CN117682973A - Sulfonamide compound and medical application thereof - Google Patents

Sulfonamide compound and medical application thereof Download PDF

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Publication number
CN117682973A
CN117682973A CN202311253162.1A CN202311253162A CN117682973A CN 117682973 A CN117682973 A CN 117682973A CN 202311253162 A CN202311253162 A CN 202311253162A CN 117682973 A CN117682973 A CN 117682973A
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compound
mmol
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unsubstituted
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Inventor
孙宏斌
王朝鑫
路雨霏
张尚然
李娟红
郑茹楠
周丽
于金立
戴量
袁浩亮
温小安
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China Pharmaceutical University
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China Pharmaceutical University
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Abstract

The invention discloses a sulfonamide compoundAnd the medical application of the compound as a STING inhibitor, in particular to a compound shown in a formula I or pharmaceutically acceptable salt, ester or solvate thereof, which can be used for preparing STING inhibitors or medicines for inhibiting the activation of STING signal channels and medicines for preventing or treating STING mediated diseases.

Description

Sulfonamide compound and medical application thereof
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to a novel sulfonamide compound and medical application thereof.
Background
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 invasion of pathogenic microorganisms in the body, continued activation of STING pathway can lead to the development and progression of various autoimmune and inflammatory diseases (Nature Immunology,2017,18 (7): 716-724), including AGS syndrome (airdi-Gouti re syndrome), systemic lupus erythematosus (systemic lupus erythematosus, SLE), SAVI (STING-associated vasculopathy with onset in infancy) diseases, and the like. Furthermore, in the disease model related to inflammation, such as the induction of skin cancer (Nat Commun,2014, 5:5166), tumor metastasis (Nature, 2018,553 (7689):467-472), premature senility (Nature, 2017,550 (7676):402-406), sepsis (Shock, 2017,47 (5): 621-631), acute pancreatitis (gateway, 2018,154 (6): 1822-1835), parkinson's disease (Nature, 2018,561 (7722):258-262), nonalcoholic fatty liver disease and liver fibrosis (gateway, 2018,155 (6): 1971-1984; PNAS,2017,114 (46): 12196-12201), pneumonia (Nature Communications,2018,9 (1)), chronic nephritis, renal fibrosis (Cell Metolism, 2019, DOI: 10.1016/j.cmet.2019.08.003), and ischemic reperfusion injury (Nature Medicine,2017,23 (12): 1-1487) can significantly inhibit the development of the signal. STING palmitoylation inhibitor H-151 also significantly alleviated the symptoms of progressive freezing (Cell 2020, 183:636-649). Furthermore, the studies of the present inventors showed that STING inhibitor H-151 has a significant efficacy in a murine model of psoriasis (Br J Pharmacol 2021, 178:4907-4922). In conclusion, the development of inhibitors targeting STING proteins has a broad clinical application prospect.
The STING small molecule inhibitors reported in the literature have a very weak activity and poor patentability (Nature 2018,559:269-273;Cell Reports 2018,25,3405-3421;ACS Med.Chem.Lett.2019,10:92-97). The applicant reports a novel STING inhibitor SN-011 (PNAS 2021,118: e2105465118; WO 2021068950) for the first time, however, the activity and the pharmaceutical property of the compound still need to be improved. Thus, there is an urgent clinical need to develop novel STING inhibitors.
Disclosure of Invention
The invention aims to: aiming at the problems existing in the prior art, the invention provides a novel sulfonamide compound or pharmaceutically acceptable salt thereof. The compound of the invention can obviously inhibit the activation of STING signal pathway, thus being used for preparing medicines for preventing or treating STING mediated diseases.
The invention also provides a preparation method, a pharmaceutical composition and medical application of the sulfonamide compound and the intermediate thereof.
The technical scheme is as follows: in order to achieve the above object, the present invention provides sulfonamide compounds represented by the following formula I or pharmaceutically acceptable salts, esters or solvates thereof:
R 1 selected from: H. c (C) 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl;
R 2 selected from: substituted or unsubstituted C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, (CH) 2 ) n OH、(CH 2 ) n NH 2 、(CH 2 ) n C(O)O(CH 2 ) m CH 3 Substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C 3 -C 6 Alicyclic heterocyclic group or substituted or unsubstituted aryl or heteroaryl, wherein the substituted C 1 -C 6 Alkyl is substituted with one of the following substituents: diethanolamino-amino, methanesulfonamido, acetamino, 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-dimethylamino, carboxyl, carboxylate, carboxamide or carbam-amino; the substituted C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl, aryl or heteroaryl is substituted with one or two or three substituents each independently selected from the group consisting of: c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxycarbonyl, C 1 -C 6 Alkylsulfonyl, halogen, CN, NO 2 、NH 2 、OH、CF 3 、OCF 3 、SCF 3 C (O) OH or C (O) NH 2 ；
Wherein R is 2 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 3 selected from: H. halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkyloxy, (CH) 2 ) n OH、(CH 2 ) n C(O)OH、(CH 2 ) n C(O)O(CH 2 ) m CH 3 、OC(O)(CH 2 ) n CH 3 Or (CH) 2 ) n C(O)NH 2 ；
Wherein R is 3 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 4 selected from: H. halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, (CH) 2 ) n OH、(CH 2 ) n C(O)OH、(CH 2 ) n C(O)O(CH 2 ) m CH 3 Or (CH) 2 ) n C(O)NH 2 ；
Wherein R is 4 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 5 and R is 6 Each independently selected from: H. n (CH) 3 ) 2 、N(CH 2 CH 3 ) 2 、CN、NO 2 、CHF 2 、(CH 2 ) n C(O)OH、(CH 2 ) n C(O)O(CH 2 ) m CH 3 、(CH 2 ) n CF 3 、(CH 2 ) n OCF 3 、(CH 2 ) n SCF 3 、S(CH 2 ) l SCF 3 、O(CH 2 ) l SCF 3 、(CH 2 ) n OH、(CH 2 ) n NH 2 、SO 2 CH 3 、SO 2 CF 3 Halogen, pyrrolyl, imidazolyl, triazolyl, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkyloxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino, C 1 -C 6 Alkylsulfonyl radicalsSubstituted or unsubstituted C 3 -C 8 Cycloalkyl or substituted or unsubstituted C 6 Aliphatic heterocyclic group, wherein the substituted C 3 -C 8 Cycloalkyl or C 6 The aliphatic heterocyclic group is substituted with one or two substituents independently selected from the group consisting of: c (C) 1 -C 6 Alkyl or halogen, or, alternatively, adjacent R 5 And R is 6 Together with the atoms to which they are attached may form a benzene ring, C 5 -C 6 Cycloalkane, C 5 -C 6 Alicyclic ring or C 5 -C 6 Aromatic heterocycles;
wherein R is 5 And R is 6 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4; the letter l is selected from: 1-3 any integer;
R 7 、R 8 and R is 9 Each independently selected from: H. CN, NO 2 、CHF 2 、OCHF 2 、(CH 2 ) n C(O)OH、(CH 2 ) n C(O)O(CH 2 ) m CH 3 、(CH 2 ) n CF 3 、(CH 2 ) n OCF 3 、(CH 2 ) n SCF 3 、S(CH 2 ) l SCF 3 、O(CH 2 ) l SCF 3 、(CH 2 ) n OH、(CH 2 ) n NH 2 、SO 2 CH 3 、SO 2 CF 3 Halogen, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkyloxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino, substituted or unsubstituted C 3 -C 8 Cycloalkyl or substituted or unsubstituted C 3 -C 6 A cycloaliphatic group, wherein the substituted C 3 -C 8 Cycloalkyl or C 3 -C 6 The alicyclic groups may each be independently substituted with one or two of the following substituents: OH, NH 2 Halogen, C 1 -C 6 Alkyl, or, adjacent R 7 、R 8 Or R is 9 Wherein at least two substituents, together with the atom to which they are attached, may form C 5 -C 8 Cycloalkane, benzene ring, C 5 -C 6 Aromatic heterocyclic ring, or C 5 -C 6 Aliphatic heterocycles;
wherein R is 7 、R 8 And R is 9 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4; the letter l is selected from: 1 to 3 is an arbitrary integer;
a is selected from: c (C) 3 -C 8 Cycloalkyl, phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, piperidinyl, piperazinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolin-1-one, phthalimido or 3, 4-dihydroisoquinolin-1 (2H) -one;
b is absent or selected from: c (C) 3 -C 8 Cycloalkyl, phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl;
L 1 Selected from:
wherein R is a And R is b Each independently selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 3 -C 6 Alicyclic heterocyclic group or substituted or unsubstituted aryl or heteroaryl, wherein the substituted C 3 -C 6 Cycloalkyl, C 3 -C 6 The alicyclic, aryl or heteroaryl group is substituted with one or two substituents each independently selected from the group consisting of: c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkyloxy, C 1 -C 6 Alkoxycarbonyl, C 1 -C 6 Alkylsulfonyl, halogen, OH, NH 2 、CN、NO 2 、CF 3 、OCF 3 、SCF 3 C (O) OH or C (O) NH 2 ；
L 2 May be absent or selected from:
wherein R is c And R is d Each independently selected from: H. CF (compact flash) 3 Halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Alkyloxy, C 1 -C 6 Alkylthio, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 3 -C 6 A cycloaliphatic or substituted or unsubstituted aryl or heteroaryl group, wherein the substituted C 3 -C 6 Cycloalkyl, C 3 -C 6 The alicyclic, aryl or heteroaryl group is substituted with one or two or three substituents each independently selected from the group consisting of: c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxycarbonyl, C 1 -C 6 Alkylsulfonyl, halogen, OH, NH 2 、CN、NO 2 、CF 3 、OCF 3 、SCF 3 C (O) OH or C (O) NH 2 Alternatively, R's attached to the same carbon atom c Or R is d Can form C together with the atoms to which they are attached 3 -C 6 Cycloalkane or C 3 -C 6 A alicyclic ring;
x is selected from: CH (CH) 2 、O、S、NH、NR e A sulfoxide group or sulfone group;
wherein R is e Selected from: c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl or t-butoxycarbonyl, or R e R on ring A or B 5 、R 6 、R 7 、R 8 Or R is 9 Wherein one substituent, together with the atom to which they are attached, may form C 5 -C 6 A heterocycle;
p and q are each independently selected from: an arbitrary integer of 0 to 4.
In certain preferred embodiments, the sulfonamide compound, or a pharmaceutically acceptable salt or ester or solvate thereof, wherein:
R 1 selected from: H. c (C) 1 -C 3 Alkyl or cyclopropyl;
R 2 selected from: c (C) 1 -C 4 Alkyl, (CH) 2 ) n OH、(CH 2 ) n NH 2 、(CH 2 ) n C(O)O(CH 2 ) m CH 3 、(CH 2 ) n C (O) OH, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 6 A cycloaliphatic or substituted or unsubstituted aryl or heteroaryl group, wherein the cycloaliphatic is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl; the aryl or heteroaryl groups are each independently selected from phenyl, pyridyl, pyrimidinyl, thienyl, furyl or thiazolyl; the substituted C 3 -C 6 Cycloalkyl, alicyclic, aryl or heteroaryl is substituted with one or two or three substituents each independently selected from the group consisting of: c (C) 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, halogen, CN, CF 3 、OCF 3 Or SCF 3 ；
Wherein R is 2 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 3 Selected from: H. halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkyloxy, C 1 -C 3 Alkylamino, (CH) 2 ) n OH、(CH 2 ) n C (O) OH or (CH) 2 ) n C(O)O(CH 2 ) m CH；
Wherein R is 3 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 4 selected from: H. OH, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkyloxy, cyclopropyl, C (O) OCH 3 Or C (O) OH;
R 5 and R is 6 Each independently selected from: H. OH, NH 2 、N(CH 3 ) 2 、N(CH 2 CH 3 ) 2 、C(O)OH、CN、NO 2 、CHF 2 、(CH 2 ) k CF 3 、(CH 2 ) k OCF 3 、(CH 2 ) k SCF 3 、S(CH 2 ) l SCF 3 、O(CH 2 ) l SCF 3 、SO 2 CH 3 、SO 2 CF 3 Halogen, pyrrolyl, imidazolyl, triazolyl, C 1 -C 4 Alkyl, C 1 -C 4 Alkyloxy, C 1 -C 4 Alkylthio, substituted or unsubstituted C 3 -C 8 Cycloalkyl or substituted or unsubstituted C 6 Aliphatic heterocyclic group, wherein, the C 6 The aliphatic heterocyclic group is selected from piperidyl, piperazinyl or morpholinyl; the substituted C 3 -C 8 Cycloalkyl or C 6 The aliphatic heterocyclic group is substituted with one or two substituents each independently selected from the group consisting of: c (C) 1 -C 4 Alkyl or halogen, or, alternatively, adjacent R 5 And R is 6 Can form C together with the atoms to which they are attached 5 -C 6 Aromatic heterocyclic ring, wherein the C 5 -C 6 The aromatic heterocycle is selected from: pyrrole, imidazole, oxazole, thiazole, oxadiazole, pyridine or pyrimidine;
wherein R is 5 And R is 6 K in the substituents is selected from: 0,1 or 2; the letter l is selected from: 1,2 or 3;
R 7 、R 8 and R is 9 Each independently selected from: H. OH, NH 2 、CN、NO 2 、CHF 2 、OCHF 2 、C(O)OH、(CH 2 ) k CF 3 、(CH 2 ) k OCF 3 、(CH 2 ) k SCF 3 、S(CH 2 ) l SCF 3 、O(CH 2 ) l SCF 3 、SO 2 CH 3 、SO 2 CF 3 Halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkyloxy, C 1 -C 4 Alkylthio or C 3 -C 6 Cycloalkyl, or, adjacent R 7 、R 8 Or R is 9 Wherein at least two substituents together with the atoms to which they are attached may form a benzene ring, a cycloalkane, an aromatic heterocycle or a substituted or unsubstituted alicyclic heterocycle, wherein the cycloalkane is selected from cyclopentane or cyclohexane; the aromatic heterocycle is selected from pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyridine or pyrimidine; the alicyclic ring is selected from piperidine, piperazine, morpholine or 1, 4-dioxane; the substituted alicyclic ring may be substituted with one of the following substituents: c (C) 1 -C 3 Alkyl or C 1 -C 3 An alkylsulfonyl group;
wherein R is 7 、R 8 And R is 9 K in the substituents is selected from: 0,1 or 2; the letter l is selected from: 1,2 or 3;
a is selected from: c (C) 3 -C 6 Cycloalkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, indolyl, piperidinyl or piperazinyl;
b is absent or selected from: c (C) 3 -C 8 Cycloalkyl, phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, triazolyl, indolyl, benzoxazolyl, benzothiazolyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl;
L 1 Selected from:
R a and R is b Each independently selected from: H. c (C) 1 -C 3 Alkyl or C 3 -C 6 Cycloalkyl;
L 2 may be absent or selected from:
wherein, when L 2 Is absent, and L 1 The method comprises the following steps:when a is selected from only: />And B is absent;
R c and R is d Each independently selected from: H. f, cl, CF 3 Oxo, C 1 -C 4 Alkyl, C 1 -C 4 Alkyloxy, C 1 -C 4 Alkylthio or C 3 -C 6 Cycloalkyl, or R, attached to the same carbon atom c Or R is d Can form C together with the atoms to which they are attached 3 -C 6 A cycloalkane ring;
x is selected from: CH (CH) 2 、O、S、NH、NR e A sulfoxide group or sulfone group;
R e selected from: c (C) 1 -C 3 Alkyl, C 1 -C 3 Alkylcarbonyl or t-butoxycarbonyl, or R e R on ring A or B 5 、R 6 、R 7 、R 8 Or R is 9 Wherein one substituent, together with the atom to which they are attached, may form C 5 -C 6 A heterocycle, wherein the C 5 -C 6 The heterocycle is selected from: pyrrole, piperidine, pyrrolidone, piperidone, succinimide, glutarimide;
p and q are each independently selected from: an arbitrary integer of 0 to 3.
The invention provides sulfonamide compounds shown in the following formula I or pharmaceutically acceptable salts, esters or solvates thereof:
wherein,
R 1 selected from: H. c (C) 1 -C 3 Alkyl or C 1 -C 3 An alkylcarbonyl group;
R 2 selected from: substituted or unsubstituted C 1 -C 4 Alkyl, cyclopropyl, CF 3 Vinyl, substituted or unsubstituted aryl or heteroaryl, NH 2 、C 1 -C 4 Alkylamino, hydroxy-C 1 -C 3 Alkylamino or morpholinyl, said aryl or heteroaryl being selected from phenyl, naphthyl, pyridinyl, pyrazolyl, furyl or thienyl, said substituted C 1 -C 4 Alkyl is substituted with one or two or three substituents independently selected from the group consisting of: F. cl, NH 2 OH, diethanolamino-amino, 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-dimethylamino, carboxyl, carboxylate, carboxamide or carbamylamino, said substituted aryl or heteroaryl being substituted with one or two substituents independently selected from the group consisting of: c (C) 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxycarbonyl, C 1 -C 3 Alkylsulfonyl, F, cl, br, I, CN, NO 2 、NH 2 、OH、CF 3 、CF 2 CF 3 、OCF 3 、OCF 2 CF 3 C (O) OH or C (O) NH 2 ；
R 3 Selected from: H. OH, halogen, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylcarbonyloxy, C 1 -C 3 Alkoxycarbonyl, (CH) 2 ) n C(O)OH、(CH 2 ) n C(O)NH 2 Or C (O) NHSO 2 CH 3 ；
n is selected from: 0. 1, 2 or 3;
R 4 selected from: H. OH, halogen, C 1 -C 3 Alkyl, COOCH 3 COOH or CONH 2 ；
L 1 Selected from:
R a and R is b Each independently selected from: H. c (C) 1 -C 3 Alkyl, C 3- C 6 Cycloalkyl;
A is selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, cyclohexyl, piperidinyl or piperazinyl;
R 5 and R is 6 Each independently selected from: H. OH, halogen, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 、C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Cycloalkenyl, C 1 -C 6 Heterocycloalkyl, C 1 -C 6 Heterocycloalkenyl, C 1 -C 6 Alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, said substituted phenyl being independently substituted with 1 to 2 substituents: halogen, OH, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 Or C 1 -C 6 Alkylsulfonyl, or, R 5 And R is 6 Together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ringA substituted or unsubstituted heterocycloalkyl ring, or a substituted or unsubstituted heterocycloalkene ring;
L 2 absent or selected from:
x is selected from: C. o, S, NH, sulfoxide or sulfone groups;
p and q are each independently selected from: an arbitrary integer of 0 to 5;
b is selected from: H. halogen CN, OH, NH 2 、NO 2 、CF 3 、CHF 2 、OCF 3 、SCF 3 、C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, substituted or unsubstituted phenyl, naphthyl, pyridinyl, imidazolyl, pyrazolyl, furanyl, or thiophenyl, C 3 -C 8 Cycloalkyl or a 4-7 membered nitrogen-containing heterocycle;
R 7 and R is 8 Each independently selected from: H. OH, halogen, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 、C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Cycloalkenyl, C 1 -C 6 Heterocycloalkyl, C 1 -C 6 Heterocycloalkenyl, C 1 -C 6 Alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, said substituted phenyl being independently substituted with 1 to 2 substituents: halogen, OH, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 Or C 1 -C 6 Alkylsulfonyl, or, R 5 And R is 6 Together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkyl ring, or a substituted or unsubstitutedHeterocyclic olefin rings of (c).
In certain preferred embodiments, the sulfonamide compound, or a pharmaceutically acceptable salt or ester or solvate thereof, wherein:
R 1 selected from: h or C 1 -C 3 An alkyl group;
R 2 selected from: substituted or unsubstituted C 1 -C 4 Alkyl, cyclopropyl, CF 3 Vinyl, substituted or unsubstituted aryl or heteroaryl, hydroxy-C 1 -C 3 An alkylamino or morpholino group selected from phenyl, naphthyl, pyridinyl, pyrazolyl, furanyl or thiophenyl, said substituted aryl or heteroaryl group being substituted with one or two substituents independently selected from: c (C) 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxycarbonyl, C 1 -C 3 Alkylsulfonyl, F, cl, br, I, CN, NO 2 、NH 2 、OH、CF 3 、CF 2 CF 3 、OCF 3 、OCF 2 CF 3 C (O) OH or C (O) NH 2 ；
R 3 Selected from: H. OH, halogen, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Alkoxy or (CH) 2 ) n C(O)OH；
Wherein n is selected from: 0. 1, 2 or 3;
R 4 selected from: H. OH, halogen, C 1 -C 3 Alkyl, COOCH 3 COOH or CONH 2 ；
L 1 Selected from:
R a and R is b Each independently selected from: H. c (C) 1 -C 3 Alkyl or C 3- C 6 Cycloalkyl;
a is selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, cyclohexyl, piperidinyl or piperazinyl;
R 5 and R is 6 Each independently selected from: H. OH, halogen, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、OCF 3 、SCF 3 、C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Heterocycloalkyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, said substituted phenyl being independently substituted with 1 to 2 substituents selected from the group consisting of: halogen, OH, CN, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 Or C 1 -C 6 Alkylsulfonyl, or, R 5 And R is 6 Together with the atoms to which they are attached, may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkyl ring, or a substituted or unsubstituted heterocycloalkene ring;
L 2 Absent or selected from:
x is selected from: C. o, S, NH, sulfoxide or sulfone groups;
p and q are each independently selected from: 0. 1, 2 or 3;
b is selected from: H. halogen CN, OH, NH 2 、NO 2 、CF 3 、CHF 2 、OCF 3 、SCF 3 、C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, substituted or unsubstituted phenyl, naphthyl, pyridyl, imidazolyl, pyrazolyl, furyl, or thienyl, C 3 -C 8 Cycloalkyl or a 4-7 membered nitrogen-containing heterocycle;
R 7 and R is 8 Each independently selected from: H. OH, halogen, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、OCF 3 、SCF 3 、C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Heterocycloalkyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, said substituted phenyl being independently substituted with 1 to 2 substituents selected from the group consisting of: halogen, OH, CN, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 Or C 1 -C 6 Alkylsulfonyl, or, R 5 And R is 6 Together with the atoms to which they are attached, may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkyl ring, or a substituted or unsubstituted heterocycloalkene ring.
In certain more preferred embodiments, the sulfonamide compound, or pharmaceutically acceptable salt or ester or solvate thereof, is selected from any one of table 1 below:
TABLE 1 Structure and nomenclature of Compounds
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The compounds of the present invention may also be used as pharmaceutically acceptable salts. The salt may be an acid salt of at least one of the following acids: galactose diacid, D-glucuronic acid, glycerophosphate, 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-dodecyl sulfuric 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, saccharin acid, salicylic acid, gentisic acid, p-toluenesulfonic acid, valeric acid, palmitic acid, sebacic acid, stearic acid, lauric acid, acetic acid, adipic acid, carbonic acid, benzenesulfonic acid, ethanedisulfonic acid, ethylsuccinic acid, fumaric acid, 3-hydroxynaphthalene-2-carboxylic acid, oleic acid, undecylenic acid, ascorbic acid, camphoric acid, dichloroacetic acid, ethanesulfonic acid. On the other hand, the salt may also be a salt of the compound of the present invention with a metal (including sodium, potassium, calcium, etc.) ion or a pharmaceutically acceptable amine (including ethylenediamine, tromethamine, etc.), ammonium ion or choline.
The compounds of the invention may also be formulated in the form of esters, prodrugs, N-oxides, or solvates thereof as pharmaceutical compositions. The present invention includes all prodrugs of the compounds of the present invention which, upon administration to the human or animal body, are capable of providing (directly or indirectly) the compounds of the present invention or active metabolites or residues thereof. The present invention includes various deuterated forms of the compounds of the present invention. Each available hydrogen atom attached to a carbon atom may be independently substituted with a deuterium atom.
The invention provides application of the compound shown in the formula I or pharmaceutically acceptable salt thereof in preparing medicines for inhibiting the activation of STING signal channels.
The invention provides application of the compound shown in the formula I or pharmaceutically acceptable salt thereof in preparing medicines for preventing or treating STING-mediated diseases.
The STING-mediated diseases include one or more of infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, cancers and precancerous syndromes.
The invention provides application of the compound shown in the formula I or pharmaceutically acceptable salt thereof in preparation of an immunoadjuvant drug.
The invention is based on the crystal structure of C-terminal domain of human STING protein (hSTING-CTD-139-379, PDB:4 EF5), and uses The Glide docking module in 2009, was used for computer-aided drug design and molecular docking studies of active compounds. The docking results show that the sulfonamide compound can inhibit the activation of STING signal pathway by directly combining STING protein and maintaining the dimer conformation in the resting state.
The compounds of the present invention may 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.
The compounds of the present invention may 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, cerebral apoplexy, hemorrhagic encephalopathy, cerebral hemorrhage, cerebral edema, diabetic cardiomyopathy, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy and diabetic ulcer, nonalcoholic fatty liver, nonalcoholic steatohepatitis, alcoholic fatty liver, liver cirrhosis, gout, stroke or cerebral infarction, etc.), musculoskeletal muscle inflammation (inflammation of hands, wrists, elbows, shoulders, necks, knees, ankles and feet, such as osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, acute and chronic infectious arthritis, etc.), ocular inflammation (keratitis, scleritis, conjunctivitis, etc.), digestive system inflammation (colitis, hepatitis, cholangitis, cholecystitis, pancreatitis, gastritis, enteritis, enteropathy, proctitis), 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, emphysema, bronchiolitis obliterans, idiopathic pulmonary fibrosis, cystic fibrosis pulmonary disease), other inflammatory disorders including appendicitis, myocarditis, parotitis, gingivitis, prostatitis, peritonitis, pleurisy, vasculitis, phlebitis, edema.
The compounds of the present invention may be used for the prevention or treatment of autoimmune diseases. Comprising the following steps: ai Kaer Di syndrome (AGS), STING-related vasculitis (SAVI) with childhood onset, retinopathy (RCVL) with brain protein dystrophy, systemic Lupus Erythematosus (SLE), familial lupus Chilblain (CHBL), behcet's disease, chagas's disease, psoriasis, multiple sclerosis, scleroderma, behcet's disease, and the like.
The compounds of the present invention can be used for preventing or treating T cell mediated hypersensitivity reactions having an inflammatory component, including urticaria, skin allergy, allergic rhinitis, contact dermatitis, respiratory allergy, etc.
The compounds of the invention may be used to treat cancers of various tissue 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. Such as 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 myelogenous leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, acute lymphocytic leukemia, multiple myeloma, malignant lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, neuroblastoma.
The compounds of the present invention may be used alone or in combination with other therapeutic agents. As immunomodulators, the compounds of the present invention are useful in monotherapy or in combination with other therapeutic agents for the treatment of STING-mediated disorders, including infectious diseases, inflammatory diseases, autoimmune diseases, cardiovascular and cerebrovascular diseases, cancer and pre-cancerous syndromes.
The invention comprises a pharmaceutical composition for preventing or treating STING-mediated diseases, which contains a therapeutically effective amount of sulfonamide compounds shown in a formula I or pharmaceutically acceptable salts thereof as an active ingredient and pharmaceutically acceptable auxiliary materials. The optionally mixed adjuvants may be changed according to dosage form, administration form, etc. Examples of excipients include excipients, binders, disintegrants, lubricants, flavoring agents, coloring agents or sweeteners, and the like. The pharmaceutical composition can be in the form of conventional preparations such as capsules, powder, tablets, granules, pills, injection, syrup, oral liquid, inhalants, ointments, suppositories or patches.
The compounds of the present invention may be prepared by reference to the methods and synthetic routes described in the examples, or by modified methods.
The beneficial effects are that: compared with the prior art, the invention has the following advantages:
(1) The sulfonamide compound synthesized by the novel design is a novel STING inhibitor, and has the characteristics of strong STING inhibition activity and good patentability.
(2) The compound can be used for preparing medicines for inhibiting the activation of STING signal channels and medicines for preventing or treating STING mediated diseases, and has good effects on treating infectious diseases, inflammatory diseases, autoimmune diseases, organ fibrosis diseases, cancers or cancer stage syndromes.
(3) The compound has the advantages of simple structure, ingenious design of synthetic route, cheap and easily available raw materials, safe and environment-friendly synthetic process and easy mass production.
Drawings
FIG. 1 is a graph showing the effect of compounds B-80, C-22, C-51, D-60, D-75 and D-88 on the model of psoriasis in mice caused by imiquimod cream.
Detailed Description
The following is a detailed description of the present invention by way of examples. In the present invention, the following examples are given for better illustration of the present invention and are not intended to limit the scope of the present invention. Various changes and modifications can be made to the present invention without departing from the spirit and scope of the invention.
The materials and equipment used in the embodiments of the present invention are all known products and are commercially available.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR was performed using a (Bruker) nuclear magnetic resonance apparatus with deuterated dimethyl sulfoxide (DMSO-d) 6 ) Deuterated chloroform (CDCl) 3 ) Deuterated Acetone (Acetone-d) 6 ) The internal standard is Tetramethylsilane (TMS).
Column chromatography generally uses 200-300 mesh silica gel from Qingdao ocean chemical plant as carrier.
The known starting materials of the present invention may be synthesized using or according to methods known in the art, or may be purchased from Adamas, leaching, pichia, allatin, an Naiji, and the like.
Example 1
4-cyclopentyl-N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (Compound A-1)
Synthesis of intermediate I-1
2-amino-4-nitrophenol (1 g,6.49 mmol) and pyridine (1.5 mL,19.47 mmol) were added to dichloromethane (10 mL), and 4-fluorobenzenesulfonyl chloride (1.4 g,7.27 mmol) was added dropwise, with ice, as dichloroMethane (5 mL) solution, after the addition of the solution, was allowed to react at room temperature for 8 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate (20 mL) and a 2N aqueous hydrogen chloride solution (10 mL) were added, shaking and separating the liquid, and the organic phase was washed with a 1N aqueous hydrogen chloride solution (10 mL x 1), water (10 mL x 1), saturated brine (10 mL x 1) in this order, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was purified by beating (dichloromethane), and the obtained solid was dried to constant weight to give intermediate I-1 (yellow solid, 1.46 g): 1 H NMR(300MHz,DMSO-d 6 )δ11.35(s,1H),9.97(s,1H),8.05(d,J＝2.8Hz,1H),7.93(dd,J＝9.0,2.8Hz,1H),7.87-7.77(m,2H),7.39(t,J＝8.9Hz,2H),6.90(d,J＝9.0Hz,1H).ESI-MS:m/z 311.0[M-H] - .
Synthesis of intermediate I-2
Intermediate I-1 (1.46 g,4.68 mmol) and 10% palladium on carbon (300 mg) were added to a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the solvent was distilled off from the filtrate under reduced pressure to obtain a crude intermediate I-2 which was used directly in the next reaction without further purification.
Synthesis of intermediate I-3
Intermediate I-15 (14.0 g,49.59 mmol) and N, N-diisopropylethylamine (4.1 g,59.51 mmol) were added to dichloromethane (150 mL), a solution of t-butyldimethylchlorosilane (9.0 g,59.51 mmol) in dichloromethane (50 mL) was added dropwise under ice water, and the mixture was allowed to react at room temperature for 12 hours. Dichloromethane (100 mL) was added for dilution, water (50 mL x 2) was washed, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=4:1) to give intermediate I-3 (off-white solid, 19.4 g): 1 H NMR(300MHz,DMSO-d 6 )δ8.58(s,1H),7.79(dd,J＝8.8,5.2Hz,2H),7.40(t,J＝8.9Hz,2H),6.53(d,J＝8.6Hz,1H),6.37(d,J＝2.6Hz,1H),6.25(dd,J＝8.6,2.7Hz,1H),4.71(s,2H),0.90(s,9H),0.07(s,6H).ESI-MS:m/z 395.1[M-H] - .
synthesis of intermediate I-4
Cyclopenten-1-ylboronic acid (224 mg,2 mmol), potassium carbonate (276 mg,2 mmol) and tetrakis (triphenylphosphine) palladium (58 mg,0.1 mmol) were added toIn a Schlenk tube, a solution of ethyl 4-bromobenzoate (229 mg,1 mmol) in 1, 4-dioxane (4 mL) and water (0.4 mL) was added under argon and reacted at 100℃for 8 hours. After the reaction was completed, the system was cooled to room temperature, the solvent was distilled off under reduced pressure, diluted with water (15 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and 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(300MHz,CDCl 3 )δ8.00(d,J＝8.3Hz,2H),7.49(d,J＝8.2Hz,2H),6.34(s,1H),4.39(dd,J＝14.2,7.1Hz,2H),2.81-2.71(m,2H),2.59(d,J＝7.2Hz,2H),2.15-2.00(m,2H),1.41(t,J＝7.1Hz,3H).
Synthesis of intermediate I-5
Intermediate I-4 (205 mg,0.95 mmol) and 10% palladium on carbon (40 mg) were added to methanol (2 mL) and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the solvent was distilled off from the filtrate under reduced pressure to obtain crude intermediate I-5, which was used in the next reaction without further purification.
Synthesis of intermediate I-6
The crude intermediate I-5 was dissolved in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (1.5 mL), and 1M aqueous sodium hydroxide solution (1.5 mL) was added thereto, followed by reaction at 60℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride was added to adjust the pH to 1 to 2, ethyl acetate (10 ml x 3) was used for extraction, the organic phases were combined, washed with saturated brine (10 ml x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate I-6 (white solid, 113 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.74(s,1H),7.86(d,J＝8.2Hz,2H),7.37(d,J＝8.1Hz,2H),3.09-2.99(m,1H),2.08-1.98(m,2H),1.82-1.72(m,2H),1.70-1.61(m,2H),1.59-1.48(m,2H).ESI-MS:m/z 189.1[M-H] - .
synthesis of intermediate I-7
Intermediate I-6 (50 mg,0.26 mmol) and N, N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), oxalyl chloride (33. Mu.L, 0.39 mmol) was slowly added dropwise under ice-bath, and the drops were completedThe reaction mixture was warmed to room temperature and allowed to react for 4 hours. After the completion of 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 acid chloride, which was added under ice-bath conditions to a solution of I-3 (115 mg,0.29 mmol) and pyridine (31. Mu.L, 0.39 mmol) in tetrahydrofuran (1 mL), and reacted at room temperature for 6 hours. After the reaction was completed, 2N aqueous hydrogen chloride was added to the reaction solution to adjust the pH to 3 to 4, ethyl acetate (5 ml x 3) was extracted, the organic phases were combined, washed with water (10 ml x 1) and saturated brine (10 ml x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate I-7 (white solid, 123 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.06(s,1H),9.04(s,1H),7.89-7.78(m,4H),7.65(d,J＝2.7Hz,1H),7.50-7.36(m,5H),6.83(d,J＝8.8Hz,1H),3.10-3.01(m,1H),2.14-2.02(m,2H),1.84-1.74(m,2H),1.72-1.52(m,4H),0.93(s,9H),0.14(s,6H).
Synthesis of Compound A-1
Intermediate I-7 (107 mg,0.19 mmol) and triethylamine trihydrofluoride (50. Mu.L, 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, filtered, and the cake was washed (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(300MHz,DMSO-d 6 )δ9.98(s,1H),9.33(s,2H),7.87-7.80(m,4H),7.66(d,J＝2.4Hz,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 FN 2 O 4 S[M+H] + 455.1435,found 455.1437.
example 2
4-cyclohexyl-N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (Compound A-2)
Synthesis of Compound A-2
Referring to the procedure of example 1, substituting intermediate I-6 with 4-cyclohexylbenzoic acid produced compound A-2: 1 H NMR(300MHz,DMSO-d 6 )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＝8.7Hz,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 FN 2 O 4 S[M+H] + 469.1592,found 469.1622.
example 3
4- (4, 4-Difluorocyclohexyl) -N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (compound A-3)
Synthesis of intermediate I-8
Partolylsulfonyl hydrazine (268 mg,2 mmol) is added to methanol (4 mL), the temperature is raised to 60℃to dissolve the tosyl hydrazide, 4-difluorocyclohexanone (369 mg,2 mmol) is added in portions, and the reaction is continued for 1 hour at 60 ℃. After the reaction, the system was cooled to room temperature, and the solvent was distilled off under reduced pressure to give crude compound I-8, which was used directly in the next reaction without further purification.
Synthesis of intermediate I-9
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, protected by argon, and suspended in 1, 4-dioxane (3 mL) and allowed to react at 110℃for 8 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered off with suction, the filter cake was washed with ethyl acetate (5 mL), the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate I-9 (colorless oily liquid, 149 mg): 1 H NMR(300MHz,CDCl 3 )δ8.00(d,J＝8.2Hz,2H),7.31(d,J＝8.3Hz,2H),3.93(s,3H),2.68(dd,J＝13.9,6.7Hz,1H),2.29-2.20(m,2H),1.99-1.94(m,2H),1.93-1.86(m,2H),1.86-1.80(m,2H).
synthesis of intermediate I-10
Intermediate I-9 (129 mg,0.51 mmol) was dissolved in a mixture of methanol (1.5 mL) and tetrahydrofuran (1.5 mL)1M aqueous sodium hydroxide (1.5 mL) was added and the mixture was allowed to react at 60℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the solvent organic phase was distilled off under reduced pressure, 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust pH to 1 to 2, solids were precipitated, suction filtration was performed, the cake was washed with water (2 mL) and N-hexane (2 mL), infrared drying was performed to constant weight, to obtain intermediate I-10 (white solid, 82 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.74(s,1H),7.86(d,J＝8.2Hz,2H),7.37(d,J＝8.1Hz,2H),3.09-2.99(m,1H),2.08-1.98(m,2H),1.82-1.72(m,2H),1.70-1.61(m,2H),1.59-1.48(m,2H).ESI-MS:m/z 189.1[M-H] - .
synthesis of Compound A-3
Referring to the procedure of example 1, substituting intermediate I-6 for intermediate I-10 produced compound A-3: 1 H NMR(300MHz,DMSO-d 6 )δ10.03(s,1H),9.41(s,1H),9.34(s,1H),7.90-7.80(m,4H),7.69(d,J＝1.8Hz,1H),7.43-7.34(m,5H),6.69(d,J＝8.7Hz,1H),2.80(t,J＝11.7Hz,1H),2.19-2.02(m,3H),1.91(d,J＝12.2Hz,3H),1.77-1.64(m,2H).HRMS(ESI)calcd.for C 25 H 23 F 3 N 2 O 4 S[M+H] + 505.1403,found 505.1404.
example 4
4- (4, 4-dimethylcyclohexyl) -N- (3- ((4-fluorophenyl) sulphonamido) -4-hydroxyphenyl) benzamide (Compound A-4)
Synthesis of Compound A-4
Referring to the procedure of example 3, 4-difluorocyclohexanone was replaced with 4, 4-dimethylcyclohexanone to produce compound a-4: 1 H NMR(300MHz,DMSO-d 6 )δ9.99(s,1H),9.35(s,2H),7.87-7.79(m,4H),7.67(d,J＝2.4Hz,1H),7.40(d,J＝1.7Hz,2H),7.37(d,J＝2.2Hz,2H),7.33(s,1H),6.68(d,J＝8.7Hz,1H),2.49-2.45(m,1H),1.68-1.59(m,4H),1.47(d,J＝12.2Hz,2H),1.38-1.27(m,2H),0.99(s,3H),0.95(s,3H).HRMS(ESI)calcd.for C 27 H 29 FN 2 O 4 S[M+H] + 497.1905,found 497.1898.
example 5
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (1H-imidazol-1-yl) benzamide (Compound A-5)
Synthesis of intermediate I-11
Imidazole (442 mg,6.49 mmol) was added to N, N-dimethylformamide (7 mL), methyl 4-fluorobenzoate (500 mg,3.24 mmol) and potassium carbonate (897 mg,6.49 mmol) were added in this order, and the mixture was reacted at 100℃for 10 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was poured into ice water (70 mL) to quench, ethyl acetate (15 ml×3) was extracted, and the organic phases were combined, washed with water (20 ml×1) and saturated brine (20 ml×1) in this order, and the solvent was distilled off under reduced pressure to obtain crude intermediate I-11 which was used in the next reaction without further purification.
Synthesis of intermediate I-12
The crude intermediate I-11 was dissolved in a mixed solvent of tetrahydrofuran (5 mL) and methanol (5 mL), and 1M aqueous sodium hydroxide solution (5 mL) was added thereto, followed by reaction at 60℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, 6N aqueous hydrogen chloride was added dropwise to the reaction solution to adjust the pH to 6 to 7, solids were precipitated, and the mixture was filtered, the cake was washed with water (5 mL) and dichloromethane (5 mL) in this order, and the residue was purified by beating (dichloromethane/methanol=20:1), and the obtained solid was dried to constant weight to give intermediate I-12 (white solid, 287 mg): 1 H NMR(300MHz,DMSO-d 6 )δ13.14(s,1H),8.42(s,1H),8.06(d,J＝8.5Hz,2H),7.88(s,1H),7.82(d,J＝8.5Hz,2H),7.16(s,1H).ESI-MS:m/z 187.1[M-H] - .
Synthesis of intermediate I-13
Intermediate I-12 (50 mg,0.27 mmol) was added to tetrahydrofuran (2 mL), N, N-diisopropylethylamine (88. Mu.L, 0.53 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (152 mg,0.40 mmol) were added under ice-bath, and a solution of intermediate I-3 (111 mg,0.28 mmol) in tetrahydrofuran (1 mL) was added dropwise after the addition was completed and allowed to react for 1 hour at room temperatureThe reaction was continued at room temperature for 6 hours. After the completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (5 ml×3), the organic phases were combined, washed with saturated brine (5 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=75:1) to give intermediate I-13 (pale yellow solid, 62.4 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),9.10(s,1H),8.42(s,1H),8.05(d,J＝8.6Hz,2H),7.89(s,1H),7.86-7.77(m,4H),7.67(d,J＝2.4Hz,1H),7.48(dd,J＝8.8,2.5Hz,1H),7.40(t,J＝8.8Hz,2H),7.15(s,1H),6.84(d,J＝8.8Hz,1H),0.91(s,9H),0.12(s,6H).ESI-MS:m/z 565.2[M-H] - .
synthesis of Compound A-5
Referring to the procedure of example 1, substituting intermediate I-7 for intermediate I-13 produced compound A-5: 1 H NMR(300MHz,DMSO-d 6 )δ10.16(s,1H),9.43(s,1H),8.43(s,1H),8.09(d,J＝8.6Hz,2H),7.90(s,1H),7.87-7.79(m,4H),7.71(d,J＝2.3Hz,1H),7.44-7.34(m,3H),7.16(s,1H),6.71(d,J＝8.7Hz,1H).HRMS(ESI)calcd.for C 22 H 17 FN 4 O 4 S[M+H] + 453.1027,found453.1048.
example 6
5-fluoro-N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -1H-indole-3-carboxamide (Compound A-6)
Synthesis of intermediate I-14
5-fluoroindole (270 mg,2 mmol) was dissolved in N, N-dimethylformamide (4 mL), and trifluoroacetic anhydride (TFAA) (1.11 mL,8 mmol) was added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 4 hours. After the reaction, the reaction solution is poured into ice water (20 mL) to quench superfluous trifluoroacetic anhydride, solid is separated out, the solution is filtered, and a filter cake is washed by water (5 mL) to obtain a crude intermediate I-14 which is directly used for the next reaction without further purification
Synthesis of intermediate I-15
Suspension of crude intermediate I-14 in 20% aqueous sodium hydroxide (4 mL)The reaction was continued for 4 hours at 100 ℃. After the reaction was completed, the system was cooled to room temperature, ethyl acetate (5 mL) was added to the reaction solution to separate the organic phase impurities, then a 2N aqueous hydrogen chloride solution was added to adjust the pH to 1 to 2, ethyl acetate (5 ml×3) was extracted, the organic phases were combined, washed with saturated brine (5 ml×1), the solvent was distilled off under reduced pressure, the residue was purified by beating (diethyl ether), and the obtained solid was dried to constant weight to obtain intermediate I-15 (white solid, 178.9 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.04(s,1H),11.93(s,1H),8.07(d,J＝3.0Hz,1H),7.65(dd,J＝10.0,2.5Hz,1H),7.48(dd,J＝8.8,4.6Hz,1H),7.04(td,J＝9.2,2.6Hz,1H).ESI-MS:m/z 178.0[M-H] - .
synthesis of Compound A-6
Referring to the procedure of example 1, substituting intermediate I-6 for intermediate I-15 produced compound A-6: 1 H NMR(300MHz,DMSO-d 6 )δ12.85(s,1H),7.87(d,J＝8.1Hz,2H),7.62(d,J＝8.3Hz,2H),7.44(dd,J＝13.7,8.3Hz,4H),3.37(t,J＝7.2Hz,2H),3.00(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 21 H 15 F 2 N 3 O 4 S[M+H] + 444.0824,found 444.0827.
example 7
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((trifluoromethyl) thio) benzamide (Compound A-7)
Synthesis of intermediate I-16
2-amino-4-nitrophenol (1.5 g,9.73 mmol) and pyridine (1.2 mL,14.60 mmol) were added to dichloromethane (30 mL), a solution of methylsulfonyl chloride (904. Mu.L, 11.68 mmol) in dichloromethane (10 mL) was added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 8 hours. After the completion of the reaction, excess pyridine and methylsulfonyl chloride were quenched by adding concentrated hydrochloric acid (1 mL), the solvent was distilled off under reduced pressure, the residue was added with a 1N aqueous hydrogen chloride solution (30 mL), ethyl acetate (20 mL. Times.3) was extracted, and the organic phases were combined, washed successively with a 1N aqueous hydrogen chloride solution (10 mL. Times.1), water (10 mL. Times.1), saturated brine (10 mL. Times.1), and under reduced pressure The solvent was distilled off, and to the residue was added ethanol (10 mL) for dissolution, followed by addition of a solution of sodium hydroxide (480 mg,12 mmol) in water (10 mL), and the mixture was reacted at 60℃for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2-3, solids were precipitated, and the mixture was filtered, and the cake was washed with water (5 mL) and methylene chloride (5 mL) in this order, and the residue was purified by beating (methylene chloride/methanol=100:1), and the obtained solid was dried to constant weight to give intermediate I-16 (yellow solid, 1.54 g): 1 H NMR(300MHz,DMSO-d 6 )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).
synthesis of intermediate I-17
Intermediate I-16 (1.54 g,6.63 mmol) and 10% palladium on carbon (210 mg) were added to a mixed solvent of methanol (15 mL) and tetrahydrofuran (15 mL), and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (20 mL), and the solvent was distilled off from the filtrate under reduced pressure to obtain crude intermediate I-17, which was used in the next reaction without further purification.
Synthesis of intermediate I-18
Crude intermediate I-17 and N, N-diisopropylethylamine (1.65 mL,10 mmol) were added to dichloromethane (20 mL), a solution of t-butyldimethylchlorosilane (1.3 g,8.62 mmol) in dichloromethane (15 mL) was added dropwise under ice-water bath, and the mixture was allowed to react at room temperature for 12 hours. After the reaction was completed, a saturated sodium hydrogencarbonate solution (30 mL) was added to the reaction solution for dilution, dichloromethane (20 ml×3) was extracted, the organic phases were combined, saturated brine (30 ml×1) was washed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=4:1) to give intermediate I-18 (brown solid, 1.2 g): 1 H NMR(300MHz,DMSO-d 6 )δ8.58(s,1H),7.79(dd,J＝8.8,5.2Hz,2H),7.40(t,J＝8.9Hz,2H),6.53(d,J＝8.6Hz,1H),6.37(d,J＝2.6Hz,1H),6.25(dd,J＝8.6,2.7Hz,1H),4.71(s,2H),0.90(s,9H),0.07(s,6H).ESI-MS:m/z 395.1[M-H] - .
Synthesis of intermediate I-19
4-Trifluoromethylthiobenzoic acid (40 mg,0.18 mmol) and N, N-dimethylformamide (2 drops) are added to the anhydrousOxalyl chloride (23 μl,0.27 mmol) was slowly added dropwise to tetrahydrofuran (3 mL) under ice bath, and the mixture was allowed to react at room temperature for 4 hours. After the completion of 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 acid chloride, which was added to a solution of I-18 (63 mg,0.20 mmol) and pyridine (22. Mu.L, 0.27 mmol) in tetrahydrofuran (1 mL) under ice-bath conditions, and reacted at room temperature for 6 hours. After the reaction was completed, 2N aqueous hydrogen chloride was added to the reaction solution to adjust the pH to 3 to 4, ethyl acetate (5 ml x 3) was extracted, the organic phases were combined, washed with water (10 ml x 1) and saturated brine (10 ml x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate I-19 (white solid, 54 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.38(s,1H),8.48(s,1H),8.04(d,J＝8.3Hz,2H),7.87(d,J＝8.2Hz,2H),7.76(d,J＝2.6Hz,1H),7.56(dd,J＝8.8,2.6Hz,1H),6.94(d,J＝8.8Hz,1H),3.04(s,3H),1.00(s,9H),0.25(s,6H).
synthesis of Compound A-7
Intermediate I-19 (48 mg,0.09 mmol) and triethylamine trihydrofluoride (23. Mu.L, 0.14 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, filtered, and the cake was washed (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(300MHz,DMSO-d 6 )δ10.29(s,1H),9.18(s,2H),8.04(d,J＝8.3Hz,2H),7.86(d,J＝8.2Hz,2H),7.63(d,J＝2.4Hz,1H),7.50(dd,J＝8.7,2.4Hz,1H),6.87(d,J＝8.7Hz,1H),2.97(s,3H).HRMS(ESI)calcd.for C 15 H 13 F 3 N 2 O 4 S 2 [M+H] + 407.0342,found 407.0345.
Example 8
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (trifluoromethoxy) benzamide (Compound A-8)
Synthesis of Compound A-8
Reference to example 7The method comprises the steps of replacing 4-trifluoromethylthiobenzoic acid with 4-trifluoromethoxybenzoic acid to obtain a compound A-8: 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),9.67(s,1H),8.79(s,1H),8.07(d,J＝8.7Hz,2H),7.63(d,J＝2.1Hz,1H),7.56-7.46(m,3H),6.87(d,J＝8.7Hz,1H),2.98(s,3H).HRMS(ESI)calcd.for C 15 H 13 F 3 N 2 O 5 S[M+H] + 391.0570,found 391.0575.
example 9
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (trifluoromethyl) benzamide (Compound A-9)
Synthesis of Compound A-9
Referring to the procedure of example 7, the substitution of 4-trifluoromethylthiobenzoic acid with 4-trifluoromethylbenzoic acid gives compound A-9: 1 H NMR(300MHz,DMSO-d 6 )δ10.32(s,1H),9.68(s,1H),8.78(s,1H),8.13(d,J＝8.1Hz,2H),7.89(d,J＝8.2Hz,2H),7.64(d,J＝2.1Hz,1H),7.51(dd,J＝8.8,2.2Hz,1H),6.88(d,J＝8.7Hz,1H),2.97(s,3H).HRMS(ESI)calcd.for C 15 H 13 F 3 N 2 O 4 S[M+H] + 375.0621,found 375.0636.
example 10
4- (difluoromethyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound A-10)
Synthesis of Compound A-10
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid with 4-difluoromethylbenzoic acid produced compound a-10: 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),9.19(s,2H),8.06(d,J＝7.9Hz,2H),7.71(d,J＝7.9Hz,2H),7.64(d,J＝2.1Hz,1H),7.50(dd,J＝8.7,2.1Hz,1H),7.12(t,J＝55.7Hz,1H),6.87(d,J＝8.7Hz,1H),2.97(s,3H).HRMS(ESI)calcd.for C 15 H 14 F 2 N 2 O 4 S[M+H] + 357.0715,found 357.0706.
example 11
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4-isopropylbenzamide (Compound A-11)
Synthesis of Compound A-11
Referring to the procedure of example 7, the substitution of 4-trifluoromethylthiobenzoic acid for 4-isopropylbenzoic acid gives compound a-11: 1 H NMR(300MHz,DMSO-d 6 )δ10.04-9.97(m,2H),8.06(s,0H),7.86(d,J＝8.2Hz,2H),7.62(d,J＝2.5Hz,1H),7.48(dd,J＝8.7,2.6Hz,1H),7.37(d,J＝8.2Hz,2H),6.85(d,J＝8.7Hz,1H),3.05-2.88(m,1H),2.97(s,3H),1.23(d,J＝6.9Hz,6H).HRMS(ESI)calcd.for C 17 H 20 N 2 O 4 S[M+H] + 349.1217,found 349.1221.
example 12
4-bromo-N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (compound A-12)
Synthesis of Compound A-12
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid for 4-bromobenzoic acid produced compound a-12: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.71(s,1H),8.73(s,1H),7.89(d,2H),7.73(d,2H),7.61(d,J＝2.5Hz,1H),7.49(dd,J＝8.7,2.5Hz,1H),6.86(d,J＝8.7Hz,1H),2.97(s,3H).HRMS(ESI)calcd.for C 14 H 13 BrN 2 O 4 S[M+H] + 384.9852,found 384.9849.
example 13
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4-propylbenzamide (Compound A-13)
Synthesis of Compound A-13
Referring to the procedure of example 1, substituting 4-trifluoromethylthiobenzoic acid for 4-propylbenzoic acid produced compound a-13: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(s,1H),9.47(s,1H),8.86(s,1H),7.86(d,J＝8.2Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.32(d,J＝8.3Hz,2H),6.85(d,J＝8.7Hz,1H),2.97(s,3H),2.63(t,J＝7.6Hz,2H),1.62(h,J＝7.2Hz,2H),0.90(t,J＝7.3Hz,3H).ESI-MS:m/z 349.1219[M+H] + .HRMS(ESI)calcd.for C 17 H 20 N 2 O 4 S[M+H] + 349.1217,found 349.1219.
example 14
4-cyclopropyl-N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound A-14)
Synthesis of Compound A-14
Referring to the procedure of example 7, the substitution of 4-trifluoromethylthiobenzoic acid with 4-cyclopropylbenzoic acid gives compound a-14: 1 H NMR(300MHz,DMSO-d 6 )δ9.98(s,1H),9.11(s,2H),7.84(d,J＝8.1Hz,2H),7.62(d,J＝2.1Hz,1H),7.49(dd,J＝8.7,2.1Hz,1H),7.19(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),2.97(s,3H),2.05-1.95(m,1H),1.06-0.98(m,2H),0.80-0.72(m,2H).HRMS(ESI)calcd.for C 17 H 18 N 2 O 4 S[M+H] + 347.1060,found 347.1065.
example 15
4-cyclopentyl-N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound A-15)
Synthesis of Compound A-15
Referring to the procedure of example 7, the substitution of 4-trifluoromethylthiobenzoic acid for intermediate I-6 gives compound A-15: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(s,1H),9.35(s,1H),9.06(s,1H),7.86(d,J＝8.2Hz,2H),7.63(d,J＝2.4Hz,1H),7.49(dd,J＝8.7,2.4Hz,1H),7.38(d,J＝8.2Hz,2H),6.85(d,J＝8.7Hz,1H),3.11-3.01(m,1H),2.98(s,3H),2.14-1.99(m,2H),1.85-1.73(m,2H),1.73-1.49(m,4H).HRMS(ESI)calcd.for C 19 H 22 N 2 O 4 S[M+H] + 375.1373,found375.1378.
example 16
4- (4, 4-Difluorocyclohexyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound A-16)
Synthesis of Compound A-16
Referring to the procedure of example 7, the substitution of 4-trifluoromethylthiobenzoic acid for intermediate I-10 gives compound A-16: 1 H NMR(300MHz,DMSO-d 6 )δ10.03(s,1H),9.67(s,1H),8.70(s,1H),7.88(d,J＝8.2Hz,2H),7.63(d,J＝2.3Hz,1H),7.49(dd,J＝8.7,2.4Hz,1H),7.39(d,J＝8.2Hz,2H),6.85(d,J＝8.7Hz,1H),2.97(s,3H),2.84-2.75(m,1H),2.20-2.01(m,4H),1.92-1.88(m,2H),1.76-1.65(m,2H).HRMS(ESI)calcd.for C 20 H 22 F 2 N 2 O 4 S[M+H] + 425.1341,found 425.1340.
example 17
4-cycloheptyl-N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound A-17)
Synthesis of intermediate I-20
Potassium carbonate (509 mg,4.8 mmol) was added to a dry three-necked flask under argon, a solution of cycloheptanone (353. Mu.L, 3 mmol) in anhydrous dichloromethane (10 mL) was added, and a solution of trifluoromethanesulfonic anhydride (1 mL,6 mmol) in anhydrous dichloromethane (5 mL) was slowly added to react at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was quenched with saturated sodium bicarbonate solution (10 mL), extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, washed with saturated brine (10 mL. Times.1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate I-20 (colorless oily liquid, 509 mg).
Synthesis of intermediate I-21
4-Methoxycarbonylphenylboronic acid (433 mg,2.4 mmol), sodium carbonate (680 mg,5 mmol) and tetrakis (triphenylphosphine) palladium (116 mg,0.1 mmol) were added to the reaction flask under argon, followed by a toluene (10 mL) solution of intermediate I-20 (488 mg,2 mmol), water (5 mL) and methanol (5 mL) and stirred under reflux for 8 hours. After the reaction was completed, water (15 mL) was added to the reaction mixture to dilute it, ethyl acetate (10 mL x 3) was used for extraction, the organic phases were combined, saturated brine (10 mL x 1) was used for washing, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give a crude intermediate I-21.
Synthesis of Compound A-17
Referring to the procedure of example 1, substituting intermediate I-5 for crude intermediate I-21 and intermediate I-3 for intermediate I-18 produced compound A-17: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(s,1H),9.35(s,1H),9.06(s,1H),7.86(d,J＝8.2Hz,2H),7.63(d,J＝2.4Hz,1H),7.49(dd,J＝8.7,2.4Hz,1H),7.38(d,J＝8.2Hz,2H),6.85(d,J＝8.7Hz,1H),3.11-3.01(m,1H),2.98(s,3H),2.14-1.99(m,2H),1.85-1.73(m,2H),1.73-1.49(m,4H).HRMS(ESI)calcd.for C 21 H 26 N 2 O 4 S[M+H] + 403.1686,found 403.1689.
example 18
4- (diethylamino) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound A-18)
Synthesis of Compound A-18
With reference to the procedure of example 7, 4-trifluormet powderReplacement of thiobenzoic acid with 4- (N, N-diethylamino) -benzoic acid gives compound a-18: 1 H NMR(300MHz,DMSO-d 6 )δ9.71(s,1H),9.60(s,1H),8.65(s,1H),7.84(d,J＝8.4Hz,2H),7.61(d,J＝2.5Hz,1H),7.47(dd,J＝8.7,2.2Hz,1H),6.83(d,J＝8.8Hz,2H),6.73(d,J＝15.1Hz,1H),3.49-3.35(m,4H),2.96(s,3H),1.11(t,J＝6.9Hz,6H).HRMS(ESI)calcd.for C 18 H 23 N 3 O 4 S[M+H] + 378.1488,found 378.1494.
example 19
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4-methylpiperazin-1-yl) benzamide (Compound A-19)
Synthesis of Compound A-19
Referring to the procedure of example 7, the substitution of 4-trifluoromethylthiobenzoic acid with 4- (4-methylpiperazine) benzoic acid gives compound a-19: 1 H NMR(300MHz,DMSO-d 6 )δ9.82(s,1H),9.63(s,1H),8.68(s,1H),7.88(d,J＝8.4Hz,2H),7.61(d,J＝2.5Hz,1H),7.48(dd,J＝8.7,2.5Hz,1H),7.04(d,J＝8.7Hz,2H),6.84(d,J＝8.7Hz,1H),3.48-3.37(m,4H),2.97(s,3H),2.94-2.80(m,4H),2.55(s,3H).HRMS(ESI)calcd.for C 19 H 24 N 4 O 4 S[M+H] + 405.1591,found 405.1594.
example 20
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (piperidin-1-yl) benzamide (compound A-20)
Synthesis of Compound A-20
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid for 4-piperazine benzoic acid produced compound a-20: 1 H NMR(300MHz,DMSO-d 6 )δ9.76(s,1H),9.60(s,1H),8.66(s,1H),7.83(d,J＝8.5Hz,2H),7.60(d,J＝2.5Hz,1H),7.47(dd,J＝8.8,2.6Hz,1H),6.96(d,J＝8.6Hz,2H),6.83(d,J＝8.7Hz,1H),3.31-3.28(m,4H),2.97(s,3H),1.63-1.56(m,6H).ESI-MS:m/z390.1486[M+H] + .HRMS(ESI)calcd.for C 19 H 23 N 3 O 4 S[M+H] + 390.1482,found 390.1486.
example 21
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4-morpholinobenzamide (Compound A-21)
Synthesis of Compound A-21
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid for 4-morpholinylbenzoic acid produced compound a-21: 1 H NMR(300MHz,DMSO-d 6 )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.for C 18 H 21 N 3 O 5 S[M+H] + 392.1275,found 392.1277.
Example 22
4- (4, 4-Dihalopiperidin-1-yl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (compound A-22)
Synthesis of intermediate I-22
4, 4-Dihaloperidol hydrochloride (158 mg,1 mmol) and triethylamine (416. Mu.L, 3 mmol) were added to anhydrous dichloromethane (4 mL), stirred at room temperature for 10 min, followed by the sequential addition of p-methoxycarbonylphenylboronic acid (360 mg,2 mmol), anhydrous copper acetate (362 mg,2 mmol),Molecular sieves (1.5 g) and pyridine (161. Mu.L, 2 mmol) were reacted at room temperature for 10 hours after addition. After the reaction was completed, the reaction solution was filtered through celite, the solvent was distilled off 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): 1 H NMR(300MHz,Chloroform-d)δ7.93(d,J＝8.7Hz,2H),6.89(d,J＝8.6Hz,2H),3.87(s,3H),3.51(t,J＝5.8Hz,4H),2.07(tt,J＝13.3,5.7Hz,4H).
synthesis of Compound A-22
Referring to the procedure of example 1, substituting intermediate I-5 for intermediate I-22 and substituting intermediate I-3 for intermediate I-18 produced compound A-22: 1 H NMR(300MHz,DMSO-d 6 )δ9.82(s,1H),9.43(s,1H),8.73(s,1H),7.86(d,2H),7.61(d,J＝2.5Hz,1H),7.47(dd,J＝8.8,2.5Hz,1H),7.07(d,J＝8.6Hz,2H),6.83(d,J＝8.7Hz,1H),3.49(t,J＝5.8Hz,4H),2.97(s,3H),2.11-1.96(m,4H).HRMS(ESI)calcd.for C 19 H 21 F 2 N 3 O 4 S[M+H] + 426.1294,found 426.1328.
example 23
4' -fluoro-N- (3- ((4-fluorophenyl) sulfonylamino) -4-hydroxyphenyl) -3' -sulfamoyl [1,1' -biphenyl ] -4-carboxamide (compound A-23)
Synthesis of intermediate I-23
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid with tert-butyl 4- (4-carboxyphenyl) piperazine-1-carboxylate produced intermediate I-23 (white solid, 68 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.82(s,1H),9.63(s,1H),8.68(s,1H),7.86(d,J＝8.6Hz,2H),7.61(d,J＝2.5Hz,1H),7.48(dd,J＝8.7,2.5Hz,1H),7.01(d,J＝8.7Hz,2H),6.83(d,J＝8.7Hz,1H),3.46(d,J＝5.7Hz,4H),3.27(t,J＝5.3Hz,4H),2.96(s,3H),1.42(s,9H).
Synthesis of Compound A-23
Intermediate I-23 (87 mg,0.18 mmol) was added to dichloromethane (2 mL) and 4M hydrogen chloride-dioxane was added dropwiseRing solution (1 mL), reaction at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by pulping (ethyl acetate), and the obtained solid was dried to constant weight to obtain compound a-23 (white solid, 63 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.87(s,1H),9.19(s,2H),8.71(s,1H),7.90(d,J＝8.6Hz,2H),7.61(d,J＝2.6Hz,1H),7.48(dd,J＝8.8,2.6Hz,1H),7.06(d,J＝8.6Hz,2H),6.85(d,J＝8.7Hz,1H),3.52(t,J＝5.2Hz,4H),3.21(s,4H),2.96(s,3H).HRMS(ESI)calcd.for C 18 H 22 N 4 O 4 S[M-HCl+H] + 391.1435,found 391.1433.
example 24
N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzo [ c ] [1,2,5] oxadiazole-5-carboxamide (Compound A-24)
Synthesis of Compound A-24
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid with benzofurazan-5-carboxylic acid produced compound a-24: 1 H NMR(300MHz,DMSO-d 6 )δ10.50(s,1H),9.46(s,1H),9.08(s,1H),8.65(s,1H),8.17(d,J＝9.4Hz,1H),7.99(d,J＝9.4Hz,1H),7.66(d,J＝2.5Hz,1H),7.52(d,J＝2.6Hz,1H),6.89(d,J＝8.7Hz,1H),2.98(s,3H).HRMS(ESI)calcd.for C 14 H 12 N 4 O 5 S[M+H] + 349.0601,found 349.0606.
example 25
5-hydroxy-4- (methylsulfonamide) -2- (4 '- (trifluoromethyl) - [1,1' -biphenyl ] -4-carboxamide) benzoic acid (compound A-25)
Synthesis of intermediate I-24
Methyl 4-amino-3-methoxybenzoate (3 g,16.57 mmol) and pyridine (2.01 mL,24.86 mmol) were added to dichloromethane (30 mL), and methylsulfonic anhydride (3.75 g,21.55 mmol) was added in portions while ice-bath, and the reaction was allowed to proceed to room temperature for 8 hours. After the completion of the reaction, excess pyridine and methylsulfonic anhydride were quenched by adding concentrated hydrochloric acid (2 mL), the solvent was distilled off under reduced pressure, 1N aqueous hydrogen chloride solution (50 mL) was added to the residue and extracted with ethyl acetate (25 ml×3), and the organic phases were combined, washed with 1N aqueous hydrogen chloride solution (30 ml×1), water (30 ml×1), saturated brine (30 ml×1) in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give intermediate I-24 (orange-red solid, 3.80 g).
Synthesis of intermediate I-25
Intermediate I-24 (3.80 g,14.67 mmol) was added to concentrated sulfuric acid (98%, 15 mL), a solution of potassium nitrate (1.2 g,17.60 mmol) in concentrated sulfuric acid (98%, 15 mL) was slowly added dropwise under ice water bath, and the reaction was continued under ice bath for 20 minutes. After the reaction was completed, the reaction solution was slowly dropped into ice water (200 mL), ethyl acetate (100 mL x 3) was extracted, the organic phases were combined, washed with water (100 mL x 1), saturated brine (100 mL x 1) in this order, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, the residue was slurried (petroleum ether/ethyl acetate=3:1) and purified, and the obtained solid was dried to constant weight to obtain intermediate I-25 (earthy yellow solid, 3.41 g): 1 H NMR(300MHz,DMSO-d 6 )δ9.69(s,1H),8.03(s,1H),7.42(s,1H),3.98(s,3H),3.85(s,3H),3.14(s,3H).
synthesis of intermediate I-26
Intermediate I-25 (3.75 g,12.34 mmol) and lithium chloride (1.55 g,37.01 mmol) were added to N, N-dimethylformamide (30 mL) and reacted under reflux for 1.5 h. After the reaction was completed, the system was cooled to room temperature, water (300 mL) was added to the reaction solution to dilute and a 2N aqueous hydrogen chloride solution (10 mL) was added to adjust the pH to acidity, the aqueous phase was extracted with ethyl acetate (100 mL x 3), the organic phases were combined, washed with water (100 mL x 1) and saturated brine (100 mL x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=80:1) to give intermediate I-26 (earthy yellow solid, 2.40 g): 1 H NMR(300MHz,DMSO-d 6 )δ11.97(s,1H),9.47(s,1H),7.98(s,1H),7.10(s,1H),3.82(s,3H),3.12(s,3H).
Synthesis of intermediate I-27
Intermediate I-26 (2.40 g,8.28 mmol) and 10% palladium on carbon (360 mg) were added to tetrahydrofuran (20 mL), methanol (5 mL) and reacted at room temperature under a hydrogen atmosphere for 12 hours, after the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the solvent was distilled off from the filtrate under reduced pressure to give crude intermediate I-27 which was used directly for the next reaction without further purification.
Synthesis of intermediate I-28
Crude intermediate I-27 and N, N-diisopropylethylamine (2.88 mL,16.55 mmol) were added to dichloromethane (20 mL), a solution of tert-butyldimethylchlorosilane (TBSCl) (1.87 g,12.41 mmol) in dichloromethane (5 mL) was added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 8 hours. After the reaction was completed, the reaction mixture was quenched with saturated sodium bicarbonate solution (50 mL), extracted with dichloromethane (30 ml×3), and the organic phases were combined, washed with water (30 ml×1) and saturated brine (30 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate I-28 (white solid, 1.40 g): 1 H NMR(300MHz,DMSO-d 6 )δ8.29(s,1H),7.17(s,1H),6.82(s,1H),6.43(s,2H),3.74(s,2H),3.13(s,2H),0.96(s,9H),0.18(s,6H).
synthesis of intermediate I-29
The compound 4-trifluoromethyl bromobenzene (270 mg,1.20 mmol), p-methoxycarbonylphenylboronic acid (180 mg,1.00 mmol), potassium carbonate (279 mg,3.00 mmol) and tetrakis (triphenylphosphine) palladium (58 mg,0.05 mmol) were added to a mixed solvent of toluene (3.6 mL) and methanol (0.4 mL) and reacted at 80℃under argon atmosphere for 4 hours. After the completion of the reaction, the system was cooled to room temperature, diluted with water (30 mL), extracted with ethyl acetate (15 ml×3), and the organic phases were combined, washed with water (10 ml×1), saturated brine (10 ml×1), dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate I-29 (white solid, 255 mg).
Synthesis of intermediate I-30
Intermediate I-29 (250 mg,0.89 mmol) was added to a mixed solvent of tetrahydrofuran (2 mL) and methanol (2 mL), and 1M aqueous sodium hydroxide solution (3 mL) was added dropwise to react at 60℃for 4 hours. After the reaction, the mixture was distilled under reduced pressureThe organic solvent was removed, 2N aqueous hydrogen chloride was added dropwise to the residue to adjust the pH to 2-3, solids were precipitated, filtered, the filter cake was washed with water (5 mL), diethyl ether (5 mL), and the resulting solid was dried to constant weight to give intermediate I-30 (white solid, 205 mg): 1 H NMR(300MHz,DMSO-d 6 )δ13.10(s,1H),8.06(d,J＝8.0Hz,2H),7.96(d,J＝8.2Hz,2H),7.86(dd,J＝8.2,5.7Hz,4H).
synthesis of intermediate I-31
Intermediate I-30 (90 mg,0.34 mmol) and N, N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), oxalyl chloride (44. Mu.L, 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 completion of 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 acid chloride, which was added to a solution of I-28 (120 mg,0.32 mmol) and pyridine (100. Mu.L, 0.39 mmol) in tetrahydrofuran (1 mL) under ice-bath conditions, and reacted at room temperature for 6 hours. After the completion of the reaction, 2N aqueous hydrogen chloride was added to the reaction mixture to adjust the pH to 3-4, ethyl acetate (5 ml x 3) was used for extraction, the organic phases were combined, washed with water (10 ml x 1) and saturated brine (10 ml x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate I-31 (white solid, 102 mg).
Synthesis of intermediate I-32
Intermediate I-31 (70 mg,0.11 mmol) and triethylamine trihydrofluoride (22. Mu.L, 0.51 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, filtered, and the cake was washed (dichloromethane/methanol=20:1), and the obtained solid was dried to constant weight to obtain intermediate I-32 (white solid, 57 mg).
Synthesis of Compound A-25
Intermediate I-32 (57 mg,0.11 mmol) and lithium hydroxide monohydrate (14 mg,0.14 mmol) were added to a mixed solvent of tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), and reacted at 60℃for 6 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, water (15 mL) was added to the reaction mixture, the pH was adjusted to 2-3 with a 2N aqueous hydrogen chloride solution, extraction was performed with ethyl acetate (5 mL. Times.3), and the organic phases were combined, followed by water (5 mL. Times.1) and saturated brineThe organic phase was washed (5 ml x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol/acetic acid=30:1:0.03) to give compound a-25 (white solid, 12 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.44(s,1H),10.12(s,1H),9.04(s,1H),8.73(s,1H),8.06(d,J＝8.4Hz,2H),8.01-7.92(m,4H),7.85(d,J＝8.2Hz,2H),7.56(s,1H),3.11(s,3H).HRMS(ESI)calcd.for C 22 H 17 F 3 N 2 O 6 S[M+H] + 495.0832,found 495.0829.
example 26
4- ((4-fluorophenyl) sulfonamide) -2- (4 '- (trifluoromethyl) - [1,1' -biphenyl ] -4-carboxamide) benzoic acid (compound A-26)
Synthesis of intermediate I-33
4-amino-2-nitrobenzoic acid (300 mg,1.65 mmol) and potassium carbonate (45 mg,3.29 mmol) were added to N, N-dimethylformamide (3 mL), and iodoethane (158. Mu.L, 1.98 mmol) was slowly added dropwise under an ice-water bath, and the mixture was allowed to react at room temperature for 3 hours. After the reaction was completed, excess iodoethane was distilled off under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with water (10 ml×2) and saturated brine (5 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2:1) to give intermediate I-33 (yellow solid, 325 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.61(d,J＝8.6Hz,1H),6.82(s,1H),6.74(d,J＝8.6Hz,1H),6.54(s,2H),4.17(q,J＝7.1Hz,2H),1.21(t,J＝7.0Hz,3H).ESI-MS:m/z 233.1[M+Na] + .
Synthesis of intermediate I-34
Intermediate I-33 (324 mg,1.54 mmol) and pyridine (186. Mu.L, 2.31 mmol) were added to 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, and the mixture was allowed to react at room temperature for 8 hours. After the completion of the reaction, 1N aqueous hydrogen chloride (5 mL) was added to the reaction mixture to quench the excess pyridine, followed by extraction with ethyl acetate (10 mL. Times.3)The organic phases were combined, 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=3:1) to give intermediate I-34 (orange oily liquid, 447 mg): 1 H NMR(300MHz,DMSO-d 6 )δ11.37(s,1H),7.94(dd,J＝8.9,5.1Hz,2H),7.79(d,J＝8.5Hz,1H),7.61(d,J＝2.1Hz,1H),7.49(d,J＝2.5Hz,1H),7.45(t,J＝5.9Hz,2H),4.24(q,J＝7.1Hz,2H),1.21(t,J＝6.6Hz,3H).ESI/MS:m/z 367.0[M-H] - .
synthesis of intermediate I-35
Intermediate I-34 (610 mg,1.66 mmol) and 10% palladium on carbon (122 mg) were added to tetrahydrofuran (5 mL) and reacted at room temperature under a hydrogen atmosphere for 15 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with ethyl acetate (5 mL), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=7:1) to give crude intermediate I-35 (pale yellow solid, 187 mg) which was used in the next reaction without further purification.
Synthesis of Compound A-26
Referring to the procedure of example 25, intermediate I-28 was replaced with intermediate I-35, and direct ester hydrolysis after condensation gave compound A-26: 1 H NMR(300MHz,DMSO-d 6 )δ13.63(s,1H),12.45(s,1H),10.48(s,1H),8.72(s,1H),8.09(d,J＝8.2Hz,2H),8.05-8.01(m,2H),7.99(d,J＝7.6Hz,3H),7.88(d,J＝8.3Hz,2H),7.02(d,J＝8.7Hz,1H),3.16(s,3H).HRMS(ESI)calcd.for C 27 H 18 F 4 N 2 O 5 S[M+H] + 559.0945,found 559.0945.
Example 27
4- (methylsulfonamide) -2- (4 '- (trifluoromethyl) - [1,1' -biphenyl ] -4-carboxamide) benzoic acid (Compound A-27)
Synthesis of intermediate I-36
Intermediate I-33 (4638 mg,2.23 mmol) was added to anhydrous dichloromethane (3 mL), pyridine (269. Mu.L, 3.35 mmol) was added, and the absence of methylsulfonic anhydride (463 mg,2.67 mmol) was added under ice-bathAqueous dichloromethane (2 mL) was reacted at room temperature for 14 hours. After the reaction was completed, 1N aqueous hydrogen chloride (8 mL) was added to the system to quench excess pyridine and methylsulfonic anhydride, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (5 ml×2), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate I-36 (yellow solid, 554 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.76(s,1H),7.87(d,J＝8.5Hz,1H),7.68(d,J＝2.0Hz,1H),7.52(dd,J＝8.5,2.1Hz,1H),4.28(q,J＝7.1Hz,2H),3.21(s,3H),1.26(t,J＝7.1Hz,3H).ESI/MS:m/z 287.0[M-H] - .
synthesis of intermediate I-37
Intermediate I-36 (447 mg,1.21 mmol) and 10% palladium on carbon (89 mg) were added to tetrahydrofuran (5 mL) and reacted at room temperature under hydrogen atmosphere for 15 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with ethyl acetate (5 mL), the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate I-37 (pale yellow solid, 337 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.15(s,1H),7.75(dd,J＝8.7,5.2Hz,2H),7.40(t,J＝8.8Hz,2H),6.91(d,J＝8.8Hz,1H),6.34-6.29(m,2H),5.07(s,2H),4.97(t,1H),4.13(d,J＝4.6Hz,2H).ESI/MS:m/z 337.1[M-H] - .
synthesis of Compound A-27
Referring to the procedure of example 25, intermediate I-28 was replaced with intermediate I-37, and direct ester hydrolysis after condensation gave compound A-27: 1 H NMR(300MHz,DMSO-d 6 )δ13.63(s,1H),10.81(s,1H),8.67(s,1H),8.09(d,J＝8.2Hz,2H),7.96(dd,J＝11.3,5.7Hz,5H),7.92(t,J＝6.2Hz,2H),7.86(d,J＝8.3Hz,2H),7.43(t,J＝8.7Hz,2H),6.88(dd,J＝8.7Hz,1H).HRMS(ESI)calcd.for C 22 H 17 F 3 N 2 O 5 S[M+H] + 479.0883,found 479.0884.
