CN120265626A

CN120265626A - Aromatic amide derivatives, preparation methods thereof and their use in medicine

Info

Publication number: CN120265626A
Application number: CN202380081519.4A
Authority: CN
Inventors: 张盼盼; 何智鹏; 金晓阳; 王哲宇; 张剑波; 叶成; 徐代旺; 徐肖杰; 周厚江
Original assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Current assignee: Zhejiang Hisun Pharmaceutical Co Ltd; Shanghai Aryl Pharmtech Co Ltd
Priority date: 2022-12-14
Filing date: 2023-12-12
Publication date: 2025-07-04
Also published as: WO2024125488A1

Abstract

提供一种芳香酰胺类衍生物、其制备方法及含有该衍生物的药物组合物在医药上的应用。具体而言，提供一种通式(I)所示的芳香酰胺类衍生物、其制备方法及其可药用的盐，以及它们作为治疗剂，特别是KIF18A抑制剂的用途。 Provided are aromatic amide derivatives, preparation methods thereof, and pharmaceutical compositions containing the derivatives for use in medicine. Specifically, provided are aromatic amide derivatives represented by general formula (I), preparation methods thereof, and pharmaceutically acceptable salts thereof, and their use as therapeutic agents, particularly KIF18A inhibitors.

Description

Aromatic amide derivative, preparation method thereof and application thereof in medicine

Technical Field

The invention relates to an aromatic amide derivative, a preparation method thereof, a pharmaceutical composition containing the derivative and application of the derivative as a therapeutic agent, in particular to an KIF18A inhibitor.

Background

Kinesin molecules are motor proteins that take microtubules as a rail and play an important role in processes such as organelle migration, tissue and organ development, signal transduction, mitosis, and meiosis. The various microtubule-binding proteins of the kinesin kinesin-8 family (microtubule-associatedprotein, MAP) play a role in regulating microtubule dynamic instability by affecting the polymerization and depolymerization of microtubules. KIF18A is a member of kinesin-8 family, can move towards the positive electrode by taking microtubules as tracks, tends to combine with longer microtubules, has length dependence on activity and influences the length of spindles, can ensure timely and smooth completion of sister chromosome alignment, has very similar functions in different species, and has conservation.

KIF18A is a molecular motor protein that moves towards the positive end of microtubules using microtubules as a track, and functions in the mitosis stage by affecting the medium plate set of the microtubule end dynamic instability regulatory chromosome. In the later stage of mitosis, the protein is degraded by ubiquitin, so that the accurate separation of chromosomes in the mitosis process is ensured, and the mitosis and cytokinesis are promoted to be completed smoothly. In the early stage of mitosis, the positioning of KIF18A at the positive end of a microtubule near the kinetochore is a necessary condition for the function of the KIF18A, the positioning not only depends on the activity of a motor at the N end of the KIF, but also plays a key role in the tail domain with microtubule binding capacity. KIF18A is also subject to reversible protein phosphorylation/dephosphorylation modifications, but there is no systematic study on how this posttranslational modification of proteins modulates KIF18A function. The estrogen receptor ER alpha can bind with KIF18A and promote the transcription thereof, but whether the KIF18A is regulated by other transcription factors is still unclear, so that the gene transcription regulation mechanism of the KIF18A is still under deep research. During meiosis, cells lacking KIF18A will not be able to complete meiosis, which in turn can lead to male dysspermatia and testicular dysplasia.

The research shows that the KIF18A protein has high expression in various cancers, including but not limited to hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostatic cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma and the like, which predicts that the KIF18A is closely related to the occurrence and development of tumors and can be used as a target for molecular diagnosis and treatment of various tumors. Expression of KIF18A is associated with clinical colorectal cancer progression. The research shows that KIF18A can induce Akt to phosphorylate, and the knocking out of KIF18A in mice can obviously promote apoptosis, and the KIF18A is presumed to promote the occurrence and development of colorectal cancer by activating PI3K-Akt signaling pathway. KIF18A is also highly expressed in human breast cancer cells and its overexpression is associated with grading, migration and prognosis of breast tumors. Studies on breast cancer cells show that overexpression of KIF18A can lead to the generation of multinucleated cells, and low expression can greatly weaken the proliferation capacity of cells in vitro and in vivo, and apoptosis is induced by stabilizing microtubules at the ends of the microtubules and inactivating PI3K-Akt signal transduction pathways by the KIF 18A. In addition, in lung adenocarcinoma KIF18A is upregulated on both transcriptional and translational levels, and abnormal expression of KIF18A is associated with clinical pathological malignancy. Mutations in the KIF18 gene can be observed in lung adenocarcinoma, expression is also regulated by DNA copy number, and KIF18A gene knockout can inhibit proliferation of lung adenocarcinoma cells in vivo and in vitro, induce apoptosis and G2/M phase arrest. Genes which are simultaneously and highly expressed with the KIF18A are concentrated in a cell cycle signal path, so that the deep research on the action mechanism of the KIF18A in tumors has important clinical significance.

Inhibitors against the KIF18A target have not been marketed as a new drug, and only the AMG-650 compound of the american security company has entered clinical phase I. As a comparative leading direction of research, there is a tremendous search space for the relevant research of KIF18A targets, and it is necessary to continue to study their mechanism of action and develop new inhibitors.

Disclosure of Invention

In view of the above technical problems, the present invention provides a compound represented by general formula (I):

Wherein:

R is selected from

Ring A is selected from 3-8 membered heterocyclic group or C ₃-C₈ cycloalkyl;

Each X ₁、X₂、X₃ is independently selected from the group consisting of absent, CR ^a, N, or S atoms, and up to two of X ₁、X₂、X₃ are simultaneously N atoms, and up to one of X ₁、X₂、X₃ is absent;

Each a ₁、A₂、A₃ is independently selected from CR ^a or an N atom, and up to two atoms in a ₁、A₂、A₃ are simultaneously N atoms;

Each of G ₁ and G ₂ is independently selected from the group consisting of a bond, (CR ^aR^b)_p、C(O)、NR^c, O, or S (O) r; G ₁ and G ₂ are not both bonds;

G ₃ is selected from a bond, (CR ^aR^b)_p、C(O)、NR^c) or O;

R ^a and R ^b are each independently selected from hydrogen, halogen, hydroxy, cyano, alkyl or alkoxy, wherein said alkyl or alkoxy is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

R ^c is each independently selected from a hydrogen atom or an alkyl group, wherein said alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

L ₁ is selected from a bond, C _0-4 alkyl-SO ₂-C_0-4 alkyl, C _0-4 alkyl-S (=O) (=NH) -C _0-4 alkyl, C _0-4 alkyl-NR ^dSO₂-C_0-4 alkyl, C _0-4 alkyl-SO ₂NR^d-C_0-4 alkyl, C _0-4 alkyl-O-C _0-4 alkyl, c _0-4 alkyl- (OH) -C _0-4 alkyl, C _0-4 alkyl-NR ^d-C_0-4 alkyl, C _0-4 alkyl-NR ^dSO₂NR^d-C_0-4 alkyl, C _0-4 alkyl-NR ^d-C(O)NR^d-C_0-4 alkyl, C _0-4 alkyl-C (O) NR ^d-C_0-4 alkyl or C _0-4 alkyl-NR ^dC(O)-C_0-4 alkyl;

R ^d is each independently selected from a hydrogen atom or an alkyl group;

l ₂ is selected from

R ¹ is selected from the group consisting of hydrogen, cyano, halogen, alkyl, hydroxy, NR ⁹R¹⁰, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R⁸、-C(O)OR⁸、-OC(O)R⁸、-NR⁹R¹⁰、-C(O)NR⁹R¹⁰、-SO₂NR⁹R¹⁰, or-NR ⁹C(O)R¹⁰;

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

Or two R ² taken together with the atoms to which they are attached form a 3-8 membered heterocyclyl or cycloalkyl, wherein the 3-8 membered heterocyclyl contains one or more N, O or S (O) R, and said 4-8 membered heterocyclyl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R⁸、-C(O)OR⁸、-OC(O)R⁸、-NR⁹R¹⁰、-C(O)NR⁹R¹⁰、-SO₂NR⁹R¹⁰ or-NR ⁹C(O)R¹⁰;

R ³ is each independently selected from a hydrogen atom or an alkyl group, wherein said alkyl group is optionally further substituted with one or more substituents selected from halogen, hydroxy, cyano or alkoxy;

R ⁴, which are identical or different, are each independently selected from the group consisting of hydrogen, cyano, halogen, alkyl, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、-OR⁵、-C(O)R⁵、-C(O)OR⁵、-NHC(O)R⁵、-NHC(O)OR⁵、-NR⁶R⁷、-C(O)NR⁶R⁷、-CH₂NHC(O)OR⁵、-CH₂NR⁶R⁷ and-S (O) _rR⁵, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R⁸、-C(O)OR⁸、-OC(O)R⁸、-NR⁹R¹⁰、-C(O)NR⁹R¹⁰、-SO₂NR⁹R¹⁰ and-NR ⁹C(O)R¹⁰;

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

R ⁵ is each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R⁸、-C(O)OR⁸、-OC(O)R⁸、-NR⁹R¹⁰、-C(O)NR⁹R¹⁰、-SO₂NR⁹R¹⁰, or-NR ⁹C(O)R¹⁰;

R ⁶ and R ⁷ are each independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R⁸、-C(O)OR⁸、-OC(O)R⁸、-NR⁹R¹⁰、-C(O)NR⁹R¹⁰、-SO₂NR⁹R¹⁰, or-NR ⁹C(O)R¹⁰;

Or R ⁶ and R ⁷ together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S (O) R groups and said 4-8 membered heterocyclic group is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl 、＝O、-C(O)R⁸、-C(O)OR⁸、-OC(O)R⁸、-NR⁹R¹⁰、-C(O)NR⁹R¹⁰、-SO₂NR⁹R¹⁰ or-NR ⁹C(O)R¹⁰;

R ⁸ is selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, or a heteroaryl group, wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl group, heteroaryl group, carboxyl group, or carboxylate group;

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, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl group, heteroaryl group, carboxyl group, or carboxylate group;

Each m is independently 0,1 or 2, m is preferably 0;

n is 0,1,2,3 or 4;

p are each independently 1,2 or 3;

r are each independently 0,1 or 2.

In a preferred embodiment of the present invention, a compound of formula (I) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (II):

Wherein X ₁～X₃、A₁～A₃、G₁、G₂、G₃, ring A, R ¹、R²、R⁴、L₁、L₂, m and n are as defined in formula (I).

In a preferred embodiment of the present invention, a compound of formula (II) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (III):

Wherein X ₁～X₃、A₁～A₃、G₁、G₂, ring A, R ¹、R²、R⁴、L₁、L₂, m and n are as defined in formula (I).

In a preferred embodiment of the present invention, a compound of formula (III) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof is a compound of formula (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

Wherein X ₁～X₃、A₁～A₃、G₁、G₂, ring A, R ¹、R³、R⁴、L₁ and n are as defined in formula (I).

In a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein ring a is selected from:

In a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L ₁ is selected from the group consisting of bond 、-NHSO₂CH₂CH₂-、-SO₂NHCH₂CH₂-、-SO₂-、-CH₂SO₂-、-NHSO₂-、-NHSO₂NH-、-SO₂NH-、-S(＝O)(＝NH)CH₂CH₂、-S(＝O)(＝NH)-、-NHC(CH₃)₂CH2-、-C(O)NHCH₂CH₂-、-C(O)NHC(CH₃)₂CH2-、-C(O)N(CH₃)CH₂CH₂-、-CH(CH₃)(OH)CH₂-、-NHSO₂CH(CH3)CH₂-、-SO₂NHC(CH3)₂CH₂-、-C(O)NH-、-NHC(O)-、-NHCH₂CH₂ and-CH ₂SO₂CH₂CH₂ -.

In a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of hydrogen, hydroxy, alkyl, heterocyclyl, cycloalkyl, and heteroaryl, wherein the alkyl, heterocyclyl, cycloalkyl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy and alkyl.

In a preferred embodiment of the invention, a compound of the general formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, whereinSelected from:

In a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ³ is a hydrogen atom.

In a preferred embodiment of the invention, a compound of formula (I), (II), (III), (IV) or (V) or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

R ⁴ is selected from a hydrogen atom, halogen, alkyl, cycloalkyl, heterocyclyl or-C (O) R ⁵, wherein said alkyl, cycloalkyl or heterocyclyl is optionally further substituted with one or more halogens;

R ⁵ is selected from alkyl.

In a preferred embodiment of the invention, the compound of formula (la) is selected from:

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

Note that if there is a difference between the drawn structure and the name given to the structure, the drawn structure will be given more weight.

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

The invention provides an application of a compound shown in a general formula (I), (II), (III), (IV) or (V), a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in preparing a KIF18A inhibitor.

The invention also provides application of the compound shown in the general formula (I), (II), (III), (IV) or (V) or stereoisomer, tautomer or pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating diseases mediated by KIF18A, wherein the diseases mediated by KIF18A are preferably cancers, and the diseases mediated by KIF18A are selected from hepatocellular carcinoma, glioblastoma, colon carcinoma, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostate cancer, bladder cancer, head cancer, neck cancer, cervical cancer, ovarian cancer, synovial sarcoma, rhabdomyosarcoma, colorectal cancer and lung adenocarcinoma.

The invention further provides application of the compound shown in the general formula (I), (II), (III), (IV) or (V) or stereoisomer, tautomer or pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof in preparing medicines for treating cancers.

The invention provides an application of a compound shown in a general formula (I), (II), (III), (IV) or (V) or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof in preparing medicines for treating hepatocellular carcinoma, glioblastoma, colon cancer, breast cancer, lung cancer, cholangiocarcinoma, pancreatic cancer, prostatic 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 stated to the contrary, 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 part of a group is meant to include C ₁-C₂₀ straight or branched chain aliphatic hydrocarbon groups. Preferably a C ₁-C₁₀ alkyl group, more preferably a C ₁-C₆ alkyl group. 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-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl, and the like. Alkyl groups may be substituted or unsubstituted.

"Alkylene" refers to a saturated C ₁-C₂₀ straight or branched aliphatic hydrocarbon group having 2 residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of the parent alkane, preferably a C ₁-C₁₀ alkylene group, more preferably a C ₁-C₆ alkylene group. Examples of alkylene groups include, but are not limited to, methylene, 1-ethylene, 1, 2-ethylene, 1-propylene, 1, 2-propylene, 1, 3-propylene, 1, 4-butylene, and the like. The alkylene group may be substituted or unsubstituted.

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

"Spirocycloalkyl" refers to a 5 to 18 membered, two or more cyclic structure, and monocyclic polycyclic groups sharing one carbon atom (called spiro atom) with each other, containing 1 or more double bonds within the ring, but no ring has a completely conjugated pi-electron aromatic system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro group, a double spiro group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably single spiro group and double spirocycloalkyl group, preferably 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. 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 ring alkyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of carbon atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group. Non-limiting examples of "fused ring alkyl" groups include, but are not limited to, bicyclo [3.1.0] hexyl, bicyclo [3.2.0] hept-1-enyl, bicyclo [3.2.0] heptyl, decalin, or tetradecaphthenyl.

"Bridged cycloalkyl" means an aromatic system having 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups with one another that are not directly attached to a carbon atom, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron, preferably 6 to 12 members, more preferably 7 to 10 members. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged cycloalkyl" include, but are not limited to, (1 s,4 s) -bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, (1 s,5 s) -bicyclo [3.3.1] nonyl, bicyclo [2.2.2] octyl, (1 r,5 r) -bicyclo [3.3.2] decyl.

"Heterocyclyl", "heterocycloalkyl", "heterocycle" or "heterocyclic" are used interchangeably herein to refer to a non-aromatic heterocyclic group in which one or more of the ring-forming atoms is selected from nitrogen, oxygen or a heteroatom of S (O) _t (wherein t is selected from 0,1 or 2), including monocyclic, polycyclic, fused, bridged and spiro rings. Preferably having a 5 to 7 membered single ring or a 7 to 10 membered double or triple ring, which may contain 1,2 or 3 atoms selected from nitrogen, oxygen and/or sulphur. Examples of "heterocyclyl" include, but are not limited to, morpholinyl, oxetanyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, 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.

"Spiroheterocyclyl" refers to a5 to 18 membered, two or more cyclic structure, polycyclic group wherein the monocyclic rings share one atom with each other, the rings contain 1 or more double bonds, but none of the rings have a fully conjugated pi-electron aromatic system wherein one or more of the ring atoms is selected from nitrogen, oxygen or a heteroatom of S (O) _t (wherein t is selected from 0,1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spirocycloalkyl group is classified into a single spiro heterocyclic group, a double spiro heterocyclic group or a multiple spiro heterocyclic group according to the number of common spiro atoms between rings, and preferably a single spiro heterocyclic group and a double spiro heterocyclic group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro 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 heterocyclyl" refers to an all-carbon polycyclic group containing two or more cyclic structures sharing a pair of atoms with each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen, or a heteroatom of S (O) _t (where t is selected from 0, 1, or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of "fused heterocyclyl" groups include, but are not limited to, octahydropyrrolo [3,4-c ] pyrrolyl, octahydro-1H-isoindolyl, 3-azabicyclo [3.1.0] hexyl, octahydrobenzo [ b ] [1,4] dioxin (dioxine).

"Bridged heterocyclyl" means a 5 to 14 membered, 5 to 18 membered, polycyclic group containing two or more cyclic structures sharing two atoms not directly attached to each other, one or more of the rings may contain one or more double bonds, but none of the rings has a fully conjugated pi electron aromatic system in which one or more of the ring atoms is selected from nitrogen, oxygen or a heteroatom of S (O) _t (wherein t is selected from 0, 1 or 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of "bridged heterocyclyl" include, but are not limited to, 2-azabicyclo [2.2.1] heptyl, 2-azabicyclo [2.2.2] octyl, 2-azabicyclo [3.3.2] decyl.

"Aryl" refers to a carbocyclic aromatic system containing one or two rings, wherein the rings may be linked together in a fused manner. The term "aryl" includes monocyclic or bicyclic aryl groups such as phenyl, naphthyl, tetrahydronaphthyl aromatic groups. Preferably aryl is C ₆-C₁₀ aryl, more preferably aryl is phenyl and naphthyl, most preferably naphthyl. Aryl groups 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, furyl, pyridyl, 2-oxo-1, 2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2, 3-thiadiazolyl, benzodioxolyl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, 1, 3-dioxo-isoindolyl, quinolinyl, indazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl isothiazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl, pyridyl, pyrimidinyl, pyrazin-2 (1H) -onyl, pyrimidin-4 (3H) -onyl, pyridazin-3 (2H) -onyl, 1H-indolyl, 1H-benzo [ d ] imidazolyl, 1H-pyrrolo [2,3-c ] pyridyl, 3H-imidazo [4,5-c ] pyridyl, isoquinolyl, quinazolinyl, 2H-isoindolyl, furo [3,2-b ] pyridyl, furo [2,3-c ] pyridyl, thieno [2,3-c ] pyridyl, benzofuranyl, benzo [ b ] thienyl, 1H-pyrrolo [3,2-b ] pyridyl, 2H-pyrrolo [3,4-c ] pyridyl. Heteroaryl groups may be substituted or unsubstituted.

"Alkoxy" refers to a group of (alkyl-O-). Wherein alkyl is as defined herein. Alkoxy of C ₁-C₆ is a preferred choice. Examples include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

"Nitro" refers to the-NO ₂ group.

"Hydroxy" refers to an-OH group.

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

"Amino" refers to-NH ₂.

"Cyano" refers to-CN.

"Benzyl" means-CH ₂ -phenyl.

"Carboxy" means-C (O) OH.

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

"Hydroxyalkyl" refers to hydroxy-substituted alkyl groups, wherein alkyl is as defined above.

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

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

"Haloalkoxy" refers to a halogen substituted alkoxy group, wherein the definition of alkoxy is as described above.

"DMSO" refers to dimethyl sulfoxide.

"BOC" refers to t-butoxycarbonyl.

"Bn" refers to benzyl.

"THP" refers to 2-tetrahydropyranyl.

"TFA" refers to trifluoroacetic acid.

"Ts" refers to p-toluenesulfonyl.

The term "leaving group (leaving group)", or leaving group, is used in the terms nucleophilic substitution reaction and elimination reaction as an atom or functional group that breaks away from a larger molecule in a chemical reaction. In nucleophilic substitution reactions, the reactant that is attacked by a nucleophile is referred to as a substrate (substrate), and the atom or group of atoms that breaks away from a pair of electrons in the substrate molecule is referred to as a leaving group. Groups that accept electrons easily and bear a strong negative charge are good leaving groups. The smaller the pKa of the leaving group conjugate acid, the easier the leaving group will be to disengage from the other molecule. The reason is that when the pKa of its conjugate acid is smaller, the corresponding leaving group does not need to be bound to other atoms, and the tendency to exist in anionic (or charge neutral leaving group) form is enhanced. Common leaving groups include, but are not limited to, halogen, methanesulfonyl, -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 independently substituted with a corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions, and that the person skilled in the art is able to determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxyl groups having free hydrogen may be unstable when bound to carbon atoms having unsaturated (e.g., olefinic) bonds.

