CN107098846B

CN107098846B - N-acyl sulfonamide FBPase inhibitor, preparation method thereof, pharmaceutical composition and application thereof

Info

Publication number: CN107098846B
Application number: CN201610105864.9A
Authority: CN
Inventors: 徐柏玲; 申竹芳; 别建波; 穆永钊; 陈华龙; 刘率男; 周洁; 李彩娜; 曹冉; 环奕; 孙淑娟
Original assignee: Institute of Materia Medica of CAMS
Current assignee: Institute of Materia Medica of CAMS
Priority date: 2016-02-26
Filing date: 2016-02-26
Publication date: 2020-10-09
Anticipated expiration: 2036-02-26
Also published as: CN107098846A

Abstract

The invention discloses an N-acyl sulfonamide FBPase inhibitor with a novel structure, a preparation method thereof, a pharmaceutical composition and application thereof. Specifically, the invention relates to an N-acyl sulfonamide FBPase inhibitor shown in a general formula I, a pharmaceutically acceptable salt thereof, a preparation method thereof, a composition containing one or more compounds, application of the compounds in preparation of FBPase inhibitors or FBPase related disease treatment medicines, and application in preparation of diabetes prevention and/or treatment medicines.

Description

N-acyl sulfonamide FBPase inhibitor, preparation method thereof, pharmaceutical composition and application thereof

Technical Field

The invention relates to an N-acyl sulfonamide FBPase inhibitor with a novel structure shown in a formula I, a pharmaceutically acceptable salt thereof, a preparation method thereof, a composition containing one or more compounds, and application of the compounds in inhibiting FBPase and treating FBPase related diseases and preparing, preventing and/or treating diabetes.

Background

Diabetes mellitus is a polygenic regulated chronic metabolic disease, mainly manifested by persistent hyperglycemia and diabetes mellitus. Persistent hyperglycemia can lead to many complications, such as retinal, renal, neurological and vascular complications. The incidence of Chinese diabetes is rapidly increasing, and more than 9200 million Chinese diabetes patients are predicted, and about 1.48 million people are high-risk people with diabetes (New. Engl. J. Med.,2010,362: 1090-one 1101).

Diabetes mellitus is divided into two types, insulin-dependent (type I) and non-insulin-dependent (type II), wherein the type II diabetes mellitus patients account for 90-95% of the total number of diabetes mellitus patients. Biological studies have shown that the major pathological bases responsible for diabetes are insufficient insulin secretion, insulin resistance and increased hepatic glucose production. The currently clinically applied drugs are mainly of two types: one is to overcome insulin hyposecretion, such as: sulfonylureas and meglitinide insulinotropic agents; secondly, improving insulin resistance, such as: thiazolidinediones insulin sensitizers. To date, no antidiabetic agent that reduces endogenous glucose production has been clinically used. Metformin reduces hepatic glucose output, but the molecular targets of action are not yet clear.

It has been shown that increased endogenous glucose production is the primary cause of elevated fasting glucose levels in diabetic patients. Endogenous glucose is mainly derived from the liver. There are two pathways for glucose production by the liver, one is endogenous synthesis of glucose, gluconeogenesis (gluconeogenesis); the other is hepatic glycogenolysis (glycogenolysis). Therefore, the regulation of gluconeogenesis pathway and the reduction of endogenous glucose generation are potential new strategies for developing new mechanism-of-action antidiabetic drugs.

Gluconeogenesis is the process of converting lactic acid, glycine, glycerol and other three-carbon precursors into glucose under the catalytic action of various enzymes. In gluconeogenesis, Fructose-1,6-bisphosphatase (FBPase) catalyzes the conversion of Fructose-1, 6-diphosphate to Fructose-6-phosphate, releasing a molecule of phosphoric acid. The catalytic reaction is one of the speed control steps of endogenous glucose generation, inhibits the activity of FBPase, can reduce the generation of endogenous glucose, and reduces the blood sugar level. Therefore, the FBPase inhibitor is likely to become an antidiabetic with a new action mechanism, and has more significant meaning particularly in reducing fasting blood glucose level.

To date, many researchers have conducted studies on FBPase inhibitors, and various structural types of FBPase inhibitors have been reported. In 2003, Pfizer pharmaceutical company obtained indole carboxylic acid compounds through high-throughput screening, and FBPase inhibitory activity IC₅₀Values were at micromolar (bioorg. med. chem. lett.,2003,13: 2055-. In 2006, von Geldern et al reported that benzoxazole-2-benzenesulfonamide compounds have an inhibitory activity IC on FBPase₅₀Value of 10^-6-10^-7Molar levels (bioorg.med.chem.lett.,2006,16: 1811-. In 2010, Roche pharmaceutical company reported thiazole-substituted sulfonylurea FBPase inhibitors discovered by high-throughput screening, which inhibit the activity IC ₅₀Value of 10^-7-10^-8Molar levels (bioorg.med.chem.lett.,2010,20: 594-. In 2007-2010, the pharmaceutical company of Metasis reported that AMP analogs were discovered by using a structure-based drug molecule design strategy, and FBPase inhibition was soughtThrough continuous structural optimization, the benzimidazole FBPase inhibitors (J.Am.chem.Soc.,2007,129: 15480-15490; J.Med.chem.2010, 53:441-451) and the thiazole FBPase inhibitors (J.Am.chem.Soc.,2007,129: 15491-15502; J.Med.chem.2011, 54:153-165) are obtained by the agents, and MB07803 is a diamide prodrug of the thiazole compounds, and is currently in phase II clinical research (US, 225259A 1[ P. sub.P. ]].2007-09-27.)。

Although FBPase inhibitors of various structural types have been reported, only FBPase inhibitors CS-917 and MB07803 developed by metabasas pharmaceutical have been in phase II clinical study to date. However, both candidate drugs contain phosphonic acid groups, and are in clinical research in the form of phosphonic acid diamide prodrugs, so as to overcome the problem of low oral bioavailability (4%) of the phosphonic acid prodrug (MB 05032). Due to the complex in vivo metabolic process of the prodrug, the prospect of clinical research is more difficult to predict. Therefore, the search for FBPase inhibitors with excellent pharmacokinetic properties as antidiabetic drugs with a new mechanism has very important clinical significance.

The invention designs and synthesizes the N-acyl sulfonamide FBPase inhibitor with a new structure, does not contain phosphonic acid or phosphate groups, and lays a structural foundation for obtaining the FBPase inhibitor which has good pharmacological property and can be orally taken. The invention aims to find a novel antidiabetic medicament which has strong antidiabetic activity, good pharmacokinetic property and oral administration effectiveness.

Disclosure of Invention

The invention aims to provide an N-acyl sulfonamide derivative shown in a formula I and a physiologically acceptable salt, a preparation method thereof, a pharmaceutical composition, an application of the N-acyl sulfonamide derivative in preparation of an FBPase inhibitor and a potential pharmaceutical application thereof, and an application in preparation of an antidiabetic medicament.

In order to solve the technical problem, the invention provides the following technical scheme:

the first aspect of the technical scheme of the invention provides N-acyl sulfonamide derivatives shown as a general formula I and physiologically acceptable salts thereof:

in the formula I, the compound is shown in the specification,

a is selected from NR₁、O、S、Se、CR₈R₉C ═ O, where R₁、R₈And R₉Independently selected from hydrogen, substituted or unsubstituted C1-6 linear or branched alkyl, substituted or unsubstituted C2-6 linear or branched alkenyl or alkynyl, wherein the substituents are selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl wherein Ra ₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

b is selected from CR₃N, wherein R₃Selected from hydrogen, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, F, Cl, Br, substituted C1-3 straight or branched chain alkyl, wherein the substituents are selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, methyl, ethyl;

d is selected from CR₄N; e is selected from CR₅N; f is selected from CR₆N; g is selected from CR₇N; D. e, F, G may be individuallyN, two are N at the same time and/or three are N at the same time; r₄And R₇Not hydrogen at the same time;

R₄and R₇Is independently selected from the group consisting of atoms or groups or moieties, including

(1)H、F、Cl、Br、CN、NO₂、CONRc₁Rd₁、COORc₂、SO₂Rc₃、SO₂NRc₄Rd₂Wherein said Rc₁、Rd₁、Rc₂、Rc₃、Rc₄、Rd₂Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(2) substituted or unsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl or alkynyl, wherein the substituents are selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(3) Substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(4) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(5)ORe₁、NRe₂Rf₁、SRe₃、NRe₄CORf₂、NRe₅COORf₃、NRe₆SO₂Rf₄Wherein said Re₁、Re₂、Rf₁、Re₃、Re₄、Rf₂、Re₅、Rf₃、Re₆、Rf₄Independently selected from H, substituted or unsubstituted C1-8 straight chain or branched chain alkyl, substituted or unsubstituted C2-8 straight chain or branched chain alkenyl, substituted or unsubstituted C2-8 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

said Re₁、Re₂、Rf₁、Re₃、Re₄、Rf₂、Re₅、Rf₃、Re₆、Rf₄Can also be independently selected from substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-8 membered rings, substituted or unsubstituted azacycloalkyl with 3-8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(6)OAr_a1、NRg₁Ar_a2、SAr_a3、CH₂Ar_a4、COAr_a5、NRg₂COAr_a6、NRg₃COOAr_a7、NRg₄SO₂Ar_a8wherein said Rg₁、Rg₂、Rg₃、Rg₄Selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; ar is_a1、Ar_a2、Ar_a3、Ar_a4、Ar_a5、Ar_a6、Ar_a7、Ar_a8Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(7)OCH₂Ar_a9、NHCH₂Ar_a10、SCH₂Ar_a11、CH₂CH₂Ar_a12ar of_a9、Ar_a10、Ar_a11、Ar_a12Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

R₅And R₆Is independently selected from the group consisting of atoms or groups or moieties, including

(1)H、F、Cl、Br、CN、NO₂、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂Wherein Rh is₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂Independent of each otherIs selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) substituted or unsubstituted C1-4 straight chain or branched chain alkyl, substituted or unsubstituted C2-4 straight chain or branched chain alkenyl, substituted or unsubstituted C2-4 alkynyl, wherein the substituent is selected from F, Cl, Br, CN, NO₂、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂Wherein Rh is₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(3) substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, CF₃、CH₂CF₃、CHF₂、F、Cl、Br、CN、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂、ORh₅、SRh₆、NRh₇Ri₃、NRh₈CORi₄、NRh₉COORi₅Wherein Rh is₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂、Rh₅、Rh₆、Rh₇、Ri₃、Rh₈、Ri₄、Rh₉、Ri₅Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the oxacycloalkyl group having 3-6 membered rings or the azacycloalkyl group having 3-6 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(4)ORj₁、NRj₂Rk₁、SRj₃、NRj₄CORk₂、NRj₅COORk₃、NRj₆SO₂Rk₄wherein Rj is₁、Rj₂、Rk₁、Rj₃、Rj₄、Rk₂、Rj₅、Rk₃、Rj₆、Rk₄Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF ₃，CH₂CF₃，CHF₂；

R is selected from the group consisting of:

(1) substituted or unsubstituted C1-10 straight chain or branched chain alkyl, substituted or unsubstituted C2-10 straight chain or branched chain alkenyl, substituted or unsubstituted C2-10 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORx₁、SRx₂、NRx₃Ry₁、NRx₄CORy₂、COORx₅、CONRx₆Ry₃、NRx₇COORy₄、SO₂NRx₈Ry₅Said Rx₁、Rx₂、Rx₃、Ry₁、Rx₄、Ry₂、Rx₅、Rx₆、Ry₃、Rx₇、Ry₄、Rx₈、Ry₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(2) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl with 3 to 8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORx₁、SRx₂、NRx₃Ry₁、NRx₄CORy₂、COORx₅、CONRx₆Ry₃、NRx₇COORy₄、SO₂NRx₈Ry₅Said Rx₁、Rx₂、Rx₃、Ry₁、Rx₄、Ry₂、Rx₅、Rx₆、Ry₃、Rx₇、Ry₄、Rx₈、Ry₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl group having 3 to 8 membered rings and the azacycloalkyl group having 3 to 8 membered rings may contain 1 hetero atom or the sameWhen containing a plurality of heteroatoms;

(3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(4) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds of the invention according to formula I of the invention and physiologically acceptable salts include, but are not limited to, compounds of formula (IA):

in the formula IA,

a is selected from NR₁、O、S、Se、CR₈R₉C ═ O, where R₁、R₈And R₉Independently selected from hydrogen, substituted or unsubstituted C1-6 linear or branched alkyl, substituted or unsubstituted C2-6 linear or branched alkenyl or alkynyl, wherein the substituents are selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl wherein Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight chain or branched chain alkylAlkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

b is selected from CR₃N, wherein R₃Selected from hydrogen, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, F, Cl, Br, substituted C1-3 straight or branched chain alkyl, wherein the substituents are selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, methyl, ethyl; r₄And R₇Not hydrogen at the same time;

(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(4) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra' ₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

said Re₁、Re₂、Rf₁、Re₃、Re₄、Rf₂、Re₅、Rf₃、Re₆、Rf₄And may also be independently selected from the group consisting of substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted aza of 3-8 membered ringCycloalkyl, wherein said substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa ₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(6)OAr_a1、NRg₁Ar_a2、SAr_a3、CH₂Ar_a4、COAr_a5、NRg₂COAr_a6、NRg₃COOAr_a7、NRg₄SO₂Ar_a8wherein said Rg₁、Rg₂、Rg₃、Rg₄Selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; ar is_a1、Ar_a2、Ar_a3、Ar_a4、Ar_a5、Ar_a6、Ar_a7、Ar_a8Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(1)H、F、Cl、Br、CN、NO₂、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂Wherein Rh is₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(2) substituted or unsubstituted C1-4 straight chain or branched chain alkyl, substituted or unsubstituted C2-4 straight chain or branched chain alkenyl, substituted or unsubstituted C2-4 straight chain or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, NO ₂、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂Wherein Rh is₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

(3) substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, CF₃、CH₂CF₃、CHF₂、F、Cl、Br、CN、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂、ORh₅、SRh₆、NRh₇Ri₃、NRh₈CORi₄、NRh₉COORi₅Wherein Rh is₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂、Rh₅、Rh₆、Rh₇、Ri₃、Rh₈、Ri₄、Rh₉、Ri₅

Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the oxacycloalkyl group having 3-6 membered rings or the azacycloalkyl group having 3-6 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(4)ORj₁、NRj₂Rk₁、SRj₃、NRj₄CORk₂、NRj₅COORk₃、NRj₆SO₂Rk₄wherein Rj is₁、Rj₂、Rk₁、Rj₃、Rj₄、Rk₂、Rj₅、Rk₃、Rj₆、Rk₄Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF₃，CH₂CF₃，CHF₂(ii) a R is selected from the group consisting of:

(2) Substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstitutedAn oxacycloalkyl group having 3 to 8 membered ring, an azacycloalkyl group having 3 to 8 membered ring, substituted or unsubstituted, wherein said substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORx₁、SRx₂、NRx₃Ry₁、NRx₄CORy₂、COORx₅、CONRx₆Ry₃、NRx₇COORy₄、SO₂NRx₈Ry₅Said Rx₁、Rx₂、Rx₃、Ry₁、Rx₄、Ry₂、Rx₅、Rx₆、Ry₃、Rx₇、Ry₄、Rx₈、Ry₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl group having 3-to 8-membered ring or the azacycloalkyl group having 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(3) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle or the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; five membered heteroaromatic ring The ring may contain one or more heteroatoms selected from O, N, S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Preferred compounds and physiologically acceptable salts of the present invention according to formula IA of the present invention include, but are not limited to, compounds represented by formula (IAa):

In the case of the formula IAa,

a and substituents R, R₄，R₅，R₆，R₇The definitions are as for general formula (IA); r₄And R₇Not hydrogen at the same time; r₃Selected from hydrogen, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, F, Cl, Br, substituted C1-3 straight or branched chain alkyl, wherein the substituents are selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, methyl, ethyl.

Preferred compounds and physiologically acceptable salts of the present invention according to formula IAa of the present invention include, but are not limited to, compounds represented by formula (IAa-1):

in the formula IAa-1, the,

R₁selected from hydrogen, substituted or unsubstituted C1-6 straight or branched chain alkyl, substituted or unsubstituted C2-6 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl wherein Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, ringTrimethylene, cyclobutyl;

R₃selected from hydrogen, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, F, Cl, Br, substituted C1-3 straight or branched chain alkyl, wherein the substituents are selected from F, Cl, Br, CN, ORa ₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, methyl, ethyl;

the substituents R, R₄，R₅，R₆，R₇The definitions are as for general formula (IAa); r₄And R₇Not hydrogen at the same time.

Preferred compounds and physiologically acceptable salts of the present invention according to formula IAa-1 of the present invention include, but are not limited to, compounds represented by formula (IAa-1 a):

in the formula IAa-1a,

R₁selected from hydrogen, substituted or unsubstituted C1-6 straight or branched chain alkyl, substituted or unsubstituted C2-6 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl wherein Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

R₃selected from hydrogen, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclopropylmethylene, F, Cl, Br, substituted C1-3 straight or branched chain alkyl, wherein the substituents are selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, methyl, ethyl;

the substituents R, R₅，R₆，R₇The definition is the same as that of the general formula IAa-1;

y is selected from O, S, NRp₁、CH₂、CO、NRp₂CO、OCH₂、NHCH₂、SCH₂、CH₂CH₂(ii) a Wherein Rp is₁、Rp₂Selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

Ar₁Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds and physiologically acceptable salts of the present invention according to formula IAa-1a of the present invention include, but are not limited to, compounds represented by formula (IAa-1 a-1):

in the formula IAa-1a-1,

R'₁selected from hydrogen, methyl, ethyl, propyl, isopropyl, CHF₂、CF₃、CH₂CF₃Cyclopropyl, cyclopropylmethylene, oxetanyl;

y is selected from O, S, NH, CH₂、CO、NHCO、OCH₂、NHCH₂、SCH₂、CH₂CH₂；

Ar₁Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

R'₇selected from the group consisting of atoms or groups or structural fragments, including

H、F、Cl、Br、CN、NO₂、CONH₂、CONHCH₃、CON(CH₃)₂、SO₂CH₃、SO₂NH₂、SO₂NHCH₃Methyl, ethyl, CF₃、CHF₂、CH₂CF₃Cyclopropyl, OCH₃、OCF₃、OCF₂CH₃、OCH₂CF₃、NH₂、NHCH₃、N(CH₃)₂、NHCOCH₃、NHCOOCH₃；

R'₅And R'₆Is independently selected from the group consisting of atoms or groups or moieties, including

H、F、Cl、Br、CN、NO₂、CONH₂、CONHCH₃、CON(CH₃)₂、SO₂CH₃、SO₂NH₂、SO₂NHCH₃Methyl, ethyl, ethynyl, ethenyl, propynyl, propenyl, CF₃、CHF₂、CH₂CF₃Cyclopropyl, methylene cyclopropyl, OCH₃、OCH₂CH₃、OCF₃、OCF₂CH₃、OCH₂CF₃、NH₂、NHCH₃、N(CH₃)₂、NHCOCH₃、NHCOOCH₃；

Ar' is selected from the group consisting of:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzoSix-membered heterocycle, substituted or unsubstituted benzo five-membered heterocycle, wherein the substituent is selected from C1-4 straight chain or branched chain alkyl, halogen substituted C1-4 straight chain or branched chain alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds and physiologically acceptable salts of the present invention according to formula IAa-1a-1 of the present invention include, but are not limited to, compounds represented by formula (IAa-1a-1 a):

in the formula IAa-1a-1a,

Ar₁selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched-chain alkylHalogen-substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Ar' is selected from the group consisting of:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds of the invention according to formula IAa-1a-1 of the invention and physiologically acceptable salts thereof include, but are not limited to, compounds of formula (IAa-1a-1 b):

in the formula IAa-1a-1b,

Ar₁selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Ar' is selected from the group consisting of:

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 linear or branched alkyl, cyclopropyl, cyclopropylmethyleneAlkyl, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds of the invention according to formula IAa-1 of the invention and physiologically acceptable salts thereof include, but are not limited to, compounds of formula (IAa-1 b):

in the formula IAa-1b,

Ar₂selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds of the invention according to formula IAa of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds of formula (IAa-2):

in the formula IAa-2, the,

x is selected from O, S, Se, C ═ O;

the substituents R, R₄，R₅，R₆，R₇The definition is the same as that of the general formula IAa; r₄And R₇Not hydrogen at the same time.

Preferred compounds of the invention according to formula IAa-2 of the invention and physiologically acceptable salts thereof include, but are not limited to, compounds of formula (IAa-2 a):

in the formula IAa-2a,

x is selected from O, S, Se, C ═ O;

Ar₃selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra' ₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; a six-membered heteroaromatic ring may contain 1N atom,may also contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

the substituents R, R₄，R₅，R₆The definition is the same as that of the general formula IAa-2.

Preferred compounds of the invention according to formula IAa-2a of the invention and physiologically acceptable salts thereof include, but are not limited to, compounds of formula (IAa-2 a-1):

in the formula IAa-2a-1,

x is selected from O, S, Se, C ═ O;

R'₃selected from hydrogen, methyl, ethyl, propyl, isopropyl, CHF₂、CF₃、CH₂CF₃Cyclopropyl, cyclopropylmethylene, oxetanyl;

Ar₃Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

R'₄selected from the group consisting of atoms or groups or structural fragments, including

Ar' is selected from the group consisting of:

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds of the invention according to formula IAa-2a-1 of the invention and physiologically acceptable salts thereof include, but are not limited to, compounds of formula (IAa-2a-1 a):

in the formula IAa-2a-1a,

x is selected from O, S, Se, C ═ O;

Ar₃selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Ar' is selected from the group consisting of:

(2) substituted or unsubstituted aromatic condensed ring or condensed heterocyclic ring, substituted or unsubstituted non-aromatic condensed ring or condensed heterocyclic ring, including substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocyclic ring, substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Is independently selected fromH. C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds of the present invention according to formula IA of the present invention and physiologically acceptable salts thereof include, but are not limited to, compounds represented by formula (IAb):

in the formula IAb, the process is represented by,

a and substituents R, R₄，R₅，R₆，R₇As defined for formula IA.

Preferred compounds of the present invention and physiologically acceptable salts thereof according to formula IAb of the present invention include, but are not limited to, compounds represented by formula (IAb-1):

in the formula IAb-1, the first,

R₁selected from hydrogen, substituted or unsubstituted C1-6 straight or branched chain alkyl, substituted or unsubstituted C2-6 straight or branched chain alkenyl or alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl wherein Ra ₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

the substituents R, R₄，R₅，R₆，R₇The definition is the same as that of formula IAb; r₄And R₇Not hydrogen at the same time.

Preferred compounds of the present invention and physiologically acceptable salts thereof according to formula IAb-1 of the present invention include, but are not limited to, compounds represented by formula (IAb-1 a):

in the formula IAb-1a,

the substituents R, R₅，R₆，R₇The definition is the same as that of formula IAb-1;

Ar₄selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds of the present invention and physiologically acceptable salts thereof according to formula IAb-1a of the present invention include, but are not limited to, compounds represented by formula (IAb-1 a-1):

in formula IAb-1a-1,

Ar₄Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa' ₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Ar' is selected from the group consisting of:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs ₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 linear or branched alkyl, cyclopropyl, cyclopropylmethyleneAlkyl, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Preferred compounds of the present invention and physiologically acceptable salts thereof according to formula IAb-1a-1 of the present invention include, but are not limited to, compounds represented by formula (IAb-1a-1 a):

in formula IAb-1a-1a,

Ar₄selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、SRa′₂、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、SO₂NRa′₇Rb′₄、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₂、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₇、Rb′₄、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Ar' is selected from the group consisting of:

(2) substituted or unsubstituted aromatic condensed rings or condensed hetero compoundsThe ring, the substituted or unsubstituted non-aromatic condensed ring or the fused heterocyclic ring comprises a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted benzo six-membered heterocyclic ring, a substituted or unsubstituted benzo five-membered heterocyclic ring, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br.

Preferred compounds of the present invention and physiologically acceptable salts thereof according to formula IAb of the present invention include, but are not limited to, compounds represented by formula (IAb-2):

in the formula IAb-2, the first,

x is selected from O, S, Se, C ═ O;

the substituents R, R₄，R₅，R₆，R₇The definition is the same as that of formula IAb.

Preferred compounds of the invention according to formula I of the invention and their physiologically acceptable salts include, but are not limited to, compounds of formula (IB):

in the formula IB, the compound represented by the formula IB,

a is selected from NR₁、O、S、Se、CR₈R₉C ═ O, where R₁、R₈And R₉Independently selected from hydrogen, substituted or unsubstituted C1-6 linear or branched alkyl, substituted or unsubstituted C2-6 linear or branched alkenyl or alkynyl, wherein the substituents are selected from F, Cl, Br, CN, ORa ₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Cyclopropyl, cyclopropylmethylene, cyclobutyl, oxetanyl, cyclopentyl wherein Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl;

R₄selected from the group consisting of atoms or groups or structural fragments, including

(3) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORa ₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight chain or branched chainAlkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl and azacycloalkyl groups of the 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(5)ORe₁、NRe₂Rf₁、SRe₃、NRe₄CORf₂、NRe₅COORf₃、NRe₆SO₂Rf₄wherein said Re₁、Re₂、Rf₁、Re₃、Re₄、Rf₂、Re₅、Rf₃、Re₆、Rf₄Independently selected from H, substituted orUnsubstituted C1-8 straight or branched chain alkyl, substituted or unsubstituted C2-8 straight or branched chain alkenyl, substituted or unsubstituted C2-8 straight or branched chain alkynyl, wherein the substituent is selected from F, Cl, Br, CN, ORa ₁、SRa₂、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、SO₂NRa₇Rb₄、NRa₈CORb₅Wherein said Ra₁、Ra₂、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₇、Rb₄、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl;

(3) substituted or unsubstituted C3-6 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3-6 membered rings, substituted or unsubstituted azacycloalkyl with 3-6 membered rings, wherein the substituents are selected from methyl, ethyl, propyl, isopropyl, CF₃、CH₂CF₃、CHF₂、F、Cl、Br、CN、CONRh₁Ri₁、COORh₂、SO₂Rh₃、SO₂NRh₄Ri₂、ORh₅、SRh₆、NRh₇Ri₃、NRh₈CORi₄、NRh₉COORi₅Wherein Rh is₁、Ri₁、Rh₂、Rh₃、Rh₄、Ri₂、Rh₅、Rh₆、Rh₇、Ri₃、Rh₈、Ri₄、Rh₉、Ri₅Independently selected from H, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl; the oxacycloalkyl group having 3-6 membered rings and the azacycloalkyl group having 3-6 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(4)ORj₁、NRj₂Rk₁、SRj₃、NRj₄CORk₂、NRj₅COORk₃、NRj₆SO₂Rk₄wherein Rj is₁、Rj₂、Rk₁、Rj₃、Rj₄、Rk₂、Rj₅、Rk₃、Rj₆、Rk₄Is independently selected fromH, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, CF₃，CH₂CF₃，CHF₂；

R is selected from the group consisting of:

(2) Substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl with 3 to 8 membered rings, substituted or unsubstituted azacycloalkyl with 3 to 8 membered rings, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, Br, CN, ORx₁、SRx₂、NRx₃Ry₁、NRx₄CORy₂、COORx₅、CONRx₆Ry₃、NRx₇COORy₄、SO₂NRx₈Ry₅Said Rx₁、Rx₂、Rx₃、Ry₁、Rx₄、Ry₂、Rx₅、Rx₆、Ry₃、Rx₇、Ry₄、Rx₈、Ry₅Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the oxacycloalkyl group having 3-to 8-membered ring and the azacycloalkyl group having 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(3) substituted or unsubstituted phenyl, substituted orUnsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、SRs₂、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、SO₂NRs₈Rt₅、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₂、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₈、Rt₅、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl, cyclopropylmethylene, cyclobutyl, cyclopentyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen comprises F, Cl and Br;

Preferred compounds of the invention and physiologically acceptable salts thereof, including, but not limited to, said R₁Selected from H, methyl, ethyl, n-propyl, isopropyl, ethenyl and ethynyl.

Preferred compounds of the present invention and physiologically acceptable salts thereof, including, but not limited to, said R' ₁Selected from H, methyl, ethyl, n-propyl, isopropyl, ethenyl and ethynyl.

Preferred compounds of the invention and physiologically acceptable salts thereof, including, but not limited to, said R₃Selected from H, methyl, ethyl, ethenyl and ethynyl.

Preferred compounds of the present invention and physiologically acceptable salts thereof, including, but not limited to, said R'₃Selected from H, methyl, ethyl, ethenyl and ethynyl.

For the purposes of the present invention, preferred compounds include, but are not limited to:

in a second aspect of the present invention, there is provided a process for the preparation of a compound of the first aspect, which comprises the steps of:

(1) performing hydrolysis reaction on the compound A under alkaline conditions to obtain a compound B;

(2) carrying out condensation reaction on the compound B and a corresponding sulfonamide compound to obtain the compound of the first aspect of the invention;

wherein A, B, D, E, F, G, R is as defined for the compound according to the first aspect of the invention.

In addition, the starting materials and intermediates in the above reactions are readily available, and the reactions in each step can be readily synthesized according to reported literature or by conventional methods in organic synthesis to those skilled in the art. The compounds of formula I may exist in the form of solvates or non-solvates, and crystallization using different solvents may give different solvates. Pharmaceutically acceptable salts of formula I include salts of various acids, such as the following inorganic or organic acids: hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, lycinic acid, maleic acid, tartaric acid, fumaric acid, citric acid, lactic acid. The pharmaceutically acceptable salts of formula I also include salts of various alkali metal (lithium, sodium, potassium), alkaline earth metal (calcium, magnesium) and ammonium salts, and salts of organic bases which provide physiologically acceptable cations, such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine and tris (2-hydroxyethyl) amine. All such salts within the scope of the present invention may be prepared by conventional methods.

In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention also provides a pharmaceutical composition which takes the compound as an active ingredient and comprises at least one compound in the invention and a pharmaceutically acceptable carrier. The medicine composition is selected from tablets, capsules, pills, injections, sustained-release preparations, controlled-release preparations or various particle delivery systems. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the invention may be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The compounds of the present invention are generally present in the pharmaceutical compositions in an amount of from 0.1 to 95% by weight.

The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like.

The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.

The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.

These formulations are prepared according to methods well known to those skilled in the art. Adjuvants used for the manufacture of tablets, capsules, coatings are the customary auxiliaries, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils, such as corn oil, peanut oil, olive oil, etc. The formulations containing the compounds of the present invention may also contain other adjuvants such as surfactants, lubricants, disintegrants, preservatives, flavoring agents, coloring agents, and the like.

For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.

The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.

To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention.

In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.

In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.

For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.

The dosage of the pharmaceutical composition of the compound of the present invention to be administered may vary widely depending on the nature and severity of the disease to be prevented or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, a suitable dosage range per day for a compound of the invention is from 0.01 to 500mg/Kg body weight, preferably from 0.1 to 300mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.

The compounds or compositions of the present invention may be administered alone or in combination with other therapeutic or symptomatic agents. When the compound of the present invention is used in a synergistic manner with other therapeutic agents, the dosage thereof should be adjusted according to the actual circumstances.

The fourth aspect of the technical scheme of the invention provides application of the compound and the medicinal salt thereof in the first aspect of the invention in preparing FBPase inhibitors and medicaments for preventing and/or treating diseases and symptoms related to FBPase. The use, characterized in that diseases and conditions associated with FBPase are selected from diabetes, chronic complications of diabetes and obesity. The diabetes is selected from type I diabetes and type II diabetes; the chronic complications of diabetes are selected from retinal, renal, nervous system and vascular complications, ischemic heart disease or atherosclerosis.

Detailed Description

The present invention will be further illustrated with reference to the following examples, but the scope of the present invention is not limited thereto.

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or High Resolution Mass Spectrometry (HRMS). NMR was measured using a Varian marcry 300 or Varian marcry 400 solvent in CDCl₃、DMSO-d₆、acetone-d₆、CD₃OD, internal standard TMS, chemical shifts are given in ppm. Ms were determined using a Thermo active Plus type mass spectrometer. m.p. is the melting point given in ° c, the temperature is uncorrected. Silica gel column chromatography generally uses 200-300 mesh silica gel as a carrier.

The reagents used in the experiments were either chemically pure or analytically pure. The solvents used were all analytical grade, the anhydrous solvent used was obtained from the solvent purification system produced by Innovative TECHNOLOGY, USA, and the other solvents were not treated unless otherwise specified.

List of abbreviations:

TLC: thin-layer chromatography PPA: polyphosphoric acid

DMSO, DMSO: dimethyl sulfoxide DMAP: 4-dimethylaminopyridine

CDCl₃: deuterated chloroform DMSO-d₆: deuterated dimethyl sulfoxide

acetone-d₆: deuterated acetone CD₃OD: deuterated methanol

HOBt: 1-hydroxybenzotriazole Pd (OAc)₂: palladium acetate

DCM: dichloromethane NBS: n-bromosuccinimide

NCS: n-chlorosuccinimide TFA: trifluoroacetic acid

DMF: n, N-dimethylformamide THF: tetrahydrofuran (THF)

DMAP: 4-dimethylaminopyridine Et₃N: triethylamine

TBAB: tetrabutylammonium bromide TBAF: tetrabutylammonium fluoride

EA: ethyl acetate

EDCI: 1-Ethyl- (3-dimethylaminopropyl) carbodiimides hydrochloride

HATU: 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethylurea hexafluorophosphate

XantPhos: 4, 5-bis-diphenylphosphino-9, 9-dimethylxanthene

DavePhos: 2-dicyclohexylphosphino-2' - (N, N-dimethylamine) -biphenyl

PdCl₂(dppf): [1,1' -bis (diphenylphosphino) ferrocene]Palladium dichloride

Pd₃(dba)₂: tris (dibenzylideneacetone) dipalladium

(tBu)₃P·HBF₄: tri (tert-butylphosphine) tetrafluoroborate

TBDMSCl: tert-butyldimethylsilyl chloride

min: the method comprises the following steps of (1) taking minutes; h: hour(s)

P/E: petroleum ether/ethyl acetate; D/M: methylene chloride/methanol

Josiphos: (R) -1- [ (SP) -2- (diphenylphosphino) ferrocene ] ethyldicyclohexylphosphine

Preparation of intermediate 1:

7-Nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester

a) 2-nitro-5-chlorophenylhydrazine hydrochloride

2-Nitro-5-chloroaniline (5g, 29.0mmol) was dissolved in concentrated hydrochloric acid (57.2g, 580mmol) and reacted at 40 ℃ for 2 hours. Then, the mixture was cooled to-10 ℃ and an aqueous solution (20mL) of sodium nitrite (2.1g, 30.45mmol) was added dropwise to the mixture, followed by reaction for 2 hours. Cooling to-30 deg.C, and adding SnCl which is precooled to-30 deg.C ₂(19.6g, 87mmol) in concentrated HCl (30mL) at-20 ℃ for 1h, warmed to room temperature, filtered and dried to give 7.0g of a pale yellow solid with a yield of 100%, mp: 178-.

¹H NMR(DMSO-d₆)(ppm):9.39(brs,1H),8.15(d,J＝8.8Hz,1H),7.45(s,1H),7.06(d,J＝8.4Hz,1H),3.83(brs,3H)；HRMS(ESI):m/z,calcd for C₆H₇ClN₃O₂[M+H⁺]:188.0221,found 188.0220.

b)2- (2- (2-Nitro-5-chlorophenyl) hydrazono) propionic acid ethyl ester

2-nitro-5-chlorophenylhydrazine hydrochloride (1g, 4.46mmol) was dissolved in methanol (20mL), ethyl pyruvate (544mg, 4.69mmol) was added dropwise, stirring was carried out at room temperature for 5min to precipitate a pale yellow solid, which was filtered to obtain 469mg of pale yellow solid, yield 36.8%, mp: 107-.

¹H NMR(acetone-d₆)(ppm):10.82(br,1H),8.24(d,J＝8.8Hz,1H),7.95(s,1H),7.10(dd,J₁＝9.2Hz,J₂＝1.6Hz,1H),4.32(q,J＝7.2Hz,2H),2.26(s,3H),1.35(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₁H₁₃ClN₃O₄[M+H⁺]:286.0589,found 286.0582.

c) 7-Nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester

Ethyl 2- (2- (2-nitro-5-chlorophenyl) hydrazono) propionate (2.84g, 9.94mmol) was added to PPA (57g) and reacted at 80 ℃ for 12h, and the starting material disappeared. Cooled to room temperature, added with 50mL of ice water under ice water bath, stirred, extracted by EA (30 mL. times.3), and subjected to column chromatography (P/E is 50:1) to obtain a pale yellow solid 810mg with a yield of 30%, mp:170 and 171 ℃.

¹H NMR(acetone-d₆)(ppm):11.01(brs,1H),8.31(d,J＝8.7Hz,1H),7.45(d,J＝8.4Hz,1H),7.40(s,1H),4.45(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₁H₁₀ClN₂O₄[M+H⁺]:269.0324,found 269.0318.

Example 1: 7-nitro-4-chloro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

a) 7-nitro-4-chloro-1H-indole-2-carboxylic acid

7-Nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester (350mg, 1.3mmol) was dissolved in THF (8mL) and EtOH (4mL), NaOH solution (260mg, 6.5mmol, 4mL H) was added₂O), reacting at room temperature, standing overnight, evaporating to remove the solvent, adding 20mL of water, washing with EA (20mL of × 2), adjusting the pH of the aqueous phase to about 2-3 with 1M hydrochloric acid, separating out the solid, filtering, and drying to obtain the off-white powdery solid of 310mg with the yield of 99%, mp: 220-.

¹H NMR(DMSO-d₆)(ppm):13.74(brs,1H),11.57(s,1H),8.26(d,J＝8.8Hz,1H),7.46(d,J＝8.4Hz,1H),7.32(s,1H).

b) 7-nitro-4-chloro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

7-Nitro-4-chloro-1H-indole-2-carboxylic acid (80mg, 0.33mmol) was dissolved in DCM (10mL) and EDCI (82mg, 0.43mmol), DMAP (21mg, 0.17mmol) and Et were added successively₃N (67mg, 0.66mmol), stirring well, adding benzenesulfonamide (78mg, 0.50mmol), stirring at room temperature for 3D, removing the starting material, evaporating to remove the solvent, dissolving the residue with EA (30mL), washing with 1M diluted hydrochloric acid (20mL × 3), washing with water (20mL × 2), column chromatography (D/M ═ 10:1) to give 80mg of a pale yellow powdery solid, recrystallizing EA to 58mg, yield 46%, mp:>250℃。

¹H NMR(DMSO-d₆)(ppm):11.97(brs,1H),8.28(d,J＝8.8Hz,1H),8.05(d,J＝7.2Hz,2H),7.75(t,J＝7.2Hz,1H),7.67(t,J＝7.2Hz,2H),7.61(s,1H),7.46(d,J＝8.4Hz,1H).

example 2: 7-nitro-4-chloro-N- (methylsulfonyl) -1H-indole-2-carboxamide

7-Nitro-4-chloro-1H-indole-2-carboxylic acid (80mg, 0.33mmol) was dissolved in DCM (10mL) and HATU (188mg, 0.50mmol), DMAP (20mg, 0.17mmol) and Et were added sequentially₃N (67mg, 0.66mmol), after stirring well, methanesulfonamide (63mg, 0.66mmol) was added, stirring at room temperature overnight, the starting material disappeared, the solvent was evaporated, EA (30mL) dissolved the residue, washed with 1M dilute hydrochloric acid (20mL × 3), washed with water (20mL × 2), EA recrystallized to give 72mg of off-white powdery solid, yield 69%, mp: >250℃。

¹H NMR(DMSO-d₆)(ppm):12.08(s,1H),8.31(d,J＝8.4Hz,1H),7.67(s,1H),7.49(d,J＝8.8Hz,1H),3.44(s,3H).

Example 3: 4- ((3-methoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

7-Nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester (220mg, 0.82mmol) was dissolved in toluene (12mL), and Pd was added successively₂(dba)₃(75mg, 0.082mmol), XantPhos (95mg, 0.16mmol) and Na₂CO₃(261mg，2.46mmol,2mL H₂O), stirring uniformly, adding 3-methoxyaniline (302mg, 2.46mmol), refluxing for 5h under the protection of argon, cooling to room temperature, evaporating to remove the solvent, dissolving the residue with EA (30mL), washing with saturated brine (20mL × 3), washing with water (20mL × 2), and performing column chromatography (P/E is 20:1) to obtain a light yellow powdery solid 285mg with a yield of 98% and an mp: 188-.

¹H NMR(DMSO-d₆)(ppm):10.94(s,1H),9.64(s,1H),8.13(d,J＝9.3Hz,1H),7.84(s,1H),7.35(t,J＝7.8Hz,1H),6.96(d,J＝7.8Hz,1H),6.92-6.93(m,1H),6.77-6.82(m,2H),4.37(q,J＝7.5Hz,2H),3.78(s,3H),1.36(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcdfor C₁₈H₁₈N₃O₅[M+H⁺]:356.1241,found 356.1231.

b)4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Ethyl 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate (250mg, 0.70mmol) was dissolved in THF (6mL) and EtOH (3mL), NaOH solution (140mg, 3.5mmol, 3mL H) was added₂O), reacting at room temperature, standing overnight, evaporating to remove solvent, adding 15mL of water, washing with EA (10mL of × 2), adjusting pH of the water phase to about 2-3 with 1M hydrochloric acid, precipitating solid, filtering, and drying to obtain red brown powdery solid 227mg with yield of 99%. mp :217-219℃。

¹H NMR(DMSO-d₆)(ppm):10.73(s,1H),9.62(s,1H),8.12(d,J＝9.2Hz,1H),7.75(s,1H),7.35(t,J＝8.0Hz,1H),6.96(d,J＝8.0Hz,1H),6.92(s,1H),6.77-6.80(m,2H),3.77(s,3H)；HRMS(ESI):m/z,calcd for C₁₆H₁₄N₃O₅[M+H⁺]:328.0928,found 328.0921.

c)4- ((3-methoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid (80mg, 0.244mmol) was dissolved in DCM (10mL) and HATU (139mg, 0.366mmol), DMAP (15mg, 0.122mmol) and Et were added successively₃N (49mg, 0.482mmol), after stirring well, benzenesulfonamide (58mg, 0.366mmol) was added, stirring at room temperature overnight, the starting material disappeared, the solvent was evaporated, EA (30mL) dissolved the residue, washed with 2M diluted hydrochloric acid (20mL × 3), washed with water (20mL × 2), EA recrystallized to give 90mg of a yellow powdery solid, yield 79%, mp:>250℃。

¹H NMR(DMSO-d₆)(ppm):13.10(brs,1H),11.90(brs,1H),9.65(s,1H),8.15(d,J＝8.8Hz,1H),8.05(d,J＝7.6Hz,2H),7.86(s,1H),7.75(t,J＝7.2Hz,1H),7.67(t,J＝7.6Hz,2H),7.35(t,J＝8.4Hz,1H),6.95(d,J＝8.0Hz,1H),6.91(s,1H),6.78(d,J＝9.6Hz,2H),3.78(s,3H).

example 4: 4- ((3-methoxyphenyl) amino) -7-amino-N- (benzenesulfonyl) -1H-indole-2-carboxamide

4- ((3-methoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide (80mg, 0.17mmol) was dissolved in water (2mL), Fe powder (35mg, 0.62mmol) and ammonium chloride (10mg, 0.17mmol) were added, and microwave reaction was carried out (100w, 100 ℃, 40min, 150 psi). Dissolving the reaction solution in DCM and methanol, filtering, and concentrating the filtrate to obtain an off-white solid. EA (20mL) was added, washed with water (10 mL. times.2), concentrated, and the solid was stirred with a small amount of EA and DCM in that order and filtered to give 13mg of a pale green solid in 18% yield, mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.38(brs,1H),6.35-7.98(m,16H),3.63(s,3H).

Example 5: 4- ((3-methoxyphenyl) amino) -7-nitro-N- (methylsulfonyl) -1H-indole-2-carboxamide

4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid (80mg, 0.244mmol) was dissolved in DCM (10mL) and HATU (139mg, 0.366mmol), DMAP (15mg, 0.122mmol) and Et were added successively₃N (49mg, 0.482mmol), after stirring well, methanesulfonamide (35mg, 0.366mmol) was added, stirring at room temperature overnight, the starting material disappeared, the solvent was evaporated, EA (30mL) dissolved the residue, washed with 2M diluted hydrochloric acid (20mL × 3), washed with water (20mL × 2), EA recrystallized to give 74mg of yellow powdery solid, yield 75%, mp:>250℃。

¹H NMR(DMSO-d₆)(ppm):12.67(brs,1H),11.99(s,1H),9.69(s,1H),8.17(d,J＝9.3Hz,1H),7.98(s,1H),7.36(t,J＝8.1Hz,1H),6.98(d,J＝8.1Hz,1H),6.93(s,1H),6.81(d,J＝9.0Hz,2H),3.79(s,3H),3.43(s,3H).

example 6: 4- ((3-methoxyphenyl) amino) -7-nitro-N- (cyclopropylsulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and cyclopropylsulfonamide, to give 44mg of a yellow solid in 83% yield mp:270-272 ℃.

¹H NMR(DMSO-d₆)(ppm):12.63(brs,1H),11.95(s,1H),9.69(s,1H),8.17(d,J＝9.2Hz,1H),7.98(s,1H),7.36(t,J＝8.0Hz,1H),6.98(d,J＝8.0Hz,1H),6.94(s,1H),6.81(d,J＝8.8Hz,2H),3.79(s,3H),3.18(m,1H),1.16-1.19(m,4H).

Example 7: 4- (phenylamino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide 1928

a)4- (phenylamino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and aniline, gave 70mg of a yellow solid in 76% yield mp:237-240 ℃.

¹H NMR(DMSO-d₆)(ppm):13.37(brs,1H),10.72(s,1H),9.65(s,1H),8.11(d,J＝9.2Hz,1H),7.74(s,1H),7.46(t,J＝7.6Hz,2H),7.38(d,J＝7.6Hz,1H),7.22(t,J＝6.8Hz,1H),6.71(q,J＝9.2Hz,1H)；HRMS(ESI):m/z,calcd for C₁₅H₁₂N₃O₄[M+H⁺]:298.0822,found298.0811.

b)4- (phenylamino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- (phenylamino) -7-nitro-1H-indole-2-carboxylate, the preparation is as in b) of example 3, giving 70mg of a yellow solid in 76% yield mp:237-240 ℃.

c)4- (phenylamino) -7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 4- (phenylamino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, gives 122mg of a yellow solid in 76% yield mp:272-273 ℃.

¹H NMR(DMSO-d₆)(ppm):13.10(brs,1H),11.89(s,1H),9.70(s,1H),8.14(d,J＝9.2Hz,1H),8.05(d,J＝7.6Hz,2H),7.85(s,1H),7.75(t,J＝7.2Hz,1H),7.67(t,J＝7.6Hz,2H),7.45(t,J＝7.6Hz,2H),7.37(d,J＝8.0Hz,1H),7.23(t,J＝7.6Hz,1H),6.70(d,J＝9.2Hz,1H).

Example 8: 4- ((2-methoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((2-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 2-methoxyaniline, gave 270mg of a yellow solid in 82% yield mp:137-139 ℃.

¹H NMR(CDCl₃)(ppm):10.46(brs,1H),8.20(d,J＝9.2Hz,1H),7.51(d,J＝8.0Hz,1H),7.39(d,J＝1.2Hz,1H),7.16(t,J＝8.0Hz,2H),7.00-7.04(m,3H),6.92(d,J＝8.8Hz,1H),4.46(q,J＝7.2Hz,2H),3.92(s,3H),1.45(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcdfor C₁₈H₁₈N₃O₅[M+H⁺]:356.1241,found 356.1231.

b)4- ((2-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((2-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 130mg of a yellow solid in 78% yield mp:245-246 ℃.

¹H NMR(DMSO-d₆)(ppm):10.65(s,1H),9.38(s,1H),8.05(d,J＝9.2Hz,1H),7.70(s,1H),7.33-7.37(m,2H),7.21(d,J＝8.0Hz,1H),7.06(t,J＝7.6Hz,1H),6.14(d,J＝9.2Hz,1H),3.78(s,3H)；HRMS(ESI):m/z,calcd for C₁₆H₁₄N₃O₅[M+H⁺]:328.0928,found328.0923.

c)4- ((2-methoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((2-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, the preparation is carried out as described in c) of example 3 to give 80mg of an orange-powdery solid in 92% yield mp:245-246 ℃.

¹H NMR(DMSO-d₆)(ppm):13.10(brs,1H),11.83(brs,1H),9.38(s,1H),8.07(d,J＝9.6Hz,1H),8.04(d,J＝8.0Hz,2H),7.79(s,1H),7.74(t,J＝7.2Hz,1H),7.66(t,J＝7.2Hz,2H),7.36-7.30(m,2H),7.19(d,J＝8.4Hz,1H),7.04(t,J＝7.6Hz,1H),6.12(d,J＝9.2Hz,1H),3.76(s,3H).

Example 9: 4- ((4-methoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials, gave 389mg of a yellow solid, 84% yield, mp:209-211 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.14(d,J＝9.3Hz,1H),7.33(d,J＝2.4Hz,1H),7.25(d,J＝8.7Hz,2H),6.98(d,J＝9.0Hz,1H),6.72(brs,1H),6.50(d,J＝9.0Hz,1H),4.43(q,J＝7.2Hz,2H),3.86(s,1H),1.43(t,J＝7.5Hz,3H)；HRMS(ESI):m/z,calcd forC₁₈H₁₈N₃O₅[M+H⁺]:356.1231,found 356.1241.

b)4- ((4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) in example 3 to give 300mg of a yellow solid in 99% yield mp:254-255 ℃.

¹H NMR(DMSO-d₆)(ppm):10.59(s,1H),9.55(s,1H),8.05(d,J＝9.3Hz,1H),7.61(s,1H),7.31(d,J＝8.4Hz,2H),7.04(d,J＝8.4Hz,2H),6.48(d,J＝9.3Hz,1H),3.80(s,3H)；HRMS(ESI):m/z,calcd for C₁₆H₁₄N₃O₅[M+H⁺]:328.0928,found 328.0921.

c)4- ((4-methoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, to give 65mg of a reddish brown powdery solid in a yield of 45% and mp:258-260 ℃.

¹H NMR(DMSO-d₆)(ppm):13.10(brs,1H),11.86(brs,1H),9.61(s,1H),8.10(d,J＝9.0Hz,1H),8.04(d,J＝7.5Hz,2H),7.80(s,1H),7.75(t,J＝7.2Hz,1H),7.67(t,J＝7.5Hz,2H),7.28(d,J＝9.0Hz,2H),7.03(d,J＝9.0Hz,2H),6.46(d,J＝9.0Hz,1H),3.79(s,3H).

Example 10: 4- ((3, 4-Dimethoxyphenyl) amino) -7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

a)4- ((3, 4-Dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3, 4-dimethoxyaniline as starting materials was carried out as described in a) of example 3 to give 420mg of an orange-red solid with a yield of 98% and mp:205-206 ℃.

¹H NMR(CDCl₃)(ppm):10.46(brs,1H),8.15(d,J＝9.0Hz,1H),7.35(d,J＝1.8Hz,1H),6.78-6.95(m,4H),6.55(d,J＝8.7Hz,1H),4.43(q,J＝7.2Hz,2H),3.93(s,1H),3.88(s,3H),1.42(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₉H₂₀N₃O₆[M+H⁺]:386.1347,found 386.1333.

b)4- ((3, 4-Dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3, 4-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation is carried out as described in b) of example 3 to give 291mg of yellow solid in 98% yield mp:267-269 ℃.

