Sulfur derivatives as chemokine receptor modulators
11046644 · 2021-06-29
Assignee
Inventors
- Haiqing Yuan (Irvine, CA)
- Richard L. Beard (Newport Beach, CA)
- Xiaoxia Liu (Lake Forest, CA)
- John E. Donello (Dana Point, CA)
- Veena Viswanath (Irvine, CA)
- Michael E. Garst (Newport Beach, CA)
Cpc classification
A61P29/00
HUMAN NECESSITIES
A61P31/00
HUMAN NECESSITIES
C07C323/56
CHEMISTRY; METALLURGY
C07C311/21
CHEMISTRY; METALLURGY
C07D207/09
CHEMISTRY; METALLURGY
C07C317/34
CHEMISTRY; METALLURGY
A61P43/00
HUMAN NECESSITIES
C07C317/44
CHEMISTRY; METALLURGY
C07F9/3229
CHEMISTRY; METALLURGY
C07C323/60
CHEMISTRY; METALLURGY
C07F9/4021
CHEMISTRY; METALLURGY
C07C317/36
CHEMISTRY; METALLURGY
C07C323/67
CHEMISTRY; METALLURGY
C07C323/52
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
C07D233/64
CHEMISTRY; METALLURGY
C07D207/46
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D307/82
CHEMISTRY; METALLURGY
C07C317/50
CHEMISTRY; METALLURGY
C07F9/5325
CHEMISTRY; METALLURGY
C07C321/30
CHEMISTRY; METALLURGY
C07D413/12
CHEMISTRY; METALLURGY
International classification
C07C311/21
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07C317/36
CHEMISTRY; METALLURGY
C07C317/50
CHEMISTRY; METALLURGY
C07C323/67
CHEMISTRY; METALLURGY
C07C321/30
CHEMISTRY; METALLURGY
C07D207/09
CHEMISTRY; METALLURGY
C07D207/46
CHEMISTRY; METALLURGY
C07C317/44
CHEMISTRY; METALLURGY
C07C323/52
CHEMISTRY; METALLURGY
C07C323/56
CHEMISTRY; METALLURGY
C07C323/60
CHEMISTRY; METALLURGY
C07F9/30
CHEMISTRY; METALLURGY
C07F9/53
CHEMISTRY; METALLURGY
C07D307/82
CHEMISTRY; METALLURGY
C07C317/34
CHEMISTRY; METALLURGY
C07C311/44
CHEMISTRY; METALLURGY
C07D233/64
CHEMISTRY; METALLURGY
Abstract
The present invention relates to novel sulfur derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of chemokine receptors.
Claims
1. A method of modulating chemokine receptors, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I ##STR00417## wherein: R.sup.1 is H or ##STR00418## R.sup.2 is substituted or unsubstituted C.sub.1-6 alkyl or substituted or unsubstituted C.sub.3-8 cycloalkyl; R.sup.5 is —S—, —S(O)—, or —S(O).sub.2—; R.sup.6 is selected from the group consisting of: ##STR00419## R.sup.17 is H; R.sup.18 is H; R.sup.7 is H, halogen, —OC.sub.1-6 alkyl, or substituted or unsubstituted C.sub.1-6 alkyl; and R.sup.8 is H, halogen, or CN; with the proviso that R.sup.7, R.sup.8, R.sup.17 and R.sup.18 cannot be H in same time.
2. The method according to claim 1, wherein: R.sup.5 is —S—.
3. The method according to claim 1, wherein: R.sup.5 is —S(O)—.
4. The method according to claim 1, wherein: R.sup.5 is —S(O).sub.2—.
5. The method according to claim 1, wherein the compound is selected from the group consisting of: 3,4-dichloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide; 3,4-dichloro-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-methylbenzenesulfonamide; N-[5-chloro-2-(methylsulfinyl)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide; 4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-[5-chloro-2-(ethylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-[5-chloro-2-(ethylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide; tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate; tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate; tert-butyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1H-pyrazole-1-carboxylate; 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylpropanamide; 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylpropanamide; 3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide; 3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N-dimethylpropanamide; 3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N-dimethylpropanamide; 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide; 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N-dimethylpropanamide; 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N-dimethylpropanamide; N-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide; N-(5-methoxy-2-((3-nitrobenzyl)sulfonyl)phenyl)benzofuran-2-sulfonamide; N-(5-chloro-2-((2-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide; 4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-[5-chloro-2-(isopropylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-[5-chloro-2-(isopropylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; methyl 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanoate; 4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; ethyl {[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}acetate; 4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-[5-chloro-2-(ethylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide; 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylacetamide; 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-methylacetamide; 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylacetamide; 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylacetamide; 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-methylacetamide; 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N-methylacetamide; N-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide; N-{2-[(2-aminoethyl)sulfonyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide; N-{2-[(2-aminoethyl)sulfinyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide; N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}ethyl)acetamide; N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}ethyl)acetamide; N-[5-chloro-2-(methylsulfinyl)phenyl]-4-isopropylbenzenesulfonamide; 4-bromo-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide; N-[5-chloro-2-(methylthio)phenyl]-4-iodobenzenesulfonamide; 4-bromo-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide; N-[5-chloro-2-(methylsulfinyl)phenyl]-4-iodobenzenesulfonamide; 4-bromo-N-[5-chloro-2-(methylsulfonyl)phenyl]benzenesulfonamide; N-[5-chloro-2-(methylsulfonyl)phenyl]-4-iodobenzenesulfonamide; N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide; N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide; N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide; N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}benzenesulfonamide; N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4-chlorobenzenesulfonamide; N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-3-chlorobenzenesulfonamide; N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}benzenesulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}benzenesulfonamide; N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4-chlorobenzenesulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4-chlorobenzenesulfonamide; N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-3-chlorobenzenesulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-3-chlorobenzenesulfonamide; 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-isopropylpropanamide; 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylpropanamide; 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-isopropylpropanamide; 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanamide; N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide; N-[5-chloro-2-(methylthio)phenyl]thiophene-2-sulfonamide; N-[5-chloro-2-(methylsulfinyl)phenyl]thiophene-2-sulfonamide; 4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; N-[5-chloro-2-(methylthio)phenyl]-4-methyl-3-nitrobenzenesulfonamide; chloro-2-(methylsulfinyl)phenyl]-4-methyl-3-nitrobenzenesulfonamide; N-[5-chloro-2-(methylsulfonyl)phenyl]-4-methyl-3-nitrobenzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]benzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-methylbenzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-methylbenzenesulfonamide; N-[5-chloro-2-(methylthio)phenyl]-4-nitro-3-(trifluoromethyl)benzenesulfonamide; N-[5-chloro-2-(methylsulfonyl)phenyl]-4-nitro-3-(trifluoromethyl)benzenesulfonamide; N-[5-chloro-2-(methylthio)phenyl]-2,4-difluorobenzenesulfonamide; N-[5-chloro-2-(methylsulfonyl)phenyl]-2,4-difluorobenzenesulfonamide; N-[5-chloro-2-(methylsulfinyl)phenyl]-2,4-difluorobenzenesulfonamide; N-[5-chloro-2-(methylthio)phenyl]-5-methylfuran-2-sulfonamide; N-[5-chloro-2-(methylsulfinyl)phenyl]-5-methylfuran-2-sulfonamide; N-[5-chloro-2-(methylsulfonyl)phenyl]-5-methylfuran-2-sulfonamide; N-[5-chloro-2-(methylthio)phenyl]furan-2-sulfonamide; N-[5-chloro-2-(methylsulfinyl)phenyl]furan-2-sulfonamide; N-[5-chloro-2-(methylsulfonyl)phenyl]furan-2-sulfonamide; 4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2-fluorobenzenesulfonamide; 4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2-fluorobenzenesulfonamide; 3-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide; 3-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2-fluorobenzenesulfonamide; 3-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2-fluorobenzenesulfonamide; 4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide; N-[5-chloro-2-(methylsulfonyl)phenyl]-4-isopropylbenzenesulfonamide; N-(5-methoxy-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide; N-[2-(benzylsulfanyl)-5-chlorophenyl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide; N-[2-(benzylsulfinyl)-5-chlorophenyl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide; N-[2-(benzylsulfonyl)-5-chlorophenyl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide; N-[2-(benzylsulfanyl)-4-cyanophenyl]-1-benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-4-cyanophenyl]-1-benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-4-cyanophenyl]-1-benzofuran-2-sulfonamide; methyl 4-(((4-chloro-2-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)phenyl)thio)methyl)benzoate; 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid; 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid; 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid; tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)phenyl]carbonyl}amino)acetate; tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)phenyl]carbonyl}amino)acetate; tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)phenyl]carbonyl}amino)acetate; ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)phenyl]carbonyl}amino)acetic acid; ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)phenyl]carbonyl}amino)acetic acid; ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)phenyl]carbonyl}amino)acetic acid; methyl 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate; methyl 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoate; methyl 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoate; 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid; 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid; 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid; 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide; 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide; 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide; 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide; 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide; 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide; 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide; 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide; 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide; 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide; 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide; methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate; 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid; methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoate; 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid; methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoate; 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid; 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzamide; 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N,N-dimethylbenzamide; 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-ethylbenzamide; 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N,N-diethylpropanamide; 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-diethylpropanamide; 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-diethylpropanamide; 4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1-yl)propyl]sulfanyl}phenyl)-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1-yl)propyl]sulfinyl}phenyl)-3-(trifluoromethyl)benzenesulfonamide; 4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1-yl)propyl]sulfonyl}phenyl)-3-(trifluoromethyl)benzenesulfonamide; methyl 2-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)benzoate; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]benzoic acid; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]benzoic acid; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]benzoic acid; methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoic acid; methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoate; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoic acid; methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoate; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoic acid; methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate; 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoic acid; methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoate; 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoicacid; methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoate; 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoic acid; methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate; 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoic acid; methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoate; 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoic acid; methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoate; 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoic acid; methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfanyl)methyl]benzoate; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfanyl)methyl]benzoic acid; methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfinyl)methyl]benzoate; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfinyl)methyl]benzoic acid; methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfonyl)methyl]benzoate; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfonyl)methyl]benzoic acid; N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]phenyl}acetamide; N-(2-{[3-(acetylamino)benzyl]sulfanyl}-5-chlorophenyl)-N-(1-benzofuran-2-ylsulfonyl)acetamide; N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfanyl)phenyl]-1-benzofuran-2-sulfonamide; N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]phenyl}acetamide; N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]phenyl}acetamide; N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfinyl)phenyl]-1-benzofuran-2-sulfonamide; N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfonyl)phenyl]-1-benzofuran-2-sulfonamide; ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)acetic acid; ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)acetic acid; ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)acetic acid; methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate; 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoic acid; methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)propanoate; methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)propanoate; methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate; 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid; methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]propanoate; methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]propanoate; 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]propanoic acid; 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]propanoic acid; 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]-N-ethyl-N-methylpropanamide; 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N-ethyl-N-methylpropanamide; 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N-ethyl-N-methylpropanamide; methyl 2-(((2-(benzofuran-2-sulfonamido)-5-chlorophenyl)thio)methyl)benzoate; and 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-5-chlorophenyl}sulfanyl)methyl]benzoic acid.
6. A method of modulating chemokine receptors, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound selected from the group consisting of: benzofuran-2-sulfonic acid [2-(3-nitro-benzylsulfanyl)-phenyl]-amide; N-[6-(benzylsulfanyl)-1-oxo-2,3-dihydro-1H-inden-5-yl]-1-benzofuran-2-sulfonamide; N-[6-(benzylsulfinyl)-1-oxo-2,3-dihydro-1H-inden-5-yl]-1-benzofuran-2-sulfonamide; N-[6-(benzylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-5-yl]-1-benzofuran-2-sulfonamide; methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfanyl)methyl]benzoate; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfanyl)methyl]benzoic acid; methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfinyl)methyl]benzoate; 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfinyl)methyl]benzoic acid; methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfonyl)methyl]benzoate; and 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfonyl)methyl]benzoic acid.
Description
DETAILED DESCRIPTION OF THE INVENTION
(1) It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise.
(2) It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that the compounds may exist in enantiomeric as well as in diastereomeric forms.
(3) Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also within the scope of the invention.
(4) The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium .sup.2H (or D) in place of protium .sup.1H (or H) or use of .sup.13C enriched material in place of .sup.12C and the like. Similar substitutions can be employed for N, O and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents.
(5) As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diastereoisomeric isomers, chromatographic separation may be employed.
(6) Compound names were generated with ACD version 8 and some intermediates' and reagents' names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1. In general, characterization of the compounds is performed according to the following methods:
(7) NMR spectra are recorded on Varian 600 or Varian 300, in the indicated solvent at ambient temperature; chemical shifts in [ppm], coupling constants in [Hz].
(8) All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some known intermediates, were prepared according to published procedures. Solvents were purchased from commercial sources in appropriate quality and used as received. Air and/or moisture-sensitive reactions were run under an Ar- or N.sub.2-atmosphere.
(9) Usually the compounds of the invention were purified by chromatography: CombiFlash Companion and RediSep Rf silica gel 60 (0.04-0.063 mm); Preparative thin layer chromatography (PTLC): Analtech (silica gel 60 F.sub.254, 500 or 1000 μm).
(10) The following abbreviations are used in the examples: NH.sub.3 ammonia CH.sub.3CN acetonitrile CH.sub.2Cl.sub.2 dichloromethane DMF N,N-dimethylformamide NaOH sodium hydroxide MeOH methanol CD.sub.3OD deuterated methanol HCl hydrochloric acid Na.sub.2SO.sub.4 sodium sulfate HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) DIPEA N,N-Diisopropylethylamine CuI copper iodide Cs.sub.2CO.sub.3 cesium carbonate DMEDA N,N′-dimethylethylenediamine MgSO.sub.4 magnesium sulfate EtOAc ethyl acetate CDCl.sub.3 deuterated chloroform DMSO-d.sub.6 deuterated dimethyl sulfoxide TFA trifluoroacetic acid THF tetrahydrofuran K.sub.2CO.sub.3 potassium carbonate mCPBA meta-Chloroperoxybenzoic acid NaBH.sub.4 sodium borohydride CaCl.sub.2 calcium chloride
(11) The following examples are for illustrative purposes only and are not intended, nor should they be construed as limiting the invention in any manner. Those skilled in the art will appreciate that variations and modifications of the following examples can be made without exceeding the spirit or scope of the invention.
Specific Examples
General Procedure A
Intermediate 1
5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]aniline
(12) ##STR00003##
(13) A mixture of 2-amino-4-chlorobenzenethiol (CAS 1004-00-8) (1.1 g, 7.1 mmol), 4-(chloromethyl)-1H-imidazole hydrochloride (721 mg, 4.71 mmol) and K.sub.2CO.sub.3 (3.2 g, 23.6 mmol) in DMF (10 ml) was stirred at room temperature over night. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×50 ml). The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0.fwdarw.100% ethyl acetate in hexane) to give Intermediate 1 as a solid (1.0 g, 60%).
(14) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.58 (s, 1H), 7.06 (d, J=8.20 Hz, 1H), 6.73 (d, J=2.34 Hz, 1H), 6.65 (s, 1H), 6.48 (dd, J=2.34, 8.20 Hz, 1H), 3.86 (s, 2H).
General Procedure B
Compound 1
N-{5-chloro-2-[(1H-imidazol-4-yl methyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(15) ##STR00004##
(16) A mixture of Intermediate 1 (300 mg, 1.26 mmol) and 1-benzofuran-2-sulfonyl chloride (273 mg, 1.26 mmol) in pyridine (4 ml) was heated at 100° C. overnight. Pyridine was removed under reduced pressure and the residue was purified by column chromatography on silica gel (10% MeOH in CH.sub.2Cl.sub.2) to give Compound 1 (157 mg, 30%).
(17) .sup.1H NMR (600 MHz, acetone-d.sub.6) δ 7.94 (s, 1H), 7.73 (d, J=7.92 Hz, 1H), 7.64 (d, J=2.35 Hz, 1H), 7.56 (d, J=8.51 Hz, 1H), 7.52 (d, J=8.22 Hz, 1H), 7.44-7.49 (m, 1H), 7.42 (s, 1H), 7.28-7.37 (m, 1H), 7.11 (dd, J=2.35, 8.22 Hz, 1H), 6.97 (s, 1H), 3.91 (s, 2H).
Compound 2
N-[5-chloro-2-(methylthio)phenyl]-1-benzofuran-2-sulfonamide
(18) ##STR00005##
(19) Following General Procedure B, the title compound (243 mg, 60%) was prepared from 5-chloro-2-(methylthio)aniline (CAS 16423-54-4) (200 mg, 1.15 mmol) and 1-benzofuran-2-sulfonyl chloride (249 mg, 1.152 mmol).
(20) .sup.1H NMR (600 MHz, acetone-d.sub.6) δ 7.75 (d, J=7.92 Hz, 1H), 7.60 (d, J=8.51 Hz, 1H), 7.48-7.54 (m, 2H), 7.47 (d, J=2.35 Hz, 1H), 7.29-7.38 (m, 2H), 7.22 (dd, J=2.35, 8.51 Hz, 1H), 2.22 (s, 3H).
General Procedure C
Compound 3
N-[5-chloro-2-(methylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide
(21) ##STR00006##
(22) To a solution of Compound 2 (194 mg, 0.554 mmol) in CH.sub.2Cl.sub.2 (6 ml) at 0° C. was added mCPBA (111 mg, ˜0.554 mmol). After it was stirred for 30 min at 0° C., the mixture was separated into two portions. One portion (2 ml) was concentrated in vacuo and purified by column chromatography on silica gel (0.fwdarw.100% ethyl acetate in hexane followed by 0.fwdarw.10% MeOH in CH.sub.2Cl.sub.2) to give the title compound as a solid (35 mg, 52%).
(23) Alternatively, the title compound can be prepared by treating Compound 2 with 1 equivalent of NaIO.sub.4 in MeOH/CH.sub.3CN and H.sub.2O at 0° C. to room temperature.
(24) In another alternative procedure, the title compound can be prepared by treating Compound 2 with 1-1.4 equivalent of Oxone® in MeOH/CH.sub.3CN and H.sub.2O at room temperature.
(25) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.74 (d, J=1.76 Hz, 1H), 7.71 (d, J=8.22 Hz, 1H), 7.52-7.59 (m, 2H), 7.49 (td, J=1.17, 7.78 Hz, 1H), 7.32-7.39 (m, 1H), 7.25 (d, J=8.22 Hz, 1H), 7.15 (dd, J=1.91, 8.36 Hz, 1H), 2.88 (s, 3H).
General Procedure D
Compound 4
N-[5-chloro-2-(methylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide
(26) ##STR00007##
(27) To the other portion (4 ml) of solution from Compound 3 was added mCPBA (111 mg, 0.554 mmol) and the reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0.fwdarw.100% ethyl acetate in hexane) to give the title compound as a solid (75 mg, 53%).
(28) Alternatively, the title compound can be prepared by treating Compound 2 with 2-3 equivalents of mCPBA at room temperature.
(29) In another alternative procedure, the title compound can be prepared by treating Compound 2 with 3 equivalents of Oxone® in MeOH/CH.sub.3CN and H.sub.2O at room temperature.
(30) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 9.43 (s, 1H), 7.88 (d, J=1.76 Hz, 1H), 7.81 (d, J=8.51 Hz, 1H), 7.72 (d, J=7.92 Hz, 1H), 7.61 (s, 1H), 7.47-7.57 (m, 2H), 7.34-7.40 (m, 1H), 7.26 (s, 1H), 7.23 (dd, J=2.05, 8.51 Hz, 1H), 3.05 (s, 3H).
Intermediate 2
5-chloro-2-(methylsulfinyl)aniline
(31) ##STR00008##
(32) Following General Procedure C, the title compound (914 mg, 84%) was prepared from 5-chloro-2-(methylthio)aniline (1 g, 5.758 mmol).
(33) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.32 (d, J=8.20 Hz, 1H), 6.81 (d, J=2.05 Hz, 1H), 6.72 (dd, J=1.76, 8.20 Hz, 1H), 2.86 (s, 3H).
Compound 5
3,4-dichloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide
(34) ##STR00009##
(35) Following General Procedure B, the title compound (52 mg, 21%) was prepared from 5-chloro-2-(methylsulfinyl)aniline (Intermediate 2) (120 mg, 0.635 mmol) and 3,4-dichlorobenzene-1-sulfonyl chloride (156 mg, 0.635 mmol).
(36) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.87 (d, J=1.76 Hz, 1H), 7.55-7.70 (m, 2H), 7.38 (s, 1H), 7.17-7.27 (m, 2H), 2.22 (s, 3H).
Compound 6
3,4-dichloro-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide
(37) ##STR00010##
(38) Following General Procedure C, the title compound (28 mg, 52%) was prepared from 3,4-dichloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide (52 mg, 0.136 mmol).
(39) .sup.1H NMR (300 MHz, acetone-d.sub.6) δ 10.70 (br. s., 1H), 8.06 (s, 1H), 7.86 (s, 2H), 7.44-7.59 (m, 2H), 7.34 (dd, J=1.90, 8.35 Hz, 1H), 2.84 (s, 3H).
Compound 7
4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-methylbenzenesulfonamide
(40) ##STR00011##
(41) Following General Procedure B and C, the title compound (90 mg) was prepared from 5-chloro-2-(methylthio)aniline and 4-chloro-3-methylbenzene-1-sulfonyl chloride.
(42) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 10.62 (s, 1H), 7.82 (d, J=2.05 Hz, 1H), 7.71 (dd, J=1.91, 8.36 Hz, 1H), 7.63 (d, J=2.05 Hz, 1H), 7.48 (d, J=8.51 Hz, 1H), 7.02-7.15 (m, 2H), 2.81 (s, 3H), 2.43 (s, 3H).
Compound 8
N-[5-chloro-2-(methylsulfinyl)phenyl]-4-nitro-3-(trifluoromethyl)benzenesulfonamide
(43) ##STR00012##
(44) Following General Procedure B and C, the title compound (43 mg) was prepared from 5-chloro-2-(methylthio)aniline and 4-nitro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.
(45) .sup.1H NMR (600 MHz, acetone-d.sub.6) δ 8.25-8.35 (m, 2H), 8.11 (d, J=8.22 Hz, 1H), 7.39-7.48 (m, 2H), 6.75 (dd, J=2.05, 8.22 Hz, 1H), 2.70 (s, 3H).
Compound 9
4-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide
(46) ##STR00013##
(47) Following General Procedure B, the title compound (380 mg, 66%) was prepared from 5-chloro-2-(methylthio)aniline (273 mg, 1.57 mmol) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride (360 mg, 1.57 mmol).
(48) .sup.1H NMR (300 MHz, acetone-d.sub.6) δ 8.77 (br. s., 1H), 7.84 (t, J=8.06 Hz, 1H), 7.53 (dd, J=1.90, 9.82 Hz, 1H), 7.35-7.48 (m, 3H), 7.25 (dd, J=2.20, 8.35 Hz, 1H), 2.34 (s, 3H).
Compound 10
4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(49) ##STR00014##
(50) Following General Procedure B and D, the title compound (95 mg, 36%) was prepared from 5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]aniline (301 mg, 1.26 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (351 mg, 1.26 mmol).
(51) .sup.1H NMR (600 MHz, acetone-d.sub.6) δ 8.27 (s, 1H), 8.15 (d, J=8.22 Hz, 1H), 7.81 (br. s., 1H), 7.73 (d, J=8.51 Hz, 1H), 7.68 (d, J=8.51 Hz, 1H), 7.30 (s, 1H), 6.91 (dd, J=1.47, 8.51 Hz, 1H), 4.56 (br. s., 2H).
Intermediate 3
tert-butyl [4-(chloromethyl)-1,3-thiazol-2-yl]carbamate
(52) ##STR00015##
(53) A solution of 4-(chloromethyl)-1,3-thiazol-2-amine hydrochloride (530 mg, 2.86 mmol), di-tert-butyl dicarbonate (750 mg, 3.44 mmol), triethylamine (0.6 ml, 4.30 mmol) and DMAP (cat. amount) in THF (10 ml) was stirred at room temperature overnight. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by column chromatography (30% ethyl acetate in hexane) to give the title compound as a solid (391 mg, 45%).
(54) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.02 (s, 1H), 4.56 (s, 2H), 1.54 (s, 9H).
