Azetidine compound and medical use thereof

Abstract

The present invention relates to an azetidine compound and a medical use thereof. Specifically, the compound has a structure as shown in formula (I), and can be used as a secretion regulator for type I interferons, especially as a cGAS / STING signal pathway-targeted inhibitor, and can be used for preparing drugs for preventing and / or treating inflammatory diseases and autoimmune diseases.

Description

Azetidine compounds and their medical uses Technical Field

[0001] The present invention belongs to the field of medicinal chemistry and pharmacotherapy, and specifically relates to azetidine compounds and their medical uses, as well as pharmaceutical compositions of the compounds and their use as type I interferon secretion regulators, especially as cGAS / STING signaling pathway targeted inhibitors, in the preparation of drugs for preventing and / or treating inflammatory diseases and autoimmune diseases. Background Art

[0002] STING, also known as transmembrane protein 173 (TMEM173), MPYS, MITA, or ERIS, is a protein encoded by the human TMEM173 gene. The cGAS / STING signaling pathway plays a crucial role in innate immunity. When the DNA sensor cGAS (cyclic GMP-AMP synthase) detects pathogen DNA, it induces the production of cGAMP (cyclic GMP-AMP); cGAMP then activates the stimulator of interferon genes (STNG) to recruit TANK-binding kinase 1 (TBK1), a downstream enzyme in STING. This phosphorylation of interferon regulatory factor 3 (IRF3) induces the secretion of type I interferons and cytokines. This cascade activates the acquired immune system, activating T cells and thus exerting anti-tumor immunity. However, abnormal activation of the innate immune system can induce a variety of diseases. Research on the molecular mechanisms of the cGAS / STING signaling pathway provides new insights into the development of targeted drugs.

[0003] The cGAS / STING signaling pathway can be precisely regulated through the body's physiological processes and drug methods, including protein post-translational modification (phosphorylation, ubiquitination, etc.), small molecule antagonists (such as H-151, C-176) and agonists (such as DMXAA, MSA-2). When the cGAS / STING signaling pathway is abnormally activated or overactivated, it can cause inflammatory diseases and autoimmune diseases, such as AGS syndrome, systemic lupus erythematosus (SLE), and amyotrophic lateral sclerosis (ALS). Therefore, unlike the immune killing effect of cGAS / STING activators on tumor cells, targeted inhibition of the cGAS / STING signaling pathway can be used to treat such inflammatory diseases and autoimmune diseases.

[0004] Although research on small-molecule compounds that target and inhibit the cGAS / STING signaling pathway is still in its infancy, it remains a hot topic in medical physiology. In 2018, Haag et al. reported a class of nitrofuran and indole urea compounds in Nature (Nature 2018, 559, 269-273). These compounds covalently bind to Cys91 on the STING protein, blocking STING activation-induced palmitoylation, thereby interfering with its assembly into multimeric complexes in the Golgi apparatus and inhibiting downstream signaling pathways. Furthermore, these inhibitors can inhibit STING-mediated inflammatory cytokine secretion in mouse cells, alleviating the pathological features of autoinflammatory diseases in mice. In 2019, Lama et al. published a series of indolepiperidine compounds in Nature Communications (Nat. Commun. 2019, 10, 2261). These compounds effectively inhibit cGAS activity in human bone marrow-derived macrophages (BMDMs). In 2021, Wang Chen's team from China Pharmaceutical University reported the sulfonamide compound SN-011, which binds to the cyclic dinucleotide binding domain of the STING protein to exert STING inhibitory activity. - / - It can strongly inhibit inflammation and autoimmune diseases in mice (Proc. Natl. Acad. Sci. US A. 2021, 118, e2105465118.). Therefore, small molecule inhibitors that target the cGAS / STING signaling pathway are expected to become important therapeutic drugs for autoimmune diseases.

[0005] In recent years, renowned pharmaceutical companies such as Novartis, Bayer, and Eli Lilly have joined the research and development of small-molecule inhibitors targeting the cGAS / STING signaling pathway. Most research on these compounds is still in the cellular activity validation phase, and no small-molecule inhibitors are currently in clinical development. Therefore, there is an urgent need to develop highly active and druggable small-molecule inhibitors targeting the cGAS / STING signaling pathway to develop therapeutics for autoimmune diseases.

[0006] Summary of the Invention

[0007] The purpose of the present invention is to provide a highly active and druggable small molecule inhibitor targeting the cGAS / STING signaling pathway, which can be used as a therapeutic drug for autoimmune diseases.

[0008] The first aspect of the present invention provides a compound represented by formula (I), or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0009] wherein Ring B is selected from the following substituted or unsubstituted groups: six-membered aryl, six-membered heteroaryl, or five-membered heteroaryl, wherein the heteroatom in the heteroaryl is selected from N, S, and O; and the number of the heteroatoms is 1-3;

[0010] Ring A and Ring C are independently selected from the following groups: substituted or unsubstituted 3-8 membered heterocyclic group, C3-C8 cycloalkyl, five-membered heteroaryl, six-membered aryl, six-membered heteroaryl, Wherein, the substitution refers to 1-5 R 1 Replacement; wherein each R 1 independently selected from the group consisting of hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COOC1-C6 alkyl, nitro, -CO(3-8 membered substituted or unsubstituted heterocyclyl), -CO(C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 arylC1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroarylC1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C R is a 2-C6 alkynyl group, a substituted or unsubstituted C1-C6 alkoxy group, a substituted or unsubstituted C1-C6 alkylacyl group, a substituted or unsubstituted aminoacyl group, a substituted or unsubstituted C1-C6 alkylamido group, a substituted or unsubstituted C1-C4 alkylamino group, a substituted or unsubstituted C6-C12 arylamino group, a substituted or unsubstituted 3-8 membered heterocyclyl group, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted 5-12 membered heteroaryl group, or a substituted or unsubstituted C6-C12 aryl group; 1 The substitution mentioned herein refers to substitution by one or more groups selected from the group consisting of halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl;

[0011] Ring D and Ring E are each independently a C5-C6 alkane ring, a benzene ring, a 5-6 membered heteroalkane ring or a 5-6 membered heteroaromatic ring;

[0012] L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene-, -(substituted or unsubstituted C1-C6 alkylene)-sulfonyl-, substituted or unsubstituted monocyclic or bicyclic C3-C6 cycloalkyl, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C2-C6 alkynylene-, -substituted or unsubstituted C1-C6 alkylene-O-, -substituted or unsubstituted C1-C6 alkylene-OCO-, substituted or unsubstituted monocyclic or bicyclic C6-C12 aryl, substituted or unsubstituted monocyclic or bicyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic or bicyclic 3-8 membered heterocyclyl, wherein m and p are each independently 0-3; x and y are each independently selected from 0-4; wherein “*” indicates connection with ring C;

[0013] L 2 Selected from: Wherein “*” indicates connection with ring B;

[0014] X and Y are each independently selected from S, SO, SO2, O, NR 2 or CR 3 R 4 ;

[0015] Q and Z are each independently selected from CO or a chemical bond;

[0016] Provided that, when ring B is a six-membered aromatic group, and L 1 Not for When L 2 for in The “*” in indicates that it is connected to ring C. The “*” in indicates that it is connected to ring B;

[0017] R 2 、R 3 、R 4 Each is independently selected from the following group: hydrogen atom, halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclic group; or R 3 、R 4 The C atoms connected thereto form a 3-5 membered cycloalkyl or heterocyclic group; or R 3 or R 4 The C atom connected thereto forms a C2-C6 alkenyl group;

[0018] n is 0 or 1, wherein when n is 0, X is directly connected to C=O;

[0019] The substitution refers to substitution by one or more groups selected from the following groups: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

[0020] In another preferred embodiment, ring B is selected from the following structures:

[0021] Among them, "*" indicates that it is connected to the C atom adjacent to N, "**" indicates that it is connected to the C atom adjacent to X; L 2 Connected to any unsubstituted position of ring B.

[0022] In another preferred embodiment, the compound is not the following compound:

[0023] In another preferred embodiment, the compound has the structure shown in Formula II to VII:

[0024] In the formula, ring A, ring C, R 3 、R 4 , X, L 1 , L 2 is defined as described herein.

[0025] In another preferred embodiment, the compound has the structure shown in Formula II to VII:

[0026] In the formula, ring A, ring C, L 1 , L 2 is defined as described herein;

[0027] R 3 、R 4 Each independently is C1-C6 alkyl, halogen, or R 3 、R 4 The C atoms connected thereto form a 3-5 membered cycloalkyl or heterocyclic group; or R 3 or R 4 The C atom connected thereto forms a C2-C6 alkenyl group;

[0028] X is selected from O or S atoms;

[0029] Preferably, R 3 、R 4 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, fluorine, chlorine, bromine, or R 3 、R 4 The C atom to which it is attached forms a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; or R 3 or R 4 The C atom connected thereto forms a vinyl group, a propenyl group or an allyl group;

[0030] X is selected from O or S atoms, more preferably S atoms.

[0031] In another preferred embodiment, the compound has the structure shown in Formula II to VII:

[0032] In the formula, ring A, ring C, L 1 , L 2 is defined as described herein;

[0033] R 3 、R 4 is methyl;

[0034] X is selected from O or S atoms.

[0035] In another preferred embodiment, in Formula II or Formula V,

[0036] L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene-, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C2-C6 alkynylene-, -substituted or unsubstituted C1-C6 alkylene-O-, The condition is that when L 1 Not for When L 2 for wherein The "*" in represents connection with ring C, The “*” in the figure indicates that it is connected to the mother nucleus, and the other end is connected to ring A.

[0037] In another preferred embodiment, in Formula II or Formula V,

[0038] L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene- (preferably -substituted or unsubstituted C1-C3 alkylene-), The condition is that when L 1 Not for When L 2 for wherein The "*" in represents connection with ring C, The “*” in the figure indicates that it is connected to the mother nucleus, and the other end is connected to ring A.

[0039] In another preferred embodiment, in Formula II or Formula V,

[0040] L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene-, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C2-C6 alkynylene-, -substituted or unsubstituted C1-C6 alkylene-O-;

[0041] L 2 Selected from: The “*” indicates that it is connected to the mother nucleus, and the other end is connected to ring A.

[0042] In another preferred embodiment, in Formula II or Formula V,

[0043] L 1 is a substituted or unsubstituted C1-C6 alkylene group (preferably a substituted or unsubstituted C1-C3 alkylene group);

[0044] L 2 for The “*” indicates that it is connected to the mother nucleus, and the other end is connected to ring A.

[0045] In another preferred embodiment, in Formula II or Formula V, L 1 Selected from: Wherein "*" indicates connection with ring C.

[0046] In another preferred embodiment, in Formula II or Formula V, L 1 for wherein x and y are each independently selected from 0-2; wherein “*” indicates connection with ring C.

[0047] In another preferred embodiment, in Formula III or Formula IV or Formula VI or Formula VII, L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene-, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C2-C6 alkynylene-, -substituted or unsubstituted C1-C6 alkylene-O-.

[0048] In another preferred embodiment, in Formula III or Formula IV or Formula VI or Formula VII, L 1 is a substituted or unsubstituted C1-C6 alkylene group (preferably a substituted or unsubstituted C1-C3 alkylene group).

[0049] In another preferred embodiment, ring A is

[0050] In another preferred embodiment, when ring A is When , ring D and ring E are each independently selected from the following group of substituted or unsubstituted groups: benzene ring, 5-6 membered heteroaryl ring.

[0051] In another preferred embodiment, when ring A is When , ring D and ring E are each independently selected from the following substituted or unsubstituted groups: benzene ring, pyrrole ring, furan ring, thiophene ring.

[0052] In another preferred embodiment, when ring A is When one of ring D and ring E is a substituted or unsubstituted benzene ring, the other is a substituted or unsubstituted group consisting of a pyrrole ring, a furan ring or a thiophene ring.

[0053] In another preferred embodiment, ring A is selected from the following substituted or unsubstituted groups:

[0054] In another preferred embodiment, ring A is selected from the following substituted or unsubstituted groups:

[0055] In another preferred embodiment, ring A is selected from the following substituted or unsubstituted groups:

[0056] In another preferred embodiment, ring A is selected from the following groups which are halogen-substituted (preferably F-substituted) or unsubstituted:

[0057] In another preferred embodiment, ring C is selected from the following groups: substituted or unsubstituted 3-6 membered heterocyclic group, C3-C6 cycloalkyl, six membered aryl, six membered heteroaryl, five membered heteroaryl,

[0058] In another preferred embodiment, ring C is selected from the following groups: substituted or unsubstituted C3-C6 cycloalkyl, six-membered aryl, six-membered heteroaryl, five-membered heteroaryl,

[0059] In another preferred embodiment, when ring C is When , ring D and ring E are each independently selected from the following substituted or unsubstituted groups: a benzene ring, a 5-6 membered heteroalkyl ring, a 5-6 membered heteroaryl ring.

[0060] In another preferred embodiment, when ring C is When , ring D and ring E are each independently selected from the following substituted or unsubstituted groups: a benzene ring, a 5-membered heteroalkyl ring, and a 5-membered heteroaryl ring.

[0061] In another preferred embodiment, when ring C is When one of ring D and ring E is a substituted or unsubstituted benzene ring, the other is a substituted or unsubstituted group consisting of a 5-membered heteroalkyl ring and a 5-membered heteroaryl ring.

[0062] In another preferred embodiment, when ring C is When one of ring D and ring E is a substituted or unsubstituted benzene ring, the other is a substituted or unsubstituted group selected from the group consisting of dioxolane, dioxane, thiophene, furan, pyrrole, pyrazole, imidazole, oxazole, and isoxazole.

[0063] In another preferred embodiment, ring C is selected from the following substituted or unsubstituted groups: phenyl, thienyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, cyclopropane, cyclobutane, cyclopentane, benzofuranyl, benzothienyl, indolyl, In another preferred embodiment, ring C is selected from the following substituted or unsubstituted groups:

[0064] In another preferred embodiment, R 1 Selected from halogen, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylhydroxy, C1-C4 alkylamino, C6 aryl.

[0065] In another preferred embodiment, R 1 Selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6 aryl.

[0066] In another preferred embodiment, R 1 Selected from fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl, propenyl, allyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, phenyl.

[0067] In another preferred embodiment, L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene-, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C1-C6 alkylene-O-, wherein m and p are each independently 0-3; x and y are each independently selected from 0-4; Q and Z are each independently selected from CO or a chemical bond; wherein “*” indicates connection with ring C.

[0068] In another preferred embodiment, L 1 is a substituted or unsubstituted C1-C3 alkylene group.

[0069] In another preferred embodiment, L 1 When L is a substituted or unsubstituted C1-C6 alkylene group (preferably a C1-C3 alkylene group), 2 Selected from: Wherein “*” indicates connection with ring B.

[0070] In another preferred embodiment, L 1 Selected from: Wherein "*" indicates connection with ring C.

[0071] In another preferred embodiment, m and p are each independently 0, 1, 2 or 3.

[0072] In another preferred embodiment, x and y are each independently 0, 1, or 2.

[0073] In another preferred embodiment, L 1 Selected from: Wherein "*" indicates connection with ring C.

[0074] In another preferred embodiment, L 1 for wherein x and y are each independently selected from 0-2; wherein “*” indicates connection with ring C.

[0075] In another preferred embodiment, R 2 、R 3 、R 4 Each is independently selected from the following group: hydrogen atom, halogen, hydroxyl, amino, 1-C4 alkyl-OH, C1-C4 alkylamino, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy, halogenated C1-C4 alkoxy; or R 3 、R 4 The C atoms connected thereto form a 3-5 membered cycloalkyl or heterocyclic group; or R 3 or R 4 The C atom connected thereto forms a C2-C4 alkenyl group.

[0076] In another preferred embodiment, R 2 、R 3 、R 4 are independently selected from the following groups: hydrogen atom, halogen, C1-C4 alkyl, halogenated C1-C4 alkyl, C1-C4 alkoxy; or R 3 、R 4 The C atoms connected thereto form a 3-5 membered cycloalkyl or heterocyclic group; or R 3 or R 4 The C atom connected thereto forms a C2-C4 alkenyl group.

[0077] In another preferred embodiment, R 2 、R 3 、R 4 Each independently selected from the following group: C1-C6 alkyl, halogen, or R 3 、R 4 The C atoms connected thereto form a 3-5 membered cycloalkyl or heterocyclic group; or R 3 or R 4 The C atom connected thereto forms a C2-C6 alkenyl group.

[0078] In another preferred embodiment, R 2 、R 3 、R 4 Each independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, fluorine, chlorine, bromine, or R 3 、R 4 The C atom to which it is attached forms a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; or R 3 or R 4 The C atom connected thereto forms a vinyl group, a propenyl group or an allyl group.

[0079] In another preferred embodiment, R 3 、R 4 Each independently selected from the group consisting of methyl, ethyl, chlorine, or R 3 、R 4 The C atom to which it is connected forms a cyclopropyl group or a vinyl group.

[0080] In another preferred embodiment, R 3 、R 4 It is a methyl group.

[0081] In another preferred embodiment, X is S, O or CR 3 R 4 , where R 3 、R 4 Each independently selected from the group consisting of methyl, ethyl, chlorine, or R 3 、R 4 The C atom to which it is connected forms a cyclopropyl group or a vinyl group.

[0082] In another preferred embodiment, X is S or CR 3 R 4 , where R 3 、R 4 It is a methyl group.

[0083] In another preferred embodiment, n is 0 or 1, wherein when n is 0, X is directly connected to C=O, and when n is 1, Y is CR 3 R 4 , where R 3 、R 4 For H.

[0084] In another preferred embodiment, ring A, ring B, ring C, X, Y, L 1 , L 2 , n are independently defined as the corresponding groups in compounds I-1 to I-129.

[0085] In another preferred embodiment, the compound has the structure shown in Formula II to VII:

[0086] In the formula, ring A is Wherein, ring D and ring E are independently selected from the following groups: substituted or unsubstituted benzene ring, 5-6 membered heteroaromatic ring; the substitution refers to the substitution of 1-5 R 1 Substitute, where R 1 Selected from: hydrogen, halogen, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylhydroxy, C1-C4 alkylamino;

[0087] Ring C is selected from the following groups: substituted or unsubstituted: 3-6 membered heterocyclic group, C3-C6 cycloalkyl, six membered aryl, six membered heteroaryl, five membered heteroaryl, Wherein, ring D and ring E are each independently selected from the following groups: substituted or unsubstituted benzene ring, 5-6 membered heteroalkyl ring, 5-6 membered heteroaryl ring; the substitution refers to the substitution of 1-5 R 1 Substitute, where R 1 Selected from: hydrogen, halogen, hydroxy, amino, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylhydroxy, C1-C4 alkylamino, C6 aryl;

[0088] L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene-, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C1-C6 alkylene-O-, wherein m and p are each independently 0, 1, 2 or 3; x and y are each independently selected from 0, 1, 2, 3 or 4; Q and Z are each independently selected from CO or a chemical bond; wherein “*” indicates connection to ring C;

[0089] L 2 Selected from: in The “*” in the molecule indicates that it is connected to the mother nucleus, and the other end is connected to ring A;

[0090] R 3 、R 4 Each independently is C1-C6 alkyl, halogen, or R 3 、R 4 The C atoms connected thereto form a 3-5 membered cycloalkyl or heterocyclic group; or R 3 or R 4 The C atom connected thereto forms a C2-C6 alkenyl group;

[0091] X is selected from O or S atoms;

[0092] Provided that, in Formula II or Formula V, L 1 Not for When L 2 for wherein The "*" in represents connection with ring C, The “*” in the molecule indicates that it is connected to the mother nucleus, and the other end is connected to ring A;

[0093] The substitution refers to substitution by one or more groups selected from the following groups: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl-OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

[0094] In another preferred embodiment, the compound has the structure shown in Formula II to VII:

[0095] In the formula, ring A is Wherein, one of ring D and ring E is a substituted or unsubstituted benzene ring, and the other is a substituted or unsubstituted group of the following groups: pyrrole ring, furan ring or thiophene ring; the substitution refers to the substitution of 1-5 R 1 Substitute, where R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy;

[0096] Ring C is selected from the following groups: substituted or unsubstituted: 3-6 membered heterocyclic group, C3-C6 cycloalkyl, six membered aryl, six membered heteroaryl, five membered heteroaryl, Wherein, one of ring D and ring E is a substituted or unsubstituted benzene ring, and the other is a substituted or unsubstituted group of the following groups: a 5-membered heteroalkyl ring, a 5-membered heteroaryl ring; the substitution refers to the substitution of 1-5 R 1 Substitute, where R 1 Selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6 aryl;

[0097] L 1 Selected from: -C1-C6 alkylene-, wherein m and p are each independently 0, 1 or 2; x and y are each independently selected from 0, 1, 2; Q and Z are each independently selected from CO or a chemical bond; wherein “*” indicates connection to ring C;

[0098] L 2 Selected from: in The “*” in the figure indicates connection with the parent nucleus;

[0099] R 3 、R 4 Each is independently a C1-C6 alkyl group;

[0100] X is selected from S atoms;

[0101] Provided that, in Formula II or Formula V, L 1 Not for When L 2 for wherein The "*" in represents connection with ring C, The “*” in the figure indicates that it is connected to the mother nucleus, and the other end is connected to ring A.

[0102] In another preferred embodiment, the compound has a structure shown in Formula II, Formula IV, Formula V or Formula VI:

[0103] In the formula, ring A is selected from the following substituted or unsubstituted groups: The substitution refers to 1-5 R 1 Substitute, where R 1 Selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy;

[0104] Ring C is selected from the following groups: substituted or unsubstituted: 3-6 membered heterocyclic group, C3-C6 cycloalkyl, six membered aryl, six membered heteroaryl, five membered heteroaryl, Wherein, one of ring D and ring E is a substituted or unsubstituted benzene ring, and the other is a substituted or unsubstituted group of the following groups: a 5-membered heteroalkyl ring, a 5-membered heteroaryl ring; the substitution refers to the substitution of 1-5 R 1 Substitute, where R 1 Selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6 aryl;

[0105] L 1 Selected from: -C1-C6 alkylene-, wherein x and y are each independently selected from 0, 1 or 2; wherein “*” indicates connection with ring C;

[0106] L 2 Selected from: described The “*” in the molecule indicates that it is connected to the mother nucleus, and the other end is connected to ring A;

[0107] R 3 、R4 Each is independently a C1-C6 alkyl group;

[0108] X is an S atom;

[0109] Provided that, in Formula II or Formula V, L 1 Not for When L 2 for wherein The "*" in represents connection with ring C, The “*” in the figure indicates that it is connected to the mother nucleus, and the other end is connected to ring A.

[0110] In another preferred embodiment, the compound has the following structure:

[0111] The second aspect of the present invention provides a method for preparing the compound according to the first aspect of the present invention, or its prodrug, enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising the following steps:

[0112] Method 1:

[0113] 1) Intermediate (Ia) and intermediate (Ib) undergo a nucleophilic substitution reaction in the presence of sodium hydroxide, sodium carbonate, or cesium carbonate to obtain a compound represented by formula (I); wherein M is selected from chlorine, bromine, iodine, or methanesulfonate (MsO);

[0114] Method 2:

[0115] 2) Intermediate (Ia) and intermediate (Ic) undergo Mitsunobu reaction in the presence of triphenylphosphine and diisopropyl azodicarboxylate to obtain a compound represented by formula (I).

[0116] The third aspect of the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of the compounds described in the first aspect, or their prodrugs, enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof; and optionally a pharmaceutically acceptable carrier.

[0117] The fourth aspect of the present invention provides a use of the compound described in the first aspect, or its prodrug, enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt or the pharmaceutical composition described in the second aspect, characterized in that it is used to prepare a cGAS / STING pathway targeted inhibitor; or

[0118] Used for preparing drugs for preventing and / or treating inflammatory diseases and / or autoimmune diseases.

[0119] In another preferred embodiment, the inflammatory disease is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, intestinal malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease and neurodegenerative disease;

[0120] In another preferred embodiment, the autoimmune disease is Singleton-Merten syndrome (SMS), Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), amyotrophic lateral sclerosis (ALS), familial pernio lupus erythematosus (FCL), multiple sclerosis, autoimmune colitis, retinal vasculopathy and leukodystrophy (RVCL), STING-associated vasculopathy of infancy (SAVI), scleroderma, psoriasis, Sjögren's syndrome, and rheumatoid arthritis.

[0121] In a fifth aspect, the present invention provides a cGAS / STING pathway targeted inhibitor, which comprises the compound described in the first aspect of the present invention, or its prodrug, enantiomers, diastereomers, racemates and mixtures thereof, or pharmaceutically acceptable salts thereof.

[0122] In a sixth aspect, the present invention provides a method for inhibiting the activity of STING protein, wherein the compound described in the first aspect is contacted with cells capable of expressing STING protein, thereby inhibiting the secretion of interferon by inhibiting the activity of STING protein.

[0123] In another preferred embodiment, the method is an in vitro method for non-diagnostic and non-therapeutic purposes.

[0124] In another preferred embodiment, the cells are of human and / or mouse origin.

[0125] In another preferred embodiment, the cells are THP1-Blue-ISG cells, THP1-Dual cells and / or Raw-lucia cells containing an interferon-stimulated gene ISG reporter system.

[0126] The seventh aspect of the present invention provides a method for preventing and / or treating inflammatory diseases and / or autoimmune diseases, which comprises the steps of administering the compound described in the first aspect of the present invention, or its prodrug, its enantiomers, diastereomers, racemates and mixtures thereof, or its pharmaceutically acceptable salt to a subject in need thereof.

[0127] In another preferred embodiment, the subject is a human or non-human mammal, such as a mouse, rat, rabbit, gorilla, pig, dog, or sheep.

[0128] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0129] FIG1 shows the secretion levels of cytokines CXCL10 and IL6 in plasma after injection in Example 133.

[0130] FIG2 shows the changes in cytokine gene expression in mouse kidney tissue after injection in Example 133.

[0131] FIG3 shows the changes in cytokine gene expression in mouse heart tissue after injection administration in Example 133.

[0132] FIG4 shows the secretion levels of cytokines CXCL10 and IL6 in mouse plasma after oral administration in Example 134.

[0133] FIG5 shows the changes in cytokine gene expression in mouse kidney tissue after oral administration in Example 134.

[0134] FIG6 shows the changes in cytokine gene expression in mouse heart tissue after oral administration in Example 134.

[0135] FIG7 shows the survival curve of mice in Example 135.

[0136] FIG8 shows the changes in cytokine gene expression in mouse kidney tissue in Example 135.

[0137] FIG9 shows the changes in cytokine gene expression in mouse heart tissue in Example 135.

[0138] FIG10 shows the changes in cytokine gene expression in mouse heart tissue in Example 136. DETAILED DESCRIPTION

[0139] After extensive and in-depth research, the inventors of this application developed a dihydroisoquinoline compound that can be used as a targeted inhibitor of the cGAS / STING signaling pathway for the treatment of inflammatory and autoimmune diseases. Based on this, the present invention was completed.

[0140] the term

[0141] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0142] As used herein, the terms "comprise," "include," and "contain" are used interchangeably to include not only closed definitions but also semi-closed and open definitions. In other words, the terms include "consisting of," "consisting essentially of."

[0143] In the present invention, the halogen is F, Cl, Br or I.

[0144] In the present invention, unless otherwise specified, the terms used have the general meanings commonly known to those skilled in the art.

[0145] In the present invention, the term "C1-C6" refers to having 1, 2, 3, 4, 5 or 6 carbon atoms, "C1-C8" refers to having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and so on.

[0146] "5-12 membered" means having 5-12 ring atoms, and so on.

[0147] In the present invention, the term "alkyl" refers to a saturated linear or branched hydrocarbon moiety. For example, the term "C1-C6 alkyl" refers to a straight or branched alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl and hexyl, etc.; preferably ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

[0148] In the present invention, the term "alkoxy" refers to an -O-(alkyl) group. For example, the term "C1-C6 alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy.

[0149] In the present invention, the term "alkenyl" refers to a straight chain or branched hydrocarbon moiety containing at least one double bond. For example, the term "C2-C6 alkenyl" refers to a straight chain or branched alkenyl group containing one double bond having 2 to 6 carbon atoms, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0150] In the present invention, the term "alkynyl" refers to a straight-chain or branched alkynyl group containing a triple bond. For example, the term "C2-C6 alkynyl" refers to a straight-chain or branched alkynyl group containing a triple bond having 2 to 6 carbon atoms, including but not limited to ethynyl, propynyl, butynyl, isobutynyl, pentynyl and hexynyl.

[0151] In the present invention, the term "cycloalkyl" refers to a saturated cyclic hydrocarbon moiety. For example, the term "C3-C10 cycloalkyl" refers to a cyclic alkyl group having 3 to 10 carbon atoms in the ring, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclodecyl. The terms "C3-C8 cycloalkyl", "C3-C7 cycloalkyl", and "C3-C6 cycloalkyl" have similar meanings.

[0152] The term "heterocyclyl" refers to a saturated or partially saturated cyclic group having a heteroatom selected from N, S and O, which may be a monocyclic or bicyclic form, such as a bridged ring or a spirocyclic form. The heterocyclyl is preferably a 3-8 membered heterocyclyl, more preferably a 4-6 membered heterocyclyl, more preferably a 5-6 membered heterocyclyl. Examples of heterocyclyls include, but are not limited to, oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl, wait.

[0153] In the present invention, the term "aryl" refers to a hydrocarbon moiety comprising one or more aromatic rings. For example, the term "C6-C12 aryl" refers to an aromatic ring radical having 6 to 12 carbon atoms and containing no heteroatoms on the ring, such as phenyl, naphthyl, etc. The term "C6-C12 aryl" has a similar meaning. Examples of aryl include, but are not limited to, phenyl (Ph), naphthyl, pyrenyl, anthracenyl, and phenanthrenyl.

[0154] The term "heteroaryl" refers to a cyclic aromatic group having 1 to 3 heteroatoms selected from the group consisting of N, S, and O, which may be a monocyclic or condensed ring. In the present invention, the heteroaryl group is preferably a 5-12 membered heteroaryl group, more preferably a 5-10 membered group, and even more preferably a 5-8 membered group. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, carbazole, indolyl, indazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzothiadiazolyl, benzoxazolyl, isomerized quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl or naphthyridinyl, and tetrazolyl. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the heteroaryl ring. The heteroaryl group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, alkylthio, alkylamino, halogen, amino, nitro, hydroxy, mercapto, cyano, cycloalkyl, heterocyclic, aryl, heteroaryl, cycloalkylthio, oxo, amide, sulfonamide, formyl, formamide, carboxyl, and carboxylate groups. In the present invention, in the substituent, "heteroaromatic ring", "aromatic heterocycle" and "heteroaryl" have the same meaning.

[0155] In the present invention, "amino" refers to a group having the structure -N(R)(R'), where R and R' can independently represent hydrogen, alkyl or substituted alkyl, cycloalkyl or substituted cycloalkyl, aryl or substituted aryl, or heterocycle or substituted heterocycle, as defined above. R and R' can be the same or different in the dialkylamine moiety. Examples of amino groups include NH2, NHCH3, and N(CH3)2.

[0156] Unless otherwise specified, the alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups described herein are substituted and unsubstituted groups. Possible substituents on alkyl, alkoxy, cycloalkyl, heterocyclyl and aryl groups include, but are not limited to, hydroxy, amino, nitro, nitrile, halogen, C1-C6 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C20 cycloalkyl, C3-C20 cycloalkenyl, C1-C20 heterocycloalkyl, C1-C20 heterocycloalkenyl, C1-C6 alkoxy, aryl, heteroaryl, heteroaryloxy, C1-C10 alkylamino ... C20 dialkylamino, arylamino, diarylamino, C1-C10 alkylsulfamoyl, arylsulfamoyl, C1-C10 alkylimino, C1-C10 alkylsulfoimino, arylsulfoimino, mercapto, C1-C10 alkylthio, C1-C10 alkylsulfonyl, arylsulfonyl, acylamino, aminoacyl, aminothioacyl, guanidino, urea, cyano, acyl, thioacyl, acyloxy, carboxyl, and carboxylate groups. On the other hand, cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl groups may be fused to each other.

[0157] In the present invention, the substitution is mono- or poly-substituted, and the poly-substituted is di-, tri-, tetra-, or penta-substituted. The di-substituted refers to having two substituents, and so on.

[0158] In the present invention, the term "plurality" independently refers to 2, 3, 4, or 5.

[0159] The term prodrug, also known as prodrug, drug precursor, or prodrug, refers to a compound that has been chemically modified to produce a drug that is inactive or minimally active in vitro but releases the active drug in vivo through enzymatic or non-enzymatic conversion to exert its pharmacological effect. Examples include ester forms of compounds containing carboxyl groups.

[0160] The term "pharmaceutically acceptable salt" refers to a salt (including internal salts such as zwitterions) that has efficacy similar to that of the parent compound and is biologically or otherwise (e.g., non-toxic and harmless to the subject). Therefore, embodiments of the present invention provide pharmaceutically acceptable salts of the compounds of the present invention. The term "salt" as used herein refers to any of the following acid salts formed from inorganic and / or organic acids, and basic salts formed from inorganic and / or organic bases. Salts of the compounds of the present invention can be formed by methods known to those of ordinary skill in the art, for example, by reacting the compound of the present invention with a certain amount of acid or base (e.g., an equivalent amount of acid or base) in a medium (e.g., a medium in which the salt can be precipitated; or water is used as a medium and then lyophilized).

[0161] Active ingredient

[0162] As used herein, the terms "compound of the present invention" or "active ingredient of the present invention" are used interchangeably to refer to a compound of formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, isotope compound (such as a deuterated compound), or prodrug thereof. The term also includes racemates and optical isomers.

[0163] The compounds are understood to include their salts. The term "salt" as used herein refers to acidic or basic salts formed with inorganic or organic acids and bases. In addition, when the compound of the present invention contains a basic fragment, which includes but is not limited to pyridine or imidazole, and contains an acidic fragment, including but not limited to carboxylic acid, the zwitterions ("inner salts") that may be formed are included within the scope of the term "salt". Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in separation or purification steps during the preparation process. The compounds of the present invention may form salts, for example, compound I reacts with a certain amount, such as an equivalent amount, of an acid or base, salts out in a medium, or freeze-dried from an aqueous solution.

[0164] The compounds of the present invention contain basic moieties, including but not limited to amines or pyridine or imidazole rings, which may form salts with organic or inorganic acids. Typical acids that can form salts include acetates (e.g., acetic acid or trihaloacetic acid, such as trifluoroacetic acid), adipates, alginate, ascorbate, aspartate, benzoate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor, camphorsulfonate, cyclopentanepropionate, diglycolate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxyethanesulfonate (e.g., 2-hydroxyethanesulfonate), lactate, maleate, methanesulfonate, naphthalenesulfonate (e.g., 2-naphthalenesulfonate), nicotinate, nitrate, oxalate, pectinate, persulfate, Phenylpropionate (e.g., 3-phenylpropionate), phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate (e.g., with sulfuric acid), sulfonate, tartrate, thiocyanate, toluenesulfonate such as p-toluenesulfonate, dodecanoate, and the like.

[0165] Certain compounds of the present invention may contain acidic moieties, including but not limited to carboxylic acids, which may form salts with various organic or inorganic bases. Typical base-forming salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, and salts formed with organic bases (e.g., organic amines), such as benzathine, dicyclohexylamine, hepamine (salt formed with N,N-di(dehydroabietyl)ethylenediamine), N-methyl-D-glucamine, N-methyl-D-glucamide, tert-butylamine, and salts formed with amino acids such as arginine, lysine, and the like. Basic nitrogen-containing groups can react with halide quaternary ammonium salts, such as small molecular alkyl halides (such as chlorides, bromides and iodides of methyl, ethyl, propyl and butyl), dialkyl sulfates (such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate and dipentyl sulfate), long chain halides (such as chlorides, bromides and iodides of decyl, dodecyl, tetradecyl and tetradecyl), aralkyl halides (such as benzyl and phenyl bromide), etc.

[0166] Prodrugs and solvates of the compounds of the present invention are also encompassed. The term "prodrug" herein refers to a compound that undergoes chemical transformation via metabolic or chemical processes to produce a compound, salt, or solvate of the present invention when used to treat a relevant disease. The compounds of the present invention include solvates, such as hydrates.

[0167] The compounds, salts or solvates of the present invention may exist in tautomeric forms (such as amides and imino ethers). All such tautomers are part of the present invention.

[0168] All stereoisomers of the compounds (e.g., those that may exist due to asymmetric carbon atoms for various substitutions), including enantiomeric and diastereomeric forms, are contemplated by the present invention. Individual stereoisomers of the compounds of the present invention may not exist with other isomers (e.g., as a pure or substantially pure optical isomer having a particular activity), or may be mixtures, such as racemates, or mixtures with all other stereoisomers or portions thereof. The chiral centers of the present invention have either S or R configurations, as defined by the 1974 recommendations of the International Union of Pure and Applied Chemistry (IUPAC). Racemic forms can be resolved by physical methods, such as fractional crystallization, or by crystallization of diastereomers derived from them, or by separation by chiral column chromatography. Individual optical isomers can be obtained from the racemate by suitable methods, including but not limited to conventional methods, such as salt formation with an optically active acid followed by recrystallization.

[0169] The compounds of the present invention, obtained by sequential preparation, isolation, and purification, are described in the text to a concentration of 90% or greater by weight, for example, 95% or greater, or 99% or greater ("very pure" compounds). Such "very pure" compounds of the present invention are also considered part of the present invention.

[0170] All configurational isomers of the compounds of the present invention are encompassed, whether in mixture, pure or very pure form. The definition of the compounds of the present invention includes both cis (Z) and trans (E) olefin isomers, as well as cis and trans isomers of carbocyclic and heterocyclic rings.

[0171] Throughout the specification, groups and substituents may be chosen to provide stable fragments and compounds.

[0172] Certain compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention encompasses all compounds, including their cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures, and other mixtures. Additionally, asymmetric carbon atoms may represent substituents, such as alkyl groups. All isomers and mixtures thereof are encompassed by the present invention.

