Sulfonamide compounds and medical uses thereof

Abstract

The application discloses a sulfonamide compound and a medical use thereof as a STING inhibitor, and specifically relates to a compound as shown in the formula I or a pharmaceutically acceptable salt or ester or solvate thereof, which can be used for preparing a STING inhibitor or a medicine with the function of inhibiting the activation of a STING signal path and for preparing a medicine for preventing or treating a STING-mediated disease.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of biological medicine, and particularly relates to a new type of sulfonamide compound and a medical use thereof. BACKGROUND

[0002] 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 process of the body resisting the invasion of pathogenic microorganisms, continuous activation of the STING pathway can lead to the occurrence and development of various autoimmune diseases and inflammatory diseases (Nature Immunology, 2017, 18(7): 716-724), including Aicardi-Goutières syndrome (AGS), systemic lupus erythematosus (SLE), SAVI (STING-associated vasculopathy with onset in infancy) disease, etc. In addition, in the models of inflammation-related diseases, such as the induction of skin cancer (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 (Gastroenterology, 2018, 155(6): 1971-1984; PNAS, 2017, 114(46): 12196-12201), pneumonia (Nature Communications, 2018, 9(1)), chronic nephritis and kidney fibrosis (Cell Metabolism, 2019, DOI: 10.1016 / j.cmet.2019.08.003) and ischemic reperfusion injury (Nature Medicine, 2017, 23(12): 1481-1487), etc., the inhibition of the activation of the STING signaling pathway can significantly improve the occurrence and development of the above diseases. The STING palmitoylation inhibitor H-151 can also significantly alleviate the symptoms of amyotrophic lateral sclerosis (Cell 2020, 183: 636-649). In addition, the research of the present inventors shows that the STING inhibitor H-151 has a significant therapeutic effect on a mouse model of psoriasis (Br J Pharmacol 2021, 178: 4907-4922). In summary, the development of inhibitors targeting the STING protein has broad clinical application prospects.

[0003] Currently reported STING small molecule inhibitors in the literature are few in number, and they 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). Applicants first reported a new type of STING inhibitor SN-011 (PNAS 2021, 118: e2105465118; WO2021068950), however, the activity and drugability of this class of compounds still need to be improved. Therefore, there is an urgent clinical need to develop new STING inhibitors. SUMMARY

[0004] The present application provides a novel sulfamide compound or a pharmaceutically acceptable salt thereof to solve the problems in the prior art. The compound of the present application can significantly inhibit the activation of the STING signaling pathway, and thus can be used for preparing a drug for preventing or treating a STING-mediated disease.

[0005] The present application also provides a preparation method, a pharmaceutical combination and a medical use of the sulfamide compound and intermediates thereof.

[0006] Technical scheme: In order to achieve the above-mentioned purpose, the present application provides a sulfamide compound or a pharmaceutically acceptable salt or ester or solvate thereof as shown in the following formula I:

[0007]

[0008] R 1 selected from: H, C1-C6 alkyl or C3-C6 cycloalkyl;

[0009] R 2 selected from: substituted or non-substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2) n OH, (CH2) n NH2, (CH2) n C(O)O(CH2) mCH3, substituted or non-substituted C3-C8 cycloalkyl, substituted or non-substituted C3-C6 aliphatic heterocyclyl, or substituted or non-substituted aryl or heteroaryl, wherein said substituted C1-C6 alkyl is substituted with one diethanolamino, methanesulfonamido, acetamido, aminoacetamido, pyrrolidin-1-yl, piperidin-1-yl, substituted piperidin-1-yl, piperazin-1-yl, substituted piperazin-1-yl, morpholin-4-yl, thiomorpholin-1,1-dioxo-4-yl, N,N-dimethylamino, carboxyl, carboxylate, formamido or carbamoyl; said substituted C3-C8 cycloalkyl, C3-C6 cycloalkyl, aryl or heteroaryl is substituted with one or two or three substituents each independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, C1-C6 alkylsulfonyl, halogen, CN, NO2, NH2, OH, CF3, OCF3, SCF3, C(O)OH or C(O)NH2;

[0010] wherein R 2 n and m in the substituents are each independently selected from any integer from 0 to 4;

[0011] R 3 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, (CH2) n OH, (CH2) n C(O)OH, (CH2) n C(O)O(CH2) m CH3, OC(O)(CH2) n CH3or (CH2) n C(O)NH2;

[0012] wherein R 3 n and m in the substituents are each independently selected from any integer from 0 to 4;

[0013] R 4 is selected from H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, C3-C6 cycloalkyl, (CH2) n OH, (CH2) n C(O)OH, (CH2) n C(O)O(CH2) m CH3or (CH2) n C(O)NH2;

[0014] wherein R 4 n and m in the substituents are each independently selected from any integer from 0 to 4;

[0015] R 5 and R 6each independently selected from the group consisting of: H, N(CH3)2, N(CH2CH3)2, CN, NO2, CHF2, (CH2) n C(O)OH, (CH2) n C(O)O(CH2) m CH3, (CH2) n CF3, (CH2) n OCF3, (CH2) n SCF3, S(CH2) l SCF3, O(CH2) l SCF3, (CH2) n OH, (CH2) n NH2, SO2CH3, SO2CF3, halogen, pyrrolyl, imidazolyl, triazolyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyloxy, C1-C6alkylthio, C1-C6alkylamino, C1-C6alkylsulfonyl, substituted or unsubstituted C3-C8cycloalkyl or substituted or unsubstituted C6aliphatic heterocyclyl, wherein the substituted C3-C8cycloalkyl or C6aliphatic heterocyclyl is substituted with one or two substituents independently selected from C1-C6alkyl or halogen, or, adjacent R 5 and R 6 and R

[0016] wherein R 5 and R 6 n and m in the substituents are each independently selected from any integer from 0 to 4; the letter I is selected from any integer from 1 to 3;

[0017] R 7 , R 8 and R 9 each independently selected from the group consisting of: H, CN, NO2, CHF2, OCHF2, (CH2) n C(O)OH, (CH2) n C(O)O(CH2) m CH3, (CH2) n CF3, (CH2) n OCF3, (CH2) n SCF3, S(CH2) l SCF3, O(CH2) l SCF3, (CH2) n OH, (CH2) nNH2, SO2CH3, SO2CF3, halogen, C1-C6alkylsulfonyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkyloxy, C1-C6alkylthio, C1-C6alkylamino, substituted or unsubstituted C3-C8cycloalkyl or substituted or unsubstituted C3-C6aliphatic heterocyclyl, wherein the substituted C3-C8cycloalkyl or C3-C6aliphatic heterocyclyl can each independently be substituted with one or two OH, NH2, halogen, C1-C6alkyl, or, adjacent R 7 8 9 wherein at least two substituents together with the atoms to which they are attached can form a C5-C8cycloalkane, phenyl ring, C5-C6aromatic heterocyclic ring, or C5-C6aliphatic heterocyclic ring;

[0018] wherein R 7 8 9 n and m in the substituents R

[0019] A is selected from C3-C8cycloalkyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, piperidinyl, piperazinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolin-1-onyl, phthalimidyl, or 3,4-dihydroisoquinolin-1(2H)-onyl;

[0020] B is absent or selected from C3-C8cycloalkyl, 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;

[0021] L 1 is selected from:

[0022] wherein R a and R b ​​​​each independently selected from the group consisting of: H, C1-C6alkyl, C1-C6alkylcarbonyl, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6aliphatic heterocyclyl, or substituted or unsubstituted aryl or heteroaryl, wherein said substituted C3-C6cycloalkyl, C3-C6aliphatic heterocyclyl, aryl or heteroaryl is substituted with one or two substituents each independently selected from the group consisting of: C1-C6alkyl, C1-C6alkyloxy, C1-C6alkoxycarbonyl, C1-C6alkylsulfonyl, halogen, OH, NH2, CN, NO2, CF3, OCF3, SCF3, C(O)OH or C(O)NH2;

[0023] L 2 may be absent or selected from the group consisting of:

[0024] wherein R c and R d each independently selected from the group consisting of: H, CF3, halogen, oxo, C1-C6alkyl, C1-C6alkyloxy, C1-C6alkylthio, substituted or unsubstituted C3-C6cycloalkyl, substituted or unsubstituted C3-C6aliphatic heterocyclyl, or substituted or unsubstituted aryl or heteroaryl, wherein said substituted C3-C6cycloalkyl, C3-C6aliphatic heterocyclyl, aryl or heteroaryl is substituted with one or two or three substituents each independently selected from the group consisting of: C1-C6alkyl, C1-C6alkyloxy, C1-C6alkoxycarbonyl, C1-C6alkylsulfonyl, halogen, OH, NH2, CN, NO2, CF3, OCF3, SCF3, C(O)OH or C(O)NH2, or R c or R d together with the atom to which they are attached can form a C3-C6cycloalkane or a C3-C6aliphatic heterocycle;

[0025] X is selected from the group consisting of: CH2, O, S, NH, NR e , sulfoxide or sulfone;

[0026] wherein R e is selected from the group consisting of: C1-C6alkyl, C1-C6alkylcarbonyl or tert-butoxycarbonyl, or R e together with R 5 , R 6 , R 7 , R 8 or R 9 one of the substituents together with the atom to which they are attached can form a C5-C6heterocycle;

[0027] p and q are each independently selected from the group consisting of: any integer from 0 to 4.

[0028] In certain preferred embodiments, the sulfamide compound or a pharmaceutically acceptable salt or ester or solvate thereof, wherein:

[0029] R 1 is selected from: H, C1-C3 alkyl or cyclopropyl;

[0030] R 2 is selected from: C1-C4 alkyl, (CH2) n OH, (CH2) n NH2, (CH2) n C(O)O(CH2) m CH3, (CH2) n C(O)OH, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C6 aliphatic heterocyclyl or substituted or unsubstituted aryl or heteroaryl, wherein the aliphatic heterocyclyl is selected from piperidinyl, piperazinyl, morpholinyl; the aryl or heteroaryl is each independently selected from phenyl, pyridyl, pyrimidinyl, thienyl, furanyl or thiazolyl; the substituted C3-C6 cycloalkyl, aliphatic heterocyclyl, aryl or heteroaryl is substituted with one or two or three substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, halogen, CN, CF3, OCF3 or SCF3;

[0031] wherein R 2 n and m in the substituents are each independently selected from any integer from 0 to 4;

[0032] R 3 is selected from: H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkylamino, (CH2) n OH, (CH2) n C(O)OH or (CH2) n C(O)O(CH2) m CH;

[0033] wherein R 3 n and m in the substituents are each independently selected from any integer from 0 to 4;

[0034] R 4 is selected from: H, OH, halogen, C1-C3 alkyl, C1-C3 alkoxy, cyclopropyl, C(O)OCH3 or C(O)OH;

[0035] R 5 and R 6 are each independently selected from: H, OH, NH2, N(CH3)2, N(CH2CH3)2, C(O)OH, CN, NO2, CHF2, (CH2) k CF3, (CH2) kOCF3, (CH2) k SCF3, S(CH2) l SCF3, O(CH2) l SCF3, SO2CH3, SO2CF3, halogen, pyrrolyl, imidazolyl, triazolyl, C1-C4alkyl, C1-C4alkyloxy, C1-C4alkylthio, substituted or unsubstituted C3-C8cycloalkyl or substituted or unsubstituted C6aliphatic heterocyclyl, wherein the C6aliphatic heterocyclyl is selected from piperidinyl, piperazinyl or morpholinyl; the substituted C3-C8cycloalkyl or C6aliphatic heterocyclyl is substituted with one or two substituents each independently selected from C1-C4alkyl or halogen, or, adjacent R 5 and R 6 may together form a C5-C6aromatic heterocyclic ring, wherein the C5-C6aromatic heterocyclic ring is selected from pyrrole, imidazole, oxazole, thiazole, oxadiazole, pyridine or pyrimidine;

[0036] wherein R 5 and R 6 the substituents k is selected from 0, 1 or 2; the letter 1 is selected from 1, 2 or 3;

[0037] R 7 , R 8 and R 9 are each independently selected from H, OH, NH2, CN, NO2, CHF2, OCHF2, C(O)OH, (CH2) k CF3, (CH2) k OCF3, (CH2) k SCF3, S(CH2) l SCF3, O(CH2) l SCF3, SO2CH3, SO2CF3, halogen, C1-C4alkyl, C1-C4alkyloxy, C1-C4alkylthio or C3-C6cycloalkyl, or, adjacent R 7 , R 8 or R 9 wherein at least two substituents together with the atoms to which they are attached can form a benzene ring, a cycloalkane, an aromatic heterocyclic ring or a substituted or unsubstituted aliphatic heterocyclic ring, wherein the cycloalkane is selected from cyclopentane or cyclohexane; the aromatic heterocyclic ring is selected from pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyridine or pyrimidine; the aliphatic heterocyclic ring is selected from piperidine, piperazine, morpholine or 1,4-dioxane; the substituted aliphatic heterocyclic ring can be substituted with one C1-C3alkyl or C1-C3alkylsulfonyl;

[0038] wherein R 7 , R 8 and R 9k in the substituents is selected from: 0, 1 or 2; the letter 1 is selected from: 1, 2 or 3;

[0039] A is selected from: C3-C6cycloalkyl, phenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, indolyl, piperidinyl or piperazinyl;

[0040] B is absent or selected from: C3-C8cycloalkyl, phenyl, naphthyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, indolyl, benzoxazolyl, benzothiazolyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl;

[0041] L 1 is selected from:

[0042] R a and R b are each independently selected from: H, C1-C3alkyl or C3-C6cycloalkyl;

[0043] L 2 may be absent or is selected from:

[0044] wherein, when L 2 is absent, and L 1 is: A is only selected from: and B is absent;

[0045] R c and R d are each independently selected from: H, F, Cl, CF3, oxo, C1-C4alkyl, C1-C4alkyloxy, C1-C4alkylthio or C3-C6cycloalkyl, or, R c and R d together with the atom to which they are attached can form a C3-C6cycloalkane ring;

[0046] X is selected from: CH2, O, S, NH, NR e , sulfoxide or sulfone;

[0047] R e is selected from: C1-C3alkyl, C1-C3alkylcarbonyl or tert-butoxycarbonyl, or, R e together with R 5 , R 6 , R 7 , R 8 or R 9one of the substituents together with the atoms to which they are attached can form a C5-C6 heterocyclic ring, wherein the C5-C6 heterocyclic ring is selected from the group consisting of: pyrrole, piperidine, pyrrolidinone, piperidinone, succinimide, glutaric imide;

[0048] p and q are each independently selected from any integer from 0 to 3.

[0049] The present application provides a sulfonamide compound as shown in the following Formula I or a pharmaceutically acceptable salt or ester or solvate thereof:

[0050]

[0051] wherein,

[0052] R 1 selected from the group consisting of: H, C1-C3 alkyl or C1-C3 alkylcarbonyl;

[0053] R 2 selected from the group consisting of: 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, the aryl or heteroaryl is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazolyl, furanyl or thienyl, the substituted C1-C4 alkyl is substituted with one or two or three substituents independently selected from the group consisting of: F, Cl, NH2, OH, diethanolamino, methanesulfonamido, acetamido, aminoacetamido, pyrrolidin-1-yl, piperidin-1-yl, substituted piperidin-1-yl, piperazin-1-yl, substituted piperazin-1-yl, morpholin-4-yl, thiomorpholin-1,1-dioxo-4-yl, N,N-dimethylamino, carboxyl, carboxylate, formamido or carbamoyl, the substituted aryl or heteroaryl is substituted with one or two substituents independently selected from the group consisting of: 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;

[0054] R 3 selected from the group consisting of: H, OH, halogen, C1-C3 hydroxyalkyl, C1-C3 alkoxy, C1-C3 alkylcarbonyloxy, C1-C3 alkoxycarbonyl, (CH2) n C(O)OH, (CH2) n C(O)NH2 or C(O)NHSO2CH3;

[0055] n is selected from the group consisting of: 0, 1, 2 or 3;

[0056] R 4selected from: H, OH, halogen, C1-C3alkyl, COOCH3, COOH or CONH2;

[0057] L 1 selected from:

[0058] R a and R b each independently selected from: H, C1-C3alkyl, C 3- C6cycloalkyl;

[0059] A is selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, cyclohexyl, piperidinyl or piperazinyl;

[0060] R 5 and R 6 each independently selected from: H, OH, halogen, CN, C1-C6alkyl, CF3, CHF2, SCH3, OCF3, SCF3, C1-C6alkylsulfonyl, C1-C6alkoxy, C1-C6cycloalkyl, C1-C6cycloalkenyl, C1-C6heterocycloalkyl, C1-C6heterocycloalkenyl, C1-C6alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenoxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, said substituted phenyl can be independently substituted with 1 to 2 substituents selected from: halogen, OH, CN, C1-C6alkyl, CF3, CHF2, SCH3, OCF3, SCF3or C1-C6alkylsulfonyl, or, R 5 and R 6 together with the atoms to which they are attached can 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;

[0061] L 2 is absent or selected from:

[0062] X is selected from: C, O, S, NH, sulfoxide or sulfone;

[0063] p and q are each independently selected from: any integer from 0 to 5;

[0064] B is selected from: H, halogen CN, OH, NH2, NO2, CF3, CHF2, OCF3, SCF3, C1-C3alkyl, C1-C3alkoxy, C1-C3alkylamino, substituted or unsubstituted phenyl, naphthyl, pyridyl, imidazolyl, pyrazolyl, furanyl, or thienyl, C3-C8cycloalkyl or 4-7 membered nitrogen containing heterocycle;

[0065] R7 and R 8 each is independently selected from the group consisting of: 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 phenoxy, heteroaryl, substituted heteroaryl, fused ring aryl, or substituted fused ring aryl, said substituted phenyl can be independently substituted with 1 to 2 substituents selected from the group consisting of: halogen, OH, CN, C1-C6 alkyl, CF3, CHF2, SCH3, OCF3, SCF3, or C1-C6 alkylsulfonyl, or, R 5 and R 6 and the atoms to which they are attached can together 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.

[0066] In certain preferred embodiments, the sulfamide compound, or a pharmaceutically acceptable salt or ester or solvate thereof, wherein:

[0067] R 1 is selected from the group consisting of: H or C1-C3 alkyl;

[0068] R 2 is selected from the group consisting of: substituted or unsubstituted C1-C4 alkyl, cyclopropyl, CF3, vinyl, substituted or unsubstituted aryl or heteroaryl, hydroxy-C1-C3 alkylamino, or morpholinyl, said aryl or heteroaryl is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazolyl, furanyl, or thiophenyl, said substituted aryl or heteroaryl is substituted with one or two substituents independently selected from the group consisting of: 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;

[0069] R 3 is selected from the group consisting of: H, OH, halogen, C1-C3 hydroxyalkyl, C1-C3 alkoxy, or (CH2) n C(O)OH;

[0070] wherein n is selected from the group consisting of: 0, 1, 2, or 3;

[0071] R 4 is selected from the group consisting of: H, OH, halogen, C1-C3 alkyl, COOCH3, COOH, or CONH2;

[0072] L1 selected from:

[0073] R a and R b each independently selected from: H, C1-C3 alkyl or C 3- C6 cycloalkyl;

[0074] A is selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, cyclohexyl, piperidinyl or piperazinyl;

[0075] R 5 and R 6 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 phenoxy, heteroaryl or substituted heteroaryl, which substituted phenyl can be independently substituted with 1 to 2 substituents selected from: halogen, OH, CN, CF3, CHF2, SCH3, OCF3, SCF3 or C1-C6 alkylsulfonyl, or, R 5 and R 6 together with the atoms to which they are attached can 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;

[0076] L 2 is absent or selected from:

[0077] X is selected from: C, O, S, NH, sulfoxide or sulfone;

[0078] p and q are each independently selected from: 0, 1, 2 or 3;

[0079] B is selected from: H, halogen CN, OH, NH2, NO2, CF3, CHF2, OCF3, SCF3, C1-C3 alkyl, C1-C3 alkoxy, substituted or unsubstituted phenyl, naphthyl, pyridyl, imidazolyl, pyrazolyl, furanyl, or thiophenyl, C3-C8 cycloalkyl or 4-7 membered nitrogen containing heterocycle;

[0080] R 7 and R 8Each of the following is 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 substituted by one or two of the following substituents: halogen, OH, CN, CF3, CHF2, SCH3, OCF3, SCF3 or C1-C6 alkylsulfonyl, or, R 5 and R 6 Together with the atoms to which they are attached, they can form substituted or unsubstituted benzene rings, substituted or unsubstituted heteroaromatic rings, substituted or unsubstituted cycloalkane rings, substituted or unsubstituted heterocyclic alkane rings, or substituted or unsubstituted heterocyclic alkene rings.

[0081] In some preferred embodiments, the sulfonamide compound or its pharmaceutically acceptable salt, ester, or solvate is selected from any one of the following in Table 1:

[0082] Table 1. Structure and Nomenclature of Compounds

[0083]

[0084]

[0085]

[0086]

[0087]

[0088]

[0089]

[0090]

[0091]

[0092]

[0093]

[0094]

[0095]

[0096]

[0097]

[0098]

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115] The compounds of the present application can also be used as pharmaceutical salts. The salts can be acid salts 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-naphthalene disulfonic acid, naphthalene-2-sulfonic acid, pivalic acid, terephthalic acid, thiocyanic acid, cholic 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, hydrobromic acid, methanesulfonic acid, nicotinic acid, nitric acid, orotic acid, oxalic acid, picric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, succinic 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. In another aspect, the salts can also be salts of the compounds of the present application with metal (including sodium, potassium, calcium, etc.) ions or pharmaceutically acceptable amines (including ethylenediamine, tromethamine, etc.), ammonium ions, or choline.

[0116] The compounds of the present application can also be used in the form of esters, prodrugs, N-oxides, or solvates thereof in the pharmaceutical compositions. The present application includes all prodrugs of the compounds of the present application, which upon administration to a human or animal body are capable of providing (directly or indirectly) a compound of the present application or an active metabolite or residue thereof. The present application includes all deuterated forms of the compounds of the present application. Each hydrogen atom available for substitution on a carbon atom can be independently replaced by a deuterium atom.

[0117] The present application provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting the activation of STING signaling pathway.

[0118] The present application provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing or treating a STING-mediated disease.

[0119] The STING-mediated disease includes one or more of infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, cancers, and precancerous syndromes.

[0120] The present application provides the use of the compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of an immunoadjuvant medicament.

[0121] The present application is based on the crystal structure of the C-terminal domain of human STING protein (hSTING-CTD-139-379, PDB: 4EF5), using The Glide docking module in 2009 was used to carry out computer-aided drug design and molecular docking research of active compounds. The docking results show that the sulfonamide compounds of the present application can inhibit the activation of the STING signaling pathway by directly binding to the STING protein and maintaining the dimer conformation thereof in the resting state.

[0122] The compounds of the present application can be used for the prevention or treatment of 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.

[0123] The compounds of the present application can be used for the prevention or treatment of 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, non-alcoholic steatohepatitis, alcoholic fatty liver, cirrhosis, gout, stroke or cerebral infarction, etc.), musculoskeletal muscle inflammation (inflammation of the joints 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, rectitis), nervous system inflammation (meningitis, neuromyotonia, multiple sclerosis, CNS vasculitis), vascular or lymphatic system inflammation (vasculitis, lymphangitis, phlebitis), reproductive system inflammation (cervicitis, endometritis, epididymitis, orchitis, urethritis), respiratory system inflammation (pneumonia, asthma, chronic obstructive pulmonary disease, chronic bronchitis, pulmonary emphysema, occlusive bronchiolitis, idiopathic pulmonary fibrosis, cystic fibrosis lung disease), and other inflammatory conditions including appendicitis, myocarditis, parotitis, gingivitis, prostatitis, peritonitis, pleuritis, vasculitis, phlebitis, edema.

[0124] The compounds of the present application can be used for the prevention or treatment of autoimmune diseases. Including: Aicardi syndrome (AGS), STING-related vasculitis in infancy (SAVI), retinal vasculopathy with cerebral leukodystrophy (RCVL), systemic lupus erythematosus (SLE), familial chilblain lupus (CHBL), Behcet's disease, Chagas disease, psoriasis, multiple sclerosis, scleroderma and Behcet's disease, etc.

[0125] The compound of the present application can be used for preventing or treating T cell-mediated hypersensitivity reactions with inflammatory components, including urticaria, skin allergy, allergic rhinitis, contact dermatitis, and respiratory allergy, etc.

[0126] The compound of the present application can be used for treating 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, 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 myelocytic leukemia, chronic lymphocytic leukemia, acute myelocytic leukemia, acute lymphocytic leukemia, multiple myeloma, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, neuroblastoma.

[0127] The compound of the present application can be used alone or in combination with other therapeutic agents. As an immunomodulator, the compound of the present application can be used alone 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.

[0128] The present application includes a pharmaceutical composition for preventing or treating STING-mediated diseases, which contains a therapeutically effective amount of a sulfonamide compound represented by Formula I or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient. The excipient can be arbitrarily mixed and can be changed depending on the dosage form, administration form, etc. Examples of the excipient include excipients, binders, disintegrants, lubricants, flavoring agents, flavoring agents, coloring agents, or sweetening agents, etc. The pharmaceutical composition can be in a pharmaceutically conventional preparation form such as a capsule, a powder, a tablet, a granule, a pill, an injection, a syrup, an oral solution, an inhalant, an ointment, a suppository, or a patch, etc.

[0129] The compound of the present application can be prepared by referring to the methods and synthetic routes described in the examples, or by improved methods.

[0130] Advantages: Compared with the prior art, the present application has the following advantages:

[0131] (1) The sulfonamide compound newly designed and synthesized in the present application is a new type of STING inhibitor, which has the characteristics of strong STING inhibitory activity and good drug property.

[0132] (2) The compound of the present application can be used for preparing a drug for inhibiting the activation of the STING signaling pathway and a drug for preventing or treating STING-mediated diseases, which has a very good effect on treating infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, cancers, or precancerous syndromes.

[0133] (3) The compound of the present application has simple structure, ingenious synthetic route design, cheap and easily available raw materials, safe and environmentally friendly synthesis process, and is easy to scale up. BRIEF DESCRIPTION OF DRAWINGS

[0134] Figure 1 Figure for the effect of compound B-80, C-22, C-51, D-60, D-75 and D-88 on the mouse psoriasis model induced by imiquimod cream. DETAILED DESCRIPTION

[0135] The content of the present application is specifically illustrated by the following examples. In the present application, the following examples are described in order to better illustrate the present application, and are not intended to limit the scope of the present application. Various changes and modifications can be made to the present application without departing from the spirit and scope of the present application.

[0136] The raw materials and equipment used in the specific embodiments of the present application are known products, which can be obtained by purchasing commercially available products.

[0137] The structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). The determination of NMR is carried out by using a (Bruker) nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated acetone (Acetone-d6), and the internal standard is tetramethylsilane (TMS).

[0138] Column chromatography generally uses silica gel 200-300 mesh silica gel from Qingdao Haizhuan Chemical Factory Branch as the carrier.

[0139] The known starting materials of the present application can be synthesized according to the methods known in the art, or can be purchased from Adamas, Lygen, Bide Pharmaceutical, Aladdin, Anjie, etc.

[0140] Example 1

[0141] 4-cyclopentyl-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (compound A-1)

[0142]

[0143] Synthesis of intermediate I-1

[0144] To a solution of intermediate 1-1 (1.46 g, 4.68 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 10% palladium on carbon (300 mg) and the reaction mixture was stirred under hydrogen atmosphere at room temperature for 12 hours. After completion of the reaction, the palladium on carbon was filtered off and the filter cake was washed with tetrahydrofuran (10 mL). The filtrate was concentrated under reduced pressure to give crude intermediate 1-2 which was used for the next step without further purification. 1 H NMR (300 MHz, DMSO-d6) δ 11.35 (s, 1H), 9.97 (s, 1H), 8.05 (d, J = 2.8 Hz, 1H), 7.93 (dd, J = 9.0, 2.8 Hz, 1H), 7.87 - 7.77 (m, 2H), 7.39 (t, J = 8.9 Hz, 2H), 6.90 (d, J = 9.0 Hz, 1H). ESI-MS: m / z 311.0 [M-H] - .

[0145] Synthesis of intermediate 1-2

[0146] To a solution of intermediate 1-1 (1.46 g, 4.68 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 10% palladium on carbon (300 mg) and the reaction mixture was stirred under hydrogen atmosphere at room temperature for 12 hours. After completion of the reaction, the palladium on carbon was filtered off and the filter cake was washed with tetrahydrofuran (10 mL). The filtrate was concentrated under reduced pressure to give crude intermediate 1-2 which was used for the next step without further purification.

[0147] Synthesis of intermediate 1-3

[0148] To a solution of intermediate 1-15 (14.0 g, 49.59 mmol) and N,N- diisopropylethylamine (4.1 g, 59.51 mmol) in dichloromethane (150 mL) was added tert-butyldimethylsilyl chloride (9.0 g, 59.51 mmol) in dichloromethane (50 mL) dropwise at 0 °C. After the addition was complete, the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (50 mL x 2). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 4: 1) to give intermediate 1-3 (beige solid, 19.4 g): 1H NMR (300 MHz, DMSO-d6) 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 [M-H] - .