"Substituted" or "substituted" as used herein, unless otherwise indicated, means that the group may be substituted with one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, carboxylate 、＝O、-OR⁶、-C(O)R⁶、-C(O)OR⁶、-NHC(O)R⁶、-NHC(O)OR⁶、-NR⁷R⁸、-C(O)NR⁷R⁸、-CH₂NHC(O)OR⁶、-CH₂NR⁷R⁸, or-S (O) rR ⁶;

R ⁶ is selected from the group consisting of a hydrogen atom, alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from the group consisting of hydroxy, halogen, nitro, cyano, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R⁹、-C(O)OR⁹、-OC(O)R⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹、-SO₂NR¹⁰R¹¹, or-NR ¹⁰C(O)R¹¹;

R ⁷ and R ⁸ are each independently selected from hydrogen, hydroxy, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl 、＝O、-C(O)R⁹、-C(O)OR⁹、-OC(O)R⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹、-SO₂NR¹⁰R¹¹, or-NR ¹⁰C(O)R¹¹;

Or R ⁷ and R ⁸ together with the atoms to which they are attached form a 4-8 membered heterocyclic group, wherein the 4-8 membered heterocyclic group contains one or more N, O or S (O) R groups and said 4-8 membered heterocyclic group is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl 、＝O、-C(O)R⁹、-C(O)OR⁹、-OC(O)R⁹、-NR¹⁰R¹¹、-C(O)NR¹⁰R¹¹、-SO₂NR¹⁰R¹¹ or-NR ¹⁰C(O)R¹¹;

R ⁹、R¹⁰ and R ¹¹ 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, cycloalkyl group, heterocyclic group, aryl group, or heteroaryl group is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic group, aryl group, heteroaryl group, carboxyl group, or carboxylate group;

r is selected from 0,1 or 2;

The compounds of the invention may contain asymmetric or chiral centers and thus 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 (atropisomer) and geometric (conformational) isomers and mixtures thereof, such as racemic mixtures, are within the scope of the present invention.

Unless otherwise indicated, the structures described herein also include all stereoisomers (e.g., diastereomers, enantiomers and atropisomers and geometric (conformational) isomeric forms of such structures, e.g., the R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers.

"Pharmaceutically acceptable salts" refers to certain salts of the above compounds which retain the original biological activity and are suitable for pharmaceutical use. The pharmaceutically acceptable salts of the compounds represented by the general formula (I) may be metal salts, amine salts with suitable acids.

"Pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically acceptable salt or prodrug thereof, and other chemical components, such as physiologically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

Synthesis method of compound of the invention

To better illustrate the synthesis of the present invention, the compounds of general formula (I) may be further specified by the following structure:

The general formula (I) can be achieved by the following three steps:

(1) Synthesis of left-hand ring 1 Compounds

(2) Synthesis of right-side Ring 2 Compounds

(3) Linking a Ring 1 Compound and a Ring 2 Compound

The above provides a reference for the synthesis of compounds, and different L ₁-R¹ needs to be achieved by adjusting the synthesis sequence.

Further, the compounds of formula (I) may be specifically of the structure:

The general formula (I-1) and the general formula (I-2) can be achieved by the following three steps:

(1) Synthesis of carboxylic acid derivatives

(2) Synthesis of amine derivatives

(3) The two side fragments are connected under amide condensation condition, and the corresponding compound is synthesized through reasonable conversion of-L1-R1.

Further, taking the synthesis of (I-1) as an example:

The compound of the general formula (IA) and the compound of the general formula (IB) undergo condensation reaction to obtain a compound of the general formula (IC), and the compound of the general formula (IC) undergoes combined metal catalytic reaction, substitution reaction and the like to obtain (I-1);

Wherein:

X is selected from leaving groups such as OH, cl;

Y is selected from halogen, such as Cl, br, I;

the definitions of X ₁～X₃、A₁～A₃、G₁、G₂、G₃, the ring A, R, R ¹、R³、R⁴、L₁、L₂ and n are as described in the general formula (I).

Detailed Description

The invention will be further described with reference to the following examples, which are not intended to limit the scope of the invention.

Examples

The preparation of representative compounds represented by formula (I) and related structural identification data are presented in the examples. It must be noted that the following examples are given by way of illustration and not by way of limitation. ¹ The H NMR spectrum was determined with a Bruker instrument (400 MHz) and the chemical shifts were 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, m = multiple peak(s), br=the width of the strip to be widened. If coupling constants are provided, they are in Hz.

The mass spectrum is measured by an LC/MS instrument, and the ionization mode can be ESI or APCI.

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Column chromatography generally uses a tobacco stand yellow sea silica gel of 200-300 meshes as a carrier.

In the following examples, unless otherwise indicated, all temperatures are in degrees celsius and, unless otherwise indicated, various starting materials and reagents are either commercially available or synthesized according to known methods, all of which are used without further purification and, unless otherwise indicated, commercially available manufacturers include, but are not limited to, ALDRICH CHEMICAL Company, ABCR GmbH & co.kg, acros Organics, praise chemical technology co.ltd, and beauty chemical technology co.ltd.

CD ₃ OD deuterated methanol.

CDCl ₃ deuterated chloroform.

DMSO-d ₆ deuterated dimethyl sulfoxide.

The argon atmosphere means that the reaction flask is connected to an argon balloon of about 1L volume.

The examples are not particularly described, and the solution in the reaction is an aqueous solution.

Purifying the compound by adopting a silica gel column chromatography method and a reversed phase column chromatography method, wherein the eluent system is selected from the group consisting of a petroleum ether and ethyl acetate system, a methylene dichloride and methanol system, a methylene dichloride and ethyl acetate system, a trifluoroacetic acid aqueous solution and acetonitrile system and a water and methanol system. The volume ratio of the solvent is different according to the polarity of the compound, and can be adjusted by adding a small amount of acidic or alkaline reagent, such as acetic acid or triethylamine.

Example 1

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

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

4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid

2-Fluoro-4-iodobenzoic acid 1a (9.06 g,34.06 mmol), 6-azaspiro [2.5] octane hydrochloride 1b (6.03 g,40.9 mmol), anhydrous potassium carbonate (16.5 g,119.2 mmol) was added to a round bottom flask, dimethyl sulfoxide (30 mL) was added, and the mixture was warmed to 140℃and stirred for 7 hours, and LC-MS monitored that the reaction was complete. The reaction solution was poured into 300mL of ice water, and concentrated hydrochloric acid was added dropwise to adjust the pH to about 5, a large amount of a brown yellow solid was precipitated, stirred for 0.5 hour, then filtered, the cake was rinsed with ice water, dried, slurried with petroleum ether (100 mL), and concentrated under reduced pressure to give 1c (11.08 g, yield 91.1%) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid.

Second step

(4-bromo-2-iodophenyl)methanol

(4-Bromo-2-iodophenyl) methanol

Methyl 4-bromo-2-iodobenzoate 1d (10 g,29.33 mmol) was dissolved in dichloromethane (500 mL), nitrogen protected, cooled to-78℃and diisobutylaluminum hydride (8.34 g,58.66 mmol) was slowly added dropwise thereto and reacted for 1 hour at a maintained temperature, and after warming to room temperature, the reaction was continued for 1 hour, and TLC detection of the completion of the reaction of the starting material was performed. The reaction solution was poured into saturated aqueous ammonium chloride (500 mL), extracted with ethyl acetate (500 mL. Times.3), and the combined organic phases were washed successively with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: A system) to give (4-bromo-2-iodophenyl) methanol 1e (6.1 g, yield 66.5%).

Third step

4-bromo-1-(chloromethyl)-2-iodobenzene

4-Bromo-1- (chloromethyl) -2-iodobenzene

(4-Bromo-2-iodophenyl) methanol 1e (6 g,19.17 mmol) was dissolved in dichloromethane (100 mL), N-dimethylformamide (2.1 g,28.76 mmol) was added, cooled to 0℃and thionyl chloride (4.56 g,38.35 mmol) was slowly added dropwise, the reaction was continued for 0.5 hour at the end of the dropwise addition, and continued for 1 hour at room temperature, and TLC detected completion of the starting material reaction. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution (100 mL), extracted with ethyl acetate (150 mL. Times.3), and the organic phases were combined, washed with saturated brine (100 mL) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the obtained residue was further separated and purified by silica gel column chromatography (eluent: A system) to give 4-bromo-1- (chloromethyl) -2-iodobenzene 1f (5.3 g, yield 83.4%).

Fourth step

6'-bromo-4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]

6' -Bromo-4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ]

4-Bromo-1- (chloromethyl) -2-iodobenzene 1f (5 g,15.09 mmol) was dissolved in tetrahydrofuran (200 mL), nitrogen protected, cooled to-40℃and slowly added dropwise isopropyl magnesium chloride-lithium chloride (2.61 g,18.11 mmol), kept at temperature for 0.5h, 4-difluorocyclohexanone 1g (2.02 g,15.09 mmol) was added, and the reaction was continued for 1h at room temperature with TLC detection of complete reaction of starting material. The reaction mixture was poured into water (200 mL), extracted with ethyl acetate (300 mL. Times.3), and the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: A system) to give 6' -bromo-4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ]1h (0.94 g, yield 20.2%).

Fifth step

4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-amine

4, 4-Difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -amine

6' -Bromo-4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ]1h (0.5 g,1.65 mmol), tert-butyl carbamate (0.58 g,4.95 mmol), tris (dibenzylideneacetone) dipalladium (0.23 g,0.25 mmol), dicyclohexyl [3, 6-dimethoxy-2 ',4',6' -triisopropyl [1,1' -biphenyl ] -2-yl ] phosphine (BrettPhos, 0.27g,0.49 mmol), cesium carbonate (1.61 g,4.95 mmol), 4A molecular sieve (0.14 g,0.33 mmol) were added to the lock tube, 1, 4-dioxane (15 mL) was added, and the reaction was monitored by LC-MS at 110℃for 4 hours. The mixture was filtered through celite, the filter cake was rinsed with ethyl acetate (50 mL. Times.3), the filtrates were dried by spin, 10mL of hydrochloric acid-dioxane solvent was added, and the mixture was stirred at room temperature for 2 hours, and the reaction was complete as monitored by LC-MS. The reaction solution was concentrated under reduced pressure, ethyl acetate (20 mL. Times.3) and a saturated aqueous sodium carbonate solution were added to conduct extraction, the aqueous phase was alkaline in pH, and the organic phases were combined, washed successively with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -amine 1i (0.14 g, yield 35.9%).

MS m/z(ESI):240.1[M+1]⁺

Sixth step

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

4, 4-Difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -amine 1i (0.13 g,0.54 mmol), 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid 1c (0.21 g,0.6 mmol), 2- (7-azabenzotriazol) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (HATU, 0.31g,0.82 mmol) was added to the round bottom flask, N, N-dimethylformamide (3 mL), diisopropylethylamine (DIPEA, 0.14g,1.1 mmol) was added and stirred at room temperature for 2 hours and LC-MS monitored complete reaction of the starting materials. Ethyl acetate (10 mL x 3) and saturated brine were added thereto, the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: a system), and spin-dried to give N- (4, 4-difluoro-3 ' h-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 1j (0.26 g, yield 82.7%).

MS m/z(ESI):579.2[M+1]⁺

Seventh step

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 1j (60 mg,0.1 mmol), cuprous iodide (5.93 mg,0.031 mmol), sarcosine (13.9 mg,0.15 mmol), potassium phosphate trihydrate (82.9 mg,0.3 mmol), 2-hydroxyethyl-1-sulfonamide 1k (19.5 mg,0.15 mmol) was added to the vial, N-dimethylformamide (2 mL) was added, and the mixture was stirred at 110℃for 3 hours under nitrogen protection, and the reaction was complete by LC-MS. Ethyl acetate (10 mL. Times.3) and saturated brine were added thereto for extraction, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: A system), concentrated to give 1 (50 mg, yield 83.7%),

MS m/z(ESI):576.3[M+1]⁺

Example 2

4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(2',3',5',6'-tetrahydro-3H-spiro[isobenzofuran-1,4'-pyran]-6-yl)benzamide

4- ((2-Hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (2 ',3',5',6' -tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ] -6-yl) benzamide

First step

2-((4-bromo-2-iodobenzyl)oxy)tetrahydro-2H-pyran

2- ((4-Bromo-2-iodobenzyl) oxy) tetrahydro-2H-pyran

(4-Bromo-2-iodophenyl) methanol 1e (16.2 g,51.77 mmol) and 3, 4-dihydropyran (7.40 g,88.01 mmol) were added to dichloromethane (160 mL), and 4-methylbenzenesulfonic acid pyridine (520.38 mg,2.07 mmol) was slowly added under nitrogen, and stirring was continued under ice for 1 hour, followed by warming to room temperature and stirring for 16 hours. After completion of TLC detection, water (200 mL) was added, dichloromethane (150 mL. Times.3) was added to extract, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: A system), and spin-dried to give 2- ((4-bromo-2-iodobenzyl) oxygen) tetrahydro-2H-pyran 2a (16.1 g, yield 78.3%).

Second step

4-(5-bromo-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)tetrahydro-2H-pyran-4-ol

4- (5-Bromo-2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) tetrahydro-2H-pyran-4-ol

2- ((4-Bromo-2-iodobenzyl) oxy) tetrahydro-2H-pyran 2a (10 g,25.19 mmol) was added to tetrahydrofuran (100 mL), nitrogen protected, cooled to-40℃and a solution of isopropyl magnesium chloride-lithium chloride in tetrahydrofuran (1.3M, 29.06 mL) was added dropwise, after the addition was completed, the temperature was maintained for 0.5 hour, a solution of tetrahydropyranone 2b (5.04 g,50.37 mmol) in tetrahydrofuran (30 mL) was added dropwise, the reaction was allowed to warm naturally to room temperature overnight, the liquid mass was detected to completion, quenched with saturated aqueous ammonium chloride solution, ethyl acetate (150 mL. Times.3) was added, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: E system) to give 4- (5-bromo-2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) tetrahydro-2H-pyran-4-ol 2C (7.1 g, 75.9%)

Third step

4-(5-bromo-2-(hydroxymethyl)phenyl)tetrahydro-2H-pyran-4-ol

4- (5-Bromo-2- (hydroxymethyl) phenyl) tetrahydro-2H-pyran-4-ol

4- (5-Bromo-2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) tetrahydro-2H-pyran-4-ol 2c (7.1 g,19.12 mmol) was dissolved in methanol (100 mL), hydrochloric acid (1M, 19.12 mL) was added, the reaction was carried out at room temperature for 2 hours, TLC detection was complete, saturated sodium bicarbonate solution (100 mL) was added to the system, ethyl acetate (100 mL. Times.2) was added for extraction, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 4- (5-bromo-2- (hydroxymethyl) phenyl) tetrahydro-2H-pyran-4-ol 2d (4.1 g, yield 74.7%)

Fourth step

4-bromo-2-(4-hydroxytetrahydro-2H-pyran-4-yl)benzyl methanesulfonate

4-Bromo-2- (4-hydroxytetrahydro-2H-pyran-4-yl) benzyl methanesulfonate

4- (5-Bromo-2- (hydroxymethyl) phenyl) tetrahydro-2H-pyran-4-ol 2d (3.8 g,13.23 mmol) was dissolved in tetrahydrofuran (70 mL), triethylamine (6.7 g,66.17 mmol) was added, cooled to 0℃and methylsulfonyl chloride (1.82 g,15.88 mmol) was added dropwise and the mixture was allowed to react at room temperature for 2 hours. The reaction was complete by TLC, the reaction solution was poured into water (50 mL), dichloromethane (100 mL. Times.2) was added and extracted, the combined organic phases were washed successively with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 4-bromo-2- (4-hydroxytetrahydro-2H-pyran-4-yl) benzyl mesylate 2e (4.2 g, yield 86.9%).

Fifth step

6-bromo-2',3',5',6'-tetrahydro-3H-spiro[isobenzofuran-1,4'-pyran]

6-Bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ]

4-Bromo-2- (4-hydroxytetrahydro-2H-pyran-4-yl) benzylmethanesulfonate 2e (4.2 g,11.5 mmol) was dissolved in methanol (50 mL), anhydrous potassium carbonate (4.77 g,34.5 mmol) was added, the reaction was completed at room temperature, TLC was checked for completion, the reaction solution was poured into water (100 mL), extracted with methylene chloride (100 mL. Times.3), the combined organic phases were successively washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: A system) to give 6-bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ]2f (3 g, yield 96.9%).

Sixth step

2',3',5',6'-tetrahydro-3H-spiro[isobenzofuran-1,4'-pyran]-6-amine

2',3',5',6' -Tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ] -6-amine

6-Bromo-2 ',3',5',6' -tetrahydro-3H-spiro [ isobenzofuran-1, 4 '-pyran ]2f (3 g,11.15 mmol) was added to acetonitrile (20 mL), aqueous ammonia (13.47 g,111.47 mmol) was added, cuprous oxide (0.16 g,1.11 mmol) was reacted overnight at 120℃in a closed pot, LC-MS monitored complete reaction, saturated aqueous ammonium chloride (100 mL) was added, ethyl acetate (100 mL. Times.3) was used to extract, the combined organic phases were successively washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further isolated and purified by silica gel column chromatography (eluent: B system) to give 2',3',5',6 '-tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ] -6-amine 2g (2.02 g, 88.3% yield).

Seventh step

4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(2',3',5',6'-tetrahydro-3H-spiro[isobenzofuran-1,4'-pyran]-6-yl)benzamide

4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (2 ',3',5',6' -tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ] -6-yl) benzamide

2',3',5',6' -Tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ] -6-amine 2g (0.2 g,0.97 mmol) and 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid 1c (0.38 g,1.07 mmol), 2- (7-azabenzotriazol) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (HATU, 0.56g,1.46 mmol) were added to a round bottom flask, N, N-dimethylformamide (4 mL), diisopropylethylamine (DIPEA, 0.38g,2.92 mmol) were added and stirred at room temperature for 1 hour. Ethyl acetate (10 mL x 3) and saturated brine were added thereto, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (eluent: a system) and spin-dried to give 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (2 ',3',5',6' -tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ] -6-yl) benzamide as a pale yellow oil for 2H (0.49 g, yield 92.4%).

MS m/z(ESI):545.2[M+1]⁺

Eighth step

4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (2 ',3',5',6' -tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ] -6-yl) benzamide (100 mg,0.18 mmol), cuprous iodide (10.5 mg,0.06 mmol), sarcosine (24.6 mg,0.27 mmol), potassium phosphate trihydrate (146.8 mg,0.55 mmol), 2-hydroxyethyl-1-sulfonamide 1k (34.5 mg,0.27 mmol) was added to the lock tube, N-dimethylformamide (3 mL) was added, and the mixture was stirred under nitrogen protection at 110℃for 3 hours, and the reaction was complete. Ethyl acetate (10 mL x 3) and saturated brine were added thereto, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure, and the resulting residue was further separated and purified by silica gel column chromatography (system a) to give 4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (2 ',3',5',6' -tetrahydro-3H-spiro [ isobenzofuran-1, 4' -pyran ] -6-yl) benzamide 2 (61 mg, yield 61.6%).

MS m/z(ESI):542.3[M+1]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.67(s,1H),7.88–7.75(m,2H),7.55(d,J＝8.1Hz,1H),7.30(d,J＝8.1Hz,1H),7.15(d,J＝2.3Hz,1H),7.01(dd,J＝8.6,2.0Hz,1H),4.98(s,2H),3.85(dd,J＝12.1,4.2Hz,2H),3.78–3.61(m,4H),2.98(t,J＝5.3Hz,4H),1.89(dt,J＝12.8,6.6Hz,2H),1.62(d,J＝13.3Hz,2H),1.54(s,4H),0.35(s,4H).

Example 3

N-(4,4-difluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

5'-Bromo-4,4-difluorospiro [ cyclohexane-1,3' -indole ] 5'-bromo-4,4-difluorospiro [ cyclohexane-1,3' -indole ]

P-bromophenylhydrazine 3a (1.26 g,6.75mmol, commercially available) and 4, 4-difluorocyclohexylformaldehyde 3b (1.0 g,6.75mmol, commercially available) were dissolved in dichloromethane (20 mL) and trifluoroacetic acid (2 mL) and stirred at room temperature for 16 hours. The reaction was monitored by mass spectrometry, the pH of the reaction mixture was adjusted to be alkaline by adding a saturated aqueous sodium hydrogencarbonate solution, extraction was performed with methylene chloride (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtration and concentration under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: A system) to give 5 '-bromo-4, 4-difluorospiro [ cyclohexane-1, 3' -indole ]3c (1.35 g), yield was 66.5%.

MS m/z(ESI):300.0[M+H]⁺

Second step

5'-bromo-4,4-difluorospiro[cyclohexane-1,3'-indolin]-2'-one

5' -Bromo-4, 4-difluorospiro [ cyclohexane-1, 3' -indoline ] -2' -one

5 '-Bromo-4, 4-difluorospiro [ cyclohexane-1, 3' -indole ]3c (0.77 g,2.57 mmol) was dissolved in1, 2-dichloroethane (10 mL), and m-chloroperoxybenzoic acid (1.04 g,5.13 mmo) was added and stirred for 3 hours. The reaction was monitored by mass spectrometry, quenched by adding saturated aqueous sodium carbonate, adjusted to pH to basicity, extracted with dichloromethane (50 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: A system) to give 5' -bromo-4, 4-difluorospiro [ cyclohexane-1, 3' -indoline ] -2' -one 3d (0.64 g), yield 79.6%.