¹H NMR(DMSO-d₆)(ppm):13.34(brs,1H),10.69(s,1H),9.61(s,1H),8.09(d,J＝9.3Hz,1H),7.72(d,J＝2.1Hz,1H),7.04(d,J＝8.7Hz,1H),6.91-6.97(m,2H),6.58(d,J＝9.3Hz,1H),3.79(s,3H),3.77(s,3H)；HRMS(ESI):m/z,calcd for C₁₇H₁₆N₃O₆[M+H⁺]:358.1034,found 358.1029.

c)4- ((3, 4-Dimethoxyphenyl) amino) -7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3, 4-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, to give 116mg of a reddish brown powdery solid in 83% yield mp:198-199 ℃.

¹H NMR(DMSO-d₆)(ppm):13.10(brs,1H),11.60(brs,1H),9.59(s,1H),8.09(d,J＝9.3Hz,1H),8.02(d,J＝7.5Hz,2H),7.73-7.62(m,4H),7.03(d,J＝8.4Hz,1H),6.95-6.88(m,2H),6.56(d,J＝9.3Hz,1H),3.79(s,3H),3.76(s,3H).

Example 11: 4- ((3, 5-Dimethoxyphenyl) amino) -7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

a)4- ((3, 5-Dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3, 5-dimethoxyaniline as starting materials was carried out as described in a) of example 3 to give 324mg of an orange-red solid with a yield of 99% and mp:171-172 ℃.

¹H NMR(DMSO-d₆)(ppm):10.95(s,1H),9.60(s,1H),8.15(d,J＝9.0Hz,1H),7.84(s,1H),6.88(d,J＝9.3Hz,1H),6.54(d,J＝1.8Hz,2H),6.37(t,J＝2.1Hz,1H),4.38(q,J＝7.5Hz,2H),3.77(s,6H),1.37(t,J＝7.5Hz,3H).

b)4- ((3, 5-Dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation is carried out as described in b) of example 3 to give 186mg of a reddish brown solid in 91% yield mp:242-243 ℃.

¹H NMR(DMSO-d₆)(ppm):10.76(s,1H),9.66(s,1H),8.14(d,J＝9.0Hz,1H),7.78(d,J＝1.8Hz,1H),6.86(d,J＝9.6Hz,1H),6.55(d,J＝1.5Hz,2H),6.37(s,1H),3.77(s,6H).

c)4- ((3, 5-Dimethoxyphenyl) amino) -7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, to give 95mg of a reddish-orange solid in the form of a powder, yield 98%, mp:171-172 ℃.

¹H NMR(DMSO-d₆)(ppm):13.08(brs,1H),11.87(brs,1H),9.60(s,1H),8.16(d,J＝9.2Hz,1H),8.05(d,J＝8.0Hz,2H),7.85(s,1H),7.74(t,J＝7.6Hz,1H),7.67(d,J＝7.6Hz,2H),6.83(d,J＝9.2Hz,1H),6.51(s,2H),6.36(s,1H),3.75(s,6H)；¹³C NMR(125MHz,DMSO-d₆):161.05,146.89,140.94,129.20,127.70,124.17,102.67,100.83,96.79,55.30.HRMS(ESI):m/z,calcd.for C₂₃H₂₁N₄O₇S[M+H]⁺:497.1126,found 497.1115.

Example 12: 4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation process was the same as that described in a) of example 3 using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3,4, 5-trimethoxyaniline as starting materials to give 292mg of an orange-red solid with a yield of 94% and mp:179-181 ℃.

¹H NMR(CDCl₃)(ppm):10.46(brs,1H),8.18(d,J＝9.2Hz,1H),7.35(d,J＝1.2Hz,1H),6.75(brs,1H),6.70(d,J＝9.2Hz,1H),6.56(s,2H),4.44(q,J＝7.2Hz,2H),3.89(s,1H),3.86(s,6H),1.43(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₂₀H₂₂N₃O₇[M+H⁺]:416.1452,found 416.1439.

b)4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 145mg of a yellow solid in 82% yield mp:278-280 ℃.

¹H NMR(DMSO-d₆)(ppm):10.73(brs,1H),9.66(s,1H),8.12(d,J＝9.0Hz,1H),7.76(d,J＝2.1Hz,1H),6.78(d,J＝9.3Hz,1H),6.70(s,2H),3.80(s,6H),3.69(s,3H)；HRMS(ESI):m/z,calcd for C₁₈H₁₈N₃O₇[M+H⁺]:388.1139,found 388.1133.

c)4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, to give 40mg of a reddish brown powdery solid in 35% yield mp:212-214 ℃.

¹H NMR(DMSO-d₆)(ppm):9.51(brs,1H),8.06(d,J＝8.8Hz,1H),7.94(brs,2H),7.53(brs,4H),6.76(d,J＝9.2Hz,1H),6.67(s,2H),3.78(s,6H),3.68(s,3H)；HRMS(ESI):m/z,calcd.for C₂₄H₂₃N₄O₈S[M+H]⁺:527.1231,found 527.1224.

Example 13: 4- ((3-methylphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3-Methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-methylaniline as starting materials, gave 260mg of a yellow solid in 93% yield mp:190-191 ℃.

¹H NMR(DMSO-d₆)(ppm):10.89(s,1H),9.62(s,1H),8.13(d,J＝9.2Hz,1H),7.83(s,1H),7.33(t,J＝8.0Hz,1H),7.16-7.19(m,2H),7.04(d,J＝7.6Hz,1H),6.72(d,J＝9.2Hz,1H),4.37(q,J＝7.2Hz,2H),2.34(s,3H),1.36(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₈H₁₈N₃O₄[M+H⁺]:340.1292,found 340.1289.

b)4- ((3-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation is carried out as described in b) of example 3 to give 90mg of a yellow solid in 80% yield, mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.43(s,1H),9.49(s,1H),8.03(d,J＝8.8Hz,1H),7.47(s,1H),7.31(t,J＝8.0Hz,1H),7.16-7.19(m,2H),7.01(d,J＝7.6Hz,1H),6.69(d,J＝9.2Hz,1H),2.33(s,3H)；HRMS(ESI):m/z,calcd for C₁₆H₁₄N₃O₄[M+H+]:312.0979,found312.0976.

c)4- ((3-methylphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, to give 20mg of a reddish brown powdery solid in a yield of 23% and mp:216-218 ℃.

¹H NMR(DMSO-d₆)(ppm):9.52(s,1H),8.07(d,J＝8.8Hz,1H),7.95(m,2H),7.55(brs,4H),7.32(t,J＝7.6Hz,1H),7.18-7.15(m,2H),7.03(d,J＝7.6Hz,1H),6.69(d,J＝9.2Hz,1H),2.34(s,3H).

Example 14: 4- ((4-methylphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((4-Methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 4-methylaniline as starting materials, gave 256mg of a yellow solid in 81% yield mp:232-234 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.16(d,J＝9.2Hz,1H),7.33(s,1H),7.25(d,J＝7.2Hz,2H),7.21(d,J＝8.0Hz,2H),6.71(brs,1H),6.65(d,J＝8.8Hz,2H),4.44(q,J＝7.2Hz,2H),2.40(s,3H),1.43(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₈H₁₈N₃O₄[M+H⁺]:340.1292,found 340.1281.

b)4- ((4-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

The preparation was carried out as described in b) of example 3, starting from 4- ((4-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester, to give 160mg of a yellow solid in 97% yield mp:257-259 ℃.

¹H NMR(DMSO-d₆)(ppm):10.70(s,1H),9.61(s,1H),8.09(d,J＝9.2Hz,1H),7.74(s,1H),7.27(s,4H),6.62(d,J＝9.2Hz,1H),2.34(s,3H)；HRMS(ESI):m/z,calcd forC₁₆H₁₄N₃O₄[M+H⁺]:312.0979,found 312.0973.

c)4- ((4-methylphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 4- ((4-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, gives 102mg of a reddish brown powdery solid in 92% yield mp:237-239 ℃.

¹H NMR(DMSO-d₆)(ppm):13.10(brs,1H),11.87(brs,1H),9.64(s,1H),8.12(d,J＝9.2Hz,1H),8.04(d,J＝7.6Hz,2H),7.83(s,1H),7.74(t,J＝7.2Hz,1H),7.67(t,J＝7.6Hz,2H),7.28-7.23(m,4H),6.60(d,J＝9.2Hz,1H),2.33(s,3H).

Example 15: 4- ((3-cyanophenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3-cyanophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-cyanoaniline as starting materials in the same manner as in a) of example 3 gave 259mg of a yellow solid in 90% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.97(s,1H),9.71(s,1H),8.13(d,J＝9.2Hz,1H),7.70-7.60(m,5H),6.86(d,J＝9.2Hz,1H),4.36(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H).

b)4- ((3-cyanophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-cyanophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 117mg of a yellow solid in 99% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.83(s,1H),9.71(s,1H),8.14(d,J＝8.8Hz,1H),7.79(s,1H),7.71-7.61(m,4H),6.87(d,J＝9.2Hz,1H).

c)4- ((3-cyanophenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was followed starting from 4- ((3-cyanophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide to give 58mg of a reddish brown powdery solid in 81% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.10(brs,1H),11.92(brs,1H),9.76(brs,1H),8.18(d,J＝8.8Hz,1H),8.05(d,J＝8.0Hz,2H),7.82-7.62(m,8H),6.85(d,J＝9.2Hz,1H).

Example 16:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (3-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 3-methoxybenzenesulphonamide, to give 40mg of a yellow powdery solid in 88% yield mp:153-154 ℃.

¹H NMR(DMSO-d₆)(ppm):11.84(brs,2H),9.63(s,1H),8.14(d,J＝9.2Hz,1H),7.84(s,1H),7.61-7.55(m,2H),7.51(s,1H),7.36-7.29(m,2H),6.94(d,J＝8.0Hz,1H),6.90(s,1H),6.78(t,J＝9.2Hz,2H),3.84(s,3H),3.76(s,3H)；HRMS(ESI):m/z,calcd.forC₂₃H₂₁N₄O₇S[M+H]⁺:497.1131,found 497.1117.

Example 17:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 50mg of a yellow powdery solid in 55% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.85(brs,1H),9.62(brs,1H),8.13(d,J＝9.2Hz,1H),7.96(d,J＝8.4Hz,2H),7.82(s,1H),7.33(t,J＝8.0Hz,1H),7.15(d,J＝8.4Hz,2H),6.94(d,J＝8.0Hz,2H),6.89(s,1H),6.77(t,J＝9.6Hz,2H),3.85(s,3H),3.76(s,3H)；¹³C NMR(100MHz,DMSO-d₆):163.22,160.10,157.24,147.05,140.34,131.96,130.68,130.25,130.17,128.61,127.17,124.10,116.71,114.98,114.29,110.48,110.39,108.47,102.26,55.78,55.16.HRMS(ESI):m/z,calcd.for C₂₃H₂₁N₄O₇S[M+H]⁺:497.1126,found 497.1117.

Example 18:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (2-fluorobenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 2-fluorobenzenesulfonamide, the preparation was carried out as described in c) of example 11 to give 70mg of a yellow powdery solid in 79% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.93(brs,1H),9.65(s,1H),8.16(d,J＝9.3Hz,1H),8.04(t,J＝6.9Hz,1H),7.85-7.79(m,2H),7.48(t,J＝7.8Hz,2H),7.34(t,J＝8.1Hz,1H),6.94(d,J＝8.4Hz,1H),6.90(s,1H),6.78(t,J＝6.3Hz,2H),3.77(s,3H).

Example 19:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (3-fluorobenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 3-fluorobenzenesulfonamide, the preparation was carried out as described in c) of example 3 to give 48mg of a yellow powdery solid in 54% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.84(brs,1H),9.66(s,1H),8.15(d,J＝9.2Hz,1H),7.91-7.83(m,3H),7.74(dd,J₁＝13.6Hz,J₂＝8.0Hz,1H),7.63(t,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.91(s,1H),6.79(t,J＝9.2Hz,2H),3.78(s,3H)；HRMS(ESI):m/z,calcd.for C₂₂H₁₈N₄O₆FS[M+H]⁺:485.0931,found 485.0918.

Example 20:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-fluorophenylsulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-fluorobenzenesulfonamide, the preparation was carried out as described in c) of example 3 to give 66mg of a yellow powdery solid in 74% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.88(brs,1H),9.66(s,1H),8.16-8.11(m,3H),7.86(s,1H),7.51(t,J＝8.8Hz,2H),7.35(t,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.91(s,1H),6.79(t,J＝9.6Hz,2H),3.78(s,3H)；HRMS(ESI):m/z,calcd.for C₂₂H₁₈N₄O₆FS[M+H]⁺:485.0931,found 485.0919.

Example 21:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methylbenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methylbenzenesulfonamide as starting materials, was as described in c) to give 77mg of a yellow-orange powdery solid in 75% yield mp:240-242 ℃.

¹H NMR(DMSO-d₆)(ppm):12.98(brs,1H),11.89(brs,1H),9.67(s,1H),8.15(d,J＝9.2Hz,1H),7.93(d,J＝8.4Hz,2H),7.85(s,1H),7.46(d,J＝8.4Hz,1H),7.35(t,J＝8.4Hz,1H),6.95(d,J＝8.4Hz,1H),6.91(s,1H),6.81-6.76(m,2H),3.77(s,3H),2.41(s,3H)；¹³C NMR(125MHz,DMSO-d₆):160.12,157.31,147.11,144.48,140.35,136.40,132.02,130.31,129.65,128.54,127.83,127.30,124.10,167.73,115.02,110.53,108.49,102.28,55.19,21.13.HRMS(ESI):m/z,calcd.forC₂₃H₂₁N₄O₆S[M+H]⁺:481.1176,found 481.1167.

Example 22:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-trifluoromethylbenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-trifluoromethylbenzenesulfonamide, to give 68mg of an orange powdery solid in 69% yield mp:259-260 ℃.

¹H NMR(DMSO-d₆)(ppm):11.74(brs,1H),9.64(s,1H),8.24(d,J＝8.4Hz,2H),8.15(d,J＝9.2Hz,1H),8.04(d,J＝8.0Hz,2H),7.82(s,1H),7.35(d,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.90(s,1H),6.79(d,J＝8.8Hz,1H),6.77(d,J＝9.2Hz,1H),3.77(s,3H).

Example 23:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (3-nitrobenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 3-nitrobenzenesulfonamide, to give 74mg of an orange powdery solid in 79% yield mp:255-256 ℃.

¹H NMR(DMSO-d₆)(ppm):11.74(brs,1H),9.64(s,1H),8.75(s,1H),8.56(d,J＝8.4Hz,1H),8.46(d,J＝8.0Hz,1H),8.15(d,J＝9.2Hz,1H),7.97(t,J＝8.0Hz,1H),7.85(s,1H),7.35(t,J＝8.4Hz,1H),6.50(d,J＝8.0Hz,1H),6.91(s,1H),6.79(d,J＝8.4Hz,1H),6.77(d,J＝9.2Hz,1H),3.78(s,3H).

Example 24:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-nitrobenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-nitrobenzenesulfonamide, the preparation was carried out as described in c) of example 3 to give 70mg of an orange powdery solid in 86% yield mp:259-261 ℃.

¹H NMR(DMSO-d₆)(ppm):11.73(brs,1H),9.67(s,1H),8.45(d,J＝8.8Hz,2H),8.29(d,J＝8.8Hz,2H),8.15(d,J＝9.2Hz,1H),7.84(s,1H),7.35(t,J＝8.0Hz,1H),6.95(d,J＝8.4Hz,1H),6.91(s,1H),6.78(t,J＝9.2Hz,2H),3.78(s,3H).

Example 25:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-difluoromethoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-difluoromethoxybenzenesulfonamide, to give 68mg of an orange powdery solid in 70% yield mp:260-262 ℃.

¹H NMR(DMSO-d₆)(ppm):13.10(brs,1H),11.87(brs,1H),9.66(s,1H),8.15(d,J＝9.2Hz,1H),8.11(d,J＝8.4Hz,2H),7.85(s,1H),7.43(t,J＝73.6Hz,1H),7.43(d,J＝8.4Hz,2H),7.35(t,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.91(s,1H),6.78(t,J＝9.2Hz,2H),3.79(s,3H).

Example 26:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-trifluoromethoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-trifluoromethoxybenzenesulfonamide, to give 75mg of an orange powdery solid in 74% yield mp:263-265 ℃.

¹H NMR(DMSO-d₆)(ppm):11.80(brs,1H),9.66(s,1H),8.19-8.14(m,3H),7.85(s,1H),7.65(d,J＝8.4Hz,2H),7.35(d,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.91(s,1H),6.79(t,J＝9.2Hz,2H),3.78(s,3H).

Example 27:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-cyanobenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-cyanobenzenesulfonamide, the preparation was carried out as described in c) of example 3 to give 70mg of an orange powdery solid in 78% yield mp:239-240 ℃.

¹H NMR(DMSO-d₆)(ppm):11.84(brs,1H),9.64(s,1H),8.18(d,J＝8.4Hz,2H),8.14(d,J＝8.8Hz,1H),8.12(d,J＝8.4Hz,2H),7.80(s,1H),7.35(d,J＝8.4Hz,1H),6.95(d,J＝8.0Hz,2H),6.91(s,1H),6.80(d,J＝8.4Hz,1H),6.77(d,J＝9.2Hz,1H),3.78(s,3H).

Example 28:

4- ((3-methoxyphenyl) amino) -7-nitro-N- ((4, 5-dichlorothien-2-yl) sulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4, 5-dichlorothiophene-2-sulfonylsulfonamide, to give 80mg of an orange powdery solid in 80mg yield, mp:246-248 ℃.

¹H NMR(DMSO-d₆)(ppm):10.28(brs,1H),9.50(s,1H),8.05(d,J＝9.3Hz,1H),7.50-7.48(m,2H),7.34(t,J＝8.1Hz,1H),8.47(d,J＝7.5Hz,1H),6.93(s,1H),6.80-6.76(m,2H),3.78(s,3H)；HRMS(ESI):m/z,calcd.for C₂₀H₁₅N₄O₆Cl₂S₂[M+H]⁺:540.9810,found540.9798.

Example 29:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (thien-2-ylsulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and thiophene-2-sulfonylsulfonamide, the preparation was carried out as described under c) in example 3 to give 70mg of an orange powdery solid in 81% yield mp:249-251 ℃.

¹H NMR(DMSO-d₆)(ppm):11.84(brs,1H),9.67(s,1H),8.15(d,J＝9.2Hz,1H),8.08(d,J＝4.8Hz,1H),7.91(d,J＝4.8Hz,2H),7.35(t,J＝8.4Hz,1H),7.24(t,J＝4.4Hz,1H),6.96(d,J＝8.0Hz,1H),6.92(s,1H),6.80(d,J＝8.0Hz,1H),6.78(d,J＝9.2Hz,1H),3.78(s,3H).

Example 30:

4- ((3-methoxyphenyl) amino) -7-nitro-N- (naphthalen-2-ylsulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and naphthalene-2-sulfonylsulfonamide as starting materials, was as described in c) to give 80mg of an orange-red powdery solid in 84% yield, mp:254-255 ℃.

¹H NMR(DMSO-d₆)(ppm):13.16(brs,1H),11.88(brs,1H),9.63(s,1H),8.73(s,1H),8.27(d,J＝8.0Hz,1H),8.18(d,J＝8.8Hz,1H),8.15(d,J＝9.2Hz,1H),8.08(d,J＝8.0Hz,1H),8.01(d,J＝8.8Hz,1H),7.82(s,1H),7.78-7.69(m,2H),7.34(t,J＝8.0Hz,1H),6.93(d,J＝8.0Hz,1H),6.89(s,1H),6.77(t,J＝9.2Hz,2H),3.76(s,3H)；HRMS(ESI):m/z,calcd.for C₂₆H₂₁N₄O₆S[M+H]⁺:517.1182,found 517.1193.

Example 31:

4- ((3-methylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 11, using 4- ((3-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide as starting materials, gave 53mg of an orange-red powdery solid in 88% yield, mp:265-267 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.88(brs,1H),9.63(s,1H),8.13(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,2H),7.84(s,1H),7.33(t,J＝8.0Hz,1H),7.18-7.15(m,4H),7.05(d,J＝7.2Hz,1H),6.69(d,J＝9.2Hz,1H),3.86(s,3H),2.34(s,3H).¹³C NMR(125MHz,DMSO-d₆):147.42,139.01,138.96,132.01,130.21,129.36,127.32,125.76,123.88,123.71,120.29,116.52,114.33,101.96,55.82,21.01.HRMS(ESI):m/z,calcd.forC₂₃H₂₁N₄O₆S[M+H]⁺:481.1182,found481.1171.

Example 32: 4- ((3-trifluoromethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3-trifluoromethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation procedure was the same as that described in a) of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-trifluoromethoxy aniline as starting materials, to give 300mg of an orange-red solid, 89% yield, mp:220-221 ℃.

¹H NMR(CDCl₃)(ppm):10.48(brs,1H),8.22(d,J＝8.8Hz,1H),7.45(t,J＝8.0Hz,1H),7.34(s,1H),7.26(m,1H),7.18(s,1H),7.08(d,J＝8.0Hz,1H),6.84(d,J＝9.2Hz,1H),6.72(s,1H),4.45(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

b)4- ((3-trifluoromethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((3-trifluoromethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3, giving 200mg of a tan solid, 98% yield, mp:280-282 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.82(s,1H),9.81(s,1H),8.16(d,J＝9.0Hz,1H),7.76(d,J＝2.4Hz,1H),7.56(t,J＝8.12Hz,1H),7.45(d,J＝7.8Hz,1H),7.35(s,1H),7.16(d,J＝8.4Hz,1H),6.87(d,J＝9.0Hz,1H).

c)4- ((3-trifluoromethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((3-trifluoromethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, was as described in c) to give 68mg of a red-orange powdery solid in 52% yield mp:234-235 ℃.

¹H NMR(DMSO-d₆)(ppm):12.93(brs,1H),11.91(brs,1H),9.74(s,1H),8.18(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,2H),7.81(s,1H),7.55(t,J＝8.4Hz,1H),7.43(d,J＝8.4Hz,1H),7.31(s,1H),7.20-7.16(m,3H),6.85(d,J＝8.8Hz,1H),3.86(s,3H).

Example 33:

4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure is as described in c) of example 3, starting from 4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide to give 33mg of a reddish brown powdery solid in 42% yield mp:268-270 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.88(brs,1H),9.62(s,1H),8.13(d,J＝9.2Hz,1H),7.98(d,J＝8.4Hz,2H),7.83(s,1H),7.17(d,J＝8.4Hz,1H),6.75(d,J＝9.2Hz,1H),6.66(s,2H),3.86(s,3H),3.78(s,6H),3.68(s,3H)；¹³CNMR(125MHz,DMSO-d₆):163.26,157.26,153.35,147.60,134.83,134.80,132.03,130.24,127.45,123.75,116.36,114.34,110.45,102.24,101.12,60.16,55.93,55.82.HRMS(ESI):m/z,calcd.forC₂₅H₂₅N₄O₉S[M+H]⁺:557.1325,found557.1337.

Example 34: 4- ((3-ethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3-ethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 258mg of orange-red solid was carried out as described in example 3 under a) using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-ethoxyaniline as starting materials, with a yield of 94% and mp:193-195 ℃.

¹HNMR(DMSO-d₆)(ppm):10.92(s,1H),9.63(s,1H),8.14(d,J＝9.2Hz,1H),7.84(s,1H),7.34(t,J＝8.0Hz,1H),6.96(d,J＝8.0Hz,1H),6.91(s,1H),6.80(d,J＝8.8Hz,1H),6.78(d,J＝6.4Hz,1H),4.38(q,J＝7.2Hz,2H),4.05(q,J＝7.2Hz,2H),1.39-1.33(m,6H).

b)4- ((3-ethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

The procedure of example 3, using 4- ((3-ethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester as starting material, was as described in b) to give 156mg of a tan solid, 98% yield, mp:231-233 ℃.

¹H NMR(DMSO-d₆)(ppm):10.73(s,1H),9.61(s,1H),8.13(d,J＝9.2Hz,1H),7.74(s,1H),7.35(t,J＝8.0Hz,1H),6.96(d J＝8.0Hz,1H),6.91(s,1H),6.79(d,J＝9.2Hz,2H),4.05(q,J＝7.2Hz,1H),1.34(t,J＝7.2Hz,1H).

c)4- ((3-ethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-ethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 60mg of a yellow powdery solid in 57% yield mp:225-227 ℃.

¹H NMR(DMSO-d₆)(ppm):12.98(brs,1H),11.88(brs,1H),9.65(s,1H),8.15(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,1H),7.84(s,1H),7.33(t,J＝8.0Hz,1H),7.17(d,J＝8.8Hz,1H),6.93(d,J＝8.0Hz,1H),6.89(s,1H),6.78(d,J＝6.4Hz,1H),6.76(d,J＝8.8Hz,1H),4.04(q,J＝6.8Hz,2H),3.86(s,3H),1.33(t,J＝6.8Hz,3H)；HRMS(ESI):m/z,calcd.for C₂₄H₂₃N₄O₇S[M+H]⁺:511.1287,found511.1277.

Example 35:

4- ((3, 5-Dimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((3, 4-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials was as described in c) to give 70mg of a solid in the form of an orange-red powder with a yield of 80% and mp:180-182 ℃.

¹H NMR(DMSO-d₆)(ppm):12.90(brs,1H),11.89(brs,1H),9.60(s,1H),8.16(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,2H),7.85(s,1H),7.17(d,J＝8.8Hz,2H),6.83(d,J＝9.2Hz,1H),6.52(d,J＝1.6Hz,2H),6.36(s,1H),3.86(s,3H),3.76(s,6H).

Example 36: 4- ((3, 4-methylenedioxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3, 4-methylenedioxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 3 was repeated, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 3, 4-dimethoxyanilide, to give 316mg of a reddish brown solid in 92% yield mp:169-170 ℃.

¹H NMR(DMSO-d₆)(ppm):10.88(s,1H),9.57(s,1H),8.10(d,J＝9.2Hz,1H),7.80(s,1H),7.00(d,J＝8.4Hz,1H),6.98(s,1H),6.84(d,J＝8.4Hz,1H),6.55(d,J＝8.8Hz,1H),6.09(s,2H),4.37(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H).

b)4- ((3, 4-methylenedioxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3, 4-dimethoxyphe-nyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 216mg of a reddish-brown solid in 100% yield mp:240-242 ℃.

¹H NMR(DMSO-d₆)(ppm):13.40(brs,1H),10.70(s,1H),9.59(s,1H),8.09(d,J＝8.8Hz,1H),7.72(s,1H),7.01(d,J＝8.0Hz,1H),6.98(s,1H),6.84(d,J＝8.4Hz,1H),6.54(d,J＝9.2Hz,1H),6.09(s,2H).

c)4- ((3, 4-methylenedioxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, c) was repeated using 4- ((3, 4-methylenedioxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide as starting materials to give 75mg of a reddish brown powdery solid in 70% yield mp:250-252 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.87(brs,1H),9.57(s,1H),8.11(d,J＝9.2Hz,1H),7.97(d,J＝8.8Hz,2H),7.78(s,1H),7.17(d,J＝8.8Hz,2H),6.99(d,J＝8.0Hz,1H),6.95(s,1H),6.81(d,J＝9.2Hz,1H),6.51(d,J＝9.2Hz,1H),6.08(s,2H),3.86(s,3H).

Example 37: c)4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 3-methoxy-4-chloroaniline, was as described in a) to give 296mg of a reddish brown solid in 81% yield mp:242-244 ℃.

¹H NMR(DMSO-d₆)(ppm):10.98(s,1H),9.69(s,1H),8.14(d,J＝9.2Hz,1H),7.83(s,1H),7.47(d,J＝8.4Hz,1H),7.13(s,1H),6.99(d,J＝8.4Hz,1H),6.87(d,J＝9.2Hz,1H),4.38(q,J＝7.2Hz,2H),3.88(s,3H),1.37(t,J＝7.2Hz,3H).

b)4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 185mg of an orange solid in 100% yield mp:255-258 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.79(s,1H),9.69(s,1H),8.14(d,J＝9.2Hz,1H),7.75(s,1H),7.47(d,J＝8.8Hz,1H),7.14(s,1H),6.99(d,J＝8.4Hz,1H),6.85(d,J＝9.2Hz,1H),3.88(s,3H).

c)4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 94mg of an orange powdery solid in a yield of 91% mp:275-277 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.90(brs,1H),9.70(s,1H),8.15(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,2H),7.83(s,1H),7.46(d,J＝8.4Hz,1H),7.17(d,J＝8.4Hz,2H),7.11(s,1H),6.96(d,J＝8.4Hz,1H),6.82(d,J＝9.2Hz,1H),3.86(s,6H)；¹³CNMR(125MHz,DMSO-d₆):163.26,155.05,146.65,139.47,131.92,130.31,130.23,127.12,124.43,118.99,116.97,116.47,115.27,114.34,107.42,102.52,56.11,55.82.HRMS(ESI):m/z,calcd.for C₂₃H₂₀N₄O₇ClS[M+H]⁺:531.0741,found 531.0732.

Example 38:

4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, to give 47mg of a yellow powdery solid in 85% yield, mp: >280 ℃ C

¹H NMR(DMSO-d₆)(ppm):13.05(brs,1H),11.88(brs,1H),9.70(s,1H),8.15(d,J＝9.2Hz,1H),8.05(d,J＝7.6Hz,2H),7.83(s,1H),7.74(t,J＝7.2Hz,1H),7.67(t,J＝7.6Hz,2H),7.46(d,J＝8.8Hz,1H),7.11(s,1H),6.96(d,J＝8.4Hz,1H),6.82(d,J＝9.2Hz,1H),3.86(s,3H).

Example 39: 4- ((3-methoxy-4-fluorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3-methoxy-4-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 3-methoxy-4-fluoroaniline, is as described in example 3 a) to give 120mg of a yellow solid in 58% yield mp:224-225 ℃.

¹H NMR(CDCl₃)(ppm):10.48(brs,1H),8.18(d,J＝9.6Hz,1H),7.32(d,J＝2.1Hz,1H),7.15(d,J＝9.0Hz,1H),6.92(d,J＝7.2Hz,1H),6.86(d,J＝8.4Hz,1H),6.63(d,J＝8.7Hz,2H),4.45(q,J＝7.2Hz,2H),3.90(s,3H),1.44(t,J＝7.2Hz,3H).

b)4- ((3-methoxy-4-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxy-4-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 90mg of a brick-red solid in 88% yield mp:268-270 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.74(s,1H),9.64(s,1H),8.11(d,J＝8.8Hz,1H),7.73(s,1H),7.30(dd,J₁＝9.2Hz,J₂＝10.8Hz,1H),7.16(d,J＝7.6Hz,1H),6.95(d,J＝8.4Hz,1H),6.70(d,J＝9.2Hz,1H),3.86(s,3H).

c)4- ((3-methoxy-4-fluorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-methoxy-4-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 24mg of a yellow powdery solid in 65% yield and mp: >290 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.89(s,1H),9.65(s,1H),8.13(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,2H),7.81(s,1H),7.28(dd,J₁＝11.2Hz,J₁＝8.8Hz,1H),7.17(d,J＝8.8Hz,2H),7.13(d,J＝7.6Hz,1H),6.93-6.91(m,1H),6.67(d,J＝9.2Hz,1H),3.86(s,3H),3.84(s,3H)；HRMS(ESI):m/z,calcd.for C₂₃H₂₀N₄O₇FS[M+H]⁺:515.1037,found515.1025.

Example 40: 4- ((3-methoxy-5-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3-methoxy-5-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 3-methoxy-5-chloroaniline, was as described in example 3 a) to give 285mg of an orange solid in 98% yield mp:225-227 ℃.

¹H NMR(DMSO-d₆)(ppm):11.02(s,1H),9.63(s,1H),8.18(d,J＝8.8Hz,1H),7.81(s,1H),7.01(s,1H),6.91(s,2H),6.85(s,1H),4.38(q,J＝7.2Hz,2H),3.81(s,3H),1.37(t,J＝7.2Hz,3H).

b)4- ((3-methoxy-5-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Using ethyl 4- ((3-methoxy-5-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate as starting material, the preparation was carried out as described in b) of example 3 to give 183mg of an orange-red solid in a yield of 96% and mp:269-272 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.81(s,1H),9.62(s,1H),8.17(d,J＝9.2Hz,1H),7.72(s,1H),7.01(s,1H),6.90(s,1H),6.89(d,J＝9.6Hz,1H),6.85(s,1H),3.80(s,3H).

c)4- ((3-methoxy-5-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 4- ((3-methoxy-5-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide in the form of a yellow powder in the amount of 91mg of 80% yield mp:278-280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.90(brs,1H),9.64(s,1H),8.19(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,2H),7.82(s,1H),7.17(d,J＝8.8Hz,2H),6.99(s,1H),6.88(s,1H),6.87(d,J＝9.6Hz,1H),6.84(s,1H),3.86(s,3H),3.79(s,3H)；HRMS(ESI):m/z,calcd.for C₂₃H₂₀N₄O₇ClS[M+H]⁺:531.0741,found531.0732.

Example 41.4- ((3-methoxy-5-chlorophenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

The procedure described in c) of example 3 was repeated, starting from 4- ((3-methoxy-5-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, to give 44mg of a yellow powdery solid in 80% yield mp:269-271 ℃.

¹H NMR(DMSO-d₆)(ppm):13.05(brs,1H),11.88(brs,1H),9.64(s,1H),8.19(d,J＝9.2Hz,1H),8.04(d,J＝7.6Hz,2H),7.81(s,1H),7.74(t,J＝7.2Hz,1H),7.66(t,J＝7.6Hz,2H),6.99(s,1H),6.88(s,1H),6.87(d,J＝9.2Hz,1H),6.84(s,1H),3.79(s,3H).

Example 42- ((5-methoxy-2-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((5-methoxy-2-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 5-methoxy-2-chloroaniline, was as described in a) to give 180mg of a yellow solid in 83% yield mp:175-177 ℃.

¹H NMR(CDCl₃)(ppm):10.48(brs,1H),8.23(d,J＝8.8Hz,1H),7.39(d,J＝10.0Hz,2H),7.10(d,J＝2.4Hz,1H),6.91(d,J＝9.2Hz,1H),6.85(s,1H),6.69(dd,J₁＝2.1Hz,J₂＝9.2Hz,1H),4.46(q,J＝7.2Hz,2H),3.81(s,3H),1.45(t,J＝7.2Hz,3H).

b)4- ((5-methoxy-2-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Using 4- ((5-methoxy-2-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester as starting material, the preparation was carried out as described in b) of example 3 to give 110mg of an orange-red solid, yield 97%, mp:220-222 ℃.

¹H NMR(DMSO-d₆)(ppm):10.71(s,1H),9.63(s,1H),8.07(d,J＝8.8Hz,1H),7.68(s,1H),7.53(d,J＝8.8Hz,1H),7.07(d,J＝2.4Hz,1H),7.16(d,J₁＝2.1Hz,J₂＝8.8Hz,1H),6.14(d,J＝9.2Hz,1H),3.76(s,3H).

c)4- ((5-methoxy-2-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure described in example 3, c) was repeated starting from 4- ((5-methoxy-2-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and p-methoxybenzenesulphonamide to give 55mg of a yellow powdery solid in 63% yield and mp: >290 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.85(brs,1H),9.58(s,1H),8.11(d,J＝9.2Hz,1H),7.97(d,J＝8.8Hz,2H),7.75(d,J＝8.4Hz,1H),7.54(d,J＝8.8Hz,1H),7.16(d,J＝8.4Hz,2H),7.07(d,J＝2.1Hz,1H),6.99(dd,J₁＝2.1Hz,J₂＝8.8Hz,1H),6.15(d,J＝8.8Hz,1H),3.86(s,3H),3.78(s,3H).

Example 43- ((5-methoxy-2, 4-dichlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((5-methoxy-2, 4-dichlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation process was the same as that described in a) of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 5-methoxy-2, 4-dichloroaniline as starting materials, to give 206mg of an orange-yellow solid with a yield of 81% and mp:215-217 ℃.

¹H NMR(CDCl₃)(ppm):10.48(s,1H),8.23(d,J＝8.8Hz,1H),7.51(s,1H),7.36(s,1H),7.10(s,1H),6.82(d,J＝8.8Hz,1H),6.76(s,1H),4.47(q,J＝7.2Hz,2H),3.87(s,3H),1.45(t,J＝7.2Hz,3H).

b)4- ((5-methoxy-2, 4-dichlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

The procedure of b) in example 3 was repeated, starting from ethyl 4- ((5-methoxy-2, 4-dichlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, to give 86mg of an orange-red solid in 77% yield mp:264-266 ℃.

¹H NMR(DMSO-d₆)(ppm):10.77(s,1H),9.64(s,1H),8.09(d,J＝8.8Hz,1H),7.80(s,1H),7.72(s,1H),7.32(s,1H),6.23(d,J＝8.8Hz,1H),3.87(s,3H).

c)4- ((5-methoxy-2, 4-dichlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure is as described in c) of example 3, starting from 4- ((5-methoxy-2, 4-dichlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, giving 44mg of a reddish-brown powdery solid in 78% yield, mp:289-291 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.88(brs,1H),9.63(s,1H),8.11(d,J＝8.8Hz,1H),7.97(d,J＝8.8Hz,2H),7.79(s,1H),7.77(s,1H),7.29(s,1H),7.17(d,J＝8.8Hz,1H),6.21(d,J＝9.2Hz,1H),3.86(s,3H),3.85(s,3H).

Example 444- ((3-fluorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((3-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-fluoroaniline as starting materials, was as described in example 3 a) to give 242mg of a yellow solid in 95% yield mp:215-216 ℃.

¹H NMR(acetone-d₆)(ppm):10.59(brs,1H),8.87(s,1H),8.20(d,J＝9.2Hz,1H),7.66(s,1H),7.51-7.45(m,1H),7.30(d,J＝8.0Hz,1H),7.22(d,J＝10.4Hz,1H),7.01-6.95(m,2H),4.41(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H).

b)4- ((3-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 60mg of a yellow solid in 48% yield and mp: >250 ℃.

¹HNMR(DMSO-d₆)(ppm):13.32(brs,1H),10.77(s,1H),9.66(s,1H),8.13(d,J＝9.2Hz,1H),7.73(s,1H),7.49-7.43(m,1H),7.23-7.19(m,2H),7.00(t,J＝8.0Hz,1H),6.85(d,J＝9.2Hz,1H).

c)4- ((3-fluorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure described in c) of example 3 was repeated, starting from 4- ((3-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 29mg of a pale yellow powdery solid in 59% yield and mp: >290 ℃.

¹H NMR(DMSO-d₆)(ppm):12.87(brs,1H),11.92(s,1H),9.70(s,1H),8.18(d,J＝9.0Hz,1H),7.98(d,J＝9.0Hz,2H),7.83(d,J＝2.1Hz,1H),7.48-7.43(m,1H),7.23-7.20(m,2H),7.17(d,J＝8.7Hz,2H),7.02(t,J＝9.0Hz,2H),6.84(d,J＝9.0Hz,1H),3.86(s,3H).

Example 45.4- ((4-fluorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((4-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 4-fluoroaniline as starting materials was carried out as described in a) of example 3 to give 250mg of a yellow solid in 98% yield mp:205-207 ℃.

¹H NMR(acetone-d₆)(ppm):10.59(brs,1H),8.82(s,1H),8.16(d,J＝9.2Hz,1H),7.67(s,1H),7.51-7.48(m,2H),7.25(t,J＝8.8Hz,1H),6.74(dd,J₁＝4.0Hz,J₂＝8.8Hz,1H),4.41(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H).

b)4- ((4-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((4-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 113mg of a yellow solid in 81% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.72(s,1H),9.61(s,1H),8.09(d,J＝9.2Hz,1H),7.70(s,1H),7.42-7.39(m,2H),7.29(t,J＝8.8Hz,2H),6.59(d,J＝9.2Hz,1H).

c)4- ((4-fluorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((4-fluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 56mg of a reddish-brown powdery solid in 73% yield and mp: >290 ℃.

¹H NMR(DMSO-d₆)(ppm):12.93(brs,1H),11.90(brs,1H),9.66(s,1H),8.13(d,J＝9.3Hz,1H),7.98(d,J＝8.7Hz,2H),7.81(d,J＝2.1Hz,1H),7.42-7.38(m,2H),7.30(t,J＝8.4Hz,2H),7.18(d,J＝8.7Hz,2H),6.58(d,J＝9.0Hz,1H),3.86(s,3H).

Example 46.4- ((2-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a)4- ((2-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation procedure was the same as that described in a) of example 3, except that 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 2-chloroaniline were used as starting materials, and 130mg of an orange-red solid was obtained with a yield of 65% and mp:136-137 ℃.

¹H NMR(CDCl₃)(ppm):10.48(brs,1H),8.21(d,J＝8.8Hz,1H),7.57(d,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),7.37(s,1H),7.34(t,J＝8.0Hz,1H),7.15(t,J＝8.0Hz,1H),6.87(s,1H),6.83(d,J＝9.2Hz,1H),4.46(q,J＝7.2Hz,2H),3.86(s,3H),1.45(t,J＝7.2Hz,3H).

b)4- ((2-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((2-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 118mg of a yellow solid in 98% yield, mp:265-267 ℃.

¹H NMR(DMSO-d₆)(ppm):10.72(s,1H),9.62(s,1H),8.09(d,J＝8.8Hz,1H),7.68(d,J＝8.0Hz,1H),7.65(s,1H),7.54(d,J＝7.6Hz,1H),7.49(t,J＝7.2Hz,1H),7.42(t,J＝7.2Hz,1H),6.12(t,J＝9.2Hz,1H).

c)4- ((2-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((2-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, the preparation is carried out as described in c) of example 3 to give 42mg of a yellow powdery solid in 70% yield mp:285-287 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.88(brs,1H),9.60(s,1H),8.11(d,J＝9.2Hz,1H),7.97(d,J＝8.8Hz,2H),7.72(s,1H),7.66(d,J＝8.0Hz,1H),7.52-7.45(m,2H),7.41(t,J＝6.8Hz,2H),7.17(d,J＝8.8Hz,2H),6.10(d,J＝8.8Hz,1H),3.86(s,3H).

Example 47.4- ((3-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, gave 54mg of a red-orange powdery solid in 72% yield mp:275-277 ℃.

¹H NMR(DMSO-d₆)(ppm):12.93(brs,1H),11.90(brs,1H),9.68(s,1H),8.18(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,2H),7.81(s,1H),7.46(t,J＝8.4Hz,1H),7.41(s,1H),7.35(d,J＝8.0Hz,1H),7.24(d,J＝7.6Hz,1H),7.17(d,J＝8.8Hz,2H),6.81(d,J＝8.8Hz,1H),3.86(s,3H).

Example 48.4- ((4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 4-chloroaniline as starting materials was carried out as described in a) of example 3 to give 265mg of a yellow solid in 99% yield mp:244-245 ℃.

¹H NMR(acetone-d₆)(ppm):10.63(brs,1H),8.87(s,1H),8.19(d,J＝9.2Hz,1H),7.69(s,1H),7.48(m,4H),6.89-6.91(m,1H),4.41(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₇H₁₅ClN₃O₄[M+H⁺]:360.0746,found360.0736.

b) 4- ((4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 145mg of a yellow solid in 82% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.78(s,1H),10.77(s,1H),9.65(s,1H),8.12(d,J＝9.2Hz,1H),7.72(s,1H),7.49(d,J＝8.8Hz,2H),7.40(d,J＝8.4Hz,2H),6.74(d,J＝9.2Hz,1H)；HRMS(ESI):m/z,calcd for C₁₅H₁₁ClN₃O₄[M+H⁺]:332.0432,found 332.0430.

c) 4- ((4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, the preparation was carried out as described in c) of example 3 to give 44mg of an orange powdery solid in 73% yield and mp: >290 ℃.

¹H NMR(DMSO-d₆)(ppm):12.93(brs,1H),11.89(brs,1H),9.68(s,1H),8.15(d,J＝9.0Hz,1H),7.98(d,J＝8.7Hz,2H),7.81(d,J＝1.5Hz,1H),7.49(d,J＝8.7Hz,2H),7.38(d,J＝8.7Hz,2H),7.17(d,J＝9.0Hz,2H),6.73(d,J＝9.3Hz,1H),3.86(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.24,157.29,146.66,138.28,131.89,130.73,130.22,129.44,128.84,128.39,127.06,124.45,124.39,116.94,114.32,110.30,102.12,55.81.HRMS(ESI):m/z,calcd.for C₂₂H₁₈N₄O₆ClS[M+H]⁺:501.0636,found 501.0619.

Example 49: 4- ((3, 4-dichlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3, 4-dichlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 3 was carried out using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3, 4-dichloroaniline as starting materials to give 152mg of a yellow solid in 69% yield mp:227-229 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.21(d,J＝8.8Hz,1H),7.49(d,J＝8.8Hz,1H),7.43(d,J＝1.5Hz,1H),7.34(d,J＝1.2Hz,1H),7.17(d,J₁＝1.2Hz,J₂＝8.8Hz,1H),6.78(d,J＝8.8Hz,1H),6.66(s,1H),4.45(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

b) 4- ((3, 4-dichlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

The procedure of b) in example 3 was repeated, starting from ethyl 4- ((3, 4-dichlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, to give 78mg of a yellow solid in 76% yield mp:280-282 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.84(s,1H),9.69(s,1H),8.16(d,J＝8.8Hz,1H),7.72(d,J＝1.2Hz,1H),7.67(d,J＝8.8Hz,1H),7.62(d,J＝1.5Hz,1H),7.16(d,J₁＝1.5Hz,J₂＝8.8Hz,1H),6.87(d,J＝8.8Hz,1H).

c) 4- ((3, 4-dichlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure described in example 3 c) was repeated, starting from 4- ((3, 4-dichlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 43mg of a yellow powdery solid in 74% yield and mp: >290 ℃.

¹H NMR(DMSO-d₆)(ppm):12.93(brs,1H),11.92(brs,1H),9.71(s,1H),8.18(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,2H),7.80(s,1H),7.66(d,J＝8.8Hz,1H),7.60(s,1H),7.37(d,J＝8.8Hz,1H),7.17(d,J＝8.4Hz,2H),6.84(d,J＝8.8Hz,1H),3.86(s,3H).

Example 50: 4- ((3, 4-difluorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) Ethyl 4- ((3, 4-difluorophenyl) amino) -7-nitro-1H-indole-2-carboxylate

The preparation process was the same as that described in a) of example 3 using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 2-chloroaniline as starting materials to give 160mg of an orange-red solid with a yield of 79% and mp:240-242 ℃.

¹H NMR(CDCl₃)(ppm):10.47(s,1H),8.20(d,J＝8.8Hz,1H),7.32(s,1H),7.26-7.16(m,3H),7.05(d,J＝8.4Hz,1H),6.68(d,J＝8.8Hz,1H),6.61(s,1H),4.45(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

b) 4- ((3, 4-difluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((3, 4-difluorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 100mg of a reddish brown solid in 90% yield mp:269-272 ℃.

¹H NMR(DMSO-d₆)(ppm):13.40(brs,1H),10.80(s,1H),9.66(s,1H),8.14(d,J＝9.2Hz,1H),7.72(s,1H),7.55-7.45(m,2H),7.23(d,J＝8.8Hz,1H),7.75(d,J＝9.2Hz,1H).

c) 4- ((3, 4-difluorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3, 4-difluorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 51mg of a yellow powdery solid in 85% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.91(brs,1H),9.66(s,1H),8.15(d,J＝9.2Hz,1H),7.97(d,J＝8.8Hz,2H),7.79(s,1H),7.54-7.43(m,2H),7.21-7.16(m,3H),6.73(d,J＝9.2Hz,1H),3.86(s,3H).

Example 51: 4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 4-fluoro-3-chloroaniline as starting materials, gave 140mg of an orange solid in 67% yield, mp:230-232 ℃.

¹H NMR(acetone-d₆)(ppm):10.61(brs,1H),8.82(brs,1H),8.19(d,J＝9.0Hz,1H),7.66(d,J＝1.8Hz,1H),7.60(dd,J₁＝2.7Hz,J₂＝6.3Hz,1H),7.51-7.44(m,1H),7.41(t,J＝8.7Hz,1H),6.86(d,J＝8.7Hz,1H),4.41(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H).

b) 4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 90mg of a reddish brown solid in 97% yield mp:242-244 ℃.

¹H NMR(DMSO-d₆)(ppm):10.80(s,1H),9.71(s,1H),8.14(d,J＝9.2Hz,1H),7.74(s,1H),7.60(dd,J₁＝1.8Hz,J₂＝6.4Hz,1H),7.50(t,J＝8.8Hz,1H),7.43-7.40(m,1H),6.72(d,J＝9.2Hz,1H).

c) 4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure described in example 3 c) was repeated, starting from 4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 57mg of a yellow powdery solid in 78% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.91(brs,1H),9.69(s,1H),8.16(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,2H),7.80(s,1H),7.57(d,J₁＝1.5Hz,J₂＝6.4Hz,1H),7.49(t,J＝9.6Hz,1H),7.39-7.37(m,1H),7.17(d,J＝8.8Hz,2H),6.69(d,J＝9.2Hz,1H),3.86(s,3H).¹³C NMR(125MHz,DMSO-d₆):163.28,156.24(J_CF＝244.5Hz),153.32,146.73,136.59(J_CF＝3.0Hz),131.85,130.62,130.25,128.85,127.12,124.86,124.58,123.65(J_CF＝7.1Hz),120.07(J_CF＝18.6Hz),117.67(J_CF＝21.9Hz),116.86,114.35,110.19,101.97,55.82.HRMS(ESI):m/z,calcd.for C₂₂H₁₇N₄O₆FClS[M+H]⁺:519.0536,found 519.0532.

Example 52: 4- ((3-fluoro-4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-fluoro-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-fluoro-4-chloroaniline as starting materials, gave 155mg of an orange solid in 74% yield, mp:230-232 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.21(d,J＝9.2Hz,1H),7.44(t,J＝8.4Hz,1H),7.34(s,1H),7.14(d,J＝10.0Hz,1H),7.05(d,J＝8.4Hz,1H),6.82(d,J＝9.2Hz,1H),6.68(s,1H),4.45(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

b) 4- ((3-fluoro-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((3-fluoro-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 115mg of a yellow solid in 96% yield mp:255-258 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.84(s,1H),9.71(s,1H),8.16(d,J＝8.8Hz,1H),7.73(s,1H),7.62(t,J＝8.8Hz,1H),7.43(d,J＝10.8Hz,1H),7.26(d,J＝8.4Hz,1H),6.90(d,J＝9.2Hz,1H).

c) 4- ((3-fluoro-4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-fluoro-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, the preparation is carried out as described in c) of example 3 to give 62mg of a yellow powdery solid in 84% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.95(brs,1H),11.90(brs,1H),9.73(s,1H),8.17(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,2H),7.80(s,1H),7.61(t,J＝8.8Hz,1H),7.41(d,J＝11.2Hz,1H),7.23(d,J＝8.8Hz,1H),7.17(d,J＝8.8Hz,2H),6.88(d,J＝8.8Hz,1H),3.86(s,3H).

Example 53: 4- ((2-fluoro-5-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((2-fluoro-5-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 2-fluoro-5-chloroaniline, is as described in a) to give 166mg of a yellow solid in 79% yield mp:199-200 ℃.