[0149] Synthesis of intermediate I-4

[0150] 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 into a Schlenk tube under argon atmosphere, then a solution of ethyl 4-bromobenzoate (229 mg, 1 mmol) in 1,4-dioxane (4 mL), water (0.4 mL) was added into the system, and the reaction was carried out at 100 °C for 8 h. After the reaction was completed, the system was cooled to room temperature, the solvent was evaporated under reduced pressure, diluted with water (15 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was 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 give intermediate I-4 (white solid, 212 mg): 1 H NMR (300 MHz, CDCl3) δ 8.00 (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).

[0151] Synthesis of intermediate I-5

[0152] Intermediate I-4 (205 mg, 0.95 mmol) and 10% palladium on carbon (40 mg) were added into methanol (2 mL) and the reaction was carried out at room temperature for 12 h under hydrogen atmosphere. After the reaction was completed, the palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the filtrate was evaporated under reduced pressure to give the crude intermediate I-5, which was used directly in the next step without further purification.

[0153] Synthesis of intermediate I-6

[0154] The intermediate I-5 crude product 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 reaction was carried out at 60°C for 6 hours. After the reaction was completed, the system was cooled to room temperature, 2 N aqueous hydrogen chloride solution was added to adjust the pH to 1-2, and ethyl acetate (10 mL x 3) was added for extraction. The combined organic phase was washed with saturated brine (10 mL x 1), and the solvent was removed under reduced pressure. 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-d6) δ 12.74 (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 [M-H] - .

[0155] Synthesis of intermediate I-7

[0156] 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. After the dropwise addition was completed, the reaction was carried out at room temperature for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare an acyl chloride tetrahydrofuran solution. The solution 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, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed, 2 N aqueous hydrogen chloride solution was added to adjust the pH to 3-4, and ethyl acetate (5 mL x 3) was added for extraction. The combined organic phase was washed with water (10 mL x 1) and saturated brine (10 mL x 1), and the solvent was removed 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): 1H NMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.04 (s, 1H), 7.89 - 7.78 (m, 4H), 7.65 (d, J = 2.7 Hz, 1H), 7.50 - 7.36 (m, 5H), 6.83 (d, J = 8.8 Hz, 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).

[0157] Synthesis of Compound A-1

[0158] Intermediate I-7 (107 mg, 0.19 mmol) and triethylamine trifluoride hydrochloride (50 μL, 0.28 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, which was filtered, the filter cake was washed with dichloromethane / methanol = 20: 1, and the obtained solid was dried to constant weight to obtain Compound A-1 (white solid, 57 mg): 1 H NMR (300 MHz, DMSO-d6) δ 9.98 (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 C 24 H 23 FN2O4S [M+H] + 455.1435, found 455.1437.

[0159] Example 2

[0160] 4-cyclohexyl-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (Compound A-2)

[0161]

[0162] Synthesis of Compound A-2

[0163] Compound A-2 was prepared according to the method of Reference Example 1, replacing intermediate I-6 with 4-cyclohexylbenzoic acid: 1HNMR(300MHz,DMSO-d6)δ9.97(s,1H),9.32(s,2H),7.86-7.79(m,4H),7.67(d,J=2.3Hz,1H),7.41-7.33(m,5H),6.68(d,J=8.7H z,1H),2.63-2.54(m,1H),1.81(d,J=9.3Hz,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 FN₂O₄S[M+H] + 469.1592, found 469.1622.

[0164] Example 3

[0165] 4-(4,4-difluorocyclohexyl)-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)benzamide (compound A-3)

[0166]

[0167] Synthesis of intermediate I-8

[0168] p-Toluenesulfonylhydrazine (268 mg, 2 mmol) was added to methanol (4 mL), and the mixture was heated to 60 °C to dissolve the p-toluenesulfonylhydrazine. Then, 4,4-difluorocyclohexanone (369 mg, 2 mmol) was added in portions. After the addition was complete, the reaction was continued at 60 °C for 1 hour. After the reaction was completed, the system was cooled to room temperature, and the solvent was evaporated from the reaction solution under reduced pressure to obtain crude compound I-8, which was used directly in the next reaction without further purification.

[0169] Synthesis of intermediate I-9

[0170] Intermediate I-8 (374 mg, 1 mmol), 4-methoxycarbonylphenylboronic acid (270 mg, 1.5 mmol), and potassium carbonate (207 mg, 1.5 mmol) were added to a dry Schlenk tube under argon protection. Then, 1,4-dioxane (3 mL) was added to suspend the mixture, and the reaction was carried out at 110 °C for 8 hours. After the reaction was complete, the system was cooled to room temperature, the reaction mixture was filtered, the filter cake was washed with ethyl acetate (5 mL), 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 I-9 (colorless oily liquid, 149 mg). 1H NMR (300 MHz, CDC13) δ 8.00 (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).

[0171] Synthesis of intermediate 1-10

[0172] Intermediate 1-9 (129 mg, 0.51 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (1.5 mL), 1M aqueous sodium hydroxide solution (1.5 mL) was added, and the reaction was carried out at 60°C for 6 hours. After the reaction was completed, the system was cooled to room temperature, the organic phase was distilled off under reduced pressure, 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 1-2, a solid was precipitated, and the solid was filtered, washed with water (2 mL) and n-hexane (2 mL), and dried in an infrared ray to a constant weight to obtain intermediate 1-10 (white solid, 82 mg): 1 H NMR (300 MHz, DMSO-d6) δ 12.74 (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 [M-H] - .

[0173] Synthesis of compound A-3

[0174] Compound A-3 was prepared according to the method of Example 1, replacing intermediate 1-6 with intermediate 1-10: 1 H NMR (300 MHz, DMSO-d6) 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 F3N2O4S [M+H] +505.1403, found 505.1404.

[0175] Example 4

[0176] 4-(4, 4-dimethylcyclohexyl)-N-(3-((4-fluorophenyl)sulfonamido)-4- hydroxyphenyl)benzamide (Compound A-4)

[0177]

[0178] Synthesis of Compound A-4

[0179] Compound A-4 was prepared according to the procedure of Example 3, replacing 4, 4-difluorocyclohexanone with 4, 4-dimethylcyclohexanone: 1 H NMR (300 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.35 (s, 2H), 7.87 - 7.79 (m, 4H), 7.67 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 1.7 Hz, 2H), 7.37 (d, J = 2.2 Hz, 2H), 7.33 (s, 1H), 6.68 (d, J = 8.7 Hz, 1H), 2.49 - 2.45 (m, 1H), 1.68 - 1.59 (m, 4H), 1.47 (d, J = 12.2 Hz, 2H), 1.38 - 1.27 (m, 2H), 0.99 (s, 3H), 0.95 (s, 3H). HRMS (ESI) calcd. for C 27 H 29 FN2O4S [M+H] + 497.1905, found 497.1898.

[0180] Example 5

[0181] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(1H-imidazol-1-yl)benzamide (Compound A-5)

[0182]

[0183] Synthesis of Intermediate 1-11

[0184] Imidazole (442 mg, 6.49 mmol) was added to N,N-dimethylformamide (7 mL), followed by the addition of methyl 4-fluorobenzoate (500 mg, 3.24 mmol), potassium carbonate (897 mg, 6.49 mmol), and the mixture was heated to 100 °C for 10 h. After the reaction was completed, the system was cooled to room temperature, and the reaction solution was poured into ice water (70 mL) to quench, extracted with ethyl acetate (15 mL x 3), and the combined organic phase was washed with water (20 mL x 1), saturated brine (20 mL x 1), and the solvent was removed under reduced pressure to obtain the crude intermediate I-11, which was used directly in the next step without further purification.

[0185] Synthesis of intermediate I-12

[0186] The crude intermediate I-11 was dissolved in a mixture of tetrahydrofuran (5 mL) and methanol (5 mL), and 1 M aqueous sodium hydroxide solution (5 mL) was added, and the mixture was heated to 60 °C for 6 h. After the reaction was completed, the system was cooled to room temperature, and 6 N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 6-7, and a solid was precipitated, which was filtered, and the filter cake was washed with water (5 mL), dichloromethane (5 mL), and the residue was purified by slurry (dichloromethane / methanol = 20:1) to obtain the solid, which was dried to constant weight to obtain intermediate I-12 (white solid, 287 mg): 1 H NMR (300 MHz, DMSO-d6) 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 [M-H] - .

[0187] Synthesis of intermediate I-13

[0188] 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-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (152 mg, 0.40 mmol) were added under ice bath, and the mixture was heated to room temperature for 1 h, and a tetrahydrofuran (1 mL) solution of intermediate I-3 (111 mg, 0.28 mmol) was added dropwise, and the reaction was continued at room temperature for 6 h. After the reaction was completed, water (10 mL) was added to dilute the reaction solution, and ethyl acetate (5 mL x 3) was added to extract, and the combined organic phase was washed with saturated brine (5 mL x 1), and the solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 75:1) to obtain intermediate I-13 (pale yellow solid, 62.4 mg):1 H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.10 (s, 1H), 8.42 (s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.89 (s, 1H), 7.86 - 7.77 (m, 4H), 7.67 (d, J = 2.4 Hz, 1H), 7.48 (dd, J = 8.8, 2.5 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.15 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 0.91 (s, 9H), 0.12 (s, 6H). ESI-MS: m / z 565.2 [M-H] - .

[0189] Synthesis of compound A-5

[0190] Compound A-5 was prepared according to the procedure of Reference Example 1, replacing intermediate I-7 with intermediate I-13: 1 H NMR (300 MHz, DMSO-d6) δ 10.22 (s, 1H), 9.10 (s, 1H), 8.42 (s, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.89 (s, 1H), 7.86 - 7.77 (m, 4H), 7.67 (d, J = 2.4 Hz, 1H), 7.48 (dd, J = 8.8, 2.5 Hz, 1H), 7.40 (t, J = 8.8 Hz, 2H), 7.15 (s, 1H), 6.84 (d, J = 8.8 Hz, 1H), 0.91 (s, 9H), 0.12 (s, 6H). ESI-MS: m / z 565.2 [M-H] 22 H 17 FN4O4S [M+H] + 453.1027, found 453.1048.

[0191] Example 6

[0192] 5-Fluoro-N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-lH-indole-3- carboxamide (Compound A-6)

[0193]

[0194] Synthesis of intermediate I-14

[0195] Intermediate I-14 was prepared according to the following procedure: 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 ice-bath cooling. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 4 h. After the reaction was completed, the reaction mixture was poured into ice water (20 mL) to quench the excess TFAA, and a solid was precipitated. The solid was collected by filtration, and the filter cake was washed with water (5 mL) to give crude intermediate I-14, which was used in the next step without further purification.

[0196] Synthesis of intermediate I-15

[0197] The crude intermediate I-14 was suspended in 20% aqueous sodium hydroxide solution (4 mL), and the reaction mixture was allowed to warm to 100°C and stirred for 4 h. After the reaction was completed, the reaction mixture was cooled to room temperature, and ethyl acetate (5 mL) was added to the reaction mixture to remove the organic impurities. The pH of the reaction mixture was adjusted to 1-2 by adding 2N aqueous hydrogen chloride solution, and the reaction mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (5 mL x 1), and the solvent was evaporated under reduced pressure. The residue was purified by trituration (diethyl ether) to give intermediate I-15 (white solid, 178.9 mg): 1 H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 11.93 (s, 1H), 8.07 (d, J = 3.0 Hz, 1H), 7.65 (dd, J = 10.0, 2.5 Hz, 1H), 7.48 (dd, J = 8.8, 4.6 Hz, 1H), 7.04 (td, J = 9.2, 2.6 Hz, 1H). ESI-MS: m / z 178.0 [M-H] - .

[0198] Synthesis of compound A-6

[0199] Compound A-6 was prepared according to the procedure of Example 1, using intermediate I-15 instead of intermediate I-6: 1 H NMR (300 MHz, DMSO-d6) 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 F2N3O4S [M+H] + 444.0824, found 444.0827.

[0200] Example 7

[0201] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((trifluoromethyl)thio)benzamide (Compound A-7)

[0202]

[0203] Synthesis of Intermediate 1-16

[0204] To a solution of 2-amino-4-nitrophenol (1.5 g, 9.73 mmol) and pyridine (1.2 mL, 14.60 mmol) in dichloromethane (30 mL) was added a solution of methylsulfonyl chloride (904 μL, 11.68 mmol) in dichloromethane (10 mL) dropwise at ice bath. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 8 hours. After the reaction was completed, the reaction mixture was quenched by the addition of concentrated hydrochloric acid (1 mL) to remove excess pyridine and methylsulfonyl chloride. The solvent was removed under reduced pressure. The residue was dissolved in 1 N aqueous hydrogen chloride solution (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with 1 N aqueous hydrogen chloride solution (10 mL x 1), water (10 mL x 1), and saturated brine (10 mL x 1), and then the solvent was removed under reduced pressure. The residue was dissolved in ethanol (10 mL), and sodium hydroxide (480 mg, 12 mmol) in water (10 mL) was added. The reaction mixture was heated at 60 °C for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure. The residue was adjusted to pH 2-3 by the dropwise addition of 2 N aqueous hydrogen chloride solution. The precipitated solid was collected by filtration, and the filter cake was washed with water (5 mL) and dichloromethane (5 mL). The residue was purified by trituration (dichloromethane / methanol = 100:1) to give Intermediate 1-16 (yellow solid, 1.54 g). 1 H NMR (300 MHz, DMSO-d6) 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).

[0205] Synthesis of Intermediate 1-17

[0206] To a solution of Intermediate 1-16 (1.54 g, 6.63 mmol) and 10% palladium on carbon (210 mg) in a mixture of methanol (15 mL) and tetrahydrofuran (15 mL) was added hydrogen gas at room temperature for 12 hours. After the reaction was completed, the palladium on carbon was filtered off, and the filter cake was washed with tetrahydrofuran (20 mL). The filtrate was concentrated under reduced pressure to give crude Intermediate 1-17, which was used in the next step without further purification.

[0207] Synthesis of Intermediate 1-18

[0208] Intermediate I-17 crude and N,N-diisopropylethylamine (1.65 mL, 10 mmol) were added into dichloromethane (20 mL), a solution of tert-butyldimethylsilyl chloride (1.3 g, 8.62 mmol) in dichloromethane (15 mL) was added dropwise under ice-water bath, after the dropwise addition, the reaction solution was allowed to warm to room temperature and stirred for 12 hours. After the reaction was completed, saturated sodium bicarbonate solution (30 mL) was added to dilute the reaction solution, dichloromethane (20 mL x 3) was used to extract the reaction solution, the combined organic phase was washed with saturated brine (30 mL x 1), and the solvent was removed 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-d6) 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 [M-H] - .

[0209] Synthesis of intermediate I-19

[0210] 4-Trifluoromethylthiophenylcarboxylic acid (40 mg, 0.18 mmol) and N,N- dimethylformamide (2 drops) were added into anhydrous tetrahydrofuran (3 mL), oxalyl chloride (23 μL, 0.27 mmol) was added dropwise slowly under ice bath, after the dropwise addition, the reaction solution was allowed to warm to room temperature and stirred for 4 hours. After the reaction was completed, the solvent was removed under reduced pressure, the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a solution of acyl chloride in tetrahydrofuran, which was added to a solution of I-18 (63 mg, 0.20 mmol) and pyridine (22 μL, 0.27 mmol) in tetrahydrofuran (1 mL) under ice bath, and the reaction solution was allowed to warm to room temperature and stirred for 6 hours. After the reaction was completed, 2N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 3-4, ethyl acetate (5 mL x 3) was used to extract the reaction solution, the combined organic phase was washed with water (10 mL x 1) and saturated brine (10 mL x 1) in sequence, and the solvent was removed 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): 1H NMR (300 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.48 (s, 1H), 8.04 (d, J = 8.3 Hz, 2H), 7.87 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 2.6 Hz, 1H), 7.56 (dd, J = 8.8, 2.6 Hz, 1H), 6.94 (d, J = 8.8 Hz, 1H), 3.04 (s, 3H), 1.00 (s, 9H), 0.25 (s, 6H).

[0211] Synthesis of compound A-7

[0212] Intermediate I-19 (48 mg, 0.09 mmol) and triethylamine trifluoride (23 μL, 0.14 mmol) were added into dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, which was filtered, the filter cake was washed with dichloromethane / methanol = 20:1, and the obtained solid was dried to constant weight to obtain compound A-7 (white solid, 23 mg): 1 H NMR (300 MHz, DMSO-d6) δ 10.29 (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 F3N2O4S2[M+H] + 407.0342, found 407.0345.

[0213] Example 8

[0214] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(trifluoromethoxy)benzamide (compound A-8)

[0215]

[0216] Synthesis of compound A-8

[0217] Referring to the method of Example 7, 4-trifluoromethylthiophenylcarboxylic acid was replaced with 4-trifluoromethoxybenzoic acid to obtain compound A-8: 1H NMR (300 MHz, DMSO-d6) 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 F3N2O5S [M+H] + 391.0570, found 391.0575.

[0218] Example 9

[0219] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(trifluoromethyl)benzamide (Compound A-9)

[0220]

[0221] Synthesis of Compound A-9

[0222] Referring to the method of Example 7, 4-trifluoromethylthiophenzoic acid was replaced with 4-trifluoromethylbenzoic acid to give Compound A-9: 1 H NMR (300 MHz, DMSO-d6) 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 F3N2O4S [M+H] + 375.0621, found 375.0636.

[0223] Example 10

[0224] 4-(difluoromethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-10)

[0225]

[0226] Synthesis of Compound A-10

[0227] Referring to the method of Example 7, 4-trifluoromethylthiophenzoic acid was replaced with 4-difluoromethylbenzoic acid to give Compound A-10:1 H NMR (300 MHz, DMSO-d6) 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 F2N2O4S [M+H] + 357.0715, found 357.0706.

[0228] Example 11

[0229] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-isopropylbenzamide (Compound A-11)

[0230]

[0231] Synthesis of Compound A-11

[0232] Referring to the method of Example 7, 4-trifluoromethylsulfanylbenzoic acid was replaced with 4-isopropylbenzoic acid to give Compound A-11: 1 H NMR (300 MHz, DMSO-d6) 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 17 H 20 N2O4S [M+H] + 349.1217, found 349.1221.

[0233] Example 12

[0234] 4-bromo-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-12)

[0235]

[0236] Synthesis of Compound A-12

[0237] Compound A-12 was prepared according to the procedure of Example 7, substituting 4- trifluoromethylthiophenylcarboxylic acid for 4-trifluoromethylthiophenylcarboxylic acid: 1 H NMR (300 MHz, DMSO-d6) 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 BrN2O4S[M+H] + 384.9852, found 384.9849.

[0238] Example 13

[0239] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-propylbenzamide (Compound A-13)

[0240]

[0241] Synthesis of Compound A-13

[0242] Compound A-13 was prepared according to the procedure of Example 1, substituting 4- trifluoromethylthiophenylcarboxylic acid for 4-trifluoromethylthiophenylcarboxylic acid: 1 H NMR (300 MHz, DMSO-d6) 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 N2O4S[M+H] + 349.1217, found 349.1219.

[0243] Example 14

[0244] 4-cyclopentyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-15)

[0245]

[0246] Synthesis of Compound A-14

[0247] Referring to the method of Example 7, 4-trifluoromethylsulfanylbenzoic acid was replaced with 4-cyclopropylbenzoic acid to give Compound A-14: 1 H NMR (300 MHz, DMSO-d6) 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 N2O4S [M+H] + 347.1060, found 347.1065.

[0248] Example 15

[0249] 4-cyclopentyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-15)

[0250]

[0251] Synthesis of Compound A-15

[0252] Referring to the method of Example 7, 4-trifluoromethylsulfanylbenzoic acid was replaced with 4-cyclopropylbenzoic acid to give Compound A-14: 1 H NMR (300 MHz, DMSO-d6) 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 C19 H 22 N2O4S[M+H] + 375.1373, found 375.1378.

[0253] Example 16

[0254] 4-(4, 4-difluorocyclohexyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-16)

[0255]

[0256] Synthesis of Compound A-16

[0257] Following the procedure of Reference Example 7, replacing 4-trifluoromethylsulfanylbenzoic acid with Intermediate I-10, Compound A-16 was obtained: 1 H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.67 (s, 1H), 8.70 (s, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 2.3 Hz, 1H), 7.49 (dd, J = 8.7, 2.4 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.7 Hz, 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 F2N2O4S[M+H] + 425.1341, found 425.1340.

[0258] Example 17

[0259] 4-cycloheptyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-17)

[0260]

[0261] Synthesis of Intermediate I-20

[0262] Potassium carbonate (509 mg, 4.8 mmol) was added to a dry three-necked flask under argon protection, and a solution of cycloheptanone (353 μL, 3 mmol) in anhydrous dichloromethane (10 mL) was added, followed by a solution of triflic anhydride (1 mL, 6 mmol) in anhydrous dichloromethane (5 mL) slowly. The reaction was stirred at room temperature for 12 h. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added to quench the excess triflic anhydride, and dichloromethane (10 mL x 3) was used to extract the reaction mixture. The combined organic phase was washed with saturated brine (10 mL x 1), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether) to give intermediate I-20 (colorless oily liquid, 509 mg).

[0263] Synthesis of intermediate I-21

[0264] Potassium carbonate (509 mg, 4.8 mmol) was added to a dry three-necked flask under argon protection, and a solution of cycloheptanone (353 μL, 3 mmol) in anhydrous dichloromethane (10 mL) was added, followed by a solution of triflic anhydride (1 mL, 6 mmol) in anhydrous dichloromethane (5 mL) slowly. The reaction was stirred at room temperature for 12 h. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added to quench the excess triflic anhydride, and dichloromethane (10 mL x 3) was used to extract the reaction mixture. The combined organic phase was washed with saturated brine (10 mL x 1), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether) to give intermediate I-20 (colorless oily liquid, 509 mg).

[0265] Synthesis of compound A-17

[0266] Compound A-17 was prepared according to the method of Example 1, by replacing intermediate I-5 with the crude intermediate I-21, and replacing intermediate I-3 with intermediate I-18. 1 H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.35 (s, 1H), 9.06 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 8.7, 2.4 Hz, 1H), 7.38 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.7 Hz, 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 N2O4S [M+H] + 403.1686, found 403.1689.

[0267] Example 18

[0268] 4-(Diethylamino)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-18)

[0269]

[0270] Synthesis of Compound A-18

[0271] Compound A-18 was prepared according to the procedure of Example 7, replacing 4-trifluoromethylsulfanylbenzoic acid with 4-(N,N-diethylamino)-benzoic acid: 1 H NMR (300 MHz, DMSO-d6) 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 N3O4S [M+H] + 378.1488, found 378.1494.

[0272] Example 19

[0273] N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-(4-methylpiperazin-1-yl)benzamide (Compound A-19)

[0274]

[0275] Synthesis of Compound A-19

[0276] Compound A-19 was prepared according to the procedure of Example 7, replacing 4-trifluoromethylsulfanylbenzoic acid with 4-(4-methylpiperazin)benzoic acid: 1H NMR (300 MHz, DMSO-d6) 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 N4O4S[M+H] + 405.1591, found 405.1594.

[0277] Example 20

[0278] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(piperidin-l- yl)benzamide (Compound A-20)

[0279]

[0280] Synthesis of Compound A-20

[0281] Compound A-20 was prepared according to the procedure of Reference Example 7, replacing 4-trifluoromethylthiobenzoic acid with 4-piperazinobenzoic acid: 1 H NMR (300 MHz, DMSO-d6) 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 N3O4S[M+H] + 390.1482, found 390.1486.

[0282] Example 21

[0283] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-morpholinobenzamide (Compound A-21)

[0284]

[0285] Synthesis of compound A-21

[0286] Following the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-morpholinobenzoic acid to prepare compound A-21: 1 H NMR (300MHz, DMSO-d6) δ9.82(s,1H),9.16(s,2H),7.87(d,J=8.7Hz,2H),7.62(d,J=2.3Hz,1H),7.48(dd,J=8.7,2.3Hz,1H),7 .01(d,J=8.8Hz,2H),6.84(d,J=8.7Hz,1H),3.75(t,J=4.6Hz,4H),3.25(t,J=4.8Hz,4H),2.97(s,3H).HRMS(ESI)calcd.forC 18 H 21 N3O5S[M+H] + 392.1275, found 392.1277.

[0287] Example 22

[0288] 4-(4,4-difluoropiperidin-1-yl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (compound A-22)

[0289]

[0290]

[0291] Synthesis of intermediate I-22

[0292] 4,4-Difluoropiperidine hydrochloride (158 mg, 1 mmol) and triethylamine (416 μL, 3 mmol) were added to anhydrous dichloromethane (4 mL), and stirred at room temperature for 10 minutes. Then, p-methoxycarbonylphenylboronic acid (360 mg, 2 mmol) and anhydrous copper acetate (362 mg, 2 mmol) were added sequentially. Molecular sieve (1.5 g) and pyridine (161 μL, 2 mmol) were added, and the reaction was carried out at room temperature for 10 hours. After the reaction was completed, the reaction solution was filtered through diatomaceous earth, the solvent was evaporated from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give intermediate I-22 (white solid, 89 mg): 1H NMR (300 MHz, Chloroform-d) δ 7.93 (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).

[0293] Synthesis of compound A-22

[0294] Compound A-22 was prepared according to the procedure of Reference Example 1, replacing I-5 with intermediate I-22, and replacing intermediate I-3 with intermediate I-18: 1 H NMR (300 MHz, DMSO-d6) 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 F2N3O4S [M+H] + 426.1294, found 426.1328.

[0295] Example 23

[0296] 4'-fluoro-N-(3-((4-fluorophenyl)sulfonylamido)-4-hydroxyphenyl)-3'- sulfamoyl[l,l'-biphenyl]-4-carboxamide (Compound A-23)

[0297]

[0298] Synthesis of intermediate I-23

[0299] Intermediate I-23 was prepared according to the procedure of Reference Example 7, replacing 4-trifluoromethylsulfanylbenzoic acid with tert-butyl 4-(4- carboxyphenyl)piperazine- 1 -carboxylate, as a white solid (68 mg): 1H NMR (300 MHz, DMSO-d6) 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).

[0300] Synthesis of compound A-23

[0301] Intermediate I-23 (87 mg, 0.18 mmol) was added into dichloromethane (2 mL), 4M hydrogen chloride-dioxane solution (1 mL) 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, and the residue was purified by trituration (ethyl acetate) to obtain compound A-23 (white solid, 63 mg): 1 H NMR (300 MHz, DMSO-d6) 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 N4O4S [M-HCl+H] + 391.1435, found 391.1433.

[0302] Example 24

[0303] N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzo[c][l,2,5]oxadiazole-5- carboxamide (compound A-24)

[0304]

[0305] Synthesis of compound A-24

[0306] Compound A-24 was prepared according to the method of Reference Example 7, by replacing 4-trifluoromethylthiobenzoic acid with benzo furazan-5-carboxylic acid: 1H NMR (300 MHz, DMSO-d6) 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 N4O5S [M+H] + 349.0601, found 349.0606.

[0307] Example 25

[0308] 5-Hydroxy-4-(methylsulfonamido)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4- carboxamide)benzoic acid (Compound A-25)

[0309]

[0310] Synthesis of Intermediate 1-24

[0311] Methyl 4-amino-3-methoxybenzoate (3 g, 16.57 mmol) and pyridine (2.01 mL, 24.86 mmol) were added into dichloromethane (30 mL), methylsulfonic anhydride (3.75 g, 21.55 mmol) was added portionwise under ice-bath, after addition, the reaction was allowed to warm to room temperature for 8 hours. After the reaction was completed, concentrated hydrochloric acid (2 mL) was added into the reaction solution to quench the excess pyridine and methylsulfonic anhydride, the solvent was evaporated under reduced pressure, 1N aqueous hydrogen chloride solution (50 mL) was added into the residue and extracted with ethyl acetate (25 mL x 3), the organic phase was combined and washed with 1N aqueous hydrogen chloride solution (30 mL x 1), water (30 mL x 1), saturated brine (30 mL x 1) successively, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give Intermediate 1-24 (orange-red solid, 3.80 g).

[0312] Synthesis of Intermediate 1-25

[0313] Intermediate 1-24 (3.80 g, 14.67 mmol) was added into concentrated sulfuric acid (98%, 15 mL), and a solution of potassium nitrate (1.2 g, 17.60 mmol) in concentrated sulfuric acid (98%, 15 mL) was added dropwise under ice water bath. After the addition, the reaction was continued for 20 minutes under ice water bath. After the reaction was completed, the reaction solution was added dropwise into ice water (200 mL), and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with water (100 mL x 1), saturated brine (100 mL x 1) successively, dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by trituration (petroleum ether / ethyl acetate = 3:1), and the obtained solid was dried to constant weight to give intermediate 1-25 (yellow solid, 3.41 g): 1 H NMR (300 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.03 (s, 1H), 7.42 (s, 1H), 3.98 (s, 3H), 3.85 (s, 3H), 3.14 (s, 3H).