Example 28
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (4- ((trifluoromethyl) thio) benzyl) benzamide (Compound A-28)
Synthesis of Compound A-28
Referring to the procedure of example 3, substituting 4, 4-difluorocyclohexanone with 4-trifluoromethylbenzaldehyde gives compound a-28: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(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＝8.7Hz,1H),4.10(s,2H).HRMS(ESI)calcd.for C 27 H 20 F 4 N 2 O 4 S 2 [M+H] + 577.0873,found 577.0883.
example 29
4- (cyclohexylmethyl) -N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (compound A-29)
Synthesis of intermediate I-38
Ethyl 4- (bromomethyl) benzoate (2.92 g,12 mmol) was added to toluene (6 mL), and after stirring to dissolve the solid, triethyl phosphite (2.3 mL,13.2 mmol) was added, and the mixture was reacted at 150 ℃ for 8 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure to give a crude intermediate I-38 (colorless oily liquid, 3.6 g) which was used in the next reaction without further purification.
Synthesis of intermediate I-39
Sodium hydride (120 mg,3 mmol) was added to a dry Schlenk tube, protected by argon, suspended in anhydrous tetrahydrofuran (1 mL), a solution of intermediate I-38 (360 mg,1.2 mmol) in anhydrous tetrahydrofuran (2 mL) was slowly added under ice, the mixture was slowly warmed to room temperature to react for 1 hour after dropping, a solution of cyclohexanone (107. Mu.L, 1 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added dropwise under ice, and the mixture was stirred for 24 hours after dropping to room temperature. After the completion of the reaction, excess sodium hydride was quenched by adding a saturated ammonium chloride solution (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×2), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate I-39 (white solid, 260 mg).
Synthesis of Compound A-29
Referring to the procedure of example 1, substituting intermediate I-4 for intermediate I-39 produced compound A-29: 1 H NMR(300MHz,DMSO-d 6 )δ9.98(s,1H),9.34(s,2H),7.85-7.78(m,4H),7.67(d,J＝2.5Hz,1H),7.41-7.34(m,3H),7.28(d,J＝8.0Hz,2H),6.68(d,J＝8.7Hz,1H),1.71-1.58(m,6H),1.58-1.47(m,1H),1.25-0.83(m,6H).HRMS(ESI)calcd.for C 26 H 27 FN 2 O 4 S[M+H] + 483.1748,found 483.1748.
example 30
4- ((4, 4-difluorocyclohexyl) methyl) -N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (compound A-30)
Synthesis of Compound A-30
Referring to the procedure of example 29, substituting cyclohexanone for 4, 4-difluorocyclohexanone produced compound a-30: 1 H NMR(300MHz,DMSO-d 6 )δ9.99(s,1H),9.34(s,2H),7.90-7.74(m,4H),7.66(d,J＝2.5Hz,1H),7.41-7.25(m,5H),6.67(d,J＝8.7Hz,1H),2.60(d,J＝6.8Hz,2H),2.05-1.90(m,2H),1.86-1.76(m,1H),1.74-1.60(m,4H),1.25-1.13(m,2H).HRMS(ESI)calcd.for C 26 H 25 F 3 N 2 O 4 S[M+H] + 519.1560,found 519.1562.
example 31
4- (cycloheptylmethyl) -N- (3- ((4-fluorophenyl) sulphonamido) -4-hydroxyphenyl) benzamide (Compound A-31)
Synthesis of Compound A-31
Referring to the procedure of example 29, the substitution of cyclohexanone for cycloheptanone produced compound a-31: 1 H NMR(300MHz,DMSO-d 6 )δ9.99(s,1H),9.34(s,2H),7.89-7.77(m,4H),7.67(d,J＝2.5Hz,1H),7.42-7.25(m,5H),6.68(d,J＝8.7Hz,1H),2.56(d,J＝7.3Hz,2H),1.84-1.73(m,1H),1.67-1.30(m,10H),1.17(d,J＝10.5Hz,2H).HRMS(ESI)calcd.for C 27 H 29 FN 2 O 4 S[M+H] + 497.1905,found 497.1898.
example 32
4- (cyclopentylmethyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound A-32)
Synthesis of Compound A-32
Referring to the procedure of example 29, substituting cyclohexanone for cyclopentanone and substituting intermediate I-3 for intermediate I-18 produced compound A-32: 1 H NMR(300MHz,DMSO-d 6 )δ10.02(s,1H),9.05(s,2H),7.85(d,J＝8.1Hz,2H),7.63(d,J＝2.4Hz,1H),7.49(dd,J＝8.7,2.5Hz,1H),7.32(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),2.98(s,3H),2.65(d,J＝7.4Hz,2H),2.17-2.05(m,1H),1.70-1.58(m,4H),1.56-1.43(m,2H),1.25-1.14(m,2H).HRMS(ESI)calcd.for C 20 H 24 N 2 O 4 S[M+H] + 389.1530,found 389.1537.
example 33
4- (cyclohexylmethyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound A-33)
Synthesis of Compound A-33
Referring to the procedure of example 29, substituting intermediate I-3 for intermediate I-18 produced compound A-33: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(s,1H),9.46(s,1H),8.94(s,1H),7.85(d,J＝8.0Hz,2H),7.63(d,J＝2.3Hz,1H),7.49(dd,J＝8.7,2.3Hz,1H),7.28(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),2.98(s,3H),2.54(d,J＝6.9Hz,2H),1.71-1.49(m,6H),1.23-1.09(m,3H),1.01-0.88(m,2H).HRMS(ESI)calcd.for C 21 H 26 N 2 O 4 S[M+H] + 403.1686,found 403.1694.
Example 34
4- (cycloheptylmethyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound A-34)
Synthesis of Compound A-34
Referring to the procedure of example 29, the substitution of cyclohexanone for cycloheptanone and the substitution of intermediate I-3 for intermediate I-18 produced compound A-34: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(s,1H),9.32(s,1H),8.97(s,1H),7.85(d,J＝7.9Hz,2H),7.63(d,J＝1.8Hz,1H),7.49(dd,J＝8.7,2.0Hz,1H),7.30(d,J＝7.9Hz,2H),6.85(d,J＝8.7Hz,1H),2.98(s,3H),2.56(d,J＝7.2Hz,2H),1.84-1.73(m,1H),1.67-1.29(m,10H),1.24-1.10(m,2H).HRMS(ESI)calcd.for C 22 H 28 N 2 O 4 S[M+H] + 417.1843,found 417.1846.
example 35
4- ((1H-imidazol-1-yl) methyl) -N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (Compound A-35)
Synthesis of intermediate I-40
Imidazole (99 mg,1.65 mmol) was added to acetonitrile (3 mL), followed by ethyl 4- (bromomethyl) benzoate (200 mg,0.82 mmol) and potassium carbonate (227 mg,1.65 mmol), and the mixture was reacted at 80℃for 10 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=100:1) to give intermediate I-40 (colorless oily liquid, 112 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.94(d,J＝8.2Hz,2H),7.77(s,1H),7.35(d,J＝8.2Hz,2H),7.20(s,1H),6.93(s,1H),5.30(s,2H),4.30(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H).
synthesis of Compound A-35
Referring to the procedure of example 5, substituting intermediate I-11 for intermediate I-40 produced compound A-35: 1 H NMR(300MHz,DMSO-d 6 )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＝1.9Hz,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 FN 4 O 4 S[M+H] + 467.1184,found467.1188.
example 36
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (morpholinomethyl) benzamide hydrochloride (Compound A-36)
Synthesis of intermediate I-41
Referring to the procedure of example 7, the substitution of 4-trifluoromethylthiobenzoic acid with 4-aldehyde benzoic acid afforded crude intermediate I-41 (yellow solid, 216 mg) which was used in the next reaction without further purification.
Synthesis of intermediate I-42
Crude intermediate I-41 (100 mg,0.24 mmol) and morpholine (32. Mu.L, 0.36 mmol) were added to dichloromethane (15 mL), glacial acetic acid (2 drops) was added, sodium triacetoxyborohydride (153 mg,0.72 mmol) was added in portions under ice bath, and the addition was completed and allowed to warm to room temperature and stir for 12 hours. After the reaction was completed, the reaction mixture was quenched by addition of saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=75:1) to give intermediate I-42 (white solid, 82 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),8.48(s,1H),7.90(d,J＝7.9Hz,2H),7.75(d,J＝2.4Hz,1H),7.55(dd,J＝8.7,2.4Hz,1H),7.45(d,J＝7.8Hz,2H),6.92(d,J＝8.8Hz,1H),3.59(s,4H),3.54(s,2H),3.04(s,3H),2.37(s,4H),0.99(s,9H),0.24(s,6H).
synthesis of intermediate I-43
Intermediate I-42 (80 mg,0.15 mmol) and triethylamine trihydrofluoride (40. Mu.L, 0.23 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the end of the reaction, a solid precipitated, filtered, and the filter cake washed (dichloromethane/methanol=20:1) to give crude intermediate I-43 (white solid, 47 mg) which was used in the next reaction without further purification.
Synthesis of Compound A-36
Intermediate I-43 (47 mg) was added to dichloromethane (2 mL), and 4M hydrogen chloride-dioxane solution (1 mL) was added dropwise, and the mixture was reacted at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by pulping (ethyl acetate), and the obtained solid was dried to constant weight to obtain compound a-36 (white solid, 33 mg): 1 H NMR(300MHz,DMSO-d 6 )δ11.09(s,1H),10.19(s,1H),9.78(s,1H),8.75(s,1H),8.02(d,J＝7.8Hz,2H),7.73(d,J＝7.8Hz,2H),7.64(d,J＝2.5Hz,1H),7.50(dd,J＝8.7,2.6Hz,1H),6.88(d,J＝8.7Hz,1H),4.41(d,J＝5.2Hz,2H),3.93(t,2H),3.77(t,J＝11.7Hz,2H),3.24(t,J＝11.8Hz,2H),3.10(t,2H),2.97(s,3H).HRMS(ESI)calcd.for C 19 H 23 N 3 O 5 S[M-HCl+H] + 406.1431,found 406.1435.
Example 37
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (piperazin-1-ylmethyl) benzamide hydrochloride (Compound A-37)
Synthesis of Compound A-37
Referring to the procedure of example 36, substituting morpholine for 1-Boc-piperazine produced compound a-37: 1 H NMR(300MHz,DMSO-d 6 )δ12.12(s,1H),10.18(s,1H),9.78(s,1H),9.48(s,2H),8.75(s,1H),8.01(d,J＝7.9Hz,2H),7.74(s,2H),7.64(d,J＝2.5Hz,1H),7.51(dd,J＝8.7,2.6Hz,1H),6.88(d,J＝8.7Hz,1H),3.92(s,2H),3.41(s,4H),3.23(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 19 H 24 N 4 O 4 S[M+H] + 405.1591,found 405.1575.
example 38
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4-methylpiperazin-1-yl) methyl) benzamide hydrochloride (Compound A-38)
Synthesis of Compound A-38
Referring to the procedure of example 36, substituting morpholine for N-methylpiperazine produced compound a-38: 1 H NMR(300MHz,DMSO-d 6 )δ12.23(s,1H),11.37(s,1H),10.18(s,1H),9.80(s,1H),8.77(s,1H),8.01(d,J＝7.8Hz,2H),7.84-7.59(m,3H),7.51(dd,J＝8.8,2.6Hz,1H),6.88(d,J＝8.7Hz,1H),4.29(s,2H),3.90(s,4H),3.38(s,4H),2.97(s,3H),2.80(s,3H).HRMS(ESI)calcd.for C 20 H 26 N 4 O 4 S[M-HCl+H] + 419.1748,found 419.1749.
example 39
4- ((4, 4-difluoropiperidin-1-yl) methyl) -N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (compound A-39)
Synthesis of Compound A-39
Referring to the procedure of example 36, substituting morpholine to 4, 4-difluoropiperidine hydrochloride produced compound a-39: 1 H NMR(300MHz,DMSO-d 6 )δ11.36(s,1H),10.15(s,1H),9.47(s,1H),9.36(s,1H),8.00(d,J＝7.8Hz,2H),7.87-7.77(m,2H),7.78-7.70(m,2H),7.69(d,J＝2.6Hz,1H),7.45-7.31(m,3H),6.70(d,J＝8.8Hz,1H),4.46(s,2H),3.43(s,4H),2.36(s,4H).HRMS(ESI)calcd.for C 25 H 24 F 3 N 3 O 4 S[M-HCl+H] + 520.1512,found 520.1518.
example 40
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -1- (4- (trifluoromethyl) benzyl) -1H-imidazole-4-carboxamide (Compound A-40)
Synthesis of intermediate I-44
Imidazole-4-carboxylic acid methyl ester (502 mg,2 mmol) and 4- (trifluoromethyl) benzyl bromide (526 mg,2.2 mmol) were added to N, N-dimethylformamide (5 mL), cesium carbonate (720 mg,2.2 mmol) was added in portions, and the reaction was carried out at room temperature for 12 hours. After the completion of the reaction, water (50 mL) was added to the reaction mixture to dilute, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, washed with water (20 ml×1) and saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1:2) to give intermediate I-44 (white solid, 377 mg): 1 H NMR(300MHz,Chloroform-d)δ7.65(d,J＝7.9Hz,2H),7.60(s,2H),7.29(d,J＝7.6Hz,2H),5.24(s,2H),3.88(s,3H).
Synthesis of intermediate I-45
Intermediate I-44 (350 mg,1.23 mmol) was added to a mixed solvent of tetrahydrofuran (3 mL) and water (1.5 mL), lithium hydroxide monohydrate (155 mg,3.70 mmol) was added, and the mixture was reacted at room temperature for 6 hours. After the completion of the reaction, the solvent organic phase was distilled off under reduced pressure, and 1N aqueous hydrogen chloride solution was added dropwise to the residue to adjust pH to 5-6, and solids were precipitated, filtered, and the cake was washed with methylene chloride (2 mL), and the obtained solid was dried to constant weight to give intermediate I-45 (white solid, 266 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.17(s,1H),7.91(d,J＝6.8Hz,2H),7.76(d,J＝8.0Hz,2H),7.50(d,J＝8.0Hz,2H),5.37(s,2H).
synthesis of Compound A-40
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid for intermediate I-45, compound A-40 is prepared: 1 H NMR(300MHz,Methanol-d 4 )δ7.85(s,1H),7.78(s,1H),7.70(d,J＝7.2Hz,3H),7.47(d,J＝8.1Hz,2H),7.40(dd,J＝8.8,2.6Hz,1H),6.86(d,J＝8.8Hz,1H),5.39(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C 19 H 17 F 3 N 4 O 4 S[M+H] + 455.0995,found 455.0996.
example 41
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -1- (4- (trifluoromethyl) benzyl) -1H-1,2, 4-triazole-3-carboxamide (Compound A-41)
Synthesis of Compound A-41
Referring to the procedure of example 40, imidazole-4-carboxylic acid methyl ester was replaced with 1,2, 4-triazole-3-carboxylic acid methyl ester to produce compound a-41: 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),9.62(s,1H),8.90(s,1H),8.68(s,1H),7.77(d,J＝8.0Hz,2H),7.65(d,J＝2.1Hz,1H),7.54(d,J＝8.0Hz,2H),7.48(dd,J＝8.8,2.1Hz,1H),6.84(d,J＝8.7Hz,1H),5.64(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C 18 H 16 F 3 N 5 O 4 S[M+H] + 456.0948,found 456.0927.
example 42
N- (4-hydroxy-3- (methylsulfonylamino) phenyl) -1- (4- (trifluoromethoxy) benzyl) -1H-1,2, 4-triazole-3-carboxamide (Compound A-42)
Synthesis of Compound A-42
Referring to the procedure of example 40, substituting methyl imidazole-4-carboxylate with methyl 1,2, 4-triazole-3-carboxylate and substituting 4- (trifluoromethyl) benzyl bromide with 4- (trifluoromethoxy) benzyl bromide, compound a-42 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.22(s,1H),9.63(s,1H),8.95-8.60(m,2H),7.64(s,1H),7.47(d,J＝8.7Hz,3H),7.39(d,J＝8.3Hz,2H),6.83(d,J＝8.8Hz,1H),5.56(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C 18 H 16 F 3 N 5 O 5 S[M+H] + 472.0897,found 472.0705.
Example 43
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (4- ((trifluoromethyl) thio) phenoxy) benzamide (Compound A-43)
Synthesis of intermediate I-46
4-trifluoromethylthiophenol (194 mg,1 mmol) and methyl 4-fluorobenzoate (259. Mu.L, 2 mmol) were added to dimethyl sulfoxide (3 mL), followed by addition of potassium carbonate (276 mg,2 mmol) in portions, and heating to 110℃for 18 hours. After the completion of the reaction, the system was cooled to room temperature, water (30 mL) was added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate I-46 (colorless oily liquid, 215 mg).
Synthesis of Compound A-43
Referring to the procedure of example 1, substituting intermediate I-5 for intermediate I-46 produced compound A-43: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.42(s,1H),9.36(s,1H),8.03(d,J＝8.6Hz,2H),7.83(dd,J＝8.7,5.3Hz,2H),7.78(d,J＝8.6Hz,2H),7.68(d,J＝2.3Hz,1H),7.43-7.38(m,2H),7.36(d,J＝8.8Hz,1H),7.22(dd,J＝11.5,8.7Hz,4H),6.70(d,J＝8.7Hz,1H).HRMS(ESI)calcd.for C 26 H 18 F 4 N 2 O 5 S 2 [M+H] + 579.0666,found 579.0676.
example 44
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) oxy) benzamide (Compound B-1)
Synthesis of intermediate II-1
4-trifluoromethylthiobenzyl bromide (200 mg,0.74 mmol), methyl 4-hydroxybenzoate (168 mg,1.11 mmol) and potassium iodide (12 mg,0.07 mmol) were added to acetonitrile (3 mL), cesium carbonate (481 mg,1.48 mmol) was added with stirring, and the reaction was carried out at 80℃for 8 hours. After the completion of the reaction, the reaction mixture was filtered, and the cake was washed with ethyl acetate (5 mL). To the filtrate was added water (10 mL) for dilution, ethyl acetate (10 mL. Times.3) for extraction, and the organic phases were combined, washed successively with 1M aqueous sodium hydroxide (5 mL. Times.2) and saturated brine (15 mL. Times.1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crude intermediate II-1, which was used in the next reaction without further purification.
Synthesis of intermediate II-2
The crude intermediate II-1 was added to a mixed solvent of tetrahydrofuran (1.5 mL) and methanol (1.5 mL), and 1M aqueous sodium hydroxide solution (1.5 mL) was added dropwise, followed by reaction at 60℃for 4 hours. After the reaction was completed, the organic solvent was distilled off under reduced pressure, the pH of the residue was adjusted to 2-3 with a 2N aqueous hydrogen chloride solution, solids were precipitated, and the residue was filtered, and the cake was washed with water (5 mL) and diethyl ether (5 mL) in this order, and the solids were dried to constant weight to give intermediate II-2 (white solid, 142 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.66(s,1H),7.91(d,J＝8.8Hz,2H),7.76(d,J＝8.0Hz,2H),7.62(d,J＝8.1Hz,2H),7.11(d,J＝8.8Hz,2H),5.28(s,2H).
synthesis of intermediate II-3
Intermediate II-2 (45 mg,0.14 mmol) and N, N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), oxalyl chloride (17. Mu.L, 0.21 mmol) was slowly added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 4 hours. After the completion of 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 acid chloride, which was added to a solution of I-3 (60 mg,0.15 mmol) and pyridine (17. Mu.L, 0.21 mmol) in tetrahydrofuran (1 mL) under ice-bath conditions, and reacted at room temperature for 6 hours. After the completion of the reaction, 2N aqueous hydrogen chloride was added to the reaction mixture to adjust the pH to 3-4, ethyl acetate (5 mL. Times.3) was used for extraction, the organic phases were combined, washed successively with water (10 mL. Times.1) and saturated brine (10 mL. Times.1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (Petroleum ether) Ethyl acetate = 5: 1) Purification gave intermediate III-3 (white solid, 123 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.99(s,1H),9.01(s,1H),7.92(d,J＝8.5Hz,2H),7.82(d,J＝5.2Hz,1H),7.80-7.74(m,3H),7.64(d,J＝7.6Hz,3H),7.46(dd,J＝8.8,2.4Hz,1H),7.43-7.36(m,2H),7.14(d,J＝8.6Hz,2H),6.82(d,J＝8.7Hz,1H),5.30(s,2H),0.92(s,9H),0.13(s,6H).
synthesis of Compound B-1
Intermediate II-3 (107 mg,0.19 mmol) and triethylamine trihydrofluoride (50. Mu.L, 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, filtered, and the cake was washed (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(300MHz,DMSO-d 6 )δ9.91(s,1H),9.32(s,2H),7.93(d,J＝8.7Hz,2H),7.82(dd,J＝8.8,5.3Hz,2H),7.77(d,J＝8.1Hz,2H),7.66(d,J＝2.4Hz,1H),7.64(d,J＝8.2Hz,2H),7.38(dd,J＝8.7,2.7Hz,2H),7.33(d,J＝9.0Hz,1H),7.14(d,J＝8.7Hz,2H),6.68(d,J＝8.7Hz,1H),5.30(s,2H).HRMS(ESI)calcd.for C 27 H 20 F 4 N 2 O 5 S 2 [M+H] + 593.0823,found593.0827.
example 45
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- (trifluoromethyl) benzyl) oxy) benzamide (Compound B-2)
Synthesis of Compound B-2
Referring to the procedure of example 44, intermediate II-2 was replaced with 4-benzyloxybenzoic acid to give compound B-2: 1 H NMR(300MHz,DMSO-d 6 )δ9.91(s,1H),9.34(s,2H),7.92(d,J＝8.8Hz,2H),7.86-7.79(m,2H),7.66(d,J＝2.5Hz,1H),7.48(d,J＝7.0Hz,2H),7.44-7.33(m,6H),7.12(d,J＝8.9Hz,2H),6.67(d,J＝8.6Hz,1H),5.20(s,2H).HRMS(ESI)calcd.for C 26 H 21 FN 2 O 5 S[M+H] + 493.1228,found 493.1231.
example 46
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- (trifluoromethyl) benzyl) oxy) benzamide (Compound B-3)
Synthesis of Compound B-3
Referring to the procedure of example 44, the substitution of 4-trifluoromethylthio benzyl bromide for 4-trifluoromethylbenzyl bromide gives compound B-3: 1 H NMR(300MHz,DMSO-d 6 )δ9.92(s,1H),9.32(s,2H),7.93(d,J＝8.5Hz,2H),7.85-7.76(m,4H),7.73-7.65(m,3H),7.36(t,J＝8.9Hz,3H),7.14(d,J＝8.4Hz,2H),6.68(d,J＝8.6Hz,1H),5.33(s,2H).HRMS(ESI)calcd.for C 27 H 20 F 4 N 2 O 5 S[M+H] + 561.1102,found 561.1108.
example 47
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- ((trifluoromethyl) sulfonyl) benzyl) oxy) benzamide (Compound B-4)
Synthesis of intermediate II-4
Intermediate II-2 (50 mg,0.15 mmol) was added to trifluoroacetic acid (1 mL), and 30% aqueous hydrogen peroxide (73 μl,0.8 eqv.) was added dropwise under ice bath, and the mixture was allowed to react at room temperature for 21 hours. After the reaction was completed, the reaction solution was poured into ice water (5 mL), solids were precipitated, suction filtration was performed, the cake was washed with water (5 mL), and the residue was purified by beating (n-hexane/diethyl ether=10:1), and the obtained solid was dried to constant weight to obtain intermediate II-4 (white solid, 46 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.70(s,1H),8.19(d,J＝8.2Hz,2H),7.92(dd,J＝8.5,2.6Hz,4H),7.14(d,J＝8.8Hz,2H),5.45(s,2H).ESI-MS:m/z 359.0[M-H] - .
synthesis of Compound B-4
With reference to the method of example 44, an intermediateReplacement of the body II-2 with the intermediate II-4 gives the compound B-4: 1 H NMR(300MHz,DMSO-d 6 )δ9.94(s,1H),9.33(s,2H),8.20(d,J＝8.2Hz,2H),7.94(dd,J＝8.0,6.2Hz,4H),7.82(dd,J＝8.6,5.3Hz,2H),7.66(d,J＝2.2Hz,1H),7.36(t,J＝8.8Hz,3H),7.16(d,J＝8.7Hz,2H),6.67(d,J＝8.7Hz,1H),5.46(s,2H).HRMS(ESI)calcd.for C 27 H 20 F 4 N 2 O 7 S 2 [M+H] + 625.0721,found 625.0713.
example 48
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- (methylsulfonyl) benzyl) oxy) benzamide (compound B-5)
Synthesis of Compound B-5
Referring to the procedure of example 44, substituting 4-trifluoromethylthio benzyl bromide for 4-methylsulfonylbenzyl bromide produced compound B-5: 1 H NMR(300MHz,DMSO-d 6 )δ9.92(s,1H),9.32(s,2H),7.95(dd,J＝11.9,8.3Hz,4H),7.81(dd,J＝8.5,5.2Hz,2H),7.74(d,J＝8.0Hz,2H),7.65(d,J＝2.5Hz,1H),7.36(t,J＝12.1,5.4Hz,3H),7.14(d,J＝8.6Hz,2H),6.67(d,J＝8.7Hz,1H),5.35(s,2H),3.23(s,3H).HRMS(ESI)calcd.for C 27 H 23 FN 2 O 7 S 2 [M+H] + 571.1003,found 571.1002.
example 49
4- (Cyclohexylmethoxy) -N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (Compound B-6)
Synthesis of intermediate II-5
Methyl 4-hydroxybenzoate (200 mg,1.31 mmol), cyclohexylmethanol (330 mg,2.89 mmol) and triphenylphosphine (578 mg,2.76 mmol) were added to a dry three-necked flask, protected by argon, dissolved in anhydrous tetrahydrofuran (3 mL), and slowly added under ice-bath Diisopropyl azodicarboxylate (560. Mu.L, 2.76 mmol) in anhydrous tetrahydrofuran (1 mL) was added and the mixture was allowed to react at room temperature for 12 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate II-5 (colorless oily liquid, 320 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.89(d,J＝8.8Hz,1H),7.02(d,J＝8.8Hz,1H),3.85(d,J＝6.1Hz,1H),3.80(s,1H),1.83-1.63(m,3H),1.28-1.17(m,2H),1.09-0.97(m,1H).
synthesis of Compound B-6
Referring to the procedure of example 44, intermediate II-1 was replaced with intermediate II-5 to give compound B-6: 1 H NMR(300MHz,DMSO-d 6 )δ9.90(s,1H),9.33(s,2H),7.91(d,J＝8.6Hz,2H),7.81(dd,J＝8.8,5.3Hz,2H),7.66(d,J＝2.5Hz,1H),7.40-7.32(m,3H),7.02(d,J＝8.7Hz,2H),6.67(d,J＝8.7Hz,1H),3.86(d,J＝6.1Hz,2H),1.87-1.63(m,6H),1.31-1.17(m,3H),1.12-1.02(m,2H).HRMS(ESI)calcd.for C 26 H 27 FN 2 O 5 S[M+H] + 499.1697,found499.1698.
example 50
N- (4-chloro-3- ((4-fluorophenyl) sulfamido) phenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) oxy) benzamide (Compound B-7)
Synthesis of intermediate II-6
2-chloro-5-nitroaniline (345 mg,2 mmol) and pyridine (241. Mu.L, 3 mmol) were added to dichloromethane (5 mL), a solution of 4-fluorobenzenesulfonyl chloride (467 mg,2.4 mmol) in dichloromethane (2 mL) was added dropwise under ice-water bath, and the mixture was allowed to react at room temperature for 8 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, excess pyridine was quenched by addition of 2N aqueous hydrogen chloride (10 mL), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed successively with 1N aqueous hydrogen chloride (10 mL x 1), water (10 mL x 1), saturated brine (10 mL x 1), distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give crude intermediate II-6 (yellow solid, 544 mg).
Synthesis of intermediate II-7
Crude intermediate II-6 (544 mg,1.74 mmol) and 10% palladium on carbon (100 mg) were added to tetrahydrofuran (5 mL) and reacted at room temperature under hydrogen atmosphere for 12 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (5 mL), the solvent was distilled off from the filtrate under reduced pressure, and 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(300MHz,DMSO-d 6 )δ9.64(s,1H),7.75(dd,J＝8.8,5.2Hz,2H),7.39(t,J＝8.8Hz,2H),6.94(d,J＝8.6Hz,1H),6.52(d,J＝2.6Hz,1H),6.37(dd,J＝8.6,2.6Hz,1H),5.35(s,2H).ESI-MS:m/z 299.0[M-H] - .
synthesis of Compound B-7
Referring to the procedure of example 44, intermediate I-3 was replaced with intermediate II-7 to give compound B-7: 1 H NMR(300MHz,DMSO-d 6 )δ10.27(s,1H),10.03(s,1H),8.04-7.88(m,4H),7.79(d,4H),7.64(dd,J＝8.0Hz,3H),7.42(d,J＝8.8Hz,1H),7.38-7.32(m,1H),7.16(d,J＝8.6Hz,2H),5.31(s,2H).HRMS(ESI)calcd.for C 27 H 19 ClF 4 N 2 O 4 S 2 [M+H] + 595.0779,found595.0797
example 51
N- (4-fluoro-3- ((4-fluorophenyl) sulfamido) phenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) oxy) benzamide (Compound B-8)
Synthesis of Compound B-8
Referring to the procedure of example 50, substituting 2-chloro-5-nitroaniline with 2-fluoro-5-nitroaniline produced compound B-8: 1 H NMR(300MHz,DMSO-d 6 )δ10.23(s,1H),10.18(s,1H),7.94(d,J＝8.6Hz,2H),7.86-7.81(m,2H),7.77(d,J＝8.6Hz,3H),7.64(d,J＝8.0Hz,2H),7.58(s,1H),7.41(t,J＝8.8Hz,2H),7.19-7.08(m,3H),5.31(s,2H).HRMS(ESI)calcd.for C 27 H 19 F 5 N 2 O 4 S 2 [M+H] + 595.0779,found 595.0797.
example 52
N- (3- ((4-fluorophenyl) sulfamido) -4- (hydroxymethyl) phenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) oxy) benzamide (Compound B-9)
Synthesis of intermediate II-8
2-amino-4-nitrobenzoic acid (500 mg,2.75 mmol) was added to a dry Schlenk tube, protected with argon, dissolved in tetrahydrofuran (5.5 mL), 1M borane-tetrahydrofuran complex (5.5 mL,5.5 mmol) was slowly added under ice-bath, and the mixture was allowed to react at 65℃for 4 hours. After the reaction was completed, the system was cooled to room temperature, ice water (20 mL) was added dropwise to the reaction solution to quench excess borane, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate II-8 (yellow solid, 431 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.46(s,1H),7.37(t,2H),5.57(s,2H),5.34(t,J＝5.4Hz,1H),4.43(d,J＝5.4Hz,2H).ESI-MS:m/z 167.0[M-H] - .
Synthesis of Compound B-9
Referring to the procedure of example 50, substituting 2-chloro-5-nitroaniline for intermediate II-8 produced compound B-9: 1 H NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),9.49(s,1H),7.93(d,J＝8.8Hz,2H),7.82-7.72(m,4H),7.62(dd,J＝12.9,7.8Hz,4H),7.40(t,J＝8.8Hz,2H),7.30(d,J＝8.7Hz,1H),7.15(d,J＝8.8Hz,2H),5.30(s,2H),5.17(s,1H),4.28(s,2H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 5 S 2 [M+H] + 607.0979,found 607.1010.
example 53
2- ((4-fluorophenyl) sulfamido) -4- (4- ((4- ((trifluoromethyl) thio) benzyl) oxy) benzamide) benzoic acid (compound B-10)
Synthesis of intermediate II-9
The compound 2-amino-4-nitrobenzoic acid (300 mg,1.65 mmol) and potassium carbonate (45 mg,3.3 mmol) were added to N, N-dimethylformamide (3 mL), and iodoethane (158. Mu.L, 1.98 mmol) was added dropwise under ice bath, and the mixture was allowed to react at room temperature for 6 hours. After the completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate II-9 (orange solid, 325 mg).
Synthesis of intermediate II-10
Intermediate II-9 (160 mg,0.76 mmol) and pyridine (92. Mu.L, 1.14 mmol) were added to anhydrous dichloromethane (2 mL), a solution of 4-fluorobenzenesulfonyl chloride (178 mg,0.91 mmol) in dichloromethane (1 mL) was added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 8 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate (10 mL) and a 2N aqueous hydrogen chloride solution (5 mL) were added, the mixture was shaken and separated, and the organic phase was washed with a 1N aqueous hydrogen chloride solution (5 ml×1), water (5 ml×1) and saturated brine (5 ml×1) in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to give intermediate II-10 (yellow oily liquid, 117 mg).
Synthesis of intermediate II-11
Intermediate II-10 (117 mg,0.32 mmol) and 10% palladium on carbon (23 mg) were added to tetrahydrofuran (3 mL), and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (5 mL), the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=4:1) to give intermediate II-11 (white solid, 92 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.98(s,1H),7.89(dd,J＝8.9,5.1Hz,2H),7.56(d,J＝8.8Hz,1H),7.43(t,J＝8.8Hz,2H),6.70(d,J＝2.0Hz,1H),6.35(s,2H),6.23(dd,J＝8.8,2.1Hz,1H),4.20(q,J＝7.1Hz,2H),1.25(t,J＝7.1Hz,3H).ESI-MS:m/z337.1[M-H] - .
synthesis of intermediate II-12
Intermediate II-3 (60 mg,0.18 mmol) and N, N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (2 mL), oxalyl chloride (23. Mu.L, 0.27 mmol) was slowly added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 4 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to give a tetrahydrofuran solution of acid chloride, which was then added to a solution of intermediate II-11 (68 mg,0.20 mmol) and pyridine (22. Mu.L, 0.27 mmol) in tetrahydrofuran (1 mL) with ice-bath, and the mixture was allowed to react at room temperature 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 extracted, the organic phases were combined, washed with water (10 ml x 1) and saturated brine (10 ml x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate II-12 (white solid, 112 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.69(s,1H),10.51(s,1H),8.21(d,1H),8.01-7.97(m,2H),7.95(d,J＝7.1Hz,2H),7.86(d,J＝8.8Hz,1H),7.77(d,J＝8.1Hz,2H),7.65(s,1H),7.63-7.57(m,2H),7.42(t,J＝8.8Hz,2H),7.18(d,J＝8.8Hz,2H),5.32(s,2H),4.26(q,2H),1.29(t,J＝7.1Hz,3H).ESI-MS:m/z 671.1[M+Na] + .
Synthesis of Compound B-10
Intermediate II-12 (95 mg,0.15 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL), methanol (1 mL) and water (1 mL), and sodium hydroxide (12 mg,0.29 mmol) was added in portions while ice-bath, and the mixture was heated to 60℃for 6 hours. After the reaction was completed, the organic solvent was distilled off under reduced pressure, a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2 to 3, solids were precipitated, the reaction solution was filtered, the cake was washed with water (2 mL) and N-hexane (2 mL) in this order, and the residue was slurried (N-hexane/dichloromethane=1:1) and purified, and the obtained solid was dried to constant weight to give compound B-10 (white solid, 74 mg): 1 H NMR(300MHz,DMSO-d 6 )δ13.71(s,1H),11.29(s,1H),10.49(s,1H),8.22(d,1H),8.02-7.94(m,4H),7.87(d,J＝8.8Hz,1H),7.77(d,J＝8.0Hz,2H),7.64(d,J＝8.1Hz,2H),7.56(dd,J＝8.8Hz,1H),7.43(t,J＝8.8Hz,2H),7.18(d,J＝8.7Hz,2H),5.32(s,2H).HRMS(ESI)calcd.for C 28 H 20 F 4 N 2 O 6 S 2 [M+H] + 621.0772,found 621.0779.
example 54
4- ((4-fluorophenyl) sulfonamide) -2- (4- ((4- ((trifluoromethyl) thio) benzyl) oxy) benzamide) benzoic acid (compound B-11)
Synthesis of Compound B-11
Referring to the procedure of example 53, substituting intermediate II-11 with intermediate I-37 produced compound B-11: 1 H NMR(300MHz,DMSO-d 6 )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 F 4 N 2 O 6 S 2 [M+H] + 621.0772,found621.0771.
example 55
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) oxy) benzamide (Compound B-12)
Synthesis of intermediate II-13
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), oxalyl chloride (27. Mu.L, 0.32 mmol) was slowly added dropwise under ice bath, and the reaction was allowed to proceed to room temperature for 4 hours. After the completion of 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 acid chloride, which was added under ice bath conditions I-18 (74 mg,0.23 mmol) and pyridine (26. Mu.L, 0.32 mmol) in tetrahydrofuran (1 mL) were reacted at room temperature for 6 hours. After the reaction was completed, 2N aqueous hydrogen chloride was added to the reaction solution to adjust the pH to 3 to 4, ethyl acetate (5 ml x 3) was extracted, the organic phases were combined, washed with water (10 ml x 1) and saturated brine (10 ml x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate II-13 (white solid, 133 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),8.42(s,1H),7.95(d,J＝8.6Hz,2H),7.77(d,J＝8.3Hz,2H),7.74(d,J＝3.4Hz,1H),7.64(d,J＝8.0Hz,2H),7.53(dd,J＝8.7,2.0Hz,1H),7.15(d,J＝8.6Hz,2H),6.91(d,J＝8.8Hz,1H),5.30(s,2H),3.04(s,3H),1.00(s,9H),0.24(s,6H).
synthesis of Compound B-12
Intermediate II-13 (121 mg,0.19 mmol) and triethylamine trihydrofluoride (37. Mu.L, 0.29 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, filtered, and the filter cake was washed (dichloromethane/methanol=20:1), and the obtained solid was dried to constant weight to obtain compound B-12 (white solid, 57 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.94(s,1H),9.44(s,1H),8.90(s,1H),7.94(d,J＝8.7Hz,2H),7.77(d,J＝8.0Hz,2H),7.64(d,J＝9.1Hz,2H),7.61(d,J＝2.9Hz,1H),7.48(dd,J＝8.8,2.2Hz,1H),7.14(d,J＝8.7Hz,2H),6.85(d,J＝8.7Hz,1H),5.30(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 5 S 2 [M+H] + 513.0760,found 513.0757.
example 56
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethyl) benzyl) oxy) benzamide (Compound B-13)
Synthesis of Compound B-13
Referring to the procedure of example 55, substituting 4-trifluoromethylthio benzyl bromide for 4-trifluoromethylbenzyl bromide produced compound B-13: 1 H NMR(300MHz,DMSO-d 6 )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 F 3 N 2 O 5 S[M+H] + 481.1040,found 481.1044.
example 57
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -6- ((4- ((trifluoromethyl) thio) benzyl) oxy) nicotinamide (Compound B-14)
Synthesis of intermediate II-14
Referring to the procedure of example 44, substituting methyl 4-hydroxybenzoate with ethyl 6-hydroxynicotinate produced intermediate II-14: 1 H NMR(300MHz,DMSO-d 6 )δ12.94(s,1H),8.68(d,J＝2.3Hz,1H),7.85(dd,J＝9.5,2.4Hz,1H),7.73(d,J＝8.1Hz,2H),7.44(d,J＝8.1Hz,2H),6.49(d,J＝9.5Hz,1H),5.29(s,2H).ESI-MS:m/z 328.0[M-H] - .
synthesis of Compound B-14
Referring to the procedure of example 55, substituting intermediate II-2 for intermediate II-14 produced compound B-14: 1 H NMR(300MHz,DMSO-d 6 )δ9.87(s,1H),9.21(s,2H),8.62(s,1H),8.02(d,J＝9.7Hz,1H),7.72(d,J＝7.8Hz,2H),7.52(s,1H),7.48-7.37(m,3H),6.85(d,J＝8.7Hz,1H),6.51(d,J＝9.5Hz,1H),5.25(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 21 H 18 F 3 N 3 O 5 S 2 [M+H] + 514.0713,found 514.0722.
example 58
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) benzyl) oxy) benzamide (Compound B-15)
Synthesis of Compound B-15
Referring to the procedure of example 55, substituting 4-trifluoromethylthio benzyl bromide for 4-trifluoromethoxybenzyl bromide produced compound B-15: 1 H NMR(300MHz,DMSO-d 6 )δ9.94(s,1H),9.64(s,1H),8.68(s,1H),7.94(d,J＝8.7Hz,2H),7.62(dd,J＝5.6,2.8Hz,3H),7.48(dd,J＝8.7,2.3Hz,1H),7.41(d,J＝8.1Hz,2H),7.13(d,J＝8.8Hz,2H),6.85(d,J＝8.7Hz,1H),5.24(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 6 S[M+H] + 497.0989,found 497.0998.
example 59
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylsulfonyl) benzyl) oxy) benzamide (Compound B-16)
Synthesis of Compound B-16
Referring to the procedure of example 55, substituting intermediate II-2 for intermediate II-4 produced compound B-16: 1 H NMR(400MHz,DMSO-d 6 )δ9.96(s,1H),9.64(s,1H),8.73(s,1H),8.19(d,J＝8.4Hz,2H),7.94(dd,J＝12.2,8.7Hz,4H),7.61(d,J＝2.6Hz,1H),7.48(dd,J＝8.8,2.6Hz,1H),7.16(d,J＝9.0Hz,2H),6.84(d,J＝8.8Hz,1H),5.45(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 7 S 2 [M+H] + 545.0659,found 545.0663.
example 60
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylsulfonyl) benzyl) oxy) benzamide (Compound B-17)
Synthesis of Compound B-17
Referring to the procedure of example 47, methyl 4-hydroxybenzoate was replaced with 3-fluoro-4-hydroxybenzoateMethyl ester, intermediate I-3 was replaced with intermediate I-18 to give compound B-17: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.72(s,1H),8.75(s,1H),8.26-8.17(m,2H),7.93(d,J＝8.5Hz,2H),7.88(dd,J＝12.2,2.1Hz,1H),7.81(dt,J＝8.8,1.6Hz,1H),7.60(d,J＝2.6Hz,1H),7.48(dd,J＝8.7,2.6Hz,1H),7.38(t,J＝8.6Hz,1H),6.85(d,J＝8.7Hz,1H),5.53(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 F 4 N 2 O 7 S 2 [M+H] + 563.0564,found 563.0570.
Example 61
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylthio) benzyl) oxy) benzamide (Compound B-18)
Synthesis of intermediate II-15
4-fluoro-2-methoxy-5-nitroaniline (500 mg,2.69 mmol) and pyridine (320. Mu.L, 4.03 mmol) were added to dichloromethane (10 mL), and a solution of methylsulfonyl chloride (250. Mu.L, 3.22 mmol) in dichloromethane (5 mL) was slowly added dropwise under ice bath, and the mixture was allowed to react at room temperature for 8 hours. After the completion of the reaction, excess pyridine and methylsulfonyl chloride were quenched by adding concentrated hydrochloric acid (1 mL), the solvent was distilled off under reduced pressure, 1N aqueous hydrogen chloride (20 mL) was added to the residue, ethyl acetate (10 mL x 3) was extracted, the organic phase was washed with 1N aqueous hydrogen chloride (10 mL x 2), water (10 mL x 1), saturated brine (10 mL x 1) in this order, the solvent was distilled off under reduced pressure, the residue was purified by beating (diethyl ether), and the obtained solid was dried to constant weight to obtain intermediate II-15 (yellow solid, 522 mg): 1 H NMR(300MHz,DMSO-d 6 )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).
synthesis of intermediate II-16
Intermediate II-15 (520 mg,1.98 mmol) was added to a dry three-necked flask, protected with argon, dissolved in anhydrous dichloromethane (5 mL), and then added dropwise under ice bath to a solution of boron tribromide (286 μL,2.97 mmol) in anhydrous dichloromethane (5 mL)The solution was slowly warmed to room temperature and reacted for 3 hours after the dropping. After the reaction was completed, ice water (20 mL) was added dropwise to the reaction solution to quench it, then a 2N aqueous hydrogen chloride solution was added dropwise to adjust the pH to 1 to 2, ethyl acetate (10 mL x 3) was used for extraction, the organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give intermediate II-16 (brown solid, 582 mg): 1 H NMR(300MHz,DMSO-d 6 )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).
Synthesis of intermediate II-17
Intermediate II-16 (552 mg,2.33 mmol) and 10% palladium on carbon (120 mg) were added to a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the solvent was distilled off from the filtrate under reduced pressure to obtain a crude intermediate I-17 which was used directly in the next reaction without further purification.
Synthesis of intermediate II-18
Crude intermediate II-17 (2.33 mmol) and N, N-diisopropylethylamine (810. Mu.L, 4.66 mmol) were added to dichloromethane (5 mL), a solution of tert-butyldimethylchlorosilane (4819 mg,3.26 mmol) in dichloromethane (5 mL) was added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was diluted with saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (10 ml×3), the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and 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 H NMR(300MHz,DMSO-d 6 )δ8.28(s,1H),6.76(d,J＝9.8Hz,1H),6.59(d,J＝12.1Hz,1H),4.80(s,2H),2.93(s,3H),0.96(s,9H),0.19(s,6H).
synthesis of Compound B-18
Referring to the procedure of example 55, substituting intermediate I-18 for intermediate II-18 produced compound B-18: 1 H NMR(300MHz,DMSO-d 6 )δ10.31(s,1H),9.82(s,1H),8.92(s,1H),7.95(d,J＝8.9Hz,2H),7.77(d,J＝8.1Hz,2H),7.64(d,J＝8.3Hz,2H),7.27(d,J＝8.4Hz,1H),7.15(d,J＝8.9Hz,2H),6.77(d,J＝11.4Hz,1H),5.30(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 F 4 N 2 O 5 S 2 [M+H] + 531.0666,found 531.0667.
example 62
3-fluoro-N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylthio) benzyl) oxy) benzamide (Compound B-19)
Synthesis of Compound B-19
Referring to the procedure of example 44, substituting methyl 4-hydroxybenzoate with methyl 3-fluoro-4-hydroxybenzoate and substituting intermediate I-3 with intermediate II-17, compound B-19 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.31(s,1H),9.89(s,1H),8.87(s,1H),7.87-7.77(m,4H),7.65(d,J＝8.3Hz,2H),7.40(t,J＝8.5Hz,1H),7.27(d,J＝8.3Hz,1H),6.77(d,J＝11.3Hz,1H),5.38(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 17 F 5 N 2 O 5 S 2 [M+H] + 549.0572,found 549.0555.
example 63
4- (Cyclohexylmethoxy) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound B-20)
Synthesis of Compound B-20
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-5 produced compound B-20: 1 H NMR(300MHz,DMSO-d 6 )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 N 2 O 5 S[M+H] + 419.1635,found 419.1638.
example 64
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((5- (trifluoromethyl) furan-2-yl) methoxy) benzamide (Compound B-21)
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Synthesis of intermediate II-19
5-iodo-2-furaldehyde (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, and the mixture was slowly warmed to room temperature to react for 4 hours. After the reaction was completed, the reaction mixture was poured into ice water (20 mL) and quenched, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate II-19, which was used in the next reaction without further purification.
Synthesis of intermediate II-20
Methyl 4-hydroxybenzoate (319 mg,4 mmol) and triphenylphosphine (1.2 g,4.5 mmol) were added to a dry three-necked flask, protected by argon, a solution of crude 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 the mixture was slowly warmed to room temperature to react for 12 hours. After the completion of the reaction, water (20 mL) was added to the reaction mixture to dilute, ethyl acetate (10 ml×3) was extracted, and the organic phase was washed with a saturated sodium carbonate solution (10 ml×2) and a saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate II-20 (colorless oily liquid, 278 mg): 1 H NMR(300MHz,Chloroform-d)δ8.02(d,J＝8.9Hz,2H),7.00(d,J＝8.9Hz,2H),6.57(d,J＝3.3Hz,1H),6.40(d,J＝3.3Hz,1H),5.06(s,2H),3.91(s,3H).
synthesis of intermediate II-21
Intermediate II-20 (275 mg,0.77 mmol) and copper chloride (21 mg,0.15 mmol) were added to anhydrous N, N-dimethylformamide (3 mL), and Chen Shiji (445 mg,2.31 mmol) was added dropwise under argon and the reaction was continued at 110℃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 the filtrate to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=75:1) to give intermediate II-21 (yellow oily liquid, 192 mg): 1 H NMR(300MHz,Chloroform-d)δ8.04(d,J＝8.3Hz,2H),7.01(d,J＝8.4Hz,2H),6.82(s,1H),6.55(s,1H),5.11(s,2H),3.92(s,3H).
Synthesis of Compound B-21
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-21 produced compound B-21: 1 H NMR(300MHz,DMSO-d 6 )δ9.97(s,1H),9.65(s,1H),8.73(s,1H),7.94(d,J＝8.6Hz,2H),7.61(d,J＝2.5Hz,1H),7.48(dd,J＝8.8,2.6Hz,1H),7.26(d,J＝2.7Hz,1H),7.16(d,J＝8.8Hz,2H),6.88(d,J＝3.6Hz,1H),6.84(d,J＝8.7Hz,1H),5.26(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 20 H 17 F 3 N 2 O 6 S[M+H] + 471.0838,found 471.0842.
example 65
N- (4-hydroxy-3- (thiophene-2-sulfanyl) phenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) oxy) benzamide (Compound B-22)
Synthesis of Compound B-22
Referring to the procedure of example 1, substituting 4-fluorobenzenesulfonyl chloride with 2-thiophenesulfonyl chloride and substituting intermediate I-6 with intermediate II-2 produced compound B-22: 1 H NMR(300MHz,DMSO-d 6 )δ9.96(s,1H),9.42(s,2H),7.94(d,J＝8.8Hz,2H),7.88(dd,J＝5.0Hz,1H),7.77(d,J＝8.1Hz,2H),7.69(d,J＝2.4Hz,1H),7.64(d,J＝8.2Hz,2H),7.53(dd,1H),7.42(dd,J＝8.7,2.4Hz,1H),7.13(d,J＝8.9Hz,2H),7.10(d,J＝4.9Hz,1H),6.71(d,J＝8.7Hz,1H),5.30(s,2H).HRMS(ESI)calcd.for C 25 H 19 F 3 N 2 O 5 S 3 [M+H] + 581.0481,found 581.0470.
example 66
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (Compound B-23)
Synthesis of intermediate II-22
4-trifluoromethylthiophenol (200 mg,1.03 mmol), ethyl 4- (bromomethyl) benzoate (376 mg,1.55 mmol) and potassium iodide (17 mg,0.1 mmol) were added to acetonitrile (4 mL), cesium carbonate (675mg, 2.06 mmol) was added in portions with stirring, and the mixture was reacted at 80℃for 8 hours. After the completion of the reaction, the system was cooled to room temperature, the reaction mixture was filtered, and the cake was washed with ethyl acetate (5 mL). To the filtrate was added water (10 mL) for dilution, ethyl acetate (10 mL x 3) was extracted, and the organic phases were combined, washed with 1M aqueous sodium hydroxide solution (5 mL x 2), saturated brine (15 mL x 1) in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate II-22 (colorless oily liquid, 320 mg): 1 H NMR(300MHz,CDCl 3 )δ8.07(d,J＝8.0Hz,2H),7.58(d,J＝8.5Hz,2H),7.49(d,J＝8.0Hz,2H),6.99(d,J＝8.5Hz,2H),5.15(s,2H),4.39(q,J＝7.1Hz,2H),1.40(t,J＝7.1Hz,3H).ESI-MS:m/z 379.1[M+Na] + .
Synthesis of Compound B-23
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-22 produced compound B-23: 1 H NMR(300MHz,DMSO-d 6 )δ10.12(s,1H),9.67(s,1H),8.82(s,1H),7.97(d,J＝8.1Hz,2H),7.68(s,1H),7.65(s,1H),7.63(d,J＝2.4Hz,1H),7.59(d,J＝8.2Hz,2H),7.50(dd,J＝8.8,2.4Hz,1H),7.19(d,J＝8.7Hz,2H),6.86(d,J＝8.7Hz,1H),5.28(s,2H),2.97(s,3H).ESI-MS:m/z 511.0[M-H] - .HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 5 S 2 [M+H] + 513.0760,found 513.0786.
example 67
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (phenoxymethyl) benzamide (Compound B-24)
Synthesis of Compound B-24
Referring to the procedure of example 55, substituting intermediate II-2 with 4- (phenoxymethyl) benzoic acid produced compound B-24: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.68(s,1H),8.74(s,1H),7.95(d,J＝8.2Hz,2H),7.63(d,J＝2.4Hz,1H),7.57(d,J＝8.2Hz,2H),7.50(dd,J＝8.7,2.5Hz,1H),7.30(t,J＝7.9Hz,2H),7.03(d,J＝7.9Hz,2H),6.95(t,J＝7.3Hz,1H),6.86(d,J＝8.7Hz,1H),5.20(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 21 H 20 N 2 O 5 S[M+H] + 413.1171,found413.1175.
example 68
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((p-tolyloxy) methyl) benzamide (Compound B-25)
Synthesis of Compound B-25
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-methylphenol, compound B-25 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.35(s,1H),8.99(s,1H),7.94(d,J＝7.6Hz,2H),7.63(s,1H),7.55(d,J＝7.7Hz,2H),7.50(d,J＝8.8Hz,1H),7.09(d,J＝8.0Hz,2H),6.91(d,J＝7.7Hz,2H),6.86(d,J＝8.9Hz,1H),5.16(s,2H),2.97(s,3H),2.23(s,3H).HRMS(ESI)calcd.for C 22 H 22 N 2 O 5 S[M+H] + 427.1328,found 427.1334.
example 69
4- (4-Cyclopropylphenoxy) methyl-N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound B-26)
Synthesis of intermediate II-23
4-bromophenol (803 mg,2.09 mmol), ethyl 4- (bromomethyl) benzoate (400 mg,1.75 mmol) and potassium iodide (29 mg,0.18 mmol) were added to acetonitrile (5 mL), followed by addition of potassium carbonate (326 mg,2.36 mmol) in portions, and the mixture was reacted at 70℃for 8 hours. After the completion of the reaction, the reaction mixture was filtered, and the cake was washed with ethyl acetate (5 mL). To the filtrate was added water (10 mL) for dilution, ethyl acetate (10 mL x 3) was extracted, and the organic phases were combined, washed with 1M aqueous sodium hydroxide solution (5 mL x 2), saturated brine (15 mL x 1) in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate II-23 (colorless oily liquid, 531 mg): 1 H NMR(300MHz,CDCl 3 )δ8.06(d,J＝8.1Hz,2H),7.47(d,J＝8.0Hz,2H),7.37(d,J＝8.8Hz,2H),6.84(d,J＝8.8Hz,2H),5.09(s,2H),4.38(q,J＝7.1Hz,2H),1.39(t,J＝7.1Hz,3H).
Synthesis of intermediate II-24
Intermediate II-23 (354 mg,1.06 mmol), cyclopropylboronic acid (118 mg,1.38 mmol), tricyclohexylphosphine (30 mg,0.11 mmol), potassium phosphate (832 mg,3.71 mmol) and palladium acetate (12 mg,0.05 mmol) were added to a Schlenk tube, and toluene (3 mL) and water (0.1 mL) were added to the system under argon protection to suspend the mixture, and the mixture was reacted at 100℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate II-24 (white solid, 276 mg): 1 H NMR(300MHz,CDCl 3 )δ8.05(d,J＝8.2Hz,2H),7.49(d,J＝8.1Hz,2H),7.01(d,J＝8.7Hz,2H),6.86(d,J＝8.7Hz,2H),5.10(s,2H),4.38(q,J＝7.1Hz,2H),1.91-1.80(m,1H),1.40(t,J＝7.1Hz,3H),0.95-0.84(m,2H),0.67-0.57(m,2H).
synthesis of Compound B-26
With reference to the method of example 55, intermediate II-1 was replaced with intermediate II-24 to produceCompound B-26: 1 HNMR(300MHz,DMSO-d 6 )δ10.09(s,1H),9.61(s,1H),8.77(s,1H),7.94(d,J＝7.9Hz,2H),7.63(d,J＝1.4Hz,1H),7.55(d,J＝7.9Hz,2H),7.50(d,J＝8.8Hz,1H),7.00(d,J＝8.4Hz,2H),6.93-6.83(m,3H),5.15(s,2H),2.97(s,3H),1.90-1.80(m,1H),0.87(d,J＝7.2Hz,2H),0.57(d,J＝4.3Hz,2H).HRMS(ESI)calcd.for C 24 H 24 N 2 O 5 S[M+H] + 453.1479,found 453.1477.
example 70
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4-methoxyphenoxy) methylbenzamide (Compound B-27)
Synthesis of Compound B-27
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-methoxyphenol produces compound B-27: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.55(s,1H),8.75(s,1H),7.94(d,J＝8.1Hz,2H),7.63(d,J＝2.3Hz,1H),7.55(d,J＝8.1Hz,2H),7.49(dd,J＝8.8,2.3Hz,1H),6.96(d,J＝9.1Hz,2H),6.86(d,J＝9.2Hz,3H),5.13(s,2H),3.69(s,3H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 22 N 2 O 6 S[M+H] + 443.1271,found 443.1276.
example 71
4- (4-fluorophenoxy) methyl-N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound B-28)
Synthesis of Compound B-28
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-fluorophenol produces compound B-28: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.55(s,1H),8.77(s,1H),7.95(d,J＝8.1Hz,2H),7.63(d,J＝2.2Hz,1H),7.56(d,J＝8.0Hz,2H),7.50(dd,J＝8.6Hz,1H),7.13(t,J＝8.8Hz,2H),7.08-6.99(m,2H),6.86(d,J＝8.7Hz,1H),5.18(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 21 H 19 FN 2 O 5 S[M+H] + 431.1071,found 431.1074.
Example 72
4- (4-chlorophenoxy) methyl-N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound B-29)
Synthesis of Compound B-29
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-chlorophenol produced compound B-29: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.65(s,1H),8.73(s,1H),7.95(d,J＝8.0Hz,2H),7.63(s,1H),7.56(d,J＝7.9Hz,2H),7.50(dd,J＝8.6,1.6Hz,1H),7.34(d,J＝8.8Hz,2H),7.05(d,J＝8.8Hz,2H),6.86(d,J＝8.7Hz,1H),5.20(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 21 H 19 ClN 2 O 5 S[M+H] + 447.0776,found 447.0778.
example 73
4- (4-bromophenoxy) methyl-N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound B-30)
Synthesis of Compound B-30
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-chlorophenol produced compound B-30: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.20(s,2H),7.95(d,J＝8.1Hz,2H),7.63(d,J＝2.4Hz,1H),7.56(d,J＝8.2Hz,2H),7.52-7.42(m,3H),7.01(d,J＝8.9Hz,2H),6.85(d,J＝8.7Hz,1H),5.20(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 21 H 19 BrN 2 O 5 S[M+H] + 491.0271,found 491.0277.
example 74
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethyl) phenoxy) methyl) benzamide (Compound B-31)
Synthesis of Compound B-31
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-trifluoromethylphenol produced compound B-31: 1 H NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),9.50(s,1H),8.85(s,1H),7.95(d,J＝8.2Hz,2H),7.67(d,J＝8.6Hz,2H),7.62(d,J＝2.3Hz,1H),7.58(d,J＝8.2Hz,2H),7.49(dd,J＝8.7,2.3Hz,1H),7.21(d,J＝8.5Hz,2H),6.85(d,J＝8.7Hz,1H),5.29(s,2H),2.96(s,3H).ESI-MS:m/z 481.1039[M+H] + .HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 5 S[M+H] + 481.1040,found 481.1039.
example 75
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) phenoxy) methyl) benzamide (Compound B-32)
Synthesis of Compound B-32
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-trifluoromethoxyphenol produces compound B-32: 1 H NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),9.21(s,2H),7.95(d,J＝8.1Hz,2H),7.62(d,J＝2.3Hz,1H),7.57(d,J＝8.1Hz,1H),7.49(dd,J＝8.7,2.3Hz,1H),7.30(d,J＝8.8Hz,2H),7.12(d,J＝9.1Hz,2H),6.85(d,J＝8.7Hz,1H),5.22(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 6 S[M+H] + 497.0989,found 497.0992.
example 76
4- ((4-cyanophenoxy) methyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (compound B-33)
Synthesis of Compound B-33
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-hydroxybenzonitrile gives compound B-33: 1 H NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),9.18(s,2H),7.95(d,J＝8.1Hz,2H),7.78(d,J＝8.7Hz,2H),7.62(d,J＝2.1Hz,1H),7.57(d,J＝8.1Hz,2H),7.49(dd,J＝8.7,2.1Hz,1H),7.20(d,J＝8.8Hz,2H),6.85(d,J＝8.7Hz,1H),5.30(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 19 N 3 O 5 S[M+H] + 438.1118found 438.1122.
example 77
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (((trifluoromethyl) thio) methyl) phenoxy) methyl) benzamide (compound B-34)
Synthesis of intermediate II-25
Ethyl 4- (bromomethyl) benzoate (500 mg,2.06 mmol), p-hydroxybenzaldehyde (301 mg,2.46 mmol) and potassium iodide (34 mg,0.21 mmol) were added to acetonitrile (10 mL), cesium carbonate (1 g,3.09 mmol) was added in portions, and the mixture was reacted at 80℃for 6 hours. After the completion of the reaction, the reaction mixture was filtered, and the cake was washed with ethyl acetate (5 mL). To the filtrate was added water (10 mL) for dilution, ethyl acetate (10 mL x 3) was extracted, and the organic phases were combined, washed with 1M aqueous sodium hydroxide solution (10 mL x 2), saturated brine (10 mL x 1) in this order, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate II-25 (white solid, 603 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.86(s,1H),7.98(d,J＝8.1Hz,2H),7.87(d,J＝8.7Hz,2H),7.60(d,J＝8.1Hz,2H),7.21(d,J＝8.6Hz,2H),5.33(s,2H),4.31(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H).
synthesis of intermediate II-26
Intermediate II-25 (600 mg,2.06 mmol) was addedSodium borohydride (215 mg,6.37 mmol) was added in portions to methanol (8 mL) in ice bath, and the reaction was continued at 0deg.C for 4 hours. After the reaction was completed, the reaction solution was poured into ice water (20 mL) to quench, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate II-26, which was directly used for the next reaction without further purification: 1 H NMR(300MHz,DMSO-d 6 )δ7.96(d,J＝8.1Hz,2H),7.57(d,J＝8.1Hz,2H),7.22(d,J＝8.4Hz,2H),6.95(d,J＝8.5Hz,2H),5.18(s,2H),5.03(t,J＝5.6Hz,1H),4.40(d,J＝5.4Hz,2H),4.30(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H).ESI-MS:m/z 309.1[M+Na] + .
Synthesis of intermediate II-27
Intermediate II-26 (589 mg,2.06 mmol) and triphenylphosphine (756 mg,2.88 mmol) were added to dichloromethane (5 mL), a solution of carbon tetrabromide (1.02 g,3.09 mmol) in dichloromethane (5 mL) was slowly added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate II-27 (white solid, 370 mg).
Synthesis of intermediate II-28
Intermediate II-27 (370 mg,1.06 mmol) and sodium thiocyanate (129 mg,1.59 mmol) were added to acetonitrile (4 mL) and reacted at 80℃for 4 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crude intermediate II-28, which was used in the next reaction without further purification.
Synthesis of intermediate II-29
Intermediate II-28 (273 mg,0.83 mmol) and (trifluoromethyl) Trimethylsilane (TMSCF) 3 ) (185. Mu.L, 1.25 mmol) was added to tetrahydrofuran (2 mL), and a solution of 1M tetrabutylammonium fluoride in tetrahydrofuran (1.25 mL,1.25 mmol) in anhydrous tetrahydrofuran (5 mL) was slowly added dropwise under ice bath, and the mixture was slowly warmed to room temperature and reacted for 8 hours. After the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/acetic acid Ethyl = 50: 1) Purification, intermediate II-29 (white solid, 158 mg): 1 H NMR(300MHz,CDCl 3 )δ8.04(d,J＝7.9Hz,2H),7.47(d,J＝7.4Hz,2H),7.26(d,J＝3.9Hz,2H),6.91(d,J＝8.4Hz,2H),5.12(d,J＝8.7Hz,2H),4.39(q,J＝15.8,7.3Hz,2H),4.08(d,J＝8.7Hz,2H),1.40(t,3H).
synthesis of Compound B-34
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-29 produced compound B-34: 1 H NMR(300MHz,DMSO-d 6 )δ10.09(s,1H),9.19(s,2H),7.94(d,J＝8.1Hz,2H),7.62(d,J＝2.1Hz,1H),7.56(d,J＝8.1Hz,2H),7.49(dd,J＝8.8,2.0Hz,1H),7.32(d,J＝8.4Hz,2H),7.01(d,J＝8.5Hz,2H),6.85(d,J＝8.6Hz,1H),5.19(s,2H),4.25(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0914.
example 78
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((6- (trifluoromethyl) thiopyridin-3-yl) oxy) methyl) benzamide (Compound B-35)
Synthesis of intermediate II-30
Referring to the procedure of example 66, 4-trifluoromethylthiophenol was replaced with 2-bromo-5-hydroxypyridine to produce intermediate II-30.
Synthesis of intermediate II-31
Intermediate II-30 (275 mg,0.82 mmol), silver trifluormethanethiol (256 mg,1.23 mmol), cuprous iodide (155 mg,0.82 mmol) and 2,2' -bipyridine (191 mg,1.23 mmol) were added to the vial, suspended in acetonitrile (3 mL) and reacted at 110℃for 12 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the filter cake was washed with ethyl acetate (5 mL), the solvent was distilled off 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(300MHz,DMSO-d 6 )δ8.48(d,J＝2.9Hz,1H),7.99(d,J＝8.2Hz,2H),7.77(d,J＝8.6Hz,1H),7.61(d,J＝8.3Hz,3H),5.35(s,2H),4.31(q,J＝7.1Hz,2H),1.31(t,J＝7.1Hz,3H).
synthesis of Compound B-35
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate I-31 produced compound B-35: 1 HNMR(300MHz,DMSO-d 6 )δ10.11(s,1H),9.22(s,2H),8.49(d,J＝2.9Hz,1H),7.96(d,J＝8.1Hz,2H),7.78(d,J＝8.7Hz,1H),7.64-7.56(m,4H),7.49(dd,J＝8.7,2.3Hz,1H),6.85(d,J＝8.7Hz,1H),5.34(s,2H),2.96(s,3H).ESI-MS:m/z 514.0718[M+H] + .HRMS(ESI)calcd.for C 21 H 18 F 3 N 3 O 5 S 2 [M+H] + 514.0713,found 514.0718.
Example 79
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (5- (trifluoromethyl) thiopyridin-2-yloxy) methyl) benzamide (compound B-36)
Synthesis of Compound B-36
Referring to the procedure of example 78, substituting 2-bromo-5-hydroxypyridine with 2-hydroxy-5-bromopyridine produces compound B-36: 1 H NMR(300MHz,DMSO-d 6 )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.for C 21 H 18 F 3 N 3 O 5 S 2 [M+H] + 514.0713,found 514.0707.
example 80
4- ((cyclohexyloxy) methyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (compound B-37)
Synthesis of intermediate II-32
Sodium hydride (102 mg,2.55 mmol) was added to a dry Schlenk tube, protected by argon, suspended in anhydrous tetrahydrofuran (2 mL), then a solution of cyclohexanol (225 mg,2.25 mmol) in anhydrous tetrahydrofuran (2 mL) was added under ice, the mixture was stirred at room temperature for 1 hour after dropping, then a solution of ethyl 4- (bromomethyl) benzoate (365 mg,1.5 mmol) in anhydrous tetrahydrofuran (2 mL) was added dropwise under ice, and the mixture was reacted at room temperature for 10 hours. After the reaction was completed, water (20 mL) was added to the reaction mixture to quench, ethyl acetate (10 mL x 3) was extracted, the organic phases were combined, washed with saturated sodium chloride (10 mL x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give crude intermediate II-32, which was used in the next reaction without further purification.
Synthesis of Compound B-37
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-32 produced compound B-37: 1 H NMR(300MHz,DMSO-d 6 )δ10.06(s,1H),9.68(s,1H),8.71(s,1H),7.91(d,J＝8.0Hz,2H),7.63(d,J＝2.6Hz,1H),7.50(dd,J＝8.7,2.5Hz,1H),7.44(d,J＝8.0Hz,2H),6.85(d,J＝8.7Hz,1H),4.57(s,2H),3.40-3.33(m,1H),2.97(s,3H),1.94-1.81(m,2H),1.74-1.63(m,2H),1.55-1.42(m,1H),1.35-1.18(m,5H).HRMS(ESI)calcd.for C 21 H 26 N 2 O 5 S[M+H] + 419.1635,found 419.1638.
example 81
4- (((4, 4-difluorocyclohexyl) oxy) methyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (compound B-38)
Synthesis of intermediate II-33
4, 4-Difluorocyclohexanone (335 mg,2.5 mmol) was added to methanol (10 mL), sodium borohydride (189 mg,5 mmol) was added in portions under ice bath, and the mixture was allowed to react slowly to room temperature for 2 hours. After the completion of the reaction, the reaction mixture was quenched by pouring it into ice water (20 mL), extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated brine (10 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give intermediate II-33 (pale yellow oily liquid, 300 mg).
Synthesis of intermediate II-34
Intermediate II-33 (295 mg,2.17 mmol) was added to dichloromethane (5 mL), triethylamine (600. Mu.L, 4.33 mmol) was added, and a solution of trimethyltrisilicon triflate (TMSOTF) (588. Mu.L, 3.25 mmol) in dichloromethane (2 mL) was slowly added dropwise under ice-bath, and the mixture was allowed to react slowly to room temperature for 1 hour. After the completion of the reaction, the reaction mixture was washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate II-34 (colorless oily liquid, 223 mg).
Synthesis of intermediate II-35
Ferric trichloride (17 mg,0.3 mmol) was added to ethyl acetate (10 mL), trimethylchlorosilane (TMSCl) (174 mg,1.6 mmol) was added under stirring, and the reaction was continued at room temperature until the solid was dissolved, to prepare a catalytic liquid. Intermediate II-34 (280 mg,1.34 mmol) and methyl paraformylbenzoate (221 mg,1.34 mmol) were added to the reaction flask, followed by the above-mentioned catalytic solution (1.4 mL), triethylsilane (225. Mu.L, 1.41 mmol) and the reaction at room temperature for 8 hours. After the completion of the reaction, the reaction mixture was quenched by adding saturated sodium bicarbonate solution (3 mL), extracted with ethyl acetate (10 ml×3), and the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate II-35 (pale yellow oily liquid, 245 mg).
Synthesis of Compound B-38
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-35 produced compound B-38: 1 H NMR(300MHz,DMSO-d 6 )δ10.07(s,1H),9.12(s,2H),7.92(d,J＝7.8Hz,2H),7.63(s,1H),7.54-7.42(m,3H),6.85(d,J＝8.6Hz,1H),4.59(s,2H),3.63(s,1H),2.96(s,3H),2.07-1.73(m,8H).HRMS(ESI)calcd.for C 21 H 24 F 2 N 2 O 5 S[M+H] + 455.1447,found455.1454.
example 82
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylthio) phenoxy) methyl) benzamide (compound B-39)
Synthesis of Compound B-39
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate with methyl 3-fluoro-4- (bromomethyl) benzoate produced compound B-39: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.21(s,2H),7.82(d,J＝8.5Hz,2H),7.71(d,J＝7.6Hz,1H),7.66(d,J＝8.5Hz,2H),7.62(d,J＝2.2Hz,1H),7.49(dd,J＝8.7,2.3Hz,1H),7.21(d,J＝8.7Hz,2H),6.86(d,J＝8.7Hz,1H),5.29(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 F 4 N 2 O 5 S 2 [M+H] + 531.0666,found531.0665.
example 83
3-fluoro-4- ((trifluoromethyl) thio) phenoxy) methyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (compound B-40)
Synthesis of intermediate II-36
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 3-fluoro-4-nitrophenol and substituting ethyl 4- (bromomethyl) benzoate for methyl 3-fluoro-4- (bromomethyl) benzoate, compound II-36 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ8.19(t,J＝9.2Hz,1H),7.86(dd,J＝7.9,1.6Hz,1H),7.81-7.73(m,2H),7.38(dd,J＝13.6,2.6Hz,1H),7.14-7.08(m,1H),5.41(s,2H),3.89(s,3H).
synthesis of intermediate II-37
Intermediate II-36 (150 mg,0.51 mmol) was added to N, N-dimethylformamide (2 mL), tetrahydroxydiboron (131 mg,1.46 mmol) and 4,4' -bipyridine (1 mg,0.005 mmol) were added sequentially under ice-bath, and the reaction was allowed to proceed to room temperature for 15 minutes. After the reaction was completed, water (20 mL) was added to the reaction mixture to dilute it, ethyl acetate (10 mL x 3) was used for extraction, the organic phases were combined, washed with water (10 mL x 1), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate II-37, which was used for the next reaction without further purification.
Synthesis of intermediate II-38
Intermediate II-37 (275 mg,0.82 mmol) was added to ethanol (1.5 mL), followed by 40% fluoroboric acid (120. Mu.L) and tert-butyl nitrite (130. Mu.L) in sequence under ice bath, and the mixture was slowly warmed to room temperature and reacted for 1 hour. After the completion of the reaction, diethyl ether (2 mL) was added to the reaction mixture to precipitate a solid completely, the reaction mixture was filtered, and the cake was washed with diethyl ether (2 mL) and dried under reduced pressure. The diazonium salt thus obtained, silver trifluoromethane thiolate (128 mg,0.61 mmol), cuprous iodide (97 mg,0.51 mmol) and potassium carbonate (141 mg,1.02 mmol) were added to acetonitrile (2 mL), and the mixture was reacted at room temperature in an air atmosphere for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filter cake was washed with ethyl acetate (2 ml×2), the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate II-38 (white solid, 125 mg).
Synthesis of intermediate II-39
Intermediate II-38 (126 mg,0.33 mmol) was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL), and 1M aqueous sodium hydroxide solution (1 mL) was added thereto, followed by reaction at 60℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the organic solvent was distilled off under reduced pressure, a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2 to 3, solids were precipitated, and the cake was washed with water (2 mL) and N-hexane (2 mL) in this order, and the obtained solid was dried to constant weight to obtain intermediate II-39 (white solid, 86 mg): 1 H NMR(300MHz,DMSO-d 6 )δ13.39(s,1H),7.83(dd,J＝7.9,1.5Hz,1H),7.76-7.74(m,1H),7.74-7.70(m,2H),7.29(dd,J＝11.0,2.6Hz,1H),7.07(dd,J＝8.8,2.7Hz,1H),5.33(s,2H).
synthesis of Compound B-40
Referring to example 55, the compound was prepared by substituting intermediate II-2 for intermediate II-39B-40： 1 H NMR(300MHz,DMSO-d 6 )δ10.21(s,1H),9.66(s,1H),8.88(s,1H),7.84(d,J＝8.5Hz,2H),7.77-7.69(m,2H),7.63(d,J＝2.5Hz,1H),7.51(dd,J＝8.7,2.5Hz,1H),7.30(dd,J＝11.0,2.6Hz,1H),7.08(dd,J＝8.8,2.4Hz,1H),6.87(d,J＝8.7Hz,1H),5.34(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C 22 H 17 F 5 N 2 O 5 S 2 [M+H] + 549.0572,found 549.0547.
Example 84
3-fluoro-4- (2-fluoro-4- ((trifluoromethyl) thio) phenoxy) methyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (compound B-41)
Synthesis of Compound B-41
Referring to the procedure of example 83, substituting 3-fluoro-4-nitrophenol with 2-fluoro-4-nitrophenol produced compound B-41: 1 H NMR(300MHz,DMSO-d 6 )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 F 5 N 2 O 5 S 2 [M+H] + 549.0572,found 549.0570.
example 85
3-fluoro-N- (4-hydroxy-3- (methylsulfonamide) phenyl) -4- (4- (trifluoromethylphenoxy) methyl) benzamide (Compound B-42)
Synthesis of Compound B-42
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate with methyl 3-fluoro-4- (bromomethyl) benzoate and substituting 4-trifluoromethylthiophenol with 4-trifluoromethylphenol gives compound B-42: 1 H NMR(400MHz,DMSO-d 6 )δ10.19(s,1H),9.65(s,1H),8.89(s,1H),7.84(s,1H),7.82(s,1H),7.72(d,J＝7.7Hz,1H),7.71-7.68(m,2H),7.63(d,J＝2.5Hz,1H),7.51(dd,J＝8.8,2.5Hz,1H),7.26(d,J＝8.6Hz,2H),6.87(d,J＝8.7Hz,1H),5.33(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C 22 H 18 F 4 N 2 O 5 S[M+H] + 499.0945,found 499.0940.
Example 86
3-chloro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (Compound B-43)
Synthesis of intermediate II-40
Methyl 3-chloro-4-methylbenzoate (185 mg,1 mmol) was added to carbon tetrachloride (3 mL), azobisisobutyronitrile (AIBN) (33 mg,0.2 mmol) and N-bromosuccinimide (NBS) (87 mg,1.05 mmol) were successively added in portions under an ice bath, and the mixture was reacted at 70℃for 4 hours. After the reaction was completed, the system was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give crude intermediate II-40, which was used in the next reaction without further purification.