¹H NMR(CDCl₃)(ppm):10.48(brs,1H),8.25(d,J＝9.2Hz,1H),7.52-7.51(m,1H),7.37(d,J＝1.6Hz,1H),7.19-7.11(m,2H),6.85(d,J＝8.8Hz,1H),6.61(s,1H),4.46(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

b) 4- ((2-fluoro-5-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((2-fluoro-5-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 76mg of a yellow solid in 72% yield mp:234-236 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.82(s,1H),9.58(s,1H),8.14(d,J＝9.2Hz,1H),7.71(s,1H),7.60-7.58(m,1H),7.50-7.41(m,2H),6.36(d,J₁＝1.5Hz,J₂＝8.8Hz,1H).

c) 4- ((2-fluoro-5-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((2-fluoro-5-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, the preparation was carried out as described in c) of example 3 to give 43mg of a yellow powdery solid in 73% yield and mp: >280 ℃.

¹HNMR(DMSO-d₆)(ppm):12.94(brs,1H),11.90(brs,1H),9.58(s,1H),8.16(d,J＝9.2Hz,1H),7.97(d,J＝8.4Hz,2H),7.77(s,1H),7.56(d,J＝6.8Hz,1H),7.49-7.42(m,2H),7.17(d,J＝8.4Hz,2H),6.35(d,J＝8.8Hz,1H),3.86(s,3H).

Example 54: 4- ((3-trifluoromethylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 3-trifluoromethylaniline, gives 360mg of a yellow solid in 98% yield and mp: >250 ℃.

¹H NMR(acetone-d₆)(ppm):10.62(s,1H),8.96(s,1H),8.21(d,J＝9.2Hz,1H),7.67-7.80(m,4H),7.52(d,J＝7.6Hz,1H),6.99-7.01(m,1H),4.41(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₈H₁₅F₃N₃O₄[M+H⁺]:394.1009,found394.0997.

b) 4- ((3-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 42mg of a yellow solid in 37% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.81(s,1H),9.75(s,1H),8.16(d,J＝9.2Hz,1H),7.64-7.71(m,4H),7.51(d,J＝7.2Hz,1H),6.85(d,J＝9.2Hz,1H)；HRMS(ESI):m/z,calcd forC₁₆H₁₁F₃N₃O₄[M+H⁺]:366.0696,found 366.0694.

c) 4- ((3-trifluoromethylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 34mg of a yellow powdery solid in 67% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.93(brs,1H),11.92(brs,1H),9.78(s,1H),8.19(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,2H),7.82(s,1H),7.72-7.65(m,3H),7.52(d,J＝7.6Hz,1H),7.17(d,J＝8.4Hz,2H),6.84(d,J＝8.8Hz,1H),3.86(s,3H).

Example 55: 4- ((4-trifluoromethylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 4-trifluoromethylaniline as starting materials was carried out as described in a) of example 3 to give 250mg of a yellow solid in 86% yield mp:239-241 ℃.

¹H NMR(acetone-d₆)(ppm):10.67(brs,1H),9.05(s,1H),8.23(d,J＝8.8Hz,1H),7.77(d,J＝8.4Hz,2H),7.69(s,1H),7.66(d,J＝8.4Hz,2H),7.12-7.15(m,1H),4.41(q,J＝7.2Hz,2H),1.39(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd forC₁₈H₁₅F₃N₃O₄[M+H⁺]:394.1009,found 394.0997.

b) 4- ((4-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((4-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3, giving 90mg of a yellow solid in 69% yield mp:244-246 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.84(s,1H),9.79(s,1H),8.15(d,J＝8.8Hz,1H),7.74-7.76(m,3H),7.55(d,J＝8.0Hz,2H),6.98(d,J＝8.8Hz,1H)；HRMS(ESI):m/z,calcd for C₁₆H₁₁F₃N₃O₄[M+H⁺]:366.0696,found 366.0694.

c) 4- ((4-trifluoromethylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((4-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, was as described in c) to give 45mg of a solid as an orange-red powder in 76% yield mp:278-280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.88(brs,1H),11.92(brs,1H),9.83(s,1H),8.19(d,J＝8.8Hz,1H),7.98(d,J＝8.4Hz,2H),7.84(s,1H),7.76(d,J＝8.0Hz,2H),7.55(d,J＝8.0Hz,2H),7.17(d,J＝8.4Hz,2H),6.97(d,J＝8.8Hz,1H),3.86(s,3H).

Example 56: 4- ((4-cyanophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-cyanophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 4-cyanoaniline as starting materials in the same manner as in a) of example 3 gave 242mg of a yellow solid in 84% yield mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.08(s,1H),9.83(s,1H),8.17(d,J＝8.8Hz,1H),7.82(d,J＝8.4Hz,2H),7.78(s,1H),7.50(d,J＝8.8Hz,2H),7.04(d,J＝9.2Hz,1H),4.37(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H).

b) 4- ((4-cyanophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((4-cyanophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 107mg of a yellow solid in 97% yield, mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.44(brs,1H),10.90(s,1H),9.83(s,1H),8.17(d,J＝8.8Hz,1H),7.82(d,J＝8.4Hz,2H),7.77(s,1H),7.50(d,J＝8.4Hz,2H),7.04(d,J＝8.8Hz,1H).

c) 4- ((4-cyanophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((4-cyanophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 45mg of an orange powdery solid in 74% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.98(brs,1H),11.93(brs,1H),9.89(s,1H),8.22(d,J＝9.3Hz,1H),7.98(d,J＝9.0Hz,2H),7.83(d,J＝8.1Hz,3H),7.49(d,J＝8.7Hz,2H),7.17(d,J＝8.7Hz,2H),7.03(t,J＝9.3Hz,1H),3.86(s,3H).

Example 57: 4- ((3-nitrophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-Nitrophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-nitroaniline starting from the starting materials was as described in a) of example 3 to give 265mg of a yellow solid in 87% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.05(s,1H),9.84(s,1H),8.17(d,J＝9.2Hz,1H),8.14(s,1H),7.96(d,J＝8.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.79(s,1H),7.69(t,J＝8.0Hz,1H),6.96(d,J＝8.8Hz,1H),4.37(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₇H₁₅N₄O₆[M+H⁺]:371.0986,found371.0981.

b) 4- ((3-nitrophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-nitrophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3, giving 105mg of a yellow solid in 93% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.42(brs,1H),10.86(s,1H),9.84(s,1H),8.15-8.17(m,2H),7.96(d,J＝8.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.72(s,1H),7.69(t,J＝8.0Hz,1H),6.95(d,J＝9.2Hz,1H)；HRMS(ESI):m/z,calcd forC₁₅H₁₀N₄O₆[M+H⁺]:343.0673,found343.0665.

c) 4- ((3-Nitrophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-nitrophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3, giving 50mg of an orange powdery solid in 83% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.94(brs,1H),11.93(s,1H),9.89(s,1H),8.20(d,J＝9.0Hz,1H),8.15(t,J＝2.1Hz,1H),7.98(d,J＝8.7Hz,3H),7.84-7.82(m,2H),7.70(t,J＝7.8Hz,1H),6.17(d,J＝9.0Hz,2H),6.95(d,J＝9.3Hz,1H),3.86(s,3H).

Example 58: 4- ((4-Nitrophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-Nitrophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 4-nitroaniline starting from the starting materials was as described in a) of example 3 to give 259mg of a yellow solid in 90% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.16(s,1H),10.00(s,1H),8.24(d,J＝8.8Hz,2H),8.21(d,J＝9.2Hz,1H),7.78(s,1H),7.53(d,J＝9.2Hz,2H),7.15(d,J＝8.8Hz,1H),4.37(q,J＝7.2Hz,2H),1.36(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcdfor C₁₇H₁₄N₄O₆[M+H⁺]:371.0986,found 371.0973.

b) 4- ((4-nitrophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((4-nitrophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3, giving 113mg of a yellow solid in 88% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.97(s,1H),10.03(s,1H),8.25(d,J＝8.8Hz,2H),8.21(d,J＝8.8Hz,1H),7.12(s,1H),7.53(d,J＝8.8Hz,2H),7.15(d,J＝9.2Hz,1H)；HRMS(ESI):m/z,calcd for C₁₅H₁₁N₄O₆[M+H⁺]:343.0673,found343.0672.

c) 4- ((4-Nitrophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((4-nitrophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3, giving 50mg of an orange powdery solid in 83% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.95(brs,1H),11.94(brs,1H),10.09(s,1H),8.25(d,J＝9.0Hz,3H),7.98(d,J＝9.0Hz,2H),7.82(d,J＝1.8Hz,1H),7.52(d,J＝9.0Hz,2H),7.16(t,J＝8.7Hz,3H),3.86(s,3H).

Example 59: 4- ((2, 4-Dimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) Ethyl 4- ((2, 4-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate

The procedure is as described in example 3 a) starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 2, 4-dimethoxyaniline to give 156mg of a yellow solid in 73% yield mp:219-220 ℃.

¹H NMR(CDCl₃)(ppm):10.45(brs,1H),8.15(d,J＝9.0Hz,1H),7.36-7.34(m,2H),6.73(s,1H),6.61(d,J＝9.6Hz,1H),6.59-6.53(m,2H),4.44(q,J＝7.2Hz,2H),3.86(s,3H),3.85(s,3H),1.44(t,J＝7.2Hz,3H).

b) 4- ((2, 4-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((2, 4-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 87mg of a yellow solid in 90% yield mp:220-222 ℃.

¹H NMR(DMSO-d₆)(ppm):13.28(brs,1H),10.62(s,1H),9.31(s,1H),8.02(d,J＝9.0Hz,1H),7.67(d,J＝2.1Hz,1H),7.23(d,J＝8.4Hz,1H),6.76(d,J＝2.1Hz,1H),7.16(d,J₁＝2.4Hz,J₂＝8.4Hz,1H),6.04(d,J＝9.0Hz,1H),3.83(s,3H),3.76(s,3H).

c) 4- ((2, 4-dimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((2, 4-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 55mg of a reddish-brown powdery solid in 89% yield mp:254-255 ℃.

¹H NMR(DMSO-d₆)(ppm):12.89(brs,1H),11.82(brs,1H),9.30(s,1H),8.04(d,J＝9.2Hz,1H),7.97(d,J＝8.0Hz,2H),7.75(s,1H),7.22-7.16(m,3H),6.74(s,1H),6.61(d,J＝8.4Hz,1H),6.02(d,J＝9.2Hz,1H),3.86(s,3H),3.82(s,3H),3.73(s,3H).

Example 60: 4- ((2, 3-Dimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) Ethyl 4- ((2, 3-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate

The procedure of a) in example 3 was repeated, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 2, 3-dimethoxyaniline, to give 176mg of a yellow solid in 82% yield mp:160-161 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.22(d,J＝9.3Hz,1H),7.39(d,J＝2.1Hz,1H),7.15-7.07(m,3H),6.97(d,J＝9.0Hz,1H),6.75(dd,J₁＝1.8Hz,J₂＝7.5Hz,1H),4.46(q,J＝7.2Hz,2H),3.93(s,3H),3.87(s,3H),1.45(t,J＝7.2Hz,3H).

b) 4- ((2, 3-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((2, 3-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3, giving 95mg of a yellow solid, yield 90%, mp:244-247 ℃.

¹H NMR(DMSO-d₆)(ppm):13.32(brs,1H),10.68(s,1H),9.40(s,1H),8.07(d,J＝9.2Hz,1H),7.74(s,1H),7.16(t,J＝8.4Hz,1H),7.06(d,J＝8.4Hz,1H),6.95(d,J＝8.0Hz,1H),6.23(d,J＝8.8Hz,1H),3.87(s,3H),3.64(s,3H).

c) 4- ((2, 3-dimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((2, 3-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 60mg of a red-brown powdery solid in a yield of 95% and mp:220-222 ℃.

¹H NMR(DMSO-d₆)(ppm):12.90(brs,1H),11.85(s,1H),9.40(s,1H),8.09(d,J＝9.6Hz,1H),7.97(d,J＝8.8Hz,2H),7.81(s,1H),7.17(d,J＝8.8Hz,2H),7.15(t,J＝8.0Hz,1H),7.04(d,J＝8.4Hz,1H),6.92(d,J＝8.0Hz,1H),6.21(d,J＝9.2Hz,1H),3.86(s,3H),3.85(s,3H),3.60(s,3H).

EXAMPLE 61 4- ((2, 5-dimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) Ethyl 4- ((2, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate

The preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 2, 5-dimethoxyaniline as starting materials was carried out as described under a) in example 3 to give 185mg of an orange-yellow solid in 86% yield mp:167-169 ℃.

¹H NMR(CDCl₃)(ppm):10.46(brs,1H),8.21(d,J＝8.8Hz,1H),7.39(d,J＝1.6Hz,1H),7.11(d,J＝2.8Hz,1H),7.06(s,1H),7.00(d,J＝9.2Hz,1H),6.91(d,J＝9.2Hz,1H),6.65(dd,J₁＝2.4Hz,J₂＝8.8Hz,1H),4.46(q,J＝7.2Hz,2H),3.88(s,3H),3.80(s,3H),1.45(t,J＝7.2Hz,3H).

b) 4- ((2, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

The procedure of b) in example 3 was repeated using 4- ((2, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester as starting material to give 94mg of an orange-red powdery solid in 92% yield mp:255-258 ℃.

¹H NMR(DMSO-d₆)(ppm):13.31(brs,1H),10.66(s,1H),9.38(s,1H),8.06(d,J＝9.2Hz,1H),7.71(s,1H),7.13(d,J＝8.8Hz,1H),6.93-6.90(m,2H),6.20(d,J＝9.2Hz,1H),3.74(s,3H),3.72(s,3H).

c) 4- ((2, 5-dimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, c) was repeated, starting from 4- ((2, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 55mg of a red-brown powdery solid in 83% yield, mp:274-276 ℃.

¹H NMR(DMSO-d₆)(ppm):12.90(brs,1H),11.83(s,1H),9.36(s,1H),8.08(d,J＝9.2Hz,1H),7.97(d,J＝8.8Hz,2H),7.80(s,1H),7.17(d,J＝8.8Hz,2H),7.12-7.10(m,1H),6.90(s,2H),6.18(d,J＝8.8Hz,1H),3.86(s,3H),3.72(s,3H),3.69(s,3H).

Example 62- ((4-methyl-3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-methyl-3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 4-methyl-3-methoxyaniline, gave 160mg of a yellow solid in 78% yield mp:186-188 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.16(d,J＝9.0Hz,1H),7.35(d,J＝2.1Hz,1H),7.18(d,J＝8.1Hz,1H),6.83(dd,J₁＝2.1Hz,J₂＝8.1Hz,1H),6.78(d,J＝1.8Hz,1H),6.69(d,J＝9.3Hz,1H),4.44(q,J＝7.2Hz,2H),3.83(s,3H),2.24(s,3H),1.43(t,J＝7.5Hz,3H).

b) 4- ((4-methyl-3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((4-methyl-3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 101mg of a solid in the form of a red-orange powder with a yield of 99%, mp:265-267 ℃.

¹H NMR(DMSO-d₆)(ppm):13.34(brs,1H),10.71(s,1H),9.65(s,1H),8.10(d,J＝9.0Hz,1H),7.75(d,J＝1.8Hz,1H),7.21(d,J＝8.1Hz,1H),6.93(s,1H),6.89(d,J＝7.8Hz,1H),6.72(d,J＝9.0Hz,1H),3.80(s,3H),2.17(s,3H).

c) 4- ((4-methyl-3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 4- ((4-methyl-3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, is as described in c) of example 3, gives 57mg of a reddish-brown powdery solid in 89% yield, mp:268-270 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.88(s,1H),9.66(s,1H),8.12(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,2H),7.84(s,1H),7.18(t,J＝7.6Hz,3H),6.91(s,1H),6.86(d,J＝8.0Hz,1H),6.69(d,J＝9.2Hz,1H),3.86(s,3H),3.79(s,3H),2.16(s,3H).

Example 63- ((2-methyl-5-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((2-methyl-5-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 2-methyl-5-methoxyaniline as starting materials was as described in a) of example 3 to give 190mg of a yellow solid in 92% yield mp:185-187 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.15(d,J＝9.2Hz,1H),7.35(d,J＝1.6Hz,1H),7.24(d,J＝8.4Hz,1H),6.90(d,J＝2.0Hz,1H),6.81(dd,J₁＝2.4Hz,J₂＝8.4Hz,1H),6.57(s,1H),6.37(d,J＝7.2Hz,1H),4.44(q,J＝7.2Hz,2H),3.80(s,3H),2.20(s,3H),1.43(t,J＝7.2Hz,3H).

b) 4- ((2-methyl-5-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((2-methyl-5-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 89mg of a brown powdery solid in 80% yield mp:250-252 ℃.

¹H NMR(DMSO-d₆)(ppm):13.32(brs,1H),10.69(s,1H),9.45(s,1H),8.07(d,J＝9.2Hz,1H),7.67(s,1H),7.31(d,J＝8.0Hz,1H),6.89(d,J＝7.6Hz,2H),6.10(d,J＝8.8Hz,1H),3.75(s,3H),2.11(s,3H).

c) 4- ((2-methyl-5-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((2-methyl-5-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 30mg of a yellow powdery solid in a yield of 45% and mp:245-246 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.87(brs,1H),9.46(s,1H),8.09(d,J＝9.2Hz,1H),7.97(d,J＝8.8Hz,2H),7.75(s,1H),7.29(d,J＝8.4Hz,1H),6.88(d,J＝8.8Hz,1H),6.85(s,1H),6.07(d,J＝9.2Hz,1H),3.86(s,3H),3.74(s,3H),2.07(s,3H).

Example 64- ((3-methoxy-5-trifluoromethylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxy-5-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation procedure was the same as that described in a) of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxy-5-trifluoromethylaniline as starting materials, to give 190mg of an orange-red solid with a yield of 81%, mp:214-216 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.22(d,J＝8.8Hz,1H),7.38(d,J＝1.2Hz,1H),7.15(s,1H),7.03(s,1H),6.97(s,1H),6.85(d,J＝8.8Hz,1H),6.80(s,1H),4.45(q,J＝7.2Hz,2H),3.88(s,3H),1.43(t,J＝7.2Hz,3H).

b) 4- ((3-methoxy-5-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxy-5-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the procedure is as described in b) of example 3 to give 117mg of an orange powdery solid in 95% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.85(s,1H),9.76(s,1H),8.19(d,J＝8.8Hz,1H),7.74(s,1H),7.25(s,1H),7.24(s,1H),7.04(s,1H),6.93(d,J＝8.8Hz,1H),3.87(s,3H).

c) 4- ((3-methoxy-5-trifluoromethylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure used in example 3 c) was carried out starting from 4- ((3-methoxy-5-trifluoromethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide to give 68mg of an orange powdery solid in 96% yield mp:275-277 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.93(s,1H),9.75(s,1H),8.20(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,2H),7.83(s,1H),7.22(s,1H),7.21(s,1H),7.17(d,J＝8.8Hz,2H),7.03(s,1H),6.90(d,J＝8.8Hz,1H),3.86(s,3H),3.85(s,3H).

Example 65- ((3-fluoro-4-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-fluoro-4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation procedure was the same as that described in a) of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-fluoro-4-methoxyaniline as starting materials, to give a solid as an orange-red powder 170mg, at 82% yield, mp:210-212 ℃.

¹H NMR(acetone-d₆)(ppm):10.59(brs,1H),8.77(s,1H),8.16(d,J＝9.2Hz,1H),7.66(s,1H),7.28-7.23(m,3H),6.76-6.73(m,1H),4.41(q,J＝7.2Hz,2H),3.94(s,3H),1.40(t,J＝7.2Hz,3H).

b) 4- ((3-fluoro-4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-fluoro-4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) in example 3 to give 100mg of a yellow powdery solid in 103% yield mp:258-260 ℃.

¹HNMR(DMSO-d₆)(ppm):10.73(s,1H),9.62(s,1H),8.11(d,J＝9.2Hz,1H),7.72(s,1H),7.30-7.24(m,2H),7.19-7.17(m,1H),6.60(d,J＝8.8Hz,1H),3.88(s,3H).

c) 4- ((3-fluoro-4-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-fluoro-4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 42mg of an orange powdery solid in 56% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.90(brs,1H),11.87(s,1H),9.59(s,1H),8.11(d,J＝9.2Hz,1H),7.97(d,J＝8.8Hz,2H),7.78(s,1H),7.26-7.21(m,2H),7.17-7.13(m,3H),6.56(d,J＝9.2Hz,1H),3.85(s,6H)；HRMS(ESI):m/z,calcd.forC₂₃H₂₀N₄O₇FS[M+H]⁺:515.7037,found 515.1025.

Example 66- ((3, 5-dimethyl-4-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3, 5-dimethyl-4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used in example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 3, 5-dimethyl-4-methoxyaniline, gives 160mg of a yellow solid in the form of a powder with a yield of 75% and mp:188-189 ℃.

¹H NMR(CDCl₃)(ppm):10.46(brs,1H),8.16(d,J＝9.2Hz,1H),7.33(d,J＝1.6Hz,1H),6.98(s,2H),6.68(brs,1H),6.63(d,J＝9.2Hz,1H),4.43(q,J＝7.2Hz,2H),3.77(s,3H),2.32(s,3H),1.43(t,J＝7.2Hz,3H).

b) 4- ((3, 5-dimethyl-4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3, 5-dimethyl-4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 136mg of a brick-red solid in the form of a powder with a yield of 98% and mp:235-237 ℃.

¹H NMR(DMSO-d₆)(ppm):13.31(brs,1H),10.69(s,1H),9.52(s,1H),8.10(d,J＝8.8Hz,1H),7.74(s,1H),7.05(s,2H),6.61(d,J＝8.8Hz,1H),3.69(s,3H),2.26(s,6H).

c) 4- ((3, 5-dimethyl-4-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure used in c) of example 3 was followed, starting from 4- ((3, 5-dimethyl-4-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 63mg of a solid in the form of a reddish-orange powder with a yield of 86% and mp:260-263 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.87(s,1H),9.54(s,1H),8.12(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,2H),7.83(s,1H),7.17(d,J＝8.8Hz,2H),7.03(s,2H),6.58(d,J＝9.2Hz,1H),3.86(s,3H),3.68(s,3H),2.25(s,6H).

Example 67- ((4-trifluoromethoxy-3-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-trifluoromethoxy-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 3 was repeated, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 4-trifluoromethoxy-3-chloroaniline, to give 175mg of a yellow powdery solid in 71% yield mp:260-263 ℃.

¹H NMR(CDCl₃)(ppm):10.46(brs,1H),8.22(d,J＝8.8Hz,1H),7.45(d,J＝2.0Hz,1H),7.38(d,J＝7.6Hz,2H),7.23-7.24(m,1H),6.81(d,J＝8.8Hz,1H),6.78(s,1H),4.44(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H).

b) 4- ((4-trifluoromethoxy-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((4-trifluoromethoxy-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 110mg of a red-orange powdery solid in 98% yield mp:255-258 ℃.

¹H NMR(DMSO-d₆)(ppm):13.43(brs,1H),10.87(s,1H),9.72(s,1H),8.18(d,J＝9.2Hz,1H),7.21(d,J＝0.8Hz,1H),7.65(d,J＝2.0Hz,1H),7.62(d,J＝8.8Hz,1H),7.16(dd,J₁＝2.4Hz,J₂＝9.2Hz,1H),6.92(d,J＝8.8Hz,1H).

c) 4- ((4-trifluoromethoxy-3-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((4-trifluoromethoxy-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, was as described in c) to give 69mg of a solid as an orange-red powder in 99% yield, mp:274-277 ℃.

¹H NMR(DMSO-d₆)(ppm):12.94(brs,1H),11.93(brs,1H),9.73(s,1H),8.19(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,2H),7.81(s,1H),7.63-7.60(m,2H),7.45(dd,J₁＝2.0Hz,J₂＝8.8Hz,1H),7.17(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,1H),3.86(s,3H).

Example 68- ((3-Difluoromethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-Difluoromethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation process was the same as that described in a) of example 3 using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-difluoromethoxyaniline as starting materials to give a solid as an orange-red powder of 180mg with a yield of 83% and mp:226-228 ℃.

¹H NMR(CDCl₃)(ppm):10.48(brs,1H),8.21(d,J＝8.7Hz,1H),7.42(t,J＝8.1Hz,1H),7.34(d,J＝2.4Hz,1H),7.17(d,J＝7.8Hz,1H),7.10(s,1H),6.99(d,J＝8.7Hz,1H),6.84(d,J＝8.7Hz,1H),6.71(s,1H),6.56(d,J＝73.2Hz,1H),4.45(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

b) 4- ((3-difluoromethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-difluoromethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 109mg of an orange powdery solid in 95% yield mp:243-245 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(brs,1H),10.81(s,1H),9.71(s,1H),8.15(d,J＝8.8Hz,1H),7.76(d,J＝2.0Hz,1H),7.49(t,J＝8.4Hz,1H),7.30(s,1H),7.28(t,J＝81.2Hz,1H),7.18(s,1H),7.00(d,J＝6.8Hz,1H),6.86(d,J＝9.2Hz,1H).

c) 4- ((3-difluoromethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-difluoromethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 49mg of an orange powdery solid in 80% yield mp:259-261 ℃.

¹H NMR(DMSO-d₆)(ppm):12.93(brs,1H),11.91(s,1H),9.71(s,1H),8.17(d,J＝9.2Hz,1H),7.98(d,J＝8.8Hz,2H),7.83(s,1H),7.48(t,J＝8.0Hz,1H),7.28(t,J＝74.0Hz,1H),7.17(d,J＝8.8Hz,2H),7.15(s,1H),7.00(d,J＝8.4Hz,1H),6.83(d,J＝9.2Hz,1H),3.86(s,3H),.

Example 69 4- ((3-Acylaminophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-Acylaminophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and 3-acetaminoaniline, gave 170mg of a brick-red solid in 54% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.91(s,1H),10.05(s,1H),9.69(s,1H),8.12(d,J＝9.3Hz,1H),7.85-7.86(m,1H),7.79(s,1H),7.29-7.35(m,2H),7.04(d,J＝6.9Hz,1H),6.77(d,J＝9.3Hz,1H),4.37(q,J＝7.2Hz,2H),2.05(s,3H),1.35(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₉H₁₉N₄O₅[M+H⁺]:383.1350,found383.1336.

b) 4- ((3-Acylaminophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-acetylaminophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give a reddish-brown solid 100mg in 98% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.72(s,1H),10.08(s,1H),9.69(s,1H),8.11(d,J＝9.2Hz,1H),7.78(m,2H),7.33-7.36(m,2H),7.04(d,J＝5.6Hz,1H),6.75(d,J＝8.8Hz,1H),2.05(s,3H)；HRMS(ESI):m/z,calcd for C₁₇H₁₅N₄O₅[M+H⁺]:355.1037,found 355.1033.

c) 4- ((3-Acylaminophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-acetamidophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 15mg of a yellow powdery solid in 42% yield mp:235-237 ℃.

¹HNMR(DMSO-d₆)(ppm):12.92(brs,1H),10.04(s,1H),9.64(s,1H),8.09(s,1H),7.93(s,2H),7.75(s,2H),7.33(d,2H),7.11(s,2H),7.03(s,1H),6.73(d,J＝8.8Hz,1H),3.84(s,3H),2.05(s,3H).

Example 70- ((3-carbamoylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-carbamoylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-carbamoylaniline, gave 265mg of a yellow solid in 77% yield mp:232-234 ℃.

¹H NMR(DMSO-d₆)(ppm):11.24(brs,1H),10.60(brs,1H),8.32(d,J＝8.8Hz,1H),8.02(d,J＝8.8Hz,1H),7.94(s,1H),7.19(t,J＝7.6Hz,1H),7.13-7.10(m,2H),6.80(t,J＝8.0Hz,1H),5.38(s,2H),4.38(q,J＝6.8Hz,2H),1.35(t,J＝6.8Hz,3H).

b) 4- ((3-carbamoylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((3-carbamoylphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 33mg of a yellow solid in 71% yield, mp:218-220 ℃.

¹H NMR(DMSO-d₆)(ppm):11.08(brs,1H),10.72(brs,1H),8.33(d,J＝9.2Hz,1H),8.03(d,J＝8.8Hz,1H),7.86(s,1H),7.56(d,J＝6.8Hz,1H),7.50(s,1H),7.42(t,J＝7.6Hz,1H),7.17(d,J＝6.8Hz,1H).

c) 4- ((3-carbamoylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- ((3-carbamoylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 10mg of a yellow powdery solid in 16% yield mp:270-272 ℃.

¹H NMR(DMSO-d₆)(ppm):9.59(brs,1H),8.13-8.01(m,2H),7.86(m,3H),7.67(m,2H),7.51-7.41(m,4H),6.98(m,2H),6.78-6.72(m,2H),3.80(s,3H).

Example 71- ((3-ethylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-ethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation procedure was the same as that described in a) of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-ethylaniline as starting materials, to give a red-orange powder as a solid 116mg, with a yield of 59%, mp:156-157 ℃.

¹H NMR(DMSO-d₆)(ppm):10.46(s,1H),8.17(d,J＝8.8Hz,1H),7.35(t,J＝7.6Hz,2H),7.15(s,2H),7.10(d,J＝7.6Hz,1H),6.81(s,1H),4.44(q,J＝7.2Hz,2H),2.69(q,J＝7.6Hz,2H),1.43(t,J＝7.2Hz,3H),1.44(t,J＝7.2Hz,3H).

b) 4- ((3-ethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-ethylphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3, giving 80mg of a yellow powdery solid in 96% yield mp:258-260 ℃.

¹HNMR(DMSO-d₆)(ppm):10.28(s,1H),9.47(s,1H),8.01(d,J＝9.2Hz,1H),7.34(t,J＝7.6Hz,2H),7.21(d,J＝10.4Hz,2H),7.04(d,J＝7.2Hz,1H),6.70(d,J＝8.8Hz,1H),2.64(q,J＝7.2Hz,2H),1.21(t,J＝7.2Hz,3H).

c) 4- ((3-ethylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-ethylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 33mg of a yellow powdery solid in 54% yield mp:231-233 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.88(brs,1H),9.65(s,1H),8.14(d,J＝9.2Hz,1H),7.98(d,J＝8.4Hz,2H),7.83(s,1H),7.36(t,J＝7.6Hz,1H),7.22-7.13(m,4H),7.08(d,J＝7.6Hz,1H),6.69(d,J＝8.8Hz,1H),3.86(s,3H),2.63(q,J＝7.2Hz,2H),1.20(t,J＝7.2Hz,3H).

Example 72- ((3- (methoxymethyl) phenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3- (methoxymethyl) phenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3- (methoxymethyl) aniline as starting materials was as described in a) of example 3 to give 159mg of a yellow powdery solid in 77% yield mp:171-173 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.18(d,J＝9.3Hz,1H),7.42(t,J＝7.8Hz,1H),7.35(d,J＝1.8Hz,1H),7.32(s,1H),7.19-7.24(m,2H),6.82(s,1H),6.76(d,J＝9.0Hz,1H),4.49(s,2H),4.44(q,J＝7.2Hz,2H),3.44(s,3H),1.43(t,J＝6.9Hz,3H).

b) 4- ((3- (methoxymethyl) phenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((3- (methoxymethyl) phenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 97mg of a tan powdery solid in 87% yield mp:248-250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.33(brs,1H),10.75(s,1H),9.67(s,1H),8.13(d,J＝9.2Hz,1H),7.76(d,J＝1.2Hz,1H),7.44(t,J＝7.6Hz,1H),7.32(d,J＝7.6Hz,2H),7.17(d,J＝7.6Hz,1H),6.74(d,J＝9.2Hz,1H),4.46(s,2H),3.32(s,3H).

c) 4- ((3- (methoxymethyl) phenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 4- ((3- (methoxymethyl) phenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, is as described in c) of example 3, gives 42mg of a yellow powdery solid in 64% yield mp:230-232 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.90(s,1H),9.69(s,1H),8.15(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,2H),7.84(s,1H),7.42(t,J＝7.6Hz,1H),7.30(d,J＝7.2Hz,2H),7.18-7.11(m,3H),6.71(d,J＝9.2Hz,1H),4.45(s,2H),3.86(s,3H),3.31(s,3H).

Example 73- ((3-Morpholinylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-Morpholinylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-morpholinylaniline as starting materials, was as described in example 3 a) to give 182mg of a yellow powder as a solid in 79% yield, mp:186-188 ℃.

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.18(d,J＝9.0Hz,1H),7.35-7.31(m,2H),6.83-6.76(m,5H),4.45(q,J＝7.2Hz,2H),3.88(t,J＝4.2Hz,4H),3.20(t,J＝4.2Hz,4H),1.44(t,J＝6.9Hz,3H).

b) 4- ((3-morpholinylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-morpholinophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 110mg of a yellow powdery solid in 103% yield mp:188-190 ℃.

¹H NMR(DMSO-d₆)(ppm):10.73(s,1H),9.72(s,1H),8.12(d,J＝9.0Hz,1H),7.78(d,J＝2.1Hz,1H),7.36(t,J＝8.1Hz,1H),7.10(s,1H),6.97(m,2H),6.77(d,J＝9.6Hz,1H),3.81(m,4H),3.23(m,4H).

c) 4- ((3-Morpholinylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-morpholinophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 70mg of an orange powdery solid in 97% yield mp:188-189 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.90(s,1H),9.64(s,1H),8.14(d,J＝9.3Hz,1H),7.98(d,J＝8.4Hz,2H),7.84(s,1H),7.31(t,J＝7.8Hz,1H),7.18(d,J＝8.7Hz,2H),6.92(s,1H),6.85(t,J＝7.8Hz,2H),6.72(d,J＝9.0Hz,1H),3.86(s,3H),3.75(m,4H),3.15(m,4H)；HRMS(ESI):m/z,calcd.forC₂₆H₂₆N₅O₇S[M+H]⁺:552.1553,found 552.1538.

Example 74- ((4-Morpholinylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-Morpholinylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of starting material 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 4-morpholinylaniline was carried out as described in example 3 under a) to give 197mg of a yellow powdery solid in 86% yield mp 262-265 ℃.

¹H NMR(acetone-d₆)(ppm):10.58(brs,1H),8.76(brs,1H),8.14(d,J＝9.0Hz,1H),7.68(d,J＝2.4Hz,1H),7.33(d,J＝8.7Hz,2H),7.09(d,J＝8.7Hz,2H),6.65(dd,J₁＝2.7Hz,J₂＝9.3Hz,1H),4.41(q,J＝7.2Hz,2H),3.81(t,J＝4.8Hz,4H),3.20(q,J＝4.8Hz,4H),1.40(t,J＝6.9Hz,3H).

b) 4- ((4-morpholinylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((4-morpholinylphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 106mg of a yellow powdery solid in 99% yield mp:196-198 ℃.

¹H NMR(DMSO-d₆)(ppm):10.70(brs,1H),9.67(s,1H),8.09(d,J＝9.2Hz,1H),7.75(s,1H),7.32(d,J＝8.4Hz,2H),7.26(m,2H),6.58(d,J＝8.8Hz,1H),3.85(s,4H),3.26(s,4H).

c) 4- ((4-Morpholinylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((4-morpholinophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 56mg of an orange powdery solid in 78% yield mp:180-182 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.89(s,1H),9.67(s,1H),8.11(d,J＝9.0Hz,1H),7.98(d,J＝9.0Hz,2H),7.83(d,J＝1.8Hz,1H),7.28(d,J＝9.0Hz,2H),7.18(d,J＝8.7Hz,4H),6.54(d,J＝9.0Hz,1H),3.86(s,3H),3.82(s,4H),3.22(s,4H).

Example 75- ((3- ((tert-Butoxycarbonyl) amino) phenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester (200mg, 0.744mmol) was dissolved in toluene (12mL), and Pd was added sequentially₂(dba)₃(34mg, 0.037mmol), Davephos (29mg, 0.074mmol) and K₃PO₄(474mg，2.23mmol，2.5mL H₂O), stirring well, adding N-Boc-m-phenylenediamine (310mg, 1.49mmol), refluxing under argon for 1h, cooling to room temperature, concentrating, adding EA (30mL) to dissolve the residue, washing with saturated brine (20mL × 3), washing with water (20mL × 2), performing column chromatography (P/E ═ 10:1-D) to obtain a yellow powdery solid, washing with a P/E ═ 10:1 mixed solution (2mL), filtering, and drying to obtain 266mg of a yellow powdery solid with a yield of 81%, mp:205-207 ℃.

¹H NMR(CDCl₃)(ppm):10.46(brs,1H),8.18(d,J＝8.8Hz,1H),7.61(s,1H),7.34-7.30(m,2H),6.70(d,J＝8.0Hz,2H),6.82(d,J＝8.8Hz,1H),6.78(s,1H),6.56(s,1H),4.45(q,J＝7.2Hz,2H),1.52(s,9H),1.44(t,J＝7.2Hz,3H).

b) 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 65mg of a yellow powdery solid in 98% yield mp:210-212 ℃.

¹H NMR(DMSO-d₆)(ppm):13.38(s,1H),10.71(s,1H),9.64(s,1H),9.49(s,1H),8.11(d,J＝5.2Hz,1H),7.74(s,1H),7.61(s,1H),7.31(t,J＝8.0Hz,1H),7.26(d,J＝8.0Hz,1H),6.74(d,J＝9.2Hz,1H),1.48(s,9H).

c) 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure was as described in c) of example 3, starting from 4- ((3- ((tert-butoxycarbonyl) amino) phenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide to give 67mg of an orange powdery solid in 73% yield mp:213-215 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.87(brs,1H),9.67(s,1H),9.48(s,1H),8.13(d,J＝9.2Hz,1H),7.98(d,J＝8.4Hz,2H),7.85(s,1H),7.58(s,1H),7.30(t,J＝8.0Hz,1H),7.25(d,J＝7.6Hz,1H),7.17(d,J＝8.4Hz,2H),6.96(d,J＝7.2Hz,1H),6.71(d,J＝9.2Hz,1H),3.86(s,3H),1.47(s,9H).

Example 76- ((3-aminophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

4- ((3- ((tert-Butoxycarbonyl) amino) phenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide (23mg, 0.040mmol) was dissolved in DCM (2mL) and TFA (1mL) was added and reacted at room temperature for 2H. The solvent was evaporated, 3mL of ether was added, sonicated, filtered, and dried to give 18mg of an orange-red powdery solid with a yield of 95% mp:235-237 ℃.

¹H NMR(DMSO-d₆)(ppm):11.90(s,1H),9.61(s,1H),8.14(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,2H),7.84(s,1H),7.23-7.16(m,3H),6.82(m,2H),6.73(d,J＝9.2Hz,1H),6.68(d,J＝6.8Hz,1H),3.86(s,3H).

Example 77-Nitro-4-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 7-nitro-4-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide as starting materials, gave 300mg of a yellow powdery solid in 98% yield, mp:246-248 ℃.

¹H NMR(DMSO-d₆)(ppm):11.94(s,1H),8.26(d,J＝8.4Hz,1H),7.96(d,J＝8.4Hz,2H),7.58(s,1H),7.44(d,J＝8.4Hz,1H),7.15(d,J＝8.8Hz,2H),3.84(s,3H).

Example 78- ((3-hydroxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure used in example 3, starting from 7-nitro-4-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide and 3-acetoxyaniline, gave 90mg of an orange-yellow powder as a solid in 85% yield, mp:185-187 ℃.

¹H NMR(DMSO-d₆)(ppm):12.90(s,1H),11.84(s,1H),9.62(s,1H),9.55(s,1H),8.12(d,J＝9.2Hz,1H),7.95(d,J＝8.0Hz,2H),7.78(brs,1H),7.22(t,J＝8.0Hz,1H),7.14(d,J＝6.8Hz,2H),6.79(d,J＝8.0Hz,1H),6.75(s,1H),6.73(d,J＝9.2Hz,1H),6.62(d,J＝8.0Hz,1H),3.85(s,3H)；¹³C NMR(125MHz,DMSO-d₆):158.31,147.23,140.19,130.22,130.04,123.90,116.71,114.11,113.57,112.08,109.81,102.26,55.74.HRMS(ESI):m/z,calcd for C₂₂H₁₉N₄O₇S[M+H⁺]:483.0974,found 483.0959.

Example 79 4- (pyridin-3-ylamino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (pyridin-3-ylamino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-aminopyridine as starting materials, was as described in example 3 a) to give 221mg of a yellow solid in 73% yield mp:201-203 ℃.

¹H NMR(DMSO-d₆)(ppm):10.98(s,1H),9.67(s,1H),8.63(s,1H),8.40(d,J＝4.4Hz,1H),8.13(d,J＝9.2Hz,1H),7.82(d,J＝9.2Hz,1H),7.81(s,1H),7.47(dd,J₁＝4.8Hz,J₂＝8.0Hz,1H),6.75(d,J＝9.2Hz,1H),4.37(q,J＝6.8Hz,2H),1.36(t,J＝7.2Hz,3H).

b) 4- (pyridin-3-ylamino) -7-nitro-1H-indole-2-carboxylic acid

Starting from 4- (pyridin-3-ylamino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 115mg of a yellow solid in 100% yield mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.96(brs,1H),10.52(brs,1H),8.90(s,1H),8.54(d,J＝5.2Hz,1H),8.47(d,J＝8.4Hz,1H),8.18(d,J＝8.8Hz,1H),7.94(dd,J₁＝5.8Hz,J₂＝8.0Hz,1H),7.83(s,1H),7.08(t,J＝8.8Hz,1H).

c) 4- (pyridin-3-ylamino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- (pyridin-3-ylamino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) of example 3 to give 51mg of an orange powdery solid in 81% yield mp:257-260 ℃.

¹H NMR(DMSO-d₆)(ppm):11.88(s,1H),9.96(s,1H),8.67(s,1H),8.43(s,1H),8.16(d,J＝8.8Hz,1H),7.98(d,J＝8.4Hz,2H),7.88(s,2H),7.52(s,1H),7.17(d,J＝8.0Hz,2H),6.76(d,J＝8.8Hz,1H),3.86(s,3H).

EXAMPLE 80 4- (pyridin-4-ylamino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (pyridin-4-ylamino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used in example 3, starting from 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 4-aminopyridine, gives 258mg of a yellow solid in 85% yield mp:227-229 ℃.

¹H NMR(DMSO-d₆)(ppm):11.16(s,1H),9.78(s,1H),8.46(m,2H),8.21(d,J＝8.8Hz,1H),7.80(s,1H),7.33(d,J＝5.2Hz,2H),7.17(d,J＝8.8Hz,1H),4.37(q,J＝6.8Hz,2H),1.36(t,J＝7.2Hz,3H).

b) 4- (pyridin-4-ylamino) -7-nitro-1H-indole-2-carboxylic acid

Starting from 4- (pyridin-4-ylamino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 115mg of a yellow solid in 97% yield mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.35(s,1H),11.19(s,1H),8.47(d,J＝6.8Hz,2H),8.33(d,J＝8.8Hz,1H),7.56(s,1H),7.52(d,J＝6.4Hz,2H),7.39(d,J＝8.8Hz,1H).

c) 4- (pyridin-4-ylamino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- (pyridin-4-ylamino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) of example 3 to give 35mg of an orange powdery solid in 56% yield mp:255-258 ℃.

¹H NMR(DMSO-d₆)(ppm):10.23(s,1H),9.64(s,1H),8.42(d,J＝6.0Hz,2H),8.10(d,J＝8.7Hz,2H),7.80(d,J＝9.0Hz,2H),7.35(s,1H),7.30(d,J＝5.7Hz,2H),7.11(d,J＝9.3Hz,1H),6.93(d,J＝8.7Hz,2H),3.78(s,3H).

Example 81 4- (3-Methoxyphenoxy) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (3-Methoxyphenoxy) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

Ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate (150mg, 0.56mmol) was dissolved in DME (2mL), and potassium carbonate (139mg, 1.12mmol) and 3-methoxyphenol (139mg, 1.12mmol) were added in that order and reacted by microwave (60w, 130 ℃, 45min, 150 psi). To the reaction mixture was added water (30mL), EA (20mL × 2) for extraction, washed with saturated brine (20mL × 3), washed with water (20mL × 3), and subjected to column chromatography (P/E20: 1) to give 144mg of a yellow powdery solid in 73% yield, mp:73-75 ℃.

¹H NMR(CDCl₃)(ppm):10.39(brs,1H),8.20(d,J＝9.2Hz,1H),7.46(s,1H),7.35(t,J＝8.0Hz,1H),6.84(d,J＝8.0Hz,1H),7.74(d,J＝8.4Hz,1H),6.72(s,1H),6.52(d,J＝8.8Hz,1H),4.46(q,J＝7.2Hz,2H),3.82(s,3H),1.44(t,J＝7.2Hz,3H).

b) 4- (3-methoxyphenoxy) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- (3-methoxyphenoxy) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 171mg of a yellow powdery solid in 71% yield mp:203-205 ℃.

¹H NMR(DMSO-d₆)(ppm):13.57(brs,1H),11.22(s,1H),8.26(d,J＝9.2Hz,1H),7.42(t,J＝8.4Hz,1H),7.25(s,1H),6.92(d,J＝8.0Hz,1H),6.88(s,1H),6.82(d,J＝8.0Hz,1H),6.58(d,J＝9.2Hz,1H),3.78(s,3H).

c) 4- (3-methoxyphenoxy) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- (3-methoxyphenoxy) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 78mg of a pale yellow powdery solid in 86% yield mp:242-244 ℃.

¹H NMR(DMSO-d₆)(ppm):12.90(brs,1H),11.79(s,1H),8.27(d,J＝9.2Hz,1H),7.97(d,J＝8.8Hz,2H),7.52(s,1H),7.41(d,J＝8.4Hz,1H),7.17(d,J＝8.8Hz,2H),6.92(d,J＝8.4Hz,1H),6.85(s,1H),6.79(d,J＝8.0Hz,1H),6.56(d,J＝8.8Hz,1H),3.86(s,3H),3.77(s,3H)；HRMS(ESI):m/z,calcd.for C₂₃H₂₀N₃O₈S[M+H]⁺:498.0971,found498.0957.

Example 82 4-benzoyl-7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4-benzyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester

4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester (100mg, 0.37mmol), Pd (dppf) Cl₂(27mg，0.037)、K₃PO₄(237mg, 1.12mmol), CsF (57mg, 0.37mmol) and benzylboronic acid pinacol ester (243mg, 1.12mmol) were dissolved in 1,4-dioxane (2mL) and water (0.5mL), protected by argon, and reacted by microwave (60w, 100 ℃, 120min, 150 p)si). concentration, the residue was dissolved by adding EA (30mL), washed with saturated brine (20mL × 3), washed with water (20mL × 2), and column chromatographed (P/E200: 1-100:1) to give 88mg of an off-white solid in 58% yield, mp:126-128 ℃.

¹H NMR(acetone-d₆)(ppm):10.74(brs,1H),8.27(d,J＝8.4Hz,1H),7.55(s,1H),7.36-7.29(m,4H),7.24-7.22(m,2H),4.47(s,2H),4.43(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H).

b) 4-benzoyl-7-nitro-1H-indole-2-carboxylic acid

Starting from 4-benzyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3, giving 40mg of a brown powdery solid in 60% yield, mp:179-182 ℃.

¹H NMR(DMSO-d₆)(ppm):11.51(s,1H),8.36(d,J＝8.0Hz,1H),7.80(d,J＝7.6Hz,2H),7.74(t,J＝7.6Hz,1H),7.59(t,J＝7.2Hz,2H),7.55(d,J＝8.0Hz,1H),7.21(s,1H)；HRMS(ESI):m/z,calcd for C₁₆H₁₁N₂O₅[M+H⁺]:311.0668,found311.0653.

c) 4-benzoyl-7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 4-benzoyl-7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, gave 15mg of a yellow powdery solid in 38% yield mp:235-237 ℃.

¹H NMR(DMSO-d₆)(ppm):12.98(brs,1H),11.94(s,1H),8.39(d,J＝8.4Hz,1H),7.96(d,J＝8.8Hz,2H),7.79-7.73(m,3H),7.59(t,J＝7.6Hz,2H),7.55(t,J＝8.0Hz,2H),7.16(d,J＝8.8Hz,2H),3.85(s,3H)；HRMS(ESI):m/z,calcd forC₂₃H₂₇N₃O₇S[M+H⁺]:480.0865,found 480.0844.

Example 83- ((3-Methoxybenzene) thio) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxybenzene) thio) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 81 was carried out using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxythiophenol as starting materials to give 188mg of a yellow powder as a solid in 56% yield mp:119-120 ℃.

¹H NMR(acetone-d₆)(ppm):10.48(brs,1H),8.18(d,J＝8.4Hz,1H),7.47(t,J＝8.0Hz,1H),7.38(s,1H),7.20(d,J＝7.2Hz,2H),7.11(d,J＝9.2Hz,1H),6.85(d,J＝8.4Hz,1H),4.44(q,J＝7.2Hz,2H),3.85(s,3H),1.42(t,J＝7.2Hz,3H).

b) 4- ((3-methoxybenzene) thio) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxybenzene) thio) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3, giving 110mg of a pale yellow powdery solid in 99% yield, mp:188-190 ℃.

¹H NMR(DMSO-d₆)(ppm):11.19(s,1H),8.16(d,J＝8.4Hz,1H),7.45(t,J＝8.1Hz,1H),7.22(s,1H),7.17-7.09(m,3H),6.78(d,J＝8.4Hz,1H),3.78(s,3H).

c) 4- ((3-methoxybenzene) thio) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxybenzene) thio) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 50mg of a pale yellow powdery solid in 73% yield mp:200-202 ℃.

¹H NMR(DMSO-d₆)(ppm):12.88(brs,1H),11.81(s,1H),8.48(d,J＝9.0Hz,1H),7.98(d,J＝9.0Hz,2H),7.59(s,1H),7.45(t,J＝7.2Hz,1H),7.19-7.10(m,5H),6.75(d,J＝8.4Hz,1H),3.86(s,1H),3.78(s,3H).

Example 84- ((3-trifluoromethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxyphenyl) (methyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75 was followed using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxy-N-methylaniline as starting materials to give 124mg of an orange solid in 53% yield mp:101-103 ℃.

¹H NMR(CDCl₃)(ppm):10.44(brs,1H),8.22(d,J＝9.6Hz,1H),7.36(t,J＝8.4Hz,1H),6.90(dd,J₁＝2.1Hz,J₂＝8.7Hz,1H),6.83(dd,J₁＝1.2Hz,J₂＝8.1Hz,1H),6.77(t,J＝2.1Hz,1H),6.50(d,J＝9.0Hz,1H),6.26(d,J＝2.7Hz,1H),4.34(q,J＝7.2Hz,2H),3.81(s,3H),3.60(s,3H),1.35(t,J＝7.5Hz,3H).

b) 4- ((3-methoxyphenyl) (methyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting with ethyl 4- ((3-methoxyphenyl) (methyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) in example 3 to give 90mg of a yellow solid in 98% yield mp:213-215 ℃.

¹H NMR(DMSO-d₆)(ppm):10.61(s,1H),8.19(d,J＝9.0Hz,1H),7.40(t,J＝8.1Hz,1H),6.99(d,J＝8.4Hz,1H),6.94(s,1H),6.88(d,J＝6.9Hz,1H),6.69(d,J＝9.3Hz,1H),5.92(s,1H),3.76(s,3H),3.55(s,3H).

c) 4- ((3-trifluoromethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) (methyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 73mg of an orange powdery solid in 90% yield mp:245-247 ℃.

¹H NMR(DMSO-d₆)(ppm):12.82(brs,1H),11.66(s,1H),8.19(d,J＝9.2Hz,1H),7.90(d,J＝8.8Hz,2H),7.37(t,J＝8.0Hz,1H),7.14(d,J＝8.4Hz,2H),6.96(d,J＝8.4Hz,1H),6.90(s,1H),6.82(d,J＝7.6Hz,1H),6.61(d,J＝9.2Hz,1H),6.37(s,1H),3.85(s,3H),3.75(s,3H),3.55(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.21,160.54,150.49,148.33,132.52,130.86,130.21,126.41,124.04,118.24,116.51,114.31,112.78,111.76,105.90,55.79,55.39,42.93.HRMS(ESI):m/z,calcd.for C₂₄H₂₃N₄O₇S[M+H]⁺:511.1287,found511.1277.

