WO2024067560A1

WO2024067560A1 - Sulfonamide compound and medical use thereof

Info

Publication number: WO2024067560A1
Application number: PCT/CN2023/121478
Authority: WO
Inventors: 孙宏斌; 王朝鑫; 路雨霏; 张尚然; 李娟红; 郑茹楠; 周丽; 于金立; 戴量; 袁浩亮; 温小安
Original assignee: 中国药科大学
Priority date: 2022-09-26
Filing date: 2023-09-26
Publication date: 2024-04-04
Also published as: CN117682973A

Abstract

Disclosed in the present invention are a sulfonamide compound and the medical use thereof as a STING inhibitor, specifically, a compound as represented by formula (I) or a pharmaceutically acceptable salt or ester or solvate thereof, which can be used for preparing a STING inhibitor or drug for inhibiting the activation of a STING signal pathway, and used for preparing a drug for preventing or treating STING-mediated diseases.

Description

Sulfonamide compounds and their medical uses

Technical Field

The present invention belongs to the field of biomedicine, and specifically relates to a novel sulfonamide compound and its medical use.

Background technique

Although the activation of the innate immune signaling pathway mediated by STING (also known as TMEM173, MITA, ERIS or MPYS) plays an important role in the body's resistance to the invasion of pathogenic microorganisms, sustained activation of the STING pathway can lead to the occurrence and development of a variety of autoimmune and inflammatory diseases (Nature Immunology, 2017, 18(7): 716-724), including AGS syndrome (Aicardi-Goutières syndrome), systemic lupus erythematosus (SLE), SAVI (STING-associated vasculopathy with onset in infancy) disease, etc. In addition, in inflammation-related disease models, such as skin cancer induction (Nat Commun, 2014, 5:5166), tumor metastasis (Nature, 2018, 553(7689):467-472), progeria (Nature, 2017, 550(7676):402-406), sepsis (Shock, 2017, 47(5):621-631), acute pancreatitis (Gastroenterology, 2018, 154(6):1822-1835), Parkinson's disease (Nature, 2018, 561(7722):258-262), non-alcoholic fatty liver disease and liver fibrosis (G The STING signaling pathway can significantly improve the occurrence and development of the above diseases. The palmitoylation inhibitor H-151 can also significantly alleviate the symptoms of ALS (Cell 2020, 183: 636-649). In addition, the inventors' research has shown that the STING inhibitor H-151 has significant therapeutic effects in a psoriasis mouse model (Br J Pharmacol 2021, 178: 4907-4922). In short, the development of inhibitors targeting the STING protein has broad clinical application prospects.

At present, there are only a handful of STING small molecule inhibitors reported in the literature, which have weak activity and poor drugability (Nature 2018, 559: 269-273; Cell Reports 2018, 25, 3405–3421; ACS Med. Chem. Lett. 2019, 10: 92-97). The applicant first reported a new STING inhibitor SN-011 (PNAS 2021, 118: e2105465118; WO2021068950), however, the activity and drugability of this type of compound still need to be improved. Therefore, there is an urgent clinical need to develop a new type of STING inhibitor.

Summary of the invention

Purpose of the invention: In view of the problems existing in the prior art, the present invention provides a novel sulfonamide compound or a pharmaceutically acceptable salt thereof. The compound of the present invention can significantly inhibit the activation of the STING signaling pathway, and thus can be used to prepare a drug for preventing or treating STING-mediated diseases.

The present invention also provides a preparation method of the sulfonamide compound and its intermediate, a drug combination and medical use thereof.

Technical solution: In order to achieve the above object, the present invention provides a sulfonamide compound or a pharmaceutically acceptable salt, ester or solvate thereof as shown in the following formula I:

R ¹ is selected from: H, C ₁ -C ₆ alkyl or C ₃ -C ₆ cycloalkyl;

^R2 is selected from: substituted or unsubstituted _C1 - _C6 alkyl, _C2 - _C6 alkenyl, C2- _C6 alkynyl, ( _CH2 ) _nOH , ( _CH2 ) _nNH2 _, (CH2) _nC ₍ _O )O( _CH2 ) _mCH3 _, substituted or unsubstituted _C3 - _C8 cycloalkyl, substituted or unsubstituted _C3 - _C6 alicyclic group or substituted or unsubstituted aryl or heteroaryl, wherein the substituted _C1 - _C6 alkyl is replaced by a The following substituents are substituted: diethanolamine, methanesulfonylamino, acetylamino, aminoacetylamino, pyrrolidin-1-yl, piperidin-1-yl, substituted piperidin-1-yl, piperazin-1-yl, substituted piperazin-1-yl, morpholin-4-yl, thiomorpholin-1,1-dioxol-4-yl, N,N-dimethylamino, carboxyl, carboxylate, formamide or aminoformamide; the substituted C ₃ -C ₈ cycloalkyl, C ₃ -C ₆ cycloalkyl, aryl or heteroaryl is substituted by one or two or three substituents each independently selected from _the following: C ₁ -C ₆ alkyl, C 1 -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylsulfonyl, halogen, CN, NO ₂ , NH ₂ , OH, CF ₃ , OCF ₃ , SCF ₃ , C(O)OH or C(O)NH ₂ ;

Wherein, n and m in the ^R2 substituent are each independently selected from: any integer from 0 to 4;

^R3 is selected from the group consisting of: H, halogen, _C1 - _C6 alkyl, _C1 - _C6 alkyloxy, ( _CH2 ) _nOH , ( _CH2 ) _nC (O)OH, ( _CH2 _{)nC(O)O(CH2)mCH3, OC(O)(CH2)nCH3} _or ₍ _CH2 ₎ _nC ₍ _O ₎ _NH2 ;

Wherein, n and m in the R ³ substituent are independently selected from: any integer from 0 to 4;

R ⁴ is selected from: H, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₃ -C ₆ cycloalkyl, (CH ₂ ) _n OH, (CH ₂ ) _n C(O)OH, (CH ₂ ) _n C(O)O(CH ₂ ) _m CH ₃ or (CH ₂ ) _n C(O)NH ₂ ;

Wherein, n and m in the R ⁴ substituent are independently selected from: any integer from 0 to 4;

^R5 and ^R6 are each independently selected _from the group consisting of H, N( _CH3 ) ₂ , N( _CH2CH3 ) ₂ , CN, _NO2 , _CHF2 , ( _CH2 ) _nC (O)OH, ( _CH2 ) _nC (O)O( _CH2 ₎ _mCH3 , ( _CH2 ₎ _nCF3 _, ( _CH2 ) _nOCF3 , ( _CH2 ₎ _nSCF3 , S ₍ _CH2 ) _1SCF3 , _O ( _CH2 ) _1SCF3 , ₍ CH2) _nOH , ( _CH2 ) _nNH2 , _SO2CH3 , _SO2CF3 _, halogen, pyrrolyl, imidazolyl _, triazolyl, C1- _C6 alkyl, _C2 - _C6 _alkenyl , _C2 - _C6 _alkynyl , _C1 -C6 C ₁ -C 6 alkyloxy, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkylamino, C ₁ -C 6 alkylsulfonyl, substituted or unsubstituted C ₃ -C ₈ cycloalkyl or substituted or unsubstituted _C ₆ aliphatic heterocyclic group, wherein the substituted C ₃ -C ₈ cycloalkyl or C ₆ aliphatic heterocyclic group is substituted by one or two substituents independently selected from the following: C ₁ -C ₆ alkyl or halogen, or adjacent R ⁵ and R ⁶ together with the atoms to which they are connected can form a benzene ring, a C ₅ -C ₆ cycloalkane, a C ₅ -C ₆ aliphatic heterocyclic ring or a C ₅ -C ₆ aromatic heterocyclic ring;

Wherein, n and m in the substituents ^R5 and ^R6 are independently selected from any integer from 0 to 4; the letter l is selected from any integer from 1 to 3;

R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of H, CN, NO ₂ , CHF ₂ , OCHF ₂ , (CH ₂ ) _n C(O)OH, (CH ₂ ) _n C(O)O(CH ₂ ) _m CH ₃ , (CH ₂ ) _n CF ₃ , (CH ₂ ) _n OCF ₃ , (CH ₂ ) _n SCF ₃ , S(CH ₂ ) _l SCF ₃ , O(CH ₂ ) _l SCF ₃ , (CH ₂ ) _n OH, (CH ₂ ) _n NH ₂ , SO ₂ CH ₃ , SO ₂ CF ₃ , halogen, C ₁ -C ₆ alkylsulfonyl, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkylthio, C _{1 -C 6} -C ₆ alkylamino, substituted or unsubstituted C ₃ -C ₈ cycloalkyl or substituted or unsubstituted C ₃ -C ₆ alicyclic heterocyclic group, wherein the substituted C ₃ -C ₈ cycloalkyl or C ₃ -C ₆ alicyclic heterocyclic group may be substituted independently by one or two of the following substituents: OH, NH ₂ , halogen, C ₁ -C ₆ alkyl, or at least two of the adjacent R ⁷ , R ⁸ or R ⁹ substituents and the atoms to which they are attached may together form a C ₅ -C ₈ cycloalkane, a benzene ring, a C ₅ -C ₆ aromatic heterocycle, or a C ₅ -C ₆ alicyclic heterocycle;

Wherein, n and m in the substituents R ⁷ , R ⁸ and R ⁹ are independently selected from any integer from 0 to 4; the letter l is selected from any integer from 1 to 3;

A is selected from the group consisting of C ₃ -C ₈ cycloalkyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, piperidinyl, piperazinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolin-1-one, phthalimido or 3,4-dihydroisoquinolin-1(2H)-one;

B is absent or selected from: C ₃ -C ₈ cycloalkyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl;

L ¹ is selected from:

wherein ^Ra and ^Rb are each independently selected from: H, _C1 - _C6 alkyl, _C1 - _C6 alkylcarbonyl, substituted or unsubstituted _C3 - _C6 cycloalkyl, substituted or unsubstituted _C3 - _C6 alicyclic heterocyclic group, or substituted or unsubstituted aryl or heteroaryl, wherein the substituted C3- _C6 cycloalkyl, _C3 - _C6 alicyclic heterocyclic group, aryl or heteroaryl is substituted by one or _two substituents each independently selected from: _C1 - _C6 alkyl, C1- _C6 alkyloxy, _C1 _- _C6 alkoxycarbonyl, _C1 - _C6 alkylsulfonyl, halogen, OH, _NH2 , CN, _NO2 , _CF3 , _OCF3 , _SCF3 , C(O)OH or C(O) _NH2 ;

^L2 may be absent or selected from:

wherein R ^c and R ^d are each independently selected from: H, CF ₃ , halogen, oxo, C ₁ -C ₆ alkyl, C 1 -C 6 alkyloxy, C ₁ -C ₆ alkylthio, substituted or unsubstituted C ₃ -C ₆ cycloalkyl, substituted or unsubstituted C ₃ -C ₆ alicyclic heterocyclic group or substituted or unsubstituted aryl or heteroaryl group, wherein the substituted C 3 -C 6 cycloalkyl, C ₃ -C 6 alicyclic heterocyclic group, aryl or heteroaryl group is substituted by one, two or three substituents each independently selected from: C 1 -C ₆ alkyl, C 1 -C ₆ alkoxy, C ₁ -C _{6 alkoxycarbonyl, C 1 -C 6} alkylsulfonyl, halogen, OH, NH 2 , CN, NO 2 , CF 3 , OCF 3 , SCF 3 , C(O)OH or C(O)NH ₂ , or R c and R d are each independently selected from: H, CF 3 , oxo, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyloxy, C 1 -C 6 alkylthio, substituted or unsubstituted C 3 -C ₆ cycloalkyl, C 3 -C 6 alicyclic heterocyclic group, substituted or unsubstituted aryl or heteroaryl group, wherein the substituted C ₃ -C 6 cycloalkyl, C ₃ -C ₆ alicyclic heterocyclic group, aryl or heteroaryl group is substituted by one, two or _three substituents each independently selected from: C 1 -C 6 alkyl, C 1 -C ₆ alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl, halogen, OH, NH ₂ , CN, NO ₂ , CF ₃ , OCF ₃ , SCF 3 , C ^c or R ^d and the atoms to which they are attached may together form a C ₃ -C ₆ cycloalkane or a C ₃ -C ₆ aliphatic heterocycle;

X is selected from: CH ₂ , O, S, NH, NR ^e , sulfoxide or sulfone;

Wherein, ^Re is selected from: C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl or tert-butyloxycarbonyl, or, ^Re and one of the substituents of R ⁵ , R ⁶ , R ⁷ , R ⁸ or R ⁹ on the A ring or the B ring and the atoms to which they are attached can form a C ₅ -C ₆ heterocycle together;

p and q are each independently selected from any integer of 0-4.

In certain preferred embodiments, the sulfonamide compound or a pharmaceutically acceptable salt, ester or solvate thereof, wherein:

R ¹ is selected from: H, C ₁ -C ₃ alkyl or cyclopropyl;

^R2 is selected from: _C1 - _C4 alkyl, ( _CH2 ) _nOH , ( _CH2 ) _nNH2 _, ( _CH2 ) _nC (O)O( _CH2 ) _mCH3 , ( _CH2 ) _nC (O)OH, substituted or unsubstituted _C3 - _C6 cycloalkyl, substituted or unsubstituted _C6 alicyclic group or substituted _or unsubstituted aryl or heteroaryl, wherein the alicyclic group is selected from piperidinyl, piperazinyl, morpholinyl; the aryl or heteroaryl is independently selected from phenyl, pyridinyl, pyrimidinyl, thienyl, furanyl or thiazolyl; the substituted _C3 - _C6 cycloalkyl, alicyclic group, aryl or heteroaryl is substituted by one, two or three substituents independently selected from the following: _C1 - _C4 alkyl, _C1 - _C4 alkoxy, halogen, CN, _CF3 , _OCF3 or _SCF3 ;

R ³ is selected from: H, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyloxy, C ₁ -C ₃ alkylamino, (CH ₂ ) _n OH, (CH ₂ ) _n C(O)OH or (CH ₂ ) _n C(O)O(CH ₂ ) _m CH;

R ⁴ is selected from: H, OH, halogen, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkyloxy, cyclopropyl, C(O)OCH ₃ or C(O)OH;

R ⁵ and R ⁶ are each independently selected from the group consisting of H, OH, NH ₂ , N(CH ₃ ) ₂ , N(CH ₂ CH ₃ ) ₂ , C(O)OH, CN, NO ₂ , CHF ₂ , (CH ₂ ) _k CF ₃ , (CH ₂ ) _k OCF ₃ , (CH ₂ ) _k SCF ₃ , S(CH ₂ ) _l SCF ₃ , O(CH ₂ ) _l SCF ₃ , SO ₂ CH ₃ , SO ₂ CF ₃ , halogen, pyrrolyl, imidazolyl, triazolyl, C ₁ -C ₄ alkyl, C 1 -C 4 alkyloxy, C ₁ -C ₄ alkylthio, substituted or unsubstituted C ₃ _-C ₈ cycloalkyl or substituted or unsubstituted C ₆ aliphatic heterocyclic group, wherein the C 6 aliphatic heterocyclic group is selected from piperidinyl, piperazinyl or morpholinyl; the substituted C ₆ aliphatic heterocyclic group is selected _from piperidinyl, piperazinyl or morpholinyl; _{The 3} -C ₈ cycloalkyl or C ₆ aliphatic heterocyclic group is substituted by one or two substituents independently selected from the following: C ₁ -C ₄ alkyl or halogen, or adjacent R ⁵ and R ⁶ together with the atoms to which they are attached can form a C ₅ -C ₆ aromatic heterocycle, wherein the C ₅ -C ₆ aromatic heterocycle is selected from: pyrrole, imidazole, oxazole, thiazole, oxadiazole, pyridine or pyrimidine;

Wherein, k in the R ⁵ and R ⁶ substituents is selected from: 0, 1 or 2; the letter l is selected from: 1, 2 or 3;

R ⁷ , R ⁸ and R ⁹ are each independently selected from the group consisting of H, OH, NH ₂ , CN, NO ₂ , CHF ₂ , OCHF ₂ , C(O)OH, (CH ₂ ) _k CF ₃ , (CH _{2 ) k OCF 3 , (CH 2} ) _k SCF ₃ , S(CH ₂ ) _l SCF ₃ , O(CH ₂ ) _l SCF 3 , SO 2 CH 3 , SO 2 CF 3 , halogen, C 1 -C 4 _alkyl , C 1 -C ₄ alkyloxy, C ₁ -C 4 alkylthio or C _{3 -C 6 cycloalkyl; or, adjacent R 7 , R 8 or R 9 are each independently selected from the group consisting of H, OH, NH 2 , CN, NO 2 , CHF 2 , OCHF 2 , C(O)OH, (CH 2 ) k CF 3 , (CH 2 ) k OCF 3 , (CH 2 ) k SCF 3 , S(CH 2 ) l SCF 3 , O(CH 2 ) l SCF 3 , SO 2 CH 3 , SO 2 CF 3 , halogen, C 1} _-C ₄ _alkyl _, _C ₁ _-C ⁴ _alkyloxy _, _C 1 -C ⁴ alkylthio or C ₃ -C ₆ cycloalkyl. ⁹ wherein at least two substituents together with the atoms to which they are attached can form a benzene ring, a cycloalkane, an aromatic heterocycle or a substituted or unsubstituted aliphatic heterocycle, wherein the cycloalkane is selected from cyclopentane or cyclohexane; the aromatic heterocycle is selected from pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyridine or pyrimidine; the aliphatic heterocycle is selected from piperidine, piperazine, morpholine or 1,4-dioxane; the substituted aliphatic heterocycle can be substituted by one of the following substituents: C ₁ -C ₃ alkyl or C ₁ -C ₃ alkylsulfonyl;

Wherein, k in the substituents R ⁷ , R ⁸ and R ⁹ is selected from: 0, 1 or 2; the letter l is selected from: 1, 2 or 3;

A is selected from: C ₃ -C ₆ cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, indolyl, piperidinyl or piperazinyl;

B is absent or selected from: C ₃ -C ₈ cycloalkyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, indolyl, benzoxazolyl, benzothiazolyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl;

L ¹ is selected from:

^Ra and ^Rb are each independently selected from: H, _C1 - _C3 alkyl or _C3 - _C6 cycloalkyl;

^L2 may be absent or selected from:

Where, when ^L2 does not exist and ^L1 is: When A is selected only from: and B does not exist;

R ^c and R ^d are each independently selected from: H, F, Cl, CF ₃ , oxo, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkyloxy, C ₁ -C ₄ alkylthio or C ₃ -C ₆ cycloalkyl, or, R ^c or R ^d attached to the same carbon atom and the atoms to which they are attached may together form a C ₃ -C ₆ cycloalkane ring;

X is selected from: CH ₂ , O, S, NH, NR ^e , sulfoxide or sulfone;

^Re is selected from: _C1 - _C3 alkyl, _C1 - _C3 alkylcarbonyl or tert-butyloxycarbonyl, or ^Re and one of the substituents of ^R5 , ^R6 , ^R7 , ^R8 or ^R9 on the A ring or the B ring and the atoms to which they are attached can form a _C5 - _C6 heterocycle, wherein the _C5 - _C6 heterocycle is selected from: pyrrole, piperidine, pyrrolidone, piperidone, succinimide, glutarimide;

p and q are each independently selected from any integer of 0-3.

The present invention provides a sulfonamide compound represented by the following formula I or a pharmaceutically acceptable salt, ester or solvate thereof:

in,

R ¹ is selected from: H, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkylcarbonyl;

^R2 is selected from: substituted or unsubstituted _C1 - _C4 alkyl, cyclopropyl, _CF3 , vinyl, substituted or unsubstituted aryl or heteroaryl, _NH2 , _C1 - _C4 alkylamino, hydroxy- _C1 - _C3 alkylamino or morpholinyl, wherein the aryl or heteroaryl is selected from phenyl, naphthyl, pyridyl, pyrazolyl, furanyl or thiophene, wherein the substituted _C1 - _C4 alkyl is substituted by one, two or three substituents independently selected from the following: F, Cl, _NH2 , OH, diethanolamino, methanesulfonyl, acetylamino, aminoacetylamino, pyrrolidin-1-yl, piperidin-1-yl, substituted piperidin-1-yl, piperazin-1-yl, substituted piperazin-1-yl, morpholin-4-yl, thiomorpholin-1,1-dioxol-4-yl, N,N-dimethylamino, carboxyl, carboxylate, formylamino or aminoformylamino, wherein the substituted aryl or heteroaryl is substituted by one or two substituents independently selected from the group consisting of C ₁ -C ₃ alkyl, C ₁ -C _{3 alkoxy, C 1 -C 3} _{alkoxycarbonyl} , C ₁ _-C ₃ alkylsulfonyl, F, Cl, Br, I, CN, NO ₂ , NH ₂ , OH, CF ₃ , CF ₂ CF ₃ , OCF ₃ , OCF ₂ CF ₃ , C(O)OH or C(O)NH ₂ ;

R ³ is selected from: H, OH, halogen, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylcarbonyloxy, C ₁ -C ₃ alkoxycarbonyl, (CH ₂ ) _n C(O)OH, (CH ₂ ) _n C(O)NH ₂ or C(O)NHSO ₂ CH ₃ ;

n is selected from: 0, 1, 2 or 3;

R ⁴ is selected from: H, OH, halogen, C ₁ -C ₃ alkyl, COOCH ₃ , COOH or CONH ₂ ;

L ¹ is selected from:

^Ra and ^Rb are each independently selected from: H, _C1 - _C3 alkyl, C3 _- _C6 cycloalkyl;

A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, cyclohexyl, piperidinyl or piperazinyl;

R ⁵ and R ⁶ are each independently selected from: H, OH, halogen, CN, C ₁ -C ₆ alkyl, CF ₃ , CHF ₂ , SCH ₃ , _OCF3 , _SCF3 , _C1 - _C6 alkylsulfonyl, C1- _C6 alkoxy, _C1 -C6 cycloalkyl, _C1 - _C6 cycloalkenyl, _C1 - _C6 heterocycloalkyl, _C1 - _C6 heterocycloalkenyl, _C1 _-C6 _alkynyl , phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, the substituted phenyl may be independently substituted by 1 to 2 of the following substituents: _halogen , OH, CN, _C1 - _C6 alkyl, _CF3 , _CHF2 , _SCH3 , _OCF3 , _SCF3 or _C1 - _C6 alkylsulfonyl, or, ^R5 and R ⁶ together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring;

^L2 is absent or selected from:

X is selected from: C, O, S, NH, sulfoxide or sulfone;

p and q are each independently selected from: any integer from 0 to 5;

B is selected from: H, halogen CN, OH, NH ₂ , NO ₂ , CF ₃ , CHF ₂ , OCF ₃ , SCF ₃ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylamino, substituted or unsubstituted phenyl, naphthyl, pyridyl, imidazolyl, pyrazolyl, furanyl, or thienyl, C ₃ -C ₈ cycloalkyl or 4-7 membered nitrogen-containing heterocycle;

^R7 and ^R8 are each independently selected from: H, OH, halogen, CN, _C1 - _C6 alkyl, _CF3 , _CHF2 , _SCH3 , _OCF3 , _SCF3 , _C1 - _{C6 alkylsulfonyl, C1-C6} _alkoxy , _C1 - _C6 cycloalkyl, _C1 - _C6 cycloalkenyl _, _C1 - _C6 heterocycloalkyl, _C1 - _C6 heterocycloalkenyl, _C1 - _C6 alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, the substituted phenyl may be independently substituted by 1 to 2 substituents: halogen, OH, CN, _C1 - _C6 alkyl, _CF3 , _CHF2 , _SCH3 , _OCF3 , _SCF3 or _C1 - _C6 alkylsulfonyl, or, R R ⁵ and R ⁶ together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring.

R ¹ is selected from: H or C ₁ -C ₃ alkyl;

^R2 is selected from: substituted or unsubstituted _C1 - _C4 alkyl, cyclopropyl, _CF3 , vinyl, substituted or unsubstituted aryl or heteroaryl, hydroxy- _C1 - _C3 alkylamino or morpholinyl, wherein the aryl or heteroaryl is selected from phenyl, naphthyl, pyridyl, pyrazolyl, furyl or thienyl, and the substituted aryl or heteroaryl is substituted by one or two substituents independently selected from the following: _C1 - _C3 alkyl, C1- _C3 alkoxy _{, C1-C3 alkoxycarbonyl, C1-C3} _{alkylsulfonyl} _, _F _, Cl, Br, I, CN, _NO2 , _NH2 , _OH , _CF3 , _CF2CF3 , _OCF3 _, _OCF2CF3 , C(O)OH or C(O) _NH2 ;

R ³ is selected from: H, OH, halogen, C ₁ -C ₃ hydroxyalkyl, C ₁ -C ₃ alkoxy or (CH ₂ ) _n C(O)OH;

Wherein n is selected from: 0, 1, 2 or 3;

L ¹ is selected from:

^Ra and ^Rb are each independently selected from: H, _C1 - _C3 alkyl or C3 _- _C6 cycloalkyl;

^R5 and ^R6 are each independently selected from: H, OH, halogen, CN, _C1 - _C6 alkyl, _CF3 , _CHF2 , _OCF3 , _SCF3 , _C1 - _C6 alkylsulfonyl _, C1- _C6 alkoxy, _C1 -C6 cycloalkyl, _C1 - _C6 heterocycloalkyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, wherein the substituted phenyl may be independently substituted by 1 to 2 of the following substituents: halogen, OH, _CN , CF3, _CHF2 , SCH3, OCF3, SCF3 or C1- _C6 alkylsulfonyl, or, ^R5 and R6 are each independently selected from: H, OH, CN, CF3, _CHF2 , _SCH3 , _OCF3 , _SCF3 or _C1 -C6 alkylsulfonyl, or, ⁶ together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring;

^L2 is absent or selected from:

X is selected from: C, O, S, NH, sulfoxide or sulfone;

p and q are each independently selected from: 0, 1, 2 or 3;

B is selected from: H, halogen CN, OH, NH ₂ , NO ₂ , CF ₃ , CHF ₂ , OCF ₃ , SCF ₃ , C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, substituted or unsubstituted phenyl, naphthyl, pyridyl, imidazolyl, pyrazolyl, furanyl, or thienyl, C ₃ -C ₈ cycloalkyl or 4-7 membered nitrogen-containing heterocycle;

^R7 and ^R8 are each independently selected from: H, OH, halogen, CN, _C1 - _C6 alkyl, _CF3 , _CHF2 , OCF3, _SCF3 , _C1 - _C6 alkylsulfonyl, C1- _C6 alkoxy, _C1 - _C6 cycloalkyl, _C1 - _C6 heterocycloalkyl, phenyl _, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, wherein the substituted phenyl may be independently substituted by 1 to 2 of the following substituents: halogen, OH, CN, CF3, CHF2, SCH3, OCF3, SCF3 or _C1 -C6 alkylsulfonyl, or, R5 and R8 are each independently selected from: H, OH, CN, _CF3 , _CHF2 , _SCH3 , _OCF3 , _SCF3 or _C1 - _C6 alkylsulfonyl, or, ^R5 and R8 are each independently selected from: ⁶ and the atoms to which they are attached may form together a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring.

In certain more preferred embodiments, the sulfonamide compound or a pharmaceutically acceptable salt, ester or solvate thereof is selected from any one of the following Table 1:

Table 1. Structure and nomenclature of compounds

The compounds of the present invention can also be used as pharmaceutically acceptable salts. The salt can be an acid salt of at least one of the following acids: galactaric acid, D-glucuronic acid, glycerophosphoric acid, hippuric acid, isethionic acid, lactobionic acid, maleic acid, 1,5-naphthalenedisulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, bile acid, n-dodecylsulfuric acid, benzenesulfonic acid, citric acid, D-glucose, glycolic acid, lactic acid, malic acid, malonic acid, mandelic acid, phosphoric acid, propionic acid, hydrochloric acid, sulfuric acid, tartaric acid, succinic acid, formic acid, hydroiodic acid, hydrochloric acid Bromic acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharinic acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, 1-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecylenic acid, ascorbic acid, camphoric acid, camphorsulfonic acid, dichloroacetic acid, ethanesulfonic acid. On the other hand, the salt can also be a salt formed by a compound of the present invention and a metal (including sodium, potassium, calcium, etc.) ion or a pharmaceutically acceptable amine (including ethylenediamine, tromethamine, etc.), an ammonium ion or choline.

The compounds of the present invention may also be in the form of esters, prodrugs, N-oxides or solvates thereof to form pharmaceutical compositions. The present invention includes all prodrugs of the compounds of the present invention which are capable of providing (directly or indirectly) the compounds of the present invention or their active metabolites or residues after administration to a human or animal body. The present invention includes various deuterated forms of the compounds of the present invention. Each available hydrogen atom attached to a carbon atom may be independently substituted by a deuterium atom.

The present invention provides use of the compound of formula I or a pharmaceutically acceptable salt thereof in preparing a drug for inhibiting activation of the STING signaling pathway.

The present invention provides use of the compound of formula I or a pharmaceutically acceptable salt thereof in preparing a medicament for preventing or treating a STING-mediated disease.

The STING-mediated diseases include one or more of infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, cancer and precancerous syndromes.

The present invention provides use of the compound of formula I or a pharmaceutically acceptable salt thereof in preparing an immune adjuvant drug.

The present invention is based on the crystal structure of the C-terminal domain of human STING protein (hSTING-CTD-139-379, PDB: 4EF5). The Glide docking module in the PCR product was used to conduct computer-aided drug design and molecular docking studies of active compounds. The docking results showed that the sulfonamide compounds of the present invention can inhibit the activation of the STING signaling pathway by directly binding to the STING protein and maintaining its dimer conformation in the resting state.

The compounds of the present invention can be used to prevent or treat infectious diseases, including: Mycobacterium tuberculosis infection, Chlamydia infection, herpes virus (herpes simplex virus) infection, adenovirus infection, hepatitis B virus infection, orthomyxovirus infection and coronavirus infection.

The compounds of the present invention can be used to prevent or treat inflammatory diseases, including: metabolic inflammation-related diseases (such as insulin resistance, metabolic syndrome, type 1 or type 2 diabetes, hyperlipidemia, obesity, atherosclerosis, myocardial ischemia, myocardial infarction, arrhythmia, coronary heart disease, hypertension, heart failure, myocardial hypertrophy, myocarditis, ischemic encephalopathy, stroke, hemorrhagic encephalopathy, cerebral hemorrhage, cerebral edema, diabetic cardiomyopathy, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy and diabetic ulcer, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease, alcoholic fatty liver disease, cirrhosis, gout, stroke or cerebral infarction, etc.), musculoskeletal muscle inflammation (inflammation of the hands, wrists, elbows, shoulders, neck, knees, ankles and feet, such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, etc.), eye inflammation (keratitis, scleritis, conjunctivitis, etc.), digestive system inflammation (colitis, hepatitis, cholangitis, cholecystitis, pancreatitis, gastritis, enteritis, inflammatory bowel disease, proctitis), inflammation of the nervous system (meningitis, neuromyotonia, multiple sclerosis, CNS vasculitis), inflammation of the vascular system or lymphatic system (vasculitis, lymphangitis, phlebitis), inflammation of the reproductive system (cervicitis, endometritis, epididymitis, orchitis, urethritis), inflammation of the respiratory system (pneumonia, asthma, chronic obstructive pulmonary disease, chronic bronchitis, emphysema, bronchiolitis obliterans, idiopathic pulmonary fibrosis, cystic fibrosis), other inflammatory conditions include appendicitis, myocarditis, mumps, gingivitis, prostatitis, peritonitis, pleurisy, vasculitis, phlebitis, edema.

The compounds of the present invention can be used to prevent or treat autoimmune diseases, including: Aicardi syndrome (AGS), STING-associated vasculitis of infancy (SAVI), retinal vasculopathy with cerebral protein dystrophy (RCVL), systemic lupus erythematosus (SLE), familial pernio lupus (CHBL), Behcet's disease, Chagas' disease, psoriasis, multiple sclerosis, scleroderma and Behcet's disease.

The compounds of the present invention can be used to prevent or treat T cell-mediated hypersensitivity reactions with inflammatory components, including urticaria, skin allergies, allergic rhinitis, contact dermatitis and respiratory allergies.

The compounds of the present invention can be used to treat cancers of various tissues and organs of the body, including but not limited to cancers of the lung, bone, pancreas, liver, kidney, head, uterus, ovary, stomach, colon, esophagus, small intestine, endocrine system, prostate, bladder, cervix, and vagina. For example, liver cancer, kidney cancer, cervical cancer, lung cancer, skin cancer, uterine cancer, adenocarcinoma, prostate cancer, sarcoma, osteosarcoma, thyroid cancer, non-small cell lung cancer, esophageal cancer, chronic myeloid leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, acute lymphocytic leukemia, multiple myeloma, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and neuroblastoma.

The compounds of the present invention can be used alone or in combination with other therapeutic agents. As immunomodulators, the compounds of the present invention can be used as a single therapy or in combination with other therapeutic agents to treat STING-mediated diseases, including infectious diseases, inflammatory diseases, autoimmune diseases, cardiovascular and cerebrovascular diseases, cancers and precancerous syndromes.

The present invention includes a pharmaceutical composition for preventing or treating a STING-mediated disease, which contains a therapeutically effective amount of a sulfonamide compound of Formula I or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient. The excipients that can be mixed arbitrarily can be changed according to the dosage form, the form of administration, etc. Examples of excipients include excipients, binders, disintegrants, lubricants, flavoring agents, flavoring agents, colorants or sweeteners, etc. The pharmaceutical composition can be a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch, etc., in conventional pharmaceutical forms.

The compounds of the present invention can be prepared by referring to the methods and synthetic routes described in the examples, or by improved methods.

Beneficial effects: Compared with the prior art, the present invention has the following advantages:

(1) The newly designed and synthesized sulfonamide compounds of the present invention are a new type of STING inhibitors, which have the characteristics of strong STING inhibitory activity and good drugability.

(2) The compounds of the present invention can be used to prepare drugs for inhibiting the activation of the STING signaling pathway and for preparing drugs for preventing or treating STING-mediated diseases, and have a good effect on the treatment of infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, cancer or cancer syndrome.

(3) The compound of the present invention has a simple structure, an ingenious synthetic route design, cheap and readily available raw materials, a safe and environmentally friendly synthetic process, and is easy to mass produce.

Detailed ways

The content of the present invention is specifically described below by examples. In the present invention, the following examples are for better illustrating the present invention and are not intended to limit the scope of the present invention. Various changes and modifications can be made to the present invention without departing from the spirit and scope of the present invention.

The raw materials and equipment used in the specific embodiments of the present invention are all known products and are obtained by purchasing from the market.

The structure of a compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The measurement was performed using a Bruker nuclear magnetic spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated acetone (Acetone-d ₆ ), and the internal standard was tetramethylsilane (TMS).

Column chromatography generally uses 200-300 mesh silica gel from Qingdao Ocean Chemical Plant Branch as the carrier.

The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Adamas, Leyan, Bid Pharmaceuticals, Aladdin, and Anergy.

Example 1

4-Cyclopentyl-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-1)

Synthesis of intermediate I-1

2-amino-4-nitrophenol (1 g, 6.49 mmol) and pyridine (1.5 mL, 19.47 mmol) were added to dichloromethane (10 mL), and a dichloromethane (5 mL) solution of 4-fluorobenzenesulfonyl chloride (1.4 g, 7.27 mmol) was added dropwise under an ice bath. After the addition, the mixture was heated to room temperature for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, ethyl acetate (20 mL) and 2N aqueous hydrogen chloride solution (10 mL) were added, and the liquid was separated by shaking. The organic phase was washed with 1N aqueous hydrogen chloride solution (10 mL x 1), water (10 mL x 1), and saturated brine (10 mL x 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by beating (dichloromethane), and the obtained solid was dried to constant weight to obtain intermediate I-1 (yellow solid, 1.46 g): ¹ H NMR (300 MHz, DMSO-d ₆ )δ11.35(s,1H),9.97(s,1H),8.05(d,J＝2.8Hz,1H),7.93(dd,J＝9.0,2.8Hz,1H),7.87–7.77(m,2H),7.39(t,J＝8.9Hz,2H),6.90(d,J＝9.0Hz,1H).ESI-MS:m/z 311.0[MH] ^- .

Synthesis of intermediate I-2

Intermediate I-1 (1.46 g, 4.68 mmol) and 10% palladium on carbon (300 mg) were added to a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and reacted at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the filtrate was decompressed to evaporate the solvent to obtain a crude intermediate I-2, which was directly used in the next step without further purification.

Synthesis of intermediate I-3

Intermediate I-15 (14.0 g, 49.59 mmol) and N,N-diisopropylethylamine (4.1 g, 59.51 mmol) were added to distilled water. To chloromethane (150 mL), add dropwise a solution of tert-butyldimethylsilyl chloride (9.0 g, 59.51 mmol) in dichloromethane (50 mL) under an ice-water bath. After the addition is complete, warm the mixture to room temperature and react for 12 hours. Dichloromethane (100 mL) was added for dilution, and the mixture was washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 4:1) to obtain intermediate I-3 (off-white solid, 19.4 g): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.58 (s, 1H), 7.79 (dd, J = 8.8, 5.2 Hz, 2H), 7.40 (t, J = 8.9 Hz, 2H), 6.53 (d, J = 8.6 Hz, 1H), 6.37 (d, J = 2.6 Hz, 1H), 6.25 (dd, J = 8.6, 2.7 Hz, 1H), 4.71 (s, 2H), 0.90 (s, 9H), 0.07 (s, 6H). ESI-MS: m/z 395.1 [MH] ^- .

Synthesis of intermediate I-4

Cyclopenten-1-ylboronic acid (224 mg, 2 mmol), potassium carbonate (276 mg, 2 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.1 mmol) were added to a Schlenk tube under argon protection, and then a solution of ethyl 4-bromobenzoate (229 mg, 1 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was added to the system. After the addition was completed, the reaction was carried out at 100 °C for 8 hours. After the reaction, the system was cooled to room temperature, the solvent was evaporated under reduced pressure, water (15 mL) was added for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 200:1) to obtain intermediate I-4 (white solid, 212 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ8.00 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 6.34 (s, 1H), 4.39 (dd, J = 14.2, 7.1 Hz, 2H), 2.81–2.71 (m, 2H), 2.59 (d, J = 7.2 Hz, 2H), 2.15–2.00 (m, 2H), 1.41 (t, J = 7.1 Hz, 3H).

Synthesis of intermediate I-5

Intermediate I-4 (205 mg, 0.95 mmol) and 10% palladium on carbon (40 mg) were added to methanol (2 mL) and reacted at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the filtrate was decompressed to evaporate the solvent to obtain a crude intermediate I-5, which was directly used in the next step without further purification.

Synthesis of intermediate I-6

The crude intermediate I-5 was dissolved in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (1.5 mL), and a 1 M aqueous sodium hydroxide solution (1.5 mL) was added, and the temperature was raised to 60° C. to react for 6 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution was added to adjust the pH to 1-2, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate I-6 (white solid, 113 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.74 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 3.09-2.99 (m, 1H), 2.08-1.98 (m, 2H), 1.82-1.72 (m, 2H), 1.70-1.61 (m, 2H), 1.59-1.48 (m, 2H).ESI-MS: m/z 189.1 [MH] ^- .

Synthesis of intermediate I-7

Intermediate I-6 (50 mg, 0.26 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), and oxalyl chloride (33 μL, 0.39 mmol) was slowly added dropwise under ice bath, and the mixture was heated to room temperature for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added to a tetrahydrofuran (1 mL) solution of I-3 (115 mg, 0.29 mmol) and pyridine (31 μL, 0.39 mmol) under ice bath conditions, and reacted at room temperature for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 3-4, and extracted with ethyl acetate (5 mL x 3). The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate I-7 (white solid, 123 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.06(s,1H),9.04(s,1H),7.89–7.78(m,4H),7.65(d,J＝2.7Hz,1H),7.50–7.36(m,5H),6.83(d,J＝8.8Hz,1H),3.10–3.01(m,1H),2.14–2.02(m,2H),1.84–1.74(m,2H),1.72–1.52(m,4H),0.93(s,9H),0.14(s,6H).

Synthesis of Compound A-1

Intermediate I-7 (107 mg, 0.19 mmol) and triethylamine trihydrofluoride (50 μL, 0.28 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction, solids were precipitated, filtered, and the filter cake was washed (dichloromethane). ^1H NMR (300MHz, DMSO- _d6 ) δ9.98 (s, 1H), 9.33 (s, 2H), 7.87-7.80 (m, 4H), 7.66 (d, J = 2.4 Hz, 1H), 7.41-7.33 (m, 5H), 6.69 (d, 1H), 3.10-3.00 (m, 1H), 2.09-1.99 (m, 2H), 1.83-1.75 ₍ m, 2H), 1.71-1.51 (m, 4H). HRMS (ESI) calcd. for _C24H23FN2O4S [M + H] ⁺ 455.1435, found _455.1437 _.

Example 2

4-Cyclohexyl-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-2)

Synthesis of Compound A-2

Referring to the method of Example 1, the intermediate I-6 was replaced with 4-cyclohexylbenzoic acid to prepare compound A-2: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 9.32 (s, 2H), 7.86-7.79 (m, 4H), 7.67 (d, J = 2.3 Hz, 1H), 7.41-7.33 (m, 5H), 6.68 (d, J = 8.7 Hz, 1H), 2.63-2.54 (m, 1H), 1.81 (d, J = 9.3 Hz, 4H), 1.75-1.69 (m, 1H), 1.49-1.35 (m, 4H), 1.32-1.23 (m, 1H). HRMS (ESI) calcd. for C ₂₅ H ₂₅ FN ₂ O ₄ S [M+H] ⁺ 469.1592, found 469.1622.

Example 3

4-(4,4-difluorocyclohexyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-3)

Synthesis of intermediate I-8

Add p-toluenesulfonyl hydrazide (268 mg, 2 mmol) to methanol (4 mL), heat to 60°C to dissolve p-toluenesulfonyl hydrazide, then add 4,4-difluorocyclohexanone (369 mg, 2 mmol) in batches, and continue to react at 60°C for 1 hour. After the reaction is completed, the system is cooled to room temperature, and the solvent is evaporated off the reaction solution under reduced pressure to obtain a crude compound I-8, which is directly used in the next step without further purification.

Synthesis of intermediate I-9

Add intermediate I-8 (374 mg, 1 mmol), 4-methoxycarbonylphenylboronic acid (270 mg, 1.5 mmol) and potassium carbonate (207 mg, 1.5 mmol) into a dry Schlenk tube, protect with argon, add 1,4-dioxane (3 mL) to suspend, and heat to 110 °C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, the filter cake was washed with ethyl acetate (5 mL), the filtrate was decompressed to remove the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate I-9 (colorless oily liquid, 149 mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.00(d, J = 8.2 Hz, 2H), 7.31(d, J = 8.3 Hz, 2H), 3.93(s, 3H), 2.68(dd, J = 13.9, 6.7 Hz, 1H), 2.29-2.20(m, 2H), 1.99-1.94(m, 2H), 1.93-1.86(m, 2H), 1.86-1.80(m, 2H).

Synthesis of intermediate I-10

Intermediate I-9 (129 mg, 0.51 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (1.5 mL), 1 M aqueous sodium hydroxide solution (1.5 mL) was added, and the temperature was raised to 60° C. to react for 6 hours. After the reaction, the system was cooled to room temperature, the organic phase was evaporated under reduced pressure, 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 1-2, solid was precipitated, and the filter cake was washed with water (2 mL) and n-hexane (2 mL), and infrared drying was performed to constant weight to obtain intermediate I-10 (white solid, 82 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.74(s,1H),7.86(d,J＝8.2Hz,2H),7.37(d,J＝8.1Hz,2H),3.09–2.99(m,1H),2.08–1.98(m,2H),1.82–1.72(m,2H),1.70–1.61(m,2H),1.59–1.48(m,2H).ESI-MS:m/z 189.1[MH] ^- .

Synthesis of Compound A-3

Referring to the method of Example 1, intermediate I-6 was replaced by intermediate I-10 to prepare compound A-3: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 9.41 (s, 1H), 9.34 (s, 1H), 7.90-7.80 (m, 4H), 7.69 (d, J = 1.8 Hz, 1H), 7.43-7.34 (m, 5H), 6.69 (d, J = 8.7 Hz, 1H), 2.80 (t, J = 11.7 Hz, 1H), 2.19-2.02 (m, 3H), 1.91 (d, J = 12.2 Hz, 3H), 1.77-1.64 (m, 2H). HRMS (ESI) calcd. for C ₂₅ H ₂₃ F ₃ N ₂ O ₄ S [M+H] ⁺ 505.1403, found 505.1404.

Example 4

4-(4,4-dimethylcyclohexyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-4)

Synthesis of Compound A-4

Referring to the method of Example 3, 4,4-difluorocyclohexanone was replaced with 4,4-dimethylcyclohexanone to obtain compound A-4: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.99(s,1H),9.35(s,2H),7.87–7.79(m,4H),7.67(d,J＝2.4Hz,1H),7.40(d,J＝1.7Hz,2H),7.37(d,J＝2.2Hz,2H),7.33(s,1H),6.68(d,J＝8.7Hz,1H),2.49–2.45(m,1H),1.68–1.59(m,4H),1.47(d,J＝12.2Hz,2H),1.38–1.27(m,2H),0.99(s,3H),0.95(s,3H).HRMS(ESI)calcd.for C _{2 7} H _{2 9} FN ₂ O ₄ S[M+H] ⁺ 497.1905,found 497.1898.

Example 5

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(1H-imidazol-1-yl)benzamide (Compound A-5)

Synthesis of intermediate I-11

Imidazole (442 mg, 6.49 mmol) was added to N,N-dimethylformamide (7 mL), followed by methyl 4-fluorobenzoate (500 mg, 3.24 mmol) and potassium carbonate (897 mg, 6.49 mmol). After the addition was complete, the temperature was raised to 100 °C for 10 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was poured into ice water (70 mL) for quenching, and ethyl acetate was added. The organic phases were combined and washed with water (20 mL x 1) and saturated brine (20 mL x 1) in sequence. The solvent was evaporated under reduced pressure to obtain the crude intermediate I-11, which was used directly in the next step without further purification.

Synthesis of intermediate I-12

The crude intermediate I-11 was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL), and 1 M aqueous sodium hydroxide solution (5 mL) was added. After the addition was completed, the temperature was raised to 60° C. and the reaction was carried out for 6 hours. After the reaction, the system was cooled to room temperature, and 6N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 6-7. Solid precipitated and was filtered. The filter cake was washed with water (5 mL) and dichloromethane (5 mL) in turn. The residue was purified by slurrying (dichloromethane/methanol = 20:1). The obtained solid was dried to constant weight to obtain intermediate I-12 (white solid, 287 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.14 (s, 1H), 8.42 (s, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.88 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.16 (s, 1H). ESI-MS: m/z 187.1 [MH] ^- .

Synthesis of intermediate I-13

The intermediate I-12 (50 mg, 0.27 mmol) was added to tetrahydrofuran (2 mL), and N,N-diisopropylethylamine (88 μL, 0.53 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (152 mg, 0.40 mmol) were added under ice bath. After the addition was completed, the temperature was raised to room temperature for reaction for 1 hour, and a solution of the intermediate I-3 (111 mg, 0.28 mmol) in tetrahydrofuran (1 mL) was added dropwise, and the reaction was continued at room temperature for 6 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined and washed with saturated brine (5 mL x 1). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol = 75:1) to obtain intermediate I-13 (light yellow solid, 62.4 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.22(s,1H),9.10(s,1H),8.42(s,1H),8.05(d,J＝8.6Hz,2H),7.89(s,1H),7.86–7.77(m,4H),7.67(d,J＝2.4Hz,1H),7.48(dd,J＝8.8,2.5Hz,1H),7.40(t,J＝8.8Hz,2H),7.15(s,1H),6.84(d,J＝8.8Hz,1H),0.91(s,9H),0.12(s,6H).ESI-MS:m/z 565.2[MH] ^- .

Synthesis of Compound A-5

Referring to the method of Example 1, intermediate I-7 was replaced by intermediate I-13 to obtain compound A-5: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.16 (s, 1H), 9.43 (s, 1H), 8.43 (s, 1H), 8.09 (d, J = 8.6 Hz, 2H), 7.90 (s, 1H), 7.87-7.79 (m, 4H), 7.71 (d, J = 2.3 Hz, 1H), 7.44-7.34 (m, 3H), 7.16 (s, 1H), 6.71 (d, J = 8.7 Hz, 1H). HRMS (ESI) calcd. for C ₂₂ H ₁₇ FN ₄ O ₄ S [M+H] ⁺ 453.1027, found 453.1048.

Example 6

5-Fluoro-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-1H-indole-3-carboxamide (Compound A-6)

Synthesis of intermediate I-14

5-Fluoroindole (270 mg, 2 mmol) was dissolved in N,N-dimethylformamide (4 mL), and trifluoroacetic anhydride (TFAA) (1.11 mL, 8 mmol) was added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 4 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL) to quench the excess trifluoroacetic anhydride. Solids precipitated and were filtered. The filter cake was washed with water (5 mL) to obtain a crude intermediate I-14, which was directly used in the next reaction without further purification.

Synthesis of intermediate I-15

The crude intermediate I-14 was suspended in a 20% aqueous solution of sodium hydroxide (4 mL), and the temperature was raised to 100° C. to react for 4 hours. After the reaction, the system was cooled to room temperature, ethyl acetate (5 mL) was added to the reaction solution for separation, impurities in the organic phase were removed, and 2N aqueous hydrogen chloride solution was added to adjust the pH to 1-2, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (5 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by beating (ether), and the obtained solid was dried to constant weight to obtain intermediate I-15 (white solid, 178.9 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.04(s,1H),11.93(s,1H),8.07(d,J＝3.0Hz,1H),7.65(dd,J＝10.0,2.5Hz,1H),7.48(dd,J＝8.8,4.6Hz,1H),7.04(td,J＝9.2,2.6Hz,1H).ESI-MS:m/z 178.0[MH] ^- .

Synthesis of Compound A-6

Referring to the method of Example 1, intermediate I-6 was replaced by intermediate I-15 to obtain compound A-6: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.44 (dd, J = 13.7, 8.3 Hz, 4H), 3.37 (t, J = 7.2 Hz, 2H), 3.00 (t, J = 7.4 Hz, 2H). HRMS (ESI) calcd. for C ₂₁ H ₁₅ F ₂ N ₃ O ₄ S [M + H] ⁺ 444.0824, found 444.0827.

Example 7

N-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-4-((trifluoromethyl)thio)benzamide (Compound A-7)

Synthesis of intermediate I-16

2-Amino-4-nitrophenol (1.5 g, 9.73 mmol) and pyridine (1.2 mL, 14.60 mmol) were added to dichloromethane (30 mL), and a solution of methanesulfonyl chloride (904 μL, 11.68 mmol) in dichloromethane (10 mL) was added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature for 8 hours. After the reaction was completed, concentrated hydrochloric acid (1 mL) was added to the reaction solution to quench the excess pyridine and methanesulfonyl chloride, and the solvent was evaporated under reduced pressure. 1N aqueous hydrogen chloride solution (30 mL) was added to the residue, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined and washed with 1N aqueous hydrogen chloride solution (10 mL x 1), water (10 mL x 1), and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and ethanol (10 mL) was added to the residue to dissolve it, and then a solution of sodium hydroxide (480 mg, 12 mmol) in water (10 mL) was added. After the addition was completed, the mixture was heated to 60°C for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3. Solid precipitated and filtered. The filter cake was washed with water (5 mL) and dichloromethane (5 mL) in sequence. The residue was purified by beating (dichloromethane/methanol = 100:1). The obtained solid was dried to constant weight to obtain intermediate I-16 (yellow solid, 1.54 g): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.63 (s, 1H), 9.20 (s, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.98 (dd, J = 9.0, 2.8 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 3.04 (s, 3H).

Synthesis of intermediate I-17

Intermediate I-16 (1.54 g, 6.63 mmol) and 10% palladium on carbon (210 mg) were added to a mixed solvent of methanol (15 mL) and tetrahydrofuran (15 mL), and reacted at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (20 mL), and the filtrate was decompressed to evaporate the solvent to obtain a crude intermediate I-17, which was directly used in the next step without further purification.

Synthesis of intermediate I-18

The crude intermediate I-17 and N,N-diisopropylethylamine (1.65 mL, 10 mmol) were added to dichloromethane (20 mL), and a solution of tert-butyldimethylsilyl chloride (1.3 g, 8.62 mmol) in dichloromethane (15 mL) was added dropwise under an ice-water bath. After completion, the mixture was heated to room temperature for 12 hours. After completion of the reaction, saturated sodium bicarbonate solution (30 mL) was added to the reaction solution for dilution, and dichloromethane (20 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (30 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 4:1) to obtain intermediate I-18 (brown solid, 1.2 g): ¹ H NMR (300 MHz, DMSO-d ₆ )δ8.58(s,1H),7.79(dd,J＝8.8,5.2Hz,2H),7.40(t,J＝8.9Hz,2H),6.53(d,J＝8.6Hz,1H),6.37(d,J＝2.6Hz,1H),6.25(dd,J＝8.6,2.7Hz,1H),4.71(s,2H),0.90(s,9H),0.07(s,6H).ESI-MS:m/z 395.1[MH] ^- .

Synthesis of intermediate I-19

4-Trifluoromethylthiobenzoic acid (40 mg, 0.18 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), and oxalyl chloride (23 μL, 0.27 mmol) was slowly added dropwise under ice bath, and the temperature was raised to room temperature for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added to a tetrahydrofuran (1 mL) solution of I-18 (63 mg, 0.20 mmol) and pyridine (22 μL, 0.27 mmol) under ice bath conditions, and reacted at room temperature for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 3-4, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate I-19 (white solid, 54 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.38(s,1H),8.48(s,1H),8.04(d,J＝8.3Hz,2H),7.87(d,J＝8.2Hz,2H),7.76(d,J＝2.6Hz,1H),7.56(dd,J＝8.8,2.6Hz,1H),6.94(d,J＝8.8Hz,1H),3.04(s,3H),1.00(s,9H),0.25(s,6H).

Synthesis of Compound A-7

Intermediate I-19 (48 mg, 0.09 mmol) and triethylamine trihydrofluoride (23 μL, 0.14 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction, solids were precipitated, which were filtered and the filter cake was washed (dichloromethane/methanol=20:1). The solids were dried to constant weight to obtain compound A-7 (white solid, 23 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ10.29 (s, 1H), 9.18 (s, 2H), 8.04 (d, J=8.3 Hz, 2H), 7.86 (d, J=8.2 Hz, 2H), 7.63 (d, J=2.4 Hz, 1H), 7.50 (dd, J=8.7, 2.4 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₁₅ H ₁₃ F ₃ N ₂ O ₄ S ₂ [M+H] ⁺ 407.0342, found 407.0345.

Example 8

N-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-4-(trifluoromethoxy)benzamide (Compound A-8)

Synthesis of Compound A-8

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced by 4-trifluoromethoxybenzoic acid to obtain compound A-8: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.67 (s, 1H), 8.79 (s, 1H), 8.07 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 2.1 Hz, 1H), 7.56-7.46 (m, 3H), 6.87 (d, J = 8.7 Hz, 1H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₁₅ H ₁₃ F ₃ N ₂ O ₅ S [M + H] ⁺ 391.0570, found 391.0575.

Example 9

N-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-4-(trifluoromethyl)benzamide (Compound A-9)

Synthesis of Compound A-9

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-trifluoromethylbenzoic acid to obtain compound A-9: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.32(s,1H),9.68(s,1H),8.78(s,1H),8.13(d,J＝8.1Hz,2H),7.89(d,J＝8.2Hz,2H),7.64(d,J＝2.1Hz,1H),7.51(dd,J＝8.8,2.2 Hz,1H),6.88(d,J＝8.7Hz,1H),2.97(s,3H).HRMS(ESI)calcd.for C _{1 5} H _{1 3} F ₃ N ₂ O ₄ S[M+H] ⁺ 375.0621,found 375.0636.

Example 10

4-(Difluoromethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-10)

Synthesis of Compound A-10

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced by 4-difluoromethylbenzoic acid to obtain compound A-10: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.19 (s, 2H), 8.06 (d, J = 7.9 Hz, 2H), 7.71 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 2.1 Hz, 1H), 7.50 (dd, J = 8.7, 2.1 Hz, 1H), 7.12 (t, J = 55.7 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₁₅ H ₁₄ F ₂ N ₂ O ₄ S [M + H] ⁺ 357.0715, found 357.0706.

Embodiment 11

N-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-4-isopropylbenzamide (Compound A-11)

Synthesis of Compound A-11

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-isopropylbenzoic acid to obtain compound A-11: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.04–9.97 (m, 2H), 8.06 (s, 0H), 7.86 (d, J=8.2 Hz, 2H), 7.62 (d, J=2.5 Hz, 1H), 7.48 (dd, J=8.7, 2.6 Hz, 1H), 7.37 (d, J=8.2 Hz, 2H), 6.85 (d, J=8.7 Hz, 1H), 3.05–2.88 (m, 1H), 2.97 (s, 3H), 1.23 (d, J=6.9 Hz, 6H). HRMS (ESI) calcd. for C ₁₇ H ₂₀ N ₂ O ₄ S[M+H] ⁺ 349.1217, found 349.1221.

Example 12

4-Bromo-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound A-12)

Synthesis of Compound A-12

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced by 4-bromobenzoic acid to prepare compound A-12: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.71 (s, 1H), 8.73 (s, 1H), 7.89 (d, 2H), 7.73 (d, 2H), 7.61 (d, J = 2.5 Hz, 1H), 7.49 (dd, J = 8.7, 2.5 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₁₄ H ₁₃ BrN ₂ O ₄ S [M + H] ⁺ 384.9852, found 384.9849.

Example 13

N-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-4-propylbenzamide (Compound A-13)

Synthesis of Compound A-13

Referring to the method of Example 1, 4-trifluoromethylthiobenzoic acid was replaced with 4-propylbenzoic acid to prepare compound A-13: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 9.47 (s, 1H), 8.86 (s, 1H), 7.86 (d, J =8.2 Hz, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.49 (dd, J = 8.7, 2.6 Hz, 1H), 7.32 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 2.97 (s, 3H), 2.63 (t, J = 7.6 Hz, 2H), 1.62 (h, J = 7.2 Hz, 2H), 0.90 (t, J = 7.3 Hz, 3H).ESI-MS: m/z 349.1219 [M+H] ⁺ .HRMS (ESI) calcd. for C ₁₇ H ₂₀ N ₂ O ₄ S [M+H] ⁺ 349.1217, found 349.1219.

Embodiment 14

4-Cyclopropyl-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound A-14)

Synthesis of Compound A-14

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-cyclopropylbenzoic acid to obtain compound A-14: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.98 (s, 1H), 9.11 (s, 2H), 7.84 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 2.1 Hz, 1H), 7.49 (dd, J = 8.7, 2.1 Hz, 1H), 7.19 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 2.97 (s, 3H), 2.05–1.95 (m, 1H), 1.06–0.98 (m, 2H), 0.80–0.72 (m, 2H). HRMS (ESI) calcd. for C ₁₇ H ₁₈ N ₂ O ₄ S [M+H] ⁺ 347.1060, found 347.1065.

Embodiment 15

4-Cyclopentyl-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound A-15)

Synthesis of Compound A-15

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with intermediate I-6 to obtain compound A-15: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.01(s,1H),9.35(s,1H),9.06(s,1H),7.86(d,J＝8.2Hz,2H),7.63(d,J＝2.4Hz,1H),7.49(dd,J＝8.7,2.4Hz,1H),7.38(d,J＝8.2Hz,2H),6.85(d,J＝8.7Hz,1H),3.11–3.01(m,1H),2.98(s,3H),2.14–1.99(m,2H),1.85–1.73(m,2H),1.73–1.49(m,4H).HRMS(ESI)calcd.for C ₁₉ H ₂₂ N ₂ O ₄ S[M+H] ⁺ 375.1373,found 375.1378.

Example 16

4-(4,4-difluorocyclohexyl)-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound A-16)

Synthesis of Compound A-16

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with intermediate I-10 to obtain compound A-16: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.03(s,1H),9.67(s,1H),8.70(s,1H),7.88(d,J＝8.2Hz,2H),7.63(d,J＝2.3Hz,1H),7.49(dd,J＝8.7,2.4Hz,1H),7.39(d,J＝8.2Hz,2H),6.85(d,J＝8.7Hz,1H),2.97(s,3H),2.84–2.75(m,1H),2.20–2.01(m,4H),1.92–1.88(m,2H),1.76–1.65(m,2H).HRMS(ESI)calcd.for C ₂₀ H ₂₂ F ₂ N ₂ O ₄ S[M+H] ⁺ 425.1341,found 425.1340.

Embodiment 17

4-Cycloheptyl-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound A-17)

Synthesis of intermediate I-20

Potassium carbonate (509 mg, 4.8 mmol) was added to a dry three-necked flask, and argon was used as protection. A solution of cycloheptanone (353 μL, 3 mmol) in anhydrous dichloromethane (10 mL) was added, and then a solution of trifluoromethanesulfonic anhydride (1 mL, 6 mmol) in anhydrous dichloromethane (5 mL) was slowly added, and the mixture was reacted for 12 hours at room temperature. After the reaction was completed, a saturated sodium bicarbonate solution (10 mL) was added to the reaction solution to quench the excess trifluoromethanesulfonic anhydride, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether) to obtain intermediate I-20 (colorless oily liquid, 509 mg).

Synthesis of intermediate I-21

4-Methoxycarbonylphenylboronic acid (432 mg, 2.4 mmol), sodium carbonate (680 mg, 5 mmol) and tetrakis(triphenylphosphine)palladium (116 mg, 0.1 mmol) were added to the reaction flask, and argon was used as protection. Then, a toluene (10 mL) solution of intermediate I-20 (488 mg, 2 mmol), water (5 mL) and methanol (5 mL) were added, and stirred at reflux for 8 hours. After the reaction was completed, water (15 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain a crude intermediate I-21.

Synthesis of Compound A-17

Referring to the method of Example 1, the intermediate I-5 was replaced by the crude intermediate I-21, and the intermediate I-3 was replaced by the intermediate I-18 to obtain compound A-17: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.01(s,1H),9.35(s,1H),9.06(s,1H),7.86(d,J＝8.2Hz,2H),7.63(d,J＝2.4Hz,1H),7.49(dd,J＝8.7,2.4Hz,1H),7.38(d,J＝8.2Hz,2H),6.85(d,J＝8.7Hz,1H),3.11–3.01(m,1H),2.98(s,3H),2.14–1.99(m,2H),1.85–1.73(m,2H),1.73–1.49(m,4H).HRMS(ESI)calcd.for C ₂₁ H ₂₆ N ₂ O ₄ S[M+H] ⁺ 403.1686,found 403.1689.

Embodiment 18

4-(Diethylamino)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-18)

Synthesis of Compound A-18

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-(N,N-diethylamino)-benzoic acid to prepare compound A-18: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 9.60 (s, 1H), 8.65 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 2.5 Hz, 1H), 7.47 (dd, J = 8.7, 2.2 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 15.1 Hz, 1H), 3.49-3.35 (m, 4H), 2.96 (s, 3H), 1.11 (t, J = 6.9 Hz, 6H). HRMS (ESI) calcd. for C ₁₈ H ₂₃ N ₃ O ₄ S[M+H] ⁺ 378.1488, found 378.1494.

Embodiment 19

N-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-4-(4-methylpiperazin-1-yl)benzamide (Compound A-19)

Synthesis of Compound A-19

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-(4-methylpiperazine)benzoic acid to obtain compound A-19: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 9.63 (s, 1H), 8.68 (s, 1H), 7.88 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 2.5 Hz, 1H), 7.48 (dd, J = 8.7, 2.5 Hz, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 3.48-3.37 (m, 4H), 2.97 (s, 3H), 2.94-2.80 (m, 4H), 2.55 (s, 3H). HRMS (ESI) calcd. for C ₁₉ H ₂₄ N ₄ O ₄ S[M+H] ⁺ 405.1591, found 405.1594.

Embodiment 20

N-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-4-(piperidin-1-yl)benzamide (Compound A-20)

Synthesis of Compound A-20

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-piperazinebenzoic acid to prepare compound A-20: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.76 (s, 1H), 9.60 (s, 1H), 8.66 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.47 (dd, J = 8.8, 2.6 Hz, 1H), 6.96 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.7 Hz, 1H), 3.31-3.28 (m, 4H), 2.97 (s, 3H), 1.63-1.56 (m, 6H). ESI-MS: m/z 390.1486 [M+H] ^{+ .} HRMS (ESI) calcd. for C ₁₉ H ₂₃ N ₃ O ₄ S[M+H] ⁺ 390.1482, found 390.1486.

Embodiment 21

N-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-4-morpholinobenzamide (Compound A-21)

Synthesis of Compound A-21

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-morpholinobenzoic acid to prepare compound A-21: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 9.16 (s, 2H), 7.87 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 2.3 Hz, 1H), 7.48 (dd, J = 8.7, 2.3 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 3.75 (t, J = 4.6 Hz, 4H), 3.25 (t, J = 4.8 Hz, 4H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₁₈ H ₂₁ N ₃ O ₅ S [M+H] ⁺ 392.1275, found 392.1277.

Embodiment 22

4-(4,4-difluoropiperidin-1-yl)-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound A-22)

Synthesis of intermediate I-22

4,4-Difluoropiperidine hydrochloride (158 mg, 1 mmol) and triethylamine (416 μL, 3 mmol) were added to anhydrous dichloromethane (4 mL), stirred at room temperature for 10 minutes, and then p-methoxycarbonylphenylboronic acid (360 mg, 2 mmol), anhydrous copper acetate (362 mg, 2 mmol), Molecular sieves (1.5 g) and pyridine (161 μL, 2 mmol) were added and reacted at room temperature for 10 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the filtrate was decompressed to evaporate the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate I-22 (white solid, 89 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.93 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 3.87 (s, 3H), 3.51 (t, J = 5.8 Hz, 4H), 2.07 (tt, J = 13.3, 5.7 Hz, 4H).

Synthesis of Compound A-22

Referring to the method of Example 1, I-5 was replaced by intermediate I-22, and intermediate I-3 was replaced by intermediate I-18 to prepare compound A-22: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 9.43 (s, 1H), 8.73 (s, 1H), 7.86 (d, 2H), 7.61 (d, J = 2.5 Hz, 1H), 7.47 (dd, J = 8.8, 2.5 Hz, 1H), 7.07 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.7 Hz, 1H), 3.49 (t, J = 5.8 Hz, 4H), 2.97 (s, 3H), 2.11-1.96 (m, 4H). HRMS (ESI) calcd. for C ₁₉ H ₂₁ F ₂ N ₃ O ₄ S [M+H] ⁺ 426.1294, found 426.1328.

Embodiment 23

4'-Fluoro-N-(3-((4-fluorophenyl)sulfonylamino)-4-hydroxyphenyl)-3'-sulfamoyl[1,1'-biphenyl]-4-carboxamide (Compound A-23)

Synthesis of intermediate I-23

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-(4-carboxyphenyl)piperazine-1-carboxylic acid tert-butyl ester to obtain intermediate I-23 (white solid, 68 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.82 (s, 1H), 9.63 (s, 1H), 8.68 (s, 1H), 7.86 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 2.5 Hz, 1H), 7.48 (dd, J = 8.7, 2.5 Hz, 1H), 7.01 (d, J = 8.7 Hz, 2H), 6.83 (d, J = 8.7 Hz, 1H), 3.46 (d, J = 5.7 Hz, 4H), 3.27 (t, J = 5.3 Hz, 4H), 2.96 (s, 3H), 1.42 (s, 9H).

Synthesis of Compound A-23

Intermediate I-23 (87 mg, 0.18 mmol) was added to dichloromethane (2 mL), and 4 M hydrogen chloride-dioxane solution (1 mL) was added dropwise, and the mixture was reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was purified by beating (ethyl acetate), and the obtained solid was dried to constant weight to obtain compound A-23 (white solid, 63 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 9.19 (s, 2H), 8.71 (s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 2.6 Hz, 1H), 7.48 (dd, J = 8.8, 2.6 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.52 (t, J = 5.2 Hz, 4H), 3.21 (s, 4H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₁₈ H ₂₂ N ₄ O ₄ S[M-HCl+H] ⁺ 391.1435, found 391.1433.

Embodiment 24

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)benzo[c][1,2,5]oxadiazole-5-carboxamide (Compound A-24)

Synthesis of Compound A-24

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with benzofurazan-5-carboxylic acid to prepare compound A-24: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.50 (s, 1H), 9.46 (s, 1H), 9.08 (s, 1H), 8.65 (s, 1H), 8.17 (d, J = 9.4 Hz, 1H), 7.99 (d, J = 9.4 Hz, 1H), 7.66 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 2.6 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₁₄ H ₁₂ N ₄ O ₅ S [M + H] ⁺ 349.0601, found 349.0606.

Embodiment 25

5-Hydroxy-4-(methylsulfonamide)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamide)benzoic acid (Compound A-25)

Synthesis of intermediate I-24

Methyl 4-amino-3-methoxybenzoate (3g, 16.57mmol) and pyridine (2.01mL, 24.86mmol) were added to dichloromethane (30mL), and methylsulfonic anhydride (3.75g, 21.55mmol) was added in batches under an ice bath. After addition, the mixture was heated to room temperature for 8 hours. After the reaction was completed, concentrated hydrochloric acid (2mL) was added to the reaction solution to quench excess pyridine and methylsulfonic anhydride, and the solvent was evaporated under reduced pressure. 1N aqueous hydrogen chloride solution (50mL) was added to the residue and extracted with ethyl acetate (25mL x 3), and the organic phases were combined, washed with 1N aqueous hydrogen chloride solution (30mL x 1), water (30mL x 1), and saturated brine (30mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate I-24 (orange-red solid, 3.80g).

Synthesis of intermediate I-25

Add intermediate I-24 (3.80 g, 14.67 mmol) to concentrated sulfuric acid (98%, 15 mL), and slowly add a solution of potassium nitrate (1.2 g, 17.60 mmol) in concentrated sulfuric acid (98%, 15 mL) dropwise under an ice-water bath. After the addition is complete, continue the reaction under an ice bath for 20 minutes. After the reaction, the reaction solution was slowly added dropwise to ice water (200 mL), extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with water (100 mL x 1) and saturated brine (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by slurrying (petroleum ether/ethyl acetate = 3:1), and the obtained solid was dried to constant weight to obtain intermediate I-25 (khaki solid, 3.41 g): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.69(s,1H),8.03(s,1H),7.42(s,1H),3.98(s,3H),3.85(s,3H),3.14(s,3H).

Synthesis of intermediate I-26

Intermediate I-25 (3.75 g, 12.34 mmol) and lithium chloride (1.55 g, 37.01 mmol) were added to N,N-dimethylformamide (30 mL) and reacted under reflux for 1.5 hours. After the reaction was completed, the system was cooled to room temperature, water (300 mL) was added to the reaction solution to dilute it, and 2N aqueous hydrogen chloride solution (10 mL) was added to adjust the pH to acidic. The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined and washed with water (100 mL x 1) and saturated brine (100 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol = 80:1) to obtain intermediate I-26 (khaki solid, 2.40 g): ¹ H NMR (300 MHz, DMSO-d ₆ )δ11.97 (s, 1H), 9.47 (s, 1H), 7.98 (s, 1H), 7.10 (s, 1H), 3.82 (s, 3H), 3.12 (s, 3H).

Synthesis of intermediate I-27

Intermediate I-26 (2.40 g, 8.28 mmol) and 10% palladium on carbon (360 mg) were added to tetrahydrofuran (20 mL) and methanol (5 mL), and the mixture was reacted at room temperature for 12 hours under a hydrogen atmosphere. After the reaction, palladium on carbon was filtered out, the filter cake was washed with tetrahydrofuran (10 mL), and the solvent was evaporated from the filtrate under reduced pressure to obtain a crude intermediate I-27, which was directly used in the next reaction without further purification.

Synthesis of intermediate I-28

The crude intermediate I-27 and N,N-diisopropylethylamine (2.88 mL, 16.55 mmol) were added to dichloromethane (20 mL), and a solution of tert-butyldimethylsilyl chloride (TBSCl) (1.87 g, 12.41 mmol) in dichloromethane (5 mL) was added dropwise under an ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction was completed, saturated sodium bicarbonate solution (50 mL) was added to the reaction solution to quench, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phases were combined and washed with water (30 mL x 1) and saturated brine (30 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate I-28 (white solid, 1.40 g): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.29 (s, 1H), 7.17 (s, 1H), 6.82 (s, 1H), 6.43 (s, 2H), 3.74 (s, 2H), 3.13 (s, 2H), 0.96 (s, 9H), 0.18 (s, 6H).

Synthesis of intermediate I-29

Compound 4-trifluoromethyl bromobenzene (270 mg, 1.20 mmol), p-methoxycarbonylphenylboronic acid (180 mg, 1.00 mmol), potassium carbonate (279 mg, 3.00 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) were added to a mixed solvent of toluene (3.6 mL) and methanol (0.4 mL) under argon protection and reacted at 80 °C for 4 hours. After the reaction, the system was cooled to room temperature, water (30 mL) was added to the reaction solution for dilution, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in turn, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate I-29 (white solid, 255 mg).

Synthesis of intermediate I-30

The intermediate I-29 (250 mg, 0.89 mmol) was added to a mixed solvent of tetrahydrofuran (2 mL) and methanol (2 mL), and a 1 M sodium hydroxide aqueous solution (3 mL) was added dropwise, and the mixture was reacted at 60°C for 4 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3. Solids were precipitated, filtered, and the filter cake was washed with water (5 mL) and ether (5 mL). The obtained solid was dried to constant weight to obtain the intermediate I-30 (white solid, 205 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.10 (s, 1H), 8.06 (d, J=8.0 Hz, 2H), 7.96 (d, J=8.2 Hz, 2H), 7.86 (dd, J=8.2, 5.7 Hz, 4H).

