Aromatic compounds, methods for their preparation and use

Abstract

Disclosed are compounds shown in Formula I, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof or isotopic compounds thereof. The compounds have high P2X4 antagonistic activity, good safety and pharmacokinetic properties.

Description

[0001] The present application claims priority to the prior application with the patent application number 202110113303.4, filed on January 27, 2021, to the Chinese National Intellectual Property Office, with the name of "Aromatic compound, preparation method and application thereof", and to the prior application with the patent application number 202110638504.6, filed on June 08, 2021, to the Chinese National Intellectual Property Office, with the name of "Aromatic compound, preparation method and application thereof", and to the prior application with the patent application number 202210055268.X, filed on January 18, 2022, to the Chinese National Intellectual Property Office, with the name of "Aromatic compound, preparation method and application thereof". The entire contents of the three prior applications are incorporated herein by reference. TECHNICAL FIELD

[0002] The present application relates to an aromatic compound, a preparation method and application thereof. BACKGROUND

[0003] ATP receptors are classified into two major families, P2Y- and P2X-purinergic receptors, based on molecular structure, transduction mechanism and pharmacological properties. P2X-purinergic receptors are a family of ATP-gated cation channels, several subtypes have been cloned, including: six homomeric receptors, P2X1; P2X2; P2X3; P2X4; P2X5; and P2X7; and three heteromeric receptors P2X2 / 3, P2X4 / 6, P2X1 / 5. P2X4 receptor is the only subtype of P2X family whose crystal structure has been solved, and its resolution is as high as And researches have found that P2X4 is the P2X subtype with the strongest permeability. 2+

[0004] Cough is the main symptom of respiratory diseases, and 70% to 80% of patients in the respiratory clinic have cough symptoms. With the increasing prevalence of COPD, IPF, and other diseases, the demand for cough as the main symptom of most expiratory tract diseases is also increasing. As a defensive reflex of the body, cough is beneficial to the removal of respiratory secretions and harmful factors, but frequent and severe cough can have a serious impact on the patient's work, life and social activities.

[0005] Currently, the indications of the drugs under research related to the P2X4 target are mostly neuropathic pain or inflammation, and there is no information on the research of drugs for cough indications. And there is no drug on the market for treating many diseases including chronic cough through P2X4 inhibition pathway. Therefore, the development of new compounds that can inhibit the activity of P2X4 has positive significance for the treatment of diseases. SUMMARY

[0006] ​The application provides an aromatic compound, a preparation method and application thereof. The compound has high P2X4 antagonistic activity, good safety and pharmacokinetic properties.

[0007] The application provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic compound thereof, a crystal form thereof, a nitroxide thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

[0008]

[0009] R 2 is selected from

[0010] R 2-1 is selected from the following groups which are unsubstituted or optionally substituted by one, two or more Ra: C1-C 20 alkyl, C3-C 20 cycloalkyl, 3-20 membered heterocyclyl, C6-C 20 aryl, 5-20 membered heteroaryl;

[0011] each Ra is the same or different, independently of one another, selected from halogen, OH, CN, NO2, oxo (=O), COOH, the following groups which are unsubstituted or optionally substituted by one, two or more Ra1: C1-C 20 alkyl, C3-C 20 cycloalkyl, C1-C 20 alkoxy, C1-C 20 alkylthio, -C(=O)-C1-C 20 alkyl, -C(=O)-OC1-C 20 alkyl, -O-C(=O)-C1-C 20 alkyl, -SO2-C1-C 20 alkyl, -S(=O)-C1-C 20 alkyl, 3-20 membered heterocyclyl, C6-C 20 aryl, 5-20 membered heteroaryl, NH2;

[0012] each Ra1 is the same or different, independently of one another, selected from halogen, OH, COOH, CN, NO2, oxo (=O), the following groups which are unsubstituted or optionally substituted by one, two or more Ra2: C1-C 20 alkyl, C3-C 20 cycloalkyl, C1-C 20 alkoxy, NH2;

[0013] Each Ra2 may be identical or different, and each is independently selected from halogens, OH, CN, NO2, oxo (=O), C1~C. 20 Alkyl, C1-C 20 Alkoxy;

[0014] R 2-2 Selected from hydrogen, halogens, OH, CN, NO2, and unsubstituted or optionally substituted with one, two or more Rb groups: C1 to C2 20 Alkyl, C1-C 20 Alkyl groups; each Rb may be the same or different, and is independently selected from halogens, OH, CN, NO2;

[0015] R 3-1 Selected from halogens, OH, CN, NO2, and unsubstituted or optionally substituted with one, two or more Rc groups: C1 to C2 20 Alkyl, C1-C 20 Alkoxy or C3~C 20 Cycloalkyl; each Rc may be the same or different, and is independently selected from halogens, OH, CN, NO2;

[0016] n is selected from 0, 1, 2, 3 or 4.

[0017] In one embodiment of the present invention, R 2 Selected from

[0018] R 2-1 Selected from the following groups, either unsubstituted or optionally substituted with one, two or more Ra groups: C1 to C2 12 Alkyl, C3-C 12 Cycloalkyl, 3-12 membered heterocyclic, C6-C 14 Aryl, 5-14 membered heteroaryl; each Ra may be the same or different, and each is independently selected from halogens, OH, CN, NO2, oxo (=O). The following groups are unsubstituted or optionally substituted with one, two or more Ra1 groups: C1 to C2 12 Alkyl, C3-C 12 cycloalkyl, C1-C 12 Alkoxy, C1-C 12 Alkylthio, -C(=O)-C1~C 12 Alkyl group, -C(=O)-OC1~C 12 Alkyl group, -OC(=O)-C1~C 12 Alkyl group, -SO2-C1~C 12 Alkyl group, -S(=O)-C1~C 12 Alkyl, 3-12 membered heterocyclic, C6-C 14 Aryl, 5-14 heteroaryl, NH2;

[0019] each Ra1is the same or different, independently of one another, selected from halogen, OH, COOH, CN, NO2, oxo (=0), the following radicals, which are unsubstituted or optionally substituted by one, two or more Ra2: C1-C 12 alkyl, C1-C 12 alkoxy, C3-C 12 cycloalkyl, NH2; each Ra2is the same or different, independently of one another, selected from halogen, OH, CN, NO2, oxo (=0), C1-C 12 alkyl, C1-C 12 alkoxy;

[0020] R 2-2 selected from hydrogen, halogen, OH, CN, NO2, the following radicals, which are unsubstituted or optionally substituted by one, two or more Rb: C1-C 12 alkyl, C1-C 12 alkoxy; each Rb is the same or different, independently of one another, selected from halogen, OH, CN, NO2;

[0021] R 3-1 selected from halogen, OH, CN, NO2, the following radicals, which are unsubstituted or optionally substituted by one, two or more Rc: C1-C 12 alkyl, C1-C 12 alkoxy or C3-C 12 cycloalkyl; each Rc is the same or different, independently of one another, selected from halogen, OH, CN, NO2;

[0022] n is selected from 0, 1, 2, 3 or 4.

[0023] According to an embodiment of the present application, R 2 is or is wherein R 2-1 is as defined above, R 2-3 selected from halogen, OH, CN, NO2, the following radicals, which are unsubstituted or optionally substituted by one, two or more Rb: C1-C 20 alkyl, C1-C 20 alkoxy; each Rb is the same or different, independently of one another, selected from halogen, OH, CN, NO2;

[0024] According to an embodiment of the present application, R 2 is or is

[0025] R 2-1 is C1-C 10 alkyl, which is substituted by one or more R 2-1aReplacement of C1~C 10 Alkyl, C3-C 10 Cycloalkyl, "a 3- to 10-membered heterocycloalkyl group having one, two, or three heteroatoms selected from one or more of N, O, S, and S(=O)2", and being surrounded by one or more R 2-1c The substituted substance is a 3- to 10-membered heterocyclic alkyl group with one, two, or three heteroatoms selected from N, O, S, and S(=O)2, and has a C6 to C6 number of heteroatoms. 10 aryl, with one or more R 2-1d Replacement of C6~C 10 aryl, "a 5- to 10-membered heteroaryl group having one, two, or three heteroatoms selected from N, O, and S", or being surrounded by one or more R 2-1e The substituted "is one, two or three heteroatoms, and the heteroatoms are selected from one or more 5- to 10-membered heteroaryl groups selected from N, O and S";

[0026] R 2-3 Halogen, OH, C1-C 10 Alkyl, C1-C 10 Alkoxy;

[0027] R 2-1a Independently, it is a C3-C6 cycloalkyl group or "a 3- to 6-membered heterocycloalkyl group having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S";

[0028] R 2-1c R 2-1d and R 2-1e Independently cyano, halogen, C1-C6 alkyl, or formed by one or more R groups 2-1c-1 Substituted C1–C6 alkyl, C1–C6 alkoxy, -C(=O)R 2-1c-2 -S(=O)2R 2-1c-3 , C3~C 10 Cycloalkyl, the heteroatom being selected from one or more 3- to 10-membered heterocycloalkyl groups selected from N, O, S, and S(=O)2;

[0029] R 2-1c-1 R 2-1c-2 and R 2-1c-3 The following groups are independently halogen, OH, COOH, CN, NO2, oxo (=O), unsubstituted or optionally substituted by one, two or more Ra2: C1-C6 alkyl, C1-C6 alkoxy, NH2;

[0030] each Ra2is the same or different, independently of one another, selected from the group consisting of halogen, OH, CN, NO2, oxo (=0), Ci-C6-alkyl, Ci-C6-alkoxy, C3-C6-cycloalkyl;

[0031] n is 0, 1, 2 or 3;

[0032] R 3-1 independently halogen, hydroxy, cyano, Ci-C6-alkyl, halogen-substituted Ci-C6-alkyl, Ci-C6-alkoxy or C3-C6-cycloalkyl. 10 C3-C6-cycloalkyl.

[0033] In one embodiment of the present application, R 2 is

[0034] R 2-1 is Ci-C 10 alkyl, Ci-C 2-1a alkyl substituted by one or more R 10 alkyl, C3-C 10 cycloalkyl, "3- to 10-membered heterocycloalkyl having one, two or three heteroatoms, selected from the group consisting of N, O, S and S(=0)2", "3- to 10-membered heterocycloalkyl having one, two or three heteroatoms, selected from the group consisting of N, O, S and S(=0)2", substituted by one or more R 2-1c alkyl, C6-C 10 aryl, C6-C 2-1d aryl substituted by one or more R 10 alkyl, "5- to 6-membered heteroaryl having one, two or three heteroatoms, selected from the group consisting of N, O and S", or "5- to 6-membered heteroaryl having one, two or three heteroatoms, selected from the group consisting of N, O and S", substituted by one or more R 2 -1e alkyl, "5- to 6-membered heteroaryl having one, two or three heteroatoms, selected from the group consisting of N, O and S", or "5- to 6-membered heteroaryl having one, two or three heteroatoms, selected from the group consisting of N, O and S", substituted by one or more R

[0035] R 2-1a independently C3-C6-cycloalkyl or "3- to 6-membered heterocycloalkyl having one, two or three heteroatoms, selected from the group consisting of N, O and S";

[0036] R 2-1c , R 2-1d and R 2-1e independently cyano, halogen, Ci-C6-alkyl, Ci-C6-alkyl substituted by one or more R 2-1c-1 independently C3-C6-cycloalkyl or "3- to 6-membered heterocycloalkyl having one, two or three heteroatoms, selected from the group consisting of N, O and S"; 2-1c-2 , -S(=0)2R 2-1c-3 or

[0037] R 2-1c-1 independently NH2;

[0038] R 2-1c-2 and R 2-1c-3 independently NH2or C1-C6alkyl;

[0039] n is 0, 1, 2, or 3;

[0040] R 3-1 independently halogen, hydroxyl, cyano, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy, or C3-C6cycloalkyl.

[0041] In a certain embodiment, the definitions of certain groups in the above-mentioned compounds according to Formula I, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or isotopically enriched compounds thereof, wherein the groups not defined are as described in any of the previous embodiments (hereinafter "in a certain embodiment"), are as follows,

[0042] R 2 is

[0043] R 2-1 is C1-C 10 alkyl, C1-C 2-1a alkyl substituted with one or more R 10 alkyl, "3-10 membered heterocycloalkyl having 1, 2, or 3 heteroatoms each independently selected from N, O, S, and S(=0)2," "3-10 membered heterocycloalkyl having 1, 2, or 3 heteroatoms each independently selected from N, O, S, and S(=0)2" substituted with one or more R 2-1c alkyl, "3-10 membered heterocycloalkyl having 1, 2, or 3 heteroatoms each independently selected from N, O, S, and S(=0)2," "3-10 membered heterocycloalkyl having 1, 2, or 3 heteroatoms each independently selected from N, O, S, and S(=0)2" substituted with one or more R 10 aryl, C6-C 2-1d aryl substituted with one or more R 10 aryl, "5-6 membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S," or "5-6 membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S" substituted with one or more R 2-1e aryl, "5-6 membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S," or "5-6 membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S" substituted with one or more R

[0044] R 2-2 is selected from hydrogen, halogen, OH, C1-C6alkyl, C1-C6alkoxy;

[0045] R 2-1a independently C3-C6cycloalkyl or "3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S";

[0046] R2-1c , R 2-1d and R 2-1e independently are cyano, halogen, Ci-C6alkyl, Ci-C6alkyl substituted with one or more R 2-1c-1 , Ci-C6alkoxy, -C(=O)R 2-1c-2 , -S(=O)2R 2-1c-3 , C3-C6cycloalkyl, 3-6 membered heterocycloalkyl having one, two or three heteroatoms selected from the group consisting of N, O, S and S(=O)2;

[0047] R 2-1c-1 independently are halogen, NH2, C3-C6cycloalkyl;

[0048] R 2-1c-2 and R 2-1c-3 independently are NH2or Ci-C6alkyl;

[0049] n is 0, 1, 2 or 3;

[0050] R 3-1 independently are halogen, hydroxy, cyano, Ci-C6alkyl, halogen-substituted Ci-C6alkyl, Ci-C6alkoxy or C3-C6cycloalkyl.

[0051] In a certain embodiment

[0052] R 2 is

[0053] R 2-1 is Ci-C 10 alkyl, Ci-C 2-1a alkyl substituted with one or more R 10 , 3-10 membered heterocycloalkyl having one, two or three heteroatoms selected from the group consisting of N, O, S and S(=O)2, 3-10 membered heterocycloalkyl having one, two or three heteroatoms selected from the group consisting of N, O, S and S(=O)2substituted with one or more R 2-1c , C6-C 10 aryl, C6-C 2-1d aryl substituted with one or more R 10 , 5-6 membered heteroaryl having one, two or three heteroatoms selected from the group consisting of N, O and S, 5-6 membered heteroaryl having one, two or three heteroatoms selected from the group consisting of N, O and S substituted with one or more R 2-1e ;

[0054] R 2-1aindependently C3-C6cycloalkyl or "3-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S, and wherein the heterocycloalkyl is optionally substituted with one or more R

[0055] R 2-1c , R 2-1d and R 2-1e are independently cyano, halogen, C1-C6alkyl, C1-C6alkyl substituted with one or more R 2-1c-1 , C1-C6alkoxy, -C(=O)R 2-1c-2 , -S(=O)2R 2-1c-3 or

[0056] R 2-1c-1 is independently NH2;

[0057] R 2-1c-2 and R 2-1c-3 are independently NH2or C1-C6alkyl;

[0058] n is 0, 1, 2 or 3;

[0059] R 3-1 is independently halogen, hydroxy, cyano, C1-C6alkyl, halogen-substituted C1-C6alkyl, C1-C6alkoxy or C3-C6cycloalkyl.

[0060] In one embodiment, when R 2-1 is C1-C 10 alkyl, or C1-C 2-1a alkyl substituted with one or more R 10 , said C1-C 10 alkyl can be C1-C6alkyl, and can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or t-butyl, for example methyl.

[0061] In one embodiment, when R 2-1 is "3-10 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and S(=O)2, and wherein the heterocycloalkyl is optionally substituted with one or more R 2-1cIn the case of "3- to 10-membered heterocycloalkyl having 1, 2 or 3 heteroatoms, selected from N, O, S and S(=0)2, substituted by one or more R

[0062] In a certain embodiment, when R 2-1 is C6- C 10 aryl, or C6- C 2-1d aryl substituted by one or more R 10 , said C6- C 10 aryl can be phenyl.

[0063] In a certain embodiment, when R 2-1 is "5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms, selected from N, O and S, substituted by one or more R 2-1e , said "5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms, selected from N, O and S, substituted by one or more R

[0064] In a certain embodiment, when R 2-1a is independently C3- C6cycloalkyl, said C3- C6cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl, cyclobutyl or cyclopentyl.

[0065] In a certain embodiment, when R 2-1aWhen independently defined as "a 3- to 6-membered heterocyclic alkyl group having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S," the phrase "a 3- to 6-membered heterocyclic alkyl group having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" can be either "a 3- to 6-membered heterocyclic alkyl group having 1 or 2 heteroatoms selected from one or more of N, O, and S," or "a 3- to 6-membered heterocyclic alkyl group having 1 or 2 heteroatoms, with O as the heteroatom," such as oxobutyryl or tetrahydrofuranyl, or for example...

[0066] In a certain scheme, when R 2-1c R 2-1d and R 2-1e When it is a halogen on its own, the halogen can be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0067] In a certain scheme, when R 2-1c R 2-1d and R 2-1e It is independently a C1 to C6 alkyl group, or is composed of one or more R groups. 2-1c-1 When the substituted C1-C6 alkyl group is used, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0068] In a certain scheme, when R 2-1c R 2-1d and R 2-1e Independently C3~C 10 In the case of cycloalkyl groups, the C3-C3... 10 The cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl.

[0069] In a certain scheme, when R 2-1c R 2-1d and R 2-1e When independently a C1-C6 alkoxy group, the C1-C6 alkoxy group may be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, for example, methoxy.

[0070] In a certain scheme, when R 2-1c-1 When it is a C3 to C6 alkyl group, the C3 to C6 alkyl group... 10 The cycloalkyl group is cyclopropyl, cyclobutyl, or cyclopentyl.

[0071] In a certain scheme, when R 2-1c-2 and R 2-1c-3 When independently a C1-C6 alkyl group, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0072] In a certain scheme, when R 2-2 When the alkyl group is C1 to C6, the C1 to C6 alkyl group can be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, for example, methyl.

[0073] In a certain scheme, when R 3-1 When the halogen is independently a halogen or a C1-C6 alkyl group substituted with a halogen, the halogen may be fluorine, chlorine, bromine or iodine, for example fluorine or chlorine.

[0074] In a certain scheme, when R 3-1 When the C1-C6 alkyl group is independently C1-C6 alkyl or C1-C6 alkyl group substituted with halogen, the C1-C6 alkyl group may be methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.

[0075] In a certain scheme, when R 3-1 When independently a C1-C6 alkoxy group, the C1-C6 alkoxy group may be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

[0076] In a certain scheme, when R 3-1 When independently a C3-C6 cycloalkyl group, the C3-C6 cycloalkyl group may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0077] In a certain scheme, when R 2-1 For one or more R 2-1a Replacement of C1~C 10 When alkyl, the substance is subjected to one or more R 2-1a Replacement of C1~C 10 Alkyl groups can be

[0078] In a certain scheme, when R 2-1 For one or more R 2-1d Replacement of C6~C 10 When aryl, the substance is subjected to one or more R 2-1d Replacement of C6~C 10 Aryl can be

[0079] as well as,

[0080] In a certain scheme, when R 2-1 For one or more R 2-1e When the substituted "5- to 6-membered heteroaryl group having 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", the term "substituted with one or more R" refers to... 2-1esubstituted C6-Ci2-aryl, "5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" or "5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" substituted by one or more R and

[0081] In a particular embodiment, R 2 may be fluorine or chlorine.

[0082] and

[0083] In a particular embodiment, R 3-1 may be fluorine or chlorine.

[0084] In a particular embodiment, R 2-1 is Ci-C4-alkyl, Ci-C4-alkyl substituted by one or more R 10 , C3-C6-cycloalkyl, "3- to 10-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and S(=0)2", C6-Ci2-aryl, C6-Ci2-aryl substituted by one or more R 2-1a , "5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" or "5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" substituted by one or more R 10 . 10 10 2-1d 10 2-1e

[0085] In a particular embodiment, R 2-1 is Ci-C4-alkyl, Ci-C4-alkyl substituted by one or more R 10 , C3-C6-cycloalkyl, "3- to 10-membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O, S and S(=0)2", C6-Ci2-aryl, C6-Ci2-aryl substituted by one or more R 2-1a , "5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" or "5- to 6-membered heteroaryl having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" substituted by one or more R 10 . 10 2-1d 10 2-1e ​​​​​​​​​

[0086] In one particular scheme, R 2-1 For one or more R 2-1a Replacement of C1~C 10 Alkyl group, with an R 2-1d Replacement of C6~C 10 aryl, "a 5- to 6-membered heteroaryl group having one, two, or three heteroatoms selected from one or more of N, O, and S", or being surrounded by one or more R 2-1e The number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more 5- to 6-membered heteroaryl groups selected from N, O and S.

[0087] In one particular scheme, R 2-1 For one or more R 2-1d Replacement of C6~C 10 aryl, "a 5- to 6-membered heteroaryl group having one, two, or three heteroatoms selected from one or more of N, O, and S", or being surrounded by one or more R 2-1e The number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more 5- to 6-membered heteroaryl groups selected from N, O and S.

[0088] In one particular scheme, R 2-2 Hydrogen, halogen, hydroxyl, C1-C 10 Alkyl, C1-C 10 Alkyl group.

[0089] In one particular scheme, R 2-1a Independently defined as "a 3- to 6-membered heterocyclic alkyl group having one, two, or three heteroatoms selected from one or more of N, O, and S".

[0090] In one particular scheme, R 2-1d and R 2-1e Independently cyano, halogen, C1-C6 alkyl, or formed by one or more R groups 2-1c-1 Substituted C1–C6 alkyl, C1–C6 alkoxy, -C(=O)R 2-1c-2 -S(=O)2R 2-1c-3 , C3 to C6 cycloalkyl groups.

[0091] In one particular scheme, R 2-1d and R 2-1e Independently cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)R 2-1c-2 -S(=O)2R 2-1c-3 , C3 to C6 cycloalkyl groups.

[0092] In one particular scheme, R 2-1dand R 2-1e independently cyano, halogen, C1-C6alkyl, -C(=O)R 2-1c-2 or -S(=O)2R 2-1c-3 .

[0093] In one aspect, R 2-1c-1 independently halogen, NH2, C3-C6cycloalkyl;

[0094] In one aspect, R 2-1c-2 and R 2-1c-3 independently C1-C6alkyl.

[0095] In one aspect, R 2-2 is hydrogen, C1-C 10 alkyl, C1-C 10 alkoxy.

[0096] In one aspect, R 3-1 independently halogen.

[0097] In one aspect,

[0098] R 2 is

[0099] R 2-1 is C1-C 10 alkyl, C1-C 2-1a alkyl substituted by one or more R 10 , C3-C 10 cycloalkyl, "3-10 membered heterocycloalkyl having one, two, or three heteroatoms each independently selected from N, O, S, and S(=O)2", C6-C 10 aryl, C6-C 2-1d aryl substituted by one or more R 10 , "5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from N, O, and S", or "5-6 membered heteroaryl having one, two, or three heteroatoms each independently selected from N, O, and S" substituted by one or more R 2-1e ;

[0100] R 2-2 is hydrogen, C1-C6alkyl, C1-C6alkoxy;

[0101] R 2-1a independently C3-C6cycloalkyl or "3-6 membered heterocycloalkyl having one, two, or three heteroatoms each independently selected from N, O, and S";

[0102] R 2-1d and R2-1e independently cyano, halogen, C1-C6alkyl, C1-C6alkyl substituted with one or more R 2-1c-1 substituted C1-C6alkyl, C1-C6alkoxy, -C(=O)R 2-1c-2 , -S(=O)2R 2-1c-3 , C3-C6cycloalkyl;

[0103] R 2-1c-1 independently halogen, NH2, C3-C6cycloalkyl;

[0104] R 2-1c-2 and R 2-1c-3 are independently NH2or C1-C6alkyl;

[0105] n is 0, 1, 2, or 3;

[0106] R 3-1 is independently halogen.

[0107] In one aspect,

[0108] R 2 is

[0109] R 2-1 is C1-C 10 alkyl, C1-C6alkyl substituted with one or more R 2-1a substituted C1-C 10 alkyl, 3- to 10-membered heterocycloalkyl having one, two, or three heteroatoms each independently selected from N, O, S, and S(=O)2, C6-C 10 aryl, C6-C 2-1d aryl substituted with one or more R 10 substituted C6-C 2-1e aryl, 5- to 6-membered heteroaryl having one, two, or three heteroatoms each independently selected from N, O, and S, or 5- to 6-membered heteroaryl having one, two, or three heteroatoms each independently selected from N, O, and S substituted with one or more R

[0110] R 2-2 is hydrogen, C1-C6alkyl;

[0111] R 2-1a is independently C3-C6cycloalkyl or 3- to 6-membered heterocycloalkyl having one, two, or three heteroatoms each independently selected from N, O, and S;

[0112] R 2-1d and R 2-1e are independently cyano, halogen, C1-C6alkyl, C1-C6alkyl substituted with one or more R 2-1c-1substituted C1-C6alkyl, C1-C6alkoxy, -C(=O)R 2-1c-2 , -S(=O)2R 2-1c-3 , C3-C6cycloalkyl;

[0113] R 2-1c-1 is independently halogen, NH2, cyclopropyl;

[0114] R 2-1c-2 and R 2-1c-3 are independently NH2or C1-C6alkyl;

[0115] n is 0, 1, 2 or 3;

[0116] R 3-1 is independently halogen.

[0117] In one aspect,

[0118] R 2 is

[0119] R 2-1 is C1-C 10 alkyl, C1-C 2-1a alkyl substituted by one or more R 10 , 3-10 membered heterocycloalkyl having one, two or three heteroatoms each independently selected from the group consisting of N, O, S and S(=O)2, C6-C 10 aryl, C6-C 2-1d aryl substituted by one or more R 10 , 5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from the group consisting of N, O and S, or 5-6 membered heteroaryl having one, two or three heteroatoms each independently selected from the group consisting of N, O and S substituted by one or more R 2-1e ;

[0120] R 2-2 is hydrogen, C1-C6alkyl;

[0121] R 2-1a is independently C3-C6cycloalkyl or 3-6 membered heterocycloalkyl having one, two or three heteroatoms each independently selected from the group consisting of N, O and S;

[0122] R 2-1d and R 2-1e are independently cyano, halogen, C1-C6alkyl, C1-C6alkoxy, -C(=O)R 2-1c-2 , -S(=O)2R 2-1c-3 , C3~C6 cycloalkyl;

[0123] R 2-1c-2 and R 2-1c-3 It is independently NH2 or C1-C6 alkyl;

[0124] n is 0, 1, 2, or 3;

[0125] R 3-1 Halogens are independent of each other.

[0126] In one of the solutions,

[0127] R 2 for

[0128] R 2-1 For one or more R 2-1a Replacement of C1~C 10 Alkyl group, with an R 2-1d Replacement of C6~C 10 aryl, "a 5- to 6-membered heteroaryl group having one, two, or three heteroatoms selected from one or more of N, O, and S", or being surrounded by one or more R 2-1e The substituted "is one, two, or three heteroatoms, and the heteroatoms are selected from one or more five- to six-membered heteroaryl groups selected from N, O, and S";

[0129] R 2-2 It is hydrogen or C1-C3 alkyl;

[0130] R 2-1a Independently defined as "having one, two, or three heteroatoms, the heteroatoms being selected from one or more of N, O, and S, consisting of 3- to 6-membered heterocyclic alkyl groups";

[0131] R 2-1d and R 2-1e Independently cyano, halogen, C1-C6 alkyl, C1-C6 alkoxy, -C(=O)R 2-1c-2 -S(=O)2R 2-1c-3 , Cyclopropane;

[0132] R 2-1c-2 and R 2-1c-3 Independently, it is a C1 to C6 alkyl group;

[0133] n is 0, 1, 2, or 3;

[0134] R 3-1 Halogens are independent of each other.

[0135] In one of the solutions,

[0136] R2 R

[0137] R 2-1 C6-C10aryl, "5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S," or "5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S" substituted by one or more R 2-1d C6-C10aryl, "5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S," or "5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S" substituted by one or more R 10 C6-C10aryl, "5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S," or "5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S" substituted by one or more R 2-1e C6-C10aryl, "5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S," or "5- to 6-membered heteroaryl having 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S" substituted by one or more R

[0138] R 2-2 C1-C6alkyl, -C(=O)R

[0139] R 2-1d C1-C6alkyl, -C(=O)R 2-1e 2-1c-2 C1-C6alkyl, -C(=O)R 2-1c-3 ;

[0140] R 2-1c-2 C1-C6alkyl, -C(=O)R 2-1c-3

[0141] n is 0, 1, 2, or 3.

[0142] R 3-1 halogen.

