phosphate trihydrate (483.52 mg, 1.82 mmol) and racemic-(1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (86.09 mg, 605.21 μmol) were added to N,N-dimethylformamide (3 mL) at room temperature, and the atmosphere was replaced with nitrogen three times. The reaction was carried out at 100 °C for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)carbamate 20d (110 mg) in a yield of 61%.

[0583] MS m / z(ESI):298.2[M+1]

[0584] Step 4

[0585] 3-(difluoromethyl)-1-methyl-1H-indazol-5-amine

[0586] 3-(Difluoromethyl)-1-methyl-1H-indazol-5-amine

[0587] Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)carbamate 20d (110 mg, 370.00 μmol) in dichloromethane (3 mL) at room temperature and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (5 mL). Saturated aqueous sodium carbonate (5 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 3-(difluoromethyl)-1-methyl-1H-indazol-5-amine 20e (55 mg) in a 75% yield.

[0588] MS m / z(ESI):198.2[M+1]

[0589] Step 5

[0590] N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0591] N-(3-(Difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0592] At room temperature, 3-(difluoromethyl)-1-methyl1H-indazol-5-amine 20e (48.58 mg, 246.37 μmol), 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid 8a (80 mg, 223.97 μmol), and 1-methylimidazole (55.84 mg, 671.92 μmol) were added to N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 10 minutes, followed by the addition of N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (188.53 mg, 671.92 μmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 20f (110 mg) in a 36% yield.

[0593] MS m / z(ESI):537.1[M+1]

[0594] Step 6

[0595] N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0596] N-(3-(Difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0597] At room temperature, N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 20f (40 mg, 74.58 μmol), 2-hydroxyethane-1-sulfonamide 1 g (10.27 mg, 82.04 μmol), 2-(methylamino)acetic acid (9.97 mg, 111.87 μmol), cuprous iodide (4.26 mg, 22.37 μmol) and potassium phosphate trihydrate (99.30 mg, 372.89 μmol) were added to N,N-dimethylformamide (2 mL) solution, the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 90 ° C for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 20 (6 mg) in a yield of 14.82%.

[0598] MS m / z(ESI):534.2[M+1]

[0599] 1H NMR (400MHz, DMSO-d6) δ11.30(s,1H),9.87(s,1H),8.34(s,1H),7.58(dd,J=11.4,8.7Hz,2H),7.45–7.33(m,1H),7.25–6.92(m,2H),6.81( dd,J=8.4,2.0Hz,1H),3.86(s,3H),3.53(t,J=6.6Hz,2H),3.11(t,J=6.5Hz,2H),2.85-2.72(m,4H),2.31-2.22(m,5H),1.37-1.22(m,4H).

[0600] Example 21

[0601] N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0602] N-(3-(Difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0603] At room temperature, N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 20f (40 mg, 74.58 μmol), ethanesulfonamide 8c (8.95 mg, 82.04 μmol), 2-(methylamino)acetic acid (9.97 mg, 111.87 μmol), cuprous iodide (4.26 mg, 22.37 μmol) and potassium phosphate trihydrate (99.30 mg, 372.89 μmol) were added to N,N-dimethylformamide (2 mL), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 90 °C for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 21 (13 mg) in a yield of 31.0%.

[0604] MS m / z(ESI):518.2[M+1]

[0605] 1H NMR (400MHz, DMSO-d6) δ11.54(s,1H),10.15(s,1H),8.58(s,1H),7.81(t,J=8.4Hz,2H),7.62(dd,J=9.1,1.9Hz,1H),7.48–7.15(m,2H),7.0 5(dd,J=8.5,2.0Hz,1H),4.10(s,3H),3.20(q,J=7.3Hz,2H),3.08-2.91(m,4H),1.61-1.45(m,4H),1.22(t,J=7.3Hz,3H),0.37-0.29(m,4H).

[0606] Example 22

[0607] N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0608] N-(3-((3,3-Difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0609] first step

[0610] 1-methyl-5-nitro-1H-indazole-3-carbaldehyde

[0611] 1-Methyl-5-nitro-1H-indazole-3-carbaldehyde

[0612] To a solution of 5-nitro-1H-indazole-3-carbaldehyde 22a (2.0 g, 10.46 mmol) and iodomethane (1.49 g, 10.46 mmol) in N,N-dimethylformamide (1 mL) was added potassium carbonate (2.17 g, 15.70 mmol). The mixture was stirred at room temperature for 2 h. The reaction was completed under mass spectrometry. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-methyl-5-nitro-1H-indazole-3-carbaldehyde 22b (2.12 g) in a yield of 98.8%.

[0613] MS m / z(ESI):206.1[M+1]

[0614] Step 2

[0615] 3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-5-nitro-1H-indazole

[0616] 3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-5-nitro-1H-indazole

[0617] To a solution of 3,3-difluoroazetidine (226.82 mg, 2.44 mmol) in methanol (1 mL) were added 1-methyl-5-nitro-1H-indazole-3-carbaldehyde 22b (500 mg, 2.44 mmol) and acetic acid (14.63 mg, 243.70 μmol). After stirring at room temperature for 30 minutes, sodium cyanoborohydride (153.14 mg, 2.44 mmol) was added and the mixture was stirred at room temperature for 1 hour. The reaction was completed by mass spectrometry monitoring. The reaction mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to obtain 3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-5-nitro-1H-indazole 22c (500 mg) in a yield of 72.69%. MS m / z (ESI): 283.2 [M+1].

[0618] Step 3

[0619] 3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine

[0620] 3-((3,3-Difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine

[0621] 3-((3,3-Difluoroazetidin-1-yl)methyl)-1-methyl-5-nitro-1H-indazole 22c (400 mg, 1.42 mmol) and zinc powder (92.67 mg, 1.42 mmol) were added to a solution of ammonium chloride (75.81 mg, 1.42 mmol) in ethanol (3 mL) and water (1 mL) at room temperature. The mixture was stirred at 80°C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used directly in the next reaction to afford 3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine 22d (220 mg) in a yield of 61.54%.

[0622] MS m / z(ESI):253.1[M+1]

[0623] Step 4

[0624] N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0625] N-(3-((3,3-Difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0626] At room temperature, 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (300 mg, 839.90 μmol) and 3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine 22d (65.59 mg, 279.97 μmol) were added to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161.01 mg, 839.90 μmol) and 1-hydroxybenzotriazole (113.49 mg, 839.90 μmol) in N,N-dimethylformamide (4 mL). The mixture was stirred at room temperature for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (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 N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22e (202 mg) in a yield of 40.66%.

[0627] MS m / z(ESI):592.2[M+1]

[0628] Step 5

[0629] N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0630] N-(3-((3,3-Difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0631] At room temperature, N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22e (200.00 mg, 338.16 μmol) and 2-hydroxyethane-1-sulfonamide 1 g (84.64 mg, 676.32 μmol) were added to 2-(methylamino)acetic acid (30.13 mg, 338.16 μmol), and iodinated. Cuprous (64.40 mg, 338.16 μmol) and potassium phosphate (71.78 mg, 338.16 μmol) in N,N-dimethylformamide (3 mL) solvent were replaced with nitrogen three times and stirred at 100 ° C for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 22 (80 mg), yield: 31.02%.

[0632] MS m / z(ESI):589.1[M+1]

[0633] 1H NMR (400MHz, DMSO-d6) δ11.50(s,1H),10.08(s,1H),8.62(s,1H),7.82(d,J=8.5Hz, 1H),7.74(d,J=9.0Hz,1H),7.52(d,J=9.1Hz,1H),7.17(d,J=2.1Hz,1H),7.04(dd,J= 8.5,2.1Hz,1H),4.78(s,3H),4.58(s,4H),4.06(s,3H),3.77(t,J=6.6Hz,2H),3.34(t,J=6.6Hz,2H),3.00(m,4H),1.52(s,4H),0.34(s,4H).

[0634] Example 23

[0635] N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0636] N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0637] first step

[0638] 5-bromo-3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazole

[0639] 5-Bromo-3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazole

[0640] 5-Bromo-1-methyl-indazole-3-carbaldehyde 23a (100 mg, 418.29 μmol) and 4,4-difluoropiperidine (101.33 mg, 836.58 μmol) were added to a solution of acetic acid (2.51 mg, 41.83 μmol) in methanol (0.5 mL) at room temperature. The mixture was stirred at room temperature for 30 minutes, followed by the addition of sodium cyanoborohydride (105.14 mg, 1.67 mmol). Stirring was continued for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (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 5-bromo-3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazole 23b (120 mg) in an 83.35% yield.

[0641] MS m / z(ESI):346.0[M+1]

[0642] Step 2

[0643] tert-butyl(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)carbamate

[0644] tert-Butyl (3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)carbamate

[0645] To a solution of trisdibenzylideneacetone dipalladium (31.93 mg, 34.86 μmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (20.17 mg, 34.86 μmol) and sodium tert-butoxide (67.01 mg, 697.27 μmol) in toluene (1 mL) was added 5-bromo-3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazole 23b (120 mg, 348.64 μmol) and tert-butyl carbamate (81.68 mg, 697.27 μmol) at room temperature. The mixture was stirred at 100°C for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Tert-butyl (3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)carbamate 23c (100 mg) was obtained and the crude product was used directly in the next reaction.

[0646] MS m / z(ESI):381.1[M+1]

[0647] Step 3

[0648] 3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine

[0649] 3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine

[0650] A mixture of tert-butyl (3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)carbamate 23c (100 mg, 262.86 μmol) and trifluoroacetic acid (1 mL) was stirred at room temperature for 1 hour. The reaction was monitored for completion by mass spectrometry. The organic phase was concentrated under reduced pressure to afford 3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine 23d (39.24 mg), which was used directly in the next step.

[0651] MS m / z(ESI):281.1[M+1]

[0652] Step 4

[0653] N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0654] N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0655] To a solution of 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (50 mg, 139.98 μmol) and 3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine 23d (39.24 mg, 139.98 μmol) in N,N-dimethylformamide (1 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.67 mg, 279.97 μmol) and 1-hydroxybenzotriazole (37.83 mg, 279.97 μmol) at room temperature. The mixture was stirred at room temperature for 4 h. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to afford N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 23e (70 mg) in 80.72% yield. MS m / z (ESI): 620.1 [M+1].

[0656] Step 5

[0657] N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0658] N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0659] At room temperature, N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 23e (70 mg, 113.00 μmol) and 2-hydroxyethane-1-sulfonamide 1 g (42.42 mg, 338.99 μmol) were added to 2-(methylamino)acetic acid (20.13 mg, 225.99 μmol), cuprous iodide (43. 04 mg, 225.99 μmol) and potassium phosphate (47.97 mg, 225.99 μmol) in N, N-dimethylformamide (1 mL), replaced with nitrogen three times, stirred at 100 ° C for 16 hours, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (30 mL × 3), the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250×21.2mm ID; 5μm, 20mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 23 (5 mg), yield: 7.17%.

[0660] MS m / z(ESI):618.1[M+1]

[0661] 1H NMR (400MHz, DMSO-d6) δ11.57(s,1H),10.11(s,1H),8.68(s,1H),7.81(dd,J=18 .4,8.7Hz,2H),7.51(dd,J=9.0,1.9Hz,1H),7.20–7.12(m,1H),7.08–6.98(m,1H) ,4.78(s,2H),4.11(s,3H),3.77(s,2H),3.75(s,2H),3.34(t,J=6.6Hz,4H),3.0 0(t,J=5.2Hz,4H),2.32(s,4H),1.52(t,J=5.2Hz,4H),1.24(s,1H),0.35(s,4H).

[0662] Example 24

[0663] N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0664] N-(3-((3,3-Difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0665] To a solution of 2-(methylamino)acetic acid (30.13 mg, 338.16 μmol), cuprous iodide (64.40 mg, 338.16 μmol) and potassium phosphate (71.78 mg, 338.16 μmol) in N,N-dimethylformamide (1 mL) was added N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide 22e (100 mg, 169.08 μmol) and ethanesulfonamide 8c (36.91 mg, 338.16 μmol) at room temperature. The atmosphere was replaced with nitrogen three times and the mixture was stirred at 100°C for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 24 (5.0 mg) in a yield of 3.96%.

