WO2024078569A1 - Aromatic amide derivative, preparation method therefor, and use thereof - Google Patents

Abstract

The present invention relates to an aromatic amide derivative, a preparation method therefor, and a use of a pharmaceutical composition comprising same in medicine. Specifically, the present invention relates to an aromatic amide derivative represented by general formula (I), a preparation method therefor, a pharmaceutically acceptable salt thereof, and a use thereof as a therapeutic agent, especially, a KIF18A inhibitor, wherein the definitions of substituents in general formula (I) are the same as those in the description.

Description

Aromatic amide derivatives and preparation method and use thereof Technical Field

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 technique

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) of the kinesin-8 family of kinesins regulate the dynamic instability of microtubules by affecting the polymerization and depolymerization of microtubules. KIF18A is a member of the kinesin-8 family. It can move toward the positive pole using microtubules as tracks and tends to bind to longer microtubules. Its activity is length-dependent and affects the length of the spindle, which can ensure the timely and smooth completion of the alignment of sister chromosomes. Its functions in different species are very similar and conservative.

KIF18A is a molecular motor protein that moves toward the positive end of microtubules using microtubules as tracks. It regulates the midplate assembly of chromosomes by affecting the dynamic instability of microtubule ends and functions during mitosis. In late mitosis, the protein is ubiquitinated and degraded to ensure the precise separation of chromosomes during mitosis and promote the smooth completion of mitosis and cytokinesis. In early mitosis, the localization of KIF18A at the positive end of microtubules close to the kinetochore is a necessary condition for its function. The localization depends not only on the motor activity of its N-terminus, but also on the tail domain with microtubule binding ability. KIF18A is also reversibly phosphorylated/dephosphorylated, but there is still a lack of systematic research on how the post-translational modification of this protein regulates the function of KIF18A. Estrogen receptor ERɑ can bind to KIF18A and promote its transcription, but it is still unclear whether KIF18A is also regulated by other transcription factors. Therefore, the research on the gene transcription regulation mechanism of KIF18A needs to be deepened. During meiosis, cells lacking KIF18A will be unable to complete meiosis, which will lead to sperm formation disorders and testicular dysplasia in male animals.

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, rhabdomyosarcoma, etc., which indicates that KIF18A is closely related to the occurrence and development of tumors and can become a target for molecular diagnosis and treatment of a variety of tumors. The expression of KIF18A is related to the development of clinical colorectal cancer. Studies have found that KIF18A can induce Akt phosphorylation, and knocking out KIF18A in mice can significantly promote cell apoptosis. It is speculated that KIF18A can promote the occurrence and development of colorectal cancer by activating the PI3K-Akt signaling pathway. KIF18A is also highly expressed in human breast cancer cells, and its overexpression is related to the grade, migration and prognosis of breast tumors. Studies on breast cancer cells have found that overexpression of KIF18A can lead to the production of multinucleated cells, while low expression can significantly reduce the proliferation ability of cells both in vivo and in vitro. This is through KIF18A stabilizing microtubules at the ends of microtubules and inactivating the PI3K-Akt signal transduction pathway, which induces cell apoptosis. In addition, KIF18A is upregulated at both the transcriptional and translational levels in lung adenocarcinoma, and abnormal expression of KIF18A is associated with clinical pathological malignancy. KIF18 gene mutations can be observed in lung adenocarcinoma, and its expression is also affected by the DNA copy number. Regulation, KIF18A gene knockout can inhibit the proliferation of lung adenocarcinoma cells in vivo and in vitro, induce apoptosis and G2/M phase arrest. The genes that are highly expressed at the same time as KIF18A are concentrated in the cell cycle signaling pathway, so in-depth research on the mechanism of action of KIF18A in tumors is of great clinical significance.

There are no new drugs targeting KIF18A on the market, and currently only one compound, AMG-650 from Amgen, has entered Phase I clinical trials. As a relatively cutting-edge research direction, there is still a huge room for exploration in the research of KIF18A targets, and it is necessary to continue to study its mechanism of action and develop new inhibitors.

Summary of the invention

In view of the above technical problems, the present invention provides a compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

in:

Ring A is selected from a 5- to 7-membered heterocyclic group, a C ₃ -C ₆ cycloalkyl group, a 5- to 7-membered aryl group or a 5- to 7-membered heteroaryl group;

X ₁ , X ₂ , and X ₃ are each independently selected from CR ^a or a N atom, and at most two atoms among X ₁ , X ₂ , and X ₃ are N atoms at the same time;

R ^a is selected from hydrogen atom, halogen, hydroxyl, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy;

L ₁ is selected from a bond or a C ₁ -C ₆ alkylene group, wherein the alkylene group is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano or alkoxy, and wherein the one or more methylene groups of the alkylene group are optionally replaced by one or more O, S(O) _r , C(O) or NR ^b ; wherein the “one or more methylene groups” include any one, multiple or all of the methylene groups in the C ₁ -C ₆ alkylene group.

L ₂ is selected from

R ^b is selected from a hydrogen atom or an alkyl group;

^R1 is selected from hydrogen, cyano, halogen, alkyl, hydroxyl, cycloalkyl, heterocyclic, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more selected from hydroxyl, halogen, nitro ⁸ , -C(O) ^OR8 , -OC(O ⁾ _R8 , ^-NR9R10 , -C(O) ^{NR9R10 , -SO2NR9R10} or ^{-NR9C ( O} ) ^R10 ;

^R2 are the same or different and are 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 is preferably a hydrogen atom;

R ⁴ are the same or different and are 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 , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ ; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from ^RA ;

^{wherein RA} is selected from hydroxy, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, ^OR8 , -C(O) ^R8 , -C(O) ^OR8 , ^{-OC(O)R8, -NR9R10 , -C} (O) ^NR9R10 , _-SO2NR9R10 or ^-NR9C (O) ^R10 ; wherein the alkyl, ^cycloalkyl , ^heterocyclyl , aryl or ^heteroaryl is optionally further substituted by one or more selected from cyano, halogen, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O) ^R8 , -C(O) ^OR8 , -OC(O) ^R8 , ^{-NR9R10 ,} -C(O) ^NR9R10 , _-SO2NR9R10 or ^{-NR9C (} O ^{) R10} . C(O)R is substituted by a substituent of ¹⁰ ;

Alternatively, two R ⁴ and the same carbon atom to which they are attached form a -C(O)-;

R ⁵ is each 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 substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ ;

^R6 and ^R7 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy 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 hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, ^a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O) ^R8 , -C(O)OR8, -OC(O) ^R8 , ^-NR9R10 , ^-C (O ⁾ _NR9R10 ^{, -SO2NR9R10} or ^-NR9C ( ^O ) ^R10 ;

Alternatively, ^R6 and ^R7 together with the atoms to which they are attached 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 substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy ^, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O) ^R8 , -C(O) ^OR8 , -OC(O) _R8 ^{, -NR9R10,} -C(O ^{) NR9R10, -SO2NR9R10 or -NR9C} (O) ^R10 ;

R ⁸ , R ⁹ and R ¹⁰ are each 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.

A preferred embodiment of the present invention is a compound of general formula (I) or its stereoisomer, tautomer or pharmaceutically acceptable salt, which is a compound of general formula (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt:

Ring A, R ¹ , R ³ , R ⁴ , L ₁ and n are as defined in the general formula (I).

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 ring A is selected from:

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

L ₁ is selected from a bond or C ₁ -C ₆ alkylene, wherein the alkylene is optionally further substituted with one or more hydroxyl groups, and wherein the one or more methylene groups of the alkylene are optionally replaced with one or more O, S(O) _r , C(O) or NR ^b ;

r is 2;

R ^b is selected from a hydrogen atom or a methyl group.

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-, -NHCH ₂ CH ₂ or -CH ₂ SO ₂ CH ₂ CH ₂ -.

A preferred embodiment of the present invention is a compound of the general formula (I), (II) or (III) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, wherein ^R1 is selected from a hydrogen atom, a hydroxyl group, an alkyl group, a heterocyclic group, a cycloalkyl group or a heteroaryl group, wherein the alkyl group, the heterocyclic group, the cycloalkyl group or the heteroaryl group is optionally further substituted by one or more substituents selected from a hydroxyl group or an alkyl group.

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

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

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 R ⁴ is the same or different and is independently selected from halogen, alkyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroaryl, -OR ⁵ , -C(O)R ⁵ or -NR ⁶ R ⁷ ; wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more ^RA ;

Alternatively, two R ⁴ groups and the same carbon atom to which they are attached form a -C(O)-.

^RA is selected from halogen, cyano, alkyl, cycloalkyl, ^heterocyclic , ^-OR8 , ^-NR9R10 , wherein the alkyl, cycloalkyl, heterocyclic is optionally further substituted by one or more substituents selected from halogen and haloalkyl;

R ⁵ is 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;

^R6 and ^R7 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 is 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;

^R9 and ^R10 are each independently selected from a hydrogen atom, an alkyl group, and a halogenated alkyl group.

In a preferred embodiment of the present invention, a compound of formula (I), (II) or (III) or its stereoisomers, tautomers or a pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from methyl, difluoromethyl, cyclopropyl,

Alternatively, two R ⁴ groups and the same carbon atom to which they are attached form a -C(O)-.

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

or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

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.

Furthermore, the present invention provides a pharmaceutical composition comprising an effective dose of a compound of general formula (I), (II) or (III) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.

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

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 drug 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.

The present invention further 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 drug for treating cancer.

The present invention provides a compound described by general formula (I), (II) or (III) or its stereoisomer, tautomer or pharmaceutically acceptable salt, or its pharmaceutical composition for use in preparing a drug 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.

Detailed description of the invention

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

"Alkyl" when used as a group or a part of a group refers to a straight or branched aliphatic hydrocarbon group including _C1 - _C20 . Preferably, it is _C1 - _C10 alkyl, and 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.

"Alkylene" refers to a saturated C ₁ -C ₂₀ 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 by removing two hydrogen atoms, preferably C ₁ -C ₁₀ alkylene, more preferably C ₁ -C ₆ 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. Alkylene can be substituted or unsubstituted.

"Cycloalkyl" refers to a non-aromatic cyclic alkyl group in which one or more of the atoms forming the ring are carbon atoms, including monocyclic, polycyclic, condensed, 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.

"Spirocycloalkyl" 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, and more preferably 7 to 10 members. According to the number of spiro atoms shared between the rings, the spirocycloalkyl is divided into single spiro, double spiro or multiple spirocycloalkyl, preferably single spiro and double spirocycloalkyl, preferably 4/5 members, 4/6 members, 5/5 members or 5/6 members. Non-limiting examples of "spirocycloalkyl" include, but are not limited to, spiro[4.5]decyl, spiro[4.4]nonyl, spiro[3.5]nonyl, spiro[2.4]heptyl.

"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, preferably 6 to 12 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. 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 tetradecahydrophenanthryl.

"Bridged cycloalkyl" refers to a 5- to 18-membered, all-carbon polycyclic group containing two or more cyclic structures that share two carbon atoms that are not directly connected to each other. One or more rings may contain one or more double bonds, but none of the rings has a complete A conjugated π-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. 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 cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, 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)-bicycloo[3.3.1]nonyl, bicyclo[2.2.2]octyl, (1r, 5r)-bicyclo[3.3.2]decyl.

"Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably in this application and refer to non-aromatic heterocyclic groups, wherein one or more of the atoms forming the ring are selected from nitrogen, oxygen or S(O) _t (wherein t is selected from 0, 1 or 2) heteroatoms, including monocyclic, polycyclic, fused, bridged and spirocyclic rings. Preferably, it has a 5-7 membered monocyclic ring or a 7-10 membered bicyclic or tricyclic ring, which may contain 1, 2 or 3 atoms selected from nitrogen, oxygen and/or sulfur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo-piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl, piperazinyl, hexahydropyrimidine,

The heterocyclic group may be substituted or unsubstituted.

"Spiro heterocyclic group" refers to a polycyclic group with 5 to 18 members, two or more cyclic structures, and one 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, 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 spiral atoms between the rings, the spiro alkyl group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4-member/4-member, 4-member/5-member, 4-member/6-member, 5-member/5-member or 5-member/6-member single spiral heterocyclic group. Non-limiting examples of "spiroheterocyclyl" 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,

"Fused heterocyclic group" refers to an all-carbon polycyclic group containing two or more ring structures that share a pair of atoms with 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 (where 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]dioxine.

"Bridged heterocyclic group" refers to a 5-14-membered, 5-18-membered, polycyclic group containing two or more cyclic structures, sharing 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, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclic group" include, but are not limited to: 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl, 2-azabicyclo[3.3.2]decyl.

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be connected together in a fused manner. The term "aryl" includes monocyclic or bicyclic aromatic groups, such as phenyl, naphthyl, and tetrahydronaphthyl aromatic groups. Preferably, the aryl group is a C ₆ -C ₁₀ aromatic group, more preferably, the aryl group is phenyl and naphthyl, and most preferably, naphthyl. The aryl group may be substituted or unsubstituted.

"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, quinolyl, 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, isoquinolyl, quinazolinyl, 2H-isoindolyl, furano[3,2-b]pyridinyl, furano[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, A heteroaryl group can be substituted or unsubstituted.

"Alkoxy" refers to a group of (alkyl-O-), wherein alkyl is as defined herein. C ₁ -C ₆ alkoxy is preferred, and examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, and the like.

"Nitro" refers to a _-NO2 radical.

"Hydroxy" refers to an -OH group.

"Halogen" refers to fluorine, chlorine, bromine and iodine.

"Amino" refers to _-NH2 .

"Cyano" refers to -CN.

"Benzyl" refers to _-CH2 -phenyl.

"Carboxy" refers to -C(O)OH.

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

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

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

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

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

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to tert-butoxycarbonyl.

"Bn" refers to benzyl.

"THP" refers to 2-tetrahydropyranyl.

"TFA" refers to trifluoroacetic acid.

"Ts" refers to p-toluenesulfonyl.