[0143] In one aspect, the compound of Formula I can be any one of the following structures,

[0144]

[0145]

[0146]

[0147]

[0148]

[0149] In accordance with embodiments of the present application, the compound of Formula I can be any one of the following compounds,

[0150] Compound 1: N-(4-((3-acetylphenoxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide,

[0151] ​​N-(4-((3-acetylphenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0152] Compound 2: 2-(2-chlorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0153] 2-(2-chlorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0154] Compound 3: 2-(2-chlorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0155] 2-(2-chlorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0156] Compound 4: N-(4-((4-chlorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide,

[0157] N-(4-((4-chlorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0158] Compound 5: 2-(2-chlorophenyl)-N-(4-((2,4-dichlorophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0159] 2-(2-chlorophenyl)-N-(4-((2,4-dichlorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0160] Compound 6: 2-(2-chlorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0161] 2-(2-chlorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0162] Compound 7: 2-(2-chlorophenyl)-N-(4-((2,4-difluorophenoxy)methyl)-3-aminosulfonylphenyl)acetamide,

[0163] 2-(2-chlorophenyl)-N-(4-((2,4-difluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0164] Compound 8: 2-(2-chlorophenyl)-N-(4-(((4,5-dichloro-1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-aminosulfonylphenyl)acetamide,

[0165] 2-(2-chlorophenyl)-(4-(((4,5-dichloro-1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0166] Compound 9: 2-(2-chlorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-aminosulfonylphenyl)acetamide,

[0167] 2-(2-chlorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0168] Compound 10: 2-(2-chlorophenyl)-N-(4-((3-cyano-4-fluorophenoxy)methyl)-3-aminosulfonylphenyl)acetamide,

[0169] 2-(2-chlorophenyl)-N-(4-((3-cyano-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0170] Compound 11: N-(4-((3-chloro-4-fluorophenoxy)methyl)-3-aminosulfonylphenyl)-2-(2-chlorophenyl)acetamide,

[0171] N-(4-((3-chloro-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0172] Compound 12: 2-(2-chlorophenyl)-N-(4-((3-(methylsulfonyl)phenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0173] 2-(2-chlorophenyl)-N-(4-((3-(methylsulfonyl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0174] Compound 13: 2-(2-chlorophenyl)-N-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)oxy)methyl)- 3-sulfamoylphenyl)acetamide,

[0175] 2-(2-chlorophenyl)-N-(4-(((1,1-dioxidotetrahydrothiophen-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0176] Compound 14: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)acetamide,

[0177] 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydrofuran-3-yl)oxy)methyl)phenyl)acetamide,

[0178] Compound 15: N-(4-((3-acetyl-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide,

[0179] N-(4-((3-acetyl-4-fluorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0180] Compound 16: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((p-tolyloxy)methyl)phenyl)acetamide,

[0181] 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((p-tolyloxy)methyl)phenyl)acetamide,

[0182] Compound 17: 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-methylphenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0183] 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-methylphenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0184] Compound 18: 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-methoxyphenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0185] 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-methoxyphenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0186] Compound 19: 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-(2-oxopyrrolidin-l- yl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0187] 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-(2-oxopyrrolidin-l- yl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0188] Compound 20: 2-(2-chloro-6-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0189] 2-(2-chloro-6-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0190] Compound 21: 2-(2-chloro-4-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0191] 2-(2-chloro-4-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0192] Compound 22: 2-(2-chloro-5-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0193] 2-(2-chloro-5-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0194] Compound 23: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0195] 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0196] Compound 24: 2-(2-chlorophenyl)-N-(4-(((3-fluoro-1-methyl-1H-pyrazol-5-yl)oxy)methyl)- 3-sulfamoylphenyl)acetamide,

[0197] 2-(2-chlorophenyl)-N-(4-(((3-fluoro-1-methyl-1H-pyrazol-5-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0198] Compound 25: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-5-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0199] 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0200] Compound 26: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-2-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0201] 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0202] Compound 27: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-4-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0203] 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-imidazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0204] Compound 28: 2-(2-chlorophenyl)-N-(4-((cyclopropylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0205] 2-(2-chlorophenyl)-N-(4-((cyclopropylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0206] Compound 29: 2-(2-chlorophenyl)-N-(4-((cyclobutylmethoxy)methyl)-3-sulfamoylphenyl)acetamide

[0207] 2-(2-chlorophenyl)-N-(4-((cyclobutylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0208] Compound 30: 2-(2-chlorophenyl)-N-(4-((cyclopentylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0209] 2-(2-chlorophenyl)-N-(4-((cyclopentylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0210] Compound 31: 2-(2-chlorophenyl)-N-(4-(cyclobutoxymethyl)-3-sulfamoylphenyl)acetamide,

[0211] 2-(2-chlorophenyl)-N-(4-(cyclobutoxymethyl)-3-sulfamoylphenyl)acetamide,

[0212] Compound 32: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((((tetrahydro-2H-pyran-4- yl)oxy)methyl)phenyl)acetamide,

[0213] 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydro-2H-pyran-4-yl)oxy)methyl)phenyl)acetamide,

[0214] Compound 33: 2-(2-chlorophenyl)-N-(4-((oxetan-3-ylmethoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0215] 2-(2-chlorophenyl)-N-(4-((oxetan-3-ylmethoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0216] Compound 34: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydrofuran-3- yl)methoxy)methyl)phenyl)acetamide,

[0217] 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydrofuran-3-yl)methoxy)methyl)phenyl)acetamide,

[0218] Compound 35: 2-(2-chlorophenyl)-N-(4-((oxetan-3-yloxy)methyl)-3- sulfamoylphenyl)acetamide,

[0219] 2-(2-chlorophenyl)-N-(4-((oxetan-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide,

[0220] Compound 36: N-(4-((azetidin-3-yloxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide,

[0221] N-(4-((azetidin-3-yloxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0222] Compound 37: 2-(2-chlorophenyl)-N-(4-((pyrrolidin-3-yloxy)methyl)-3- sulfamoylphenyl)acetamide,

[0223] 2-(2-chlorophenyl)-N-(4-((pyrrolidin-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide,

[0224] Compound 38: 2-(2-chlorophenyl)-N-(4-((piperidin-4-yloxy)methyl)-3- sulfamoylphenyl)acetamide,

[0225] 2-(2-chlorophenyl)-N-(4-((piperidin-4-yloxy)methyl)-3-sulfamoylphenyl)acetamide,

[0226] Compound 39: 2-(2-chlorophenyl)-N-(4-((piperidin-3-yloxy)methyl)-3- sulfamoylphenyl)acetamide,

[0227] 2-(2-chlorophenyl)-N-(4-((piperidin-3-yloxy)methyl)-3-sulfamoylphenyl)acetamide,

[0228] Compound 40: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((((tetrahydro-2H-pyran-3- yl)oxy)methyl)phenyl)acetamide,

[0229] 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydro-2H-pyran-3-yl)oxy)methyl)phenyl)acetamide,

[0230] Compound 41 : N-(4-(((2-azabicyclo[2.2.1]heptan-5-yl)oxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0231] N-(4-(((2-azabicyclo[2.2.1]heptan-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0232] Compound 42: N-(4-(((3-azabicyclo[3.1.1]heptan-6-yl)oxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0233] N-(4-(((3-azabicyclo[3.1.1]heptan-6-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide,

[0234] Compound 43: N-(4-(((2-azabicyclo[2.2.2]octan-5-yl)oxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0235] N-(4-(((2-azabicyclo[2.2.2]octan-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0236] Compound 44: 2-(2-chlorophenyl)-N-(4-((3-cyanophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0237] 2-(2-chlorophenyl)-N-(4-((3-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0238] Compound 45: N-(4-((3-(aminomethyl)phenoxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide,

[0239] N-(4-((3-(aminomethyl)phenoxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide,

[0240] Compound 46: 2-(2-chloro-6-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)- 3-sulfamoylphenyl)acetamide,

[0241] 2-(2-chloro-6-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0242] Compound 47: 2-(2-chloro-5-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)- 3-sulfamoylphenyl)acetamide,

[0243] 2-(2-chloro-5-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0244] Compound 48: 2-(2-chloro-4-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0245] 2-(2-chloro-4-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0246] Compound 49: 2-(2-chloro-6-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0247] 2-(2-chloro-6-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0248] Compound 50: 2-(2-chloro-5-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0249] 2-(2-chloro-5-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0250] Compound 51 : 2-(2-chloro-4-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0251] 2-(2-chloro-4-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0252] Compound 52: 2-(2-chloro-3-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0253] 2-(2-chloro-3-fluorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide,

[0254] Compound 53: 2-(2-chloro-6-fluorophenyl)-N-(4-((((5-fluoropyridin-2-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0255] 2-(2-chloro-6-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0256] Compound 54: 2-(2-chloro-5-fluorophenyl)-N-(4-((((5-fluoropyridin-2-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0257] 2-(2-chloro-5-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0258] Compound 55: 2-(2-chloro-4-fluorophenyl)-N-(4-((((5-fluoropyridin-2-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0259] 2-(2-chloro-4-fluorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0260] Compound 56: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0261] 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0262] Compound 57: 2-(2-chlorophenyl)-N-(4-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide,

[0263] 2-(2-chlorophenyl)-N-(4-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide.

[0264] Compound 58: 2-(2-chlorophenyl)-N-(4-((3-(S-methylsulfonimidoyl)phenoxy)methyl)-3- sulfamoylphenyl)acetamide,

[0265] 2-(2-chlorophenyl)-N-(4-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide.

[0266] Compound 59: 2-(2-chlorophenyl)-N-(4-(1-((6-fluoropyridin-3-yl)oxy)ethyl)-3- sulfamoylphenyl)acetamide,

[0267] 2-(2-chlorophenyl)-N-(4-(1-((6-fluoropyridin-3-yl)oxy)ethyl)-3-sulfamoylphenyl)acetamide.

[0268] Compound 60: N-(4-(((4-chloro-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide,

[0269] N-(4-(((4-chloro-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chlorophenyl)acetamide.

[0270] Compound 61: 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)- 3-sulfamoylphenyl)acetamide,

[0271] 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide.

[0272] Compound 62: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0273] 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0274] Compound 63: 2-(2-chlorophenyl)-N-(4-(((1-(cyclopropylmethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0275] 2-(2-chlorophenyl)-N-(4-(((1-(cyclopropylmethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0276] Compound 64: 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0277] 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0278] Compound 65: 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0279] 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0280] Compound 66: 2-(2-chlorophenyl)-N-(4-(((1-(1,1-difluoropropyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0281] 2-(2-chlorophenyl)-N-(4-(((1-(1,1-difluoropropyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0282] Compound 67: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0283] 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0284] Compound 67: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0285] N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide,

[0286] Compound 67: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0287] N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide,

[0288] Compound 67: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0289] N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-5-fluorophenyl)acetamide,

[0290] Compound 72: 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0291] 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0292] Compound 73: 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-5- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0293] 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-5- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0294] Compound 74: 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0295] 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0296] Compound 75: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide,

[0297] 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acet amide,

[0298] This invention provides a method for preparing the compound shown in Formula I, which is either Method 1 or Method 2.

[0299] Method 1 includes the following steps: in a solvent, in the presence of an acid, the compound shown in Formula II is reacted with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH) to generate the compound shown in Formula IV, and then the compound of Formula IV is reacted with ammonia to obtain the compound shown in Formula I.

[0300]

[0301] Method 2 includes the following steps: reacting the compound shown in Formula III with hydrazine hydrate in an organic solvent to obtain the compound shown in Formula I;

[0302]

[0303] Among them, R in equations I, II, III, and IV 3-1 n, R 2 They are the same or different, and each has the definition described above independently.

[0304] In one embodiment, Method 1, the compound shown in Formula IV does not require separation; the reaction solution from the previous step is directly reacted with ammonia. Specifically, the compound shown in Formula II is reacted with 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), and then the reaction solution is reacted with ammonia to obtain the compound shown in Formula I.

[0305] In one embodiment, in method one, the solvent can be a conventional solvent in the art, or a nitrile solvent, or a mixed solvent of a nitrile solvent and water, such as a mixed solvent of acetonitrile and water.

[0306] In one embodiment, in method one, the acid can be a conventional acid in the art, an organic acid, or an organic carboxylic acid, such as acetic acid.

[0307] In one embodiment, in method one, the molar ratio of the DCDMH and the compound shown in formula II can be 1:1 to 5:1, for example, 2:1 or 3:1.

[0308] In an embodiment, in Method I, the molar ratio of the acid to the compound of Formula II can be 3: 1 to 30: 1, for example, 5: 1, 6: 1, 8: 1, 13: 1, 17: 1, or 25: 1.

[0309] In an embodiment, in Method I, the molar concentration of the compound of Formula II in the solvent can be 0.01 to 0.3 mol / L, for example, 0.05 mol / L, 0.09 mol / L, 0.1 mol / L, 0.15 mol / L, 0.18 mol / L.

[0310] In an embodiment, in Method I, the temperature during the reaction with the DCDMH can be 10 to 40 °C.

[0311] In an embodiment, in Method I, the time for the reaction with the DCDMH can be 5 to 120 min, for example, 10 min, 15 min, 60 min.

[0312] In an embodiment, in Method I, the molar volume ratio of the compound of Formula II to the aqueous ammonia can be 0.01 to 0.5 mol / L, for example, 0.015 mol / L, 0.02 mol / L, 0.08 mol / L, 0.034 mol / L, 0.2 mol / L, 0.33 mol / L, or 0.39 mol / L.

[0313] In an embodiment, in Method I, the temperature during the reaction with the aqueous ammonia can be 10 to 40 °C.

[0314] In an embodiment, in Method I, the time for the reaction with the aqueous ammonia can be 5 to 60 min, for example, 10 min, 30 min.

[0315] In an embodiment, in Method I, after the reaction with the aqueous ammonia, the work-up can include the following steps: removing the solvent from the reaction mixture, and isolating and purifying, if necessary. The removal of the solvent from the reaction mixture can be by a conventional method in the art, for example, concentration under reduced pressure to dryness. The isolation and purification can be by a conventional method in the art, for example, purification by preparative HPLC.

[0316] In an embodiment, in Method II, the organic solvent can be a conventional organic solvent in the art, and can also be an alcohol solvent and / or an ether solvent, for example, methanol and / or tetrahydrofuran.

[0317] In an embodiment, in Method II, the molar ratio of the hydrazine hydrate to the compound of Formula III can be 2: 1 to 8: 1, for example, 5: 1.

[0318] In an embodiment, in Method 2, the molar concentration of the compound of Formula III in the organic solvent can be 0.01-0.3 mol / L, for example, 0.06 mol / L.

[0319] In an embodiment, in Method 2, the temperature of the reaction can be 10-40℃.

[0320] In an embodiment, in Method 2, the time of the reaction can be 0.5-3 h, for example, 1 h.

[0321] In an embodiment, in Method 2, the post-treatment of the reaction can include the following steps: removing the solvent in the reaction solution, and separating and purifying, if necessary. The way of removing the solvent in the reaction solution can be a conventional way in the art, for example, concentrating to dryness under reduced pressure. The way of separating and purifying can be a conventional way in the art, for example, purifying by preparative HPLC.

[0322] The present application also provides an intermediate compound as shown in Formula II, III or IV, which can be used for preparing the compound of Formula I:

[0323]

[0324] wherein, R 2 , R 3-1 and n are as defined in any of the above embodiments.

[0325] The present application also provides an intermediate compound as shown below, which can be used for preparing the compound of Formula I:

[0326]

[0327]

[0328]

[0329]

[0330] The present application provides a pharmaceutical composition comprising Substance A and at least one pharmaceutical excipient.

[0331] The Substance A is the compound of Formula I, pharmaceutically acceptable salt thereof, stereoisomer thereof, tautomer thereof, isotopic compound thereof, crystal form thereof, nitroxide thereof, solvate thereof or solvate of the pharmaceutically acceptable salt thereof.

[0332] In the pharmaceutical composition, the dose of the Substance A can be a therapeutically effective amount.

[0333] The application also provides a use of the substance A in the preparation of a P2X4 receptor antagonist or a drug.

[0334] The substance A is the compound as shown in the above formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic compound thereof, a crystal form thereof, a nitroxide thereof, a solvate thereof or a solvate of the pharmaceutically acceptable salt thereof.

[0335] In a certain embodiment, the P2X4 receptor antagonist can be used in vitro.

[0336] In a certain embodiment, the drug can be used for treating or preventing a urinary tract disease, a respiratory disease, a pain-related disease, an autoimmune disease, an inflammation, a sleep disorder, a mental disease, arthritis, a neurodegenerative disease, a traumatic brain injury, a thrombosis, a digestive tract disease, a sexual dysfunction, a cardiovascular disease, endometriosis, a muscle-skeletal and connective tissue development disorder, a cancer or an ophthalmic disease in an animal (e.g., a human). The urinary tract disease is, for example, urinary incontinence, overactive bladder, dysuria or cystitis. The respiratory disease is, for example, a respiratory disorder, including respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm or cough (e.g., chronic cough). The pain-related disease is, for example, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, chronic pain or itch. The neurodegenerative disease is, for example, senile dementia, Parkinson, epilepsy or stroke. The cardiovascular disease is, for example, myocardial infarction, atherosclerosis, heart failure, hypertension or a blood disease. The digestive tract disease is, for example, colonic syndrome, inflammatory bowel disease or gastrointestinal dysfunction. The autoimmune disease is, for example, arthritis (e.g., rheumatoid arthritis). The ophthalmic disease is, for example, dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma and postoperative ocular pain.

[0337] In a certain embodiment, the drug can be used for preventing or treating a disease mediated at least in part by P2X4 in an animal (e.g., a human).

[0338] The disease mediated at least in part by P2X4 is, for example, a urinary tract disease, a respiratory disease, a pain-related disease, an autoimmune disease, inflammation, a sleep disorder, a mental disease, arthritis, a neurodegenerative disease, a traumatic brain injury, thrombosis, a digestive tract disease, sexual dysfunction, a cardiovascular system disease, endometriosis, a muscle, bone and connective tissue development disorder, cancer or an ophthalmic disease. The urinary tract disease is, for example, urinary incontinence, overactive bladder, dysuria or cystitis. The respiratory disease is, for example, a respiratory disorder including respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm or cough (e.g., chronic cough). The pain-related disease is, for example, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain caused by burns, migraine, cluster headache, chronic pain or itch. The neurodegenerative disease is, for example, senile dementia, Parkinson, epilepsy or stroke. The cardiovascular system disease is, for example, myocardial infarction, atherosclerosis, heart failure, hypertension or a blood disease. The digestive tract disease is, for example, colonic syndrome, inflammatory bowel disease or gastrointestinal dysfunction. The autoimmune disease is, for example, arthritis (e.g., rheumatoid arthritis). The ophthalmic disease is, for example, dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma and postoperative ocular pain.

[0339] The present application also provides a method for treating or preventing a disease, which comprises administering to a patient (e.g., a human) a therapeutically effective amount of a substance A;

[0340] The disease is a urinary tract disease, a respiratory disease, a pain-related disease, an autoimmune disease, inflammation, a sleep disorder, a mental disease, arthritis, a neurodegenerative disease, a traumatic brain injury, thrombosis, a digestive tract disease, sexual dysfunction, a cardiovascular system disease, endometriosis, a muscle, bone and connective tissue development disorder, cancer or an ophthalmic disease.

[0341] The substance A is a compound represented by Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic compound thereof, a crystal form thereof, a nitroxide thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof.

[0342] In one aspect, the urinary tract disease is, for example, urinary incontinence, overactive bladder, dysuria or cystitis.

[0343] In one aspect, the respiratory disease is, for example, a respiratory disorder including respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm or cough (e.g., chronic cough).

[0344] In certain embodiments, the pain-related disease is, for example, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain from burns, migraine, cluster headache, chronic pain, or itch.

[0345] In certain embodiments, the neurodegenerative disease is, for example, Alzheimer's disease, Parkinson's disease, epilepsy, or stroke.

[0346] In certain embodiments, the cardiovascular disease is, for example, myocardial infarction, atherosclerosis, heart failure, hypertension, or a blood disease.

[0347] In certain embodiments, the gastrointestinal disease is, for example, colonic syndrome, inflammatory bowel disease, or gastrointestinal dysfunction. The autoimmune disease is, for example, arthritis (e.g., rheumatoid arthritis).

[0348] In certain embodiments, the ophthalmic disease is, for example, dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma, and postoperative ocular pain.

[0349] The present application also provides a method for treating or preventing a disease mediated at least in part by P2X4, comprising administering to a patient (e.g., a human) a therapeutically effective amount of Material A;

[0350] The Material A is a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, an isotopic compound thereof, a crystal form thereof, a nitroxide thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof.

[0351] In certain embodiments, the disease can be a urinary tract disease, a respiratory disease, a pain-related disease, an autoimmune disease, inflammation, a sleep disorder, a mental disease, arthritis, a neurodegenerative disease, a traumatic brain injury, thrombosis, a gastrointestinal disease, sexual dysfunction, a cardiovascular disease, endometriosis, a musculoskeletal and connective tissue development disorder, or cancer.

[0352] In certain embodiments, the urinary tract disease is, for example, urinary incontinence, overactive bladder, dysuria, or cystitis.

[0353] In certain embodiments, the respiratory disease is, for example, a respiratory disorder, including respiratory failure, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, bronchospasm, or cough (e.g., chronic cough).

[0354] In certain embodiments, the pain-related disease is, for example, inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain from burns, migraine, cluster headache, chronic pain, or itch.

[0355] In certain embodiments, the neurodegenerative disease is, for example, Alzheimer's disease, Parkinson's disease, epilepsy or stroke.

[0356] In certain embodiments, the cardiovascular disease is, for example, myocardial infarction, atherosclerosis, heart failure, hypertension or a blood disease.

[0357] In certain embodiments, the gastrointestinal disease is, for example, colitis syndrome, inflammatory bowel disease or gastrointestinal dysfunction. The autoimmune disease is, for example, arthritis (e.g., rheumatoid arthritis).

[0358] In certain embodiments, the ophthalmic disease is, for example, dry eye syndrome, dry eye, ocular neuropathic pain, ocular trauma and postoperative ocular pain.

[0359] Beneficial effects

[0360] The aromatic compounds of the present application have high P2X4 antagonistic activity, good safety and good pharmacokinetic properties.

[0361] Definitions and explanations of terms

[0362] All patents and publications mentioned in the present application are hereby incorporated by reference in their entirety.

[0363] General principles of organic chemistry can be found, for example, in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry" by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the contents of which are hereby incorporated by reference in their entirety.

[0364] Unless otherwise indicated, the terms used in the present application have the following definitions, and the definitions of terms not mentioned below are as generally understood by a person of ordinary skill in the art to which the present application pertains.

[0365] Unless otherwise indicated, the description and claims herein contain one or both of the following: (1) an integral number or a range of integral numbers, which is equivalent to at least reciting each individual integer within the range, and (2) one, two, or more of a substituent, which is equivalent to at least reciting each individual integer number of the substituent. For example, the numerical range "1-20" is equivalent to reciting each individual integer number within the range "1-10" i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and each individual integer number within the range "11-20" i.e., 11, 12, 13, 14, 15, 16, 17, 18, 19, 20. It is understood that, in describing substituents herein, "more than one" or "more than two" shall mean an integer number of ≥3, such as 3, 4, 5, 6, 7, 8, 9, or 10. The term "a plurality" means an integer number of ≥2, such as 2, 3, 4, 5, etc.

[0366] The term "pharmaceutically acceptable salt" refers to a salt prepared from the compounds of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable base with the neutral form of such compounds in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, and diethanolamine salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting a sufficient amount of a pharmaceutically acceptable acid with the neutral form of such compounds in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acids include inorganic acids, including but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, and sulfuric acid. The pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acidic citric acid, oleic acid, tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentian acid, fumaric acid, gluconic acid, succinic acid, formic acid, ethanesulfonic acid, dihydroxynaphthyl acid (i.e., 4,4'-methylene-bis(3-hydroxy-2-naphthylcarboxylic acid)), amino acids (e.g., glutamic acid, arginine), etc. When the compounds of the present invention contain relatively acidic and relatively basic functional groups, they can be converted into base addition salts or acid addition salts. For details, see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl and Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0367] The term "solvate" refers to a substance formed by the combination of the compound of this invention with a stoichiometric or non-stoichiometric solvent. Solvent molecules in a solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to, water, methanol, and ethanol.

[0368] As described above, the terms "pharmaceutical-acceptable salt" and "solvent" in the term "pharmaceutical-acceptable salt solvate" refer to substances formed by combining the compounds of the present invention with 1, substances prepared with a relatively non-toxic, pharmaceutically acceptable acid or base, or substances formed with a stoichiometric or non-stoichiometric solvent.

[0369] The term "stereoisomers" refers to isomers that have the same order of connectivity of atoms but differ in the orientation of atoms in space. These stereoisomers can be separated by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotary chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by chiral resolution through bonding (chemical bonding, etc.) or salification (physical bonding, etc.) with other chiral compounds.

[0370] The term "tautomers" refers to isomers of a functional group due to the rapid movement of an atom in the molecule between two positions. For example, acetone and 1-propen-2-ol can be converted into each other by the rapid movement of hydrogen atoms on the oxygen and the alpha-carbon.

[0371] The term "isotopic compounds" refers to compounds in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present application include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur, and chlorine (e.g. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl). Isotopic compounds of the present application can generally be prepared in accordance with the procedures described herein by substituting isotopically labeled reagents for non-isotopically labeled reagents.

[0372] The term "crystal form" refers to a state in which ions or molecules are arranged in a strict periodicity in three-dimensional space in a certain way, and have a regular period of repetition at a certain distance; due to the different periodic arrangements described above, there can be multiple crystal forms, i.e. polymorphism.

[0373] The term "nitrogen oxide" refers to the oxidation of one or more nitrogen atoms to form N-oxides when a compound contains several amine functional groups. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with oxidizing agents such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids) to form N-oxides (see Advanced Organic Chemistry, Wiley Interscience, 4th ed., Jerry March, pages). In particular, N-oxides can be prepared using the LWDeady method (Syn. Comm. 1977, 7, 509-514), in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0374] When any variable (e.g., R) 2-1a When a variable appears multiple times in the definition of a compound, the definition at each position is independent of the definitions at the other positions; their meanings are independent and do not affect each other. Therefore, if a group is surrounded by one, two, or three R... 2-1a Group substitution, meaning that the group can be replaced by up to 3 R groups. 2-1a Replace, the position R 2-1a Definition and other positions R 2-1a The definitions are independent of each other. Furthermore, combinations of substituents and / or variables are only permitted if the combination produces a stable compound.

[0375] The structural formulas of the groups described in this invention use This refers to the connection of the corresponding functional group to other fragments or functional groups in the compound through this site.

[0376] Linking substituents are described in various parts of this invention. When the structure clearly requires a linking group, the Markush variables listed for that group should be understood as linking groups. For example, C1-C6 alkyl in the group “halogenated-C1-C6 alkyl” should be understood as C1-C6 alkylene.

[0377] Unless otherwise stated, any abbreviations for protecting groups, amino acids and other compounds used in this invention shall be those that are commonly used and recognized, or refer to the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 11: 942-944).

[0378] The term "oxo" refers to the substitution of a carbon, nitrogen, or sulfur atom in a substituent with an oxygen atom (=O) formed by oxidation.

[0379] The term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0380] The term "C1~C" 20 "Alkyl" should be understood as a straight-chain or branched saturated hydrocarbon group having 1 to 20 carbon atoms. For example, "C1-C6 alkyl" represents a straight-chain or branched alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. The alkyl group may optionally be substituted by one or more substituents described in this invention. In some embodiments, the alkyl group contains 1-12 carbon atoms or 13-20 carbon atoms; in other embodiments, the alkyl group contains 1-6 carbon atoms; and in still other embodiments, the alkyl group contains 1-4 carbon atoms. Examples of alkyl groups include, but are not limited to, specific examples. Limited to methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, etc., or their isomers.

[0381] The term "C1~C" 20 "Alkoxy" refers to the group -O-C1~C 20 Alkyl groups, for example, C1 to C2. 12 Alkoxy or C 13 ~C 20 Alkoxy groups, preferably C1 to C6 alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, and similar alkoxy groups.

[0382] The term "C3~C" 20 "Cycloalkyl" should be understood to refer to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring having 3 to 20 carbon atoms, preferably "C3 to C4". 12 "Cycloalkyl", and its bicyclic and tricyclic hydrocarbon rings include bridged or spirocyclic hydrocarbon rings. The term "C3-C6" is also used. 12 "Cycloalkyl" should be understood to mean a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms, and its bicyclic and tricyclic hydrocarbon rings include bridged or spirocyclic hydrocarbon rings. The C 3-10 Cycloalkyl groups can be monocyclic hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or cyclodecyl, or bicyclic hydrocarbon groups such as decahydronaphthalene ring.

[0383] The term "3-20 membered heterocyclic group" should be understood to refer to a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, S, and S(=O)2, forming a non-aromatic cyclic group with a total ring atomic number of 3-20 (e.g., 3, 4, 5, 6, 7, 8, 9, 10, etc.), and its bicyclic and tricyclic hydrocarbon rings contain bridged or spirocyclic hydrocarbon rings, preferably "3-10 membered heterocyclic group". The term "3-10 membered heterocyclic group" means a saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring containing 1-5, preferably 1-3, heteroatoms independently selected from N, O, S, and S(=O)2, for example, 1, 2, or 3 heteroatoms independently selected from N, O, S, and S(=O)2, and its bicyclic and tricyclic hydrocarbon rings contain bridged or spirocyclic hydrocarbon rings. More preferably, it is a 3-8 member saturated monocyclic or bicyclic system containing one, two, or three cyclic heteroatoms independently selected from N, O, S, and S(=O)2, or a 3-6 member saturated monocyclic system containing one, two, or three cyclic heteroatoms independently selected from N, O, and S. According to the present invention, the heterocyclic group is non-aromatic. When the 3-20 member heterocyclic group is linked to other groups to form the compounds of the present invention, the carbon atom on the 3-20 member heterocyclic group can be linked to other groups, or the heterocyclic atom on the ring of the 3-20 member heterocyclic group can be linked to other groups. Specifically, the heterocyclic group may include, but is not limited to: 4-membered rings, such as azirrobutyl and oxobutyl; 5-membered rings, such as tetrahydrofuranyl, dioxacyclopentenyl, pyrrolyl, imidazoyl, pyrazolyl, or pyrrololinyl; or 6-membered rings, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl, or trithiaalkyl; or 7-membered rings, such as diazacycloheptyl. Optionally, the heterocyclic group may be benzofused. The heterocyclic group may be bicyclic, for example, but not limited to, 5,5-membered rings, such as hexahydrocyclopenta[c]pyrrolo-2(1H)-yl rings, or 5,6-membered bicyclic rings, such as hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl rings. The nitrogen-containing ring can be partially unsaturated, meaning it can contain one or more double bonds, such as, but not limited to, 2,5-dihydro-1H-pyrrole, 4H-[1,3,4]thiadiazinyl, 4,5-dihydrooxazolyl, or 4H-[1,4]thiazinyl, or it can be benzofused, such as, but not limited to, dihydroisoquinolinyl.

[0384] The term "C6~C" 20 "Aryl" should be understood as representing a monocyclic, bicyclic, or tricyclic hydrocarbon ring with 6 to 20 carbon atoms, preferably "C6 to C6". 14 Aromatic. The term "C6-C6" 14 "Aryl" should preferably be understood to represent an aromatic or partially aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring ("C6-C14") having 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. 14Aryl), particularly a ring with 6 carbon atoms (“C6 aryl”), such as phenyl; or biphenyl, or a ring with 9 carbon atoms (“C9 aryl”), such as indenyl or indenyl, or a ring with 10 carbon atoms (“C9 aryl”). 10 Aryl groups, such as tetrahydronaphthyl, dihydronaphthyl, or naphthyl, or rings with 13 carbon atoms (“C”). 13 Aryl groups, such as fluorene groups, or rings with 14 carbon atoms (“C”). 14 Aryl), for example, anthracene. When the C6-C6... 20 When the aryl group is substituted, it can be monosubstituted or polysubstituted. Furthermore, there are no restrictions on the substitution site; for example, it can be ortho, para, or meta substituted.

[0385] The term "5-20 membered heteroaryl" is to be understood as including aromatic or partially aromatic monocyclic, bicyclic or tricyclic aromatic ring systems having 5 to 20 ring atoms and comprising 1 to 5 heteroatoms independently selected from N, O and S, for example "5-14 membered heteroaryl". The term "5-14 membered heteroaryl" is to be understood as including monovalent monocyclic, bicyclic or tricyclic aromatic ring systems having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 5 or 6 or 9 or 10 carbon atoms, and comprising 1 to 5, preferably 1 to 3, heteroatoms independently selected from N, O and S. Also, it can be benzo-fused in each case additionally. In particular, the heteroaryl group is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, thia-4H-pyrazolyl and the like as well as their benzo derivatives, for example benzo furanyl, benzo thienyl, benzo oxazolyl, benzo isoxazolyl, benzo imidazolyl, benzo triazolyl, indazolyl, indolyl, isoindolyl and the like; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like as well as their benzo derivatives, for example quinolinyl, quinazolinyl, isoquinolinyl and the like; or azocinyl, indolizinyl, purinyl and the like as well as their benzo derivatives; or cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenoxazinyl, phenothiazinyl, phenoxazinyl and the like. Examples of heteroaryl groups include, but are not limited to, furanyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl and the like. When the 5-20 membered heteroaryl group is attached to another group to form a compound of the present application, it can be attached to the other group via a carbon atom of the 5-20 membered heteroaryl ring or via a heteroatom of the 5-20 membered heteroaryl ring. When the 5-20 membered heteroaryl group is substituted, it can be mono- or polysubstituted. Also, there is no limitation as to the substitution site, for example, the hydrogen attached to a carbon atom of the heteroaryl ring can be substituted or the hydrogen attached to a heteroatom of the heteroaryl ring can be substituted.