[0666] MS m / z(ESI):573.2[M+1]

[0667] Examples 25-27 were synthesized according to the synthesis method of Examples 22-24 of the present invention. The spectrum parameters of Examples 25-27 are shown in the following table:

[0668] Example 28

[0669] N-(3-(((2,2-difluoroethyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0670] N-(3-(((2,2-difluoroethyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0671] first step

[0672] 2,2-difluoro-N-((1-methyl-5-nitro-1H-indazol-3-yl)methyl)ethan-1-amine

[0673] 2,2-Difluoro-N-((1-methyl-5-nitro-1H-indazol-3-yl)methyl)ethan-1-amine

[0674] At room temperature, 2,2-difluoroethylamine (79.02 mg, 974.8 μmol) and 1-methyl-5-nitro-1H-indazole-3-carbaldehyde 22b (200 mg, 974.8 μmol) were added to a solution of acetic acid (5.85 mg, 97.48 μmol) in methanol (2 mL). The mixture was stirred for 30 minutes, followed by the addition of sodium cyanoborohydride (61.26 mg, 974.8 μmol). Stirring was continued for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to afford 2,2-difluoro-N-((1-methyl-5-nitro-1H-indazol-3-yl)methyl)ethan-1-amine 28a (240 mg) in a yield of 91.116%.

[0675] MS m / z(ESI):271.2[M+1]

[0676] Step 2

[0677] tert-butyl(2,2-difluoroethyl)((1-methyl-5-nitro-1H-indazol-3-yl)methyl)carbamate

[0678] tert-Butyl (2,2-difluoroethyl)((1-methyl-5-nitro-1H-indazol-3-yl)methyl)carbamate

[0679] 2,2-Difluoro-N-((1-methyl-5-nitro-1H-indazol-3-yl)methyl)ethan-1-amine 28a (200 mg, 740.10 μmol) and di-tert-butyl dicarbonate (161.53 mg, 740.10 μmol) were added to a solution of 4-dimethylaminopyridine (9.04 mg, 74.01 μmol) in dichloromethane (3 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (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 tert-butyl (2,2-difluoroethyl)((1-methyl-5-nitro-1H-indazol-3-yl)methyl)carbamate 28b (170 mg) in a yield of 62.02%.

[0680] MS m / z(ESI):371.3[M+1]

[0681] Step 3

[0682] tert-butyl((5-amino-1-methyl-1H-indazol-3-yl)methyl)(2,2-difluoroethyl)carbamate

[0683] tert-Butyl (5-amino-1-methyl-1H-indazol-3-yl)methyl)(2,2-difluoroethyl)carbamate

[0684] At room temperature, tert-butyl (2,2-difluoroethyl)((1-methyl-5-nitro-1H-indazol-3-yl)methyl)carbamate 28b (170 mg, 459.02 μmol) and iron powder (51.27 mg, 918.05 μmol) were added to a mixture of ammonium chloride (49.11 mg, 918.05 μmol) in ethanol (2 mL) and water (1 mL). The mixture was stirred at 75°C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (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 tert-butyl (5-amino-1-methyl-1H-indazol-3-yl)methyl)(2,2-difluoroethyl)carbamate 28c (100 mg) in a yield of 64.01%.

[0685] MS m / z(ESI):341.3[M+1]

[0686] Step 4

[0687] tert-butyl

[0688] (2,2-difluoroethyl)((5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate

[0689] tert-Butyl (2,2-difluoroethyl)((5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate

[0690] At room temperature, 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (100 mg, 279.97 μmol) and tert-butyl (5-amino-1-methyl-1H-indazol-3-yl)methyl)(2,2-difluoroethyl)carbamate 28c (95.29 mg, 279.97 μmol) were added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (107.34 mg, 559.93 μmol) and 1-hydroxybenzotriazole (75.66 mg, 559.93 μmol) in N,N-dimethylformamide (1 mL). The reaction solution was added dropwise to ice water, and a solid precipitated. The filter cake was collected to obtain tert-butyl (2,2-difluoroethyl)((5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate 28d (170 mg). The crude product was used directly in the next reaction. MS m / z (ESI): 680.1 [M+1]

[0691] Step 5

[0692] tert-butyl

[0693] (2,2-difluoroethyl)((5-(4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate

[0694] tert-Butyl (2,2-difluoroethyl)((5-(4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate

[0695] To a solution of sarcosine (22.29 mg, 250.17 μmol), cuprous iodide (23.82 mg, 125.09 μmol), and potassium phosphate (265.52 mg, 1.25 mmol) in N,N-dimethylformamide (1 mL) was added tert-butyl (2,2-difluoroethyl)((5-(4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate 28d (170 mg, 250.17 μmol) and ethanesulfonamide 8c (54.61 mg, 500.34 μmol) at room temperature. The atmosphere was replaced with nitrogen three times and stirred at 100°C for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (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 tert-butyl (2,2-difluoroethyl)((5-(4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate 28e (108 mg) in a yield of 65.33%.

[0696] MS m / z(ESI):661.0[M+1]

[0697] Step 6

[0698] N-(3-(((2,2-difluoroethyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0699] N-(3-(((2,2-difluoroethyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0700] To a solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) was added tert-butyl (2,2-difluoroethyl)((5-(4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamido)-1-methyl-1H-indazol-3-yl)methyl)carbamate 28e (108 mg, 163.44 μmol) at room temperature. The mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to give N-(3-(((2,2-difluoroethyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 28 (30 mg) in a yield of 32.38%.

[0701] MS m / z(ESI):560.9[M+1]

[0702] 1H NMR (400MHz, DMSO-d6) δ11.52(s,1H),10.13(s,1H),8.41(d,J=1.8Hz,1H),7.84(d,J=8.4Hz,1H),7.66–7.50(m,2H),7.18(d,J=2.1Hz,1H),7.04(d d,J=8.5,2.1Hz,1H),4.05(d,J=6.3Hz,2H),3.99(s,3H),3.20(q,J=7.3Hz ,2H),3.03–2.88(m,7H),1.53(s,4H),1.21(t,J=7.4Hz,3H),0.34(s,4H).

[0703] Example 29

[0704] N-(3-(((2,2-difluoroethyl)(methyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0705] N-(3-(((2,2-difluoroethyl)(methyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0706] At room temperature, N-(3-(((2,2-difluoroethyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 28 (15 mg, 26.75 μmol) was added to a solution of paraformaldehyde (2.41 mg, 80.26 μmol) in methanol (0.5 mL) and stirred at room temperature for 2 hours. The reaction solution was poured into water and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5μm, 20mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN), to obtain N-(3-(((2,2-difluoroethyl)(methyl)amino)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 29 (12 mg), yield: 76.98%.

[0707] MS m / z(ESI):575.3[M+1]

[0708] 1H NMR (400MHz, DMSO-d6) δ11.63(s,1H),8.29(d,J=1.9Hz,1H),7.85(d,J=8.5Hz,1H),7.71(dd,J= 9.1,1.9Hz,1H),7.62(d,J=9.0Hz,1H),7.18(d,J=2.2Hz,1H),7.03(dd,J=8.4,2.1Hz,1H),6.21( dt,J=55.9,4.3Hz,1H),4.00(s,3H),3.92(s,2H),3.18(q,J=7.2Hz,2H),2.99(t,J=5.3Hz,4H), 2.85(d,J=15.4,4.3Hz,2H),2.32(s,3H),1.53(t,J=6.0Hz,3H),1.25–1.18(m,4H),0.34(s,4H).

[0709] Examples 30-34 were synthesized according to the synthesis method of Example 7 of the present invention. The spectrum parameters of Examples 30-34 are shown in the following table:

[0710] Example 35 & Example 36

[0711] (S)-N-(3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0712] (S)-N-(3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0713] (R)-N-(3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0714] (R)-N-(3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0715] first step

[0716] 1-(1-methyl-5-nitro-1H-indazol-3-yl)ethan-1-one

[0717] 1-(1-Methyl-5-nitro-1H-indazol-3-yl)ethan-1-one

[0718] To a solution of 1-(1-methyl-1H-indazol-3-yl)ethan-1-one 35a (1 g, 5.74 mmol, commercially available) in trifluoroacetic acid (9 mL) was added nitric acid (1.04 g, 16.53 mmol), and the resulting mixture was stirred at 25°C for 5 hours. The reaction mixture was added to water (50 mL), and the pH was adjusted to 7 with saturated sodium bicarbonate solution. 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 under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford 1-(1-methyl-5-nitro-1H-indazol-3-yl)ethan-1-one 35b (667 mg) in a 55.0% yield.

[0719] MS m / z(ESI):220.0[M+1]

[0720] Step 2

[0721] 3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-5-nitro-1H-indazole

[0722] 3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-5-nitro-1H-indazole

[0723] To a solution of 1-(1-methyl-5-nitro-1H-indazol-3-yl)ethan-1-one 35b (550 mg, 2.51 mmol), 3,3-difluorotrimethyleneimine hydrochloride (1.25 g, 7.53 mmol) and acetic acid (30 mg, 0.502 mmol) in methanol (12 mL) was added sodium cyanoborohydride (473 mg, 7.53 mmol), and the resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was concentrated, and the crude product was purified by silica gel column chromatography (eluent: System A) to give 3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-5-nitro-1H-indazole 35c (530 mg) in a yield of 71.1%.

[0724] MS m / z(ESI):297.0[M+1]

[0725] Step 3

[0726] 3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-amine

[0727] 3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-amine

[0728] To a suspension of 3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-5-nitro-1H-indazole 35c (530 mg, 1.79 mmol) in methanol (10 mL) was added palladium on carbon (57 mg, 0.054 mmol, 10% purity), replaced with hydrogen three times, and stirred under a hydrogen atmosphere (15 psi) at 25 ° C. for 16 hours. After filtration, the mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: System A) to give 3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-amine 35d (476 mg) in a yield of 99%.

[0729] MS m / z(ESI):267.0[M+1]

[0730] Step 4

[0731] 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0732] 4-(Ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid

[0733] 2-(6-Azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid 8a (1.0 g, 2.80 mmol) and ethanesulfonamide 8c (458.36 mg, 4.20 mmol) were dissolved in DMF (10 mL). 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, and the temperature was raised to 110°C and stirred for 6 hours. The reaction mixture was cooled to room temperature and poured into ice water (200 mL). The pH was adjusted to 6 with dilute hydrochloric acid (2 M). Dichloromethane was added for extraction (200 mL × 3), and the organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to give 4-(ethylsulfonyl)-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid 35e (0.75 g) in a yield of 79.16%.

[0734] MS m / z(ESI):339.4[M+1]

[0735] Step 5

[0736] (S)-N-(3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0737] (S)-N-(3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0738] (R)-N-(3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0739] (R)-N-(3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0740] To a solution of 3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-amine 35d (476 mg, 1.79 mmol), 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (696 mg, 2.06 mmol), and N,N-diisopropylethylamine (693 mg, 5.36 mmol) in N,N-dimethylformamide (10 mL) was added (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (1.40 g, 2.68 mmol), and the resulting mixture was stirred at 60° C. for 16 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (60 mL×2). The combined organic phases were washed with a saturated sodium chloride solution (50 mL) and dried over anhydrous sodium sulfate. The crude product was separated by preparative liquid chromatography (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give N-(3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (500 mg) in a yield of 47%. The product was purified by SFC (Column: Chiralpak AD-3 50 ID,3um Mobile phase:A:CO2B:Methanol(0.05%DEA)Gradient:from 5%to 40% of B in 4min and from 40%to 5%of B in 0.2min,then hold 5% of B for1.8minFlow rate:3mL / minColumn temp.:35 1500 psi) to obtain a single configuration compound (shorter retention time) and a single configuration compound (longer retention time).

[0741] Single configuration compound (shorter retention time):

[0742] 157 mg; retention time: 2.50 minutes, chiral purity: 100% ee.

[0743] MS m / z(ESI):587.2[M+1]

[0744] 1H NMR (400MHz, DMSO-d6) δ11.70(s,1H),10.15(s,1H),8.40(s,1H),7.86(d,J=8.4Hz,1H),7.73( dd,J=8.8,1.7Hz,1H),7.62(d,J=8.8Hz,1H),7.19(d,J=2.0Hz,1H),7.05(dd,J=8.4,1.9Hz,1H ),3.98(s,3H),3.96(d,J=6.8Hz,1H),3.68-3.56(m,2H),3.54-3.42(m,2H),3.20(q,J=7.2Hz, 2H),3.04-294(m,4H),1.55(s,4H),1.38(d,J=6.4Hz,3H),1.21(t,J=7.2Hz,3H),0.34(s,4H).