Synthesis of Compound B-43
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate for the crude intermediate II-40 gives compound B-43: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.21(s,2H),7.82(d,J＝8.5Hz,2H),7.71(d,J＝7.6Hz,1H),7.66(d,J＝8.5Hz,2H),7.62(d,J＝2.2Hz,1H),7.49(dd,J＝8.7,2.3Hz,1H),7.21(d,J＝8.7Hz,2H),6.86(d,J＝8.7Hz,1H),5.29(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 ClF 3 N 2 O 5 S 2 [M+H] + 547.0371,found 547.0378.
example 87
3-bromo-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (compound B-44)
Synthesis of Compound B-44
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate with methyl 3-bromo-4-methylbenzoate produced compound B-44: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.21(s,2H),7.82(d,J＝8.5Hz,2H),7.71(d,J＝7.6Hz,1H),7.66(d,J＝8.5Hz,2H),7.62(d,J＝2.2Hz,1H),7.49(dd,J＝8.7,2.3Hz,1H),7.21(d,J＝8.7Hz,2H),6.86(d,J＝8.7Hz,1H),5.29(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 BrF 3 N 2 O 5 S 2 [M+H] + 590.9865,found 590.9874.
example 88
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -3-methoxy-4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (Compound B-45)
Synthesis of Compound B-45
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate with methyl 3-methoxy-4-bromomethyl benzoate produced compound B-45: 1 H NMR(300MHz,DMSO-d 6 )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.for C 23 H 21 F 3 N 2 O 6 S 2 [M+H] + 543.0866,found 543.0865.
example 89
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -3- (trifluoromethyl) -4- (4- (trifluoromethyl) thio) phenoxy) methylbenzamide (Compound B-46)
Synthesis of intermediate II-41
4-trifluoromethylthiophenol (147 mg,0.75 mmol), 4-bromo-2-trifluoromethylbromobenzyl (200 mg,0.63 mmol) and potassium iodide (10 mg,0.06 mmol) were added to acetonitrile (3 mL), followed by addition of potassium carbonate (117 mg,0.85 mmol) in portions, and reaction was carried out at 60℃for 8 hours. After the completion of the reaction, the system was cooled to room temperature, 1M aqueous sodium hydroxide solution (10 mL) was added to the reaction solution to neutralize the excess phenol, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with 1M aqueous sodium hydroxide solution (5 ml×2), saturated brine (15 ml×1) in this order, the solvent was distilled off 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,CDCl 3 )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).
synthesis of intermediate II-42
Intermediate II-41 (255 mg,0.59 mmol), oxalic acid dihydrate (224 mg,1.78 mmol), palladium acetate (4 mg,0.02 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthenes (Xantphos) (10 mg,0.02 mmol) and acetic anhydride (167. Mu.L, 1.78 mmol) were added to anhydrous N, N-dimethylformamide (2 mL), the system was cooled to-78℃and frozen, N-diisopropylethylamine (310. Mu.L, 1.78 mmol) was added, and the system was allowed to spontaneously return to room temperature under argon atmosphere and stirred for 30 minutes and then allowed to react at 100℃for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL), water (20 mL) were added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1), saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate II-42 (white solid, 185 mg): 1 H NMR(300MHz,DMSO-d 6 )δ13.55(s,1H),8.26(d,J＝7.9Hz,2H),7.93(d,J＝7.9Hz,1H),7.68(d,J＝8.6Hz,2H),7.18(d,J＝8.7Hz,2H),5.39(s,2H).
synthesis of Compound B-46
Referring to the procedure of example 7, substituting intermediate 4-trifluoromethylthiobenzoic acid for intermediate II-42 produced compound B-46: 1 H NMR(300MHz,DMSO-d 6 )δ10.35(s,1H),9.18(s,2H),8.32(s,1H),8.27(d,J＝7.1Hz,1H),7.92(d,J＝7.7Hz,1H),7.68(d,J＝8.3Hz,2H),7.62(s,1H),7.51(d,J＝8.0Hz,1H),7.19(d,J＝8.5Hz,2H),6.88(d,J＝8.7Hz,1H),5.39(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 18 F 6 N 2 O 5 S 2 [M+H] + 581.0634,found 581.0638.
example 90
3-cyano-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylthio) phenoxy) methyl) benzamide (compound B-47)
Synthesis of intermediate II-43
Methyl 3-iodo-4-methylbenzoate (500 mg,1.81 mmol) and cuprous cyanide (487 mg,5.43 mmol) were added to N, N-dimethylformamide (6 mL), and the mixture was reacted at 100℃for 12 hours. After the completion of the reaction, the system was cooled to room temperature, water (60 mL) was added to the reaction solution to dilute, ethyl acetate (15 ml×3) was extracted, and the organic phases were combined, washed with water (15 ml×2), saturated brine (15 ml×1) in this order, the solvent was distilled off 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).
Synthesis of Compound B-47
Referring to the procedure of example 86, substituting methyl 3-chloro-4-methylbenzoate for intermediate II-43, compound B-47 was prepared: 1 H NMR(300MHz,DMSO-d 6 )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 F 3 N 3 O 5 S 2 [M+H] + 538.0713,found 538.0712.
example 91
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -6- ((4- ((trifluoromethyl) thio) phenoxy) methyl) nicotinamide (compound B-48)
Synthesis of Compound B-48
Referring to the procedure of example 86, substituting methyl 3-chloro-4-methylbenzoate with methyl 6-methylnicotinate produced compound B-48: 1 H NMR(300MHz,DMSO-d 6 )δ10.30(s,1H),9.20(s,2H),9.07(s,1H),8.32(dd,J＝8.2,1.9Hz,1H),7.66(d,J＝8.1Hz,3H),7.62(d,J＝2.3Hz,1H),7.49(dd,J＝8.8,2.2Hz,1H),7.20(d,J＝8.8Hz,2H),6.86(d,J＝8.7Hz,1H),5.35(s,2H),2.96(s,3H).ESI-MS:m/z 514.0721[M+H] + .HRMS(ESI)calcd.for C 21 H 18 F 3 N 3 O 5 S 2 [M+H] + 514.0713,found 514.0721.
example 92
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -2- (4- (trifluoromethyl) phenoxy) methyl) pyrimidine-5-carboxamide (Compound B-49)
Synthesis of intermediate II-44
2-methyl-5-bromopyrimidine (800 mg,4.62 mmol) was added to carbon tetrachloride (10 mL), azobisisobutyronitrile (AIBN) (759 mg,4.62 mmol) and N-bromosuccinimide (NBS) (905 mg,5.09 mmol) were successively added in portions under an ice bath, and the mixture was allowed to react at 70℃for 8 hours. After the reaction was completed, the system was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give a crude intermediate II-44 which was used in the next reaction without further purification.
Synthesis of intermediate II-45
Crude intermediate II-44, 4-trifluoromethylthiophenol (191 mg,0.99 mmol) and potassium iodide (18 mg,0.11 mmol) were added to acetonitrile (4 mL), cesium carbonate (534 mg,1.64 mmol) was added in portions, and the reaction was continued at 70℃for 8 hours. After the completion of the reaction, the system was cooled to room temperature, water (20 mL) was added to the reaction solution, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (15 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate II-45 (white solid, 260 mg).
Synthesis of intermediate II-46
Intermediate II-45 (260 mg,0.71 mmol), oxalic acid dihydrate (399 mg,2.14 mmol), palladium acetate (5 mg,0.02 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthenes (Xantphos) (12 mg,0.02 mmol) and acetic anhydride (200. Mu.L, 2.14 mmol) were added to anhydrous N, N-dimethylformamide (3 mL), the system was cooled to-78℃and frozen, N-diisopropylethylamine (353. Mu.L, 2.14 mmol) was added, and the system was allowed to spontaneously return to room temperature under argon atmosphere and stirred for 30 minutes, and then allowed to react at 100℃for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL), water (20 mL) were added to the reaction solution to dilute, ethyl acetate (10 mL x 3) was extracted, the organic phases were combined, washed with water (10 mL x 1), saturated brine (10 mL x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=50:1) to give crude intermediate II-46, which was slurried (dichloromethane/methanol=20:1) and purified to give intermediate II-46 (white solid, 135 mg): 1 H NMR(400MHz,DMSO-d 6 )δ13.84(s,1H),9.23(s,2H),7.63(d,J＝8.8Hz,2H),7.13(d,J＝8.9Hz,2H),5.49(s,2H).
Synthesis of Compound B-49
Intermediate II-46 (100 mg,0.30 mmol), intermediate I-18 (105 mg,0.33 mmol) and N, N-dimethylformamide (2 mL) were added, N, N-diisopropylethylamine (150. Mu.L, 0.91 mmol) was added, and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (138 mg,0.36 mmol) was added while ice-bath, and the reaction was allowed to proceed to room temperature for 16 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL) and ethyl acetate (10 mL. Times.3)) The organic phases were combined by extraction, washed successively with water (10 ml x 1), saturated brine (10 ml x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=50: 1) Purification gave crude compound B-49, which was slurried (dichloromethane/methanol=20: 1) Purification gave compound B-49 (white solid, 108 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.47(s,1H),9.55(s,1H),9.25(s,2H),8.93(s,1H),7.66(s,1H),7.64-7.60(m,2H),7.49(dd,J＝8.7,2.6Hz,1H),7.14(d,J＝8.9Hz,2H),6.89(d,J＝8.7Hz,1H),5.49(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 20 H 17 F 3 N 4 O 5 S 2 [M+H] + 515.0665,found515.0672.
example 93
3-cyclopropyl-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (Compound B-50)
Synthesis of intermediate II-47
Referring to the procedure of example 86, substituting methyl 3-chloro-4-methylbenzoate with methyl 3-bromo-4-methylbenzoate produced intermediate II-47: 1 H NMR(300MHz,CDCl 3 )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).
synthesis of intermediate II-48
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, protected by argon, and toluene (4 mL), water (0.2 mL) were added to the system and suspended, and the mixture was allowed to react at 90℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the solvent was distilled off 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).
Synthesis of Compound B-50
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-48 produced compound B-50: 1 H NMR(300MHz,DMSO-d 6 )δ10.05(s,1H),9.19(s,2H),7.75(d,J＝7.9Hz,1H),7.67(d,J＝8.6Hz,2H),7.59(d,J＝2.3Hz,1H),7.54(d,J＝7.9Hz,2H),7.48-7.41(m,1H),7.21(d,J＝8.8Hz,2H),6.85(d,J＝8.7Hz,1H),5.40(s,2H),2.96(s,3H),2.14-2.04(m,1H),1.03-0.92(m,2H),0.84-0.72(m,2H).HRMS(ESI)calcd.for C 25 H 23 F 3 N 2 O 5 S 2 [M+H] + 553.1079,found 553.1084.
example 94
2-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylthio) phenoxy) methyl) benzamide (compound B-51)
Synthesis of Compound B-51
Referring to the procedure of example 89, substituting 4-bromo-2-trifluoromethyl bromobenzyl with 3-fluoro-4-bromobenzyl gave compound B-51: 1 H NMR(400MHz,DMSO-d 6 )δ10.25(s,1H),9.44(s,1H),9.13(s,1H),7.69-7.65(m,3H),7.59(d,J＝2.5Hz,1H),7.47-7.43(m,1H),7.42(d,J＝7.3Hz,1H),7.40(d,J＝8.0Hz,1H),7.19(d,J＝8.9Hz,2H),6.86(d,J＝8.7Hz,1H),5.28(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 18 F 4 N 2 O 5 S 2 [M+H] + 531.0666,found 531.0670.
example 95
2-fluoro-N- (4-hydroxy-3- (methylsulfonamide) phenyl) -4- (4- (trifluoromethylphenoxy) methyl) benzamide (Compound B-52)
Synthesis of Compound B-52
With reference to the method of example 89, 4-bromo-2-trifluoromethyl-bromobenzyl is replaced by 3-fluoro-4-bromobenzyl, and 4-trifluoromethylthioSubstitution of phenol for 4-trifluoromethylphenol gives compound B-52: 1 H NMR(400MHz,DMSO-d 6 )δ10.24(s,1H),9.74(s,1H),8.77(s,1H),7.70-7.67(m,3H),7.66(d,J＝7.5Hz,1H),7.58(d,J＝2.5Hz,1H),7.46-7.40(m,2H),7.39(d,J＝8.1Hz,1H),7.22(d,J＝8.6Hz,2H),6.86(d,J＝8.7Hz,1H),5.31(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 F 4 N 2 O 5 S[M+H] + 499.0945,found 499.0937.
example 96
2-chloro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylthio) phenoxy) methyl) benzamide (compound B-53)
Synthesis of intermediate II-49
4-bromo-3-chlorobenzaldehyde (250 mg,1.14 mmol) was added to methanol (5 mL), sodium borohydride (77 mg,2.28 mmol) was added in portions under ice bath, and the mixture was slowly warmed to room temperature and reacted for 4 hours. After the reaction was completed, the reaction mixture was poured into ice water (20 mL) and quenched, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate II-49, which was used in the next reaction without further purification.
Synthesis of intermediate II-50
Crude intermediate II-49 and triphenylphosphine (418 mg,1.59 mmol) were added to tetrahydrofuran (5 mL), carbon tetrabromide (567 mg,1.71 mmol) was added in portions under ice bath, and the mixture was allowed to react at room temperature for 6 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate II-50 (colorless oily liquid, 271 mg).
Synthesis of intermediate II-51
Intermediate II-50 (270 mg,0.95 mmol), 4-trifluoromethylphenol (203 mg,1.04 mmol) and potassium iodide (16 mg,0.09 mmol) were added to acetonitrile (3 mL), cesium carbonate (460 mg,1.42 mmol) was added in portions, and the addition was completed and the temperature was raised to 70℃for reaction for 8 hours. Reaction junctionAfter the completion of the reaction, the system was cooled to room temperature, water (20 mL) was added to the reaction solution, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (15 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate II-51 (white solid, 364 mg): 1 H NMR(400MHz,CDCl 3 )δ7.66(d,J＝8.2Hz,1H),7.61(d,J＝8.8Hz,2H),7.56(d,J＝1.9Hz,1H),7.20(dd,J＝8.2,2.0Hz,1H),7.00(d,J＝8.8Hz,2H),5.04(s,2H).
synthesis of intermediate II-52
Intermediate II-51 (345 mg,0.87 mmol), oxalic acid dihydrate (328 mg,2.60 mmol), palladium acetate (6 mg,0.03 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthenes (Xantphos) (15 mg,0.03 mmol) and acetic anhydride (244. Mu.L, 2.60 mmol) were added to anhydrous N, N-dimethylformamide (2.5 mL), the system was cooled to-78℃and frozen, N-diisopropylethylamine (430. Mu.L, 2.60 mmol) was added, and the system was allowed to spontaneously return to room temperature under stirring for 30 minutes under argon, and then allowed to react at 100℃for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL), water (20 mL) were added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=75:1) to give intermediate II-52 (pale yellow solid, 248 mg): 1 H NMR(400MHz,DMSO-d 6 )δ13.40(s,1H),7.83(d,J＝8.0Hz,1H),7.67(d,J＝8.7Hz,2H),7.64(d,J＝1.3Hz,1H),7.50(dd,J＝8.0,1.5Hz,1H),7.18(d,J＝8.9Hz,2H),5.26(s,2H).
Synthesis of Compound B-53
Referring to the procedure of example 55, substituting intermediate II-2 for intermediate II-52 produced compound B-53: 1 HNMR(400MHz,DMSO-d 6 )δ10.33(s,1H),9.74(s,1H),8.74(s,1H),7.70-7.64(m,3H),7.59(t,J＝5.0Hz,2H),7.52(d,J＝7.9Hz,1H),7.45(dd,J＝8.7,2.5Hz,1H),7.19(d,J＝8.9Hz,2H),6.86(d,J＝8.7Hz,1H),5.27(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 18 ClF 3 N 2 O 5 S 2 [M+H] + 547.0371,found 547.0379.
example 97
2-chloro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylthio) phenoxy) methyl) benzamide (compound B-54)
Synthesis of Compound II-53
Referring to the procedure of example 86, 3-chloro-4-methylbenzoate was replaced with 4-bromo-2, 6-difluorotoluene to give intermediate II-53.
Synthesis of Compound B-54
Referring to the procedure of example 96, substituting intermediate II-50 for intermediate II-53 produced compound B-54: 1 H NMR(400MHz,DMSO-d 6 )δ10.26(s,1H),9.64(s,1H),8.88(s,1H),7.77(d,J＝8.2Hz,2H),7.69(d,J＝8.7Hz,2H),7.63(d,J＝2.5Hz,1H),7.51(dd,J＝8.8,2.5Hz,1H),7.23(d,J＝8.9Hz,2H),6.89(d,J＝8.7Hz,1H),5.27(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C 22 H 17 F 5 N 2 O 5 S 2 [M+H] + 549.0572,found 549.0575.
example 98
Ethyl 2- (N- (5- (3-fluoro-4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide) -2-hydroxyphenyl) sulfamoyl) acetate (compound B-55)
Synthesis of intermediate II-54
2-nitro-4-aminophenol (500 mg,3.24 mmol) was added to dichloromethane (10 mL), N-diisopropylethylamine (1.1 mL,6.49 mmol) was added dropwise under ice bath, and a solution of t-butyldimethylchlorosilane (733 mg,4.87 mmol) in dichloromethane (5 mL) was added dropwise and the mixture was allowed to react at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off 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(400MHz,DMSO-d 6 )δ6.98(d,J＝2.7Hz,1H),6.84(d,J＝8.8Hz,1H),6.79(dd,J＝8.8,2.7Hz,1H),5.26(s,2H),0.93(s,9H),0.15(s,6H).
Synthesis of intermediate II-55
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate with methyl 3-fluoro-4- (bromomethyl) benzoate produced intermediate II-55: 1 H NMR(300MHz,DMSO-d 6 )δ13.37(s,1H),7.81(d,J＝7.5Hz,1H),7.72(s,1H),7.68(d,J＝2.3Hz,2H),7.65(s,1H),7.20(d,J＝7.0Hz,2H),5.29(s,2H).
synthesis of intermediate II-56
Intermediate II-55 (630 mg,1.83 mmol) and N, N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (6 mL), oxalyl chloride (232. Mu.L, 2.74 mmol) was slowly added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (6 mL) to prepare a tetrahydrofuran solution of acid chloride, which was added dropwise to a solution of II-54 (641 mg,1.92 mmol) and pyridine (220. Mu.L, 2.74 mmol) in tetrahydrofuran (1 mL) under ice bath conditions, and the mixture was allowed to react at room temperature for 6 hours. After the completion of the reaction, 2N aqueous hydrogen chloride was added dropwise to the reaction solution to adjust the pH to 3-4, ethyl acetate (5 ml x 3) was extracted, the organic phases were combined, washed with saturated brine (10 ml x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate II-56 (yellow solid, 986 mg).
Synthesis of intermediate II-57
Intermediate II-56 (858 mg,1.44 mmol) was added to N, N-dimethylformamide (2 mL), tetrahydroxydiboron (387 mg,4.31 mmol) and 4,4' -bipyridine (2 mg,0.01 mmol) were added sequentially while ice-cooling, and the reaction was carried out at room temperature for 15 minutes. After the completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with water (10 ml×1), washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=7.5:1) to give intermediate II-57 (pale yellow solid, 607 mg): 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),7.82-7.77(m,2H),7.71(d,J＝8.0Hz,1H),7.68(d,J＝8.7Hz,2H),7.22(d,J＝8.9Hz,2H),7.18(d,J＝2.5Hz,1H),6.82(dd,J＝8.5,2.5Hz,1H),6.65(d,J＝8.5Hz,1H),5.30(s,2H),4.61(s,2H),0.98(s,9H),0.20(s,6H).
Synthesis of intermediate II-58
Intermediate II-57 (100 mg,0.18 mmol) was added to anhydrous dichloromethane (2 mL), pyridine (21. Mu.L, 0.26 mmol) was added, and a solution of ethyl (chlorosulfonyl) acetate (40 mg,0.21 mmol) in dichloromethane (1 mL) was added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 8 hours. After the completion of the reaction, 1N aqueous hydrogen chloride (5 mL), water (5 mL) and excess pyridine were added to the reaction mixture, ethyl acetate (5 ml×3) were quenched, the organic phases were combined, washed with saturated brine (5 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=6:1) to give intermediate II-58 (pale yellow oily liquid, 97 mg): 1 H NMR(400MHz,DMSO-d 6 )δ10.30(s,1H),8.84(s,1H),7.86-7.81(m,2H),7.78(d,J＝2.6Hz,1H),7.73(t,J＝7.8Hz,1H),7.68(d,J＝8.7Hz,2H),7.57(dd,J＝8.9,2.6Hz,1H),7.22(d,J＝8.9Hz,2H),6.96(d,J＝8.8Hz,1H),5.32(s,2H),4.29(s,2H),4.14(q,J＝7.1Hz,2H),1.18(t,3H),1.00(s,9H),0.26(s,6H).
synthesis of Compound B-55
Intermediate II-58 (156 mg,0.22 mmol) was added to dichloromethane (2 mL), triethylamine trihydrofluoride (53. Mu.L, 0.33 mmol) was added dropwise, and the reaction was carried out at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, filtered, and the cake was washed (dichloromethane/methanol=20:1), and the obtained solid was dried to constant weight to obtain intermediate B-55 (white solid, 113 mg): 1 H NMR(400MHz,DMSO-d 6 )δ10.20(s,1H),9.66(s,1H),9.29(s,1H),7.85-7.81(m,2H),7.73(d,J＝7.8Hz,1H),7.68(d,J＝8.8Hz,2H),7.64(d,J＝2.5Hz,1H),7.52(dd,J＝8.8,2.5Hz,1H),7.22(d,J＝8.9Hz,2H),6.88(d,J＝8.7Hz,1H),5.31(s,2H),4.24(s,2H),4.12(q,J＝7.1Hz,2H),1.19(t,J＝7.1Hz,3H).HRMS(ESI)calcd.for C 25 H 22 F 4 N 2 O 7 S 2 [M+H] + 603.0877,found 603.0887.
example 99
2-chloro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylthio) phenoxy) methyl) benzamide (compound B-56)
Synthesis of Compound B-56
Compound B-55 (50 mg,0.08 mmol) was added to tetrahydrofuran (2 mL), a 2M solution of lithium borohydride in tetrahydrofuran (105. Mu.L, 0.21 mmol) was added dropwise under ice bath, and the mixture was reacted at 60℃for 3 hours. After the reaction was completed, the system was cooled to room temperature, water (10 mL) was added dropwise to the reaction solution under ice bath to quench excess lithium borohydride, ethyl acetate was extracted (5 ml×3), the organic phases were combined, saturated brine (10 ml×1) was washed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=30:1) to give crude compound B-56, which was slurried (dichloromethane/methanol=20:1) to give compound B-56 (pale yellow solid, 34 mg): 1 H NMR(400MHz,DMSO-d 6 )δ10.19(s,1H),9.78(s,1H),8.73(s,1H),7.86-7.81(m,2H),7.72(d,J＝7.7Hz,1H),7.68(d,J＝8.8Hz,2H),7.65(d,J＝2.5Hz,1H),7.50(dd,J＝8.8,2.5Hz,1H),7.22(d,J＝8.9Hz,2H),6.86(d,J＝8.7Hz,1H),5.31(s,2H),5.01(t,J＝5.6Hz,1H),3.80(q,J＝12.4,6.7Hz,2H),3.25(t,J＝6.8Hz,2H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 6 S 2 [M+H] + 561.0772,found 561.0776.
example 100
Methyl 3- (N- (5- (3-fluoro-4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide) -2-hydroxyphenyl) sulfamoyl) propanoate (Compound B-57)
Synthesis of Compound B-57
Referring to the procedure of example 98, substituting ethyl (chlorosulfonyl) acetate for methyl 3- (chlorosulfonyl) propionate produced compound B-57: 1 H NMR(400MHz,DMSO-d 6 )δ10.19(s,1H),9.82(s,1H),9.09(s,1H),7.85-7.80(m,2H),7.73(d,J＝7.7Hz,1H),7.68(d,J＝8.8Hz,2H),7.62(d,J＝2.6Hz,1H),7.53(dd,J＝8.8,2.6Hz,1H),7.22(d,J＝8.9Hz,2H),6.87(d,J＝8.7Hz,1H),5.31(s,2H),3.62(s,3H),3.30(t,J＝7.5Hz,2H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 25 H 22 F 4 N 2 O 7 S 2 [M+H] + 603.0877,found 603.0881.
example 101
2-chloro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylthio) phenoxy) methyl) benzamide (compound B-58)
Synthesis of Compound B-58
Referring to the procedure of example 99, substituting compound B-55 with compound B-57 produced compound B-58: 1 H NMR(400MHz,DMSO-d 6 )δ10.19(s,1H),9.77(s,1H),8.73(s,1H),7.86-7.80(m,2H),7.72(d,J＝7.6Hz,1H),7.68(d,J＝8.8Hz,2H),7.64(d,J＝2.5Hz,1H),7.50(dd,J＝8.7,2.5Hz,1H),7.22(d,J＝8.8Hz,2H),6.86(d,J＝8.7Hz,1H),5.31(s,2H),4.62(t,J＝5.1Hz,1H),3.46(q,J＝11.3,5.9Hz,2H),3.12-3.05(m,2H),1.91-1.83(m,2H).HRMS(ESI)calcd.for C 24 H 22 F 4 N 2 O 6 S 2 [M+H] + 575.0928,found 575.0900.
example 102
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (compound B-59)
Synthesis of Compound B-59
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-22 and substituting intermediate I-18 for intermediate II-18 produced compound B-59: 1 H NMR(300MHz,DMSO-d 6 )δ10.34(s,1H),9.96(s,1H),8.87(s,1H),7.98(d,J＝7.9Hz,2H),7.66(d,J＝8.4Hz,2H),7.59(d,J＝7.9Hz,2H),7.29(d,J＝8.3Hz,1H),7.18(d,J＝8.4Hz,2H),6.77(d,J＝11.3Hz,1H),5.28(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 18 F 4 N 2 O 5 S 2 [M+H] + 531.0666,found 531.0667.
example 103
N- (2-chloro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (compound B-60)
Synthesis of intermediate II-59
4-chloro-2-methoxyaniline (865 mg,5.49 mmol) was added to concentrated sulfuric acid (6 mL), potassium nitrate (610 mg,6.04 mmol) was added in portions under ice bath, and stirring was continued at 0deg.C for 1 hour. After the reaction, the reaction solution was added dropwise to ice water, then sodium bicarbonate was added in portions to adjust the pH to 7 to 8 to precipitate a solid, ethyl acetate (20 ml x 3) was extracted, the organic phases were combined, washed with water (20 ml x 1) and saturated brine (20 ml x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=6:1) to give intermediate II-59 (yellow solid, 795 mg): 1 HNMR(400MHz,DMSO-d 6 )δ7.32(s,1H),7.04(s,1H),5.53(s,2H),3.90(s,3H).
Synthesis of intermediate II-60
Referring to the procedure of example 61, substituting 4-fluoro-2-methoxy-5-nitroaniline for intermediate II-59, intermediate II-60 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ8.30(s,1H),6.83(s,1H),6.72(s,1H),5.01(s,2H),2.99(s,3H),0.96(s,9H),0.19(s,6H).
synthesis of Compound B-60
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-22 and substituting intermediate I-18 for intermediate II-60 produced compound B-60: 1 H NMR(300MHz,DMSO-d 6 )δ10.26-8.87(m,3H),7.99(d,J＝8.1Hz,2H),7.66(d,J＝8.8Hz,2H),7.59(d,J＝8.2Hz,2H),7.31(s,1H),7.18(d,J＝8.9Hz,2H),7.01(s,1H),5.28(s,2H),2.99(s,3H).HRMS(ESI)calcd.for C 22 H 18 ClF 3 N 2 O 5 S 2 [M+H] + 547.0371,found 547.0374.
example 104
N- (2-bromo-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (compound B-61)
Synthesis of intermediate II-61
4-bromo-2-methoxyaniline (853 mg,4.22 mmol) was added to concentrated sulfuric acid (6 mL), potassium nitrate (640 mg,6.33 mmol) was added in portions while ice-bath, and stirring was continued at 0deg.C for 10 min. After the reaction, the reaction solution was added dropwise to ice water, then sodium bicarbonate was added in portions to adjust the pH to 7 to 8 to precipitate a solid, ethyl acetate (20 ml x 3) was extracted, the organic phases were combined, washed with water (20 ml x 1) and saturated brine (20 ml x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=15:1) to give intermediate II-61 (yellow solid, 762 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.32(s,1H),7.15(s,1H),5.58(s,2H),3.90(s,3H).
synthesis of intermediate II-62
Intermediate II-61 (762 mg,3.08 mmol) and pyridine (496. Mu.L, 6.17 mmol) were added to dichloromethane (7 mL), a solution of methylsulfonic anhydride (752 mg,4.32 mmol) in dichloromethane (5 mL) was added dropwise under ice-bath, and the reaction was allowed to proceed to room temperature for 8 hours. After the completion of the reaction, excess pyridine and methylsulfonic anhydride were quenched by adding concentrated hydrochloric acid (0.5 mL), the solvent was distilled off under reduced pressure, 1N aqueous hydrogen chloride (20 mL) was added to the residue and extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (30 ml×1), dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2:1) to give intermediate II-62 (pale yellow solid, 880 mg): 1 H NMR(400MHz,Chloroform-d)δ8.20(s,1H),7.22(s,1H),6.94(s,1H),4.03(s,3H),3.10(s,3H).
Synthesis of intermediate II-63
Intermediate II-62 (100 mg,0.31 mmol) and reduced iron powder (86 mg,1.54 mmol) were added to ethanol (2 mL), and a 6N aqueous hydrogen chloride solution (615. Mu.L, 3.69 mmol) was added thereto and reacted at 60℃for 30 minutes. After the reaction was completed, the system was cooled to room temperature, 1M aqueous sodium hydroxide solution was added dropwise to the reaction solution under ice bath to adjust pH to alkaline, ethyl acetate (8 ml×3) was extracted, the organic phases were combined, saturated brine (10 ml×1) was washed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=4:1) to give intermediate II-63 (white solid, 74 mg): 1 H NMR(400MHz,DMSO-d 6 )δ8.77(s,1H),7.07(s,1H),6.84(s,1H),4.95(s,2H),3.72(s,3H),2.94(s,3H).
synthesis of intermediate II-64
Intermediate II-22 (1.46 g,4.10 mmol) was dissolved in a mixed solvent of methanol (5 mL) and tetrahydrofuran (5 mL), and 1M aqueous sodium hydroxide solution (5 mL) was added thereto, followed by reaction at 60℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the organic solvent was distilled off under reduced pressure, a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2 to 3, solids were precipitated, and the cake was washed with water (2 mL) and N-hexane (2 mL) in this order, and the obtained solid was dried to constant weight to obtain intermediate II-64 (white solid, 1.21 g): 1 H NMR(300MHz,DMSO-d 6 )δ12.99(s,1H),7.97(d,J＝8.1Hz,2H),7.66(d,J＝8.6Hz,2H),7.57(d,J＝8.0Hz,2H),7.17(d,J＝8.6Hz,2H),5.27(s,2H).
synthesis of intermediate II-65
Intermediate II-64 (50 mg,0.15 mmol) and N, N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (2 mL), oxalyl chloride (19. Mu.L, 0.23 mmol) was slowly added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (1 mL) to prepare a tetrahydrofuran solution of acid chloride, which was added dropwise to a solution of II-63 (47 mg,0.16 mmol) and pyridine (18. Mu.L, 0.23 mmol) in tetrahydrofuran (2 mL) under ice bath conditions, and the mixture was allowed to react at room temperature for 6 hours. After the reaction is finished, 2N hydrogen chloride aqueous solution is added dropwise into the reaction solution to adjust the pH to 3-4Ethyl acetate (8 ml x 3) and the organic phases were combined, washed with saturated brine (10 ml x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2:1) to give intermediate II-65 (white solid, 80 mg): 1 H NMR(300MHz,Chloroform-d)δ8.60(s,1H),8.18(s,1H),7.97(d,J＝8.3Hz,2H),7.62(d,J＝8.7Hz,2H),7.58(d,J＝7.2Hz,2H),7.13(s,1H),7.03(d,J＝8.8Hz,2H),6.88(s,1H),5.20(s,2H),3.92(s,3H),3.17(s,3H).
synthesis of intermediate B-61
Intermediate II-65 (76 mg,0.13 mmol) was added to anhydrous dichloromethane (2 mL), a 1M solution of boron tribromide in dichloromethane (314. Mu.L, 0.31 mmol) was added dropwise at 0deg.C, and stirring was continued for 1 hour at 0deg.C. After the reaction was completed, ice water (10 mL) was added dropwise to the reaction solution for quenching, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=150:1) to give a crude product of compound B-61 (brown solid, 47 mg), which was slurried (dichloromethane/methanol=20:1) and purified to give compound B-61 (pale red solid, 35 mg): 1 H NMR(400MHz,DMSO-d 6 )δ10.33(s,1H),9.94(s,1H),9.06(s,1H),8.00(d,J＝8.0Hz,2H),7.66(d,J＝8.8Hz,2H),7.60(d,J＝8.5Hz,2H),7.31(s,1H),7.19(d,J＝9.0Hz,2H),7.17(s,1H),5.29(s,2H),3.00(s,3H).HRMS(ESI)calcd.for C 22 H 18 BrF 3 N 2 O 5 S 2 [M+H] + 590.9865,found 590.9857.
Example 105
N- (3-hydroxy-5- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (Compound B-62)
Synthesis of intermediate II-66
3-bromo-5-nitroaniline (217 mg,1 mmol) and pyridine (121. Mu.L, 1.5 mmol) were added to dichloromethane (2 mL), a solution of methylsulfonic anhydride (226 mg,1.3 mmol) in dichloromethane (2 mL) was slowly added dropwise under ice-water bath, and the mixture was allowed to react at room temperature for 8 hours. After the reaction was completed, 2N aqueous hydrogen chloride (10 mL) was added to the reaction mixture to quench excess pyridine and methylsulfonic anhydride, extracted with ethyl acetate (10 mL. Times.3), washed with saturated brine (10 mL. Times.1) with organic phase-dependent water (10 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give crude intermediate II-66, which was used directly in the next reaction without further purification.
Synthesis of intermediate II-67
The crude intermediate II-66 (1 mmol) and ammonium chloride (535 mg,10 mmol) were added to a mixed solvent of ethanol (3 mL) and water (3 mL), and reduced iron powder (280 mg,5 mmol) was added thereto in portions with stirring, and the mixture was heated to 80℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, water (30 mL) was added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×2), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate II-67 (yellow solid, 238 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.60(s,1H),6.46(s,1H),6.45(s,1H),6.43(s,1H),5.51(s,2H),2.96(s,3H).ESI-MS:m/z 262.9[M-H] - .
Synthesis of intermediate II-68
Referring to the procedure of example 55, intermediate II-1 was replaced with intermediate II-22, intermediate I-18 was replaced with intermediate II-67, and intermediate II-68 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.45(s,1H),10.04(s,1H),7.97(d,J＝7.9Hz,2H),7.83(s,1H),7.73(s,1H),7.65(d,J＝8.3Hz,2H),7.60(d,J＝7.6Hz,2H),7.18(d,J＝8.5Hz,2H),7.08(d,J＝1.6Hz,1H),5.28(s,2H),3.06(s,3H).
synthesis of intermediate II-69
Intermediate II-68 (146 mg,0.25 mmol), pinacol biborate (77 mg,0.3 mmol), [1,1' -bis (diphenylphosphine) ferrocene]Palladium dichloride dichloromethane Complex (PdCl) 2 (dppf). DCM) (21 mg,0.03 mmol) and potassium acetate (75 mg,0.76 mmol) were added to a dry Schlenk tube, under argon, 1, 4-dioxane (2 mL) was added and the mixture was allowed to react at 80℃for 8 hours. After the completion of the reaction, the reaction mixture,the system was cooled to room temperature, the reaction solution was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate II-69 (pale yellow solid, 73 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.31(s,1H),9.73(s,1H),8.00(d,J＝8.1Hz,2H),7.94(s,1H),7.87(s,1H),7.65(d,J＝8.6Hz,2H),7.59(d,J＝8.2Hz,2H),7.25(s,1H),7.18(d,J＝8.8Hz,2H),5.28(s,2H),2.98(s,3H),1.30(s,12H).ESI-MS:m/z 645.1[M+Na] + .
synthesis of Compound B-62
Intermediate II-69 (68 mg,0.11 mmol) was added to tetrahydrofuran (2 mL), 1M aqueous sodium hydroxide solution (55. Mu.L) was added, and then 30% aqueous hydrogen peroxide solution (110. Mu.L) was added dropwise under ice bath, and the mixture was allowed to slowly warm to room temperature for reaction for 6 hours. After the reaction was completed, 2N aqueous hydrogen chloride was added dropwise to the reaction solution to adjust the pH to 2 to 3, ethyl acetate (5 ml×3) was extracted, the organic phases were combined, washed with saturated brine (5 ml×1), the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (dichloromethane/methanol=75:1), and then purified by beating (dichloromethane/methanol=20:1), and the obtained solid was dried to constant weight to give compound B-62 (white solid, 37 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.63(s,1H),9.54(s,1H),7.94(d,J＝8.0Hz,2H),7.65(d,J＝8.4Hz,2H),7.58(d,J＝8.0Hz,2H),7.17(d,J＝8.6Hz,2H),7.12(d,J＝8.0Hz,2H),6.41(s,1H),5.27(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 5 S 2 [M+H] + 513.0760,found513.0761.
Example 106
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4- (trifluoromethyl) phenoxy) methylbenzamide (Compound B-63)
Synthesis of Compound B-63
With reference to the method of example 66, 4-trifluoromethylthiophenol was replaced with 4-trifluoromethylphenol and intermediate I-18 was replaced with intermediate II-18Obtaining a compound B-63: 1 H NMR(300MHz,DMSO-d 6 )δ10.32(s,1H),9.98(s,1H),8.93(s,1H),7.99(d,J＝8.3Hz,2H),7.68(d,J＝8.7Hz,2H),7.60(d,J＝8.3Hz,2H),7.30(d,J＝8.3Hz,1H),7.23(d,J＝8.6Hz,2H),6.78(d,J＝11.4Hz,1H),5.32(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 F 4 N 2 O 5 S[M+H] + 499.0945,found499.0943.
example 107
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4- (trifluoromethoxy) phenoxy) methylbenzamide (Compound B-64)
Synthesis of Compound B-64
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-trifluoromethoxyphenol and substituting intermediate I-18 for intermediate II-18, compound B-64 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.37(s,1H),9.98(s,1H),8.94(s,1H),7.98(d,J＝8.2Hz,2H),7.59(d,J＝8.3Hz,2H),7.31(t,J＝8.5Hz,3H),7.13(d,J＝9.2Hz,2H),6.78(d,J＝11.4Hz,1H),5.24(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 F 4 N 2 O 6 S[M+H] + 515.0894,found 515.0898.
example 108
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4-fluorophenoxy) methylbenzamide (Compound B-65)
Synthesis of Compound B-65
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 4-fluorophenol and substituting intermediate I-18 for intermediate II-18, compound B-65 was prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.13(s,1H),9.95(s,1H),8.98(s,1H),7.98(d,J＝8.2Hz,2H),7.58(d,J＝8.3Hz,2H),7.30(d,J＝8.3Hz,1H),7.14(t,J＝8.8Hz,2H),7.07-7.01(m,2H),6.78(d,J＝11.4Hz,1H),5.19(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 21 H 18 F 2 N 2 O 5 S[M+H] + 499.0977,found 449.0983.
example 109
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((naphthalene-2-oxy) methyl) benzamide (compound B-66)
Synthesis of Compound B-66
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for β -naphthol and substituting intermediate I-18 for intermediate II-18, compound B-66 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),9.98(s,1H),8.89(s,1H),8.00(d,J＝7.9Hz,2H),7.87(d,J＝6.5Hz,1H),7.85(d,J＝5.8Hz,1H),7.80(d,J＝8.2Hz,1H),7.65(d,J＝8.0Hz,2H),7.50-7.45(m,1H),7.44(d,J＝2.6Hz,1H),7.41-7.32(m,1H),7.30(d,J＝8.3Hz,1H),7.29(dd,J＝9.0,2.5Hz,1H),6.78(d,J＝11.3Hz,1H),5.34(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 25 H 21 FN 2 O 5 S[M+H] + 481.1228,found 481.1224.
Example 110
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((quinolin-6-yloxy) methyl) benzamide (compound B-67)
Synthesis of Compound B-67
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 6-hydroxyquinoline and substituting intermediate I-18 for intermediate II-18, compound B-67 was prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.26(s,1H),9.99(s,1H),9.20(s,1H),8.76(dd,J＝4.2,1.7Hz,1H),8.25(dd,J＝8.5,1.7Hz,1H),8.00(d,J＝8.0Hz,2H),7.96(d,J＝9.0Hz,1H),7.66(d,J＝8.1Hz,2H),7.52(dd,J＝9.0,2.8Hz,1H),7.51-7.47(m,2H),7.30(d,J＝8.3Hz,1H),6.78(d,J＝11.3Hz,1H),5.36(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 24 H 20 FN 3 O 5 S[M+H] + 482.1180,found 482.1209.
example 111
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((isoquinolin-6-yloxy) methyl) benzamide (compound B-68)
Synthesis of Compound B-68
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 6-hydroxyisoquinoline and substituting intermediate I-18 for intermediate II-18, compound B-68 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.38(s,1H),9.99(s,1H),9.28(s,1H),8.90(s,1H),8.45(d,J＝5.9Hz,1H),8.15(d,J＝8.9Hz,1H),8.01(d,J＝8.1Hz,2H),7.82(d,J＝5.9Hz,1H),7.67(d,J＝8.1Hz,2H),7.55(d,J＝2.5Hz,1H),7.48(dd,J＝9.0,2.5Hz,1H),7.30(d,J＝8.3Hz,1H),6.78(d,J＝11.3Hz,1H),5.41(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 24 H 20 FN 3 O 5 S[M+H] + 482.1180,found482.1185.
example 112
4- ((benzo [ d ] thiazol-5-yloxy) methyl) -N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) benzamide (compound B-69)
Synthesis of Compound B-69
Referring to the procedure of example 66, substituting 4-trifluoromethylthiophenol for 5-hydroxybenzothiazole and substituting intermediate I-18 for intermediate II-18, compound B-69 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.17(s,0H),9.95(s,1H),9.37(s,1H),8.97(s,1H),8.06(d,J＝8.8Hz,1H),7.99(d,J＝8.2Hz,2H),7.72(d,J＝2.5Hz,1H),7.63(d,J＝8.1Hz,2H),7.30(d,J＝8.3Hz,1H),7.24(dd,J＝8.8,2.5Hz,1H),6.78(d,J＝11.3Hz,1H),5.34(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 FN 3 O 5 S 2 [M+H] + 488.0745,found 488.0750.
example 113
4- ((benzo [ d ] oxazol-5-yloxy) methyl) -N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) benzamide (compound B-70)
Synthesis of Compound B-70
Referring to the procedure of example 66, 4-trifluoromethylthiophenol was replaced with benzo [ d ] ]Oxazol-5-ol, replacing intermediate I-18 with intermediate II-18, gives compound B-70: 1 H NMR(300MHz,DMSO-d 6 )δ10.27(s,1H),9.98(s,1H),8.97(s,1H),8.70(s,1H),7.98(d,J＝8.0Hz,2H),7.69(d,J＝8.9Hz,1H),7.62(d,J＝8.1Hz,2H),7.46(d,J＝2.5Hz,1H),7.29(d,J＝8.3Hz,1H),7.14(dd,J＝8.9,2.5Hz,1H),6.78(d,J＝11.3Hz,1H),5.28(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 18 FN 3 O 6 S[M+H] + 472.0973,found 472.0976.
example 114
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (((2-methyl-1, 2,3, 4-tetrahydroisoquinolin-6-yl) oxy) methyl) benzamide (compound B-71)
Synthesis of intermediate II-70
6-bromo-1, 2,3, 4-tetrahydroisoquinoline (1 g,4.17 mmol) and 4-Dimethylaminopyridine (DMAP) (115 mg,0.94 mmol) were added to dichloromethane (14 mL), followed by triethylamine (1 mL,7.07 mmol) and di-tert-butyl dicarbonate (2.16 mL,9.42 mmol) and reacted at room temperature for 12 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate II-70 (colorless oily liquid, 1.37 g).
Synthesis of intermediate II-71
Intermediate II-70 (1.37 g,4.37 mmol), pinacol biborate (1.33 g,5.24 mmol) ferrocene, [1,1' -bis (diphenylphosphine)]Palladium dichloride dichloromethane Complex (PdCl) 2 (dppf). DCM) (625 mg,0.77 mmol) and potassium acetate (1.29 g,13.11 mmol) were added to a dry Schlenk tube, under argon, 1, 4-dioxane (13 mL) was added and the mixture was allowed to react at 80℃for 8 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate II-71 (pale yellow solid, 1.41 g): 1 H NMR(400MHz,Chloroform-d)δ7.64(d,J＝8.0Hz,1H),7.62(s,1H),7.14(d,J＝7.6Hz,1H),4.60(s,2H),3.68-3.63(m,2H),2.86(t,J＝5.8Hz,2H),1.51(s,9H),1.36(s,12H).
Synthesis of Compound II-72
Intermediate II-71 (1.41 g,3.94 mmol) was added to tetrahydrofuran (4 mL), 1M aqueous sodium hydroxide (2 mL) was added, and then 30% aqueous hydrogen peroxide (4 mL) was added dropwise under ice bath, and the mixture was allowed to slowly warm to room temperature for reaction for 6 hours. After the completion of the reaction, saturated sodium thiosulfate (10 mL), a 2N aqueous hydrogen chloride solution (10 mL) and methylene chloride (15 ml×3) were added dropwise to the reaction solution in an ice bath, the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give compound II-72 (yellow oily liquid, 1.03 g): 1 H NMR(300MHz,DMSO-d 6 )δ9.21(s,1H),6.94(d,J＝8.2Hz,1H),6.59(dd,J＝8.2,2.6Hz,1H),6.54(d,J＝2.5Hz,1H),4.36(s,2H),3.49(t,J＝6.0Hz,2H),2.67(t,J＝6.0Hz,2H),1.42(s,9H).
synthesis of intermediate II-73
Intermediate II-72 (853 mg,3.42 mmol), ethyl 4- (bromomethyl) benzoate (756 mg,3.11 mmol) and potassium iodide (52 mg,0.31 mmol) were added to N, N-dimethylformamide (8 mL), and potassium carbonate (640 mg,4.67 mmol) was added in portions with stirring and reacted at 70℃for 6 hours. After the completion of the reaction, the system was cooled to room temperature, diluted with water (80 mL), extracted with ethyl acetate (15 ml×3), and the organic phases were combined, washed with water (15 ml×2), saturated brine (15 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=15:1) to give intermediate II-73 (yellow solid, 652 mg).
Synthesis of intermediate II-74
Intermediate II-73 (304 mg,0.74 mmol) was added to ethyl acetate (3 mL), and a 4M hydrogen chloride-ethyl acetate solution (1.85 mL,7.4 mmol) was added dropwise and reacted at room temperature for 6 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, 1M aqueous sodium hydroxide solution (10 mL) was added to the residue, stirred at room temperature for 10 minutes, extracted with ethyl acetate (10 ml×3), and the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate II-74 (pale yellow oily liquid, 213 mg).
Synthesis of intermediate II-75
Intermediate II-74 (355 mg,1.14 mmol) was added to formic acid (1 mL), followed by the addition of 37% aqueous formaldehyde (1.5 mL,1.37 mmol) and the reaction was completed at 100deg.C for 4 hours. After the reaction was completed, the system was cooled to room temperature, quenched by dropwise addition of 1M aqueous sodium hydroxide solution (20 mL) to the reaction solution in an ice bath, then adjusted to pH 9 to 10 by dropwise addition of saturated sodium bicarbonate solution, solid precipitated, suction-filtered, and the filter cake was washed with water (2 mL) and n-hexane (2 mL), and the obtained solid was dried to constant weight to obtain intermediate II-75 (off-white solid, 344 mg): 1 H NMR(400MHz,Chloroform-d)δ8.07(d,J＝8.2Hz,2H),7.51(d,J＝8.0Hz,2H),6.96(d,J＝8.3Hz,1H),6.77(dd,J＝8.3,2.7Hz,1H),6.73(d,J＝2.6Hz,1H),5.11(s,2H),4.40(q,J＝7.1Hz,2H),3.54(s,2H),2.91(t,J＝6.0Hz,2H),2.68(t,J＝5.9Hz,2H),2.47(s,3H),1.42(t,J＝7.1Hz,3H).
synthesis of Compound B-71
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-75 and substituting intermediate I-18 for intermediate II-18 produced compound B-71: 1 H NMR(300MHz,DMSO-d 6 )δ9.97(s,1H),7.97(d,J＝8.2Hz,2H),7.56(d,J＝8.1Hz,2H),7.28(d,J＝8.4Hz,1H),6.96(d,J＝9.2Hz,1H),6.85-6.75(m,3H),5.16(s,2H),3.40(s,2H),2.95(s,3H),2.78(t,J＝6.0Hz,2H),2.55(t,J＝6.0Hz,2H),2.32(s,3H).HRMS(ESI)calcd.for C 25 H 26 FN 3 O 5 S[M+H] + 500.1650,found500.1681.
Example 115
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (((2- (methylsulfonyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) oxy) methyl) benzamide (compound B-72)
Synthesis of intermediate II-76
6-bromo-1, 2,3, 4-tetrahydroisoquinoline (200 mg,0.94 mmol) and triethylamine (262. Mu.L, 1.89 mmol) were added to dichloromethane (3 mL), methanesulfonyl chloride (109. Mu.L, 1.41 mmol) was added in portions while ice-cooling, and the mixture was allowed to react at room temperature for 8 hours. After the completion of the reaction, the reaction mixture was quenched by addition of water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (30 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate II-76 (white solid, 273 mg).
Synthesis of Compound B-72
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-76 and substituting intermediate I-18 for intermediate II-18 produced compound B-72: 1 H NMR(300MHz,DMSO-d 6 )δ10.32(s,1H),9.97(s,1H),8.91(s,1H),7.97(d,J＝8.2Hz,2H),7.57(d,J＝8.3Hz,2H),7.29(d,J＝8.3Hz,1H),7.12(d,J＝9.1Hz,1H),6.92-6.84(m,2H),6.78(d,J＝11.3Hz,1H),5.19(s,2H),4.29(s,2H),3.40(t,J＝6.0Hz,2H),2.96(s,3H),2.93(s,3H),2.88(t,J＝5.9Hz,2H).HRMS(ESI)calcd.for C 25 H 26 FN 3 O 7 S 2 [M+H] + 564.1269,found 564.1269.
example 116
3-fluoro-N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (Compound B-73)
Synthesis of Compound B-73
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate with methyl 3-fluoro-4- (bromomethyl) benzoate and substituting intermediate I-18 with intermediate II-18, compound B-73 was prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.19(s,1H),10.07(s,1H),9.10(s,1H),7.84(t,J＝8.7Hz,2H),7.72(t,J＝7.8Hz,1H),7.68(d,J＝8.7Hz,2H),7.31(d,J＝8.3Hz,1H),7.22(d,J＝8.9Hz,2H),6.79(d,J＝11.3Hz,1H),5.31(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 17 F 5 N 2 O 5 S 2 [M+H] + 549.0572,found 549.0562.
Example 117
3-chloro-N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4- ((trifluoromethyl) thio) phenoxy) methyl) benzamide (Compound B-74)
Synthesis of Compound B-74
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate for the crude intermediate II-40 and substituting intermediate I-18 for intermediate II-18, compound B-74 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.13(s,1H),9.00(s,2H),8.10(d,J＝1.4Hz,1H),7.96(dd,J＝8.0,1.5Hz,1H),7.76(d,J＝8.1Hz,1H),7.69(d,J＝8.7Hz,2H),7.31(d,J＝8.3Hz,1H),7.23(d,J＝8.9Hz,2H),6.79(d,J＝11.4Hz,1H),5.32(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 17 ClF 4 N 2 O 5 S 2 [M+H] + 565.0282,found 565.0287.HRMS(ESI)calcd.for C 22 H 17 F 5 N 2 O 5 S 2 [M+H] + 549.0572,found549.0562.
example 118
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -6- ((4- ((trifluoromethyl) thio) phenoxy) methyl) nicotinamide (compound B-75)
Synthesis of intermediate II-77
Referring to the procedure of example 92, substituting 2-methyl-5-bromopyrimidine with 5-bromo-2-methylpyridine produced intermediate II-77: 1 H NMR(300MHz,DMSO-d 6 )δ9.05(s,1H),8.30(d,J＝7.9Hz,1H),7.67(d,J＝8.3Hz,2H),7.63(d,J＝7.7Hz,1H),7.18(d,J＝8.6Hz,2H),5.33(s,2H).
synthesis of intermediate II-78
Intermediate II-77 (80 mg,0.24 mmol) and intermediate II-18 (85 mg,0.26 mmol) were added to anhydrous dichloromethane (2 mL), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (70 mg,0.36 mmol) was added in portions while ice-cooling, and the reaction was allowed to proceed to room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate II-78 (pale yellow solid, 53 mg).
Synthesis of Compound B-75
Intermediate II-78 (53 mg,0.08 mmol) and triethylamine trihydrofluoride (20. Mu.L, 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, filtered, and the filter cake was washed (dichloromethane/methanol=50:1), and was beaten (dichloromethane/methanol=50:1) and purified, and the obtained solid was dried to constant weight to give compound B-75 (white solid, 32 mg): 1 H NMR(400MHz,DMSO-d 6 )δ10.41(s,1H),10.21(s,1H),9.11(d,J＝2.2Hz,1H),8.93(s,1H),8.35(dd,J＝8.1,2.3Hz,1H),7.70-7.66(m,3H),7.34(d,J＝8.3Hz,1H),7.21(d,J＝8.8Hz,2H),6.79(d,J＝11.3Hz,1H),5.37(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 21 H 17 F 4 N 3 O 5 S 2 [M+Na] + 554.0438,found 554.0445.
Example 119
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -5- ((4- ((trifluoromethyl) thio) phenoxy) methyl) pyridine amide (compound B-76)
Synthesis of Compound B-76
Referring to the procedure of example 118, substituting 2-bromo-5-methylpyridine for 5-bromo-2-methylpyridine produced compound B-76: 1 H NMR(400MHz,DMSO-d 6 )δ10.34(s,1H),10.25(s,1H),8.91(s,1H),8.83(d,J＝1.6Hz,1H),8.19(dd,J＝8.0,1.0Hz,1H),8.16(d,J＝2.0Hz,1H),7.76(d,J＝8.5Hz,1H),7.69(d,J＝8.7Hz,2H),7.23(d,J＝8.8Hz,2H),6.81(d,J＝11.6Hz,1H),5.37(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 21 H 17 F 4 N 3 O 5 S 2 [M+Na] + 554.0438,found 554.0444.
example 120
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -2- ((4- ((trifluoromethyl) thio) phenoxy) methyl) pyrimidine-5-carboxamide (Compound B-77)
Synthesis of Compound B-77
Referring to the procedure of example 118, substituting 5-bromo-2-methylpyridine with 2-methyl-5-bromopyrimidine gave compound B-77: 1 H NMR(400MHz,DMSO)δ10.44(s,1H),10.36(s,1H),9.27(s,2H),8.93(s,1H),7.64(d,J＝8.8Hz,2H),7.39(d,J＝8.3Hz,1H),7.14(d,J＝8.9Hz,2H),6.80(d,J＝11.4Hz,1H),5.50(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 20 H 16 F 4 N 4 O 5 S 2 [M+H] + 533.0576,found 533.0583.
example 121
N- (4-fluoro-2-hydroxy-5- ((4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzyl) amino) phenyl) methanesulfonamide hydrochloride (compound B-78)
Synthesis of intermediate II-79
Referring to the procedure of example 66, ethyl 4- (bromomethyl) benzoate was exchanged for 4-bromomethyl benzaldehyde to give intermediate II-79: 1 H NMR(300MHz,Chloroform-d)δ10.06(s,1H),7.95(d,J＝8.2Hz,2H),7.62(dd,J＝8.6,2.2Hz,4H),7.02(d,J＝8.8Hz,2H),5.20(s,2H).
synthesis of intermediate II-80
Intermediate II-79 (295 mg,0.94 mmol) and intermediate II-18 (261 mg,0.78 mmol) were added to dichloromethane (5 mL), glacial acetic acid (45. Mu.L, 0.78 mmol) was added, stirred at room temperature for 1 hour, sodium triacetoxyborohydride (496 mg,2.34 mmol) was added in portions under ice bath, and the mixture was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction mixture was quenched by addition of saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate II-80 (pale yellow solid, 126 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.19(s,1H),8.49(s,1H),7.64(d,J＝8.7Hz,2H),7.38(d,J＝2.3Hz,4H),7.15(d,J＝8.9Hz,2H),6.62(d,J＝12.6Hz,1H),6.45(d,J＝9.5Hz,1H),5.70-5.61(m,1H),5.12(s,2H),4.23(d,J＝5.4Hz,2H),2.76(s,3H).
Synthesis of Compound B-78
Intermediate II-80 (96 mg,0.19 mmol) was added to ethyl acetate (1 mL), and a hydrogen chloride-ethyl acetate solution (1.16 mL,0.93 mmol) was added dropwise, and the reaction was completed at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by pulping (ethyl acetate), and the obtained solid was dried to constant weight to give compound B-78 (white solid, 57 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.02(s,1H),8.74(s,1H),7.65(d,J＝8.2Hz,2H),7.44-7.38(m,4H),7.15(d,J＝8.3Hz,2H),6.82(s,1H),6.76(d,J＝12.8Hz,1H),5.15(s,2H),4.32(s,2H),2.81(s,3H).HRMS(ESI)calcd.for C 22 H 21 ClF 4 N 2 O 4 S 2 [M-HCl+H] + 517.0879,found 517.0885.
example 122
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) thio) benzamide (Compound B-79)
Synthesis of intermediate II-81
4-trifluoromethylthiobenzyl bromide (400 mg,1.48 mmol) and 4-bromothiophenol (362 mg,1.92 mmol) were added to acetone (5 mL), cesium carbonate (649 mg,1.99 mmol) was added in portions, and the mixture was reacted at 60℃for 8 hours. After the completion of the reaction, the system was cooled to room temperature, 1M aqueous sodium hydroxide solution (10 mL) was added to the reaction solution to quench the excess 4-bromophenylthiophenol, ethyl acetate (15 ml×3) was extracted, the organic phases were combined, washed with 1M aqueous sodium hydroxide solution (5 ml×2) and saturated brine (15 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate II-81 (white solid, 523 mg): 1 H NMR(300MHz,CDCl 3 )δ7.58(d,J＝8.1Hz,2H),7.39(d,J＝8.5Hz,2H),7.31(d,J＝8.1Hz,2H),7.15(d,J＝8.5Hz,2H),4.09(s,2H).
Synthesis of intermediate II-82
Intermediate II-81 (200 mg,0.53 mmol), oxalic acid dihydrate (199mg, 1.58 mmol), palladium acetate (3.5 mg,0.016 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthenes (Xantphos) (9 mg,0.016 mmol) and acetic anhydride (149. Mu.L, 1.58 mmol) were added to anhydrous N, N-dimethylformamide (2.5 mL), the system was cooled to-78deg.C and frozen, N-diisopropylethylamine (207. Mu.L, 1.58 mmol) was added, and the system was allowed to spontaneously return to room temperature under stirring for 30 minutes, and then allowed to react at 100deg.C for 8 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL) and water (20 mL) were added to the reaction mixture, the mixture was diluted with water, ethyl acetate (10 mL. Times.3) was extracted, the organic phases were combined, washed successively with water (10 mL. Times.1) and saturated brine (10 mL. Times.1), the solvent was distilled off under reduced pressure, and the residue was purified byPurification by column chromatography (petroleum ether/ethyl acetate=3:1) afforded intermediate II-82 (white solid, 181 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.88(s,1H),7.83(d,J＝8.4Hz,2H),7.67(d,J＝8.1Hz,2H),7.57(d,J＝8.2Hz,2H),7.43(d,J＝8.4Hz,2H),4.43(s,2H).ESI-MS:m/z 343.0[M-H] - .
synthesis of Compound B-79
Referring to the procedure of example 1, substituting intermediate I-6 for intermediate II-82 produced compound B-79: 1 H NMR(300MHz,DMSO-d 6 )δ10.00(s,1H),9.33(s,2H),7.89-7.79(m,4H),7.68(d,J＝7.8Hz,3H),7.59(d,J＝8.1Hz,2H),7.45(d,J＝8.4Hz,2H),7.36(t,J＝8.8Hz,3H),6.68(d,J＝8.7Hz,1H),4.44(s,2H).ESI-MS:m/z 607.0[M-H] - .
example 123
N- (4- ((tert-Butyldimethylsilyl) oxy) -3- ((4-fluorophenyl) sulfamido) phenyl) -4- ((4- (trifluoromethyl) benzyl) thio) benzamide (Compound B-80)
Synthesis of Compound B-80
Referring to the procedure of example 122, substituting 4-trifluoromethylthio benzyl bromide for 4-trifluoromethylbenzyl bromide produced compound B-80: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(s,1H),9.35(s,2H),7.88-7.77(m,4H),7.72-7.62(m,5H),7.45(d,J＝8.1Hz,2H),7.36(t,J＝8.8Hz,3H),6.67(d,J＝8.7Hz,1H),4.47(s,2H).HRMS(ESI)calcd.for C 27 H 20 F 4 N 2 O 4 S 2 [M+H] + 577.0873,found577.0855.
example 124
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- (trifluoromethoxy) benzyl) thio) benzamide (Compound B-81)
Synthesis of Compound B-81
Referring to the procedure of example 122, substituting 4-trifluoromethylthio benzyl bromide for 4-trifluoromethoxybenzyl bromide produced compound B-81: 1 H NMR(300MHz,DMSO-d 6 )δ10.02(s,1H),9.37(s,2H),7.89-7.77(m,4H),7.66(d,J＝2.5Hz,1H),7.55(d,2H),7.44(d,J＝8.5Hz,2H),7.40-7.29(m,5H),6.67(d,J＝8.7Hz,1H),4.40(s,2H).HRMS(ESI)calcd.for C 27 H 20 F 4 N 2 O 5 S 2 [M+H] + 593.0823,found 593.0823.
example 125
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- (((trifluoromethyl) thio) methyl) benzyl) thio) benzamide (compound B-82)
Synthesis of intermediate II-83
Referring to the procedure of example 122, substituting 4-trifluoromethylthio benzyl bromide for ethyl 4- (bromomethyl) benzoate produced intermediate II-83: 1 H NMR(300MHz,Chloroform-d)δ7.98(d,J＝7.9Hz,2H),7.51(d,J＝8.0Hz,2H),7.39(d,J＝7.9Hz,2H),7.27(d,J＝6.8Hz,2H),4.37(q,J＝7.1Hz,2H),4.19(s,2H),1.39(t,J＝7.1Hz,3H).
synthesis of intermediate II-84
Intermediate II-83 (1 g,3 mmol) was added to anhydrous tetrahydrofuran (4 mL), 1M solution of lithium triethylborohydride in tetrahydrofuran (7.5 mL,7.5 mmol) was slowly added dropwise under ice-bath, and the mixture was allowed to react slowly to room temperature for 2 hours. After the completion of the reaction, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate II-84 (white solid, 542 mg).
Synthesis of intermediate II-85
Intermediate II-84 (42 mg,0.13 mmol) and triphenylphosphine (50 mg,0.19 mmol) were added to dichloromethane (2 mL) and carbon tetrabromide (67 mg,0.20 mmol) was slowly added dropwise to the solution in iceMethane (2 mL) solution, after the addition of the solution, was allowed to react at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=150:1) to give intermediate II-85 (white solid, 33 mg): 1 H NMR(300MHz,Chloroform-d)δ7.37(d,J＝8.5Hz,2H),7.31(d,J＝8.1Hz,2H),7.24(d,J＝8.1Hz,2H),7.14(d,J＝8.5Hz,2H),4.47(s,2H),4.07(s,2H).
synthesis of intermediate II-86
Intermediate II-85 (372 mg,1 mmol) and potassium thiocyanate (124 mg,1.5 mmol) were added to acetonitrile (15 mL) and reacted at 80℃for 4 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was diluted with water (30 mL), ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate II-85 (white solid, 311 mg).
Synthesis of intermediate II-87
Intermediate II-86 (270 mg,0.76 mmol) was added to a dry Schlenk tube, protected with argon, anhydrous tetrahydrofuran (2 mL) was added, and (trifluoromethyl) trimethylsilane (162 mg,1.14 mmol) was added to anhydrous tetrahydrofuran (1 mL) under ice-bath, followed by slowly dropwise addition of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (1.14 mL,1.14 mmol) in anhydrous tetrahydrofuran (3 mL), and after dropwise addition, the reaction was continued at 0deg.C for 2 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and 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(300MHz,CDCl 3 )δ7.35(d,1H),7.26-7.22(m,2H),7.13(d,1H),4.09(s,1H),4.06(s,1H).
Synthesis of Compound B-82
Referring to the procedure of example 122, substituting intermediate II-81 for intermediate II-87 produced compound B-82: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(s,1H),9.35(s,2H),7.84(d,2H),7.83-7.78(m,2H),7.66(d,J＝2.6Hz,1H),7.48-7.30(m,9H),6.67(d,J＝8.8Hz,1H),4.35(s,2H),4.27(s,2H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 4 S 3 [M+H] + 623.0751,found 623.0787.
example 126
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) thio) benzamide (Compound B-83)
Synthesis of Compound B-83
Referring to the procedure of example 55, substituting intermediate II-2 for intermediate II-82 produced compound B-83: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.60(s,1H),8.75(s,1H),7.87(d,J＝8.4Hz,2H),7.67(d,J＝8.1Hz,2H),7.60(dd,J＝8.3,5.4Hz,3H),7.49(dd,J＝2.5Hz,1H),7.45(d,J＝8.4Hz,2H),6.85(d,J＝8.7Hz,1H),4.44(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 4 S 3 [M+H] + 529.0532,found 529.0536.
example 127
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) benzyl) thio) benzamide (Compound B-84)
Synthesis of Compound B-84
Referring to the procedure of example 122, substituting 4-trifluoromethylthio-benzyl bromide for 4-trifluoromethoxybenzyl bromide and substituting intermediate I-3 for intermediate I-18, compound B-84 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.03(s,1H),9.67(s,1H),8.69(s,1H),7.87(d,J＝8.4Hz,2H),7.61(d,J＝2.2Hz,1H),7.55(d,J＝8.5Hz,2H),7.49(dd,J＝2.3Hz,1H),7.44(d,J＝8.3Hz,2H),7.31(d,J＝8.3Hz,2H),6.85(d,J＝8.7Hz,1H),4.40(s,2H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 5 S 2 [M+H] + 513.0760,found 513.0776.
example 128
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethyl) benzyl) thio) benzamide (Compound B-85)
Synthesis of Compound B-85
Referring to the procedure of example 122, substituting 4-trifluoromethylthio-benzyl bromide for 4-trifluoromethylbenzyl bromide and substituting intermediate I-3 for intermediate I-18, compound B-85 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.03(s,1H),9.66(s,1H),8.66(s,1H),7.86(d,J＝8.5Hz,2H),7.72-7.62(m,4H),7.60(d,J＝2.5Hz,1H),7.52-7.41(m,3H),6.84(d,J＝8.7Hz,1H),4.46(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 4 S 2 [M+H] + 497.0811,found 497.0814.
example 129
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (((4- ((trifluoromethyl) thio) phenyl) thio) methyl) benzamide (compound B-86)
Synthesis of intermediate II-88
Ethyl 4- (bromomethyl) benzoate (1.76 g,7.25 mmol), copper sulfate pentahydrate (26 mg,0.1 mmol), 2' -bipyridine (16 mg,0.1 mmol) and sodium thiosulfate pentahydrate (1.8 g,7.25 mmol) were added to a mixed solvent of methanol (5 mL) and water (5 mL) and reacted at 80℃for 4 hours. After the reaction was completed, the system was cooled to room temperature, 4-trifluoromethylthioaniline (200 mg,1.04 mmol) and t-butyl nitrite (185. Mu.L, 1.55 mmol) were added under ice bath, and after the addition, the mixture was stirred at room temperature for 10 minutes and then heated to 80℃to react for 5 hours. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate II-88 (white solid, 152 mg): 1 H NMR(300MHz,CDCl 3 )δ7.98(d,J＝8.2Hz,2H),7.51(d,J＝8.3Hz,2H),7.40(d,J＝8.2Hz,2H),7.28(d,J＝7.9Hz,2H),4.36(q,2H),4.20(s,2H),1.39(t,J＝7.1Hz,3H).
synthesis of Compound B-86
Referring to the procedure of example 44, substituting intermediate II-1 for intermediate II-88 produced compound B-86: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.36(s,2H),7.91-7.78(m,4H),7.67-7.58(m,3H),7.55(d,J＝8.1Hz,2H),7.48(d,J＝8.4Hz,2H),7.36(t,J＝8.8Hz,3H),6.67(d,J＝8.7Hz,1H),4.44(s,2H).HRMS(ESI)calcd.for C 27 H 20 F 4 N 2 O 4 S 3 [M+H] + 609.0594,found609.0596.
example 130
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (((4- (trifluoromethyl) phenyl) thio) methyl) benzamide (compound B-87)
Synthesis of Compound B-87
Referring to the procedure of example 129, substituting 4-trifluoromethylthioaniline for 4-trifluoromethylaniline produced compound B-87: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.63(s,1H),9.54(s,1H),7.94(d,J＝8.0Hz,2H),7.65(d,J＝8.4Hz,2H),7.58(d,J＝8.0Hz,2H),7.17(d,J＝8.6Hz,2H),7.12(d,J＝8.0Hz,2H),6.41(s,1H),5.27(s,2H),2.98(s,3H).HRMS(ESI)calcd.for C 27 H 20 F 4 N 2 O 4 S 2 [M+H] + 577.0873,found 577.0881.
Example 131
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (((4- (trifluoromethoxy) phenyl) thio) methyl) benzamide (compound B-88)
Synthesis of Compound B-88
Referring to the procedure of example 129, substituting 4-trifluoromethylthioaniline for 4-trifluoromethoxy aniline produced compound B-88: 1 H NMR(300MHz,DMSO-d6)δ10.02(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＝8.7Hz,1H),4.36(s,2H).HRMS(ESI)calcd.for C 27 H 20 F 4 N 2 O 5 S 2 [M+H] + 593.0823,found 593.0843.
example 132
N- (4-hydroxy-3- (methylsulfonylamino) phenyl) -4- (((4- (trifluoromethoxy) phenyl) thio) methyl) benzamide (compound B-89)
Synthesis of Compound B-89
Referring to the procedure of example 129, substituting 4-trifluoromethylthioaniline with 4-trifluoromethoxy aniline and substituting intermediate I-3 with intermediate I-18, compound B-89 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.05(s,1H),9.18(s,2H),7.86(d,J＝7.9Hz,2H),7.61(s,1H),7.47(t,J＝6.8Hz,5H),7.30(d,J＝8.3Hz,2H),6.84(d,J＝8.7Hz,1H),4.36(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 3 N 2 O 5 S 2 [M+H] + 513.0760,found 513.0757.
example 133
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (((4- (trifluoromethyl) phenyl) thio) methyl) benzamide (compound B-90)
Synthesis of Compound B-90
Referring to the procedure of example 129, substituting 4-trifluoromethylthioaniline with 4-trifluoromethylaniline and substituting intermediate I-3 with intermediate I-18 produced compound B-90: 1 H NMR(300MHz,DMSO-d 6 )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＝2.8Hz,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 F 3 N 2 O 4 S 2 [M+H] + 497.0811,found497.0809.
example 134
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) amino) benzamide hydrochloride (compound B-91)
Synthesis of intermediate II-89
4-trifluoromethylthiobenzaldehyde (424 mg,2.06 mmol) and ethyl 4-aminobenzoate (200 mg,1.21 mmol) were added to methanol (5 mL), glacial acetic acid (208. Mu.L, 3.63 mmol) was added, stirred at room temperature for 1 hour, and sodium cyanoborohydride (89 mg,1.51 mmol) was added in portions under an ice bath, and the mixture was slowly warmed to room temperature to react for 24 hours. After the reaction was completed, a saturated sodium hydrogencarbonate solution (5 mL), water (5 mL) and excess sodium cyanoborohydride were added to the reaction solution, extraction was performed with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate II-89 (pale yellow solid, 426 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.68(dd,J＝8.2,6.1Hz,4H),7.49(d,J＝8.1Hz,2H),7.18(t,J＝6.1Hz,1H),6.61(d,J＝8.7Hz,2H),4.43(d,J＝6.0Hz,2H),4.23-4.16(m,2H),1.26(t,J＝7.1Hz,3H).ESI-MS:m/z 354.1[M-H] - .
synthesis of intermediate II-90
Intermediate II-89 (425 mg,1.19 mmol) and 4-dimethylaminopyridine (29 mg,0.24 mmol) were added to dichloromethane (4 mL), followed by triethylamine (499. Mu.L, 3.59 mmol) and di-tert-butyl dicarbonate (687. Mu.L, 2.99 mmol) and reacted at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give a mediumIntermediate II-90 (white solid, 526 mg): 1 H NMR(300MHz,CDCl 3 )δ7.99(d,J＝8.7Hz,2H),7.62(d,J＝8.1Hz,2H),7.30(d,J＝8.3Hz,4H),4.92(s,2H),4.38(q,J＝7.1Hz,2H),1.43(s,9H),1.39(t,J＝7.1Hz,3H).
synthesis of intermediate II-91
Referring to the procedure of example 44, substituting intermediate II-1 for intermediate II-90 produced compound II-91: 1 H NMR(300MHz,DMSO-d 6 )δ10.02(s,1H),9.40(s,1H),9.29(s,1H),7.87(d,J＝8.3Hz,2H),7.82(dd,J＝8.7,5.3Hz,2H),7.69(d,J＝7.9Hz,2H),7.65(d,J＝2.4Hz,1H),7.44-7.30(m,7H),6.68(d,J＝8.8Hz,1H),4.99(s,2H),1.39(s,9H).ESI-MS:m/z 714.1[M+Na] + .
synthesis of Compound B-91
Intermediate II-91 (100 mg,0.14 mmol) was added to dichloromethane (1 mL), and a 4M hydrogen chloride-dioxane solution (1 mL) was added dropwise and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by beating (dichloromethane/methanol=40:1), and the obtained solid was dried to constant weight to give compound B-91 (white solid, 57 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.62(s,1H),9.27(s,1H),7.81(dd,J＝8.8,5.3Hz,2H),7.70(dd,J＝8.0,6.1Hz,4H),7.63(d,J＝2.4Hz,1H),7.52(d,J＝8.1Hz,2H),7.40-7.29(m,3H),6.64(t,J＝8.7Hz,3H),4.64(s,2H),4.44(s,2H).HRMS(ESI)calcd.for C 27 H 21 F 4 N 3 O 4 S 2 [M-HCl+H] + 592.0982,found 592.0989.
example 135
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) benzyl) amino) benzamide hydrochloride (Compound B-92)
Synthesis of Compound B-92
Referring to the procedure of example 134, substituting intermediate I-3 for intermediate I-18 produced compound B-92: 1 H NMR(300MHz,DMSO-d 6 )δ9.65(s,1H),8.68(s,1H),7.75-7.66(m,4H),7.58(d,J＝2.3Hz,1H),7.51(d,J＝8.0Hz,2H),7.43(dd,J＝8.7,2.4Hz,1H),6.84(d,J＝8.7Hz,1H),6.62(d,J＝8.5Hz,2H),4.43(s,2H),3.96-3.93(m,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 4 S 2 [M-HCl+H] + 512.0920,found 512.0922.
example 136
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) benzyl) amino) benzamide hydrochloride (Compound B-93)
Synthesis of Compound B-93
Referring to the procedure of example 134, substituting 4-trifluoromethylthiobenzaldehyde for 4-trifluoromethoxybenzaldehyde and substituting intermediate I-3 for intermediate I-18 gave compound B-93: 1 H NMR(300MHz,D 2 O)δ9.64(s,1H),8.65(s,1H),7.72(d,J＝8.6Hz,2H),7.58(d,J＝2.2Hz,1H),7.51-7.41(m,3H),7.33(d,J＝8.0Hz,2H),6.82(d,J＝8.7Hz,1H),6.63(d,J＝8.5Hz,2H),5.79-5.55(m,2H),4.38(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 5 S[M-HCl+H] + 496.1149,found 496.1150.
example 137
(4- ((2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) carbamoyl) benzyl) (4- ((trifluoromethyl) thio) phenyl) carbamic acid tert-butyl ester (Compound B-94)
Synthesis of intermediate II-92
4-trifluoromethylthioaniline (500 mg,2.59 mmol) and ethyl 4- (bromomethyl) benzoate (812 mg,3.36 mmol) were added to N, N-dimethylformamide (7.5 mL), cesium carbonate (1.27 g,3.88 mmol) was added in portions with stirring, and the reaction was carried out at 80℃for 12 hours. After the reaction was completed, the system was cooled to room temperature, water (75 mL) was added to the reaction solution to dilute, ethyl acetate (15 ml×3) was extracted, and the organic phases were combined, washed with water (20 ml×1), saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give crude intermediate II-92 (yellow solid, 756 mg) which was used directly for the next reaction without further purification.
Synthesis of Compound B-94
Referring to the procedure of example 134, substituting intermediate II-89 for intermediate II-92 and substituting intermediate I-3 for intermediate II-18 produced compound B-94: 1 H NMR(400MHz,Chloroform-d)δ8.21(d,J＝8.0Hz,1H),7.94(d,J＝2.5Hz,1H),7.86(d,J＝8.1Hz,2H),7.60(d,J＝8.5Hz,2H),7.44(s,1H),7.40(d,J＝8.0Hz,2H),7.27(s,1H),6.82(d,J＝11.5Hz,1H),6.52(s,1H),4.96(s,2H),3.08(s,3H),1.46(s,9H).HRMS(ESI)calcd.for C 27 H 27 F 4 N 3 O 6 S 2 [M+H] + 630.1350,found630.1351.
example 138
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (((4- ((trifluoromethyl) thio) phenyl) amino) methyl) benzamide hydrochloride (compound B-95)
Synthesis of Compound B-95
Referring to the procedure of example 134, substituting intermediate II-91 with compound B-94 produced compound B-95: 1 H NMR(300MHz,DMSO-d 6 )δ10.41(s,1H),9.91(s,1H),8.90(s,1H),7.92(d,J＝8.2Hz,2H),7.47(d,J＝8.1Hz,2H),7.35(d,J＝8.7Hz,2H),7.27(d,J＝8.3Hz,1H),6.81(d,J＝11.4Hz,1H),6.66(d,J＝8.8Hz,2H),4.41(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 4 N 3 O 4 S 2 [M-HCl+H] + 530.0826,found 530.0820.