"Leaving group", or leaving group, is an atom or functional group that leaves a larger molecule in a chemical reaction. It is a term used in nucleophilic substitution reactions and elimination reactions. In nucleophilic substitution reactions, 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 are easy to accept electrons and have a strong ability to bear 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 leave other molecules. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to combine with other atoms, and the tendency to exist as an anion (or electrically neutral leaving group) is enhanced. Common leaving groups include but are not limited to halogens, mesyl, -OTs or -OH.

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

The term "substituted" or "substituted" as used herein, unless otherwise specified, means that a group may be substituted by one or more groups selected from the following: alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, 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 , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ ;

R ⁵ is independently selected from hydrogen, alkyl, 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 , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ ;

^R6 and ^R7 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy 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 hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, ^a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O) ^R8 , -C(O)OR8, -OC(O) ^R8 , ^-NR9R10 , ^-C (O ⁾ _NR9R10 ^{, -SO2NR9R10} or ^-NR9C ( ^O ) ^R10 ;

Alternatively, ^R6 and ^R7 together with the atoms to which they are attached 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 substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy ^, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O) ^R8 , -C(O) ^OR8 , -OC(O) _R8 ^{, -NR9R10,} -C(O ^{) NR9R10, -SO2NR9R10 or -NR9C} (O) ^R10 ;

R ⁸ , R ⁹ and R ¹⁰ are each independently selected from hydrogen, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted by one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylate; r is selected from 0, 1 or 2;

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 (conformation) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, structures depicted herein also encompass all isomeric (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 compounds of the invention are within the scope of the invention.

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

"Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

Synthesis method of the compound of the present invention

In order to achieve the purpose of the present invention, the present invention adopts the following technical solution:

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

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

in:

L ₂ is selected from

Y is selected from hydroxyl or chlorine;

Ring A, X ₁ , X ₂ , X ₃ , L ₁ , R ¹ to R ² , m and n are as defined in the general formula (I).

Detailed ways

The present invention is further described below with reference to the embodiments, but these embodiments are not intended to limit the scope of the present invention.

Example

The examples give the preparation of representative compounds represented by formula (I) and the relevant 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. Tetramethylsilane internal standard (0.00 ppm) was used. ¹ H NMR representation method: s = singlet, d = doublet, t = triplet, m = multiplet, br = broadened, dd = doublet of doublets, dt = doublet of triplet. If coupling constants are provided, their units are Hz.

The mass spectrum is obtained by LC/MS, and the ionization method can be ESI or APCI.

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

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

In the following examples, unless otherwise indicated, all temperatures are 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.

CD ₃ OD: deuterated methanol.

CDCl ₃ : deuterated chloroform.

DMSO-d ₆ : deuterated dimethyl sulfoxide.

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

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

The compound is purified by silica gel column chromatography and reverse phase column chromatography, wherein the eluent system is selected from: A: petroleum ether and ethyl acetate system; B: dichloromethane and methanol system; C: dichloromethane: ethyl acetate; D: trifluoroacetic acid aqueous solution and acetonitrile system. The volume ratio of the solvent varies according to the polarity of the compound, and a small amount of acidic or alkaline reagents, such as acetic acid or triethylamine, can also be added for adjustment.

Example 1

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

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

first step

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

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

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). The mixture was reacted at 25°C for 2 hours. The mixture was poured into water (300 mL) and extracted with ethyl acetate (150 mL×3). 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 obtain 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), yield: 88%.

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

Step 2

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

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

At room temperature, 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 with 10% palladium on carbon (1.50 g, 14.1 mmol), and the atmosphere was replaced with hydrogen three times. The reaction was carried out at 25°C for 18 hours. The mixture was filtered and concentrated under reduced pressure to obtain a crude product, which 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% NH ₄ HCO ₃ +H ₂ O, mobile phase B: CH ₃ CN) to obtain 1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-amine 1d-1 (600 mg), yield: 21%; 1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-5-amine 1d-2 (1.00 g), yield: 35%.

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

third step

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

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

At room temperature, 1-(2,2,2-trifluoroethyl)-1H-benzo[d]imidazol-6-amine 1d-1 (100 mg, 0.460 mmol), 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (216 mg, 0.700 mmol, prepared by the known method "Patent WO-2020132648") were added to N,N-dimethylformamide (5 mL) for dissolution, 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 above reaction solution, and the reaction was carried out at 25°C for 18 hours. The mixture was poured into water (20 mL) and extracted with ethyl acetate (30 mL×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), yield: 51%.

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

the fourth step

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

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

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 above reaction solution, nitrogen was replaced three times, and the reaction was carried out 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 separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to give 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 1 (37.0 mg), yield: 28%.

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

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.64 (s, 1H), 8.25 (d, J = 1.8 Hz, 1H), 8.09 (s, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 8.6 Hz, 1H), 7.27 (dd, J = 8.6, 1.8 Hz, 1H), 7.03 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.6, 2.0 Hz, 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)

Example 2

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

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

first step

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

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

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 above 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×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: A system) to obtain 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), yield: 51%.

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

Step 2

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

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

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 above reaction solution, nitrogen was replaced three times, and the reaction was carried out 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 separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to give 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 2 (39 mg), yield: 30%.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.57 (s, 1H), 8.29 (s, 1H), 8.24 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.6 Hz, 1H), 7.72 (d, J=8.6 Hz, 1H), 7.62 (dd, J=8.6, 2.0 Hz, 1H), 7.16 (d, J=2.0 Hz, 1H), 7.02 (dd, J=8.6, 2.0 Hz, 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).

Example 3

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

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

first step

methyl 2-(bromomethyl)-4-nitrobenzoate

Methyl 2-(bromomethyl)-4-nitrobenzoate

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, and stirred at 100°C for 20 hours. After the reaction cooled to room temperature, it was concentrated, and ethyl acetate (5 mL) and petroleum ether (15 mL) were added. After the solid precipitated, it was filtered and the filter cake was dried to obtain methyl 2-(bromomethyl)-4-nitrobenzoate 3b (2.6 g), with a yield of 92.58%.

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

Step 2

5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

5-Nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

At room temperature, methyl 2-(bromomethyl)-4-nitrobenzoate 3b (4.10 g, 14.9 mmol) was dissolved in methanol (50 mL), triethylamine (6.06 g, 59.8 mmol) and 2,2,2-trifluoroethylamine 3c (1.78 g, 17.9 mmol, commercially available) were added in sequence, and the reaction was carried out in a sealed tank at 80 ° C for 18 hours to obtain a brown solution. The cooled reaction solution was spin-dried, then poured into water (80 mL), and extracted with ethyl acetate (40 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one 3d (3.80 g), with a yield of 97%. The crude product was directly used for the next reaction.

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

third step

5-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one

5-Amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one

At room temperature, 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 (10mL), iron powder (3.26g, 58.4mmol) and ammonium chloride (3.18g, 58.4mmol) were added in sequence, and the reaction was carried out at 84°C for 3 hours to obtain a black solution. LCMS detected that the raw material reaction was complete and the product was generated. The cooled reaction solution was adjusted to pH = 9 with saturated sodium bicarbonate solution and filtered, the filter cake was washed with ethyl acetate (50mL), the combined filtrate was diluted with water (100mL), and extracted with ethyl acetate (40mL×2). The combined organic phase was washed with saturated sodium chloride solution (60mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: A system) to obtain 5-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 3e (1.00g), with a yield of 29%.

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

the fourth step

2-(2,2,2-trifluoroethyl)isoindolin-5-amine

2-(2,2,2-Trifluoroethyl)isoindolin-5-amine

Borane tetrahydrofuran solution (1M, 5.43mmol, 5.43mL) was added dropwise to a solution of 5-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 3e (250mg, 1.09mmol) in tetrahydrofuran (10mL) 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 (10mL). After stirring at 85°C for 2 hours, the mixture was concentrated under reduced pressure to obtain 2-(2,2,2-trifluoroethyl)isoindolin-5-amine 3f (200mg) with a yield of 85%.

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

the fifth step

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

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

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)tripyrrolphosphonium hexafluorophosphate (724 mg, 1.39 mmol) and N,N-diisopropylethylamine (478 mg, 3.70 mmol) were added to the above reaction solution, and the reaction was carried out at 65°C for 18 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The 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 4-bromo-2-(6-azaspiro[2.5]octane-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindoline-5-yl)benzamide 3 g (180 mg) in a yield of 38%.

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

Step 6

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

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

At room temperature, 4-bromo-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide 3g (180 mg, 0.354 mmol) and 2-hydroxyethane-1-sulfonamide 1g (88.6 mg, 0.708 mmol) 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 above reaction solution, and nitrogen was replaced three times at 90 °C. The reaction was continued 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 (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2-(2,2,2-trifluoroethyl)isoindolin-5-yl)benzamide 3 (125 mg), yield: 64%.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.42 (s, 1H), 10.08 (s, 1H), 7.85 (m, 2H), 7.46 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.02 (dd, J=8.0, 2.0 Hz, 1H), 4.96 (s, 1H), 4.09 (d, J=17.0 Hz, 4H), 3.76 (t, J=6.6 Hz, 2H), 3.56 (m, 2H), 3.32 (t, J=6.6 Hz, 2H), 2.97 (t, J=5.4 Hz, 4H), 1.51 (t, J=5.4 Hz, 4H), 0.35 (s, 4H).

Example 4

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

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

first step

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

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

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)tripyrrolphosphonium hexafluorophosphate (907 mg, 1.74 mmol) and N,N-diisopropylethylamine (449 mg, 3.48 mmol) were added to the above reaction solution, and the reaction was carried out at 65°C for 18 hours. The mixture was poured into water (100 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was 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 obtain 4-bromo-N-(1-oxo-2-(2,2,2-trifluoro)- 5-(4-(2-(6-(2-( ...

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

Step 2

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

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

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 2-hydroxyethane-1-sulfonamide 1 g (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 above reaction solution, nitrogen was replaced 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 separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) to give 4-((2-hydroxyethyl)sulfonamido)-N-(1-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 4 (40.0 mg), yield: 37%.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.66 (s, 1H), 10.12 (s, 1H), 8.26 (s, 1H), 7.78 (m, 2H), 7.70 (m, 1H), 7.15 (d, J = 2.2 Hz, 1H), 7.02 (m, 1H), 4.99 (s, 1H), 4.64 (s, 2H), 4.37 (q, J = 9.8 Hz, 2H), 3.76 (m, 2H), 3.32 (s, 2H), 2.99 (t, J = 5.6 Hz, 4H), 1.50 (s, 4H), 0.34 (s, 4H)

Example 5

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

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

first step

methyl 2-(bromomethyl)-5-nitrobenzoate

Methyl 2-(bromomethyl)-5-nitrobenzoate

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 above reaction solution, nitrogen was replaced three times, and the reaction was carried out at 80°C for 18 hours. The reaction solution was filtered, concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to obtain methyl 2-(bromomethyl)-5-nitrobenzoate 5b (1.80 g), with a yield of 64%. MS m/z (ESI): 274.2 [M+1]

Step 2

6-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

6-Nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one

At room temperature, methyl 2-(bromomethyl)-5-nitrobenzoate 5b (1.80 g, 6.57 mmol) was added to anhydrous methanol (20 mL), and triethylamine (1.99 g, 19.7 mmol) and 2,2,2-trifluoroethylamine 3c (1.95 g, 19.7 mmol) were added, and nitrogen was replaced three times, and the reaction was carried out at 70°C for 18 hours. The reaction solution was filtered, concentrated to dryness under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to obtain 6-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5c (500 mg), with a yield of 29%.

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

third step

6-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one

6-Amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one

At room temperature, 6-nitro-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5c (500 mg, 1.92 mmol) was added to anhydrous methanol (10 mL), 10% palladium carbon (102 mg, 0.961 mmol) was added to the reaction solution, hydrogen was replaced three times, and the reaction was carried out at 25°C for 2 hours. The reaction solution was filtered, the filter cake was washed with anhydrous methanol (3 mL×3), and the filtrate was collected and concentrated under reduced pressure to obtain 6-amino-2-(2,2,2-trifluoroethyl)isoindolin-1-one 5d (400 mg), with a yield of 90.4%.

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

the fourth step

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

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

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) was 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 above reaction solution, nitrogen was replaced 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), yield: 46.3%.

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

the fifth step

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

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

At room temperature, 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), and 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, and the atmosphere was replaced with nitrogen three times. The reaction was carried out at 90 °C for 18 hours. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The organic 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 (separation column AKZONOBEL Kromasil; 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 4-((2-hydroxyethyl)sulfonamido)-N-(3-oxo-2-(2,2,2-trifluoroethyl)isoindolin-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 5 (30.0 mg), yield: 27.7%.

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

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.54 (s, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.90-7.83 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.14-7.08 (m, 1H), 7.03-6.96 (m, 1H), 4.59 (s, 2H), 4.45-4.35 (m, 2H), 3.75 (t, J = 6.4 Hz, 2H), 3.32-3.28 (m, 2H), 3.02-2.93 (m, 4H), 1.48 (s, 4H), 0.33 (s, 4H).

Example 6

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

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

first step

2-hydroxy-5-nitrobenzoic acid

2-Hydroxy-5-nitrobenzoic acid

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

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

Step 2

2-hydroxy-5-nitrobenzoyl chloride

2-Hydroxy-5-nitrobenzoyl chloride

At 0°C, oxalyl chloride (13.9 g, 109 mmol) and N,N-dimethylformamide (159.66 mg, 2.18 mmol) were added to a solution of 2-hydroxy-5-nitrobenzoic acid 6b (4.00 g, 21.8 mmol) in dichloromethane (40 mL), and 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) with a yield of 99%. The crude product was used directly in the next step without further purification.

third step

N,2-dihydroxy-5-nitrobenzamide

N,2-Dihydroxy-5-nitrobenzamide

At 0°C, a solution of 2-hydroxy-5-nitrobenzoyl chloride 6c (4.40 g, 21.8 mmol) in dichloromethane (40 mL) was added to an aqueous solution of hydroxylamine (42.8 g, 648 mmol, 50% purity). The reaction mixture 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, and the filter cake was washed with ethyl acetate (30 mL) and then dried under reduced pressure to obtain N,2-dihydroxy-5-nitrobenzamide 6d (4.70 g) with a yield of 85%.