[0386] Unless otherwise indicated, heterocyclyl, heteroaryl or heteroarylenyl includes all possible isomeric forms thereof, e.g. positional isomers. Thus, for some illustrative, non-limiting examples, forms which can be included are substitution or bonding at one, two or more positions in its 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-positions, etc. (if present) including pyridin-2-yl, pyridin-2-yl ene, pyridin-3-yl, pyridin-3-yl ene, pyridin-4-yl and pyridin-4-yl ene; thienyl or thienylene including thien-2-yl, thien-2-yl ene, thien-3-yl and thien-3-yl ene; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl.

[0387] The term "pharmaceutically acceptable excipient" refers to an excipient that is useful in preparing pharmaceutical compositions; i.e., carriers and additives that are nontoxic to recipients at the dosages used. The term "pharmaceutically acceptable excipient" also refers to an excipient that is approved or approvable by a regulatory agency of the Federal or state government or the EMA or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans. Excipients can be inert or non-inert. See, for example, the U.S. Pharmacopeia (USP 32 - National Formulary (NF 27) (2009), or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009 Sixth Edition)

[0388] The term "treatment" refers to therapeutic treatment. With respect to a particular condition, treatment refers to: (1) alleviating or abrogating one or more of the biological manifestations of the disease or condition, (2) interfering with (a) one or more points in the biological cascade leading to or causing the condition or (b) one or more of the biological manifestations of the condition, (3) ameliorating one or more symptoms, effects or side effects associated with the condition or one or more symptoms, effects or side effects associated with treatment of the condition, or (4) slowing the development of the condition or one or more of the biological manifestations of the condition.

[0389] The term "prevention" refers to a reduction in the risk of acquiring or developing a disease or disorder.

[0390] The term "therapeutically effective amount" refers to the amount of a compound that, when administered to a patient, is sufficient to effect treatment for a disease or condition as described herein. The "therapeutically effective amount" will vary depending on the compound, the condition and its severity, and the age of the patient to be treated, but can be adjusted by those skilled in the art as needed.

[0391] The term "patient" refers to any animal, mammal, and most preferably a human, to which the compounds or compositions according to embodiments of the present application will be administered. The term "mammal" includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like, with humans being most preferred.

[0392] The biological activity of the compounds of the present application can be assessed by using any conventionally known method. Appropriate test methods are well known in the art. For example, the P2X4 inhibitory activity, pharmacokinetic activity, and / or liver microsomal stability of the compounds of the present application can be tested by appropriate conventional methods. The test methods provided in the present application are presented only as examples and do not limit the present application. The compounds of the present application have activity in at least one of the test methods provided in the present application.

[0393] Unless otherwise specified, "room temperature" in the present application means 10-40°C. "min" means minute(s). "h" means hour(s).

[0394] On the basis of common general knowledge in the art, the above-mentioned preferred conditions can be combined arbitrarily, i.e. to obtain each preferred example of the present application. DETAILED DESCRIPTION

[0395] The technical solutions of the present application will be further described in detail below in combination with specific examples. It should be understood that the following examples are only illustratively used to explain and describe the present application, and should not be interpreted as limiting the scope of protection of the present application. Any technology realized based on the above description of the present application is encompassed within the scope of protection intended by the present application.

[0396] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods. The experimental methods not specified in the following examples are selected according to conventional methods and conditions, or according to the instructions of the commercial product.

[0397] The abbreviations used in the example part of the present application are shown below:

[0398] ACN: Acetonitrile

[0399] AIBN: 2,2'-Azobis(2-methylpropionitrile)

[0400] Boc2O: Di-tert-butyl dicarbonate

[0401] B2pin2: Bis(pinacolato)diboron

[0402] CAN: Ceric ammonium nitrate

[0403] DIAD: diisopropyl azodiformate

[0404] Dioxane: 1,4-Dioxane

[0405] DCM: Methylene chloride

[0406] DIEA: N,N-Diisopropylethylamine

[0407] DCDMH: 1,3-Dichloro-5,5-dimethylhydantoin

[0408] DME: 1,2-dimethoxy-ethan

[0409] DMF: N,N-Dimethylformamide

[0410] DMF-DMA: N,N-Dimethylformamide dimethylacetal

[0411] DMSO: Dimethyl sulfoxide

[0412] EA: ethyl acetate

[0413] FA: Formic acid

[0414] HATU: N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate, (2-(7-azabenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate)

[0415] NBS: N-Bromosuccinimide

[0416] NCS: N-Chlorosuccinimide

[0417] PPh3: triphenylphosphine

[0418] Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium

[0419] Pd(dppf)Cl2: 1,1'-Bis(diphenylphosphino)ferrocene palladium dichloride

[0420] [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II))

[0421] PMBNH2: 4-Methoxybenzylamine

[0422] THF: Tetrahydrofuran

[0423] Tween80: Tween 80

[0424] T3P: Propyl phosphate tricyclic anhydride solution

[0425] TEA: Triethylamine

[0426] TFA: trifluoroacetic acid

[0427] t-BuOK: Potassium tert-butoxide

[0428] t-Bu3P: Tri-tert-butylphosphine

[0429] Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

[0430] PE / EA: Petroleum ether / Ethyl acetate

[0431] LAH: Lithium Aluminum Hydride

[0432] Comparative Example 1

[0433] Preparation of Compound D1: 2-(2-Chlorophenyl)-N-{4-[(4-cyanobenzyl)oxy]-3- sulfamoylphenyl}acetamide

[0434]

[0435] Synthetic Route

[0436]

[0437] Preparation of Intermediate D1-IN-01 in Step (1)

[0438] The weighed intermediate D1-SM-01 (2.0 g, 9.012 mmol) was dissolved in 150 mL of THF, and intermediate D1-SM-02 (1.0 g, 7.51 mmol) and PPh3 (4.0 g, 15.02 mmol) were added. After addition, the temperature was lowered to 0°C, and DIAD (4.5 g, 22.53 mmol) was added dropwise. After addition, the temperature was naturally lowered to room temperature, and the reaction was carried out for 3 h. The reaction liquid was added with water, and EA was used for extraction. The organic phase was washed with saturated brine, dried over sodium sulfate, and the reaction liquid was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain 2.0 g of intermediate D1-IN-01 product as a white solid.

[0439] Preparation of intermediate D1-IN-02 in step (2)

[0440] The weighed intermediate D1-IN-01 (2.0 g, 6.003 mmol) was dissolved in 80 mL of ethanol and 20 mL of water, and iron powder (1.7 g, 30.017 mmol) and ammonium chloride (1.6 g, 30.017 mmol) were added. After addition, the reaction was carried out at 80°C for 2 h, and the product was generated. The reaction liquid was lowered to room temperature, quenched with saturated sodium bicarbonate solution, and adjusted to pH 8.0-10.0. EA was used for extraction, and the organic phase was washed with saturated brine, dried over sodium sulfate, and the reaction liquid was concentrated under reduced pressure to obtain 1.7 g of intermediate D1-IN-02 product as a light yellow solid. LC-MS: [M+H] + = 305.

[0441] Preparation of intermediate D1-IN-03 in step (3)

[0442] The weighed intermediate D1-IN-02 (1.7 g, 5.608 mmol) was dissolved in 80 mL of DCM, and 2-chlorobenzenacetic acid (intermediate 1-3) (1.15 g, 6.729 mmol), T3P (7.1 g, 11.216 mmol), and TEA (1.7 g, 16.824 mmol) were added. After addition, the reaction was carried out at room temperature for 1 h, and the reaction liquid was directly concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 2.4 g of intermediate D1-IN-03 product as a light yellow solid.

[0443] Preparation of intermediate D1-IN-04 in step (4)

[0444] Weighed intermediate D1-IN-03 (1.2 g, 2.633 mmol) was dissolved in 1,4-dioxane (40 mL), added intermediate 1-9 (benzyl mercaptan) (655 mg, 5.266 mmol), Pd2(dba)3 (240 mg, 0.263 mmol), Xantphos (153 mg, 0.263 mmol), DIEA (982 mg, 7.899 mmol) after adding, under the condition of nitrogen protection, 100°C, the reaction was carried out overnight, the reaction liquid was reduced to room temperature, added water, extracted with EA, the organic phase was washed with saturated brine, dried with sodium sulfate, the reaction liquid was directly concentrated under reduced pressure to obtain the crude product, the crude product was purified by silica gel column chromatography (PE / EA = 3 / 1 ~ 1 / 1) to obtain 900 mg of intermediate D1-IN-04 product as a light yellow solid. LC-MS: [M+H] = 499.10. +

[0445] Step (5) Preparation of compound D1

[0446] Intermediate D1-IN-04 (900 mg, 1.803 mmol) was dissolved in CH3CN (40 mL), AcOH (5 mL) and H2O (5 mL), added intermediate 1-11 (DCDMH) (711 mg, 3.607 mmol), reacted at room temperature for 10 min, the reaction liquid was added to the stirred ammonia water (10 mL), then stirred at room temperature for 10 min, the reaction liquid was added with water, extracted with EA, the combined organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, then the reaction liquid was directly concentrated under reduced pressure to obtain the crude product, the crude product was purified by Prep-HPLC to obtain 365.3 mg of compound D1 product as a white solid. LC-MS: [M+H] = 456.10. +

[0447] 1 H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.07 (d, J = 2.6 Hz, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.70 (dd, J = 8.5, 4.6 Hz, 3H), 7.42 (ddd, J = 11.2, 5.8, 3.7 Hz, 2H), 7.35 - 7.26 (m, 2H), 7.22 - 7.08 (m, 3H), 5.42 (s, 2H), 3.80 (s, 2H).

[0448] Comparative Example 2

[0449] Preparation of compound D2: 2-(2-chlorophenyl)-N-(4-((4-fluorobenzyl)oxy)-3- sulfamoylphenyl)acetamide

[0450] ​​

[0451] Synthesis route

[0452]

[0453] Preparation of intermediate D2-IN-01 in step (1)

[0454] The weighed intermediate D1-SM-01 (1.04 g, 4.757 mmol) was dissolved in 75 mL of THF, and intermediate D2-SM-01 (500 mg, 3.964 mmol) and PPh3 (2.08 g, 7.928 mmol) were added. After addition, the temperature was lowered to 0°C, and DIAD (2.4 g, 11.892 mmol) was added dropwise. After addition, the reaction was carried out at room temperature for 3 h. The reaction liquid was added with water, and extracted with EA. The organic phase was washed with saturated brine, and then dried with sodium sulfate. The reaction liquid was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 20:1) to obtain 1.1 g of intermediate D2-IN-01 product as a light yellow solid.

[0455] Preparation of intermediate D2-IN-02 in step (2)

[0456] The weighed intermediate D2-IN-01 (1.1 g, 3.373 mmol) was dissolved in 40 mL of ethanol and 10 mL of water, and iron powder (945 mg, 16.865 mmol) and ammonium chloride (902 mg, 16.865 mmol) were added. After addition, the reaction was carried out at 80°C for 2 h. The reaction liquid was lowered to room temperature, quenched with saturated sodium bicarbonate solution, and adjusted to pH 8.0-10.0. The product was extracted with EA, and the organic phase was washed with saturated brine, dried with sodium sulfate, and concentrated under reduced pressure to obtain 1.0 g of intermediate D2-IN-02 product as a light yellow solid.

[0457] Preparation of intermediate D2-IN-03 in step (3)

[0458] The weighed intermediate D2-IN-02 (1.0 g, 3.377 mmol) was dissolved in 40 mL of DCM, and 2-chlorobenzenacetic acid (692 g, 4.052 mmol), T3P (4.3 g, 6.754 mmol), and TEA (1.03 g, 10.131 mmol) were added. After addition, the reaction was carried out at room temperature for 1 h. The reaction liquid was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1-3 / 1) to obtain 900 mg of intermediate D2-IN-03 product as a light yellow solid.

[0459] Preparation of intermediate D2-IN-04 in step (4)

[0460] Weighed intermediate D2-IN-03 (900 mg, 2.202 mmol) was dissolved in 1,4-dioxane (30 mL), added intermediate 1-9 (benzyl mercaptan) (547 mg, 4.404 mmol), Pd2(dba)3 (201 mg, 0.221 mmol), Xantphos (128 mg, 0.221 mmol), DIEA (854 mg, 6.606 mmol), and protected with nitrogen at 100 °C overnight. The reaction solution was reduced to room temperature, water was added, and EA was used for extraction. The organic phase was washed with saturated brine, dried with sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1 ~ 1 / 1) to obtain 700 mg of intermediate D2-IN-04 product as a light yellow solid.

[0461] Step (5) Preparation of compound D2

[0462] Intermediate D2-IN-04 (700 mg, 1.422 mmol) was dissolved in CH3CN (40 mL), AcOH (5 mL), and H2O (5 mL), and intermediate 1-11 (DCDMH) (561 mg, 2.845 mmol) was added. The reaction solution was added to ammonia water (10 mL) under stirring at room temperature for 10 min, and then stirred at room temperature for 10 min. The reaction solution was added to water, and EA was used for extraction. The combined organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by Prep-HPLC obtained 256.6 mg of compound D2 product as a white solid. LC-MS: [M+H] + = 449.00.

[0463] 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.05 (d, J = 2.7 Hz, 1H), 7.70 (dd, J = 9.0, 2.7 Hz, 1H), 7.60 - 7.52 (m, 2H), 7.47 - 7.36 (m, 2H), 7.35 - 7.27 (m, 2H), 7.24 - 7.13 (m, 3H), 7.09 (s, 2H), 5.30 (s, 2H), 3.80 (s, 2H).

[0464] Example 1

[0465] Preparation of compound 1: N-(4-((3-acetylphenoxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide

[0466]

[0467] Synthetic route

[0468]

[0469] Preparation of intermediate 1-2 in step (1)

[0470] Intermediate 1-1 (10 g, 0.038 mol), iron powder (11 g, 0.196 mol), NH4Cl (20 g, 0.38 mol) were dissolved in ethanol / water (100 mL / 20 mL) and the reaction was stirred at 70 °C for 2 h. After work-up, water and EA were added to the reaction solution, and after stirring well, the EA phase was separated, the water phase was extracted with EA twice, and the EA phases were combined. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 10:1-5:1) to obtain intermediate 1-2. LC-MS: [M+H] + = 230.

[0471] Preparation of intermediate 1-4 in step (2)

[0472] Intermediate 1-2 (9 g, 0.039 mol), intermediate 1-3 (2-chlorobenzenacetic acid) (8 g, 0.0468 mol), TEA (12 g, 0.117 mol), T3P (25 g, 0.078 mol) were dissolved in DCM (90 mL), and the reaction was stirred at room temperature for 0.5 h. Water and DCM were added to the reaction solution, and after stirring well, the DCM phase was separated, the water phase was extracted with DCM twice, and the DCM phases were combined. After drying, the reaction solution was concentrated under reduced pressure to obtain the product. LC-MS: [M+H] + = 382.

[0473] Preparation of intermediate 1-5 in step (3)

[0474] Intermediate 1-4 (14 g, 0.037 mol) was dissolved in THF (100 mL) and cooled to 0 °C. LiAlH4(4.22 g, 0.111 mol) was added, and the reaction was stirred at room temperature for 10 min. After work-up, 1 mL of water and 3 mL of 2M NaOH aqueous solution were added to the reaction solution, followed by the addition of a large amount of EA, filtration, and concentration of the filtrate under reduced pressure to obtain the product. LC-MS: [M+H] + = 354.

[0475] Preparation of intermediate 1-6 in step (4)

[0476] Intermediate 1-5 (10 g, 0.028 mol) was dissolved in DCM (100 mL) and cooled to 0 °C. SOCl2(6.61 g, 0.056 mol) was added, the temperature was raised to room temperature, and the reaction was stirred for 1 h. After work-up, the reaction solution was concentrated under reduced pressure to obtain intermediate 1-6 (8.1 g). LC-MS: [M+H] + = 372.

[0477] Preparation of intermediate 1-8 in step (5)

[0478] Intermediate 1-6 (500 mg, 1.34 mmol), intermediate 1-7 (182 mg, 1.34 mmol), K2CO3 (370 mg, 2.68 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 1 h. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (20 mL) twice. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1 ~ 1 / 1) to obtain intermediate 1-8 (385 mg, yield 60.9%). LC-MS: [M+H] + = 472.

[0479] Preparation of intermediate 1-10 in step (6)

[0480] Intermediate 1-8 (385 mg, 0.82 mmol), intermediate 1-9 (303 mg, 2.45 mmol), Pd2(dba)3 (116 mg, 0.164 mmol), Xantphos (94 mg, 0.164 mmol), DIEA (316 mg, 2.449 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 1-10 (340 mg, yield 80.4%). LC-MS: [M+H] + = 516.

[0481] Preparation of compound 1 in step (7)

[0482] Intermediate 1-10 (340 mg, 0.6 mmol), intermediate 1-11 (DCDMH) (238 mg, 1.2 mmol) were dissolved in CH3CN (4 mL), AcOH (0.2 mL), and H2O (0.1 mL) and reacted at room temperature for 1 hour to obtain intermediate 1-12. TLC showed that the reaction was complete. The reaction solution was not separated, but was added dropwise to stirring ammonia water (10 mL). After stirring at room temperature for 0.5 hours, TLC showed that the reaction was complete. The reaction solution was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using an H2O / ACN system, and lyophilized to obtain compound 1 (2.5 mg). LC-MS: [M+H] + = 473.

[0483] 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.5, 2.2 Hz, 1H), 7.66 - 7.52 (m, 5H), 7.48 - 7.38 (m, 3H), 7.34 - 7.24 (m, 3H), 5.47 (s, 2H), 3.84 (s, 2H), 2.54 (s, 3H).

[0484] Intermediate 1-12 LC-MS: [M+H] + = 492.

[0485] The acyl chloride intermediates similar to Intermediate 1-12 in the following examples were not isolated and were directly reacted with ammonia water.

[0486] Example 2

[0487] Preparation of compound 2: 2-(2-chlorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3- sulfamoylphenyl)acetamide

[0488]

[0489] Synthetic route:

[0490]

[0491] Preparation of intermediate 2-2 in step (1)

[0492] Intermediate 1-6 (600 mg, 1.69 mmol), intermediate 2-1 (228 mg, 2.03 mmol), K2CO3 (467 mg, 3.384 mmol) were dissolved in DMF (15 mL) and stirred at 60 °C for 1 h. The reaction solution was extracted with ethyl acetate (20 mL) twice after adding water (50 mL), and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain intermediate 2-2 (360 mg, as a light yellow solid).

[0493] Preparation of intermediate 2-4 in step (3)

[0494] Intermediate 2-2 (360 mg, 0.802 mmol), intermediate 1-9 (benzyl mercaptan) (150 mg, 1.203 mmol), Pd2(dba)3 (74 mg, 0.08 mmol), Xantphos (47 mg, 0.08 mmol), DIEA (312 mg, 2.407 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen protection, and the mixture was reacted at 100 °C overnight. The reaction solution was added with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1 ~ 5 / 1) to obtain intermediate 2-4 (340 mg, yellow solid).

[0495] Step (4) Preparation of compound 2

[0496] Intermediate 2-4 (340 mg, 0.691 mmol), intermediate 1-11 (DCDMH) (409 mg, 2.073 mmol) were dissolved in CH3CN (8 mL), AcOH (1 mL) and H2O (1 mL), and the mixture was reacted at room temperature for 0.5 h. The reaction solution was added dropwise to stirring ammonia water (2 mL), stirred at room temperature for 10 min, added with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain compound 2 (29 mg, white solid). LC-MS: [M+H] + = 449.05.

[0497] 1 H NMR (600 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 8.5, 2.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.58 (s, 2H), 7.46 - 7.41 (m, 2H), 7.33 - 7.29 (m, 2H), 7.16 - 7.11 (m, 2H), 7.05 - 7.01 (m, 2H), 5.40 (s, 2H), 3.86 (s, 2H).

[0498] Example 2-1

[0499] Preparation of compound 2-1: 2-(2-chlorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3- sulfamoylphenyl)acetamide

[0500]

[0501] Synthetic route:

[0502]

[0503] Preparation of intermediate 2-8 in step (1)

[0504] Intermediate 2-7 (8 g, 33.9 mmol) was added to ammonia water (100 mL) and THF (20 mL), and the reaction was stirred at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate 2-8 (11.0 g, white solid).

[0505] Preparation of intermediate 2-9 in step (2)

[0506] Intermediate 2-8 (11 g, 50.9 mmol) and DMF-DMA (30.3 g, 254 mmol) were dissolved in DMF (150 mL) and reacted at room temperature for 1 hour. After dilution with H2O (200 mL), extraction was performed twice with EA (100 mL). The EA phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2-9 (10.0 g, red solid). LC-MS: [M+H] + = 272.05.

[0507] 1 H NMR (400 MHz, DMSO-d6) 8.09 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 8.0, 2.4 Hz, 1H), 5.28 (s, 2H), 3.12 (s, 3H), 2.92 (s, 3H), 2.35 (s, 3H).

[0508] Preparation of intermediate 2-10 in step (3)

[0509] Intermediate 2-9 (9 g, 33.2 mmol), iron powder (18.5 g, 332 mmol), and NH4Cl (26.6 g, 498 mmol) were dissolved in EtOH (120 mL) and water (24 mL) and reacted at 60°C for 1 hour. The ethanol was evaporated from the reaction solution, filtered, water (200 mL) was added to the filtrate, and extraction was performed twice with EA (80 mL). The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 2-10 (6.20 g, purity 98.9%, yellow solid). LC-MS: [M+H] + = 242.1.

[0510] 1H NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.12 (d, J = 2.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.61 (dd, J = 8.0, 2.4 Hz, 1H), 5.28 (s, 2H), 3.12 (s, 3H), 2.92 (s, 3H), 2.35 (s, 3H).

[0511] Preparation of intermediate 2-11 in step (4)

[0512] Intermediate 2-10 (5.5 g, 22.8 mmol), Boc20 (7.45 g, 34.2 mmol), DIEA (5.89 g, 45.6 mmol) were dissolved in DMF (51.5 mL) and reacted at 60 °C for 12 hours. The reaction was cooled to room temperature, diluted with H20 (100 mL), and then extracted with EA (30 mL) three times. The EA phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1-2 / 1) to obtain intermediate 2-11 (3.60 g, purity 86.7%, white solid). LC-MS: [M+H] + = 342.1.

[0513] 1 H NMR (400 MHz, CD3OD-d4) δ 8.12 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.4, 2.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 3.15 (s, 3H), 3.03 (t, J = 2.0 Hz, 3H), 2.56 (s, 3H), 1.50 (s, 9H).

[0514] Preparation of intermediate 2-12 in step (5)

[0515] Intermediate 2-11 (1.30 g, 3.81 mmol), AIBN (0.187 g, 1.14 mmol), NBS (0.881 g, 4.95 mmol) were added to CCI4(51.5 mL) and reacted at 75 °C for 2 h. The reaction was cooled to room temperature and added dropwise to a mixture of intermediate 2-1 (4-fluorophenol) (0.133 g, 1.19 mmol), K2CO3(0.411 g, 2.97 mmol) and DMF (6 mL). The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The reaction was diluted with H2O (100 mL) and extracted with DCM (30 mL) twice. The organic phase was washed with saturated brine twice, dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1-5 / 1) to give intermediate 2-12 (150 mg, 80% purity, yellow solid). LC-MS: [M+H] = 452.1. +

[0516] 1 H NMR (400 MHz, CD3OD-d4) 8.13 (d, J = 7.2 Hz, 2H), 7.54 (d, J = 2.4 Hz, 2H), 7.02 - 6.94 (m, 4H), 5.47 (s, 2H), 3.09 (s, 3H), 2.99 (s, 3H), 1.52 (s, 9H).

[0517] Step (6) Preparation of intermediate 2-13

[0518] Intermediate 2-12 (150 mg, 332 pmol) was added to HC1·EA (4 M, 2 mL) and reacted at room temperature for 2 h. LCMS showed the reaction was complete. The reaction was concentrated under reduced pressure to give intermediate 2-13 (90.0 mg, 85.5% purity, red solid). LC-MS: [M+H] = 352.1. +

[0519] Step (7) Preparation of intermediate 2-14

[0520] ​​Intermediate 1-3 (2-chlorobenzenecetic acid) (48.1 mg, 281 μmol), HATU (146 mg, 384 μmol), DIEA (99.3 mg, 768 μmol) were added to DMF (2.5 mL), after reaction at room temperature for 0.5 h, intermediate 2-13 (90.0 mg, 256 μmol) was added to the reaction. Reaction at room temperature for 12 h. After dilution with H2O (10 mL), EA (5 mL) was added to extract twice, the organic phase was washed with saturated brine twice, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative thin-layer chromatography (PE / EA = 1 / 1) to obtain intermediate 2-14 (30.0 mg, 85.0% purity, yellow solid). LC-MS: [M+H] = 504.1. +

[0521] 1 H NMR (400 MHz, CD3OD-d4) 8.05 (s, 1H), 7.92 (dd, J = 8.4, 2.0 Hz, 1H), 7.83 (d, J = 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.47 - 7.38 (m, 3H), 7.32 - 7.29 (m, 2H), 6.95 - 6.86 (m, 4H), 5.53 (s, 2H), 3.87 (s, 2H), 3.04 (s, 3H), 2.96 (s, 3H).

[0522] Step (8) Preparation of compound 2

[0523] Intermediate 2-14 (30.0 mg, 59.5 μmol), hydrazine hydrate (15.0 mg, 298 μmol) were added to MeOH (0.5 mL) and THF (0.5 mL) solvent, and the reaction was carried out at 27 °C for 1 h. The reaction was concentrated under reduced pressure to obtain a crude product, which was separated by prep-HPLC using a FA.H2O / ACN system. Compound 2 (11.4 mg, 99.8% purity, white powder) was obtained after lyophilization of the preparation. LC-MS: [M+H] = 449.05. +

[0524] 1 ​​H NMR (400 MHz, DMSO-d6) 10.59 (s, 1H), 8.46 (s, 1H), 8.26 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.56 (s, 1H), 7.44 - 7.38 (m, 2H), 7.29 (dd, J = 5.6, 3.2 Hz, 2H), 7.11 (dd, J = 12.0, 5.6 Hz, 2H), 7.03 - 6.98 (m, 2H), 5.38 (s, 2H), 3.84 (s, 2H).

[0525] Example 3

[0526] Compound 3: 2-(2-chlorophenyl)-N-(4-(((5-fluoropyridin-2-yl)oxy)methyl)-3- sulfamoylphenyl)acetamide

[0527]

[0528] Synthetic route

[0529]

[0530] Preparation of intermediate 3-2 in step (1)

[0531] Intermediate 1-5 (500 mg, 1.41 mmol) was dissolved in THF (4 mL), intermediate 3-1 (162 mg, 1.41 mmol), t-BuOK (317.9 mg, 2.82 mmol) was added and stirred at room temperature for 1 h. The reaction was stopped and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA = 10:1 ~ 1:1) to obtain intermediate 3-2 (145 mg, yield 33.4%, light yellow solid). LC-MS: [M+H] + = 489.

[0532] Preparation of intermediate 3-3 in step (2)

[0533] Intermediate 3-2 (87 mg, 0.193 mmol), intermediate 1-9 (benzyl mercaptan) (71.6 mg, 0.578 mmol), Pd2(dba)3 (27.4 mg, 0.0386 mmol), Xantphos (22 mg, 0.0386 mmol), DIEA (74.5 mg, 0.578 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 3-3 (50 mg, yield 52.9%, yellow solid). LC-MS: [M+H]+ = 492.

[0534] Step (3) Preparation of compound 3

[0535] Intermediate 3-3 (50 mg, 0.102 mmol), intermediate 1-11 (DCDMH) (40 mg, 0.204 mmol) were dissolved in CH3CN (2 mL), AcOH (0.1 mL) and H2O (0.1 mL) and reacted at room temperature for 1 hour. The reaction solution was added dropwise to stirring ammonia water (5 mL), and then stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL) and then extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using an H2O / ACN system, and then lyophilized to obtain compound 3 (12.4 mg, purity 99.745%, white solid). LC-MS: [M+H] + = 450.

[0536] 1 H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 3.1 Hz, 1H), 7.79 (dd, J = 8.5, 2.0 Hz, 1H), 7.72 (ddd, J = 9.0, 8.1, 3.1 Hz, 1H), 7.56 (d, J = 8.5 Hz, 1H), 7.48 (s, 1H), 7.45 - 7.38 (m, 2H), 7.33 - 7.25 (m, 2H), 7.01 (dd, J = 9.1, 3.6 Hz, 1H), 5.64 (s, 2H), 3.84 (s, 2H).

[0537] Example 4

[0538] Compound 4: N-(4-((4-chlorophenoxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide

[0539]

[0540] Synthetic route:

[0541]

[0542] Step (1) Preparation of intermediate 4-2

[0543] Intermediate 1-6 (500 mg, 1.34 mmol), intermediate 4-1 (170 mg, 1.3 mmol), K2CO3(358 mg, 2.6 mmol) were dissolved in DMF (10 mL), stirred at 60 °C for 1 h. The reaction solution was added with water (50 mL) and extracted with ethyl acetate (20 mL) twice. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column to obtain intermediate 4-2 (280 mg, yield 46.3%, yellow solid). LC-MS: [M+H]=465. + = 465.

[0544] Preparation of intermediate 4-3 in step (2)

[0545] Intermediate 4-2 (280 mg, 0.6 mmol), intermediate 1-9 (benzyl mercaptan) (148.8 mg, 1.2 mmol), Pd2(dba)3(85.3 mg, 0.12 mmol), Xantphos (70 mg, 0.12 mmol), DIEA (232.2 mg, 1.8 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 115 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 4-3 (230 mg, yield 75.7%, yellow solid). LC-MS: [M+H]=508. + = 508.

[0546] Preparation of compound 4 in step (3)

[0547] Intermediate 4-3 (230 mg, 0.45 mmol), intermediate 1-11 (DCDMH) (196 mg, 0.9 mmol) were dissolved in CH3CN (4 mL), AcOH (0.2 mL) and H2O (0.2 mL) and reacted at room temperature for 1 h. The reaction solution was added dropwise to stirring ammonia water (10 mL) and stirred at room temperature for 0.5 h. The reaction solution was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC with H2O / ACN system, and freeze-dried to obtain compound 4 (24.8 mg, purity 95.2%, white solid). LC-MS: [M+H]=465. + = 465.