[0745] Single configuration compound (longer retention time):

[0746] 149 mg; retention time: 2.676 minutes, chiral purity: 98.4% ee.

[0747] MS m / z(ESI):587.4[M+1]

[0748] 1H NMR (400MHz, DMSO-d6) δ11.70(s,1H),10.16(s,1H),8.41(s,1H),7.86(d,J=8.8Hz,1H ),7.76–7.68(m,1H),7.62(d,J=8.8Hz,1H),7.19(d,J=2.0Hz,1H),7.05(dd,J=8.4,2.0 Hz,1H),3.98(s,3H),3.96-3.91(m,1H),3.70-3.56(dd,J=22.4,11.6Hz,2H),3.54-3.42(dd,J=22.1,11.3Hz,2H),3.2 0(q,J=7.2Hz,2H),3.04-2.92(t,J=5.0Hz,4H),1.55(s,4H),1.38(d,J=6.4Hz,3H),1.21(t,J=7.2Hz,3H),0.34(s,4H).

[0749] Example 37 was synthesized according to the synthesis method of Examples 35-36 of the present invention. The spectrum parameters of Example 37 are shown in the following table:

[0750] Example 38

[0751] 4-(ethylsulfonamido)-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0752] 4-(Ethylsulfonamido)-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0753] first step

[0754] 1-methyl-5-nitro-1,2-dihydro-3H-indazol-3-one

[0755] 1-Methyl-5-nitro-1,2-dihydro-3H-indazol-3-one

[0756] Methylhydrazine sulfate (2.17 g, 15.1 mmol) and triethylamine (3.05 g, 30.1 mmol) were added to a solution of methyl 2-fluoro-5-nitrobenzoate 38a (2 g, 10 mmol) in ethanol (40 mL) at room temperature. The reaction mixture was allowed to react at 80°C for 16 hours. The reaction mixture was poured into water and extracted three times with ethyl acetate (150 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was slurried with a mixture of ethyl acetate and methanol, filtered, and the filter cake was washed three times with ethyl acetate (10 mL). This afforded 1-methyl-5-nitro-1,2-dihydro-3H-indazol-3-one 38b (1.8 g) in a 93% yield.

[0757] MS m / z(ESI):194.0[M+1]

[0758] 1H NMR (400MHz, DMSO-d6) δ11.39(s,1H),8.66(d,J=2.0Hz,1H),8.40–7.94(m,1H),7.62(d,J=9.2Hz,1H),3.88(s,3H).

[0759] Step 2

[0760] 1-methyl-5-nitro-3-(2,2,2-trifluoroethoxy)-1H-indazole

[0761] 1-Methyl-5-nitro-3-(2,2,2-trifluoroethoxy)-1H-indazole

[0762] Potassium carbonate (286 mg, 2.07 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate 1b (360 mg, 1.55 mmol) were added to a solution of 1-methyl-5-nitro-1,2-dihydro-3H-indazol-3-one 38b (200 mg, 1.04 mmol) in dimethyl sulfoxide (5 mL) at room temperature. The reaction mixture was allowed to react at 80°C for 16 hours. The reaction mixture was poured into water and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated sodium chloride solution (30 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 1-methyl-5-nitro-3-(2,2,2-trifluoroethoxy)-1H-indazole 38c (270 mg) in a 95% yield.

[0763] MS m / z(ESI):276.0[M+1]

[0764] 1H NMR (400MHz, DMSO-d6) δ8.50(d,J=1.6Hz,1H),8.30–8.16(m,1H),7.74(d,J=9.6Hz,1H),5.25–4.80(m,2H),3.97(s,3H).

[0765] Step 3

[0766] 1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-amine

[0767] 1-Methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-amine

[0768] Palladium on carbon (50.00 mg, 10%) was added to a solution of 1-methyl-5-nitro-3-(2,2,2-trifluoroethoxy)-1H-indazole 38c (370 mg, 1.34 mmol) in methanol (20 mL) at room temperature. The atmosphere was replaced three times with a hydrogen balloon, and the mixture was allowed to react at room temperature for 2 hours. The reaction mixture was filtered, the filter cake rinsed with methanol (100 mL), and the filtrate concentrated under reduced pressure. This afforded 1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-amine 38d (300 mg) in a 91% yield. The crude product was used directly in the next step.

[0769] MS m / z(ESI):246.0[M+1]

[0770] Step 4

[0771] 4-bromo-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0772] 4-Bromo-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0773] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (465 mg, 1.22 mmol) and N,N-diisopropylethylamine (211 mg, 1.63 mmol) were added to a solution of 1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-amine 38d (200 mg, 0.82 mmol) and 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (329 mg, 1.06 mmol) in N,N-dimethylformamide (5 mL) at room temperature. The reaction mixture was reacted at 60°C for 16 hours. The reaction solution was poured into water and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated sodium chloride solution (30 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-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 38e (300 mg) in a yield of 68%.

[0774] MS m / z(ESI):537.2[M+1]

[0775] Step 5

[0776] 4-(ethylsulfonamido)-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0777] 4-(Ethylsulfonamido)-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0778] To a solution of 4-bromo-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 38e (80 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) was added ethanesulfonamide 8c (24.4 mg, 0.22 mmol), cuprous iodide (28.4 mg, 0.15 mmol), potassium phosphate (63.2 mg, 0.3 mmol), and (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10.6 mg, 0.07 mmol) at room temperature. The atmosphere was replaced with nitrogen three times, and the reaction was continued at 100°C for 16 h. The reaction solution was poured into water and extracted three times with ethyl acetate (50 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-(ethylsulfonyl)-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 38 (19.7 mg) in a yield of 23%.

[0779] MS m / z(ESI):566.2[M+1]

[0780] 1H NMR (400MHz, DMSO-d6) δ11.43(s,1H),10.12(s,1H),8.32(s,1H),7.79(d,J=8.4Hz,1H),7.59(d,J=9.2Hz,1H),7.54(d,J=8.8Hz,1H),7.16(s ,1H),7.03(d,J=8.4Hz,1H),5.10–4.91(m,2H),3.88(s,3H),3.25–3.1 3(m,2H),2.98(s,4H),1.50(s,4H),1.22(t,J=7.2Hz,3H),0.33(s,4H).

[0781] Example 39

[0782] N-(3-(3,3-difluorocyclobutoxy)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0783] N-(3-(3,3-Difluorocyclobutyloxy)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0784] first step

[0785] 3-(3,3-difluorocyclobutoxy)-1-methyl-5-nitro-1H-indazole

[0786] 3-(3,3-difluorocyclobutyloxy)-1-methyl-5-nitro-1H-indazole

[0787] 1-Methyl-5-nitro-1,2-dihydro-3H-indazol-3-one 38b (200 mg, 1.04 mmol), triphenylphosphine (473 mg, 1.55 mmol), and 3,3-difluorocyclobutanol 39a (168 mg, 1.55 mmol, commercially available) were added to ultra-dry tetrahydrofuran (5 mL) at room temperature. The mixture was stirred at 25°C for 5 minutes. Diethyl azodicarboxylate (270 mg, 1.55 mmol) was then slowly added, and the reaction mixture was allowed to react at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to afford 3-(3,3-difluorocyclobutyloxy)-1-methyl-5-nitro-1H-indazole 39b (210 mg) in a 72% yield.

[0788] MS m / z(ESI):284.0[M+1]

[0789] 1H NMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 8.17 (d, J = 9.2, 1.7 Hz, 1H), 7.64 (d, J = 12. 4Hz,1H),5.19–4.92(m,1H),3.92(s,3H),3.30–3.11(m,2H),3.04–2.72(m,2H).

[0790] Step 2

[0791] 3-(3,3-difluorocyclobutoxy)-1-methyl-1H-indazol-5-amine

[0792] 3-(3,3-difluorocyclobutyloxy)-1-methyl-1H-indazol-5-amine

[0793] Palladium on carbon (30.0 mg, 10%) was added to a solution of 3-(3,3-difluorocyclobutyloxy)-1-methyl-5-nitro-1H-indazole 39b (210 mg, 0.74 mmol) in methanol (30 mL) at room temperature. The atmosphere was replaced three times with a hydrogen balloon, and the mixture was allowed to react at room temperature for 1 hour. The reaction mixture was filtered, the filter cake rinsed with methanol (100 mL), and the filtrate concentrated under reduced pressure. This afforded 3-(3,3-difluorocyclobutyloxy)-1-methyl-1H-indazol-5-amine 39c (160 mg) in an 85.1% yield.

[0794] MS m / z(ESI):254.0[M+1]

[0795] Step 3

[0796] N-(3-(3,3-difluorocyclobutoxy)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0797] N-(3-(3,3-Difluorocyclobutyloxy)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0798] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (90.1 mg, 0.27 mmol) and N,N-diisopropylethylamine (40.8 mg, 0.32 mmol) were added to a solution of 3-(3,3-difluorocyclobutyloxy)-1-methyl-1H-indazol-5-amine 39c (40 mg, 0.16 mmol) and 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (53.5 mg, 0.16 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction was allowed to react at 25°C for 16 hours. The reaction solution was poured into water and extracted three times with ethyl acetate (30 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to obtain N-(3-(3,3-difluorocyclobutyloxy)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 39 (19.6 mg) in a yield of 22%.

[0799] MS m / z(ESI):574.2[M+1]

[0800] 1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),10.07(s,1H),8.34(s,1H),7.78(d,J =8.4Hz,1H),7.55(d,J=9.2Hz,1H),7.48(d,J=9.2Hz,1H),7.14(s,1H),7.0 2(d,J=8.4Hz,1H),5.21–4.89(m,1H),3.85(s,3H),3.29–3.07(m,4H),2.98 (s,4H),2.91–2.75(m,2H),1.49(s,4H),1.21(t,J=7.2Hz,3H),0.33(s,4H).

[0801] Examples 40-42 were synthesized according to the synthesis method of Example 39 of the present invention. The spectrum parameters of Examples 40-42 are shown in the following table:

[0802] Example 43

[0803] N-(3-((3,3-difluorocyclobutoxy)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0804] N-(3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0805] first step

[0806] tert-butyl 2-(3,3-difluorocyclobutoxy)acetate

[0807] tert-Butyl 2-(3,3-difluorocyclobutoxy)acetate

[0808] To a solution of 3,3-difluorocyclobutanol 39a (1.00 g, 9.25 mmol) in toluene (15 mL) and water (7 mL) were added tert-butyl bromoacetate 43a (1.50 g, 7.71 mmol), sodium hydroxide (3.08 g, 77.1 mmol), and tetrabutylammonium hydrogen sulfate (262 mg, 0.771 mmol) at 0°C. The mixture was reacted at 25°C for 4 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude tert-butyl 2-(3,3-difluorocyclobutoxy)acetate 43b (1.70 g) in a 99% yield.

[0809] Step 2

[0810] 2-(3,3-difluorocyclobutoxy)acetic acid

[0811] 2-(3,3-difluorocyclobutyloxy)acetic acid

[0812] Tert-butyl 2-(3,3-difluorocyclobutyloxy)acetate 43b (1.00 g, 9.25 mmol) was added to formic acid (15 mL) and stirred for 1 hour at 25° C. The mixture was concentrated under reduced pressure to give crude 2-(3,3-difluorocyclobutyloxy)acetic acid 43c (1.00 g).

[0813] Step 3

[0814] 2-(3,3-difluorocyclobutoxy)-N-methoxy-N-methylacetamide

[0815] 2-(3,3-Difluorocyclobutyloxy)-N-methoxy-N-methylacetamide

[0816] To a solution of 2-(3,3-difluorocyclobutoxy)acetic acid 43c (1.00 g, crude) in dichloromethane (5 mL) was added dimethylhydroxylamine hydrochloride (330 mg, 5.40 mmol) and N,N'-carbonyldiimidazole (777 mg, 5.40 mmol) at 5°C. The mixture was reacted at 25°C for 3 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (100 mL). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude 2-(3,3-difluorocyclobutoxy)-N-methoxy-N-methylacetamide 43d (700 mg) in a 74% yield.