Synthesis of intermediate I-31

Intermediate I-30 (90 mg, 0.34 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), and oxalyl chloride (44 μL, 0.51 mmol) was slowly added dropwise under ice bath, and the mixture was heated to room temperature for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added to a tetrahydrofuran (1 mL) solution of I-28 (120 mg, 0.32 mmol) and pyridine (100 μL, 0.39 mmol) under ice bath conditions, and reacted at room temperature for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 3-4, and extracted with ethyl acetate (5 mL x 3). The organic phases were combined and washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give intermediate I-31 (white solid, 102 mg).

Synthesis of intermediate I-32

Intermediate I-31 (70 mg, 0.11 mmol) and triethylamine trihydrofluoride (22 μL, 0.51 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction, solids were precipitated, filtered, and the filter cake was washed (dichloromethane/methanol = 20:1). The obtained solid was dried to constant weight to obtain intermediate I-32 (white solid, 57 mg).

Synthesis of Compound A-25

Intermediate I-32 (57 mg, 0.11 mmol) and lithium hydroxide monohydrate (14 mg, 0.14 mmol) were added to a mixed solvent of tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), and reacted at 60°C for 6 hours. After the reaction, the system was cooled to room temperature, water (15 mL) was added to the reaction solution, the pH was adjusted to 2-3 with 2N aqueous hydrogen chloride solution, and extracted with ethyl acetate (5 mL x 3), the organic phases were combined, and the organic phases were washed with water (5 mL x 1) and saturated brine (5 mL x 1) in turn, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol/acetic acid = 30:1:0.03) to obtain compound A-25 (white solid, 12 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.44(s,1H),10.12(s,1H),9.04(s,1H),8.73(s,1H),8.06(d,J＝8.4Hz,2H),8.01–7.92(m,4H),7.85(d,J＝8.2Hz,2H),7.56(s,1H),3.11(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 7} F ₃ N ₂ O ₆ S[M+H] ⁺ 495.0832,found 495.0829.

Embodiment 26

4-((4-Fluorophenyl)sulfonamido)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamido)benzoic acid (Compound A-26)

Synthesis of intermediate I-33

4-Amino-2-nitrobenzoic acid (300 mg, 1.65 mmol) and potassium carbonate (455 mg, 3.29 mmol) were added to N,N-dimethylformamide (3 mL), and iodoethane (158 μL, 1.98 mmol) was slowly added dropwise under an ice-water bath. After the addition was completed, the temperature was raised to room temperature for reaction for 3 hours. After the reaction was completed, the excess iodoethane was evaporated under reduced pressure, water (20 mL) was added to the residue for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with water (10 mL x 2) and saturated brine (5 mL x 1) in turn. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to obtain intermediate I-33 (yellow solid, 325 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ7.61(d, J = 8.6 Hz, 1H), 6.82(s, 1H), 6.74 (d, J = 8.6 Hz, 1H), 6.54 (s, 2H), 4.17 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.0 Hz, 3H). ESI-MS: m/z 233.1 [M + Na] ⁺ .

Synthesis of intermediate I-34

The intermediate I-33 (324 mg, 1.54 mmol) and pyridine (186 μL, 2.31 mmol) were added to anhydrous dichloromethane (3 mL), and a solution of 4-fluorobenzenesulfonyl chloride (360 mg, 1.85 mmol) in dichloromethane (1.5 mL) was added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature for 8 hours. After the reaction was completed, 1N aqueous hydrogen chloride solution (5 mL) was added to the reaction solution to quench the excess pyridine, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (5 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain the intermediate I-34 (orange oily liquid, 447 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ11.37(s,1H),7.94(dd,J＝8.9,5.1Hz,2H),7.79(d,J＝8.5Hz,1H),7.61(d,J＝2.1Hz,1H),7.49(d,J＝2.5Hz,1H),7.45(t,J＝5.9Hz,2H),4.24(q,J＝7.1Hz,2H),1.21(t,J＝6.6Hz,3H).ESI/MS:m/z 367.0[MH] ^- .

Synthesis of intermediate I-35

Intermediate I-34 (610 mg, 1.66 mmol) and 10% palladium on carbon (122 mg) were added to tetrahydrofuran (5 mL) and reacted at room temperature under a hydrogen atmosphere for 15 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with ethyl acetate (5 mL), the filtrate was evaporated to remove the solvent under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 7:1) to obtain a crude intermediate I-35 (light yellow solid, 187 mg), which was directly used in the next step without further purification.

Synthesis of Compound A-26

Referring to the method of Example 25, intermediate I-28 was replaced by intermediate I-35, and after condensation, the ester was directly hydrolyzed to obtain compound A-26: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.63 (s, 1H), 12.45 (s, 1H), 10.48 (s, 1H), 8.72 (s, 1H), 8.09 (d, J = 8.2 Hz, 2H), 8.05-8.01 (m, 2H), 7.99 (d, J = 7.6 Hz, 3H), 7.88 (d, J = 8.3 Hz, 2H), 7.02 (d, J = 8.7 Hz, 1H), 3.16 (s, 3H). HRMS (ESI) calcd. for C ₂₇ H ₁₈ F ₄ N ₂ O ₅ S [M + H] ⁺ 559.0945, found 559.0945.

Embodiment 27

4-(Methylsulfonamide)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamide)benzoic acid (Compound A-27)

Synthesis of intermediate I-36

Intermediate I-33 (468 mg, 2.23 mmol) was added to anhydrous dichloromethane (3 mL), and pyridine (269 μL, 3.35 mmol) was added. A solution of methanesulfonic anhydride (466 mg, 2.67 mmol) in anhydrous dichloromethane (2 mL) was added under ice bath, and the mixture was reacted at room temperature for 14 hours. After the reaction, 1N aqueous hydrogen chloride solution (8 mL) was added to the system to quench the excess pyridine and methanesulfonic anhydride, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (5 mL x 2), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate I-36 (yellow solid, 554 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.76 (s, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.5, 2.1 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 3.21 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). ESI/MS: m/z 287.0 [MH] ^- .

Synthesis of intermediate I-37

Intermediate I-36 (447 mg, 1.21 mmol) and 10% palladium on carbon (89 mg) were added to tetrahydrofuran (5 mL) and reacted at room temperature for 15 hours under a hydrogen atmosphere. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with ethyl acetate (5 mL), the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate I-37 (light yellow Solid, 337 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.15 (s, 1H), 7.75 (dd, J = 8.7, 5.2 Hz, 2H), 7.40 (t, J = 8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 1H), 6.34-6.29 (m, 2H), 5.07 (s, 2H), 4.97 (t, 1H), 4.13 (d, J = 4.6 Hz, 2H). ESI/MS: m/z 337.1 [MH] ^- .

Synthesis of Compound A-27

Referring to the method of Example 25, intermediate I-28 was replaced by intermediate I-37, and after condensation, the ester was directly hydrolyzed to obtain compound A-27: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.63 (s, 1H), 10.81 (s, 1H), 8.67 (s, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.96 (dd, J = 11.3, 5.7 Hz, 5H), 7.92 (t, J = 6.2 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.43 (t, J = 8.7 Hz, 2H), 6.88 (dd, J = 8.7 Hz, 1H). HRMS (ESI) calcd. for C ₂₂ H ₁₇ F ₃ N ₂ O ₅ S [M+H] ⁺ 479.0883, found 479.0884.

Embodiment 28

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-((trifluoromethyl)thio)benzyl)benzamide (Compound A-28)

Synthesis of Compound A-28

Referring to the method of Example 3, 4,4-difluorocyclohexanone was replaced by 4-trifluoromethylbenzaldehyde to prepare compound A-28: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 9.37 (s, 2H), 7.89–7.78 (m, 4H), 7.71–7.61 (m, 3H), 7.46–7.32 (m, 7H), 6.68 (d, J=8.7 Hz, 1H), 4.10 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₀ F ₄ N ₂ O ₄ S ₂ [M+H] ⁺ 577.0873, found 577.0883.

Embodiment 29

4-(Cyclohexylmethyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-29)

Synthesis of intermediate I-38

Ethyl 4-(bromomethyl)benzoate (2.92 g, 12 mmol) was added to toluene (6 mL), and after stirring to dissolve the solid, triethyl phosphite (2.3 mL, 13.2 mmol) was added. After the addition was complete, the temperature was raised to 150° C. and reacted for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain a crude intermediate I-38 (colorless oily liquid, 3.6 g), which was directly used in the next step without further purification.

Synthesis of intermediate I-39

Sodium hydride (120 mg, 3 mmol) was added to a dry Schlenk tube, and anhydrous tetrahydrofuran (1 mL) was added under argon protection to suspend the mixture. Anhydrous tetrahydrofuran (2 mL) solution of intermediate I-38 (360 mg, 1.2 mmol) was slowly added under ice bath. After the addition, the mixture was slowly heated to room temperature for 1 hour. Then, anhydrous tetrahydrofuran (1 mL) solution of cyclohexanone (107 μL, 1 mmol) was slowly added under ice bath. After the addition, the mixture was heated to room temperature and stirred for 24 hours. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to the reaction solution to quench the excess sodium hydride, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 2), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate I-39 (white solid, 260 mg).

Synthesis of Compound A-29

Referring to the method of Example 1, intermediate I-4 was replaced by intermediate I-39 to obtain compound A-29: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.98 (s, 1H), 9.34 (s, 2H), 7.85–7.78 (m, 4H), 7.67 (d, J=2.5 Hz, 1H), 7.41–7.34 (m, 3H), 7.28 (d, J=8.0 Hz, 2H), 6.68 (d, J=8.7 Hz, 1H), 1.71–1.58 (m, 6H), 1.58–1.47 (m, 1H), 1.25–0.83 (m, 6H). HRMS (ESI) calcd. for C ₂₆ H ₂₇ FN ₂ O ₄ S [M+H] ⁺ 483.1748, found 483.1748.

Embodiment 30

4-((4,4-difluorocyclohexyl)methyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-30)

Synthesis of Compound A-30

Referring to the method of Example 29, cyclohexanone was replaced with 4,4-difluorocyclohexanone to prepare compound A-30: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 9.34 (s, 2H), 7.90–7.74 (m, 4H), 7.66 (d, J=2.5 Hz, 1H), 7.41–7.25 (m, 5H), 6.67 (d, J=8.7 Hz, 1H), 2.60 (d, J=6.8 Hz, 2H), 2.05–1.90 (m, 2H), 1.86–1.76 (m, 1H), 1.74–1.60 (m, 4H), 1.25–1.13 (m, 2H). HRMS (ESI) calcd. for C ₂₆ H ₂₅ F ₃ N ₂ O ₄ S[M+H] ⁺ 519.1560, found 519.1562.

Embodiment 31

4-(Cycloheptylmethyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-31)

Synthesis of Compound A-31

Referring to the method of Example 29, cyclohexanone was replaced by cycloheptanone to obtain compound A-31: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 9.34 (s, 2H), 7.89–7.77 (m, 4H), 7.67 (d, J=2.5 Hz, 1H), 7.42–7.25 (m, 5H), 6.68 (d, J=8.7 Hz, 1H), 2.56 (d, J=7.3 Hz, 2H), 1.84–1.73 (m, 1H), 1.67–1.30 (m, 10H), 1.17 (d, J=10.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₉ FN ₂ O ₄ S [M+H] ⁺ 497.1905, found 497.1898.

Embodiment 32

4-(Cyclopentylmethyl)-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound A-32)

Synthesis of Compound A-32

Referring to the method of Example 29, cyclohexanone was replaced by cyclopentanone, and intermediate I-3 was replaced by intermediate I-18 to obtain compound A-32: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.02(s,1H),9.05(s,2H),7.85(d,J＝8.1Hz,2H),7.63(d,J＝2.4Hz,1H),7.49(dd,J＝8.7,2.5Hz,1H),7.32(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),2.98(s,3H),2.65(d,J＝7.4Hz,2H),2.17–2.05(m,1H),1.70–1.58(m,4H),1.56–1.43(m,2H),1.25–1.14(m,2H).HRMS(ESI)calcd.for C ₂₀ H ₂₄ N ₂ O ₄ S[M+H] ⁺ 389.1530,found 389.1537.

Embodiment 33

4-(Cyclohexylmethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-33)

Synthesis of Compound A-33

Referring to the method of Example 29, intermediate I-3 was replaced by intermediate I-18 to obtain compound A-33: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.01(s,1H),9.46(s,1H),8.94(s,1H),7.85(d,J＝8.0Hz,2H),7.63(d,J＝2.3Hz,1H),7.49(dd,J＝8.7,2.3Hz,1H),7.28(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),2.98(s,3H),2.54(d,J＝6.9Hz,2H),1.71–1.49(m,6H),1.23–1.09(m,3H),1.01–0.88(m,2H).HRMS(ESI)calcd.for C ₂₁ H ₂₆ N ₂ O ₄ S[M+H] ⁺ 403.1686,found 403.1694.

Embodiment 34

4-(Cycloheptylmethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-34)

Synthesis of Compound A-34

Referring to the method of Example 29, cyclohexanone was replaced by cycloheptanone, and intermediate I-3 was replaced by intermediate I-18 to obtain compound A-34: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.01(s,1H),9.32(s,1H),8.97(s,1H),7.85(d,J＝7.9Hz,2H),7.63(d,J＝1.8Hz,1H),7.49(dd,J＝8.7,2.0Hz,1H),7.30(d,J＝7.9Hz,2H),6.85(d,J＝8.7Hz,1H),2.98(s,3H),2.56(d,J＝7.2Hz,2H),1.84–1.73(m,1H),1.67–1.29(m,10H),1.24–1.10(m,2H).HRMS(ESI)calcd.for C _{2 2} H ₂ 8 N ₂ O ₄ S[M+H] ⁺ 417.1843,found 417.1846.

Embodiment 35

4-((1H-imidazol-1-yl)methyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-35)

Synthesis of intermediate I-40

Imidazole (99 mg, 1.65 mmol) was added to acetonitrile (3 mL), and then ethyl 4-(bromomethyl)benzoate (200 mg, 0.82 mmol) and potassium carbonate (227 mg, 1.65 mmol) were added in sequence. After the addition was completed, the temperature was raised to 80° C. and the mixture was reacted for 10 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=100:1) to obtain intermediate I-40 (colorless oily liquid, 112 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ7.94 (d, J=8.2 Hz, 2H), 7.77 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.20 (s, 1H), 6.93 (s, 1H), 5.30 (s, 2H), 4.30 (q, J=7.1 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H).

Synthesis of Compound A-35

Referring to the method of Example 5, intermediate I-11 was replaced by intermediate I-40 to obtain compound A-35: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 9.43 (s, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.86-7.74 (m, 3H), 7.67 (d, J = 1.9 Hz, 1H), 7.43-7.31 (m, 5H), 7.24 (s, 1H), 6.96 (s, 1H), 6.68 (d, J = 8.7 Hz, 1H), 5.30 (s, 2H). HRMS (ESI) calcd. for C ₂₃ H ₁₉ FN ₄ O ₄ S [M+H] ⁺ 467.1184, found 467.1188.

Embodiment 36

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-(morpholinomethyl)benzamide hydrochloride (Compound A-36)

Synthesis of intermediate I-41

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-formylbenzoic acid to obtain the crude intermediate I-41 (yellow solid, 216 mg), which was directly used in the next reaction without further purification.

Synthesis of intermediate I-42

The crude intermediate I-41 (100 mg, 0.24 mmol) and morpholine (32 μL, 0.36 mmol) were added to dichloromethane (15 mL), glacial acetic acid (2 drops) was added, and sodium triacetoxyborohydride (153 mg, 0.72 mmol) was added in batches under an ice bath. After the addition was completed, the mixture was heated to room temperature and stirred for 12 hours. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added to the reaction solution to quench, and ethyl acetate was used for extraction (10 mL x 3). The organic phases were combined and washed with saturated brine (10 mL x 1). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol = 75:1) to obtain intermediate I-42 (white solid, 82 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.17(s,1H),8.48(s,1H),7.90(d,J＝7.9Hz,2H),7.75(d,J＝2.4Hz,1H),7.55(dd,J＝8.7,2.4Hz,1H),7.45(d,J＝7.8Hz,2H),6.92(d,J＝8.8Hz,1H),3.59(s,4H),3.54(s,2H),3.04(s,3H),2.37(s,4H),0.99(s,9H),0.24(s,6H).

Synthesis of intermediate I-43

Intermediate I-42 (80 mg, 0.15 mmol) and triethylamine trihydrofluoride (40 μL, 0.23 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction, solids were precipitated, filtered, and the filter cake was washed (dichloromethane/methanol = 20:1) to obtain the crude intermediate I-43 (white solid, 47 mg), which was directly used in the next step without further purification.

Synthesis of Compound A-36

The intermediate I-43 (47 mg) was added to dichloromethane (2 mL), and a 4M hydrogen chloride-dioxane solution (1 mL) was added dropwise. After the addition, the mixture was reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by pulping (ethyl acetate). The obtained solid was dried to constant weight to obtain compound A-36 (white solid, 33 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ11.09(s,1H),10.19(s,1H),9.78(s,1H),8.75(s,1H),8.02(d,J＝7.8Hz,2H),7.73(d,J＝7.8Hz,2H),7.64(d,J＝2.5Hz,1H),7.50(dd,J＝8.7,2.6Hz,1H),6.88(d,J＝8.7Hz,1H),4.41(d,J＝5.2Hz,2H),3.93(t,2H),3.77(t,J＝11.7Hz,2H),3.24(t,J＝11.8Hz,2H),3.10(t,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₁₉ H ₂₃ N ₃ O ₅ S[M-HCl+H] ⁺ 406.1431, found 406.1435.

Embodiment 37

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-(piperazin-1-ylmethyl)benzamide hydrochloride (Compound A-37)

Synthesis of Compound A-37

Referring to the method of Example 36, morpholine was replaced with 1-Boc-piperazine to prepare compound A-37: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.12 (s, 1H), 10.18 (s, 1H), 9.78 (s, 1H), 9.48 (s, 2H), 8.75 (s, 1H), 8.01 (d, J = 7.9 Hz, 2H), 7.74 (s, 2H), 7.64 (d, J = 2.5 Hz, 1H), 7.51 (dd, J = 8.7, 2.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 3.92 (s, 2H), 3.41 (s, 4H), 3.23 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₁₉ H ₂₄ N ₄ O ₄ S[M+H] ⁺ 405.1591, found 405.1575.

Embodiment 38

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide hydrochloride (Compound A-38)

Synthesis of Compound A-38

Referring to the method of Example 36, morpholine was replaced with N-methylpiperazine to prepare compound A-38: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.23 (s, 1H), 11.37 (s, 1H), 10.18 (s, 1H), 9.80 (s, 1H), 8.77 (s, 1H), 8.01 (d, J = 7.8 Hz, 2H), 7.84-7.59 (m, 3H), 7.51 (dd, J = 8.8, 2.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 4.29 (s, 2H), 3.90 (s, 4H), 3.38 (s, 4H), 2.97 (s, 3H), 2.80 (s, 3H). HRMS (ESI) calcd. for C ₂₀ H ₂₆ N ₄ O ₄ S[M-HCl+H] ⁺ 419.1748, found 419.1749.

Embodiment 39

4-((4,4-difluoropiperidin-1-yl)methyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-39)

Synthesis of Compound A-39

Referring to the method of Example 36, morpholine was replaced with 4,4-difluoropiperidine hydrochloride to prepare compound A-39: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.36 (s, 1H), 10.15 (s, 1H), 9.47 (s, 1H), 9.36 (s, 1H), 8.00 (d, J = 7.8 Hz, 2H), 7.87-7.77 (m, 2H), 7.78-7.70 (m, 2H), 7.69 (d, J = 2.6 Hz, 1H), 7.45-7.31 (m, 3H), 6.70 (d, J = 8.8 Hz, 1H), 4.46 (s, 2H), 3.43 (s, 4H), 2.36 (s, 4H). HRMS (ESI) calcd. for C ₂₅ H ₂₄ F ₃ N ₃ O ₄ S[M-HCl+H] ⁺ 520.1512, found 520.1518.

Embodiment 40

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-imidazole-4-carboxamide (Compound A-40)

Synthesis of intermediate I-44

Imidazole-4-carboxylic acid methyl ester (502 mg, 2 mmol) and 4-(trifluoromethyl)benzyl bromide (526 mg, 2.2 mmol) were added N, N-dimethylformamide (5mL), and then cesium carbonate (720mg, 2.2mmol) was added in batches, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, water (50mL) was added to the reaction solution for dilution, and ethyl acetate (10mL x 3) was used for extraction. The organic phases were combined, washed with water (20mL x 1) and saturated brine (20mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1:2) to obtain intermediate I-44 (white solid, 377mg): ^1H NMR (300MHz, Chloroform-d) δ7.65 (d, J = 7.9Hz, 2H), 7.60 (s, 2H), 7.29 (d, J = 7.6Hz, 2H), 5.24 (s, 2H), 3.88 (s, 3H).

Synthesis of intermediate I-45

The intermediate I-44 (350 mg, 1.23 mmol) was added to a mixed solvent of tetrahydrofuran (3 mL) and water (1.5 mL), and lithium hydroxide monohydrate (155 mg, 3.70 mmol) was added, and the mixture was reacted at room temperature for 6 hours. After the reaction was completed, the organic phase of the solvent was evaporated under reduced pressure, and a 1N aqueous solution of hydrogen chloride was added dropwise to the residue to adjust the pH to 5-6. Solids precipitated, filtered, and the filter cake was washed with dichloromethane (2 mL). The obtained solid was dried to constant weight to obtain the intermediate I-45 (white solid, 266 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.17 (s, 1H), 7.91 (d, J = 6.8 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 5.37 (s, 2H).

Synthesis of Compound A-40

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with intermediate I-45 to obtain compound A-40: ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 7.85 (s, 1H), 7.78 (s, 1H), 7.70 (d, J = 7.2 Hz, 3H), 7.47 (d, J = 8.1 Hz, 2H), 7.40 (dd, J = 8.8, 2.6 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 5.39 (s, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₁₉ H ₁₇ F ₃ N ₄ O ₄ S [M + H] ⁺ 455.0995, found 455.0996.

Embodiment 41

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4-triazole-3-carboxamide (Compound A-41)

Synthesis of Compound A-41

Referring to the method of Example 40, methyl imidazole-4-carboxylate was replaced with methyl 1,2,4-triazole-3-carboxylate to prepare compound A-41: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.62 (s, 1H), 8.90 (s, 1H), 8.68 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.1 Hz, 1H), 7.54 (d, J = 8.0 Hz, 2H), 7.48 (dd, J = 8.8, 2.1 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 5.64 (s, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₁₈ H ₁₆ F ₃ N ₅ O ₄ S [M+H] ⁺ 456.0948, found 456.0927.

Embodiment 42

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-1-(4-(trifluoromethoxy)benzyl)-1H-1,2,4-triazole-3-carboxamide (Compound A-42)

Synthesis of Compound A-42

Referring to the method of Example 40, imidazole-4-carboxylic acid methyl ester was replaced by 1,2,4-triazole-3-carboxylic acid methyl ester, and 4-(trifluoromethyl)benzyl bromide was replaced by 4-(trifluoromethoxy)benzyl bromide to prepare compound A-42: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.63 (s, 1H), 8.95–8.60 (m, 2H), 7.64 (s, 1H), 7.47 (d, J=8.7 Hz, 3H), 7.39 (d, J=8.3 Hz, 2H), 6.83 (d, J=8.8 Hz, 1H), 5.56 (s, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₁₈ H ₁₆ F ₃ N ₅ O ₅ S [M+H] ⁺ 472.0897, found 472.0705.

Embodiment 43

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-((trifluoromethyl)thio)phenoxy)benzamide (Compound A-43)

Synthesis of intermediate I-46

4-Trifluoromethylthiophenol (194 mg, 1 mmol) and methyl 4-fluorobenzoate (259 μL, 2 mmol) were added to dimethyl sulfoxide (3 mL), and potassium carbonate (276 mg, 2 mmol) was added in batches. After the addition was completed, the temperature was raised to 110 ° C and heated for 18 hours. After the reaction was completed, the system was cooled to room temperature, water (30 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with water (10 mL x 1) and saturated brine (10 mL x 1) in turn. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100: 1) to obtain intermediate I-46 (colorless oily liquid, 215 mg).

Synthesis of Compound A-43

Referring to the method of Example 1, intermediate I-5 was replaced by intermediate I-46 to prepare compound A-43: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 9.42 (s, 1H), 9.36 (s, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.83 (dd, J = 8.7, 5.3 Hz, 2H), 7.78 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 2.3 Hz, 1H), 7.43-7.38 (m, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.22 (dd, J = 11.5, 8.7 Hz, 4H), 6.70 (d, J = 8.7 Hz, 1H). HRMS (ESI) calcd. for C ₂₆ H ₁₈ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 579.0666, found 579.0676.

Embodiment 44

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-1)

Synthesis of intermediate II-1

4-Trifluoromethylthiobenzyl bromide (200 mg, 0.74 mmol), methyl 4-hydroxybenzoate (168 mg, 1.11 mmol) and potassium iodide (12 mg, 0.07 mmol) were added to acetonitrile (3 mL), and cesium carbonate (481 mg, 1.48 mmol), reacted at 80°C for 8 hours. After the reaction was completed, the reaction solution was filtered and the filter cake was washed with ethyl acetate (5 mL). Water (10 mL) was added to the filtrate for dilution, extracted with ethyl acetate (10 mL x 3), and the organic phases were combined and washed with 1M sodium hydroxide aqueous solution (5 mL x 2) and saturated brine (15 mL x 1) in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude intermediate II-1, which was directly used in the next step without further purification.

Synthesis of intermediate II-2

The crude intermediate II-1 was added to a mixed solvent of tetrahydrofuran (1.5 mL) and methanol (1.5 mL), and 1 M sodium hydroxide aqueous solution (1.5 mL) was added dropwise. After the addition, the temperature was raised to 60°C for 4 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and the pH of the residue was adjusted to 2-3 with 2N hydrogen chloride aqueous solution. Solids precipitated and were filtered. The filter cake was washed with water (5 mL) and ether (5 mL) in turn. The solid was dried to constant weight to obtain intermediate II-2 (white solid, 142 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ12.66 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.8 Hz, 2H), 5.28 (s, 2H).

Synthesis of intermediate II-3

Intermediate II-2 (45 mg, 0.14 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), and oxalyl chloride (17 μL, 0.21 mmol) was slowly added dropwise under ice bath, and the mixture was heated to room temperature for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added to a tetrahydrofuran (1 mL) solution of I-3 (60 mg, 0.15 mmol) and pyridine (17 μL, 0.21 mmol) under ice bath conditions, and reacted at room temperature for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 3-4, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate III-3 (white solid, 123 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.99(s,1H),9.01(s,1H),7.92(d,J＝8.5Hz,2H),7.82(d,J＝5.2Hz,1H),7.80–7.74(m,3H),7.64(d,J＝7.6Hz,3H),7.46(dd,J＝8.8,2.4Hz,1H),7.43–7.36(m,2H),7.14(d,J＝8.6Hz,2H),6.82(d,J＝8.7Hz,1H),5.30(s,2H),0.92(s,9H),0.13(s,6H).

Synthesis of compound B-1

Intermediate II-3 (107 mg, 0.19 mmol) and triethylamine trihydrofluoride (50 μL, 0.28 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction, solids were precipitated, filtered, and the filter cake was washed (dichloromethane/methanol = 20:1). The obtained solid was dried to constant weight to obtain compound B-1 (white solid, 57 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.91(s,1H),9.32(s,2H),7.93(d,J＝8.7Hz,2H),7.82(dd,J＝8.8,5.3Hz,2H),7.77(d,J＝8.1Hz,2H),7.66(d,J＝2.4Hz,1H),7.64(d,J＝8.2Hz,2H),7.38(dd,J＝8.7,2.7Hz,2H),7.33(d,J＝9.0Hz,1H),7.14(d,J＝8.7Hz,2H),6.68(d,J＝8.7Hz,1H),5.30(s,2H).HRMS(ESI)calcd.for C _{2 7} H _{2 0} F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 593.0823,found 593.0827.

Embodiment 45

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide (Compound B-2)

Synthesis of compound B-2

Referring to the method of Example 44, intermediate II-2 was replaced with 4-benzyloxybenzoic acid to obtain compound B-2: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 9.34 (s, 2H), 7.92 (d, J = 8.8 Hz, 2H), 7.86-7.79 (m, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.48 (d, J = 7.0 Hz, 2H), 7.44-7.33 (m, 6H), 7.12 (d, J = 8.9 Hz, 2H), 6.67 (d, J = 8.6 Hz, 1H), 5.20 (s, 2H). HRMS (ESI) calcd. for C ₂₆ H ₂₁ FN ₂ O ₅ S [M+H] ⁺ 493.1228, found 493.1231.

Embodiment 46

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide (Compound B-3)

Synthesis of compound B-3

Referring to the method of Example 44, 4-trifluoromethylthiobenzyl bromide was replaced by 4-trifluoromethylbenzyl bromide to obtain compound B-3: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 9.32 (s, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.85-7.76 (m, 4H), 7.73-7.65 (m, 3H), 7.36 (t, J = 8.9 Hz, 3H), 7.14 (d, J = 8.4 Hz, 2H), 6.68 (d, J = 8.6 Hz, 1H), 5.33 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₀ F ₄ N ₂ O ₅ S [M+H] ⁺ 561.1102, found 561.1108.

Embodiment 47

N-(3-((4-fluorophenyl)sulfonylamido)-4-hydroxyphenyl)-4-((4-((trifluoromethyl)sulfonyl)benzyl)oxy)benzamide (Compound B-4)

Synthesis of intermediate II-4

Intermediate II-2 (50 mg, 0.15 mmol) was added to trifluoroacetic acid (1 mL), and 30% aqueous hydrogen peroxide solution (73 μL, 0.8 eqv.) was added dropwise under ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 21 hours. After the reaction, the reaction solution was poured into ice water (5 mL), solid precipitated, filtered, the filter cake was washed with water (5 mL), the residue was purified by slurrying (n-hexane/ether=10:1), the obtained solid was dried to constant weight, and intermediate II-4 (white solid, 46 mg) was obtained: ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.70(s,1H),8.19(d,J＝8.2Hz,2H),7.92(dd,J＝8.5,2.6Hz,4H),7.14(d,J＝8.8Hz,2H),5.45(s,2H).ESI-MS:m/z 359.0[MH] ^- .

Synthesis of compound B-4

Referring to the method of Example 44, intermediate II-2 was replaced by intermediate II-4 to obtain compound B-4: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 9.33 (s, 2H), 8.20 (d, J = 8.2 Hz, 2H), 7.94 (dd, J = 8.0, 6.2 Hz, 4H), 7.82 (dd, J = 8.6, 5.3 Hz, 2H), 7.66 (d, J = 2.2 Hz, 1H), 7.36 (t, J = 8.8 Hz, 3H), 7.16 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 8.7 Hz, 1H), 5.46 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₀ F ₄ N ₂ O ₇ S ₂ [M+H] ⁺ 625.0721, found 625.0713.

Embodiment 48

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-(methylsulfonyl)benzyl)oxy)benzamide (Compound B-5)

Synthesis of compound B-5

Referring to the method of Example 44, 4-trifluoromethylthiobenzyl bromide was replaced by 4-methylsulfonylbenzyl bromide to prepare compound B-5: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 9.32 (s, 2H), 7.95 (dd, J = 11.9, 8.3 Hz, 4H), 7.81 (dd, J = 8.5, 5.2 Hz, 2H), 7.74 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 2.5 Hz, 1H), 7.36 (t, J = 12.1, 5.4 Hz, 3H), 7.14 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.7 Hz, 1H), 5.35 (s, 2H), 3.23 (s, 3H). HRMS (ESI) calcd. for C ₂₇ H ₂₃ FN ₂ O ₇ S ₂ [M+H] ⁺ 571.1003, found 571.1002.

Embodiment 49

4-(Cyclohexylmethoxy)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound B-6)

Synthesis of intermediate II-5

Methyl 4-hydroxybenzoate (200 mg, 1.31 mmol), cyclohexylmethanol (330 mg, 2.89 mmol) and triphenylphosphine (558 mg, 2.76 mmol) were added to a dry three-necked flask under argon protection. Anhydrous tetrahydrofuran (3 mL) was added to dissolve the mixture. Then, a solution of diisopropyl azodicarboxylate (560 μL, 2.76 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added under ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to obtain intermediate II-5 (colorless oily liquid, 320 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.89 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 8.8 Hz, 1H), 3.85 (d, J = 6.1 Hz, 1H), 3.80 (s, 1H), 1.83–1.63 (m, 3H), 1.28–1.17 (m, 2H), 1.09–0.97 (m, 1H).

Synthesis of compound B-6

Referring to the method of Example 44, intermediate II-1 was replaced with intermediate II-5 to obtain compound B-6: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 9.33 (s, 2H), 7.91 (d, J = 8.6 Hz, 2H), 7.81 (dd, J = 8.8, 5.3 Hz, 2H), 7.66 (d, J = 2.5 Hz, 1H), 7.40-7.32 (m, 3H), 7.02 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 8.7 Hz, 1H), 3.86 (d, J = 6.1 Hz, 2H), 1.87-1.63 (m, 6H), 1.31-1.17 (m, 3H), 1.12-1.02 (m, 2H). HRMS (ESI) calcd. for C ₂₆ H ₂₇ FN ₂ O ₅ S[M+H] ⁺ 499.1697, found 499.1698.

Embodiment 50

N-(4-chloro-3-((4-fluorophenyl)sulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-7)

Synthesis of intermediate II-6

2-Chloro-5-nitroaniline (345 mg, 2 mmol) and pyridine (241 μL, 3 mmol) were added to dichloromethane (5 mL), and a solution of 4-fluorobenzenesulfonyl chloride (467 mg, 2.4 mmol) in dichloromethane (2 mL) was added dropwise under an ice-water bath. After the addition was completed, the mixture was heated to room temperature for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, 2N aqueous hydrogen chloride solution (10 mL) was added to quench the excess pyridine, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with 1N aqueous hydrogen chloride solution (10 mL x 1), water (10 mL x 1), and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain a crude intermediate II-6 (yellow solid, 544 mg).

Synthesis of intermediate II-7

The crude intermediate II-6 (544 mg, 1.74 mmol) and 10% palladium on carbon (100 mg) were added to tetrahydrofuran (5 mL) and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction, palladium carbon was filtered off, the filter cake was washed with tetrahydrofuran (5 mL), the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate II-7 (orange oily liquid, 431 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.64 (s, 1H), 7.75 (dd, J = 8.8, 5.2 Hz, 2H), 7.39 (t, J = 8.8 Hz, 2H), 6.94 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 2.6 Hz, 1H), 6.37 (dd, J = 8.6, 2.6 Hz, 1H), 5.35 (s, 2H). ESI-MS: m/z 299.0 [MH] ^- .

Synthesis of compound B-7

Referring to the method of Example 44, intermediate I-3 was replaced by intermediate II-7 to obtain compound B-7: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.27 (s, 1H), 10.03 (s, 1H), 8.04-7.88 (m, 4H), 7.79 (d, 4H), 7.64 (dd, J=8.0 Hz, 3H), 7.42 (d, J=8.8 Hz, 1H), 7.38-7.32 (m, 1H), 7.16 (d, J=8.6 Hz, 2H), 5.31 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₁₉ ClF ₄ N ₂ O ₄ S ₂ [M+H] ⁺ 595.0779, found 595.0797

Embodiment 51

N-(4-fluoro-3-((4-fluorophenyl)sulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-8)

Synthesis of compound B-8

Referring to the method of Example 50, 2-chloro-5-nitroaniline was replaced by 2-fluoro-5-nitroaniline to prepare compound B-8: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.23 (s, 1H), 10.18 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.86-7.81 (m, 2H), 7.77 (d, J = 8.6 Hz, 3H), 7.64 (d, J = 8.0 Hz, 2H), 7.58 (s, 1H), 7.41 (t, J = 8.8 Hz, 2H), 7.19-7.08 (m, 3H), 5.31 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₁₉ F ₅ N ₂ O ₄ S ₂ [M+H] ⁺ 595.0779, found 595.0797.

Embodiment 52

N-(3-((4-fluorophenyl)sulfonamido)-4-(hydroxymethyl)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-9)

Synthesis of intermediate II-8

2-Amino-4-nitrobenzoic acid (500 mg, 2.75 mmol) was added into a dry Schlenk tube. Under argon protection, tetrahydrofuran (5.5 mL) was added to dissolve it. 1 M borane-tetrahydrofuran complex (5.5 mL, 5.5 mmol) was slowly added under ice bath. After the addition was completed, the temperature was raised to 65 °C and reacted for 4 hours. After the reaction, the system was cooled to room temperature, ice water (20 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate II-8 (yellow solid, 431 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.46 (s, 1H), 7.37 (t, 2H), 5.57 (s, 2H), 5.34 (t, J = 5.4 Hz, 1H), 4.43 (d, J = 5.4 Hz, 2H). ESI-MS: m/z 167.0 [MH] ^- .

Synthesis of compound B-9

Referring to the method of Example 50, 2-chloro-5-nitroaniline was replaced with intermediate II-8 to obtain compound B-9: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.49 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.82-7.72 (m, 4H), 7.62 (dd, J = 12.9, 7.8 Hz, 4H), 7.40 (t, J = 8.8 Hz, 2H), 7.30 (d, J = 8.7 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 5.30 (s, 2H), 5.17 (s, 1H), 4.28 (s, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₂ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 607.0979, found 607.1010.

Embodiment 53

2-((4-Fluorophenyl)sulfonamido)-4-(4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamido)benzoic acid (Compound B-10)

Synthesis of intermediate II-9

Compound 2-amino-4-nitrobenzoic acid (300 mg, 1.65 mmol) and potassium carbonate (455 mg, 3.3 mmol) were added to N, N-dimethylformamide (3 mL), and iodoethane (158 μL, 1.98 mmol) was added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature for 6 hours. After the reaction was completed, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate II-9 (orange solid, 325 mg).

Synthesis of intermediate II-10

Intermediate II-9 (160 mg, 0.76 mmol) and pyridine (92 μL, 1.14 mmol) were added to anhydrous dichloromethane (2 mL), and a solution of 4-fluorobenzenesulfonyl chloride (178 mg, 0.91 mmol) in dichloromethane (1 mL) was added dropwise under ice bath. The mixture was heated to room temperature and reacted for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, ethyl acetate (10 mL) and 2N aqueous hydrogen chloride solution (5 mL) were added, and the liquid was separated by shaking. The organic phase was washed with 1N aqueous hydrogen chloride solution (5 mL x 1), water (5 mL x 1), and saturated brine (5 mL x 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate II-10 (yellow oily liquid, 117 mg).

Synthesis of intermediate II-11

Intermediate II-10 (117 mg, 0.32 mmol) and 10% palladium on carbon (23 mg) were added to tetrahydrofuran (3 mL), and the mixture was reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction, palladium carbon was filtered off, the filter cake was washed with tetrahydrofuran (5 mL), the filtrate was evaporated to remove the solvent under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 4:1) to obtain intermediate II-11 (white solid, 92 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.98 (s, 1H), 7.89 (dd, J = 8.9, 5.1 Hz, 2H), 7.56 (d, J = 8.8 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H), 6.70 (d, J = 2.0 Hz, 1H), 6.35 (s, 2H), 6.23 (dd, J = 8.8, 2.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).ESI-MS: m/z 337.1 [MH] ^- .

Synthesis of intermediate II-12

Intermediate II-3 (60 mg, 0.18 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (2 mL), and oxalyl chloride (23 μL, 0.27 mmol) was slowly added dropwise under ice bath, and the mixture was heated to room temperature for 4 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was then added to a tetrahydrofuran (1 mL) solution of intermediate II-11 (68 mg, 0.20 mmol) and pyridine (22 μL, 0.27 mmol) under ice bath, and the mixture was heated to room temperature for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 3-4, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate II-12 (white solid, 112 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.69(s,1H),10.51(s,1H),8.21(d,1H),8.01–7.97(m,2H),7.95(d,J＝7.1Hz,2H),7.86(d,J＝8.8Hz,1H),7.77(d,J＝8.1Hz,2H),7.65(s,1H),7.63–7.57(m,2H),7.42(t,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,2H),5.32(s,2H),4.26(q,2H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 671.1[M+Na] ⁺ .

Synthesis of Compound B-10

The intermediate II-12 (95 mg, 0.15 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), and sodium hydroxide (12 mg, 0.29 mmol) was added in batches under an ice bath. After the addition was completed, the temperature was raised to 60°C for reaction for 6 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and a 2N aqueous solution of hydrogen chloride was added dropwise to the residue to adjust the pH to 2-3. Solids precipitated, the reaction solution was filtered, and the filter cake was washed with water (2 mL) and n-hexane (2 mL) in turn. The residue was purified by beating (n-hexane/dichloromethane = 1:1), and the obtained solid was dried to constant weight to obtain compound B-10 (white solid, 74 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ13.71(s,1H),11.29(s,1H),10.49(s,1H),8.22(d,1H),8.02–7.94(m,4H),7.87(d,J＝8.8Hz,1H),7.77(d,J＝8.0Hz,2H),7.64(d,J＝8.1Hz,2H),7.56(dd,J＝8.8Hz,1H),7.43(t,J＝8.8Hz,2H),7.18(d,J＝8.7Hz,2H),5.32(s,2H).HRMS(ESI)calcd.for C ₂₈ H ₂₀ F ₄ N ₂ O ₆ S ₂ [M+H] ⁺ 621.0772,found 621.0779.

Embodiment 54

4-((4-Fluorophenyl)sulfonamido)-2-(4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamido)benzoic acid (Compound B-11)

Synthesis of compound B-11

Referring to the method of Example 53, intermediate II-11 was replaced with intermediate I-37 to obtain compound B-11: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.56 (s, 1H), 12.20 (s, 1H), 10.98 (s, 1H), 8.68 (d, J = 2.0 Hz, 1H), 7.97 (dd, J = 8.8, 5.2 Hz, 2H), 7.91 (d, J = 8.6 Hz, 3H), 7.77 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.44 (t, J = 8.8 Hz, 2H), 7.22 (d, J = 8.8 Hz, 2H), 6.90 (dd, J = 8.8, 2.0 Hz, 1H), 5.31 (s, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₀ F ₄ N ₂ O ₆ S ₂ [M+H] ⁺ 621.0772, found 621.0771.

Embodiment 55

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-12)

Synthesis of intermediate II-13

Intermediate II-1 Synthesis of II-2 Referring to Example 44, intermediate II-2 (70 mg, 0.21 mmol) and N, N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), and oxalyl chloride (27 μL, 0.32 mmol) was slowly added dropwise under ice bath, and the temperature was raised to room temperature for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added to a tetrahydrofuran (1 mL) solution of I-18 (74 mg, 0.23 mmol) and pyridine (26 μL, 0.32 mmol) under ice bath conditions, and reacted at room temperature for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 3-4, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate II-13 (white solid, 133 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.04(s,1H),8.42(s,1H),7.95(d,J＝8.6Hz,2H),7.77(d,J＝8.3Hz,2H),7.74(d,J＝3.4Hz,1H),7.64(d,J＝8.0Hz,2H),7.53(dd,J＝8.7,2.0Hz,1H),7.15(d,J＝8.6Hz,2H),6.91(d,J＝8.8Hz,1H),5.30(s,2H),3.04(s,3H),1.00(s,9H),0.24(s,6H).

Synthesis of compound B-12

Intermediate II-13 (121 mg, 0.19 mmol) and triethylamine trihydrofluoride (37 μL, 0.29 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction, solids were precipitated, filtered, and the filter cake was washed (dichloromethane/methanol = 20:1). The obtained solid was dried to constant weight to obtain compound B-12 (white solid, 57 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.94(s,1H),9.44(s,1H),8.90(s,1H),7.94(d,J＝8.7Hz,2H),7.77(d,J＝8.0Hz,2H),7.64(d,J＝9.1Hz,2H),7.61(d,J＝2.9Hz,1H),7.48(dd,J＝8.8,2.2Hz,1H),7.14(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,1H),5.30(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 9} F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 513.0760,found 513.0757.

Embodiment 56

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide (Compound B- 13)

Synthesis of compound B-13

Referring to the method of Example 55, 4-trifluoromethylthiobenzyl bromide was replaced by 4-trifluoromethylbenzyl bromide to prepare compound B-13: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.95 (s, 1H), 9.65 (s, 1H), 8.71 (s, 1H), 7.94 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.48 (dd, J = 8.8, 2.4 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 5.34 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₃ N ₂ O ₅ S[M+H] ⁺ 481.1040, found 481.1044.

Embodiment 57

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-6-((4-((trifluoromethyl)thio)benzyl)oxy)nicotinamide (Compound B-14)

Synthesis of intermediate II-14

Referring to the method of Example 44, 4-hydroxybenzoic acid methyl ester was replaced by 6-hydroxynicotinate ethyl ester to obtain intermediate II-14: ¹ H NMR (300MHz, DMSO-d ₆ ) δ12.94 (s, 1H), 8.68 (d, J=2.3Hz, 1H), 7.85 (dd, J=9.5, 2.4Hz, 1H), 7.73 (d, J=8.1Hz, 2H), 7.44 (d, J=8.1Hz, 2H), 6.49 (d, J=9.5Hz, 1H), 5.29 (s, 2H). ESI-MS: m/z 328.0 [MH] ^- .

Synthesis of compound B-14

Referring to the method of Example 55, intermediate II-2 was replaced by intermediate II-14 to obtain compound B-14: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.87 (s, 1H), 9.21 (s, 2H), 8.62 (s, 1H), 8.02 (d, J = 9.7 Hz, 1H), 7.72 (d, J = 7.8 Hz, 2H), 7.52 (s, 1H), 7.48-7.37 (m, 3H), 6.85 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 9.5 Hz, 1H), 5.25 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₁ H ₁₈ F ₃ N _{3 O 5} _S ₂ [M+H] ⁺ 514.0713, found 514.0722.

Embodiment 58

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)benzyl)oxy)benzamide (Compound B-15)

Synthesis of compound B-15

Referring to the method of Example 55, 4-trifluoromethylthiobenzyl bromide was replaced by 4-trifluoromethoxybenzyl bromide to prepare compound B-15: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 9.64 (s, 1H), 8.68 (s, 1H), 7.94 (d, J = 8.7 Hz, 2H), 7.62 (dd, J = 5.6, 2.8 Hz, 3H), 7.48 (dd, J = 8.7, 2.3 Hz, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 5.24 (s, 2H), 2.97 (s, 3H). HRMS (ESI)calcd.for C ₂₂ H ₁₉ F ₃ N ₂ O ₆ S[M+H] ⁺ 497.0989,found 497.0998.

Embodiment 59

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(4-(trifluoromethylsulfonyl)benzyl)oxy)benzamide (Compound B-16)

Synthesis of compound B-16

Referring to the method of Example 55, intermediate II-2 was replaced by intermediate II-4 to prepare compound B-16: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (s, 1H), 9.64 (s, 1H), 8.73 (s, 1H), 8.19 (d, J = 8.4 Hz, 2H), 7.94 (dd, J = 12.2, 8.7 Hz, 4H), 7.61 (d, J = 2.6 Hz, 1H), 7.48 (dd, J = 8.8, 2.6 Hz, 1H), 7.16 (d, J = 9.0 Hz, 2H), 6.84 (d, J = 8.8 Hz, 1H), 5.45 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₃ N ₂ O ₇ S ₂ [M+H] ⁺ 545.0659, found 545.0663.

Embodiment 60

3-Fluoro-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(4-(trifluoromethylsulfonyl)benzyl)oxy)benzamide (Compound B-17)

Synthesis of compound B-17

Referring to the method of Example 47, 4-hydroxybenzoic acid methyl ester was replaced by 3-fluoro-4-hydroxybenzoic acid methyl ester, and intermediate I-3 was replaced by intermediate I-18 to obtain compound B-17: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.04(s,1H),9.72(s,1H),8.75(s,1H),8.26–8.17(m,2H),7.93(d,J＝8.5Hz,2H),7.88(dd,J＝12.2,2.1Hz,1H),7.81(dt,J＝8.8,1.6Hz,1H),7.60(d,J＝2.6Hz,1H),7.48(dd,J＝8.7,2.6Hz,1H),7.38(t,J＝8.6Hz,1H),6.85(d,J＝8.7Hz,1H),5.53(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 8} F ₄ N ₂ O ₇ S ₂ [M+H] ⁺ 563.0564,found 563.0570.

Embodiment 61

N-(2-Fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-(4-(trifluoromethylthio)benzyl)oxy)benzamide (Compound B-18)

Synthesis of intermediate II-15

4-Fluoro-2-methoxy-5-nitroaniline (500 mg, 2.69 mmol) and pyridine (320 μL, 4.03 mmol) were added to dichloromethane (10 mL), and methanesulfonyl chloride (250 μL, 3.22 mmol) in dichloromethane (5 mL) was slowly added dropwise under ice bath. After the addition was complete, the mixture was heated to room temperature and reacted for 8 hours. After the reaction was completed, concentrated hydrochloric acid (1 mL) was added to the reaction solution to quench the excess pyridine and methanesulfonyl chloride, the solvent was evaporated under reduced pressure, 1N aqueous hydrogen chloride solution (20 mL) was added to the residue, and ethyl acetate (10 mL x 3) was used for extraction. The organic phase was washed with 1N aqueous hydrogen chloride solution (10 mL x 2), water (10 mL x 1), and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by beating (ether). The obtained solid was dried to constant weight to obtain intermediate II-15 (yellow solid, 522 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ11.63 (s, 1H), 9.20 (s, 1H), 8.11 (d, J = 2.8 Hz, 1H), 7.98 (dd, J = 9.0, 2.8 Hz, 1H), 7.04 (d, J = 9.0 Hz, 1H), 3.04 (s, 3H).

Synthesis of intermediate II-16

Add intermediate II-15 (520 mg, 1.98 mmol) into a dry three-necked flask, protect with argon, add anhydrous dichloromethane (5 mL) to dissolve, then add boron tribromide (286 μL, 2.97 mmol) in anhydrous dichloromethane (5 mL) dropwise in an ice bath. After the addition is complete, slowly warm to room temperature and react for 3 hours. After the reaction was completed, ice water (20 mL) was added dropwise to the reaction solution to quench, and then 2N aqueous hydrogen chloride solution was added dropwise to adjust the pH to 1-2, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate II-16 (brown solid, 582 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.29 (s, 1H), 9.28 (s, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.00 (d, J = 13.1 Hz, 1H), 3.01 (s, 3H).

Synthesis of intermediate II-17

Intermediate II-16 (582 mg, 2.33 mmol) and 10% palladium on carbon (120 mg) were added to a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and reacted at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the filtrate was decompressed to evaporate the solvent to obtain a crude intermediate I-17, which was directly used in the next step without further purification.

Synthesis of intermediate II-18

The crude intermediate II-17 (2.33 mmol) and N,N-diisopropylethylamine (810 μL, 4.66 mmol) were added to dichloromethane (5 mL), and a solution of tert-butyldimethylsilyl chloride (489 mg, 3.26 mmol) in dichloromethane (5 mL) was added dropwise under an ice bath. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 12 hours. After the reaction, saturated sodium bicarbonate solution (20 mL) was added to the reaction solution for dilution, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 7.5:1) to obtain intermediate II-18 (brown oily liquid, 492 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.28 (s, 1H), 6.76 (d, J = 9.8 Hz, 1H), 6.59 (d, J = 12.1 Hz, 1H), 4.80 (s, 2H), 2.93 (s, 3H), 0.96 (s, 9H), 0.19 (s, 6H).

Synthesis of compound B-18

Referring to the method of Example 55, intermediate I-18 was replaced by intermediate II-18 to prepare compound B-18: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 9.82 (s, 1H), 8.92 (s, 1H), 7.95 (d, J = 8.9 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.15 (d, J = 8.9 Hz, 2H), 6.77 (d, J = 11.4 Hz, 1H), 5.30 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 531.0666, found 531.0667.

Embodiment 62

3-Fluoro-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)benzyl)oxy)benzamide (Compound B-19)

Synthesis of compound B-19

Referring to the method of Example 44, 4-hydroxybenzoic acid methyl ester was replaced by 3-fluoro-4-hydroxybenzoic acid methyl ester. Intermediate I-3 was replaced with intermediate II-17 to obtain compound B-19: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 9.89 (s, 1H), 8.87 (s, 1H), 7.87–7.77 (m, 4H), 7.65 (d, J=8.3 Hz, 2H), 7.40 (t, J=8.5 Hz, 1H), 7.27 (d, J=8.3 Hz, 1H), 6.77 (d, J=11.3 Hz, 1H), 5.38 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₇ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 549.0572, found 549.0555.

Embodiment 63

4-(Cyclohexylmethoxy)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-20)

Synthesis of compound B-20

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate II-5 to obtain compound B-20: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 9.61 (s, 1H), 8.72 (s, 1H), 7.92 (d, 3H), 7.61 (d, J = 2.6 Hz, 1H), 7.48 (dd, J = 8.8, 2.5 Hz, 1H), 7.02 (d, 2H), 6.84 (d, J = 8.7 Hz, 1H), 3.86 (d, J = 6.1 Hz, 2H), 2.96 (d, J = 1.8 Hz, 3H), 1.86-1.67 (m, 7H), 1.31-1.18 (m, 3H), 1.13-1.00 (m, 2H). HRMS (ESI) calcd. for C ₂₁ H ₂₆ N ₂ O ₅ S[M+H] ⁺ 419.1635, found 419.1638.

Embodiment 64

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((5-(trifluoromethyl)furan-2-yl)methoxy)benzamide (Compound B-21)

Synthesis of intermediate II-19

5-iodo-2-furancarboxaldehyde (666 mg, 3 mmol) was added to a mixed solvent of ethanol (5 mL) and tetrahydrofuran (10 mL), and sodium borohydride (227 mg, 6 mmol) was added in batches under an ice bath. After the addition, the mixture was slowly heated to room temperature for 4 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL) for quenching, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude intermediate II-19, which was directly used in the next step without further purification.

Synthesis of intermediate II-20

Methyl 4-hydroxybenzoate (609 mg, 4 mmol) and triphenylphosphine (1.2 g, 4.5 mmol) were added to a dry three-necked flask. Under argon protection, a solution of the crude intermediate II-19 (3 mmol) in anhydrous tetrahydrofuran (10 mL) was added. Then, a solution of diisopropyl azodicarboxylate (909 mg, 4.5 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature and the reaction was carried out for 12 hours. After the reaction, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phase was washed with saturated sodium carbonate solution (10 mL x 2) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100: 1) to obtain intermediate II-20 (colorless oily liquid, 278 mg): ¹ H NMR (300 MHz, Chloroform-d) δ8.02 (d, J = 8.9 Hz, 2H), 7.00 (d, J = 8.9 Hz, 2H), 6.57 (d, J = 3.3 Hz, 1H), 6.40 (d, J = 3.3 Hz, 1H), 5.06 (s, 2H), 3.91 (s, 3H).

Synthesis of intermediate II-21

Intermediate II-20 (275 mg, 0.77 mmol) and copper chloride (21 mg, 0.15 mmol) were added to anhydrous N,N-dimethylformamide (3 mL) under argon protection, and the aged reagent (445 mg, 2.31 mmol) was added dropwise. After the addition was completed, the temperature was raised to 110°C and reacted for 12 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, water (30 mL) was added to the filtrate for dilution, ethyl acetate (10 mL x 3) was used for extraction, the organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 75:1) to obtain intermediate II-21 (yellow oily liquid, 192 mg): ¹ H NMR (300 MHz, Chloroform-d) δ8.04 (d, J = 8.3 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.82 (s, 1H), 6.55 (s, 1H), 5.11 (s, 2H), 3.92 (s, 3H).

Synthesis of compound B-21

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate II-21 to obtain compound B-21: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 9.65 (s, 1H), 8.73 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.61 (d, J = 2.5 Hz, 1H), 7.48 (dd, J = 8.8, 2.6 Hz, 1H), 7.26 (d, J = 2.7 Hz, 1H), 7.16 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 3.6 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 5.26 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₀ H ₁₇ F ₃ N ₂ O ₆ S[M+H] ⁺ 471.0838, found 471.0842.

Embodiment 65

N-(4-Hydroxy-3-(thiophene-2-sulfonyl)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-22)

Synthesis of compound B-22

Referring to the method of Example 1, 4-fluorobenzenesulfonyl chloride was replaced by 2-thiophenesulfonyl chloride, and intermediate I-6 was replaced by intermediate II-2 to obtain compound B-22: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.96(s,1H),9.42(s,2H),7.94(d,J＝8.8Hz,2H),7.88(dd,J＝5.0Hz,1H),7.77(d,J＝8.1Hz,2H),7.69(d,J＝2.4Hz,1H),7.64(d,J＝8.2Hz,2H),7.53(dd,1H),7.42(dd,J＝8.7,2.4Hz,1H),7.13(d,J＝8.9Hz,2H),7.10(d,J＝4.9Hz,1H),6.71(d,J＝8.7Hz,1H),5.30(s,2H).HRMS(ESI)calcd.for C ₂ 5 H _{1 9} F ₃ N ₂ O ₅ S ₃ [M+H] ⁺ 581.0481,found 581.0470.

Embodiment 66

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-23)

Synthesis of intermediate II-22

4-Trifluoromethylthiophenol (200 mg, 1.03 mmol), ethyl 4-(bromomethyl)benzoate (376 mg, 1.55 mmol) and potassium iodide (17 mg, 0.1 mmol) were added to acetonitrile (4 mL), and cesium carbonate (672 mg, 2.06 mmol) was added in batches under stirring. After the addition was completed, the temperature was raised to 80°C and reacted for 8 hours. After the reaction was completed, the system was cooled to room temperature and the reaction solution was Filter and wash the filter cake with ethyl acetate (5 mL). Water (10 mL) was added to the filtrate for dilution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 1 M aqueous sodium hydroxide solution (5 mL x 2) and saturated brine (15 mL x 1) in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain intermediate II-22 (colorless oily liquid, 320 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ8.07 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 5.15 (s, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H). ESI-MS: m/z 379.1 [M+Na] ⁺ .

Synthesis of compound B-23

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate II-22 to obtain compound B-23: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 9.67 (s, 1H), 8.82 (s, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.68 (s, 1H), 7.65 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 8.2 Hz, 2H), 7.50 (dd, J = 8.8, 2.4 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.28 (s, 2H), 2.97 (s, 3H). ESI-MS: m/z 511.0 [MH] ^- .HRMS(ESI)calcd.for C ₂₂ H ₁₉ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 513.0760,found 513.0786.

Embodiment 67

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-(phenoxymethyl)benzamide (Compound B-24)

Synthesis of compound B-24

Referring to the method of Example 55, the intermediate II-2 was replaced with 4-(phenoxymethyl)benzoic acid to obtain compound B-24: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.10(s,1H),9.68(s,1H),8.74(s,1H),7.95(d,J＝8.2Hz,2H),7.63(d,J＝2.4Hz,1H),7.57(d,J＝8.2Hz,2H),7.50(dd,J＝8.7,2.5Hz,1H),7.30(t,J＝7.9Hz,2H),7.03(d,J＝7.9Hz,2H),6.95(t,J＝7.3Hz,1H),6.86(d,J＝8.7Hz,1H),5.20(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₁ H ₂₀ N ₂ O ₅ S[M+H] ⁺ 413.1171,found 413.1175.

Embodiment 68

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((p-tolyloxy)methyl)benzamide (Compound B-25)

Synthesis of compound B-25

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-methylphenol to prepare compound B-25: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 9.35 (s, 1H), 8.99 (s, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.63 (s, 1H), 7.55 (d, J = 7.7 Hz, 2H), 7.50 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 7.7 Hz, 2H), 6.86 (d, J = 8.9 Hz, 1H), 5.16 (s, 2H), 2.97 (s, 3H), 2.23 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₂ N ₂ O ₅ S[M+H] ⁺ 427.1328, found 427.1334.

Embodiment 69

4-(4-cyclopropylphenoxy)methyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-26)

Synthesis of intermediate II-23

4-Bromophenol (363 mg, 2.09 mmol), ethyl 4-(bromomethyl)benzoate (400 mg, 1.75 mmol) and potassium iodide (29 mg, 0.18 mmol) were added to acetonitrile (5 mL), and potassium carbonate (326 mg, 2.36 mmol) was added in batches. After the addition was completed, the temperature was raised to 70°C for reaction for 8 hours. After the reaction was completed, the reaction solution was filtered and the filter cake was washed with ethyl acetate (5 mL). Water (10 mL) was added to the filtrate for dilution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 1 M sodium hydroxide aqueous solution (5 mL x 2) and saturated brine (15 mL x 1) in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain intermediate II-23 (colorless oily liquid, 531 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ8.06 (d, J = 8.1 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.8 Hz, 2H), 5.09 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H).

Synthesis of intermediate II-24

Intermediate II-23 (354 mg, 1.06 mmol), cyclopropylboronic acid (118 mg, 1.38 mmol), tricyclohexylphosphine (30 mg, 0.11 mmol), potassium phosphate (832 mg, 3.71 mmol) and palladium acetate (12 mg, 0.05 mmol) were added to a Schlenk tube. Under argon protection, toluene (3 mL) and water (0.1 mL) were added to the system for suspension, and the temperature was raised to 100 °C for reaction for 6 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, the solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate II-24 (white solid, 276 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.05 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 7.01 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.10 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.91-1.80 (m, 1H), 1.40 (t, J = 7.1 Hz, 3H), 0.95-0.84 (m, 2H), 0.67-0.57 (m, 2H).

Synthesis of compound B-26

Referring to the method of Example 55, intermediate II-1 was replaced with intermediate II-24 to obtain compound B-26: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.09(s,1H),9.61(s,1H),8.77(s,1H),7.94(d,J＝7.9Hz,2H),7.63(d,J＝1.4Hz,1H),7.55(d,J＝7.9Hz,2H),7.50(d,J＝8.8Hz,1H),7.00(d,J＝8.4Hz,2H),6.93–6.83(m,3H),5.15(s,2H),2.97(s,3H),1.90–1.80(m,1H),0.87(d,J＝7.2Hz,2H),0.57(d,J＝4.3Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₄ N ₂ O ₅ S[M+H] ⁺ 453.1479,found 453.1477.

Embodiment 70

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(4-methoxyphenoxy)methylbenzamide (Compound B-27)

Synthesis of compound B-27

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-methoxyphenol to prepare compound B-27: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 9.55 (s, 1H), 8.75 (s, 1H), 7.94 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 2.3 Hz, 1H), 7.55 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 8.8, 2.3 Hz, 1H), 6.96 (d, J = 9.1 Hz, 2H), 6.86 (d, J = 9.2 Hz, 3H), 5.13 (s, 2H), 3.69 (s, 3H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₂ N ₂ O ₆ S[M+H] ⁺ 443.1271, found 443.1276.

Embodiment 71

4-(4-Fluorophenoxy)methyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-28)

Synthesis of compound B-28

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-fluorophenol to prepare compound B-28: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 9.55 (s, 1H), 8.77 (s, 1H), 7.95 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 2.2 Hz, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.50 (dd, J = 8.6 Hz, 1H), 7.13 (t, J = 8.8 Hz, 2H), 7.08-6.99 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.18 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₁ H ₁₉ FN ₂ O ₅ S[M+H] ⁺ 431.1071, found 431.1074.

Embodiment 72

4-(4-Chlorophenoxy)methyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-29)

Synthesis of compound B-29

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-chlorophenol to prepare compound B-29: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 9.65 (s, 1H), 8.73 (s, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.63 (s, 1H), 7.56 (d, J = 7.9 Hz, 2H), 7.50 (dd, J = 8.6, 1.6 Hz, 1H), 7.34 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.20 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₁ H ₁₉ ClN ₂ O ₅ S[M+H] ⁺ 447.0776, found 447.0778.

Embodiment 73

4-(4-bromophenoxy)methyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-30)

Synthesis of compound B-30

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-chlorophenol to prepare compound B-30: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 9.20 (s, 2H), 7.95 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.52-7.42 (m, 3H), 7.01 (d, J = 8.9 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 5.20 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₁ H ₁₉ BrN ₂ O ₅ S [M + H] ⁺ 491.0271, found 491.0277.

Embodiment 74

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound B-31)

Synthesis of compound B-31

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced with 4-trifluoromethylphenol to prepare compound B-31: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.50 (s, 1H), 8.85 (s, 1H), 7.95 (d, J= 8.2 Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.62 (d, J = 2.3 Hz, 1H), 7.58 (d, J = 8.2 Hz, 2H), 7.49 (dd, J = 8.7, 2.3 Hz, 1H), 7.21 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 5.29 (s, 2H), 2.96 (s, 3H).ESI-MS: m/z 481.1039 [M+H] ⁺ .HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₃ N ₂ O ₅ S [M+H] ⁺ 481.1040, found 481.1039.

Embodiment 75

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)phenoxy)methyl)benzamide (Compound B-32)

Synthesis of compound B-32

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-trifluoromethoxyphenol to prepare compound B-32: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.21 (s, 2H), 7.95 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 2.3 Hz, 1H), 7.57 (d, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.7, 2.3 Hz, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 9.1 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 5.22 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₃ N ₂ O ₆ S[M+H] ⁺ 497.0989, found 497.0992.

Embodiment 76

4-((4-cyanophenoxy)methyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-33)

Synthesis of compound B-33

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced with 4-hydroxybenzonitrile to prepare compound B-33: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.18 (s, 2H), 7.95 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 2.1 Hz, 1H), 7.57 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 8.7, 2.1 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 5.30 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ N ₃ O ₅ S [M+H] ⁺ 438.1118 found 438.1122.

Embodiment 77

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(((trifluoromethyl)thio)methyl)phenoxy)methyl)benzamide (Compound B-34)

Synthesis of intermediate II-25

Ethyl 4-(bromomethyl)benzoate (500 mg, 2.06 mmol), p-hydroxybenzaldehyde (301 mg, 2.46 mmol) and potassium iodide (34 mg, 0.21 mmol) were added to acetonitrile (10 mL), and cesium carbonate (1 g, 3.09 mmol) was added in batches. After the addition was completed, the temperature was raised to 80° C. and reacted for 6 hours. After the reaction was completed, the reaction solution was filtered and the filter cake was washed with ethyl acetate (5 mL). Water (10 mL) was added to the filtrate for dilution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with 1 M aqueous sodium hydroxide solution (10 mL x 2) and saturated brine (10 mL x 1) in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain intermediate II-25 (white solid, 603 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 7.98 (d, J = 8.1 Hz, 2H), 7.87 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H), 5.33 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

Synthesis of intermediate II-26

The intermediate II-25 (600 mg, 2.06 mmol) was added to methanol (8 mL), and sodium borohydride (215 mg, 6.37 mmol) was added in batches under an ice bath. After the addition was completed, the reaction was continued at 0°C for 4 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL) for quenching, extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude intermediate II-26, which was directly used in the next step without further purification: ¹ H NMR (300 MHz, DMSO-d ₆ )δ7.96(d,J＝8.1Hz,2H),7.57(d,J＝8.1Hz,2H),7.22(d,J＝8.4Hz,2H),6.95(d,J＝8.5Hz,2H),5.18(s,2H),5.03(t,J＝5.6Hz,1H),4.40(d,J＝5.4Hz,2H),4.30(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H).ESI-MS:m/z 309.1[M+Na] ⁺ .

Synthesis of intermediate II-27

Intermediate II-26 (589 mg, 2.06 mmol) and triphenylphosphine (756 mg, 2.88 mmol) were added to dichloromethane (5 mL), and a dichloromethane (5 mL) solution of carbon tetrabromide (1.02 g, 3.09 mmol) was slowly added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate II-27 (white solid, 370 mg).

Synthesis of intermediate II-28

Intermediate II-27 (370 mg, 1.06 mmol) and sodium thiocyanate (129 mg, 1.59 mmol) were added to acetonitrile (4 mL) and heated to 80 ° C for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude intermediate II-28, which was directly used in the next step without further purification.

Synthesis of intermediate II-29

The intermediate II-28 (273 mg, 0.83 mmol) and (trifluoromethyl)trimethylsilane (TMSCF ₃ ) (185 μL, 1.25 mmol) were added to tetrahydrofuran (2 mL), and then a 1M tetrabutylammonium fluoride tetrahydrofuran solution (1.25 mL, 1.25 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain the intermediate II-29 (white solid, 158 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ8.04 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 7.4 Hz, 2H), 7.26 (d, J = 3.9 Hz, 2H), 6.91 (d, J = 8.4 Hz, 2H), 5.12 (d, J = 8.7 Hz, 2H), 4.39 (q, J = 15.8, 7.3 Hz, 2H), 4.08 (d, J = 8.7 Hz, 2H), 1.40 (t, 3H).

Synthesis of compound B-34

Referring to the method of Example 55, intermediate II-1 was replaced with intermediate II-29 to prepare compound B-34: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 9.19 (s, 2H), 7.94 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 2.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 2H), 7.49 (dd, J = 8.8, 2.0 Hz, 1H), 7.32 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.5 Hz, 2H), 6.85 (d, J = 8.6 Hz, 1H), 5.19 (s, 2H), 4.25 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917, found 527.0914.

Embodiment 78

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((6-(trifluoromethyl)thiopyridin-3-yl)oxy)methyl)benzamide (Compound B-35)

Synthesis of intermediate II-30

Referring to the method of Example 66, replacing 4-trifluoromethylthiophenol with 2-bromo-5-hydroxypyridine, intermediate II-30 was prepared.

Synthesis of intermediate II-31

Add intermediate II-30 (275 mg, 0.82 mmol), silver trifluoromethanethiol (256 mg, 1.23 mmol), cuprous iodide (155 mg, 0.82 mmol) and 2,2'-bipyridine (191 mg, 1.23 mmol) into a sealed tube, add acetonitrile (3 mL) to suspend, and heat to 110°C for reaction for 12 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the filter cake was washed with ethyl acetate (5 mL), the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate II-31 (white solid, 289 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.48 (d, J = 2.9 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.3 Hz, 3H), 5.35 (s, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

Synthesis of compound B-35

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate I-31 to prepare compound B-35: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.22 (s, 2H), 8.49 (d, J = 2.9 Hz, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 8.7 Hz, 1H), 7.64-7.56 (m, 4H), 7.49 (dd, J = 8.7, 2.3 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.34 (s, 2H), 2.96 (s, 3H). ESI-MS: m/z 514.0718 [M+H] ^{+ .} HRMS (ESI) calcd. for C ₂₁ H ₁₈ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 514.0713, found 514.0718.

Embodiment 79

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(5-(trifluoromethyl)thiopyridin-2-oxy)methyl)benzamide (Compound B-36)

Synthesis of compound B-36

Referring to the method of Example 78, 2-bromo-5-hydroxypyridine was replaced with 2-hydroxy-5-bromopyridine to prepare compound B-36: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 9.53 (s, 1H), 8.83 (s, 1H), 8.20 (s, 1H), 7.88 (d, J = 7.0 Hz, 2H), 7.63-7.52 (m, 2H), 7.47 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 7.1 Hz, 2H), 6.84 (d, J = 8.8 Hz, 1H), 6.43 (d, J = 9.7 Hz, 1H), 5.13 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₁ H ₁₈ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 514.0713, found 514.0707.

Embodiment 80

4-((Cyclohexyloxy)methyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-37)

Synthesis of intermediate II-32

Sodium hydride (102 mg, 2.55 mmol) was added to a dry Schlenk tube, and anhydrous tetrahydrofuran (2 mL) was added under argon protection to suspend the mixture. A solution of cyclohexanol (225 mg, 2.25 mmol) in anhydrous tetrahydrofuran (2 mL) was added under ice bath. After the addition, the mixture was heated to room temperature and stirred for 1 hour. A solution of ethyl 4-(bromomethyl)benzoate (365 mg, 1.5 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise under ice bath. After the addition, the mixture was reacted at room temperature for 10 hours. After the reaction was completed, water (20 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated sodium chloride (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain a crude intermediate II-32, which was directly used in the next step without further purification.

Synthesis of compound B-37

Referring to the method of Example 55, intermediate II-1 was replaced with intermediate II-32 to obtain compound B-37: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.06(s,1H),9.68(s,1H),8.71(s,1H),7.91(d,J＝8.0Hz,2H),7.63(d,J＝2.6Hz,1H),7.50(dd,J＝8.7,2.5Hz,1H),7.44(d,J＝8.0Hz,2H),6.85(d,J＝8.7Hz,1H),4.57(s,2H),3.40–3.33(m,1H),2.97(s,3H),1.94–1.81(m,2H),1.74–1.63(m,2H),1.55–1.42(m,1H),1.35–1.18(m,5H).HRMS(ESI)calcd.for C ₂₁ H ₂₆ N ₂ O ₅ S[M+H] ⁺ 419.1635, found 419.1638.

Embodiment 81

4-(((4,4-difluorocyclohexyl)oxy)methyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-38)

Synthesis of intermediate II-33

4,4-Difluorocyclohexanone (335 mg, 2.5 mmol) was added to methanol (10 mL), and borohydride was added in portions under ice bath. Sodium (189 mg, 5 mmol) was added, and the temperature was slowly raised to room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL) for quenching, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed to evaporate the solvent to obtain intermediate II-33 (light yellow oily liquid, 300 mg).

Synthesis of intermediate II-34

The intermediate II-33 (295 mg, 2.17 mmol) was added to dichloromethane (5 mL), and triethylamine (600 μL, 4.33 mmol) was added. Then, a dichloromethane (2 mL) solution of trimethylsilyl trifluoromethanesulfonate (TMSOTf) (588 μL, 3.25 mmol) was slowly added dropwise under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature for 1 hour. After the reaction was completed, the reaction solution was washed with water (10 mL x 1) and saturated brine (10 mL x 1) in turn, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain the intermediate II-34 (colorless oily liquid, 223 mg).