[0314] Synthesis of intermediate 1-26

[0315] Intermediate 1-25 (3.75 g, 12.34 mmol) and lithium chloride (1.55 g, 37.01 mmol) were added into N,N-dimethylformamide (30 mL), and the reaction was carried out under reflux for 1.5 hours. After the reaction was completed, the system was cooled to room temperature, and water (300 mL) was added to dilute the reaction solution and adjust the pH to acidic by adding 2N aqueous hydrogen chloride solution (10 mL). The aqueous phase was extracted with ethyl acetate (100 mL x 3), and the combined organic phase was washed with water (100 mL x 1), saturated brine (100 mL x 1) successively. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 80:1) to give intermediate 1-26 (yellow solid, 2.40 g): 1 H NMR (300 MHz, DMSO-d6) δ 11.97 (s, 1H), 9.47 (s, 1H), 7.98 (s, 1H), 7.10 (s, 1H), 3.82 (s, 3H), 3.12 (s, 3H).

[0316] Synthesis of intermediate 1-27

[0317] Intermediate 1-26 (2.40 g, 8.28 mmol) and 10% palladium-carbon (360 mg) were added into tetrahydrofuran (20 mL), and methanol (5 mL). The reaction was carried out under hydrogen atmosphere at room temperature for 12 hours. After the reaction was completed, the palladium-carbon was filtered off, and the filter cake was washed with tetrahydrofuran (10 mL). The filtrate was concentrated under reduced pressure to give intermediate 1-27 as a crude product, which was used directly in the next reaction without further purification.

[0318] Synthesis of intermediate 1-28

[0319] The crude intermediate 1-27 and N,N-diisopropylethylamine (2.88 mL, 16.55 mmol) were added into 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 ice bath. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 8 hours. After the reaction was completed, the reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (50 mL), and extracted with dichloromethane (30 mL x 3). The combined organic phase was washed with water (30 mL x 1), saturated brine (30 mL x 1), and then the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give intermediate 1-28 (white solid, 1.40 g): 1 H NMR (300 MHz, DMSO-d6) 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).

[0320] Synthesis of intermediate 1-29

[0321] Compound 4-trifluoromethylbromobenzene (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 into a mixture of toluene (3.6 mL) and methanol (0.4 mL) under argon protection. The reaction mixture was heated at 80 °C for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with water (10 mL x 1), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to give intermediate 1-29 (white solid, 255 mg).

[0322] Synthesis of intermediate 1-30

[0323] Intermediate I-29 (250 mg, 0.89 mmol) was added into a mixture of tetrahydrofuran (2 mL) and methanol (2 mL), 1 M aqueous sodium hydroxide 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, 2 N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3, a solid was precipitated, and the solid was filtered, washed with water (5 mL) and diethyl ether (5 mL), and dried to constant weight to obtain intermediate I-30 (white solid, 205 mg): 1 H NMR (300 MHz, DMSO-d6) δ 13.10 (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).

[0324] Synthesis of intermediate I-31

[0325] Intermediate I-30 (90 mg, 0.34 mmol) and N,N-dimethylformamide (2 drops) were added into anhydrous tetrahydrofuran (3 mL), and oxalyl chloride (44 μL, 0.51 mmol) was slowly added dropwise under ice bath, and the mixture was allowed to react at 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 an oxalyl chloride solution in tetrahydrofuran, 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, and the mixture was allowed to react at room temperature for 6 hours. After the reaction was completed, 2 N aqueous hydrogen chloride solution was added to the reaction mixture to adjust the pH to 3-4, and ethyl acetate (5 mL x 3) was added to extract the mixture, and the combined organic phase was washed with water (10 mL x 1) and saturated brine (10 mL x 1), and 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-31 (white solid, 102 mg).

[0326] Synthesis of intermediate I-32

[0327] Intermediate I-31 (70 mg, 0.11 mmol) and triethylamine trihydrofluoride (22 μL, 0.51 mmol) were added into dichloromethane (2 mL), and the mixture was allowed to react at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, which was filtered, washed with dichloromethane / methanol (20:1), and dried to constant weight to obtain intermediate I-32 (white solid, 57 mg).

[0328] Synthesis of compound A-25

[0329] Intermediate I-32 (57 mg, 0.11 mmol) and lithium hydroxide monohydrate (14 mg, 0.14 mmol) were added to a mixture of tetrahydrofuran (1 mL), methanol (1 mL), water (1 mL) and the reaction was allowed to proceed at 60 °C for 6 hours. After the reaction was completed, the system was cooled to room temperature, water (15 mL) was added to the reaction solution, 2N hydrogen chloride aqueous solution was used to adjust the pH to 2-3, and ethyl acetate (5 mL x 3) was used for extraction. The organic phase was combined and washed with water (5 mL x 1) and saturated brine (5 mL x 1), respectively. The solvent was evaporated under reduced pressure, and 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-d6) δ 12.44 (s, 1H), 10.12 (s, 1H), 9.04 (s, 1H), 8.73 (s, 1H), 8.06 (d, J = 8.4 Hz, 2H), 8.01-7.92 (m, 4H), 7.85 (d, J = 8.2 Hz, 2H), 7.56 (s, 1H), 3.11 (s, 3H). HRMS (ESI) calcd. for C 22 H 17 F3N2O6S[M+H] + 495.0832, found 495.0829.

[0330] Example 26

[0331] 4-((4-Fluorophenyl)sulfonamido)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4- carboxamido)benzoic acid (Compound A-26)

[0332]

[0333] Synthesis of intermediate I-33

[0334] 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 dropwise addition was completed, the reaction was allowed to proceed at room temperature for 3 hours. After the reaction was completed, the excess iodoethane was evaporated under reduced pressure, and the residue was diluted with water (20 mL). The organic phase was extracted with ethyl acetate (10 mL x 3), and the combined organic phase was washed with water (10 mL x 2), saturated brine (5 mL x 1), and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain intermediate I-33 (yellow solid, 325 mg): 1H NMR (300 MHz, DMSO-d6) δ 7.61 (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] + .

[0335] Synthesis of intermediate 1-34

[0336] Intermediate 1-33 (324 mg, 1.54 mmol) and pyridine (186 μL, 2.31 mmol) were added into anhydrous dichloromethane (3 mL), a solution of 4-fluorobenzenesulfonyl chloride (360 mg, 1.85 mmol) in dichloromethane (1.5 mL) was added dropwise under ice-bath, after the dropwise addition, the reaction mixture was allowed to warm to room temperature and stirred for 8 hours. After the reaction was completed, 1 N aqueous hydrogen chloride solution (5 mL) was added to quench the excess pyridine, and the reaction mixture was extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (5 mL x 1), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give intermediate 1-34 (orange oily liquid, 447 mg): 1 H NMR (300 MHz, DMSO-d6) δ 7.61 (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] - .

[0337] Synthesis of intermediate 1-35

[0338] Intermediate 1-34 (610 mg, 1.66 mmol) and 10% palladium-carbon (122 mg) were added into tetrahydrofuran (5 mL), and the reaction mixture was stirred under hydrogen atmosphere at room temperature for 15 hours. After the reaction was completed, the palladium-carbon was filtered off, and the filter cake was washed with ethyl acetate (5 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 7:1) to give intermediate 1-35 (pale yellow solid, 187 mg) which was used in the next step without further purification.

[0339] Synthesis of compound A-26

[0340] Referring to the method of Example 25, intermediate 1-28 was replaced by intermediate 1-35, and after condensation, the ester was directly hydrolyzed to give compound A-26: 1 H NMR (300 MHz, DMSO-d6) 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 F4N2O5S[M+H] + 559.0945, found 559.0945.

[0341] Example 27

[0342] 4-(Methylsulfonamido)-2-(4'-(trifluoromethyl)-[1,1'-biphenyl]-4-carboxamide)benzoic acid (Compound A-27)

[0343]

[0344] Synthesis of intermediate 1-36

[0345] Intermediate 1-33 (468 mg, 2.23 mmol) was added to anhydrous dichloromethane (3 mL), pyridine (269 μL, 3.35 mmol) was added, and a solution of methylsulfonic anhydride (466 mg, 2.67 mmol) in anhydrous dichloromethane (2 mL) was added under ice bath, and the reaction was allowed to proceed at room temperature for 14 hours. After the reaction was completed, 1 N aqueous hydrogen chloride solution (8 mL) was added to quench the excess pyridine and methylsulfonic anhydride, and ethyl acetate (10 mL x 3) was extracted, the organic phase was 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 1-36 (yellow solid, 554 mg): 1 H NMR (300 MHz, DMSO-d6) 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 [M-H] - .

[0346] Synthesis of intermediate 1-37

[0347] Intermediate 1-36 (447 mg, 1.21 mmol) and 10% palladium on carbon (89 mg) were added into tetrahydrofuran (5 mL) and stirred at room temperature under hydrogen atmosphere for 15 hours. After the reaction was completed, the palladium on carbon was filtered off, the filter cake was washed with ethyl acetate (5 mL), and the filtrate was evaporated under reduced pressure to remove the solvent. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain intermediate 1-37 (light yellow solid, 337 mg): 1 H NMR (300 MHz, DMSO-d6) 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 [M-H] - .

[0348] Synthesis of compound A-27

[0349] Referring to the method of Example 25, intermediate 1-28 was replaced by intermediate 1-37, and after condensation, the ester was directly hydrolyzed to obtain compound A-27: 1 H NMR (300 MHz, DMSO-d6) 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 F3N2O5S [M+H] + 479.0883, found 479.0884.

[0350] Example 28

[0351] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-((trifluoromethyl)thio)benzyl)benzamide (Compound A-28)

[0352]

[0353] Synthesis of compound A-28

[0354] Compound A-28 was prepared according to the procedure of Example 3 by replacing 4,4-difluorocyclohexanone with 4-trifluoromethylbenzaldehyde: 1 H NMR (300 MHz, DMSO-d6) 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 F4N2O4S2[M+H] + 577.0873, found 577.0883.

[0355] Example 29

[0356] 4-(Cyclohexylmethyl)-N-(3-((4-fluorophenyl)sulfonamido)-4- hydroxyphenyl)benzamide (Compound A-29)

[0357]

[0358] Synthesis of Intermediate 1-38

[0359] Ethyl 4-(bromomethyl)benzoate (2.92 g, 12 mmol) was added into toluene (6 mL), after the solid was dissolved by stirring, triethyl phosphite (2.3 mL, 13.2 mmol) was added, after the addition, the reaction was heated to 150 °C for 8 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to obtain crude Intermediate 1-38 (colorless oily liquid, 3.6 g), which was used directly in the next step without further purification.

[0360] Synthesis of Intermediate 1-39

[0361] Sodium hydride (120 mg, 3 mmol) was added into a dry Schlenk tube, which was protected by argon, and then suspended in anhydrous tetrahydrofuran (1 mL). A solution of Intermediate 1-38 (360 mg, 1.2 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise into the above mixture under ice bath, and then the reaction was slowly warmed to room temperature for 1 hour. A solution of cyclohexanone (107 μL, 1 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise into the above mixture under ice bath, and then the reaction was warmed to room temperature for 24 hours. After the reaction was completed, saturated ammonium chloride solution (10 mL) was added into the reaction mixture to quench the excess sodium hydride, and then the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL x 2), and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain Intermediate 1-39 (white solid, 260 mg).

[0362] Synthesis of compound A-29

[0363] Compound A-29 was prepared according to the procedure of Example 1 by replacing intermediate 1-4 with intermediate 1-39: 1 H NMR (300 MHz, DMSO-d6) 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 FN2O4S [M+H] + 483.1748, found 483.1748.

[0364] Example 30

[0365] 4-((4,4-difluorocyclohexyl)methyl)-N-(3-((4-fluorophenyl)sulfonamido)-4- hydroxyphenyl)benzamide (Compound A-30)

[0366]

[0367] Synthesis of compound A-30

[0368] Compound A-30 was prepared according to the procedure of Example 29 by replacing cyclohexanone with 4,4-difluorocyclohexanone: 1 H NMR (300 MHz, DMSO-d6) 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 F3N2O4S [M+H] + 519.1560, found 519.1562.

[0369] Example 31

[0370] 4-(Cycloheptylmethyl)-N-(3-((4-fluorophenyl)sulfonamido)-4- hydroxyphenyl)benzamide (Compound A-31)

[0371]

[0372] Synthesis of Compound A-31

[0373] Compound A-31 was prepared according to the procedure of Example 29, replacing cyclohexanone with cycloheptanone, and replacing intermediate 1-3 with intermediate 1-18: 1 H NMR (300 MHz, DMSO-d6) 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 FN2O4S [M+H] + 497.1905, found 497.1898.

[0374] Example 32

[0375] 4-(Cyclopentylmethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound A-32)

[0376]

[0377] Synthesis of Compound A-32

[0378] Compound A-32 was prepared according to the procedure of Example 29, replacing cyclohexanone with cyclopentanone, and replacing intermediate 1-3 with intermediate 1-18: 1 H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.05 (s, 2H), 7.85 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.49 (dd, J = 8.7, 2.5 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 2.98 (s, 3H), 2.65 (d, J = 7.4 Hz, 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 C20 H 24 N₂O₄S[M+H] + 389.1530, found 389.1537.

[0379] Example 33

[0380] 4-(cyclohexylmethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (compound A-33)

[0381]

[0382] Synthesis of compound A-33

[0383] Referring to the method of Example 29, intermediate I-3 was replaced with intermediate I-18 to obtain compound A-33: 1 H NMR (300MHz, DMSO-d6) 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 N₂O₄S[M+H] + 403.1686, found 403.1694.

[0384] Example 34

[0385] 4-(cycloheptylmethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (compound A-34)

[0386]

[0387] Synthesis of compound A-34

[0388] Following the method of Example 29, cyclohexanone was replaced with cycloheptanone, and intermediate I-3 was replaced with intermediate I-18 to obtain compound A-34: 1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.32 (s, 1H), 8.97 (s, 1H), 7.85 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 8.7, 2.0 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 2.98 (s, 3H), 2.56 (d, J = 7.2 Hz, 2H), 1.84 - 1.73 (m, 1H), 1.67 - 1.29 (m, 10H), 1.24 - 1.10 (m, 2H). HRMS (ESI) calcd. for C 22 H 28 N2O4S[M+H] + 417.1843, found 417.1846.

[0389] Example 35

[0390] 4-((1H-Imidazol-1-yl)methyl)-N-(3-((4-fluorophenyl)sulfonamido)-4- hydroxyphenyl)benzamide (Compound A-35)

[0391]

[0392] Synthesis of Intermediate 1-40

[0393] Imidazole (99 mg, 1.65 mmol) was added to acetonitrile (3 mL), followed by the addition of ethyl 4-(bromomethyl)benzoate (200 mg, 0.82 mmol) and potassium carbonate (227 mg, 1.65 mmol). After the addition was completed, the reaction mixture was heated to 80 °C 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 give Intermediate 1-40 (colorless oily liquid, 112 mg): 1 H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.32 (s, 1H), 8.97 (s, 1H), 7.85 (d, J = 7.9 Hz, 2H), 7.63 (d, J = 1.8 Hz, 1H), 7.49 (dd, J = 8.7, 2.0 Hz, 1H), 7.30 (d, J = 7.9 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 2.98 (s, 3H), 2.56 (d, J = 7.2 Hz, 2H), 1.84 - 1.73 (m, 1H), 1.67 - 1.29 (m, 10H), 1.24 - 1.10 (m, 2H). HRMS (ESI) calcd. for C

[0394] Synthesis of Compound A-35

[0395] Compound A-35 was prepared according to the method of Reference Example 5, replacing Intermediate 1-11 with Intermediate 1-40: 1H NMR (300MHz, DMSO-d6) δ10.07(s,1H),9.43(s,2H),7.90(d,J=8.0Hz,2H),7.86-7.74(m,3H),7.67(d,J=1.9H z,1H),7.43-7.31(m,5H),7.24(s,1H),6.96(s,1H),6.68(d,J=8.7Hz,1H),5.30(s,2H).HRMS(ESI)calcd.for C 23 H 19 FN4O4S[M+H] + 467.1184, found 467.1188.

[0396] Example 36

[0397] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(morpholinomethyl)benzamide hydrochloride (compound A-36)

[0398]

[0399] Synthesis of intermediate I-41

[0400] Following the method of Example 7, 4-trifluoromethylthiobenzoic acid was replaced with 4-aldehyde benzoic acid to obtain crude intermediate I-41 (yellow solid, 216 mg), which was used directly in the next reaction without further purification.

[0401] Synthesis of intermediate I-42

[0402] Crude intermediate I-41 (100 mg, 0.24 mmol) and morpholine (32 μL, 0.36 mmol) were added to dichloromethane (15 mL), followed by glacial acetic acid (2 drops). Then, sodium triacetoxyborohydride (153 mg, 0.72 mmol) was added in portions under ice bath conditions. After the addition was complete, the mixture was stirred at room temperature for 12 hours. After the reaction was complete, the reaction solution was quenched with saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined. The mixture was 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 = 75:1) to obtain intermediate I-42 (white solid, 82 mg). 1H NMR (300 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.48 (s, 1H), 7.90 (d, J = 7.9 Hz, 2H), 7.75 (d, J = 2.4 Hz, 1H), 7.55 (dd, J = 8.7, 2.4 Hz, 1H), 7.45 (d, J = 7.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 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).

[0403] Synthesis of intermediate 1-43

[0404] Intermediate 1-42 (80 mg, 0.15 mmol) and triethylamine trifluoride hydrochloride (40 μL, 0.23 mmol) were added into dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, which was filtered and the filter cake was washed with dichloromethane / methanol (20:1) to obtain crude intermediate 1-43 (white solid, 47 mg), which was used in the next reaction without further purification.

[0405] Synthesis of compound A-36

[0406] Intermediate 1-43 (47 mg) was added into dichloromethane (2 mL), and 4M hydrogen chloride-dioxane solution (1 mL) was added dropwise. After the dropwise addition was completed, the reaction was carried out at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by trituration (ethyl acetate) to obtain a solid, which was dried to constant weight to obtain compound A-36 (white solid, 33 mg): 1 H NMR (300 MHz, DMSO-d6) δ 11.09 (s, 1H), 10.19 (s, 1H), 9.78 (s, 1H), 8.75 (s, 1H), 8.02 (d, J = 7.8 Hz, 2H), 7.73 (d, J = 7.8 Hz, 2H), 7.64 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 8.7, 2.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 1H), 4.41 (d, J = 5.2 Hz, 2H), 3.93 (t, 2H), 3.77 (t, J = 11.7 Hz, 2H), 3.24 (t, J = 11.8 Hz, 2H), 3.10 (t, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 19 H 23 N3O5S [M - HCl + H] + 406.1431, found 406.1435.

[0407] Example 37

[0408] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(piperazin-l- ylmethyl)benzamide hydrochloride (Compound A-37)

[0409]

[0410] Synthesis of Compound A-37

[0411] Compound A-37 was prepared according to the procedure of Example 36, replacing morpholine with 1-Boc-piperazine: 1 H NMR (300 MHz, DMSO-d6) 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 N4O4S [M+H] + 405.1591, found 405.1575.

[0412] Example 38

[0413] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-methylpiperazin-l- yl)methyl)benzamide hydrochloride (Compound A-38)

[0414]

[0415] Synthesis of Compound A-38

[0416] Compound A-38 was prepared according to the procedure of Example 36, replacing morpholine with N-methylpiperazine: 1H NMR (300 MHz, DMSO-d6) 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 N4O4S[M-HCl + H] + 419.1748, found 419.1749.

[0417] Example 39

[0418] 4-((4,4-difluoropiperidin-l-yl)methyl)-N-(3-((4-fluorophenyl)sulfonamido)-4- hydroxyphenyl)benzamide (Compound A-39)

[0419]

[0420] Synthesis of Compound A-39

[0421] Compound A-39 was prepared according to the procedure described in Example 36 by replacing morpholine with 4,4-difluoropiperidine hydrochloride: 1 H NMR (300 MHz, DMSO-d6) 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 F3N3O4S[M-HCl + H] + 520.1512, found 520.1518.

[0422] Example 40

[0423] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-l-(4-(trifluoromethyl)benzyl)-lH- imidazole-4-carboxamide (Compound A-40)

[0424]

[0425]

[0426] Synthesis of intermediate 1-44

[0427] Methyl imidazole-4-carboxylate (502 mg, 2 mmol) and 4-(trifluoromethyl)benzyl bromide (526 mg, 2.2 mmol) were added into N,N-dimethylformamide (5 mL), and then cesium carbonate (720 mg, 2.2 mmol) was added portionwise. The reaction was allowed to proceed at room temperature for 12 hours. After the reaction was completed, water (50 mL) was added to dilute the reaction solution, and ethyl acetate (10 mL x 3) was used to extract the reaction solution. The organic phase was combined and washed with water (20 mL x 1) and saturated brine (20 mL x 1), respectively. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain intermediate 1-44 (white solid, 377 mg): 1 H NMR (300 MHz, Chloroform-d) d 7.65 (d, J = 7.9 Hz, 2H), 7.60 (s, 2H), 7.29 (d, J = 7.6 Hz, 2H), 5.24 (s, 2H), 3.88 (s, 3H).

[0428] Synthesis of intermediate 1-45

[0429] Intermediate 1-44 (350 mg, 1.23 mmol) was added into a mixture of tetrahydrofuran (3 mL) and water (1.5 mL), and lithium hydroxide monohydrate (155 mg, 3.70 mmol) was added. The reaction was allowed to proceed at room temperature for 6 hours. After the reaction was completed, the solvent was removed under reduced pressure, and 1N aqueous hydrogen chloride solution was added dropwise to the organic phase to adjust the pH to 5-6. A solid was precipitated, which was filtered, and the filter cake was washed with dichloromethane (2 mL). The obtained solid was dried to constant weight to obtain intermediate 1-45 (white solid, 266 mg): 1 H NMR (300 MHz, DMSO-d6) d 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).

[0430] Synthesis of compound A-40

[0431] Compound A-40 was prepared according to the method of Example 7, by replacing 4-trifluoromethylthiobenzoic acid with intermediate 1-45: 1H NMR (300 MHz, Methanol-d4) 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 F3N4O4S [M+H] + 455.0995, found 455.0996.

[0432] Example 41

[0433] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-1-(4-(trifluoromethyl)benzyl)-1H-1,2,4- triazole-3-carboxamide (Compound A-41)

[0434]

[0435] Synthesis of Compound A-41

[0436] Referring to the method of Example 40, methyl imidazole-4-carboxylate was replaced with methyl 1,2,4-triazole-3-carboxylate to produce Compound A-41: 1 H NMR (300 MHz, DMSO-d6) 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 F3N5O4S [M+H] + 456.0948, found 456.0927.

[0437] Example 42

[0438] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-1-(4-(trifluoromethoxy)benzyl)-1H-1,2,4- triazole-3-carboxamide (Compound A-42)

[0439]

[0440] Synthesis of compound A-42

[0441] Referring to the method of example 40, methyl imidazole-4-carboxylate was replaced with methyl 1,2,4-triazole-3-carboxylate, and 4-(trifluoromethyl)benzyl bromide was replaced with 4-(trifluoromethoxy)benzyl bromide to prepare compound A-42: 1 H NMR (300 MHz, DMSO-d6) 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 F3N5O5S[M+H] + 472.0897, found 472.0705.

[0442] Example 43

[0443] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-((trifluoromethyl)thio)phenoxy)benzamide (Compound A-43)

[0444]

[0445] Synthesis of intermediate I-46

[0446] 4-Trifluoromethylsulfanylphenol (194 mg, 1 mmol) and methyl 4-fluorobenzoate (259 μL, 2 mmol) were added into dimethyl sulfoxide (3 mL), and potassium carbonate (276 mg, 2 mmol) was added portionwise. After the addition was completed, the system was heated at 110 °C for 18 hours. After the reaction was completed, the system was cooled to room temperature, water (30 mL) was added to dilute the reaction solution, and ethyl acetate (10 mL x 3) was used for extraction. The combined organic phase was 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 = 100:1) to obtain intermediate I-46 (colorless oily liquid, 215 mg).

[0447] Synthesis of compound A-43

[0448] Referring to the method of example 1, intermediate I-5 was replaced with intermediate I-46 to prepare compound A-43: 1H NMR (300 MHz, DMSO-d6) 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 F4N2O5S2[M+H] + 579.0666, found 579.0676.

[0449] Example 44

[0450] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-1)

[0451]

[0452]

[0453] Synthesis of Intermediate II-1

[0454] Synthesis of Intermediate II-2

[0455] Synthesis of Intermediate II-2

[0456] The crude intermediate II-1 was added into a mixture of tetrahydrofuran (1.5 mL) and methanol (1.5 mL), 1 M aqueous sodium hydroxide solution (1.5 mL) was added dropwise, after the addition was completed, the reaction was elevated to 60 °C for 4 hours. After the reaction was completed, the organic solvent was evaporated under reduced pressure, the residue was adjusted to pH 2-3 with 2 N aqueous hydrogen chloride solution, a solid was precipitated, which was filtered, the filter cake was washed with water (5 mL) and diethyl ether (5 mL) in turn, and the solid was dried to constant weight to obtain intermediate II-2 (white solid, 142 mg): 1 H NMR (300 MHz, DMSO-d6) δ 12.66 (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).

[0457] Synthesis of intermediate II-3

[0458] Intermediate II-2 (45 mg, 0.14 mmol) and N,N-dimethylformamide (2 drops) were added into anhydrous tetrahydrofuran (3 mL), oxalyl chloride (17 μL, 0.21 mmol) was slowly added dropwise under ice bath, after the addition was completed, the reaction was elevated to room temperature for 4 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of the 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, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed, 2 N aqueous hydrogen chloride solution was added to the reaction solution to adjust pH to 3-4, and ethyl acetate (5 mL x 3) was added for extraction, the combined organic phase was 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 = 5:1) to obtain intermediate III-3 (white solid, 123 mg): 1 H NMR (300 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.01 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.82 (d, J = 5.2 Hz, 1H), 7.80-7.74 (m, 3H), 7.64 (d, J = 7.6 Hz, 3H), 7.46 (dd, J = 8.8, 2.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.14 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.7 Hz, 1H), 5.30 (s, 2H), 0.92 (s, 9H), 0.13 (s, 6H).

[0459] Synthesis of compound B-1

[0460] Intermediate II-3 (107 mg, 0.19 mmol) and triethylamine trifluoride (50 μL, 0.28 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, which was filtered, the filter cake was washed with dichloromethane / methanol (20:1), and the obtained solid was dried to constant weight to obtain Compound B-1 (white solid, 57 mg): 1 H NMR (300 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.32 (s, 2H), 7.93 (d, J = 8.7 Hz, 2H), 7.82 (dd, J = 8.8, 5.3 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.38 (dd, J = 8.7, 2.7 Hz, 2H), 7.33 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.7 Hz, 1H), 5.30 (s, 2H). HRMS (ESI) calcd. for C 27 H 20 F4N2O5S2[M+H] + 593.0823, found 593.0827.

[0461] Example 45

[0462] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4- (trifluoromethyl)benzyl)oxy)benzamide (Compound B-2)

[0463]

[0464] Synthesis of Compound B-2

[0465] 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-d6) δ 9.91 (s, 1H), 9.32 (s, 2H), 7.93 (d, J = 8.7 Hz, 2H), 7.82 (dd, J = 8.8, 5.3 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 2.4 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.38 (dd, J = 8.7, 2.7 Hz, 2H), 7.33 (d, J = 9.0 Hz, 1H), 7.14 (d, J = 8.7 Hz, 2H), 6.68 (d, J = 8.7 Hz, 1H), 5.30 (s, 2H). HRMS (ESI) calcd. for C 26 H 21 FN2O5S[M+H]+ 493.1228, found 493.1231.

[0466] Example 46

[0467] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4- (trifluoromethyl)benzyl)oxy)benzamide (Compound B-3)

[0468]

[0469] Synthesis of Compound B-3

[0470] Referring to the method of Example 44, 4-trifluoromethylbenzyl bromide was replaced by 4-trifluoromethylbenzyl bromide to obtain Compound B-3: 1 H NMR (300 MHz, DMSO-d6) 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 F4N2O5S [M+H] + 561.1102, found 561.1108.

[0471] Example 47

[0472] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4- (trifluoromethyl)benzyl)oxy)benzamide (Compound B-3)

[0473]

[0474] Synthesis of Intermediate II-4

[0475] Intermediate II-2 (50 mg, 0.15 mmol) was added into trifluoroacetic acid (1 mL), 30% hydrogen peroxide aqueous solution (73 μL, 0.8 eqv.) was added dropwise under ice bath, after dropwise addition, the reaction was elevated to room temperature for 21 hours. After the reaction was completed, the reaction solution was poured into ice water (5 mL), solid was precipitated, suction filtration, the filter cake was washed with water (5 mL), the residue was purified by trituration (n-hexane / ethyl ether = 10:1), the obtained solid was dried to constant weight to obtain intermediate II-4 (white solid, 46 mg): 1H NMR (300 MHz, DMSO-d6) δ 12.70 (s, 1H), 8.19 (d, J = 8.2 Hz, 2H), 7.92 (dd, J = 8.5, 2.6 Hz, 4H), 7.14 (d, J = 8.8 Hz, 2H), 5.45 (s, 2H). ESI-MS: m / z 359.0 [M-H] - .

[0476] Synthesis of compound B-4

[0477] Following the procedure of Reference Example 44, intermediate II-2 was replaced with intermediate II-4 to give compound B-4: 1 H NMR (300 MHz, DMSO-d6) 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 F4N2O7S2[M+H] + 625.0721, found 625.0713.