Intermediate 4
tert-butyl (4-{[(2-amino-4-chlorophenyl)thio]methyl}-1,3-thiazol-2-yl)carbamate
(55) ##STR00016##
(56) Following General Procedure A, the title compound (588 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (376 mg, 2.36 mmol), tert-butyl [4-(chloromethyl)-1,3-thiazol-2-yl]carbamate (391 mg, 1.57 mmol) and K.sub.2CO.sub.3 (1.08 g, 3.45 mmol) in DMF (10 ml).
(57) .sup.1H NMR (300 MHz, acetone-d.sub.6) δ 10.18 (br. s., 1H), 7.17 (d, J=8.21 Hz, 1H), 6.79 (d, J=2.34 Hz, 1H), 6.62 (s, 1H), 6.51 (dd, J=2.05, 8.20 Hz, 1H), 5.30 (br. s., 1H), 3.88 (s, 2H), 1.53 (s, 9H).
Compound 11
tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}carbamate
(58) ##STR00017##
(59) Following General Procedure B, the title compound (380 mg, 54%) was prepared from tert-butyl (4-{[(2-amino-4-chlorophenyl)thio]methyl}-1,3-thiazol-2-yl)carbamate (640 mg, 1.72 mmol) and 1-benzofuran-2-sulfonyl chloride (372 mg, 1.72 mmol) in pyridine (5 ml).
(60) .sup.1H NMR (300 MHz, acetone-d.sub.6) δ 11.20 (br. s., 1H), 9.82 (br. s., 1H), 7.78 (d, J=7.91 Hz, 2H), 7.67 (d, J=2.34 Hz, 1H), 7.62 (s, 1H), 7.45-7.60 (m, 3H), 7.31-7.43 (m, 1H), 7.07-7.22 (m, 1H), 6.77 (s, 1H), 3.93 (s, 2H), 1.55 (s, 9H).
General Procedure E
Compound 12
N-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(61) ##STR00018##
(62) A solution of tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}carbamate Compound 11 (62 mg, 0.11 mmol), TFA (0.2 ml) in CH.sub.2Cl.sub.2 (1 ml) was stirred overnight. The solvent was removed in vacuo and the crude product was purified by column chromatography on silica gel (50% ethyl acetate in hexane) to afford the title compound (45 mg, 88%).
(63) .sup.1H NMR (600 MHz, acetone-d.sub.6) δ 8.78 (br. s., 1H), 7.77 (d, J=7.92 Hz, 0H), 7.55-7.66 (m, 3H), 7.45-7.55 (m, 2H), 7.29-7.41 (m, 1H), 7.17 (dd, J=2.20, 8.36 Hz, 1H), 6.33 (s, 1H), 3.90 (s, 2H).
Compound 13
4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide
(64) ##STR00019##
(65) Following General Procedure B and C, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.
(66) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.07 (s, 1H), 7.96 (d, J=8.50 Hz, 1H), 7.82 (d, J=8.21 Hz, 1H), 7.76 (d, J=8.50 Hz, 1H), 7.41 (d, J=7.91 Hz, 1H), 7.07 (s, 1H), 2.83 (s, 3H).
General Procedure F
Intermediate 5
N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide]
(67) ##STR00020##
(68) To a solution of 2,2′-dithiobis(5-chloroaniline) (CAS 29124-55-8)(1.59 g, 5.0 mmol) in pyridine (20 ml) was added 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (2.76 g, 10.0 mmol) and the reaction was stirred at room temperature for 16 h. Additional 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (2.76 g, 10.0 mmol) and pyridine (20 ml) was added, and the reaction was stirred for 20 h. The mixture was concentrated in vacuo and H.sub.2O was added. A gum-like semi-solid was formed. After decanting H.sub.2O, the semi-solid was rinsed with H.sub.2O (×2), taken in EtOAc, extracted with 1M HCl (×2), washed with H.sub.2O, brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to give a brown thick syrup (6.5 g). To a solution of the crude syrup in methanol (100 ml) was added 4M NaOH (12 ml), and the mixture was heated at 100° C. for 15 min, cooled to room temperature, quenched slowly with 1M HCl (˜50 ml) with stirring and cooling to pH 4-5. The volume of the resulting suspension was reduced in vacuo, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude solid containing sulfonic acid was pulverized in saturated NaHCO.sub.3, and filtered, rinsed with minimal amount of diethyl ether to yield the title compound as an off-white solid (3.11 g).
(69) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.08 (d, J=2.05 Hz, 2H), 7.93 (dd, J=2.20, 8.36 Hz, 2H), 7.81 (d, J=8.51 Hz, 2H), 7.22 (d, J=2.05 Hz, 2H), 7.18-7.20 (m, 2H), 7.10 (d, J=8.51 Hz, 2H).
Compound 14
4-chloro-N-[5-chloro-2-(ethylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide
(70) ##STR00021##
(71) To a solution of N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide] Intermediate 5 (0.32 g, 0.40 mmol) in CH.sub.2Cl.sub.2 (10 ml) was added saturated aqueous NaHCO.sub.3 (1.0 ml), polymer-bound triphenylphosphine (˜3 mmol/g triphenylphosphine loading, 0.27 g, 0.80 mmol), and ethyl iodide (64 μl, 0.80 mmol). The reaction was stirred at room temperature for 2 h and was diluted with EtOAc, filtered, and washed with brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel (0-25% ethyl acetate in hexane) to yield the title compound as a yellow syrup (204 mg, 59%).
(72) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.12 (d, J=2.35 Hz, 1H), 7.88 (dd, J=2.35, 8.22 Hz, 1H), 7.82 (br. s., 1H), 7.64 (d, J=2.35 Hz, 1H), 7.59 (d, J=8.51 Hz, 1H), 7.32 (d, J=8.22 Hz, 1H), 7.06 (dd, J=2.20, 8.36 Hz, 1H), 2.60 (q, J=7.34 Hz, 2H), 1.10 (t, J=7.34 Hz, 3H).
Compound 15
4-chloro-N-[5-chloro-2-(ethylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide
(73) ##STR00022##
(74) Following General Procedure C, the title compound was prepared from 4-chloro-N-[5-chloro-2-(ethylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide.
(75) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.15 (d, J=2.35 Hz, 1H), 8.00 (dd, J=2.20, 8.36 Hz, 1H), 7.72 (d, J=8.51 Hz, 1H), 7.44 (d, J=8.51 Hz, 1H), 7.27 (d, J=2.05 Hz, 1H), 7.01 (dd, J=2.05, 8.51 Hz, 1H), 3.10-3.18 (m, 1H), 2.89-2.97 (m, 1H), 1.11 (t, J=7.34 Hz, 3H).
Intermediate 6
ethyl 6-[(tert-butoxycarbonyl)amino]pyridine-2-carboxylate
(76) ##STR00023##
(77) A mixture of ethyl 6-aminopyridine-2-carboxylate (1.57 g, 9.43 mmol), DMAP (1.12 g, 9.18 mmol), and di-tert-butyl dicarbonate (2.46 g, 11.3 mmol) in THF (45 ml) was heated at 60° C. for 16 h. The solvent was removed and the residue was purified by chromatography on silica gel (10.fwdarw.15% ethyl acetate in hexane) to yield the title compound as a white solid (2.50 g, 100%).
Intermediate 7
tert-butyl [6-(chloromethyl)pyridin-2-yl]carbamate
(78) ##STR00024##
(79) To a solution of ethyl 6-[(tert-butoxycarbonyl)amino]pyridine-2-carboxylate (456 mg, 1.71 mmol) in anhydrous ethanol (20 ml) was added pulverized CaCl.sub.2 (395 mg, 3.42 mmol). The suspension was stirred and cooled to 0° C. and NaBH.sub.4 (325 mg, 8.55 mmol) was added slowly. The reaction was stirred at 0° C. for 2 h, quenched with water, and extracted with CHCl.sub.3 (×3). The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel (30.fwdarw.50% ethyl acetate in hexane) to yield a colorless syrup (308 mg) as a mixture containing tert-butyl [6-(hydroxymethyl)pyridin-2-yl]carbamate as the major component (˜4:1 ratio). To a solution of the above mixture in CH.sub.2Cl.sub.2 (10 ml) was added pyridine (144 μl, 1.79 mmol) and SOCl.sub.2 (120 μl, 1.65 mmol). The reaction was stirred at room temperature for 4 h, quenched with water and saturated Na.sub.2CO.sub.3, and extracted with CHCl.sub.3. The combined organic layer was dried over Na.sub.2SO.sub.4 and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexane) to yield the title compound as a colorless syrup (208 mg, 50% over 2 steps).
Intermediate 8
N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide)
(80) ##STR00025##
(81) Following General Procedure F, the title compound was prepared from 2,2′-dithiobis(5-chloroaniline) and 1-benzofuran-2-sulfonyl chloride.
(82) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.72 (d, J=7.92 Hz, 2H), 7.55 (dd, J=0.59, 8.51 Hz, 2H), 7.48 (s, 2H), 7.32-7.37 (m, 4H), 7.22 (d, J=2.05 Hz, 2H), 6.99-7.02 (m, 2H), 6.96-6.99 (m, 2H).
General Procedure G
Compound 16
tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate
(83) ##STR00026##
(84) To a solution of N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide) (271 mg, 0.40 mmol) in CH.sub.2Cl.sub.2 (4 ml) and dioxane (4 ml) was added saturated aqueous NaHCO.sub.3 (4 ml), polymer-bound triphenylphosphine (˜3 mmol/g triphenylphosphine loading, 0.40 g, 1.20 mmol), tert-butyl [6-(chloromethyl)pyridin-2-yl]carbamate (195 mg, 0.80 mmol), and tetrabutylammonium iodide (30 mg, 0.08 mmol). The reaction was stirred at room temperature for 4 h and was diluted with EtOAc, filtered, and washed with brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel (10.fwdarw.15% ethyl acetate in hexane) to yield the title compound as a yellow solid (260 mg, 59%).
(85) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.74 (d, J=8.22 Hz, 1H), 7.70 (d, J=7.63 Hz, 1H), 7.50-7.57 (m, 2H), 7.44-7.50 (m, 2H), 7.41 (s, 1H), 7.31-7.36 (m, 2H), 7.09 (d, J=8.22 Hz, 1H), 6.65 (d, J=7.34 Hz, 1H), 3.88 (s, 2H), 1.54 (s, 9H).
Compound 17
N-(2-{[(6-aminopyridin-2-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(86) ##STR00027##
(87) Following General Procedure E, the title compound (33 mg, 78%) was prepared from tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.
(88) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.63 (d, J=7.92 Hz, 1H), 7.58 (d, J=2.35 Hz, 1H), 7.40-7.44 (m, 1H), 7.35-7.40 (m, 2H), 7.31-7.35 (m, 2H), 7.26 (ddd, J=0.88, 7.04, 7.92 Hz, 1H), 6.95 (dd, J=2.35, 8.22 Hz, 1H), 6.55 (d, J=8.51 Hz, 1H), 6.31 (d, J=7.04 Hz, 1H), 3.78 (s, 2H).
Compound 18
tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]pyridin-2-yl}carbamate
(89) ##STR00028##
(90) Following General Procedure C, the title compound (98 mg, 91%) was prepared from tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.
(91) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.67 (d, J=8.22 Hz, 1H), 7.64 (d, J=7.04 Hz, 1H), 7.47 (d, J=2.05 Hz, 1H), 7.42-7.46 (m, 1H), 7.36-7.39 (m, 1H), 7.29-7.33 (m, 1H), 7.22-7.26 (m, 2H), 7.09 (d, J=8.22 Hz, 1H), 6.77 (dd, J=1.91, 8.36 Hz, 1H), 6.68 (d, J=7.34 Hz, 1H), 4.59 (d, J=12.62 Hz, 1H), 4.16 (d, J=12.62 Hz, 1H), 1.52 (s, 9H).
Compound 19
N-(2-{[(6-aminopyridin-2-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(92) ##STR00029##
(93) Following General Procedure E, the title compound (71 mg, 91%) was prepared from tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]pyridin-2-yl}carbamate.
(94) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.65 (d, J=7.91 Hz, 1H), 7.52-7.62 (m, 1H), 7.50 (d, J=1.47 Hz, 1H), 7.39-7.46 (m, 1H), 7.29-7.38 (m, 2H), 7.20-7.29 (m, 2H), 6.89 (dd, J=1.47, 8.50 Hz, 1H), 6.79 (d, J=8.79 Hz, 1H), 6.44 (d, J=7.03 Hz, 1H), 4.60 (d, J=13.48 Hz, 1H), 4.25 (d, J=13.19 Hz, 1H).
Compound 20
tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate
(95) ##STR00030##
(96) Following General Procedure D, the title compound (60 mg, 56%) was prepared from tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.
(97) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.79 (d, J=1.76 Hz, 1H), 7.65 (d, J=7.62 Hz, 1H), 7.55 (d, J=8.50 Hz, 1H), 7.44 (s, 1H), 7.18-7.40 (m, 5H), 6.72 (dd, J=1.76, 8.50 Hz, 1H), 6.60 (d, J=7.33 Hz, 1H), 4.97 (s, 2H), 1.51 (s, 9H).
Compound 21
N-(2-{[(6-aminopyridin-2-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(98) ##STR00031##
(99) Following General Procedure E, the title compound (47 mg, 94%) was prepared from tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate.
(100) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.73 (d, J=2.05 Hz, 1H), 7.66 (d, J=7.62 Hz, 1H), 7.52 (d, J=8.79 Hz, 1H), 7.20-7.44 (m, 4H), 7.14 (t, J=7.77 Hz, 1H), 6.73 (dd, J=1.76, 8.50 Hz, 1H), 6.48 (d, J=8.20 Hz, 1H), 6.28 (d, J=7.33 Hz, 1H), 4.91 (s, 2H).
Compound 22
tert-butyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1H-pyrazole-1-carboxylate
(101) ##STR00032##
(102) Following General Procedure G, the title compound (206 mg, 36%) was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide) and tert-butyl 3-(bromomethyl)-1H-pyrazole-1-carboxylate.
(103) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.30 (br. s., 1H), 7.93 (d, J=2.64 Hz, 1H), 7.62-7.67 (m, 2H), 7.47-7.52 (m, 1H), 7.42-7.45 (m, 1H), 7.41 (s, 1H), 7.34 (d, J=8.22 Hz, 1H), 7.28-7.32 (m, 1H), 7.00 (dd, J=2.20, 8.36 Hz, 1H), 6.03 (d, J=2.64 Hz, 1H), 3.88 (s, 2H), 1.64 (s, 9H).
Compound 23
N-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(104) ##STR00033##
(105) Following General Procedure E, the title compound (15 mg, 66%) was prepared from tert-butyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1H-pyrazole-1-carboxylate.
(106) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.70 (d, J=7.92 Hz, 1H), 7.51-7.55 (m, 1H), 7.45-7.50 (m, 2H), 7.37-7.44 (m, 2H), 7.34 (t, J=7.19 Hz, 1H), 7.25-7.31 (m, 1H), 7.11 (dd, J=1.76, 8.22 Hz, 1H), 5.88 (br. s., 1H), 3.89 (s, 2H).
General Procedure H
Intermediate 9
3-[(2-amino-4-chlorophenyl)thio]-N,N-dimethylpropanamide
(107) ##STR00034##
(108) A mixture of 2-amino-4-chlorobenzenethiol (327 mg, 2.05 mmol), N,N-dimethylacrylamide (203 mg, 2.05 mmol) and HOAc (0.5 ml) in CH.sub.2Cl.sub.2 (5 ml) was stirred at room temperature for 3 days. The reaction was quenched with NaHCO.sub.3 (aq.) and then extracted with CH.sub.2Cl.sub.2 (2×10 ml). The organic layer was washed with water and brine and concentrated in vacuo. The crude product was purified by chromatography on silica gel (50% ethyl acetate in hexane) to yield the title compound (284 mg, 54%).
(109) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.26 (d, J=8.21 Hz, 1H), 6.76 (d, J=2.05 Hz, 1H), 6.56 (dd, J=2.34, 8.20 Hz, 1H), 2.85-3.02 (m, 8H), 2.57 (t, J=7.03 Hz, 2H).
Compound 24
3-{[4-Chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylpropanamide
(110) ##STR00035##
(111) Following General Procedure B and C, the title compound (280 mg) was prepared from 3-[(2-amino-4-chlorophenyl)thio]-N,N-dimethylpropanamide (284 mg, 1.11 mmol).
(112) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.16 (d, J=1.76 Hz, 1H), 8.00 (dd, J=2.05, 8.22 Hz, 1H), 7.75 (d, J=8.51 Hz, 1H), 7.57 (d, J=8.51 Hz, 1H), 7.32 (s, 1H), 7.21 (d, J=7.92 Hz, 1H), 3.26 (br. s., 1H), 3.18 (br. s., 1H), 3.02 (s, 3H), 2.95 (s, 3H), 2.83-2.91 (m, 1H), 2.62-2.76 (m, 1H).
Compound 25
tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}carbamate
(113) ##STR00036##
(114) Following General Procedure C, tert-butyl (4-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)thiazol-2-yl)carbamate (138 mg, 0.25 mmol) was oxidized to the title compound (97 mg, 68%).
(115) 1H NMR (600 MHz, acetone-d6) δ 10.43 (br. s., 1H), 7.75-7.84 (m, 2H), 7.66 (d, J=2.05 Hz, 1H), 7.62 (dd, J=0.88, 8.51 Hz, 1H), 7.50 (ddd, J=1.32, 7.26, 8.44 Hz, 1H), 7.32-7.41 (m, 1H), 7.11-7.24 (m, 2H), 6.74 (s, 1H), 4.47 (d, J=12.91 Hz, 1H), 4.37 (d, J=12.91 Hz, 1H), 1.50 (s, 9H).
Compound 26
N-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(116) ##STR00037##
(117) Following General Procedure E, tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}carbamate (87 mg, 0.153 mmol) was de-Boc to give the title compound (58 mg, 82%).
(118) 1H NMR (600 MHz, acetone-d6) δ 10.43 (br. s., 1H), 7.75-7.84 (m, 2H), 7.66 (d, J=2.05 Hz, 1H), 7.62 (dd, J=0.88, 8.51 Hz, 1H), 7.50 (ddd, J=1.32, 7.26, 8.44 Hz, 1H), 7.32-7.41 (m, 1H), 7.11-7.24 (m, 2H), 6.74 (s, 1H), 4.47 (d, J=12.91 Hz, 1H), 4.37 (d, J=12.91 Hz, 1H), 1.50 (s, 9H).
Compound 27
tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1,3-thiazol-2-yl}carbamate
(119) ##STR00038##
(120) Following General Procedure D, the title compound (112 mg, 90%) was prepared from tert-butyl (4-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)thiazol-2-yl)carbamate (117 mg, 0.212 mmol).
(121) 1H NMR (600 MHz, acetone-d6) δ 7.80 (d, J=7.92 Hz, 2H), 7.78 (d, J=1.76 Hz, 1H), 7.67 (d, J=8.51 Hz, 1H), 7.59 (d, J=7.92 Hz, 1H), 7.50 (t, J=7.63 Hz, 1H), 7.37 (t, J=7.48 Hz, 1H), 6.99 (s., 1H), 4.70 (s., 2H), 1.53 (s, 9H)
(122) 1H NMR (600 MHz, acetone-d6) δ 7.80 (d, J=7.92 Hz, 2H), 7.67 (d, J=8.51 Hz, 1H), 7.60 (br. s., 1H), 7.50 (t, J=7.63 Hz, 1H), 7.33-7.41 (m, 1H), 6.99 (br. s., 1H), 4.70 (br. s., 2H), 1.53 (s, 9H).
Compound 28
N-(2-{[(2-amino-1,3-thiazol-4-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(123) ##STR00039##
(124) Following General Procedure E, the title compound (54 mg, 86%) was prepared from tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}carbamate (77 mg, 0.153 mmol).
(125) 1H NMR (600 MHz, acetone-d6) δ 7.74-7.85 (m, 2H), 7.68 (d, J=2.35 Hz, 1H), 7.64 (dd, J=0.88, 8.51 Hz, 1H), 7.53 (ddd, J=1.32, 7.19, 8.51 Hz, 1H), 7.39 (ddd, J=0.88, 7.26, 8.00 Hz, 1H), 7.16-7.24 (m, 2H), 6.74 (s, 1H), 4.32-4.46 (m, 2H), 1.47-1.55 (m, 9H).
Intermediate 10
5-chloro-2-(((5-nitro-1H-pyrazol-3-yl)methyl)thio)aniline
(126) ##STR00040##
(127) (5-Nitro-1H-pyrazol-3-yl)methanol (524 mg, 3.66 mmol) was first treated with SOCl.sub.2 (3 ml) in CH.sub.2Cl.sub.2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 3-(chloromethyl)-5-nitro-1H-pyrazole. Then following General Procedure A, the title compound (515 mg, 49%) was prepared from 2-amino-4-chlorobenzenethiol (161 mg, 1.01 mmol), crude 3-(chloromethyl)-5-nitro-1H-pyrazole, K.sub.2CO.sub.3 (468 mg, 3.39 mmol) in DMF (3 ml).
(128) 1H NMR (600 MHz, CD.sub.3OD) δ 7.05 (d, J=8.22 Hz, 1H), 6.77 (d, J=2.35 Hz, 1H), 6.60 (s, 1H), 6.49 (dd, J=2.05, 8.22 Hz, 1H), 3.95 (s, 2H).
Compound 29
N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide
(129) ##STR00041##
(130) Following General Procedure B, the title compound (580 mg, 71%) was prepared from 5-chloro-2-(((5-nitro-1H-pyrazol-3-yl)methyl)thio)aniline (503 mg, 1.77 mmol) and benzofuran-2-sulfonyl chloride (384 mg, 1.77 mmol) in pyridine (5 ml).
(131) 1H NMR (600 MHz, CD.sub.3OD) δ 7.70-7.73 (m, 1H), 7.53-7.56 (m, 1H), 7.49 (d, J=1.47 Hz, 1H), 7.47-7.49 (m, 1H), 7.47 (d, J=1.17 Hz, 1H), 7.45 (d, J=2.35 Hz, 1H), 7.44 (d, J=0.88 Hz, 1H), 7.35 (ddd, J=0.88, 7.26, 8.00 Hz, 1H), 7.15 (dd, J=2.35, 8.22 Hz, 1H), 6.42 (s, 1H), 3.97 (s, 2H).
Compound 30
N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(132) ##STR00042##
(133) Following General Procedure C, the title compound (155 mg, 61%) was prepared from N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide (245 mg, 0.528 mmol).
(134) 1H NMR (600 MHz, CD.sub.3OD) δ 7.67 (dt, J=0.77, 7.56 Hz, 1H), 7.42-7.45 (m, 2H), 7.35 (td, J=1.32, 7.85 Hz, 1H), 7.24-7.29 (m, 2H), 7.09 (d, J=8.22 Hz, 1H), 6.85 (d, J=8.22 Hz, 1H), 6.33 (s, 1H), 4.61 (d, J=14.09 Hz, 1H), 4.48 (d, J=14.09 Hz, 1H).
General Procedure I
Compound 31
N-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(135) ##STR00043##
(136) N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide (77 mg, 0.166 mmol) was reduced to the title compound under H.sub.2 balloon in the present of Pd/C (10% wt, 18 mg) in MeOH (3 ml).
(137) 1H NMR (600 MHz, CD.sub.3OD) δ 7.70 (d, J=7.92 Hz, 1H), 7.52-7.56 (m, 2H), 7.48 (ddd, J=1.17, 7.12, 8.44 Hz, 1H), 7.44 (s, 1H), 7.40 (s, 1H), 7.34 (t, J=7.48 Hz, 1H), 7.28 (d, J=8.51 Hz, 1H), 7.11 (dd, J=2.20, 8.36 Hz, 1H), 3.74 (s, 2H).
Compound 32
N-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(138) ##STR00044##
(139) Following the General Procedure I, the title compound (39 mg, 91%) was reduced from N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide (46 mg, 0.096 mmol).
(140) 1H NMR (600 MHz, CD.sub.3OD) δ 7.91-7.99 (m, 1H), 7.67-7.72 (m, 1H), 7.56-7.62 (m, 1H), 7.50-7.55 (m, 1H), 7.41-7.48 (m, 2H), 7.29-7.40 (m, 2H), 7.13 (dd, J=1.91, 8.36 Hz, 1H), 4.55 (d, J=13.79 Hz, 1H), 4.05 (d, J=13.79 Hz, 1H)
Compound 33
N-(2-{[(5-amino-1H-pyrazol-3-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(141) ##STR00045##
(142) Following General Procedure D and H, the title compound (27 mg) was prepared from N-(5-chloro-2-{[(5-nitro-1H-pyrazol-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(143) 1H NMR (600 MHz, CD.sub.3OD) δ 7.69-7.74 (m, 2H), 7.62-7.58 (m, 3H), 7.51 (dd, J=0.59, 8.51 Hz, 1H), 7.44 (ddd, J=1.17, 7.12, 8.44 Hz, 1H), 7.26-7.35 (m, 1H), 7.09 (dd, J=1.91, 8.66 Hz, 1H), 4.59 (s, 2H).