Synthesis of intermediate II-35

Add ferric chloride (17 mg, 0.3 mmol) to ethyl acetate (10 mL), add trimethylsilyl chloride (TMSCl) (174 mg, 1.6 mmol) under stirring, continue to react at room temperature until the solid dissolves, and prepare a catalyst solution. Add intermediate II-34 (280 mg, 1.34 mmol) and methyl p-formylbenzoate (221 mg, 1.34 mmol) to a reaction bottle, then add the above catalyst solution (1.4 mL) and triethylsilane (225 μL, 1.41 mmol) in sequence, add and react at room temperature for 8 hours. After the reaction, saturated sodium bicarbonate solution (3 mL) was added to the reaction solution to quench the reaction, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate II-35 (light yellow oily liquid, 245 mg).

Synthesis of compound B-38

Referring to the method of Example 55, intermediate II-1 was replaced with intermediate II-35 to obtain compound B-38: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 9.12 (s, 2H), 7.92 (d, J = 7.8 Hz, 2H), 7.63 (s, 1H), 7.54-7.42 (m, 3H), 6.85 (d, J = 8.6 Hz, 1H), 4.59 (s, 2H), 3.63 (s, 1H), 2.96 (s, 3H), 2.07-1.73 (m, 8H). HRMS (ESI) calcd. for C ₂₁ H ₂₄ F ₂ N ₂ O ₅ S [M + H] ⁺ 455.1447, found 455.1454.

Embodiment 82

3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-39)

Synthesis of compound B-39

Referring to the method of Example 66, 4-(bromomethyl)benzoic acid ethyl ester was replaced with 3-fluoro-4-(bromomethyl)benzoic acid methyl ester to prepare compound B-39: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.21 (s, 2H), 7.82 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.7, 2.3 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.29 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 531.0666, found 531.0665.

Embodiment 83

3-Fluoro-4-(3-fluoro-4-((trifluoromethyl)thio)phenoxy)methyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-40)

Synthesis of intermediate II-36

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 3-fluoro-4-nitrophenol, and ethyl 4-(bromomethyl)benzoate was replaced by methyl 3-fluoro-4-(bromomethyl)benzoate to obtain compound II-36: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.19 (t, J = 9.2 Hz, 1H), 7.86 (dd, J = 7.9, 1.6 Hz, 1H), 7.81-7.73 (m, 2H), 7.38 (dd, J = 13.6, 2.6 Hz, 1H), 7.14-7.08 (m, 1H), 5.41 (s, 2H), 3.89 (s, 3H).

Synthesis of intermediate II-37

Intermediate II-36 (150 mg, 0.51 mmol) was added to N, N-dimethylformamide (2 mL), and tetrahydroxydiboron (131 mg, 1.46 mmol) and 4,4'-bipyridine (1 mg, 0.005 mmol) were added in turn under ice bath. After addition, the mixture was heated to room temperature for 15 minutes. After the reaction, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude intermediate II-37, which was directly used in the next step without further purification.

Synthesis of intermediate II-38

The intermediate II-37 (275 mg, 0.82 mmol) was added to ethanol (1.5 mL), and 40% fluoroboric acid (120 μL) and tert-butyl nitrite (130 μL) were added in turn under ice bath. After the addition, the temperature was slowly raised to room temperature for reaction for 1 hour. After the reaction was completed, ether (2 mL) was added to the reaction solution to completely precipitate the solid, the reaction solution was filtered, the filter cake was washed with ether (2 mL), and dried under reduced pressure. The obtained diazonium salt, silver trifluoromethanethiol (128 mg, 0.61 mmol), cuprous iodide (97 mg, 0.51 mmol), and potassium carbonate (141 mg, 1.02 mmol) were added to acetonitrile (2 mL) and reacted at room temperature in air atmosphere for 12 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate (2 mL x 2), the filtrate was decompressed to evaporate the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain the intermediate II-38 (white solid, 125 mg).

Synthesis of intermediate II-39

Intermediate II-38 (126 mg, 0.33 mmol) was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL), 1 M aqueous sodium hydroxide solution (1 mL) was added, and the temperature was raised to 60° C. to react for 6 hours. After the reaction, the system was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3. Solid precipitated and filtered. The filter cake was washed with water (2 mL) and n-hexane (2 mL) in turn. The obtained solid was dried to constant weight to obtain intermediate II-39 (white solid, 86 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.39 (s, 1H), 7.83 (dd, J = 7.9, 1.5 Hz, 1H), 7.76-7.74 (m, 1H), 7.74-7.70 (m, 2H), 7.29 (dd, J = 11.0, 2.6 Hz, 1H), 7.07 (dd, J = 8.8, 2.7 Hz, 1H), 5.33 (s, 2H).

Synthesis of compound B-40

Referring to the method of Example 55, intermediate II-2 was replaced by intermediate II-39 to prepare compound B-40: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 9.66 (s, 1H), 8.88 (s, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.77-7.69 (m, 2H), 7.63 (d, J = 2.5 Hz, 1H), 7.51 (dd, J = 8.7, 2.5 Hz, 1H), 7.30 (dd, J = 11.0, 2.6 Hz, 1H), 7.08 (dd, J = 8.8, 2.4 Hz, 1H), 6.87 (d, J = 8.7 Hz, 1H), 5.34 (s, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₇ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 549.0572, found 549.0547.

Embodiment 84

3-Fluoro-4-(2-fluoro-4-((trifluoromethyl)thio)phenoxy)methyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-41)

Synthesis of compound B-41

Referring to the method of Example 83, 3-fluoro-4-nitrophenol was replaced by 2-fluoro-4-nitrophenol to prepare compound B-41: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.71 (s, 1H), 8.87 (s, 1H), 7.84 (d, J = 8.7 Hz, 2H), 7.75-7.72 (m, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.58 (d, J = 9.1 Hz, 1H), 7.53-7.47 (m, 2H), 6.87 (d, J = 8.7 Hz, 1H), 5.40 (s, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₇ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 549.0572, found 549.0570.

Embodiment 85

3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylphenoxy)methyl)benzamide (Compound B-42)

Synthesis of compound B-42

Referring to the method of Example 66, 4-(bromomethyl)benzoic acid ethyl ester was replaced by 3-fluoro-4-(bromomethyl)benzoic acid methyl ester, and 4-trifluoromethylthiophenol was replaced by 4-trifluoromethylphenol to prepare compound B-42: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.19(s,1H),9.65(s,1H),8.89(s,1H),7.84(s,1H),7.82(s,1H),7.72(d,J＝7.7Hz,1H),7.71–7.68(m,2H),7.63(d,J＝2.5Hz,1H),7.51(dd,J＝8.8,2.5Hz,1H),7.26(d,J＝8.6Hz,2H),6.87(d,J＝8.7Hz,1H),5.33(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 8} F ₄ N ₂ O ₅ S[M+H] ⁺ 499.0945,found 499.0940.

Embodiment 86

3-Chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-43)

Synthesis of intermediate II-40

Methyl 3-chloro-4-methylbenzoate (185 mg, 1 mmol) was added to carbon tetrachloride (3 mL), and azobisisobutyronitrile (AIBN) (33 mg, 0.2 mmol) and N-bromosuccinimide (NBS) (187 mg, 1.05 mmol) were added in batches under an ice bath. After the addition was completed, the temperature was raised to 70°C for 4 hours. After the reaction was completed, the system was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain a crude intermediate II-40, which was directly used in the next step without further purification.

Synthesis of compound B-43

Referring to the method of Example 66, ethyl 4-(bromomethyl)benzoate was replaced with the crude intermediate II-40 to obtain compound B-43: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.21 (s, 2H), 7.82 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.7, 2.3 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.29 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ ClF ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 547.0371, found 547.0378.

Embodiment 87

3-Bromo-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-44)

Synthesis of compound B-44

Referring to the method of Example 66, ethyl 4-(bromomethyl)benzoate was replaced with methyl 3-bromo-4-methylbenzoate to prepare compound B-44: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.21 (s, 2H), 7.82 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 7.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.7, 2.3 Hz, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.29 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ BrF ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 590.9865, found 590.9874.

Embodiment 88

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-3-methoxy-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-45)

Synthesis of compound B-45

Referring to the method of Example 66, 4-(bromomethyl)benzoic acid ethyl ester was replaced with 3-methoxy-4-bromomethylbenzoic acid methyl ester to prepare compound B-45: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.09 (s, 1H), 9.22 (s, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.56 (s, 2H), 7.53-7.45 (m, 2H), 7.17 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.19 (s, 2H), 3.93 (s, 3H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₆ S ₂ [M+H] ⁺ 543.0866, found 543.0865.

Embodiment 89

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-3-(trifluoromethyl)-4-(4-(trifluoromethyl)thio)phenoxy)methylbenzamide (Compound B-46)

Synthesis of intermediate II-41

4-Trifluoromethylthiophenol (147 mg, 0.75 mmol), 4-bromo-2-trifluoromethylbenzyl bromide (200 mg, 0.63 mmol) and potassium iodide (10 mg, 0.06 mmol) were added to acetonitrile (3 mL), and potassium carbonate (117 mg, 0.85 mmol) was added in batches. After the addition was completed, the temperature was raised to 60°C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 1M sodium hydroxide aqueous solution (10 mL) was added to the reaction solution to neutralize excess phenol, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with 1M sodium hydroxide aqueous solution (5 mL x 2) and saturated brine (15 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to obtain intermediate II-41 (white solid, 278 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.85 (s, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 8.6 Hz, 3H), 6.98 (d, J = 8.6 Hz, 2H), 5.23 (s, 2H).

Synthesis of intermediate II-42

Intermediate II-41 (255 mg, 0.59 mmol), oxalic acid dihydrate (224 mg, 1.78 mmol), palladium acetate (4 mg, 0.02 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (10 mg, 0.02 mmol) and acetic anhydride (167 μL, 1.78 mmol) were added to anhydrous N,N-dimethylformamide (2 mL), the system was cooled to -78 ° C and frozen, N,N-diisopropylethylamine (310 μL, 1.78 mmol) was added, and argon was protected. The system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 ° C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate II-42 (white solid, 185 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.55 (s, 1H), 8.26 (d, J = 7.9 Hz, 2H), 7.93 (d, J = 7.9 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.18 (d, J = 8.7 Hz, 2H), 5.39 (s, 2H).

Synthesis of compound B-46

Referring to the method of Example 7, the intermediate 4-trifluoromethylthiobenzoic acid was replaced with the intermediate II-42 to prepare compound B-46: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 9.18 (s, 2H), 8.32 (s, 1H), 8.27 (d, J = 7.1 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.62 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.7 Hz, 1H), 5.39 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₁₈ F ₆ N ₂ O ₅ S ₂ [M+H] ⁺ 581.0634, found 581.0638.

Embodiment 90

3-Cyano-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-47)

Synthesis of intermediate II-43

Methyl 3-iodo-4-methylbenzoate (500 mg, 1.81 mmol) and cuprous cyanide (487 mg, 5.43 mmol) were added to N,N-dimethylformamide (6 mL) and the temperature was raised to 100 ° C for 12 hours. After the reaction, the system was cooled to room temperature, water (60 mL) was added to the reaction solution for dilution, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined and washed with water (15 mL x 2) and saturated brine (15 mL x 1) in turn. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate II-43 (white solid, 277 mg).

Synthesis of compound B-47

Referring to the method of Example 86, 3-chloro-4-methylbenzoic acid methyl ester was replaced with intermediate II-43 to obtain compound B-47: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 9.29 (s, 2H), 8.46 (s, 1H), 8.26 (d, J= 7.9 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 1.9 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 6.88 (d, J = 8.7 Hz, 1H), 5.42 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₁₈ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 538.0713, found 538.0712.

Embodiment 91

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-6-((4-((trifluoromethyl)thio)phenoxy)methyl)nicotinamide (Compound B-48)

Synthesis of compound B-48

Referring to the method of Example 86, 3-chloro-4-methylbenzoic acid methyl ester was replaced with 6-methylnicotinate to prepare compound B-48: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 9.20 (s, 2H), 9.07 (s, 1H), 8.32 (dd, J = 8.2, 1.9 Hz, 1H), 7.66 (d, J = 8.1 Hz, 3H), 7.62 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 8.8, 2.2 Hz, 1H), 7.20 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.35 (s, 2H), 2.96 (s, 3H). ESI-MS: m/z 514.0721 [M+H] ⁺ .HRMS(ESI)calcd.for C ₂₁ H ₁₈ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 514.0713,found 514.0721.

Embodiment 92

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-2-(4-(trifluoromethyl)phenoxy)methyl)pyrimidine-5-carboxamide (Compound B-49)

Synthesis of intermediate II-44

2-Methyl-5-bromopyrimidine (800 mg, 4.62 mmol) was added to carbon tetrachloride (10 mL), and azobisisobutyronitrile (AIBN) (759 mg, 4.62 mmol) and N-bromosuccinimide (NBS) (905 mg, 5.09 mmol) were added in batches under an ice bath. After the addition was completed, the temperature was raised to 70°C for 8 hours. After the reaction was completed, the system was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain a crude intermediate II-44, which was directly used in the next step without further purification.

Synthesis of intermediate II-45

The crude intermediate II-44, 4-trifluoromethylthiophenol (191 mg, 0.99 mmol) and potassium iodide (18 mg, 0.11 mmol) were added to acetonitrile (4 mL), and cesium carbonate (536 mg, 1.64 mmol) was added in batches. After the addition was completed, the temperature was raised to 70 ° C for 8 hours. After the reaction was completed, the system was cooled to room temperature, water (20 mL) was added to the reaction solution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (15 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate II-45 (white solid, 260 mg).

Synthesis of intermediate II-46

Intermediate II-45 (260 mg, 0.71 mmol), oxalic acid dihydrate (269 mg, 2.14 mmol), palladium acetate (5 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (12 mg, 0.02 mmol) and acetic anhydride (200 μL, 2.14 mmol) were added to anhydrous N,N-dimethylformamide (3 mL), the system was cooled to -78 ° C and frozen, N,N-diisopropylethylamine (353 μL, 2.14 mmol) was added, and argon was used for protection. The system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 ° C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 50:1) to obtain a crude intermediate II-46, which was purified by slurrying (dichloromethane/methanol = 20:1) to obtain intermediate II-46 (white solid, 135 mg): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.84 (s, 1H), 9.23 (s, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.9 Hz, 2H), 5.49 (s, 2H).

Synthesis of compound B-49

Intermediate II-46 (100 mg, 0.30 mmol) and intermediate I-18 (105 mg, 0.33 mmol) were added to N,N-dimethylformamide (2 mL), and N,N-diisopropylethylamine (150 μL, 0.91 mmol) was added, and then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg, 0.36 mmol) was added under ice bath. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 16 hours. After the reaction, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol = 50:1) to obtain a crude compound B-49, which was purified by slurrying (dichloromethane/methanol = 20:1) to obtain compound B-49 (white solid, 108 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.47(s,1H),9.55(s,1H),9.25(s,2H),8.93(s,1H),7.66(s,1H),7.64–7.60(m,2H),7.49(dd,J＝8.7,2.6Hz,1H),7.14(d,J＝8.9Hz,2H),6.89(d,J＝8.7Hz,1H),5.49(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₀ H ₁₇ F ₃ N ₄ O ₅ S ₂ [M+H] ⁺ 515.0665,found 515.0672.

Embodiment 93

3-Cyclopropyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-50)

Synthesis of intermediate II-47

Referring to the method of Example 86, 3-chloro-4-methylbenzoic acid methyl ester was replaced by 3-bromo-4-methylbenzoic acid methyl ester to obtain Intermediate II-47: ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.27 (d, J = 1.3 Hz, 1H), 8.02 (dd, J = 8.0, 1.2 Hz, 1H), 7.63 (d, J = 5.3 Hz, 1H), 7.60 (d, J = 6.4 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.19 (s, 2H), 3.94 (s, 3H).

Synthesis of intermediate II-48

The intermediate II-47 (200 mg, 0.47 mmol), cyclopropylboronic acid (61 mg, 0.71 mmol), potassium phosphate (302 mg, 1.42 mmol) and tetrakis(triphenylphosphine)palladium (27 mg, 0.02 mmol) were added to the Schlenk tube, and toluene (4 mL) and water (0.2 mL) were added to the system under argon protection, and the mixture was suspended at 90°C for 6 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, the solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain the intermediate II-48 (white solid, 184 mg).

Synthesis of compound B-50

Referring to the method of Example 55, intermediate II-1 was replaced with intermediate II-48 to obtain compound B-50: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.05(s,1H),9.19(s,2H),7.75(d,J＝7.9Hz,1H),7.67(d,J＝8.6Hz,2H),7.59(d,J＝2.3Hz,1H),7.54(d,J＝7.9Hz,2H),7.48–7.41(m,1H),7.21(d,J＝8.8Hz,2H),6.85(d,J＝8.7Hz,1H),5.40(s,2H),2.96(s,3H),2.14–2.04(m,1H),1.03–0.92(m,2H),0.84–0.72(m,2H).HRMS(ESI)calcd.for C _{2 5} H _{2 3} F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 553.1079, found 553.1084.

Embodiment 94

2-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-51)

Synthesis of compound B-51

Referring to the method of Example 89, 4-bromo-2-trifluoromethylbenzyl bromide was replaced by 3-fluoro-4-bromobenzyl bromide to prepare compound B-51: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.44 (s, 1H), 9.13 (s, 1H), 7.69-7.65 (m, 3H), 7.59 (d, J=2.5 Hz, 1H), 7.47-7.43 (m, 1H), 7.42 (d, J=7.3 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.19 (d, J=8.9 Hz, 2H), 6.86 (d, J=8.7 Hz, 1H), 5.28 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 531.0666, found 531.0670.

Embodiment 95

2-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylphenoxy)methyl)benzamide (Compound B-52)

Synthesis of compound B-52

Referring to the method of Example 89, 4-bromo-2-trifluoromethylbenzyl bromide was replaced by 3-fluoro-4-bromobenzyl bromide, and 4-trifluoromethylthiophenol was replaced by 4-trifluoromethylphenol to prepare compound B-52: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.24(s,1H),9.74(s,1H),8.77(s,1H),7.70–7.67(m,3H),7.66(d,J＝7.5Hz,1H),7.58(d,J＝2.5Hz,1H),7.46–7.40(m,2H),7.39(d,J＝8.1Hz,1H),7.22(d,J＝8.6Hz,2H),6.86(d,J＝8.7Hz,1H),5.31(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 8} F ₄ N ₂ O ₅ S[M+H] ⁺ 499.0945,found 499.0937.

Embodiment 96

2-Chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-53)

Synthesis of intermediate II-49

4-Bromo-3-chlorobenzaldehyde (250 mg, 1.14 mmol) was added to methanol (5 mL), and sodium borohydride (77 mg, 2.28 mmol) was added in batches under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature for 4 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL) for quenching, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude intermediate II-49, which was directly used in the next step without further purification.

Synthesis of intermediate II-50

The crude intermediate II-49 and triphenylphosphine (418 mg, 1.59 mmol) were added to tetrahydrofuran (5 mL), and carbon tetrabromide (567 mg, 1.71 mmol) was added in batches under an ice bath. After the addition was complete, the mixture was heated to room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to obtain intermediate II-50 (colorless oily liquid, 271 mg).

Synthesis of intermediate II-51

Intermediate II-50 (270 mg, 0.95 mmol), 4-trifluoromethylthiophenol (203 mg, 1.04 mmol) and potassium iodide (16 mg, 0.09 mmol) were added to acetonitrile (3 mL), and cesium carbonate (464 mg, 1.42 mmol) was added in batches. After the addition was completed, the temperature was raised to 70°C and the reaction was carried out for 8 hours. After the reaction, the system was cooled to room temperature, water (20 mL) was added to the reaction solution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (15 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether) to obtain intermediate II-51 (white solid, 364 mg): ¹ H NMR (400 MHz, CDCl ₃ ) δ7.66 (d, J = 8.2 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.56 (d, J = 1.9 Hz, 1H), 7.20 (dd, J = 8.2, 2.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 5.04 (s, 2H).

Synthesis of intermediate II-52

Intermediate II-51 (345 mg, 0.87 mmol), oxalic acid dihydrate (328 mg, 2.60 mmol), palladium acetate (6 mg, 0.03 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (15 mg, 0.03 mmol) and acetic anhydride (244 μL, 2.60 mmol) were added to anhydrous N,N-dimethylformamide (2.5 mL), the system was cooled to -78 ° C and frozen, N,N-diisopropylethylamine (430 μL, 2.60 mmol) was added, and argon was used for protection. The system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 ° C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 75:1) to obtain intermediate II-52 (light yellow solid, 248 mg): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.64 (d, J = 1.3 Hz, 1H), 7.50 (dd, J = 8.0, 1.5 Hz, 1H), 7.18 (d, J = 8.9 Hz, 2H), 5.26 (s, 2H).

Synthesis of compound B-53

Referring to the method of Example 55, intermediate II-2 was replaced by intermediate II-52 to prepare compound B-53: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.33 (s, 1H), 9.74 (s, 1H), 8.74 (s, 1H), 7.70-7.64 (m, 3H), 7.59 (t, J = 5.0 Hz, 2H), 7.52 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 8.7, 2.5 Hz, 1H), 7.19 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.27 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ ClF ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 547.0371, found 547.0379.

Embodiment 97

2-Chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-54)

Synthesis of compound II-53

Referring to the method of Example 86, methyl 3-chloro-4-methylbenzoate was replaced with 4-bromo-2,6-difluorotoluene to prepare Intermediate II-53.

Synthesis of compound B-54

Referring to the method of Example 96, intermediate II-50 was replaced by intermediate II-53 to prepare compound B-54: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 9.64 (s, 1H), 8.88 (s, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 2.5 Hz, 1H), 7.51 (dd, J = 8.8, 2.5 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.7 Hz, 1H), 5.27 (s, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₇ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 549.0572, found 549.0575.

Embodiment 98

Ethyl 2-(N-(5-(3-fluoro-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamido)-2-hydroxyphenyl)aminosulfonyl)acetate (Compound B-55)

Synthesis of intermediate II-54

2-Nitro-4-aminophenol (500 mg, 3.24 mmol) was added to dichloromethane (10 mL), and N,N-diisopropylethylamine (1.1 mL, 6.49 mmol) was added dropwise. A solution of tert-butyldimethylsilyl chloride (733 mg, 4.87 mmol) in dichloromethane (5 mL) was added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate II-54 (orange solid, 632 mg): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 6.98 (d, J = 2.7 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6.79 (dd, J = 8.8, 2.7 Hz, 1H), 5.26 (s, 2H), 0.93 (s, 9H), 0.15 (s, 6H).

Synthesis of intermediate II-55

Referring to the method of Example 66, ethyl 4-(bromomethyl)benzoate was replaced with methyl 3-fluoro-4-(bromomethyl)benzoate to obtain Intermediate II-55: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.37 (s, 1H), 7.81 (d, J = 7.5 Hz, 1H), 7.72 (s, 1H), 7.68 (d, J = 2.3 Hz, 2H), 7.65 (s, 1H), 7.20 (d, J = 7.0 Hz, 2H), 5.29 (s, 2H).

Synthesis of intermediate II-56

Intermediate II-55 (632 mg, 1.83 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (6 mL), and oxalyl chloride (232 μL, 2.74 mmol) was slowly added dropwise under ice bath, and the mixture was heated to room temperature for 2 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (6 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added dropwise to a tetrahydrofuran (1 mL) solution of II-54 (641 mg, 1.92 mmol) and pyridine (220 μL, 2.74 mmol) under ice bath conditions, and the mixture was heated to room temperature for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 3-4, extracted with ethyl acetate (5 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give intermediate II-56 (yellow solid, 986 mg).

Synthesis of intermediate II-57

The intermediate II-56 (858 mg, 1.44 mmol) was added to N, N-dimethylformamide (2 mL), and tetrahydroxydiboron (387 mg, 4.31 mmol) and 4,4'-bipyridine (2 mg, 0.01 mmol) were added in turn under ice bath. After the addition, the mixture was heated to room temperature for reaction for 15 minutes. After the reaction was completed, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 7.5:1) to obtain the intermediate II-57 (light yellow solid, 607 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.98(s,1H),7.82–7.77(m,2H),7.71(d,J＝8.0Hz,1H),7.68(d,J＝8.7Hz,2H),7.22(d,J＝8.9Hz,2H),7.18(d,J＝2.5Hz,1H),6.82(dd,J＝8.5,2.5Hz,1H),6.65(d,J＝8.5Hz,1H),5.30(s,2H),4.61(s,2H),0.98(s,9H),0.20(s,6H).

Synthesis of intermediate II-58

The intermediate II-57 (100 mg, 0.18 mmol) was added to anhydrous dichloromethane (2 mL), pyridine (21 μL, 0.26 mmol) was added, and a solution of (chlorosulfonyl) ethyl acetate (40 mg, 0.21 mmol) in dichloromethane (1 mL) was added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature for 8 hours. After the reaction was completed, 1N aqueous hydrogen chloride solution (5 mL) and water (5 mL) were added to the reaction solution to quench the excess pyridine, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (5 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 6:1) to obtain the intermediate II-58 (light yellow oily liquid, 97 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.30(s,1H),8.84(s,1H),7.86–7.81(m,2H),7.78(d,J＝2.6Hz,1H),7.73(t,J＝7.8Hz,1H),7.68(d,J＝8.7Hz,2H),7.57(dd,J＝8.9,2.6Hz,1H),7.22(d,J＝8.9Hz,2H),6.96(d,J＝8.8Hz,1H),5.32(s,2H),4.29(s,2H),4.14(q,J＝7.1Hz,2H),1.18(t,3H),1.00(s,9H),0.26(s,6H).

Synthesis of compound B-55

The intermediate II-58 (156 mg, 0.22 mmol) was added to dichloromethane (2 mL), and triethylamine trihydrofluoride (53 μL, 0.33 mmol) was added dropwise, and the mixture was reacted at room temperature for 6 hours. After the reaction, a solid was precipitated, which was filtered and the filter cake was washed (dichloromethane/methanol = 20:1). The obtained solid was dried to constant weight to obtain the intermediate B-55 (white solid, 113 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.20(s,1H),9.66(s,1H),9.29(s,1H),7.85–7.81(m,2H),7.73(d,J＝7.8Hz,1H),7.68(d,J＝8.8Hz,2H),7.64(d,J＝2.5Hz,1H),7.52(dd,J＝8.8,2.5Hz,1H),7.22(d,J＝8.9Hz,2H),6.88(d,J＝8.7Hz,1H),5.31(s,2H),4.24(s,2H),4.12(q,J＝7.1Hz,2H),1.19(t,J＝7.1Hz,3H).HRMS(ESI)calcd.for C ₂ 5 H _{2 2} F ₄ N ₂ O ₇ S ₂ [M+H] ⁺ 603.0877, found 603.0887.

Embodiment 99

2-Chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-56)

Synthesis of compound B-56

Compound B-55 (50 mg, 0.08 mmol) was added to tetrahydrofuran (2 mL), and a 2M tetrahydrofuran solution of lithium borohydride (105 μL, 0.21 mmol) was added dropwise under an ice bath. After the addition, the temperature was raised to 60°C for reaction for 3 hours. After the reaction, the system was cooled to room temperature, and water (10 mL) was added dropwise to the reaction solution under an ice bath to quench the excess lithium borohydride. The mixture was extracted with ethyl acetate (5 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 30:1) to obtain a crude compound B-56, which was purified by slurrying (dichloromethane/methanol = 20:1) to obtain compound B-56 (light yellow solid, 34 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.19(s,1H),9.78(s,1H),8.73(s,1H),7.86–7.81(m,2H),7.72(d,J＝7.7Hz,1H),7.68(d,J＝8.8Hz,2H),7.65(d,J＝2.5Hz,1H),7.50(dd,J＝8.8,2.5Hz,1H),7.22(d,J＝8.9Hz,2H),6.86(d,J＝8.7Hz,1H),5.31(s,2H),5.01(t,J＝5.6Hz,1H),3.80(q,J＝12.4,6.7Hz,2H),3.25(t,J＝6.8Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₀ F ₄ N ₂ O ₆ S ₂ [M+H] ⁺ 561.0772, found 561.0776.

Embodiment 100

3-(N-(5-(3-fluoro-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamido)-2-hydroxyphenyl)aminosulfonyl)propanoic acid methyl ester (Compound B-57)

Synthesis of compound B-57

Referring to the method of Example 98, ethyl (chlorosulfonyl)acetate was replaced with methyl 3-(chlorosulfonyl)propionate to obtain compound B-57: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.19(s,1H),9.82(s,1H),9.09(s,1H),7.85–7.80(m,2H),7.73(d,J＝7.7Hz,1H),7.68(d,J＝8.8Hz,2H),7.62(d,J＝2.6Hz,1H),7.53(dd,J＝8.8,2.6Hz,1H),7.22(d,J＝8.9Hz,2H),6.87(d,J＝8.7Hz,1H),5.31(s,2H),3.62(s,3H),3.30(t,J＝7.5Hz,2H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂ 5 H _{2 2} F ₄ N ₂ O ₇ S ₂ [M+H] ⁺ 603.0877, found 603.0881.

Embodiment 101

2-Chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-58)

Synthesis of compound B-58

Referring to the method of Example 99, compound B-55 was replaced by compound B-57 to obtain compound B-58: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.19(s,1H),9.77(s,1H),8.73(s,1H),7.86–7.80(m,2H),7.72(d,J＝7.6Hz,1H),7.68(d,J＝8.8Hz,2H),7.64(d,J＝2.5Hz,1H),7.50(dd,J＝8.7,2.5Hz,1H),7.22(d,J＝8.8Hz,2H),6.86(d,J＝8.7Hz,1H),5.31(s,2H),4.62(t,J＝5.1Hz,1H),3.46(q,J＝11.3,5.9Hz,2H),3.12–3.05(m,2H),1.91–1.83(m,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₂ F ₄ N ₂ O ₆ S ₂ [M+H] ⁺ 575.0928, found 575.0900.

Embodiment 102

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-59)

Synthesis of compound B-59

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate II-22, and intermediate I-18 was replaced by intermediate II-18 to obtain compound B-59: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 9.96 (s, 1H), 8.87 (s, 1H), 7.98 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H), 7.59 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 8.3 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 6.77 (d, J = 11.3 Hz, 1H), 5.28 (s, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 531.0666, found 531.0667.

Embodiment 103

N-(2-chloro-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-60)

Synthesis of intermediate II-59

4-Chloro-2-methoxyaniline (865 mg, 5.49 mmol) was added to concentrated sulfuric acid (6 mL), potassium nitrate (610 mg, 6.04 mmol) was added in batches under ice bath, and stirring was continued for 1 hour at 0°C. After the reaction was completed, the reaction solution was added dropwise to ice water, and sodium bicarbonate was added in batches to adjust the pH to 7-8 to precipitate solids, extracted with ethyl acetate (20 mL x 3), combined organic phases, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 6:1) to obtain intermediate II-59 (yellow solid, 795 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.32 (s, 1H), 7.04 (s, 1H), 5.53 (s, 2H), 3.90 (s, 3H).

Synthesis of intermediate II-60

Referring to the method of Example 61, 4-fluoro-2-methoxy-5-nitroaniline was replaced with Intermediate II-59 to obtain Intermediate II-60: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.30 (s, 1H), 6.83 (s, 1H), 6.72 (s, 1H), 5.01 (s, 2H), 2.99 (s, 3H), 0.96 (s, 9H), 0.19 (s, 6H).

Synthesis of compound B-60

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate II-22, and intermediate I-18 was replaced by intermediate II-60 to obtain compound B-60: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.26–8.87 (m, 3H), 7.99 (d, J=8.1 Hz, 2H), 7.66 (d, J=8.8 Hz, 2H), 7.59 (d, J=8.2 Hz, 2H), 7.31 (s, 1H), 7.18 (d, J=8.9 Hz, 2H), 7.01 (s, 1H), 5.28 (s, 2H), 2.99 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ ClF ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 547.0371, found 547.0374.

Embodiment 104

N-(2-bromo-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-61)

Synthesis of intermediate II-61

4-Bromo-2-methoxyaniline (853 mg, 4.22 mmol) was added to concentrated sulfuric acid (6 mL), potassium nitrate (640 mg, 6.33 mmol) was added in batches under ice bath, and stirring was continued for 10 minutes at 0°C. After the reaction was completed, the reaction solution was added dropwise to ice water, and sodium bicarbonate was added in batches to adjust the pH to 7-8 to precipitate solids, extracted with ethyl acetate (20 mL x 3), combined organic phases, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 15:1) to obtain intermediate II-61 (yellow solid, 762 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ7.32 (s, 1H), 7.15 (s, 1H), 5.58 (s, 2H), 3.90 (s, 3H).

Synthesis of intermediate II-62

Intermediate II-61 (762 mg, 3.08 mmol) and pyridine (496 μL, 6.17 mmol) were added to dichloromethane (7 mL), and a solution of methanesulfonic anhydride (752 mg, 4.32 mmol) in dichloromethane (5 mL) was added dropwise under ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction was completed, concentrated hydrochloric acid (0.5 mL) was added to the reaction solution to quench the excess pyridine and methanesulfonic anhydride, the solvent was evaporated under reduced pressure, 1N aqueous hydrogen chloride solution (20 mL) was added to the residue and extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (30 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to obtain intermediate II-62 (light yellow solid, 880 mg): ¹ H NMR (400 MHz, Chloroform-d) δ8.20 (s, 1H), 7.22 (s, 1H), 6.94 (s, 1H), 4.03 (s, 3H), 3.10 (s, 3H).

Synthesis of intermediate II-63

Intermediate II-62 (100 mg, 0.31 mmol) and reduced iron powder (86 mg, 1.54 mmol) were added to ethanol (2 mL). Then, 6N aqueous hydrogen chloride solution (615 μL, 3.69 mmol) was added and reacted at 60°C for 30 minutes. After the reaction, the system was cooled to room temperature, and 1M aqueous sodium hydroxide solution was added dropwise to the reaction solution under ice bath to adjust the pH to alkaline, extracted with ethyl acetate (8 mL x 3), combined organic phases, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 4:1) to obtain intermediate II-63 (white solid, 74 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ8.77 (s, 1H), 7.07 (s, 1H), 6.84 (s, 1H), 4.95 (s, 2H), 3.72 (s, 3H), 2.94 (s, 3H).

Synthesis of intermediate II-64

Intermediate II-22 (1.46 g, 4.10 mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), 1 M aqueous sodium hydroxide solution (5 mL) was added, and the temperature was raised to 60° C. to react for 6 hours. After the reaction, the system was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3. Solid precipitated and filtered. The filter cake was washed with water (2 mL) and n-hexane (2 mL) in turn. The obtained solid was dried to constant weight to obtain intermediate II-64 (white solid, 1.21 g): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.99 (s, 1H), 7.97 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 5.27 (s, 2H).

Synthesis of intermediate II-65

Intermediate II-64 (50 mg, 0.15 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (2 mL), and oxalyl chloride (19 μL, 0.23 mmol) was slowly added dropwise under ice bath, and the temperature was raised to room temperature for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (1 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added dropwise to a tetrahydrofuran (2 mL) solution of II-63 (47 mg, 0.16 mmol) and pyridine (18 μL, 0.23 mmol) under ice bath conditions, and the temperature was raised to room temperature for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 3-4, and ethyl acetate (8 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to obtain intermediate II-65 (white solid, 80 mg): ¹ H NMR (300 MHz, Chloroform-d) δ8.60 (s, 1H), 8.18 (s, 1H), 7.97 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 7.2 Hz, 2H), 7.13 (s, 1H), 7.03 (d, J = 8.8 Hz, 2H), 6.88 (s, 1H), 5.20 (s, 2H), 3.92 (s, 3H), 3.17 (s, 3H).

Synthesis of intermediate B-61

The intermediate II-65 (76 mg, 0.13 mmol) was added to anhydrous dichloromethane (2 mL), and a 1M dichloromethane solution of boron tribromide (314 μL, 0.31 mmol) was added dropwise at 0°C. After the addition, stirring was continued at 0°C for 1 hour. After the reaction was completed, ice water (10 mL) was added dropwise to the reaction solution to quench, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 150:1) to obtain a crude compound B-61 (brown solid, 47 mg), which was purified by slurrying (dichloromethane/methanol = 20:1) to obtain compound B-61 (light red solid, 35 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.33(s,1H),9.94(s,1H),9.06(s,1H),8.00(d,J＝8.0Hz,2H),7.66(d,J＝8.8Hz,2H),7.60(d,J＝8.5Hz,2H),7.31(s,1H),7.19(d,J＝9.0Hz,2H),7.17(s,1H),5.29(s,2H),3.00(s,3H).HRMS(ESI)calcd.for C ₂₂ H ₁₈ BrF ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 590.9865,found 590.9857.

Embodiment 105

N-(3-Hydroxy-5-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-62)

Synthesis of intermediate II-66

3-Bromo-5-nitroaniline (217 mg, 1 mmol) and pyridine (121 μL, 1.5 mmol) were added to dichloromethane (2 mL), and a solution of methanesulfonic anhydride (226 mg, 1.3 mmol) in dichloromethane (2 mL) was slowly added dropwise under an ice-water bath. After the addition was completed, the mixture was heated to room temperature for 8 hours. After the reaction was completed, 2N aqueous hydrogen chloride solution (10 mL) was added to the reaction solution to quench the excess pyridine and methanesulfonic anhydride, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water (10 mL x 1) and saturated brine (10 mL x 1) in turn, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude intermediate II-66, which was directly used in the next step without further purification.

Synthesis of intermediate II-67

The crude intermediate II-66 (1 mmol) and ammonium chloride (535 mg, 10 mmol) were added to a mixed solvent of ethanol (3 mL) and water (3 mL), and reduced iron powder (280 mg, 5 mmol) was added in batches under stirring. After the addition was completed, the temperature was raised to 80°C and reacted for 6 hours. After the reaction, the system was cooled to room temperature, water (30 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 2), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate II-67 (yellow solid, 238 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.60 (s, 1H), 6.46 (s, 1H), 6.45 (s, 1H), 6.43 (s, 1H), 5.51 (s, 2H), 2.96 (s, 3H). ESI-MS: m/z 262.9 [MH] ^- .

Synthesis of intermediate II-68

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate II-22, and intermediate I-18 was replaced by intermediate II-67 to obtain intermediate II-68: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.45 (s, 1H), 10.04 (s, 1H), 7.97 (d, J = 7.9 Hz, 2H), 7.83 (s, 1H), 7.73 (s, 1H), 7.65 (d, J = 8.3 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 1.6 Hz, 1H), 5.28 (s, 2H), 3.06 (s, 3H).

Synthesis of intermediate II-69

Intermediate II-68 (146 mg, 0.25 mmol), pinacol diboron (77 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex ( _PdCl2 (dppf)·DCM) (21 mg, 0.03 mmol) and potassium acetate (75 mg, 0.76 mmol) were added to a dry Schlenk tube, protected by argon, 1,4-dioxane (2 mL) was added to suspend, and the temperature was raised to 80°C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate II-69 (light yellow solid, 73 mg): ¹ H NMR (300MHz, DMSO-d ₆ )δ10.31(s, 1H), 9.73(s, 1H), 8.00(d, J = 8.1 Hz, 2H), 7.94(s, 1H), 7.87(s, 1H), 7.65(d, J = 8.6 Hz, 2H), 7.59(d, J = 8.2 Hz, 2H), 7.25(s, 1H), 7.18(d, J = 8.8 Hz, 2H), 5.28(s, 2H), 2.98(s, 3H), 1.30(s, 12H).ESI-MS:m/z 645.1[M+Na] ⁺ .

Synthesis of compound B-62

The intermediate II-69 (68 mg, 0.11 mmol) was added to tetrahydrofuran (2 mL), and a 1M sodium hydroxide aqueous solution (55 μL) was added. Then, a 30% hydrogen peroxide aqueous solution (110 μL) was added dropwise under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature for reaction for 6 hours. After the reaction was completed, a 2N hydrogen chloride aqueous solution was added dropwise to the reaction solution to adjust the pH to 2-3, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (5 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 75:1), and then purified by slurrying (dichloromethane/methanol = 20:1). The obtained solid was dried to constant weight to obtain compound B-62 (white solid, 37 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.17(s,1H),9.63(s,1H),9.54(s,1H),7.94(d,J＝8.0Hz,2H),7.65(d,J＝8.4Hz,2H),7.58(d,J＝8.0Hz,2H),7.17(d,J＝8.6Hz,2H),7.12(d,J＝8.0Hz,2H),6.41(s,1H),5.27(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 9} F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 513.0760,found 513.0761.

Embodiment 106

N-(2-Fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-(4-(trifluoromethyl)phenoxy)methylbenzamide (Compound B-63)

Synthesis of compound B-63

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-trifluoromethylphenol, and intermediate I-18 was replaced by intermediate II-18 to prepare compound B-63: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 9.98 (s, 1H), 8.93 (s, 1H), 7.99 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 6.78 (d, J = 11.4 Hz, 1H), 5.32 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ F ₄ N ₂ O ₅ S[M+H] ⁺ 499.0945, found 499.0943.

Embodiment 107

N-(2-Fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-(4-(trifluoromethoxy)phenoxy)methylbenzamide (Compound B-64)

Synthesis of compound B-64

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-trifluoromethoxyphenol, and intermediate I-18 was replaced by intermediate II-18 to prepare compound B-64: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 9.98 (s, 1H), 8.94 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.3 Hz, 2H), 7.31 (t, J = 8.5 Hz, 3H), 7.13 (d, J = 9.2 Hz, 2H), 6.78 (d, J = 11.4 Hz, 1H), 5.24 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₈ F ₄ N ₂ O ₆ S [M+H] ⁺ 515.0894, found 515.0898.

Embodiment 108

N-(2-Fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-(4-fluorophenoxy)methylbenzamide (Compound B-65)

Synthesis of compound B-65

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-fluorophenol, and intermediate I-18 was replaced by intermediate II-18 to prepare compound B-65: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 9.95 (s, 1H), 8.98 (s, 1H), 7.98 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.14 (t, J = 8.8 Hz, 2H), 7.07-7.01 (m, 2H), 6.78 (d, J = 11.4 Hz, 1H), 5.19 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₁ H ₁₈ F ₂ N ₂ O ₅ S[M+H] ⁺ 499.0977, found 449.0983.

Embodiment 109

N-(2-Fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-((naphthalene-2-oxy)methyl)benzamide (Compound B-66)

Synthesis of compound B-66

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by β-naphthol, and intermediate I-18 was replaced by intermediate II-18 to obtain compound B-66: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.36 (s, 1H), 9.98 (s, 1H), 8.89 (s, 1H), 8.00 (d, J = 7.9 Hz, 2H), 7.87 (d, J = 6.5 Hz, 1H), 7.85 (d, J = 5.8 Hz, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.50-7.45 (m ,1H),7.44(d,J＝2.6Hz,1H),7.41–7.32(m,1H),7.30(d,J＝8.3Hz,1H),7.29(dd,J＝9.0,2.5Hz,1H),6.78(d,J＝11.3Hz,1H),5.34(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C _{2 5} H _{2 1} FN ₂ O ₅ S[M+H] ⁺ 481.1228,found 481.1224.

Embodiment 110

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((quinolin-6-oxy)methyl)benzamide (Compound B-67)

Synthesis of compound B-67

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 6-hydroxyquinoline, and intermediate I-18 was replaced by intermediate II-18 to obtain compound B-67: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.26(s,1H),9.99(s,1H),9.20(s,1H),8.76(dd,J＝4.2,1.7Hz,1H),8.25(dd,J＝8.5,1.7Hz,1H),8.00(d,J＝8.0Hz,2H),7.96(d,J＝9.0Hz,1H),7.66(d,J＝8.1Hz,2H),7.52(dd,J＝9.0,2.8Hz,1H),7.51–7.47(m,2H),7.30(d,J＝8.3Hz,1H),6.78(d,J＝11.3Hz,1H),5.36(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₄ H ₂₀ FN ₃ O ₅ S[M+H] ⁺ 482.1180, found 482.1209.

Embodiment 111

N-(2-Fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-((isoquinolin-6-oxy)methyl)benzamide (Compound B-68)

Synthesis of compound B-68

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 6-hydroxyisoquinoline, and intermediate I-18 was replaced by intermediate II-18 to obtain compound B-68: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.38 (s, 1H), 9.99 (s, 1H), 9.28 (s, 1H), 8.90 (s, 1H), 8.45 (d, J = 5.9 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.82 (d, J = 5.9 Hz, 1H), 7.67 (d, J = 8.1 Hz, 2H), 7.55 (d, J = 2.5 Hz, 1H), 7.48 (dd, J = 9.0, 2.5 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 11.3 Hz, 1H), 5.41 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₄ H ₂₀ FN ₃ O ₅ S [M + H] ⁺ 482.1180, found 482.1185.

Embodiment 112

4-((Benzo[d]thiazol-5-oxy)methyl)-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)benzamide (Compound B-69)

Synthesis of compound B-69

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 5-hydroxybenzothiazole, and intermediate I-18 was replaced by intermediate II-18 to obtain compound B-69: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.17(s,0H),9.95(s,1H),9.37(s,1H),8.97(s,1H),8.06(d,J＝8.8Hz,1H),7.99(d,J＝8.2Hz,2H),7.72(d,J＝2.5Hz,1H),7.63(d,J＝8.1Hz,2H),7.30(d,J＝8.3Hz,1H),7.24(dd,J＝8.8,2.5Hz,1H),6.78(d,J＝11.3Hz,1H),5.34(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 8} FN ₃ O ₅ S ₂ [M+H] ⁺ 488.0745,found 488.0750.

Embodiment 113

4-((Benzo[d]oxazol-5-oxy)methyl)-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)benzamide (Compound B-70)

Synthesis of compound B-70

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced with benzo[d]oxazol-5-ol, and intermediate I-18 was replaced with intermediate II-18 to obtain compound B-70: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.27(s,1H),9.98(s,1H),8.97(s,1H),8.70(s,1H),7.98(d,J＝8.0Hz,2H),7.69(d,J＝8.9Hz,1H),7.62(d,J＝8.1Hz,2H),7.46(d,J＝2.5Hz,1H),7.29(d,J＝8.3Hz,1H),7.14(dd,J＝8.9,2.5Hz,1H),6.78(d,J＝11.3Hz,1H),5.28(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 8} FN ₃ O ₆ S[M+H] ⁺ 472.0973,found 472.0976.

Embodiment 114

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(((2-methyl-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)methyl)benzamide (Compound B-71)

Synthesis of intermediate II-70

6-Bromo-1,2,3,4-tetrahydroisoquinoline (1 g, 4.17 mmol) and 4-dimethylaminopyridine (DMAP) (115 mg, 0.94 mmol) were added to dichloromethane (14 mL), and triethylamine (1 mL, 7.07 mmol) and di-tert-butyl dicarbonate (2.16 mL, 9.42 mmol) were added in sequence, and the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate II-70 (colorless oily liquid, 1.37 g).

Synthesis of intermediate II-71

Intermediate II-70 (1.37 g, 4.37 mmol), pinacol diboron (1.33 g, 5.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex ( _PdCl2 (dppf)·DCM) (625 mg, 0.77 mmol) and potassium acetate (1.29 g, 13.11 mmol) were added to a dry Schlenk tube, protected by argon, 1,4-dioxane (13 mL) was added to suspend, and the temperature was raised to 80°C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, the solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate II-71 (light yellow solid, 1.41 g): ¹ H NMR (400MHz, Chloroform-d) δ7.64 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.14 (d, J = 7.6 Hz, 1H), 4.60 (s, 2H), 3.68-3.63 (m, 2H), 2.86 (t, J = 5.8 Hz, 2H), 1.51 (s, 9H), 1.36 (s, 12H).

Synthesis of Compound II-72

Add intermediate II-71 (1.41 g, 3.94 mmol) to tetrahydrofuran (4 mL), add 1 M sodium hydroxide aqueous solution (2 mL), and then add 30% hydrogen peroxide aqueous solution (4 mL) dropwise under ice bath. After the addition is completed, slowly warm to room temperature and react for 6 hours. After the reaction was completed, saturated sodium thiosulfate (10 mL) and 2N aqueous hydrogen chloride solution (10 mL) were added dropwise to the reaction solution under ice bath, extracted with dichloromethane (15 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 1), the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain compound II-72 (yellow oily liquid, 1.03 g): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.21 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.59 (dd, J = 8.2, 2.6 Hz, 1H), 6.54 (d, J = 2.5 Hz, 1H), 4.36 (s, 2H), 3.49 (t, J = 6.0 Hz, 2H), 2.67 (t, J = 6.0 Hz, 2H), 1.42 (s, 9H).

Synthesis of intermediate II-73

Intermediate II-72 (853 mg, 3.42 mmol), ethyl 4-(bromomethyl)benzoate (756 mg, 3.11 mmol) and potassium iodide (52 mg, 0.31 mmol) were added to N, N-dimethylformamide (8 mL), and potassium carbonate (645 mg, 4.67 mmol) was added in batches under stirring. The temperature was raised to 70 ° C for 6 hours. After the reaction, the system was cooled to room temperature, water (80 mL) was added to the reaction solution for dilution, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined, washed with water (15 mL x 2) and saturated brine (15 mL x 1) in turn, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 15:1) to obtain intermediate II-73 (yellow solid, 652 mg).

Synthesis of intermediate II-74

Intermediate II-73 (304 mg, 0.74 mmol) was added to ethyl acetate (3 mL), and 4 M hydrogen chloride-ethyl acetate solution (1.85 mL, 7.4 mmol) was added dropwise, and the mixture was reacted at room temperature for 6 hours. After the reaction was completed, the mixture was evaporated under reduced pressure. To the residue was added 1 M aqueous sodium hydroxide solution (10 mL), stirred at room temperature for 10 minutes, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain intermediate II-74 (light yellow oily liquid, 213 mg).

Synthesis of intermediate II-75

The intermediate II-74 (355 mg, 1.14 mmol) was added to formic acid (1 mL), and then a 37% formaldehyde aqueous solution (1.5 mL, 1.37 mmol) was added. After the addition was completed, the reaction was carried out at 100°C for 4 hours. After the reaction was completed, the system was cooled to room temperature, and a 1M sodium hydroxide aqueous solution (20 mL) was added dropwise to the reaction solution under an ice bath to quench, and then a saturated sodium bicarbonate solution was added dropwise to adjust the pH to 9-10. Solids precipitated, and the filter cake was filtered with water (2 mL) and n-hexane (2 mL). The obtained solid was dried to constant weight to obtain the intermediate II-75 (off-white solid, ³⁴⁴ mg): NMR (400 MHz, Chloroform-d) δ 8.07 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 8.3 Hz, 1H), 6.77 (dd, J = 8.3, 2.7 Hz, 1H), 6.73 (d, J = 2.6 Hz, 1H), 5.11 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.54 (s, 2H), 2.91 (t, J = 6.0 Hz, 2H), 2.68 (t, J = 5.9 Hz, 2H), 2.47 (s, 3H), 1.42 (t, J = 7.1 Hz, 3H).

Synthesis of compound B-71

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate II-75, and intermediate I-18 was replaced by intermediate II-18 to obtain compound B-71: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 9.2 Hz, 1H), 6.85-6.75 (m, 3H), 5.16 (s, 2H), 3.40 (s, 2H), 2.95 (s, 3H), 2.78 (t, J = 6.0 Hz, 2H), 2.55 (t, J = 6.0 Hz, 2H), 2.32 (s, 3H). HRMS (ESI) calcd. for C ₂₅ H ₂₆ FN ₃ O ₅ S[M+H] ⁺ 500.1650, found 500.1681.

Embodiment 115

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(((2-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)methyl)benzamide (Compound B-72)

Synthesis of intermediate II-76

6-Bromo-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.94 mmol) and triethylamine (262 μL, 1.89 mmol) were added to dichloromethane (3 mL), and methylsulfonyl chloride (109 μL, 1.41 mmol) was added in batches under an ice bath. After the addition was completed, the mixture was heated to room temperature for 8 hours. After the reaction was completed, water (10 mL) was added to the reaction solution to quench, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (30 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate II-76 (white solid, 273 mg).

Synthesis of compound B-72

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate II-76, and intermediate I-18 was replaced by intermediate II-18 to obtain compound B-72: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.32(s,1H),9.97(s,1H),8.91(s,1H),7.97(d,J＝8.2Hz,2H),7.57(d,J＝8.3Hz,2H),7.29(d,J＝8.3Hz,1H),7.12(d,J＝9.1Hz,1H),6.92–6.84(m,2H),6.78(d,J＝11.3Hz,1H),5.19(s,2H),4.29(s,2H),3.40(t,J＝6.0Hz,2H),2.96(s,3H),2.93(s,3H),2.88(t,J＝5.9Hz,2H).HRMS(ESI)calcd.for C _{2 5} H _{2 6} FN ₃ O ₇ S ₂ [M+H] ⁺ 564.1269, found 564.1269.

Embodiment 116

3-Fluoro-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-73)

Synthesis of compound B-73

Referring to the method of Example 66, ethyl 4-(bromomethyl)benzoate was replaced with methyl 3-fluoro-4-(bromomethyl)benzoate, and intermediate I-18 was replaced with intermediate II-18 to obtain compound B-73: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 10.07 (s, 1H), 9.10 (s, 1H), 7.84 (t, J = 8.7 Hz, 2H), 7.72 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 6.79 (d, J = 11.3 Hz, 1H), 5.31 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₇ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 549.0572, found 549.0562.

Embodiment 117

3-Chloro-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-74)

Synthesis of compound B-74

Referring to the method of Example 66, ethyl 4-(bromomethyl)benzoate was replaced by the crude intermediate II-40, and intermediate I-18 was replaced by intermediate II-18 to obtain compound B-74: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 9.00 (s, 2H), 8.10 (d, J = 1.4 Hz, 1H), 7.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.23 (d, J = 8.9 Hz, 2H), 6.79 (d, J = 11.4 Hz, 1H), 5.32 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₇ ClF ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 565.0282, found 565.0287.HRMS(ESI)calcd.for C ₂₂ H ₁₇ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 549.0572, found 549.0562.

Embodiment 118

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-6-((4-((trifluoromethyl)thio)phenoxy)methyl)nicotinamide (Compound B-75)

Synthesis of intermediate II-77

Referring to the method of Example 92, 2-methyl-5-bromopyrimidine was replaced by 5-bromo-2-methylpyridine to obtain Intermediate II-77: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.30 (d, J = 7.9 Hz, 1H), 7.67 (d, J = 8.3 Hz, 2H), 7.63 (d, J = 7.7 Hz, 1H), 7.18 (d, J = 8.6 Hz, 2H), 5.33 (s, 2H).

Synthesis of intermediate II-78

Intermediate II-77 (80 mg, 0.24 mmol) and intermediate II-18 (85 mg, 0.26 mmol) were added to anhydrous dichloromethane (2 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (70 mg, 0.36 mmol) was added in batches under an ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate II-78 (light yellow solid, 53 mg).

Synthesis of compound B-75

Intermediate II-78 (53 mg, 0.08 mmol) and triethylamine trihydrofluoride (20 μL, 0.12 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction, solids were precipitated, filtered, the filter cake was washed (dichloromethane/methanol = 50:1), the filter cake was slurried (dichloromethane/methanol = 50:1) for purification, and the obtained solid was dried to constant weight to obtain compound B-75 (white solid, 32 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.41(s,1H),10.21(s,1H),9.11(d,J＝2.2Hz,1H),8.93(s,1H),8.35(dd,J＝8.1,2.3Hz,1H),7.70–7.66(m,3H),7.34(d,J＝8.3Hz,1H),7.21(d,J＝8.8Hz,2H),6.79(d,J＝11.3Hz,1H),5.37(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₁ H ₁₇ F ₄ N ₃ O ₅ S ₂ [M+Na] ⁺ 554.0438,found 554.0445.

Embodiment 119

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-5-((4-((trifluoromethyl)thio)phenoxy)methyl)picolinamide (Compound B-76)

Synthesis of compound B-76

Referring to the method of Example 118, 5-bromo-2-methylpyridine was replaced by 2-bromo-5-methylpyridine to prepare compound B-76: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 10.25 (s, 1H), 8.91 (s, 1H), 8.83 (d, J = 1.6 Hz, 1H), 8.19 (dd, J = 8.0, 1.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 7.23 (d, J = 8.8 Hz, 2H), 6.81 (d, J = 11.6 Hz, 1H), 5.37 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₁ H ₁₇ F ₄ N ₃ O ₅ S ₂ [M+Na] ⁺ 554.0438, found 554.0444.

Embodiment 120

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-2-((4-((trifluoromethyl)thio)phenoxy)methyl)pyrimidine-5-carboxamide (Compound B-77)

Synthesis of compound B-77

Referring to the method of Example 118, 5-bromo-2-methylpyridine was replaced with 2-methyl-5-bromopyrimidine to obtain compound B-77: ¹ H NMR (400 MHz, DMSO) δ 10.44 (s, 1H), 10.36 (s, 1H), 9.27 (s, 2H), 8.93 (s, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 11.4 Hz, 1H), 5.50 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₀ H ₁₆ F ₄ N ₄ O ₅ S ₂ [M+H] ⁺ 533.0576, found 533.0583.

Embodiment 121

N-(4-Fluoro-2-hydroxy-5-((4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzyl)amino)phenyl)methanesulfonamide hydrochloride (Compound B-78)

Synthesis of intermediate II-79

Referring to the method of Example 66, 4-(bromomethyl)benzoic acid ethyl ester was replaced with 4-bromomethylbenzaldehyde to obtain Intermediate II-79: ¹ H NMR (300 MHz, Chloroform-d) δ 10.06 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.62 (dd, J = 8.6, 2.2 Hz, 4H), 7.02 (d, J = 8.8 Hz, 2H), 5.20 (s, 2H).

Synthesis of intermediate II-80

Intermediate II-79 (295 mg, 0.94 mmol) and intermediate II-18 (261 mg, 0.78 mmol) were added to dichloromethane (5 mL), glacial acetic acid (45 μL, 0.78 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (496 mg, 2.34 mmol) was added in batches under an ice bath. After the addition was completed, the mixture was heated to room temperature and stirred for 12 hours. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added to the reaction solution to quench, and ethyl acetate was used for extraction (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate II-80 (light yellow solid, 126 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.19(s,1H),8.49(s,1H),7.64(d,J＝8.7Hz,2H),7.38(d,J＝2.3Hz,4H),7.15(d,J＝8.9Hz,2H),6.62(d,J＝12.6Hz,1H),6.45(d,J＝9.5Hz,1H),5.70–5.61(m,1H),5.12(s,2H),4.23(d,J＝5.4Hz,2H),2.76(s,3H).

Synthesis of compound B-78

Intermediate II-80 (96 mg, 0.19 mmol) was added to ethyl acetate (1 mL), and hydrogen chloride-ethyl acetate solution (1.16 mL, 0.93 mmol) was added dropwise. After the addition was completed, the mixture was reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was purified by beating (ethyl acetate), and the obtained solid was dried to constant weight to obtain compound B-78 (white solid, 57 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 8.74 (s, 1H), 7.65 (d, J = 8.2 Hz, 2H), 7.44–7.38 (m, 4H), 7.15 (d, J = 8.3 Hz, 2H), 6.82 (s, 1H), 6.76 (d, J = 12.8 Hz, 1H), 5.15 (s, 2H), 4.32 (s, 2H), 2.81 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₁ ClF ₄ N ₂ O ₄ S ₂ [M-HCl+H] ⁺ 517.0879, found 517.0885.

Embodiment 122

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-((trifluoromethyl)thio)benzyl)thio)benzamide (Compound B-79)

Synthesis of intermediate II-81

4-Trifluoromethylthiobenzyl bromide (400 mg, 1.48 mmol) and 4-bromobenzenethiol (362 mg, 1.92 mmol) were added to acetone (5 mL), and cesium carbonate (649 mg, 1.99 mmol) was added in batches. After the addition was completed, the temperature was raised to 60° C. and reacted for 8 hours. After the reaction, the system was cooled to room temperature, 1M sodium hydroxide aqueous solution (10mL) was added to the reaction solution to quench the excess 4-bromobenzenethiol, and ethyl acetate (15mL x 3) was used for extraction. The organic phases were combined and washed with 1M sodium hydroxide aqueous solution (5mL x 2) and saturated brine (15mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to obtain intermediate II-81 (white solid, 523 mg): ¹ H NMR (300MHz, CDCl ₃ )δ7.58(d, J＝8.1Hz,2H),7.39(d, J＝8.5Hz,2H),7.31(d, J＝8.1Hz,2H),7.15(d, J＝8.5Hz,2H),4.09(s,2H).

Synthesis of intermediate II-82

Intermediate II-81 (200 mg, 0.53 mmol), oxalic acid dihydrate (199 mg, 1.58 mmol), palladium acetate (3.5 mg, 0.016 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (9 mg, 0.016 mmol) and acetic anhydride (149 μL, 1.58 mmol) were added to anhydrous N,N-dimethylformamide (2.5 mL), the system was cooled to -78 ° C and frozen, N,N-diisopropylethylamine (207 μL, 1.58 mmol) was added, and argon was used for protection. The system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 ° C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate II-82 (white solid, 181 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.88(s,1H),7.83(d,J＝8.4Hz,2H),7.67(d,J＝8.1Hz,2H),7.57(d,J＝8.2Hz,2H),7.43(d,J＝8.4Hz,2H),4.43(s,2H).ESI-MS:m/z 343.0[MH] ^- .

Synthesis of compound B-79

Referring to the method of Example 1, intermediate I-6 was replaced by intermediate II-82 to obtain compound B-79: ¹ H NMR (300MHz, DMSO-d ₆ ) δ10.00 (s, 1H), 9.33 (s, 2H), 7.89–7.79 (m, 4H), 7.68 (d, J＝7.8Hz, 3H), 7.59 (d, J＝8.1Hz, 2H), 7.45 (d, J＝8.4Hz, 2H), 7.36 (t, J＝8.8Hz, 3H), 6.68 (d, J＝8.7Hz, 1H), 4.44 (s, 2H). ESI-MS: m/z 607.0 [MH] ^- .

Embodiment 123

N-(4-((tert-butyldimethylsilyl)oxy)-3-((4-fluorophenyl)sulfonamido)phenyl)-4-((4-(trifluoromethyl)benzyl)thio)benzamide (Compound B-80)

Synthesis of compound B-80

Referring to the method of Example 122, 4-trifluoromethylthiobenzyl bromide was replaced by 4-trifluoromethylbenzyl bromide to prepare compound B-80: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 9.35 (s, 2H), 7.88-7.77 (m, 4H), 7.72-7.62 (m, 5H), 7.45 (d, J=8.1 Hz, 2H), 7.36 (t, J=8.8 Hz, 3H), 6.67 (d, J=8.7 Hz, 1H), 4.47 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₀ F ₄ N ₂ O ₄ S ₂ [M+H] ⁺ 577.0873, found 577.0855.

Embodiment 124

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-(trifluoromethoxy)benzyl)thio)benzamide (Compound B-81)

Synthesis of compound B-81

Referring to the method of Example 122, 4-trifluoromethylthiobenzyl bromide was replaced by 4-trifluoromethoxybenzyl bromide to prepare compound B-81: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 9.37 (s, 2H), 7.89–7.77 (m, 4H), 7.66 (d, J=2.5 Hz, 1H), 7.55 (d, 2H), 7.44 (d, J=8.5 Hz, 2H), 7.40–7.29 (m, 5H), 6.67 (d, J=8.7 Hz, 1H), 4.40 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₀ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 593.0823, found 593.0823.

Embodiment 125

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-(((trifluoromethyl)thio)methyl)benzyl)thio)benzamide (Compound B-82)

Synthesis of intermediate II-83

Referring to the method of Example 122, 4-trifluoromethylthiobenzyl bromide was replaced with ethyl 4-(bromomethyl)benzoate to obtain Intermediate II-83: ¹ H NMR (300 MHz, Chloroform-d) δ 7.98 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 6.8 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 4.19 (s, 2H), 1.39 (t, J = 7.1 Hz, 3H).

Synthesis of intermediate II-84

Intermediate II-83 (1g, 3mmol) was added to anhydrous tetrahydrofuran (4mL), and 1M lithium triethylborohydride tetrahydrofuran solution (7.5mL, 7.5mmol) was slowly added dropwise under ice bath. After the addition, the temperature was slowly raised to room temperature for 2 hours. After the reaction was completed, water (20mL) was added to the reaction solution to quench, and ethyl acetate (15mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (20mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate II-84 (white solid, 542mg).

Synthesis of intermediate II-85

Intermediate II-84 (42 mg, 0.13 mmol) and triphenylphosphine (50 mg, 0.19 mmol) were added to dichloromethane (2 mL), and a solution of carbon tetrabromide (67 mg, 0.20 mmol) in dichloromethane (2 mL) was slowly added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 150:1) to obtain intermediate II-85 (white solid, 33 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.37 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 4.47 (s, 2H), 4.07 (s, 2H).

Synthesis of intermediate II-86

Intermediate II-85 (372 mg, 1 mmol) and potassium thiocyanate (124 mg, 1.5 mmol) were added to acetonitrile (15 mL). The temperature was raised to 80°C and the reaction was continued for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was diluted with water (30 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 1), the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate II-85 (white solid, 311 mg).

Synthesis of intermediate II-87

Add intermediate II-86 (270 mg, 0.76 mmol) to a dry Schlenk tube, add anhydrous tetrahydrofuran (2 mL) under argon protection, add (trifluoromethyl)trimethylsilane (162 mg, 1.14 mmol) in anhydrous tetrahydrofuran (1 mL) under ice bath, and then slowly add 1M tetrabutylammonium fluoride tetrahydrofuran solution (1.14 mL, 1.14 mmol) in anhydrous tetrahydrofuran (3 mL) dropwise. After the dropwise addition, continue the reaction at 0°C for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 200:1) to obtain intermediate II-87 (white solid, 143 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.35 (d, 1H), 7.26–7.22 (m, 2H), 7.13 (d, 1H), 4.09 (s, 1H), 4.06 (s, 1H).

Synthesis of compound B-82

Referring to the method of Example 122, intermediate II-81 was replaced by intermediate II-87 to obtain compound B-82: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 9.35 (s, 2H), 7.84 (d, 2H), 7.83-7.78 (m, 2H), 7.66 (d, J=2.6 Hz, 1H), 7.48-7.30 (m, 9H), 6.67 (d, J=8.8 Hz, 1H), 4.35 (s, 2H), 4.27 (s, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₂ F ₄ N ₂ O ₄ S ₃ [M+H] ⁺ 623.0751, found 623.0787.

Embodiment 126

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)thio)benzamide (Compound B-83)

Synthesis of compound B-83

Referring to the method of Example 55, intermediate II-2 was replaced by intermediate II-82 to prepare compound B-83: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 9.60 (s, 1H), 8.75 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.60 (dd, J = 8.3, 5.4 Hz, 3H), 7.49 (dd, J = 2.5 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 4.44 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₃ N ₂ O ₄ S ₃ [M+H] ⁺ 529.0532, found 529.0536.

Embodiment 127

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)benzyl)thio)benzamide (Compound B-84)

Synthesis of compound B-84

Referring to the method of Example 122, 4-trifluoromethylthiobenzyl bromide was replaced by 4-trifluoromethoxybenzyl bromide, and intermediate I-3 was replaced by intermediate I-18 to obtain compound B-84: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.03(s,1H),9.67(s,1H),8.69(s,1H),7.87(d,J＝8.4Hz,2H),7.61(d,J＝2.2Hz,1H),7.55(d,J＝8.5Hz,2H),7.49(dd,J＝2.3Hz,1H),7.44(d,J＝8.3Hz,2H),7.31(d,J＝8.3Hz,2H),6.85(d,J＝8.7Hz,1H),4.40(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 9} F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 513.0760,found 513.0776.

Embodiment 128

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-((4-(trifluoromethyl)benzyl)thio)benzamide (Compound B-85)

Synthesis of compound B-85

Referring to the method of Example 122, 4-trifluoromethylthiobenzyl bromide was replaced by 4-trifluoromethylbenzyl bromide, and intermediate I-3 was replaced by intermediate I-18 to prepare compound B-85: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 9.66 (s, 1H), 8.66 (s, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.72-7.62 (m, 4H), 7.60 (d, J = 2.5 Hz, 1H), 7.52-7.41 (m, 3H), 6.84 (d, J = 8.7 Hz, 1H), 4.46 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₃ N ₂ O ₄ S ₂ [M+H] ⁺ 497.0811, found 497.0814.

Embodiment 129

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(((4-((trifluoromethyl)thio)phenyl)thio)methyl)benzamide (Compound B-86)

Synthesis of intermediate II-88

Ethyl 4-(bromomethyl)benzoate (1.76 g, 7.25 mmol), copper sulfate pentahydrate (26 mg, 0.1 mmol), 2,2'-bipyridine (16 mg, 0.1 mmol) and sodium thiosulfate pentahydrate (1.8 g, 7.25 mmol) were added to a mixed solvent of methanol (5 mL) and water (5 mL), and the mixture was heated to 80°C for 4 hours. After the reaction, the system was cooled to room temperature, and 4-trifluoromethylthioaniline (200 mg, 1.04 mmol) and tert-butyl nitrite (185 μL, 1.55 mmol) were added under ice bath. After the addition, the mixture was stirred at room temperature for 10 minutes, and then heated to 80°C for 5 hours. After the reaction, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate II-88 (white solid, 152 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.98 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 4.36 (q, 2H), 4.20 (s, 2H), 1.39 (t, J = 7.1 Hz, 3H).

Synthesis of compound B-86

Referring to the method of Example 44, intermediate II-1 was replaced with intermediate II-88 to obtain compound B-86: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 9.36 (s, 2H), 7.91–7.78 (m, 4H), 7.67–7.58 (m, 3H), 7.55 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 7.36 (t, J=8.8 Hz, 3H), 6.67 (d, J=8.7 Hz, 1H), 4.44 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₀ F ₄ N ₂ O ₄ S ₃ [M+H] ⁺ 609.0594, found 609.0596.

Embodiment 130

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(((4-(trifluoromethyl)phenyl)thio)methyl)benzamide (Compound B-87)

Synthesis of compound B-87

Referring to the method of Example 129, 4-trifluoromethylthioaniline was replaced by 4-trifluoromethylaniline to prepare compound B-87: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.63 (s, 1H), 9.54 (s, 1H), 7.94 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.41 (s, 1H), 5.27 (s, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₂₇ H ₂₀ F ₄ N ₂ O ₄ S ₂ [M+H] ⁺ 577.0873, found 577.0881.

Embodiment 131

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(((4-(trifluoromethoxy)phenyl)thio)methyl)benzamide (Compound B-88)

Synthesis of compound B-88

Referring to the method of Example 129, 4-trifluoromethylthioaniline was replaced by 4-trifluoromethoxyaniline to obtain compound B-88: ¹ H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.34 (s, 2H), 7.89-7.74 (m, 4H), 7.65 (s, 1H), 7.53-7.41 (m, 4H), 7.41-7.25 (m, 5H), 6.67 (d, J = 8.7 Hz, 1H), 4.36 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₀ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 593.0823, found 593.0843.

Embodiment 132

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(((4-(trifluoromethoxy)phenyl)thio)methyl)benzamide (Compound B-89)

Synthesis of compound B-89

Referring to the method of Example 129, 4-trifluoromethylthioaniline was replaced by 4-trifluoromethoxyaniline, and intermediate I-3 was replaced by intermediate I-18 to obtain compound B-89: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 9.18 (s, 2H), 7.86 (d, J = 7.9 Hz, 2H), 7.61 (s, 1H), 7.47 (t, J = 6.8 Hz, 5H), 7.30 (d, J = 8.3 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 4.36 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 513.0760, found 513.0757.

Embodiment 133

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(((4-(trifluoromethyl)phenyl)thio)methyl)benzamide (Compound B-90)

Synthesis of compound B-90

Referring to the method of Example 129, 4-trifluoromethylthioaniline was replaced by 4-trifluoromethylaniline, and the intermediate I- 3 was replaced with intermediate I-18 to obtain compound B-90: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 9.63 (s, 1H), 8.68 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.8 Hz, 1H), 7.61 (d, J = 2.8 Hz, 2H), 7.59–7.51 (m, 4H), 7.48 (dd, J = 8.7, 2.6 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.45 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₃ N ₂ O ₄ S ₂ [M+H] ⁺ 497.0811, found 497.0809.

Embodiment 134

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-((trifluoromethyl)thio)benzyl)amino)benzamide hydrochloride (Compound B-91)

Synthesis of intermediate II-89

4-Trifluoromethylthiobenzaldehyde (424mg, 2.06mmol) and ethyl 4-aminobenzoate (200mg, 1.21mmol) were added to methanol (5mL), and glacial acetic acid (208μL, 3.63mmol) was added. The mixture was stirred at room temperature for 1 hour, and sodium cyanoborohydride (89mg, 1.51mmol) was added in batches under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature for 24 hours. After the reaction was completed, saturated sodium bicarbonate solution (5mL) and water (5mL) were added to the reaction solution to quench the excess sodium cyanoborohydride, and the mixture was extracted with ethyl acetate (10mL x 3). The organic phases were combined, washed with saturated brine (10mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate II-89 (light yellow solid, 426mg): ^1H NMR (300MHz, DMSO-d ₆ )δ7.68(dd,J＝8.2,6.1Hz,4H),7.49(d,J＝8.1Hz,2H),7.18(t,J＝6.1Hz,1H),6.61(d,J＝8.7Hz,2H),4.43(d,J＝6.0Hz,2H),4.23–4.16(m,2H),1.26(t,J＝7.1Hz,3H).ESI-MS:m/z 354.1[MH] ^- .

Synthesis of intermediate II-90

Intermediate II-89 (425 mg, 1.19 mmol) and 4-dimethylaminopyridine (29 mg, 0.24 mmol) were added to dichloromethane (4 mL), and then triethylamine (499 μL, 3.59 mmol) and di-tert-butyl dicarbonate (687 μL, 2.99 mmol) were added in sequence, and the mixture was reacted at room temperature for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate II-90 (white solid, 526 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.99 (d, J = 8.7 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.3 Hz, 4H), 4.92 (s, 2H), 4.38 (q, J = 7.1 Hz, 2H), 1.43 (s, 9H), 1.39 (t, J = 7.1 Hz, 3H).