[0478] Example 48

[0479] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4- (methylsulfonyl)benzyl)oxy)benzamide (Compound B-5)

[0480]

[0481] Synthesis of compound B-5

[0482] Following the procedure of Reference Example 44, 4-trifluoromethylsulfanylbenzyl bromide was replaced with 4-methylsulfonylbenzyl bromide to give compound B-5: 1H NMR (300 MHz, DMSO-d6) 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 FN2O7S2[M+H] + 571.1003, found 571.1002.

[0483] Example 49

[0484] 4-(Cyclohexylmethoxy)-N-(3-((4-fluorophenyl)sulfonamido)-4- hydroxyphenyl)benzamide (Compound B-6)

[0485]

[0486] Synthesis of Intermediate II-5

[0487] Methyl 4-hydroxybenzoate (200 mg, 1.31 mmol), cyclohexylmethanol (330 mg, 2.89 mmol) and triphenylphosphine (558 mg, 2.76 mmol) were added into a dry three-necked flask, which was protected by argon, dissolved in anhydrous tetrahydrofuran (3 mL), and then a solution of diisopropyl azodicarboxylate (560 μL, 2.76 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added under ice-bath cooling. After the dropwise addition was completed, the reaction was allowed to warm to room temperature and stirred 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-d6) 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).

[0488] Synthesis of Compound B-6

[0489] Referring to the method of Example 44, Intermediate II-1 was replaced by Intermediate II-5 to obtain Compound B-6: 1H NMR (300 MHz, DMSO-d6) 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 FN2O5S[M+H] + 499.1697, found 499.1698.

[0490] Example 50

[0491] N-(4-chloro-3-((4-fluorophenyl)sulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-7)

[0492]

[0493] Synthesis of Intermediate II-6

[0494] To a solution of 2-chloro-5-nitroaniline (345 mg, 2 mmol) and pyridine (241 μL, 3 mmol) in dichloromethane (5 mL) was added dropwise a solution of 4-fluorobenzenesulfonyl chloride (467 mg, 2.4 mmol) in dichloromethane (2 mL) at 0 °C. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 8 h. The reaction was quenched by the addition of 2 N aqueous HCl (10 mL) and the mixture was stirred for 10 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with 1 N aqueous HCl (10 mL x 1), water (10 mL x 1), and brine (10 mL x 1), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 10:1) to give the crude intermediate II-6 (yellow solid, 544 mg).

[0495] Synthesis of Intermediate II-7

[0496] Intermediate II-6 crude (544 mg, 1.74 mmol) and 10% palladium on carbon (100 mg) were added to tetrahydrofuran (5 mL) and stirred at room temperature under hydrogen atmosphere for 12 h. After the reaction was completed, the palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (5 mL), and the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give intermediate II-7 (orange oily liquid, 431 mg): 1 H NMR (300 MHz, DMSO-d6) δ 9.64 (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 [M-H] - .

[0497] Synthesis of compound B-7

[0498] Referring to the method of Example 44, intermediate I-3 was replaced with intermediate II-7 to give compound B-7: 1 H NMR (300 MHz, DMSO-d6) 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 ClF4N2O4S2[M+H] + 595.0779, found 595.0797

[0499] Example 51

[0500] N-(4-Fluoro-3-((4-fluorophenyl)sulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-8)

[0501]

[0502] Synthesis of compound B-8

[0503] Referring to the method of Example 50, 2-chloro-5-nitroaniline was replaced with 2-fluoro-5-nitroaniline to give compound B-8: 1H NMR (300 MHz, DMSO-d6) 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 F5N2O4S2[M+H] + 595.0779, found 595.0797.

[0504] Example 52

[0505] N-(3-((4-Fluorophenyl)sulfonamido)-4-(hydroxymethyl)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-9)

[0506]

[0507] Synthesis of Intermediate II-8

[0508] 2-Amino-4-nitrobenzoic acid (500 mg, 2.75 mmol) was added into a dry Schlenk tube, argon protection, dissolved in tetrahydrofuran (5.5 mL), 1M borane-tetrahydrofuran complex (5.5 mL, 5.5 mmol) was slowly added under ice bath, after dropping, the temperature was raised to 65°C and reacted for 4 hours. After the reaction was completed, the system was cooled to room temperature, ice water (20 mL) was added dropwise to quench the excess borane, and ethyl acetate (10 mL x 3) was extracted, the organic phase was combined, washed with water (10 mL x 1), 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 = 3:1) to obtain intermediate II-8 (yellow solid, 431 mg): 1 H NMR (300 MHz, DMSO-d6) δ 7.46 (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 [M-H] - .

[0509] Synthesis of Compound B-9

[0510] According to the method of Example 50, intermediate II-8 was replaced with 2-chloro-5-nitroaniline to prepare Compound B-9:1 HNMR (300 MHz, DMSO-d6) 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 F4N2O5S2[M+H] + 607.0979, found 607.1010.

[0511] Example 53

[0512] 2-((4-Fluorophenyl)sulfonamido)-4-(4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamido)benzoic acid (Compound B-10)

[0513]

[0514]

[0515] Synthesis of Intermediate II-9

[0516] Compound 2-amino-4-nitrobenzoic acid (300 mg, 1.65 mmol) and potassium carbonate (455 mg, 3.3 mmol) were added into N,N-dimethylformamide (3 mL), iodoe thane (158 μL, 1.98 mmol) was added dropwise under ice-bath, after dropwise, the reaction solution was warmed to room temperature for 6 hours. After the reaction was completed, water (20 mL) was added to dilute the reaction solution, and ethyl acetate (10 mL x 3) was used to extract the reaction solution, and the combined organic phase was washed with saturated brine (10 mL x 1), and the solvent was removed 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).

[0517] Synthesis of Intermediate II-10

[0518] 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 cooling. After the dropwise addition, the reaction mixture was allowed to warm to room temperature and stirred for 8 hours. After the completion of the reaction, the solvent was evaporated under reduced pressure, and ethyl acetate (10 mL) and 2 N aqueous hydrogen chloride solution (5 mL) were added. The mixture was shaken well, and the organic phase was washed with 1 N aqueous hydrogen chloride solution (5 mL x 1), water (5 mL x 1), and saturated brine (5 mL x 1) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated 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).

[0519] Synthesis of intermediate II-11

[0520] Intermediate II-10 (117 mg, 0.32 mmol) and 10% palladium-carbon (23 mg) were added to tetrahydrofuran (3 mL), and the mixture was stirred under a hydrogen atmosphere at room temperature for 12 hours. After the completion of the reaction, the palladium-carbon was filtered off, and the filter cake was washed with tetrahydrofuran (5 mL). The filtrate was concentrated 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 HNMR (300 MHz, DMSO-d6) δ 10.98 (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 [M-H] - .

[0521] Synthesis of intermediate II-12

[0522] Intermediate II-3 (60 mg, 0.18 mmol) and N,N-dimethylformamide (2 drops) were added into anhydrous tetrahydrofuran (2 mL), oxalyl chloride (23 μL, 0.27 mmol) was added dropwise under ice-bath, after the addition, the reaction solution was allowed to warm to room temperature and stirred for 4 h. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of the acyl chloride. The solution was added dropwise 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, after the addition, the reaction solution was allowed to warm to room temperature and stirred for 6 h. After the reaction was completed, 2 N 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 added. The combined organic phase was washed with water (10 mL x 1) and saturated brine (10 mL x 1), and the solvent was removed by evaporation 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-d6) δ 10.69 (s, 1H), 10.51 (s, 1H), 8.21 (d, 1H), 8.01-7.97 (m, 2H), 7.95 (d, J = 7.1 Hz, 2H), 7.86 (d, J = 8.8 Hz, 1H), 7.77 (d, J = 8.1 Hz, 2H), 7.65 (s, 1H), 7.63-7.57 (m, 2H), 7.42 (t, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 5.32 (s, 2H), 4.26 (q, 2H), 1.29 (t, J = 7.1 Hz, 3H). ESI-MS: m / z 671.1 [M+Na] + .

[0523] Synthesis of compound B-10

[0524] Intermediate II-12 (95 mg, 0.15 mmol) was added into a mixture of tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), and sodium hydroxide (12 mg, 0.29 mmol) was added portionwise under ice-bath. After the addition, the reaction solution was allowed to warm to 60 °C and stirred for 6 h. After the reaction was completed, the organic solvent was removed by evaporation under reduced pressure, and 2 N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3. A solid was precipitated, and the reaction solution was filtered. The filter cake was washed with water (2 mL) and n-hexane (2 mL), and the residue was purified by slurry (n-hexane / dichloromethane = 1:1). The obtained solid was dried to constant weight to obtain compound B-10 (white solid, 74 mg): 1H NMR (300MHz, DMSO-d6) 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 F4N2O6S2[M+H] + 621.0772, found 621.0779.

[0525] Example 54

[0526] 4-((4-fluorophenyl)sulfonamido)-2-(4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamido)benzoic acid (compound B-11)

[0527]

[0528] Synthesis of compound B-11

[0529] Following the method of Example 53, intermediate II-11 was replaced with intermediate I-37 to obtain compound B-11: 1 HNMR (300MHz, DMSO-d6) δ13.56(s,1H),12.20(s,1H),10.98(s,1H),8.68(d,J=2.0Hz,1H),7.97(dd,J=8.8,5.2Hz,2H),7.91(d,J=8.6Hz,3H),7.77( d,J=8.1Hz,2H),7.64(d,J=8.2Hz,2H),7.44(t,J=8.8Hz,2H),7.22(d,J=8.8Hz,2H),6.90(dd,J=8.8,2.0Hz,1H),5.31(s,2H).HRMS(ESI)calcd.for C 28 H 20 F4N2O6S2[M+H] + 621.0772, found621.0771.

[0530] Example 55

[0531] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-12)

[0532]

[0533] Synthesis of Intermediate II-13

[0534] Synthesis of Intermediate II-1 II-2 Reference 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 added dropwise slowly under ice-bath cooling. After the dropwise addition, the reaction mixture was allowed to warm to room temperature and reacted for 4 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of the acid chloride. This 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 cooling, and the mixture was allowed to warm to room temperature and reacted for 6 hours. After the reaction, the reaction mixture was adjusted to pH 3-4 by adding 2 N aqueous hydrogen chloride solution, and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with water (10 mL x 1), saturated brine (10 mL x 1), and the solvent was distilled off 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-d6) δ 10.04 (s, 1H), 8.42 (s, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.77 (d, J = 8.3 Hz, 2H), 7.74 (d, J = 3.4 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.53 (dd, J = 8.7, 2.0 Hz, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.8 Hz, 1H), 5.30 (s, 2H), 3.04 (s, 3H), 1.00 (s, 9H), 0.24 (s, 6H).

[0535] Synthesis of Compound B-12

[0536] Intermediate II-13 (121 mg, 0.19 mmol) and triethylamine trifluoride acid salt (37 μL, 0.29 mmol) were added to dichloromethane (2 mL), and the mixture was allowed to react at room temperature for 6 hours. After the reaction, a solid was precipitated, which was filtered, and the filter cake was washed with dichloromethane / methanol (20:1). The obtained solid was dried to constant weight to obtain Compound B-12 (white solid, 57 mg): 1H NMR (300MHz, DMSO-d6) 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.forC 22 H 19 F3N2O5S2[M+H] + 513.0760, found 513.0757.

[0537] Example 56

[0538] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethyl)benzyl)oxy)benzamide (compound B-13)

[0539]

[0540] Synthesis of compound B-13

[0541] Following the method of Example 55, 4-trifluoromethylthiobenzyl bromide was replaced with 4-trifluoromethylbenzyl bromide to prepare compound B-13: 1 H NMR (300MHz, DMSO-d6) δ9.95(s,1H),9.65(s,1H),8.71(s,1H),7.94(d,J=8.8Hz,2H),7.79(d,J=8.2Hz,2H),7.70(d,J=8.2Hz,2H),7.62( d,J=2.4Hz,1H),7.48(dd,J=8.8,2.4Hz,1H),7.14(d,J=8.8Hz,2H),6.85(d,J=8.7Hz,1H),5.34(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 19 F3N2O5S[M+H] + 481.1040, found 481.1044.

[0542] Example 57

[0543] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-6-((4-((trifluoromethyl)thio)benzyl)oxy)nicotinamide (Compound B-14)

[0544]

[0545] Synthesis of Intermediate II-14

[0546] Refer to the method of Example 44, replace 4-hydroxybenzoic acid methyl ester with 6-hydroxy nicotinic acid ethyl ester to produce Intermediate II-14: 1 H NMR (300 MHz, DMSO-d6) δ 12.94 (s, 1H), 8.68 (d, J = 2.3 Hz, 1H), 7.85 (dd, J = 9.5, 2.4 Hz, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 6.49 (d, J = 9.5 Hz, 1H), 5.29 (s, 2H). ESI-MS: m / z 328.0 [M-H] - .

[0547] Synthesis of Compound B-14

[0548] Refer to the method of Example 55, replace Intermediate II-2 with Intermediate II-14 to produce Compound B-14: 1 H NMR (300 MHz, DMSO-d6) 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 F3N3O5S2 [M+H] + 514.0713, found 514.0722.

[0549] Example 58

[0550] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)benzyl)oxy)benzamide (Compound B-15)

[0551]

[0552] Synthesis of Compound B-15

[0553] Compound B-15 was prepared according to the procedure of Example 55, replacing 4- trifluoromethylthiobenzyl bromide with 4-trifluoromethoxybenzyl bromide: 1 H NMR (400 MHz, DMSO-d6) 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 F3N2O7S2[M + H] + 497.0989, found 497.0998.

[0554] Example 59

[0555] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylsulfonyl)benzyl)oxy)benzamide (Compound B-16)

[0556]

[0557] Synthesis of Compound B-16

[0558] Compound B-16 was prepared according to the procedure of Example 55, replacing Intermediate II-2 with Intermediate II-4: 1 H NMR (400 MHz, DMSO-d6) 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 F3N2O7S2[M + H] + 545.0659, found 545.0663.

[0559] Example 60

[0560] 3-fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylsulfonamido)benzyl)oxy)benzamide (Compound B-17)

[0561]

[0562] Synthesis of Compound B-17

[0563] Compound B-17 was prepared according to the procedure of Reference Example 47, replacing methyl 4-hydroxybenzoate with methyl 3-fluoro-4-hydroxybenzoate, and replacing intermediate I-3 with intermediate I-18: 1 H NMR (300 MHz, DMSO-d6) δ 10.04 (s, 1H), 9.72 (s, 1H), 8.75 (s, 1H), 8.26-8.17 (m, 2H), 7.93 (d, J = 8.5 Hz, 2H), 7.88 (dd, J = 12.2, 2.1 Hz, 1H), 7.81 (dt, J = 8.8, 1.6 Hz, 1H), 7.60 (d, J = 2.6 Hz, 1H), 7.48 (dd, J = 8.7, 2.6 Hz, 1H), 7.38 (t, J = 8.6 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 5.53 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 22 H 18 F4N2O7S2 [M+H] + 563.0564, found 563.0570.

[0564] Example 61

[0565] N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylsulfanyl)benzyl)oxy)benzamide (Compound B-18)

[0566]

[0567] Synthesis of Intermediate II-15

[0568] 4-Fluoro-2-methoxy-5-nitroaniline (500 mg, 2.69 mmol) and pyridine (320 μL, 4.03 mmol) were added to dichloromethane (10 mL). A solution of methanesulfonyl chloride (250 μL, 3.22 mmol) in dichloromethane (5 mL) was slowly added dropwise under ice bath conditions. After the addition was complete, the mixture was allowed to react at room temperature for 8 hours. After the reaction was complete, concentrated hydrochloric acid (1 mL) was added to the reaction solution to quench excess pyridine and methanesulfonyl chloride. The solvent was removed by vacuum distillation. The residue was extracted with 1N hydrogen chloride aqueous solution (20 mL) and ethyl acetate (10 mL x 3). The organic phase was washed successively with 1N hydrogen chloride aqueous solution (10 mL x 2), water (10 mL x 1), and saturated brine (10 mL x 1). The solvent was removed by vacuum distillation. The residue was purified by pulping (with diethyl ether). The resulting solid was dried to constant weight to give intermediate II-15 (yellow solid, 522 mg). 1 H NMR (300MHz, DMSO-d6) δ11.63(s,1H),9.20(s,1H),8.11(d,J=2.8Hz,1H),7.98(dd,J=9.0,2.8Hz,1H),7.04(d,J=9.0Hz,1H),3.04(s,3H).

[0569] Synthesis of intermediate II-16

[0570] Intermediate II-15 (520 mg, 1.98 mmol) was added to a dry three-necked flask under argon protection. Anhydrous dichloromethane (5 mL) was added to dissolve it, followed by dropwise addition of boron tribromide (286 μL, 2.97 mmol) in anhydrous dichloromethane (5 mL) under ice bath conditions. After the addition was complete, the mixture was slowly brought to room temperature for 3 hours. After the reaction was complete, ice water (20 mL) was added dropwise to quench the reaction mixture, followed by dropwise addition of 2N hydrogen chloride aqueous solution to adjust the pH to 1–2. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined. The mixture was washed successively 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 intermediate II-16 (brown solid, 582 mg). 1 H NMR (300MHz, DMSO-d6) δ12.29(s,1H),9.28(s,1H),8.00(d,J=8.3Hz,1H),7.00(d,J=13.1Hz,1H),3.01(s,3H).

[0571] Synthesis of intermediate II-17

[0572] Intermediate II-16 (582 mg, 2.33 mmol) and 10% palladium on carbon (120 mg) were added to a mixture of methanol (5 mL) and tetrahydrofuran (5 mL) and the reaction was stirred under a hydrogen atmosphere at room temperature for 12 hours. After the reaction was complete, the palladium on carbon was filtered off and the filter cake was washed with tetrahydrofuran (10 mL). The solvent was removed from the filtrate under reduced pressure to give crude intermediate I-17 which was used in the next step without further purification.

[0573] Synthesis of intermediate II-18

[0574] Intermediate II-17 (2.33 mmol) and N,N-diisopropylethylamine (810 μL, 4.66 mmol) were added to dichloromethane (5 mL) and tert-butyldimethylsilyl chloride (489 mg, 3.26 mmol) in dichloromethane (5 mL) was added dropwise over an ice bath. After the dropwise addition was complete, the reaction was allowed to warm to room temperature and stirred for 12 hours. After the reaction was complete, the reaction was diluted with saturated sodium bicarbonate solution (20 mL) and extracted with dichloromethane (10 mL x 3). The combined organic layers were washed with saturated brine (20 mL x 1) and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 7.5: 1) to give intermediate II-18 (brown oily liquid, 492 mg): 1 HNMR (300 MHz, DMSO-d6) 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).

[0575] Synthesis of compound B-18

[0576] Compound B-18 was prepared according to the procedure of Example 55, substituting intermediate II-18 for intermediate I-18: 1 HNMR (300 MHz, DMSO-d6) 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 F4N2O5S2[M+H] + 531.0666, found 531.0667.

[0577] Example 62

[0578] 3-fluoro-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylthio)benzyl)oxyl)benzamide (Compound B-19)

[0579]

[0580] Synthesis of Compound B-19

[0581] Compound B-19 was prepared according to the procedure described in Example 44 by replacing methyl 4-hydroxybenzoate with methyl 3-fluoro-4-hydroxybenzoate and replacing intermediate I-3 with intermediate II-17: 1 H NMR (400 MHz, DMSO-d6) 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 F5N2O5S2 [M+H] + 549.0572, found 549.0555.

[0582] Example 63

[0583] 4-(cyclohexylmethoxy)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-20)

[0584]

[0585] Synthesis of Compound B-20

[0586] Compound B-20 was prepared according to the procedure described in Example 55 by replacing intermediate II-1 with intermediate II-5: 1H NMR (300MHz, DMSO-d6) δ9.93(s,1H),9.61(s,1H),8.72(s,1H),7.92(d,3H),7.61(d,J=2.6Hz,1H),7.48(dd,J=8.8,2.5Hz,1H),7.02(d,2H),6. 84(d,J=8.7Hz,1H),3.86(d,J=6.1Hz,2H),2.96(d,J=1.8Hz,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 N₂O₅S[M+H] + 419.1635, found 419.1638.

[0587] Example 64

[0588] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((5-(trifluoromethyl)furan-2-yl)methoxy)benzamide (compound B-21)

[0589]

[0590]

[0591] Synthesis of Intermediate II-19

[0592] 5-Iodo-2-furanaldehyde (666 mg, 3 mmol) was added to a mixed solvent of ethanol (5 mL) and tetrahydrofuran (10 mL). Sodium borohydride (227 mg, 6 mmol) was added in portions under ice bath conditions. After the addition was complete, the mixture was slowly heated to room temperature and reacted for 4 hours. After the reaction was completed, the reaction solution was quenched in ice 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, filtered, and the solvent was evaporated under reduced pressure to obtain crude intermediate II-19, which was used directly in the next reaction without further purification.

[0593] Synthesis of Intermediate II-20

[0594] Methyl 4-hydroxybenzoate (609 mg, 4 mmol) and triphenylphosphine (1.2 g, 4.5 mmol) were added to a dry three-necked flask, which was protected by argon, a solution of intermediate II-19 (3 mmol) in anhydrous tetrahydrofuran (10 mL) was added, and a solution of diisopropyl azodicarboxylate (909 mg, 4.5 mmol) in anhydrous tetrahydrofuran (5 mL) was added dropwise under ice bath, and then the reaction was slowly warmed to room temperature for 12 hours. After the reaction was completed, water (20 mL) was added to dilute the reaction solution, and ethyl acetate (10 mL x 3) was used for extraction, and the organic phase was washed with saturated sodium carbonate solution (10 mL x 2), saturated brine (10 mL x 1) in sequence, and 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) δ 8.02 (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).

[0595] Synthesis of intermediate II-21

[0596] 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), which was protected by argon, and Tschugaeff reagent (445 mg, 2.31 mmol) was added dropwise, and then the reaction was warmed to 110°C for 12 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, water (30 mL) was added to dilute the filtrate, and ethyl acetate (10 mL x 3) was used for extraction, and the combined organic phase was washed with water (10 mL x 1), saturated brine (10 mL x 1) in sequence, and 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) δ 8.02 (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).

[0597] Synthesis of compound B-21

[0598] According to the method of Example 55, intermediate II-1 was replaced by intermediate II-21 to prepare compound B-21: 1H NMR (300 MHz, DMSO-d6) 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 F3N2O6S [M+H] + 471.0838, found 471.0842.

[0599] Example 65

[0600] N-(4-hydroxy-3-(thiophene-2-sulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)oxy)benzamide (Compound B-22)

[0601]

[0602] Synthesis of Compound B-22

[0603] Compound B-22 was prepared according to the procedure of Reference Example 1, replacing 4-fluorobenzenesulfonyl chloride with 2-thiophenesulfonyl chloride, and replacing intermediate I-6 with intermediate II-2: 1 H NMR (300 MHz, DMSO-d6) 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 25 H 19 F3N2O5S3 [M+H] + 581.0481, found 581.0470.

[0604] Example 66

[0605] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-23)

[0606]

[0607] Synthesis of intermediate II-22

[0608] Synthesis of intermediate II-22 1 H NMR (300 MHz, CDCl3) δ 8.07 (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] + .

[0609] Synthesis of compound B-23

[0610] Compound B-23 was prepared according to the method of Reference Example 55, by replacing intermediate II-1 with intermediate II-22: 1 H NMR (300 MHz, DMSO-d6) 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 [M-H] -H NMR (300 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.68 (s, 1H), 8.74 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.50 (dd, J = 8.7, 2.5 Hz, 1H), 7.30 (t, J = 7.9 Hz, 2H), 7.03 (d, J = 7.9 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.20 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 22 H 19 F3N2O5S2[M+H] + 513.0760, found 513.0786.

[0611] Example 67

[0612] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((p- tolyloxy)methyl)benzamide (Compound B-25)

[0613]

[0614] Synthesis of Compound B-24

[0615] Compound B-24 was prepared according to the procedure of Example 55, replacing intermediate II-2 with 4-(phenoxy methyl)benzoic acid: 1 H NMR (300 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.68 (s, 1H), 8.74 (s, 1H), 7.95 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 2.4 Hz, 1H), 7.57 (d, J = 8.2 Hz, 2H), 7.50 (dd, J = 8.7, 2.5 Hz, 1H), 7.30 (t, J = 7.9 Hz, 2H), 7.03 (d, J = 7.9 Hz, 2H), 6.95 (t, J = 7.3 Hz, 1H), 6.86 (d, J = 8.7 Hz, 1H), 5.20 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 21 H 20 N2O5S[M+H] + 413.1171, found 413.1175.

[0616] Example 68

[0617] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((p- tolyloxy)methyl)benzamide (Compound B-25)

[0618]

[0619] Synthesis of Compound B-25

[0620] Compound B-25 was prepared according to the procedure of Example 66, replacing 4- trifluoromethylsulfenyl phenol with 4-methylphenol: 1H NMR (300 MHz, DMSO-d6) 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 N2O5S[M+H] + 427.1328, found 427.1334.

[0621] Example 69

[0622] 4-(4-cyclopropylphenoxy)methyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-26)

[0623]

[0624] Synthesis of Intermediate II-23

[0625] 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 into acetonitrile (5 mL), then potassium carbonate (326 mg, 2.36 mmol) was added portionwise, after addition, the reaction was heated to 70 °C for 8 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate (5 mL). Water (10 mL) was added to the filtrate to dilute, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with 1M aqueous sodium hydroxide solution (5 mL x 2), saturated brine (15 mL x 1) successively, 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, DMSO-d6) 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

[0626] Synthesis of Intermediate II-24

[0627] 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, which was protected by argon. Toluene (3 mL) and water (0.1 mL) were added to the system, which was heated to 100 °C for 6 hours. After the reaction was completed, the system was cooled to room temperature. The reaction solution was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. 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 (300 MHz, CDC13) δ 8.05 (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).

[0628] Synthesis of compound B-26

[0629] Compound B-26 was prepared according to the method of Reference Example 55, replacing intermediate II-1 with intermediate II-24: 1 H NMR (300 MHz, CDC13) δ 8.05 (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). 24 H 24 N2O5S[M+H] + 453.1479, found453.1477.

[0630] Example 70

[0631] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-methoxyphenoxy)methylbenzamide (Compound B-27)

[0632]

[0633] Synthesis of Compound B-27

[0634] Compound B-27 was prepared according to the procedure of Reference Example 66, replacing 4-trifluoromethylsulfenyl phenol with 4-methoxyphenol: 1 H NMR (300 MHz, DMSO-d6) 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 N2O6S [M+H] + 443.1271, found 443.1276.

[0635] Example 71

[0636] 4-(4-Fluorophenoxy)methyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-28)

[0637]

[0638] Synthesis of Compound B-28

[0639] Compound B-28 was prepared according to the procedure of Reference Example 66, replacing 4-trifluoromethylsulfenyl phenol with 4-fluorophenol: 1 H NMR (300 MHz, DMSO-d6) 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 C21 H 19 FN2O5S[M+H] + 431.1071, found 431.1074.

[0640] Example 72

[0641] 4-(4-Chlorophenoxy)methyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-29)

[0642]

[0643] Synthesis of Compound B-29

[0644] Compound B-29 was prepared according to the procedure of Example 66, replacing 4-trifluoromethylsulfenyl phenol with 4-chlorophenol: 1 HNMR (300 MHz, DMSO-d6) 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 ClN2O5S[M+H] + 447.0776, found 447.0778.

[0645] Example 73

[0646] 4-(4-Bromophenoxy)methyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-30)

[0647]

[0648] Synthesis of Compound B-30

[0649] Compound B-30 was prepared according to the procedure of Example 66, replacing 4-trifluoromethylsulfenyl phenol with 4-chlorophenol: 1HNMR (300 MHz, DMSO-d6) 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 BrN2O5S[M+H] + 491.0271, found 491.0277.

[0650] Example 74

[0651] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethyl)phenoxy)methyl)benzamide (Compound B-31)

[0652]

[0653] Synthesis of Compound B-31

[0654] Compound B-31 was prepared according to the procedure described in Reference Example 66, by replacing 4-trifluoromethylphenol with 4-trifluoromethylphenol: 1 H NMR (300 MHz, DMSO-d6) 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 + .HRMS (ESI) calcd. for C 22 H 19 F3N2O5S[M+H] + 481.1040, found481.1039.

[0655] Example 75

[0656] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4- (trifluoromethoxy)phenoxy)methyl)benzamide (Compound B-32)

[0657]

[0658] Synthesis of Compound B-32

[0659] Compound B-32 was prepared according to the procedure of Example 66, replacing 4-trifluoromethylsulfenyl phenol with 4-hydroxybenzonitrile: 1 H NMR (300 MHz, DMSO-d6) 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 F3N2O6S [M+H] + 497.0989, found 497.0992.

[0660] Example 76

[0661] 4-((4-cyanophenoxy)methyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-33)

[0662]

[0663] Synthesis of Compound B-33

[0664] Compound B-33 was prepared according to the procedure of Example 66, replacing 4-trifluoromethylsulfenyl phenol with 4-hydroxybenzonitrile: 1H NMR (300 MHz, DMSO-d6) 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 N3O5S[M+H] + 438.1118 found 438.1122.