Example 139
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((methyl (4- ((trifluoromethyl) thio) phenyl) amino) methyl) benzamide (compound B-96)
Synthesis of intermediate II-93
Sodium hydride (42 mg,1.06 mmol) was added to a dry three-necked flask, protected by argon, suspended in anhydrous N, N-dimethylformamide (1 mL), a solution of intermediate II-92 (187 mg,0.53 mmol) in anhydrous N, N-dimethylformamide (1 mL) was added dropwise under ice bath, the mixture was allowed to react at 0℃for 30 minutes, and a solution of methyl iodide (49. Mu.L, 0.79 mmol) in anhydrous N, N-dimethylformamide (0.5 mL) was then slowly added dropwise under ice bath, and the mixture was stirred at room temperature for 6 hours. After the reaction was completed, a saturated ammonium chloride solution (20 mL) was added to the reaction solution to quench, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, washed with water (20 ml×1) and saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=100:1) to give crude intermediate II-93, which was slurried (dichloromethane/methanol=50:1) to give crude intermediate II-93 (white solid, 90 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.89(s,1H),7.91(d,J＝8.3Hz,2H),7.44(d,J＝8.9Hz,2H),7.31(d,J＝8.3Hz,2H),6.78(d,J＝9.0Hz,2H),4.73(s,2H),3.13(s,3H).
synthesis of Compound B-96
Referring to the procedure of example 118, substituting intermediate II-77 with compound II-93 produced compound B-96: 1 H NMR(300MHz,DMSO-d 6 )δ10.28(s,1H),9.91(s,1H),8.93(s,1H),7.91(d,J＝8.2Hz,2H),7.44(d,J＝8.9Hz,2H),7.33(d,J＝8.1Hz,2H),7.28(d,J＝8.3Hz,1H),6.80(d,J＝6.1Hz,2H),6.76(d,J＝8.3Hz,1H),4.74(s,2H),3.15(s,3H),2.95(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 4 N 3 O 4 S 2 [M+H] + 544.0982,found 544.0983.
Example 140
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -2- (4- ((trifluoromethyl) thio) phenyl) -1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound B-97)
Synthesis of intermediate II-94
4-trifluoromethylthiobromobenzene (643 mg,2.5 mmol), 6-bromo-1, 2,3, 4-tetrahydroisoquinoline (795 mg,3.75 mmol), palladium acetate (28 mg,0.125 mmol), 1 '-binaphthyl-2, 2' -Bisdiphenylphosphine (BINAP) (156 mg,0.25 mmol) and cesium carbonate (1.63 g,5 mmol) were added to a dry schlenk tube, protected by argon, suspended in toluene (7.5 mL) and reacted at 100℃for 10 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered with suction, the filter cake was washed with ethyl acetate (5 mL), the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=150:1) to give intermediate II-94 (white solid, 470 mg): 1 H NMR(300MHz,Chloroform-d)δ7.55(d,J＝6.6Hz,2H),7.40-7.32(m,2H),7.07(d,J＝8.7Hz,1H),6.91(d,J＝8.9Hz,2H),4.43(s,2H),3.62(t,J＝5.9Hz,2H),2.98(t,J＝5.8Hz,2H).
synthesis of Compound B-97
Referring to the procedure of example 89, substituting intermediate II-41 with compound II-94 produced compound B-97: 1 H NMR(400MHz,DMSO-d 6 )δ10.05(s,1H),9.70(s,1H),8.71(s,1H),7.79(d,J＝9.6Hz,2H),7.63(d,J＝2.6Hz,1H),7.53(d,J＝8.7Hz,2H),7.51(dd,J＝8.6,2.6Hz,1H),7.39(d,J＝7.9Hz,1H),7.09(d,J＝8.9Hz,2H),6.86(d,J＝8.7Hz,1H),4.58(s,2H),3.67(t,J＝5.9Hz,2H),3.02(t,J＝6.0Hz,2H),2.98(s,3H).HRMS(ESI)calcd.for C 24 H 22 F 3 N 3 O 4 S 2 [M+H] + 538.1077,found 538.1077.
example 141
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -2- (4- ((trifluoromethyl) thio) phenyl) -1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound B-98)
Synthesis of Compound B-98
Referring to the procedure of example 89, substituting intermediate II-41 for intermediate II-94 and substituting intermediate I-18 for compound II-18 produced compound B-98: 1 H NMR(300MHz,DMSO-d 6 )δ10.36(s,1H),9.92(s,1H),8.90(s,1H),7.80(d,J＝10.3Hz,2H),7.53(d,J＝8.8Hz,2H),7.39(d,J＝8.0Hz,1H),7.28(d,J＝8.3Hz,1H),7.09(d,J＝9.0Hz,2H),6.78(d,J＝11.3Hz,1H),4.59(s,2H),3.67(t,J＝5.8Hz,2H),3.02(t,J＝5.5Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 24 H 21 F 4 N 3 O 4 S 2 [M+H] + 556.0982,found 556.0986.
Example 142
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -2- (4- (trifluoromethyl) phenyl) -1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound B-99)
Synthesis of Compound B-99
Referring to the procedure of example 140, substituting 4-trifluoromethylthiobromobenzene for 4-trifluoromethyl bromobenzene and substituting intermediate I-18 for compound II-18, compound B-99 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.16(s,1H),9.91(s,1H),9.03(s,1H),7.82(s,1H),7.80(d,J＝7.9Hz,1H),7.54(d,J＝8.7Hz,2H),7.40(d,J＝8.0Hz,1H),7.29(d,J＝8.3Hz,1H),7.13(d,J＝8.7Hz,2H),6.78(d,J＝11.4Hz,1H),4.60(s,2H),3.69(t,J＝5.9Hz,2H),3.01(t,J＝5.9Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 24 H 21 F 4 N 3 O 4 S[M+H] + 524.1262,found 524.1266.
example 143
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (4- ((trifluoromethyl) thio) phenethyl) benzamide (Compound B-100)
Synthesis of intermediate II-95
4-trifluoromethylthiophenol (500 mg,2.58 mmol) was added to a three-necked flask under argon, anhydrous dichloromethane (8 mL) and triethylamine (1 mL,7.72 mmol) were added thereto, and trifluoromethanesulfonic anhydride (520. Mu.L, 3.09 mmol) was added dropwise under ice bath, and the mixture was allowed to react at room temperature for 8 hours after the dropwise addition. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate II-95 (pale yellow oily liquid, 581 mg).
Synthesis of intermediate II-96
Intermediate II-95 (100 mg,0.31 mmol), ethyl 4-ethynylbenzoate (80 mg,0.46 mmol), ditriphenylphospholadium dichloride (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, N-dimethylformamide (2 mL) and triethylamine (3 mL,10 eq.) were added and reacted at 60℃for 7 hours. After the reaction was completed, the reaction solution was filtered, the filter cake was washed with ethyl acetate (10 mL), the filtrate was diluted with water (20 mL), ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off 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,CDCl 3 )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).
Synthesis of intermediate II-97
Intermediate II-96 (123 mg,0.35 mmol) was added to ethanol (3 mL), and glacial acetic acid (0.5 mL) and palladium on carbon hydroxide (24 mg) were added thereto and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction, palladium hydroxide carbon was filtered off, the cake was washed with ethyl acetate (10 mL), and the filtrate was distilled off under reduced pressure to dissolveThe agent and residue were purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate II-97 (white solid, 118 mg): 1 H NMR(300MHz,DMSO-d 6 )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).
synthesis of Compound B-100
Referring to the procedure of example 44, substituting intermediate II-1 for intermediate II-97 produced compound B-100: 1 H NMR(300MHz,DMSO-d 6 )δ9.99(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＝8.8Hz,1H),2.99(s,4H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 4 S 2 [M+H] + 591.1030,found 591.1035.
example 144
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- ((trifluoromethyl) thio) phenethyl) benzamide (Compound B-101)
Synthesis of Compound B-101
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate II-97 produced compound B-101: 1 HNMR(300MHz,DMSO-d 6 )δ10.02(s,1H),9.21(s,2H),7.86(d,J＝8.1Hz,2H),7.64(d,J＝8.2Hz,3H),7.49(dd,1H),7.43(d,J＝8.1Hz,2H),7.37(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),3.00(s,4H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 4 S 2 [M+H] + 511.0968,found 511.0970.
example 145
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethyl) phenethyl) benzamide (Compound B-102)
Synthesis of Compound B-102
Referring to the procedure of example 143, substituting 4-trifluoromethylthiophenol for 4-trifluoromethylphenol and substituting intermediate I-3 for intermediate I-18 gave compound B-102: 1 H NMR(400MHz,DMSO-d 6 )δ10.03(s,1H),9.70(s,1H),8.72(s,1H),7.86(d,J＝8.3Hz,2H),7.64(d,J＝8.3Hz,2H),7.62(d,J＝2.6Hz,1H),7.51-7.45(m,3H),7.36(d,J＝8.3Hz,2H),6.85(d,J＝8.7Hz,1H),3.06-2.99(m,4H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 4 S[M+H] + 479.1247,found479.1248.
Example 146
4- (2-Cyclohexylethyl) -N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (Compound B-103)
Synthesis of Compound B-103
Referring to the procedure of example 29, substituting cyclohexanone for cyclohexylformaldehyde produced compound B-103: 1 H NMR(300MHz,DMSO-d 6 )δ9.99(s,1H),9.36(s,2H),7.89-7.76(m,4H),7.67(d,J＝2.5Hz,1H),7.42-7.34(m,3H),7.32(d,J＝8.2Hz,2H),6.67(d,J＝8.7Hz,1H),2.66(t,J＝8.0Hz,2H),1.80-1.59(m,5H),1.55-1.44(m,2H),1.25-1.10(m,4H),0.99-0.85(m,2H).HRMS(ESI)calcd.for C 27 H 29 FN 2 O 4 S[M+H] + 497.1905,found 497.1889.
example 147
4- (2- (4, 4-Difluorocyclohexyl) ethyl) -N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) benzamide (compound B-104)
Synthesis of intermediate II-98
4, 4-Difluorocyclohexanecarboxylic acid (328 mg,2 mmol) was added to a dry three-necked flask, and was dissolved in anhydrous tetrahydrofuran (6 mL) under argon, and 1M borane-tetrahydrofuran complex (3 mL,3 mmol) was added dropwise under ice bath, and the mixture was allowed to react slowly to room temperature for 6 hours after the dropwise addition. After the reaction was completed, ice water (30 mL) was added dropwise to the reaction solution to quench excess borane, ethyl acetate (15 mL x 3) was extracted, and the organic phases were combined, washed successively with water (10 mL x 1), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate II-98, which was used in the next reaction without further purification.
Synthesis of intermediate II-99
The crude intermediate II-98 (2 mmol) was added to dichloromethane (10 mL), and dess-Martin oxidant (DMP) (1.17 g,2.75 mmol) was added in portions under ice bath and allowed to react at room temperature for 2 hours. After the reaction was completed, a saturated sodium thiosulfate solution (10 mL), a saturated sodium bicarbonate solution (10 mL) and a redundant dess-martin oxidant were added to the reaction solution, dichloromethane (10 mL x 3) was added for extraction, the organic phases were combined, washed with a saturated sodium thiosulfate solution (10 mL x 1) and a saturated sodium bicarbonate solution (10 mL x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate II-99 (pale yellow liquid, 270 mg) which was directly weighed for the next feeding due to instability.
Synthesis of Compound B-104
Referring to the procedure of example 29, substituting cyclohexanone for intermediate II-99 produced compound B-104: 1 H NMR(300MHz,DMSO-d 6 )δ9.99(s,1H),9.34(s,2H),7.90-7.76(m,4H),7.67(d,J＝2.5Hz,1H),7.44-7.28(m,5H),6.68(d,J＝8.7Hz,1H),2.68(t,J＝8.0Hz,2H),2.05-1.93(m,2H),1.88-1.76(m,3H),1.74-1.63(m,1H),1.56(q,J＝7.3Hz,2H),1.45-1.33(m,1H),1.26-1.13(m,2H).HRMS(ESI)calcd.for C 27 H 27 F 3 N 2 O 4 S[M+H] + 533.1716,found533.1744.
example 148
4- (2-Cyclohexylethyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound B-105)
Synthesis of Compound B-105
Referring to the procedure of example 29, substituting cyclohexanone for cyclohexylformaldehyde and substituting intermediate I-3 for intermediate I-18, compound B-105 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.00(s,1H),9.66(s,1H),8.67(s,1H),7.85(d,J＝7.9Hz,2H),7.62(s,1H),7.48(dd,J＝8.5,1.8Hz,1H),7.32(d,J＝8.0Hz,2H),6.85(d,J＝8.8Hz,1H),2.97(s,3H),2.71-2.61(m,2H),1.79-1.56(m,5H),1.49(dd,J＝15.0,6.9Hz,2H),1.26-1.10(m,4H),0.99-0.84(m,2H).ESI-MS:m/z 415.2[M-H] - .HRMS(ESI)calcd.for C 22 H 28 N 2 O 4 S[M+H] + 417.1843,found 417.1841.
example 149
4- (2-Cyclopropylethyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound B-106)
Synthesis of intermediate II-100
Referring to the procedure of example 29, cyclohexanone was replaced with cyclopropylaldehyde to produce intermediate II-100.
Synthesis of intermediate II-101
Intermediate II-100 (100 mg,0.53 mmol) was added to a mixed solvent of tetrahydrofuran (5 mL) and water (5 mL), and p-toluenesulfonyl hydrazine (989 mg,5.31 mmol) and sodium acetate trihydrate (940 mg,6.91 mmol) were added in this order, followed by reaction at 70℃for 24 hours. After the completion of the reaction, 2N aqueous hydrogen chloride (10 mL) was added to the reaction mixture to quench, ethyl acetate (5 ml×3) was extracted, the organic phases were combined, washed with saturated brine (5 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate II-101 (white solid, 107 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.74(s,1H),7.85(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),2.72(t,2H),1.48(dd,J＝15.0,7.2Hz,2H),0.72-0.60(m,1H),0.42-0.34(m,2H),0.06--0.01(m,2H).
Synthesis of Compound B-106
Referring to the procedure of example 55, substituting intermediate II-2 for intermediate II-101 produced compound B-106: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(s,1H),9.67(s,1H),8.69(s,1H),7.86(d,J＝8.1Hz,2H),7.62(d,J＝2.2Hz,1H),7.49(dd,J＝8.7,2.2Hz,1H),7.34(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),2.97(s,3H),2.73(t,J＝7.6Hz,2H),1.50(dd,J＝15.0,7.1Hz,2H),0.76-0.63(m,1H),0.44-0.33(m,2H),0.10-0.01(m,2H).HRMS(ESI)calcd.for C 19 H 22 N 2 O 4 S[M+H] + 375.1373,found 375.1375.
example 150
4- (2-cycloheptylethyl) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound B-107)
Synthesis of Compound B-107
Referring to the procedure of example 147, substituting Cheng Huangeng formic acid for 4, 4-difluorocyclohexanecarboxylic acid and substituting intermediate I-3 for intermediate I-18 gave compound B-107: 1 H NMR(300MHz,DMSO-d 6 )δ10.02(s,1H),9.62(s,1H),8.75(s,1H),7.85(d,J＝7.9Hz,2H),7.62(d,J＝2.5Hz,1H),7.49(dd,J＝8.8,2.5Hz,1H),7.32(d,J＝8.0Hz,2H),6.84(d,J＝8.7Hz,1H),2.97(s,3H),2.63(t,J＝8.0Hz,2H),1.77-1.68(m,2H),1.69-1.30(m,11H),1.27-1.15(m,2H).HRMS(ESI)calcd.for C 23 H 30 N 2 O 4 S[M+H] + 431.1999,found 431.2001.
example 151
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (4- ((trifluoromethyl) thio) phenylethoxy) benzamide (Compound C-1)
Synthesis of intermediate III-1
4-TrifluoromethylthioThe phenylacetic acid (2 g,8.47 mmol) was added to a dry three-necked flask, protected by argon, dissolved in anhydrous tetrahydrofuran (30 mL), and 1M borane-tetrahydrofuran complex (17 mL,16.9 mmol) was slowly added under ice bath, and the mixture was slowly warmed to room temperature and reacted for 6 hours. After the reaction was completed, excess borane was quenched by dropwise addition of ice water (30 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, washed with water (20 ml×1) and saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and 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(300MHz,DMSO-d 6 )δ7.62(d,J＝8.0Hz,2H),7.40(d,J＝8.1Hz,2H),4.68(t,J＝5.2Hz,1H),3.64(q,J＝5.3Hz,2H),2.78(t,J＝6.7Hz,2H).
Synthesis of intermediate III-2
Intermediate III-1 (200 mg,0.90 mmol), methyl 4-hydroxybenzoate (260 mg,1.71 mmol) and triphenylphosphine (470 mg,1.80 mmol) were added to a dry three-necked flask, protected by argon, dissolved in anhydrous tetrahydrofuran (2 mL), slowly added dropwise with ice to a solution of diisopropyl azodicarboxylate (360. Mu.L, 1.80 mmol) in anhydrous tetrahydrofuran (2 mL), and the mixture was allowed to react at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to give intermediate III-2 (white solid, 198 mg): 1 H NMR(300MHz,CDCl 3 )δ8.00(d,J＝8.9Hz,2H),7.63(d,J＝8.1Hz,2H),7.37(d,J＝8.1Hz,2H),6.92(d,J＝8.9Hz,2H),4.26(t,J＝6.7Hz,2H),3.90(s,3H),3.17(t,J＝6.7Hz,2H).
synthesis of Compound C-1
Referring to the procedure of example 1, substituting intermediate I-5 for intermediate III-2 produced compound C-1: 1 H NMR(300MHz,DMSO-d 6 )δ9.91(s,0H),9.34(s,1H),7.91(d,J＝8.6Hz,1H),7.81(dd,J＝8.8,5.3Hz,1H),7.72-7.63(m,1H),7.53(d,J＝8.0Hz,1H),7.42-7.30(m,1H),7.05(d,J＝8.8Hz,1H),6.67(d,J＝8.7Hz,0H),4.32(t,J＝6.7Hz,1H),3.14(t,J＝6.6Hz,1H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 5 S 2 [M+H] + 607.0979,found 607.0981.
example 152
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (4- (trifluoromethoxy) phenylethoxy) benzamide (Compound C-2)
Synthesis of Compound C-2
Referring to the procedure of example 151, substituting 4-trifluoromethylthiophenylacetic acid with 4-trifluoromethoxyphenylacetic acid produced compound C-2: 1 H NMR(300MHz,DMSO-d 6 )δ9.91(s,1H),9.33(s,2H),7.91(d,J＝8.7Hz,2H),7.81(dd,J＝8.7,5.3Hz,2H),7.66(d,J＝2.2Hz,1H),7.48(d,J＝8.5Hz,2H),7.39(d,1H),7.34(d,J＝8.1Hz,3H),7.30(s,1H),7.04(d,J＝8.7Hz,2H),6.67(d,J＝8.7Hz,1H),4.29(t,J＝6.6Hz,2H),3.11(t,J＝6.6Hz,2H).ESI-MS:m/z 589.1[M-H] - .
example 153
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- (4- (trifluoromethoxy) phenylethoxy) benzamide (compound C-3)
Synthesis of Compound C-3
Referring to the procedure of example 151, 4-trifluoromethylthiophenylacetic acid was replaced with 4-trifluoromethylphenylacetic acid to produce compound C-3: 1 H NMR(300MHz,DMSO-d 6 )δ9.92(s,1H),9.35(s,2H),7.92(d,J＝8.6Hz,2H),7.82(dd,J＝8.6,5.3Hz,2H),7.68(dd,J＝9.1,5.3Hz,3H),7.59(d,J＝8.0Hz,2H),7.36(t,J＝8.8Hz,3H),7.05(d,J＝8.7Hz,2H),6.67(d,J＝8.7Hz,1H),4.33(t,J＝6.6Hz,2H),3.18(t,J＝6.5Hz,2H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 5 S[M+H] + 575.1258,found 575.1260.
example 154
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- ((trifluoromethyl) thio) phenylethoxy) benzamide (Compound C-4)
Synthesis of Compound C-4
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate III-2 produced compound C-4: 1 H NMR(300MHz,DMSO-d 6 )δ9.93(s,1H),9.44(s,1H),8.80(s,1H),7.92(d,J＝8.7Hz,2H),7.68(d,J＝8.0Hz,2H),7.61(d,J＝2.3Hz,1H),7.52(d,J＝8.1Hz,2H),7.48(dd,J＝8.9,2.4Hz,1H),7.05(d,J＝8.8Hz,2H),6.84(d,J＝8.7Hz,1H),4.32(t,J＝6.6Hz,2H),3.15(t,J＝6.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0917.
example 155
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethoxy) phenylethoxy) benzamide (Compound C-5)
Synthesis of Compound C-5
Referring to the procedure of example 151, substituting 4-trifluoromethylthiophenylacetic acid with 4-trifluoromethoxyphenylacetic acid and substituting intermediate I-3 with intermediate I-18 gave compound C-5: 1 H NMR(300MHz,DMSO-d 6 )δ9.93(s,1H),9.30(s,1H),8.92(s,1H),7.92(d,J＝8.5Hz,2H),7.61(s,1H),7.48(d,J＝8.2Hz,3H),7.31(d,J＝8.0Hz,2H),7.04(d,J＝8.5Hz,2H),6.84(d,J＝8.7Hz,1H),4.29(t,J＝6.5Hz,2H),3.10(t,J＝6.4Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 6 S[M+H] + 511.1145,found 511.1161.
example 156
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (methylsulfonyl) phenylethoxy) benzamide (compound C-6)
Synthesis of Compound C-6
Referring to the procedure of example 151, substituting 4-trifluoromethylthiophenylacetic acid with 4-methanesulfonyl phenylacetic acid and substituting intermediate I-3 with intermediate I-18, compound C-6 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.94(s,1H),9.52(s,1H),8.74(s,1H),7.92(d,J＝8.6Hz,2H),7.88(d,J＝8.2Hz,2H),7.63(d,J＝8.8Hz,3H),7.48(dd,J＝8.6,1.7Hz,1H),7.05(d,J＝8.6Hz,2H),6.84(d,J＝8.7Hz,1H),4.34(t,J＝6.3Hz,2H),3.20(s,3H),3.20-3.14(m,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 24 N 2 O 7 S 2 [M+H] + 505.1098,found 505.1101.
example 157
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- ((trifluoromethyl) sulfonyl) phenylethoxy) benzamide (compound C-7)
Synthesis of intermediate III-3
Referring to the procedure of example 151, intermediate III-2 was hydrolyzed to afford compound intermediate III-3: 1 H NMR(300MHz,DMSO-d 6 )δ12.59(s,1H),7.87(d,J＝8.8Hz,2H),7.67(d,J＝7.9Hz,2H),7.51(d,J＝8.1Hz,2H),7.02(d,J＝8.8Hz,2H),4.32(t,J＝6.6Hz,2H),3.14(t,J＝6.5Hz,2H).ESI-MS:m/z 341.1[M-H] - .
synthesis of intermediate III-4
Intermediate III-3 (74 mg,0.22 mmol) was added to trifluoroacetic acid (1.1 mL), and a 30% aqueous hydrogen peroxide solution (486. Mu.L) was added dropwise under ice bath, and the mixture was allowed to react at room temperature for 21 hours. After the reaction, the reaction mixture was poured into ice water (10 mL), solids were precipitated, the mixture was filtered, the cake was washed with water (5 mL), and the residue was slurried (n-hexane)Alkane/ether = 10: 1) Purification, drying of the resulting solid to constant weight, gives intermediate III-4 (white solid, 39 mg): ESI-MS: m/z 373.0[ M-H ]] - .
Synthesis of Compound C-7
Replacement of 4-trifluoromethylthiobenzoic acid with intermediate III-4 by the procedure of example 7 gives Compound C-7: 1 H NMR(300MHz,DMSO-d 6 )δ9.95(s,1H),9.68(s,1H),8.72(s,1H),8.10(d,J＝8.1Hz,2H),7.93(d,J＝8.7Hz,2H),7.84(d,J＝8.2Hz,2H),7.61(d,J＝2.1Hz,1H),7.48(dd,J＝8.6,2.0Hz,1H),7.05(d,J＝8.6Hz,2H),6.84(d,J＝8.7Hz,1H),4.39(t,J＝6.2Hz,2H),3.29(t,J＝6.1Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 7 S 2 [M+H] + 559.0815,found 559.0815.
example 158
4- (2-Cyclohexylethoxy) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound C-8)
Synthesis of Compound C-8
Referring to the procedure of example 49, substituting cyclohexylmethanol for 2-cyclohexylethanol and substituting intermediate I-3 for intermediate I-18 produced compound C-8: 1 H NMR(300MHz,DMSO-d 6 )δ9.93(s,1H),9.58(s,1H),8.75(s,1H),7.91(d,2H),7.61(d,J＝2.5Hz,1H),7.48(dd,J＝8.7,2.6Hz,1H),7.02(d,2H),6.84(d,J＝8.7Hz,1H),4.07(t,J＝6.6Hz,2H),2.97(s,3H),1.79-1.57(m,6H),1.52-1.42(m,0H),1.32-1.13(m,3H),1.03-0.90(m,1H).HRMS(ESI)calcd.for C 22 H 28 N 2 O 5 S[M+H] + 433.1792,found 433.1791.
example 159
4- (2- (4, 4-difluoropiperidin-1-yl) ethoxy) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (compound C-9)
Synthesis of intermediate III-5
Methyl 4-hydroxybenzoate (304 mmol,2 mmol) was added to N, N-dimethylformamide (5 mL), 2-bromoethanol (185. Mu.L, 2.6 mmol) was added, potassium carbonate (418 mg,3 mmol) was added in portions, and the reaction was carried out at 80℃for 8 hours. After the reaction was completed, the system was cooled to room temperature, water (50 mL) was added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, and water (20 ml×1) and saturated brine (20 ml×1) were sequentially used, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate III-5 (white solid, 430 mg): 1 H NMR(300MHz,CDCl 3 )δ8.02(d,J＝8.7Hz,2H),6.96(d,J＝8.8Hz,2H),4.16(t,2H),4.02(dd,J＝9.6,5.4Hz,2H),3.91(s,3H),2.06(t,J＝6.2Hz,1H).
synthesis of intermediate III-6
Triphenylphosphine (870 mg,3.32 mmol) and imidazole (226 mg,3.32 mmol) were added to tetrahydrofuran (6 mL), a tetrahydrofuran solution (3 mL) of iodine (842 mg,3.32 mmol) was added dropwise under ice bath, stirred at 0℃for 30 minutes, and a tetrahydrofuran (3 mL) solution of intermediate III-5 (404 mg,2.21 mmol) was added dropwise, and the mixture was allowed to react at room temperature for 8 hours. After the completion of the reaction, a sodium thiosulfate solution (10 mL) was added to the reaction solution to quench the excess iodine simple substance, ethyl acetate (10 mL x 3) was extracted, and the organic phases were combined, washed with a sodium thiosulfate solution (10 mL x 1) and saturated brine (10 mL x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate III-6 (white solid, 626 mg).
Synthesis of intermediate III-7
Intermediate III-6 (200 mg,0.65 mmol) and 4, 4-difluoropiperidine hydrochloride (154 mg,0.98 mmol) were added to acetonitrile (2 mL), potassium carbonate (271mg, 1.96 mmol) was added in portions, and the reaction was continued at 80℃for 12 hours. After the reaction was completed, the system was cooled to room temperature, 1N aqueous hydrogen chloride solution was added dropwise to the reaction solution to adjust pH to 7 to 8, ethyl acetate (5 mL. Times.4) was used for extraction, the organic phases were combined, washed with saturated brine (10 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give crude intermediate III-7, which was used for the next reaction without further purification.
Synthesis of intermediate III-8
The crude intermediate III-7 was added to a mixed solvent of tetrahydrofuran (1.5 mL) and methanol (1.5 mL), and 1M aqueous sodium hydroxide solution (2 mL) was added thereto, followed by reaction at 60℃for 4 hours. After the reaction was completed, the system was cooled to room temperature, 1N aqueous hydrogen chloride was added dropwise to the reaction solution to adjust the pH to 8 to 9, ethyl acetate (5 ml×3) was extracted, the organic phases were combined, washed with saturated brine (5 ml×1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give intermediate III-8 (pale yellow solid, 109 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.65(s,1H),7.88(d,J＝8.8Hz,2H),7.03(d,J＝8.8Hz,2H),4.18(s,2H),2.83(s,2H),2.65(s,4H),2.08-1.90(m,4H).ESI-MS:m/z 284.1[M-H] - .
synthesis of Compound C-9
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid for intermediate III-8, compound C-9 is prepared: 1 H NMR(300MHz,DMSO)δ9.95(s,1H),9.68(s,1H),8.72(s,1H),7.94(d,J＝8.6Hz,2H),7.61(s,1H),7.49(dd,J＝8.9,1.9Hz,1H),7.06(d,J＝8.6Hz,2H),6.85(d,J＝8.8Hz,1H),4.18(t,J＝5.6Hz,2H),2.97(s,3H),2.83(t,2H),2.72-2.57(m,4H),1.97(ddd,J＝19.0,13.6,5.3Hz,4H).HRMS(ESI)calcd.for C 21 H 25 F 2 N 3 O 5 S[M+H] + 470.1556,found470.1563.
Example 160
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethoxy) phenylethoxy) benzamide (compound C-10)
Synthesis of Compound C-10
Referring to the method of example 151, 4-threeThe fluoromethylthio phenylacetic acid is replaced by 4-trifluoromethoxy phenylacetic acid, methyl 4-hydroxybenzoate is replaced by 3-fluoro-4-hydroxybenzoate, and intermediate I-3 is replaced by intermediate I-18 to prepare a compound C-10: 1 H NMR(300MHz,DMSO-d 6 )δ9.99(s,1H),9.70(s,1H),8.71(s,1H),7.82(dd,J＝10.2,2.3Hz,1H),7.79(d,J＝3.2Hz,1H),7.60(d,J＝2.6Hz,1H),7.52-7.43(m,3H),7.35(d,J＝6.4Hz,1H),7.32(d,J＝7.6Hz,2H),6.85(d,J＝8.7Hz,1H),4.37(t,J＝6.8Hz,2H),3.13(t,J＝6.7Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 6 S[M+H] + 529.1051,found 529.1060.
example 161
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (4- (trifluoromethylsulfonyl) phenylethoxy) benzamide (Compound C-11)
Synthesis of Compound C-11
Referring to the procedure of example 157, substituting methyl 4-hydroxybenzoate with methyl 3-fluoro-4-hydroxybenzoate produced compound C-11: 1 H NMR(300MHz,DMSO-d 6 )δ10.00(s,1H),9.71(s,1H),8.74(s,1H),8.10(d,J＝8.3Hz,2H),7.88-7.76(m,4H),7.59(d,J＝2.6Hz,1H),7.47(dd,J＝8.8,2.6Hz,1H),7.35(t,J＝8.8Hz,1H),6.85(d,J＝8.8Hz,1H),4.46(t,J＝6.5Hz,2H),3.30(d,J＝6.6Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 7 S 2 [M+H] + 577.0721,found577.0724.
example 162
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -6- (4- ((trifluoromethyl) thio) phenylethoxy) nicotinamide (Compound C-12)
Synthesis of intermediate III-9
Will be inThe intermediate III-1 (150 mg,0.67 mmol), ethyl 6-hydroxynicotinate (248 mg,1.48 mmol) and triphenylphosphine (178 mg,1.42 mmol) were added to a dry three-necked flask, protected by argon, dissolved in anhydrous tetrahydrofuran (2 mL), slowly added in anhydrous tetrahydrofuran (1 mL) under ice bath with diethyl azodicarboxylate (222. Mu.L, 1.42 mmol) and allowed to react at room temperature for 12 hours after dropwise addition. After the completion of the reaction, water (10 mL) was added to the reaction mixture, extraction was performed with ethyl acetate (5 ml×3), the organic phases were combined, saturated brine (5 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate III-9 (white solid, 113 mg): 1 H NMR(300MHz,CDCl 3 )δ8.80(s,1H),8.15(dd,J＝6.6Hz,1H),7.59(d,J＝7.8Hz,2H),7.34(d,J＝7.8Hz,2H),6.73(d,J＝8.7Hz,1H),4.61(t,J＝6.8Hz,2H),4.37(q,J＝7.1Hz,2H),3.13(t,J＝6.8Hz,2H),1.39(t,J＝13.4,6.3Hz,3H).ESI-MS:m/z 394.0[M+Na] + .
Synthesis of Compound C-12
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate III-9 produced compound C-12: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.62-8.84(m,2H),8.75(d,J＝2.1Hz,1H),8.21(dd,J＝8.7,2.3Hz,1H),7.67(d,J＝8.0Hz,2H),7.60(d,J＝2.3Hz,1H),7.50(d,J＝8.0Hz,1H),7.45(dd,J＝2.4Hz,1H),6.88(dd,J＝13.2,8.7Hz,2H),4.59(t,J＝6.6Hz,2H),3.14(t,J＝6.6Hz,2H),2.50(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 5 S 2 [M+H] + 528.0869,found 528.0869.
example 163
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -6- (4- (trifluoromethylsulfonyl) phenylethoxy) nicotinamide (Compound C-13)
Synthesis of Compound C-13
Referring to the procedure of example 157, substituting methyl 4-hydroxybenzoate with ethyl 6-hydroxynicotinate produced compound C-13: 1 H NMR(400MHz,DMSO-d 6 )δ10.09(s,1H),9.71(s,1H),8.74(d,J＝2.1Hz,1H),8.70(s,1H),8.21(dd,J＝8.7,2.5Hz,1H),8.08(d,J＝8.4Hz,2H),7.81(d,J＝8.5Hz,2H),7.60(d,J＝2.6Hz,1H),7.46(dd,J＝8.8,2.6Hz,1H),6.89(d,J＝8.7Hz,1H),6.85(d,J＝8.7Hz,1H),4.65(t,J＝6.5Hz,2H),3.28(t,J＝6.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 7 S 2 [M+H] + 560.0768,found 560.0776.
example 164
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4- ((trifluoromethyl) thio) phenylethoxy) benzamide (Compound C-14)
Synthesis of Compound C-14
Referring to the procedure of example 1, substituting intermediate I-5 for intermediate III-2 and intermediate I-3 for intermediate II-18 produced compound C-14: 1 H NMR(300MHz,DMSO-d 6 )δ10.31(s,1H),9.78(s,1H),8.85(s,1H),7.92(d,J＝8.5Hz,2H),7.68(d,J＝7.9Hz,2H),7.52(d,J＝8.0Hz,2H),7.26(d,J＝8.3Hz,1H),7.05(d,J＝8.4Hz,2H),6.75(d,J＝11.4Hz,1H),4.32(t,J＝6.7Hz,2H),3.14(t,J＝6.7Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 5 S 2 [M+H] + 545.0823,found 545.0823.
example 165
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- (4- ((trifluoromethyl) thio) phenoxy) ethyl) benzamide (Compound C-15)
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Synthesis of intermediate III-10
4-trifluoromethylthiophenol (300 mg,1.55 mmol), 4-bromophenyl ethanol (683 mg,3.40 mmol) and triphenylphosphine (851 mg,3.24 mmol) were added to a dry three-necked flask under argon,anhydrous tetrahydrofuran (3 mL) was added for dissolution, and a solution of diisopropyl azodicarboxylate (639 μl,3.24 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added under ice bath, and after dropping, the reaction was allowed to proceed to room temperature for 12 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate III-10 (colorless oily liquid, 367 mg): 1 H NMR(300MHz,CDCl 3 )δ7.57(d,J＝8.6Hz,2H),7.46(d,J＝8.3Hz,2H),7.18(d,J＝8.2Hz,2H),6.92(d,J＝8.8Hz,2H),4.19(t,J＝6.7Hz,2H),3.08(t,J＝6.7Hz,2H).
Synthesis of Compound C-15
Referring to the procedure of example 89, substituting intermediate II-41 for intermediate III-10 produced compound C-15: 1 H NMR(300MHz,DMSO-d 6 )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),7.46(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 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0919.
example 166
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- (4- (trifluoromethoxy) phenoxy) ethyl) benzamide (Compound C-16)
Synthesis of Compound C-16
Referring to the procedure of example 165, substituting 4-trifluoromethylthiophenol for 4-trifluoromethoxyphenol produces compound C-16: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.64(s,1H),8.71(s,1H),7.89(d,J＝8.0Hz,2H),7.63(d,J＝2.5Hz,1H),7.50(ds,J＝2.4Hz,1H),7.46(d,J＝8.0Hz,2H),7.28(d,J＝8.6Hz,2H),7.04(d,2H),6.85(d,J＝8.7Hz,1H),4.26(t,J＝6.6Hz,2H),3.12(t,J＝6.7Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 6 S[M+H] + 511.1145,found 511.1145.
example 167
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- (4- (trifluoromethoxy) phenoxy) ethyl) benzamide (compound C-17)
Synthesis of intermediate III-11
4-bromo-2-fluorophenylacetic acid (816 mg,3.5 mmol) was added to anhydrous tetrahydrofuran (7 mL), and 1M borane-tetrahydrofuran complex (5.3 mL,5.3 mmol) was added dropwise while ice-bath, and the mixture was allowed to react slowly to room temperature for 4 hours. After the completion of the reaction, excess borane was quenched by dropwise addition of ice water (30 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, washed with water (20 ml×1) and saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate III-11 (colorless oily liquid, 721 mg).
Synthesis of Compound C-17
Referring to the procedure of example 165, substituting 4-trifluoromethylthiophenol for 4-trifluoromethoxyphenol and substituting 4-bromophenylethanol for intermediate III-11, compound C-17: 1 H NMR(300MHz,DMSO-d 6 )δ10.13(s,1H),9.75(s,1H),8.75(s,1H),7.77(s,1H),7.78-7.70(m,1H),7.62(d,J＝2.6Hz,1H),7.57(t,J＝7.8Hz,1H),7.49(dd,J＝8.8,2.6Hz,1H),7.28(d,J＝8.2Hz,1H),7.03(d,J＝9.1Hz,2H),6.86(d,J＝8.7Hz,1H),4.26(t,J＝6.6Hz,2H),3.15(t,J＝6.5Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 6 S[M+H] + 529.1051,found 529.1057.
example 168
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- (4- (trifluoromethoxy) phenoxy) ethyl) benzamide (Compound C-18)
Synthesis of intermediate III-12
4-trifluoromethoxy-phenylacetic acid (1 g,4.54 mmol) was added to a dry three-necked flask, protected by argon, dissolved in anhydrous tetrahydrofuran (10 mL), and 1M borane-tetrahydrofuran complex (9.1 mL,9.1 mmol) was slowly added under ice-bath to react at room temperature for 6 hours. After the completion of the reaction, excess borane was quenched by dropwise addition of ice water (30 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, washed successively with water (20 ml×1), saturated brine (20 ml×1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate III-12 (pale yellow oily liquid, 916 mg).
Synthesis of intermediate III-13
Intermediate III-12 (300 mg,0.49 mmol) and 4-dimethylaminopyridine (6 mg,0.05 mmol) were added to dichloromethane (3 mL), triethylamine (136. Mu.L, 0.98 mmol) was added, p-toluenesulfonyl chloride (139 mg,0.73 mmol) was added in portions while ice, and the mixture was warmed to room temperature and reacted for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate III-13 (colorless oily liquid, 160 mg): 1 H NMR(300MHz,Chloroform-d)δ7.66(d,J＝8.2Hz,2H),7.27(d,J＝8.1Hz,2H),7.13(d,J＝8.7Hz,2H),7.09(d,J＝9.0Hz,2H),4.21(t,J＝6.7Hz,2H),2.96(t,J＝6.7Hz,2H),2.43(s,3H).ESI-MS:m/z 383.06[M+Na] + .
Synthesis of intermediate III-14
Intermediate III-13 (139 mg,0.39 mmol), 4-bromophenylthiophenol (109 mg,0.58 mmol) and potassium iodide (7 mg,0.04 mmol) were added to acetonitrile (3 mL), and potassium carbonate (108 mg,0.78 mmol) was added in portions with stirring, and the mixture was reacted at 80℃for 8 hours. After the completion of the reaction, the system was cooled to room temperature, quenched by adding 1M aqueous sodium hydroxide (5 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate III-14 (colorless oily liquid, 136 mg): 1 H NMR(300MHz,CDCl 3 )δ7.44(d,J＝8.4Hz,2H),7.22(d,J＝8.4Hz,4H),7.16(d,J＝8.5Hz,2H),3.16(t,J＝7.7Hz,2H),2.94(t,J＝7.6Hz,2H).
synthesis of intermediate III-15
Intermediate III-14 (110 mg,0.29 mmol), oxalic acid dihydrate (111 mg,0.88 mmol), palladium acetate (2 mg,0.009 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethyl xanthenes (Xantphos) (5 mg,0.009 mmol) and acetic anhydride (83. Mu.L, 0.88 mmol) were added to anhydrous N, N-dimethylformamide (2 mL), the system was cooled to-78deg.C and frozen, N-diisopropylethylamine (154. Mu.L, 0.88 mmol) was added and the system was allowed to spontaneously return to room temperature under argon protection, stirring for 30 minutes, and then allowed to react at 100deg.C for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL), water (20 mL) were added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1), saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate III-15 (white solid, 55 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.87(s,1H),7.85(d,J＝8.4Hz,2H),7.43(d,J＝5.3Hz,2H),7.40(d,J＝5.2Hz,2H),7.29(d,J＝8.2Hz,2H),3.40-3.29(m,2H),2.96(t,J＝7.4Hz,2H).
Synthesis of Compound C-18
Referring to the procedure of example 1, substituting intermediate I-6 for intermediate III-15 produced compound C-18: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.37(s,2H),7.89(d,J＝8.2Hz,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＝8.7Hz,1H),3.36(t,J＝10.0Hz,2H),2.96(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 5 S 2 [M+H] + 607.0985,found 607.0991.
example 169
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- (trifluoromethyl) phenethyl) thio) benzamide (Compound C-19)
Synthesis of Compound C-19
Referring to the procedure of example 168, substituting 4-trifluoromethoxy phenylacetic acid with 4-trifluoromethyl phenylacetic acid produced compound C-19: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.37(s,2H),7.90(d,J＝8.3Hz,2H),7.82(dd,J＝8.6,5.3Hz,2H),7.70-7.65(m,3H),7.53(d,J＝8.0Hz,2H),7.47-7.34(m,5H),6.69(d,J＝8.7Hz,1H),3.39(t,J＝7.5Hz,2H),3.03(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 4 S 2 [M+H] + 591.1030,found 591.1033.
example 170
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((4- ((trifluoromethyl) thio) phenethyl) thio) benzamide (Compound C-20)
Synthesis of Compound C-20
Referring to the procedure of example 168, substituting 4-trifluoromethoxy phenylacetic acid with 4-trifluoromethylthiophenylacetic acid produced compound C-20: 1 H NMR(300MHz,DMSO-d 6 )δ10.03(s,1H),9.35(s,2H),7.89(d,J＝8.3Hz,2H),7.81(dd,J＝8.6,5.3Hz,2H),7.70-7.63(m,3H),7.46(t,J＝7.6Hz,4H),7.41-7.32(m,3H),6.68(d,J＝8.7Hz,1H),3.39(t,J＝7.3Hz,2H),2.99(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 4 S 3 [M+H] + 623.0751,found 623.0751.
example 171
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethyl) phenethyl) thio) benzamide (Compound C-21)
Synthesis of Compound C-21
With reference to the method of example 168, 4-trifluoromethoxy-phenylacetic acid was replaced with 4-trifluoromethylphenylacetic acid and intermediate I-3 was replaced with intermediate I-18Compound C-21: 1 H NMR(300MHz,DMSO-d 6 )δ10.07(s,1H),9.70(s,1H),8.74(s,1H),7.90(d,2H),7.68(d,J＝8.0Hz,2H),7.62(d,J＝2.6Hz,1H),7.53(d,J＝7.9Hz,2H),7.49(dd,1H),7.45(d,J＝8.2Hz,2H),6.85(d,J＝8.7Hz,1H),3.39(t,J＝7.6Hz,2H),3.02(t,J＝7.6Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 4 S 2 [M+H] + 511.0968,found 511.0968.
example 172
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenethyl) thio) benzamide (Compound C-22)
Synthesis of Compound C-22
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-trifluoromethylthiophenylacetic acid and substituting intermediate I-3 with intermediate I-18 gave compound C-22: 1 H NMR(300MHz,DMSO-d 6 )δ10.06(s,1H),9.68(s,1H),8.69(s,1H),7.91(d,J＝8.3Hz,2H),7.67(d,J＝7.9Hz,2H),7.63(dd,1H),7.52-7.43(m,5H),6.86(d,J＝8.8Hz,1H),3.38(t,2H),3.01(t,J＝7.9Hz,2H),2.98(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 4 S 3 [M+H] + 543.0688,found543.0687.
example 173
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide (Compound C-23)
Synthesis of Compound C-23
Referring to the procedure of example 168, substituting intermediate I-3 for intermediate I-18 produced compound C-23: 1 H NMR(300MHz,DMSO-d 6 )δ10.05(s,1H),9.62(s,1H),8.70(s,1H),7.90(d,J＝8.2Hz,2H),7.62(d,J＝1.9Hz,1H),7.51(dd,1H),7.47-7.41(m,4H),7.30(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),3.36(t,J＝7.4Hz,2H),2.97(s,3H),2.93(t,2H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0945.
example 174
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (phenylethylthio) benzamide (Compound C-24)
Synthesis of Compound C-24
Referring to the procedure of example 168, substituting 4-trifluoromethoxy phenylacetic acid with phenylacetic acid and substituting intermediate I-3 with intermediate I-18 produced compound C-24: 1 H NMR(300MHz,DMSO-d 6 )δ10.07(s,1H),9.72(s,1H),8.74(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.5Hz,1H),7.49(dd,J＝8.8,2.6Hz,1H),7.44(d,J＝8.5Hz,2H),7.35-7.26(m,4H),7.26-7.19(m,1H),6.85(d,J＝8.7Hz,1H),3.34-3.28(m,2H),2.97(s,3H),2.91(t,J＝7.9Hz,2H).HRMS(ESI)calcd.for C 22 H 22 N 2 O 4 S 2 [M+H] + 443.1094,found 443.1097.
example 175
4- ((4-Fluorophenethyl) thio) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound C-25)
Synthesis of Compound C-25
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-fluorophenylacetic acid and substituting intermediate I-3 with intermediate I-18 gave compound C-25: 1 H NMR(300MHz,DMSO-d 6 )δ10.07(s,1H),9.72(s,1H),8.73(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.5Hz,2H),7.33(dd,J＝8.6,5.7Hz,2H),7.13(t,J＝8.9Hz,2H),6.85(d,J＝8.7Hz,1H),3.34-3.28(m,2H),2.97(s,3H),2.91(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 22 H 21 FN 2 O 4 S 2 [M+H] + 461.1000,found 461.1004.
example 176
4- ((4-Chloroethyl) thio) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound C-26)
Synthesis of Compound C-26
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-chloroacetic acid and substituting intermediate I-3 with intermediate I-18 produced compound C-26: 1 H NMR(400MHz,DMSO-d 6 )δ10.07(s,1H),9.71(s,1H),8.73(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.6Hz,2H),7.37(d,J＝8.5Hz,2H),7.32(d,J＝8.5Hz,2H),6.85(d,J＝8.7Hz,1H),3.33(t,J＝7.6Hz,2H),2.97(s,3H),2.91(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 22 H 21 ClN 2 O 4 S 2 [M+H] + 477.0704,found 477.0710.
example 177
4- ((4-bromophenylethyl) thio) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound C-27)
Synthesis of intermediate III-16
4-Bromobenzeneethanol (452 mg,2.25 mmol) and methyl 4- (chlorosulfonyl) benzoate (351 mg,1.5 mmol) were added to N, N-dimethylformamide (3 mL), a solution of tributylphosphine (1.36 g,6.75 mmol) in N, N-dimethylformamide (1.5 mL) was added dropwise under an ice bath under argon blanket, stirred for 10 minutes, a solution of diisopropyl azodicarboxylate (306 mg,1.5 mmol) in N, N-dimethylformamide (2 mL) was added dropwise under an ice bath, and the mixture was allowed to react to 6℃until the reaction time was reachedHours. After the completion of the reaction, water (60 mL) was added to the reaction solution, ethyl acetate (10 mL x 3) was extracted, and the organic phases were combined, washed with 1M aqueous sodium hydroxide (10 mL x 1), water (10 mL x 1), saturated brine (10 mL x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate III-16 (white solid, 110 mg): 1 H NMR(300MHz,CDCl 3 )δ7.94(d,J＝8.6Hz,2H),7.43(d,J＝8.3Hz,2H),7.30(d,J＝8.5Hz,2H),7.09(d,J＝8.3Hz,2H),3.91(s,3H),3.21(t,2H),2.92(t,J＝7.7Hz,2H).
synthesis of Compound C-27
Referring to the procedure of example 55, substituting intermediate II-1 for intermediate III-16 produced compound C-27: 1 H NMR(300MHz,Methanol-d 4 )δ7.93(d,J＝8.5Hz,2H),7.73(d,J＝2.6Hz,1H),7.50(dt,J＝8.0,3.9Hz,5H),7.25(d,J＝8.1Hz,2H),6.97(d,J＝8.6Hz,1H),3.35(d,J＝7.8Hz,2H),3.07(s,3H),3.02(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 22 H 21 BrN 2 O 4 S 2 [M+H] + 521.0199,found 521.0196.
example 178
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4-methylphenylethyl) thio) benzamide (Compound C-28)
Synthesis of Compound C-28
Referring to the procedure of example 168, substituting 4-trifluoromethoxy phenylacetic acid with 4-methyl phenylacetic acid and substituting intermediate I-3 with intermediate I-18 produced compound C-28: 1 H NMR(400MHz,DMSO-d 6 )δ10.07(s,1H),9.71(s,1H),8.73(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.5Hz,2H),7.17(d,J＝8.0Hz,2H),7.11(d,J＝7.9Hz,2H),6.85(d,J＝8.7Hz,1H),3.29(t,J＝7.0Hz,2H),2.97(s,3H),2.87(t,J＝7.6Hz,2H),2.27(s,3H).HRMS(ESI)calcd.for C 23 H 24 N 2 O 4 S 2 [M+H] + 457.1250,found 457.1254.
example 179
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4-isopropylphenethyl) thio) benzamide (Compound C-29)
Synthesis of Compound C-29
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-isopropylphenylacetic acid and substituting intermediate I-3 with intermediate I-18 gave compound C-29: 1 H NMR(400MHz,DMSO-d 6 )δ10.07(s,1H),9.72(s,1H),8.73(s,1H),7.89(d,J＝8.5Hz,2H),7.62(d,J＝2.5Hz,1H),7.49(dd,J＝8.8,2.5Hz,1H),7.43(d,J＝8.5Hz,2H),7.20(d,J＝8.4Hz,2H),7.17(d,J＝8.4Hz,2H),6.85(d,J＝8.8Hz,1H),3.30(t,J＝8.1Hz,2H),2.97(s,3H),2.87(t,J＝7.9Hz,2H),2.85-2.81(m,1H),1.18(d,J＝6.9Hz,6H).HRMS(ESI)calcd.for C 25 H 28 N 2 O 4 S 2 [M+H] + 485.1563,found 485.1564.
example 180
4- ((4-Cyclopropylphenyl) thio) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound C-30)
Synthesis of intermediate III-17
Ethyl 4-bromophenylacetate (350 mg,1.44 mmol), cyclopropylboronic acid (371 mg,4.32 mmol), tricyclohexylphosphine (40 mg,0.14 mmol), potassium phosphate (1.13 g,5.04 mmol) and palladium acetate (16 mg,0.07 mmol) were charged into a Schlenk tube, and toluene (3 mL), water (150. Mu.L) were added to the system under argon atmosphere to be suspended, and the mixture was reacted at 100℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate III-17 (white solid, 200 mg): 1 H NMR(400MHz,Chloroform-d)δ7.17(d,J＝6.5Hz,2H),7.03(d,J＝8.2Hz,2H),4.14(q,J＝7.1Hz,2H),3.56(s,2H),1.91-1.84(m,1H),1.25(t,J＝7.1Hz,3H),0.97-0.91(m,2H),0.70-0.65(m,2H).
Synthesis of intermediate III-18
Intermediate III-17 (160 mg,0.78 mmol) was added to tetrahydrofuran (4 mL), a 2M solution of lithium borohydride in tetrahydrofuran (784. Mu.L, 1.57 mmol) was added dropwise under ice-bath, and the reaction was continued at 60℃for 3 hours. After the reaction was completed, the system was cooled to room temperature, water (10 mL) was added dropwise to the reaction solution under ice bath to quench excess lithium borohydride, ethyl acetate was extracted (100 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate III-18 (colorless oily liquid, 113 mg).
Synthesis of Compound C-30
Referring to the procedure of example 168, substituting intermediate III-12 for intermediate III-18 and substituting intermediate I-3 for intermediate I-18 produced compound C-30: 1 H NMR(400MHz,DMSO-d 6 )δ10.07(s,1H),9.70(s,1H),8.74(s,1H),7.89(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.42(d,J＝8.6Hz,2H),7.15(d,J＝8.2Hz,2H),7.00(d,J＝8.1Hz,2H),6.85(d,J＝8.7Hz,1H),3.28(t,J＝7.5Hz,2H),2.97(s,3H),2.85(t,J＝7.6Hz,2H),1.93-1.83(m,1H),0.95-0.88(m,2H),0.67-0.60(m,2H).HRMS(ESI)calcd.for C 25 H 26 N 2 O 4 S 2 [M+H] + 483.1407,found 483.1409.
example 181
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4-methoxyphenylethyl) thio) benzamide (Compound C-31)
Synthesis of Compound C-31
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-methoxyphenylacetic acid and substituting intermediate I-3 with intermediate I-18 gave compound C-31: 1 H NMR(400MHz,Methanol-d 4 )δ10.07(s,1H),9.72(s,1H),8.73(s,1H),7.89(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.5Hz,2H),7.20(d,J＝8.6Hz,2H),6.87(d,J＝6.8Hz,2H),6.85(d,J＝6.9Hz,1H),3.73(s,3H),3.32-3.24(m,2H),2.97(s,3H),2.85(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 23 H 24 N 2 O 5 S 2 [M+H] + 473.1199,found 473.1203.
example 182
4- ((4-Cyanophenethyl) thio) -N- (4-hydroxy-3- (methylsulfonyl) phenyl) benzamide (Compound C-32)
Synthesis of Compound C-32
Referring to the procedure of example 168, substituting 4-trifluoromethylphenylacetic acid with 4-cyanophenylacetic acid and substituting intermediate I-3 with intermediate I-18 produced compound C-32: 1 H NMR(400MHz,DMSO-d 6 )δ10.07(s,1H),9.71(s,1H),8.75(s,1H),7.90(d,J＝8.6Hz,2H),7.79(d,J＝8.3Hz,2H),7.62(d,J＝2.6Hz,1H),7.51(d,J＝8.2Hz,2H),7.49(dd,J＝8.5,2.6Hz,1H),7.44(d,J＝8.5Hz,2H),6.85(d,J＝8.7Hz,1H),3.38(t,J＝7.5Hz,2H),3.01(t,J＝7.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 N 3 O 4 S 2 [M+H] + 468.1046,found 468.1052.
example 183
4- ((4- (difluoromethoxy) phenethyl) thio) -N- (4-hydroxy-3- (methylsulfonamide) phenyl) benzamide (Compound C-33)
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Synthesis of intermediate III-19
4-Hydroxyphenethyl bromide (603 mg,3 mmol), 3, 4-dihydro-2H-pyran (252 mg,9 mmol) and pyridine 4-methylbenzenesulfonate (150 mg,0.6 mmol) were added to dichloromethane (15 mmol) and reacted at room temperature for 48 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate III-19 (colorless oily liquid, 494 mg).
Synthesis of intermediate III-20
Intermediate III-19 (490 mg,1.73 mmol) and 4-bromothiophenol (459 mg,2.43 mmol) were added to acetone (10 mL), potassium carbonate (399 mg,2.59 mmol) was added in portions, and the reaction was continued at 60℃for 8 hours. After the completion of the reaction, excess 4-bromophenylthiophenol was quenched by adding 1M aqueous sodium hydroxide (10 mL), extracted with ethyl acetate (10 ml×3), and the organic phases were combined, washed successively with 1M aqueous sodium hydroxide (5 ml×2) and saturated brine (15 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate III-20 (colorless oily liquid, 645 mg).
Synthesis of intermediate III-21
Intermediate III-20 (640 mg,1.63 mmol) and p-toluene sulfonic acid (PTSA) (31 mg,0.16 mmol) were added to a mixed solvent of dichloromethane (5 mL) and methanol (5 mL) and reacted at room temperature for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate III-21 (colorless oily liquid, 466 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.21(s,1H),7.49(d,J＝8.6Hz,2H),7.28(d,J＝8.6Hz,2H),7.03(d,2H),6.67(d,J＝8.4Hz,2H),3.16(t,J＝7.6Hz,2H),2.74(t,J＝7.6Hz,2H).
synthesis of intermediate III-22
Potassium hydroxide (90 mg,1.62 mmol) was added to a mixed solvent of acetonitrile (1 mL) and water (1 mL), intermediate III-21 (50 mg,0.16 mmol) was added under ice bath, and after the addition, stirring was carried out at 0℃for 15 minutes, and diethyl bromofluoromethylphosphonate (57. Mu.L, 0.32 mmol) was slowly added dropwise under ice bath, and the mixture was slowly warmed to room temperature and reacted for 1 hour. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, ethyl acetate (5 mL x 3) was extracted, and the organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate III-22 (white solid, 39 mg): 1 H NMR(300MHz,Chloroform-d)δ7.41(d,J＝8.5Hz,2H),7.24-7.13(m,4H),7.05(d,J＝8.5Hz,2H),6.48(t,J＝74.0Hz,1H),3.16-3.10(m,2H),2.94-2.86(m,2H).
synthesis of Compound C-33
Referring to the procedure of example 168, substituting intermediate III-14 for intermediate III-22 produced compound C-33: 1 H NMR(300MHz,DMSO-d 6 )δ10.06(s,1H),9.68(s,1H),8.71(s,1H),7.90(d,J＝8.4Hz,2H),7.62(d,J＝2.5Hz,1H),7.49(dd,J＝8.7,2.5Hz,1H),7.44(d,J＝8.5Hz,2H),7.35(d,2H),7.20(s,1H),7.11(d,2H),6.85(d,J＝8.7Hz,1H),3.30(t,2H),2.97(s,3H),2.92(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 23 H 22 F 2 N 2 O 5 S 2 [M+H] + 509.1011,found509.1013.
Example 184
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (methylsulfanyl) phenethyl) thio) benzamide (Compound C-34)
Synthesis of Compound C-34
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-methylthiophenylacetic acid and substituting intermediate I-3 with intermediate I-18 produced compound C-34: 1 H NMR(300MHz,DMSO-d 6 )δ10.05(s,1H),9.66(s,1H),8.73(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.5Hz,2H),7.24(d,J＝9.1Hz,2H),7.20(d,J＝8.8Hz,2H),6.85(d,J＝8.7Hz,1H),3.29(d,J＝7.8Hz,2H),2.97(s,3H),2.88(t,J＝7.5Hz,2H),2.45(s,3H).HRMS(ESI)calcd.for C 23 H 24 N 2 O 4 S 3 [M+H] + 489.0971,found 489.0972.
example 185
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (methylsulfonyl) phenethyl) thio) benzamide (compound C-35)
Synthesis of Compound C-35
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-methanesulfonylphenylacetic acid and substituting intermediate I-3 with intermediate I-18 gave compound C-35: 1 H NMR(400MHz,DMSO-d 6 )δ10.07(s,1H),9.71(s,1H),8.72(s,1H),7.90(d,J＝8.5Hz,2H),7.86(d,J＝8.4Hz,2H),7.62(d,J＝2.5Hz,1H),7.57(d,J＝8.4Hz,2H),7.49(dd,J＝8.8,2.6Hz,1H),7.45(d,J＝8.6Hz,2H),6.85(d,J＝8.7Hz,1H),3.39(t,J＝7.5Hz,2H),3.20(s,3H),3.04(t,J＝7.4Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 24 N 2 O 6 S 3 [M+H] + 521.0869,found 521.0878.
example 186
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((3- (trifluoromethoxy) phenethyl) thio) benzamide (Compound C-36)
Synthesis of Compound C-36
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 3-trifluoromethoxyphenylacetic acid and substituting intermediate I-3 with intermediate I-18 gave compound C-36: 1 H NMR(300MHz,DMSO-d 6 )δ10.07(s,1H),9.72(s,1H),8.74(s,1H),7.90(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.49(dd,J＝8.9,2.7Hz,1H),7.46-7.42(m,3H),7.33(d,J＝5.7Hz,2H),7.22(d,J＝8.0Hz,1H),6.85(d,J＝8.7Hz,1H),3.38(d,J＝7.1Hz,2H),2.98(t,J＝7.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0919.
example 187A
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((2- (trifluoromethoxy) phenethyl) thio) benzamide (Compound C-37)
Synthesis of Compound C-37
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 2-trifluoromethoxyphenylacetic acid and substituting intermediate I-3 with intermediate I-18 gave compound C-37: 1 H NMR(300MHz,DMSO-d 6 )δ10.08(s,1H),9.73(s,1H),8.74(s,1H),7.91(d,J＝8.5Hz,2H),7.62(d,J＝2.6Hz,1H),7.54-7.45(m,2H),7.45(d,J＝8.5Hz,2H),7.41-7.32(m,3H),6.85(d,J＝8.7Hz,1H),3.31(t,J＝8.3Hz,2H),2.98(t,J＝8.2Hz,2H),2.97(s,1H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0920.
example 188
2-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide (compound C-38)
Synthesis of intermediate III-23
Referring to the procedure of example 177, substituting 4-bromophenyl ethanol with 4-trifluoromethoxy phenyl ethanol and substituting methyl 4- (chlorosulfonyl) benzoate with 3-fluoro-4-bromophenyl sulfonyl chloride produced intermediate III-23: 1 H NMR(300MHz,CDCl 3 )δ7.46(t,J＝7.8Hz,1H),7.23(d,J＝8.6Hz,2H),7.17(d,J＝8.6Hz,2H),7.08(dd,J＝9.1,1.9Hz,1H),6.98(dd,J＝8.3,1.9Hz,1H),3.18(t,J＝7.6Hz,2H),2.96(t,J＝7.6Hz,2H).
synthesis of Compound C-38
Referring to the procedure of example 89, substituting intermediate II-41 for intermediate III-23 produced compound C-38: 1 H NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),9.73(s,1H),8.74(s,1H),7.58(t,J＝7.9Hz,2H),7.47-7.41(m,3H),7.33(t,J＝8.7Hz,3H),7.25(d,J＝8.2Hz,1H),6.86(d,J＝8.8Hz,1H),3.38(t,2H),2.97(s,3H),2.94(t,2H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 5 S 2 [M+H] + 545.0823,found 545.0822.
example 189
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide (compound C-39)
Synthesis of intermediate III-24
Referring to the procedure of example 177, substituting 4-bromophenyl ethanol for 4-trifluoromethoxy phenyl ethanol and substituting methyl 4- (chlorosulfonyl) benzoate for 4-bromo-2-fluorobenzenesulfonyl chloride produced intermediate III-24: 1 H NMR(300MHz,CDCl 3 )δ7.28(s,1H),7.25(d,J＝4.2Hz,2H),7.22(d,J＝8.7Hz,2H),7.15(d,J＝8.4Hz,2H),3.15(t,J＝7.6Hz,2H),2.91(t,J＝7.6Hz,2H).
synthesis of Compound C-39
Referring to the procedure of example 89, substituting intermediate II-41 for intermediate III-24 produced compound C-39: 1 H NMR(300MHz,DMSO-d 6 )δ10.13(s,1H),9.74(s,1H),8.75(s,1H),7.85-7.75(m,2H),7.62(d,J＝2.4Hz,1H),7.59(d,J＝7.9Hz,1H),7.50(dd,J＝8.7,2.1Hz,1H),7.43(d,J＝8.5Hz,2H),7.30(d,J＝8.3Hz,2H),6.87(d,J＝8.7Hz,1H),3.37(t,2H),2.98(s,3H),2.95(t,2H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 5 S 2 [M+H] + 545.0823,found 545.0820.
Example 190
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide (Compound C-40)
Synthesis of Compound C-40
Referring to the procedure of example 168, intermediate I-3 was replaced with intermediate II-18 to give the compoundC-40： 1 H NMR(400MHz,DMSO-d 6 )δ10.34(s,1H),9.91(s,1H),8.88(s,1H),7.90(d,J＝8.4Hz,2H),7.44(d,J＝8.5Hz,2H),7.41(d,J＝8.5Hz,2H),7.30(dd,J＝8.8,1.0Hz,2H),7.27(d,J＝8.3Hz,1H),6.77(d,J＝11.3Hz,1H),3.35(t,J＝7.6Hz,2H),2.95(t,J＝8.4Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 5 S 2 [M+H] + 545.0828,found 545.0833.
Example 191
3-fluoro-N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide (Compound C-41)
Synthesis of Compound C-41
Referring to the procedure of example 168, substituting intermediate III-14 for intermediate III-24 and substituting intermediate I-3 for intermediate II-18 produced compound C-41: 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),9.43(s,2H),7.76(d,J＝7.9Hz,1H),7.72(d,J＝10.7Hz,1H),7.56-7.49(m,1H),7.48(d,J＝8.8Hz,2H),7.33(d,J＝8.3Hz,2H),7.29(s,1H),7.01(s,1H),3.31(t,J＝7.4Hz,2H),2.99(t,J＝7.6Hz,2H),2.99(s,3H).HRMS(ESI)calcd.for C 23 H 19 F 5 N 2 O 5 S 2 [M+H] + 563.0728,found563.0711.
example 192
N- (2-chloro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide (compound C-42)
Synthesis of Compound C-42
Referring to the procedure of example 168, substituting intermediate I-3 for intermediate II-60 produced compound C-42: 1 H NMR(400MHz,DMSO-d 6 )δ10.41(s,1H),9.91(s,1H),8.98(s,1H),7.91(d,J＝8.5Hz,2H),7.45(d,J＝8.5Hz,2H),7.42(d,J＝8.6Hz,2H),7.31(d,J＝3.2Hz,2H),7.29(s,1H),7.00(s,1H),3.35(d,J＝5.9Hz,2H),2.99(s,3H),2.95(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 23 H 20 ClF 3 N 2 O 5 S 2 [M+H] + 561.0527,found 561.0532.
example 193
N- (4- (hydroxymethyl) -3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide (Compound C-43)
Synthesis of intermediate III-25
2-amino-4-nitrobenzoic acid (500 mg,2.75 mmol) was added to a dry three-necked flask, and was dissolved in anhydrous tetrahydrofuran (5 mL) under argon, and then 1M borane-tetrahydrofuran complex (5.5 mL,5.5 mmol) was slowly added under ice bath, and after dropping, the mixture was stirred at 0℃for 15 minutes and then heated to 65℃for 4 hours. After the completion of the reaction, excess borane was quenched by dropwise addition of ice water (30 mL), extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with water (15 mL x 1), saturated brine (15 mL x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate III-25 (yellow solid, 477 mg).
Synthesis of intermediate III-26
Intermediate III-25 (447 mg,2.66 mmol) and pyridine (321. Mu.L, 3.99 mmol) were added to dichloromethane (5 mL), a solution of methylsulfonic anhydride (554 mg,3.19 mmol) in dichloromethane (5 mL) was added dropwise under ice-water bath, and the mixture was allowed to react at room temperature for 8 hours. After the reaction was completed, excess pyridine and methylsulfonic anhydride were quenched by adding concentrated hydrochloric acid (1 mL) to the reaction solution, the solvent was distilled off under reduced pressure, the residue was added with 1N aqueous hydrogen chloride (20 mL), ethyl acetate (10 mL x 3) was extracted, the organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2:1) to give intermediate III-26 (yellow solid, 363 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.44(s,1H),8.12(dd,2H),7.75(d,J＝8.4Hz,1H),5.62(s,1H),4.71(s,2H),3.10(s,3H).ESI-MS:m/z 245.0[M-H] - .
synthesis of intermediate III-27
Intermediate III-26 (340 mg,1.38 mmol) and 10% palladium on carbon (68 mg) were added to methanol (4 mL) and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2:1) to give intermediate III-27 (yellow solid, 187 mg): 1 H NMR(300MHz,DMSO-d 6 )δ8.61(s,1H),6.98(d,J＝8.2Hz,1H),6.59(d,J＝1.9Hz,1H),6.37(dd,J＝8.1,1.9Hz,1H),5.13(s,2H),5.02(s,1H),4.42(s,2H),2.97(s,3H).ESI-MS:m/z 215.0[M-H] - .
synthesis of Compound C-43
Referring to the procedure of example 168, substituting intermediate I-3 for intermediate III-27, compound C-43 was prepared directly after condensation: 1 H NMR(300MHz,DMSO-d 6 )δ10.28(s,1H),8.88(s,1H),7.92(d,J＝7.9Hz,2H),7.78(s,1H),7.67(d,J＝8.4Hz,1H),7.46(d,J＝8.9Hz,3H),7.38(t,J＝8.6Hz,2H),7.31(d,J＝8.2Hz,2H),5.31(s,1H),4.58(s,2H),3.37(t,2H),3.04(s,3H),2.96(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 5 S 2 [M+H] + 541.1079,found 541.1085.
Example 194
2- (methylsulfonamide) -4- (4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide) benzoic acid (Compound C-44)
Synthesis of Compound C-44
Referring to the procedure of example 53, substituting 4-fluorobenzenesulfonyl chloride with methanesulfonic anhydride and substituting intermediate II-3 with intermediate III-15 produced compound C-44: 1 H NMR(300MHz,DMSO-d 6 )δ13.65(s,1H),10.85(s,1H),10.59(s,1H),8.08(s,1H),7.99(d,J＝8.8Hz,1H),7.93(d,J＝8.3Hz,2H),7.67(d,J＝10.0Hz,1H),7.47(d,J＝8.4Hz,2H),7.43(d,J＝8.5Hz,2H),7.30(d,J＝8.3Hz,2H),3.37(t,J＝6.2Hz,2H),3.24(s,3H),2.97(t,J＝7.3Hz,2H).HRMS(ESI)calcd.for C 24 H 21 F 3 N 2 O 6 S 2 [M+H] + 555.0866,found 555.0867.
example 195
4- (methylsulfonamide) -2- (4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide) benzoic acid (Compound C-45)
Synthesis of Compound C-45
Referring to the procedure of example 53, substituting intermediate II-3 for intermediate III-15 and substituting intermediate II-11 for intermediate I-35 produced compound C-45: 1 H NMR(300MHz,DMSO-d 6 )δ13.58(s,1H),12.46(s,1H),10.41(s,1H),8.68(d,J＝1.8Hz,1H),8.00(d,J＝8.7Hz,1H),7.88(d,J＝8.4Hz,2H),7.51(d,J＝8.4Hz,2H),7.43(d,J＝8.5Hz,2H),7.29(d,J＝8.1Hz,2H),6.99(dd,J＝8.7Hz,1H),3.37(t,J＝7.4Hz,2H),3.14(s,3H),2.97(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 24 H 21 F 3 N 2 O 6 S 2 [M+H] + 555.0866,found 555.0863.
example 196
5-hydroxy-4- (methylsulfonyl) -2- (4- (4- (trifluoromethoxy) phenylethoxy) benzamide) benzoic acid (Compound C-46)
Synthesis of Compound C-46
Referring to the procedure of example 25, substituting intermediate I-30 for intermediate III-15 produced compound C-46: 1 H NMR(300MHz,DMSO-d 6 )δ13.57(s,1H),12.17(s,1H),10.07(s,1H),9.00(s,1H),8.70(s,1H),7.85(d,J＝8.4Hz,2H),7.53(s,1H),7.48(d,J＝8.2Hz,2H),7.42(d,J＝8.6Hz,2H),7.28(d,J＝8.2Hz,2H),3.39-3.33(m,2H),3.10(s,3H),2.96(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 24 H 21 F 3 N 2 O 7 S 2 [M+H] + 571.0821,found 571.0825.
example 197
N- (4-hydroxy-3- ((1-methylethyl) sulfamido) phenyl) -4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide (Compound C-47)
Synthesis of Compound C-47
Referring to the procedure of example 1, substituting 4-fluorobenzenesulfonyl chloride with isopropyl sulfonyl chloride and substituting intermediate I-6 with intermediate III-15 produced compound C-47: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.70(s,1H),8.60(s,1H),7.90(d,J＝8.4Hz,2H),7.65(d,J＝2.3Hz,1H),7.49-7.45(m,2H),7.44-7.39(m,3H),7.30(d,J＝8.1Hz,2H),6.82(d,J＝8.7Hz,1H),3.35(t,J＝6.1Hz,2H),3.24-3.15(m,1H),2.95(t,J＝7.5Hz,2H),1.29(s,3H),1.27(s,3H).HRMS(ESI)calcd.for C 25 H 25 F 3 N 2 O 5 S 2 [M+H] + 555.1230,found 555.1232.
Example 198
N- (3- (cyclopropanesulfonamide) -4-hydroxyphenyl) -4- ((4- (trifluoromethoxy) phenethyl) thio) benzamide (Compound C-48)
Synthesis of Compound C-48
Referring to the procedure of example 1, substituting 4-fluorobenzenesulfonyl chloride for cyclopropanesulfonyl chloride and substituting intermediate I-6 for intermediate III-15 will produce compound C-48: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.57(s,1H),8.64(s,1H),7.89(d,J＝7.9Hz,2H),7.68(d,1H),7.48-7.37(m,5H),7.30(d,J＝8.0Hz,2H),6.83(d,J＝8.5Hz,1H),3.35(t,2H),2.95(t,J＝7.3Hz,2H),2.65-2.57(m,1H),0.92(s,2H),0.90(s,2H).ESI-MS:m/z 551.1[M-H] - .
example 199
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- ((4- ((trifluoromethyl) thio) phenyl) thio) ethyl) benzamide (Compound C-49)
Synthesis of intermediate III-28
4-trifluoromethylthioaniline (200 mg,1.04 mmol) was added to concentrated hydrochloric acid (1 mL), a solution of sodium nitrite (107 mg,1.55 mmol) in water (1 mL) was added dropwise under ice-salt bath, stirred for 15 minutes, and after TLC monitoring the disappearance of the starting material, sodium iodide (6271 mg,4.14 mmol) was added in portions and the reaction was continued under ice-salt bath for 90 minutes. After the completion of the reaction, ice water (10 mL) was added dropwise to the reaction mixture for dilution, ethyl acetate (5 mL x 3) was extracted, and the organic phases were combined, washed with water (10 mL x 1) and saturated brine (10 mL x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate III-28 (pale yellow solid, 255 mg).
Synthesis of intermediate III-29
Cuprous iodide (16 mg,0.08 mmol), potassium carbonate (227 mg,1.64 mmol) and elemental sulfur (79 mg,2.47 mmol) were added to a dry Schlenk tube under argon, and a solution of intermediate III-28 (250 mg,0.82 mmol) in N, N-dimethylformamide (3 mL) was added and the addition was completed and the temperature was raised to 90℃for reaction for 8 hours. After the reaction was completed, the system was cooled to room temperature, and sodium borohydride (94 mg,2.47 mmol) was added in portions under an ice bath, and after the addition, the system was heated to 40℃to react for 2 hours. After the reaction was completed, the system was cooled to room temperature, and a solution of potassium iodide (205 mg,1.23 mmol) and 4- (2-bromoethyl) benzoic acid (283 mg,1.23 mmol) in N, N-dimethylformamide (2 mL) was added thereto, and the reaction was continued at room temperature for 8 hours. After the reaction, water (40 mL) was added to the reaction mixture to dilute it, ethyl acetate (10 mL x 3) was used for extraction, the organic phase was washed with water (10 mL x 2) and saturated brine (10 mL x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give To intermediate III-29 (white solid, 149 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.85(s,1H),7.87(d,J＝8.1Hz,2H),7.62(d,J＝8.3Hz,2H),7.44(dd,J＝13.7,8.3Hz,4H),3.37(t,J＝7.2Hz,2H),3.00(t,J＝7.4Hz,2H).ESI-MS:m/z 357.0[M-H] - .
synthesis of Compound C-49
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid for intermediate III-29, compound C-49 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.06(s,1H),9.71(s,1H),8.73(s,1H),7.88(d,J＝8.0Hz,2H),7.64(d,J＝7.8Hz,3H),7.56-7.39(m,5H),6.85(d,J＝8.8Hz,1H),3.39(t,J＝7.5Hz,2H),3.02(t,J＝7.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 4 S 3 [M+H] + 543.0688,found 543.0686.
example 200
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-50)
Synthesis of intermediate III-30
4-Bromophenylacetic acid (500 mg,2.33 mmol) was added to anhydrous tetrahydrofuran (7 mL), 1M borane-tetrahydrofuran complex (4.7 mL,4.7 mmol) was slowly added under ice-bath, and the mixture was allowed to react at room temperature for 4 hours. After the completion of the reaction, excess borane was quenched by dropwise addition of ice water (20 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate III-30 (pale yellow oily liquid, 462 mg).