Intermediate 11
1-propyl-1H-imidazole-4-carbaldehyde
(144) ##STR00046##
(145) To a suspension of NaH (95%, 231 mg, 9.18 mmol) in THF (20 ml) was added 4-imidazole carboxaldehyde (588 mg, 6.12 mmol) under ice cooling. The mixture was refluxed for 2 hours under nitrogen atmosphere. The mixture was cooled to room temperature and 1-iodopropane (5 ml) was added to the mixture and then refluxed for another 2 hours. The mixture was cooled down to rt and quenched with water. The solution was extracted with EtOAc (2×50 ml), washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo. The crude product was purified by column chromatography on silica gel (0-10% MeOH in CH.sub.2Cl.sub.2) to give the title compound (487 mg, 58%).
(146) 1H NMR (600 MHz, CD.sub.3OD) δ 9.73 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 4.07 (t, J=7.04 Hz, 2H), 1.73-1.92 (m, 2H), 0.93 (t, J=7.34 Hz, 3H).
Intermediate 12
(1-propyl-1H-imidazol-4-yl)methanol
(147) ##STR00047##
(148) To a solution of LAH (2.0 M in THF, 1.9 ml, 3.882 mmol) in THF (10 ml) was added dropwise a solution of 1-propyl-1H-imidazole-4-carbaldehyde (487 mg, 3.529 mmol) in THF (4 ml) at 0° C. After stirred at 0° C. for 5 min, water (0.2 ml), 15% NaOH (0.2 ml) was added dropwise to the reaction mixture under 0° C. The mixture was further stirred at room temperature for 2 hours. MgSO.sub.4 was added to the mixture and the solid was filtered away and the filtrate was concentrated in vacuo to get a yellow oil and used without further purification.
(149) 1H NMR (600 MHz, CDCl) δ 7.42 (s, 1H), 6.86 (s, 1H), 4.59 (s, 2H), 3.87 (t, J=7.04 Hz, 2H), 1.73-1.82 (m, 2H), 0.93 (t, J=7.34 Hz, 3H).
Intermediate 13
5-chloro-2-(((1-propyl-1H-imidazol-4-yl)methyl)thio)aniline
(150) ##STR00048##
(151) (1-propyl-1H-imidazol-4-yl)methanol (535 mg, 3.11 mmol) was first treated with SOCl.sub.2 (3 ml) in CH.sub.2CO.sub.2 (5 ml) at 35° C. for 2 hrs. The solvent was removed to get a crude 4-(chloromethyl)-1-propyl-1H-imidazole. Then following General Procedure A, the title compound (587 mg, 67%) was prepared from 2-amino-4-chlorobenzenethiol (744 mg, 4.66 mmol), 4-(chloromethyl)-1-propyl-1H-imidazole, K.sub.2CO.sub.3 (2.1 g, 15.54 mmol) in DMF (10 ml).
(152) 1H NMR (600 MHz, CDCL.sub.3) δ 7.38 (s, 1H), 7.17 (d, J=8.22 Hz, 1H), 6.67 (d, J=2.05 Hz, 1H), 6.57 (dd, J=2.20, 8.07 Hz, 1H), 6.51 (s, 1H), 3.85 (s, 2H), 3.79 (t, J=7.04 Hz, 2H), 1.67-1.76 (m, 2H), 0.88 (t, J=7.34 Hz, 3H).
Compound 34
N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide
(153) ##STR00049##
(154) Following General Procedure B, the title compound (463 mg, 48%) was prepared from 5-chloro-2-(((1-propyl-1H-imidazol-4-yl)methyl)thio)aniline (587 mg, 2.082 mmol) and benzofuran-2-sulfonyl chloride (451 mg, 2.082 mmol) in pyridine (10 ml).
(155) 1H NMR (600 MHz, CD.sub.3OD) δ 7.71 (dt, J=1.03, 7.92 Hz, 1H), 7.57 (d, J=1.17 Hz, 1H), 7.52-7.55 (m, 1H), 7.44-7.51 (m, 2H), 7.42 (d, J=0.88 Hz, 1H), 7.34 (td, J=1.03, 7.56 Hz, 1H), 7.27 (d, J=8.22 Hz, 1H), 7.07 (dd, J=2.35, 8.51 Hz, 1H), 6.44-6.51 (m, 1H), 3.75-3.81 (m, 4H), 1.63 (quin, J=7.19, 7.34 Hz, 2H), 0.74-0.82 (m, 3H).
Compound 35
N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(156) ##STR00050##
(157) Following General Procedure C, the title compound (148 mg, 75%) was prepared from N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(158) 1H NMR (600 MHz, CD.sub.3OD) δ 8.46 (s, 1H), 7.70 (dd, J=1.47, 8.22 Hz, 1H), 7.49 (dd, J=0.88, 8.51 Hz, 1H), 7.38-7.43 (m, 2H), 7.35 (d, J=0.88 Hz, 1H), 7.30 (ddd, J=1.03, 7.19, 7.92 Hz, 1H), 7.12 (d, J=8.51 Hz, 1H), 6.91 (dd, J=1.91, 8.36 Hz, 1H), 6.80 (s, 1H), 4.57 (d, J=14.38 Hz, 1H), 4.43 (d, J=14.09 Hz, 1H), 3.84-3.99 (m, 2H), 1.57-1.71 (m, 2H), 0.81 (t, J=7.34 Hz, 3H).
Compound 36
N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(159) ##STR00051##
(160) Following General Procedure D, the title compound (115 mg, 60%) was prepared from N-(5-chloro-2-{[(1-propyl-1H-imidazol-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(161) 1H NMR (300 MHz, CD.sub.3OD) δ 7.82 (s, 1H), 7.71 (dd, J=1.32, 7.77 Hz, 1H), 7.67 (d, J=2.05 Hz, 1H), 7.55 (d, J=8.50 Hz, 1H), 7.44-7.50 (m, 2H), 7.41 (td, J=1.32, 7.69 Hz, 1H), 7.25-7.35 (m, 1H), 6.85 (dd, J=2.05, 8.79 Hz, 1H), 6.76 (s, 1H), 4.57 (s, 2H), 3.74 (t, J=7.03 Hz, 2H), 1.54 (quin, J=6.89, 7.07 Hz, 2H), 0.69 (t, J=7.47 Hz, 3H).
Intermediate 14
tert-butyl (4-(hydroxymethyl)pyridin-2-yl)carbamate
(162) ##STR00052##
(163) A solution of (2-aminopyridin-4-yl)methanol (547 mg, 4.408 mmol), di-tert-butyl dicarbonate (1.25 g, 5.730 mmol), in t-BuOH (20 ml) was stirred at room temperature overnight. The solvent was removed and added ethyl acetate, filtered away the solid and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (10% MeOH in CH.sub.2Cl.sub.2) to give the title compound as a white solid (703 mg, 71%).
(164) 1H NMR (600 MHz, CDCl.sub.3) δ 8.18 (d, J=5.28 Hz, 1H), 8.00 (s, 1H), 6.92-7.10 (m, 1H), 4.75 (s, 2H), 1.32-1.66 (m, 9H).
Intermediate 15
tert-butyl (4-(((2-amino-4-chlorophenyl)thio)methyl)pyridin-2-yl)carbamate
(165) ##STR00053##
(166) tert-butyl (4-(hydroxymethyl)pyridin-2-yl)carbamate (600 mg, 2.679 mmol) was first treated with SOCl.sub.2 (3 ml) in CH.sub.2CO.sub.2 (5 ml) at rt for 2 hrs. The solvent was removed to get a crude tert-butyl (4-(chloromethyl)pyridin-2-yl)carbamate. Then following General Procedure A, the title compound (667 mg, 68%) was prepared from 2-amino-4-chlorobenzenethiol (641 mg, 4.019 mmol), K.sub.2CO.sub.3 (1.8 g, 13.39 mmol) in DMF (20 ml).
(167) 1H NMR (600 MHz, CDCl.sub.3) δ 9.83 (br. s., 1H), 8.20 (d, J=4.70 Hz, 1H), 7.85 (s, 1H), 6.92-7.18 (m, 1H), 6.60-6.75 (m, 2H), 6.55 (dd, J=2.05, 8.22 Hz, 1H), 4.42 (br. s., 2H), 3.78 (s, 2H), 1.54 (s, 9H).
Compound 37
tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate
(168) ##STR00054##
(169) Following General Procedure B, the title compound (555 mg, 56%) was prepared from tert-butyl (4-(((2-amino-4-chlorophenyl)thio)methyl)pyridin-2-yl)carbamate (667 mg, 1.827 mmol) and benzofuran-2-sulfonyl chloride (396 mg, 1.827 mmol) in pyridine (10 ml).
(170) 1H NMR (600 MHz, CD.sub.3OD) δ 7.99 (d, J=4.99 Hz, 1H), 7.64-7.73 (m, 2H), 7.59 (d, J=1.17 Hz, 1H), 7.50-7.55 (m, 1H), 7.42-7.50 (m, 2H), 7.30-7.39 (m, 1H), 7.15 (dd, J=1.03, 8.36 Hz, 1H), 6.96-7.05 (m, 1H), 6.56 (d, J=5.28 Hz, 1H), 3.77 (s, 2H), 1.48-1.61 (m, 9H).
Compound 38
N-(2-{[(2-aminopyridin-4-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(171) ##STR00055##
(172) Following General Procedure E, the title compound (76 mg, 100%) was prepared from tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate (96 mg, 0.176 mmol).
(173) 1H NMR (600 MHz, CD.sub.3OD) δ 7.72-7.76 (m, 2H), 7.65 (d, J=6.46 Hz, 2H), 7.58 (dd, J=0.73, 8.36 Hz, 1H), 7.46-7.53 (m, 2H), 7.42 (d, J=2.05 Hz, 1H), 7.37 (td, J=1.03, 7.56 Hz, 1H), 7.31 (d, J=8.51 Hz, 1H), 7.16 (dd, J=2.35, 8.51 Hz, 1H), 6.64 (dd, J=1.61, 6.60 Hz, 1H), 6.50 (s, 1H), 3.90 (s, 2H).
Compound 39
tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate
(174) ##STR00056##
(175) Following General Procedure D, the title compound (49 mg) was prepared from tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.
(176) 1H NMR (600 MHz, CD.sub.3OD) δ 7.93 (d, J=6.75 Hz, 1H), 7.78 (s, 1H), 7.73 (d, J=2.05 Hz, 1H), 7.63 (d, J=7.63 Hz, 1H), 7.41 (d, J=8.80 Hz, 1H), 7.33 (s, 1H), 7.29 (d, J=3.81 Hz, 1H), 7.23 (dt, J=3.96, 7.92 Hz, 2H), 6.85 (dd, J=2.20, 6.60 Hz, 1H), 6.68 (d, J=7.92 Hz, 1H), 4.56 (br. s., 2H), 1.47 (s, 9H).
Compound 40
tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1-oxidopyridin-2-yl}carbamate
(177) ##STR00057##
(178) Following General Procedure D, the title compound (82 mg) was prepared from tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.
(179) 1H NMR (600 MHz, CD.sub.3OD) δ 8.22 (d, J=6.46 Hz, 1H), 7.96 (s, 1H), 7.76 (d, J=16.73 Hz, 1H), 7.60-7.68 (m, 1H), 7.43 (d, J=8.51 Hz, 1H), 7.37 (s, 1H), 7.31 (br. s., 1H), 7.21-7.27 (m, 1H), 7.09 (d, J=6.46 Hz, 1H), 6.85 (d, J=6.75 Hz, 1H), 6.72 (d, J=7.63 Hz, 1H), 4.60 (br. s., 2H), 1.55 (s, 9H).
Compound 41
N-(2-{[(2-aminopyridin-4-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(180) ##STR00058##
(181) Following General Procedure E, the title compound (32 mg, 100%) was prepared from tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]pyridin-2-yl}carbamate.
(182) 1H NMR (600 MHz, acetone-d6) δ 7.74-7.85 (m, 3H), 7.61-7.70 (m, 2H), 7.52-7.58 (m, 1H), 7.45 (td, J=1.17, 7.92 Hz, 1H), 7.28-7.38 (m, 1H), 7.09 (dd, J=2.05, 8.51 Hz, 1H), 6.88 (s, 1H), 6.57-6.66 (m, 1H), 4.89 (s, 2H).
Compound 42
N-(2-{[(2-amino-1-oxidopyridin-4-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(183) ##STR00059##
(184) Following General Procedure E, the title compound (43 mg, 67%) was prepared from tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1-oxidopyridin-2-yl}carbamate (77 mg, 0.130 mmol).
(185) 1H NMR (600 MHz, acetone-d6) δ 8.07 (d, J=4.70 Hz, 3H), 7.76-7.81 (m, 2H), 7.74 (s, 1H), 7.64 (d, J=8.51 Hz, 1H), 7.58 (d, J=8.51 Hz, 1H), 7.46-7.49 (m, 1H), 7.32-7.37 (m, 1H), 7.15 (dd, J=1.32, 8.36 Hz, 1H), 6.94 (br. s., 1H), 6.52 (d, J=4.99 Hz, 1H), 4.76 (s, 2H).
Compound 43
N-(2-{[(2-aminopyridin-4-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(186) ##STR00060##
(187) Following General Procedure C and General Procedure E, the title compound (103 mg) was prepared from tert-butyl {4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.
(188) 1H NMR (600 MHz, acetone-d6) δ 8.29 (br. s., 1H), 7.74 (dd, J=7.04, 18.19 Hz, 2H), 7.40-7.61 (m, 4H), 7.25-7.37 (m, 2H), 7.05 (d, J=7.04 Hz, 1H), 6.84 (s, 1H), 6.49 (d, J=6.16 Hz, 1H), 4.50 (d, J=12.62 Hz, 2H), 4.40 (d, J=12.62 Hz, 1H).
Intermediate 16
3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide
(189) ##STR00061##
(190) The solution of 2-amino-4-chlorobenzenethiol (824 mg, 5.126 mmol), N,N-dimethylacrylamide (512 mg, 5.162 mmol), and HOAc (1 ml) in CH.sub.2Cl.sub.2 (10 ml) was stirred at room temperature for 4 days. The solvent was removed and the residue was loaded on silica column and purified to yield a white solid (1.08 g, 83%).
(191) 1H NMR (600 MHz, CD.sub.3OD) δ 7.26 (d, J=8.22 Hz, 1H), 6.76 (d, J=2.05 Hz, 1H), 6.56 (dd, J=2.05, 8.22 Hz, 1H), 2.93-2.97 (m, 5H), 2.90 (s, 3H), 2.58 (t, J=7.04 Hz, 2H).
Compound 44
3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylpropanamide
(192) ##STR00062##
(193) Following General Procedure B and D, the title compound (73 mg) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide (104 mg, 0.405 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (113 mg, 0.405 mmol).
(194) 1H NMR (600 MHz, CD.sub.3OD) δ 8.31 (d, J=1.47 Hz, 1H), 8.12 (dd, J=1.76, 8.51 Hz, 1H), 7.70 (dd, J=8.51, 18.49 Hz, 2H), 7.58 (s, 1H), 6.90 (s., 1H), 3.73 (br. s., 2H), 3.01 (s, 3H), 2.95 (s, 3H), 2.78 (t, J=6.75 Hz, 2H).
Compound 45
3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide
(195) ##STR00063##
(196) Following General Procedure B, the title compound (364 mg, 72%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide (300 mg, 1.167 mmol) and 2,4-difluorobenzene-1-sulfonyl chloride (248 mg, 1.167 mmol) in pyridine (5 ml).
(197) 1H NMR (600 MHz, CD.sub.3OD) δ 7.86 (td, J=6.02, 8.44 Hz, 1H), 7.38-7.45 (m, 2H), 7.13-7.21 (m, 2H), 7.09 (tdd, J=0.88, 2.49, 8.44 Hz, 1H), 2.95-3.01 (m, 5H), 2.93 (s, 3H), 2.56 (t, J=7.04 Hz, 2H).
Compound 46
3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N-dimethylpropanamide
(198) ##STR00064##
(199) Following General Procedure C, the title compound (130 mg, 88%) was prepared from 3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide.
(200) 1H NMR (600 MHz, CD.sub.3OD) δ 7.90 (td, J=5.87, 8.51 Hz, 1H), 7.69 (d, J=8.51 Hz, 1H), 7.43 (dd, J=2.05, 8.51 Hz, 1H), 7.31 (d, J=2.05 Hz, 1H), 7.20-7.27 (m, 1H), 7.11-7.17 (m, 1H), 3.24-3.29 (m, 1H), 3.12-3.20 (m, 1H), 3.05 (s, 3H), 2.93 (s, 3H), 2.85-2.92 (m, J=4.40 Hz, 1H), 2.72-2.80 (m, J=6.46, 6.46, 17.02 Hz, 1H).
Compound 47
3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N-dimethylpropanamide
(201) ##STR00065##
(202) Following General Procedure D, the title compound (70 mg, 71%) was prepared from 3-[(4-chloro-2-{[(2,4-difluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide.
(203) 1H NMR (600 MHz, CD.sub.3OD) δ 8.01-8.12 (m, 1H), 7.76 (d, J=8.51 Hz, 2H), 7.49-7.60 (m, 2H), 6.95-7.24 (m, 3H), 3.72 (br. s., 2H), 3.01 (s, 3H), 2.90 (s, 3H), 2.78 (t, J=7.04 Hz, 2H).
Compound 48
3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide
(204) ##STR00066##
(205) Following General Procedure B, the title compound (476 mg, 75%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-dimethylpropanamide (364 mg, 1.42 mmol) and 4-chloro-2-fluorobenzene-1-sulfonyl chloride (325 mg, 1.42 mmol) in pyridine (5 ml).
(206) 1H NMR (600 MHz, acetone-d6) δ 9.57 (br. s., 1H), 7.86 (t, J=8.07 Hz, 1H), 7.50-7.56 (m, 2H), 7.45 (dd, J=1.91, 9.83 Hz, 1H), 7.40 (dd, J=1.91, 8.36 Hz, 1H), 7.17 (dd, J=2.35, 8.22 Hz, 1H), 2.94-3.01 (m, 5H), 2.91 (s, 3H), 2.54 (t, J=6.46 Hz, 3H).
Compound 49
3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N,N-dimethylpropanamide
(207) ##STR00067##
(208) Following General Procedure C, the title compound (90 mg, 55%) was prepared from 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide.
(209) 1H NMR (600 MHz, CD.sub.3OD) δ 7.78-7.90 (m, 1H), 7.48 (d, J=8.51 Hz, 1H), 7.27-7.34 (m, 2H), 7.26 (d, J=2.05 Hz, 1H), 7.03 (d, J=7.92 Hz, 1H), 3.43 (ddd, J=6.31, 9.02, 13.43 Hz, 1H), 3.16 (ddd, J=5.58, 9.10, 13.50 Hz, 1H), 2.99 (s, 3H), 2.92 (s, 3H), 2.79-2.88 (m, J=6.46, 9.17, 16.07 Hz, 1H), 2.52-2.64 (m, 1H).
Compound 50
3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N,N-dimethylpropanamide
(210) ##STR00068##
(211) Following General Procedure D, the title compound (81 mg, 48%) was prepared from 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)thio]-N,N-dimethylpropanamide.
(212) 1H NMR (600 MHz, CD.sub.3OD) δ 7.89-7.98 (m, 1H), 7.69 (d, J=8.51 Hz, 1H), 7.46 (d, J=2.05 Hz, 1H), 7.20-7.30 (m, 2H), 6.76 (d, J=7.63 Hz, 1H), 3.86 (t, J=7.19 Hz, 2H), 2.97 (s, 3H), 2.93 (s, 3H), 2.70 (t, J=7.34 Hz, 2H).
Intermediate 17
tert-butyl (5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)carbamate
(213) ##STR00069##
(214) (5-amino-4H-1,2,4-triazol-3-yl)methanol (467 mg, 4.093 mmol), di-tert-butyl dicarbonate (1.16 g, 5.32 mmol), in t-BuOH (20 ml) was stirred at room temperature overnight. The solvent was removed and added ethyl acetate, filtered away the solid and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (10% MeOH in CH.sub.2Cl.sub.2) to give the title compound as a yellow oil (190 mg, 22%).
(215) 1H NMR (300 MHz, CD.sub.3OD) δ 4.44 (s, 2H), 1.63 (s, 9H).
General Procedure J
Intermediate 18
tert-butyl (5-(((2-amino-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate
(216) ##STR00070##
(217) A solution of tert-butyl (5-(hydroxymethyl)-4H-1,2,4-triazol-3-yl)carbamate (190 mg, 0.888 mmol), 2-amino-4-chlorobenzenethiol (213 mg, 1.332 mmol), PPh3 (466 mg, 1.776 mmol) and di-tert-butylazodicarboxylate (409 mg, 1.776 mmol) in CH2Cl2 (10 ml) was stirred at room temperature for 2 days. The solvent was then removed and the crude residues was loaded on silica gel column to get the title compound.
(218) 1H NMR (600 MHz, CD.sub.3OD) δ 7.18 (s, 1H), 6.73 (d, J=2.35 Hz, 1H), 6.49 (dd, J=2.35, 8.22 Hz, 2H), 3.68 (s, 2H), 1.60 (s, 9H).
Intermediate 19
tert-butyl (5-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate
(219) ##STR00071##
(220) Following General Procedure B, the title compound was prepared from tert-butyl (5-(((2-amino-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate (330 mg, 0.925 mmol) and benzofuran-2-sulfonyl chloride (200 mg, 0.925 mmol) in pyridine (2 ml).
(221) 1H NMR (600 MHz, CD.sub.3OD) δ 7.69 (dd, J=0.88, 7.92 Hz, 1H), 7.45-7.57 (m, 4H), 7.40 (s, 1H), 7.29-7.35 (m, 1H), 7.16 (dd, J=2.35, 8.22 Hz, 1H), 3.70 (s, 2H), 1.61 (s, 9H).
Compound 51
N-(2-{[(5-amino-4H-1,2,4-triazol-3-yl)methyl]thio}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(222) ##STR00072##
(223) Following General Procedure E, the title compound (13 mg) was prepared from tert-butyl (5-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate.
(224) 1H NMR (600 MHz, CD.sub.3OD) δ 7.71 (d, J=7.92 Hz, 1H), 7.55 (d, J=8.51 Hz, 1H), 7.39-7.51 (m, 5H), 7.31-7.37 (m, 1H), 7.16 (d, J=7.04 Hz, 1H), 3.82 (s, 2H).
Compound 52
N-(2-{[(5-amino-4H-1,2,4-triazol-3-yl)methyl]sulfinyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(225) ##STR00073##
(226) Following General Procedure C and E, the title compound (15 mg) was prepared from tert-butyl (5-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)-4H-1,2,4-triazol-3-yl)carbamate.
(227) 1H NMR (600 MHz, CD.sub.3OD) δ 7.75 (dd, J=1.17, 7.92 Hz, 1H), 7.57-7.64 (m, 2H), 7.51-7.55 (m, 1H), 7.50 (d, J=0.88 Hz, 1H), 7.44 (dd, J=1.91, 8.36 Hz, 1H), 7.35-7.41 (m, 1H), 7.20 (d, J=2.05 Hz, 1H), 4.45 (d, J=14.09 Hz, 1H), 4.24 (d, J=14.09 Hz, 1H).
Intermediate 20
5-chloro-2-((2-(pyridin-2-yl)ethyl)thio)aniline
(228) ##STR00074##
(229) 2-(Pyridin-2-yl)ethanol (1 g, 8.12 mmol) was first treated with SOCl.sub.2 (3 ml) in CH.sub.2Cl.sub.2 (10 ml) at rt for 3 hrs. The solvent was removed to get a crude 2-(2-chloroethyl)pyridine. Then following General Procedure A, the title compound (1.69 g, 79%) was prepared from 2-amino-4-chlorobenzenethiol (1.6 g, 9.74 mmol), K.sub.2CO.sub.3 (3.36 g, 24.36 mmol) in DMF (20 ml).