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

the fourth step

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

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

N, N'-carbonyldiimidazole (7.79 g, 94.9 mmol) was added to a solution of N, 2-dihydroxy-5-nitrobenzamide 6d (4.70 g, 23.7 mmol) in tetrahydrofuran (45 mL), and the mixture was stirred at 65 ° C for 1 hour to obtain a yellow suspension. The reaction solution was adjusted to pH 5 with hydrochloric acid (1 M) and extracted with ethyl acetate (100 mL × 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, and purified by silica gel column chromatography (eluent: A system) to obtain 5-nitrobenz[d]isoxazol-3(2H)-one 6e (2.50 g) with a yield of 58%.

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

the fifth step

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

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

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) were added 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), and the reaction solution 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×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%.

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

Step 6

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

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

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

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

Step 7

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

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

2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.78 mg, 0.770 mmol) was added 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 by the known method "Patent WO-2020132648") and N,N-diisopropylethylamine (1329 mg, 1.03 mmol) in N,N-dimethylformamide (1 mL), and 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×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 separation (separation column AKZONOBEL Kromasil; 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 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%.

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

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.64 (s, 1H), 10.10 (s, 1H), 8.50 (d, J = 1.76 Hz, 1H), 7.85-7.77 m, 2H), 7.66 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 8.4, 2.0 Hz, 1H), 4.98 (s, 1H), 3.76 (t, J = 6.4 Hz, 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).

Example 7

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

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

first step

3-bromo-1-methyl-5-nitro-1H-indazole

3-Bromo-1-methyl-5-nitro-1H-indazole

Under ice bath, 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). After stirring the reaction solution under ice bath for half an hour, iodomethane (1.76 g, 12.4 mmol) was added. The reaction solution was reacted at room temperature for 4 hours. The reaction solution was quenched with saturated ammonium chloride solution (100 mL), extracted with ethyl acetate (200 mL×3), and the combined organic phase was 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 obtain 3-bromo-1-methyl-5-nitro-1H-indazole 7b (2.00 g), with a yield of 95%.

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

1H NMR (400 MHz, DMSO-d ₆ ) δ 8.46 (d, J = 1.8 Hz, 1H), 8.34–8.27 (m, 1H), 7.96 (d, J = 9.2 Hz, 1H), 4.12 (s, 3H)

Step 2

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

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

At room temperature, 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), replaced with nitrogen three times, and reacted at 100°C for 16 hours. The mixture was filtered, the filter cake was rinsed with ethyl acetate (1500 mL), and the filtrate was concentrated under reduced pressure. The crude product was slurried with ethyl acetate (30 mL) to obtain 3-(4,4-difluoropiperidin-1-yl)-1-methyl-5-nitro-1H-indazole 7c (1.10 g) with a yield of 53%.

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

third step

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

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

At room temperature, palladium carbon (100.00 mg, 10%) was added to a methanol (50 mL) solution of 3-(4,4-difluoropiperidin-1-yl)-1-methyl-5-nitro-1H-indazole 7c (1 g, 3.38 mmol), and the gas was replaced three times with a hydrogen balloon, and then reacted at room temperature for 4 hours. The reaction solution was filtered, the filter cake was rinsed with methanol (300 mL), and the filtrate was concentrated under reduced pressure. The crude product was directly used in the next step. Do more processing. Obtain 3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-amine 7d (850 mg), yield: 95%. MS m/z (ESI): 267.0 [M+1]

the fourth step

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

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

At room temperature, 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). The reaction solution was reacted at 65°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 crude product was purified by silica gel chromatography (eluent: System A) to give 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 yield of 77%. MS m/z(ESI):560.2[M+1]

the fifth step

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

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

At room temperature, 2-hydroxyethane-1-sulfonamide 1g (89.6mg, 0.72mmol), cuprous iodide (68.2mg, 0.36mmol), potassium phosphate (152mg, 0.72mmol), trans-N,N'-dimethyl-1,2-cyclohexanediamine (25.5mg, 0.18mmol) were added to a solution of 4-bromo-N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 7f (200mg, 0.36mmol) in N,N-dimethylformamide (5mL), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 90°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-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 7 (84 mg) with a yield of 39%.

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

1H NMR (400 MHz, DMSO-d ₆ ) δ 11.58 (s, 1H), 10.08 (br s, 1H), 8.32 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.65–7.57 (m, 1H), 7.52 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.07–6.98 (m, 1H), 4.96 (s, 1H), 3.84 (s, 3H), 3.76 (t, J = 6.4 Hz, 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).

Example 8

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

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

first step

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

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

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-2-nitro-1-yl-2-nitro-2-nitro-1-ol (0.74 g), 4-nitro-2-nitro-1-ol (0.84 g), 2-nitro-2-ol (1-nitro-1-ol) (4-nitro-2-nitro-1-ol) (5-nitro-2-ol) (6-azaspiro[2.5]octan-6-yl)benzamide 8b (0.74 g), the yield was 58.21%.

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

Step 2

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

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

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), 2-(methylamino)acetic acid (14.7 mg, 165.16 μmol), tripotassium phosphate trihydrate (219.93 mg, 825.82 μmol) and cuprous iodide (15.73 mg, 82.58 μmol) were added, argon was replaced, the temperature was raised to 110 ° C, and stirred for 6 hours. The mass spectrum showed that the reaction was complete. Water (20 mL) was added to the reaction solution, and ethyl acetate was extracted (50 mL×2). The combined The organic phase was concentrated under reduced pressure and the residue 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+H ₂ O, mobile phase B: CH ₃ CN) to give N-(3-(4,4-difluoropiperidin-1-yl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 8 (65.7 mg) with a yield of 67.53%.

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

1H NMR (400MHz, DMSO-d6) δ11.56 (s, 1H), 10.09 (s, 1H), 8.31 (d, J = 1.7 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.61 (dd, J = 9.0, 1.8 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.17 (d, J = 2.1 Hz, 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＝5.3Hz,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).

Example 9

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

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

first step

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

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

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, 5% ethanol) was added. g, 99.10μmol), cesium carbonate (484.32mg, 1.49mmol) and bis(dibenzylideneacetone)palladium (45.37mg, 49.55μmol), argon replacement 3 times, heating to 100℃, stirring for 16 hours, mass spectrum showed that the reaction was complete, cooled to room temperature, water (20mL) was added to the reaction solution, extracted with ethyl acetate (30mL×2), the combined organic phase was washed with saturated sodium chloride solution (50mL), and dried over anhydrous sodium sulfate. 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%.

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

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

Step 2

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

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

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. The mass spectrometer 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) with a yield of 96.25%.

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

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

third step

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

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

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+H ₂ O, mobile phase B: CH ₃ CN) to obtain 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 9 (5.1 mg) with a yield of 11.97%.

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

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 = 9.1 Hz, 1H), 7.54 (d, J = 8.9 Hz, 1H), 7.16 (s, 1H), 7.03 (d, J = 8.6 Hz, 1H), 3.86 (s, 3H), 3.68 (t, J = 5.9 Hz, 2H), 3.45 (m, 6H), 3.18 (s, 3H), 2.99 (t, J = 5.2 Hz, 4H), 2.16 (tt, J = 13.8, 5.4 Hz, 4H), 1.53 (t, J = 5.2 Hz, 4H), 0.34 (s, 4H).

Example 10

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

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

first step

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

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

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), triethylamine (327.35 mg, 3.24 mmol) was added, and 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. The mass spectrum 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 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), yield: 92.20%.

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

Step 2

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

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

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, stirred for 18 hours, and 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; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN), to give 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 10 (15.0 mg), yield: 10.61%.

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

1H NMR (400MHz, DMSO-d6) δ11.52 (s, 1H), 10.46 (s, 1H), 8.31 (s, 1H), 7.87 (d, J = 8.0 Hz, 3H), 7.61 (d, J = 9.0 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.15 (s, 1H), 7.06 (d, J = 8.5 Hz, 1H), 3.86 (s, 3H), 3.47 (t, J = 9.8 Hz, 6H), 3.23–3.10 (m, 2H), 2.99 (d, J = 5.5 Hz, 4H), 2.16 (tt, J = 13.8, 5.4 Hz, 4H), 1.53 (d, J = 5.7 Hz, 4H), 0.35 (s, 4H).

Embodiment 11

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

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

first step

tert-butyl 3-(acetylthio)azetidine-1-carboxylate

tert-Butyl 3-(acetylthio)azetidine-1-carboxylate

3-iodoazetidine-1-carboxylic acid tert-butyl ester 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, the temperature was raised to 70 ° C, and stirred for 2 hours. The mass spectrum showed that the reaction was complete, water (20 mL) was added to the reaction solution, and ethyl acetate (30 mL × 2) was extracted. The combined organic phase was 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: A system) to obtain 3-(acetylthio)azetidine-1-carboxylic acid tert-butyl ester 11c (0.27 g), with a yield of 66.09%.

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

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

Step 2

tert-butyl 3-(chlorosulfonyl)azetidine-1-carboxylate

tert-Butyl 3-(chlorosulfonyl)azetidine-1-carboxylate

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), stir at room temperature for 1 hour, and mass spectrometry shows that the reaction is complete. Add water (20 mL), extract with dichloromethane (30 mL × 2), combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, filter under reduced pressure, and use the filtrate directly in the next step.

third step

tert-butyl 3-sulfamoylazetidine-1-carboxylate

tert-Butyl 3-aminosulfapyridine-1-carboxylate

The above solution was added dropwise into 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-aminosulfopyridine-1-carboxylate 11e (36 mg). The yield was 13.55%.

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

the fourth step

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

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

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-aminosulfopyridine-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) was added, and the mixture was stirred for 2 h. Potassium phosphate (87.97 mg, 330.33 μmol) and cuprous iodide (6.29 mg, 33.03 μmol) were added, replaced with argon for 5 minutes, heated to 100 °C, stirred for 18 hours, and the mass spectrum showed that the reaction was complete. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 2), and the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 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), yield: 95.42%.

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

the fifth step

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

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

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-carboxylic acid tert-butyl ester 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, stirring for 10 hours, and mass spectrometry showed that the reaction was complete. The product was 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+H ₂ O, mobile phase B: CH ₃ CN) to give 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 11 (10.8 mg). Yield: 23.54%.

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

1H NMR (400MHz, DMSO-d6) δ11.49 (s, 1H), 10.57 (s, 1H), 9.22 (d, J = 60.2 Hz, 1H), 8.30 (d, J = 1.8 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.61 (dd, J = 9.0, 1.8 Hz, 1H), 7.54 (d, J = 9.0 Hz, 1H), 7.15–7.07 (m, 1H), 7. 02 (dd, J = 8.5, 2.0 Hz, 1H), 4.51 (p, J = 7.4 Hz, 1H), 4.32 (m, 2H), 4.13 (m, 2H), 3.86 (s, 3H), 3.46 (t, J = 5.6 Hz, 4H), 2.99 (t, J = 5.2 Hz, 4H), 2.16 (tt, J = 13.8, 5.4 Hz, 4H), 1.53 (t, J = 5.2 Hz, 4H), 0.34 (s, 4H).

Example 12

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

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

first step

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

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

2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (500 mg, 1.40 mmol) was dissolved in dichloromethane (10 mL), and N,N-dimethylformamide (10.23 mg, 139.98 μmol) was added. 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. The mass spectrum showed that the reaction was complete. After 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×2), and the combined organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid methyl ester 12a (0.5 g) with a yield of 96.22%.

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

Step 2

tert-butyl

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

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

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), and 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 gas was replaced with argon three times, the temperature was raised to 100 °C, and the mixture was stirred for 18 hours. The mass spectrum showed that the reaction was complete. Water (20 mL) was added to the reaction solution, and ethyl acetate (30 mL×2) was used for extraction. The combined organic phase was washed with a 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 obtain tert-butyl 3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylate 12c (464 mg) with a yield of 79.64%.

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

third step

tert-butyl

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

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

3-((4-(methoxycarbonyl)-3-(6-azaspiro[2.5]octan-6-yl)phenyl)thio)azetidine-1-carboxylic acid tert-butyl ester 12c (410 mg, 947.81 μmol) was dissolved in 1,4-dioxane (5 mL), potassium peroxymonosulfonate (1.17 g, 1.90 mmol) in water (2.5 mL) was added, and stirred at room temperature for 18 hours. The mass spectrum showed that the reaction was complete. Water (20 mL) was added, and ethyl acetate (30 mL×2) was used for extraction. The combined organic phase was 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%.

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

the fourth step

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

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

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 lithium; hydroxide; hydrate (238.46 mg, 5.68 mmol) water (2 mL) solution was added, and stirred at room temperature for 18 hours. The mass spectrum 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, extracted with dichloromethane (30 mL×2), and the combined organic phase was 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%.

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

the fifth step

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

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

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, and 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%.

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

Step 6

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

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

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-carboxylic acid tert-butyl ester 12f (200 mg, 286.20 μmol) was dissolved in methanol (5 mL), hydrochloric acid (4 M, 715.49 μL) was added, the temperature was raised to 60 ° C, and stirred for 5 hours. The mass spectrum 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+H ₂ O, mobile phase B: CH ₃ CN) to give 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 12 (147.9 mg) with a yield of 71.78%.

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

1H NMR (400MHz, DMSO-d6) δ10.83 (s, 1H), 9.37 (d, J = 29.3 Hz, 1H), 8.26 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 7.9 Hz, 1H), 7.66-7.58 (m, 3H), 7.53 (d, J = 9.0 Hz, 1H), 4.83 (qd, J = 8.3, 7.6, 4.3 Hz, 1H), 4.36-4.16 (m, 4H), 3.86 (s, 3H), 3.46 (dd, J = 7.0, 4.4 Hz, 4H), 3.19-3.08 (m, 4H), 2.16 (tt, J = 13.9, 5.6 Hz, 4H), 1.45 (t, J = 5.2 Hz, 4H), 0.30 (s, 4H).