[0665] Example 77

[0666] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(((trifluoromethyl)thio)methyl)phenoxy)methyl)benzamide (Compound B-34)

[0667]

[0668] Synthesis of Intermediate II-25

[0669] 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 into acetonitrile (10 mL), then cesium carbonate (1 g, 3.09 mmol) was added portionwise, after addition, the reaction was heated to 80 °C for 6 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate (5 mL). Water (10 mL) was added to the filtrate to dilute, extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with 1M aqueous sodium hydroxide solution (10 mL x 2), saturated brine (10 mL x 1) successively, 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-d6) 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).

[0670] Synthesis of Intermediate II-26

[0671] Intermediate II-25 (600 mg, 2.06 mmol) was added into methanol (8 mL), sodium borohydride (215 mg, 6.37 mmol) was added portionwise under ice-bath, after addition, the reaction was continued for 4 hours at 0 °C. After the reaction was completed, the reaction solution was poured into ice water (20 mL) to quench, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain crude intermediate II-26, which was used directly in the next step without further purification: 1 H NMR (300 MHz, DMSO-d6) δ 7.96 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 6.95 (d, J = 8.5 Hz, 2H), 5.18 (s, 2H), 5.03 (t, J = 5.6 Hz, 1H), 4.40 (d, J = 5.4 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). ESI-MS: m / z 309.1 [M+Na] + .

[0672] Synthesis of intermediate II-27

[0673] Intermediate II-26 (589 mg, 2.06 mmol) and triphenylphosphine (756 mg, 2.88 mmol) were added into dichloromethane (5 mL), a solution of carbonic acid bromide (1.02 g, 3.09 mmol) in dichloromethane (5 mL) was added dropwise slowly under ice-bath, after dropwise, the reaction was continued for 6 hours at room temperature. 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).

[0674] Synthesis of intermediate II-28

[0675] Intermediate II-27 (370 mg, 1.06 mmol) and sodium thiocyanate (129 mg, 1.59 mmol) were added into acetonitrile (4 mL), and the reaction was continued for 4 hours at 80 °C. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain crude intermediate II-28, which was used directly in the next step without further purification.

[0676] Synthesis of intermediate II-29

[0677] Intermediate II-28 (273 mg, 0.83 mmol) and (trifluoromethyl)trimethylsilane (TMSCF3) (185 μL, 1.25 mmol) were added to tetrahydrofuran (2 mL) and a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.25 mL, 1.25 mmol) was added dropwise over 5 min at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 8 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to give intermediate II-29 (white solid, 158 mg): 1 H NMR (300 MHz, CDC13) δ 8.04 (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).

[0678] Synthesis of compound B-34

[0679] Compound B-34 was prepared according to the procedure described in Reference Example 55, by replacing intermediate II-1 with intermediate II-29: 1 H NMR (300 MHz, CDC13) δ 8.04 (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). 23 H 21 F3N2O5S2[M+H] + 527.0917, found 527.0914.

[0680] Example 78

[0681] N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-((6-(trifluoromethyl)thiopyridin-3- yl)oxy)methyl)benzamide (Compound B-35)

[0682]

[0683] Synthesis of intermediate II-30

[0684] Reference to the method of example 66, replace 4-trifluoromethylthiophenol with 2-bromo-5-hydroxypyridine to produce intermediate II-30.

[0685] Synthesis of intermediate II-31

[0686] Intermediate II-30 (275 mg, 0.82 mmol), silver trifluoromethanethiolate (256 mg, 1.23 mmol), cuprous iodide (155 mg, 0.82 mmol) and 2,2'-bipyridine (191 mg, 1.23 mmol) were added into a sealed tube, suspended with acetonitrile (3 mL) and heated to 110 °C for 12 h. 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 give intermediate II-31 (white solid, 289 mg): 1 H NMR (300 MHz, DMSO-d6) 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).

[0687] Synthesis of compound B-35

[0688] Reference to the method of example 55, replace intermediate II-1 with intermediate I-31 to produce compound B-35: 1 H NMR (300 MHz, DMSO-d6) 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). + .HRMS (ESI) calcd for C 21 H 18 F3N3O5S2[M+H] + 514.0713, found 514.0718.

[0689] Example 79

[0690] N-(4-hydroxy-3-(methanesulfonamide)phenyl)-4-(5-(trifluoromethyl)thiopyridine-2-oxy)methyl)benzamide (compound B-36)

[0691]

[0692] Synthesis of compound B-36

[0693] Following the method of Example 78, 2-bromo-5-hydroxypyridine was replaced with 2-hydroxy-5-bromopyridine to prepare compound B-36: 1 H NMR (300MHz, DMSO-d6) δ10.06(s,1H),9.53(s,1H),8.83(s,1H),8.20(s,1H),7.88(d,J=7.0Hz,2H),7.63-7.52(m,2H),7.47(d,J =8.5Hz,1H),7.41(d,J=7.1Hz,2H),6.84(d,J=8.8Hz,1H),6.43(d,J=9.7Hz,1H),5.13(s,2H),2.96(s,3H).HRMS(ESI)calcd.forC 21 H 18 F3N3O5S2[M+H] + 514.0713, found 514.0707.

[0694] Example 80

[0695] 4-((cyclohexyloxy)methyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (compound B-37)

[0696]

[0697] Synthesis of intermediate II-32

[0698] Sodium hydride (102 mg, 2.55 mmol) was added to a dry Schlenk tube under argon protection, and a suspension of anhydrous tetrahydrofuran (2 mL) was added. A solution of cyclohexanol (225 mg, 2.25 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise under ice bath, and the mixture was stirred at room temperature for 1 h. A solution of ethyl 4-(bromomethyl)benzoate (365 mg, 1.5 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise under ice bath, and the mixture was stirred at room temperature for 10 h. After the reaction was completed, water (20 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated sodium chloride (10 mL x 1), and the solvent was removed by reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 100:1) to give the crude intermediate II-32, which was used directly in the next step without further purification.

[0699] Synthesis of compound B-37

[0700] Compound B-37 was prepared according to the method described in Reference Example 55, by replacing intermediate II-1 with intermediate II-32. 1 HNMR (300 MHz, DMSO-d6) δ 10.06 (s, 1H), 9.68 (s, 1H), 8.71 (s, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 2.6 Hz, 1H), 7.50 (dd, J = 8.7, 2.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.7 Hz, 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 N2O5S[M+H] + 419.1635, found 419.1638.

[0701] Example 81

[0702] 4-(((4,4-difluorocyclohexyl)oxy)methyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (compound B-38)

[0703]

[0704] Synthesis of intermediate II-33

[0705] To a solution of intermediate II-33 (295 mg, 2.17 mmol) in dichloromethane (5 mL) was added triethylamine (600 μL, 4.33 mmol) followed by dropwise addition of a solution of trimethylsilyl trifluoromethanesulfonate (TMSOTf) (588 μL, 3.25 mmol) in dichloromethane (2 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched by the addition of water (10 mL) and the mixture was washed with saturated aqueous sodium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to give intermediate II-34 (223 mg) as a colorless oil.

[0706] Synthesis of intermediate II-34

[0707] To a solution of intermediate II-33 (295 mg, 2.17 mmol) in dichloromethane (5 mL) was added triethylamine (600 μL, 4.33 mmol) followed by dropwise addition of a solution of trimethylsilyl trifluoromethanesulfonate (TMSOTf) (588 μL, 3.25 mmol) in dichloromethane (2 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched by the addition of water (10 mL) and the mixture was washed with saturated aqueous sodium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to give intermediate II-34 (223 mg) as a colorless oil.

[0708] Synthesis of intermediate II-34

[0709] To a solution of intermediate II-33 (295 mg, 2.17 mmol) in dichloromethane (5 mL) was added triethylamine (600 μL, 4.33 mmol) followed by dropwise addition of a solution of trimethylsilyl trifluoromethanesulfonate (TMSOTf) (588 μL, 3.25 mmol) in dichloromethane (2 mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The reaction was quenched by the addition of water (10 mL) and the mixture was washed with saturated aqueous sodium chloride solution (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to give intermediate II-34 (223 mg) as a colorless oil.

[0710] Synthesis of compound B-38

[0711] Compound B-38 was prepared according to the procedure described in Reference Example 55 by replacing intermediate II-1 with intermediate II-35. 1HNMR (300 MHz, DMSO-d6) 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 F2N2O5S [M+H] + 455.1447, found 455.1454.

[0712] Example 82

[0713] 3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-39)

[0714]

[0715] Synthesis of Compound B-39

[0716] Refer to the method of Example 66, replace 4-(bromomethyl)benzoic acid ethyl ester with 3-fluoro-4-(bromomethyl)benzoic acid methyl ester to prepare Compound B-39: 1 HNMR (300 MHz, DMSO-d6) 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 F4N2O5S2 [M+H] + 531.0666, found 531.0665.

[0717] Example 83

[0718] 3-Fluoro-4-(3-fluoro-4-((trifluoromethyl)thio)phenoxy)methyl)-N-(4-hydroxy-3- (methylsulfonamido)phenyl)benzamide (Compound B-40)

[0719]

[0720] Synthesis of intermediate II-36

[0721] Reference to the method of example 66, replace 4-trifluoromethylsulfenyl phenol with 3-fluoro-4-nitrophenol, replace 4-(bromomethyl)benzoic acid ethyl ester with 3-fluoro-4-(bromomethyl)benzoic acid methyl ester, to produce compound II-36: 1 H NMR (300 MHz, DMSO-d6) 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).

[0722] Synthesis of intermediate II-37

[0723] Intermediate II-36 (150 mg, 0.51 mmol) was added into N,N-dimethylformamide (2 mL), tetrahydroxydiboron (131 mg, 1.46 mmol), 4,4'-dipyridine (1 mg, 0.005 mmol) were added in turn under ice-bath, and the reaction was allowed to warm to room temperature for 15 minutes. After the reaction was completed, the reaction solution was diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with water (10 mL x 1), 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 used directly in the next step without further purification.

[0724] Synthesis of intermediate II-38

[0725] Intermediate II-37 (275 mg, 0.82 mmol) was added into ethanol (1.5 mL), 40% fluoroboric acid (120 μL), tert-butyl nitrite (130 μL) were added in turn under ice-bath, and the reaction was allowed to warm to room temperature slowly for 1 hour. After the reaction was completed, the reaction solution was diluted with ethyl ether (2 mL) to make the solid completely precipitate, the reaction solution was filtered, the filter cake was washed with ethyl 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), potassium carbonate (141 mg, 1.02 mmol) were added into acetonitrile (2 mL), and the reaction was allowed to proceed under room temperature in air 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 evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain intermediate II-38 (white solid, 125 mg).

[0726] Synthesis of intermediate II-39

[0727] 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 mixture was raised to 60°C and reacted for 6 hours. After the completion of the reaction, the system was cooled to room temperature, the organic solvent was evaporated under reduced pressure, 2 N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2 to 3, a solid was precipitated, and the solid was filtered, washed with water (2 mL) and n-hexane (2 mL) in this order, and dried to constant weight to obtain intermediate II-39 (white solid, 86 mg): 1 H NMR (300 MHz, DMSO-d6) 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).

[0728] Synthesis of compound B-40

[0729] Compound B-40 was prepared according to the method of Reference Example 55, replacing intermediate II-2 with intermediate II-39: 1 H NMR (300 MHz, DMSO-d6) 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 F5N2O5S2[M+H] + 549.0572, found 549.0547.

[0730] Example 84

[0731] 3-Fluoro-4-(2-fluoro-4-((trifluoromethyl)thio)phenoxy)methyl)-N-(4-hydroxy-3- (methylsulfonamido)phenyl)benzamide (Compound B-41)

[0732]

[0733] Synthesis of compound B-41

[0734] Following the method of Example 83, 3-fluoro-4-nitrophenol was replaced with 2-fluoro-4-nitrophenol to obtain compound B-41: 1 H NMR (300MHz, DMSO-d6) δ10.22(s,1H),9.71(s,1H),8.87(s,1H),7.84(d,J=8.7Hz,2H),7.75-7.72(m,1H),7.71(d,J=8.5Hz,1H),7. 63(d,J=2.5Hz,1H),7.58(d,J=9.1Hz,1H),7.53-7.47(m,2H),6.87(d,J=8.7Hz,1H),5.40(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C 22 H 17 F5N2O5S2[M+H] + 549.0572, found 549.0570.

[0735] Example 85

[0736] 3-Fluoro-N-(4-hydroxy-3-(methylsulfonamide)phenyl)-4-(4-(trifluoromethylphenoxy)methyl)benzamide (compound B-42)

[0737]

[0738] Synthesis of compound B-42

[0739] Following the method of Example 66, ethyl 4-(bromomethyl)benzoate was replaced with methyl 3-fluoro-4-(bromomethyl)benzoate, and 4-trifluoromethylthiophenol was replaced with 4-trifluoromethylphenol to obtain compound B-42: 1 H NMR (400MHz, DMSO-d6) 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.forC 22 H 18 F4N2O5S[M+H]+ 499.0945, found 499.0940.

[0740] Example 86

[0741] 3-chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-43)

[0742]

[0743]

[0744] Synthesis of Intermediate II-40

[0745] Methyl 3-chloro-4-methylbenzoate (185 mg, 1 mmol) was added into carbon tetrachloride (3 mL), azobisisobutyronitrile (AIBN) (33 mg, 0.2 mmol), N-bromosuccinimide (NBS) (187 mg, 1.05 mmol) were added in portions successively under ice-bath, after addition, the system was elevated 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, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 100:1) to obtain the crude product of intermediate II-40, which was used directly in the next step without further purification.

[0746] Synthesis of Compound B-43

[0747] Referring to the method of Example 66, ethyl 4-(bromomethyl)benzoate was replaced by the crude product of intermediate II-40 to prepare Compound B-43: 1 H NMR (300 MHz, DMSO-d6) d 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 ClF3N2O5S2[M+H] + 547.0371, found 547.0378.

[0748] Example 87

[0749] 3-bromo-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-44)

[0750]

[0751] Synthesis of Compound B-44

[0752] Compound B-44 was prepared according to the procedure of Reference Example 66, replacing 4-(bromomethyl)benzoic acid ethyl ester with 3-bromo-4-methylbenzoic acid methyl ester: 1 H NMR (300 MHz, DMSO-d6) 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 BrF3N2O5S2[M+H] + 590.9865, found 590.9874.

[0753] Example 88

[0754] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-3-methoxy-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-45)

[0755]

[0756] Synthesis of Compound B-45

[0757] Compound B-45 was prepared according to the procedure of Reference Example 66, replacing 4-(bromomethyl)benzoic acid ethyl ester with 3-methoxy-4-bromomethylbenzoic acid methyl ester: 1H NMR (300MHz, DMSO-d6) δ10.09(s,1H),9.22(s,2H),7.65(d,J=8.7Hz,2H),7.62(d,J=2.4Hz,1H),7.56(s,2H),7.53-7. 45(m,2H),7.17(d,J=8.7Hz,2H),6.86(d,J=8.7Hz,1H),5.19(s,2H),3.93(s,3H),2.97(s,3H).HRMS(ESI)calcd.forC 23 H 21 F3N2O6S2[M+H] + 543.0866, found 543.0865.

[0758] Example 89

[0759] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-3-(trifluoromethyl)-4-(4-(trifluoromethyl)thio)phenoxy)methylbenzamide (compound B-46)

[0760]

[0761] Synthesis of intermediate II-41

[0762] 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), followed by the addition of potassium carbonate (117 mg, 0.85 mmol) in portions. After the addition was complete, the mixture was heated to 60 °C and reacted for 8 hours. After the reaction was completed, the system was cooled to room temperature, and excess phenol was neutralized by adding 1 M sodium hydroxide aqueous solution (10 mL). The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined. The mixture was washed successively with 1 M sodium hydroxide aqueous solution (5 mL x 2) and saturated brine (15 mL x 1). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate II-41 (white solid, 278 mg). 1 H NMR (300MHz, CDCl3) δ7.85 (s, 1H), 7.72 (d, J = 8.3Hz, 1H), 7.59 (d, J = 8.6Hz, 3H), 6.98 (d, J = 8.6Hz, 2H), 5.23 (s, 2H).

[0763] Synthesis of intermediate II-42

[0764] 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 (Xantphos) (10 mg, 0.02 mmol) and acetic anhydride (167 μL, 1.78 mmol) were added into anhydrous N,N-dimethylformamide (2 mL), the system was cooled to -78 °C, N,N-diisopropylethylamine (310 μL, 1.78 mmol) was added, argon was protected, the system was allowed to naturally recover to room temperature and stirred for 30 minutes, then the temperature was raised to 100 °C and reacted for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) was added into the reaction solution, 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), 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 = 3:1) to obtain intermediate II-42 (white solid, 185 mg): 1 H NMR (300 MHz, DMSO-d6) 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).

[0765] Synthesis of compound B-46

[0766] Compound B-46 was prepared according to the method of Reference Example 7, by replacing intermediate 4-trifluoromethylsulfanylbenzoic acid with intermediate II-42: 1 H NMR (300 MHz, DMSO-d6) 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 F6N2O5S2[M+H] + 581.0634, found 581.0638.

[0767] Example 90

[0768] 3-Cyano-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)phenoxy)methyl)benzamide (compound B-47)

[0769]

[0770] Synthesis of intermediate II-43

[0771] 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 mixture was heated to 100 °C and reacted for 12 hours. After the reaction was completed, the system was cooled to room temperature, and the reaction solution was diluted with water (60 mL). The mixture was extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The mixture was washed successively with water (15 mL x 2) and saturated brine (15 mL x 1). The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to give intermediate II-43 (white solid, 277 mg).

[0772] Synthesis of compound B-47

[0773] Following the method of Example 86, methyl 3-chloro-4-methylbenzoate was replaced with intermediate II-43 to prepare compound B-47: 1 H NMR (300MHz, DMSO-d6) δ10.30(s,1H),9.29(s,2H),8.46(s,1H),8.26(d,J=7.9Hz,1H),7.88(d,J=8.0Hz,1H),7.70(d,J=8.5Hz,2H),7. 63(d,J=1.9Hz,1H),7.52(d,J=8.7Hz,1H),7.23(d,J=8.5Hz,2H),6.88(d,J=8.7Hz,1H),5.42(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 18 F3N3O5S2[M+H] + 538.0713, found 538.0712.

[0774] Example 91

[0775] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-6-((4-((trifluoromethyl)thio)phenoxy)methyl)nicotinamide (compound B-48)

[0776]

[0777] Synthesis of compound B-48

[0778] Referring to the method of example 86, methyl 3-chloro-4-methylbenzoate was replaced by methyl 6-methylnicotinate to produce compound B-48: 1 H NMR (300 MHz, DMSO-d6) 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 F3N3O5S2[M+H] + 514.0713, found 514.0721.

[0779] Example 92

[0780] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-2-(4-(trifluoromethyl)phenoxy)methyl)pyrimidine-5-carboxamide (compound B-49)

[0781]

[0782] Synthesis of intermediate II-44

[0783] 2-methyl-5-bromopyrimidine (800 mg, 4.62 mmol) was added into carbon tetrachloride (10 mL), azobisisobutyronitrile (AIBN) (759 mg, 4.62 mmol), N-bromosuccinimide (NBS) (905 mg, 5.09 mmol) were added into the system in batches under ice bath, after addition, the system was heated 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 the crude product of intermediate II-44, which was directly used in the next reaction without further purification.

[0784] Synthesis of intermediate II-45

[0785] Intermediate II-44 crude, 4-trifluoromethylsulfanylphenol (191 mg, 0.99 mmol) and potassium iodide (18 mg, 0.11 mmol) were added into acetonitrile (4 mL), then cesium carbonate (536 mg, 1.64 mmol) was added portionwise, after addition, the system was raised to 70 °C and reacted 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 extracted, the organic phase was combined, washed with saturated brine (15 mL x 1), and the solvent was distilled off 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).

[0786] Synthesis of intermediate II-46

[0787] 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-bisdiphenylphosphine-9,9-dimethylxanthene (Xantphos) (12 mg, 0.02 mmol) and acetic anhydride (200 μL, 2.14 mmol) were added into anhydrous N,N-dimethylformamide (3 mL), the system was frozen to -78 °C, N,N-diisopropylethylamine (353 μL, 2.14 mmol) was added, and the system was naturally restored to room temperature and stirred for 30 minutes, then raised to 100 °C and reacted for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) was added to the reaction solution, diluted with water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was combined, washed with water (10 mL x 1), saturated brine (10 mL x 1) in turn, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 50:1) to obtain intermediate II-46 crude, which was purified by slurrying (dichloromethane / methanol = 20:1) to obtain intermediate II-46 (white solid, 135 mg): 1 HNMR (400 MHz, DMSO-d6) 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).

[0788] Synthesis of compound B-49

[0789] Intermediate II-46 (100 mg, 0.30 mmol), intermediate I-18 (105 mg, 0.33 mmol) were added into N,N-dimethylformamide (2 mL), N,N-diisopropyl ethylamine (150 μL, 0.91 mmol) was added, then 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (138 mg, 0.36 mmol) was added under ice-bath, after addition, the reaction was allowed to warm to room temperature for 16 hours. After the reaction was completed, water (20 mL) was added to dilute the reaction solution, ethyl acetate (10 mL x 3) was used to extract, the combined organic phase was washed with water (10 mL x 1) and saturated brine (10 mL x 1) successively, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (dichloromethane / methanol = 50:1) to obtain compound B-49 crude product, which was purified by trituration (dichloromethane / methanol = 20:1) to obtain compound B-49 (white solid, 108 mg): 1 H NMR (300 MHz, DMSO-d6) δ 10.47 (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, 2.6 Hz, 1H), 7.14 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 8.7 Hz, 1H), 5.49 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 20 H 17 F3N4O5S2[M+H] + 515.0665, found 515.0672.

[0790] Example 93

[0791] 3-cyclopropyl-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-50)

[0792]

[0793] Synthesis of intermediate II-47

[0794] Reference to the method of Example 86, 3-chloro-4-methylbenzoic acid methyl ester was replaced by 3-bromo-4-methylbenzoic acid methyl ester to prepare intermediate II-47: 1H NMR (300MHz, CDCl3) δ8.27 (d, J=1.3Hz, 1H), 8.02 (dd, J=8.0, 1.2Hz, 1H), 7.63 (d, J= 5.3Hz,1H),7.60(d,J=6.4Hz,2H),7.02(d,J=8.8Hz,2H),5.19(s,2H),3.94(s,3H).

[0795] Synthesis of intermediate II-48

[0796] 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 a Schlenk tube under argon protection. Toluene (4 mL) and water (0.2 mL) were added to suspend the mixture, and the reaction was carried out at 90 °C for 6 hours. 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 = 50:1) to give intermediate II-48 (white solid, 184 mg).

[0797] Synthesis of compound B-50

[0798] Following the method of Example 55, intermediate II-1 was replaced with intermediate II-48 to obtain compound B-50: 1 HNMR (300MHz, DMSO-d6) 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 25 H 23 F3N2O5S2[M+H] + 553.1079, found 553.1084.

[0799] Example 94

[0800] 2-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethylthio)phenoxy)methyl)benzamide (compound B-51)

[0801]

[0802] Synthesis of compound B-51

[0803] Following the procedure of Example 89, substituting 3-fluoro-4-bromobenzyl bromide for 4-bromo-2-trifluoromethylbenzyl bromide and 4-trifluoromethylphenol for 4-trifluoromethylthiophenol, compound B-51 was prepared: 1 H NMR (400 MHz, DMSO-d6) 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 F4N2O5S2[M+H] + 531.0666, found 531.0670.

[0804] Example 95

[0805] 2-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylphenoxy)methyl)benzamide (Compound B-52)

[0806]

[0807] Synthesis of compound B-52

[0808] Following the procedure of Example 89, substituting 3-fluoro-4-bromobenzyl bromide for 4-bromo-2-trifluoromethylbenzyl bromide and 4-trifluoromethylphenol for 4-trifluoromethylthiophenol, compound B-51 was prepared: 1 H NMR (400 MHz, DMSO-d6) 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 H18 F4N2O5S [M+H] + 499.0945, found 499.0937.

[0809] Example 96

[0810] 2-Chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-53)

[0811]

[0812] Synthesis of Intermediate II-49

[0813] 4-Bromo-3-chlorobenzaldehyde (250 mg, 1.14 mmol) was added into methanol (5 mL), sodium borohydride (77 mg, 2.28 mmol) was added portionwise under ice-bath, after addition, the reaction was slowly warmed to room temperature for 4 hours. After the reaction was completed, the reaction was quenched by pouring into ice-water (20 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give crude intermediate II-49, which was used directly in the next step without further purification.

[0814] Synthesis of Intermediate II-50

[0815] Intermediate II-49 (crude) and triphenylphosphine (418 mg, 1.59 mmol) were added into tetrahydrofuran (5 mL), carbon tetrabromide (567 mg, 1.71 mmol) was added portionwise under ice-bath, after addition, the reaction was warmed 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 give intermediate II-50 (colorless oily liquid, 271 mg).

[0816] Synthesis of Intermediate II-51

[0817] 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 into acetonitrile (3 mL), and then cesium carbonate (464 mg, 1.42 mmol) was added portionwise, after addition, the reaction was warmed to 70 °C for 8 hours. After the reaction was completed, the system was cooled to room temperature, water (20 mL) was added into the reaction, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (15 mL x 1), the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate II-51 (white solid, 364 mg): 1H NMR (400 MHz, CDC13) δ 7.66 (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).

[0818] Synthesis of intermediate II-52

[0819] 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-bisdiphenylphosphino-9,9-dimethylxanthene (Xantphos) (15 mg, 0.03 mmol) and acetic anhydride (244 μL, 2.60 mmol) were added into anhydrous N,N-dimethylformamide (2.5 mL), the system was cooled to -78 °C, N,N-diisopropylethylamine (430 μL, 2.60 mmol) was added, the system was allowed to naturally recover to room temperature, stirred for 30 minutes, and then was raised to 100 °C and reacted for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL) was added into the reaction solution, 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), saturated brine (10 mL x 1) in turn, the solvent was distilled out under reduced pressure, and 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-d6) 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).

[0820] Synthesis of compound B-53

[0821] Compound B-53 was prepared according to the method of Reference Example 55, by replacing intermediate II-2 with intermediate II-52. 1HNMR (400 MHz, DMSO-d6) 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 ClF3N2O5S2[M+H] + 547.0371, found 547.0379.

[0822] Example 97

[0823] 2-Chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-54)

[0824]

[0825] Synthesis of Compound II-53

[0826] Refer to the method of Example 86, replace 3-chloro-4-methylbenzoic acid methyl ester with 4-bromo-2,6-difluorotoluene to prepare intermediate II-53.

[0827] Synthesis of Compound B-54

[0828] Refer to the method of Example 96, replace intermediate II-50 with intermediate II-53 to prepare Compound B-54: 1 HNMR (400 MHz, DMSO-d6) 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 17 F5N2O5S2[M+H] + 549.0572, found 549.0575.

[0829] Example 98

[0830] 2-(N-(5-(3-Fluoro-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamido)-2- hydroxyphenyl)aminosulfonyl)acetic acid ethyl ester (Compound B-55)

[0831]

[0832] Synthesis of Intermediate II-54

[0833] To a solution of 2-nitro-4-aminophenol (500 mg, 3.24 mmol) in dichloromethane (10 mL) was added N,N-diisopropylethylamine (1.1 mL, 6.49 mmol) and a solution of tert-butyldimethylsilyl chloride (733 mg, 4.87 mmol) in dichloromethane (5 mL) dropwise at 0 °C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 12 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give Intermediate II-54 (orange solid, 632 mg): 1 H NMR (400 MHz, DMSO-d6) 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).

[0834] Synthesis of Intermediate II-55

[0835] Following the procedure of Reference Example 66, ethyl 4-(bromomethyl)benzoate was replaced with methyl 3-fluoro-4-(bromomethyl)benzoate to give Intermediate II-55: 1 H NMR (300 MHz, DMSO-d6) 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).

[0836] Synthesis of Intermediate II-56

[0837] 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 while being cooled in an ice bath. After the addition was completed, the reaction was allowed to warm to room temperature and was stirred for 2 hours. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (6 mL) to prepare an acyl chloride tetrahydrofuran solution. The solution was added dropwise to a tetrahydrofuran (1 mL) solution of II-54 (641 mg, 1.92 mmol) and pyridine (220 μL, 2.74 mmol) while being cooled in an ice bath. After the addition was completed, the reaction was allowed to warm to room temperature and was stirred for 6 hours. After the reaction was completed, 2 N aqueous hydrogen chloride solution was added dropwise to the reaction mixture to adjust the pH to 3 to 4, and ethyl acetate (5 mL x 3) was added. The combined organic layer was washed with saturated brine (10 mL x 1), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain intermediate II-56 (yellow solid, 986 mg).

[0838] Synthesis of intermediate II-57

[0839] Intermediate II-56 (858 mg, 1.44 mmol) was added to N,N-dimethylformamide (2 mL), and tetrahydroxyboron (387 mg, 4.31 mmol) and 4,4'-bipyridine (2 mg, 0.01 mmol) were sequentially added while being cooled in an ice bath. After the addition was completed, the reaction was allowed to warm to room temperature and was stirred for 15 minutes. After the reaction was completed, the reaction mixture was diluted with water (20 mL), and ethyl acetate (10 mL x 3) was added. The combined organic layer was washed with water (10 mL x 1) and saturated brine (10 mL x 1), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 7.5:1) to obtain intermediate II-57 (pale yellow solid, 607 mg): 1 H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.82-7.77 (m, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.9 Hz, 2H), 7.18 (d, J = 2.5 Hz, 1H), 6.82 (dd, J = 8.5, 2.5 Hz, 1H), 6.65 (d, J = 8.5 Hz, 1H), 5.30 (s, 2H), 4.61 (s, 2H), 0.98 (s, 9H), 0.20 (s, 6H).