(230) 1H NMR (600 MHz, CD.sub.3OD) δ 8.39-8.42 (m, 1H), 7.73 (td, J=1.76, 7.63 Hz, 1H), 7.28 (d, J=7.63 Hz, 1H), 7.23 (d, J=8.22 Hz, 2H), 6.75 (d, J=2.35 Hz, 1H), 6.55 (dd, J=2.35, 8.22 Hz, 1H), 3.06-3.10 (m, 2H), 2.96-3.01 (m, 2H).
Compound 53
N-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(231) ##STR00075##
(232) Following General Procedure B, the title compound was prepared from 5-chloro-2-((2-(pyridin-2-yl)ethyl)thio)aniline (439 mg, 1.663 mmol) and benzofuran-2-sulfonyl chloride (2×359 mg, 2×1.663 mmol) in pyridine (5 ml).
(233) 1H NMR (600 MHz, CD.sub.3OD) δ 8.54-8.62 (m, 1H), 7.85 (s, 1H), 7.71-7.78 (m, 1H), 7.67 (dt, J=1.03, 7.92 Hz, 1H), 7.56 (d, J=2.35 Hz, 1H), 7.39-7.48 (m, 2H), 7.36 (s, 1H), 7.27-7.32 (m, 2H), 7.15-7.22 (m, 2H), 2.98 (t, J=7.04 Hz, 2H), 2.74 (t, J=6.90 Hz, 2H).
Compound 54
N-{5-chloro-2-[(2-pyridin-2-ylethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(234) ##STR00076##
(235) Following General Procedure C, the title compound (45 mg, 79%) was prepared from N-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(236) 1H NMR (600 MHz, CD.sub.3OD) δ 8.52-8.60 (m, 1H), 7.81 (td, J=1.76, 7.63 Hz, 1H), 7.64-7.71 (m, 2H), 7.26-7.47 (m, 8H), 3.40-3.50 (m, 1H), 3.29-3.37 (m, 1H), 3.16-3.26 (m, 0H), 2.83-2.95 (m, J=7.48, 7.48, 14.97 Hz, 1H).
Compound 55
N-{5-chloro-2-[(2-pyridin-2-ylethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(237) ##STR00077##
(238) Following General Procedure D, the title compound (20 mg) was prepared from N-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(239) 1H NMR (600 MHz, CD.sub.3OD) δ 8.30 (ddd, J=1.47, 1.61, 4.55 Hz, 1H), 7.71-7.76 (m, 2H), 7.61-7.68 (m, 2H), 7.52 (d, J=0.88 Hz, 1H), 7.31-7.36 (m, 1H), 7.24-7.31 (m, 2H), 7.18-7.23 (m, 2H), 7.05 (dd, J=2.05, 8.51 Hz, 1H), 3.84-3.89 (m, 2H), 3.00-3.14 (m, 2H).
Intermediate 21
2-((2-(1H-pyrazol-4-yl)ethyl)thio)-5-chloroaniline
(240) ##STR00078##
(241) Following the General Procedure J, the title intermediate was prepared from 2-(1H-pyrazol-4-yl)ethanol (472 mg, 4.218 mmol), 2-amino-4-chlorobenzenethiol (1.01 g, 6.327 mmol), PPh3 (2.21 g, 8.436 mmol) and di-tert-butylazodicarboxylate (1.9 g, 8.436 mmol) in CH.sub.2Cl.sub.2 (20 ml).
(242) 1H NMR (600 MHz, CD.sub.3OD) δ 7.98 (d, J=0.88 Hz, 1H), 7.64 (s, 1H), 7.23 (d, J=8.22 Hz, 1H), 6.76 (d, J=2.35 Hz, 1H), 6.55 (dd, J=2.05, 8.22 Hz, 1H), 2.89-3.00 (m, 2H), 2.65-2.77 (m, 2H).
Compound 56
N-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide
(243) ##STR00079##
(244) Following General Procedure B, the title compound (123 mg) was prepared from 2-((2-(1H-pyrazol-4-yl)ethyl)thio)-5-chloroaniline (157 mg, 0.618 mmol) and benzofuran-2-sulfonyl chloride (133 mg, 0.618 mmol) in pyridine (3 ml).
(245) 1H NMR (600 MHz, CD.sub.3OD) δ 7.70 (d, J=7.92 Hz, 1H), 7.43-7.53 (m, 3H), 7.39 (s, 1H), 7.28-7.36 (m, 4H), 7.17 (dd, J=1.76, 8.51 Hz, 1H), 2.82 (t, J=7.63 Hz, 2H), 2.45 (t, J=7.63 Hz, 2H).
Compound 57
N-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(246) ##STR00080##
(247) Following General Procedure C, the title compound (52 mg, 40%) was prepared from N-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(248) 1H NMR (600 MHz, CD.sub.3OD) δ 7.75-7.81 (m, 1H), 7.72 (td, J=1.76, 7.63 Hz, 1H), 7.67 (d, J=0.88 Hz, 1H), 7.48-7.59 (m, 3H), 7.40-7.45 (m, 2H), 7.19-7.34 (m, 3H), 7.17 (d, J=2.35 Hz, 1H), 3.19-3.26 (m, 3H), 2.87 (t, J=7.63 Hz, 2H).
Compound 58
N-(5-chloro-2-{[2-(1H-pyrazol-4-yl)ethyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(249) ##STR00081##
(250) Following General Procedure D, the title compound (75 mg, 73%) was prepared from N-{5-chloro-2-[(2-pyridin-2-ylethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(251) 1H NMR (600 MHz, CD.sub.3OD) δ 7.67-7.74 (m, 2H), 7.62 (d, J=7.63 Hz, 1H), 7.39 (s, 2H), 7.31 (t, J=7.19 Hz, 2H), 7.22-7.26 (m, 1H), 7.17 (d, J=8.22 Hz, 1H), 6.80-6.90 (m, 1H), 3.89 (br. s., 2H), 2.71-2.81 (m, 2H).
Intermediate 22
5-Chloro-2-[2-(3,5-dimethyl-1H-pyrazol-4-yl)-ethylsulfanyl]-phenylamine
(252) ##STR00082##
(253) Following General Procedure A, the title compound (517 mg, 74%) was prepared from 2-Amino-4-chloro-benzenethiol (590 mg, 3.693 mmol) and 4-(2-bromo-ethyl)-3,5-dimethyl-1H-pyrazole (500 mg, 2.462 mmol), K.sub.2CO.sub.3 (1.7 g, 12.31 mmol) in DMF (20 ml).
(254) 1H NMR (600 MHz, CD.sub.3OD) δ 7.24 (d, J=8.22 Hz, 1H), 6.77 (d, J=2.05 Hz, 1H), 6.56 (dd, J=2.35, 8.22 Hz, 1H), 2.75-2.80 (m, 2H), 2.53-2.61 (m, 2H), 2.08 (s, 6H).
Compound 59
N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide
(255) ##STR00083##
(256) Following General Procedure B, the title compound (235 mg) was prepared from 2-((2-(1H-pyrazol-4-yl)ethyl)thio)-5-chloroaniline (157 mg, 0.618 mmol) and benzofuran-2-sulfonyl chloride (133 mg, 0.618 mmol) in pyridine (3 ml).
(257) 1H NMR (600 MHz, CD.sub.3OD) δ 7.68 (dd, J=0.88, 7.92 Hz, 1H), 7.52 (d, J=2.35 Hz, 1H), 7.39-7.47 (m, 3H), 7.27-7.35 (m, 2H), 7.18 (dd, J=2.35, 8.51 Hz, 1H), 2.65-2.72 (m, J=7.63 Hz, 2H), 2.28-2.35 (m, 2H), 1.97 (s, 6H).
Intermediate 23
5-chloro-2-(((2-fluoropyridin-3-yl)methyl)thio)aniline
(258) ##STR00084##
(259) (2-Fluoropyridin-3-yl)methanol (508 mg, 3.998 mmol) was first treated with SOCl.sub.2 (1.5 ml) in CH.sub.2Cl.sub.2 (5 ml) at rt for 3 hrs. The solvent was removed to get a crude 3-(chloromethyl)-2-fluoropyridine. Then following General Procedure A, the title compound (910 mg, 85%) was prepared from 2-amino-4-chlorobenzenethiol (957 mg, 5.995 mmol), K.sub.2CO.sub.3 (2.7 g, 19.98 mmol) in DMF (20 ml).
(260) 1H NMR (600 MHz, CD.sub.3OD) δ 8.01 (dt, J=0.88, 4.99 Hz, 1H), 7.42 (ddd, J=1.91, 7.48, 9.68 Hz, 1H), 7.10 (ddd, J=1.76, 5.14, 7.19 Hz, 1H), 6.91 (d, J=8.22 Hz, 1H), 6.73 (d, J=2.05 Hz, 1H), 6.42 (dd, J=2.35, 8.22 Hz, 1H), 3.90 (s, 2H).
Compound 60
N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide
(261) ##STR00085##
(262) Following General Procedure B, the title compound (235 mg) was prepared from 5-chloro-2-(((2-fluoropyridin-3-yl)methyl)thio)aniline (522 mg, 1.948 mmol) and benzofuran-2-sulfonyl chloride (421 mg, 1.948 mmol) in pyridine (5 ml).
(263) 1H NMR (600 MHz, acetone-d6) δ 9.00 (br. s., 1H), 8.05 (dt, J=1.47, 4.70 Hz, 1H), 7.79 (d, J=6.75 Hz, 1H), 7.55-7.63 (m, 3H), 7.43-7.54 (m, 2H), 7.33-7.40 (m, 1H), 7.26 (d, J=8.22 Hz, 1H), 7.07-7.17 (m, 2H), 4.01 (s, 2H).
Compound 61
N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(264) ##STR00086##
(265) Following General Procedure C, the title compound (100 mg, 59%) was prepared from N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(266) 1H NMR (600 MHz, CD.sub.3OD) δ 7.99 (dd, J=1.91, 4.84 Hz, 1H), 7.65 (d, J=7.34 Hz, 1H), 7.49 (d, J=2.05 Hz, 1H), 7.38 (d, J=8.51 Hz, 1H), 7.28-7.33 (m, 1H), 7.19-7.26 (m, 3H), 7.00 (ddd, J=1.47, 5.21, 7.12 Hz, 1H), 6.81 (d, J=8.22 Hz, 1H), 6.70 (dd, J=2.05, 8.22 Hz, 1H), 4.43-4.59 (m, 2H).
Compound 62
N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(267) ##STR00087##
(268) Following General Procedure D, the title compound (176 mg, 67%) was prepared from N-(5-chloro-2-{[(2-fluoropyridin-3-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(269) 1H NMR (600 MHz, acetone-d6) δ 8.04 (d, J=4.70 Hz, 1H), 7.91 (d, J=2.05 Hz, 1H), 7.70 (d, J=7.63 Hz, 1H), 7.18-7.44 (m, 6H), 6.90 (t, J=5.43 Hz, 1H), 6.67 (d, J=7.63 Hz, 1H), 4.96 (s, 2H).
Intermediate 24
2-(benzylthio)-5-chloroaniline
(270) ##STR00088##
(271) Following General Procedure A, the title compound (819 mg, 100%) was prepared from 2-amino-4-chlorobenzenethiol (700 mg, 4.39 mmol), (bromomethyl)benzene (560 mg, 2.92 mmol), K.sub.2CO.sub.3 (2.0 g, 14.62 mmol) in DMF (20 ml).
(272) 1H NMR (600 MHz, CD.sub.3OD) δ 7.15-7.24 (m, 3H), 7.07-7.13 (m, 2H), 6.97 (d, J=8.22 Hz, 1H), 6.73 (d, J=2.05 Hz, 1H), 6.43 (dd, J=2.05, 8.22 Hz, 1H), 3.86 (s, 2H).
Compound 63
N-[2-(benzylthio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide
(273) ##STR00089##
(274) Following General Procedure B, the title compound (235 mg) was prepared from 2-(benzylthio)-5-chloroaniline (509 mg, 2.052 mmol) and benzofuran-2-sulfonyl chloride (443 mg, 2.052 mmol) in pyridine (5 ml).
(275) 1H NMR (600 MHz, CD.sub.3OD) δ 7.73 (d, J=7.92 Hz, 3H), 7.45-7.56 (m, 3H), 7.42 (s, 1H), 7.32-7.38 (m, 1H), 7.10-7.18 (m, 4H), 7.04-7.08 (m, 1H), 6.85-6.94 (m, 2H), 3.81 (s, 2H).
Compound 64
N-[2-(benzylsulfinyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide
(276) ##STR00090##
(277) Following General Procedure C, the title compound (139 mg, 84%) was prepared from N-[2-(benzylthio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide.
(278) 1H NMR (600 MHz, CD.sub.3OD) δ 7.65 (d, J=7.92 Hz, 1H), 7.49 (d, J=2.05 Hz, 1H), 7.37 (dd, J=0.73, 8.36 Hz, 1H), 7.28-7.33 (m, 1H), 7.16-7.27 (m, 3H), 7.08-7.14 (m, 2H), 7.01 (d, J=6.75 Hz, 2H), 6.97 (d, J=8.51 Hz, 1H), 6.73 (dd, J=1.91, 8.36 Hz, 1H), 4.50 (d, J=12.91 Hz, 1H), 4.14 (d, J=12.91 Hz, 1H).
Compound 65
N-[2-(benzylsulfonyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide
(279) ##STR00091##
(280) Following General Procedure D, the title compound (212 mg, 95%) was prepared from N-[2-(benzylthio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide.
(281) 1H NMR (600 MHz, CD.sub.3OD) δ 7.63-7.73 (m, 2H), 7.40 (dd, J=0.73, 8.36 Hz, 1H), 7.30-7.37 (m, 3H), 7.23-7.29 (m, 1H), 7.08-7.16 (m, 3H), 6.98-7.05 (m, 2H), 6.60 (dd, J=2.05, 8.51 Hz, 1H), 4.99 (s, 2H).
General Procedure K
Intermediate 25
2-amino-4-fluorobenzenethiol
(282) ##STR00092##
(283) A solution of 5-fluoro-2-methylbenzo[d]thiazole (1.2 g, 7.18 mmol) in ethylene glycol and NaOH (5N, 2 ml) was degassed under N.sub.2 for 10 min, then refluxed at 129° C. for 3 hours. The solution was cooled to 0° C. and then acidified to pH 3˜4 using c. HCl. The mixture was extracted with EtOAc (2×50 ml). The organic layer was washed with brine and dried with Na.sub.2SO.sub.4 and concentrated in vacuo. The crude residue (1.01 g, 98%) was used directly in the next step without purification.
(284) 1H NMR (600 MHz, CD.sub.3OD) δ 7.24 (dd, J=6.16, 8.51 Hz, 1H), 6.97 (dd, J=6.46, 8.51 Hz, 1H), 6.20 (td, J=2.79, 8.58 Hz, 1H).
Intermediate 26
5-fluoro-2-((3-nitrobenzyl)thio)aniline
(285) ##STR00093##
(286) Following General Procedure A, the title compound (460 mg, 97%) was prepared from 2-amino-4-fluorobenzenethiol (562 g, 3.93 mmol), 1-(bromomethyl)-3-nitrobenzene (566 mg, 2.62 mmol), K.sub.2CO.sub.3 (1.8 g, 13.10 mmol) in DMF (10 ml).
(287) 1H NMR (600 MHz, CD.sub.3OD) € 8.04 (dt, J=2.09, 7.26 Hz, 1H), 7.89 (s, 1H), 7.34-7.54 (m, 2H), 6.93 (dd, J=6.46, 8.51 Hz, 1H), 6.35-6.53 (m, 1H), 6.15 (td, J=2.64, 8.51 Hz, 1H), 3.95 (s, 2H).
Compound 66
N-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide
(288) ##STR00094##
(289) Following General Procedure B, the title compound (474 mg, 63%) was prepared from 2-((3-aminobenzyl)thio)-5-fluoroaniline (460 mg, 1.655 mmol) and benzofuran-2-sulfonyl chloride (357 mg, 1.655 mmol) in pyridine (5 ml).
(290) 1H NMR (600 MHz, CD.sub.3OD) δ 7.98 (ddd, J=0.88, 2.35, 8.22 Hz, 1H), 7.68-7.79 (m, 2H), 7.49-7.54 (m, 2H), 7.42-7.48 (m, 1H), 7.25-7.39 (m, 4H), 7.16 (dd, J=6.16, 8.80 Hz, 1H), 6.78 (td, J=2.93, 8.36 Hz, 1H), 3.91 (s, 2H).
General Procedure L
Compound 67
N-{2-[(3-aminobenzyl)thio]-5-fluorophenyl}-1-benzofuran-2-sulfonamide
(291) ##STR00095##
(292) N-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide (91 mg, 0.199 mmol) was dissolved in MeOH (2 ml). Zn (322 mg, 4.967 mmol) and NH.sub.4Cl (1 ml) was added to the solution. After the mixture was stirred for 30 min at room temperature, the solid was filtered and the filtrate was concentrated in vacuo and then the crude residue was purified by column chromatography (0˜30% EtOAc in hexane) to afford the title product (50 mg, 59%).
(293) 1H NMR (600 MHz, CD.sub.3OD) δ 7.71 (d, J=7.92 Hz, 1H), 7.50-7.54 (m, 1H), 7.48 (d, J=0.88 Hz, 1H), 7.46 (ddd, J=1.32, 7.26, 8.44 Hz, 1H), 7.28-7.38 (m, 2H), 7.19 (dd, J=6.16, 8.80 Hz, 1H), 6.83-6.89 (m, 1H), 6.77 (td, J=2.79, 8.44 Hz, 1H), 6.46-6.54 (m, 1H), 6.36 (t, J=1.76 Hz, 1H), 6.22 (d, J=7.63 Hz, 1H), 3.63 (s, 2H).
Compound 68
N-{2-[(3-aminobenzyl)sulfinyl]-5-fluorophenyl}-1-benzofuran-2-sulfonamide
(294) ##STR00096##
(295) Following General Procedure L, the title compound (130 mg, 84%) was prepared from N-{5-fluoro-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide.
(296) 1H NMR (600 MHz, CD.sub.3OD) δ 7.75 (dd, J=0.88, 7.92 Hz, 1H), 7.53-7.60 (m, 2H), 7.48 (ddd, J=1.32, 7.26, 8.44 Hz, 1H), 7.33-7.38 (m, 1H), 7.28 (dd, J=6.16, 8.80 Hz, 1H), 7.14 (dd, J=2.64, 10.27 Hz, 1H), 6.88-7.02 (m, 2H), 6.71 (dt, J=1.06, 8.14 Hz, 1H), 6.57 (s, 1H), 6.41 (d, J=7.63 Hz, 1H), 4.24 (d, J=12.62 Hz, 1H), 4.06 (d, J=12.91 Hz, 1H).
Compound 69
N-{5-fluoro-2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(297) ##STR00097##
(298) Following General Procedure D, the title compound (136 mg, 74%) was prepared from N-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.
(299) 1H NMR (600 MHz, CD.sub.3OD) δ 8.10 (ddd, J=1.17, 2.13, 8.14 Hz, 1H), 7.72-7.81 (m, 3H), 7.65 (dd, J=6.02, 8.95 Hz, 1H), 7.55 (d, J=8.51 Hz, 1H), 7.45-7.51 (m, 3H), 7.41-7.45 (m, 1H), 7.33-7.39 (m, 1H), 6.80-7.09 (m, 1H), 4.70 (s, 2H).
Compound 70
N-{2-[(3-aminobenzyl)sulfonyl]-5-fluorophenyl}-1-benzofuran-2-sulfonamide
(300) ##STR00098##
(301) Following General Procedure L, the title compound (91 mg, 81%) was prepared from N-{5-fluoro-2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide.
(302) 1H NMR (600 MHz, acetone-d6) δ 7.87 (br. s., 1H), 7.84 (d, J=7.92 Hz, 2H), 7.57-7.65 (m, 2H), 7.50-7.56 (m, 2H), 7.39 (t, J=7.48 Hz, 1H), 6.94-7.02 (m, 1H), 6.83 (t, J=7.78 Hz, 1H), 6.53 (d, J=8.80 Hz, 1H), 6.38 (s, 1H), 6.13 (d, J=7.34 Hz, 1H), 4.38 (s, 2H).
Intermediate 27
5-methoxy-2-((3-nitrobenzyl)thio)aniline
(303) ##STR00099##
(304) Following General Procedure K and A, the title compound (474 mg) was prepared from 5-methoxy-2-methylbenzo[d]thiazole.
(305) 1H NMR (600 MHz, CD.sub.3OD) δ 8.03 (dt, J=2.05, 7.34 Hz, 1H), 7.84 (d, J=1.76 Hz, 1H), 7.34-7.48 (m, 2H), 6.83 (d, J=8.51 Hz, 1H), 6.32 (s, 1H), 6.06 (dd, J=2.79, 8.36 Hz, 1H), 3.90 (s, 2H), 3.69 (s, 3H).
Compound 71
N-{2-[(3-aminobenzyl)thio]-5-methoxyphenyl}-1-benzofuran-2-sulfonamide
(306) ##STR00100##
(307) Following General Procedure L, the title compound (82 mg, 70%) was prepared from N-(5-methoxy-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.
(308) 1H NMR (600 MHz, CD.sub.3OD) δ 7.69 (d, J=7.92 Hz, 1H), 7.50 (dd, J=0.88, 8.51 Hz, 1H), 7.40-7.47 (m, 2H), 7.31 (ddd, J=1.03, 7.19, 7.92 Hz, 1H), 7.07-7.13 (m, 2H), 6.84-6.90 (m, 1H), 6.57 (dd, J=2.79, 8.66 Hz, 1H), 6.50-6.54 (m, 1H), 6.37 (t, J=1.91 Hz, 1H), 6.25 (d, J=7.63 Hz, 1H), 3.72 (s, 3H), 3.57 (s, 2H).
Compound 72
N-{5-methoxy-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(309) ##STR00101##
(310) Following General Procedure C, the title compound (95 mg, 46%) was prepared from N-(5-methoxy-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.
(311) 1H NMR (600 MHz, acetone-d6) δ 10.74 (br. s., 1H), 8.16 (ddd, J=0.88, 2.35, 8.22 Hz, 1H), 7.78-7.86 (m, 2H), 7.75 (s, 1H), 7.61 (dd, J=0.88, 8.51 Hz, 1H), 7.56 (t, J=7.92 Hz, 1H), 7.44-7.52 (m, 2H), 7.35-7.40 (m, 1H), 7.09 (d, J=2.35 Hz, 1H), 7.06 (d, J=8.80 Hz, 1H), 6.69 (dd, J=2.49, 8.66 Hz, 1H), 4.45-4.53 (m, 2H), 3.77 (s, 3H).
Compound 73
N-{2-[(3-aminobenzyl)sulfinyl]-5-methoxyphenyl}-1-benzofuran-2-sulfonamide
(312) ##STR00102##
(313) Following General Procedure L, the title compound (55 mg, 65%) was prepared from N-{5-methoxy-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide.
(314) 1H NMR (600 MHz, acetone-d6) δ 7.75-7.85 (m, 2H), 7.59 (dd, J=0.59, 8.51 Hz, 1H), 7.44-7.53 (m, 1H), 7.32-7.40 (m, 1H), 7.25 (s, 1H), 6.93 (d, J=8.51 Hz, 1H), 6.85-6.90 (m, 1H), 6.61 (dd, J=2.49, 8.66 Hz, 1H), 6.53-6.58 (m, 1H), 6.40 (t, J=1.76 Hz, 1H), 6.21 (d, J=7.92 Hz, 1H), 4.25 (d, J=12.32 Hz, 1H), 4.08 (d, J=11.74 Hz, 2H), 3.78 (s, 3H).
Compound 74
N-(5-methoxy-2-((3-nitrobenzyl)sulfonyl)phenyl)benzofuran-2-sulfonamide
(315) ##STR00103##
(316) Following General Procedure D, the title compound (165 mg, 83%) was prepared from N-(5-methoxy-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.
(317) 1H NMR (600 MHz, CDCl.sub.3) δ 9.28 (s, 1H), 8.14-8.19 (m, 1H), 7.70 (d, J=7.63 Hz, 1H), 7.64 (s, 1H), 7.58 (s, 1H), 7.41-7.50 (m, 3H), 7.37 (d, J=9.10 Hz, 1H), 7.33 (td, J=1.03, 7.41 Hz, 1H), 7.29 (d, J=2.35 Hz, 1H), 7.26 (s, 1H), 6.57 (dd, J=2.35, 8.80 Hz, 1H), 4.38 (s, 2H), 3.86 (s, 3H).