Synthesis of intermediate II-91

Referring to the method of Example 44, intermediate II-1 was replaced with intermediate II-90 to obtain compound II-91: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 9.40 (s, 1H), 9.29 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.82 (dd, J = 8.7, 5.3 Hz, 2H), 7.69 (d, J = 7.9 Hz, 2H), 7.65 (d, J = 2.4 Hz, 1H), 7.44-7.30 (m, 7H), 6.68 (d, J = 8.8 Hz, 1H), 4.99 (s, 2H), 1.39 (s, 9H). ESI-MS: m/z 714.1 [M+Na] ⁺ .

Synthesis of compound B-91

Intermediate II-91 (100 mg, 0.14 mmol) was added to dichloromethane (1 mL), and 4 M hydrogen chloride- Dioxane solution (1 mL) was added and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by beating (dichloromethane/methanol=40:1). The obtained solid was dried to constant weight to obtain compound B-91 (white solid, 57 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.62 (s, 1H), 9.27 (s, 1H), 7.81 (dd, J=8.8, 5.3 Hz, 2H), 7.70 (dd, J=8.0, 6.1 Hz, 4H), 7.63 (d, J=2.4 Hz, 1H), 7.52 (d, J=8.1 Hz, 2H), 7.40–7.29 (m, 3H), 6.64 (t, J=8.7 Hz, 3H), 4.64 (s, 2H), 4.44 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₁ F ₄ N ₃ O ₄ S ₂ [M-HCl+H] ⁺ 592.0982, found 592.0989.

Embodiment 135

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)amino)benzamide hydrochloride (Compound B-92)

Synthesis of compound B-92

Referring to the method of Example 134, intermediate I-3 was replaced by intermediate I-18 to prepare compound B-92: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.65 (s, 1H), 8.68 (s, 1H), 7.75-7.66 (m, 4H), 7.58 (d, J = 2.3 Hz, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.43 (dd, J = 8.7, 2.4 Hz, 1H), 6.84 (d, J = 8.7 Hz, 1H), 6.62 (d, J = 8.5 Hz, 2H), 4.43 (s, 2H), 3.96-3.93 (m, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₀ F ₃ N ₃ O ₄ S ₂ [M-HCl+H] ⁺ 512.0920, found 512.0922.

Embodiment 136

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)benzyl)amino)benzamide hydrochloride (Compound B-93)

Synthesis of compound B-93

Referring to the method of Example 134, 4-trifluoromethylthiobenzaldehyde was replaced by 4-trifluoromethoxybenzaldehyde, and intermediate I-3 was replaced by intermediate I-18 to prepare compound B-93: ¹ H NMR (300 MHz, D ₂ O) δ 9.64 (s, 1H), 8.65 (s, 1H), 7.72 (d, J = 8.6 Hz, 2H), 7.58 (d, J = 2.2 Hz, 1H), 7.51-7.41 (m, 3H), 7.33 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.7 Hz, 1H), 6.63 (d, J = 8.5 Hz, 2H), 5.79-5.55 (m, 2H), 4.38 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₀ F ₃ N ₃ O ₅ S[M-HCl+H] ⁺ 496.1149, found 496.1150.

Embodiment 137

Tert-butyl (4-((2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)carbamoyl)benzyl)(4-((trifluoromethyl)thio)phenyl)carbamate (Compound B-94)

Synthesis of Intermediate II-92

4-Trifluoromethylthioaniline (500 mg, 2.59 mmol) and ethyl 4-(bromomethyl)benzoate (818 mg, 3.36 mmol) were added to N,N-dimethylformamide (7.5 mL), and cesium carbonate (1.27 g, 3.88 mmol) was added in batches under stirring, and the mixture was reacted at 80 °C for 12 hours. After the reaction, the system was cooled to room temperature, water (75 mL) was added to the reaction solution for dilution, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain the crude intermediate II-92 (yellow solid, 756 mg), which was directly used in the next step without further purification.

Synthesis of compound B-94

Referring to the method of Example 134, intermediate II-89 was replaced by intermediate II-92, and intermediate I-3 was replaced by intermediate II-18 to prepare compound B-94: ¹ H NMR (400 MHz, Chloroform-d) δ 8.21 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 2.5 Hz, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.44 (s, 1H), 7.40 (d, J = 8.0 Hz, 2H), 7.27 (s, 1H), 6.82 (d, J = 11.5 Hz, 1H), 6.52 (s, 1H), 4.96 (s, 2H), 3.08 (s, 3H), 1.46 (s, 9H). HRMS (ESI) calcd. for C ₂₇ H ₂₇ F ₄ N ₃ O ₆ S ₂ [M+H] ⁺ 630.1350, found 630.1351.

Embodiment 138

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(((4-((trifluoromethyl)sulfur)phenyl)amino)methyl)benzamide hydrochloride (Compound B-95)

Synthesis of compound B-95

Referring to the method of Example 134, the intermediate II-91 was replaced with compound B-94 to obtain compound B-95: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.41 (s, 1H), 9.91 (s, 1H), 8.90 (s, 1H), 7.92 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.27 (d, J = 8.3 Hz, 1H), 6.81 (d, J = 11.4 Hz, 1H), 6.66 (d, J = 8.8 Hz, 2H), 4.41 (s, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₄ N ₃ O ₄ S ₂ [M-HCl+H] ⁺ 530.0826, found 530.0820.

Embodiment 139

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((methyl(4-((trifluoromethyl)sulfur)phenyl)amino)methyl)benzamide (Compound B-96)

Synthesis of Intermediate II-93

Sodium hydride (42 mg, 1.06 mmol) was added to a dry three-necked bottle, and anhydrous N, N-dimethylformamide (1 mL) was added under argon protection to suspend the mixture. Anhydrous N, N-dimethylformamide (1 mL) solution of intermediate II-92 (187 mg, 0.53 mmol) was added dropwise under ice bath. After the addition, the mixture was reacted at 0°C for 30 minutes. Then, anhydrous N, N-dimethylformamide (0.5 mL) solution of iodomethane (49 μL, 0.79 mmol) was slowly added dropwise under ice bath. After the addition, the mixture was heated to room temperature and stirred for 6 hours. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was added to the reaction solution to quench the mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 100: 1) to obtain a crude intermediate II-93, which was purified by slurrying (dichloromethane/methanol = 50: 1) to obtain intermediate II-93 (white solid, 90 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.89 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.44 (d, J = 8.9 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 4.73 (s, 2H), 3.13 (s, 3H).

Synthesis of compound B-96

Referring to the method of Example 118, the intermediate II-77 was replaced by compound II-93 to prepare compound B-96: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 9.91 (s, 1H), 8.93 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.44 (d, J = 8.9 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.3 Hz, 1H), 6.80 (d, J = 6.1 Hz, 2H), 6.76 (d, J = 8.3 Hz, 1H), 4.74 (s, 2H), 3.15 (s, 3H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 544.0982, found 544.0983.

Embodiment 140

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-2-(4-((trifluoromethyl)thio)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound B-97)

Synthesis of Intermediate II-94

4-Trifluoromethylthiobromobenzene (643 mg, 2.5 mmol), 6-bromo-1,2,3,4-tetrahydroisoquinoline (795 mg, 3.75 mmol), palladium acetate (28 mg, 0.125 mmol), 1,1'-binaphthyl-2,2'-bis(diphenylphosphine) (BINAP) (156 mg, 0.25 mmol) and cesium carbonate (1.63 g, 5 mmol) were added into a dry schlenk tube, protected by argon, and toluene (7.5 mL) was added to suspend the mixture, and the mixture was reacted at 100 °C for 10 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the filter cake was washed with ethyl acetate (5 mL), the filtrate was decompressed to remove the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 150:1) to obtain intermediate II-94 (white solid, 470 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.55 (d, J = 6.6 Hz, 2H), 7.40–7.32 (m, 2H), 7.07 (d, J = 8.7 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 4.43 (s, 2H), 3.62 (t, J = 5.9 Hz, 2H), 2.98 (t, J = 5.8 Hz, 2H).

Synthesis of compound B-97

Referring to the method of Example 89, intermediate II-41 was replaced with compound II-94 to obtain compound B-97: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.05(s,1H),9.70(s,1H),8.71(s,1H),7.79(d,J＝9.6Hz,2H),7.63(d,J＝2.6Hz,1H),7.53(d,J＝8.7Hz,2H),7.51(dd,J＝8.6,2.6Hz,1H),7.39(d,J＝7.9Hz,1H),7.09(d,J＝8.9Hz,2H),6.86(d,J＝8.7Hz,1H),4.58(s,2H),3.67(t,J＝5.9Hz,2H),3.02(t,J＝6.0Hz,2H),2.98(s,3H).HRMS(ESI)calcd.for C ₂₄ H ₂₂ F ₃ N ₃ O ₄ S ₂ [M+H] ⁺ 538.1077, found 538.1077.

Embodiment 141

N-(2-Fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-2-(4-((trifluoromethyl)thio)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound B-98)

Synthesis of compound B-98

Referring to the method of Example 89, intermediate II-41 was replaced by intermediate II-94, and intermediate I-18 was replaced by compound II-18 to obtain compound B-98: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.36(s,1H),9.92(s,1H),8.90(s,1H),7.80(d,J＝10.3Hz,2H),7.53(d,J＝8.8Hz,2H),7.39(d,J＝8.0Hz,1H),7.28(d,J＝8.3Hz,1H),7.09(d,J＝9.0Hz,2H),6.78(d,J＝11.3Hz,1H),4.59(s,2H),3.67(t,J＝5.8Hz,2H),3.02(t,J＝5.5Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₄ H ₂₁ F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 556.0982,found 556.0986.

Embodiment 142

N-(2-Fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-2-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound B-99)

Synthesis of compound B-99

Referring to the method of Example 140, 4-trifluoromethylthiobromobenzene was replaced with 4-trifluoromethylbromobenzene, and intermediate I-18 was replaced with compound II-18 to obtain compound B-99: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.16(s,1H),9.91(s,1H),9.03(s,1H),7.82(s,1H),7.80(d,J＝7.9Hz,1H),7.54(d,J＝8.7Hz,2H),7.40(d,J＝8.0Hz,1H),7.29(d,J＝8.3Hz,1H),7.13(d,J＝8.7Hz,2H),6.78(d,J＝11.4Hz,1H),4.60(s,2H),3.69(t,J＝5.9Hz,2H),3.01(t,J＝5.9Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₄ H ₂₁ F ₄ N ₃ O ₄ S[M+H] ⁺ 524.1262,found 524.1266.

Embodiment 143

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-((trifluoromethyl)thio)phenethyl)benzamide (Compound B-100)

Synthesis of Intermediate II-95

4-Trifluoromethylthiophenol (500 mg, 2.58 mmol) was added to a three-necked flask, and anhydrous dichloromethane (8 mL) and triethylamine (1 mL, 7.72 mmol) were added under argon protection, and trifluoromethanesulfonic anhydride (520 μL, 3.09 mmol) was added dropwise under an ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate II-95 (light yellow oily liquid, 581 mg).

Synthesis of Intermediate II-96

Intermediate II-95 (100 mg, 0.31 mmol), ethyl 4-ethynylbenzoate (80 mg, 0.46 mmol), bistriphenylphosphine palladium dichloride (11 mg, 0.02 mmol), cuprous iodide (3 mg, 0.02 mmol) and lithium chloride (39 mg, 0.92 mmol) was added into a dry Schlenk tube under argon protection, and then N,N-dimethylformamide (2 mL) and triethylamine (3 mL, 10 eqv.) were added. After the addition was completed, the temperature was raised to 60°C for reaction for 7 hours. After the reaction, the reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL), the filtrate was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate II-96 (yellow solid, 62 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ8.06 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.60 (dd, J = 8.0, 5.0 Hz, 4H), 4.41 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H).

Synthesis of Intermediate II-97

Intermediate II-96 (123 mg, 0.35 mmol) was added to ethanol (3 mL), and then glacial acetic acid (0.5 mL) and palladium hydroxide on carbon (24 mg) were added, and the mixture was reacted at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was completed, palladium hydroxide on carbon was filtered off, the filter cake was washed with ethyl acetate (10 mL), the filtrate was decompressed and the solvent was evaporated, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate II-97 (white solid, 118 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.86 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 8.1 Hz, 2H), 7.38 (t, J = 8.0 Hz, 4H), 4.29 (q, J = 7.1 Hz, 2H), 2.98 (s, 4H), 1.31 (t, J = 7.1 Hz, 3H).

Synthesis of compound B-100

Referring to the method of Example 44, intermediate II-1 was replaced with intermediate II-97 to obtain compound B-100: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 9.35 (s, 2H), 7.91–7.76 (m, 4H), 7.71–7.58 (m, 3H), 7.48–7.30 (m, 7H), 6.68 (d, J=8.8 Hz, 1H), 2.99 (s, 4H). HRMS (ESI) calcd. for C ₂₈ H ₂₂ F ₄ N ₂ O ₄ S ₂ [M+H] ⁺ 591.1030, found 591.1035.

Embodiment 144

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenethyl)benzamide (Compound B-101)

Synthesis of compound B-101

Referring to the method of Example 55, intermediate II-1 was replaced with intermediate II-97 to obtain compound B-101: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 9.21 (s, 2H), 7.86 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 8.2 Hz, 3H), 7.49 (dd, 1H), 7.43 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.00 (s, 4H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₄ S ₂ [M+H] ⁺ 511.0968, found 511.0970.

Embodiment 145

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(4-(trifluoromethyl)phenethyl)benzamide (Compound B-102)

Synthesis of compound B-102

Referring to the method of Example 143, 4-trifluoromethylthiophenol was replaced by 4-trifluoromethylphenol, and intermediate I-3 was replaced by intermediate I-18 to obtain compound B-102: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 9.70 (s, 1H), 8.72 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.51-7.45 (m, 3H), 7.36 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.06-2.99 (m, 4H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₄ S[M+H] ⁺ 479.1247, found 479.1248.

Embodiment 146

4-(2-cyclohexylethyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound B-103)

Synthesis of compound B-103

Referring to the method of Example 29, cyclohexanone was replaced with cyclohexylcarboxaldehyde to prepare compound B-103: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 9.36 (s, 2H), 7.89-7.76 (m, 4H), 7.67 (d, J=2.5 Hz, 1H), 7.42-7.34 (m, 3H), 7.32 (d, J=8.2 Hz, 2H), 6.67 (d, J=8.7 Hz, 1H), 2.66 (t, J=8.0 Hz, 2H), 1.80-1.59 (m, 5H), 1.55-1.44 (m, 2H), 1.25-1.10 (m, 4H), 0.99-0.85 (m, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₉ FN ₂ O ₄ S[M+H] ⁺ 497.1905, found 497.1889.

Embodiment 147

4-(2-(4,4-difluorocyclohexyl)ethyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound B-104)

Synthesis of Intermediate II-98

4,4-Difluorocyclohexanecarboxylic acid (328 mg, 2 mmol) was added to a dry three-necked bottle, and anhydrous tetrahydrofuran (6 mL) was added to dissolve under argon protection. 1M borane-tetrahydrofuran complex (3 mL, 3 mmol) was added dropwise under an ice bath. After the dropwise addition, the temperature was slowly raised to room temperature for 6 hours. After the reaction was completed, ice water (30 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in turn, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude intermediate II-98, which was directly used in the next reaction without further purification.

Synthesis of intermediate II-99

The crude intermediate II-98 (2 mmol) was added to dichloromethane (10 mL), and Dess-Martin periodinane (DMP) (1.17 g, 2.75 mmol) was added in batches under an ice bath. After the addition was completed, the mixture was heated to room temperature for 2 hours. After the reaction was completed, saturated sodium thiosulfate solution (10 mL) and saturated sodium bicarbonate solution (10 mL) were added to the reaction solution to quench the excess Dess-Martin periodinane, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined and washed with saturated sodium thiosulfate solution (10 mL x 1) and saturated sodium bicarbonate solution (10 mL x 1) in turn. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate II-99 (light yellow liquid, 270 mg). Since the intermediate was unstable, it was directly weighed and used for the next step.

Synthesis of compound B-104

Referring to the method of Example 29, cyclohexanone was replaced with intermediate II-99 to obtain compound B-104: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.99 (s, 1H), 9.34 (s, 2H), 7.90–7.76 (m, 4H), 7.67 (d, J=2.5 Hz, 1H), 7.44–7.28 (m, 5H), 6.68 (d, J=8.7 Hz, 1H), 2.68 (t, J=8.0 Hz, 2H), 2.05–1.93 (m, 2H), 1.88–1.76 (m, 3H), 1.74–1.63 (m, 1H), 1.56 (q, J=7.3 Hz, 2H), 1.45–1.33 (m, 1H), 1.26–1.13(m,2H).HRMS(ESI)calcd.for C ₂₇ H ₂₇ F ₃ N ₂ O ₄ S[M+H] ⁺ 533.1716,found 533.1744.

Embodiment 148

4-(2-cyclohexylethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-105)

Synthesis of compound B-105

Referring to the method of Example 29, cyclohexanone was replaced by cyclohexylcarboxaldehyde, and intermediate I-3 was replaced by intermediate I-18 to obtain compound B-105: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.00(s,1H),9.66(s,1H),8.67(s,1H),7.85(d,J＝7.9Hz,2H),7.62(s,1H),7.48(dd,J＝8.5,1.8Hz,1H),7.32(d,J＝8.0Hz,2H),6.85(d,J＝8.8Hz,1H),2.97(s,3H),2.71–2.61(m,2H),1.79–1.56(m,5H),1.49(dd,J＝15.0,6.9Hz,2H),1.26–1.10(m,4H),0.99–0.84(m,2H).ESI-MS:m/z 415.2[MH] ^- .HRMS(ESI)calcd.for C _{2 2} H _{2 8} N ₂ O ₄ S[M+H] ⁺ 417.1843, found 417.1841.

Embodiment 149

4-(2-Cyclopropylethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-106)

Synthesis of intermediate II-100

Referring to the method of Example 29, cyclohexanone was replaced with cyclopropylcarboxaldehyde to prepare intermediate II-100.

Synthesis of intermediate II-101

Intermediate II-100 (100 mg, 0.53 mmol) was added to a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL), and then p-toluenesulfonyl hydrazide (989 mg, 5.31 mmol) and sodium acetate trihydrate (940 mg, 6.91 mmol) were added in sequence. After the addition was completed, the temperature was raised to 70°C and reacted for 24 hours. After the reaction was completed, 2N aqueous hydrogen chloride solution (10 mL) was added to the reaction solution to quench, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (5 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate II-101 (white solid, 107 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.74 (s, 1H), 7.85 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 2.72 (t, 2H), 1.48 (dd, J = 15.0, 7.2 Hz, 2H), 0.72–0.60 (m, 1H), 0.42–0.34 (m, 2H), 0.06–-0.01 (m, 2H).

Synthesis of Compound B-106

Referring to the method of Example 55, intermediate II-2 was replaced with intermediate II-101 to obtain compound B-106: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.01(s,1H),9.67(s,1H),8.69(s,1H),7.86(d,J＝8.1Hz,2H),7.62(d,J＝2.2Hz,1H),7.49(dd,J＝8.7,2.2Hz,1H),7.34(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),2.97(s,3H),2.73(t,J＝7.6Hz,2H),1.50(dd,J＝15.0,7.1Hz,2H),0.76–0.63(m,1H),0.44–0.33(m,2H),0.10–0.01(m,2H).HRMS(ESI)calcd.for C ₁₉ H ₂₂ N ₂ O ₄ S[M+H] ⁺ 375.1373, found 375.1375.

Embodiment 150

4-(2-Cycloheptylethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-107)

Synthesis of compound B-107

Referring to the method of Example 147, 4,4-difluorocyclohexanecarboxylic acid was replaced by cycloheptanecarboxylic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound B-107: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.02(s,1H),9.62(s,1H),8.75(s,1H),7.85(d,J＝7.9Hz,2H),7.62(d,J＝2.5Hz,1H),7.49(dd,J＝8.8,2.5Hz,1H),7.32(d,J＝8.0Hz,2H),6.84(d,J＝8.7Hz,1H),2.97(s,3H),2.63(t,J＝8.0Hz,2H),1.77–1.68(m,2H),1.69–1.30(m,11H),1.27–1.15(m,2H).HRMS(ESI)calcd.for C ₂₃ H ₃₀ N ₂ O ₄ S[M+H] ⁺ 431.1999,found 431.2001.

Embodiment 151

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-((trifluoromethyl)thio)phenethoxy)benzamide (Compound C-1)

Synthesis of intermediate III-1

4-Trifluoromethylthiophenylacetic acid (2 g, 8.47 mmol) was added to a dry three-necked flask. Anhydrous tetrahydrofuran (30 mL) was added to dissolve the mixture under argon protection. 1 M borane-tetrahydrofuran complex (17 mL, 16.9 mmol) was slowly added under ice bath. After the addition was completed, the temperature was slowly raised to room temperature and reacted for 6 hours. After the reaction was completed, ice water (30 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined and washed with water (20 mL x 1) and saturated brine (20 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate III-1 (colorless oily liquid, 1.87 g): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ7.62 (d, J = 8.0 Hz, 2H), 7.40 (d, J = 8.1 Hz, 2H), 4.68 (t, J = 5.2 Hz, 1H), 3.64 (q, J = 5.3 Hz, 2H), 2.78 (t, J = 6.7 Hz, 2H).

Synthesis of intermediate III-2

Intermediate III-1 (200 mg, 0.90 mmol), methyl 4-hydroxybenzoate (260 mg, 1.71 mmol) and triphenylphosphine (472 mg, 1.80 mmol) were added into a dry three-necked flask under argon protection, anhydrous tetrahydrofuran (2 mL) was added to dissolve, and a solution of diisopropyl azodicarboxylate (360 μL, 1.80 mmol) in anhydrous tetrahydrofuran (2 mL) was slowly added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate III-2 (white solid, 198 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.00 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 4.26 (t, J = 6.7 Hz, 2H), 3.90 (s, 3H), 3.17 (t, J = 6.7 Hz, 2H).

Synthesis of compound C-1

Referring to the method of Example 1, intermediate I-5 was replaced by intermediate III-2 to obtain compound C-1: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.91 (s, 0H), 9.34 (s, 1H), 7.91 (d, J = 8.6 Hz, 1H), 7.81 (dd, J = 8.8, 5.3 Hz, 1H), 7.72-7.63 (m, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.42-7.30 (m, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.67 (d, J = 8.7 Hz, 0H), 4.32 (t, J = 6.7 Hz, 1H), 3.14 (t, J = 6.6 Hz, 1H). HRMS (ESI) calcd. for C ₂₈ H ₂₂ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 607.0979, found 607.0981.

Embodiment 152

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-(trifluoromethoxy)phenethoxy)benzamide (Compound C-2)

Synthesis of compound C-2

Referring to the method of Example 151, 4-trifluoromethylthiophenylacetic acid was replaced with 4-trifluoromethoxyphenylacetic acid to obtain compound C-2: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.91(s,1H),9.33(s,2H),7.91(d,J＝8.7Hz,2H),7.81(dd,J＝8.7,5.3Hz,2H),7.66(d,J＝2.2Hz,1H),7.48(d,J＝8.5Hz,2H),7.39(d,1H),7.34(d,J＝8.1Hz,3H),7.30(s,1H),7.04(d,J＝8.7Hz,2H),6.67(d,J＝8.7Hz,1H),4.29(t,J＝6.6Hz,2H),3.11(t,J＝6.6Hz,2H).ESI-MS:m/z 589.1[MH] ^- .

Embodiment 153

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-(trifluoromethoxy)phenethoxy)benzamide (Compound C-3)

Synthesis of compound C-3

Referring to the method of Example 151, 4-trifluoromethylthiophenylacetic acid was replaced with 4-trifluoromethylphenylacetic acid to prepare compound C-3: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 9.35 (s, 2H), 7.92 (d, J = 8.6 Hz, 2H), 7.82 (dd, J = 8.6, 5.3 Hz, 2H), 7.68 (dd, J = 9.1, 5.3 Hz, 3H), 7.59 (d, J = 8.0 Hz, 2H), 7.36 (t, J = 8.8 Hz, 3H), 7.05 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 8.7 Hz, 1H), 4.33 (t, J = 6.6 Hz, 2H), 3.18 (t, J = 6.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₈ H _{2 2} F ₄ N ₂ O ₅ S[M+H] ⁺ 575.1258, found 575.1260.

Embodiment 154

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenethoxy)benzamide (Compound C-4)

Synthesis of compound C-4

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate III-2 to obtain compound C-4: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.93(s,1H),9.44(s,1H),8.80(s,1H),7.92(d,J＝8.7Hz,2H),7.68(d,J＝8.0Hz,2H),7.61(d,J＝2.3Hz,1H),7.52(d,J＝8.1Hz,2H),7.48(dd,J＝8.9,2.4Hz,1H),7.05(d,J＝8.8Hz,2H),6.84(d,J＝8.7Hz,1H),4.32(t,J＝6.6Hz,2H),3.15(t,J＝6.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917,found 527.0917.

Embodiment 155

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(4-(trifluoromethoxy)phenethoxy)benzamide (Compound C-5)

Synthesis of compound C-5

Referring to the method of Example 151, 4-trifluoromethylthiophenylacetic acid was replaced by 4-trifluoromethoxyphenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-5: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 9.30 (s, 1H), 8.92 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.61 (s, 1H), 7.48 (d, J = 8.2 Hz, 3H), 7.31 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 4.29 (t, J = 6.5 Hz, 2H), 3.10 (t, J = 6.4 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₆ S[M+H] ⁺ 511.1145, found 511.1161.

Embodiment 156

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(4-(methylsulfonyl)phenethoxy)benzamide (Compound C-6)

Synthesis of compound C-6

Referring to the method of Example 151, 4-trifluoromethylthiophenylacetic acid was replaced by 4-methylsulfonylphenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-6: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.94(s,1H),9.52(s,1H),8.74(s,1H),7.92(d,J＝8.6Hz,2H),7.88(d,J＝8.2Hz,2H),7.63(d,J＝8.8Hz,3H),7.48(dd,J＝8.6,1.7Hz,1H),7.05(d,J＝8.6Hz,2H),6.84(d,J＝8.7Hz,1H),4.34(t,J＝6.3Hz,2H),3.20(s,3H),3.20–3.14(m,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₄ N ₂ O ₇ S ₂ [M+H] ⁺ 505.1098,found 505.1101.

Embodiment 157

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(4-((trifluoromethyl)sulfonyl)phenethoxy)benzamide (Compound C-7)

Synthesis of intermediate III-3

Referring to the method of Example 151, the intermediate III-2 was hydrolyzed to obtain the intermediate III-3: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.59 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 7.9 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 4.32 (t, J = 6.6 Hz, 2H), 3.14 (t, J = 6.5 Hz, 2H). ESI-MS: m/z 341.1 [MH] ^- .

Synthesis of intermediate III-4

The intermediate III-3 (74 mg, 0.22 mmol) was added to trifluoroacetic acid (1.1 mL), and a 30% aqueous hydrogen peroxide solution (486 μL) was added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature for 21 hours. After the reaction was completed, the reaction solution was poured into ice water (10 mL). Solids precipitated and were filtered. The filter cake was washed with water (5 mL). The residue was purified by beating (n-hexane/ether = 10:1). The obtained solid was dried to constant weight to obtain the intermediate III-4 (white solid, 39 mg): ESI-MS: m/z 373.0 [MH] ^- .

Synthesis of compound C-7

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with intermediate III-4 to obtain compound C-7: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.95(s,1H),9.68(s,1H),8.72(s,1H),8.10(d,J＝8.1Hz,2H),7.93(d,J＝8.7Hz,2H),7.84(d,J＝8.2Hz,2H),7.61(d,J＝2.1Hz,1H),7.48(dd,J＝8.6,2.0Hz,1H),7.05(d,J＝8.6Hz,2H),6.84(d,J＝8.7Hz,1H),4.39(t,J＝6.2Hz,2H),3.29(t,J＝6.1Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₇ S ₂ [M+H] ⁺ 559.0815,found 559.0815.

Embodiment 158

4-(2-cyclohexylethoxy)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound C-8)

Synthesis of compound C-8

Referring to the method of Example 49, cyclohexylmethanol was replaced by 2-cyclohexylethanol, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-8: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.93(s,1H),9.58(s,1H),8.75(s,1H),7.91(d,2H),7.61(d,J＝2.5Hz,1H),7.48(dd,J＝8.7,2.6Hz,1H),7.02(d,2H),6.84(d,J＝8.7Hz,1H),4.07(t,J＝6.6Hz,2H),2.97(s,3H),1.79–1.57(m,6H),1.52–1.42(m,0H),1.32–1.13(m,3H),1.03–0.90(m,1H).HRMS(ESI)calcd.for C _{2 2} H _{2 8} N ₂ O ₅ S[M+H] ⁺ 433.1792,found 433.1791.

Embodiment 159

4-(2-(4,4-difluoropiperidin-1-yl)ethoxy)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound C-9)

Synthesis of intermediate III-5

Add methyl 4-hydroxybenzoate (304 mmol, 2 mmol) to N,N-dimethylformamide (5 mL), add 2-bromoethanol (185 μL, 2.6 mmol), and then add potassium carbonate (415 mg, 3 mmol) in batches. After the addition is complete, heat the temperature to 80°C and react for 8 hours. After the reaction, the system was cooled to room temperature, water (50 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, and water (20 mL x 1) and saturated brine (20 mL x 1) were used in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate III-5 (white solid, 430 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ8.02 (d, J = 8.7 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 4.16 (t, 2H), 4.02 (dd, J = 9.6, 5.4 Hz, 2H), 3.91 (s, 3H), 2.06 (t, J = 6.2 Hz, 1H).

Synthesis of intermediate III-6

Triphenylphosphine (870 mg, 3.32 mmol) and imidazole (226 mg, 3.32 mmol) were added to tetrahydrofuran (6 mL), and a tetrahydrofuran solution (3 mL) of iodine (842 mg, 3.32 mmol) was added dropwise under an ice bath, stirred at 0°C for 30 minutes, and then a tetrahydrofuran solution (3 mL) of intermediate III-5 (434 mg, 2.21 mmol) was added dropwise. After the dropwise addition, the mixture was heated to room temperature and reacted for 8 hours. After the reaction was completed, sodium thiosulfate solution (10 mL) was added to the reaction solution to quench the excess iodine, and ethyl acetate was added. The organic phases were combined and washed with sodium thiosulfate solution (10 mL x 1) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate III-6 (white solid, 626 mg).

Synthesis of intermediate III-7

Intermediate III-6 (200 mg, 0.65 mmol) and 4,4-difluoropiperidine hydrochloride (154 mg, 0.98 mmol) were added to acetonitrile (2 mL), and potassium carbonate (271 mg, 1.96 mmol) was added in batches. After the addition was completed, the temperature was raised to 80 ° C for 12 hours. After the reaction was completed, the system was cooled to room temperature, 1N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 7-8, and ethyl acetate (5 mL x 4) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude intermediate III-7, which was directly used in the next step without further purification.

Synthesis of intermediate III-8

The crude intermediate III-7 was added to a mixed solvent of tetrahydrofuran (1.5 mL) and methanol (1.5 mL), and 1 M aqueous sodium hydroxide solution (2 mL) was added. After the addition was completed, the temperature was raised to 60° C. and reacted for 4 hours. After the reaction, the system was cooled to room temperature, 1N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 8-9, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (5 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate III-8 (light yellow solid, 109 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.65(s,1H),7.88(d,J＝8.8Hz,2H),7.03(d,J＝8.8Hz,2H),4.18(s,2H),2.83(s,2H),2.65(s,4H),2.08–1.90(m,4H).ESI-MS:m/z 284.1[MH] ^- .

Synthesis of compound C-9

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with intermediate III-8 to obtain compound C-9: ¹ H NMR (300 MHz, DMSO) δ 9.95 (s, 1H), 9.68 (s, 1H), 8.72 (s, 1H), 7.94 (d, J = 8.6 Hz, 2H), 7.61 (s, 1H), 7.49 (dd, J = 8.9, 1.9 Hz, 1H), 7.06 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 4.18 (t, J = 5.6 Hz, 2H), 2.97 (s, 3H), 2.83 (t, 2H), 2.72-2.57 (m, 4H), 1.97 (ddd, J = 19.0, 13.6, 5.3 Hz, 4H). HRMS (ESI) calcd. for C ₂₁ H ₂₅ F ₂ N ₃ O ₅ S[M+H] ⁺ 470.1556, found 470.1563.

Embodiment 160

3-Fluoro-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(4-(trifluoromethoxy)phenethoxy)benzamide (Compound C-10)

Synthesis of compound C-10

Referring to the method of Example 151, 4-trifluoromethylthiophenylacetic acid was replaced by 4-trifluoromethoxyphenylacetic acid, 4-hydroxybenzoic acid methyl ester was replaced by 3-fluoro-4-hydroxybenzoic acid methyl ester, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-10: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.99(s,1H),9.70(s,1H),8.71(s,1H),7.82(dd,J＝10.2,2.3Hz,1H),7.79(d,J＝3.2Hz,1H),7.60(d,J＝2.6Hz,1H),7.52–7.43(m,3H),7.35(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,2H),6.85(d,J＝8.7Hz,1H),4.37(t,J＝6.8Hz,2H),3.13(t,J＝6.7Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₀ F ₄ N ₂ O ₆ S[M+H] ⁺ 529.1051,found 529.1060.

Embodiment 161

3-Fluoro-N-(4-hydroxy-3-(methylsulfonyl)phenyl)-4-(4-(trifluoromethylsulfonyl)phenethoxy)benzamide (Compound C-11)

Synthesis of compound C-11

Referring to the method of Example 157, methyl 4-hydroxybenzoate was replaced with methyl 3-fluoro-4-hydroxybenzoate to obtain compound C-11: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 9.71 (s, 1H), 8.74 (s, 1H), 8.10 (d, J = 8.3 Hz, 2H), 7.88-7.76 (m, 4H), 7.59 (d, J = 2.6 Hz, 1H), 7.47 (dd, J = 8.8, 2.6 Hz, 1H), 7.35 (t, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 4.46 (t, J = 6.5 Hz, 2H), 3.30 (d, J = 6.6 Hz, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₇ S ₂ [M+H] ⁺ 577.0721, found 577.0724.

Embodiment 162

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-6-(4-((trifluoromethyl)thio)phenethoxy)nicotinamide (Compound C-12)

Synthesis of intermediate III-9

The intermediate III-1 (150 mg, 0.67 mmol), ethyl 6-hydroxynicotinate (248 mg, 1.48 mmol) and triphenylphosphine (372 mg, 1.42 mmol) were added to a dry three-necked flask, and anhydrous tetrahydrofuran (2 mL) was added to dissolve under argon protection. A solution of diethyl azodicarboxylate (222 μL, 1.42 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added under an ice bath. After the dropwise addition, the mixture was heated to room temperature for 12 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, saturated brine (5 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain the intermediate III-9 (white solid, 113 mg): ¹ H NMR (300 MHz, CDCl ₃ )δ8.80(s,1H),8.15(dd,J＝6.6Hz,1H),7.59(d,J＝7.8Hz,2H),7.34(d,J＝7.8Hz,2H),6.73(d,J＝8.7Hz,1H),4.61(t,J＝6.8Hz,2H),4.37(q,J＝7.1Hz,2H),3.13(t,J＝6.8Hz,2H),1.39(t,J＝13.4,6.3Hz,3H).ESI-MS:m/z 394.0[M+Na] ⁺ .

Synthesis of compound C-12

Referring to the method of Example 55, intermediate II-1 was replaced by intermediate III-9 to obtain compound C-12: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.10(s,1H),9.62–8.84(m,2H),8.75(d,J＝2.1Hz,1H),8.21(dd,J＝8.7,2.3Hz,1H),7.67(d,J＝8.0Hz,2H),7.60(d,J＝2.3Hz,1H),7.50(d,J＝8.0Hz,1H),7.45(dd,J＝2.4Hz,1H),6.88(dd,J＝13.2,8.7Hz,2H),4.59(t,J＝6.6Hz,2H),3.14(t,J＝6.6Hz,2H),2.50(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{2 0} F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 528.0869,found 528.0869.

Embodiment 163

N-(4-hydroxy-3-(methylsulfonyl)phenyl)-6-(4-(trifluoromethylsulfonyl)phenethoxy)nicotinamide (Compound C-13)

Synthesis of compound C-13

Referring to the method of Example 157, 4-hydroxybenzoic acid methyl ester was replaced with 6-hydroxynicotinic acid ethyl ester to obtain compound C-13: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.09(s,1H),9.71(s,1H),8.74(d,J＝2.1Hz,1H),8.70(s,1H),8.21(dd,J＝8.7,2.5Hz,1H),8.08(d,J＝8.4Hz,2H),7.81(d,J＝8.5Hz,2H),7.60(d,J＝2.6Hz,1H),7.46(dd,J＝8.8,2.6Hz,1H),6.89(d,J＝8.7Hz,1H),6.85(d,J＝8.7Hz,1H),4.65(t,J＝6.5Hz,2H),3.28(t,J＝6.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{2 0} F ₃ N ₃ O ₇ S ₂ [M+H] ⁺ 560.0768, found 560.0776.

Embodiment 164

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenethoxy)benzamide (Compound C-14)

Synthesis of compound C-14

Referring to the method of Example 1, intermediate I-5 was replaced by intermediate III-2, and intermediate I-3 was replaced by intermediate II-18 to obtain compound C-14: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.31(s,1H),9.78(s,1H),8.85(s,1H),7.92(d,J＝8.5Hz,2H),7.68(d,J＝7.9Hz,2H),7.52(d,J＝8.0Hz,2H),7.26(d,J＝8.3Hz,1H),7.05(d,J＝8.4Hz,2H),6.75(d,J＝11.4Hz,1H),4.32(t,J＝6.7Hz,2H),3.14(t,J＝6.7Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₀ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 545.0823,found 545.0823.

Embodiment 165

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-(4-((trifluoromethyl)thio)phenoxy)ethyl)benzamide (Compound C-15)

Synthesis of intermediate III-10

4-Trifluoromethylthiophenol (300 mg, 1.55 mmol), 4-bromophenethyl alcohol (683 mg, 3.40 mmol) and triphenylphosphine (851 mg, 3.24 mmol) were added into a dry three-necked flask. Under argon protection, anhydrous tetrahydrofuran (3 mL) was added to dissolve. A solution of diisopropyl azodicarboxylate (639 μL, 3.24 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added under ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to obtain intermediate III-10 (colorless oily liquid, 367 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.57 (d, J = 8.6 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.2 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.19 (t, J = 6.7 Hz, 2H), 3.08 (t, J = 6.7 Hz, 2H).

Synthesis of compound C-15

Referring to the method of Example 89, intermediate II-41 was replaced by intermediate III-10 to prepare compound C-15: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 9.70 (s, 1H), 8.73 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.63 (dd, J = 5.5, 2.7 Hz, 3H), 7.50 (dd, 2H), 7.46 (d, 1H), 7.10 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 4.32 (t, J = 6.5 Hz, 2H), 3.14 (t, J = 6.4 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917, found 527.0919.

Embodiment 166

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-(4-(trifluoromethoxy)phenoxy)ethyl)benzamide (compound C-16)

Synthesis of compound C-16

Referring to the method of Example 165, 4-trifluoromethylthiophenol was replaced with 4-trifluoromethoxyphenol to obtain compound C-16: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.04(s,1H),9.64(s,1H),8.71(s,1H),7.89(d,J＝8.0Hz,2H),7.63(d,J＝2.5Hz,1H),7.50(ds,J＝2.4Hz,1H),7.46(d,J＝8.0Hz,2H),7.28(d,J＝8.6Hz,2H),7.04(d,2H),6.85(d,J＝8.7Hz,1H),4.26(t,J＝6.6Hz,2H),3.12(t,J＝6.7Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₆ S[M+H] ⁺ 511.1145,found 511.1145.

Embodiment 167

3-Fluoro-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(2-(4-(trifluoromethoxy)phenoxy)ethyl)benzamide (Compound C-17)

Synthesis of intermediate III-11

4-Bromo-2-fluorophenylacetic acid (816 mg, 3.5 mmol) was added to anhydrous tetrahydrofuran (7 mL), and 1 M borane-tetrahydrofuran complex (5.3 mL, 5.3 mmol) was added dropwise under an ice bath. After the addition, the temperature was slowly raised to room temperature for 4 hours. After the reaction was completed, ice water (30 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined and washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate III-11 (colorless oily liquid, 721 mg).

Synthesis of compound C-17

Referring to the method of Example 165, 4-trifluoromethylthiophenol was replaced by 4-trifluoromethoxyphenol, and 4-bromophenethyl alcohol was replaced by intermediate III-11 to obtain compound C-17: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.13(s,1H),9.75(s,1H),8.75(s,1H),7.77(s,1H),7.78–7.70(m,1H),7.62(d,J＝2.6Hz,1H),7.57(t,J＝7.8Hz,1H),7.49(dd,J＝8.8,2.6Hz,1H),7.28(d,J＝8.2Hz,1H),7.03(d,J＝9.1Hz,2H),6.86(d,J＝8.7Hz,1H),4.26(t,J＝6.6Hz,2H),3.15(t,J＝6.5Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₀ F ₄ N ₂ O ₆ S[M+H] ⁺ 529.1051, found 529.1057.

Embodiment 168

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-(4-(trifluoromethoxy)phenoxy)ethyl)benzamide (Compound C-18)

Synthesis of intermediate III-12

4-Trifluoromethoxyphenylacetic acid (1 g, 4.54 mmol) was added to a dry three-necked flask, and anhydrous tetrahydrofuran (10 mL) was added to dissolve under argon protection. 1M borane-tetrahydrofuran complex (9.1 mL, 9.1 mmol) was slowly added under ice bath, and the mixture was slowly heated to room temperature for 6 hours. After the reaction was completed, ice water (30 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in turn, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain intermediate III-12 (light yellow oily liquid, 916 mg).

Synthesis of intermediate III-13

Intermediate III-12 (300 mg, 0.49 mmol) and 4-dimethylaminopyridine (6 mg, 0.05 mmol) were added to dichloromethane (3 mL), and triethylamine (136 μL, 0.98 mmol) was added. p-Toluenesulfonyl chloride (139 mg, 0.73 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate III-13 (colorless oily liquid, 160 mg): ¹ H NMR (300MHz, Chloroform-d) δ7.66 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H), 4.21 (t, J = 6.7 Hz, 2H), 2.96 (t, J = 6.7 Hz, 2H), 2.43 (s, 3H). ESI-MS: m/z 383.06 [M+Na] ⁺ .

Synthesis of intermediate III-14

Intermediate III-13 (139 mg, 0.39 mmol), 4-bromobenzenethiol (109 mg, 0.58 mmol) and potassium iodide (7 mg, 0.04 mmol) were added to acetonitrile (3 mL), and potassium carbonate (108 mg, 0.78 mmol) was added in batches with stirring. After the addition, the temperature was raised to 80°C and the reaction was allowed to proceed for 8 hours. After the reaction, the system was cooled to room temperature, 1M sodium hydroxide aqueous solution (5 mL) was added to the reaction solution to quench, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether) to obtain intermediate III-14 (colorless oily liquid, 136 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.44 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4 Hz, 4H), 7.16 (d, J = 8.5 Hz, 2H), 3.16 (t, J = 7.7 Hz, 2H), 2.94 (t, J = 7.6 Hz, 2H).

Synthesis of intermediate III-15

Intermediate III-14 (110 mg, 0.29 mmol), oxalic acid dihydrate (111 mg, 0.88 mmol), palladium acetate (2 mg, 0.009 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (5 mg, 0.009 mmol) and acetic anhydride (83 μL, 0.88 mmol) were added to anhydrous N,N-dimethylformamide (2 mL), the system was cooled to -78 ° C and frozen, N,N-diisopropylethylamine (154 μL, 0.88 mmol) was added, and argon was used for protection. The system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 ° C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate III-15 (white solid, 55 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.87(s,1H),7.85(d,J＝8.4Hz,2H),7.43(d,J＝5.3Hz,2H),7.40(d,J＝5.2Hz,2H),7.29(d,J＝8.2Hz,2H),3.40–3.29(m,2H),2.96(t,J＝7.4Hz,2H).

Synthesis of compound C-18

Referring to the method of Example 1, intermediate I-6 was replaced by intermediate III-15 to obtain compound C-18: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.04 (s, 1H), 9.37 (s, 2H), 7.89 (d, J＝8.2 Hz, 2H), 7.82 (dd, 2H), 7.67 (d, 1H), 7.46 (s, 1H), 7.45-7.41 (m, 3H), 7.40-7.36 (m, 2H), 7.36-7.26 (m, 3H), 6.68 (d, J = 8.7 Hz, 1H), 3.36 (t, J = 10.0 Hz, 2H), 2.96 (t, J = 7.4 Hz, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₂ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 607.0985, found 607.0991.

Embodiment 169

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-(trifluoromethyl)phenethyl)thio)benzamide (Compound C-19)

Synthesis of compound C-19

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced with 4-trifluoromethylphenylacetic acid to prepare compound C-19: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 9.37 (s, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.82 (dd, J = 8.6, 5.3 Hz, 2H), 7.70–7.65 (m, 3H), 7.53 (d, J = 8.0 Hz, 2H), 7.47–7.34 (m, 5H), 6.69 (d, J = 8.7 Hz, 1H), 3.39 (t, J = 7.5 Hz, 2H), 3.03 (t, J = 7.4 Hz, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₂ F ₄ N ₂ O ₄ S ₂ [M+H] ⁺ 591.1030, found 591.1033.

Embodiment 170

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-((trifluoromethyl)thio)phenethyl)thio)benzamide (Compound C-20)

Synthesis of compound C-20

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced with 4-trifluoromethylthiophenylacetic acid to prepare compound C-20: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 9.35 (s, 2H), 7.89 (d, J = 8.3 Hz, 2H), 7.81 (dd, J = 8.6, 5.3 Hz, 2H), 7.70-7.63 (m, 3H), 7.46 (t, J = 7.6 Hz, 4H), 7.41-7.32 (m, 3H), 6.68 (d, J = 8.7 Hz, 1H), 3.39 (t, J = 7.3 Hz, 2H), 2.99 (t, J = 7.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₂ F ₄ N ₂ O ₄ S ₃ [M+H] ⁺ 623.0751, found 623.0751.

Embodiment 171

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethyl)phenethyl)thio)benzamide (Compound C-21)

Synthesis of compound C-21

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethylphenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-21: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.07(s,1H),9.70(s,1H),8.74(s,1H),7.90(d,2H),7.68(d,J＝8.0Hz,2H),7.62(d,J＝2.6Hz,1H),7.53(d,J＝7.9Hz,2H),7.49(dd,1H),7.45(d,J＝8.2Hz,2H),6.85(d,J＝8.7Hz,1H),3.39(t,J＝7.6Hz,2H),3.02(t,J＝7.6Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₄ S ₂ [M+H] ⁺ 511.0968,found 511.0968.

Embodiment 172

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenethyl)thio)benzamide (Compound C-22)

Synthesis of compound C-22

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethylthiophenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-22: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 9.68 (s, 1H), 8.69 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 7.9 Hz, 2H), 7.63 (dd, 1H), 7.52-7.43 (m, 5H), 6.86 (d, J = 8.8 Hz, 1H), 3.38 (t, 2H), 3.01 (t, J = 7.9 Hz, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₄ S ₃ [M+H] ⁺ 543.0688, found 543.0687.

Embodiment 173

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-23)

Synthesis of compound C-23

Referring to the method of Example 168, intermediate I-3 was replaced by intermediate I-18 to prepare compound C-23: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 9.62 (s, 1H), 8.70 (s, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.62 (d, J = 1.9 Hz, 1H), 7.51 (dd, 1H), 7.47-7.41 (m, 4H), 7.30 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.36 (t, J = 7.4 Hz, 2H), 2.97 (s, 3H), 2.93 (t, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917, found 527.0945.

Embodiment 174

N-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-4-(phenylethylthio)benzamide (Compound C-24)

Synthesis of compound C-24

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by phenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-24: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.07(s,1H),9.72(s,1H),8.74(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.5Hz,1H),7.49(dd,J＝8.8,2.6Hz,1H),7.44(d,J＝8.5Hz,2H),7.35–7.26(m,4H),7.26–7.19(m,1H),6.85(d,J＝8.7Hz,1H),3.34–3.28(m,2H),2.97(s,3H),2.91(t,J＝7.9Hz,2H).HRMS(ESI)calcd.for C _{2 2} H _{2 2} N ₂ O ₄ S ₂ [M+H] ⁺ 443.1094,found 443.1097.

Embodiment 175

4-((4-fluorophenethyl)thio)-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound C-25)

Synthesis of compound C-25

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-fluorophenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-25: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 9.72 (s, 1H), 8.73 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.49 (dd, J = 8.7, 2.6 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.33 (dd, J = 8.6, 5.7 Hz, 2H), 7.13 (t, J = 8.9 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.34–3.28 (m, 2H), 2.97 (s, 3H), 2.91 (t, J = 7.6 Hz, 2H). HRMS (ESI) calcd. for C ₂₂ H ₂₁ FN ₂ O ₄ S ₂ [M+H] ⁺ 461.1000, found 461.1004.

Embodiment 176

4-((4-chlorophenethyl)thio)-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound C-26)

Synthesis of compound C-26

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-chlorophenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-26: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.07(s,1H),9.71(s,1H),8.73(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.6Hz,2H),7.37(d,J＝8.5Hz,2H),7.32(d,J＝8.5Hz,2H),6.85(d,J＝8.7Hz,1H),3.33(t,J＝7.6Hz,2H),2.97(s,3H),2.91(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C _{2 2} H _{2 1} ClN ₂ O ₄ S ₂ [M+H] ⁺ 477.0704,found 477.0710.

Embodiment 177

4-((4-bromophenethyl)thio)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound C-27)

Synthesis of intermediate III-16

4-Bromophenethanol (452 mg, 2.25 mmol) and methyl 4-(chlorosulfonyl)benzoate (351 mg, 1.5 mmol) were added to N,N-dimethylformamide (3 mL). Under argon protection, a solution of tributylphosphine (1.36 g, 6.75 mmol) in N,N-dimethylformamide (1.5 mL) was added dropwise under ice bath. The mixture was stirred for 10 minutes. A solution of diisopropyl azodicarboxylate (306 mg, 1.5 mmol) in N,N-dimethylformamide (2 mL) was added dropwise under ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 6 hours. After the reaction, water (60 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed with 1 M sodium hydroxide aqueous solution (10 mL x 1), water (10 mL x 1), and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate III-16 (white solid, 110 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.94 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 7.09 (d, J = 8.3 Hz, 2H), 3.91 (s, 3H), 3.21 (t, 2H), 2.92 (t, J = 7.7 Hz, 2H).

Synthesis of compound C-27

Referring to the method of Example 55, intermediate II-1 was replaced with intermediate III-16 to obtain compound C-27: ¹ H NMR (300 MHz, Methanol-d ₄ ) δ 7.93 (d, J = 8.5 Hz, 2H), 7.73 (d, J = 2.6 Hz, 1H), 7.50 (dt, J = 8.0, 3.9 Hz, 5H), 7.25 (d, J = 8.1 Hz, 2H), 6.97 (d, J = 8.6 Hz, 1H), 3.35 (d, J = 7.8 Hz, 2H), 3.07 (s, 3H), 3.02 (t, J = 7.4 Hz, 2H). HRMS (ESI) calcd. for C ₂₂ H ₂₁ BrN ₂ O ₄ S ₂ [M+H] ⁺ 521.0199, found 521.0196.

Embodiment 178

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-((4-methylphenethyl)thio)benzamide (Compound C-28)

Synthesis of compound C-28

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-methylphenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-28: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.07(s,1H),9.71(s,1H),8.73(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.5Hz,2H),7.17(d,J＝8.0Hz,2H),7.11(d,J＝7.9Hz,2H),6.85(d,J＝8.7Hz,1H),3.29(t,J＝7.0Hz,2H),2.97(s,3H),2.87(t,J＝7.6Hz,2H),2.27(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₄ N ₂ O ₄ S ₂ [M+H] ⁺ 457.1250, found 457.1254.

Embodiment 179

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-((4-isopropylphenethyl)thio)benzamide (Compound C-29)

Synthesis of compound C-29

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-isopropylphenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-29: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.07(s,1H),9.72(s,1H),8.73(s,1H),7.89(d,J＝8.5Hz,2H),7.62(d,J＝2.5Hz,1H),7.49(dd,J＝8.8,2.5Hz,1H),7.43(d,J＝8.5Hz,2H),7.20(d,J＝8.4Hz,2H),7.17(d,J＝8.4Hz,2H),6.85(d,J＝8.8Hz,1H),3.30(t,J＝8.1Hz,2H),2.97(s,3H),2.87(t,J＝7.9Hz,2H),2.85–2.81(m,1H),1.18(d,J＝6.9Hz,6H).HRMS(ESI)calcd.for C ₂₅ H ₂₈ N ₂ O ₄ S ₂ [M+H] ⁺ 485.1563, found 485.1564.

Embodiment 180

4-((4-cyclopropylphenethyl)thio)-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)benzamide (Compound C-30)

Synthesis of intermediate III-17

Ethyl 4-bromophenylacetate (350 mg, 1.44 mmol), cyclopropylboronic acid (371 mg, 4.32 mmol), tricyclohexylphosphine (40 mg, 0.14 mmol), potassium phosphate (1.13 g, 5.04 mmol) and palladium acetate (16 mg, 0.07 mmol) were added to a Schlenk tube. Under argon protection, toluene (3 mL) and water (150 μL) were added to the system for suspension, and the temperature was raised to 100° C. for reaction for 6 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate III-17 (white solid, 200 mg): ¹ H NMR (400MHz, Chloroform-d) δ7.17 (d, J = 6.5 Hz, 2H), 7.03 (d, J = 8.2 Hz, 2H), 4.14 (q, J = 7.1 Hz, 2H), 3.56 (s, 2H), 1.91-1.84 (m, 1H), 1.25 (t, J = 7.1 Hz, 3H), 0.97-0.91 (m, 2H), 0.70-0.65 (m, 2H).

Synthesis of intermediate III-18

The intermediate III-17 (160 mg, 0.78 mmol) was added to tetrahydrofuran (4 mL), and a 2M tetrahydrofuran solution of lithium borohydride (784 μL, 1.57 mmol) was added dropwise under an ice bath. After the addition was completed, the temperature was raised to 60°C for reaction for 3 hours. After the reaction was completed, the system was cooled to room temperature, and water (10 mL) was added dropwise to the reaction solution under an ice bath to quench the excess lithium borohydride, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain the intermediate III-18 (colorless oily liquid, 113 mg).

Synthesis of compound C-30

Referring to the method of Example 168, intermediate III-12 was replaced by intermediate III-18, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-30: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 9.70 (s, 1H), 8.74 (s, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.49 (dd, J = 8.7, 2.6 Hz, 1H), 7.42 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 8.2 Hz, 2H), 7.00 (d, J = 8. =8.1 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.28 (t, J = 7.5 Hz, 2H), 2.97 (s, 3H), 2.85 (t, J = 7.6 Hz, 2H), 1.93–1.83 (m, 1H), 0.95–0.88 (m, 2H), 0.67–0.60 (m, 2H). HRMS (ESI) calcd. for C _{2 5} H _{2 6} N ₂ O ₄ S ₂ [M+H] ⁺ 483.1407, found 483.1409.

Embodiment 181

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-((4-methoxyphenethyl)thio)benzamide (Compound C-31)

Synthesis of compound C-31

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-methoxyphenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-31: ¹ H NMR (400 MHz, Methanol-d ₄ )δ10.07(s,1H),9.72(s,1H),8.73(s,1H),7.89(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.5Hz,2H),7.20(d,J＝8.6Hz,2H),6.87(d,J＝6.8Hz,2H),6.85(d,J＝6.9Hz,1H),3.73(s,3H),3.32–3.24(m,2H),2.97(s,3H),2.85(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₄ N ₂ O ₅ S ₂ [M+H] ⁺ 473.1199, found 473.1203.

Embodiment 182

4-((4-cyanophenethyl)thio)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound C-32)

Synthesis of compound C-32

Referring to the method of Example 168, 4-trifluoromethylphenylacetic acid was replaced by 4-cyanophenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-32: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.07(s,1H),9.71(s,1H),8.75(s,1H),7.90(d,J＝8.6Hz,2H),7.79(d,J＝8.3Hz,2H),7.62(d,J＝2.6Hz,1H),7.51(d,J＝8.2Hz,2H),7.49(dd,J＝8.5,2.6Hz,1H),7.44(d,J＝8.5Hz,2H),6.85(d,J＝8.7Hz,1H),3.38(t,J＝7.5Hz,2H),3.01(t,J＝7.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ N ₃ O ₄ S ₂ [M+H] ⁺ 468.1046,found 468.1052.

Embodiment 183

4-((4-(difluoromethoxy)phenethyl)thio)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound C-33)

Synthesis of intermediate III-19

4-Hydroxyphenethyl bromide (603 mg, 3 mmol), 3,4-dihydro-2H-pyran (252 mg, 9 mmol) and 4-methylbenzenesulfonate pyridine (150 mg, 0.6 mmol) were added to dichloromethane (15 mmol) and reacted at room temperature for 48 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate III-19 (colorless oily liquid, 494 mg).

Synthesis of intermediate III-20

Intermediate III-19 (490 mg, 1.73 mmol) and 4-bromothiophenol (459 mg, 2.43 mmol) were added to acetone (10 mL), and potassium carbonate (359 mg, 2.59 mmol) was added in batches. After the addition was completed, the temperature was raised to 60 ° C for 8 hours. After the reaction was completed, 1M sodium hydroxide aqueous solution (10 mL) was added to the reaction solution to quench the excess 4-bromothiophenol, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with 1M sodium hydroxide aqueous solution (5 mL x 2) and saturated brine (15 mL x 1) in turn. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100: 1) to obtain intermediate III-20 (colorless oily liquid, 645 mg).

Synthesis of intermediate III-21

Intermediate III-20 (640 mg, 1.63 mmol) and p-toluenesulfonic acid (PTSA) (31 mg, 0.16 mmol) were added to a mixed solvent of dichloromethane (5 mL) and methanol (5 mL) and reacted at room temperature for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate III-21 (colorless oily liquid, 466 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.21 (s, 1H), 7.49 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.6 Hz, 2H), 7.03 (d, 2H), 6.67 (d, J = 8.4 Hz, 2H), 3.16 (t, J = 7.6 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H).

Synthesis of intermediate III-22

Potassium hydroxide (90 mg, 1.62 mmol) was added to a mixed solvent of acetonitrile (1 mL) and water (1 mL), and intermediate III-21 (50 mg, 0.16 mmol) was added under ice bath. After the addition, the mixture was stirred at 0°C for 15 minutes, and diethyl bromofluoromethylphosphonate (57 μL, 0.32 mmol) was slowly added dropwise under ice bath. After the addition, the temperature was slowly raised to room temperature and reacted for 1 hour. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined and washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate III-22 (white solid, 39 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.41 (d, J = 8.5 Hz, 2H), 7.24–7.13 (m, 4H), 7.05 (d, J = 8.5 Hz, 2H), 6.48 (t, J = 74.0 Hz, 1H), 3.16–3.10 (m, 2H), 2.94–2.86 (m, 2H).

Synthesis of compound C-33

Referring to the method of Example 168, intermediate III-14 was replaced by intermediate III-22 to obtain compound C-33: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 9.68 (s, 1H), 8.71 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.62 (d, J = 2.5 Hz, 1H), 7.49 (dd, J = 8.7, 2.5 Hz, 1H), 7.44 (d, J = 8.5 Hz, 2H), 7.35 (d, 2H), 7.20 (s, 1H), 7.11 (d, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.30 (t, 2H), 2.97 (s, 3H), 2.92 (t, J = 7.6 Hz, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₂ F ₂ N ₂ O ₅ S ₂ [M+H] ⁺ 509.1011, found 509.1013.

Embodiment 184

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-((4-(methylthio)phenethyl)thio)benzamide (Compound C-34)

Synthesis of compound C-34

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-methylthiophenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-34: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 9.66 (s, 1H), 8.73 (s, 1H), 7.90 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.49 (dd, J ＝8.7,2.6 Hz,1H), 7.43(d,J＝8.5 Hz,2H),7.24(d,J＝9.1 Hz,2H),7.20(d,J＝8.8 Hz,2H),6.85(d,J＝8.7 Hz,1H),3.29(d,J＝7.8 Hz,2H),2.97(s,3H),2.88(t,J＝7.5 Hz,2H),2.45(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₄ N ₂ O ₄ S ₃ [M+H] ⁺ 489.0971,found 489.0972.

Embodiment 185

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-((4-(methylsulfonyl)phenethyl)thio)benzamide (Compound C-35)

Synthesis of compound C-35

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-methylsulfonylphenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-35: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.07(s,1H),9.71(s,1H),8.72(s,1H),7.90(d,J＝8.5Hz,2H),7.86(d,J＝8.4Hz,2H),7.62(d,J＝2.5Hz,1H),7.57(d,J＝8.4Hz,2H),7.49(dd,J＝8.8,2.6Hz,1H),7.45(d,J＝8.6Hz,2H),6.85(d,J＝8.7Hz,1H),3.39(t,J＝7.5Hz,2H),3.20(s,3H),3.04(t,J＝7.4Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₄ N ₂ O ₆ S ₃ [M+H] ⁺ 521.0869, found 521.0878.

Embodiment 186

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-((3-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-36)

Synthesis of compound C-36

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 3-trifluoromethoxyphenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-36: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.07(s,1H),9.72(s,1H),8.74(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.9,2.7Hz,1H),7.46–7.42(m,3H),7.33(d,J＝5.7Hz,2H),7.22(d,J＝8.0Hz,1H),6.85(d,J＝8.7Hz,1H),3.38(d,J＝7.1Hz,2H),2.98(t,J＝7.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917,found 527.0919.

Embodiment 187

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-((2-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-37)

Synthesis of compound C-37

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 2-trifluoromethoxyphenylacetic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-37: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.08(s,1H),9.73(s,1H),8.74(s,1H),7.91(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.54–7.45(m,2H),7.45(d,J＝8.5Hz,2H),7.41–7.32(m,3H),6.85(d,J＝8.7Hz,1H),3.31(t,J＝8.3Hz,2H),2.98(t,J＝8.2Hz,2H),2.97(s,1H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917,found 527.0920.

Embodiment 188

2-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-38)

Synthesis of intermediate III-23

Referring to the method of Example 177, 4-bromophenethanol was replaced by 4-trifluoromethoxyphenethanol, and 4-(chlorosulfonyl)benzoic acid methyl ester was replaced by 3-fluoro-4-bromobenzenesulfonyl chloride to obtain Intermediate III-23: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.46 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H), 7.08 (dd, J = 9.1, 1.9 Hz, 1H), 6.98 (dd, J = 8.3, 1.9 Hz, 1H), 3.18 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H).

Synthesis of compound C-38

Referring to the method of Example 89, intermediate II-41 was replaced by intermediate III-23 to prepare compound C-38: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.15 (s, 1H), 9.73 (s, 1H), 8.74 (s, 1H), 7.58 (t, J = 7.9 Hz, 2H), 7.47-7.41 (m, 3H), 7.33 (t, J = 8.7 Hz, 3H), 7.25 (d, J = 8.2 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 3.38 (t, 2H), 2.97 (s, 3H), 2.94 (t, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 545.0823, found 545.0822.

Embodiment 189

3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-39)

Synthesis of intermediate III-24

Referring to the method of Example 177, 4-bromophenethanol was replaced by 4-trifluoromethoxyphenethanol, and 4-(chlorosulfonyl)benzoic acid methyl ester was replaced by 4-bromo-2-fluorobenzenesulfonyl chloride to obtain Intermediate III-24: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.28 (s, 1H), 7.25 (d, J = 4.2 Hz, 2H), 7.22 (d, J = 8.7 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 3.15 (t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H).

Synthesis of compound C-39

Referring to the method of Example 89, intermediate II-41 was replaced with intermediate III-24 to obtain compound C-39: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 9.74 (s, 1H), 8.75 (s, 1H), 7.85-7.75 (m, 2H), 7.62 (d, J = 2.4 Hz, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.50 (dd, J = 8.7, 2.1 Hz, 1H), 7.43 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 3.37 (t, 2H), 2.98 (s, 3H), 2.95 (t, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 545.0823, found 545.0820.

Embodiment 190

N-(2-Fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-((4-(trifluoromethoxy)phenethyl)thio)benzamide (compound C-40)

Synthesis of compound C-40

Referring to the method of Example 168, intermediate I-3 was replaced by intermediate II-18 to obtain compound C-40: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 9.91 (s, 1H), 8.88 (s, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.5 Hz, 2H), 7.41 (d, J = 8.5 Hz, 2H), 7.30 (dd, J = 8.8, 1.0 Hz, 2H), 7.27 (d, J = 8.3 Hz, 1H), 6.77 (d, J = 11.3 Hz, 1H), 3.35 (t, J = 7.6 Hz, 2H), 2.95 (t, J = 8.4 Hz, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 545.0828, found 545.0833.

Embodiment 191

3-Fluoro-N-(2-fluoro-4-hydroxy-5-(methylsulfonylamino)phenyl)-4-((4-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-41)

Synthesis of compound C-41

Referring to the method of Example 168, intermediate III-14 was replaced by intermediate III-24, and intermediate I-3 was replaced by intermediate II-18 to prepare compound C-41: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 9.43 (s, 2H), 7.76 (d, J = 7.9 Hz, 1H), 7.72 (d, J = 10.7 Hz, 1H), 7.56-7.49 (m, 1H), 7.48 (d, J = 8.8 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 7.29 (s, 1H), 7.01 (s, 1H), 3.31 (t, J = 7.4 Hz, 2H), 2.99 (t, J = 7.6 Hz, 2H), 2.99 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₁₉ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 563.0728, found 563.0711.

Embodiment 192

N-(2-chloro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-42)

Synthesis of compound C-42

Referring to the method of Example 168, intermediate I-3 was replaced by intermediate II-60 to prepare compound C-42: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.41 (s, 1H), 9.91 (s, 1H), 8.98 (s, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 3.2 Hz, 2H), 7.29 (s, 1H), 7.00 (s, 1H), 3.35 (d, J = 5.9 Hz, 2H), 2.99 (s, 3H), 2.95 (t, J = 7.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ ClF ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 561.0527, found 561.0532.

Embodiment 193

N-(4-(Hydroxymethyl)-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-43)

Synthesis of intermediate III-25

2-Amino-4-nitrobenzoic acid (500 mg, 2.75 mmol) was added to a dry three-necked flask, and anhydrous tetrahydrofuran (5 mL) was added to dissolve under argon protection. Then 1M borane-tetrahydrofuran complex (5.5 mL, 5.5 mmol) was slowly added under ice bath. After the dropwise addition, the mixture was stirred at 0°C for 15 minutes, and then heated to 65°C for 4 hours. After the reaction was completed, ice water (30 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (15 mL x 1) and saturated brine (15 mL x 1) in turn, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate III-25 (yellow solid, 477 mg).

Synthesis of intermediate III-26

Intermediate III-25 (447 mg, 2.66 mmol) and pyridine (321 μL, 3.99 mmol) were added to dichloromethane (5 mL), and a solution of methanesulfonic anhydride (556 mg, 3.19 mmol) in dichloromethane (5 mL) was added dropwise under an ice-water bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction, concentrated hydrochloric acid (1 mL) was added to the reaction solution to quench the excess pyridine and methanesulfonic anhydride, and the solvent was evaporated under reduced pressure. The residue was added with 1N aqueous hydrogen chloride solution (20 mL), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined and washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to obtain intermediate III-26 (yellow solid, 363 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.44 (s, 1H), 8.12 (dd, 2H), 7.75 (d, J = 8.4 Hz, 1H), 5.62 (s, 1H), 4.71 (s, 2H), 3.10 (s, 3H). ESI-MS: m/z 245.0 [MH] ^- .

Synthesis of intermediate III-27

Intermediate III-26 (340 mg, 1.38 mmol) and 10% palladium on carbon (68 mg) were added to methanol (4 mL) and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction, palladium carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to obtain intermediate III-27 (yellow solid, 187 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ8.61 (s, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 1.9 Hz, 1H), 6.37 (dd, J = 8.1, 1.9 Hz, 1H), 5.13 (s, 2H), 5.02 (s, 1H), 4.42 (s, 2H), 2.97 (s, 3H). ESI-MS: m/z 215.0 [MH] ^- .

Synthesis of compound C-43

Referring to the method of Example 168, intermediate I-3 was replaced by intermediate III-27, and compound C-43 was directly obtained after condensation: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 8.88 (s, 1H), 7.92 (d, J = 7.9 Hz, 2H), 7.78 (s, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.9 Hz, 3H), 7.38 (t, J = 8.6 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 5.31 (s, 1H), 4.58 (s, 2H), 3.37 (t, 2H), 3.04 (s, 3H), 2.96 (t, J = 7.4 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₃ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 541.1079, found 541.1085.

Embodiment 194

2-(Methylsulfonamide)-4-(4-((4-(trifluoromethoxy)phenethyl)thio)benzamide)benzoic acid (Compound C-44)

Synthesis of compound C-44

Referring to the method of Example 53, 4-fluorobenzenesulfonyl chloride was replaced by methanesulfonic anhydride, and intermediate II-3 was replaced by intermediate III-15 to obtain compound C-44: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.65 (s, 1H), 10.85 (s, 1H), 10.59 (s, 1H), 8.08 (s, 1H), 7.99 (d, J＝8.8 Hz, 1H), 7.93 (d, J＝8.3 Hz, 2H), 7.67 (d, J =10.0 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.3 Hz, 2H), 3.37 (t, J = 6.2 Hz, 2H), 3.24 (s, 3H), 2.97 (t, J = 7.3 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₁ F ₃ N ₂ O ₆ S ₂ [M+H] ⁺ 555.0866, found 555.0867.

Embodiment 195

4-(Methylsulfonamide)-2-(4-((4-(trifluoromethoxy)phenethyl)thio)benzamide)benzoic acid (Compound C-45)

Synthesis of compound C-45

Referring to the method of Example 53, intermediate II-3 was replaced by intermediate III-15, and intermediate II-11 was replaced by intermediate I-35 to obtain compound C-45: ¹ H NMR (300 MHz, DMSO-d ₆ )δ13.58(s,1H),12.46(s,1H),10.41(s,1H),8.68(d,J＝1.8Hz,1H),8.00(d,J＝8.7Hz,1H),7.88(d,J＝8.4Hz,2H),7.51(d,J＝8.4Hz,2H),7.43(d,J＝8.5Hz,2H),7.29(d,J＝8.1Hz,2H),6.99(dd,J＝8.7Hz,1H),3.37(t,J＝7.4Hz,2H),3.14(s,3H),2.97(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₁ F ₃ N ₂ O ₆ S ₂ [M+H] ⁺ 555.0866,found 555.0863.

Embodiment 196

5-Hydroxy-4-(methylsulfonylamino)-2-(4-(4-(trifluoromethoxy)phenethoxy)benzylamino)benzoic acid (Compound C-46)

Synthesis of compound C-46

Referring to the method of Example 25, intermediate I-30 was replaced by intermediate III-15 to obtain compound C-46: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.57 (s, 1H), 12.17 (s, 1H), 10.07 (s, 1H), 9.00 (s, 1H), 8.70 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.53 (s, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 8.2 Hz, 2H), 3.39-3.33 (m, 2H), 3.10 (s, 3H), 2.96 (t, J = 7.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₁ F ₃ N ₂ O ₇ S ₂ [M+H] ⁺ 571.0821, found 571.0825.

Embodiment 197

N-(4-hydroxy-3-((1-methylethyl)sulfonamido)phenyl)-4-((4-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-47)

Synthesis of compound C-47

Referring to the method of Example 1, 4-fluorobenzenesulfonyl chloride was replaced by isopropylsulfonyl chloride, and intermediate I-6 was replaced by intermediate III-15 to obtain compound C-47: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.04(s,1H),9.70(s,1H),8.60(s,1H),7.90(d,J＝8.4Hz,2H),7.65(d,J＝2.3Hz,1H),7.49–7.45(m,2H),7.44–7.39(m,3H),7.30(d,J＝8.1Hz,2H),6.82(d,J＝8.7Hz,1H),3.35(t,J＝6.1Hz,2H),3.24–3.15(m,1H),2.95(t,J＝7.5Hz,2H),1.29(s,3H),1.27(s,3H).HRMS(ESI)calcd.for C _{2 5} H _{2 5} F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 555.1230,found 555.1232.

Embodiment 198

N-(3-(Cyclopropanesulfonamide)-4-hydroxyphenyl)-4-((4-(trifluoromethoxy)phenethyl)thio)benzamide (Compound C-48)

Synthesis of compound C-48

Referring to the method of Example 1, 4-fluorobenzenesulfonyl chloride was replaced by cyclopropanesulfonyl chloride, and intermediate I-6 was replaced by intermediate III-15 to obtain compound C-48: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 9.57 (s, 1H), 8.64 (s, 1H), 7.89 (d, J = 7.9 Hz, 2H), 7.68 (d, 1H), 7.48–7.37 (m, 5H), 7.30 (d, J = 8.0 Hz, 2H), 6.83 (d, J = 8.5 Hz, 1H), 3.35 (t, 2H), 2.95 (t, J = 7.3 Hz, 2H), 2.65–2.57 (m, 1H), 0.92 (s, 2H), 0.90 (s, 2H). ESI-MS: m/z 551.1[MH] ^- .

Embodiment 199

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-((4-((trifluoromethyl)thio)phenyl)thio)ethyl)benzamide (Compound C-49)

Synthesis of intermediate III-28

4-Trifluoromethylthioaniline (200 mg, 1.04 mmol) was added to concentrated hydrochloric acid (1 mL), and a solution of sodium nitrite (107 mg, 1.55 mmol) in water (1 mL) was added dropwise under an ice-salt bath, and stirred for 15 minutes. After the raw material disappeared by TLC monitoring, sodium iodide (621 mg, 4.14 mmol) was added in batches, and the reaction was continued under an ice-salt bath for 90 minutes. After the reaction was completed, ice water (10 mL) was added dropwise to the reaction solution for dilution, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in turn, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether) to obtain intermediate III-28 (light yellow solid, 255 mg).