[0173] According to the present invention, mixtures of isomers can contain various ratios of isomers. For example, mixtures containing only two isomers can have the following ratios: 50:50, 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, or 100:0. All ratios of isomers are within the scope of the present invention. Similar ratios, as well as ratios for more complex mixtures of isomers, are readily understood by those skilled in the art and are also within the scope of the present invention.

[0174] The present invention also includes isotopically labeled compounds that are equivalent to the original compounds disclosed herein. However, in practice, it is common for one or more atoms to be replaced by atoms having a different atomic mass or mass number. Examples of isotopes of the compounds of the present invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, such as 2 H. 3 H. 13 C. 11 C. 14 C. 15 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36The compounds of the present invention, or enantiomers, diastereomers, isomers, or pharmaceutically acceptable salts or solvates thereof, which contain isotopes or other isotopic atoms of the above compounds are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as 3 H and 14 Radioisotopes of C are also included and are useful in tissue distribution experiments of drugs and substrates. 3 H and carbon-14, i.e. 14 C, their preparation and detection are relatively easy. It is the first choice among isotopes. In addition, heavier isotope substitutions such as deuterium, i.e. 2 H, due to its excellent metabolic stability, has advantages in certain therapeutics, such as increasing half-life in vivo or reducing dosage, and therefore, may be preferred in some cases. Isotopically labeled compounds can be prepared using conventional methods by replacing readily available isotopically labeled reagents with non-isotopic reagents using the protocols disclosed in the examples.

[0175] If a synthesis of a specific enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and removal of the chiral auxiliary to obtain the pure enantiomer. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, diastereomeric salts can be formed with a suitable optically active acid or base, followed by separation by conventional means such as fractional crystallization or chromatography to obtain the pure enantiomer.

[0176] As described herein, the compounds of the present invention may be substituted with any number of substituents or functional groups to expand their scope. Generally, the term "substituted," whether preceded or followed by the term "optionally," in formulas of the present invention including substituents, refers to the replacement of a hydrogen radical with a substituent of the specified structure. When multiple positions in a particular structure are substituted with multiple substituents of the specified structure, the substituents may be the same or different at each position. As used herein, the term "substituted" includes all permissible substitutions in organic compounds. Broadly speaking, permissible substituents include acyclic, cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic compounds. For example, heteroatoms of nitrogen may be substituted with hydrogen or any of the permissible organic compounds described above to supplement their valences. Furthermore, the present invention is not intended to limit the permissible substitutions in any way to organic compounds. The present invention recognizes that combinations of substituents and variables are advantageous for providing stable compounds for the treatment of diseases. As used herein, the term "stable" refers to compounds that are stable and maintain the structural integrity of the compound over a period of time sufficient to be detected, preferably over a period of time sufficient to be effective, as used herein for the purposes described above.

[0177] The metabolites of the compounds and pharmaceutically acceptable salts thereof involved in the present application, as well as prodrugs that can be converted into the structures of the compounds and pharmaceutically acceptable salts involved in the present application and in vivo, are also included in the claims of the present application.

[0178] Preparation method of compound

[0179] The following schemes and examples describe methods for preparing compounds of Formula I. Starting materials and intermediates were purchased from commercial sources, prepared by known procedures, or described otherwise. In some cases, the order in which the steps of the reaction schemes are performed may be altered to facilitate the reaction or to avoid unwanted side reaction products.

[0180] Typically, in the preparation process, each reaction is carried out in an inert solvent at room temperature to reflux temperature (e.g., 0°C to 150°C, preferably 10°C to 100°C), and the reaction time is typically 0.1 to 60 hours, preferably 0.5 to 48 hours.

[0181] Preferably, the compound of formula (I) of the present invention can be prepared by the following two methods:

[0182] Method 1:

[0183] Method 2:

[0184] 1) Intermediate (Ia) and intermediate (Ib) undergo a nucleophilic substitution reaction in the presence of sodium hydroxide, sodium carbonate, or cesium carbonate to obtain a compound represented by formula (I); wherein M is selected from chlorine, bromine, iodine, or methanesulfonate (MsO);

[0185] 2) Intermediate (Ia) and intermediate (Ic) undergo Mitsunobu reaction in the presence of triphenylphosphine and diisopropyl azodicarboxylate to obtain a compound represented by formula (I).

[0186] Pharmaceutical compositions and methods of administration

[0187] Since the compounds of the present invention have excellent inhibitory activity against STING proteins, the compounds of the present invention or their stereoisomers or optical isomers, pharmaceutically acceptable salts, prodrugs or solvates, as well as pharmaceutical compositions containing the compounds of the present invention as the main active ingredient, can be used to prevent and / or treat (stabilize, alleviate or cure) STING protein-related inflammatory diseases and autoimmune diseases. The inflammatory diseases and autoimmune diseases are selected from: Singleton-Merten syndrome (SMS), Aicardi-Goutigres syndrome (AGS), systemic lupus erythematosus (SLE), amyotrophic lateral sclerosis (ALS), familial pernio lupus erythematosus (FCL), retinal vasculopathy and leukodystrophy (RVCL), STING-associated vasculopathy of infancy (SAVI), scleroderma, psoriasis, Sjogren's syndrome, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, Crohn's disease, ulcerative colitis, autoimmune colitis, small intestinal malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease and neurodegenerative diseases.

[0188] The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the present invention and a pharmaceutically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-200 mg per dose. Preferably, "one dose" is one capsule or tablet.

[0189] "Pharmaceutically acceptable carrier" refers to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0190] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration methods include (but are not limited to): oral administration, parenteral administration (intravenous administration, intramuscular administration, or subcutaneous administration).

[0191] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0192] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0193] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0194] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0195] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0196] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0197] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0198] When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately, or sequentially with the compound of the present invention to prevent and / or treat diseases related to the activity or expression of the STING protein.

[0199] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 20 to 500 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0200] A "safe and effective amount" refers to an amount of the active ingredient sufficient to significantly improve the condition without causing serious side effects. Typically, a pharmaceutical composition contains 1 to 2000 mg of active ingredient per dose, more preferably 10 to 200 mg per dose. Preferably, "one dose" is one tablet.

[0201] The main advantages of the present invention are:

[0202] 1. The compounds of the present invention have inhibitory activity against STING protein in human and / or mouse cells and can be used as targeted inhibitors of the cGAS / STING signaling pathway;

[0203] 2. The compounds of the present invention have good pharmacodynamics and pharmacokinetic properties.

[0204] The detailed experimental procedures in the following examples further illustrate the present invention. These exemplified compounds are depicted in their neutral form in the following examples. In some cases, depending on the method used for final purification and / or intrinsic molecular properties, the compounds are isolated as salts. These examples are intended to illustrate the present invention only and are not intended to limit the scope of this patent in any way. Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for exemplary purposes only.

[0205] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0206] Example

[0207] Example 1 4-Benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxamide (I-1)

[0208] Step ①: 4-bromo-5-nitrothiol-2-carboxylic acid methyl ester (1-1)

[0209] In an ice-salt bath, 1 g of methyl 4-bromothiophene-2-carboxylate was added to 5 ml of concentrated sulfuric acid. 0.5 ml of fuming nitric acid dissolved in 5 ml of concentrated sulfuric acid was then slowly added dropwise to the reaction solution. The reaction was continued in an ice-salt bath for 30 minutes. The reaction solution was slowly poured into ice water, washed three times, and dried to yield 1.167 g of methyl 4-bromo-5-nitrothiophene-2-carboxylate (1-1) as a white solid, with a yield of 97.25%. 1 H NMR (400MHz, DMSO-d6) δ8.00 (s, 1H), 3.90 (s, 3H).

[0210] Step ②: 4-((2-methoxy-2-carbonylethyl)thiol)-5-nitrothiophene-2-carboxylic acid methyl ester (1-2)

[0211] A mixture of 1 g of methyl 4-bromo-5-nitrothiophene-2-carboxylate (1-1), 400 μL of methyl thioglycolate, 1.6 mL of triethylamine, and 10 mL of tetrahydrofuran was stirred at room temperature for 4 hours. The reaction mixture was poured into water, washed three times, and dried to obtain 1.013 g of methyl 4-((2-methoxy-2-carbonylethyl)thiol)-5-nitrothiophene-2-carboxylate (1-2) as a yellow solid, with a yield of 92.13%. 1 HNMR(400MHz,DMSO-d6)δ7.82(s,1H),4.35(s,2H),3.91(s,3H),3.69(s,3H).

[0212] Step ③: 3-O-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxylic acid methyl ester (1-3)

[0213] A mixture of 500 mg of methyl 4-((2-methoxy-2-carbonylethyl)thiol)-5-nitrothiophene-2-carboxylate (1-2), 480 mg of reduced iron powder, and 10 mL of acetic acid was stirred under argon at 80°C for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using dichloromethane:methanol = 98:2 to obtain 360.3 mg of methyl 3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxylate (1-3) as a gray solid, with a yield of 91.68%. 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),7.30(s,1H),3.80(s,3H),3.63(s,2H).

[0214] Step ④: 4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxylic acid methyl ester (1-4)

[0215] A mixture of 360 mg of methyl 3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxylate (1-3), 220 μL of benzyl chloride, 440 mg of potassium carbonate, and 6 mL of N,N-dimethylformamide was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated to dryness, and the residue was purified by column chromatography using dichloromethane:methanol = 98:2 to obtain 430.4 mg of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxylate (1-4), in a yield of 85.91%. 1H NMR (400MHz, DMSO-d6) δ7.66(s,1H),7.32(dd,J=8.0,6.6Hz,2H),7.22(m,1H),7.18(m,2H),5.18(s,2H),3.85(s,2H),3.76(s,3H).

[0216] Step ⑤: 4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxylic acid (1-5)

[0217] A mixture of 200 mg of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxylate (1-4), 260 mg of lithium hydroxide monohydrate, and 4 ml of tetrahydrofuran was heated and stirred at 60°C under an argon atmosphere for 2 hours. 10% citric acid solution was slowly added dropwise to the reaction mixture to adjust the pH to 2-3. The precipitated solid was filtered and the filter cake dried to yield 256 mg of 4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxylic acid (1-5) as a solid, in a 100% yield. LCMS (ESI) m / z [M+H] + :306.0.

[0218] Step ⑥: 4-benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxamide (I-1)

[0219] A mixture of 100 mg of 4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxylic acid (1-5), 40 mg of 3-aminoindole, 200 μL of DIPEA, 150 mg of HATU, and 4 mL of N,N-dimethylformamide was stirred at room temperature for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated to dryness, and the residue was purified by column chromatography using dichloromethane:ethyl acetate (80:20) to obtain 25.5 mg of 4-benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carboxamide (I-1) as a yellow solid (yield: 20.08%). 1H NMR (400MHz, DMSO-d6) δ10.99(s,1H),10.09(s,1H),8.05(s,1H),7.71(d,J=8.0Hz,1H),7.64(d,J =2.6Hz,1H),7.41(m,6H),7.11(t,J=7.5Hz,1H),7.02(t,J=7.5Hz,1H),5.12(s,2H),3.83(s,2H).

[0220] Example 2 N-(1H-indol-3-yl)-3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-2)

[0221] Step ①: (1-phenylazetidin-3-yl)methanol (2-1)

[0222] A mixture of 1 g of 3-methylhydroxyazetidine hydrochloride, 1.81 ml of iodobenzene, 1.5 g of cuprous iodide, 940 mg of L-proline, 3.4 g of potassium carbonate, and 10 ml of dimethyl sulfoxide was heated and stirred at 90°C under an argon atmosphere for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate = 50:50 to obtain 1.188 g of (1-phenylazetidin-3-yl)methanol (2-1) as a yellow oily solid, with a yield of 90.0%. 1 H NMR(400MHz, DMSO-d6)δ7.17-7.06(m,2H),6.63(tt,J=7.3,1.2Hz,1H),6.42-6.34(m,2H),4.74(t,J=5.3H z,1H),3.79(t,J=7.5Hz,2H),3.57(dd,J=6.5,5.3Hz,2H),3.50(dd,J=7.2,5.4Hz,2H),2.81-2.70(m,1H).

[0223] Step ②: 3-(Chloromethyl)-1-phenylazetidine (2-2)

[0224] A mixture of 1.18 g of (1-phenylazetidin-3-yl)methanol (2-1), 770 μL of carbon tetrachloride, 2.1 g of triphenylphosphine, and 10 mL of dichloromethane was stirred at room temperature for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (99:1) to obtain 1 g of 3-(chloromethyl)-1-phenylazetidine (2-2) as a solid, with a yield of 77.60%. 1H NMR(400MHz, DMSO-d6)δ7.20-7.11(m,2H),6.67(tt,J=7.3,1.1Hz,1H),6.47-6.40(m,2H),3.89( t,J=7.5Hz,2H),3.78(d,J=7.6Hz,2H),3.49(dd,J=7.4,5.7Hz,2H),3.09(tt,J=7.7,5.5Hz,1H).

[0225] Step ③: 3-Oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (2-3)

[0226] A mixture of 500 mg of methyl 3-carbonyl-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate, 450 mg of 3-(chloromethyl)-1-phenylazetidine, 1.85 g of potassium carbonate, and 10 ml of N,N-dimethylformamide was heated and stirred at 80°C for 12 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated to dryness, and the residue was purified by column chromatography using dichloromethane:ethyl acetate = 95:5 to obtain 528.3 mg of methyl 3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (2-3), a white solid, in a yield of 64.03%. 1 H NMR (400MHz, DMSO-d6) δ7.84(s,1H),7.66-7.56(m,2H),7.14(t,J=7.7Hz,2H),6.66(t,J=7.3Hz,1H),6.38(d,J=7.9 Hz,2H),4.40(d,J=7.3Hz,2H),3.85(s,3H),3.76(t,J=7.4Hz,2H),3.60(s,2H),3.50(t,J=6.3Hz,2H),2.85(s,1H).

[0227] Step ④: 3-Oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (2-4)

[0228] The preparation of 3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (2-4) was the same as compound 1-5. LCMS (ESI) m / z [M+H] + :355.1.

[0229] Step ⑤: N-(1H-indol-3-yl)-3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-2)

[0230] The preparation of (1H-indol-3-yl)-3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-2) was the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ11.06-10.90 (m, 1H), 10.24 (s, 1H), 7.92 (d, J = 1.7Hz, 1H), 7.85-7. 76(m,2H),7.73(dd,J=8.1,1.6Hz,1H),7.60(d,J=8.0Hz,1H),7.37(d,J=8.1Hz,1H),7.18-7 .08(m,3H),7.05-6.98(m,1H),6.66(t,J=7.3Hz,1H),6.44-6.33(m,2H),4.47(d,J=7.3Hz, 2H), 3.81 (t, J = 7.4Hz, 2H), 3.60 (s, 2H), 3.56 (dd, J = 7.1, 5.5Hz, 2H), 2.96 (p, J = 6.7Hz, 1H).

[0231] Example 3 1-(1H-indol-3-yl)-3-(3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea (I-3)

[0232] Step ①: 3-Oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl azide (3-1)

[0233] A mixture of 179 mg of 3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (2-4), 95 μL of triethylamine, 110 μL of DPPA, and 5 mL of dichloromethane was stirred at room temperature for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (90:10) to obtain 160 mg of 3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl azide (3-1) as a solid, with a yield of 83.7%. 1H NMR(400MHz,DMSO-d6)δ7.82(d,J=1.4Hz,1H),7.63(d,J=1.8Hz,2H),7.22-7.08 (m,2H),6.66(t,J=7.3Hz,1H),6.43-6.30(m,2H),4.40(d,J=7.4Hz,2H),3.76 (t,J=7.4Hz,2H),3.62(s,2H),3.50(dd,J=7.2,5.3Hz,2H),2.96-2.75(m,1H).

[0234] Step ②: tert-Butyl (3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate (3-2)

[0235] A mixture of 160 mg of 3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-carbonyl azide (3-1) and 5 mL of tert-butanol was stirred at 90°C under an argon atmosphere for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (80:20) to obtain 78.1 mg of tert-butyl (3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate (3-2) as a solid, in a yield of 43.6%. 1 H NMR (400MHz, DMSO-d6) δ9.45(s,1H),7.46(s,1H),7.29(d,J=8.4Hz,1H),7.22(d,J=8.7Hz,1H),7.14(t,J=7.7Hz,2H),6.66(t,J=7.3Hz,1H ),6.40(d,J=7.9Hz,2H),4.21(d,J=7.2Hz,2H),3.80(t,J=7.5Hz,2H),3.59-3.51(m,2H),3.47(s,2H),2.94(p,J=6.9Hz,1H),1.47(s,9H).

[0236] Step ③: 6-amino-4-((1-phenylazetidin-3-yl)methyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (3-3)

[0237] A mixture of 75 mg of tert-butyl (3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate (3-2) and 5 mL of dioxane hydrochloride solution was stirred at room temperature for 12 hours. The reaction solution was concentrated to dryness to obtain a solid 6-amino-4-((1-phenylazetidin-3-yl)methyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (3-3), which was used directly in the next reaction. LCMS (ESI) m / z [M+H] + :326.1.

[0238] Step ④: 1-(1H-yindol-3-yl)-3-(3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea (I-3)

[0239] A mixture of 57 mg of 6-amino-4-((1-phenylazetidin-3-yl)methyl)-2H-benzo[b][1,4]thiazin-3(4H)-one (3-3), 27 mg of 3-isocyanato-1H-indole, 50 μL of triethylamine, and 2 mL of tetrahydrofuran was stirred at room temperature for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using dichloromethane:methanol = 95:5 to obtain 14.2 mg of 1-(1H-yindol-3-yl)-3-(3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea (I-3) as a solid, in a yield of 16.90%. 1 H NMR (400MHz, DMSO-d6) δ10.78(s,1H),8.73(s,1H),8.54(s,1H),7.64(d,J=2.1Hz,1 H),7.54-7.45(m,2H),7.32(dd,J=12.3,8.2Hz,2H),7.12(dt,J=20.6,7.7Hz,4H),7. 01(t,J=7.4Hz,1H),6.66(t,J=7.3Hz,1H),6.40(d,J=8.0Hz,2H),4.29(d,J=7.3Hz,2 H), 3.81 (t, J = 7.4Hz, 2H), 3.57 (t, J = 6.3Hz, 2H), 3.49 (s, 2H), 2.97 (p, J = 6.9Hz, 1H).

[0240] Example 4 1-(4-Benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea (I-4)

[0241] Step ①: 4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carbonyl azide (4-1)

[0242] The preparation of 4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazine-6-carbonyl azide (4-1) is the same as compound 3-1. 1 H NMR (400MHz, DMSO-d6) δ7.72(s,1H),7.32(t,J=7.4Hz,2H),7.25(d,J=7.2Hz,1H),7.20(d,J=7.6Hz,2H),5.19(s,2H),3.89(s,2H).

[0243] Step ②: tert-Butyl (4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazin-6-yl) carbamate (4-2)

[0244] The preparation of tert-butyl (4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazin-6-yl) carbamate (4-2) was the same as compound 3-2 and was used directly in the next reaction. LCMS (ESI) m / z [M+H] + :377.1.

[0245] Step ③: 6-amino-4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazin-3(4H)-one (4-3)

[0246] The preparation of 6-amino-4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazin-3(4H)-one (4-3) was the same as compound 3-3 and was used directly in the next reaction. LCMS (ESI) m / z [M+H] + :277.1.

[0247] Step ④: 1-(4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea (I-4)

[0248] The preparation of 1-(4-benzyl-3-oxo-3,4-dihydro-2H-thieno[3,2-b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea (I-4) is the same as compound I-3. 1H NMR(400MHz,CD3OD)δ7.45(d,J=7.9Hz,1H),7.36-7.26(m,4H),7.22(d,J=8.1Hz,3H) ,7.12(t,J=7.6Hz,1H),7.02(t,J=7.5Hz,1H),6.34(s,1H),5.06(s,2H),3.61(s,2H).

[0249] Example 5 1-(1H-indol-6-yl)-3-(3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea (I-5)

[0250] The preparation of 1-(1H-indol-6-yl)-3-(3-oxo-4-((1-phenylazetidin-3-yl)-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)urea (I-5) is the same as compound I-3. 1 H NMR (400MHz, CD3OD) δ7.68(d,J=30.7Hz,2H),7.44(d,J=8.4Hz,1H),7.28(d,J= 8.3Hz,1H),7.12(dd,J=15.6,5.4Hz,3H),7.04-6.93(m,1H),6.93-6.83(m,1H), 6.67(t,J=7.2Hz,1H),6.49-6.33(m,3H),4.35(d,J=7.4Hz,2H),3.83(t,J=7.5 Hz,2H),3.59(q,J=10.3,6.6Hz,2H),3.38(s,2H),3.02(dd,J=14.3,7.3Hz,1H).

[0251] Example 6 1-Benzyl-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-6)

[0252] Step ①: 5-((2-methoxy-2-carbonylethyl)thiol)-4-nitrothiophene-2-carboxylic acid methyl ester (6-1)

[0253] The preparation of methyl 5-((2-methoxy-2-carbonylethyl)thiol)-4-nitrothiophene-2-carboxylate (6-1) is the same as compound 1-2. 1 HNMR(400MHz,DMSO-d6)δ8.17(s,1H),4.38(s,2H),3.86(s,3H),3.73(s,3H).

[0254] Step ②: 2-Oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (6-2)

[0255] The preparation of methyl 2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carboxylate (6-2) was the same as compound 1-3. 1 H NMR (400MHz, DMSO-d6) δ11.29(s,1H),7.56(s,1H),3.77(s,3H),3.54(s,2H).

[0256] Step ③: 1-benzyl-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (6-3)

[0257] The preparation of 1-benzyl-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (6-3) was the same as compound 1-4. 1 H NMR (400MHz, DMSO-d6) δ7.62 (s, 1H), 7.36 (dd, J = 7.9, 6.6Hz, 2H), 7.31-7.25 (m, 3H), 5.09 (s, 2H), 3.80 (s, 2H), 3.74 (s, 3H).

[0258] Step ④: 1-benzyl-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carboxylic acid (6-4)

[0259] The preparation of 1-benzyl-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carboxylic acid (6-4) was the same as compound 1-5. LCMS (ESI) m / z [M+H] + :306.0.

[0260] Step ⑤: 1-benzyl-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carboxamide (I-6)

[0261] The preparation of 1-benzyl-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carboxamide (I-6) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ11.02(s,1H),10.23(s,1H),8.25(s,1H),7.81(s,1H),7.65(d,J=2.6Hz ,1H),7.40-7.22(m,6H),7.11(t,J=7.5Hz,1H),7.02(t,J=7.5Hz,1H),5.15(s,2H),3.83(s,2H).

[0262] Example 7 1-(1-benzyl-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea (I-7)

[0263] Step ①: 1-benzyl-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carbonyl azide (7-1)

[0264] The preparation method of 1-benzyl-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carbonyl azide (7-1) is the same as compound 3-1. 1 H NMR (400MHz, DMSO-d6) δ7.72(s,1H),7.32(t,J=7.4Hz,2H),7.25(d,J=7.2Hz,1H),7.20(d,J=7.6Hz,2H),5.19(s,2H),3.89(s,2H).

[0265] Step ②: tert-Butyl (1-benzyl-2-oxo-2,3-dihydro-1H-thiophene [2,3-b] [1,4] thiazin-6-yl) carbamate (7-2)

[0266] The preparation method of tert-butyl (1-benzyl-2-oxo-2,3-dihydro-1H-thiophene [2,3-b] [1,4] thiazin-6-yl) carbamate (7-2) was the same as compound 3-2 and was used directly in the next reaction. LCMS (ESI) m / z [M+H] + :377.1.

[0267] Step ③: 6-amino-1-benzyl-1H-thiophene[2,3-b][1,4]thiazin-2(3H)-one (7-3)

[0268] The preparation method of 6-amino-1-benzyl-1H-thiophene[2,3-b][1,4]thiazin-2(3H)-one (7-3) was the same as compound 3-2 and was used directly in the next reaction. LCMS (ESI) m / z [M+H] + :277.1.

[0269] Step ④: 1-(1-benzyl-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea (I-7)

[0270] The preparation method of 1-(1-benzyl-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea (I-7) is the same as compound I-3. 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),9.63(s,1H),8.50(s,1H),7.46-7.42(m,2H),7.34(dt,J=7.6,3.4Hz,3H ),7.25(dd,J=11.8,7.2Hz,3H),7.13-7.07(m,1H),7.03-6.98(m,1H),6.41(s,1H),5.04(s,2H),3.69(s,2H).

[0271] Example 8 N-(1H-indol-6-yl)-3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-8)

[0272] The preparation of N-(1H-indol-6-yl)-3-oxo-4-((1-phenylazetidin-3-yl)methyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-8) is the same as compound I-3. 1H NMR (400MHz, DMSO-d6) δ11.08(t,J=2.3Hz,1H),10.20(s,1H),8.05(d,J=1.8Hz,1H),7.89(d,J=1.7Hz ,1H),7.70(dd,J=8.1,1.6Hz,1H),7.60(d,J=8.1Hz,1H),7.49(d,J=8.5Hz,1H),7.30(t,J=2.7Hz,1H) ,7.26(dd,J=8.5,1.9Hz,1H),7.18-7.10(m,2H),6.69-6.62(m,1H),6.46-6.33(m,3H),4.46(d,J=7.3 Hz,2H),3.79(t,J=7.4Hz,2H),3.59(s,2H),3.54(dd,J=7.2,5.5Hz,2H),2.93(dq,J=15.5,7.8Hz,1H).

[0273] Example 9 4-((1-(3-fluoro-5-trifluoromethylphenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-9)

[0274] Step ①: (1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methanol (9-1)

[0275] A mixture of 1 g of 3-methylhydroxyazetidine hydrochloride, 1150 μL of 3-bromo-5-fluorobenzotrifluoride, 680 mg of tris(dibenzylideneacetone)dipalladium, 1.38 g of BINAP, 10 drops of triethylamine, 2.48 g of potassium tert-butoxide, and 15 ml of toluene was stirred under an argon atmosphere at 110°C for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (60:40) to obtain 918.4 mg of (1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methanol (9-1) as an oily solid, with a yield of 50.0%. 1 H NMR(400MHz, DMSO-d6)δ6.74(dt,J=8.9,1.9Hz,1H),6.52-6.42(m,2H),4.81(t,J=5.3Hz,1H),3.9 1(t,J=7.9Hz,2H),3.63(dd,J=7.7,5.4Hz,2H),3.57(t,J=5.7Hz,2H),2.80(tt,J=8.2,5.8Hz,1H).

[0276] Step ②: 4-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiophene-6-carboxylic acid methyl ester (9-2)

[0277] A mixture of 300 mg of methyl 3-carbonyl-3,4-dihydro-2H-1,4-benzothiazine-6-carboxylate, 395 mg of (1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methanol (9-1), 387 mg of triphenylphosphine, 290 μL of DIAD, and 5 mL of tetrahydrofuran was stirred at room temperature for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (80:20) to obtain 465.3 mg of methyl 4-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiophene-6-carboxylate (9-2) as a solid, in a yield of 76.3%. 1 H NMR (400MHz, DMSO-d6) δ7.83 (s, 1H), 7.61 (q, J = 8.1Hz, 2H), 6.77 (d, J = 8.8Hz, 1H), 6.51-6.44 (m, 2H), 4.41 (d, J = 7. 4Hz,2H),3.90(d,J=7.9Hz,2H),3.86(d,J=5.5Hz,3H),3.62(dd,J=7.6,5.2Hz,2H),3.59(s,2H),2.96-2.84(m,1H).

[0278] Step ③: 4-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiophene-6-carboxylic acid (9-3)

[0279] The preparation method of 4-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiophene-6-carboxylic acid (9-3) is the same as that of 1-5. LCMS (ESI) m / z [M+H] + :441.1.

[0280] Step ④: 4-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-9)

[0281] The preparation method of ((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-9) is the same as that of I-1. 1 H NMR (400MHz, DMSO-d6) δ10.96 (s, 1H), 10.23 (s, 1H), 7.93 (d, J = 1.7Hz, 1H), 7.85-7.78 (m, 2H), 7.73(dd,J=8.1,1.6Hz,1H),7.60(d,J=8.0Hz,1H),7.37(dt,J=8.2,0.9Hz,1H),7.16-7.09(m,1 H),7.00(ddd,J=8.0,6.9,1.0Hz,1H),6.78(d,J=8.8Hz,1H),6.53-6.46(m,2H),4.49(d,J=7.3 Hz,2H),3.93(t,J=7.8Hz,2H),3.68(dd,J=7.8,5.4Hz,2H),3.60(s,2H),3.02(d,J=7.8Hz,1H).

[0282] Example 10 4-((1-(Benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-10)

[0283] Step ①: (1-(Benzo[d][1,3]dioxolane-5-yl)azetidin-3-yl)methanol (10-1)

[0284] The preparation method of (1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methanol (10-1) is the same as compound 2-1. 1 H NMR (400MHz, DMSO-d6) δ6.71(d,J=8.2Hz,1H),6.10(d,J=2.3Hz,1H),5.86(s,2H),5.79(dd,J=8.3,2.3Hz,1H),4.72 (t,J=5.3Hz,1H),3.71(t,J=7.4Hz,2H),3.55(dd,J=6.5,5.3Hz,2H),3.43(dd,J=7.1,5.4Hz,2H),2.76-2.65(m,1H).

[0285] Step ②: 4-((1-((Benzo[d][1,3]dioxolane-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (10-2)

[0286] The preparation method of methyl 4-((1-((benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (10-2) is the same as compound 9-2. 1 H NMR (400MHz, DMSO-d6) δ7.66-7.58(m,2H),7.47(d,J=8.0Hz,1H),6.74(d,J=8.3Hz,1H),6.16(d,J=2.3Hz,1H), 5.90-5.81(m,3H),4.54(d,J=7.0Hz,2H),3.84(d,J=3.7Hz,5H),3.60-3.53(m,4H),3.08(tq,J=7.8,5.6Hz,1H).

[0287] Step ③: 4-((1-((Benzo[d][1,3]dioxolane-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (10-3)

[0288] The preparation method of 4-((1-((Benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (10-3) is the same as that of compound 9-3. LCMS (ESI) m / z [M+H] + :399.1.

[0289] Step ④: 4-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-10)

[0290] The preparation method of 4-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-10) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.23(s,1H),7.91(d,J=1.6Hz,1H),7.85-7.77(m,2H),7.72(dd,J=8. 0,1.6Hz,1H),7.59(d,J=8.1Hz,1H),7.36(dt,J=8.2,0.9Hz,1H),7.11(ddd,J=8.2,7.0,1.2Hz,1H),7.00(ddd ,J=8.0,6.9,1.1Hz,1H),6.69(d,J=8.3Hz,1H),6.10(d,J=2.2Hz,1H),5.85(s,2H),5.78(dd,J=8.3,2.3Hz,1H ),4.44(d,J=7.3Hz,2H),3.72(t,J=7.3Hz,2H),3.58(s,2H),3.49-3.46(m,2H),2.89(dd,J=13.7,7.1Hz,1H).

[0291] Example 11 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indoline-6-carboxamide (I-11)

[0292] Step ①: 6-bromo-3,3-dimethyl-1-((1-phenylazetidin-3-yl)methyl)indolin-2-one (11-1)

[0293] The preparation method of 6-bromo-3,3-dimethyl-1-((1-phenylazetidin-3-yl)methylindolin-2-one (11-1) is the same as compound 9-2. 1 H NMR (400MHz, DMSO-d6) δ7.45(d,J=1.8Hz,1H),7.31(d,J=7.9Hz,1H),7.22(dd,J=7.8,1.7Hz,1H),7.16-7.11(m,2H),6.65(t,J=7.3H z,1H),6.41-6.37(m,2H),3.98(d,J=7.4Hz,2H),3.82(t,J=7.5Hz,2H),3.54(dd,J=7.3,5.4Hz,2H),3.12-3.01(m,1H),1.25(s,6H).

[0294] Step ②: 3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)dihydroindole-6-carbonitrile (11-2)

[0295] A mixture of 540 mg of 6-bromo-3,3-dimethyl-1-((1-phenylazetidin-3-yl)methylindolin-2-one (11-1), 304 mg of zinc cyanide, 120 mg of tris(dibenzylideneacetone)dipalladium, 144 mg of DPPF, and 8 ml of N,N-dimethylformamide was heated and stirred at 100°C under an argon atmosphere for 12 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was concentrated to dryness, and the residue was purified by column chromatography using dichloromethane:ethyl acetate (85:15) to obtain 411.3 mg of 3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indolin-6-carbonitrile (11-2) as a white solid in a yield of 88.5%. 1 H NMR(400 MHz, DMSO-d6)δ7.72(d,J=1.4Hz,1H),7.59-7.53(m,2H),7.15-7.11(m,2H),6.68-6.63(m,1H),6.41-6.37(m,2H ), 4.01 (d, J = 7.3Hz, 2H), 3.83 (t, J = 7.5Hz, 2H), 3.54 (dd, J = 7.2, 5.4Hz, 2H), 3.12 (q, J = 6.6Hz, 1H), 1.29 (s, 6H).

[0296] Step ③: 3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indoline-6-carboxylic acid (11-3)

[0297] A mixture of 410 mg of 3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indoline-6-carbonitrile, 2.1 mL of 6N NaOH, and 3 mL of ethanol was heated and stirred at 80°C for 3 hours. The reaction solution was concentrated to dryness to obtain solid 3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indoline-6-carboxylic acid (11-3), which was used directly in the next step. LCMS (ESI) m / z [M+H] + :351.2.

[0298] Step ④: N-(1H-indol-3-yl)-3,3-dihydro-2-oxo-1-((1-phenylazetidin-3-yl)methyl)dihydroindole-6-carboxamide (I-11)

[0299] The preparation method of N-(1H-indol-3-yl)-3,3-dihydro-2-oxo-1-((1-phenylazetidin-3-yl)methyl)dihydroindole-6-carboxamide (I-11) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),10.13(s,1H),7.83(d,J=8.0Hz,1H),7.79(d,J=2.5Hz, 1H),7.73-7.68(m,2H),7.52(d,J=7.6Hz,1H),7.38-7.35(m,1H),7.17-7.11(m,3H),7.01(dd d,J=8.0,7.0,1.0Hz,1H),6.68-6.63(m,1H),6.43-6.39(m,2H),4.08(d,J=7.4Hz,2H),3.88( t,J=7.5Hz,2H),3.61(dd,J=7.3,5.3Hz,2H),3.20(dq,J=11.8,5.8,5.4Hz,1H),1.32(s,6H).

[0300] Example 12 1-(3,3-Dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indolin-6-yl)-3-(1H-indol-3-yl)urea (I-12)

[0301] Step ①: (3,3-Dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indoline-6-carbonyl azide (12-1)

[0302] The preparation method of (3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)dihydroindole-6-carbonyl azide (12-1) is the same as that of compound 3-1. 1 H NMR (400MHz, CDCl3) δ7.79 (dd, J=7.7, 1.5Hz, 1H), 7.51 (d, J=1.5Hz, 1H), 7.38-7.27 (m, 3H), 6.75 (tt, J=7.4, 1.1Hz, 1H), 6.47-6.42(m,2H),4.06(d,J=7.3Hz,2H),3.96(d,J=7.7Hz,2H),3.71(dd,J=7.2,5.2Hz,2H),3.16(ddd,J=12.8,7.6,5.2 Hz,1H),1.39(s,6H).

[0303] Step ②: tert-Butyl (3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indolin-6-yl)carbamate (12-2)

[0304] The preparation method of tert-butyl (3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)dihydroindole-6-yl)carbamate (12-2) is the same as compound 3-2. LCMS (ESI) m / z [M+H] + :422.2.

[0305] Step ③: 6-amino-3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indolin-2-one (12-3)

[0306] The preparation method of 6-amino-3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indolin-2-one (12-3) is the same as compound 3-3. LCMS (ESI) m / z [M+H] + :322.2.

[0307] Step ④: 1-(3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indolin-6-yl)-3-(1H-indol-3-yl)urea (I-12)

[0308] The preparation method of 1-(3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)dihydroindole-6-yl)-3-(1H-indol-3-yl)urea (I-12) is the same as compound I-3. 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.68(s,1H),8.49(s,1H),7.52(dd,J=5.3,2.8Hz,2H),7. 39(d,J=1.9Hz,1H),7.34(d,J=8.1Hz,1H),7.23(d,J=8.0Hz,1H),7.15(dd,J=8.4,7.2Hz,2H),7 .09(d,J=7.7Hz,1H),7.04-6.99(m,2H),6.67(t,J=7.3Hz,1H),6.41(d,J=7.9Hz,2H),3.96(d,J =7.3Hz,2H),3.86(t,J=7.5Hz,2H),3.60(dd,J=7.3,5.3Hz,2H),3.13-3.02(m,1H),1.25(s,6H).

[0309] Example 13 1-(4-((1-(Benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea (I-13)

[0310] Step ①: 4-((1-(Benzo[d][1,3]dioxolane-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl azide (13-1)

[0311] The preparation method of 4-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carbonyl azide (13-1) is the same as compound 3-1. 1 H NMR (400MHz, DMSO-d6) δ6.71(d,J=8.2Hz,1H),6.10(d,J=2.3Hz,1H),5.85(s,2H),5.78(dd,J=8.3,2.3Hz,1H ), 4.72 (s, 1H), 3.71 (t, J = 7.4Hz, 2H), 3.55 (d, J = 6.5Hz, 2H), 3.43 (dd, J = 7.1, 5.5Hz, 2H), 2.77-2.64 (m, 1H).

[0312] Step ②: tert-Butyl (4-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate (13-2)

[0313] The preparation method of tert-butyl (4-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)carbamate (13-2) is the same as compound 3-2. LCMS (ESI) m / z [M+H] + :470.2.

[0314] Step ③: 6-amino-4-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-3(4H)-one (13-3)

[0315] The preparation method of 6-amino-4-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-3(4H)-one (13-3) is the same as compound 3-3. LCMS (ESI) m / z [M+H] + :370.2.