Compound 75
N-{2-[(3-aminobenzyl)sulfonyl]-5-methoxyphenyl}-1-benzofuran-2-sulfonamide
(318) ##STR00104##
(319) Following General Procedure L, the title compound (67 mg, 45%) was prepared from N-(5-methoxy-2-((3-nitrobenzyl)sulfonyl)phenyl)benzofuran-2-sulfonamide.
(320) 1H NMR (600 MHz, CD.sub.3OD) δ 7.70 (d, J=7.63 Hz, 1H), 7.42-7.50 (m, 2H), 7.35-7.41 (m, 1H), 7.33 (d, J=8.80 Hz, 1H), 7.27-7.31 (m, 1H), 7.22 (d, J=2.35 Hz, 1H), 6.76 (t, J=7.78 Hz, 1H), 6.53 (dd, J=1.32, 8.07 Hz, 1H), 6.45 (s, 1H), 6.39 (d, J=8.51 Hz, 1H), 6.27 (d, J=7.63 Hz, 1H), 4.61 (br. s., 2H), 3.76 (s, 3H).
Compound 76
Benzofuran-2-sulfonic acid [2-(3-nitro-benzylsulfanyl)-phenyl]-amide
(321) ##STR00105##
(322) Following General Procedure B, the title compound (520 mg, 41%) was prepared from 2-((3-nitrobenzyl)thio)aniline (741 mg, 2.85 mmol), benzofuran-2-sulfonyl chloride (616 mg, 2.85 mmol) in pyridine (10 ml).
(323) 1H NMR (600 MHz, CD.sub.3OD) δ 7.97-8.04 (m, 1H), 7.79-7.89 (m, 1H), 7.70 (d, J=0.88 Hz, 1H), 7.50 (d, J=0.88 Hz, 1H), 7.29-7.47 (m, 6H), 7.15-7.25 (m, 2H), 7.02-7.11 (m, 1H), 3.99 (s, 2H).
Compound 77
N-{2-[(3-aminobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(324) ##STR00106##
(325) Following General Procedure L, the title compound (67 mg, 45%) was prepared from benzofuran-2-sulfonic acid [2-(3-nitro-benzylsulfanyl)-phenyl]-amide.
(326) 1H NMR (600 MHz, CD.sub.3OD) δ 7.66 (d, J=7.92 Hz, 1H), 7.47-7.52 (m, 1H), 7.38-7.46 (m, 2H), 7.26-7.35 (m, 2H), 7.12-7.22 (m, 2H), 7.04 (td, J=1.47, 7.63 Hz, 1H), 6.88 (t, J=7.78 Hz, 1H), 6.54 (dd, J=1.47, 7.92 Hz, 1H), 6.43 (t, J=1.76 Hz, 1H), 6.28 (d, J=7.63 Hz, 1H), 3.69 (s, 2H).
Compound 78
N-{2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(327) ##STR00107##
(328) Following General Procedure C, the title compound (172 mg, 73%) was prepared from benzofuran-2-sulfonic acid [2-(3-nitro-benzylsulfanyl)-phenyl]-amide.
(329) 1H NMR (600 MHz, acetone-d6) δ 10.45 (br. s., 1H), 8.15 (d, J=8.22 Hz, 1H), 7.85 (s, 1H), 7.80 (d, J=7.92 Hz, 1H), 7.66 (d, J=0.88 Hz, 1H), 7.59-7.63 (m, 1H), 7.42-7.57 (m, 5H), 7.34-7.40 (m, 1H), 7.13-7.24 (m, 2H), 4.54-4.60 (m, 1H), 4.45-4.51 (m, 1H).
Compound 79
N-{2-[(3-aminobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(330) ##STR00108##
(331) Following General Procedure L, the title compound (122 mg, 90%) was prepared from N-{2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide.
(332) 1H NMR (600 MHz, CD.sub.3OD) δ 7.73 (d, J=7.63 Hz, 1H), 7.59 (d, J=8.22 Hz, 1H), 7.43-7.53 (m, 3H), 7.29-7.42 (m, 3H), 7.20 (d, J=7.63 Hz, 1H), 6.97 (t, J=7.63 Hz, 1H), 6.66 (d, J=7.34 Hz, 1H), 6.57 (br. s., 1H), 6.43 (d, J=7.34 Hz, 1H), 4.27 (d, J=12.91 Hz, 1H), 3.99 (d, J=12.91 Hz, 1H).
Compound 80
N-{2-[(3-aminobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(333) ##STR00109##
(334) Following General Procedure L, the title compound (75 mg, 82%) was prepared from N-{2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide.
(335) 1H NMR (600 MHz, acetone-d6)) δ 7.75-7.85 (m, 3H), 7.62-7.70 (m, 1H), 7.59 (d, J=8.51 Hz, 1H), 7.56 (dd, J=1.76, 7.92 Hz, 1H), 7.49 (td, J=1.17, 7.92 Hz, 1H), 7.36 (t, J=7.48 Hz, 1H), 7.16-7.22 (m, 1H), 6.83 (t, J=7.78 Hz, 1H), 6.57 (dd, J=1.47, 7.92 Hz, 1H), 6.43 (t, J=1.91 Hz, 1H), 6.15 (d, J=7.34 Hz, 1H), 4.37 (s, 2H).
Intermediate 28
5-chloro-2-((4-nitrobenzyl)thio)aniline
(336) ##STR00110##
(337) Following General Procedure A, the title compound (624 mg, 92%) was prepared from 2-amino-4-chlorobenzenethiol (555 mg, 3.10 mmol), 1-(bromomethyl)-4-nitrobenzene (490 mg, 2.268 mmol) and K.sub.2CO.sub.3 (1.3 g, 9.50 mmol) in DMF (20 ml).
(338) 1H NMR (600 MHz, CD.sub.3OD) δ 8.07 (d, J=8.80 Hz, 2H), 7.30 (d, J=8.80 Hz, 2H), 6.93 (d, J=8.22 Hz, 1H), 6.73 (d, J=2.35 Hz, 1H), 6.43 (dd, J=2.35, 8.22 Hz, 1H), 3.97 (s, 2H).
Compound 81
N-{5-chloro-2-[(4-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(339) ##STR00111##
(340) Following General Procedure B, the title compound (475 mg, 72%) was prepared from 5-chloro-2-((4-nitrobenzyl)thio)aniline (411 mg, 1.40 mmol) and benzofuran-2-sulfonyl chloride (303 mg, 1.40 mmol) in pyridine (5 ml).
(341) 1H NMR (600 MHz, CD.sub.3OD) δ 7.94-8.00 (m, 2H), 7.72 (d, J=7.92 Hz, 1H), 7.50-7.55 (m, 1H), 7.45-7.49 (m, 2H), 7.43 (s, 1H), 7.31-7.38 (m, 1H), 7.11-7.19 (m, 3H), 7.07 (dd, J=2.35, 8.51 Hz, 1H), 3.96 (s, 2H).
Compound 82
N-{5-chloro-2-[(4-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(342) ##STR00112##
(343) Following General Procedure D, the title compound (120 mg, 85%) was prepared from N-{5-chloro-2-[(4-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(344) 1H NMR (600 MHz, acetone-d6) δ 9.59 (br. s., 1H), 8.01 (d, J=7.34 Hz, 2H), 7.86 (s, 1H), 7.76 (d, J=7.92 Hz, 1H), 7.72 (s, 1H), 7.52 (d, J=8.51 Hz, 1H), 7.39-7.49 (m, 2H), 7.25-7.36 (m, 3H), 7.00 (s, 1H), 4.96 (s, 2H).
Compound 83
N-{2-[(4-aminobenzyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(345) ##STR00113##
(346) Following General Procedure L, the title compound (68 mg, 81%) was prepared from N-{5-chloro-2-[(4-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide.
(347) 1H NMR (600 MHz, acetone-d6) δ 7.75-7.88 (m, 3H), 7.61 (d, J=8.51 Hz, 1H), 7.44-7.54 (m, 2H), 7.34-7.41 (m, 1H), 7.22 (dd, J=1.76, 8.51 Hz, 1H), 6.69 (d, J=8.51 Hz, 2H), 6.49 (d, J=8.51 Hz, 2H), 4.38 (s, 2H).
Intermediate 29
5-chloro-2-((2-nitrobenzyl)thio)aniline
(348) ##STR00114##
(349) Following General Procedure A, the title compound (548 mg, 95%) was prepared from 2-amino-4-chlorobenzenethiol (441 mg, 2.76 mmol), 1-(bromomethyl)-2-nitrobenzene (398 mg, 1.84 mmol) and K.sub.2CO.sub.3 (1.27 g, 9.21 mmol) in DMF (20 ml).
(350) 1H NMR (600 MHz, CD.sub.3OD) δ 7.89-7.98 (m, 1H), 7.37-7.46 (m, 2H), 6.99-7.04 (m, 1H), 6.81 (d, J=8.22 Hz, 1H), 6.71 (d, J=2.05 Hz, 1H), 6.37 (dd, J=2.05, 8.22 Hz, 1H), 4.22 (s, 2H).
Compound 84
N-(5-chloro-2-((2-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide
(351) ##STR00115##
(352) Following General Procedure B, the title compound (485 mg, 69%) was prepared from 5-chloro-2-((2-nitrobenzyl)thio)aniline (435 mg, 1.48 mmol) and benzofuran-2-sulfonyl chloride (320 mg, 1.48 mmol) in pyridine (5 ml).
(353) 1H NMR (600 MHz, CDCl.sub.3) δ 8.03 (dd, J=1.47, 7.92 Hz, 1H), 7.65-7.71 (m, 2H), 7.48-7.53 (m, 2H), 7.43-7.48 (m, 1H), 7.31-7.42 (m, 3H), 7.03 (d, J=8.22 Hz, 1H), 6.90 (dd, J=2.05, 8.22 Hz, 1H), 6.76 (dd, J=1.32, 7.48 Hz, 1H), 4.16 (s, 2H).
Compound 85
N-{2-[(2-aminobenzyl)thio]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(354) ##STR00116##
(355) Following General Procedure L, the title compound (44 mg, 40%) was prepared from N-(5-chloro-2-((2-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.
(356) 1H NMR (600 MHz, acetone-d6) δ 7.77 (d, J=7.92 Hz, 1H), 7.59 (dd, J=0.88, 8.51 Hz, 1H), 7.47-7.55 (m, 3H), 7.31-7.41 (m, 2H), 7.10 (dd, J=2.35, 8.51 Hz, 1H), 6.86-6.95 (m, 1H), 6.72 (dd, J=0.88, 7.92 Hz, 1H), 6.57 (dd, J=1.32, 7.48 Hz, 1H), 6.38 (td, J=1.03, 7.41 Hz, 1H), 3.97 (s, 2H).
Compound 86
N-{5-chloro-2-[(2-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(357) ##STR00117##
(358) Following General Procedure C, the title compound (160 mg, 79%) was prepared from N-(5-chloro-2-((2-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.
(359) 1H NMR (600 MHz, acetone-d6) δ 7.92 (d, J=8.22 Hz, 1H), 7.71 (dd, J=0.73, 7.78 Hz, 1H), 7.59 (d, J=2.05 Hz, 1H), 7.47 (d, J=8.51 Hz, 1H), 7.39-7.44 (m, 1H), 7.33-7.38 (m, 2H), 7.19-7.30 (m, 2H), 6.71-6.80 (m, 2H), 6.67 (d, J=8.22 Hz, 1H), 5.13 (d, J=12.91 Hz, 2H), 4.73 (d, J=12.62 Hz, 2H).
Compound 87
N-{2-[(2-aminobenzyl)sulfinyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(360) ##STR00118##
(361) Following General Procedure L, the title compound (67 mg, 50%) was prepared from N-{5-chloro-2-[(2-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide.
(362) 1H NMR (600 MHz, CD.sub.3OD) δ 7.72 (d, J=7.92 Hz, 1H), 7.56 (d, J=7.63 Hz, 1H), 7.44-7.52 (m, 2H), 7.41 (d, J=8.51 Hz, 2H), 7.31-7.37 (m, 1H), 7.28 (d, J=1.47 Hz, 1H), 7.21 (dd, J=1.76, 8.22 Hz, 1H), 7.06-7.13 (m, 1H), 6.88 (d, J=7.92 Hz, 1H), 6.75 (d, J=7.04 Hz, 1H), 6.60-6.67 (m, 1H), 4.50 (d, J=13.50 Hz, 2H), 4.23 (d, J=12.91 Hz, 2H).
Compound 88
N-{2-[(2-aminobenzyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(363) ##STR00119##
(364) Following General Procedure D and K, the title compound (52 mg) was prepared from N-(5-chloro-2-((2-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.
(365) 1H NMR (300 MHz, CD.sub.3OD) δ 7.69-7.78 (m, 2H), 7.56-7.65 (m, 2H), 7.50-7.55 (m, 1H), 7.45 (td, J=1.17, 7.77 Hz, 1H), 7.28-7.38 (m, 1H), 6.99-7.15 (m, 2H), 6.88 (d, J=7.03 Hz, 1H), 6.67-6.75 (m, 1H), 6.58-6.66 (m, 1H), 4.68 (s, 2H).
Intermediate 30
5-chloro-2-((pyrimidin-2-ylmethyl)thio)aniline
(366) ##STR00120##
(367) Following General Procedure A, the title compound (284 mg, 39%) was prepared from 2-amino-4-chlorobenzenethiol (529 mg, 3.33 mmol), 2-(chloromethyl)pyrimidine (366 mg, 2.22 mmol) and K.sub.2CO.sub.3 (1.53 g, 11.09 mmol) in DMF (10 ml).
(368) 1H NMR (600 MHz, CD.sub.3OD) δ 8.65 (d, J=4.99 Hz, 2H), 7.31 (t, J=4.99 Hz, 1H), 7.03 (d, J=8.22 Hz, 1H), 6.70 (s, 1H), 6.43 (dd, J=2.05, 8.22 Hz, 1H), 4.07 (s, 2H).
Compound 89
N-{5-chloro-2-[(pyrimidin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(369) ##STR00121##
(370) Following General Procedure B, the title compound (243 mg, 51%) was prepared from 5-chloro-2-((pyrimidin-2-ylmethyl)thio)aniline (280 mg, 1.11 mmol) and benzofuran-2-sulfonyl chloride (240 mg, 1.11 mmol) in pyridine (3 ml).
(371) 1H NMR (600 MHz, acetone-d6) δ 11.69 (br. s., 1H), 8.87 (d, J=4.99 Hz, 2H), 7.74 (dd, J=0.88, 7.92 Hz, 1H), 7.66 (s, 1H), 7.62 (d, J=8.22 Hz, 1H), 7.59 (d, J=0.59 Hz, 1H), 7.45-7.52 (m, 3H), 7.33 (ddd, J=1.76, 6.38, 8.00 Hz, 1H), 7.14 (dd, J=2.20, 8.36 Hz, 1H), 4.24 (s, 2H).
Compound 90
N-{5-chloro-2-[(pyrimidin-2-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(372) ##STR00122##
(373) Following General Procedure C, the title compound (82 mg) was prepared from N-{5-chloro-2-[(pyrimidin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(374) 1H NMR (600 MHz, CD.sub.3OD) δ 8.68 (dd, J=1.47, 4.99 Hz, 2H), 7.73 (d, J=7.92 Hz, 1H), 7.53-7.60 (m, 2H), 7.45-7.52 (m, 2H), 7.30-7.41 (m, 4H), 4.63 (d, J=13.50 Hz, 1H), 4.46 (d, J=13.50 Hz, 1H).
Compound 91
N-{5-chloro-2-[(pyrimidin-2-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(375) ##STR00123##
(376) Following General Procedure D, the title compound (60 mg) was prepared from N-{5-chloro-2-[(pyrimidin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(377) 1H NMR (600 MHz, DMSO-d6) δ 8.68 (dd, J=1.47, 4.99 Hz, 2H), 7.76 (s, 1H), 7.68 (br. s., 1H), 7.61 (d, J=8.22 Hz, 1H), 7.54-7.58 (m, 2H), 7.46 (t, J=7.34 Hz, 1H), 7.41 (t, J=4.84 Hz, 1H), 7.30-7.37 (m, 1H), 7.19 (d, J=7.92 Hz, 1H), 5.11-5.19 (m, 2H).
General Procedure M
Intermediate 31
4-mercapto-3-nitrobenzonitrile
(378) ##STR00124##
(379) To a solution of 4-chloro-3-nitrobenzonitrile (530 mg, 2.88 mmol) in dioxane (5 ml)/water (1 ml) was added Na.sub.2S.9H.sub.2O 9692 mg, 2.88 mmol). After it was stirred at room temperature for 2 hours, the reaction was quenched with HCl (1N). The mixture was extracted with EtOAc (2×50 ml). The organic layer was washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The title compound was purified by silica gel column chromatography (0˜30% EtOAc in hexane).
(380) 1H NMR (600 MHz, acetone-d6) δ 8.67 (d, J=1.76 Hz, 1H), 8.01 (s, 1H), 7.93 (dd, J=1.76, 8.51 Hz, 1H), 5.30 (s, 1H).
Intermediate 32
4-(benzylthio)-3-nitrobenzonitrile
(381) ##STR00125##
(382) Following General Procedure A, the title compound (580 mg, 82%) was prepared from 4-mercapto-3-nitrobenzonitrile (473 mg, 2.63 mmol), (bromomethyl)benzene (449 mg, 2.63 mmol), K.sub.2CO.sub.3 (1.81 g, 13.14 mmol) in DMF (10 ml).
(383) 1H NMR (600 MHz, DMSO-d.sub.6) δ 8.68 (d, J=1.76 Hz, 1H), 8.10 (dd, J=1.47, 8.51 Hz, 1H), 7.88 (d, J=8.51 Hz, 1H), 7.43 (d, J=7.34 Hz, 2H), 7.34 (t, J=7.63 Hz, 2H), 7.25-7.30 (m, 1H), 4.44 (s, 2H).
Intermediate 33
3-amino-4-(benzylthio)benzonitrile
(384) ##STR00126##
(385) Following General Procedure L, the title compound (372 mg, 81%) was prepared from 4-(benzylthio)-3-nitrobenzonitrile (518 mg, 1.92 mmol).
(386) 1H NMR (600 MHz, CD.sub.3OD) δ 7.11-7.25 (m, 6H), 6.96 (d, J=1.76 Hz, 1H), 6.71-6.78 (m, 1H), 4.00 (s, 2H).
Compound 92
N-[2-(benzylthio)-5-cyanophenyl]-1-benzofuran-2-sulfonamide
(387) ##STR00127##
(388) Following General Procedure B, the title compound (419 mg, 65%) was prepared from 3-amino-4-(benzylthio)benzonitrile (370 mg, 1.54 mmol) and benzofuran-2-sulfonyl chloride (333 mg, 1.54 mmol) in pyridine (3 ml).
(389) 1H NMR (600 MHz, CD.sub.3OD) δ 7.73 (d, J=8.51 Hz, 1H), 7.65 (d, J=1.17 Hz, 1H), 7.50-7.56 (m, 2H), 7.48 (dd, J=1.47, 8.22 Hz, 1H), 7.39 (ddd, J=2.05, 6.16, 7.92 Hz, 1H), 7.31-7.36 (m, 2H), 7.09-7.20 (m, 3H), 6.92 (d, J=7.04 Hz, 2H), 3.97 (s, 2H).
Compound 93
N-[2-(benzylsulfinyl)-5-cyanophenyl]-1-benzofuran-2-sulfonamide
(390) ##STR00128##
(391) Following General Procedure C, the title compound (109 mg) was prepared from N-[2-(benzylthio)-5-cyanophenyl]-1-benzofuran-2-sulfonamide.
(392) 1H NMR (600 MHz, CD.sub.3OD) δ 7.74 (d, J=7.63 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J=8.51 Hz, 1H), 7.50 (s, 1H), 7.45 (t, J=7.48 Hz, 1H), 7.30-7.39 (m, 2H), 7.28 (d, J=7.92 Hz, 1H), 7.20-7.25 (m, 1H), 7.16 (t, J=7.48 Hz, 2H), 6.96 (d, J=7.34 Hz, 2H), 4.47 (d, J=13.21 Hz, 1H), 4.21 (d, J=12.91 Hz, 1H).
Compound 94
N-[2-(benzylsulfonyl)-5-cyanophenyl]-1-benzofuran-2-sulfonamide
(393) ##STR00129##
(394) Following General Procedure D, the title compound (230 mg) was prepared from N-[2-(benzylthio)-5-cyanophenyl]-1-benzofuran-2-sulfonamide.
(395) 1H NMR (600 MHz, CD.sub.3OD) δ 7.97 (d, J=1.47 Hz, 1H), 7.68 (d, J=7.63 Hz, 1H), 7.52 (d, J=8.22 Hz, 1H), 7.43 (s, 1H), 7.32-7.38 (m, 2H), 7.24-7.30 (m, 1H), 7.09-7.18 (m, 3H), 6.98-7.06 (m, 2H), 6.87 (dd, J=1.47, 8.22 Hz, 1H), 5.05 (s, 2H).
Compound 95
4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide
(396) ##STR00130##
(397) Following General Procedure B and D, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.
(398) 1H NMR (300 MHz, CD.sub.3OD) δ 8.26 (s, 1H), 8.11 (d, J=8.50 Hz, 1H), 7.74-7.87 (m, 2H), 7.58 (d, J=1.47 Hz, 1H), 7.16 (d, J=8.50 Hz, 1H), 3.19 (s, 3H).
Compound 96
4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide
(399) ##STR00131##
(400) Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.
(401) 1H NMR (300 MHz, CDCl.sub.3) δ 8.13 (d, J=1.47 Hz, 1H), 7.88 (dd, J=1.90, 8.35 Hz, 1H), 7.60 (dd, J=2.64, 12.60 Hz, 2H), 7.28 (d, J=8.50 Hz, 1H), 7.10 (dd, J=2.05, 8.50 Hz, 1H), 2.21 (s, 3H).
Compound 97
4-chloro-N-[5-chloro-2-(isopropylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide
(402) ##STR00132##
(403) Following General Procedure A and B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 2-iodo-propane, and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.
(404) 1H NMR (300 MHz, CD.sub.3OD) δ 8.13 (d, J=1.47 Hz, 1H), 7.92 (dd, J=2.05, 8.50 Hz, 1H), 7.76 (d, J=8.50 Hz, 1H), 7.53 (d, J=2.05 Hz, 1H), 7.33 (d, J=8.50 Hz, 1H), 7.15-7.23 (m, 1H), 3.03-3.21 (m, 1H), 1.06 (d, J=6.45 Hz, 6H).
Compound 98
4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(405) ##STR00133##
(406) Following General Procedure A and B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 2-bromo-ethanol, and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride.
(407) 1H NMR (300 MHz, CD.sub.3OD) δ 8.09 (d, J=1.47 Hz, 1H), 7.92 (dd, J=1.90, 8.35 Hz, 1H), 7.76 (d, J=8.50 Hz, 1H), 7.51 (d, J=2.34 Hz, 1H), 7.41 (d, J=8.50 Hz, 1H), 7.20 (dd, J=2.20, 8.35 Hz, 1H), 3.49 (t, J=6.15 Hz, 2H), 2.80 (t, J=6.15 Hz, 2H).
Compound 99
4-chloro-N-[5-chloro-2-(isopropylsulfinyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide
(408) ##STR00134##
(409) Following General Procedure C, the title compound (55 mg) was prepared from 4-chloro-N-[5-chloro-2-(isopropylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide.
Compound 100
4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(410) ##STR00135##
(411) Following General Procedure C, the title compound (109 mg) was prepared from 4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.
(412) 1H NMR (300 MHz, CD.sub.3OD) δ 8.09 (d, J=1.17 Hz, 1H), 7.96-8.03 (m, 1H), 7.84 (d, J=8.20 Hz, 1H), 7.71 (d, J=8.50 Hz, 1H), 7.44 (dd, J=1.76, 8.50 Hz, 1H), 7.21 (d, J=1.76 Hz, 1H), 3.98 (td, J=4.10, 8.06 Hz, 1H), 3.77-3.88 (m, 1H), 3.19 (ddd, J=5.27, 8.42, 13.26 Hz, 1H), 2.95-3.06 (m, 1H).
Compound 101
4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(413) ##STR00136##
(414) Following General Procedure D, the title compound was prepared from 4-chloro-N-{5-chloro-2-[(2-hydroxyethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.
(415) 1H NMR (600 MHz, CD.sub.3OD) δ 8.27 (d, J=1.47 Hz, 1H), 8.11 (dd, J=2.05, 8.51 Hz, 1H), 7.74 (dd, J=8.51, 14.97 Hz, 2H), 7.54-7.59 (m, 1H), 6.96-7.08 (m, 1H), 3.82 (t, J=6.02 Hz, 2H), 3.57-3.68 (m, 2H).