[0840] Synthesis of intermediate II-58

[0841] Intermediate II-57 (100 mg, 0.18 mmol) was added to anhydrous dichloromethane (2 mL), pyridine (21 μL, 0.26 mmol) was added, and then a solution of (chlorosulfonyl)acetic acid ethyl ester (40 mg, 0.21 mmol) in dichloromethane (1 mL) was added dropwise under ice bath. After the dropwise addition was completed, the reaction was allowed to warm to room temperature and react for 8 hours. After the reaction was completed, 1 N aqueous hydrogen chloride (5 mL) and water (5 mL) were added to quench the excess pyridine, and ethyl acetate (5 mL x 3) was added to extract the product. The combined organic phase was washed with saturated brine (5 mL x 1), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to obtain intermediate II-58 (yellowish oil, 97 mg): 1 H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.84 (s, 1H), 7.86-7.81 (m, 2H), 7.78 (d, J = 2.6 Hz, 1H), 7.73 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.57 (dd, J = 8.9, 2.6 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.8 Hz, 1H), 5.32 (s, 2H), 4.29 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 1.18 (t, 3H), 1.00 (s, 9H), 0.26 (s, 6H).

[0842] Synthesis of compound B-55

[0843] Intermediate II-58 (156 mg, 0.22 mmol) was added to dichloromethane (2 mL), and triethylamine trifluorohydrofluoride (53 μL, 0.33 mmol) was added dropwise. The reaction was allowed to react at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, which was filtered, and the filter cake was washed with dichloromethane / methanol (20:1). The obtained solid was dried to constant weight to obtain intermediate B-55 (white solid, 113 mg): 1HNMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 9.66 (s, 1H), 9.29 (s, 1H), 7.85-7.81 (m, 2H), 7.73 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 2.5 Hz, 1H), 7.52 (dd, J = 8.8, 2.5 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 6.88 (d, J = 8.7 Hz, 1H), 5.31 (s, 2H), 4.24 (s, 2H), 4.12 (q, J = 7.1 Hz, 2H), 1.19 (t, J = 7.1 Hz, 3H). HRMS (ESI) calcd. for C 25 H 22 F4N2O7S2[M+H] + 603.0877, found 603.0887.

[0844] Example 99

[0845] 2-chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-56)

[0846]

[0847] Synthesis of Compound B-56

[0848] Compound B-55 (50 mg, 0.08 mmol) was added into tetrahydrofuran (2 mL), 2M lithium borohydride tetrahydrofuran solution (105 μL, 0.21 mmol) was added dropwise under ice bath, after addition, the system was elevated to 60 °C for 3 hours. After the reaction was completed, the system was cooled to room temperature, water (10 mL) was added dropwise under ice bath to quench the excess lithium borohydride, extracted with ethyl acetate (5 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 1), the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (dichloromethane / methanol = 30:1) to obtain compound B-56 crude product, which was purified by trituration (dichloromethane / methanol = 20:1) to obtain compound B-56 (pale yellow solid, 34 mg): 1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.78 (s, 1H), 8.73 (s, 1H), 7.86-7.81 (m, 2H), 7.72 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 8.8, 2.5 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.31 (s, 2H), 5.01 (t, J = 5.6 Hz, 1H), 3.80 (q, J = 12.4, 6.7 Hz, 2H), 3.25 (t, J = 6.8 Hz, 2H). HRMS (ESI) calcd. for C 23 H 20 F4N2O6S2[M+H] + 561.0772, found 561.0776.

[0849] Example 100

[0850] 3-(N-(5-(3-Fluoro-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamido)-2- hydroxyphenyl)aminosulfonyl)propanoic acid methyl ester (Compound B-57)

[0851]

[0852] Synthesis of Compound B-57

[0853] Refer to the method of Example 98, replace (chlorosulfonyl)acetic acid ethyl ester with 3-(chlorosulfonyl)propanoic acid methyl ester to prepare Compound B-57: 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.82 (s, 1H), 9.09 (s, 1H), 7.85-7.80 (m, 2H), 7.73 (d, J = 7.7 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 2.6 Hz, 1H), 7.53 (dd, J = 8.8, 2.6 Hz, 1H), 7.22 (d, J = 8.9 Hz, 2H), 6.87 (d, J = 8.7 Hz, 1H), 5.31 (s, 2H), 3.62 (s, 3H), 3.30 (t, J = 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H). HRMS (ESI) calcd. for C 25 H 22 F4N2O7S2[M+H] + 603.0877, found 603.0881.

[0854] Example 101

[0855] 2-chloro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylthio)phenoxy)methyl)benzamide (Compound B-58)

[0856]

[0857] Synthesis of Compound B-58

[0858] Following the procedure of Example 99, replacing compound B-55 with compound B-57, compound B-58 was prepared: 1 H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 9.77 (s, 1H), 8.73 (s, 1H), 7.86-7.80 (m, 2H), 7.72 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 2.5 Hz, 1H), 7.50 (dd, J = 8.7, 2.5 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 5.31 (s, 2H), 4.62 (t, J = 5.1 Hz, 1H), 3.46 (q, J = 11.3, 5.9 Hz, 2H), 3.12-3.05 (m, 2H), 1.91-1.83 (m, 2H). HRMS (ESI) calcd. for C 24 H 22 F4N2O6S2[M+H] + 575.0928, found 575.0900.

[0859] Example 102

[0860] N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-59)

[0861]

[0862] Synthesis of Compound B-59

[0863] Following the procedure of Example 55, replacing intermediate II-1 with intermediate II-22, and intermediate I-18 with intermediate II-18, compound B-59 was prepared: 1H NMR (300 MHz, DMSO-d6) 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 F4N2O5S2[M+H] + 531.0666, found 531.0667.

[0864] Example 103

[0865] N-(2-chloro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-60)

[0866]

[0867] Synthesis of Intermediate II-59

[0868] 4-chloro-2-methoxyaniline (865 mg, 5.49 mmol) was added into concentrated sulfuric acid (6 mL), potassium nitrate (610 mg, 6.04 mmol) was added portionwise under ice bath, and the stirring was continued at 0 °C for 1 h. After the reaction was completed, the reaction solution was added dropwise into ice water, and sodium bicarbonate was added portionwise to adjust the pH to 7-8 to precipitate the solid. The solid was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and washed with water (20 mL x 1), saturated brine (20 mL x 1), and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 6:1) to give intermediate II-59 (yellow solid, 795 mg): 1 HNMR (400 MHz, DMSO-d6) δ 7.32 (s, 1H), 7.04 (s, 1H), 5.53 (s, 2H), 3.90 (s, 3H).

[0869] Synthesis of Intermediate II-60

[0870] Referring to the method of Example 61, intermediate II-60 was prepared by replacing 4-fluoro-2-methoxy-5-nitroaniline with intermediate II-59: 1H NMR (400 MHz, DMSO-d6) 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).

[0871] Synthesis of compound B-60

[0872] Compound B-60 was prepared according to the procedure described in Reference Example 55, by replacing Intermediate II-1 with Intermediate II-22, and replacing Intermediate I-18 with Intermediate II-60. 1 H NMR (300 MHz, DMSO-d6) 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 ClF3N2O5S2[M+H] + 547.0371, found 547.0374.

[0873] Example 104

[0874] N-(2-bromo-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-61)

[0875]

[0876] Synthesis of intermediate II-61

[0877] 4-bromo-2-methoxyaniline (853 mg, 4.22 mmol) was added into concentrated sulfuric acid (6 mL), potassium nitrate (640 mg, 6.33 mmol) was added portionwise under ice bath, and the stirring was continued for 10 minutes at 0 °C. After the reaction was completed, the reaction solution was added dropwise into ice water, and sodium bicarbonate was added portionwise to adjust the pH to 7-8 to precipitate the solid. The solid was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined and washed with water (20 mL x 1), saturated brine (20 mL x 1), and then 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): 1H NMR (300 MHz, DMSO-d6) δ 7.32 (s, 1H), 7.15 (s, 1H), 5.58 (s, 2H), 3.90 (s, 3H).

[0878] Synthesis of Intermediate II-62

[0879] Intermediate II-61 (762 mg, 3.08 mmol) and pyridine (496 μL, 6.17 mmol) were added into dichloromethane (7 mL), a solution of methylsulfonic anhydride (752 mg, 4.32 mmol) in dichloromethane (5 mL) was added dropwise under ice-bath, after addition, the reaction system was warmed to room temperature and stirred for 8 hours. After the reaction was completed, concentrated hydrochloric acid (0.5 mL) was added to quench the excess pyridine and methylsulfonic anhydride, the solvent was evaporated under reduced pressure, 1 N 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 (yellowish solid, 880 mg): 1 H NMR (400 MHz, Chloroform-d) δ 8.20 (s, 1H), 7.22 (s, 1H), 6.94 (s, 1H), 4.03 (s, 3H), 3.10 (s, 3H).

[0880] Synthesis of Intermediate II-63

[0881] Intermediate II-62 (100 mg, 0.31 mmol) and reduced iron powder (86 mg, 1.54 mmol) were added into ethanol (2 mL), 6 N aqueous hydrogen chloride solution (615 μL, 3.69 mmol) was added, and the reaction system was stirred at 60 °C for 30 minutes. After the reaction was completed, the system was cooled to room temperature, 1 M aqueous sodium hydroxide solution was added dropwise to the reaction system under ice-bath to adjust the pH to alkaline, and the reaction system was extracted with ethyl acetate (8 mL x 3), the organic phases were combined, and the organic phase was 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 = 4:1) to obtain intermediate II-63 (white solid, 74 mg): 1 H NMR (400 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.07 (s, 1H), 6.84 (s, 1H), 4.95 (s, 2H), 3.72 (s, 3H), 2.94 (s, 3H).

[0882] Synthesis of Intermediate II-64

[0883] 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 mixture was raised to 60°C and reacted for 6 hours. After the reaction was completed, the system was cooled to room temperature, the organic solvent was distilled off under reduced pressure, 2 N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2 to 3, a solid was precipitated, and the solid was filtered, washed with water (2 mL) and n-hexane (2 mL) in this order, and dried to constant weight to obtain an intermediate II-64 (white solid, 1.21 g): 1 H NMR (300 MHz, DMSO-d6) 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).

[0884] Synthesis of Intermediate II-65

[0885] 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 after the addition was completed, the mixture was raised to room temperature and reacted for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (1 mL) to prepare an acyl chloride tetrahydrofuran solution, 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, and after the addition was completed, the mixture was raised to room temperature and reacted for 6 hours. After the reaction was completed, 2 N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 3 to 4, ethyl acetate (8 mL x 3) was added, the combined organic phase was washed with saturated brine (10 mL x 1), and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain an intermediate II-65 (white solid, 80 mg): 1 H NMR (300 MHz, Chloroform-d) δ 8.60 (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).

[0886] Synthesis of Intermediate B-61

[0887] Intermediate II-65 (76 mg, 0.13 mmol) was added to anhydrous dichloromethane (2 mL), 1M boron tribromide in dichloromethane solution (314 μL, 0.31 mmol) was added dropwise at 0 °C, and the stirring was continued at 0 °C for 1 hour. After the reaction was completed, ice water (10 mL) was added dropwise to quench the reaction, and the product was extracted with ethyl acetate (10 mL x 3). The organic phase was combined and washed with water (10 mL x 1), saturated brine (10 mL x 1), 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 compound B-61 (brown solid, 47 mg) as a crude product, which was purified by trituration (dichloromethane / methanol = 20:1) to obtain compound B-61 (light red solid, 35 mg): 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.94 (s, 1H), 9.06 (s, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.5 Hz, 2H), 7.31 (s, 1H), 7.19 (d, J = 9.0 Hz, 2H), 7.17 (s, 1H), 5.29 (s, 2H), 3.00 (s, 3H). HRMS (ESI) calcd. for C 22 H 18 BrF3N2O5S2[M+H] + 590.9865, found 590.9857.

[0888] Example 105

[0889] N-(3-hydroxy-5-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-62)

[0890]

[0891] Synthesis of intermediate II-66

[0892] To a solution of 3-bromo-5-nitroaniline (217 mg, 1 mmol) and pyridine (121 μL, 1.5 mmol) in dichloromethane (2 mL) was added a solution of methanesulfonic anhydride (226 mg, 1.3 mmol) in dichloromethane (2 mL) dropwise at 0 °C. After the addition was completed, the reaction mixture was allowed to warm to room temperature and stirred for 8 h. The reaction was quenched by the addition of 2 N aqueous HC1 (10 mL) and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic extracts were washed with water (10 mL x 1), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude intermediate II-66, which was used in the next step without further purification.

[0893] Synthesis of intermediate II-67

[0894] To a solution of the crude intermediate II-66 (1 mmol) and ammonium chloride (535 mg, 10 mmol) in a mixture of ethanol (3 mL) and water (3 mL) was added iron powder (280 mg, 5 mmol) portionwise with stirring at 80 °C. After the addition was completed, the reaction mixture was allowed to cool to room temperature and diluted with water (30 mL). The mixture was extracted with ethyl acetate (10 mL x 3), and the combined organic extracts were washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 3: 1) to give the intermediate II-67 (yellow solid, 238 mg): 1 H NMR (300 MHz, DMSO-d6) δ 9.60 (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 [M-H] - .

[0895] Synthesis of intermediate II-68

[0896] The intermediate II-68 was prepared according to the procedure described in Reference Example 55, using the intermediate II-22 instead of the intermediate II-1, and the intermediate II-67 instead of the intermediate I-18. 1 H NMR (300 MHz, DMSO-d6) 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).

[0897] Synthesis of intermediate II-69

[0898] Intermediate II-68 (146 mg, 0.25 mmol), bis(pinacolato)diboron (77 mg, 0.3 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (PdCl2(dppf)·DCM) (21 mg, 0.03 mmol) and potassium acetate (75 mg, 0.76 mmol) were added into a dry Schlenk tube, which was protected by argon, suspended in 1,4-dioxane (2 mL) and raised to 80 °C for 8 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the filtrate 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 (300 MHz, DMSO-d6) δ 10.31 (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] + .

[0899] Synthesis of compound B-62

[0900] Intermediate II-69 (68 mg, 0.11 mmol) was added to tetrahydrofuran (2 mL), 1M sodium hydroxide aqueous solution (55 μL) was added, and then 30% hydrogen peroxide aqueous solution (110 μL) was added dropwise under ice bath, after dropping, it was slowly raised to room temperature for 6 hours. After the reaction was completed, 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 extracted, the combined organic phase was 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), then by beating (dichloromethane / methanol = 20:1), and the obtained solid was dried to constant weight to obtain compound B-62 (white solid, 37 mg): 1H NMR (300 MHz, DMSO-d6) 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 22 H 19 F3N2O5S2[M + H] + 513.0760, found 513.0761.

[0901] Example 106

[0902] N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4- (trifluoromethoxy)phenoxy)methylbenzamide (Compound B-64)

[0903]

[0904] Synthesis of Compound B-63

[0905] Refer to the method of Example 66, replace 4-trifluoromethylthiophenol with 4- trifluoromethylphenol, replace intermediate I-18 with intermediate II-18 to produce Compound B-63: 1 H NMR (300 MHz, DMSO-d6) 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 F4N2O5S[M + H] + 499.0945, found 499.0943.

[0906] Example 107

[0907] N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4- (trifluoromethoxy)phenoxy)methylbenzamide (Compound B-64)

[0908]

[0909] Synthesis of compound B-64

[0910] Compound B-64 was prepared according to the procedure of Reference Example 66, replacing 4-trifluoromethylsulfenyl phenol with 4-fluorophenol, and replacing intermediate 1-18 with intermediate II-18: 1 H NMR (400 MHz, DMSO-d6) 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 22 H 18 F4N2O6S [M+H] + 515.0894, found 515.0898.

[0911] Example 108

[0912] N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4- fluorophenoxy)methylbenzamide (Compound B-65)

[0913]

[0914] Synthesis of compound B-65

[0915] Compound B-65 was prepared according to the procedure of Reference Example 66, replacing 4-trifluoromethylsulfenyl phenol with 4-fluorophenol, and replacing intermediate 1-18 with intermediate II-18: 1 H NMR (400 MHz, DMSO-d6) 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 F2N2O5S [M+H] + 499.0977, found 449.0983.

[0916] Example 109

[0917] N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((naphthalen-2-yloxy)methyl)benzamide (Compound B-66)

[0918]

[0919] Synthesis of Compound B-66

[0920] Compound B-66 was prepared according to the procedure described in Reference Example 66, replacing 4-trifluoromethylsulfenyl phenol with β-naphthol, and replacing intermediate I-18 with intermediate II-18: 1 H NMR (400 MHz, DMSO-d6) 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 = 2.6 Hz, 1H), 7.41 - 7.32 (m, 1H), 7.30 (d, J = 8.3 Hz, 1H), 7.29 (dd, J = 9.0, 2.5 Hz, 1H), 6.78 (d, J = 11.3 Hz, 1H), 5.34 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 25 H 21 FN2O5S [M+H] + 481.1228, found 481.1224.

[0921] Example 110

[0922] N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((quinolin-6-yloxy)methyl)benzamide (Compound B-67)

[0923]

[0924] Synthesis of Compound B-67

[0925] Compound B-67 was prepared according to the procedure described in Reference Example 66, replacing 4-trifluoromethylsulfenyl phenol with 6-hydroxyquinoline, and replacing intermediate I-18 with intermediate II-18: 1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.99 (s, 1H), 9.20 (s, 1H), 8.76 (dd, J = 4.2, 1.7 Hz, 1H), 8.25 (dd, J = 8.5, 1.7 Hz, 1H), 8.00 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 9.0 Hz, 1H), 7.66 (d, J = 8.1 Hz, 2H), 7.52 (dd, J = 9.0, 2.8 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.30 (d, J = 8.3 Hz, 1H), 6.78 (d, J = 11.3 Hz, 1H), 5.36 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 24 H 20 FN3O5S[M+H] + 482.1180, found 482.1209.

[0926] Example 111

[0927] N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((isoquinolin-6-yloxy)methyl)benzamide (Compound B-68)

[0928]

[0929] Synthesis of Compound B-68

[0930] Compound B-68 was prepared according to the procedure described in Reference Example 66, replacing 4-trifluoromethylsulfanylphenol with 6-hydroxyisoquinoline and replacing Intermediate I-18 with Intermediate II-18: 1 H NMR (400 MHz, DMSO-d6) 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 FN3O5S[M+H] +482.1180, found 482.1185.

[0931] Example 112

[0932] 4-((benzo[d]thiazol-5-yloxy)methyl)-N-(2-fluoro-4-hydroxy-5- (methylsulfonamido)phenyl)benzamide (Compound B-69)

[0933]

[0934] Synthesis of Compound B-69

[0935] Compound B-69 was prepared according to the procedure described in Reference Example 66, replacing 4-trifluoromethylsulfenyl phenol with benzo[d]oxazole-5-ol, and replacing intermediate I-18 with intermediate II-18: 1 H NMR (400 MHz, DMSO-d6) δ 10.17 (s, OH), 9.95 (s, 1H), 9.37 (s, 1H), 8.97 (s, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 2.5 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.3 Hz, 1H), 7.24 (dd, J = 8.8, 2.5 Hz, 1H), 6.78 (d, J = 11.3 Hz, 1H), 5.34 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 22 H 18 FN3O5S2[M+H] + 488.0745, found 488.0750.

[0936] Example 113

[0937] 4-((benzo[d]thiazol-5-yloxy)methyl)-N-(2-fluoro-4-hydroxy-5- (methylsulfonamido)phenyl)benzamide (Compound B-69)

[0938]

[0939] Synthesis of Compound B-70

[0940] Compound B-70 was prepared according to the procedure described in Reference Example 66, replacing 4-trifluoromethylsulfenyl phenol with benzo[d]oxazole-5-ol, and replacing intermediate I-18 with intermediate II-18: 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 9.98 (s, 1H), 8.97 (s, 1H), 8.70 (s, 1H), 7.98 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.9 Hz, 1H), 7.62 (d, J = 8.1 Hz, 2H), 7.46 (d, J = 2.5 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.14 (dd, J = 8.9, 2.5 Hz, 1H), 6.78 (d, J = 11.3 Hz, 1H), 5.28 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 22 H 18 FN3O6S [M+H] + 472.0973, found 472.0976.

[0941] Example 114

[0942] N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(((2-methyl-1,2,3,4- tetrahydroisoquinolin-6-yl)oxy)methyl)benzamide (Compound B-71)

[0943]

[0944] Synthesis of Intermediate II-70

[0945] Intermediate II-70 was synthesized according to the procedure described in Example 1.6, substituting 6-bromo-1,2,3,4-tetrahydroisoquinoline (1 g, 4.17 mmol) for 6-bromo-1,2,3,4-tetrahydroquinoline. Intermediate II-70 (colorless oily liquid, 1.37 g) was obtained after purification by column chromatography (petroleum ether / ethyl acetate = 30:1).

[0946] Synthesis of Intermediate II-71

[0947] Intermediate II-70 (1.37 g, 4.37 mmol), bis(pinacolato)diboron (1.33 g, 5.24 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (PdCl2(dppf)·DCM) (625 mg, 0.77 mmol) and potassium acetate (1.29 g, 13.11 mmol) were added into a dry Schlenk tube, which was protected by argon, and then 1,4-dioxane (13 mL) was added to suspend the mixture, and the reaction was carried out at 80 °C for 8 h. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the filtrate was evaporated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 30:1) to obtain intermediate II-71 (yellowish solid, 1.41 g): 1 HNMR (400MHz, Chloroform-d) δ 7.64 (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).

[0948] Synthesis of compound II-72

[0949] Intermediate II-71 (1.41 g, 3.94 mmol) was added to tetrahydrofuran (4 mL), 1M aqueous sodium hydroxide solution (2 mL) was added, and then 30% hydrogen peroxide aqueous solution (4 mL) was added dropwise under ice bath, after dropping, the reaction was slowly warmed to room temperature for 6 h. After the reaction was completed, saturated sodium thiosulfate (10 mL), 2N hydrogen chloride aqueous solution (10 mL) were added dropwise to the reaction solution under ice bath, dichloromethane (15 mL x 3) was extracted, the combined organic phase was 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 (300MHz, DMSO-d6) δ 9.21 (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).

[0950] Synthesis of intermediate II-73

[0951] Intermediate II-73 (304 mg, 0.74 mmol) was added into ethyl acetate (3 mL), 4M hydrogen chloride-ethyl acetate solution (1.85 mL, 7.4 mmol) was added dropwise, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, 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), the organic layers 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 (pale yellow oily liquid, 213 mg).

[0952] Synthesis of intermediate II-74

[0953] Intermediate II-73 (304 mg, 0.74 mmol) was added into ethyl acetate (3 mL), 4M hydrogen chloride-ethyl acetate solution (1.85 mL, 7.4 mmol) was added dropwise, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, 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), the organic layers 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 (pale yellow oily liquid, 213 mg).

[0954] Synthesis of intermediate II-75

[0955] Intermediate II-74 (355 mg, 1.14 mmol) was added into formic acid (1 mL), 37% formaldehyde aqueous solution (1.5 mL, 1.37 mmol) was added, and the mixture was stirred at 100°C for 4 hours. After the reaction was completed, the mixture was cooled to room temperature, 1M sodium hydroxide aqueous solution (20 mL) was added dropwise to the mixture under ice bath to quench the reaction, and saturated sodium bicarbonate solution was added dropwise to adjust the pH to 9-10. A solid was precipitated, which was filtered, washed with water (2 mL) and n-hexane (2 mL), and dried to constant weight to obtain intermediate II-75 (off-white solid, 344 mg): 1H 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).

[0956] Synthesis of compound B-71

[0957] Compound B-71 was prepared according to the procedure of Reference Example 55, replacing Intermediate II-1 with Intermediate II-75, and replacing Intermediate I-18 with Intermediate II-18: 1 H NMR (300 MHz, DMSO-d6) 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 FN3O5S [M+H] + 500.1650, found 500.1681.

[0958] Example 115

[0959] N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(((2-(methylsulfonyl)- 1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)methyl)benzamide (Compound B-72)

[0960]

[0961] Synthesis of intermediate II-76

[0962] Intermediate II-76 (white solid, 273 mg) was prepared by the method described in Reference Example 55, by replacing Intermediate II-1 with Intermediate II-76, and replacing Intermediate I-18 with Intermediate II-18.

[0963] Synthesis of compound B-72

[0964] Compound B-72 was prepared by the method described in Reference Example 55, by replacing Intermediate II-1 with Intermediate II-76, and replacing Intermediate I-18 with Intermediate II-18. 1 H NMR (300 MHz, DMSO-d6) d 10.32 (s, 1H), 9.97 (s, 1H), 8.91 (s, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.29 (d, J = 8.3 Hz, 1H), 7.12 (d, J = 9.1 Hz, 1H), 6.92 - 6.84 (m, 2H), 6.78 (d, J = 11.3 Hz, 1H), 5.19 (s, 2H), 4.29 (s, 2H), 3.40 (t, J = 6.0 Hz, 2H), 2.96 (s, 3H), 2.93 (s, 3H), 2.88 (t, J = 5.9 Hz, 2H). HRMS (ESI) calcd. for C 25 H 26 FN3O7S2[M+H] + 564.1269, found 564.1269.

[0965] Example 116

[0966] 3-Fluoro-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-73)

[0967]

[0968] Synthesis of compound B-73

[0969] Compound B-73 was prepared according to the procedure of Reference Example 66, replacing 4-(bromomethyl)benzoic acid ethyl ester with 3-fluoro-4- (bromomethyl)benzoic acid methyl ester, and replacing intermediate 1-18 with intermediate II-18: 1 H NMR (400 MHz, DMSO-d6) 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 F5N2O5S2[M+H] + 549.0572, found 549.0562.

[0970] Example 117

[0971] 3-chloro-N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenoxy)methyl)benzamide (Compound B-74)

[0972]

[0973] Synthesis of Compound B-74

[0974] Compound B-74 was prepared according to the procedure of Reference Example 66, replacing 4-(bromomethyl)benzoic acid ethyl ester with intermediate II-40 crude, and replacing intermediate 1-18 with intermediate II-18: 1 H NMR (300 MHz, DMSO-d6) 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 ClF4N2O5S2[M+H] +565.0282, found 565.0287. HRMS (ESI) calcd for C 22 H 17 F5N2O5S2[M+H] + 549.0572, found 549.0562.

[0975] Example 118

[0976] N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-6-((4-((trifluoromethyl)thio)phenoxy)methyl)nicotinamide (Compound B-75)

[0977]

[0978]

[0979] Synthesis of Intermediate II-77

[0980] Following the procedure of Reference Example 92, replacing 2-methyl-5-bromopyrimidine with 5-bromo-2-methylpyridine, Intermediate II-77 was prepared: 1 H NMR (300 MHz, DMSO-d6) 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).

[0981] Synthesis of Intermediate II-78

[0982] Intermediate II-77 (80 mg, 0.24 mmol) and Intermediate II-18 (85 mg, 0.26 mmol) were added to anhydrous dichloromethane (2 mL), 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (EDCI) (70 mg, 0.36 mmol) was added portionwise under ice bath, after addition, the reaction was allowed to warm to room temperature for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3: 1) to give Intermediate II-78 (pale yellow solid, 53 mg).

[0983] Synthesis of Compound B-75

[0984] Intermediate II-78 (53 mg, 0.08 mmol) and triethylamine trifluoride (20 μL, 0.12 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, which was filtered, the filter cake was washed with dichloromethane / methanol = 50:1, the filter cake was slurried with dichloromethane / methanol = 50:1 and purified, and the obtained solid was dried to constant weight to obtain Compound B-75 (white solid, 32 mg): 1 H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 10.21 (s, 1H), 9.11 (d, J = 2.2 Hz, 1H), 8.93 (s, 1H), 8.35 (dd, J = 8.1, 2.3 Hz, 1H), 7.70-7.66 (m, 3H), 7.34 (d, J = 8.3 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 11.3 Hz, 1H), 5.37 (s, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 21 H 17 F4N3O5S2[M+Na] + 554.0438, found 554.0445.

[0985] Example 119

[0986] N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-5-((4-((trifluoromethyl)thio)phenoxy)methyl)picolinamide (Compound B-76)

[0987]

[0988] Synthesis of Compound B-76

[0989] Compound B-76 was prepared according to the method described in Reference Example 118, replacing 5-bromo-2-methylpyridine with 2-bromo-5-methylpyridine: 1 H NMR (400 MHz, DMSO-d6) 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 H17 F4N3O5S2[M+Na] + 554.0438, found 554.0444.

[0990] Example 120

[0991] N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-2-((4-((trifluoromethyl)thio)phenoxy)methyl)pyrimidine-5-carboxamide (Compound B-77)

[0992]

[0993] Synthesis of Compound B-77

[0994] Refer to the method of Example 118, replace 5-bromo-2-methylpyridine with 2-methyl-5-bromopyrimidine to prepare 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 F4N4O5S2[M+H] + 533.0576, found533.0583.