[0316] Step ④: 1-(4-((1-(Benzo[d][1,3]dioxolane-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea (I-13)

[0317] The preparation method of 1-(4-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazin-6-yl)-3-(1H-indol-3-yl)urea (I-13) is the same as compound I-3. 1 H NMR (400MHz, DMSO-d6) δ10.74(d,J=2.5Hz,1H),8.84(s,1H),8.61(s,1H),7.62(d,J=2.1Hz,1H), 7.53(d,J=7.9Hz,1H),7.50(d,J=2.4Hz,1H),7.35-7.28(m,2H),7.15-7.07(m,2H),7.00(ddd,J=7 .9,7.0,1.1Hz,1H),6.71(d,J=8.3Hz,1H),6.12(d,J=2.3Hz,1H),5.86(s,2H),5.80(dd,J=8.3,2 .3Hz,1H),4.26(d,J=7.1Hz,2H),3.74(t,J=7.4Hz,2H),3.52-3.44(m,4H),2.91(p,J=6.8Hz,1H).

[0318] Example 14 N-(1H-indol-3-yl)-1-((1-4-methoxyphenylazetidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-14)

[0319] Step ①: (1-(4-methoxyphenyl)azetidin-3-yl)methanol (14-1)

[0320] The preparation of (1-(4-methoxyphenyl)azetidin-3-yl)methanol (14-1) was the same as compound 2-1. 1 H NMR (400MHz, DMSO-d6) δ6.83-6.72(m,2H),6.41-6.30(m,2H),4.70(t,J=5.3Hz,1H),3.73(t,J=7. 3Hz, 2H), 3.65 (s, 3H), 3.56 (dd, J=6.5, 5.3Hz, 2H), 3.44 (dd, J=6.9, 5.5Hz, 2H), 2.78-2.66 (m, 1H).

[0321] Step ②: 6-bromo-1-((1-(4-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (14-2)

[0322] The preparation of 6-bromo-1-((1-(4-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (14-2) was the same as compound 11-1. 1 H NMR (400MHz, DMSO-d6) δ7.43(d,J=1.8Hz,1H),7.31(d,J=7.9Hz,1H),7.24-7.20(m,1H),6.79-6.74(m,2H),6.38-6.33(m, 2H), 3.97 (d, J = 7.3Hz, 2H), 3.76 (t, J = 7.3Hz, 2H), 3.65 (s, 3H), 3.47 (t, J = 6.2Hz, 2H), 3.04 (p, J = 6.4Hz, 1H), 1.25 (s, 6H).

[0323] Step ③: 1-((1-(4-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (14-3)

[0324] The preparation of 1-((1-(4-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (14-3) was the same as compound 11-2. 1H NMR (400MHz, DMSO-d6) δ7.71(d,J=1.4Hz,1H),7.59(d,J=7.6Hz,1H),7.55-7.51(m,1H),6.79-6.74(m,2H),6.38-6.34(m,2H ), 4.00 (d, J = 7.3Hz, 2H), 3.76 (t, J = 7.4Hz, 2H), 3.64 (s, 3H), 3.47 (dd, J = 7.1, 5.4Hz, 2H), 3.07 (p, J = 6.5Hz, 1H), 1.29 (s, 6H).

[0325] Step ④: 1-((1-(4-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (14-4)

[0326] The preparation method of 1-((1-(4-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (14-4) is the same as that of compound 11-3. LCMS (ESI) m / z [M+H] + :381.2.

[0327] Step ⑤: N-(1H-indol-3-yl)-1-((1-(4-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-14)

[0328] The preparation method of N-(1H-indol-3-yl)-1-((1-(4-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-14) is the same as that of compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),10.12(s,1H),7.83(d,J=8.0Hz,1H),7.78(d,J=2.5Hz,1H),7.72(dd ,J=7.7,1.4Hz,1H),7.68(d,J=1.5Hz,1H),7.52(d,J=7.6Hz,1H),7.37(d,J=8.1Hz,1H),7.12(ddd,J=8.2, 7.0,1.2Hz,1H),7.01(ddd,J=8.0,6.9,1.0Hz,1H),6.81-6.75(m,2H),6.40-6.35(m,2H),4.07(d,J=7.3Hz ,2H),3.81(t,J=7.3Hz,2H),3.65(s,3H),3.54(dd,J=7.1,5.4Hz,2H),3.17(p,J=6.8Hz,1H),1.32(s,6H).

[0329] Example 15 N-(1H-indol-3-yl)-1-((1-3-methoxyphenylazetidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-15)

[0330] Step ①: (1-(3-methoxyphenyl)azetidin-3-yl)methanol (15-1)

[0331] The preparation of (1-(3-methoxyphenyl)azetidin-3-yl)methanol (15-1) was the same as compound 2-1. 1 H NMR (400MHz, DMSO-d6) δ7.04(td,J=8.1,1.7Hz,1H),6.22(dd,J=8.2,2.3Hz,1H),5.98(dd,J=8.0,2.1Hz,1H),5.91(q,J=2.1Hz,1H), 3.79(td,J=7.5,1.7Hz,2H), 3.69(d,J=1.8Hz,3H), 3.57(dd,J=6.5,1.8Hz,2H), 3.51(ddd,J=7.2,5.4,1.7Hz,2H), 2.81-2.68(m,1H).

[0332] Step ②: 6-bromo-1-((1-(3-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (15-2)

[0333] The preparation of 6-bromo-1-((1-(3-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (15-2) was the same as compound 11-1. 1 H NMR (400MHz, DMSO-d6) δ7.45 (d, J = 1.8 Hz, 1H), 7.31 (d, J = 7.9 Hz,1H),7.25-7.21(m,1H),7.04(t,J=8.1Hz,1H),6.24(dd,J=8.1,2.4Hz,1H),5.98(dd,J=7.9,2.1Hz,1H),5.91(t,J=2.3Hz,1H),3. 98(d,J=7.4Hz,2H),3.82(t,J=7.5Hz,2H),3.68(s,3H),3.54(dd,J=7.3,5.3Hz,2H),3.06(ddd,J=13.1,6.5,3.8Hz,1H),1.26(s,6H).

[0334] Step ③: 1-((1-(3-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (15-3)

[0335] The preparation of 1-((1-(3-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (15-3) was the same as compound 11-2. 1 H NMR (400MHz, DMSO-d6) δ7.73(d,J=1.4Hz,1H),7.59(d,J=7.6Hz,1H),7.53(dd,J =7.6,6.3Hz,1H),7.04(t,J=8.1Hz,1H),6.24(dd,J=8.1,2.4Hz,1H),5.98(dd,J =7.7,2.1Hz,1H),5.92(t,J=2.3Hz,1H),4.01(d,J=7.3Hz,2H),3.82(t,J=7.5Hz ,2H),3.68(s,3H),3.54(dd,J=7.3,5.3Hz,2H),3.17-3.05(m,1H),1.29(s,6H).

[0336] Step ④: 1-((1-(3-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (15-4)

[0337] The preparation of 1-((1-(3-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (15-4) was the same as compound 11-3. LCMS (ESI) m / z [M+H] + :381.2.

[0338] Step ⑤: N-(1H-indol-3-yl)-1-((1-(3-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-15)

[0339] The preparation of N-(1H-indol-3-yl)-1-((1-(3-methoxyphenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-15) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),10.12(s,1H),7.83(d,J=8.0Hz,1H),7.79(d,J=2.5Hz,1H),7.74-7. 68(m,2H),7.52(d,J=7.6Hz,1H),7.37(d,J=8.1Hz,1H),7.12(ddd,J=8.2,7.0,1.3Hz,1H),7.03(dt,J=12. 9,7.6Hz,2H),6.25(dd,J=8.0,2.4Hz,1H),6.01(dd,J=7.9,2.1Hz,1H),5.94(t,J=2.3Hz,1H),4.08(d,J=7 .4Hz,2H),3.87(t,J=7.5Hz,2H),3.69(s,3H),3.62(dd,J=7.3,5.3Hz,2H),3.25-3.15(m,1H),1.33(s,6H).

[0340] Example 16 N-(3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indolin-6-yl)-1H-indole-3-carboxamide (I-16)

[0341] Step ①: 3,3-dimethyl-6-nitro-1-((1-phenylazetidin-3-yl)methyl)indolin-2-one (16-1)

[0342] The preparation of 3,3-dimethyl-6-nitro-1-((1-phenylazetidin-3-yl)methyl)indolin-2-one (16-1) was the same as compound 11-1. 1H NMR (400MHz, CDCl3) δ8.00(dd,J=8.1,2.0Hz,1H),7.72(d,J=2.0Hz,1H),7.35(d,J=8.1Hz,1H),7.23-7.17(m,2H),6.75(ddd,J=8.6,6.9,1. 2Hz,1H),6.47-6.43(m,2H),4.10-4.07(m,2H),3.96(t,J=7.4Hz,2H),3.72(dd,J=7.2,5.2Hz,2H),3.16(tt,J=7.6,5.2Hz,1H),1.41(s,6H).

[0343] Step ②: 6-amino-3,3-dimethyl-1-((1-phenylazetidin-3-yl)methyl)indolin-2-one (16-2)

[0344] A mixture of 120 mg of 3,3-dimethyl-6-nitro-1-((1-phenylazetidin-3-yl)methyl)indolin-2-one (16-1), 100 mg of reduced iron powder, 370 mg of ammonium chloride, 3 mL of ethanol, and 300 μL of water was stirred at 80°C under an argon atmosphere for 2 hours. The reaction solution was concentrated to dryness, and the residue was slurried with ethyl acetate to obtain 91.1 mg of 6-amino-3,3-dimethyl-1-((1-phenylazetidin-3-yl)methyl)indolin-2-one (16-2) as a white solid, with a yield of 82.8%. 1 H NMR (400MHz, DMSO-d6) δ7.20-7.11(m,2H),6.93(d,J=7.9Hz,1H),6.66(tt,J=7.3,1.1Hz,1H),6.42-6.37(m,2H),6.31(d,J=1.9H z,1H),6.21(dd,J=7.9,1.9Hz,1H),5.11(s,2H),3.91-3.78(m,4H),3.56(dd,J=7.3,5.3Hz,2H),3.09-2.99(m,1H),1.18(s,6H).

[0345] Step ③: N-(3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indolin-6-yl)-1H-indole-3-carboxamide (I-16)

[0346] The preparation of N-(3,3-dimethyl-2-oxo-1-((1-phenylazetidin-3-yl)methyl)indolin-6-yl)-1H-indole-3-carboxamide (I-16) is the same as compound I-1. 1H NMR (600MHz, DMSO-d6) δ11.74(d,J=2.9Hz,1H),9.75(s,1H),8.30(d,J=2.9Hz,1H),8.20(d,J =7.9Hz,1H),7.61(d,J=1.9Hz,1H),7.47(d,J=8.0Hz,1H),7.41(dd,J=8.0,1.8Hz,1H),7.29( d,J=8.0Hz,1H),7.20-7.13(m,4H),6.67(t,J=7.3Hz,1H),6.42(d,J=8.0Hz,2H),3.98(d,J=7 .4Hz,2H),3.88(t,J=7.4Hz,2H),3.63(q,J=6.2,5.3Hz,2H),3.16-3.06(m,1H),1.27(s,6H).

[0347] Example 17 1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-17)

[0348] Step ①: 6-bromo-1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (17-1)

[0349] The preparation of 6-bromo-1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (17-1) was the same as compound 11-1. 1 H NMR (400MHz, CDCl3) δ7.24-7.20(m,1H),7.09(d,J=7.8Hz,1H),7.02(d,J=1.6Hz,1H),6.65(d,J=8.7Hz,1H),6.38(s ,1H),6.22(dt,J=10.5,2.3Hz,1H),4.03-3.93(m,4H),3.75(dd,J=7.5,5.1Hz,2H),3.23-3.12(m,1H),1.36(s,6H).

[0350] Step ②: 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (17-2)

[0351] The preparation of 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (17-2) was the same as compound 11-2. LCMS (ESI) m / z [M+H] + :418.2.

[0352] Step ③: 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (17-3)

[0353] The preparation of 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (17-3) was the same as compound 11-3. LCMS (ESI) m / z [M+H] + :437.1.

[0354] Step ④: 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-17)

[0355] The preparation of 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-17) is the same as compound I-1. 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),10.11 (s,1H),7.82(d,J=7.9Hz,1H),7.78(d,J=2.5Hz,1H),7.71(d,J=4.4Hz,2H),7. 52(d,J=8.0Hz,1H),7.37(d,J=8.1Hz,1H),7.11(t,J=7.5Hz,1H),7.00(t,J=7.5 Hz,1H),6.78(d,J=8.8Hz,1H),6.56-6.49(m,2H),4.09(d,J=7.5Hz,2H),4.00(t ,J=7.9Hz,2H),3.74(dd,J=7.9,5.3Hz,2H),3.27(d,J=7.2Hz,1H),1.33(s,6H).

[0356] Example 18 1-((1-(3-chloro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-18)

[0357] Step ①: (1-3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methanol (18-1)

[0358] The preparation of (1-3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methanol (18-1) was the same as compound 9-1. 1 H NMR(400MHz, CDCl3) δ6.90(d,J=1.7Hz,1H),6.49(dt,J=14.4,2.1Hz,2H),3.98(t,J =7.7Hz,2H),3.87(d,J=6.3Hz,2H),3.71(dd,J=7.4,5.1Hz,2H),3.00-2.89(m,1H).

[0359] Step ②: 6-bromo-1-((1-(3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (18-2)

[0360] The preparation of 6-bromo-1-((1-(3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (18-2) was the same as compound 11-1. 1 H NMR (400MHz, CDCl3) δ7.22(dt,J=7.9,1.4Hz,1H),7.09(dd,J=7.8,1.1Hz,1H),7.02(t,J=1.4Hz,1H),6.93(s,1H),6. 49(d,J=15.1Hz,2H),4.04-3.94(m,4H),3.80-3.72(m,2H),3.19(dq,J=12.9,6.6,5.8Hz,1H),1.36(d,J=1.1Hz,6H).

[0361] Step ③: 1-((1-(3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (18-3)

[0362] The preparation of 1-((1-(3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (18-3) was the same as compound 11-2. LCMS (ESI) m / z [M+H] + :434.1.

[0363] Step ④: 1-((1-(3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (18-4)

[0364] The preparation of 1-((1-(3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (18-4) was the same as compound 11-3. LCMS (ESI) m / z [M+H] + :453.1.

[0365] Step ⑤: 1-((1-(3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-18)

[0366] The preparation of 1-((1-(3-chloro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-18) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.11(s,1H),7.82(d,J=8.0Hz,1H),7.78(d,J=2.5Hz, 1H),7.71(dt,J=4.0,1.9Hz,2H),7.52(d,J=8.0Hz,1H),7.40-7.34(m,1H),7.11(ddd,J=8.2,7 .0,1.2Hz,1H),7.03-6.95(m,2H),6.73(t,J=2.1Hz,1H),6.62(s,1H),4.09(d,J=7.5Hz,2H), 4.01(t,J=7.9Hz,2H), 3.74(dd,J=7.9,5.2Hz,2H), 3.27(dd,J=14.0,6.3Hz,1H), 1.33(s,6H).

[0367] Example 19 1-((1-(Benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-19)

[0368] Step ①: 1-((1-(Benzo[d][1,3]dioxolane-5-yl)azetidin-3-yl)methyl)-6-bromo-3,3-dimethylindolin-2-one (19-1)

[0369] The preparation of 1-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-6-bromo-3,3-dimethylindolin-2-one (19-1) was the same as compound 11-1. 1 H NMR (400MHz, DMSO-d6) δ7.44(d,J=1.8Hz,1H),7.31(d,J=7.8Hz,1H),7.22(dd,J=7.8,1.7Hz,1H),6.71(d,J=8.3Hz,1H),6.12(d,J=2.3Hz,1H),5.8 6(s,2H),5.79(dd,J=8.3,2.3Hz,1H),3.96(d,J=7.3Hz,2H),3.75(t,J=7. 4Hz, 2H), 3.46 (dd, J = 7.2, 5.4Hz, 2H), 3.02 (p, J = 7.0Hz, 1H), 1.25 (s, 6H).

[0370] Step ②: 1-((1-(Benzo[d][1,3]dioxolane-5-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (19-2)

[0371] The preparation of 1-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carbonitrile (19-2) was the same as compound 11-2. 1H NMR (400MHz, DMSO-d6) δ7.71(d,J=1.4Hz,1H),7.59(d,J=7.6Hz,1H),7.54(dd,J=7.6,1.4Hz,1H),6.71(d,J=8.3Hz,1H),6.13(d,J=2.2Hz,1H),5.8 6(s,2H),5.80(dd,J=8.3,2.3Hz,1H),3.99(d,J=7.2Hz,2H),3.75(t,J=7. 4Hz, 2H), 3.47 (dd, J=7.2, 5.4Hz, 2H), 3.07 (q, J=7.0Hz, 1H), 1.29 (s, 6H).

[0372] Step ③: 1-((1-(Benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (19-3)

[0373] The preparation of 1-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (19-3) was the same as compound 11-3. LCMS (ESI) m / z [M+H] + :395.2.

[0374] Step ④: 1-((1-(Benzo[d][1,3]dioxolane-5-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-19)

[0375] The preparation of 1-((1-(benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-19) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.93(d,J=2.4Hz,1H),10.12(s,1H),7.83(d,J=8.0Hz,1H),7.79(d,J=2.5Hz,1H),7. 72(dd,J=7.6,1.5Hz,1H),7.69(d,J=1.5Hz,1H),7.52(d,J=7.6Hz,1H),7.38(d,J=8.1Hz,1H),7.12(t,J=7.5Hz ,1H),7.02(t,J=7.5Hz,1H),6.72(d,J=8.3Hz,1H),6.14(d,J=2.2Hz,1H),5.87(s,2H),5.82(dd,J=8.3,2.3Hz, 1H), 4.06 (d, J = 7.3Hz, 2H), 3.80 (t, J = 7.4Hz, 2H), 3.54 (dd, J = 7.2, 5.3Hz, 2H), 3.20-3.10 (m, 1H), 1.33 (s, 6H).

[0376] Example 20 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-(thien-3-yl)azetidin-3-yl)methyl)indoline-6-carboxamide (I-20)

[0377] Step ①: (1-(thiophen-3-yl)azetidin-3-yl)methanol (20-1)

[0378] The preparation of (1-(thiophen-3-yl)azetidin-3-yl)methanol (20-1) was the same as compound 2-1. 1 H NMR (400MHz, DMSO-d6) δ7.29(dd,J=5.1,3.1Hz,1H),6.51(dd,J=5.1,1.5Hz,1H),5.93(dd,J=3.1,1.5Hz,1H),4.67( t,J=5.3Hz,1H),3.70(t,J=7.4Hz,2H),3.51(dd,J=6.6,5.3Hz,2H),3.43(dd,J=7.0,5.6Hz,2H),2.73-2.62(m,1H).

[0379] Step ②: 6-bromo-3,3-dimethyl-1-((1-(thien-3-yl)azetidin-3-yl)methyl)indolin-2-one (20-2)

[0380] The preparation of 6-bromo-3,3-dimethyl-1-((1-(thiophen-3-yl)azetidin-3-yl)methyl)indolin-2-one (20-2) was the same as compound 11-1. 1 H NMR (400MHz, DMSO-d6) δ7.42(d,J=1.7Hz,1H),7.35-7.29(m,2H),7.22(dd,J=7.9,1.7Hz,1H),6.55(dd,J=5.1,1.5Hz,1H),6.00(dd,J =3.1,1.5Hz,1H),3.96(d,J=7.3Hz,2H),3.77(t,J=7.4Hz,2H),3.49(dd,J=7.1,5.5Hz,2H),3.03(tt,J=7.8,5.8Hz,1H),1.24(s,6H).

[0381] Step ③: 3,3-dimethyl-2-oxo-1-((1-(thien-3-yl)azetidin-3-yl)methyl)indoline-6-carbonitrile (20-3)

[0382] The preparation of 3,3-dimethyl-2-oxo-1-((1-(thiophen-3-yl)azetidin-3-yl)methyl)indoline-6-carbonitrile (20-3) was the same as compound 11-2. 1 H NMR (400MHz, DMSO-d6) δ7.70(d,J=1.4Hz,1H),7.59(d,J=7.6Hz,1H),7.54(dd,J=7.7,1.3Hz,1H),7.34(dd,J=5.1,3.1Hz,1H),6.56(dd,J=5.1,1.5 Hz,1H),6.02(dd,J=3.1,1.5Hz,1H),4.00(d,J=7.2Hz,2H),3.78(t,J=7.4Hz,2H),3.50(dd,J=7.1,5.5Hz,2H),3.07(p,J=6.6Hz,1H),1.29(s,6H).

[0383] Step ④: 3,3-dimethyl-2-oxo-1-((1-(thien-3-yl)azetidin-3-yl)methyl)indoline-6-carboxylic acid (20-4)

[0384] The preparation of 3,3-dimethyl-2-oxo-1-((1-(thiophen-3-yl)azetidin-3-yl)methyl)indoline-6-carboxylic acid (20-4) was the same as compound 11-3. LCMS (ESI) m / z [M+H] + :357.1.

[0385] Step ⑤: N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-(thien-3-yl)azetidin-3-yl)methyl)indoline-6-carboxamide (I-20)

[0386] The preparation of N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-(thiophen-3-yl)azetidin-3-yl)methyl)indoline-6-carboxamide (I-20) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.12(s,1H),7.83(d,J=8.0Hz,1H),7.78(d,J=2.5Hz,1H),7.71(dd,J=7.6,1.5Hz,1H),7.67(d,J =1.5Hz,1H),7.51(d,J=7.7Hz,1H),7.39-7.31(m,2H),7.15-7.08(m,1H),7.01(t,J=7.4Hz,1H),6.57(dd,J=5.0,1.5Hz,1H),6.03( dd,J=3.1,1.5Hz,1H),4.06(d,J=7.3Hz,2H),3.82(t,J=7.3Hz,2H),3.56(dd,J=7.1,5.4Hz,2H),3.16(p,J=6.6Hz,1H),1.32(s,6H).

[0387] Example 21 1-((1-(2-chloro-6-fluorophenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-21)

[0388] Example 22 1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thiophene[2,3-b][1,4]thiazine-6-carboxamide (I-22)

[0389] Example 23 1-((1-(Benzo[d][1,3]dioxolan-5-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-23)

[0390] Example 24 1-((1-(Benzo[d]isoxazol-3-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-24)

[0391] Example 25 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-(pyridin-3-yl)azetidin-3-yl)methyl)indoline-6-carboxamide (I-25)

[0392] Example 26 1-((1-(Furan-3-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-26)

[0393] Example 27 1-((1-(imidazo[1,2-a]pyridine-2-)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-27)

[0394] Example 28 N-(5-fluoro-1H-indol-3-yl)-1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-28)

[0395] The preparation of N-(5-fluoro-1H-indol-3-yl)-1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-28) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ11.04(s,J=2.7Hz,1H),10.10(s,1H),7.87(d,J=2.6Hz,1H),7.71(d d,J=9.2,1.6Hz,2H),7.61(dd,J=10.3,2.6Hz,1H),7.53(d,J=7.6Hz,1H),7.37(dd,J=8.9,4 .5Hz,1H),6.96(td,J=9.1,2.6Hz,1H),6.80-6.74(m,1H),6.58-6.46(m,2H),4.09(d,J=7.5 Hz,2H),3.99(t,J=7.9Hz,2H),3.73(dd,J=7.9,5.2Hz,2H),3.30-3.19(m,1H),1.33(s,6H).

[0396] Example 29 N-(5-chloro-1H-indol-3-yl)-1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-29)

[0397] The preparation of N-(5-chloro-1H-indol-3-yl)-1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-29) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),10.15(s,1H),7.94(d,J=2.1Hz,1H),7.87(d,J =2.5Hz,1H),7.76-7.67(m,2H),7.53(d,J=7.6Hz,1H),7.39(d,J=8.6Hz,1H),7.11(dd ,J=8.7,2.1Hz,1H),6.77(d,J=8.7Hz,1H),6.58-6.45(m,2H),4.09(d,J=7.5Hz,2H),3 .99(t,J=7.9Hz,2H),3.73(dd,J=7.9,5.2Hz,2H),3.26(t,J=7.5Hz,1H),1.33(s,6H).

[0398] Example 30 N-(5,6-difluoro-1H-indol-3-yl)-1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-30)

[0399] The preparation of N-(5,6-difluoro-1H-indol-3-yl)-1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-30) is the same as compound I-1. 1 H NMR (400MHz, CDCl3) δ8.26 (s, 1H), 7.90 (s, 1H), 7.86 (d, J = 2.6Hz, 1H), 7.58–7. 52(m,2H),7.36–7.29(m,2H),7.17(dd,J=10.3,6.5Hz,1H),6.66–6.59(m,1H), 6.37(d,J=1.9Hz,1H),6.20(dt,J=10.6,2.2Hz,1H),4.09(d,J=7.3Hz,2H),3.9 6(t,J=7.7Hz,2H),3.76(dd,J=7.4,5.1Hz,2H),3.29–3.17(m,1H),1.42(s,6H).

[0400] Example 31 1-((1-(3-chloro-5-fluorophenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-31)

[0401] Step ①: Methyl (1-(3-chloro-5-fluorophenyl)azetidin-3-yl)methanesulfonate (31-1)

[0402] The preparation of methyl (1-(3-chloro-5-fluorophenyl)azetidin-3-yl)methanesulfonate (31-1) was the same as compound 25-2. 1 H NMR(400MHz, CDCl3) δ6.45(dt,J=8.7,2.0Hz,1H),6.16(t,J=2.0Hz,1H),5.99(dt,J=10.5,2.2Hz,1H),4 .44(d,J=6.8Hz,2H),3.98(t,J=7.8Hz,2H),3.68(dd,J=7.7,5.0Hz,2H),3.14–3.07(m,1H),3.05(s,3H).

[0403] Step ②: 1-((1-(3-chloro-5-fluorophenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid methyl ester (31-2)

[0404] The preparation of methyl 1-((1-(3-chloro-5-fluorophenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylate (31-2) was the same as compound 25-3. 1 H NMR (400MHz, CDCl3) δ7.81(dd,J=7.7,1.4Hz,1H),7.51(d,J=1.4Hz,1H),7.28(d,J=7.7Hz,1H),6.42(dt,J=8.7,2.0Hz,1H),6.15(d,J=2.1Hz ,1H),5.98(dt,J=10.7,2.2Hz,1H),4.05(d,J=7.3Hz,2H),3.94(d,J=4.4Hz,5H),3.72(dd,J=7.4,5.2Hz,2H),3.16-3.24(m,1H),1.39(s,6H).

[0405] Step ③: 1-((1-(3-chloro-5-fluorophenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (31-3)

[0406] The preparation of 1-((1-(3-chloro-5-fluorophenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (31-3) was the same as compound 9-3. LCMS (ESI) m / z [M+H] + :403.1.

[0407] Step ④: 1-((1-(3-chloro-5-fluorophenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-31)

[0408] The preparation of 1-((1-(3-chloro-5-fluorophenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-31) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.92(d,J=2.4Hz,1H),10.11(s,1H),7.86–7.76(m,2H),7.72(d,J=6.7H z,2H),7.52(d,J=7.9Hz,1H),7.37(d,J=8.1Hz,1H),7.12(t,J=7.5Hz,1H),7.01(t,J=7.5Hz,1H), 6.56(dt,J=8.9,2.1Hz,1H), 6.29(d,J=2.0Hz,1H), 6.23(dt,J=11.3,2.2Hz,1H), 4.05(dd,J=18. 5,7.3Hz,3H),3.94(t,J=7.8Hz,2H),3.68(dd,J=7.8,5.2Hz,2H),3.20-3.27(m,1H),1.32(s,6H).

[0409] Example 32 1-((1-(Benzo[b]thien-3-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-32)

[0410] Step ①: (1-(Benzo[b]thiophen-3-yl)azetidin-3-yl)methanol (32-1)

[0411] The preparation of (1-(benzo[b]thiophen-3-yl)azetidin-3-yl)methanol (32-1) was the same as compound 2-1. 1 H NMR (400MHz, CDCl3) δ7.80-7.73(m,1H),7.73-7.62(m,1H),7.34-7.28(m,2H),6.09(s,1H), 4.14(t,J=7.5Hz,2H),3.93(d,J=6.3Hz,2H),3.87(dd,J=7.1,5.2Hz,2H),3.00-2.88(m,1H).

[0412] Step ②: Methyl (1-(benzo[b]thiophen-3-yl)azetidin-3-yl)methanesulfonate (32-2)

[0413] A mixture of 200 mg of (1-(benzo[b]thiophen-3-yl)azetidin-3-yl)methanol (32-1), 200 μL of methanesulfonyl chloride, 760 μL of triethylamine, 20 mg of DMAP, and 4 mL of dichloromethane was stirred at room temperature for 1 hour. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate = 60:40 to obtain methyl (1-(benzo[b]thiophen-3-yl)azetidin-3-yl)methanesulfonate (32-2) as a solid. 1 H NMR (400MHz, CDCl3) δ7.80-7.75(m,1H),7.68-7.62(m,1H),7.35-7.29(m,2H),6.11(s,1H),4.52(d ,J=7.0Hz,2H),4.17(t,J=7.6Hz,2H),3.87(dd,J=7.4,5.2Hz,2H),3.19-3.14(m,1H),3.06(s,3H).

[0414] Step ③: 1-((1-(Benzo[b]thiophen-3-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid methyl ester (32-3)

[0415] The preparation of methyl 1-((1-(benzo[b]thiophen-3-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylate (32-3) was the same as compound 1-4. 1 H NMR (400MHz, CDCl3) δ7.81(dd,J=7.7,1.4Hz,1H),7.77-7.73(m,1H),7.67-7.62(m,1H),7.56(d,J=1.4Hz,1H),7.32-7.27( m,3H),6.09(s,1H),4.11(dd,J=7.2,3.2Hz,4H),3.94(s,3H),3.88(dd,J=7.1,5.5Hz,2H),3.22-3.25(m,1H),1.40(s,6H).

[0416] Step ④: 1-((1-(Benzo[b]thiophen-3-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (32-4)

[0417] The preparation method of 1-((1-(benzo[b]thiophen-3-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (32-4) is the same as compound 9-3. LCMS (ESI) m / z [M+H] + :407.1.

[0418] Step ⑤: 1-((1-(Benzo[b]thiophen-3-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-32)

[0419] The preparation method of 1-((1-(benzo[b]thiophen-3-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-32) is the same as compound I-1. 1 H NMR (400MHz, CDCl3) δ8.19 (s, 1H), 8.09 (s, 1H), 7.97 (d, J = 2.5Hz, 1H), 7.77-7.72 ( m,1H),7.66-7.62(m,1H),7.59-7.54(m,3H),7.39(d,J=8.2Hz,1H),7.32(d,J=8.0 Hz,1H),7.30-7.27(m,2H),7.25-7.22(m,1H),7.14(t,J=7.5Hz,1H),6.08(s,1H), 4.11(t,J=7.3Hz,4H),3.88(dd,J=7.1,5.5Hz,2H),3.18-3.25(m,1H),1.42(s,6H).

[0420] Example 33 N-(Benzofuran-3-yl)-1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-33)

[0421] Example 34 1-((1-(Furan-3-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-34)

[0422] Example 35 1-((1-(3-fluoro-5-methoxyphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-35)

[0423] Step ①: 1-((1-(3-fluoro-5-methoxyphenyl)azetidin-3-yl)methyl))-3,3-dimethyl-2-indoline-6-carboxylic acid methyl ester (35-1)

[0424] The preparation of methyl 1-((1-(3-fluoro-5-methoxyphenyl)azetidin-3-yl)methyl))-3,3-dimethyl-2-indoline-6-carboxylate (35-1) was the same as compound 11-1. 1 H NMR(400MHz,Chloroform-d)δ7.80(d,J=7.8Hz,1H),7.51(s,1H),7.28(d,J=8.2Hz,1H),6.01(dd,J=10.8,2.5Hz,1H),5.68-5.79(m,2H ),4.05(d,J=7.3Hz,2H),3.94(s,3H),3.90(d,J=6.9Hz,2H),3.74(s,3H),3.70(dd,J=7.3,5.4Hz,2H),3.11-3.26(m,1H),1.38(s,6H).

[0425] Step ②: 1-((1-(3-fluoro-5-methoxyphenyl)azetidin-3-yl)methyl))-3,3-dimethyl-2-indoline-6-carboxylic acid (35-2)

[0426] The preparation of 1-((1-(3-fluoro-5-methoxyphenyl)azetidin-3-yl)methyl))-3,3-dimethyl-2-indoline-6-carboxylic acid (35-2) was the same as compound 1-5. LCMS (ESI) m / z [M+H] + :399.2.

[0427] Step ③: 1-((1-(3-fluoro-5-methoxyphenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-35)

[0428] The preparation of 1-((1-(3-fluoro-5-methoxyphenyl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-35) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.12(s,1H),7.82(d,J=8.0Hz,1H),7.78(d,J=2.5Hz,1H ),7.71(d,J=9.1Hz,2H),7.52(d,J=7.5Hz,1H),7.37(d,J=8.1Hz,1H),7.12(t,J=7.5Hz,1H),7.0 0(t,J=7.5Hz,1H),6.07(d,J=11.1Hz,1H),5.82(d,J=11.0Hz,1H),5.75(s,1H),4.07(d,J=7.5Hz ,2H),3.89(t,J=7.7Hz,2H),3.69(s,3H),3.63(t,J=6.4Hz,2H),3.15-3.23(m,1H),1.32(s,6H).

[0429] Example 36 1-((1-(Benzofuran-6-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-36)

[0430] Step ①: (1-(Benzofuran-6-yl)azetidin-3-yl)methanol (36-1)

[0431] The preparation of (1-(benzofuran-6-yl)azetidin-3-yl)methanol (36-1) was the same as compound 9-1. 1 H NMR (400MHz, CDCl3) δ7.44(d,J=2.2Hz,1H),7.40(d,J=8.3Hz,1H),6.64(dd,J=2.2,0.9Hz,1H),6.57(d,J=2.0Hz,1H),6 .44(dd,J=8.4,2.0Hz,1H),3.97(t,J=7.5Hz,2H),3.89(d,J=6.5Hz,2H),3.69(dd,J=7.1,5.0Hz,2H),2.98–2.84(m,1H).

[0432] Step ②: Methyl (1-(benzofuran-6-yl)azetidin-3-yl)methanesulfonate (36-2)

[0433] The preparation of methyl (1-(benzofuran-6-yl)azetidin-3-yl)methanesulfonate (36-2) was the same as compound 25-2. 1H NMR (400MHz, CDCl3) δ7.45(d,J=2.2Hz,1H),7.41(d,J=8.3Hz,1H),6.65(t,J=1.5Hz,1H),6.57(s,1H),6.46–6.39(m,1 H), 4.48 (d, J = 7.0Hz, 2H), 4.02 (t, J = 7.6Hz, 2H), 3.72 (dd, J = 7.4, 5.0Hz, 2H), 3.13 (q, J = 7.2, 5.3Hz, 1H), 3.05 (s, 3H).

[0434] Step ③: 1-((1-(Benzofuran-6-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid methyl ester (36-3)

[0435] The preparation of methyl 1-((1-(benzofuran-6-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylate (36-3) was the same as compound 25-3. 1 H NMR (400MHz, DMSO-d6) δ7.74–7.68(m,2H),7.64(s,1H),7.52(d,J=7.7Hz,1H),7.40(d,J=8.3Hz,1H),6.76(d,J=2.2Hz,1H),6.56(s ,1H),6.38(dd,J=8.3,1.7Hz,1H),4.07(d,J=7.4Hz,2H),3.83–3.90(m,5H),3.61(t,J=6.3Hz,2H),3.07-3.14(m,1H),1.30(s,6H).

[0436] Step ④: 1-((1-(Benzofuran-6-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (36-4)

[0437] The preparation of 1-((1-(benzofuran-6-yl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (36-4) was the same as compound 9-3. LCMS (ESI) m / z [M+H] + :391.2.

[0438] Step ⑤: 1-((1-(Benzofuran-6-yl)azetidin-3-yl)methyl-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-36)

[0439] The preparation of 1-((1-(benzofuran-6-yl)azetidin-3-yl)methyl-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-36) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.12(s,1H),7.83(d,J=8.0Hz,1H),7.80–7.77(m,1H),7.72(d,J=8.4Hz,3H),7.52( d,J=7.5Hz,1H),7.39(dd,J=14.1,8.2Hz,2H),7.11(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),6.76(d,J=2.2Hz,1H),6.58(s, 1H), 6.41 (d, J = 8.4Hz, 1H), 4.09 (d, J = 7.4Hz, 2H), 3.92 (t, J = 7.5Hz, 2H), 3.66 (t, J = 6.3Hz, 2H), 3.28–3.16 (m, 1H), 1.33 (s, 6H).

[0440] Example 37 1-((1-cyclopropylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-37)

[0441] Example 38 1-((1-(Furan-2-yl)azetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-38)

[0442] Example 39 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-(thien-2-yl)azetidin-3-yl)methyl)indoline-6-carboxamide (I-39)

[0443] Example 40 1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide (I-40)

[0444] Step ①: 5-bromo-1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (40-1)

[0445] The preparation of 5-bromo-1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethylindolin-2-one (40-1) was the same as compound 9-2. 1 H NMR (400MHz, CDCl3) δ7.40(dd,J=8.3,2.0Hz,1H),7.34(d,J=2.0Hz,1H),6.77(d,J=8.3Hz,1H),6.64(d,J=8.7Hz,1H),6.38(d ,J=10.2Hz,1H),6.21(dt,J=10.4,2.2Hz,1H),4.05-3.91(m,4H),3.73(dd,J=7.4,5.1Hz,2H),3.23-3.13(m,1H),1.37(s,6H).