[0817] MS m / z(ESI):210.0[M+1]

[0818] Step 4

[0819] 1-(5-bromo-2-fluorophenyl)-2-(3,3-difluorocyclobutoxy)ethan-1-one

[0820] 1-(5-Bromo-2-fluorophenyl)-2-(3,3-difluorocyclobutyloxy)ethan-1-one

[0821] To a solution of 2-iodo-4-bromofluorobenzene 43e (1.21 g, 4.02 mmol, commercially available) in tetrahydrofuran (10 mL) was added a solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (3.1 mL, 1.3 M). The mixture was reacted at 0°C for 1 hour, followed by the addition of a solution of 2-(3,3-difluorocyclobutyloxy)-N-methoxy-N-methylacetamide 43d (700 mg, 3.35 mmol) in tetrahydrofuran. The mixture was quenched with saturated aqueous ammonium chloride (5 mL), poured into water (20 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic phase was 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 1-(5-bromo-2-fluorophenyl)-2-(3,3-difluorocyclobutyloxy)ethan-1-one 43f (550 mg) in a yield of 51%.

[0822] MS m / z(ESI):323.0 / 325.0[M+1]

[0823] Step 5

[0824] 5-bromo-3-((3,3-difluorocyclobutoxy)methyl)-1-methyl-1H-indazole

[0825] 5-Bromo-3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazole

[0826] To a solution of 1-(5-bromo-2-fluorophenyl)-2-(3,3-difluorocyclobutyloxy)ethan-1-one 43f (200 mg, 0.619 mmol) in N-methylpyrrolidone (10 mL) at 25°C were added methylhydrazine (171 mg, 3.71 mmol), p-toluenesulfonic acid monohydrate (10.7 mg, 0.0619 mmol), and triethylamine (626 mg, 6.19 mmol). The mixture was reacted at 150°C under microwave for 1 hour. 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 (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to give 43 g (180 mg) of 5-bromo-3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazole in an 88% yield.

[0827] MS m / z(ESI):331.0 / 333.0[M+1]

[0828] 1H NMR (400MHz, DMSO-d6) δ8.02(d,J=1.6Hz,1H),7.63(d,J=8.8Hz,1H),7.52(dd,J=8.8,1.6H z,1H),4.72(s,2H),4.18–4.06(m,1H),4.02(s,3H),2.93-2.80(m,2H),2.62–2.51(m,2H).

[0829] Step 6

[0830] tert-butyl(3-((3,3-difluorocyclobutoxy)methyl)-1-methyl-1H-indazol-5-yl)carbamate

[0831] tert-Butyl (3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-yl)carbamate

[0832] To a solution of 43 g (150 mg, 0.453 mmol) of 5-bromo-3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazole in 1,4-dioxane (5 mL) at 25°C were added tert-butyl carbamate (106 mg, 0.906 mmol), cesium carbonate (443 mg, 1.36 mmol), tris(dibenzylideneacetone)dipalladium (41.5 mg, 0.0453 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (64.8 mg, 0.136 mmol). The atmosphere was purged with nitrogen three times, and the reaction was continued at 90°C for 2 hours. The mixture was filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-yl)carbamate 43h (150 mg) in a 90% yield.

[0833] MS m / z(ESI):368.2[M+1

[0834] Step 7

[0835] 3-((3,3-difluorocyclobutoxy)methyl)-1-methyl-1H-indazol-5-amine

[0836] 3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-amine

[0837] To a solution of tert-butyl (3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-yl)carbamate 43h (150 mg, 0.408 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) and reacted at 25°C for 2 hours. The mixture was concentrated under reduced pressure to give the crude product, 3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-amine 43i (109 mg). MS m / z (ESI): 268.0 [M+1]

[0838] Step 8

[0839] N-(3-((3,3-difluorocyclobutoxy)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0840] N-(3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0841] At 25°C, 3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-amine 43i (150 mg, 0.561 mmol) and 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (285 mg, 842 mmol) were added to N,N-dimethylformamide (5 mL). (7-Azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (586 mg, 1.12 mmol) and N,N-diisopropylethylamine (290 mg, 2.24 mmol) were added to the reaction solution and reacted at 65°C for 2 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 brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 43 (96.0 mg), yield: 29%.

[0842] MS m / z(ESI):586.2[M+1]

[0843] 1H NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.17(s,1H),8.37(d,J=2.0Hz,1H),7.83(d,J=8. 4Hz,1H),7.70–7.57(m,2H),7.17(d,J=2.0Hz,1H),7.03(dd,J=8.4,2.0Hz,1H),4.73(s,2 H),4.17-4.06(m,1H),4.01(s,3H),3.19(q,J=7.2Hz,2H),2.99(t,J=5.2Hz,4H),2.95–2 .83(m,2H),2.64–2.51(m,2H),1.52(t,J=5.2Hz,4H),1.21(t,J=7.2Hz,3H),0.34(s,4H).

[0844] Example 44

[0845] N-(3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0846] N-(3-(3,3-Difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0847] first step

[0848] 5-bromo-1-methyl-1H-indazole-3-carboxylic acid

[0849] 5-Bromo-1-methyl-1H-indazole-3-carboxylic acid

[0850] Lithium hydroxide monohydrate (233.92 mg, 5.57 mmol) was added to a mixture of methyl 5-bromo-1-methyl-1H-indazole-3-carboxylate 44a (500 mg, 1.86 mmol, commercially available) in water (5 mL), tetrahydrofuran (5 mL), and methanol (5 mL) at room temperature. The reaction mixture was allowed to react at 25°C for 16 hours. The pH of the reaction mixture was adjusted to 2 with dilute hydrochloric acid and extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-bromo-1-methyl-1H-indazole-3-carboxylic acid 44b (450 mg) in a 95% yield.

[0851] MS m / z(ESI):257.0[M+1]

[0852] Step 2

[0853] (5-bromo-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidin-1-yl)methanone

[0854] (5-Bromo-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidin-1-yl)methanone

[0855] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.01 g, 2.65 mmol) and N,N-diisopropylethylamine (684 mg, 5.29 mmol) were added to a solution of 5-bromo-1-methyl-1H-indazole-3-carboxylic acid 44b (450 mg, 1.76 mmol) and 3,3-difluorotrimethyleneimine hydrochloride (343 mg, 2.65 mmol) in N,N-dimethylformamide (10 mL) at room temperature. The reaction mixture was reacted at 25°C for 16 hours. The reaction solution was poured into water and extracted three times with ethyl acetate (50 mL). The extracts were combined, and the combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to give (5-bromo-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidine-1-yl)methanone 44c (550 mg) in a yield of 94%.

[0856] MS m / z(ESI):332.0[M+1]

[0857] Step 3

[0858] tert-butyl(3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)carbamate

[0859] tert-Butyl (3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)carbamate

[0860] Trisdibenzylideneacetone dipalladium (139 mg, 0.15 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (87.6 mg, 0.15 mmol), and cesium carbonate (987 mg, 3.03 mmol) were added to a solution of (5-bromo-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidin-1-yl)methanone 44c (500 mg, 1.51 mmol) and tert-butyl carbamate (266 mg, 2.27 mmol) in dioxane (20 mL) at room temperature. The atmosphere was purged with nitrogen three times, and the reaction mixture was incubated at 100°C for 2 hours. The reaction solution was filtered, and the filter cake was rinsed three times with dichloromethane (50 mL). The filtrates were combined and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)carbamate 44d (230 mg) in a yield of 41%.

[0861] MS m / z(ESI):367.0[M+1]

[0862] Step 4

[0863] (5-amino-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidin-1-yl)methanone

[0864] (5-Amino-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidin-1-yl)methanone

[0865] Tert-butyl (3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)carbamate 44d (230 mg, 0.63 mmol) was added to a solution of hydrochloric acid in dioxane (5 mL, 4 M) at room temperature. The reaction mixture was allowed to react at 25°C for 2 hours. The reaction mixture was concentrated under reduced pressure to afford (5-amino-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidine-1-yl)methanone 44e (180 mg), which was used directly in the next step.

[0866] MS m / z(ESI):267.0[M+1]

[0867] Step 5

[0868] N-(3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0869] N-(3-(3,3-Difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0870] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (85.7 mg, 0.23 mmol) and N,N-diisopropylethylamine (58.3 mg, 0.45 mmol) were added to a solution of (5-amino-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidin-1-yl)methanone 44e (40 mg, 0.15 mmol) and 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (50.8 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) at room temperature. The reaction mixture was reacted at 25°C for 16 hours. The reaction solution was poured into water and extracted three times with ethyl acetate (3 mL). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid phase separation (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 give N-(3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 44 (31.0 mg) in a yield of 35%.

[0871] MS m / z(ESI):587.4[M+1]

[0872] 1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),10.14(s,1H),8.79(d,J=1.2Hz,1H),7 .80(t,J=8.4Hz,2H),7.69(d,J=9.2,1.7Hz,1H),7.16(s,1H),7.04(d,J=8.4, 1.8Hz,1H),4.96(t,J=12.4Hz,2H),4.53(t,J=12.4Hz,2H),4.11(s,3H),3.2 5–3.14(m,2H),3.01(s,4H),1.50(s,4H),1.22(t,J=7.2Hz,3H),0.33(s,4H).

[0873] Example 45

[0874] N-(3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0875] N-(3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0876] first step

[0877] 5-bromo-3-iodo-1-methyl-1H-indazole

[0878] 5-Bromo-3-iodo-1-methyl-1H-indazole

[0879] 5-Bromo-1-methyl-1H-indazole 45a (2.00 g, 9.48 mmol, commercially available) was dissolved in N,N-dimethylformamide (6 mL). N-iodosuccinimide (5.33 g, 23.69 mmol) was added, and the atmosphere was purged with nitrogen three times. The reaction was continued at 100°C for 18 hours to yield a yellow suspension. Mass spectrometry confirmed the complete reaction of the starting material and the formation of the product. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to afford 5-bromo-3-iodo-1-methyl-1H-indazole 45b (2.20 g) in a 68.9% yield.

[0880] MS m / z(ESI):336.8 / 338.8[M+1]

[0881] Step 2

[0882] 5-bromo-3-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-indazole

[0883] 5-Bromo-3-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-indazole

[0884] 5-Bromo-3-iodo-1-methyl-1H-indazole 45b (1.00 g, 2.97 mmol) was dissolved in 1.4-dioxane (10 mL) and water (3 mL). Cesium carbonate (2.90 g, 8.90 mmol), 4,4-difluorocyclohex-1-enylboronic acid pinacol ester 45c (724.39 mg, 2.97 mmol), and 1,1-bis(diphenylphosphino)diphenylferric palladium chloride (430.71 mg, 2.97 mmol) were added sequentially. The atmosphere was purged with nitrogen three times. The reaction was stirred at 100°C for 18 hours. After checking the reaction was complete, the reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to give 5-bromo-3-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-indazole 45d (939.00 mg) in a yield of 96.71%.

[0885] MS m / z(ESI):327.0 / 329.0[M+1]

[0886] Step 3

[0887] tert-butyl(3-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-indazol-5-yl)carbamate

[0888] tert-Butyl (3-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-indazol-5-yl)carbamate

[0889] At room temperature, 5-bromo-3-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-indazole 45d (939.00 mg, 2.87 mmol) was dissolved in 1.4-dioxane (10 mL). Cesium carbonate (2.81 g, 8.61 mmol), tert-butyl carbamate (336.22 mg, 2.87 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (273.64 mg, 0.57 mmol), and tris(dibenzylideneacetone)dipalladium (262.82 mg, 0.28 mmol) were added sequentially. The atmosphere was purged with nitrogen three times. The reaction was continued at 100°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was poured into water (150 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (3-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-indazol-5-yl)carbamate 45e (896.00 mg) in a yield of 85.91%.