[0548] 1H NMR (600 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 8.4, 2.2 Hz, 1H), 7.64 - 7.51 (m, 3H), 7.46 - 7.36 (m, 2H), 7.36 - 7.18 (m, 4H), 7.09 - 6.97 (m, 2H), 5.40 (s, 2H), 3.84 (s, 2H).

[0549] Example 5

[0550] Compound 5: 2-(2-chlorophenyl)-N-(4-((2,4-dichlorophenoxy)methyl)-3- sulfamoylphenyl)acetamide

[0551]

[0552] Synthetic Route

[0553]

[0554] Step (1) Preparation of compound 5

[0555] Intermediate 4-3 (230 mg, 0.45 mmol), intermediate 1-11 (DCDMH) (196 mg, 0.9 mmol) were dissolved in CH3CN (4 mL), AcOH (0.2 mL) and H2O (0.2 mL) and reacted at room temperature for 1 hour. After the reaction solution was added dropwise to stirring ammonia water (10 mL) and stirred at room temperature for 0.5 hours. After the reaction solution was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC with a H2O / ACN system, and compound 5 (50 mg, purity 99.7%, white solid) was obtained after lyophilization. LC-MS: [M+H] + = 499.

[0556] 1 H NMR (600 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 8.4, 2.2 Hz, 1H), 7.64 - 7.51 (m, 3H), 7.46 - 7.36 (m, 2H), 7.36 - 7.18 (m, 4H), 7.09 - 6.97 (m, 2H), 5.40 (s, 2H), 3.84 (s, 2H).

[0557] Example 6

[0558] Preparation of compound 6: 2-(2-chlorophenyl)-N-(4-((4-cyanophenoxy)methyl)-3- sulfamoylphenyl)acetamide

[0559]

[0560] Synthetic route:

[0561]

[0562] Preparation of intermediate 6-2 in step (1)

[0563] Intermediate 1-6 (600 mg, 1.62 mmol), intermediate 6-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and warmed to 60 °C and stirred for 3 h. After work-up, water and EA were added to the reaction solution, and after stirring well, the EA phase was separated, and the water phase was extracted with EA three times, and the EA phases were combined and concentrated under reduced pressure to obtain the product. The reaction was successful, and intermediate 6-2 was obtained. LC-MS: [M+H] + = 455 / 457.

[0564] Preparation of intermediate 6-3 in step (2)

[0565] Intermediate 6-2 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL) and protected with nitrogen, and then stirred at 110 °C overnight. After work-up, water and EA were added to the reaction solution, and after stirring well, the EA phase was separated, and the water phase was extracted with EA twice, and the EA phases were combined and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (PE / EA = 10:1-6:1), and the column effluent was concentrated under reduced pressure to obtain intermediate 6-3. LC-MS: [M+H] + = 499 / 501.

[0566] Preparation of compound 6 in step (3)

[0567] Intermediate 6-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. Then the reaction was added dropwise into stirred ammonia water (20 mg, 1.20 mmol) and stirred at room temperature for 10 min. The reaction was concentrated under reduced pressure to give a crude product, which was purified by prep-HPLC with H2O / ACN system, and then lyophilized to give compound 6. LC-MS: [M+H]=456 / 458. +

[0568] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.82 - 7.76 (m, 3H), 7.59 (d, J = 6.7 Hz, 3H), 7.44 - 7.38 (m, 2H), 7.32 - 7.25 (m, 2H), 7.19 - 7.14 (m, 2H), 5.49 (s, 2H), 3.84 (s, 2H).

[0569] Example 7

[0570] Preparation of compound 7: 2-(2-chlorophenyl)-N-(4-((2,4-difluorophenoxy)methyl)-3- sulfamoylphenyl)acetamide

[0571]

[0572] Synthetic route:

[0573]

[0574] Preparation of intermediate 7-2 in step (1)

[0575] Intermediate 1-6 (600 mg, 1.62 mmol), intermediate 7-1 (223 mg, 1.60 mmol), K2CO3 (440 mg, 3.20 mmol) were dissolved in DMF (10 mL) and stirred at 60 °C for 1 h. The reaction was extracted with water (50 mL) and ethyl acetate (20 mL) twice, and the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 4 / 1) to give intermediate 7-2. LC-MS: [M+H]=465. +

[0576] Preparation of intermediate 7-3 in step (3)

[0577] ​​Intermediate 7-2 (520 mg, 1.1 mmol), intermediate 1-9 (benzyl mercaptan) (276 mg, 2.2 mmol), Pd2(dba)3 (156.4 mg, 0.22 mmol), Xantphos (115.6 mg, 0.22 mmol), DIEA (424 mg, 3.3 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 115 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 7-3. LC-MS: [M+H] + = 510.

[0578] Step (4) Preparation of compound 7

[0579] Intermediate 7-3 (384 mg, 0.75 mmol), intermediate 1-11 (DCDMH) (297 mg, 1.5 mmol) were dissolved in CH3CN (4 mL), AcOH (0.2 mL) and H2O (0.2 mL) and reacted at room temperature for 1 h. The reaction solution was added dropwise to stirring ammonia water (10 mL) and stirred at room temperature for 0.5 h. The reaction solution was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC with H2O / ACN system, and freeze-dried to obtain compound 7. LC-MS: [M+H] + = 467.

[0580] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.27 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.55 (s, 2H), 7.46 - 7.38 (m, 2H), 7.37 - 7.26 (m, 3H), 7.18 (td, J = 9.4, 5.5 Hz, 1H), 7.01 (t, J = 8.8 Hz, 1H), 5.45 (s, 2H), 3.85 (s, 2H).

[0581] Example 8

[0582] Preparation of compound 8: 2-(2-chlorophenyl)-N-(4-(((4,5-dichloro-1-methyl-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0583]

[0584] Synthetic route

[0585]

[0586] Step 1: Preparation of intermediate 8-2

[0587] The weighed intermediate 1-6 (500 mg, 1.34 mmol) was dissolved in THF (20 mL), and intermediate 8-1 (160 mg, 1.608 mmol), Ag2CO3 (740 mg, 2.68 mmol) were added. After refluxing at 70 °C overnight, LCMS monitoring showed that the product was generated. The reaction solution was extracted with ethyl acetate twice, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 2 / 1) to obtain intermediate 8-2. LC-MS: [M+H] + = 434.

[0588] Step 2: Preparation of intermediate 8-3

[0589] The weighed intermediate 8-2 (310 mg, 0.713 mmol) was dissolved in 1,4-dioxane (10 mL), and intermediate 1-9 (benzyl mercaptan) (178 mg, 1.423 mmol), Pd2(dba)3 (66 mg, 0.071 mmol), Xantphos (42 mg, 0.071 mmol), DIEA (277 mg, 2.139 mmol) were added. After reaction at 100 °C overnight, the reaction solution was added with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain intermediate 8-3. LC-MS: [M+Na] + = 500.15.

[0590] Step 3: Preparation of compound 8

[0591] Intermediate 8-3 (60 mg, 0.125 mmol) was dissolved in CH3CN (2 mL), AcOH (0.25 mL) and H2O (0.25 mL), and intermediate 1-11 (DCDMH) (50 mg, 0.251 mmol) was added. After reaction at room temperature for 5 min, the reaction solution was added dropwise to stirring ammonia water (0.5 mL), and the reaction solution was added with water, extracted with EA, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain compound 8. LC-MS: [M+H] + = 503.

[0592] 1H NMR (400MHz, DMSO-d6) δ10.66(s,1H),8.31(d,J=2.1Hz,1H),7.88(dd,J=8.4,2.2Hz,1H),7.64–7.55 (m,3H),7.44(ddd,J=9.5,5.1,2.3Hz,2H),7.35–7.29(m,2H),5.66(s,2H),3.88(s,2H),3.25(s,3H).

[0593] Example 9

[0594] Preparation of Compound 9: 2-(2-chlorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-aminosulfonylphenyl)acetamide

[0595]

[0596] Synthesis route:

[0597]

[0598] Step (1) Preparation of intermediate 9-2

[0599] Intermediate 1-6 (600 mg, 1.62 mmol), intermediate 9-1 (280 mg, 1.95 mmol), and K₂CO₃ (447 mg, 3.24 mmol) were dissolved in DMF (10 mL), and the mixture was heated to 60 °C and stirred for 3 h. For post-treatment, water and EA were added to the reaction solution, and after thorough stirring, the EA phase was separated. The aqueous phase was then extracted three times with EA, and the EA phases were combined and concentrated under reduced pressure to obtain intermediate 9-2. LC-MS: [M+H] + =449.

[0600] Preparation of intermediate 9-3 in step (2)

[0601] Intermediate 9-2 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), and Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen protection and stirred overnight at 110 °C. For post-processing, water and EA were added to the reaction solution, and after thorough stirring, the EA phase was separated. The aqueous phase was extracted twice with EA, and the EA phases were combined. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10:1-6:1), and concentrated under reduced pressure to obtain the crude product. The crude product was then purified by preparative silica gel column chromatography to obtain intermediate 9-3. LC-MS: [M+H] + =493.

[0602] Preparation of intermediate 9-4 in step (3)

[0603] Intermediate 9-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction was added dropwise to stirred ammonia (20 mg, 1.20 mmol) at room temperature and stirred for 10 min. Work-up, the reaction was concentrated under reduced pressure to give a crude product, which was purified by prep-HPLC and lyophilized to give compound 9. LC-MS: [M+H] + = 450.

[0604] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.95 (dd, J = 3.0, 1.8 Hz, 1H), 7.82 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.58 (s, 2H), 7.47 - 7.36 (m, 2H), 7.35 - 7.25 (m, 2H), 7.14 (dd, J = 8.9, 3.4 Hz, 1H), 5.45 (s, 2H), 3.84 (s, 2H).

[0605] Example 10

[0606] Preparation of compound 10: 2-(2-chlorophenyl)-N-(4-((3-cyano-4- fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0607]

[0608] Synthetic route

[0609]

[0610] Preparation of intermediate 10-2 in step (1)

[0611] Intermediate 1-6 (600 mg, 1.62 mmol), intermediate 10-1 (220 mg, 1.6 mmol), K2CO3 (440 mg, 3.2 mmol) were dissolved in DMF (10 mL) and stirred at 60 °C for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (20 mL) twice. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column chromatography to give intermediate 10-2. LC-MS: [M+H] = 473. +

[0612] Step (2) Preparation of intermediate 10-3

[0613] Intermediate 10-2 (450 mg, 0.95 mmol), intermediate 1-9 (benzyl mercaptan) (235 mg, 1.9 mmol), Pd2(dba)3 (90 mg, 0.1 mmol), Xantphos (60 mg, 0.1 mmol), DIEA (367 mg, 2.85 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 115 °C for 16 h. The reaction was concentrated under reduced pressure to give a crude product. The crude product was purified by silica gel column (PE / EA = 5 / 1 ~ 3 / 1) to give intermediate 10-3. LC-MS: [M+H] = 517. +

[0614] Step (4) Preparation of compound 10

[0615] Intermediate 10-3 (200 mg, 0.38 mmol), intermediate 1-11 (DCDMH) (190 mg, 0.96 mmol) were dissolved in CH3CN (4 mL), AcOH (0.2 mL), and H2O (0.2 mL) and reacted at room temperature for 1 h. The reaction was added dropwise to stirring ammonia water (10 mL) and then stirred at room temperature for 0.5 h. The reaction was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by prep-HPLC using a H2O / ACN system, and lyophilized to give compound 10. LC-MS: [M+H] = 474. +

[0616] 1 ​​​H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.26 (s, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.67 - 7.52 (m, 4H), 7.45 (dt, J = 14.2, 8.4 Hz, 4H), 7.33 - 7.25 (m, 2H), 5.42 (s, 2H), 3.85 (s, 2H).

[0617] Example 11

[0618] Preparation of compound 11: N-(4-((3-chloro-4-fluorophenoxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

[0619]

[0620] Synthetic route:

[0621]

[0622] Preparation of intermediate 11-2 in step (1)

[0623] Intermediate 1-6 (600 mg, 1.62 mmol), intermediate 11-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF, and the reaction was stirred at 60 °C for 3 h. After work-up, water and EA were added to the reaction solution, and after sufficient stirring, the EA phase was separated, and the water phase was extracted with EA three times. The EA phases were combined and concentrated under reduced pressure to obtain intermediate 11-2. LC-MS: [M+H] + = 482.

[0624] Preparation of intermediate 11-3 in step (2)

[0625] Intermediate 11-2 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction was stirred at 110 °C overnight under nitrogen protection. After work-up, water and EA were added to the reaction solution, and after sufficient stirring, the EA phase was separated, and the water phase was extracted with EA twice. The EA phases were combined and concentrated under reduced pressure to obtain a crude product, which was separated and purified by preparative silica gel column chromatography (PE / EA = 10:1-6:1) to obtain an effluent, which was concentrated under reduced pressure to obtain intermediate 11-3 (yellow solid product 290 mg). LC-MS: [M+H] + = 526.

[0626] Preparation of compound 11 in step (3)

[0627] Intermediate 11-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), and then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction was added dropwise to stirred ammonia water (20 mg, 1.20 mmol) and stirred at room temperature for 10 min. After treatment, the reaction was concentrated under reduced pressure to obtain a crude product, which was purified by preparative high performance liquid chromatography, and freeze-dried to obtain compound 11. LC-MS: [M+H] + = 483.

[0628] 1 H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.25 (s, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.58 (s, 2H), 7.46 - 7.23 (m, 6H), 7.05 - 6.97 (m, 1H), 5.39 (s, 2H), 3.84 (s, 2H).

[0629] Example 12

[0630] Preparation of compound 12: 2-(2-chlorophenyl)-N-(4-((3-(methylsulfonyl)phenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0631]

[0632] Synthetic route:

[0633]

[0634] Preparation of intermediate 12-2 in step (1)

[0635] Intermediate 1-6 (200 mg, 0.54 mmol), intermediate 12-1 (100 mg, 0.58 mmol), K2CO3 (152 mg, 1.1 mmol) were dissolved in DMF (4 mL) and stirred at room temperature for 2 h. The reaction was extracted with water (20 mL) and then ethyl acetate (10 mL) twice, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 12-2. LC-MS: [M+H] + = 508.

[0636] Preparation of intermediate 12-3 in step (2)

[0637] Intermediate 12-2 (180 mg, 0.35 mmol), intermediate 1-9 (benzyl mercaptan) (130 mg, 1.05 mmol), Pd2(dba)3 (32 mg, 0.035 mmol), Xantphos (20 mg, 0.035 mmol), DIEA (135 mg, 1.05 mmol) were dissolved in 1,4-dioxane (2 mL) and reacted at 115 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 12-3. LC-MS: [M+H] + = 552.

[0638] Step (3) Preparation of compound 12

[0639] Intermediate 12-3 (150 mg, 0.27 mmol), intermediate 1-11 (DCDMH) (108 mg, 0.54 mmol) were dissolved in CH3CN (4 mL), AcOH (0.2 mL) and H2O (0.1 mL) and reacted at room temperature for 1 h. The reaction solution was added dropwise to stirring ammonia water (5 mL), which was then stirred at room temperature for 0.5 h. The reaction solution was diluted with water (10 mL) and then extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using a H2O / ACN system, and then lyophilized to obtain compound 12. LC-MS: [M+H] + = 509.

[0640] 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.83 (dd, J = 8.4, 2.2 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.59 (t, J = 3.8 Hz, 2H), 7.56 - 7.53 (m, 1H), 7.53 - 7.49 (m, 1H), 7.46 - 7.38 (m, 2H), 7.35 (ddd, J = 8.2, 2.4, 1.0 Hz, 1H), 7.30 (ddd, J = 5.2, 4.2, 3.0 Hz, 2H), 5.49 (s, 2H), 3.85 (s, 2H), 3.21 (s, 3H).

[0641] Example 13

[0642] Preparation of compound 13: 2-(2-chlorophenyl)-N-(4-(((1,1-dioxotetrahydrothiophen-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0643]

[0644] Reference Example 1. LC-MS: [M+H] + = 473.0

[0645] Example 14

[0646] Compound 14: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydrofuran-3- yl)oxy)methyl)phenyl)acetamide

[0647]

[0648] Synthetic route:

[0649]

[0650] Preparation of intermediate 14-2 in step (1)

[0651] Intermediate 1-6 (400 mg, 1.07 mmol), intermediate 14-1 (113.2 mg, 1.29 mmol), K2CO3 (295.3 mg, 2.14 mmol) were dissolved in DMF (5 mL), stirred at 60 °C for 1 h. The reaction solution was extracted with ethyl acetate (20 mL) twice after adding water (50 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 14-2. LC-MS: [M+H] + = 423.

[0652] Preparation of intermediate 14-3 in step (2)

[0653] Intermediate 14-2 (70 mg, 0.115 mmol), intermediate 1-9 (benzyl mercaptan) (61.4 mg, 0.495 mmol), Pd2(dba)3 (23.4 mg, 0.033 mmol), Xantphos (19 mg, 0.033 mmol), DIEA (63.8 mg, 0.495 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 14-3. LC-MS: [M+H] + = 468.

[0654] Preparation of compound 14 in step (3)

[0655] Intermediate 14-3 (50 mg, 0.107 mmol), intermediate 1-11 (DCDMH) (42.1 mg, 0.214 mmol) were dissolved in CH3CN (2 mL), AcOH (0.1 mL) and H2O (0.1 mL) and reacted at room temperature for 1 hour. The reaction was added dropwise to stirring ammonia water (5 mL) and stirred at room temperature for 0.5 hours. The reaction was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC with a H2O / ACN system, and compound 14 was obtained by freeze-drying the preparation liquid. LC-MS: [M+H]=424. +

[0656] 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 2H), 8.38 (s, 8H), 8.24 (s, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.69 - 7.29 (m, 8H), 7.28 (s, 1H), 5.45 (s, 2H), 5.19 (s, 2H), 3.90 (s, 3H), 3.85 (s, 5H), 4.40 - 2.48 (m, 55H), 2.48 (s, 10H), 2.48 (s, 13H), 2.15 (dt, J = 14.4, 8.2 Hz, 2H), 1.97 (dd, J = 12.6, 6.2 Hz, 14H), 3.80 - 3.69 (m, 5H), 2.20 - 2.11 (m, 2H).

[0657] Example 15

[0658] Preparation of compound 15: N-(4-((3-acetyl-4-fluorophenoxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

[0659]

[0660] Synthetic route:

[0661]

[0662] Preparation of intermediate 15-2 in step (1)

[0663] ​Intermediate 1-6 (376 mg, 1.04 mmol), intermediate 15-1 (160 mg, 1.04 mmol), and K₂CO₃ (287 mg, 2.08 mmol) were dissolved in DMF (5 mL) and stirred at 60 °C for 1 h. The reaction mixture was then extracted twice with ethyl acetate (20 mL) after adding water (50 mL). The combined organic phases were washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 15-2. LC-MS: [M+H] + =490.

[0664] Preparation of intermediate 15-3 in step (2)

[0665] Intermediate 15-2 (87 mg, 0.18 mmol), intermediate 1-9 (benzyl mercaptan) (43.4 mg, 0.35 mmol), Pd2(dba)3 (24.9 mg, 0.035 mmol), Xantphos (20.2 mg, 0.035 mmol), and DIEA (69.7 mg, 0.54 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain intermediate 15-3. LC-MS: [M+H] + =534.

[0666] Step (3) Preparation of intermediate 15

[0667] Intermediate 15-3 (80 mg, 0.15 mmol) and intermediate 1-11 (59 mg, 0.3 mmol) were dissolved in CH3CN (2 mL), AcOH (0.1 mL), and H2O (0.1 mL) and reacted at room temperature for 1 hour. The reaction solution was added dropwise to ammonia water (10 mL) under stirring, and then stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL) and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC using an H2O / ACN system, and the prepared solution was lyophilized to obtain compound 15. LC-MS: [M+H] + =491.

[0668] 1H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.25(d,J=2.1Hz,1H),7.81(dd,J=8.4,2.2Hz,1H),7.63(d,J=8.5Hz,3H),7.5 7(s,1H),7.47–7.39(m,1H),7.38–7.35(m,0H),7.33–7.24(m,2H),5.42(s,2H),3.84(s,2H),2.55(d,J=4.3Hz,3H).

[0669] Example 16

[0670] Preparation of Compound 16: 2-(2-chlorophenyl)-N-(3-aminosulfonyl-4-((p-toluoxy)methyl)phenyl)acetamide

[0671]

[0672] Synthesis route:

[0673]

[0674] Step (1) Preparation of intermediate 16-2

[0675] Intermediate 1-6 (500 mg, 1.34 mmol), intermediate 16-1 (140 mg, 1.34 mmol), and K₂CO₃ (358 mg, 2.59 mmol) were dissolved in DMF (10 mL) and stirred at 60 °C for 1 h. The reaction mixture was then extracted twice with ethyl acetate (20 mL) after adding water (50 mL). The combined organic phases were washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography to obtain intermediate 16-2. LC-MS: [M+H] + =444.

[0676] Preparation of intermediate 16-3 in step (2)

[0677] Intermediate 16-2 (280 mg, 0.63 mmol), intermediate 1-9 (benzyl mercaptan) (150 mg, 1.26 mmol), Pd2(dba)3 (120 mg, 0.18 mmol), Xantphos (105 mg, 0.18 mmol), and DIEA (240 mg, 1.88 mmol) were dissolved in 1,4-dioxane (4 mL) and reacted at 110 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain intermediate 16-3. LC-MS: [M+H] + =488.

[0678] Step (4) Preparation of compound 16

[0679] Intermediate 16-3 (180 mg, 0.37 mmol), intermediate 1-11 (145 mg, 0.74 mmol) were dissolved in CH3CN (4 mL), AcOH (0.2 ml) and H2O (0.2 ml) and reacted at room temperature for 1 hour. The reaction solution was added dropwise to stirring ammonia water (10 mL) and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC with H2O / ACN system, and compound 16 was obtained by freeze-drying the preparation solution. LC-MS: [M+H] + = 445.

[0680] 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.25 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.55 (s, 2H), 7.45 - 7.38 (m, 2H), 7.33 - 7.26 (m, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.38 (s, 2H), 3.84 (s, 2H), 2.21 (s, 3H).

[0681] Example 17

[0682] Preparation of compound 17: 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-methylphenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0683]

[0684] Synthetic route:

[0685]

[0686] Preparation of intermediate 17-2 in step (1)

[0687] Intermediate 17-1 (203 mg, 1.608 mmol), K2CO3(369 mg, 2.68 mmol) were dissolved in DMF (20 mL), stirred at room temperature for 15 min, then intermediate 1-6 (500 mg, 1.34 mmol) was added, and the reaction was allowed to proceed at room temperature for 2 h. The reaction solution was added to water and extracted with ethyl acetate twice. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain intermediate 17-2. LC-MS: [M+H]=462. +

[0688] Step (2) Preparation of intermediate 17-3

[0689] The weighed intermediate 17-2 (180 mg, 0.389 mmol) was dissolved in 1,4-dioxane (5 mL), and intermediate 1-9 (benzyl mercaptan) (73 mg, 0.583 mmol), Pd2(dba)3(36 mg, 0.039 mmol), Xantphos (23 mg, 0.039 mmol), DIEA (151 mg, 1.167 mmol) were added, and the reaction was allowed to proceed at 90°C overnight. The reaction solution was added to water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain intermediate 17-3. LC-MS: [M+H]=506. +

[0690] Step (3) Preparation of compound 17

[0691] Intermediate 17-3 (170 mg, 0.336 mmol) was dissolved in CH3CN (4 mL), AcOH (0.5 mL), and H2O (0.5 mL), and intermediate 1-11 (DCDMH) (133 mg, 0.672 mmol) was added, and the reaction was allowed to proceed at room temperature for 0.5 h. The reaction solution was added dropwise to stirring ammonia water (1 mL) and stirred at room temperature for 10 min. The reaction solution was added to water and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by Prep-HPLC to obtain compound 17. LC-MS: [M+H]=463. +

[0692] 1 ​​​H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.29 (s, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 4.8 Hz, 2H), 7.47 - 7.28 (m, 5H), 7.22 - 6.98 (m, 2H), 5.47 (d, J = 8.3 Hz, 2H), 3.87 (s, 2H), 2.31 (d, J = 16.0 Hz, 1H), 2.21 (s, 2H).

[0693] Example 18

[0694] Preparation of compound 18: 2-(2-chlorophenyl)-N-(4-((4-fluoro-3- methoxyphenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0695]

[0696] Synthetic route:

[0697]

[0698] Preparation of intermediate 18-2 in step (1)

[0699] Intermediate 1-6 (600 mg, 1.62 mmol), intermediate 18-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF (10 mL), the reaction was stirred at 60 °C for 3 h. After work-up, water and EA were added to the reaction solution, after sufficient stirring, the EA phase was separated out, then the water phase was extracted with EA for 3 times, and the EA phases were combined to give intermediate 18-2. LC-MS: [M+H] + = 478.

[0700] Preparation of intermediate 18-3 in step (2)

[0701] Intermediate 18-2 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL), protected by nitrogen, then stirred at 110 °C overnight. After work-up, water and EA were added to the reaction solution, after sufficient stirring, the EA phase was separated out, the water phase was extracted with EA for 2 times, the EA phases were combined, the reaction solution was concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE / EA = 10:1-6:1), and the column effluent was concentrated under reduced pressure to give intermediate 18-3 product. LC-MS: [M+H]+ =522.

[0702] Step (3) Preparation of compound 18

[0703] Intermediate 18-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), and then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol) and AcOH (114 mg, 1.9 mmol) were added to the solution. The mixture was stirred at room temperature for 15 min. The reaction solution was then added dropwise to ammonia water (1 mL) under stirring, and the mixture was stirred at room temperature for 10 min. After post-treatment, the reaction solution was concentrated under reduced pressure and purified by prep-HPLC. The lyophilized solution yielded compound 18. LC-MS: [M+H] + =479.1.

[0704] 1 H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.28(s,1H),7.80(d,J=8.5Hz,1H),7.62(d,J=7.0Hz,3H),7 .48–7.38(m,3H),7.33–7.26(m,2H),6.95(d,J=7.9Hz,1H),5.51(s,2H),3.84(s,2H),3.77(s,3H).

[0705] Example 19

[0706] Compound 19: 2-(2-chlorophenyl)-N-(4-((4-fluoro-3-(2-oxopyrrolidone-1-yl)phenoxy)methyl)-3-aminosulfonylphenyl)acetamide

[0707]

[0708] Prepared according to Example 1. LC-MS: [M+H] + =532.1.

[0709] Example 20

[0710] Preparation of Compound 20: 2-(2-chloro-6-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-aminosulfonylphenyl)acetamide

[0711]

[0712] Synthetic route

[0713]

[0714] Step (1) Preparation of intermediate 20-2

[0715] Intermediate 1-2 (500 mg, 2.18 mmol) was dissolved in DCM (5 mL), and intermediate 20-1 (411.8 mg, 2.18 mmol), T3P (2.08 g, 327 mmol), Et3N (662 mg, 6.54 mmol) were added. After the reaction was stirred at room temperature for 1 h, the reaction solution was extracted with ethyl acetate (20 mL) twice after being added with water (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 5:1~2:1) to obtain intermediate 20-2. LC-MS: [M+H] + = 400.

[0716] Step (3) Preparation of intermediate 20-3

[0717] Intermediate 20-2 (640 mg, 1.6 mmol) was dissolved in THF (6 mL), and LiAlH4(182 mg, 4.8 mmol) was added. After the reaction was stirred at room temperature for 1 h, the reaction solution was filtered under suction after being added with H2O (1 mL) and NaOH solution (1 mL). The filtrate was concentrated under reduced pressure to obtain intermediate 20-3. It was used directly in the next step without treatment.

[0718] Step (4) Preparation of intermediate 20-4

[0719] Intermediate 20-3 (610 mg, 1.64 mmol) was dissolved in DCM (5 mL), and SOCl2(391 mg, 3.29 mmol) was added dropwise. After the reaction was stirred at room temperature for 1 h, the reaction solution was concentrated, and the residue was purified by column chromatography on silica gel (PE:EA = 10:1~5:1) to obtain intermediate 20-4. LC-MS: [M+H] + = 390.

[0720] Step (5) Preparation of intermediate 20-5

[0721] Intermediate 20-4 (352 mg, 0.9 mmol), intermediate 2-1 (121 mg, 1.08 mmol), and K2CO3(248.4 mg, 1.8 mmol) were dissolved in DMF (5 mL), and the reaction was stirred at room temperature for 1 h. The reaction solution was extracted with ethyl acetate (20 mL) twice after being added with water (50 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE:EA = 10:1~5:1) to obtain intermediate 20-5. LC-MS: [M+H] + = 466.

[0722] Step (6) Preparation of intermediate 20-6

[0723] Intermediate 20-5 (335 mg, 0.72 mmol), intermediate 1-9 (benzylthiol) (267 mg, 2.15 mmol), Pd2(dba)3 (102.4 mg, 0.144 mmol), Xantphos (83.2 mg, 0.144 mmol), DIEA (277.4 mg, 2.15 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 20-6. LC-MS: [M+H]=510. + = 467.

[0724] Step (7) Preparation of compound 20

[0725] Intermediate 20-6 (200 mg, 0.39 mmol), intermediate 1-11 (138.8 mg, 0.705 mmol) were dissolved in CH3CN (4 mL), AcOH (0.2 mL) and H2O (0.1 mL) and reacted at room temperature for 5 min. The reaction solution was added dropwise to stirring ammonia water (5 mL) and stirred at room temperature for 0.5 h. The reaction solution was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC with H2O / ACN system, and freeze-dried to obtain compound 20. LC-MS: [M+H]=467. + = 467.

[0726] 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.77 (dd, J = 8.5, 2.2 Hz, 1H), 7.64 - 7.51 (m, 3H), 7.40 - 7.30 (m, 2H), 7.23 (s, 1H), 7.12 (t, J = 8.8 Hz, 2H), 7.05 - 6.97 (m, 2H), 5.39 (s, 2H), 3.89 (d, J = 1.1 Hz, 2H).

[0727] Example 21

[0728] Preparation of compound 21: 2-(2-chloro-4-fluorophenyl)-N-(4-((4-fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0729]

[0730] Synthetic route

[0731]

[0732] Preparation of intermediate 21-2 in step (1)

[0733] Weighed intermediate 1-2 (2.0 g, 8.693 mmol) was dissolved in DCM (50 mL), and intermediate 21-1 (2-chloro-4-fluorophenylacetic acid) (2.0 g, 10.432 mmol), T3P (11 g, 17.386 mmol) and TEA (2.6 g, 26.079 mmol) were added. The reaction was stirred at room temperature for 1 h, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 4 / 1) to obtain intermediate 21-2. LC-MS: [M+H] + = 400.

[0734] Preparation of intermediate 21-3 in step (2)

[0735] Weighed intermediate 21-2 (2.2 g, 5.491 mmol) was dissolved in THF (50 mL), and lithium aluminum hydride (627 mg, 16.474 mmol) was slowly added with stirring. After the addition was completed, the reaction was stirred at room temperature for 10 min. TLC showed that a small amount of starting material had not reacted. After the addition of 1.0 eq of lithium aluminum hydride, there was no effect. The reaction solution was added with 1 mL of water and 1 mL of 1.0 M NaOH solution, and 200 mL of ethyl acetate was added. After filtration, the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain intermediate 21-3. LC-MS: [M+H] + = 372.