[0446] Step ②: 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-5-carbonitrile (40-2)

[0447] The preparation of 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-5-carbonitrile (40-2) was the same as compound 11-2. 1 H NMR (400MHz, CDCl3) δ7.61(dd,J=8.2,1.7Hz,1H),7.48(d,J=1.6Hz,1H),6.97(d,J=8.2Hz,1H),6.66(d,J=8.4Hz,1H),6.37(s,1H),6.22(d t,J=10.6,2.3Hz,1H),4.05(d,J=7.5Hz,2H),3.98(t,J=7.6Hz,2H),3.74(dd,J=7.5,5.0Hz,2H),3.17(tt,J=7.6,5.0Hz,1H),1.40(s,6H).

[0448] Step ③: 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-5-carboxylic acid (40-3)

[0449] The preparation of 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-5-carboxylic acid (40-3) was the same as compound 11-3. LCMS (ESI) m / z [M+H] + :437.1.

[0450] Step ④: 1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide (I-40)

[0451] 1-((1-(3-Fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide (I-40). 1 H NMR (400MHz, CDCl3) δ8.09(s,1H),7.97(d,J=2.5Hz,1H),7.93(s,1H),7.87(d,J=6.9Hz,2H ),7.59(d,J=7.8Hz,1H),7.42(d,J=8.1Hz,1H),7.24(s,1H),7.16-7.18(m,1H),7.00(d,J=8 .6Hz,1H),6.66(d,J=8.5Hz,1H),6.39(s,1H),6.23(dt,J=10.5,2.3Hz,1H),4.08(d,J=7.4 Hz,2H),4.00(t,J=7.6Hz,2H),3.77(dd,J=7.4,5.1Hz,2H),3.29–3.17(m,1H),1.44(s,6H).

[0452] Example 41 1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-41)

[0453] Step ①: (1-(3-Fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methanol (41-1)

[0454] 1 g of 3-hydroxymethyltetrahydropyrrolidine, 2.2 g of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene, 82 mg of tris(dibenzylidene-base acetone)dipalladium, 165 mg of S-(-)-1,1'-binaphthyl-2,2'-bisdiphenylphosphine, and 3 g of potassium tert-butoxide were dissolved in 30 ml of toluene. 1 ml of triethylamine was then added and stirred at 110°C for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (80:20) to obtain 725 mg of (1-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methanol (41-1) as a yellow oil in a 31% yield. 1H NMR (400MHz, DMSO-d6) δ6.67(dt,J=8.8,2.0Hz,1H),6.59-6.53(m,2H),4.72(t,J=5.3Hz,1H),3.47-3.33(m,4H),3 .31-3.24(m,1H),3.03-3.09(m,1H),2.40-2.47(m,1H),1.97-2.07(m,1H),1.70-1.80(m,1H).LRMS(ESI)m / z[M+H] + :264.1.

[0455] Step ②: 3-(Chloromethyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidine (41-2)

[0456] 600 mg of compound 41-1 was dissolved in 5 ml of dichloromethane. 661 μL of thionyl chloride was then added dropwise under ice-cooling, and the mixture was stirred at room temperature for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography with ethyl acetate to obtain 138 mg of 3-(chloromethyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidine (41-2) as a yellow oil, with a yield of 21%. 1 H NMR (400MHz, DMSO-d6) δ6.71(d,J=8.7Hz,1H),6.60(dt,J=14.1,2.1Hz,2H),3.74(dd,J=6.8,1.7Hz,2H),3.45-3.52(m, 1H),3.38-3.44(m,,1H),3.26-3.31(m,1H),3.08-3.15(m,1H),2.67-2.77(m,1H),2.20-2.12(m,1H),1.77-1.87(m,1H).

[0457] Step ③: 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (41-3)

[0458] The preparation method of methyl 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)-3,3-dimethyl-2-oxoindolin-6-carboxylate (41-3) is the same as compound 1-4. 1H NMR(400MHz, CDCl3) δ7.81(dd,J=7.7,1.4Hz,1H),7.49(d,J=1.4Hz,1H),7.30(d,J=7.7Hz,1H), 6.59(dt,J=8.7,1.9Hz,1H),6.49(t,J=1.9Hz,1H),6.32(dt,J=11.7,2.3Hz,1H),3.95-3.80(m, 4H),3.74-3.81(m,1H),3.45-3.53(m,1H),3.40-3.45(m,1H),3.27-3.35(m,1H),3.17-3.22(m, 1H),2.85-2.95(m,1H),2.08-2.18(m,1H),1.85-1.95(m,1H),1.41(s,6H).LRMS(ESI)m / z[M+H] + :465.2

[0459] Step ④: 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (41-4)

[0460] The preparation method of 1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)pyrrolidin-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (41-4) is the same as compound 1-5. 1 H NMR (400MHz, DMSO-d6) δ12.99 (s, 1H), 7.69 (dd, J = 7.7, 1.4Hz, 1H), 7.61 (d, J = 1. 4Hz,1H),7.50(d,J=7.7Hz,1H),6.69(d,J=8.8Hz,1H),6.54(dd,J=10.5,2.2Hz, 2H),3.89-3.76(m,2H),3.37-3.47(m,2H),3.08-3.14(m,1H),2.75-2.85(m,1H) ,2.00-2.10(m,1H),1.70-1.80(m,1H),1.32(d,J=1.7Hz,6H),1.20-1.25(m,1H).

[0461] Step ⑤: 1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-41)

[0462] The preparation method of 1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-41) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),10.12(s,1H),7.82(d,J=8.0Hz,1H),7.77(d,J=2.5Hz,1H),7.75-7.69 (m,2H),7.54(d,J=7.6Hz,1H),7.37(d,J=8.1Hz,1H),7.11(t,J=7.4Hz,1H),7.00(t,J=7.5Hz,1H),6.69(d,J= 8.6Hz,1H),6.57(dd,J=11.1,2.1Hz,2H),3.80-3.90(m,2H),3.40-3.50(m,2H),3.31-3.25(m,1H),3.10-3.2 0(m,1H),2.85-2.95(m,1H),2.00-2.10(m,1H),1.75-1.85(m,1H),1.35(d,J=1.8Hz,6H).LRMS(ESI)m / z[M+H] + :565.0.

[0463] Example 42 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-phenylpyrrol-3-yl)methyl)indoline-6-carboxamide (I-42)

[0464] Step ①: (1-phenylpyrrolidin-3-yl)methanol (42-1)

[0465] A mixture of 1 g of 3-hydroxymethyltetrahydropyrrolidine, 2.2 g of iodobenzene, 1.9 g of cuprous iodide, 1.14 g of L-proline, 4.1 g of potassium carbonate, and 10 ml of dimethyl sulfoxide was stirred at 90°C for 12 hours. Water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was concentrated to dryness. The residue was purified by column chromatography using petroleum ether:ethyl acetate (80:20) to obtain 795 mg of (1-phenylpyrrolidin-3-yl)methanol (42-1) as a purple oil, in a 45% yield. 1H NMR (400MHz, DMSO-d6) δ7.14(t,J=7.9Hz,2H),6.56(t,J=7.2Hz,1H),6.50(d,J=8.1Hz,2H),4.69(t,J=5.2Hz,1H),3.47-3.3 4(m,2H),3.31-3.15(m,3H),2.95-3.05(m,1H),2.35-2.45(m,1H),1.95-2.05(m,1H),1.68-1.78(m,1H).LRMS(ESI)m / z[M+H] + :178.2.

[0466] Step ②: 3-(Chloromethyl)-1-phenylpyrrolidine (42-2)

[0467] A mixture of 875 mg of compound 42-1, 1.4 g of triphenylphosphine, 952 μL of carbon tetrachloride, and 15 mL of dichloromethane was stirred at room temperature for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (90:10) to obtain 716 mg of 3-(chloromethyl)-1-phenylpyrrolidine (42-2) as a purple oil, in a 74% yield. 1 H NMR (400MHz, DMSO-d6) δ7.19-7.12(m,2H),6.59(tt,J=7.3,1.2Hz,1H),6.55-6.49(m,2H),3.71-3.76(m,2H),3.40(dd,J=9.5,7.5Hz,1H),3. 36-3.32(m,1H),3.20-3.28(m,1H),3.05(dd,J=9.6,6.8Hz,1H),2.65-2.75(m,1H),2.10-2.20(m,1H),1.75-1.88(m,1H).LRMS(ESI)m / z[M+H] + :196.1.

[0468] Step ③: 3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (42-3)

[0469] 2 g of methyl 2-oxoindoline-6-carboxylate and 6.8 g of cesium carbonate were dissolved in 40 ml of anhydrous dimethyl sulfoxide. Under an argon atmosphere, 1.3 ml of iodomethane was slowly added dropwise and stirred at room temperature for 0.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic phase was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (90:10) to obtain 1.2 g of methyl 3,3-dimethyl-2-oxoindoline-6-carboxylate (42-3) as a white solid, in a 52% yield. 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),7.62(dd,J=7.7,1.2Hz,1H),7.44(d,J=7.7Hz,1H),7.38-7.36(m,1H),3.84(s,3H),1.27(s,6H).

[0470] Step ④: 3,3-Dimethyl-2-oxo-1-((1-phenylpyrrolidin-3-yl)methyl)dihydroindole-6-carboxylic acid methyl ester (42-4)

[0471] The preparation of methyl 3,3-dimethyl-2-oxo-1-((1-phenylpyrrolidin-3-yl)methyl)dihydroindole-6-carboxylate (42-4) was the same as compound 1-4. 1 H NMR(400MHz, CDCl3)δ7.80(dd,J=7.7,1.4Hz,1H),7.53-7.51(m,2H),7.29(d,J=7.7Hz,1H),7.24-7.19(m,2 H),6.67(tt,J=7.3,1.1Hz,1H),6.54(d,J=7.9Hz,2H),3.96-3.91(m,1H),3.90(s,3H),3.77(dd,J=14.1,7. 0Hz,1H),3.53-3.44(m,1H),3.41(dd,J=9.3,7.1Hz,1H),3.30(dt,J=9.2,7.3Hz,1H),3.18(dd,J=9.3,6.3H z,1H),2.93-2.81(m,1H),2.14-2.03(m,1H),1.86(dq,J=12.4,7.6Hz,1H),1.41(s,6H).LRMS(ESI)m / z[M+H] + :379.2

[0472] Step ⑤: 3,3-Dimethyl-2-oxo-1-((1-phenylpyrrolidin-3-yl)methyl)dihydroindole-6-carboxylic acid (42-5)

[0473] The preparation of 3,3-dimethyl-2-oxo-1-((1-phenylpyrrolidin-3-yl)methyl)dihydroindole-6-carboxylic acid (42-5) was the same as compound 1-5. 1H NMR (400MHz, DMSO-d6) δ13.00 (s, 1H), 7.70 (dd, J=7.7, 1.4Hz, 1H), 7.62 (d, J= 1.4Hz,1H),7.53-7.48(m,1H),7.19-7.09(m,2H),6.57(t,J=7.3Hz,1H),6.48( d,J=8.1Hz,2H),3.84(d,J=7.6Hz,2H),3.27-3.15(m,2H),3.06(dd,J=9.5,6.3 Hz,1H),2.84-2.74(m,1H),2.08-1.96(m,1H),1.80-1.69(m,1H),1.32(s,7H).

[0474] Step ⑥: N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-phenylpyrrol-3-yl)methyl)indoline-6-carboxamide (I-42)

[0475] The preparation of N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-phenylpyrrol-3-yl)methyl)indoline-6-carboxamide (I-42) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.12(s,1H),7.82(d,J=7.9Hz,1H),7.77(d,J=2.5Hz,1H),7.75-7.6 6(m,2H),7.54(d,J=7.6Hz,1H),7.37(d,J=8.2Hz,1H),7.20-7.07(m,3H),7.01(td,J=7.4,1.0Hz,1H),6.57( t,J=7.2Hz,1H),6.50(d,J=8.1Hz,2H),3.82-3.92(m,2H),3.34-3.41(m,2H),3.20-3.26(m,1H),3.06-3.12 (m,1H),2.87-2.95(m,1H),2.00-2.10(m,1H),1.73-1.83(m,1H),1.35(s,6H).LRMS(ESI)m / z[M+H]+:479.3.

[0476] Example 43 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-phenylpiperidin-4-yl)methyl)indoline-6-carboxamide (I-43)

[0477] Step ①: (1-phenylpiperidin-4-yl)methanol (43-1)

[0478] The preparation method of (1-phenylpiperidin-4-yl)methanol (43-1) is the same as compound 42-1. 1 H NMR (400MHz, DMSO-d6) δ7.18(t,J=7.9Hz,2H),6.91(d,J=8.2Hz,2H),6.72(t,J=7.2Hz,1H),4.46(t,J=5.4Hz,1H),3.68(dt,J=12.6,3.5Hz,2H), 3.28(t,J=5.7Hz,2H),2.61(td,J=12.3,2.6Hz,2H),1.73(d,J=12.5Hz,2H),1.44-1.54(m,1H),1.22(qd,J=12.4,4.0Hz,2H).LRMS(ESI)m / z[M+H] + :192.1.

[0479] Step ②: 6-bromo-3,3-dimethyl-1-((1-phenylpiperidin-4-yl)methyl)indolin-2-one (43-2)

[0480] The preparation of 6-bromo-3,3-dimethyl-1-((1-phenylpiperidin-4-yl)methyl)indolin-2-one (43-2) was the same as compound 9-2. 1 H NMR (400MHz, CD3OD) δ7.27-7.18(m,5H),6.99-6.95(m,2H),6.82(t,J=7.3Hz,1H),3.70-3.62(m,4H),2.65(td,J=12.2 ,2.5Hz,2H),1.90-2.00(m,1H),1.75(d,J=12.6Hz,2H),1.50(td,J=12.0,3.4Hz,2H),1.35(s,6H).LRMS(ESI)m / z[M+H] + :413.1.

[0481] Step ③: 6-cyano-3,3-dimethyl-1-((1-phenylpiperidin-4-yl)methyl)indolin-2-one (43-3)

[0482] The preparation of 6-cyano-3,3-dimethyl-1-((1-phenylpiperidin-4-yl)methyl)indolin-2-one (43-3) was the same as compound 11-2. 1H NMR (400MHz, CD3OD-d4) δ7.49(dd,J=11.6,7.7Hz,3H),7.21(t,J=8.0Hz,2H),6.97(d,J=8.1Hz,2H),6.81(t,J=7.4Hz,1H),3.72(d,J=7.3Hz,2H),3.66( d,J=12.2Hz,2H),2.65(t,J=12.1Hz,2H),1.75(d,J=12.1Hz,2H),1.50(td, J=12.2,3.8Hz,2H),1.39(s,6H),1.24(t,J=7.2Hz,1H).LRMS(ESI)m / z[M+H] + :360.2.

[0483] Step ④: 3,3-Dimethyl-2-oxo-1-((1-phenylpiperidin-4-yl)methyl)dihydroindole-6-carboxylic acid (43-4)

[0484] The preparation method of 3,3-dimethyl-2-oxo-1-((1-phenylpiperidin-4-yl)methyl)dihydroindole-6-carboxylic acid (43-4) is the same as compound 11-3. 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),7.69(dd,J=7.7,1.4Hz,1H),7.58(d,J=1.4Hz,1H),7.50(d,J=7.7Hz,1H),7.30(s,5H),3 .69(d,J=7.2Hz,2H),3.63(d,J=11.9Hz,2H),1.99(s,2H),1.74(s,2H),1.31(s,6H),1.26-1.21(m,1H),1.17(t,J=7.1Hz,2H).

[0485] Step ⑤: N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-phenylpiperidin-4-yl)methyl)indoline-6-carboxamide (I-43)

[0486] The preparation method of N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-phenylpiperidin-4-yl)methyl)indoline-6-carboxamide (I-43) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.12(s,1H),7.83(d,J=7.9Hz,1H),7.78(d,J=2.5Hz,1H),7.72(dd,J=7.7,1.4Hz ,1H),7.63(d,J=1.6Hz,1H),7.52(d,J=7.7Hz,1H),7.37(d,J=8.1Hz,1H),7.20-7.15(m,2H),7.11(t,J=7.4 Hz,1H),7.01(t,J=7.5Hz,1H),6.91(d,J=8.2Hz,2H),6.72(t,J=7.2Hz,1H),3.73-3.65(m,4H),2.63(t,J=1 2.0Hz,2H),2.08-1.97(m,1H),1.68(d,J=12.7Hz,2H),1.43-1.35(m,2H),1.34(s,6H).LRMS(ESI)m / z[M+H] + :493.3.

[0487] Example 44 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-(thien-3-yl)pyrrol-3-yl)methyl)indoline-6-carboxamide (I-44)

[0488] Step ①: (1-(Thien-3-yl)pyrrolidin-3-yl)methanol (44-1)

[0489] A mixture of 1.4 g of 3-hydroxymethyltetrahydropyrrolidine, 2 g of 3-iodothiophene, 182.3 mg of cuprous iodide, 6.2 g of cesium carbonate, 641 mg of 2-isobutyrylcyclohexanone, and 10 ml of N,N-dimethylformamide was stirred at room temperature for 12 hours under an argon atmosphere. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (80:20) to obtain 1.4 g of (1-(thiophen-3-yl)pyrrolidin-3-yl)methanol (44-1) as a red oil, with a yield of 80%. 1 H NMR (400MHz, DMSO-d6) δ7.35 (dd, J=5.2, 3.1Hz, 1H), 6.71 (dd, J=5.1, 1.5Hz, 1H), 5.87 (dd, J=3.1, 1.5Hz, 1H), 4.67(t,J=5.2Hz,1H),3.44-3.36(m,2H),3.26-3.09(m,3H),2.91-2.96(m,1H),2.30-2.45(m,1H),1.92-2.02(m,1H),1.61-1.71(m,1H).

[0490] Step ②: Methyl (1-(thiophen-3-yl)pyrrolidin-3-yl)4-methylbenzenesulfonate (44-2)

[0491] 500 mg of compound 44-1 and 33.3 mg of 4-dimethylaminopyridine were dissolved in 8 mL of dichloromethane. 1.1 mL of triethylamine was then added dropwise, followed by 624 mg of p-toluenesulfonyl chloride, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate (80:20) to obtain 355 mg of methyl (1-(thiophen-3-yl)pyrrolidin-3-yl)-4-methylbenzenesulfonate (44-2) as a pink solid, in a 38% yield. 1 H NMR (400MHz, DMSO-d6) δ7.81(d,J=8.1Hz,2H),7.48(d,J=8.0Hz,2H),7.35(dd,J=5.1,3.1Hz,1H),6.67(dd,J=5.2,1.5Hz,1H),3.98-4.08( m,3H),3.24-3.02(m,4H),2.80-2.87(m,1H),2.59(p,J=7.1Hz,1H),2.42(s,3H),1.94-2.04(m,1H),1.67-1.53(m,1H).LRMS(ESI)m / z[M+H] + :338.1.

[0492] Step ③: 3,3-Dimethyl-2-oxo-1-((1-(thien-3-yl)pyrrolidin-3-yl)methyl)dihydroindole-6-carboxylic acid methyl ester (44-3)

[0493] The preparation method of methyl 3,3-dimethyl-2-oxo-1-((1-(thien-3-yl)pyrrolidin-3-yl)methyl)dihydroindole-6-carboxylate (44-3) is the same as compound 1-4. 1H NMR (400MHz, DMSO-d6) δ7.71(dd,J=7.7,1.4Hz,1H),7.61(d,J=1.4Hz,1H),7.53(d,J=7.7Hz,1H ),7.36(dd,J=5.1,3.1Hz,1H),6.68(dd,J=5.2,1.5Hz,1H),5.87(dd,J=3.1,1.5Hz,1H),3.85(s ,3H),3.79-3.83(m,2H),3.32-3.28(m,1H),3.22-3.26(m,1H),3.10-3.17(m,1H),2.98-3.04(m ,1H),2.72-2.80(m,1H),1.93-2.03(m,1H),1.65-1.75(m,1H),1.32(s,6H).LRMS(ESI)m / z[M+H] + :385.3.

[0494] Step ④: 3,3-Dimethyl-2-oxo-1-((1-(thien-3-yl)pyrrolidin-3-yl)methyl)dihydroindole-6-carboxylic acid (44-4)

[0495] The preparation method of 3,3-dimethyl-2-oxo-1-((1-(thien-3-yl)pyrrolidin-3-yl)methyl)dihydroindole-6-carboxylic acid (44-4) is the same as compound 1-5. 1 H NMR (400MHz, DMSO-d6) δ12.99(s,1H),7.69(dd,J=7.7,1.4Hz,1H),7.60(d,J=1.4Hz,1 H),7.50(d,J=7.7Hz,1H),7.35(dd,J=5.2,3.1Hz,1H),6.68(dd,J=5.1,1.5Hz,1H),5. 87(dd,J=3.2,1.5Hz,1H),3.75-3.85(m,2H),3.22-3.32(m,2H),3.18-3.10(m,1H),2. 95-3.05(m,1H),2.70-2.80(m,1H),1.95-2.05(m,1H),1.65-1.75(m,1H),1.32(s,6H).

[0496] Step ⑤: N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-(thien-3-yl)pyrrol-3-yl)methyl)indoline-6-carboxamide (I-44)

[0497] The preparation method of N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((1-(thiophen-3-yl)pyrrol-3-yl)methyl)indoline-6-carboxamide (I-44) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),10.12(s,1H),7.82(d,J=8.0Hz,1H),7.77(d,J=2.5Hz,1H),7.72(dd,J=7. 7,1.5Hz,1H),7.68(s,1H),7.53(d,J=7.6Hz,1H),7.40-7.33(m,2H),7.11(t,J=7.5Hz,1H),7.01(t,J=7.5Hz,1H) ,6.70(dd,J=5.2,1.5Hz,1H),5.89(dd,J=3.2,1.5Hz,1H),3.81-3.88(m,2H),3.27-3.30(m,2H),3.15-3.20(m,1 H),3.02-3.07(m,1H),2.85-2.97(m,1H),1.97-2.06(m,1H),1.68-1.78(m,1H),1.35(s,6H).LRMS(ESI)m / z[M+H] + :485.2.

[0498] Example 45 N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-4-((1-phenylazetidin-3-yl)methyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-45)

[0499] Example 46 1-(1-benzylazetidin-3-yl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-46)

[0500] Example 47 1-(1-benzylazetidin-3-yl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide (I-47)

[0501] Example 48 1'-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-2'-oxospiro[cyclopropane-1,3'-indoline]-6'-carboxamide (I-48)

[0502] Example 49 1-((1-benzylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-49)

[0503] Example 50 1-((1-benzylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-5-carboxamide (I-50)

[0504] Example 51 1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3-methyl-2-oxoindoline-6-carboxamide (I-51)

[0505] Example 52 1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-3-methylene-2-oxoindoline-6-carboxamide (I-52)

[0506] Example 53 3,3-Dichloro-1-((1-(3-fluoro-5-trifluoromethylphenylazetidin-3-yl)methyl)-N-(1H-indol-3-yl)-2-oxoindoline-6-carboxamide (I-53)

[0507] Example 54 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-((2-oxo-1-phenylazetidin-3-yl)methyl)indoline-6-carboxamide (I-54)

[0508] Example 55 N-(1H-indol-3-yl)-3-oxo-4-(thien-3-ylmethyl)-3,4-dihydro-2H-benzothiophene[b][1,4]thiazine-6-carboxamide (I-55)

[0509] Step ①: 3-O-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzothiophene[b][1,4]thiazine-6-carboxylic acid methyl ester (55-1)

[0510] The preparation of 3-oxo-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzothiophene[b][1,4]thiazine-6-carboxylic acid methyl ester (55-1) was the same as compound 2-3 with a yield of 54%. 1H NMR(400MHz,DMSO-d6)δ7.71(s,1H),7.59-7.54(m,2H),7.54-7.46(m,1H),7.29-7.24(m ,1H),6.99(d,J=4.9Hz,1H),5.19(s,2H),3.80(s,3H),3.73(s,2H).LRMS(ESI)m / z[M+H] + 320.1.

[0511] Step ②: 3-Oxo-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (55-2)

[0512] The preparation of 3-oxo-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (55-2) was similar to that of compound 1-5, with a yield of 91%. 1 H NMR(400MHz, DMSO-d6)δ13.04(s,1H),7.70(s,1H),7.63-7.44(m,3H),7.29(s,1H),7.00(d,J=5.0Hz,1H),5.19(s,2H),3.73(s,2H).LRMS(ESI)m / z[MH] - 304.0.

[0513] Step ③: N-(1H-indol-3-yl)-3-oxo-4-(thien-3-ylmethyl)-3,4-dihydro-2H-benzothiophene[b][1,4]thiazine-6-carboxamide (I-55)

[0514] The preparation of N-(1H-indol-3-yl)-3-oxo-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzothiophene[b][1,4]thiazine-6-carboxamide (I-55) was the same as compound I-1, with a yield of 68%. 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),10.18(s,1H),7.83-7.75(m,3H),7.70(d,J=7.4Hz,1H),7.58(d,J=8.1Hz ,1H),7.56-7.49(m,1H),7.38-7.33(m,2H),7.12(t,J=7.5Hz,1H),7.05-6.98(m,2H),5.29(s,2H),3.72(s,2H).

[0515] Example 56 4-(Furan-3-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-56)

[0516] Step ①: 4-(Furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (56-1)

[0517] The preparation of methyl 4-(furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (56-1) was similar to that of compound 2-3, with a yield of 41%. 1 H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.66-7.46(m,4H),6.37(s,1H),5.05(s,2H),3.84(s,3H),3.70(s,2H).LRMS(ESI)m / z[M+H] + 304.1.

[0518] Step ②: 4-(Furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (56-2)

[0519] The preparation of 4-(furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (56-2) was similar to that of compound 1-5, with a yield of 76%. 1 H NMR(400MHz,DMSO-d6)δ13.12(s,1H),7.77(s,1H),7.64-7.60(m,1H),7.60-7.50(m,3H),6.37(s,1H),5.04(s,2H),3.69(s,2H).LRMS(ESI)m / z[MH] - 288.0.

[0520] Step ③: 4-(Furan-3-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-56)

[0521] The preparation of 4-(furan-3-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-56) was the same as compound I-1, with a yield of 83%. 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.21(s,1H),7.88-7.74(m,3H),7.71(d,J=8.0Hz,1H),7.63-7.53(m,3 H),7.37(d,J=8.2Hz,1H),7.12(t,J=7.5Hz,1H),7.03(t,J=7.5Hz,1H),6.40(s,1H),5.13(s,2H),3.68(s,2H).

[0522] Example 57 4-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]triazine-6-carboxamide (I-57)

[0523] Step ①: 4-(Benzofuran-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (57-1)

[0524] The preparation of 4-(Benzofuran-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (57-1) was similar to that of compound 2-3, with a yield of 57%. 1 H NMR(400MHz,DMSO-d6)δ7.99-7.92(m,1H),7.75-7.63(m,1H),7.61-7.44(m,4H),7.20(d,J =8.9Hz,1H),6.97-6.86(m,1H),5.34(s,2H),3.79(s,2H),3.76(s,3H).LRMS(ESI)m / z[M+H] + 354.2.

[0525] Step ②: 4-(Benzofuran-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (57-2)

[0526] The preparation of 4-(Benzofuran-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (57-2) was similar to that of compound 1-5, with a yield of 54%. 1H NMR(400MHz,DMSO-d6)δ12.62(s,1H),8.25-7.82(m,1H),7.67(s,1H),7.60-7.51(m,3H), 7.48(s,1H),7.20(d,J=8.5Hz,1H),6.91(s,1H),5.34(s,2H),3.79(s,2H).LRMS(ESI)m / z 338.1.

[0527] Step ③: 4-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-57)

[0528] The preparation of 4-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-57) was the same as compound I-1, with a yield of 40%. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.14(s,1H),7.99-7.95(m,1H),7.79-7.71(m,3H),7.68(d,J=8.1Hz,1H),7.63-7.53(m,3H),7 .35(d,J=8.1Hz,1H),7.25(d,J=8.7Hz,1H),7.11(t,J=7.6Hz,1H),7.02(t,J=7.4Hz,1H),6.91-6.88(m,1H),5.43(s,2H),3.79(s,2H).

[0529] Example 58 4-(Benzo[d][1,3]dioxolan-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-58)

[0530] Step ①: 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (58-1)

[0531] The preparation of 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (58-1) was the same as compound 2-3 with a yield of 97%. 1H NMR(400MHz,DMSO-d6)δ7.67(s,1H),7.56(s,2H),6.89-6.83(m,1H),6.77-6.75(m,1H),6.7 0(d,J=7.9Hz,1H),5.97(s,2H),5.16(s,2H),3.80(s,3H),3.75(s,2H).LRMS(ESI)m / z358.1.

[0532] Step ③: 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (58-2)

[0533] The preparation of 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (58-2) was similar to that of compound 1-5 with a yield of 94%. 1 H NMR (400MHz, DMSO-d6) δ7.65(s,1H),7.54(q,J=7.9Hz,2H),6.85(d,J=7.8Hz,1H),6.76( s,1H),6.69(d,J=8.0Hz,1H),5.98(s,2H),5.14(s,2H),3.74(s,2H).LRMS(ESI)m / z[MH] - 342.0.

[0534] Step ③: 4-(Benzo[d][1,3]dioxolan-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-58)

[0535] The preparation of 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-58) was the same as compound I-1, with a yield of 55%. 1H NMR (400MHz, DMSO-d6) δ10.94(s,1H),10.16(s,1H),7.80-7.74(m,3H),7.70(d,J=8.1Hz,1H),7.58(d,J=8.0Hz,1H),7.36(d,J=8.2H z,1H),7.12(t,J=7.7Hz,1H),7.02(t,J=7.4Hz,1H),6.87-6.80(m,2H),6.76(d,J=8.2Hz,1H),5.97(s,2H),5.25(s,2H),3.75(s,2H).

[0536] Example 59 N-(1H-indol-3-yl)-3-oxo-4-(thien-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-59)

[0537] Step ①: 3-Oxo-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (59-1)

[0538] The preparation of methyl 3-oxo-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (59-1) was similar to compound 2-3 with a yield of 98%. 1 H NMR (400MHz, DMSO-d6) δ7.91 (s, 1H), 7.71-7.48 (m, 2H), 7.41 (d, J = 5.0Hz, 1H), 7.12-6.99 (m,1H),6.95(t,J=4.4Hz,1H),5.40(s,2H),3.84(s,3H),3.69(s,2H).LRMS(ESI)m / z[M+H] + 320.2.

[0539] Step ②: 3-Oxo-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (59-2)

[0540] The preparation of 3-oxo-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (59-2) was the same as compound 1-5, with a yield of 73%. LRMS (ESI) m / z [MH] - 304.1.

[0541] Step ③: N-(1H-indol-3-yl)-3-oxo-4-(thien-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-59)

[0542] The preparation of N-(1H-indol-3-yl)-3-oxo-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-59) was the same as compound I-1, with a yield of 44%. 1 H NMR(600MHz,DMSO-d6)δ10.94(s,1H),10.19(s,1H),7.99(d,J=1.7Hz,1H),7.8 2(d,J=8.0Hz,1H),7.79(d,J=2.5Hz,1H),7.70(dd,J=8.0,1.6Hz,1H),7.57(d,J =8.0Hz,1H),7.41(d,J=5.1,1.2Hz,1H),7.37(d,J=8.1Hz,1H),7.15-7.10(m,2 H),7.03(t,J=7.4Hz,1H),6.95(t,J=5.1,3.5Hz,1H),5.49(s,2H),3.69(s,2H).

[0543] Example 60 4-(Furan-2-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-60)

[0544] Step ①: 4-(Furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (60-1)

[0545] The preparation of methyl 4-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (60-1) was the same as compound 9-2, with a yield of 66%. 1 H NMR(400MHz,DMSO-d6)δ7.92(d,J=1.6Hz,1H),7.64-7.53(m,3H),6.43-6.35(m,1H) ,6.29(d,J=2.7Hz,1H),5.21(s,2H),3.85(s,3H),3.67(s,2H).LRMS(ESI)m / z[M+H] + 304.0.

[0546] Step ②: 4-(Furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (60-2)

[0547] The preparation of 4-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (60-2) was the same as compound 1-5, with a yield of 79%. LRMS (ESI) m / z [MH] - 288.0.

[0548] Step ③: 4-(Furan-2-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-60)

[0549] The preparation of 4-(furan-2-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-60) was the same as compound I-1, with a yield of 30%. 1 H NMR(400MHz,DMSO-d6)δ10.94(s,1H),10.20(s,1H),7.99(s,1H),7.83-7.76(m,2H),7.75-7.69(m,1H),7.63-7.53(m,2H),7.37 (d,J=8.2Hz,1H),7.12(t,J=7.6Hz,1H),7.02(t,J=7.5Hz,1H),6.43-6.37(m,1H),6.35-6.31(m,1H),5.29(s,2H),3.66(s,2H).

[0550] Example 61 N-(1H-indol-3-yl)-4-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-61)

[0551] Step ①: 4-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (61-1)

[0552] The preparation of methyl 4-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylate (61-1) was the same as compound 2-3, with a yield of 78%. 1H NMR(400MHz, DMSO-d6)δ8.00(d,J=1.6Hz,1H),7.79-7.37(m,3H),6.04(d,J=2.2 Hz,1H),5.07(s,2H),3.83(s,3H),3.78(s,3H),3.65(s,2H).LRMS(ESI)m / z[M+H] + 318.1.

[0553] Step ②: 4-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (61-2)

[0554] The preparation of 4-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (61-2) was the same as compound 1-5, with a yield of 70%. LRMS (ESI) m / z [M+H] + 304.1.

[0555] Step ③: N-(1H-indol-3-yl)-4-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-61)

[0556] The preparation of N-(1H-indol-3-yl)-4-((1-methyl-1H-pyrazol-3-yl)methyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-61) was the same as compound I-1, with a yield of 63%. 1 H NMR (400MHz, DMSO-d6) δ10.94(s,1H),10.17(s,1H),7.98(s,1H),7.83(d,J=8.0Hz,1H),7.79-7.74(m,1H),7.66(d,J=8.1Hz,1H),7.60-7 .52(m,2H),7.36(d,J=8.1Hz,1H),7.12(t,J=7.5Hz,1H),7.02(t,J=7.5Hz,1H),6.10-5.99(m,1H),5.19(s,2H),3.75(s,3H),3.65(s,2H).

[0557] Example 62 4-(Cyclopropylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-62)

[0558] Step ①: 4-cyclopropylmethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (62-1)

[0559] The preparation of 4-cyclopropylmethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (62-1) was the same as compound 2-3 with a yield of 94%. 1 H NMR (400MHz, DMSO-d6) δ7.88 (s, 1H), 7.65-7.44 (m, 2H), 3.94 (d, J = 6.7Hz, 2H), 3.87 (s, 3H) ,3.59(s,2H),1.38-0.77(m,1H),0.49-0.39(m,2H),0.35-0.22(m,2H).LRMS(ESI)m / z[M+H] + 278.0.

[0560] Step ②: 4-cyclopropylmethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (62-2)

[0561] The preparation of 4-cyclopropylmethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (62-2) was the same as compound 1-5, with a yield of 96%. LRMS (ESI) m / z [M+H] + 264.1.

[0562] Step ③: 4-cyclopropylmethyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-62)

[0563] The preparation of 4-(cyclopropylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-62) was similar to that of compound I-1, with a yield of 42%. 1H NMR (600MHz, DMSO-d6) δ10.94(s,1H),10.22(s,1H),7.96(s,1H),7.83(d,J=8 .0Hz,1H),7.80-7.78(m,1H),7.73(d,J=8.0Hz,1H),7.58(d,J=8.0Hz,1H),7.3 7(d,J=8.2Hz,1H),7.12(t,J=7.5Hz,1H),7.02(t,J=7.5Hz,1H),4.02(d,J=6.8 Hz,2H),3.58(s,2H),1.13-1.03(m,1H),0.53-0.44(m,2H),0.37-0.31(m,2H).

[0564] Example 63 N-(1H-indol-3-yl)-3-oxo-4-(thien-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-63)

[0565] Step ①: 3-O-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid methyl ester (63-1)

[0566] The preparation of methyl 3-oxo-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylate (63-1) was the same as compound 2-3 with a yield of 96%. 1 H NMR(400MHz, DMSO-d6)δ7.93(d,J=2.0Hz,1H),7.77(dd,J=8.6,2.1Hz,1H),7.52-7.44(m,1H),7.35(d,J=8.7Hz, 1H),7.31-7.28(m,1H),6.98(dd,J=5.0,1.3Hz,1H),5.21(s,2H),3.82(s,3H),3.71(s,2H).LRMS(ESI)m / z[M+H] + 320.0.

[0567] Step ②: 3-O-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (63-2)

[0568] The preparation of 3-oxo-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (63-2) was the same as compound 1-5 with a yield of 94%. 1H NMR (400MHz, DMSO-d6) δ7.90 (s, 1H), 7.74 (dd, J = 8.5, 2.0Hz, 1H), 7.55-7.44 (m, 1H), 7 .41-7.14(m,2H),6.98(d,J=5.0Hz,1H),5.21(s,2H),3.70(s,2H).LRMS(ESI)m / z[M+H] + 306.0.

[0569] Step ③: N-(1H-indol-3-yl)-3-oxo-4-(thien-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-63)

[0570] The preparation of N-(1H-indol-3-yl)-3-oxo-4-(thiophen-3-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-63) was the same as compound I-1, with a yield of 33%. 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),10.13(s,1H),8.08(s,1H),7.92-7.81(m,2H),7.7 8(s,1H),7.58-7.48(m,1H),7.44-7.30(m,3H),7.11(t,J=7.3Hz,1H),7.05-6.95(m,2H), 5.26(s,2H),3.73(s,2H).

[0571] Example 64 4-(Furan-3-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-64)

[0572] Step ①: 4-(Furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid methyl ester (64-1)

[0573] The preparation of methyl 4-(furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylate (64-1) was the same as compound 9-2 with a yield of 55%. 1H NMR(400MHz, DMSO-d6)δ7.94(d,J=2.1Hz,1H),7.81(dd,J=8.7,2.1Hz,1H),7.64-7.53(m,2H),7. 42(d,J=8.7Hz,1H),6.36(d,J=1.9Hz,1H),5.06(s,2H),3.83(s,3H),3.67(s,2H).LRMS(ESI)m / z calcd[M+H] + for C 15 H 13 NO4S 304.1,found 304.0.