[0890] MS m / z(ESI):364.2[M+1]

[0891] Step 4

[0892] tert-butyl(3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)carbamate

[0893] tert-Butyl (3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)carbamate

[0894] At room temperature, tert-butyl (3-(4,4-difluorocyclohex-1-en-1-yl)-1-methyl-1H-indazol-5-yl)carbamate 45e (100.00 mg, 0.28 mmol) was dissolved in methanol (10 mL) and palladium on carbon (38.64 mg, 0.27 mmol) was added. The mixture was then replaced with hydrogen three times. The reaction was allowed to proceed under a hydrogen atmosphere at room temperature for 18 hours. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was filtered and the filtrate was concentrated under reduced pressure to afford tert-butyl (3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)carbamate 45f (99.00 mg), which was used directly in the next step.

[0895] MS m / z(ESI):366.2[M+1]

[0896] Step 5

[0897] 3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-amine

[0898] 3-(4,4-Difluorocyclohexyl)-1-methyl-1H-indazol-5-amine

[0899] At room temperature, tert-butyl (3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)carbamate 45f (99.00 mg, 0.27 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was incubated at 25°C for 0.5 h. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was concentrated under reduced pressure to afford 3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-amine 45g (70.00 mg), which was used directly in the next step.

[0900] MS m / z(ESI):266.2[M+1]

[0901] Step 6

[0902] N-(3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0903] N-(3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0904] At room temperature, 45 g (70.00 mg, 0.26 mmol) of 3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-amine was dissolved in 1 mL of N,N-dimethylformamide. N,N-diisopropylethylamine (136.40 mg, 1.06 mmol), 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (98.22 mg, 0.29 mmol), and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (206.35 mg, 0.39 mmol) were added sequentially. The atmosphere was purged with nitrogen three times. The reaction was allowed to proceed at 25°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was poured into 100 mL of water and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 45 (53.05 mg), yield: 34.33%.

[0905] MS m / z(ESI):586.4[M+1]

[0906] 1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),10.19(s,1H),8.38(s,1H),7.84(d, J=8.4Hz,1H),7.64–7.56(m,2H),7.17(d,J=2.0Hz,1H),7.04(dd,J=8.4,2. 0Hz,1H),3.97(s,3H),3.26–3.15(m,3H),2.98(t,J=5.0Hz,4H),2.04(ddt, J=34.3,23.0,9.5Hz,8H),1.53(s,4H),1.21(t,J=7.3Hz,3H),0.34(s,4H).

[0907] Example 46

[0908] N-(3-cyclopropyl-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0909] N-(3-Cyclopropyl-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0910] first step

[0911] 3-cyclopropyl-1-methyl-5-nitro-1H-indazole

[0912] 3-Cyclopropyl-1-methyl-5-nitro-1H-indazole

[0913] To a suspension of 3-bromo-1-methyl-5-nitro-1H-indazole 7b (100 mg, 0.390 mmol), cyclopropylboronic acid 46a (40 mg, 0.470 mmol) and cesium carbonate (382 mg, 1.17 mmol) in dioxane (1 mL) and water (0.1 mL) were added tris(dibenzylideneacetone)dipalladium (36 mg, 0.039 mmol) and tricyclohexylphosphine (22 mg, 0.078 mmol). The reaction mixture was stirred at 100°C under nitrogen for 4 hours. The reaction mixture was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: System A) to give 3-cyclopropyl-1-methyl-5-nitro-1H-indazole 46b (80 mg) in a yield of 94%.

[0914] MS m / z(ESI):281.2[M+1]

[0915] Step 2

[0916] 3-cyclopropyl-1-methyl-1H-indazol-5-amine

[0917] 3-Cyclopropyl-1-methyl-1H-indazol-5-amine

[0918] To a mixture of 3-cyclopropyl-1-methyl-5-nitro-1H-indazole 46b (80 mg, 0.368 mmol) in ethanol (5 mL) was added reduced iron powder (165 mg, 2.95 mmol), and the resulting mixture was stirred at 80° C. for 2 hours to give a black suspension. The mixture was filtered and the solid was washed with ethyl acetate (20 mL×3). The filtrate was concentrated to dryness under reduced pressure to give a crude product, which was added to a saturated aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with a saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3-cyclopropyl-1-methyl-1H-indazole-5-amine 46c (55 mg), which was used directly in the next step.

[0919] MS m / z(ESI):188.1[M+1]

[0920] Step 3

[0921] N-(3-cyclopropyl-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0922] N-(3-Cyclopropyl-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0923] To a solution of 3-cyclopropyl-1-methyl-1H-indazol-5-amine 46c (35 mg, 0.187 mmol), 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (63 mg, 0.187 mmol) and N,N-diisopropylethylamine (60 mg, 0.467 mmol) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (107 mg, 0.280 mmol), and the resulting mixture was stirred at 50° C. for 2 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL×2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(3-cyclopropyl-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 46 (7.04 mg), yield: 7.42%.

[0924] MS m / z(ESI):508.2[M+1]

[0925] 1H NMR(400MHz,DMSO-d6)δ11.55(s,1H),10.86–9.73(m,1H),8.39(s,1H),7.82(d,J=8.4Hz,1 H),7.58(d,J=8.8Hz,1H),7.51(dd,J=8.8,1.7Hz,1H),7.15(d,J=1.6Hz,1H),7.02(dd,J=8 .4,1.9Hz,1H),3.916(s,3H),3.17(q,J=7.2Hz,2H),2.99(t,J=4.8Hz,4H),2.23–2.13(m,1 H),1.53(s,4H),1.21(t,J=7.2Hz,3H),1.02–0.96(m,2H),0.95–0.90(m,2H),0.34(s,4H).

[0926] Example 47

[0927] N-(3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0928] N-(3-(Cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0929] first step

[0930] 5-bromo-N-methoxy-N-methyl-1H-indazole-3-carboxamide

[0931] 5-Bromo-N-methoxy-N-methyl-1H-indazole-3-carboxamide

[0932] 5-Bromo-1H-indazole-3-carboxylic acid 47a (2.00 g, 8.30 mmol, commercially available) and dimethylhydroxylamine hydrochloride (1.13 g, 11.62 mmol) were dissolved in N,N-dimethylformamide (25 mL). 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.39 g, 12.45 mmol) and 4-dimethylaminopyridine (1.52 g, 12.45 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was continued at 25°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting materials. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (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 5-bromo-N-methoxy-N-methyl-1H-indazole-3-carboxamide 47b (2.20 g) in a yield of 93.33%.

[0933] MS m / z(ESI):284.0 / 286.0[M+1]

[0934] Step 2

[0935] 5-bromo-N-methoxy-N,1-dimethyl-1H-indazole-3-carboxamide

[0936] 5-Bromo-N-methoxy-N,1-dimethyl-1H-indazole-3-carboxamide

[0937] 5-Bromo-N-methoxy-N-methyl-1H-indazole-3-carboxamide 47b (2.20 g, 7.74 mmol) was dissolved in N,N-dimethylformamide (20 mL) at room temperature. Sodium hydride (402.87 mg, 15.49 mmol) was added, and the atmosphere was purged with nitrogen three times. The reaction was stirred at 25°C for 0.5 hour. Methyl iodide (1.65 g, 11.62 mmol) was then added dropwise under ice-cooling, and the atmosphere was purged with nitrogen three times. The reaction was continued at 25°C for 1 hour. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to give 5-bromo-N-methoxy-N,1-dimethyl-1H-indazole-3-carboxamide 47c (1.61 g) in a yield of 69.74%.

[0938] MS m / z(ESI):298.0 / 300.0[M+1]

[0939] 1H NMR (400MHz, DMSO) δ8.18(d,J=1.5Hz,1H),7.76(d,J=8.8Hz,1H),7.60(dd,J=8.8,2.0Hz,1H),4.14(s,3H),3.78(s,3H),3.45(s,3H).

[0940] Step 3

[0941] (5-bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanone

[0942] (5-Bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanone

[0943] 5-Bromo-N-methoxy-N,1-dimethyl-1H-indazole-3-carboxamide 47c (1.61 g, 5.40 mmol) was dissolved in tetrahydrofuran (15 mL). The Grignard reagent cyclopropylmagnesium bromide (3.92 g, 27.00 mmol) was added dropwise under an ice bath. The atmosphere was purged with nitrogen three times. The reaction mixture was stirred at 25°C for 1 hour. Mass spectrometry confirmed the complete reaction of the starting material. The reaction mixture was poured into water (150 mL) and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (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 (5-bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanone 47d (1.22 g) in an 80.94% yield.

[0944] MS m / z(ESI):279.0 / 281.0[M+1]

[0945] Step 4

[0946] (5-bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanol

[0947] (5-Bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanol

[0948] (5-Bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanone 47d (716.82 mg, 2.57 mmol) was dissolved in tetrahydrofuran (3 mL), and borane-tetrahydrofuran (2.21 g, 25.68 mmol) was added dropwise under ice-cooling. The atmosphere was replaced with nitrogen three times, and the reaction was incubated at 60°C for 24 hours. Mass spectrometry confirmed the complete reaction of the starting material. Methanol (30 mL) was slowly added to the reaction solution to quench the borane, and the reaction solution was then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to afford (5-bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanol 47e (700.0 mg) in a 96.95% yield.

[0949] MS m / z(ESI):281.0 / 283.0[M+1]

[0950] Step 5

[0951] 5-bromo-3-(cyclopropylmethyl)-1-methyl-1H-indazole

[0952] 5-Bromo-3-(cyclopropylmethyl)-1-methyl-1H-indazole

[0953] (5-Bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanol 47e (700.0 mg, 2.49 mmol) was dissolved in dichloromethane (5 mL) and triethoxysilane (5 mL). Trifluoroacetic acid (2.5 mL) was added dropwise under an ice bath. The atmosphere was replaced with nitrogen three times, and the reaction was incubated at 25°C for 3 hours. Mass spectrometry confirmed the complete reaction of the starting material and the formation of the product. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to afford 5-bromo-3-(cyclopropylmethyl)-1-methyl-1H-indazole 47f (1.1 g) as a crude product.

[0954] MS m / z(ESI):265.0 / 267.0[M+1]

[0955] Step 6

[0956] tert-butyl(3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)carbamate

[0957] tert-Butyl (3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)carbamate

[0958] 5-Bromo-3-(cyclopropylmethyl)-1-methyl-1H-indazole 47f (1.30 g, 3.43 mmol) was dissolved in 1.4-dioxane (5 mL). Cesium carbonate (3.35 g, 10.30 mmol), tert-butyl carbamate (442.25 mg, 3.78 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (327.22 mg, 0.69 mmol), and tris(dibenzylideneacetone)dipalladium (314.28 mg, 0.34 mmol) were added sequentially. The atmosphere was purged with nitrogen three times and the reaction was incubated at 100°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting material and the formation of the product. The reaction solution was cooled, poured into water (150 mL), and extracted with ethyl acetate (60 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 47 g (400.00 mg) of tert-butyl (3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)carbamate in a yield of 38.67%.

[0959] MS m / z(ESI):302.2[M+1]

[0960] 1H NMR (400MHz, DMSO) δ9.02(s,1H),7.67(s,1H),7.21(d,J=9.0Hz,1H),7.12(d,J=8.9Hz,1H),3.69(s,3 H),2.28–2.27(m,2H),1.26(s,9H),0.95(t,J=7.1Hz,1H),0.28–0.21(m,2H),-0.01(q,J=4.9Hz,2H).

[0961] Step 7

[0962] 3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-amine

[0963] 3-(Cyclopropylmethyl)-1-methyl-1H-indazol-5-amine

[0964] Dissolve 47 g (400.00 mg, 1.33 mmol) of tert-butyl (3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)carbamate in dichloromethane (5 mL) and slowly add trifluoroacetic acid (1 mL) dropwise. The reaction mixture is incubated at 25°C for 1 hour. Mass spectrometry indicates that the reaction is complete. The reaction mixture is concentrated to dryness under reduced pressure to obtain 3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-amine 47h (320.00 mg). The crude product is used directly in the next step.

[0965] MS m / z(ESI):202.2[M+1]

[0966] Step 8

[0967] N-(3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0968] N-(3-(Cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0969] 3-(Cyclopropylmethyl)-1-methyl-1H-indazol-5-amine 47h (32.00 mg, crude) was dissolved in N,N-dimethylformamide (4 mL) at room temperature. N,N-diisopropylethylamine (821.94 mg, 6.36 mmol), 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (538.06 mg, 1.59 mmol), and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (1.24 g, 2.38 mmol) were added sequentially. After nitrogen purging three times, the reaction was allowed to proceed at 25°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting materials and the formation of the product. The reaction solution was poured into water (100 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 47 (73.89 mg), yield: 8.91%.