Example 85- ((3-methoxybenzyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxybenzyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxybenzylamine as starting materials was carried out as described in example 81 under a) to give a yellow powdery solid 270mg in 98% yield mp:162-163 ℃.

¹H NMR(CDCl₃)(ppm):10.44(brs,1H),8.19(d,J＝8.7Hz,1H),7.31(t,J＝8.1Hz,1H),7.28(d,J＝7.8Hz,1H),6.96(d,J＝7.5Hz,1H),6.91-6.87(m,2H),6.29(d,J＝9.0Hz,1H),5.46(brs,1H),4.59(s,2H),4.42(q,J＝7.2Hz,2H),3.81(s,3H),1.42(t,J＝6.9Hz,3H).

b) 4- ((3-methoxybenzyl) amino) -7-nitro-1H-indole-2-carboxylic acid

The procedure of example 3, using 4- ((3-methoxybenzyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester as starting material, was as in b) to give 140mg of a pale yellow powdery solid in 98% yield mp:235-237 ℃.

¹H NMR(DMSO-d₆)(ppm):13.26(brs,1H),10.60(s,1H),8.60(t,J＝6.0Hz,1H),8.05(d,J＝8.8Hz,1H),7.73(s,1H),7.26(d,J＝8.0Hz,1H),6.94(d,J＝7.2Hz,1H),6.83(d,J＝8.0Hz,1H),6.33(d,J＝9.2Hz,1H),4.60(d,J＝6.0Hz,2H),3.73(s,3H).

c) 4- ((3-methoxybenzyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxybenzyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 55mg of a pale yellow powdery solid in 92% yield mp:233-234 ℃.

¹H NMR(DMSO-d₆)(ppm):12.86(brs,1H),11.78(brs,1H),8.62(t,J＝5.6Hz,1H),8.06(d,J＝9.2Hz,1H),7.96(d,J＝8.8Hz,2H),7.81(brs,1H),7.24(t,J＝8.0Hz,1H),7.16(d,J＝8.4Hz,2H),6.91(d,J＝7.2Hz,2H),6.82(d,J＝7.6Hz,1H),6.30(d,J＝9.2Hz,1H),4.58(d,J＝6.0Hz,2H),3.86(s,3H),3.71(s,3H).

Example 86-Benzoylamino-7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4-Benzylamino-7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure is as described in example 75 under a) and starting from 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and benzamide to give 235mg of a yellow powdery solid in 89% yield mp:220-222 ℃.

¹H NMR(CDCl₃)(ppm):10.48(s,1H),8.39-8.31(m,3H),7.97(d,J＝7.6Hz,2H),7.66(t,J＝7.2Hz,1H),7.58(t,J＝7.2Hz,2H),7.38(s,1H),4.48(q,J＝7.2Hz,2H),1.46(t,J＝7.2Hz,3H).

b) 4-benzoylamino-7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4-benzoylamino-7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 72mg of a yellow powdery solid in 65% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):11.03(s,1H),10.72(s,1H),8.33(d,J＝8.8Hz,1H),8.05-8.01(m,3H),7.86(s,1H),7.66(t,J＝7.2Hz,1H),7.58(t,J＝7.6Hz,2H).

c) 4-benzoylamino-7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure used in c) of example 3 was the same as starting material 4-benzoylamino-7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide to give 46mg of an orange powdery solid in 75% yield mp:253-255 ℃.

¹H NMR(DMSO-d₆)(ppm):12.94(brs,1H),11.84(s,1H),10.75(s,1H),8.36(d,J＝8.8Hz,1H),8.02-7.94(m,6H),7.66(t,J＝7.2Hz,1H),7.58(t,J＝7.2Hz,2H),7.16(d,J＝8.8Hz,2H),3.85(s,3H).

Example 87-isobutyl-7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

a) 4-isobutyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester

4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester (250mg, 0.93mmol) was dissolved in toluene (12mL), followed by the addition of Pd (OAc) ₂(21mg，0.093mmol)，(tBu)₃P·HBF₄(54mg, 0.19mmol) and K₃PO₄(987mg，4.65mmol,1mL H₂O), stirring, adding isobutylboronic acid (284mg, 2.79mmol), reacting at 90 ℃ for 2h under the protection of argon, allowing the starting material to disappear, cooling to room temperature, concentrating, adding EA (40mL) to dissolve the residue, washing with saturated brine (20mL × 3), washing with water (20mL × 2), and performing column chromatography (P/E ═ 100:1) to obtain 216mg of off-white solid with a yield of 80% and mp:108-109 ℃.

¹H NMR(CDCl₃)(ppm):10.36(s,1H),8.23(d,J＝8.0Hz,1H),7.38(s,1H),7.05(d,J＝8.0Hz,1H),4.47(q,J＝7.2Hz,2H),2.86(d,J＝7.2Hz,2H),2.04-2.15(m,1H),1.46(t,J＝7.2Hz,2H),0.97(d,J＝7.2Hz,6H)；HRMS(ESI):m/z,calcdfor C₁₅H₁₉N₂O₄[M+H⁺]:291.1339,found 291.1331.

b) 4-isobutyl-7-nitro-1H-indole-2-carboxylic acid

The procedure of example 3, starting from 4-isobutyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester, was as described in b) to give 116mg of an off-white solid in 82% yield mp:195-197 ℃.

¹H NMR(DMSO-d₆)(ppm):13.53(s,1H),11.02(s,1H),8.21(d,J＝8.4Hz,1H),7.49(s,1H),7.15(d,J＝8.0Hz,1H),2.88(d,J＝7.2Hz,2H),1.96-2.06(m,1H),0.91(d,J＝6.4Hz,6H)；HRMS(ESI):m/z,calcd for C₁₃H₁₅N₂O₄[M+H⁺]:263.1026,found 263.1024.

c) 4-isobutyl-7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4-isobutyl-7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide as starting materials, gave 60mg of a pale yellow powdery solid in 78% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.10(brs,1H),11.64(brs,1H),8.23(d,J＝8.1Hz,1H),8.07(d,J＝7.2Hz,2H),7.76-7.68(m,4H),7.14(d,J＝7.8Hz,1H),2.84(d,J＝6.6Hz,2H),2.04-2.00(m,1H),0.90(d,J＝6.0Hz,6H).

Example 88 4- (propylamino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (propylamino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and n-propylamine as described in example 81 under a) gave 193mg of a yellow powdery solid in 71% yield, mp:155-157 ℃.

¹H NMR(CDCl₃)(ppm):10.43(brs,1H),8.21(d,J＝8.8Hz,1H),6.26(d,J＝8.8Hz,1H),5.15(s,1H),4.43(q,J＝7.2Hz,2H),3.39(t,J＝7.2Hz,2H),1.78(sext,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H),1.07(t,J＝7.2Hz,3H).

b) 4- (propylamino) -7-nitro-1H-indole-2-carboxylic acid

Starting from 4- (propylamino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 86mg of a yellow powdery solid in 96% yield mp:234-236 ℃.

¹H NMR(DMSO-d₆)(ppm):13.23(brs,1H),10.56(s,1H),8.09(d,J＝9.2Hz,1H),8.02(t,J＝5.2Hz,1H),7.71(s,1H),6.38(d,J＝7.2Hz,1H),3.34(q,J＝6.4Hz,2H),1.67(sext,J＝7.2Hz,2H),0.97(t,J＝7.2Hz,3H).

c) 4- (propylamino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- (propylamino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide as starting materials, gave 50mg of a pale yellow powdery solid in 81% yield, mp:284-286 ℃.

¹H NMR(DMSO-d₆)(ppm):12.85(brs,1H),11.75(s,1H),8.10(d,J＝8.8Hz,2H),7.97(d,J＝8.8Hz,2H),7.81(s,1H),7.16(d,J＝8.8Hz,2H),6.36(d,J＝9.2Hz,1H),3.86(s,3H),3.32(q,J＝6.0Hz,2H),1.65(sext,2H),0.94(t,J＝7.2Hz,1H).

Example 89- ((2-methoxyethyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((2-methoxyethyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 81 was carried out using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 2-methoxyethylamine as starting materials to give 178mg of a yellow powder as a solid in 78% yield mp:155-156 ℃.

¹H NMR(CDCl₃)(ppm):10.44(brs,1H),8.22(d,J＝9.0Hz,1H),7.28(d,J＝2.1Hz,1H),6.27(d,J＝9.0Hz,1H),5.45(s,1H),4.43(q,J＝7.2Hz,2H),3.71(t,J＝5.1Hz,2H),3.58(t,J＝5.1Hz,2H),3.45(s,3H),1.43(t,J＝7.2Hz,3H).

b) 4- ((2-methoxyethyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((2-methoxyethyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 98mg of a yellow powdery solid in 92% yield mp:226-228 ℃.

¹H NMR(DMSO-d₆)(ppm):13.24(brs,1H),10.57(s,1H),8.09(d,J＝8.8Hz,2H),7.72(s,1H),6.43(d,J＝9.2Hz,1H),3.58(s,4H),3.29(s,3H).

c) 4- ((2-methoxyethyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((2-methoxyethyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 40mg of a pale yellow powdery solid in 58% yield mp:208-210 ℃.

¹H NMR(DMSO-d₆)(ppm):12.83(brs,1H),11.74(s,1H),8.10(d,J＝9.2Hz,1H),8.05(s,1H),7.95(d,J＝8.4Hz,2H),7.77(s,1H),7.15(d,J＝7.6Hz,2H),6.40(d,J＝9.2Hz,1H),3.85(s,3H),3.56(s,4H),3.27(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.11,150.65,131.76,130.07,127.81,122.08,114.85,114.20,70.05,58.14,55.75,42.46.HRMS(ESI):m/z,calcd.for C₁₉H₂₁N₄O₇S[M+H]⁺:449.1131,found 449.1115.

Example 90- ((3-Methoxypropyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxypropyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxypropylamine as starting materials was as described in a) of example 81 to give 135mg of a yellow powdery solid in 56% yield mp:125-127 ℃.

¹H NMR(CDCl₃)(ppm):10.43(brs,1H),8.21(d,J＝9.0Hz,1H),7.20(d,J＝2.1Hz,1H),6.24(d,J＝9.0Hz,1H),6.01(brs,1H),4.43(q,J＝7.2Hz,2H),3.62(t,J＝5.1Hz,2H),3.54(t,J＝6.0Hz,2H),3.44(s,3H),2.05-2.01(m,2H),1.43(t,J＝7.2Hz,3H).

b) 4- ((3-methoxypropyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxypropyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 49mg of a yellow powdery solid in 76% yield mp:216-218 ℃.

¹H NMR(DMSO-d₆)(ppm):10.55(s,1H),8.08(d,J＝9.3Hz,1H),7.99(brs,1H),7.67(d,J＝2.1Hz,1H),6.36(d,J＝9.3Hz,1H),3.43-3.39(m,4H),3.24(s,3H),3.83(s,3H),1.88-1.84(m,2H).

c) 4- ((3-methoxypropyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxypropyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 38mg of a pale yellow powdery solid in 69% yield mp:249-250 ℃.

¹H NMR(DMSO-d₆)(ppm):12.86(brs,1H),11.77(s,1H),8.12(d,J＝9.2Hz,1H),8.01(brs,1H),7.97(d,J＝8.4Hz,2H),7.77(s,1H),7.16(d,J＝8.8Hz,2H),6.35(d,J＝9.2Hz,1H),3.86(s,3H),3.41(t,J＝5.6Hz,4H),3.24(s,3H),1.89-1.83(m,2H).

Example 91-morpholinyl-7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4-Morpholinyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used in example 3, starting from ethyl 4-chloro-7-nitro-1H-indole-2-carboxylate and morpholine in the presence of 4-chloro-7-nitro-1H-indole-2-carboxylate, gave 147mg of a yellow solid in 50% yield mp:167-168 ℃.

¹H NMR(CDCl₃)(ppm):10.51(s,1H),8.22(d,J＝9.2Hz,1H),7.32(d,J＝1.6Hz,1H),6.53(d,J＝8.8Hz,1H),4.46(q,J＝7.2Hz,2H),3.95(t,J＝4.4Hz,4H),3.60(t,J＝4.4Hz,4H),1.45(t,J＝7.2Hz,3H).

b) 4-morpholinyl-7-nitro-1H-indole-2-carboxylic acid

The procedure of example 3, starting from ethyl 4-morpholinyl-7-nitro-1H-indole-2-carboxylate, is as described in b) to give 115mg of a yellow solid in 99% yield mp:247-248 ℃.

¹H NMR(DMSO-d₆)(ppm):13.44(brs,1H),10.81(s,1H),8.14(d,J＝9.0Hz,1H),7.46(d,J＝1.8Hz,1H),6.70(d,J＝9.6Hz,1H),3.81(t,J＝4.5Hz,4H),3.64(t,J＝4.2Hz,4H).

c) 4-morpholinyl-7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4-morpholinyl-7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide as starting materials, was as described in c) to give 62mg of a pale yellow powdery solid in 67% yield mp:258-259 ℃.

¹H NMR(DMSO-d₆)(ppm):10.99(brs,1H),8.11(d,J＝8.8Hz,1H),7.98(d,J＝7.2Hz,2H),7.64-7.56(m,3H),7.50(brs,1H),6.65(d,J＝9.2Hz,1H),3.81(t,J＝4.0Hz,4H),3.61(t,J＝4.0Hz,4H).

Example 92 4- (N-Boc-piperazin-1-yl) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (N-Boc-piperazin-1-yl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and N-Boc-piperazine as starting materials, gave 140mg of a yellow solid in 30% yield mp:143-144 ℃.

¹H NMR(CDCl₃)(ppm):10.51(s,1H),8.21(d,J＝8.8Hz,1H),7.33(s,1H),6.49(d,J＝8.8Hz,1H),4.45(q,J＝7.2Hz,2H),3.710-3.70(m,4H),3.62(t,J＝4.0Hz,4H),1.51(s,9H),1.44(t,J＝7.2Hz,3H).

b) 4- (N-Boc-piperazin-1-yl) -7-nitro-1H-indole-2-carboxylic acid

Starting from 4- (N-Boc-piperazin-1-yl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester, the procedure is as described in b) of example 3 to give 100mg of a yellow solid in 98% yield, mp:208-210 ℃.

¹H NMR(DMSO-d₆)(ppm):13.50(brs,1H),10.79(s,1H),8.13(d,J＝8.8Hz,1H),7.45(s,1H),6.63(d,J＝9.2Hz,1H),3.72(s,4H),3.59(s,4H),1.44(s,9H).

c) 4- (N-Boc-piperazin-1-yl) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- (N-Boc-piperazin-1-yl) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, the preparation was carried out as described in c) of example 3 to give 80mg of an orange powdery solid in 67% yield, mp:240-241 ℃.

¹H NMR(DMSO-d₆)(ppm):12.90(brs,1H),11.33(s,1H),8.13(d,J＝9.2Hz,1H),8.04(d,J＝7.6Hz,2H),7.77-7.73(m,2H),7.66(t,J＝7.6Hz,2H),6.60(d,J＝9.2Hz,1H),3.71(s,4H),3.59(s,4H),1.44(s,9H).

Example 93 4- (piperazin-1-yl) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

4- (N-Boc-piperazin-1-yl) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide (23mg, 0.043mmol) was dissolved in MeOH (1mL), 2.77M HCl in 1,4-dioxane (2mL) was added and the reaction was allowed to proceed at room temperature for 30min, with the starting material disappearing and solid precipitating during stirring. Filtered and dried to give 19mg of a pale yellow powdery solid in 95% yield, mp:239-241 ℃.

¹HNMR(DMSO-d₆)(ppm):13.00(brs,1H),11.50(s,1H),9.27(s,1H),8.19(d,J＝8.8Hz,1H),8.04(d,J＝7.6Hz,2H),7.76-7.73(m,2H),7.66(t,J＝7.6Hz,2H),6.74(d,J＝9.2Hz,1H),3.79(s,4H),3.33(s,4H).

Example 94 4- (cyclohexylamino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (cyclohexylamino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester and cyclohexylamine as starting materials was carried out as described under a) in example 3 to give 130mg of a yellow solid in 53% yield mp:175-178 ℃.

¹H NMR(CDCl₃)(ppm):10.44(s,1H),8.20(d,J＝8.8Hz,1H),7.24(s,1H),6.28(d,J＝9.2Hz,1H),5.01(d,J＝7.2Hz,1H),4.43(d,J＝7.2Hz,1H),3.62-3.60(m,1H),2.14(d,J＝11.6Hz,2H),1.84(d,J＝13.2Hz,2H),1.72(d,J＝15.5Hz,2H),1.51-1.28(m,8H).

b) 4- (cyclohexylamino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- (cyclohexylamino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 70mg of a yellow solid in 73% yield mp:205-208 ℃.

¹H NMR(DMSO-d₆)(ppm):13.21(s,1H),10.54(s,1H),8.06(m,1H),7.79(s,1H),7.72(m,1H),6.42(m,1H),3.62(m 1H),3.34(m,2H),1.97(m,2H),1.77(m,2H),1.66(m,1H),1.38(m,3H),1.23(m,2H).

c) 4- (cyclohexylamino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- (cyclohexylamino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3, giving 45mg of an orange powdery solid in 73% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.81(s,1H),11.74(s,1H),8.09(d,J＝8.8Hz,1H),7.96(d,J＝8.0Hz,2H),7.87(s,1H),7.73(d,J＝6.8Hz,1H),7.16(d,J＝8.4Hz,2H),6.40(d,J＝9.2Hz,1H),3.85(s,3H),3.60(s,1H),1.99-1.95(m,2H),1.75(m,2H),1.64(d,J＝11.2Hz,1H),1.37-1.35(m,4H),1.18(m,1H).

Preparation of intermediate 2:

5-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester

a) 4-methyl-2-nitro-5-chlorophenylhydrazine hydrochloride

The 4-methyl-2-nitro-5-chloroaniline hydrochloride is used as the starting material, and the preparation process is the same as that of the method in a) in the preparation 1 of the intermediate, so that 6.24g of light yellow solid is obtained, and the yield is 98%.

¹H NMR(DMSO-d₆)(ppm):9.19(s,1H),8.15(s,1H),7.51(s,1H),2.31(s,3H).

b) Ethyl 2- (2- (4-methyl-2-nitro-5-chlorophenyl) hydrazono) propionate

The preparation process is the same as that of the b) in the preparation 1 of the intermediate by using 4-methyl-2-nitro-5-chlorophenylhydrazine hydrochloride and ethyl pyruvate as starting materials to obtain 6.73g of light yellow solid, and the yield is 84%.

¹H NMR(CDCl₃)(ppm):10.82(s,1H),8.08(s,1H),8.03(s,1H),4.37(q,J＝6.8Hz,2H),2.37-2.36(m,3H),2.26-2.23(m,3H),1.41(t,J＝6.8Hz,3H).

c) 5-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester

Using ethyl 2- (2- (4-methyl-2-nitro-5-chlorophenyl) hydrazono) propionate as starting material, the preparation process was the same as that described in c) in preparation 1 of the intermediate, yielding 846mg of a pale yellow solid, 13% yield, mp:179-180 ℃.

¹H NMR(CDCl₃)(ppm):10.28(brs,1H),8.18(s,1H),7.40(s,1H),4.47(q,J＝7.2Hz,2H),2.55(s,3H),1.45(t,J＝7.2Hz,3H).

Example 95-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 5-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75 was carried out using 5-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials to give 220mg of a yellow powdery solid in 84% yield mp:190-192 ℃.

¹H NMR(CDCl₃)(ppm):10.32(brs,1H),8.18(s,1H),7.27(t,J＝8.0Hz,1H),6.77(d,J＝8.4Hz,1H),6.72(d,J＝8.0Hz,1H),6.66(d,J＝6.0Hz,2H),6.29(brs,1H),4.36(q,J＝7.2Hz,2H),3.79(s,3H),2.38(s,3H),1.36(t,J＝7.2Hz,3H).

b) 5-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 5-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 80mg of a yellow powdery solid in 64% yield mp:250-253 ℃.

¹H NMR(DMSO-d₆)(ppm):13.29(brs,1H),10.64(s,1H),8.80(s,1H),8.13(s,1H),7.27(t,J＝8.4Hz,1H),6.76(d,J＝8.4Hz,1H),6.68-6.70(m,2H),6.53(s,1H),3.73(s,3H),2.31(s,3H).

c) 5-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 5-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide in c), gave 60mg of a yellow powdery solid in 91% yield mp:215-217 ℃.

¹H NMR(DMSO-d₆)(ppm):12.83(brs,1H),11.64(brs,1H),8.76(s,1H),8.15(s,1H),7.90(d,J＝8.4Hz,2H),7.24(t,J＝8.0Hz,1H),7.13(d,J＝8.4Hz,2H),6.75-6.72(m,2H),6.65(s,1H),6.62(d,J＝8.0Hz,1H),3.84(s,3H),3.71(s,3H),2.30(s,3H).

Preparation of intermediate 3: 7-Nitro-4, 5-dichloro-1H-indole-2-carboxylic acid ethyl ester

a) 2-nitro-4, 5-dichlorohydrazinium hydrochloride

2-nitro-4, 5-chlorophenylhydrazine hydrochloride is used as a starting material, and the preparation process is the same as that of the method in a) in the preparation 1 of the intermediate, so that 2.8g of light yellow solid is obtained, and the yield is 45%.

¹H-NMR(DMSO-d₆)(ppm):9.36(s,1H),8.29(s,1H),7.72(s,1H).

b) Ethyl 2- (2- (2-nitro-4, 5-dichlorophenyl) hydrazono) propionate

2-nitro-4, 5-dichlorophenylhydrazine hydrochloride and ethyl pyruvate are used as starting materials, and the preparation process is the same as that of the method b) in the preparation 1 of the intermediate, so that 2.0g of light yellow solid is obtained, and the yield is 58%.

¹H NMR(CDCl₃)(ppm):10.82(s,1H),8.32(s,1H),8.15(s,1H),4.37(q,J＝7.2Hz,2H),2.25(s,3H),1.41(t,J＝6.8Hz,3H).

c) 7-Nitro-4, 5-dichloro-1H-indole-2-carboxylic acid ethyl ester

The preparation of ethyl 2- (2- (2-nitro-4, 5-dichlorophenyl) hydrazono) propionate as starting material was carried out as described in c) of intermediate preparation 1 to yield 710mg of a pale yellow solid in 38% yield mp:168-169 ℃.

¹H NMR(CDCl₃)(ppm):10.37(brs,1H),8.37(s,1H),7.42(s,1H),4.48(q,J＝7.2Hz,2H),1.46(t,J＝7.2Hz,3H).

Example 96- ((3-methoxyphenyl) amino) -7-nitro-5-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxyphenyl) amino) -7-nitro-5-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75 was carried out using 7-nitro-4, 5-dichloro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials to give 177mg of a yellow powder as a solid in 63% yield mp:179-180 ℃.

¹H NMR(CDCl₃)(ppm):10.39(brs,1H),8.38(s,1H),7.34(t,J＝8.0Hz,1H),7.09(s,1H),6.89(d,J＝8.4Hz,1H),6.84(d,J＝8.0Hz,1H),6.79(s,1H),6.48(s,1H),4.35(q,J＝7.2Hz,2H),3.81(s,3H),1.35(t,J＝7.2Hz,3H).

b) 4- ((3-methoxyphenyl) amino) -7-nitro-5-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxyphenyl) amino) -7-nitro-5-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) in example 3 to give 112mg of a yellow powdery solid in 99% yield mp:249-250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.41(s,1H),10.90(s,1H),9.19(s,1H),8.28(s,1H),7.32(t,J＝8.0Hz,1H),6.86(d,J＝8.4Hz,1H),6.82(s,1H),6.79(d,J＝8.0Hz,1H),6.35(s,1H),3.74(s,3H).

c) 4- ((3-methoxyphenyl) amino) -7-nitro-5-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure used in example 3 c) was carried out starting from 4- ((3-methoxyphenyl) amino) -7-nitro-5-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide to give 71mg of a yellow powdery solid in 93% yield mp:216-218 ℃.

¹H NMR(DMSO-d₆)(ppm):12.90(brs,1H),11.82(brs,1H),9.15(s,1H),8.29(s,1H),7.89(d,J＝8.4Hz,2H),7.28(t,J＝8.0Hz,1H),7.12(d,J＝8.4Hz,2H),6.83(d,J＝8.0Hz,1H),6.78(s,1H),6.73(d,J＝8.0Hz,1H),6.56(brs,1H),3.84(s,3H),3.72(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.25,159.90,143.29,141.51,131.19,130.24,129.91,125.46,124.40,117.21,115.86,114.31,111.01,110.88,109.39,55.80,55.21.HRMS(ESI):m/z,calcd.for C₂₃H₂₀N₄O₇ClS[M+H]⁺:531.0741,found 531.0729.

Preparation of intermediate 4: 7-Nitro-5-fluoro-4-chloro-1H-indole-2-carboxylic acid ethyl ester

a) 2-nitro-4-fluoro-5-chlorophenylhydrazine hydrochloride BJB-3048 and b) ethyl 2- (2- (2-nitro-4-fluoro-5-chlorophenyl) hydrazono) propionate

The 2-nitro-4-fluoro-5-chloroaniline hydrochloride is used as the starting material, and the preparation process is the same as that of the method in a) in the preparation 1 of the intermediate, so that 6.24g of light yellow solid is obtained, and the yield is 98%.

The preparation process is the same as that of the preparation method b) in the intermediate preparation 1 by using 2-nitro-4-fluoro-5-chlorophenylhydrazine hydrochloride and ethyl pyruvate as starting materials to obtain 6.30g of light yellow solid, and the yield is 79%.

¹H NMR(CDCl₃)(ppm)10.81(s,1H),8.12(d,J＝6.8Hz,1H),8.01(d,J＝8.8Hz,1H),4.37(q,J＝7.2Hz,2H),2.24(s,3H),1.41(t,J＝6.8Hz,3H).

c) 7-Nitro-5-fluoro-4-chloro-1H-indole-2-carboxylic acid ethyl ester

Taking ethyl 2- (2- (2-nitro-4-fluoro-5-chlorophenyl) hydrazono) propionate as a starting material, the preparation process is the same as that of the c) in the preparation 1 of the intermediate, and light yellow solid 681mg is obtained, the yield is 14%, and mp is 166-168 ℃.

¹H NMR(CDCl₃)(ppm):10.35(brs,1H),8.14(d,J＝9.2Hz,1H),7.45(s,1H),4.48(q,J＝7.2Hz,2H),1.46(t,J＝7.2Hz,3H).

Example 97- ((3-methoxyphenyl) amino) -7-nitro-5-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxyphenyl) amino) -7-nitro-5-fluoro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 7-nitro-5-fluoro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials was carried out as described in a) of example 75 to give 271mg of a yellow powder as a solid in 83% yield mp:165-167 ℃.

¹H NMR(CDCl₃)(ppm):10.39(brs,1H),8.14(d,J＝12.0Hz,1H),7.32(t,J＝8.0Hz,1H),6.84(t,J＝8.0Hz,2H),6.77(s,1H),6.73(brs,1H),6.68(s,1H),4.37(q,J＝7.2Hz,2H),3.81(s,3H),1.36(t,J＝7.2Hz,3H).

b) 4- ((3-methoxyphenyl) amino) -7-nitro-5-fluoro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxyphenyl) amino) -7-nitro-5-fluoro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 120mg of a yellow powdery solid in 96% yield mp:245-248 ℃.

¹H NMR(DMSO-d₆)(ppm):13.45(s,1H),10.87(s,1H),9.50(s,1H),8.16(d,J＝12.4Hz,1H),7.29(t,J＝8.0Hz,1H),6.95(s,1H),6.78-6.76(m,3H),3.74(s,3H).

c) 4- ((3-methoxyphenyl) amino) -7-nitro-5-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((3-methoxyphenyl) amino) -7-nitro-5-fluoro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, was as described in c) to give 74mg of a red-orange powdery solid in 82% yield mp:128-130 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),11.80(brs,1H),9.49(s,1H),8.17(d,J＝12.8Hz,1H),7.93(d,J＝8.8Hz,1H),7.27(t,J＝8.0Hz,1H),7.14(d,J＝8.8Hz,2H),7.10(s,1H),6.77(d,J＝8.4Hz,1H),6.72(s,2H),3.84(s,3H),3.73(s,3H).

Preparation of intermediate 5: 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester

4-chloro-7-nitro-1H-indole-2-carboxylic acid ethyl ester (200mg, 0.74mmol) was dissolved in DMF (6mL), cesium carbonate (723mg, 2.23mmol) and iodomethane (211mg, 1.49mmol) were added in that order, and the starting material disappeared at room temperature for 3H. The reaction mixture was poured into water (20mL), EA (20 mL. times.2) was extracted, washed with saturated brine (20 mL. times.3), washed with water (20 mL. times.3), concentrated, and EA was recrystallized to give 200mg of a pale yellow powdery solid with a yield of 95% mp:118-120 ℃.

¹H NMR(CDCl₃)(ppm):7.81(d,J＝8.4Hz,1H),7.52(s,1H),7.20(d,J＝8.4Hz,1H),4.42(q,J＝7.2Hz,2H),4.01(s,3H),1.44(t,J＝7.2Hz,3H).

Example 98 1-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

Starting from 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline, the preparation was carried out as described in a) of example 3, giving 197mg of a yellow solid in 84% yield mp:202-204 ℃.

¹H NMR(CDCl₃)(ppm):7.98(d,J＝8.8Hz,1H),7.43(s,1H),7.31(t,J＝8.0Hz,1H),6.87(d,J＝8.4Hz,1H),6.83(s,1H),6.82(d,J＝8.8Hz,1H),6.74(d,J＝8.0Hz,1H),6.56(s,1H),4.40(q,J＝7.2Hz,2H),4.01(s,3H),3.83(s,3H),1.42(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 157mg of a yellow powdery solid in 98% yield mp:236-238 ℃.

¹H NMR(DMSO-d₆)(ppm):13.16(brs,1H),9.32(s,1H),7.99(d,J＝8.8Hz,1H),7.90(s,1H),7.33(t,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.90(s,1H),6.80(d,J＝8.8Hz,1H),6.74(d,J＝8.0Hz,1H),3.86(s,3H),3.78(s,3H).

c) 1-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure used in example 3 c) was carried out starting from 1-methyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide to give 39mg of a yellow powdery solid in 50% yield mp:252-254 ℃.

¹H NMR(DMSO-d₆)(ppm):12.65(brs,1H),9.39(s,1H),7.99(d,J＝10.0Hz,1H),7.96(d,J＝9.2Hz,2H),7.89(s,1H),7.33(t,J＝8.4Hz,1H),7.18(d,J＝8.8Hz,2H),6.94(d,J＝8.0Hz,1H),6.89(s,1H),6.82(d,J＝8.8Hz,1H),6.75(t,J＝8.0Hz,1H),3.87(s,3H),3.78(s,3H),3.62(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.19,160.14,159.20,145.52,141.06,133.82,130.93,130.31,130.05,128.43,127.63,117.27,114.34,113.87,110.42,109.55,107.37,101.87,55.81,55.13,36.56.HRMS(ESI):m/z,calcd.forC₂₄H₂₃N₄O₇S[M+H]⁺:511.1282,found 511.1274.

EXAMPLE 99 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used in example 3, starting from 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 4-fluoro-3-chloroaniline, is as described in a) to give 152mg of a yellow solid in 73% yield mp:223-224 ℃.

¹H NMR(acetone-d₆)(ppm):8.58(s,1H),8.00(d,J＝8.8Hz,1H),7.77(s,1H),7.56(d,J＝6.4Hz,1H),7.43(m,1H),7.38(t,J＝8.8Hz,1H),6.84(d,J＝8.8Hz,1H),4.39(q,J＝7.2Hz,2H),3.98(s,3H),1.39(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the procedure is as described in b) of example 3 to give 100mg of an orange powdery solid in 98% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):9.28(s,1H),7.90(d,J＝8.8Hz,1H),7.62(s,1H),7.52(d,J＝9.2Hz,1H),7.44(t,J＝8.8Hz,1H),7.37-7.35(m,1H),6.71(d,J＝9.2Hz,1H),3.89(s,3H).

c) 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, the procedure is as in c) of example 3 to give 46mg of a yellow powdery solid in 63% yield, mp:275-277 ℃.

¹H NMR(DMSO-d₆)(ppm):12.65(brs,1H),9.42(s,1H),7.98(d,J＝8.8Hz,1H),7.95(d,J＝8.8Hz,1H),7.82(s,1H),7.51(d,J＝6.8Hz,1H),7.47(d,J＝9.2Hz,1H),7.36-7.33(m,1H),7.17(d,J＝8.8Hz,2H),6.74(d,J＝8.8Hz,1H),3.86(s,3H),3.64(s,3H).

EXAMPLE 100 1-methyl-4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used in example 3, starting from 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3, 5-dimethoxyaniline, gives 264mg of a yellow solid in 92% yield mp:190-191 ℃.

¹H NMR(CDCl₃)(ppm):7.99(d,J＝8.8Hz,1H),7.43(s,1H),6.86(d,J＝8.8Hz,1H),7.43(s,1H),6.44(s,2H),6.30(s,1H),4.40(q,J＝7.2Hz,2H),4.01(s,3H),3.80(s,6H),1.42(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from 1-methyl-4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 138mg of an orange powdery solid in 75% yield mp:243-244 ℃.

¹H NMR(DMSO-d₆)(ppm):13.17(brs,1H),9.27(s,1H),7.90(d,J＝8.0Hz,1H),7.88(s,1H),6.86(d,J＝8.8Hz,1H),6.52(s,2H),6.31(s,1H),3.86(s,3H),3.76(s,6H).

c) 1-methyl-4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure was as described in c) of example 3, starting from 1-methyl-4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide to give 59mg of a yellow powdery solid in 91% yield mp:255-257 ℃.

¹H NMR(DMSO-d₆)(ppm):12.63(brs,1H),9.34(s,1H),7.99(d,J＝8.8Hz,1H),7.95(d,J＝8.8Hz,2H),7.88(s,1H),7.18(d,J＝8.8Hz,2H),6.87(d,J＝8.8Hz,1H),6.50(s,2H),6.31(s,1H),3.86(s,3H),3.76(s,6H),3.62(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.15,161.08,159.27,145.24,141.67,133.75,131.03,130.03,128.32,127.75,177.44,114.32,110.33,102.37,99.64,95,84,55.80,55.24,36.54.HRMS(ESI):m/z,calcd.forC₂₅H₂₅N₄O₈S[M+H]⁺:541.1393,found541.1379.

EXAMPLE 101 1-methyl-4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

The procedure described in example 3 c) was repeated, starting from 1-methyl-4- ((3, 5-dimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, to give 58mg of a yellow powdery solid in 95% yield mp:253-255 ℃.

¹H NMR(DMSO-d₆)(ppm):12.80(brs,1H),9.35(s,1H),8.03(d,J＝7.6Hz,2H),8.00(d,J＝9.2Hz,1H),7.92(s,1H),7.74(t,J＝7.2Hz,1H),7.67(t,J＝7.6Hz,2H),6.88(d,J＝8.8Hz,1H),6.50(s,2H),6.32(s,1H),3.76(s,6H),3.62(s,3H)；HRMS(ESI):m/z,calcd.for C₂₄H₂₃N₄O₇S[M+H]⁺:511.1287,found 511.1274.

Example 102 1-methyl-4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used in example 3, starting from 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3,4, 5-dimethoxyaniline, gives 290mg of an orange solid with a yield of 95% and mp:203-204 ℃.

¹H NMR(CDCl₃)(ppm):7.99(d,J＝8.8Hz,1H),7.42(s,1H),6.70(d,J＝8.8Hz,1H),6.52(s,2H),6.43(brs,1H),4.40(q,J＝7.2Hz,2H),4.02(s,3H),3.88(s,3H),3.85(s,6H),1.42(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the procedure is as in b) of example 3 to give 154mg of an orange powdery solid in 82% yield mp:257-259 ℃.

¹H NMR(DMSO-d₆)(ppm):13.13(brs,1H),9.29(s,1H),7.98(d,J＝9.2Hz,1H),7.89(s,1H),6.78(d,J＝9.2Hz,1H),6.66(s,2H),3.86(s,3H),3.78(s,6H),3.68(s,3H).

c) 1-methyl-4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure is as described in c) of example 3, starting from 1-methyl-4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, giving 57mg of a yellow powdery solid in 73% yield mp:268-272 ℃.

¹H NMR(DMSO-d₆)(ppm):12.64(brs,1H),9.36(s,1H),7.99-7.96(m,3H),7.88(s,1H),7.19(d,J＝8.8Hz,2H),7.80(d,J＝8.8Hz,1H),6.63(s,2H),3.87(s,3H),3.78(s,6H),3.68(s,3H),3.62(s,3H).

Example 103 1-methyl-4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- ((3,4, 5-trimethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, the procedure is as described in c) of example 3 to give 60mg of a yellow powdery solid in 89% yield mp:258-259 ℃.

¹H NMR(DMSO-d₆)(ppm):12.80(brs,1H),9.36(s,1H),8.03(d,J＝7.6Hz,2H),7.98(d,J＝8.8Hz,1H),7.90(s,1H),7.75(d,J＝7.2Hz,1H),7.68(t,J＝7.6Hz,2H),6.80(d,J＝8.8Hz,1H),6.64(s,2H),3.78(s,6H),3.68(s,3H),3.62(s,3H).

Example 104 1-methyl-4- ((3-methylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-methylaniline starting from 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid was as described in a) of example 3 to give 150mg of an orange solid in 80% yield mp:185-187 ℃.

¹H NMR(CDCl₃)(ppm):7.99(d,J＝8.8Hz,2H),7.43(s,1H),7.30(t,J＝8.4Hz,1H),7.09(d,J＝7.2Hz,2H),7.02(d,J＝7.6Hz,1H),6.74(d,J＝8.8Hz,1H),6.52(s,1H),4.40(q,J＝7.2Hz,2H),4.02(s,3H),2.38(s,3H),1.42(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((3-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- ((3-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 100mg of an orange powdery solid in 99% yield mp:245-247 ℃.

¹H NMR(DMSO-d₆)(ppm):13.14(s,1H),9.30(s,1H),7.98(d,J＝8.8Hz,1H),7.90(s,1H),7.31(t,J＝7.6Hz,1H),7.17-7.15(m,2H),7.00(d,J＝7.6Hz,1H),6.71(d,J＝8.8Hz,1H),3.86(s,3H),2.33(s,3H).

c) 1-methyl-4- ((3-methylphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure described in example 3, c) was repeated starting from 1-methyl-4- ((3-methylphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide to give 69mg of a yellow powdery solid in 91% yield mp:255-257 ℃.

¹H NMR(DMSO-d₆)(ppm):12.63(brs,1H),9.37(s,1H),7.99-7.95(m,3H),7.89(s,1H),7.32(t,J＝7.6Hz,1H),7.19-7.13(m,4H),7.00(d,J＝7.6Hz,1H),6.73(d,J＝8.8Hz,1H),3.87(s,3H),3.68(s,3H),2.34(s,3H)；HRMS(ESI):m/z,calcd.for C₂₄H₂₃N₄O₆S[M+H]⁺:495.1338,found 495.1323.

Example 105 1-methyl-4- ((3-acetamidophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3-acetylaminophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, using 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-acetaminoaniline as starting materials, gave 155mg of an orange-red solid in 74% yield, mp:257-260 ℃.

¹H NMR(DMSO-d₆)(ppm):10.02(s,1H),9.43(s,1H),8.01-7.98(m,1H),7.78(s,1H),7.35-7.26(m,2H),7.02(d,J＝7.2Hz,1H),6.76(d,J＝8.8Hz,1H),4.36(q,J＝6.8Hz,2H),3.85(s,3H),2.06(s,3H),1.36(t,J＝6.8Hz,3H).

b) 1-methyl-4- ((3-acetamidophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from 1-methyl-4- ((3-acetamidophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 100mg of an orange powdery solid in 100% yield mp:210-212 ℃.

¹H NMR(DMSO-d₆)(ppm):10.05(s,1H),9.37(s,1H),7.96(d,J＝9.2Hz,1H),7.91(s,1H),7.76(s,1H),7.31-7.27(m,2H),7.01(d,J＝7.2Hz,1H),6.74(d,J＝8.8Hz,1H),3.84(s,3H),2.04(s,3H).

c) 1-methyl-4- ((3-acetamidophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- ((3-acetamidophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the procedure is as described in c) of example 3 to give 60mg of a yellow powdery solid in 82% yield and mp: >260 ℃.

¹H NMR(DMSO-d₆)(ppm):12.62(brs,1H),10.02(s,1H),9.44(s,1H),7.98(d,J＝8.4Hz,1H),7.96(d,J＝8.0Hz,2H),7.91(s,1H),7.78(s,1H),7.33(t,J＝8.0Hz,1H),7.26(d,J＝8.0Hz,1H),7.19(d,J＝8.4Hz,2H),7.01(d,J＝7.6Hz,1H),6.77(d,J＝8.8Hz,1H),3.87(s,3H),3.62(s,3H),2.05(s,3H)；HRMS(ESI):m/z,calcd.for C₂₅H₂₄N₅O₇S[M+H]⁺:538.1396,found 538.1384.

Example 106 methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation procedure was the same as that described in a) of example 3, using N-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxy-4-chloroaniline as starting materials, to give 173mg of an orange-red solid with a yield of 81% and mp:232-234 ℃.

¹H NMR(CDCl₃)(ppm):7.98(d,J＝8.8Hz,1H),7.42(s,1H),7.37(d,J＝8.0Hz,1H),6.85-6.82(m,2H),6.75(d,J＝8.8Hz,1H),6.48(s,1H),4.41(q,J＝7.2Hz,2H),4.02(s,3H),3.90(s,3H),1.42(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 103mg of a solid in the form of a reddish-orange powder with a yield of 96% and mp:258-260 ℃.

¹H NMR(DMSO-d₆)(ppm):9.42(s,1H),7.99(d,J＝8.8Hz,1H),7.89(s,1H),7.43(d,J＝8.4Hz,1H),7.11(s,1H),6.96(d,J＝8.4Hz,1H),6.85(d,J＝8.8Hz,1H),3.86(s,6H).

c) 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, the procedure is as in c) of example 3 to give 56mg of a yellow powdery solid in 70% yield mp:248-250 ℃.

¹H NMR(DMSO-d₆)(ppm):12.66(brs,1H),9.45(s,1H),8.00-7.95(m,3H),7.87(s,1H),7.44(d,J＝8.4Hz,1H),7.18(d,J＝8.8Hz,2H),7.08(s,1H),6.94(d,J＝8.4Hz,1H),6.88(d,J＝8.8Hz,1H),3.86(s,6H),3.63(s,3H)；HRMS(ESI):m/z,calcd.for C₂₄H₂₂N₄O₇ClS[M+H]⁺:545.0898,found 545.0884.

Example 107-methyl-4- ((3-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-chloroaniline starting materials was carried out as described in a) of example 3 to give a red-orange solid 162mg in 82% yield mp:204-206 ℃.

¹H NMR(CDCl₃)(ppm):7.99(t,J＝8.8Hz,1H),7.42(s,1H),7.33(t,J＝8.0Hz,1H),7.28(s,1H),7.17-7.14(m,2H),6.80(d,J＝8.8Hz,1H),6.49(s,1H),4.41(q,J＝7.2Hz,2H),4.02(s,3H),1.42(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- ((3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation process was as described in b) of example 3, giving 101mg of an orange-red powdery solid with a yield of 99%, mp:237-239 ℃.

¹H NMR(DMSO-d₆)(ppm):13.21(s,1H),9.42(s,1H),8.00(d,J＝8.8Hz,1H),7.87(s,1H),7.43(t,J＝8.0Hz,1H),7.39(s,1H),7.34(d,J＝8.4Hz,1H),7.18(d,J＝8.0Hz,1H),6.84(d,J＝8.8Hz,1H),3.87(s,3H).

c) 1-methyl-4- ((3-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 1-methyl-4- ((3-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 55mg of a yellow powdery solid in 75% yield mp:270-272 ℃.

¹H NMR(DMSO-d₆)(ppm):9.46(brs,1H),8.01(d,J＝8.8Hz,1H),7.96(d,J＝8.8Hz,2H),7.86(s,1H),7.44(t,J＝8.0Hz,1H),7.37(s,1H),7.32(d,J＝8.4Hz,2H),7.18(d,J＝8.4Hz,3H),6.86(d,J＝8.8Hz,1H),3.87(s,3H),3.77(s,3H).

Example 108 methyl-4- ((4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 4-chloroaniline, is as described in a) to give 170mg of a yellow solid in 86% yield mp:246-247 ℃.

¹H NMR(CDCl₃)(ppm):7.97(d,J＝8.8Hz,1H),7.42(s,1H),7.38(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,2H),6.70(d,J＝8.8Hz,1H),6.46(s,1H),4.40(q,J＝7.2Hz,2H),4.02(s,3H),1.42(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- ((4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 100mg of a reddish-orange powdery solid in 98% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):9.25(s,1H),7.88(d,J＝8.8Hz,1H),7.59(s,1H),7.43(d,J＝8.4Hz,2H),7.36(d,J＝8.8Hz,2H),6.74(d,J＝8.8Hz,1H),3.89(s,3H).

c) 1-methyl-4- ((4-chlorophenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- ((4-chlorophenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, the preparation was carried out as described in c) of example 3 to give 55mg of a yellow powdery solid in 71% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.65(brs,1H),9.44(s,1H),7.99-7.95(m,3H),7.86(s,1H),7.47(d,J＝8.4Hz,2H),7.36(d,J＝8.4Hz,2H),7.18(d,J＝8.4Hz,2H),6.77(d,J＝8.8Hz,1H),3.87(s,3H),3.63(s,3H).

Example 109 1-methyl-4- ((3-ethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3-ethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

Starting from 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-ethoxyaniline, the preparation was carried out as described in a) of example 3 to give 177mg of a yellow solid in 87% yield mp:178-180 ℃.

¹H NMR(CDCl₃)(ppm):7.99(d,J＝8.8Hz,1H),7.43(s,1H),7.30(t,J＝8.4Hz,1H),6.84(d,J＝10.0Hz,1H),6.83(s,1H),6.80(d,J＝8.8Hz,1H),6.73(d,J＝8.4Hz,1H),6.51(s,1H),4.40(q,J＝7.2Hz,2H),4.04(q,J＝8.0Hz,2H),4.02(s,3H),1.45-1.41(m,6H).

b) 1-methyl-4- ((3-ethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- ((3-ethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 110mg of a solid in the form of a reddish-orange powder with a yield of 99% and mp:238-241 ℃.

¹H NMR(DMSO-d₆)(ppm):13.16(s,1H),9.29(s,1H),7.99(d,J＝8.8Hz,1H),7.89(s,1H),7.31(t,J＝8.0Hz,1H),6.93(d,J＝8.0Hz,1H),6.88(s,1H),6.78(d,J＝8.8Hz,1H),6.73(d,J＝7.6Hz,1H),4.04(q,J＝6.8Hz,2H),3.86(s,3H),1.34(t,J＝6.8Hz,3H).

c) 1-methyl-4- ((3-ethoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 1-methyl-4- ((3-ethoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, is as described in c) of example 3, giving 67mg of a yellow powdery solid in 85% yield, mp:243-245 ℃.

¹H NMR(DMSO-d₆)(ppm):12.63(brs,1H),9.37(s,1H),7.99(d,J＝8.8Hz,1H),7.96(d,J＝8.8Hz,2H),7.88(s,1H),7.32(t,J＝8.0Hz,1H),7.18(d,J＝8.8Hz,2H),6.91(d,J＝7.6Hz,1H),6.86(s,1H),6.80(d,J＝8.8Hz,1H),6.73(d,J＝8.4Hz,1H),4.04(q,J＝7.2Hz,1H),3.87(s,3H),3.62(s,3H),1.34(t,J＝7.2Hz,3H).

Preparation of intermediate 6: 1-Ethyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester

The preparation process is the same as the preparation 5 of an intermediate by taking 4-chloro-7-nitro-1H-indole-2-ethyl formate and bromoethane as starting materials to obtain a light yellow solid of 140mg, the yield is 99 percent, and the mp is 108-109 ℃.

¹H NMR(CDCl₃)(ppm):7.74(d,J＝8.0Hz,1H),7.55(s,1H),7.20(d,J＝8.0Hz,1H),4.67(q,J＝7.2Hz,2H),4.42(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H),1.30(t,J＝7.2Hz,3H).

Example 110 1-Ethyl-4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-Ethyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 3, starting from 1-ethyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline, gave 171mg of a yellow solid in 78% yield mp:165-167 ℃.

¹H NMR(CDCl₃)(ppm):7.96(d,J＝8.8Hz,1H),7.48(s,1H),7.31(t,J＝8.0Hz,1H),6.87(d,J＝8.0Hz,1H),6.83(s,1H),6.81(d,J＝9.2Hz,1H),6.74(d,J＝8.4Hz,1H),6.50(s,1H),4.79(q,J＝7.2Hz,2H),4.40(q,J＝7.2Hz,2H),3.83(s,3H),1.43(t,J＝7.2Hz,3H),1.27(t,J＝7.2Hz,3H).

b) 1-ethyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-ethyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 105mg of a yellow powdery solid in 98% yield mp:221-224 ℃.

¹H NMR(DMSO-d₆)(ppm):13.07(brs,1H),9.32(s,1H),7.98(d,J＝6.8Hz,2H),7.33(t,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.91(s,1H),6.80(d,J＝8.8Hz,1H),6.74(d,J＝8.0Hz,1H),4.69(q,J＝6.8Hz,1H),3.77(s,3H),1.10(d,J＝6.8Hz,3H).

c) 1-Ethyl-4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-ethyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, 45mg of a yellow powdery solid are obtained in the same manner as described in c) of example 3, yield 51%, mp:241-242 ℃.

¹H NMR(DMSO-d₆)(ppm):12.70(brs,1H),9.40(s,1H),8.00-7.94(m,4H),7.34(t,J＝8.0Hz,1H),7.19(d,J＝8.4Hz,2H),6.95(d,J＝8.0Hz,1H),6.90(s,1H),6.82(d,J＝8.8Hz,1H),6.76(d,J＝8.0Hz,1H),4.39-4.38(m,2H),3.87(s,3H),3.78(s,3H),0.91(t,J＝6.8Hz,3H).

Preparation of intermediate 7: 1-isobutyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester

4-chloro-7-nitro-1H-indole-2-ethyl formate and bromoisobutane are used as starting materials, the preparation process is the same as that of an intermediate for preparation 5, and light yellow solid 206mg is obtained, the yield is 85%, and mp is 80-81 ℃.

¹H NMR(CDCl₃)(ppm):7.78(d,J＝8.4Hz,1H),7.55(s,1H),7.21(d,J＝8.0Hz,1H),4.60(s,2H),4.41(q,J＝7.2Hz,2H),1.69-1.62(m,1H),1.44(t,J＝7.2Hz,3H),0.66(d,J＝6.4Hz,6H).

Example 111-isobutyl-4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-isobutyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 1-isobutyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials was carried out as described in a) of example 3 to give 207mg of an orange solid in 76% yield mp:155-156 ℃.

¹H NMR(CDCl₃)(ppm):7.95(t,J＝8.8Hz,1H),7.47(s,1H),7.31(d,J＝8.4Hz,1H),6.88(d,J＝8.0Hz,1H),6.84(s,1H),6.82(d,J＝9.2Hz,1H),6.74(d,J＝8.4Hz,1H),6.52(brs,1H),4.71(s,2H),4.40(q,J＝7.2Hz,2H),3.83(s,3H),1.70-1.62(m,1H),1.42(t,J＝7.2Hz,3H),0.64(d,J＝6.4Hz,6H).

b) 1-isobutyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-isobutyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) in example 3 to give 115mg of a yellow powdery solid in 98% yield mp:219-222 ℃.