[0736] Preparation of intermediate 21-4 in step (3)

[0737] Weighed intermediate 21-3 (1.0 g, 2.684 mmol) was dissolved in DCM (40 mL), and SOCl2 (639 mg, 5.367 mmol) was added dropwise. The reaction was stirred at room temperature for 1 h. The reaction was stopped, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain intermediate 21-4. LC-MS: [M+H] + = 390.

[0738] Preparation of intermediate 21-5 in step (4)

[0739] Weighed intermediate 21-4 (800 mg, 2.046 mmol) was dissolved in DMF (20 mL), and intermediate 2-1 (4-fluorophenol) (276 mg, 2.455 mmol), K2CO3 (565 mg, 4.092 mmol) were added. After the addition was completed, the reaction was allowed to react at room temperature for 2 h. The reaction solution was added to water (50 mL) and extracted with ethyl acetate (20 mL) twice. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 8 / 1) to obtain intermediate 21-5. LC-MS: [M+H] = 466. +

[0740] Step (5) Preparation of intermediate 21-6

[0741] Weighed intermediate 21-5 (850 mg, 1.821 mmol) was dissolved in 30 mL of 1,4-dioxane, and intermediate 1-9 (benzyl mercaptan) (453 mg, 3.643 mmol), Pd2(dba)3 (166 mg, 0.182 mmol), Xantphos (105 mg, 0.182 mmol), and DIEA (709 mg, 5.463 mmol) were added. After the addition was completed, the reaction was protected with nitrogen and allowed to react at 100°C overnight. The reaction solution was added to water and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain intermediate 21-6. LC-MS: [M+H] = 510. +

[0742] Step (6) Preparation of compound 21

[0743] Weighed intermediate 21-6 (400 mg, 0.784 mmol) was dissolved in CH3CN (10 mL), and intermediate 1-11 (DCDMH) (232 mg, 1.176 mmol), AcOH (1 mL), and H2O (1 mL) were added. After the addition was completed, the reaction was allowed to react at room temperature for 5 min. The reaction solution was added to ammonia water (2 mL), and the reaction solution was added to water and extracted with EA. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by Prep-HPLC to obtain compound 21. LC-MS: [M+H]+ = 467.

[0744] 1 ​​H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.27 (d, J = 2.2 Hz, 1H), 7.80 (dd, J = 8.5, 2.2 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H), 7.57 (s, 2H), 7.46 (ddd, J = 11.5, 8.7, 4.5 Hz, 2H), 7.21 (td, J = 8.5, 2.7 Hz, 1H), 7.18 - 7.09 (m, 2H), 7.06 - 6.99 (m, 2H), 5.40 (s, 2H), 3.85 (s, 2H).

[0745] Example 22

[0746] Preparation of compound 22: 2-(2-chloro-5-fluorophenyl)-N-(4-((4- fluorophenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0747]

[0748] Synthetic route

[0749]

[0750] Preparation of intermediate 22-2 in step (1)

[0751] Intermediate 1-2 (9 g, 0.039 mol) of, intermediate 22-1 (2-chloro-5-fluorophenyl acetic acid) (8 g, 0.0468 mol), TEA (12 g, 0.117 mol), T3P (25 g, 0.078 mol) were dissolved in DCM (90 mL), the reaction was stirred at room temperature for 0.5 h. Water and DCM were added to the reaction solution, after stirring well, the DCM phase was separated, the aqueous phase was extracted with DCM twice, the combined DCM phase was filtered, and the filtrate was concentrated under reduced pressure to give intermediate 22-2. LC-MS: [M+H] + = 400.

[0752] Preparation of intermediate 22-3 in step (2)

[0753] Intermediate 22-2 (14 g, 0.037 mol) was dissolved in THF (100 mL) and cooled to 0 °C, LiAlH4(4.22 g, 0.111 mol) was added, and the reaction was stirred at room temperature for 10 min. After treatment, 1 mL of water and 3 mL of 2M NaOH aqueous solution were added to the reaction solution, followed by the addition of a large amount of EA, filtration, and concentration of the filtrate under reduced pressure to give intermediate 22-3. LC-MS: [M+H] + = 372.

[0754] Preparation of intermediate 22-4 in step (3)

[0755] Intermediate 22-3 (10 g, 0.028 mol) was dissolved in DCM (100 mL) and cooled to 0 °C, SOCl2(6.61 g, 0.056 mol) was added, and the reaction was stirred at room temperature for 1 h. After work-up, the reaction was concentrated under reduced pressure to give intermediate 22-4. LC-MS: [M+H] + = 390.

[0756] Step (4) Preparation of intermediate 22-5

[0757] Intermediate 22-4 (600 mg, 1.62 mmol), intermediate 2-1 (280 mg, 1.95 mmol), K2CO3(447 mg, 3.24 mmol) were dissolved in DMF (10 mL), and the reaction was stirred at 60 °C for 3 h. After work-up, water and EA were added to the reaction, and after stirring well, the EA phase was separated, and the water phase was extracted with EA three times. The EA phases were combined and concentrated under reduced pressure to give intermediate 22-5. LC-MS: [M+H] + = 466.

[0758] Step (5) Preparation of intermediate 22-6

[0759] Intermediate 22-5 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3(45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction was stirred at 110 °C overnight under nitrogen protection. After work-up, water and EA were added to the reaction, and after stirring well, the EA phase was separated, and the water phase was extracted with EA twice. The EA phases were combined and concentrated under reduced pressure to give a crude product, which was purified by silica gel column chromatography (PE / EA = 10:1-6:1). The column effluent was concentrated under reduced pressure to give intermediate 20-6. LC-MS: [M+H] + = 510.

[0760] Step (6) Preparation of compound 22

[0761] Intermediate 20-6 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction was added dropwise to stirred ammonia water (20 mg, 1.20 mmol) and stirred at room temperature for 10 min. After work-up, the reaction was concentrated under reduced pressure and purified by Prep-HPLC, and then freeze-dried to obtain compound 22. LC-MS: [M+H] + = 467.

[0762] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.24 (d, J = 2.1 Hz, 1H), 7.79 (dd, J = 8.4, 2.0 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.56 (s, 2H), 7.48 (dd, J = 8.8, 5.3 Hz, 1H), 7.33 (dd, J = 9.5, 3.1 Hz, 1H), 7.20 - 7.07 (m, 3H), 7.04 - 6.96 (m, 2H), 5.39 (s, 2H), 3.86 (s, 2H).

[0763] Example 23

[0764] Preparation of compound 23: 2-(2-chlorophenyl)-N-(4-((((1-methyl-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0765]

[0766] Synthetic route:

[0767]

[0768] Preparation of intermediate 23-2 in step (1)

[0769] Weighed intermediate 1-6 (500 mg, 1.34 mmol) was dissolved in DMF (10 mL), then intermediate 23-1 (158 mg, 1.608 mmol), K2CO3 (370 mg, 2.68 mmol) were added, and the reaction was stirred at room temperature for 2 h. The reaction was added with water and extracted with ethyl acetate twice, the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain intermediate 23-2. LC-MS: [M+H] + = 434.

[0770] Preparation of intermediate 23-3 in step (2)

[0771] The weighed intermediate 23-2 (400 mg, 0.920 mmol) was dissolved in 1,4-dioxane (20 mL), and intermediate 1-9 (benzyl mercaptan) (229 mg, 1.840 mmol), Pd2(dba)3 (85 mg, 0.092 mmol), Xantphos (54 mg, 0.092 mmol), DIEA (357 mg, 2.76 mmol) were added, and the reaction was carried out at 100 °C overnight under nitrogen protection. The reaction solution was added with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (PE / EA = 3 / 1 ~ 1 / 1) to obtain intermediate 23-3. LC-MS: [M+H] + = 478.

[0772] Preparation of compound 23 in step (3)

[0773] Intermediate 23-3 (370 mg, 0.774 mmol) was dissolved in CH3CN (16 mL), AcOH (2 mL) and H2O (2 mL), and intermediate 1-11 (DCDMH) (305 mg, 1.548 mmol) was added. The reaction was carried out at room temperature for 10 min, and then the reaction solution was added dropwise to ammonia water (4 mL) under stirring. The reaction was stirred at room temperature for 10 min, and then the reaction solution was added with water, extracted with EA, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 23 was obtained by Prep-HPLC purification. LC-MS: [M+H] + = 435.15.

[0774] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 8.5, 2.2 Hz, 1H), 7.61 (d, J = 8.5 Hz, 1H), 7.50 (s, 2H), 7.47 - 7.38 (m, 3H), 7.35 - 7.28 (m, 2H), 7.22 (s, 1H), 5.26 (s, 2H), 3.86 (s, 2H), 3.72 (s, 3H).

[0775] Example 24

[0776] Preparation of compound 24: 2-(2-chlorophenyl)-N-(4-(((3-fluoro-1-methyl-1H-pyrazol-5- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0777]

[0778] Prepared according to Reference Example 1. LC-MS: [M+H] + = 453.1.

[0779] Example 25

[0780] Preparation of compound 25: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H- imidazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0781]

[0782] Prepared according to Reference Example 1. LC-MS: [M+H] + = 435.1.

[0783] Example 26

[0784] Preparation of compound 26: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H- imidazol-2-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0785]

[0786] Prepared according to Reference Example 1. LC-MS: [M+H] + = 435.1.

[0787] Example 27

[0788] Preparation of compound 27: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H- imidazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0789]

[0790] Prepared according to Reference Example 1. LC-MS: [M+H] + = 435.1.

[0791] Example 28

[0792] Preparation of compound 28: 2-(2-chlorophenyl)-N-(4-((cyclopropylmethoxy)methyl)- 3-sulfamoylphenyl)acetamide

[0793]

[0794] Prepared according to Reference Example 1. LC-MS: [M+H] + = 409.1.

[0795] Example 29

[0796] Preparation of compound 29: 2-(2-chlorophenyl)-N-(4-((cyclobutylmethoxy)methyl)- 3-sulfamoylphenyl)acetamide

[0797]

[0798] Reference Example 1. LC-MS: [M+H] + = 423.1.

[0799] Example 30

[0800] Preparation of compound 30: 2-(2-chlorophenyl)-N-(4-((cyclopentylmethoxy)methyl)- 3-sulfamoylphenyl)acetamide

[0801]

[0802] Synthetic route:

[0803]

[0804] Preparation of intermediate 30-2 in step (1)

[0805] Weighed intermediate 1-6 (700 mg, 1.876 mmol) was dissolved in 20 mL of DMF, potassium carbonate (777 mg, 5.629 mmol) and intermediate 30-1 (376 mg, 3.753 mmol) were added, and the reaction was allowed to proceed at room temperature for 2 h. The reaction solution was added to water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain intermediate 30-2. LC-MS: [M+H] + = 436.

[0806] Preparation of intermediate 30-3 in step (2)

[0807] Weighed intermediate 30-2 (170 mg, 0.389 mmol) was dissolved in 1,4-dioxane (10 mL), and intermediate 1-9 (benzyl mercaptan) (73 mg, 0.584 mmol), Pd2(dba)3 (36 mg, 0.039 mmol), Xantphos (23 mg, 0.039 mmol), DIEA (152 mg, 1.17 mmol) were added, and the reaction was allowed to proceed at 100°C overnight under nitrogen protection. The reaction solution was added to water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA = 5 / 1) to obtain intermediate 30-3. LC-MS: [M+H] + = 480.

[0808] Step (3) Preparation of compound 30

[0809] Intermediate 30-3 (100 mg, 0.208 mmol) was dissolved in CH3CN (2 mL), AcOH (0.25 mL) and H2O (0.25 mL), intermediate 1-11 (DCDMH) (83 mg, 0.417 mmol) was added, and the reaction was stirred at room temperature for 1.0 h. The reaction was added to ammonia water (2 mL), stirred at room temperature for 10 min, and then water was added. The reaction was extracted with EA, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Compound 30 was obtained by Prep-HPLC purification. LC-MS: [M+H] + = 437.

[0810] 1 H NMR (400 MHz, DMSO-d6) δ 10.60 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 8.4, 2.1 Hz, 1H), 7.54 - 7.39 (m, 5H), 7.35 - 7.29 (m, 2H), 5.45 (s, 2H), 4.02 (d, J = 7.1 Hz, 2H), 3.87 (s, 2H), 2.18 (d, J = 7.5 Hz, 1H), 1.70 (d, J = 8.0 Hz, 2H), 1.53 (ddd, J = 15.7, 13.1, 7.7 Hz, 4H), 1.27 - 1.22 (m, 2H).

[0811] Example 31

[0812] Preparation of compound 31: 2-(2-chlorophenyl)-N-(4- (cyclobutyloxymethyl)-3-sulfamoylphenyl)acetamide

[0813]

[0814] Prepared according to Reference Example 1. LC-MS: [M+H] + = 409.1.

[0815] Example 32

[0816] Preparation of compound 32: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4- ( ((tetrahydro-2H-pyran-4-yl) oxy) methyl) phenyl) acetamide

[0817]

[0818] Prepared according to Reference Example 1. LC-MS: [M+H] + = 439.1.

[0819] Example 33

[0820] Preparation of compound 33: 2-(2-chlorophenyl)-N-(4-((oxetan-3-ylmethoxy)methyl)- 3-sulfamoylphenyl)acetamide

[0821]

[0822] Prepared according to Reference Example 1. LC-MS: [M+H] + = 425.1.

[0823] Example 34

[0824] Preparation of compound 34: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-((((tetrahydrofuran- 3-yl)methoxy)methyl)phenyl)acetamide

[0825]

[0826] Prepared according to Reference Example 1. LC-MS: [M+H] + = 439.1.

[0827] Example 35

[0828] Preparation of compound 35: 2-(2-chlorophenyl)-N-(4-((oxetan-3-yloxy)methyl)-3- sulfamoylphenyl)acetamide

[0829]

[0830] Prepared according to Reference Example 1. LC-MS: [M+H] + = 411.1.

[0831] Example 36

[0832] Preparation of compound 36: N-(4-((azetidin-3-yloxy)methyl)-3-sulfamoylphenyl)-2-(2- chlorophenyl)acetamide

[0833]

[0834] Prepared according to Reference Example 1. LC-MS: [M+H] + = 410.1.

[0835] Example 37:

[0836] Preparation of compound 37: 2-(2-chlorophenyl)-N-(4-((pyrrolidin-3-yloxy)methyl)-3- sulfamoylphenyl)acetamide

[0837]

[0838] Prepared according to Reference Example 1. LC-MS: [M+H] + = 508.1

[0839] Example 38

[0840] Preparation of compound 38: 2-(2-chlorophenyl)-N-(4-((piperidin-4-yloxy)methyl)-3- sulfamoylphenyl)acetamide

[0841]

[0842] Prepared according to Reference Example 1. LC-MS: [M+H] + = 438.1.

[0843] Example 39

[0844] Preparation of compound 39: 2-(2-chlorophenyl)-N-(4-((piperidin-3-yloxy)methyl)-3- sulfamoylphenyl)acetamide

[0845]

[0846] Prepared according to Reference Example 1. LC-MS: [M+H] + = 438.1.

[0847] Example 40

[0848] Preparation of compound 40: 2-(2-chlorophenyl)-N-(3-sulfamoyl-4-(((tetrahydro-2H- pyran-3-yl)oxy)methyl)phenyl)acetamide

[0849]

[0850] Prepared according to Reference Example 1. LC-MS: [M+H] + = 439.1.

[0851] Example 41

[0852] Preparation of compound 41 : N-(4-(((2-azabicyclo[2.2.1]heptan-5-yl)oxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

[0853]

[0854] Prepared according to Reference Example 1. LC-MS: [M+H] + = 450.1.

[0855] Example 42

[0856] Preparation of compound 42: N-(4-(((3-azabicyclo[3.1.1]heptan-6-yl)oxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

[0857]

[0858] Prepared according to Reference Example 1. LC-MS: [M+H] + = 450.1.

[0859] Example 43

[0860] Preparation of compound 43: N-(4-(((2-azabicyclo[2.2.2]octan-5-yl)oxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

[0861]

[0862] Prepared according to Reference Example 1. LC-MS: [M+H] + = 450.1.

[0863] Example 44

[0864] Preparation of compound 44: 2-(2-chlorophenyl)-N-(4-((3-cyanophenoxy)methyl)-3- sulfamoylphenyl)acetamide

[0865]

[0866] Synthetic route

[0867]

[0868] Preparation of intermediate 44-2 in Step (1)

[0869] Intermediate 1-6 (600 mg, 1.62 mmol), intermediate 44-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF (10 mL), and the reaction was warmed to 60 °C and stirred for 3 h. The reaction was worked up by adding water and EA to the reaction, stirring well, and then separating the EA phase. The aqueous phase was then extracted 3 times with EA, and the EA phases were combined and concentrated under reduced pressure to give intermediate 44-2. LC-MS: [M+H] + = 455.

[0870] Preparation of intermediate 44-3 in Step (2)

[0871] Intermediate 44-2 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (10 mL) under nitrogen protection, then the reaction was stirred at 110 °C overnight. The reaction was post-treated by adding water and EA to the reaction solution, after stirring well, the EA phase was separated, the water phase was extracted with EA twice, the EA phases were combined, the reaction solution was concentrated under reduced pressure, then purified by silica gel column chromatography (PE / EA = 10:1-6:1), and the column effluent was concentrated under reduced pressure to obtain intermediate 44-3. LC-MS: [M+H]=499. +

[0872] Step (3) Preparation of compound 44

[0873] Intermediate 44-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. After the reaction solution was added to stirring ammonia water (10 mL), the reaction was stirred at room temperature for 10 min. The reaction was post-treated by concentrating under reduced pressure, then purified by Prep-HPLC, and freeze-dried to obtain compound 44. LC-MS: [M+H]=456. +

[0874] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 8.5, 2.2 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.59 (s, 2H), 7.50 (dd, J = 10.1, 5.9 Hz, 2H), 7.45 - 7.38 (m, 3H), 7.36 (dd, J = 8.1, 2.0 Hz, 1H), 7.32 - 7.26 (m, 2H), 5.45 (s, 2H), 3.85 (s, 2H).

[0875] Example 45

[0876] Preparation of compound 45: N-(4-((3-(aminomethyl)phenoxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

[0877]

[0878] Synthetic route ​​

[0879]

[0880] Preparation of intermediate 45-2 in step (1)

[0881] Intermediate 45-1 (300 mg, 2.43 mmol) was dissolved in THF (15 mL), Boc2O (639 mg, 2.95 mmol) was added to the solution, and the reaction was carried out in an ice bath. After 2 h, the reaction solution was extracted with water (50 mL) and ethyl acetate (20 mL) twice. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was used directly in the next step. LC-MS: [M+H] + = 224.1.

[0882] Preparation of intermediate 45-3 in step (2)

[0883] Intermediate 1-6 (525 mg, 1.41 mmol), intermediate 45-2 (315 mg, 1.41 mmol), and K2CO3 (390 mg, 2.83 mmol) were dissolved in DMF (5 mL) and stirred at room temperature for 1 h. The reaction solution was extracted with water (50 mL) and ethyl acetate (20 mL) twice. The organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain intermediate 45-3. LC-MS: [M+H] + = 559.

[0884] Preparation of intermediate 45-4 in step (3)

[0885] Intermediate 45-3 (325 mg, 0.58 mmol), intermediate 1-9 (benzyl mercaptan) (216.3 mg, 1.74 mmol), Pd2(dba)3 (82.5 mg, 0.116 mmol), Xantphos (67 mg, 0.116 mmol), and DIEA (225 mg, 1.74 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115°C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain intermediate 45-4. LC-MS: [M+H] + = 603.

[0886] Preparation of intermediate 45-5 in step (4)

[0887] Intermediate 45-4 (68 mg, 0.1134 mmol) and intermediate 1-11 (DCDMH) (22.4 mg, 0.1134 mmol) were dissolved in CH3CN (4 mL), AcOH (0.2 mL), and H2O (0.1 mL). The reaction mixture was reacted at room temperature for 1 hour. The reaction solution was then added dropwise to ammonia water (10 mL) under stirring, and the mixture was stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL) and extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 45-5. LC-MS: [M+H] + =560.

[0888] Step (6) Preparation of compound 45

[0889] Intermediate 45-5 (50 mg, 0.088 mmol) was dissolved in DCM (2 mL), and HCl (1 mL) was added. The reaction mixture was allowed to react for 2 h. The reaction solution was diluted with water (10 mL), and then extracted three times with DCM (10 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC using an H2O / ACN system, and the prepared solution was lyophilized to obtain compound 45. LC-MS: [M+1] = 460.

[0890] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.25(s,3H),7.81(d,J=7.8Hz,1H),7.60(d,J=8.3Hz,1H),7.41(t,J=8.7Hz,2H),7.29(dd,J=8.1,3. 9Hz, 4H), 7.22 (d, J = 7.4Hz, 2H), 7.13 (s, 1H), 6.99 (d, J = 7.6Hz, 1H), 6.94 (d, J = 7.8Hz, 1H), 5.42 (s, 2H), 4.22 (d, J = 5.9Hz, 2H), 3.84 (s, 2H).

[0891] Example 46

[0892] Preparation of Compound 46: 2-(2-chloro-6-fluorophenyl)-N-(4-(((6-fluoropyridin-3-yl)oxy)methyl)-3-aminosulfonylphenyl)acetamide

[0893]

[0894] Synthetic route

[0895]

[0896] Preparation of intermediate 46-1 in step (1)

[0897] Intermediate 20-4 (2.15 g, 5.55 mmol), intermediate 9-1 (627 mg, 5.55 mmol), K2CO3 (1.53 g, 11.1 mmol) were dissolved in DMF (20 mL) and stirred at room temperature for 1 h. The reaction solution was extracted with ethyl acetate (20 mL) twice after adding water (50 mL), and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 46-1. LC-MS: [M+1] = 467.

[0898] Preparation of intermediate 46-2 in step (2)

[0899] Intermediate 46-1 (1.33 g, 2.85 mmol), intermediate 1-9 (benzyl mercaptan) (1.05 g, 8.5 mmol), Pd2(dba)3 (405 mg, 0.57 mmol), Xantphos (329 mg, 0.57 mmol), DIEA (1.1 g, 8.5 mmol) were dissolved in 1,4-dioxane (10 mL) and reacted at 115°C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 46-2. LC-MS: [M+1] = 511.

[0900] Preparation of compound 46 in step (3)

[0901] Intermediate 46-2 (345 mg, 0.67 mmol), intermediate 1-11 (DCDMH) (133 mg, 0.67 mmol) were dissolved in CH3CN (5 mL), AcOH (0.2 mL), and H2O (0.1 mL) and reacted at room temperature for 5 min. The reaction solution was added dropwise to stirring ammonia water (5 mL) and stirred at room temperature for 0.5 hours. The reaction solution was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using a H2O / ACN system, and freeze-dried to obtain compound 46. LC-MS: [M+1] = 468.

[0902] 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.95 (dd, J = 2.9, 1.8 Hz, 1H), 7.78 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 - 7.60 (m, 2H), 7.56 (s, 2H), 7.40 - 7.30 (m, 2H), 7.26 - 7.19 (m, 1H), 7.13 (dd, J = 8.9, 3.4 Hz, 1H), 5.45 (s, 2H), 3.89 (d, J = 1.3 Hz, 2H).

[0903] Example 47

[0904] Preparation of compound 47: 2-(2-chloro-5-fluorophenyl)-N-(4-((((6-fluoropyridin-3- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0905]

[0906] Synthetic route

[0907]

[0908] Preparation of intermediate 47-1 in step (1)

[0909] Intermediate 22-4 (600 mg, 1.62 mmol), intermediate 9-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and stirred at 60 °C for 3 h. After work-up, water and EA were added to the reaction solution, after stirring well, the EA phase was separated out, then the water phase was extracted with EA for 3 times, the EA phases were combined and concentrated under reduced pressure to obtain intermediate 47-1. LC-MS: [M+H] + = 469.

[0910] Preparation of intermediate 47-2 in step (2)

[0911] Intermediate 47-1 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL) under nitrogen protection, then the reaction was stirred at 110 °C overnight. The reaction was post-treated by adding water and EA, after stirring well, the EA phase was separated, the water phase was extracted with EA twice, the EA phases were combined, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 10:1-6:1), and the column effluent was concentrated under reduced pressure to give intermediate 47-2. LC-MS: [M+H]=511. +

[0912] Step (3) Preparation of compound 47

[0913] Intermediate 47-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), and then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction was added to stirring ammonia water (20 mg, 1.20 mmol), and stirred at room temperature for 10 min. The reaction was post-treated by concentrating under reduced pressure, and then purified by Prep-HPLC, and freeze-dried to give compound 47. LC-MS: [M+H]=468. +

[0914] 1 H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.95 (dd, J = 3.0, 1.8 Hz, 1H), 7.80 (dd, J = 8.5, 2.2 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.57 (s, 2H), 7.47 (dd, J = 8.8, 5.3 Hz, 1H), 7.32 (dd, J = 9.5, 3.1 Hz, 1H), 7.20 - 7.09 (m, 2H), 5.45 (s, 2H), 3.85 (s, 2H).

[0915] Example 48

[0916] Preparation of compound 48: 2-(2-chloro-4-fluorophenyl)-N-(4-((((6-fluoropyridin-3- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0917]

[0918] ​​Synthesis route

[0919]

[0920] Preparation of intermediate 48-1 in step (1)

[0921] Intermediate 21-4 (600 mg, 1.62 mmol), intermediate 9-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and the reaction was stirred at 60 °C for 3 h. After work-up, water and EA were added to the reaction solution, and after stirring well, the EA phase was separated, and the water phase was extracted with EA for 3 times, and the EA phases were combined. The product was obtained by concentrating the EA phase under reduced pressure. The reaction was successful, and intermediate 48-1 was obtained. LC-MS: [M+H] + = 468.

[0922] Preparation of intermediate 48-2 in step (2)

[0923] Intermediate 48-1 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL) under nitrogen protection, and then the reaction was stirred at 110 °C overnight. After work-up, water and EA were added to the reaction solution, and after stirring well, the EA phase was separated, and the water phase was extracted with EA for 2 times, and the EA phases were combined. The product was obtained by concentrating the reaction solution under reduced pressure and purifying it by silica gel column chromatography (PE / EA = 10:1-6:1). LC-MS: [M+H] + = 511.

[0924] Preparation of compound 48 in step (3)

[0925] Intermediate 48-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), and then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction solution was added to stirring ammonia water (20 mg, 1.20 mmol), and the reaction was stirred at room temperature for 10 min. After work-up, the reaction solution was concentrated under reduced pressure and purified by Prep-HPLC. The product was obtained by freeze-drying the preparation solution. LC-MS: [M+H] + = 468.

[0926] 1H NMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.97 - 7.91 (m, 1H), 7.80 (dd, J = 8.5, 2.2 Hz, 1H), 7.67 - 7.59 (m, 2H), 7.57 (s, 2H), 7.43 (ddd, J = 11.5, 8.7, 4.5 Hz, 2H), 7.22 - 7.10 (m, 2H), 5.44 (s, 2H), 3.83 (s, 2H).

[0927] Example 49

[0928] Preparation of compound 49: 2-(2-chloro-6-fluorophenyl)-N-(4-((4- cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0929]

[0930] Synthetic route

[0931]

[0932] Preparation of intermediate 49-2 in step (1)

[0933] Intermediate 1-2 (2.43 g, 10.6 mmol) was dissolved in DCM (20 mL), intermediate 20-1 (2 g, 10.6 mmol), T3P (10.1 g, 15.9 mmol), Et3N (4.8 g, 47.7 mmol) were added, the reaction was stirred at room temperature for 1 h, then the reaction solution was extracted with water (50 mL) and ethyl acetate (20 mL) twice, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 5:1 ~ 2:1) to obtain intermediate 49-2. LC-MS: [M+H] = 400. +

[0934] Preparation of intermediate 49-3 in step (2)

[0935] Intermediate 49-2 (4 g, 10 mmol) was dissolved in THF (10 mL), LiAlH4(5.7 g, 15 mmol) was added, and the reaction was stirred at room temperature for 1 h. After adding H2O (1 mL) and NaOH solution (2 mL), the reaction was filtered, and the filtrate was concentrated under reduced pressure to obtain 3.4 g of crude intermediate 49-3. It was used directly in the next step without further purification.

[0936] Preparation of intermediate 49-4 in step (3)

[0937] ​Intermediate 49-3 (3.4 g, 9.2 mmol) was dissolved in DCM (10 mL), and SOCl2 (2.2 g, 18.2 mmol) was added dropwise. The mixture was stirred at room temperature for 1 h. The reaction was stopped, and the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (PE:EA = 10:1–5:1) to obtain intermediate 49-4. LC-MS: [M+H] + =400.

[0938] Preparation of intermediate 49-5 in step (4)

[0939] Intermediate 49-4 (300 mg, 0.76 mmol), intermediate 6-1 (91.3 mg, 0.76 mmol), and K₂CO₃ (211.7 g, 1.53 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 1 h. The reaction mixture was then extracted twice with ethyl acetate (20 mL) after adding water (50 mL). The combined organic phases were washed successively with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then subjected to silica gel column chromatography (PE / EA = 5 / 1–3 / 1) to obtain intermediate 49-5. LC-MS: [M+H] + =473.

[0940] Preparation of intermediate 49-6 in step (5)

[0941] Intermediate 49-5 (255 mg, 0.54 mmol), intermediate 1-9 (benzyl mercaptan) (200.5 mg, 1.62 mmol), Pd2(dba)3 (76.7 mg, 0.108 mmol), Xantphos (62.4 mg, 0.108 mmol), and DIEA (209 mg, 1.62 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 °C for 16 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain intermediate 49-6. LC-MS: [M+H] + =517.

[0942] Step (6) Preparation of compound 49

[0943] Intermediate 49-6 (254 mg, 0.49 mmol), intermediate 1-11 (DCDMH) (97 mg, 0.49 mmol) were dissolved in CH3CN (5 mL), AcOH (0.2 mL) and H2O (0.1 mL) and reacted at room temperature for 5 min. The reaction solution was added dropwise to stirring ammonia water (5 ml) and stirred at room temperature for 0.5 h. The reaction solution was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC with a H2O / ACN system, and compound 49 was obtained by freeze-drying the preparation solution. LC-MS: [M+H]=474. + = 474.

[0944] 1 H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.78 (d, J = 8.9 Hz, 3H), 7.58 (s, 3H), 7.41 - 7.30 (m, 2H), 7.27 - 7.20 (m, 1H), 7.16 (d, J = 8.9 Hz, 2H), 5.49 (s, 2H), 3.89 (s, 2H).

[0945] Example 50

[0946] Preparation of compound 50: 2-(2-chloro-5-fluorophenyl)-N-(4-((4- cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0947]

[0948] Synthetic route

[0949]

[0950] Preparation of intermediate 50-1 in step (1)

[0951] Intermediate 22-4 (600 mg, 1.62 mmol), intermediate 6-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF (10 mL) and stirred at 60 °C for 3 h. After treatment, water and EA were added to the reaction solution, stirred well, and then the EA phase was separated. The water phase was extracted with EA three times, and the EA phases were combined and concentrated under reduced pressure to obtain intermediate 50-1. LC-MS: [M+H]=473. + = 473.