[0970] MS m / z(ESI):522.2[M+1]

[0971] 1H NMR (400MHz, DMSO) δ11.55(s,1H),10.13(s,1H),8.32(s,1H),7.84(d,J=8.4Hz,1H), 7.65–7.56(m,2H),7.18(s,1H),7.04(d,J=8.4Hz,1H),3.96(s,3H),3.20(q,J=7.4Hz, 2H),2.99(s,4H),2.80(d,J=6.8Hz,2H),1.53(m,4H),1.21(t,J=7.4Hz,3 H),1.15–1.04(m,1H),0.53–0.47(m,2H),0.34(s,4H),0.29–0.24(m,2H).

[0972] Examples 48-51 were synthesized according to the synthesis method of Examples 46-47 of the present invention. The spectrum parameters of Examples 48-51 are shown in the following table:

[0973] Example 52

[0974] N-(1-(cyanomethyl)-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0975] N-(1-(Cyanomethyl)-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0976] first step

[0977] 2-(3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazol-1-yl)acetonitrile

[0978] 2-(3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazol-1-yl)acetonitrile

[0979] 3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazole 13c (50.0 mg, 0.177 mmol) was added to N,N-dimethylformamide (1 mL) at room temperature. Bromoacetonitrile (42.5 mg, 0.354 mmol) and cesium carbonate (115 mg, 0.354 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was continued at 100°C for 18 hours. The mixture was filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to give 2-(3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazol-1-yl)acetonitrile 52a (50.0 mg) in an 87.85% yield.

[0980] MS m / z(ESI):322.0[M+1]

[0981] 1H NMR (400MHz, DMSO-d6) δ8.85(d,J=2.0Hz,1H),8.34–8.30(m,1H),7.85(d,J=9.2Hz,1H),5.71(s,2H),3.62–3.58(m,4H),2.24–2.13(m,4H).

[0982] Step 2

[0983] 2-(5-amino-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-1-yl)acetonitrile

[0984] 2-(5-amino-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-1-yl)acetonitrile

[0985] 2-(3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazol-1-yl)acetonitrile 52a (40.0 mg, 0.125 mmol) was added to anhydrous methanol (1 mL) at room temperature. 10% palladium on carbon (13.3 mg, 0.125 mmol) was added to the reaction solution, and the atmosphere was replaced with hydrogen three times. The reaction was continued at 25°C for 18 hours. The mixture was filtered and concentrated under reduced pressure to afford 2-(5-amino-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-1-yl)acetonitrile 52b (35.0 mg) in a 96.51% yield.

[0986] MS m / z(ESI):292.1[M+1]

[0987] Step 3

[0988] N-(1-(cyanomethyl)-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0989] N-(1-(Cyanomethyl)-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0990] At room temperature, 2-(5-amino-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-1-yl)acetonitrile 52b (35.0 mg, 0.120 mmol) and 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (48.8 mg, 0.144 mmol) were added to N,N-dimethylformamide (1 mL). (7-Azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (94.0 mg, 0.180 mmol) and N,N-diisopropylethylamine (31.1 mg, 0.240 mmol) were added to the reaction solution. The atmosphere was replaced with nitrogen three times and the reaction was carried out at 65°C for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(1-(cyanomethyl)-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 52 (5.00 mg), yield: 6.8%.

[0991] MS m / z(ESI):612.2[M+1]

[0992] 1H NMR(400MHz,DMSO-d6)δ11.58(s,1H),10.16(s,1H),8.38–8.35(m,1H),7. 82(d,J=8.4Hz,1H),7.75–7.68(m,2H),7.17(d,J=2.0Hz,1H),7.05–7.01(m ,1H),5.56(s,2H),3.55–3.49(m,4H),3.23–3.16(m,2H),3.01–2.95(m,4H) ,2.23–2.15(m,4H),1.58–1.47(m,4H),1.21(t,J=7.6Hz,3H),0.34(s,4H).

[0993] Example 53 was synthesized according to the synthesis method of Example 52 of the present invention. The spectrum parameters of Example 53 are shown in the following table:

[0994] Example 54

[0995] 4-((2-hydroxyethyl)sulfonamido)-N-(2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0996] 4-((2-Hydroxyethyl)sulfonamido)-N-(2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[0997] first step

[0998] tert-butyl(3-fluoro-4-nitrophenyl)carbamate

[0999] tert-Butyl (3-fluoro-4-nitrophenyl)carbamate

[1000] Di-tert-butyl dicarbonate (21.0 g, 96.1 mmol), N,N-diisopropylethylamine (16.6 g, 128 mmol), and 4-dimethylaminopyridine (783 mg, 6.41 mmol) were added to a solution of 3-fluoro-4-nitroaniline 54a (10 g, 64.1 mmol, commercially available) in dichloromethane (200 mL) at room temperature. The reaction mixture was allowed to react at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to provide tert-butyl (3-fluoro-4-nitrophenyl)carbamate 54b (2.50 g) in a 15% yield.

[1001] MS m / z(ESI):257.0[M+1]

[1002] Step 2

[1003] tert-butyl(4-nitro-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamate

[1004] tert-Butyl (4-nitro-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamate

[1005] At room temperature, 2,2,2-trifluoroethylamine (2.90 g, 29.3 mmol) and N,N-diisopropylethylamine (3.78 g, 29.3 mmol) were added to a solution of tert-butyl (3-fluoro-4-nitrophenyl)carbamate 54b (2.5 g, 9.76 mmol) in N,N-dimethylformamide (20 mL). The reaction mixture was reacted under microwave conditions for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford tert-butyl (4-nitro-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamate 54c (3.00 g), which was used directly in the next step. MS m / z (ESI): 334.0 [M+1].

[1006] Step 3

[1007] tert-butyl(4-amino-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamate

[1008] tert-Butyl (4-amino-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamate

[1009] Palladium on carbon (200.00 mg, 10%) was added to a solution of tert-butyl (4-nitro-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamate 54c (3 g, 30% purity) in methanol (50 mL) at room temperature. The atmosphere was replaced three times with a hydrogen balloon, and the mixture was allowed to react at room temperature for 4 hours. The reaction mixture was filtered, and the filter cake was rinsed with methanol (300 mL). The filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to afford tert-butyl (4-amino-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamate 54d (800 mg) in a two-step total yield of 26.8%.

[1010] MS m / z(ESI):306.0[M+1]

[1011] Step 4

[1012] tert-butyl(2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

[1013] tert-Butyl (2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

[1014] N,N'-Carbonyldiimidazole (598 mg, 3.68 mmol) was added to a solution of tert-butyl (4-amino-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamate 54d (750 mg, 2.46 mmol) in tetrahydrofuran (20 mL) at room temperature, and the reaction was refluxed at 70°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate 54e (683 mg) in 84% yield.

[1015] MS m / z(ESI):332.0[M+1]

[1016] Step 5

[1017] 6-amino-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1018] 6-Amino-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1019] Tert-butyl (2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate 54e (700 mg, 2.11 mmol) was added to a solution of hydrochloric acid (4 mol / L) in dioxane (10 mL) at room temperature. The reaction mixture was allowed to react at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to afford 6-amino-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 54f (600 mg, 80% purity), which was used directly in the next step.

[1020] MS m / z(ESI):231.8[M+1]

[1021] Step 6

[1022] 4-((2-hydroxyethyl)sulfonamido)-N-(2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1023] 4-((2-Hydroxyethyl)sulfonamido)-N-(2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1024] O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (185 mg, 0.487 mmol) and N,N-diisopropylethylamine (83.86 mg, 0.649 mmol) were added to a solution of 6-amino-1-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 54f (75 mg, 80% purity) and 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 6i (115 mg, 0.324 mmol) in N,N-dimethylformamide (2 mL) at room temperature. The reaction mixture was reacted at 65°C for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (15 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative 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 give 4-((2-hydroxyethyl)sulfonamido)-N-(2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 54 (35.9 mg), yield: 20%.

[1025] MS m / z(ESI):568.2[M+1]

[1026] 1 H NMR(400MHz,DMSO-d6)δ11.64(s,1H),11.10(s,1H),10.04(br s,1H),7.84(d,J=8.4Hz,1H),7.82(s,1H),7.38–7.30(m,1H),7.20(d,J=2.0Hz,1H),7.09–6.99(m,2H),4.96 (s,1H),4.79–4.57(m,2H),3.76(t,J=6.4Hz,2H),3.32(s,2H),3.07–2.87(m,4H),1.54(s,4H),0.34(s,4H).

[1027] Example 55

[1028] 4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1029] 4-((2-Hydroxyethyl)sulfonamido)-N-(1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1030] first step

[1031] 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1032] 1-Methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1033] To a solution of N-1-methyl-4-nitro-1,2-phenylenediamine 55a (500 mg, 2.99 mmol, commercially available) in tetrahydrofuran (15 mL) was added N,N'-carbonyldiimidazole (582 mg, 3.59 mmol) at 25°C. The mixture was reacted at 60°C for 2 hours. The mixture was filtered, and the residue was washed with tetrahydrofuran (20 mL) and dried to afford 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one 55b (500 mg) in 86% yield.

[1034] MS m / z(ESI):194.0[M+1]

[1035] Step 2

[1036] 1-methyl-5-nitro-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1037] 1-Methyl-5-nitro-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1038] To a solution of 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazol-2-one 55b (250 mg, 1.29 mmol) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.27 g, 3.88 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate 1b (601 mg, 2.59 mmol) at 25°C. The mixture was allowed to react at 25°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 saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was slurried with petroleum ether / ethyl acetate (5:1, 20 mL) and filtered to afford 1-methyl-5-nitro-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 55c (300 mg) in 84% yield.

[1039] MS m / z(ESI):276.0[M+1]

[1040] Step 3

[1041] 5-amino-1-methyl-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1042] 5-Amino-1-methyl-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1043] 1-Methyl-5-nitro-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 55c (250 mg, 0.908 mmol) was added to anhydrous methanol (6 mL) at 25°C, followed by palladium on carbon (104 mg, 0.984 mmol). The atmosphere was replaced with hydrogen three times and allowed to react for 2 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford 5-amino-1-methyl-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 55d (200 mg) in a 90% yield.

[1044] MS m / z(ESI):246.0[M+1]

[1045] Step 4

[1046] 4-bromo-N-(1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1047] 4-Bromo-N-(1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1048] To a solution of 5-amino-1-methyl-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 55d (200 mg, 0.816 mmol) in N,N-dimethylformamide (10 mL) was added 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (316 mg, 1.02 mmol), (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (639 mg, 1.22 mmol), and N,N-diisopropylethylamine (422 mg, 3.26 mmol) at 25°C. The mixture was reacted at 65°C for 2 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 55e (400 mg) in a yield of 91%.

[1049] MS m / z(ESI):537.2 / 539.2[M+1]

[1050] Step 5

[1051] 4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1052] 4-((2-Hydroxyethyl)sulfonamido)-N-(1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1053] 4-Bromo-N-(1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 55e (200 mg, 0.372 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (93 mg, 0.744 mmol) were added to N,N-dimethylformamide (10 mL) at 25°C, followed by potassium phosphate (158 mg, 0.744 mmol), cuprous iodide (82.7 mg, 0.372 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (26.5 mg, 0.186 mmol). 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 (60 mL×3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid phase separation (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-2-oxo-3-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 55 (90 mg) in a 42% yield.

[1054] MS m / z(ESI):582.2[M+1]

[1055] 1H NMR (400MHz, DMSO-d6) δ11.69(s,1H),7.90(d,J=1.6Hz,1H),7.85(d,J=8.4Hz,1H), 7.40(dd,J=8.4,2.0Hz,1H),7.23(d,J=8.4Hz,1H),7.16(d,J=2.0Hz,1H),7.03(dd,J =8.4,2.0Hz,1H),4.76(q,J=9.2Hz,2H),3.76(t,J=6.4Hz,2H),3.36(s,3H), 3.35-3.32(m,2H),2.98(t,J=5.2Hz,4H),1.53(t,J=5.2Hz,4H),0.34(s,4H).