Synthesis of intermediate III-31
Intermediate III-30 (385 mg,1.91 mmol) and 4-dimethylaminopyridine (23 mg,0.19 mmol) were added to dichloromethane (6 mL), triethylamine (532. Mu.L, 3.83 mmol) was added, and p-toluenesulfonyl chloride (268 mg,2.87 mmol) was added in portions under ice-bath, After the addition, the reaction was carried out at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate III-31 (colorless waxy liquid, 565 mg): 1 H NMR(300MHz,Chloroform-d)δ7.71(d,J＝8.2Hz,1H),7.40(d,J＝8.2Hz,1H),7.37(d,J＝8.2Hz,2H),7.25(d,J＝8.4Hz,1H),4.00(t,J＝6.5Hz,2H),3.03(t,J＝6.5Hz,1H),2.41(s,2H).
synthesis of intermediate III-32
4-trifluoromethoxybenzenesulfonyl chloride (588 mg,2.25 mmol) was added to N, N-dimethylformamide (4 mL), tributylphosphine (1.70 mL,6.76 mmol) was added dropwise while ice-cooling, and the mixture was allowed to react at 50℃for 30 minutes. After TLC monitoring the disappearance of starting material, the system was cooled to room temperature, and then a solution of intermediate III-31 (534 mg,1.50 mmol) in N, N-dimethylformamide (3 mL), potassium carbonate (312 mg,2.25 mmol), potassium iodide (25 mg,0.15 mmol) were added in this order under ice bath, and the reaction was carried out at 50℃for 6 hours after the addition. After the completion of the reaction, the system was cooled to room temperature, water (70 mL) was added to the reaction solution to dilute, ethyl acetate was extracted (15 ml×3), and the organic phases were combined, washed with water (20 ml×2) and saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate III-32 (colorless oily liquid, 505 mg): 1 H NMR(300MHz,Chloroform-d)δ7.37(d,J＝8.4Hz,1H),7.31(d,J＝7.3Hz,1H),7.22(d,J＝8.2Hz,1H),7.13(d,J＝7.3Hz,1H),3.12(t,J＝6.0Hz,1H),2.87(t,J＝6.0Hz,1H).
synthesis of intermediate III-33
Intermediate III-32 (425 mg,1.13 mmol), oxalic acid dihydrate (426 mg,3.38 mmol), palladium acetate (13 mg,0.06 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (33 mg,0.06 mmol) and acetic anhydride (324. Mu.L, 3.38 mmol) were added to anhydrous N, N-dimethylformamide (4 mL), the system was cooled to-78deg.C and frozen, N-diisopropylethylamine (589. Mu.L, 3.38 mmol) was added, and the system was allowed to spontaneously return to room temperature under argon atmosphere and stirred for 10 minutes, and then allowed to react at 100deg.C for 8 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 2N aqueous hydrogen chloride (10 mL) and water (30 mL), extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, followed by water (15 ml x 1), saturated brine (15 ml x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate III-33 (white solid, 232 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.85(s,1H),7.86(d,J＝8.2Hz,2H),7.46(d,J＝8.8Hz,2H),7.38(d,J＝8.0Hz,1H),7.31(d,J＝8.3Hz,2H),3.35-3.23(m,4H),2.95(t,J＝7.5Hz,2H).
synthesis of Compound C-50
Referring to the procedure of example 7, substituting 4-trifluoromethylthiobenzoic acid for intermediate III-33, compound C-50 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.05(s,1H),9.70(s,1H),8.74(s,1H),7.88(d,J＝7.9Hz,2H),7.63(d,J＝2.5Hz,1H),7.53-7.45(m,3H),7.40(d,J＝8.0Hz,2H),7.33(d,J＝8.4Hz,2H),6.85(d,J＝8.7Hz,1H),3.30(t,2H),3.02-2.91(m,5H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0922.
example 201
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-51)
Synthesis of intermediate III-34
4-bromo-2-fluorophenylacetic acid (350 mg,1.5 mmol) was added to a dry three-necked flask, and was then dissolved in anhydrous tetrahydrofuran (3 mL) under argon, and 1M borane-tetrahydrofuran complex (2.25 mL,2.25 mmol) was slowly added dropwise under ice bath, and the mixture was allowed to react slowly to room temperature for 6 hours. After the reaction was completed, ice water (20 mL) was added dropwise to the reaction solution to quench excess borane, ethyl acetate (10 mL x 3) was extracted, and the organic phases were combined, washed with water (10 mL x 1), saturated brine (10 mL x 1) in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate III-34 which was used directly for the next reaction without further purification.
Synthesis of intermediate III-35
Crude III-34 (1.5 mmol) and 4-trifluoromethoxybenzenesulfonyl chloride (585 mg,2.25 mmol) were added to N, N-dimethylformamide (3 mL), a solution of tributylphosphine (2.27 g,11.25 mmol) in N, N-dimethylformamide (2 mL) was added dropwise under an ice bath under argon blanket, stirred for 10 minutes, a solution of Azodicarbonyldipiperidine (ADDP) (618 mg,2.25 mmol) in N, N-dimethylformamide (2 mL) was added dropwise under an ice bath, and the mixture was slowly warmed to room temperature and reacted for 6 hours. After the completion of the reaction, water (70 mL) was added to the reaction mixture to dilute, ethyl acetate (15 ml×3) was extracted, and the organic phases were combined, washed with 1M aqueous sodium hydroxide (15 ml×2), water (15 ml×1) and saturated brine (15 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified twice by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate III-35 (colorless oily liquid, 262 mg): 1 H NMR(300MHz,Chloroform-d)δ7.35(d,J＝8.9Hz,2H),7.24-7.18(m,2H),7.15(d,J＝8.3Hz,2H),7.05(t,J＝8.1Hz,1H),3.14(t,J＝7.6Hz,2H),2.91(t,J＝7.6Hz,2H).
synthesis of Compound C-51
Referring to the procedure of example 89, substituting intermediate II-41 for intermediate III-35 produced compound C-51: 1 H NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),9.73(s,1H),8.73(s,1H),7.78-7.67(m,2H),7.62(d,J＝2.5Hz,1H),7.56-7.43(m,4H),7.33(d,J＝8.4Hz,2H),6.86(d,J＝8.8Hz,1H),3.31-3.25(m,2H),3.03-2.95(m,5H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 5 S 2 [M+H] + 545.0823,found 545.0828.
example 202
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- (4- (trifluoromethyl) thio) phenyl) ethyl) benzamide (Compound C-52)
Synthesis of intermediate III-36
Thionyl chloride (1.81 mL,25 mmol) was added dropwise to water (15 mL) in an ice bath, reacted at 0℃for 3 hours, and further cuprous chloride (25 mg,0.25 mmol) was added thereto, and stirring was continued at 0℃for 1 hour. Simultaneously, 4-trifluoromethylthioaniline (480 mg,2.5 mmol) was added to concentrated hydrochloric acid (5 mL), sodium nitrite (319 mg,3.75 mmol) was added in portions under the ice-salt bath, and stirring was continued under the ice-salt bath for 1 hour. Then the reaction solution is added into the prepared sulfur dioxide water solution drop by drop, and the reaction is continued for 2 hours under the ice salt bath. After the completion of the reaction, ice water (20 mL) was added dropwise to the reaction mixture for dilution, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate III-36 (colorless oily liquid, 110 mg).
Synthesis of Compound C-52
Referring to the procedure of example 200, substituting 4-trifluoromethoxybenzenesulfonyl chloride for intermediate III-36 and substituting intermediate III-30 for intermediate III-34 produced compound C-52: 1 H NMR(300MHz,DMSO-d 6 )δ10.13(s,1H),9.70(s,1H),8.77(s,1H),7.79-7.68(m,2H),7.68-7.58(m,3H),7.58-7.43(m,4H),6.86(d,J＝8.7Hz,1H),3.41-3.36(m,2H),3.03(t,J＝7.4Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 4 S 3 [M+H] + 561.0594,found 561.0594.
example 203
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- (4- (trifluoromethyl) phenyl) thio-ethyl) benzamide (Compound C-53)
Synthesis of Compound C-53
Referring to the procedure of example 200, substituting 4-trifluoromethoxybenzenesulfonyl chloride with 4-trifluoromethylbenzenesulfonyl chloride and substituting intermediate III-30 with intermediate III-34 produced compound C-53: 1 H NMR(400MHz,DMSO-d 6 )δ10.11(s,1H),9.65(s,1H),8.79(s,1H),7.77-7.71(m,2H),7.66(d,J＝8.3Hz,2H),7.62(d,J＝2.6Hz,1H),7.55-7.47(m,4H),6.86(d,J＝8.8Hz,1H),3.38(t,J＝7.4Hz,2H),3.03(t,J＝7.4Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 4 S 2 [M+H] + 529.0873,found 529.0877.
example 204
2-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- (4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-54)
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Synthesis of Compound C-54
Referring to the procedure of example 200, substituting 4-bromophenylacetic acid for 4-bromo-3-fluorophenylacetic acid gave compound C-54: 1 H NMR(400MHz,DMSO-d 6 )δ10.17(s,1H),9.78(s,1H),8.74(s,1H),7.65(d,J＝7.9Hz,2H),7.62(d,J＝2.6Hz,1H),7.52-7.46(m,3H),7.33(d,J＝7.9Hz,2H),6.87(d,J＝8.8Hz,1H),3.29(t,J＝7.2Hz,2H),3.00(t,J＝7.2Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 5 S 2 [M+H] + 545.0823,found 545.0818.
example 205
2-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- (4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-55)
Synthesis of Compound C-55
Referring to the procedure of example 200, substituting 4-bromophenylacetic acid with 4-bromo-2, 6-difluorophenylacetic acid produced compound C-55: 1 H NMR(300MHz,DMSO-d 6 )δ10.18(s,1H),9.79(s,1H),8.77(s,1H),7.64(d,J＝8.0Hz,2H),7.61(d,J＝2.6Hz,1H),7.52-7.44(m,3H),7.33(d,J＝7.9Hz,2H),6.87(d,J＝8.7Hz,1H),3.28(t,J＝7.2Hz,2H),3.01(d,J＝7.3Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 23 H 19 F 5 N 2 O 5 S 2 [M+H] + 563.0728,found 563.0730.
example 206
2, 5-difluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-56)
Synthesis of Compound C-56
Referring to the procedure of example 200, substituting 4-bromophenylacetic acid with 4-bromo-2, 5-difluorophenylacetic acid produced compound C-56: 1 H NMR(400MHz,DMSO-d 6 )δ10.28(s,1H),9.77(s,1H),8.76(s,1H),7.57(d,J＝2.6Hz,1H),7.49(d,J＝8.8Hz,2H),7.47-7.39(m,3H),7.34(d,J＝7.7Hz,2H),6.85(d,J＝8.7Hz,1H),3.31(t,J＝7.4Hz,2H),2.96(s,3H),2.96(t,J＝7.3Hz,2H).HRMS(ESI)calcd.for C 23 H 19 F 5 N 2 O 5 S 2 [M+H] + 563.0728,found 563.0728.
EXAMPLE 207
3-chloro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- (4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-57)
Synthesis of Compound C-57
Referring to the procedure of example 200, substituting 4-bromophenylacetic acid for 4-bromo-2-chloroacetic acid produced compound C-57: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.75(s,1H),8.76(s,1H),7.99(d,J＝1.8Hz,1H),7.85(dd,J＝8.0,1.8Hz,1H),7.61(d,J＝2.6Hz,1H),7.55(d,J＝8.1Hz,1H),7.53-7.45(m,3H),7.34(d,J＝7.9Hz,2H),6.86(d,J＝8.8Hz,1H),3.30(t,J＝7.4Hz,2H),3.06(t,J＝7.5Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 20 ClF 3 N 2 O 5 S 2 [M+H] + 561.0527,found 561.0533.
example 208
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -3-methyl-4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-58)
Synthesis of Compound C-58
Referring to the procedure of example 200, substituting 4-bromophenylacetic acid for 4-bromo-2-methylphenylacetic acid produced compound C-58: 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),9.70(s,1H),8.73(s,1H),7.73(s,1H),7.70(dd,J＝7.8,2.0Hz,1H),7.62(d,J＝2.6Hz,1H),7.54-7.46(m,3H),7.37-7.30(m,3H),6.85(d,J＝8.7Hz,1H),3.26(t,J＝7.6Hz,2H),2.97(s,3H),2.93(t,J＝7.7Hz,2H),2.31(s,3H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 5 S 2 [M+H] + 541.1073,found 541.1074.
EXAMPLE 209
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -3-methoxy-4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-59)
Synthesis of Compound C-59
Referring to the procedure of example 200, substituting 4-bromophenylacetic acid with 4-bromo-2-methoxyphenylacetic acid gave compound C-59: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.74(s,1H),8.74(s,1H),7.62(d,J＝2.6Hz,1H),7.54-7.43(m,5H),7.35(d,J＝7.9Hz,2H),7.31(d,J＝7.6Hz,1H),6.86(d,J＝8.7Hz,1H),3.89(s,3H),3.22(t,J＝8.0Hz,2H),2.97(s,3H),2.91(t,J＝6.9Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 6 S 2 [M+H] + 557.1022,found 557.1027.
Example 210
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -3- (trifluoromethoxy) -4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-60)
Synthesis of Compound C-60
Referring to the procedure of example 200, substituting 4-bromophenylacetic acid with 4-bromo-2- (trifluoromethoxy) phenylacetic acid, compound C-60 was prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.22(s,1H),9.76(s,1H),8.77(s,1H),7.96(dd,J＝8.0,1.7Hz,1H),7.84(s,1H),7.66(d,J＝8.1Hz,1H),7.61(d,J＝2.6Hz,1H),7.53-7.46(m,3H),7.34(d,J＝7.9Hz,2H),6.87(d,J＝8.7Hz,1H),3.30(t,J＝7.2Hz,2H),2.99(t,J＝7.4Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 24 H 20 F 6 N 2 O 6 S 2 [M+H] + 611.0740,found 611.0746.
example 211
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -6- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) nicotinamide (compound C-61)
Synthesis of Compound C-61
Referring to the procedure of example 200, substituting 2- (5-bromopyridin-2-yl) acetic acid for 4-bromophenylacetic acid produced compound C-61: 1 H NMR(400MHz,DMSO-d 6 )δ10.25(s,1H),9.23(s,2H),9.00(d,J＝2.3Hz,1H),8.20(dd,J＝8.1,2.4Hz,1H),7.62(d,J＝2.6Hz,1H),7.52-7.42(m,4H),7.33(d,J＝7.8Hz,2H),6.86(d,J＝8.8Hz,1H),3.44(t,J＝7.3Hz,2H),3.13(t,J＝7.3Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 5 S 2 [M+H] + 528.0869,found 528.0876.
example 212
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -3-nitro-4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-62)
Synthesis of Compound C-62
Referring to the procedure of example 200, substituting 2- (4-bromo-2-nitrophenyl) acetic acid for 4-bromophenylacetic acid produced compound C-62: 1 H NMR(400MHz,DMSO-d 6 )δ10.35(s,1H),9.79(s,1H),8.81(s,1H),8.51(d,J＝1.9Hz,1H),8.21(dd,J＝8.1,1.9Hz,1H),7.73(d,J＝8.1Hz,1H),7.62(d,J＝2.6Hz,1H),7.51(dd,J＝8.7,2.5Hz,1H),7.48(d,J＝8.8Hz,2H),7.33(d,J＝7.9Hz,2H),6.88(d,J＝8.7Hz,1H),3.37(d,J＝6.8Hz,2H),3.21(t,J＝7.4Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 3 N 3 O 7 S 2 [M+H] + 572.0768,found 572.0771.
example 213
3-fluoro-N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (2- (4- (trifluoromethoxy) phenyl) thio) ethyl) benzamide (Compound C-63)
Synthesis of Compound C-63
Referring to the procedure of example 201, substituting intermediate I-18 for intermediate II-18 produced compound C-63: 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),9.99(s,1H),8.87(s,1H),7.76(dd,J＝7.8,1.7Hz,1H),7.72(dd,J＝10.8,1.7Hz,1H),7.53(d,J＝7.7Hz,1H),7.48(d,J＝8.9Hz,2H),7.34(d,J＝7.9Hz,2H),7.29(d,J＝8.3Hz,1H),6.78(d,J＝11.4Hz,1H),3.31(d,J＝7.9Hz,2H),3.00(t,J＝7.4Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 23 H 19 F 5 N 2 O 5 S 2 [M+H] + 563.0728,found 563.0726.
Example 214
N- (3- (4-fluorophenyl) sulfamido) -5-hydroxyphenyl) -4- (2- (4- (trifluoromethoxy) phenyl) thio-ethyl) benzamide (compound C-64)
Synthesis of intermediate III-37
Referring to the procedure of example 105, replacing methylsulfonic anhydride with 4-fluorobenzenesulfonyl chloride produced intermediate III-37: 1 H NMR(300MHz,DMSO-d 6 )δ10.19(s,1H),7.87-7.77(m,2H),7.48-7.37(m,2H),6.38(s,1H),6.35(s,2H),5.48(s,2H).
synthesis of intermediate III-38
Intermediate III-33 (120 mg,0.35 mmol), N-dimethylformamide (2 drops) and oxalyl chloride (45. Mu.L, 0.53 mmol) were added dropwise to anhydrous tetrahydrofuran (3 mL) under ice bath, the reaction was slowly warmed to room temperature for 2 hours after the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acid chloride, and the residue was added dropwise to a solution of intermediate III-37 (127 mg,0.37 mmol) and pyridine (28. Mu.L, 0.53 mmol) in anhydrous tetrahydrofuran (2 mL) under ice bath after the completion of the reaction, and the reaction was warmed to room temperature for 6 hours. After the reaction was completed, 2N aqueous hydrogen chloride was added dropwise to the reaction solution to adjust the pH to 3 to 4, ethyl acetate (10 ml x 3) was used for extraction, the organic phases were combined, washed with saturated brine (15 ml x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate III-38 (pale yellow solid, 157 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.60(s,1H),10.34(s,1H),7.90-7.82(m,4H),7.75(d,J＝6.0Hz,2H),7.52-7.38(m,6H),7.33(d,J＝8.5Hz,2H),6.96(s,1H),2.97(t,J＝7.6Hz,2H),2.44(s,2H).
Synthesis of Compound C-64
Referring to the procedure of example 105, substituting intermediate II-68 for intermediate III-38 produced compound C-64: 1 H NMR(300MHz,DMSO-d 6 )δ10.18(s,1H),10.06(s,1H),9.48(s,1H),7.94-7.79(m,4H),7.55-7.27(m,8H),7.11(s,1H),7.02(s,1H),6.31(s,1H),3.32-3.31(m,2H),2.96(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 5 S 2 [M+H] + 607.0985,found 607.0989.
example 215
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenethyl) sulfonyl) benzamide (Compound C-65)
Synthesis of intermediate III-39
Intermediate III-1 (250 mg,1.12 mmol) and triphenylphosphine (413 mg,1.57 mmol) were added to dichloromethane (4 mL), carbon tetrabromide (560 mg,1.69 mmol) was added in portions under ice bath, and the reaction was allowed to proceed to room temperature for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate III-39 (white solid, 335 mg): 1 H NMR(300MHz,CDCl 3 )δ7.63(d,J＝8.0Hz,2H),7.30(d,J＝8.5Hz,2H),3.60(t,J＝7.4Hz,2H),3.23(t,J＝7.3Hz,2H).
synthesis of intermediate III-40
4-Bromophenylsulfonic acid sodium salt dihydrate (3838 mg,1.39 mmol) was added to anhydrous N, N-dimethylformamide (2 mL), a solution of intermediate III-39 (330 mg,1.16 mmol) in N, N-dimethylformamide (1 mL) was added under an argon atmosphere while ice-bath, and the mixture was allowed to react at 80℃for 12 hours. After the completion of the reaction, water (20 mL) was added to the reaction mixture to dilute, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, washed with water (15 ml×2) and saturated brine (15 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate III-40 (white solid, 305 mg): 1 H NMR(300MHz,CDCl 3 )δ7.77(dd,J＝20.2,8.6Hz,4H),7.58(d,J＝8.0Hz,2H),7.21(d,J＝8.1Hz,2H),3.42-3.34(m,2H),3.16-3.08(m,2H).ESI-MS:m/z 446.9[M+Na] + .
Synthesis of Compound C-65
Referring to the procedure of example 89, substituting intermediate II-41 for intermediate III-40 produced compound C-65: 1 H NMR(300MHz,DMSO-d 6 )δ10.35(s,1H),9.39(s,1H),8.95(s,1H),8.15(d,J＝8.4Hz,2H),8.05(d,J＝8.4Hz,2H),7.64(d,J＝2.4Hz,1H),7.60(d,J＝8.1Hz,2H),7.51(d,1H),7.40(d,J＝8.2Hz,2H),6.88(d,J＝8.7Hz,1H),3.80(t,2H),3.00(t,J＝9.4Hz,2H),2.98(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 6 S 3 [M+H] + 575.0587,found 575.0585.
example 216
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenethyl) sulfonyl) benzamide (compound C-66)
Synthesis of Compound C-66
Referring to the procedure of example 215, substituting intermediate III-1 with 4-trifluoromethoxy phenethyl alcohol produced compound C-66: 1 H NMR(300MHz,DMSO-d 6 )δ10.34(s,1H),9.71(s,1H),8.81(s,1H),8.15(d,J＝7.8Hz,2H),8.05(d,J＝8.1Hz,2H),7.64(s,1H),7.51(d,J＝8.6Hz,1H),7.36(d,J＝8.0Hz,2H),7.24(d,J＝7.8Hz,2H),6.88(d,J＝8.5Hz,1H),3.77(t,2H),2.98(s,3H),2.93(t,2H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 7 S 2 [M+H] + 559.0815,found 559.0818.
example 217
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- (trifluoromethoxy) phenethyl) sulfonyl) benzamide (compound C-67)
Synthesis of intermediate III-41
Intermediate III-24 (593 mg,1.5 mmol) was added to dichloromethane (15 mL), m-chloroperoxybenzoic acid (mCPBA) (1.22 g,6 mmol) was added in portions under an ice bath, and the mixture was allowed to react at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was quenched with saturated sodium thiosulfate solution (20 mL) and 1M sodium hydroxide solution (10 mL), extracted with methylene chloride (15 ml×3), the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was washed with column chromatography (petroleum ether/ethyl acetate=10:1) to give crude intermediate III-41 (white solid, 599 mg) which was used in the next reaction without further purification.
Synthesis of Compound C-67
Referring to the procedure of example 200, substituting intermediate III-32 for intermediate III-41 produced compound C-67: 1 H NMR(300MHz,DMSO-d 6 )δ10.36(s,1H),9.84(s,1H),8.78(s,1H),8.01-7.88(m,3H),7.61(d,J＝2.6Hz,1H),7.51(dd,J＝8.7,2.6Hz,1H),7.36(d,J＝8.7Hz,2H),7.21(d,J＝7.7Hz,2H),6.88(d,J＝8.7Hz,1H),3.84(t,J＝7.6Hz,2H),3.02(t,J＝7.7Hz,2H),2.97(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 7 S 2 [M+H] + 577.0721,found 577.0722.
example 218
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- ((4- (trifluoromethoxy) phenyl) sulfonyl) ethyl) benzamide (compound C-68)
Synthesis of Compound C-68
Referring to the procedure of example 217, substituting intermediate III-24 for intermediate III-32 produced compound C-68: 1 H NMR(400MHz,DMSO-d 6 )δ10.03(s,1H),9.71(s,1H),8.72(s,1H),8.06(d,J＝8.8Hz,2H),7.83(d,J＝8.4Hz,2H),7.64(d,J＝7.9Hz,2H),7.61(d,J＝2.5Hz,1H),7.48(dd,J＝8.8,2.6Hz,1H),7.35(d,J＝8.4Hz,2H),6.84(d,J＝8.8Hz,1H),3.80(t,J＝8.1Hz,2H),2.99(t,J＝8.5Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 7 S 2 [M+H] + 559.0815,found 559.0815.
example 219
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (2- ((4- (trifluoromethoxy) phenyl) sulfonyl) ethyl) benzamide (compound C-69)
Synthesis of Compound C-69
Referring to the procedure of example 217, substituting intermediate III-24 for intermediate III-35 produced compound C-69: 1 H NMR(400MHz,DMSO-d 6 )δ10.09(s,1H),9.75(s,1H),8.75(s,1H),8.06(d,J＝8.9Hz,2H),7.71-7.66(m,2H),7.64(d,J＝7.9Hz,2H),7.60(d,J＝2.6Hz,1H),7.48(dd,J＝8.8,3.0Hz,1H),7.46(d,J＝8.0Hz,1H),6.85(d,J＝8.8Hz,1H),3.78(t,J＝7.6Hz,2H),3.01(t,J＝8.8Hz,2H),2.96(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 7 S 2 [M+H] + 577.0721,found 577.0728.
example 220
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenethyl) amino) benzamide hydrochloride (Compound C-70)
Synthesis of intermediate III-42
Intermediate 4-trifluoromethylthiophenylacetic acid (300 mg,1.27 mmol) and N, N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (3 mL), oxalyl chloride (161. Mu.L, 1.91 mmol) was added dropwise to the ice bath, the reaction was slowly allowed to proceed to room temperature for 4 hours after the completion of the addition, the solvent was distilled off under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to prepare a tetrahydrofuran solution of acid chloride, which was then added dropwise to a solution of ethyl 4-aminobenzoate (231 mg,1.40 mmol) and pyridine (153. Mu.L, 1.91 mmol) in anhydrous tetrahydrofuran (2 mL) under ice bath, and the reaction was allowed to proceed to room temperature for 6 hours after the addition. After the completion of the reaction, 2N aqueous hydrogen chloride was added dropwise to the reaction solution to adjust the pH to 3-4, ethyl acetate (10 ml x 3) was extracted, the organic phases were combined, washed with water (15 ml x 1), saturated brine (15 ml x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate III-42 (white solid, 347 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.57(s,1H),7.92(d,J＝8.7Hz,2H),7.73(d,J＝8.8Hz,2H),7.69(d,J＝8.1Hz,2H),7.50(d,J＝8.1Hz,2H),4.28(q,J＝7.1Hz,2H),3.79(s,2H),1.31(t,J＝7.1Hz,3H).ESI-MS:m/z 382.1[M-H] - .
Synthesis of intermediate III-43
Intermediate III-42 (347mg, 0.91 mmol) was added to a dry three-necked flask, protected with argon, dissolved in anhydrous tetrahydrofuran (3 mL), and 1M borane-tetrahydrofuran complex solution (2.7 mL,2.72 mmol) was added dropwise under ice-bath, and the mixture was slowly warmed to room temperature and reacted for 12 hours. After the reaction was completed, ice water (20 mL) was added dropwise to the reaction solution to quench excess borane, ethyl acetate (10 mL x 3) was extracted, the organic phases were combined, washed with saturated brine (10 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 give intermediate III-43 (white solid, 220 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.69(d,J＝8.8Hz,2H),7.65(d,J＝8.1Hz,2H),7.46(d,J＝8.1Hz,2H),6.62(d,J＝8.6Hz,3H),4.21(q,J＝7.1Hz,2H),3.36(d,J＝6.4Hz,2H),2.92(t,J＝7.2Hz,2H),1.27(t,J＝7.1Hz,3H).
synthesis of intermediate III-44
Intermediate III-43 (220 mg,0.60 mmol) and 4-dimethylaminopyridine (15 mg,0.12 mmol) were added to dichloromethane (2 mL), triethylamine (124. Mu.L, 0.89 mmol) and di-tert-butyl dicarbonate (274. Mu.L, 1.19 mmol) were added sequentially, and the reaction was continued at room temperature for 24 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to give intermediate III-44 (colorless oily liquid, 141 mg): 1 H NMR(300MHz,CDCl 3 )δ8.00(d,J＝8.5Hz,2H),7.57(d,J＝7.9Hz,2H),7.22(d,J＝8.2Hz,2H),7.18(d,J＝8.5Hz,2H),4.40(q,J＝7.1Hz,2H),3.96(t,J＝7.5Hz,2H),2.92(t,J＝7.4Hz,2H),1.43(s,9H),1.40(t,J＝7.1Hz,3H).
synthesis of intermediate III-45
Intermediate III-44 (130 mg,0.28 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), and 1M aqueous sodium hydroxide solution (1 mL) was added dropwise to react at 60℃for 4 hours. After the reaction, the organic solvent was distilled off under reduced pressure, and a 2N aqueous hydrogen chloride solution was added dropwise to the residue to prepare a mixture pH was adjusted to 2-3, solids precipitated, filtered, and the filter cake was washed with water (2 mL), n-hexane (3 mL), and the resulting solid was dried to constant weight to give intermediate III-45 (off-white solid, 114 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.72(s,1H),7.87(d,J＝8.5Hz,2H),7.62(d,J＝7.8Hz,2H),7.34(d,J＝8.1Hz,2H),7.30(d,J＝8.6Hz,2H),3.95(t,J＝7.1Hz,2H),2.85(t,J＝7.0Hz,2H),1.34(s,9H).ESI-MS:m/z 464.1[M+Na] + .
synthesis of Compound C-70
Referring to the procedure of example 23, substituting 4-trifluoromethylthiobenzoic acid for intermediate III-45, compound C-70 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.68(s,1H),8.68(s,1H),7.78(d,J＝8.7Hz,2H),7.66(d,J＝8.1Hz,2H),7.60(d,J＝2.5Hz,1H),7.55-7.43(m,3H),6.84(d,J＝8.7Hz,1H),6.68(d,J＝8.7Hz,2H),5.29(s,2H),3.38(t,J＝7.2Hz,2H),2.97(s,3H),2.93(t,J＝7.1Hz,2H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 4 S 2 [M+H] + 526.1077,found 526.1075.
example 221
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenethyl) amino) benzamide hydrochloride (Compound C-71)
Synthesis of Compound C-71
Referring to the procedure of example 220, substituting 4-trifluoromethylthiophenylacetic acid with 4-trifluoromethoxyphenylacetic acid produced compound C-71: 1 H NMR(300MHz,DMSO-d 6 )δ9.67(s,1H),8.67(s,1H),7.77(d,J＝8.7Hz,2H),7.60(d,J＝2.4Hz,1H),7.50-7.38(m,3H),7.30(d,J＝8.1Hz,2H),6.84(d,J＝8.7Hz,1H),6.67(d,J＝8.7Hz,2H),5.19(s,2H),3.35(t,J＝7.3Hz,2H),2.97(s,3H),2.90(t,J＝7.2Hz,2H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 5 S[M-HCl+H] + 510.1311,found510.1319.
example 222
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -2- (4- ((trifluoromethyl) thio) benzyl) -1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound C-72)
Synthesis of intermediate III-46
4-trifluoromethylthiobenzaldehyde (233 mg,1.13 mmol) and 6-bromo-1, 2,3, 4-tetrahydroisoquinoline (200 mg,0.94 mmol) were added to dichloromethane (4 mL), glacial acetic acid (2 drops) was added, stirred at room temperature for 1 hour, sodium triacetoxyborohydride (400 mg,1.89 mmol) was added in portions under ice bath, and the mixture was warmed to room temperature and stirred for 12 hours. After the reaction was completed, the reaction mixture was quenched by addition of saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate III-46 (white solid, 233 mg): 1 H NMR(400MHz,Chloroform-d)δ7.64(d,J＝8.2Hz,2H),7.47(d,J＝8.2Hz,2H),7.25(dd,J＝8.1,2.1Hz,2H),6.88(d,J＝8.1Hz,2H),3.73(s,2H),3.59(s,2H),2.91(t,J＝5.9Hz,2H),2.75(t,J＝5.9Hz,2H).
Synthesis of Compound C-72
Referring to the procedure of example 89, substituting intermediate II-41 for intermediate III-46 produced compound C-72: 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),9.69(s,1H),8.70(s,1H),7.75-7.68(m,4H),7.62(d,J＝2.5Hz,1H),7.56(d,J＝7.8Hz,2H),7.50(d,J＝8.5Hz,1H),7.17(d,J＝8.0Hz,1H),6.85(d,J＝8.7Hz,1H),3.77(s,2H),3.65(s,2H),2.97(s,3H),2.92(t,J＝5.6Hz,2H),2.77-2.72(m,2H).HRMS(ESI)calcd.for C 25 H 24 F 3 N 3 O 4 S 2 [M+H] + 552.1233,found552.1238.
example 223
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -2- (4- ((trifluoromethyl) thio) benzyl) -1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound C-73)
Synthesis of Compound C-73
Referring to the procedure of example 222, substituting intermediate I-18 for intermediate II-18 produced compound C-73: 1 H NMR(400MHz,DMSO-d 6 )δ10.34(s,1H),9.87(s,1H),8.88(s,1H),7.74(s,1H),7.73-7.68(m,3H),7.56(d,J＝8.3Hz,2H),7.27(d,J＝8.3Hz,1H),7.17(d,J＝8.1Hz,1H),6.77(d,J＝11.4Hz,1H),3.77(s,2H),3.65(s,2H),2.96(s,3H),2.91(t,J＝5.6Hz,2H),2.76-2.72(m,2H).HRMS(ESI)calcd.for C 25 H 23 F 4 N 3 O 4 S 2 [M+H] + 570.1144,found 570.1151.
example 224
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (3- (4- ((trifluoromethyl) thio) phenoxy) propyl) benzamide (Compound C-74)
Synthesis of Compound C-74
Referring to the procedure of example 165, substituting 4-bromophenylethanol for 4-bromophenylpropanol gave compound C-74: 1 H NMR(300MHz,DMSO-d 6 )δ10.03(s,1H),9.09(s,2H),7.87(d,J＝8.1Hz,2H),7.63(d,J＝8.9Hz,3H),7.49(dd,J＝8.8,2.5Hz,1H),7.37(d,J＝8.1Hz,2H),7.09(d,J＝8.8Hz,2H),6.85(d,J＝8.7Hz,1H),4.05(t,J＝6.2Hz,2H),2.97(s,3H),2.82(t,J＝7.7Hz,2H),2.08(p,J＝6.9Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 5 S 2 [M+H] + 541.1073,found541.1104.
example 225
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -4- ((3- (4- (trifluoromethoxy) phenyl) propyl) thio) benzamide (Compound C-75)
Synthesis of Compound C-75
Referring to the procedure of example 168, substituting 4-trifluoromethoxy phenylacetic acid with 4-trifluoromethoxy phenylpropionic acid gave compound C-75: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.39(s,2H),7.87(d,J＝8.5Hz,2H),7.83(d,J＝5.2Hz,1H),7.80(d,J＝5.2Hz,1H),7.67(d,J＝2.5Hz,1H),7.40(d,J＝2.9Hz,2H),7.37(d,J＝3.3Hz,3H),7.34(s,2H),7.29(dd,J＝8.9,1.1Hz,2H),6.68(d,J＝8.7Hz,1H),3.07(t,J＝7.2Hz,2H),2.78(t,J＝7.6Hz,2H),1.92(p,J＝7.4Hz,3H).HRMS(ESI)calcd.for C 29 H 24 F 4 N 2 O 5 S 2 [M+H] + 621.1136,found 621.1130.
example 226
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((3- (4- (trifluoromethoxy) phenyl) propyl) thio) benzamide (Compound C-76)
Synthesis of Compound C-76
Referring to the procedure of example 168, substituting 4-trifluoromethoxybenzoic acid for 4-trifluoromethoxybenzoic acid and substituting intermediate I-3 for intermediate I-18 gave compound C-76: 1 H NMR(400MHz,DMSO-d 6 )δ10.02(s,1H),9.66(s,1H),8.71(s,1H),7.86(d,J＝8.3Hz,2H),7.62(d,J＝2.5Hz,1H),7.48(dd,J＝8.7,2.6Hz,1H),7.43(d,J＝8.8Hz,2H),7.33(d,J＝6.8Hz,2H),7.31(d,J＝6.3Hz,2H),6.85(d,J＝8.7Hz,1H),3.01(t,J＝7.1Hz,2H),2.97(s,3H),2.79(t,J＝7.5Hz,2H),1.91(p,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 5 S 2 [M+H] + 541.1073,found541.1075.
example 227
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- ((3- (4- (trifluoromethoxy) phenyl) propyl) thio) benzamide (compound C-77)
Synthesis of intermediate III-47
4-trifluoromethoxybenzoic acid (400 mg,1.71 mmol) was added to anhydrous tetrahydrofuran (4 mL), sodium borohydride (130 mg,3.41 mmol) was added in portions under ice bath, stirring was continued for 10 minutes at 0℃and after the generation of bubbles was observed to stop, boron trifluoride diethyl ether (222. Mu.L, 1.80 mmol) was added dropwise, and the mixture was allowed to react slowly to room temperature for 8 hours. After the completion of the reaction, the reaction mixture was quenched with water (20 mL), extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to give intermediate III-47 (pale yellow oily liquid, 379 mg).
Synthesis of Compound C-77
Referring to the procedure of example 168, substituting intermediate III-12 for intermediate III-47, substituting 4-bromophenylthiophenol for 4-bromo-2-fluorophenylthiophenol and substituting intermediate I-3 for intermediate I-18, produced compound C-77: 1 H NMR(300MHz,DMSO-d 6 )δ10.11(s,1H),9.69(s,1H),8.70(s,1H),7.78(d,J＝8.9Hz,2H),7.61(s,1H),7.55-7.45(m,2H),7.33(d,J＝9.2Hz,2H),7.27(d,J＝7.9Hz,2H),6.86(d,J＝8.7Hz,1H),3.07(t,J＝7.1Hz,2H),2.97(s,3H),2.77(t,2H),1.97-1.85(m,2H).HRMS(ESI)calcd.for C 24 H 22 F 4 N 2 O 5 S 2 [M+H] + 559.0979,found 559.0979.
Example 228
3-fluoro-N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((3- (4- (trifluoromethoxy) phenyl) propyl) thio) benzamide (Compound C-78)
Synthesis of Compound C-78
Referring to the procedure of example 168, substituting intermediate III-12 for intermediate III-47, substituting 4-bromophenylthiophenol for 4-bromo-2-fluorophenylthiophenol and substituting intermediate I-3 for intermediate II-18, produced compound C-78: 1 H NMR(400MHz,DMSO-d 6 )δ10.37(s,1H),10.00(s,1H),8.90(s,1H),7.82-7.73(m,2H),7.52(t,J＝8.1Hz,1H),7.35(d,J＝8.6Hz,2H),7.27(d,J＝8.2Hz,3H),6.77(d,J＝11.4Hz,1H),3.07(t,J＝7.2Hz,2H),2.95(s,3H),2.77(t,J＝7.6Hz,2H),1.91(p,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 24 H 21 F 5 N 2 O 5 S 2 [M+H] + 577.0885,found 577.0884.
example 229
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (3- (4- (trifluoromethyl) thio) phenyl) thiopropyl) benzamide (Compound C-79)
Synthesis of intermediate III-48
4-Bromophenylpropanol (640 mg,3.0 mmol) and triphenylphosphine (944 mg,3.6 mmol) were added to dichloromethane (10 mL), and carbon tetrabromide (1.29 g,3.9 mmol) was added in portions while ice-bath, and the mixture was allowed to react at room temperature for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate III-48 (white solid, 635 mg).
Synthesis of intermediate III-49
Cuprous iodide (64 mg,0.34 mmol), potassium carbonate (926 mg,6.71 mmol) and elemental sulfur (322 mg,10.07 mmol) were added to a dry Schlenk tube, protected with argon, and a solution of intermediate III-28 (1.02 g,3.36 mmol) in N, N-dimethylformamide (8 mL) was added and the addition was completed and the temperature was raised to 90℃for reaction for 8 hours. After the reaction was completed, the system was cooled to room temperature, and sodium borohydride (380 mg,10.07 mmol) was added in portions under an ice bath, and the system was heated to 40℃to react for 2 hours. After the reaction was completed, the system was cooled to room temperature, and a solution of intermediate III-48 (839 mg,3.02 mmol) in N, N-dimethylformamide (2 mL) was added thereto, and the reaction was continued at 70℃for 6 hours after the addition. After the completion of the reaction, the reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (20 mL. Times.3), washed with water (20 mL. Times.2) and saturated brine (20 mL. Times.1), and the solvent was distilled off under reduced pressure to leave a residue Purification by column chromatography (petroleum ether/ethyl acetate=150:1) afforded intermediate III-49 (white solid, 495 mg): 1 H NMR(300MHz,Chloroform-d)δ7.52(d,J＝8.2Hz,2H),7.41(d,J＝8.3Hz,2H),7.25(d,J＝7.1Hz,2H),7.05(d,J＝8.3Hz,2H),2.93(t,J＝7.3Hz,2H),2.78-2.69(m,2H),2.03-1.92(m,2H).
synthesis of Compound C-79
Referring to the procedure of example 89, substituting intermediate II-41 for intermediate III-49 produced compound C-79: 1 H NMR(300MHz,DMSO-d 6 )δ10.01(s,1H),9.64(s,1H),8.69(s,1H),7.86(d,J＝8.0Hz,2H),7.65-7.51(m,3H),7.48(dd,J＝8.3,2.5Hz,1H),7.41(d,J＝8.1Hz,2H),7.34(d,J＝8.0Hz,2H),6.84(d,J＝8.7Hz,1H),3.05(t,J＝7.2Hz,2H),2.96(s,3H),2.80(t,J＝7.6Hz,2H),2.00-1.84(m,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 4 S 3 [M+H] + 557.0845,found 557.0851.
example 230
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (3- ((4- (trifluoromethoxy) phenyl) thio) propyl) benzamide (Compound C-80)
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Synthesis of Compound C-80
Referring to the procedure of example 201, substituting intermediate III-34 with 4-bromophenylpropanol produced compound C-80: 1 H NMR(400MHz,DMSO-d 6 )δ10.04(s,1H),9.69(s,1H),8.70(s,1H),7.87(d,J＝8.5Hz,2H),7.61(d,J＝2.6Hz,1H),7.48(dd,J＝8.8,2.6Hz,1H),7.39(d,J＝8.5Hz,2H),7.34(d,J＝8.7Hz,2H),7.27(d,J＝8.9Hz,2H),6.85(d,J＝8.7Hz,1H),3.06(t,J＝7.2Hz,2H),2.97(s,3H),2.77(t,J＝7.7Hz,2H),1.91(p,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 5 S 2 [M+H] + 541.1073,found 541.1073.
example 231
3-fluoro-N- (4-hydroxy-3- (methylsulfonyl) phenyl) -4- (3- ((4- (trifluoromethoxy) phenyl) thio) propyl) benzamide (Compound C-81)
Synthesis of Compound C-81
Referring to the procedure of example 200, substituting 3- (2-fluoro-4-bromophenyl) propionic acid for 4-bromophenylacetic acid produced compound C-81: 1 H NMR(400MHz,DMSO-d 6 )δ10.09(s,1H),9.72(s,1H),8.71(s,1H),7.79-7.69(m,2H),7.61(d,J＝2.5Hz,1H),7.48(dd,J＝8.7,2.6Hz,1H),7.47-7.41(m,3H),7.32(d,J＝8.3Hz,2H),6.86(d,J＝8.7Hz,1H),3.04(t,J＝7.2Hz,2H),2.97(s,3H),2.82(t,J＝7.5Hz,2H),1.89(p,J＝7.3Hz,2H).HRMS(ESI)calcd.for C 24 H 22 F 4 N 2 O 5 S 2 [M+H] + 559.0979,found 559.0985.
example 232
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -2- (4- ((trifluoromethyl) thio) phenethyl) -1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound C-82)
Synthesis of intermediate III-50
Referring to the procedure of example 168, substituting 4-trifluoromethoxy phenylacetic acid with 4-trifluoromethylthiophenylacetic acid produced intermediate III-50: 1 H NMR(400MHz,Chloroform-d)δ7.69(d,J＝8.3Hz,2H),7.55(d,J＝8.2Hz,2H),7.30(d,J＝7.8Hz,2H),7.19(d,J＝8.2Hz,2H),4.25(t,J＝6.7Hz,2H),3.01(t,J＝6.7Hz,2H),2.46(s,3H).
synthesis of Compound C-82
Referring to example 89, 4-three fluoro methyl sulfide phenol replaced by 6-bromo-1, 2,3, 4-four hydrogen isoquinoline, 4-bromo-2-three fluoro methyl bromide replaced by intermediate III-50, compound C-82: 1 H NMR(400MHz,DMSO-d 6 )δ10.03(s,1H),9.70(s,1H),8.71(s,1H),7.73(d,J＝8.3Hz,2H),7.66(d,J＝7.8Hz,2H),7.62(d,J＝2.6Hz,1H),7.50(dd,J＝8.7,2.5Hz,1H),7.47(d,J＝8.1Hz,2H),7.22(d,J＝7.9Hz,1H),6.86(d,J＝8.7Hz,1H),3.83(s,2H),3.33(s,2H),3.02-2.83(m,3H).HRMS(ESI)calcd.for C 26 H 26 F 3 N 3 O 4 S 2 [M+H] + 566.1395,found 566.1409.
example 233
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -2- (4- ((trifluoromethyl) thio) phenethyl) -1,2,3, 4-tetrahydroisoquinoline-6-carboxamide (Compound C-83)
Synthesis of Compound C-83
Referring to example 89, 4-three fluoro methyl sulfide phenol replaced by 6-bromo-1, 2,3, 4-four hydrogen isoquinoline, 4-bromo-2-three fluoro methyl bromide substituted by intermediate III-50, intermediate I-18 replaced by II-18, compound C-83: 1 H NMR(300MHz,DMSO-d 6 )δ10.37(s,1H),9.91(s,1H),8.90(s,1H),7.75(d,J＝8.5Hz,2H),7.67(d,J＝7.9Hz,2H),7.48(d,J＝8.2Hz,2H),7.32-7.20(m,2H),6.78(d,J＝11.4Hz,1H),3.97(s,2H),3.36(s,2H),3.10-2.96(m,6H),2.95(s,3H).HRMS(ESI)calcd.for C 26 H 25 F 4 N 3 O 4 S 2 [M+H] + 584.1295,found 584.1305.
example 234
N- (5- (3- ([ 1,1' -biphenyl ] -4-yl) ureido) -2-hydroxyphenyl) -4-fluorobenzenesulfonamide (compound D-1)
Synthesis of intermediate IV-1
4-phenylbenzoic acid (300 mg,1.5 mmol) was added to dichloromethane (4 mL), triethylamine (417 μl,3 mmol) was added, stirred at room temperature for 15 minutes, diphenyl azide phosphate (DPPA) (294 μl,1.36 mmol) was added dropwise under ice bath, the reaction was warmed to room temperature for 8 hours, after completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to give intermediate IV-1 (white solid, 253 mg).
Synthesis of intermediate IV-2
Intermediate IV-1 (255 mg,1.13 mmol) was added to toluene (3 mL) and reacted at 80℃for 4 hours. After the completion of the reaction, the system was cooled to room temperature, and intermediate I-16 (470 mg,1.19 mmol) was added to the reaction mixture in portions, followed by reaction at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, filtered, and the filter cake was purified by beating (n-hexane/diethyl ether=10:1), and the obtained solid was dried to constant weight to obtain intermediate IV-2 (white solid, 667 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.06(s,1H),8.62(s,1H),8.57(s,1H),7.80(dd,J＝8.8,5.2Hz,2H),7.64(d,J＝7.5Hz,2H),7.60(d,J＝8.9Hz,2H),7.52(d,J＝8.7Hz,2H),7.48-7.43(m,2H),7.39(d,1H),7.32(t,J＝7.3Hz,1H),7.25(d,J＝2.2Hz,1H),7.20-7.13(m,2H),6.79(d,J＝8.7Hz,1H),0.92(s,9H),0.12(s,6H).ESI-MS:m/z 590.2[M-H] - .
synthesis of Compound D-1
Intermediate IV-2 (150 mg,0.25 mmol) and triethylamine trihydrofluoride (62. Mu.L, 0.38 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=100:1) to give compound D-1 (white solid, 106 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.31(s,1H),9.25(s,1H),8.59(s,1H),8.48(s,1H),7.81(dd,J＝8.8,5.2Hz,2H),7.63(d,J＝7.5Hz,2H),7.59(d,J＝8.9Hz,2H),7.52(d,J＝8.7Hz,2H),7.43(t,J＝7.7Hz,2H),7.37(t,J＝8.9Hz,2H),7.34-7.26(m,2H),7.09(dd,J＝8.7,2.5Hz,1H),6.65(d,J＝8.7Hz,1H).HRMS(ESI)calcd.for C 25 H 20 FN 3 O 4 S[M+H] + 478.1231,found478.1230.
example 235
4-fluoro-N- (2-hydroxy-5- (3- (4 '- (trifluoromethyl) - [1,1' -biphenyl ] -4-yl) ureido) phenyl) benzenesulfonamide (compound D-2)
Synthesis of Compound D-2
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid with 4' -trifluoromethyl-diphenyl-4-carboxylic acid gave compound D-2: 1 H NMR(300MHz,DMSO-d 6 )δ9.26(s,2H),8.40(s,2H),7.81(dd,J＝8.5,5.2Hz,2H),7.37(t,J＝9.2Hz,4H),7.30(d,J＝2.1Hz,1H),7.14(d,J＝8.3Hz,2H),7.07(dd,J＝8.8,2.1Hz,1H),6.64(d,J＝8.7Hz,1H),2.64(t,J＝11.8Hz,1H),2.05(d,J＝26.6Hz,3H),1.88(t,J＝14.7Hz,3H),1.65(t,J＝11.3Hz,2H).HRMS(ESI)calcd.for C 26 H 19 F 4 N 3 O 4 S[M+H] + 546.1105,found 546.1124.
example 236
4-fluoro-N- (2-hydroxy-5- (3- (4 '- ((trifluoromethyl) thio) - [1,1' -biphenyl ] -4-yl) ureido) phenyl) benzenesulfonamide (compound D-3)
Synthesis of intermediate IV-3
4-trifluoromethylthiophenol (200 mg,1.03 mmol) and 4-dimethylaminopyridine (13 mg,0.10 mmol) were added to dichloromethane (3 mL), triethylamine (286. Mu.L, 2.06 mmol) was added, and trifluoromethanesulfonic anhydride (256. Mu.L, 1.55 mmol) was added under ice bath, and the mixture was allowed to react at room temperature for 12 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate IV-3 (colorless oily liquid, 287 mg): 1 H NMR(300MHz,CDCl 3 )δ7.77(d,J＝8.7Hz,2H),7.35(d,J＝8.7Hz,2H).
synthesis of intermediate IV-4
Intermediate IV-3 (256 mg,0.79 mmol), 4-methoxycarbonylphenylboronic acid (170 mg,0.94 mmol), sodium carbonate (126 mg,1.19 mmol) and tetrakis (triphenylphosphine) palladium (46 mg,0.04 mmol) were added to a three-necked flask under argon protection, and a mixed solvent suspension of toluene (2 mL), water (1 mL) and ethanol (1 mL) was further addedStirred under reflux for 8 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=200:1) to give intermediate IV-4 (white solid, 138 mg): 1 H NMR(300MHz,CDCl 3 )δ8.13(d,J＝8.1Hz,2H),7.75(d,J＝8.1Hz,2H),7.66(d,J＝8.1Hz,4H),3.95(s,3H).
synthesis of intermediate IV-5
IV-4 (117 mg,0.37 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), and 1M aqueous sodium hydroxide solution (1 mL) was added thereto, followed by reaction at 60℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the organic solvent was distilled off under reduced pressure, a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2 to 3, solids were precipitated, and the cake was washed with water (2 mL) and N-hexane (2 mL) in this order, and the obtained solid was dried to constant weight to obtain intermediate IV-5 (white solid, 80 mg): 1 H NMR(300MHz,DMSO-d 6 )δ13.06(s,1H),8.05(d,J＝8.3Hz,2H),7.90(d,J＝8.4Hz,2H),7.83(t,J＝8.7Hz,4H).ESI-MS:m/z 297.0[M-H] - .
Synthesis of Compound D-3
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-5 produced compound D-3: 1 H NMR(300MHz,DMSO-d 6 )δ9.31(s,1H),9.25(s,1H),8.67(s,1H),8.51(s,1H),7.86-7.79(m,4H),7.76(d,J＝8.4Hz,2H),7.68(d,J＝8.7Hz,2H),7.57(d,J＝8.6Hz,2H),7.38(t,J＝8.8Hz,2H),7.33(d,J＝2.4Hz,1H),7.10(dd,J＝8.7,2.3Hz,1H),6.66(d,J＝8.6Hz,1H).HRMS(ESI)calcd.for C 26 H 19 F 4 N 3 O 4 S 2 [M+H] + 578.0826,found 578.0828.
example 237
N- (5- (3- (4-cyclohexylphenyl) ureido) -2-hydroxyphenyl) -4-fluorobenzenesulfonamide (Compound D-4)
Synthesis of Compound D-4
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for 4-cyclohexylbenzoic acid produced compound D-4: 1 H NMR(300MHz,DMSO-d 6 )δ9.25(s,1H),9.22(s,1H),8.37(s,1H),8.34(s,1H),7.81(dd,J＝8.8,5.2Hz,2H),7.44-7.25(m,5H),7.11(d,J＝8.5Hz,2H),7.06(dd,1H),6.64(d,J＝8.7Hz,1H),2.47-2.36(m,1H),1.85-1.66(m,5H),1.44-1.19(m,5H).HRMS(ESI)calcd.for C 25 H 26 FN 3 O 4 S[M+H] + 484.1701,found 484.1705.
example 238
N- (5- (3- (4, 4-difluorocyclohexyl) phenyl) ureido) -2-hydroxyphenyl) -4-fluorobenzenesulfonamide (compound D-5)
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Synthesis of Compound D-5
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate I-10, compound D-5 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.26(s,2H),8.40(s,2H),7.81(dd,J＝8.5,5.2Hz,2H),7.37(t,J＝9.2Hz,4H),7.30(d,J＝2.1Hz,1H),7.14(d,J＝8.3Hz,2H),7.07(dd,J＝8.8,2.1Hz,1H),6.64(d,J＝8.7Hz,1H),2.64(t,J＝11.8Hz,1H),2.05(d,J＝26.6Hz,3H),1.88(t,J＝14.7Hz,3H),1.65(t,J＝11.3Hz,2H).HRMS(ESI)calcd.for C 25 H 24 F 3 N 3 O 4 S[M+H] + 520.1512,found 520.1511.
example 239
N- (2-hydroxy-5- (3- (4 '- (trifluoromethyl) - [1,1' -biphenyl ] -4-yl) ureido) phenyl) methanesulfonamide (compound D-6)
Synthesis of intermediate IV-6
4' -Trifluoromethylbiphenyl-4-carboxylic acid (200 mg,0.75 mmol) was added to dichloromethane (2 mL), triethylamine (209. Mu.L, 1.5 mmol) was added, stirring was carried out at room temperature for 15 minutes, diphenyl azide phosphate (DPPA) (146. Mu.L, 0.68 mmol) was added dropwise under ice bath, the reaction was allowed to proceed to room temperature for 8 hours, after the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to give intermediate IV-6 (white solid, 100 mg).
Synthesis of intermediate IV-7
Intermediate IV-6 (100 mg,0.24 mmol) was added to toluene (3 mL) and reacted at 100℃for 4 hours. After the completion of the reaction, the system was cooled to room temperature, and intermediate I-18 (151 mg,0.38 mmol) was added to the reaction mixture in portions, followed by reaction at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, filtered, and the filter cake was purified by beating (n-hexane/diethyl ether=10:1), and the obtained solid was dried to constant weight to obtain intermediate IV-7 (white solid, 667 mg): 1 H NMR(300MHz,DMSO-d 6 )δ8.77(s,1H),8.67(s,1H),8.41(s,1H),7.88(d,J＝8.1Hz,2H),7.79(d,J＝8.3Hz,2H),7.70(d,J＝8.6Hz,2H),7.60(d,J＝8.7Hz,2H),7.49(d,J＝2.5Hz,1H),7.20(dd,1H),6.89(d,J＝8.8Hz,1H),3.04(s,3H),1.00(s,9H),0.25(s,6H).
synthesis of Compound D-6
Intermediate IV-7 (145 mg,0.25 mmol) and triethylamine trihydrofluoride (61. Mu.L, 0.38 mmol) were added to dichloromethane (4 mL) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=40:1) to give compound D-6 (white solid, 91 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.28(s,2H),8.70(s,1H),8.53(s,1H),7.86(d,J＝8.1Hz,2H),7.77(d,J＝8.2Hz,2H),7.68(d,J＝8.3Hz,2H),7.58(d,J＝8.4Hz,2H),7.33(d,J＝2.6Hz,1H),7.16(dd,J＝8.4,2.2Hz,1H),6.82(d,J＝8.7Hz,1H),2.96(s,3H).HRMS(ESI)calcd.for C 21 H 18 F 3 N 3 O 4 S[M+H] + 466.1043,found 466.1045.
example 240
N- (5- (3- (4, 4-difluorocyclohexyl) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (compound D-7)
Synthesis of Compound D-7
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate I-10, compound D-7 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.47(s,1H),8.68(s,1H),8.41(s,2H),7.42-7.27(m,3H),7.13(d,J＝8.2Hz,3H),6.79(d,J＝8.6Hz,1H),2.95(s,3H),2.69-2.57(m,1H),2.17-1.97(m,3H),1.85(d,J＝10.6Hz,3H),1.71-1.53(m,2H).HRMS(ESI)calcd.for C 20 H 23 F 2 N 3 O 4 S[M+H] + 440.1450,found 440.1447.
example 241
N- (2-hydroxy-5- (3- (4- (2- ((trifluoromethyl) thio) ethoxy) phenyl) ureido) phenyl) methanesulfonamide (compound D-8)
Synthesis of intermediate IV-8
Methyl 4-hydroxybenzoate (152 mg,1.0 mmol), 1, 2-dibromoethane (940 mg,5.0 mmol) were added to N, N-dimethylformamide (5 mL), potassium carbonate (276 mg,2.0 mmol) was added in portions with stirring, and the mixture was reacted at 60℃for 6 hours. After the completion of the reaction, the system was cooled to room temperature, water (50 mL) was added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, washed with water (15 ml×1) and saturated brine (15 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to give intermediate IV-8 (white solid, 172 mg).
Synthesis of intermediate IV-9
Intermediate IV-8 (172 mg,0.67 mmol) and sodium thiocyanate (80 mg,1.00 mmol) were added to acetonitrile (4 mL) and reacted for 4 hours at 80 ℃. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was diluted with water (20 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give crude intermediate IV-9 (131 mg, yellow oily liquid) which was used in the next reaction without further purification.
Synthesis of intermediate IV-10
Intermediate IV-9 (131 mg,0.56 mmol) and (trifluoromethyl) Trimethylsilane (TMSCF) 3 ) (170. Mu.L, 1.11 mmol) was added to anhydrous tetrahydrofuran (2 mL), and a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.56 mL,0.56 mmol) in anhydrous tetrahydrofuran (1 mL) was slowly added dropwise under ice bath, and the mixture was slowly warmed to room temperature and reacted for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=25:1) to give intermediate IV-10 (colorless oily liquid, 80 mg): 1 H NMR(400MHz,Chloroform-d)δ7.81(ddd,J＝8.5,2.1,1.2Hz,1H),7.76(dd,J＝11.6,2.0Hz,1H),6.97(t,J＝8.3Hz,1H),4.33(t,J＝6.6Hz,2H),3.90(s,3H),3.32(t,J＝6.6Hz,2H).
synthesis of intermediate IV-11
Intermediate IV-10 (80 mg,0.29 mmol) was dissolved in a mixed solvent of methanol (1 mL) and tetrahydrofuran (1 mL), and 1M aqueous sodium hydroxide solution (1 mL) was added thereto, and the mixture was reacted at 60℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the organic solvent was distilled off under reduced pressure, a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2 to 3, solids were precipitated, and the cake was washed with water (2 mL) and N-hexane (2 mL) in this order, and the obtained solid was dried to constant weight to obtain intermediate IV-11 (white solid, 70 mg): 1 H NMR(400MHz,Chloroform-d)δ8.07(d,J＝8.9Hz,2H),6.95(d,J＝9.0Hz,2H),4.29(t,J＝6.4Hz,2H),3.30(t,J＝6.5Hz,2H).
synthesis of Compound D-8
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-11 produced compound D-8: 1 H NMR(300MHz,DMSO-d 6 )δ9.53(s,1H),8.70(s,1H),8.55(s,1H),8.47(s,1H),7.48(dd,J＝13.8,2.4Hz,1H),7.29(d,J＝2.6Hz,1H),7.16-7.12(m,1H),7.10(d,J＝9.5Hz,1H),7.04(dd,J＝8.9,2.2Hz,1H),6.80(d,J＝8.7Hz,1H),4.25(t,J＝6.0Hz,2H),3.40(t,J＝6.0Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C 17 H 18 F 3 N 3 O 5 S 2 [M+H] + 466.0713,found 466.0719.
example 242
N- (5- (3- (3-fluoro-4- (2- ((trifluoromethyl) thio) ethoxy) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (Compound D-9)
Synthesis of Compound D-9
Referring to the procedure of example 241, substituting methyl 4-hydroxybenzoate with methyl 3-fluoro-4-hydroxybenzoate produced compound D-9: 1 H NMR(300MHz,DMSO-d 6 )δ9.53(s,1H),8.70(s,1H),8.55(s,1H),8.47(s,1H),7.48(dd,J＝13.8,2.4Hz,1H),7.29(d,J＝2.6Hz,1H),7.16-7.12(m,1H),7.10(d,J＝9.5Hz,1H),7.04(dd,J＝8.9,2.2Hz,1H),6.80(d,J＝8.7Hz,1H),4.25(t,J＝6.0Hz,2H),3.40(t,J＝6.0Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C 17 H 17 F 4 N 3 O 5 S 2 [M+H] + 484.0619,found 484.0608.
example 243
N- (2-hydroxy-5- (3- (4- ((2- ((trifluoromethyl) thio) ethyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-10)
Synthesis of intermediate IV-12
4-trifluoromethoxybenzenesulfonyl chloride (1.13 g,4.8 mmol) was added to N, N-dimethylformamide (10 mL), tributylphosphine (3.6 mL,14.4 mmol) was added dropwise under ice-bath, and the reaction was carried out at 50℃for 30 minutes. After TLC monitoring the disappearance of starting material, the system was cooled to room temperature, and then reacted with 2-bromoethanol (375 mg,3.0 mmol) in N, N-dimethylformamide (2 mL), potassium carbonate (662 mg,4.8 mmol), potassium iodide (50 mg,0.3 mmol) in this order under ice bath at 50℃for 6 hours. After the completion of the reaction, the system was cooled to room temperature, water (100 mL) was added to the reaction solution to dilute, ethyl acetate was extracted (20 ml×3), and the organic phases were combined, washed with water (20 ml×2) and saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate IV-12 (pale yellow oily liquid, 580 mg).
Synthesis of intermediate IV-13
Intermediate IV-12 (580 mg,2.75 mmol) and triphenylphosphine (1.08 g,4.12 mmol) were added to dichloromethane (10 mL), N-bromosuccinimide (733 mg,4.12 mmol) was added in portions while ice-bath, and the reaction was allowed to proceed to room temperature for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=200:1) to give intermediate IV-13 (white solid, 286 mg): 1 H NMR(300MHz,Chloroform-d)δ7.97(d,J＝8.5Hz,2H),7.34(d,J＝8.5Hz,2H),3.91(s,3H),3.29(dd,J＝9.8,5.8Hz,2H),3.10(dd,J＝9.8,5.8Hz,2H).
synthesis of Compound D-10
Referring to the procedure of example 241, substituting intermediate IV-6 with IV-13 produced compound D-10: 1 H NMR(300MHz,DMSO-d 6 )δ9.54(s,1H),8.69(s,1H),8.63(s,1H),8.50(s,1H),7.44(d,J＝8.7Hz,2H),7.35(d,J＝8.7Hz,2H),7.30(d,J＝2.6Hz,1H),7.14(dd,J＝8.7,2.6Hz,1H),6.80(d,J＝8.7Hz,1H),3.22-3.09(m,4H),2.95(s,3H).HRMS(ESI)calcd.for C 17 H 18 F 3 N 3 O 4 S 3 [M+H] + 482.0490,found 482.0495.
example 244
N- (5- (3- (4- (cyclohexylmethyl) phenyl) ureido) -2-hydroxyphenyl) -4-fluorobenzenesulfonamide (Compound D-11)
Synthesis of intermediate IV-14
Referring to the procedure of example 1, intermediate I-4 was replaced with intermediate I-39 to give intermediate IV-14, yielding intermediate IV-14: 1 H NMR(300MHz,DMSO-d 6 )δ12.77(s,1H),7.84(d,J＝8.1Hz,2H),7.26(d,J＝8.1Hz,2H),2.52(d,J＝7.2Hz,2H),1.67-1.49(m,6H),1.23-1.09(m,3H),0.99-0.84(m,2H).ESI-MS:m/z 217.1[M-H] - .
synthesis of Compound D-11
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-14 produced compound D-11: 1 H NMR(300MHz,DMSO-d 6 )δ9.24(s,2H),8.36(d,J＝8.2Hz,2H),7.80(dd,J＝8.7,5.3Hz,2H),7.36(t,J＝8.9Hz,2H),7.31(d,J＝8.1Hz,3H),7.10-7.05(m,1H),7.03(d,J＝8.6Hz,2H),6.63(d,J＝8.7Hz,1H),2.38(d,J＝7.0Hz,2H),1.61(d,J＝10.8Hz,5H),1.49-1.38(m,1H),1.24-1.08(m,3H),0.96-0.82(m,2H).HRMS(ESI)calcd.for C 26 H 28 FN 3 O 4 S[M+H] + 498.1857,found 498.1849.
example 245
4-fluoro-N- (2-hydroxy-5- (3- (4- ((4- ((trifluoromethyl) thio) benzyl) oxy) phenyl) ureido) phenyl) benzenesulfonamide (compound D-12)
Synthesis of Compound D-12
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate II-2 produced compound D-12: 1 H NMR(300MHz,DMSO-d 6 )δ9.27(s,1H),9.20(s,1H),8.35(s,1H),8.29(s,1H),7.80(dd,J＝8.8,5.3Hz,2H),7.75(d,J＝8.2Hz,2H),7.60(d,J＝8.1Hz,2H),7.40-7.31(m,4H),7.28(d,J＝2.4Hz,1H),7.05(dd,J＝8.7,2.4Hz,1H),6.94(d,J＝8.9Hz,2H),6.62(d,J＝8.7Hz,1H),5.15(s,2H).HRMS(ESI)calcd.for C 27 H 21 F 4 N 3 O 5 S 2 [M+H] + 608.0932,found 608.0931.
Example 246
N- (2-hydroxy-5- (3- (4- ((4- ((trifluoromethyl) thio) benzyl) oxy) phenyl) ureido) phenyl) methanesulfonamide (Compound D-13)
Synthesis of Compound D-13
Referring to the procedure of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate II-2 to obtain a compoundD-13： 1 H NMR(300MHz,DMSO-d 6 )δ9.46(s,1H),8.65(s,1H),8.38(s,1H),8.32(s,1H),7.74(d,J＝8.0Hz,2H),7.60(d,J＝8.1Hz,2H),7.31(dd,J＝14.5,5.6Hz,3H),7.13(dd,J＝8.7,2.3Hz,1H),6.94(d,J＝8.9Hz,2H),6.79(d,J＝8.7Hz,1H),5.15(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 5 S 2 [M+H] + 528.0875,found 528.0879.
Example 247
N- (5- (3- (4- ((3-fluoro-4- (2- ((trifluoromethyl) thio) ethoxy) benzyl) oxy) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (compound D-14)
Synthesis of intermediate IV-15
Referring to the procedure of example 241, methyl 4-hydroxybenzoate was replaced with methyl 3-fluoro-4-hydroxybenzoate to afford intermediate IV-15.
Synthesis of intermediate IV-16
Intermediate IV-15 (282 mg,1 mmol) was added to a dry three-necked flask, protected by argon, dissolved in anhydrous tetrahydrofuran (5 mL), and 1M borane-tetrahydrofuran complex (2 mL,2 mmol) was slowly added under ice-bath conditions and allowed to slowly warm to room temperature for reaction for 6 hours. After the completion of the reaction, ice water (30 mL) was added dropwise to the reaction solution to quench the excess borane, ethyl acetate (10 mL x 3) was extracted, and the organic phases were combined, washed with water (10 mL x 1), saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crude intermediate IV-16 (yellow oily liquid, 147 mg) which was used in the next reaction without further purification.
Synthesis of intermediate IV-17
Crude intermediate IV-16 (147 mg,0.55 mmol), methyl 4-hydroxybenzoate (126 mg,0.83 mmol) and triphenylphosphine (216 mg,0.83 mmol) were added to a dry three-necked flask, protected by argon, dissolved in anhydrous tetrahydrofuran (2 mL), slowly added dropwise with ice to a solution of diisopropyl azodicarboxylate (163 μl,0.83 mmol) in anhydrous tetrahydrofuran (2 mL), after drippingThe reaction mixture was warmed to room temperature and reacted for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate IV-17 (white solid, 117 mg): 1 H NMR(400MHz,Chloroform-d)δ8.00(d,J＝8.9Hz,2H),7.19(dd,J＝11.6,2.1Hz,1H),7.13(dd,J＝6.7,1.7Hz,1H),6.99-6.94(m,3H),5.04(s,2H),4.29(t,J＝6.6Hz,2H),3.89(s,3H),3.29(t,J＝6.6Hz,2H).
synthesis of intermediate IV-18
Intermediate IV-17 (117 mg,0.29 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), and 1M aqueous sodium hydroxide solution (1 mL) was added thereto, followed by reaction at 60℃for 4 hours. After the reaction was completed, the system was cooled to room temperature, a 2N aqueous hydrogen chloride solution was added dropwise to the residue to adjust the pH to 2 to 3, solids were precipitated, and the mixture was filtered, and the cake was washed with water (2 mL) and diethyl ether (2 mL), slurried (N-hexane/dichloromethane=4:1) and purified, and the obtained solid was dried to constant weight to give intermediate IV-18 (white solid, 79 mg).
Synthesis of Compound D-14
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-18 produced compound D-14: 1 H NMR(300MHz,DMSO-d 6 )δ9.49(s,1H),8.73(s,1H),8.38(s,1H),8.31(s,1H),7.35-7.30(m,3H),7.29(d,J＝2.7Hz,1H),7.21(d,J＝5.3Hz,2H),7.13(dd,J＝8.7,2.6Hz,1H),6.92(d,J＝9.0Hz,2H),6.79(d,J＝8.7Hz,1H),4.99(s,2H),4.31(t,J＝6.0Hz,2H),3.44(t,J＝6.0Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C 24 H 23 F 4 N 3 O 6 S 2 [M+H] + 590.1037,found 590.1036.
Example 248
N- (5- (3- (4- ((3-fluoro-4- (2- ((trifluoromethyl) thio) ethoxy) benzyl) oxy) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (compound D-15)
Synthesis of Compound D-15
Reference example 247, replacing intermediate IV-8 with IV-13 to give compound D-15: 1 H NMR(300MHz,DMSO-d 6 )δ9.48(s,1H),8.67(s,1H),8.39(s,1H),8.32(s,1H),7.41(s,4H),7.32(d,J＝9.0Hz,2H),7.28(d,J＝2.6Hz,1H),7.13(dd,J＝8.7,2.6Hz,1H),6.92(d,J＝9.0Hz,2H),6.79(d,J＝8.7Hz,1H),5.03(s,2H),3.34-3.25(m,2H),3.22-3.15(m,2H),2.95(s,3H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 5 S 3 [M+H] + 588.0903,found 588.0899.
example 249
N- (2-hydroxy-5- (3- (4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-16)
Synthesis of Compound D-16
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate II-64, compound D-16 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.27(s,1H),8.94(s,1H),8.59(s,1H),8.48(s,1H),7.64(d,J＝8.4Hz,2H),7.45(d,J＝8.3Hz,2H),7.35(d,J＝8.3Hz,2H),7.30(d,J＝2.6Hz,1H),7.15(d,J＝8.7Hz,3H),6.80(d,J＝8.6Hz,1H),5.08(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 5 S 2 [M+H] + 528.0869,found 528.0878.
example 250
N- (2-hydroxy-5- (3- (4- ((trifluoromethylphenoxy) methyl) phenyl) ureido) phenyl) methylsulfonamide (Compound D-17)
Synthesis of intermediate IV-19
Referring to the procedure of example 66, the substitution of 4-trifluoromethylthiophenol for 4-trifluoromethylphenol affords intermediate IV-19: 1 H NMR(300MHz,DMSO-d 6 )δ12.99(s,1H),7.96(d,J＝7.9Hz,2H),7.66(d,J＝8.5Hz,2H),7.56(d,J＝8.0Hz,2H),7.20(d,J＝8.5Hz,2H),5.29(s,2H).
synthesis of Compound D-17
Referring to the procedure of example 239, the substitution of 4' -trifluoromethylbiphenyl-4-carboxylic acid to intermediate IV-19 gives compound D-17: 1 H NMR(400MHz,DMSO-d 6 )δ9.51(s,1H),8.68(s,1H),8.58(s,1H),8.48(s,1H),7.65(d,J＝8.6Hz,2H),7.46(d,J＝8.6Hz,2H),7.36(d,J＝8.5Hz,2H),7.31(d,J＝2.6Hz,1H),7.19(d,J＝8.5Hz,2H),7.15(dd,J＝8.7,2.6Hz,1H),6.81(d,J＝8.7Hz,1H),5.11(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 5 S[M+H] + 496.1149,found496.1133.
example 251
N- (2-hydroxy-5- (3- (4- (trifluoromethoxyphenoxy) methyl) phenyl) ureido) phenyl) methanesulfonamide (Compound D-18)
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Synthesis of intermediate IV-20
Referring to the procedure of example 66, the substitution of 4-trifluoromethylthiophenol for 4-trifluoromethoxyphenol affords intermediate IV-20: 1 H NMR(300MHz,DMSO-d 6 )δ12.97(s,1H),7.96(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.30(d,J＝8.9Hz,2H),7.11(d,J＝9.1Hz,2H),5.21(s,2H).
synthesis of Compound D-18
Referring to the procedure of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-20 to give compound D-18: 1 H NMR(400MHz,DMSO-d 6 )δ9.50(s,1H),8.66(s,1H),8.57(s,1H),8.47(s,1H),7.45(d,J＝8.6Hz,2H),7.35(d,J＝8.6Hz,2H),7.31(d,J＝2.7Hz,2H),7.28(s,1H),7.15(dd,J＝8.7,2.6Hz,1H),7.10(d,J＝9.2Hz,2H),6.81(d,J＝8.6Hz,1H),5.03(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 6 S[M+H] + 512.1098,found 512.1096.
example 252
N- (5- (3- (4- (2-fluoro-4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) ureido) -2-hydroxyphenyl) methylsulfonamide (Compound D-19)
Synthesis of intermediate IV-21
Referring to the procedure of example 83, substituting 3-fluoro-4-nitrophenol for 2-fluoro-4-nitrophenol and substituting methyl 3-fluoro-4- (bromomethyl) benzoate for ethyl 4- (bromomethyl) benzoate produced intermediate IV-21.
Synthesis of Compound D-19
Referring to the procedure of example 239, the substitution of 4' -trifluoromethylbiphenyl-4-carboxylic acid to intermediate IV-21 gives compound D-19: 1 H NMR(400MHz,DMSO-d 6 )δ9.50(s,1H),8.65(s,1H),8.59(s,1H),8.47(s,1H),7.65(dd,J＝10.9,2.2Hz,1H),7.52(d,J＝8.6Hz,1H),7.46(d,J＝8.6Hz,2H),7.42(t,J＝8.7Hz,1H),7.36(d,J＝8.6Hz,2H),7.30(d,J＝2.6Hz,1H),7.14(dd,J＝8.7,2.6Hz,1H),6.80(d,J＝8.7Hz,1H),5.17(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 4 N 3 O 5 S 2 [M+H] + 546.0775,found 546.0767.
example 253
N- (5- (3- (4- ((3-fluoro-4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (compound D-20)
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Synthesis of intermediate IV-22
Referring to the procedure of example 83, substituting methyl 3-fluoro-4- (bromomethyl) benzoate with ethyl 4- (bromomethyl) benzoate produced intermediate IV-22.
Synthesis of Compound D-20
Referring to the procedure of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-22 to give compound D-20: 1 H NMR(300MHz,DMSO-d 6 )δ9.52(s,1H),8.68(s,1H),8.59(s,1H),8.48(s,1H),7.74-7.62(m,1H),7.46(d,J＝8.6Hz,2H),7.36(dd,J＝8.7,4.1Hz,2H),7.30(d,J＝2.6Hz,1H),7.19(dd,J＝11.1,2.6Hz,1H),7.14(dd,J＝8.7,2.6Hz,1H),7.00(dd,J＝8.8,2.5Hz,1H),6.80(d,J＝8.7Hz,1H),5.10(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 4 N 3 O 5 S 2 [M+H] + 546.0775,found 546.0764.
example 254
N- (5- (3- (4- (3-chloro-4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) ureido) -2-hydroxyphenyl) methylsulfonamide (Compound D-21)
Synthesis of intermediate IV-23
Referring to the procedure of example 83, substituting 3-fluoro-4-nitrophenol for 3-chloro-4-nitrophenol and substituting methyl 3-fluoro-4- (bromomethyl) benzoate for ethyl 4- (bromomethyl) benzoate produced intermediate IV-23.
Synthesis of Compound D-21
Referring to the procedure of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-23 to give compound D-21: 1 H NMR(400MHz,DMSO)δ9.50(s,1H),8.66(s,1H),8.58(s,1H),8.48(s,1H),7.79(d,J＝8.7Hz,1H),7.46(d,J＝8.6Hz,2H),7.41(d,J＝2.7Hz,1H),7.36(d,J＝8.6Hz,2H),7.31(d,J＝2.6Hz,1H),7.16-7.12(m,2H),6.80(d,J＝8.7Hz,1H),5.12(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 19 ClF 3 N 3 O 5 S 2 [M+H] + 562.0480,found562.0477.
example 255
N- (5- (3- (4- ((2-chloro-4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (compound D-22)
Synthesis of intermediate IV-24
Referring to the procedure of example 83, substituting 3-fluoro-4-nitrophenol for 2-chloro-4-nitrophenol and substituting methyl 3-fluoro-4- (bromomethyl) benzoate for ethyl 4- (bromomethyl) benzoate produced intermediate IV-24.
Synthesis of Compound D-22
Referring to the procedure of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-24 to give compound D-22: 1 H NMR(400MHz,DMSO)δ9.50(s,1H),8.65(s,1H),8.58(s,1H),8.48(s,1H),7.81(d,J＝2.3Hz,1H),7.67(dd,J＝8.6,2.3Hz,1H),7.48-7.44(m,2H),7.42-7.35(m,3H),7.30(d,J＝2.6Hz,1H),7.14(dd,J＝8.7,2.6Hz,1H),6.80(d,J＝8.7Hz,1H),5.20(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 19 ClF 3 N 3 O 5 S 2 [M+H] + 562.0480,found 562.0486.