[0995] Example 121

[0996] N-(4-Fluoro-2-hydroxy-5-((4-((4-((trifluoromethyl)thio)phenoxy)methyl)benzyl)amino)phenyl)methanesulfonamide hydrochloride (Compound B-78)

[0997]

[0998] Synthesis of Intermediate II-79

[0999] Refer to the method of Example 66, replace ethyl 4-(bromomethyl)benzoate with 4-bromomethylbenzaldehyde to prepare 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).

[1000] Synthesis of intermediate II-80

[1001] Intermediate II-79 (295 mg, 0.94 mmol) and intermediate II-18 (261 mg, 0.78 mmol) were added into dichloromethane (5 mL), glacial acetic acid (45 μL, 0.78 mmol) was added, stirred at room temperature for 1 hour, then sodium triacetoxyborohydride (496 mg, 2.34 mmol) was added portionwise under ice-bath, after addition, the reaction mixture was stirred at room temperature for 12 hours. After the reaction was completed, saturated sodium bicarbonate solution (10 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL x 1), the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give intermediate II-80 (light yellow solid, 126 mg): 1 H NMR (300 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.49 (s, 1H), 7.64 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 2.3 Hz, 4H), 7.15 (d, J = 8.9 Hz, 2H), 6.62 (d, J = 12.6 Hz, 1H), 6.45 (d, J = 9.5 Hz, 1H), 5.70-5.61 (m, 1H), 5.12 (s, 2H), 4.23 (d, J = 5.4 Hz, 2H), 2.76 (s, 3H).

[1002] Synthesis of compound B-78

[1003] Intermediate II-80 (96 mg, 0.19 mmol) was added into ethyl acetate (1 mL), hydrogen chloride-ethyl acetate solution (1.16 mL, 0.93 mmol) was added dropwise, after dropwise addition, the reaction mixture was stirred at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was purified by trituration (ethyl acetate), the obtained solid was dried to constant weight to give compound B-78 (white solid, 57 mg): 1 H NMR (300 MHz, DMSO-d6) 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 ClF4N2O4S2[M-HCl+H] +517.0879, found 517.0885.

[1004] Example 122

[1005] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-((trifluoromethyl)thio)benzyl)thio)benzamide (Compound B-79)

[1006]

[1007] Synthesis of Intermediate II-81

[1008] To a solution of 4-trifluoromethylsulfanylbenzyl bromide (400 mg, 1.48 mmol) and 4-bromothiophenol (362 mg, 1.92 mmol) in acetone (5 mL) was added cesium carbonate (649 mg, 1.99 mmol) portionwise. The mixture was heated to 60 °C and stirred for 8 h. The reaction was cooled to room temperature and quenched with 1 M aqueous sodium hydroxide solution (10 mL). The excess 4-bromothiophenol was extracted with ethyl acetate (15 mL x 3). The combined organic layers were washed with 1 M aqueous sodium hydroxide solution (5 mL x 2), saturated brine (15 mL x 1), and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether) to give Intermediate II-81 (white solid, 523 mg): 1 H NMR (300 MHz, CDC13) δ 7.58 (d, J = 8.1 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.5 Hz, 2H), 4.09 (s, 2H).

[1009] Synthesis of Intermediate II-82

[1010] 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 (Xantphos) (9 mg, 0.016 mmol) and acetic anhydride (149 μL, 1.58 mmol) were added into anhydrous N,N-dimethylformamide (2.5 mL), the system was cooled to -78 °C, N,N-diisopropylethylamine (207 μL, 1.58 mmol) was added, the system was allowed to naturally recover to room temperature, stirred for 30 minutes, and then the system was raised to 100 °C and reacted for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride solution (5 mL) was added to the reaction solution, 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), saturated brine (10 mL x 1) in turn, the solvent was distilled off under reduced pressure, and 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-d6) δ 12.88 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 8.2 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 4.43 (s, 2H). ESI-MS: m / z 343.0 [M-H] - .

[1011] Synthesis of compound B-79

[1012] Compound B-79 was prepared according to the method of Reference Example 1, by replacing intermediate I-6 with intermediate II-82: 1 H NMR (300 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.33 (s, 2H), 7.89-7.79 (m, 4H), 7.68 (d, J = 7.8 Hz, 3H), 7.59 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.36 (t, J = 8.8 Hz, 3H), 6.68 (d, J = 8.7 Hz, 1H), 4.44 (s, 2H). ESI-MS: m / z 607.0 [M-H] - .

[1013] Example 123

[1014] N-(4-((tert-butyldimethylsilyl)oxy)-3-((4-fluorophenyl)sulfonamido)phenyl)-4- ((4-(trifluoromethyl)benzyl)thio)benzamide (Compound B-80)

[1015]

[1016] Synthesis of Compound B-80

[1017] Compound B-80 was prepared according to the procedure of Reference Example 122, replacing 4-trifluoromethylthiobenzyl bromide with 4-trifluoromethylbenzyl bromide: 1 H NMR (300 MHz, DMSO-d6) 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 F4N2O4S2 [M+H] + 577.0873, found 577.0855.

[1018] Example 124

[1019] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4- (trifluoromethoxy)benzyl)thio)benzamide (Compound B-81)

[1020]

[1021] Synthesis of Compound B-81

[1022] Compound B-81 was prepared according to the procedure of Reference Example 122, replacing 4-trifluoromethylthiobenzyl bromide with 4-trifluoromethoxybenzyl bromide: 1 H NMR (300 MHz, DMSO-d6) 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 F4N2O5S2 [M+H] + 593.0823, found 593.0823.

[1023] Example 125

[1024] N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-(((trifluoromethyl)thio)methyl)benzyl)thio)benzamide (Compound B-82)

[1025]

[1026] Synthesis of intermediate II-83

[1027] Reference to the method of Example 122, 4-trifluoromethylsulfanylbenzyl bromide was replaced by ethyl 4-(bromomethyl)benzoate to produce intermediate II-83: 1 H NMR (300 MHz, Chloroform-d) d 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).

[1028] Synthesis of intermediate II-84

[1029] Intermediate II-83 (1 g, 3 mmol) was added to anhydrous tetrahydrofuran (4 mL), and 1M lithium tetrahydrofuran solution of triethylborohydride (7.5 mL, 7.5 mmol) was slowly added dropwise under ice bath, and after the dropwise addition was completed, the reaction was slowly warmed to room temperature for 2 hours. After the reaction was completed, water (20 mL) was added to quench the reaction, and ethyl acetate (15 mL x 3) was added to extract the product. The combined organic phase was 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 = 10:1) to obtain intermediate II-84 (white solid, 542 mg).

[1030] Synthesis of intermediate II-85

[1031] Intermediate II-84 (42 mg, 0.13 mmol) and triphenylphosphine (50 mg, 0.19 mmol) were added to dichloromethane (2 mL), and carbon tetrabromide (67 mg, 0.20 mmol) in dichloromethane (2 mL) was slowly added dropwise under ice bath, and after the dropwise addition was completed, the reaction was warmed 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): 1H NMR (300 MHz, Chloroform-d) δ 7.37 (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).

[1032] Synthesis of intermediate II-86

[1033] Intermediate II-85 (372 mg, 1 mmol) and potassium thiocyanate (124 mg, 1.5 mmol) were added into acetonitrile (15 mL) and the reaction was carried out at 80 °C for 4 h. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was 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 give intermediate II-85 (white solid, 311 mg).

[1034] Synthesis of intermediate II-87

[1035] Intermediate II-86 (270 mg, 0.76 mmol) was added into a dry Schlenk tube under argon protection. Anhydrous tetrahydrofuran (2 mL) was added, and (trifluoromethyl)trimethylsilane (162 mg, 1.14 mmol) in anhydrous tetrahydrofuran (1 mL) was added under ice bath. Then 1M tetrabutylammonium fluoride in tetrahydrofuran (1.14 mL, 1.14 mmol) was added slowly dropwise in anhydrous tetrahydrofuran (3 mL). After the dropwise addition was completed, the reaction was continued at 0 °C for 2 h. After the reaction was completed, the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 200:1) to give intermediate II-87 (white solid, 143 mg): 1 H NMR (300 MHz, Chloroform-d) δ 7.37 (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).

[1036] Synthesis of compound B-82

[1037] Compound B-82 was prepared according to the method of Reference Example 122, by replacing intermediate II-81 with intermediate II-87: 1HNMR (300 MHz, DMSO-d6) 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 F4N2O4S3 [M+H] + 623.0751, found 623.0787.

[1038] Example 126

[1039] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)thio)benzamide (Compound B-83)

[1040]

[1041] Synthesis of Compound B-83

[1042] Compound B-83 was prepared according to the procedure described in Reference Example 55, replacing Intermediate II-2 with Intermediate II-82: 1 HNMR (300 MHz, DMSO-d6) 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 F3N2O4S3 [M+H] + 529.0532, found 529.0536.

[1043] Example 127

[1044] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-(trifluoromethoxy)benzyl)thio)benzamide (Compound B-84)

[1045]

[1046] Synthesis of Compound B-84

[1047] Compound B-84 was prepared according to the procedure of Reference Example 122, replacing 4-trifluoromethylthiobenzyl bromide with 4- trifluoromethoxybenzyl bromide and replacing intermediate 1-3 with intermediate 1-18: 1 H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.67 (s, 1H), 8.69 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.49 (dd, J = 2.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 4.40 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 22 H 19 F3N2O5S2 [M+H] + 513.0760, found 513.0776.

[1048] Example 128

[1049] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4- (trifluoromethyl)benzyl)thio)benzamide (Compound B-85)

[1050]

[1051] Synthesis of Compound B-85

[1052] Compound B-85 was prepared according to the procedure of Reference Example 122, replacing 4-trifluoromethylthiobenzyl bromide with 4- trifluoromethylbenzyl bromide and replacing intermediate 1-3 with intermediate 1-18: 1 H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.67 (s, 1H), 8.69 (s, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 2.2 Hz, 1H), 7.55 (d, J = 8.5 Hz, 2H), 7.49 (dd, J = 2.3 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 4.40 (s, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 22 H 19 F3N2O4S2 [M+H] + 497.0811, found 497.0814.

[1053] Example 129

[1054] N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(((4-((trifluoromethyl)thio)phenyl)thio)methyl)benzamide (Compound B-86)

[1055]

[1056] Synthesis of intermediate II-88

[1057] 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 into a mixture solvent of methanol (5 mL) and water (5 mL), and the reaction was carried out at 80 °C for 4 hours. After the reaction was completed, the system was cooled to room temperature, 4-trifluoromethylthioaniline (200 mg, 1.04 mmol) and tert-butyl nitrite (185 μL, 1.55 mmol) were added under ice-bath cooling, and the mixture was stirred at room temperature for 10 minutes, and then the reaction was carried out at 80 °C for 5 hours. After the reaction was completed, water (10 mL) was added to dilute the reaction solution, and ethyl acetate (10 mL x 3) was used to extract the reaction solution. The combined organic phase was 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, CDC13) δ 7.98 (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).

[1058] Synthesis of compound B-86

[1059] Compound B-86 was prepared according to the method of Reference Example 44, by replacing intermediate II-1 with intermediate II-88: 1 H NMR (300 MHz, CDC13) δ 7.98 (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). 27 H 20F4N2O4S3 [M+H] + 609.0594, found 609.0596.

[1060] Example 130

[1061] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(((4- (trifluoromethyl)phenyl)thio)methyl)benzamide (Compound B-87)

[1062]

[1063] Synthesis of Compound B-87

[1064] Compound B-87 was prepared according to the procedure of Example 129, replacing 4- trifluoromethylaniline with 4-trifluoromethoxyaniline: 1 H NMR (300 MHz, DMSO-d6) 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 F4N2O4S2 [M+H] + 577.0873, found 577.0881.

[1065] Example 131

[1066] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(((4- (trifluoromethyl)phenyl)thio)methyl)benzamide (Compound B-87)

[1067]

[1068] Synthesis of Compound B-88

[1069] Compound B-88 was prepared according to the procedure of Example 129, replacing 4- trifluoromethylaniline with 4-trifluoromethoxyaniline: 1H 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 F4N2O5S2 [M+H] + 593.0823, found 593.0843.

[1070] Example 132

[1071] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(((4- (trifluoromethoxy)phenyl)sulfanyl)methyl)benzamide (Compound B-89)

[1072]

[1073] Synthesis of Compound B-89

[1074] Refer to the method of Example 129, replace 4-trifluoromethylaniline with 4- trifluoromethoxyaniline, replace intermediate I-3 with intermediate I-18 to produce Compound B-89: 1 H NMR (300 MHz, DMSO-d6) 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 F3N2O5S2 [M+H] + 513.0760, found 513.0757.

[1075] Example 133

[1076] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(((4- (trifluoromethyl)phenyl)sulfanyl)methyl)benzamide (Compound B-90)

[1077]

[1078] Synthesis of Compound B-90

[1079] Following the method of Example 129, 4-trifluoromethylthioaniline was replaced with 4-trifluoromethylaniline, and intermediate I-3 was replaced with intermediate I-18 to obtain compound B-90: 1 H NMR (300MHz, DMSO-d6) δ10.06(s,1H),9.63(s,1H),8.68(s,1H),7.87(d,J=8.3Hz,2H),7.64(d,J=8.8Hz,1H),7.61(d,J=2.8H z,2H),7.59-7.51(m,4H),7.48(dd,J=8.7,2.6Hz,1H),6.85(d,J=8.8Hz,1H),4.45(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 19 F3N2O4S2[M+H] + 497.0811, found 497.0809.

[1080] Example 134

[1081] N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4-((trifluoromethyl)thio)benzyl)amino)benzamide hydrochloride (compound B-91)

[1082]

[1083] Synthesis of intermediate II-89

[1084] 4-Trifluoromethylthiobenzaldehyde (424 mg, 2.06 mmol) and ethyl 4-aminobenzoate (200 mg, 1.21 mmol) were added to methanol (5 mL), followed by glacial acetic acid (208 μL, 3.63 mmol). The mixture was stirred at room temperature for 1 hour, and then sodium cyanoborohydride (89 mg, 1.51 mmol) was added in portions under ice bath conditions. After the addition was complete, the mixture was slowly brought to room temperature and reacted for 24 hours. After the reaction was complete, saturated sodium bicarbonate solution (5 mL) and water (5 mL) were added to the reaction solution to quench excess sodium cyanoborohydride. The mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined. The mixture was 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 give intermediate II-89 (pale yellow solid, 426 mg). 1H NMR (300 MHz, DMSO-d6) δ 7.68 (dd, J = 8.2, 6.1 Hz, 4H), 7.49 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 6.1 Hz, 1H), 6.61 (d, J = 8.7 Hz, 2H), 4.43 (d, J = 6.0 Hz, 2H), 4.23 - 4.16 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). ESI-MS: m / z 354.1 [M-H] - .

[1085] Synthesis of intermediate II-90

[1086] Intermediate II-89 (425 mg, 1.19 mmol) and 4-dimethylaminopyridine (29 mg, 0.24 mmol) were added into dichloromethane (4 mL), followed by the addition of triethylamine (499 μL, 3.59 mmol), di-tert-butyl dicarbonate (687 μL, 2.99 mmol) successively, and the reaction was allowed to proceed 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, DMSO-d6) δ 7.68 (dd, J = 8.2, 6.1 Hz, 4H), 7.49 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 6.1 Hz, 1H), 6.61 (d, J = 8.7 Hz, 2H), 4.43 (d, J = 6.0 Hz, 2H), 4.23 - 4.16 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). ESI-MS: m / z 354.1 [M-H]

[1087] Synthesis of intermediate II-91

[1088] Compound II-91 was prepared according to the method of Reference Example 44, replacing intermediate II-1 with intermediate II-90: 1 H NMR (300 MHz, DMSO-d6) δ 7.68 (dd, J = 8.2, 6.1 Hz, 4H), 7.49 (d, J = 8.1 Hz, 2H), 7.18 (t, J = 6.1 Hz, 1H), 6.61 (d, J = 8.7 Hz, 2H), 4.43 (d, J = 6.0 Hz, 2H), 4.23 - 4.16 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). ESI-MS: m / z 354.1 [M-H] + .

[1089] Synthesis of compound B-91

[1090] 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 dropwise, and the reaction was allowed to proceed at room temperature for 6 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and the residue was purified by trituration (dichloromethane / methanol = 40:1), and the obtained solid was dried to constant weight to obtain compound B-91 (white solid, 57 mg): 1 H NMR (300 MHz, DMSO-d6) δ 9.62 (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 F4N3O4S2[M-HCl + H] + 592.0982, found 592.0989.

[1091] Example 135

[1092] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4-((trifluoromethyl)thio)benzyl)amino)benzamide hydrochloride (Compound B-92)

[1093]

[1094] Synthesis of Compound B-92

[1095] Compound B-92 was prepared according to the method described in Reference Example 134, replacing intermediate I-3 with intermediate I-18: 1 H NMR (300 MHz, DMSO-d6) δ 9.62 (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 22 H 20 F3N3O4S2[M-HCl + H] +512.0920, found 512.0922.

[1096] Example 136

[1097] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-((4- (trifluoromethoxy)benzyl)amino)benzamide hydrochloride (Compound B-93)

[1098]

[1099] Synthesis of Compound B-93

[1100] Compound B-93 was prepared according to the procedure described in Reference Example 134, replacing 4-trifluoromethylthiobenzaldehyde with 4- trifluoromethoxybenzaldehyde, and replacing intermediate I-3 with intermediate I-18: 1 H NMR (300 MHz, D20) 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 F3N3O5S [M-HCl + H] + 496.1149, found 496.1150.

[1101] Example 137

[1102] tert-Butyl (4-((2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)carbamoyl)benzyl)(4- ((trifluoromethyl)thio)phenyl)carbamate (Compound B-94)

[1103]

[1104] Synthesis of Intermediate II-92

[1105] Intermediate II-92 was prepared according to the procedure described in Example 133, substituting 4-(bromomethyl)benzoic acid ethyl ester (818 mg, 3.36 mmol) for 4-(bromomethyl)-2-methylbenzoic acid ethyl ester. The crude product was used directly in the next step without further purification.

[1106] Synthesis of compound B-94

[1107] Compound B-94 was prepared according to the procedure described in Reference Example 134, substituting intermediate II-92 for intermediate II-89 and substituting intermediate II-18 for intermediate I-3. 1 H NMR (400 MHz, Chloroform-d) d 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 F4N3O6S2 [M+H] + 630.1350, found 630.1351.

[1108] Example 138

[1109] N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(((4-((trifluoromethyl)thio)phenyl)amino)methyl)benzamide hydrochloride (Compound B-95)

[1110]

[1111] Synthesis of compound B-95

[1112] Compound B-95 was prepared according to the procedure described in Reference Example 134, substituting intermediate II-91 for intermediate II-92 to give compound B-94. 1HNMR (300 MHz, DMSO-d6) 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 F4N3O4S2[M-HCl + H] + 530.0826, found 530.0820.

[1113] Example 139

[1114] N-(2-Fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-((methyl(4- ((trifluoromethyl)thio)phenyl)amino)methyl)benzamide (Compound B-96)

[1115]

[1116]

[1117] Synthesis of Intermediate II-93

[1118] Sodium hydride (42 mg, 1.06 mmol) was added into a dry three-necked flask under argon protection, and anhydrous N,N-dimethylformamide (1 mL) was added to suspend it. A solution of intermediate II-92 (187 mg, 0.53 mmol) in anhydrous N,N-dimethylformamide (1 mL) was added dropwise under ice bath. After the dropwise addition was completed, the reaction was allowed to react at 0 °C for 30 minutes. Then a solution of iodomethane (49 μL, 0.79 mmol) in anhydrous N,N-dimethylformamide (0.5 mL) was added dropwise under ice bath. After the dropwise addition was completed, the reaction was allowed to react at room temperature for 6 hours. After the reaction was completed, saturated ammonium chloride solution (20 mL) was added to quench the reaction, and ethyl acetate (10 mL x 3) was added to extract the product. The combined organic phase was washed with water (20 mL x 1) and saturated brine (20 mL x 1) in sequence. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (dichloromethane / methanol = 100:1) to obtain the crude product of intermediate II-93. Purification by trituration (dichloromethane / methanol = 50:1) gave intermediate II-93 (white solid, 90 mg): 1H NMR (300 MHz, DMSO-d6) 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).

[1119] Synthesis of compound B-96

[1120] Compound B-96 was prepared according to the procedure described in Reference Example 118, replacing intermediate II-77 with compound II-93: 1 H NMR (300 MHz, DMSO-d6) 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 F4N3O4S2[M+H] + 544.0982, found 544.0983.

[1121] Example 140

[1122] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-2-(4-((trifluoromethyl)thio)phenyl)- 1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound B-97)

[1123]

[1124] Synthesis of intermediate II-94

[1125] Into a dry schlenk tube, 4-trifluoromethylsulfanylbenzyl bromide (643 mg, 2.5 mmol), 6-bromo-l,2,3,4-tetrahydroisoquinoline (795 mg, 3.75 mmol), palladium acetate (28 mg, 0.125 mmol), 1,1'-binaphthalene-2,2'-diphosphonic acid (BINAP) (156 mg, 0.25 mmol) and cesium carbonate (1.63 g, 5 mmol) were added under argon protection, and the mixture was suspended in toluene (7.5 mL) and reacted at 100 °C for 10 h. 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), and the filtrate was evaporated under reduced pressure. 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) δ 7.55 (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).

[1126] Synthesis of compound B-97

[1127] Compound B-97 was prepared according to the method of Reference Example 89, by replacing intermediate II-41 with compound II-94: 1 H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 9.70 (s, 1H), 8.71 (s, 1H), 7.79 (d, J = 9.6 Hz, 2H), 7.63 (d, J = 2.6 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.51 (dd, J = 8.6, 2.6 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.09 (d, J = 8.9 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 4.58 (s, 2H), 3.67 (t, J = 5.9 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.98 (s, 3H). HRMS (ESI) calcd. for C 24 H 22 F3N3O4S2[M+H] + 538.1077, found 538.1077.

[1128] Example 141

[1129] N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-2-(4-((trifluoromethyl)thio)phenyl)- 1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound B-98)

[1130]

[1131] Synthesis of Compound B-98

[1132] Compound B-98 was prepared according to the procedure of Reference Example 89, replacing Intermediate II-41 with Intermediate II-94, and replacing Intermediate I-18 with Compound II-18: 1 H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1H), 9.92 (s, 1H), 8.90 (s, 1H), 7.80 (d, J = 10.3 Hz, 2H), 7.53 (d, J = 8.8 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 6.78 (d, J = 11.3 Hz, 1H), 4.59 (s, 2H), 3.67 (t, J = 5.8 Hz, 2H), 3.02 (t, J = 5.5 Hz, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 24 H 21 F4N3O4S2 [M+H] + 556.0982, found 556.0986.

[1133] Example 142

[1134] N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-2-(4-(trifluoromethyl)phenyl)- 1,2,3,4-tetrahydroisoquinoline-6-carboxamide (Compound B-99)

[1135]

[1136] Synthesis of Compound B-99

[1137] Compound B-99 was prepared according to the procedure of Example 140, replacing 4- trifluoromethylthio bromobenzene with 4-trifluoromethyl bromobenzene, and replacing Intermediate I-18 with Compound II-18: 1H NMR (400 MHz, DMSO-d6) δ 10.16 (s, 1H), 9.91 (s, 1H), 9.03 (s, 1H), 7.82 (s, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.40 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 11.4 Hz, 1H), 4.60 (s, 2H), 3.69 (t, J = 5.9 Hz, 2H), 3.01 (t, J = 5.9 Hz, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 24 H 21 F4N3O4S [M+H] + 524.1262, found 524.1266.

[1138] Example 143

[1139] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-((trifluoromethyl)thio)phenethyl)benzamide (Compound B-100)

[1140]

[1141]

[1142] Synthesis of Intermediate II-95

[1143] Into a three-necked flask, 4-trifluoromethylsulfanylphenol (500 mg, 2.58 mmol) was added under argon protection, anhydrous dichloromethane (8 mL), triethylamine (1 mL, 7.72 mmol) was added, then triflic anhydride (520 μL, 3.09 mmol) was added dropwise under ice-bath cooling, after the dropwise addition was completed, the reaction mixture was allowed to warm to room temperature and stirred 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 give Intermediate II-95 (yellowish oil, 581 mg).

[1144] Synthesis of Intermediate II-96

[1145] Intermediate II-95 (100 mg, 0.31 mmol), ethyl 4-ethynylbenzoate (80 mg, 0.46 mmol), palladium dichloride bis(triphenylphosphine) (11 mg, 0.02 mmol), cuprous iodide (3 mg, 0.02 mmol), and lithium chloride (39 mg, 0.92 mmol) were added to a dry Schlenk tube under argon protection. Then, N,N-dimethylformamide (2 mL) and triethylamine (3 mL, 10 eqv) were added. After the addition was complete, the mixture was heated to 60 °C and reacted for 7 hours. After the reaction was complete, the reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL), the filtrate was diluted with water (20 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and washed successively with water (10 mL x 1) and 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 give intermediate II-96 (yellow solid, 62 mg). 1 H NMR (300MHz, CDCl3) δ8.06(d,J=8.2Hz,2H),7.67(d,J=8.1Hz,2H),7.60(dd,J=8.0,5.0Hz,4H),4.41(q,J=7.1Hz,2H),1.43(t,J=7.1Hz,3H).

[1146] Synthesis of intermediate II-97

[1147] Intermediate II-96 (123 mg, 0.35 mmol) was added to ethanol (3 mL), followed by glacial acetic acid (0.5 mL) and palladium hydroxide on carbon (24 mg). The reaction was carried out at room temperature for 12 hours under a hydrogen atmosphere. After the reaction was completed, the palladium hydroxide on carbon was filtered off, the filter cake was washed with ethyl acetate (10 mL), 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 give intermediate II-97 (white solid, 118 mg). 1 H NMR (300MHz, DMSO-d6) δ7.86(d,J=8.2Hz,2H),7.62(d,J=8.1Hz,2H),7.38(t,J=8.0Hz,4H),4.29(q,J=7.1Hz,2H),2.98(s,4H),1.31(t,J=7.1Hz,3H).

[1148] Synthesis of compound B-100

[1149] Compound B-100 was prepared by replacing intermediate II-1 with intermediate II-97, following the method described in Example 44. 1HNMR (300 MHz, DMSO-d6) 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 F4N2O4S2[M+H] + 591.1030, found 591.1035.

[1150] Example 144

[1151] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenethyl)benzamide (Compound B-101)

[1152]

[1153] Synthesis of Compound B-101

[1154] Compound B-101 was prepared according to the procedure described in Reference Example 55, replacing Intermediate II-1 with Intermediate II-97: 1 HNMR (300 MHz, DMSO-d6) 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 F3N2O4S2[M+H] + 511.0968, found 511.0970.

[1155] Example 145

[1156] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-(trifluoromethyl)phenethyl)benzamide (Compound B-102)

[1157]

[1158] Synthesis of Compound B-102

[1159] Compound B-102 was prepared according to the procedure of Reference Example 143, replacing 4-trifluoromethylphenol with 4-trifluoromethylphenol, and replacing intermediate 1-3 with intermediate 1-18: 1 H NMR (400 MHz, DMSO-d6) 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 F3N2O4S [M+H] + 479.1247, found 479.1248.

[1160] Example 146

[1161] 4-(2-cyclohexylethyl)-N-(3-((4-fluorophenyl)sulfonamido)-4- hydroxyphenyl)benzamide (Compound B-103)

[1162]

[1163] Synthesis of Compound B-103

[1164] Compound B-103 was prepared according to the procedure of Reference Example 29, replacing cyclohexanone with cyclohexanecarboxaldehyde: 1 H NMR (300 MHz, DMSO-d6) 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 FN2O4S [M+H] + 497.1905, found 497.1889.

[1165] Example 147

[1166] 4-(2-(4,4-difluorocyclohexyl)ethyl)-N-(3-((4-fluorophenyl)sulfonamido)-4- hydroxyphenyl)benzamide (Compound B-104)

[1167]

[1168] Synthesis of intermediate II-98

[1169] Into a dry three-necked flask, 4,4-difluorocyclohexanecarboxylic acid (328 mg, 2 mmol) was added, dissolved in anhydrous tetrahydrofuran (6 mL) under argon protection, 1M borane-tetrahydrofuran complex (3 mL, 3 mmol) was added dropwise under ice-bath cooling, after the dropwise addition was completed, the reaction solution was slowly warmed 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 (15 mL x 3) was extracted, and the organic phase was combined and washed with water (10 mL x 1), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product of intermediate II-98, which was directly used in the next step without further purification.

[1170] Synthesis of intermediate II-99

[1171] Into a dry three-necked flask, 4,4-difluorocyclohexanecarboxylic acid (328 mg, 2 mmol) was added, dissolved in anhydrous tetrahydrofuran (6 mL) under argon protection, 1M borane-tetrahydrofuran complex (3 mL, 3 mmol) was added dropwise under ice-bath cooling, after the dropwise addition was completed, the reaction solution was slowly warmed 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 (15 mL x 3) was extracted, and the organic phase was combined and washed with water (10 mL x 1), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain the crude product of intermediate II-98, which was directly used in the next step without further purification.

[1172] Synthesis of compound B-104

[1173] Referring to the method of Example 29, compound B-104 was prepared by replacing cyclohexanone with intermediate II-99: 1H NMR (300 MHz, DMSO-d6) 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 F3N2O4S[M+H] + 533.1716, found 533.1744.