Compound 102
methyl 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanoate
(416) ##STR00137##
(417) Following General Procedure H, B, and C, the title compound was prepared from 2-amino-4-chlorobenzenethiol.
(418) 1H NMR (300 MHz, CD.sub.3OD) δ 8.09 (s, 1H), 7.99 (dd, J=1.76, 8.50 Hz, 1H), 7.85 (d, J=8.20 Hz, 1H), 7.71 (d, J=8.50 Hz, 1H), 7.47 (dd, J=1.61, 8.35 Hz, 1H), 7.11 (d, J=1.76 Hz, 1H), 3.63 (s, 3H), 3.24-3.39 (m, 1H), 3.08-3.22 (m, 1H), 2.54-2.82 (m, 2H).
Compound 103
4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(419) ##STR00138##
(420) Following General Procedure A and B, the title compound was prepared from 2-amino-4-chlorobenzenethiol.
(421) 1H NMR (600 MHz, CD.sub.3OD) δ 8.63 (d, J=3.81 Hz, 1H), 8.03 (d, J=2.35 Hz, 1H), 7.87 (dd, J=2.20, 8.36 Hz, 1H), 7.75 (td, J=1.76, 7.63 Hz, 1H), 7.70 (d, J=8.51 Hz, 1H), 7.54 (d, J=2.35 Hz, 1H), 7.37 (d, J=8.51 Hz, 1H), 7.32-7.35 (m, 1H), 7.21 (d, J=7.63 Hz, 1H), 7.13 (dd, J=2.35, 8.22 Hz, 1H), 4.00 (s, 2H).
Compound 104
4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(422) ##STR00139##
(423) Following General Procedure A and B, the title compound was prepared from 2-amino-4-chlorobenzenethiol.
(424) 1H NMR (600 MHz, CD.sub.3OD) δ 8.38 (d, J=3.82 Hz, 1H), 8.25 (br. s., 1H), 8.11 (d, J=2.35 Hz, 1H), 7.93 (dd, J=2.05, 8.51 Hz, 1H), 7.78 (d, J=8.51 Hz, 1H), 7.60 (dt, J=1.91, 7.92 Hz, 1H), 7.39 (d, J=2.35 Hz, 1H), 7.33 (dd, J=4.84, 7.78 Hz, 1H), 7.20 (d, J=8.51 Hz, 1H), 7.14 (s, J=2.35, 2.35, 8.51, 8.51 Hz, 1H), 3.95 (s, 2H).
Compound 105
4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(425) ##STR00140##
(426) Following General Procedure C, the title compound was prepared from 4-chloro-N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.
(427) 1H NMR (600 MHz, DMSO-d6) δ 8.44 (d, J=4.40 Hz, 1H), 8.03 (d, J=2.05 Hz, 1H), 7.98 (dd, J=2.05, 8.22 Hz, 1H), 7.88 (d, J=8.22 Hz, 1H), 7.74 (t, 1H), 7.25-7.33 (m, 2H), 7.20 (d, J=7.63 Hz, 1H), 7.14 (br. s., 1H), 7.03 (d, J=1.47 Hz, 1H), 4.49 (d, J=12.62 Hz, 1H), 4.06 (d, J=12.91 Hz, 1H).
Compound 106
4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(428) ##STR00141##
(429) Following General Procedure C, the title compound was prepared from 4-chloro-N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.
(430) 1H NMR (600 MHz, CD.sub.3OD) δ 8.35 (dd, J=1.61, 4.84 Hz, 1H), 8.24 (d, J=2.35 Hz, 1H), 8.07 (d, J=2.05 Hz, 1H), 8.03 (d, J=1.76 Hz, 1H), 7.71 (d, J=8.51 Hz, 1H), 7.38 (s, 1H), 7.27 (d, J=2.05 Hz, 1H), 7.23-7.26 (m, 1H), 6.75 (d, J=8.22 Hz, 1H), 6.65 (dd, J=1.91, 8.36 Hz, 1H), 4.45 (d, J=13.50 Hz, 1H), 4.37 (d, J=13.21 Hz, 1H).
General Procedure N
Intermediate 34
4-Chloro-N-(5-chloro-2-mercapto-phenyl)-3-trifluoromethyl-benzenesulfonamide
(431) ##STR00142##
(432) To a solution of N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide] Intermediate 5 (106 mg, 0.13 mmol) in THF (3 ml) at 0° C. was added NaBH.sub.4 (20 mg, 0.53 mmol), the mixture was stirred at room temperature for 1 h, diluted with H.sub.2O, acidified carefully with 6 M HCl, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to yield 109 mg off-white solid as the title compound.
(433) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.05 (s, 1H), 7.91 (d, J=8.51 Hz, 1H), 7.78 (d, J=8.51 Hz, 1H), 7.30 (dd, J=1.47, 8.22 Hz, 1H), 7.23-7.25 (m, 1H), 7.14 (dd, J=2.20, 8.36 Hz, 1H).
Compound 107
ethyl {[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}acetate
(434) ##STR00143##
(435) Following General Procedure A and C, the title compound was prepared from 4-Chloro-N-(5-chloro-2-mercapto-phenyl)-3-trifluoromethyl-benzenesulfonamide Intermediate 34 and ethyl 2-bromoacetate.
(436) 1H NMR (300 MHz, CD.sub.3OD) δ 8.06 (s, 1H), 7.96 (d, J=8.50 Hz, 1H), 7.84 (dd, J=8.50, 10.84 Hz, 2H), 7.52 (dd, J=1.61, 8.64 Hz, 1H), 7.06 (d, J=1.47 Hz, 1H), 4.17 (q, J=7.23 Hz, 2H), 4.06 (d, J=14.65 Hz, 1H), 3.88 (d, J=14.36 Hz, 1H), 1.22 (t, J=7.18 Hz, 3H).
General Procedure O
Intermediate 35
4-Chloro-N-[5-chloro-2-(3-oxo-cyclopentylsulfanyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide
(437) ##STR00144##
(438) To a solution of N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide] Intermediate 5 (105 mg, 0.13 mmol) in CH.sub.2Cl.sub.2 (2 ml), MeOH (0.5 ml), and H.sub.2O (0.25 ml) was added polymer-bound triphenylphosphine (˜3 mmol/g triphenylphosphine loading, 87 mg, 0.26 mmol), cyclopent-2-enone (33 μl, 0.39 mmol), and PTSA (catalytic amount). The reaction was stirred at room temperature for 4 h and was directly purified by column chromatography on silica gel (0.fwdarw.100% ethyl acetate in hexane) to yield the title compound as an off-white solid (133 mg, 100%).
(439) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 8.16 (d, J=2.35 Hz, 1H), 7.93 (dd, J=2.35, 8.51 Hz, 1H), 7.89 (s, 1H), 7.62-7.65 (m, 2H), 7.35 (d, J=8.22 Hz, 1H), 7.07 (dd, J=2.20, 8.36 Hz, 1H), 3.46 (quin, J=6.53 Hz, 1H), 2.44-2.49 (m, 1H), 2.38-2.44 (m, 1H), 2.21 (s, 2H), 2.05-2.11 (m, 1H), 1.84-1.90 (m, 1H).
Compound 108
4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(440) ##STR00145##
(441) Following General Procedure D, followed by treatment of the crude product with NaBH.sub.4 in MeOH, the title compound was prepared from 4-Chloro-N-[5-chloro-2-(3-oxo-cyclopentylsulfanyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (Intermediate 35).
(442) 1H NMR (600 MHz, CD.sub.3OD) δ 8.13 (d, J=2.05 Hz, 1H), 7.99 (dd, J=2.20, 8.36 Hz, 1H), 7.73 (d, J=8.51 Hz, 1H), 7.46 (d, J=8.51 Hz, 1H), 7.34 (d, J=2.05 Hz, 1H), 7.06 (dd, J=2.05, 8.51 Hz, 1H), 4.17-4.22 (m, 1H), 3.70-3.77 (m, 1H), 2.19-2.26 (m, 1H), 1.90-2.00 (m, 1H), 1.78-1.86 (m, 1H), 1.62-1.76 (m, 2H), 1.29-1.38 (m, 1H).
Compound 109
4-chloro-N-[5-chloro-2-(ethylsulfonyl)phenyl]-3-(trifluoromethyl)benzenesulfonamide
(443) ##STR00146##
(444) Following General Procedure D, the title compound was prepared from 4-chloro-N-[5-chloro-2-(ethylthio)phenyl]-3-(trifluoromethyl)benzenesulfonamide.
(445) 1H NMR (600 MHz, CD.sub.3OD) δ 8.30 (d, J=1.76 Hz, 1H), 8.14 (dd, J=2.20, 8.36 Hz, 1H), 7.72-7.80 (m, 2H), 7.64 (d, J=2.05 Hz, 1H), 7.10 (br. s., 1H), 3.30-3.38 (m, 2H), 1.09 (t, J=7.34 Hz, 3H)
Compound 110
2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylacetamide
(446) ##STR00147##
(447) Following General Procedure G, the title compound was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide] Intermediate 5 and 2-chloro-N,N-dimethylacetamide.
(448) 1H NMR (600 MHz, CD.sub.3OD) δ 8.09 (d, J=2.35 Hz, 1H), 7.94 (dd, J=2.05, 8.51 Hz, 1H), 7.76 (d, J=8.22 Hz, 1H), 7.47-7.50 (m, 2H), 7.18 (dd, J=2.35, 8.51 Hz, 1H), 3.68 (s, 2H), 2.97 (s, 3H), 2.93 (s, 3H).
Compound 111
2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-methylacetamide
(449) ##STR00148##
(450) Following General Procedure G, the title compound was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide] Intermediate 5 and 2-chloro-N-methylacetamide.
(451) 1H NMR (600 MHz, CD.sub.3OD) δ 8.09 (d, J=2.35 Hz, 1H), 7.93 (dd, J=2.35, 8.51 Hz, 1H), 7.76 (d, J=8.51 Hz, 1H), 7.48 (d, J=2.35 Hz, 1H), 7.44 (d, J=8.22 Hz, 1H), 7.20 (dd, J=2.35, 8.51 Hz, 1H), 3.40 (s, 2H), 2.69 (s, 3H).
Compound 112
2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-dimethylacetamide
(452) ##STR00149##
(453) Following General Procedure C, the title compound was prepared from 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylacetamide.
(454) 1H NMR (600 MHz, CD.sub.3OD) δ 8.16 (d, J=2.35 Hz, 1H), 8.01 (dd, J=2.05, 8.22 Hz, 1H), 7.68 (d, J=8.51 Hz, 1H), 7.45 (d, J=8.51 Hz, 1H), 7.28 (d, J=1.76 Hz, 1H), 6.90 (dd, J=2.05, 8.22 Hz, 1H), 4.65-4.71 (m, 1H), 3.51-3.57 (m, 1H), 3.11 (s, 3H), 2.98 (s, 3H).
Compound 113
2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-dimethylacetamide
(455) ##STR00150##
(456) Following General Procedure D, the title compound was prepared from 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylacetamide.
(457) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.29 (d, J=2.05 Hz, 1H), 8.09-8.14 (m, 1H), 7.72 (d, J=8.51 Hz, 1H), 7.68 (d, J=8.51 Hz, 1H), 7.48 (d, J=1.76 Hz, 1H), 6.81 (d, J=8.22 Hz, 1H), 3.16 (s, 3H), 3.00 (s, 3H).
Compound 114
2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-methylacetamide
(458) ##STR00151##
(459) Following General Procedure C, the title compound was prepared from 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-methylacetamide.
(460) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.15 (d, J=2.05 Hz, 1H), 8.01 (dd, J=2.20, 8.36 Hz, 1H), 7.72 (d, J=8.51 Hz, 1H), 7.51 (d, J=8.22 Hz, 1H), 7.22 (d, J=2.05 Hz, 1H), 7.02 (dd, J=1.91, 8.36 Hz, 1H), 4.21 (d, J=13.50 Hz, 1H), 3.49 (d, J=13.21 Hz, 1H), 2.76 (s, 3H)
Compound 115
2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N-methylacetamide
(461) ##STR00152##
(462) Following General Procedure D, the title compound was prepared from 2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-methylacetamide.
(463) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.29 (d, J=2.05 Hz, 1H), 8.09-8.13 (m, 1H), 7.69 (d, J=8.51 Hz, 1H), 7.66 (d, J=8.22 Hz, 1H), 7.44 (d, J=2.05 Hz, 1H), 6.75 (dd, J=1.91, 8.66 Hz, 1H), 2.77 (s, 3H).
Compound 116
N-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide
(464) ##STR00153##
(465) Following General Procedure G, the title compound was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis[4-chloro-3-(trifluoromethyl)benzenesulfonamide] Intermediate 5 and 2-bromo-ethylamine hydrobromide.
(466) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.18 (d, J=2.05 Hz, 1H), 7.99 (dd, J=2.05, 8.22 Hz, 1H), 7.65 (d, J=8.51 Hz, 1H), 7.38 (d, J=8.22 Hz, 1H), 7.30 (d, J=2.35 Hz, 1H), 6.72 (dd, J=2.35, 8.22 Hz, 1H), 2.96-3.05 (m, 4H).
Compound 117
N-{2-[(2-aminoethyl)sulfonyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide
(467) ##STR00154##
(468) Following General Procedure D, followed by treatment of the crude product with excess zinc dust in MeOH, aqueous NH.sub.4Cl and HOAc at room temperature for 2 h, the title compound was prepared from N-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide.
(469) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.27 (d, J=2.05 Hz, 1H), 8.10 (dd, J=1.91, 8.36 Hz, 1H), 7.74 (d, J=8.51 Hz, 1H), 7.67 (d, J=8.51 Hz, 1H), 7.42 (d, J=1.76 Hz, 1H), 6.80 (dd, J=2.05, 8.51 Hz, 1H), 3.88-3.92 (m, 2H), 3.45-3.51 (m, 2H).
Compound 118
N-{2-[(2-aminoethyl)sulfinyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide
(470) ##STR00155##
(471) Following General Procedure C, the title compound was prepared from N-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide.
(472) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.15 (d, J=1.76 Hz, 1H), 8.00 (dd, J=1.90, 8.35 Hz, 1H), 7.69 (d, J=8.21 Hz, 1H), 7.46 (d, J=8.50 Hz, 1H), 7.25 (d, J=2.05 Hz, 1H), 6.94 (dd, J=1.90, 8.35 Hz, 1H), 3.53-3.67 (m, 1H), 3.36-3.50 (m, 1H), 3.17-3.31 (m, 2H).
Compound 119
3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)-N,N-dimethylpropanamide
(473) ##STR00156##
(474) Following General Procedure O, the title compound was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide) Intermediate 8 and N,N-dimethyl-acrylamide.
(475) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.69 (d, J=7.92 Hz, 1H), 7.53-7.56 (m, 1H), 7.45-7.49 (m, 2H), 7.39 (s, 1H), 7.37 (d, J=8.51 Hz, 1H), 7.31-7.35 (m, 1H), 7.17-7.20 (m, 1H), 2.90 (t, J=7.19 Hz, 2H), 2.87 (s, 3H), 2.85 (s, 3H), 2.33 (t, J=7.19 Hz, 2H).
Compound 120
3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)-N,N-dimethylpropanamide
(476) ##STR00157##
(477) Following General Procedure C, the title compound was prepared from 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)-N,N-dimethylpropanamide.
(478) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.72 (d, J=7.34 Hz, 1H), 7.64 (d, J=8.22 Hz, 1H), 7.58 (d, J=8.51 Hz, 1H), 7.46-7.51 (m, 1H), 7.46 (s, 1H), 7.39 (d, J=1.76 Hz, 1H), 7.32-7.37 (m, 2H), 3.27-3.34 (m, 1H), 3.16-3.24 (m, 1H), 2.96 (s, 3H), 2.90 (s, 3H), 2.77-2.86 (m, 1H), 2.59-2.66 (m, 1H).
Compound 121
3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)-N,N-dimethylpropanamide
(479) ##STR00158##
(480) Following General Procedure D, the title compound was prepared from 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)-N,N-dimethylpropanamide.
(481) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.59-7.75 (m, 3H), 7.40-7.49 (m, 1H), 7.30-7.41 (m, 1H), 7.20-7.30 (m, 2H), 6.79 (dd, J=1.76, 8.50 Hz, 1H), 3.94 (t, J=7.47 Hz, 2H), 2.87 (s, 3H), 2.81 (s, 3H), 2.59 (t, J=7.47 Hz, 2H).
Compound 122
N-(2-{[(6-amino-1-oxidopyridin-2-yl)methyl]sulfonyl}-5-chlorophenyl)-1-benzofuran-2-sulfonamide
(482) ##STR00159##
(483) Following General Procedure D and E, the title compound was prepared from tert-butyl {6-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]pyridin-2-yl}carbamate.
(484) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.77 (d, J=1.76 Hz, 1H), 7.59-7.71 (m, 2H), 7.29-7.44 (m, 3H), 7.20-7.29 (m, 1H), 7.10 (t, J=7.91 Hz, 1H), 6.77-6.88 (m, 2H), 6.57 (d, J=7.33 Hz, 1H), 5.41 (br. s., 2H), 4.57 (br. s., 1H).
General Procedure P
Compound 123
N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}ethyl)acetamide
(485) ##STR00160##
(486) To a solution of N-{2-[(2-aminoethyl)sulfonyl]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide (23 mg, 0.048 mmol) in CH.sub.2Cl.sub.2 (2 ml) was added Et.sub.3N (14 μl, 0.10 mmol), acetic anhydride (5 μl, 0.053 mmol), and catalytic amount of DMAP. The reaction was stirred at room temperature for 1 h and was concentrated. The crude product was purified by column chromatography on silica gel (0.fwdarw.10% MeOH in ethyl acetate), followed by PTLC (10% MeOH in ethyl acetate) to give the title compound.
(487) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.29 (d, J=2.05 Hz, 1H), 8.13 (dd, J=2.05, 8.51 Hz, 1H), 7.65-7.75 (m, 2H), 7.51 (d, J=2.05 Hz, 1H), 6.82 (dd, J=2.05, 8.51 Hz, 1H), 3.75 (t, J=6.60 Hz, 2H), 3.51 (t, J=6.60 Hz, 2H), 1.86 (s, 3H).
Compound 124
N-(2-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}ethyl)acetamide
(488) ##STR00161##
(489) Following General Procedure P and C, the title compound was prepared from N-{2-[(2-aminoethyl)thio]-5-chlorophenyl}-4-chloro-3-(trifluoromethyl)benzenesulfonamide.
(490) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.12 (s, 1H), 8.01 (dd, J=1.91, 8.36 Hz, 1H), 7.77 (d, J=8.51 Hz, 1H), 7.56 (d, J=8.22 Hz, 1H), 7.17 (s, 1H), 7.13 (d, J=7.63 Hz, 1H), 3.60-3.71 (m, 1H), 3.44-3.54 (m, 1H), 3.33-3.42 (m, 1H), 3.04-3.15 (m, 1H), 1.98 (s, 3H).
Intermediate 36
4-Chloro-N,N-dimethyl-butyramide
(491) ##STR00162##
(492) To a solution of 4-chloro-butyryl chloride (1.12 ml, 10.0 mmol) and dimethyl-amine hydrochloride (4.1 g, 50.0 mmol) in THF at 5° C. was added 2M NaOH (30 ml, 60.0 mmol) dropwise over 30 minutes while maintaining reaction temperature between 5-10° C. The reaction was stirred for additional 1.5 h and was concentrated, extracted with EtOAc (×2). The combined organic layer was washed with 1 M HCl (×2), brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo to yield the title compound as colorless oil (1.5 g, ˜100%). The crude was used without further purification.
Compound 125
4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)-N,N-dimethylbutanamide
(493) ##STR00163##
(494) Following General Procedure G and C, the title compound was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide) Intermediate 8 and 4-chloro-N,N-dimethyl-butyramide.
(495) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.68 (d, J=7.62 Hz, 1H), 7.53 (d, J=2.05 Hz, 1H), 7.35-7.49 (m, 3H), 7.32 (d, J=0.88 Hz, 1H), 7.25-7.32 (m, 1H), 6.95 (dd, J=2.05, 8.20 Hz, 1H), 3.33-3.49 (m, 1H), 2.98 (s, 3H), 2.91-3.08 (m, 1H), 2.90 (s, 3H), 2.38-2.57 (m, 2H), 1.92-2.09 (m, 2H).
Compound 126
4-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)-N,N-dimethylbutanamide
(496) ##STR00164##
(497) Following General Procedure G and D, the title compound was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide) Intermediate 8 and 4-chloro-N,N-dimethyl-butyramide.
(498) .sup.1H NMR (600 MHz, CD.sub.3OD) € 7.76 (s, 1H), 7.74 (d, J=8.51 Hz, 1H), 7.70 (d, J=7.92 Hz, 1H), 7.38-7.48 (m, 3H), 7.31 (t, J=7.34 Hz, 1H), 6.86-7.05 (m, 1H), 3.46-3.69 (m, 2H), 2.97 (s, 3H), 2.91 (s, 3H), 2.43-2.59 (m, 2H), 1.93-2.09 (m, 2H).
Compound 127
5-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-1-benzofuran-2-sulfonamide
(499) ##STR00165##
(500) Following General Procedure B and C, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 5-chloro-benzofuran-2-sulfonyl chloride (CAS #: 128852-02-8) (Bioorganic & Medicinal Chemistry 13 (2005) 3927-3954).
(501) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 11.00 (br. s., 1H), 7.80 (d, J=1.47 Hz, 1H), 7.68 (d, J=1.76 Hz, 1H), 7.40-7.54 (m, 3H), 7.05-7.16 (m, 2H), 2.91 (s, 3H).
Compound 128
5-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-1-benzofuran-2-sulfonamide
(502) ##STR00166##
(503) Following General Procedure B and D, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 5-chloro-benzofuran-2-sulfonyl chloride (CAS #: 128852-02-8) (Bioorganic & Medicinal Chemistry 13 (2005) 3927-3954).
(504) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.74 (s, 1H), 7.74 (d, J=5.58 Hz, 1H), 7.64 (d, J=1.76 Hz, 1H), 7.43 (d, J=8.80 Hz, 1H), 7.30-7.35 (m, 2H), 6.88 (dd, J=2.05, 8.51 Hz, 1H), 3.33 (s, 3H).
Compound 129
N-{5-chloro-2-[(1H-pyrazol-3-yl methyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(505) ##STR00167##
(506) Following General Procedure C and E, the title compound was prepared from tert-butyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1H-pyrazole-1-carboxylate (Compound 22).
(507) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.67 (d, J=7.63 Hz, 1H), 7.42-7.47 (m, 2H), 7.41 (d, J=2.05 Hz, 1H), 7.37 (td, J=1.47, 7.78 Hz, 1H), 7.32 (d, J=0.88 Hz, 1H), 7.28 (td, J=0.88, 7.48 Hz, 1H), 7.22 (d, J=8.51 Hz, 1H), 6.96 (dd, J=1.76, 8.51 Hz, 1H), 5.92 (s, 1H), 4.56 (d, J=13.50 Hz, 1H), 4.28 (d, J=13.50 Hz, 1H).
Compound 130
N-[5-chloro-2-(methylsulfinyl)phenyl]-4-isopropylbenzenesulfonamide
(508) ##STR00168##
(509) Following General Procedure B and C, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-isopropyl-benzenesulfonyl chloride.
(510) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 10.42 (br. s., 1H), 7.80-7.86 (m, 2H), 7.68 (s, 1H), 7.35 (s, 2H), 7.05-7.08 (m, 1H), 7.01-7.03 (m, 1H), 2.94 (spt, J=6.90 Hz, 1H), 2.69 (s, 3H), 1.22 (d, J=7.04 Hz, 6H).
Compound 131
4-bromo-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide
(511) ##STR00169##
(512) Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-bromo-benzenesulfonyl chloride.
(513) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 7.65-7.68 (m, 2H), 7.61-7.63 (m, 2H), 7.58-7.60 (m, 2H), 7.29 (d, J=8.22 Hz, 1H), 7.04 (dd, J=2.20, 8.36 Hz, 1H), 2.17 (s, 3H).
Compound 132
N-[5-chloro-2-(methylthio)phenyl]-4-iodobenzenesulfonamide
(514) ##STR00170##
(515) Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-iodo-benzenesulfonyl chloride.
(516) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 7.80 (d, J=8.80 Hz, 2H), 7.62-7.64 (m, 1H), 7.61 (d, J=2.05 Hz, 1H), 7.49-7.53 (m, 2H), 7.30 (d, J=8.22 Hz, 1H), 7.04 (dd, J=2.20, 8.36 Hz, 1H), 2.17 (s, 3H).