¹H NMR(DMSO-d₆)(ppm):13.19(s,1H),9.35(s,1H),7.97(d,J＝6.4Hz,2H),7.33(t,J＝8.0Hz,1H),6.97(d,J＝8.0Hz,1H),6.93(s,1H),6.81(d,J＝9.2Hz,1H),6.75(d,J＝8.0Hz,1H),4.61(s,2H),3.78(s,3H),1.55-1.49(m,1H),0.55(d,J＝6.4Hz,6H).

c) 1-isobutyl-4- ((3-methoxyphenyl) amino) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure used in example 3 c) was repeated, starting from 1-isobutyl-4- ((3-methoxyphenyl) amino) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 14mg of a yellow powdery solid in 16% yield mp:195-196 ℃.

¹H NMR(DMSO-d₆)(ppm):12.68(brs,1H),9.38(s,1H),7.98-7.93(m,3H),7.88(s,1H),7.34(t,J＝8.0Hz,1H),7.18(t,J＝8.8Hz,2H),6.95(d,J＝8.0Hz,1H),6.90(s,1H),6.82(d,J＝8.8Hz,1H),6.76(d,J＝8.4Hz,1H),4.20(d,J＝6.4Hz,2H),3.86(s,3H),3.78(s,3H),1.24-1.29(m,1H),0.36(d,J＝6.4Hz,6H).

Example 112- ((3-ethoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75, starting from ethyl 4-bromo-1H-indole-2-carboxylate and 3-methoxyaniline in the presence of the catalyst in the solvent described in example 75 under the heading conditions a) gave 120mg of a white solid in 86% yield mp:130-131 ℃.

¹H NMR(CDCl₃)(ppm):8.88(brs,1H),7.25-7.17(m,3H),7.03(d,J＝8.7Hz,1H),7.00(d,J＝8.1Hz,1H),6.75-6.73(m,2H),6.55-6.52(m,1H),4.40(q,J＝7.2Hz,2H),3.79(s,3H),1.41(t,J＝7.5Hz,3H).

b) 4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid

The procedure of example 3, starting from ethyl 4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylate, gave 90mg of a copper-green powdery solid in 90% yield, mp:169-170 ℃.

¹H NMR(acetone-d₆)(ppm):11.10(brs,1H),10.79(s,1H),7.57(s,1H),7.39(s,1H),7.20-7.15(m,2H),7.09(d,J＝8.4Hz,1H),6.98(d,J＝7.6Hz,1H),6.84(d,J＝7.6Hz,2H),6.48(d,J＝8.8Hz,1H),3.76(s,3H).

c) 4- ((3-ethoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, was as described in c) of example 3, giving 36mg of a brown powdery solid in 56% yield mp:159-160 ℃.

¹H NMR(DMSO-d₆)(ppm):12.35(brs,1H),11.64(s,1H),8.22(s,1H),7.94(d,J＝8.8Hz,2H),7.54(s,1H),7.15(d,J＝8.4Hz,2H),7.13-7.10(m,2H),6.95(d,J＝8.4Hz,1H),6.83(d,J＝7.6Hz,1H),6.69(d,J＝8.4Hz,1H),6.65(s,1H),6.41(d,J＝8.0Hz,1H),3.85(s,3H),3.70(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.10,160.10,159.23,145.19,138.93,137.21,131.12,130.06,129.75,126.79,126.09,119.87,114.21,109.42,106.79,106.64,105.20,105.04,102.49,55.79,54.79.HRMS(ESI):m/z,calcd.for C₂₃H₂₂N₃O₅S[M+H]⁺:452.1280,found 452.1264.

Example 113- ((4-fluoro-3-chlorophenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid methyl ester

The procedure of example 75 was carried out using 4-bromo-1H-indole-2-carboxylic acid methyl ester and 4-fluoro-3-chloroaniline as starting materials to give 155mg of a white solid in 73% yield mp:168-170 ℃.

¹H NMR(acetone-d₆)(ppm):10.93(brs,1H),7.68(s,1H),7.32-7.29(m,2H),7.23-7.19(m,3H),7.15(d,J＝8.4Hz,1H),6.92(d,J＝7.6Hz,1H),3.87(s,3H).

b) 4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid

Starting from methyl 4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 90mg of a copper-green powdery solid in 94% yield mp:182-183 ℃.

¹H NMR(acetone-d₆)(ppm):10.87(brs,1H),7.34(s,1H),7.31(d,J＝5.6Hz,1H),7.24-7.14(m,4H),6.92(d,J＝7.2Hz,1H).

c) 4- ((4-fluoro-3-chlorophenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 44mg of a brown powdery solid in a yield of 63% and mp:245-247 ℃.

¹H NMR(DMSO-d₆)(ppm):12.35(brs,1H),11.71(d,J＝0.6Hz,1H),8.38(s,1H),7.94(d,J＝8.7Hz,1H),7.47(s,1H),7.27(t,J＝9.0Hz,1H),7.20-7.12(m,4H),7.00(d,J＝8.4Hz,2H),6.79(d,J＝7.5Hz,1H),3.84(s,3H).

Example 114- ((3,4, 5-trimethoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) Methyl 4- ((3,4, 5-trimethoxyphenyl) amino) -1H-indole-2-carboxylate

The procedure used in example 75, starting from methyl 4-bromo-1H-indole-2-carboxylate and 3,4, 5-trimethoxyaniline in the presence of 5-methoxy-p-tert-butyl-phenyl-aniline in the amount indicated in a), gave 210mg of a white solid in 83% yield mp:219-220 ℃.

¹H NMR(acetone-d₆)(ppm):10.85(brs,1H),7.42(s,1H),7.17(t,J＝8.0Hz,1H),7.04(d,J＝8.0Hz,1H),6.85(d,J＝7.6Hz,1H),6.69(s,1H),6.60(s,2H),3.87(s,3H),3.78(s,6H),3.70(s,3H).

b) 4- ((3,4, 5-trimethoxyphenyl) amino) -1H-indole-2-carboxylic acid

The procedure of example 3, b) was repeated, starting from methyl 4- ((3,4, 5-trimethoxyphenyl) amino) -1H-indole-2-carboxylate, to give 93mg of a copper-green powdery solid in 81% yield mp:223-225 ℃.

¹H NMR(acetone-d₆)(ppm):10.98(brs,1H),10.77(s,1H),7.46(s,1H),7.42(s,1H),7.16(t,J＝8.0Hz,1H),7.05(d,J＝8.4Hz,1H),6.95(d,J＝7.6Hz,1H),6.59(s,2H),3.78(s,6H),3.70(s,3H).

c) 4- ((3,4, 5-trimethoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3,4, 5-trimethoxyphenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 56mg of a brown powdery solid in 84% yield mp:129-130 ℃.

¹H NMR(DMSO-d₆)(ppm):12.36(brs,1H),11.61(s,1H),8.12(s,1H),7.94(d,J＝8.7Hz,2H),7.56(s,1H),7.15(d,J＝9.0Hz,2H),7.10(t,J＝7.8Hz,1H),6.90(d,J＝8.4Hz,1H),6.81(d,J＝7.2Hz,1H),6.43(s,2H),3.85(s,3H),3.70(s,6H),3.62(s,3H).

Preparation of intermediate 8: 6-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (4-chloro-2-bromophenyl) acrylate

Sodium ethoxide (272mg, 4.00mmol) was dissolved in anhydrous ethanol (2mL) and cooled to-5 ℃. 4-chloro-2-bromobenzaldehyde (220mg, 0.56mmol) and ethyl azidoacetate (527mg, 4.00mmol) were dissolved in anhydrous ethanol (4mL), added dropwise to the above solution, reacted at 0 ℃ for 12h, and the starting material disappeared. Pouring the reaction solution into NH₄In an aqueous Cl solution (20mL), a solid precipitated, filtered and dried to give 50mg of a white flocculent solid with a yield of 27%.

¹H NMR(CDCl₃)(ppm):8.10(d,J＝8.4Hz,1H),7.62(s,1H),7.32(d,J＝8.0Hz,1H),7.18(s,1H),4.40(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H).

b) 6-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Ethyl 2-azido-3- (4-chloro-2-bromophenyl) acrylate (100mg, 0.30mmol) was dissolved in Xylene (6mL) and refluxed for 6h, leaving a small amount of starting material. Column chromatography (P/E20: 1) gave 75mg of a white solid in 82% yield, mp:190-192 ℃.

¹H NMR(CDCl₃)(ppm):8.98(brs,1H),7.38(s,1H),7.35(s,1H),7.23(s,1H),4.43(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H).

Example 115- ((3-methoxyphenyl) amino) -6-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxyphenyl) amino) -6-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75, using 6-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials, gave 190mg of a white solid in 67% yield mp:120-121 ℃.

¹H NMR(acetone-d₆)(ppm):10.97(brs,1H),7.80(s,1H),7.41(s,1H),7.25(t,J＝8.0Hz,1H),7.05(s,1H),6.92-6.87(m,3H),6.60(d,J＝8.4Hz,1H),4.35(q,J＝7.2Hz,2H),3.79(s,3H),1.35(t,J＝7.2Hz,3H).

b) 4- ((3-methoxyphenyl) amino) -6-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxyphenyl) amino) -6-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 144mg of a white powdery solid in 98% yield, mp:179-180 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.78(s,1H),8.45(s,1H),7.37(s,1H),7.22(d,J＝8.0Hz,1H),6.89(s,1H),6.83(d,J＝8.0Hz,1H),6.77(s,1H),6.72(s,1H),6.55(d,J＝8.0Hz,1H),3.74(s,3H).

c) 4- ((3-methoxyphenyl) amino) -6-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -6-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 48mg of a brown powdery solid in 56% yield mp:253-255 ℃.

¹H NMR(acetone-d₆)(ppm):10.94(brs,1H),10.88(s,1H),8.03(d,J＝9.0Hz,2H),7.70(s,1H),7.49(s,1H),7.22(t,J＝7.8Hz,1H),7.12(d,J＝9.0Hz,2H),7.06(s,1H),6.86(s,1H),6.80-6.76(m,2H),6.58(s,J₁＝1.8Hz,J₂＝8.4Hz,1H),3.91(s,3H),3.77(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.12,160.12,159.06,143.75,138.98,138.72,131.06,130.53,130.07,130.00,127.43,117.62,114.22,110.89,106.84,106.55,105.05,104.25,103.70,55.80,54.91.HRMS(ESI):m/z,calcd.for C₂₃H₂₁N₃O₅ClS[M+H]⁺:486.0890,found486.0877.

Example 116- ((4-fluoro-3-chlorophenyl) amino) -6-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-fluoro-3-chlorophenyl) amino) -6-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 75 was repeated, starting from 6-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 4-fluoro-3-chloroaniline, to give 294mg of a white solid in 81% yield mp:212-213 ℃.

¹H NMR(CDCl₃)(ppm):8.87(brs,1H),7.21(d,J＝5.2Hz,1H),7.13-7.09(m,2H),7.05-7.01(m,2H),6.75(s,1H),5.89(s,1H),4.41(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H).

b) 4- ((4-fluoro-3-chlorophenyl) amino) -6-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((4-fluoro-3-chlorophenyl) amino) -6-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 130mg of a white powdery solid in 94% yield mp:205-207 ℃.

¹H NMR(DMSO-d₆)(ppm):11.85(s,1H),8.60(brs,1H),7.41-7.32(m,4H),7.24-7.21(m,1H),6.94(s,1H),6.65(s,1H).

c) 4- ((4-fluoro-3-chlorophenyl) amino) -6-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((4-fluoro-3-chlorophenyl) amino) -6-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, was as described in c) of example 3, giving 32mg of a ginger-yellow powdery solid in 38% yield, mp:276-278 ℃.

¹H NMR(acetone-d₆)(ppm):10.99(s,1H),10.85(brs,1H),8.02(d,J＝8.8Hz,2H),7.83(s,1H),7.43(s,1H),7.28-7.23(m,2H),7.17-7.11(m,4H),6.79(s,1H),3.91(s,3H).

Example 117- ((3,4, 5-trimethoxyphenyl) amino) -6-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) Ethyl 4- ((3,4, 5-trimethoxyphenyl) amino) -6-chloro-1H-indole-2-carboxylate

The procedure used in example 75 was carried out starting from ethyl 6-chloro-4-bromo-1H-indole-2-carboxylate and 3,4, 5-trimethoxyaniline to give 247mg of white solid in 81% yield mp:206-207 ℃.

¹H NMR(CDCl₃)(ppm):8.90(brs,1H),7.18(s,1H),6.96(s,1H),6.82(s,1H),6.45(s,2H),5.90(brs,1H),4.41(q,J＝7.2Hz,2H),3.86(s,3H),3.83(s,6H),1.41(t,J＝7.2Hz,3H).

b) 4- ((3,4, 5-trimethoxyphenyl) amino) -6-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3,4, 5-trimethoxyphenyl) amino) -6-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 110mg of a white powdery solid in 94% yield mp:145-147 ℃.

¹H NMR(DMSO-d₆)(ppm):12.91(brs,1H),11.76(s,1H),8.37(s,1H),7.38(s,1H),6.85(s,1H),6.68(s,1H),6.55(s,2H),3.75(s,6H),3.64(s,3H).

c) 4- ((3,4, 5-trimethoxyphenyl) amino) -6-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4- ((3,4, 5-trimethoxyphenyl) amino) -6-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials was as described in c) of example 3, gave 35mg of a ginger-yellow powdery solid in 44% yield, mp:155-157 ℃.

¹H NMR(acetone-d₆)(ppm):10.89(brs,1H),8.02(d,J＝8.8Hz,2H),7.60(s,1H),7.49(s,1H),7.11(d,J＝8.0Hz,1H),7.02(s,1H),6.79(s,1H),6.51(s,2H),3.90(s,3H),3.77(s,6H),3.71(s,3H).

Preparation of intermediate 9: 6-fluoro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (4-fluoro-2-bromophenyl) acrylate

The preparation process was the same as that described in a) for preparation 8 of intermediate using 4-fluoro-2-bromobenzaldehyde as starting material to give 743mg of white solid with a yield of 16%.

¹H NMR(CDCl₃)(ppm):8.17(dd,J₁＝8.8Hz,J₂＝6.4Hz,1H),8.17(dd,J₁＝8.4Hz,J₂＝2.4Hz,1H),7.20(s,1H),7.07(dt,J₁＝8.8Hz,J₂＝2.0Hz,1H),4.40(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H).

b) 6-fluoro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Using 2-azido-3- (4-fluoro-2-bromophenyl) ethyl acrylate as starting material, the preparation process was as described in b) of preparation 8 of intermediate to give 636mg of white solid, 79% yield, mp:172-173 ℃.

¹H NMR(CDCl₃)(ppm):9.23(s,1H),7.24(s,1H),7.16(d,J＝8.8Hz,1H),7.07(d,J＝8.8Hz,1H),4.43(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H).

Example 118- ((3-methoxyphenyl) amino) -6-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxyphenyl) amino) -6-fluoro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75 was carried out using 6-fluoro-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials to give 228mg of a white solid in 79% yield mp:121-122 ℃.

¹H NMR(CDCl₃)(ppm):8.93(brs,1H),7.24-7.21(m,2H),6.80-6.72(m,3H),6.64(d,J＝9.2Hz,1H),6.61(d,J＝8.8Hz,1H),6.10(brs,1H),4.40(q,J＝7.2Hz,2H),3.81(s,3H),1.41(t,J＝7.2Hz,3H).

b) 4- ((3-methoxyphenyl) amino) -6-fluoro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxyphenyl) amino) -6-fluoro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 146mg of a white powdery solid in 99% yield mp:228-230 ℃.

¹H NMR(DMSO-d₆)(ppm):12.79(brs,1H),11.72(s,1H),8.47(s,1H),7.40(s,1H),7.22(t,J＝8.0Hz,1H),6.86(d,J＝8.0Hz,1H),6.79(s,1H),6.59(s,1H),6.56-6.53(m,2H),3.74(s,3H).

c) 4- ((3-methoxyphenyl) amino) -6-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -6-fluoro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 44mg of a brown powdery solid in 47% yield mp:235-237 ℃.

¹H NMR(DMSO-d₆)(ppm):12.35(s,1H),11.70(s,1H),8.49(s,1H),7.94(d,J＝8.4Hz,2H),7.57(s,1H),7.20(t,J＝8.0Hz,1H),7.15(d,J＝8.4Hz,2H),6.79(d,J＝8.0Hz,1H),6.74(s,1H),6.60(s,1H),6.57(d,J＝4.4Hz,1H),6.53(d,J＝8.0Hz,1H),3.85(s,3H),3.73(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.08,161.84(J_CF＝235.6Hz),160.13,158.99,143.69,139.17(J_CF＝13.6Hz),138.38(J_CF＝15.8Hz),131.17,130.04,129.98,127.14,115.59,114.20,110.87,107.07,106.61,104.21,93.73(J_CF＝29.1Hz),89.54(J_CF＝26.3Hz),55.79,54.92.HRMS(ESI):m/z,calcd.for C₂₃H₂₁N₃O₅FS[M+H]⁺:470.1186,found470.1170.

Example 119- ((4-fluoro-3-chlorophenyl) amino) -6-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-fluoro-3-chlorophenyl) amino) -6-fluoro-1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 75 was repeated, starting from ethyl 6-fluoro-4-bromo-1H-indole-2-carboxylate and 3-methoxyaniline, to give 250mg of a white solid in 82% yield mp:183-185 ℃.

¹H NMR(CDCl₃)(ppm):8.94(s,1H),7.24(s,1H),7.17(s,1H),7.12(t,J＝8.8Hz,1H),7.06-7.04(m,1H),6.67(d,J＝9.2Hz,1H),6.53(d,J＝11.6Hz,1H),5.94(brs,1H),4.40(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H)

b) 4- ((4-fluoro-3-chlorophenyl) amino) -6-fluoro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((4-fluoro-3-chlorophenyl) amino) -6-fluoro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 146mg of a white powdery solid in 93% yield mp:226-229 ℃.

¹H NMR(DMSO-d₆)(ppm):12.83(s,1H),11.78(s,1H),8.59(s,1H),7.37-7.33(m,3H),7.25-7.23(m,1H),6.63(d,J＝9.2Hz,1H),6.53(d,J＝12.4Hz,1H)

c) 4- ((4-fluoro-3-chlorophenyl) amino) -6-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((4-fluoro-3-chlorophenyl) amino) -6-fluoro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 42mg of a brown powdery solid in 46% yield mp:256-258 ℃.

¹H NMR(DMSO-d₆)(ppm):12.35(s,1H),11.76(s,1H),8.62(s,1H),7.94(d,J＝8.4Hz,2H),7.50(s,1H),7.34(t,J＝8.8Hz,1H),7.27(dd,J₁＝6.0Hz,J₂＝1.6Hz,1H),7.15(d,J＝8.8Hz,3H),6.64(d,J＝9.2Hz,1H),6.54(d,J＝8.0Hz,1H),3.85(s,1H)

Preparation of intermediate 10: 4-trifluoromethyl-6-chloro-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (2-trifluoromethyl-4-chlorophenyl) acrylate

2-trifluoromethyl-4-chlorobenzaldehyde is used as a starting material, and the preparation process is the same as that of a) in the preparation 8 of an intermediate, so that 912mg of white solid is obtained, and the yield is 30%.

¹H NMR(CDCl₃)(ppm):8.10(d,J＝8.4Hz,1H),7.67(s,1H),7.54(d,J＝8.4Hz,1H),7.14(s,1H),4.39(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H).

b) 4-trifluoromethyl-6-chloro-1H-indole-2-carboxylic acid ethyl ester

Using 2-azido-3- (2-trifluoromethyl-4-chlorophenyl) ethyl acrylate as starting material, the preparation process was as described in b) of preparation 8 of intermediate to give 147mg of white solid, 43% yield, mp:190-191 ℃.

¹H NMR(CDCl₃)(ppm):9.27(brs,1H),7.61(s,1H),7.46(s,1H),7.35(s,1H),4.45(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H).

Example 120-trifluoromethyl-6-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4-trifluoromethyl-6-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 4-trifluoromethyl-6-chloro-1H-indole-2-carboxylate, the preparation is carried out as described in b) of example 3 to give 103mg of a white powdery solid in 103% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.19(s,1H),7.71(s,1H),7.43(s,1H),6.93(s,1H).

b) 4-trifluoromethyl-6-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4-trifluoromethyl-6-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide as starting materials, gave 42mg of a white powdery solid in 51% yield mp:235-237 ℃.

¹H NMR(DMSO-d₆)(ppm):12.59(brs,1H),12.43(s,1H),7.96(d,J＝8.8Hz,2H),7.76-7.72(m,1H),7.70(s,1H),7.52(s,1H),7.08(d,J＝8.4Hz,2H),3.85(s,3H).

Preparation of intermediate 11: 4, 6-bis (trifluoromethyl) -1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (2, 4-bis (trifluoromethyl) phenyl) acrylate

Starting from 2, 4-difluoromethylbenzaldehyde, the preparation was carried out as described in a) for the intermediate preparation 8 to give 268mg of a white solid in 18% yield.

¹H NMR(CDCl₃)(ppm):8.24(d,J＝8.4Hz,1H),7.93(s,1H),7.82(d,J＝8.4Hz,1H),7.17(s,1H),4.41(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).

b) 4, 6-bis (trifluoromethyl) -1H-indole-2-carboxylic acid ethyl ester

Taking 2-azido-3- (2, 4-bis (trifluoromethyl) phenyl) ethyl acrylate as a starting material, the preparation process is the same as that of b) in the preparation 8 of an intermediate, and 144mg of white solid is obtained, the yield is 42%, and mp is 190-191 ℃.

¹H NMR(CDCl₃)(ppm):9.48(brs,1H),7.93(s,1H),7.70(s,1H),7.43(s,1H),4.48(q,J＝7.2Hz,2H),1.46(t,J＝7.2Hz,3H).

Example 121, 6-bis (trifluoromethyl) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4, 6-bis (trifluoromethyl) -1H-indole-2-carboxylic acid

Starting from ethyl 4, 6-bis (trifluoromethyl) -1H-indole-2-carboxylate, the preparation is carried out as described in b) of example 3 to give 89mg of a white powdery solid in 89% yield mp:214-216 ℃.

¹H NMR(DMSO-d₆)(ppm):13.75(brs,1H),12.88(s,1H),8.05(s,1H),7.73(s,1H),7.19(s,1H).

b) 4, 6-bis (trifluoromethyl) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4, 6-bis (trifluoromethyl) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 39mg of a white powdery solid in 42% yield mp:262-264 ℃.

¹H NMR(DMSO-d₆)(ppm):12.78(s,1H),8.01(s,1H),7.98(d,J＝8.8Hz,2H),7.81(brs,1H),7.72(s,1H),7.16(d,J＝8.8Hz,2H),3.85(s,3H)

Preparation of intermediate 12: 7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (5-chloro-2-bromophenyl) acrylate

5-chloro-2-bromobenzaldehyde is used as a starting material, and the preparation process is the same as that described in a) of preparation 8 of an intermediate, so that 1.06g of a white solid is obtained with a yield of 23%.

¹H NMR(CDCl₃)(ppm):8.13(s,1H),7.53(d,J＝8.4Hz,1H),7.15(s,2H),4.40(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).

b) 7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Starting with ethyl 2-azido-3- (5-chloro-2-bromophenyl) acrylate, the preparation was as described in b) for intermediate preparation 8, yielding 500mg of a white solid at 44% yield, mp:154-155 ℃.

¹H NMR(CDCl₃)(ppm):9.11(brs,1H),7.27(d,J＝8.4Hz,2H),7.18(d,J＝8.0Hz,1H),4.44(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

Example 122-chloro-2-bromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 7-chloro-4-bromo-1H-indole-2-carboxylic acid

Starting from ethyl 7-chloro-4-bromo-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 110mg of a white powdery solid in 93% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.38(s,1H),12.48(s,1H),7.33(d,J＝8.0Hz,1H),7.29(d,J＝8.0Hz,1H),7.07(d,J＝2.0Hz,1H).

b) 7-chloro-2-bromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 7-chloro-4-bromo-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, was as described in c) to give 30mg of a white-like powdery solid in 31% yield mp:123-125 ℃.

¹H NMR(DMSO-d₆)(ppm):12.25(brs,1H),7.97(d,J＝8.8Hz,2H),7.55(brs,1H),7.32-7.33(m,2H),7.16(d,J＝8.8Hz,2H),3.85(s,3H),3.75(s,3H).

Example 123- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75, using 7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials, was as described in a) to give 160mg of a white solid in 66% yield mp:112-113 ℃.

¹H NMR(CDCl₃)(ppm):8.98(brs,1H),7.23(s,1H),7.19(d,J＝10.4Hz,2H),6.91(d,J＝8.0Hz,1H),6.70(d,J＝10.4Hz,2H),6.54(d,J＝8.0Hz,1H),5.96(brs,1H),4.42(q,J＝7.2Hz,2H),3.78(s,3H),1.41(t,J＝7.2Hz,3H).HRMS(ESI):m/z,calcd forC₁₈H₁₈N₂O₃Cl[M+H]⁺:345.1006,found 345.0994.

b) 4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 105mg of a white powdery solid in 100% yield mp:145-146 ℃.

¹H NMR(DMSO-d₆)(ppm):12.96(s,1H),11.78(s,1H),8.31(s,1H),7.46(s,1H),7.19-7.14(m,2H),6.84(d,J＝8.0Hz,1H),6.79(d,J＝8.0Hz,1H),6.74(s,1H),6.47(d,J＝8.0Hz,1H),3.72(s,1H).

c) 4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 21mg of a pale yellow powdery solid in 27% yield mp:124-125 ℃.

¹H NMR(DMSO-d₆)(ppm):12.34(brs,1H),11.68(s,1H),8.35(s,1H),7.96(d,J＝8.8Hz,2H),7.59(s,1H),7.20-7.15(m,4H),6.83(d,J＝8.4Hz,1H),6.73(d,J＝8.0Hz,2H),6.69(s,1H),6.47(d,J＝8.0Hz,1H),3.85(s,3H),3.71(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.21,160.10,158.21,144.23,136.67,135.39,130.82,130.19,129.88,128.04,125.51,120.38,114.28,110.27,108.82,107.19,106.00,105.97,103.51,55.82,54.86.HRMS(ESI):m/z,calcd.for C₂₃H₂₁N₃O₅ClS[M+H]⁺:486.0890,found 486.0877.

Example 124- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 75 was repeated, starting from ethyl 7-chloro-4-bromo-1H-indole-2-carboxylate and 4-fluoro-3-chloroaniline, to give 210mg of a white solid in 75% yield mp:159-160 ℃.

¹H NMR(CDCl₃)(ppm):9.01(s,1H),7.19(d,J＝8.4Hz,1H),7.17(d,J＝1.6Hz,1H),7.15(dd,J₁＝6.4Hz,J₂＝2.4Hz,1H),7.07(t,J＝8.4Hz,1H),6.94(dt,J₁＝8.8Hz,J₂＝3.2Hz,1H),6.77(d,J＝8.4Hz,1H),5.82(brs,1H),4.42(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).

b) 4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 122mg of a brown powdery solid in 98% yield mp:237-239 ℃.

¹H NMR(DMSO-d₆)(ppm):13.02(brs,1H),11.87(s,1H),8.45(s,1H),7.41(s,1H),7.33-7.27(m,2H),7.18-7.14(m,2H),6.79(d,J＝8.4Hz,1H).

c) 4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 40mg of a pale yellow powdery solid in 44% yield mp:210-212 ℃.

¹H NMR(DMSO-d₆)(ppm):12.35(s,1H),11.77(s,1H),8.48(s,1H),7.96(d,J＝8.8Hz,2H),7.53(s,1H),7.30(t,J＝8.8Hz,1H),7.22(d,J＝8.0Hz,2H),7.16(d,J＝8.4Hz,2H),7.09-7.07(m,1H),6.78(d,J＝8.0Hz,1H),3.85(s,3H)；¹³C NMR(100MHz,DMSO-d₆):163.22,158.09,151.50(J_CF＝238.0Hz),140.61,136.16,135.39,130.75,130.17,128.27,125.48,120.45,119.56(J_CF＝18.2Hz),118.74,117.71(J_CF＝6.1Hz),117.20(J_CF＝21.4Hz),114.26,108.46,108.09,106.40,55.78.HRMS(ESI):m/z,calcd.forC₂₂H₁₇N₃O₄Cl₂FS[M+H]⁺:508.0301,found508.0289.

Preparation of intermediate 13: 7-fluoro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (5-fluoro-2-bromophenyl) acrylate

5-fluoro-2-bromobenzaldehyde is used as a starting material, and the preparation process is the same as that of a) in the preparation 8 of an intermediate, so that 250mg of a white solid is obtained, and the yield is 23%.

¹H NMR(CDCl₃)(ppm):7.94(dd,J₁＝10.0Hz,J₂＝2.8Hz,1H),7.56(dd,J₁＝8.8Hz,J₂＝5.6Hz,1H),7.19(s,1H),6.92(dt,J₁＝8.0Hz,J₂＝2.8Hz,1H),4.40(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).

b) 7-fluoro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Taking 2-azido-3- (5-fluoro-2-bromophenyl) ethyl acrylate as a starting material, the preparation process is the same as that of b) in the preparation 8 of an intermediate, and 354mg of white solid is obtained, wherein the yield is 32%, and mp is 184-186 ℃.

¹H NMR(CDCl₃)(ppm):9.16(s,1H),7.23(dd,J₁＝8.0Hz,J₂＝4.0Hz,1H),6.92(t,J＝9.2Hz,1H),4.44(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

Example 125- ((3-methoxyphenyl) amino) -7-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((3-methoxyphenyl) amino) -7-fluoro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75, starting from ethyl 7-fluoro-4-bromo-1H-indole-2-carboxylate and 3-methoxyaniline in the presence of hydrogen peroxide in the solvent was as described in a) to give 130mg of a white solid in 51% yield mp:150-151 ℃.

¹H NMR(CDCl₃)(ppm):9.08(s,1H),7.20-7.15(m,2H),6.94(t,J＝8.4Hz,1H),6.87-6.85(m,1H),6.61(d,J＝8.4Hz,1H),6.59(s,1H),6.48(d,J＝8.0Hz,1H),4.41(q,J＝7.2Hz,2H),3.77(s,1H),1.41(t,J＝7.2Hz,3H).

b) 4- ((3-methoxyphenyl) amino) -7-fluoro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxyphenyl) amino) -7-fluoro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 100mg of a white powdery solid in 72% yield mp:163-165 ℃.

¹H NMR(DMSO-d₆)(ppm):12.92(brs,1H),12.16(s,1H),8.12(s,1H),7.33(s,1H),7.12(t,J＝8.0Hz,1H),6.94(t,J＝10.4Hz,1H),6.75(dd,J₁＝8.8Hz,J₂＝3.2Hz,1H),6.69(d,J＝8.4Hz,1H),6.65(s,1H),6.40(d,J＝8.0Hz,1H),3.70(s,3H)

c) 4- ((3-methoxyphenyl) amino) -7-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((3-methoxyphenyl) amino) -7-fluoro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 25mg of a pale yellow powdery solid in 27% yield mp:151-152 ℃.

¹H NMR(DMSO-d₆)(ppm):12.39(s,1H),12.09(s,1H),8.14(s,1H),7.94(d,J＝8.4Hz,2H),7.55(s,1H),7.16(d,J＝8.8Hz,2H),7.10(t,J＝8.0Hz,1H),6.98(t,J＝8.8Hz,1H),6.75(dd,J₁＝8.0Hz,J₂＝2.8Hz,1H),6.60(d,J＝8.0Hz,1H),6.56(s,1H),6.38(d,J＝8.4Hz,1H),3.85(s,3H),3.69(s,3H)；¹³C NMR(125MHz,DMSO-d₆):163.17,160.15,158.74,145.75,144.40(J_CF＝238.4Hz),133.16,130.94,130.13,129.79,128.42,126.28(J_CF＝15.1Hz),123.37(J_CF＝4.9Hz),114.26,110.01(J_CF＝16.4Hz),108.72,107.76,107.41(J_CF＝5.0Hz),104.69,101.81,55.81,54.78.HRMS(ESI):m/z,calcd.for C₂₃H₂₁N₃O₅FS[M+H]⁺:470.1186,found470.1175.

Example 126- ((4-fluoro-3-chlorophenyl) amino) -7-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((4-fluoro-3-chlorophenyl) amino) -7-fluoro-1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 75 was repeated, starting from ethyl 7-fluoro-4-bromo-1H-indole-2-carboxylate and 4-fluoro-3-chloroaniline, to give 200mg of a white solid in 65% yield mp:182-183 ℃.

¹H NMR(CDCl₃)(ppm):9.02(s,1H),7.13(t,J＝1.5Hz,1H),7.05-7.01(m,2H),6.95(t,J＝8.8Hz,1H),6.85-6.81(m,1H),6.75(dd,J₁＝8.0Hz,J₂＝3.2Hz,1H),5.65(brs,1H),4.41(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H).

b) 4- ((4-fluoro-3-chlorophenyl) amino) -7-fluoro-1H-indole-2-carboxylic acid

Starting from ethyl 4- ((4-fluoro-3-chlorophenyl) amino) -7-fluoro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 120mg of a white powdery solid in 100% yield mp:135-137 ℃.

¹H NMR(DMSO-d₆)(ppm):13.02(brs,1H),12.24(s,1H),8.27(s,1H),7.27-7.24(m,2H),7.17-7.15(m,1H),7.05-7.03(m,1H),6.97(t,J＝8.8Hz,1H),6.73(dd,J₁＝8.0Hz,J₂＝2.8Hz,1H).

c) 4- ((4-fluoro-3-chlorophenyl) amino) -7-fluoro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- ((4-fluoro-3-chlorophenyl) amino) -7-fluoro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 40mg of a pale yellow powdery solid in 44% yield mp:259-261 ℃.

¹H NMR(DMSO-d₆)(ppm):12.39(s,1H),12.16(s,1H),8.29(s,1H),7.94(d,J＝8.4Hz,2H),7.47(s,1H),7.24(t,J＝9.2Hz,1H),7.15(d,J＝8.4Hz,2H),7.04(d,J＝5.6Hz,1H),7.00(t,J＝9.6Hz,1H),6.92-6.90(m,1H),6.73(d,J＝5.6Hz,1H),3.85(s,3H).

Preparation of intermediate 14: 4, 7-dibromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (2, 5-dibromophenyl) acrylate

2, 5-dibromobenzaldehyde is used as a starting material, and the preparation process is the same as that of a) in the preparation 8 of an intermediate, so that 1.6g of white solid is obtained, and the yield is 23%.

¹H NMR(CDCl₃)(ppm):8.27(d,J＝2.0Hz,1H),7.46(d,J＝8.4Hz,1H),7.29(dd,J₁＝1.6Hz,J₂＝8.4Hz,1H),7.13(s,1H),4.40(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H).

b) 4, 7-dibromo-1H-indole-2-carboxylic acid ethyl ester

Using 2-azido-3- (2, 5-dibromophenyl) ethyl acrylate as a starting material and o-dichlorobenzene as a solvent, the preparation process is the same as that of b) in the preparation 8 of the intermediate, and 880mg of white solid is obtained, the yield is 59%, and mp is 129-130 ℃.

¹H NMR(CDCl₃)(ppm):9.06(brs,1H),7.33(d,J＝8.4Hz,2H),7.22(d,J＝8.0Hz,1H),4.45(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

Example 127-dibromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4, 7-dibromo-1H-indole-2-carboxylic acid

Starting from ethyl 4, 7-dibromo-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 130mg of a white powdery solid in 95% yield mp:180-182 ℃.

¹H NMR(DMSO-d₆)(ppm):13.27(brs,1H),12.20(brs,1H),7.41(d,J＝8.0Hz,1H),7.25(d,J＝8.0Hz,1H),7.07(s,1H).

b) 4, 7-dibromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4, 7-dibromo-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide as starting materials, was as described in c) to give 50mg of a white-like powdery solid in 51% yield mp:214-215 ℃.

¹H NMR(DMSO-d₆)(ppm):12.52(brs,1H),12.11(brs,1H),7.99(d,J＝8.8Hz,2H),7.54(s,1H),7.46(d,J＝8.0Hz,1H),7.30(d,J＝8.0Hz,1H),7.19(d,J＝8.8Hz,2H),3.87(s,3H).

Preparation of intermediate 15: 6-methyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (4-methyl-2-bromophenyl) acrylate

4-methyl-2-bromobenzaldehyde is used as a starting material in the same preparation process as in a) of preparation 8 of the intermediate, giving 2.13g of a white solid with a yield of 27%.

¹H-NMR(400MHz,CDCl₃)(ppm):8.03(d,J＝8.4Hz,1H),7.44(s,1H),7.25(s,1H),7.15(d,J＝8.4Hz,1H),4.39(q,J＝7.2Hz,2H),2.34(s,3H),1.41(t,J＝7.2Hz,3H).

b) 6-methyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Starting from ethyl 2-azido-3- (4-methyl-2-bromophenyl) acrylate, the preparation process is as described in b) of preparation 8 of the intermediate, giving 1.70g of a white solid, 93% yield, mp:152-153 ℃.

¹H NMR(CDCl₃)(ppm):8.93(brs,1H),7.21-7.20(m,2H),7.19(s,1H),7.14(s,1H),4.41(q,J＝7.2Hz,2H),2.44(s,3H),1.42(t,J＝7.2Hz,3H).

Example 128-methyl-4-bromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 6-methyl-4-bromo-1H-indole-2-carboxylic acid

Starting from ethyl 6-methyl-4-bromo-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 134mg of a white powdery solid in 100% yield mp:241-243 ℃.

¹H NMR(DMSO-d₆)(ppm):13.09(s,1H),12.01(s,1H),7.22(s,1H),7.17(s,1H),6.92(s,1H),2.40(s,3H).

b) 6-methyl-4-bromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 6-methyl-4-bromo-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, gave 44mg of a pale yellow powdery solid in 44% yield, mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.49(brs,1H),11.96(s,1H),7.96(d,J＝9.0Hz,2H),7.50(s,1H),7.14-7.10(m,4H),3.85(s,3H),2.37(s,3H).

Example 129 6-methyl-4- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 6-methyl-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of 6-methyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials was as described in a) of example 75 to give 236mg of a white solid in 82% yield mp:132-133 ℃.

¹H NMR(CDCl₃)(ppm):8.72(s,1H),7.20(t,J＝8.4Hz,1H),7.16(s,1H),6.83(s,2H),6.73(d,J＝9.2Hz,2H),6.53(d,J＝8.4Hz,1H),4.38(q,J＝7.2Hz,2H),3.79(s,3H),2.40(s,3H),1.40(t,J＝7.2Hz,3H).

b) 6-methyl-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid

Starting from 6-methyl-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 120mg of a white powdery solid in 97% yield mp:91-93 ℃.

¹H NMR(DMSO-d₆)(ppm):12.65(brs,1H),11.49(s,1H),8.14(s,1H),7.25(s,1H),7.15(t,J＝7.2Hz,1H),6.77(d,J＝11.2Hz,1H),6.74(s,2H),6.69(s,1H),6.43(dd,J₁＝6.8Hz,J₂＝2.4Hz,1H),3.71(s,3H),2.31(s,3H).

c) 6-methyl-4- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 6-methyl-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 36mg of a pale yellow powdery solid in 33% yield mp:223-225 ℃.

¹H NMR(DMSO-d₆)(ppm):12.27(s,1H),11.48(s,1H),8.16(s,1H),7.93(d,J＝8.8Hz,2H),7.47(s,1H),7.13(t,J＝9.2Hz,3H),6.74(s,1H),6.67(d,J＝8.0Hz,3H),6.41(d,J＝8.0Hz,1H),3.84(s,3H),3.70(s,3H),2.31(s,3H)；HRMS(ESI):m/z,calcd.forC₂₄H₂₄N₃O₅S[M+H]⁺:466.1437,found 466.1425.

Example 130-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 6-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 75 was repeated, starting from 6-methyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 4-fluoro-3-chloroaniline, to give 245mg of a white solid in 80% yield mp:166-167 ℃.

¹H NMR(CDCl₃)(ppm):8.73(s,1H),7.15(dd,J₁＝6.0Hz,J₂＝2.0Hz,1H),7.09(s,1H),7.05(t,J＝8.8Hz,1H),6.98-6.95(m,1H),6.85(s,1H),6.67(s,1H),5.75(brs,1H),4.39(q,J＝7.2Hz,2H),2.41(s,3H),1.40(t,J＝7.2Hz,3H).

b) 6-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid

Starting from 6-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 120mg of a brown powdery solid in 94% yield mp:155-157 ℃.

¹H NMR(DMSO-d₆)(ppm):11.57(s,1H),8.28(brs,1H),7.29(t,J＝12Hz,1H),7.23(dd,J₁＝8.8Hz,J₂＝2.8Hz,1H),7.19(s,1H),7.16-7.12(m,1H),6.79(s,1H),6.63(s,1H),2.33(s,3H).

c) 6-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 6-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, to give 61mg of a pale yellow powdery solid in 57% yield mp:264-266 ℃.

¹H NMR(DMSO-d₆)(ppm):12.27(s,1H),11.55(s,1H),8.31(s,1H),7.93(d,J＝8.8Hz,2H),7.39(s,1H),7.27(t,J＝8.8Hz,1H),7.15-7.11(m,3H),7.00-6.98(m,1H),6.80(s,1H),6.62(s,1H),3.84(s,3H),2.32(s,3H).

Preparation of intermediate 16: 7-methyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (5-methyl-2-bromophenyl) acrylate

5-methyl-2-bromobenzaldehyde is used as a starting material, and the preparation process is the same as that of a) in the preparation 8 of an intermediate, so that 1.0g of a white solid is obtained with the yield of 32%.

¹H NMR(CDCl₃)(ppm):7.90(s,1H),7.48(d,J＝8.4Hz,1H),7.23(s,1H),6.99(d,J＝8.4Hz,1H),4.39(q,J＝7.2Hz,2H),2.35(s,3H),1.41(t,J＝7.2Hz,3H).

b) 7-methyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Taking 2-azido-3- (5-methyl-2-bromophenyl) ethyl acrylate as a starting material, the preparation process is the same as that of b) in the preparation 8 of an intermediate, and 450mg of white solid is obtained, the yield is 92%, and mp is 120-122 ℃.

¹H NMR(CDCl₃)(ppm):8.91(brs,1H),7.26(s,1H),7.24(d,J＝8.0Hz,1H),6.97(d,J＝7.6Hz,1H),4.43(q,J＝7.2Hz,2H),2.48(s,3H),1.43(t,J＝7.2Hz,3H).

Example 131 methyl-4-bromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 7-methyl-4-bromo-1H-indole-2-carboxylic acid

Starting from ethyl 7-methyl-4-bromo-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 80mg of a white powdery solid in 84% yield and mp: >280 ℃.

¹H NMR(acetone-d₆)(ppm):11.41(s,1H),10.95(s,1H),7.25(d,J＝7.6Hz,1H),7.17(s,1H),7.04(d,J＝7.2Hz,1H),2.57(s,3H).

b) 7-methyl-4-bromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 7-methyl-4-bromo-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide as starting materials, gave 52mg of an off-white powdery solid in 63% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):12.52(brs,1H),11.91(s,1H),7.96(d,J＝9.0Hz,2H),7.46(s,1H),7.20(d,J＝7.5Hz,1H),6.14(d,J＝8.4Hz,2H),6.96(d,J＝7.2Hz,1H),3.84(s,3H),2.43(s,3H).

Example 132 methyl-4- ((4-fluoro-3-chlorophenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 7-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid ethyl ester

The procedure used in example 75 was carried out using 7-methyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 4-fluoro-3-chloroaniline as starting materials to give 156mg of a white solid in 58% yield mp:173-174 ℃.

¹H NMR(CDCl₃)(ppm):8.80(s,1H),7.15(s,1H),7.09(d,J＝4.0Hz,1H),7.05-7.01(m,2H),6.90(s,1H),6.82(d,J＝6.8Hz,1H),4.41(q,J＝7.2Hz,2H),2.48(s,3H),1.40(t,J＝7.2Hz,3H).

b) 7-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid

Starting from 7-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 87mg of a white powdery solid in 95% yield mp:224-226 ℃.

¹H NMR(DMSO-d₆)(ppm):12.82(s,1H),11.58(s,1H),8.21(s,1H),7.24(t,J＝8.8Hz,2H),7.15(dd,J₁＝6.0Hz,J₂＝1.6Hz,1H),7.03-7.01(m,1H),6.92(d,J＝7.2Hz,1H),6.75(d,J＝7.6Hz,1H),2.44(s,3H).

c) 7-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 7-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide in the same manner as in c) gave 40mg of a yellowish powdery solid in 52% yield mp:191-193 ℃.

¹H NMR(DMSO-d₆)(ppm):12.30(s,1H),11.50(s,1H),8.24(s,1H),7.95(d,J＝8.4Hz,2H),7.44(s,1H),7.23(t,J＝9.2Hz,1H),7.15(t,J＝8.8Hz,2H),7.05(d,J＝6.4Hz,1H),6.96-6.91(m,2H),6.74(d,J＝7.6Hz,1H),3.85(s,3H),2.41(s,3H)；HRMS(ESI):m/z,calcd.for C₂₃H₂₀N₃O₄FClS[M+H]⁺:488.0847,found 488.0835.

Preparation of intermediate 17: 7-methoxy-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (5-methoxy-2-bromophenyl) acrylate

5-methoxy-2-bromobenzaldehyde is used as a starting material, and the preparation process is the same as that in a) of the preparation 8 of an intermediate, so 2.5g of a white solid is obtained with the yield of 40%.

¹H NMR(CDCl₃)(ppm):7.72(d,J＝3.0Hz,1H),7.49(d,J＝8.7Hz,1H),7.22(s,1H),6.76(dd,J₁＝3.0Hz,J₂＝8.7Hz,1H),4.39(q,J＝7.2Hz,2H),3.83(s,3H),1.41(t,J＝7.2Hz,3H).

b) 7-methoxy-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Using 2-azido-3- (5-methoxy-2-bromophenyl) ethyl acrylate as starting material, as described in b) of preparation 8 of intermediate in the preparation process, 1.32g of white solid was obtained, yield 58%, mp:140-141 ℃.

¹H NMR(CDCl₃)(ppm)9.14(s,1H),7.20(d,J＝7.6Hz,2H),6.59(d,J＝8.0Hz,1H),4.42(q,J＝7.2Hz,2H),3.96(s,3H),1.42(t,J＝7.2Hz,3H).

Example 133 methoxy-4- ((4-fluoro-3-chlorophenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 7-methoxy-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75 was carried out using 7-methoxy-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 4-fluoro-3-chloroaniline as starting materials to give 176mg of a white solid in 72% yield mp:160-162 ℃.

¹H NMR(CDCl₃)(ppm):9.10(s,1H),7.08(s,1H),7.00-6.96(m,2H),6.84-6.78(m,2H),6.65(d,J＝8.4Hz,1H),4.39(q,J＝7.2Hz,2H),3.97(s,3H),1.39(t,J＝7.2Hz,3H).

b) 7-methoxy-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid

Starting from 7-methoxy-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 55mg of a brownish green powdery solid in 100% yield mp:193-195 ℃.

¹H NMR(DMSO-d₆)(ppm):12.76(brs,1H),11.70(s,1H),8.04(s,1H),7.19(t,J＝8.8Hz,1H),7.09(s,1H),7.00(d,J＝5.2Hz,1H),6.91-6.88(m,1H),6.76(d,J＝8.0Hz,1H),6.70(d,J＝8.0Hz,1H),3.87(s,3H).

c) 7-methoxy-4- ((4-fluoro-3-chlorophenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 7-methoxy-4- ((4-fluoro-3-chlorophenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide in the form of a yellowish powder, gives 26mg of a solid in the form of a yellowish powder with a yield of 43% and mp:125-126 ℃.

¹H NMR(DMSO-d₆)(ppm):12.19(s,1H),11.68(s,1H),8.06(s,1H),7.20-7.13(m,3H),6.92(d,J＝4.8Hz,1H),6.81-6.71(m,3H),3.87(s,3H),3.83(s,3H)；HRMS(ESI):m/z,calcd.for C₂₃H₂₀N₃O₅FClS[M+H]⁺:504.0796,found504.0782.

Preparation of intermediate 18: 7-cyano-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) 3- (dibromomethyl) -4-bromoxynil

3-methyl-4-bromoxynil (10g, 51mmol) was dissolved in carbon tetrachloride (100mL), NBS (22.6g, 127.5mmol) and benzoyl peroxide (272mg, 2.5mmol) were added, and the starting material was essentially disappeared by refluxing for 14 h. After cooling to room temperature, water (400mL) was added, EA extraction (200mL × 2) was performed, and column chromatography (P/E ═ 20:1) was performed to obtain 15g of a white solid with a yield of 83%.

¹H NMR(CDCl₃)(ppm):8.31(s,1H),7.66(d,J＝8.4Hz,1H),7.44(d,J＝8.0Hz,1H),7.00(s,1H).

b) 3-Methylaldehyde-4-bromoxynil

Sodium acetate (14.96g, 182.3mmol), calcium carbonate (9.34g, 93.28mmol) and TBAB (3.14g, 9.75mmol) were added to water (700mL) and, after stirring, 3- (dibromomethyl) -4-bromoxynil (15g, 42.4mmol) was added and the mixture refluxed for 29h, leaving a starting material portion. DCM extraction (200mL × 3) and column chromatography (P/E ═ 20:1-D) gave 6.17g of white solid in 69% yield.

¹H NMR(CDCl₃)(ppm):10.35(s,1H),8.18(s,1H),7.82(d,J＝8.0Hz,1H),7.70(d,J＝8.4Hz,1H),7.00(s,1H).

c) Ethyl 2-azido-3- (5-cyano-2-bromophenyl) acrylate

3-formaldehyde-4-bromoxynil was used as the starting material, and the preparation was as described in a) for intermediate preparation 8, to give 1.12g of a white solid with a yield of 12%.

¹H NMR(CDCl₃)(ppm):8.44(s,1H),7.73(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.13(s,1H),4.42(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).

d) 7-cyano-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Using 2-azido-3- (5-cyano-2-bromophenyl) ethyl acrylate as starting material, the preparation process is as described in b) of preparation 8 of intermediate, 300mg of white solid is obtained, yield is 30%, mp:193-194 ℃.

¹H NMR(CDCl₃)(ppm)9.55(s,1H),7.50(d,J＝7.6Hz,1H),7.42(d,J＝8.0Hz,1H),7.34(s,1H),4.48(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H).

Example 134-cyano-4- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 7-cyano-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid ethyl ester

The procedure used for the preparation of the starting material, ethyl 7-cyano-4-bromo-1H-indole-2-carboxylate and 3-methoxyaniline, was as in a) of example 75 to give 164mg of a white solid in 89% yield mp:189-191 ℃.

¹H NMR(CDCl₃)(ppm):9.29(s,1H),7.49(d,J＝8.4Hz,2H),7.31-7.27(m,2H),6.89-6.82(m,3H),6.71(d,J＝8.0Hz,1H),6.42(s,1H),4.44(q,J＝7.2Hz,2H),3.82(s,3H),1.43(t,J＝7.2Hz,3H).

b) 7-cyano-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid

Starting from 7-cyano-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 120mg of a white powdery solid in 95% yield mp:265-267 ℃.