Example 256
N- (5- (3- (3- (3-fluoro-4- (4- (trifluoromethylthio) phenoxy) methyl) phenyl) ureido) -2-hydroxyphenyl) methylsulfonamide (Compound D-23)
Synthesis of Compound D-23
Referring to the procedure of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate II-55 to give compound D-23: 1 H NMR(400MHz,DMSO)δ9.53(s,1H),8.81(s,1H),8.67(s,1H),8.56(s,1H),7.64(d,J＝8.7Hz,2H),7.53(dd,J＝12.8,2.1Hz,1H),7.43(t,J＝8.5Hz,1H),7.30(d,J＝2.6Hz,1H),7.17(d,J＝8.9Hz,2H),7.15-7.10(m,2H),6.80(d,J＝8.7Hz,1H),5.10(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 4 N 3 O 5 S 2 [M+H] + 546.0775,found546.0760.
example 257
N- (5- (3- (2-fluoro-4- (4- (trifluoromethyl) thio) phenoxy) methyl) phenyl) ureido) -2-hydroxyphenyl) methylsulfonamide (Compound D-24)
Synthesis of intermediate IV-25
Referring to the procedure of example 89, substituting 4-bromo-2-trifluoromethyl bromobenzyl with 3-fluoro-4-bromobenzyl gives intermediate IV-25: 1 H NMR(400MHz,DMSO-d 6 )δ13.26(s,1H),7.90(t,J＝8.0Hz,1H),7.66(d,J＝5.9Hz,2H),7.39(t,J＝8.3Hz,2H),7.20-7.16(m,2H),5.27(s,2H).
synthesis of Compound D-24
Referring to the procedure of example 239, the substitution of 4' -trifluoromethylbiphenyl-4-carboxylic acid to intermediate IV-25 gives compound D-24: 1 H NMR(300MHz,DMSO-d 6 )δ9.57(s,1H),8.90(s,1H),8.71(s,1H),8.45(d,J＝2.8Hz,1H),8.17(t,J＝8.4Hz,1H),7.65(d,J＝8.7Hz,2H),7.34(dd,J＝15.0,2.3Hz,2H),7.23(d,J＝8.5Hz,1H),7.19-7.11(m,3H),6.82(d,J＝8.7Hz,1H),5.11(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 4 N 3 O 5 S 2 [M+H] + 546.0775,found 546.0770.
example 258
N- (5- (3- (3-chloro-4- (4- (trifluoromethylthio) phenoxy) methyl) phenyl) ureido) -2-hydroxyphenyl) methylsulfonamide (Compound D-25)
Synthesis of intermediate IV-26
Referring to the procedure of example 66, ethyl 4- (bromomethyl) benzoate was replaced with crude intermediate II-40 to afford intermediate IV-26.
Synthesis of Compound D-25
Referring to the procedure of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid was replaced with the intermediate Body IV-26, compound D-25: 1 H NMR(400MHz,DMSO-d 6 )δ9.55(s,1H),8.81(s,1H),8.68(s,1H),8.58(s,1H),7.80(d,J＝2.1Hz,1H),7.66(d,J＝8.7Hz,2H),7.49(d,J＝8.4Hz,1H),7.32(d,J＝2.6Hz,1H),7.29(dd,J＝8.4,2.1Hz,1H),7.18(d,J＝8.9Hz,2H),7.15(dd,J＝8.7,2.6Hz,1H),6.82(d,J＝8.6Hz,1H),5.14(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 19 ClF 3 N 3 O 5 S 2 [M+H] + 562.0480,found 562.0483.
example 259
N- (5- (3- (2-chloro-4- (4- (trifluoromethylthio) phenoxy) methyl) phenyl) ureido) -2-hydroxyphenyl) methylsulfonamide (Compound D-26)
Synthesis of Compound D-26
Referring to the procedure of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate II-52 to give compound D-26: 1 H NMR(300MHz,DMSO-d 6 )δ9.59(s,1H),9.27(s,1H),8.71(s,1H),8.21(d,J＝8.8Hz,2H),7.65(d,J＝8.7Hz,2H),7.57(d,J＝1.9Hz,1H),7.38(dd,J＝8.6,2.0Hz,1H),7.32(d,J＝2.6Hz,1H),7.22-7.15(m,3H),6.83(d,J＝8.7Hz,1H),5.11(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 4 N 3 O 5 S 2 [M+H] + 546.0775,found 546.0767.
example 260
N- (2-hydroxy-5- (3- (6- (((trifluoromethyl) thio) phenoxy) methyl) pyridin-3-yl) ureido) phenyl) methanesulfonamide (compound D-27)
Synthesis of intermediate IV-27
Referring to the procedure of example 92, substituting 2-methyl-5-bromopyrimidine with 2-methyl-5-bromopyridine produced intermediate IV-27: 1 H NMR(300MHz,DMSO-d 6 )δ9.05(s,1H),8.30(d,J＝7.9Hz,1H),7.64(t,J＝8.0Hz,3H),7.18(d,J＝8.6Hz,2H),5.33(s,2H).
synthesis of Compound D-27
Referring to the procedure of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid was replaced with intermediate IV-27 to give compound D-27: 1 H NMR(300MHz,DMSO-d 6 )δ9.58(s,1H),8.81(s,1H),8.71(s,1H),8.66(s,1H),8.60(d,J＝2.6Hz,1H),7.96(dd,J＝8.5,2.6Hz,1H),7.65(d,J＝8.8Hz,2H),7.46(d,J＝8.5Hz,1H),7.32(d,J＝2.6Hz,1H),7.20-7.13(m,3H),6.82(d,J＝8.7Hz,1H),5.17(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 21 H 19 F 3 N 4 O 5 S 2 [M+H] + 529.0822,found529.0829.
example 261
N- (4-fluoro-2-hydroxy-5- (3- (4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) ureido) phenyl methanesulfonamide (compound D-28)
Synthesis of Compound D-28
Referring to the procedure of example 234, the substitution of 4-phenylbenzoic acid for intermediate II-64 and the substitution of intermediate I-3 for intermediate II-18 gives compound D-28: 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),8.97(s,1H),8.76(s,1H),8.24(d,J＝1.9Hz,1H),7.83(d,J＝8.8Hz,1H),7.64(d,J＝8.7Hz,2H),7.47(d,J＝8.6Hz,2H),7.37(d,J＝8.6Hz,2H),7.16(d,J＝8.9Hz,2H),6.75(d,J＝12.1Hz,1H),5.09(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 4 N 3 O 5 S 2 [M+H] + 546.0775,found 546.0778.
example 262
N- (4-fluoro-2-hydroxy-5- (3- (4- ((4- (trifluoromethoxy) phenoxy) methyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-29)
Synthesis of Compound D-29
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-20 and substituting intermediate I-3 for intermediate II-18 gave compound D-29: 1 H NMR(400MHz,DMSO-d 6 )δ9.97(s,1H),8.95(s,1H),8.75(s,1H),8.23(d,J＝1.9Hz,1H),7.82(d,J＝8.9Hz,1H),7.45(d,J＝8.6Hz,2H),7.35(d,J＝8.6Hz,2H),7.29(d,J＝8.8Hz,2H),7.09(d,J＝9.2Hz,2H),6.74(d,J＝12.1Hz,1H),5.03(s,2H),2.93(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 4 N 3 O 6 S[M+H] + 530.1003,found 530.1009.
example 263
N- (4-fluoro-2-hydroxy-5- (3- (4- ((4- (trifluoromethyl) phenoxy) methyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-30)
Synthesis of Compound D-30
Referring to the procedure of example 234, the replacement of 4-phenylbenzoic acid with intermediate IV-19 and the replacement of intermediate I-3 with intermediate II-18 gives compound D-30: 1 H NMR(400MHz,DMSO-d 6 )δ9.97(s,1H),8.96(s,1H),8.75(s,1H),8.24(s,1H),7.82(d,J＝8.8Hz,1H),7.65(d,J＝8.5Hz,2H),7.46(d,J＝8.6Hz,2H),7.37(d,J＝8.5Hz,2H),7.19(d,J＝8.6Hz,2H),6.74(d,J＝12.1Hz,1H),5.11(s,2H),2.93(s,3H).HRMS(ESI)calcd.for C 22 H 19 F 4 N 3 O 5 S[M+H] + 514.1054,found514.1049.
example 264
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) piperidine-1-carboxamide (Compound D-31)
Synthesis of intermediate IV-28
Intermediate II-18 (60 mg,0.18 mmol) was added to dichloromethane (2 mL), N-diisopropylethylamine (47. Mu.L, 0.27 mmol) was added, phenyl chloroformate (34. Mu.L, 0.27 mmol) was added under ice-bath, and the mixture was warmed to room temperature and reacted for 4 hours. After the reaction was completed, water (10 mL) was added to the reaction mixture for dilution, ethyl acetate (10 mL. Times.3) was used for extraction, the organic phases were combined, washed with saturated brine (10 mL. Times.1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude compound IV-28, which was used for the next reaction without further purification.
Synthesis of intermediate IV-29
4-trifluoromethylthiophenol (400 mg,2.06 mmol), N-Boc-4-piperidinemethanol (665 mg,3.09 mmol) and triphenylphosphine (7516 mg,2.88 mmol) were added to a dry three-necked flask, and a solution of diisopropyl azodicarboxylate (566. Mu.L, 2.88 mmol) in anhydrous tetrahydrofuran (2 mL) was slowly added dropwise under ice bath under the protection of argon and the mixture was allowed to react at room temperature for 12 hours. After completion of the reaction, the reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate IV-29 (white solid, 786 mg).
Synthesis of intermediate IV-30
Intermediate IV-29 (785 mg,2 mmol) was added to a 4M solution of hydrogen chloride in dioxane (2.5 mL,10 mmol) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by pulping (ethyl acetate), and the obtained solid was dried to constant weight to give compound IV-30 (white solid, 608 mg): 1 H NMR(400MHz,Chloroform-d)δ9.77(s,1H),9.49(s,1H),7.59(d,J＝8.7Hz,2H),6.91(d,J＝8.8Hz,2H),3.89(d,J＝5.9Hz,2H),3.60(d,J＝12.3Hz,2H),2.96(q,J＝12.1Hz,2H),2.10(d,J＝13.6Hz,3H),1.87(q,J＝13.1Hz,2H).
synthesis of intermediate IV-31
Intermediate IV-30 (65 mg,0.2 mmol) was added to dichloromethane (1.5 mL), N-diisopropylethylamine (94. Mu.L, 0.54 mmol) was added, stirred at room temperature for 10 minutes, and then a dichloromethane solution (1.5 mL) of crude intermediate IV-28 (0.18 mmol) was added under ice bath, and stirred at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2:1) to give intermediate IV-31 (white solid, 43 mg): 1 H NMR(300MHz,Chloroform-d)δ8.03(d,J＝8.5Hz,1H),7.59(d,J＝8.7Hz,2H),6.94(d,J＝8.8Hz,2H),6.66(d,J＝11.5Hz,1H),6.47(s,1H),6.34(s,1H),4.16(d,J＝13.4Hz,2H),3.88(d,J＝6.2Hz,2H),3.07(s,3H),2.98(t,J＝12.7Hz,2H),2.12-2.04(m,1H),1.95(d,J＝13.1Hz,2H),1.52-1.38(m,2H),1.03(s,9H),0.30(s,6H).
Synthesis of Compound D-31
Intermediate IV-31 (44 mg,0.07 mmol) and triethylamine trihydrofluoride (16. Mu.L, 0.10 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=50:1) to give a crude product of compound D-31 (pale yellow solid, 35 mg), which was purified by beating (dichloromethane/methanol=50:1), and the obtained solid was dried to constant weight to give compound D-31 (white solid, 23 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),8.79(s,1H),8.09(s,1H),7.64(d,J＝8.6Hz,2H),7.10(d,J＝9.0Hz,3H),6.68(d,J＝11.4Hz,1H),4.10(d,J＝12.9Hz,2H),3.93(d,J＝6.2Hz,2H),2.92(s,3H),2.81(t,J＝12.3Hz,2H),2.03-1.97(m,1H),1.78(d,J＝11.8Hz,2H),1.33-1.19(m,2H).HRMS(ESI)calcd.for C 21 H 23 F 4 N 3 O 5 S 2 [M+H] + 538.1088,found 538.1088.
example 265
4-fluoro-N- (2-hydroxy-5- (3- (4- ((4- ((trifluoromethyl) thio) benzyl) thio) phenyl) ureido) phenyl) benzenesulfonamide (compound D-32)
Synthesis of Compound D-32
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate II-82 produced compound D-32: 1 H NMR(300MHz,DMSO-d 6 )δ9.27(s,2H),8.53(s,1H),8.43(s,1H),7.80(dd,J＝8.7,5.3Hz,2H),7.62(d,J＝8.0Hz,2H),7.43(s,1H),7.42-7.32(m,5H),7.29(d,J＝2.3Hz,1H),7.23(d,J＝8.5Hz,2H),7.05(dd,J＝8.7,2.4Hz,1H),6.63(d,J＝8.7Hz,1H),4.19(s,2H).HRMS(ESI)calcd.for C 27 H 21 F 4 N 3 O 4 S 3 [M+H] + 624.0709,found 624.0715.
example 266
4-fluoro-N- (2-hydroxy-5- (3- (4- ((4- (trifluoromethyl) benzyl) thio) phenyl) ureido) phenyl) benzenesulfonamide (compound D-33)
Synthesis of intermediate IV-32
Referring to the procedure of example 122, substituting 4-trifluoromethylthio benzyl bromide for 4-trifluoromethylbenzyl bromide produced intermediate IV-32: 1 H NMR(300MHz,DMSO-d 6 )δ12.91(s,1H),7.82(d,J＝6.6Hz,1H),7.68(d,J＝7.4Hz,1H),7.63(d,J＝8.1Hz,2H),7.43(d,J＝6.7Hz,1H),4.46(s,2H).ESI-MS:m/z311.0[M-H] - .
synthesis of Compound D-33
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-32 produced compound D-33: 1 H NMR(300MHz,DMSO-d 6 )δ8.43(s,1H),9.25(s,2H),8.52(s,1H),7.80(dd,J＝8.9,5.2Hz,2H),7.64(d,J＝8.1Hz,2H),7.47(d,J＝8.0Hz,2H),7.36(dt,J＝8.7,4.5Hz,4H),7.29(d,J＝2.5Hz,1H),7.24(d,J＝8.6Hz,2H),7.05(dd,J＝8.7,2.6Hz,1H),6.63(d,J＝8.7Hz,1H),4.22(s,2H).HRMS(ESI)calcd.for C 27 H 21 F 4 N 3 O 4 S 2 [M+H] + 592.0988,found592.0995.
Example 267
4-fluoro-N- (2-hydroxy-5- (3- (4- (((4- ((trifluoromethyl) thio) phenyl) thio) methyl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-34)
Synthesis of intermediate IV-33
Intermediate II-88 (145 mg,0.39 mmol) was added to a mixed solvent of tetrahydrofuran (1 mL) and methanol (1 mL), 1M aqueous sodium hydroxide solution (1 mL) was added, and the mixture was reacted at 60℃for 4 hours. After the reaction was completed, the system was cooled to room temperature, the solvent 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, the solid was precipitated, suction filtration was performed, the cake was washed with water (2 mL), n-hexane (2 mL), infrared-dried to constant weight, intermediate IV-33 (white solid, 74 mg): 1 H NMR(300 MHz,DMSO-d 6 )δ12.94(s,1H),7.88(d,J＝8.1Hz,2H),7.60(d,J＝8.2 Hz,2H),7.53(d,J＝8.1 Hz,2H),7.46(d,J＝8.4 Hz,2H),3.33(s,2H).ESI-MS:m/z 343.0[M-H] - .
synthesis of Compound D-34
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-33, compound D-34 is prepared: 1 H NMR(300 MHz,DMSO-d 6 )δ9.24(s,2H),8.48(s,1H),8.42(s,1H),7.80(dd,J＝8.9,5.2 Hz,2H),7.61(d,J＝8.2 Hz,2H),7.45(d,J＝8.4 Hz,2H),7.42-7.25(m,7H),7.05(dd,J＝8.7,2.7 Hz,1H),6.63(d,J＝8.7 Hz,1H),4.28(s,2H).HRMS(ESI)calcd.for C 27 H 21 F 4 N 3 O 4 S 3 [M+H] + 624.0703,found 624.0694.
example 268
N- (2-hydroxy-5- (3- (4- (((4- ((trifluoromethyl) thio) phenyl) thio) methyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-35)
Synthesis of Compound D-35
Referring to the procedure of example 239, substituting 4-phenylbenzoic acid for IV-33, compound D-35 is prepared: 1 H NMR(300 MHz,DMSO-d 6 )δ9.39(s,1H),8.84(s,1H),8.51(s,1H),8.46(s,1H),7.61(d,J＝8.4 Hz,2H),7.45(d,J＝8.4 Hz,2H),7.37(d,J＝8.6 Hz,2H),7.34-7.25(m,3H),7.13(dd,J＝8.7,2.6 Hz,1H),6.79(d,J＝8.7 Hz,1H),4.28(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 22 H 20 F 3 N 3 O 4 S 3 [M+H] + 544.0641,found 544.0645.
example 269
N- (2-fluoro-4-hydroxy-5- (methylsulfonyl) phenyl) -4- (4- ((trifluoromethyl) thio) phenethyl) piperazine-1-carboxamide (compound D-36)
Synthesis of intermediate IV-34
Intermediate III-50 (300 mg,0.8 mmol), N-Boc-piperazine (178 mg,0.96 mmol) and potassium iodide (13 mg,0.08 mmol) were added to acetonitrile (4 mL), and potassium carbonate (165 mg,1.2 mmol) was added in portions with stirring, and the mixture was reacted at 70℃for 8 hours. After the completion of the reaction, water (10 mL) was added to the filtrate for dilution, ethyl acetate (10 mL x 3) was extracted, the organic phases were combined, washed with saturated brine (15 mL x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate IV-34 (colorless oily liquid, 206 mg).
Synthesis of intermediate IV-35
Intermediate IV-34 (206 mg,0.53 mmol) was added to ethyl acetate (1 mL), and a 4M hydrogen chloride-ethyl acetate solution (1.3 mL,5.4 mmol) was added dropwise and reacted at room temperature for 6 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, 1M aqueous sodium hydroxide solution (10 mL) was added to the residue, stirred at room temperature for 10 minutes, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give intermediate IV-35 (pale yellow oily liquid, 158 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.62(d,J＝8.1Hz,2H),7.40(d,J＝8.2Hz,2H),2.79(t,J＝8.2,7.2Hz,2H),2.68(t,J＝4.8Hz,4H),2.55-2.48(m,1H),2.48(t,J＝7.1Hz,2H),2.35(t,J＝4.7Hz,4H).
synthesis of Compound D-36
Intermediate IV-35 (95 mg,0.21 mmol) and intermediate IV-28 (66 mg,0.23 mmol) were added to N, N-dimethylformamide (1.5 mL), pyridine (25. Mu.L, 0.31 mmol) was added, and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=30:1) to give a crude compound D-36, which was slurried (dichloromethane/methanol=40:1) and purified to give compound D-36 (white solid, 32 mg): 1 H NMR(400MHz,DMSO-d 6 )δ10.11(s,1H),8.76(s,1H),8.10(s,1H),7.64(d,J＝8.0Hz,2H),7.43(d,J＝8.2Hz,2H),7.11(d,J＝8.6Hz,1H),6.68(d,J＝11.4Hz,1H),3.40(t,J＝5.0Hz,4H),2.92(s,3H),2.84(t,J＝7.6Hz,2H),2.59(t,J＝7.7Hz,2H),2.46(t,J＝5.0,4.4Hz,4H).HRMS(ESI)calcd.for C 21 H 24 F 4 N 4 O 4 S 2 [M+H] + 537.1248,found 537.1268.
Example 270
4-fluoro-N- (2-hydroxy-5- (3- (4- (4- (trifluoromethoxy) phenylethoxy) phenyl) ureido) phenyl) benzenesulfonamide (compound D-37)
Synthesis of Compound D-37
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate III-3 produced compound D-37: 1 H NMR(300MHz,DMSO-d 6 )δ9.23(s,2H),8.33(s,1H),8.26(s,1H),7.80(dd,J＝8.7,5.3Hz,2H),7.67(d,J＝8.0Hz,2H),7.51(d,J＝8.1Hz,2H),7.41-7.27(m,5H),7.06(dd,J＝8.7,2.3Hz,1H),6.86(d,J＝8.9Hz,2H),6.63(d,J＝8.7Hz,1H),4.19(t,J＝6.6Hz,2H),3.09(t,J＝6.5Hz,2H).HRMS(ESI)calcd.for C 28 H 23 F 4 N 3 O 5 S 2 [M+H] + 622.1088,found 622.1091.
example 271
4-fluoro-N- (2-hydroxy-5- (3- (4- (4- (trifluoromethoxy) phenylethoxy) phenyl) ureido) phenyl) benzenesulfonamide (compound D-38)
Synthesis of intermediate IV-36
Referring to the procedure of example 151, 4-trifluoromethylthiophenylacetic acid was replaced with 4-trifluoromethoxyphenylacetic acid, and the resulting ester was subjected to ester hydrolysis to afford intermediate IV-36: 1 H NMR(300MHz,DMSO-d 6 )δ12.60(s,1H),7.87(d,J＝8.7Hz,2H),7.47(d,J＝8.5Hz,2H),7.30(d,J＝8.0Hz,2H),7.02(d,J＝8.8Hz,2H),4.28(t,J＝6.7Hz,2H),3.09(t,J＝6.6Hz,2H).ESI/MS:m/z 325.08[M-H] - .
synthesis of Compound D-38
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-36 produced compound D-38: 1 H NMR(300MHz,DMSO-d 6 )δ9.24(s,1H),9.21(s,1H),8.32(s,1H),8.25(s,1H),7.80(dd,J＝8.6,5.2Hz,2H),7.46(d,J＝8.4Hz,2H),7.40-7.31(m,4H),7.29(s,3H),7.05(dd,J＝8.6,2.2Hz,1H),6.85(d,J＝8.8Hz,2H),6.62(d,J＝8.7Hz,1H),4.15(t,J＝6.6Hz,2H),3.05(t,J＝6.6Hz,2H).HRMS(ESI)calcd.for C 28 H 23 F 4 N 3 O 6 S[M+H] + 606.1316,found 606.1319.
example 272
N- (2-hydroxy-5- (3- (4- (4- (trifluoromethoxy) phenylethoxy) phenyl) ureido) phenyl) methanesulfonamide (compound D-39)
Synthesis of Compound D-39
Referring to the procedure of example 239, substituting 4-phenylbenzoic acid for intermediate IV-36, compound D-39 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.24(s,1H),9.21(s,1H),8.32(s,1H),8.25(s,1H),7.80(dd,J＝8.6,5.2Hz,2H),7.46(d,J＝8.4Hz,2H),7.40-7.31(m,4H),7.29(s,3H),7.05(dd,J＝8.6,2.2Hz,1H),6.85(d,J＝8.8Hz,2H),6.62(d,J＝8.7Hz,1H),4.15(t,J＝6.6Hz,2H),3.05(t,J＝6.6Hz,2H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 6 S[M+H] + 526.1260,found 478.1266.
example 273
N- (2-hydroxy-5- (3- (4- (4- (trifluoromethyl) phenethyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-40)
Synthesis of intermediate IV-37
Referring to the procedure of example 151, 4-trifluoromethylthiophenylacetic acid was replaced with 4-trifluoromethylphenylacetic acid, and the resulting ester was subjected to ester hydrolysis to afford intermediate IV-37: 1 H NMR(300MHz,DMSO-d 6 )δ12.63(s,1H),7.88(d,J＝7.1Hz,2H),7.68(d,J＝7.7Hz,2H),7.57(d,J＝8.0Hz,2H),7.02(d,J＝7.1Hz,2H),4.32(t,J＝6.5Hz,2H),3.16(t,J＝6.6Hz,2H).
synthesis of Compound D-40
Referring to the procedure of example 239, substituting 4-phenylbenzoic acid for intermediate IV-37, compound D-40 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.47(s,1H),8.66(s,1H),8.36(s,1H),8.29(s,1H),7.66(d,J＝8.1Hz,2H),7.55(d,J＝8.1Hz,2H),7.30(d,J＝9.0Hz,2H),7.27(d,J＝2.6Hz,1H),7.11(dd,J＝8.7,2.6Hz,1H),6.84(d,J＝9.0Hz,2H),6.77(d,J＝8.7Hz,1H),4.17(t,J＝6.6Hz,2H),3.10(t,J＝6.6Hz,2H),2.93(s,3H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 5 S[M+H] + 510.1305,found 510.1295.
example 274
4-fluoro-N- (2-hydroxy-5- (3- (4- (2- ((trifluoromethyl) thio) phenoxy) ethyl) phenyl) ureido) benzenesulfonamide (compound D-41)
Synthesis of intermediate IV-38
Referring to the procedure of example 165, intermediate IV-38 is obtained: 1 H NMR(300MHz,DMSO-d 6 )δ12.84(s,1H),7.89(d,J＝8.1Hz,2H),7.61(d,J＝8.6Hz,2H),7.45(d,J＝8.1Hz,2H),7.08(d,J＝8.8Hz,2H),4.30(t,J＝6.6Hz,2H),3.13(t,J＝6.6Hz,2H).ESI/MS:m/z 341.04[M-H] - .
synthesis of Compound D-41
Referring to the procedure of example 176, substituting 4-phenylbenzoic acid for intermediate IV-38, compound D-41 is prepared: 1 H NMR(300MHz,DMSO)δ9.22(s,2H),8.39(s,1H),8.38(s,1H),7.79(dd,J＝8.5,5.4Hz,2H),7.61(d,J＝8.5Hz,2H),7.39-7.31(m,4H),7.28(d,J＝2.1Hz,1H),7.21(d,J＝8.2Hz,2H),7.08(d,J＝8.4Hz,2H),7.04(d,J＝2.0Hz,1H),6.62(d,J＝8.7Hz,1H),4.21(t,J＝6.7Hz,2H),2.98(t,J＝6.6Hz,2H).HRMS(ESI)calcd.for C 28 H 23 F 4 N 3 O 5 S 2 [M+H] + 622.1088,found 622.1086.
example 275
4-fluoro-N- (2-hydroxy-5- (3- (4- (2- (4- (trifluoromethoxy) phenoxy) ethyl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-42)
Synthesis of intermediate IV-39
Referring to the procedure of example 165, the substitution of 4-trifluoromethylthiophenol for 4-trifluoromethoxyphenol affords intermediate IV-39: 1 H NMR(300MHz,DMSO)δ12.83(s,1H),7.89(d,J＝7.9Hz,2H),7.45(d,J＝7.9Hz,2H),7.27(d,J＝8.8Hz,2H),7.03(d,J＝8.9Hz,2H),4.25(t,J＝6.6Hz,2H),3.12(t,J＝6.5Hz,2H).ESI-MS:m/z 325.1[M-H] - .
synthesis of Compound D-42
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-39 produced compound D-42: 1 H NMR(300MHz,DMSO-d 6 )δ9.22(s,2H),8.39(s,1H),8.38(s,1H),7.79(dd,J＝8.2,5.1Hz,2H),7.39-7.32(m,4H),7.26(d,J＝9.5Hz,3H),7.20(d,J＝8.1Hz,2H),7.08-7.00(m,3H),6.63(d,J＝8.5Hz,1H),4.16(t,J＝6.5Hz,2H),2.97(t,2H).HRMS(ESI)calcd.for C 28 H 23 F 4 N 3 O 6 S[M+H] + 606.1316,found 606.1319.
example 276
4-fluoro-N- (2-hydroxy-5- (3- (4- ((4- ((trifluoromethyl) thio) phenethyl) thio) phenyl) ureido) phenyl) benzenesulfonamide (compound D-43)
Synthesis of intermediate IV-40
Referring to the procedure of example 168, substituting 4-trifluoromethylphenylacetic acid for 4-trifluoromethylthiophenylacetic acid produced intermediate IV-40: 1 H NMR(300MHz,DMSO-d 6 )δ12.88(s,1H),7.84(d,2H),7.65(d,J＝7.9Hz,2H),7.47(d,J＝8.0Hz,2H),7.41(d,J＝8.4Hz,2H),3.38(t,J＝7.4Hz,2H),2.99(t,J＝7.5Hz,2H).ESI-MS:m/z 357.0[M-H] - .
synthesis of Compound D-43
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-40, compound D-43 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.27(s,2H),8.54(s,1H),8.45(s,1H),7.80(dd,J＝8.8,5.3Hz,2H),7.64(d,J＝8.0Hz,2H),7.41(d,J＝7.7Hz,4H),7.35(d,J＝8.9Hz,2H),7.33-7.28(m,3H),7.06(dd,J＝8.7,2.4Hz,1H),6.64(d,J＝8.7Hz,1H),3.18(t,J＝7.5Hz,2H),2.89(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 28 H 23 F 4 N 3 O 4 S 3 [M+H] + 638.0860,found 638.0887.
example 277
4-fluoro-N- (2-hydroxy-5- (3- (4- ((4- (trifluoromethoxy) phenethyl) thio) phenyl) ureido) phenyl) benzenesulfonamide (compound D-44)
Synthesis of Compound D-44
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate III-15 produced compound D-44: 1 H NMR(300MHz,DMSO-d 6 )δ9.27(s,2H),8.54(s,1H),8.45(s,1H),7.80(dd,J＝8.7,5.3Hz,2H),7.44-7.38(m,3H),7.38-7.33(m,3H),7.32(s,1H),7.31-7.25(m,4H),7.06(dd,J＝8.7,2.4Hz,1H),6.64(d,J＝8.7Hz,1H),3.15(t,J＝7.5Hz,2H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 28 H 23 F 4 N 3 O 5 S 2 [M+H] + 622.1088,found 622.1095.
example 278
4-fluoro-N- (2-hydroxy-5- (3- (4- ((trifluoromethyl) thiomethyl) phenethyl) thio) phenyl) ureido) benzenesulfonamide (compound D-45)
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Synthesis of intermediate IV-41
4- (2-bromoethyl) benzoic acid (1.5 g,6.5 mmol) was added to absolute ethanol (15 mL), concentrated sulfuric acid (3.3 mL) was slowly added dropwise under ice bath, and the mixture was allowed to react at 70℃for 3 hours. After the reaction was completed, the system was cooled to room temperature, ice water (30 mL) was added dropwise to the reaction solution for dilution, ethyl acetate (20 ml×3) was extracted, the organic phases were combined, washed with saturated brine (20 ml×1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate IV-41, which was used in the next reaction without further purification.
Synthesis of intermediate IV-42
Intermediate IV-41 (500 mg,1.95 mmol), 4-bromophenylthiophenol (45 mg,2.34 mmol) and potassium iodide (32 mg,0.20 mmol) were added to acetonitrile (6 mL), and potassium carbonate (803 mg,2.63 mmol) was added in portions to the mixture, followed by reaction at 80℃for 8 hours. Reaction junctionAfter the completion of the reaction, the system was cooled to room temperature, 1M aqueous sodium hydroxide solution (10 mL) was added to the reaction solution to quench the excess 4-bromophenylthiophenol, ethyl acetate (15 ml×3) was extracted, the organic phases were combined, washed successively with 1M aqueous sodium hydroxide solution (10 ml×2), saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate IV-42 (colorless oily liquid, 706 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.88(d,J＝8.0Hz,2H),7.50(d,J＝8.4Hz,2H),7.40(d,J＝8.0Hz,2H),7.30(d,J＝8.4Hz,2H),4.30(q,J＝7.0Hz,2H),3.27(t,J＝7.6Hz,2H),2.94(t,J＝7.4Hz,2H),1.31(t,J＝7.0Hz,3H).
synthesis of intermediate IV-43
Referring to the procedure of example 125, intermediate II-83 was replaced with intermediate IV-42 to afford intermediate IV-43: 1 H NMR(300MHz,DMSO-d 6 )δ7.49(d,J＝8.5Hz,2H),7.32(d,J＝8.6Hz,3H),7.25(t,J＝6.9Hz,3H),4.27(s,2H),3.23(t,J＝7.5Hz,2H),2.85(t,J＝7.5Hz,2H).
synthesis of intermediate IV-44
Intermediate IV-43 (210 mg,0.52 mmol), oxalic acid dihydrate (196 mg,1.55 mmol), palladium acetate (4 mg,0.016 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (9 mg,0.016 mmol) and acetic anhydride (145. Mu.L, 1.55 mmol) were added to anhydrous N, N-dimethylformamide (2 mL), the system was cooled to-78deg.C and frozen, then N, N-diisopropylethylamine (270. Mu.L, 1.55 mmol) was added, and the system was allowed to return to room temperature naturally under argon protection, stirred for 30 minutes, and then allowed to react at 100deg.C for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL), water (20 mL) were added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate IV-44 (white solid, 142 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.86(s,1H),7.85(d,J＝8.4Hz,2H),7.40(d,J＝8.3Hz,2H),7.30(dd,J＝17.3,8.0Hz,4H),4.28(s,2H),3.32-3.29(m,2H),2.91(t,J＝7.4Hz,2H).
Synthesis of Compound D-45
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-44, compound D-45 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.24(s,2H),8.52(s,1H),8.43(s,1H),7.83-7.77(m,2H),7.40(t,J＝10.1Hz,4H),7.33(s,1H),7.32-7.28(m,4H),7.22(d,J＝7.8Hz,2H),7.07(d,J＝8.9Hz,1H),6.64(d,J＝8.7Hz,1H),4.27(s,2H),3.13(t,J＝7.4Hz,2H),2.81(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 29 H 25 F 4 N 3 O 4 S 3 [M+H] + 652.1016,found652.1013.
example 279
4-fluoro-N- (3-hydroxy-5- (3- (4- ((trifluoromethyl) thio) phenethyl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-46)
Synthesis of intermediate IV-45
Intermediate IV-40 (150 mg,0.42 mmol) was added to dichloromethane (2 mL), triethylamine (117 μl,0.84 mmol) was added, stirred at room temperature for 15 minutes, diphenyl azide phosphate (86 μl,0.40 mmol) was added dropwise under ice bath, the reaction was warmed to room temperature for 8 hours, after completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate IV-45 (white solid, 104 mg).
Synthesis of intermediate IV-46
Intermediate IV-45 (103 mg,0.27 mmol) was added to toluene (3 mL) and reacted at 80℃for 4 hours. After the completion of the reaction, the system was cooled to room temperature, and intermediate III-37 (102 mg,0.30 mmol) was added to the reaction mixture in portions, followed by reaction at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, filtered, and the cake was purified by beating (n-hexane), and the obtained solid was dried to constant weight to obtain intermediate IV-46 (white solid, 118 mg): 1 H NMR(300MHz,DMSO-d 6 )δ10.55(s,1H),8.96(s,1H),8.71(s,1H),7.86(dd,J＝8.7,5.1Hz,2H),7.65(d,J＝7.9Hz,2H),7.49(d,J＝5.2Hz,2H),7.45-7.38(m,5H),7.33(d,J＝8.5Hz,2H),7.21(s,1H),6.85(s,1H),3.20(t,J＝7.5Hz,2H),2.90(t,J＝7.2Hz,2H).
Synthesis of Compound D-46
Referring to the procedure of example 105, substituting intermediate II-68 for intermediate IV-46 produced compound D-46: 1 H NMR(300MHz,DMSO-d 6 )δ10.13(s,1H),9.41(s,1H),8.57(d,J＝13.8Hz,2H),7.82(t,2H),7.64(d,J＝7.7Hz,2H),7.46-7.36(m,6H),7.31(d,J＝8.4Hz,2H),6.69(d,J＝27.7Hz,2H),6.20(s,1H),3.18(t,2H),2.89(t,2H).ESI-MS:m/z 638.0878[M+H] + .
example 280
N- (2-hydroxy-5- (3- (4- ((4- ((trifluoromethyl) thio) phenethyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-47)
Synthesis of Compound D-47
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-40 produced compound D-47: 1 H NMR(400MHz,DMSO-d 6 )δ9.51(s,1H),8.67(s,1H),8.57(s,1H),8.48(s,1H),7.64(d,J＝7.9Hz,2H),7.43(d,J＝3.9Hz,2H),7.41(d,J＝3.4Hz,2H),7.31(dd,J＝5.7,2.9Hz,3H),7.15(dd,J＝8.7,2.7Hz,1H),6.81(d,J＝8.7Hz,1H),3.18(t,J＝7.5Hz,2H),2.96(s,3H),2.94-2.85(m,2H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 4 S 3 [M+H] + 558.0797,found 558.0801.
example 281
N- (2-hydroxy-5- (3- (4- ((4- (trifluoromethoxy) phenethyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-48)
Synthesis of Compound D-48
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate III-15, compound D-48 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.52(s,1H),8.61(s,1H),8.57(s,1H),8.47(s,1H),7.42(d,J＝8.6Hz,2H),7.36(d,J＝8.6Hz,2H),7.33-7.25(m,5H),7.14(dd,J＝8.7,2.4Hz,1H),6.80(d,J＝8.7Hz,1H),3.15(t,J＝7.4Hz,2H),2.95(s,3H),2.85(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 5 S 2 [M+H] + 542.1031,found 542.1039.
example 282
N- (2-hydroxy-5- (3- (4- ((4- (trifluoromethyl) phenethyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-49)
Synthesis of intermediate IV-47
Referring to the procedure of example 168, substituting 4-trifluoromethoxy phenylacetic acid for 4-trifluoromethyl phenylacetic acid produced intermediate IV-47: 1 H NMR(300MHz,DMSO-d 6 )δ12.63(s,1H),7.88(d,J＝7.5Hz,2H),7.68(d,J＝7.7Hz,2H),7.57(d,J＝7.7Hz,2H),7.02(d,J＝7.6Hz,2H),4.32(t,J＝6.2Hz,2H),3.17(t,J＝6.2Hz,2H).ESI-MS:m/z 325.1[M-H] - .
synthesis of Compound D-49
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-47, compound D-49 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.51(s,1H),8.68(s,1H),8.57(s,1H),8.48(s,1H),7.65(d,J＝8.0Hz,2H),7.47(d,J＝8.1Hz,2H),7.43(d,J＝8.7Hz,2H),7.34-7.28(m,3H),7.15(dd,J＝8.6,2.4Hz,1H),6.81(d,J＝8.7Hz,1H),3.18(t,J＝7.4Hz,2H),2.96(s,3H),2.91(t,J＝7.2Hz,2H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 4 S 2 [M+H] + 526.1077,found 526.1079.
example 283
N- (5- (3- (3-fluoro-4- ((4- (trifluoromethyl) phenyl) thio) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (Compound D-50)
Synthesis of intermediate IV-48
Referring to the procedure of example 168, substituting 4-trifluoromethoxy-phenylacetic acid with 4-trifluoromethyl-phenylacetic acid and substituting 4-bromothiophenol with 4-bromo-2-fluorobenzenethiol produced intermediate IV-48.
Synthesis of Compound D-50
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-48, compound D-50 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.57(s,1H),8.83(s,1H),8.70(s,1H),8.58(s,1H),7.64(d,J＝8.0Hz,2H),7.53(dd,J＝12.3,2.2Hz,1H),7.46(d,J＝8.0Hz,2H),7.43-7.34(m,1H),7.30(d,J＝2.6Hz,1H),7.13(td,J＝7.9,2.4Hz,2H),6.81(d,J＝8.7Hz,1H),3.15(t,J＝7.4Hz,2H),2.95(s,3H),2.90(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 23 H 21 F 4 N 3 O 4 S 2 [M+H] + 544.0982,found 544.0981.
example 284
N- (5- (3- (2-fluoro-4- ((4- (trifluoromethyl) phenyl) thio) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (Compound D-51)
Synthesis of intermediate IV-49
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-trifluoromethylphenylacetic acid and substituting 4-bromophenylthiophenol with 4-bromo-3-fluorophenylthiophenol produced intermediate IV-49.
Synthesis of Compound D-51
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-49, compound D-51 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.57(s,1H),8.88(s,1H),8.70(s,1H),8.41(d,J＝2.8Hz,1H),8.10(t,J＝8.7Hz,1H),7.65(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.29(dd,J＝12.0,2.3Hz,2H),7.14(dd,J＝8.7,2.6Hz,2H),6.81(d,J＝8.7Hz,1H),3.25(t,J＝7.4Hz,2H),2.95(s,3H),2.95-2.89(m,2H).HRMS(ESI)calcd.for C 23 H 21 F 4 N 3 O 4 S 2 [M+H] + 544.0982,found 544.0981.
example 285
N- (5- (3- (3-chloro-4- ((4- (trifluoromethyl) phenyl) thio) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (Compound D-52)
Synthesis of intermediate IV-50
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-trifluoromethylphenylacetic acid and substituting 4-bromophenylthiophenol with 4-bromo-2-chlorophenylthiol produced intermediate IV-50.
Synthesis of Compound D-52
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-50, compound D-52 was prepared: 1 H NMR(400MHz,DMSO-d 6 )δ9.54(s,1H),8.74(s,1H),8.67(s,1H),8.56(s,1H),7.75(d,J＝2.3Hz,1H),7.65(d,J＝8.0Hz,2H),7.50(d,J＝7.9Hz,2H),7.40(d,J＝8.7Hz,1H),7.31(d,J＝2.6Hz,1H),7.29(dd,J＝8.6,2.3Hz,1H),7.14(dd,J＝8.7,2.7Hz,1H),6.81(d,J＝8.7Hz,1H),3.24(t,J＝7.5Hz,2H),2.96(t,J＝7.7Hz,2H),2.95(s,3H).HRMS(ESI)calcd.for C 23 H 21 ClF 3 N 3 O 4 S 2 [M+H] + 560.0687,found 560.0705.
example 286
N- (5- (3- (2-chloro-4- ((4- (trifluoromethyl) phenyl) thio) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (Compound D-53)
Synthesis of intermediate IV-51
Referring to the procedure of example 168, substituting 4-trifluoromethoxyphenylacetic acid with 4-trifluoromethylphenylacetic acid and substituting 4-bromophenylthiophenol with 4-bromo-3-chlorophenylthiol produced intermediate IV-51.
Synthesis of Compound D-53
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-51, compound D-53 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.59(s,1H),9.25(s,1H),8.71(s,1H),8.19(s,1H),8.14(d,J＝8.7Hz,1H),7.65(d,J＝8.0Hz,2H),7.48(d,J＝7.9Hz,2H),7.44(d,J＝2.2Hz,1H),7.32(dd,J＝6.0,2.1Hz,1H),7.30(d,J＝2.2Hz,1H),7.19(dd,J＝8.7,2.6Hz,1H),6.83(d,J＝8.7Hz,1H),3.27(t,J＝7.4Hz,2H),3.00-2.88(m,5H).HRMS(ESI)calcd.for C 23 H 21 ClF 3 N 3 O 4 S 2 [M+H] + 560.0687,found 560.0684.
example 287
N- (5- (3- (3-fluoro-4- ((4- (trifluoromethoxy) phenethyl) thio) phenyl) ureido) -2-hydroxyphenyl) methanesulfonamide (compound D-54)
Synthesis of intermediate IV-52
Referring to the procedure of example 168, intermediate III-14 was replaced with intermediate III-24 to afford intermediate IV-52: 1 H NMR(300MHz,DMSO-d 6 )δ13.18(s,1H),7.74(d,J＝8.2Hz,1H),7.62(d,J＝10.7Hz,1H),7.56(t,J＝7.9Hz,1H),7.42(d,J＝8.4Hz,2H),7.29(d,J＝8.1Hz,2H),3.38(t,J＝7.3Hz,2H),2.97(t,J＝7.4Hz,2H).ESI-MS:m/z 359.0[M-H] - .
synthesis of Compound D-54
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-52 produced compound D-54: 1 H NMR(300MHz,DMSO-d 6 )δ9.51(s,1H),8.68(s,1H),8.57(s,1H),8.48(s,1H),7.65(d,J＝8.0Hz,2H),7.47(d,J＝8.1Hz,2H),7.43(d,J＝8.7Hz,2H),7.34-7.28(m,3H),7.15(dd,J＝8.6,2.4Hz,1H),6.81(d,J＝8.7Hz,1H),3.18(t,J＝7.4Hz,2H),2.96(s,3H),2.91(t,J＝7.2Hz,2H).HRMS(ESI)calcd.for C 23 H 21 F 4 N 3 O 5 S 2 [M+H] + 560.0932,found 560.0934.
example 288
N- (4-fluoro-2-hydroxy-5- (3- (4- ((4- (trifluoromethyl) phenyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-55)
Synthesis of Compound D-55
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-47 and substituting intermediate I-3 for intermediate II-18, compound D-55 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ9.98(s,1H),8.94(s,1H),8.75(s,1H),8.22(d,J＝1.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.64(d,J＝8.1Hz,2H),7.46(d,J＝8.0Hz,2H),7.41(d,J＝8.7Hz,2H),7.31(d,J＝8.7Hz,2H),6.73(d,J＝12.1Hz,1H),3.18(t,J＝8.3,6.6Hz,2H),2.93(s,3H),2.93-2.87(m,2H).HRMS(ESI)calcd.for C 23 H 21 F 4 N 3 O 4 S 2 [M+H] + 544.0982,found 544.0977.
example 289
4-fluoro-N- (2-hydroxy-5- (3- (4- ((trifluoromethyl) thio) phenyl) phenylsulfamide (Compound D-56)
Synthesis of Compound D-56
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate III-29, compound D-56 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.24(s,2H),8.40(d,J＝5.2Hz,2H),7.81(t,J＝7.2Hz,2H),7.63(d,J＝7.8Hz,2H),7.45(d,J＝8.0Hz,2H),7.36(t,J＝7.4Hz,4H),7.29(s,1H),7.18(d,J＝8.2Hz,2H),7.07(d,J＝9.0Hz,1H),6.64(d,J＝8.7Hz,1H),3.27(d,J＝7.4Hz,2H),2.87(t,J＝7.3Hz,2H).HRMS(ESI)calcd.for C 28 H 23 F 4 N 3 O 4 S 3 [M+H] + 638.0860,found 638.0858.
example 290
4-fluoro-N- (2-hydroxy-5- (3- (4- (2- ((trifluoromethyl) thio) pyridine-2-ethyl) thio) phenyl) ureido) phenyl) benzenesulfonamide (compound D-57)
Synthesis of intermediate IV-53
Referring to the procedure of example 83, substituting 3-fluoro-4-nitrophenol with 2-mercapto-5-nitropyridine and substituting methyl 3-fluoro-4- (bromomethyl) benzoate with methyl 4- (2-bromoethyl) benzoate produced compound IV-53: 1 H NMR(400MHz,DMSO-d 6 )δ12.83(s,1H),8.70(d,J＝2.3Hz,1H),7.95(dd,J＝8.4,2.4Hz,1H),7.88(d,J＝8.2Hz,2H),7.48(d,J＝8.5Hz,1H),7.41(d,J＝8.2Hz,2H),3.47(t,J＝7.5Hz,2H),3.04(t,J＝7.5Hz,2H).
synthesis of Compound D-57
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-53, compound D-57 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.23(s,2H),8.71(d,J＝1.8Hz,1H),8.40(s,1H),8.38(s,1H),7.95(dd,J＝8.4,2.0Hz,1H),7.82(d,J＝5.3Hz,1H),7.79(d,J＝5.2Hz,1H),7.48(d,J＝8.5Hz,1H),7.42-7.30(m,4H),7.29(d,J＝2.4Hz,1H),7.18(d,J＝8.4Hz,2H),7.06(dd,J＝8.7,2.4Hz,1H),6.64(d,J＝8.7Hz,1H),3.41(t,J＝7.5Hz,2H),2.90(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 27 H 22 F 4 N 4 O 4 S 3 [M+H] + 639.0818,found 639.0823.ESI-MS:m/z 639.0823[M+H] + .
example 291
4-fluoro-N- (2-hydroxy-5- (3- (6- (2- ((trifluoromethyl) thio) phenyl) thio) ethyl) pyridin-3-yl) ureido) phenyl) benzenesulfonamide (compound D-58)
Synthesis of intermediate IV-54
2- (5-Bromopyridin-2-yl) acetic acid (826 mg,3.82 mmol) was added to a dry three-necked flask, and the flask was then cooled under argon, and then dissolved in anhydrous tetrahydrofuran (7 mL), and then 1M borane-tetrahydrofuran complex (7.65 mL,7.65 mmol) was slowly added to the flask under ice bath, and the flask was warmed slowly to room temperature and allowed to react for 6 hours. After the reaction was completed, ice water (30 mL) was added dropwise to the reaction solution to quench the excess borane, ethyl acetate (15 mL x 3) was extracted, and the organic phases were combined, washed with water (15 mL x 1), saturated brine (15 mL x 1) in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate IV-54 which was used in the next reaction without further purification.
Synthesis of intermediate IV-55
Intermediate IV-54 (242 mg,1.2 mmol) and 4-dimethylaminopyridine (15 mg,0.12 mmol) were added to dichloromethane (5 mL), triethylamine (334. Mu.L, 2.4 mmol) was added, p-toluenesulfonyl chloride (343 mg,1.8 mmol) was added in portions while ice-cooling, and the reaction was continued at room temperature for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate IV-55 (pale yellow solid, 344 mg): 1 H NMR(300MHz,DMSO-d 6 )δ8.45(d,J＝2.5Hz,1H),7.90(dd,J＝8.2,2.6Hz,1H),7.61(d,J＝8.0Hz,2H),7.39(d,J＝8.0Hz,2H),7.20(d,J＝8.3Hz,1H),4.38(t,J＝6.1Hz,2H),3.01(t,J＝6.1Hz,2H),2.42(s,3H).
synthesis of intermediate IV-56
Intermediate III-36 (304 mg,1.1 mmol) was dissolved in toluene (2 mL) in a dry three-necked flask, a solution of triphenylphosphine (1.43 g,5.5 mmol) in toluene (5 mL) was added dropwise in ice, and the mixture was allowed to react at room temperature for 1 hour. After TLC monitoring the disappearance of starting material, water (1.5 mL) was added to the reaction solution, and the reaction was continued at room temperature for 2 hours. After the reaction, the reaction solution was directly subjected to the next reaction without further treatment.
Synthesis of intermediate IV-57
Intermediate IV-56 (220 mg,1.1 mmol), potassium carbonate (204 mg,1.5 mmol), potassium iodide (18 mg,0.11 mmol) and anhydrous N, N-dimethylformamide (3 mL) were directly added to the reaction mixture, and the mixture was reacted at 80℃for 8 hours. After the completion of the reaction, the system was cooled to room temperature, water (30 mL) was added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate IV-57 (pale yellow solid, 95 mg).
Synthesis of intermediate IV-58
Intermediate IV-57 (90 mg,0.23 mmol), oxalic acid dihydrate (86 mg,0.68 mmol), palladium acetate (2 mg, 0.0070 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (4 mg, 0.0070 mmol) and acetic anhydride (64. Mu.L, 1.55 mmol) were added to anhydrous N, N-dimethylformamide (2 mL), the system was cooled to-78deg.C and frozen, then N, N-diisopropylethylamine (113. Mu.L, 1.55 mmol) was added, and the system was allowed to return to room temperature naturally under argon and stirred for 30 minutes and then allowed to react at 100deg.C for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL), water (20 mL) were added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=50:1) to give intermediate IV-58 (white solid, 52 mg): 1 H NMR(300MHz,DMSO)δ8.98(d,J＝1.2Hz,1H),8.16(dd,J＝8.1,1.8Hz,1H),7.61(d,J＝8.2Hz,2H),7.44(dd,J＝8.2,2.7Hz,3H),3.50-3.44(m,2H),3.19-3.14(m,2H).
Synthesis of Compound D-58
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-58 produced compound D-58: 1 H NMR(300MHz,DMSO-d 6 )δ9.25(s,2H),8.58(s,1H),8.53(s,1H),8.49(s,1H),7.86-7.76(m,3H),7.62(d,J＝8.2Hz,2H),7.44(d,J＝8.1Hz,2H),7.35(t,J＝8.3Hz,2H),7.29(s,1H),7.22(d,J＝8.3Hz,1H),7.06(d,J＝8.5Hz,1H),6.63(d,J＝8.7Hz,1H),3.42-3.37(m,2H),3.01(t,J＝7.2Hz,2H).HRMS(ESI)calcd.for C 27 H 22 F 4 N 4 O 4 S 3 [M+H] + 639.0812,found 639.0822.
example 292
4-fluoro-N- (2-hydroxy-5- (3- (4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-59)
Synthesis of Compound D-59
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate III-33, compound D-59 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.25(s,2H),8.41(d,J＝4.0Hz,2H),7.80(dd,J＝8.7,5.2Hz,2H),7.46(d,J＝8.8Hz,2H),7.41-7.32(m,5H),7.31(s,1H),7.29(d,J＝2.4Hz,1H),7.15(d,J＝8.4Hz,2H),7.06(dd,J＝8.6,2.3Hz,1H),6.63(d,J＝8.6Hz,1H),3.23(t,J＝7.5Hz,2H),2.81(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 28 H 23 F 4 N 3 O 5 S 2 [M+H] + 622.1088,found 622.1080.
example 293
4-fluoro-N- (2-hydroxy-5- (3- (4- (4- (trifluoromethoxy) phenyl) thio) butan-2-phenyl) ureido) phenyl) benzenesulfonamide (compound D-60)
Synthesis of intermediate IV-59
Methyl 4-bromophenylacetate (500 mg,2.18 mmol) was added to a dry three-necked flask, and the flask was purged with argon, and then dissolved in anhydrous tetrahydrofuran (5 mL), a 1M solution of potassium t-butoxide in tetrahydrofuran (2.6 mL,2.62 mmol) was slowly added dropwise under ice-salt bath, and stirring was continued for 30 minutes under ice-salt bath after dropping, and a solution of ethyl iodide (209. Mu.L, 2.62 mmol) in tetrahydrofuran (1 mL) was further added dropwise, and the mixture was slowly warmed to room temperature after dropping, and reacted for 2 hours. After the completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (10 mL) dropwise, extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=200:1) to give intermediate IV-59 (pale yellow oily liquid, 483 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.53(d,J＝8.3Hz,2H),7.25(d,J＝8.3Hz,2H),3.59(s,3H),3.58-3.54(m,1H),1.97-1.90(m,1H),1.68(dt,J＝14.1,7.3Hz,1H),0.80(t,J＝7.3Hz,3H).
Synthesis of intermediate IV-60
Intermediate IV-59 (463 mg,1.81 mmol) was added to anhydrous tetrahydrofuran (4 mL), 1M solution of lithium triethylborohydride in tetrahydrofuran (3.6 mL,3.61 mmol) was slowly added dropwise under ice-bath, and the mixture was slowly warmed to room temperature and reacted for 2 hours. After the completion of the reaction, excess lithium triethylborohydride was quenched by adding water (20 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate IV-60 (colorless oily liquid, 327 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.46(d,J＝7.8Hz,2H),7.15(d,J＝7.5Hz,2H),4.57(s,1H),3.53-3.46(m,2H),2.59-2.53(m,1H),1.80-1.71(m,1H),1.49-1.40(m,1H),0.72(t,J＝7.3Hz,3H).
synthesis of intermediate IV-61
Intermediate IV-60 (300 mg,1.32 mmol) and 4-dimethylaminopyridine (16 mg,0.13 mmol) were added to dichloromethane (5 mL), triethylamine (367. Mu.L, 2.64 mmol) was added, p-toluenesulfonyl chloride (376 mg,1.97 mmol) was added in portions under ice bath, and the reaction was allowed to proceed to room temperature for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate IV-61 (colorless oily liquid, 464 mg): 1 H NMR(300MHz,DMSO)δ7.61(d,J＝8.0Hz,2H),7.44-7.38(m,4H),7.07(d,J＝8.0Hz,2H),4.18-4.10(m,2H),2.81-2.76(m,1H),2.42(s,3H),1.66-1.59(m,1H),1.50-1.42(m,1H),0.66(t,J＝7.2Hz,3H).
synthesis of intermediate IV-62
Intermediate IV-61 (424 mg,1.11 mmol), 4-trifluoromethoxybenzene thiol (258 mg,1.33 mmol) and potassium iodide (18 mg,0.11 mmol) were added to acetonitrile (5 mL), and potassium carbonate (205 mg,1.50 mmol) was added in portions with stirring, and the mixture was reacted at 80℃for 8 hours. After completion of the reaction, the filtrate was diluted with water (20 mL), extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated brine (15 mL. Times.1), and the solvent was distilled off under reduced pressure to give intermediate IV-62 (colorless oily liquid, 400 mg).
Synthesis of intermediate IV-63
Intermediate IV-62 (400 mg,0.99 mmol), oxalic acid dihydrate (374 mg,2.97 mmol), palladium acetate (7 mg,0.03 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (17 mg,0.03 mmol) and acetic anhydride (279. Mu.L, 2.97 mmol) were added to anhydrous N, N-dimethylformamide (3 mL), the system was cooled to-78deg.C and frozen, N-diisopropylethylamine (517. Mu.L, 2.97 mmol) was added, and the system was allowed to return to room temperature naturally under argon protection, stirred for 30 minutes, and then allowed to react at 100deg.C for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL), water (20 mL) were added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate IV-63 (yellow oily liquid, 312 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.80(s,1H),7.86(d,J＝8.2Hz,2H),7.38(d,J＝8.9Hz,2H),7.34(d,J＝8.3Hz,2H),7.27(d,J＝8.2Hz,2H),3.39(d,J＝6.3Hz,1H),3.24(d,J＝12.8Hz,1H),2.83-2.73(m,1H),1.92-1.81(m,1H),1.70-1.59(m,1H),0.71(t,J＝7.3Hz,3H).
synthesis of Compound D-60
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-63, compound D-60 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.23(s,2H),8.39(s,2H),7.80(dd,J＝8.8,5.3Hz,2H),7.42-7.37(m,3H),7.35(d,J＝9.0Hz,3H),7.32-7.26(m,3H),7.11(d,J＝8.5Hz,2H),7.07(dd,J＝8.8,2.4Hz,1H),6.64(d,J＝8.7Hz,1H),3.29-3.15(m,2H),2.66-2.60(m,1H),1.90-1.78(m,1H),1.64-1.53(m,1H),0.73(t,J＝7.3Hz,3H).HRMS(ESI)calcd.for C 30 H 27 F 4 N 3 O 5 S 2 [M+H] + 650.1401,found 650.1403.
example 294
4-fluoro-N- (2-hydroxy-5- (3- (4- (1- ((4- (trifluoromethoxy) phenyl) thio) propan-2-yl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-61)
Synthesis of Compound D-61
Referring to the procedure of example 293, substituting ethyl iodide for methyl iodide produced compound D-61: 1 H NMR(300MHz,DMSO-d 6 )δ9.24(s,2H),8.40(s,1H),8.39(s,1H),7.80(dd,J＝8.6,5.2Hz,2H),7.41(d,J＝8.8Hz,3H),7.34(d,J＝9.3Hz,4H),7.32-7.27(m,3H),7.16(d,J＝8.5Hz,2H),7.07(d,J＝8.7Hz,1H),6.63(d,J＝8.6Hz,1H),3.22(d,J＝7.4Hz,2H),2.93-2.85(m,1H),1.30(d,J＝6.8Hz,3H).HRMS(ESI)calcd.for C 29 H 25 F 4 N 3 O 5 S 2 [M+H] + 636.1250,found 636.1274.
example 295
4-fluoro-N- (2-hydroxy-5- (3- (4- (1- ((4- (trifluoromethoxy) phenyl) thio) pent-2-yl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-62)
Synthesis of Compound D-62
Referring to the procedure of example 293, substituting ethyl iodide for 1-iodopropane produced compound D-62: 1 H NMR(300MHz,DMSO-d 6 )δ9.28(s,2H),8.42(s,2H),7.82(d,J＝5.2Hz,1H),7.79(d,J＝5.2Hz,1H),7.41-7.32(m,6H),7.32-7.28(m,3H),7.12(d,J＝8.5Hz,2H),7.07(dd,J＝8.7,2.6Hz,1H),6.64(d,J＝8.7Hz,1H),3.29(dd,J＝12.6,6.5Hz,1H),3.19(dd,J＝12.5,8.2Hz,1H),2.77-2.67(m,1H),1.86-1.68(m,1H),1.67-1.49(m,1H),1.10(p,J＝7.4Hz,2H),0.80(t,J＝7.3Hz,3H).HRMS(ESI)calcd.for C 31 H 29 F 4 N 3 O 5 S 2 [M+H] + 664.1558,found 664.1563.
example 296
4-fluoro-N- (2-hydroxy-5- (3- (4- (3-methyl-1- ((4- (trifluoromethoxy) phenyl) thio) butan-2-yl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-63)
Synthesis of Compound D-63
Referring to the procedure of example 293, substituting ethyl iodide for 2-iodopropane produced compound D-63: 1 H NMR(300MHz,DMSO-d 6 )δ9.27(s,2H),8.42(s,1H),8.41(s,1H),7.81(dd,J＝8.9,5.2Hz,2H),7.41-7.33(m,5H),7.32(s,1H),7.31-7.26(m,3H),7.13-7.02(m,3H),6.64(d,J＝8.7Hz,1H),3.43(dd,J＝12.4,4.8Hz,1H),3.32(d,J＝11.2Hz,1H),2.62-2.52(m,1H),1.95(h,J＝6.7Hz,1H),0.94(d,J＝6.6Hz,3H),0.72(d,J＝6.7Hz,3H).HRMS(ESI)calcd.for C 31 H 29 F 4 N 3 O 5 S 2 [M+H] + 664.1558,found 664.1559.
example 297
N- (5- (3- (4- (1-cyclopropyl-2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) phenyl) ureido) -2-hydroxyphenyl) -4-fluorobenzenesulfonamide (Compound D-64)
Synthesis of intermediate IV-64
Methyl triphenylphosphine bromide (238 mg,0.67 mmol) was added to anhydrous tetrahydrofuran (2 mL), potassium tert-butoxide (75 mL,0.67 mmol) was added in portions under ice bath, the mixture was stirred at 0℃for 30 minutes, a solution of (4-bromophenyl) cyclopropylmethanone (50 mg,0.22 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise, and the mixture was allowed to react naturally to room temperature for 12 hours. After the completion of the reaction, a saturated ammonium chloride solution (10 mL) was added to the reaction mixture in an ice bath to quench, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate IV-64 (colorless oily liquid, 51 mg): 1 H NMR(300MHz,Chloroform-d)δ7.48(s,4H),5.14(d,J＝94.9Hz,2H),1.65-1.59(m,1H),0.92-0.75(m,2H),0.65-0.54(m,2H).
Synthesis of intermediate IV-65
Intermediate IV-64 (47 mg,0.21 mmol) was added to tetrahydrofuran (1 mL), 1M borane-tetrahydrofuran complex (420. Mu.L, 0.42 mmol) was added dropwise under ice-bath, and stirring was continued at 0deg.C for 2 hours. After the TLC monitoring of complete consumption of the starting material, 3M aqueous sodium hydroxide (210. Mu.L, 0.63 mmol) and 30% hydrogen peroxide (200. Mu.L, 2.1 mmol) were added sequentially in an ice bath, and the reaction was allowed to proceed to room temperature for 12 hours. After the completion of the reaction, a saturated sodium thiosulfate solution (5 mL), water (5 mL) and ethyl acetate were added to the reaction mixture to quench, the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=15:1) to give intermediate IV-65 (colorless oily liquid, 37 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.46(d,J＝8.4Hz,2H),7.23(d,J＝8.3Hz,2H),4.56(t,J＝5.2Hz,1H),3.77-3.57(m,2H),1.91(ddd,J＝9.8,7.4,5.2Hz,1H),1.06-0.83(m,1H),0.61-0.46(m,1H),0.40-0.26(m,1H),0.24(td,J＝9.4,9.0,4.9Hz,1H),-0.01(td,J＝8.7,5.1Hz,1H).
synthesis of Compound D-64
Referring to the procedure of example 293, intermediate IV-60 was replaced with intermediate IV-65 to produce compound D-64: 1 H NMR(400MHz,DMSO-d 6 )δ9.24(s,2H),8.41(s,1H),8.40(s,1H),7.81(dd,J＝8.9,5.2Hz,2H),7.42-7.33(m,5H),7.33(s,1H),7.32-7.27(m,3H),7.17(d,J＝8.6Hz,2H),7.08(dd,J＝8.7,2.6Hz,1H),6.64(d,J＝8.7Hz,1H),3.45(dd,J＝12.4,5.8Hz,1H),3.37(dd,J＝11.0,7.4Hz,1H),2.07(td,J＝9.0,5.8Hz,1H),1.10(ddt,J＝13.1,9.2,4.8Hz,1H),0.57(tt,J＝8.7,4.2Hz,1H),0.35(dt,J＝8.8,4.5Hz,1H),0.29(dt,J＝9.6,5.2Hz,1H),0.07(dq,J＝9.0,5.1Hz,1H).HRMS(ESI)calcd.for C 31 H 27 F 4 N 3 O 5 S 2 [M+H] + 662.1401,found 662.1405.
example 298
4-fluoro-N- (2-hydroxy-5- (3- (4- (1-methoxy-2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-65)
Synthesis of intermediate IV-66
2,4' -dibromoacetophenone (893 mg,3.21 mmol) and 4-trifluoromethylthiophenol (686 mg,3.53 mmol) were added to acetone (12 mL), cesium carbonate (1.36 g,4.18 mmol) was added with stirring, and the mixture was reacted at 60℃for 4 hours. After the reaction was completed, water (20 mL) was added for dilution, ethyl acetate (15 ml×3) was extracted, the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate=300:1) to give intermediate IV-66 (white solid, 1.26 g): 1 H NMR(300MHz,Chloroform-d)δ7.82(d,J＝8.6Hz,2H),7.64(d,J＝8.6Hz,2H),7.43(d,J＝8.8Hz,2H),7.16(dd,J＝8.9,1.0Hz,2H),4.23(s,2H).
Synthesis of intermediate IV-67
Intermediate IV-66 (850 mg,2.17 mmol) was added to methanol (8 mL), sodium borohydride (82 mg,2.17 mmol) was added in portions on ice, and the reaction was allowed to slowly warm to room temperature for 2 hours after the addition. After the reaction was completed, the reaction solution was quenched by pouring it into ice water (30 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, washed with saturated brine (15 ml×1), the solvent was distilled off from the filtrate under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate=20:1) to give intermediate IV-67 (colorless oily liquid, 827 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.91(d,J＝8.3Hz,2H),7.54(d,J＝8.2Hz,2H),7.43(d,J＝8.8Hz,2H),7.27(dd,J＝9.0,1.0Hz,2H),5.90(d,J＝4.6Hz,1H),4.83(q,J＝5.8Hz,1H),3.30(d,J＝1.3Hz,1H),3.28(d,J＝2.5Hz,2H).
synthesis of intermediate IV-68
Sodium hydride (107 mg,2.67 mmol) was added to a dry three-necked flask, protected by argon, suspended in anhydrous N, N-dimethylformamide (1 mL), a solution of intermediate IV-67 (350 mg,0.89 mmol) in anhydrous N, N-dimethylformamide (1.5 mL) was added dropwise under ice bath, the mixture was allowed to react slowly at room temperature for 30 minutes after the dropwise addition, a solution of methyl iodide (111. Mu.L, 1.78 mmol) in anhydrous N, N-dimethylformamide (1 mL) was slowly added dropwise under ice bath after the dropwise addition, and the mixture was stirred at room temperature for 6 hours. After the completion of the reaction, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and water (15 mL), extracted with ethyl acetate (10 mL. Times.3), and combinedThe organic phase was washed with water (20 ml x 1), saturated brine (20 ml x 1) and the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate IV-68 (pale yellow oily liquid, 356 mg): 1 H NMR(400MHz,Chloroform-d)δ7.50(d,J＝8.4Hz,2H),7.35(d,J＝8.8Hz,2H),7.20(d,J＝8.4Hz,2H),7.14(dd,J＝8.9,1.0Hz,2H),4.28(dd,J＝7.7,5.3Hz,1H),3.30(dd,J＝13.4,7.7Hz,1H),3.26(s,3H),3.10(dd,J＝13.4,5.4Hz,1H).
Synthesis of Compound D-65
Referring to the procedure of example 293, intermediate IV-62 was replaced with intermediate IV-68 to produce compound D-65: 1 H NMR(400MHz,DMSO-d 6 )δ9.27(s,2H),8.53(s,1H),8.45(s,1H),7.81(dd,J＝8.9,5.2Hz,2H),7.46-7.39(m,4H),7.37(t,J＝8.9Hz,2H),7.31(d,J＝2.2Hz,2H),7.29(s,1H),7.25(d,J＝8.6Hz,2H),7.07(dd,J＝8.7,2.6Hz,1H),6.64(d,J＝8.7Hz,1H),4.30(dd,J＝7.7,5.3Hz,1H),3.41-3.38(m,1H),3.22(dd,J＝13.2,5.3Hz,1H),3.13(s,3H).HRMS(ESI)calcd.for C 29 H 25 F 4 N 3 O 6 S 2 [M+H] + 652.1194,found 652.1201.
example 299
N- (5- (3- (4- (1-ethoxy-2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) phenyl) ureido) -2-hydroxyphenyl) -4-fluorobenzenesulfonamide (Compound D-66)
Synthesis of Compound D-66
Referring to the procedure of example 298, substituting methyl iodide for ethyl iodide produced compound D-66: 1 H NMR(300MHz,DMSO-d 6 )δ9.26(s,2H),8.52(s,1H),8.45(s,1H),7.81(dd,J＝8.9,5.2Hz,2H),7.46(d,J＝8.8Hz,2H),7.43-7.34(m,4H),7.31(d,J＝2.5Hz,2H),7.28(d,J＝1.1Hz,1H),7.26(d,J＝8.6Hz,2H),7.08(dd,J＝8.7,2.6Hz,1H),6.64(d,J＝8.7Hz,1H),4.41(dd,J＝7.7,5.1Hz,1H),3.30(q,J＝6.9Hz,2H),3.20(dd,J＝13.1,5.1Hz,1H),3.09(q,J＝7.3Hz,1H),1.05(t,J＝7.0Hz,3H).HRMS(ESI)calcd.for C 30 H 27 F 4 N 3 O 6 S 2 [M+H] + 666.1350,found 666.1354.
example 300
4-fluoro-N- (2-hydroxy-5- (3- (4- (2- ((4- (trifluoromethoxy) phenyl) thio) propyl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-67)
Synthesis of intermediate IV-69
4-bromophenylacetone (500 mg,2.35 mmol) was added to methanol (9 mL), and sodium borohydride (89 mg,2.35 mmol) was added in portions under ice bath, and the mixture was slowly warmed to room temperature and reacted for 2 hours. After the reaction was completed, the reaction solution was quenched by pouring it into ice water (30 mL), extracted with ethyl acetate (15 ml×3), the organic phases were combined, washed with saturated brine (15 ml×1), the solvent was distilled off from the filtrate under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate=15:1) to give intermediate IV-69 (colorless oily liquid, 464 mg): 1 H NMR(400MHz,Chloroform-d)δ7.46(d,J＝8.3Hz,2H),7.12(d,J＝8.4Hz,2H),4.09-3.96(m,1H),2.76(dd,J＝13.6,4.9Hz,1H),2.68(dd,J＝13.6,7.8Hz,1H),1.26(d,J＝6.2Hz,3H).
synthesis of intermediate IV-70
Intermediate IV-69 (460 mg,2.14 mmol) and 4-dimethylaminopyridine (26 mg,0.21 mmol) were added to dichloromethane (7 mL), triethylamine (595. Mu.L, 4.28 mmol) was added, and p-toluenesulfonyl chloride (612 mg,3.21 mmol) was added in portions under ice bath and allowed to react at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate IV-70 (white solid, 733 mg): 1 H NMR(300MHz,Chloroform-d)δ7.53(d,J＝6.6Hz,2H),7.26(d,J＝8.3Hz,2H),7.21(d,J＝7.7Hz,2H),6.88(d,J＝8.3Hz,2H),4.77-4.60(m,1H),2.90-2.69(m,2H),2.46(s,3H),1.40(d,J＝6.2Hz,3H).
Synthesis of intermediate IV-71
4-trifluoromethoxybenzenesulfonyl chloride (751mg, 2.88 mmol) was added to N, N-dimethylformamide (5 mL), and the mixture was added dropwise under ice-bathTributylphosphine (2.16 mL,8.65 mmol) was added and the mixture was reacted at 50℃for 30 minutes. After TLC monitoring the disappearance of the starting material, the system was cooled to room temperature, and then N, N-dimethylformamide (3 mL) solution of intermediate IV-70 (710 mg,1.92 mmol), potassium carbonate (399 mg,2.88 mmol), potassium iodide (32 mg,0.19 mmol) were added in this order under ice bath, and the reaction was carried out at 50℃for 6 hours. After the completion of the reaction, the system was cooled to room temperature, water (80 mL) was added to the reaction solution to dilute, ethyl acetate was extracted (15 ml×3), and the organic phases were combined, washed with water (20 ml×2) and saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate IV-71 (colorless oily liquid, 611 mg): 1 H NMR(300MHz,Chloroform-d)δ7.43(d,J＝8.6Hz,4H),7.17(dd,J＝8.9,1.0Hz,2H),7.05(d,J＝8.3Hz,2H),3.49-3.31(m,1H),2.95(dd,J＝13.8,5.8Hz,1H),2.68(dd,J＝13.7,8.4Hz,1H),1.25(d,J＝6.7Hz,3H).
synthesis of intermediate IV-72
Intermediate IV-71 (399mg, 1 mmol), oxalic acid dihydrate (378 mg,3 mmol), palladium acetate (7 mg,0.03 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (17 mg,0.03 mmol) and acetic anhydride (281. Mu.L, 3 mmol) were added to anhydrous N, N-dimethylformamide (3 mL), the system was cooled to-78deg.C and frozen, N-diisopropylethylamine (523. Mu.L, 3 mmol) was added, and the system was allowed to return to room temperature naturally under argon protection, stirred for 10 minutes, and then allowed to react at 100deg.C for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (10 mL), water (20 mL) were added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (15 ml×1), saturated brine (15 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give crude intermediate IV-72, which was slurried (dichloromethane/methanol=100:1) and purified to give intermediate IV-72 (white solid, 154 mg): 1 H NMR(400MHz,DMSO-d 6 )δ12.85(s,1H),7.87(d,J＝8.1Hz,2H),7.51(d,J＝8.7Hz,2H),7.37(d,J＝8.0Hz,2H),7.32(d,J＝8.3Hz,2H),3.73(h,J＝6.8Hz,1H),2.96(dd,J＝13.7,6.4Hz,1H),2.84(dd,J＝13.7,7.9Hz,1H),1.19(d,J＝6.6Hz,3H).
Synthesis of Compound D-67
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-72, compound D-67 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ9.24(s,2H),8.42(s,1H),8.40(s,1H),7.81(dd,J＝8.9,5.2Hz,2H),7.52(d,J＝8.8Hz,2H),7.40-7.34(m,4H),7.34(d,J＝3.8Hz,2H),7.30(d,J＝2.6Hz,1H),7.14(d,J＝8.5Hz,2H),7.07(dd,J＝8.8,2.6Hz,1H),6.64(d,J＝8.7Hz,1H),3.64(dq,J＝12.8,6.6Hz,1H),2.85(dd,J＝13.8,5.9Hz,1H),2.66(dd,J＝13.7,8.2Hz,1H),1.18(d,J＝6.6Hz,3H).HRMS(ESI)calcd.for C 29 H 25 F 4 N 3 O 5 S 2 [M+H] + 636.1245,found 636.1249.
example 301
4-fluoro-N- (2-hydroxy-5- (3- (4- (2- ((4- (trifluoromethoxy) phenyl) thio) butyl) phenyl) ureido) phenyl) benzenesulfonamide (compound D-68)
Synthesis of intermediate IV-73
4-Bromophenylacetic acid (100 mg,0.47 mmol) was added to methylene chloride (2.5 mL), N-methyl-N-methoxyamine (43 mg,0.70 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (134 mg,0.70 mmol) and 4-dimethylaminopyridine (85 mg,0.70 mmol) were added successively under ice bath, and the mixture was stirred at room temperature for 12 hours. After the completion of the reaction, water (10 mL) was added to the reaction mixture to dilute it, ethyl acetate (10 ml×3) was added to extract, the organic phases were combined, saturated brine (10 ml×1) was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=7.5:1) to give intermediate IV-73 (white solid, 97 mg): 1 H NMR(300MHz,Chloroform-d)δ7.46(d,J＝8.4Hz,2H),7.19(d,J＝8.4Hz,2H),3.74(s,2H),3.65(s,3H),3.21(s,3H).
synthesis of intermediate IV-74
Intermediate IV-73 (48 mg,0.19 mmol) was added to anhydrous tetrahydrofuran (1 mL), 2M ethyl magnesium chloride-tetrahydrofuran solution (1 mL,1.94 mmol) was added dropwise under ice, and the reaction was continued at 0deg.C for 30 min. Reaction junction After the completion of the reaction, a saturated ammonium chloride solution (10 mL) was added to the reaction mixture in an ice bath, ethyl acetate (5 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate IV-74 (colorless oily liquid, 26 mg): 1 H NMR(300MHz,Chloroform-d)δ7.47(d,J＝8.4Hz,2H),7.10(d,J＝8.4Hz,2H),3.67(s,2H),2.50(q,J＝7.3Hz,2H),1.06(t,J＝7.3Hz,3H).
synthesis of Compound D-68
Referring to the procedure of example 300, substituting 4-bromophenyl acetone for intermediate IV-74 produced compound D-68: 1 H NMR(400MHz,DMSO-d 6 )δ9.26(s,2H),8.42(s,1H),8.41(s,1H),7.81(dd,J＝8.9,5.2Hz,2H),7.49(d,J＝8.8Hz,2H),7.41-7.32(m,3H),7.34-7.31(m,3H),7.30(d,J＝2.6Hz,1H),7.13(d,J＝8.6Hz,2H),7.06(dd,J＝8.7,2.6Hz,1H),6.64(d,J＝8.7Hz,1H),3.55-3.44(m,1H),2.78(d,J＝7.0Hz,2H),1.66-1.55(m,1H),1.46(dp,J＝14.2,7.1Hz,1H),0.98(t,J＝7.3Hz,3H).HRMS(ESI)calcd.for C 30 H 27 F 4 N 3 O 5 S 2 [M+H] + 650.1407,found 650.1414.
example 302
4-fluoro-N- (2-hydroxy-5- (3- (4- (2-methyl-1- (4- (trifluoromethoxy) phenyl) thio) propan-2-yl) phenylurea) phenyl) benzenesulfonamide (compound D-69)
Synthesis of intermediate IV-75
2- (4-bromophenyl) -2-methylpropanoic acid (481 mg,2 mmol) was added to anhydrous tetrahydrofuran (8 mL), lithium aluminum hydride (92 mg,2.4 mmol) was added in portions while ice-bath, and the mixture was slowly warmed to room temperature and reacted for 2 hours. After the reaction, adding water (2 mL) to the reaction solution for quenching, adding 4M sodium hydroxide aqueous solution (2 mL) after no bubbles are generated, stirring for 5 minutes at room temperature, adding water (6 mL) and anhydrous sodium sulfate (2 g), continuously stirring for 30 minutes at room temperature, carrying out suction filtration on the reaction solution by diatomite, drying the filtrate by anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a crude intermediate IV-75 product, which is directly used for the next reaction without further purification.