Compound 133
4-bromo-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide
(517) ##STR00171##
(518) Following General Procedure C, the title compound was prepared from 4-bromo-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide.
(519) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 10.63-10.77 (m, 1H), 7.79-7.82 (m, 2H), 7.64-7.68 (m, 3H), 7.05 (dd, J=1.17, 2.35 Hz, 2H), 2.79 (s, 3H).
Compound 134
N-[5-chloro-2-(methylsulfinyl)phenyl]-4-iodobenzenesulfonamide
(520) ##STR00172##
(521) Following General Procedure C, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-4-iodobenzenesulfonamide.
(522) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 10.69 (br. s., 1H), 7.83-7.91 (m, 2H), 7.61-7.69 (m, 3H), 7.01-7.08 (m, 2H), 2.79 (s, 3H).
Compound 135
4-bromo-N-[5-chloro-2-(methylsulfonyl)phenyl]benzenesulfonamide
(523) ##STR00173##
(524) Following General Procedure D, the title compound was prepared from 4-bromo-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide.
(525) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 9.20-9.27 (m, 1H), 7.80 (dd, J=1.32, 8.36 Hz, 2H), 7.76 (d, J=8.51 Hz, 1H), 7.68 (dd, J=1.47, 8.80 Hz, 2H), 7.25 (d, J=1.47 Hz, 1H), 7.18-7.21 (m, 1H), 2.93 (d, J=1.47 Hz, 3H).
Compound 136
N-[5-chloro-2-(methylsulfonyl)phenyl]-4-iodobenzenesulfonamide
(526) ##STR00174##
(527) Following General Procedure D, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-4-iodobenzenesulfonamide.
(528) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 9.17-9.25 (m, 1H), 7.90 (d, J=8.51 Hz, 2H), 7.76 (d, J=8.51 Hz, 1H), 7.67 (d, J=1.76 Hz, 1H), 7.64 (d, J=8.51 Hz, 2H), 7.19 (dd, J=1.76, 8.51 Hz, 1H), 2.93 (s, 3H).
Compound 137
N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(529) ##STR00175##
(530) Following General Procedure A and B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 2-bromomethyl-pyridine hydrobromide, and benzofuran-2-sulfonyl chloride.
(531) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 12.32 (br. s, 1H), 8.87 (dt, J=0.77, 4.92 Hz, 1H), 7.76 (d, J=2.05 Hz, 1H), 7.58-7.65 (m, 2H), 7.44 (dd, J=0.88, 8.22 Hz, 1H), 7.34-7.42 (m, 3H), 7.25-7.30 (m, 2H), 7.06 (d, J=7.63 Hz, 1H), 6.96-7.01 (m, 1H), 3.98 (s, 2H).
Compound 138
N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(532) ##STR00176##
(533) Following General Procedure A and B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 3-bromomethyl-pyridine hydrobromide, and benzofuran-2-sulfonyl chloride.
(534) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 8.42 (dd, J=1.61, 4.84 Hz, 1H), 8.12 (d, J=1.76 Hz, 2H), 7.66-7.70 (m, 2H), 7.50 (d, J=1.17 Hz, 1H), 7.46-7.49 (m, 1H), 7.42-7.46 (m, 1H), 7.33 (ddd, J=1.17, 6.97, 8.00 Hz, 1H), 7.26-7.29 (m, 1H), 7.13 (ddd, J=0.88, 4.70, 7.92 Hz, 1H), 7.00 (d, J=8.51 Hz, 1H), 6.89 (dd, J=2.20, 8.36 Hz, 1H), 3.75 (s, 2H).
Compound 139
N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(535) ##STR00177##
(536) Following General Procedure C, the title compound was prepared from N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(537) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.28 (d, J=4.11 Hz, 1H), 7.86 (br. s., 1H), 7.68-7.71 (m, J=0.73, 1.32 Hz, 1H), 7.54 (d, J=1.76 Hz, 1H), 7.36-7.41 (m, 2H), 7.31-7.35 (m, 1H), 7.25-7.29 (m, J=1.03, 7.78 Hz, 1H), 7.24 (d, J=7.92 Hz, 1H), 7.12 (dd, J=4.99, 7.63 Hz, 1H), 6.73 (d, J=8.51 Hz, 1H), 6.68 (dd, J=2.05, 8.51 Hz, 1H), 4.55 (s, 2H).
Compound 140
N-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(538) ##STR00178##
(539) Following General Procedure C, the title compound was prepared from N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(540) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.10-8.14 (m, 1H), 8.01 (t, J=1.47 Hz, 1H), 7.66-7.68 (m, 1H), 7.42-7.49 (m, 2H), 7.34 (ddd, J=1.17, 7.12, 8.44 Hz, 1H), 7.23-7.29 (m, 2H), 7.14 (dd, J=6.60, 7.78 Hz, 1H), 6.87 (d, J=7.92 Hz, 1H), 6.83 (d, J=8.22 Hz, 1H), 6.71 (dd, J=2.05, 8.22 Hz, 1H), 4.63 (d, J=13.21 Hz, 1H), 4.37 (d, J=13.21 Hz, 1H).
Compound 141
N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(541) ##STR00179##
(542) Following General Procedure D, the title compound was prepared from N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(543) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.27 (d, J=4.11 Hz, 1H), 8.04 (br. s., 1H), 7.78 (t, J=1.76 Hz, 1H), 7.65 (d, J=7.92 Hz, 1H), 7.46 (d, J=0.88 Hz, 1H), 7.31-7.37 (m, 2H), 7.27-7.31 (m, 1H), 7.21-7.26 (m, 2H), 7.06 (dd, J=5.14, 7.48 Hz, 1H), 6.67 (dt, J=1.76, 8.51 Hz, 1H), 4.98 (s, 2H).
Compound 142
N-(5-chloro-2-{[(1-oxidopyridin-3-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(544) ##STR00180##
(545) Following General Procedure D, the title compound was prepared from N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(546) .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.01-8.08 (m, 2H), 7.68 (d, J=7.92 Hz, 1H), 7.53 (d, J=8.22 Hz, 1H), 7.46-7.48 (m, 1H), 7.31-7.37 (m, 2H), 7.23-7.27 (m, 2H), 7.11-7.15 (m, 1H), 6.98 (d, J=7.92 Hz, 1H), 6.58-6.61 (m, 1H), 5.09 (s, 2H).
Compound 143
N-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(547) ##STR00181##
(548) Following General Procedure G, the title compound was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide) Intermediate 8 and 1-bromomethyl-3-nitro-benzene.
(549) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 8.08 (s, 1H), 8.02 (ddd, J=1.17, 2.35, 8.22 Hz, 1H), 7.77 (t, J=2.05 Hz, 1H), 7.65-7.69 (m, 2H), 7.50 (d, J=0.88 Hz, 1H), 7.45-7.48 (m, 1H), 7.41-7.45 (m, 1H), 7.30-7.36 (m, 2H), 7.21 (dq, J=0.88, 7.63 Hz, 1H), 7.03 (d, J=8.22 Hz, 1H), 6.89 (dd, J=2.05, 8.22 Hz, 1H), 3.84 (s, 2H).
Compound 144
N-{5-chloro-2-[(3-methoxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(550) ##STR00182##
(551) Following General Procedure G, the title compound was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide) Intermediate 8 and 1-bromomethyl-3-methoxy-benzene.
(552) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 8.11 (s, 1H), 7.64-7.68 (m, 2H), 7.40-7.50 (m, 3H), 7.31 (ddd, J=0.88, 7.04, 7.92 Hz, 1H), 7.07-7.13 (m, 2H), 6.90 (dd, J=2.05, 8.22 Hz, 1H), 6.73 (ddd, J=1.17, 2.49, 8.36 Hz, 1H), 6.53-6.56 (m, 1H), 6.48 (t, J=2.35 Hz, 1H), 3.74 (s, 2H), 3.66 (s, 3H).
Compound 145
N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(553) ##STR00183##
(554) Following General Procedure C, the title compound was prepared from N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(555) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.46 (d, J=4.70 Hz, 1H), 7.64-7.73 (m, 2H), 7.48 (d, J=8.51 Hz, 1H), 7.38-7.45 (m, 3H), 7.25-7.34 (m, 3H), 7.07-7.17 (m, 2H), 4.58 (d, J=12.91 Hz, 1H), 4.35 (d, J=12.91 Hz, 1H).
Compound 146
N-{5-chloro-2-[(pyridin-2-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(556) ##STR00184##
(557) Following General Procedure D, the title compound was prepared from N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(558) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.42 (dt, J=0.84, 4.77 Hz, 1H), 7.75 (d, J=2.05 Hz, 1H), 7.67 (d, J=7.63 Hz, 1H), 7.41-7.49 (m, 3H), 7.31-7.39 (m, 2H), 7.22-7.29 (m, 2H), 7.07 (d, J=7.63 Hz, 1H), 6.76 (dd, J=1.91, 8.66 Hz, 1H), 5.07 (s, 2H).
Compound 147
N-(5-chloro-2-{[(1-oxidopyridin-2-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(559) ##STR00185##
(560) Following General Procedure D, the title compound was prepared from N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(561) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.35 (d, J=6.46 Hz, 1H), 7.74 (d, J=2.05 Hz, 1H), 7.66 (d, J=7.92 Hz, 1H), 7.60 (d, J=8.51 Hz, 1H), 7.38 (s, 2H), 7.34 (d, J=10.56 Hz, 3H), 7.25 (s, 2H), 6.77 (dd, J=1.32, 8.36 Hz, 1H), 5.54 (br. s, 2H).
Compound 148
N-(5-chloro-2-{[(1-oxidopyridin-2-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(562) ##STR00186##
(563) Following General Procedure D, the title compound was prepared from N-{5-chloro-2-[(pyridin-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(564) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.31 (d, J=6.16 Hz, 1H), 7.66 (d, J=7.92 Hz, 1H), 7.46-7.50 (m, 1H), 7.38-7.42 (m, 1H), 7.30-7.38 (m, 2H), 7.28 (s, 3H), 7.19 (d, J=8.51 Hz, 1H), 7.05 (d, J=7.63 Hz, 1H), 6.82 (d, J=8.22 Hz, 1H), 5.14 (d, J=12.62 Hz, 1H), 4.68 (d, J=12.32 Hz, 1H).
Compound 149
N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(565) ##STR00187##
(566) Following General Procedure L, the title compound was prepared from N-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(567) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 7.64-7.68 (m, 2H), 7.47-7.51 (m, 1H), 7.40-7.46 (m, 2H), 7.29-7.34 (m, 1H), 7.14 (d, J=8.22 Hz, 1H), 6.97 (t, J=7.78 Hz, 1H), 6.92 (dd, J=2.35, 8.22 Hz, 1H), 6.48-6.52 (m, 1H), 6.35 (dd, J=0.59, 7.63 Hz, 1H), 6.28 (t, J=1.91 Hz, 1H), 3.67 (s, 2H).
Compound 150
N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(568) ##STR00188##
(569) Following General Procedure C and K, the title compound was prepared from N-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(570) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.69 (d, J=7.92 Hz, 1H), 7.48 (d, J=8.51 Hz, 1H), 7.37-7.43 (m, 3H), 7.30 (td, J=0.88, 7.48 Hz, 1H), 7.20 (d, J=8.51 Hz, 1H), 7.01 (dd, J=2.05, 8.51 Hz, 1H), 6.95 (t, J=7.78 Hz, 1H), 6.70-6.74 (m, 1H), 6.64 (t, J=1.76 Hz, 1H), 6.45 (d, J=7.63 Hz, 1H), 4.40 (d, J=12.62 Hz, 1H), 4.00 (d, J=12.62 Hz, 1H).
Compound 151
N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(571) ##STR00189##
(572) Following General Procedure D and K, the title compound was prepared from N-{5-chloro-2-[(3-nitrobenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(573) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.80 (d, J=2.05 Hz, 1H), 7.69 (d, J=7.63 Hz, 1H), 7.52 (d, J=0.59 Hz, 1H), 7.40 (d, J=8.51 Hz, 1H), 7.35 (td, J=1.32, 7.70 Hz, 1H), 7.31 (d, J=8.51 Hz, 1H), 7.26-7.30 (m, J=7.92 Hz, 1H), 6.78 (dd, J=2.05, 8.51 Hz, 1H), 6.65 (t, J=7.78 Hz, 1H), 6.49 (dd, J=1.91, 7.78 Hz, 1H), 6.33 (t, J=1.76 Hz, 1H), 6.05 (d, J=7.34 Hz, 1H), 4.66 (s, 2H).
Compound 152
N-{5-chloro-2-[(3-hydroxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(574) ##STR00190##
(575) To a solution of N-{5-chloro-2-[(3-methoxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide (315 mg, 0.69 mmol) in CH.sub.2Cl.sub.2 (5 ml) at room temperature was added BBr.sub.3 (1M solution in CH.sub.2Cl.sub.2, 2.1 ml, 2.1 mmol) and the reaction was stirred for 2 h, diluted with EtOAc, washed with brine, dried over Na.sub.2SO.sub.4, concentrated in vacuo. The crude product was purified by column chromatography on silica gel (25% ethyl acetate in hexane) to give the title compound (196 mg, 64%).
(576) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 8.10 (br. s., 1H), 7.63-7.69 (m, 2H), 7.41-7.51 (m, 3H), 7.32 (td, J=0.88, 7.48 Hz, 1H), 7.12 (d, J=8.22 Hz, 1H), 7.05 (t, J=7.92 Hz, 1H), 6.91 (dd, J=2.35, 8.22 Hz, 1H), 6.66 (ddd, J=0.73, 2.57, 8.14 Hz, 1H), 6.51 (d, J=7.92 Hz, 1H), 6.45-6.48 (m, 1H), 5.07 (br. s., 1H), 3.71 (s, 2H).
Compound 153
N-{5-chloro-2-[(3-hydroxybenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(577) ##STR00191##
(578) Following General Procedure C, the title compound was prepared from N-{5-chloro-2-[(3-hydroxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(579) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 10.27-11.14 (m, 1H), 7.73 (d, J=2.05 Hz, 1H), 7.67 (d, J=7.92 Hz, 1H), 7.53 (s, 1H), 7.43-7.47 (m, 1H), 7.38-7.42 (m, 1H), 7.28-7.33 (m, 1H), 7.04 (t, J=7.92 Hz, 1H), 6.92 (dd, J=1.47, 8.22 Hz, 1H), 6.79 (d, J=8.22 Hz, 1H), 6.74 (dd, J=2.05, 8.22 Hz, 1H), 6.59 (s, 1H), 6.40 (d, J=7.34 Hz, 1H), 4.33 (d, J=12.32 Hz, 1H), 4.16 (d, J=12.62 Hz, 1H).
Compound 154
N-{5-chloro-2-[(3-hydroxybenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(580) ##STR00192##
(581) Following General Procedure D, the title compound was prepared from N-{5-chloro-2-[(3-hydroxybenzyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(582) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 7.76 (br. s., 1H), 7.65-7.72 (m, 1H), 7.56 (br. s., 1H), 7.44 (br. s., 3H), 7.33 (s, 1H), 7.02 (br. s., 2H), 6.77 (br. s., 1H), 6.58 (br. s., 1H), 6.39-6.47 (m, 1H), 4.28 (br. s., 2H).
Intermediate 37
benzofuran-2-sulfonic acid (5-chloro-2-mercapto-phenyl)-amide
(583) ##STR00193##
(584) Following General Procedure N, the title compound was prepared from N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide) Intermediate 8 and was used without further purification.
Compound 155
N-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(585) ##STR00194##
(586) To a solution of benzofuran-2-sulfonic acid (5-chloro-2-mercapto-phenyl)-amide (332 mg, 0.98 mmol) in CH.sub.2Cl.sub.2 (10 ml) at −78° C. was added 3,3-dimethyl-1-(trifluoromethyl)-1,2benzodioxole (CAS #: 887144-97-0, 354 mg, 1.07 mmol) and the reaction was stirred for 1 h, and was concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH.sub.2Cl.sub.2) to give the title compound (375 mg, 94%).
(587) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 7.88 (s, 1H), 7.82 (d, J=2.05 Hz, 1H), 7.67 (dd, J=0.59, 7.92 Hz, 1H), 7.49-7.54 (m, 3H), 7.44-7.49 (m, 1H), 7.33 (td, J=1.03, 7.56 Hz, 1H), 7.11 (dd, J=2.20, 8.36 Hz, 1H).
Compound 156
N-{5-chloro-2-[(trifluoromethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(588) ##STR00195##
(589) Following General Procedure D using 10 equivalents of mCPBA in refluxing CH.sub.2Cl.sub.2, the title compound was prepared from N-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(590) .sup.1H NMR (600 MHz, acetone-d6) δ 7.90 (d, J=2.05 Hz, 1H), 7.78 (d, J=8.80 Hz, 1H), 7.71 (d, J=7.92 Hz, 1H), 7.51 (d, J=8.22 Hz, 1H), 7.36-7.43 (m, 2H), 7.29 (t, J=7.48 Hz, 1H), 6.92 (d, J=6.46 Hz, 1H).
Compound 157
N-{5-chloro-2-[(trifluoromethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(591) ##STR00196##
(592) Following General Procedure D using 10 equivalents of mCPBA in refluxing CH.sub.2Cl.sub.2, the title compound was prepared from N-{5-chloro-2-[(trifluoromethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(593) .sup.1H NMR (600 MHz, acetone-d6) δ 10.00 (br. s., 1H), 7.89 (d, J=8.22 Hz, 1H), 7.78-7.81 (m, 1H), 7.63-7.66 (m, 1H), 7.50-7.59 (m, 4H), 7.39 (ddd, J=0.88, 7.26, 8.00 Hz, 1H).
Compound 158
N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide
(594) ##STR00197##
(595) Following General Procedure A, B, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 2,4-difluoro-benzenesulfonyl chloride.
(596) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 7.92 (td, J=6.16, 8.51 Hz, 1H), 7.47 (d, J=2.35 Hz, 1H), 7.19 (d, J=8.22 Hz, 1H), 7.01-7.06 (m, 1H), 6.95-7.01 (m, 1H), 6.88-6.94 (m, 2H), 6.57 (dd, J=1.47, 8.80 Hz, 1H), 6.40-6.45 (m, 2H), 3.72 (s, 2H).
Compound 159
N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide
(597) ##STR00198##
(598) Following General Procedure A, B, D, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 2,4-difluoro-benzenesulfonyl chloride.
(599) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.05 (td, J=6.16, 8.51 Hz, 1H), 7.48-7.54 (m, 2H), 7.14-7.25 (m, 2H), 7.09 (dd, J=2.05, 8.51 Hz, 1H), 6.96 (t, J=7.78 Hz, 1H), 6.66-6.71 (m, 1H), 6.54 (t, J=1.91 Hz, 1H), 6.34 (d, J=7.63 Hz, 1H), 4.44 (s, 2H).
Compound 160
N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide
(600) ##STR00199##
(601) Following General Procedure A, B, D, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 4-chloro-2-fluoro-benzenesulfonyl chloride.
(602) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.97 (t, J=8.51 Hz, 1H), 7.54 (d, J=8.51 Hz, 1H), 7.43-7.52 (m, 3H), 7.13-7.17 (m, 1H), 6.98 (t, J=7.78 Hz, 1H), 6.67-6.72 (m, 1H), 6.53 (s, 1H), 6.33 (d, J=7.63 Hz, 1H), 4.42 (s, 2H).
Compound 161
N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide
(603) ##STR00200##
(604) Following General Procedure A, B, C, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 4-chloro-2-fluoro-benzenesulfonyl chloride.
(605) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.85 (t, J=8.07 Hz, 1H), 7.49 (dd, J=1.76, 9.98 Hz, 1H), 7.40 (dd, J=1.91, 8.36 Hz, 1H), 7.33 (d, J=8.22 Hz, 1H), 7.23 (dd, J=1.91, 8.36 Hz, 1H), 7.16 (d, J=2.05 Hz, 1H), 7.04 (t, J=7.78 Hz, 1H), 6.72-6.75 (m, 1H), 6.63 (t, J=1.91 Hz, 1H), 6.50 (d, J=7.34 Hz, 1H), 4.30 (d, J=12.91 Hz, 1H), 4.04 (d, J=12.62 Hz, 1H).
Compound 162
N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}benzenesulfonamide
(606) ##STR00201##
(607) Following General Procedure A, B, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and benzenesulfonyl chloride.
(608) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.75-7.79 (m, 2H), 7.57-7.62 (m, 1H), 7.48-7.53 (m, 2H), 7.44 (d, J=2.05 Hz, 1H), 7.14 (d, J=8.22 Hz, 1H), 6.99 (dd, J=2.35, 8.22 Hz, 1H), 6.95 (t, J=7.78 Hz, 1H), 6.56-6.60 (m, 1H), 6.45 (t, J=1.91 Hz, 1H), 6.35 (d, J=7.34 Hz, 1H), 3.58 (s, 2H).
Compound 163
N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4-chlorobenzenesulfonamide
(609) ##STR00202##
(610) Following General Procedure A, B, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 4-chloro-benzenesulfonyl chloride.
(611) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 7.69-7.72 (m, 2H), 7.54 (d, J=2.35 Hz, 1H), 7.40-7.44 (m, 2H), 7.17 (d, J=8.22 Hz, 1H), 7.03 (t, J=7.78 Hz, 1H), 6.95 (dd, J=2.20, 8.36 Hz, 1H), 6.58 (dd, J=1.76, 7.92 Hz, 1H), 6.34-6.39 (m, 2H), 3.61 (s, 2H).
Compound 164
N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-3-chlorobenzenesulfonamide
(612) ##STR00203##
(613) Following General Procedure A, B, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 3-chloro-benzenesulfonyl chloride.
(614) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 7.80 (t, J=1.91 Hz, 1H), 7.63-7.66 (m, 1H), 7.56 (d, J=2.35 Hz, 1H), 7.52 (ddd, J=0.88, 1.98, 8.00 Hz, 1H), 7.39 (t, J=7.92 Hz, 1H), 7.16 (d, J=8.51 Hz, 1H), 7.02 (t, J=7.78 Hz, 1H), 6.96 (dd, J=2.05, 8.22 Hz, 1H), 6.55-6.59 (m, 1H), 6.35 (d, J=7.63 Hz, 1H), 6.32 (t, J=1.91 Hz, 1H), 3.56 (s, 2H).
Compound 165
N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}benzenesulfonamide
(615) ##STR00204##
(616) Following General Procedure A, B, D, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and benzenesulfonyl chloride.
(617) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.90-7.93 (m, 2H), 7.63-7.68 (m, 1H), 7.56-7.62 (m, 3H), 7.42 (d, J=8.51 Hz, 1H), 7.11 (dd, J=2.05, 8.51 Hz, 1H), 6.93 (t, J=7.78 Hz, 1H), 6.66 (ddd, J=0.73, 2.27, 8.14 Hz, 1H), 6.39 (t, J=1.91 Hz, 1H), 6.16 (d, J=7.34 Hz, 1H), 4.18 (s, 2H).
Compound 166
N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}benzenesulfonamide
(618) ##STR00205##
(619) Following General Procedure A, B, C, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and benzenesulfonyl chloride.
(620) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.82-7.86 (m, 2H), 7.64-7.69 (m, 1H), 7.56-7.62 (m, 2H), 7.27-7.31 (m, 1H), 7.22-7.27 (m, 1H), 7.08 (d, J=2.05 Hz, 1H), 6.99 (t, J=7.78 Hz, 1H), 6.67 (ddd, J=0.88, 2.35, 8.22 Hz, 1H), 6.50 (t, J=1.91 Hz, 1H), 6.36 (d, J=7.63 Hz, 1H), 4.12 (d, J=12.62 Hz, 1H), 3.95 (d, J=12.91 Hz, 1H).
Compound 167
N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-4-chlorobenzenesulfonamide
(621) ##STR00206##
(622) Following General Procedure A, B, D, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 4-chloro-benzenesulfonyl chloride.
(623) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.85-7.88 (m, 2H), 7.58-7.62 (m, 2H), 7.55 (d, J=2.05 Hz, 1H), 7.49 (d, J=8.51 Hz, 1H), 7.15 (dd, J=1.91, 8.66 Hz, 1H), 6.95 (t, J=7.78 Hz, 1H), 6.68 (ddd, J=0.88, 2.20, 8.07 Hz, 1H), 6.45 (t, J=1.91 Hz, 1H), 6.21 (d, J=7.63 Hz, 1H), 4.28 (s, 2H).