MS m/z(ESI):317.0[M+H]⁺

Third step

5'-bromo-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-2'-one

5 '-Bromo-4, 4-difluoro-1' -methyl-spiro [ cyclohexane-1, 3 '-indoline ] -2' -one

5' -Bromo-4, 4-difluorospiro [ cyclohexane-1, 3' -indoline ] -2' -one 3d (0.63 g,1.99 mmol) was dissolved in N, N-dimethylformamide (8 mL), sodium hydride (0.18 g,3.99mmol,60% purity) was added under nitrogen atmosphere, methyl iodide (0.57 g,3.99 mmol) was added after stirring at room temperature for 30 minutes, and stirring was continued at room temperature for 2 hours. The reaction was monitored by mass spectrometry and was quenched with ice water, diluted with ethyl acetate, washed with water, saturated sodium chloride solution in this order, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 5 '-bromo-4, 4-difluoro-1' -methyl spiro [ cyclohexane-1, 3 '-indoline ] -2' -one 3e (0.38 g), yield 57.9%.

MS m/z(ESI):330.0[M+H]⁺

Fourth step

5'-amino-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-2'-one

5 '-Amino-4, 4-difluoro-1' -methyl-spiro [ cyclohexane-1, 3 '-indoline ] -2' -one

5 '-Bromo-4, 4-difluoro-1' -methyl-spiro [ cyclohexane-1, 3 '-indoline ] -2' -one 3e (0.36 g,1.09 mmol) was dissolved in 1, 4-dioxane (15 mL), tert-butyl carbamate (0.38 g,3.28 mmol), tris (dibenzylideneacetone) dipalladium (0.2 g,0.22 mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 '-4' -6 '-tris-I-propyl-11' -biphenyl (0.23 g,0.44 mmol), cesium carbonate (1.07 g,3.28 mmol) was added and reacted under a nitrogen atmosphere at 110℃for 5 hours. The mass spectrum monitors that the raw materials are completely reacted, the reaction liquid is filtered by diatomite, the filter cake is washed by ethyl acetate, and the filtrate is concentrated. To the concentrate was added hydrochloric acid-dioxane solvent (20 mL), and the mixture was stirred at room temperature for 4 hours. The mass spectrum was monitored to complete the reaction of the starting materials, the reaction solution was concentrated, dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 5 '-amino-4, 4-difluoro-1' -methylspiro [ cyclohexane-1, 3 '-indoline ] -2' -one 3f (0.19 g), 66.5% yield.

MS m/z(ESI):269.1[M+H]⁺

Fifth step

N-(4,4-difluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

5 '-Amino-4, 4-difluoro-1' -methyl-spiro [ cyclohexane-1, 3 '-indoline ] -2' -one 3f (0.19 g,0.71 mmol) was dissolved in N, N-dimethylformamide (3 mL), followed by addition of 1c (0.26 g,0.71 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.41 g,1.06 mmol), N, N-diisopropylethylamine (0.28 g,2.1 mmol), and stirring at room temperature for 2 hours. The reaction of the raw materials was monitored by mass spectrometry to completion, the reaction solution was diluted with ethyl acetate, washed with water, saturated sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (eluent: A system) to give 3g (0.32 g) of N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide in 74.5% yield.

MS m/z(ESI):606.2[M+H]⁺

Sixth step

3G (322 mg,0.53 mmol) of N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide (322 mg,0.53 mmol) was dissolved in N, N-dimethylformamide (10 mL), cuprous iodide (30 mg,0.16 mmol), sarcosine (71 mg,0.8 mmol), potassium phosphate trihydrate (425 mg,1.6 mmol), and 2-hydroxyethyl-1-sulfonamide 1k (100 mg,0.8 mmol) were added and stirred under nitrogen atmosphere at 110℃for 3 hours. The mass spectrum detection raw materials are completely reacted, the reaction liquid is diluted by ethyl acetate, water, saturated sodium chloride solution are sequentially used for washing, an organic phase is separated, anhydrous sodium sulfate is dried, filtered and concentrated under reduced pressure, and residues are separated by silica gel column chromatography (eluent: A system) for purification, so that N- (4, 4-difluoro-1 '-methyl-2' -oxo spiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -4- ((2-hydroxyethyl) sulfonamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 3 (170 mg) is obtained, and the yield is 53.1%.

MS m/z(ESI):603.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.56(s,1H),7.92-7.79(m,2H),7.75(dd,J=8.4,2.0Hz,

1H),7.15(d,J＝2.1Hz,1H),7.09(d,J＝8.4Hz,1H),7.02(dd,J＝8.5,2.0Hz,1H),3.76(t,J＝6.6Hz,2H),3.15(s,3H),2.97(d,J＝5.4Hz,4H),2.13(d,J＝13.1Hz,2H),1.92(d,J＝6.7Hz,2H),1.86-1.75(m,2H),1.53(s,4H),0.34(s,4H).

Example 4

N-(4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-5'-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1,3' -indoline ] -5' -yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

4,4-difluorospiro[cyclohexane-1,3'-indole]

4, 4-Difluorospiro [ cyclohexane-1, 3' -indole ]

Phenylhydrazine 4a (1.0 g,9.25mmol, commercially available) and 4, 4-difluorocyclohexylformaldehyde 3b (1.37 g,9.25 mmol) were dissolved in dichloromethane (20 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 16 hours. The reaction was monitored by mass spectrometry and was adjusted to pH to alkaline by adding saturated aqueous sodium bicarbonate, extracting with dichloromethane, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating, and purifying the residue by column chromatography on silica gel (eluent: A system) to give 4, 4-difluorospiro [ cyclohexane-1, 3' -indole ]4b (1.75 g), 85.5% yield.

MS m/z(ESI):222.1[M+H]⁺

Second step

4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indoline]

4, 4-Difluoro-1 '-methyl-spiro [ cyclohexane-1, 3' -indoline ]

4, 4-Difluorospiro [ cyclohexane-1, 3' -indole ]4b (1.75 g,7.91 mmol) was dissolved in methanol (30 mL), and formaldehyde (5 mL) and sodium cyanoborohydride (1.99 g,31.64 mmol) were added and stirred at room temperature for 16 hours. The reaction was monitored by mass spectrometry and was completed, the reaction solution was concentrated, dissolved in ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4, 4-difluoro-1 '-methylspiro [ cyclohexane-1, 3' -indoline ]4c (1.54 g), yield 82.1%.

MS m/z(ESI):238.1[M+H]⁺

Third step

5'-bromo-4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indoline]

5' -Bromo-4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1, 3' -indoline ]

4, 4-Difluoro-1 '-methyl spiro [ cyclohexane-1, 3' -indoline ]4c (1.27 g,5.35 mmol) was dissolved in acetic acid (20 mL), and a solution of bromine (0.85 g,5.35 mmol) in acetic acid (2 mL) was added dropwise and reacted at room temperature for 2 hours. The reaction was monitored by mass spectrometry and was completed, the reaction solution was diluted with ethyl acetate, washed successively with a saturated sodium thiosulfate solution, a saturated sodium carbonate aqueous solution, a saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 5' -bromo-4, 4-difluoro-1 ' -methyl spiro [ cyclohexane-1, 3' -indoline ]4d (1.53 g), yield 90.4%. MS m/z (ESI): 316.1[ M+H ] ⁺

Fourth step

4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-5'-amine

4, 4-Difluoro-1 ' -methyl-spiro [ cyclohexane-1, 3' -indoline ] -5' -amine

5' -Bromo-4, 4-difluoro-1 ' -methyl spiro [ cyclohexane-1, 3' -indoline ]4d (1.53 g,4.84 mmol) was dissolved in 1, 4-dioxane (20 mL), tert-butyl carbamate (1.7 g,14.52 mmol), tris (dibenzylideneacetone) dipalladium (0.44 g,0.48 mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tris-I-propyl-11 ' -biphenyl (0.52 g,0.97 mmol), cesium carbonate (3.15 g,9.68 mmol) was added and reacted under a nitrogen atmosphere at 110℃for 5 hours. The mass spectrum monitors that the raw materials are completely reacted, the reaction liquid is filtered by diatomite, the filter cake is washed by ethyl acetate, and the filtrate is concentrated. To the concentrate was added a hydrochloric acid-dioxane solution (20 mL), and the mixture was stirred at room temperature for 2 hours. The mass spectrum monitoring raw materials react completely, the reaction liquid is concentrated, ethyl acetate is added for dissolution, the mixture is washed by saturated sodium bicarbonate water solution and saturated sodium chloride solution in sequence, the organic phase is separated, dried by anhydrous sodium sulfate, filtered and concentrated to obtain 4, 4-difluoro-1 ' -methyl spiro [ cyclohexane-1, 3' -indoline ] -5' -amine 4e (0.97 g), and the yield is 79.7%.

MS m/z(ESI):253.1[M+H]⁺

Fifth step

N-(4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-5'-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1C (1.32 g,3.69 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in N, N-dimethylformamide (10 mL), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (2.1 g,5.53 mmol), N, N-diisopropylethylamine (1.43 g,11.06 mmol), 4-difluoro-1 ' -methyl spiro [ cyclohexane-1, 3' -indoline ] -5' -amine 4e (0.93 g,3.69 mmol) was added and stirred at room temperature for 2 hours. The reaction of the starting materials was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (4, 4-difluoro-1 ' -methylspiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 4f (0.72 g), 33.0% yield.

MS m/z(ESI):592.2[M+H]⁺

Sixth step

N- (4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 4f (250 mg,0.42 mmol) was dissolved in N, N-dimethylformamide (10 mL), cuprous iodide (24 mg,0.17 mmol), sarcosine (56 mg,0.63 mmol), potassium phosphate trihydrate (338 mg,1.27 mmol), 2-hydroxyethyl-1-sulfonamide 1k (79 mg,0.63 mmol) was added, and stirred under nitrogen atmosphere at 110℃for 3 hours. The mass spectrum detection raw materials are completely reacted, the reaction liquid is diluted by ethyl acetate, water, saturated sodium chloride solution are sequentially used for washing, an organic phase is separated, anhydrous sodium sulfate is dried, filtered and concentrated, and residues are purified by silica gel column chromatography (eluent: A system) to obtain N- (4, 4-difluoro-1 ' -methyl spiro [ cyclohexane-1, 3' -indoline ] -5' -group) -4- ((2-hydroxyethyl) sulfonamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 4 (133 mg), and the yield is 53.6%.

MS m/z(ESI):589.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.51(s,1H),7.82(d,J＝8.5Hz,1H),7.58(d,J＝2.1Hz,1H),7.37(dd,J＝8.4,2.0Hz,1H),7.14(d,J＝2.2Hz,1H),7.01(dd,J＝8.5,2.1Hz,1H),6.56(d,J＝8.4Hz,1H),3.75(t,J＝6.6Hz,2H),3.30(d,J＝6.6Hz,2H),3.23(s,2H),2.96(t,J＝5.2Hz,4H),2.71(s,3H),2.15-1.92(m,4H),1.78(dd,J＝8.4,4.5Hz,4H),1.55(d,J＝6.5Hz,4H),0.36(s,4H).

Example 5

4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- ((2-Hydroxyethyl) sulphonamido) -N- (1-methyl-2-oxo-2 ',3',5',6' -tetrahydrospiro [ indolin-3, 4' -pyran ] -5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

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

4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid methyl ester

1C (2.0 g,5.60 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in methylene chloride (30 mL), N-dimethylformamide (0.5 mL) and oxalyl chloride (1.42 g,11.20 mmol) were added, and stirred at room temperature for 2 hours. The reaction mixture was concentrated, and methanol (20 mL) was added thereto and stirring was continued for 3 hours. The mass spectrum was examined to find that most of the product, the reaction solution was concentrated, redissolved in ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give methyl 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoate 5a (1.80 g), yield 86.5%.

MS m/z(ESI):372.0[M+H]⁺

Second step

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

4- ((2-Hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid methyl ester

Methyl 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoate 5a (1.71 g,4.61 mmol) was dissolved in N, N-dimethylformamide (12 mL), hydroxyethylsulfonamide (692 mg,5.53 mmol), cuprous iodide (439 mg,2.30 mmol), sarcosine (616 mg,6.91 mmol), potassium phosphate trihydrate (4.91 g,18.43 mmol) was added, and the reaction was heated under nitrogen atmosphere at 120℃for 8 hours. The reaction was completely examined by mass spectrometry, ethyl acetate was added to the reaction mixture to dilute it, followed by washing with water, saturated sodium chloride solution, drying of the organic phase, filtration, concentration and separation of the residue by silica gel column chromatography (eluent: A system) to give methyl 4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzoate 5b (1.36 g) in 80% yield.

MS m/z(ESI):369.1[M+H]⁺

Third step

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

4- ((2-Hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid

Methyl 4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzoate 5b (2.1 g,5.7 mmol) was dissolved in methanol (20 mL) and water (5 mL), lithium hydroxide monohydrate (0.958 g,22.8 mmol) was added and stirred at 70 ℃ for 2 hours. The reaction solution was concentrated, redissolved in water, pH adjusted to weak acidity with 1M hydrochloric acid, extracted with dichloromethane (50 mL. Times.3), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to give 5c (890 mg) of 4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid in 44% yield.

MS m/z(ESI):355.2[M+H]⁺

Fourth step

5-bromo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

5-Bromo-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one

2',3',5',6' -Tetrahydrospiro [ 3H-indoline-3, 4' - [4H ] pyran ] -2 (1H) -one 5d (300 mg,1.48 mmol) was dissolved in glacial acetic acid (10 mL), and bromine water (236 mg,1.48 mmol) was added to react at room temperature for 16 hours. The mass spectrum detection raw materials are completely reacted, the reaction liquid is diluted by ethyl acetate, the saturated sodium thiosulfate solution, water and the saturated sodium chloride solution are sequentially used for washing, the organic phase is separated, anhydrous sodium sulfate is dried, filtered and concentrated, and the residue is purified by silica gel column chromatography (eluent: A system) to obtain 5-bromo-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-ketone 5e (0.35 g), and the yield is 84%.

MS m/z(ESI):282.1[M+H]⁺

Fifth step

5-bromo-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

5-Bromo-1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one

5-Bromo-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one 5e (300 mg,1.06 mmol) was dissolved in N, N-dimethylformamide (10 mL), sodium hydride (60% purity, 69.14mg,1.59 mmol) was added under nitrogen atmosphere at 0℃and methyl iodide (226 mg,1.59 mmol) was added after stirring for 10 minutes and stirring was performed at room temperature for 16 hours. Mass spectrum detection shows that the reaction of the raw materials is complete, the reaction solution is quenched by adding ice water, extracted by ethyl acetate (50 mL×3), the organic phase is washed by saturated sodium chloride solution, dried by anhydrous sodium sulfate, filtered, concentrated, and the residue is purified by silica gel column chromatography (eluent: A system) to obtain 5-bromo-1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one 5f (315 mg), yield: 95%.

MS m/z(ESI):296.1[M+H]⁺

Sixth step

tert-butyl(1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)carbamate

(1-Methyl-2-oxo-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) carbamic acid tert-butyl ester

5-Bromo-1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one 5f (300 mg,1.01 mmol), tert-butyl carbamate (593 mg,5.06 mmol), tris (dibenzylideneacetone) dipalladium (93 mg,0.1 mol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tris-I-propyl-11 ' -biphenyl (54 mg,0.1 mmol), cesium carbonate (990 mg,3.04 mmol), 1, 4-dioxane (10 mL) were reacted under nitrogen atmosphere at 80 ℃ for 4 hours. The mass spectrum detection raw material is completely reacted, the reaction liquid is filtered by diatomite, the filtrate is concentrated, and the residue is purified by silica gel column chromatography (eluent: A system) to obtain 5g (337 mg) of (1-methyl-2-oxo-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) carbamic acid tert-butyl ester with 71 percent yield.

MS m/z(ESI):333.3[M+H]⁺

Seventh step

5-amino-1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-2-one

5-Amino-1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one

5G (240 mg,0.72 mmol) of tert-butyl (1-methyl-2-oxo-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) carbamate (tert-butyl) was dissolved in trifluoroacetic acid (10 mL) and reacted at room temperature for 2 hours. The reaction of the starting materials was completed by mass spectrometry, the pH of the reaction solution was adjusted to neutrality with saturated sodium bicarbonate under ice bath, dichloromethane was extracted (50 mL. Times.3), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 5-amino-1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one (168 mg) in 83% yield.

MS m/z(ESI):233.2[M+H]⁺

Eighth step

5-Amino-1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one (50 mg,0.22 mmol) was dissolved in N, N-dimethylformamide (2 mL), 5c (92 mg,0.26 mmol) of 4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid, 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (164 mg,0.43 mmol), N, N-diisopropylethylamine (56 mg,0.43 mmol) was added and stirred at room temperature for 16 hours. The mass spectrum detection raw materials are completely reacted, the reaction liquid is diluted by ethyl acetate, water, saturated sodium chloride solution are sequentially used for washing, an organic phase is separated, anhydrous sodium sulfate is dried, filtered and concentrated, and residues are separated by silica gel column chromatography (eluent: A system) for purification, so that 4- ((2-hydroxyethyl) sulfonamide) -N- (1-methyl-2-oxo-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 5 (25 mg) is obtained, and the yield is 19%.

MS m/z(ESI):569.3[M+H]⁺

¹H NMR(400MHz,DMSO)δ11.63(s,1H),8.03(d,J＝2.1Hz,1H),7.82(d,J＝8.5Hz,1H),7.74(dd,J＝8.5,2.0Hz,1H),7.14(d,J＝2.1Hz,1H),7.06(d,J＝8.4Hz,1H),7.01(dd,J＝8.4,2.1Hz,1H),4.05(ddd,J＝11.1,6.5,3.9Hz,2H),3.85(ddd,J＝11.9,8.0,3.4Hz,2H),3.76(t,J＝6.6Hz,2H),3.30(s,2H),3.14(s,3H),2.98(t,J＝5.3Hz,4H),1.83(td,J＝8.7,7.8,4.3Hz,2H),1.67-1.58(m,2H),1.54(s,4H),0.35(s,4H).

Example 6

4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- ((2-Hydroxyethyl) sulphonamido) -N- (1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-amine

1-Methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-amine

5-Amino-1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one (200 mg,0.86 mmol) was dissolved in dry tetrahydrofuran (9 mL), and a solution of borane in tetrahydrofuran (1M, 0.37mg,4.31 mmol) was added dropwise under nitrogen atmosphere at 0℃and the reaction at 80℃was completed for 3 hours. The reaction was monitored by mass spectrometry to be complete, the reaction solution was cooled, methanol was added at 0℃until no bubbles were formed, the reaction solution was refluxed for 2 hours at 80℃and pH was adjusted to be weakly alkaline with saturated sodium bicarbonate solution, and then concentrated directly, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-amine 6a (160 mg) in 85% yield.

MS m/z(ESI):219.2[M+H]⁺

Second step

4-iodo-N-(1-methyl-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Iodo-N- (1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

2- (6-Azaspiro [2.5] oct-6-yl) -4-iodo-benzoic acid 1c (251.98 mg,0.71 mmol) was dissolved in N, N-dimethylformamide (6 mL), 1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-amine 6a (140 mg,0.64 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (88 mg,1.28 mmol), N, N-diisopropylethylamine (166 mg,1.28 mmol) was added and reacted at room temperature for 2 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-iodo-N- (1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 6b (300 mg) in 83% yield.

MS m/z(ESI):558.2[M+H]⁺

Third step

4-Iodo-N- (1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 6b (300 mg,0.54 mmol) was dissolved in N, N-dimethylformamide (4 mL), 2-hydroxyethyl-1-sulfonamide 1k (101 mg,0.81 mmol), sarcosine (72 mg,0.81 mmol), cuprous iodide (31 mg,0.16 mmol), potassium phosphate trihydrate (420 mg,2.69 mmol), and stirred under nitrogen atmosphere at 100℃for 5 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4- ((2-hydroxyethyl) sulfonamide) -N- (1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 6 (5 mg), 1.5% yield.

MS m/z(ESI):555.2[M+H]⁺

¹H NMR(400MHz,DMS-d6)δ11.47(s,1H),7.82(d,J＝8.5Hz,1H),7.57(s,1H),7.37(d,J＝8.0Hz,1H),7.14(s,1H),7.01(d,J＝8.4Hz,1H),6.54(d,J＝8.4Hz,1H),3.84(d,J＝11.6Hz,2H),3.75(t,J＝6.5Hz,2H),3.53(d,J＝11.0Hz,2H),3.27(m,4H),2.96(s,4H),2.71(s,3H),2.04-1.93(m,1H),1.78(t,J＝10.2Hz,2H),1.60(s,1H),1.55(s,4H),0.36(s,4H).