[0574] Step ②: 4-(Furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (64-2)

[0575] The preparation of 4-(furan-3-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (64-2) was the same as compound 1-5 with a yield of 92%. 1 H NMR (400MHz, DMSO-d6) δ12.51 (s, 1H), 7.97-7.87 (m, 1H), 7.78 (dd, J = 8.6, 2.0Hz, 1H), 7.64-7.53 ( m,2H),7.40(d,J=8.6Hz,1H),6.36(d,J=1.9Hz,1H),5.05(s,2H),3.66(s,2H).LRMS(ESI)m / z[M+H] + 289.9.

[0576] Step ③: 4-(Furan-3-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-64)

[0577] The preparation of 4-(furan-3-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-64) was the same as compound I-1, with a yield of 36%. 1H NMR (600MHz, DMSO-d6) δ10.90(s,1H),10.11(s,1H),8.07(s,1H),7.86(t,J=8.3Hz,2H),7.78(s,1H),7.60(d,J=17.0Hz,2H),7. 45(d,J=8.6Hz,1H),7.35(d,J=8.2Hz,1H),7.11(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),6.37(s,1H),5.10(s,2H),3.68(s,2H).

[0578] Example 65 4-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-65)

[0579] Step ①: 4-(Benzofuran-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid methyl ester (65-1)

[0580] The preparation of methyl 4-(benzofuran-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylate (65-1) was the same as compound 2-3 with a yield of 97%. 1 H NMR (400MHz, DMSO-d6) δ8.00-7.89(m,2H),7.77-7.68(m,1H),7.53(d,J=8.6Hz,1H),7.48(s,1H),7.34(d,J=8 .6,2.1Hz,1H),7.17(d,J=8.5Hz,1H),6.89(s,1H),3.80(s,3H),5.36(s,2H),3.76(s,2H).LRMS(ESI)m / z[M+H] + 354.1.

[0581] Step ②: 4-(Benzofuran-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (65-2)

[0582] The preparation of 4-(Benzofuran-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (65-2) was the same as compound 1-5 with a yield of 96%. 1H NMR (400MHz, DMSO-d6) δ12.87(s,1H),8.04-7.83(m,2H),7.70(dd,J=8.6,2.0Hz,1H),7.54(d,J=8.5Hz,1H),7.51-7.46(m ,1H),7.32(d,J=8.7Hz,1H),7.18(dd,J=8.5,1.9Hz,1H),6.94-6.85(m,1H),5.36(s,2H),3.76(s,2H).LRMS(ESI)m / z[M+H] + 340.1.

[0583] Step ③: 4-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-65)

[0584] The preparation of 4-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-65) was the same as compound I-1, with a yield of 30%. 1 H NMR(600MHz,DMSO-d6)δ10.88(s,1H),10.07(s,1H),8.06(s,1H),8.01-7.93(m,1H) ,7.83(d,J=8.0Hz,1H),7.79(d,J=8.0Hz,1H),7.76-7.74(m,1H),7.55(d,J=8.5Hz,1 H),7.51(s,1H),7.39(d,J=8.6Hz,1H),7.34(d,J=8.2Hz,1H),7.21(d,J=8.6Hz,1H), 7.09(t,J=7.5Hz,1H),6.98(t,J=7.5Hz,1H),6.91(s,1H),5.40(s,2H),3.77(s,2H).

[0585] Example 66 4-(Benzo[d][1,3]dioxolan-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-66)

[0586] Step ①: 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid methyl ester (66-1)

[0587] The preparation of 4-(benzo[d][1,3]dioxolane-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid methyl ester (66-1) was the same as compound 2-3 with a yield of 99%. 1 H NMR (400MHz, DMSO-d6) δ7.94(d,J=2.0Hz,1H),7.75(dd,J=8.7,2.1Hz,1H),7.32(d,J=8.6Hz,1H),6.84(d,J=7.9Hz ,1H),6.76(s,1H),6.69(d,J=8.0Hz,1H),5.97(s,2H),5.18(s,2H),3.82(s,3H),3.74(s,2H).LRMS(ESI)m / z[M+H] + 358.1.

[0588] Step ②: 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (66-2)

[0589] The preparation of 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (66-2) was the same as compound 1-5 with a yield of 92%. 1 H NMR (400MHz, DMSO-d6) δ12.96(s,1H),7.90(d,J=2.0Hz,1H),7.72(dd,J=8.6,2.0Hz,1H),7.28(d,J=8.7Hz,1H),6.83(d,J= 8.0Hz,1H),6.75(d,J=1.7Hz,1H),6.68(dd,J=8.1,1.8Hz,1H),5.96(s,2H),5.16(s,2H),3.71(s,2H).LRMS(ESI)m / z[M+H] + 344.0.

[0590] Step ③: 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-66)

[0591] The preparation of 4-(Benzo[d][1,3]dioxolane-5-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-66) was the same as compound I-1, with a yield of 49%.1 H NMR(600MHz,DMSO-d6)δ10.89(s,1H),10.10(s,1H),8.11-8.01(m,1H),7. 85(d,J=8.0Hz,1H),7.81(d,J=9.1Hz,1H),7.78-7.70(m,1H),7.40-7.33(m ,2H),7.10(t,J=7.5Hz,1H),6.99(t,J=7.5Hz,1H),6.85(d,J=8.0Hz,1H), 6.78(s,1H),6.72(d,J=8.0Hz,1H),5.97(s,2H),5.22(s,2H),3.74(s,2H).

[0592] Example 67 N-(1H-indol-3-yl)-3-oxo-4-(thien-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-67)

[0593] Step ①: 3-O-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid methyl ester (67-1)

[0594] The preparation of methyl 3-oxo-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylate (67-1) was similar to compound 2-3 with a yield of 92%. 1 H NMR (400MHz, DMSO-d6) δ7.92(d,J=2.0Hz,1H),7.80(dd,J=8.7,2.1Hz,1H),7.55(d,J=8.7Hz,1H),7.40-7.38 (m,1H),7.07(d,J=3.3Hz,1H),6.96-6.93(m,1H),5.41(s,2H),3.82(s,3H),3.67(s,2H).LRMS(ESI)m / z[M+H] + 320.0.

[0595] Step ②: 3-Oxo-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (67-2)

[0596] The preparation of 3-oxo-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (67-2) was similar to that of compound 1-5 with a yield of 96%. 1H NMR(400MHz,DMSO-d6)δ7.90(d,J=2.0Hz,1H),7.78(dd,J=8.6,2.1Hz,1H),7.53(d,J=8.7Hz,1H), 7.40(d,1H),7.12-7.04(m,1H),6.96-6.92(m,1H),5.42(s,2H),3.67(s,2H).LRMS(ESI)m / z[M+H] + 305.8.

[0597] Step ③: N-(1H-indol-3-yl)-3-oxo-4-(thien-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-67)

[0598] The preparation of N-(1H-indol-3-yl)-3-oxo-4-(thiophen-2-ylmethyl)-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-67) was the same as compound I-1, with a yield of 36%. 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),10.12(s,1H),8.06(s,1H),7.86(t,J=7.8Hz,2H),7.79-7.75(m,1H),7.57(d,J=8.7Hz,1H),7. 40(d,J=5.1Hz,1H),7.35(d,J=8.1Hz,1H),7.14-7.07(m,2H),7.00(t,J=7.4Hz,1H),6.94(t,J=4.4Hz,1H),5.46(s,2H),3.69(s,2H).

[0599] Example 68 4-(Furan-2-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-68)

[0600] Step ①: 4-(Furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid methyl ester (68-1)

[0601] The preparation of methyl 4-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylate (68-1) was the same as compound 9-2 with a yield of 67%. 1H NMR (400MHz, DMSO-d6) δ7.93(d,J=2.0Hz,1H),7.82(dd,J=8.7,2.1Hz,1H),7.56(s,1H),7.52( d,J=8.7Hz,1H),6.38-6.35(m,1H),6.32-6.29(m,1H),5.22(s,2H),3.83(s,3H),3.65(s,2H). LRMS(ESI)m / z[M+H] + 304.1.

[0602] Step ②: 4-(Furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (68-2)

[0603] The preparation of 4-(furan-2-ylmethyl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (68-2) was similar to that of compound 1-5, with a yield of 89%. 1 H NMR(400MHz,DMSO-d6)δ12.98(s,1H),7.92(s,1H),7.84-7.70(m,1H),7.59(s,1H),7.51( d,J=8.3Hz,1H),6.39(s,1H),6.32(s,1H),5.23(s,2H),3.65(s,2H).LRMS(ESI)m / z[M+H] + 290.1.

[0604] Step ③: 4-(Furan-2-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-68)

[0605] The preparation of 4-(furan-2-ylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-68) was the same as compound I-1, with a yield of 21%. 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),10.13(s,1H),8.07(d,J=2.1Hz,1H),7.93-7.83(m,2H),7.78(d,J=2.5Hz,1H),7.60-7.47(m,2H),7.3 6(d,J=8.1Hz,1H),7.11(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),6.38(t,J=3.3,1.9Hz,1H),6.33(d,J=3.2Hz,1H),5.27(s,2H),3.67(s,2H).

[0606] Example 69 4-(Cyclopropylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-69)

[0607] Step ①: 4-cyclopropylmethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid methyl ester (69-1)

[0608] The preparation of methyl 4-cyclopropylmethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylate (69-1) was the same as compound 2-3 with a yield of 55%. 1 H NMR (400MHz, DMSO-d6) δ7.95(d,J=2.1Hz,1H),7.85(dd,J=8.6,2.1Hz,1H),7.56(d,J=8.7Hz,1H),3.96(d,J=6.8 Hz,2H),3.85(s,3H),3.57(s,2H),1.10-0.98(m,1H),0.53-0.37(m,2H),0.34-0.24(m,2H).LRMS(ESI)m / z[M+H] + 278.0.

[0609] Step ②: 4-cyclopropylmethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (69-2)

[0610] The preparation of 4-cyclopropylmethyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid (69-2) was the same as compound 1-5 with a yield of 98%. 1H NMR (400MHz, DMSO-d6) δ12.98(s,1H),7.92(d,J=2.0Hz,1H),7.83(dd,J=8.6,2.1Hz,1H),7.52 (d,J=8.7Hz,1H),3.95(d,J=6.8Hz,2H),3.56(s,2H),1.08-0.96(m,1H),0.45-0.39(m,2H),0.35-0.18(m,2H).LRMS(ESI)m / z[M+H] + 264.0.

[0611] Step ③: 4-(cyclopropylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-69)

[0612] The preparation of 4-(cyclopropylmethyl)-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-69) was similar to that of compound I-1, with a yield of 46%. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.14(s,1H),8.10(s,1H),7.93(d,J=8. 6Hz,1H),7.87(d,J=7.9Hz,1H),7.79(s,1H),7.57(d,J=8.7Hz,1H),7.36(d,J= 8.2Hz,1H),7.11(t,J=7.6Hz,1H),7.01(t,J=7.6Hz,1H),3.99(d,J=6.8Hz,2H) ,3.58(s,2H),1.14-0.94(m,1H),0.43(d,J=7.8Hz,2H),0.32(d,J=5.0Hz,2H).

[0613] Example 70 4-Benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-70)

[0614] Step ①: 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (70-1)

[0615] The preparation of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid methyl ester (70-1) was similar to that of compound 2-3, with a yield of 58%. 1H NMR(400MHz,DMSO-d6)δ7.63(s,1H),7.56(s,2H),7.38-7.29(m,2H),7.27-7.16(m,3H),5.25(s,2H),3.77(s,3H),3.76(s,2H).LRMS(ESI)m / z[M+H] + 314.1.

[0616] Step ②: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (70-2)

[0617] The preparation of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxylic acid (70-2) was similar to that of compound 1-5 with a yield of 92%. 1 H NMR(400MHz,DMSO-d6)δ12.97(s,1H),7.63-7.59(m,1H),7.56-7.55(m,2H),7.3 7-7.30(m,2H),7.28-7.16(m,3H),5.25(s,2H),3.77(s,2H).LRMS(ESI)m / z[MH] - 298.1.

[0618] Step ③: 4-benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-70)

[0619] The preparation of 4-benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-70) was similar to that of compound I-1, with a yield of 62%. 1 H NMR(400MHz,DMSO-d6)δ10.93(s,1H),10.14(s,1H),7.79-7.74(m,2H),7.73-7.68(m,2H),7.5 9(d,J=8.0Hz,1H),7.38-7.30(m,3H),7.29-7.21(m,3H),7.11(t,J=7.5Hz,1H),7.02(t,J=7.5 Hz,1H),5.35(s,2H),3.77(s,2H).

[0620] Example 71 4-Benzyl-N-(1H-indol-6-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-71)

[0621] The preparation of 4-benzyl-N-(1H-indol-6-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-6-carboxamide (I-71) was the same as compound I-1, with a yield of 87%. 1 H NMR (400MHz, DMSO-d6) δ11.05(s,1H),10.12(s,1H),7.99(s,1H),7.71(s,1H),7.66(d,J=8.2Hz,1H),7.59(d,J= 8.0Hz,1H),7.47(d,J=8.4Hz,1H),7.37-7.28(m,3H),7.27-7.12(m,4H),6.37(s,1H),5.33(s,2H),3.76(s,2H).

[0622] Example 72 4-Benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (I-72)

[0623] Step ①: 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid methyl ester (72-1)

[0624] The preparation of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (72-1) was similar to compound 2-3 with a yield of 91%. 1 HNMR(400MHz, DMSO-d6)δ7.60(dd,J=8.3,1.9Hz,1H),7.52(d,J=1.9Hz,1H),7.41-7.32(m,2H),7. 32-7.24(m,3H),7.13(d,J=8.4Hz,1H),5.21(s,2H),4.95(s,2H),3.76(s,3H).LRMS(ESI)m / z[M+H] + 298.1.

[0625] Step ②: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (72-2)

[0626] The preparation of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (72-2) was similar to that of compound 1-5 with a yield of 99%. 1H NMR(400MHz,DMSO-d6)δ7.57(dd,J=8.3,1.9Hz,1H),7.51-7.46(m,1H),7.38-7.32(m,2H) ,7.30-7.23(m,3H),7.08(d,J=8.3Hz,1H),5.18(s,2H),4.91(s,2H).LRMS(ESI)m / z[M+Na] + 306.1.

[0627] Step ③: 4-Benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (I-72)

[0628] The preparation of 4-benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxamide (I-72) was similar to that of compound I-1, with a yield of 37%. 1 H NMR (400MHz, DMSO-d6) δ10.92 (s, 1H), 10.04 (s, 1H), 7.78 (d, J = 8.1Hz, 1H), 7.76-7.66 (m, 2H), 7 .62(s,1H),7.41-7.30(m,5H),7.30-7.22(m,2H),7.18-7.08(m,1H),7.03(t,J=7.8Hz,1H),5.27 (s,2H),4.93(s,2H).

[0629] Example 73 4-Benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-73)

[0630] Step ①: 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylic acid methyl ester (73-1)

[0631] The preparation of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxylate (73-1) was similar to compound 2-3 with a yield of 88%. 1 H NMR (400MHz, DMSO-d6) δ7.95(d,J=2.1Hz,1H),7.73(dd,J=8.5,2.1Hz,1H),7.35-7.17(m,7H),5.28(s,2H),3.81(s,3H),3.75(s,2H).

[0632] Step ②: 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (73-2)

[0633] The preparation of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (73-2) was the same as compound 1-5, with a yield of 95%. LRMS (ESI) m / z [M+H] + 300.1.

[0634] Step ③: 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carbonyl chloride (73-3)

[0635] Place 50 mg of compound 73-3 in a dry reaction flask, add 2 ml of tetrahydrofuran, add one drop of DMF solution, replace the argon atmosphere and place in an ice-water bath. Slowly add 20 μl of dichlorothionyl to the reaction flask. After the addition is complete, move the reaction flask to room temperature and stir for 2 hours. After the reaction is complete, concentrate to dryness to obtain a light yellow solid 73-3.

[0636] Step ④: 4-Benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-73)

[0637] A mixture of 25 mg of 3-aminoindole, 87 μl of DIPEA, and 1 ml of THF was placed in an ice-water bath. A THF solution of compound 73-3 was slowly added dropwise. After completion of the dropwise addition, the reaction mixture was brought to room temperature and stirred. After completion of the reaction, the reaction mixture was concentrated to dryness, and the residue was thinly layered with dichloromethane:methanol (50:1) to yield 41 mg of a pale yellow solid (60% yield). 1 H NMR(400MHz,DMSO-d6)δ10.92(s,1H),10.12(s,1H),8.08(s,1H),7.88-7.75(m,3H),7.39-7.29( m,4H),7.27-7.20(m,3H),7.11(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),5.33(s,2H),3.77(s,2H).

[0638] Example 74 4-Benzyl-N-(1H-indol-6-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-74)

[0639] The preparation of 4-benzyl-N-(1H-indol-6-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]thiazine-7-carboxamide (I-74) was similar to that of compound I-1, with a yield of 30%. 1 H NMR (400MHz, DMSO-d6) δ11.06(s,1H),10.11(s,1H),8.04(s,2H),7.77(dd,J=8.7,2.1Hz,1H),7. 46(d,J=8.5Hz,1H),7.35-7.26(m,3H),7.25-7.20(m,5H),6.37(s,1H),5.32(s,2H),3.76(s,2H).

[0640] Example 75 4-Benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (I-75)

[0641] Step ①: 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid methyl ester (75-1)

[0642] The preparation of methyl 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylate (75-1) was similar to compound 2-3 with a yield of 84%. 1 H NMR (400MHz, CD3OD) δ7.66-7.48(m,2H),7.37-7.20(m,5H),7.07(d,J=8.9Hz,1H),5.23(s,2H),4.80(s,2H),3.85(s,3H).LRMS(ESI)m / z[M+H] + 298.1.

[0643] Step ②: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (75-2)

[0644] The preparation of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxylic acid (75-2) was similar to that of compound 1-5 with a yield of 97%. 1 H NMR(400MHz,DMSO-d6)δ12.60(s,1H),7.39-7.29(m,4H),7.25-7.19(m,2H),6.50-6.29(m,2H),4.76(s,2H),4.43(d,J=5.8Hz,2H).LRMS(ESI)m / z[M+H]+ 284.0.

[0645] Step ③: 4-Benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonyl chloride (75-3)

[0646] The preparation of 4-benzyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonyl chloride (75-3) was the same as compound 73-3.

[0647] Step ④: 4-Benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (I-75)

[0648] The preparation of 4-benzyl-N-(1H-indol-3-yl)-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carboxamide (I-75) was similar to that of compound I-73, with a yield of 23%. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),10.06(s,1H),7.83(d,J=8.0Hz,1H),7.76(s,1H),7.69-7.61(m,2H),7. 40-7.24(m,6H),7.16(d,J=8.3Hz,1H),7.09(t,J=7.4Hz,1H),6.99(t,J=7.8Hz,1H),5.24(s,2H),4.90(s,2H).

[0649] Example 76 1-Benzyl-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-76)

[0650] Step ①: 1-benzyl-6-bromo-3,3-dimethylindolin-2-one (76-1)

[0651] The preparation of 1-benzyl-6-bromo-3,3-dimethylindolin-2-one (76-1) was the same as compound 2-3, with a yield of 93%. 1 H NMR (400MHz, DMSO-d6) δ7.38-7.32(m,3H),7.31-7.24(m,3H),7.22(dd,J=7.9,1 .8Hz,1H),7.14(d,J=1.7Hz,1H),4.92(s,1H),1.33(s,6H).LRMS(ESI)m / z[M+H] + 330.0.

[0652] Step ②: 1-benzyl-3,3-dimethyl-2-oxoindoline-6-acetonitrile (76-2)

[0653] The preparation of 1-benzyl-3,3-dimethyl-2-oxoindoline-6-acetonitrile (76-2) was the same as compound 11-2, with a yield of 76%. 1 H NMR(400MHz, DMSO-d6)δ7.62(d,J=7.6Hz,1H),7.53(dd,J=7.6,1.5Hz,1H),7.43(s,1H),7.39-7.24(m,5H),4.93(s,2H),1.35(s,6H).LRMS(ESI)m / z[M+Na] + 299.0.

[0654] Step ③: 1-benzyl-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (76-3)

[0655] The preparation of 1-benzyl-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (76-3) was the same as compound 11-3, with a yield of 80%. 1 H NMR (400MHz, DMSO-d6) δ12.92(s,1H),7.67(dd,J=7.7,1.5Hz,1H),7.52(d,J=7.7Hz,1 H),7.38-7.33(m,3H),7.30-7.24(m,3H),4.97(s,2H),1.38(s,6H).LRMS(ESI)m / z[MH] - 294.0.

[0656] Step ④: 1-benzyl-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-76)

[0657] The preparation of 1-benzyl-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-76) was similar to that of compound I-1, with a yield of 48%. 1H NMR (400MHz, DMSO-d6) δ10.90(s,1H),10.06(s,1H),7.79(d,J=8.0Hz,1H),7.76-7.69(m,2H),7.55(d,J=7.7H z,1H),7.44(s,1H),7.39-7.23(m,6H),7.10(t,J=7.5Hz,1H),7.00(t,J=7.5Hz,1H),4.99(s,2H),1.39(s,6H).

[0658] Example 77 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(thien-3-ylmethyl)indoline-6-carboxamide (I-77)

[0659] Step ①: 3,3-dimethyl-2-oxo-1-(thien-3-ylmethyl)indoline-6-carboxylic acid methyl ester (77-1)

[0660] The preparation of methyl 3,3-dimethyl-2-oxo-1-(thiophen-3-ylmethyl)indoline-6-carboxylate (77-1) was the same as compound 2-3, with a yield of 93%. 1 H NMR (400MHz, DMSO-d6) δ7.69 (dd, J=7.7, 1.5Hz, 1H), 7.57-7.48 (m, 2H), 7.45 (s, 1H), 7.37-7.32 (m,1H),6.98(dd,J=5.0,1.3Hz,1H),4.95(s,2H),3.82(s,3H),1.34(s,6H).LRMS(ESI)m / z[M+H] + 316.0.

[0661] Step ③: 3,3-Dimethyl-2-oxo-1-(thien-3-ylmethyl)indoline-6-carboxylic acid (77-2)

[0662] The preparation of 3,3-dimethyl-2-oxo-1-(thiophen-3-ylmethyl)indoline-6-carboxylic acid (77-2) was the same as compound 1-5, with a yield of 99%. 1 H NMR(400MHz,DMSO-d6)δ7.73-7.62(m,1H),7.55-7.45(m,2H),7.44(s,1H),7.36(d, J=2.9Hz,1H),6.98(d,J=5.0Hz,1H),4.95(s,2H),1.35(s,6H).LRMS(ESI)m / z[M+H] + 302.0.

[0663] Step ④: N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(thien-3-ylmethyl)indoline-6-carboxamide (I-77)

[0664] The preparation of N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(thiophen-3-ylmethyl)indoline-6-carboxamide (I-77) was the same as compound I-1, with a yield of 53%. 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),10.07(s,1H),7.81(d,J=8.0Hz,1H),7.76(d,J=2.5Hz,1H),7.71(d,J=7.5,1.6Hz,1H) ,7.55-7.49(m,3H),7.41(s,1H),7.36(d,J=8.1Hz,1H),7.11(t,J=7.5Hz,1H),7.04-6.96(m,2H),4.96(s,2H),1.36(s,6H).

[0665] Example 78 1-Cyclopropylmethyl-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-78)

[0666] Step ①: 6-bromo-1-cyclopropylmethyl-3,3-dimethylindolin-2-one (78-1)

[0667] The preparation of 6-bromo-1-cyclopropylmethyl-3,3-dimethylindolin-2-one (78-1) was the same as compound 2-3 to give a white solid in a yield of 91%. 1 H NMR (400MHz, DMSO-d6) δ7.38(d,J=1.8Hz,1H),7.32(d,J=7.8Hz,1H),7.21(dd,J=7.8,1.7Hz,1H),3.58(d ,J=6.9Hz,2H),1.25(s,6H),1.17-0.95(m,1H),0.51-0.39(m,2H),0.37-0.23(m,2H).LRMS(ESI)m / z[M+H] + 294.0.

[0668] Step ②: 1-cyclopropylmethyl-3,3-dimethyl-2-oxoindoline-6-carbonitrile (78-2)

[0669] The preparation of 1-cyclopropylmethyl-3,3-dimethyl-2-oxoindoline-6-carbonitrile (78-2) was the same as compound 11-2 to give a white solid in a yield of 78%. 1 H NMR(400MHz,DMSO-d6)δ7.65(s,1H),7.59(d,J=7.6Hz,1H),7.54-7.46(m,1H),3.60(d,J=7.0Hz ,2H),1.29(s,6H),1.26-1.08(m,1H),0.48-0.38(m,2H),0.34-0.27(m,2H).LRMS(ESI)m / z[M+H] + 241.1.

[0670] Step ③: 1-cyclopropylmethyl-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (78-3)

[0671] The preparation of 1-cyclopropylmethyl-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (78-3) was the same as compound 11-3, with a yield of 93%. 1 H NMR (400MHz, DMSO-d6) δ12.97(s,1H),7.68(dd,J=7.6,1.4Hz,1H),7.57(d,J=1.4Hz,1H),7.49(d,J=7.6Hz,1H), 3.63(d,J=6.8Hz,2H),1.29(s,6H),1.19-1.07(m,1H),0.49-0.42(m,2H),0.35-0.27(m,2H).LRMS(ESI)m / z[M+H] + 260.1.

[0672] Step ④: 1-cyclopropylmethyl-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-78)

[0673] The preparation of 1-cyclopropylmethyl-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-78) was the same as compound I-1, with a yield of 36%. 1H NMR (400MHz, DMSO-d6) δ10.93(s,1H),10.13(s,1H),7.83(d,J=8.0Hz,1H),7.78(d,J=2.5Hz,1H),7.75-7.66(m,2H),7.52(d,J=7.6Hz,1H),7.37(d, J=8.1Hz,1H),7.12(t,J=7.1Hz,1H),7.02(t,J=7.5Hz,1H),3.66(d,J=6.9 Hz,2H),1.33(s,6H),1.29-1.22(m,1H),0.52-0.44(m,2H),0.40-0.32(m, 2H).

[0674] Example 79 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(thien-2-ylmethyl)indoline-6-carboxamide (I-79)

[0675] Step ①: 6-bromo-3,3-dimethyl-1-(thien-2-ylmethyl)indolin-2-one (79-1)

[0676] The preparation of 6-bromo-3,3-dimethyl-1-(thiophen-2-ylmethyl)indolin-2-one (79-1) was the same as compound 2-3 to give a transparent oil in a yield of 92%. 1 H NMR (400MHz, DMSO-d6) δ7.42(dd,J=5.1,1.3Hz,1H),7.37-7.33(m,1H),7.32(s,1H),7.22(dd,J=7. 9,1.8Hz,1H),7.19-7.17(m,1H),7.03-6.83(m,1H),5.10(s,2H),1.28(s,6H).LRMS(ESI)m / z[M+H] + 335.9.

[0677] Step ②: 3,3-dimethyl-2-oxo-1-(thien-2-ylmethyl)indoline-6-carbonitrile (79-2)

[0678] The preparation of 3,3-dimethyl-2-oxo-1-(thiophen-2-ylmethyl)indoline-6-carbonitrile (79-2) was the same as compound 11-2 to give a white solid in a yield of 98%. 1H NMR (400MHz, DMSO-d6) δ7.62-7.60(m,1H),7.59(s,1H),7.53(dd,J=7.6,1.4Hz,1H),7.42(dd,J=5. 1,1.3Hz,1H),7.28-7.21(m,1H),7.00-6.94(m,1H),5.11(s,2H),1.31(s,6H).LRMS(ESI)m / z[M+H] + :283.1.

[0679] Step ③: 3,3-dimethyl-2-oxo-1-(thiophen-2-ylmethyl)indoline-6-carboxylic acid (79-3)

[0680] The preparation of 3,3-dimethyl-2-oxo-1-(thiophen-2-ylmethyl)indoline-6-carboxylic acid (79-3) was the same as compound 11-3 to give a white solid in 80% yield. 1 H NMR (400MHz, DMSO-d6) δ12.94(s,1H),7.67(dd,J=7.6,1.4Hz,1H),7.55(d,J=1.5Hz,1H),7.50(d,J=7.7Hz,1H), 7.41(dd,J=5.1,1.3Hz,1H),7.19-7.08(m,1H),7.06-6.89(m,1H),5.15(s,2H),1.32(s,6H).LRMS(ESI)m / z[M+H] + 302.1.

[0681] Step ④: N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(thien-2-ylmethyl)indoline-6-carboxamide (I-79)

[0682] The preparation of N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(thiophen-2-ylmethyl)indoline-6-carboxamide (I-79) was the same as compound I-1, with a yield of 58%. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.09(s,1H),7.82(d,J=8.0Hz,1H),7.77(s,1H),7.72(d,J=7.4Hz,1H),7.63(s,1H) ,7.53(d,J=7.6Hz,1H),7.44-7.32(m,2H),7.19(s,1H),7.11(t,J=7.5Hz,1H),7.07-6.92(m,2H),5.17(s,2H),1.35(s,6H).

[0683] Example 80 1-(Furan-2-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-80)

[0684] Step ①: 1-(Furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (80-1)

[0685] The preparation of methyl 1-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (80-1) was similar to that of compound 9-2, with a yield of 35%. 1 H NMR(400MHz, DMSO-d6)δ7.70(dd,J=7.7,1.5Hz,1H),7.60-7.57(m,2H),7.53(d,J=7.7 Hz,1H),6.41-6.38(m,2H),4.98(s,2H),3.85(s,3H),1.32(s,6H).LRMS(ESI)m / z[M+H] + 300.1.

[0686] Step ②: 1-(Furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (80-2)

[0687] The preparation of 1-(furan-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (80-2) was the same as compound 1-5, with a yield of 85%. 1 H NMR(400MHz,DMSO-d6)δ12.93(s,1H),7.68(d,J=7.7,1.4Hz,1H),7.58(d,2H),7.49 (d,J=7.7Hz,1H),6.48-6.36(m,2H),4.96(s,2H),1.31(s,6H).LRMS(ESI)m / z[M+H] + 286.2.

[0688] Step ③: 1-(Furan-2-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-80)

[0689] The preparation of 1-(furan-2-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-80) was the same as compound I-1, with a yield of 49%. 1H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.10(s,1H),7.83(d,J=8.0Hz,1H),7.79(d,J=2.5Hz,1H),7.75-7.69(m,1H),7.66-7.57(m,2 H),7.53(d,J=7.7Hz,1H),7.37(d,J=8.1Hz,1H),7.16-7.07(m,1H),7.06-6.95(m,1H),6.45-6.37(m,2H),4.99(s,2H),1.35(s,6H).

[0690] Example 81 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-phenylethylindoline-6-carboxamide (I-81)

[0691] Step ①: 6-bromo-3,3-dimethyl-1-phenylethylindolin-2-one (81-1)

[0692] The preparation of 6-bromo-3,3-dimethyl-1-phenylethylindolin-2-one (81-1) was the same as compound 9-2. 1 H NMR (400MHz, CDCl3) δ7.31–7.27(m,2H),7.22(tt,J=7.7,1.5Hz,3H),7.17(dd,J=7.8,1.7Hz,1H),7. 05(d,J=7.9Hz,1H),6.90(d,J=1.7Hz,1H),3.94(t,J=7.4Hz,2H),2.99(t,J=7.4Hz,2H),1.30(s,6H).

[0693] Step ②: 3,3-dimethyl-2-oxo-1-phenylethylindolin-6-carbonitrile (81-2)

[0694] The preparation of 3,3-dimethyl-2-oxo-1-phenylethylindoline-6-carbonitrile (81-2) was the same as compound 9-3. 1 H NMR(400MHz, CDCl3)δ7.32(dd,J=7.6,1.3Hz,1H),7.27(d,J=2.0Hz,1H),7.25–7.20(m,3H),7.1 8–7.13(m,2H),6.86(d,J=1.4Hz,1H),3.95(t,J=7.2Hz,2H),2.97(t,J=7.2Hz,2H),1.31(s,6H).

[0695] Step ③: 3,3-dimethyl-2-oxo-1-phenylethylindoline-6-carboxylic acid (81-3)

[0696] The preparation of 3,3-dimethyl-2-oxo-1-phenylethylindoline-6-carboxylic acid (81-3) is the same as compound 11-3. LCMS (ESI) m / z [M+H] + :310.0.

[0697] Step ④: N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-phenylethylindoline-6-carboxamide (I-81)

[0698] The preparation of N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-phenylethylindoline-6-carboxamide (I-26) is the same as compound I-1. 1 H NMR (600MHz, DMSO-d6) δ10.93(s,1H),10.12(s,1H),7.85(d,J=8.0Hz,1H),7.80(d ,J=2.0Hz,1H),7.69(d,J=7.7Hz,1H),7.62(s,1H),7.49–7.46(m,1H),7.38(d,J=8. 1Hz,1H),7.23(dt,J=14.0,7.4Hz,4H),7.16(t,J=7.0Hz,1H),7.13(t,J=7.5Hz,1H ),7.03(t,J=7.5Hz,1H),4.00(t,J=7.3Hz,2H),3.00(t,J=7.3Hz,2H),1.22(s,6H).

[0699] Example 82 N-(1H-indol-3-yl)-2'-oxo-1'-(thien-3-ylmethyl)spiro[cyclopropane-1,3'-dihydroindole]-6'-carboxamide (I-82)

[0700] Step ①: 2'-Oxospiro[cyclopropane-1,3'-dihydroindole]-6'-carboxylic acid methyl ester (82-1)

[0701] A mixture of 500 mg of methyl 2-oxoindole-6-carboxylate, 1.8 g of (2-bromoethyl)diphenylsulfonium trifluoromethanesulfonate, 1.1 mL of triethylamine, and 10 mL of N,N-dimethylformamide was stirred at room temperature under argon for 7 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using ethyl acetate:petroleum ether (1:5) to obtain 400 mg of methyl 2'-oxospiro[cyclopropane-1,3'-dihydroindole]-6'-carboxylate (82-1), in a 71% yield.1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),7.58(dd,J=7.8,1.5Hz,1H),7.42(d,J=1.4Hz,1H),7.11(d, J=7.8Hz,1H),3.84(s,3H),1.67(q,J=3.8,3.2Hz,2H),1.55(q,J=3.8Hz,2H).LCMS(ESI)m / z[M+H] + :218.1.

[0702] Step ②: 2'-Oxo-1'-(thiophen-3-ylmethyl)spiro[cyclopropane-1,3'-dihydroindole]-6'-carboxylic acid methyl ester (82-2)

[0703] A mixture of 100 mg of methyl 2'-oxospiro[cyclopropane-1,3'-dihydroindole]-6'-carboxylate, 106 mg of 3-bromomethylthiophene, 450 mg of cesium carbonate, and 2 mL of N,N-dimethylformamide was stirred at room temperature for 5 hours. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was concentrated to dryness and then thin-layered with ethyl acetate:petroleum ether (1:2) to obtain 95 mg of methyl 2'-oxo-1'-(thiophen-3-ylmethyl)spiro[cyclopropane-1,3'-dihydroindole]-6'-carboxylate (82-2), in a 66% yield. 1 H NMR (400MHz, DMSO-d6) δ7.65(dd,J=7.8,1.3Hz,1H),7.55(s,1H),7.51(dd,J=5.0,3.0Hz,1H),7.40(d,J=2.8Hz,1H),7.19(d,J=7.8 Hz,1H),7.01(d,J=5.0Hz,1H),5.03(s,2H),3.83(s,3H),1.78(q,J=3.9,3.3Hz,2H),1.68(q,J=4.2,3.8Hz,2H).LCMS(ESI)m / z[M+H] + :314.1.

[0704] Step ③: 2'-Oxo-1'-(thiophen-3-ylmethyl)spiro[cyclopropane-1,3'-dihydroindole]-6'-carboxylic acid (82-3)

[0705] The preparation of 2'-oxo-1'-(thiophen-3-ylmethyl)spiro[cyclopropane-1,3'-dihydroindole]-6'-carboxylic acid (82-3) was the same as compound 1-5. 1H NMR (400MHz, DMSO-d6) δ7.62(d,J=7.7Hz,1H),7.60-7.45(m,2H),7.40(d,J=2.8Hz,1H),7.14(d,J=7.7Hz,1H ),7.00(d,J=5.0Hz,1H),5.01(s,2H),1.75(q,J=3.8,3.2Hz,2H),1.66(t,J=3.8Hz,2H).LCMS(ESI)m / z[M+H] + :300.1.

[0706] Step ④: N-(1H-indol-3-yl)-2'-oxo-1'-(thien-3-ylmethyl)spiro[cyclopropane-1,3'-dihydroindole]-6'-carboxamide (I-82)

[0707] The preparation of N-(1H-indol-3-yl)-2'-oxo-1'-(thien-3-ylmethyl)spiro[cyclopropane-1,3'-dihydroindole]-6'-carboxamide (I-82) was the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),10.06(s,1H),7.82(d,J=8.0Hz,1H),7.77(d,J=2.4Hz,1H) ,7.73(d,J=7.8Hz,1H),7.68(s,1H),7.51(dd,J=5.0,2.8Hz,1H),7.46(d,J=2.8Hz,1H),7.36(d, J=8.1Hz,1H),7.20(d,J=7.7Hz,1H),7.11(t,J=7.5Hz,1H),7.06(d,J=5.0Hz,1H),7.01(t,J=7.5 Hz,1H),5.04(s,2H),1.76(q,J=3.9,3.3Hz,2H),1.66(q,J=4.2,3.7Hz,2H).LCMS(ESI)m / z[M+H] + :414.2.