[0952] Preparation of intermediate 50-2 in step (2)

[0953] Intermediate 50-1 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL) under nitrogen protection, then the reaction was stirred at 110 °C overnight. After work-up, water and EA were added to the reaction solution, after stirring well, the EA phase was separated, the water phase was extracted with EA twice, the EA phases were combined, and the EA phase was concentrated under reduced pressure, then purified by silica gel column chromatography (PE / EA = 10:1-6:1), and the column effluent was concentrated under reduced pressure to obtain intermediate 50-2. LC-MS: [M+H]=517. +

[0954] Step (3) Preparation of compound 50

[0955] Intermediate 50-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction solution was added to stirring ammonia water (20 mg, 1.20 mmol), and the reaction was stirred at room temperature for 10 min. After work-up, the reaction solution was concentrated under reduced pressure, then purified by Prep-HPLC, and freeze-dried to obtain the product. The reaction was successful, and compound 50 was obtained. LC-MS: [M+H]=474. +

[0956] 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.25 (d, J = 2.2 Hz, 1H), 7.82-7.73 (m, 3H), 7.60 (s, 1H), 7.58 (d, J = 2.5 Hz, 2H), 7.47 (dd, J = 8.8, 5.3 Hz, 1H), 7.32 (dd, J = 9.5, 3.1 Hz, 1H), 7.17 (td, J = 9.0, 2.8 Hz, 3H), 5.48 (s, 2H), 3.85 (s, 2H).

[0957] Example 51

[0958] Preparation of compound 51: 2-(2-chloro-4-fluorophenyl)-N-(4-((4- cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0959]

[0960] Synthetic route​​

[0961]

[0962] Preparation of intermediate 51-1 in step (1)

[0963] Intermediate 21-4 (600 mg, 1.62 mmol), intermediate 6-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF (10 mL), and the reaction was stirred at 60 °C for 3 h. After work-up, water and EA were added to the reaction solution, and after sufficient stirring, the EA phase was separated out, and the water phase was extracted with EA three times. The EA phases were combined and concentrated under reduced pressure to obtain intermediate 51-1. LC-MS: [M+H] + = 473.

[0964] Preparation of intermediate 51-2 in step (2)

[0965] Intermediate 51-1 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), and the reaction was stirred at 110 °C overnight under nitrogen protection. After work-up, water and EA were added to the reaction solution, and after sufficient stirring, the EA phase was separated out, and the water phase was extracted with EA twice. The EA phases were combined and concentrated, and the product was separated and purified by column chromatography (PE / EA = 10:1-6:1). The column effluent was concentrated under reduced pressure to obtain intermediate 51-2. LC-MS: [M+H] + = 517.

[0966] Preparation of compound 51 in step (3)

[0967] Intermediate 51-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), and intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction solution was added to stirring ammonia water (20 mg, 1.20 mmol), and the reaction was stirred at room temperature for 10 min. After work-up, the reaction solution was concentrated under reduced pressure, and purified by Prep-HPLC, and freeze-dried to obtain compound 51. LC-MS: [M+H] + = 474.

[0968] 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.80 (ddt, J = 7.0, 4.7, 2.5 Hz, 3H), 7.65 - 7.55 (m, 3H), 7.46 (ddd, J = 11.5, 8.7, 4.5 Hz, 2H), 7.25 - 7.15 (m, 3H), 5.51 (s, 2H), 3.85 (s, 2H).

[0969] Example 52

[0970] Preparation of compound 52: 2-(2-chloro-3-fluorophenyl)-N-(4-((4- cyanophenoxy)methyl)-3-sulfamoylphenyl)acetamide

[0971]

[0972] Synthetic route

[0973]

[0974] Preparation of intermediate 52-2 in step (1)

[0975] Intermediate 1-2 (9 g, 0.039 mol), intermediate 52-1 (2-chloro-3-fluorophenylacetic acid) (8 g, 0.0468 mol), TEA (12 g, 0.117 mol), T3P (25 g, 0.078 mol) were dissolved in DCM (90 mL), the reaction was stirred at room temperature for 0.5 h. Water and DCM were added to the reaction, after stirring well, the DCM phase was separated, the water phase was extracted with DCM twice, the DCM phases were combined, and the reaction was concentrated under reduced pressure to give intermediate 52-2. LC-MS: [M+H] = 400. +

[0976] Preparation of intermediate 52-3 in step (2)

[0977] Intermediate 52-2 (14 g, 0.037 mol) was dissolved in THF (100 mL) and cooled to 0 °C, and LiAlH4(4.22 g, 0.111 mol) was added and stirred at room temperature for 10 min. After treatment, 1 mL of water and 3 mL of 2M NaOH aqueous solution were added to the reaction, followed by a large amount of EA, filtration, and concentration of the filtrate under reduced pressure to give intermediate 52-3. LC-MS: [M+H] = 372. +

[0978] Preparation of intermediate 52-4 in step (3)

[0979] ​​Intermediate 52-3 (10 g, 0.028 mol) was dissolved in DCM (100 mL) and cooled to 0 °C, SOCl2 (6.61 g, 0.056 mol) was added, and the reaction was stirred at room temperature for 1 h. Work-up, the reaction was concentrated under reduced pressure to give intermediate 52-4. LC-MS: [M+H] + = 390.

[0980] Step (4) Preparation of intermediate 52-5

[0981] Intermediate 52-4 (600 mg, 1.62 mmol), intermediate 6-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF (10 mL), and the reaction was stirred at 60 °C for 3 h. Work-up, water and EA were added to the reaction, and after stirring well, the EA phase was separated, and the water phase was extracted with EA for 3 times, and the EA phases were combined, and the EA phase was concentrated under reduced pressure to give intermediate 52-5. LC-MS: [M+H] + = 473.

[0982] Step (5) Preparation of intermediate 52-6

[0983] Intermediate 52-5 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), and the reaction was stirred at 110 °C overnight under nitrogen protection. Work-up, water and EA were added to the reaction, and after stirring well, the EA phase was separated, and the water phase was extracted with EA for 2 times, and the EA phases were combined, and the EA phase was concentrated under reduced pressure, and then purified by silica gel column chromatography (PE / EA = 10:1-6:1), and the column effluent was concentrated under reduced pressure to give intermediate 52-6. LC-MS: [M+H] + = 517.

[0984] Step (6) Preparation of compound 52

[0985] Intermediate 52-6 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), and then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction was added dropwise to stirred ammonia water (20 mg, 1.20 mmol), and the reaction was stirred at room temperature for 10 min. Work-up, the reaction was concentrated under reduced pressure, and then purified by Prep-HPLC, and freeze-dried to give compound 52. LC-MS: [M+H]+ = 474.

[0986] 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.78 (ddt, J = 7.1, 4.7, 2.5 Hz, 3H), 7.60 (d, J = 8.1 Hz, 3H), 7.39 - 7.22 (m, 3H), 7.21 - 7.12 (m, 2H), 5.49 (s, 2H), 3.90 (s, 2H).

[0987] Example 53

[0988] Preparation of compound 53: 2-(2-chloro-6-fluorophenyl)-N-(4-((((5-fluoropyridin-2- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[0989]

[0990] Synthetic route

[0991]

[0992] Preparation of intermediate 53-2 in step (1)

[0993] Intermediate 20-4 (500 mg, 1.278 mmol) was dissolved in THF (5 mL), intermediate 53-1 (162 mg, 1.41 mmol), Ag2CO3 (702.9 mg, 2.56 mmol) were added, and stirring was performed at 70 °C for 8 h. The reaction was stopped, the reaction liquid was diluted with water (10 mL), and then extracted with DCM (10 mL) three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA = 10:1 ~ 1:1) to obtain intermediate 53-2. LC-MS: [M+H] + = 467.

[0994] Preparation of intermediate 53-3 in step (2)

[0995] Intermediate 53-2 (217 mg, 0.46 mmol), intermediate 1-9 (benzyl mercaptan) (173.6 mg, 1.4 mmol), Pd2(dba)3 (65.4 mg, 0.092 mmol), Xantphos (53.2 mg, 0.092 mmol), DIEA (180.6 mg, 1.4 mmol) were dissolved in 1,4-dioxane (5 mL) and reacted at 115 °C for 16 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain intermediate 53-3. LC-MS: [M+H]=511. +

[0996] Step (3) Preparation of compound 53

[0997] Intermediate 53-3 (175 mg, 0.34 mmol), intermediate 1-11 (DCDMH) (67 mg, 0.34 mmol) were dissolved in CH3CN (4 mL), AcOH (0.1 mL) and H2O (0.1 mL) and reacted at room temperature for 1 h. The reaction solution was added dropwise to stirring ammonia water (5 mL) and stirred at room temperature for 0.5 h. The reaction solution was diluted with water (10 mL) and extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using a H2O / ACN system, and compound 53 was obtained by freeze-drying the preparation solution. LC-MS: [M+H]=468. +

[0998] 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.13 (d, J = 3.1 Hz, 1H), 7.78 - 7.67 (m, 2H), 7.56 (d, J = 8.5 Hz, 1H), 7.48 (s, 2H), 7.40 - 7.31 (m, 2H), 7.26 - 7.17 (m, 1H), 7.07 - 6.97 (m, 1H), 5.64 (s, 2H), 3.90 (d, J = 8.9 Hz, 2H).

[0999] Example 54

[1000] Preparation of compound 54: 2-(2-chloro-5-fluorophenyl)-N-(4-(((5-fluoropyridin-2- yloxy)methyl)methyl)-3-sulfamoylphenyl)acetamide

[1001]

[1002] ​​Synthesis route:

[1003]

[1004] Preparation of intermediate 54-1 in step (1)

[1005] Intermediate 22-4 (600 mg, 1.62 mmol), intermediate 53-1 (280 mg, 1.95 mmol), Ag2CO3 (447 mg, 3.24 mmol) were dissolved in THF (10 mL), and the reaction was stirred at 60 °C for 3 h. After work-up, water and EA were added to the reaction solution, and after stirring well, the EA phase was separated out, and the water phase was extracted with EA three times, and the EA phases were combined and concentrated under reduced pressure to obtain intermediate 54-1. LC-MS: [M+H] + = 469.

[1006] Preparation of intermediate 54-2 in step (2)

[1007] Intermediate 54-1 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), and the reaction was stirred at 110 °C overnight under nitrogen protection. After work-up, water and EA were added to the reaction solution, and after stirring well, the EA phase was separated out, and the water phase was extracted with EA twice, and the EA phases were combined, and the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography (PE / EA = 10:1-6:1), and the column effluent was concentrated under reduced pressure to obtain intermediate 54-2. LC-MS: [M+H] + = 511.

[1008] Preparation of compound 54 in step (3)

[1009] Intermediate 54-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), and then DCDMH (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction solution was added dropwise to stirring ammonia water (20 mg, 1.20 mmol), and the reaction was stirred at room temperature for 10 min. After work-up, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC with a H2O / ACN system, and the freeze-dried preparation solution to obtain compound 54. LC-MS: [M+H] + = 468.

[1010] 1H NMR (400MHz, DMSO-d6) δ10.57(s,1H),8.23(d,J=2.2Hz,1H),8.13(d,J=3.1Hz,1H),7.80–7.69(m,2H),7.56(d,J=8.5Hz,1H),7.48(d d,J=8.7,5.3Hz,3H),7.33(dd,J=9.5,3.1Hz,1H),7.17(td,J=8.5,3.1Hz,1H),7.01(dd,J=9.1,3.6Hz,1H),5.64(s,2H),3.86(s,2H).

[1011] Example 55

[1012] Preparation of Compound 55: 2-(2-chloro-4-fluorophenyl)-N-(4-((((5-fluoropyridin-2-yloxy)methyl)methyl)-3-aminosulfonylphenyl)acetamide

[1013]

[1014] Synthetic route

[1015]

[1016] Step (1) Preparation of intermediate 55-1

[1017] Intermediate 21-4 (600 mg, 1.62 mmol), intermediate 53-1 (280 mg, 1.95 mmol), and Ag₂CO₃ (447 mg, 3.24 mmol) were dissolved in THF (10 mL), and the mixture was heated to 60 °C and stirred for 3 h. For post-processing, water and EA were added to the reaction solution, and after thorough stirring, the EA phase was separated. The aqueous phase was then extracted three times with EA, and the EA phases were combined and concentrated under reduced pressure to obtain intermediate 55-1. LC-MS: [M+H] + =469.

[1018] Preparation of intermediate 55-2 in step (2)

[1019] Intermediate 55-1 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3(45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL) under nitrogen protection, then the reaction was stirred at 110 °C overnight. The reaction was post-treated by adding water and EA, after stirring well, the EA phase was separated, the water phase was extracted with EA twice, the EA phases were combined, the reaction solution was concentrated under reduced pressure, then purified by silica gel column chromatography (PE / EA = 10:1-6:1), and the column effluent was concentrated under reduced pressure to obtain intermediate 55-2. LC-MS: [M+H]=511. +

[1020] Step (3) Preparation of compound 55

[1021] Intermediate 55-2 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction solution was added dropwise to stirring ammonia water (20 mg, 1.20 mmol), and the reaction was stirred at room temperature for 10 min. The reaction was post-treated by concentrating under reduced pressure to obtain a crude product. The crude product was purified by prep-HPLC using a H2O / ACN system, and freeze-dried to obtain compound 55. LC-MS: [M+H]=468. +

[1022] 1 H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.78 (dd, J = 8.4, 2.1 Hz, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.44 (ddd, J = 11.6, 8.8, 4.5 Hz, 2H), 7.32 (s, 2H), 7.19 (td, J = 8.6, 2.7 Hz, 2H), 5.37 (t, J = 5.6 Hz, 1H), 4.81 (d, J = 5.5 Hz, 2H), 3.82 (s, 2H).

[1023] Example 56

[1024] Preparation of compound 56: 2-(2-chlorophenyl)-N-(4-(((1-methyl-1H-pyrazol-3- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1025] ​​

[1026] Synthesis route

[1027]

[1028] Preparation of intermediate 56-1 in step (1)

[1029] Intermediate 1-4 (5 g, 0.013 mol) was dissolved in 1,4-dioxane (50 mL), and intermediate 1-9 (benzyl mercaptan) (4.8 g, 0.039 mol), DIEA (5 g, 0.039 mol), Pd2(dba)3 (2.4 g, 0.0026 mol), xantphos (1.35 g, 0.0026 mol) were added, and the reaction was carried out at 110°C overnight after N2 replacement. EA was added, the organic phase was extracted with water, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and 50 mL of PE:EA (10:1) was added to the filtrate, which was then filtered after being washed. The product of intermediate 56-1 was obtained in a yield of 5 g, 90.9%.

[1030] Preparation of intermediate 56-2 in step (2)

[1031] Intermediate 56-1 (5 g, 0.012 mol) was dissolved in ACN (50 mL), and AcOH (3.6 g, 0.06 mol), H2O (5 mL), and NCS (N-chlorosuccinimide) (3.2 g, 0.024 mol) were added in batches under ice bath conditions, and the reaction was stirred at room temperature for 1 h. The reaction solution was extracted twice with ethyl acetate, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the product of intermediate 56-2 in an amount of 4 g.

[1032] Preparation of intermediate 56-3 in step (3)

[1033] Intermediate 56-2 (4 g, 0.01 mol) was dissolved in acetonitrile (40 mL), and 4-methoxybenzylamine (2.9 g, 0.02 mmol) was added, and the reaction was carried out at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain the product of intermediate 56-3 in an amount of 3.8 g.

[1034] Preparation of intermediate 56-4 in step (4)

[1035] Intermediate 56-3 (3.5 g, 7 mmol) was dissolved in THF (35 mL), and LAH (lithium aluminum hydride, 518 mg, 14 mmol) was added in batches under ice bath conditions, and the reaction was carried out at room temperature for 30 min. After quenching with 1 mL of an aqueous NaOH (3M) solution, the mixture was filtered, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 5:1 to 1:1) to obtain the product of intermediate 56-4 in an amount of 2.6 g.

[1036] Preparation of intermediate 56-5 in step (5)

[1037] Intermediate 56-4 (1.34 g, 0.03 mol) was dissolved in DCM (5 mL), SOCl2(0.67 g. 0.06 mmol) was added at room temperature, and the reaction was allowed to proceed at room temperature for 1 h. Directly concentrated under reduced pressure to obtain the product of intermediate 56-5, 1.4 g.

[1038] Preparation of intermediate 56-6 in step (6)

[1039] Intermediate 76-5 (1.4 g, 2.8 mmol) was dissolved in THF (15 mL), and intermediate 8-1 (1-methyl-1H-pyrazol-3-ol) (329 mg, 3.6 mmol) and silver carbonate (1.54 g, 5.6 mmol) were added, and the reaction was allowed to proceed at 70 °C for 3 h. After filtration, EA (20*3 mL) was added for extraction three times, and after drying, the product of intermediate 56-6, 490 mg, was obtained by silica gel column chromatography (PE / EA = 5:1~1:1) and concentration under reduced pressure.

[1040] Preparation of compound 56 in step (7)

[1041] Intermediate 56-6 (375 mg, 0.67 mmol) was dissolved in DCM (4 mL), and TFA (2 mL) was added, and the reaction was allowed to proceed at room temperature overnight. After direct concentration under reduced pressure, a yellow crude product was obtained. The crude product was separated by prep-HPLC using a H2O / ACN system, and after lyophilization, the product of compound 56, 32.6 mg, was obtained with a purity of 99.298% and a yield of 11.2%. LC-MS: [M+H] + = 435.

[1042] 1 H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 7.79 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 (d, J = 8.5 Hz, 1H), 7.47 (s, 1H), 7.46 (s, 2H), 7.44 - 7.39 (m, 2H), 7.30 (ddd, J = 5.1, 4.1, 3.0 Hz, 2H), 5.68 (d, J = 2.3 Hz, 1H), 5.44 (s, 2H), 3.84 (s, 2H), 3.65 (s, 3H).

[1043] Example 57

[1044] Preparation of Compound 57: 2-(2-chlorophenyl)-N-(4-(((1-cyclopropyl-1H-pyrazol-4-yl)oxy)methyl)-3-aminosulfonylphenyl)acetamide

[1045]

[1046] Synthetic route

[1047]

[1048] Step (1) Preparation of intermediate 57-2

[1049] In a 25 mL reaction flask, intermediate 57-1 (900 mg, 4.8 mmol), B2pin2 (pinacol diboronate, 2.54 g, 9.8 mmol), potassium acetate (1.41 g, 14.4 mmol), Pd(dppf)Cl2 (731 mg, 1.0 mmol), and 1,4-dioxane (3 mL) were added. The reaction was carried out overnight at 100°C under nitrogen protection. Treatment: Water (30 mL) was added, and the aqueous phase was extracted twice with ethyl acetate (30 mL). The organic phases were combined, washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 3 / 1) to obtain 1.2 g of intermediate 57-2.

[1050] Preparation of intermediate 57-3 in step (2)

[1051] Add 1.2 g of intermediate 57-2 obtained in step (1) to methanol (10 mL) and hydrogen peroxide (3 mL 30%), and react overnight at room temperature. Add water (30 mL), quench the reaction with sodium sulfite, concentrate under reduced pressure to remove methanol, and then extract the product with EA 30 mL*3. Dry, concentrate under reduced pressure to obtain 900 mg of intermediate 57-3, and directly proceed to the next step.

[1052] Preparation of intermediate 57-4 in step (3)

[1053] In a 25 mL reaction flask, intermediate 57-3 (900 mg, 4.8 mmol), intermediate 1-6 (1.19 g, 3.2 mmol), potassium carbonate (1.33 g, 9.6 mmol), and DMF (10 mL) were added. Under nitrogen protection, the reaction was carried out overnight at room temperature. Water (100 mL) was added, and the aqueous phase was extracted twice with ethyl acetate (40 mL). The organic phases were combined, washed twice with saturated sodium chloride (100 mL), dried, concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) to obtain 230 mg of intermediate 57-4.

[1054] Preparation of intermediate 57-5 in step (4)

[1055] In a 25 mL reaction bottle, intermediate 57-4 (230 mg, 0.5 mmol), intermediate 1-9 (benzyl mercaptan) (186 mg, 1.5 mmol), Pd2(dba)3 (100 mg, 0.1 mmol), Xantphos (58 mg, 0.1 mmol), DIEA (194 mg, 1.5 mmol), 1,4-dioxane (6 mL), nitrogen protection, 110 Celsius reaction overnight. The reaction was filtered to obtain the crude product, which was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain 230 mg of intermediate 57-5 product.

[1056] Step (5) Preparation of compound 57

[1057] In a 25 mL reaction bottle, intermediate 57-5 (230 mg, 0.46 mmol), acetic acid 30 μL, acetonitrile 3 mL, water 10 μL, intermediate 1-11 (DCDMH) (184 mg, 0.92 mmol) was added in batches under ice bath conditions, and the sample was sent after 10 min. LCMS showed about 40% product. Ammonia water (5 mL) was added to the reaction system, stirred in water (20 mL) for 10 min, the organic phase was extracted twice with ethyl acetate (30 mL), washed with saturated sodium chloride (50 mL), dried with anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, which was separated and purified by prep-HPLC with H2O / ACN system, and freeze-dried to obtain the product 40 mg of compound 57. LC-MS: [M+H] + = 461.05

[1058] 1 H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.22 (s, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.53 (s, 1H), 7.49 (s, 2H), 7.46-7.37 (m, 2H), 7.33-7.25 (m, 2H), 7.20 (s, 1H), 5.23 (s, 2H), 3.84 (s, 2H), 3.64-3.51 (m, 1H), 0.97-0.90 (m, 2H), 0.90-0.84 (m, 2H).

[1059] Example 58

[1060] Preparation of compound 58: 2-(2-chlorophenyl)-N-(4-((3-(methylsulfonyl imidoyl) phenoxy) methyl)-3-sulfamoylphenyl)acetamide

[1061]

[1062] Synthesis route:

[1063]

[1064] Preparation of intermediate 58-2 in step (1)

[1065] Weighed intermediate 1-6 (1.0 g, 2.68 mmol) was dissolved in DMF (15 mL), and intermediate 58-1 (414 mg, 2.949 mmol), K2CO3 (741 mg, 5.36 mmol) were added. After the addition was completed, the reaction was allowed to react at room temperature for 2 h. The reaction solution was extracted with ethyl acetate twice after the addition of water, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was purified by silica gel column chromatography (PE / EA = 10 / 1 to 5 / 1) to obtain 900 mg of the product of intermediate 58-2.

[1066] Preparation of intermediate 58-3 in step (2)

[1067] Weighed intermediate 58-2 (850 mg, 1.783 mmol) was dissolved in 30 mL of methanol, and ammonium carbonate (686 mg, 7.132 mmol) was added. While stirring, iodobenzene acetate (1.7 g, 5.348 mmol) was added, and after the addition was completed, the reaction was allowed to react at room temperature for 1 h. The reaction solution was quenched with saturated sodium sulfite solution and extracted with EA. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was purified by silica gel column chromatography (PE / EA = 2 / 1 to 1 / 2) to obtain 800 mg of the product of intermediate 58-3. LC-MS: [M+H] = 509. +

[1068] Preparation of intermediate 58-4 in step (3)

[1069] Weighed intermediate 58-3 (600 mg, 1.181 mmol) was dissolved in 1,4-dioxane (20 mL), and intermediate 1-9 (benzyl mercaptan) (294 mg, 2.363 mmol), Pd2(dba)3 (108 mg, 0.118 mmol), Xantphos (69 mg, 0.118 mmol), and DIEA (610 mg, 4.726 mol) were added. The reaction was allowed to react at 100°C overnight under nitrogen protection. The reaction solution was added with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was purified by silica gel column chromatography (DCM / MeOH = 100 / 1) to obtain 600 mg of the product of intermediate 58-4. LC-MS: [M+H] = 551. +

[1070] Preparation of compound 58 in step (4) ​​

[1071] Weighed intermediate 58-4 (350 mg, 0.635 mmol) was dissolved in CH3CN (8 mL), added intermediate 1-11 (DCDMH) (150 mg, 0.762 mmol), AcOH (1 mL) and H2O (1 mL), reacted at room temperature for 5 min, the reaction solution was added to ammonia water (2 mL), the reaction solution was added to water, extracted with EA, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC with a H2O / ACN system to obtain 78.1 mg of compound 58 product. LC-MS: [M+H] + = 508.1

[1072] 1 H NMR (400 MHz, DMSO-d6): δ 10.61 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.86 (dd, J = 8.5, 2.2 Hz, 1H), 7.69 - 7.59 (m, 6H), 7.47 - 7.41 (m, 3H), 7.32 (ddd, J = 5.1, 4.1, 3.0 Hz, 2H), 5.52 (s, 2H), 3.87 (s, 2H), 3.52 (s, 3H).

[1073] Example 59

[1074] Preparation of compound 59: 2-(2-chlorophenyl)-N-(4-(1-((6-fluoropyridin-3- yl)oxy)ethyl)-3-sulfamoylphenyl)acetamide

[1075]

[1076] Synthetic route

[1077]

[1078] Preparation of intermediate 59-2 in step (1)

[1079] Intermediate 59-1 (3 g, 0.01 mol), tributyl(1-ethoxyvinyl)tin (5.6 g, 0.015 mol), Pd2(dba)3 (915 mg, 0.001 mol), CsF (3 g, 0.02 mol), t-Bu3P (0.2 g, 0.001 mol) were dissolved in 1,4-dioxane (30 mL), replaced with nitrogen, and stirred at 110 °C overnight. After treatment, KF aqueous solution and EA were added to the reaction solution, and after stirring, the EA phase was separated, the water phase was extracted with EA twice, and the combined EA phase was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 3:1-1:1), and the column effluent was concentrated under reduced pressure to obtain the product of intermediate 59-2, 600 mg. LC-MS: [M+H] + = 328.

[1080] Preparation of intermediate 59-3 in step (2)

[1081] Intermediate 59-2 (600 mg, 1.83 mmol) was dissolved in 1M HCl / 1,4-dioxane (12 mL, 9.17 mmol), and stirred at room temperature for 0.5 h. After treatment, the reaction solution was concentrated under reduced pressure to obtain the product of intermediate 59-3, 510 mg. LC-MS: [M+H] + = 300.

[1082] Preparation of intermediate 59-4 in step (3)

[1083] Intermediate 59-3 (530 mg, 1.77 mmol), Fe (495 mg, 8.85 mmol), NH4Cl (938 mg, 17.7 mmol) were dissolved in EtOH / H2O (6 mL / 1.5 mL), and stirred at 70 °C for 2 h. After treatment, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the product of intermediate 59-4, 500 mg. LC-MS: [M+H] + = 270.

[1084] Preparation of intermediate 59-5 in step (4)

[1085] Intermediate 59-4 (500 mg, 1.86 mmol), intermediate 1-3 (2-chlorobenzenacetic acid) (316 mg, 1.86 mmol), TEA (563 mg, 5.58 mmol), T3P (887 mg, 2.79 mmol) were dissolved in DCM (8.0 mL) and stirred at room temperature for 2 h. Work-up was performed by adding water and DCM to the reaction mixture, and after stirring well, the DCM phase was separated. The aqueous phase was extracted twice with DCM, and the combined DCM phases were concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA = 3:1-2:1) to give intermediate 59-5 (440 mg). LC-MS: [M+H] = 422. + = 422.

[1086] Step (5) Preparation of intermediate 59-6

[1087] Intermediate 59-5 (100 mg, 0.24 mmol) was dissolved in MeOH (2.0 mL), and NaBH4 (18 mg, 0.48 mmol) was added to the reaction mixture under ice bath. The reaction mixture was stirred at room temperature for 0.5 h. Work-up was performed by purification of the reaction mixture by PREP-TLC. After soaking the scraped plate, the soaked solution was concentrated under reduced pressure to give intermediate 59-6 (42 mg). LC-MS: [M+H] = 406. + = 406.

[1088] Step (6) Preparation of intermediate 59-7

[1089] Intermediate 59-6 (40 mg, 0.096 mmol), SOCl2 (24 mg, 0.192 mmol) were dissolved in DCM, and the reaction mixture was stirred at room temperature for 2 h. Work-up was performed by direct concentration under reduced pressure to give intermediate 59-7 (30 mg). LC-MS: [M+H] = 442. + = 442.

[1090] Step (7) Preparation of intermediate 59-8

[1091] Intermediate 59-7 (30 mg, 0.069 mmol), intermediate 9-1 (2-fluoro-5-hydroxypyridine) (12 mg, 0.083 mmol), K2CO3 (20 mg, 0.138 mmol) were dissolved in DMF (1.0 mL), and the reaction mixture was stirred at 40 °C overnight. Work-up was performed by washing the reaction mixture with water and extracting twice with EA. The combined EA phases were concentrated under reduced pressure to 2-3 mL of a crude product, which was purified by PREP-TLC. After soaking the scraped plate, the soaked solution was concentrated under reduced pressure to give intermediate 59-8 (26 mg). LC-MS: [M+H] = 519 / 521. + = 519 / 521.

[1092] Step (8) Preparation of compound 59

[1093] Intermediate 59-8 (30 mg, 0.058 mmol) was dissolved in methanol (0.5 mL), and hydrazine hydrate (15 mg, 0.29 mmol) was added. The reaction was stirred at room temperature for 0.5 h. The reaction was concentrated under reduced pressure to give a crude product. The crude product was separated and purified by prep-HPLC with a H2O / ACN system, and the product of compound 59 was obtained by lyophilization of the preparation solution. LC-MS: [M+H] + = 464 / 466.

[1094] 1 H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.41 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.88-7.82 (m, 2H), 7.73 (dd, J = 8.5, 2.1 Hz, 2H), 7.54 (dt, J = 7.4, 2.9 Hz, 2H), 7.40 (ddd, J = 9.3, 4.8, 2.5 Hz, 2H), 7.31-7.25 (m, 2H), 6.98 (dd, J = 8.9, 3.4 Hz, 1H), 6.11-6.06 (m, 1H), 3.81 (s, 2H), 1.59 (d, J = 6.2 Hz, 3H).

[1095] Example 60

[1096] Preparation of compound 60: N-(4-(((4-chloro-lH-pyrazol-3-yl)oxy)methyl)-3- sulfamoylphenyl)-2-(2-chlorophenyl)acetamide

[1097]

[1098] Synthetic route

[1099]

[1100] Preparation of intermediate 60-1 in step (1)

[1101] A weighed amount of 1,2-dihydro-3H-pyrazol-3-one (1.0 g, 11.893 mmol) was dissolved in DCM (20 mL), and Boc anhydride (2.9 g, 13.083 mmol) and TEA (triethylamine) (3.6 g, 35.679 mmol) were added. After the addition was completed, the reaction was stirred at room temperature for 12 h. The reaction was directly rotary evaporated to dryness, diluted with EA, and the pH was adjusted to 5.6-6.0 with 0.1 N hydrochloric acid. The organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the product of intermediate 60-1, 2.0 g, as a yellow oily liquid.

[1102] Preparation of intermediate 60-2 in step (2)

[1103] The weighed intermediate 1-6 (500 mg, 1.34 mmol) was dissolved in THF (20 mL), and intermediate 60-1 (297 mg, 1.609 mmol), Ag2CO3 (740 mg, 2.68 mmol) were added, and the reaction was refluxed at 70 °C for 24 h. LCMS monitoring showed that the product was generated, and the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE / EA = 10 / 1 ~ 5 / 1) to obtain 420 mg of the product of intermediate 60-2.