¹H NMR(DMSO-d₆)(ppm):11.70(brs,1H),8.78(s,1H),7.44(d,J＝8.0Hz,1H),7.35(s,1H),7.24(t,J＝8.0Hz,1H),6.89(d,J＝8.0Hz,1H),6.84(s,1H),6.80(d,J＝8.4Hz,1H),6.61(d,J＝8.4Hz,1H),3.74(s,3H).

c) 7-cyano-4- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure described in example 3 c) was repeated, starting from 7-cyano-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 16mg of a yellowish, powdery solid in 34% yield mp:236-238 ℃.

¹H NMR(DMSO-d₆)(ppm):12.28(brs,1H),12.16(s,1H),8.99(s,1H),7.97(d,J＝8.8Hz,2H),7.69(s,1H),7.56(d,J＝8.0Hz,1H),7.28(t,J＝8.0Hz,2H),7.17(d,J＝8.4Hz,2H),6.88(d,J＝8.0Hz,1H),6.83(s,1H),6.81(d,J＝8.8Hz,1H),6.67(d,J＝8.0Hz,1H),3.86(s,3H),3.75(s,3H).

Preparation of intermediate 19: 7-trifluoromethyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (5-trifluoromethyl-2-bromophenyl) acrylate

5-trifluoromethyl-2-bromobenzaldehyde was used as starting material in the same preparation as described in preparation 8 of the intermediate under a) to give 1.23g of a white solid with a yield of 17%.

¹H NMR(CDCl₃)(ppm):8.38(s,1H),7.73(d,J＝8.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.20(s,1H),4.42(q,J＝7.2Hz,2H),1.42(t,J＝7.2Hz,3H).

b) 7-trifluoromethyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester

Using 2-azido-3- (5-trifluoromethyl-2-bromophenyl) ethyl acrylate as a starting material and o-dichlorobenzene as a solvent, the preparation process is the same as that of b) in the preparation of the intermediate 8, and 624mg of white solid is obtained, the yield is 60%, and mp is 123-124 ℃.

¹H NMR(CDCl₃)(ppm):9.21(brs,1H),7.46-7.43(m,2H),7.34(s,1H),4.46(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H).

Example 135-trifluoromethyl-4- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 7-trifluoromethyl-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid ethyl ester

The preparation of 7-trifluoromethyl-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials was carried out as described in a) in example 75 to give 181mg of a white solid in 80% yield mp:129-130 ℃.

¹H NMR(CDCl₃)(ppm):9.07(brs,1H),7.44(d,J＝8.0Hz,1H),7.28-7.25(m,2H),6.94(d,J＝8.0Hz,1H),6.83-6.80(m,2H),6.65(d,J＝8.4Hz,1H),6.20(brs,1H),4.43(q,J＝7.2Hz,2H),3.81(s,3H),1.43(t,J＝7.2Hz,3H).

b) 7-trifluoromethyl-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid

Starting from 7-trifluoromethyl-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 95mg of a brown powdery solid in 95% yield, mp:162-164 ℃.

¹H NMR(DMSO-d₆)(ppm):11.51(s,1H),8.69(s,1H),7.64(s,1H),7.42(m,J＝8.4Hz,1H),7.25(t,J＝8.0Hz,1H),6.94-6.86(m,3H),6.60(d,J＝8.0Hz,1H),3.75(s,3H).

c) 7-trifluoromethyl-4- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 7-trifluoromethyl-4- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 28mg of a yellowish, powdery solid in 34% yield mp:119-120 ℃.

¹H NMR(DMSO-d₆)(ppm):12.46(brs,1H),11.47(s,1H),8.75(s,1H),7.97(d,J＝8.8Hz,2H),7.72(s,1H),7.46(d,J＝8.4Hz,1H),7.25(t,J＝8.0Hz,1H),7.16(d,J＝8.4Hz,2H),6.87(d,J＝8.0Hz,2H),6.83(s,1H),6.61(d,J＝8.0Hz,1H),3.86(s,3H),3.74(s,3H).

Preparation of intermediate 20: 4-chloro-7-bromo-1H-indole-2-carboxylic acid ethyl ester

a) Ethyl 2-azido-3- (2-chloro-5-bromophenyl) acrylate

2-chloro-5-bromobenzaldehyde was used as starting material in the same procedure as described in a) for preparation 8 of the intermediate to give 1.49g of a white solid with a yield of 20%.

¹H NMR(CDCl₃)(ppm):8.33(d,J＝1.6Hz,1H),6.88(d,J₁＝1.6Hz,J₂＝8.8Hz,1H),7.27(d,J＝8.8Hz,1H),7.18(s,1H),4.40(q,J＝7.2Hz,2H),1.41(t,J＝7.2Hz,3H).

b) 4-chloro-7-bromo-1H-indole-2-carboxylic acid ethyl ester

Taking 2-azido-3- (2-chloro-5-bromophenyl) ethyl acrylate as a starting material and o-dichlorobenzene as a solvent, the preparation process is the same as that of b) in the preparation of an intermediate 8, and obtaining white solid 825mg, wherein the yield is 66%, and mp is 130-131 ℃.

¹HNMR(CDCl₃)(ppm):9.03(brs,1H),7.39(d,J＝8.4Hz,2H),7.06(d,J＝8.0Hz,1H),4.45(q,J＝7.2Hz,2H),1.44(t,J＝7.2Hz,3H).

Example 136-chloro-7- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4-chloro-7- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 75 was repeated, starting from ethyl 4-chloro-7-bromo-1H-indole-2-carboxylate and 3-methoxyaniline, to give 42mg of a white solid in 18% yield mp:102-103 ℃.

¹H NMR(CDCl₃)(ppm):8.96(brs,1H),7.32-7.31(m,2H),7.14-7.09(m,3H),6.40-6.36(m,3H),4.38(q,J＝7.2Hz,2H),3.74(s,3H),1.39(t,J＝7.2Hz,3H).

b) 4-chloro-7- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid

Starting from ethyl 4-chloro-7- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylate, the procedure is as described in b) of example 3 to give 32mg of a grey, powdery solid in 97% yield mp:84-86 ℃.

¹H NMR(DMSO-d₆)(ppm):13.27(brs,1H),11.89(s,1H),8.09(s,1H),7.19(t,J＝8.0Hz,2H),7.08(d,J＝8.4Hz,1H),7.03-7.02(m,2H),6.76(d,J＝8.0Hz,2H),6.70(s,1H),6.49(d,J＝8.0Hz,1H),3.73(s,3H).

c) 4-chloro-7- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4-chloro-7- ((3-methoxyphenyl) amino) -1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, to give 10mg of a yellowish powdery solid in 10mg yield and mp:169-170 ℃.

¹H NMR(acetone-d₆)(ppm):11.01(brs,1H),10.89(brs,1H),8.06(d,J＝8.8Hz,2H),7.55(s,1H),7.46(s,1H),7.20-7.06(m,5H),6.71-6.68(m,2H),6.49(d,J＝8.4Hz,1H),3.91(s,3H),3.75(s,3H).

Preparation of intermediate 21: 1-methyl-4-chloro-7-bromo-1H-indole-2-carboxylic acid ethyl ester

The procedure was as described for intermediate preparation 5 using 4-chloro-7-bromo-1H-indole-2-carboxylic acid ethyl ester and methyl iodide as starting materials to give 309mg of white solid in 99% yield mp:92-93 ℃.

¹H NMR(CDCl₃)(ppm):7.40(d,J＝8.0Hz,1H),7.37(s,1H),6.98(d,J＝8.0Hz,1H),4.47(s,3H),4.39(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H).

Example 137 methyl-7- ((3-methoxyphenyl) amino) -4-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-7- ((3-methoxyphenyl) amino) -4-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of preparation of 1-methyl-4-chloro-7-bromo-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials was as described in a) of example 3 to give 80mg of a pale yellow solid in 28% yield mp:40-41 ℃.

¹H NMR(CDCl₃)(ppm):7.40(s,1H),7.10-7.08(m,2H),7.01(d,J＝8.0Hz,1H),6.39(d,J＝7.2Hz,1H),6.23(d,J＝8.0Hz,1H),6.15(s,1H),5.40(brs,1H),4.37(q,J＝7.2Hz,2H),4.20(s,3H),3.72(s,3H),1.41(t,J＝7.2Hz,3H).

b) 1-methyl-7- ((3-methoxyphenyl) amino) -4-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-7- ((3-methoxyphenyl) amino) -4-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 83mg of a grey powdery solid in 94% yield mp:219-221 ℃.

¹H NMR(DMSO-d₆)(ppm):13.17(brs,1H),7.89(s,1H),7.19(s,1H),7.16(d,J＝8.0Hz,1H),7.07-7.02(m,2H),6.32-6.29(m,1H),6.20-6.18(m,2H),4.09(s,3H),3.65(s,3H).

c) 1-methyl-7- ((3-methoxyphenyl) amino) -4-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-7- ((3-methoxyphenyl) amino) -4-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, 45mg of a yellow powdery solid are obtained in the same manner as in c) of example 3, yield 60%, mp:180-182 ℃.

¹H NMR(DMSO-d₆)(ppm):12.50(brs,1H),7.94(d,J＝8.4Hz,2H),7.86(s,1H),7.57(brs,1H),7.18-7.14(m,3H),7.05(d,J＝8.4Hz,1H),7.00(d,J＝8.4Hz,1H),6.30(m,1H),6.14(m,2H),3.91(s,3H),3.84(s,3H),3.63(s,3H).

Example 138- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-7-azaindole-2-carboxamide

a) 4- ((3-methoxyphenyl) amino) -1H-7-azaindole-2-carboxylic acid ethyl ester

The procedure used in example 75 was carried out using 4-chloro-1H-7-azaindole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials to give 194mg of a white solid in 64% yield mp:215-217 ℃.

¹H NMR(DMSO-d₆)(ppm):12.16(brs,1H),8.93(s,1H),8.05(d,J＝5.6Hz,1H),7.50(s,1H),7.28(t,J＝8.4Hz,1H),6.93(d,J＝8.0Hz,1H),6.87(s,1H),6.76(d,J＝5.6Hz,1H),6.66(d,J＝8.4Hz,1H),4.32(q,J＝7.2Hz,2H),3.77(s,3H),1.34(t,J＝7.2Hz,3H).

b) 4- ((3-methoxyphenyl) amino) -1H-7-azaindole-2-carboxylic acid

Starting from ethyl 4- ((3-methoxyphenyl) amino) -1H-7-azaindole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 103mg of a gray powdery solid in 100% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):13.20(brs,1H),12.68(brs,1H),9.80(s,1H),8.02(d,J＝6.4Hz,1H),7.49(s,1H),7.35(t,J＝8.0Hz,1H),6.95(d,J＝8.0Hz,1H),6.92(s,1H),6.80(d,J＝8.0Hz,1H),6.73(d,J＝6.4Hz,1H),3.77(s,3H).

c) 4- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -1H-7-azaindole-2-carboxamide

Starting from 4- ((3-methoxyphenyl) amino) -1H-7-azaindole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 30mg of a yellowish powdery solid in 19% yield and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):9.32(brs,1H),7.97-7.87(m,2H),7.33(m,2H),7.04-6.73(m,7H),3.81(s,3H),3.77(s,3H).

Preparation of intermediate 22: 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

The preparation process is the same as the preparation 5 of an intermediate by using 7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester and iodomethane as starting materials to obtain 436mg of white solid, the yield is 93%, and mp is 75-76 ℃.

¹H NMR(CDCl₃)(ppm):7.32(s,1H),7.19(d,J＝8.0Hz,1H),7.13(d,J＝8.0Hz,1H),4.46(s,3H),4.39(q,J＝7.2Hz,2H),1.43(t,J＝7.2Hz,3H).

Example 139-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of a) in example 75 was repeated, starting from ethyl 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylate and 3-methoxyaniline, to give 146mg of a white solid in 86% yield mp:119-120 ℃.

¹H NMR(CDCl₃)(ppm):7.30(s,1H),7.20(t,J＝8.4Hz,1H),7.15(d,J＝8.4Hz,1H),6.88(d,J＝7.2Hz,1H),6.69(m,2H),6.53(d,J＝6.8Hz,1H),4.47(s,3H),4.37(q,J＝7.2Hz,2H),3.79(s,3H),1.40(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 90mg of an off-white powdery solid in 98% yield mp:184-185 ℃.

¹H NMR(DMSO-d₆)(ppm):13.00(s,1H),8.34(s,1H),7.61(s,1H),7.17(t,J＝8.0Hz,2H),6.84(d,J＝8.4Hz,1H),6.79(d,J＝8.0Hz,1H),6.75(s,1H),6.49(d,J＝8.0Hz,1H),4.35(s,3H),3.72(s,3H).

c) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure used in example 3 c) was carried out starting from 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide to give 40mg of a pale yellow powdery solid in 53% yield mp:182-183 ℃.

¹H NMR(DMSO-d₆)(ppm):12.48(brs,1H),8.35(s,1H),7.94(d,J＝8.4Hz,2H),7.66(s,1H),7.19-7.15(m,4H),6.84(d,J＝8.4Hz,1H),6.75(d,J＝8.0Hz,1H),6.71(s,1H),6.48(d,J＝8.4Hz,1H),4.11(s,3H),3.85(s,3H),3.71(s,3H)；¹³C NMR(100MHz,DMSO-d₆):163.09,160.09,159.63,144.06,136.99,135.29,131.01,130.00,129.88,128.79,127.87,120.31,116.27,114.25,110.23,109.41,106.70,106.06,103.54,55.75,54.85,33.89.HRMS(ESI):m/z,calcd.for C₂₄H₂₃N₃O₅ClS[M+H]⁺:500.1047,found 500.1036.

Example 140 methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and benzenesulfonamide, the preparation was carried out as described in c) of example 3 to give 89mg of a pale yellow powdery solid in 89% yield mp:172-173 ℃.

¹H NMR(DMSO-d₆)(ppm):12.66(brs,1H),8.38(s,4H),8.02(d,J＝7.4Hz,1H),7.76-7.720(m,2H),7.67(t,J＝7.6Hz,1H),7.20-7.16(m,2H),6.86(d,J＝8.0Hz,1H),6.76(d,J＝8.0Hz,1H),6.73(s,1H),6.50(d,J＝8.0Hz,1H),4.11(s,3H),3.73(s,3H).

Example 141 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 3-methoxybenzenesulfonamide in the amount of 1-methyl-4- ((c) methoxy-phenyl) amino), gave 75mg of a pale yellow powdery solid in 71% yield, mp:145-146 ℃.

¹H NMR(acetone-d₆)(ppm):7.68(d,J＝8.0Hz,1H),7.64(s,1H),7.59(s,1H),7.56(d,J＝8.0Hz,1H),7.30(d,J＝8.4Hz,1H),7.21(d,J＝8.4Hz,1H),7.19(t,J＝8.4Hz,1H),6.93(d,J＝8.0Hz,1H),6.78-6.75(m,2H),6.53(d,J＝8.4Hz,1H),4.25(s,3H),3.91(s,3H),3.76(s,3H)；¹³C NMR(100MHz,DMSO-d₆):160.09,159.67,159.14,144.02,140.87,137.03,135.37,130.43,129.88,128.66,127.99,120.27,119.45,119.23,112.63,110.28,109.66,106.67,106.11,105.87,103.58,55.65,54.85,33.91.

Example 142 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-hydroxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((tert-butyldimethylsilyl) oxy) benzenesulfonamide

4-hydroxybenzenesulfonamide (200mg, 1.15mmol) was dissolved in DMF (5mL), TBDMSCl (260mg, 1.73mmol) and imidazole (118mg, 1.73mmol) were added, the reaction was allowed to proceed at room temperature overnight, and the starting material disappeared. The reaction mixture was poured into ice water to precipitate a white solid, which was filtered and dried to obtain 260mg of white crystals with a yield of 79% mp:114-115 ℃.

¹H NMR(CDCl₃)(ppm):7.81(d,J＝8.4Hz,2H),6.92(d,J＝8.4Hz,2H),4.74(s,2H),0.99(s,9H),0.24(s,6H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- ((4-TBDMSO) benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4- ((tert-butyldimethylsilyl) oxy) benzenesulfonamide as starting materials, gave 90mg of a pale yellow powdery solid in 55% yield, mp:204-206 ℃.

¹H NMR(DMSO-d₆)(ppm):12.51(s,1H),8.37(s,1H),7.92(d,J＝8.8Hz,2H),7.68(s,1H),7.20-7.16(m,2H),7.10(d,J＝8.4Hz,2H),6.86(d,J＝8.4Hz,1H),6.76(d,J＝8.0Hz,1H),6.72(s,1H),6.49(d,J＝8.4Hz,1H),4.12(s,3H),3.72(s,3H),0.96(s,9H),0.25(s,6H).

c) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-hydroxybenzenesulfonyl) -1H-indole-2-carboxamide

1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- ((4-TBDMSO) benzenesulfonyl) -1H-indole-2-carboxamide (60mg, 0.10mmol) was dissolved in anhydrous THF (2mL), TBAF (48mg, 0.15mmol) in THF (2mL) was added and the reaction was allowed to proceed at room temperature for 30min and the starting material disappeared. The solvent was distilled off, EA (20mL) was added, washed with dilute hydrochloric acid, and column chromatography (D/M: 40:1) was performed to give 35mg of a yellow-green solid in 73% yield, mp:135-137 ℃.

¹H NMR(DMSO-d₆)(ppm):12.40(s,1H),10.62(s,1H),8.36(s,1H),7.84(d,J＝8.4Hz,2H),7.66(s,1H),7.20-7.16(m,2H),6.96(d,J＝8.8Hz,2H),6.85(d,J＝8.0Hz,1H),6.76(d,J＝8.0Hz,1H),6.72(s,1H),6.49(d,J＝8.0Hz,1H),4.12(s,3H),3.72(s,3H).

EXAMPLE 143 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (2-methoxyethoxy) benzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (2-methoxyethoxy) benzenesulfonamide

4-hydroxybenzenesulfonamide (100mg, 0.58mmol) was dissolved in DMF (6mL) and 2-bromoethyl methyl ether (88mg, 0.64mmol) and C were added_S2CO₃(373mg, 1.15mmol), reaction at 50 ℃ for 6h, disappearance of starting material, pouring the reaction mixture into water (20mL), EA extraction (20mL × 3), column chromatography (D/M50: 1) to give 140mg of white crystals, 52% yield, mp:155-157 ℃.

¹H NMR(DMSO-d₆)(ppm):7.73(d,J＝8.8Hz,2H),7.20(s,2H),7.09(d,J＝8.8Hz,2H),4.17(t,J＝4.4Hz,2H),3.67(t,J＝4.4Hz,2H),3.31(s,3H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (2-methoxyethoxy) benzenesulfonyl) -1H-indole-2-carboxamide

The procedure was carried out as described in c) of example 3, starting from 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4- (2-methoxyethoxy) benzenesulfonamide, to give 58mg of a pale yellow powdery solid in 51% yield and mp:179-180 ℃.

¹H NMR(DMSO-d₆)(ppm):12.49(s,1H),8.35(s,1H),7.92(d,J＝8.8Hz,1H),7.67(s,1H),7.18-7.15(m,4H),6.84(d,J＝8.4Hz,1H),6.75(d,J＝8.0Hz,1H),6.71(s,1H),6.48(d,J＝8.4Hz,1H),4.20(t,J＝4.0Hz,2H),4.11(s,3H),3.71(s,3H),3.67(t,J＝4.0Hz,2H),3.30(s,3H).

Example 144 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (2-hydroxyethoxy) benzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (2- (TBDMSO) ethoxy) benzenesulfonamide

The procedure is as described in example 143 a) using 4-hydroxybenzenesulfonamide and 2- (TBDMSO) bromoethane as starting materials to give 134mg of white crystals in 35% yield, mp:103-105 ℃.

¹H NMR(DMSO-d₆)(ppm):7.73(d,J＝8.4Hz,2H),7.19(s,2H),7.07(d,J＝8.4Hz,2H),4.10(t,J＝4.4Hz,2H),3.93(t,J＝4.4Hz,1H),0.87(s,9H),0.07(s,6H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (2- (TBDMSO) ethoxy) benzenesulfonyl) -1H-indole-2-carboxamide and 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (2-hydroxyethoxy) benzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4- (2- (TBDMSO) ethoxy) benzenesulfonamide, preparation was carried out as described in c) of example 3, by column chromatography (D/M ═ 500:1) to give 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (2- (TBDMSO) ethoxy) benzenesulfonyl) -1H-indole-2-carboxamide: 4mg of light yellow solid, mp is 166-168 ℃;¹H NMR(acetone-d₆)(ppm):8.05(d,J＝8.8Hz,2H),7.56(s,1H),7.21-7.16(m,3H),6.93(d,J＝8.0Hz,1H),6.78-6.75(m,2H),6.52(d,J＝8.8Hz,1H),4.25(s,3H),4.23(t,J＝4.4Hz,1H),4.04(t,J＝4.4Hz,1H),3.76(m,3H),0.89(s,9H),0.10(s,6H).

column chromatography (D/M ═ 20:1) to give 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (2-hydroxyethoxy) benzenesulfonyl) -1H-indole-2-carboxamide as a yellowish solid 78mg, mp:177-179 ℃;

¹H NMR(acetone-d₆)(ppm):8.05(d,J＝8.8Hz,2H),7.56(s,1H),7.21-7.15(m,4H),6.93(d,J＝8.4Hz,1H),6.78-6.75(m,2H),6.53(d,J＝8.0Hz,1H),4.25(s,3H),4.21(t,J＝4.4Hz,2H),3.90(t,J＝4.8Hz,2H),3.76(s,3H).

example 145 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (3-methoxypropoxy) benzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (3-Methoxypropoxy) benzenesulfonamide

The procedure is as described in example 143 a) except that starting materials are 4-hydroxybenzenesulfonamide and 1-bromo-3-methoxypropane, 120mg of white crystals are obtained in 47% yield, mp:94-96 ℃.

¹H NMR(CDCl₃)(ppm):7.85(d,J＝8.4Hz,2H),6.98(d,J＝8.8Hz,2H),4.74(s,2H),4.12(t,J＝6.0Hz,2H),3.55(t,J＝6.4Hz,2H),3.56(s,3H),2.07(t,J＝6.0Hz,2H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (3-methoxypropoxy) benzenesulfonyl) -1H-indole-2-carboxamide

The procedure was carried out as described in c) of example 3, starting from 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4- (3-methoxypropoxy) benzenesulfonamide, to give 82mg of a pale yellow powdery solid in 69% yield, mp:189-190 ℃.

¹H NMR(DMSO-d₆)(ppm):8.36(s,1H),7.93(d,J＝8.8Hz,2H),7.68(s,1H),7.20-7.16(m,4H),6.86(d,J＝8.0Hz,1H),6.76(d,J＝8.0Hz,1H),6.72(s,1H),6.49(d,J＝8.4Hz,1H),4.14-4.12(m,5H),3.72(s,3H),3.47(t,J＝6.0Hz,2H),3.25(s,3H),1.97(quint,J＝6.4Hz,2H).

EXAMPLE 146 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (3-hydroxypropoxy) benzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (3- (TBDMSO) propoxy) benzenesulfonamide

Starting from 4-hydroxybenzenesulfonamide and 3- (TBDMSO) bromopropane, the procedure is as described in a) of example 143 to give 447mg of white crystals in 56% yield mp:91-92 ℃.

¹H NMR(CDCl₃)(ppm):7.85(d,J＝8.4Hz,2H),6.98(d,J＝8.8Hz,21H),4.66(s,2H),4.13(t,J＝6.4Hz,2H),3.80(t,J＝5.6Hz,2H),2.00(t,J＝6.0Hz,2H),0.88(s,9H),0.04(s,6H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (3- (TBDMSO) propoxy) benzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4- (3- (TBDMSO) propoxy) benzenesulfonamide, the procedure is as described in c) of example 3, giving 100mg of a yellowish solid in 68% yield mp:209-210 ℃.

¹H NMR(DMSO-d₆)(ppm):12.47(s,1H),8.35(s,1H),7.92(d,J＝8.8Hz,2H),7.67(s,1H),7.16-7.14(m,4H),6.84(d,J＝8.4Hz,1H),6.75(d,J＝7.6Hz,1H),6.71(s,1H),6.48(d,J＝7.6Hz,1H),4.15-4.10(m,5H),3.75-3.71(m,5H),1.91(quint,J＝6.0Hz,2H),0.82(s,9H),0.00(s,6H).

c) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (3-hydroxypropoxy) benzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (3- (TBDMSO) propoxy) benzenesulfonyl) -1H-indole-2-carboxamide, preparation was carried out as described in c) of example 142 to give 41mg of a yellow solid in 82% yield, mp:170 and 172 ℃.

¹H NMR(DMSO-d₆)(ppm):12.47(s,1H),8.36(s,1H),7.92(d,J＝8.8Hz,1H),7.67(s,1H),7.19-7.15(m,4H),6.85(d,J＝8.4Hz,1H),6.75(d,J＝7.6Hz,1H),6.72(m,1H),6.48(d,J＝8.0Hz,1H),4.14(t,J＝6.4Hz,2H),4.11(s,3H),3.72(s,3H),3.55(t,J＝6.4Hz,2H),1.88(quint,J＝6.4Hz,2H)；HRMS(ESI):m/z,calcd.for C₂₆H₂₇N₃O₆ClS[M+H]⁺:544.1309,found 544.1298.

Example 147 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-isobutylbenzenesulfonyl) -1H-indole-2-carboxamide and example 148: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-bromobenzenesulfonyl) -1H-indole-2-carboxamide

a) 3-isobutylbenzenesulfonamide

3-bromobenzenesulfonamide (500mg, 2.12mmol) was dissolved in toluene (30mL) and Pd (dppf) Cl was added in that order₂(78mg, 0.11mmol) and Cs₂CO₃(2.06g，6.36mmol，6mL H₂O), stirring well, adding isobutylboronic acid (648mg, 6.36mmol), refluxing under argon for 4h, cooling to room temperature, concentrating, adding EA (30mL) to dissolve the residue, washing with saturated brine (20mL × 3), washing with water (20mL × 2), performing column chromatography (D/M ═ 100:1) to obtain 400mg (impure) of a white powdery solid, and taking 60mg of preparative TLC to obtain 20mg of a white powdery solid, which is the target product, mp:95-97 ℃.

¹H NMR(CDCl₃)(ppm):7.75(d,J＝7.6Hz,1H),7.72(s,1H),7.43(t,J＝7.6Hz,1H),7.36(d,J＝7.6Hz,1H),4.72(s,2H),2.55(d,J＝7.2Hz,2H),1.90(quint,J＝6.8Hz,1H),0.92(d,J＝6.8Hz,6H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-isobutylbenzenesulfonyl) -1H-indole-2-carboxamide BJB-3418-1 and 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-bromobenzenesulfonyl) -1H-indole-2-carboxamide

Using 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and the mixture of 3-isobutylbenzenesulfonamide and 3-bromobenzenesulfonamide as starting materials, the preparation process was the same as that described in c) of example 3, and preparative TLC separation was carried out to obtain 55mg of 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-isobutylbenzenesulfonyl) -1H-indole-2-carboxamide, mp: 178-;

¹H NMR(acetone-d₆)(ppm):7.94-7.93(m,2H),7.57-7.56(m,3H),7.21-7.16(m,2H),6.93(d,J＝8.0Hz,1H),6.78-6.76(m,2H),6.53(d,J＝8.0Hz,1H),4.23(s,3H),3.76(s,3H),2.63(d,J＝7.2Hz,2H),1.98-1.89(m,1H),0.92(d,J＝6.4Hz,6H)；HRMS(ESI):m/z,calcd for C₂₇H₂₉N₃O₄ClS[M+H⁺]:526.1567,found526.1553.

to obtain 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-bromobenzenesulfonyl) -1H-indole-2-carboxamide, 45mg, mp: 230-.

¹H NMR(acetone-d₆)(ppm):8.13(s,1H),7.96(d,J＝7.6Hz,1H),7.60(t,J＝8.0Hz,1H),7.38(t,J＝8.0Hz,1H),7.31(s,1H),7.14(t,J＝8.4Hz,1H),7.03(d,J＝8.4Hz,1H),6.89-6.84(m,3H),6.46(d,J＝8.0Hz,1H),4.37(s,3H),3.75(s,3H)；HRMS(ESI):m/z,calcd for C₂₃H₂₀N₃O₄BrClS[M+H⁺]:550.0026,found 550.0004.

Example 149: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- ((1-Boc-piperidin-4-yl) oxy) benzenesulfonyl) -1H-indole-2-carboxamide

a) 4- ((1-Boc-piperidin-4-yl) oxy) benzenesulfonamide

4-hydroxybenzenesulfonamide (100mg, 0.58mmol) was dissolved in acetone (2mL) and N-Boc-4-bromopiperidine (304mg, 1.15mmol) and K were added₂CO₃(160mg, 1.15mmol), microwave reaction (100w, 120 ℃, 12h, 150psi), raw material portion remained, pouring the reaction solution into water (20mL), EA extraction (20mL × 3), column chromatography (D/M50: 1) to obtain colorless oil, solidifying with diethyl ether, filtering to obtain white crystal 60mg, yield 24%, mp: 185-.

¹H NMR(CDCl₃)(ppm):7.86(d,J＝8.8Hz,2H),6.98(d,J＝8.8Hz,2H),4.72(s,2H),4.57(m,1H),3.71-3.67(m,2H),3.40-3.34(m,2H),1.94(m,2H),1.78(m,2H),1.47(s,9H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- ((1-Boc-piperidin-4-yl) oxy) benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4- ((1-Boc-piperidin-4-yl) oxy) benzenesulfonamide as starting materials, gave 61mg of a pale yellow powdery solid in 60% yield, mp: 143-.

¹H NMR(DMSO-d₆)(ppm):12.49(s,2H),8.37(s,1H),7.93(d,J＝8.8Hz,2H),7.68(s,1H),7.22-7.16(m,4H),6.86(d,J＝8.0Hz,1H),6.76(d,J＝8.4Hz,1H),6.72(s,1H),6.49(d,J＝8.4Hz,1H),4.72(s,1H),4.13(s,3H),3.72(s,3H),3.69-3.62(m,2H),3.19-3.13(m,2H),1.95-1.93(d,J＝11.2Hz,2H),1.56-1.51(m,2H),1.40(s,9H)；HRMS(ESI):m/z,calcd for C₃₃H₃₈N₄O₇ClS[M+H⁺]:669.2150,found 669.2065.

Example 150: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- ((piperidin-4-yl) oxy) benzenesulfonyl) -1H-indole-2-carboxamide

1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- ((1-Boc-piperidin-4-yl) oxy) benzenesulfonyl) -1H-indole-2-carboxamide (33mg, 0.049mmol) was dissolved in 4N HCl 1,4-dioxane (2mL) and reacted at room temperature for 2H with disappearance of starting material. Concentration, addition of ethanol (1mL), and filtration gave 30mg of a pale yellow solid with a yield of 100%, mp: 230-.

¹H NMR(DMSO-d₆)(ppm):12.52(brs,1H),8.71(s,2H),8.37(s,1H),7.95(d,J＝8.4Hz,2H),7.69(s,1H),7.23(d,J＝8.8Hz,2H),7.20-7.15(m,2H),6.86(d,J＝8.8Hz,1H),6.76(d,J＝8.4Hz,1H),6.72(s,1H),6.49(d,J＝8.0Hz,1H),4.81(s,1H),4.13(s,3H),3.72(s,3H),3.24(brs,2H),3.09(brs,2H),2.13(m,2H),1.85-1.83(m,2H).

Example 151: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (2-morpholinoethoxy) benzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (2-morpholinoethoxy) benzenesulfonamide

The procedure was carried out as described in a) of example 143, starting from 4-hydroxybenzenesulfonamide and 4- (2-bromoethyl) morpholine to give 244mg of white crystals in 74% yield and mp:168-169 ℃.

¹H NMR(CDCl₃)(ppm):7.86(d,J＝8.8Hz,2H),6.99(d,J＝8.4Hz,2H),4.74(s,2H),4.20(s,2H),3.76(s,4H),2.86(s,2H),2.61(s,4H).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4- (2-morpholinoethoxy) benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4- (2-morpholinoethoxy) benzenesulfonamide as starting materials, was as described in c) of example 3, giving a yellowish solid of 87mg, a yield of 69%, mp: 137-.

¹H NMR(acetone-d₆)(ppm):8.03(d,J＝7.6Hz,2H),7.55(s,1H),7.18-7.11(m,4H),6.93(d,J＝7.6Hz,1H),6.80-6.77(m,2H),6.52(d,J＝6.8Hz,1H),4.29-4.25(m,5H),3.76(s,3H),3.66(m,4H),2.91(s,2H),2.67(s,4H)；HRMS(ESI):m/z,calcd forC₂₉H₃₂N₄O₆ClS[M+H⁺]:599.1731,found 599.1700.

Preparation of intermediate 23: 1-Ethyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester

The preparation process is the same as the preparation 5 of the intermediate by using 7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester and bromoethane as starting materials to obtain 207mg of white solid, the yield is 95%, and mp is 93-95 ℃.

¹H NMR(CDCl₃)(ppm):7.35(s,1H),7.21(d,J＝8.0Hz,1H),7.14(d,J＝8.0Hz,1H),5.05(q,J＝7.2Hz,1H),4.40(q,J＝7.2Hz,1H),1.44(q,J＝7.6Hz,1H).

Example 152: 1-Ethyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-Ethyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75 was repeated using 1-ethyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 3-methoxyaniline as starting materials to give 100mg of a white solid in 54% yield mp:120 and 122 ℃.

¹H NMR(CDCl₃)(ppm):7.62(m,1H),7.42(m,1H),7.32(m,1H),7.21(d,J＝8.0Hz,1H),7.16(d,J＝8.8Hz,1H),6.88(d,J＝8.0Hz,1H),6.71(d,J＝8.4Hz,1H),6.53(d,J＝8.0Hz,1H),5.05(q,J＝6.8Hz,2H),4.37(q,J＝6.8Hz,2H),3.79(s,3H),1.47(t,J＝7.2Hz,3H),1.41(t,J＝7.2Hz,3H).

b) 1-ethyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 1-ethyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3, giving 80mg of an off-white powdery solid in 96% yield mp: 189-.

¹H NMR(DMSO-d₆)(ppm):13.00(s,1H),8.33(s,1H),7.63(s,1H),7.19-7.16(m,2H),6.85(d,J＝8.4Hz,1H),6.80(d,J＝8.0Hz,1H),7.56(s,1H),6.49(d,J＝8.0Hz,1H),4.97(q,J＝6.8Hz,2H),3.72(s,3H),1.35(t,J＝6.8Hz,3H).

c) 1-ethyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 1-ethyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide in the same manner as described in c) of example 3, gave 53mg of a pale yellow powdery solid in 60% yield, mp: 197-.

¹H NMR(DMSO-d₆)(ppm):12.46(s,1H),8.37(s,1H),7.96(m,2H),7.71(s,1H),7.18(m,4H),6.87(m,1H),6.74(m,3H),6.50(m,1H),4.69(m,2H),3.86(s,3H),3.73(s,3H),1.22(m,3H).

Example 153: 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75 was carried out using 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 3-methoxy-4-chloroaniline as starting materials to give 130mg of a white solid in 52% yield and mp: 120-.

¹H NMR(CDCl₃)(ppm):7.26-7.16(m,3H),7.16(m,2H),6.83(m,1H),6.70(m,1H),6.64(m,1H),5.77(m,1H),4.47(s,3H),4.36(q,J＝7.2Hz,2H),3.84(s,3H),1.40(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid

The preparation of 92mg of a pale yellow powdery solid with a yield of 99% and mp: 230-.

¹H NMR(DMSO-d₆)(ppm):13.04(s,1H),8.48(s,1H),7.58(s,1H),7.26(d,J＝8.4Hz,1H),7.18(d,J＝8.4Hz,1H),6.94(s,1H),6.88(d,J＝8.4Hz,1H),6.78(d,J＝8.4Hz,1H),4.36(s,3H),3.81(s,3H).

c) 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure was carried out as described in c) of example 3, starting from 1-methyl-4- ((3-methoxy-4-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide to give 70mg of a pale yellow powdery solid in 97% yield and mp: 188-.

¹H NMR(DMSO-d₆)(ppm):8.51(s,1H),7.95(d,J＝8.8Hz,2H),7.66(s,1H),7.26(d,J＝8.8Hz,1H),7.21-7.16(m,3H),6.91-6.88(m,2H),6.74(d,J＝8.4Hz,1H),4.13(s,3H),3.86(s,3H),3.80(s,3H).

Example 154: 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid ethyl ester

The procedure of example 75 was carried out using 1-methyl-7-chloro-4-bromo-1H-indole-2-carboxylic acid ethyl ester and 4-fluoro-3-chloroaniline as starting materials to give 160mg of a white solid in 74% yield and mp: 129-.

¹H NMR(CDCl₃)(ppm):7.64-7.62(m,1H),7.43-7.42(m,1H),7.24(s,1H),7.17-7.04(m,2H),6.94(m,1H),6.73(m,1H),4.47(s,3H),4.37(q,J＝7.2Hz,2H),1.40(t,J＝7.2Hz,3H).

b) 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 87mg of a pale yellow powdery solid in 92% yield mp: 235-.

¹H NMR(DMSO-d₆)(ppm):13.05(s,1H),8.46(s,1H),7.55(s,1H),7.34-7.28(m,2H),7.20-7.15(m,2H),6.79(d,J＝8.0Hz,1H),4.36(s,3H).

c) 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure was carried out as described in c) of example 3, starting from 1-methyl-4- ((4-fluoro-3-chlorophenyl) amino) -7-chloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide to give 46mg of a pale yellow powdery solid in 78% yield mp: 241-.

¹H NMR(DMSO-d₆)(ppm):12.49(brs,1H),8.48(s,1H),7.93(d,J＝8.4Hz,2H),7.60(s,1H),7.31(t,J＝9.2Hz,1H),7.23(d,J＝6.4Hz,1H),7.19(d,J＝8.4Hz,1H),7.16(d,J＝8.8Hz,2H),7.11-7.09(m,1H),6.79(d,J＝8.4Hz,1H),4.12(s,3H),3.85(s,3H)；HRMS(ESI):m/z,calcd.for C₂₃H₁₉N₃O₄FClS[M+H]⁺:522.0457,found 522.0448.

Example 155: 4, 6-dichloro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

a) 4, 6-dichloro-1H-indole-2-carboxylic acid

Using 4, 6-dichloro-1H-indole-2-carboxylic acid ethyl ester as starting material, the preparation was carried out as described in b) of example 3, giving 160mg of an off-white powdery solid in 100% yield, mp: 226-.

¹H NMR(DMSO-d₆)(ppm):12.31(s,1H),7.44(m,1H),7.27(d,J＝1.8Hz,1H),7.07-7.06(m,1H),6.86(t,J＝7.6Hz,1H),3.24(t,J＝7.6Hz,2H),2.56(t,J＝7.2Hz,2H).

b) 4, 6-dichloro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 4, 6-dichloro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials, was as described in c) of example 3, giving 52mg of a white powdery solid in 36% yield, mp: 294-.

¹H NMR(DMSO-d₆)(ppm):12.62(brs,1H),12.25(s,1H),7.96(d,J＝8.8Hz,2H),7.63(s,1H),7.39(s,1H),7.28(s,1H),7.16(d,J＝8.4Hz,1H),3.85(s,3H).

Preparation of intermediate 24: 4-nitro-1H-benzimidazole-2-carboxylic acid

a) 2-trichloromethyl-4-nitro-1H-benzimidazole

3-Nitrophthalenediamine (500mg, 3.27mmol) was dissolved in diethyl ether (12mL) and DCM (8mL), trichloroacetimidate methyl ester (720mg, 4.08mmol) was added, and after stirring, trifluoroacetic acid (1.79g, 15.67mmol) was added and the reaction was carried out at room temperature for 1h, whereupon the starting material was substantially disappeared. The solvent was distilled off, EA (20mL) was added, washed with water (20 mL. times.2), and column chromatography (P/E20: 1) was performed to give 834mg of a pale yellow powdery solid in 91% yield, mp:128 and 129 ℃.

¹H NMR(acetone-d₆)(ppm):12.97(brs,1H),8.35(d,J＝8.1Hz,1H),8.26(d,J＝7.8Hz,1H),7.61(t,J＝8.1Hz,2H).

b) 4-Nitro-1H-benzimidazole-2-carboxylic acid

Under an ice-water bath, a 2N NaOH solution (975mg, 24.4mmol, 12mL H) ₂O) is dropped into 2-trichloromethyl-4-nitro-1H-benzimidazole (1.37g, 4.87mmol), stirred and reacted for 2 hours at room temperature, and the reaction product is pasty. Adjusting pH2-3 with 1N diluted hydrochloric acid to turn yellow to off-white, filtering, and dryingDrying to obtain 988mg of white powdery solid with the yield of 98 percent and mp: 227-.

¹H NMR(DMSO-d₆)(ppm):8.46(s,1H),8.15(d,J＝7.8Hz,2H),7.42(t,J＝7.8Hz,1H).

Example 156: 4-Nitro- (N-sulfonyl) -1H-benzimidazole-2-carboxamide

The procedure of example 3, using 4-nitro-1H-benzimidazole-2-carboxylic acid and benzenesulfonamide as starting materials, was as described in c) to give 135mg of a white powdery solid in 81% yield, mp: 227-.

¹H NMR(DMSO-d₆)(ppm):8.27(d,J＝8.0Hz,1H),8.18(d,J＝8.4Hz,1H),8.06(d,J＝7.6Hz,2H),7.73(t,J＝7.2Hz,1H),7.66(t,J＝7.6Hz,2H),7.56(d,J＝8.0Hz,2H).

Example 157: 4-amino- (N-sulfonyl) -1H-benzimidazole-2-carboxylic acid amine

4-Nitro- (N-sulfonyl) -1H-benzimidazole-2-carboxamide (190mg, 0.55mmol) was dissolved in ethanol (25mL), 10% Pd/C (55mg) was added, and hydrogenation was carried out under normal pressure overnight, whereupon the starting material disappeared. Filtration, concentration and EA recrystallization gave 147mg of a brown powdery solid in 85% yield, mp: 235-.

¹H NMR(DMSO-d₆)(ppm):7.94(d,J＝7.2Hz,2H),7.52-7.47(m,3H),7.20(t,J＝8.0Hz,1H),6.78(d,J＝8.0Hz,1H),6.62(d,J＝8.0Hz,1H).

Preparation of intermediate 25: 1-methyl-4-amino-7-chloro-1H-benzimidazole-2-carboxylic acid ethyl ester

a) 4-Nitro-1H-benzimidazole-2-carboxylic acid ethyl ester

2-trichloromethyl-4-nitro-1H-benzimidazole (4.0g, 14.26mmol) was dissolved in ethanol (40mL), sodium carbonate (3.02g, 28.5mmol) was added, and the mixture was refluxed for 48H, whereupon the starting material disappeared. DCM (50mL) and methanol (10mL) were added and the insolubles were filtered off. Concentration and EA recrystallization gave 3.05g of a brown solid with a yield of 91%, mp: 146-.

¹H NMR(CDCl₃)(ppm):11.19(brs,1H),8.35(d,J＝8.4Hz,1H),8.29(d,J＝8.1Hz,1H),7.55-7.49(m,1H),4.63-4.56(m,2H),1.56-1.50(m,3H).

b) 1-methyl-4-nitro-1H-benzimidazole-2-carboxylic acid ethyl ester

Ethyl 4-nitro-1H-benzimidazole-2-carboxylate (1.5g, 6.38mmol) was dissolved in DMF (20mL), cesium carbonate (4.13g, 12.76mmol) and iodomethane (1.36g, 9.57mmol) were added and the reaction was carried out at room temperature for 48H with a small amount of starting material remaining. The reaction solution was poured into ice water and filtered to give a yellow solid, and EA was recrystallized to give a yellowish solid (1.29 g) with a yield of 81%, mp: 125-.

¹H NMR(CDCl₃)(ppm):8.24(d,J＝8.0Hz,1H),7.80(d,J＝8.4Hz,1H),7.55(t,J＝8.0Hz,1H),4.56(q,J＝7.2Hz,2H),4.25(s,3H),1.51(t,J＝7.2Hz,3H).

c) 1-methyl-4-amino-1H-benzimidazole-2-carboxylic acid ethyl ester

Ethyl 1-methyl-4-nitro-1H-benzimidazole-2-carboxylate (2.60g, 10.43mmol) was dissolved in ethanol (40mL), 10% Pd/C (260mg) was added, and hydrogenation was carried out under normal pressure overnight, whereupon the starting material disappeared. Filtration, concentration and column chromatography (P/E4: 1-D/M40: 1) gave 2.10g of an off-white powdery solid in 92% yield at 116 ℃ mp: 114-.

¹H NMR(CDCl₃)(ppm):7.22(t,J＝8.0Hz,1H),6.77(d,J＝8.4Hz,1H),6.55(d,J＝7.6Hz,1H),4.53(q,J＝7.2Hz,2H),4.18(s,3H),1.49(t,J＝7.2Hz,3H).

d) 1-methyl-4-amino-7-chloro-1H-benzimidazole-2-carboxylic acid ethyl ester

Ethyl 1-methyl-4-amino-1H-benzimidazole-2-carboxylate (600mg, 2.74mmol) was dissolved in DMF (20mL), and NCS (402mg, 3.01mmol) in DMF (10mL) was added and reacted at room temperature for 1.5H, whereupon the starting material disappeared. Performing column chromatography (P/E is 2:1) to obtain: point 1, 73mg of a yellowish solid; point 2, light yellow solid 215 mg; point 3, orange solid 353mg, was the target product in 51% yield, mp: 141-.

¹H NMR(CDCl₃) (ppm):7.23(s,1H),4.84(s,2H),4.53(q, J ═ 7.2Hz,2H),4.45(s,3H),1.48(t, J ═ 7.2Hz,3H) (point 1)

¹H NMR(CDCl₃) (ppm):7.28(d, J ═ 8.8Hz,1H),7.70(d, J ═ 8.8Hz,1H),4.89(s,2H),4.54(q, J ═ 7.2Hz,2H),4.09(s,3H),1.49(t, J ═ 7.2Hz,3H) · (point 2)

¹H NMR(CDCl₃) (ppm):7.11(d, J ═ 8.0Hz,1H),6.44(d, J ═ 8.4Hz,1H),4.78(brs,2H),4.53(q, J ═ 7.2Hz,2H),4.47(s,3H),1.49(t, J ═ 7.2Hz,3H) · (point 3)

Example 158: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) Ethyl 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-benzimidazole-2-carboxylate

The procedure used in example 75 was carried out using 1-methyl-4-amino-7-chloro-1H-benzimidazole-2-carboxylic acid ethyl ester and 3-methoxy-1-bromobenzene as starting materials to give 146mg of a yellow solid in 46% yield mp:89-91 ℃.

¹H NMR(CDCl₃)(ppm):7.26-7.21(m,1H),7.18(d,J＝8.8Hz,1H),7.08(s,1H),7.05(d,J＝8.4Hz,1H),6.86(d,J＝8.4Hz,1H),6.84(s,1H),6.58(d,J＝8.4Hz,1H),4.55(q,J＝7.2Hz,2H),4.50(s,3H),3.81(s,3H),1.50(t,J＝7.2Hz,3H).

b) Mixtures of 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-benzimidazole-2-carboxylic acid and 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-benzimidazole

Starting from ethyl 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-benzimidazole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 70mg of a pale yellow powdery solid in a yield of 81%, which was shown by hydrogen spectroscopy and high-resolution mass spectroscopy as a mixture in a ratio of about 9:1, mp: 125-.

¹H NMR(DMSO-d₆)(ppm):8.15(s,1H),7.15(t,J＝8.0Hz,1H),7.10(d,J＝8.0Hz,1H),7.00(d,J＝8.0Hz,1H),6.90-6.84(m,2H),6.46(d,J＝7.2Hz,1H),4.07(s,3H),3.71(s,3H).

The procedure of example 3, using a mixture of 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-benzimidazole-2-carboxylic acid and 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-benzimidazole and 4-methoxybenzenesulfonamide as starting materials, was as described in c) of example 3, gave 48mg of a pale yellow powdery solid in 64% yield, mp: 206-.

¹H NMR(DMSO-d₆)(ppm):8.31(s,1H),7.99(d,J＝7.5Hz,2H),7.24(d,J＝8.5Hz,1H),7.22(d,J＝7.5Hz,1H),7.18(d,J＝7.5Hz,2H),7.06(d,J＝7.5Hz,1H),6.90(d,J＝7.5Hz,1H),6.87(s,1H),6.56(d,J＝7.0Hz,1H),4.24(s,3H),3.86(s,3H),3.75(s,3H)；HRMS(ESI):m/z,calcd.for C₂₃H₂₂N₄O₅ClS[M+H]⁺:501.0999,found 501.0985.