[1174] Example 148

[1175] 4-(2-cyclohexylethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-105)

[1176]

[1177] Synthesis of Compound B-105

[1178] Compound B-105 was prepared according to the procedure of Reference Example 29, replacing cyclohexanone with cyclohexylcarboxaldehyde, and replacing intermediate I-3 with intermediate I-18: 1 H NMR (300 MHz, DMSO-d6) δ 10.00 (s, 1H), 9.66 (s, 1H), 8.67 (s, 1H), 7.85 (d, J = 7.9 Hz, 2H), 7.62 (s, 1H), 7.48 (dd, J = 8.5, 1.8 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.8 Hz, 1H), 2.97 (s, 3H), 2.71 - 2.61 (m, 2H), 1.79 - 1.56 (m, 5H), 1.49 (dd, J = 15.0, 6.9 Hz, 2H), 1.26 - 1.10 (m, 4H), 0.99 - 0.84 (m, 2H). ESI-MS: m / z 415.2 [M-H] - HRMS (ESI) calcd. for C 22 H 28 N2O4S[M+H] + 417.1843, found 417.1841.

[1179] Example 149

[1180] 4-(2-cyclopropylethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-106)

[1181]

[1182] Synthesis of intermediate II-100

[1183] Reference to the method of example 29, cyclohexanone was replaced by cyclopropylcarboxaldehyde to produce intermediate II-100.

[1184] Synthesis of intermediate II-101

[1185] Intermediate II-100 (100 mg, 0.53 mmol) was added to a mixture of tetrahydrofuran (5 mL) and water (5 mL), and then p-toluenesulfonylhydrazide (989 mg, 5.31 mmol) and sodium acetate trihydrate (940 mg, 6.91 mmol) were added successively. After the addition, the reaction mixture was heated to 70 °C and stirred for 24 hours. After the reaction was completed, 2N aqueous hydrogen chloride solution (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (5 mL x 1), and the solvent was distilled off 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-d6) δ 12.74 (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).

[1186] Synthesis of compound B-106

[1187] Reference to the method of example 55, intermediate II-2 was replaced by intermediate II-101 to produce compound B-106: 1H NMR (300 MHz, DMSO-d6) δ 10.01 (s, 1H), 9.67 (s, 1H), 8.69 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.62 (d, J = 2.2 Hz, 1H), 7.49 (dd, J = 8.7, 2.2 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 2.97 (s, 3H), 2.73 (t, J = 7.6 Hz, 2H), 1.50 (dd, J = 15.0, 7.1 Hz, 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 N2O4S [M+H] + 375.1373, found 375.1375.

[1188] Example 150

[1189] 4-(2-cycloheptylethyl)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound B-107)

[1190]

[1191] Synthesis of Compound B-107

[1192] Compound B-107 was prepared according to the procedure of Reference Example 147, replacing 4,4-difluorocyclohexanecarboxylic acid with cycloheptanecarboxylic acid and replacing intermediate I-3 with intermediate I-18: 1 H NMR (300 MHz, DMSO-d6) δ 10.02 (s, 1H), 9.62 (s, 1H), 8.75 (s, 1H), 7.85 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 2.5 Hz, 1H), 7.49 (dd, J = 8.8, 2.5 Hz, 1H), 7.32 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 2.97 (s, 3H), 2.63 (t, J = 8.0 Hz, 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 N2O4S [M+H] + 431.1999, found 431.2001.

[1193] Example 151

[1194] N-(3-((4-fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4-((trifluoromethyl)thio)phenethyl- oxyl)benzamide (Compound C-1)

[1195]

[1196] Synthesis of intermediate III-1

[1197] Into a dry three-necked flask, 4-trifluoromethylsulfanylbenzoic acid (2 g, 8.47 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL) under argon protection, 1M borane-tetrahydrofuran complex (17 mL, 16.9 mmol) was added slowly under ice-bath cooling, after the dropwise addition was completed, the reaction was slowly warmed to room temperature for 6 hours. After the reaction was completed, the excess borane was quenched by dropwise adding ice-water (30 mL) into the reaction solution, extracted with ethyl acetate (20 mL x 3), the organic phase was combined and washed with water (20 mL x 1), saturated brine (20 mL x 1) successively, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to give intermediate III-1 (colorless oily liquid, 1.87 g): 1 H NMR (300 MHz, DMSO-d6) δ 7.62 (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).

[1198] Synthesis of intermediate III-2

[1199] Into a dry three-necked flask, intermediate III-1 (200 mg, 0.90 mmol), methyl 4-hydroxybenzoate (260 mg, 1.71 mmol) and triphenylphosphine (472 mg, 1.80 mmol) were dissolved in anhydrous tetrahydrofuran (2 mL) under argon protection, a solution of diisopropyl azodicarboxylate (360 μL, 1.80 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise slowly under ice-bath cooling, after the dropwise addition was completed, the reaction was warmed to room temperature for 12 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20:1) to give intermediate III-2 (white solid, 198 mg): 1H NMR (300 MHz, CDC13) 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).

[1200] Synthesis of compound C-1

[1201] Compound C-1 was prepared according to the procedure of Reference Example 1, replacing intermediate I-5 with intermediate III-2: 1 H NMR (300 MHz, DMSO-d6) δ 9.91 (s, OH), 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, OH), 4.32 (t, J = 6.7 Hz, 1H), 3.14 (t, J = 6.6 Hz, 1H). HRMS (ESI) calcd. for C 28 H 22 F4N2O5S2[M+H] + 607.0979, found 607.0981.

[1202] Example 152

[1203] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4- (trifluoromethoxy)phenethoxy)benzamide (Compound C-2)

[1204]

[1205] Synthesis of compound C-2

[1206] Compound C-2 was prepared according to the procedure of Reference Example 151, replacing 4-trifluoromethylthiophenylacetic acid with 4- trifluoromethoxyphenylacetic acid: 1H NMR (300 MHz, DMSO-d6) δ 9.91 (s, 1H), 9.33 (s, 2H), 7.91 (d, J = 8.7 Hz, 2H), 7.81 (dd, J = 8.7, 5.3 Hz, 2H), 7.66 (d, J = 2.2 Hz, 1H), 7.48 (d, J = 8.5 Hz, 2H), 7.39 (d, 1H), 7.34 (d, J = 8.1 Hz, 3H), 7.30 (s, 1H), 7.04 (d, J = 8.7 Hz, 2H), 6.67 (d, J = 8.7 Hz, 1H), 4.29 (t, J = 6.6 Hz, 2H), 3.11 (t, J = 6.6 Hz, 2H). ESI-MS: m / z 589.1 [M-H] - .

[1207] Example 153

[1208] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-(4- (trifluoromethoxy)phenethoxy)benzamide (Compound C-3)

[1209]

[1210] Synthesis of Compound C-3

[1211] Compound C-3 was prepared according to the procedure of Example 151, replacing 4-trifluoromethylphenylacetic acid with 4-trifluoromethylphenylacetic acid: 1 H NMR (300 MHz, DMSO-d6) 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 22 F4N2O5S [M+H] + 575.1258, found 575.1260.

[1212] Example 154

[1213] N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenethoxy)benzamide (Compound C-4)

[1214]

[1215] Synthesis of compound C-4

[1216] Compound C-4 was prepared according to the procedure of Reference Example 55, replacing intermediate II-1 with intermediate III-2: 1 H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.44 (s, 1H), 8.80 (s, 1H), 7.92 (d, J = 8.7 Hz, 2H), 7.68 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 2.3 Hz, 1H), 7.52 (d, J = 8.1 Hz, 2H), 7.48 (dd, J = 8.9, 2.4 Hz, 1H), 7.05 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 4.32 (t, J = 6.6 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 23 H 21 F3N2O5S2[M+H] + 527.0917, found 527.0917.

[1217] Example 155

[1218] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethoxy)phenethoxy)benzamide (Compound C-5)

[1219]

[1220] Synthesis of compound C-5

[1221] Compound C-5 was prepared according to the procedure of Example 151, replacing 4- trifluoromethylthiophenylacetic acid with 4-trifluoromethoxyphenylacetic acid, and replacing intermediate I-3 with intermediate I-18: 1 H NMR (300 MHz, DMSO-d6) 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 C23 H 21 F3N2O6S[M+H] + 511.1145, found 511.1161.

[1222] Example 156

[1223] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)sulfonyl)phenethoxy)benzamide (Compound C-7)

[1224]

[1225] Synthesis of Compound C-6

[1226] Referring to the procedure of Example 151, replace 4-trifluoromethylthiophenylacetic acid with 4-methanesulfonylphenylacetic acid, and replace intermediate I-3 with intermediate I-18 to produce Compound C-6: 1 H NMR (300 MHz, DMSO-d6) δ 9.94 (s, 1H), 9.52 (s, 1H), 8.74 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.8 Hz, 3H), 7.48 (dd, J = 8.6, 1.7 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 4.34 (t, J = 6.3 Hz, 2H), 3.20 (s, 3H), 3.20 - 3.14 (m, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 23 H 24 N2O7S2[M+H] + 505.1098, found 505.1101.

[1227] Example 157

[1228] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)sulfonyl)phenethoxy)benzamide (Compound C-7)

[1229]

[1230]

[1231] Synthesis of Intermediate III-3

[1232] Referring to the procedure of Example 151, hydrolyze intermediate III-2 to produce Compound Intermediate III-3: 1H NMR (300 MHz, DMSO-d6) 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 [M-H] - .

[1233] Synthesis of intermediate III-4

[1234] Intermediate III-3 (74 mg, 0.22 mmol) was added into trifluoroacetic acid (1.1 mL), 30% hydrogen peroxide aqueous solution (486 μL) was added dropwise under ice-bath, after the dropwise addition was completed, the reaction was allowed to warm to room temperature for 21 hours. After the reaction was completed, the reaction solution was poured into ice-water (10 mL), solid was precipitated, filtered, the filter cake was washed with water (5 mL), the residue was purified by trituration (n-hexane / ethyl ether = 10:1), the obtained solid was dried to constant weight to give intermediate III-4 (white solid, 39 mg): ESI-MS: m / z 373.0 [M-H] - .

[1235] Synthesis of compound C-7

[1236] Compound C-7 was prepared according to the method of Example 7 by replacing 4-trifluoromethylsulfanylbenzoic acid with intermediate III-4: 1 H NMR (300 MHz, DMSO-d6) δ 9.95 (s, 1H), 9.68 (s, 1H), 8.72 (s, 1H), 8.10 (d, J = 8.1 Hz, 2H), 7.93 (d, J = 8.7 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 2.1 Hz, 1H), 7.48 (dd, J = 8.6, 2.0 Hz, 1H), 7.05 (d, J = 8.6 Hz, 2H), 6.84 (d, J = 8.7 Hz, 1H), 4.39 (t, J = 6.2 Hz, 2H), 3.29 (t, J = 6.1 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 23 H 21 F3N2O7S2[M+H] + 559.0815, found 559.0815.

[1237] Example 158

[1238] 4-(2-cyclohexylethoxy)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound C-8)

[1239]

[1240] Synthesis of Compound C-8

[1241] Compound C-8 was prepared according to the procedure of Reference Example 49, replacing cyclohexanemethanol with 2-cyclohexylethanol, and replacing intermediate I-3 with intermediate I-18: 1 H NMR (300 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.58 (s, 1H), 8.75 (s, 1H), 7.91 (d, 2H), 7.61 (d, J = 2.5 Hz, 1H), 7.48 (dd, J = 8.7, 2.6 Hz, 1H), 7.02 (d, 2H), 6.84 (d, J = 8.7 Hz, 1H), 4.07 (t, J = 6.6 Hz, 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 22 H 28 N2O5S [M+H] + 433.1792, found 433.1791.

[1242] Example 159

[1243] 4-(2-(4,4-difluoropiperidin-l-yl)ethoxy)-N-(4-hydroxy-3-(methylsulfonamido)phenyl)benzamide (Compound C-9)

[1244]

[1245]

[1246] Synthesis of Intermediate III-5

[1247] Methyl 4-hydroxybenzoate (304 mmol, 2 mmol) was added into N,N- dimethylformamide (5 mL), 2-bromoethanol (185 μL, 2.6 mmol) was added, then potassium carbonate (415 mg, 3 mmol) was added portionwise, after addition, the system was elevated to 80 °C for 8 hours. After the reaction was completed, the system was cooled to room temperature, water (50 mL) was added to dilute the reaction solution, ethyl acetate (10 mL x 3) was extracted, the organic phase was combined, and then water (20 mL x 1), saturated brine (20 mL x 1) was sequentially washed, the solvent was distilled out 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, CDC13) δ 8.02 (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).

[1248] Synthesis of intermediate III-6

[1249] Triphenylphosphine (870 mg, 3.32 mmol) and imidazole (226 mg, 3.32 mmol) were added into tetrahydrofuran (6 mL), a tetrahydrofuran solution (3 mL) of iodine (842 mg, 3.32 mmol) was added dropwise under ice bath, and stirred at 0 °C for 30 minutes, then a tetrahydrofuran (3 mL) solution of intermediate III-5 (434 mg, 2.21 mmol) was added dropwise, and the system was elevated to room temperature for 8 hours. After the reaction was completed, sodium thiosulfate solution (10 mL) was added to the reaction solution to quench the excess iodine, ethyl acetate (10 mL x 3) was extracted, the organic phase was combined, and then sodium thiosulfate solution (10 mL x 1), saturated brine (10 mL x 1) was sequentially washed, the solvent was distilled out 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).

[1250] Synthesis of intermediate III-7

[1251] Intermediate III-6 (200 mg, 0.65 mmol) and 4,4-difluoropiperidine hydrochloride (154 mg, 0.98 mmol) were added into acetonitrile (2 mL), potassium carbonate (271 mg, 1.96 mmol) was added portionwise, after addition, the system was elevated to 80 °C for 12 hours. After the reaction was completed, the system was cooled to room temperature, 1 N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 7-8, ethyl acetate (5 mL x 4) was extracted, the combined organic phase was 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 product of intermediate III-7, which was directly used in the next step without further purification.

[1252] Synthesis of intermediate III-8

[1253] The crude product of intermediate III-7 was added into a mixture of tetrahydrofuran (1.5 mL) and methanol (1.5 mL), 1 M aqueous sodium hydroxide solution (2 mL) was added, after addition, the system was elevated to 60 °C for 4 hours. After the reaction was completed, the system was cooled to room temperature, 1 N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust the pH to 8-9, ethyl acetate (5 mL x 3) was extracted, the combined organic phase was 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 (pale yellow solid, 109 mg): 1 H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 8.8 Hz, 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 [M-H] - .

[1254] Synthesis of compound C-9

[1255] Referring to the method of Example 7, 4-trifluoromethylthiophenylcarboxylic acid was replaced by intermediate III-8 to prepare compound C-9: 1H 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 F2N3O5S [M+H] + 470.1556, found 470.1563.

[1256] Example 160

[1257] 3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethoxy)phenethoxy)benzamide (Compound C-10)

[1258]

[1259] Synthesis of Compound C-10

[1260] Compound C-10 was prepared according to the procedure of Reference Example 151, replacing 4-trifluoromethylthiophenylacetic acid with 4- trifluoromethoxyphenylacetic acid, replacing methyl 4-hydroxybenzoate with methyl 3-fluoro-4-hydroxybenzoate, and replacing Intermediate I-3 with Intermediate I-18: 1 H NMR (300 MHz, DMSO-d6) δ 9.99 (s, 1H), 9.70 (s, 1H), 8.71 (s, 1H), 7.82 (dd, J = 10.2, 2.3 Hz, 1H), 7.79 (d, J = 3.2 Hz, 1H), 7.60 (d, J = 2.6 Hz, 1H), 7.52 - 7.43 (m, 3H), 7.35 (d, J = 6.4 Hz, 1H), 7.32 (d, J = 7.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 1H), 4.37 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.7 Hz, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 23 H 20 F4N2O6S [M+H] + 529.1051, found 529.1060.

[1261] Example 161

[1262] 3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(4- (trifluoromethylsulfonamido)phenethoxy)benzamide (Compound C-11)

[1263]

[1264] Synthesis of Compound C-11

[1265] Following the procedure of Reference Example 157, substituting methyl 3-fluoro-4- hydroxybenzoate for methyl 4-hydroxybenzoate, Compound C-11 was prepared: 1 H NMR (300 MHz, DMSO-d6) 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 F4N2O7S2[M+H] + 577.0721, found 577.0724.

[1266] Example 162

[1267] N-(4-Hydroxy-3-(methylsulfonamido)phenyl)-6-(4-((trifluoromethyl)thio)phenethoxy)nicotinamide (Compound C-12)

[1268]

[1269] Synthesis of Intermediate III-9

[1270] Intermediate III-1 (150 mg, 0.67 mmol), ethyl 6-hydroxy nicotinate (248 mg, 1.48 mmol) and triphenylphosphine (372 mg, 1.42 mmol) were added into a dry three-necked flask, which was protected by argon, dissolved in anhydrous tetrahydrofuran (2 mL), and a solution of diethyl azodicarboxylate (222 μL, 1.42 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added under ice-bath cooling. After the dropwise addition was completed, the reaction was allowed to react at room temperature for 12 hours. After the reaction was completed, water (10 mL) was added to the reaction solution, which was extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with saturated brine (5 mL x 1). The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 50:1) to obtain intermediate III-9 (white solid, 113 mg): 1 H NMR (300 MHz, CDC13) δ 8.80 (s, 1H), 8.15 (dd, J = 6.6 Hz, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 6.73 (d, J = 8.7 Hz, 1H), 4.61 (t, J = 6.8 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H), 1.39 (t, J = 13.4, 6.3 Hz, 3H). ESI-MS: m / z 394.0 [M+Na] + .

[1271] Synthesis of compound C-12

[1272] Compound C-12 was prepared according to the method of Reference Example 55, by replacing intermediate II-1 with intermediate III-9: 1 H NMR (300 MHz, CDC13) δ 8.80 (s, 1H), 8.15 (dd, J = 6.6 Hz, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.34 (d, J = 7.8 Hz, 2H), 6.73 (d, J = 8.7 Hz, 1H), 4.61 (t, J = 6.8 Hz, 2H), 4.37 (q, J = 7.1 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H), 1.39 (t, J = 13.4, 6.3 Hz, 3H). ESI-MS: m / z 394.0 [M+Na] 22 H 20 F3N3O5S2[M+H] + 528.0869, found528.0869.

[1273] Example 163

[1274] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-6-(4- (trifluoromethylsulfonamido)phenethoxy)nicotinamide (Compound C-13)

[1275]

[1276] Synthesis of Compound C-13

[1277] Compound C-13 was prepared according to the procedure of Reference Example 157, replacing methyl 4-hydroxybenzoate with ethyl 6-hydroxynicotinate: 1 H NMR (400 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.71 (s, 1H), 8.74 (d, J = 2.1 Hz, 1H), 8.70 (s, 1H), 8.21 (dd, J = 8.7, 2.5 Hz, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 2.6 Hz, 1H), 7.46 (dd, J = 8.8, 2.6 Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.85 (d, J = 8.7 Hz, 1H), 4.65 (t, J = 6.5 Hz, 2H), 3.28 (t, J = 6.5 Hz, 2H), 2.97 (s, 3H). HRMS (ESI) calcd. for C 22 H 20 F3N3O7S2[M+H] + 560.0768, found 560.0776.

[1278] Example 164

[1279] N-(2-fluoro-4-hydroxy-5-(methylsulfonamido)phenyl)-4-(4-((trifluoromethyl)thio)phenethoxy)benzamide (Compound C-14)

[1280]

[1281] Synthesis of Compound C-14

[1282] Compound C-14 was prepared according to the procedure of Reference Example 1, replacing Intermediate I-5 with Intermediate III-2, and replacing Intermediate I-3 with Intermediate II-18: 1H NMR (300 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.78 (s, 1H), 8.85 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 7.9 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 11.4 Hz, 1H), 4.32 (t, J = 6.7 Hz, 2H), 3.14 (t, J = 6.7 Hz, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C 23 H 20 F4N2O5S2[M+H] + 545.0823, found 545.0823.

[1283] Example 165

[1284] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-(4-((trifluoromethyl)thio)phenoxy)ethyl)benzamide (Compound C-15)

[1285]

[1286] Synthesis of Intermediate III-10

[1287] Into a dry three-necked flask, 4-trifluoromethylsulfanylphenol (300 mg, 1.55 mmol), 4-bromo-phenethyl alcohol (683 mg, 3.40 mmol) and triphenylphosphine (851 mg, 3.24 mmol) were added under argon protection, dissolved in anhydrous tetrahydrofuran (3 mL), and a solution of diisopropyl azodicarboxylate (639 μL, 3.24 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise slowly under ice-bath cooling, and the mixture was allowed to react 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) to obtain Intermediate III-10 (colorless oily liquid, 367 mg): 1 H NMR (300 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.78 (s, 1H), 8.85 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.68 (d, J = 7.9 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.3 Hz, 1H), 7.05 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 11.4 Hz, 1H), 4.32 (t, J = 6.7 Hz, 2H), 3.14 (t, J = 6.7 Hz, 2H), 2.95 (s, 3H). HRMS (ESI) calcd. for C

[1288] Synthesis of Compound C-15

[1289] Following the method of Example 89, intermediate II-41 was replaced with intermediate III-10 to obtain compound C-15: 1 HNMR(300MHz,DMSO-d6)δ10.06(s,1H),9.70(s,1H),8.73(s,1H),7.90(d,J=8.0Hz,2H),7.63(dd,J=5.5,2.7Hz,3H),7.50(dd,2H),7.4 6(d,1H),7.10(d,J=8.6Hz,2H),6.86(d,J=8.7Hz,1H),4.32(t,J=6.5Hz,2H),3.14(t,J=6.4Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F3N2O5S2[M+H] + 527.0917, found 527.0919.

[1290] Example 166

[1291] N-(4-hydroxy-3-(methylsulfonamide)phenyl)-4-(2-(4-(trifluoromethoxy)phenoxy)ethyl)benzamide (compound C-16)

[1292]

[1293] Synthesis of compound C-16

[1294] Following the method of Example 165, 4-trifluoromethylthiophenol was replaced with 4-trifluoromethoxyphenol to obtain compound C-16: 1 H NMR (300MHz, DMSO-d6) 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 F3N2O6S[M+H] + 511.1145, found 511.1145.

[1295] Example 167

[1296] 3-Fluoro-N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-(4- (trifluoromethoxy)phenoxy)ethyl)benzamide (Compound C-17)

[1297]

[1298] Synthesis of Intermediate III-11

[1299] To a solution of 4-bromo-2-fluorophenylacetic acid (816 mg, 3.5 mmol) in anhydrous tetrahydrofuran (7 mL) was added 1 M borane-tetrahydrofuran complex (5.3 mL, 5.3 mmol) dropwise at ice bath. After the addition, the mixture was allowed to warm to room temperature slowly and stirred for 4 h. After the reaction was completed, the excess borane was quenched by the addition of ice water (30 mL) dropwise. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with water (20 mL x 1), saturated brine (20 mL x 1), and the solvent was removed under reduced pressure. The residue was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give Intermediate III-11 (colorless oily liquid, 721 mg).

[1300] Synthesis of Compound C-17

[1301] Following the procedure of Reference Example 165, replacing 4- trifluoromethylsulfanylphenol with 4-trifluoromethoxyphenol and replacing 4- bromophenethyl alcohol with Intermediate III-11, Compound C-17 was prepared: 1 H NMR (300 MHz, DMSO-d6) δ 10.13 (s, 1H), 9.75 (s, 1H), 8.75 (s, 1H), 7.77 (s, 1H), 7.78-7.70 (m, 1H), 7.62 (d, J = 2.6 Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.49 (dd, J = 8.8, 2.6 Hz, 1H), 7.28 (d, J = 8.2 Hz, 1H), 7.03 (d, J = 9.1 Hz, 2H), 6.86 (d, J = 8.7 Hz, 1H), 4.26 (t, J = 6.6 Hz, 2H), 3.15 (t, J = 6.5 Hz, 2H), 2.96 (s, 3H). HRMS (ESI) calcd. for C 23 H 20 F4N2O6S [M+H] + 529.1051, found 529.1057.

[1302] Example 168

[1303] N-(4-hydroxy-3-(methylsulfonamido)phenyl)-4-(2-(4- (trifluoromethoxy)phenoxy)ethyl)benzamide (Compound C-18)

[1304]

[1305] Synthesis of Intermediate III-12

[1306] Into a dry three-necked flask, 4-trifluoromethoxybenzoic acid (1 g, 4.54 mmol) was added, dissolved in anhydrous tetrahydrofuran (10 mL), and argon was bubbled through the solution. 1M borane-tetrahydrofuran complex (9.1 mL, 9.1 mmol) was added slowly under ice-bath cooling. After the addition was completed, the reaction mixture was allowed to warm up to room temperature slowly. After 6 hours, the reaction was quenched by the dropwise addition of ice-water (30 mL) to the reaction mixture. The excess borane was removed by extraction with ethyl acetate (20 mL x 3). The combined organic phase was washed with water (20 mL x 1), saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Intermediate III-12 (pale yellow oily liquid, 916 mg).

[1307] Synthesis of Intermediate III-13

[1308] Into a dry three-necked flask, 4-trifluoromethoxybenzoic acid (1 g, 4.54 mmol) was added, dissolved in anhydrous tetrahydrofuran (10 mL), and argon was bubbled through the solution. 1M borane-tetrahydrofuran complex (9.1 mL, 9.1 mmol) was added slowly under ice-bath cooling. After the addition was completed, the reaction mixture was allowed to warm up to room temperature slowly. After 6 hours, the reaction was quenched by the dropwise addition of ice-water (30 mL) to the reaction mixture. The excess borane was removed by extraction with ethyl acetate (20 mL x 3). The combined organic phase was washed with water (20 mL x 1), saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give Intermediate III-12 (pale yellow oily liquid, 916 mg). 1 H NMR (300 MHz, Chloroform-d) δ 7.66 (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] + .

[1309] Synthesis of Intermediate III-14

[1310] Intermediate III-13 (139 mg, 0.39 mmol), 4-bromothiophenol (109 mg, 0.58 mmol) and potassium iodide (7 mg, 0.04 mmol) were added into acetonitrile (3 mL), potassium carbonate (108 mg, 0.78 mmol) was added portionwise with stirring, after addition, the system was raised to 80 °C and reacted for 8 hours. After the reaction was completed, the system was cooled to room temperature, 1M sodium hydroxide aqueous solution (5 mL) was added to quench the reaction, and ethyl acetate (10 mL x 3) was used for extraction, the combined organic phase was 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, CDCl3) δ 7.44 (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).

[1311] Synthesis of intermediate III-15

[1312] 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-bisdiphenylphosphine-9,9-dimethylxanthene (Xantphos) (5 mg, 0.009 mmol) and acetic anhydride (83 μL, 0.88 mmol) were added into anhydrous N,N-dimethylformamide (2 mL), the system was cooled to -78 °C, N,N-diisopropylethylamine (154 μL, 0.88 mmol) was added, and the system was allowed to naturally recover to room temperature and stirred for 30 minutes. Then the system was raised to 100 °C and reacted for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N hydrogen chloride aqueous solution (5 mL) and water (20 mL) were added to dilute the reaction solution, and ethyl acetate (10 mL x 3) was used for extraction. The combined organic phase was 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-d6) δ 12.87 (s, 1H), 7.85 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 5.3 Hz, 2H), 7.40 (d, J = 5.2 Hz, 2H), 7.29 (d, J = 8.2 Hz, 2H), 3.40-3.29 (m, 2H), 2.96 (t, J = 7.4 Hz, 2H).

[1313] Synthesis of compound C-18

[1314] Compound C-18 was prepared according to the procedure of Reference Example 1, replacing intermediate 1-6 with intermediate III-15: 1 H NMR (300 MHz, DMSO-d6) δ 10.04 (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 F4N2O5S2[M+H] + 607.0985, found 607.0991.

[1315] Example 169

[1316] N-(3-((4-Fluorophenyl)sulfonamido)-4-hydroxyphenyl)-4-((4- (trifluoromethyl)phenethyl)thio)benzamide (Compound C-19)

[1317]

[1318] Synthesis of compound C-19

[1319] Compound C-19 was prepared according to the procedure of Example 168, replacing 4- trifluoromethoxyphenylacetic acid with 4-trifluoromethylphenylacetic acid: 1 H NMR (300 MHz, DMSO-d6) δ 10.04 (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),...

Claims

1. A sulfonamide compound or a pharmaceutically acceptable salt thereof, characterized in that, The sulfonamide compound or its pharmaceutically acceptable salt is selected from any one of the following: 。 2. Use of a sulfonamide compound of claim 1 or a pharmaceutically acceptable salt or ester thereof in the preparation of a medicament for inhibiting activation of the STING signaling pathway.

3. Use of a sulfonamide compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of STING-mediated diseases.

4. The use according to claim 3, wherein the STING-mediated diseases include infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, cancer, or cancer syndromes.

5. Use of a sulfonamide compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of an immunoadjuvant medicament.

6. A pharmaceutical composition for the prevention or treatment of STING-mediated diseases, comprising a sulfonamide compound as claimed in claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient and a pharmaceutically acceptable excipient.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition is in the form of capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, or patches.

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