[0708] Example 83 1-((2-bromothien-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-83)

[0709] Step ①: 1-((2-bromothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (83-1)

[0710] The preparation of methyl 1-((2-bromothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (83-1) was the same as compound 82-2. 1 H NMR(400MHz,DMSO-d6)δ7.69(dd,J=7.7,1.5Hz,1H),7.60-7.52(m,2H),7.43(d,J=1.5Hz ,1H),6.76(d,J=5.7Hz,1H),4.85(s,2H),3.82(s,3H),1.34(s,6H).LC-MS(ESI)m / z[M+H] + :394.0.

[0711] Step ②: 1-((2-bromothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (83-2)

[0712] The preparation of 1-((2-bromothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (83-2) was the same as compound 1-5. 1 H NMR (400MHz, DMSO-d6) δ12.91(s,1H),7.68(dd,J=7.7,1.5Hz,1H),7.57(d,J=5.6Hz,1H),7.51(d,J=7 .7Hz,1H),7.39(d,J=1.4Hz,1H),6.75(d,J=5.7Hz,1H),4.84(s,2H),1.34(s,6H).LC-MS(ESI)m / z[MH] + :377.8.

[0713] Step ③: 1-((2-bromothien-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-83)

[0714] The preparation method of 1-((2-bromothiophen-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-83) is the same as compound I-1. 1H NMR (400MHz, CDCl3) δ8.11(s,1H),7.98(d,J=2.5Hz,1H),7.92(s,1H),7.64(dd,J=7.7,1.6Hz,1H),7.56(dd,J=7.9,1.1Hz,1H),7.44(d,J=1. 5Hz,1H),7.45-7.35(m,1H),7.33(d,J=7.7Hz,1H),7.25-7.15(m,3H),6.85(d,J=5.7Hz,1H),4.93(s,2H),1.45(s,6H).LC-MS(ESI)m / z[M+H] + :494.0.

[0715] Example 84 1-((5-chlorothien-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-84)

[0716] Step ①: 1-((5-chlorothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (84-1)

[0717] The preparation method of methyl 1-((5-chlorothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (84-1) is the same as compound 2-3. 1 H NMR (400MHz, CD3OD) δ7.79(dd,J=7.7,1.5Hz,1H),7.55(d,J=1.5Hz,1H),7.43(dd,J= 7.7,0.5Hz,1H),7.16(dd,J=1.8,1.0Hz,1H),6.89(d,J=1.7Hz,1H),4.89(d,J=1.0Hz,2H),3.89(s,3H),1.40(s,6H).LC-MS(ESI)m / z[M+H] + :350.1.

[0718] Step ②: 1-((5-chlorothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (84-2)

[0719] The preparation method of 1-((5-chlorothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (84-2) is the same as compound 1-5. 1H NMR (400MHz, DMSO-d6) δ12.91(s,1H),7.68(dd,J=7.7,2.9Hz,1H),7.51(dd,J=7.9,3.4Hz,1H),7.4 8-7.42(m,1H),7.26-7.22(m,1H),6.99-6.95(m,1H),4.88(d,J=3.2Hz,2H),1.35(d,J=3.5Hz,6H).

[0720] Step ③: 1-((5-chlorothien-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-84)

[0721] The preparation method of 1-((5-chlorothien-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-84) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),10.10(s,1H),7.82(d,J=8.0Hz,1H),7.76(d,J=2.5Hz,1H),7.73(dd,J=7.7,1.4Hz,1H),7.59-7.51( m,2H),7.36(d,J=8.2Hz,1H),7.29(d,J=1.7Hz,1H),7.15-7.06(m,1H),7.04-6.98(m,2H),4.90(s,2H),1.37(s,6H).LC-MS(ESI)m / z[M+H] + :450.2.

[0722] Example 85 N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-4-(thien-3-ylmethyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-85)

[0723] Step ①: Dimethyl 2-(3-nitrothiophen-2-yl)malonate (85-1)

[0724] 12.7 g of potassium tert-butoxide and 30 ml of ultra-dry dimethyl sulfoxide were added to a dried two-necked flask and stirred at room temperature under argon for 30 minutes. 15 g of dimethyl malonate was added, and the mixture was stirred at room temperature for 1 hour. 5.3 g of 2-chloro-3-nitrothiophene was added, and the mixture was stirred at 100°C for 1 hour. The reaction solution was acidified by adding 100 ml of 1M hydrochloric acid and extracted with ethyl acetate. The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10 / 90) to obtain 8.3 g of dimethyl 2-(3-nitrothiophene-2-yl)malonate (85-1) as a yellow oil, in a yield of 99%. 1 H NMR(400MHz, DMSO-d6)δ7.76(d,J=5.7Hz,1H),7.69(d,J=5.7Hz,1H),5.91(s,1H),3.74(s,6H).LC-MS(ESI)m / z[M+H] + :260.0.

[0725] Step ②: 2-(3-nitrothiophen-2-yl)acetic acid (85-2)

[0726] 8.3 g of compound 85-1 and 5 M aqueous hydrochloric acid were added to a round-bottom flask and stirred at 110°C overnight. The reaction mixture was added to 50 ml of water and extracted with ethyl acetate. The organic phase was concentrated to dryness to obtain 5.8 g of 2-(3-nitrothiophen-2-yl)acetic acid (85-2) as a brown solid, with a yield of 96%. LC-MS (ESI) m / z [MH] - :186.0.

[0727] Step ③: 2-(3-nitrothiophen-2-yl)acetic acid methyl ester (85-3)

[0728] 5.8 g of compound 85-2, 1 ml of sulfuric acid, and 100 ml of methanol were added to a round-bottom flask and stirred overnight at 65°C. The reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 15 / 85) to obtain 6.1 g of methyl 2-(3-nitrothiophen-2-yl)acetate (85-3) as a yellow oil, with a yield of 99%. 1 H NMR (400MHz, CD3OD) δ7.63 (d, J = 5.7Hz, 1H), 7.43 (d, J = 5.7Hz, 1H), 4.25 (s, 2H), 3.72 (s, 3H). LC-MS (ESI) m / z [M+H] + :202.1.

[0729] Step ④: 2-(3-aminothiophen-2-yl)acetic acid methyl ester (85-4)

[0730] 6.1 g of compound 85-3, 5.1 g of reduced iron powder, 40 ml of ethanol, and 40 ml of water were added to a round-bottom flask and stirred at room temperature under argon for 18 hours. The reaction mixture was adjusted to a neutral pH by adding saturated sodium bicarbonate aqueous solution, filtered through celite, and the filtrate was extracted with ethyl acetate. The organic phase was concentrated to dryness to obtain 4.9 g of methyl 2-(3-aminothiophen-2-yl)acetate (85-4) as a brown oil, with a yield of 93%. LC-MS (ESI) m / z [M+H] + :172.1.

[0731] Step ⑤: 4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one (85-5)

[0732] 4.9 g of compound 85-4 and 50 ml of ultra-dry toluene were added to a dry two-necked flask. 35 ml of a 2M trimethylaluminum solution in toluene was added dropwise at 0°C under argon protection, and the mixture was stirred at 0°C for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride, filtered through celite, and extracted with ethyl acetate. The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 25 / 75) to obtain 2.4 g of 4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one (85-5) as a yellow solid in a 61% yield. 1 H NMR(600MHz,DMSO-d6)δ10.30(s,1H),7.42(d,J=5.1Hz,1H),6.77(d,J=5.0Hz,1H),3.52(s,2H).LC-MS(ESI)m / z[M+H] + :140.0.

[0733] Step ⑥: tert-Butyl 5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxylate (86-6)

[0734] 2.4 g of compound 85-5, 9.4 g of di-tert-butyl dicarbonate, 5.1 g of sodium bicarbonate, and 40 ml of tetrahydrofuran were added to a round-bottom flask and stirred overnight at 60°C under argon. The reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5 / 95) to obtain 3.4 g of tert-butyl 5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxylate (85-6) as a red oil, in an 82% yield. 1 H NMR (400MHz, CD3OD) δ7.39 (dd, J=5.2, 1.0Hz, 1H), 7.20 (d, J=5.2Hz, 1H), 3.82-3.72 (m, 2H), 1.63 (s, 9H). LC-MS (ESI) m / z [M+H] + :262.0.

[0735] Step ⑦: tert-Butyl 6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxylate (85-7)

[0736] 3.4 g of compound 85-6, 4.0 g of iodomethane, 9.3 g of cesium carbonate, and 40 ml of ultra-dry N,N-dimethylformamide were added to a round-bottom flask and stirred at room temperature for 1 hour under argon. The reaction mixture was added to 50 ml of water and extracted with ethyl acetate. The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate / dichloromethane = 5 / 95) to obtain 2.2 g of tert-butyl 6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxylate (85-7) as a yellow oil in a 58% yield. 1 H NMR (400MHz, CD3OD) δ7.41(d,J=5.2Hz,1H),7.22(d,J=5.2Hz,1H),1.63(s,9H),1.44(s,6H).LC-MS(ESI)m / z[M+Na] + :290.2.

[0737] Step ⑧: tert-Butyl 2-bromo-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxylate (85-8)

[0738] 2.2 g of compound 85-7 and 30 ml of ultra-dry tetrahydrofuran were added to a dry two-necked flask. 1.5 g of N-bromosuccinimide was added at 0°C, and the mixture was stirred in the dark at 0°C for 2 hours. The reaction solution was concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5 / 95) to obtain 2.3 g of tert-butyl 2-bromo-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-4-carboxylate (85-8) as a purple oil, with a yield of 80%. 1 H NMR (400MHz, CD3OD) δ7.27(s,1H),1.62(s,9H),1.42(s,6H).

[0739] Step ⑨: 2-Bromo-6,6-dimethyl-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one (85-9)

[0740] 1 gram of compound 85-8, 2 milliliters of trifluoroacetic acid, and 10 milliliters of dichloromethane were added to a round-bottom flask and stirred at room temperature for 2 hours. Saturated sodium bicarbonate was added to the reaction mixture to adjust the pH to neutral, and the mixture was extracted with dichloromethane. The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5 / 95) to obtain 698.0 mg of 2-bromo-6,6-dimethyl-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one (85-9) as a purple solid, in a 97% yield. 1 H NMR (400MHz, DMSO-d6) δ10.37(s,1H),6.97(s,1H),1.26(s,6H).

[0741] Step ⑩: 2-cyano-6,6-dimethyl-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one (85-10)

[0742] 698 mg of compound 85-9, 666 mg of zinc cyanide, 328 mg of tetrakis(triphenylphosphine)palladium, and 10 mL of N,N-dimethylformamide were added to a sealed tube and stirred at 180°C overnight under argon. The reaction was stopped upon completion of the reaction, as monitored by TLC. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness, and the residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 10 / 90) to yield 25.4 mg of 2-cyano-6,6-dimethyl-4,6-dihydro-5H-thieno[3,2-b]pyrrol-5-one (85-10) as a yellow solid (yield: 5%). 1 H NMR (400MHz, CD3OD) δ7.40 (s, 1H), 1.42 (s, 6H).

[0743] step 6,6-Dimethyl-5-oxo-4-(thien-3-ylmethyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carbonitrile (85-11)

[0744] The preparation method of 6,6-dimethyl-5-oxo-4-(thien-3-ylmethyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carbonitrile (85-11) is the same as compound 2-3. 1 H NMR (400MHz, CD3OD) δ7.41 (s, 1H), 7.41-7.36 (m, 2H), 7.00 (dd, J = 4.8, 1.5Hz, 1H), 4.89 (s, 2H), 1.43 (s, 6H).

[0745] step 6,6-Dimethyl-5-oxo-4-(thien-3-ylmethyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (85-12)

[0746] The preparation method of 6,6-dimethyl-5-oxo-4-(thien-3-ylmethyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (85-12) is the same as compound 11-3. 1 H NMR (400MHz, DMSO-d6) δ7.57-7.42(m,3H),7.05-6.95(m,1H),4.85(s,1H),1.35(d,J=6.6Hz,6H).

[0747] step N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-4-(thien-3-ylmethyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-85)

[0748] The preparation method of N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-4-(thien-3-ylmethyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-85) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.09(s,1H),7.88(s,1H),7.76(d,J=8.0Hz,1H),7.67(d,J=2.5Hz,1H),7.56(dd,J=5.0,2.9Hz, 1H),7.41(d,J=2.9Hz,1H),7.36(d,J=8.1Hz,1H),7.15-7.08(m,1H),7.07-6.99(m,2H),4.86(s,2H),1.38(s,6H).LC-MS(ESI)m / z[M+H] + :422.0.

[0749] Example 86 4-(Furan-3-ylmethyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-86)

[0750] Step ①: 4-(Furan-3-ylmethyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carbonitrile (86-1)

[0751] The preparation method of 4-(furan-3-ylmethyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carbonitrile (86-1) is the same as compound 2-3. 1 H NMR (400MHz, CD3OD) δ7.63-7.56(m,1H),7.52(s,1H),7.49-7.43(m,1H),6.35(dd,J=1.9,0.9Hz,1H),4.75(s,1H),1.43(s,6H).

[0752] Step ②: 4-(Furan-3-ylmethyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (86-2)

[0753] The preparation method of 4-(furan-3-ylmethyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (86-2) is the same as compound 11-3. LC-MS (ESI) m / z [MH] + :290.1.

[0754] Step ③: 4-(Furan-3-ylmethyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-86)

[0755] The preparation method of 4-(furan-3-ylmethyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-86) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.98(s,1H),10.14(s,1H),7.96(s,1H),7.79(d,J=8.0Hz,1H),7.75(s,1H),7.72-7.61(m,2H),7.3 7(d,J=8.1Hz,1H),7.16-7.08(m,1H),7.06-6.98(m,1H),6.48-6.40(m,1H),4.71(s,2H),1.36(s,6H).LC-MS(ESI)m / z[M+H] + :406.2.

[0756] Example 87 4-Benzyl-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-87)

[0757] Step ①: 4-benzyl-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carbonitrile (87-1)

[0758] The preparation method of 4-benzyl-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carbonitrile (87-1) is the same as compound 2-3. 1 H NMR(400MHz,CD3OD)δ7.37-7.26(m,6H),4.89(s,2H),1.45(s,6H).LC-MS(ESI)m / z[M+H] + :283.1.

[0759] Step ②: 4-benzyl-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (87-2)

[0760] The preparation method of 4-benzyl-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carbonitrile (87-2) is the same as compound 11-3. LC-MS (ESI) m / z [MH] - :299.8.

[0761] Step ③: 4-benzyl-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-87)

[0762] The preparation method of 4-benzyl-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-87) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.09(s,1H),7.83(s,1H),7.73(d,J=8.0Hz,1H),7.65(d,J=2.5Hz,1 H),7.42-7.27(m,6H),7.14-7.08(m,1H),7.05-6.95(m,1H),4.88(s,2H),1.41(s,6H).LC-MS(ESI)m / z[M+H] + :416.2.

[0763] Example 88 4-(3-Fluoro-5-(trifluoromethyl)benzyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-88)

[0764] Step ①: Dimethyl 2-(5-(methoxycarbonyl)-3-nitrothiophen-2-yl)malonate (88-1)

[0765] The preparation method of dimethyl 2-(5-(methoxycarbonyl)-3-nitrothiophen-2-yl)malonate (88-1) is the same as compound 85-1. 1 H NMR (400MHz, DMSO-d6) δ8.20(s,1H),6.01(s,1H),3.88(s,3H),3.76(s,6H).

[0766] Step ②: 5-(2-methoxy-2-oxoethyl)-4-nitrothiophene-2-carboxylic acid methyl ester (88-2)

[0767] 5.3 g of compound 88-1 and glacial acetic acid were added to a round-bottom flask and stirred at 110°C for 22 hours. The reaction solution was concentrated to dryness, ethyl acetate was added, and the pH was adjusted to neutral with saturated aqueous sodium bicarbonate. The solution was extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 5 / 95) to obtain 1.8 g of methyl 5-(2-methoxy-2-oxoethyl)-4-nitrothiophene-2-carboxylate (88-2) as a yellow solid, in a 42% yield. 1 H NMR (400MHz, DMSO-d6) δ8.18(s,1H),4.44(s,2H),3.88(s,3H),3.67(s,3H).

[0768] Step ③: 5-(2-methoxy-2-oxoethyl)-4-aminothiophene-2-carboxylic acid methyl ester (88-3)

[0769] The preparation method of 5-(2-methoxy-2-oxoethyl)-4-aminothiophene-2-carboxylic acid methyl ester (88-3) is the same as compound 85-4. 1 H NMR (400MHz, DMSO-d6) δ7.19(s,1H),4.97(s,2H),3.75(s,3H),3.74(s,2H),3.63(s,3H).

[0770] Step ④: 5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (88-4)

[0771] The preparation method of methyl 6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylate (88-4) is the same as compound 85-5. 1 H NMR(400MHz,DMSO-d6)δ10.45(s,1H),7.33(s,1H),3.81(s,3H),3.65(s,2H).LC-MS(ESI)m / z[M+H] + :198.1.

[0772] Step ⑤: 4-Boc-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (88-5)

[0773] The preparation method of 4-Boc-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (88-5) is the same as compound 85-6. 1 H NMR (400MHz, DMSO-d6) δ7.73(s,1H),3.90(s,2H),3.83(s,3H),1.55(s,9H).

[0774] Step ⑥: 4-Boc-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (88-6)

[0775] The preparation method of 4-Boc-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (88-6) is the same as compound 85-7. 1 H NMR (400MHz, CD3OD) δ7.86(s,1H),3.89(s,3H),1.64(s,9H),1.47(s,6H).

[0776] Step ⑦: 6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (88-7)

[0777] The preparation method of 6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (88-7) is the same as compound 85-8. 1 H NMR(400MHz, CDCl3)δ8.51(s,1H),7.43(s,1H),3.88(s,3H),1.45(s,6H).LC-MS(ESI)m / z[M+H] + :226.1.

[0778] Step ⑧: 4-(3-fluoro-5-(trifluoromethyl)benzyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (88-8)

[0779] The preparation method of 4-(3-fluoro-5-(trifluoromethyl)benzyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (88-8) is the same as compound 2-3. 1 H NMR (400MHz, CD3OD) δ7.48-7.44(m,2H),7.44-7.34(m,2H),3.84(s,3H),1.46(s,6H).

[0780] Step ⑨: 4-(3-Fluoro-5-(trifluoromethyl)benzyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (88-9)

[0781] The preparation method of 4-(3-fluoro-5-(trifluoromethyl)benzyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (88-9) is the same as compound 1-5. LC-MS (ESI) m / z [MH] + :386.1.

[0782] Step ⑩: 4-(3-Fluoro-5-(trifluoromethyl)benzyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-88)

[0783] The preparation method of 4-(3-fluoro-5-(trifluoromethyl)benzyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-88) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.07(s,1H),7.84(s,1H),7.73(d,J=8.0Hz,1H),7.6 9-7.64(m,2H),7.52(s,1H),7.45(d,J=9.1Hz,1H),7.36(dt,J=8.2,0.9Hz,1H),7.14-7.04(m 1H),7.03-6.99(m,1H),5.02(s,2H),1.42(s,6H).LC-MS(ESI)m / z[M+H] + :502.2.

[0784] Example 89 1-((4-chlorothien-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-89)

[0785] Step ①: 1-((4-chlorothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (89-1)

[0786] The preparation method of methyl 1-((4-chlorothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (89-1) is the same as compound 2-3. 1 H NMR (400MHz, CD3OD) δ7.42 (s, 1H), 7.18-7.13 (m, 1H), 6.83 (d, J = 1.8Hz, 1H), 4.75 (s, 2H), 3.80 (s, 3H), 1.37 (s, 6H). LC-MS (ESI) m / z [M+H] + :356.2.

[0787] Step ②: 1-((4-chlorothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (89-2)

[0788] The preparation method of 1-((4-chlorothiophen-3-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (89-2) is the same as compound 1-5. LC-MS (ESI) m / z [MH] + :340.1.

[0789] Step ③: 1-((4-chlorothien-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-89)

[0790] The preparation method of 1-((4-chlorothiophen-3-yl)methyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-89) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),10.09(s,1H),7.87(s,1H),7.76(d,J=8.0Hz,1H),7.67(d,J=2.5Hz,1H),7.36(d,J=8.1Hz,1H),7.27(d,J=1. 8Hz,1H),7.12(ddd,J=8.2,6.9,1.2Hz,1H),7.06(d,J=1.8Hz,1H),7.02(ddd,J=7.9,6.9,1.0Hz,1H),4.79(s,2H),1.39(s,6H).LC-MS(ESI)m / z[MH] + :456.0.

[0791] Example 90 N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-4-((5-(trifluoromethyl)thien-3-yl)methyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-90)

[0792] Step ①: 4-((5-bromothien-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (90-1)

[0793] The preparation method of methyl 4-((5-bromothiophen-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylate (90-1) is the same as compound 2-3. 1 H NMR (400MHz, CD3OD) δ7.45(s,1H),7.31(dd,J=1.7,0.9Hz,1H),6.99(d,J=1.7Hz,1H),4.81(s,2H),3.83(s,3H),1.41(s,6H).LC-MS(ESI)m / z[M+H] + :400.0.

[0794] Step ②: 4-((5-trifluoromethylthiophen-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (90-2)

[0795] 74 mg of compound 90-1, 355 mg of methyl fluorosulfonyldifluoroacetate, 352.1 mg of iodide, and 1 mL of DMF were added to a round-bottom flask and stirred at 130°C overnight under argon. The reaction mixture was extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was purified using silica gel preparative thin layer chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain 20.0 mg of methyl 4-((5-trifluoromethylthien-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylate (90-2) as a yellow solid in a 28% yield. 1 H NMR (400MHz, CD3OD) δ7.66 (d, J = 1.5Hz, 1H), 7.51 (s, 1H), 7.48-7.45 (m, 1H), 4.91 (s, 2H), 3.84 (s, 3H), 1.43 (s, 6H).

[0796] Step ③: 4-((5-trifluoromethylthiophen-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (90-3)

[0797] The preparation method of 4-((5-trifluoromethylthiophen-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (90-3) is the same as compound 1-5. LC-MS (ESI) m / z [MH] + :374.0.

[0798] Step ④: N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-4-((5-(trifluoromethyl)thien-3-yl)methyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-90)

[0799] The preparation method of N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-4-((5-(trifluoromethyl)thiophen-3-yl)methyl)-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-90) is the same as compound I-1. 1H NMR(400MHz,DMSO-d6)δ10.96(s,1H), 10.08(s,1H),7.89(s,1H),7.79-7.70(m,2H),7.68-7.64(m,2H),7.39-7.33(m,1H), 7.15-7.06(m,1H),7.04-6.96(m,1H),4.90(s,2H),1.40(s,6H).LC-MS(ESI)m / z[M+H] + :490.2.

[0800] Example 91 4-((5-chlorofuran-3-yl)methyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-91)

[0801] Step ①: 4-((5-chlorofuran-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid methyl ester (91-1)

[0802] The preparation method of methyl 4-((5-chlorofuran-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylate (91-1) is the same as compound 2-3. 1 H NMR (400MHz, CD3OD) δ7.55-7.50(m,2H),6.20(d,J=1.1Hz,1H),4.70(d,J=1.0Hz,2H),3.85(s,3H),1.40(s,6H).LC-MS(ESI)m / z[M+H] + :340.0.

[0803] Step ②: 4-((5-chlorofuran-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (91-2)

[0804] The preparation method of 4-((5-chlorofuran-3-yl)methyl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxylic acid (91-2) is the same as compound 1-5. 1H NMR(400MHz, CDCl3)δ9.92(s,1H),7.39(s,1H),7.33(s,1H),6.11(s,1H),4.66(s,2H),1.46(s,6H).LC-MS(ESI)m / z[MH] - :324.0.

[0805] Step ③: 4-((5-chlorofuran-3-yl)methyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-91)

[0806] The preparation method of 4-((5-chlorofuran-3-yl)methyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-91) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.96(s,1H),10.10(s,1H),7.88(s,1H),7.77(d,J=8.0Hz,1H),7.73(s,1H),7.68(d,J=2.5Hz,1H),7.3 7(d,J=8.1Hz,1H),7.15-7.09(m,1H),7.06-7.00(m,1H),6.46(d,J=1.2Hz,1H),4.69(s,2H),1.37(s,6H).LC-MS(ESI)m / z[M+H] + :440.1.

[0807] Example 92 1-(Benzo[d][1,3]dihydroxy-5-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindole-6-carboxamide (I-92)

[0808] Step ①: 1-(Benzo[d][1,3]dihydroxy-5-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (92-1)

[0809] The preparation method of 1-(benzo[d][1,3]dihydroxy-5-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (92-1) is the same as compound 2-3. 1H NMR (400MHz, CD3OD) δ7.70(dd,J=7.7,1.5Hz,1H),7.45(d,J=1.4Hz,1H),7.34(d,J=7.7Hz,1H),6.76(dd,J=7 .9,1.7Hz,1H),6.72-6.66(m,2H),5.82(s,2H),4.81(s,2H),3.81(s,3H),1.37(s,6H).LC-MS(ESI)m / z[M+H] + :354.1.

[0810] Step ②: 1-(Benzo[d][1,3]dihydroxy-5-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (92-2)

[0811] The preparation method of 1-(benzo[d][1,3]dihydroxy-5-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (92-2) is the same as compound 1-5. 1 H NMR (400MHz, DMSO-d6) δ12.95(s,1H),7.66(dd,J=7.7,1.4Hz,1H),7.50(d,J=7.7Hz,1H),7.39(d,J=1.4Hz,1H),6.87(d,J= 8.0Hz,1H),6.83(d,J=1.7Hz,1H),6.75(dd,J=8.0,1.8Hz,1H),5.98(s,2H),4.86(s,2H),1.35(s,6H).LC-MS(ESI)m / z[MH] + :338.1.

[0812] Step ③: 1-(Benzo[d][1,3]dihydroxy-5-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindole-6-carboxamide (I-92)

[0813] The preparation method of 1-(benzo[d][1,3]dihydroxy-5-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindole-6-carboxamide (I-92) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),10.07(s,1H),7.81(d,J=8.0Hz,1H),7.76(d,J =2.5Hz,1H),7.71(dd,J=7.7,1.5Hz,1H),7.53(d,J=7.6Hz,1H),7.47(d,J=1.5Hz,1H) ,7.36(d,J=8.1Hz,1H),7.15-7.06(m,1H),7.03-6.96(m,1H),6.90-6.85(m,2H),6.8 0(dd,J=8.0,1.7Hz,1H),5.98(s,2H),4.88(s,2H),1.37(s,6H).LC-MS(ESI)m / z[M+H] + :454.3.

[0814] Example 93 1-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-93)

[0815] Step ①: 1-(Benzofuran-5-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (93-1)

[0816] The preparation method of 1-(benzofuran-5-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (93-1) is the same as compound 2-3. 1 H NMR(400MHz, DMSO-d6)δ7.98(d,J=2.2Hz,1H),7.68(dd,J=7.8,1.5Hz,1H),7.59-7.53(m,3H),7.40(d,J=1.4Hz,1H), 7.24(dd,J=8.6,1.8Hz,1H),6.94(dd,J=2.2,1.0Hz,1H),5.06(s,2H),3.79(s,3H),1.38(s,6H).LC-MS(ESI)m / z[M+H] + :350.3.

[0817] Step ②: 1-(Benzofuran-5-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (93-2)

[0818] The preparation method of 1-(benzofuran-5-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (93-2) is the same as compound 1-5. 1H NMR (400MHz, DMSO-d6) δ12.97(s,1H),7.98(d,J=2.2Hz,1H),7.65(dd,J=7.7,1.4Hz,1H),7.57(d,J=8.5Hz,1H),7.54(d,J=1.8Hz,1H),7.5 0(d,J=7.7Hz,1H),7.38(d,J=1.4Hz,1H),7.24(dd,J=8.5,1.8Hz,1H),6.94(d,J=2.3Hz,1H),5.05(s,2H),1.38(s,6H).LC-MS(ESI)m / z[MH] + :334.2.

[0819] Step ③: 1-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-93)

[0820] The preparation method of 1-(benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-93) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),10.06(s,1H),7.97(d,J=2.2Hz,1H),7.79(d,J=8.0Hz,1H),7.73 (d,J=2.4Hz,1H),7.71(dd,J=7.7,1.5Hz,1H),7.61(d,J=1.8Hz,1H),7.58(d,J=8.5Hz,1H),7.54(d,J=7 .7Hz,1H),7.49(d,J=1.5Hz,1H),7.35(d,J=8.1Hz,1H),7.29(dd,J=8.5,1.8Hz,1H),7.14-7.06(m,1.2 Hz,1H),7.05-6.95(m,1H),6.94(dd,J=2.2,0.9Hz,1H),5.07(s,2H),1.40(s,6H).LC-MS(ESI)m / z[M+H] + :450.0.

[0821] Example 94 1-(Indol-5-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-94)

[0822] Step ①: tert-Butyl 5-((6-(methoxycarbonyl)-3,3-dimethyl-2-oxoindole-1-yl)methyl)-1H-indole-1-carboxylate (94-1)

[0823] The preparation method of tert-butyl 5-((6-(methoxycarbonyl)-3,3-dimethyl-2-oxoindole-1-yl)methyl)-1H-indole-1-carboxylate (94-1) is the same as compound 2-3. 1 H NMR (400MHz, CD3OD) δ8.06(d,J=8.6Hz,1H),7.74(dd,J=7.7,1.5Hz,1H),7.58(d,J=3.8Hz,1H),7.48(d,J=1.5Hz,2H),7.40(d,J=7. 7Hz,1H),7.23(dd,J=8.6,1.8Hz,1H),6.58-6.52(m,1H),5.04(s,2H),3.82(s,3H),1.63(s,9H),1.43(s,6H).LC-MS(ESI)m / z[M+Na] + :449.1.

[0824] Step ②: 5-((6-(methoxycarbonyl)-3,3-dimethyl-2-oxoindole-1-yl)methyl)-1H-indole-1-carboxylic acid (94-2)

[0825] The preparation method of 5-((6-(methoxycarbonyl)-3,3-dimethyl-2-oxoindole-1-yl)methyl)-1H-indole-1-carboxylic acid (94-2) is the same as compound 1-5. 1 H NMR (400MHz, DMSO-d6) δ12.80(s,1H),11.10(s,1H),7.63(dd,J=7.7,1.4Hz,1H),7.50(d,J=7.7Hz,1H),7.45(d,J=1.5Hz,1H),7.38(d,J=1.4H z,1H),7.35(d,J=8.4Hz,1H),7.36-7.29(m,1H),7.00(dd,J=8.4,1.7Hz,1H),6.40-6.36(m,1H),5.00(s,2H),1.37(s,6H).LC-MS(ESI)m / z[MH] - :333.1.

[0826] Step ③: 1-(Indol-5-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-94)

[0827] The preparation method of 1-(indol-5-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-94) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ11.08(s,1H),10.89(s,1H),10.05(s,1H),7.80(d,J=7.9Hz, 1H),7.73(d,J=2.5Hz,1H),7.69(dd,J=7.7,1.5Hz,1H),7.54-7.49(m,3H),7.35(dd,J =8.3,3.2Hz,2H),7.34-7.28(m,1H),7.14-7.06(m,1H),7.06(dd,J=8.4,1.7Hz,1H), 7.05-6.96(m,1H),6.40-6.37(m,1H),5.02(s,2H),1.39(s,6H).LC-MS(ESI)m / z[M+H] + :449.0.

[0828] Example 95 1-([1,1'-biphenyl]-2-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-95)

[0829] Step ①: 1-([1,1'-biphenyl]-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (95-1)

[0830] The preparation method of methyl 1-([1,1'-biphenyl]-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (95-1) is the same as compound 2-3. 1 H NMR (400MHz, DMSO-d6) δ7.63 (dd, J=7.7, 1.5Hz, 1H), 7.56-7.48 (m, 5H), 7.45 (td, J=6.6, 2.2Hz, 1H), 7.38-7.28 (m,3H),7.08-7.04(m,1H),6.97(d,J=1.5Hz,1H),4.87(s,2H),3.81(s,3H),1.31(s,6H).LC-MS(ESI)m / z[M+H] + :386.2.

[0831] Step ②: 1-([1,1'-biphenyl]-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (95-2)

[0832] The preparation method of 1-([1,1'-biphenyl]-2-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (95-2) is the same as compound 1-5. 1 H NMR (400MHz, DMSO-d6) δ12.87 (s, 1H), 7.62 (dd, J = 7.7, 1.5Hz, 1H), 7.51-7.41 (m, 6H), 7.3 6-7.28(m,3H),7.03(dt,J=4.1,2.3Hz,2H),4.86(s,2H),1.31(s,6H).LC-MS(ESI)m / z[MH] + :370.1.

[0833] Step ③: 1-([1,1'-biphenyl]-2-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-95)

[0834] The preparation method of 1-([1,1'-biphenyl]-2-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-95) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),10.05(s,1H),7.80(d,J=8.0Hz,1H),7.75(d,J=2.5Hz,1H),7.66(dd,J=7.7,1.5Hz,1H) ,7.54-7.46(m,5H),7.44-7.39(m,1H),7.37-7.28(m,4H),7.14-6.99(m,4H),4.90(s,2H),1.35(s,6H).LC-MS(ESI)m / z[M+H] + :486.4.

[0835] Example 96 N-(1H-indol-3-yl)-3,3-dimethyl-1-((1-methylpiperidin-4-yl)methyl)-2-oxoindolin-6-carboxamide (I-96)

[0836] Step ①: 1-((1-(tert-Butyloxycarbonyl)piperidin-4-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (96-1)

[0837] The preparation method of methyl 1-((1-(tert-butyloxycarbonyl)piperidin-4-yl)methyl)-3,3-dimethyl-2-oxoindoline-6-carboxylate (96-1) is the same as compound 2-3. 1 H NMR (400MHz, DMSO-d6) δ7.69(dd,J=7.7,1.4Hz,1H),7.56(d,J=1.5Hz,1H),7.51(d,J=7.7Hz,1H),3.95-3.85(m,5H),3.6 3(d,J=7.4Hz,2H),2.75-2.55(m,2H),1.98-1.87(m,1H),1.59-1.49(m,2H),1.38(s,9H),1.30(s,6H),1.14-1.03(m,2H).

[0838] Step ②: 3,3-dimethyl-2-oxo-1-(piperidin-4-ylmethyl)indoline-6-carboxylic acid methyl ester (96-2)

[0839] The preparation method of methyl 3,3-dimethyl-2-oxo-1-(piperidin-4-ylmethyl)indoline-6-carboxylate (96-2) is the same as compound 85-9. 1 H NMR (400MHz, DMSO-d6) δ8.38(s,1H),7.71(dd,J=7.6,1.4Hz,1H),7.57(d,J=1.4Hz,1H),7.53(d,J=7.7Hz,1H),3.87(s,3H),3.6 7(d,J=7.3Hz,2H),3.29-3.22(m,2H),2.88-2.79(m,2H),2.10-2.02(m,1H),1.78-1.70(m,2H),1.43-1.34(m,2H),1.31(s,6H).

[0840] Step ③: 3,3-dimethyl-1-((1-methylpiperidin-4-yl)methyl)-2-oxoindoline-6-carboxylic acid methyl ester (96-3)

[0841] Compound 96-2 (100 mg), acetic acid (95 mg), formaldehyde (77 mg), and methanol (1 mL) were stirred at room temperature for 1 hour. Sodium cyanoborohydride was then added and stirred at room temperature for 1 hour. Finally, saturated aqueous sodium bicarbonate was added and stirred at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was then thin-layered with dichloromethane:methanol (10:1) to yield 88.3 mg of methyl 3,3-dimethyl-1-((1-methylpiperidin-4-yl)methyl)-2-oxoindolin-6-carboxylate (96-3) as a yellow oil, in an 84.6% yield. 1H NMR (400MHz, CD3OD) δ7.81(dd,J=7.7,1.4Hz,1H),7.64(d,J=1.4Hz,1H),7.44(d,J=7.7Hz,1H),3.92(s,3H),3.78(d,J=7.3Hz, 2H),3.53-3.46(m,2H),3.05-2.94(m,2H),2.84(s,3H),2.25-2.14(m,,1H),2.01-1.92(m,2H),1.70-1.58(m,2H),1.39(s,6H).

[0842] Step ④: 3,3-dimethyl-1-((1-methylpiperidin-4-yl)methyl)-2-oxoindoline-6-carboxylic acid (96-4)

[0843] The preparation method of 3,3-dimethyl-1-((1-methylpiperidin-4-yl)methyl)-2-oxoindoline-6-carboxylic acid (96-4) is the same as compound 1-5. LC-MS (ESI) m / z [MH] - :315.1.

[0844] Step ⑤: N-(1H-indol-3-yl)-3,3-dimethyl-1-((1-methylpiperidin-4-yl)methyl)-2-oxoindoline-6-carboxamide (I-96)

[0845] The preparation method of N-(1H-indol-3-yl)-3,3-dimethyl-1-((1-methylpiperidin-4-yl)methyl)-2-oxoindoline-6-carboxamide (I-96) is the same as compound I-1. 1 H NMR (400MHz, CD3OD) δ7.78(d,J=7.7Hz,1H),7.70(d,J=8.0Hz,1H),7.67-7.64(m,2H ),7.48(d,J=7.6Hz,1H),7.39(d,J=8.2Hz,1H),7.16(t,J=7.5Hz,1H),7.06(t,J=7.5 Hz,1H),3.79(d,J=7.3Hz,2H),3.47-3.40(m,2H),2.95-2.85(m,2H),2.24(s,1H),1 .98-1.90(m,2H),1.68-1.54(m,2H),1.42(s,6H),1.29(s,3H).LC-MS(ESI)m / z[M+H] + :431.2.

[0846] Example 97 1-(Benzofuran-7-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-97)

[0847] Step ①: 1-(Benzofuran-7-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (97-1)

[0848] The preparation method of 1-(benzofuran-7-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid methyl ester (97-1) is the same as compound 2-3. 1 H NMR (400MHz, CD3OD) δ7.80(d,J=1.7Hz,1H),7.74(d,J=7.7Hz,1H),7.58-7.54(m,1H),7.51(s,1H),7.4 1(d,J=7.8Hz,1H),7.19(d,J=4.4Hz,2H),6.86(t,J=1.4Hz,1H),5.29(s,2H),3.83(s,3H),1.44(s,6H).