Example 13

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

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

first step

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

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

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 stirred at room temperature for 4 hours. Water (20 mL) was added, and ethyl acetate (30 mL×2) was used for extraction. The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated and purified by silica column chromatography (eluent: A system) to obtain 3-bromo-5-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole 13a (0.62 g), with a yield of 92.02%.

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

Step 2

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

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

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), sodium tert-butoxide (265.19 mg, 2.76 mmol) were added, argon was replaced, the temperature was raised to 100 ° C, stirred for 18 hours, and the mass spectrum showed that the reaction was complete. Water (20 mL) was added, and ethyl acetate (30 mL × 2) was used for extraction. The combined organic phase was 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%.

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

third step

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

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

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 (4M, 818.86 μL) was added dropwise, the temperature was raised to 60°C, and stirred for 6 hours. The mass spectrum showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, ethyl acetate (30 mL) was added, the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, water (10 mL) was added, and ethyl acetate (30 mL×2) was used for extraction. 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 obtain 3-(4,4-difluoropiperidin-1-yl)-5-nitro 1H-indazole 13c (230 mg), with a yield of 99.52%.

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

the fourth step

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

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

3-(4,4-difluoropiperidin-1-yl)-5-nitro1H-indazole 13c (250 mg, 885.75 μmol) and cyclopropylboronic acid (152.17 mg, 1.77 mmol) were dissolved in 1,2-dichloroethane (5 mL), and 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. The mass spectrum 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). Yield: 56.04%.

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

the fifth step

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

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

1-Cyclopropyl-3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazole 13d (160 mg, 496.42 μmol) was dissolved in ethanol (3 mL), and an aqueous solution (1 mL) of ammonium chloride (185.88 mg, 3.47 mmol) was added. Zinc powder (162.30 mg, 2.48 mmol) was added, and the argon gas was replaced 3 times. The temperature was raised to 80 ° C. and stirred for 2 hours. The mass spectrum showed that the reaction was complete. The reaction solution 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 × 2), and 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%.

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

Step 6

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

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

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, and 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%.

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

Step 7

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

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

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 hours. The 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+H ₂ O, mobile phase B: CH ₃ CN) to give 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 13 (48.2 mg) with a yield of 47.40%.

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

1H NMR (400MHz, DMSO-d6) δ11.59 (s, 1H), 10.07 (s, 1H), 8.29 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 9.0 Hz, 1H), 7.59 (d, J = 8.9 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.06–7.00 (m, 1H), 4.97 (s, 1H), 3.76 (t, J = 6.6 Hz, 2H), 3.47 (m, 5H), 3.35 (s, 2H), 2.99 (t, J = 5.3 Hz, 4H), 2.16 (td, J = 14.4, 13.8, 6.7 Hz, 4H), 1.53 (t, J = 5.3 Hz, 4H), 1.05 (d, J = 5.2 Hz, 4H), 0.34 (s, 4H).

Embodiment 14

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

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

first step

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

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

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) at room temperature were added zinc powder (35.70 mg, 545.91 μmol) and ammonium chloride (14.60 mg, 272.95 μmol). 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 the product 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%.

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

Step 2

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

N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

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, and stirred at room temperature for 30 minutes before adding 3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro 2H-pyran-2-yl)-1H-indazol-5-amine 14a (56.50 mg, 167.98 μmol). Stirring was continued for 16 hours until the reaction was complete. 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 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%.

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

third step

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

N-(3-(4,4-difluoropiperidin-1-yl)-1-(tetrahydro2H-pyran-2-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

At room temperature, 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 a solution of cuprous iodide (5.64 mg, 29.61 μmol), sarcosine (5.28 mg, 59.21 μmol) and potassium phosphate (62.84 mg, 296.06 μmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at 100 °C for 16 hours under nitrogen atmosphere. After the reaction was completed, the reaction solution was poured into water and extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The 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%.

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

the fourth step

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

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

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 at room temperature for 1 hour. The reaction was completed. 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 N-(3-(4,4-difluoropiperidin-1-yl)-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 14 (2 mg) with a yield of 6.66%.

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

Embodiment 15

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

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

first step

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

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

3-Bromo-1-methyl-5-nitro-1H-indazole 7b (300 mg, 1.17 mmol), 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, argon was replaced 3 times, the temperature was raised to 100 ° C, stirred for 20 hours, and the mass spectrum showed that the reaction was complete. The reaction solution was poured into water (20 mL), extracted with dichloromethane (20 mL × 3), and the combined organic phase was 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: A system) to give 1-methyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazol-3-amine 15b (235 mg) in a yield of 73.15%.

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

Step 2

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

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

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, sodium hydride (62.72 mg, 1.57 mmol, 60% purity) was added, stirred at 0°C for 30 minutes, iodomethane (166.94 mg, 1.18 mmol) was added, stirred at 0°C for 1 hour, and mass spectrometry showed that the reaction was complete. The reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was 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: A system) 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%.

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

third step

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

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

N,1-dimethyl-5-nitro-N-(2,2,2-trifluoroethyl)-1H-indazole-3-amine 15c (120 mg, 416.34 μmol) was dissolved in methanol (10 mL), palladium carbon (10%) (4.43 mg, 41.63 μmol) was added, and stirred at room temperature for 4 hours. Mass spectrometry showed that the reaction was complete. Filter and concentrate under reduced pressure to obtain N3,1-dimethyl-N3-(2,2,2-trifluoroethyl)-1H-indazole-3,5-diamine 15d (100 mg), yield: 93.01%.

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

the fourth step

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

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

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, and the mixture was stirred at room temperature for 1 hour. Mass spectrometry showed that the reaction was complete. The residue 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]octan-6-yl)benzamide 15e (160 mg) in a yield of 76.53%.

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

the fifth step

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

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

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), and 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. The mass spectrum 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×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The 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% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 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) with a yield of 36.27%.

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

1H NMR (400MHz, DMSO-d6) δ11.53 (s, 1H), 10.08 (s, 1H), 8.32 (d, J = 1.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.69 (dd, J = 9.1, 1.8 Hz, 1H), 7.51 (d, J = 9.1 Hz, 1H), 7.16 (d, J = 2.1 Hz, 1H), 7.02 (dd, J = 8.5, 2.1 Hz, 1H), 4.96 (s, 1H), 4.25 (q, J = 9.6 Hz, 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 = 5.3 Hz, 4H), 1.57-1.44 (m 4H), 0.33 (s, 4H).

Example 16

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

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

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), and 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. The mass spectrum 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×3). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The 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% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain 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) with a yield of 13.56%.

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

1H NMR (400MHz, DMSO-d6) δ11.53 (s, 1H), 10.10 (s, 1H), 8.31 (d, J = 1.8 Hz, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.69 (dd, J = 9.1, 1.8 Hz, 1H), 7.50 (d, J = 9.0 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7.03 (dd, J = 8.4, 2.1 Hz, 1H), 4.25 (q, J = 9.6 Hz, 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 = 7.3 Hz, 3H), 0.33 (s, 4H).

Embodiment 17

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

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

first step

6-nitro-1-(2,2,2-trifluoroethyl)-1H-indazole

6-Nitro-1-(2,2,2-trifluoroethyl)-1H-indazole

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 above reaction solution, nitrogen was replaced three times, and the reaction was carried out at 25°C for 18 hours. The mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: A system) to obtain 6-nitro-1-(2,2,2-trifluoroethyl)-1H-indazole 17b (200 mg), with a yield of 26.62%.

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

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).

Step 2

1-(2,2,2-trifluoroethyl)-1H-indazol-6-amine

1-(2,2,2-Trifluoroethyl)-1H-indazol-6-amine

At room temperature, 6-nitro-1-(2,2,2-trifluoroethyl)-1H-indazole 17b (200 mg, 0.816 mmol) was added to anhydrous methanol (5 mL), followed by palladium carbon (10%) (43.4 mg, 0.408 mmol), hydrogen was replaced three times, and the reaction was carried out at 30°C for 2 hours. The reaction solution was filtered, the filter cake was washed with anhydrous methanol (5 mL×3), and the organic phase was collected and concentrated to dryness under reduced pressure to obtain 1-(2,2,2-trifluoroethyl)-1H-indazole-6-amine 17c (170 mg), with a yield of 96.84%.

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

third step

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

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

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), and 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 the mixture was 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, 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% TFA+H ₂ O, mobile phase B: CH ₃ CN) to give 4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-1H-indazol-6-yl)benzamide 17 (50 mg), yield: 19.51%.

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

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).

Embodiment 18

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

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

first step

6-bromo-1-(4,4-difluorocyclohexyl)-1H-indazole

6-Bromo-1-(4,4-difluorocyclohexyl)-1H-indazole

At 0°C, 6-bromo-1H-indazole 18a (1.00 g, 5.08 mmol, commercially available) and 4,4-difluorocyclohexane-1-ol 18b (760 mg, 5.58 mmol, commercially available) were added to tetrahydrofuran (10 mL), followed by diisopropyl azodicarboxylate (1.54 g, 7.61 mmol) and triphenylphosphine (2.00 g, 7.61 mmol), nitrogen replacement three times, and reaction 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: A system) to obtain 6-bromo-1-(4,4-difluorocyclohexyl)-1H-indazole 18c (500 mg), yield: 31.26%.

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

Step 2

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

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

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-dicyclohexylphospho-2,4,6-triisopropylbiphenyl (68.1 mg, 0.143 mmol), nitrogen replacement three times, and reaction at 90°C for 18 hours. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)carbamate 18d (330 mg), yield: 98.66%.

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

third step

1-(4,4-difluorocyclohexyl)-1H-indazol-6-amine

1-(4,4-difluorocyclohexyl)-1H-indazol-6-amine

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

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

the fourth step

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

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

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)tripyrrolphosphonium hexafluorophosphate (746.98 mg, 1.43 mmol) and N,N-diisopropylethylamine (277.74 mg, 2.15 mmol), and 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 the mixture was extracted with ethyl acetate (10 mL×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), yield: 38.53%.

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

the fifth step

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

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

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), followed by 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), nitrogen replacement three times, and reaction at 90°C for 18 hours. The mixture was poured into water (10 mL), and the mixture was extracted with ethyl acetate (10 mL×3). The 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+H ₂ O, mobile phase B: CH ₃ CN) to give N-(1-(4,4-difluorocyclohexyl)-1H-indazol-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 18 (30 mg) in a yield of 27.74%.

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

1H NMR (400MHz, DMSO-d6) δ11.76 (s, 1H), 8.49 (s, 1H), 8.01 (s, 1H), 7.85 (d, J＝8.4Hz, 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), 2.25–2.20 (m, 2H), 2.19–2.11 (m, 4H), 2.06–1.99 (m, 2H), 1.61–1.48 (m, 4H), 0.35 (s, 4H).

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:

Embodiment 20

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

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

first step

5-bromo-3-(difluoromethyl)-1H-indazole

5-Bromo-3-(difluoromethyl)-1H-indazole

Under ice bath, diethylaminosulfur trifluoride (1.97 g, 12.22 mmol) was added dropwise to a solution of 5-bromo-1H-indazole-3-carboxaldehyde 20a (1.1 g, 4.89 mmol) in dichloromethane (20 mL), and stirred at room temperature for 4 hours. The reaction solution was quenched with saturated aqueous sodium carbonate solution (20 mL), extracted with dichloromethane (20 mL × 3), and the combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-bromo-3-(difluoromethyl)-1H-indazole 20b (0.8 g), with a yield of 66%.

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

Step 2

5-bromo-3-(difluoromethyl)-1-methyl-1H-indazole

5-Bromo-3-(difluoromethyl)-1-methyl-1H-indazole

Under ice bath, 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), stirred under ice bath for 30 minutes, and then iodomethane (919.29 mg, 6.48 mmol) was added. Stir at room temperature for 4 hours. The reaction solution was quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (20 mL×3), and the combined organic phase was 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: A system) to obtain 5-bromo-3-(difluoromethyl)-1-methyl-1H-indazole 20c (632 mg), yield: 75%.

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

third step

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

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

At room temperature, 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), replaced with nitrogen three times, and reacted at 100 °C for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl (3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)carbamate 20d (110 mg) with a yield of 61%.

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

the fourth step

3-(difluoromethyl)-1-methyl-1H-indazol-5-amine

3-(Difluoromethyl)-1-methyl-1H-indazol-5-amine

At room temperature, 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), and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (5 mL). A saturated aqueous sodium carbonate solution (5 mL) was added, and the aqueous phase was extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with a saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 3-(difluoromethyl)-1-methyl1H-indazol-5-amine 20e (55 mg), with a yield of 75%.

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

the fifth step

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

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

At room temperature, 3-(difluoromethyl)-1-methyl 1H-indazol-5-amine 20e (48.58 mg, 246.37 μmol), 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (80 mg, 223.97 μmol), 1-methylimidazole (55.84 mg, 671.92 μmol) were added to N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, and then N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (188.53 mg, 671.92 μmol) was added and stirred at room temperature for 4 hours. The reaction solution was poured into water and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The 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 yield of 36%.

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

Step 6

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

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

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, replaced with nitrogen three times, and reacted at 90 ° C for 16 hours. The reaction solution was poured into water and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 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 N-(3-(difluoromethyl)-1-methyl-1H-indazol-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 20 (6 mg) in a yield of 14.82%.

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

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

Embodiment 21

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

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

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), replaced with nitrogen three times, and reacted at 90 °C for 16 hours. 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 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]octan-6-yl)benzamide 21 (13 mg) with a yield of 31.0%.

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

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), 7.05 (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).

Embodiment 22

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

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

first step

1-methyl-5-nitro-1H-indazole-3-carbaldehyde

1-Methyl-5-nitro-1H-indazole-3-carbaldehyde

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 hours. 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) with a yield of 98.8%.

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

Step 2

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

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

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. The mixture was stirred at room temperature for 1 hour. The reaction was completed under mass spectrometry monitoring. The reaction solution was poured into water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: System A) to obtain 3-((3,3-difluoroazetidine-1-yl)methyl)-1-methyl-5-nitro-1H-indazole 22c (500 mg). Yield: 72.69%. MS m/z(ESI):283.2[M+1]

third step

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

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

At room temperature, 3-((3,3-difluoroazetidine-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), stirred at 80 ° C for 2 hours, the reaction solution was poured into water, extracted with ethyl acetate (30 mL × 3), and the combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used directly The next step of reaction afforded 3-((3,3-difluoroazetidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine 22d (220 mg) with a yield of 61.54%.