Synthesis of Compound D-69
Referring to the procedure of example 293, intermediate IV-60 was replaced with intermediate IV-75 to produce compound D-69: 1 H NMR(300MHz,DMSO-d 6 )δ9.28(s,2H),8.40(d,J＝4.0Hz,2H),7.83-7.77(m,2H),7.38(d,J＝8.9Hz,4H),7.34-7.27(m,5H),7.25(d,J＝8.1Hz,2H),7.06(dd,J＝8.7,2.6Hz,1H),6.63(d,J＝8.7Hz,1H),3.32(s,2H),1.38(s,6H).HRMS(ESI)calcd.for C 30 H 27 F 4 N 3 O 5 S 2 [M+H] + 650.1401,found 650.1406.
example 303
4-fluoro-N- (2-hydroxy-5- (3- (4- (trifluoromethoxy) phenyl) thiomethyl) cyclopropylphenyl) ureido) phenyl) benzenesulfonamide (compound D-70)
Synthesis of Compound D-70
Referring to the procedure of example 302, substituting 2- (4-bromophenyl) -2-methylpropanoic acid with 1- (4-bromophenyl) cyclopropanecarboxylic acid gave compound D-70: 1 H NMR(300MHz,DMSO-d 6 )δ9.22(s,2H),8.38(d,J＝5.1Hz,2H),7.79(dd,J＝8.8,5.2Hz,2H),7.38-7.29(m,6H),7.28(d,J＝2.4Hz,1H),7.23(t,J＝7.8Hz,4H),7.05(dd,J＝8.7,2.6Hz,1H),6.62(d,J＝8.7Hz,1H),3.32(s,2H),0.86(d,J＝5.0Hz,4H).HRMS(ESI)calcd.for C 30 H 25 F 4 N 3 O 5 S 2 [M+H] + 648.1245,found 648.1247.
example 304
4-fluoro-N- (2-hydroxy-5- (3- (4- (trifluoromethoxy) phenyl) thiomethyl) cyclobutylphenyl) ureido) phenyl) benzenesulfonamide (compound D-71)
Synthesis of Compound D-71
Referring to the procedure of example 302, substituting 2- (4-bromophenyl) -2-methylpropanoic acid with 1- (4-bromophenyl) cyclobutanecarboxylic acid gave compound D-71: 1 H NMR(300MHz,DMSO-d 6 )δ9.23(s,2H),8.38(s,2H),7.80(dd,J＝8.7,5.2Hz,2H),7.42-7.26(m,7H),7.22(d,J＝8.2Hz,2H),7.15-7.01(m,3H),6.63(d,J＝8.6Hz,1H),3.47(s,2H),2.37-2.20(m,4H),2.16-2.00(m,1H),1.86-1.75(m,1H).HRMS(ESI)calcd.for C 31 H 27 F 4 N 3 O 5 S 2 [M+H] + 662.1401,found 662.1409.
example 305
4-fluoro-N- (3-hydroxy-5- (3- (4- (3- (trifluoromethoxy) phenyl) thioethyl) phenyl) ureido) benzenesulfonamide (compound D-72)
Synthesis of Compound D-72
Referring to the procedure of example 279, substituting intermediate IV-40 for intermediate III-33 produced compound D-72: 1 H NMR(300MHz,DMSO-d 6 )δ10.12(s,1H),9.40(s,1H),8.55(s,1H),8.43(s,1H),7.83(dd,J＝8.8,5.2Hz,2H),7.48-7.38(m,4H),7.37-7.28(m,4H),7.16(d,J＝8.1Hz,2H),6.74(s,1H),6.63(s,1H),6.19(s,1H),3.23(t,J＝7.6Hz,2H),2.81(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 28 H 23 F 4 N 3 O 5 S 2 [M+H] + 622.1088,found 622.1090.
example 306
3, 5-difluoro-N- (2-hydroxy-5- (3- (4- (4- (trifluoromethoxy) phenyl) thio) phenyl) phenylurea) benzenesulfonamide (compound D-73)
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Synthesis of intermediate IV-76
Referring to the procedure of example 1, substituting 4-fluorobenzenesulfonyl chloride with 3, 5-difluorobenzenesulfonyl chloride produced intermediate IV-76: 1 H NMR(300MHz,DMSO-d 6 )δ9.08(s,1H),7.62(t,J＝9.2Hz,1H),7.38(d,J＝4.7Hz,2H),6.55(d,J＝8.7Hz,1H),6.29(d,J＝7.5Hz,2H),4.73(s,2H),0.89(s,9H),0.08(s,6H).
synthesis of Compound D-73
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate III-33 and substituting intermediate I-3 for intermediate IV-76, compound D-73 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.61(s,1H),9.34(s,1H),8.40(d,J＝7.2Hz,2H),7.62-7.55(m,1H),7.46(s,1H),7.43(s,3H),7.38-7.27(m,5H),7.14(d,J＝8.4Hz,2H),7.04(dd,J＝8.8,2.3Hz,1H),6.66(d,J＝8.7Hz,1H),3.22(t,J＝7.5Hz,2H),2.85-2.76(m,2H).HRMS(ESI)calcd.for C 28 H 22 F 5 N 3 O 5 S 2 [M+H] + 640.0994,found 640.1000.
example 307
2, 4-difluoro-N- (2-hydroxy-5- (3- (4- (4- (trifluoromethoxy) phenyl) thio) phenyl) phenylurea) benzenesulfonamide (compound D-74)
Synthesis of intermediate IV-77
Referring to the procedure of example 1, the substitution of 4-fluorobenzenesulfonyl chloride for 2, 4-difluorobenzenesulfonyl chloride produced intermediate IV-77.
Synthesis of Compound D-74
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate III-33 and substituting intermediate I-3 for intermediate IV-77, compound D-74 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.38(s,1H),9.23(s,1H),8.39(s,1H),8.37(s,1H),7.72(dd,J＝14.9,8.3Hz,1H),7.53-7.42(m,3H),7.41-7.28(m,4H),7.24(s,1H),7.21-7.10(m,3H),7.07(d,J＝8.9Hz,1H),6.63(d,J＝8.7Hz,1H),3.22(t,J＝7.5Hz,2H),2.80(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 28 H 22 F 5 N 3 O 5 S 2 [M+H] + 640.0994,found 640.0992.
example 308
N- (2-hydroxy-5- (3- (4- (2- ((4- ((trifluoromethyl) thio) phenyl) thio) ethyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-75)
Synthesis of Compound D-75
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate III-29, compound D-75 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.06(s,2H),8.44(d,J＝4.7Hz,2H),7.63(d,J＝8.3Hz,2H),7.45(d,J＝8.4Hz,2H),7.36(d,J＝8.3Hz,2H),7.30(d,J＝2.4Hz,1H),7.17(d,J＝8.5Hz,2H),7.13(d,J＝2.4Hz,1H),6.80(d,J＝8.7Hz,1H),3.27(t,J＝7.7Hz,2H),2.95(s,3H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 4 S 3 [M+H] + 558.0797,found 558.0801.
example 309
N- (2-hydroxy-5- (3- (4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-76)
Synthesis of Compound D-76
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate III-33, compound D-76 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.04(s,2H),8.42(s,2H),7.46(d,J＝8.3Hz,2H),7.38-7.24(m,5H),7.15(d,J＝7.5Hz,3H),6.80(d,J＝8.5Hz,1H),3.23(t,2H),2.95(s,3H),2.81(t,J＝7.2Hz,2H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 5 S 2 [M+H] + 542.1031,found 542.1038.
example 310
N- (4-fluoro-2-hydroxy-5- (3- (4- (2- ((4- ((trifluoromethyl) thio) phenyl) thio) ethyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-77)
Synthesis of Compound D-77
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate III-29 and substituting intermediate I-3 for intermediate II-18, compound D-77 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.00(s,1H),8.86(s,1H),8.79(s,1H),8.21(d,J＝1.9Hz,1H),7.82(d,J＝8.8Hz,1H),7.62(d,J＝8.4Hz,2H),7.45(d,J＝8.5Hz,2H),7.36(d,J＝8.5Hz,2H),7.18(d,J＝8.5Hz,2H),6.73(d,J＝12.0Hz,1H),3.28(t,J＝7.6Hz,2H),2.92(s,3H),2.85(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 23 H 21 F 4 N 3 O 4 S 3 [M+H] + 576.0703,found 576.0709.
example 311
N- (4-fluoro-2-hydroxy-5- (3- (4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-78)
Synthesis of Compound D-78
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate III-33 and substituting intermediate I-3 for intermediate II-18, compound D-78 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),8.86(s,1H),8.81(s,1H),8.22(d,J＝1.9Hz,1H),7.83(d,J＝8.8Hz,1H),7.46(d,J＝8.9Hz,2H),7.36(d,J＝8.5Hz,2H),7.33(d,J＝7.6Hz,2H),7.17(d,J＝8.6Hz,2H),6.74(d,J＝12.0Hz,1H),3.24(t,J＝7.7Hz,2H),2.93(s,3H),2.81(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 23 H 21 F 4 N 3 O 5 S 2 [M+H] + 560.0932,found 560.0936.
example 312
N- (4-fluoro-2-hydroxy-5- (3- (4- (2- ((4- (trifluoromethyl) phenyl) thio) ethyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-79)
Synthesis of intermediate IV-78
Referring to the procedure of example 200, the replacement of trifluoromethoxybenzenesulfonyl chloride with trifluoromethylbenzenesulfonyl chloride produced intermediate IV-78.
Synthesis of Compound D-79
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-78 and substituting intermediate I-3 for intermediate II-18, compound D-79 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),8.87(s,1H),8.81(s,1H),8.22(d,J＝1.9Hz,1H),7.83(d,J＝8.8Hz,1H),7.65(d,J＝8.3Hz,2H),7.51(d,J＝8.2Hz,2H),7.37(d,J＝8.5Hz,2H),7.19(d,J＝8.6Hz,2H),6.74(d,J＝12.1Hz,1H),3.30(t,J＝7.6Hz,2H),2.93(s,3H),2.86(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 23 H 21 F 4 N 3 O 4 S 2 [M+H] + 544.0982,found 544.0990.
Example 313
N- (2-hydroxy-5- (3- (2- (4- ((trifluoromethyl) thio) benzyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) ureido) phenyl) methanesulfonamide (Compound D-80)
Synthesis of intermediate IV-79
Intermediate III-46 (227 mg,0.56 mmol), oxalic acid dihydrate (213 mg,1.69 mmol), palladium acetate (4 mg,0.02 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (10 mg,0.02 mmol) and acetic anhydride (159. Mu.L, 1.69 mmol) were added to anhydrous N, N-dimethylformamide (2 mL), the system was cooled to-78deg.C and frozen, and N, N-diisopropylethylamine (295. Mu.L, 1.69 mmol) was addedAnd under the protection of argon, the system naturally returns to room temperature, is stirred for 30 minutes, and is then heated to 100 ℃ to react for 8 hours. After the reaction was completed, the system was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL), water (20 mL) were added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1) and saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=50:1) to give intermediate IV-79 (pale yellow solid, 106 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.82(s,1H),7.72(d,J＝2.3Hz,1H),7.70(d,J＝4.0Hz,2H),7.67(dd,J＝7.9,1.8Hz,1H),7.54(d,J＝8.2Hz,2H),7.15(d,J＝8.0Hz,1H),3.75(s,2H),3.63(s,2H),2.89(t,J＝5.9Hz,2H),2.71(t,J＝5.9Hz,2H).
synthesis of Compound D-80
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-79 produced compound D-80: 1 H NMR(300MHz,DMSO-d 6 )δ9.51(s,1H),8.68(s,1H),8.43(s,1H),8.40(s,1H),7.71(d,J＝7.9Hz,2H),7.55(d,J＝7.8Hz,2H),7.30(d,J＝2.6Hz,1H),7.25(s,1H),7.12(dd,J＝8.7,2.6Hz,2H),6.91(d,J＝8.4Hz,1H),6.79(d,J＝8.7Hz,1H),3.75(s,2H),3.52(s,2H),2.95(s,3H),2.86-2.77(m,2H),2.75-2.61(m,2H).HRMS(ESI)calcd.for C 25 H 25 F 3 N 4 O 4 S 2 [M+H] + 567.1348,found 567.1355.
Example 314
N- (2-hydroxy-5- (3- (1-oxo-2- (4- ((trifluoromethyl) thio) benzyl) isoindolin-5-yl) ureido) phenyl) methanesulfonamide (Compound D-81)
Synthesis of intermediate IV-80
Sodium hydride (62 mg,1.56 mmol) was added to a dry three-necked flask, protected by argon, suspended in anhydrous N, N-dimethylformamide (2 mL), dropwise added dropwise under ice bath with a solution of 5-bromo-2, 3-isoindolin-1-one (254 mg,1.2 mmol) in anhydrous N, N-dimethylformamide (2 mL), and the dropwise added was reacted at 0deg.CA solution of 4-trifluoromethylthiobenzyl bromide (325 mg,1.2 mmol) in anhydrous N, N-dimethylformamide (2 mL) was slowly added dropwise thereto over 30 minutes in an ice bath, and the mixture was stirred at room temperature for 6 hours after the completion of the addition. After the completion of the reaction, a saturated ammonium chloride solution (20 mL) was added to the reaction mixture to quench, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, washed with water (20 ml×1) and saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to give intermediate IV-80 (yellow oily liquid, 201 mg): 1 H NMR(300MHz,Chloroform-d)δ7.75(d,J＝8.1Hz,1H),7.63(d,J＝8.1Hz,3H),7.57(d,J＝1.4Hz,1H),7.34(d,J＝8.1Hz,2H),4.81(s,2H),4.28(s,2H).
synthesis of Compound D-81
Referring to the procedure of example 313, substituting intermediate III-46 for intermediate IV-80 produced compound D-81: 1 H NMR(300MHz,DMSO-d 6 )δ9.57(s,1H),8.91(s,1H),8.70(s,1H),8.59(s,1H),7.78(d,J＝1.6Hz,1H),7.70(d,J＝7.9Hz,2H),7.62(d,J＝8.3Hz,1H),7.47-7.37(m,3H),7.33(d,J＝2.6Hz,1H),7.14(dd,J＝8.7,2.6Hz,1H),6.81(d,J＝8.7Hz,1H),4.77(s,2H),4.38(s,2H),2.95(s,3H).HRMS(ESI)calcd.for C 24 H 21 F 3 N 4 O 5 S 2 [M+H] + 567.0984,found567.0988.
example 315
N- (5- (3- (1, 3-dioxo-2- (4- ((trifluoromethyl) thio) benzyl) isoindolin-5-yl) ureido) -2-hydroxyphenyl) methanesulfonamide (Compound D-82)
Synthesis of Compound D-82
Referring to the procedure of example 278, substituting intermediate IV-41 with 4-trifluoromethylthio benzyl bromide, substituting 4-bromophenylthiol with 4-bromophthalimide, substituting intermediate I-3 with intermediate I-18, produced compound D-82: 1 H NMR(400MHz,DMSO-d 6 )δ9.60(s,1H),9.30(s,1H),8.76(s,1H),8.67(s,1H),8.12(d,J＝2.0Hz,1H),7.80(d,J＝8.2Hz,1H),7.68(d,J＝8.0Hz,3H),7.46(d,J＝8.3Hz,2H),7.34(d,J＝2.6Hz,1H),7.18(dd,J＝8.7,2.6Hz,1H),6.83(d,J＝8.7Hz,1H),4.81(s,2H),2.96(s,3H).HRMS(ESI)calcd.for C 24 H 19 F 3 N 4 O 6 S 2 [M+H] + 581.0771,found 581.0776.
example 316
N- (2-hydroxy-5- (3- (1-oxo-2- (4- ((trifluoromethyl) thio) benzyl) -1,2,3, 4-tetrahydroisoquinolin-6-yl) ureido) phenyl) methanesulfonamide (Compound D-83)
Synthesis of Compound D-83
Referring to the procedure of example 278, substituting intermediate IV-41 with 4-trifluoromethylthio benzyl bromide, substituting 4-bromothiophenol with 6-bromo-3, 4-dihydro-2H-isoquinolin-1-one, substituting intermediate I-3 with intermediate I-18, the compound D-83 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ9.54(s,1H),8.81(s,1H),8.69(s,1H),8.58(s,1H),7.81(d,J＝8.5Hz,1H),7.70(d,J＝8.2Hz,2H),7.47(d,J＝8.3Hz,2H),7.45(d,J＝2.0Hz,1H),7.34(dd,J＝6.4,2.4Hz,2H),7.15(dd,J＝8.7,2.6Hz,1H),6.82(d,J＝8.7Hz,1H),4.75(s,2H),3.51(t,J＝6.6Hz,2H),2.96(s,3H),2.95(t,J＝6.6Hz,2H).HRMS(ESI)calcd.for C 25 H 23 F 3 N 4 O 5 S 2 [M+H] + 581.1135,found 581.1136.
example 317
N- (2-hydroxy-5- (3- (4- (3- (4- ((trifluoromethyl) thio) phenyl) propoxy) phenyl) ureido) phenyl) methanesulfonamide (compound D-84)
Synthesis of intermediate IV-81
Sodium hydride (500 mg,12.5 mmol) was added to a dry three-necked flask under argon, anhydrous tetrahydrofuran (5 mL) was added to the flask to suspend the flask, and triethyl phosphorylacetate (1.68 g,7.5 mmol) was added dropwise under ice bath Furan (10 mL) solution, after the completion of the dropwise addition, the reaction was carried out at 0℃for 30 minutes, and then a solution of 4-trifluoromethylthiobenzaldehyde (1.03 g,5 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added dropwise under an ice bath, after the completion of the dropwise addition, the mixture was naturally warmed to room temperature and stirred for 2 hours. After the reaction was completed, a saturated ammonium chloride solution (100 mL) was added to the reaction solution to quench, ethyl acetate (20 ml×3) was extracted, and the organic phases were combined, washed with water (30 ml×1) and saturated brine (30 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=80:1) to give intermediate IV-81 (colorless oily liquid, 1.38 g): 1 H NMR(400MHz,Chloroform-d)δ7.71-7.62(m,3H),7.55(d,J＝8.3Hz,2H),6.49(d,J＝16.1Hz,1H),4.28(q,J＝7.2Hz,2H),1.34(t,J＝7.1Hz,3H).
synthesis of intermediate IV-82
Intermediate IV-81 (138 mg,0.5 mmol) and 10% palladium on carbon (14 mg) were added to a tetrahydrofuran (4 mL) mixed solvent, and reacted at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, palladium on carbon was filtered off, the filter cake was washed with tetrahydrofuran (10 mL), and the solvent was distilled off from the filtrate under reduced pressure to give intermediate IV-82 (yellow oily liquid, 123 mg): 1 H NMR(300MHz,Chloroform-d)δ7.57(d,J＝8.1Hz,2H),7.25(d,J＝4.0Hz,2H),4.12(q,J＝7.1Hz,2H),2.98(t,J＝7.7Hz,2H),2.63(t,J＝7.7Hz,2H),1.22(t,J＝7.1Hz,3H).
synthesis of intermediate IV-83
Intermediate IV-82 (123 mg,0.44 mmol) was added to tetrahydrofuran (2 mL), a 2M solution of lithium borohydride in tetrahydrofuran (440. Mu.L, 0.88 mmol) was added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 6 hours. After the reaction was completed, water (10 mL) was added dropwise to the reaction solution under ice bath to quench excess lithium borohydride, ethyl acetate was extracted (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crude intermediate IV-83, which was used in the next reaction without further purification.
Synthesis of intermediate IV-84
Intermediate IV-83 (354 mg,1.5 mmol), methyl 4-hydroxybenzoate (152 mg,1 mmol) and triphenylphosphine (393 mg,1.5 mmol) were added to a dry three-necked flask under argon, and anhydrous tetrahydrofuran (3 mL) was addedA solution of diisopropyl azodicarboxylate (300. Mu.L, 1.5 mmol) in anhydrous tetrahydrofuran (2 mL) was slowly added dropwise under ice bath, and the mixture was allowed to react at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate IV-84 (white solid, 77 mg): 1 H NMR(300MHz,Chloroform-d)δ7.98(d,J＝8.9Hz,2H),7.57(d,J＝8.0Hz,2H),7.26(d,J＝8.2Hz,2H),6.89(d,J＝8.9Hz,2H),4.02(t,J＝6.1Hz,2H),3.89(s,3H),2.86(t,J＝7.6Hz,2H),2.21-2.06(m,2H).
synthesis of Compound D-84
Referring to the procedure of example 247, intermediate IV-17 was replaced with intermediate IV-84 to give compound D-84: 1 H NMR(400MHz,DMSO-d 6 )δ9.46(s,1H),8.71(s,1H),8.38(s,1H),8.30(s,1H),7.64(d,J＝8.1Hz,2H),7.42(d,J＝8.2Hz,2H),7.31(d,J＝9.0Hz,2H),7.29(d,J＝2.6Hz,1H),7.13(dd,J＝8.7,2.6Hz,1H),6.84(d,J＝9.1Hz,2H),6.79(d,J＝8.6Hz,1H),3.93(t,J＝6.3Hz,2H),2.95(s,3H),2.81(t,2H),2.03(p,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 5 S 2 [M+H] + 556.1188,found 556.1193.
example 318
N- (2-hydroxy-5- (3- (4- (3- (4-trifluoromethoxy) phenyl) propoxy) phenyl) ureido) phenyl) methanesulfonamide (compound D-85)
Synthesis of Compound D-85
Referring to the procedure of example 317, substituting intermediate IV-83 for intermediate III-47 produced compound D-85: 1 H NMR(300MHz,DMSO-d 6 )δ9.50(s,1H),8.68(s,1H),8.38(s,1H),8.30(s,1H),7.36(dd,J＝9.2,6.9Hz,3H),7.30(d,J＝1.9Hz,3H),7.28(d,J＝5.9Hz,1H),7.13(dd,J＝8.7,2.6Hz,1H),6.85(d,J＝9.0Hz,2H),6.79(d,J＝8.7Hz,1H),3.92(t,J＝6.3Hz,2H),2.95(s,3H),2.77(t,J＝7.7Hz,2H),2.00(p,J＝6.5Hz,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 6 S[M+H] + 540.1411,found 540.1429.
example 319
N- (2-hydroxy-5- (3- (4- (3- (4-trifluoromethyl) phenyl) propoxy) phenyl) ureido) phenyl) methanesulfonamide (compound D-86)
Synthesis of Compound D-86
Referring to the procedure of example 317, substituting intermediate IV-83 with 4-trifluoromethylphenylpropanol produced compound D-86: 1 H NMR(300MHz,DMSO-d 6 )δ9.49(s,1H),8.67(s,1H),8.37(s,1H),8.30(s,1H),7.65(d,J＝8.0Hz,2H),7.47(d,J＝7.9Hz,2H),7.31(d,J＝9.3Hz,2H),7.29(d,J＝2.6Hz,1H),7.13(dd,J＝8.4,2.3Hz,1H),6.85(d,J＝8.6Hz,2H),6.79(d,J＝8.7Hz,1H),3.92(t,J＝6.3Hz,2H),2.95(s,3H),2.83(t,J＝7.8Hz,2H),2.02(p,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 5 S[M+H] + 524.1462,found 524.1447.
Example 320
N- (2-hydroxy-5- (3- (4- (3- (4-trifluoromethoxy) phenoxy) propyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-87)
Synthesis of Compound D-87
Referring to the procedure of example 247, substituting intermediate IV-15 with 3- (4-methoxycarbonylphenyl) propionic acid and substituting methyl 4-hydroxybenzoate with 4-trifluoromethoxyphenol produced compound D-87: 1 H NMR(300MHz,DMSO-d 6 )δ9.52(s,1H),8.68(s,1H),8.43(s,1H),8.42(s,1H),7.34(d,J＝8.4Hz,2H),7.30(s,1H),7.28(d,J＝7.1Hz,2H),7.19-7.08(m,3H),7.03(d,J＝9.1Hz,2H),6.80(d,J＝8.7Hz,1H),3.97(t,J＝6.3Hz,2H),2.95(s,3H),2.67(t,J＝7.6Hz,2H),1.99(p,J＝6.6Hz,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 6 S[M+H] + 540.1411,found 540.1420.
example 321
N- (2-hydroxy-5- (3- (4- (3- (4- ((trifluoromethyl) thio) phenoxy) propyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-88)
Synthesis of Compound D-88
Referring to the procedure of example 247, substituting intermediate IV-15 with 3- (4-methoxycarbonylphenyl) propionic acid and substituting methyl 4-hydroxybenzoate with 4-trifluoromethylthiophenol gave compound D-88: 1 H NMR(400MHz,DMSO-d 6 )δ9.50(s,1H),8.68(s,1H),8.43(s,1H),8.41(s,1H),7.63(d,J＝8.8Hz,2H),7.34(d,J＝8.5Hz,2H),7.30(d,J＝2.6Hz,1H),7.16-7.11(m,3H),7.09(d,J＝8.8Hz,2H),6.80(d,J＝8.7Hz,1H),4.02(t,J＝6.3Hz,2H),2.95(s,3H),2.68(t,J＝7.6Hz,2H),2.01(p,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 5 S 2 [M+H] + 556.1182,found 556.1188.
example 322
4-fluoro-N- (2-hydroxy-5- (3- (4- (3- (4-trifluoromethoxy) phenyl) propyl) thio) phenyl) ureido) phenyl) benzenesulfonamide (compound D-89)
Synthesis of intermediate IV-85
Referring to the procedure of example 168, intermediate III-12 was replaced with intermediate III-47 to afford intermediate IV-85: 1 H NMR(300MHz,DMSO-d 6 )δ12.84(s,1H),7.83(d,J＝7.9Hz,2H),7.34(d,J＝8.3Hz,4H),7.26(d,J＝8.1Hz,2H),3.04(t,J＝7.1Hz,2H),2.76(t,J＝7.6Hz,2H),1.96-1.86(m,2H).ESI-MS:m/z 355.1[M-H] - .
synthesis of Compound D-89
Referring to the procedure of example 234, 4-phenylbenzoic acid was replaced with intermediate IV-85Compound D-89 is obtained: 1 H NMR(300MHz,DMSO-d 6 )δ9.29(s,2H),8.54(s,1H),8.45(s,1H),7.81(dd,J＝9.0,5.2Hz,2H),7.41(d,J＝4.3Hz,1H),7.38(d,J＝4.5Hz,2H),7.34(d,J＝2.9Hz,1H),7.33-7.22(m,7H),7.06(dd,J＝8.7,2.6Hz,1H),6.64(d,J＝8.7Hz,1H),2.87(t,J＝7.1Hz,2H),2.73(t,J＝7.7Hz,2H),1.81(p,J＝7.1Hz,2H).HRMS(ESI)calcd.for C 29 H 25 F 4 N 3 O 5 S 2 [M+H] + 636.1245,found 636.1252.
example 323
N- (2-hydroxy-5- (3- (4- ((3- (4- (trifluoromethoxy) phenyl) propyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-90)
Synthesis of Compound D-90
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-85, compound D-90 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ8.98(s,2H),8.55(s,1H),8.46(s,1H),7.40(d,J＝8.2Hz,2H),7.34-7.18(m,3H),7.14(d,J＝7.8Hz,1H),6.80(d,J＝8.7Hz,1H),2.86(t,J＝7.1Hz,2H),2.72(t,J＝7.2Hz,2H),1.86-1.74(m,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 5 S 2 [M+H] + 556.1182,found 556.1185.
example 324
N- (2-hydroxy-5- (3- (4- ((3- (4- (trifluoromethyl) phenyl) propyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-91)
Synthesis of intermediate IV-86
Referring to the procedure of example 168, substituting 4-trifluoromethoxy phenylacetic acid with 4-trifluoromethylphenyl propionic acid produced intermediate IV-86.
Synthesis of Compound D-91
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-86, compound D-91 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.55(s,1H),8.70(s,1H),8.57(s,1H),8.48(s,1H),7.64(d,J＝8.0Hz,2H),7.46-7.38(m,4H),7.34-7.24(m,3H),7.14(dd,J＝8.7,2.7Hz,1H),6.81(d,J＝8.7Hz,1H),2.96(s,3H),2.88(t,J＝7.2Hz,2H),2.79(t,J＝7.6Hz,2H),1.83(p,J＝7.3Hz,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 4 S 2 [M+H] + 540.1239,found 540.1246.
example 325
N- (2-hydroxy-5- (3- (4- ((3- (4- ((trifluoromethyl) thio) phenyl) propyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-92)
Synthesis of intermediate IV-87
Referring to the procedure of example 168, intermediate III-12 was replaced with intermediate IV-83 to afford intermediate IV-87: 1 H NMR(300MHz,DMSO-d 6 )δ12.91(s,1H),7.83(d,J＝8.5Hz,2H),7.64(d,J＝8.0Hz,2H),7.39(d,J＝8.2Hz,2H),7.35(d,J＝8.5Hz,2H),3.06(t,J＝7.3Hz,2H),2.80(t,J＝7.6Hz,2H),1.93(p,J＝7.6Hz,2H).
synthesis of Compound D-92
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-87, compound D-92 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.52(s,1H),8.69(s,1H),8.57(s,1H),8.48(s,1H),7.62(d,J＝8.1Hz,2H),7.40(d,J＝8.7Hz,2H),7.35(d,J＝8.2Hz,2H),7.30(d,J＝2.6Hz,1H),7.27(d,J＝8.7Hz,2H),7.14(dd,J＝8.7,2.6Hz,1H),6.80(d,J＝8.7Hz,1H),2.95(s,3H),2.86(t,J＝7.2Hz,2H),2.75(t,J＝7.6Hz,2H),1.82(p,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 4 S 3 [M+H] + 572.0954,found 572.0952.
Example 326
N- (4-fluoro-2-hydroxy-5- (3- (4- ((3- (4- (trifluoromethoxy) phenyl) propyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-93)
Synthesis of Compound D-93
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-85 and substituting intermediate I-3 for intermediate II-18 produced compound D-93: 1 H NMR(300MHz,DMSO-d 6 )δ10.02(s,1H),8.95(s,1H),8.79(s,1H),8.24(s,1H),7.81(d,J＝8.9Hz,1H),7.41(d,J＝8.7Hz,2H),7.34-7.29(m,3H),7.29-7.24(m,3H),6.75(d,J＝12.1Hz,1H),2.94(s,3H),2.87(t,J＝7.2Hz,2H),2.72(t,J＝7.6Hz,2H),1.81(p,J＝7.3Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 4 N 3 O 5 S 2 [M+H] + 574.1088,found 574.1091.
example 327
N- (4-fluoro-2-hydroxy-5- (3- (4- ((3- (4- (trifluoromethyl) thio) phenyl) propyl) thio) phenyl) ureido) phenyl) methanesulfonamide (compound D-94)
Synthesis of Compound D-94
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-87 and substituting intermediate I-3 for intermediate II-18 produced compound D-94: 1 H NMR(300MHz,DMSO-d 6 )δ10.00(s,1H),8.95(s,1H),8.79(s,1H),8.24(d,J＝1.8Hz,1H),7.80(d,J＝8.8Hz,1H),7.62(d,J＝8.0Hz,2H),7.40(d,J＝8.7Hz,2H),7.35(d,J＝8.2Hz,2H),7.28(d,J＝8.7Hz,2H),6.74(d,J＝12.1Hz,1H),2.93(s,3H),2.87(t,J＝7.1Hz,2H),2.75(t,J＝7.7Hz,2H),1.82(p,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 4 N 3 O 4 S 3 [M+H] + 590.0860,found 590.0863.
example 328
4-fluoro-N- (2-hydroxy-5- (3- (4- (3- (3- (trifluoromethoxy) phenyl) propyl) phenyl) benzenesulfonamide (compound D-95)
Synthesis of intermediate IV-88
4-trifluoromethoxybenzenesulfonyl chloride (782 mg,3 mmol) and 4-bromophenylpropanol (430 mg,2 mmol) were added to N, N-dimethylformamide (4 mL), a solution of tributylphosphine (3.03 g,15 mmol) in N, N-dimethylformamide (2 mL) was added dropwise under an ice bath under the protection of argon, stirred for 10 minutes, a solution of azodicarbonyl dipiperidine (757 mg,3 mmol) in N, N-dimethylformamide (2 mL) was added dropwise under an ice bath, and the mixture was slowly warmed to room temperature to react for 6 hours after the dropwise addition. After completion of the reaction, the reaction mixture was diluted with water (80 mL), extracted with ethyl acetate (20 ml×3), and the organic phases were combined, washed with 1M aqueous sodium hydroxide (15 ml×2), water (15 ml×1), saturated brine (15 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether) to give intermediate IV-88 (colorless oily liquid, 546 mg).
Synthesis of intermediate IV-89
Intermediate IV-88 (150 mg,0.38 mmol), oxalic acid dihydrate (145 mg,1.15 mmol), palladium acetate (5 mg,0.019 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (12 mg,0.019 mmol) and acetic anhydride (110. Mu.L, 1.15 mmol) were added to anhydrous N, N-dimethylformamide (2 mL), the system was cooled to-78deg.C and frozen, then N, N-diisopropylethylamine (191. Mu.L, 1.15 mmol) was added, and the system was allowed to return to room temperature naturally under argon protection, stirred for 30 minutes, and then allowed to react at 100deg.C for 8 hours. After the completion of the reaction, the reaction mixture was cooled to room temperature, 2N aqueous hydrogen chloride (5 mL) and water (20 mL) were added to the reaction mixture, the mixture was diluted with water, ethyl acetate (10 mL. Times.3) was extracted, the organic phases were combined, washed successively with water (10 mL. Times.1) and saturated brine (10 mL. Times.1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate)Ethyl acid = 5: 1) Purification gave intermediate IV-89 (white solid, 108 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.78(s,1H),7.85(d,J＝7.8Hz,2H),7.42(d,J＝6.5Hz,2H),7.36-7.25(m,4H),2.99(t,J＝7.7Hz,2H),2.77(t,J＝8.1Hz,2H),1.89(dt,J＝15.3,8.8Hz,2H).
synthesis of Compound D-95
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-89, compound D-95 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.22(s,2H),8.37(s,2H),7.80(dd,J＝8.8,5.3Hz,2H),7.43-7.27(m,9H),7.12-7.03(m,3H),6.63(d,J＝8.7Hz,1H),2.97(t,J＝7.1Hz,2H),2.64(t,J＝7.5Hz,2H),1.92-1.76(m,2H).HRMS(ESI)calcd.for C 29 H 25 F 4 N 3 O 5 S 2 [M+H] + 636.1245,found 636.1249.
example 329
4-fluoro-N- (2-hydroxy-5- (3- (4- (4- ((trifluoromethyl) thio) phenyl) thio) propyl) phenyl) ureido) benzenesulfonamide (compound D-96)
Synthesis of intermediate IV-90
Intermediate III-49 (492 mg,1.21 mmol), oxalic acid dihydrate (457 mg,3.63 mmol), palladium acetate (14 mg,0.06 mmol), 4, 5-bis-diphenylphosphine-9, 9-dimethylxanthene (35 mg,0.06 mmol) and acetic anhydride (348. Mu.L, 3.63 mmol) were added to anhydrous N, N-dimethylformamide (5 mL), the system was cooled to-78deg.C and frozen, N-diisopropylethylamine (632. Mu.L, 3.63 mmol) was added, and the system was allowed to return to room temperature under argon and stirred for 30 minutes, and reacted at 100deg.C for 8 hours. After the completion of the reaction, the system was cooled to room temperature, 2N aqueous hydrogen chloride (10 mL) and water (40 mL) were added to the reaction mixture to dilute, ethyl acetate (15 ml×3) was extracted, the organic phases were combined, washed with water (20 ml×1) and saturated brine (20 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=2:1) to give intermediate IV-90.
Synthesis of Compound D-96
Referring to the procedure of example 234, substituting 4-phenylbenzoic acid for intermediate IV-90 produced compound D-96: 1 H NMR(300MHz,DMSO-d 6 )δ9.22(s,2H),8.37(s,2H),7.80(dd,J＝8.7,5.3Hz,2H),7.61(d,J＝8.2Hz,2H),7.44-7.25(m,7H),7.14-7.01(m,3H),6.63(d,J＝8.7Hz,1H),3.03(t,J＝7.3Hz,2H),2.66(t,J＝7.5Hz,2H),1.97-1.80(m,2H).HRMS(ESI)calcd.for C 29 H 25 F 4 N 3 O 4 S 3 [M+H] + 652.1016,found 652.1019.
example 330
N- (2-hydroxy-5- (3- (4- (3- ((4-trifluoromethoxy) phenyl) thio) propyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-97)
Synthesis of Compound D-97
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-89, compound D-97 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.43(s,1H),8.71(s,1H),8.42(s,1H),8.42(s,1H),7.41(d,J＝8.9Hz,2H),7.33(d,J＝7.0Hz,1H),7.31(s,1H),7.29(d,J＝2.6Hz,2H),7.13(dd,J＝8.7,2.6Hz,1H),7.08(d,J＝8.4Hz,2H),6.79(d,J＝8.7Hz,1H),2.98(t,J＝7.1Hz,2H),2.95(s,3H),2.64(t,J＝7.5Hz,2H),1.83(p,J＝7.3Hz,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 5 S 2 [M+H] + 556.1188,found 556.1195.
example 331
N- (2-hydroxy-5- (3- (4- ((trifluoromethyl) thio) phenyl) propyl) ureido) phenyl) methanesulfonamide (compound D-98)
Synthesis of Compound D-98
Referring to the method of example 239, 4' -trifluoromethylbiphenyl-4-carboxylic acid methyl esterAcid substitution to intermediate IV-90 produced compound D-98: 1 H NMR(300MHz,DMSO-d 6 )δ9.04(s,2H),8.40(s,2H),7.61(d,J＝8.2Hz,2H),7.42-7.22(m,5H),7.19-7.00(m,3H),6.79(d,J＝8.7Hz,1H),3.02(t,J＝7.3Hz,2H),2.95(s,3H),2.65(t,J＝7.6Hz,2H),1.96-1.79(m,2H).HRMS(ESI)calcd.for C 24 H 24 F 3 N 3 O 4 S 3 [M+H] + 572.0954,found 572.0955.
example 332
N- (2-hydroxy-5- (3- (4- (4- (4- (trifluoromethoxy) phenyl) butyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-99)
Synthesis of intermediate IV-91
Intermediate III-47 (170 mg,0.77 mmol) was added to dichloromethane (2 mL), and dess-Martin oxidant (655 mg,1.54 mmol) was added in portions while ice-bath, and the reaction was allowed to proceed to room temperature for 2 hours. After the reaction was completed, a saturated sodium thiosulfate solution (5 mL) and a saturated sodium bicarbonate solution (5 mL) were added to the reaction solution, quenched, extracted with ethyl acetate (10 ml×3), and the organic phases were combined, washed with a saturated sodium thiosulfate solution (10 ml×1) and a saturated saline solution (10 ml×1) in this order, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain a crude intermediate IV-91, which was used directly for the next feeding due to instability.
Synthesis of intermediate IV-92
Sodium hydride (93 mg,2.31 mmol) was added to a dry Schlenk tube, protected by argon, suspended in anhydrous tetrahydrofuran (1 mL), a solution of intermediate I-38 (277 mg,0.92 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise under ice bath, and after dropping, the mixture was slowly warmed to room temperature and stirred for 1 hour, and then a solution of crude intermediate IV-91 (0.77 mmol) in anhydrous tetrahydrofuran (1 mL) was added dropwise under ice bath, and after dropping, the mixture was warmed to room temperature and reacted for 24 hours. After the completion of the reaction, a saturated ammonium chloride solution (10 mL) was added to the reaction mixture to quench excess sodium hydride, ethyl acetate (10 mL. Times.3) was used for extraction, and the organic phase was washed with saturated brine (10 mL. Times.2) and distilled off under reduced pressureThe agent and residue were purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate IV-92 (yellow solid, 224 mg): 1 H NMR(300MHz,DMSO-d 6 )δ13.09(s,1H),7.99(d,J＝7.9Hz,1H),7.87(d,J＝8.2Hz,1H),7.71(dd,J＝7.7,1.5Hz,1H),7.52-7.45(m,2H),7.36(t,J＝7.8Hz,1H),7.32-7.20(m,3H),6.50(s,1H),2.91-2.70(m,2H),2.67-2.53(m,2H).ESI-MS:m/z 335.1[M-H] - .
synthesis of intermediate IV-93
Intermediate IV-92 (50 mg,0.15 mmol) was added to a mixed solvent of tetrahydrofuran (2 mL) and water (2 mL), p-toluenesulfonylhydrazide (279 mg,1.5 mmol) and sodium acetate trihydrate (265 mg,1.95 mmol) were added in this order, and the mixture was reacted at 70℃for 24 hours. After the completion of the reaction, 1N aqueous hydrogen chloride (10 mL) was added to the reaction mixture to quench, ethyl acetate (5 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=15:1) to give intermediate IV-93 (white solid, 23 mg): 1 H NMR(300MHz,DMSO-d 6 )δ12.89(s,1H),7.96(dd,J＝10.9,7.8Hz,1H),7.84(d,J＝8.0Hz,1H),7.54-7.44(m,1H),7.30(d,J＝7.5Hz,3H),7.24(d,J＝7.8Hz,2H),2.71-2.57(m,3H),1.59(s,3H),1.36-1.24(m,2H).ESI-MS:m/z 337.1[M-H] - .
Synthesis of Compound D-99
Referring to the procedure of example 239, substituting 4' -trifluoromethylbiphenyl-4-carboxylic acid with intermediate IV-93, compound D-99 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.47(s,1H),8.64(s,1H),8.39(d,J＝8.3Hz,2H),7.32-7.22(m,7H),7.13(dd,J＝8.6Hz,1H),7.06(d,J＝8.2Hz,2H),6.79(d,J＝8.5Hz,1H),2.95(s,3H),2.62(s,4H),1.56(s,4H).ESI-MS:HRMS(ESI)calcd.for C 25 H 26 F 3 N 3 O 5 S[M+H] + 538.1624,found 538.1631.
example 333
N- (2-hydroxy-5- (3- (4- (4- ((trifluoromethyl) thio) phenyl) butyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-100)
Synthesis of Compound D-100
Referring to the procedure of example 332, substituting intermediate III-47 for intermediate IV-83 produced compound D-100: 1 H NMR(400MHz,DMSO-d 6 )δ9.48(s,1H),8.65(s,1H),8.41(s,1H),8.38(s,1H),7.62(d,J＝8.1Hz,2H),7.36(d,J＝8.2Hz,2H),7.31(d,J＝8.5Hz,2H),7.30(d,J＝2.6Hz,1H),7.13(dd,J＝8.7,2.6Hz,1H),7.06(d,J＝8.5Hz,2H),6.80(d,J＝8.7Hz,1H),2.95(s,3H),2.67(t,J＝7.0Hz,2H),2.54(t,J＝6.6Hz,2H),1.58(p,J＝4.4Hz,4H).HRMS(ESI)calcd.for C 25 H 25 F 4 N 3 O 5 S[M+H] + 554.1390,found 554.1397.
example 334
N- (4-fluoro-2-hydroxy-5- (3- (4- (4- (trifluoromethoxy) phenyl) butyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-101)
Synthesis of Compound D-101
Referring to the procedure of example 332, substituting intermediate I-18 for intermediate II-18 produced compound D-101: 1 H NMR(300MHz,DMSO-d 6 )δ9.99(s,1H),8.80(s,1H),8.77(s,1H),8.19(s,1H),7.83(d,J＝8.9Hz,1H),7.33(d,J＝3.3Hz,2H),7.30(d,J＝3.6Hz,2H),7.25(d,J＝8.4Hz,2H),7.08(d,J＝8.3Hz,2H),6.74(d,J＝12.1Hz,1H),2.93(s,3H),2.66-2.60(m,2H),2.57-2.51(m,2H),1.63-1.45(m,4H).HRMS(ESI)calcd.for C 25 H 25 F 4 N 3 O 5 S[M+H] + 556.1524,found 556.1531.
example 335
N- (4-fluoro-2-hydroxy-5- (3- (4- (4- ((trifluoromethyl) thio) phenyl) butyl) phenyl) ureido) phenyl) methanesulfonamide (compound D-102)
Synthesis of Compound D-102
Referring to the procedure of example 332, substituting intermediate III-47 for intermediate IV-83 and substituting intermediate I-18 for intermediate II-18 produced compound D-102: 1 H NMR(300MHz,DMSO-d 6 )δ9.97(s,1H),8.79(s,1H),8.75(s,1H),8.19(d,J＝2.0Hz,1H),7.82(d,J＝8.9Hz,1H),7.61(d,J＝8.1Hz,2H),7.36(d,J＝8.2Hz,2H),7.32(d,J＝8.5Hz,2H),7.07(d,J＝8.5Hz,2H),6.73(d,J＝12.1Hz,1H),2.93(s,3H),2.69-2.61(m,2H),2.59-2.51(m,2H),1.64-1.50(m,4H).HRMS(ESI)calcd.for C 25 H 25 F 4 N 3 O 4 S 2 [M+H] + 572.1295,found 572.1296.
example 336
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -2- (4- ((4- (trifluoromethyl) benzyl) oxy) piperidin-1-yl) acetamide (Compound E-1)
Synthesis of intermediate V-1
Intermediate I-18 (250 mg,0.79 mmol) and pyridine (100. Mu.L, 1.19 mmol) were added to anhydrous tetrahydrofuran (3 mL), chloroacetyl chloride (76. Mu.L, 0.95 mmol) was added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 4 hours. After the completion of the reaction, 1N aqueous hydrogen chloride (10 mL) was added to the reaction mixture to quench, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, washed with 1N aqueous hydrogen chloride (10 ml×1), saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate V-1 (white solid, 240 mg): 1 H NMR(300MHz,CDCl 3 )δ7.56(d,J＝8.8Hz,2H),6.96(d,J＝8.7Hz,2H),4.28-4.10(m,2H),3.86(d,J＝6.4Hz,2H),2.78(t,J＝12.9Hz,2H),2.07-1.92(m,1H),1.85(d,J＝12.5Hz,2H),1.49(s,9H),1.31-1.24(m,2H).
synthesis of intermediate V-2
Sodium hydride (44 mg,1.1 mmol) was added to a dry Schlenk tube under argon, suspended in anhydrous tetrahydrofuran (1 mL), and ice-cooledA solution of N-Boc-4-hydroxy piperidine (201 mg,1 mmol) in anhydrous tetrahydrofuran (1 mL) was added, the solution was slowly warmed to room temperature and stirred for 2 hours, a solution of 4-trifluoromethyl benzyl bromide (290 mg,1.2 mmol) in anhydrous tetrahydrofuran (4 mL) was added dropwise under ice bath, and the mixture was allowed to react at 50℃for 24 hours. After the reaction was completed, the system was cooled to room temperature, quenched by adding water (10 mL), extracted with ethyl acetate (5 ml×3), the organic phases were combined, washed with saturated sodium chloride (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=15:1) to give intermediate V-2 (white solid, 203 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.71(d,J＝8.0Hz,2H),7.56(d,J＝7.9Hz,2H),4.62(s,2H),3.69-3.55(m,3H),3.05(t,J＝10.3Hz,2H),1.90-1.78(m,2H),1.47-1.40(m,2H),1.39(s,9H).
Synthesis of intermediate V-3
Intermediate V-2 (200 mg,0.56 mmol) was added to dichloromethane (2 mL), and a 4M hydrogen chloride-dioxane solution (1.5 mL,6 mmol) was added dropwise and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by beating (ethyl acetate), and the obtained solid was dried to constant weight to give compound V-3 (white solid, 150 mg): 1 H NMR(300MHz,DMSO-d 6 )δ8.88(s,2H),7.73(d,J＝7.9Hz,2H),7.57(d,J＝7.9Hz,2H),3.74-3.66(m,1H),3.22-3.12(m,2H),3.01-2.91(m,2H),2.06-1.98(m,2H),1.82-1.72(m,2H).
synthesis of Compound E-1
Intermediate V-3 (83 mg,0.28 mmol), intermediate V-1 (100 mg,0.25 mmol) and potassium iodide (5 mg,0.03 mmol) were added to anhydrous acetonitrile (3 mL), cesium carbonate (124 mg,0.38 mmol) was added in portions, and the reaction was completed at room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, the residue was added dropwise to a 1N aqueous hydrogen chloride solution to adjust the pH to 7 to 8, extracted with ethyl acetate (5 ml×3), the organic phases were combined, washed with saturated brine (5 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=75:1) to give compound E-1 (white solid, 20 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.53(s,1H),8.74(s,2H),7.72(d,J＝8.1Hz,2H),7.56(d,J＝8.1Hz,2H),7.49(d,J＝2.4Hz,1H),7.34(dd,J＝8.7,2.4Hz,1H),6.81(d,J＝8.7Hz,1H),4.62(s,2H),3.48-3.41(m,1H),3.06(s,2H),2.95(s,3H),2.75(t,2H),2.29(t,J＝9.3Hz,2H),1.97-1.88(m,2H),1.69-1.56(m,2H).HRMS(ESI)calcd.for C 22 H 26 F 3 N 3 O 5 S[M+H] + 502.1618,found 502.1621.
example 337
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- ((4- (trifluoromethoxy) benzyl) oxy) phenyl) acetamide (Compound E-2)
Synthesis of intermediate V-4
Intermediate 4-trifluoromethoxybenzyl bromide (200 mg,0.78 mmol), 4-nitrophenol (125 mg,0.90 mmol) and potassium iodide (13 mg,0.08 mmol) were added to acetonitrile (4 mL), and potassium carbonate (140 mg,1.01 mmol) was added in portions with stirring, and the mixture was reacted at 70℃for 8 hours. After the reaction was completed, water (10 mL) was added to the filtrate for dilution, ethyl acetate (10 mL x 3) was extracted, the organic phases were combined, washed with saturated brine (15 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 give intermediate V-4 (white solid, 205 mg): 1 H NMR(400MHz,Chloroform-d)δ8.22(d,J＝9.2Hz,2H),7.46(d,J＝6.6Hz,2H),7.26(d,J＝5.7Hz,2H),7.03(d,J＝9.2Hz,2H),5.15(s,2H).
Synthesis of intermediate V-5
Intermediate V-4 (185 mg,0.59 mmol) was added to N, N-dimethylformamide (2 mL), tetrahydroxydiboron (160 mg,1.77 mmol) and 4,4' -bipyridine (1 mg, 0.006mmol) were added sequentially while ice-cooling, and the reaction was continued at room temperature for 10 minutes. After the completion of the reaction, water (20 mL) was added to the reaction mixture to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with water (10 ml×1), washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate V-5 (yellow solid, 140 mg): 1 H NMR(400MHz,DMSO-d 6 )δ7.53(d,J＝8.6Hz,2H),7.36(d,J＝7.6Hz,2H),6.72(d,J＝8.8Hz,2H),6.50(d,J＝8.8Hz,2H),4.97(s,2H),4.63(s,2H).
synthesis of intermediate V-6
4-hydroxy-3-nitrobenzoic acid (2 g,10 mmol) and potassium carbonate (5.5 g,40 mmol) were added to N, N-dimethylformamide (45 mL), 3-bromopropene (2.6 mL,30 mmol) was added dropwise under ice, and the mixture was allowed to react at room temperature for 18 hours after completion of the dropwise addition. After the completion of the reaction, 1N aqueous hydrogen chloride was added to the reaction mixture to adjust the pH to 6 to 7, ethyl acetate (20 ml x 3) was used for extraction, the organic phases were combined, washed with water (30 ml x 2) and saturated brine (30 ml x 1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=20:1) to give intermediate V-6 (pale yellow oily liquid, 3.92 g): 1 H NMR(300MHz,DMSO-d 6 )δ7.83(d,J＝2.1Hz,1H),7.56(dd,J＝8.6,2.1Hz,1H),7.33(d,J＝8.7Hz,1H),6.11-5.98(m,1H),5.98-5.84(m,1H),5.43(dd,J＝17.3,1.6Hz,1H),5.31(s,1H),5.24(ddd,J＝11.8,8.1,1.4Hz,2H),4.75(d,J＝4.9Hz,2H),4.58(d,J＝5.4Hz,2H),3.79(s,2H).
Synthesis of intermediate V-7
Intermediate V-6 (3.92 g,14 mmol) and ammonium chloride (7.49 g,140 mmol) were added to a mixed solvent of ethanol (25 mL) and water (25 mL), and reduced iron powder (3.96 g,70 mmol) was added in portions with stirring, and the mixture was allowed to react under reflux for 4 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the cake was washed with ethyl acetate (15 mL) and water (15 mL), ethyl acetate (20 ml×3) was extracted from the filtrate, the organic phases were combined, washed with saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=7.5:1) to give intermediate V-7 (yellow oily liquid, 3 g): 1 H NMR(300MHz,DMSO-d 6 )δ6.72(d,J＝8.1Hz,1H),6.56(d,J＝1.9Hz,1H),6.39(dd,J＝8.1,1.8Hz,1H),6.06(ddd,J＝22.5,10.4,5.1Hz,1H),5.90(ddd,J＝22.5,10.6,5.4Hz,1H),5.42(dd,J＝17.4,1.6Hz,1H),5.27(dd,J＝7.4,1.5Hz,1H),5.23(d,J＝1.1Hz,1H),5.19(dd,J＝10.5,1.4Hz,1H),4.73(s,2H),4.53(dd,J＝10.2,5.2Hz,4H),3.47(s,2H).
synthesis of intermediate V-8
Intermediate V-7 (3 g,12 mmol) and pyridine (1.5 mL,18 mmol) were added to anhydrous dichloromethaneTo an alkane (20 mL) was added dropwise a solution of methylsulfonic anhydride (2.55 g,14.4 mmol) in methylene chloride (10 mL) under ice bath, and after the addition, the mixture was allowed to react at room temperature for 8 hours. After the reaction, 1N aqueous hydrogen chloride was added to adjust the pH to 6 to 7, ethyl acetate (20 ml x 3) was added to extract, the organic phases were combined, washed with saturated brine (20 ml x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate V-8 (pale yellow waxy liquid, 2.78 g): 1 H NMR(300MHz,DMSO-d 6 )δ8.91(s,1H),7.18(d,J＝2.0Hz,1H),7.08(dd,J＝8.4,2.1Hz,1H),7.01(d,J＝8.5Hz,1H),6.07(ddt,J＝17.3,10.4,5.1Hz,1H),5.90(ddt,J＝17.2,10.6,5.4Hz,1H),5.46(dd,J＝17.3,1.7Hz,1H),5.29(d,J＝1.5Hz,1H),5.24(dd,J＝6.0,1.6Hz,1H),5.19(dd,J＝10.5,1.5Hz,1H),4.61(d,J＝5.1Hz,2H),4.56(d,J＝5.4Hz,2H),3.64(s,2H),2.94(s,3H).
Synthesis of intermediate V-9
Intermediate V-8 (3.24 g,9.97 mmol) and tetrakis (triphenylphosphine) palladium (1.15 g,1.0 mmol) were added to a three-necked flask, and suspended in dichloromethane (100 mL) under argon, diethylamine (20 mL, 199mmol) was added, and the reaction was completed at room temperature for 16 hours. After the reaction was completed, 2N aqueous hydrogen chloride (10 mL) was added to adjust the pH to 1 to 2, dichloromethane (20 mL x 3) was extracted, the organic phases were combined, washed with saturated brine (20 mL x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=50:1) to give intermediate V-9 (pale yellow solid, 1.72 g): 1 H NMR(300MHz,DMSO-d 6 )δ12.24(s,1H),9.76(s,1H),8.69(s,1H),7.08(d,J＝2.1Hz,1H),6.92(dd,J＝8.3,2.2Hz,1H),6.81(d,J＝8.2Hz,1H),3.43(s,2H),2.93(s,3H).
synthesis of Compound E-2
Intermediate V-9 (70 mg,0.29 mmol) and N, N-dimethylformamide (2 drops) were added to anhydrous tetrahydrofuran (2 mL), oxalyl chloride (37. Mu.L, 0.44 mmol) was slowly added dropwise under ice-bath, and the mixture was allowed to react at room temperature for 1 hour. After the completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was dissolved in anhydrous tetrahydrofuran (2 mL) to give a tetrahydrofuran solution of acid chloride, which was added under ice-bath conditions to a solution of V-5 (85 mg,0.30 mmol) and pyridine (35. Mu.L, 0.44 mmol) in tetrahydrofuran (1 mL), followed by reaction at room temperature of 6Hours. After the reaction was completed, 2N aqueous hydrogen chloride solution was added to the reaction solution to adjust the pH to 3 to 4, ethyl acetate (10 ml x 3) was extracted, the organic phases were combined, washed with water (10 ml x 1) and saturated brine (10 ml x 1) in this order, the solvent was distilled off under reduced pressure, the residue was purified by column chromatography (dichloromethane/methanol=75:1) to give a crude compound E-2, which was slurried (dichloromethane/methanol=50:1) for purification, and the obtained solid was dried to constant weight to give compound E-2 (white solid, 50 mg): 1 H NMR(400MHz,DMSO-d 6 )δ9.96(s,1H),9.72(s,1H),8.70(s,1H),7.56(d,J＝8.6Hz,2H),7.49(d,J＝9.1Hz,2H),7.38(d,J＝8.2Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.95(d,J＝9.1Hz,2H),6.83(d,J＝8.2Hz,1H),5.09(s,2H),3.46(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 6 S[M+H] + 511.1145,found 511.1141.
Example 338
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -2- (4- ((4- (trifluoromethyl) phenoxy) methyl) piperidin-1-yl) acetamide (Compound E-3)
Synthesis of intermediate V-10
N-Boc-4-piperidinemethanol (215 mg,1 mmol), 4-trifluoromethylphenol (210 mg,1.3 mmol) and triphenylphosphine (393 mg,1.5 mmol) were added to a dry three-necked flask, and the flask was cooled under argon, dissolved in anhydrous tetrahydrofuran (5 mL), and then a solution of diisopropyl azodicarboxylate (303 mg,1.5 mmol) in anhydrous tetrahydrofuran (5 mL) was added under ice bath to react at room temperature for 12 hours. After the completion of the reaction, water (10 mL) was added to the reaction mixture to dilute, ethyl acetate (10 ml×3) was extracted, and the organic phase was washed with a saturated sodium carbonate solution (10 ml×2) and a saturated brine (10 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate V-10 (white solid, 350 mg): 1 H NMR(300MHz,CDCl 3 )δ7.56(d,J＝8.8Hz,2H),6.96(d,J＝8.7Hz,2H),4.28-4.10(m,2H),3.86(d,J＝6.4Hz,2H),2.78(t,J＝12.9Hz,2H),2.07-1.92(m,1H),1.85(d,J＝12.5Hz,2H),1.49(s,9H),1.31-1.24(m,2H).
synthesis of Compound E-3
Referring to the procedure of example 336, substituting intermediate V-2 for intermediate V-10 produced compound E-3: 1 H NMR(300MHz,DMSO-d 6 )δ9.52(s,1H),8.77(s,2H),7.64(d,J＝8.5Hz,2H),7.47(d,J＝2.5Hz,1H),7.34(dd,J＝8.7,2.6Hz,1H),7.12(d,J＝8.5Hz,2H),6.80(d,J＝8.7Hz,1H),3.93(d,J＝5.8Hz,2H),3.06(s,2H),2.95(s,3H),2.90(t,J＝11.0Hz,2H),2.15(t,J＝11.0Hz,2H),1.84-1.68(m,3H),1.49-1.34(m,2H).HRMS(ESI)calcd.for C 22 H 26 F 3 N 3 O 5 S[M+H] + 502.1618,found 502.1618.
example 339
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -2- (4- (4- (trifluoromethylthio) phenoxy) phenyl) acetamide (Compound E-4)
Synthesis of Compound E-4
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate with methyl 4-bromomethylphenylacetate produced compound E-4: 1 H NMR(300MHz,DMSO-d 6 )δ9.52(s,1H),8.77(s,2H),7.64(d,J＝8.5Hz,2H),7.47(d,J＝2.5Hz,1H),7.34(dd,J＝8.7,2.6Hz,1H),7.12(d,J＝8.5Hz,2H),6.80(d,J＝8.7Hz,1H),3.93(d,J＝5.8Hz,2H),3.06(s,2H),2.95(s,3H),2.90(t,J＝11.0Hz,2H),2.15(t,J＝11.0Hz,2H),1.84-1.68(m,3H),1.49-1.34(m,2H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0923.
example 340
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (4- (trifluoromethylthio) phenoxy) phenyl) acetamide (Compound E-5)
Synthesis of intermediate V-11
4-trifluoromethylthiophenol (258 mg,1.33 mmol) and 4-nitrobenzyl bromide (250 mg,1.16 mmol) were added to acetone (6 mL), cesium carbonate (510 mg,1.57 mmol) was added with stirring, and the mixture was reacted at 60℃for 4 hours. After the reaction was completed, water (20 mL) was added for dilution, ethyl acetate (10 mL x 3) was extracted, the organic phases were combined, washed with saturated brine (20 mL x 1), the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate=30:1) to give intermediate V-11 (white solid, 325 mg): 1 H NMR(300MHz,DMSO-d 6 )δ8.27(d,J＝8.8Hz,2H),7.73(d,J＝8.8Hz,2H),7.67(d,J＝8.7Hz,2H),7.19(d,J＝8.9Hz,2H),5.36(s,2H).
synthesis of intermediate V-12
Intermediate V-11 (50 mg,0.15 mmol) was added to N, N-dimethylformamide (1 mL), tetrahydroxydiboron (41 mg,0.46 mmol) and 4,4' -bipyridine (0.2 mg,0.001 mmol) were added sequentially while ice-cooling, and the reaction was allowed to proceed to room temperature for 15 minutes. After the reaction was completed, water (10 mL) was added to the reaction solution for dilution, ethyl acetate (5 mL x 3) was extracted, the organic phases were combined, washed with water (10 mL x 1), washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate V-12, which was slurried (petroleum ether/ethyl acetate=30:1) and purified to obtain intermediate V-12 (pale yellow solid, 34 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.62(d,J＝8.7Hz,2H),7.12(d,J＝5.6Hz,2H),7.09(d,J＝5.1Hz,2H),6.55(d,J＝8.4Hz,2H),5.17(s,2H),4.92(s,2H).
Synthesis of Compound E-5
Intermediate V-9 (100 mg,0.41 mmol) and intermediate V-12 (128 mg,0.43 mmol) were added to anhydrous dichloromethane (5 mL), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (118 mg,0.62 mmol) was added in portions while ice-cooling, and the reaction was allowed to proceed to room temperature for 12 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=100:1), and was purified by beating (dichloromethane/methanol=20:1), and the obtained solid was dried to constant weight to give compound E-5 (white solid, 45 mg): 1 H NMR(400MHz,DMSO-d 6 )δ10.16(s,1H),9.74(s,1H),8.67(s,1H),7.62(t,J＝8.8Hz,4H),7.38(d,J＝8.6Hz,2H),7.19(d,J＝2.2Hz,1H),7.15(d,J＝8.9Hz,2H),7.01(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),5.09(s,2H),3.51(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+Na] + 549.0736,found 549.0729.
example 341
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- ((4- (trifluoromethoxy) phenoxy) methyl) phenyl) acetamide (Compound E-6)
Synthesis of Compound E-6
Referring to the procedure of example 337, substituting 4-trifluoromethoxybenzyl bromide with 4-nitrobenzyl bromide and substituting 4-nitrophenol with 4-trifluoromethoxyphenol, compound E-6 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.67(s,1H),8.90(s,1H),7.60(d,J＝8.6Hz,2H),7.37(d,J＝8.6Hz,2H),7.29(d,J＝9.2Hz,2H),7.18(d,J＝2.2Hz,1H),7.08(d,J＝9.2Hz,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),5.04(s,2H),3.50(s,2H),2.93(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 6 S[M+H] + 511.1151,found 511.1156.
example 342
N- (3-fluoro-4- (4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-7)
Synthesis of intermediate V-13
2-fluoro-4-nitrotoluene (400 mg,2.58 mmol) was added to carbon tetrachloride (8 mL), azobisisobutyronitrile (85 mg,0.52 mmol) and N-bromosuccinimide (480 mg,2.71 mmol) were added sequentially in portions under an ice bath, and the mixture was reacted at 70℃for 4 hours. After the reaction was completed, the system was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give crude intermediate V-13, which was used in the next reaction without further purification.
Synthesis of Compound E-7
Referring to the procedure of example 340, substituting 4-nitrobenzyl bromide for the crude intermediate V-13 gives compound E-7: 1 H NMR(400MHz,DMSO-d 6 )δ10.39(s,1H),9.69(s,1H),8.69(s,1H),7.68-7.63(m,3H),7.48(t,J＝8.4Hz,1H),7.31(dd,J＝8.3,2.0Hz,1H),7.17(dd,J＝9.2,2.4Hz,3H),7.00(dd,J＝8.3,2.2Hz,1H),6.84(d,J＝8.2Hz,1H),5.12(s,2H),3.53(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 4 N 2 O 5 S 2 [M+H] + 545.0823,found 545.0817.
example 343
N- (3-chloro-4- (4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-8)
Synthesis of Compound E-8
Referring to the procedure of example 342, substituting 2-fluoro-4-nitrotoluene for 2-chloro-4-nitrotoluene produced compound E-8: 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),9.76(s,1H),8.68(s,1H),7.90(d,J＝2.0Hz,1H),7.65(d,J＝8.7Hz,2H),7.53(d,J＝8.4Hz,1H),7.48(dd,J＝8.4,2.0Hz,1H),7.19(s,2H),7.17(s,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.84(d,J＝8.2Hz,1H),5.14(s,2H),3.52(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C 23 H 20 ClF 3 N 2 O 5 S 2 [M+H] + 561.0533,found 561.0541.
example 344
N- (3-cyclopropyl-4- (4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-9)
Synthesis of intermediate V-14
Referring to the procedure of example 342, substituting 2-fluoro-4-nitrotoluene for 2-bromo-4-nitrotoluene produced intermediate V-14: 1 H NMR(400MHz,CDCl 3 )δ8.51(d,J＝2.2Hz,1H),8.25(dd,J＝8.6,2.2Hz,1H),7.79(d,J＝8.6Hz,1H),7.65(d,J＝8.7Hz,2H),7.05(d,J＝8.8Hz,2H),5.24(s,2H).
synthesis of intermediate V-15
Intermediate V-14 (264 mg,0.65 mmol), cyclopropylboronic acid (72 mg,0.84 mmol), tricyclohexylphosphine (18 mg,0.07 mmol), potassium phosphate (510 mg,2.28 mmol) and palladium acetate (7 mg,0.03 mmol) were added to a Schlenk tube, and toluene (2 mL) and water (0.1 mL) were added to the system under argon atmosphere to suspend the mixture, and the mixture was reacted at 100℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate V-15 (white solid, 222 mg): 1 H NMR(400MHz,CDCl 3 )δ8.10(dd,J＝8.4,2.3Hz,1H),7.96(d,J＝2.3Hz,1H),7.66(d,J＝6.7Hz,1H),7.64(d,J＝6.9Hz,2H),7.05(d,J＝8.9Hz,2H),5.36(s,2H),2.04-1.97(m,1H),1.15-1.09(m,2H),0.87-0.82(m,2H).
Synthesis of Compound E-9
Referring to the procedure of example 340, substituting intermediate V-11 for intermediate V-15 produced compound E-9: 1 H NMR(400MHz,DMSO-d 6 )δ10.08(s,1H),9.74(s,1H),8.68(s,1H),7.64(d,J＝8.8Hz,2H),7.44(dd,J＝8.3,2.1Hz,1H),7.32(d,J＝8.3Hz,1H),7.25(d,J＝2.1Hz,1H),7.20-7.16(m,3H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.3Hz,1H),5.23(s,2H),3.48(s,2H),2.94(s,3H),2.05-1.98(m,1H),0.94-0.89(m,2H),0.62-0.57(m,2H).HRMS(ESI)calcd.for C 26 H 25 F 3 N 2 O 5 S 2 [M+H] + 567.1235,found 567.1252.
example 345
N- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -2- (4- ((4- ((trifluoromethyl) thio) benzyl) thio) phenyl) acetamide (Compound E-10)
Synthesis of intermediate V-16
The intermediate cuprous iodide (65 mg,0.34 mmol), potassium carbonate (951 mg,6.89 mmol) and elemental sulfur (331 mg,10.34 mmol) were added to a dry Schlenk tube under argon, and a solution of ethyl 4-iodophenylacetate (1 g,3.45 mmol) in N, N-dimethylformamide (8 mL) was added and the addition was completed and the temperature was raised to 90℃for 8 hours. After TLC monitoring the disappearance of starting material, the system was cooled to room temperature and sodium borohydride (393 mg,10.34 mmol) was added in portions under ice bath, after which the reaction was carried out for 2 hours at 40 ℃. After TLC monitoring the disappearance of the starting material, the system was cooled to room temperature, and then a solution of potassium iodide (858 mg,5.17 mmol) and 4-trifluoromethylthio benzyl bromide (1.4 g,5.17 mmol) in N, N-dimethylformamide (5 mL) was added in this order, and the reaction was continued at room temperature for 8 hours after the addition. After the completion of the reaction, water (100 mL) was added to the reaction mixture for dilution, ethyl acetate (20 ml×3) was extracted, the organic phase was washed with water (20 ml×2) and saturated brine (20 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=75:1) to give intermediate V-16 (white solid, 147 mg): 1 H NMR(300MHz,CDCl 3 )δ7.57(d,J＝8.0Hz,2H),7.33(d,J＝8.1Hz,2H),7.26(d,J＝8.3Hz,2H),7.19(d,J＝8.2Hz,2H),4.16(q,2H),4.11(s,2H),3.59(s,2H),1.27(t,J＝3.5Hz,3H).
Synthesis of Compound E-10
Referring to the procedure of example 1, substituting intermediate I-5 for intermediate V-16 produced compound E-10: 1 H NMR(300MHz,DMSO-d 6 )δ9.94(s,1H),9.33(s,2H),7.78(dd,J＝8.8,5.2Hz,2H),7.64(d,J＝8.1Hz,2H),7.51(d,J＝8.2Hz,2H),7.45(d,J＝2.4Hz,1H),7.38-7.27(m,4H),7.26-7.20(m,3H),6.62(d,J＝8.7Hz,1H),4.30(s,2H),3.52(s,2H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 4 S 3 [M+H] + 623.0751,found 623.0756.
example 346
2- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -N- (4- ((4- ((trifluoromethyl) thio) benzyl) thio) phenyl) acetamide (Compound E-11)
Synthesis of intermediate V-17
Referring to the procedure of example 337, replacing methylsulfonic anhydride with 4-fluorobenzenesulfonyl chloride produced intermediate V-17: 1 H NMR(300MHz,DMSO-d 6 )δ12.26(s,1H),9.40(s,2H),7.77(dd,J＝8.7,5.3Hz,2H),7.40-7.28(m,2H),7.07(d,J＝2.1Hz,1H),6.84(dd,J＝8.4,2.2Hz,1H),6.65(d,J＝8.1Hz,1H),3.39(s,2H).
synthesis of Compound E-11
Referring to the procedure of example 340, substituting 4-trifluoromethylthiophenol for 4-nitrophenylthiophenol, substituting 4-nitrobenzyl bromide for 4-trifluoromethylthiobenzyl bromide, substituting intermediate V-9 for intermediate V-17, produced compound E-11: 1 H NMR(300MHz,DMSO-d 6 )δ10.10(s,1H),9.39(s,1H),9.30(s,1H),7.75(dd,J＝8.8,5.3Hz,2H),7.60(d,J＝8.0Hz,2H),7.51(d,J＝8.6Hz,2H),7.41(d,J＝8.2Hz,2H),7.30-7.19(m,4H),7.15(d,J＝1.8Hz,1H),6.88(dd,J＝8.2,1.8Hz,1H),6.65(d,J＝8.2Hz,1H),4.21(s,2H),3.42(s,2H).HRMS(ESI)calcd.for C 28 H 22 F 4 N 2 O 4 S 3 [M+H] + 623.0751,found 623.0751.
example 347
2- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -N- (4- ((4- ((trifluoromethyl) thio) benzyl) thio) phenyl) acetamide (Compound E-12)
Synthesis of Compound E-12
Referring to the procedure of example 340, substituting 4-trifluoromethylthiophenol for 4-nitrophenylthiophenol and substituting 4-nitrobenzyl bromide for 4-trifluoromethoxybenzyl bromide, compound E-12 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),9.78(s,1H),8.71(s,1H),7.53(d,J＝8.7Hz,2H),7.39(d,J＝8.7Hz,2H),7.28(d,J＝1.6Hz,2H),7.26(s,2H),7.18(d,J＝2.1Hz,1H),7.00(dd,J＝8.3,2.1Hz,1H),6.83(d,J＝8.2Hz,1H),4.19(s,2H),3.49(s,2H),2.94(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0938.
example 348
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (((4- (trifluoromethoxy) phenyl) thio) methyl) phenyl) acetamide (Compound E-13)
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Synthesis of Compound E-13
Referring to the procedure of example 337, substituting 4-nitrophenol with 4-trifluoromethoxybenzene thiol and substituting 4-trifluoromethoxybenzyl bromide with 4-nitrobenzyl bromide gave compound E-13: 1 H NMR(400MHz,DMSO-d 6 )δ10.12(s,1H),9.78(s,1H),8.71(s,1H),7.51(d,J＝8.5Hz,2H),7.42(d,J＝8.8Hz,2H),7.29(d,J＝6.0Hz,2H),7.27(d,J＝6.3Hz,2H),7.17(d,J＝2.1Hz,1H),6.99(dd,J＝8.3,2.2Hz,1H),6.82(d,J＝8.3Hz,1H),4.21(s,2H),3.48(s,2H),2.93(s,3H).HRMS(ESI)calcd.for C 23 H 21 F 3 N 2 O 5 S 2 [M+H] + 527.0917,found 527.0924.
example 349
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (4- (trifluoromethoxy) phenylethoxy) phenyl) acetamide (Compound E-14)
Synthesis of intermediate V-18
Intermediate III-12 (200 mg,0.97 mmol), 4-nitrophenol (301 mg,1.94 mmol) and triphenylphosphine (534 mg,2.0 mmol) were added to a dry three-necked flask, protected by argon, dissolved in anhydrous tetrahydrofuran (3 mL), added with a solution of diisopropyl azodicarboxylate (351. Mu.L, 2.0 mmol) in anhydrous tetrahydrofuran (2 mL) under ice bath, and the mixture was allowed to react at room temperature for 12 hours after dropping. After the completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate V-18 (white solid, 260 mg): 1 H NMR(300MHz,Chloroform-d)δ8.18(d,J＝9.3Hz,2H),7.30(d,J＝8.6Hz,2H),7.17(d,J＝7.7Hz,2H),6.93(d,J＝9.3Hz,2H),4.23(t,J＝6.7Hz,2H),3.13(t,J＝6.7Hz,2H).
synthesis of Compound E-14
Referring to the procedure of example 337, substituting intermediate V-4 for intermediate V-18 and substituting 4-trifluoromethoxybenzyl bromide for 4-nitrobenzyl bromide, compound E-14 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ9.96(s,1H),9.75(s,1H),8.70(s,1H),7.47(d,J＝7.0Hz,2H),7.44(d,J＝6.6Hz,2H),7.30(d,J＝7.8Hz,2H),7.17(d,J＝2.2Hz,1H),6.99(dd,J＝8.3,2.2Hz,1H),6.86(d,J＝9.0Hz,2H),6.82(d,J＝8.2Hz,1H),4.14(t,J＝6.7Hz,2H),3.45(s,2H),3.04(t,J＝6.7Hz,2H),2.93(s,3H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 6 S[M+H] + 525.1307,found 525.1312.
Example 350
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (2- (4- (trifluoromethoxy) phenoxy) ethyl) phenyl) acetamide (Compound E-15)
Synthesis of Compound E-15
Referring to the procedure of example 349, intermediate III-12 was replaced with 4-nitrophenyl alcohol, 4-nitrophenol was replaced with 4-trifluoromethoxyphenol,to obtain the compound E-15: 1 H NMR(400MHz,DMSO-d 6 )δ10.08(s,1H),9.78(s,1H),8.70(s,1H),7.51(d,J＝8.3Hz,2H),7.27(d,J＝8.9Hz,2H),7.24(d,J＝8.2Hz,2H),7.17(d,J＝2.1Hz,1H),7.01(d,J＝9.0Hz,2H),6.99(d,J＝2.3Hz,1H),6.82(d,J＝8.2Hz,1H),4.15(t,J＝6.9Hz,2H),3.48(s,2H),2.97(t,J＝6.8Hz,2H),2.93(s,3H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 6 S[M+H] + 525.1302,found 525.1317.
example 351
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -2- (4- ((4- (trifluoromethoxy) phenethyl) thio) phenyl) acetamide (Compound E-16)
Synthesis of intermediate V-19
4-mercaptophenylacetic acid (200 mg,1.19 mmol) was added to absolute ethanol (4 mL), concentrated sulfuric acid (357. Mu.L, 0.3. 0.3 eqv.) was slowly added dropwise under ice bath, and the mixture was allowed to react at 60℃for 3 hours. After the reaction was completed, the system was cooled to room temperature, ice water (20 mL) was added dropwise to the reaction solution for dilution, ethyl acetate (10 mL x 3) was used for extraction, the organic phases were combined, washed with saturated brine (10 mL x 1), dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain crude intermediate V-19, which was used for the next reaction without further purification.