[0849] Step ②: 1-(Benzofuran-7-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (97-2)

[0850] The preparation method of 1-(benzofuran-7-ylmethyl)-3,3-dimethyl-2-oxoindoline-6-carboxylic acid (97-2) is the same as compound 1-5. 1 H NMR (400MHz, DMSO-d6) δ12.88(s,1H),8.02(d,J=2.2Hz,1H),7.64(d,J=7.7Hz,1H),7.58(d,J=7.8Hz,1H),7.51(d,J=7 .7Hz,1H),7.34(s,1H),7.21(t,J=7.6Hz,1H),7.09(d,J=7.4Hz,1H),6.98(d,J=2.2Hz,1H),5.25(s,2H),1.39(s,6H).

[0851] Step ③: 4-((5-chlorofuran-3-yl)methyl)-N-(1H-indol-3-yl)-6,6-dimethyl-5-oxo-5,6-dihydro-4H-thieno[3,2-b]pyrrole-2-carboxamide (I-97)

[0852] The preparation method of 1-(benzofuran-7-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-97) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),10.03(s,1H),8.02(d,J=2.2Hz,1H),7.76(d,J=7.9Hz,1H),7.73-7.65(m,2H),7.60-7.53(m,2H),7.41( s,1H),7.34(d,J=8.1Hz,1H),7.21(t,J=7.6Hz,1H),7.09(t,J=8.1Hz,2H),7.04-6.93(m,2H),5.28(s,2H),1.42(s,6H).LC-MS(ESI)m / z[M+H] + :450.2.

[0853] Example 98 N-(Benzo[b]thiophen-3-yl)-1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-98)

[0854] The preparation method of N-(benzo[b]thiophen-3-yl)-1-((1-(3-fluoro-5-(trifluoromethyl)phenyl)azetidin-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-98) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.39(s,1H),8.08(dd,J=6.1,3.3Hz,1H),7.99(d,J=7.9Hz,2H),7.73(d,J=7.1Hz,2H),7.55(d,J=7.7Hz,1H),7.42-7.44(m,2 H),6.78(d,J=8.8Hz,1H),6.48-6.57(m,2H),4.10(d,J=7.5Hz,2H),3.99(t ,J=8.0Hz,2H),3.74(dd,J=7.6,5.5Hz,2H),3.26-3.28(m,1H),1.33(s,6H).

[0855] Example 99 N-(1H-indol-3-yl)-3,3,7-trimethyl-2-oxo-1-(thien-3-ylmethyl)indoline-6-carboxamide (I-99)

[0856] Step ①: N'-(3-bromo-2-methylphenyl)isobutyric acid hydrazide (99-1)

[0857] A mixture of 330 μL of 3-bromo-2-methylaniline, 3 mL of 3N hydrochloric acid, and 205 mg of an aqueous sodium nitrite solution was allowed to react at -10°C for 30 minutes. Then, 1.5 g of tin chloride dissolved in concentrated hydrochloric acid was slowly added dropwise to the reaction mixture for one hour. The reaction mixture was filtered, and the filter cake was washed with ice water, 2N hydrochloric acid, and ethyl acetate, dried, and dissolved in 5 mL of methanol. A mixture of 370 μL of triethylamine and 135 μL of isobutyryl chloride was added and allowed to react at 0°C for one hour. The reaction mixture was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate in a ratio of 2:1 to yield 291 mg of N'-(3-bromo-2-methylphenyl)isobutyrylhydrazide (99-1), a 40% yield. 1 H NMR(400MHz,DMSO-d6)δ9.69(d,J=2.4Hz,1H),7.35(d,J=2.5Hz,1H),6.92-6.97(m,2H ),6.60(dd,J=6.4,2.9Hz,1H),2.49-2.54(m,1H),2.23(s,3H),1.08(d,J=6.8Hz,6H).

[0858] Step ②: 6-bromo-3,3,7-trimethylindolin-2-one (99-2)

[0859] A mixture of 200 mg of N'-(3-bromo-2-methylphenyl)isobutyric acid hydrazide (99-1), 60 mg of calcium hydride, and 3 mL of tetralin was reacted at 200°C for 17 hours. After the reaction mixture was cooled to below 0°C, 100 μL each of methanol and water were added. Concentrated hydrochloric acid was added to adjust the pH to 1, and the mixture was heated under reflux for 1 hour. After the reaction mixture was cooled to room temperature, 3N sodium hydroxide solution was added to adjust the pH to 5. The mixture was extracted with ethyl acetate, and the organic phase was concentrated to dryness. The residue was purified by column chromatography using petroleum ether:ethyl acetate in a ratio of 3:1 to obtain 110 mg of 6-bromo-3,3,7-trimethylindolin-2-one (99-2) in a 41% yield. 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),7.20(d,J=7.9Hz,1H),7.07(d,J=7.9Hz,1H),2.26(s,3H),1.23(s,6H).

[0860] Step ③: 3,3,7-trimethyl-2-oxoindoline-6-carboxylic acid methyl ester (99-3)

[0861] A mixture of 500 mg of 6-bromo-3,3,7-trimethylindolin-2-one (99-2), 150 mg of 1,1'-bis(diphenylphosphino)ferrocenepalladium dichloride, 850 ml of triethylamine, and 4 ml of methanol was heated and stirred at 100°C under a carbon monoxide atmosphere for 12 hours. The reaction solution was concentrated to dryness, and the residue was purified by column chromatography using petroleum ether:ethyl acetate in a ratio of 3:1 to obtain 164 mg of methyl 3,3,7-trimethyl-2-oxoindolin-6-carboxylate (99-3), a 36% yield. 1 H NMR (400MHz, Chloroform-d) δ8.81(s,1H),7.63(d,J=7.8Hz,1H),7.08(d,J=7.8Hz,1H),3.90(s,3H),2.51(s,3H),1.41(s,6H).

[0862] Step ④: 3,3,7-trimethyl-2-oxo-1-(thien-3-ylmethyl)indoline-6-carboxylic acid methyl ester (99-4)

[0863] The preparation method of methyl 3,3,7-trimethyl-2-oxo-1-(thiophen-3-ylmethyl)indoline-6-carboxylate (99-4) is the same as 2-3. 1 H NMR(400MHz,Chloroform-d)δ7.45(d,J=7.7Hz,1H),7.29(dd,J=4.9,3.1Hz,1H),7.11( d,J=7.8Hz,1H),6.90-6.97(m,2H),5.22(s,2H),3.86(s,3H),2.50(s,3H),1.42(s,6H).

[0864] Step ⑤: 3,3,7-trimethyl-2-oxo-1-(thiophen-3-ylmethyl)indoline-6-carboxylic acid (99-5)

[0865] The preparation method of 3,3,7-trimethyl-2-oxo-1-(thiophen-3-ylmethyl)indoline-6-carboxylic acid (99-5) is the same as that of 1-5. LCMS (ESI) m / z [M+H] + :316.1.

[0866] Step ⑥: N-(1H-indol-3-yl)-3,3,7-trimethyl-2-oxo-1-(thien-3-ylmethyl)indoline-6-carboxamide (I-99)

[0867] The preparation method of N-(1H-indol-3-yl)-3,3,7-trimethyl-2-oxo-1-(thiophen-3-ylmethyl)indoline-6-carboxamide (I-99) is the same as I-1. 1 H NMR (400MHz, Chloroform-d) δ8.13(s,1H),7.94(d,J=2.5Hz,1H),7.57(s,1H),7.46(d,J=7.9Hz,1H),7.38(d,J=8.3Hz,1H),7.30(dd,J=5.0 ,3.0Hz,1H),7.23(td,J=7.8,1.6Hz,2H),7.11-7.18(m,2H),6.96(ddd,J=6.4,4.0,1.4Hz,2H),5.20-5.25(m,2H),2.50(s,3H),1.46(s,6H).

[0868] Example 100 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(1-phenylethyl)indoline-6-carboxamide (I-100)

[0869] Step ①: 3,3-dimethyl-2-carbonyl-1-(1-phenylethyl)indoline-6-carboxylic acid methyl ester (100-1)

[0870] The preparation of methyl 3,3-dimethyl-2-carbonyl-1-(1-phenylethyl)indoline-6-carboxylate (100-1) was the same as compound 2-3. 1 H NMR(400MHz, CDCl3)δ7.70(dd,J=7.7,1.5Hz,1H),7.33-7.36(m,4H),7.26-7.29(m,1H),7.24(d,J=7.7Hz,1 H),7.21(d,J=1.4Hz,1H),5.84(q,J=7.2Hz,1H),3.83(s,3H),1.86(d,J=7.2Hz,3H),1.43(d,J=6.5Hz,6H).

[0871] Step ②: 3,3-dimethyl-2-carbonyl-1-(1-phenylethyl)indoline-6-carboxylic acid (100-2)

[0872] The preparation of 3,3-dimethyl-2-carbonyl-1-(1-phenylethyl)indoline-6-carboxylic acid (100-2) is the same as compound 1-5. LCMS (ESI) m / z [M+H] + :310.1.

[0873] Step ③: N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(1-phenylethyl)indoline-6-carboxamide (I-100)

[0874] The preparation of N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(1-phenylethyl)indoline-6-carboxamide (I-100) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.89(d,J=2.6Hz,1H),10.04(s,1H),7.77(d,J=8.0Hz,1H),7.72 (d,J=2.5Hz,1H),7.67(dd,J=7.7,1.4Hz,1H),7.52(d,J=7.7Hz,1H),7.32-7.38(m,5H),7 .24-7.29(m,1H),7.17(d,J=1.6Hz,1H),7.10(ddd,J=8.2,6.9,1.2Hz,1H),7.00(ddd,J=8 .0,6.9,1.1Hz,1H),5.71(t,J=7.2Hz,1H),1.85(d,J=7.1Hz,3H),1.38(d,J=11.0Hz,6H).

[0875] Example 102 1-phenyl-3-ethyl-N-(1H-indol-3-yl)-3-methyl-2-indoline-6-carboxamide (I-101)

[0876] Step ①: 6-bromo-3-ethyl-3-methylindolin-2-one (101-1)

[0877] A mixture of 500 mg of 6-bromo-3-methylindolin-2-one, 1.9 ml of n-butyllithium in n-hexane, 1 ml of N,N,N',N'-tetramethylethylenediamine, and 3 ml of extra-dry tetrahydrofuran was stirred at -78°C under an argon atmosphere for 0.5 hour. 270 μL of ethyl iodide dissolved in tetrahydrofuran was then added dropwise to the reaction mixture, and the reaction was continued at 0°C for 2 hours. The reaction mixture was quenched and concentrated to dryness. The residue was purified by column chromatography using petroleum ether:ethyl acetate in a ratio of 3:1 to afford 246 mg of 6-bromo-3-ethyl-3-methylindolin-2-one (101-1), in a 44% yield. 1H NMR (400MHz, CDCl3) δ7.73 (s, 1H), 7.18 (dd, J = 7.9, 1.7Hz, 1H), 7.05 (d, J = 1.7Hz, 1H), 7.01 (d,J=7.9Hz,1H),1.87-1.98(m,1H),1.70-1.80(m,1H),1.36(s,3H),0.65(t,J=7.4Hz,3H).

[0878] Step ②: 1-phenyl-6-bromo-3-ethyl-3-methylindolin-2-one (101-2)

[0879] The preparation method of 1-phenyl-6-bromo-3-ethyl-3-methylindolin-2-one (101-2) is the same as compound 2-3. 1 H NMR (400MHz, CDCl3) δ7.30-7.35(m,2H),7.28(dt,J=3.5,1.7Hz,3H),7.16(dd,J=7.8,1.7Hz,1H),7.02(d,J=7.8Hz,1H),6. 86(d,J=1.7Hz,1H),4.77-5.01(m,2H),1.93-2.06(m,1H),1.80(dq,J=13.5,7.4Hz,1H),1.39(s,3H),0.63(t,J=7.4Hz,3H).

[0880] Step ③: 1-phenyl-3-ethyl-3-methyl-2-indoline-6-carbonitrile (101-3)

[0881] The preparation of 1-phenyl-3-ethyl-3-methyl-2-indoline-6-carbonitrile (101-3) was the same as compound 11-2. 1 H NMR (400MHz, CDCl3) δ7.29-7.37(m,4H),7.26-7.28(m,2H),7.264-7.26(m,1H),6.91(d,J=1.4Hz,1H), 4.81-5.02(m,2H),2.00-2.10(m,1H),1.84(dq,J=13.6,7.4Hz,1H),1.42(s,3H),0.63(t,J=7.4Hz,3H).

[0882] Step ④: 1-phenyl-3-ethyl-3-methyl-2-indoline-6-carboxylic acid (101-4)

[0883] The preparation of 1-phenyl-3-ethyl-3-methyl-2-indoline-6-carboxylic acid (101-4) is the same as compound 11-3. LCMS (ESI) m / z [M+H] + :310.1.

[0884] Step ⑤: 1-phenyl-3-ethyl-N-(1H-indol-3-yl)-3-methyl-2-indoline-6-carboxamide (I-101)

[0885] The preparation method of 1-phenyl-3-ethyl-N-(1H-indol-3-yl)-3-methyl-2-indoline-6-carboxamide (I-101) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.90 (s, 1H), 10.09 (s, 1H), 7.81 (d, J = 7.9Hz, 1H), 7.71-7. 76(m,2H),7.49(d,J=7.7Hz,1H),7.46(d,J=1.6Hz,1H),7.31-7.38(m,5H),7.27(td ,J=5.9,2.6Hz,1H),7.10(ddd,J=8.2,7.0,1.2Hz,1H),7.00(ddd,J=8.0,7.0,1.1Hz ,1H),4.99(q,J=15.9Hz,2H),1.83-1.95(m,2H),1.36(s,3H),0.56(t,J=7.4Hz,3H).

[0886] Example 102 N-(1H-indol-3-yl-3,3-dimethyl-2-carbonyl-1-((5-(trifluoromethyl)thiophen-3-yl)methyl)indoline-6-carboxamide (I-102)

[0887] Step ①: 1-((5-bromothiophen-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylic acid methyl ester (102-1)

[0888] The preparation method of methyl 1-((5-bromothiophen-3-yl)methyl)-3,3-dimethyl-2-indoline-6-carboxylate (102-1) is the same as compound 2-3. 1H NMR(400MHz, CDCl3)δ7.77(dd,J=7.7,1.4Hz,1H),7.44(d,J=1.5Hz,1H),7.25-7.29(m,1H) ,7.07(dd,J=1.8,0.9Hz,1H),6.96(d,J=1.7Hz,1H),4.84(s,2H),3.90(s,3H),1.41(s,6H).

[0889] Step ②: 3,3-Dimethyl-2-carbonyl-1-((5-(trifluoromethyl)thiophen-3-yl)methyl)indoline-6-carboxylic acid methyl ester (102-2)

[0890] The preparation of methyl 3,3-dimethyl-2-carbonyl-1-((5-(trifluoromethyl)thiophen-3-yl)methyl)indoline-6-carboxylate (102-2) was the same as compound 90-2. 1 H NMR (400MHz, CDCl3) δ7.80 (dd, J=7.7, 1.5Hz, 1H), 7.44 (d, J=1.5Hz, 1H), 7.35 (dd, J=6 .6,1.4Hz,2H),7.29(d,J=7.7Hz,1H),4.90(d,J=1.0Hz,2H),3.91(s,3H),1.42(s,6H).

[0891] Step ⑤: 3,3-Dimethyl-2-carbonyl-1-((5-(trifluoromethyl)thiophen-3-yl)methyl)indoline-6-carboxylic acid (102-3)

[0892] The preparation method of 3,3-dimethyl-2-carbonyl-1-((5-(trifluoromethyl)thiophen-3-yl)methyl)indoline-6-carboxylic acid (102-3) is the same as compound 1-5. LCMS (ESI) m / z [M+H] + :370.1.

[0893] Step ⑥: N-(1H-indol-3-yl-3,3-dimethyl-2-carbonyl-1-((5-(trifluoromethyl)thiophen-3-yl)methyl)indoline-6-carboxamide (I-102)

[0894] The preparation method of N-(1H-indol-3-yl-3,3-dimethyl-2-carbonyl-1-((5-(trifluoromethyl)thiophen-3-yl)methyl)indoline-6-carboxamide (I-102) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),10.08(s,1H),7.81(d,J=8.0Hz,1H),7.76(t,J=2.1Hz,2H),7.73(dd,J=7.7,1.5Hz,1H),7.64(q,J=1 .4Hz,1H),7.60(d,J=1.5Hz,1H),7.55(d,J=7.7Hz,1H),7.35-7.38(m,1H),7.09-7.14(m,1H),6.98-7.02(m,1H),5.00(s,2H),1.38(s,6H).

[0895] Example 103 N-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-2-carbonyl-1-((5-(trifluoromethyl)thiophen-3-yl)methyl)indoline-6-carboxamide (I-103)

[0896] The preparation method of N-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-2-carbonyl-1-((5-(trifluoromethyl)thiophen-3-yl)methyl)indoline-6-carboxamide (I-103) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ11.02 (s, 1H), 10.07 (s, 1H), 7.85 (d, J = 2.6Hz, 1H), 7.68-7.78 (m, 2H) ,7.51-7.65(m,4H),7.36(dd,J=8.8,4.5Hz,1H),6.93-6.98(m,1H),5.00(s,2H),1.37(s,6H).

[0897] Example 104 1-(3-Fluoro-5-(trifluoromethyl)phenyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-104)

[0898] Step ①: 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3,3-dimethyl-2-indoline-6-carboxylic acid methyl ester (104-1)

[0899] The preparation method of methyl 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3,3-dimethyl-2-indoline-6-carboxylate (104-1) is the same as compound 2-3. 1H NMR (400MHz, CDCl3) δ7.81 (d, J=7.7Hz, 1H), 7.33 (dd, J=14.1, 6.9Hz, 3H), 7.24 (d,J=8.4Hz,1H),7.12(d,J=8.9Hz,1H),4.98(s,2H),3.89(s,3H),1.46(s,6H).

[0900] Step ②: 1-(3-Fluoro-5-(trifluoromethyl)phenyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (104-2)

[0901] The preparation method of 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (104-2) is the same as compound 1-5. LCMS (ESI) m / z [M+H] + :382.1.

[0902] Step ③: 1-(3-Fluoro-5-(trifluoromethyl)phenyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-104)

[0903] The preparation method of 1-(3-fluoro-5-(trifluoromethyl)phenyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-104) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.90(d,J=2.5Hz,1H),10.08(s,1H),7.80(d,J=8.0Hz,1H),7.72-7.77(m,2H),7.64(d,J=8.7Hz,1H),7.5 4-7.59(m,3H),7.46(d,J=9.2Hz,1H),7.35(dt,J=8.2,0.9Hz,1H),7.09-7.13(m,1H),6.97-7.01(m,1H),5.12(s,2H),1.40(s,6H).

[0904] Example 106 1-phenyl-N-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-105)

[0905] The preparation method of 1-phenyl-N-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-105) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),10.05(s,1H),7.82(d,J=2.6Hz,1H),7.71(d,J=7.7Hz,1H),7.50-7.63(m ,2H),7.42(s,1H),7.35(dd,J=8.9,5.0Hz,3H),7.24-7.32(m,3H),6.90-7.00(m,1H),4.99(s,2H),1.39(s,6H).

[0906] Example 106 N-(5-Fluoro-1H-indol-3-yl)-3,3-dimethyl-2-carbonyl-1-(thien-3-ylmethyl)indoline-6-carboxamide (I-106)

[0907] The preparation method of N-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-2-carbonyl-1-(thiophen-3-ylmethyl)indoline-6-carboxamide (I-106) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ11.02(s,1H),10.07(s,1H),7.85(d,J=2.6Hz,1H),7.71(dd,J=7.7,1.6Hz,1H),7.60(dd,J=10.3,2.5Hz,1H),7. 48-7.55(m,3H),7.41(d,J=2.9Hz,1H),7.36(dd,J=8.9,4.5Hz,1H),7.02(d,J=5.0Hz,1H),6.91-6.99(m,1H),4.96(s,2H),1.36(s,6H).

[0908] Example 107 N-(5-Fluoro-1H-indol-3-yl)-3,3-dimethyl-2-carbonyl-1-phenylethylindoline-6-carboxamide (I-107)

[0909] The preparation method of N-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-2-carbonyl-1-phenylethylindoline-6-carboxamide (I-107) is the same as that of compound I-1. 1H NMR (400MHz, DMSO-d6) δ11.04(s,1H),10.11(s,1H),7.88(d,J=2.6Hz,1H),7.58-7.72(m,3H),7.48(d,J=7.6Hz,1H),7.3 8(dd,J=8.9,4.5Hz,1H),7.14-7.26(m,5H),6.93-7.01(m,1H),4.00(t,J=7.1Hz,2H),2.99(t,J=7.2Hz,2H),1.22(s,6H).

[0910] Example 108 N-(1H-indol-3-yl)-3,3-dimethyl-2-carbonyl-1-(2-(thien-3-yl)ethyl)indoline-6-carboxamide (I-108)

[0911] Step ①: 3,3-Dimethyl-2-carbonyl-1-(2-(thien-3-yl)ethyl)indoline-6-carboxylic acid methyl ester (108-1)

[0912] The preparation method of methyl 3,3-dimethyl-2-carbonyl-1-(2-(thiophen-3-yl)ethyl)indoline-6-carboxylate (108-1) is the same as compound 2-3. 1 H NMR (400MHz, CDCl3) δ7.76(dd,J=7.7,1.3Hz,1H),7.43(d,J=1.4Hz,1H),7.24(d,J=3.4Hz,1H),7.23(d,J= 2.6Hz,1H),6.97(t,J=4.4Hz,2H),4.01(t,J=7.3Hz,2H),3.94(s,3H),3.05(t,J=7.3Hz,2H),1.31(s,6H).

[0913] Step ②: 3,3-Dimethyl-2-carbonyl-1-(2-(thien-3-yl)ethyl)indoline-6-carboxylic acid (108-2)

[0914] The preparation method of 3,3-dimethyl-2-carbonyl-1-(2-(thiophen-3-yl)ethyl)indoline-6-carboxylic acid (108-2) is the same as compound 1-5. LCMS (ESI) m / z [M+H] + :316.1.

[0915] Step ③: N-(1H-indol-3-yl)-3,3-dimethyl-2-carbonyl-1-(2-(thien-3-yl)ethyl)indoline-6-carboxamide (I-108)

[0916] The preparation method of N-(1H-indol-3-yl)-3,3-dimethyl-2-carbonyl-1-(2-(thiophen-3-yl)ethyl)indoline-6-carboxamide (I-108) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),10.11(s,1H),7.84(d,J=8.0Hz,1H),7.79(d,J =2.5Hz,1H),7.69(d,J=7.7Hz,1H),7.61(s,1H),7.48(d,J=7.6Hz,1H),7.42(dd,J=4. 9,2.9Hz,1H),7.37(d,J=8.1Hz,1H),7.20(d,J=2.9Hz,1H),7.12(t,J=7.5Hz,1H),7. 03(dd,J=10.1,5.8Hz,2H),4.01(t,J=5.6Hz,2H),3.02(t,J=7.3Hz,2H),1.25(s,6H).

[0917] Example 109 1-(Benzo[b]thiophen-3-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-109)

[0918] Step ①: 1-(Benzo[b]thiophen-3-ylmethyl)-3,3-dimethyl-2-indoline-6-carboxylic acid methyl ester (109-1)

[0919] The preparation method of 1-(benzo[b]thiophen-3-ylmethyl)-3,3-dimethyl-2-indoline-6-carboxylic acid methyl ester (109-1) is the same as compound 2-3. 1 H NMR (400MHz, CDCl3) δ7.94(d,J=7.8Hz,1H),7.84(d,J=7.8Hz,1H),7.75(d,J=7.7Hz,1H),7.52(s,1 H),7.38(dt,J=18.1,7.2Hz,2H),7.32(s,1H),7.25(s,2H),5.19(s,2H),3.87(s,3H),1.44(s,6H).

[0920] Step ②: 1-(Benzo[b]thiophen-3-ylmethyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (109-2)

[0921] The preparation method of 1-(Benzo[b]thiophen-3-ylmethyl)-3,3-dimethyl-2-indoline-6-carboxylic acid (109-2) is the same as compound 1-5. LCMS (ESI) m / z [M+H] + :352.1.

[0922] Step ③: 1-(Benzo[b]thiophen-3-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-109)

[0923] The preparation method of 1-(benzo[b]thiophen-3-ylmethyl)-N-(1H-indol-3-yl)-3,3-dimethyl-2-indoline-6-carboxamide (I-109) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ10.84-10.96(m,1H),10.05(s,1H),7.99(td,J=7.4,1.8Hz,2H),7.78(d,J=8.0Hz,1H),7.68-7.76(m,3H),7.57(d,J=1.5Hz ,1H),7.53(d,J=7.7Hz,1H),7.41(td,J=7.6,1.6Hz,2H),7.35(d,J=8.1H z,1H),7.07-7.13(m,1H),7.00(t,J=7.5Hz,1H),5.24(s,2H),1.39(s,6H)

[0924] Example 110 N-(5-fluoro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-110)

[0925] The preparation method of N-(5-fluoro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-110) is the same as that of compound I-1. 1H NMR (400MHz, DMSO-d6) δ11.01(s,1H),10.08(s,1H),7.84(d,J=2.6Hz,1H),7.73(dd,J=7.7,1.5Hz,1H),7.63(d,J=8.7Hz,1H),7.57(d dd,J=15.4,7.8,2.0Hz,4H),7.47(d,J=9.0Hz,1H),7.35(dd,J=8.9,4.5Hz,1H),6.95(td,J=9.1,2.6Hz,1H),5.12(s,2H),1.39(s,6H).

[0926] Example 111 N-(5,6-difluoro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-111)

[0927] The preparation method of N-(5,6-difluoro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-3,3-dimethyl-2-indoline-6-carboxamide (I-111) is the same as that of compound I-1. 1 H NMR (400MHz, DMSO-d6) δ11.07(d,J=2.6Hz,1H),10.12(s,1H),7.78-7.86(m,2H),7.71(dd,J=7.7,1.5Hz,1H),7.64(d,J=8.7Hz ,1H),7.55-7.59(m,2H),7.53(d,J=1.5Hz,1H),7.46(d,J=9.3Hz,1H),7.37(dd,J=11.2,7.0Hz,1H),5.11(s,2H),1.39(s,6H).

[0928] Example 112 N-(1H-indol-3-yl)-2-oxo-1-(thien-3-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-112)

[0929] Step ①: 2-oxo-1-(thien-3-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (112-1)

[0930] The preparation of methyl 2-oxo-1-(thiophen-3-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylate (112-1) was the same as compound 2-3. 1H NMR(400MHz, DMSO-d6)δ7.72(s,1H),7.48-7.54(m,1H),7.30(s,1H),6.95(d,J=5.0Hz,1H),5.13(s,2H),3.77(s,2H),3.80(s,3H).LCMS(ESI)m / z[M+H] + :326.0.

[0931] Step ②: 2-Oxo-1-(thiophen-3-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (112-2)

[0932] The preparation of 2-oxo-1-(thiophen-3-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (112-2) was the same as compound 1-5. 1 H NMR(400MHz, DMSO-d6)δ7.61(s,1H),7.50(t,J=4.0Hz,1H),7.30(s,1H),6.96(d,J=5.0Hz,1H),5.11(s,2H),3.80(s,2H).LCMS(ESI)m / z[M+H] + :312.0.

[0933] Step ③: N-(1H-indol-3-yl)-2-oxo-1-(thien-3-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-112)

[0934] The preparation of N-(1H-indol-3-yl)-2-oxo-1-(thien-3-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-112) is the same as compound I-1. 1 H NMR (400MHz, CD3OD) δ7.69 (d, J=7.2Hz, 1H), 7.38-7.50 (m, 2H), 6.33 (dd, J=1.9, 0.9Hz,1H),4.98(d,J=0.9Hz,2H),3.84(s,3H),3.67(s,2H).LCMS(ESI)m / z[M+H] + :426.2.

[0935] Example 113 1-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-113)

[0936] Step ①: 1-(Benzofuran-5-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (113-1)

[0937] The preparation of 1-(benzofuran-5-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (113-1) was the same as compound 2-3. 1 H NMR (400MHz, DMSO-d6) δ7.97(d,J=1.9Hz,1H),7.71(s,1H),7.55(d,J=8.5Hz,1H),7.50( s,1H),7.19(d,J=8.5Hz,1H),6.93(s,1H),5.27(s,2H),3.87(s,2H).LCMS(ESI)m / z[M+H] + :360.0.

[0938] Step ②: 1-(Benzofuran-5-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (113-2)

[0939] The preparation of 1-(benzofuran-5-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (113-2) was the same as compound 1-5. 1 H NMR(400MHz, DMSO-d6)δ7.98(s,1H),7.54-7.60(m,2H),7.50(s,1H),7.19(d,J=8.5Hz,1H),6.93(s,1H),5.24(s,2H),3.85(s,2H).LCMS(ESI)m / z[M+H] + :346.0.

[0940] Step ③: 1-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-113)

[0941] 1-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-113) was prepared in the same manner as compound I-100.1 H NMR (400MHz, CD3OD) δ7.88(s,1H),7.72(d,J=2.3Hz,1H),7.61(d,J=7.5Hz,1H),7.56(d,J=6.9Hz,2H),7.47(d,J=8.4Hz,1H),7.34(d,J=8 .1Hz,1H),7.27(d,J=9.1Hz,1H),7.12(d,J=8.0Hz,1H),7.04(t,J=7.5Hz,1H),6.80(s,1H),5.30(s,2H),3.76(s,2H).LCMS(ESI)m / z[M+H] + :460.1.

[0942] Example 114 N-(1H-indol-3-yl)-2-oxo-1-(thien-2-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-114)

[0943] Step ①: 2-oxo-1-(thiophen-2-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (114-1)

[0944] The preparation of methyl 2-oxo-1-(thiophen-2-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylate (114-1) was the same as compound 2-3. 1 H NMR (400MHz, DMSO-d6) δ7.93 (s, 1H), 7.40 (d, J = 5.1Hz, 1H), 7.04 (d, J = 3.4Hz, 1H ),6.94(t,J=4.3Hz,1H),5.33(s,2H),3.80(d,J=6.8Hz,5H).LCMS(ESI)m / z[M+H] + :326.0.

[0945] Step ②: 2-Oxo-1-(thiophen-2-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (114-2)

[0946] The preparation of 2-oxo-1-(thiophen-2-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (114-2) was the same as compound 1-5. LCMS (ESI) m / z [M+H] + :312.0.

[0947] Step ③: N-(1H-indol-3-yl)-2-oxo-1-(thien-2-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-114)

[0948] The preparation of N-(1H-indol-3-yl)-2-oxo-1-(thien-2-ylmethyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-114) is the same as compound I-1. 1 H NMR (400MHz, CD3OD) δ8.00(s,1H),7.67(d,J=8.0Hz,1H),7.59(s,1H),7.36(d,J=8.1Hz,1H),7.31(dd,J=5.1,1.3Hz,1H ),7.11-7.17(m,2H),7.06(t,J=7.5Hz,1H),6.94(dd,J=5.1,3.5Hz,1H),5.33(s,2H),3.69(s,2H).LCMS(ESI)m / z[M+H] + :426.0.

[0949] Example 115 1-(3-Fluoro-5-(trifluoromethyl)benzyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-115)

[0950] Step ①: 1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (115-1)

[0951] The preparation of methyl 1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylate (115-1) was the same as compound 2-3. 1 H NMR (400MHz, DMSO-d6) δ7.75 (s, 1H), 7.59 (d, J = 8.7Hz, 1H), 7.47 (s, 1H), 7.34 (d,J=9.4Hz,1H),5.30(s,2H),4.04(s,3H),3.89(s,2H).LCMS(ESI)m / z[M+H] + :406.0.

[0952] Step ②: 1-(3-Fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (115-2)

[0953] The preparation of 1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (115-2) was the same as compound 1-5. 1 H NMR(400MHz,DMSO-d6)δ7.59(d,J=7.0Hz,2H),7.47(s,1H),7.35(d,J=9.5Hz,1H),5.28(s,2H),3.88(s,2H).LCMS(ESI)m / z[M+H] + :392.0.

[0954] Step ③: 1-(3-fluoro-5-(trifluoromethyl)benzyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-115)

[0955] The preparation of 1-(3-fluoro-5-(trifluoromethyl)benzyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-115) is the same as compound I-1. 1 H NMR(400MHz,CD3OD)δ7.84(s,1H),7.63(d,J=7.9Hz,1H),7.57(s,1H),7.47(s,1H),7.30-7.40( m,4H),7.12-7.17(m,1H),7.05(t,J=7.5Hz,1H),5.28(s,2H),3.79(s,2H).LCMS(ESI)m / z[M+H] + :506.0.

[0956] Example 116 1-(Cyclopropylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-116)

[0957] Step ①: 1-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (116-1)

[0958] The preparation of methyl 1-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylate (116-1) was the same as compound 2-3. 1 H NMR(400MHz, DMSO-d6)δ7.86(s,1H),3.82-3.88(m,5H),3.71(s,2H),1.25(d,J=5.1Hz,1H),0.38-0.47(m,2H),0.24-0.31(m,2H).LCMS(ESI)m / z[M+H] + :284.0.

[0959] Step ②: 1-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (116-2)

[0960] The preparation of 1-(cyclopropylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (116-2) was the same as compound 1-5. 1 H NMR (400MHz, DMSO-d6) δ7.75 (s, 1H), 3.83 (d, J = 6.9Hz, 2H), 3.69 (s, 2H), 1.00 (m, 1H), 0.39-0.45 (m, 2H), 0.24-0.30 (m, 2H).

[0961] Step ③: 1-(cyclopropylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-116)

[0962] The preparation of 1-(cyclopropylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-116) is the same as compound I-1. 1 H NMR (400MHz, CD3OD) δ8.02(s,1H),7.71(d,J=8.0Hz,1H),7.62(s,1H),7.37(d,J=8.2Hz,1H),7.12-7.18(m,1H), 7.03-7.10(m,1H),3.90(d,J=6.9Hz,2H),3.63(s,2H),0.50-0.57(m,2H),0.38-0.45(m,2H).LCMS(ESI)m / z[M+H] + :384.0.

[0963] Example 117 1-(Furan-3-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-117)

[0964] Step ①: 1-(Furan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (117-1)

[0965] The preparation of methyl 1-(furan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylate (117-1) was the same as compound 2-3. 1 H NMR(400MHz, DMSO-d6)δ7.77(s,1H),7.57-7.59(m,2H),6.31(dd,J=1.8,0.9Hz,1H),4.98(s,2H),3.80(s,3H),3.78(s,2H).LCMS(ESI)m / z[M+H] + :310.0.

[0966] Step ②: 1-(Furan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (117-2)

[0967] The preparation of 1-(furan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (117-2) was the same as compound 1-5. 1 H NMR (400MHz, DMSO-d6) δ13.28(br s,1H),7.67(s,1H),7.55-7.63(m,2H),6.32(dd,J=1.8Hz,0.9Hz,1H),4.96(s,2H),3.77(s,2H).

[0968] Step ③: 1-(Furan-3-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-117)

[0969] The preparation of 1-(furan-3-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-117) was the same as that of compound I-1. NMR (400MHz, DMSO-d6) δ10.99(s,1H),8.09(s,1H),7.75(d,J=8.0Hz,1H),7.70(s,1H),7.67(d,J=2.5Hz,1H),7.63(d,J=1.8Hz,1H),7. 37(d,J=8.1Hz,1H),7.13(t,J=7.5Hz,1H),7.04(t,J=7.4Hz,1H),6.44(d,J=1.9Hz,1H),4.92(s,2H),3.76(s,2H).LCMS(ESI)m / z[M+H] + :410.0.

[0970] Example 118 1-(Furan-2-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-118)

[0971] Step ①: 1-(Furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (118-1)

[0972] The preparation of methyl 1-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylate (118-1) was the same as compound 9-2. 1 H NMR(400MHz,DMSO-d6)δ7.87(s,1H),7.57-7.59(m,2H),6.37-6.39(m,1H),5.15(s,2H),3.81(s,3H),3.77(s,2H).LCMS(ESI)m / z[M+H] + :310.0.

[0973] Step ②: 1-(Furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (118-2)

[0974] The preparation of 1-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (118-2) was the same as compound 1-5.1 H NMR (400MHz, CD3OD) δ7.75 (s, 1H), 7.42 (d, J = 1.9Hz, 1H), 6.29-6.37 (m, 2H), 5.11 (s, 2H), 3.65 (s, 2H).

[0975] Step ③: 1-(Furan-2-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-118)

[0976] The preparation of 1-(furan-2-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-118) is the same as compound I-1. 1 H NMR (400MHz, CD3OD) δ8.05(s,1H),7.70(d,J=8.0Hz,1H),7.62(s,1H),7.47(s,1H),7.39(d,J=8.1Hz,1H),7. 17(t,J=7.6Hz,1H),7.08(t,J=7.5Hz,1H),6.34-6.41(m,2H),5.17(s,2H),3.69(s,2H).LCMS(ESI)m / z[M+H] + :410.0.

[0977] Example 119 N-(1H-indol-3-yl)-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-119)

[0978] Step ①: 2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (119-1)

[0979] The preparation of methyl 2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylate (119-1) was the same as compound 2-3. LCMS (ESI) m / z [M+H] + :328.0.

[0980] Step ②: 2-Oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (119-2)

[0981] The preparation of 2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (119-2) was the same as compound 1-5. 1 H NMR(400MHz,DMSO-d6)δ7.77(s,1H),3.85(d,J=7.5Hz,2H),3.79(dt,J=10.0,3.6Hz,2H), 3.68(s,2H),3.15-3.22(m,2H),1.72-1.84(m,1H),1.42-1.50(m,2H),1.17-1.27(m,2H).