Example 7

4-((2-hydroxyethyl)sulfonamido)-N-(1'-methyl-5'-oxo-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- ((2-Hydroxyethyl) sulphonamido) -N- (1 ' -methyl-5 ' -oxo-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin ] -6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

ethyl 2-(6-bromo-1-cyano-2,3-dihydro-1H-inden-1-yl)acetate

2- (6-Bromo-1-cyano-2, 3-dihydro-1H-inden-1-yl) acetic acid ethyl ester

6-Bromo-2, 3-dihydro-1H-indene-1-carbonitrile 7a (2.0 g,9.01mmol, commercially available) was dissolved in dry tetrahydrofuran (30 mL), -lithium diisopropylamide (1.93 g,18.01 mmol) was added dropwise at 78℃and stirred at-78℃for 15 minutes, and ethyl bromoacetate 7b (2.0 mL,18.01mmol, commercially available) was added dropwise and the reaction was completed at room temperature for 3 hours. The reaction was monitored by mass spectrometry and was completed, the reaction mixture was quenched with water, extracted with ethyl acetate (50 mL. Times.3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give ethyl 2- (6-bromo-1-cyano-2, 3-dihydro-1H-inden-1-yl) acetate 7c (2.56 g) in 92% yield.

Second step

ethyl 2-(1-(aminomethyl)-6-bromo-2,3-dihydro-1H-inden-1-yl)acetate

2- (1- (Aminomethyl) -6-bromo-2, 3-dihydro-1H-inden-1-yl) acetic acid ethyl ester

Ethyl 2- (6-bromo-1-cyano-2, 3-dihydro-1H-inden-1-yl) acetate 7c (2.83 g,9.18 mmol) was dissolved in methanol (30 mL) and water (3 mL), cobalt chloride hexahydrate (8.71 g,36.73 mmol) and sodium borohydride (1.02 g,27.55 mmol) were added while ice-bath, and the system was reacted at room temperature for 4 hours. The reaction was monitored by mass spectrometry to completion, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system) to give ethyl 2- (1- (aminomethyl) -6-bromo-2, 3-dihydro-1H-inden-1-yl) acetate 7d (1.7 g) in 59% yield.

MS m/z(ESI):312.1[M+H]⁺

Third step

6-bromo-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one

6-Bromo-2, 3-dihydrospiro [ indene-1, 3 '-pyrrolidin-5' -one

Ethyl 2- (1- (aminomethyl) -6-bromo-2, 3-dihydro-1H-inden-1-yl) acetate 7d (1.7 g,5.45 mmol) was dissolved in methanol (20 mL), sodium hydroxide (435.62 mg,10.89 mmol) was added, and the system was reacted at room temperature for 16 hours. After the completion of the reaction, the reaction mixture was neutralized with acetic acid and concentrated directly, and the residue was purified by silica gel column chromatography (eluent: B system) to give 6-bromo-2, 3-dihydrospiro [ indene-1, 3 '-pyrrolidine ] -5' -one 7e (1.1 g) in 75% yield.

MS m/z(ESI):268.0[M+H]⁺

Fourth step

6-bromo-1'-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one

6-Bromo-1 ' -methyl-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin ] -5' -one

6-Bromo-2, 3-dihydrospiro [ indene-1, 3 '-pyrrolidin ] -5' -one 7e (1.1 g,4.13 mmol) was dissolved in dry N, N-dimethylformamide (20 mL), sodium hydride (60% purity, 215.01mg,8.27 mmol) was added under an ice bath under nitrogen atmosphere, stirring under ice bath was completed for 10 minutes, methyl iodide (0.51 mL,8.27 mmol) was further added dropwise, and the system was stirred at room temperature for 16 hours. The reaction was monitored by mass spectrometry and was completed, the reaction mixture was quenched with water, diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system) to give 6-bromo-1 ' -methyl-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidine ] -5' -one 7f (1.05 g), yield 90%.

MS m/z(ESI):282.0[M+H]⁺

Fifth step

N-(1'-methyl-5'-oxo-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-6-yl)acetamide

N- (1 ' -methyl-5 ' -oxo-2, 3-dihydro-spiro [ inden-1, 3' -pyrrolidin ] -6-yl) acetamide

6-Bromo-1 '-methyl-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin ] -5 '-one 7f (1.05 g,3.75 mmol) was dissolved in N, N-dimethylformamide (20 mL), acetamide (1.11 g,18.74 mmol), cuprous iodide (855 mg,4.50 mmol), trans- (1R, 2R) -N, N' -dimethyl-1, 2-cyclohexanediamine (798 mg,5.62 mmol) and potassium phosphate (4.77 g,22.49 mmol) were added and reacted under a nitrogen atmosphere at 120℃for 6.5 hours. Mass spectrum monitoring shows that a small amount of raw materials remain, the solubility of the product in N, N-dimethylformamide is poor, part of the product is separated out, the reaction solution is diluted by ethyl acetate, water and saturated sodium chloride solution are sequentially used for washing, part of the product forms an emulsion layer, most of N, N-dimethylformamide is separated and removed, the residual emulsion layer and an organic phase are directly concentrated, and 7g (919 mg) of N- (1 ' -methyl-5 ' -oxo-2, 3-dihydro spiro [ indene-1, 3' -pyrrolidine ] -6-yl) acetamide is obtained, and the next step is directly added. MS m/z (ESI): 259.2[ M+H ] ⁺

Sixth step

6-amino-1'-methyl-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-5'-one

6-Amino-1 ' -methyl-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin ] -5' -one

7G (919 mg,3.56 mmol) of N- (1 ' -methyl-5 ' -oxo-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin ] -6-yl) acetamide was dissolved in concentrated hydrochloric acid (10 mL) and water (40 mL), and the system was reacted at 100℃for 3 hours. The reaction was completed by mass spectrometry, the reaction mixture was neutralized with 1M sodium hydroxide, extracted with ethyl acetate (50 mL. Times.3), the organic phase was washed with saturated sodium chloride solution, separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system) to give 6-amino-1 ' -methyl-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin ] -5' -one (74 mg) in 9% yield.

MS m/z(ESI):217.1[M+H]⁺

Seventh step

4-iodo-N-(1'-methyl-5'-oxo-2,3-dihydrospiro[indene-1,3'-pyrrolidin]-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Iodo-N- (1 ' -methyl-5 ' -oxo-2, 3-dihydro-spiro [ indene-1, 3' -pyrrolidin ] -6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

2- (6-Azaspiro [2.5] oct-6-yl) -4-iodo-benzoic acid 1c (121 mg,0.34 mmol) was dissolved in N, N-dimethylformamide (5 mL), 6-amino-1 ' -methyl-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin ] -5' -one (74 mg,0.34 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (155 mg,0.41 mmol), N, N-diisopropylethylamine (88 mg,0.68 mmol) was added and the system was reacted at room temperature for 16 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-iodo-N- (1 ' -methyl-5 ' -oxo-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin-6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 7i (102 mg) in 54% yield.

MS m/z(ESI):556.2[M+H]⁺

Eighth step

4-Iodo-N- (1 ' -methyl-5 ' -oxo-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin ] -6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 7i (102 mg,0.18 mmol) was dissolved in N, N-dimethylformamide (5 mL), 2-hydroxyethyl-1-sulfonamide 1k (35 mg,0.28 mmol), sarcosine (25 mg,0.28 mmol), cuprous iodide (10 mg,0.06 mmol), potassium phosphate trihydrate (244 mg,0.92 mmol) was added and the system was reacted under nitrogen atmosphere at 110℃for 5 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give 4- ((2-hydroxyethyl) sulfonamide) -N- (1 ' -methyl-5 ' -oxo-2, 3-dihydrospiro [ indene-1, 3' -pyrrolidin-6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 7 (34 mg) in 45% yield.

MS m/z(ESI):553.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.62(s,1H),7.82(d,J＝8.5Hz,1H),7.70(d,J＝1.1Hz,1H),7.53(dd,J＝8.1,1.6Hz,1H),7.23(d,J＝8.1Hz,1H),7.15(d,J＝1.7Hz,1H),7.02(dd,J＝8.5,1.8Hz,1H),3.75(t,J＝6.5Hz,2H),3.45(dd,J＝30.8,9.7Hz,2H),3.03–2.91(m,4H),2.85(t,J＝6.9Hz,2H),2.81(s,3H),2.49–2.38(m,4H),2.13(dtd,J＝19.4,12.6,6.9Hz,2H),1.52(s,4H),0.35(s,4H).

Example 8

4-((2-hydroxyethyl)sulfonamido)-N-(2-methyl-2',3',5',6'-tetrahydrospiro[isoindoline-1,4'-pyran]-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- ((2-Hydroxyethyl) sulphonamido) -N- (2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

6-bromo-2-methyl-2',3',5',6'-tetrahydrospiro[isoindoline-1,4'-pyran]-3-one

6-Bromo-2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -3-one

5-Bromo-2-methyl-1, 3-dihydro-isoindolin-1-one 8a (2.0 g,8.85mmol, commercially available) was dissolved in N, N-dimethylformamide (20 mL), sodium hydride (60% purity, 690.32mg,26.54 mmol) was added under an ice bath in a nitrogen atmosphere, stirring was completed under an ice bath for 20 minutes, and 2,2' -dibromodiethyl ether 8b (2.67 g,11.50 mmol) was added dropwise thereto and the reaction was completed at room temperature for 6.5 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 6-bromo-2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -3-one 8c (1.78 g), 67% yield. MS m/z (ESI): 296.0[ M+H ] ⁺

Second step

tert-butyl(2-methyl-3-oxo-2',3',5',6'-tetrahydrospiro[isoindoline-1,4'-pyran]-6-yl)carbamate

(2-Methyl-3-oxo-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-yl) carbamic acid tert-butyl ester

6-Bromo-2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -3-one 8C (1.78 g,6.01 mmol), tert-butyl carbamate (7.04 g,60.10 mmol), tris (dibenzylideneacetone) dipalladium (550 mg,0.6 mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tris-I-propyl-11 ' -biphenyl (323 mg,0.6 mmol), cesium carbonate (5.87 g,18.03 mmol) were dissolved in 1, 4-dioxane (30 mL) and reacted under nitrogen atmosphere at 100 ℃ for 5 hours. The reaction was monitored by mass spectrometry, and was completed, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system) to give tert-butyl (2-methyl-3-oxo-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-yl) carbamate 8d (2.23 g), yield 100%.

MS m/z(ESI):333.2[M+H]⁺

Third step

6-amino-2-methyl-2',3',5',6'-tetrahydrospiro[isoindoline-1,4'-pyran]-3-one

6-Amino-2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -3-one

Tert-butyl (2-methyl-3-oxo-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-yl) carbamate 8d (2.23 g,6.71 mmol) was dissolved in dichloromethane (40 mL), trifluoroacetic acid (10 mL) was added and the system was reacted at room temperature for 2.5 hours. TLC monitored completion of the reaction, quenching of the reaction mixture with saturated sodium bicarbonate solution, extraction with dichloromethane (50 mL. Times.3), drying of the organic phase, filtration, concentration, beating of dichloromethane, concentration of the filtrate, purification of the residue by column chromatography on silica gel (eluent: B system) gave 6-amino-2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -3-one 8e (856 mg), 54% yield.

MS m/z(ESI):233.1[M+H]⁺

Fourth step

2-methyl-2',3',5',6'-tetrahydrospiro[isoindoline-1,4'-pyran]-6-amine

2-Methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-amine

6-Amino-2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -3-one 8e (600 mg,2.59 mmol) was dissolved in dry tetrahydrofuran (250 mL), lithium aluminum hydride (2.87 g,77.7 mmol) was added under an ice bath in a nitrogen atmosphere, and the addition was reacted at 65℃for 6 hours. The reaction was monitored by mass spectrometry and was completed, the reaction mixture was cooled to room temperature, quenched with sodium sulfate decahydrate added under ice bath, the reaction mixture was filtered through celite, and the filtrate was concentrated to give 2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-amine 8f (469 mg) which was directly added to the next step.

MS m/z(ESI):219.1[M+H]⁺

Fifth step

4-iodo-N-(2-methyl-2',3',5',6'-tetrahydrospiro[isoindoline-1,4'-pyran]-6-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Iodo-N- (2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

2- (6-Azaspiro [2.5] oct-6-yl) -4-iodo-benzoic acid 1c (639 mg,1.79 mmol) was dissolved in N, N-dimethylformamide (20 mL), 2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-amine 8f (469 mg,2.15 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (816 mg,2.15 mmol), N, N-diisopropylethylamine (0.62 mL,3.58 mmol) was added, and the system was reacted at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system) to give 8g (606 mg) of 4-iodo-N- (2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide in 60% yield.

MS m/z(ESI):558.2[M+H]⁺

Sixth step

8G (200 mg,0.36 mol) of 4-iodo-N- (2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindoline-1, 4' -pyran ] -6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide, 1k (67 mg,0.54 mmol) of 2-hydroxyethyl-1-sulfonamide, cuprous iodide (20 mg,0.11 mmol), sarcosine (48 mg,0.54 mmol), and potassium phosphate trihydrate (383mg, 1.79 mmol) were added to N, N-dimethylformamide (6 mL) and reacted under a nitrogen atmosphere at 110℃for 5 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil;250×21.2mm i.d.;5 μm,20mL/min; mobile phase a:0.05% tfa+h ₂ O, mobile phase B: CH ₃ CN) to give 4- ((2-hydroxyethyl) sulfonamide) -N- (2-methyl-2 ',3',5',6' -tetrahydrospiro [ isoindolin-1, 4' -pyran ] -6-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 8 (84 mg), 40% yield.

MS m/z(ESI):555.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.70(s,1H),8.15(s,1H),8.06(s,1H),7.85(d,J＝8.5Hz,1H),7.77(dd,J＝8.0,1.0Hz,1H),7.26(d,J＝8.1Hz,1H),7.17(d,J＝1.6Hz,1H),7.03(dd,J＝8.5,1.7Hz,1H),3.95–3.80(m,6H),3.76(t,J＝6.5Hz,2H),3.33(t,J＝6.5Hz,2H),2.98(s,4H),2.40(s,3H),1.95(dt,J＝16.3,8.3Hz,2H),1.55(s,4H),1.45(d,J＝13.4Hz,2H),0.34(s,4H).

Example 9

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- (ethylsulfonamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

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

4- (Ethylsulfonamide) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid methyl ester

Methyl 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoate 5a (800 mg,2.16 mmol), ethylsulfonamide 9a (353 mg,3.23mmol, commercially available), cuprous iodide (123 mg,0.64 mmol), sarcosine (284 mg,3.23 mmol), potassium phosphate trihydrate (1.72 g,6.47 mmol), N, N-dimethylformamide (10 mL) were added to the tube, and the reaction was carried out under a nitrogen atmosphere at 110℃for 5 hours. The reaction was completed by mass spectrometry, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give methyl 4- (ethylsulfamidyl) -2- (6-azaspiro [2.5] oct-6-yl) benzoate 9b (0.75 g), yield 98.7%.

MS m/z(ESI):353.2[M+H]⁺

Second step

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

4- (Ethylsulfonamide) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid

Methyl 4- (ethylsulfanomido) -2- (6-azaspiro [2.5] oct-6-yl) benzoate 9b (0.75 g,2.13 mmol) was dissolved in methanol (15 mL) and water (5 mL), sodium hydroxide (0.85 g,32.28 mmol) was added, and stirred at 60℃for 16 hours. The reaction was completed by mass spectrometry, methanol was removed by concentration, diluted with 20mL of water, adjusted to a weak acid by adding 1M hydrochloric acid, a large amount of white solid was precipitated, extracted with dichloromethane/methanol=10/1 (20 ml×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give 9c (0.62 g) of 4- (ethylsulfanomido) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid in 86.1% yield. MS m/z (ESI): 339.2[ M+H ] ⁺

Third step

9C (0.16 g,0.46 mmol) of 4- (ethylsulfanomido) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in N, N-dimethylformamide (4 mL), 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -amine 1i (0.1 g,0.42 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (0.24 g,0.63 mmol), N, N-diisopropylethylamine (0.16 g,1.25 mmol) was added and stirred at room temperature for 3 hours. Mass spectrometry was monitored for complete reaction of the starting materials, diluted with ethyl acetate, washed sequentially with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by column chromatography on silica gel (eluent: A system) to give N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- (ethylsulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 9 (0.2 g) in 85.5% yield.

MS m/z(ESI):560.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.63(s,1H),10.15(s,1H),7.82(dt,J＝8.6,2.6Hz,2H),7.56-7.45(m,1H),7.31(d,J＝7.9Hz,1H),7.17(d,J＝2.5Hz,1H),7.08-6.98(m,1H),5.00(d,J＝2.9Hz,2H),3.20(q,J＝7.3Hz,2H),2.97(t,J＝5.2Hz,4H),2.09(m,4H),1.88(d,J＝15.1Hz,4H),1.53(s,4H),1.21(m,3H),0.34(d,J＝2.8Hz,4H).

Example 10

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-4-((N-methylsulfamoyl)amino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- ((N-methylsulfamoyl) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

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

4-Nitro-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid

2-Fluoro-4-nitrobenzoic acid 10a (500 mg,2.70 mmol) and 6-azaspiro [2.5] octane hydrochloride 1b (178 mg,3.24 mmol) were dissolved in N-methylpyrrolidone (5 mL), anhydrous potassium carbonate (933 mg,6.75 mmol) was added, and the mixture was heated and stirred for 1 hour at 160 ℃. The reaction was monitored by mass spectrometry to completion, the reaction solution was poured into 100mL of water, a small amount of ethyl acetate was added to extract and discard, the pH of the aqueous phase was adjusted to 5-6 with 1M hydrochloric acid, dichloromethane was added to extract (20 mL. Times.3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system) to give 10B (700 mg) of 4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid in 93.8% yield.

MS m/z(ESI):275.1[M-H]

Second step

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Nitro-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid 10b (138 mg,0.501 mmol) was dissolved in N, N-dimethylformamide (3 mL), 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -amine 1i (0.1 g,0.418 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (317 mg,0.836 mmol), N, N-diisopropylethylamine (439 mg,1.25 mmol) was added and stirred at room temperature for 2 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzamide 10c (246 mg), yield 91.7%. MS m/z (ESI): 498.3[ M+H ] ⁺

Third step

4-amino-N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Amino-N- (4, 4-difluoro-3 ' h-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzamide 10C (226 mg,0.454 mmol) was dissolved in ethanol (4 mL) and water (1 mL), iron powder (76 mg,1.36 mmol) and ammonium chloride (145 mg,2.73 mmol) were added, and stirred under nitrogen atmosphere at 80℃for 4 hours. The reaction was completed by mass spectrometry, saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to weakly alkaline, the mixture was filtered, the cake was washed 3 times with a mixture of ethyl acetate and methanol, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-amino-N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 10d (130 mg) in 61.2% yield.

MS m/z(ESI):468.2[M+H]⁺

Fourth step

4-Amino-N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 10d (110 mg,0.235 mmol) was dissolved in dichloromethane (2 mL), triethylamine (71 mg,0.705 mmol) and N-methylsulfamoyl chloride 10e (33 mg,0.258 mmol) were added under an ice bath of nitrogen, and the ice bath was stirred for 4 hours. After completion of the mass spectrometry, methylene chloride was added to the reaction mixture to dilute it, followed by washing with water, saturated sodium chloride solution, drying the organic phase, filtering, concentrating, and separating the residue by silica gel column chromatography (eluent: A system) to obtain N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- ((N-methylsulfamoyl) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 10 (120 mg), yield 86.7%.

MS m/z(ESI):561.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.84(s,1H),10.08(s,1H),7.86(d,J＝1.7Hz,1H),7.84(d,J＝8.6Hz,1H),7.59(d,J＝5.0Hz,1H),7.54(dd,J＝8.2,1.8Hz,1H),7.34(d,J＝8.1Hz,1H),7.16(d,J＝2.1Hz,1H),7.02(dd,J＝8.6,2.1Hz,1H),5.03(s,2H),3.01(t,J＝5.3Hz,4H),2.51(d,J＝5.0Hz,3H),2.11(s,4H),1.89(s,4H),1.57(s,4H),0.38(s,4H).

Example 11

4-((2-hydroxyethyl)sulfonamido)-N-(1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- ((2-Hydroxyethyl) sulphonamido) -N- (1-methyl-3 ' h-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

6’-bromo-3’H-spiro[azetidine-3,1’-isobenzofuran]

6' -Bromo-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ]

6' -Bromo-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -1-carboxylic acid tert-butyl ester 11a (0.8 g,2.35 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred at room temperature for 2 hours. The reaction was monitored by mass spectrometry, trifluoroacetic acid was removed by concentration, pH was adjusted to be alkaline with a saturated aqueous potassium carbonate solution, extraction was performed with ethyl acetate (20 mL. Times.3), and the organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated to give 6' -bromo-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ]11b (0.52 g), yield 91.2%.