[1056] Example 56

[1057] N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1058] N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1059] first step

[1060] 5-bromo-N-(4,4-difluorocyclohexyl)-2-nitroaniline

[1061] 5-Bromo-N-(4,4-difluorocyclohexyl)-2-nitroaniline

[1062] 4-Bromo-2-fluoro-1-nitrobenzene 56a (3.00 g, 13.64 mmol, commercially available) was dissolved in N,N-dimethylformamide (30 mL). Cesium carbonate (13.33 g, 40.91 mmol) and 4,4-difluorocyclohexane-1-amine hydrochloride 56b (3.51 g, 20.45 mmol, commercially available) were added to the mixture. After nitrogen substitution three times, the mixture was reacted at 20°C for 18 hours. Mass spectrometry confirmed the complete reaction of the starting material. The resulting product was poured into water (150 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 5-bromo-N-(4,4-difluorocyclohexyl)-2-nitroaniline 56c (3.50 g), which was used directly in the next step.

[1063] MS m / z(ESI):335.0 / 337.0[M+1]

[1064] Step 2

[1065] 5-bromo-N1-(4,4-difluorocyclohexyl)benzene-1,2-diamine

[1066] 5-Bromo-N1-(4,4-difluorocyclohexyl)benzene-1,2-diamine

[1067] 5-Bromo-N-(4,4-difluorocyclohexyl)-2-nitroaniline 56c (3.50 g, 10.44 mmol) was dissolved in a mixture of ethanol (10 mL) and water (10 mL). Iron powder (1.75 g, 31.33 mmol) and ammonium chloride (2.23 g, 41.77 mmol) were added sequentially, and the mixture was reacted at 60°C for 2 hours. Mass spectrometry confirmed the complete reaction of the starting material. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 5-bromo-N-(4,4-difluorocyclohexyl)benzene-1,2-diamine 56d (1.70 g) in a 53.34% yield.

[1068] MS m / z(ESI):305.0 / 307.0[M+1]

[1069] Step 3

[1070] 6-bromo-1-(4,4-difluorocyclohexyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1071] 6-Bromo-1-(4,4-difluorocyclohexyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1072] N,N'-Carbonyldiimidazole (873.55 mg, 5.39 mmol) was added to a solution of 5-bromo-N1-(4,4-difluorocyclohexyl)benzene-1,2-diamine 56d (1.37 g, 4.49 mmol) in tetrahydrofuran (15 mL) at room temperature. The reaction was allowed to proceed for 3 hours. Mass spectrometry confirmed the complete reaction of the starting material. The mixture was poured into water (100 mL) and extracted with ethyl acetate (60 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 6-bromo-1-(4,4-difluorocyclohexyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 56e (1.34 g) in a 90.12% yield.

[1073] MS m / z(ESI):331.0 / 333.0[M+1]

[1074] Step 4

[1075] 5-bromo-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1076] 5-Bromo-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1077] To a solution of 6-bromo-1-(4,4-difluorocyclohexyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 56e (300 mg, 0.906 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (78.6 mg, 1.81 mmol, 60% purity) and iodomethane (257 mg, 1.81 mmol) at 0°C. The mixture was reacted at 25°C for 18 hours. The mixture was quenched by addition of saturated ammonium chloride solution (5 mL), poured into water (50 mL), and extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 5-bromo-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 56f (230 mg) in a yield of 74%.

[1078] MS m / z(ESI):345.0 / 347.0[M+1]

[1079] Step 5

[1080] tert-butyl

[1081] (3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

[1082] tert-Butyl (3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

[1083] To a solution of 5-bromo-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 56f (50 mg, 0.145 mmol) in 1,4-dioxane (3 mL) were added tert-butyl carbamate (33.94 mg, 0.290 mmol), cesium carbonate (142 mg, 0.435 mmol), tris(dibenzylideneacetone)dipalladium (13.3 mg, 0.0145 mmol), and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (20.7 mg, 0.0435 mmol) at 25°C. The atmosphere was purged with nitrogen three times and the reaction was continued at 100°C for 18 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 56 g (50 mg) of tert-butyl (3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate in a yield of 91%.

[1084] MS m / z(ESI):382.2[M+1]

[1085] Step 6

[1086] 5-amino-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1087] 5-Amino-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

[1088] To a solution of tert-butyl (3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate 56 g (50.0 mg, 0.131 mmol) in dichloromethane (1 mL) was added a 1,4-dioxane solution of hydrochloric acid (4 M, 1 mL) and the mixture was reacted at 25°C for 2 hours. The mixture was concentrated under reduced pressure to afford 5-amino-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 56h (40.0 mg), which was used directly in the next step.

[1089] MS m / z(ESI):282.2[M+1]

[1090] Step 7

[1091] 4-bromo-N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1092] 4-Bromo-N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1093] To a solution of 5-amino-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 56h (50.0 mg, 0.178 mmol) in N,N-dimethylformamide (3 mL) was added 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (82.7 mg, 0.267 mmol), (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (139 mg, 0.267 mmol), and N,N-diisopropylethylamine (91.9 mg, 0.711 mmol) at 25°C. The mixture was reacted at 65°C for 2 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 4-bromo-N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 56i (50.0 mg) in a yield of 49%.

[1094] MS m / z(ESI):573.3 / 575.3[M+1]

[1095] Step 8

[1096] N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1097] N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1098] 4-Bromo-N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 56i (50.0 mg, 0.0872 mmol) and 2-hydroxyethane-1-sulfonamide 1 g (21.8 mg, 0.174 mmol) were added to N,N-dimethylformamide (3 mL) at 5°C, followed by potassium phosphate (37.0 mg, 0.174 mmol), cuprous iodide (19.4 mg, 0.0872 mmol) and (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (6.20 mg, 0.0436 mmol). 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 (60 mL×3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid phase separation (AKZONOBEL Kromasil column; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give N-(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 56 (14.0 mg) in a yield of 26%.

[1099] MS m / z(ESI):618.4[M+1]

[1100] 1 H NMR(400MHz,DMSO-d6)δ11.55(s,1H),7.88–7.77(m,2H),7.43(dd,J=8.4,2.0Hz, 1H),7.21–7.11(m,2H),7.02(dd,J=8.4,2.0Hz,1H),4.49-4.44(m,1H),3.76(t,J= 6.8Hz,2H),3.33(t,J=6.8Hz,2H),3.31(s,3H),2.98(t,J=5.2Hz,4H),2.42-2.39 (m,2H),2.23–2.06(m,4H),1.83-1.80(m,2H),1.54(t,J=5.2Hz,4H),0.34(s,4H).

[1101] Examples 57-64 were synthesized according to the synthesis method of Examples 54-56 of the present invention. The spectrum parameters of Examples 57-64 are shown in the following table:

[1102] Example 64

[1103] 4-(ethylsulfonamido)-N-(4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1104] 4-(Ethylsulfonamido)-N-(4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1105] first step

[1106] (E)-6-bromochroman-4-one oxime

[1107] (E)-6-Bromochroman-4-one oxime

[1108] 6-Bromochroman-4-one 64a (5.00 g, 22.02 mmol, commercially available) was added to anhydrous methanol (50 mL) at room temperature, followed by anhydrous sodium acetate (3.61 g, 44.04 mmol) and hydroxylamine hydrochloride (3.06 g, 44.04 mmol). The atmosphere was replaced with nitrogen three times and the reaction was continued at 25°C for 18 hours. The mixture was poured into water (50 mL), stirred for 1 hour, filtered, and concentrated to dryness under reduced pressure to afford (E)-6-bromochroman-4-one oxime 64b (5.00 g) in a 93.08% yield.

[1109] MS m / z(ESI):242.1[M+1]

[1110] Step 2

[1111] 7-bromo-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

[1112] 7-Bromo-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

[1113] (E)-6-Bromochroman-4-one oxime 64b (3.00 g, 12.39 mmol) was added to polyphosphoric acid (30 mL) at room temperature and allowed to react at 125°C for 1 hour. The reaction mixture was cooled and poured into ice water (100 mL). The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (eluent: System A) to afford 7-bromo-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 64c (500 mg) in a 16.67% yield.

[1114] MS m / z(ESI):242.0[M+1]

[1115] 1H NMR (400MHz, DMSO-d6) δ9.84(s,1H),7.24(d,J=2.4Hz,1H),7.18–7.10(m,1H),6.95(d,J=8.4Hz,1H),4.34(t,J=5.6Hz,2H),2.73(t,J=5.6Hz,2H).

[1116] Step 3

[1117] 7-bromo-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

[1118] 7-Bromo-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

[1119] 7-Bromo-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 64c (250 mg, 1.03 mmol) was added to N,N-dimethylformamide (5 mL) at room temperature, followed by cesium carbonate (673 mg, 2.07 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate 1b (360 mg, 1.55 mmol). The atmosphere was replaced with nitrogen three times and the reaction was continued at 25°C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to afford 7-bromo-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 64d (100 mg) in a yield of 29.88%. MS m / z (ESI): 324.0 [M+1].

[1120] Step 4

[1121] tert-butyl

[1122] (4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)carbamate

[1123] tert-Butyl (4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)carbamate

[1124] At room temperature, 7-bromo-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 64d (100 mg, 0.309 mmol) and tert-butyl carbamate (43.4 mg, 0.370 mmol) were added to 1,4-dioxane (5 mL). 2-Dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (22.1 mg, 0.0463 mmol), tris(dibenzylideneacetone)dipalladium (28.3 mg, 0.0309 mmol) and cesium carbonate (201 mg, 0.617 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 under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: System A) to give tert-butyl (4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)carbamate 64e (70.0 mg) in a yield of 62.96%.

[1125] MS m / z(ESI):361.3[M+1]

[1126] Step 5

[1127] 7-amino-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

[1128] 7-Amino-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

[1129] Tert-butyl (4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)carbamate 64e (70.0 mg, 0.194 mmol) was added to dichloromethane (1 mL) at room temperature. A solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to the reaction mixture and reacted at 25°C for 18 hours. The mixture was concentrated to dryness under reduced pressure to afford 7-amino-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 64f (50.0 mg) in a 98.91% yield.

[1130] MS m / z(ESI):261.2[M+1]

[1131] Step 6

[1132] 4-(ethylsulfonamido)-N-(4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1133] 4-(Ethylsulfonamido)-N-(4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1134] 7-Amino-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 64f (38.5 mg, 0.148 mmol) and 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (50.0 mg, 0.148 mmol) were added to N,N-dimethylformamide (1 mL) at room temperature, followed by N,N-diisopropylethylamine (57.3 mg, 0.443 mmol) and (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (154 mg, 0.295 mmol). The atmosphere was replaced with nitrogen three times and the reaction was carried out at 70°C for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-(ethylsulfonyl)-N-(4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 64 (20.0 mg), yield: 23.31%.

[1135] MS m / z(ESI):581.2[M+1]

[1136] 1H NMR (400MHz, DMSO-d6) δ11.60 (s, 1H), 10.18 (s, 1H), 7.96 (d, J = 2.4Hz, 1H), 7. 82(d,J=8.4Hz,1H),7.62–7.54(m,1H),7.26–7.15(m,2H),7.06–7.00(m,1H),4 .68–4.53(m,2H),4.46(t,J=6.4Hz,2H),3.24–3.16(m,2H),3.03–2.92(m,4H) ,2.64(t,J=6.8Hz,2H),1.60–1.42(m,4H),1.20(t,J=7.2Hz,3H),0.34(s,4H).

[1137] Example 65

[1138] 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)benzamide

[1139] 4-(Ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)benzamide

[1140] first step

[1141] 5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-amine

[1142] 5-(2,2,2-Trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-7-amine

[1143] 7-Amino-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 64f (70.0 mg, 0.269 mmol) was added to borane tetrahydrofuran complex (1 mL) and the atmosphere was replaced with nitrogen three times at room temperature. The reaction was continued at 65°C for 18 hours. The mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: System A) to give 5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-amine 65a (40.0 mg) in a yield of 60.39%.