Synthesis of intermediate V-20
The crude intermediate V-19 (228 mg,1.16 mmol) was added to acetonitrile (4 mL), potassium carbonate (321 mg,2.32 mmol) was added in portions, the mixture was allowed to react at 70℃for 30 minutes, intermediate III-13 (502 mg,1.39 mmol) was added, and the reaction was continued at 70℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, water (20 mL) was added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=50:1) to give intermediate V-20 (colorless oily liquid, 372 mg): 1 H NMR(300MHz,DMSO-d 6 )δ7.28(dd,J＝19.1,8.6Hz,4H),7.10(d,J＝8.4Hz,2H),6.52(d,J＝8.5Hz,2H),5.24(s,2H),2.96(t,J＝7.4Hz,2H),2.76(t,J＝7.4Hz,2H).
Synthesis of Compound E-16
Referring to the procedure of example 1, substituting intermediate I-5 for intermediate V-20 produced compound E-16: 1 H NMR(300MHz,DMSO-d 6 )δ9.90(s,1H),9.54(s,1H),8.73(s,1H),7.47-7.38(m,3H),7.35-7.25(m,3H),7.21(d,J＝8.4Hz,2H),6.87(d,J＝8.4Hz,2H),6.78(d,J＝8.7Hz,1H),4.16(t,J＝6.7Hz,2H),3.47(s,2H),3.05(t,J＝6.7Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 5 S 2 [M+H] + 541.1073,found 541.1038.
example 352
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- ((4- (trifluoromethoxy) phenethyl) thio) phenyl) acetamide (Compound E-17)
Synthesis of Compound E-17
Referring to the procedure of example 340, substituting 4-trifluoromethylthiophenol for 4-nitrobenzylthiophenol and substituting 4-nitrobenzyl bromide for intermediate III-13, compound E-17 is prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.14(s,1H),9.75(s,1H),8.67(s,1H),7.57(d,J＝8.6Hz,2H),7.32(dt,J＝13.4,8.4Hz,6H),7.19(d,J＝1.9Hz,1H),7.01(dd,J＝8.2,1.9Hz,1H),6.84(d,J＝8.2Hz,1H),3.50(s,2H),3.17(t,J＝7.5Hz,2H),2.94(s,3H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 5 S 2 [M+H] + 541.1073,found 541.1070.
example 353
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (4- (trifluoromethyl) thio) phenyl) phenylacetamide (Compound E-18)
Synthesis of Compound E-18
Referring to the procedure of example 340, substituting 4-trifluoromethylthiophenol for 4-nitrobenzylthiophenol and substituting 4-nitrobenzyl bromide for intermediate III-50, compound E-18 is prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.78(s,1H),8.69(s,1H),7.63(d,J＝8.2Hz,2H),7.57(d,J＝8.7Hz,2H),7.40(d,J＝8.2Hz,2H),7.31(d,J＝8.7Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.19(t,J＝7.5Hz,2H),2.94(s,3H),2.88(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 4 S 3 [M+H] + 557.0850,found 557.0856.
example 354
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (4- (trifluoromethyl) phenethyl) thio) acetamide (Compound E-19)
Synthesis of Compound E-19
Referring to the procedure of example 349, substituting 4-trifluoromethylphenol for intermediate III-12 and 4-nitrophenol for 4-nitrophenol produced compound E-19: 1 H NMR(300MHz,DMSO)δ10.16(s,1H),9.77(s,1H),8.71(s,1H),7.64(d,J＝8.0Hz,2H),7.57(d,J＝8.7Hz,2H),7.46(d,J＝8.0Hz,2H),7.32(d,J＝8.7Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.20(t,J＝7.4Hz,2H),2.94(s,3H),2.89(d,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 4 S 2 [M+H] + 525.1124,found 525.1125.
example 355
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (4-methylphenylsulfanyl) phenyl) acetamide (Compound E-20)
Synthesis of Compound E-20
Referring to the procedure of example 349, substituting 4-methylphenylethanol for intermediate III-12 and 4-nitrophenol for 4-nitrophenylthiophenol produced compound E-20: 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.75(s,1H),8.67(s,1H),7.56(d,J＝8.8Hz,2H),7.33-7.28(m,2H),7.18(d,J＝2.2Hz,1H),7.12-7.09(m,2H),7.09-7.06(m,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.11(t,2H),2.94(s,3H),2.76(t,2H),2.25(s,3H).HRMS(ESI)calcd.for C 24 H 26 N 2 O 4 S 2 [M+H] + 471.1407,found 471.1411.ESI-MS:m/z 471.1411[M+H] + .
example 356
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (4-methoxyphenylethylthio) phenyl) acetamide (Compound E-21)
Synthesis of Compound E-21
Referring to the procedure of example 349, substituting 4-methoxyphenylethanol for intermediate III-12 and 4-nitrophenol for 4-nitrophenylthiophenol produced compound E-21: 1 H NMR(400MHz,DMSO-d 6 )δ10.13(s,1H),9.74(s,1H),8.67(s,1H),7.56(d,J＝8.7Hz,2H),7.30(d,J＝8.7Hz,2H),7.18(d,J＝2.2Hz,1H),7.13(d,J＝8.6Hz,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(dd,J＝8.5,2.2Hz,3H),3.71(s,3H),3.49(s,2H),3.10(t,J＝7.6Hz,2H),2.94(s,3H),2.75(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 24 H 26 N 2 O 5 S 2 [M+H] + 487.1356,found 487.1365.
example 357
N- (4- (4-fluorophenylethyl) thiophenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-22)
Synthesis of Compound E-22
Referring to the procedure of example 349, substituting 4-fluorophenylethanol for intermediate III-12 and 4-nitrophenol for 4-nitrophenylthiophenol produced compound E-22: 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.74(s,1H),8.67(s,1H),7.56(d,J＝8.7Hz,2H),7.31(d,J＝8.7Hz,2H),7.26(dd,J＝8.5,5.7Hz,2H),7.18(d,J＝2.2Hz,1H),7.09(t,J＝8.9Hz,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.14(t,J＝7.6Hz,2H),2.94(s,3H),2.80(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 23 H 23 FN 2 O 4 S 2 [M+H] + 475.1156,found 475.1165.
example 358
N- (4- (4-Chloroethyl) thiophenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-23)
Synthesis of Compound E-23
Referring to the procedure of example 349, substituting 4-chlorophenyl ethanol for intermediate III-12 and 4-nitrophenol for 4-nitrophenol gave compound E-23: 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.75(s,1H),8.67(s,1H),7.57(d,J＝8.7Hz,2H),7.32(t,J＝8.9Hz,4H),7.25(d,J＝8.4Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.14(t,J＝7.5Hz,2H),2.94(s,3H),2.81(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 23 H 23 ClN 2 O 4 S 2 [M+H] + 491.0861,found 491.0858.
Example 359
N- (4- ((4-bromophenylethyl) thio) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-24)
Synthesis of Compound E-24
Referring to the procedure of example 349, substituting 4-bromophenyl ethanol for intermediate III-12 and 4-nitrophenol for 4-nitrophenol produced compound E-24: 1 H NMR(400MHz,DMSO-d 6 )δ10.16(s,1H),9.77(s,1H),8.70(s,1H),7.57(d,J＝8.7Hz,2H),7.46(d,J＝8.4Hz,2H),7.31(d,J＝8.7Hz,2H),7.19(d,J＝8.3Hz,2H),7.18(d,J＝2.3Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.14(t,J＝7.5Hz,2H),2.94(s,3H),2.78(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 23 H 23 BrN 2 O 4 S 2 [M+H] + 535.0361,found 535.0366.
example 360
N- (4- (4-cyclopropylphenylthio) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-25)
Synthesis of intermediate V-21
Referring to the procedure of example 349, substituting intermediate III-12 with 4-bromophenyl ethanol and substituting 4-nitrophenol with 4-nitrophenol produced intermediate V-21: 1 H NMR(300MHz,Chloroform-d)δ8.13(d,J＝8.9Hz,2H),7.44(d,J＝8.4Hz,2H),7.32(d,J＝9.0Hz,2H),7.10(d,J＝8.4Hz,2H),3.25(t,J＝7.6Hz,2H),2.96(t,J＝7.6Hz,2H).
synthesis of intermediate V-22
Intermediate V-21 (270 mg,0.80 mmol), cyclopropylboronic acid (89 mg,1.04 mmol), tricyclohexylphosphine (22 mg,0.08 mmol), potassium phosphate (6278 mg,2.8 mmol) and palladium acetate (9 mg,0.04 mmol) were added to a Schlenk tube, and toluene (2 mL) and water (0.1 mL) were added to the system under argon atmosphere to suspend the mixture, and the mixture was reacted at 100℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=100:1) to give intermediate V-22 (white solid, 160 mg).
Synthesis of Compound E-25
Referring to the procedure of example 337, substituting intermediate V-4 for intermediate V-22 produced compound E-25: 1 HNMR(300MHz,DMSO-d 6 )δ10.16(s,1H),9.20(s,2H),7.56(d,J＝8.7Hz,2H),7.30(d,J＝8.7Hz,2H),7.18(d,J＝2.2Hz,1H),7.08(d,J＝8.1Hz,2H),7.02-6.95(m,3H),6.83(d,J＝8.3Hz,1H),3.49(s,2H),3.10(t,J＝7.6Hz,2H),2.94(s,3H),2.75(t,2H),1.90-1.81(m,1H),0.94-0.86(m,2H),0.64-0.56(m,2H).HRMS(ESI)calcd.for C 26 H 28 N 2 O 4 S 2 [M+H] + 497.1563,found 497.1571.
example 361
N- (3-fluoro-4- (4- (trifluoromethoxyphenyl ethyl) thio) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-26)
Synthesis of intermediate V-23
Thionyl chloride (464. Mu.L, 6.4 mmol) was added dropwise to water (3 mL) in an ice bath, reacted at 0℃for 3 hours, and cuprous chloride (3 mg,0.03 mmol) was added thereto, and stirring was continued at 0℃for 1 hour. Simultaneously, 2-fluoro-4-nitroaniline (200 mg,1.28 mmol) was added to concentrated hydrochloric acid (1.8 mL), sodium nitrite (133 mg,1.92 mmol) was added in portions under the ice salt bath, and stirring was continued under the ice salt bath for 1 hour. Then the reaction solution is added into the prepared sulfur dioxide water solution drop by drop, and the reaction is continued for 2 hours under the ice salt bath. After the reaction was completed, ice water (10 mL) was added dropwise to the reaction solution for dilution, ethyl acetate (5 mL x 3) was extracted, the organic phases were combined, saturated brine (10 mL x 1) was washed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give crude intermediate V-23 which was used in the next reaction without further purification.
Synthesis of intermediate V-24
The crude intermediate V-23 is added into a dry three-necked bottle, protected by argon, added with toluene (2 mL) for dissolution, added dropwise with toluene (5 mL) solution of triphenylphosphine (1.68 g,6.4 mmol) in ice bath, and cooled to room temperature for reaction for 1 hour. After TLC monitoring the disappearance of starting material, water (1.5 mL) was added to the reaction solution, and the reaction was continued at room temperature for 2 hours. After the reaction, the reaction solution was directly subjected to the next reaction without further treatment.
Synthesis of intermediate V-25
Intermediate III-13 (343 mg,1.28 mmol), potassium carbonate (238 mg,1.73 mmol), potassium iodide (21 mg,0.13 mmol) and N, N-dimethylformamide (4 mL) were directly added to the reaction mixture, and the mixture was reacted at 80℃for 8 hours. After the reaction was completed, the system was cooled to room temperature, water (40 mL) was added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate V-25 (pale yellow solid, 184 mg): 1 H NMR(300MHz,CDCl 3 )δ7.98(ddd,J＝8.7,2.3,0.8Hz,1H),7.90(dd,J＝9.6,2.3Hz,1H),7.34(dd,J＝8.6,7.3Hz,1H),7.24(d,J＝8.6Hz,2H),7.16(d,J＝8.1Hz,2H),3.27(t,J＝7.5Hz,2H),3.01(t,J＝7.6Hz,2H).
synthesis of Compound E-26
Referring to the procedure of example 337, substituting intermediate V-4 for intermediate V-25 produced compound E-26: 1 H NMR(400MHz,DMSO-d 6 )δ10.36(s,1H),9.74(s,1H),8.68(s,1H),7.63(dd,J＝12.2,2.2Hz,1H),7.43(t,J＝8.5Hz,1H),7.35(d,J＝8.7Hz,2H),7.30(dd,J＝8.6,2.2Hz,1H),7.26(d,J＝7.6Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.3Hz,1H),3.51(s,2H),3.15(t,J＝7.5Hz,2H),2.94(s,3H),2.84(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 24 H 22 F 4 N 2 O 5 S 2 [M+H] + 559.0979,found 559.0984.
example 362
N- (3-chloro-4- (4- (trifluoromethoxyphenyl ethyl) thio) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-27)
Synthesis of Compound E-27
Referring to the procedure of example 361, substituting 2-fluoro-4-nitroaniline with 2-chloro-4-nitroaniline produced compound E-27: 1 H NMR(300MHz,DMSO-d 6 )δ10.30(s,1H),9.76(s,1H),8.72(s,1H),7.86(d,J＝2.1Hz,1H),7.47(dd,J＝8.6,2.1Hz,1H),7.44-7.39(m,2H),7.39(s,1H),7.28(d,J＝8.4Hz,2H),7.17(d,J＝2.2Hz,1H),6.99(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.50(s,2H),3.23(t,J＝7.6Hz,2H),2.93(s,3H),2.90(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 24 H 22 ClF 3 N 2 O 5 S 2 [M+H] + 575.0684,found 575.0690.
example 363
N- (2-fluoro-4- (4- (trifluoromethoxyphenyl ethyl) thio) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-28)
Synthesis of Compound E-28
Referring to the procedure of example 361, substituting 2-fluoro-4-nitroaniline with 3-fluoro-4-nitroaniline produced compound E-28: 1 H NMR(300MHz,DMSO-d 6 )δ9.89(s,1H),9.77(s,1H),8.70(s,1H),7.82(t,J＝8.5Hz,1H),7.38(dd,J＝6.5,2.2Hz,2H),7.31-7.25(m,3H),7.19(d,J＝2.1Hz,1H),7.12(dd,J＝8.4,2.1Hz,1H),7.00(dd,J＝8.3,1.9Hz,1H),6.83(d,J＝8.3Hz,1H),3.58(s,2H),3.25(t,J＝7.5Hz,2H),2.94(s,3H),2.88(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 24 H 22 F 4 N 2 O 5 S 2 [M+H] + 559.0979,found 559.0972.
example 364
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (3-methyl-4- ((4- (trifluoromethoxy) phenylethyl) thio) phenyl) acetamide (Compound E-29)
Synthesis of Compound E-29
Referring to the procedure of example 361, substituting 2-fluoro-4-nitroaniline with 2-methyl-4-nitroaniline produced compound E-29: 1 H NMR(400MHz,DMSO-d 6 )δ10.07(s,1H),9.76(s,1H),8.70(s,1H),7.47(d,J＝2.3Hz,1H),7.44(dd,J＝8.5,2.4Hz,1H),7.36(d,J＝8.7Hz,2H),7.30(d,J＝8.5Hz,1H),7.27(d,J＝8.2Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.3Hz,1H),3.48(s,2H),3.14(t,J＝7.6Hz,2H),2.93(s,3H),2.85(t,J＝7.6Hz,2H),2.24(s,3H).HRMS(ESI)calcd.for C 25 H 25 F 3 N 2 O 5 S 2 [M+H] + 555.1230,found 555.1248.
example 365
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (3-methoxy-4- ((4- (trifluoromethoxy) phenylethyl) thio) phenyl) acetamide (Compound E-30)
Synthesis of Compound E-30
Referring to the procedure of example 361, substituting 2-fluoro-4-nitroaniline with 2-methoxy-4-nitroaniline produced compound E-30: 1 H NMR(300MHz,DMSO-d 6 )δ10.17(s,1H),9.77(s,1H),8.71(s,1H),7.38(d,J＝1.9Hz,1H),7.36(d,J＝8.6Hz,2H),7.27(d,J＝8.3Hz,2H),7.22(d,J＝8.4Hz,1H),7.18(d,J＝2.2Hz,1H),7.15(dd,J＝8.4,1.9Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.76(s,3H),3.49(s,2H),3.08(t,J＝7.5Hz,2H),2.94(s,3H),2.82(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 25 H 25 F 3 N 2 O 6 S 2 [M+H] + 571.1179,found571.1187.
Example 366
N- (3-cyclopropyl-4- (4- (trifluoromethoxyphenyl ethyl) thio) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-31)
Synthesis of intermediate V-26
Referring to the procedure of example 361, substituting 2-fluoro-4-nitroaniline for 2-bromo-4-nitroaniline produced intermediate V-26: 1 H NMR(300MHz,Chloroform-d)δ8.38(d,J＝2.4Hz,1H),8.10(dd,J＝8.8,2.4Hz,1H),7.25(dd,2H),7.20(d,J＝8.8Hz,1H),7.16(d,J＝7.7Hz,2H),3.24(t,J＝7.4Hz,2H),3.04(t,2H).
synthesis of intermediate V-27
Intermediate V-26 (178 mg,1.22 mmol), cyclopropylboronic acid (136 mg,1.59 mmol), tricyclohexylphosphine (34 mg,0.12 mmol), potassium phosphate (957 mg,4.27 mmol) and palladium acetate (14 mg,0.06 mmol) were added to a Schlenk tube, and toluene (4 mL) and water (0.2 mL) were added to the system under argon atmosphere to suspend the mixture, and the mixture was reacted at 100℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, the reaction solution was filtered, the filter cake was rinsed with ethyl acetate (5 mL), the solvent was distilled off from the filtrate under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give intermediate V-27 (white solid, 338 mg): 1 H NMR(400MHz,Chloroform-d)δ8.01(dd,J＝8.7,2.6Hz,1H),7.73(d,J＝2.6Hz,1H),7.54(d,J＝8.8Hz,1H),7.46(d,J＝8.6Hz,2H),7.30(d,J＝8.1Hz,2H),3.42(t,J＝7.6Hz,2H),3.03(t,J＝7.6Hz,2H),1.96-1.88(m,1H),1.05-0.97(m,2H),0.76-0.68(m,2H).
synthesis of intermediate V-28
Intermediate V-27 (315 mg,0.87 mmol) and ammonium chloride (418 mg,7.83 mmol) were added to a mixture of ethanol (8 mL) and water (2 mL), and reduced iron powder (244 mg,4.36 mmol) was added in portions with stirring and reacted at 80℃for 6 hours. After the reaction was completed, the system was cooled to room temperature, water (30 mL) was added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, the organic phases were combined, washed with saturated brine (10 ml×2), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate V-28 (yellow solid, 252 mg): 1 H NMR(400MHz,DMSO-d 6 )δ7.32(d,J＝8.7Hz,2H),7.25(dd,J＝8.9,1.1Hz,2H),7.12(d,J＝8.2Hz,1H),6.34(dd,J＝8.3,2.4Hz,1H),6.08(d,J＝2.5Hz,1H),5.13(s,2H),2.95(t,J＝7.4Hz,2H),2.78(t,J＝7.5Hz,2H),2.36-2.29(m,1H),0.94-0.85(m,2H),0.54(dt,J＝6.3,3.1Hz,2H).
Synthesis of Compound E-31
Referring to the procedure of example 337, substituting intermediate V-5 for intermediate V-28 produced compound E-31: 1 H NMR(400MHz,DMSO-d 6 )δ10.08(s,1H),9.74(s,1H),8.68(s,1H),7.64(d,J＝8.8Hz,2H),7.44(dd,J＝8.3,2.1Hz,1H),7.32(d,J＝8.3Hz,1H),7.25(d,J＝2.1Hz,1H),7.20-7.16(m,3H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.3Hz,1H),5.23(s,2H),3.48(s,2H),2.94(s,3H),2.05-1.98(m,1H),0.94-0.89(m,2H),0.62-0.57(m,2H).HRMS(ESI)calcd.for C 27 H 27 F 3 N 2 O 5 S 2 [M+H] + 581.1386,found 581.1395.
example 367
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- ((4- (trifluoromethoxy) phenethyl) thio) -3- (trifluoromethyl) phenyl) acetamide (Compound E-32)
Synthesis of Compound E-32
Referring to the procedure of example 361, substituting 2-fluoro-4-nitroaniline with 2-trifluoromethyl-4-nitroaniline produced compound E-32: 1 H NMR(400MHz,DMSO-d 6 )δ10.45(s,1H),9.79(s,1H),8.71(s,1H),8.07(d,J＝2.4Hz,1H),7.80(dd,J＝8.7,2.3Hz,1H),7.66(d,J＝8.7Hz,1H),7.37(d,J＝8.7Hz,2H),7.27(d,J＝7.4Hz,2H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.52(s,2H),3.27(t,J＝7.7Hz,2H),2.94(s,3H),2.87(t,J＝7.7Hz,2H).HRMS(ESI)calcd.for C 25 H 22 F 6 N 2 O 5 S 2 [M+H] + 609.0947,found 609.1044.
example 368
N- (3-cyano-4- ((4- (trifluoromethoxy) phenethyl) thio) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-33)
Synthesis of intermediate V-29
Referring to the procedure of example 361, substituting 2-fluoro-4-nitroaniline with 2-iodo-4-nitroaniline produced intermediate V-29: 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J＝2.4Hz,1H),8.15(dd,J＝8.8,2.4Hz,1H),7.26(d,J＝8.6Hz,2H),7.16(t,J＝8.3Hz,3H),3.23(t,J＝7.7Hz,2H),3.05(t,J＝7.7Hz,2H).
synthesis of intermediate V-30
Intermediate V-29 (128 mg,0.27 mmol) and cuprous cyanide (73 mg,0.82 mmol) were added to N, N-dimethylformamide (2 mL) and reacted at 100℃for 12 hours. After the reaction was completed, the system was cooled to room temperature, water (20 mL) was added to the reaction solution to dilute, ethyl acetate (10 ml×3) was extracted, and the organic phases were combined, washed with water (15 ml×1) and saturated brine (15 ml×1) in this order, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate V-30 (white solid, 74 mg): 1 H NMR(400MHz,Chloroform-d)δ8.43(d,J＝2.5Hz,1H),8.29(dd,J＝8.9,2.5Hz,1H),7.37(d,J＝8.9Hz,1H),7.27(d,J＝1.9Hz,2H),7.17(d,J＝7.6Hz,2H),3.36(t,J＝7.6Hz,2H),3.07(t,J＝7.6Hz,2H).
Synthesis of Compound E-33
Referring to the procedure of example 337, substituting intermediate V-4 for intermediate V-30 produced compound E-33: 1 H NMR(300MHz,DMSO-d 6 )δ10.47(s,1H),9.80(s,1H),8.72(s,1H),8.07(d,J＝2.3Hz,1H),7.75(dd,J＝8.8,2.4Hz,1H),7.61(d,J＝8.8Hz,1H),7.39(d,J＝8.6Hz,2H),7.27(d,J＝7.7Hz,2H),7.17(d,J＝2.1Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.34(s,2H),3.34-3.29(m,2H),2.94(s,3H),2.90(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 25 H 22 F 3 N 3 O 5 S 2 [M+H] + 566.1026,found 566.1027.
example 369
N- (3-cyclopropyl-4- (4- (trifluoromethoxyphenyl ethyl) thio) phenyl) -2- (4-hydroxy-3- (methylsulfonyl) phenyl) acetamide (Compound E-34)
Synthesis of Compound E-34
Referring to the procedure of example 361, intermediate V-24 was replaced with intermediate 2-mercapto-5-nitropyridine to produce compound E-34: 1 H NMR(400MHz,DMSO-d 6 )δ10.27(s,1H),9.76(s,1H),8.68(s,1H),8.66(d,J＝1.9Hz,1H),7.88(dd,J＝8.7,2.6Hz,1H),7.39(d,J＝8.6Hz,2H),7.28(d,J＝8.8Hz,2H),7.24(d,J＝9.1Hz,1H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.84(d,J＝8.3Hz,1H),3.52(s,2H),3.36(t,J＝7.6Hz,2H),2.94(t,J＝7.5Hz,2H),2.94(s,3H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 5 S 2 [M+H] + 542.1026,found 542.1007.
example 370
2- (4-hydroxy-3- ((1-methylethyl) sulphonamido) phenyl) -N- (4- ((4- (trifluoromethoxy) phenylethyl) thio) phenyl) acetamide (Compound E-35)
Synthesis of Compound E-35
Referring to the procedure of example 337, substituting 4-trifluoromethoxybenzyl bromide for intermediate III-13, substituting 4-nitrophenol for 4-nitrophenylsulfol, and substituting methylsulfonic anhydride for isopropylsulfonyl chloride gave compound E-35: 1 H NMR(400MHz,DMSO-d 6 )δ10.15(s,1H),9.77(s,1H),8.60(s,1H),7.56(d,J＝8.7Hz,2H),7.36(d,J＝8.6Hz,2H),7.31(d,J＝8.7Hz,2H),7.27(d,J＝8.0Hz,2H),7.23(d,J＝2.2Hz,1H),6.96(dd,J＝8.3,2.2Hz,1H),6.79(d,J＝8.2Hz,1H),3.48(s,2H),3.17(t,J＝7.6Hz,2H),3.15-3.10(m,1H),2.84(t,J＝7.5Hz,2H),1.25(d,J＝6.8Hz,6H).HRMS(ESI)calcd.for C 26 H 27 F 3 N 2 O 5 S 2 [M+H] + 569.1386,found 569.1404.
example 371
2- (3- (cyclopropanesulphonylamino) -4-hydroxyphenyl) -N- (4- ((4- (trifluoromethoxy) phenylethyl) thio) phenyl) acetamide (Compound E-36)
Synthesis of Compound E-36
Referring to the procedure of example 337, substituting 4-trifluoromethoxybenzyl bromide for intermediate III-13, substituting 4-nitrophenol for 4-nitrophenylsulfol, and substituting methylsulfonic anhydride for cyclopropylsulfonyl chloride gave compound E-36: 1 H NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),9.66(s,1H),8.62(s,1H),7.57(d,J＝8.7Hz,2H),7.36(d,J＝8.6Hz,2H),7.31(d,J＝8.7Hz,2H),7.27(d,J＝8.3Hz,2H),7.23(d,J＝2.1Hz,1H),6.97(dd,J＝8.3,2.2Hz,1H),6.81(d,J＝8.2Hz,1H),3.49(s,2H),3.17(t,J＝7.4Hz,2H),2.84(t,J＝7.5Hz,2H),2.57(p,J＝6.4Hz,1H),0.86(d,J＝6.4Hz,4H).HRMS(ESI)calcd.for C 26 H 25 F 3 N 2 O 5 S 2 [M+H] + 567.1230,found 567.1235.
Example 372
2- (4-hydroxy-3- (thiophene-2-sulfonylamino) phenyl) -N- (4- ((4- (trifluoromethoxy) phenylethyl) thio) phenyl) acetamide (Compound E-37)
Synthesis of Compound E-37
Referring to the procedure of example 337, substituting 4-trifluoromethoxybenzyl bromide for intermediate III-13, substituting 4-nitrophenol for 4-nitrophenylsulfol, and substituting methylsulfonic anhydride for 2-thiophenesulfonyl chloride gave compound E-37: 1 H NMR(300MHz,DMSO-d 6 )δ10.15(s,1H),9.54(s,1H),9.38(s,1H),7.81(dd,J＝5.0,1.4Hz,1H),7.57(d,J＝8.7Hz,2H),7.46(dd,J＝3.8,1.4Hz,1H),7.36(d,J＝8.6Hz,2H),7.33(d,J＝8.7Hz,2H),7.27(d,J＝8.3Hz,2H),7.21(d,J＝2.2Hz,1H),7.01(dd,J＝5.0,3.7Hz,1H),6.94(dd,J＝8.2,2.2Hz,1H),6.70(d,J＝8.2Hz,1H),3.46(s,2H),3.17(t,J＝7.5Hz,2H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 27 H 23 F 3 N 2 O 5 S 3 [M+H] + 609.0794,found 609.0816.
example 373
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (2- (4- (trifluoromethoxy) phenyl) thio) ethyl) phenyl) acetamide (Compound E-38)
Synthesis of intermediate V-31
4-Nitrophenyl alcohol (893 mg,5.35 mmol) and 4-dimethylaminopyridine (65 mg,0.54 mmol) were added to dichloromethane (20 mL), triethylamine (1.5 mL,10.7 mmol) was added, p-toluenesulfonyl chloride (1.53 g,8.02 mmol) was added in portions under ice bath, and the mixture was allowed to react at room temperature for 8 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate V-31 (pale yellow solid, 1.28 g): 1 H NMR(400MHz,CDCl 3 )δ8.11(d,J＝8.7Hz,2H),7.68(d,J＝8.3Hz,2H),7.30(s,2H),7.28(s,2H),4.30(t,J＝6.4Hz,2H),3.08(t,J＝6.4Hz,2H),2.42(s,3H).
synthesis of Compound E-38
Referring to the procedure of example 337, substituting 4-trifluoromethoxybenzyl bromide for intermediate V-31 and substituting 4-nitrophenol for 4-trifluoromethoxybenzene thiophenol, compound E-38 was prepared: 1 H NMR(300MHz,DMSO-d 6 )δ10.06(s,1H),9.76(s,1H),8.70(s,1H),7.50(d,J＝8.5Hz,2H),7.45(d,J＝8.9Hz,1H),7.32(d,J＝8.9Hz,2H),7.20-7.15(m,3H),7.00(dd,J＝8.2,2.1Hz,1H),6.83(d,J＝8.2Hz,1H),3.48(s,2H),3.22(t,2H),2.93(s,3H),2.81(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 5 S 2 [M+H] + 541.1079,found 541.1085.
Example 374
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (2- (4- (trifluoromethyl) thio) phenyl) thio-ethyl) phenyl) acetamide (Compound E-39)
Synthesis of Compound E-39
Referring to the procedure of example 361, substituting 2-fluoro-4-nitroaniline with 4-trifluoromethylthioaniline and substituting intermediate III-13 with intermediate V-31 gave compound E-39: 1 H NMR(300MHz,DMSO-d 6 )δ10.07(s,1H),9.73(s,1H),8.66(s,1H),7.62(d,J＝8.4Hz,2H),7.51(d,J＝8.5Hz,2H),7.44(d,J＝8.5Hz,2H),7.21(s,1H),7.18(d,J＝2.7Hz,2H),7.00(dd,J＝8.2,2.1Hz,1H),6.83(d,J＝8.2Hz,1H),3.48(s,2H),3.28(t,J＝7.6Hz,2H),2.93(s,3H),2.85(t,J＝7.5Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 4 S 3 [M+H] + 557.0845,found 557.0870.
example 375
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (2- (4- (trifluoromethyl) phenyl) thio) ethyl) phenyl) acetamide (Compound E-40)
Synthesis of Compound E-40
Referring to the procedure of example 337, substituting 4-trifluoromethoxybenzyl bromide for intermediate V-31 and substituting 4-nitrophenol for 4-trifluoromethylphenol, compound E-40 was prepared: 1 H NMR(400MHz,DMSO-d 6 )δ10.05(s,1H),9.73(s,1H),8.63(s,1H),7.64(d,J＝8.3Hz,2H),7.50(dd,J＝8.4,1.9Hz,4H),7.21-7.17(m,3H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),3.29(t,J＝7.6Hz,2H),2.94(s,3H),2.85(t,J＝7.6Hz,2H).HRMS(ESI)calcd.for C 24 H 23 F 3 N 2 O 4 S 2 [M+H] + 525.1124,found 525.1131.
example 376
N- (3-fluoro-4- (2- ((4- (trifluoromethoxy) phenyl) thio) ethyl) phenyl) -2- (4-hydroxy-3- (methylsulfonamide) phenyl) acetamide (Compound E-41)
Synthesis of intermediate V-32
Referring to the procedure of example 151, 4-trifluoromethylthiophenylacetic acid was replaced with 2-fluoro-4-nitrophenylacetic acid and methyl 4-hydroxybenzoate was replaced with 4-trifluoromethoxybenzene thiol to give intermediate V-32.
Synthesis of Compound E-41
Referring to the procedure of example 337, substituting intermediate V-4 for intermediate V-32 produced compound E-41: 1 H NMR(300MHz,DMSO)δ10.27(s,1H),9.78(s,1H),8.70(s,1H),7.54(d,J＝12.6Hz,1H),7.45(d,J＝8.7Hz,2H),7.32(d,J＝8.4Hz,2H),7.24(d,J＝10.0Hz,2H),7.17(d,J＝1.3Hz,1H),6.99(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.50(s,2H),3.21(t,J＝7.5Hz,2H),2.93(s,3H),2.84(t,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 24 H 22 F 4 N 2 O 5 S 2 [M+H] + 559.0979,found 559.0988.
Example 377
2- (3- ((4-fluorophenyl) sulfamido) -4-hydroxyphenyl) -N- (4- ((3- (4- (trifluoromethoxy) phenyl) propyl) thio) phenyl) acetamide (Compound E-42)
Synthesis of intermediate V-33
Referring to the procedure of example 168, substituting 4-trifluoromethoxy phenylacetic acid with 4-trifluoromethoxy phenylpropionic acid and substituting 4-bromothiophenol with 4-nitrothiophenol, the intermediate V-33 was prepared: 1 H NMR(400MHz,Chloroform-d)δ8.13(d,J＝9.0Hz,2H),7.30(d,J＝8.9Hz,2H),7.23(d,J＝8.7Hz,2H),7.17(d,J＝7.7Hz,2H),3.04(t,J＝7.2Hz,2H),2.83(t,J＝7.5Hz,2H),2.06(p,J＝7.4Hz,2H).
synthesis of Compound E-42
Referring to the procedure of example 337, substituting intermediate V-4 for intermediate V-33 and substituting intermediate V-9 for intermediate V-17 produced compound E-42: 1 H NMR(300MHz,DMSO-d 6 )δ10.14(s,1H),9.40(s,2H),7.77(dd,J＝8.9,5.2Hz,2H),7.56(d,J＝8.7Hz,2H),7.30(d,J＝7.0Hz,3H),7.28(d,J＝6.1Hz,2H),7.26(d,J＝2.4Hz,2H),7.24-7.22(m,1H),7.18(d,J＝2.1Hz,1H),6.90(dd,J＝8.3,2.3Hz,1H),6.67(d,J＝8.2Hz,1H),3.44(s,2H),2.89(t,J＝7.2Hz,2H),2.72(t,J＝7.3Hz,2H),1.81(p,J＝7.4Hz,2H).HRMS(ESI)calcd.for C 30 H 26 F 4 N 2 O 5 S 2 [M+H] + 635.1292,found 635.1284.
example 378
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (3- (4- (trifluoromethoxy) phenyl) propyl) thiophenyl) acetamide (Compound E-43)
Synthesis of Compound E-43
Referring to the procedure of example 337, substituting intermediate V-4 for intermediate V-33 produced compound E-43: 1 H NMR(400MHz,DMSO-d 6 )δ10.13(s,1H),9.72(s,1H),8.68(s,1H),7.54(d,J＝8.7Hz,2H),7.32-7.28(m,3H),7.27-7.23(m,3H),7.18(d,J＝2.2Hz,1H),7.00(dd,J＝8.3,2.2Hz,1H),6.83(d,J＝8.2Hz,1H),3.49(s,2H),2.94(s,3H),2.88(t,J＝7.2Hz,2H),2.71(t,2H),1.85-1.76(m,2H).HRMS(ESI)calcd.for C 25 H 25 F 3 N 2 O 5 S 2 [M+H] + 555.1230,found555.1238.
example 379
2- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- (3- ((4- (trifluoromethoxy) phenyl) thio) propyl) phenyl) acetamide (Compound E-44)
Synthesis of Compound E-44
Referring to the procedure of example 349, substituting 3- (4-nitrophenyl) -1-propanol for intermediate III-12 and substituting 4-trifluoromethoxybenzene for 4-trifluoromethoxybenzene thiol produced compound E-44: 1 H NMR(300MHz,DMSO-d 6 )δ10.04(s,1H),9.71(s,1H),8.77(s,1H),7.48(d,J＝8.5Hz,2H),7.40(d,J＝8.8Hz,2H),7.30(dd,J＝8.9,0.8Hz,2H),7.17(d,J＝2.1Hz,1H),7.10(d,J＝8.5Hz,2H),7.00(dd,J＝8.3,2.2Hz,1H),6.82(d,J＝8.3Hz,1H),3.47(s,2H),2.96(t,J＝7.1Hz,2H),2.93(s,3H),2.64(t,J＝7.5Hz,2H),1.82(p,J＝7.3Hz,2H).HRMS(ESI)calcd.for C 25 H 25 F 3 N 2 O 5 S 2 [M+H] + 555.1230,found 555.1229.
Example 380
N- (2-hydroxy-5- (3- (4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) benzyl) ureido) phenyl) methanesulfonamide (compound E-45)
Synthesis of intermediate V-34
Referring to the procedure of example 66, substituting ethyl 4- (bromomethyl) benzoate for methyl 4-bromomethylphenylacetate produced intermediate V-34: 1 H NMR(300MHz,DMSO)δ12.34(s,1H),7.64(d,J＝8.7Hz,2H),7.39(d,J＝8.1Hz,2H),7.28(d,J＝8.1Hz,2H),7.14(d,2H),5.14(s,2H),3.57(s,2H).
synthesis of intermediate V-35
Intermediate V-34 (75 mg,0.22 mmol) and triethylamine (68. Mu.L, 0.48 mmol) were added to toluene (2 mL), diphenyl azide phosphate (52. Mu.L, 0.24 mmol) was added dropwise under ice-bath, and the reaction was continued at 90℃for 5 hours. After the completion of the reaction, the system was cooled to room temperature, and intermediate I-18 (70 mg,0.22 mmol) was added to the reaction mixture in portions, followed by reaction at room temperature for 8 hours. After the completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (10 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=3:1) to give intermediate V-35 (brown solid, 79 mg).
Synthesis of Compound E-45
Intermediate V-35 (79 mg,0.12 mmol) and triethylamine trihydrofluoride (60. Mu.L, 0.36 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (dichloromethane/methanol=80:1) to give a crude product of compound E-45 (white solid, 32 mg), which was purified by beating (n-hexane/dichloromethane=1:1), and the obtained solid was dried to constant weight to give compound E-45 (white solid, 22 mg): 1 H NMR(300MHz,DMSO-d 6 )δ9.36(s,1H),8.58(s,1H),8.33(s,1H),7.63(d,J＝8.7Hz,2H),7.41(d,J＝8.1Hz,2H),7.30(d,J＝8.0Hz,2H),7.23(d,J＝2.6Hz,1H),7.14(d,J＝8.9Hz,2H),7.10(dd,J＝8.7,2.6Hz,1H),6.74(d,J＝8.7Hz,1H),6.44(t,J＝6.0Hz,1H),5.14(s,2H),4.27(d,J＝5.8Hz,2H),2.92(s,3H).HRMS(ESI)calcd.for C 23 H 22 F 3 N 3 O 5 S 2 [M+H] + 542.1026,found 542.1019.
Example 381
N 1 - (4-hydroxy-3- (methylsulfonyl) phenyl) -N 2 - (4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) oxamide (compound E-46)
Synthesis of intermediate V-36
Intermediate V-12 (158 mg,0.53 mmol) and pyridine (64. Mu.L, 0.80 mmol) were added to dichloromethane (3 mL), added dropwise (60. Mu.L, 0.63 mmol) in ice bath, and allowed to react at room temperature for 8 hours. After the reaction was completed, 1N aqueous hydrogen chloride (10 mL) was added to the reaction solution to quench excess pyridine, ethyl acetate (10 mL x 3) was extracted, the organic phases were combined, washed with saturated brine (10 mL x 1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1), and the resulting solid was dried to constant weight to give intermediate V-36 (white solid, 166 mg): 1 H NMR(300MHz,Chloroform-d)δ8.88(s,1H),7.68(d,J＝8.6Hz,2H),7.57(d,J＝8.7Hz,2H),7.44(d,J＝8.4Hz,2H),6.99(d,J＝8.9Hz,2H),5.07(s,2H),3.99(s,3H).
synthesis of intermediate V-37
Intermediate V-36 (166 mg,0.43 mmol) was dissolved in a mixed solvent of methanol (1.5 mL) and tetrahydrofuran (1.5 mL), and 1M aqueous sodium hydroxide solution (1 mL) was added to the mixture to react at room temperature for 6 hours. After the completion of the reaction, 1N aqueous hydrogen chloride was added to the reaction mixture to adjust the pH to 2 to 3, extracted with ethyl acetate (10 mL. Times.3), and the organic phases were combined, washed with saturated brine (10 mL. Times.1), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give intermediate V-37 (yellow solid, 133 mg).
Synthesis of intermediate V-38
Intermediate V-37 (93 mg,0.25 mmol), intermediate I-18 (87 mg,0.28 mmol) and N, N-diisopropylethylamine (131. Mu.L, 0.75 mmol) were added to dichloromethane (2 mL), stirred at room temperature for 10 minutes, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (143 mg,0.38 mmol) was added in portions while ice-bath, and the reaction was allowed to proceed to room temperature for 3 hours. After the completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (8 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=5:1) to give intermediate V-38 (white solid, 88 mg): 1 H NMR(400MHz,DMSO-d 6 )δ10.90(s,1H),10.84(s,1H),8.48(s,1H),7.95(d,J＝2.6Hz,1H),7.89(d,J＝8.6Hz,2H),7.65(d,J＝8.8Hz,2H),7.59(dd,J＝8.9,2.6Hz,1H),7.47(d,J＝8.6Hz,2H),7.16(d,J＝8.9Hz,2H),6.94(d,J＝8.8Hz,1H),5.14(s,2H),3.07(s,3H),0.99(s,9H),0.24(s,6H).
synthesis of Compound E-46
Intermediate V-38 (88 mg,0.13 mmol) and triethylamine trihydrofluoride (64. Mu.L, 0.39 mmol) were added to dichloromethane (2 mL) and reacted at room temperature for 6 hours. After the reaction was completed, a solid was precipitated, filtered, and the filter cake was washed with methylene chloride (2 mL) to give a crude compound E-46 (white solid, 50 mg), which was purified by beating (methylene chloride/n-hexane=1:1), and the obtained solid was dried to constant weight to give compound E-46 (white solid, 44 mg): 1 H NMR(400MHz,DMSO-d 6 )δ10.87(s,1H),10.71(s,1H),9.82(s,1H),8.73(s,1H),7.88(d,J＝8.6Hz,2H),7.83(d,J＝2.6Hz,1H),7.65(d,J＝8.7Hz,2H),7.50(dd,J＝8.8,2.6Hz,1H),7.47(d,J＝8.6Hz,2H),7.16(d,J＝8.8Hz,2H),6.87(d,J＝8.7Hz,1H),5.14(s,2H),2.99(s,3H).HRMS(ESI)calcd.for C 23 H 20 F 3 N 3 O 6 S 2 [M+H] + 556.0818,found 556.0812.
example 382
N- (4-hydroxy-3- (methylsulfonyl) phenyl) -N- (4- ((4- ((trifluoromethyl) thio) phenoxy) methyl) phenyl) cyclopropane-1, 1-dicarboxamide (Compound E-47)
Synthesis of intermediate V-39
Intermediate V-12 (211 mg,0.71 mmol), monomethyl 1, 1-cyclopropyl-dicarboxylate (112 mg,0.78 mmol) and N, N-diisopropylethylamine (375. Mu.L, 2.13 mmol) were added to dichloromethane (3 mL), stirred at room temperature for 10 min, 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU) (405 mg,1.07 mmol) was added in portions while ice-bath, and the reaction was continued until room temperature was reached for 3 hours. After the completion of the reaction, the reaction mixture was diluted with water (10 mL), extracted with ethyl acetate (8 ml×3), the organic phases were combined, washed with saturated brine (10 ml×1), the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate=8:1) to give intermediate V-39 (white solid, 172 mg): 1 H NMR(300MHz,Chloroform-d)δ10.91(s,1H),7.62(d,J＝8.5Hz,2H),7.56(d,J＝8.7Hz,2H),7.37(d,J＝8.4Hz,2H),6.99(d,J＝8.8Hz,2H),5.04(s,2H),3.74(s,3H),1.85-1.80(m,2H),1.70-1.65(m,2H).
synthesis of Compound E-47
Referring to the procedure of example 381, intermediate E-47 was prepared by substituting intermediate V-36 for intermediate V-39: 1 H NMR(400MHz,DMSO-d 6 )δ10.20(s,1H),9.77(s,1H),9.59(s,1H),8.81(s,1H),7.63(d,J＝8.4Hz,4H),7.46(d,J＝2.6Hz,1H),7.39(d,J＝8.4Hz,2H),7.30(dd,J＝8.8,2.6Hz,1H),7.15(d,J＝8.8Hz,2H),6.80(d,J＝8.7Hz,1H),5.11(s,2H),2.94(s,3H),1.59-1.32(m,4H).HRMS(ESI)calcd.for C 26 H 24 F 3 N 3 O 6 S 2 [M+H] + 596.1131,found 596.1125.
example 383
Evaluation of inhibitory Activity of Compounds on THP1 cell STING Signal pathway
Experimental principle: THP1 cells express cGAS and STING proteins, and introduction of exogenous double-stranded DNA activates the cGAS-STING signaling pathway, thereby enhancing IRF transcriptional activity. Thus, using transfected exogenous HT-DNA to activate intracellular cGAS-STING-IRF signaling pathway, the inhibitory activity of a compound on STING signaling pathway can be assessed by detecting the level of IFN- β gene expression of the target gene downstream of IRF after the addition of the compound to interfere with STING signaling pathway.
Experimental reagents and materials: heat-inactivated serum (Biological Industries), 1640 medium (Biological Industries), penicillin-streptomycin double antibody (Biological Industries), THP1 cells (Saikovia), HT-DNA (Sigma Aldrich, formulated as 2.5mg/mL stock), opti-MEM (Gibco), lipo6000 (bi cloud).
The experimental method comprises the following steps: activity test method of wild-type THP-1 cells: cells with cell viability greater than 90% were inoculated into 12 well plates at 30 ten thousand cells/well, incubated with the addition of compound (compound dissolved in DMSO, final test concentrations of compound in culture medium: 0.1 and 1 μm, with DMSO as a blank), incubated for 6h, and then transfected with 0.5 μg/mL HT-DNA using Lipo6000 transfection reagent for 12h. The cell suspension was collected in a 1.5mL EP tube and centrifuged at 3000g for 10min to collect the cells. And detecting the expression of IFN-beta gene. The experiment uses STING inhibitors H-151 and SN-011 reported in the literature as positive control compounds.
The extraction process of total RNA in cells is as follows: 1) After cells were fully lysed with Trizol, RNA in the lysate was extracted with chloroform, and centrifuged at 4 12000g for 15 min; 2) Adding isopropanol into the supernatant solution to precipitate RNA in the solution; 3) Washing the RNA precipitate with 75% ethanol to remove impurities; 4) RNA was dried and transparent, dissolved in an appropriate amount of DEPC water, and the concentration of RNA was measured at OD 260. After the extraction of the total RNA is completed, the total RNA can be used for detecting the expression of the target gene by the subsequent fluorescent quantitative PCR, and the experimental steps are as follows: mixing RNA with a reverse transcription reagent, carrying out reverse transcription to obtain cDNA, mixing the cDNA with IFN-beta and GAPDH gene primers, DNA polymerase and fluorescent dye, amplifying and detecting in an ABI Step-One-Plus instrument, and carrying out relative quantitative calculation on the expression of a target gene by using a GAPDH as an internal reference of gene expression and a 2-delta CT method. The primer sequences used for detecting the target gene are as follows:
Name of the name Sequence(s)
GAPDH forward primer 5’-CGGAGTCAACGGATTTGGTC-3’
GAPDH reverse primer 5’-GACAAGCTTCCCGTTCTCAG-3’
IFN-beta forward primers 5’-ATTGCCTCAAGGACAGGATG-3’
IFN-beta reverse primer 5’-GGCCTTCAGGTAATGCAGAA-3’
The inhibition rate of the compound on STING signal pathway after HT-DNA stimulation at 1 and 0.1. Mu.M concentration is calculated according to IFN-beta gene expression fold: {100-100 [ IFN- β (dosing group +HT-DNA)/IFN- β (DMSO blank +HT-DNA) ] }.
Experimental results: the results of the inhibitory activity of the compounds on STING signaling pathway of wild-type THP1 cells are shown in table 2.
TABLE 2 inhibitory Activity of Compounds on THP1 cell STING signaling pathway
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In addition, some compounds were tested for activity using THP-1dual cells and the results of the compounds' inhibitory activity on THP-1dual cell STING signaling pathway are shown in Table 3.
The experimental method comprises the following steps: HT-DNA complexes were mixed with THP-1dual cells, seeded in 96-well plates, 4X 10 per well 4 Each well was filled with 100. Mu.L of the mixture, and the compound was diluted in a gradient at a concentration of 10. Mu.MAfter releasing 6 concentrations, 100. Mu.L of IFN- β gene was assayed 16-18 hours after each well addition.
TABLE 3 inhibitory Activity of Compounds on THP 1Dual cell STING signaling pathway
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Experimental results (Table 2 and Table 3) show that the sulfonamide compounds of the invention significantly inhibit the expression of the IFN- β gene downstream of the THP-1 cell STING signaling pathway induced by stimulation with 2'3' -cGAMP, and that the wild-type THP-1 cell assay results show that there are a plurality of compounds with an inhibition rate of approximately 90% or greater at a concentration of 0.1. Mu.M (e.g., compounds B-12, B-15, B-39, B-59, B-74, B-79, B-82, B-83, B-100, C-4, C-14, C-22, C-49, C-51, C-70, C-77, D-41, D-56, D-57, D-59, D-70, D-71, D-73, D-74, D-95, D-96, E-17), and IC for some of the compounds 50 The values reach nanomolar levels (e.g., compounds B-39, B-59, B-80, C-22, C-51, C-77, D-49), where compound B-59 (IC) 50 =3.67 nM) 50 The value reaches the level of single digit nanomole, and the activity of the compound is obviously superior to that of positive molecule H-151 (IC 50 =116.5 nM) and SN-011 (IC 50 =458 nM). In addition, THP-1dual cell test results showed IC of a portion of the compounds 50 The value is better than that of positive molecule H-151 (IC) 50 =1368nm) and SN-011 (IC 50 =5104 nM), (as follows: compounds D-61, D-62, D-63, D-88, D-91). Other compounds of the invention also showed significant STING signaling pathway inhibitory activity. This shows that the sulfonamide compound or pharmaceutically acceptable salt thereof can be used as a novel small molecule inhibitor for targeting STING, and can effectively inhibit the activation of STING signal channels.
Example 384
Liver microsome stability test
A methanol/water (1:1) solution of the compound at a concentration of 100. Mu.M was prepared and diluted to a drug working solution of 1.11. Mu.M with a mixed solution of 0.01M magnesium chloride and 0.1M potassium phosphate, and the drug working solution was co-incubated with a human liver microsome working solution at a final concentration of 0.7mg/mL and an NADPH solution (at a final concentration of 10 mM), and the incubation was terminated by adding methanol/water solutions at 0, 15, 30, 45 and 60min, respectively. The residual amount of the residual compound in each time point system was detected by LC/MS, and the absolute value k of the slope was measured by plotting the natural logarithm of the percentage of the residual compound against time, and calculated according to the formula: t1/2 (half-life) =ln2/k=0.693/k. The experimental results are shown in table 4.
TABLE 4 results of the metabolic stability of the human liver microsomes of the compounds
Numbering of compounds T 1/2 (min)
B-39 67.9
B-59 217
C-51 1155
E-17 57.3
H-151 8.81
The experimental results (Table 4) show that the compounds B-39 and E-17 have better metabolic stability of the human liver microsomes, the compounds B-59 and C-51 have very good metabolic stability of the human liver microsomes, and the metabolic stability of the four compounds on the human liver microsomes is far better than that of the positive control drug H-151 under the same test condition. Other compounds of the invention also have good metabolic stability of human liver microsomes.
Example 385
In vivo pharmacokinetic evaluation of Compound B-59 in mice
Animals: male SD rats were 6, derived from the su state topology vitamin animal reservoir.
Grouping: rats were divided into 2 groups of 3 animals, one group being orally administered and the other group being intravenously administered. The dosage of the oral administration group was 10mpk, and the dosage of the intravenous injection was 2mpk.
The experimental method comprises the following steps: after intravenous injection administration, the intravenous injection administration group takes about 0.03mL of blood through the eye sockets at 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours respectively, and after taking the blood, the ethylene diamine tetraacetic acid dipotassium salt is rapidly added for anticoagulation, and the blood is placed on ice after being collected. Mice in the orally administered group were fasted for 12 hours before administration and for 4 hours after administration; after oral administration, the mice were bled at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours via the orbit for about 0.03mL, and after bled, the ethylene diamine tetraacetic acid dipotassium salt was rapidly added for anticoagulation, and the blood was collected and placed on ice. All samples were centrifuged at 18000g in a cryocentrifuge for 7 min, plasma was isolated, the content of compounds in the plasma was detected via LC-MS/MS-18, and relevant pharmacokinetic parameters were calculated from the plasma concentration data at different time points. The experimental results are shown in table 5.
TABLE 5 pharmacokinetic parameters of Compound B-59 for intravenous and oral administration in mice
The results of the experiment (Table 5) show that compound B-59 has an oral half-life of 4.29 hours, and that compound B-59 has an oral bioavailability of 18.7% and good pharmacokinetic properties. Other compounds of the invention also have good pharmacokinetic properties.
Example 386
Effect of Compounds B-80, C-22, C-51, D-60, D-75 and D-88 on mice psoriasis model caused by imiquimod cream
To verify the effect of the compounds of the present invention on autoimmune diseases, the efficacy of the compounds was verified using a model of mouse psoriasis caused by imiquimod cream.
Experimental animals: balb/c female mice, 8 week old, were purchased from Viola Zhejiang laboratory animal Co.
Test drug configuration: 7.2g PEG400 is heated to 55-60 ℃, 200mg of the test agent is added for stirring, an ultrasonic cleaner is used for ultrasonic dissolution, the mixture is repeatedly reversed and mixed for a plurality of times, after dissolution, 2.8g PEG3350 is heated to 55-60 ℃ for dissolution, and then the mixture is mixed with the PEG400 mixed with the test agent, and the mixture is packaged into 1 g/tube to prepare 2% of test agent ointment, and the back of the mouse is smeared with 0.2 g/mouse. Control ointments without compound were also prepared, and the test groups were ointments containing B-80, C-22, C-51, D-60, D-75 and D-88, respectively.
Molding and drug administration: mice were randomly divided into blank, model, B-80 (2% B-80 ointment applied), C-22 (2% C-22 ointment applied), C-51 (2% C-51 ointment applied), D-60 (2% D-60 ointment applied), D-75 (2% D-75 ointment applied) and D-88 (2% D-88 ointment applied) groups of 5 animals each. The mice were dehaired on their backs, exposing a 2cm x 3cm area of skin. Adaptation was 2 days after dehairing. The back is applied with 50mg of 5% Imiquimod (IMQ) cream, once daily, and molded for 7 days. The corresponding test ointment, control ointment and model animal control ointment were administered simultaneously to the dosing group, 0.2 g/dose, 1 time a day for a total of 7 days. The back photographs were taken and PASI (psoriasis lesions area and severity index) scored daily.
Experimental results (figure 1) show that the compounds B-80, C-22, C-51, D-60, D-75 and D-88 can effectively reduce PASI scoring of the mice with psoriasis caused by imiquimod cream, and demonstrate that the pathological characteristics such as inflammatory injury, skin thickening and scaling of the model mice with the back psoriasis pattern can be reduced. The compounds have obvious immunoregulation effect and can be used for treating psoriasis. This suggests that compounds B-80, C-22, C-51, D-60, D-75 and D-88 are useful for the prevention and treatment of autoimmune diseases, organ transplant rejection, infectious diseases and inflammatory diseases. Other compounds of the invention also have similar therapeutic effects.

Claims (11)

1. Sulfonamide compounds of formula I or a pharmaceutically acceptable salt or ester or solvate thereof:
R 1 selected from: H. c (C) 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl;
R 2 selected from: substituted or unsubstituted C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, (CH) 2 ) n OH、(CH 2 ) n NH 2 、(CH 2 ) n C(O)O(CH 2 ) m CH 3 Substituted or unsubstituted C 3 -C 8 Cycloalkyl, substituted or unsubstituted C 3 -C 6 Alicyclic heterocyclic group or substituted or unsubstituted aryl or heteroaryl, wherein the substituted C 1 -C 6 Alkyl is substituted with one of the following substituents: diethanolamino-amino, methanesulfonamido, acetamino, 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-dimethylamino, carboxyl, carboxylate, carboxamide or carbam-amino; the substituted C 3 -C 8 Cycloalkyl, C 3 -C 6 Cycloalkyl, aryl or heteroaryl is selected from one, two or three ofThe substituents of the columns are substituted: c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxycarbonyl, C 1 -C 6 Alkylsulfonyl, halogen, CN, NO 2 、NH 2 、OH、CF 3 、OCF 3 、SCF 3 C (O) OH or C (O) NH 2 ；
Wherein R is 2 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 3 selected from: H. halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkyloxy, (CH) 2 ) n OH、(CH 2 ) n C(O)OH、(CH 2 ) n C(O)O(CH 2 ) m CH 3 、OC(O)(CH 2 ) n CH 3 Or (CH) 2 ) n C(O)NH 2 ；
Wherein R is 3 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 4 selected from: H. halogen, C 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 3 -C 6 Cycloalkyl, (CH) 2 ) n OH、(CH 2 ) n C(O)OH、(CH 2 ) n C(O)O(CH 2 ) m CH 3 Or (CH) 2 ) n C(O)NH 2 ；
Wherein R is 4 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 5 and R is 6 Each independently selected from: H. n (CH) 3 ) 2 、N(CH 2 CH 3 ) 2 、CN、NO 2 、CHF 2 、(CH 2 ) n C(O)OH、(CH 2 ) n C(O)O(CH 2 ) m CH 3 、(CH 2 ) n CF 3 、(CH 2 ) n OCF 3 、(CH 2 ) n SCF 3 、S(CH 2 ) l SCF 3 、O(CH 2 ) l SCF 3 、(CH 2 ) n OH、(CH 2 ) n NH 2 、SO 2 CH 3 、SO 2 CF 3 Halogen, pyrrolyl, imidazolyl, triazolyl, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkyloxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino, C 1 -C 6 Alkylsulfonyl, substituted or unsubstituted C 3 -C 8 Cycloalkyl or substituted or unsubstituted C 6 Aliphatic heterocyclic group, wherein the substituted C 3 -C 8 Cycloalkyl or C 6 The aliphatic heterocyclic group is substituted with one or two substituents independently selected from the group consisting of: c (C) 1 -C 6 Alkyl or halogen, or, alternatively, adjacent R 5 And R is 6 Together with the atoms to which they are attached may form a benzene ring, C 5 -C 6 Cycloalkane, C 5 -C 6 Alicyclic ring or C 5 -C 6 Aromatic heterocycles;
wherein R is 5 And R is 6 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4; the letter l is selected from: 1-3 any integer;
R 7 、R 8 and R is 9 Each independently selected from: H. CN, NO 2 、CHF 2 、OCHF 2 、(CH 2 ) n C(O)OH、(CH 2 ) n C(O)O(CH 2 ) m CH 3 、(CH 2 ) n CF 3 、(CH 2 ) n OCF 3 、(CH 2 ) n SCF 3 、S(CH 2 ) l SCF 3 、O(CH 2 ) l SCF 3 、(CH 2 ) n OH、(CH 2 ) n NH 2 、SO 2 CH 3 、SO 2 CF 3 Halogen, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, C 1 -C 6 Alkyloxy, C 1 -C 6 Alkylthio, C 1 -C 6 Alkylamino, substituted or unsubstituted C 3 -C 8 Cycloalkyl or substituted or unsubstituted C 3 -C 6 A cycloaliphatic group, wherein the substituted C 3 -C 8 Cycloalkyl or C 3 -C 6 The alicyclic groups are each independently substituted with one or two of the following substituents: OH, NH 2 Halogen, C 1 -C 6 Alkyl, or, adjacent R 7 、R 8 Or R is 9 Wherein at least two substituents, together with the atom to which they are attached, may form C 5 -C 8 Cycloalkane, benzene ring, C 5 -C 6 Aromatic heterocyclic ring, or C 5 -C 6 Aliphatic heterocycles;
wherein R is 7 、R 8 And R is 9 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4; the letter l is selected from: 1 to 3 is an arbitrary integer;
a is selected from: c (C) 3 -C 8 Cycloalkyl, phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, piperidinyl, piperazinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, isoindolin-1-one, phthalimido or 3, 4-dihydroisoquinolin-1 (2H) -one;
b is absent or selected from: c (C) 3 -C 8 Cycloalkyl, phenyl, naphthyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furanyl, thiazolyl, oxazolyl, triazolyl, indolyl, benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl;
L 1 Selected from:
wherein R is a And R is b Each independently selected from: H. c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 3 -C 6 Alicyclic heterocyclic group or substituted or unsubstituted aryl or heteroaryl, wherein the substituted C 3 -C 6 Cycloalkyl, C 3 -C 6 The alicyclic, aryl or heteroaryl group is substituted with one or two substituents each independently selected from the group consisting of: c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkyloxy, C 1 -C 6 Alkoxycarbonyl, C 1 -C 6 Alkylsulfonyl, halogen, OH, NH 2 、CN、NO 2 、CF 3 、OCF 3 、SCF 3 C (O) OH or C (O) NH 2 ；
L 2 May be absent or selected from:
wherein R is c And R is d Each independently selected from: H. CF (compact flash) 3 Halogen, oxo, C 1 -C 6 Alkyl, C 1 -C 6 Alkyloxy, C 1 -C 6 Alkylthio, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 3 -C 6 A cycloaliphatic or substituted or unsubstituted aryl or heteroaryl group, wherein the substituted C 3 -C 6 Cycloalkyl, C 3 -C 6 The alicyclic, aryl or heteroaryl group is substituted with one or two or three substituents each independently selected from the group consisting of: c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Alkoxycarbonyl, C 1 -C 6 Alkylsulfonyl, halogen, OH, NH 2 、CN、NO 2 、CF 3 、OCF 3 、SCF 3 C (O) OH or C (O) NH 2 Alternatively, R's attached to the same carbon atom c Or R is d Can form C together with the atoms to which they are attached 3 -C 6 Cycloalkane or C 3 -C 6 A alicyclic ring;
x is selected from: CH (CH) 2 、O、S、NH、NR e A sulfoxide group or sulfone group;
wherein R is e Selected from: c (C) 1 -C 6 Alkyl, C 1 -C 6 Alkylcarbonyl or t-butoxycarbonyl, or R e R on ring A or B 5 、R 6 、R 7 、R 8 Or R is 9 Wherein one substituent, together with the atom to which they are attached, may form C 5 -C 6 A heterocycle;
p and q are each independently selected from: an arbitrary integer of 0 to 4.
2. The sulfonamide compound according to claim 1, or a pharmaceutically acceptable salt or ester or solvate thereof, characterized in that:
R 1 selected from: H. c (C) 1 -C 3 Alkyl or cyclopropyl;
R 2 selected from: c (C) 1 -C 4 Alkyl, (CH) 2 ) n OH、(CH 2 ) n NH 2 、(CH 2 ) n C(O)O(CH 2 ) m CH 3 、(CH 2 ) n C (O) OH, substituted or unsubstituted C 3 -C 6 Cycloalkyl, substituted or unsubstituted C 6 A cycloaliphatic or substituted or unsubstituted aryl or heteroaryl group, wherein the cycloaliphatic is selected from the group consisting of piperidinyl, piperazinyl, morpholinyl; the aryl or heteroaryl groups are each independently selected from phenyl, pyridyl, pyrimidinyl, thienyl, furyl or thiazolyl; the substituted C 3 -C 6 Cycloalkyl, alicyclic, aryl or heteroaryl is substituted with one or two or three substituents each independently selected from the group consisting of: c (C) 1 -C 4 Alkyl, C 1 -C 4 Alkoxy, halogen, CN, CF 3 、OCF 3 Or SCF 3 ；
Wherein R is 2 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 3 Selected from: H. halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkyloxy, C 1 -C 3 Alkylamino, (CH) 2 ) n OH、(CH 2 ) n C (O) OH or (CH) 2 ) n C(O)O(CH 2 ) m CH；
Wherein R is 3 N and m in the substituents are each independently selected from: an arbitrary integer of 0 to 4;
R 4 selected from: H. OH, halogen, C 1 -C 3 Alkyl, C 1 -C 3 Alkyloxy, cyclopropyl, C (O) OCH 3 Or C (O) OH;
R 5 and R is 6 Each independently selected from: H. OH, NH 2 、N(CH 3 ) 2 、N(CH 2 CH 3 ) 2 、C(O)OH、CN、NO 2 、CHF 2 、(CH 2 ) k CF 3 、(CH 2 ) k OCF 3 、(CH 2 ) k SCF 3 、S(CH 2 ) l SCF 3 、O(CH 2 ) l SCF 3 、SO 2 CH 3 、SO 2 CF 3 Halogen, pyrrolyl, imidazolyl, triazolyl, C 1 -C 4 Alkyl, C 1 -C 4 Alkyloxy, C 1 -C 4 Alkylthio, substituted or unsubstituted C 3 -C 8 Cycloalkyl or substituted or unsubstituted C 6 Aliphatic heterocyclic group, wherein, the C 6 The aliphatic heterocyclic group is selected from piperidyl, piperazinyl or morpholinyl; the substituted C 3 -C 8 Cycloalkyl or C 6 The aliphatic heterocyclic group is substituted with one or two substituents each independently selected from the group consisting of: c (C) 1 -C 4 Alkyl or halogen, or, alternatively, adjacent R 5 And R is 6 And to which they are connectedTogether the atoms of (2) may form C 5 -C 6 Aromatic heterocyclic ring, wherein the C 5 -C 6 The aromatic heterocycle is selected from: pyrrole, imidazole, oxazole, thiazole, oxadiazole, pyridine or pyrimidine;
wherein R is 5 And R is 6 K in the substituents is selected from: 0,1 or 2; the letter l is selected from: 1,2 or 3;
R 7 、R 8 and R is 9 Each independently selected from: H. OH, NH 2 、CN、NO 2 、CHF 2 、OCHF 2 、C(O)OH、(CH 2 ) k CF 3 、(CH 2 ) k OCF 3 、(CH 2 ) k SCF 3 、S(CH 2 ) l SCF 3 、O(CH 2 ) l SCF 3 、SO 2 CH 3 、SO 2 CF 3 Halogen, C 1 -C 4 Alkyl, C 1 -C 4 Alkyloxy, C 1 -C 4 Alkylthio or C 3 -C 6 Cycloalkyl, or, adjacent R 7 、R 8 Or R is 9 Wherein at least two substituents together with the atoms to which they are attached may form a benzene ring, a cycloalkane, an aromatic heterocycle or a substituted or unsubstituted alicyclic heterocycle, wherein the cycloalkane is selected from cyclopentane or cyclohexane; the aromatic heterocycle is selected from pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyridine or pyrimidine; the alicyclic ring is selected from piperidine, piperazine, morpholine or 1, 4-dioxane; the substituted alicyclic ring is substituted with one substituent as follows: c (C) 1 -C 3 Alkyl or C 1 -C 3 An alkylsulfonyl group;
wherein R is 7 、R 8 And R is 9 K in the substituents is selected from: 0,1 or 2; the letter l is selected from: 1,2 or 3;
a is selected from: c (C) 3 -C 6 Cycloalkyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, indolyl, piperidinyl or piperazinyl;
b is absent or selected from: c (C) 3 -C 8 Cycloalkyl, phenyl, naphthyl, pyridyl,Pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, thienyl, furyl, thiazolyl, oxazolyl, triazolyl, indolyl, benzoxazolyl, benzothiazolyl, piperidinyl, piperazinyl, morpholinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl;
L 1 Selected from:
R a and R is b Each independently selected from: H. c (C) 1 -C 3 Alkyl or C 3 -C 6 Cycloalkyl;
L 2 may be absent or selected from:
wherein, when L 2 Is absent, and L 1 The method comprises the following steps:when a is selected from only: />And B is absent;
R c and R is d Each independently selected from: H. f, cl, CF 3 Oxo, C 1 -C 4 Alkyl, C 1 -C 4 Alkyloxy, C 1 -C 4 Alkylthio or C 3 -C 6 Cycloalkyl, or R, attached to the same carbon atom c Or R is d Can form C together with the atoms to which they are attached 3 -C 6 A cycloalkane ring;
x is selected from: CH (CH) 2 、O、S、NH、NR e A sulfoxide group or sulfone group;
R e selected from: c (C) 1 -C 3 Alkyl, C 1 -C 3 Alkylcarbonyl or t-butoxycarbonyl, or R e R on ring A or B 5 、R 6 、R 7 、R 8 Or R is 9 Wherein one substituent, together with the atom to which they are attached, may form C 5 -C 6 A heterocycle, wherein the C 5 -C 6 The heterocycle is selected from: pyrrole, piperidine, pyrrolidone, piperidone, succinimide, glutarimide;
p and q are each independently selected from: an arbitrary integer of 0 to 3.
3. Sulfonamide compounds of formula I or a pharmaceutically acceptable salt or ester or solvate thereof:
R 1 selected from: H. c (C) 1 -C 3 Alkyl or C 1 -C 3 An alkylcarbonyl group;
R 2 selected from: substituted or unsubstituted C 1 -C 4 Alkyl, cyclopropyl, CF 3 Vinyl, substituted or unsubstituted aryl or heteroaryl, NH 2 、C 1 -C 4 Alkylamino, hydroxy-C 1 -C 3 Alkylamino or morpholinyl, said aryl or heteroaryl being selected from phenyl, naphthyl, pyridinyl, pyrazolyl, furyl or thienyl, said substituted C 1 -C 4 Alkyl is substituted with one or two or three substituents independently selected from the group consisting of: F. cl, NH 2 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-dimethylamino, carboxy, carboxylate, carboxamide or carbamoylamino, said substituted aryl or heteroaryl being substituted with one or two substituents independently selected from the group consisting of: c (C) 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxycarbonyl, C 1 -C 3 Alkylsulfonyl, F, cl, br, I, CN, NO 2 、NH 2 、OH、CF 3 、CF 2 CF 3 、OCF 3 、OCF 2 CF 3 C (O) OH or C (O) NH 2 ；
R 3 Selected from: H. OH, halogen, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylcarbonyloxy, C 1 -C 3 Alkoxycarbonyl, (CH) 2 ) n C(O)OH、(CH 2 ) n C(O)NH 2 Or C (O) NHSO 2 CH 3 ；
n is selected from: 0. 1, 2 or 3;
R 4 selected from: H. OH, halogen, C 1 -C 3 Alkyl, COOCH 3 COOH or CONH 2 ；
L 1 Selected from:
R a and R is b Each independently selected from: H. c (C) 1 -C 3 Alkyl or C 3- C 6 Cycloalkyl;
a is selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, cyclohexyl, piperidinyl or piperazinyl;
R 5 and R is 6 Each independently selected from: H. OH, halogen, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 、C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Cycloalkenyl, C 1 -C 6 Heterocycloalkyl, C 1 -C 6 Heterocycloalkenyl, C 1 -C 6 Alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, said substituted phenyl being independently substituted with 1 to 2 substituents: halogen, OH, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 Or C 1 -C 6 Alkylsulfonyl, or, R 5 And R is 6 Together with the atoms to which they are attached, may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkyl ring, or a substituted or unsubstituted heterocycloalkene ring;
L 2 absent or selected from:
x is selected from: C. o, S, NH, sulfoxide or sulfone groups;
p and q are each independently selected from: an arbitrary integer of 0 to 5;
b is selected from: H. halogen CN, OH, NH 2 、NO 2 、CF 3 、CHF 2 、OCF 3 、SCF 3 、C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkylamino, substituted or unsubstituted phenyl, naphthyl, pyridyl, imidazolyl, pyrazolyl, furyl, thienyl, C 3 -C 8 Cycloalkyl or a 4-7 membered nitrogen-containing heterocycle;
R 7 and R is 8 Each independently selected from: H. OH, halogen, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 、C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Cycloalkenyl, C 1 -C 6 Heterocycloalkyl, C 1 -C 6 Heterocycloalkenyl, C 1 -C 6 Alkynyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl, substituted heteroaryl, fused ring aryl or substituted fused ring aryl, said substituted phenyl being independently substituted with 1 to 2 substituents: halogen, OH, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 Or C 1 -C 6 Alkylsulfonyl, or, R 5 And R is 6 Together with the atoms to which they are attached, may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkyl ring, or a substituted or unsubstituted heterocycloalkene ring.
4. A sulfonamide compound according to claim 3, or a pharmaceutically acceptable salt or ester or solvate thereof, characterized in that:
R 1 selected from: h or C 1 -C 3 An alkyl group;
R 2 selected from: substituted or unsubstituted C 1 -C 4 Alkyl, cyclopropyl, CF 3 Vinyl, substituted or unsubstituted aryl or heteroaryl, hydroxy-C 1 -C 3 An alkylamino or morpholino group selected from phenyl, naphthyl, pyridinyl, pyrazolyl, furanyl or thiophenyl, said substituted aryl or heteroaryl group being substituted with one or two substituents independently selected from: c (C) 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, C 1 -C 3 Alkoxycarbonyl, C 1 -C 3 Alkylsulfonyl, F, cl, br, I, CN, NO 2 、NH 2 、OH、CF 3 、CF 2 CF 3 、OCF 3 、OCF 2 CF 3 C (O) OH or C (O) NH 2 ；
R 3 Selected from: H. OH, halogen, C 1 -C 3 Hydroxyalkyl, C 1 -C 3 Alkoxy or (CH) 2 ) n C(O)OH；
Wherein n is selected from: 0. 1, 2 or 3;
R 4 selected from: H. OH, halogen, C 1 -C 3 Alkyl, COOCH 3 COOH or CONH 2 ；
L 1 Selected from:
R a and R is b Each independently selected from: H. c (C) 1 -C 3 Alkyl or C 3- C 6 Cycloalkyl;
a is selected from: phenyl, pyridyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, cyclohexyl, piperidinyl or piperazinyl;
R 5 and R is 6 Each independently selected from: H. OH, halogen, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、OCF 3 、SCF 3 、C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Heterocycloalkyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, said substituted phenyl being independently substituted with 1 to 2 substituents selected from the group consisting of: halogen, OH, CN, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 Or C 1 -C 6 Alkylsulfonyl, or, R 5 And R is 6 Together with the atoms to which they are attached may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkyl ring, or a substituted or unsubstituted hetero ringA cycloolefin ring;
L 2 Absent or selected from:
x is selected from: C. o, S, NH, sulfoxide or sulfone groups;
p and q are each independently selected from: 0. 1, 2 or 3;
b is selected from: H. halogen CN, OH, NH 2 、NO 2 、CF 3 、CHF 2 、OCF 3 、SCF 3 、C 1 -C 3 Alkyl, C 1 -C 3 Alkoxy, substituted or unsubstituted phenyl, naphthyl, pyridyl, imidazolyl, pyrazolyl, furyl, thienyl, C 3 -C 8 Cycloalkyl or a 4-7 membered nitrogen-containing heterocycle;
R 7 and R is 8 Each independently selected from: H. OH, halogen, CN, C 1 -C 6 Alkyl, CF 3 、CHF 2 、OCF 3 、SCF 3 、C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkoxy, C 1 -C 6 Cycloalkyl, C 1 -C 6 Heterocycloalkyl, phenyl, substituted phenyl, phenoxy, substituted phenyloxy, heteroaryl or substituted heteroaryl, said substituted phenyl being independently substituted with 1 to 2 substituents selected from the group consisting of: halogen, OH, CN, CF 3 、CHF 2 、SCH 3 、OCF 3 、SCF 3 Or C 1 -C 6 Alkylsulfonyl, or, R 5 And R is 6 Together with the atoms to which they are attached, may form a substituted or unsubstituted benzene ring, a substituted or unsubstituted heteroaryl ring, a substituted or unsubstituted cycloalkane ring, a substituted or unsubstituted heterocycloalkyl ring, or a substituted or unsubstituted heterocycloalkene ring.
5. A sulfonamide compound according to claim 1 or 3, or a pharmaceutically acceptable salt or ester or solvate thereof, wherein the sulfonamide compound or pharmaceutically acceptable salt thereof is selected from any one of the following:
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6. Use of a sulfonamide compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or ester or solvate thereof, for the manufacture of a medicament for inhibiting the activation of STING signalling pathway.
7. Use of a sulfonamide compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or ester or solvate thereof, in the manufacture of a medicament for the prophylaxis or treatment of STING-mediated disorders.
8. The use of claim 7, wherein the STING-mediated disorder comprises an infectious disease, an inflammatory disease, an autoimmune disease, an organ fibrosis disease, cancer, or a cancerous syndrome.
9. Use of a sulfonamide compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt or ester or solvate thereof, in the manufacture of an immunoadjuvant drug.
10. A pharmaceutical composition for preventing or treating STING-mediated diseases, which comprises the sulfonamide compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt or ester or solvate thereof as an active ingredient and a pharmaceutically acceptable adjuvant.
11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition is in the form of a capsule, powder, tablet, granule, pill, injection, syrup, oral liquid, inhalant, ointment, suppository or patch.
CN202311253162.1A 2022-09-26 2023-09-26 Sulfonamide compound and medical application thereof Pending CN117682973A (en)

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TWI239942B (en) * 2001-06-11 2005-09-21 Dainippon Pharmaceutical Co N-arylphenylacetamide derivative and pharmaceutical composition containing the same
EP1402888A1 (en) * 2002-09-18 2004-03-31 Jerini AG The use of substituted carbocyclic compounds as rotamases inhibitors
EP1402887A1 (en) * 2002-09-18 2004-03-31 Jerini AG New compounds for the inhibition of undesired cell proliferation and use thereof
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