Example 159 4-chloro-7- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -3-methyl-benzofuran-2-carboxamide

a)2- (2-bromo-5-chloro-phenoxy) -3-oxobutanoic acid ethyl ester

To a solution of 2-bromo-5-chlorophenol (1.495g, 7.2mmol) in ethanol (13mL) was slowly added a solution of cesium carbonate (2.58g, 7.92mmol) in ethanol (33mL), and the mixture was stirred at room temperature for half an hour, ethyl 2-chloroacetoacetate (1.4g, 8.43mmol) was added, and stirred at 50 ℃. The mixture was cooled to room temperature and column chromatographed (60: 1 petroleum ether/ethyl acetate) to give 1.4g of a colourless oil, 54% yield;¹H NMR(CDCl₃)(ppm):11.35(s,0.45H),7.51(d,J＝8.0Hz,0.45H),7.48(d,J＝8.0Hz,0.55H),6.94(d,J＝8.0Hz,0.45H),6.89(d,J＝8.0Hz,0.55H),6,78(s,0.55H),6,74(s,0.45H),5.02(s，0.55H),4.33(q,J＝7.2Hz,0.45H),4.22(q,J＝7.2Hz,0.55H),2.05(s,0.45H),1.53(s,0.55H),1.31(t,J＝6.8Hz,0.45H),1.19(t,J＝7.2Hz,0.55H)。

b) 7-bromo-4-chloro-3-methylbenzofuran-2-carboxylic acid ethyl ester

Ethyl 2- (2-bromo-5-chloro-phenoxy) -3-oxobutanoate (168mg, 0.5mmol) dissolved in anhydrous dichloromethane (8mL), cooled to 0 deg.C, to which CF was slowly added ₃SO₃H (1.2mL), stirred at 0 ℃ for 50min, then moved to room temperature to continue the reaction until the starting material disappeared. The reaction solution is cooled to 0 ℃ again, saturated aqueous sodium bicarbonate solution (7mL) is added to quench the reaction, and the reaction solution is divided intoThe organic layer was separated and the aqueous layer was extracted three times with dichloromethane to give 135mg of a white solid after recrystallization (petroleum ether/ethyl acetate 10: 1) in 85% yield; m.p.68-69 ℃;¹H NMR(CDCl₃)(ppm):7.48(d,J＝8.4Hz,1H),7.13(d,J＝8.4Hz,1H),4.46(q,J＝7.2Hz,2H),2.80(s,3H),1.41(t,J＝8Hz,3H)。

c) 4-chloro-7- (3-methoxyphenylamino) -3-methylbenzofuran-2-carboxylic acid ethyl ester

Ethyl 7-bromo-4-chloro-3-methylbenzofuran-2-carboxylate (25mg,0.08mmol) was dissolved in xylene (0.6mL), and Pd was added successively₂(dba)₃(7mg,0.008mmol), tri-tert-butylphosphine tetrafluoroborate (4.6mg,0.016mmol) and K₃PO₄(51mg,0.242mmol), stirring well, adding m-anisidine (29mg,0.24mmol), reacting under argon protection at 140 deg.C for 45min, removing raw material, and performing column chromatography (P/E ═ 20:1) to obtain 30mg of brown solid with yield of 46%; m.p.98-100 ℃;¹H NMR(DMSO-d₆)(ppm):8.39(s,1H),7.25(q,J＝8.0Hz,2H),7.15(t，J＝8.0Hz,1H),6.70～6.67(m，2H),6.46(d，J＝8.0Hz，1H),4.37(q,J＝6.8Hz,2H),3.70(s,3H),2.77(s,3H),1.34(t,J＝6.8Hz,3H)；HRMS(ESI):m/z,calcd for C₁₉H₁₈ClNO₄[M+H]⁺:360.0997,found 360.0983。

d) 4-chloro-7- (3-methoxyphenylamino) -3-methylbenzofuran-2-carboxylic acid

Ethyl 4-chloro-7- (3-methoxyphenylamino) -3-methylbenzofuran-2-carboxylate (120mg, 0.33mmol) was dissolved in a mixed solvent of THF (2.4mL) and ethanol (4.8mL), a solution of NaOH (67mg, 1.67mmol) in water (2.4mL) was added dropwise, the reaction mixture was stirred at room temperature for 5.5h, and the starting material disappeared. THF and ethanol were distilled off, 6mL of water was added, the pH was adjusted to 2 with 1M dilute hydrochloric acid, a yellow solid precipitated, filtered off with suction, dried to give 103mg of a yellow-green solid, The yield is 93 percent; m.p.192-193 ℃;¹HNMR(CDCl₃)(ppm):8.39(s,1H),7.25(m,2H),7.15(t，J＝8.0Hz,1H),6.70～6.67(m，2H),6.46(d，J＝8.0Hz，1H),3.70(s,3H),2.77(s,3H)；HRMS(ESI),[M-H]^-:m/z,330.0304。

e) 4-chloro-7- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -3-methyl-benzofuran-2-carboxamide

4-chloro-7- (3-methoxyphenylamino) -3-methylbenzofuran-2-carboxylic acid (57mg, 0.17mmol) was dissolved in DCM (10mL) under ice-bath, triethylamine (34mg, 0.34mmol) was added, and after stirring for 0.5h, HATU (99mg, 0.26mmol) and DMAP (10mg, 0.085mmol) and p-methoxybenzenesulfonamide (48mg, 0.26mmol) were added and stirred until the starting material disappeared. Column chromatography (DCM/methanol 40:1) gave 38mg of yellow solid in 45% yield; m.p.176-178 ℃;¹H NMR(DMSO-d₆)(ppm):11.96(s,1H),8.11(s,1H),7.97(d,J＝8.0Hz,2H),7.24(m,2H),7.18(d,J＝8.0Hz,3H),6.85(d,J＝8.0Hz,1H),6.80(s,1H),6.60(d,J＝8.0Hz,1H),3.86(s,3H),3.76(s,3H),2.64(s,3H)；HRMS(ESI):m/z,calcd for C₂₄H₂₁ClN₂O₆S[M+H]⁺:501.0882,found 501.0872。

example 160 chloro-7- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -3-methyl-benzothiophene-2-carboxamide

a) 4-chloro-3-methylbenzothiophene-2-carboxylic acid ethyl ester

Ethyl thioglycolate (2mL,21.8mmol) and DBU (4.35mL,29mmol) were added to a solution of 2-fluoro-6-chloroacetophenone (2.5g, 14.5mmol) in dry toluene (14.5mL) at 0 deg.C, the mixture was allowed to warm slowly to room temperature, stirring was continued for 5h,the reaction was quenched with water (70mL), EA extracted (2X 100mL), acid washed, water washed, and recrystallized to give 4.83g of a white solid, yield 65%, m.p.96-97 ℃.¹H NMR(CDCl₃)(ppm):7.69(d,J＝8.0Hz,1H),7.37(t,J＝8.0Hz,1H),7.31(d,J＝8.0Hz,1H),4.39(q,J＝7.2Hz,2H),3.12(s,3H),1.41(t,J＝7.2Hz,3H)。

b) 4-chloro-3-methyl-7-nitrobenzothiophene-2-carboxylic acid ethyl ester

4-chloro-3-methylbenzothiophene-2-carboxylic acid ethyl ester (893mg, 3.5mmol) in CF₃COOH (13mL), cool to-5 ℃ and add NaNO₃(894mg, 10.5mmol), maintaining the mixture at 0 deg.C for 7h, pouring into 34mL water, adjusting pH to 8 with saturated sodium bicarbonate, filtering, and performing column chromatography on filter cake (P/E ═ 10:1) to obtain 520mg of off-white solid with 50% yield; m.p.153-154 ℃.¹HNMR(CDCl₃)(ppm):8.38(d,J＝8.0Hz,1H),7.55(d,J＝8.0Hz,1H),4.44(q,J＝7.2Hz，2H),3.14(s,3H),1.47(t,J＝6.8Hz,3H)。

c) 7-amino-4-chloro-3-methylbenzothiophene-2-carboxylic acid ethyl ester

Ethyl 4-chloro-3-methyl-7-nitrobenzothiophene-2-carboxylate (100mg,0.33mmol) was dissolved in ethyl acetate (10mL), 10% Pd/C (30mg) was added, hydrogenation was carried out at normal temperature and pressure for 12h, filtration, concentration, and column chromatography (petroleum ether/ethyl acetate 8:1) gave 56mg of an off-white solid in 60% yield.¹H NMR(CDCl₃)(ppm):7.20(d,J＝8.0Hz,1H),6.65(d,J＝8.0Hz,1H),4.39(q,J＝7.2Hz，2H),3.85(brs,2H),3.10(s,3H),1.42(t,J＝6.8Hz,3H)。

d) 4-chloro-7- (3-methoxyphenylamino) -3-methylbenzothiophene-2-carboxylic acid ethyl ester

Reacting 7-amino-4-chloro-3-methylbenzothiophene-2-carboxylic acid ethyl ester (227mg,0.84mmol) was dissolved in xylene (9mL), followed by the addition of Pd₂(dba)₃(77mg,0.084mmol), tri-tert-butylphosphine tetrafluoroborate (49mg,0.168mmol) and K₃PO₄(535mg,2.52mmol) and after stirring to homogeneity, m-methoxybromobenzene (472mg,2.52mmol) was added and reacted at 110 ℃ for 12h under argon protection, the starting material disappeared and column chromatography (PE/EA ═ 20:1) gave 39.5mg of a red solid in 13% yield m.p.164-165 ℃. ¹H NMR(CDCl₃)(ppm):7.32～7.17(m,3H),6.61(m,1H),6.55(m,2H),4.38(q,J＝7.2Hz，2H),3.77(s,3H),3.12(s,3H),1.40(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcdfor C₁₉H₁₈ClNO₃S[M+H]⁺:376.0769,found 376.0754。

e) 4-chloro-7- (3-methoxyphenylamino) -3-methylbenzothiophene-2-carboxylic acid

Ethyl 4-chloro-7- (3-methoxyphenylamino) -3-methylbenzothiophene-2-carboxylate (60mg, 0.16mmol) was dissolved in a mixed solvent of THF (1.2mL) and ethanol (2.4mL), a solution of NaOH (32mg, 0.8mmol) in water (1.2mL) was added dropwise, the reaction mixture was stirred at room temperature for 4h, and the starting material disappeared. THF and ethanol were evaporated off, 5mL of water was added, the pH was adjusted to 2 with 1M dilute hydrochloric acid, a yellow-green solid precipitated, filtered off with suction, and dried to give 49mg of a yellow-green solid, yield 88%, m.p.200-202 ℃.¹H NMR(CDCl₃)(ppm):7.35～7.15(m,3H),6.65～6.52(m,3H),4.39(q,J＝7.2Hz，2H),3.79(s,3H),3.11(s,3H)。HRMS(ESI),[M-H]^-:m/z,346.0056。

f) 4-chloro-7- ((3-methoxyphenyl) amino) -N- (4-methoxybenzenesulfonyl) -3-methyl-benzothiophene-2-carboxamide

4-chloro-7- (3-methoxyphenylamino) -3-methylbenzothiophene-2-carboxylic acid (50mg, 0.14mmol), HATU (98mg, 0.26mmol), DMAP (9mg, 0.07mmol), triethylamine (7)3mg, 0.72mmol) was dissolved in DCM (5mL), stirred for 2h, p-methoxybenzenesulphonamide (48mg,0.26mmol) was added, reacted overnight at room temperature and column chromatographed (EA: methanol 20:1) to give 30mg of off-white powder in 48% yield m.p.284-285 ℃.¹H NMR(CDCl₃)(ppm):8.00(s,1H),7.56(d,J＝8.0Hz,2H),7.28(d,J＝8.0Hz,1H),7.12(m,J＝8.0Hz,2H),6.90(d,J＝8.0Hz,2H),6.56(d,J＝8.0Hz,2H),6.40(d,J＝8.0Hz,1H),3.78(s,3H),3.69(s,3H),2.98(s,3H)。HRMS(ESI),[M-H]^-:m/z,516.06。

Example 161 chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- (pyridine-3-sulfonyl) -1H-indole-2-carboxamide

a) 3-pyridinesulfonamides

Adding excessive ammonia water (4.5mL, ammonia content: 25-28%) into 3-pyridine sulfonyl chloride (1.457g) under the protection of Ar, heating to 40 ℃ for reaction, stopping the reaction after 30min, removing unreacted ammonia water by rotary evaporation, adding 10mL of water to precipitate a yellow solid, filtering, and performing thermal recrystallization on ethanol (1.1g, 85%), and mp: 244-.¹H NMR(400MHz,DMSO-d₆)(ppm):8.98(s,1H),8.79(d,J＝4.7Hz,1H),8.19(d,J＝8.0Hz,1H),7.67–7.57(m,3H)；HRMS(ESI):m/z,159.1836[M+H]⁺.

b) 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- (pyridine-3-sulfonyl) -1H-indole-2-carboxamide

Dissolving 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (65mg,0.197mmol) in dry DCM under the protection of Ar, sequentially adding HATU (113mg, 0.295mmol), DMAP (12mg, 0.10mmol) and TEA (40mg,0.40mmol), stirring uniformly, adding pyridine-3-sulfonamide (47mg,0.295mmol), standing overnight at room temperature, stopping reaction, evaporating to remove the solvent, sequentially washing with dilute hydrochloric acid and water, combining EA layers, and separating the column to obtain a light yellow-green solid (50mg, 55%); mp:218-220 ℃.¹H NMR(400MHz,DMSO-d₆)(ppm)：8.99(s,1H),8.64(s,1H),8.23(d,J＝17.2Hz,2H),7.50(s,1H),7.39(s,1H),7.13(d,J＝7.8Hz,1H),7.03(d,J＝7.8Hz,1H),6.77(dd,J＝21.1,8.4Hz,3H),6.43(d,J＝8.0Hz,1H),4.25(s,3H),3.71(s,3H).HRMS(ESI):m/z,471.1045[M+H]⁺

Example 162: 7-chloro-N- [ (5-isobutylthiophene-2-) -sulfonyl ] -4- [ (3-methoxyphenyl) -amino ] -1-methyl-1H-indole-2-carboxamide

a) Thiophene-2-isopropyl ketone

PPA (3g, excess) was added to thiophene (505mg,6.02mmol) and isobutyric acid (441mg,5.01mmol), this time the reaction was a light brown viscous mass, warmed to 80 ℃ for 4h, quenched, added with water and stirred well, extracted with DCM, washed sequentially with water, brine, combined organic layers and dried to give a dark brown-yellow viscous oil (618mg, 80%). HRMS (ESI) M/z 155.1610[ M + H [ ] ]⁺

b) 2-isobutyl thiophene

Dissolving thiophene-2-isopropyl ketone (840mg, 5.45mmol), KOH (1.23g, 21.92mmol) and hydrazine hydrate (1.64g, 32.76mmol) in diethylene glycol, heating to 210 ℃, cooling to room temperature after reacting for 3h, adding water for dilution, extracting with diethyl ether, washing an organic layer with water and brine in turn, combining the organic layers, and separating the column to obtain a light yellow oily substance (635mg, 83%); HRMS (ESI) M/z 139.1294[ M-H [ ]]^-

c) 5-isobutyl thiophene-2-sulfonyl chloride

Under the protection of argon, anhydrous DMF (40mL) is added into sulfonyl chloride (780mg, 5.78mmol) under the ice salt bath, 2-isobutyl thiophene (660mg, 4.71mmol) is added after 10min, the temperature is raised to 100 ℃ (the oil bath temperature) for reaction, the reaction system is a brown yellow solution, the reaction is stopped after 1h, excessive crushed ice is added for stirring, EA is rapidly extracted after dissolution, and EA/PE (poly (ethylene) amide) is separated into light yellow oily matters (506mg, 45%) by a 1/10 column.¹H NMR(400MHz,CDCl₃)(ppm)：7.72(d,J＝3.9Hz,1H),6.84(d,J＝3.9Hz,1H),2.76(d,J＝7.1Hz,2H),1.95(m,J＝13.6,6.8Hz,1H),0.99(d,J＝6.6Hz,6H)；HRMS(ESI):m/z,239.2363[M+H]⁺。

d) 5-isobutylthiophene-2-sulfonamides

Adding excessive ammonia water (4.0mL) into 5-isobutylthiophene-2-sulfonyl chloride (238mg, 1.00mmol) under the protection of Ar, heating to 40 ℃ for reaction, stopping the reaction after 1h, performing rotary evaporation to remove unreacted ammonia water, adding 10mL of water for washing, performing EA extraction for three times, and performing column separation to obtain a light yellow viscous oily substance (165mg, 75%) directly performing the next step. HRMS (ESI) M/z 220.0390[ M + H [ ] ]⁺。

e) 7-chloro-N- [ (5-isobutylthiophene-2-) -sulfonyl ] -4- [ (3-methoxyphenyl) -amino ] -1-methyl-1H-indole-2-carboxamide

Under the protection of Ar, dissolving 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (115mg, 0.35mmol) in dry DCM, sequentially adding HATU (190mg, 0.50mmol), DMAP (22mg, 0.175mmol) and TEA (72mg, 0.7mmol), stirring uniformly, adding 5-isobutylthiophene-2-sulfonamide (110mg, 0.5mmol), standing overnight at room temperature, evaporating to remove the solvent after stopping the reaction, sequentially washing with dilute hydrochloric acid and water, combining EA layers, and separating the column to obtain a light yellow solid, wherein the yield is 58.8%; mp 212-215 ℃.¹H NMR(400MHz,DMSO-d₆)(ppm)：12.76(s,1H),8.35(s,1H),7.67(d,J＝14.9Hz,2H),7.16(t,J＝7.7Hz,2H),6.95(s,1H),6.84(d,J＝8.3Hz,1H),6.79–6.65(m,2H),6.47(d,J＝8.1Hz,1H),4.16(s,3H),3.70(s,3H),2.73(d,J＝6.8Hz,2H),1.92–1.78(m,1H),0.89(d,J＝6.5Hz,6H)；HRMS(ESI):m/z,532.1165[M+H]⁺。

Example 163: 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (1-methylindoline-5-) -sulfonyl ] -1H-indole-2-carboxamide

a) 1-methylindoline

Under Ar protection and ice bath conditions, NaH (2.46g, 102.5mmol) is added into anhydrous THF, indoline (8.21g, 68.9mmol) and slow release agent are addedMethyl iodide (14.55g, 102.5mmol) was slowly added and the reaction was cooled to room temperature overnight. After the reaction was stopped, it was concentrated, diluted with water, extracted with DCM and dried, and the column was isolated as a pale yellow oil (4.77g, 52%).¹H NMR(400MHz,CDCl₃)(ppm)：7.14–7.06(m,2H),6.69(t,J＝7.3Hz,1H),6.51(d,J＝8.1Hz,1H),3.30(t,J＝8.1Hz,2H),2.96(t,J＝8.1Hz,2H),2.77(s,3H)；HRMS(ESI):m/z,134.0989[M+H]⁺。

b) 1-methylindoline-5-sulfonic acid

Under the ice-bath condition, dissolving 1-methylindoline (2.66g, 20mmol) in anhydrous ether, slowly adding an ether solution of sulfuric acid (2.0g, 20.4mmol), stirring, removing ether by rotation, and heating for reaction for 4 h. After the reaction was stopped, the mixture was diluted with methanol to precipitate a yellowish solid, which was filtered and recrystallized from EA/PE to obtain the product as a white solid (2.1g, 49%). HRMS (ESI) M/z 212.0441[ M-H [ ] ]^-

c) 1-methylindoline-5-sulfonyl chloride

Under the protection of argon and under the condition of ice bath, 1-methylindoline-5-sulfonic acid (450mg, 2.12mmol) is dissolved in anhydrous DCM, a solution of oxalyl chloride (1.35g, 10.60mmol) in DCM is slowly added, DMF (0.2mL) is dropwise added, and then the mixture is reacted for 2.5h at room temperature in ice bath. After the reaction is stopped, washing with water, removing DCM by rotation, and recrystallizing EA/PE to obtain a light yellow solid product, and directly carrying out the next step (260mg, 53%) after drying; HRMS (ESI) M/z 232.0196[ M-H [ ]]^-

d) Synthesis of 1-methylindoline-5-sulfonamide

Adding excessive ammonia methanol solution (5mL, 35mmol) into 1-methylindoline-5-sulfonyl chloride (377mg, 2.12mmol) under the protection of Ar, reacting at room temperature in an ice bath, stopping the reaction after 1h, steaming the solution in a rotary manner, adding 10mL of ice water, extracting with DCM, combining organic phases, and separating by using a column to obtain a light yellow solid (140mg, 41%); mp 172-174 ℃.¹H NMR(400MHz,DMSO-d₆)(ppm):7.47(d,J＝8.2Hz,1H),7.41(s,1H),6.92(s,2H),6.50(d,J＝8.3Hz,1H),3.40(t,J＝8.4Hz,2H),2.94(t,J＝8.4Hz,2H),2.77(s,3H)；HRMS(ESI):m/z,213.0703[M+H]⁺。

e) 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (1-methylindoline-5-) -sulfonyl ] -1H-indole-2-carboxamide

Dissolving 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (105mg, 0.32mmol) in dry DCM under the protection of Ar, sequentially adding HATU (182mg, 0.48mmol), DMAP (20mg, 0.16mmol) and TEA (66mg, 0.66mmol), stirring uniformly, adding 1-methylindoline-5-sulfonamide (101mg, 0.48mmol), standing overnight at room temperature, stopping reaction, evaporating to remove the solvent, washing with dilute hydrochloric acid and water sequentially, combining EA layers, and separating to obtain a pale yellow solid (60mg, 36%); mp:210 ℃ and 212 ℃. ¹H NMR(400MHz,DMSO-d₆)(ppm):12.22(s,1H),8.34(s,1H),7.71–7.59(m,2H),7.52(s,1H),7.17(t,J＝7.9Hz,2H),6.85(d,J＝8.3Hz,1H),6.78–6.69(m,2H),6.50(dd,J＝23.4,8.3Hz,2H),4.14(s,3H),3.72(s,3H),3.48(t,J＝8.2Hz,2H),2.99(t,J＝8.4Hz,2H),2.81(s,3H)；HRMS(ESI):m/z,525.1279[M+H]⁺。

Example 164: 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (1-methyl-1, 2,3, 4-tetrahydroquinoline-6-) -sulfonyl ] -1H-indole-2-carboxamide

a) 1-methyl-1, 2,3, 4-tetrahydroquinoline

Under Ar gas protection and ice bath conditions, NaH (2.4g, 99.1mmol) was added to anhydrous THF, 1,2,3, 4-tetrahydroquinoline (8.8g, 66.1mmol) was added, MeI (16.9g, 66.1mmol) was slowly added, and the reaction was cooled to room temperature overnight. After the reaction was stopped, it was concentrated, diluted with water, extracted with DCM, dried and column isolated as a light brown oil (5.5g, 56%).¹H NMR(400MHz,CDCl₃)(ppm):7.08(t,J＝7.8Hz,1H),6.96(d,J＝7.0Hz,1H),6.61(t,J＝7.0Hz,2H),3.26–3.19(m,2H),2.89(s,3H),2.77(t,J＝6.5Hz,2H),2.03–1.94(m,2H)；HRMS(ESI):m/z,148.1177[M+H]⁺。

b) 1-methyl-1, 2,3, 4-tetrahydroquinoline-6-sulfonic acid

Under the ice-bath condition, 1-methyl-1, 2,3, 4-tetrahydroquinoline (2.94g, 20mmol) is dissolved in anhydrous ether, a solution of sulfuric acid (2.35g, 24mmol) in ether is slowly added, the ether is removed by rotation after stirring, and the temperature is raised for reaction for 5.5 h. After the reaction is stopped, the mixture is diluted by adding methanol and has a nearly white colorThe solid was isolated, filtered and recrystallized from EA/PE to give the product as a white solid (1.62g, 36%), dried under vacuum and protected with argon for the next step. HRMS (ESI) M/z 228.0700[ M + H [ ]]⁺。

c) Synthesis of 1-methyl-1, 2,3, 4-tetrahydroquinoline-6-sulfonyl chloride

Under the protection of Ar and under the condition of ice bath, 1-methyl-1, 2,3, 4-tetrahydroquinoline-6-sulfonic acid (455mg, 2.0mmol) is dissolved in anhydrous DCM, oxalyl chloride (1.27g, 10.0mmol) solution in DCM is slowly added, DMF (0.1mL) is dropped in, and then the reaction is carried out for 2.5h at room temperature in ice bath. After the reaction was stopped, the reaction was washed with water, after removal of DCM, and recrystallized EA/PE to give the product as a pale yellow solid, which was dried and directly carried on to the next step (152mg, 31%).

d) Synthesis of 1-methyl-1, 2,3, 4-tetrahydroquinoline-6-sulfonamide

Adding excessive ammonia methanol solution (4mL, 28mmol) into 1-methylindoline-6-sulfonyl chloride (245mg, 1.0mmol) under the protection of Ar, reacting at room temperature in an ice bath, stopping the reaction after 1h, steaming the solution in a rotary manner, adding 10mL of ice water, extracting with DCM, combining organic phases, and separating by using a column to obtain a light yellow solid (110mg, 45%); mp:202 ℃ and 204 ℃.¹H NMR(400MHz,DMSO-d₆)(ppm):7.39(d,J＝7.1Hz,1H),7.28(s,1H),6.86(s,2H),6.57(d,J＝8.7Hz,1H),3.29–3.22(m,2H),2.88(s,3H),2.69(t,J＝6.2Hz,2H),1.92–1.80(m,2H)；HRMS(ESI):m/z,227.0872[M+H]⁺。

e) 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (1-methyl-1, 2,3, 4-tetrahydroquinoline-6-) -sulfonyl ] -1H-indole-2-carboxamide

Dissolving 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (85mg, 0.26mmol) in dry DCM under the protection of Ar, adding HATU (147mg, 0.39mmol), DMAP (16mg, 0.13mmol) and TEA (52mg, 0.52mmol) in sequence, stirring uniformly, adding 1-methyl-1, 2,3, 4-tetrahydroquinoline-6-sulfonamide (88mg, 0.39mmol), standing overnight at room temperature, evaporating the solvent after stopping the reaction, washing with dilute hydrochloric acid and water in sequence, combining EA layers, and separating by a column to obtain a light yellow solid (55mg, 40%); mp 222 and 224 ℃.¹H NMR(400MHz,DMSO-d₆)(ppm):12.19(s,1H),8.34(s,1H),7.62(s,2H),7.44(s,1H),7.16(d,J＝8.0Hz,2H),6.85(d,J＝8.5Hz,1H),6.79–6.61(m,3H),6.48(d,J＝7.9Hz,1H),4.14(s,3H),3.72(s,3H),3.31–3.24(m,2H),2.94(s,3H),2.73(s,2H),1.87(s,2H)；HRMS(ESI):m/z,539.1378[M+H]⁺。

Example 165: 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (1-methylindoline-6-) -sulfonyl ] -1H-indole-2-carboxamide

(a) Synthesis of 1-methylindoline-6-sulfonyl chloride

Under the protection of Ar and ice salt bath, dissolving 1-methylindoline (7.7g, 57.8mmol) in anhydrous DCM, adding chlorosulfonic acid (45mL), stirring for reacting for 16h, after the reaction is stopped, slowly adding 1L of ice water into the system, stirring vigorously, after 4h, completely quenching the reaction, extracting DCM, drying the organic phase, and directly carrying out the next step after drying. HRMS (ESI) M/z 232.0192[ M + H [ ]]⁺。

(b) Synthesis of 1-methylindoline-6-sulfonamide

Adding excessive ammonia methanol solution (3.5mL, 24.5mmol) into 1-methylindoline-6-sulfonyl chloride (345mg, 1.49mmol) under the protection of Ar, reacting at room temperature in ice bath, stopping the reaction after 0.5h, performing rotary evaporation on the solution, adding 10mL of ice water, performing DCM extraction, combining organic phases, and performing column separation to obtain a light yellow solid (92mg, 29%); mp: 116-.¹H NMR(400MHz,DMSO-d₆)(ppm):7.14(d,J＝10.0Hz,3H),7.04(d,J＝7.5Hz,1H),6.84(s,1H),3.35(d,J＝8.4Hz,2H),2.92(t,J＝8.2Hz,2H),2.74(s,3H)；HRMS(ESI):m/z,213.0699[M+H]⁺。

(c) 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (1-methylindoline-6-) -sulfonyl ] -1H-indole-2-carboxamide

Under the protection of Ar, dissolving 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (75mg, 0.23mmol) in dry DCM, sequentially adding HATU (130mg, 0.34mmol), DMAP (14mg, 0.12mmol) and TEA (51mg, 0.50mmol), stirring uniformly, adding 1-methylindoline-6-sulfonamide (72mg, 0.34mmol), standing overnight at room temperature, distilling off the solvent after stopping the reaction, sequentially washing with dilute hydrochloric acid and water, combining EA layers, and separating to obtain a light yellow solid (4) through a column 0mg，34％)；mp:239-241℃。¹H NMR(400MHz,DMSO-d₆)(ppm):8.35(s,1H),7.67(s,2H),7.15(d,J＝7.4Hz,2H),6.84(d,J＝7.8Hz,1H),6.78–6.67(m,2H),6.47(d,J＝7.8Hz,1H),4.09(d,J＝18.9Hz,4H),3.87(d,J＝19.0Hz,2H),3.70(s,3H),2.95(t,J＝8.1Hz,2H),2.74(s,3H)；HRMS(ESI):m/z,525.1265[M+H]⁺。

Example 166: 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (1-methyl-1, 2,3, 4-tetrahydroquinoline-7-) -sulfonyl ] -1H-indole-2-carboxamide

(a) Synthesis of 1-methyl-1, 2,3, 4-tetrahydroquinoline-7-sulfonyl chloride

Under the protection of Ar and ice salt bath, dissolving 1-methyltetrahydroquinoline (6.5g, 44.2mmol) in anhydrous DCM, adding chlorosulfonic acid (30mL), stirring for reaction for 20h, slowly adding ice water into the system after the reaction is stopped, extracting the mixture with DCM, drying the organic phase, and directly carrying out the next reaction.

(b) Synthesis of 1-methyl-1, 2,3, 4-tetrahydroquinoline-7-sulfonamide

Adding excessive ammonia methanol solution (3.0mL and 21mmol) into 1-methyl-1, 2,3, 4-tetrahydroquinoline-7-sulfonyl chloride (995mg and 4.1mmol) under the protection of Ar, carrying out ice bath to room temperature for reaction, stopping the reaction after 0.5h, carrying out rotary evaporation on the solution, adding 10mL of ice water, carrying out DCM extraction, combining organic phases, and carrying out column separation to obtain a light yellow solid (172mg and 19%); (ii) a mp 136 ℃ and 138 ℃.¹H NMR(400MHz,CDCl₃)(ppm):7.65(d,J＝8.1Hz,1H),7.12–6.99(m,3H),5.11(s,2H),3.20–3.11(m,2H),2.91(s,3H),2.86(t,J＝6.6Hz,2H),1.92–1.84(m,2H)；HRMS(ESI):m/z,227.1000[M+H]⁺。

(c) 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (1-methyl-1, 2,3, 4-tetrahydroquinoline-7-) -sulfonyl ] -1H-indole-2-carboxamide

1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (85mg, 0.26mmol) was dissolved in dry DCM under Ar protection, HATU (147mg, 0.39mmol), DMAP (16mg, 0.13mmol) and TEA (78mg, 0.77mmol) were added sequentially and stirred well Then adding 1-methyl-1, 2,3, 4-tetrahydroquinoline-7-sulfonamide (88mg, 0.39mmol), standing overnight at room temperature, evaporating the solvent after stopping the reaction, washing with dilute hydrochloric acid and water in turn, combining EA layers, and separating by a column to obtain a light yellow solid (45mg, 33%); mp:209 ℃ and 211 ℃.¹H NMR(400MHz,CDCl₃)9.38(s,1H),7.91(d,J＝8.1Hz,1H),7.31(s,1H),7.17(dt,J＝21.0,7.1Hz,3H),6.86(d,J＝8.1Hz,1H),6.68(d,J＝9.3Hz,2H),6.55(d,J＝8.1Hz,1H),6.06(s,1H),4.28(s,3H),3.80(s,3H),3.11(s,2H),2.84(s,5H),1.85(s,2H)；HRMS(ESI):m/z,537.1207[M-H]^-。

Example 167: 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-) -sulfonyl ] -1H-indole-2-carboxamide

(a) Synthesis of 3-methylbenzoxazolones

Under Ar gas protection and ice bath conditions, NaH (910mg, 47.9mmol) was added to anhydrous THF, benzoxazolone (3.6g, 26.6mmol) was added dissolved in anhydrous THF, methyl iodide (5.7g, 40mmol) was slowly added, and the reaction was ice-cooled to room temperature overnight. After the reaction was stopped, it was concentrated, diluted with water, extracted with DCM, dried and column isolated as a light reddish brown solid (2.8g, 71%).¹HNMR(400MHz,CDCl₃)(ppm):7.19(t,J＝7.2Hz,2H),7.12(t,J＝7.7Hz,1H),6.96(d,J＝7.6Hz,1H),3.41(s,3H)；HRMS(ESI):m/z,150.1635[M+H]⁺。

(b) Synthesis of 3-methylbenzoxazolone-6-sulfonyl chloride

3-methylbenzoxazolone (2.2g, 14.8mmol) is dissolved in anhydrous DCM under the protection of Ar and ice salt bath, chlorosulfonic acid (38mL) is added, the reaction is stirred for 10h, ice water is slowly added into the system after the reaction is stopped, DCM is used for extraction, the organic phase is dried and steamed in a rotary manner, and the mixture is placed in a vacuum drying oven and directly used for the next reaction. HRMS (ESI) M/z 248.0232[ M + H [ ] ]⁺。

(c) Synthesis of 3-methylbenzoxazolone-6-sulfonamide

3-methylbenzoxazolone-6-sulfonyl chloride (915mg, 3.7) under Ar protectionmmol), adding excessive ammonia methanol solution (4.0mL, 28mmol), reacting at room temperature in ice bath, stopping reaction after 1.5h, removing solvent by spinning, and separating with column to obtain brown yellow solid (140mg, 17%); mp:179 and 181 ℃.¹H NMR(400MHz,CDCl₃)(ppm):7.84(s,1H),7.77(s,1H),7.07(d,J＝8.4Hz,1H),4.77(s,2H),3.47(s,3H)；HRMS(ESI):m/z,229.0888[M+H]⁺。

(d) 7-chloro-4- [ (3-methoxyphenyl) -amino ] -1-methyl-N- [ (3-methyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-) -sulfonyl ] -1H-indole-2-carboxamide

Dissolving 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (105mg, 0.32mmol) in dry DCM under the protection of Ar, sequentially adding HATU (183mg, 0.48mmol), DMAP (20mg, 0.15mmol) and TEA (97mg, 0.96mmol), stirring uniformly, adding 1.5mL of DMF-dissolved sulfonamide (110mg, 0.48mmol), standing overnight at room temperature, distilling off the solvent after stopping the reaction, washing with dilute hydrochloric acid and water sequentially, combining EA layers, and separating the column to obtain a light yellow solid (65mg, 38%); mp: 229-.¹H NMR(400MHz,DMSO-d₆)(ppm):8.31(s,1H),7.92–7.77(m,2H),7.53(s,1H),7.40(d,J＝8.1Hz,1H),7.24–7.06(m,2H),6.89–6.69(m,3H),6.46(d,J＝7.6Hz,1H),4.19(s,3H),3.72(s,3H),2.84(s,3H)；HRMS(ESI):m/z,539.0864[M-H]^-。

Example 168: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-fluorophenylsulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (100mg,0.30mmol) is dissolved in dry DCM, HATU (172mg, 0.45mmol), DMAP (18mg, 0.15mmol) and TEA (92mg,0.90mmol) are sequentially added, after uniform stirring, 4-fluorobenzenesulfonamide (80mg,0.45mmol) is added, the reaction is stopped overnight at room temperature, the solvent is evaporated, dilute hydrochloric acid and water are sequentially used for washing, EA layers are combined, and light yellow green solid (75mg, 51.4%) is obtained by column separation. mp 115-117 ℃; MS (ESI) M/z (%): 486.0633[ M-H ]^-。

¹H NMR(400MHz,DMSO-d₆)(ppm):8.20(s,1H),7.86(s,2H),7.35–7.03(m,4H),6.97(s,1H),6.74(d,J＝16.7Hz,3H),6.40(s,1H),4.27(s,3H),3.69(s,3H)。

Example 169: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-trifluoromethylbenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 3-trifluoromethylbenzenesulfonamide (82mg,0.36mmol) is added, the reaction is stopped overnight at room temperature, the solvent is evaporated, diluted hydrochloric acid and water are sequentially used for washing, EA layers are combined, and the column is separated to obtain a light yellow-green solid (65mg, 50.4%). mp is 69-70 ℃; MS (ESI) M/z (%): 536.0545[ M-H]^-。

¹H NMR(400MHz,DMSO-d₆)(ppm):8.31(m,3H),8.13(d,J＝6.8Hz,1H),7.93(d,J＝6.7Hz,1H),7.72(s,1H),7.16(s,2H),6.84(d,J＝8.0Hz,1H),6.79–6.65(m,2H),6.48(d,J＝7.5Hz,1H),4.10(s,3H),3.71(s,3H).。

Example 170: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-trifluoromethylbenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 4-trifluoromethylbenzenesulfonamide (82mg,0.36mmol) is added, the reaction is stopped overnight at room temperature, the solvent is evaporated, diluted hydrochloric acid and water are sequentially used for washing, EA layers are combined, and the column is separated to obtain a light yellow-green solid (70mg, 54.3%). . mp is 80-81 ℃; MS (ESI) M/z (%): 536.0569[ M-H ]^-。

¹H NMR(400MHz,DMSO-d₆)(ppm):8.21(s,1H),8.00(m,2H),7.77(m,2H),7.31(s,1H),7.11(s,1H),6.98(s,1H),6.76(m,3H),6.40(s,1H),4.25(s,3H),3.69(s,3H)。

Example 171: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-fluorobenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (100mg,0.30mmol) is dissolved in dry DCM, HATU (172mg, 0.45mmol), DMAP (18mg, 0.15mmol) and TEA (92mg,0.90mmol) are sequentially added, after uniform stirring, 3-fluorobenzenesulfonamide (79mg,0.45mmol) is added, the reaction is stopped overnight at room temperature, the solvent is evaporated, dilute hydrochloric acid and water are sequentially used for washing, EA layers are combined, and light yellow green solid (82mg, 56.2%) is obtained by column separation. mp:108-110 ℃; MS (ESI) M/z (%): 486.0622[ M-H]^-。

¹H NMR(400MHz,DMSO-d₆)(ppm):8.21(s,1H),7.60(d,J＝18.7Hz,2H),7.45(s,1H),7.29(s,2H),7.11(s,1H),6.98(s,1H),6.74(d,J＝17.1Hz,3H),6.41(s,1H),4.27(s,3H),3.69(s,3H)。

Example 172: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (2-fluorobenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (100mg,0.30mmol) is dissolved in dry DCM, HATU (172mg, 0.45mmol), DMAP (18mg, 0.15mmol) and TEA (92mg,0.90mmol) are sequentially added, after stirring uniformly, 2-fluorobenzenesulfonamide (79mg,0.45mmol) is added, the reaction is stopped overnight, the solvent is evaporated, dilute hydrochloric acid and water are sequentially used for washing, EA layers are combined, and a light yellow green solid (72mg, 50.0%) is obtained by column separation. mp:105-107 ℃; MS (ESI) M/z (%): 486.0624[ M-H ]^-。

¹H NMR(400MHz,DMSO-d₆)8.20(s,1H),7.86(s,2H),7.35–7.03(m,4H),6.97(s,1H),6.74(d,J＝16.7Hz,3H),6.40(s,1H),4.27(s,3H),3.69(s,3H)。

Example 173: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-cyanobenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 4-cyanobenzenesulfonamide (66mg,0.36mmol) is added, the reaction is stopped overnight, the solvent is evaporated, diluted hydrochloric acid and water are sequentially used for washing, EA layers are combined, and a light yellow green solid (85mg, 71.4%) is obtained by column separation. mp is 60-62 ℃; MS (ESI) M/z (%): 495.6751[ M + H]⁺.

¹H NMR(400MHz,DMSO-d₆)(ppm):8.33(s,1H),8.08(m,4H),7.62(s,1H),7.13(m,2H),6.77(m,3H),6.46(s,1H),4.14(s,3H),3.70(s,3H).

Example 174: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (2-trifluoromethoxybenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 2-trifluoromethoxybenzenesulfonamide (87mg,0.36mmol) is added, the reaction is carried out overnight at room temperature, the solvent is evaporated after the reaction is stopped, diluted hydrochloric acid and water are sequentially used for washing, EA layers are combined, and the column is separated to obtain a light yellow-green solid (67mg, 50.8%). mp 136-138 ℃; MS (ESI) M/z (%): 552.0520[ M-H ]^-.

¹H NMR(400MHz,DMSO-d₆)(ppm):8.26(s,1H),8.02(s,1H),7.44(m,4H),7.12(s,1H),7.03(s,1H),6.88–6.67(m,3H),6.42(s,1H),4.21(s,3H),3.69(s,3H).

Example 175: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-chlorobenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 3-chlorobenzenesulfonamide (69mg,0.36mmol) is added, the reaction is stopped overnight at room temperature, the solvent is evaporated, dilute hydrochloric acid and water are sequentially used for washing, EA layers are combined, and a light yellow-green solid (55mg, 45.8%) is obtained by column separation. mp is 71-73 ℃; MS (ESI) M/z (%): 502.0302[ M-H]^-.

¹H NMR(400MHz,DMSO-d₆)(ppm):8.37(s,1H),7.95(d,J＝9.1Hz,2H),7.81(d,J＝7.9Hz,1H),7.74–7.64(m,2H),7.22–7.11(m,2H),6.84(d,J＝8.3Hz,1H),6.79–6.68(m,2H),6.47(d,J＝8.0Hz,1H),4.12(s,3H),3.71(s,3H).

Example 176: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-cyanobenzenesulfonyl) -1H-indole-2-carboxamide

a) Synthesis of 3-cyanobenzenesulfonamide

Excess methanolic ammonia (3.5mL, 17.5mmol) was added to 3-cyanobenzenesulfonyl chloride (400mg, 2.0mmol) under Ar protection, the reaction was cooled to room temperature in ice bath, stopped after 0.5h, the solution was evaporated by rotary evaporation, 10mL ice water was added, DCM was extracted four times, the organic phases were combined and recrystallized to give a pale yellow solid (206mg, 56.6%). MS (ESI) M/z (%): 183.0320[ M + H]⁺.

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-cyanobenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 3-cyanobenzenesulfonamide (66mg,0.36mmol) is added, the reaction is stopped overnight at room temperature, the solvent is evaporated, dilute hydrochloric acid and water are sequentially used for washing, EA layers are combined, and the column is separated to obtain a light yellow-green solid (65mg, 55.1%). mp is 80-82 ℃; MS (ESI) M/z (%): 493.0905[ M-H]^-.

¹H NMR(400MHz,DMSO-d₆)(ppm):8.49–8.07(m,4H),7.85(s,1H),7.68(s,1H),7.15(d,J＝7.7Hz,2H),6.79(dd,J＝37.0,13.4Hz,3H),6.47(s,1H),4.12(s,3H),3.70(s,3H).

Example 177: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-methylbenzenesulfonyl) -1H-indole-2-carboxamide

a) Synthesis of 3-methylbenzenesulfonamide

Excess methanolic ammonia (3.5mL, 24.5mmol) was added to 3-methylbenzenesulfonyl chloride (380mg, 2.0mmol) under the protection of Ar, the reaction was cooled to room temperature in an ice bath, stopped after 0.5h, the solution was rotary evaporated, 10mL of ice water was added, DCM was extracted four times, the organic phases were combined, and white solid (275mg, 79.0%) was obtained by recrystallization. MS (ESI) M/z (%): 172.2120[ M + H]⁺.

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-methylbenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 3-methylbenzenesulfonamide (70mg,0.41mmol) is added, the reaction is stopped overnight at room temperature, the solvent is evaporated, diluted hydrochloric acid and water are sequentially used for washing, EA layers are combined, and the column is separated to obtain a light yellow-green solid (70mg, 59.8%). mp is 72-73 ℃; MS (ESI) m- z(％):483.10[M-H]^-.

¹H NMR(400MHz,DMSO-d₆)(ppm):12.58(s,1H),8.36(s,1H),7.79(s,2H),7.68(s,1H),7.52(d,J＝5.1Hz,2H),7.16(dt,J₁＝8.0Hz,J₂＝3.9Hz,2H),6.84(d,J＝8.3Hz,1H),6.77–6.70(m,2H),6.47(d,J＝8.2Hz,1H),4.10(s,3H),3.71(s,3H),2.41(s,3H).

Example 178: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-chlorobenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 4-chlorobenzenesulfonamide (70mg,0.36mmol) is added, the reaction is stopped overnight at room temperature, the solvent is evaporated, dilute hydrochloric acid and water are sequentially used for washing, EA layers are combined, and a light yellow-green solid (56mg, 46.3%) is obtained by column separation. mp is 59-61 ℃; MS (ESI) M/z (%): 502.0553[ M-H]^-.

¹H NMR(400MHz,DMSO-d₆)(ppm):12.71(s,1H),8.36(s,1H),7.99(d,J＝8.3Hz,2H),7.79–7.66(m,3H),7.17(d,J＝5.2Hz,2H),6.84(d,J＝8.2Hz,1H),6.78–6.69(m,2H),6.47(d,J＝8.1Hz,1H),4.10(s,3H),3.71(s,3H).

Example 179: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methylbenzenesulfonyl) -1H-indole-2-carboxamide

a) Synthesis of 4-methylbenzenesulfonamide

Excess methanolic ammonia (3.5mL, 24.5mmol) was added to 4-methylbenzenesulfonyl chloride (380mg, 2.0mmol) under the protection of Ar, the reaction was allowed to cool to room temperature, the reaction was stopped after 1.0h, the solution was rotary evaporated, 10mL of ice water was added, DCM was extracted four times, the organic phases were combined, and recrystallization was carried out to give a white solid (238mg, 68.0%).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-methylbenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are added in sequence, p-toluenesulfonamide (70mg,0.41mmol) is added after stirring uniformly, the reaction is stopped overnight at room temperature, the solvent is evaporated, dilute hydrochloric acid and water are used in sequence, the EA layers are combined, and the column is separated to obtain a light yellow-green solid (75mg, 64.1%). mp is 75-76 ℃; MS (ESI) M/z (%): 482.1079[ M-H]^-.

¹H NMR(400MHz,DMSO-d₆)(ppm):12.50(s,1H),8.34(s,1H),7.86(d,J＝8.1Hz,2H),7.64(s,1H),7.42(d,J＝7.9Hz,2H),7.16(t,J＝8.4Hz,2H),6.83(d,J＝8.3Hz,1H),6.79–6.69(m,2H),6.47(d,J＝8.1Hz,1H),4.11(s,3H),3.70(s,3H),2.39(s,3H).

Example 180: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-trifluoromethoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) Synthesis of 4-trifluoromethoxybenzenesulfonamide

Adding excessive ammonia methanol solution (5mL, 35mmol) into 4-trifluoromethoxybenzenesulfonyl chloride (520mg, 2.0mmol) under the protection of Ar, reacting at room temperature in an ice bath, stopping the reaction after 40min, evaporating the solution in a rotary manner, adding 20mL of ice water, extracting with DCM for four times, combining organic phases, and recrystallizing to obtain a white solid (425mg, 88.5%).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (4-trifluoromethoxybenzenesulfonyl) -1H-indole-2-carboxamide

Dissolving 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) in dry DCM under the protection of Ar, adding HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) in sequence, stirring uniformly, adding 2-trifluoromethoxybenzenesulfonamide (88mg,0.36mmol), standing overnight at room temperature, stopping reaction After reaction, the solvent was evaporated, washed with dilute hydrochloric acid, water, and the EA layer was combined and column-separated to give a pale yellow-green solid (70mg, 52.0%). mp is 96-98 ℃; MS (ESI) M/z (%): 552.0772[ M-H]^-.

¹H NMR(400MHz,DMSO-d₆)(ppm):12.78(s,1H),8.36(s,1H),8.11(d,J＝8.5Hz,2H),7.73–7.59(m,3H),7.16(m,2H),6.84(d,J＝8.3Hz,1H),6.79–6.69(m,2H),6.47(d,J＝8.2Hz,1H),4.12(s,3H),3.71(s,3H).

Example 181: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- [ (5-methylpyridine-2-) sulfonyl ] -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 5-methylpyridine-2-sulfonamide (63mg,0.36mmol) is added, the reaction is kept overnight at room temperature, the solvent is evaporated after the reaction is stopped, diluted hydrochloric acid and water are sequentially used for washing, EA layers are combined, and the column is separated to obtain light yellow-green solid (65mg, 55.6%). mp is 58-60 ℃; MS (ESI) M/z (%): 483.1021[ M-H]^-.

¹H NMR(400MHz,DMSO-d₆)(ppm):12.83(s,1H),8.53(s,1H),8.36(s,1H),8.02(d,J＝8.0Hz,1H),7.93(s,1H),7.68(s,1H),7.16(t,J＝8.1Hz,2H),6.84(d,J＝8.2Hz,1H),6.79–6.69(m,2H),6.46(d,J＝8.3Hz,1H),4.09(s,3H),3.71(s,3H),2.39(s,3H).

Example 182: 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-trifluoromethoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) Synthesis of 3-trifluoromethoxybenzenesulfonamide

Adding excessive ammonia methanol solution (4mL, 28mmol) into 3-trifluoromethoxybenzenesulfonyl chloride (200mg, 0.77mmol) under the protection of Ar, reacting at room temperature in an ice bath, stopping the reaction after 40min, evaporating the solution in a rotary manner, adding 20mL of ice water, extracting with DCM for four times, combining organic phases, and recrystallizing to obtain a white solid (115mg, 62.2%).

b) 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-N- (3-trifluoromethoxybenzenesulfonyl) -1H-indole-2-carboxamide

Under the protection of Ar, 1-methyl-4- ((3-methoxyphenyl) amino) -7-chloro-1H-indole-2-carboxylic acid (80mg,0.24mmol) is dissolved in dry DCM, HATU (140mg, 0.36mmol), DMAP (15mg, 0.12mmol) and TEA (73mg,0.72mmol) are sequentially added, after stirring uniformly, 3-trifluoromethoxybenzenesulfonamide (88mg,0.36mmol) is added, the reaction is carried out overnight at room temperature, the solvent is evaporated after the reaction is stopped, diluted hydrochloric acid and water are sequentially used for washing, EA layers are combined, and the column is separated to obtain light yellow green solid (68mg, 50.7%). mp is 75-77 ℃; MS (ESI) M/z (%): 552.0750[ M-H]^-.

¹H NMR(400MHz,DMSO-d₆)(ppm):8.37(s,1H),8.02(d,J＝7.4Hz,1H),7.91(s,1H),7.85–7.68(m,3H),7.16(m,2H),6.84(d,J＝8.3Hz,1H),6.79–6.69(m,2H),6.48(d,J＝7.7Hz,1H),4.11(s,3H),3.71(s,3H).

Example 183- ((3-Acylaminophenyl) -7-nitro-N- (trifluoromethanesulfonyl) -1H-indole-2-carboxamide

a) 4- (3-Acylaminophenyl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation process is the same as that of a) in example 3 with ethyl 7-nitro-4-chloro-1H-indole-2-carboxylate and 3-acetaminophenylboronic acid as starting materials to obtain a pale yellow solid 248mg with a yield of 60%, mp: 183-;

¹H NMR(CDCl₃)(ppm):10.45(s,1H),8.33(d,J＝8.0Hz,1H),7.84(s,1H),7.63(d,J＝7.6Hz,1H),7.47-7.51(m,3H),7.39(d,J＝7.6Hz,1H),7.30(d,J＝8.4Hz,1H),4.45(q,J＝7.2Hz,2H),2.23(s,3H),1.43(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₉H₁₈N₃O₅[M+H⁺]:368.1241,found 368.1228.

b) 4- (3-Acylaminophenyl) -7-nitro-1H-indole-2-carboxylic acid

Starting from 4- (3-acetylaminophenyl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester, the preparation was carried out as described in b) of example 3 to give 65mg of a pale yellow solid in 78% yield mp >250 ℃.

¹H NMR(DMSO-d₆)(ppm):13.60(brs,1H),11.27(s,1H),10.17(s,1H),8.35(d,J＝8.4Hz,1H),8.02(s,1H),7.70(d,J＝8.1Hz,1H),7.50(t,J＝7.8Hz,1H),7.36-7.42(m,3H),2.08(s,3H)；HRMS(ESI):m/z,calcd for C₁₇H₁₄N₃O₅[M+H⁺]:340.0928,found 340.0921.

c) 4- ((3-Acylaminophenyl) -7-nitro-N- (trifluoromethanesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 4- (3-acetamidophenyl) -7-nitro-1H-indole-2-carboxylic acid and trifluoromethanesulfonamide, gave 60mg of a yellow powdery solid in 72% yield, mp: 190-.

¹H NMR(DMSO-d₆)(ppm):10.53(s,1H),10.20(s,1H),8.29(d,J＝9.6Hz,1H),7.95(s,1H),7.80(d,J＝8.0Hz,1H),7.51(t,J＝8.0Hz,1H),7.37(t,J＝8.0Hz,1H),7.14(s,1H),2.08(s,3H).

Example 184- ((3-Acylaminophenyl) -7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

Starting from 4- (3-acetylaminophenyl) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, the preparation is carried out as described in c) of example 3 to give 45mg of a yellow powdery solid in 80% yield mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.75(brs,1H),10.18(s,1H),8.38(d,J＝8.4Hz,1H),8.04(d,J＝8.0Hz,2H),7.94(s,1H),7.77-7.64(m,5H),7.52(t,J＝8.0Hz,2H),7.41-7.36(m,2H),2.09(s,3H).

Example 185- ((3-Acylaminophenyl) -7-amino-N- (phenylsulfonyl) -1H-indole-2-carboxamide

Dissolving 4- ((3-acetamidophenyl) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide (120mg, 0.25mmol) in methanol (10mL), adding Pd/C (20mg), catalytically hydrogenating for 5H, removing raw materials, filtering, concentrating the filtrate, dissolving EA (20mL), washing with water, and performing column chromatography (D/M ═ 50:1) to obtain an off-white powdery solid 33mg, mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.87(brs,1H),10.22(brs,2H),10.02(s,1H),7.88-7.86(m,2H),7.70(s,1H),7.59(d,J＝8.4Hz,1H),7.40-7.38(m,3H),7.31(t,J＝7.8Hz,1H),7.19(d,J＝7.2Hz,1H),6.86(brs,1H),6.80(d,J＝7.5Hz,1H),6.36(d,J＝7.8Hz,1H),5.48(brs,1H),2.06(s,3H).