Synthesis of intermediate III-29

Cuprous iodide (16 mg, 0.08 mmol), potassium carbonate (227 mg, 1.64 mmol) and elemental sulfur (79 mg, 2.47 mmol) were added to a dry Schlenk tube, and then an N, N-dimethylformamide (3 mL) solution of intermediate III-28 (250 mg, 0.82 mmol) was added under argon protection. After the addition was completed, the temperature was raised to 90°C for reaction for 8 hours. After the reaction was completed, the system was cooled to room temperature, and sodium borohydride (94 mg, 2.47 mmol) was added in batches under an ice bath. After the addition was completed, the temperature was raised to 40°C for reaction for 2 hours. After the reaction was completed, the system was cooled to room temperature, and potassium iodide (205 mg, 1.23 mmol) and 4-(2-bromoethyl)benzoic acid (283 mg, 1.23 mmol) in N, N-dimethylformamide (2 mL) were added. After the addition was completed, the reaction was continued at room temperature for 8 hours. After the reaction, water (40 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phase was washed with water (10 mL x 2) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate III-29 (white solid, 149 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.85 (s, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 8.3 Hz, 2H), 7.44 (dd, J = 13.7, 8.3 Hz, 4H), 3.37 (t, J = 7.2 Hz, 2H), 3.00 (t, J = 7.4 Hz, 2H). ESI-MS: m/z 357.0 [MH] ^- .

Synthesis of compound C-49

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with intermediate III-29 to prepare compound C-49: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 9.71 (s, 1H), 8.73 (s, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 7.8 Hz, 3H), 7.56-7.39 (m, 5H), 6.85 (d, J = 8.8 Hz, 1H), 3.39 (t, J = 7.5 Hz, 2H), 3.02 (t, J = 7.5 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₄ S ₃ [M+H] ⁺ 543.0688, found 543.0686.

Embodiment 200

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-50)

Synthesis of intermediate III-30

4-Bromophenylacetic acid (500 mg, 2.33 mmol) was added to anhydrous tetrahydrofuran (7 mL), and 1 M borane-tetrahydrofuran complex (4.7 mL, 4.7 mmol) was slowly added under ice bath. After the addition, the mixture was naturally warmed to room temperature for 4 hours. After the reaction, ice water (20 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate III-30 (light yellow oily liquid, 462 mg).

Synthesis of intermediate III-31

Intermediate III-30 (385 mg, 1.91 mmol) and 4-dimethylaminopyridine (23 mg, 0.19 mmol) were added to dichloromethane (6 mL), and triethylamine (532 μL, 3.83 mmol) was added. Then p-toluenesulfonyl chloride (548 mg, 2.87 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate III-31 (colorless waxy liquid, 565 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.71 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.25 (d, J = 8.4 Hz, 1H), 4.00 (t, J = 6.5 Hz, 2H), 3.03 (t, J = 6.5 Hz, 1H), 2.41 (s, 2H).

Synthesis of intermediate III-32

4-Trifluoromethoxybenzenesulfonyl chloride (588 mg, 2.25 mmol) was added to N, N-dimethylformamide (4 mL), and tributylphosphine (1.70 mL, 6.76 mmol) was added dropwise under ice bath. After the addition was completed, the temperature was raised to 50°C for reaction for 30 minutes. After TLC monitoring of the disappearance of the raw material, the system was cooled to room temperature, and the intermediate III-31 (534 mg, 1.50 mmol) in N, N-dimethylformamide (3 mL) solution, potassium carbonate (312 mg, 2.25 mmol), and potassium iodide (25 mg, 0.15 mmol) were added in turn under ice bath. After the addition was completed, the reaction was carried out at 50°C for 6 hours. After the reaction, the system was cooled to room temperature, water (70 mL) was added to the reaction solution for dilution, and ethyl acetate was used for extraction (15 mL x 3). The organic phases were combined, washed with water (20 mL x 2) and saturated brine (20 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether) to obtain intermediate III-32 (colorless oily liquid, 505 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.37 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.22 (d, J = 8.2 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 3.12 (t, J = 6.0 Hz, 1H), 2.87 (t, J = 6.0 Hz, 1H).

Synthesis of intermediate III-33

Intermediate III-32 (425 mg, 1.13 mmol), oxalic acid dihydrate (426 mg, 3.38 mmol), palladium acetate (13 mg, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33 mg, 0.06 mmol) and acetic anhydride were added. (324 μL, 3.38 mmol) was added into anhydrous N,N-dimethylformamide (4 mL), the system was cooled to -78 °C and frozen, and then N,N-diisopropylethylamine (589 μL, 3.38 mmol) was added. Under argon protection, the system was allowed to naturally return to room temperature and stirred for 10 minutes, and then the temperature was raised to 100 °C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (10 mL) and water (30 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (15 mL x 1) and saturated brine (15 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate III-33 (white solid, 232 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.85 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.38 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.3 Hz, 2H), 3.35–3.23 (m, 4H), 2.95 (t, J = 7.5 Hz, 2H).

Synthesis of compound C-50

Referring to the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with intermediate III-33 to prepare compound C-50: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.05 (s, 1H), 9.70 (s, 1H), 8.74 (s, 1H), 7.88 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 2.5 Hz, 1H), 7.53-7.45 (m, 3H), 7.40 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.30 (t, 2H), 3.02-2.91 (m, 5H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917, found 527.0922.

Embodiment 201

3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-51)

Synthesis of intermediate III-34

4-Bromo-2-fluorophenylacetic acid (350 mg, 1.5 mmol) was added to a dry three-necked bottle, and anhydrous tetrahydrofuran (3 mL) was added to dissolve under argon protection. 1M borane-tetrahydrofuran complex (2.25 mL, 2.25 mmol) was slowly added dropwise under ice bath. After the dropwise addition, the temperature was slowly raised to room temperature for 6 hours. After the reaction was completed, ice water (20 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in turn, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude intermediate III-34, which was directly used in the next reaction without further purification.

Synthesis of intermediate III-35

The crude III-34 (1.5 mmol) and 4-trifluoromethoxybenzenesulfonyl chloride (585 mg, 2.25 mmol) were added to N,N-dimethylformamide (3 mL). Under argon protection, a solution of tributylphosphine (2.27 g, 11.25 mmol) in N,N-dimethylformamide (2 mL) was added dropwise under ice bath. The mixture was stirred for 10 minutes. A solution of azodicarbonyl dipyridine (ADDP) (568 mg, 2.25 mmol) in N,N-dimethylformamide (2 mL) was added dropwise under ice bath. After the addition was completed, the temperature was slowly raised to room temperature and reacted for 6 hours. After the reaction was completed, water (70 mL) was added to the reaction solution for dilution, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined and washed with 1 M sodium hydroxide aqueous solution (15 mL x 2), water (15 mL x 1), and saturated brine (15 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified twice by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate III-35 (colorless oily liquid, 262 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.35 (d, J = 8.9 Hz, 2H), 7.24–7.18 (m, 2H), 7.15 (d, J = 8.3 Hz, 2H), 7.05 (t, J = 8.1 Hz, 1H), 3.14 (t, J = 7.6 Hz, 2H), 2.91 (t, J = 7.6 Hz, 2H).

Synthesis of compound C-51

Referring to the method of Example 89, intermediate II-41 was replaced by intermediate III-35 to obtain compound C-51: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.73 (s, 1H), 8.73 (s, 1H), 7.78–7.67 (m, 2H), 7.62 (d, J=2.5 Hz, 1H), 7.56–7.43 (m, 4H), 7.33 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.8 Hz, 1H), 3.31–3.25 (m, 2H), 3.03–2.95 (m, 5H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 545.0823, found 545.0828.

Embodiment 202

3-Fluoro-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(2-(4-(trifluoromethyl)thiophenyl)thio)ethyl)benzamide (Compound C-52)

Synthesis of intermediate III-36

Sulfonyl chloride (1.81 mL, 25 mmol) was added dropwise to water (15 mL) under an ice bath, and the mixture was reacted at 0°C for 3 hours. Cuprous chloride (25 mg, 0.25 mmol) was then added, and stirring was continued for 1 hour at 0°C. At the same time, 4-trifluoromethylthioaniline (482 mg, 2.5 mmol) was added to concentrated hydrochloric acid (5 mL), and sodium nitrite (259 mg, 3.75 mmol) was added in batches under an ice-salt bath, and stirring was continued for 1 hour under an ice-salt bath. The reaction solution was then added dropwise to the prepared sulfur dioxide aqueous solution, and the reaction was continued for 2 hours under an ice-salt bath. After the reaction was completed, ice water (20 mL) was added dropwise to the reaction solution to dilute it, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate III-36 (colorless oily liquid, 110 mg).

Synthesis of compound C-52

Referring to the method of Example 200, 4-trifluoromethoxybenzenesulfonyl chloride was replaced by intermediate III-36, and intermediate III-30 was replaced by intermediate III-34 to prepare compound C-52: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 9.70 (s, 1H), 8.77 (s, 1H), 7.79-7.68 (m, 2H), 7.68-7.58 (m, 3H), 7.58-7.43 (m, 4H), 6.86 (d, J = 8.7 Hz, 1H), 3.41-3.36 (m, 2H), 3.03 (t, J = 7.4 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₄ S ₃ [M+H] ⁺ 561.0594, found 561.0594.

Embodiment 203

3-Fluoro-N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(2-(4-(trifluoromethyl)phenyl)thioethyl)benzamide (Compound C-53)

Synthesis of compound C-53

Referring to the method of Example 200, 4-trifluoromethoxybenzenesulfonyl chloride was replaced by 4-trifluoromethylbenzenesulfonyl chloride, and intermediate III-30 was replaced by intermediate III-34 to obtain compound C-53: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 9.65 (s, 1H), 8.79 (s, 1H), 7.77-7.71 (m, 2H), 7.66 (d, J = 8.3 Hz, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.55-7.47 (m, 4H), 6.86 (d, J = 8.8 Hz, 1H), 3.38 (t, J = 7.4 Hz, 2H), 3.03 (t, J = 7.4 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₄ S ₂ [M+H] ⁺ 529.0873, found 529.0877.

Embodiment 204

2-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-(4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-54)

Synthesis of compound C-54

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 4-bromo-3-fluorophenylacetic acid to prepare compound C-54: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.78 (s, 1H), 8.74 (s, 1H), 7.65 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.52-7.46 (m, 3H), 7.33 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 8.8 Hz, 1H), 3.29 (t, J = 7.2 Hz, 2H), 3.00 (t, J = 7.2 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 545.0823, found 545.0818.

Embodiment 205

2-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-(4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-55)

Synthesis of compound C-55

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 4-bromo-2,6-difluorophenylacetic acid to prepare compound C-55: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.18 (s, 1H), 9.79 (s, 1H), 8.77 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 2.6 Hz, 1H), 7.52-7.44 (m, 3H), 7.33 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 3.28 (t, J = 7.2 Hz, 2H), 3.01 (d, J = 7.3 Hz, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₁₉ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 563.0728, found 563.0730.

Embodiment 206

2,5-Difluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-56)

Synthesis of compound C-56

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 4-bromo-2,5-difluorophenylacetic acid to prepare compound C-56: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.28 (s, 1H), 9.77 (s, 1H), 8.76 (s, 1H), 7.57 (d, J = 2.6 Hz, 1H), 7.49 (d, J = 8.8 Hz, 2H), 7.47-7.39 (m, 3H), 7.34 (d, J = 7.7 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 3.31 (t, J = 7.4 Hz, 2H), 2.96 (s, 3H), 2.96 (t, J = 7.3 Hz, 2H). HRMS (ESI) calcd. for C ₂₃ H ₁₉ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 563.0728, found 563.0728.

Embodiment 207

3-Chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-(4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-57)

Synthesis of compound C-57

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 4-bromo-2-chlorophenylacetic acid to obtain compound C-57: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.17(s,1H),9.75(s,1H),8.76(s,1H),7.99(d,J＝1.8Hz,1H),7.85(dd,J＝8.0,1.8Hz,1H),7.61(d,J＝2.6Hz,1H),7.55(d,J＝8.1Hz,1H),7.53–7.45(m,3H),7.34(d,J＝7.9Hz,2H),6.86(d,J＝8.8Hz,1H),3.30(t,J＝7.4Hz,2H),3.06(t,J＝7.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₀ ClF ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 561.0527,found 561.0533.

Embodiment 208

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-3-methyl-4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-58)

Synthesis of compound C-58

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 4-bromo-2-methylphenylacetic acid to prepare compound C-58: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 9.70 (s, 1H), 8.73 (s, 1H), 7.73 (s, 1H), 7.70 (dd, J = 7.8, 2.0 Hz, 1H), 7.62 (d, J = 2.6 Hz, 1H), 7.54-7.46 (m, 3H), 7.37-7.30 (m, 3H), 6.85 (d, J = 8.7 Hz, 1H), 3.26 (t, J = 7.6 Hz, 2H), 2.97 (s, 3H), 2.93 (t, J = 7.7 Hz, 2H), 2.31 (s, 3H). HRMS (ESI) calcd. for C ₂₄ H ₂₃ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 541.1073, found 541.1074.

Embodiment 209

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-3-methoxy-4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-59)

Synthesis of compound C-59

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 4-bromo-2-methoxyphenylacetic acid to prepare compound C-59: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.04 (s, 1H), 9.74 (s, 1H), 8.74 (s, 1H), 7.62 (d, J = 2.6 Hz, 1H), 7.54-7.43 (m, 5H), 7.35 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 7.6 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 3.89 (s, 3H), 3.22 (t, J = 8.0 Hz, 2H), 2.97 (s, 3H), 2.91 (t, J = 6.9 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₃ F ₃ N ₂ O ₆ S ₂ [M+H] ⁺ 557.1022, found 557.1027.

Embodiment 210

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-3-(trifluoromethoxy)-4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-60)

Synthesis of Compound C-60

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 4-bromo-2-(trifluoromethoxy)phenylacetic acid to obtain compound C-60: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.22 (s, 1H), 9.76 (s, 1H), 8.77 (s, 1H), 7.96 (dd, J = 8.0, 1.7 Hz, 1H), 7.84 (s, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.61 (d, J = 2.6 Hz, 1H), 7.53-7.46 (m, 3H), 7.34 (d, J = 7.9 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 3.30 (t, J = 7.2 Hz, 2H), 2.99 (t, J = 7.4 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₄ H ₂₀ F ₆ N ₂ O ₆ S ₂ [M+H] ⁺ 611.0740, found 611.0746.

Embodiment 211

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-6-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)nicotinamide (Compound C-61)

Synthesis of compound C-61

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 2-(5-bromopyridin-2-yl)acetic acid to prepare compound C-61: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.25 (s, 1H), 9.23 (s, 2H), 9.00 (d, J = 2.3 Hz, 1H), 8.20 (dd, J = 8.1, 2.4 Hz, 1H), 7.62 (d, J = 2.6 Hz, 1H), 7.52-7.42 (m, 4H), 7.33 (d, J = 7.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 3.44 (t, J = 7.3 Hz, 2H), 3.13 (t, J = 7.3 Hz, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₀ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 528.0869, found 528.0876.

Embodiment 212

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-3-nitro-4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-62)

Synthesis of compound C-62

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 2-(4-bromo-2-nitrophenyl)acetic acid to obtain compound C-62: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.35(s,1H),9.79(s,1H),8.81(s,1H),8.51(d,J＝1.9Hz,1H),8.21(dd,J＝8.1,1.9Hz,1H),7.73(d,J＝8.1Hz,1H),7.62(d,J＝2.6Hz,1H),7.51(dd,J＝8.7,2.5Hz,1H),7.48(d,J＝8.8Hz,2H),7.33(d,J＝7.9Hz,2H),6.88(d,J＝8.7Hz,1H),3.37(d,J＝6.8Hz,2H),3.21(t,J＝7.4Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₀ F ₃ N ₃ O ₇ S ₂ [M+H] ⁺ 572.0768, found 572.0771.

Embodiment 213

3-Fluoro-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(2-(4-(trifluoromethoxy)phenyl)thio)ethyl)benzamide (Compound C-63)

Synthesis of compound C-63

Referring to the method of Example 201, intermediate I-18 was replaced by intermediate II-18 to obtain compound C-63: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.36(s,1H),9.99(s,1H),8.87(s,1H),7.76(dd,J＝7.8,1.7Hz,1H),7.72(dd,J＝10.8,1.7Hz,1H),7.53(d,J＝7.7Hz,1H),7.48(d,J＝8.9Hz,2H),7.34(d,J＝7.9Hz,2H),7.29(d,J＝8.3Hz,1H),6.78(d,J＝11.4Hz,1H),3.31(d,J＝7.9Hz,2H),3.00(t,J＝7.4Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₁₉ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 563.0728, found 563.0726.

Embodiment 214

N-(3-(4-fluorophenyl)sulfonamido)-5-hydroxyphenyl)-4-(2-(4-(trifluoromethoxy)phenyl)thioethyl)benzoyl Amine (Compound C-64)

Synthesis of intermediate III-37

Referring to the method of Example 105, methylsulfonic anhydride was replaced with 4-fluorobenzenesulfonyl chloride to obtain intermediate III-37: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.19 (s, 1H), 7.87-7.77 (m, 2H), 7.48-7.37 (m, 2H), 6.38 (s, 1H), 6.35 (s, 2H), 5.48 (s, 2H).

Synthesis of intermediate III-38

The intermediate III-33 (120 mg, 0.35 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), and oxalyl chloride (45 μL, 0.53 mmol) was added dropwise under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature for reaction for 2 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added dropwise to an anhydrous tetrahydrofuran (2 mL) solution of the intermediate III-37 (127 mg, 0.37 mmol) and pyridine (28 μL, 0.53 mmol) under an ice bath. After the addition was completed, the temperature was raised to room temperature for reaction for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 3-4, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (15 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate III-38 (light yellow solid, 157 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 10.34 (s, 1H), 7.90–7.82 (m, 4H), 7.75 (d, J = 6.0 Hz, 2H), 7.52–7.38 (m, 6H), 7.33 (d, J = 8.5 Hz, 2H), 6.96 (s, 1H), 2.97 (t, J = 7.6 Hz, 2H), 2.44 (s, 2H).

Synthesis of Compound C-64

Referring to the method of Example 105, intermediate II-68 was replaced by intermediate III-38 to prepare compound C-64: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.18 (s, 1H), 10.06 (s, 1H), 9.48 (s, 1H), 7.94-7.79 (m, 4H), 7.55-7.27 (m, 8H), 7.11 (s, 1H), 7.02 (s, 1H), 6.31 (s, 1H), 3.32-3.31 (m, 2H), 2.96 (t, J=7.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₂ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 607.0985, found 607.0989.

Embodiment 215

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenethyl)sulfonyl)benzamide (Compound C-65)

Synthesis of intermediate III-39

Intermediate III-1 (250 mg, 1.12 mmol) and triphenylphosphine (413 mg, 1.57 mmol) were added to dichloromethane (4 mL), and carbon tetrabromide (560 mg, 1.69 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature for reaction for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate III-39 (white solid, 335 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.63 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.5 Hz, 2H), 3.60 (t, J = 7.4 Hz, 2H), 3.23 (t, J = 7.3 Hz, 2H).

Synthesis of intermediate III-40

4-Bromophenylsulfonic acid sodium salt dihydrate (388 mg, 1.39 mmol) was added to anhydrous N,N-dimethylformamide (2 mL). Under argon protection, a solution of intermediate III-39 (330 mg, 1.16 mmol) in N,N-dimethylformamide (1 mL) was added under ice bath. After the addition was completed, the temperature was raised to 80 °C and reacted for 12 hours. After the reaction, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with water (15 mL x 2) and saturated brine (15 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate III-40 (white solid, 305 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.77 (dd, J = 20.2, 8.6 Hz, 4H), 7.58 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.1 Hz, 2H), 3.42–3.34 (m, 2H), 3.16–3.08 (m, 2H). ESI-MS: m/z 446.9 [M+Na] ⁺ .

Synthesis of compound C-65

Referring to the method of Example 89, intermediate II-41 was replaced by intermediate III-40 to prepare compound C-65: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.35 (s, 1H), 9.39 (s, 1H), 8.95 (s, 1H), 8.15 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 2.4 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.51 (d, 1H), 7.40 (d, J = 8.2 Hz, 2H), 6.88 (d, J = 8.7 Hz, 1H), 3.80 (t, 2H), 3.00 (t, J = 9.4 Hz, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₆ S ₃ [M+H] ⁺ 575.0587, found 575.0585.

Embodiment 216

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenethyl)sulfonyl)benzamide (Compound C-66)

Synthesis of Compound C-66

Referring to the method of Example 215, the intermediate III-1 was replaced with 4-trifluoromethoxyphenylethanol to obtain compound C-66: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 9.71 (s, 1H), 8.81 (s, 1H), 8.15 (d, J = 7.8 Hz, 2H), 8.05 (d, J = 8.1 Hz, 2H), 7.64 (s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 8.5 Hz, 1H), 3.77 (t, 2H), 2.98 (s, 3H), 2.93 (t, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₃ N ₂ O ₇ S ₂ [M+H] ⁺ 559.0815, found 559.0818.

Embodiment 217

3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)phenethyl)sulfonyl)benzamide (Compound C-67)

Synthesis of intermediate III-41

Intermediate III-24 (593 mg, 1.5 mmol) was added to dichloromethane (15 mL), and m-chloroperbenzoic acid (mCPBA) (1.22 g, 6 mmol) was added in batches under ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 12 hours. Saturated sodium thiosulfate solution (20 mL) and 1 M sodium hydroxide solution (10 mL) were added to the reaction solution to quench, and the mixture was extracted with dichloromethane (15 mL x 3). The organic phases were combined and washed with saturated brine (20 mL x 1). The solvent was evaporated under reduced pressure, and the residue was washed with column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain a crude intermediate III-41 (white solid, 599 mg), which was used directly in the next step without further purification.

Synthesis of compound C-67

Referring to the method of Example 200, intermediate III-32 was replaced with intermediate III-41 to obtain compound C-67: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.36 (s, 1H), 9.84 (s, 1H), 8.78 (s, 1H), 8.01-7.88 (m, 3H), 7.61 (d, J = 2.6 Hz, 1H), 7.51 (dd, J = 8.7, 2.6 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.21 (d, J = 7.7 Hz, 2H), 6.88 (d, J = 8.7 Hz, 1H), 3.84 (t, J = 7.6 Hz, 2H), 3.02 (t, J = 7.7 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₇ S ₂ [M+H] ⁺ 577.0721, found 577.0722.

Embodiment 218

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-(2-((4-(trifluoromethoxy)phenyl)sulfonyl)ethyl)benzamide (Compound C-68)

Synthesis of compound C-68

Referring to the method of Example 217, intermediate III-24 was substituted with intermediate III-32 to obtain compound C-68: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.03(s,1H),9.71(s,1H),8.72(s,1H),8.06(d,J＝8.8Hz,2H),7.83(d,J＝8.4Hz,2H),7.64(d,J＝7.9Hz,2H),7.61(d,J＝2.5Hz,1H),7.48(dd,J＝8.8,2.6Hz,1H),7.35(d,J＝8.4Hz,2H),6.84(d,J＝8.8Hz,1H),3.80(t,J＝8.1Hz,2H),2.99(t,J＝8.5Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₇ S ₂ [M+H] ⁺ 559.0815,found 559.0815.

Embodiment 219

3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-((4-(trifluoromethoxy)phenyl)sulfonyl)ethyl)benzamide (Compound C-69)

Synthesis of compound C-69

Referring to the method of Example 217, intermediate III-24 was replaced by intermediate III-35 to obtain compound C-69: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.09(s,1H),9.75(s,1H),8.75(s,1H),8.06(d,J＝8.9Hz,2H),7.71–7.66(m,2H),7.64(d,J＝7.9Hz,2H),7.60(d,J＝2.6Hz,1H),7.48(dd,J＝8.8,3.0Hz,1H),7.46(d,J＝8.0Hz,1H),6.85(d,J＝8.8Hz,1H),3.78(t,J＝7.6Hz,2H),3.01(t,J＝8.8Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₀ F ₄ N ₂ O ₇ S ₂ [M+H] ⁺ 577.0721,found 577.0728.

Embodiment 220

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenethyl)amino)benzamide hydrochloride (Compound C-70)

Synthesis of intermediate III-42

The intermediate 4-trifluoromethylthiophenylacetic acid (300 mg, 1.27 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), and oxalyl chloride (161 μL, 1.91 mmol) was added dropwise under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature for reaction for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added dropwise to an anhydrous tetrahydrofuran (2 mL) solution of ethyl 4-aminobenzoate (231 mg, 1.40 mmol) and pyridine (153 μL, 1.91 mmol) under an ice bath. After the addition was completed, the temperature was raised to room temperature for reaction for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 3-4, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (15 mL x 1) and saturated brine (15 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate III-42 (white solid, 347 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.57(s,1H),7.92(d,J＝8.7Hz,2H),7.73(d,J＝8.8Hz,2H),7.69(d,J＝8.1Hz,2H),7.50(d,J＝8.1Hz,2H),4.28(q,J＝7.1Hz,2H),3.79(s,2H),1.31(t,J＝7.1Hz,3H).ESI-MS:m/z 382.1[MH] ^- .

Synthesis of intermediate III-43

The intermediate III-42 (347 mg, 0.91 mmol) was added into a dry three-necked flask, and anhydrous tetrahydrofuran (3 mL) was added to dissolve under argon protection. 1 M borane-tetrahydrofuran complex solution (2.7 mL, 2.72 mmol) was added dropwise under ice bath. After the addition was completed, the temperature was slowly raised to room temperature and reacted for 12 hours. After the reaction was completed, ice water (20 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate III-43 (white solid, 220 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.69 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 8.1 Hz, 2H), 6.62 (d, J = 8.6 Hz, 3H), 4.21 (q, J = 7.1 Hz, 2H), 3.36 (d, J = 6.4 Hz, 2H), 2.92 (t, J = 7.2 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).

Synthesis of intermediate III-44

Intermediate III-43 (220 mg, 0.60 mmol) and 4-dimethylaminopyridine (15 mg, 0.12 mmol) were added to dichloromethane (2 mL), and then triethylamine (124 μL, 0.89 mmol) and di-tert-butyl dicarbonate (274 μL, 1.19 mmol) were added in sequence. After the addition was completed, the mixture was reacted at room temperature for 24 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate III-44 (colorless oily liquid, 141 mg): ¹ H NMR (300MHz, CDCl ₃ ) δ8.00 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 7.9 Hz, 2H), 7.22 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 3.96 (t, J = 7.5 Hz, 2H), 2.92 (t, J = 7.4 Hz, 2H), 1.43 (s, 9H), 1.40 (t, J = 7.1 Hz, 3H).

Synthesis of intermediate III-45

The intermediate III-44 (130 mg, 0.28 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), and a 1 M sodium hydroxide aqueous solution (1 mL) was added dropwise, and the mixture was reacted at 60°C for 4 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, and a 2 N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3. A solid precipitated, which was filtered, and the filter cake was washed with water (2 mL) and n-hexane (3 mL). The obtained solid was dried to constant weight to obtain the intermediate III-45 (off-white solid, 114 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.72(s,1H),7.87(d,J＝8.5 Hz, 2H), 7.62 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 3.95 (t, J = 7.1 Hz, 2H), 2.85 (t, J = 7.0 Hz, 2H), 1.34 (s, 9H). ESI-MS: m/z 464.1 [M + Na] ⁺ .

Synthesis of compound C-70

Referring to the method of Example 23, 4-trifluoromethylthiobenzoic acid was replaced with intermediate III-45 to obtain compound C-70: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.68 (s, 1H), 8.68 (s, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 2.5 Hz, 1H), 7.55-7.43 (m, 3H), 6.84 (d, J = 8.7 Hz, 1H), 6.68 (d, J = 8.7 Hz, 2H), 5.29 (s, 2H), 3.38 (t, J = 7.2 Hz, 2H), 2.97 (s, 3H), 2.93 (t, J = 7.1 Hz, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₂ F ₃ N ₃ O ₄ S ₂ [M+H] ⁺ 526.1077, found 526.1075.

Embodiment 221

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenethyl)amino)benzamide hydrochloride (Compound C-71)

Synthesis of compound C-71

Referring to the method of Example 220, 4-trifluoromethylthiophenylacetic acid was replaced with 4-trifluoromethoxyphenylacetic acid to prepare compound C-71: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.67 (s, 1H), 8.67 (s, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 7.50–7.38 (m, 3H), 7.30 (d, J = 8.1 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 6.67 (d, J = 8.7 Hz, 2H), 5.19 (s, 2H), 3.35 (t, J = 7.3 Hz, 2H), 2.97 (s, 3H), 2.90 (t, J = 7.2 Hz, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₂ F ₃ N ₃ O ₅ S[M-HCl+H] ⁺ 510.1311, found 510.1319.

Embodiment 222

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-2-(4-((trifluoromethyl)thio)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound C-72)

Synthesis of intermediate III-46

4-Trifluoromethylthiobenzaldehyde (233 mg, 1.13 mmol) and 6-bromo-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.94 mmol) were added to dichloromethane (4 mL), and glacial acetic acid (2 drops) was added. The mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (400 mg, 1.89 mmol) was added in portions under ice bath. After the addition was completed, the mixture was heated to room temperature and stirred for 12 hours. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added to the reaction solution to quench, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate III-46 (white solid, 233 mg): ¹ H NMR (400 MHz, Chloroform-d) δ7.64 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.25 (dd, J = 8.1, 2.1 Hz, 2H), 6.88 (d, J = 8.1 Hz, 2H), 3.73 (s, 2H), 3.59 (s, 2H), 2.91 (t, J = 5.9 Hz, 2H), 2.75 (t, J = 5.9 Hz, 2H).

Synthesis of compound C-72

Referring to the method of Example 89, intermediate II-41 was replaced by intermediate III-46 to obtain compound C-72: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 (s, 1H), 9.69 (s, 1H), 8.70 (s, 1H), 7.75-7.68 (m, 4H), 7.62 (d, J=2.5 Hz, 1H), 7.56 (d, J=7.8 Hz, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.17 (d, J=8.0 Hz,1H),6.85(d,J＝8.7Hz,1H),3.77(s,2H),3.65(s,2H),2.97(s,3H),2.92(t,J＝5.6Hz,2H),2.77–2.72(m,2H).HRMS(ESI)calcd.for C ₂ 5 H _{2 4} F ₃ N ₃ O ₄ S ₂ [M+H] ⁺ 552.1233,found 552.1238.

Embodiment 223

N-(2-Fluoro-4-hydroxy-5-(methylsulfonyl)phenyl)-2-(4-((trifluoromethyl)thio)benzyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound C-73)

Synthesis of compound C-73

Referring to the method of Example 222, intermediate I-18 was replaced by intermediate II-18 to prepare compound C-73: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 9.87 (s, 1H), 8.88 (s, 1H), 7.74 (s, 1H), 7.73-7.68 (m, 3H), 7.56 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 1H), 7.17 (d, J = 8.1 Hz, 1H), 6.77 (d, J = 11.4 Hz, 1H), 3.77 (s, 2H), 3.65 (s, 2H), 2.96 (s, 3H), 2.91 (t, J = 5.6 Hz, 2H), 2.76-2.72 (m, 2H). HRMS (ESI) calcd. for C ₂₅ H ₂₃ F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 570.1144, found 570.1151.

Embodiment 224

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(3-(4-((trifluoromethyl)thio)phenoxy)propyl)benzamide (Compound C-74)

Synthesis of compound C-74

Referring to the method of Example 165, 4-bromophenylethanol was replaced by 4-bromophenylpropanol to prepare compound C-74: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 9.09 (s, 2H), 7.87 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.9 Hz, 3H), 7.49 (dd, J = 8.8, 2.5 Hz, 1H), 7.37 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 4.05 (t, J = 6.2 Hz, 2H), 2.97 (s, 3H), 2.82 (t, J = 7.7 Hz, 2H), 2.08 (p, J = 6.9 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₃ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 541.1073, found 541.1104.

Embodiment 225

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((3-(4-(trifluoromethoxy)phenyl)propyl)thio)benzamide (Compound C-75)

Synthesis of compound C-75

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced with 4-trifluoromethoxyphenylpropionic acid to obtain compound C-75: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.04(s,1H),9.39(s,2H),7.87(d,J＝8.5Hz,2H),7.83(d,J＝5.2Hz,1H),7.80(d,J＝5.2Hz,1H),7.67(d,J＝2.5Hz,1H),7.40(d,J＝2.9Hz,2H),7.37(d,J＝3.3Hz,3H),7.34(s,2H),7.29(dd,J＝8.9,1.1Hz,2H),6.68(d,J＝8.7Hz,1H),3.07(t,J＝7.2Hz,2H),2.78(t,J＝7.6Hz,2H),1.92(p,J＝7.4Hz,3H).HRMS(ESI)calcd.for C ₂₉ H ₂₄ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 621.1136, found 621.1130.

Embodiment 226

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-4-((3-(4-(trifluoromethoxy)phenyl)propyl)thio)benzamide (Compound C-76)

Synthesis of Compound C-76

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethoxyphenylpropionic acid, and intermediate I-3 was replaced by intermediate I-18 to obtain compound C-76: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.02(s,1H),9.66(s,1H),8.71(s,1H),7.86(d,J＝8.3Hz,2H),7.62(d,J＝2.5Hz,1H),7.48(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.8Hz,2H),7.33(d,J＝6.8Hz,2H),7.31(d,J＝6.3Hz,2H),6.85(d,J＝8.7Hz,1H),3.01(t,J＝7.1Hz,2H),2.97(s,3H),2.79(t,J＝7.5Hz,2H),1.91(p,J＝7.4Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 541.1073, found 541.1075.

Embodiment 227

3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((3-(4-(trifluoromethoxy)phenyl)propyl)thio)benzamide (Compound C-77)

Synthesis of intermediate III-47

4-Trifluoromethoxybenzenepropionic acid (400 mg, 1.71 mmol) was added to anhydrous tetrahydrofuran (4 mL), sodium borohydride (130 mg, 3.41 mmol) was added in batches under an ice bath, and stirring was continued at 0°C for 10 minutes. After the bubbles stopped being generated, boron trifluoride ether (222 μL, 1.80 mmol) was added dropwise. After the dropwise addition, the temperature was slowly raised to room temperature for 8 hours. After the reaction was completed, water (20 mL) was added to the reaction solution to quench, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain intermediate III-47 (light yellow oily liquid, 379 mg).

Synthesis of compound C-77

Referring to the method of Example 168, the intermediate III-12 was replaced by the intermediate III-47, 4-bromothiophenol was replaced by 4-bromo-2-fluorothiophenol, and the intermediate I-3 was replaced by the intermediate I-18 to obtain compound C-77: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.11(s,1H),9.69(s,1H),8.70(s,1H),7.78(d,J＝8.9Hz,2H),7.61(s,1H),7.55–7.45(m,2H),7.33(d,J＝9.2Hz,2H),7.27(d,J＝7.9Hz,2H),6.86(d,J＝8.7Hz,1H),3.07(t,J＝7.1Hz,2H),2.97(s,3H),2.77(t,2H),1.97–1.85(m,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₂ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 559.0979,found 559.0979.

Embodiment 228

3-Fluoro-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((3-(4-(trifluoromethoxy)phenyl)propyl)thio)benzamide (Compound C-78)

Synthesis of compound C-78

Referring to the method of Example 168, the intermediate III-12 was replaced by the intermediate III-47, 4-bromothiophenol was replaced by 4-bromo-2-fluorothiophenol, and the intermediate I-3 was replaced by the intermediate II-18 to obtain compound C-78: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.37(s,1H),10.00(s,1H),8.90(s,1H),7.82–7.73(m,2H),7.52(t,J＝8.1Hz,1H),7.35(d,J＝8.6Hz,2H),7.27(d,J＝8.2Hz,3H),6.77(d,J＝11.4Hz,1H),3.07(t,J＝7.2Hz,2H),2.95(s,3H),2.77(t,J＝7.6Hz,2H),1.91(p,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₁ F ₅ N ₂ O ₅ S ₂ [M+H] ⁺ 577.0885,found 577.0884.

Embodiment 229

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(3-(4-(trifluoromethyl)thiophenyl)thiopropyl)benzamide (Compound C-79)

Synthesis of intermediate III-48

4-Bromophenylpropanol (645 mg, 3.0 mmol) and triphenylphosphine (944 mg, 3.6 mmol) were added to dichloromethane (10 mL), and carbon tetrabromide (1.29 g, 3.9 mmol) was added in batches under an ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate III-48 (white solid, 635 mg).

Synthesis of intermediate III-49

Cuprous iodide (64 mg, 0.34 mmol), potassium carbonate (926 mg, 6.71 mmol) and elemental sulfur (322 mg, 10.07 mmol) were added to a dry Schlenk tube, and then an argon gas protection was added to the intermediate III-28 (1.02 g, 3.36 mmol) in N, N-dimethylformamide (8 mL) solution. After the addition was completed, the temperature was raised to 90 ° C for 8 hours. After the reaction was completed, the system was cooled to room temperature, and sodium borohydride (380 mg, 10.07 mmol) was added in batches under an ice bath. After the addition was completed, the system was raised to 40 ° C for 2 hours. After the reaction was completed, the system was cooled to room temperature, and then the intermediate III-48 (839 mg, 3.02 mmol) in N, N-dimethylformamide (2 mL) solution was added. After the addition was completed, the temperature was raised to 70 ° C and the reaction was continued for 6 hours. After the reaction was completed, water (100 mL) was added to the reaction solution for dilution, and ethyl acetate (20 mL x 3) was used for extraction. The organic phase was washed with water (20 mL x 2) and saturated brine (20 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 150:1) to obtain intermediate III-49 (white solid, 495 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.52 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 7.1 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 2.93 (t, J = 7.3 Hz, 2H), 2.78–2.69 (m, 2H), 2.03–1.92 (m, 2H).

Synthesis of compound C-79

Referring to the method of Example 89, intermediate II-41 was replaced with intermediate III-49 to obtain compound C-79: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.01(s,1H),9.64(s,1H),8.69(s,1H),7.86(d,J＝8.0Hz,2H),7.65–7.51(m,3H),7.48(dd,J＝8.3,2.5Hz,1H),7.41(d,J＝8.1Hz,2H),7.34(d,J＝8.0Hz,2H),6.84(d,J＝8.7Hz,1H),3.05(t,J＝7.2Hz,2H),2.96(s,3H),2.80(t,J＝7.6Hz,2H),2.00–1.84(m,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₄ S ₃ [M+H] ⁺ 557.0845,found 557.0851.

Embodiment 230

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-(3-((4-(trifluoromethoxy)phenyl)thio)propyl)benzamide (compound C-80)

Synthesis of Compound C-80

Referring to the method of Example 201, the intermediate III-34 was replaced with 4-bromophenylpropanol to obtain compound C-80: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.04(s,1H),9.69(s,1H),8.70(s,1H),7.87(d,J＝8.5Hz,2H),7.61(d,J＝2.6Hz,1H),7.48(dd,J＝8.8,2.6Hz,1H),7.39(d,J＝8.5Hz,2H),7.34(d,J＝8.7Hz,2H),7.27(d,J＝8.9Hz,2H),6.85(d,J＝8.7Hz,1H),3.06(t,J＝7.2Hz,2H),2.97(s,3H),2.77(t,J＝7.7Hz,2H),1.91(p,J＝7.6Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 541.1073, found 541.1073.

Embodiment 231

3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(3-((4-(trifluoromethoxy)phenyl)thio)propyl)benzamide (Compound C-81)

Synthesis of compound C-81

Referring to the method of Example 200, 4-bromophenylacetic acid was replaced with 3-(2-fluoro-4-bromophenyl)propionic acid to obtain compound C-81: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.09(s,1H),9.72(s,1H),8.71(s,1H),7.79–7.69(m,2H),7.61(d,J＝2.5Hz,1H),7.48(dd,J＝8.7,2.6Hz,1H),7.47–7.41(m,3H),7.32(d,J＝8.3Hz,2H),6.86(d,J＝8.7Hz,1H),3.04(t,J＝7.2Hz,2H),2.97(s,3H),2.82(t,J＝7.5Hz,2H),1.89(p,J＝7.3Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₂ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 559.0979,found 559.0985.

Embodiment 232

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-2-(4-((trifluoromethyl)thio)phenethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound C-82)

Synthesis of intermediate III-50

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced with 4-trifluoromethylthiophenylacetic acid to obtain Intermediate III-50: ¹ H NMR (400 MHz, Chloroform-d) δ7.69 (d, J = 8.3 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 4.25 (t, J = 6.7 Hz, 2H), 3.01 (t, J = 6.7 Hz, 2H), 2.46 (s, 3H).

Synthesis of compound C-82

Referring to the method of Example 89, 4-trifluoromethylthiophenol was replaced by 6-bromo-1,2,3,4-tetrahydroisoquinoline, and 4-bromo-2-trifluoromethylbenzyl bromide was replaced by intermediate III-50 to obtain compound C-82: ¹ H NMR (400 MHz, DMSO- _d6 ) δ10.03(s,1H),9.70(s,1H),8.71(s,1H),7.73(d,J＝8.3Hz,2H),7.66(d,J＝7.8Hz,2H),7.62(d,J＝2.6Hz,1H),7.50(dd,J＝8.7,2.5Hz,1H),7.47(d,J＝8.1Hz,2H),7.22(d,J＝7.9Hz,1H), _6.86 (d,J _＝ 8.7Hz,1H ₎ ,3.83( _s ,2H),3.33(s,2H),3.02–2.83(m, _3H ).HRMS(ESI)calcd.for _{C26H26F3N3O4S2} [M+H] ⁺ 566.1395,found 566.1409.

Embodiment 233

N-(4-hydroxy-3-(methylsulfonylamino)phenyl)-2-(4-((trifluoromethyl)thio)phenethyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound C-83)

Synthesis of compound C-83

Referring to the method of Example 89, 4-trifluoromethylthiophenol was replaced by 6-bromo-1,2,3,4-tetrahydroisoquinoline, 4-bromo-2-trifluoromethylbenzyl bromide was replaced by intermediate III-50, and intermediate I-18 was replaced by II-18 to obtain compound C-83: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.37(s,1H),9.91(s,1H),8.90(s,1H),7.75(d,J＝8.5Hz,2H),7.67(d,J＝7.9Hz,2H),7.48(d,J＝8.2Hz,2H),7.32–7.20(m,2H),6.78(d,J＝11.4Hz,1H),3.97(s,2H),3.36(s,2H),3.10–2.96(m,6H),2.95(s,3H).HRMS(ESI)calcd.for C _{2 6} H _{2 5} F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 584.1295,found 584.1305.

Embodiment 234

N-(5-(3-([1,1'-biphenyl]-4-yl)ureido)-2-hydroxyphenyl)-4-fluorobenzenesulfonamide (Compound D-1)

Synthesis of intermediate IV-1

4-Phenylbenzoic acid (300 mg, 1.5 mmol) was added to dichloromethane (4 mL), and triethylamine (417 μL, 3 mmol) was added. The mixture was stirred at room temperature for 15 minutes. Diphenylphosphoryl azide (DPPA) (294 μL, 1.36 mmol) was added dropwise under an ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate IV-1 (white solid, 253 mg).

Synthesis of intermediate IV-2

The intermediate IV-1 (253 mg, 1.13 mmol) was added to toluene (3 mL), and the temperature was raised to 80 ° C for 4 hours. After the reaction was completed, the system was cooled to room temperature, and the intermediate I-16 (470 mg, 1.19 mmol) was added to the reaction solution in batches. After the addition was completed, the reaction was carried out at room temperature for 6 hours. After the reaction was completed, a solid precipitated, which was filtered and the filter cake was purified by beating (n-hexane/ether = 10: 1). The obtained solid was dried to constant weight to obtain the intermediate IV-2 (white solid, 667 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.06(s,1H),8.62(s,1H),8.57(s,1H),7.80(dd,J＝8.8,5.2Hz,2H),7.64(d,J＝7.5Hz,2H),7.60(d,J＝8.9Hz,2H),7.52(d,J＝8.7Hz,2H),7.48–7.43(m,2H),7.39(d,1H),7.32(t,J＝7.3Hz,1H),7.25(d,J＝2.2Hz,1H),7.20–7.13(m,2H),6.79(d,J＝8.7Hz,1H),0.92(s,9H),0.12(s,6H).ESI-MS:m/z 590.2[MH] ^- .

Synthesis of compound D-1

Intermediate IV-2 (150 mg, 0.25 mmol) and triethylamine trihydrofluoride (62 μL, 0.38 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol = 100:1) to obtain compound D-1 (white solid, 106 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.31(s,1H),9.25(s,1H),8.59(s,1H),8.48(s,1H),7.81(dd,J＝8.8,5.2Hz,2H),7.63(d,J＝7.5Hz,2H),7.59(d,J＝8.9Hz,2H),7.52(d,J＝8.7Hz,2H),7.43(t,J＝7.7Hz,2H),7.37(t,J＝8.9Hz,2H),7.34–7.26(m,2H),7.09(dd,J＝8.7,2.5Hz,1H),6.65(d,J＝8.7Hz,1H).HRMS(ESI)calcd.for C _{2 5} H _{2 0} FN ₃ O ₄ S[M+H] ⁺ 478.1231,found 478.1230.

Embodiment 235

4-Fluoro-N-(2-hydroxy-5-(3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ureido)phenyl)benzenesulfonamide (Compound D-2)

Synthesis of compound D-2

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with 4'-trifluoromethyl-diphenyl-4-carboxylic acid to obtain compound D-2: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.26(s,2H),8.40(s,2H),7.81(dd,J＝8.5,5.2Hz,2H),7.37(t,J＝9.2Hz,4H),7.30(d,J＝2.1Hz,1H),7.14(d,J＝8.3Hz,2H),7.07(dd,J＝8.8,2.1Hz,1H),6.64(d,J＝8.7Hz,1H),2.64(t,J＝11.8Hz,1H),2.05(d,J＝26.6Hz,3H),1.88(t,J＝14.7Hz,3H),1.65(t,J＝11.3Hz,2H).HRMS(ESI)calcd.for C _{2 6} H _{1 9} F ₄ N ₃ O ₄ S[M+H] ⁺ 546.1105,found 546.1124.

Embodiment 236

4-Fluoro-N-(2-hydroxy-5-(3-(4'-((trifluoromethyl)thio)-[1,1'-biphenyl]-4-yl)ureido)phenyl)benzenesulfonamide (Compound D-3)

Synthesis of intermediate IV-3

4-Trifluoromethylthiophenol (200 mg, 1.03 mmol) and 4-dimethylaminopyridine (13 mg, 0.10 mmol) were added to dichloromethane (3 mL), and triethylamine (286 μL, 2.06 mmol) was added. Then trifluoromethanesulfonic anhydride (256 μL, 1.55 mmol) was added under ice bath. After the addition was complete, the mixture was heated to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to obtain intermediate IV-3 (colorless oily liquid, 287 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.77 (d, J＝8.7 Hz, 2H), 7.35 (d, J＝8.7 Hz, 2H).

Synthesis of intermediate IV-4

Intermediate IV-3 (256 mg, 0.79 mmol), 4-methoxycarbonylphenylboronic acid (170 mg, 0.94 mmol), sodium carbonate (126 mg, 1.19 mmol) and tetrakis(triphenylphosphine)palladium (46 mg, 0.04 mmol) were added to a three-necked flask and the mixture was stirred under argon atmosphere. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 200:1) to obtain intermediate IV-4 (white solid, 138 mg): ¹ H NMR (300MHz, CDCl ₃ )δ8.13(d, J＝8.1Hz,2H),7.75(d, J＝8.1Hz,2H),7.66(d, J＝8.1Hz,4H),3.95(s,3H).

Synthesis of intermediate IV-5

IV-4 (117 mg, 0.37 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), and a 1 M aqueous sodium hydroxide solution (1 mL) was added, and the temperature was raised to 60°C for reaction for 6 hours. After the reaction was completed, the system was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3, and a solid precipitated. The filter cake was washed with water (2 mL) and n-hexane (2 mL) in turn, and the obtained solid was dried to constant weight to obtain intermediate IV-5 (white solid, 80 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ13.06 (s, 1H), 8.05 (d, J＝8.3 Hz, 2H), 7.90 (d, J＝8.4 Hz, 2H), 7.83 (t, J＝8.7 Hz, 4H). ESI-MS: m/z 297.0 [MH] ^- .

Synthesis of compound D-3

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-5 to prepare compound D-3: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.31 (s, 1H), 9.25 (s, 1H), 8.67 (s, 1H), 8.51 (s, 1H), 7.86-7.79 (m, 4H), 7.76 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 8.6 Hz, 2H), 7.38 (t, J = 8.8 Hz, 2H), 7.33 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 8.7, 2.3 Hz, 1H), 6.66 (d, J = 8.6 Hz, 1H). HRMS (ESI) calcd. for C ₂₆ H ₁₉ F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 578.0826, found 578.0828.

Embodiment 237

N-(5-(3-(4-cyclohexylphenyl)ureido)-2-hydroxyphenyl)-4-fluorobenzenesulfonamide (Compound D-4)

Synthesis of compound D-4

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with 4-cyclohexylbenzoic acid to prepare compound D-4: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.25 (s, 1H), 9.22 (s, 1H), 8.37 (s, 1H), 8.34 (s, 1H), 7.81 (dd, J = 8.8, 5.2 Hz, 2H), 7.44-7.25 (m, 5H), 7.11 (d, J = 8.5 Hz, 2H), 7.06 (dd, 1H), 6.64 (d, J = 8.7 Hz, 1H), 2.47-2.36 (m, 1H), 1.85-1.66 (m, 5H), 1.44-1.19 (m, 5H). HRMS (ESI) calcd. for C ₂₅ H ₂₆ FN ₃ O ₄ S [M+H] ⁺ 484.1701, found 484.1705.

Embodiment 238

N-(5-(3-(4-(4,4-difluorocyclohexyl)phenyl)ureido)-2-hydroxyphenyl)-4-fluorobenzenesulfonamide (Compound D-5)

Synthesis of compound D-5

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate I-10 to obtain compound D-5: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.26(s,2H),8.40(s,2H),7.81(dd,J＝8.5,5.2Hz,2H),7.37(t,J＝9.2Hz,4H),7.30(d,J＝2.1Hz,1H),7.14(d,J＝8.3Hz,2H),7.07(dd,J＝8.8,2.1Hz,1H),6.64(d,J＝8.7Hz,1H),2.64(t,J＝11.8Hz,1H),2.05(d,J＝26.6Hz,3H),1.88(t,J＝14.7Hz,3H),1.65(t,J＝11.3Hz,2H).HRMS(ESI)calcd.for C ₂ 5 H _{2 4} F ₃ N ₃ O ₄ S[M+H] ⁺ 520.1512,found 520.1511.

Embodiment 239

N-(2-Hydroxy-5-(3-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)ureido)phenyl)methanesulfonamide (Compound D-6)

Synthesis of intermediate IV-6

4'-Trifluoromethylbiphenyl-4-carboxylic acid (200 mg, 0.75 mmol) was added to dichloromethane (2 mL), and triethylamine (209 μL, 1.5 mmol) was added. The mixture was stirred at room temperature for 15 minutes. Diphenylphosphoryl azide (DPPA) (146 μL, 0.68 mmol) was added dropwise under an ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate IV-6 (white solid, 100 mg).

Synthesis of intermediate IV-7

Intermediate IV-6 (100 mg, 0.24 mmol) was added to toluene (3 mL), and the temperature was raised to 100°C for 4 hours. After the reaction, the system was cooled to room temperature, and intermediate I-18 (151 mg, 0.38 mmol) was added to the reaction solution in batches, and the reaction was continued at room temperature for 6 hours. After the reaction, solids were precipitated, filtered, and the filter cake was purified by slurrying (hexane/ether=10:1). The solids were dried to constant weight to obtain intermediate IV-7 (white solid, 667 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ8.77(s,1H),8.67(s,1H),8.41(s,1H),7.88(d,J＝8.1Hz,2H),7.79(d,J＝8.3Hz,2H),7.70(d,J＝8.6Hz,2H),7.60(d,J＝8.7Hz,2H),7.49(d,J＝2.5Hz,1H),7.20(dd,1H),6.89(d,J＝8.8Hz,1H),3.04(s,3H),1.00(s,9H),0.25(s,6H).

Synthesis of compound D-6

Intermediate IV-7 (145 mg, 0.25 mmol) and triethylamine trihydrofluoride (61 μL, 0.38 mmol) were added to dichloromethane (4 mL) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (dichloromethane/methanol=40:1) to obtain compound D-6 (white solid, 91 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.28(s, 2H),8.70(s, 1H),8.53(s, 1H),7.86(d, J＝8.1Hz, 2H),7.77(d, J＝8.2Hz, 2H),7.68(d, J＝8.3Hz, 2H),7.58(d, J＝8.4Hz, 2H),7.33(d, J＝2.6Hz, 1H),7.16(dd, J＝8.4,2.2Hz, 1H),6.82(d, J＝8.7Hz, 1H),2.96(s, 3H).HRMS(ESI)calcd.for C ₂₁ H ₁₈ F ₃ N ₃ O ₄ S[M+H] ⁺ 466.1043, found 466.1045.

Embodiment 240

N-(5-(3-(4-(4,4-difluorocyclohexyl)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-7)

Synthesis of compound D-7

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate I-10 to obtain compound D-7: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.47 (s, 1H), 8.68 (s, 1H), 8.41 (s, 2H), 7.42-7.27 (m, 3H), 7.13 (d, J=8.2 Hz, 3H), 6.79 (d, J=8.6 Hz, 1H), 2.95 (s, 3H), 2.69-2.57 (m, 1H), 2.17–1.97 (m, 3H), 1.85 (d, J＝10.6 Hz, 3H), 1.71–1.53 (m, 2H). HRMS (ESI) calcd. for C ₂₀ H ₂₃ F ₂ N ₃ O ₄ S [M+H] ⁺ 440.1450, found 440.1447.

Embodiment 241

N-(2-Hydroxy-5-(3-(4-(2-((trifluoromethyl)thio)ethoxy)phenyl)ureido)phenyl)methanesulfonamide (Compound D-8)

Synthesis of intermediate IV-8

Methyl 4-hydroxybenzoate (152 mg, 1.0 mmol) and 1,2-dibromoethane (940 mg, 5.0 mmol) were added to N,N-dimethylformamide (5 mL), and potassium carbonate (276 mg, 2.0 mmol) was added in batches under stirring. The temperature was raised to 60 ° C for 6 hours. After the reaction, the system was cooled to room temperature, water (50 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with water (15 mL x 1) and saturated brine (15 mL x 1) in turn. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate IV-8 (white solid, 172 mg).

Synthesis of intermediate IV-9

Intermediate IV-8 (172 mg, 0.67 mmol) and sodium thiocyanate (80 mg, 1.00 mmol) were added to acetonitrile (4 mL) and the temperature was raised to 80 ° C for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude intermediate IV-9 (131 mg, yellow oily liquid), which was directly used in the next step without further purification.

Synthesis of intermediate IV-10

Intermediate IV-9 (131 mg, 0.56 mmol) and (trifluoromethyl)trimethylsilane (TMSCF ₃ ) (170 μL, 1.11 mmol) were added to anhydrous tetrahydrofuran (2 mL), and then a 1M tetrabutylammonium fluoride tetrahydrofuran solution (0.56 mL, 0.56 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added dropwise under ice bath. After the addition was completed, the temperature was slowly raised to room temperature for reaction for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 25:1) to obtain intermediate IV-10 (colorless oily liquid, 80 mg): ¹ H NMR (400 MHz, Chloroform-d) δ7.81 (ddd, J = 8.5, 2.1, 1.2 Hz, 1H), 7.76 (dd, J = 11.6, 2.0 Hz, 1H), 6.97 (t, J = 8.3 Hz, 1H), 4.33 (t, J = 6.6 Hz, 2H), 3.90 (s, 3H), 3.32 (t, J = 6.6 Hz, 2H).

Synthesis of intermediate IV-11

The intermediate IV-10 (80 mg, 0.29 mmol) was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL), and a 1M sodium hydroxide aqueous solution (1 mL) was added, and the temperature was raised to 60°C for 6 hours. After the reaction was completed, the system was cooled to room temperature, the organic solvent was evaporated under reduced pressure, and a 2N hydrogen chloride aqueous solution was added dropwise to the residue to adjust the pH to 2-3. Solids precipitated, filtered, and the filter cake was washed with water (2 mL) and n-hexane (2 mL) in turn. The obtained solid was dried to constant weight to obtain the intermediate IV-11 (white solid, 70 mg): ¹ H NMR (400 MHz, Chloroform-d) δ8.07 (d, J = 8.9 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 4.29 (t, J = 6.4 Hz, 2H), 3.30 (t, J = 6.5 Hz, 2H).

Synthesis of compound D-8

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-11 to obtain compound D-8: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.53 (s, 1H), 8.70 (s, 1H), 8.55 (s, 1H), 8.47 (s, 1H), 7.48 (dd, J = 13.8, 2.4 Hz, 1H), 7.29 (d, J = 2.6 Hz, 1H), 7.16–7.12 (m, 1H), 7.10 (d, J = 9.5 Hz, 1H), 7.04 (dd, J = 8.9, 2.2 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 4.25 (t, J = 6.0 Hz, 2H), 3.40 (t, J = 6.0 Hz, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₁₇ H ₁₈ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 466.0713, found 466.0719.

Embodiment 242

N-(5-(3-(3-fluoro-4-(2-((trifluoromethyl)thio)ethoxy)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-9)

Synthesis of compound D-9

Referring to the method of Example 241, 4-hydroxybenzoic acid methyl ester was replaced with 3-fluoro-4-hydroxybenzoic acid methyl ester to obtain compound D-9: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.53(s,1H),8.70(s,1H),8.55(s,1H),8.47(s,1H),7.48(dd,J＝13.8,2.4Hz,1H),7.29(d,J＝2.6Hz,1H),7.16–7.12(m,1H),7.10(d,J＝9.5Hz,1H),7.04(dd,J＝8.9,2.2Hz,1H),6.80(d,J＝8.7Hz,1H),4.25(t,J＝6.0Hz,2H),3.40(t,J＝6.0Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C ₁₇ H ₁₇ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 484.0619,found 484.0608.

Embodiment 243

N-(2-Hydroxy-5-(3-(4-((2-((trifluoromethyl)thio)ethyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-10)

Synthesis of intermediate IV-12

4-Trifluoromethoxybenzenesulfonyl chloride (1.13 g, 4.8 mmol) was added to N,N-dimethylformamide (10 mL), and tributylphosphine (3.6 mL, 14.4 mmol) was added dropwise under ice bath. After the addition was completed, the temperature was raised to 50°C for reaction for 30 minutes. After the disappearance of the raw material monitored by TLC, the system was cooled to room temperature, and then 2-bromoethanol (375 mg, 3.0 mmol) in N,N-dimethylformamide (2 mL) solution, potassium carbonate (662 mg, 4.8 mmol), and potassium iodide (50 mg, 0.3 mmol) were added in turn under ice bath. After the addition was completed, the reaction was carried out at 50°C for 6 hours. After the reaction, the system was cooled to room temperature, water (100 mL) was added to the reaction solution for dilution, and ethyl acetate was used for extraction (20 mL x 3). The organic phases were combined and washed with water (20 mL x 2) and saturated brine (20 mL x 1) in sequence. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate IV-12 (light yellow oily liquid, 580 mg).

Synthesis of intermediate IV-13

Intermediate IV-12 (580 mg, 2.75 mmol) and triphenylphosphine (1.08 g, 4.12 mmol) were added to dichloromethane (10 mL), and N-bromosuccinimide (733 mg, 4.12 mmol) was added in batches under ice bath. After the addition, the mixture was heated to room temperature for 8 hours. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 200:1) to obtain intermediate IV-13 (white solid, 286 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.97 (d, J = 8.5 Hz, 2H), 7.34 (d, J = 8.5 Hz, 2H), 3.91 (s, 3H), 3.29 (dd, J = 9.8, 5.8 Hz, 2H), 3.10 (dd, J = 9.8, 5.8 Hz, 2H).

Synthesis of compound D-10

Referring to the method of Example 241, intermediate IV-6 was replaced by IV-13 to obtain compound D-10: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.54 (s, 1H), 8.69 (s, 1H), 8.63 (s, 1H), 8.50 (s, 1H), 7.44 (d, J = 8.7 Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 2.6 Hz, 1H), 7.14 (dd, J = 8.7, 2.6 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 3.22–3.09 (m, 4H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₁₇ H ₁₈ F ₃ N ₃ O ₄ S ₃ [M+H] ⁺ 482.0490, found 482.0495.

Embodiment 244

N-(5-(3-(4-(cyclohexylmethyl)phenyl)ureido)-2-hydroxyphenyl)-4-fluorobenzenesulfonamide (Compound D-11)

Synthesis of intermediate IV-14

Referring to the method of Example 1, intermediate I-4 was replaced by intermediate I-39 to obtain intermediate IV-14: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.77 (s, 1H), 7.84 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 2.52 (d, J = 7.2 Hz, 2H), 1.67–1.49 (m, 6H), 1.23–1.09 (m, 3H), 0.99–0.84 (m, 2H). ESI-MS: m/z 217.1 [MH] ^- .

Synthesis of compound D-11

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-14 to obtain compound D-11: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.24(s,2H),8.36(d,J＝8.2Hz,2H),7.80(dd,J＝8.7,5.3Hz,2H),7.36(t,J＝8.9Hz,2H),7.31(d,J＝8.1Hz,3H),7.10–7.05(m,1H),7.03(d,J＝8.6Hz,2H),6.63(d,J＝8.7Hz,1H),2.38(d,J＝7.0Hz,2H),1.61(d,J＝10.8Hz,5H),1.49–1.38(m,1H),1.24–1.08(m,3H),0.96–0.82(m,2H).HRMS(ESI)calcd.for C _{2 6} H _{2 8} FN ₃ O ₄ S[M+H] ⁺ 498.1857, found 498.1849.

Embodiment 245

4-Fluoro-N-(2-hydroxy-5-(3-(4-((4-((trifluoromethyl)thio)benzyl)oxy)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-12)

Synthesis of compound D-12

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate II-2 to obtain compound D-12: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.27(s,1H),9.20(s,1H),8.35(s,1H),8.29(s,1H),7.80(dd,J＝8.8,5.3Hz,2H),7.75(d,J＝8.2Hz,2H),7.60(d,J＝8.1Hz,2H),7.40–7.31(m,4H),7.28(d,J＝2.4Hz,1H),7.05(dd,J＝8.7,2.4Hz,1H),6.94(d,J＝8.9Hz,2H),6.62(d,J＝8.7Hz,1H),5.15(s,2H).HRMS(ESI)calcd.for C _{2 7} H _{2 1} F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 608.0932,found 608.0931.

Embodiment 246

N-(2-Hydroxy-5-(3-(4-((4-((trifluoromethyl)thio)benzyl)oxy)phenyl)ureido)phenyl)methanesulfonamide (Compound D-13)

Synthesis of compound D-13

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate II-2 to prepare compound D-13: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.46 (s, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.1 Hz, 2H), 7.31 (dd, J = 14.5, 5.6 Hz, 3H), 7.13 (dd, J = 8.7, 2.3 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.79 (d, J = 8.7 Hz, 1H), 5.15 (s, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₀ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 528.0875, found 528.0879.

Embodiment 247

N-(5-(3-(4-((3-fluoro-4-(2-((trifluoromethyl)thio)ethoxy)benzyl)oxy)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-14)

Synthesis of Intermediate IV-15

Referring to the method of Example 241, methyl 4-hydroxybenzoate was replaced with methyl 3-fluoro-4-hydroxybenzoate to prepare Intermediate IV-15.

Synthesis of Intermediate IV-16

The intermediate IV-15 (282 mg, 1 mmol) was added to a dry three-necked bottle, and anhydrous tetrahydrofuran (5 mL) was added to dissolve under argon protection. 1M borane-tetrahydrofuran complex (2 mL, 2 mmol) was slowly added under ice bath. After the dropwise addition, the temperature was slowly raised to room temperature for 6 hours. After the reaction was completed, ice water (30 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in turn, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain the crude intermediate IV-16 (yellow oily liquid, 147 mg), which was directly used in the next reaction without further purification.

Synthesis of intermediate IV-17

The crude intermediate IV-16 (147 mg, 0.55 mmol), methyl 4-hydroxybenzoate (126 mg, 0.83 mmol) and triphenylphosphine (216 mg, 0.83 mmol) were added into a dry three-necked flask under argon protection, anhydrous tetrahydrofuran (2 mL) was added to dissolve, and a solution of diisopropyl azodicarboxylate (163 μL, 0.83 mmol) in anhydrous tetrahydrofuran (2 mL) was slowly added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate IV-17 (white solid, 117 mg): ¹ H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 8.9 Hz, 2H), 7.19 (dd, J = 11.6, 2.1 Hz, 1H), 7.13 (dd, J = 6.7, 1.7 Hz, 1H), 6.99-6.94 (m, 3H), 5.04 (s, 2H), 4.29 (t, J = 6.6 Hz, 2H), 3.89 (s, 3H), 3.29 (t, J = 6.6 Hz, 2H).

Synthesis of intermediate IV-18

The intermediate IV-17 (117 mg, 0.29 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), and a 1M aqueous sodium hydroxide solution (1 mL) was added. After the addition was completed, the temperature was raised to 60°C for 4 hours. After the reaction was completed, the system was cooled to room temperature, and a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3. Solids precipitated and were filtered. The filter cake was washed with water (2 mL) and ether (2 mL), and purified by slurrying (n-hexane/dichloromethane = 4:1). The obtained solid was dried to constant weight to obtain the intermediate IV-18 (white solid, 79 mg).

Synthesis of compound D-14

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-18 to obtain compound D-14: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.49(s,1H),8.73(s,1H),8.38(s,1H),8.31(s,1H),7.35–7.30(m,3H),7.29(d,J＝2.7Hz,1H),7.21(d,J＝5.3Hz,2H),7.13(dd,J＝8.7,2.6Hz,1H),6.92(d,J＝9.0Hz,2H),6.79(d,J＝8.7Hz,1H),4.99(s,2H),4.31(t,J＝6.0Hz,2H),3.44(t,J＝6.0Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₄ N ₃ O ₆ S ₂ [M+H] ⁺ 590.1037,found 590.1036.

Embodiment 248

N-(5-(3-(4-((3-fluoro-4-(2-((trifluoromethyl)thio)ethoxy)benzyl)oxy)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-15)

Synthesis of compound D-15

Referring to the method of Example 247, intermediate IV-8 was replaced by IV-13 to obtain compound D-15: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.67 (s, 1H), 8.39 (s, 1H), 8.32 (s, 1H), 7.41 (s, 4H), 7.32 (d, J = 9.0 Hz, 2H), 7.28 (d, J = 2.6 Hz, 1H), 7.13 (dd, J = 8.7, 2.6 Hz, 1H), 6.92 (d, J = 9.0 Hz, 2H), 6.79 (d, J = 8.7 Hz, 1H), 5.03 (s, 2H), 3.34-3.25 (m, 2H), 3.22-3.15 (m, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₄ H ₂₄ F ₃ N ₃ O ₅ S ₃ [M+H] ⁺ 588.0903, found 588.0899.

Embodiment 249

N-(2-Hydroxy-5-(3-(4-((4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-16)

Synthesis of compound D-16

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate II-64 to prepare compound D-16: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.27 (s, 1H), 8.94 (s, 1H), 8.59 (s, 1H), 8.48 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 7.35 (d, J = 8.3 Hz, 2H), 7.30 (d, J = 2.6 Hz, 1H), 7.15 (d, J = 8.7 Hz, 3H), 6.80 (d, J = 8.6 Hz, 1H), 5.08 (s, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₀ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 528.0869, found 528.0878.

Embodiment 250

N-(2-Hydroxy-5-(3-(4-((trifluoromethylphenoxy)methyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-17)

Synthesis of intermediate IV-19

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-trifluoromethylphenol to obtain Intermediate IV-19: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.99 (s, 1H), 7.96 (d, J = 7.9 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 5.29 (s, 2H).

Synthesis of compound D-17

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-19 to obtain compound D-17: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.51(s,1H),8.68(s,1H),8.58(s,1H),8.48(s,1H),7.65(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,2H),7.36(d,J＝8.5Hz,2H),7.31(d,J＝2.6Hz,1H),7.19(d,J＝8.5Hz,2H),7.15(dd,J＝8.7,2.6Hz,1H),6.81(d,J＝8.7Hz,1H),5.11(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{2 0} F ₃ N ₃ O ₅ S[M+H] ⁺ 496.1149,found 496.1133.

Embodiment 251

N-(2-Hydroxy-5-(3-(4-(trifluoromethoxyphenoxy)methyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-18)

Synthesis of intermediate IV-20

Referring to the method of Example 66, 4-trifluoromethylthiophenol was replaced by 4-trifluoromethoxyphenol to obtain Intermediate IV-20: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.97 (s, 1H), 7.96 (d, J = 8.1 Hz, 2H), 7.56 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 9.1 Hz, 2H), 5.21 (s, 2H).

Synthesis of compound D-18

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-20 to obtain compound D-18: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.50 (s, 1H), 8.66 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.45 (d, J = 8.6 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 2.7 Hz, 2H), 7.28 (s, 1H), 7.15 (dd, J = 8.7, 2.6 Hz, 1H), 7.10 (d, J = 9.2 Hz, 2H), 6.81 (d, J = 8.6 Hz, 1H), 5.03 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₀ F ₃ N ₃ O ₆ S[M+H] ⁺ 512.1098, found 512.1096.

Embodiment 252

N-(5-(3-(4-(2-fluoro-4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)ureido)-2-hydroxyphenyl)methylsulfonamide (Compound D-19)

Synthesis of intermediate IV-21

Referring to the method of Example 83, 3-fluoro-4-nitrophenol was replaced by 2-fluoro-4-nitrophenol, and 3-fluoro-4-(bromomethyl)benzoic acid methyl ester was replaced by 4-(bromomethyl)benzoic acid ethyl ester to prepare Intermediate IV-21.

Synthesis of compound D-19

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-21 to obtain compound D-19: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.50(s,1H),8.65(s,1H),8.59(s,1H),8.47(s,1H),7.65(dd,J＝10.9,2.2Hz,1H),7.52(d,J＝8.6Hz,1H),7.46(d,J＝8.6Hz,2H),7.42(t,J＝8.7Hz,1H),7.36(d,J＝8.6Hz,2H),7.30(d,J＝2.6Hz,1H),7.14(dd,J＝8.7,2.6 Hz,1H),6.80(d,J＝8.7Hz,1H),5.17(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C ₂₂ H ₁₉ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 546.0775,found 546.0767.

Embodiment 253

N-(5-(3-(4-((3-fluoro-4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-20)

Synthesis of intermediate IV-22

Referring to the method of Example 83, replacing methyl 3-fluoro-4-(bromomethyl)benzoate with ethyl 4-(bromomethyl)benzoate, intermediate IV-22 was prepared.

Synthesis of compound D-20

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-22 to obtain compound D-20: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.52(s,1H),8.68(s,1H),8.59(s,1H),8.48(s,1H),7.74–7.62(m,1H),7.46(d,J＝8.6Hz,2H),7.36(dd,J＝8.7,4.1Hz,2H),7.30(d,J＝2.6Hz,1H),7.19(dd,J＝11.1,2.6Hz,1H),7.14(dd,J＝8.7,2.6Hz,1H),7.00(dd,J＝8.8,2.5Hz,1H),6.80(d,J＝8.7Hz,1H),5.10(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 9} F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 546.0775, found 546.0764.

Embodiment 254

N-(5-(3-(4-(3-chloro-4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)ureido)-2-hydroxyphenyl)methylsulfonamide (Compound D-21)

Synthesis of intermediate IV-23

Referring to the method of Example 83, 3-fluoro-4-nitrophenol was replaced by 3-chloro-4-nitrophenol, and 3-fluoro-4-(bromomethyl)benzoic acid methyl ester was replaced by 4-(bromomethyl)benzoic acid ethyl ester to prepare Intermediate IV-23.

Synthesis of compound D-21

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-23 to obtain compound D-21: ¹ H NMR (400 MHz, DMSO) δ9.50 (s, 1H), 8.66 (s, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 7.79 (d, J = 8.7 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 2.7 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 2.6 Hz, 1H), 7.16-7.12 (m, 2H), 6.80 (d, J = 8.7 Hz, 1H), 5.12 (s, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ ClF ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 562.0480, found 562.0477.

Embodiment 255

N-(5-(3-(4-((2-chloro-4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Chem. Compound D-22)

Synthesis of intermediate IV-24

Referring to the method of Example 83, 3-fluoro-4-nitrophenol was replaced by 2-chloro-4-nitrophenol, and 3-fluoro-4-(bromomethyl)benzoic acid methyl ester was replaced by 4-(bromomethyl)benzoic acid ethyl ester to prepare Intermediate IV-24.

Synthesis of compound D-22

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-24 to obtain compound D-22: ¹ H NMR (400 MHz, DMSO) δ9.50 (s, 1H), 8.65 (s, 1H), 8.58 (s, 1H), 8.48 (s, 1H), 7.81 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 8.6, 2.3 Hz, 1H), 7.48-7.44 (m, 2H), 7.42-7.35 (m, 3H), 7.30 (d, J = 2.6 Hz, 1H), 7.14 (dd, J = 8.7, 2.6 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 5.20 (s, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ ClF ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 562.0480, found 562.0486.