MS m/z(ESI):240.1[M+H]⁺

Second step

6'-bromo-1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran]

6' -Bromo-1-methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ]

6' -Bromo-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ]11b (0.5 g,2.08 mmol) was dissolved in methanol (6 mL), formaldehyde (1 mL), sodium cyanoborohydride (0.26 g,4.16 mmol) was added, and stirred at room temperature for 2.5 hours. The reaction was monitored by mass spectrometry to completion, the reaction solution was concentrated, dissolved in ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the residue was purified by column chromatography on silica gel (eluent: B system) to give 6' -bromo-1-methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ]11c (0.43 g), 82.7% yield.

MS m/z(ESI):254.1[M+H]⁺

Third step

1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'-amine

1-Methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -amine

6' -Bromo-1-methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ]11C (0.42 g,1.69 mmol) was dissolved in 1, 4-dioxane (15 mL), tert-butyl carbamate (0.39 g,3.38 mmol), tris (dibenzylideneacetone) dipalladium (0.23 g,0.25 mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tris-I-propyl-11 ' -biphenyl (0.27 g,0.51 mmol), cesium carbonate (1.65 g,5.08 mmol) were added and reacted under a nitrogen atmosphere at 110℃for 5 hours. The mass spectrum monitors that the raw materials are completely reacted, the reaction liquid is filtered by diatomite, the filter cake is washed by ethyl acetate, and the filtrate is concentrated. To the concentrate was added a hydrochloric acid-dioxane solution (10 mL), and the mixture was stirred at room temperature for 2 hours. Mass spectrum monitoring the reaction of the raw materials was complete, the reaction solution was concentrated, ethyl acetate was added, washed successively with saturated sodium bicarbonate solution, saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered and concentrated to give 1-methyl-3 ' h-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -amine 11d (0.11 g), 34.3% yield.

MS m/z(ESI):191.1[M+H]⁺

Fourth step

4-iodo-N-(1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Iodo-N- (1-methyl-3 ' h-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

1C (0.21 g,0.6 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in N, N-dimethylformamide (3 mL), 1-methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -amine 11d (0.11 g,0.58 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (0.33 g,0.87 mmol), N, N-diisopropylethylamine (0.22 g,1.74 mmol) was added and stirred at room temperature for 3 hours. The reaction of the starting materials was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-iodo-N- (1-methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 11e (0.22 g) in 71.9% yield.

MS m/z(ESI):530.1[M+H]⁺

Fifth step

4-Iodo-N- (1-methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 11e (50 mg,0.09 mmol), cuprous iodide (5.4 mg,0.028 mmol), sarcosine (12.7 mg,0.14 mmol), potassium phosphate trihydrate (75.3 mg,0.28 mmol), 2-hydroxyethyl-1-sulfonamide 1k (17.6 mg,0.14 mmol) and N, N-dimethylformamide (2 mL) were added to the vial and stirred under nitrogen atmosphere at 110℃for 3 hours. The reaction was completed by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system), and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 4- ((2-hydroxyethyl) sulfonamide) -N- (1-methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 11 (1.5 mg), yield 3%.

MS m/z(ESI):527.3[M+H]⁺

¹H NMR(400MHz,Chloroform-d)δ12.38(s,1H),8.45(s,1H),8.01(d,J＝8.4Hz,1H),7.49(d,J＝8.2Hz,1H),7.42(d,J＝1.8Hz,1H),7.21(dd,J＝17.4,8.3Hz,2H),5.15(s,2H),4.82(d,J＝10.9Hz,2H),4.06(q,J＝5.4Hz,4H),3.36(t,J＝5.1Hz,3H),3.04(m,7H),1.61(s,4H),0.39(s,4H).

Example 12

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-4-(methylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- (methylsulfonyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 1j (100 mg,0.17 mmol) was dissolved in N, N-dimethylformamide (4 mL), cuprous iodide (9.9 mg,0.05 mmol), sarcosine (23.1 mg,0.26 mmol), potassium phosphate trihydrate (138.1 mg,0.52 mmol), methylsulfonamide 12a (24.7 mg,0.26mmol, commercially available) was added and stirred under nitrogen atmosphere at 110℃for 4 hours. The reaction of the starting materials was completed by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- (methylsulfonyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 12 (56 mg), 59.6% in yield.

MS m/z(ESI):546.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.70(s,1H),10.18(s,1H),7.92-7.72(m,2H),7.51(dd,J＝8.1,1.9Hz,1H),7.31(d,J＝8.1Hz,1H),7.14(d,J＝2.2Hz,1H),7.03(dd,J＝8.4,2.1Hz,1H),5.00(s,2H),3.08(s,3H),2.98(t,J＝5.3Hz,4H),2.14(m,4H),1.89(m,4H),1.53(t,J＝5.2Hz,4H),0.35(s,4H).

Example 13

4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'-yl)benzamide

4- ((2-Hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (1- (2, 2-trifluoroethyl) -3' h-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) benzamide

First step

1-(6'-bromo-3'H-spiro[azetidine-3,1'-isobenzofuran]-1-yl)-2,2,2-trifluoroethan-1-one

1- (6 ' -Bromo-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -1-yl) -2, 2-trifluoroethan-1-one

6' -Bromo-3 ' -H-spiro [ azetidine-3, 1' -isobenzofuran ]11b (0.2 g,0.83 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic anhydride (0.35 g,1.66 mmol), triethylamine (0.25 g,2.49 mmol) and 4, 4-dimethylaminopyridine (20 mg,0.17 mmol) were added and stirred at room temperature for 3 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was neutralized with saturated aqueous sodium bicarbonate, extracted with methylene chloride, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 1- (6 ' -bromo-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -1-yl) -2, 2-trifluoroethan-1-one 13a (250 mg), 89.3% yield.

MS m/z(ESI):336.1[M+H]⁺

Second step

6'-bromo-1-(2,2,2-trifluoroethyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]

6' -Bromo-1- (2, 2-trifluoroethyl) -3' H-spiro [ azetidine-3, 1' -isobenzofuran ]

1- (6 ' -Bromo-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -1-yl) -2, 2-trifluoroethan-1-one 13a (0.23 g,0.68 mmol) was dissolved in tetrahydrofuran (5 mL), borane tetrahydrofuran complex (1M, 2mL,2.1 mmol) was added and stirred under nitrogen atmosphere at 60℃for 6 hours. The reaction was monitored by mass spectrometry and was quenched by methanol, the reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 6' -bromo-1- (2, 2-trifluoroethyl) -3' H-spiro [ azetidine-3, 1' -isobenzofuran ]13b (0.15 g), yield 68.1%.

MS m/z(ESI):322.0[M+1]⁺

Third step

1-(2,2,2-trifluoroethyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'-amine

1- (2, 2-Trifluoroethyl) -3' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -amine

6' -Bromo-1- (2, 2-trifluoroethyl) -3' H-spiro [ azetidine-3, 1' -isobenzofuran ]13b (0.13 g,0.40 mmol) was dissolved in 1, 4-dioxane (10 mL), tert-butyl carbamate (0.14 g,1.21 mmol), tris (dibenzylideneacetone) dipalladium (55.4 mg,0.06 mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tris-I-propyl-11 ' -biphenyl (64.9 mg,0.12 mmol), cesium carbonate (0.39 g,1.21 mmol) was added,Molecular sieves (100 mg) were reacted under a nitrogen atmosphere at 110 ℃ for 4 hours. The mass spectrum monitors that the raw materials are completely reacted, the reaction liquid is filtered by diatomite, the filter cake is washed by ethyl acetate, and the filtrate is concentrated. To the concentrate was added hydrochloric acid-dioxane solution (3 mL), and the mixture was stirred at room temperature for 0.5 hour, and mass spectrometry was performed to monitor the completion of the reaction of the starting materials. The reaction solution was concentrated, water was added, pH was adjusted to be alkaline with anhydrous potassium carbonate, extraction was performed with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 1- (2, 2-trifluoroethyl) -3' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -amine 13c (73 mg), yield 70.2%.

MS m/z(ESI):259.1[M+H]⁺

Fourth step

4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(1-(2,2,2-trifluoroethyl)-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'-yl)benzamide

4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (1- (2, 2-trifluoroethyl) -3' h-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) benzamide

1C (0.10 g,0.28 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in N, N-dimethylformamide (4 mL), 1- (2, 2-trifluoroethyl) -3' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -amine 13c (73 mg,0.28 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (0.16 g,0.42 mmol), N, N-diisopropylethylamine (0.11 g,0.85 mmol) was added, and stirred at room temperature for 2 hours. The reaction of the starting materials was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (1- (2, 2-trifluoroethyl) -3' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) benzamide 13d (0.15 g), 86.5% yield.

MS m/z(ESI):598.2[M+H]⁺

Fifth step

4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (1- (2, 2-trifluoroethyl) -3' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) benzamide 13d (80 mg,0.13 mmol) was dissolved in N, N-dimethylformamide (4 mL), cuprous iodide (7.6 mg,0.04 mmol), sarcosine (17.9 mg,0.2 mmol), potassium phosphate trihydrate (106.9 mg,0.4 mmol), 2-hydroxyethyl-1-sulfonamide 1k (25.1 mg,0.2 mmol) was added and stirred under nitrogen atmosphere at 110℃for 5 hours. The reaction was completed by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system), and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 4- ((2-hydroxyethyl) sulfonamide) -2- (6-azaspiro [2.5] oct-6-yl) -N- (1- (2, 2-trifluoroethyl) -3' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) benzamide 13 (25.8 mg), 29.2% yield.

MS m/z(ESI):595.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.75(d,J＝2.7Hz,1H),10.09(s,1H),8.15(s,1H),7.85(dd,J＝8.5,2.6Hz,1H),7.69(dt,J＝8.2,2.4Hz,1H),7.29(dd,J＝8.3,2.5Hz,1H),7.18(s,1H),7.04(dt,J＝8.5,2.4Hz,1H),5.00(s,2H),4.97-4.89(m,1H),3.77(qd,J＝6.5,2.5Hz,2H),3.66(m,4H),3.40-3.33(m,4H),2.98(d,J＝6.1Hz,4H),1.55(m,4H),0.35(d,J＝2.5Hz,4H).

Example 14

4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(3'H-spiro[cyclobutane-1,1'-isobenzofuran]-6'-yl)benzamide

4- ((2-Hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (3 ' h-spiro [ cyclobutan-1, 1' -isobenzofuran ] -6' -yl) benzamide

First step

1-(5-bromo-2-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)phenyl)cyclobutan-1-ol

1- (5-Bromo-2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) cyclobutan-1-ol

2- ((4-Bromo-2-iodobenzyl) oxy) tetrahydro-2H-pyran 2a (5.0 g,12.59 mmol) was dissolved in dry tetrahydrofuran (50 mL), cooled to-40℃under nitrogen, slowly added dropwise isopropyl magnesium chloride-lithium chloride (1.3M, 14.6 mL), stirred for 30min, and then azetidinone 14a (1.77 g,25.19 mmol) was added dropwise at-40℃and the reaction was allowed to continue slowly at room temperature for 16H. The reaction solution was poured into saturated aqueous ammonium chloride solution, extracted with ethyl acetate (50 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 1- (5-bromo-2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) cyclobutan-1-ol 14b (7.1 g), 100% yield.

Second step

1-(5-bromo-2-(hydroxymethyl)phenyl)cyclobutan-1-ol

1- (5-Bromo-2- (hydroxymethyl) phenyl) cyclobutan-1-ol

1- (5-Bromo-2- (((tetrahydro-2H-pyran-2-yl) oxy) methyl) phenyl) cyclobutan-1-ol 14b (7.1 g,20.81 mmol) was dissolved in methanol (70 mL), and aqueous hydrochloric acid (1M, 15 mL) was added and reacted at room temperature for 2 hours. TLC was used to monitor completion of the reaction, and saturated sodium hydrogencarbonate solution was added to the reaction solution to neutralize, extracted with ethyl acetate (50 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give 1- (5-bromo-2- (hydroxymethyl) phenyl) cyclobutan-1-ol 14c (3.5 g), in 65% yield, which was used directly in the next step.

Third step

6'-bromo-3'H-spiro[cyclobutane-1,1'-isobenzofuran]

6' -Bromo-3 ' H-spiro [ cyclobutane-1, 1' -isobenzofuran ]

1- (5-Bromo-2- (hydroxymethyl) phenyl) cyclobutan-1-ol 14C (3.5 g,13.61 mmol) was dissolved in chloroform (40 mL), triethylamine (6.89 g,68.06 mmol) was added, and a solution of 4-methylbenzenesulfonyl chloride (3.11 g,16.33 mmol) in chloroform (20 mL) was slowly dropped into the reaction solution under a nitrogen atmosphere at 0℃to react at room temperature for 16 hours. TLC was used to monitor completion of the reaction, the reaction mixture was quenched with water, extracted with dichloromethane (50 mL. Times.3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 6' -bromo-3 ' -spiro [ cyclobutane-1, 1' -isobenzofuran ]14d (1.5 g), 46% yield.

Fourth step

tert-butyl(3'H-spiro[cyclobutane-1,1'-isobenzofuran]-6'-yl)carbamate

(3 ' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) carbamic acid tert-butyl ester

6' -Bromo-3 ' -spiro [ cyclobutane-1, 1' -isobenzofuran ]14d (950 mg,3.97 mmol) was dissolved in 1, 4-dioxane (15 mL), tert-butyl carbamate (931 mg,7.95 mmol), tris (dibenzylideneacetone) dipalladium (264 mg,0.4 mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tris-I-propyl-11 ' -biphenyl (427 mg,0.8 mmol) was added, and cesium carbonate (3.88 g,11.92 mmol) was reacted under a nitrogen atmosphere at 100℃for 16 hours. The reaction was monitored by mass spectrometry to completion, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give tert-butyl (3 ' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) carbamate 14e (660 mg), 60% yield.

Fifth step

3'H-spiro[cyclobutane-1,1'-isobenzofuran]-6'-amine

3' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -amine

Tert-butyl (3 ' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) carbamate 14e (660 mg,2.40 mmol) was dissolved in dioxane hydrochloride solution (4M, 10 mL) and stirred at 15℃for 12 hours. The reaction was monitored by mass spectrometry to be complete. The reaction solution was concentrated, ethyl acetate (6 mL) was added and stirred for 10 minutes, and the mixture was filtered, and the cake was washed with ethyl acetate (3 mL) and dried under reduced pressure to give 3' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -amine hydrochloride 14f (465 mg), yield 100%.

MS m/z(ESI):176.2[M+H]⁺

Sixth step

4-iodo-2-(6-azaspiro[2.5]octan-6-yl)-N-(3'H-spiro[cyclobutane-1,1'-isobenzofuran]-6'-yl)benzamide

4-Iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (3 ' h-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) benzamide

1C (182 mg,0.51 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in N, N-dimethylformamide (1 mL), 3' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -amine hydrochloride 14f (90 mg,0.43 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (323 mg0.85 mmol) and N, N-diisopropylethylamine (219 mg,1.70 mmol) were added, and stirred at room temperature for 3 hours. The reaction was monitored by mass spectrometry to completion, diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 14g (198 mg) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (3 ' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) benzamide in 90.5% yield.

MS m/z(ESI):515.2[M+H]⁺

Seventh step

14G (178 mg,0.346 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (3 ' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) benzamide (178 mg,0.346 mmol) was dissolved in N, N-dimethylformamide (2 mL), cuprous iodide (20 mg,0.103 mmol) was added, sarcosine (30 mg,0.346 mmol), potassium phosphate trihydrate (276 mg,1.04 mmol), and 2-hydroxyethyl-1-sulfonamide 1k (51 mg, 0.418 mmol) were stirred under nitrogen atmosphere at 100℃for 3 hours. The reaction was completely examined by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4- ((2-hydroxyethyl) sulfamido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (3 ' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) benzamide 14 (144 mg), yield 77.2%.

MS m/z(ESI):512.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.74(s,1H),10.11(s,1H),8.08(s,1H),7.85(d,J＝8.5Hz,1H),7.60(d,J＝8.2Hz,1H),7.26(d,J＝8.2Hz,1H),7.18(d,J＝2.1Hz,1H),7.04(dd,J＝8.5,2.1Hz,1H),4.97(t,J＝5.9Hz,1H),4.94(s,2H),3.77(q,J＝6.2Hz,2H),3.35(d,J＝6.6Hz,2H),2.99(t,J＝5.2Hz,4H),2.58-2.52(m,2H),2.34(d,J＝8.8Hz,2H),1.96-1.75(m,2H),1.56(t,J＝5.0Hz,4H),0.35(s,4H).

Example 15

N-(2,3-dihydrospiro[indene-1,2'-[1,3]dithiolan]-6-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (2, 3-dihydrospiro [ indene-1, 2' - [1,3] dithiol ] -6-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

6-nitro-2,3-dihydrospiro[indene-1,2’-[1,3]dithiolane]

6-Nitro-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dithiolane ]

6-Nitro-2, 3-dihydro-1H-inden-1-one 15a (300 mg,1.69mmol, commercially available), ethanedithiol 15b (156. Mu.L, 1.86mmol, commercially available), p-toluenesulfonic acid (58 mg,0.34 mmol), toluene (10 mL) were added to a round bottom flask and reacted at 100℃for 2 hours. TLC showed that the starting material was reacted completely, the reaction solution was concentrated directly, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 6-nitro-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dithiolane ]15c (390 mg), yield 91%.

Second step

2,3-dihydrospiro[indene-1,2'-[1,3]dithiolan]-6-amine

2, 3-Dihydrospiro [ indene-1, 2' - [1,3] dithiolane ] -6-amine

6-Nitro-2, 3-dihydrospiro [ indene-1, 2' - [1,3] dithiolane ]15C (360 mg,1.42 mmol), ammonium chloride (458 mg,8.53 mmol), iron powder (238.09 mg,4.26 mmol), ethanol (12 mL), water (3 mL) were added to a round bottom flask and reacted at 80℃for 2 hours under nitrogen. The mass spectrum detection raw materials are completely reacted, the reaction liquid is filtered by diatomite, filter residues are filtered after being treated by methanol ultrasonic treatment, the filtration is repeated twice, the pH value of the filtrate is adjusted to be weak alkaline by saturated sodium bicarbonate, the filtrate is concentrated, the residue is purified by silica gel column chromatography (eluent: A system), and 2, 3-dihydrospiro [ indene-1, 2' - [1,3] dithiolane ] -6-amine 15d (310 mg) is obtained, and the yield is 98%.

MS m/z(ESI):224.0[M+H]⁺

Third step

N-(2,3-dihydrospiro[indene-1,2'-[1,3]dithiolan]-6-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (2, 3-dihydrospiro [ indene-1, 2' - [1,3] dithiol ] -6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

2, 3-Dihydropiro [ indene-1, 2' - [1,3] dithiolane ] -6-amine 15d (510 mg,1.43 mmol), N-methylimidazole (320 mg,3.90 mmol), N, N, N ', N ' -tetramethyl chloroformyl amidine hexafluorophosphate (140.38 mg,3.90 mmol), 1c 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid (290 mg,1.30 mmol), acetonitrile (10 mL) were added to the round bottom flask and reacted at room temperature for 16 hours. The mass spectrum was examined for the remainder of the starting material, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (2, 3-dihydrospiro [ indene-1, 2' - [1,3] dithiocyclopenta ] -6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 15e (150 mg), 21% in yield.

MS m/z(ESI):563.1[M+H]⁺

Fourth step

N- (2, 3-Dihydropiro [ indene-1, 2' - [1,3] dithiol ] -6-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 15e (130 mg,0.23 mmol), 2-hydroxyethyl-1-sulfonamide 1k (43 mg,0.35 mmol), cuprous iodide (13 mg,0.07 mmol), sarcosine (31 mg,0.35 mmol), potassium phosphate trihydrate (180 mg,1.16 mmol), N, N-dimethylformamide (3 mL) was added to the vial and reacted at 100℃under nitrogen atmosphere for 5 hours. The reaction of the raw materials was completed by mass spectrometry, the reaction solution was diluted with ethyl acetate, washed with water, saturated sodium chloride solution in this order, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (2, 3-dihydrospiro [ indene-1, 2' - [1,3] dithiocyclopenta ] -6-yl) -4- ((2-hydroxyethyl) sulfonamide) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 15 (17 mg), 13% yield.

MS m/z(ESI):560.2[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ11.80(s,1H),8.04(d,J＝1.4Hz,1H),7.84(d,J＝8.5Hz,1H),7.51(dd,J＝8.1,1.7Hz,1H),7.22(d,J＝8.2Hz,1H),7.15(d,J＝1.5Hz,1H),7.02(dd,J＝8.5,1.7Hz,1H),3.75(t,J＝6.5Hz,2H),3.61-3.50(m,2H),3.50-3.42(m,2H),3.29(s,2H),3.01-2.93(m,3H),2.86(t,J＝6.5Hz,2H),2.62(t,J＝6.6Hz,2H),1.55(s,4H),0.36(s,4H).