Example 186- ((3-Acylaminophenyl) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 4- (3-acetylaminophenyl) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, the preparation was carried out as described under c) in example 3 to give 69mg of a yellow powdery solid in 92% yield and mp: >290 ℃.

¹H NMR(DMSO-d₆)(ppm):12.98(brs,1H),11.75(brs,1H),10.18(s,1H),8.38(d,J＝8.0Hz,1H),7.97(d,J＝8.8Hz,2H),7.95(s,1H),7.76(d,J＝8.0Hz,1H),7.70(s,1H),7.52(t,J＝8.0Hz,1H),7.41-7.36(m,2H),7.17(d,J＝8.8Hz,2H),3.85(s,3H),1.99(s,3H)；¹³C NMR(125MHz,DMSO-d₆):168.63,163.35,157.66,143.56,139.92,138.13,132.31,131.87,130.48,130.33,130.01,129.59,127.91,123.41,123.10,119.98,119.47,119.13,114.36,109.63,55.84,24.10.HRMS(ESI):m/z,calcd.for C₂₄H₂₁N₄O₇S[M+H]⁺:509.1126,found 509.1119.

Example 187 4- ((3-cyanophenyl) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (3-cyanophenyl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation process was the same as that described in a) of example 3 using 7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-cyanophenylboronic acid as starting materials to obtain 178mg of pale yellow solid with a yield of 57% and mp:195-197 deg.C;

¹H NMR(acetone-d₆)(ppm):10.95(brs,1H),8.44(d,J＝8.4Hz,1H),8.17(s,1H),8.12(d,J＝8.0Hz,1H),7.96(d,J＝7.6Hz,1H),7.85(t,J＝8.0Hz,1H),7.55(d,J＝8.4Hz,1H),7.48(s,1H),4.44(q,J＝7.2Hz,2H),1.39(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcdfor C₁₈H₁₄N₃O₄[M+H⁺]:336.0979,found 336.0968.

b) 4- (3-cyanophenyl) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 4- (3-cyanophenyl) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3, giving 96mg of a pale yellow solid in 95% yield and mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):11.32(s,1H),8.33(d,J＝8.4Hz,1H),8.17(s,1H),8.05(d,J＝7.6Hz,1H),7.98(d,J＝7.2Hz,1H),7.78(t,J＝7.6Hz,1H),7.47(d,J＝8.4Hz,1H),7.32(s,1H)；HRMS(ESI):m/z,calcd for C₁₆H₁₀N₃O₄[M+H⁺]:308.0666,found 308.0652.

c) 4- ((3-cyanophenyl) -7-nitro-N- (benzenesulfonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was repeated, starting from 4- (3-cyanophenyl) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, to give 50mg of a pale yellow powdery solid in 86% yield mp: >290 ℃.

¹H NMR(DMSO-d₆)(ppm):11.74(brs,1H),8.38(d,J＝8.4Hz,1H),8.19(s,1H),8.07-8.01(m,4H),7.81(t,J＝8.0Hz,1H),7.74(t,J＝7.2Hz,1H),7.68-7.64(m,3H),7.50(d,J＝8.4Hz,1H).

Example 188- ((3-methoxyphenyl) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (3-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation process was the same as that described in a) of example 3 using ethyl 7-nitro-4-chloro-1H-indole-2-carboxylate and 3-methoxyphenylboronic acid as starting materials to give 268mg of pale yellow solid with a yield of 85%, mp: 182-;

¹H NMR(CDCl₃)(ppm):10.47(s,1H),8.35(d,J＝8.4Hz,1H),7.45-7.47(m,2H),7.31(d,J＝8.4Hz,1H),7.25(d,J＝9.2Hz,1H),7.18(s,1H),7.04(d,J＝8.4Hz,1H),4.46(q,J＝7.2Hz,2H),3.89(s,3H),1.43(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd forC₁₈H₁₇N₂O₅[M+H⁺]:341.1132,found 341.1119.

b) 4- (3-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid

The preparation of 4- (3-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester as starting material was carried out as described in b) of example 3 to give 106mg of a pale yellow solid in 91% yield mp:248-249 ℃.

¹H NMR(DMSO-d₆)(ppm):13.59(brs,1H),11.27(s,1H),8.33(d,J＝8.4Hz,1H),7.51(t,J＝8.0Hz,1H),7.44(d,J＝8.4Hz,1H),7.31(s,1H),7.30(d,J＝7.6Hz,1H),7.22(s,1H),7.11(d,J＝8.4Hz,1H),3.80(s,3H)；HRMS(ESI):m/z,calcdfor C₁₆H₁₃N₂O₅[M+H⁺]:313.0819,found 313.0817.

c) 4- ((3-methoxyphenyl) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3 c) was repeated using 4- (3-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials to give 51mg of a pale yellow powdery solid in 82% yield mp:244 and 246 ℃.

¹H NMR(DMSO-d₆)(ppm):12.98(brs,1H),11.63(brs,1H),8.35(d,J＝8.4Hz,1H),7.97(d,J＝8.8Hz,2H),7.72(s,1H),7.52(t,J＝8.0Hz,1H),7.44(d,J＝8.0Hz,1H),7.28(d,J＝7.6Hz,1H),7.23(s,1H),7.17(d,J＝8.8Hz,2H),7.13(d,J＝8.8Hz,4H),3.86(s,3H),3.85(s,3H).

Example 189- ((4-methoxyphenyl) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 4- (4-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation process is the same as the method in a) in example 3 with 7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 4-methoxyphenylboronic acid as starting materials to obtain a pale yellow solid 260mg with a yield of 93%, and mp: 144-;

¹H NMR(CDCl₃)(ppm):10.47(brs,1H),8.34(d,J＝8.4Hz,1H),7.63(d,J＝8.4Hz,2H),7.48(s,1H),7.27(d,J＝10.4Hz,1H),7.08(d,J＝8.4Hz,2H),4.46(q,J＝7.2Hz,2H),3.91(s,3H),1.44(t,J＝7.2Hz,3H).

b) 4- (4-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid

The preparation of 4- (4-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester as starting material was carried out as described in b) of example 3 to give 152mg of a pale yellow solid in 89% yield mp: 235-.

¹H NMR(DMSO-d₆)(ppm):13.59(brs,1H),11.22(s,1H),8.33(d,J＝8.4Hz,1H),7.71(d,J＝8.4Hz,2H),7.40(d,J＝8.4Hz,1H),7.35(s,1H),7.17(d,J＝8.8Hz,2H),3.86(s,3H).

c) 4- ((4-methoxyphenyl) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The preparation of 4- (4-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide as starting materials was carried out as described in c) of example 3 to give 85mg of a pale yellow powdery solid in 85% yield at mp: 253-.

¹HNMR(DMSO-d₆)(ppm):12.98(brs,1H),11.59(brs,1H),8.33(d,J＝8.4Hz,1H),7.97(d,J＝8.8Hz,2H),7.69(d,J＝8.4Hz,3H),7.38(d,J＝8.4Hz,1H),7.16(d,J＝8.4Hz,4H),3.86(s,3H),3.85(s,3H)；HRMS(ESI):m/z,calcd.forC₂₃H₂₀N₃O₇S[M+H]⁺:482.1022,found 482.1009.

Example 190 methyl-4- (4-methoxyphenyl) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- (4-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 4-methoxyphenylboronic acid as starting materials was carried out as described in a) of example 3 to give 155mg of a pale yellow solid in 82% yield mp: 156-.

¹H NMR(CDCl₃)(ppm):7.96(d,J＝8.4Hz,1H),7.57(d,J＝8.4Hz,2H),7.50(s,1H),7.18(d,J＝8.0Hz,1H),7.07(d,J＝8.4Hz,2H),4.39(q,J＝7.2Hz,2H),4.01(s,3H),3.90(s,3H),1.40(t,J＝7.2Hz,3H).

b) 1-methyl-4- (4-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 1-methyl-4- (4-methoxyphenyl) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 120mg of a pale yellow powdery solid in 93% yield and mp:257 ℃ and 259 ℃.

¹H NMR(DMSO-d₆)(ppm):8.06(d,J＝8.0Hz,1H),7.64(d,J＝8.4Hz,2H),7.39(s,1H),7.32(d,J＝8.4Hz,1H),7.15(d,J＝8.4Hz,2H),3.90(s,3H),3.85(s,3H).

c) 1-methyl-4- (4-methoxyphenyl) -7-nitro-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- (4-methoxyphenyl) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulfonamide, 46mg of a yellow powdery solid were obtained in the same manner as in c) of example 3, in a yield of 75%, mp:145-247 ℃.

¹H NMR(DMSO-d₆)(ppm):12.62(brs,1H),8.06(d,J＝8.0Hz,1H),7.95(d,J＝8.8Hz,2H),7.79(s,1H),7.68(d,J＝8.4Hz,2H),7.32(d,J＝8.0Hz,1H),7.19-7.15(m,4H),3.87(s,3H),3.85(s,3H),3.69(s,3H)；HRMS(ESI):m/z,calcd.for C₂₄H₂₂N₃O₇S[M+H]⁺:496.1179,found 496.1166.

Example 191-methyl-4- (3-acetamidophenyl) -N- (phenylsulfonyl) -1H-indole-2-carboxamide

a) 1-methyl-4- (3-acetylaminophenyl) -7-nitro-1H-indole-2-carboxylic acid methyl ester

The procedure of a) in example 75 was repeated using 1-methyl-7-nitro-4-chloro-1H-indole-2-carboxylic acid ethyl ester and 3-acetamidophenylboronic acid as starting materials to give 105mg of a pale yellow powdery solid in 79% yield mp:165 and 166 ℃.

¹H NMR(CDCl₃)(ppm):7.95(d,J＝8.0Hz,1H),7.75(s,1H),7.63(d,J＝8.0Hz,1H),7.51(s,1H),7.49(t,J＝8.0Hz,1H),7.36(d,J＝7.2Hz,1H),7.22(d,J＝8.0Hz,1H),4.40(q,J＝7.2Hz,2H),4.01(s,3H),2.23(s,3H),1.40(t,J＝7.2Hz,3H).

b) 1-methyl-4- (3-acetamidophenyl) -7-nitro-1H-indole-2-carboxylic acid

Starting from methyl 1-methyl-4- (3-acetamidophenyl) -7-nitro-1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 143mg of an orange powdery solid in 99% yield mp: 199-.

¹H NMR(DMSO-d₆)(ppm):13.48(brs,1H),10.17(s,1H),8.08(d,J＝8.0Hz,1H),7.97(s,1H),7.70(d,J＝8.0Hz,1H),7.50(t,J＝8.0Hz,1H),7.44(s,1H),7.35-7.32(m,2H),3.91(s,3H),2.08(s,3H).

c) 1-methyl-4- (3-acetamidophenyl) -N- (benzenesulfonyl) -1H-indole-2-carboxamide

Starting from 1-methyl-4- (3-acetylaminophenyl) -7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide, 49mg of a brown powdery solid were obtained in the same manner as in c) of example 3, in a yield of 78% and mp: >280 ℃.

¹H NMR(DMSO-d₆)(ppm):10.22(brs,1H),8.10(d,J＝8.0Hz,1H),8.02(d,J＝8.0Hz,2H),7.89(s,1H),7.81(s,1H),7.78(d,J＝8.4Hz,1H),7.74(t,J＝7.6Hz,1H),7.66(t,J＝7.6Hz,2H),7.55(t,J＝8.0Hz,1H),7.38(d,J＝7.6Hz,1H),7.33(d,J＝8.0Hz,1H),3.68(s,3H),2.10(s,3H).

Example 192-methyl-4- (3-acetamidophenyl) -N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, starting from 1-methyl-4- (3-acetamidophenyl) -7-nitro-1H-indole-2-carboxylic acid and 4-methoxybenzenesulphonamide, gave 46mg of a brown powdery solid in 70% yield mp: 240-.

¹H NMR(DMSO-d₆)(ppm):12.63(brs,1H),10.22(s,1H),8.10(d,J＝8.0Hz,1H),7.95(d,J＝8.8Hz,2H),7.89(s,1H),7.78(d,J＝8.8Hz,2H),7.54(t,J＝8.0Hz,1H),7.37(d,J＝7.6Hz,1H),7.32(d,J＝8.0Hz,1H),7.17(d,J＝8.8Hz,2H),3.85(s,3H),3.68(s,3H),2.10(s,3H)；HRMS(ESI):m/z,calcd.for C₂₅H₂₃N₄O₇S[M+H]⁺:523.1287,found523.1276.

Example 193- (3-Acylaminophenyl) -N- (phenylsulfonyl) -1H-indole-2-carboxamide

a) 4- (3-Acetaminophenyl) -1H-indole-2-carboxylic acid ethyl ester

4-bromo-1H-indole-2-carboxylic acid ethyl ester (150mg, 0.56mmol) was dissolved in 1,4-dioxane (15mL), and Pd was added sequentially₂(dppf)Cl₂(41mg, 0.056mmol) and Na₂CO₃(178mg，1.68mmol,2mL H₂O), stirring uniformly, adding 3-acetaminophenylboronic acid (300mg, 1.68mmol), reacting for 2h at 100 ℃ under the protection of argon, cooling to room temperature, evaporating to remove the solvent, dissolving the residue with EA (30mL), washing with saturated brine (20mL × 3), washing with water (20mL × 3), and performing column chromatography (P/E is 10:1-D/M is 200:1) to obtain 190mg of white powdery solid, wherein the yield is 88%, and the mp: 229-.

¹H NMR(DMSO-d₆)(ppm):12.08(s,1H),10.08(s,1H),7.91(s,1H),7.65(d,J＝8.4Hz,1H),7.49-7.29(m,4H),7.23(d,J＝1.2Hz,1H),7.15(d,J＝7.2Hz,1H),4.35(q,J＝6.9Hz,2H),2.08(s,3H),1.34(t,J＝7.2Hz,3H).

b) 4- (3-Acetaminophenyl) -1H-indole-2-carboxylic acid

Starting with ethyl 4- (3-acetamidophenyl) -1H-indole-2-carboxylate, the preparation was carried out as described in b) of example 3 to give 100mg of an off-white powdery solid in 78% yield mp: 256-sodium benzoate 257 ℃.

¹H NMR(DMSO-d₆)(ppm):12.99(brs,1H),11.95(s,1H),10.08(s,1H),7.94(s,1H),7.63(d,J＝7.6Hz,1H),7.47-7.41(m,2H),7.36-7.30(m,2H),7.21(s,1H),7.15(d,J＝7.2Hz,1H),2.08(s,3H).

c) 4- (3-Acylaminophenyl) -N- (phenylsulfonyl) -1H-indole-2-carboxamide

The procedure of example 3 c) was repeated, starting from 4- (3-acetylaminophenyl) -1H-indole-2-carboxylic acid and benzenesulfonamide, to give 71mg of a white powdery solid in a yield of 96%, mp:255 and 257 ℃.

¹H NMR(DMSO-d₆)(ppm):12.59(brs,1H),11.90(s,1H),10.09(s,1H),8.01(d,J＝8.0Hz,1H),7.83(s,1H),7.71(d,J＝8.0Hz,3H),7.64(t,J＝7.6Hz,2H),7.46(t,J＝8.0Hz,1H),7.40(d,J＝8.0Hz,1H),7.34(t,J＝8.0Hz,2H),7.11(d,J＝7.2Hz,1H),2.09(s,3H).

Preparation of intermediate 26:

7-Nitro-3-bromo-1H-indole-2-carboxylic acid ethyl ester

a)2- (2- (2-Nitrophenyl) hydrazono) propionic acid ethyl ester

Ortho-nitrophenylhydrazine hydrochloride (5.0g, 26.4mmol) was dissolved in ethanol (30mL), ethyl pyruvate (3.7g, 32mmol) was added dropwise, and the reaction was carried out at room temperature for 10 min. The reaction solution was poured into ice water and filtered to obtain 5.56g of a yellow powdery solid in 82% yield, mp: 106-.

¹H NMR(CDCl₃)(ppm):10.96(brs,1H),8.21(q,J＝8.4Hz,1H),8.04(d,J＝8.4Hz,1H),7.62(t,J＝8.0Hz,1H),7.00(t,J＝8.0Hz,1H),4.36(q,J＝7.2Hz,2H),2.25(s,3H),1.40(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₁H₁₄N₃O₄[M+H⁺]:252.0979,found252.0986.

b) 7-Nitro-1H-indole-2-carboxylic acid ethyl ester

Ethyl 2- (2- (2-nitrophenyl) hydrazono) propionate (5.3g, 21mmol) was added to PPA (26.5g) and reacted at 90-100 ℃ for 2h, with disappearance of starting material. Cooling to room temperature, adding 30mL ice water in ice water bath, EA extraction (40mL multiplied by 2), concentration, and EA recrystallization to obtain 2.02g of light yellow solid with the yield of 41% and mp:94-95 ℃.

¹H NMR(CDCl₃)(ppm):10.34(brs,1H),8.30(d,J＝8.0Hz,1H),8.05(d,J＝7.6Hz,1H),7.36(s,1H),7.28(t,J＝7.6Hz,1H),4.47(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₁H₁₁N₂O₄[M+H⁺]:235.0713,found235.0722.

c) 7-Nitro-3-bromo-1H-indole-2-carboxylic acid ethyl ester

7-Nitro-1H-indole-2-carboxylic acid ethyl ester (100mg, 0.43mmol) was dissolved in DMF (2mL), and a solution of NBS (84mg, 0.473mmol) in DMF (2mL) was slowly added dropwise in an ice-water bath, followed by reaction at room temperature for 1.5H, whereupon the starting material disappeared. The reaction solution was poured into ice water to precipitate a solid, which was filtered and dried to obtain 115mg of an off-white powdery solid with a yield of 85%, mp: 135-.

¹H NMR(CDCl₃)(ppm):10.41(brs,1H),8.37(d,J＝8.1Hz,1H),8.07(d,J＝7.8Hz,1H),7.37(t,J＝7.8Hz,1H),4.52(q,J＝7.2Hz,2H),1.49(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₁H₁₀BrN₂O₄[M+H⁺]:312.9819,found 312.9815.

Example 194: 3-ethyl-7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

a) 3-Ethyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester

Dissolving 7-nitro-3-bromo-1H-indole-2-carboxylic acid ethyl ester (200mg, 0.64mmol) in toluene (15mL), sequentially adding Pd (OAc)₂(7mg, 0.032mmol), Josiphos (20mg, 0.032mmol) and K₃PO₄(679mg，3.2mmol,1mL H₂O), stirring well, adding ethylboronic acid (142mg, 1.92mmol), reacting at 80 ℃ for 4h under the protection of argon, allowing the starting material to disappear, cooling to room temperature, concentrating, adding EA (40mL) to dissolve the residue, washing with saturated brine (20mL × 3), washing with water (20mL × 2), and performing column chromatography (P/E ═ 100:1) to obtain an off-white powdery solid 165mg, with a yield of 99%, mp:94-96 ℃.

¹H NMR(CDCl₃)(ppm):10.13(brs,1H),8.29(d,J＝8.0Hz,1H),8.05(d,J＝8.0Hz,1H),7.25(t,J＝8.0Hz,1H),4.47(q,J＝7.2Hz,2H),3.16(q,J＝7.2Hz,2H),1.46(t,J＝6.8Hz,3H),1.30(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₃H₁₅N₂O₄[M+H⁺]:263.1026,found 263.1024.

b) 3-ethyl-7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 3-ethyl-7-nitro-1H-indole-2-carboxylate, the preparation process is as described in b) of example 3, giving 60mg of a pale yellow solid with a yield of 67%, mp: 231-.

¹H NMR(DMSO-d₆)(ppm):13.58(brs,1H),10.58(s,1H),8.28(d,J＝8.0Hz,2H),7.34(t,J＝8.0Hz,1H),3.12(q,J＝7.2Hz,2H),1.22(t,J＝7.6Hz,3H)；HRMS(ESI):m/z,calcd for C₁₁H₁₁N₂O₄[M+H⁺]:235.0713,found 235.0710.

c) 3-ethyl-7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

The preparation of 3-ethyl-7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide as starting materials was carried out as described in c) of example 3 to give 38mg of a pale yellow solid in 80% yield mp: 228-.

¹H NMR(DMSO-d₆)(ppm):11.84(brs,1H),8.32(d,J＝8.0Hz,1H),8.25(d,J＝8.0Hz,1H),8.06(d,J＝7.6Hz,2H),7.75(t,J＝7.2Hz,1H),7.67(t,J＝7.6Hz,2H),7.34(t,J＝8.0Hz,1H),3.03(q,J＝7.2Hz,2H),1.07(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd.forC₁₇H₁₆N₃O₅S[M+H]⁺:374.0811,found 374.0797.

Example 195: 3-isobutyl-7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

a) 3-isobutyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 7-nitro-3-bromo-1H-indole-2-carboxylic acid ethyl ester and isobutylboronic acid as starting materials was carried out as described in example 194 a) to give 177mg of a pale yellow solid in 85% yield mp:95-96 ℃.

¹H NMR(CDCl₃)(ppm):10.19(brs,1H),8.29(d,J＝8.1Hz,1H),8.03(d,J＝7.8Hz,1H),7.24(t,J＝8.1Hz,1H),4.46(q,J＝7.2Hz,2H),3.01(d,J＝7.5Hz,2H),1.98-2.07(m,1H),1.46(t,J＝7.2Hz,3H),0.96(d,J＝6.6Hz,3H)；HRMS(ESI):m/z,calcd for C₁₅H₁₉N₂O₄[M+H⁺]:291.1339,found 291.1335.

b) 3-ethyl-7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 3-isobutyl-7-nitro-1H-indole-2-carboxylate, the preparation process is as described in b) of example 3, giving 60mg of a pale yellow solid with a yield of 56%, mp: 185-.

¹H NMR(DMSO-d₆)(ppm):13.54(s,1H),10.60(s,1H),8.27(d,J＝8.8Hz,1H),8.24(d,J＝8.4Hz,1H),7.33(t,J＝8.0Hz,1H),2.99(d,J＝6.8Hz,2H),1.93-1.99(m,1H),0.89(d,J＝6.4Hz,3H)；HRMS(ESI):m/z,calcd for C₁₃H₁₅N₂O₄[M+H⁺]:263.1026,found263.1023.

c) 3-isobutyl-7-nitro-N- (phenylsulfonyl) -1H-indole-2-carboxamide

The preparation of 3-isobutyl-7-nitro-1H-indole-2-carboxylic acid and benzenesulfonamide starting from 3-isobutyl-7-nitro-1H-indole-2-carboxylic acid was carried out as described in c) of example 3, giving 60mg of a pale yellow solid with a yield of 78% and mp:194 and 196 ℃.

¹H NMR(CDCl₃)(ppm):10.29(brs,1H),8.62(brs,1H),8.29(d,J＝8.0Hz,1H),8.19(d,J＝7.6Hz,2H),8.00(d,J＝8.0Hz,1H),7.70(t,J＝7.6Hz,1H),7.60(t,J＝7.6Hz,2H),7.27(t,J＝8.4Hz,1H),2.94(d,J＝7.2Hz,2H),2.00-1.97(m,1H),1.03(d,J＝6.4Hz,6H).

Preparation of intermediate 27:

7-Nitro-5-bromo-1H-indole-2-carboxylic acid ethyl ester

a)2- (2- (2-Nitro-4-bromophenyl) hydrazono) propionic acid ethyl ester

2-Nitro-4-bromoaniline (20g,92mmol) was dissolved in concentrated hydrochloric acid (100mL) and reacted at 40 ℃ for 2 h. Then, the mixture was cooled to-10 ℃ and an aqueous solution (50mL) of sodium nitrite (6.98g, 101.2mmol) was added dropwise to the mixture, followed by reaction for 2 hours. Cooling to-30 deg.C, and adding SnCl which is precooled to-30 deg.C ₂(62g, 276mmol) in concentrated HCl (30mL) at-20 deg.C for 1h, warmed to room temperature, filtered, and dried to give 24g of a pale yellow solid with a yield of 97%.

The solid (24g, 89.33mmol) obtained above was dissolved in ethanol (100mL), ethyl pyruvate (11.4g, 98.26mmol) was added dropwise, and the mixture was stirred at room temperature for 10min to precipitate a pale yellow solid, which was then filtered to obtain 27g of a pale yellow solid with a yield of 94%, mp:124 and 125 ℃.

¹H NMR(CDCl₃)(ppm):13.91(brs,1H),8.34(s,1H),7.92(d,J＝9.2Hz,1H),7.62(d,J＝9.2Hz,1H),4.39(q,J＝7.2Hz,2H),2.25(s,3H),1.40(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd for C₁₁H₁₃BrN₃O₄[M+H⁺]:330.0084,found 330.0074.

b) 7-Nitro-5-bromo-1H-indole-2-carboxylic acid ethyl ester

By using ethyl 2- (2- (2-nitro-4-bromophenyl) hydrazono) propionate as the starting material, the preparation process is the same as that of b) in the preparation of the intermediate 26, and 11.7g of light yellow solid is obtained, the yield is 44%, and mp:135-137 ℃.

¹H NMR(CDCl₃)(ppm):10.31(brs,1H),8.40(s,1H),8.17(s,1H),7.30(s,1H),4.47(q,J＝7.2Hz,2H),1.45(t,J＝7.2Hz,3H)；HRMS(ESI):m/z,calcd forC₁₁H₁₀BrN₂O₄[M+H⁺]:312.9818,found 312.9807.

Example 196-Nitro-5-bromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

a) 7-nitro-5-bromo-1H-indole-2-carboxylic acid

Using 7-nitro-5-bromo-1H-indole-2-carboxylic acid ethyl ester as starting material, the preparation was carried out as described in b) of example 3, giving 180mg of a yellow solid in 99% yield, mp: 192-.

¹H NMR(DMSO-d₆)(ppm):10.48(brs,1H),8.31(s,1H),8.18(s,1H),6.90(s,1H).

b) 7-nitro-5-bromo-N- (4-methoxybenzenesulfonyl) -1H-indole-2-carboxamide

The preparation process was the same as that described in c) of example 3 using 7-nitro-5-bromo-1H-indole-2-carboxylic acid and p-methoxybenzenesulfonamide as starting materials to give 68mg of a pale yellow solid with a yield of 55%, mp: 262-.

¹H NMR(DMSO-d₆)(ppm):11.93(brs,2H),8.47(s,1H),8.34(s,1H),7.98(d,J＝8.8Hz,2H),7.53(s,1H),7.17(d,J＝8.8Hz,2H),3.86(s,3H).

Example 197: 5-isobutyl-7-nitro-N- (4-fluorobenzenesulfonyl) -1H-indole-2-carboxamide

a) 5-isobutyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester

Ethyl 7-nitro-5-bromo-1H-indole-2-carboxylate (291mg, 0.93mmol) was dissolved in toluene (12)mL), Pd (OAc) is added in sequence₂(21mg，0.093mmol)，(tBu)₃P·HBF₄(54mg, 0.19mmol) and K₃PO₄(987mg，4.65mmol,1mL H₂O), stirring, adding isobutylboronic acid (284mg, 2.79mmol), reacting at 90 ℃ for 2h under the protection of argon, cooling to room temperature, concentrating, adding EA (40mL) to dissolve the residue, washing with saturated brine (20mL × 3), washing with water (20mL × 2), and performing column chromatography (P/E100: 1) to obtain 238mg of off-white solid, with a yield of 88%, mp:99-100 ℃.

¹H NMR(CDCl₃)(ppm):10.23(brs,1H),8.11(s,1H),7.81(s,1H),7.29(s,1H),4.46(q,J＝7.2Hz,2H),2.65(d,J＝7.2Hz,2H),1.91-1.98(m,1H),1.44(t,J＝7.2Hz,3H),0.94(d,J＝6.8Hz,6H)；HRMS(ESI):m/z,calcd for C₁₅H₁₉N₂O₄[M+H⁺]:291.1339,found291.1330.

b) 5-isobutyl-7-nitro-1H-indole-2-carboxylic acid

Starting from ethyl 5-isobutyl-7-nitro-1H-indole-2-carboxylate, the preparation is carried out as described in b) of example 3 to give 155mg of a yellow solid in 100% yield mp: >300 ℃.

¹H NMR(DMSO-d₆)(ppm):10.25(brs,1H),7.93(s,1H),7.89(s,1H),6.86(s,1H),2.63(d,J＝7.2Hz,2H),1.86-1.94(m,1H),0.89(d,J＝6.9Hz,6H)；HRMS(ESI):m/z,calcdfor C₁₃H₁₅N₂O₄[M+H⁺]:263.1026,found 263.1026.

c) 5-isobutyl-7-nitro-N- (4-fluorobenzenesulfonyl) -1H-indole-2-carboxamide

The procedure of example 3, using 5-isobutyl-7-nitro-1H-indole-2-carboxylic acid and 4-fluorobenzenesulfonamide as starting materials, was as described in c) to give a tan solid 65mg in 54% yield mp: 156-.

¹H NMR(CDCl₃)(ppm):10.32(brs,1H),9.22(s,1H),8.26-8.22(m,2H),8.12(d,J＝1.2Hz,1H),7.80(s,1H),7.31-7.21(m,3H),2.63(d,J＝7.5Hz,2H),1.95-1.90(m,1H),0.92(d,J＝6.9Hz,6H).

Example 198: 3-ethyl-5-isobutyl-7-nitro-N- (4-fluorophenylsulphonyl) -1H-indole-2-carboxamide

a) 5-isobutyl-3-bromo-7-nitro-1H-indole-2-carboxylic acid ethyl ester

5-isobutyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester (250mg, 0.86mmol) was dissolved in DMF (4mL), a solution of NBS (168mg, 0.95mmol) in DMF was added dropwise in an ice-water bath, and the reaction was carried out for 2H in an ice-water bath, whereupon the starting material disappeared. Pouring the reaction solution into ice water, precipitating light yellow solid, filtering, drying to obtain 295mg of light yellow powdery solid with the yield of 93 percent and mp:84-86 ℃.

¹H NMR(CDCl₃)(ppm):10.29(brs,1H),8.17(s,1H),7.80(s,1H),4.50(q,J＝7.2Hz,2H),2.69(d,J＝7.2Hz,2H),1.96-2.01(m,1H),1.48(t,J＝7.2Hz,3H),0.96(d,J＝6.8Hz,6H)；HRMS(ESI):m/z,calcd for C₁₅H₁₈BrN₂O₄[M+H⁺]:369.0445,found 369.0441.

b) 3-Ethyl-5-isobutyl-7-nitro-1H-indole-2-carboxylic acid ethyl ester

The preparation of 5-isobutyl-3-bromo-7-nitro-1H-indole-2-carboxylic acid ethyl ester and ethylboronic acid was carried out as described in a) of example 194 using 5-isobutyl-3-bromo-7-nitro-1H-indole-2-carboxylic acid ethyl ester and ethylboronic acid to give 171mg of a pale yellow solid, 80% yield, mp:72-73 ℃.

¹H NMR(CDCl₃)(ppm):10.03(brs,1H),8.11(s,1H),7.79(s,1H),4.46(q,J＝7.2Hz,2H),3.14(q,J＝7.2Hz,2H),2.66(d,J＝7.2Hz,2H),1.91-1.98(m,1H),1.45(t,J＝7.2Hz,3H),1.29(t,J＝7.2Hz,3H),0.95(d,J＝6.4Hz,6H)；HRMS(ESI):m/z,calcd forC₁₇H₂₃N₂O₄[M+H⁺]:319.1652,found 319.16510.

c) 3-ethyl-5-isobutyl-7-nitro-1H-indole-2-carboxylic acid

The preparation of ethyl 3-ethyl-5-isobutyl-7-nitro-1H-indole-2-carboxylate starting from ethyl 3-ethyl-5-isobutyl-7-nitro-1H-indole-2-carboxylate was carried out as described in b) of example 3, giving 97mg of a pale yellow solid with a yield of 89%, mp: 168-.

¹H NMR(DMSO-d₆)(ppm):10.47(s,1H),8.08(s,1H),8.05(s,1H),3.10(q,J＝6.9Hz,2H),2.68(d,J＝6.9Hz,2H),1.90-1.94(m,1H),1.21(t,J＝7.2Hz,3H),0.90(d,J＝6.6Hz,6H)；HRMS(ESI):m/z,calcd for C₁₅H₁₉N₂O₄[M+H⁺]:291.1339,found 291.1337.

d) 3-ethyl-5-isobutyl-7-nitro-N- (4-fluorophenylsulphonyl) -1H-indole-2-carboxamide

The procedure of c) in example 3 was followed starting from 3-ethyl-5-isobutyl-7-nitro-1H-indole-2-carboxylic acid and 4-fluorobenzenesulfonamide to give 20mg of a reddish brown solid in 54% yield mp: >250 ℃.

¹H NMR(DMSO-d₆)(ppm):10.00(brs,1H),7.95-7.89(m,4H),7.23(t,J＝9.3Hz,2H),3.09(q,J＝7.5Hz,2H),2.64(d,J＝6.3Hz,2H),1.90(m,1H),1.13(t,J＝7.5Hz,3H),0.89(d,J＝6.6Hz,6H).

Pharmacological experiments:

experimental example 1: evaluation of FBP enzyme inhibitory Activity of Compounds

Experimental methods and results:

1. recombinant expression of human liver FBP enzyme (FBPase)

100ul of the constructed human liver FBPase gene plasmid PET alpha 8a-FBP transformed competent bacteria BL21(DE3) Rosettacells (Novagen, Inc.) are taken and smeared on an LB solid culture plate containing kanamycin (30ug/mL), and cultured in an incubator at 37 ℃ for 12-14h until obvious single colonies grow out. Individual colonies were picked from the solid medium, inoculated into LB liquid medium containing kanamycin (30ug/ml), and subjected to amplification culture at 37 ℃ and 200rpm for 12 hours. IPTG (final concentration of 0.1mM in the bacterial solution) was added to the bacterial solution after the scale-up culture, and the mixture was cultured at 200rpm for 24 hours in a shaker at 16 ℃ to induce protein expression. Then, the bacterial solution was centrifuged at 5500rpm at 4 ℃ for 5min, the supernatant was discarded, and the pellet (cells) was resuspended in FBPaseTris-Buffer. The cells were disrupted by sonication, and then centrifuged at 12,000rpm for 1min at 4 ℃. Collecting supernatant, measuring enzyme activity, subpackaging, and storing at-80 deg.C for use.

Determination of FBP enzymatic Activity

FBPase activity assay principle: the coupling reaction of FBPase and phosphoglucose isomerase and glucose-6-phosphate dehydrogenase is used, and the concentration of the reaction product is detected by a spectrophotometer to reflect the activity of the enzyme. NADP consumption by the reaction⁺NADPH is produced, and the change in absorbance at 340nm directly reflects the activity of the enzyme. First, FBPase Tris-Buffer (100mM Tris, 2mM MgCl) was added to the reaction well₂0.1mM EDTA, pH7.5), inhibitor (final concentration 0.08uM, 0.4uM, 2uM or 10uM, full reaction well FBPaseTris-Buffer instead) and FBPase (final concentration 0.72 unit). After incubation at 37 ℃ for 10min, the reaction substrate mixture (final concentration 0.2mM NADP) was added⁺0.01units glucose phosphate isomerase, 0.01units glucose-6-phosphate dehydrogenase and 0.2mM FBP). The absorbance values of the reaction products (NADPH) were monitored dynamically. The inhibition rate of the inhibitor reaction well, i.e., the inhibition intensity against the enzyme activity, was calculated by taking the absorbance value of the whole reaction well as 100%. The inhibition curve is obtained by the concentration of the inhibitor and the activity of the enzyme.

TABLE 1 FBPase inhibitory activity of some compounds of the invention.

Experimental example 2: pharmacodynamic experiment in animal body

Experimental methods and results:

1. Experimental methods

Spontaneous type 2 diabetes KKAy mouse model, 12 weeks old, female, body weight 37-42 g. The special feed for KKAY mice is fed in a standard environment (7:00am-7:00pm day and night circulation, temperature of 22 +/-1 ℃) provided by the research institute of laboratory animals of Chinese medical academy of sciences, and the mice are fed with the special feed for KKAY mice to freely eat drinking water. KKAy mice were randomly assigned to 2 groups (10 per group) before the experiment with reference to fasting plasma glucose (> 200mg/dL), triglyceride (> 200mg/dL), total cholesterol (> 150mg/dL), and body weight (45-55 g), and insulin tolerance 40min blood glucose changes, among other criteria, one group of gavage water was used as a model control group, and one group of gavage compound example 139(200mg/kg b.w.) suspension was used as an administration group. Gavage was performed once a day for 35 consecutive days. Mice were monitored dynamically for fasting blood glucose levels during the experiment. Random blood glucose was measured on day 11, glycated hemoglobin level was measured on day 27, and sodium Pyruvate Tolerance Test (PTT) was performed on day 35.

2. Results of the experiment

Compound example 139 was able to significantly reduce fasting blood glucose levels in spontaneously type 2 diabetic KKAy mice (table 1) compared to the model control group, with a blood glucose reduction of 29% (P >0.05) at day 5 of dosing, all with statistical differences in blood glucose reduction (P < 0.001); also significantly reduced random blood glucose levels in KKAy mice (P <0.001, table 2); and significantly decreased the level of glycaemic hemoglobin in KKAy mice (P <0.001, table 3). Compound example 139 significantly improved the blood glucose rise level and the area under the blood glucose-time curve (AUC) after administration of the sodium pyruvate load 35 days after administration (table 4).

Table 1: example 139 Effect of Long-term administration on fasting plasma glucose in spontaneously type 2 diabetic KKAy mice

P < 0.005 compared to model group.

Table 2: effect of compound example 139 on random blood glucose in KKAy mice (day 11)

P < 0.005 compared to model group.

Table 3: effect of Compound example 139 administration on glycated hemoglobin levels in KKAY mice (day 27)

P < 0.005 compared to model group.

Table 4: effect of compound example 139 on sodium pyruvate tolerance in KKAy mice (day 35)

P < 0.05, P < 0.005 compared to model control.

Claims

1. The compound shown as the general formula IAa-1 and the medicinal salt thereof are characterized in that,

in the formula IAa-1, the,

R₁selected from hydrogen, substituted or unsubstituted C1-6 straight or branched chain alkyl, wherein the substituent is selected from F, ORa₁Wherein said Ra₁Independently selected from H, C1 alkyl;

R₃selected from hydrogen, methyl, ethyl, F, substituted C1 alkyl, wherein the substituents are selected from F;

R₄selected from the group consisting of:

substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein said substituents are selected from the group consisting of C1-5 straight or branched chain alkyl, COORa₄、CONRa₅Rb₂、NRa₆COORb₃、NRa₈CORb₅Wherein said Ra ₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₈、Rb₅Independently selected from H, C1-4 straight or branched chain alkyl; the oxacycloalkyl or azacycloalkyl group having 3 to 8 membered rings may contain 1 heteroatom or a plurality of heteroatoms at the same time;

R₇selected from the group consisting of:

(1)F、Cl、Br、CN、NO₂、CONRc₁Rd₁、COORc₂wherein said Rc₁、Rd₁、Rc₂Independently selected from H, C1 alkyl;

(2) substituted or unsubstituted C1 alkyl, wherein the substituents are selected from F, Cl, ORa₁、NRa₃Rb₁Wherein said Ra₁、Ra₃、Rb₁Independently selected from H, C1 alkyl;

(3)ORe₁、NRe₂Rf₁、NRe₄CORf₂、NRe₅COORf₃wherein said Re₁、Re₂、Rf₁、Re₄、Rf₂、Re₅、Rf₃Independently selected from H, substituted or unsubstituted C1 alkyl, wherein said substituents are selected from F;

R₅and R₆Independently selected from the group consisting of:

(1)H、F、Cl、Br、CN、CONRh₁Ri₁、COORh₂wherein Rh is₁、Ri₁、Rh₂Independently selected from H, methyl, ethyl;

(2) substituted or unsubstituted C1 alkyl, wherein the substituents are selected from F, Cl;

(3)ORj₁、NRj₂Rk₁、NRj₄CORk₂、NRj₅COORk₃wherein Rj is₁、Rj₂、Rk₁、Rj₄、Rk₂、Rj₅、Rk₃Independently selected from H, methyl, ethyl, CF₃、CHF₂；

R is selected from the following groups or structural fragments:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs ₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

(2) substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo-six-membered heterocycle, substituted or unsubstituted benzo-fiveA heterocyclic ring, wherein the substituent is selected from C1-4 straight chain or branched alkyl, halogen substituted C1-4 straight chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br.

2. The compound shown as the general formula IAa-1a and the medicinal salt thereof are characterized in that,

In the formula IAa-1a,

R₇independently selected from the group consisting of:

(2) substituted or unsubstituted C1 alkyl, wherein the substituents are selected from F, Cl, Br, CN, ORa₁、NRa₃Rb₁、COORa₄、CONRa₅Rb₂、NRa₆COORb₃、NRa₈CORb₅Wherein said Ra₁、Ra₃、Rb₁、Ra₄、Ra₅、Rb₂、Ra₆、Rb₃、Ra₈、Rb₅Independently selected from H, C1 alkyl;

R₅and R₆Independently selected from the group consisting of:

R is selected from the following groups or structural fragments:

(1) substituted or unsubstituted C3-7 cycloalkyl, substituted or unsubstituted oxacycloalkyl of 3-8 membered ring, substituted or unsubstituted azacycloalkyl of 3-8 membered ring, wherein the substituents are selected from C1-5 straight or branched chain alkyl, F, Cl, ORx ₁、NRx₃Ry₁、NRx₄CORy₂、COORx₅、CONRx₆Ry₃、NRx₇COORy₄Said Rx₁、Rx₃、Ry₁、Rx₄、Ry₂、Rx₅、Rx₆、Ry₃、Rx₇、Ry₄Independently selected from H, C1-4 straight or branched chain alkyl; the oxacycloalkyl group having 3-to 8-membered ring and the azacycloalkyl group having 3-to 8-membered ring may contain 1 heteroatom or a plurality of heteroatoms at the same time;

(2) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

(3) substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocycle, substituted or unsubstituted benzo five-membered heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

y is selected from O, S, NRp₁、CH₂、CO、NRp₂CO、OCH₂、NHCH₂、SCH₂、CH₂CH₂(ii) a Wherein Rp is₁、Rp₂Is selected from H;

Ar₁selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom or may contain a plurality of nitrogen atomsA seed; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br.

3. The compound shown as the general formula IAa-1a-1 and the medicinal salt thereof are characterized in that,

in the formula IAa-1a-1,

R'₁selected from hydrogen, methyl, ethyl, propyl, isopropyl, CHF₂、CF₃、CH₂CF₃；

Ar₁Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring may contain a heteroatomMay also contain a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

R'₇selected from the following atoms or groups or structural fragments: F. cl, Br, CN, NO₂、CONH₂、CONHCH₃、CON(CH₃)₂Methyl, ethyl, CF₃、CHF₂、CH₂CF₃、OCH₃、OCF₃、OCF₂CH₃、OCH₂CF₃、NH₂、NHCH₃、N(CH₃)₂、NHCOCH₃、NHCOOCH₃；

R'₅And R'₆Independently selected from the group consisting of:

H、F、Cl、Br、CN、NO₂、CONH₂、CONHCH₃、CON(CH₃)₂methyl, ethyl, CF₃、CHF₂、CH₂CF₃、OCH₃、OCH₂CH₃、OCF₃、NH₂、NHCH₃、N(CH₃)₂、NHCOCH₃、NHCOOCH₃；

Ar' is selected from the following groups or structural fragments:

(1) Substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight chain or branched chain alkyl,A cyclopropyl group; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

(2) substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocycle, substituted or unsubstituted benzo five-membered heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br.

4. A compound according to claim 3, characterized in that said compound is of the general formula IAa-1a-1a

In the formula IAa-1a-1a,

Ar₁Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

R'₅and R'₆Independently selected from the group consisting of:

Ar' is selected from the following groups or structural fragments:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic Heterocycle, wherein said substituent is selected from the group consisting of C1-4 straight or branched chain alkyl, halogen substituted C1-4 straight or branched chain alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

(2) substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocycle, substituted or unsubstituted benzo five-membered heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo-six-membered heterocycle or benzo-five-membered heterocycle may contain a heteroatom Optionally, a plurality of heteroatoms selected from O, N, S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br.

5. A compound according to claim 3, characterized in that said compound is of the general formula IAa-1a-1b and pharmaceutically acceptable salts thereof

In the formula IAa-1a-1b,

R'₅and R'₆Independently selected from the group consisting of:

Ar' is selected from the following groups or structural fragments:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

(2) substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocycle, substituted or unsubstituted benzo five-membered heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br.

6. A compound shown as a general formula IAa-1b and medicinal salts thereof, which are characterized in that,

in the formula IAa-1b,

R₁selected from hydrogen, substituted or unsubstituted C1-6 straight or branched chain alkyl, wherein the substituent is selected from F;

R₇independently selected from the group consisting of:

(2)ORe₁、NRe₂Rf₁、NRe₄CORf₂、NRe₅COORf₃wherein said Re₁、Re₂、Rf₁、Re₄、Rf₂、Re₅、Rf₃Independently of each otherSelected from H, substituted or unsubstituted C1 alkyl, wherein the substituents are selected from F;

R₅and R₆Independently selected from the group consisting of the following groups or structural fragments,

R is selected from the following groups or structural fragments:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2 3, 3; wherein the halogen is selected from F, Cl and Br;

(2) substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocycle, substituted or unsubstituted benzo five-membered heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

Ar₂selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br.

7. The compound shown as the general formula IAa-2a-1a and the medicinal salt thereof are characterized in that,

in the formula IAa-2a-1a,

x is selected from O, S;

R'₃selected from hydrogen, methyl, ethyl, propyl, CHF₂、CF₃、CH₂CF₃；

Ar₃Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or poly-substitutedSubstitution; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

R'₅and R'₆Independently selected from the group consisting of:

Ar' is selected from the following groups or structural fragments:

(1) substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocyclic ring and the five-membered aromatic heterocyclic ring can be mono-substituted or multi-substituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

(2) substituted orUnsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocycle, substituted or unsubstituted benzo five-membered heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br.

8. A compound shown as a general formula IAb-1a-1a and a medicinal salt thereof,

in formula IAb-1a-1a,

Ar₄Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl, cyclopropyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

R'₅and R'₆Independently selected from the group consisting of:

H、F、Cl、Br、CN、CONH₂、CONHCH₃、CON(CH₃)₂methyl, ethyl, CF₃、CHF₂、CH₂CF₃、OCH₃、OCH₂CH₃、OCF₃、NH₂、NHCH₃、N(CH₃)₂、NHCOCH₃、NHCOOCH₃；

Ar' is selected from the following groups or structural fragments:

9. A compound shown as a general formula IB and medicinal salts thereof,

in the formula IB, the compound represented by the formula IB,

a is selected from NR₁Wherein R is₁Selected from hydrogen, substituted or unsubstituted C1-6 straight or branched chain alkyl, wherein the substituent is selected from F, Cl;

b is selected from CR₃Wherein R is₃Selected from hydrogen, methyl, ethyl, F, substituted C1 alkyl, wherein the substituents are selected from F;

R₄selected from the group consisting of:

OAr_a1、NRg₁Ar_a2wherein said Rg₁Is selected from H; ar is_a1、Ar_a2Selected from substituted or unsubstituted phenyl, substituted or unsubstituted nitrogen-containing six-membered aromatic heterocycle, substituted or unsubstituted five-membered aromatic heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen-substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO₂CN, methylenedioxy, ORa'₁、NRa′₃Rb′₁、COORa′₄、CONRa′₅Rb′₂、NRa′₆COORb′₃、NRa′₈CORb′₅、(CH₂)nNRa′₉Rb′₆、(CH₂)nORa′₁₀Wherein Ra'₁、Ra′₃、Rb′₁、Ra′₄、Ra′₅、Rb′₂、Ra′₆、Rb′₃、Ra′₈、Rb′₅、Ra′₉、Rb′₆、Ra′₁₀Independently selected from H, C1-4 straight or branched chain alkyl; the benzene ring, the nitrogen-containing six-membered aromatic heterocycle and the five-membered aromatic heterocycle can be mono-substituted or polysubstituted; the six-membered aromatic heterocyclic ring may contain 1N atom, or may contain a plurality of nitrogen atoms; the five-membered aromatic heterocyclic ring can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br;

R₅And R₆Independently selected from the group consisting of:

(1)H、F、Cl、Br、CN；

r is selected from the following groups or structural fragments:

(2) substituted or unsubstituted naphthalene ring, substituted or unsubstituted benzo six-membered heterocycle, substituted or unsubstituted benzo five-membered heterocycle, wherein the substituent is selected from C1-4 straight-chain or branched alkyl, halogen substituted C1-4 straight-chain or branched alkyl, F, Cl, Br, NO ₂CN, methylenedioxy, ORs₁、NRs₃Rt₁、NRs₄CORt₂、COORs₅、CONRs₆Rt₃、NRs₇COORt₄、(CH₂)nNRs₉Rt₆、(CH₂)nORs₁₀Wherein said Rs₁、Rs₃、Rt₁、Rs₄、Rt₂、Rs₅、Rs₆、Rt₃、Rs₇、Rt₄、Rs₉、Rt₆、Rs₁₀Independently selected from H, C1-4 straight or branched chain alkyl; wherein the naphthalene ring, the benzo six-membered heterocyclic ring or the benzo five-membered heterocyclic ring can be mono-substituted or multi-substituted; the benzo six-membered heterocycle or the benzo five-membered heterocycle can contain one heteroatom or a plurality of heteroatoms, and the heteroatoms are selected from O, N and S; n is selected from 1,2, 3; wherein the halogen is selected from F, Cl and Br.

10. A compound and pharmaceutically acceptable salt according to any one of claims 1,2, 6, wherein R is₁Selected from H, methyl, ethyl, n-propyl and isopropyl.

11. A compound and pharmaceutically acceptable salt according to any one of claims 3, 4, 5, and 8, wherein R'₁Selected from H, methyl, ethyl, n-propyl and isopropyl.

12. A compound and pharmaceutically acceptable salt according to any one of claims 1,2, 6, wherein R is₃Selected from H, methyl, ethyl.

13. A compound and pharmaceutically acceptable salt according to claim 7, wherein R'₃Selected from H, methyl, ethyl.

14. A compound and a medicinal salt thereof are characterized in that the compound is selected from:

15. A compound according to any one of claims 1 to 9 and 14, characterized in that the pharmaceutically acceptable salt of the compound is selected from the group consisting of salts formed in combination with inorganic acids, organic acids, alkali metal ions, alkaline earth metal ions or organic bases capable of providing physiologically acceptable cations, and ammonium salts.

16. A compound according to claim 15, characterized in that said inorganic acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid; the organic acid is selected from methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, maleic acid, tartaric acid, fumaric acid, citric acid or lactic acid; the alkali metal ions are selected from lithium ions, sodium ions and potassium ions; the alkaline earth metal ions are selected from calcium ions and magnesium ions; the organic base capable of providing a physiologically acceptable cation is selected from methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris (2-hydroxyethyl) amine.

17. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-14 and a pharmaceutically acceptable carrier.

18. The use of a compound according to any one of claims 1 to 14, and pharmaceutically acceptable salts thereof, for the manufacture of FBPase inhibitors.

19. The use of compounds according to any of claims 1 to 14 as well as their pharmaceutically acceptable salts for the preparation of medicaments for the prophylaxis and/or treatment of diseases which are associated with FBPase.

20. The use according to claim 19, wherein the diseases associated with FBPase are selected from diabetes, diabetic complications and obesity.

21. The use according to claim 20, wherein said diabetes is selected from the group consisting of type I diabetes and type II diabetes; the diabetic complication is selected from retinopathy, nephropathy, nervous system diseases and vascular complications, ischemic heart disease or atherosclerosis.