[0982] Step ③: N-(1H-indol-3-yl)-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-119)

[0983] The preparation of N-(1H-indol-3-yl)-2-oxo-1-((tetrahydro-2H-pyran-4-yl)methyl)-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-119) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ11.00(s,1H),10.10(s,1H),8.10(s,1H),7.75(d,J=8.0Hz,1H),7.67(d,J=2.5Hz,1H),7.38(d,J=8.1Hz,1H),7.13(t,J=7.4 Hz,1H),7.04(t,J=7.5Hz,1H),3.80-3.88(m,4H),3.70(s,2H),3.24(t,J=11 .3Hz,2H),1.97(d,J=14.1Hz,1H),1.52(d,J=12.9Hz,2H),1.20-1.36(m,2H).

[0984] Example 120 N-(5-fluoro-1H-indol-3-yl)-1-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-120)

[0985] Step ①: 1-(Benzofuran-7-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (120-1)

[0986] The preparation of 1-(benzofuran-7-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid methyl ester (120-1) was the same as compound 2-3. 1 H NMR (400MHz, DMSO-d6) δ8.05(d,J=2.3Hz,1H),7.64(s,1H),7.56(d,J=7.7Hz,1H),7.18(t,J =7.6Hz,1H),6.98-7.03(m,2H),5.45(s,2H),3.88(s,2H),3.75(s,3H).LCMS(ESI)m / z[M+H] + :360.0.

[0987] Step ②: 1-(Benzofuran-7-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (120-2)

[0988] The preparation of 1-(benzofuran-7-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxylic acid (120-2) was the same as compound 1-5. LCMS (ESI) m / z [M+H] + :346.0.

[0989] Step ③: 1-(Benzofuran-5-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-120)

[0990] 1-(Benzofuran-7-ylmethyl)-N-(1H-indol-3-yl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-120) was prepared in the same manner as compound I-1. 1H NMR (400MHz, DMSO-d6) δ10.95(s,1H),10.05(s,1H),8.08(d,J=2.2Hz,1H),8.03(s,1H),7.56-7.67(m,3H),7.34(d,J=8. 2Hz,1H),7.21(t,J=7.6Hz,1H),7.09(t,J=7.6Hz,1H),6.96-7.05(m,3H),5.42(s,2H),3.87(s,2H).LCMS(ESI)m / z[M+H] + :460.1.

[0991] Example 121 N-(5-fluoro-1H-indol-3-yl)-1-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-121)

[0992] The preparation of N-(5-fluoro-1H-indol-3-yl)-1-(furan-2-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-121) is the same as compound I-1. 1 H NMR (400MHz, CD3OD) δ8.01 (s, 1H), 7.65 (s, 1H), 7.45 (d, J = 1.5Hz, 1H), 7.30-7.39 (m, 2H), 6. 92(td,J=9.2,2.6Hz,1H),6.32-6.38(m,2H),5.15(s,2H),3.67(s,2H).LCMS(ESI)m / z[M+H] + :428.0.

[0993] Example 122 N-(5-fluoro-1H-indol-3-yl)-1-(furan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-122)

[0994] The preparation of N-(5-fluoro-1H-indol-3-yl)-1-(furan-3-ylmethyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-122) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.10(s,1H),8.06(s,1H),7.75(d,J=2.6Hz,1H),7.70(s,1H),7.62(s,1H),7.51(m ,1H),7.38(dd,J=8.8,4.5Hz,1H),6.97(td,J=9.1,2.6Hz,1H),6.43(s,1H),4.92(s,2H),3.76(s,2H).LCMS(ESI)m / z[M+H] + :428.0.

[0995] Example 123 N-(5-chloro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-123)

[0996] The preparation method of N-(5-chloro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-123) is the same as compound I-1. 1 H NMR (400MHz, DMSO-d6) δ11.20(s,1H),10.10(s,1H),7.98(s,1H),7.79(d,J=2.1Hz,1H),7.75(d,J=2.6Hz,1H),7 .56-7.68(m,2H),7.35-7.47(m,2H),7.12(dd,J=8.6,2.1Hz,1H),5.22(s,2H),3.90(s,2H).LCMS(ESI)m / z[M+H] + :540.1.

[0997] Example 124 N-(5-fluoro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-124)

[0998] The preparation method of N-(5-fluoro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-124) is the same as compound I-1. 1H NMR (400MHz, DMSO-d6) δ11.10(s,1H),10.05(s,1H),7.96(s,1H),7.72(d,J=2.6Hz,1H),7.55-7.68( m,2H),7.33-7.49(m,3H),6.97(td,J=9.1,2.6Hz,1H),5.22(s,2H),3.89(s,2H).LCMS(ESI)m / z[M+H] + :524.2.

[0999] Example 125 N-(5,6-difluoro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-125)

[1000] The preparation method of N-(5,6-difluoro-1H-indol-3-yl)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-2-oxo-2,3-dihydro-1H-thieno[2,3-b][1,4]thiazine-6-carboxamide (I-125) is the same as compound I-1. 1 H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.09(s,1H),7.95(s,1H),7.56-7.74(m,4H),7.34-7.45(m,2H),5.22(s,2H),3.89(s,2H).LCMS(ESI)m / z[M+H] + :541.2.

[1001] Example 126 1-(Benzofuran-7-ylmethyl)-N-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-126)

[1002] The preparation of 1-(benzofuran-7-ylmethyl)-N-(5-fluoro-1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-126) is the same as compound I-1. 1H NMR (400MHz, CD3OD) δ7.76(d,J=2.2Hz,1H),7.68(dd,J=7.7,1.6Hz,1H),7.66(s,1H),7.53-7.57(m,1H),7.49(d,J=1.5Hz,1H),7.45(d,J=7.7H z,1H),7.28-7.34(m,2H),7.17-7.23(m,2H),6.91(td,J=9.1,2.5Hz,1H),6.84(d,J=2.3Hz,1H),5.33(s,2H),1.47(s,6H).LCMS(ESI)m / z[M+H] + :468.2.

[1003] Example 127 1-(Benzofuran-7-ylmethyl)-N-(5,6-difluoro-1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-127)

[1004] The preparation of 1-(benzofuran-7-ylmethyl)-N-(5,6-difluoro-1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-127) is the same as compound I-1. 1 H NMR (400MHz, CD3OD) δ7.76(d,J=2.3Hz,1H),7.68(dd,J=7.7,1.6Hz,1H),7.64(s,1H),7.53-7.57(m,1H),7.48(d,J=1 .7Hz,1H),7.47-7.43(m,2H),7.17-7.23(m,3H),6.84(d,J=2.2Hz,1H),5.33(s,2H),1.47(s,6H).LCMS(ESI)m / z[M+H] + :486.2.

[1005] Example 128 1-(Benzofuran-7-ylmethyl)-N-(5-chloro-1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-128)

[1006] The preparation of 1-(benzofuran-7-ylmethyl)-N-(5-chloro-1H-indol-3-yl)-3,3-dimethyl-2-oxoindoline-6-carboxamide (I-129) is the same as compound I-1. 1H NMR (400MHz, CD3OD) δ7.77(t,J=1.8Hz,1H),7.66-7.70(m,2H),7.65(d,J=2. 0Hz,1H),7.53-7.58(m,1H),7.49(d,J=1.5Hz,1H),7.45(dd,J=7.7,1.7Hz,1 H),7.32(d,J=8.7Hz,1H),7.18-7.24(m,2H),7.10(dd,J=8.7,2.1Hz,1H),6. 85(t,J=1.8Hz,1H),5.33(d,J=1.7Hz,2H),1.47(s,6H).LCMS(ESI)m / z[M+H] + :484.1.

[1007] Example 129 N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(thien-3-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide (I-129)

[1008] Step ①: Diethyl 2-(5-(methoxycarbonyl)-3-nitropyridin-2-yl)malonate (129-1)

[1009] 83 mg of sodium hydride and 10 ml of dry tetrahydrofuran were mixed in a two-necked round-bottom flask equipped with a condenser. 444 mg of diethyl malonate was then added to the flask, and the mixture was stirred at 0°C for 15 minutes under an argon atmosphere. The mixture was then allowed to return to room temperature, and a tetrahydrofuran solution containing 500 mg of methyl 6-chloro-5-nitroponictinate was added to the reaction mixture. The reaction mixture was stirred at 0°C for 2 hours and then heated at 80°C for 3 hours. Saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness. 601 mg of diethyl 2-(5-(methoxycarbonyl)-3-nitropyridin-2-yl)malonate (129-1) was obtained as a pale yellow solid, with a yield of 76%. 1 H NMR (400MHz, DMSO-d6) δ9.32(d,J=1.9Hz,1H),8.88(d,J=2.0Hz,1H),5.71(s,1H),4.13-4.28(m,4H),3.95(s,3H),1.19(t,J=7.1Hz,6H).

[1010] Step ②: 6-(2-ethoxy-2-oxoethyl)-5-nitronicotinic acid methyl ester (129-2)

[1011] A mixture of 500 mg of 129-1 and 10 ml of acetic acid was stirred at 120°C overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phase was concentrated to dryness, and the residue was purified by column chromatography using ethyl acetate:petroleum ether = 5:95 to give 474 mg of methyl 6-(2-ethoxy-2-oxoethyl)-5-nitronicotinate (129-2) as a red oil in a 60% yield. 1 H NMR (400MHz, DMSO-d6) δ9.29(d,J=1.9Hz,1H),8.83(d,J=1.9Hz,1H),4.34(s,2H),4.11(q,J=7.1Hz,2H),3.95(s,3H),1.17(t,J=7.1Hz,3H).

[1012] Step ③: 6-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-5-nitronicotinic acid methyl ester (129-3)

[1013] The preparation of methyl 6-(1-ethoxy-2-methyl-1-oxopropan-2-yl)-5-nitronicotinate (129-3) was the same as compound 85-7. 1 H NMR (400MHz, DMSO-d6) δ9.32(d,J=2.0Hz,1H),8.75(d,J=2.0Hz,1H),4.04(q,J=7.1Hz,2H),3.95(s,3H),1.65(s,6H),1.11(t,J=7.1Hz,3H).

[1014] Step ④: 3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid methyl ester (129-4)

[1015] The preparation of methyl 3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (129-4) was the same as compound 1-3. 1 H NMR (400MHz, DMSO-d6) δ10.75(s,1H),8.67(d,J=1.8Hz,1H),7.56(d,J=1.8Hz,1H),3.89(s,3H),1.29(s,6H).

[1016] Step ⑤: 3,3-dimethyl-2-oxo-1-(thien-3-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid methyl ester (129-5)

[1017] The preparation method of methyl 3,3-dimethyl-2-oxo-1-(thiophen-3-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylate (129-5) is the same as compound 2-3. 1 H NMR(400MHz,DMSO-d6)δ8.72(d,J=1.7Hz,1H),7.74(d,J=1.8Hz,1H),7.52-7.55(m,1H) ,7.42-7.45(m,1H),7.01(dd,J=4.9,1.3Hz,1H),5.01(s,2H),3.87(s,3H),1.36(s,6H).

[1018] Step ⑥: 3,3-dimethyl-2-oxo-1-(thien-3-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (129-6)

[1019] The preparation method of 3,3-dimethyl-2-oxo-1-(thiophen-3-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxylic acid (129-6) is the same as compound 1-5. 1 H NMR(400MHz,DMSO-d6)δ13.40(br s,1H),8.71(d,J=1.7Hz,1H),7.71(d,J=1.7Hz,1H),7.51-7.55(m,1H),7 .42-7.46(m,1H),7.01(dd,J=4.9,1.3Hz,1H),5.00(s,2H),1.36(s,6H).

[1020] Step ⑦: N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(thien-3-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide (I-129)

[1021] The preparation of N-(1H-indol-3-yl)-3,3-dimethyl-2-oxo-1-(thien-3-ylmethyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide (I-129) is the same as compound I-1. 1H NMR (400MHz, CD3OD) δ8.78(d,J=1.8Hz,1H),7.84(d,J=1.8Hz,1H),7.68-7.71(m,2H),7.40-7.42(m,2H),7.35-7 .39(m,1H),7.15(ddd,J=8.1,7.0,1.2Hz,1H),7.05-7.09(m,2H),5.04(s,2H),1.46(s,6H).LCMS(ESI)m / z[M+H] + :417.2.

[1022] Example 130 Compound IC inhibitor of interferon-stimulated gene (ISG) expression in human THP1-Blue-ISG cells 50

[1023] 1. Experimental methods:

[1024] 10 μL of compound diluted in PBS / saline was added to each well of a 96-well cell culture plate. The STING agonist was MSA-2 and added to the counted cell suspension to a final concentration of 10 μM. A control group without compound was added with 10 μL of PBS / saline containing 2% DMSO. Three replicate wells were set up for each well. THP1-Blue-ISG cells were counted and the cell concentration was adjusted to 4 × 10 5 Each well was incubated with 190 μL of cells treated with a STING agonist. The final volume of each test well was 200 μL, the DMSO content was 0.1%, and the final test concentrations of the compounds were 10, 3.3, 1.1, 0.4, 0.13, 0.04, 0.013, and 0.004 μM. The cells were incubated for 24 hours. A blank control group was incubated with 190 μL of cells without a STING agonist and 10 μL of saline containing 2% DMSO. Three replicate wells were set up for each well.

[1025] After 24 hours, take 20 μL of culture medium from each well into a new 96-well plate and add 180 μL of Quanti-Blue colorimetric solution. Place the plate in a 37°C incubator and measure the OD650 value after 2 hours.

[1026] Result analysis:

[1027] Inhibition rate (%) = (Con (OD650) - Treated (OD650)) / Con (OD650) × 100%

[1028] The inhibitor IC50 was calculated using the Graphpad Prism 8 software using the log(inhibitor) vs. response--Variable slope (four parameters) method, with the constraint interval set to 0-100.

[1029] 2. Experimental results

[1030] The test results are shown in Table 1 below.

[1031] Table 1: IC values ​​of the compounds of the present invention for inhibition of ISG gene expression induced by human THP1-Blue-ISG cells MSA-2 50

[1032] The experimental results show that the compound of the present invention has the function of inhibiting MSA-2-induced ISG gene expression in human THP1-Blue-ISG cells, and the inhibitory activity of the compound on STING protein is significantly better than that of other positive compounds. Among them, the structure of compound A is: Derived from Example 18 of patent WO2021161230A1. The structure of compound B is: The structure of compound C is: The structure of H151 is

[1033] Example 131 Inhibitory Activity IC of Compounds on ISG Gene Expression in Murine RAW-Lucia Cells 50

[1034] 1. Experimental methods:

[1035] 10 μL of compound diluted in PBS / normal saline was added to each well of a 96-well cell culture plate. The STING agonist was DMXAA. This was added to the counted cell suspension to a final concentration of 50 μM. A control group without compound was added with 10 μL of PBS / normal saline containing 2% DMSO. Three replicate wells were set up for each well. RAW-Lucia cells were counted and the cell concentration was adjusted to 4 × 10 5 / mL, 180 μL of cells were added to each well for incubation. Therefore, the final volume of each test well was 200 μL, the DMSO content was 0.1%, and the final test concentrations of the compounds were 10 / 3.3 / 1.1 / 0.4 / 0.13 / 0.04 / 0.013 / 0.004 μM. The STING agonist DMXAA was used at a final concentration of 50 μM and incubated for 24 hours. A blank control was also added with 200 μL of culture medium. Three replicate wells were set up for each well.

[1036] After 24 hours, 20 μL of culture medium was taken from each well to a new 96-well plate with a transparent bottom, 50 μL of luciferase detection reagent QUANTI-LucTM was added, and the fluorescence value was immediately measured (protected from light).

[1037] Result analysis:

[1038] Inhibition rate (%) = (Con (Lum) - Treated (Lum)) / Con (Lum) × 100%

[1039] Inhibitor IC 50 The calculation was performed using the log(inhibitor) vs. response--Variable slope (four parameters) method of Graphpad Prism 8, with the constraint interval set to 0-100.

[1040] 2. Experimental results

[1041] The experimental results are shown in Table 2 below.

[1042] Table 2: IC values ​​of the compounds of the present invention for inhibition of DMXAA-induced ISG gene expression in mouse RAW-Lucia cells 50

[1043] The experimental results show that the compound of the present invention has the function of inhibiting DMXAA-induced ISG gene expression in mouse RAW-Lucia cells, and the compound's inhibitory activity on STING protein is significantly better than other positive compounds.

[1044] Example 132 Compound IC activity inhibitor on interferon-stimulated gene (ISG) expression in human THP1-Dual cells 50

[1045] 1. Experimental methods:

[1046] 10 μL of compound diluted in PBS / saline was added to each well of a 96-well cell culture plate. The STING agonist was MSA-2. This was added to the counted cell suspension to a final concentration of 10 μM. A control group without compound was added with 10 μL of PBS / saline containing 2% DMSO. Three replicate wells were set up for each well. THP1-Dual cells were counted and the cell concentration was adjusted to 4 × 10 5Each well was incubated with 190 μL of cells treated with a STING agonist. The final volume of each test well was 200 μL, the DMSO content was 0.1%, and the final test concentrations of the compounds were 10, 3.3, 1.1, 0.4, 0.13, 0.04, 0.013, and 0.004 μM. The cells were incubated for 24 hours. A blank control group was incubated with 190 μL of cells without a STING agonist and 10 μL of saline containing 2% DMSO. Three replicate wells were set up for each well.

[1047] After 24 hours, 20 μl of culture medium was taken from each well of THP1-Dual cells and transferred to a new bottom transparent 96-well plate, and the luciferase detection reagent QUANTI-Luc was added. TM 50 μl was added and the fluorescence value was measured immediately (protected from light).

[1048] Result analysis: Inhibition rate (%) = (Con (Lum) - Treated (Lum)) / Con (Lum) × 100%

[1049] Inhibitor IC 50 The calculation was performed using the log(inhibitor) vs. response--Variable slope (four parameters) method of Graphpad Prism 8, with the constraint interval set to 0-100.

[1050] 2. Experimental results

[1051] The test results are shown in Table 3 below.

[1052] Table 3: IC values ​​of the compounds of the present invention for inhibition of ISG gene expression induced by human THP1-Dual cells MSA-2 50

[1053] The experimental results show that the compounds of the present invention have the function of inhibiting MSA-2-induced ISG gene expression in human THP1-Dual cells, and the inhibitory activity of some compounds on STING protein is significantly better than that of the positive compound H151.

[1054] Example 133 Inhibitory effect of compound I-77 on inflammation stimulated by STING agonist (MSA-2) in vivo

[1055] Inflammatory responses stimulated by STING activation include inflammatory bowel disease, Crohn's disease, ulcerative colitis, irritable bowel syndrome, uveitis, mucositis, etc.

[1056] 1. Experimental methods

[1057] 6-8 week old C57BL6 female mice were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. Compound preparation method: 2 mg of I-77 powder was dissolved in 12 μL of PEG400 by ultrasonication, and then 8 μL of Tween 80 was added by ultrasonication to prepare a 100 mg / mL stock solution.

[1058] Experimental groups: The control group received a solvent control; the model group received MSA-2 (10 mpk, dissolved in 40% PEG400); and the treatment group (I-77) received both MSA-2 and I-77 (10 mpk, IP). 200 μL of I-77 solution, diluted with double-distilled water to a final concentration of 10 mg / mL, was injected intraperitoneally into the treatment group mice. The control and MSA-2 groups received 200 μL of a 10-fold diluted solvent control solution. Three hours later, the model and I-77 treatment groups received 200 μL of 10 mg / mL MSA-2 intraperitoneally, while the control group received 200 μL of 40% PEG400 solution. Three hours later, kidney and heart samples were collected at the endpoint. Blood samples were centrifuged at high speed, and plasma was diluted 2-fold for analysis of plasma CXCL10 and IL6 levels using Lianke ELISA kits. RNA was extracted from heart and kidney samples and converted to cDNA. Quantitative polymerase chain reaction (qPCR) was used to detect changes in inflammatory cytokines (ISG15, ISG56, IL6, and IP10). Statistical analysis: One-way ANOVA, *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.

[1059] 2. Experimental results

[1060] The above experimental results are shown in Figures 1, 2 and 3. The injection of I-77 can significantly inhibit the increase in the levels of IL6 and IP10 in plasma stimulated by MSA-2, and inhibit the inflammatory response of the heart and kidney caused by MSA-2 stimulation.

[1061] Example 134 Inhibitory effect of oral administration of compound I-77 on inflammation stimulated by STING agonist (MSA-2) in vivo

[1062] 1. Experimental methods

[1063] 6-8 week old C57BL6 female mice were purchased from Shanghai Jihui Experimental Animal Breeding Co., Ltd. Compound preparation method: 2 mg of I-77 powder was dissolved in 12 μL of PEG400 by ultrasonication, and then 8 μL of Tween 80 was added by ultrasonication to prepare a 100 mg / mL stock solution.

[1064] Experimental groups: The control group received a solvent control; the model group received MSA-2 (10 mpk, dissolved in 40% PEG 400); and the treatment group (I-77) received both MSA-2 and I-77 (20 mpk, orally). 200 μL of I-77 solution, diluted with double-distilled water to a final concentration of 20 mg / mL, was administered orally to the treatment group, while the control and MSA-2 groups received 200 μL of a 10-fold diluted solvent control solution. One hour later, the model and I-77 treatment groups received an intraperitoneal injection of 200 μL of 10 mg / mL MSA-2 dissolved in 40% PEG 400, respectively, while the control group received 200 μL of 40% PEG 400 solution. Four hours after treatment, endpoint samples were collected from blood, kidneys, and hearts. Blood samples were centrifuged at high speed, and plasma was diluted 2-fold for analysis of plasma CXCL10 and IL-6 levels using a Lianke ELISA kit. RNA was extracted from heart and kidney samples and converted to cDNA. qPCR was used to detect changes in inflammatory cytokines (ISG15, ISG56, IL6, IP10) in tissues. Statistical method: One-way ANOVA, * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001.

[1065] 2. Experimental results

[1066] The above experimental results are shown in Figures 4, 5 and 6. Oral administration of I-77 significantly reduced the levels of IL6 and IP10 in plasma induced by MSA-2 injection and inhibited the inflammatory response of the heart and kidney induced by MSA-2 stimulation.

[1067] Example 135 Oral administration of compound I-77 inhibits inflammation in the STING-V154M mutation autoimmune mouse disease model

[1068] The STING-V154M autoimmune model mouse represents a disease model of STING pathway self-activation, including STING-associated vasculopathy of infancy (SAVI), Singleton-Merten syndrome (SMS), autoimmune colitis, scleroderma, psoriasis, Sjögren's syndrome, rheumatoid arthritis, etc.

[1069] 1. Experimental methods

[1070] The mouse model was purchased from Jiangsu Jicui Pharmaceutical Kang Biotechnology Co., Ltd., and wild-type C57 / BL6 mice were also purchased from Jiangsu Jicui Pharmaceutical Kang Biotechnology Co., Ltd. Compound preparation method: 2 mg of I-77 powder was dissolved in 12 μL of PEG400 by ultrasonication, and then 8 μL of Tween 80 was added by ultrasonication to prepare a 100 mg / mL stock solution.

[1071] Experimental groups: Wild-type mouse control group (Control) was given solvent control; model mouse group (Model) was given solvent; treatment group (I-77) was model mice given I-77 (20 mpk, PO). Mice in the compound I-77 treatment group were gavage-administered 200 μL of I-77 solution diluted with double-distilled water to a final concentration of 20 mg / mL; the other groups were given the same dose of solvent until the mortality rate in the model group exceeded 50%. At the end of the experiment, samples from the kidney and heart were collected. RNA was extracted from heart and kidney samples and converted into cDNA. qPCR technology was used to detect changes in the gene expression of inflammatory-related cytokines (ISG15, CCL5, IP10, ISG56) in the tissues. Statistical method: One-way ANOVA, *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

[1072] 2. Experimental results

[1073] The experimental results are shown in Figures 7, 8 and 9. Oral administration of I-77 can significantly prolong the survival of STING V154M mutation model mice, effectively treat autoimmune diseases, and inhibit cardiac and renal inflammatory responses in STING V154M mutation model mice.

[1074] Example 136 Oral administration of compound I-77 inhibits inflammation in the Trex1-D18N autoimmune mouse model

[1075] Trex1-D18N autoimmune disease model mice represent disease models with upstream activation of the STING pathway, such as arrhythmia syndrome (AGS), systemic lupus erythematosus (SLE), amyotrophic lateral sclerosis (ALS), multiple sclerosis (EAE), familial chilblain lupus erythematosus (FCL), and neurodegenerative diseases.

[1076] 1. Experimental methods

[1077] The mouse model was purchased from Jiangsu Jicui Pharmaceutical Kang Biotechnology Co., Ltd., and wild-type C57 / BL6 mice were also purchased from Jiangsu Jicui Pharmaceutical Kang Biotechnology Co., Ltd. Compound preparation method: 2 mg of I-77 powder was dissolved in 12 μL of PEG400 by ultrasonication, and then 8 μL of Tween 80 was added by ultrasonication to prepare a 100 mg / mL stock solution.

[1078] Experimental groups: wild-type mouse control group (Control) was given solvent; model mouse group (Model) was given solvent; treatment group (I-77) was model mice given I-77 (20mpk, PO). Every day, mice in the compound I-77 group were gavaged with 200μL of I-77 solution diluted with double distilled water to a final concentration of 20mg / mL; the other groups were given the same dose of solvent for one month. At the end of the experiment, the heart samples were collected, RNA was extracted from the heart samples, and the RNA was reversed into cDNA. qPCR technology was used to detect changes in inflammatory-related cytokines (Cxcl10 / IP10, ISG15, ISG56, IFN-β, IFN-γ, STAT2) in the tissues. Statistical method: One-way ANOVA, * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001.

[1079] 2. Experimental results

[1080] The experimental results are shown in Figure 10. Oral administration of I-77 can significantly inhibit the increased expression of cardiac inflammation-related cytokines caused by excessive autoimmunity in the Trex1-D18N model, and effectively inhibit inflammation in autoimmune model mice.

[1081] Example 137 Preparation of Pharmaceutical Composition

[1082] pill

[1083] The above substances are mixed uniformly and 1000 tablets are prepared by conventional processes. Appropriate aqueous or non-aqueous coatings may be used to improve palatability, appearance and stability, or to delay absorption.

[1084] capsule

[1085] Compound I-10 150 g

[1086] 140 grams of starch

[1087] 80g microcrystalline cellulose

[1088] According to conventional methods, the above substances were mixed evenly and filled into ordinary gelatin capsules to prepare 1000 capsules.

[1089] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A compound represented by formula (I), or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, in, Ring B is selected from the following substituted or unsubstituted groups: six-membered aryl, six-membered heteroaryl, or five-membered heteroaryl, wherein the heteroatom in the heteroaryl is selected from N, S, and O; the number of the heteroatoms is 1-3; Ring A and Ring C are independently selected from the following groups: substituted or unsubstituted: 3-8 membered heterocyclyl, C3-C8 cycloalkyl, 5-membered heteroaryl, 6-membered aryl, 6-membered heteroaryl, Wherein, the substitution refers to 1-5 R 1 Replacement; wherein each R 1 independently selected from: hydrogen, halogen, carboxyl, hydroxyl, cyano, amino, -COO-C1-C6 alkyl, nitro, -CO-(3-8 membered substituted or unsubstituted heterocyclyl), -CO-(C3-C8 substituted or unsubstituted cycloalkyl), substituted or unsubstituted C6-C12 aryl-C1-C6 alkyl, substituted or unsubstituted 5-12 membered heteroaryl-C1-C6 alkyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C1-C6 alkylacyl, substituted or unsubstituted aminoacyl, substituted or unsubstituted C1-C6 alkylamido, substituted or unsubstituted C1-C4 alkylamino, substituted or unsubstituted C6-C12 arylamino, substituted or unsubstituted 3-8 membered heterocyclyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 5-12 membered heteroaryl, substituted or unsubstituted C6-C12 aryl; R 1 The substitution mentioned in the above refers to substitution by one or more groups selected from the group consisting of halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl-OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl; Ring D and Ring E are each independently selected from the following substituted or unsubstituted groups: C5-C6 alkyl ring, benzene ring, 5-6 membered heteroalkyl ring or 5-6 membered heteroaryl ring; L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene-, -(substituted or unsubstituted C1-C6 alkylene)-sulfonyl-, substituted or unsubstituted monocyclic or bicyclic C3-C6 cycloalkyl, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C2-C6 alkynylene-, -substituted or unsubstituted C1-C6 alkylene-O-, -substituted or unsubstituted C1-C6 alkylene-OCO-, substituted or unsubstituted monocyclic or bicyclic C6-C12 aryl, substituted or unsubstituted monocyclic or bicyclic 5-10 membered heteroaryl, substituted or unsubstituted monocyclic or bicyclic 3-8 membered heterocyclyl, wherein m and p are each independently 0-3; x and y are each independently selected from 0-4; wherein "*" indicates connection with ring C; L 2 Selected from: Wherein "*" indicates connection with ring B; X and Y are each independently selected from S, SO, SO2, O, NR 2 or CR 3 R 4 ; Q and Z are each independently selected from CO or a chemical bond; Provided that, when ring B is a six-membered aromatic group, and L 1 Not for When L 2 for Wherein "*" indicates connection with ring B; R 2 , R 3 , R 4 Each is independently selected from the following group: hydrogen atom, halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl-OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclic group; or R 3 , R 4 The C atom connected thereto forms a 3-5 membered cycloalkyl or heterocyclic group; or R 3 or R 4 The C atom connected thereto forms a C2-C6 alkenyl group; n is 0 or 1, wherein when n is 0, X is directly connected to C=O; The substitution refers to substitution by one or more groups selected from the following groups: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl-OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

2. The compound according to claim 1, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, characterized in that: Ring B is selected from the following structures: Wherein, "*" indicates that it is connected to the C atom adjacent to N, and "**" indicates that it is connected to the C atom adjacent to X; L 2 Connected to any unsubstituted position of Ring B.

3. The compound according to claim 1, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, characterized in that: The compound has the structure shown in formula II to VII: In the formula, ring A, ring C, R 3 , R 4 ,X,L 1 , L 2 The definition as in claim 1.

4. The compound according to claim 3, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, characterized in that: In another preferred embodiment, the compound has a structure shown in Formula II to VII: In the formula, ring A is Wherein, ring D and ring E are each independently selected from the following substituted or unsubstituted groups: benzene ring, 5-6 membered heteroaromatic ring; the substitution refers to the substitution of 1-5 R 1 Replacement, where R 1 Selected from: hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylhydroxyl, C1-C4 alkylamino; Ring C is selected from the following groups: substituted or unsubstituted: 3-6 membered heterocyclyl, C3-C6 cycloalkyl, 6-membered aryl, 6-membered heteroaryl, 5-membered heteroaryl, Wherein, ring D and ring E are each independently selected from the following substituted or unsubstituted groups: benzene ring, 5-6 membered heteroalkyl ring, 5-6 membered heteroaryl ring; the substitution refers to the substitution of 1-5 R 1 Replacement, where R 1 Selected from: hydrogen, halogen, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylhydroxyl, C1-C4 alkylamino, C6 aryl; L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene-, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C1-C6 alkylene-O-, wherein m and p are each independently 0, 1, 2 or 3; x and y are each independently selected from 0, 1, 2, 3 or 4; Q and Z are each independently selected from CO or a chemical bond; wherein "*" indicates connection with ring C; L 2 Selected from: Said The "*" in indicates that it is connected to the mother nucleus, and the other end is connected to ring A; R 3 , R 4 Each is independently C1-C6 alkyl, halogen, or R 3 , R 4 The C atom connected thereto forms a 3-5 membered cycloalkyl or heterocyclic group; or R 3 or R 4 The C atom connected thereto forms a C2-C6 alkenyl group; X is selected from O or S atoms; Provided that, in Formula II or Formula V, L 1 Not for When L 2 for Among them, the The "*" in indicates that it is connected to ring C. The "*" in indicates that it is connected to the mother nucleus, and the other end is connected to ring A; The substitution refers to substitution by one or more groups selected from the following groups: halogen, carboxyl, hydroxyl, cyano, amino, nitro, benzyl, C1-C6 alkyl-OH, C1-C6 alkylamino, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, C3-C8 cycloalkyl or 3-8 membered heterocyclyl.

5. The compound according to any one of claims 1 to 4, or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: In Formula II or Formula V, L 1 is selected from: -substituted or unsubstituted C1-C6 alkylene-, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C2-C6 alkynylene-, -substituted or unsubstituted C1-C6 alkylene-O-, and L 2 Selected from: Where "*" indicates connection to the mother nucleus, and the other end is connected to ring A; or, In Formula II or Formula V, L 1 Selected from: Wherein "*" indicates connection with ring C; or, In Formula III, Formula IV, Formula VI or Formula VII, L 1 Selected from: -substituted or unsubstituted C1-C6 alkylene-, -substituted or unsubstituted C2-C6 alkenylene-, -substituted or unsubstituted C2-C6 alkynylene-, -substituted or unsubstituted C1-C6 alkylene-O-.

6. The compound according to any one of claims 1 to 5, or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: Ring A is Ring C is selected from the group consisting of substituted or unsubstituted C3-C6 cycloalkyl, six-membered aryl, six-membered heteroaryl, five-membered heteroaryl, 7. The compound according to any one of claims 1 to 6, or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: L 1 Selected from: Wherein "*" indicates connection with ring C.

8. The compound according to any one of claims 1 to 7, or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown in formula II to VII: In the formula, ring A, ring C, L 1 , L 2 The definition as in any one of claims 1 to 7; R 3 , R 4 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, fluorine, chlorine, bromine, or R 3 , R 4 The C atom to which it is attached forms a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group; or R 3 or R 4 The C atom connected thereto forms a vinyl group, a propenyl group or an allyl group; X is selected from O or S atoms, more preferably S atoms.

9. The compound according to any one of claims 1 to 8, or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound has the structure shown in formula II to VII: In the formula, ring A is Wherein, one of ring D and ring E is a substituted or unsubstituted benzene ring, and the other is a substituted or unsubstituted group of the following groups: pyrrole ring, furan ring or thiophene ring; the substitution refers to the substitution of 1-5 R 1 Replacement, where R 1 is halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy; Ring C is selected from the following groups: substituted or unsubstituted: 3-6 membered heterocyclyl, C3-C6 cycloalkyl, 6-membered aryl, 6-membered heteroaryl, 5-membered heteroaryl, Wherein, one of ring D and ring E is a substituted or unsubstituted benzene ring, and the other is a substituted or unsubstituted group of the following groups: a 5-membered heteroalkyl ring, a 5-membered heteroaryl ring; the substitution refers to the substitution of 1 to 5 R 1 Replacement, where R 1 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6 aryl; L 1 Selected from: -C1-C6 alkylene-, Wherein, m and p are each independently 0, 1 or 2; x and y are each independently selected from 0, 1, 2; Q and Z are each independently selected from CO or a chemical bond; wherein "*" indicates connection with ring C; L 2 Selected from: Said The "*" in indicates that it is connected to the mother nucleus, and the other end is connected to ring A; R 3 , R 4 Each is independently a C1-C6 alkyl group; X is selected from S atoms; Provided that, in Formula II or Formula V, L 1 Not for When L 2 for It is stated The "*" in indicates that it is connected to ring C. The "*" in indicates that it is connected to the mother nucleus, and the other end is connected to ring A.

10. The compound according to any one of claims 1 to 9, or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound has a structure shown in Formula II, Formula IV, Formula V or Formula VI: In the formula, ring A is selected from the following substituted or unsubstituted groups: The substitution refers to the substitution of 1 to 5 R 1 Replacement, where R 1 Selected from halogen, C1-C6 alkyl, C1-C6 halogen Haloalkyl, C1-C6 alkoxy; Ring C is selected from the following groups: substituted or unsubstituted: 3-6 membered heterocyclyl, C3-C6 cycloalkyl, 6-membered aryl, 6-membered heteroaryl, 5-membered heteroaryl, Wherein, one of ring D and ring E is a substituted or unsubstituted benzene ring, and the other is a substituted or unsubstituted group of the following groups: a 5-membered heteroalkyl ring, a 5-membered heteroaryl ring; the substitution refers to the substitution of 1 to 5 R 1 Replacement, where R 1 is selected from halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C6 aryl; L 1 Selected from: -C1-C6 alkylene-, Wherein, x and y are each independently selected from 0, 1 or 2; wherein "*" indicates connection with ring C; L 2 Selected from: Said The "*" in indicates that it is connected to the mother nucleus, and the other end is connected to ring A; R 3 , R 4 Each is independently a C1-C6 alkyl group; X is an S atom; Provided that, in Formula II or Formula V, L 1 Not for When L 2 for It is stated The "*" in indicates that it is connected to ring C. The "*" in indicates that it is connected to the mother nucleus, and the other end is connected to ring A.

12. The compound according to any one of claims 1 to 11, or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from the following compounds:

13. A pharmaceutical composition comprising a therapeutically effective amount of one or more of a compound selected from any one of claims 1 to 12, or a prodrug thereof, an enantiomer, a diastereomer, a racemate and a mixture thereof, or a pharmaceutically acceptable salt thereof; and optionally a pharmaceutically acceptable carrier.

14. Use of the compound according to any one of claims 1 to 12, or its prodrug, its enantiomer, diastereomer, racemate and mixture thereof, or its pharmaceutically acceptable salt, or the pharmaceutical composition according to claim 13, characterized in that: For the preparation of cGAS / STING pathway targeted inhibitors; or Used for preparing drugs for preventing and / or treating inflammatory diseases and / or autoimmune diseases.

15. The use according to claim 14, characterized in that The inflammatory disease is selected from inflammatory bowel disease, Crohn's disease, ulcerative colitis, intestinal malabsorption syndrome, irritable bowel syndrome, uveitis, mucositis, diabetes, cardiovascular disease and neurodegenerative disease, and / or, The autoimmune disease is selected from Singleton-Merten syndrome (SMS), Aicardi-Goutières syndrome (AGS), Systemic lupus erythematosus (SLE), amyotrophic lateral sclerosis (ALS), familial chilblain lupus erythematosus (FCL), multiple sclerosis, autoimmune colitis, retinal vasculopathy and leukodystrophy (RVCL), STING-associated vasculopathy of infancy (SAVI), scleroderma, psoriasis, Sjögren's syndrome, and rheumatoid arthritis.

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