Example 16

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-4-(N-methylsulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- (N-methylsulfamoyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

4-(benzylthio)-N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- (Benzylthio) -N- (4, 4-difluoro-3 ' h-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 1j (500 mg,0.86 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (200 mg,0.35 mmol), tris (dibenzylideneacetone) dipalladium (158 mg,0.17 mmol) and N, N-diisopropylethylamine (335 mg,2.59 mmol) were dissolved in 1, 4-dioxane (10 mL), and benzyl mercaptan 16a (0.11 mL,0.91mmol, commercially available) was added under nitrogen atmosphere and the system was reacted at 50℃for 5 hours. The mass spectrum detection raw material is reacted completely, the reaction liquid is directly concentrated, the residue is purified by silica gel column chromatography (eluent: A system), 4- (benzylthio) -N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -group) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 16b (240 mg) is obtained, and the yield is 48%.

MS m/z(ESI):575.3[M+H]⁺

Second step

4-((4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)carbamoyl)-3-(6-azaspiro[2.5]octan-6-yl)benzenesulfonyl chloride

4- (4, 4-Difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) carbamoyl) -3- (6-azaspiro [2.5] oct-6-yl) benzenesulfonyl chloride

4- (Benzylthio) -N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 16b (80 mg,0.14 mmol) was dissolved in a mixed solution of acetonitrile (4 mL), water (0.1 mL), acetic acid (0.15 mL), and 1, 3-dichloro-5, 5-dimethylhydantoin 16C (44 mg,0.22 mmol) was added at 0℃to react at room temperature for 2 hours. TLC was used to check completion of the reaction, saturated sodium bicarbonate was added to quench the reaction, extraction was performed with ethyl acetate (20 mL. Times.3), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 4- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) carbamoyl) -3- (6-azaspiro [2.5] oct-6-yl) benzenesulfonyl chloride 16d (76 mg), which was directly added to the next step.

Third step

The above 4- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) carbamoyl) -3- (6-azaspiro [2.5] oct-6-yl) benzenesulfonyl chloride 16d (76 mg,0.14 mmol) was dissolved in dichloromethane (4 mL), N-diisopropylethylamine (53 mg,0.41 mmol) was added, and methylamine hydrochloride (19 mg,0.28 mmol) was reacted at room temperature for 16 hours. The mass spectrum detection raw materials are reacted completely, the reaction liquid is directly concentrated, the residue is purified by silica gel column chromatography (eluent: A system) to obtain N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -group) -4- (N-methylsulfamoyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 16 (18 mg), and the yield is 20%.

MS m/z(ESI):546.2[M+H]⁺

¹HNMR(400MHz,DMSO-d6)δ11.01(s,1H),7.83(d,J＝8.0Hz,1H),7.77(s,1H),7.55(d,J＝5.6Hz,2H),7.50(d,J＝8.0Hz,1H),7.31(d,J＝7.7Hz,1H),5.00(s,2H),3.06(s,4H),2.45(s,3H),2.08(s,4H),1.86(s,4H),1.46(s,4H),0.31(s,4H).

Example 17

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-2-(6-azaspiro[2.5]octan-6-yl)-4-sulfamoylbenzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) -4-sulfamoyl benzamide

First step

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-4-(N-(2,4-dimethoxybenzyl)sulfamoyl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- (N- (2, 4-dimethoxybenzyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

4- (4, 4-Difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) carbamoyl) -3- (6-azaspiro [2.5] oct-6-yl) benzenesulfonyl chloride 16d (200 mg,0.36 mmol) was dissolved in dichloromethane (5 mL), N-diisopropylethylamine (141 mg,1.09 mmol) was added, and 2, 4-dimethoxybenzylamine 17a (121 mg,0.73 mmol) was reacted at room temperature for 3 hours. The mass spectrum detection raw materials are completely reacted, the reaction liquid is directly concentrated to obtain N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -group) -4- (N- (2, 4-dimethoxy benzyl) sulfonamide) -2- (6-aza spiro [2.5] oct-6-yl) benzamide 17b (250 mg), and the next step is directly added.

MS m/z(ESI):682.3[M+H]⁺

Second step

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -4- (N- (2, 4-dimethoxybenzyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 17b (250 mg,0.37 mmol) was dissolved in trifluoroacetic acid (5 mL) and reacted at 0℃for 8 hours. Mass spectrometry detection of complete reaction of the starting material, reaction solution neutralization with saturated sodium bicarbonate, ethyl acetate extraction (20 mL. Times.3), washing of the organic phase with saturated sodium chloride solution, drying over anhydrous sodium sulfate, filtration, concentration, purification of the residue by column chromatography on silica gel (eluent: A system) gave N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) -4-sulfamoyl benzamide 17 (60 mg), 29% yield.

MS m/z(ESI):532.2[M+H]⁺

¹H NMR(400MHz,DMSO-d6)δ11.12(s,1H),7.82(d,J＝8.0Hz,1H),7.78(s,1H),7.67(s,1H),7.56(d,J＝8.1Hz,2H),7.47(s,2H),7.31(d,J＝8.0Hz,1H),5.01(s,2H),3.06(s,4H),2.29-1.98(m,4H),1.88(d,J＝11.7Hz,4H),1.47(s,4H),0.32(s,4H).

Example 18

4-(ethylsulfonamido)-N-(1-methyl-2-oxo-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]-5-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- (Ethylsulphonamido) -N- (1-methyl-2-oxo-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

4- (Ethylsulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid 9c (87.4 mg,0.26 mmol) was dissolved in N, N-dimethylformamide (4 mL), 5-amino-1-methyl-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -2-one (50.0 mg,0.22 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (0.12 g,0.32 mmol), N, N-diisopropylethylamine (83.5 mg,0.65 mmol) was added and stirred at room temperature for 2 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, the residue was purified by column chromatography on silica gel (eluent: A system), the residue was separated by preparative liquid phase (column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 4- (ethylsulfonamide) -N- (1-methyl-2-oxo-2 ',3',5',6' -tetrahydrospiro [ indoline-3, 4' -pyran ] -5-yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 18 (29.6 mg), yield 23.6%.

MS m/z(ESI):553.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.57(s,1H),10.12(s,1H),8.04(dd,J＝3.8,2.1Hz,1H),7.83(dd,J＝8.4,3.5Hz,1H),7.75(dq,J＝8.6,1.9Hz,1H),7.17(dd,J＝3.8,2.1Hz,1H),7.05(m,2H),4.06(m,2H),3.85(m,2H),3.20(m,2H),3.14(s,3H),2.98(m,4H),1.83(m,2H),1.63(m,2H),1.54(s,4H),1.21(s,3H),0.35(s,4H).

Example 19

4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)-N-(3'H-spiro[cyclobutane-1,1'-isobenzofuran]-6'-yl)benzamide

4- (Ethylsulfanyl) -2- (6-azaspiro [2.5] oct-6-yl) -N- (3 ' h-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) benzamide

14G (148 mg,0.287 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) -N- (3 ' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) benzamide (148 mg,0.287 mmol) was dissolved in N, N-dimethylformamide (3 mL), cuprous iodide (16 mg,0.086 mmol), sarcosine (25 mg,0.287 mmol), potassium phosphate trihydrate (229 mg,0.863 mmol), ethyl sulfonamide 9a (37 mg,0.345 mmol) and stirred under nitrogen atmosphere at 100℃for 4 hours. The reaction was completely examined by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4- (ethylsulfanomido) -2- (6-azaspiro [2.5] oct-6-yl) -N- (3 ' H-spiro [ cyclobutane-1, 1' -isobenzofuran ] -6' -yl) benzamide 19 (141 mg), 93.9% yield.

MS m/z(ESI):496.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.75(s,1H),10.19(s,1H),8.07(s,1H),7.84(dt,J＝8.4,3.3Hz,1H),7.63-7.56(m,1H),7.25(d,J＝8.0Hz,1H),7.17(t,J＝3.0Hz,1H),7.04(td,J＝5.5,5.1,2.6Hz,1H),4.93(d,J＝3.2Hz,2H),3.20(dq,J＝7.8,4.0Hz,2H),2.98(s,4H),2.32(s,2H),1.89(s,2H),1.55(s,4H),1.20(dt,J＝7.3,3.4Hz,3H),0.35(d,J＝3.2Hz,4H).

Example 20

N-(4,4-difluoro-3'H-spiro[cyclohexane-1,1'-isobenzofuran]-6'-yl)-2-(6-azaspiro[2.5]octan-6-yl)-4-(sulfamoylamino)benzamide

N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) -4- (sulfamoyl) benzamide

4-Amino-N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 10d (150 mg,0.32 mmol) was dissolved in dichloromethane (5 mL), triethylamine (97 mg, 0.962mmol) and sulfamoyl chloride 20a (44 mg,0.384 mmol) were added under an ice bath under nitrogen atmosphere, and stirred under an ice bath for 4 hours. The reaction was completely examined by mass spectrometry, the reaction mixture was diluted with methylene chloride, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (4, 4-difluoro-3 ' H-spiro [ cyclohexane-1, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) -4- (sulfamoyl) benzamide 20 (141 mg), 76.3% yield.

MS m/z(ESI):547.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.98(s,1H),9.93(s,1H),7.88-7.80(m,2H),7.51(dd,J＝8.1,1.9Hz,1H),7.37-7.29(m,3H),7.14(d,J＝2.1Hz,1H),7.00(dd,J＝8.5,2.1Hz,1H),5.00(s,2H),2.98(t,J＝5.2Hz,4H),2.13(d,J＝29.9Hz,4H),1.89(d,J＝18.4Hz,4H),1.55(s,4H),0.36(s,4H).

Example 21

N-(4,4-difluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1,3 '-indoline ] -5' -yl) -4- (ethylsulfanyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

N-(4,4-difluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Nitro-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid 10b (0.42 g,1.50 mmol) was dissolved in N, N-dimethylformamide (10 mL), 5 '-amino-4, 4-difluoro-1' -methyl-spiro [ cyclohexane-1, 3 '-indoline ] -2' -one 3f (0.40 g,1.50 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.86 g,2.25 mmol), N, N-diisopropylethylamine (0.58 g,4.51 mmol) was added and stirred at room temperature for 2 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzamide 21a (0.65 g), 82.3% in yield.

MS m/z(ESI):525.2[M+H]⁺

Second step

4-amino-N-(4,4-difluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Amino-N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzamide 21a (0.65 g,1.24 mmol) was dissolved in ethanol (25 mL) and water (5 mL), iron powder (0.28 g,4.96 mmol) and ammonium chloride (0.40 g,7.44 mmol) were added, and stirred under a nitrogen atmosphere at 85℃for 2.5 hours. After the reaction solution was cooled to room temperature, sodium hydrogencarbonate was added to adjust the pH to be alkaline, the reaction solution was filled with celite, the cake was washed with methanol, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-amino-N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 21b (0.38 g), 62.3% yield.

MS m/z(ESI):495.2[M+H]⁺

Third step

4-Amino-N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 21b (0.15 g,0.30 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.18 g,1.80 mmol) and ethylsulfonamide 9a (0.16 g,1.20 mmol) were added, and the mixture was stirred at room temperature under nitrogen for 3 hours. The reaction was completed by mass spectrometry, the reaction mixture was diluted with methylene chloride, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system), and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indolin ] -5' -yl) -4- (ethylsulfanyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 21 (14.5 mg), yield 7.3%.

MS m/z(ESI):587.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.61(s,1H),7.85(d,J＝2.0Hz,1H),7.81(d,J＝8.5Hz,1H),7.75(d,J＝7.6Hz,1H),7.14(d,J＝2.0Hz,1H),7.09(d,J＝8.4Hz,1H),7.01(dd,J＝8.4,2.1Hz,1H),3.17(m,2H),3.15(s,3H),2.97(t,J＝5.3Hz,4H),2.42(m,2H),2.15(m,2H),1.92(m,2H),1.82(m,2H),1.53(s,4H),1.21(s,3H),0.35(s,4H).

Example 22

N-(4,4-difluoro-1'-methyl-2'-oxospiro[cyclohexane-1,3'-indolin]-5'-yl)-4-((N-methylsulfamoyl)amino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -4- ((N-methylsulfamoyl) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Amino-N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 21b (80.1 mg,0.16 mmol) was dissolved in dichloromethane (4 mL), triethylamine (81.8 mg,0.82 mmol) and methylaminosulfonyl chloride 10e (62.7 mg,0.49 mmol) were added under nitrogen atmosphere, and stirred at room temperature for 3 hours. The reaction was completed by mass spectrometry, the reaction mixture was diluted with methylene chloride, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system), and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give N- (4, 4-difluoro-1 '-methyl-2' -oxospiro [ cyclohexane-1, 3 '-indolin ] -5' -yl) -4- ((N-methylsulfamoyl) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 22 (38.2 mg), yield: 38.2%.

MS m/z(ESI):588.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.67(s,1H),10.03(s,1H),7.86(d,J＝2.1Hz,1H),7.81(d,J＝8.4Hz,1H),7.78-7.71(m,1H),7.55(d,J＝5.4Hz,1H),7.12(d,J＝2.1Hz,1H),7.09(d,J＝8.4Hz,1H),6.99(dd,J＝8.5,2.0Hz,1H),3.15(s,3H),2.98(t,J＝5.3Hz,4H),2.48(s,3H),2.46(m,2H),2.15(m,2H),1.92(m,2H),1.83(m,2H),1.54(s,4H),0.35(s,4H).

Example 23

4-(ethylsulfonamido)-N-(1-methyl-3'H-spiro[azetidine-3,1'-isobenzofuran]-6'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- (Ethylsulphonamido) -N- (1-methyl-3 ' h-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Iodo-N- (1-methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 11e (0.13 g,0.24 mmol) was dissolved in N, N-dimethylformamide (5 Ml), cuprous iodide (13.5 mg,0.071 mmol), sarcosine (31.6 mg,0.35 mmol), potassium phosphate trihydrate (188.6 mg,0.71 mmol), ethylsulfonamide 9a (38.7 mg,0.35 mmol) was added and stirred under nitrogen atmosphere at 110℃for 2 hours. The reaction was completely detected by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system), and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 4- (ethylsulfonamide) -N- (1-methyl-3 ' H-spiro [ azetidine-3, 1' -isobenzofuran ] -6' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 23 (16.8 mg), 13.3% yield. MS m/z (ESI) 512.2[ M+H ] ⁺

¹H NMR(400MHz,DMSO-d₆)δ11.72(s,1H),8.30(s,1H),7.84(s,1H),7.53(s,1H),7.27(s,1H),7.18(s,1H),7.04(s,1H),4.97(s,2H),3.52(s,4H),3.20(s,4H),2.99(s,5H),2.37(s,4H),1.55(s,4H),0.36(s,4H).

Example 24

N-(4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-5'-yl)-4-((N-methylsulfamoyl)amino)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1,3' -indoline ] -5' -yl) -4- ((N-methylsulfamoyl) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

N-(4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-5'-yl)-4-nitro-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzamide

4-Nitro-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid 10b (0.43 g,1.55 mmol) was dissolved in N, N-dimethylformamide (5 mL), 4-difluoro-1 ' -methylspiro [ cyclohexane-1, 3' -indoline ] -5' -amine 4e (0.30 g,1.19 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (0.68 g,1.78 mmol), N, N-diisopropylethylamine (0.46 g,3.57 mmol) was added and stirred at room temperature for 4 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (4, 4-difluoro-1 ' -methylspiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzamide 24a (0.6 g), 98.8% yield.

MS m/z(ESI):511.3[M+H]⁺

Second step

4-amino-N-(4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Amino-N- (4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

N- (4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -4-nitro-2- (6-azaspiro [2.5] oct-6-yl) benzamide 24a (0.60 g,1.18 mmol) was dissolved in ethanol (20 mL) and water (5 mL), iron powder (0.26 g,4.70 mmol) and ammonium chloride (0.31 g,5.88 mmol) were added, and stirred under nitrogen atmosphere at 85℃for 2 hours. After the reaction was completed by mass spectrometry, the pH was adjusted to be alkaline by adding sodium bicarbonate to the reaction solution, the reaction solution was filtered through celite, the cake was washed with methanol, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-amino-N- (4, 4-difluoro-1 ' -methylspiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 24b (0.26 g), yield 46.0%.

MS m/z(ESI):481.3[M+H]⁺

Third step

4-Amino-N- (4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 24b (0.12 g,0.25 mmol) was dissolved in dichloromethane (5 mL), triethylamine (75.8 mg,0.75 mmol) and methylaminosulfonyl chloride 10e (64.7 mg,0.50 mmol) were added under nitrogen, and stirred at room temperature for 0.5 hours. The reaction was completely detected by mass spectrometry, the reaction mixture was diluted with dichloromethane, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system), and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give N- (4, 4-difluoro-1 ' -methylspiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -4- ((N-methylsulfamoyl) amino) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 24 (9.8 mg), yield 6.2%. MS m/z (ESI): 574.3[ M+H ] ⁺

¹H NMR(400MHz,DMSO-d₆)δ11.64(s,1H),7.82(d,J＝8.6Hz,1H),7.58(s,1H),7.53(d,J＝5.7Hz,1H),7.37(d,J＝8.2Hz,1H),7.12(s,1H),6.99(d,J＝8.6Hz,1H),6.56(d,J＝8.2Hz,1H),3.22(s,3H),2.97(m,4H),2.71(s,3H),2.47(m,2H),2.04(m,4H),1.78(m,4H),1.55(s,4H),0.36(s,4H).

Example 25

4-(ethylsulfonamido)-N-(1'-methylspiro[cyclopropane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- (Ethylsulfanyl) -N- (1 ' -methyl-spiro [ cyclopropane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

5’-bromospiro[cyclopropane-1,3’-indolin]-2’-one

5' -Bromospiro [ cyclopropane-1, 3' -indoline ] -2' -one

5-Bromoindolin-2-one 25a (15.0 g,70.74 mmol) was dissolved in dry tetrahydrofuran (250 mL), cooled to 0℃and lithium diisopropylamide (2M, 141.48 mL) was slowly added dropwise, stirred at 0℃for 30 minutes, then 1, 2-dibromoethane 25b (17.54 g,93.38 mmol) was added dropwise, and the reaction was completed at room temperature for 16 hours. The reaction was monitored by mass spectrometry to completion, the reaction solution was poured into ice water, followed by extraction with ethyl acetate (300 mL. Times.3), the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system) to give 5' -bromospiro [ cyclopropane-1, 3' -indoline ] -2' -one 25c (14 g), yield 83%.

MS m/z(ESI):238.0[M+H]⁺

Second step

5'-bromospiro[cyclopropane-1,3'-indoline]

5 '-Bromospiro [ cyclopropane-1, 3' -indoline ]

5' -Bromopiro [ cyclopropane-1, 3' -indoline ] -2' -ketone 25C (7 g,29.40 mmol) was dissolved in dry tetrahydrofuran (70 mL) under nitrogen atmosphere, cooled to 0 ℃, and a tetrahydrofuran solution of lithium aluminum hydride (2.5M, 58.80 mL) was slowly dropped, and the temperature was raised to 50 ℃ after the dropping to react for 16 hours. The mass spectrum monitoring shows that the target product is generated, the reaction solution is cooled to 0 ℃, water (11.5 mL) is slowly dripped, then 10 percent of sodium hydroxide aqueous solution (11.5 mL) is dripped, 35mL of water is continuously dripped, the filtration is carried out, the filter cake is washed by ethyl acetate, the filtrate is concentrated, the residue is purified by silica gel column chromatography (eluent: A system), and 5 '-bromospiro [ cyclopropane-1, 3' -indoline ]25d (6 g) is obtained, and the yield is 91 percent.

MS m/z(ESI):224.0[M+H]⁺

Third step

5'-bromo-1'-methylspiro[cyclopropane-1,3'-indoline]

5' -Bromo-1 ' -methyl spiro [ cyclopropane-1, 3' -indoline ]

5 '-Bromopiro [ cyclopropane-1, 3' -indoline ]25d (4.3 g,19.19 mmol) was dissolved in methanol (20 mL) and methylene chloride (20 mL), a formaldehyde solution (16.00 g,191.88mmol,36% content) and acetic acid (882.65 mg,19.19 mmol) were added, and after 30 minutes at room temperature, borane-2-pyridine complex (2.05 g,19.19 mmol) was added and the mixture reacted at room temperature for 12 hours. The formation of the target product was monitored by mass spectrometry, a saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with ethyl acetate (100 mL. Times.3), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by silica gel column chromatography (eluent: A system) to give 5' -bromo-1 ' -methyl spiro [ cyclopropane-1, 3' -indoline ]25e (2.25 g), in 49.2% yield.

MS m/z(ESI):238.0[M+H]⁺

Fourth step

tert-butyl(1'-methylspiro[cyclopropane-1,3'-indolin]-5'-yl)carbamate

(1 ' -Methyl-spiro [ cyclopropane-1, 3' -indoline ] -5' -yl) carbamic acid tert-butyl ester

5' -Bromo-1 ' -methyl spiro [ cyclopropane-1, 3' -indoline ]25e (2.25 g,9.45 mmol) was dissolved in 1, 4-dioxane (22 mL), tert-butyl carbamate (5.53 g,47.24 mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ' -4' -6' -tri-I-propyl-11 ' -biphenyl (429 mg,0.47 mmol) and cesium carbonate (9.24 g,28.35 mmol) were added and reacted under nitrogen atmosphere at 100℃for 16 hours. The mass spectrum was monitored for the formation of the product, the reaction solution was filtered through celite, the filtrate was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give tert-butyl (1 ' -methyl spiro [ cyclopropane-1, 3' -indoline ] -5' -yl) carbamate 25f (1.7 g), yield 65.5%.