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

the fourth step

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

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

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) solvent, and the mixture was stirred at room temperature 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 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%.

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

the fifth step

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

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

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, replaced with nitrogen three times, stirred at 100 ° C for 16 hours, the reaction solution was put into water, 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, 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% NH ₄ HCO ₃ +H ₂ O, mobile phase B: CH ₃ CN) 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]octan-6-yl)benzamide 22 (80 mg), yield: 31.02%.

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

1H NMR (400 MHz, DMSO-d6) δ 11.50 (s, 1H), 10.08 (s, 1H), 8.62 (s, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.74 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 9.1 Hz, 1H), 7.17 (d, J = 2.1 Hz, 1H), 7.04 (dd, J = 8.5,2.1 Hz,1H),4.78(s,3H),4.58(s,4H),4.06(s,3H),3.77(t,J＝6.6 Hz,2H),3.34(t,J＝6.6 Hz,2H),3.00(m,4H),1.52(s,4H),0.34(s,4H).

Embodiment 23

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

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

first step

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

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

At room temperature, 5-bromo-1-methyl-indazole-3-carboxaldehyde 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). After stirring at room temperature for 30 minutes, sodium cyanoborohydride (105.14 mg, 1.67 mmol) was added and stirred for 1 hour. 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 crude product was purified by silica gel column chromatography (eluent: System A) to obtain 5-bromo-3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazole 23b (120 mg) with a yield of 83.35%.

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

Step 2

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

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

At room temperature, 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) were added to a toluene (1 mL) solution of tridibenzylideneacetone 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) 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 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 step.

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

third step

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

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

At room temperature, 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 for 1 hour, and the reaction was completed under mass spectrometry. The organic phase was concentrated under reduced pressure to obtain 3-((4,4-difluoropiperidin-1-yl)methyl)-1-methyl-1H-indazol-5-amine 23d (39.24 mg), which was directly used in the next step.

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

the fourth step

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

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

At room temperature, 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) were added to a solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (53.67 mg, 279.97 μmol) and 1-hydroxybenzotriazole (37.83 mg, 279.97 μmol) in N,N-dimethylformamide (1 mL). The mixture was stirred at room temperature for 4 hours. 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 give 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 a yield of 80.72%. MS m/z (ESI): 620.1 [M+1]

the fifth step

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

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

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. 04mg, 225.99μmol) and potassium phosphate (47.97mg, 225.99μmol) in N,N-dimethylformamide (1mL), replaced with nitrogen three times, stirred at 100°C for 16 hours, the reaction solution was put into water (10mL), extracted with ethyl acetate (30mL×3), the combined organic phase was washed with saturated sodium chloride solution (50mL), dried over anhydrous sodium sulfate, 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% NH ₄ HCO ₃ +H ₂ O, mobile phase B: CH ₃ CN) 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]octan-6-yl)benzamide 23 (5 mg), yield: 7.17%.

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

1H NMR (400MHz, DMSO-d6) δ11.57 (s, 1H), 10.11 (s, 1H), 8.68 (s, 1H), 7.81 (dd, J＝18.4, 8.7 Hz, 2H), 7.51 (dd, J＝9.0, 1.9 Hz, 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＝6.6 Hz, 4H), 3.00 (t, J＝5.2 Hz, 4H), 2.32 (s, 4H), 1.52 (t, J＝5.2 Hz, 4H), 1.24 (s, 1H), 0.35 (s, 4H).

Embodiment 24

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

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

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 (100 mg, 169.08 μmol) and ethanesulfonamide 8c (36.91 mg, 338.16 μmol) were added 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), and the atmosphere was replaced with nitrogen three times at 100 °C. The reaction mixture was stirred for 16 hours. The reaction solution was put 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 (separation column AKZONOBEL Kromasil; 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 obtain N-(3-((3,3-difluoroazetidine-1-yl)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 24 (5.0 mg) with a yield of 3.96%.

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

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:

Embodiment 28

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

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

first step

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

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

At room temperature, 2,2-difluoroethylamine (79.02 mg, 974.8 μmol) and 1-methyl-5-nitro-1H-indazole-3-carboxaldehyde 22b (200 mg, 974.8 μmol) were added to a methanol (2 mL) solvent of acetic acid (5.85 mg, 97.48 μmol), stirred for 30 minutes, and then sodium cyanoborohydride (61.26 mg, 974.8 μmol) was added. Stirring was continued for 1 hour, and the reaction solution was poured into water, extracted with ethyl acetate (30 mL×3), and the combined organic phase was 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 obtain 2,2-difluoro-N-((1-methyl-5-nitro-1H-indazol-3-yl)methyl)ethan-1-amine 28a (240 mg), with a yield of 91.116%.

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

Step 2

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

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

At room temperature, 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), 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. Crude The 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%.

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

third step

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

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

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 mixed solution of ammonium chloride (49.11 mg, 918.05 μmol) in ethanol (2 mL) and water (1 mL), and stirred at 75°C for 2 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 crude product was purified by silica gel column chromatography (eluent: System A) to obtain tert-butyl (5-amino-1-methyl-1H-indazol-3-yl)methyl)(2,2-difluoroethyl)carbamate 28c (100 mg) with a yield of 64.01%.

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

the fourth step

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

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

At room temperature, 2-(6-azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (100 mg, 279.97 μmol) and (5-amino-1-methyl-1H-indazol-3-yl)methyl)(2,2-difluoroethyl)carbamic acid tert-butyl ester 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), and the reaction solution was added dropwise to ice water, and 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), and the crude product was directly used in the next step. MS m/z(ESI):680.1[M+1]

the fifth step

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

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

At room temperature, 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) were added to 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) solution was replaced with nitrogen three times and stirred at 100 ° C for 16 hours. The reaction solution was put 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 crude product was purified by silica gel column chromatography (eluent: A system) to obtain 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), yield: 65.33%.

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

Step 6

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

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

At room temperature, 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) was added to a solution of hydrogen chloride in ethyl acetate (1 mL, 4 M) and 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: A system) 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%.

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

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

Embodiment 29

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

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

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 the mixture was 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; 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 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 29 (12 mg) in a yield of 76.98%.

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

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),6.2 1(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).

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:

Example 35 & Example 36

(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

(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

(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

(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

first step

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

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

Nitric acid (1.04 g, 16.53 mmol) was added 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), 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 a saturated sodium bicarbonate solution, and extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with a saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to give 1-(1-methyl-5-nitro-1H-indazol-3-yl)ethan-1-one 35b (667 mg), yield: 55.0%.

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

Step 2

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

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

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: A system) 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%.

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

third step

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

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

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

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

the fourth step

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

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

2-(6-Azaspiro[2.5]octan-6-yl)-4-iodo-benzoic acid 8a (1.0 g, 2.80 mmol) and ethanesulfonamide 8c (458.36 mg, 4.20 mmol) were dissolved in DMF (10 mL), and cuprous iodide (266.60 mg, 1.40 mmol), sarcosine (249.43 mg, 2.80 mmol) and potassium phosphate (3.73 g, 14.00 mmol) were added, and the atmosphere was replaced with argon, and the temperature was raised to 110°C and stirred for 6 hours. The temperature was cooled to room temperature, and the reaction solution was poured into ice water (200 mL), and the pH was adjusted to 6 with dilute hydrochloric acid (2M). 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 obtain 4-(ethylsulfonylamino)-2-(6-azaspiro[2.5]octane-6-yl)benzoic acid 35e (0.75 g), with a yield of 79.16%.

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

the fifth step

(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

(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

(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

(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

To a solution of 3-(1-(3,3-difluoroazetidin-1-yl)ethyl)-1-methyl-1H-indazol-5-amine 35d (476 mg, 1.79 mmol) and 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)tripyrrolphosphonium 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 phase was washed with a saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and 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% NH ₄ HCO ₃ +H ₂ O, mobile phase B: CH ₃ CN) to obtain 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), yield: 47%. The obtained 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 1500psi) to obtain a single configuration compound (shorter retention time) and a single configuration compound (longer retention time).

Single configuration compound (short retention time):

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

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

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

Single configuration compound (longer retention time):

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

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

1H NMR (400MHz, DMSO-d6) δ11.70 (s, 1H), 10.16 (s, 1H), 8.41 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.76–7.68 (m, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 2.0 Hz, 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, 11.6 Hz, 2H), 3.54-3.42 (dd, J = 22.1, 11.3 Hz, 2H), 3.20 (q, J = 7.2 Hz, 2H), 3.04-2.92 (t, J = 5.0 Hz, 4H), 1.55 (s, 4H), 1.38 (d, J = 6.4 Hz, 3H), 1.21 (t, J = 7.2 Hz, 3H), 0.34 (s, 4H).

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:

Embodiment 38

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

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

first step

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

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

At room temperature, methylhydrazine sulfate (2.17 g, 15.1 mmol) and triethylamine (3.05 g, 30.1 mmol) were added to an ethanol (40 mL) solution of methyl 2-fluoro-5-nitrobenzoate 38a (2 g, 10 mmol). The reaction solution was reacted at 80°C for 16 hours. The reaction solution was put into water and extracted three times with ethyl acetate (150 mL). The combined organic phase was 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 mixed solution of (ethyl acetate/methanol system), filtered, and the filter cake was washed three times with ethyl acetate (10 mL). 1-Methyl-5-nitro-1,2-dihydro-3H-indazol-3-one 38b (1.8 g) was obtained with a yield of 93%.

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

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).

Step 2

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

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

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, and the reaction solution was reacted at 80°C for 16 hours. The reaction solution was poured into water and extracted three times with ethyl acetate (50 mL). The combined organic phase was 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 obtain 1-methyl-5-nitro-3-(2,2,2-trifluoroethoxy)-1H-indazole 38c (270 mg) with a yield of 95%.

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

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).

third step

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

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

Palladium 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, and the gas was replaced three times with a hydrogen balloon, and then reacted at room temperature for 2 hours. The reaction solution was filtered, the filter cake was rinsed with methanol (100 mL), and the filtrate was concentrated under reduced pressure. 1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazole-5-amine 38d (300 mg) was obtained with a yield of 91%. The crude product was used directly in the next step.

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

the fourth step

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

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

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 phase was 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%.

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

the fifth step

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

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

At room temperature, ethanesulfonamide 8c (24.4 mg, 0.22 mmol), cuprous iodide (28.4 mg, 0.15 mmol), potassium phosphate (63.2 mg, 0.3 mmol), (1R,2R)-(-)-N,N'-dimethyl-1,2-cyclohexanediamine (10.6 mg, 0.07 mmol) were added to a solution of 4-bromo-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octane-6-yl)benzamide 38e (80 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL), the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 100°C for 16 hours. The reaction solution was poured into water and extracted three times with ethyl acetate (50 mL). The combined organic phase was 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 obtain 4-(ethylsulfonamido)-N-(1-methyl-3-(2,2,2-trifluoroethoxy)-1H-indazol-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 38 (19.7 mg) in a yield of 23%.

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

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), 3.25–3.13 (m, 2H), 2.98 (s, 4H), 1.50 (s, 4H), 1.22 (t, J＝7.2Hz, 3H), 0.33 (s, 4H).

Embodiment 39

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

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

first step

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

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

At room temperature, 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), and the mixture was stirred at 25°C for 5 minutes, and diethyl azodicarboxylate (270 mg, 1.55 mmol) was slowly added, and the reaction solution was reacted at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to obtain 3-(3,3-difluorocyclobutyloxy)-1-methyl-5-nitro-1H-indazole 39b (210 mg) with a yield of 72%.

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

1H NMR (400MHz, DMSO-d6) δ8.41 (s, 1H), 8.17 (d, J＝9.2, 1.7Hz, 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).

Step 2

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

3-(3,3-Difluorocyclobutyloxy)-1-methyl-1H-indazol-5-amine

Palladium carbon (30.0 mg, 10%) was added to a methanol (30 mL) solution of 3-(3,3-difluorocyclobutyloxy)-1-methyl-5-nitro-1H-indazole 39b (210 mg, 0.74 mmol) at room temperature, and the gas was replaced three times with a hydrogen balloon, and then reacted at room temperature for 1 hour. The reaction solution was filtered, the filter cake was rinsed with methanol (100 mL), and the filtrate was concentrated under reduced pressure. 3-(3,3-difluorocyclobutyloxy)-1-methyl-1H-indazole-5-amine 39c (160 mg) was obtained with a yield of 85.1%.

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

third step

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

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

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 mixture was reacted 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 phase was 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 separation (separation column AKZONOBEL Kromasil; 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 N-(3-(3,3-difluorocyclobutyloxy)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 39 (19.6 mg) with a yield of 22%.

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

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), 7.02 (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).

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:

Embodiment 43

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

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

first step

tert-butyl 2-(3,3-difluorocyclobutoxy)acetate

tert-Butyl 2-(3,3-difluorocyclobutyloxy)acetate

At 0°C, 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) were added to a mixed solution of 3,3-difluorocyclobutanol 39a (1.00 g, 9.25 mmol) in toluene (15 mL) and water (7 mL). 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 phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product tert-butyl 2-(3,3-difluorocyclobutoxy)acetate 43b (1.70 g) with a yield of 99%.

Step 2

2-(3,3-difluorocyclobutoxy)acetic acid

2-(3,3-Difluorocyclobutyloxy)acetic acid

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

third step

2-(3,3-difluorocyclobutoxy)-N-methoxy-N-methylacetamide

2-(3,3-Difluorocyclobutyloxy)-N-methoxy-N-methylacetamide

At 5°C, dimethylhydroxylamine hydrochloride (330 mg, 5.40 mmol) and N,N'-carbonyldiimidazole (777 mg, 5.40 mmol) were added to a solution of 2-(3,3-difluorocyclobutyloxy)acetic acid 43c (1.00 g, crude) in dichloromethane (5 mL). 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 phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 2-(3,3-difluorocyclobutyloxy)-N-methoxy-N-methylacetamide 43d (700 mg) with a yield of 74%.