Embodiment 256

N-(5-(3-(3-(3-fluoro-4-(4-(trifluoromethylthio)phenoxy)methyl)phenyl)ureido)-2-hydroxyphenyl)methylsulfonamide (Compound D-23)

Synthesis of compound D-23

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate II-55 to obtain compound D-23: ¹ H NMR (400 MHz, DMSO) δ9.53 (s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.53 (dd, J = 12.8, 2.1 Hz, 1H), 7.43 (t, J = 8.5 Hz, 1H), 7.30 (d, J = 2.6 Hz, 1H), 7.17 (d, J = 8.9 Hz, 2H), 7.15-7.10 (m, 2H), 6.80 (d, J = 8.7 Hz, 1H), 5.10 (s, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 546.0775, found 546.0760.

Embodiment 257

N-(5-(3-(2-fluoro-4-(4-(trifluoromethyl)thio)phenoxy)methyl)phenyl)ureido)-2-hydroxyphenyl)methylsulfonamide (Compound D-24)

Synthesis of Intermediate IV-25

Referring to the method of Example 89, 4-bromo-2-trifluoromethylbenzyl bromide was replaced by 3-fluoro-4-bromobenzyl bromide to obtain Intermediate IV-25: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.26 (s, 1H), 7.90 (t, J = 8.0 Hz, 1H), 7.66 (d, J = 5.9 Hz, 2H), 7.39 (t, J = 8.3 Hz, 2H), 7.20-7.16 (m, 2H), 5.27 (s, 2H).

Synthesis of Compound D-24

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-25 to obtain compound D-24: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.57 (s, 1H), 8.90 (s, 1H), 8.71 (s, 1H), 8.45 (d, J = 2.8 Hz, 1H), 8.17 (t, J = 8.4 Hz, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.34 (dd, J = 15.0, 2.3 Hz, 2H), 7.23 (d, J = 8.5 Hz, 1H), 7.19-7.11 (m, 3H), 6.82 (d, J = 8.7 Hz, 1H), 5.11 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 546.0775, found 546.0770.

Embodiment 258

N-(5-(3-(3-chloro-4-(4-(trifluoromethylthio)phenoxy)methyl)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-25)

Synthesis of intermediate IV-26

Referring to the method of Example 66, ethyl 4-(bromomethyl)benzoate was replaced with the crude intermediate II-40 to obtain intermediate IV-26.

Synthesis of compound D-25

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-26 to obtain compound D-25: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.55(s,1H),8.81(s,1H),8.68(s,1H),8.58(s,1H),7.80(d,J＝2.1Hz,1H),7.66(d,J＝8.7Hz,2H),7.49(d,J＝8.4Hz,1H),7.32(d,J＝2.6Hz,1H),7.29(dd,J＝8.4,2.1Hz,1H),7.18(d,J＝8.9Hz,2H),7.15(dd,J＝8.7,2.6Hz,1H),6.82(d,J＝8.6Hz,1H),5.14(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C _{2 2} H _{1 9} ClF ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 562.0480, found 562.0483.

Embodiment 259

N-(5-(3-(2-chloro-4-(4-(trifluoromethylthio)phenoxy)methyl)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-26)

Synthesis of compound D-26

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate II-52 to obtain compound D-26: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 9.27 (s, 1H), 8.71 (s, 1H), 8.21 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.7 Hz, 2H), 7.57 (d, J = 1.9 Hz, 1H), 7.38 (dd, J = 8.6, 2.0 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.22-7.15 (m, 3H), 6.83 (d, J = 8.7 Hz, 1H), 5.11 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 546.0775, found 546.0767.

Embodiment 260

N-(2-Hydroxy-5-(3-(6-(((trifluoromethyl)thio)phenoxy)methyl)pyridin-3-yl)ureido)phenyl)methanesulfonamide (Compound D-27)

Synthesis of intermediate IV-27

Referring to the method of Example 92, 2-methyl-5-bromopyrimidine was replaced with 2-methyl-5-bromopyridine to obtain Intermediate IV-27: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.05 (s, 1H), 8.30 (d, J=7.9 Hz, 1H), 7.64 (t, J=8.0 Hz, 3H), 7.18 (d, J=8.6 Hz, 2H), 5.33 (s, 2H).

Synthesis of compound D-27

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-27 to obtain compound D-27: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.58 (s, 1H), 8.81 (s, 1H), 8.71 (s, 1H), 8.66 (s, 1H), 8.60 (d, J = 2.6 Hz, 1H), 7.96 (dd, J = 8.5, 2.6 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 2.6 Hz, 1H), 7.20-7.13 (m, 3H), 6.82 (d, J = 8.7 Hz, 1H), 5.17 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C ₂₁ H ₁₉ F ₃ N ₄ O ₅ S ₂ [M+H] ⁺ 529.0822, found 529.0829.

Embodiment 261

N-(4-Fluoro-2-hydroxy-5-(3-(4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-28)

Synthesis of compound D-28

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate II-64, and intermediate I-3 was replaced by intermediate II-18 to obtain compound D-28: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.98 (s, 1H), 8.97 (s, 1H), 8.76 (s, 1H), 8.24 (d, J = 1.9 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.9 Hz, 2H), 6.75 (d, J = 12.1 Hz, 1H), 5.09 (s, 2H), 2.94 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 546.0775, found 546.0778.

Embodiment 262

N-(4-Fluoro-2-hydroxy-5-(3-(4-((4-(trifluoromethoxy)phenoxy)methyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-29)

Synthesis of compound D-29

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate IV-20, and intermediate I-3 was replaced by intermediate II-18 to obtain compound D-29: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 8.95 (s, 1H), 8.75(s,1H), 8.23(d, J＝1.9Hz,1H), 7.82(d, J＝8.9Hz,1H), 7.45(d, J＝8.6Hz,2H), 7.35(d, J＝8.6Hz,2H), 7.29(d, J＝8.8Hz,2H), 7.09(d, J＝9.2Hz,2H), 6.74(d, J＝12.1Hz,1H), 5.03(s,2H), 2.93(s,3H). HRMS(ESI) calcd. for C _{2 2} H _{1 9} F ₄ N ₃ O ₆ S[M+H] ⁺ 530.1003, found 530.1009.

Embodiment 263

N-(4-Fluoro-2-hydroxy-5-(3-(4-((4-(trifluoromethyl)phenoxy)methyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-30)

Synthesis of compound D-30

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate IV-19, and intermediate I-3 was replaced by intermediate II-18 to obtain compound D-30: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 8.96 (s, 1H), 8.75 (s, 1H), 8.24 (s, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 6.74 (d, J = 12.1 Hz, 1H), 5.11 (s, 2H), 2.93 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₁₉ F ₄ N ₃ O ₅ S[M+H] ⁺ 514.1054, found 514.1049.

Embodiment 264

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)piperidine-1-carboxamide (Compound D-31)

Synthesis of intermediate IV-28

The intermediate II-18 (60 mg, 0.18 mmol) was added to dichloromethane (2 mL), and N, N-diisopropylethylamine (47 μL, 0.27 mmol) was added, and phenyl chloroformate (34 μL, 0.27 mmol) was added under ice bath. After the addition was completed, the mixture was heated to room temperature for 4 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude compound IV-28, which was directly used in the next step without further purification.

Synthesis of intermediate IV-29

4-Trifluoromethylthiophenol (400 mg, 2.06 mmol), N-Boc-4-piperidinemethanol (665 mg, 3.09 mmol) and triphenylphosphine (756 mg, 2.88 mmol) were added to a dry three-necked flask, and anhydrous tetrahydrofuran (2 mL) was added under argon protection to dissolve. A solution of diisopropyl azodicarboxylate (566 μL, 2.88 mmol) in anhydrous tetrahydrofuran (2 mL) was slowly added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature for 12 hours. After the reaction was completed, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate IV-29 (white solid, 786 mg).

Synthesis of intermediate IV-30

The intermediate IV-29 (785 mg, 2 mmol) was added to a 4M hydrogen chloride-dioxane solution (2.5 mL, 10 mmol) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was purified by beating (ethyl acetate), and the obtained solid was dried to constant weight to obtain compound IV-30 (white solid, 608 mg): ¹ H NMR (400 MHz, Chloroform-d) δ9.77 (s, 1H), 9.49 (s, 1H), 7.59 (d, J = 8.7 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.89 (d, J = 5.9 Hz, 2H), 3.60 (d, J = 12.3 Hz, 2H), 2.96 (q, J = 12.1 Hz, 2H), 2.10 (d, J = 13.6 Hz, 3H), 1.87 (q, J = 13.1 Hz, 2H).

Synthesis of intermediate IV-31

Add intermediate IV-30 (65 mg, 0.2 mmol) to dichloromethane (1.5 mL), add N,N-diisopropylethylamine (94 μL, 0.54 mmol), stir at room temperature for 10 minutes, then add dichloromethane solution (1.5 mL) of crude intermediate IV-28 (0.18 mmol) under ice bath, stir at room temperature for 12 hours. After the reaction is completed, evaporate the solvent under reduced pressure, and purify the residue by column chromatography (petroleum ether/ethyl acetate = 2: ¹ ) to obtain intermediate IV-31 (white solid, 43 mg): NMR (300 MHz, Chloroform-d) δ 8.03 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.7 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.66 (d, J = 11.5 Hz, 1H), 6.47 (s, 1H), 6.34 (s, 1H), 4.16 (d, J = 13.4 Hz, 2H), 3.88 (d, J = 6.2 Hz, 2H), 3.07 (s, 3H), 2.98 (t, J = 12.7 Hz, 2H), 2.12–2.04 (m, 1H), 1.95 (d, J = 13.1 Hz, 2H), 1.52–1.38 (m, 2H), 1.03 (s, 9H), 0.30 (s, 6H).

Synthesis of compound D-31

Intermediate IV-31 (44 mg, 0.07 mmol) and triethylamine trihydrofluoride (16 μL, 0.10 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol = 50:1) to obtain a crude compound D-31 (light yellow solid, 35 mg), which was purified by slurrying (dichloromethane/methanol = 50:1), and the obtained solid was dried to constant weight to obtain compound D-31 (white solid, 23 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.10(s,1H),8.79(s,1H),8.09(s,1H),7.64(d,J＝8.6Hz,2H),7.10(d,J＝9.0Hz,3H),6.68(d,J＝11.4Hz,1H),4.10(d,J＝12.9Hz,2H),3.93(d,J＝6.2Hz,2H),2.92(s,3H),2.81(t,J＝12.3Hz,2H),2.03–1.97(m,1H),1.78(d,J＝11.8Hz,2H),1.33–1.19(m,2H).HRMS(ESI)calcd.for C ₂₁ H ₂₃ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 538.1088,found 538.1088.

Embodiment 265

4-Fluoro-N-(2-hydroxy-5-(3-(4-((4-((trifluoromethyl)thio)benzyl)thio)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-32)

Synthesis of compound D-32

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate II-82 to prepare compound D-32: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.27 (s, 2H), 8.53 (s, 1H), 8.43 (s, 1H), 7.80 (dd, J = 8.7, 5.3 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.43 (s, 1H), 7.42-7.32 (m, 5H), 7.29 (d, J = 2.3 Hz, 1H), 7.23 (d, J = 8.5 Hz, 2H), 7.05 (dd, J = 8.7, 2.4 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 4.19 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₁ F ₄ N ₃ O ₄ S ₃ [M+H] ⁺ 624.0709, found 624.0715.

Embodiment 266

4-Fluoro-N-(2-hydroxy-5-(3-(4-((4-(trifluoromethyl)benzyl)thio)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-33)

Synthesis of intermediate IV-32

Referring to the method of Example 122, 4-trifluoromethylthiobenzyl bromide was replaced by 4-trifluoromethylbenzyl bromide to obtain Intermediate IV-32: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ12.91 (s, 1H), 7.82 (d, J=6.6 Hz, 1H), 7.68 (d, J=7.4 Hz, 1H), 7.63 (d, J=8.1 Hz, 2H), 7.43 (d, J=6.7 Hz, 1H), 4.46 (s, 2H). ESI-MS: m/z 311.0 [MH] ^- .

Synthesis of compound D-33

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-32 to obtain compound D-33: ¹ H NMR (300 MHz, DMSO-d ₆ )δ8.43(s,1H),9.25(s,2H),8.52(s,1H),7.80(dd,J＝8.9,5.2Hz,2H),7.64(d,J＝8.1Hz,2H),7.47(d,J＝8.0Hz,2H),7.36(dt,J＝8.7,4.5Hz,4H),7.29(d,J＝2.5Hz,1H),7.24(d,J＝8.6Hz,2H),7.05(dd,J＝8.7,2.6Hz,1H),6.63(d,J＝8.7Hz,1H),4.22(s,2H).HRMS(ESI)calcd.for C ₂ _{7 H 2 1} F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 592.0988,found 592.0995.

Embodiment 267

4-Fluoro-N-(2-hydroxy-5-(3-(4-(((4-((trifluoromethyl)thio)phenyl)thio)methyl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-34)

Synthesis of intermediate IV-33

Intermediate II-88 (145 mg, 0.39 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), and 1 M aqueous sodium hydroxide solution (1 mL) was added. After the addition was completed, the temperature was raised to 60° C. and reacted for 4 hours. After the reaction, the system was cooled to room temperature, the organic phase was evaporated under reduced pressure, 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 1-2, solid was precipitated, and the filter cake was washed with water (2 mL) and n-hexane (2 mL), and infrared drying was performed to constant weight to obtain intermediate IV-33 (white solid, 74 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ12.94 (s, 1H), 7.88 (d, J＝8.1 Hz, 2H), 7.60 (d, J＝8.2 Hz, 2H), 7.53 (d, J＝8.1 Hz, 2H), 7.46 (d, J＝8.4 Hz, 2H), 3.33 (s, 2H). ESI-MS: m/z 343.0 [MH] ^- .

Synthesis of compound D-34

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-33 to obtain compound D-34: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.24 (s, 2H), 8.48 (s, 1H), 8.42 (s, 1H), 7.80 (dd, J = 8.9, 5.2 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.42-7.25 (m, 7H), 7.05 (dd, J = 8.7, 2.7 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 4.28 (s, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₁ F ₄ N ₃ O ₄ S ₃ [M+H] ⁺ 624.0703, found 624.0694.

Embodiment 268

N-(2-Hydroxy-5-(3-(4-(((4-((trifluoromethyl)thio)phenyl)thio)methyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-35)

Synthesis of compound D-35

Referring to the method of Example 239, 4-phenylbenzoic acid was replaced with IV-33 to prepare compound D-35: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.39 (s, 1H), 8.84 (s, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 7.61 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 7.34-7.25 (m, 3H), 7.13 (dd, J = 8.7, 2.6 Hz, 1H), 6.79 (d, J = 8.7 Hz, 1H), 4.28 (s, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₂ H ₂₀ F ₃ N ₃ O ₄ S ₃ [M+H] ⁺ 544.0641, found 544.0645.

Embodiment 269

N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenethyl)piperazine-1-carboxamide (Compound D-36)

Synthesis of intermediate IV-34

Intermediate III-50 (300 mg, 0.8 mmol), N-Boc-piperazine (178 mg, 0.96 mmol) and potassium iodide (13 mg, 0.08 mmol) were added to acetonitrile (4 mL), and potassium carbonate (165 mg, 1.2 mmol) was added in batches under stirring. After the addition, the temperature was raised to 70 ° C for 8 hours. After the reaction was completed, water (10 mL) was added to the filtrate for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (15 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate IV-34 (colorless oily liquid, 206 mg).

Synthesis of Intermediate IV-35

Intermediate IV-34 (206 mg, 0.53 mmol) was added to ethyl acetate (1 mL), and 4 M hydrogen chloride-ethyl acetate solution (1.3 mL, 5.4 mmol) was added dropwise, and the mixture was reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and a 1M sodium hydroxide aqueous solution (10 mL) was added to the residue, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated brine (10 mL x 1), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain intermediate IV-35 (light yellow oily liquid, 158 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.62 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 8.2 Hz, 2H), 2.79 (t, J = 8.2, 7.2 Hz, 2H), 2.68 (t, J = 4.8 Hz, 4H), 2.55–2.48 (m, 1H), 2.48 (t, J = 7.1 Hz, 2H), 2.35 (t, J = 4.7 Hz, 4H).

Synthesis of compound D-36

Intermediate IV-35 (95 mg, 0.21 mmol) and intermediate IV-28 (66 mg, 0.23 mmol) were added to N,N-dimethylformamide (1.5 mL), and pyridine (25 μL, 0.31 mmol) was added. After the addition was completed, the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=30:1) to obtain a crude compound D-36, which was then purified by slurrying (dichloromethane/methanol=40:1) to obtain compound D-36 (white solid, 32 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.11(s,1H),8.76(s,1H),8.10(s,1H),7.64(d,J＝8.0Hz,2H),7.43(d,J＝8.2Hz,2H),7.11(d,J＝8.6Hz,1H),6.68(d,J＝11.4Hz,1H),3.40(t,J＝5.0Hz,4H),2.92(s,3H),2.84(t,J＝7.6Hz,2H),2.59(t,J＝7.7Hz,2H),2.46(t,J＝5.0,4.4Hz,4H).HRMS(ESI)calcd.for C ₂₁ H ₂₄ F ₄ N ₄ O ₄ S ₂ [M+H] ⁺ 537.1248,found 537.1268.

Embodiment 270

4-Fluoro-N-(2-hydroxy-5-(3-(4-(4-(trifluoromethoxy)phenethoxy)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-37)

Synthesis of compound D-37

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate III-3 to obtain compound D-37: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.23 (s, 2H), 8.33 (s, 1H), 8.26 (s, 1H), 7.80 (dd, J = 8.7, 5.3 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 7.41-7.27 (m, 5H), 7.06 (dd, J = 8.7, 2.3 Hz, 1H), 6.86 (d, J = 8.9 Hz, 2H), 6.63 (d, J = 8.7 Hz, 1H), 4.19 (t, J = 6.6 Hz, 2H), 3.09 (t, J = 6.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₃ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 622.1088, found 622.1091.

Embodiment 271

4-Fluoro-N-(2-hydroxy-5-(3-(4-(4-(trifluoromethoxy)phenethoxy)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-38)

Synthesis of intermediate IV-36

Referring to the method of Example 151, 4-trifluoromethylthiophenylacetic acid was replaced with 4-trifluoromethoxyphenylacetic acid, and the obtained ester was hydrolyzed to obtain Intermediate IV-36: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.60 (s, 1H), 7.87 (d, J = 8.7 Hz, 2H), 7.47 (d, J = 8.5 Hz, 2H), 7.30 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 4.28 (t, J = 6.7 Hz, 2H), 3.09 (t, J = 6.6 Hz, 2H). ESI/MS: m/z 325.08 [MH] ^- .

Synthesis of compound D-38

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-36 to obtain compound D-38: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.24(s,1H),9.21(s,1H),8.32(s,1H),8.25(s,1H),7.80(dd,J＝8.6,5.2Hz,2H),7.46(d,J＝8.4Hz,2H),7.40–7.31(m,4H),7.29(s,3H),7.05(dd,J＝8.6,2.2Hz,1H),6.85(d,J＝8.8Hz,2H),6.62(d,J＝8.7Hz,1H),4.15(t,J＝6.6Hz,2H),3.05(t,J＝6.6Hz,2H).HRMS(ESI)calcd.for C ₂₈ H ₂₃ F ₄ N ₃ O ₆ S[M+H] ⁺ 606.1316,found 606.1319.

Embodiment 272

N-(2-Hydroxy-5-(3-(4-(4-(trifluoromethoxy)phenethoxy)phenyl)ureido)phenyl)methanesulfonamide (Compound D-39)

Synthesis of compound D-39

Referring to the method of Example 239, 4-phenylbenzoic acid was replaced with intermediate IV-36 to obtain compound D-39: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.24(s,1H),9.21(s,1H),8.32(s,1H),8.25(s,1H),7.80(dd,J＝8.6,5.2Hz,2H),7.46(d,J＝8.4Hz,2H),7.40–7.31(m,4H),7.29(s,3H),7.05(dd,J＝8.6,2.2Hz,1H),6.85(d,J＝8.8Hz,2H),6.62(d,J＝8.7Hz,1H),4.15(t,J＝6.6Hz,2H),3.05(t,J＝6.6Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₂ F ₃ N ₃ O ₆ S[M+H] ⁺ 526.1260,found 478.1266.

Embodiment 273

N-(2-Hydroxy-5-(3-(4-(4-(trifluoromethyl)phenethoxy)phenyl)ureido)phenyl)methanesulfonamide (Compound D-40)

Synthesis of intermediate IV-37

Referring to the method of Example 151, 4-trifluoromethylthiophenylacetic acid was replaced with 4-trifluoromethylphenylacetic acid, and the obtained ester was hydrolyzed to obtain Intermediate IV-37: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.63 (s, 1H), 7.88 (d, J = 7.1 Hz, 2H), 7.68 (d, J = 7.7 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 7.1 Hz, 2H), 4.32 (t, J = 6.5 Hz, 2H), 3.16 (t, J = 6.6 Hz, 2H).

Synthesis of compound D-40

Referring to the method of Example 239, 4-phenylbenzoic acid was replaced with intermediate IV-37 to obtain compound D-40: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.47(s,1H),8.66(s,1H),8.36(s,1H),8.29(s,1H),7.66(d,J＝8.1Hz,2H),7.55(d,J＝8.1Hz,2H),7.30(d,J＝9.0Hz,2H),7.27(d,J＝2.6Hz,1H),7.11(dd,J＝8.7,2.6Hz,1H),6.84(d,J＝9.0Hz,2H),6.77(d,J＝8.7Hz,1H),4.17(t,J＝6.6Hz,2H),3.10(t,J＝6.6Hz,2H),2.93(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₂ F ₃ N ₃ O ₅ S[M+H] ⁺ 510.1305, found 510.1295.

Embodiment 274

4-Fluoro-N-(2-hydroxy-5-(3-(4-(2-((trifluoromethyl)thio)phenoxy)ethyl)phenyl)ureido)benzenesulfonamide (Compound D-41)

Synthesis of intermediate IV-38

Referring to the method of Example 165, intermediate IV-38 was obtained: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ12.84 (s, 1H), 7.89 (d, J=8.1 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.08 (d, J=8.8 Hz, 2H), 4.30 (t, J=6.6 Hz, 2H), 3.13 (t, J=6.6 Hz, 2H). ESI/MS: m/z 341.04 [MH] ^- .

Synthesis of compound D-41

Referring to the method of Example 176, 4-phenylbenzoic acid was replaced with intermediate IV-38 to obtain compound D-41: ¹ H NMR (300 MHz, DMSO) δ9.22 (s, 2H), 8.39 (s, 1H), 8.38 (s, 1H), 7.79 (dd, J = 8.5, 5.4 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.39-7.31 (m, 4H), 7.28 (d, J = 2.1 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 2.0 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 4.21 (t, J = 6.7 Hz, 2H), 2.98 (t, J = 6.6 Hz, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₃ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 622.1088, found 622.1086.

Embodiment 275

4-Fluoro-N-(2-hydroxy-5-(3-(4-(2-(4-(trifluoromethoxy)phenoxy)ethyl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-42)

Synthesis of intermediate IV-39

Referring to the method of Example 165, 4-trifluoromethylthiophenol was replaced by 4-trifluoromethoxyphenol to obtain intermediate IV-39: ¹ H NMR (300 MHz, DMSO) δ12.83 (s, 1H), 7.89 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.9 Hz, 2H), 4.25 (t, J = 6.6 Hz, 2H), 3.12 (t, J = 6.5 Hz, 2H). ESI-MS: m/z 325.1 [MH] ^- .

Synthesis of compound D-42

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-39 to prepare compound D-42: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.22 (s, 2H), 8.39 (s, 1H), 8.38 (s, 1H), 7.79 (dd, J = 8.2, 5.1 Hz, 2H), 7.39-7.32 (m, 4H), 7.26 (d, J = 9.5 Hz, 3H), 7.20 (d, J = 8.1 Hz, 2H), 7.08-7.00 (m, 3H), 6.63 (d, J = 8.5 Hz, 1H), 4.16 (t, J = 6.5 Hz, 2H), 2.97 (t, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₃ F ₄ N ₃ O ₆ S [M+H] ⁺ 606.1316, found 606.1319.

Embodiment 276

4-Fluoro-N-(2-hydroxy-5-(3-(4-((4-((trifluoromethyl)thio)phenethyl)thio)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-43)

Synthesis of Intermediate IV-40

Referring to the method of Example 168, 4-trifluoromethylphenylacetic acid was replaced by 4-trifluoromethylthiophenylacetic acid to obtain Intermediate IV-40: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 7.84 (d, 2H), 7.65 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 3.38 (t, J = 7.4 Hz, 2H), 2.99 (t, J = 7.5 Hz, 2H). ESI-MS: m/z 357.0 [MH] ^- .

Synthesis of compound D-43

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-40 to obtain compound D-43: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.27(s,2H),8.54(s,1H),8.45(s,1H),7.80(dd,J＝8.8,5.3Hz,2H),7.64(d,J＝8.0Hz,2H),7.41(d,J＝7.7Hz,4H),7.35(d,J＝8.9Hz,2H),7.33–7.28(m,3H),7.06(dd,J＝8.7,2.4Hz,1H),6.64(d,J＝8.7Hz,1H),3.18(t,J＝7.5Hz,2H),2.89(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C ₂₈ H ₂₃ F ₄ N ₃ O ₄ S ₃ [M+H] ⁺ 638.0860,found 638.0887.

Embodiment 277

4-Fluoro-N-(2-hydroxy-5-(3-(4-((4-(trifluoromethoxy)phenethyl)thio)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-44)

Synthesis of compound D-44

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate III-15 to obtain compound D-44: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.27 (s, 2H), 8.54 (s, 1H), 8.45 (s, 1H), 7.80 (dd, J = 8.7, 5.3 Hz, 2H), 7.44-7.38 (m, 3H), 7.38-7.33 (m, 3H), 7.32 (s, 1H), 7.31-7.25 (m, 4H), 7.06 (dd, J = 8.7, 2.4 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H), 3.15 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₃ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 622.1088, found 622.1095.

Embodiment 278

4-Fluoro-N-(2-hydroxy-5-(3-(4-((trifluoromethyl)thiomethyl)phenethyl)thiophenyl)ureido)phenyl)benzenesulfonamide (Compound D-45)

Synthesis of intermediate IV-41

4-(2-bromoethyl)benzoic acid (1.5 g, 6.5 mmol) was added to anhydrous ethanol (15 mL), and concentrated sulfuric acid (3.3 mL) was slowly added dropwise under an ice bath. After the addition, the temperature was raised to 70 ° C for 3 hours. After the reaction, the system was cooled to room temperature, ice water (30 mL) was added dropwise to the reaction solution for dilution, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude intermediate IV-41, which was directly used in the next step without further purification.

Synthesis of Intermediate IV-42

The intermediate IV-41 (500 mg, 1.95 mmol), 4-bromothiophenol (455 mg, 2.34 mmol) and potassium iodide (32 mg, 0.20 mmol) were added to acetonitrile (6 mL), and potassium carbonate (363 mg, 2.63 mmol) was added in batches. After the addition was completed, the temperature was raised to 80 ° C for 8 hours. After the reaction was completed, the system was cooled to room temperature, 1M sodium hydroxide aqueous solution (10 mL) was added to the reaction solution to quench the excess 4-bromothiophenol, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined and washed with 1M sodium hydroxide aqueous solution (10 mL x 2) and saturated brine (10 mL x 1) in turn. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100: 1) to obtain the intermediate IV-42 (colorless oily liquid, 706 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ7.88(d, J＝8.0 Hz, 2H),7.50(d, J＝8.4 Hz, 2H),7.40(d, J＝8.0 Hz, 2H),7.30(d, J＝8.4 Hz, 2H),4.30(q, J＝7.0 Hz, 2H),3.27(t, J＝7.6 Hz, 2H),2.94(t, J＝7.4 Hz, 2H),1.31(t, J＝7.0 Hz, 3H).

Synthesis of intermediate IV-43

Referring to the method of Example 125, intermediate II-83 was replaced by intermediate IV-42 to obtain intermediate IV-43: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.49 (d, J = 8.5 Hz, 2H), 7.32 (d, J = 8.6 Hz, 3H), 7.25 (t, J = 6.9 Hz, 3H), 4.27 (s, 2H), 3.23 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H).

Synthesis of Intermediate IV-44

Intermediate IV-43 (210 mg, 0.52 mmol), oxalic acid dihydrate (196 mg, 1.55 mmol), palladium acetate (4 mg, 0.016 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (9 mg, 0.016 mmol) and acetic anhydride (145 μL, 1.55 mmol) were added to anhydrous N,N-dimethylformamide (2 mL), the system was cooled to -78 °C and frozen, and N,N-diisopropylethylamine (270 μL, 1.55 mmol) was added. Under argon protection, the system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 °C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate IV-44 (white solid, 142 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.86(s,1H),7.85(d,J＝8.4Hz,2H),7.40(d,J＝8.3Hz,2H),7.30(dd,J＝17.3,8.0Hz,4H),4.28(s,2H),3.32–3.29(m,2H),2.91(t,J＝7.4Hz,2H).

Synthesis of compound D-45

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-44 to obtain compound D-45: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.24 (s, 2H), 8.52 (s, 1H), 8.43 (s, 1H), 7.83-7.77 (m, 2H), 7.40 (t, J=10.1 Hz, 4H), 7.33 (s, 1H), 7.32-7.28 (m, 4H), 7.22 (d, J=7.8 Hz, 2H), 7.07 (d, J=8.9 Hz, 1H), 6.64 (d, J=8.7 Hz, 1H), 4.27 (s, 2H), 3.13 (t, J=7.4 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₉ H ₂₅ F ₄ N ₃ O ₄ S ₃ [M+H] ⁺ 652.1016, found 652.1013.

Embodiment 279

4-Fluoro-N-(3-hydroxy-5-(3-(4-((trifluoromethyl)thio)phenethyl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-46)

Synthesis of Intermediate IV-45

The intermediate IV-40 (150 mg, 0.42 mmol) was added to dichloromethane (2 mL), and triethylamine (117 μL, 0.84 mmol) was added. The mixture was stirred at room temperature for 15 minutes. Diphenylphosphoryl azide (86 μL, 0.40 mmol) was added dropwise under an ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain the intermediate IV-45 (white solid, 104 mg).

Synthesis of Intermediate IV-46

Intermediate IV-45 (103 mg, 0.27 mmol) was added to toluene (3 mL) and the temperature was raised to 80°C for 4 hours. After the reaction was completed, the system was cooled to room temperature, and intermediate III-37 (102 mg, 0.30 mmol) was added to the reaction solution in batches. After the addition was completed, the reaction was continued at room temperature for 6 hours. After the reaction, solids were precipitated, filtered, and the filter cake was purified by slurrying (n-hexane). The solids were dried to constant weight to obtain intermediate IV-46 (white solid, 118 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 8.96 (s, 1H), 8.71 (s, 1H), 7.86 (dd, J = 8.7, 5.1 Hz, 2H), 7.65 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 5.2 Hz, 2H), 7.45–7.38 (m, 5H), 7.33 (d, J = 8.5 Hz, 2H), 7.21 (s, 1H), 6.85 (s, 1H), 3.20 (t, J = 7.5 Hz, 2H), 2.90 (t, J = 7.2 Hz, 2H).

Synthesis of compound D-46

Referring to the method of Example 105, intermediate II-68 was replaced by intermediate IV-46 to obtain compound D-46: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 9.41 (s, 1H), 8.57 (d, J = 13.8 Hz, 2H), 7.82 (t, 2H), 7.64 (d, J = 7.7 Hz, 2H), 7.46-7.36 (m, 6H), 7.31 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 27.7 Hz, 2H), 6.20 (s, 1H), 3.18 (t, 2H), 2.89 (t, 2H). ESI-MS: m/z 638.0878 [M+H] ⁺ .

Embodiment 280

N-(2-Hydroxy-5-(3-(4-((4-((trifluoromethyl)thio)phenethyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-47)

Synthesis of compound D-47

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-40 to obtain compound D-47: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.51(s,1H),8.67(s,1H),8.57(s,1H),8.48(s,1H),7.64(d,J＝7.9Hz,2H),7.43(d,J＝3.9Hz,2H),7.41(d,J＝3.4Hz,2H),7.31(dd,J＝5.7,2.9Hz,3H),7.15(dd,J＝8.7,2.7Hz,1H),6.81(d,J＝8.7Hz,1H),3.18(t,J＝7.5Hz,2H),2.96(s,3H),2.94–2.85(m,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₂ F ₃ N ₃ O ₄ S ₃ [M+H] ⁺ 558.0797,found 558.0801.

Embodiment 281

N-(2-Hydroxy-5-(3-(4-((4-(trifluoromethoxy)phenethyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-48)

Synthesis of compound D-48

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate III-15 to obtain compound D-48: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.52 (s, 1H), 8.61 (s, 1H), 8.57 (s, 1H), 8.47 (s, 1H), 7.42 (d, J=8.6 Hz, 2H), 7.36 (d, J=8.6 Hz, 2H), 7.33-7.25 (m, 5H), 7.14 (dd, J=8.7, 2.4 Hz, 1H), 6.80 (d, J=8.7 Hz, 1H), 3.15 (t, J=7.4 Hz, 2H), 2.95 (s, 3H), 2.85 (t, J=7.4 Hz, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₂ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 542.1031, found 542.1039.

Embodiment 282

N-(2-Hydroxy-5-(3-(4-((4-(trifluoromethyl)phenethyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-49)

Synthesis of Intermediate IV-47

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethylphenylacetic acid to obtain Intermediate IV-47: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.63 (s, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.68 (d, J = 7.7 Hz, 2H), 7.57 (d, J = 7.7 Hz, 2H), 7.02 (d, J = 7.6 Hz, 2H), 4.32 (t, J = 6.2 Hz, 2H), 3.17 (t, J = 6.2 Hz, 2H). ESI-MS: m/z 325.1 [MH] ^- .

Synthesis of compound D-49

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-47 to obtain compound D-49: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.51(s,1H),8.68(s,1H),8.57(s,1H),8.48(s,1H),7.65(d,J＝8.0Hz,2H),7.47(d,J＝8.1Hz,2H),7.43(d,J＝8.7Hz,2H),7.34-7.28(m,3H),7.15(dd,J＝8.6,2.4Hz,1H),6.81(d,J＝8.7Hz,1H),3.18(t,J＝7.4Hz,2H),2.96 (s, 3H), 2.91 (t, J = 7.2 Hz, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₂ F ₃ N ₃ O ₄ S ₂ [M+H] ⁺ 526.1077, found 526.1079.

Embodiment 283

N-(5-(3-(3-fluoro-4-((4-(trifluoromethyl)phenyl)thio)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-50)

Synthesis of intermediate IV-48

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethylphenylacetic acid, and 4-bromobenzenethiol was replaced by 4-bromo-2-fluorobenzenethiol to prepare Intermediate IV-48.

Synthesis of compound D-50

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-48 to obtain compound D-50: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.57(s,1H),8.83(s,1H),8.70(s,1H),8.58(s,1H),7.64(d,J＝8.0Hz,2H),7.53(dd,J＝12.3,2.2Hz,1H),7.46(d,J＝8.0Hz,2H),7.43–7.34(m,1H),7.30(d,J＝2.6Hz,1H),7.13(td,J＝7.9,2.4Hz,2H),6.81(d,J＝8.7Hz,1H),3.15(t,J＝7.4Hz,2H),2.95(s,3H),2.90(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 544.0982, found 544.0981.

Embodiment 284

N-(5-(3-(2-fluoro-4-((4-(trifluoromethyl)phenyl)thio)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-51)

Synthesis of Intermediate IV-49

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethylphenylacetic acid, and 4-bromobenzenethiol was replaced by 4-bromo-3-fluorobenzenethiol to prepare Intermediate IV-49.

Synthesis of compound D-51

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-49 to obtain compound D-51: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.57(s,1H),8.88(s,1H),8.70(s,1H),8.41(d,J＝2.8Hz,1H),8.10(t,J＝8.7Hz,1H),7.65(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.29(dd,J＝12.0,2.3Hz,2H),7.14(dd,J＝8.7,2.6Hz,2H),6.81(d,J＝8.7Hz,1H),3.25(t,J＝7.4Hz,2H),2.95(s,3H),2.95–2.89(m,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 544.0982,found 544.0981.

Embodiment 285

N-(5-(3-(3-chloro-4-((4-(trifluoromethyl)phenyl)thio)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-52)

Synthesis of Intermediate IV-50

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethylphenylacetic acid, and 4-bromobenzenethiol was replaced by 4-bromo-2-chlorobenzenethiol to prepare Intermediate IV-50.

Synthesis of compound D-52

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-50 to obtain compound D-52: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.54(s,1H),8.74(s,1H),8.67(s,1H),8.56(s,1H),7.75(d,J＝2.3Hz,1H),7.65(d,J＝8.0Hz,2H),7.50(d,J＝7.9Hz,2H),7.40(d,J＝8.7Hz,1H),7.31(d,J＝2.6Hz,1H),7.29(dd,J＝8.6,2.3Hz,1H),7.14(dd,J＝8.7,2.7Hz,1H),6.81(d,J＝8.7Hz,1H),3.24(t,J＝7.5Hz,2H),2.96(t,J＝7.7Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ ClF ₃ N ₃ O ₄ S ₂ [M+H] ⁺ 560.0687, found 560.0705.

Embodiment 286

N-(5-(3-(2-chloro-4-((4-(trifluoromethyl)phenyl)thio)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-53)

Synthesis of intermediate IV-51

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethylphenylacetic acid, and 4-bromobenzenethiol was replaced by 4-bromo-3-chlorobenzenethiol to prepare Intermediate IV-51.

Synthesis of compound D-53

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-51 to obtain compound D-53: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.59(s,1H),9.25(s,1H),8.71(s,1H),8.19(s,1H),8.14(d,J＝8.7Hz,1H),7.65(d,J＝8.0Hz,2H),7.48(d,J＝7.9Hz,2H),7.44(d,J＝2.2Hz,1H),7.32(dd,J＝6.0,2.1Hz,1H),7.30(d,J＝2.2Hz,1H),7.19(dd,J＝8.7,2.6Hz,1H),6.83(d,J＝8.7Hz,1H),3.27(t,J＝7.4Hz,2H),3.00–2.88(m,5H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ ClF ₃ N ₃ O ₄ S ₂ [M+H] ⁺ 560.0687, found 560.0684.

Embodiment 287

N-(5-(3-(3-fluoro-4-((4-(trifluoromethoxy)phenethyl)thio)phenyl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-54)

Synthesis of Intermediate IV-52

Referring to the method of Example 168, intermediate III-14 was replaced by intermediate III-24 to obtain intermediate IV-52: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.18 (s, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 10.7 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.42 (d, J = 8.4 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 3.38 (t, J = 7.3 Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H). ESI-MS: m/z 359.0 [MH] ^- .

Synthesis of compound D-54

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-52 to obtain compound D-54: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.51(s,1H),8.68(s,1H),8.57(s,1H),8.48(s,1H),7.65(d,J＝8.0Hz,2H),7.47(d,J＝8.1Hz,2H),7.43(d,J＝8.7Hz,2H),7.34–7.28(m,3H),7.15(dd,J＝8.6,2.4Hz,1H),6.81(d,J＝8.7Hz,1H),3.18(t,J＝7.4Hz,2H),2.96(s,3H),2.91(t,J＝7.2Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 560.0932,found 560.0934.

Embodiment 288

N-(4-Fluoro-2-hydroxy-5-(3-(4-((4-(trifluoromethyl)phenyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-55)

Synthesis of compound D-55

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate IV-47, and intermediate I-3 was replaced by intermediate II-18 to obtain compound D-55: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.98(s,1H),8.94(s,1H),8.75(s,1H),8.22(d,J＝1.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.64(d,J＝8.1Hz,2H),7.46(d,J＝8.0Hz,2H),7.41(d,J＝8.7Hz,2H),7.31(d,J＝8.7Hz,2H),6.73(d,J＝12.1Hz,1H),3.18(t,J＝8.3,6.6Hz,2H),2.93(s,3H),2.93–2.87(m,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 544.0982,found 544.0977.

Embodiment 289

4-Fluoro-N-(2-hydroxy-5-(3-(4-((trifluoromethyl)thio)phenyl)phenyl)phenylsulfamide (Compound D-56)

Synthesis of compound D-56

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate III-29 to obtain compound D-56: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.24(s,2H),8.40(d,J＝5.2Hz,2H),7.81(t,J＝7.2Hz,2H),7.63(d,J＝7.8Hz,2H),7.45(d,J＝8.0Hz,2H),7.36(t,J＝7.4Hz,4H),7.29(s,1H),7.18(d,J＝8.2Hz,2H),7.07(d,J＝9.0Hz,1H),6.64(d,J＝8.7Hz,1H),3.27(d,J＝7.4Hz,2H),2.87(t,J＝7.3Hz,2H).HRMS(ESI)calcd.for C ₂₈ H ₂₃ F ₄ N ₃ O ₄ S ₃ [M+H] ⁺ 638.0860,found 638.0858.

Embodiment 290

4-Fluoro-N-(2-hydroxy-5-(3-(4-(2-((trifluoromethyl)thio)pyridine-2-ethyl)thio)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-57)

Synthesis of Intermediate IV-53

Referring to the method of Example 83, 3-fluoro-4-nitrophenol was replaced by 2-mercapto-5-nitropyridine, and 3-fluoro-4-(bromomethyl)benzoic acid methyl ester was replaced by 4-(2-bromoethyl)benzoic acid methyl ester to obtain compound IV-53: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.83 (s, 1H), 8.70 (d, J = 2.3 Hz, 1H), 7.95 (dd, J = 8.4, 2.4 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.5 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 3.47 (t, J = 7.5 Hz, 2H), 3.04 (t, J = 7.5 Hz, 2H).

Synthesis of compound D-57

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-53 to obtain compound D-57: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.23 (s, 2H), 8.71 (d, J=1.8 Hz, 1H), 8.40 (s, 1H), 8.38 (s, 1H), 7.95 (dd, J=8.4, 2.0 Hz, 1H), 7.82 (d, J=5.3 Hz, 1H), 7.79 (d, J=5.2 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.42-7.30 (m, 4H), 7.29 (d, J = 2.4 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.06 (dd, J = 8.7, 2.4 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H), 3.41 (t, J = 7.5 Hz, 2H), 2.90 (t, J = 7.4 Hz, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₂ F ₄ N ₄ O ₄ S ₃ [M+H] ⁺ 639.0818, found 639.0823. ESI-MS: m/z 639.0823 [M+H] ⁺ .

Embodiment 291

4-Fluoro-N-(2-hydroxy-5-(3-(6-(2-((trifluoromethyl)thio)phenyl)thio)ethyl)pyridin-3-yl)ureido)phenyl)benzenesulfonamide (Compound D-58)

Synthesis of Intermediate IV-54

2-(5-bromopyridin-2-yl)acetic acid (826 mg, 3.82 mmol) was added to a dry three-necked bottle, and anhydrous tetrahydrofuran (7 mL) was added to dissolve under argon protection. 1M borane-tetrahydrofuran complex (7.65 mL, 7.65 mmol) was slowly added under ice bath, and the mixture was slowly heated to room temperature for 6 hours. After the reaction was completed, ice water (30 mL) was added dropwise to the reaction solution to quench the excess borane, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined, washed with water (15 mL x 1) and saturated brine (15 mL x 1) in turn, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude intermediate IV-54, which was directly used in the next reaction without further purification.

Synthesis of Intermediate IV-55

Intermediate IV-54 (242 mg, 1.2 mmol) and 4-dimethylaminopyridine (15 mg, 0.12 mmol) were added to dichloromethane (5 mL), and triethylamine (334 μL, 2.4 mmol) was added. p-Toluenesulfonyl chloride (343 mg, 1.8 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature for reaction for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate IV-55 (light yellow solid, 344 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ8.45 (d, J = 2.5 Hz, 1H), 7.90 (dd, J = 8.2, 2.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.3 Hz, 1H), 4.38 (t, J = 6.1 Hz, 2H), 3.01 (t, J = 6.1 Hz, 2H), 2.42 (s, 3H).

Synthesis of Intermediate IV-56

The intermediate III-36 (304 mg, 1.1 mmol) was added to a dry three-necked flask and toluene (2 mL) was added to dissolve it. A toluene (5 mL) solution of triphenylphosphine (1.43 g, 5.5 mmol) was added dropwise under an ice bath. After the dropwise addition, the mixture was heated to room temperature for 1 hour. After TLC monitoring of the disappearance of the raw material, water (1.5 mL) was added to the reaction solution, and the reaction was continued at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly subjected to the next step of reaction without further treatment.

Synthesis of Intermediate IV-57

The intermediate IV-56 (220 mg, 1.1 mmol), potassium carbonate (204 mg, 1.5 mmol), potassium iodide (18 mg, 0.11 mmol) and anhydrous N, N-dimethylformamide (3 mL) were directly added to the reaction solution of the previous step. After the addition was completed, the temperature was raised to 80 ° C for 8 hours. After the reaction was completed, the system was cooled to room temperature, water (30 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10: 1) to obtain the intermediate IV-57 (light yellow solid, 95 mg).

Synthesis of intermediate IV-58

Intermediate IV-57 (90 mg, 0.23 mmol), oxalic acid dihydrate (86 mg, 0.68 mmol), palladium acetate (2 mg, 0.007 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (4 mg, 0.007 mmol) and acetic anhydride (64 μL, 1.55 mmol) were added to anhydrous N,N-dimethylformamide (2 mL), the system was cooled to -78 °C and frozen, and N,N-diisopropylethylamine (113 μL, 1.55 mmol) was added. Under argon protection, the system was naturally restored to room temperature and stirred for 30 minutes, and then the temperature was raised to 100 °C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 50:1) to obtain intermediate IV-58 (white solid, 52 mg): ¹ H NMR (300 MHz, DMSO) δ8.98 (d, J = 1.2 Hz, 1H), 8.16 (dd, J = 8.1, 1.8 Hz, 1H), 7.61 (d, J = 8.2 Hz, 2H), 7.44 (dd, J = 8.2, 2.7 Hz, 3H), 3.50–3.44 (m, 2H), 3.19–3.14 (m, 2H).

Synthesis of compound D-58

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-58 to obtain compound D-58: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.25(s,2H),8.58(s,1H),8.53(s,1H),8.49(s,1H),7.86–7.76(m,3H),7.62(d,J＝8.2Hz,2H),7.44(d,J＝8.1Hz,2H),7.35(t,J＝8.3Hz,2H),7.29(s,1H),7.22(d,J＝8.3Hz,1H),7.06(d,J＝8.5Hz,1H),6.63(d,J＝8.7Hz,1H),3.42–3.37(m,2H),3.01(t,J＝7.2Hz,2H).HRMS(ESI)calcd.for C ₂ 7 H _{2 2} F ₄ N ₄ O ₄ S ₃ [M+H] ⁺ 639.0812,found 639.0822.

Embodiment 292

4-Fluoro-N-(2-hydroxy-5-(3-(4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-59)

Synthesis of compound D-59

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate III-33 to obtain compound D-59: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.25(s,2H),8.41(d,J＝4.0Hz,2H),7.80(dd,J＝8.7,5.2Hz,2H),7.46(d,J＝8.8Hz,2H),7.41–7.32(m,5H),7.31(s,1H),7.29(d,J＝2.4Hz,1H),7.15(d,J＝8.4Hz,2H),7.06(dd,J＝8.6,2.3Hz,1H),6.63(d,J＝8.6Hz,1H),3.23(t,J＝7.5Hz,2H),2.81(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C ₂₈ H ₂₃ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 622.1088,found 622.1080.

Embodiment 293

4-Fluoro-N-(2-hydroxy-5-(3-(4-(4-(trifluoromethoxy)phenyl)thio)butan-2-phenyl)ureido)phenyl)benzenesulfonamide (Compound D-60)

Synthesis of intermediate IV-59

Methyl 4-bromophenylacetate (500 mg, 2.18 mmol) was added to a dry three-necked flask under argon protection. Anhydrous tetrahydrofuran (5 mL) was added to dissolve the mixture. A 1 M solution of potassium tert-butoxide in tetrahydrofuran (2.6 mL, 2.62 mmol) was slowly added dropwise under an ice-salt bath. After the addition was completed, stirring was continued under an ice-salt bath for 30 minutes. A solution of iodoethane (209 μL, 2.62 mmol) in tetrahydrofuran (1 mL) was then added dropwise. After the addition was completed, the temperature was slowly raised to room temperature for reaction for 2 hours. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added dropwise to the reaction solution to quench the excess, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 200:1) to obtain intermediate IV-59 (light yellow oily liquid, 483 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.53 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 3.59 (s, 3H), 3.58–3.54 (m, 1H), 1.97–1.90 (m, 1H), 1.68 (dt, J = 14.1, 7.3 Hz, 1H), 0.80 (t, J = 7.3 Hz, 3H).

Synthesis of Intermediate IV-60

Intermediate IV-59 (463 mg, 1.81 mmol) was added to anhydrous tetrahydrofuran (4 mL), and 1 M lithium triethylborohydride tetrahydrofuran solution (3.6 mL, 3.61 mmol) was slowly added dropwise under ice bath. After the addition was completed, the temperature was slowly raised to room temperature and reacted for 2 hours. After the reaction was completed, water (20 mL) was added to the reaction solution to quench the excess lithium triethylborohydride, and the mixture was extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with saturated brine (20 mL x 1). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate IV-60 (colorless oily liquid, 327 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ7.46 (d, J = 7.8 Hz, 2H), 7.15 (d, J = 7.5 Hz, 2H), 4.57 (s, 1H), 3.53–3.46 (m, 2H), 2.59–2.53 (m, 1H), 1.80–1.71 (m, 1H), 1.49–1.40 (m, 1H), 0.72 (t, J = 7.3 Hz, 3H).

Synthesis of Intermediate IV-61

Intermediate IV-60 (300 mg, 1.32 mmol) and 4-dimethylaminopyridine (16 mg, 0.13 mmol) were added to dichloromethane (5 mL), and triethylamine (367 μL, 2.64 mmol) was added. p-Toluenesulfonyl chloride (376 mg, 1.97 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate IV-61 (colorless oily liquid, 464 mg): ¹ H NMR (300 MHz, DMSO) δ7.61 (d, J = 8.0 Hz, 2H), 7.44-7.38 (m, 4H), 7.07 (d, J = 8.0 Hz, 2H), 4.18-4.10 (m, 2H), 2.81-2.76 (m, 1H), 2.42 (s, 3H), 1.66-1.59 (m, 1H), 1.50-1.42 (m, 1H), 0.66 (t, J = 7.2 Hz, 3H).

Synthesis of Intermediate IV-62

Intermediate IV-61 (424 mg, 1.11 mmol), 4-trifluoromethoxythiophenol (258 mg, 1.33 mmol) and potassium iodide (18 mg, 0.11 mmol) were added to acetonitrile (5 mL), and potassium carbonate (205 mg, 1.50 mmol) was added in batches under stirring. After the addition, the temperature was raised to 80 ° C for 8 hours. After the reaction was completed, water (20 mL) was added to the filtrate for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (15 mL x 1), and the solvent was evaporated under reduced pressure to obtain intermediate IV-62 (colorless oily liquid, 400 mg).

Synthesis of Intermediate IV-63

Intermediate IV-62 (400 mg, 0.99 mmol), oxalic acid dihydrate (374 mg, 2.97 mmol), palladium acetate (7 mg, 0.03 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (17 mg, 0.03 mmol) and acetic anhydride (279 μL, 2.97 mmol) were added to anhydrous N,N-dimethylformamide (3 mL), the system was cooled to -78 °C and frozen, and N,N-diisopropylethylamine (517 μL, 2.97 mmol) was added. Under argon protection, the system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 °C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate IV-63 (yellow oily liquid, 312 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.80(s,1H),7.86(d,J＝8.2Hz,2H),7.38(d,J＝8.9Hz,2H),7.34(d,J＝8.3Hz,2H),7.27(d,J＝8.2Hz,2H),3.39(d,J＝6.3Hz,1H),3.24(d,J＝12.8Hz,1H),2.83–2.73(m,1H),1.92–1.81(m,1H),1.70–1.59(m,1H),0.71(t,J＝7.3Hz,3H).

Synthesis of compound D-60

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-63 to obtain compound D-60: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.23(s,2H),8.39(s,2H),7.80(dd,J＝8.8,5.3Hz,2H),7.42–7.37(m,3H),7.35(d,J＝9.0Hz,3H),7.32–7.26(m,3H),7.11(d,J＝8.5Hz,2H),7.07(dd,J＝8.8,2.4Hz,1H),6.64(d,J＝8.7Hz,1H),3.29–3.15(m,2H),2.66–2.60(m,1H),1.90–1.78(m,1H),1.64–1.53(m,1H),0.73(t,J＝7.3Hz,3H).HRMS(ESI)calcd.for C _{3 0} H _{2 7} F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 650.1401, found 650.1403.

Embodiment 294

4-Fluoro-N-(2-hydroxy-5-(3-(4-(1-((4-(trifluoromethoxy)phenyl)thio)propan-2-yl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-61)

Synthesis of compound D-61

Referring to the method of Example 293, iodoethane was replaced with iodomethane to obtain compound D-61: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.24(s,2H),8.40(s,1H),8.39(s,1H),7.80(dd,J＝8.6,5.2Hz,2H),7.41(d,J＝8.8Hz,3H),7.34(d,J＝9.3Hz,4H),7.32–7.27(m,3H),7.16(d,J＝8.5Hz,2H),7.07(d,J＝8.7Hz,1H),6.63(d,J＝8.6Hz,1H),3.22(d,J＝7.4Hz,2H),2.93–2.85(m,1H),1.30(d,J＝6.8Hz,3H).HRMS(ESI)calcd.for C ₂₉ H ₂₅ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 636.1250,found 636.1274.

Embodiment 295

4-Fluoro-N-(2-hydroxy-5-(3-(4-(1-((4-(trifluoromethoxy)phenyl)thio)pentan-2-yl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-62)

Synthesis of compound D-62

Referring to the method of Example 293, iodoethane was replaced with 1-iodopropane to prepare compound D-62: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.28 (s, 2H), 8.42 (s, 2H), 7.82 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 5.2 Hz, 1H), 7.41-7.32 (m, 6H), 7.32-7.28 (m, 3H), 7.12 (d, J = 8.5 Hz, 2H), 7.07 (dd, J = 8.7, 2.6 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H) ,3.29(dd,J＝12.6,6.5Hz,1H),3.19(dd,J＝12.5,8.2Hz,1H),2.77–2.67(m,1H),1.86–1.68(m,1H),1.67–1.49(m,1H),1.10(p,J＝7.4Hz,2H),0.80(t,J＝7.3Hz,3H).HRMS(ESI)calcd.for C ₃₁ H ₂₉ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 664.1558,found 664.1563.

Embodiment 296

4-Fluoro-N-(2-hydroxy-5-(3-(4-(3-methyl-1-((4-(trifluoromethoxy)phenyl)thio)butan-2-yl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-63)

Synthesis of compound D-63

Referring to the method of Example 293, ethyl iodide was replaced with 2-iodopropane to obtain compound D-63: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.27(s,2H),8.42(s,1H),8.41(s,1H),7.81(dd,J＝8.9,5.2Hz,2H),7.41–7.33(m,5H),7.32(s,1H),7.31–7.26(m,3H),7.13–7.02(m,3H),6.64(d,J＝8.7Hz,1H),3.43(dd,J＝12.4,4.8Hz,1H),3.32(d,J＝11.2Hz,1H),2.62–2.52(m,1H),1.95(h,J＝6.7Hz,1H),0.94(d,J＝6.6Hz,3H),0.72(d,J＝6.7Hz,3H).HRMS(ESI)calcd.for C ₃₁ H ₂₉ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 664.1558, found 664.1559.

Embodiment 297

N-(5-(3-(4-(1-cyclopropyl-2-((4-(trifluoromethoxy)phenyl)thio)ethyl)phenyl)ureido)-2-hydroxyphenyl)-4-fluorobenzenesulfonamide (Compound D-64)

Synthesis of Intermediate IV-64

Methyltriphenylphosphonium bromide (238 mg, 0.67 mmol) was added to anhydrous tetrahydrofuran (2 mL), and potassium tert-butoxide (75 mL, 0.67 mmol) was added in batches under ice bath. After completion of the addition, the mixture was stirred at 0°C for 30 minutes. A solution of (4-bromophenyl)cyclopropyl ketone (50 mg, 0.22 mmol) in anhydrous tetrahydrofuran (1 mL) was then added dropwise. After completion of the addition, the mixture was naturally warmed to room temperature and reacted for 12 hours. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to the reaction solution under ice bath to quench, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether) to obtain intermediate IV-64 (colorless oily liquid, 51 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.48 (s, 4H), 5.14 (d, J = 94.9 Hz, 2H), 1.65–1.59 (m, 1H), 0.92–0.75 (m, 2H), 0.65–0.54 (m, 2H).

Synthesis of Intermediate IV-65

The intermediate IV-64 (47 mg, 0.21 mmol) was added to tetrahydrofuran (1 mL), and 1 M borane-tetrahydrofuran complex (420 μL, 0.42 mmol) was added dropwise under ice bath. After the addition was completed, stirring was continued at 0°C for 2 hours. After TLC monitoring, 3 M sodium hydroxide aqueous solution (210 μL, 0.63 mmol) and 30% hydrogen peroxide solution (200 μL, 2.1 mmol) were added in turn under ice bath. After the addition was completed, the temperature was raised to room temperature for reaction for 12 hours. After the reaction was completed, Saturated sodium thiosulfate solution (5 mL) and water (5 mL) were added to the reaction solution to quench, and extracted with ethyl acetate (5 mL x 3). The organic phases were combined and washed with saturated brine (10 mL x 1). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 15:1) to obtain intermediate IV-65 (colorless oily liquid, 37 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ7.46(d,J＝8.4Hz,2H),7.23(d,J＝8.3Hz,2H),4.56(t,J＝5.2Hz,1H),3.77–3.57(m,2H),1.91(ddd,J＝9.8,7.4,5.2Hz,1H),1.06–0.83(m,1H),0.61–0.46(m,1H),0.40–0.26(m,1H),0.24(td,J＝9.4,9.0,4.9Hz,1H),-0.01(td,J＝8.7,5.1Hz,1H).

Synthesis of compound D-64

Referring to the method of Example 293, intermediate IV-60 was replaced by intermediate IV-65 to obtain compound D-64: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.24 (s, 2H), 8.41 (s, 1H), 8.40 (s, 1H), 7.81 (dd, J=8.9, 5.2 Hz, 2H), 7.42-7.33 (m, 5H), 7.33 (s, 1H), 7.32-7.27 (m, 3H), 7.17 (d, J=8.6 Hz, 2H), 7.08 (dd, J=8.7, 2.6 Hz, 1H), 6.64 (d, J=8.7 Hz, 1H), 3.45 (dd, J=12.4, 5.8 Hz, 1H), 3. 37 (dd, J = 11.0, 7.4 Hz, 1H), 2.07 (td, J = 9.0, 5.8 Hz, 1H), 1.10 (ddt, J = 13.1, 9.2, 4.8 Hz, 1H), 0.57 (tt, J = 8.7, 4.2 Hz, 1H), 0.35 (dt, J = 8.8, 4.5 Hz, 1H), 0.29 (dt, J = 9.6, 5.2 Hz, 1H), 0.07 (dq, J = 9.0, 5.1 Hz, 1H). HRMS (ESI) calcd. for C ₃₁ H ₂₇ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 662.1401, found 662.1405.

Embodiment 298

4-Fluoro-N-(2-hydroxy-5-(3-(4-(1-methoxy-2-((4-(trifluoromethoxy)phenyl)thio)ethyl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-65)

Synthesis of Intermediate IV-66

2,4'-Dibromoacetophenone (893 mg, 3.21 mmol) and 4-trifluoromethylthiophenol (686 mg, 3.53 mmol) were added to acetone (12 mL), and cesium carbonate (1.36 g, 4.18 mmol) was added under stirring. After the addition was completed, the temperature was raised to 60°C and reacted for 4 hours. After the reaction, water (20 mL) was added for dilution, and ethyl acetate (15 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 300:1) to obtain intermediate IV-66 (white solid, 1.26 g): ¹ H NMR (300 MHz, Chloroform-d) δ7.82 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.16 (dd, J = 8.9, 1.0 Hz, 2H), 4.23 (s, 2H).

Synthesis of Intermediate IV-67

The intermediate IV-66 (850 mg, 2.17 mmol) was added to methanol (8 mL), and sodium borohydride (82 mg, 2.17 mmol) was added in batches under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (30 mL) for quenching, extracted with ethyl acetate (15 mL x 3), the organic phases were combined, washed with saturated brine (15 mL x 1), and the filtrate was decompressed to evaporate the solvent. The residue was subjected to column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain the intermediate IV-67 (colorless oily liquid, 827 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ7.91(d,J＝8.3Hz,2H),7.54(d,J＝8.2Hz,2H),7.43(d,J＝8.8Hz,2H),7.27(dd,J＝9.0,1.0Hz,2H),5.90(d,J＝4.6Hz,1H),4.83(q,J＝5.8Hz,1H),3.30(d,J＝1.3Hz,1H),3.28(d,J＝2.5Hz,2H).

Synthesis of Intermediate IV-68

Sodium hydride (107 mg, 2.67 mmol) was added to a dry three-necked flask, and anhydrous N,N-dimethylformamide (1 mL) was added under argon protection to suspend. A solution of intermediate IV-67 (350 mg, 0.89 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was added dropwise under ice bath. After the addition was completed, the temperature was slowly raised to room temperature and reacted for 30 minutes. Then, a solution of iodomethane (111 μL, 1.78 mmol) in anhydrous N,N-dimethylformamide (1 mL) was slowly added dropwise under ice bath. After the addition was completed, the temperature was raised to room temperature and stirred for 6 hours. After the reaction was completed, saturated ammonium chloride solution (20 mL) and water (15 mL) were added to the reaction solution to quench, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (20 mL x 1) and saturated brine (20 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate IV- ⁶⁸ (light yellow oily liquid, 356 mg): NMR (400 MHz, Chloroform-d) δ 7.50 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.20 (d, J = 8.4 Hz, 2H), 7.14 (dd, J = 8.9, 1.0 Hz, 2H), 4.28 (dd, J = 7.7, 5.3 Hz, 1H), 3.30 (dd, J = 13.4, 7.7 Hz, 1H), 3.26 (s, 3H), 3.10 (dd, J = 13.4, 5.4 Hz, 1H).

Synthesis of compound D-65

Referring to the method of Example 293, intermediate IV-62 was replaced by intermediate IV-68 to obtain compound D-65: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.27(s,2H),8.53(s,1H),8.45(s,1H),7.81(dd,J＝8.9,5.2Hz,2H),7.46–7.39(m,4H),7.37(t,J＝8.9Hz,2H),7.31(d,J＝2.2Hz,2H),7.29(s,1H),7.25(d,J＝8.6Hz,2H),7.07(dd,J＝8.7,2.6Hz,1H),6.64(d,J＝8.7Hz,1H),4.30(dd,J＝7.7,5.3Hz,1H),3.41–3.38(m,1H),3.22(dd,J＝13.2,5.3Hz,1H),3.13(s,3H).HRMS(ESI)calcd.for C ₂₉ H ₂₅ F ₄ N ₃ O ₆ S ₂ [M+H] ⁺ 652.1194, found 652.1201.

Embodiment 299

N-(5-(3-(4-(1-ethoxy-2-((4-(trifluoromethoxy)phenyl)thio)ethyl)phenyl)ureido)-2-hydroxyphenyl)-4-fluorobenzenesulfonamide (Compound D-66)

Synthesis of compound D-66

Referring to the method of Example 298, iodomethane was replaced by iodoethane to prepare compound D-66: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.26 (s, 2H), 8.52 (s, 1H), 8.45 (s, 1H), 7.81 (dd, J＝8.9, 5.2 Hz, 2H), 7.46 (d, J＝8.8 Hz, 2H), 7.43-7.34 (m, 4H), 7.31 (d, J＝2.5 Hz, 2H), 7.28 (d, J＝1.1 Hz, 1H), 7.26 (d, J＝8.6 Hz, 2H), 7.08 (dd, 3H). HRMS (ESI) calcd. for C 30 H 27 F 4 N ₃ _O ₆ _S ₂ [ _M +H] ⁺ 666.1350, found 666.1354.

Embodiment 300

4-Fluoro-N-(2-hydroxy-5-(3-(4-(2-((4-(trifluoromethoxy)phenyl)thio)propyl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-67)

Synthesis of Intermediate IV-69

4-Bromophenylacetone (500 mg, 2.35 mmol) was added to methanol (9 mL), and sodium borohydride (89 mg, 2.35 mmol) was added in portions under ice bath. After the addition, the temperature was slowly raised to room temperature and the reaction was carried out for 2 hours. After the reaction, the reaction solution was poured into ice water (30 mL) for quenching, extracted with ethyl acetate (15 mL x 3), the organic phases were combined, washed with saturated brine (15 mL x 1), the filtrate was decompressed to remove the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 15:1) to obtain intermediate IV-69 (colorless oily liquid, 464 mg): ¹ H NMR (400 MHz, Chloroform-d) δ7.46 (d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 4.09–3.96 (m, 1H), 2.76 (dd, J = 13.6, 4.9 Hz, 1H), 2.68 (dd, J = 13.6, 7.8 Hz, 1H), 1.26 (d, J = 6.2 Hz, 3H).

Synthesis of Intermediate IV-70

Intermediate IV-69 (460 mg, 2.14 mmol) and 4-dimethylaminopyridine (26 mg, 0.21 mmol) were added to dichloromethane (7 mL), and triethylamine (595 μL, 4.28 mmol) was added. Then p-toluenesulfonyl chloride (612 mg, 3.21 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature and the reaction was carried out for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate IV-70 (white solid, 733 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.53 (d, J = 6.6 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 7.21 (d, J = 7.7 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 4.77-4.60 (m, 1H), 2.90-2.69 (m, 2H), 2.46 (s, 3H), 1.40 (d, J = 6.2 Hz, 3H).

Synthesis of Intermediate IV-71

4-Trifluoromethoxybenzenesulfonyl chloride (752 mg, 2.88 mmol) was added to N, N-dimethylformamide (5 mL), and tributylphosphine (2.16 mL, 8.65 mmol) was added dropwise under ice bath. After the addition was completed, the temperature was raised to 50°C for reaction for 30 minutes. After TLC monitoring of the disappearance of the raw material, the system was cooled to room temperature, and the intermediate IV-70 (710 mg, 1.92 mmol) in N, N-dimethylformamide (3 mL) solution, potassium carbonate (399 mg, 2.88 mmol), and potassium iodide (32 mg, 0.19 mmol) were added in turn under ice bath. After the addition was completed, the reaction was carried out at 50°C for 6 hours. After the reaction, the system was cooled to room temperature, water (80 mL) was added to the reaction solution for dilution, and ethyl acetate was used for extraction (15 mL x 3). The organic phases were combined and washed with water (20 mL x 2) and saturated brine (20 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to obtain intermediate IV-71 (colorless oily liquid, 611 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.43 (d, J = 8.6 Hz, 4H), 7.17 (dd, J = 8.9, 1.0 Hz, 2H), 7.05 (d, J = 8.3 Hz, 2H), 3.49–3.31 (m, 1H), 2.95 (dd, J = 13.8, 5.8 Hz, 1H), 2.68 (dd, J = 13.7, 8.4 Hz, 1H), 1.25 (d, J = 6.7 Hz, 3H).

Synthesis of Intermediate IV-72

Intermediate IV-71 (391 mg, 1 mmol), oxalic acid dihydrate (378 mg, 3 mmol), palladium acetate (7 mg, 0.03 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethyloxanthene (17 mg, 0.03 mmol) and acetic anhydride (281 μL, 3 mmol) were added to anhydrous N,N-dimethylformamide (3 mL), the system was cooled to -78 °C and frozen, and N,N-diisopropylethylamine (523 μL, 3 mmol) was added. Under argon protection, the system was naturally restored to room temperature and stirred for 10 minutes, and then the temperature was raised to 100 °C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (10 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (15 mL x 1) and saturated brine (15 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain a crude intermediate IV-72, which was purified by slurrying (dichloromethane/methanol = 100:1) to obtain an intermediate IV-72 (white solid, 154 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ12.85(s,1H),7.87(d,J＝8.1Hz,2H),7.51(d,J＝8.7Hz,2H),7.37(d,J＝8.0Hz,2H),7.32(d,J＝8.3Hz,2H),3.73(h,J＝6.8Hz,1H),2.96(dd,J＝13.7,6.4Hz,1H),2.84(dd,J＝13.7,7.9Hz,1H),1.19(d,J＝6.6Hz,3H).

Synthesis of compound D-67

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-72 to obtain compound D-67: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.24 (s, 2H), 8.42 (s, 1H), 8.40 (s, 1H), 7.81 (dd, J＝8.9, 5.2 Hz, 2H), 7.52 (d, J＝8.8 Hz, 2H), 7.40–7.34 (m, 4H), 7.34 (d, J＝3.8 Hz, 2H), 7.30 (d, J＝3.8 Hz, 2H). ＝2.6 Hz, 1H), 7.14 (d, J＝8.5 Hz, 2H), 7.07 (dd, J＝8.8, 2.6 Hz, 1H), 6.64 (d, J＝8.7 Hz, 1H), 3.64 (dq, J＝12.8, 6.6 Hz, 1H), 2.85 (dd, J＝13.8, 5.9 Hz, 1H), 2.66 (dd, J＝13.7, 8.2 Hz, 1H), 1.18 (d, J＝6.6 Hz, 3H). HRMS (ESI) calcd. for C ₂₉ H ₂₅ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 636.1245, found 636.1249.

Embodiment 301

4-Fluoro-N-(2-hydroxy-5-(3-(4-(2-((4-(trifluoromethoxy)phenyl)thio)butyl)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-68)

Synthesis of Intermediate IV-73

4-Bromophenylacetic acid (100 mg, 0.47 mmol) was added to dichloromethane (2.5 mL), and N-methyl-N-methoxylamine (43 mg, 0.70 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (134 mg, 0.70 mmol) and 4-dimethylaminopyridine (85 mg, 0.70 mmol) were added in sequence under ice bath. After the addition was complete, the mixture was warmed to room temperature and stirred for 12 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, and saturated brine (10 mL x 1) was added. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 7.5:1) to obtain intermediate IV-73 (white solid, 97 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.46 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 3.74 (s, 2H), 3.65 (s, 3H), 3.21 (s, 3H).

Synthesis of Intermediate IV-74

Intermediate IV-73 (48 mg, 0.19 mmol) was added to anhydrous tetrahydrofuran (1 mL), and 2M ethylmagnesium chloride-tetrahydrofuran solution (1 mL, 1.94 mmol) was added dropwise under ice bath. After the addition was completed, the reaction was continued at 0°C for 30 minutes. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to the reaction solution under ice bath, extracted with ethyl acetate (5 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 1), the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate IV-74 (colorless oily liquid, 26 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.47 (d, J = 8.4 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 3.67 (s, 2H), 2.50 (q, J = 7.3 Hz, 2H), 1.06 (t, J = 7.3 Hz, 3H).

Synthesis of compound D-68

Referring to the method of Example 300, 4-bromophenylacetone was replaced with intermediate IV-74 to obtain compound D-68: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.26(s,2H),8.42(s,1H),8.41(s,1H),7.81(dd,J＝8.9,5.2Hz,2H),7.49(d,J＝8.8Hz,2H),7.41-7.32(m,3H),7.34-7.31(m,3H),7.30(d,J＝2.6Hz,1H),7.13(d,J＝8.6Hz,2H),7.06 (dd, J = 8.7, 2.6 Hz, 1H), 6.64 (d, J = 8.7 Hz, 1H), 3.55-3.44 (m, 1H), 2.78 (d, J = 7.0 Hz, 2H), 1.66-1.55 (m, 1H), 1.46 (dp, J = 14.2, 7.1 Hz, 1H), 0.98 (t, J = 7.3 Hz, 3H). HRMS (ESI) calcd. for C ₃₀ H ₂₇ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 650.1407, found 650.1414.

Embodiment 302

4-Fluoro-N-(2-hydroxy-5-(3-(4-(2-methyl-1-(4-(trifluoromethoxy)phenyl)thio)propan-2-yl)phenylurea)phenyl)benzenesulfonamide (Compound D-69)

Synthesis of Intermediate IV-75

2-(4-bromophenyl)-2-methylpropionic acid (486 mg, 2 mmol) was added to anhydrous tetrahydrofuran (8 mL), and lithium aluminum hydride (92 mg, 2.4 mmol) was added in batches under an ice bath. After the addition, the temperature was slowly raised to room temperature for reaction for 2 hours. After the reaction was completed, water (2 mL) was added to the reaction solution to quench it, and 4M sodium hydroxide aqueous solution (2 mL) was added after no more bubbles were generated, and the mixture was stirred at room temperature for 5 minutes. Water (6 mL) and anhydrous sodium sulfate (2 g) were added, and stirring was continued at room temperature for 30 minutes. The reaction solution was filtered with diatomaceous earth, the filtrate was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude intermediate IV-75, which was directly used in the next step without further purification.

Synthesis of compound D-69

Referring to the method of Example 293, intermediate IV-60 was replaced by intermediate IV-75 to prepare compound D-69: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.28 (s, 2H), 8.40 (d, J = 4.0 Hz, 2H), 7.83-7.77 (m, 2H), 7.38 (d, J = 8.9 Hz, 4H), 7.34-7.27 (m, 5H), 7.25 (d, J = 8.1 Hz, 2H), 7.06 (dd, J = 8.7, 2.6 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 3.32 (s, 2H), 1.38 (s, 6H). HRMS (ESI) calcd. for C ₃₀ H ₂₇ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 650.1401, found 650.1406.