MS m/z(ESI):275.2[M+H]⁺

Fifth step

1'-methylspiro[cyclopropane-1,3'-indolin]-5'-amine

1' -Methyl spiro [ cyclopropane-1, 3' -indoline ] -5' -amine

Tert-butyl (1 ' -methyl spiro [ cyclopropane-1, 3' -indoline ] -5' -yl) carbamate 25f (1.7 g,6.20 mmol) was dissolved in dioxane hydrochloride solution (20 mL) and reacted at room temperature for 1 hour. The mass spectrum was monitored to be complete, concentrated directly, the concentrate was purified with diethyl ether, filtered and the filter cake dried to give 25g (1.62 g) of 1' -methyl spiro [ cyclopropane-1, 3' -indoline ] -5' -amine hydrochloride in 62% yield.

MS m/z(ESI):175.2[M+H]⁺

Sixth step

4-iodo-N-(1'-methylspiro[cyclopropane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Iodo-N- (1 ' -methyl-spiro [ cyclopropane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

1C (400 mg,1.120 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in acetonitrile (8 mL), 25g (283 mg,1.34 mmol) of 1' -methyl spiro [ cyclopropane-1, 3' -indoline ] -5' -amine, tetramethyl chlorourea hexafluorophosphate (268 mg,2.240 mmol) and N-methylimidazole (459 mg,5.60 mmol) were added, and stirred at room temperature for 3 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was concentrated, dissolved in methylene chloride, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-iodo-N- (1 ' -methyl-spiro [ cyclopropane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide (682 mg) in 100% yield for 25 h.

MS m/z(ESI):514.1[M+H]⁺

Seventh step

4-Iodo-N- (1 ' -methyl-spiro [ cyclopropane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 25h (574 mg,1.12 mmol) solution N, N-dimethylformamide (4 mL), cuprous iodide (63 mg,0.335 mmol), sarcosine (99 mg,1.120 mmol), potassium phosphate trihydrate (893 mg,3.350 mmol), ethylsulfonamide 9a (146 mg,1.340 mmol) were added and stirred under nitrogen atmosphere at 100℃for 4 h. The reaction was completely detected by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system), and the residue was separated by preparative liquid phase (separation column AKZONOBEL Kromasil; 250X 21.2mm I.D.;5 μm,20mL/min; mobile phase A:0.05% TFA+H ₂ O; mobile phase B: CH ₃ CN) to give 4- (ethylsulfonamide) -N- (1 ' -methylspiro [ cyclopropan-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 25 (50 mg), yield 8.1%.

MS m/z(ESI):495.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.55(s,1H),10.14(s,1H),8.11(t,J＝1.3Hz,1H),7.87(d,J＝8.5Hz,1H),7.38(d,J＝1.9Hz,2H),7.18(d,J＝2.1Hz,1H),7.08(s,1H),7.04(dd,J＝8.5,2.1Hz,1H),3.72(s,3H),3.19(q,J＝7.3Hz,2H),2.99(t,J＝5.2Hz,4H),2.68(q,J＝7.5Hz,2H),1.55(d,J＝6.1Hz,4H),1.24-1.19(m,4H),0.35(s,4H).

Example 26

4-(ethylsulfonamido)-N-(1'-methyl-2'-oxospiro[cyclopentane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- (Ethylsulphonamido) -N- (1 '-methyl-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

5’-bromospiro[cyclopentane-1,3’-indolin]-2’-one

5' -Bromospiro [ cyclopentane-1, 3' -indoline ] -2' -one

5-Bromoindol-2-one 25a (5.0 g,23.58 mmol) was dissolved in dry tetrahydrofuran (50 mL), potassium tert-butoxide (1.0M, 70.74 mL) was added under nitrogen at-15℃and after stirring for 10min 1, 4-dibromobutane 26a (6.11 g,28.30 mmol) was added to the system and the reaction at 0℃was completed for 1 hour. The reaction was monitored by mass spectrometry and quenched by addition of 2M hydrochloric acid to the reaction mixture in ice bath, extraction with ethyl acetate, drying of the organic phase over anhydrous sodium sulfate, filtration, concentration and purification of the residue by column chromatography on silica gel (eluent: A system) gave 5' -bromospiro [ cyclopentane-1, 3' -indoline ] -2' -one 26b (3 g) in 47.8% yield.

MS m/z(ESI):265.9[M+H]⁺

Second step

5'-bromo-1'-methylspiro[cyclopentane-1,3'-indolin]-2'-one

5 '-Bromo-1' -methyl spiro [ cyclopentane-1, 3 '-indoline ] -2' -one

5' -Bromopiro [ cyclopentane-1, 3' -indolin ] -2' -one 26b (4.7 g,17.66 mmol) was dissolved in dry N, N-dimethylformamide (50 mL), sodium hydride (918.8 mg,21.19mmol,60% purity) was added under nitrogen atmosphere at 0℃and then slowly warmed to room temperature for 30 minutes, cooled to 0℃and methyl iodide (5.01 g,35.32 mmol) was added, and the reaction was completed at room temperature for 16 hours. The reaction was completed by mass spectrometry, the reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate (300 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 5 '-bromo-1' -methyl spiro [ cyclopentane-1, 3 '-indoline ] -2' -one 26c (1.5 g), yield 30.3%.

MS m/z(ESI):280.0[M+H]⁺

Third step

5'-amino-1'-methylspiro[cyclopentane-1,3'-indolin]-2'-one

5 '-Amino-1' -methyl-spiro [ cyclopentane-1, 3 '-indoline ] -2' -one

5 '-Bromo-1' -methyl spiro [ cyclopentane-1, 3 '-indolin ] -2' -one 26C (0.9 g,3.21 mmol) was dissolved in acetonitrile (2 mL), and ammonia (2 mL) and cuprous oxide (459.7 mg,3.21 mmol) were added to react at 100℃for 16 hours. The reaction was monitored by mass spectrometry to completion, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system) to give 5 '-amino-1' -methyl spiro [ cyclopentane-1, 3 '-indoline ] -2' -one 26d (544 mg), yield 78.3%.

MS m/z(ESI):217.3[M+H]⁺

Fourth step

4-iodo-N-(1'-methyl-2'-oxospiro[cyclopentane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Iodo-N- (1 '-methyl-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

1C (135 mg,0.378 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in N, N-dimethylformamide (4 mL), 5 '-amino-1' -methyl-spiro [ cyclopentane-1, 3 '-indoline ] -2' -one 26d (90 mg,0.416 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethyl urea hexafluorophosphate (215 mg,0.567 mmol) and N, N-diisopropylethylamine (146 mg,1.13 mmol) were added, and stirred at room temperature for 3 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-iodo-N- (1 '-methyl-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 26e (223 mg), and the crude product was directly used for the next reaction. MS m/z (ESI): 556.2[ M+H ] ⁺

Fifth step

4-Iodo-N- (1 '-methyl-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 26e (203 mg,0.365 mmol) was dissolved in N, N-dimethylformamide (3 mL), cuprous iodide (20 mg,0.109 mmol), sarcosine (32 mg,0.365 mmol), potassium phosphate trihydrate (2911 mg,1.100 mmol), ethylsulfonamide 9a (47 mg,0.438 mmol) was added, and stirred under nitrogen atmosphere at 100℃for 4 hours. The reaction was completely examined by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4- (ethylsulfamido) -N- (1 '-methyl-2' -oxospiro [ cyclopentane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 26 (111 mg), yield 53.7%.

MS m/z(ESI):537.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.67(s,1H),10.15(s,1H),7.83(d,J＝8.5Hz,1H),7.74(d,J＝2.0Hz,1H),7.66(dd,J＝8.4,2.1Hz,1H),7.17(d,J＝2.1Hz,1H),7.06-6.98(m,2H),3.18(q,J＝7.3Hz,2H),3.13(s,3H),2.97(t,J＝5.3Hz,4H),2.04-1.91(m,6H),1.80-1.71(m,2H),1.54(t,J＝5.0Hz,4H),1.20(t,J＝7.3Hz,3H),0.35(s,4H).

Example 27

N-(4',4'-difluoro-2H-spiro[benzofuran-3,1'-cyclohexan]-5-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4 ',4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-yl) -4- ((2-hydroxyethyl) sulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

1,4-dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate

1, 4-Dioxospiro [4.5] dec-7-en-8-yl triflate

1, 4-Dioxyspiro [4.5] decan-8-one 27a (20.0 g,128.06 mmol) and 1, 1-trifluoro-N-phenyl-N- (trifluoromethylsulfonyl) methanesulfonamide 27b (50.32 g,140.86 mmol) were dissolved in dry tetrahydrofuran (150 mL), and lithium bis trimethylsilylamide (1M, 140.86 mL) was slowly added dropwise under nitrogen at-78℃and stirred at-78℃for 0.5 hours, and the mixture was slowly warmed to room temperature for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (200 mL. Times.3), the organic phase was washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 1, 4-dioxaspiro [4.5] dec-7-en-8-yl triflate 27c (30 g), yield 83%.

Second step

methyl 1,4-dioxaspiro[4.5]dec-7-ene-8-carboxylate

1, 4-Dioxospiro [4.5] dec-7-ene-8-carboxylic acid methyl ester

1, 4-Dioxospiro [4.5] dec-7-en-8-yl triflate 27c (30 g,104.08 mmol) was dissolved in methanol (500 mL) and N, N-dimethylformamide (500 mL), triphenylphosphine (5.46 g,20.82 mmol), palladium acetate (701 mg,3.12 mmol) and triethylamine (21 g,208.16 mmol) were added and reacted at room temperature for 16 hours with carbon monoxide (50 Psi). TLC monitoring reaction completion, reaction solution concentration to remove methanol, ethyl acetate dilution, water, saturated sodium chloride solution washing, organic phase separation, anhydrous sodium sulfate drying, filtration, concentration, residue through silica gel column chromatography separation (eluent: A system) purification, 1, 4-two oxygen spiral [4.5] dec-7-alkene-8-carboxylic acid methyl ester 27d (20 g), yield 100%.

Third step

(1,4-dioxaspiro[4.5]dec-7-en-8-yl)methanol

(1, 4-Dioxospiro [4.5] dec-7-en-8-yl) methanol

1, 4-Dioxyspiro [4.5] dec-7-ene-8-carboxylic acid methyl ester 27d (20 g,100.90 mmol) was dissolved in dry dichloromethane (200 mL), diisobutylaluminum hydride (1.5M, 168.17 mL) was added dropwise under a nitrogen atmosphere at-78℃and reacted at-78℃for 1 hour after the addition. TLC monitoring reaction completion, reaction liquid-78 ℃ drop methanol quenching, heating to room temperature, adding saturated sodium potassium tartrate solution stirring, reaction liquid extracting with dichloromethane (200 mL x 3), organic phase drying with anhydrous sodium sulfate, filtering, concentrating to obtain 1, 4-dioxyspiro [4.5] dec-7-en-8-yl methanol 27e (15 g), yield 74.2%.

Fourth step

8-((2-bromophenoxy)methyl)-1,4-dioxaspiro[4.5]dec-7-ene

8- ((2-Bromophenoxy) methyl) -1, 4-dioxaspiro [4.5] dec-7-ene

1, 4-Dioxyspiro [4.5] dec-7-en-8-ylmethanol 27e (14 g,82.25 mmol) was dissolved in dry tetrahydrofuran (150 mL), triphenylphosphine (32.36 g,123.38 mmol) and 2-bromophenol 27f (14.23 g,82.25 mmol) were added, diethyl azodicarboxylate (23.64 g,135.72 mmol) was added dropwise under nitrogen atmosphere at 0℃and the reaction was allowed to proceed slowly at room temperature for 12 hours. TLC was used to monitor completion of the reaction, the reaction solution was concentrated directly, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 27g (18.5 g) of 8- ((2-bromophenoxy) methyl) -1, 4-dioxaspiro [4.5] dec-7-ene in 69.2% yield.

Fifth step

2H-dispiro[benzofuran-3,1'-cyclohexane-4',2”-[1,3]dioxolane]

2H-dipyrrole [ benzofuran-3, 1 '-cyclohexane-4', 2"- [1,3] dioxolane ]

8- ((2-Bromophenoxy) methyl) -1, 4-dioxaspiro [4.5] dec-7-ene 27g (16 g,49.20 mmol) was dissolved in toluene (400 mL), azobisisobutyronitrile (807.93 mg,4.92 mmol) and tributyltin hydride (17.90 g,61.50 mmol) were added and reacted under a nitrogen atmosphere at 100℃for 1 hour. TLC monitored completion of the reaction, quenching of the reaction mixture with saturated potassium fluoride, extraction with ethyl acetate (200 mL. Times.3), drying of the organic phase over anhydrous sodium sulfate, filtration, concentration, and purification of the residue by column chromatography on silica gel (eluent: A system) gave 2H-dipyrrole [ benzofuran-3, 1 '-cyclohexane-4', 2"- [1,3] dioxolane ]27H (10 g), 82.5% yield.

Sixth step

2H-spiro[benzofuran-3,1'-cyclohexan]-4'-one

2H-spiro [ benzofuran-3, 1 '-cyclohexane ] -4' -one

2H-dipyrrole [ benzofuran-3, 1 '-cyclohexane-4', 2"- [1,3] dioxolane ]27H (5.0 g,20.3 mmol) was dissolved in tetrahydrofuran (50 mL) and water (50 mL), hydrochloric acid (12M, 10 mL) was added, and the reaction was carried out at room temperature for 3 hours. TLC was used to monitor completion of the reaction, the reaction mixture was extracted with ethyl acetate (200 mL. Times.3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give crude 2H-spiro [ benzofuran-3, 1 '-cyclohexane ] -4' -one 27i (11.6 g).

Seventh step

4',4'-difluoro-2H-spiro[benzofuran-3,1'-cyclohexane]

4',4' -Difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ]

2H-spiro [ benzofuran-3, 1 '-cyclohexane ] -4' -one 27i (11.6 g,57.36 mmol) was dissolved in dry dichloromethane (97 mL), diethylaminosulfur trifluoride (27.74 g,172.07 mmol) was added dropwise under nitrogen at-78℃and the temperature was raised to 25℃for reaction for 1 hour. TLC monitored the reaction completion, the reaction solution was cooled to 0 ℃, quenched by slowly adding saturated sodium bicarbonate solution, extracted with ethyl acetate (200 mL. Times.3), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by column chromatography on silica gel (eluent: A system) to give 4',4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ]27j (5.5 g), 42.7% yield.

Eighth step

5-bromo-4',4'-difluoro-2H-spiro[benzofuran-3,1'-cyclohexane]

5-Bromo-4 ' -,4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ]

4',4' -Difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ]27j (4 g,17.84 mmol) was dissolved in (80 mL) and N-bromosuccinimide (3.17 g,17.84 mmol) was added and the mixture reacted at 25℃for 3 hours. The reaction was monitored by mass spectrometry and quenched by addition of saturated sodium bicarbonate solution at 0deg.C, extracted with ethyl acetate (100 mL. Times.3), the organic phase dried over anhydrous sodium sulfate, filtered, concentrated, and the residue purified by column chromatography on silica gel (eluent: A system) to give 5-bromo-4 ' -,4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ]27k (8.2 g) in 100% yield.

Ninth step

tert-butyl(4',4'-difluoro-2H-spiro[benzofuran-3,1'-cyclohexan]-5-yl)carbamate

(4 ',4' -Difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-yl) carbamic acid tert-butyl ester

5-Bromo-4 ' -,4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ]27k (7.7 g,25.4 mmol) was dissolved in 1, 4-dioxane (80 mL), tert-butyl carbamate (14.88 g,127.0 mmol), cesium carbonate (24.83 g,76.20 mmol), methanesulfonic acid (2-dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6' -triisopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (1.15 g,1.27 mmol) was added and reacted under a nitrogen atmosphere at 100℃for 5 hours. The reaction was monitored by mass spectrometry to completion, the reaction solution was filtered through celite, the filtrate was concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 27l (17 g) of tert-butyl (4 ',4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-yl) carbamate in 59.2% yield.

MS m/z(ESI):284.2[M-55]

Tenth step

4',4'-difluoro-2H-spiro[benzofuran-3,1'-cyclohexan]-5-amine

4' -,4' -Difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-amine

(4 ',4' -Difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-yl) carbamic acid tert-butyl ester 27l (16 g,47.15 mmol) was dissolved in dioxane hydrochloride solution (4M, 80 mL) and reacted at 25℃for 2 hours. The reaction was monitored by mass spectrometry to completion, the reaction solution was concentrated, ethyl acetate (50 mL) was added to the concentrate, the pH was adjusted to 7 with saturated sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrate was slurried with diethyl ether, filtered, and the filter cake dried to give 4' -,4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-amine 27m (3.38 g) in 29.9% yield.

MS m/z(ESI):240.4[M+H]⁺

Eleventh step

N-(4',4'-difluoro-2H-spiro[benzofuran-3,1'-cyclohexan]-5-yl)-4-iodo-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4 ' -,4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide

1C (149 mg,0.417 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in N, N-dimethylformamide (3 mL), 4 '-difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-amine 27m (100 mg,0.417 mmol), 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (238 mg, 0.418 mmol), N, N-diisopropylethylamine (129 mg,1.25 mmol) was added and stirred at room temperature for 3 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (4 ' -,4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 27N (203 mg) in 83.9% yield.

MS m/z(ESI):579.1[M+H]⁺

Twelfth step

N- (4 ' -,4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-yl) -4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzamide 27N (183mg, 0.316 mmol) was dissolved in N, N-dimethylformamide (4 mL), cuprous iodide (18 mg,0.094 mmol), sarcosine (28 mg,0.316 mmol), potassium phosphate trihydrate (252 mg,0.949 mmol), 2-hydroxyethyl-1-sulfonamide 1k (47 mg,0.379 mmol) was added and stirred under nitrogen atmosphere at 100℃for 4 hours. The reaction was completely examined by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (4 ',4' -difluoro-2H-spiro [ benzofuran-3, 1' -cyclohexane ] -5-yl) -4- ((2-hydroxyethyl) sulfamoyl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 27 (121 mg), yield 63.1%.

MS m/z(ESI):576.2[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.49(s,1H),10.07(s,1H),7.80(d,J＝8.5Hz,1H),7.74(d,J＝2.2Hz,1H),7.40(dd,J＝8.6,2.2Hz,1H),7.15(d,J＝2.1Hz,1H),7.02(dd,J＝8.5,2.1Hz,1H),6.82(d,J＝8.5Hz,1H),4.98(s,1H),4.44(s,2H),3.35-3.31(m,3H),2.96(t,J＝5.3Hz,4H),2.14-1.92(m,5H),1.84(dd,J＝8.8,4.3Hz,4H),1.52(s,4H),1.23(s,3H),0.34(s,4H).

Example 28

N-(4,4-difluoro-1'-methylspiro[cyclohexane-1,3'-indolin]-5'-yl)-4-(ethylsulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

N- (4, 4-difluoro-1 ' -methyl-spiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -4- (ethylsulphonamido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

4- (Ethylsulfanomido) -2- (6-azaspiro [2.5] oct-6-yl) benzoic acid 9c (53.6 mg,0.16 mmol) was dissolved in N, N-dimethylformamide (3 mL), 4-difluoro-1 ' -methylspiro [ cyclohexane-1, 3' -indoline ] -5' -amine 4e (40.0 mg,0.16 mmol), 2- (7-azabenzotriazol) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (90.4 mg,0.24 mmol), diisopropylethylamine (61.5 mg,0.48 mmol) was added and stirred at room temperature for 4 hours. The mass spectrum was examined for completion of the reaction, diluted with ethyl acetate, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give N- (4, 4-difluoro-1 ' -methylspiro [ cyclohexane-1, 3' -indoline ] -5' -yl) -4- (ethylsulfanomido) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 28 (42.4 mg), yield 44.4%. MS m/z (ESI): 573.3[ M+H ] ⁺

¹H NMR(400MHz,DMSO-d₆)δ11.47(s,1H),10.10(s,1H),7.83(d,J＝8.5Hz,1H),7.57(d,J＝2.1Hz,1H),7.37(dd,J＝8.4,2.1Hz,1H),7.16(d,J＝2.1Hz,1H),7.03(dd,J＝8.5,2.1Hz,1H),6.56(d,J＝8.4Hz,1H),3.23(s,2H),3.18(q,J＝7.3Hz,2H),2.96(t,J＝5.3Hz,4H),2.71(s,3H),2.15-1.88(m,4H),1.79(dd,J＝8.6,4.5Hz,4H),1.55(d,J＝5.3Hz,4H),1.22(q,J＝7.3,6.6Hz,3H),0.35(s,4H).