[1104] Step (3) Preparation of intermediate 60-3

[1105] The weighed intermediate 60-2 (370 mg, 0.879 mmol) was dissolved in 1,4-dioxane (15 mL), and intermediate 1-9 (benzyl mercaptan) (219 mg, 1.759 mmol), Pd2(dba)3 (81 mg, 0.088 mmol), Xantphos (51 mg, 0.088 mmol), DIEA (341 mg, 2.639 mmol) were added, and the reaction was carried out at 110 °C under nitrogen protection overnight. The reaction solution was added with water, extracted with EA, and the organic phase was saturated with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The reaction solution was purified by silica gel column chromatography (PE / EA = 5 / 1) to obtain 270 mg of the product of intermediate 60-3.

[1106] Step (4) Preparation of intermediate 60-4

[1107] Intermediate 60-3 (170 mg, 0.301 mmol) was dissolved in CH3CN (2 mL), AcOH (0.25 mL) and H2O (0.25 mL), and intermediate 1-11 (DCDMH) (116 mg, 0.603 mmol) was added, and the reaction was carried out at room temperature for 10 min. The reaction solution was added dropwise to stirring ammonia water (0.5 mL), and the reaction solution was added with water, extracted with EA, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 200 mg of the product of intermediate 60-4, which was directly used in the next reaction.

[1108] Step (5) Preparation of compound 60

[1109] Weighed intermediate 60-4 (200 mg, 0.361 mmol) was dissolved in DME (2 mL), added sodium carbonate (46 mg, 0.432 mmol), and the mixture was reacted at 100 °C for 0.5 h. The reaction solution was added to water and extracted with EA. The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC using a H2O / ACN system, and the product of compound 60 was obtained by freeze-drying the preparation solution. LC-MS: [M+H]=455.05. + = 455.05.

[1110] 1 H NMR (400 MHz, DMSO-d6): δ 12.29 (s, 1H), 10.58 (s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 7.89-7.79 (m, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.54-7.38 (m, 4H), 7.35-7.27 (m, 2H), 5.58 (s, 2H), 3.86 (s, 2H).

[1111] Example 61

[1112] Preparation of compound 61: 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1113]

[1114] Synthetic route

[1115]

[1116] Preparation of intermediate 61-2 in step (1)

[1117] Intermediate 1-6 (400 mg, 1.08 mmol), intermediate 61-1 (217 mg, 1.62 mmol), and K2CO3 (300 mg, 2.16 mmol) were dissolved in DMF (5 mL) and stirred at room temperature overnight. The reaction solution was added to water and EA, stirred thoroughly, and then the EA phase was separated. The water phase was extracted twice with EA (15 mL*2), and the combined EA phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EA = 5:1-3:1), and the product of intermediate 61-2 was obtained by concentrating the column eluate under reduced pressure. LC-MS: [M+H]=470 / 472. + = 470 / 472.

[1118] Preparation of intermediate 61-3 in step (2)

[1119] Intermediate 61-2 (300 mg, 0.64 mmol), intermediate 1-9 (benzyl mercaptan) (120 mg, 0.96 mmol), Pd2(dba)3 (58 mg, 0.064 mmol), DIEA (250 mg, 1.92 mmol), Xantphos (37 mg, 0.064 mmol) were dissolved in 1,4-dioxane (3 mL) under nitrogen protection, then the reaction was stirred at 110 °C overnight. The raw material was completely reacted. After treatment, water (15 mL) and EA (15 mL) were added to the reaction solution, and after stirring, the EA phase was separated, the water phase was extracted with EA (10 mL*2) twice, the EA phases were combined, and the reaction solution was concentrated under reduced pressure, then purified by silica gel column chromatography (PE / EA = 10:1-0:1), and the column eluent was concentrated under reduced pressure to obtain intermediate 61-3 product 300 mg. LC-MS: [M+H]=514 / 516. +

[1120] Step (3) Preparation of compound 61

[1121] Intermediate 61-3 (200 mg, 0.40 mmol) was dissolved in acetonitrile / water (2 mL / 0.2 mL), and then intermediate 1-11 (DCDMH) (110 mg, 0.60 mmol), AcOH (120 mg, 2.0 mmol) were added. The reaction was stirred at room temperature for 15 min. The reaction solution was added dropwise to stirring ammonia water (1 mL), and the reaction was stirred at room temperature for 20 min. After treatment, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC with H2O / ACN system, and freeze-dried to obtain a white solid 20 mg. LC-MS: [M+H]=471 / 473. +

[1122] 1 H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 8.28 (d, J = 2.2 Hz, 1H), 7.99 (s, 1H), 7.85 (dd, J = 8.4, 1.9 Hz, 1H), 7.70 (d, J = 5.9 Hz, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.55 (d, J = 5.1 Hz, 2H), 7.49 - 7.41 (m, 2H), 7.35 - 7.30 (m, 2H), 5.34 (s, 2H), 3.88 (s, 2H).

[1123] Example 62

[1124] Preparation of compound 62: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4- yl)oxy)methyl)-3-sulfamoylphenyl)acetamide ​​

[1125]

[1126] Synthesis route

[1127]

[1128] Preparation of intermediate 62-2 in step (1)

[1129] Intermediate 21-4 (600 mg, 1.62 mmol), intermediate 23-1 (280 mg, 1.95 mmol), K2CO3 (447 mg, 3.24 mmol) were dissolved in DMF (10 mL), and the reaction was stirred at 60 °C for 3 h. After work-up, water and EA were added to the reaction solution, and after stirring well, the EA phase was separated out, and the water phase was extracted with EA three times, and the EA phases were combined and concentrated under reduced pressure to obtain 460 mg of the product intermediate 62-2. LC-MS: [M+H] + = 452 / 454.

[1130] Preparation of intermediate 62-3 in step (2)

[1131] Intermediate 62-2 (450 mg, 0.94 mmol), intermediate 1-9 (benzyl mercaptan) (233 mg, 1.88 mmol), Pd2(dba)3 (45 mg, 0.047 mmol), DIEA (365 mg, 2.82 mmol), Xantphos (27 mg, 0.047 mmol) were dissolved in 1,4-dioxane (5 mL), and the reaction was stirred at 110 °C overnight under nitrogen protection. After work-up, water and EA were added to the reaction solution, and after stirring well, the EA phase was separated out, and the water phase was extracted with EA twice, and the EA phases were combined and concentrated under reduced pressure, and then separated and purified by silica gel column chromatography (PE / EA = 10:1-6:1), and the column effluent was concentrated under reduced pressure to obtain 290 mg of the product as a yellow solid. LC-MS: [M+H] + = 496 / 498.

[1132] Preparation of intermediate 62-4 in step (3)

[1133] Intermediate 62-3 (200 mg, 0.38 mmol) was dissolved in acetonitrile / water (4 mL / 0.4 mL), and then intermediate 1-11 (DCDMH) (150 mg, 0.76 mmol), AcOH (114 mg, 1.9 mmol) were added. The reaction was stirred at room temperature for 15 min. After work-up, the reaction solution was directly concentrated under reduced pressure to obtain 150 mg of the product intermediate 62-4. LC-MS: [M+H] + = 472 / 474.

[1134] Preparation of compound 62 in step (4)

[1135] Intermediate 62-4 (120 mg, 0.24 mmol) was added to ammonia water (1 mL), the reaction was stirred at room temperature for 10 min. The reaction was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC with H2O / ACN system, and the product of compound 62 was obtained by freeze-drying the preparation solution, 39 mg. LC-MS: [M+H] + = 453 / 455.

[1136] 1 H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 8.22 (d, J = 2.2 Hz, 1H), 7.79 (dd, J = 8.5, 2.2 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.48 (s, 2H), 7.47 - 7.38 (m, 3H), 7.19 (td, J = 8.4, 2.7 Hz, 2H), 5.24 (s, 2H), 3.82 (d, J = 8.2 Hz, 2H), 3.70 (s, 3H).

[1137] Example 63

[1138] Preparation of compound 63: 2-(2-chlorophenyl)-N-(4-(((1-(cyclopropylmethyl)-1H- pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1139]

[1140] Synthetic route

[1141]

[1142] Preparation of intermediate 63-2 in step (1)

[1143] Intermediate 63-1 (1 g, 5.2 mmol) was dissolved in DMF (10 mL), cyclopropylmethyl bromide (696 mg, 5.2 mmol), potassium carbonate (1.42 g, 10.4 mmol) were added, and the reaction was stirred at room temperature for 2 h. The reaction was extracted with water and ethyl acetate twice, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and separated and purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain the product of intermediate 63-2, 1.1 g. LC-MS: [M+H] + = 249.20.

[1144] Preparation of intermediate 63-3 in step (2)

[1145] Intermediate 63-2 (1 g, 4 mmol) was dissolved in MeOH (10 mL) and hydrogen peroxide (2.28 g, 20 mmol) was added. The reaction was stirred at room temperature for 5 h. The reaction was quenched with sodium sulfite solution and extracted with ethyl acetate twice. The organic phase was combined and washed with saturated brine solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA = 5 / 1 to 3 / 1) to give the product 63-3 (478 mg). LC-MS: [M+H] + = 139.

[1146] Step (3) Preparation of intermediate 63-4

[1147] Intermediate 1-6 (500 mg, 1.35 mmol) was dissolved in DMF (5 mL) and intermediate 63-3 (225 mg, 1.62 mmol) and potassium carbonate (375.3 mg, 2.7 mmol) were added. The reaction was stirred at room temperature for 2 h. The reaction was diluted with water and extracted with ethyl acetate twice. The organic phase was combined and washed with saturated brine solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE / EA = 5 / 1 to 3 / 1) to give the product 63-4 (650 mg). LC-MS: [M+H] + = 474.

[1148] Step (4) Preparation of intermediate 63-5

[1149] Intermediate 63-4 (660 mg, 1.4 mmol) was dissolved in 1,4-dioxane (8 mL) and intermediate 1-9 (benzyl mercaptan) (518 mg, 4.2 mmol), Pd2(dba)3 (256 mg, 0.28 mmol), Xantphos (145 mg, 0.28 mmol), and DIEA (520 mg, 1.2 mmol) were added. The reaction was stirred at 110 °C for 16 h. The reaction was concentrated under reduced pressure and purified by column chromatography on silica gel (PE / EA = 5 / 1 to 3 / 1) to give the product 63-5 (460 mg). LC-MS: [M+H] + = 517.

[1150] Step (5) Preparation of compound 63

[1151] Intermediate 63-5 (200 mg, 0.38 mmol) and intermediate 1-11 (DCDMH) (151 mg, 0.774 mmol) were dissolved in CH3CN (1 mL), AcOH (116 mg), and H2O (0.1 mL) and reacted at room temperature for 5 min. The reaction mixture was then added dropwise to ammonia water (10 mL) under stirring and stirred at room temperature for 0.5 h. The reaction mixture was diluted with water (20 mL) and extracted three times with DCM (10 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC using an H2O / ACN system, and lyophilized to obtain 24.2 mg of compound 63. LC-MS: [M+H] + =476.

[1152] 1 H NMR (400MHz, DMSO-d6): δ10.54(s,1H),8.23(d,J=2.2Hz,1H),7.80(dd,J=8.4,2.2Hz,1H),7.61(d,J=8.4Hz,1H),7.52(s,1H),7.42(ddd,J=8.9,5 .2,2.3Hz,3H),7.33–7.26(m,2H),7.21(d,J=0.6Hz,1H),5.24(s,2H),3. 89–3.77(m,4H),1.19–1.08(m,1H),0.52–0.43(m,2H),0.32–0.26(m,2H).

[1153] Example 64

[1154] Preparation of Compound 64: 2-(2-chloro-5-fluorophenyl)-N-(4-(((1-methyl-1H-pyrazol-4-yl)oxy)methyl)-3-aminosulfonylphenyl)acetamide

[1155]

[1156] 1. Synthetic route

[1157]

[1158] Step (1) Preparation of intermediate 64-1

[1159] Intermediate 22-4 (400 mg, 1.03 mmol) was dissolved in DMF (3 mL), and intermediate 23-1 (100 mg, 1.03 mmol), potassium carbonate (284 mg, 2.06 mmol) were added, and stirred at room temperature for 2 h. The reaction solution was extracted with ethyl acetate twice, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain 400 mg of the product of intermediate 64-1, with a yield of 86.3%. LC-MS: [M+H] = 452. + = 452.

[1160] Preparation of intermediate 64-2 in step (2)

[1161] Intermediate 64-1 (400 mg, 0.88 mmol) was dissolved in 1,4-dioxane (4 mL), and intermediate 1-9 (benzyl mercaptan) (329 mg, 2.65 mmol), Pd2(dba)3 (161 mg, 0.176 mmol), Xantphos (101.7 mg, 0.1 mmol), DIEA (330 mg, 2.65 mmol) were added, and reacted at 110°C for 16 h. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain 400 mg of the product of intermediate 64-2, with a yield of 90.1%. LC-MS: [M+H] = 496. + = 496.

[1162] Preparation of compound 64 in step (3)

[1163] Intermediate 64-2 (65 mg, 0.13 mmol), and intermediate 1-11 (DCDMH) (38.7 mg, 0.197 mmol) were dissolved in CH3CN (1 mL), AcOH (39 mg), and H2O (0.1 mL), and reacted at room temperature for 5 min.

[1164] The reaction solution was added dropwise to stirring ammonia water (10 mL), and stirred at room temperature for 0.5 h. The reaction solution was diluted with water (20 mL), and extracted with DCM (10 mL) three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using a H2O / ACN system, and lyophilized to obtain 10 mg of the product of compound 64, with a yield of 16.9%. LC-MS: [M+H] = 454. + = 454.

[1165] 1H NMR (400 MHz, DMSO-d6): δ 10.55 (s, 1H), 8.21 (d, J = 2.0 Hz, 1H), 7.78 (dd, J = 8.6, 1.9 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.52 - 7.40 (m, 4H), 7.32 (dd, J = 9.5, 3.0 Hz, 1H), 7.19 (d, J = 3.7 Hz, 1H), 7.16 (dd, J = 8.5, 3.1 Hz, 1H), 5.24 (s, 2H), 3.85 (s, 2H), 3.70 (s, 3H).

[1166] Example 65

[1167] Preparation of compound 65: 2-(2-chloro-5-fluorophenyl)-N-(4-(((1- (difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1168]

[1169] Synthetic route

[1170]

[1171] Preparation of intermediate 65-1 in step (1)

[1172] Intermediate 61-1 (207 mg, 1.5 mmol) was dissolved in DMF (3 mL), after adding intermediate 22-4 (400 mg, 1.0 mmol), potassium carbonate (282 mg, 2.04 mmol), it was stirred at room temperature for 2 h. The reaction solution was extracted with ethyl acetate twice, the organic phase was combined, washed with saturated brine successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to give 250 mg of product of intermediate 65-1 with a yield of 50%. LC-MS: [M+H] = 488. +

[1173] Preparation of intermediate 65-2 in step (2)

[1174] ​Intermediate 65-1 (250 mg, 0.5 mmol) was dissolved in 1,4-dioxane (5 mL), intermediate 1-9 (benzyl mercaptan) (190 mg, 1.5 mmol), Pd2(dba)3 (93.9 mg, 0.1 mmol), Xantphos (59 mg, 0.1 mmol), DIEA (191 mg, 1.5 mmol) were added, and the reaction was carried out at 110 °C for 16 h. The reaction was concentrated under reduced pressure and purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain 218 mg of intermediate 65-2 product, with a yield of 81.9%. LC-MS: [M+H] = 532. + = 532.

[1175] Step (3) Preparation of compound 65

[1176] Intermediate 65-2 (204 mg, 0.39 mmol), intermediate 1-11 (DCDMH) (150.6 mg, 0.76 mmol) were dissolved in CH3CN (2 mL), AcOH (115 mg) and H2O (0.1 mL), and the reaction was carried out at room temperature for 5 min (to obtain intermediate 65-3). The reaction was added dropwise to stirring ammonia water (10 ml) and stirred at room temperature for 0.5 h. The reaction was diluted with water (20 mL) and extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC with a H2O / ACN system, and freeze-dried to obtain 26.2 mg of compound 65 product, with a yield of 13.7%. LC-MS: [M+H] = 489. + = 489.

[1177] 1 H NMR (400 MHz, DMSO-d6): δ 10.58 (s, 1H), 8.23 (s, 1H), 7.96 (s, 1H), 7.81 (d, J = 6.3 Hz, 1H), 7.67 (d, J = 5.9 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.57 - 7.42 (m, 3H), 7.33 (dd, J = 9.3, 2.6 Hz, 1H), 7.22 - 7.12 (m, 1H), 5.31 (s, 2H), 3.86 (s, 2H).

[1178] Example 66

[1179] Preparation of compound 66: 2-(2-chlorophenyl)-N-(4-(((1-(1,1-difluoropropyl)-1H- pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1180]

[1181] Synthesis route

[1182]

[1183] Preparation of intermediate 66-2 in step (1)

[1184] Intermediate 63-1 (500 mg, 2.57 mmol) was dissolved in DMF (5 mL), and then intermediate 66-1 (bromodifluoropropene) (605 mg, 3.85 mmol) and K2CO3 (709 mg, 5.14 mmol) were added. After reaction at room temperature under N2 protection overnight, the reaction was stopped, water was added to the reaction solution, and then EA was added for extraction. The EA phases were combined, and the reaction solution was concentrated under reduced pressure. Purification by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) yielded 410 mg of intermediate 66-2 product, with a yield of 59.2%. LC-MS: [M+H] + = 271.

[1185] Preparation of intermediate 66-3 in step (2)

[1186] Intermediate 66-2 (410 mg, 1.51 mmol) was dissolved in methanol (10 mL), and then palladium-carbon (100 mg) was added. After stirring at room temperature under hydrogen protection for 5 h, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain 410 mg of intermediate 66-3 product. LC-MS: [M+H] + = 273.

[1187] Preparation of intermediate 66-4 in step (3)

[1188] Intermediate 66-3 (410 mg, 1.51 mmol) was dissolved in methanol (5 mL), and then hydrogen peroxide (5 mL, 30%) was added. After stirring at room temperature for 2 h, the reaction solution was quenched with saturated sodium sulfite at 0°C, and then extracted twice with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel column chromatography (PE / EA = 5 / 1 to 3 / 1) yielded 180 mg of intermediate 66-4 product, with a yield of 72.8%. LC-MS: [M+H] + = 163.

[1189] Preparation of intermediate 66-5 in step (4)

[1190] Intermediate 66-4 (180 mg, 1.1 mmol) was dissolved in DMF (4 mL), and intermediate 1-6 (410 mg, 1.1 mmol), potassium carbonate (455 mg, 3.3 mmol) were added, and stirred at room temperature for 2 h. The reaction solution was extracted with ethyl acetate twice, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain 360 mg of the product of intermediate 66-5, with a yield of 65.6%. LC-MS: [M+H] = 499. + = 542.

[1191] Preparation of intermediate 66-6 in step (5)

[1192] Intermediate 66-5 (360 mg, 0.72 mmol) was dissolved in 1,4-dioxane (5 mL), and intermediate 1-9 (benzyl mercaptan) (267 mg, 2.16 mmol), Pd2(dba)3 (64 mg, 0.07 mmol), Xantphos (40 mg, 0.07 mmol), DIEA (280 mg, 2.16 mmol) were added, and reacted at 110°C for 16 h. The reaction solution was concentrated under reduced pressure, and purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain the product, and 300 mg of intermediate 66-6 was obtained with a yield of 76.9%. LC-MS: [M+H] = 542. + = 542.

[1193] Preparation of compound 66 in step (6)

[1194] Intermediate 66-6 (300 mg, 0.55 mmol), intermediate 1-11 (DCDMH) (216 mg, 1.1 mmol), were dissolved in CH3CN (3 mL), AcOH (165 mg, 2.75 mmol), and H2O (0.1 mL), and reacted at room temperature for 5 min. The reaction solution was added dropwise to stirring ammonia water (10 mL), and stirred at room temperature for 0.5 h. The reaction solution was diluted with water (20 mL), and extracted with DCM (10 mL) three times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by prep-HPLC using a H2O / ACN system, and lyophilized to obtain 83.4 mg of the product of compound 66 with a yield of 30.3%. LC-MS: [M+H] = 499. + = 542.

[1195] 1H NMR (400 MHz, DMSO-d6): δ 10.54 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 7.81 (dd, J = 8.4, 2.2 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.55 (s, 1H), 7.49 (s, 2H), 7.42 (ddd, J = 8.4, 5.4, 2.2 Hz, 2H), 7.34 - 7.24 (m, 3H), 6.20 (t, J = 4.4 Hz, 1H), 6.06 (t, J = 4.4 Hz, 1H), 5.92 (t, J = 4.4 Hz, 1H), 5.25 (s, 2H), 4.13 (t, J = 7.2 Hz, 2H), 3.84 (s, 2H), 2.41 - 2.22 (m, 2H).

[1196] Example 67

[1197] Preparation of compound 67: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1- (difluoromethyl)-1H-pyrazol-4-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1198]

[1199] Synthetic route

[1200]

[1201] Preparation of intermediate 67-1 in step (1)

[1202] Intermediate 61-1 (200 mg, 1.5 mmol) was dissolved in DMF (3 mL), after adding intermediate 21-4 (400 mg, 1.0 mmol), potassium carbonate (410 mg, 3.0 mmol), it was stirred at room temperature for 2 h. The reaction solution was extracted with ethyl acetate twice, the organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, and then purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 3 / 1) to obtain 240 mg of intermediate 67-1 product with a yield of 50%. LC-MS: [M+H] = 488. +

[1203] Preparation of intermediate 67-2 in step (2)

[1204] ​Intermediate 67-1 (240 mg, 0.5 mmol) was dissolved in 1,4-dioxane (5 mL), intermediate 1-9 (benzyl mercaptan) (124 mg, 1.0 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), Xantphos (30 mg, 0.05 mmol), DIEA (200 mg, 1.5 mmol) were added and the reaction was stirred at 110 °C for 16 h. The reaction was concentrated under reduced pressure and purified by silica gel column (PE / EA = 5 / 1 ~ 3 / 1) to give intermediate 67-2 product 210 mg, yield 78.9%. LC-MS: [M+H] = 532. + = 532.

[1205] Step (3) Preparation of compound 67

[1206] Intermediate 67-2 (210 mg, 0.39 mmol), intermediate 1-11 (DCDMH) (156 mg, 0.78 mmol) were dissolved in CH3CN (2 mL), AcOH (120 mg) and H2O (0.1 mL) and the reaction was stirred at room temperature for 5 min. The reaction was added dropwise to stirring ammonia water (10 ml) and stirred at room temperature for 0.5 h. The reaction was diluted with water (20 mL) and extracted with DCM (10 mL) three times. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude product. The crude product was separated by prep-HPLC with H2O / ACN system, and lyophilized to give compound 67 product 13.1 mg, yield 6.9%. LC-MS: [M+H]+ = 489.

[1207] 1 H NMR (400 MHz, DMSO-d6): δ 10.56 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 7.96 (s, 1H), 7.84-7.78 (m, 1H), 7.67 (d, J = 5.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 6.0 Hz, 2H), 7.44 (ddd, J = 11.4, 8.8, 4.4 Hz, 2H), 7.19 (td, J = 8.6, 2.8 Hz, 1H), 5.31 (s, 2H), 3.83 (s, 2H).

[1208] Example 68

[1209] Preparation of compound 68: N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide

[1210] Preparation of Compound 69: N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-5-yl)oxy)methyl)-3-aminosulfonylphenyl)-2-(2-chloro-4-fluorophenyl)acetamide

[1211]

[1212] Synthetic route

[1213]

[1214] Step (1) Preparation of intermediate 68-1

[1215] The weighed intermediate 21-4 (500 mg, 1.286 mmol) was dissolved in THF (20 mL), and intermediate 60-1 (355 mg, 1.928 mmol) and Ag₂CO₃ (709 mg, 2.571 mmol) were added. The mixture was refluxed at 70 °C overnight. LCMS monitoring showed product formation. The reaction solution was extracted twice with ethyl acetate and water. The organic phases were combined, washed successively with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product was purified by silica gel column chromatography (PE / EA = 10 / 1) to obtain 560 mg of intermediate 68-1.

[1216] Preparation of intermediate 68-2 in step (2)

[1217] The weighed intermediate 68-1 (560 mg, 1.039 mmol) was dissolved in DME / H2O (7.5 mL / 7.5 mL), and Na2CO3 (133 mg, 1.247 mmol) was added. The reaction mixture was reacted at 100 °C for 1 h. The reaction solution was extracted twice with ethyl acetate and water was added. The organic phases were combined, washed successively with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain 320 mg of intermediate 68-2.

[1218] Preparation of intermediates 68-3 and 69-1 in step (3)

[1219] The weighed intermediate 68-2 (320 mg, 0.729 mmol) was dissolved in acetonitrile (10 mL), and diethyl bromofluoromethyl phosphate (585 mg, 2.188 mmol) and KF (170 mg, 2.916 mmol) were added. The reaction mixture was reacted overnight at 70 °C. The reaction solution was extracted twice with ethyl acetate with water. The organic phases were combined, washed successively with saturated brine, dried over anhydrous sodium sulfate, and purified by Prep-TLC (PE / EA = 2 / 1) to obtain 90 mg of intermediate 68-3 and 90 mg of its isomer intermediate 69-1.

[1220] Preparation of intermediate 68-4 and intermediate 69-2 in step (4)

[1221] The weighed intermediate 68-3 (90 mg, 0.184 mmol) and intermediate 69-1 (90 mg, 0.184 mmol) were dissolved in 1,4-dioxane (2 mL) in two pots respectively, and intermediate 1-9 (benzyl mercaptan) (46 mg, 0.368 mmol), Pd2(dba)3(17 mg, 0.018 mmol), Xantphos (11 mg, 0.018 mmol), DIEA (72 mg, 0.555 mmol) were added respectively, and the reaction was carried out at 100 °C overnight under nitrogen protection. The reaction liquid was added with water, extracted with EA, and the organic phase was saturated with brine, dried over anhydrous sodium sulfate, and purified by Prep-TLC (PE / EA = 2 / 1) to obtain the product, 80 mg of intermediate 68-4 and 80 mg of its isomer intermediate 69-2.

[1222] Preparation of compound 68 and compound 69 in step (5)

[1223] Intermediate 68-4 (80 mg, 0.150 mmol) and intermediate 69-2 (80 mg, 0.150 mmol) were dissolved in CH3CN (2 ml), AcOH (0.25 mL) and H2O (0.25 mL) in two pots respectively, and intermediate 1-11 (DCDMH) (45 mg, 0.226 mmol) was added, and the reaction was carried out at room temperature for 5 min. The reaction liquid was added dropwise to the stirred ammonia water (0.5 mL), and the reaction liquid was added with water, extracted with EA, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the reaction liquid was concentrated under reduced pressure to obtain the crude product. The crude product was separated by prep-HPLC with H2O / ACN system to obtain the product compound 68 (10.2 mg) and compound 69 (13.6 mg) as white solids.

[1224] Compound 68: LC-MS: M fragment = 355.05.

[1225] 1 H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 8.47 (d, J = 10.7 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 8.4, 2.2 Hz, 1H), 7.76 (s, 1H), 7.65-7.60 (m, 2H), 7.57-7.40 (m, 4H), 7.22 (td, J = 8.5, 2.7 Hz, 1H), 5.61 (s, 2H), 3.86 (s, 2H).

[1226] Compound 69: LC-MS: M frag = 355.05.

[1227] 1 H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 8.30 (d, J = 2.2 Hz, 1H), 7.92 - 7.79 (m, 2H), 7.72 (s, 1H), 7.62 (dd, J = 19.7, 10.3 Hz, 4H), 7.47 (ddd, J = 11.5, 8.7, 4.4 Hz, 2H), 7.22 (td, J = 8.5, 2.7 Hz, 1H), 5.74 (s, 2H), 3.87 (s, 2H).

[1228] Example 69

[1229] Preparation of compound 70: N-(4-(((4-chloro-1-(difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)-2-(2-chloro-5-fluorophenyl)acetamide

[1230]

[1231] Synthetic route

[1232]

[1233] Preparation of intermediate 70-1 in step (1)

[1234] The weighed intermediate 22-4 (1.0 g, 2.571 mmol) was dissolved in THF (20 mL), and intermediate 60-1 (710 mg, 3.857 mmol) and Ag2CO3 (1.4 g, 5.142 mmol) were added. The reaction was refluxed at 70 °C overnight. The reaction solution was added with water and extracted with ethyl acetate twice. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE / EA = 8 / 1) to obtain the product of intermediate 70-1, 1.2 g.

[1235] Preparation of intermediate 70-2 in step (2)

[1236] The weighed intermediate 70-1 (1.2 g, 2.227 mmol) was dissolved in DME / H2O (7.5 mL / 7.5 mL), and Na2CO3 (284 mg, 2.673 mmol) was added. The reaction was reacted at 100 °C for 2 h. The reaction solution was added with water and extracted with ethyl acetate twice. The organic phase was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE / EA = 2 / 1) to obtain the product of intermediate 70-2, 900 mg.

[1237] Preparation of intermediate 70-3 and intermediate 71-1 in step (3)

[1238] Weighed intermediate 70-2 (900 mg, 2.052 mmol) was dissolved in acetonitrile (25 mL), bromofluoromethyl phosphonic acid diethyl ester (1.6 g, 6.155 mmol) and KF (477 mg, 8.206 mmol) were added, and the reaction was carried out at 70°C overnight. The reaction solution was added with water and extracted with ethyl acetate twice, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE / EA = 8 / 1 ~ 4 / 1) to obtain the product, 400 mg of intermediate 70-3 and 200 mg of isomer intermediate 71-1.

[1239] Preparation of intermediate 70-4 and intermediate 71-2 in step (4)

[1240] Weighed intermediate 70-3 (400 mg, 0.818 mmol) and intermediate 71-1 (200 mg, 0.409 mmol) were dissolved in 1,4-dioxane (2 mL / 1 mL) in two pots, respectively, and intermediate 1-9 (benzyl mercaptan) (204 mg / 102 mg, 1.637 mmol / 0.818 mmol), Pd2(dba)3 (76 mg / 38 mg, 0.082 mmol / 0.041 mmol), Xantphos (48 mg / 24 mg, 0.082 mmol / 0.041 mmol), DIEA (318 mg / 159 mg, 2.456 mmol / 1.228 mmol) were added, and the reaction was carried out at 100°C overnight under nitrogen protection. The reaction solution was added with water and extracted with EA, and the organic phase was washed with saturated brine, dried over sodium sulfate, and purified by silica gel column chromatography (PE / EA = 6 / 1 ~ 3 / 1) to obtain the product, 400 mg of intermediate 70-4 and 200 mg of isomer intermediate 71-2.