Embodiment 303

4-Fluoro-N-(2-hydroxy-5-(3-(4-(trifluoromethoxy)phenyl)thiomethyl)cyclopropylphenyl)ureido)phenyl)benzenesulfonamide (Compound D-70)

Synthesis of compound D-70

Referring to the method of Example 302, 2-(4-bromophenyl)-2-methylpropanoic acid was replaced with 1-(4-bromophenyl)cyclopropanecarboxylic acid to prepare compound D-70: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.22 (s, 2H), 8.38 (d, J = 5.1 Hz, 2H), 7.79 (dd, J = 8.8, 5.2 Hz, 2H), 7.38-7.29 (m, 6H), 7.28 (d, J = 2.4 Hz, 1H), 7.23 (t, J = 7.8 Hz, 4H), 7.05 (dd, J = 8.7, 2.6 Hz, 1H), 6.62 (d, J = 8.7 Hz, 1H), 3.32 (s, 2H), 0.86 (d, J = 5.0 Hz, 4H). HRMS (ESI) calcd. for C ₃₀ H ₂₅ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 648.1245, found 648.1247.

Embodiment 304

4-Fluoro-N-(2-hydroxy-5-(3-(4-(trifluoromethoxy)phenyl)thiomethyl)cyclobutylphenyl)ureido)phenyl)benzenesulfonamide (Compound D-71)

Synthesis of compound D-71

Referring to the method of Example 302, 2-(4-bromophenyl)-2-methylpropanoic acid was replaced with 1-(4-bromophenyl)cyclobutanecarboxylic acid to prepare compound D-71: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.23 (s, 2H), 8.38 (s, 2H), 7.80 (dd, J = 8.7, 5.2 Hz, 2H), 7.42-7.26 (m, 7H), 7.22 (d, J = 8.2 Hz, 2H), 7.15-7.01 (m, 3H), 6.63 (d, J = 8.6 Hz, 1H), 3.47 (s, 2H), 2.37-2.20 (m, 4H), 2.16-2.00 (m, 1H), 1.86-1.75 (m, 1H). HRMS (ESI) calcd. for C ₃₁ H ₂₇ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 662.1401, found 662.1409.

Embodiment 305

4-Fluoro-N-(3-hydroxy-5-(3-(4-(3-(trifluoromethoxy)phenyl)phenyl)thioethyl)phenyl)ureido)benzenesulfonamide (Compound D-72)

Synthesis of compound D-72

Referring to the method of Example 279, intermediate IV-40 was replaced by intermediate III-33 to prepare compound D-72: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 9.40 (s, 1H), 8.55 (s, 1H), 8.43 (s, 1H), 7.83 (dd, J = 8.8, 5.2 Hz, 2H), 7.48-7.38 (m, 4H), 7.37-7.28 (m, 4H), 7.16 (d, J = 8.1 Hz, 2H), 6.74 (s, 1H), 6.63 (s, 1H), 6.19 (s, 1H), 3.23 (t, J = 7.6 Hz, 2H), 2.81 (t, J = 7.6 Hz, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₃ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 622.1088, found 622.1090.

Embodiment 306

3,5-Difluoro-N-(2-hydroxy-5-(3-(4-(4-(trifluoromethoxy)phenyl)thio)phenyl)phenylurea)benzenesulfonamide (Compound D-73)

Synthesis of Intermediate IV-76

Referring to the method of Example 1, 4-fluorobenzenesulfonyl chloride was replaced by 3,5-difluorobenzenesulfonyl chloride to obtain intermediate IV-76: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 7.62 (t, J = 9.2 Hz, 1H), 7.38 (d, J = 4.7 Hz, 2H), 6.55 (d, J = 8.7 Hz, 1H), 6.29 (d, J = 7.5 Hz, 2H), 4.73 (s, 2H), 0.89 (s, 9H), 0.08 (s, 6H).

Synthesis of compound D-73

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate III-33, and intermediate I-3 was replaced by intermediate IV-76 to obtain compound D-73: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.61(s,1H),9.34(s,1H),8.40(d,J＝7.2Hz,2H),7.62–7.55(m,1H),7.46(s,1H),7.43(s,3H),7.38–7.27(m,5H),7.14(d,J＝8.4Hz,2H),7.04(dd,J＝8.8,2.3Hz,1H),6.66(d,J＝8.7Hz,1H),3.22(t,J＝7.5Hz,2H),2.85–2.76(m,2H).HRMS(ESI)calcd.for C ₂₈ H ₂₂ F ₅ N ₃ O ₅ S ₂ [M+H] ⁺ 640.0994,found 640.1000.

Embodiment 307

2,4-Difluoro-N-(2-hydroxy-5-(3-(4-(4-(trifluoromethoxy)phenyl)thio)phenyl)phenylurea)benzenesulfonamide (Compound D-74)

Synthesis of Intermediate IV-77

Referring to the method of Example 1, 4-fluorobenzenesulfonyl chloride was replaced with 2,4-difluorobenzenesulfonyl chloride to obtain intermediate IV- 77.

Synthesis of compound D-74

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate III-33, and intermediate I-3 was replaced by intermediate IV-77 to obtain compound D-74: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.38(s,1H),9.23(s,1H),8.39(s,1H),8.37(s,1H),7.72(dd,J＝14.9,8.3Hz,1H),7.53–7.42(m,3H),7.41–7.28(m,4H),7.24(s,1H),7.21–7.10(m,3H),7.07(d,J＝8.9Hz,1H),6.63(d,J＝8.7Hz,1H),3.22(t,J＝7.5Hz,2H),2.80(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C ₂₈ H ₂₂ F ₅ N ₃ O ₅ S ₂ [M+H] ⁺ 640.0994,found 640.0992.

Embodiment 308

N-(2-Hydroxy-5-(3-(4-(2-((4-((trifluoromethyl)thio)phenyl)thio)ethyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-75)

Synthesis of compound D-75

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate III-29 to obtain compound D-75: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.06(s,2H),8.44(d,J＝4.7Hz,2H),7.63(d,J＝8.3Hz,2H),7.45(d,J＝8.4Hz,2H),7.36(d,J＝8.3Hz,2H),7.30(d,J＝2.4Hz,1H),7.17(d,J＝8.5Hz,2H),7.13(d,J＝2.4Hz,1H),6.80(d,J＝8.7Hz,1H),3.27(t,J＝7.7Hz,2H),2.95(s,3H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₂ F ₃ N ₃ O ₄ S ₃ [M+H] ⁺ 558.0797,found 558.0801.

Embodiment 309

N-(2-Hydroxy-5-(3-(4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-76)

Synthesis of compound D-76

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate III-33 to obtain compound D-76: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 8.42 (s, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.38-7.24 (m, 5H), 7.15 (d, J = 7.5 Hz, 3H), 6.80 (d, J = 8.5 Hz, 1H), 3.23 (t, 2H), 2.95 (s, 3H), 2.81 (t, J = 7.2 Hz, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₂ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 542.1031, found 542.1038.

Embodiment 310

N-(4-Fluoro-2-hydroxy-5-(3-(4-(2-((4-((trifluoromethyl)thio)phenyl)thio)ethyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-77)

Synthesis of compound D-77

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate III-29, and intermediate I-3 was replaced by intermediate II-18 to obtain compound D-77: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.00 (s, 1H), 8.86 (s, 1H), 8.79 (s, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 7.62 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.5 Hz, 2H), 7.36 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 6.73 (d, J = 12.0 Hz, 1H), 3.28 (t, J = 7.6 Hz, 2H), 2.92 (s, 3H), 2.85 (t, J = 7.6 Hz, 2H). HRMS (ESI) calcd. for C ₂₃ H ₂₁ F ₄ N ₃ O ₄ S ₃ [M+H] ⁺ 576.0703, found 576.0709.

Embodiment 311

N-(4-Fluoro-2-hydroxy-5-(3-(4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-78)

Synthesis of compound D-78

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate III-33, and intermediate I-3 was replaced by intermediate II-18 to obtain compound D-78: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.01(s,1H),8.86(s,1H),8.81(s,1H),8.22(d,J＝1.9Hz,1H),7.83(d,J＝8.8Hz,1H),7.46(d,J＝8.9Hz,2H),7.36(d,J＝8.5Hz,2H),7.33(d,J＝7.6Hz,2H),7.17(d,J＝8.6Hz,2H),6.74(d,J＝12.0Hz,1H),3.24(t,J＝7.7Hz,2H),2.93(s,3H),2.81(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 560.0932,found 560.0936.

Embodiment 312

N-(4-Fluoro-2-hydroxy-5-(3-(4-(2-((4-(trifluoromethyl)phenyl)thio)ethyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-79)

Synthesis of Intermediate IV-78

Referring to the method of Example 200, replacing trifluoromethoxybenzenesulfonyl chloride with trifluoromethylbenzenesulfonyl chloride, intermediate IV-78 was prepared.

Synthesis of compound D-79

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate IV-78, and intermediate I-3 was replaced by intermediate II-18 to obtain compound D-79: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.01(s,1H),8.87(s,1H),8.81(s,1H),8.22(d,J＝1.9Hz,1H),7.83(d,J＝8.8Hz,1H),7.65(d,J＝8.3Hz,2H),7.51(d,J＝8.2Hz,2H),7.37(d,J＝8.5Hz,2H),7.19(d,J＝8.6Hz,2H),6.74(d,J＝12.1Hz,1H),3.30(t,J＝7.6Hz,2H),2.93(s,3H),2.86(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 544.0982,found 544.0990.

Embodiment 313

N-(2-Hydroxy-5-(3-(2-(4-((trifluoromethyl)thio)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ureido)phenyl)methanesulfonamide (Compound D-80)

Synthesis of Intermediate IV-79

The intermediate III-46 (227 mg, 0.56 mmol), oxalic acid dihydrate (213 mg, 1.69 mmol), palladium acetate (4 mg, 0.02 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (10 mg, 0.02 mmol) and acetic anhydride (159 μL, 1.69 mmol) were added to anhydrous N,N-dimethylformamide (2 mL), the system was cooled to -78 ° C and frozen, and N,N-diisopropylethylamine (295 μL, 1.69 mmol) was added. Under argon protection, the system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 ° C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 50:1) to obtain intermediate IV-79 (light yellow solid, 106 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.82(s,1H),7.72(d,J＝2.3Hz,1H),7.70(d,J＝4.0Hz,2H),7.67(dd,J＝7.9,1.8Hz,1H),7.54(d,J＝8.2Hz,2H),7.15(d,J＝8.0Hz,1H),3.75(s,2H),3.63(s,2H),2.89(t,J＝5.9Hz,2H),2.71(t,J＝5.9Hz,2H).

Synthesis of compound D-80

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-79 to obtain compound D-80: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.51(s,1H),8.68(s,1H),8.43(s,1H),8.40(s,1H),7.71(d,J＝7.9Hz,2H),7.55(d,J＝7.8Hz,2H),7.30(d,J＝2.6Hz,1H),7.25(s,1H),7.12(dd,J＝8.7,2.6Hz,2H),6.91(d,J＝8.4Hz,1H),6.79(d,J＝8.7Hz,1H),3.75(s,2H),3.52(s,2H),2.95(s,3H),2.86–2.77(m,2H),2.75–2.61(m,2H).HRMS(ESI)calcd.for C _{2 5} H _{2 5} F ₃ N ₄ O ₄ S ₂ [M+H] ⁺ 567.1348, found 567.1355.

Embodiment 314

N-(2-Hydroxy-5-(3-(1-oxo-2-(4-((trifluoromethyl)thio)benzyl)isoindolin-5-yl)ureido)phenyl)methanesulfonamide (Compound D-81)

Synthesis of Intermediate IV-80

Sodium hydride (62 mg, 1.56 mmol) was added to a dry three-necked flask, and anhydrous N,N-dimethylformamide (2 mL) was added under argon protection to suspend the mixture. A solution of 5-bromo-2,3-dihydroisoindol-1-one (254 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (2 mL) was added dropwise under an ice bath. After the addition was completed, the mixture was reacted at 0°C for 30 minutes. Then, a solution of 4-trifluoromethylthiobenzyl bromide (325 mg, 1.2 mmol) in anhydrous N,N-dimethylformamide (2 mL) was slowly added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature and stirred for 6 hours. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to the reaction solution to quench, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with water (20 mL x 1) and saturated brine (20 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate IV-80 (yellow oily liquid, 201 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.75 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 8.1 Hz, 3H), 7.57 (d, J = 1.4 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 4.81 (s, 2H), 4.28 (s, 2H).

Synthesis of compound D-81

Referring to the method of Example 313, intermediate III-46 was replaced by intermediate IV-80 to obtain compound D-81: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.57 (s, 1H), 8.91 (s, 1H), 8.70 (s, 1H), 8.59 (s, 1H), 7.78 (d, J=1.6 Hz, 1H), 7.70 (d, J=7.9 Hz, 2H), 7.62 (d, J=8.3 Hz, 1H), 7.47-7.37 (m, 3H), 7.33 (d, J = 2.6 Hz, 1H), 7.14 (dd, J = 8.7, 2.6 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 4.77 (s, 2H), 4.38 (s, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C ₂₄ H ₂₁ F ₃ N ₄ O ₅ S ₂ [M+H] ⁺ 567.0984, found 567.0988.

Embodiment 315

N-(5-(3-(1,3-dioxo-2-(4-((trifluoromethyl)thio)benzyl)isoindolin-5-yl)ureido)-2-hydroxyphenyl)methanesulfonamide (Compound D-82)

Synthesis of compound D-82

Referring to the method of Example 278, the intermediate IV-41 was replaced by 4-trifluoromethylthiobenzyl bromide, 4-bromothiophenol was replaced by 4-bromophthalimide, and the intermediate I-3 was replaced by the intermediate I-18 to obtain compound D-82: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.60(s,1H),9.30(s,1H),8.76(s,1H),8.67(s,1H),8.12(d,J＝2.0Hz,1H),7.80(d,J＝8.2Hz,1H),7.68(d,J＝8.0Hz,3H),7.46(d,J＝8.3Hz,2H),7.34(d,J＝2.6Hz,1H),7.18(dd,J＝8.7,2.6Hz,1H),6.83(d,J＝8.7Hz,1H),4.81(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C ₂₄ H ₁₉ F ₃ N ₄ O ₆ S ₂ [M+H] ⁺ 581.0771,found 581.0776.

Embodiment 316

N-(2-Hydroxy-5-(3-(1-oxo-2-(4-((trifluoromethyl)thio)benzyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)ureido)phenyl)methanesulfonamide (Compound D-83)

Synthesis of compound D-83

Referring to the method of Example 278, the intermediate IV-41 was replaced with 4-trifluoromethylthiobenzyl bromide, 4-bromothiophenol was replaced with 6-bromo-3,4-dihydro-2H-isoquinolin-1-one, and the intermediate I-3 was replaced with intermediate I-18 to obtain compound D-83: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.54(s,1H),8.81(s,1H),8.69(s,1H),8.58(s,1H),7.81(d,J＝8.5Hz,1H),7.70(d,J＝8.2Hz,2H),7.47(d,J＝8.3Hz,2H),7.45(d,J＝2.0Hz,1H),7.34(dd,J＝6.4,2.4Hz,2H),7.15(dd,J＝8.7,2.6Hz,1H),6.82(d,J＝8.7Hz,1H),4.75(s,2H),3.51(t,J＝6.6Hz,2H),2.96(s,3H),2.95(t,J＝6.6Hz,2H).HRMS(ESI)calcd.for C _{2 5} H _{2 3} F ₃ N ₄ O ₅ S ₂ [M+H] ⁺ 581.1135, found 581.1136.

Embodiment 317

N-(2-Hydroxy-5-(3-(4-(3-(4-((trifluoromethyl)thio)phenyl)propoxy)phenyl)ureido)phenyl)methanesulfonamide (Compound D-84)

Synthesis of Intermediate IV-81

Sodium hydride (500 mg, 12.5 mmol) was added to a dry three-necked flask, and anhydrous tetrahydrofuran (5 mL) was added under argon protection to suspend. A solution of triethyl phosphoacetate (1.68 g, 7.5 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise under an ice bath. After the addition was completed, the mixture was reacted at 0°C for 30 minutes. Then, a solution of 4-trifluoromethylthiobenzaldehyde (1.03 g, 5 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise under an ice bath. After the addition was completed, the mixture was naturally warmed to room temperature and stirred for 2 hours. After the reaction was completed, saturated ammonium chloride solution (100 mL) was added to the reaction solution to quench, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined and washed with water (30 mL x 1) and saturated brine (30 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 80:1) to obtain intermediate IV-81 (colorless oily liquid, 1.38 g): ¹ H NMR (400 MHz, Chloroform-d) δ7.71–7.62 (m, 3H), 7.55 (d, J = 8.3 Hz, 2H), 6.49 (d, J = 16.1 Hz, 1H), 4.28 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.1 Hz, 3H).

Synthesis of Intermediate IV-82

Intermediate IV-81 (138 mg, 0.5 mmol) and 10% palladium carbon (14 mg) were added to a tetrahydrofuran (4 mL) mixed solvent and reacted at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was completed, palladium carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the filtrate was decompressed to evaporate the solvent to obtain intermediate IV-82 (yellow oily liquid, 123 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.57 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 4.0 Hz, 2H), 4.12 (q, J = 7.1 Hz, 2H), 2.98 (t, J = 7.7 Hz, 2H), 2.63 (t, J = 7.7 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H).

Synthesis of Intermediate IV-83

The intermediate IV-82 (123 mg, 0.44 mmol) was added to tetrahydrofuran (2 mL), and a 2M solution of lithium borohydride in tetrahydrofuran (440 μL, 0.88 mmol) was added dropwise under an ice bath. After the addition, the mixture was heated to room temperature for 6 hours. After the reaction, water (10 mL) was added dropwise to the reaction solution under an ice bath to quench the excess lithium borohydride, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a crude intermediate IV-83, which was used directly in the next step without further purification.

Synthesis of Intermediate IV-84

Intermediate IV-83 (354 mg, 1.5 mmol), methyl 4-hydroxybenzoate (152 mg, 1 mmol) and triphenylphosphine (393 mg, 1.5 mmol) were added into a dry three-necked flask under argon protection, anhydrous tetrahydrofuran (3 mL) was added to dissolve, and a solution of diisopropyl azodicarboxylate (300 μL, 1.5 mmol) in anhydrous tetrahydrofuran (2 mL) was slowly added dropwise under an ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate IV-84 (white solid, 77 mg): ¹ H NMR (300 MHz, Chloroform-d) δ7.98 (d, J = 8.9 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.2 Hz, 2H), 6.89 (d, J = 8.9 Hz, 2H), 4.02 (t, J = 6.1 Hz, 2H), 3.89 (s, 3H), 2.86 (t, J = 7.6 Hz, 2H), 2.21–2.06 (m, 2H).

Synthesis of compound D-84

Referring to the method of Example 247, intermediate IV-17 was replaced by intermediate IV-84 to obtain compound D-84: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.46(s,1H),8.71(s,1H),8.38(s,1H),8.30(s,1H),7.64(d,J＝8.1Hz,2H),7.42(d,J＝8.2Hz,2H),7.31(d,J＝9.0Hz,2H),7.29(d,J＝2.6Hz,1H),7.13(dd,J＝8.7,2.6Hz,1H),6.84(d,J＝9.1Hz,2H),6.79(d,J＝8.6Hz,1H),3.93(t,J＝6.3Hz,2H),2.95(s,3H),2.81(t,2H),2.03(p,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₄ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 556.1188, found 556.1193.

Embodiment 318

N-(2-Hydroxy-5-(3-(4-(3-(4-trifluoromethoxy)phenyl)propoxy)phenyl)ureido)phenyl)methanesulfonamide (Compound D-85)

Synthesis of compound D-85

Referring to the method of Example 317, intermediate IV-83 was replaced by intermediate III-47 to obtain compound D-85: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.50(s,1H),8.68(s,1H),8.38(s,1H),8.30(s,1H),7.36(dd,J＝9.2,6.9Hz,3H),7.30(d,J＝1.9Hz,3H),7.28(d,J＝5.9Hz,1H),7.13(dd,J＝8.7,2.6Hz,1H),6.85(d,J＝9.0Hz,2H),6.79(d,J＝8.7Hz,1H),3.92(t,J＝6.3Hz,2H),2.95(s,3H),2.77(t,J＝7.7Hz,2H),2.00(p,J＝6.5Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₄ F ₃ N ₃ O ₆ S[M+H] ⁺ 540.1411, found 540.1429.

Embodiment 319

N-(2-Hydroxy-5-(3-(4-(3-(4-trifluoromethyl)phenyl)propoxy)phenyl)ureido)phenyl)methanesulfonamide (Compound D-86)

Synthesis of compound D-86

Referring to the method of Example 317, the intermediate IV-83 was replaced with 4-trifluoromethylphenylpropanol to obtain compound D-86: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.49(s,1H),8.67(s,1H),8.37(s,1H),8.30(s,1H),7.65(d,J＝8.0Hz,2H),7.47(d,J＝7.9Hz,2H),7.31(d,J＝9.3Hz,2H),7.29(d,J＝2.6Hz,1H),7.13(dd,J＝8.4,2.3Hz,1H),6.85(d,J＝8.6Hz,2H),6.79(d,J＝8.7Hz,1H),3.92(t,J＝6.3Hz,2H),2.95(s,3H),2.83(t,J＝7.8Hz,2H),2.02(p,J＝7.6Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₄ F ₃ N ₃ O ₅ S[M+H] ⁺ 524.1462, found 524.1447.

Embodiment 320

N-(2-Hydroxy-5-(3-(4-(3-(4-trifluoromethoxy)phenoxy)propyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-87)

Synthesis of compound D-87

Referring to the method of Example 247, the intermediate IV-15 was replaced with 3-(4-methoxycarbonylphenyl)propionic acid, and 4-hydroxybenzoic acid methyl ester was replaced with 4-trifluoromethoxyphenol to obtain compound D-87: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.52(s,1H),8.68(s,1H),8.43(s,1H),8.42(s,1H),7.34(d,J＝8.4Hz,2H),7.30(s,1H),7.28(d,J＝7.1Hz,2H),7.19–7.08(m,3H),7.03(d,J＝9.1Hz,2H),6.80(d,J＝8.7Hz,1H),3.97(t,J＝6.3Hz,2H),2.95(s,3H),2.67(t,J＝7.6Hz,2H),1.99(p,J＝6.6Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₄ F ₃ N ₃ O ₆ S[M+H] ⁺ 540.1411,found 540.1420.

Embodiment 321

N-(2-Hydroxy-5-(3-(4-(3-(4-((trifluoromethyl)thio)phenoxy)propyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-88)

Synthesis of compound D-88

Referring to the method of Example 247, the intermediate IV-15 was replaced with 3-(4-methoxycarbonylphenyl)propionic acid, and 4-hydroxybenzoic acid methyl ester was replaced with 4-trifluoromethylthiophenol to prepare compound D-88: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.50 (s, 1H), 8.68 (s, 1H), 8.43 (s, 1H), 8.41 (s, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.30 (d, J=2.6 Hz, 1H), 7.16-7.11 (m, 3H), 7.09 (d, J=8.8 Hz, 2H), 6.80(d, J＝8.7 Hz, 1H), 4.02(t, J＝6.3 Hz, 2H), 2.95(s, 3H), 2.68(t, J＝7.6 Hz, 2H), 2.01(p, 2H). HRMS(ESI)calcd.for C ₂₄ H ₂₄ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 556.1182, found 556.1188.

Embodiment 322

4-Fluoro-N-(2-hydroxy-5-(3-(4-(3-(4-trifluoromethoxy)phenyl)propyl)thio)phenyl)ureido)phenyl)benzenesulfonamide (Compound D-89)

Synthesis of Intermediate IV-85

Referring to the method of Example 168, intermediate III-12 was replaced by intermediate III-47 to obtain intermediate IV-85: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.84 (s, 1H), 7.83 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 8.3 Hz, 4H), 7.26 (d, J = 8.1 Hz, 2H), 3.04 (t, J = 7.1 Hz, 2H), 2.76 (t, J = 7.6 Hz, 2H), 1.96-1.86 (m, 2H). ESI-MS: m/z 355.1 [MH] ^- .

Synthesis of compound D-89

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-85 to obtain compound D-89: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.29(s,2H),8.54(s,1H),8.45(s,1H),7.81(dd,J＝9.0,5.2Hz,2H),7.41(d,J＝4.3Hz,1H),7.38(d,J＝4.5Hz,2H),7.34(d,J＝2.9Hz,1H),7.33–7.22(m,7H),7.06(dd,J＝8.7,2.6Hz,1H),6.64(d,J＝8.7Hz,1H),2.87(t,J＝7.1Hz,2H),2.73(t,J＝7.7Hz,2H),1.81(p,J＝7.1Hz,2H).HRMS(ESI)calcd.for C ₂₉ H ₂₅ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 636.1245, found 636.1252.

Embodiment 323

N-(2-Hydroxy-5-(3-(4-((3-(4-(trifluoromethoxy)phenyl)propyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-90)

Synthesis of compound D-90

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-85 to prepare compound D-90: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.98 (s, 2H), 8.55 (s, 1H), 8.46 (s, 1H), 7.40 (d, J = 8.2 Hz, 2H), 7.34-7.18 (m, 3H), 7.14 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 2.86 (t, J = 7.1 Hz, 2H), 2.72 (t, J = 7.2 Hz, 2H), 1.86-1.74 (m, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₄ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 556.1182, found 556.1185.

Embodiment 324

N-(2-Hydroxy-5-(3-(4-((3-(4-(trifluoromethyl)phenyl)propyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-91)

Synthesis of Intermediate IV-86

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced with 4-trifluoromethylphenylpropionic acid to prepare Intermediate IV-86.

Synthesis of compound D-91

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-86 to obtain compound D-91: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.55(s,1H),8.70(s,1H),8.57(s,1H),8.48(s,1H),7.64(d,J＝8.0Hz,2H),7.46–7.38(m,4H),7.34–7.24(m,3H),7.14(dd,J＝8.7,2.7Hz,1H),6.81(d,J＝8.7Hz,1H),2.96(s,3H),2.88(t,J＝7.2Hz,2H),2.79(t,J＝7.6Hz,2H),1.83(p,J＝7.3Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₄ F ₃ N ₃ O ₄ S ₂ [M+H] ⁺ 540.1239,found 540.1246.

Embodiment 325

N-(2-Hydroxy-5-(3-(4-((3-(4-((trifluoromethyl)thio)phenyl)propyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-92)

Synthesis of Intermediate IV-87

Referring to the method of Example 168, intermediate III-12 was replaced by intermediate IV-83 to obtain intermediate IV-87: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.91 (s, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.5 Hz, 2H), 3.06 (t, J = 7.3 Hz, 2H), 2.80 (t, J = 7.6 Hz, 2H), 1.93 (p, J = 7.6 Hz, 2H).

Synthesis of compound D-92

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-87 to obtain compound D-92: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.52(s,1H),8.69(s,1H),8.57(s,1H),8.48(s,1H),7.62(d,J＝8.1Hz,2H),7.40(d,J＝8.7Hz,2H),7.35(d,J＝8.2Hz,2H),7.30(d,J＝2.6Hz,1H),7.27(d,J＝8.7Hz,2H),7.14(dd,J＝8.7,2.6Hz,1H),6.80(d,J＝8.7Hz,1H),2.95(s,3H),2.86(t,J＝7.2Hz,2H),2.75(t,J＝7.6Hz,2H),1.82(p,J＝7.4Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₄ F ₃ N ₃ O ₄ S ₃ [M+H] ⁺ 572.0954, found 572.0952.

Embodiment 326

N-(4-Fluoro-2-hydroxy-5-(3-(4-((3-(4-(trifluoromethoxy)phenyl)propyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-93)

Synthesis of compound D-93

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate IV-85, and intermediate I-3 was replaced by intermediate II-18 to obtain compound D-93: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.02 (s, 1H), 8.95 (s, 1H), 8.79 (s, 1H), 8.24 (s, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 8.7 Hz, 2H), 7.34-7.29 (m, 3H), 7.29-7.24 (m, 3H), 6.75 (d, J = 12.1 Hz, 1H), 2.94 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 2.72 (t, J = 7.6 Hz, 2H), 1.81 (p, J = 7.3 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₃ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 574.1088, found 574.1091.

Embodiment 327

N-(4-Fluoro-2-hydroxy-5-(3-(4-((3-(4-(trifluoromethyl)thio)phenyl)propyl)thio)phenyl)ureido)phenyl)methanesulfonamide (Compound D-94)

Synthesis of compound D-94

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced by intermediate IV-87, and intermediate I-3 was replaced by intermediate II-18 to obtain compound D-94: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.00(s,1H),8.95(s,1H),8.79(s,1H),8.24(d,J＝1.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.62(d,J＝8.0Hz,2H),7.40(d,J＝8.7Hz,2H),7.35(d,J＝8.2Hz,2H),7.28(d,J＝8.7Hz,2H),6.74(d,J＝12.1Hz,1H),2.93(s,3H),2.87(t,J＝7.1Hz,2H),2.75(t,J＝7.7Hz,2H),1.82(p,J＝7.4Hz,2H).HRMS(ESI)calcd.for C _{2 4} H _{2 3} F ₄ N ₃ O ₄ S ₃ [M+H] ⁺ 590.0860, found 590.0863.

Embodiment 328

4-Fluoro-N-(2-hydroxy-5-(3-(4-(3-(3-(3-(trifluoromethoxy)phenyl)phenyl)propyl)phenyl)benzenesulfonamide (Compound D-95)

Synthesis of Intermediate IV-88

4-Trifluoromethoxybenzenesulfonyl chloride (782 mg, 3 mmol) and 4-bromophenylpropanol (430 mg, 2 mmol) were added to N,N-dimethylformamide (4 mL). Under argon protection, a solution of tributylphosphine (3.03 g, 15 mmol) in N,N-dimethylformamide (2 mL) was added dropwise under ice bath. The mixture was stirred for 10 minutes. A solution of azodicarbonyl dipyridine (757 mg, 3 mmol) in N,N-dimethylformamide (2 mL) was added dropwise under ice bath. After the addition was completed, the temperature was slowly raised to room temperature and reacted for 6 hours. After the reaction, water (80 mL) was added to the reaction solution for dilution, and extracted with ethyl acetate (20 mL x 3). The organic phases were combined and washed with 1 M aqueous sodium hydroxide solution (15 mL x 2), water (15 mL x 1), and saturated brine (15 mL x 1) in sequence. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether) to obtain intermediate IV-88 (colorless oily liquid, 546 mg).

Synthesis of Intermediate IV-89

Intermediate IV-88 (150 mg, 0.38 mmol), oxalic acid dihydrate (145 mg, 1.15 mmol), palladium acetate (5 mg, 0.019 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (12 mg, 0.019 mmol) and acetic anhydride (110 μL, 1.15 mmol) were added to anhydrous N,N-dimethylformamide (2 mL), the system was cooled to -78 °C and frozen, and N,N-diisopropylethylamine (191 μL, 1.15 mmol) was added. Under argon protection, the system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 °C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) and water (20 mL) were added to the reaction solution for dilution, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography. (petroleum ether/ethyl acetate=5:1) to obtain intermediate IV-89 (white solid, 108 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ12.78 (s, 1H), 7.85 (d, J=7.8 Hz, 2H), 7.42 (d, J=6.5 Hz, 2H), 7.36-7.25 (m, 4H), 2.99 (t, J=7.7 Hz, 2H), 2.77 (t, J=8.1 Hz, 2H), 1.89 (dt, J=15.3, 8.8 Hz, 2H).

Synthesis of compound D-95

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-89 to obtain compound D-95: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.22 (s, 2H), 8.37 (s, 2H), 7.80 (dd, J = 8.8, 5.3 Hz, 2H), 7.43-7.27 (m, 9H), 7.12-7.03 (m, 3H), 6.63 (d, J = 8.7 Hz, 1H), 2.97 (t, J = 7.1 Hz, 2H), 2.64 (t, J = 7.5 Hz, 2H), 1.92-1.76 (m, 2H). HRMS (ESI) calcd. for C ₂₉ H ₂₅ F ₄ N ₃ O ₅ S ₂ [M+H] ⁺ 636.1245, found 636.1249.

Embodiment 329

4-Fluoro-N-(2-hydroxy-5-(3-(4-(4-((trifluoromethyl)thio)phenyl)thio)propyl)phenyl)ureido)benzenesulfonamide (Compound D-96)

Synthesis of Intermediate IV-90

The intermediate III-49 (492 mg, 1.21 mmol), oxalic acid dihydrate (457 mg, 3.63 mmol), palladium acetate (14 mg, 0.06 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyloxanthene (35 mg, 0.06 mmol) and acetic anhydride (348 μL, 3.63 mmol) were added to anhydrous N,N-dimethylformamide (5 mL), the system was cooled to -78 ° C and frozen, and N,N-diisopropylethylamine (632 μL, 3.63 mmol) was added. Under argon protection, the system was naturally restored to room temperature and stirred for 30 minutes, and then raised to 100 ° C for reaction for 8 hours. After the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (10 mL) and water (40 mL) were added to the reaction solution for dilution, and extracted with ethyl acetate (15 mL x 3). The organic phases were combined and washed with water (20 mL x 1) and saturated brine (20 mL x 1) in sequence. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 2:1) to obtain intermediate IV-90.

Synthesis of compound D-96

Referring to the method of Example 234, 4-phenylbenzoic acid was replaced with intermediate IV-90 to prepare compound D-96: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.22 (s, 2H), 8.37 (s, 2H), 7.80 (dd, J = 8.7, 5.3 Hz, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.44-7.25 (m, 7H), 7.14-7.01 (m, 3H), 6.63 (d, J = 8.7 Hz, 1H), 3.03 (t, J = 7.3 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H), 1.97-1.80 (m, 2H). HRMS (ESI) calcd. for C ₂₉ H ₂₅ F ₄ N ₃ O ₄ S ₃ [M+H] ⁺ 652.1016, found 652.1019.

Embodiment 330

N-(2-Hydroxy-5-(3-(4-(3-((4-trifluoromethoxy)phenyl)thio)propyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-97)

Synthesis of compound D-97

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-89 to obtain compound D-97: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ9.43 (s, 1H), 8.71 (s, 1H), 8.42 (s, 1H), 8.42 (s, 1H), 7.41 (d, J＝8.9 Hz, 2H), 7.33 (d, J＝7.0 Hz, 1H), 7.31 (s, 1H), 7.29 (d, J＝2.6 Hz, 2H), 7.13 (dd, J = 8.7, 2.6 Hz, 1H), 7.08 (d, J = 8.4 Hz, 2H), 6.79 (d, J = 8.7 Hz, 1H), 2.98 (t, J = 7.1 Hz, 2H), 2.95 (s, 3H), 2.64 (t, J = 7.5 Hz, 2H), 1.83 (p, J = 7.3 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₄ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 556.1188, found 556.1195.

Embodiment 331

N-(2-Hydroxy-5-(3-(4-((trifluoromethyl)thio)phenyl)phenyl)propyl)ureido)phenyl)methanesulfonamide (Compound D-98)

Synthesis of compound D-98

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-90 to prepare compound D-98: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.04 (s, 2H), 8.40 (s, 2H), 7.61 (d, J = 8.2 Hz, 2H), 7.42-7.22 (m, 5H), 7.19-7.00 (m, 3H), 6.79 (d, J = 8.7 Hz, 1H), 3.02 (t, J = 7.3 Hz, 2H), 2.95 (s, 3H), 2.65 (t, J = 7.6 Hz, 2H), 1.96-1.79 (m, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₄ F ₃ N ₃ O ₄ S ₃ [M+H] ⁺ 572.0954, found 572.0955.

Embodiment 332

N-(2-Hydroxy-5-(3-(4-(4-(4-(trifluoromethoxy)phenyl)butyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-99)

Synthesis of Intermediate IV-91

The intermediate III-47 (170 mg, 0.77 mmol) was added to dichloromethane (2 mL), and Dess-Martin periodinane (655 mg, 1.54 mmol) was added in batches under an ice bath. After the addition was completed, the mixture was heated to room temperature for 2 hours. After the reaction was completed, saturated sodium thiosulfate solution (5 mL) and saturated sodium bicarbonate solution (5 mL) were added to the reaction solution to quench, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with saturated sodium thiosulfate solution (10 mL x 1) and saturated brine (10 mL x 1) in turn, dried over anhydrous magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude intermediate IV-91, which was directly used for the next step because the intermediate was unstable.

Synthesis of Intermediate IV-92

Sodium hydride (93 mg, 2.31 mmol) was added to a dry Schlenk tube, and anhydrous tetrahydrofuran (1 mL) was added under argon protection to suspend. A solution of intermediate I-38 (277 mg, 0.92 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise under an ice bath. After the addition was completed, the temperature was slowly raised to room temperature and stirred for 1 hour. A solution of the crude intermediate IV-91 (0.77 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise under an ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 24 hours. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added to the reaction solution to quench excess sodium hydride, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated brine (10 mL x 2), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate IV-92 (yellow solid, 224 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ13.09(s, 1H),7.99(d, J＝7.9 Hz, 1H),7.87(d, J＝8.2 Hz, 1H),7.71(dd, J＝7.7, 1.5 Hz, 1H),7.52 –7.45 (m, 2H), 7.36 (t, J＝7.8 Hz, 1H), 7.32–7.20 (m, 3H), 6.50 (s, 1H), 2.91–2.70 (m, 2H), 2.67–2.53 (m, 2H). ESI-MS: m/z 335.1 [MH] ^- .

Synthesis of Intermediate IV-93

The intermediate IV-92 (50 mg, 0.15 mmol) was added to a mixed solvent of tetrahydrofuran (2 mL) and water (2 mL), and p-toluenesulfonyl hydrazide (279 mg, 1.5 mmol) and sodium acetate trihydrate (265 mg, 1.95 mmol) were added in sequence. After the addition was completed, the temperature was raised to 70°C for 24 hours. After the reaction was completed, 1N aqueous hydrogen chloride solution (10 mL) was added to the reaction solution to quench, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 15:1) to obtain the intermediate IV-93 (white solid, 23 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ12.89(s,1H),7.96(dd,J＝10.9,7.8Hz,1H),7.84(d,J＝8.0Hz,1H),7.54–7.44(m,1H),7.30(d,J＝7.5Hz,3H),7.24(d,J＝7.8Hz,2H),2.71–2.57(m,3H),1.59(s,3H),1.36–1.24(m,2H).ESI-MS:m/z 337.1[MH] ^- .

Synthesis of compound D-99

Referring to the method of Example 239, 4'-trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-93 to prepare compound D-99: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.47 (s, 1H), 8.64 (s, 1H), 8.39 (d, J = 8.3 Hz, 2H), 7.32-7.22 (m, 7H), 7.13 (dd, J = 8.6 Hz, 1H), 7.06 (d, J = 8.2 Hz, 2H), 6.79 (d, J = 8.5 Hz, 1H), 2.95 (s, 3H), 2.62 (s, 4H), 1.56 (s, 4H). ESI-MS: HRMS (ESI) calcd. for C ₂₅ H ₂₆ F ₃ N ₃ O ₅ S [M+H] ⁺ 538.1624, found 538.1631.

Embodiment 333

N-(2-Hydroxy-5-(3-(4-(4-((trifluoromethyl)thio)phenyl)butyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-100)

Synthesis of compound D-100

Referring to the method of Example 332, intermediate III-47 was replaced by intermediate IV-83 to obtain compound D-100: ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.48(s,1H),8.65(s,1H),8.41(s,1H),8.38(s,1H),7.62(d,J＝8.1Hz,2H),7.36(d,J＝8.2Hz,2H),7.31(d,J＝8.5Hz,2H),7.30(d,J＝2.6Hz,1H),7.13(dd,J＝8.7,2.6Hz,1H),7.06(d,J＝8.5Hz,2H),6.80(d,J＝8.7Hz,1H),2.95(s,3H),2.67(t,J＝7.0Hz,2H),2.54(t,J＝6.6Hz,2H),1.58(p,J＝4.4Hz,4H).HRMS(ESI)calcd.for C _{2 5} H _{2 5} F ₄ N ₃ O ₅ S[M+H] ⁺ 554.1390, found 554.1397.

Embodiment 334

N-(4-Fluoro-2-hydroxy-5-(3-(4-(4-(trifluoromethoxy)phenyl)butyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-101)

Synthesis of compound D-101

Referring to the method of Example 332, intermediate I-18 was replaced by intermediate II-18 to obtain compound D-101: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.99(s,1H),8.80(s,1H),8.77(s,1H),8.19(s,1H),7.83(d,J＝8.9Hz,1H),7.33(d,J＝3.3Hz,2H),7.30(d,J＝3.6Hz,2H),7.25(d,J＝8.4Hz,2H),7.08(d,J＝8.3Hz,2H),6.74(d,J＝12.1Hz,1H),2.93(s,3H),2.66–2.60(m,2H),2.57–2.51(m,2H),1.63–1.45(m,4H).HRMS(ESI)calcd.for C _{2 5} H _{2 5} F ₄ N ₃ O ₅ S[M+H] ⁺ 556.1524,found 556.1531.

Embodiment 335

N-(4-Fluoro-2-hydroxy-5-(3-(4-(4-((trifluoromethyl)thio)phenyl)butyl)phenyl)ureido)phenyl)methanesulfonamide (Compound D-102)

Synthesis of Compound D-102

Referring to the method of Example 332, intermediate III-47 was replaced by intermediate IV-83, and intermediate I-18 was replaced by intermediate II-18 to obtain compound D-102: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.97(s,1H),8.79(s,1H),8.75(s,1H),8.19(d,J＝2.0Hz,1H),7.82(d,J＝8.9Hz,1H),7.61(d,J＝8.1Hz,2H),7.36(d,J＝8.2Hz,2H),7.32(d,J＝8.5Hz,2H),7.07(d,J＝8.5Hz,2H),6.73(d,J＝12.1Hz,1H),2.93(s,3H),2.69–2.61(m,2H),2.59–2.51(m,2H),1.64–1.50(m,4H).HRMS(ESI)calcd.for C _{2 5} H _{2 5} F ₄ N ₃ O ₄ S ₂ [M+H] ⁺ 572.1295, found 572.1296.

Embodiment 336

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-2-(4-((4-(trifluoromethyl)benzyl)oxy)piperidin-1-yl)acetamide (Compound E-1)

Synthesis of intermediate V-1

Intermediate I-18 (250 mg, 0.79 mmol) and pyridine (100 μL, 1.19 mmol) were added to anhydrous tetrahydrofuran (3 mL), and chloroacetyl chloride (76 μL, 0.95 mmol) was added dropwise under an ice bath. After the addition, the mixture was heated to room temperature for 4 hours. After the reaction was completed, 1N aqueous hydrogen chloride solution (10 mL) was added to the reaction solution for quenching, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with 1N aqueous hydrogen chloride solution (10 mL x 1) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate V-1 (white solid, 240 mg): ¹ H NMR (300 MHz, CDCl ₃ )δ7.56(d,J＝8.8Hz,2H),6.96(d,J＝8.7Hz,2H),4.28–4.10(m,2H),3.86(d,J＝6.4Hz,2H),2.78(t,J＝12.9Hz,2H),2.07–1.92(m,1H),1.85(d,J＝12.5Hz,2H),1.49(s,9H),1.31–1.24(m,2H).

Synthesis of intermediate V-2

Sodium hydride (44 mg, 1.1 mmol) was added to a dry Schlenk tube, and anhydrous tetrahydrofuran (1 mL) was added under argon protection to suspend the mixture. A solution of N-Boc-4-hydroxypiperidine (201 mg, 1 mmol) in anhydrous tetrahydrofuran (1 mL) was added under ice bath. After the addition was completed, the mixture was slowly heated to room temperature and stirred for 2 hours. 4-trifluoromethylbenzyl bromide (290 mg, 1.2 mmol) in anhydrous tetrahydrofuran (4 mL), and after the addition, the temperature was raised to 50°C for reaction for 24 hours. After the reaction, the system was cooled to room temperature, water (10 mL) was added to the reaction solution to quench, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with saturated sodium chloride (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 15:1) to obtain intermediate V-2 (white solid, 203 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.71 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 7.9 Hz, 2H), 4.62 (s, 2H), 3.69–3.55 (m, 3H), 3.05 (t, J = 10.3 Hz, 2H), 1.90–1.78 (m, 2H), 1.47–1.40 (m, 2H), 1.39 (s, 9H).

Synthesis of intermediate V-3

The intermediate V-2 (200 mg, 0.56 mmol) was added to dichloromethane (2 mL), and a 4M hydrogen chloride-dioxane solution (1.5 mL, 6 mmol) was added dropwise, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was purified by slurrying (ethyl acetate), and the obtained solid was dried to constant weight to obtain compound V-3 (white solid, 150 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.88 (s, 2H), 7.73 (d, J = 7.9 Hz, 2H), 7.57 (d, J = 7.9 Hz, 2H), 3.74–3.66 (m, 1H), 3.22–3.12 (m, 2H), 3.01–2.91 (m, 2H), 2.06–1.98 (m, 2H), 1.82–1.72 (m, 2H).

Synthesis of compound E-1

Intermediate V-3 (83 mg, 0.28 mmol), intermediate V-1 (100 mg, 0.25 mmol) and potassium iodide (5 mg, 0.03 mmol) were added to anhydrous acetonitrile (3 mL), and cesium carbonate (124 mg, 0.38 mmol) was added in batches. After the addition was completed, the reaction was carried out at room temperature for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was dropwise added with 1N aqueous hydrogen chloride solution to adjust the pH to 7-8, and extracted with ethyl acetate (5 mL x 3), the organic phases were combined, washed with saturated brine (5 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 75:1) to obtain compound E-1 (white solid, 20 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.53(s,1H),8.74(s,2H),7.72(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.49(d,J＝2.4Hz,1H),7.34(dd,J＝8.7,2.4Hz,1H),6.81(d,J＝8.7Hz,1H),4.62(s,2H),3.48–3.41(m,1H),3.06(s,2H),2.95(s,3H),2.75(t,2H),2.29(t,J＝9.3Hz,2H),1.97–1.88(m,2H),1.69–1.56(m,2H).HRMS(ESI)calcd.for C _{2 2} H _{2 6} F ₃ N ₃ O ₅ S[M+H] ⁺ 502.1618, found 502.1621.

Embodiment 337

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-((4-(trifluoromethoxy)benzyl)oxy)phenyl)acetamide (Compound E-2)

Synthesis of intermediate V-4

The intermediate 4-trifluoromethoxybenzyl bromide (200 mg, 0.78 mmol), 4-nitrophenol (125 mg, 0.90 mmol) and potassium iodide (13 mg, 0.08 mmol) were added to acetonitrile (4 mL), and potassium carbonate (140 mg, 1.01 mmol) was added in batches with stirring. After the addition was completed, the temperature was raised to 70°C and reacted for 8 hours. After the reaction, water (10 mL) was added to the filtrate for dilution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (15 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate V-4 (white solid, 205 mg): ¹ H NMR (400 MHz, Chloroform-d) δ8.22 (d, J = 9.2 Hz, 2H), 7.46 (d, J = 6.6 Hz, 2H), 7.26 (d, J = 5.7 Hz, 2H), 7.03 (d, J = 9.2 Hz, 2H), 5.15 (s, 2H).

Synthesis of intermediate V-5

Intermediate V-4 (185 mg, 0.59 mmol) was added to N,N-dimethylformamide (2 mL), and tetrahydroxydiboron (160 mg, 1.77 mmol) and 4,4'-bipyridine (1 mg, 0.006 mmol) were added in turn under ice bath. After the addition was completed, the mixture was heated to room temperature and reacted for 10 minutes. After the reaction was completed, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate V-5 (yellow solid, 140 mg): ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.53 (d, J = 8.6 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 6.72 (d, J = 8.8 Hz, 2H), 6.50 (d, J = 8.8 Hz, 2H), 4.97 (s, 2H), 4.63 (s, 2H).

Synthesis of Intermediate V-6

4-Hydroxy-3-nitrophenylacetic acid (2g, 10mmol) and potassium carbonate (5.5g, 40mmol) were added to N,N-dimethylformamide (45mL), and 3-bromopropylene (2.6mL, 30mmol) was added dropwise under ice bath. After the addition, the mixture was heated to room temperature for 18 hours. After the reaction, 1N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 6-7, and ethyl acetate (20mL x 3) was used for extraction. The organic phases were combined and washed with water (30mL x 2) and saturated brine (30mL x 1) in turn. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 20:1) to obtain intermediate V-6 (light yellow oily liquid, 3.92g): ¹ H NMR (300MHz, DMSO-d ₆ )δ7.83(d,J＝2.1Hz,1H),7.56(dd,J＝8.6,2.1Hz,1H),7.33(d,J＝8.7Hz,1H),6.11–5.98(m,1H),5.98–5.84(m,1H),5.43(dd,J＝17.3,1.6Hz,1H),5.31(s,1H),5.24(ddd,J＝11.8,8.1,1.4Hz,2H),4.75(d,J＝4.9Hz,2H),4.58(d,J＝5.4Hz,2H),3.79(s,2H).

Synthesis of Intermediate V-7

The intermediate V-6 (3.92 g, 14 mmol) and ammonium chloride (7.49 g, 140 mmol) were added to a mixed solvent of ethanol (25 mL) and water (25 mL), and reduced iron powder (3.96 g, 70 mmol) was added in batches under stirring. After the addition was completed, the mixture was heated to reflux for 4 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the filter cake was washed with ethyl acetate (15 mL) and water (15 mL), the filtrate was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (20 mL x 1), the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 7.5:1) to obtain the intermediate V-7 (yellow oily liquid, 3 g): ¹ H NMR (300 MHz, DMSO-d ₆ )δ6.72(d, J＝8.1Hz,1H),6.56(d, J＝1.9Hz,1H),6.39(dd, J＝8.1,1.8Hz,1H),6.06(ddd, J＝22.5,10.4,5.1Hz,1H),5.90(ddd, J＝22.5,10.6,5.4Hz,1H),5.42(dd, J＝17.4,1.6Hz,1H),5.27(dd, J＝7.4,1.5Hz,1H),5.23(d, J＝1.1Hz,1H),5.19(dd, J＝10.5,1.4Hz,1H),4.73(s,2H),4.53(dd, J＝10.2,5.2Hz,4H),3.47(s,2H).

Synthesis of Intermediate V-8

Intermediate V-7 (3 g, 12 mmol) and pyridine (1.5 mL, 18 mmol) were added to anhydrous dichloromethane (20 mL), and a dichloromethane (10 mL) solution of methylsulfonic anhydride (2.55 g, 14.4 mmol) was added dropwise under an ice bath. After the addition was completed, the mixture was heated to room temperature for 8 hours. After the reaction was completed, 1N aqueous hydrogen chloride solution was added to adjust the pH to 6-7, and ethyl acetate (20 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate V-8 (light yellow waxy liquid, 2.78 g): ¹ H NMR (300 MHz, DMSO-d ₆ )δ8.91(s, 1H),7.18(d, J = 2.0 Hz, 1H),7.08(dd, J = 8.4, 2.1 Hz, 1H), 7.01 (d, J = 8.5 Hz, 1H), 6.07 (ddt, J = 17.3, 10.4, 5.1 Hz, 1H), 5.90 (ddt, J = 17.2, 10.6, 5.4 Hz, 1H), 5.46 (dd, J = 17.3, 1.7 Hz, 1H), 5.29 (d, J = 1.5 Hz, 1H), 5.24 (dd, J = 6.0, 1.6 Hz, 1H), 5.19 (dd, J = 10.5, 1.5 Hz, 1H), 4.61 (d, J = 5.1 Hz, 2H), 4.56 (d, J = 5.4 Hz, 2H), 3.64 (s, 2H), 2.94 (s, 3H).

Synthesis of Intermediate V-9

Add intermediate V-8 (3.24 g, 9.97 mmol) and tetrakis(triphenylphosphine)palladium (1.15 g, 1.0 mmol) into a three-necked flask, protect with argon, add dichloromethane (100 mL) to suspend, then add diethylamine (20 mL, 199 mmol), and react at room temperature for 16 hours. After the reaction, 2N aqueous hydrogen chloride solution (10 mL) was added to adjust the pH to 1-2, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol = 50:1) to obtain intermediate V-9 (light yellow solid, 1.72 g): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.24 (s, 1H), 9.76 (s, 1H), 8.69 (s, 1H), 7.08 (d, J = 2.1 Hz, 1H), 6.92 (dd, J = 8.3, 2.2 Hz, 1H), 6.81 (d, J = 8.2 Hz, 1H), 3.43 (s, 2H), 2.93 (s, 3H).

Synthesis of compound E-2

Intermediate V-9 (70 mg, 0.29 mmol) and N,N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (2 mL), and oxalyl chloride (37 μL, 0.44 mmol) was slowly added dropwise under ice bath, and the mixture was heated to room temperature for 1 hour. After the reaction, the solvent was evaporated under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acyl chloride, which was added to a tetrahydrofuran (1 mL) solution of V-5 (85 mg, 0.30 mmol) and pyridine (35 μL, 0.44 mmol) under ice bath conditions, and the reaction was carried out at room temperature for 6 hours. After the reaction, 2N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 3-4, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol = 75:1) to obtain a crude compound E-2, which was purified by beating (dichloromethane/methanol = 50:1). The obtained solid was dried to constant weight to obtain compound E-2 (white solid, 50 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ9.96(s,1H),9.72(s,1H),8.70(s,1H),7.56(d,J＝8.6Hz,2H),7.49(d,J＝9.1Hz,2H),7.38(d,J＝8.2Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝9.1Hz,2H),6.83(d,J＝8.2Hz,1H),5.09(s,2H),3.46(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₆ S[M+H] ⁺ 511.1145,found 511.1141.

Embodiment 338

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-2-(4-((4-(trifluoromethyl)phenoxy)methyl)piperidin-1-yl)acetamide (Compound E-3)

Synthesis of Intermediate V-10

Add N-Boc-4-piperidinemethanol (215 mg, 1 mmol), 4-trifluoromethylphenol (210 mg, 1.3 mmol) and triphenylphosphine (393 mg, 1.5 mmol) into a dry three-necked flask, protect with argon, add anhydrous tetrahydrofuran (5 mL) to dissolve, then add a solution of diisopropyl azodicarboxylate (303 mg, 1.5 mmol) in anhydrous tetrahydrofuran (5 mL) under ice bath, after the dropwise addition, warm to room temperature and react for 12 hours. After the reaction, water (10 mL) was added to the reaction solution for dilution, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saturated sodium carbonate solution (10 mL x 2) and saturated brine (10 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate V-10 (white solid, 350 mg): ¹ H NMR (300 MHz, CDCl ₃ )δ7.56 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 4.28–4.10 (m, 2H), 3.86 (d, J = 6.4 Hz, 2H), 2.78 (t, J = 12.9 Hz, 2H), 2.07– 1.92 (m, 1H), 1.85 (d, J＝12.5 Hz, 2H), 1.49 (s, 9H), 1.31–1.24 (m, 2H).

Synthesis of compound E-3

Referring to the method of Example 336, intermediate V-2 was replaced by intermediate V-10 to obtain compound E-3: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.52(s,1H),8.77(s,2H),7.64(d,J＝8.5Hz,2H),7.47(d,J＝2.5Hz,1H),7.34(dd,J＝8.7,2.6Hz,1H),7.12(d,J＝8.5Hz,2H),6.80(d,J＝8.7Hz,1H),3.93(d,J＝5.8Hz,2H),3.06(s,2H),2.95(s,3H),2.90(t,J＝11.0Hz,2H),2.15(t,J＝11.0Hz,2H),1.84–1.68(m,3H),1.49–1.34(m,2H).HRMS(ESI)calcd.for C _{2 2} H _{2 6} F ₃ N ₃ O ₅ S[M+H] ⁺ 502.1618, found 502.1618.

Embodiment 339

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-2-(4-(4-(trifluoromethylthio)phenoxy)phenyl)acetamide (Compound E-4)

Synthesis of compound E-4

Referring to the method of Example 66, 4-(bromomethyl)benzoic acid ethyl ester was replaced with 4-bromomethylphenylacetic acid methyl ester to obtain compound E-4: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.52(s,1H),8.77(s,2H),7.64(d,J＝8.5Hz,2H),7.47(d,J＝2.5Hz,1H),7.34(dd,J＝8.7,2.6Hz,1H),7.12(d,J＝8.5Hz,2H),6.80(d,J＝8.7Hz,1H),3.93(d,J＝5.8Hz,2H),3.06(s,2H),2.95(s,3H),2.90(t,J＝11.0Hz,2H),2.15(t,J＝11.0Hz,2H),1.84–1.68(m,3H),1.49–1.34(m,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917, found 527.0923.

Embodiment 340

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(4-(trifluoromethylthio)phenoxy)phenyl)acetamide (Compound E-5)

Synthesis of intermediate V-11

4-Trifluoromethylthiophenol (258 mg, 1.33 mmol) and 4-nitrobenzyl bromide (250 mg, 1.16 mmol) were added to acetone (6 mL), and cesium carbonate (510 mg, 1.57 mmol) was added under stirring. After the addition was completed, the temperature was raised to 60° C. and reacted for 4 hours. After the reaction, water (20 mL) was added for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (20 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 30:1) to obtain intermediate V-11 (white solid, 325 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.27 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.7 Hz, 2H), 7.19 (d, J = 8.9 Hz, 2H), 5.36 (s, 2H).

Synthesis of Intermediate V-12

Intermediate V-11 (50 mg, 0.15 mmol) was added to N,N-dimethylformamide (1 mL), and then added Tetrahydroxydiboron (41 mg, 0.46 mmol) and 4,4'-bipyridine (0.2 mg, 0.001 mmol) were added, and the mixture was heated to room temperature for 15 minutes. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude intermediate V-12. The crude intermediate V-12 was purified by slurrying (petroleum ether/ethyl acetate = 30:1) to obtain intermediate V-12 (light yellow solid, 34 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.62 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 5.6 Hz, 2H), 7.09 (d, J = 5.1 Hz, 2H), 6.55 (d, J = 8.4 Hz, 2H), 5.17 (s, 2H), 4.92 (s, 2H).

Synthesis of compound E-5

Intermediate V-9 (100 mg, 0.41 mmol) and intermediate V-12 (128 mg, 0.43 mmol) were added to anhydrous dichloromethane (5 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (118 mg, 0.62 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature for reaction for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol = 100: 1), and then purified by slurrying (dichloromethane/methanol = 20: 1). The obtained solid was dried to constant weight to obtain compound E-5 (white solid, 45 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.16(s,1H),9.74(s,1H),8.67(s,1H),7.62(t,J＝8.8Hz,4H),7.38(d,J＝8.6Hz,2H),7.19(d,J＝2.2Hz,1H),7.15(d,J＝8.9Hz,2H),7.01(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),5.09(s,2H),3.51(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+Na] ⁺ 549.0736,found 549.0729.

Embodiment 341

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-((4-(trifluoromethoxy)phenoxy)methyl)phenyl)acetamide (Compound E-6)

Synthesis of compound E-6

Referring to the method of Example 337, 4-trifluoromethoxybenzyl bromide was replaced by 4-nitrobenzyl bromide, and 4-nitrophenol was replaced by 4-trifluoromethoxyphenol to prepare compound E-6: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.17(s,1H),9.67(s,1H),8.90(s,1H),7.60(d,J＝8.6Hz,2H),7.37(d,J＝8.6Hz,2H),7.29(d,J＝9.2Hz,2H),7.18(d,J＝2.2Hz,1H),7.08(d,J＝9.2Hz,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),5.04(s,2H),3.50(s,2H),2.93(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₆ S[M+H] ⁺ 511.1151,found 511.1156.

Embodiment 342

N-(3-fluoro-4-(4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-7)

Synthesis of intermediate V-13

2-Fluoro-4-nitrotoluene (400 mg, 2.58 mmol) was added to carbon tetrachloride (8 mL), and azobisisobutyronitrile (85 mg, 0.52 mmol) and N-bromosuccinimide (482 mg, 2.71 mmol) were added in batches under ice bath. After completion, the temperature was raised to 70°C for 4 hours. After the reaction was completed, the system was cooled to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain a crude intermediate V-13, which was directly used in the next step without further purification.

Synthesis of compound E-7

Referring to the method of Example 340, 4-nitrobenzyl bromide was replaced with the crude intermediate V-13 to obtain compound E-7: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.39 (s, 1H), 9.69 (s, 1H), 8.69 (s, 1H), 7.68-7.63 (m, 3H), 7.48 (t, J = 8.4 Hz, 1H), 7.31 (dd, J = 8.3, 2.0 Hz, 1H), 7.17 (dd, J = 9.2, 2.4 Hz, 3H), 7.00 (dd, J = 8.3, 2.2 Hz, 1H), 6.84 (d, J = 8.2 Hz, 1H), 5.12 (s, 2H), 3.53 (s, 2H), 2.94 (s, 3H). HRMS (ESI) calcd. for C ₂₃ H ₂₀ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 545.0823, found 545.0817.

Embodiment 343

N-(3-chloro-4-(4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-8)

Synthesis of compound E-8

Referring to the method of Example 342, 2-fluoro-4-nitrotoluene was replaced with 2-chloro-4-nitrotoluene to obtain compound E-8: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.36(s,1H),9.76(s,1H),8.68(s,1H),7.90(d,J＝2.0Hz,1H),7.65(d,J＝8.7Hz,2H),7.53(d,J＝8.4Hz,1H),7.48(dd,J＝8.4,2.0Hz,1H),7.19(s,2H),7.17(s,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.84(d,J＝8.2Hz,1H),5.14(s,2H),3.52(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₀ ClF ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 561.0533,found 561.0541.

Embodiment 344

N-(3-cyclopropyl-4-(4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-9)

Synthesis of intermediate V-14

Referring to the method of Example 342, 2-fluoro-4-nitrotoluene was replaced by 2-bromo-4-nitrotoluene to obtain Intermediate V-14: ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.51 (d, J = 2.2 Hz, 1H), 8.25 (dd, J = 8.6, 2.2 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 5.24 (s, 2H).

Synthesis of Intermediate V-15

The intermediate V-14 (264 mg, 0.65 mmol), cyclopropylboronic acid (72 mg, 0.84 mmol), tricyclohexylphosphine (18 mg, 0.07 mmol), potassium phosphate (510 mg, 2.28 mmol) and palladium acetate (7 mg, 0.03 mmol) were added to the Schlenk tube, and toluene (2 mL) and water (0.1 mL) were added to the system under argon protection, and the mixture was suspended at 100 ° C. and reacted for 6 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the filtrate was decompressed to evaporate the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain the intermediate V-15 (white solid, ²²² mg): NMR (400 MHz, CDCl ₃ ) δ 8.10 (dd, J = 8.4, 2.3 Hz, 1H), 7.96 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 6.7 Hz, 1H), 7.64 (d, J = 6.9 Hz, 2H), 7.05 (d, J = 8.9 Hz, 2H), 5.36 (s, 2H), 2.04–1.97 (m, 1H), 1.15–1.09 (m, 2H), 0.87–0.82 (m, 2H).

Synthesis of compound E-9

Referring to the method of Example 340, intermediate V-11 was replaced with intermediate V-15 to obtain compound E-9: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.08(s,1H),9.74(s,1H),8.68(s,1H),7.64(d,J＝8.8Hz,2H),7.44(dd,J＝8.3,2.1Hz,1H),7.32(d,J＝8.3Hz,1H),7.25(d,J＝2.1Hz,1H),7.20–7.16(m,3H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.3Hz,1H),5.23(s,2H),3.48(s,2H),2.94(s,3H),2.05–1.98(m,1H),0.94–0.89(m,2H),0.62–0.57(m,2H).HRMS(ESI)calcd.for C ₂₆ H ₂₅ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 567.1235, found 567.1252.

Embodiment 345

N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-2-(4-((4-((trifluoromethyl)thio)benzyl)thio)phenyl)acetamide (Compound E-10)

Synthesis of Intermediate V-16

The intermediate cuprous iodide (65 mg, 0.34 mmol), potassium carbonate (951 mg, 6.89 mmol) and elemental sulfur (331 mg, 10.34 mmol) were added to a dry Schlenk tube, and the mixture was protected by argon. Then, a solution of ethyl 4-iodophenylacetate (1 g, 3.45 mmol) in N, N-dimethylformamide (8 mL) was added. After the addition was completed, the temperature was raised to 90°C for reaction for 8 hours. After TLC monitoring of the disappearance of the raw material, the system was cooled to room temperature, and sodium borohydride (393 mg, 10.34 mmol) was added in batches under an ice bath. After the addition was completed, the temperature was raised to 40°C for reaction for 2 hours. After TLC monitoring of the disappearance of the raw material, the system was cooled to room temperature, and potassium iodide (858 mg, 5.17 mmol) and a solution of 4-trifluoromethylthiobenzyl bromide (1.4 g, 5.17 mmol) in N, N-dimethylformamide (5 mL) were added in sequence. After the addition was completed, the reaction was continued at room temperature for 8 hours. After the reaction, water (100 mL) was added to the reaction solution for dilution, and ethyl acetate (20 mL x 3) was used for extraction. The organic phase was washed with water (20 mL x 2) and saturated brine (20 mL x 1) in sequence. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 75:1) to obtain intermediate V-16 (white solid, 147 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.57 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.2 Hz, 2H), 4.16 (q, 2H), 4.11 (s, 2H), 3.59 (s, 2H), 1.27 (t, J = 3.5 Hz, 3H).

Synthesis of compound E-10

Referring to the method of Example 1, intermediate I-5 was replaced by intermediate V-16 to obtain compound E-10: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 9.33 (s, 2H), 7.78 (dd, J = 8.8, 5.2 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 2.4 Hz, 1H), 7.38-7.27 (m, 4H), 7.26-7.20 (m, 3H), 6.62 (d, J = 8.7 Hz, 1H), 4.30 (s, 2H), 3.52 (s, 2H). HRMS (ESI) calcd. for C ₂₈ H ₂₂ F ₄ N ₂ O ₄ S ₃ [M+H] ⁺ 623.0751, found 623.0756.

Embodiment 346

2-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-N-(4-((4-((trifluoromethyl)thio)benzyl)thio)phenyl)acetamide (Compound E-11)

Synthesis of intermediate V-17

Referring to the method of Example 337, methylsulfonic anhydride was replaced with 4-fluorobenzenesulfonyl chloride to obtain intermediate V-17: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 12.26 (s, 1H), 9.40 (s, 2H), 7.77 (dd, J = 8.7, 5.3 Hz, 2H), 7.40-7.28 (m, 2H), 7.07 (d, J = 2.1 Hz, 1H), 6.84 (dd, J = 8.4, 2.2 Hz, 1H), 6.65 (d, J = 8.1 Hz, 1H), 3.39 (s, 2H).

Synthesis of compound E-11

Referring to the method of Example 340, 4-trifluoromethylthiophenol was replaced by 4-nitrothiophenol, 4-nitrobenzyl bromide was replaced by 4-trifluoromethylthiobenzyl bromide, and intermediate V-9 was replaced by intermediate V-17 to obtain compound E-11: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.10(s,1H),9.39(s,1H),9.30(s,1H),7.75(dd,J＝8.8,5.3Hz,2H),7.60(d,J＝8.0Hz,2H),7.51(d,J＝8.6Hz,2H),7.41(d,J＝8.2Hz,2H),7.30–7.19(m,4H),7.15(d,J＝1.8Hz,1H),6.88(dd,J＝8.2,1.8Hz,1H),6.65(d,J＝8.2Hz,1H),4.21(s,2H),3.42(s,2H).HRMS(ESI)calcd.for C ₂₈ H ₂₂ F ₄ N ₂ O ₄ S ₃ [M+H] ⁺ 623.0751,found 623.0751.

Embodiment 347

2-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-N-(4-((4-((trifluoromethyl)thio)benzyl)thio)phenyl)acetamide (Compound E-12)

Synthesis of compound E-12

Referring to the method of Example 340, 4-trifluoromethylthiophenol was replaced by 4-nitrothiophenol, and 4-nitrobenzyl bromide was replaced by 4-trifluoromethoxybenzyl bromide to prepare compound E-12: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.15(s,1H),9.78(s,1H),8.71(s,1H),7.53(d,J＝8.7Hz,2H),7.39(d,J＝8.7Hz,2H),7.28(d,J＝1.6Hz,2H),7.26(s,2H),7.18(d,J＝2.1Hz,1H),7.00(dd,J＝8.3,2.1Hz,1H),6.83(d,J＝8.2Hz,1H),4.19(s,2H),3.49(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917,found 527.0938.

Embodiment 348

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(((4-(trifluoromethoxy)phenyl)thio)methyl)phenyl)acetamide (Compound E-13)

Synthesis of compound E-13

Referring to the method of Example 337, 4-nitrophenol was replaced by 4-trifluoromethoxythiophenol, and 4-trifluoromethoxybenzyl bromide was replaced by 4-nitrobenzyl bromide to prepare compound E-13: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.12(s,1H),9.78(s,1H),8.71(s,1H),7.51(d,J＝8.5Hz,2H),7.42(d,J＝8.8Hz,2H),7.29(d,J＝6.0Hz,2H),7.27(d,J＝6.3Hz,2H),7.17(d,J＝2.1Hz,1H),6.99(dd,J＝8.3,2.2Hz,1H),6.82(d,J＝8.3Hz,1H),4.21(s,2H),3.48(s,2H),2.93(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₁ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 527.0917,found 527.0924.

Embodiment 349

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(4-(trifluoromethoxy)phenethoxy)phenyl)acetamide (Compound E-14)

Synthesis of intermediate V-18

Add intermediate III-12 (200 mg, 0.97 mmol), 4-nitrophenol (301 mg, 1.94 mmol) and triphenylphosphine (534 mg, 2.0 mmol) into a dry three-necked flask, protect with argon, add anhydrous tetrahydrofuran (3 mL) to dissolve, then add a solution of diisopropyl azodicarboxylate (351 μL, 2.0 mmol) in anhydrous tetrahydrofuran (2 mL) under ice bath, after the addition is complete, warm to room temperature and react for 12 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 100:1) to obtain intermediate V-18 (white solid, 260 mg): ¹ H NMR (300 MHz, Chloroform-d) δ 8.18 (d, J = 9.3 Hz, 2H), 7.30 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 7.7 Hz, 2H), 6.93 (d, J = 9.3 Hz, 2H), 4.23 (t, J = 6.7 Hz, 2H), 3.13 (t, J = 6.7 Hz, 2H).

Synthesis of compound E-14

Referring to the method of Example 337, intermediate V-4 was replaced by intermediate V-18, and 4-trifluoromethoxybenzyl bromide was replaced by 4-nitrobenzyl bromide to obtain compound E-14: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.96(s,1H),9.75(s,1H),8.70(s,1H),7.47(d,J＝7.0Hz,2H),7.44(d,J＝6.6Hz,2H),7.30(d,J＝7.8Hz,2H),7.17(d,J＝2.2Hz,1H),6.99(dd,J＝8.3,2.2Hz,1H),6.86(d,J＝9.0Hz,2H),6.82(d,J＝8.2Hz,1H),4.14(t,J＝6.7Hz,2H),3.45(s,2H),3.04(t,J＝6.7Hz,2H),2.93(s,3H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₆ S[M+H] ⁺ 525.1307, found 525.1312.

Embodiment 350

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(2-(4-(trifluoromethoxy)phenoxy)ethyl)phenyl)acetamide (Compound E-15)

Synthesis of compound E-15

Referring to the method of Example 349, the intermediate III-12 was replaced by 4-nitrophenylethanol, and 4-nitrophenol was replaced by 4-trifluoromethoxyphenol to obtain compound E-15: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.08(s,1H),9.78(s,1H),8.70(s,1H),7.51(d,J＝8.3Hz,2H),7.27(d,J＝8.9Hz,2H),7.24(d,J＝8.2Hz,2H),7.17(d,J＝2.1Hz,1H),7.01(d,J＝9.0Hz,2H),6.99(d,J＝2.3Hz,1H),6.82(d,J＝8.2Hz,1H),4.15(t,J＝6.9Hz,2H),3.48(s,2H),2.97(t,J＝6.8Hz,2H),2.93(s,3H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₆ S[M+H] ⁺ 525.1302, found 525.1317.

Embodiment 351

N-(4-hydroxy-3-(methylsulfonamido)phenyl)-2-(4-((4-(trifluoromethoxy)phenethyl)thio)phenyl)acetamide (Compound E-16)

Synthesis of intermediate V-19

4-Mercaptophenylacetic acid (200 mg, 1.19 mmol) was added to anhydrous ethanol (4 mL), and concentrated sulfuric acid (357 μL, 0.3 eqv.) was slowly added dropwise under an ice bath. After the addition was completed, the temperature was raised to 60 ° C for 3 hours. After the reaction was completed, the system was cooled to room temperature, ice water (20 mL) was added dropwise to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain a crude intermediate V-19, which was directly used in the next step without further purification.

Synthesis of Intermediate V-20

The crude intermediate V-19 (228 mg, 1.16 mmol) was added to acetonitrile (4 mL), and potassium carbonate (321 mg, 2.32 mmol) was added in batches. After the addition was completed, the temperature was raised to 70°C for reaction for 30 minutes. Then, the intermediate III-13 (502 mg, 1.39 mmol) was added. After the addition was completed, the temperature was raised to 70°C for reaction for 6 hours. After the reaction, the system was cooled to room temperature, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 50:1) to obtain intermediate V-20 (colorless oily liquid, 372 mg): ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.28 (dd, J = 19.1, 8.6 Hz, 4H), 7.10 (d, J = 8.4 Hz, 2H), 6.52 (d, J = 8.5 Hz, 2H), 5.24 (s, 2H), 2.96 (t, J = 7.4 Hz, 2H), 2.76 (t, J = 7.4 Hz, 2H).

Synthesis of compound E-16

Referring to the method of Example 1, intermediate I-5 was replaced by intermediate V-20 to prepare compound E-16: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 9.54 (s, 1H), 8.73 (s, 1H), 7.47-7.38 (m, 3H), 7.35-7.25 (m, 3H), 7.21 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.78 (d, J = 8.7 Hz, 1H), 4.16 (t, J = 6.7 Hz, 2H), 3.47 (s, 2H), 3.05 (t, J = 6.7 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₃ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 541.1073, found 541.1038.

Embodiment 352

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-((4-(trifluoromethoxy)phenethyl)thio)phenyl)acetamide (Compound E-17)

Synthesis of compound E-17

Referring to the method of Example 340, 4-trifluoromethylthiophenol was replaced by 4-nitrothiophenol, and 4-nitrobenzyl bromide was replaced by intermediate III-13 to obtain compound E-17: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.14(s,1H),9.75(s,1H),8.67(s,1H),7.57(d,J＝8.6Hz,2H),7.32(dt,J＝13.4,8.4Hz,6H),7.19(d,J＝1.9Hz,1H),7.01(dd,J＝8.2,1.9Hz,1H),6.84(d,J＝8.2Hz,1H),3.50(s,2H),3.17(t,J＝7.5Hz,2H),2.94(s,3H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 541.1073,found 541.1070.