Example 29

4-(ethylsulfonamido)-N-(1'-methylspiro[cyclobutane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- (Ethylsulfanyl) -N- (1 ' -methyl-spiro [ cyclobutane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

5'-bromospiro[cyclobutane-1,3'-indolin]-2'-one

5' -Bromospiro [ cyclobutane-1, 3' -indoline ] -2' -one

5-Bromoindolin-2-one 25a (20 g,94.32 mmol) was dissolved in dry tetrahydrofuran (200 mL), n-butyllithium (2.5M, 113.18 mL) was slowly added dropwise under nitrogen at-30℃and stirred for 30 minutes at 0℃after the addition, and then 1, 3-dibromopropane 29a (57.13 g,282.96 mmol) was added and reacted overnight at room temperature. Mass spectrometry detects the formation of product. The reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 5' -bromospiro [ cyclobutane-1, 3' -indoline ] -2' -one 29b (13 g), yield 54.6%.

MS m/z(ESI):251.9[M+H]⁺

Second step

5'-bromo-1'-methylspiro[cyclobutane-1,3'-indolin]-2'-one

5 '-Bromo-1' -methyl spiro [ cyclobutane-1, 3 '-indoline ] -2' -one

5' -Bromospiro [ cyclobutane-1, 3' -indolin ] -2' -one 29b (10 g,39.67 mmol) was dissolved in N, N-dimethylformamide (150 mL), sodium hydride (2.06 g,47.60mmol,60% purity) was added under nitrogen atmosphere at 0℃and methyl iodide (7.32 g,51.57 mmol) was added after stirring for 10 minutes, and the reaction was slowly warmed to room temperature for 16 hours. The formation of the target product was detected by mass spectrometry, the reaction solution was quenched with ice water, then extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: B system) to give 5 '-bromo-1' -methyl spiro [ cyclobutane-1, 3 '-indoline ] -2' -one 29c (6.2 g), yield 58.7%.

MS m/z(ESI):266.0[M+H]⁺

Third step

5'-amino-1'-methylspiro[cyclobutane-1,3'-indolin]-2'-one

5 '-Amino-1' -methyl-spiro [ cyclobutane-1, 3 '-indoline ] -2' -one

5 '-Bromo-1' -methyl spiro [ cyclobutane-1, 3 '-indoline ] -2' -one 29C (2.6 g,9.77 mmol) was dissolved in acetonitrile (10 mL), cuprous oxide (1.40 g,9.77 mmol) was added, and aqueous ammonia (10 mL) was reacted in a closed tube at 100℃for 16 hours. The reaction was completed by mass spectrometry, the reaction solution was filtered through celite, extracted with ethyl acetate and water, the organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was separated and purified by reverse phase C ₁₈ column to give 5 '-amino-1' -methyl spiro [ cyclobutane-1, 3 '-indoline ] -2' -one 29d (1.4 g), yield 70.8%.

MS m/z(ESI):203.3[M+H]⁺

Fourth step

1'-methylspiro[cyclobutane-1,3'-indolin]-5'-amine

1' -Methyl-spiro [ cyclobutane-1, 3' -indoline ] -5' -amine

5 '-Amino-1' -methyl-spiro [ cyclobutane-1, 3 '-indolin ] -2' -one 29d (1.4 g,6.92 mmol) was dissolved in dry tetrahydrofuran (10 mL), and borane tetrahydrofuran solution (1M, 69.22 mL) was added and reacted at 50℃for 16 hours. Mass spectrometry detection showed that a small amount of starting material remained, dropwise adding methanol (100 mL) for quenching reaction, concentrating, and separating and purifying the residue by reversed phase C ₁₈ column to obtain 1' -methyl spiro [ cyclobutane-1, 3' -indoline ] -5' -amine 29e (560 mg), yield 42.9%.

MS m/z(ESI):189.3[M+H]⁺

Fifth step

4-iodo-N-(1'-methylspiro[cyclobutane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Iodo-N- (1 ' -methyl-spiro [ cyclobutane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

1C (150 mg,0.42 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in N, N-dimethylformamide (5 mL), 1' -methyl-spiro [ cyclobutane-1, 3' -indoline ] -5' -amine 29e (79 mg,0.42 mmol), 2- (7-azobenzotriazole) -N, N, N ', N ' -tetramethylurea hexafluorophosphate (192 mg,0.5 mmol), N, N-diisopropylethylamine (109 mg,0.84 mmol) was added, and stirred at room temperature for 2 hours. The reaction was monitored by mass spectrometry to completion, the reaction mixture was diluted with ethyl acetate, washed successively with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-iodo-N- (1 ' -methyl-spiro [ cyclobutane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 29f (181 mg), 81% in yield.

MS m/z(ESI):528.2[M+H]⁺

Sixth step

4-Iodo-N- (1 ' -methyl-spiro [ cyclobutane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 29f (181 mg,0.53 mmol) was dissolved in N, N-dimethylformamide (5 mL), cuprous iodide (20 mg,0.1 mmol), sarcosine (45 mg,0.51 mmol), potassium phosphate trihydrate (458 mg,1.72 mmol), ethylsulfonamide 9a (56 mg,0.51 mmol) was added, and stirred under nitrogen atmosphere at 110℃for 5 hours. The reaction was completely detected by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative method to give 4- (ethylsulfanomido) -N- (1 ' -methylspiro [ cyclobutane-1, 3' -indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 29 (47 mg), yield 25%.

MS m/z(ESI):509.3[M+H]⁺

1H NMR(400MHz,DMSO-d₆)δ11.52(s,1H),10.19(s,1H),7.85(d,J＝8.5Hz,1H),7.80(d,J＝1.9Hz,1H),7.34(dd,J＝8.3,1.9Hz,1H),7.17(d,J＝1.8Hz,1H),7.04(dd,J＝8.5,1.9Hz,1H),6.51(d,J＝8.4Hz,1H),3.31(s,2H),3.19(q,J＝7.3Hz,2H),2.97(t,J＝4.9Hz,4H),2.66(s,3H),2.20(t,J＝7.8Hz,4H),2.05-1.92(m,2H),1.56(s,4H),1.21(t,J＝7.3Hz,3H),0.35(s,4H).

Example 30

4-(ethylsulfonamido)-N-(1'-methyl-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4- (Ethylsulfanyl) -N- (1 '-methyl-2' -oxospiro [ cyclobutane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

First step

4-iodo-N-(1'-methyl-2'-oxospiro[cyclobutane-1,3'-indolin]-5'-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide

4-Iodo-N- (1 '-methyl-2' -oxospiro [ cyclobutane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide

1C (0.30 g,0.84 mmol) of 4-iodo-2- (6-azaspiro [2.5] oct-6-yl) benzoic acid was dissolved in N, N-dimethylformamide (3 mL), 5 '-amino-1' -methyl-spiro [ cyclobutane-1, 3 '-indoline ] -2' -one 29d (0.17 g,0.84 mmol), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate (0.48 g,1.26 mmol) was added, diisopropylethylamine (0.33 g,2.5 mmol) was added, and stirred overnight at room temperature. The reaction of the raw materials was completed by mass spectrometry, the reaction solution was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography on silica gel (eluent: A system) to give 4-iodo-N- (1 '-methyl-2' -oxospiro [ cyclobutane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 30a (0.38 g), yield 83.6%.

MS m/z(ESI):542.1[M+H]⁺

Second step

4-Iodo-N- (1 '-methyl-2' -oxospiro [ cyclobutane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 30a (0.17 g,0.31 mmol) was dissolved in N, N-dimethylformamide (8 mL), cuprous iodide (17.9 mg,0.094 mmol), sarcosine (5.2 mg,0.28 mmol), potassium phosphate trihydrate (0.17 g,0.63 mmol), and ethylsulfonamide 9a (51.4 mg,0.47 mmol) were added and reacted under a nitrogen atmosphere at 100℃for 5 hours. The reaction of the starting materials was completed by mass spectrometry, the reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by preparative method to give 4- (ethylsulfamido) -N- (1 '-methyl-2' -oxospiro [ cyclobutane-1, 3 '-indoline ] -5' -yl) -2- (6-azaspiro [2.5] oct-6-yl) benzamide 30 (66.6 mg), yield 38.6%.

MS m/z(ESI):523.3[M+H]⁺

¹H NMR(400MHz,DMSO-d₆)δ11.61(s,1H),10.17(s,1H),8.19(d,J＝2.1Hz,1H),7.83(d,J＝8.5Hz,1H),7.52(dd,J＝8.4,2.1Hz,1H),7.16(d,J＝2.1Hz,1H),7.03(dd,J＝8.4,2.1Hz,1H),6.98(d,J＝8.4Hz,1H),3.18(q,J＝7.3Hz,2H),3.11(s,3H),2.98(t,J＝5.2Hz,4H),2.35-2.12(m,4H),1.56(m,4H),1.21(t,J＝7.3Hz,3H),0.35(s,4H).

Biological evaluation

Test example 1 measurement of the inhibition of OVCAR-3 cell proliferation by the Compounds of the invention

The following method was used to determine the effect of the compounds of the invention on OVCAR-3 cell proliferation. OVCAR-3 cells (containing TP53R248Q mutation) were purchased from Shanghai institute of life sciences cell resource center, academy of sciences of China and cultured in RPMI 1640 medium containing 10% fetal bovine serum, 100U penicillin and 100. Mu.g/mL streptomycin. Cell viability byLuminescent Cell Viability Assay kit (Promega, cat. G7573) was used for the measurement.

The experimental method is operated according to the steps of the instruction book of the kit, and is briefly described as follows, the test compound is firstly dissolved in DMSO to prepare 10mM stock solution, then diluted by a culture medium to prepare a test sample, and the final concentration of the compound ranges from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded at a density of 1000 cells per well in 96-well cell culture plates and incubated overnight in a 37 ℃ 5% co ₂ incubator, followed by additional incubation for 72 hours after the addition of the test compound. After the incubation was completed, a 50uL volume of CellTiter-Glo assay was added to each well, and after shaking for 5 minutes, the wells were allowed to stand for 10 minutes, followed by reading the Luminescence values of each well of the sample on a microplate reader using the Luminescence mode. The percent inhibition of compounds at each concentration point was calculated by comparison with the values of the control group (0.3% dmso), after which nonlinear regression analysis was performed in GRAPHPAD PRISM software with the compound concentration log-inhibition to obtain IC ₅₀ values for compounds inhibiting cell proliferation, see table 1.

The IC ₅₀ value results for the compounds of the invention are indicated at A, B, C, D and are:

A:IC₅₀≤50nM,B:50nM<IC₅₀≤100nM,C:100nM<IC₅₀≤200nM,D:200nM<IC₅₀≤500nM.

TABLE 1 IC ₅₀ data for inhibition of OVCAR-3 cell proliferation by the compounds of the invention

The conclusion is that the compound has better inhibition effect on the proliferation IC ₅₀ <500nM of the OVCAR-3 cells.

Test example 2 inhibition of HT-29 cell proliferation assay by Compounds of the invention

The following methods were used to determine the effect of the compounds of the invention on HT-29 cell proliferation. HT-29 cells (harboring the TP53R273H mutation) were purchased from the Shanghai institute of life sciences cell resource center of China academy of sciences and cultured in McCOY's 5A medium containing 10% fetal bovine serum, 100U penicillin and 100. Mu.g/mL streptomycin. Cell viability byLuminescent Cell Viability Assay kit (Promega, cat. G7573) was used for the measurement.

The experimental method is operated according to the steps of the instruction book of the kit, and is briefly described as follows, the test compound is firstly dissolved in DMSO to prepare 10mM stock solution, then diluted by a culture medium to prepare a test sample, and the final concentration of the compound ranges from 1000nM to 0.015nM. Cells in the logarithmic growth phase were seeded at a density of 1000 cells per well in 96-well cell culture plates and incubated overnight in a 37 ℃ 5% co ₂ incubator, followed by additional incubation for 120 hours after the addition of the test compound. After the incubation was completed, a 50uL volume of CellTiter-Glo assay was added to each well, and after shaking for 5 minutes, the wells were allowed to stand for 10 minutes, followed by reading the Luminescence values of each well of the sample on a microplate reader using the Luminescence mode. The percent inhibition of compounds at each concentration point was calculated by comparison with the values of the control group (0.3% dmso), after which nonlinear regression analysis was performed in GRAPHPAD PRISM software with the compound concentration log-inhibition to obtain IC ₅₀ values for compounds inhibiting cell proliferation, see table 2.

TABLE 2 IC ₅₀ data for inhibition of HT-29 cell proliferation by the compounds of the invention

The conclusion is that the compound has better inhibition effect on HT-29 cell proliferation IC ₅₀ <500 nM.

Test example 3 test of inhibition of KIF18A Activity by Compounds of the invention

The following methods were used to determine the extent of inhibition of the enzymatic activity of recombinant human KIF18A by the compounds of the invention under in vitro conditions. The method uses ADP-Glo ^TM KINASE ASSAY kit (cat No. V9102) from Promega company. For detailed experimental procedures reference is made to the kit instructions.

The experimental procedure is briefly described as follows, the test compound is first dissolved in DMSO to prepare a stock solution, then the stock solution is subjected to gradient dilution by using a reaction buffer A (15mM Tris,pH 7.5,10mM MgCl2,0.01%Pluronic F-68), the final concentration of the test compound in the reaction system is 10000 nM-0.15 nM, and the KIF18A protein and the ATP working solution are prepared by using a reaction buffer B (15mM Tris,pH 7.5,10mM MgCl2,0.01%Pluronic F-68,37.5ug/ml tubulin,1.25uM paclitaxel). The reaction was performed in 384 well microwell plates, first compound and recombinant human KIF18A protein (final concentration 100nM, delegated auruseri expression) were added to the wells and incubated at room temperature for 20 minutes, followed by addition of ATP solution (from ADP-Glo ^TM KINASE ASSAY kit component V915A, final concentration 60 uM) to the reaction solution and incubation at room temperature for 20 minutes. Subsequently, 5. Mu.L of ADP-Glo Reagent was added to the reaction system, and incubated at room temperature for 50 minutes. Then 10 μ L Kinase Detection Reagent was added to the reaction system and incubated for 30 minutes at room temperature. After the incubation, the chemiluminescent intensity value of each well was measured in a luminometer in the luminometer mode. The percent inhibition of the compounds at each concentration was calculated by comparison with the ratio of the luminescence intensities of the control group (0.1% dmso) and nonlinear regression analysis was performed by GRAPHPAD PRISM software on the compound concentration vs. inhibition to obtain IC ₅₀ values for the compounds, see table 3.

A:IC₅₀≤50nM,B:50nM<IC₅₀≤100nM,C:100nM<IC₅₀≤200nM,D:200nM<IC₅₀≤500nM

TABLE 3 IC ₅₀ data for compounds of the invention that inhibit KIF18A enzymatic activity

The conclusion is that the compound has remarkable inhibition effect on the inhibition IC ₅₀ <500nM of the KIF18A enzyme activity.

Claims

A compound represented by general formula (I) or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

in:

R is selected from

Ring A is selected from a 3- to 8-membered heterocyclic group or a C ₃ -C ₈ cycloalkyl group;

X ₁ , X ₂ , and X ₃ are each independently selected from the group consisting of non-existent, CR ^a , N or S atoms, and at most two atoms among X ₁ , X ₂ , and X ₃ are simultaneously N atoms, and at most one of X ₁ , X ₂ , and X ₃ is non-existent;

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

_G1 and _G2 are each independently selected from ^a bond, ( ^CRaRb ) _p , C(O), ^NRc , O or S(O)r; _G1 and _G2 are not bonds at the same time;

_G3 is selected from ^a bond, ( ^CRaRb ) _p , C(O), ^NRc or O;

^Ra and ^Rb are each independently selected from a hydrogen atom, a halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group; wherein the alkyl group or the alkoxy group is optionally further substituted by one or more substituents selected from halogen, a hydroxyl, a cyano group, an alkyl group or an alkoxy group;

R ^c 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, alkyl or alkoxy;

_L is selected from a bond, C _0-4 alkyl-SO ₂ -C _0-4 alkyl, C _0-4 alkyl-S(═O)(═NH)-C _0-4 alkyl, C _0-4 alkyl-NR ^d SO ₂ -C _0-4 alkyl, C _0-4 alkyl-SO ₂ NR ^d -C _0-4 alkyl, C _0-4 alkyl-OC _0-4 alkyl, C _0-4 alkyl-(OH)-C _0-4 alkyl, C _0-4 alkyl-NR ^d -C _0-4 alkyl, C _0-4 alkyl-NR ^d SO ₂ NR ^d -C _0-4 alkyl, C _0-4 alkyl-NR ^d -C(O)NR ^d -C _0-4 alkyl, C _0-4 alkyl-C(O)NR ^d -C _0-4 alkyl or C _0-4 alkyl-NR ^d C(O)-C _0-4 alkyl;

R ^d is each independently selected from a hydrogen atom or an alkyl group;

L ₂ is selected from

R ¹ is selected from hydrogen, cyano, halogen, alkyl, hydroxy, NR ⁹ R ¹⁰ , 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 by one or more substituents selected from halogen, hydroxy, cyano, alkyl or alkoxy;

Alternatively, two R ² together with the atoms to which they are attached form a 3- to 8-membered heterocyclic group or a cycloalkyl group, wherein the 3- 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)R ⁸ , -C(O)OR ⁸ , -OC(O)R ⁸ , -NR ⁹ R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R ¹⁰ ;

R 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;

^R4 are the same or different and are each independently selected from a hydrogen atom, a cyano group, a halogen ^, an alkyl group, a hydroxyl group, a cycloalkyl group, a heterocyclic group, an aryl group, a ^heteroaryl group, ^-OR5 , -C(O) ^R5 , -C(O) ^OR5 , -NHC(O ^)R5 ^, ^-NHC (O) ^OR5 , _-NR6R7 , -C(O) ^NR6R7 , _-CH2NHC (O) ^OR5 , ^-CH2NR6R7 or -S(O ⁾ _rR5 ; wherein the alkyl, cycloalkyl, heterocyclic group, aryl or heteroaryl group is optionally further substituted by one or more groups selected from hydroxyl, halogen, nitro, cyano group, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocyclic group, aryl, heteroaryl, =O, -C(O) ^R8 , -C(O) ^OR8 , -OC(O) ^R8 , ^-NR9R ¹⁰ , -C(O)NR ⁹ R ¹⁰ , -SO ₂ NR ⁹ R ¹⁰ or -NR ⁹ C(O)R 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 is selected from hydrogen, alkyl, amino, cycloalkyl, heterocyclic, aryl or heteroaryl, wherein the alkyl, cycloalkyl, heterocyclic, aryl or heteroaryl is optionally further substituted with one or more substituents selected from hydroxy, halogen, nitro, amino, cyano, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, carboxyl or carboxylate;

^R9 and ^R10 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 each independently 0, 1 or 2; m is preferably 0;

n is 0, 1, 2, 3 or 4;

p is each independently 1, 2 or 3;

r is independently 0, 1 or 2.

The compound according to claim 1 or its stereoisomer, tautomer or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer or pharmaceutically acceptable salt described by general formula (II):

wherein: X ₁ -X ₃ , A ₁ -A ₃ , G ₁ , G ₂ , G ₃ , Ring A, R ¹ , R ² , R ⁴ , L ₁ , L ₂ , m and n are as defined in claim 1.

The compound according to claim 2, or its stereoisomer, tautomer, or pharmaceutically acceptable salt, which is a compound or its stereoisomer, tautomer, or pharmaceutically acceptable salt described by general formula (III):

wherein: X ₁ to X ₃ , A ₁ to A ₃ , G ₁ , G ₂ , Ring A, R ¹ , R ² , R ⁴ , L ₁ , L ₂ , m and n are as defined in claim 1.

The compound according to claim 3, 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 (IV) or (V):

wherein: X ₁ -X ₃ , A ₁ -A ₃ , G ₁ , G ₂ , 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 to 4, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

The compound _according to claim 1 to 5, or a stereoisomer, tautomer or _a _{pharmaceutically} acceptable salt thereof, wherein _L1 is selected _from _a bond, _{-NHSO2CH2CH2-} _, _{-SO2NHCH2CH2-} _, _-SO2- , -CH2SO2-, -NHSO2-, -NHSO2NH-, _-SO2NH- , -S(＝O) ₍ ＝NH) _CH2CH2 , -S(＝O)( _＝ NH)-, -NHC( _CH3 ) _2CH2- , -C(O)NHCH2CH2-, _-C (O)NHC( _CH3 ₎ _2CH2- _, -C(O)N( _CH3 ₎ _CH2CH2- , _-CH (CH3)(OH)CH2-, -NHSO2CH( _CH3 ₎ CH2- _, -SO2NHC(CH3 ₎ _2CH2 -, -C(O)NH-, -NHC(O)-, -NHCH ₂ CH ₂ or -CH ₂ SO ₂ CH ₂ CH ₂ -.

The compound according to any one of claims 1 to 6, 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.

The compound according to any one of claims 1 to 5, or its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Selected from:

The compound according to any one of claims 1 to 8, 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 9, or its stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein:

R ⁴ is selected from hydrogen, halogen, alkyl, cycloalkyl, heterocyclic or -C(O)R ⁵ ; wherein the alkyl, cycloalkyl or heterocyclic is optionally further substituted by one or more halogens;

^R5 is selected from alkyl groups.

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 the compound according to any one of claims 1 to 11 or its stereoisomer, tautomer or pharmaceutically acceptable salt, 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, or the pharmaceutical composition according to claim 11 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.