[1144] MS m / z(ESI):247.2[M+1]

[1145] Step 2

[1146] 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)benzamide

[1147] 4-(Ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)benzamide

[1148] 5-(2,2,2-Trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-amine 65a (40.0 mg, 0.163 mmol) and 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (50.0 mg, 0.148 mmol) were added to N,N-dimethylformamide (2 mL) at room temperature, followed by N,N-diisopropylethylamine (57.3 mg, 0.443 mmol) and (7-azabenzotriazole-1-oxy)tripyrrolidone hexafluorophosphate (154 mg, 0.295 mmol). The atmosphere was replaced with nitrogen three times and the reaction was continued at 25°C for 18 hours. The mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% TFA+H2O, mobile phase B: CH3CN) to give 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octane-6-yl)-N-(5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)benzamide 65 (25.0 mg), yield: 29.86%.

[1149] MS m / z(ESI):567.2[M+1]

[1150] 1 H NMR (400MHz, DMSO-d6) δ11.55(s,1H),10.13(s,1H),7.85(d,J=8.4Hz,1H),7.36(d ,J=2.4Hz,1H),7.32–7.27(m,1H),7.18(d,J=2.4Hz,1H),7.06–7.00(m,1H),6.83(d ,J=8.4Hz,1H),4.10–3.98(m,4H),3.47–3.42(m,2H),3.22–3.15(m,2H),3.00–2.9 1(m,4H),2.04–1.96(m,2H),1.62–1.44(m,4H),1.20(t,J=7.2Hz,3H),0.34(s,4H).

[1151] Example 66

[1152] 4-((2-hydroxyethyl)sulfonamido)-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1153] 4-((2-Hydroxyethyl)sulfonamido)-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1154] first step

[1155] 6-nitro-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[1156] 6-Nitro-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[1157] Lithium bis(trimethylsilyl)amide (1 M, 7.73 mL) was added dropwise to a solution of 6-nitro-4H-1,4-benzoxazin-3-one 66a (1 g, 5.15 mmol) in N,N-dimethylformamide (10 mL) under ice-cooling. The mixture was stirred for 30 minutes under ice-cooling. 2,2,2-Trifluoroethyl trifluoromethanesulfonate 1b (1.43 g, 6.18 mmol) was then added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to afford 6-nitro-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 66b (850 mg) in 60% yield.

[1158] MS m / z(ESI):277.1[M+1]

[1159] Step 2

[1160] 6-amino-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[1161] 6-Amino-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

[1162] Ammonium chloride (559.35 mg, 10.55 mmol) and iron powder (589.38 mg, 10.55 mmol) were added to a solution of 6-nitro-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 66b (291.46 mg, 1.06 mmol) in water (20 mL) and ethanol (20 mL) at room temperature and stirred at 80°C for 2 hours. The reaction mixture was filtered through celite and the filtrate was extracted with ethyl acetate (20 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 6-amino-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 66c (192 mg), which was used directly in the next step.

[1163] MS m / z(ESI):247.1[M+1]

[1164] Step 3

[1165] 4-iodo-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1166] 4-iodo-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1167] At room temperature, 6-amino-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 66c (66.17 mg, 268.77 μmol), 2-(6-azaspiro[2.5]octan-6-yl)-4-iodobenzoic acid 8a (80 mg, 223.97 μmol), and 1-methylimidazole (55.84 mg, 671.92 μmol) were added to N,N-dimethylformamide (2 mL). The mixture was stirred at room temperature for 10 minutes. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (188.53 mg, 671.92 μmol) was then added and stirred at room temperature for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to give 4-iodo-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 66d (95 mg) in 72% yield.

[1168] MS m / z(ESI):586.1[M+1]

[1169] Step 4

[1170] 4-((2-hydroxyethyl)sulfonamido)-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1171] 4-((2-Hydroxyethyl)sulfonamido)-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

[1172] At room temperature, 4-iodo-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 66d (95 mg, 162.29 μmol), 2-hydroxyethane-1-sulfonamide 1 g (24.37 mg, 194.75 μmol), 2-(methylamino)acetic acid (21.69 mg, 243.44 μmol), cuprous iodide (9.27 mg, 48.69 μmol) and potassium phosphate trihydrate (129.66 mg, 486.88 μmol) were added to N,N-dimethylformamide (2 mL). After argon replacement, the mixture was heated at 100°C and stirred for 16 h. The reaction solution was poured into water and extracted with ethyl acetate (10 mL×3). The combined organic phases were washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL / min; mobile phase A: 0.05% NH4HCO3+H2O, mobile phase B: CH3CN) to give 4-((2-hydroxyethyl)sulfonamido)-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 66 (39 mg) in a yield of 39%.

[1173] MS m / z(ESI):583.2[M+1]

[1174] 1 H NMR (400MHz, DMSO-d6) δ11.57(s,1H),10.13(s,1H),7.85(d,J=8.5Hz,1H),7.71(d,J=2.2Hz,1H),7.55(dd,J=8.7,2.2Hz,1H),7.19(d,J=2.1H z,1H),7.14–7.01(m,2H),4.90–4.72(m,3H),3.34(t,J=6.5Hz,2H),3.0 –2.95(m,4H),2.53–2.48(m,4H),1.60–1.42(m,4H),0.40–0.30(m,4H).

[1175] Examples 67-73 were synthesized according to the synthesis method of Example 66 of the present invention. The spectrum parameters of Examples 67-73 are shown in the following table:

[1176] Biological evaluation

[1177] Test Example 1: Determination of the Inhibitory Effect of the Compounds of the Invention on OVCAR-3 Cell Proliferation

[1178] 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 TP53R248Q 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).

[1179] 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.

[1180] Table 1 IC of the compounds of the present invention on the inhibition of OVCAR-3 cell proliferation 50 data

[1181] Conclusion: The compounds of the present invention have an IC inhibitory effect on the proliferation of OVCAR-3 cells. 50 <50nM, with significant inhibitory effect.

[1182] Note: The structure of AMG 650 (prepared according to Example 4 of patent publication WO2020132648A1) is as follows:

[1183] Test Example 2: Determination of the Inhibitory Effect of the Compounds of the Invention on HT-29 Cell Proliferation

[1184] 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).

[1185] 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 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 2.

[1186] Table 2 IC of the compounds of the present invention on the inhibition of HT-29 cell proliferation 50 data

[1187] Conclusion: The compounds of the present invention have an inhibitory effect on the proliferation of HT-29 cells. 50 <50nM, with significant inhibitory effect.

[1188] Test Example 3: Test of the Inhibition of KIF18A Enzyme Activity by the Compounds of the Invention

[1189] 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.

[1190] 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.

[1191] Table 3 IC values ​​of the compounds of the present invention for inhibiting KIF18A enzyme activity 50 data

[1192] Conclusion: The compounds of the present invention have an inhibitory effect on KIF18A enzyme activity. 50 <200nM, with significant inhibitory effect.

[1193] Test Example 4: Pharmacokinetics of the Compounds of the Invention in Mice

[1194] 1. Experimental Purpose

[1195] ICR mice were used as test animals, and the pharmacokinetic characteristics of the compounds of the present invention in mice were studied by measuring the drug concentrations in plasma at different times after oral administration of the control compound AMG650 and compounds 8, 39 and 45 of the present invention.

[1196] 2. Experimental plan

[1197] 2.1 Experimental drugs and animals;

[1198] control compound AMG650, compounds 8, 39, and 45;

[1199] ICR mice, male, 27.1-30.4 g, were purchased from Weitonglihua Laboratory Animal Technology Co., Ltd.

[1200] 2.2 Drug preparation

[1201] 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).

[1202] 2.3 Administration

[1203] 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.

[1204] 3. Operation

[1205] 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.

[1206] The levels of the test compounds in mouse plasma after oral administration were determined by LC-MS / MS.

[1207] 4. Pharmacokinetic parameter results

[1208] The pharmacokinetic parameters of the compounds of the present invention are shown in Table 4 below.

[1209] Table 4 Pharmacokinetic parameters of the compounds of the present invention in mice

[1210] Conclusion: The plasma concentrations and areas under the curve of compounds 8, 39 and 45 of the present invention are relatively high, and they have 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 C3-C6 cycloalkyl, a 5- to 7-membered aryl, or a 5- to 7-membered heteroaryl; X1, X2, and X3 are each independently selected from CR a or N atoms, and at most two atoms among X1, X2, and X3 are N atoms at the same time; R a is selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; 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 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; R 2 are the same or different, each independently selected from halogen, hydroxy, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy; 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 The same or different, each independently selected from cyano, halogen, alkyl, alkenyl, alkynyl, hydroxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 、-C(O)OR 5 、-NHC(O)R 5 、-NHC(O)OR 5 、-NR 6 R 7 、-C(O)NR 6 R 7 、-CH2NHC(O)OR 5 、-CH2NR 6 R 7 or -S(O) r R 5 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more groups selected from R A substituted by a substituent; R A Selected from hydroxy, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, OR 8 、-C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more alkyl radicals selected from cyano, halogen, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached; R 5 Each is independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted by one or more hydroxyl groups, halogen groups, nitro groups, cyano groups, alkyl groups, alkoxy groups, haloalkyl groups, haloalkoxy groups, cycloalkyl groups, heterocyclic groups, aryl groups, heteroaryl groups, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; R 6 and R 7 Each is independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; Or, R 6 and R 7 Together with the atoms to which they are attached, they form a 4- to 8-membered heterocyclic group, wherein the 4- to 8-membered heterocyclic group contains one or more N, O, or S(O)r, and the 4- to 8-membered heterocyclic group is optionally further substituted by one or more selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R 8 、-C(O)OR 8 、-OC(O)R 8 、-NR 9 R 10 、-C(O)NR 9 R 10 、-SO2NR 9 R 10 or -NR 9 C(O)R 10 substituted by a substituent; R 8 、R 9 and R 10 Each is independently selected from a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group is optionally further substituted 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 , L1 and n are as defined in claim 1.

3. The compound according to any one of claims 1 or 2, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

4. The compound according to any one of claims 1 to 3, 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 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; r is 2; R b is selected from a hydrogen atom or a methyl group.

5. The compound according to claim 4, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L1 is selected from a bond, -NHSO2CH2CH2-, -NHSO2CH2CH2O-, -NHSO2CH2CH2NH-, -SO2NHCH2CH2-, -SO2-, -CH2SO2-, -NHSO2-, -SO2NH-, -NHC(CH3)2CH2-, -C(O)NHCH2CH2-, -C(O)NHC(CH3)2CH2-, -C(O)N(CH3)CH2CH2-, -C(CH3)(OH)CH2-, -NHSO2CH(CH3)CH2-, -SO2NHC(CH3)2CH2-, -C(O)NH-, -NHCH2CH2 or -CH2SO2CH2CH2-.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from hydrogen atom, hydroxyl, alkyl, heterocyclic, cycloalkyl or heteroaryl, wherein the alkyl, heterocyclic, cycloalkyl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxyl or alkyl.

7. The compound according to any one of claims 5 to 6, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Selected from 8. The compound according to any one of claims 1 to 7, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 3 A hydrogen atom.

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 4 The same or different, each independently selected from halogen, alkyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 5 、-C(O)R 5 or -NR 6 R 7 wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more R A replace; Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached. R A Selected from halogen, cyano, alkyl, cycloalkyl, heterocyclic, -OR 8 、-NR 9 R 10 wherein the alkyl, cycloalkyl, and heterocyclic group are optionally further substituted by one or more substituents selected from halogen and haloalkyl; R 5 are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group or a haloheterocyclic group; R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, an alkoxy group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, R 8 are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a cycloalkyl group, a halocycloalkyl group, a heterocyclic group or a haloheterocyclic group; R 9 and R 10 Each independently selected from hydrogen atom, alkyl, halogenated alkyl 10. The compound according to claim 9, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein R 4 Selected from methyl, difluoromethyl, cyclopropyl, Or, two R 4 It forms a -C(O)- with the same carbon atom to which it is attached.

11. The compound according to any one of claims 1 to 10, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, wherein the compound is:

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

13. Use of the compound according to any one of claims 1 to 11, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 12, in the preparation of a KIF18A inhibitor.

14. Use of the compound according to any one of claims 1 to 11, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 12, in the preparation of a medicament for treating a disease mediated by KIF18A, wherein the disease mediated by KIF18A is preferably cancer.

15. The use according to claim 14, 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.

16. Use of the compound according to any one of claims 1 to 11, or its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, or the pharmaceutical composition according to claim 12, in the preparation of a drug for treating cancer.

17. The use according to claim 16, 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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