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

the fourth step

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

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

At 0°C, a solution of 2-iodo-4-bromofluorobenzene 43e (1.21 g, 4.02 mmol, commercially available) in tetrahydrofuran (10 mL) was added with a solution of isopropylmagnesium chloride-lithium chloride in tetrahydrofuran (3.1 mL, 1.3 M), and 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 solution (5 mL), poured into water (20 mL) and extracted with ethyl acetate (100 mL×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%.

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

the fifth step

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

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

At 25°C, methylhydrazine (171 mg, 3.71 mmol), p-toluenesulfonic acid monohydrate (10.7 mg, 0.0619 mmol) and triethylamine (626 mg, 6.19 mmol) were added 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). The mixture was reacted under microwave at 150°C for 1 hour. The mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL×3). The combined organic phase was 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 obtain 5-bromo-3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazole 43g (180 mg) with a yield of 88%.

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

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, 1.6Hz, 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).

Step 6

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

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

At 25°C, 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) were added 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. The atmosphere was replaced with nitrogen three times and the reaction was carried out 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). Yield: 90%.

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

Step 7

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

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

Trifluoroacetic acid (1 mL) was added 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) at 25°C and reacted for 2 hours at 25°C. 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]

Step 8

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

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

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), and (7-azabenzotriazole-1-oxy)tripyrrolphosphonium hexafluorophosphate (586 mg, 1.12 mmol) and N,N- Diisopropylethylamine (290 mg, 2.24 mmol) was added to the above 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×2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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% TFA+H ₂ O, mobile phase B: CH ₃ CN) to obtain N-(3-((3,3-difluorocyclobutyloxy)methyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 43 (96.0 mg), yield: 29%.

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

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 , 2H), 4.17-4.06 (m, 1H), 4.01 (s, 3H), 3.19 (q, J = 7.2 Hz, 2H), 2.99 (t, J = 5.2 Hz, 4H), 2.95-2.83 (m, 2H), 2.64-2.51 (m, 2H), 1.52 (t, J = 5.2 Hz, 4H), 1.21 (t, J = 7.2 Hz, 3H), 0.34 (s, 4H).

Embodiment 44

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

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

first step

5-bromo-1-methyl-1H-indazole-3-carboxylic acid

5-Bromo-1-methyl-1H-indazole-3-carboxylic acid

At room temperature, lithium hydroxide monohydrate (233.92 mg, 5.57 mmol) was added to a mixed solution of 5-bromo-1-methyl-1H-indazole-3-carboxylic acid methyl ester 44a (500 mg, 1.86 mmol, commercially available) in water (5 mL), tetrahydrofuran (5 mL) and methanol (5 mL), and the reaction solution was reacted at 25°C for 16 hours. The reaction solution was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 5-bromo-1-methyl-1H-indazole-3-carboxylic acid 44b (450 mg), with a yield of 95%.

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

Step 2

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

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

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%.

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

third step

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

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

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 (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 replaced with nitrogen three times and the reaction mixture was reacted 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 obtain tert-butyl (3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)carbamate 44d (230 mg) in a yield of 41%.

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

the fourth step

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

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

At room temperature, 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). The reaction solution was reacted at 25°C for 2 hours. The reaction solution was concentrated under reduced pressure to obtain (5-amino-1-methyl-1H-indazol-3-yl)(3,3-difluoroazetidine-1-yl)methanone 44e (180 mg), and the crude product was used directly in the next step.

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

the fifth step

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

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

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 phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by preparative liquid separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% NH ₄ HCO ₃ +H ₂ O, mobile phase B: CH ₃ CN) to give N-(3-(3,3-difluoroazetidine-1-carbonyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 44 (31.0 mg) with a yield of 35%.

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

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), 3.25–3.14(m, 2H), 3.01(s, 4H), 1.50(s, 4H), 1.22(t, J＝7.2Hz, 3H), 0.33(s, 4H).

Embodiment 45

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

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

first step

5-bromo-3-iodo-1-methyl-1H-indazole

5-Bromo-3-iodo-1-methyl-1H-indazole

5-Bromo-1-methyl-1H-indazole 45a (2.00 g, 9.48 mmol, commercially available) was dissolved in N,N-dimethylformamide (6 mL) solution, N-iodosuccinimide (5.33 g, 23.69 mmol) was added, nitrogen was replaced three times, and the reaction was carried out at 100 ° C for 18 hours to obtain a yellow suspension. Mass spectrometry showed that the raw material reaction was complete and the product was generated. The reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL × 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: A system) to obtain 5-bromo-3-iodo-1-methyl-1H-indazole 45b (2.20 g) with a yield of 68.9%.

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

Step 2

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

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

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) solution, and 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(diphenylphosphine)diferronichloridopalladium (430.71 mg, 2.97 mmol) were added in sequence, and nitrogen was replaced three times. The reaction was stirred at 100 ° C for 18 hours. The reaction of the raw materials was detected to be complete, and the reaction solution was poured into water (150 mL) and extracted with ethyl acetate (60 mL × 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%.

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

third step

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

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

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) solution, and cesium carbonate (2.81 g, 8.61 mmol), tert-butyl carbamate were added in sequence. (336.22 mg, 2.87 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (273.64 mg, 0.57 mmol) and tris(dibenzylidene-acetone)dipalladium (262.82 mg, 0.28 mmol), after nitrogen replacement three times. The reaction was carried out at 100°C for 18 hours, and the reaction of the raw materials was complete by mass spectrometry. The reaction solution was poured into water (150 mL) and extracted with ethyl acetate (60 mL×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: A system) to obtain tert-butyl (3-(4,4-difluorocyclohex-1-ene-1-yl)-1-methyl-1H-indazol-5-yl)carbamate 45e (896.00 mg), yield: 85.91%.

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

the fourth step

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

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

At room temperature, tert-butyl (3-(4,4-difluorocyclohex-1-ene-1-yl)-1-methyl-1H-indazole-5-yl)carbamate 45e (100.00 mg, 0.28 mmol) was dissolved in methanol (10 mL) solution, palladium carbon (38.64 mg, 0.27 mmol) was added, and hydrogen was replaced three times. The reaction was reacted at room temperature under a hydrogen atmosphere for 18 hours, and the reaction of the raw material was complete by mass spectrometry. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain tert-butyl (3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazole-5-yl)carbamate 45f (99.00 mg), which was directly used in the next step.

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

the fifth step

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

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

At room temperature, tert-butyl (3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazole-5-yl)carbamate 45f (99.00 mg, 0.27 mmol) was dissolved in dichloromethane (1 mL) solution, and trifluoroacetic acid (0.5 mL) was added dropwise. The reaction was reacted at 25 ° C for 0.5 hours. Mass spectrometry detected that the raw material reacted completely. The reaction solution was concentrated under reduced pressure to obtain 3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazole-5-amine 45g (70.00 mg), and the crude product was directly used in the next step.

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

Step 6

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

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

At room temperature, 45g (70.00mg, 0.26mmol) of 3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-amine was dissolved in N,N-dimethylformamide (1mL) solution, and N,N-diisopropylethylamine (136.40mg, 1.06mmol), 4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 35e (98.22mg, 0.29mmol), (7-azabenzotriazole-1-oxy)tripyrrolphosphonium hexafluorophosphate (206.35mg, 0.39mmol) were added in sequence, and nitrogen was replaced three times. The reaction was carried out at 25°C for 18 hours, and the reaction of the raw materials was complete by mass spectrometry. The reaction solution was poured into (100mL) water and extracted with ethyl acetate (60mL×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 purified by Liquid phase separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) gave N-(3-(4,4-difluorocyclohexyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 45 (53.05 mg) with a yield of 34.33%.

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

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).

Embodiment 46

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

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

first step

3-cyclopropyl-1-methyl-5-nitro-1H-indazole

3-Cyclopropyl-1-methyl-5-nitro-1H-indazole

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 solution was stirred at 100 °C under nitrogen protection for 4 hours. The reaction solution was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (eluent: A system) to give 3-cyclopropyl-1-methyl-5-nitro-1H-indazole 46b (80 mg) in a yield of 94%.

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

Step 2

3-cyclopropyl-1-methyl-1H-indazol-5-amine

3-Cyclopropyl-1-methyl-1H-indazol-5-amine

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 obtain a black suspension. The mixture was filtered and the solid was washed with ethyl acetate (20 mL × 3), and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was added with saturated sodium bicarbonate aqueous solution (20 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3-cyclopropyl-1-methyl-1H-indazole-5-amine 46c (55 mg), which was used directly in the next step.

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

third step

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

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

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]octan-6-yl)benzamide 46 (7.04 mg), yield: 7.42%.

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

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, 1H), 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,1H),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).

Embodiment 47

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

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

first step

5-bromo-N-methoxy-N-methyl-1H-indazole-3-carboxamide

5-Bromo-N-methoxy-N-methyl-1H-indazole-3-carboxamide

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) solution, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.39 g, 12.45 mmol) and 4-dimethylaminopyridine (1.52 g, 12.45 mmol) were added in sequence, nitrogen was replaced three times, and the reaction was carried out at 25°C for 18 hours. The reaction of the raw materials was complete by mass spectrometry, and the reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL×2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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%.

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

Step 2

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

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

At room temperature, 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) solution, sodium hydride (402.87 mg, 15.49 mmol) was added, nitrogen was replaced three times, and the reaction was stirred at 25 ° C for 0.5 hours. Then iodomethane (1.65 g, 11.62 mmol) was added dropwise under ice bath, nitrogen was replaced three times, and the reaction was carried out at 25 ° C for 1 hour. The reaction of the raw material was complete by mass spectrometry, and the reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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) with a yield of 69.74%.

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

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).

third step

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

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

5-Bromo-N-methoxy-N,1-dimethyl-1H-indazole-3-carboxamide 47c (1.61 g, 5.40 mmol) was dissolved in tetrahydrofuran (15 mL) solution, and Grignard reagent cyclopropylmagnesium bromide (3.92 g, 27.00 mmol) was added dropwise under ice bath, and nitrogen was replaced three times. The reaction was moved to 25 ° C and stirred for 1 hour. Mass spectrometry showed that the raw material reaction was complete. The reaction solution was poured into water (150 mL) and extracted with ethyl acetate (60 mL × 2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: A system) to obtain (5-bromo-1-methyl-1H-indazole-3-yl) (cyclopropyl) ketone 47d (1.22 g), yield: 80.94%.

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

the fourth step

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

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

(5-bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanone 47d (716.82 mg, 2.57 mmol) was dissolved in tetrahydrofuran (3 mL) solution, and borane-tetrahydrofuran (2.21 g, 25.68 mmol) was added dropwise under ice bath. Nitrogen was replaced three times, and the reaction was carried out at 60°C for 24 hours. The reaction of the raw material was complete by mass spectrometry. Methanol (30 mL) was slowly added to the reaction solution to quench the borane, and then the reaction solution was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluent: A system) to obtain (5-bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanol 47e (700.0 mg) with a yield of 96.95%.

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

the fifth step

5-bromo-3-(cyclopropylmethyl)-1-methyl-1H-indazole

5-Bromo-3-(cyclopropylmethyl)-1-methyl-1H-indazole

Dissolve (5-bromo-1-methyl-1H-indazol-3-yl)(cyclopropyl)methanol 47e (700.0 mg, 2.49 mmol) in dichloromethane (5 mL) and triethoxysilane (5 mL) solution, and add trifluoroacetic acid (2.5 mL) dropwise under ice bath. Replace with nitrogen three times, and react at 25 ° C for 3 hours. Mass spectrometry shows that the raw material reacts completely and the product is generated. The reaction solution is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: A system) to obtain 5-bromo-3-(cyclopropylmethyl)-1-methyl-1H-indazole 47f (1.1 g) as a crude product.

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

Step 6

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

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

5-Bromo-3-(cyclopropylmethyl)-1-methyl-1H-indazole 47f (1.30 g, 3.43 mmol) was dissolved in 1.4-dioxane (5 mL) solution, and cesium carbonate (3.35 g, 10.30 mmol), tert-butyl carbamate (442.25 mg, 3.78 mmol), 2- Dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (327.22 mg, 0.69 mmol) and tris(dibenzylideneacetone)dipalladium (314.28 mg, 0.34 mmol). Nitrogen was replaced three times and the reaction was carried out at 100°C for 18 hours. The reaction of the raw materials was complete and the product was generated by mass spectrometry. After cooling, the reaction solution was poured into water (150 mL) and extracted with ethyl acetate (60 mL×2). The combined organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain 47 g (400.00 mg) of tert-butyl (3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)carbamate, with a yield of 38.67%.

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

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, 3H), 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).

Step 7

3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-amine

3-(Cyclopropylmethyl)-1-methyl-1H-indazol-5-amine

Dissolve tert-butyl (3-(cyclopropylmethyl)-1-methyl-1H-indazole-5-yl)carbamate 47g (400.00mg, 1.33mmol) in dichloromethane (5mL) solution, slowly add trifluoroacetic acid (1mL). The reaction is placed at 25°C for 1 hour. The reaction of the raw materials is complete by mass spectrometry. The reaction solution is concentrated to dryness under reduced pressure to obtain 3-(cyclopropylmethyl)-1-methyl-1H-indazole-5-amine 47h (320.00mg), and the crude product is directly used in the next step.

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

Step 8

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

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

At room temperature, 3-(cyclopropylmethyl)-1-methyl-1H-indazol-5-amine 47h (32.00 mg, crude product) was dissolved in N,N-dimethylformamide (4 mL) solution, and 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), (7-azabenzotriazole-1-oxy)tripyrrolylphosphonium hexafluorophosphate (1.24 g, 2.38 mmol) were added in sequence. After nitrogen replacement three times, the reaction was carried out at 25°C for 18 hours. The reaction of the raw materials was complete and the product was generated by mass spectrometry. The reaction solution was poured into water (100 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-(cyclopropylmethyl)-1-methyl-1H-indazol-5-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide 47 (73.89 mg), yield: 8.91%.