[1241] Preparation of compound 70 and compound 71 in step (5)

[1242] Intermediate 70-4 (400 mg, 0.752 mmol) and intermediate 71-2 (200 mg, 0.376 mmol) were separately dissolved in CH3CN (4 mL), AcOH (0.5 mL) and H2O (0.5 mL) in two pots, respectively, and intermediate 1-11 (DCDMH) (224 mg / 112 mg, 1.128 mmol / 0.564 mmol) was added, respectively, and the reaction was stirred at room temperature for 5 min, and the reaction was added dropwise to stirring ammonia water (0.5 mL), and the reaction was added with water, extracted with EA, and the organic phase was combined and washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC with a H2O / ACN system to obtain the product of compound 70, 155.8 mg, and the product of compound 71, 14.7 mg.

[1243] Compound 70: LC-MS: [M+H] + = 522.95.

[1244] 1 H NMR (400 MHz, DMSO-d6): δ 10.63 (s, 1H), 8.45 (s, 1H), 8.29 (d, J = 2.1 Hz, 1H), 7.84 (dd, J = 8.5, 2.1 Hz, 1H), 7.76 (s, 1H), 7.67 - 7.60 (m, 2H), 7.59 - 7.41 (m, 3H), 7.35 (dd, J = 9.5, 3.1 Hz, 1H), 7.19 (td, J = 8.5, 3.1 Hz, 1H), 5.62 (s, 2H), 3.89 (s, 2H).

[1245] Compound 71: LC-MS: Ms fragment = 355.00.

[1246] 1 H NMR (400 MHz, DMSO-d6): δ 10.50 (s, 1H), 8.15 (d, J = 2.1 Hz, 1H), 7.80 (dd, J = 8.4, 2.0 Hz, 1H), 7.65 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 8.8, 5.3 Hz, 1H), 7.34 (dd, J = 8.6, 3.9 Hz, 3H), 7.19 (td, J = 8.5, 3.1 Hz, 1H), 5.38 (t, J = 3.7 Hz, 1H), 4.84 (d, J = 5.6 Hz, 2H), 3.87 (s, 2H).

[1247] Example 70

[1248] Preparation of compound 72: 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H- pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1249] Preparation of compound 73: 2-(2-chlorophenyl)-N-(4-(((1-(difluoromethyl)-1H- pyrazol-5-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1250]

[1251] Synthetic route

[1252]

[1253] Preparation of intermediate 72-1 in step (1)

[1254] Weighed intermediate 60-3 (1.5 g, 2.659 mmol) was dissolved in DME (10 mL) and water (10 mL), sodium carbonate (339 mg, 3.191 mmol) was added, and the reaction was carried out at 100 °C for 2 h. A new point was generated, the reaction liquid was added with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and purified by silica gel column chromatography (PE / EA = 5 / 1 ~ 2 / 1) to obtain 880 mg of product of intermediate 72-1.

[1255] Preparation of intermediates 72-2 and 73-1 in step (2)

[1256] Weighed intermediate 72-1 (880 mg, 1.897 mmol) was dissolved in acetonitrile (25 mL), bromofluoromethyl diethyl phosphate (1.5 g, 5.690 mmol) and KF (441 mg, 7.587 mmol) were added, and the reaction was carried out at 70 °C overnight. The reaction liquid was added with water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 1.1 g of a mixture of product of intermediate 72-2 and isomer intermediate 73-1, which was used directly in the next step without purification.

[1257] Preparation of compound 72 and compound 73 in step (3)

[1258] A mixture of the intermediate 72-2 and its isomer intermediate 73-1 (1.1 g, 2.141 mmol) obtained in the previous step was dissolved in glacial acetic acid (30 mL) and water (10 mL), NCS (858 mg, 6.421 mmol) was added portionwise, the reaction was allowed to proceed at room temperature for 3 h, the reaction solution was added water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product 1.1 g. The crude product was dissolved in 20 mL THF, and added dropwise to 20 mL ammonia water under stirring, the reaction was allowed to proceed at room temperature for 10 min, LCMS monitoring showed that the product was generated, the reaction solution was added water, extracted with EA, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by prep-HPLC with H2O / ACN system to obtain 240 mg of compound 72 product and 103.3 mg of isomer compound 73 product.

[1259] Compound 72: LC-MS: [M+H] + = 471.05.

[1260] 1 H NMR (400 MHz, DMSO-d6): δ 10.59 (s, 1H), 8.26 (d, J = 2.1 Hz, 1H), 8.07 (d, J = 2.8 Hz, 1H), 7.84 (dd, J = 8.5, 2.1 Hz, 1H), 7.75 (s, 1H), 7.63 (s, 1H), 7.61 (d, J = 4.0 Hz, 1H), 7.51 (s, 2H), 7.47 - 7.40 (m, 2H), 7.32 (dd, J = 9.3, 4.9 Hz, 2H), 6.12 (d, J = 2.8 Hz, 1H), 5.55 (s, 2H), 3.87 (s, 2H).

[1261] Compound 73: LC-MS: [M+H] + = 471.05.

[1262] 1 H NMR (400 MHz, DMSO-d6): δ 10.62 (s, 1H), 8.29 (d, J = 2.2 Hz, 1H), 7.84 (dd, J = 8.5, 2.2 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 7.65 (s, 1H), 7.63 (s, 2H), 7.57 (d, J = 1.7 Hz, 1H), 7.54 (s, 1H), 7.44 (ddd, J = 6.6, 5.8, 3.7 Hz, 2H), 7.34 - 7.29 (m, 2H), 5.87 (d, J = 1.8 Hz, 1H), 5.55 (s, 2H), 3.87 (s, 2H).

[1263] Example 71

[1264] Preparation of compound 74: 2-(2-chloro-5-fluorophenyl)-N-(4-(((1- (difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1265]

[1266] Synthetic route

[1267]

[1268] Preparation of intermediate 74-1 in step (1)

[1269] Into a 250 mL reaction flask was placed intermediate 22-2 (4.807 g, 12 mmol), intermediate 1-9 (benzyl mercaptan) (4.471 g, 36 mmol), Pd2(dba)3 (2.197 g, 2.4 mmol), DIEA (4.652 g, 36 mmol), Xantphos (1.388 g, 2.4 mmol), 1,4-dioxane (95 mL), and nitrogen protection. Reaction at 110 degrees Celsius overnight. Treatment: the reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography with eluent (PE / EA = 5:1) to obtain 4.2 g of the product of intermediate 74-1.

[1270] Preparation of intermediate 74-2 in step (2)

[1271] Into a 250 mL reaction flask was placed intermediate 74-1 (4.2 g, 9.46 mmol), NCS (3.59 g, 28.38 mmol), AcOH (1.556 g, 2.84 mmol), ACN / H2O (84 mL / 0.84 mL). After reaction at room temperature for 30 minutes, PMBNH2 (1.946 g, 14.192 mmol) was added and the reaction continued at room temperature for another 30 minutes. Treatment: the reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography with eluent (PE / EA = 6:1) to obtain 3.8 g of the product of intermediate 74-2.

[1272] Preparation of intermediate 74-3 in step (3)

[1273] Into a 100 mL reaction flask was placed intermediate 74-2 (3.8 g, 7.294 mmol), THF 76 mL, and lithium aluminum hydride (553 mg, 14.588 mmol) was added portionwise at room temperature. The reaction was continued at room temperature for 2 hours. Treatment: the reaction solution was quenched with 3.8 ml of water, adjusted to weakly acidic, extracted with ethyl acetate twice, the organic phases were combined, dried, and concentrated under reduced pressure to obtain 2.3 g of the product of intermediate 74-3.

[1274] Preparation of intermediate 74-4 in step (4)

[1275] In a 100 mL reaction bottle, intermediate 74-3 (2.135 g, 4.331 mmol), DCM 20 mL, SOCl2(1.031 g, 8.662 mmol) was added dropwise, and the reaction was carried out at room temperature overnight. Treatment: the reaction solution was concentrated under reduced pressure, and then purified by silica gel column chromatography with eluent (PE / EA = 6:1) to obtain 2.4 g of the product of intermediate 74-4.

[1276] Preparation of intermediate 74-5 in step (5)

[1277] In a 50 mL reaction bottle, intermediate 74-4 (2.328 g, 4.55 mmol), THF 23 mL, intermediate 60-1 (1.006 g, 5.463 mmol), Ag2CO3(2.51 g, 9.105 mmol) were added, and the reaction was carried out at 70 degrees Celsius overnight. Treatment: the reaction solution was extracted twice with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and then purified by silica gel column chromatography with eluent (PE / EA = 8:1) to obtain 2.3 g of the product of intermediate 74-5.

[1278] Preparation of intermediate 74-6 in step (6)

[1279] In a 50 mL reaction bottle, intermediate 74-5 (2.3 g, 3.49 mmol), DME / H2O (15 mL / 15 mL), Na2CO3(517 mg, 4.885 mmol) were added, and the reaction was carried out at 100 degrees Celsius for 6 hours. Treatment: the reaction solution was extracted twice with ethyl acetate, the organic phases were combined, dried and concentrated to obtain 2.0 g of the product of intermediate 74-6.

[1280] Preparation of intermediate 74-7 in step (7)

[1281] In a 50 mL reaction bottle, intermediate 74-6 (1.0 g, 1.7 mmol), MeCN 20 mL, bromofluoromethyl diethyl phosphate (1.4 g, 5.1 mmol) KF (415 mg, 7.1 mmol) were added, and the reaction was carried out at 70 degrees Celsius overnight. Treatment: the reaction solution was extracted twice with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and then purified by silica gel column chromatography with eluent (PE / EA = 5:1) to obtain 567 mg of the product of intermediate 74-7.

[1282] Preparation of compound 74 in step (8)

[1283] In a 25 mL reaction vial, was added intermediate 74-7 (188 mg, 0.31 mmol), MeCN / H20 (0.8 mL / 0.8 mL), CAN (509 mg, 0.9 mmol), and allowed to react at room temperature overnight. Workup: the reaction was extracted with ethyl acetate twice, the organic phases were combined, dried, and concentrated to give 27 mg of product of compound 74. LC-MS: [M+H] + = 355.

[1284] 1 H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.29 (d, J = 1.9 Hz, 1H), 7.84 (dd, J = 8.2, 2.0 Hz, 1H), 7.73 - 7.61 (m, 4H), 7.58 (d, J = 1.1 Hz, 1H), 7.54 (s, 1H), 7.50 (dd, J = 8.8, 5.3 Hz, 1H), 7.35 (dd, J = 9.4, 3.0 Hz, 1H), 7.20 (td, J = 8.5, 3.0 Hz, 1H), 5.87 (d, J = 1.5 Hz, 1H), 5.56 (s, 2H), 3.89 (s, 2H).

[1285] Example 72

[1286] Preparation of compound 75: 2-(2-chloro-4-fluorophenyl)-N-(4-(((1- (difluoromethyl)-1H-pyrazol-3-yl)oxy)methyl)-3-sulfamoylphenyl)acetamide

[1287]

[1288] Synthetic route

[1289]

[1290] Experimental procedure

[1291] Preparation of intermediate 75-1 in step (1)

[1292] In a 250 mL reaction vial, was added intermediate 21-2 (4.01 g, 10 mmol), intermediate 1-9 (benzyl mercaptan) (3.72 g, 30 mmol), Pd2(dba)3 (1.831 g, 2 mmol), DIEA (3.87 g, 30 mmol), Xantphos (1.15 g, 2 mmol), 1,4-dioxane (10 mL), and protected with nitrogen. The reaction was allowed to react at 110 degrees Celsius overnight. Workup: the reaction was concentrated under reduced pressure and then purified by silica gel column chromatography with eluent (PE / EA = 5:1) to give 4.3 g of product of intermediate 75-1.

[1293] Preparation of intermediate 75-2 in step (2)

[1294] Into a 250 mL reaction vial was placed intermediate 75-1 (2.3 g, 5.181 mmol), NCS (1.97 g, 15.543 mmol), AcOH (1.556 g, 25.905 mmol), ACN / H2O (46 mL / 0.46 mL). After 30 min of reaction at room temperature, PMBNH2 (1.066 g, 7.772 mmol) was added and the reaction continued at room temperature for another 30 min. Work-up: the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent (PE / EA = 6:1) to give the product of intermediate 75-2, 1.65 g.

[1295] Preparation of intermediate 75-3 in step (3)

[1296] Into a 100 mL reaction vial was placed intermediate 75-2 (1.45 g, 2.78 mmol), THF (29 mL), and lithium aluminum hydride (159 mg, 4.17 mmol) was added portionwise at room temperature. After 2 h of reaction at room temperature, the reaction mixture was quenched with 1.45 mL of water, adjusted to weakly acidic, extracted with ethyl acetate twice, and the combined organic phase was dried and concentrated to give the product of intermediate 75-3, 1.25 g.

[1297] Preparation of intermediate 75-4 in step (4)

[1298] Into a 100 mL reaction vial was placed intermediate 75-3 (1.15 g, 2.33 mmol), DCM (12 mL), and SOCl2 (556 mg, 4.66 mmol) was added dropwise at room temperature. After overnight reaction at room temperature, the reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography with eluent (PE / EA = 6:1) to give the product of intermediate 75-4, 1.17 g.

[1299] Preparation of intermediate 75-5 in step (5)

[1300] Into a 50 mL reaction vial was placed intermediate 75-4 (1.17 g, 2.29 mmol), THF (12 mL), intermediate 60-1 (506 mg, 2.75 mmol), and Ag2CO3 (1.26 g, 4.57 mmol). After overnight reaction at 70 °C, the reaction mixture was extracted with ethyl acetate twice, and the combined organic phase was concentrated under reduced pressure and purified by silica gel column chromatography with eluent (PE / EA = 8:1) to give the product of intermediate 75-5, 800 mg.

[1301] Preparation of intermediate 75-6 in step (6)

[1302] Intermediate 75-5 (395 mg, 0.6 mmol), DME / H2O (4 mL / 4 mL), and Na2CO3 (77 mg, 0.72 mmol) were added to a 50 mL reaction flask, and the reaction was carried out at 100 °C for 6 hours. Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, dried, and concentrated to give 315 mg of intermediate 75-6.

[1303] Preparation of intermediate 75-7 in step (7)

[1304] In a 50 mL reaction flask, intermediate 75-6 (336 mg, 0.6 mmol), 5 mL of MeCN, diethyl bromofluoromethyl phosphate (480 mg, 1.8 mmol), and KF (139 mg, 2.4 mmol) were added, and the reaction was carried out overnight at 70°C. Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, concentrated under reduced pressure, and purified by silica gel column chromatography using PE / EA = 5:1 as the eluent to give 130 mg of intermediate 75-7.

[1305] Step (8) Preparation of compound 75

[1306] Intermediate 75-7 (250 mg, 0.41 mmol), MeCN / H₂O (1.3 mL / 1.3 mL), and CAN (cerium ammonium nitrate, 675 mg, 1.23 mmol) were added to a 25 mL reaction flask, and the mixture was reacted overnight at room temperature. Treatment: The reaction solution was extracted twice with ethyl acetate, the organic phases were combined, dried, and concentrated. The crude product was separated by prep-HPLC using an H₂O / ACN system. 38 mg of compound 75 was obtained. LC-MS: [M+H] + =355.

[1307] 1 H NMR (400MHz, DMSO-d6) δ10.62(s,1H),8.29(d,J=2.1Hz,1H),7.84(dd,J=8.3,2.2Hz,1H),7.66(dd,J=14.2,5.6Hz,4H),7.58(d,J=1.7 Hz,1H),7.54(s,1H),7.47(ddd,J=11.5,8.7,4.5Hz,2H),7.22(td,J=8.5,2.7Hz,1H),5.87(d,J=1.8Hz,1H),5.56(s,2H),3.86(s,2H).

[1308] Biological experiments

[1309] Example A: In vitro bioactivity evaluation

[1310] The antagonistic properties of the compounds of the present application were determined using the FLIPR (fluorometric imaging plate reader) method as inhibitors of intracellular calcium elevation induced by activation of hP2X4 (human purinergic P2X receptor subtype 4, Accession Number NM_001256796.2) expressed in HEK293 cells (human embryonic kidney 293 cell line, ATCC).

[1311] HEK293 cells stably expressing hP2X4 were maintained in a cell incubator at 37°C, 5% humidity, in DMEM high glucose medium containing 10% FBS (fetal bovine serum, Biosera, FB-1058 / 500), 1% penicillin-streptomycin (Gibco, 15140-122), and 1 mg / mL G418 (CABIOCHE, 345810). 18-24 hours prior to the FLIPR experiment, cells were seeded at a density of 400,000 cells / mL into 384-well plates (10,000 cells / well) and incubated overnight in the cell incubator. On the day of the experiment, the medium was removed and the cells were washed in FLIPR buffer (0.3 mL probenecid (Thermo, P36400), 0.6 mL 1 M HEPES (Invitrogen, 15630080), and 29.1 mL HBSS (Invitrogen, 14065056) per 30 mL of buffer). 20 μL of 0.5x Calcium 6 fluorescent dye (Molecular Devices, R8190) was added to each well and the dye loading incubation was performed at 37°C for 1.5 hours. Subsequently, 10 μL of test compound (dissolved at a concentration of 10 mM in DMSO and serially diluted with buffer) or vehicle was added to each well and allowed to pre-incubate at 37°C for 30 min. The cell plate was then placed in the FLIPR and baseline fluorescence measurements were taken (excitation wavelength 485 nm, emission wavelength 525-535 nm). Agonist (BZ-ATP (Sigma, B6396) at a final concentration of 5 μM) or vehicle (ultrapure water) was then added at 10 μL / well and fluorescence values were measured for 2 minutes at 1 second intervals, and the output fluorescence counts were finally analyzed.

[1312] IC50values obtained using the above method 50 are shown in Table 1.

[1313] Table 1. IC50values obtained for the compounds of the examples on P2X4 receptor 50

[1314] Compound No. IC 50 / nM]]> Compound No. IC 50 / nM]]> Compound No. IC 50 / nM]]> 1 24.3 27 B 56 67.6 2 27.10 30 C 57 51.2 3 25.1 33 C 59 B 4 124 34 C 60 12.8 6 9.8 35 C 61 17.7 7 88.4 39 C 62 13.7 9 7.6 40 C 63 B 10 18.3 42 C 64 17.3 12 13.0 43 C 65 3 16 70.5 46 5.9 66 B 18 C 47 3.8 67 5.8 19 C 48 4.6 68 71.9 20 31.8 49 32.8 69 27.0 21 54.2 50 59.9 70 112.9 22 32.4 51 189.9 72 30.5 23 16.5 52 166.5 73 35.9 24 B 53 12.2 74 17.9 25 B 54 18.6 75 13.5 26 C 55 B

[1315] wherein A: IC 50 ≤ 10 nM, B: 10 < IC 50≤ 50 nM, C: 50 < IC 50 ≤ 200 nM.

[1316] From the data in Table 1, it can be seen that the compounds of the present application have good P2X4 inhibitory activity, and we particularly prefer compounds having IC 50 ≤ 200 nM, more preferably IC 50 ≤ 50 nM.

[1317] Example B: In vitro cytotoxicity test

[1318] The in vitro cytotoxicity test of the compounds in the present application was determined in HepG2 cells using the CCK-8 method. Logarithmic phase HepG2 cells (Beina Biological Technology Co., Ltd.) were collected, the cell suspension concentration was adjusted, and 50,000 cells / well were plated in a 96-well cell culture plate. The cells were incubated in a 5% cell incubator at 37°C overnight, and when the cell confluence in the plate reached 80-90%, the medium was replaced with various concentrations of test compounds or solvent (DMSO), and incubated in a 5% cell incubator at 37°C for 48 hours. After the treatment was completed, the medium in the plate was discarded, and the cells were washed twice with PBS. 100 μL of CCK-8 working solution (Bi Yun Tian Biological Technology Co., Ltd.) was added to each well, and incubated at 37°C for 1.5 hours in the dark. The OD 450nm value of each well was detected on an enzyme marker, and the CC 50 of each compound was calculated.

[1319] The CC 50 obtained using the above method is shown in Table 2.

[1320] Table 2. CC 50

[1321] Compound HepG2 CC 50 (μM)]]> Compound Compound HepG2 CC 50 (μM)]]> 1 >100 54 >100 2 >100 55 54.3 3 53.6 57 >100 6 >100 60 >100 9 94.92 61 >100 10 >100 62 >100 20 41.62 63 51.72 21 >100 64 >100 22 >100 65 >100 23 >100 66 >100 44 >100 67 >100 46 54.8 72 >100 47 55.5 73 51.23 48 67.9 74 99.78 49 >100 75 54.42

[1322] From the data in Table 2, it can be seen that most of the compounds of the present application have good safety, and the CC 50 range is > 40 μM, which meets the general requirements of in vitro cytotoxicity of compounds, and we prefer compounds having CC 50 > 40 μM, more preferably CC 50 > 100 μM.

[1323] Example C: In vitro metabolic stability test

[1324] The in-vitro metabolic stability of the compounds in the present application is determined by using various in-vitro incubation methods of liver microsomes. In the liver microsomal reaction system (1 mg / mL liver microsomal protein, 25 U / mL 6-phosphoglucose dehydrogenase, 1 mM NADP, 6 mM D-6-phosphoglucose, 5 mM MgCl2), an appropriate amount of the test compound is added, and the reaction is started by incubation in a 37°C water bath. At each time point, 100 μL of the reaction solution is added to a centrifuge tube containing 400 μL of 0°C pre-cooled internal standard working solution (containing 200 ng / mL dexamethasone, diclofenac, tolbutamide, labetalol in acetonitrile) to terminate the reaction. The mixture is centrifuged at 10000 rpm for 10 min at 4°C, and the supernatant is analyzed by LC-MS to obtain the in-vitro metabolic half-life of the test compound in various liver microsomes.

[1325] T 1 / 2 The results are shown in Table 3.

[1326] Table 3. T 1 / 2

[1327]

[1328]

[1329] Note: NA means substantially no metabolism; " / " means not tested.

[1330] As can be seen from the data in Table 3, the compounds of the present application have good metabolic stability in humans, rats and guinea pigs.

[1331] Example D: Pharmacokinetic (PK) analysis of rats

[1332] The rat pharmacokinetic experiments of several compounds in the above examples and their control compounds D1 and D2 are carried out, and the relevant experimental conditions are as follows:

[1333] Rats: SD rats, SPF level, 6, male, body weight range 180-200 g (source & certificate number: provided by Haipu Biological);

[1334] Dosing method: PO / IV

[1335] Dosing dose: PO / IV: 1 mg / kg

[1336] Preparation: PO group dissolved in DMSO, 4% Tween 80 was added, and ultrasonic dissolution was performed for 10 min;

[1337] IV group: ethanol and PEG400, ultrasonic dissolution for 5 min, and the required volume of pure water was added, and ultrasonic dissolution was performed for 5 min.

[1338] Suspension take the upper, middle, lower each 2 parts, clear solution take the middle layer 2 parts, each 100 μL to 1.5 mL EP tube, sample before administration, sample after placed in -80 ℃ refrigerator, with plasma sample together to sample bioanalysis detection.

[1339] Sampling point: PO group blood sampling time point is 0.167, 0.5, 1, 2, 3, 4, 6, 8, 10 and 24 h;

[1340] IV group blood sampling time point is 0.033, 0.167, 0.5, 1, 2, 4, 6, 8, 10 and 24 h.

[1341] PO group animals overnight fasting without water before administration, 4 h after administration return food, IV group whole process without fasting without water;

[1342] Sample processing:

[1343] 1, two groups of rats after administration, according to the sampling time point, from the rat jugular vein to collect blood, each time point about 0.2-0.3 mL blood in anticoagulant EP tube (containing 4 μL EDTA-K2, 375 mg / mL), slowly up and down inversion 3 times, placed in ice box (not more than 30 minutes),

[1344] 2, using 3500xg centrifugation at 4 ℃ for 10 minutes, remove the supernatant to the labeled EP tube, sample needs to be stored at -80 ℃.

[1345] 3, using Tolbutamide as internal standard compound (IS), protein precipitation extraction of samples. Sample extract is analyzed by LC-MS / MS system, which uses Sciex Exion LC AD high performance liquid chromatography system and XBridge BEH C18 (2.1x50mm, 2.5 μm) chromatographic column for gradient elution, AB Sciex Qtrap 4500 mass spectrometry for analysis. Mass spectrometry uses electrospray ion source (ESI) positive ion mode to monitor Tolbutamide, its parent ion→daughter ion mass-to-charge ratio (m / z) is 433→263.2 and 271.1→155 respectively.

[1346] Data analysis:

[1347] Data will be analyzed by non-compartment model using WinNonlin (version 5.2.1 Pharsight, Mountain View, CA), to obtain PK parameters (select C max , T max , AUC last , T 1 / 2 , F and other parameters according to different administration routes). The results are shown in Table 4.

[1348] Table 4 Pharmacokinetic parameters of some compounds in animals

[1349]

[1350]

[1351] Note: C max represents the peak concentration, T max represents the peak time, T 1 / 2 represents the elimination half-life, AUC last represents the area under the plasma concentration-time curve from 0 time to the last quantifiable time point, F represents the bioavailability, and " / " represents not measured.

[1352] Conclusion: From the above table, it can be seen that the pharmacokinetic properties of the compounds of the present application are good, among which, the bioavailability of most of the compounds is high, and the performance of some compounds in C max , T 1 / 2 is also good.

[1353] The above describes the embodiments of the present application. However, the present application is not limited to the above-described embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included in the protection scope of the present application.

Claims

1. A compound as shown in Formula I, and a pharmaceutically acceptable salt thereof; in, R 2 Selected from R 2-1 "A 5- to 6-membered heteroaryl group having one, two, or three heteroatoms selected from one or more of N, O, and S", or being affected by one or more R... 2-1e The number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more 5- to 6-membered heteroaryl groups selected from N, O and S. R 2-2 Selected from hydrogen; R 2-1e Halogen, C1-C6 alkyl, or with one or more R 2-1c-1 Substituted C1-C6 alkyl groups and C3-C6 cycloalkyl groups; R 2-1c-1 It can be independently a halogen, NH2, or a C3-C6 cycloalkyl group; n is 1, 2, or 3; R 3-1 It is independently a halogen, hydroxyl, C1-C6 alkyl, halogen-substituted C1-C6 alkyl, or C1-C6 alkoxy.

2. The compound of formula I as claimed in claim 1, and its pharmaceutically acceptable salt, characterized in that, When R 2-1 "A 5- to 6-membered heteroaryl group having one, two, or three heteroatoms selected from one or more of N, O, and S", or being affected by one or more R... 2-1e When replacing "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, the phrase "the number of heteroatoms is 1, 2 or 3, and the heteroatoms are selected from one or more of N, O and S, and the phrase "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S, and the phrase "the number of heteroatoms is 1 or 2, and the heteroatoms are selected from one or more of N, O and S, and the phrase "" And / or, R 2-1e When it is a halogen on its own, the halogen is fluorine, chlorine, bromine or iodine; And / or, R 2-1e It is independently a C1 to C6 alkyl group, or is composed of one or more R groups. 2-1c-1 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. And / or, when R 3-1 When the halogen is independently a halogen or a C1-C6 alkyl group substituted with a halogen, the halogen is fluorine, chlorine, bromine or iodine; And / or, when R 3-1 When the C1-C6 alkyl group is independently C1-C6 alkyl or C1-C6 alkyl group substituted with halogen, the C1-C6 alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl. And / or, when R 3-1 When independently a C1-C6 alkoxy group, the C1-C6 alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy.

3. The compound of formula I as described in claim 2, and its pharmaceutically acceptable salt, characterized in that, When R 2-1 "A 5- to 6-membered heteroaryl group having one, two, or three heteroatoms selected from one or more of N, O, and S", or being affected by one or more R... 2-1e When replacing "a 5- to 6-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S", the phrase "a 5- to 6-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" is replaced by "a 5- to 6-membered heteroaryl group with 1 or 2 heteroatoms, where the heteroatom is N". And / or, R 2-1e When it is a halogen on its own, the halogen is fluorine or chlorine; And / or, R 2-1e It is independently a C1 to C6 alkyl group, or is composed of one or more R groups. 2-1c-1 When the C1-C6 alkyl group is substituted, the C1-C6 alkyl group is methyl, ethyl or propyl; And / or, R 2-1e It is cyclopropyl, cyclobutyl, or cyclopentyl; And / or, when R 2-1c-1 When the alkyl group is C3 to C6, the C3 to C6 cycloalkyl group is cyclopropyl; And / or, when R 3-1 When the halogen is independently a halogen or a C1-C6 alkyl group substituted with a halogen, the halogen is fluorine or chlorine.

4. The compound of formula I as claimed in claim 3, and its pharmaceutically acceptable salt, characterized in that, When R 2-1 "A 5- to 6-membered heteroaryl group having one, two, or three heteroatoms selected from one or more of N, O, and S", or being affected by one or more R... 2-1e When the "5- to 6-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" is replaced, the "5- to 6-membered heteroaryl group with 1, 2, or 3 heteroatoms selected from one or more of N, O, and S" is pyrazolyl, imidazolyl, or pyridinyl.

5. The compound of formula I as claimed in claim 2, and its pharmaceutically acceptable salt, characterized in that, When R 2-1 "A 5- to 6-membered heteroaryl group having one, two, or three heteroatoms selected from one or more of N, O, and S", or being affected by one or more R... 2-1e When the substituted "having one, two, or three heteroatoms, and the heteroatoms being selected from one or more 5- to 6-membered heteroaryl groups selected from N, O, and S" is replaced by "having one, two, or three heteroatoms, and the heteroatoms being selected from one or more 5- to 6-membered heteroaryl groups selected from N, O, and S", then the "having one, two, or three heteroatoms, and the heteroatoms being selected from one or more 5- to 6-membered heteroaryl groups selected from N, O, and S" is...

6. The compound of formula I as claimed in claim 3, and its pharmaceutically acceptable salt, characterized in that, When R 2-1 For one or more R 2-1e When the number of heteroatoms is 1, 2, or 3, and the heteroatoms are selected from one or more 5- to 6-membered heteroaryl groups selected from N, O, and S, the term "substituted with one or more R" refers to the substitution of one or more R groups. 2-1e The substituted "5-6 membered heteroaryl groups having one, two, or three heteroatoms selected from one or more of N, O, and S" is 7. The compound of formula I as claimed in claim 6, and its pharmaceutically acceptable salt, characterized in that, R 2 for And / or, R 3-1 It is either fluorine or chlorine.

8. The following compounds, and their pharmaceutically acceptable salts, 9. A method for preparing a compound of formula I as described in any one of claims 1-8, wherein the method is method one or method two. Method 1 includes the following steps: In a solvent, in the presence of an acid, the compound shown in Formula II is reacted with 1,3-dichloro-5,5-dimethylhydantoin to generate the compound shown in Formula IV. The compound of Formula IV is then reacted with ammonia to obtain the compound shown in Formula I. Method 2 includes the following steps: reacting the compound shown in Formula III with hydrazine hydrate in an organic solvent to obtain the compound shown in Formula I; Among them, R in equations I, II, III, and IV 3-1 n, R 2 They may be the same or different, and each has independently the definition of any one of claims 1-8.

10. An intermediate compound as shown in Formula II, Formula III, or Formula IV, in, R 2 R 3-1 The definitions of n are as described in claim 1.

11. A pharmaceutical composition comprising substance A and at least one pharmaceutical excipient; The substance A is a compound of Formula I as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof.

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