Embodiment 353

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(4-(trifluoromethyl)thio)phenyl)phenylacetamide (Compound E-18)

Synthesis of compound E-18

Referring to the method of Example 340, 4-trifluoromethylthiophenol was replaced by 4-nitrothiophenol, and 4-nitrobenzyl bromide was replaced by intermediate III-50 to obtain compound E-18: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.14(s,1H),9.78(s,1H),8.69(s,1H),7.63(d,J＝8.2Hz,2H),7.57(d,J＝8.7Hz,2H),7.40(d,J＝8.2Hz,2H),7.31(d,J＝8.7Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.19(t,J＝7.5Hz,2H),2.94(s,3H),2.88(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₄ S ₃ [M+H] ⁺ 557.0850, found 557.0856.

Embodiment 354

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(4-(trifluoromethyl)phenethyl)thiophenyl)acetamide (Compound E-19)

Synthesis of compound E-19

Referring to the method of Example 349, the intermediate III-12 was replaced by 4-trifluoromethylphenethyl alcohol, and 4-nitrophenol was replaced by 4-nitrothiophenol to obtain compound E-19: ¹ H NMR (300 MHz, DMSO) δ 10.16 (s, 1H), 9.77 (s, 1H), 8.71 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 2.2 Hz, 1H), 7.00 (dd, J = 8.3, 2.2 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 3.49 (s, 2H), 3.20 (t, J = 7.4 Hz, 2H), 2.94 (s, 3H), 2.89 (d, J = 7.4 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₃ F ₃ N ₂ O ₄ S ₂ [M+H] ⁺ 525.1124, found 525.1125.

Embodiment 355

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(4-methylphenethylthio)phenyl)acetamide (Compound E-20)

Synthesis of compound E-20

Referring to the method of Example 349, the intermediate III-12 was replaced by 4-methylphenethyl alcohol, and 4-nitrophenol was replaced by 4-nitrothiophenol to prepare compound E-20: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.14(s,1H),9.75(s,1H),8.67(s,1H),7.56(d,J＝8.8Hz,2H),7.33–7.28(m,2H),7.18(d,J＝2.2Hz,1H),7.12–7.09(m,2H),7.09–7.06(m,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.11(t,2H),2.94(s,3H),2.76(t,2H),2.25(s,3H).HRMS(ESI)calcd.for C ₂₄ H ₂₆ N ₂ O ₄ S ₂ [M+H] ⁺ 471.1407,found 471.1411.ESI-MS:m/z 471.1411[M+H] ⁺ .

Embodiment 356

2-(4-Hydroxy-3-(methylsulfonylamino)phenyl)-N-(4-(4-methoxyphenethylthio)phenyl)acetamide (Compound E-21)

Synthesis of compound E-21

Referring to the method of Example 349, the intermediate III-12 was replaced by 4-methoxyphenylethanol, and 4-nitrophenol was replaced by 4-nitrothiophenol to obtain compound E-21: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.13(s,1H),9.74(s,1H),8.67(s,1H),7.56(d,J＝8.7Hz,2H),7.30(d,J＝8.7Hz,2H),7.18(d,J＝2.2Hz,1H),7.13(d,J＝8.6Hz,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(dd,J＝8.5,2.2Hz,3H),3.71(s,3H),3.49(s,2H),3.10(t,J＝7.6Hz,2H),2.94(s,3H),2.75(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₆ N ₂ O ₅ S ₂ [M+H] ⁺ 487.1356, found 487.1365.

Embodiment 357

N-(4-(4-fluorophenethyl)thiophenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-22)

Synthesis of compound E-22

Referring to the method of Example 349, the intermediate III-12 was replaced by 4-fluorophenethyl alcohol, and 4-nitrophenol was replaced by 4-nitrothiophenol to obtain compound E-22: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.14(s,1H),9.74(s,1H),8.67(s,1H),7.56(d,J＝8.7Hz,2H),7.31(d,J＝8.7Hz,2H),7.26(dd,J＝8.5,5.7Hz,2H),7.18(d,J＝2.2Hz,1H),7.09(t,J＝8.9Hz,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.14(t,J＝7.6Hz,2H),2.94(s,3H),2.80(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₃ FN ₂ O ₄ S ₂ [M+H] ⁺ 475.1156, found 475.1165.

Embodiment 358

N-(4-(4-chlorophenethyl)thiophenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-23)

Synthesis of compound E-23

Referring to the method of Example 349, the intermediate III-12 was replaced by 4-chlorophenylethanol, and 4-nitrophenol was replaced by 4-nitrothiophenol to obtain compound E-23: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.14(s,1H),9.75(s,1H),8.67(s,1H),7.57(d,J＝8.7Hz,2H),7.32(t,J＝8.9Hz,4H),7.25(d,J＝8.4Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.14(t,J＝7.5Hz,2H),2.94(s,3H),2.81(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₃ ClN ₂ O ₄ S ₂ [M+H] ⁺ 491.0861,found 491.0858.

Embodiment 359

N-(4-((4-bromophenethyl)thio)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-24)

Synthesis of compound E-24

Referring to the method of Example 349, the intermediate III-12 was replaced by 4-bromophenethyl alcohol, and 4-nitrophenol was replaced by 4-nitrothiophenol to prepare compound E-24: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.16(s,1H),9.77(s,1H),8.70(s,1H),7.57(d,J＝8.7Hz,2H),7.46(d,J＝8.4Hz,2H),7.31(d,J＝8.7Hz,2H),7.19(d,J＝8.3Hz,2H),7.18(d,J＝2.3Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.14(t,J＝7.5Hz,2H),2.94(s,3H),2.78(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₃ H ₂₃ BrN ₂ O ₄ S ₂ [M+H] ⁺ 535.0361, found 535.0366.

Embodiment 360

N-(4-(4-cyclopropylphenethylthio)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-25)

Synthesis of Intermediate V-21

Referring to the method of Example 349, intermediate III-12 was replaced by 4-bromophenethyl alcohol, and 4-nitrophenol was replaced by 4-nitrothiophenol to obtain intermediate V-21: ¹ H NMR (300 MHz, Chloroform-d) δ 8.13 (d, J = 8.9 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 8.4 Hz, 2H), 3.25 (t, J = 7.6 Hz, 2H), 2.96 (t, J = 7.6 Hz, 2H).

Synthesis of Intermediate V-22

The intermediate V-21 (270 mg, 0.80 mmol), cyclopropylboronic acid (89 mg, 1.04 mmol), tricyclohexylphosphine (22 mg, 0.08 mmol), potassium phosphate (628 mg, 2.8 mmol) and palladium acetate (9 mg, 0.04 mmol) were added to the Schlenk tube, and toluene (2 mL) and water (0.1 mL) were added to the system under argon protection, and the mixture was suspended at 100 ° C. and reacted for 6 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, the filtrate was decompressed to evaporate the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 100: 1) to obtain the intermediate V-22 (white solid, 160 mg).

Synthesis of compound E-25

Referring to the method of Example 337, intermediate V-4 was replaced by intermediate V-22 to obtain compound E-25: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.16(s,1H),9.20(s,2H),7.56(d,J＝8.7Hz,2H),7.30(d,J＝8.7Hz,2H),7.18(d,J＝2.2Hz,1H),7.08(d,J＝8.1Hz,2H),7.02–6.95(m,3H),6.83(d,J＝8.3Hz,1H),3.49(s,2H),3.10(t,J＝7.6Hz,2H),2.94(s,3H),2.75(t,2H),1.90–1.81(m,1H),0.94–0.86(m,2H),0.64–0.56(m,2H).HRMS(ESI)calcd.for C _{2 6} H _{2 8} N ₂ O ₄ S ₂ [M+H] ⁺ 497.1563, found 497.1571.

Embodiment 361

N-(3-Fluoro-4-(4-(trifluoromethoxyphenethyl)thio)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-26)

Synthesis of Intermediate V-23

Sulfonyl chloride (464 μL, 6.4 mmol) was added dropwise to water (3 mL) under an ice bath, and the mixture was reacted at 0°C for 3 hours. Cuprous chloride (3 mg, 0.03 mmol) was then added, and stirring was continued for 1 hour at 0°C. At the same time, 2-fluoro-4-nitroaniline (200 mg, 1.28 mmol) was added to concentrated hydrochloric acid (1.8 mL), and sodium nitrite (133 mg, 1.92 mmol) was added in batches under an ice-salt bath, and stirring was continued for 1 hour under an ice-salt bath. The reaction solution was then added dropwise to the prepared sulfur dioxide aqueous solution, and the reaction was continued for 2 hours under an ice-salt bath. After the reaction was completed, ice water (10 mL) was added dropwise to the reaction solution to dilute it, and ethyl acetate (5 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain the crude intermediate V-23, which was directly used in the next reaction without further purification.

Synthesis of Intermediate V-24

The crude intermediate V-23 was added into a dry three-necked flask under argon protection, and toluene (2 mL) was added to dissolve it. A solution of triphenylphosphine (1.68 g, 6.4 mmol) in toluene (5 mL) was added dropwise, and the mixture was heated to room temperature for 1 hour. After TLC monitoring of the disappearance of the raw material, water (1.5 mL) was added to the reaction solution, and the reaction was continued at room temperature for 2 hours. After the reaction was completed, the reaction solution was directly subjected to the next step of reaction without further treatment.

Synthesis of Intermediate V-25

Add intermediate III-13 (343 mg, 1.28 mmol), potassium carbonate (238 mg, 1.73 mmol), potassium iodide (21 mg, 0.13 mmol) and N,N-dimethylformamide (4 mL) directly to the reaction solution of the previous step. After the addition is completed, heat the temperature to 80°C and react for 8 hours. After the reaction, the system was cooled to room temperature, water (40 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain intermediate V-25 (light yellow solid, 184 mg): ¹ H NMR (300 MHz, CDCl ₃ ) δ7.98 (ddd, J = 8.7, 2.3, 0.8 Hz, 1H), 7.90 (dd, J = 9.6, 2.3 Hz, 1H), 7.34 (dd, J = 8.6, 7.3 Hz, 1H), 7.24 (d, J = 8.6 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 3.27 (t, J = 7.5 Hz, 2H), 3.01 (t, J = 7.6 Hz, 2H).

Synthesis of compound E-26

Referring to the method of Example 337, intermediate V-4 was replaced by intermediate V-25 to obtain compound E-26: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.36(s,1H),9.74(s,1H),8.68(s,1H),7.63(dd,J＝12.2,2.2Hz,1H),7.43(t,J＝8.5Hz,1H),7.35(d,J＝8.7Hz,2H),7.30(dd,J＝8.6,2.2Hz,1H),7.26(d,J＝7.6Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.3Hz,1H),3.51(s,2H),3.15(t,J＝7.5Hz,2H),2.94(s,3H),2.84(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₂ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 559.0979, found 559.0984.

Embodiment 362

N-(3-chloro-4-(4-(trifluoromethoxyphenethyl)thio)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-27)

Synthesis of compound E-27

Referring to the method of Example 361, 2-fluoro-4-nitroaniline was replaced with 2-chloro-4-nitroaniline to obtain compound E-27: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.30(s,1H),9.76(s,1H),8.72(s,1H),7.86(d,J＝2.1Hz,1H),7.47(dd,J＝8.6,2.1Hz,1H),7.44–7.39(m,2H),7.39(s,1H),7.28(d,J＝8.4Hz,2H),7.17(d,J＝2.2Hz,1H),6.99(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.50(s,2H),3.23(t,J＝7.6Hz,2H),2.93(s,3H),2.90(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₂ ClF ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 575.0684, found 575.0690.

Embodiment 363

N-(2-Fluoro-4-(4-(trifluoromethoxyphenethyl)thio)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-28)

Synthesis of compound E-28

Referring to the method of Example 361, 2-fluoro-4-nitroaniline was replaced with 3-fluoro-4-nitroaniline to obtain compound E-28: ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.89(s,1H),9.77(s,1H),8.70(s,1H),7.82(t,J＝8.5Hz,1H),7.38(dd,J＝6.5,2.2Hz,2H),7.31–7.25(m,3H),7.19(d,J＝2.1Hz,1H),7.12(dd,J＝8.4,2.1Hz,1H),7.00(dd,J＝8.3,1.9Hz,1H),6.83(d,J＝8.3Hz,1H),3.58(s,2H),3.25(t,J＝7.5Hz,2H),2.94(s,3H),2.88(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₂ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 559.0979, found 559.0972.

Embodiment 364

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(3-methyl-4-((4-(trifluoromethoxy)phenylethyl)thio)phenyl)acetamide (Compound E-29)

Synthesis of compound E-29

Referring to the method of Example 361, 2-fluoro-4-nitroaniline was replaced by 2-methyl-4-nitroaniline to prepare compound E-29: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 9.76 (s, 1H), 8.70 (s, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.44 (dd, J = 8.5, 2.4 Hz, 1H), 7.36 (d, J = 8.7 Hz, 2H), 7.30 (d, J = 8.5 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.18 (d, 3H), 3.84(t, J＝7.6 Hz, 2H), 2.23(s, 3H). HRMS (ESI) calcd. for C ₂ ₅ H 2 5 F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 555.1230, found 555.1248.

Embodiment 365

2-(4-hydroxy-3-(methylsulfonamido)phenyl)-N-(3-methoxy-4-((4-(trifluoromethoxy)phenylethyl)thio)phenyl)acetamide (Compound E-30)

Synthesis of compound E-30

Referring to the method of Example 361, 2-fluoro-4-nitroaniline was replaced by 2-methoxy-4-nitroaniline to obtain compound E-30: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 9.77 (s, 1H), 8.71 (s, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.36 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.15 (dd, J = 8. 4,1.9 Hz,1H),7.00(dd,J＝8.3,2.2 Hz,1H),6.83(d,J＝8.2 Hz,1H),3.76(s,3H),3.49(s,2H),3.08(t,J＝7.5 Hz,2H),2.94(s,3H),2.82(t,J＝7.5 Hz,2H).HRMS(ESI)calcd.for C _{2 5} H _{2 5} F ₃ N ₂ O ₆ S ₂ [M+H] ⁺ 571.1179,found 571.1187.

Embodiment 366

N-(3-cyclopropyl-4-(4-(trifluoromethoxyphenethyl)thio)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-31)

Synthesis of Intermediate V-26

Referring to the method of Example 361, 2-fluoro-4-nitroaniline was replaced by 2-bromo-4-nitroaniline to obtain intermediate V-26: ¹ H NMR (300 MHz, Chloroform-d) δ 8.38 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 8.8, 2.4 Hz, 1H), 7.25 (dd, 2H), 7.20 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 7.7 Hz, 2H), 3.24 (t, J = 7.4 Hz, 2H),3.04(t,2H).

Synthesis of Intermediate V-27

The intermediate V-26 (478 mg, 1.22 mmol), cyclopropylboronic acid (136 mg, 1.59 mmol), tricyclohexylphosphine (34 mg, 0.12 mmol), potassium phosphate (957 mg, 4.27 mmol) and palladium acetate (14 mg, 0.06 mmol) were added to the Schlenk tube, and toluene (4 mL) and water (0.2 mL) were added to the system under argon protection, and the mixture was suspended at 100 °C for 6 hours. After the reaction, the system was cooled to room temperature, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (5 mL), the filtrate was decompressed to evaporate the solvent, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 10:1) to obtain the intermediate V-27 (white solid, 338 mg) ^: NMR (400 MHz, Chloroform-d) δ 8.01 (dd, J = 8.7, 2.6 Hz, 1H), 7.73 (d, J = 2.6 Hz, 1H), 7.54 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 3.42 (t, J = 7.6 Hz, 2H), 3.03 (t, J = 7.6 Hz, 2H), 1.96–1.88 (m, 1H), 1.05–0.97 (m, 2H), 0.76–0.68 (m, 2H).

Synthesis of Intermediate V-28

The intermediate V-27 (315 mg, 0.87 mmol) and ammonium chloride (415 mg, 7.83 mmol) were added to a mixed solvent of ethanol (8 mL) and water (2 mL), and reduced iron powder (244 mg, 4.36 mmol) was added in batches under stirring. After the addition was completed, the temperature was raised to 80°C for reaction for 6 hours. After the reaction was completed, the system was cooled to room temperature, water (30 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 2), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain the intermediate V-28 (yellow solid, 252 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ7.32(d, J＝8.7Hz,2H),7.25(dd, J＝8.9,1.1Hz,2H),7.12(d, J＝8.2Hz,1H),6.34(dd, J＝8.3,2.4Hz,1H),6.08(d, J＝2.5Hz,1H),5.13(s,2H),2.95(t, J＝7.4Hz,2H),2.78(t, J＝7.5Hz,2H),2.36–2.29(m,1H),0.94–0.85(m,2H),0.54(dt, J＝6.3,3.1Hz,2H).

Synthesis of compound E-31

Referring to the method of Example 337, intermediate V-5 was replaced by intermediate V-28 to obtain compound E-31: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.08(s,1H),9.74(s,1H),8.68(s,1H),7.64(d,J＝8.8Hz,2H),7.44(dd,J＝8.3,2.1Hz,1H),7.32(d,J＝8.3Hz,1H),7.25(d,J＝2.1Hz,1H),7.20–7.16(m,3H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.3Hz,1H),5.23(s,2H),3.48(s,2H),2.94(s,3H),2.05–1.98(m,1H),0.94–0.89(m,2H),0.62–0.57(m,2H).HRMS(ESI)calcd.for C ₂₇ H ₂₇ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 581.1386, found 581.1395.

Embodiment 367

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-((4-(trifluoromethoxy)phenethyl)thio)-3-(trifluoromethyl)phenyl)acetamide (Compound E-32)

Synthesis of compound E-32

Referring to the method of Example 361, 2-fluoro-4-nitroaniline was replaced with 2-trifluoromethyl-4-nitroaniline to obtain compound E-32: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.45(s,1H),9.79(s,1H),8.71(s,1H),8.07(d,J＝2.4Hz,1H),7.80(dd,J＝8.7,2.3Hz,1H),7.66(d,J＝8.7Hz,1H),7.37(d,J＝8.7Hz,2H),7.27(d,J＝7.4Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.52(s,2H),3.27(t,J＝7.7Hz,2H),2.94(s,3H),2.87(t,J＝7.7Hz,2H).HRMS(ESI)calcd.for C ₂₅ H ₂₂ F ₆ N ₂ O ₅ S ₂ [M+H] ⁺ 609.0947, found 609.1044.

Embodiment 368

N-(3-cyano-4-((4-(trifluoromethoxy)phenethyl)thio)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-33)

Synthesis of Intermediate V-29

Referring to the method of Example 361, 2-fluoro-4-nitroaniline was replaced by 2-iodo-4-nitroaniline to obtain intermediate V-29: ¹ H NMR (400 MHz, Chloroform-d) δ 8.62 (d, J = 2.4 Hz, 1H), 8.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.26 (d, J = 8.6 Hz, 2H), 7.16 (t, J = 8.3 Hz, 3H), 3.23 (t, J = 7.7 Hz, 2H), 3.05 (t, J = 7.7 Hz, 2H).

Synthesis of Intermediate V-30

Intermediate V-29 (128 mg, 0.27 mmol) and cuprous cyanide (73 mg, 0.82 mmol) were added to N,N-dimethylformamide (2 mL), and the temperature was raised to 100° C. to react for 12 hours. After the reaction, the system was cooled to room temperature, water (20 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with water (15 mL x 1) and saturated brine (15 mL x 1) in sequence, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate V-30 (white solid, 74 mg): ¹ H NMR (400 MHz, Chloroform-d) δ8.43 (d, J = 2.5 Hz, 1H), 8.29 (dd, J = 8.9, 2.5 Hz, 1H), 7.37 (d, J = 8.9 Hz, 1H), 7.27 (d, J = 1.9 Hz, 2H), 7.17 (d, J = 7.6 Hz, 2H), 3.36 (t, J = 7.6 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H).

Synthesis of compound E-33

Referring to the method of Example 337, intermediate V-4 was replaced by intermediate V-30 to obtain compound E-33: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.47(s,1H),9.80(s,1H),8.72(s,1H),8.07(d,J＝2.3Hz,1H),7.75(dd,J＝8.8,2.4Hz,1H),7.61(d,J＝8.8Hz,1H),7.39(d,J＝8.6Hz,2H),7.27(d,J＝7.7Hz,2H),7.17(d,J＝2.1Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.34(s,2H),3.34–3.29(m,2H),2.94(s,3H),2.90(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C _{2 5} H _{2 2} F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 566.1026, found 566.1027.

Embodiment 369

N-(3-cyclopropyl-4-(4-(trifluoromethoxyphenethyl)thio)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-34)

Synthesis of compound E-34

Referring to the method of Example 361, intermediate V-24 was replaced with intermediate 2-mercapto-5-nitropyridine to obtain compound E-34: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.27(s,1H),9.76(s,1H),8.68(s,1H),8.66(d,J＝1.9Hz,1H),7.88(dd,J＝8.7,2.6Hz,1H),7.39(d,J＝8.6Hz,2H),7.28(d,J＝8.8Hz,2H),7.24(d,J＝9.1Hz,1H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.84(d,J＝8.3Hz,1H),3.52(s,2H),3.36(t,J＝7.6Hz,2H),2.94(t,J＝7.5Hz,2H),2.94(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₂ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 542.1026, found 542.1007.

Embodiment 370

2-(4-Hydroxy-3-((1-methylethyl)sulfonamido)phenyl)-N-(4-((4-(trifluoromethoxy)phenylethyl)thio)phenyl)acetamide (Compound E-35)

Synthesis of compound E-35

Referring to the method of Example 337, 4-trifluoromethoxybenzyl bromide was replaced by intermediate III-13, 4-nitrophenol was replaced by 4-nitrothiophenol, and methylsulfonic anhydride was replaced by isopropylsulfonyl chloride to obtain compound E-35: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.15(s,1H),9.77(s,1H),8.60(s,1H),7.56(d,J＝8.7Hz,2H),7.36(d,J＝8.6Hz,2H),7.31(d,J＝8.7Hz,2H),7.27(d,J＝8.0Hz,2H),7.23(d,J＝2.2Hz,1H),6.96(dd,J＝8.3,2.2Hz,1H),6.79(d,J＝8.2Hz,1H),3.48(s,2H),3.17(t,J＝7.6Hz,2H),3.15–3.10(m,1H),2.84(t,J＝7.5Hz,2H),1.25(d,J＝6.8Hz,6H).HRMS(ESI)calcd.for C ₂₆ H ₂₇ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 569.1386, found 569.1404.

Embodiment 371

2-(3-(Cyclopropanesulfonamido)-4-hydroxyphenyl)-N-(4-((4-(trifluoromethoxy)phenylethyl)thio)phenyl)acetamide (Compound E-36)

Synthesis of compound E-36

Referring to the method of Example 337, 4-trifluoromethoxybenzyl bromide was replaced by intermediate III-13, 4-nitrophenol was replaced by 4-nitrothiophenol, and methylsulfonic anhydride was replaced by cyclopropylsulfonyl chloride to obtain compound E-36: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.15(s,1H),9.66(s,1H),8.62(s,1H),7.57(d,J＝8.7Hz,2H),7.36(d,J＝8.6Hz,2H),7.31(d,J＝8.7Hz,2H),7.27(d,J＝8.3Hz,2H),7.23(d,J＝2.1Hz,1H),6.97(dd,J＝8.3,2.2Hz,1H),6.81(d,J＝8.2Hz,1H),3.49(s,2H),3.17(t,J＝7.4Hz,2H),2.84(t,J＝7.5Hz,2H),2.57(p,J＝6.4Hz,1H),0.86(d,J＝6.4Hz,4H).HRMS(ESI)calcd.for C ₂₆ H ₂₅ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 567.1230, found 567.1235.

Embodiment 372

2-(4-Hydroxy-3-(thiophene-2-sulfonamido)phenyl)-N-(4-((4-(trifluoromethoxy)phenylethyl)thio)phenyl)acetamide (Compound E-37)

Synthesis of compound E-37

Referring to the method of Example 337, 4-trifluoromethoxybenzyl bromide was replaced by intermediate III-13, 4-nitrophenol was replaced by 4-nitrothiophenol, and methylsulfonic anhydride was replaced by 2-thiophenesulfonyl chloride to prepare compound E-37: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.15(s,1H),9.54(s,1H),9.38(s,1H),7.81(dd,J＝5.0,1.4Hz,1H),7.57(d,J＝8.7Hz,2H),7.46(dd,J＝3.8,1.4Hz,1H),7.36(d,J＝8.6Hz,2H),7.33(d,J＝8.7Hz,2H),7.27(d,J＝8.3Hz, 2H), 7.21 (d, J = 2.2 Hz, 1H), 7.01 (dd, J = 5.0, 3.7 Hz, 1H), 6.94 (dd, J = 8.2, 2.2 Hz, 1H), 6.70 (d, J = 8.2 Hz, 1H), 3.46 (s, 2H), 3.17 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H). HRMS (ESI) calcd. for C ₂₇ H ₂₃ F ₃ N ₂ O ₅ S ₃ [M+H] ⁺ 609.0794, found 609.0816.

Embodiment 373

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(2-(4-(trifluoromethoxy)phenyl)thioethyl)phenyl)acetamide (Compound E-38)

Synthesis of Intermediate V-31

4-Nitrophenylethanol (893 mg, 5.35 mmol) and 4-dimethylaminopyridine (65 mg, 0.54 mmol) were added to dichloromethane (20 mL), and triethylamine (1.5 mL, 10.7 mmol) was added. p-Toluenesulfonyl chloride (1.53 g, 8.02 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate V-31 (light yellow solid, 1.28 g): ¹ H NMR (400 MHz, CDCl ₃ ) δ8.11 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.30 (s, 2H), 7.28 (s, 2H), 4.30 (t, J = 6.4 Hz, 2H), 3.08 (t, J = 6.4 Hz, 2H), 2.42 (s, 3H).

Synthesis of compound E-38

Referring to the method of Example 337, 4-trifluoromethoxybenzyl bromide was replaced by intermediate V-31, and 4-nitrophenol was replaced by 4-trifluoromethoxybenzenethiol to obtain compound E-38: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.06(s,1H),9.76(s,1H),8.70(s,1H),7.50(d,J＝8.5Hz,2H),7.45(d,J＝8.9Hz,1H),7.32(d,J＝8.9Hz,2H),7.20–7.15(m,3H),7.00(dd,J＝8.2,2.1Hz,1H),6.83(d,J＝8.2Hz,1H),3.48(s,2H),3.22(t,2H),2.93(s,3H),2.81(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 541.1079,found 541.1085.

Embodiment 374

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(2-(4-(trifluoromethyl)thio)phenyl)thioethyl)phenyl)acetamide (Compound E-39)

Synthesis of compound E-39

Referring to the method of Example 361, 2-fluoro-4-nitroaniline was replaced by 4-trifluoromethylthioaniline, and intermediate III-13 was replaced by intermediate V-31 to obtain compound E-39: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.07(s,1H),9.73(s,1H),8.66(s,1H),7.62(d,J＝8.4Hz,2H),7.51(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),7.21(s,1H),7.18(d,J＝2.7Hz,2H),7.00(dd,J＝8.2,2.1Hz,1H),6.83(d,J＝8.2Hz,1H),3.48(s,2H),3.28(t,J＝7.6Hz,2H),2.93(s,3H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₄ S ₃ [M+H] ⁺ 557.0845, found 557.0870.

Embodiment 375

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(2-(4-(trifluoromethyl)phenyl)thioethyl)phenyl)acetamide (Compound E-40)

Synthesis of compound E-40

Referring to the method of Example 337, 4-trifluoromethoxybenzyl bromide was replaced by intermediate V-31, and 4-nitrophenol was replaced by 4-trifluoromethylthiophenol to prepare compound E-40: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.05(s,1H),9.73(s,1H),8.63(s,1H),7.64(d,J＝8.3Hz,2H),7.50(dd,J＝8.4,1.9Hz,4H),7.21–7.17(m,3H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.29(t,J＝7.6Hz,2H),2.94(s,3H),2.85(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C ₂₄ H ₂₃ F ₃ N ₂ O ₄ S ₂ [M+H] ⁺ 525.1124,found 525.1131.

Embodiment 376

N-(3-Fluoro-4-(2-((4-(trifluoromethoxy)phenyl)thio)ethyl)phenyl)-2-(4-hydroxy-3-(methylsulfonamido)phenyl)acetamide (Compound E-41)

Synthesis of Intermediate V-32

Referring to the method of Example 151, 4-trifluoromethylthiophenylacetic acid was replaced by 2-fluoro-4-nitrophenylacetic acid, and 4-hydroxybenzoic acid methyl ester was replaced by 4-trifluoromethoxybenzenethiol to prepare intermediate V-32.

Synthesis of compound E-41

Referring to the method of Example 337, intermediate V-4 was replaced by intermediate V-32 to obtain compound E-41: ¹ H NMR (300 MHz, DMSO) δ 10.27 (s, 1H), 9.78 (s, 1H), 8.70 (s, 1H), 7.54 (d, J = 12.6 Hz, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 10.0 Hz, 2H), 7.17 (d, J = 1.3 Hz, 1H), 6.99 (dd, J = 8.3, 2.2 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 3.50 (s, 2H), 3.21 (t, J = 7.5 Hz, 2H), 2.93 (s, 3H), 2.84 (t, J = 7.4 Hz, 2H). HRMS (ESI) calcd. for C ₂₄ H ₂₂ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 559.0979, found 559.0988.

Embodiment 377

2-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-N-(4-((3-(4-(trifluoromethoxy)phenyl)propyl)thio)phenyl)acetamide (Compound E-42)

Synthesis of Intermediate V-33

Referring to the method of Example 168, 4-trifluoromethoxyphenylacetic acid was replaced by 4-trifluoromethoxyphenylpropionic acid, and 4-bromobenzenethiol was replaced by 4-nitrobenzenethiol to obtain intermediate V-33: ¹ H NMR (400 MHz, Chloroform-d) δ 8.13 (d, J = 9.0 Hz, 2H), 7.30 (d, J = 8.9 Hz, 2H), 7.23 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 7.7 Hz, 2H), 3.04 (t, J = 7.2 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.06 (p, J = 7.4 Hz, 2H).

Synthesis of compound E-42

Referring to the method of Example 337, intermediate V-4 was replaced by intermediate V-33, and intermediate V-9 was replaced by intermediate V-17 to obtain compound E-42: ¹ H NMR (300 MHz, DMSO-d ₆ ) δ10.14 (s, 1H), 9.40 (s, 2H), 7.77 (dd, J＝8.9, 5.2 Hz, 2H), 7.56 (d, J＝8.7 Hz, 2H), 7.30 (d, J＝7.0 Hz, 3H), 7.28 (d, J＝6.1 Hz, 2H), 7.26 (d, J＝2.4 Hz, 2H), 7.24-7.22 (m, 1H), 7.1 8 (d, J = 2.1 Hz, 1H), 6.90 (dd, J = 8.3, 2.3 Hz, 1H), 6.67 (d, J = 8.2 Hz, 1H), 3.44 (s, 2H), 2.89 (t, J = 7.2 Hz, 2H), 2.72 (t, J = 7.3 Hz, 2H), 1.81 (p, J = 7.4 Hz, 2H). HRMS (ESI) calcd. for C ₃₀ H ₂₆ F ₄ N ₂ O ₅ S ₂ [M+H] ⁺ 635.1292, found 635.1284.

Embodiment 378

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(3-(4-(trifluoromethoxy)phenyl)propyl)thiophenyl)acetamide (Compound E-43)

Synthesis of compound E-43

Referring to the method of Example 337, intermediate V-4 was replaced by intermediate V-33 to obtain compound E-43: ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.13(s,1H),9.72(s,1H),8.68(s,1H),7.54(d,J＝8.7Hz,2H),7.32–7.28(m,3H),7.27–7.23(m,3H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),2.94(s,3H),2.88(t,J＝7.2Hz,2H),2.71(t,2H),1.85–1.76(m,2H).HRMS(ESI)calcd.for C _{2 5} H _{2 5} F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 555.1230,found 555.1238.

Embodiment 379

2-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-(3-((4-(trifluoromethoxy)phenyl)thio)propyl)phenyl)acetamide (Compound E-44)

Synthesis of compound E-44

Referring to the method of Example 349, the intermediate III-12 was replaced with 3-(4-nitrophenyl)-1-propanol, and 4-nitrophenol was replaced with 4-trifluoromethoxythiophenol to obtain compound E-44: ¹ H NMR (300 MHz, DMSO-d ₆ )δ10.04(s,1H),9.71(s,1H),8.77(s,1H),7.48(d,J＝8.5Hz,2H),7.40(d,J＝8.8Hz,2H),7.30(dd,J＝8.9,0.8Hz,2H),7.17(d,J＝2.1Hz,1H),7.10(d,J＝8.5Hz,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.82(d,J＝8.3Hz,1H),3.47(s,2H),2.96(t,J＝7.1Hz,2H),2.93(s,3H),2.64(t,J＝7.5Hz,2H),1.82(p,J＝7.3Hz,2H).HRMS(ESI)calcd.for C ₂₅ H ₂₅ F ₃ N ₂ O ₅ S ₂ [M+H] ⁺ 555.1230, found 555.1229.

Embodiment 380

N-(2-Hydroxy-5-(3-(4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzyl)ureido)phenyl)methanesulfonamide (Compound E-45)

Synthesis of Intermediate V-34

Referring to the method of Example 66, 4-(bromomethyl)benzoic acid ethyl ester was replaced with 4-bromomethylphenylacetic acid methyl ester to obtain intermediate V-34: ¹ H NMR (300 MHz, DMSO) δ 12.34 (s, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.1 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 7.14 (d, 2H), 5.14 (s, 2H), 3.57 (s, 2H).

Synthesis of Intermediate V-35

Intermediate V-34 (75 mg, 0.22 mmol) and triethylamine (68 μL, 0.48 mmol) were added to toluene (2 mL), and diphenylphosphoryl azide (52 μL, 0.24 mmol) was added dropwise under an ice bath. After the addition was completed, the temperature was raised to 90 ° C for 5 hours. After the reaction was completed, the system was cooled to room temperature, and intermediate I-18 (70 mg, 0.22 mmol) was added to the reaction solution in batches. After the addition was completed, the reaction was continued at room temperature for 8 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 3:1) to obtain intermediate V-35 (brown solid, 79 mg).

Synthesis of compound E-45

Intermediate V-35 (79 mg, 0.12 mmol) and triethylamine trihydrofluoride (60 μL, 0.36 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=80:1) to obtain a crude compound E-45 (white solid, 32 mg), which was purified by slurrying (n-hexane/dichloromethane=1:1), and the obtained solid was dried to constant weight to obtain compound E-45 (white solid, 22 mg): ¹ H NMR (300 MHz, DMSO-d ₆ )δ9.36(s,1H),8.58(s,1H),8.33(s,1H),7.63(d,J＝8.7Hz,2H),7.41(d,J＝8.1Hz,2H),7.30(d,J＝8.0Hz,2H),7.23(d,J＝2.6Hz,1H),7.14(d,J＝8.9Hz,2H),7.10(dd,J＝8.7,2.6Hz,1H),6.74(d,J＝8.7Hz,1H),6.44(t,J＝6.0Hz,1H),5.14(s,2H),4.27(d,J＝5.8Hz,2H),2.92(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₂ F ₃ N ₃ O ₅ S ₂ [M+H] ⁺ 542.1026, found 542.1019.

Embodiment 381

N ¹ -(4-hydroxy-3-(methylsulfonamido)phenyl)-N ² -(4-((4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)oxalamide (Compound E-46)

Synthesis of Intermediate V-36

Intermediate V-12 (158 mg, 0.53 mmol) and pyridine (64 μL, 0.80 mmol) were added to dichloromethane (3 mL), and (60 μL, 0.63 mmol) was added dropwise under ice bath. After the addition was completed, the temperature was raised to room temperature and reacted for 8 hours. After the reaction was completed, 1N aqueous hydrogen chloride solution (10 mL) was added to the reaction solution to quench the excess pyridine, and ethyl acetate (10 mL x 3) was used for extraction. The organic phases were combined and washed with saturated brine (10 mL x 1). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1). The obtained solid was dried to constant weight to obtain intermediate V-36 (white solid, 166 mg): ¹ H NMR (300 MHz, Chloroform-d) δ8.88 (s, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 8.7 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.9 Hz, 2H), 5.07 (s, 2H), 3.99 (s, 3H).

Synthesis of Intermediate V-37

The intermediate V-36 (166 mg, 0.43 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (1.5 mL), and a 1 M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at room temperature for 6 hours. After the reaction, a 1 N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 2-3, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain the intermediate V-37 (yellow solid, 133 mg).

Synthesis of Intermediate V-38

Intermediate V-37 (93 mg, 0.25 mmol), intermediate I-18 (87 mg, 0.28 mmol) and N, N-diisopropylethylamine (131 μL, 0.75 mmol) were added to dichloromethane (2 mL), stirred at room temperature for 10 minutes, and then 2-(7-azobenzotriazole)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU) (143 mg, 0.38 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature for reaction for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (8 mL x 3) was used for extraction. The organic phases were combined, washed with saturated brine (10 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to obtain intermediate V-38 (white solid, 88 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.90(s,1H),10.84(s,1H),8.48(s,1H),7.95(d,J＝2.6Hz,1H),7.89(d,J＝8.6Hz,2H),7.65(d,J＝8.8Hz,2H),7.59(dd,J＝8.9,2.6Hz,1H),7.47(d,J＝8.6Hz,2H),7.16(d,J＝8.9Hz,2H),6.94(d,J＝8.8Hz,1H),5.14(s,2H),3.07(s,3H),0.99(s,9H),0.24(s,6H).

Synthesis of compound E-46

Intermediate V-38 (88 mg, 0.13 mmol) and triethylamine trihydrofluoride (64 μL, 0.39 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction, solids were precipitated, filtered, and the filter cake was washed with dichloromethane (2 mL) to obtain a crude compound E-46 (white solid, 50 mg), which was purified by slurrying (dichloromethane/n-hexane = 1:1), and the obtained solid was dried to constant weight to obtain compound E-46 (white solid, 44 mg): ¹ H NMR (400 MHz, DMSO-d ₆ )δ10.87(s,1H),10.71(s,1H),9.82(s,1H),8.73(s,1H),7.88(d,J＝8.6Hz,2H),7.83(d,J＝2.6Hz,1H),7.65(d,J＝8.7Hz,2H),7.50(dd,J＝8.8,2.6Hz,1H),7.47(d,J＝8.6Hz,2H),7.16(d,J＝8.8Hz,2H),6.87(d,J＝8.7Hz,1H),5.14(s,2H),2.99(s,3H).HRMS(ESI)calcd.for C ₂₃ H ₂₀ F ₃ N ₃ O ₆ S ₂ [M+H] ⁺ 556.0818,found 556.0812.

Embodiment 382

N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-N-(4-((4-((trifluoromethyl)thio)phenoxy)methyl)phenyl)cyclopropane-1,1-dicarboxamide (Compound E-47)

Synthesis of Intermediate V-39

Intermediate V-12 (211 mg, 0.71 mmol), 1,1-cyclopropyldicarboxylic acid monomethyl ester (112 mg, 0.78 mmol) and N,N-diisopropylethylamine (375 μL, 2.13 mmol) were added to dichloromethane (3 mL), stirred at room temperature for 10 minutes, and then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (405 mg, 1.07 mmol) was added in batches under ice bath. After the addition was completed, the temperature was raised to room temperature for reaction for 3 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, and ethyl acetate (8 mL x 3) was used for extraction. The organic phases were combined and washed with saturated brine (10 mL x 1). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 8:1) to obtain intermediate V-39 (white solid, 172 mg): ¹ H NMR (300 MHz, Chloroform-d) δ 10.91 (s, 1H), 7.62 (d, J = 8.5 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.37 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.8 Hz, 2H), 5.04 (s, 2H), 3.74 (s, 3H), 1.85–1.80 (m, 2H), 1.70–1.65 (m, 2H).

Synthesis of compound E-47

Referring to the method of Example 381, intermediate V-36 was replaced by intermediate V-39 to obtain intermediate E-47: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.20 (s, 1H), 9.77 (s, 1H), 9.59 (s, 1H), 8.81 (s, 1H), 7.63 (d, J = 8.4 Hz, 4H), 7.46 (d, J = 2.6 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.30 (dd, J = 8.8, 2.6 Hz, 1H), 7.15 (d, J = 8.8 Hz, 2H), 6.80 (d, J = 8.7 Hz, 1H), 5.11 (s, 2H), 2.94 (s, 3H), 1.59-1.32 (m, 4H). HRMS (ESI) calcd. for C ₂₆ H ₂₄ F ₃ N ₃ O ₆ S ₂ [M+H] ⁺ 596.1131, found 596.1125.

Embodiment 383

Evaluation of the inhibitory activity of compounds on the STING signaling pathway in THP1 cells

Experimental principle: THP1 cells express cGAS and STING proteins. The introduction of exogenous double-stranded DNA can activate the cGAS-STING signaling pathway, thereby enhancing the transcriptional activity of IRF. Therefore, the cGAS-STING-IRF signaling pathway in cells is activated by transfection of exogenous HT-DNA. After adding compounds to intervene in the STING signaling pathway, the inhibitory activity of the compounds on the STING signaling pathway can be evaluated by detecting the gene expression level of the IRF downstream target gene IFN-β.

Experimental reagents and materials: heat-inactivated serum (Biological Industries), 1640 culture medium (Biological Industries), penicillin-streptomycin dual antibody (Biological Industries), THP1 cells (Saiku Biotechnology), HT-DNA (Sigma Aldrich, prepared as a 2.5 mg/mL storage solution), Opti-MEM (Gibco), Lipo6000 (Biyuntian).

Experimental method: Activity test method of wild-type THP-1 cells: Take cells with cell viability greater than 90%, inoculate 300,000 cells/well in a 12-well plate, and add compounds for co-incubation (the compound is dissolved in DMSO, and the final test concentration of the compound in the culture medium is 0.1 and 1μM, with DMSO as a blank control). After incubation for 6 hours, use Lipo6000 transfection reagent to transfect 0.5μg/mL HT-DNA to stimulate the cells for 12 hours. The cell suspension was collected in a 1.5mL EP tube and centrifuged at 3000g for 10 minutes to collect the cells. Detect the expression of the IFN-β gene. This experiment used the STING inhibitors H-151 and SN-011 reported in the literature as positive control compounds.

The extraction process of total RNA in cells is as follows: 1) After the cells are fully lysed with Trizol, chloroform is added to extract the RNA in the lysate, and centrifuged at 4℃12000g for 15min; 2) Isopropanol is added to the supernatant solution to precipitate the RNA in the solution; 3) The RNA precipitate is washed with 75% ethanol to remove impurities; 4) After the RNA is dried and transparent, it is dissolved with an appropriate amount of DEPC water, and the RNA concentration is detected at OD260. After the total RNA is extracted, it can be used for subsequent fluorescent quantitative PCR to detect the expression of the target gene. The experimental steps are as follows: RNA is mixed with the reverse transcription reagent and reversely transcribed into cDNA. The cDNA is mixed with the primers of IFN-β and GAPDH genes, DNA polymerase and fluorescent dye, respectively, and amplified and detected in the ABI Step-One-Plus instrument. GAPDH is the internal reference for gene expression, and the 2-ΔΔCT method is used to relatively quantify the expression of the target gene. The primer sequences used to detect the target gene are as follows:

The inhibition rate of the compound on the STING signaling pathway after HT-DNA stimulation at concentrations of 1 and 0.1 μM was calculated based on the IFN-β gene expression multiple: {100-100*[IFN-β(drug group+HT-DNA)/IFN-β(DMSO blank group+HT-DNA)]}%.

Experimental results: The inhibitory activity of the compounds on the STING signaling pathway of wild-type THP1 cells is shown in Table 2. Show.

Table 2. Inhibitory activity of compounds on STING signaling pathway in THP1 cells

In addition, the activity of some compounds was tested using THP-1 dual cells. The inhibitory activity results of the compounds on the STING signaling pathway of THP-1 dual cells are shown in Table 3.

Experimental method: HT-DNA complex was mixed with THP-1 dual cells, seeded into 96-well plates, 4×10 ⁴ cells per well, 100 μL of the mixture was added to each well, the compound with a concentration of 10 μM was gradiently diluted into 6 concentrations, 100 μL was added to each well, and the expression of IFN-β gene was detected after 16-18 hours.

Table 3. Inhibitory activity of compounds on STING signaling pathway in THP1 dual cells

The experimental results (Table 2 and Table 3) show that the sulfonamide compounds of the present invention can significantly inhibit the expression of IFN-β gene downstream of the STING signaling pathway in THP-1 cells induced by 2'3'-cGAMP stimulation. The test results of wild-type THP-1 cells show that the inhibition rate of multiple compounds at a concentration of 0.1 μM is close to or greater than 90% (such as: compounds B-12, B-15, B-39, B-59, B-74, B-79, B-82, B-83, B-100, C-4, C-14, C-22, C-49, C-51, C-70, C-77, D-41, D-56, D-57, D-59, D-70, D-71, D-73, D-74, D-95, D-96, E-17), and the IC of some compounds is The IC ₅₀ values of the compounds of the present invention reached the nanomolar level (such as compounds B-39, B-59, B-80, C-22, C-51, C-77, D-49), among which the IC ₅₀ value of compound B-59 (IC ₅₀ =3.67nM) reached the single-digit nanomolar level, and under the same test system, its activity was significantly better than the positive molecules H-151 (IC ₅₀ =116.5nM) and SN-011 (IC ₅₀ =458nM). In addition, the THP-1 dual cell test results showed that the IC ₅₀ values of some compounds were better than the positive molecules H-151 (IC ₅₀ =1368nM) and SN-011 (IC ₅₀ =5104nM), (such as compounds D-61, D-62, D-63, D-88, D-91). Other compounds in the present invention also showed significant STING signaling pathway inhibitory activity. This indicates that the sulfonamide compounds of the present invention or pharmaceutically acceptable salts thereof can be used as novel small molecule inhibitors targeting STING, and can effectively inhibit the activation of the STING signaling pathway.

Embodiment 384

Liver microsome stability test

A methanol/water (1:1) solution of the compound with a concentration of 100 μM was prepared and diluted to a 1.11 μM drug working solution with a mixed solution of 0.01 M magnesium chloride and 0.1 M potassium phosphate. The drug working solution was incubated with a human liver microsome working solution with a final concentration of 0.7 mg/mL and a NADPH solution (final concentration of 10 mM). The methanol/water solution was added at 0, 15, 30, 45 and 60 min to terminate the incubation. The volume of each time point was detected by LC/MS. The remaining amount of the compound in the system is measured by plotting the natural logarithm of the percentage of the remaining amount of the compound against time to obtain the absolute value of the slope k, which is calculated according to the formula: T1/2 (half-life) = ln2/k = 0.693/k. The experimental results are shown in Table 4.

Table 4. Metabolic stability results of compounds in human liver microsomes

The experimental results (Table 4) show that compounds B-39 and E-17 have good metabolic stability in human liver microsomes, compounds B-59 and C-51 have very good metabolic stability in human liver microsomes, and the metabolic stability of the above four compounds in human liver microsomes is much better than that of the positive control drug H-151 under the same test conditions. Some other compounds of the present invention also have good metabolic stability in human liver microsomes.

Embodiment 385

Pharmacokinetic evaluation of compound B-59 in mice

Animals: Six male SD rats were obtained from Suzhou Tuowei Biological Animal Reserve.

Grouping: Rats were divided into 2 groups, 3 rats in each group, one group was an oral administration group, and the other group was an intravenous administration group. The oral administration group had a dosage of 10 mpk, and the intravenous administration group had a dosage of 2 mpk.

Experimental method: After the intravenous administration group was administered by tail vein injection, about 0.03 mL of blood was collected from the eye socket at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, and dipotassium ethylenediaminetetraacetic acid was quickly added for anticoagulation after blood collection. The blood was placed on ice after collection. The mice in the oral administration group fasted for 12 hours before administration and were fed 4 hours after administration; after oral administration, about 0.03 mL of blood was collected from the eye socket at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours, and dipotassium ethylenediaminetetraacetic acid was quickly added for anticoagulation after blood collection. The blood was placed on ice after collection. All samples were centrifuged at 18000g for 7 minutes in a low-temperature centrifuge to separate plasma. The content of the compound in the plasma was detected by LC-MS/MS-18, and the relevant pharmacokinetic parameters were calculated based on the blood drug concentration data at different time points. The experimental results are shown in Table 5.

Table 5. Pharmacokinetic parameters of compound B-59 after intravenous and oral administration in mice

The experimental results (Table 5) show that the oral half-life of compound B-59 is 4.29 hours, the oral bioavailability of compound B-59 is 18.7%, and the pharmacokinetic properties are good. Some other compounds of the present invention also have good pharmacokinetic properties.

Embodiment 386

Effects of compounds B-80, C-22, C-51, D-60, D-75 and D-88 on the mouse psoriasis model induced by imiquimod cream

In order to verify the effect of the compound of the present invention on autoimmune diseases, the psoriasis model of mice induced by imiquimod cream was used to verify the efficacy of the compound.

Experimental animals: Balb/c female mice, 8 weeks old, were purchased from Zhejiang Weitonglihua Experimental Animal Co., Ltd.

Preparation of test drugs: Heat 7.2g PEG400 to 55-60℃, add 200mg test drug and stir, and use ultrasonic cleaner to dissolve, repeatedly invert and mix several times, and after dissolving, heat 2.8g PEG3350 to 55-60℃ and dissolve, mix with PEG400 mixed with test drug, and pack into 1g/tube to prepare 2% test drug ointment, and apply 0.2g/mouse on the back of mice. At the same time, prepare a control ointment without compound, and the test groups are ointments containing B-80, C-22, C-51, D-60, D-75 and D-88 respectively.

Modeling and drug administration: The mice were randomly divided into a blank group, a model group, a B-80 group (applied with 2% B-80 ointment), a C-22 group (applied with 2% C-22 ointment), a C-51 group (applied with 2% C-51 ointment), a D-60 group (applied with 2% D-60 ointment), a D-75 group (applied with 2% D-75 ointment) and a D-88 group (applied with 2% D-88 ointment), with 5 mice in each group. The back of the mice was depilated to expose a 2cm×3cm skin area. After depilation, the mice were allowed to adapt for 2 days. 5% Imiquimod (IMQ) cream was applied to the back at 50 mg/mouse, once a day, for 7 days of modeling. At the same time, the corresponding test drug ointment was given to the drug administration group, and the control ointment of the control group and the model group was given at 0.2 g/mouse, once a day, for a total of 7 days. The mice were weighed every day, back photos were taken and PASI (psoriasis area and severity index) was scored.

The experimental results (Figure 1) show that compounds B-80, C-22, C-51, D-60, D-75 and D-88 can effectively reduce the PASI score of psoriasis mice caused by imiquimod cream, indicating that the pathological characteristics such as psoriasis-like inflammatory damage, skin thickening and scale formation on the back of model mice can be reduced. It shows that these compounds have significant immunomodulatory effects and can be used for the treatment of psoriasis. This suggests that compounds B-80, C-22, C-51, D-60, D-75 and D-88 can be used to prevent and treat autoimmune diseases, organ transplant rejection, infectious diseases and inflammatory diseases. Other compounds of the present invention also have similar therapeutic effects.

Claims

A sulfonamide compound represented by the following formula I or a pharmaceutically acceptable salt, ester or solvate thereof:

R 1 is selected from: H, C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl;

R2 is selected from: substituted or unsubstituted C1 - C6 alkyl, C2 - C6 alkenyl, C2- C6 alkynyl, ( CH2 ) nOH , ( CH2 ) nNH2 , (CH2) nC ( O )O( CH2 ) mCH3 , substituted or unsubstituted C3 - C8 cycloalkyl, substituted or unsubstituted C3 - C6 alicyclic group or substituted or unsubstituted aryl or heteroaryl, wherein the substituted C1 -C6 wherein the substituted C 3 -C 8 cycloalkyl, C 3 -C 6 cycloalkyl, aryl or heteroaryl is substituted by one or two or three substituents independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl , halogen, CN, NO 2 , NH 2 , OH , CF 3 , OCF 3 , SCF 3 , C(O)OH or C(O)NH 2 ;

Wherein, n and m in the R2 substituent are each independently selected from: any integer from 0 to 4;

R3 is selected from the group consisting of: H, halogen, C1 - C6 alkyl, C1 - C6 alkyloxy, ( CH2 ) nOH , ( CH2 ) nC (O)OH, ( CH2 )nC(O)O(CH2)mCH3, OC(O)(CH2)nCH3 or ( CH2 ) nC ( O ) NH2 ;

Wherein, n and m in the R 3 substituent are independently selected from: any integer from 0 to 4;

R 4 is selected from: H, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, (CH 2 ) n OH, (CH 2 ) n C(O)OH, (CH 2 ) n C(O)O(CH 2 ) m CH 3 or (CH 2 ) n C(O)NH 2 ;

Wherein, n and m in the R 4 substituent are independently selected from: any integer from 0 to 4;

R5 and R6 are each independently selected from the group consisting of H, N( CH3 ) 2 , N( CH2CH3 ) 2 , CN, NO2 , CHF2 , ( CH2 ) nC (O)OH, ( CH2 ) nC (O)O( CH2 ) mCH3 , ( CH2 ) nCF3 , ( CH2 ) nOCF3 , ( CH2 ) nSCF3 , S ( CH2 ) 1SCF3 , O ( CH2 ) 1SCF3 , ( CH2) nOH , ( CH2 ) nNH2 , SO2CH3 , SO2CF3 , halogen, pyrrolyl, imidazolyl , triazolyl, C1- C6 alkyl, C2 - C6 alkenyl , C2 - C6 alkynyl , C1 -C6 C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylamino, C 1 -C 6 alkylsulfonyl, substituted or unsubstituted C 3 -C 8 cycloalkyl or substituted or unsubstituted C 6 aliphatic heterocyclic group, wherein the substituted C 3 -C 8 cycloalkyl or C 6 aliphatic heterocyclic group is substituted by one or two substituents independently selected from the following: C 1 -C 6 alkyl or halogen, or adjacent R 5 and R 6 together with the atoms to which they are connected can form a benzene ring, a C 5 -C 6 cycloalkane, a C 5 -C 6 aliphatic heterocyclic ring or a C 5 -C 6 aromatic heterocyclic ring;

Wherein, n and m in the substituents R5 and R6 are independently selected from any integer from 0 to 4; the letter l is selected from any integer from 1 to 3;

R 7 , R 8 and R 9 are each independently selected from the group consisting of H, CN, NO 2 , CHF 2 , OCHF 2 , (CH 2 ) n C(O)OH, (CH 2 ) n C(O)O(CH 2 ) m CH 3 , (CH 2 ) n CF 3 , (CH 2 ) n OCF 3 , (CH 2 ) n SCF 3 , S(CH 2 ) l SCF 3 , O(CH 2 ) l SCF 3 , (CH 2 ) n OH, (CH 2 ) n NH 2 , SO 2 CH 3 , SO 2 CF 3 , halogen, C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, C 1 -C 6 -C 6 alkylamino, substituted or unsubstituted C 3 -C 8 cycloalkyl or substituted or unsubstituted C 3 -C 6 alicyclic heterocyclic group, wherein the substituted C 3 -C 8 cycloalkyl or C 3 -C 6 alicyclic heterocyclic group is independently substituted by one or two of the following substituents: OH, NH 2 , halogen, C 1 -C 6 alkyl, or, at least two of the adjacent R 7 , R 8 or R 9 substituents together with the atoms to which they are attached can form a C 5 -C 8 cycloalkane, a benzene ring, a C 5 -C 6 aromatic heterocycle, or a C 5 -C 6 alicyclic heterocycle;

Wherein, n and m in the substituents R 7 , R 8 and R 9 are independently selected from any integer from 0 to 4; the letter l is selected from any integer from 1 to 3;

A is selected from the group consisting of C 3 -C 8 cycloalkyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, piperidinyl, piperazinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolin-1-one, phthalimido or 3,4-dihydroisoquinolin-1(2H)-one;

B is absent or selected from: C 3 -C 8 cycloalkyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl;

L 1 is selected from:

wherein Ra and Rb are each independently selected from: H, C1 - C6 alkyl, C1 - C6 alkylcarbonyl, substituted or unsubstituted C3 - C6 cycloalkyl, substituted or unsubstituted C3 - C6 alicyclic heterocyclic group, or substituted or unsubstituted aryl or heteroaryl, wherein the substituted C3- C6 cycloalkyl, C3 - C6 alicyclic heterocyclic group, aryl or heteroaryl is substituted by one or two substituents each independently selected from: C1 - C6 alkyl, C1- C6 alkyloxy, C1 - C6 alkoxycarbonyl, C1 - C6 alkylsulfonyl, halogen, OH, NH2 , CN, NO2 , CF3 , OCF3 , SCF3 , C(O)OH or C(O) NH2 ;

L2 may be absent or selected from:

wherein R c and R d are each independently selected from: H, CF 3 , halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 3 -C 6 alicyclic heterocyclic group or substituted or unsubstituted aryl or heteroaryl group, wherein the substituted C 3 -C 6 cycloalkyl, C 3 -C 6 alicyclic heterocyclic group, aryl or heteroaryl group is substituted by one, two or three substituents each independently selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl, halogen, OH, NH 2 , CN, NO 2 , CF 3 , OCF 3 , SCF 3 , C(O)OH or C(O)NH 2 , or R c and R d are each independently selected from: H, CF 3 , oxo, C 1 -C 6 alkyl, C 1 -C 6 alkyloxy, C 1 -C 6 alkylthio, substituted or unsubstituted C 3 -C 6 cycloalkyl, C 3 -C 6 alicyclic heterocyclic group, substituted or unsubstituted aryl or heteroaryl group, wherein the substituted C 3 -C 6 cycloalkyl, C 3 -C 6 alicyclic heterocyclic group, aryl or heteroaryl group is substituted by one, two or three substituents each independently selected from: C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkylsulfonyl, halogen, OH, NH 2 , CN, NO 2 , CF 3 , OCF 3 , SCF 3 , C c or R d and the atoms to which they are attached may together form a C 3 -C 6 cycloalkane or a C 3 -C 6 aliphatic heterocycle;

X is selected from: CH 2 , O, S, NH, NR e , sulfoxide or sulfone;

Wherein, Re is selected from: C 1 -C 6 alkyl, C 1 -C 6 alkylcarbonyl or tert-butyloxycarbonyl, or, Re and one of the substituents of R 5 , R 6 , R 7 , R 8 or R 9 on the A ring or the B ring and the atoms to which they are attached can form a C 5 -C 6 heterocycle together;

p and q are each independently selected from any integer of 0-4.
The sulfonamide compound or its pharmaceutically acceptable salt, ester or solvate according to claim 1, characterized in that:

R 1 is selected from: H, C 1 -C 3 alkyl or cyclopropyl;

R2 is selected from: C1 - C4 alkyl, ( CH2 ) nOH , ( CH2 ) nNH2 , ( CH2 ) nC (O)O( CH2 ) mCH3 , ( CH2 ) nC (O)OH, substituted or unsubstituted C3 - C6 cycloalkyl, substituted or unsubstituted C6 alicyclic group or substituted or unsubstituted aryl or heteroaryl, wherein the alicyclic group is selected from piperidinyl, piperazinyl, morpholinyl; the aryl or heteroaryl is independently selected from phenyl, pyridinyl, pyrimidinyl, thienyl, furanyl or thiazolyl; the substituted C3 - C6 cycloalkyl, alicyclic group, aryl or heteroaryl is substituted by one, two or three substituents independently selected from the following: C1 - C4 alkyl, C1 - C4 alkoxy, halogen, CN, CF3 , OCF3 or SCF3 ;

Wherein, n and m in the R2 substituent are each independently selected from: any integer from 0 to 4;

R 3 is selected from: H, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkyloxy, C 1 -C 3 alkylamino, (CH 2 ) n OH, (CH 2 ) n C(O)OH or (CH 2 ) n C(O)O(CH 2 ) m CH;

Wherein, n and m in the R 3 substituent are independently selected from: any integer from 0 to 4;

R 4 is selected from: H, OH, halogen, C 1 -C 3 alkyl, C 1 -C 3 alkyloxy, cyclopropyl, C(O)OCH 3 or C(O)OH;

R 5 and R 6 are each independently selected from the group consisting of H, OH, NH 2 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , C(O)OH, CN, NO 2 , CHF 2 , (CH 2 ) k CF 3 , (CH 2 ) k OCF 3 , (CH 2 ) k SCF 3 , S(CH 2 ) l SCF 3 , O(CH 2 ) l SCF 3 , SO 2 CH 3 , SO 2 CF 3 , halogen, pyrrolyl, imidazolyl, triazolyl, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, C 1 -C 4 alkylthio, substituted or unsubstituted C 3 -C 8 cycloalkyl or substituted or unsubstituted C 6 aliphatic heterocyclic group, wherein the C 6 aliphatic heterocyclic group is selected from piperidinyl, piperazinyl or morpholinyl; the substituted C 6 aliphatic heterocyclic group is selected from piperidinyl, piperazinyl or morpholinyl; The 3 -C 8 cycloalkyl or C 6 aliphatic heterocyclic group is substituted by one or two substituents independently selected from the following: C 1 -C 4 alkyl or halogen, or adjacent R 5 and R 6 together with the atoms to which they are attached can form a C 5 -C 6 aromatic heterocycle, wherein the C 5 -C 6 aromatic heterocycle is selected from: pyrrole, imidazole, oxazole, thiazole, oxadiazole, pyridine or pyrimidine;

Wherein, k in the R 5 and R 6 substituents is selected from: 0, 1 or 2; the letter l is selected from: 1, 2 or 3;

R 7 , R 8 and R 9 are each independently selected from the group consisting of H, OH, NH 2 , CN, NO 2 , CHF 2 , OCHF 2 , C(O)OH, (CH 2 ) k CF 3 , (CH 2 ) k OCF 3 , (CH 2 ) k SCF 3 , S(CH 2 ) l SCF 3 , O(CH 2 ) l SCF 3 , SO 2 CH 3 , SO 2 CF 3 , halogen, C 1 -C 4 alkyl , C 1 -C 4 alkyloxy, C 1 -C 4 alkylthio or C 3 -C 6 cycloalkyl; or, adjacent R 7 , R 8 or R 9 are each independently selected from the group consisting of H, OH, NH 2 , CN, NO 2 , CHF 2 , OCHF 2 , C(O)OH, (CH 2 ) k CF 3 , (CH 2 ) k OCF 3 , (CH 2 ) k SCF 3 , S(CH 2 ) l SCF 3 , O(CH 2 ) l SCF 3 , SO 2 CH 3 , SO 2 CF 3 , halogen, C 1 -C 4 alkyl , C 1 -C 4 alkyloxy , C 1 -C 4 alkylthio or C 3 -C 6 cycloalkyl. 9 wherein at least two substituents together with the atoms to which they are attached can form a benzene ring, a cycloalkane, an aromatic heterocycle or a substituted or unsubstituted aliphatic heterocycle, wherein the cycloalkane is selected from cyclopentane or cyclohexane; the aromatic heterocycle is selected from pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyridine or pyrimidine; the aliphatic heterocycle is selected from piperidine, piperazine, morpholine or 1,4-dioxane; the substituted aliphatic heterocycle is substituted by a substituent as follows: C 1 -C 3 alkyl or C 1 -C 3 alkylsulfonyl;

Wherein, k in the substituents R 7 , R 8 and R 9 is selected from: 0, 1 or 2; the letter l is selected from: 1, 2 or 3;

A is selected from: C 3 -C 6 cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, indolyl, piperidinyl or piperazinyl;

B is absent or selected from: C 3 -C 8 cycloalkyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, indolyl, benzoxazolyl, benzothiazolyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl;

L 1 is selected from:

Ra and Rb are each independently selected from: H, C1 - C3 alkyl or C3 - C6 cycloalkyl;

L2 may be absent or selected from:

Where, when L2 does not exist and L1 is: When A is selected only from: and B does not exist;

R c and R d are each independently selected from: H, F, Cl, CF 3 , oxo, C 1 -C 4 alkyl, C 1 -C 4 alkyloxy, C 1 -C 4 alkylthio or C 3 -C 6 cycloalkyl, or, R c or R d attached to the same carbon atom and the atoms to which they are attached may together form a C 3 -C 6 cycloalkane ring;

X is selected from: CH 2 , O, S, NH, NR e , sulfoxide or sulfone;

Re is selected from: C1 - C3 alkyl, C1 - C3 alkylcarbonyl or tert-butyloxycarbonyl, or Re and one of the substituents of R5 , R6 , R7 , R8 or R9 on the A ring or the B ring and the atoms to which they are attached can form a C5 - C6 heterocycle, wherein the C5 - C6 heterocycle is selected from: pyrrole, piperidine, pyrrolidone, piperidone, succinimide, glutarimide;

p and q are each independently selected from any integer of 0-3.
A sulfonamide compound represented by the following formula I or a pharmaceutically acceptable salt, ester or solvate thereof:

R 1 is selected from: H, C 1 -C 3 alkyl or C 1 -C 3 alkylcarbonyl;

R2 is selected from: substituted or unsubstituted C1 - C4 alkyl, cyclopropyl, CF3 , vinyl, substituted or unsubstituted aryl or heteroaryl, NH2 , C1 - C4 alkylamino, hydroxy- C1 - C3 alkylamino or morpholinyl, wherein the aryl or heteroaryl is selected from phenyl, naphthyl, pyridyl, pyrazolyl, furanyl or thiophene, wherein the substituted C1 - C4 alkyl is substituted by one, two or three substituents independently selected from the following: F, Cl, NH2 , OH, diethanolamino, methanesulfonyl, acetylamino, aminoacetylamino, pyrrolidin-1-yl, piperidin-1-yl, substituted piperidin-1-yl, piperazin-1-yl, substituted piperazin-1-yl, morpholin-4-yl, thiomorpholin-1,1-dioxol-4-yl, N,N-dimethylamino, carboxyl, carboxylate, formylamino or aminoformylamino, wherein the substituted aryl or heteroaryl is substituted by one or two substituents independently selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl , C 1 -C 3 alkylsulfonyl, F, Cl, Br, I, CN, NO 2 , NH 2 , OH, CF 3 , CF 2 CF 3 , OCF 3 , OCF 2 CF 3 , C(O)OH or C(O)NH 2 ;

R 3 is selected from: H, OH, halogen, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylcarbonyloxy, C 1 -C 3 alkoxycarbonyl, (CH 2 ) n C(O)OH, (CH 2 ) n C(O)NH 2 , or C(O)NHSO 2 CH 3 ;

n is selected from: 0, 1, 2 or 3;

R 4 is selected from: H, OH, halogen, C 1 -C 3 alkyl, COOCH 3 , COOH or CONH 2 ;

L 1 is selected from:

Ra and Rb are each independently selected from: H, C1 - C3 alkyl or C3 - C6 cycloalkyl;

A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, cyclohexyl, piperidinyl or piperazinyl;

R 5 and R 6 are each independently selected from: H, OH, halogen, CN, C 1 -C 6 alkyl, CF 3 , CHF 2 , SCH 3 , OCF 3 , SCF 3 , C 1 -C 6 alkylsulfonyl, C 1 -C 6 alkoxy, C 1 -C 6 cycloalkyl, C 1 -C 6 cycloalkenyl, C 1 -C 6 heterocycloalkyl, C 1 -C 6 heterocycloalkenyl, C 1 -C 6 alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, the substituted phenyl may be independently substituted by 1 to 2 of the following substituents: halogen, OH, CN, C 1 -C 6 alkyl, CF 3 , CHF 2 , SCH 3 , OCF 3 , SCF 3 or C 1 -C 6 alkylsulfonyl, or, R R 5 and R 6 together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring;

L2 is absent or selected from:

X is selected from: C, O, S, NH, sulfoxide or sulfone;

p and q are each independently selected from: any integer from 0 to 5;

B is selected from: H, halogen CN, OH, NH 2 , NO 2 , CF 3 , CHF 2 , OCF 3 , SCF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylamino, substituted or unsubstituted phenyl, naphthyl, pyridyl, imidazolyl, pyrazolyl, furyl, thienyl, C 3 -C 8 cycloalkyl or 4-7 membered nitrogen-containing heterocycle;

R7 and R8 are each independently selected from: H, OH, halogen, CN, C1 - C6 alkyl, CF3 , CHF2 , SCH3 , OCF3 , SCF3 , C1 - C6 alkylsulfonyl, C1-C6 alkoxy , C1 - C6 cycloalkyl, C1 - C6 cycloalkenyl , C1 - C6 heterocycloalkyl, C1 - C6 heterocycloalkenyl, C1 - C6 alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, the substituted phenyl may be independently substituted by 1 to 2 substituents: halogen, OH, CN, C1 - C6 alkyl, CF3 , CHF2 , SCH3 , OCF3 , SCF3 or C1 - C6 alkylsulfonyl, or, R R 5 and R 6 together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring.
The sulfonamide compound or its pharmaceutically acceptable salt, ester or solvate according to claim 3, characterized in that:

R 1 is selected from: H or C 1 -C 3 alkyl;

R2 is selected from: substituted or unsubstituted C1 - C4 alkyl, cyclopropyl, CF3 , vinyl, substituted or unsubstituted aryl or heteroaryl, hydroxy- C1 - C3 alkylamino or morpholinyl, wherein the aryl or heteroaryl is selected from phenyl, naphthyl, pyridyl, pyrazolyl, furanyl or thienyl, and the substituted aryl or heteroaryl is substituted by one or two substituents independently selected from the following: C1 - C3 alkyl, C1- C3 alkoxy, C1 - C3 alkoxycarbonyl, C1 - C3 alkylsulfonyl, F, Cl, Br, I, CN, NO2 , NH2 , OH, CF3 , CF2CF3 , OCF3 , OCF2CF3 , C(O)OH or C(O)NH 2 ;

R 3 is selected from: H, OH, halogen, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy or (CH 2 ) n C(O)OH;

Wherein n is selected from: 0, 1, 2 or 3;

R 4 is selected from: H, OH, halogen, C 1 -C 3 alkyl, COOCH 3 , COOH or CONH 2 ;

L 1 is selected from:

Ra and Rb are each independently selected from: H, C1 - C3 alkyl or C3 - C6 cycloalkyl;

A is selected from the group consisting of phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, cyclohexyl, piperidinyl or piperazinyl;

R5 and R6 are each independently selected from: H, OH, halogen, CN, C1 - C6 alkyl, CF3 , CHF2 , OCF3 , SCF3 , C1 - C6 alkylsulfonyl , C1- C6 alkoxy, C1 -C6 cycloalkyl, C1 - C6 heterocycloalkyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, wherein the substituted phenyl may be independently substituted by 1 to 2 of the following substituents: halogen, OH, CN , CF3, CHF2 , SCH3, OCF3, SCF3 or C1- C6 alkylsulfonyl, or, R5 and R6 are each independently selected from: H, OH, CN, CF3, CHF2 , SCH3 , OCF3 , SCF3 or C1 -C6 alkylsulfonyl, or, 6 together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring;

L2 is absent or selected from:

X is selected from: C, O, S, NH, sulfoxide or sulfone;

p and q are each independently selected from: 0, 1, 2 or 3;

B is selected from: H, halogen CN, OH, NH 2 , NO 2 , CF 3 , CHF 2 , OCF 3 , SCF 3 , C 1 -C 3 alkyl, C 1 -C 3 alkoxy, substituted or unsubstituted phenyl, naphthyl, pyridyl, imidazolyl, pyrazolyl, furyl, thienyl, C 3 -C 8 cycloalkyl or 4-7 membered nitrogen-containing heterocycle;

R7 and R8 are each independently selected from: H, OH, halogen, CN, C1 - C6 alkyl, CF3 , CHF2 , OCF3, SCF3 , C1 - C6 alkylsulfonyl, C1- C6 alkoxy, C1 - C6 cycloalkyl, C1 - C6 heterocycloalkyl, phenyl , substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, wherein the substituted phenyl may be independently substituted by 1 to 2 of the following substituents: halogen, OH, CN, CF3, CHF2, SCH3, OCF3, SCF3 or C1 -C6 alkylsulfonyl, or, R5 and R8 are each independently selected from: H, OH, CN, CF3 , CHF2 , SCH3 , OCF3 , SCF3 or C1 - C6 alkylsulfonyl, or, R5 and R8 are each independently selected from: 6 and the atoms to which they are attached may form together a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaromatic ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkane ring, or a substituted or unsubstituted heterocycloalkene ring.
The sulfonamide compound or its pharmaceutically acceptable salt, ester or solvate according to claim 1 or 3, characterized in that the sulfonamide compound or its pharmaceutically acceptable salt is selected from any one of the following:
A use of a sulfonamide compound or a pharmaceutically acceptable salt, ester or solvate thereof according to any one of claims 1 to 5 in the preparation of a drug for inhibiting activation of a STING signaling pathway.
A use of the sulfonamide compound or a pharmaceutically acceptable salt, ester or solvate thereof according to any one of claims 1 to 5 in the preparation of a medicament for preventing or treating a STING-mediated disease.
According to the use of claim 7, the STING-mediated disease includes infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, cancer or cancer syndrome.
A use of the sulfonamide compound or a pharmaceutically acceptable salt, ester or solvate thereof according to any one of claims 1 to 5 in the preparation of an immune adjuvant drug.
A pharmaceutical composition for preventing or treating a STING-mediated disease, comprising a sulfonamide compound or a pharmaceutically acceptable salt, ester or solvate thereof as claimed in any one of claims 1 to 5 as an active ingredient and a pharmaceutically acceptable excipient.
The pharmaceutical composition according to claim 10, characterized in that the pharmaceutical composition is a capsule, powder, tablet, granule, pill, injection, syrup, oral solution, inhalant, ointment, suppository or patch.