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

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

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:

Embodiment 52

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

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

first step

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

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

At room temperature, 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), bromoacetonitrile (42.5 mg, 0.354 mmol) and cesium carbonate (115 mg, 0.354 mmol) were added to the above reaction solution, nitrogen was replaced three times, and the reaction was carried out at 100°C for 18 hours. The mixture was filtered and concentrated under reduced pressure, and the product was purified by silica gel column chromatography (eluent: A system) to obtain 2-(3-(4,4-difluoropiperidin-1-yl)-5-nitro-1H-indazole-1-yl)acetonitrile 52a (50.0 mg), yield: 87.85%.

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

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).

Step 2

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

2-(5-Amino-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-1-yl)acetonitrile

At room temperature, 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), and 10% palladium carbon (13.3 mg, 0.125 mmol) was added to the above reaction solution, and hydrogen was replaced three times, and the reaction was carried out at 25°C for 18 hours. The mixture was filtered and concentrated under reduced pressure to obtain 2-(5-amino-3-(4,4-difluoropiperidin-1-yl)-1H-indazol-1-yl)acetonitrile 52b (35.0 mg), with a yield of 96.51%.

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

third step

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

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

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)tripyrrolphosphonium hexafluorophosphate (94.0 mg, 0.180 mmol) and N,N-diisopropylethylamine (31.1 mg, 0.240 mmol) were added to the above reaction solution, nitrogen was replaced three times, and the reaction was carried out at 65°C for 18 hours. The mixture was poured into water (10 mL), and the mixture was 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, 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%.

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

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).

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:

Embodiment 54

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

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

first step

tert-butyl(3-fluoro-4-nitrophenyl)carbamate

tert-Butyl (3-fluoro-4-nitrophenyl)carbamate

At room temperature, 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), and the reaction solution was reacted at 25°C for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) to obtain tert-butyl (3-fluoro-4-nitrophenyl)carbamate 54b (2.50 g), with a yield of 15%.

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

Step 2

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

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

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 (3-fluoro-4-nitrophenyl)carbamic acid tert-butyl ester 54b (2.5 g, 9.76 mmol) in N,N-dimethylformamide (20 mL), and the reaction solution was reacted under microwave for 2 hours. The reaction solution was put into water and extracted with ethyl acetate (50 mL×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 to obtain (4-nitro-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamic acid tert-butyl ester 54c (3.00 g), which was used directly in the next step. MS m/z(ESI):334.0[M+1]

third step

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

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

Palladium 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, and the gas was replaced with a hydrogen balloon three times, and then reacted at room temperature for 4 hours. The reaction solution was filtered, 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: A system) to obtain tert-butyl (4-amino-3-((2,2,2-trifluoroethyl)amino)phenyl)carbamate 54d (800 mg), with a total yield of 26.8% in two steps.

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

the fourth step

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

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

At room temperature, 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), and the reaction solution 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 a yield of 84%.

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

the fifth step

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

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

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 reacted at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain 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.

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

Step 6

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

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

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×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% NH ₄ HCO ₃ +H ₂ O, mobile phase B: CH ₃ CN) 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%.

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.64 (s, 1H), 11.10 (s, 1H), 10.04 (br s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.82 (s, 1H), 7.38–7.30 (m, 1H), 7.20 (d, J = 2.0 Hz, 1H), 7.09–6.99 (m, 2H), 4.96 (s, 1H), 4.79–4.57 (m, 2H), 3.76 (t, J = 6.4 Hz, 2H), 3.32 (s, 2H), 3.07–2.87 (m, 4H), 1.54 (s, 4H), 0.34 (s, 4H).

Embodiment 55

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

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

first step

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

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

N,N'-Carbonyldiimidazole (582 mg, 3.59 mmol) was added to a solution of N1-methyl-4-nitro-1,2-phenylenediamine 55a (500 mg, 2.99 mmol, commercially available) in tetrahydrofuran (15 mL) 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 give 1-methyl-5-nitro-1,3-dihydro-2H-benzo[d]imidazole-2-one 55b (500 mg) in a yield of 86%.

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

Step 2

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

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

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 reacted at 25°C for 18 hours. The mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL×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 slurried with petroleum ether/ethyl acetate (5:1, 20 mL) and filtered to give 1-methyl-5-nitro-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazole-2-one 55c (300 mg) in a yield of 84%.

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

third step

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

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

At 25°C, 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), followed by palladium carbon (104 mg, 0.984 mmol), and the hydrogen atmosphere was replaced by 3 The mixture was filtered and the filtrate was concentrated under reduced pressure to give 5-amino-1-methyl-3-(2,2,2-trifluoroethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one 55d (200 mg) in a yield of 90%.

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

the fourth step

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

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

4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (316 mg, 1.02 mmol), (7-azabenzotriazole-1-oxy)tripyrrolphosphonium hexafluorophosphate (639 mg, 1.22 mmol) and N,N-diisopropylethylamine (422 mg, 3.26 mmol) were added 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) 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×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), yield: 91%.

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

the fifth step

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

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

At 25°C, 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), 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 hours. The mixture was poured into water (50 mL) and extracted with ethyl acetate (60 mL×3). The combined organic phase was 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 (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) 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), yield: 42%.

MS m/z(ESI):582.2[M+1]

¹ H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.40 (dd, J = 8.4, 2.0 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 2.0 Hz, 1H), 7.03 (dd, J =8.4,2.0 Hz,1H),4.76(q,J=9.2 Hz,2H),3.76(t,J=6.4 Hz,2H),3.36(s,3H),3.35-3.32(m,2H),2.98(t,J=5.2 Hz,4H),1.53(t,J=5.2 Hz,4H),0.34(s,4H).

Embodiment 56

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

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

first step

5-bromo-N-(4,4-difluorocyclohexyl)-2-nitroaniline

5-Bromo-N-(4,4-difluorocyclohexyl)-2-nitroaniline

4-Bromo-2-fluoro-1-nitrobenzene 56a (3.00 g, 13.64 mmol, commercially available) was dissolved in N,N-dimethylformamide (30 mL), and 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 mixed solution. After nitrogen replacement three times, the reaction was reacted at 20°C for 18 hours. The reaction of the raw materials was complete by mass spectrometry. The obtained product was poured into water (150 mL) and extracted with ethyl acetate (60 mL×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 to obtain 5-bromo-N-(4,4-difluorocyclohexyl)-2-nitroaniline 56c (3.50 g), and the crude product was directly used in the next step.

MS m/z(ESI):335.0/337.0[M+1]

Step 2

5-bromo-N1-(4,4-difluorocyclohexyl)benzene-1,2-diamine

5-Bromo-N1-(4,4-difluorocyclohexyl)benzene-1,2-diamine

5-Bromo-N-(4,4-difluorocyclohexyl)-2-nitroaniline 56c (3.50 g, 10.44 mmol) was dissolved in a mixed solution of ethanol (10 mL) and water (10 mL), and iron powder (1.75 g, 31.33 mmol) and ammonium chloride (2.23 g, 41.77 mmol) were added in sequence, and the reaction was carried out at 60°C for 2 hours. The reaction of the raw material was complete according to mass spectrometry, and the reaction solution was diluted with water (150 mL) and extracted with ethyl acetate (60 mL×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: A system) to obtain 5-bromo-N1-(4,4-difluorocyclohexyl)benzene-1,2-diamine 56d (1.70 g) with a yield of 53.34%.

MS m/z(ESI):305.0/307.0[M+1]

third step

6-bromo-1-(4,4-difluorocyclohexyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

6-Bromo-1-(4,4-difluorocyclohexyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one

At room temperature, N,N'-carbonyldiimidazole (873.55 mg, 5.39 mmol) was added to a tetrahydrofuran (15 mL) solution of 5-bromo-N1-(4,4-difluorocyclohexyl)benzene-1,2-diamine 56d (1.37 g, 4.49 mmol) and reacted at room temperature for 3 hours. The reaction of the starting material was complete by mass spectrometry. The mixture was poured into water (100 mL) and extracted with ethyl acetate (60 mL×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: A system) to obtain 6-bromo-1-(4,4-difluorocyclohexyl)-1,3-dihydro 2H-benzo[d]imidazole-2-one 56e (1.34 g) with a yield of 90.12%.

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

the fourth step

5-bromo-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

5-Bromo-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

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. After the mixture was quenched with saturated ammonium chloride solution (5 mL), the mixture was poured into water (50 mL) and extracted with ethyl acetate (60 mL×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]imidazole-2-one 56f (230 mg) in a yield of 74%.

MS m/z(ESI):345.0/347.0[M+1]

the fifth step

tert-butyl

(3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

tert-Butyl (3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate

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) was 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-dicyclohexylphosphine at 25 °C. -2',4',6'-triisopropylbiphenyl (20.7 mg, 0.0435 mmol). Nitrogen was replaced three times and the reaction was carried out 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: A system) to obtain tert-butyl (3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate 56 g (50 mg), yield: 91%.

MS m/z(ESI):382.2[M+1]

Step 6

5-amino-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

5-Amino-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one

At 25°C, a solution of tert-butyl (3-(4,4-difluorocyclohexyl)-1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)carbamate 56g (50.0mg, 0.131mmol) in dichloromethane (1mL) was added with a solution of hydrochloric acid in 1,4-dioxane (4M, 1mL) and reacted at 25°C for 2 hours. The mixture was concentrated under reduced pressure to obtain 5-amino-3-(4,4-difluorocyclohexyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one 56h (40.0mg), which was used directly in the next step.

MS m/z(ESI):282.2[M+1]

Step 7

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

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

4-Bromo-2-(6-azaspiro[2.5]octan-6-yl)benzoic acid 1e (82.7 mg, 0.267 mmol), (7-azabenzotriazole-1-oxy)tripyrrolphosphonium hexafluorophosphate (139 mg, 0.267 mmol) and N,N-diisopropylethylamine (91.9 mg, 0.711 mmol) were added 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) 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×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), yield: 49%.

MS m/z(ESI):573.3/575.3[M+1]

Step 8

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

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

At 5°C, 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), 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), nitrogen replacement three times, reaction at 90°C for 2 hours. 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 separation (separation column AKZONOBEL Kromasil; 250×21.2 mm ID; 5 μm, 20 mL/min; mobile phase A: 0.05% TFA+H ₂ O, mobile phase B: CH ₃ CN) 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), yield: 26%.

MS m/z(ESI):618.4[M+1]

¹ H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 7.88–7.77 (m, 2H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.21–7.11 (m, 2H), 7.02 (dd, J = 8.4, 2.0 Hz, 1H), 4.49-4.44 (m, 1H), 3.76 (t, J = 6.8 Hz, 2H), 3.33 (t, J = 6.8 Hz, 2H), 3.31 (s, 3H), 2.98 (t, J = 5.2 Hz, 4H), 2.42-2.39 (m, 2H), 2.23–2.06 (m, 4H), 1.83-1.80 (m, 2H), 1.54 (t, J = 5.2 Hz, 4H), 0.34 (s, 4H).

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:

Embodiment 64

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

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

first step

(E)-6-bromochroman-4-one oxime

(E)-6-Bromochroman-4-one oxime

At room temperature, 6-bromochroman-4-one 64a (5.00 g, 22.02 mmol, commercially available) was added to anhydrous methanol (50 mL), followed by anhydrous sodium acetate (3.61 g, 44.04 mmol) and hydroxylamine hydrochloride (3.06 g, 44.04 mmol), replaced with nitrogen three times, and reacted 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 obtain (E)-6-bromochroman-4-one oxime 64b (5.00 g) with a yield of 93.08%.

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

Step 2

7-bromo-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

7-Bromo-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

At room temperature, (E)-6-bromochroman-4-one oxime 64b (3.00 g, 12.39 mmol) was added to polyphosphoric acid (30 mL) and reacted at 125°C for 1 hour. The reaction was cooled and then poured into ice water (100 mL), and the mixture was extracted with dichloromethane (30 mL×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: A system) to obtain 7-bromo-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one 64c (500 mg) with a yield of 16.67%.

MS m/z(ESI):242.0[M+1]

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).

third step

7-bromo-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

7-Bromo-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

At room temperature, 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), followed by cesium carbonate (673 mg, 2.07 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate 1b (360 mg, 1.55 mmol), and the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 25°C for 18 hours. The mixture was poured into water (20 mL), and the mixture was extracted with ethyl acetate (20 mL×3). 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 residue was purified by silica gel column chromatography (eluent: System A) to give 7-bromo-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one 64d (100 mg) in a yield of 29.88%. MS m/z(ESI):324.0[M+1]

the fourth step

tert-butyl

(4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)carbamate

tert-Butyl (4-oxo-5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-yl)carbamate

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-dicyclohexylphospho-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 above reaction solution, and nitrogen was replaced three times. 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%.

MS m/z(ESI):361.3[M+1]

the fifth step

7-amino-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

7-Amino-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one

At room temperature, 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), and a solution of hydrogen chloride in 1,4-dioxane (1 mL) was added to the reaction solution, and the reaction was carried out at 25°C for 18 hours. The mixture was concentrated to dryness under reduced pressure to obtain 7-amino-5-(2,2,2-trifluoroethyl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one 64f (50.0 mg) with a yield of 98.91%.

MS m/z(ESI):261.2[M+1]

Step 6

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

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

At room temperature, 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), followed by N,N-diisopropylethylamine (57.3 mg, 0.443 mmol) and (7-azabenzotriazole-1-oxy)tripyrrolphosphonium hexafluorophosphate (154 mg, 0.295 mmol), and 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 the mixture was 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+H ₂ O, mobile phase B: CH ₃ CN) to give 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 64 (20.0 mg), yield: 23.31%.

MS m/z(ESI):581.2[M+1]

¹ H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 10.18 (s, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.82 (d, J = 8.4 Hz, 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 = 6.4 Hz, 2H), 3.24–3.16 (m, 2H), 3.03–2.92 (m, 4H), 2.64 (t, J = 6.8 Hz, 2H), 1.60–1.42 (m, 4H), 1.20 (t, J = 7.2 Hz, 3H), 0.34 (s, 4H).

Embodiment 65

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

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

first step

5-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-amine

5-(2,2,2-Trifluoroethyl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-7-amine

At room temperature, 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 replaced with nitrogen three times, and reacted at 65°C for 18 hours. The mixture was filtered and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: A system) 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%.

MS m/z(ESI):247.2[M+1]

Step 2

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

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

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)tripyrrolylphosphonium hexafluorophosphate (154 mg, 0.295 mmol), replaced with nitrogen three times, and reacted at 25° C. for 18 hours. The mixture was poured into water (10 mL), and the mixture was 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+H ₂ O, mobile phase B: CH ₃ CN) to give 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 65 (25.0 mg), yield: 29.86%.

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

¹ H NMR (400 MHz, DMSO-d6) δ 11.55 (s, 1H), 10.13 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 2.4 Hz, 1H), 7.32–7.27 (m, 1H), 7.18 (d, J = 2.4 Hz, 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),3.00–2.91(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).

Embodiment 66

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

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

first step

6-nitro-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

6-Nitro-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

Under ice bath, lithium bis(trimethylsilyl)amide (1M, 7.73mL) was added dropwise to a solution of 6-nitro-4H-1,4-benzoxazin-3-one 66a (1g, 5.15mmol) in N,N-dimethylformamide (10mL), stirred under ice bath for 30 minutes, 2,2,2-trifluoroethyl trifluoromethanesulfonate 1b (1.43g, 6.18mmol) was added, and stirred at room temperature for 3 hours. The reaction solution was quenched with saturated ammonium chloride solution (20mL), extracted with ethyl acetate (20mL×3), and the combined organic phase was washed with saturated sodium chloride solution (30mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (eluent: A system) to obtain 6-nitro-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one 66b (850mg), yield: 60%.

MS m/z(ESI):277.1[M+1]

Step 2

6-amino-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

6-Amino-4-(2,2,2-trifluoroethyl)-2H-benzo[b][1,4]oxazin-3(4H)-one

At room temperature, ammonium chloride (559.35 mg, 10.55 mmol) and iron powder (589.38 mg, 10.55 mmol) were added to a mixed 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), and the mixture was heated at 80°C and stirred for 2 hours. The reaction solution was filtered through celite, and the filtrate was extracted with ethyl acetate (20 mL×3). The combined organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 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.

MS m/z(ESI):247.1[M+1]

third step

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

4-iodo-N-(3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydro2H-benzo[b][1,4]oxazin-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

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-iodo-benzoic acid 8a (80 mg, 223.97 μmol), 1-methylimidazole (55.84 mg, 671.92 μmol) were added to N,N-dimethylformamide (2 mL), stirred at room temperature for 10 minutes, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (188.53 mg, 671.92 μmol) was added, and stirred at room temperature for 4 hours. The reaction solution was poured into water, extracted with ethyl acetate (10 mL×3), and the combined organic phase was 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.

MS m/z(ESI):586.1[M+1]

the fourth step

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

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

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), the atmosphere was replaced with argon and the mixture was heated at 100 °C with stirring for 16 hours. 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% NH ₄ HCO ₃ +H ₂ O, mobile phase B: CH ₃ CN) 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]octan-6-yl)benzamide 66 (39 mg), yield: 39%.

MS m/z(ESI):583.2[M+1]

¹ H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 10.13 (s, 1H), 7.85 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.55 (dd, J = 8.7, 2.2 Hz, 1H), 7.19 (d, J = 2.1 Hz, 1H), 7.14–7.01 (m, 2H), 4.90–4.72 (m, 3H), 3.34 (t, J = 6.5 Hz, 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).

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:

Biological evaluation

Test Example 1: Determination of the inhibitory effect of the compounds of the present invention on OVCAR-3 cell proliferation

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, Catalog No. G7573).

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, and the final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded into a 96-well cell culture plate 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 continued to be 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, and then the luminescence value of each well of the sample was 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), and then a nonlinear regression analysis was performed in GraphPad Prism 5 software using the logarithm of the compound concentration-inhibition rate to obtain the IC ₅₀ value of the compound inhibiting cell proliferation, as shown in Table 1.

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

Conclusion: The compound of the present invention has a significant inhibitory effect on the proliferation of OVCAR-3 cells with an IC ₅₀ of <50 nM.

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

Test Example 2: Determination of the inhibitory effect of the compounds of the present invention on HT-29 cell proliferation

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, Catalog No. G7573).

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, and the final concentration of the compound ranged from 1000nM to 0.015nM. Cells in the logarithmic growth phase were inoculated into a 96-well cell culture plate 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 continued to be 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, and then the luminescence value of each well of the sample was 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), and then a nonlinear regression analysis was performed in GraphPad Prism 5 software using the logarithm of the compound concentration-inhibition rate to obtain the IC ₅₀ value of the compound inhibiting cell proliferation, as shown in Table 2.

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

Conclusion: The compound of the present invention has a significant inhibitory effect on HT-29 cell proliferation with an IC ₅₀ of <50 nM.

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

The following method is used to determine the degree of inhibition of the compound of the present invention on the recombinant human KIF18A enzyme activity under in vitro conditions. This method uses the ADP-Glo ^™ Kinase Assay kit (Cat. No. V9102) from Promega. For detailed experimental procedures, please refer to the kit instructions.

The experimental process is briefly described as follows: the test compound is first dissolved in DMSO to prepare a storage solution, and then gradiently diluted using reaction buffer A (15mM Tris, pH 7.5, 10mM MgCl2, 0.01% Pluronic F-68). The final concentration range of the test compound in the reaction system is 10000nM to 0.15nM; reaction buffer B (15mM Tris, pH 7.5, 10mM MgCl2, 0.01% Pluronic F-68, 37.5ug/ml tubulin, 1.25uM paclitaxel) is used to prepare KIF18A protein and ATP working solution. The reaction was carried out in a 384-well microplate. First, the compound and recombinant human KIF18A protein (final concentration 100nM, entrusted to GenScript for expression) were added to the wells and incubated at room temperature for 20 minutes. Then, ATP solution (from ADP-Glo ^TM Kinase Assay kit component V915A, final concentration 60uM) was added to the reaction solution and incubated at room temperature for 20 minutes. Then 5μL ADP-Glo Reagent was added to the reaction system and incubated at room temperature for 50 minutes. Then 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 ELISA reader in Luminescence mode. The percentage inhibition rate of the compound at each concentration was calculated by comparing the luminescence intensity ratio with the control group (0.1% DMSO), and the IC ₅₀ value of the compound was obtained by nonlinear regression analysis of the compound concentration logarithm-inhibition rate by GraphPad Prism 5 software, as shown in Table 3.

Table 3 IC ₅₀ data of the compounds of the present invention for inhibiting KIF18A enzyme activity

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

Test Example 4: Pharmacokinetics of the Compounds of the Invention in Mice

1. Experimental purpose

ICR mice were used as test animals, and the drug concentrations in plasma at different times after oral administration of the control compound AMG650 and the compounds 8, 39 and 45 of the present invention were determined by LC/MS/MS to study the pharmacokinetic characteristics of the compounds of the present invention in mice.

2. Experimental plan

2.1 Experimental drugs and animals;

control compound AMG650, compounds 8, 39, and 45;

ICR mice, male, 27.1-30.4 g, were purchased from Weitonglihua Laboratory Animal Technology Co., Ltd.

2.2 Drug preparation

Weigh an appropriate amount of drug compound, add appropriate amount of DMA, CrEL and 5% GS in sequence, mix by ultrasonic vortex, and prepare a 1 mg/mL dosing preparation, wherein DMA, CrEL and 5% GS = 10:10:80 (v:v:v).

2.3 Administration

ICR mice were fasted overnight and then intragastrically administered with each test compound injection group (9 mice per group) (PO, compound dosage was 10 mg/kg, administration volume was 10 mL/kg), and food was allowed to be consumed 4 hours after administration.

3. Operation

Before administration and at 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 10 hours and 24 hours after administration, approximately 0.1 mL of blood was collected through the eye socket, and the whole blood samples were placed in anticoagulant tubes containing EDTA-K2. After blood samples were collected, they were placed on ice and centrifuged to separate plasma (centrifugation conditions: 1500g, 10 minutes). The collected plasma was stored at -40 to -20°C before analysis.

The content of the test compound in mouse plasma after oral administration was determined by LC-MS/MS.

4. Pharmacokinetic parameter results

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

Table 4 Pharmacokinetic parameters of the compounds of the present invention in mice

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 (17)

A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
in: Ring A is selected from a 5- to 7-membered heterocyclic group, a C ₃ -C ₆ cycloalkyl group, a 5- to 7-membered aryl group or a 5- to 7-membered heteroaryl group; X ₁ , X ₂ , and X ₃ are each independently selected from CR ^a or a N atom, and at most two atoms among X ₁ , X ₂ , and X ₃ are N atoms at the same time; R ^a is selected from hydrogen atom, halogen, hydroxyl, cyano, alkyl or alkoxy; wherein the alkyl or alkoxy is optionally further substituted by one or more substituents selected from halogen, hydroxyl, cyano, alkyl or alkoxy; L ₁ is selected from a bond or C ₁ -C ₆ alkylene, wherein the alkylene is optionally further substituted by one or more substituents selected from halogen, hydroxy, cyano or alkoxy, and wherein one or more methylene groups of the alkylene are optionally replaced by one or more O, S(O) _r , C(O) or NR ^b ; L ₂ 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 substituents 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 , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ ; ^R2 are the same or different and are 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 is preferably a hydrogen atom; R ⁴ are the same or different and are 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 , -CH ₂ NHC(O)OR ⁵ , -CH ₂ NR ⁶ R ⁷ or -S(O) _r R ⁵ ; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more substituents selected from ^RA ; ^{wherein RA} is selected from hydroxy, halogen, nitro, cyano, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, ^OR8 , -C(O) ^R8 , -C(O) ^OR8 , ^{-OC(O)R8, -NR9R10 , -C} (O) ^NR9R10 , _-SO2NR9R10 or ^-NR9C (O) ^R10 ; wherein the alkyl, ^cycloalkyl , ^heterocyclyl , aryl or ^heteroaryl is optionally further substituted by one or more selected from cyano, halogen, alkyl, hydroxy, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, =O, -C(O) ^R8 , -C(O) ^OR8 , -OC(O) ^R8 , ^{-NR9R10 ,} -C(O) ^NR9R10 , _-SO2NR9R10 or ^{-NR9C (} O ^{) R10} . C(O)R is substituted by a substituent of ¹⁰ ; Alternatively, two R ⁴ and the same carbon atom to which they are attached form a -C(O)-; R ⁵ is each 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 substituents selected from hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ ; ^R6 and ^R7 are each independently selected from a hydrogen atom, a hydroxyl group, a halogen, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, the alkoxy 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 hydroxyl group, a halogen, a nitro group, a cyano group, an alkyl group, an alkoxy group, ^a cycloalkyl group, a heterocyclic group, an aryl group, a heteroaryl group, =O, -C(O) ^R8 , -C(O)OR8, -OC(O) ^R8 , ^-NR9R10 , ^-C (O ⁾ _NR9R10 ^{, -SO2NR9R10} or ^-NR9C ( ^O ) ^R10 ; Alternatively, ^R6 and ^R7 together with the atoms to which they are attached 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 substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy ^, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O) ^R8 , -C(O) ^OR8 , -OC(O) _R8 ^{, -NR9R10,} -C(O ^{) NR9R10, -SO2NR9R10 or -NR9C} (O) ^R10 ; R ⁸ , R ⁹ and R ¹⁰ are each 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. The compound according to claim 1, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof according to general formula (II) or (III):
Ring A, R ¹ , R ³ , R ⁴ , L ₁ and n are as defined in claim 1 . 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:
The compound according to any one of claims 1 to 3, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: L ₁ is selected from a bond or C ₁ -C ₆ alkylene, wherein the alkylene is optionally further substituted with one or more hydroxyl groups, and wherein the one or more methylene groups of the alkylene are optionally replaced with one or more O, S(O) _r , C(O) or NR ^b ; r is 2; R ^b is selected from a hydrogen atom or a methyl group. The compound according to claim 4, 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)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- _, -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-, _{-NHCH2CH 2} or -CH ₂ SO ₂ CH ₂ CH ₂ -. 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 a hydrogen atom, a hydroxyl group, an alkyl group, a heterocyclic group, a cycloalkyl group, or a heteroaryl group, wherein the alkyl group, the heterocyclic group, the cycloalkyl group, or the heteroaryl group is optionally further substituted by one or more selected from a hydroxyl group or an alkyl group. replaced by the base. The compound according to any one of claims 5 to 6, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Selected from The compound according to any one of claims 1 to 7, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom. The compound according to any one of claims 1 to 8, or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, wherein R ⁴ are the same or different and are 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 ^RA ; Alternatively, two R ⁴ groups and the same carbon atom to which they are attached form a -C(O)-. ^RA is selected from halogen, cyano, alkyl, cycloalkyl, ^heterocyclic , ^-OR8 , ^-NR9R10 , wherein the alkyl, cycloalkyl, heterocyclic is optionally further substituted by one or more substituents selected from halogen and haloalkyl; R ⁵ is 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; ^R6 and ^R7 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 is 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; ^R9 and ^R10 are each independently selected from a hydrogen atom, an alkyl group, a halogenated alkyl group The compound according to claim 9 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ⁴ is selected from methyl, difluoromethyl, cyclopropyl, Alternatively, two R ⁴ groups and the same carbon atom to which they are attached form a -C(O)-. The compound according to any one of claims 1 to 10 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound is:






A pharmaceutical composition comprising an effective dose of a compound according to any one of claims 1 to 11 or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Carrier, excipient or a combination thereof. Use of the compound according to any one of claims 1 to 11 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12 in the preparation of a KIF18A inhibitor. Use of the compound according to any one of claims 1 to 11 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, 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. The use according to claim 14, wherein the cancer is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma. Use of the compound according to any one of claims 1 to 11 or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 12 in the preparation of a drug for treating cancer. The use according to claim 16, wherein the cancer is selected from hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, bile duct cancer, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.