Compound 168
N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-4-chlorobenzenesulfonamide
(624) ##STR00207##
(625) Following General Procedure A, B, C, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 4-chloro-benzenesulfonyl chloride.
(626) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.79 (d, J=8.51 Hz, 2H), 7.59 (d, J=8.80 Hz, 2H), 7.32 (d, J=8.51 Hz, 1H), 7.24-7.29 (m, 1H), 7.06 (d, J=1.76 Hz, 1H), 6.99 (t, J=7.78 Hz, 1H), 6.65-6.69 (m, 1H), 6.52 (s, 1H), 6.38 (d, J=7.34 Hz, 1H), 4.16 (d, J=12.91 Hz, 1H), 3.97 (d, J=12.91 Hz, 1H).
Compound 169
N-{2-[(3-aminobenzyl)sulfonyl]-5-chlorophenyl}-3-chlorobenzenesulfonamide
(627) ##STR00208##
(628) Following General Procedure A, B, D, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 3-chloro-benzenesulfonyl chloride.
(629) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 8.00 (t, J=1.91 Hz, 1H), 7.89-7.93 (m, 1H), 7.42-7.51 (m, 3H), 7.38 (d, J=8.51 Hz, 1H), 6.89 (t, J=7.78 Hz, 1H), 6.66 (dd, J=1.76, 8.51 Hz, 1H), 6.59 (d, J=8.22 Hz, 1H), 6.55 (s, 1H), 6.37 (d, J=7.63 Hz, 1H), 4.69 (s, 2H).
Compound 170
N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-3-chlorobenzenesulfonamide
(630) ##STR00209##
(631) Following General Procedure A, B, C, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 3-chloro-benzenesulfonyl chloride.
(632) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.85 (s, 1H), 7.77 (d, J=7.63 Hz, 1H), 7.51-7.55 (m, 1H), 7.47 (t, J=7.92 Hz, 1H), 7.22 (d, J=8.22 Hz, 1H), 7.19 (d, J=1.76 Hz, 1H), 6.93-7.00 (m, 2H), 6.65 (dd, J=2.20, 8.07 Hz, 1H), 6.58 (s, 1H), 6.43 (d, J=7.63 Hz, 1H), 4.35 (d, J=12.91 Hz, 1H), 3.82 (d, J=12.91 Hz, 1H).
Compound 171
3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N-isopropylpropanamide
(633) ##STR00210##
(634) Following General Procedure H, B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, N-isopropyl-acrylamide, and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.
(635) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.19 (d, J=1.47 Hz, 1H), 7.98 (d, J=8.20 Hz, 1H), 7.60 (d, J=8.20 Hz, 1H), 7.23 (d, J=2.05 Hz, 1H), 7.06 (d, J=8.20 Hz, 1H), 6.75 (dd, J=2.20, 8.35 Hz, 1H), 3.85-4.03 (m, 1H), 3.00 (t, J=7.33 Hz, 2H), 2.39 (t, J=7.47 Hz, 2H), 1.12 (d, 6H).
Compound 172
3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylpropanamide
(636) ##STR00211##
(637) Following General Procedure H, B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, N,N-dimethyl-acrylamide, and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.
(638) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.11 (s, 1H), 7.90 (d, J=7.91 Hz, 1H), 7.71-7.79 (m, 1H), 7.49 (d, J=2.34 Hz, 1H), 7.39 (d, J=8.50 Hz, 1H), 7.21 (none, J=2.34, 8.50 Hz, 1H), 2.96 (d, J=7.62 Hz, 6H), 2.90 (t, J=7.03 Hz, 2H), 2.51 (t, J=7.03 Hz, 2H).
Compound 173
3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N-isopropylpropanamide
(639) ##STR00212##
(640) Following General Procedure C, the title compound was prepared from 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]thio}-N,N-dimethylpropanamide.
(641) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.17 (d, J=1.76 Hz, 1H), 8.01 (d, J=8.20 Hz, 1H), 7.67 (d, J=8.50 Hz, 1H), 7.39 (d, J=8.20 Hz, 1H), 7.24 (d, J=1.76 Hz, 1H), 6.88 (dd, J=1.90, 8.35 Hz, 1H), 3.91 (quin, J=6.59 Hz, 1H), 3.37-3.52 (m, 1H), 3.09-3.25 (m, 1H), 2.58 (ddd, J=5.71, 9.89, 15.16 Hz, 1H), 2.26 (ddd, J=5.86, 9.74, 15.16 Hz, 1H), 1.10 (dd, 4H).
Compound 174
3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}propanamide
(642) ##STR00213##
(643) Following General Procedure H, B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, acrylamide, and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.
(644) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.16 (d, J=1.76 Hz, 1H), 8.00 (dd, J=2.05, 8.22 Hz, 1H), 7.75 (d, J=8.51 Hz, 1H), 7.57 (d, J=8.51 Hz, 1H), 7.32 (s, 1H), 7.21 (d, J=7.92 Hz, 1H), 3.26 (br. s., 1H), 3.18 (br. s., 1H), 2.99-3.07 (m, 3H), 2.95 (s, 3H), 2.88 (dt, J=7.37, 16.95 Hz, 1H), 2.62-2.77 (m, 1H).
Compound 175
N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide
(645) ##STR00214##
(646) Following General Procedure B, C, the title compound was prepared from 5-chloro-2-(methylsulfinyl)aniline and benzenesulfonyl chloride.
(647) .sup.1H NMR (300 MHz, acetone-d6) δ 10.64 (br. s., 1H), 7.93 (d, J=7.03 Hz, 2H), 7.59-7.79 (m, 3H), 7.55 (d, J=1.76 Hz, 1H), 7.45 (d, J=8.50 Hz, 1H), 7.26 (dd, J=1.90, 8.35 Hz, 1H), 2.74 (s, 3H).
Compound 176
N-[5-chloro-2-(methylthio)phenyl]thiophene-2-sulfonamide
(648) ##STR00215##
(649) Following General Procedure B, the title compound was prepared from 5-chloro-2-(methylsulfinyl)aniline and thiophene-2-sulfonyl chloride.
(650) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.75 (dd, J=1.17, 4.98 Hz, 1H), 7.50 (dd, J=1.32, 3.66 Hz, 1H), 7.40 (d, J=2.05 Hz, 1H), 7.26-7.34 (m, 1H), 7.15-7.24 (m, 1H), 7.08 (dd, J=3.81, 4.98 Hz, 1H), 2.23 (s, 3H).
Compound 177
N-[5-chloro-2-(methylsulfinyl)phenyl]thiophene-2-sulfonamide
(651) ##STR00216##
(652) Following General Procedure C, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]thiophene-2-sulfonamide.
(653) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.81 (d, J=4.40 Hz, 1H), 7.75 (d, J=8.51 Hz, 1H), 7.51-7.57 (m, 1H), 7.43 (d, J=7.92 Hz, 1H), 7.15 (dd, J=4.84, 8.66 Hz, 2H), 2.79 (s, 3H).
Compound 178
N-{2-[(3-nitrobenzyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(654) ##STR00217##
(655) Following General Procedure D, the title compound (136 mg, 82%) was prepared from benzofuran-2-sulfonic acid [2-(3-nitro-benzylsulfanyl)-phenyl]-amide.
(656) 1H NMR (600 MHz, acetone-d6) δ 9.57 (br. s., 1H), 8.17 (dt, J=2.53, 6.38 Hz, 1H), 7.93 (d, J=0.88 Hz, 1H), 7.74-7.83 (m, 3H), 7.69 (td, J=1.47, 7.92 Hz, 1H), 7.63 (dd, J=1.47, 7.92 Hz, 1H), 7.52-7.59 (m, 3H), 7.47 (ddd, J=1.17, 7.41, 8.44 Hz, 1H), 7.30-7.38 (m, 1H), 7.23 (t, J=7.63 Hz, 1H), 4.85 (s, 2H).
Compound 179
N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(657) ##STR00218##
(658) Following General Procedure C, the title compound (79 mg, 73%) was prepared from N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(659) 1H NMR (600 MHz, CD.sub.3OD) δ 7.61 (d, J=7.92 Hz, 1H), 7.46 (d, J=2.05 Hz, 1H), 7.44 (d, J=8.22 Hz, 1H), 7.28-7.32 (m, 1H), 7.21-7.26 (m, 1H), 7.19 (dd, J=0.73, 8.36 Hz, 1H), 7.15 (d, J=0.88 Hz, 1H), 6.92 (dd, J=1.91, 8.36 Hz, 1H), 3.52-3.62 (m, 1H), 2.80-2.91 (m, 2H), 2.56-2.65 (m, 1H), 2.11 (s, 6H).
Compound 180
4-chloro-N-{5-chloro-2-[(3-hydroxycyclopentyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(660) ##STR00219##
(661) Following General Procedure D, followed by treatment of the crude product with NaBH.sub.4 in MeOH, the title compound was prepared from 4-Chloro-N-[5-chloro-2-(3-oxo-cyclopentylsulfanyl)-phenyl]-3-trifluoromethyl-benzenesulfonamide (Intermediate 35).
(662) 1H NMR (600 MHz, CD.sub.3OD) δ 8.34 (s, 1H), 8.18 (dd, J=1.91, 8.36 Hz, 1H), 7.70-7.79 (m, 2H), 7.65 (s, 1H), 7.00 (br. s., 1H), 4.12-4.18 (m, 2H), 1.98-2.10 (m, 2H), 1.72-1.84 (m, 2H), 1.63-1.71 (m, 2H).
Compound 181
N-[5-chloro-2-(methylthio)phenyl]-4-methyl-3-nitrobenzenesulfonamide
(663) ##STR00220##
(664) Following General Procedure B, the title compound (197 mg, 61%) was prepared from 5-Chloro-2-methylsulfanyl-phenylamine (150 mg, 0.87 mmol) and 4-Methyl-3-nitro-benzenesulfonyl chloride (235 mg, 0.87 mmol).
(665) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.29 (d, J=1.76 Hz, 1H), 7.85 (dd, J=1.91, 8.07 Hz, 1H), 7.57 (d, J=8.22 Hz, 1H), 7.39 (d, J=2.05 Hz, 1H), 7.17-7.25 (m, 2H), 2.60 (s, 3H), 2.20 (s, 3H).
Compound 182
chloro-2-(methylsulfinyl)phenyl]-4-methyl-3-nitrobenzenesulfonamide
(666) ##STR00221##
(667) Following General Procedure C, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-4-methyl-3-nitrobenzenesulfonamide.
(668) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 10.88 (br. s., 1H), 8.53 (d, J=2.05 Hz, 1H), 8.05 (dd, J=1.91, 8.07 Hz, 1H), 7.64 (d, J=1.76 Hz, 1H), 7.54 (d, J=8.22 Hz, 1H), 7.04-7.16 (m, 2H), 2.87 (s, 3H), 2.67 (s, 3H).
Compound 183
N-[5-chloro-2-(methylsulfonyl)phenyl]-4-methyl-3-nitrobenzenesulfonamide
(669) ##STR00222##
(670) Following General Procedure D, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-4-methyl-3-nitrobenzenesulfonamide
(671) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 9.36 (br. s., 1H), 8.52 (d, J=2.05 Hz, 1H), 8.05 (dd, J=2.05, 8.22 Hz, 1H), 7.79 (d, J=8.51 Hz, 1H), 7.67 (d, J=2.05 Hz, 1H), 7.58 (d, J=7.92 Hz, 1H), 7.23 (dd, J=1.76, 8.51 Hz, 1H), 3.04 (s, 3H), 2.68 (s, 3H).
Compound 184
4-chloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide
(672) ##STR00223##
(673) Following General Procedure B, the title compound (150 mg, 68%) was prepared from 5-Chloro-2-methylsulfanyl-phenylamine (110 mg, 0.64 mmol) and 4-Chloro-benzenesulfonyl chloride (134 mg, 0.64 mmol).
(674) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.72 (d, J=9.10 Hz, 2H), 7.51 (d, J=8.80 Hz, 2H), 7.37 (d, J=2.05 Hz, 1H), 7.25 (d, J=8.51 Hz, 1H), 7.19 (dd, J=2.05, 8.22 Hz, 1H), 2.20 (s, 3H).
Compound 185
4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]benzenesulfonamide
(675) ##STR00224##
(676) Following General Procedure C, the title compound was prepared from 4-chloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide.
(677) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 10.67 (br. s., 1H), 7.89 (d, J=8.80 Hz, 2H), 7.66 (d, J=1.76 Hz, 1H), 7.50 (d, J=8.80 Hz, 2H), 6.91-7.16 (m, 2H), 2.80 (none, 3H).
Compound 186
4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]benzenesulfonamide
(678) ##STR00225##
(679) Following General Procedure D, the title compound was prepared from 4-chloro-N-[5-chloro-2-(methylthio)phenyl]benzenesulfonamide.
(680) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.89 (d, J=8.80 Hz, 2H), 7.78 (d, J=8.51 Hz, 1H), 7.68 (d, J=1.76 Hz, 1H), 7.53 (d, J=8.80 Hz, 2H), 7.20 (dd, J=2.05, 8.51 Hz, 1H), 2.96 (s, 3H).
Compound 187
4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-methylbenzenesulfonamide
(681) ##STR00226##
(682) Following General Procedure B, the title compound (205 mg, 59%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (165 mg, 0.95 mmol) and 4-chloro-3-methyl-benzenesulfonyl chloride (215 mg, 0.95 mmol).
(683) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.71 (d, 1H), 7.65 (s, 1H), 7.62 (d, J=2.05 Hz, 1H), 7.57 (dd, J=2.05, 8.22 Hz, 1H), 7.41 (d, J=8.22 Hz, 1H), 7.32 (d, J=8.51 Hz, 1H), 7.04 (dd, J=2.20, 8.36 Hz, 1H), 2.39 (s, 3H), 2.19 (s, 3H).
Compound 188
4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-3-methylbenzenesulfonamide
(684) ##STR00227##
(685) Following General Procedure C, the title compound was prepared from 4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-methylbenzenesulfonamide.
(686) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 10.62 (s, 1H), 7.82 (d, J=2.05 Hz, 1H), 7.71 (dd, J=1.91, 8.36 Hz, 1H), 7.63 (d, J=2.05 Hz, 1H), 7.48 (d, J=8.51 Hz, 1H), 7.02-7.15 (m, 2H), 2.81 (s, 3H), 2.43 (s, 3H).
Compound 189
4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-3-methylbenzenesulfonamide
(687) ##STR00228##
(688) Following General Procedure D, the title compound was prepared from 4-chloro-N-[5-chloro-2-(methylthio)phenyl]-3-methylbenzenesulfonamide.
(689) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 9.24 (br. s., 1H), 7.83 (d, J=2.05 Hz, 1H), 7.78 (d, J=8.51 Hz, 1H), 7.71 (dd, J=2.05, 8.51 Hz, 1H), 7.67 (d, J=1.76 Hz, 1H), 7.50 (d, J=8.22 Hz, 1H), 7.19 (dd, J=1.76, 8.51 Hz, 1H), 2.97 (s, 3H), 2.44 (s, 3H).
Compound 190
N-[5-chloro-2-(methylthio)phenyl]-4-nitro-3-(trifluoromethyl)benzenesulfonamide
(690) ##STR00229##
(691) Following General Procedure B, the title compound (176 mg, 43%)was prepared from 5-chloro-2-methylsulfanyl-phenylamine (167 mg, 0.95 mmol) and 4-nitro-3-trifluoromethyl-benzenesulfonyl chloride (278 mg, 0.95 mmol).
(692) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.04-8.22 (m, 3H), 7.42 (d, J=2.05 Hz, 1H), 7.16-7.32 (m, 2H), 2.20 (s, 3H).
Compound 191
N-[5-chloro-2-(methylsulfonyl)phenyl]-4-nitro-3-(trifluoromethyl)benzenesulfonamide
(693) ##STR00230##
(694) Following General Procedure D, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide.
(695) .sup.1H NMR (600 MHz, acetone-d6) δ 9.64 (br. s., 1H), 8.49-8.65 (m, 2H), 8.33 (d, J=8.51 Hz, 1H), 7.89 (d, J=8.51 Hz, 1H), 7.70 (d, J=1.76 Hz, 1H), 7.39 (d, J=8.22 Hz, 1H), 3.24 (s, 3H).
Compound 192
N-[5-chloro-2-(methylsulfinyl)phenyl]-4-nitro-3-(trifluoromethyl)benzenesulfonamide
(696) ##STR00231##
(697) Following General Procedure D, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-3-nitro-4-(trifluoromethyl)benzenesulfonamide.
(698) .sup.1H NMR (600 MHz, acetone-d6) δ 8.25-8.35 (m, 2H), 8.11 (d, J=8.22 Hz, 1H), 7.39-7.48 (m, 2H), 6.75 (dd, J=2.05, 8.22 Hz, 1H), 2.70 (s, 3H).
Compound 193
N-[5-chloro-2-(methylthio)phenyl]-2,4-difluorobenzenesulfonamide
(699) ##STR00232##
(700) Following General Procedure B, the title compound (358 mg, 94%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (189 mg, 1.09 mmol) and 2,4-Difluoro-benzenesulfonyl chloride (231 mg, 1.09 mmol).
(701) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.82 (td, J=6.15, 8.50 Hz, 1H), 7.34 (d, J=2.05 Hz, 1H), 7.16-7.30 (m, 3H), 7.00-7.16 (m, 1H), 2.27 (s, 3H).
Compound 194
N-[5-chloro-2-(methylsulfonyl)phenyl]-2,4-difluorobenzenesulfonamide
(702) ##STR00233##
(703) Following General Procedure D, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-2,4-difluorobenzenesulfonamide.
(704) .sup.1H NMR (300 MHz, acetone-d6) δ 9.81 (br. s., 1H), 8.15-8.32 (m, 1H), 7.91 (d, J=8.50 Hz, 1H), 7.63 (d, J=1.76 Hz, 1H), 7.24-7.46 (m, 3H), 3.27 (s, 3H).
Compound 195
N-[5-chloro-2-(methylsulfinyl)phenyl]-2,4-difluorobenzenesulfonamide
(705) ##STR00234##
(706) Following General Procedure D, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-2,4-difluorobenzenesulfonamide.
(707) .sup.1H NMR (600 MHz, acetone-d6) δ 10.97 (br. s., 1H), 8.10 (td, J=6.16, 8.51 Hz, 1H), 7.51 (d, J=8.22 Hz, 1H), 7.46 (d, J=2.05 Hz, 1H), 7.30-7.38 (m, 1H), 7.24-7.31 (m, 2H), 2.90 (s, 3H).
Compound 196
N-[5-chloro-2-(methylthio)phenyl]-5-methylfuran-2-sulfonamide
(708) ##STR00235##
(709) Following General Procedure B, the title compound (212 mg, 48%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (189 mg, 1.09 mmol) and 5-methyl-furan-2-sulfonyl chloride (250 mg, 1.38 mmol).
(710) .sup.1H NMR (300 MHz, acetone-d6) δ 8.53 (br. s., 1H), 7.37-7.49 (m, 2H), 7.25 (dd, J=2.34, 8.50 Hz, 1H), 6.96 (d, J=3.22 Hz, 1H), 6.24 (d, J=2.64 Hz, 1H), 2.38 (s, 3H), 2.34 (s, 3H).
Compound 197
N-[5-chloro-2-(methylsulfinyl)phenyl]-5-methylfuran-2-sulfonamide
(711) ##STR00236##
(712) Following General Procedure C, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-5-methylfuran-2-sulfonamide.
(713) .sup.1H NMR (600 MHz, acetone-d6) δ 10.74 (br. s., 1H), 7.55 (d, J=2.05 Hz, 1H), 7.51 (d, J=8.22 Hz, 1H), 7.30 (dd, J=1.91, 8.36 Hz, 1H), 7.18 (d, J=3.23 Hz, 1H), 6.24-6.35 (m, 1H), 2.90 (s, 3H), 2.34 (s, 3H).
Compound 198
N-[5-chloro-2-(methylsulfonyl)phenyl]-5-methylfuran-2-sulfonamide
(714) ##STR00237##
(715) Following General Procedure D, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]-5-methylfuran-2-sulfonamide.
(716) .sup.1H NMR (600 MHz, acetone-d6) δ 9.54 (br. s., 1H), 7.90 (d, J=8.51 Hz, 1H), 7.73 (d, J=2.05 Hz, 1H), 7.39 (dd, J=1.76, 8.51 Hz, 1H), 7.31 (d, J=3.52 Hz, 1H), 6.32 (d, J=3.23 Hz, 1H), 3.24 (s, 3H), 2.33 (s, 3H).
Compound 199
N-[5-chloro-2-(methylthio)phenyl]furan-2-sulfonamide
(717) ##STR00238##
(718) Following General Procedure B, the title compound (215 mg, 47%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (260 mg, 1.50 mmol) and furan-2-sulfonyl chloride (250 mg, 1.50 mmol).
(719) .sup.1H NMR (300 MHz, acetone-d6) δ 8.67 (br. s., 1H), 7.84 (s, 1H), 7.32-7.46 (m, 2H), 7.26 (dd, J=2.20, 8.35 Hz, 1H), 7.07 (d, J=3.52 Hz, 1H), 6.63 (dd, J=1.76, 3.52 Hz, 1H), 2.36 (s, 3H).
Compound 200
N-[5-chloro-2-(methylsulfinyl)phenyl]furan-2-sulfonamide
(720) ##STR00239##
(721) Following General Procedure C, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]furan-2-sulfonamide.
(722) .sup.1H NMR (600 MHz, acetone-d6) δ 10.85 (br. s., 1H), 7.89 (s, 1H), 7.49-7.59 (m, 2H), 7.28-7.36 (m, 2H), 6.68 (dd, J=1.76, 3.52 Hz, 1H), 2.88 (s, 3H).
Compound 201
N-[5-chloro-2-(methylsulfonyl)phenyl]furan-2-sulfonamide
(723) ##STR00240##
(724) Following General Procedure D, the title compound was prepared from N-[5-chloro-2-(methylthio)phenyl]furan-2-sulfonamide.
(725) .sup.1H NMR (600 MHz, acetone-d6) δ 9.62 (br. s., 1H), 7.90 (d, J=8.51 Hz, 2H), 7.74 (d, J=2.05 Hz, 1H), 7.27-7.48 (m, 2H), 6.70 (dd, J=1.76, 3.52 Hz, 1H), 3.22 (s, 3H).
Compound 202
4-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide
(726) ##STR00241##
(727) Following General Procedure B, the title compound (380 mg, 66%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (273 mg, 1.57 mmol) and 4-chloro-2-fluoro-benzenesulfonyl chloride (360 mg, 1.57 mmol).
(728) .sup.1H NMR (300 MHz, acetone-d6) δ 8.77 (br. s., 1H), 7.84 (t, J=8.06 Hz, 1H), 7.53 (dd, J=1.90, 9.82 Hz, 1H), 7.35-7.48 (m, 3H), 7.25 (dd, J=2.20, 8.35 Hz, 1H), 2.34 (s, 3H).
Compound 203
4-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2-fluorobenzenesulfonamide
(729) ##STR00242##
(730) Following General Procedure C, the title compound was prepared from 4-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide.
(731) .sup.1H NMR (300 MHz, acetone-d6) δ 10.95 (br. s., 1H), 8.03 (t, J=8.20 Hz, 1H), 7.39-7.61 (m, 4H), 7.28 (dd, J=1.90, 8.35 Hz, 1H), 2.93 (s, 3H).
Compound 204
4-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2-fluorobenzenesulfonamide
(732) ##STR00243##
(733) Following General Procedure D, the title compound was prepared from 4-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide.
(734) .sup.1H NMR (300 MHz, acetone-d6) δ 9.84 (br. s., 1H), 8.12 (t, J=8.20 Hz, 1H), 7.90 (d, J=8.50 Hz, 1H), 7.46-7.69 (m, 3H), 7.33 (dd, J=1.47, 8.50 Hz, 1H), 3.27 (s, 3H).
Compound 205
3-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide
(735) ##STR00244##
(736) Following General Procedure B, the title compound (386 mg, 62%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (297 mg, 1.71 mmol) and 3-chloro-2-fluoro-benzenesulfonyl chloride (392 mg, 1.71 mmol).
(737) .sup.1H NMR (300 MHz, acetone-d6) δ 8.87 (br. s., 1H), 7.70-7.93 (m, 2H), 7.32-7.47 (m, 3H), 7.20-7.31 (m, 1H), 2.32 (s, 3H).
Compound 206
3-chloro-N-[5-chloro-2-(methylsulfonyl)phenyl]-2-fluorobenzenesulfonamide
(738) ##STR00245##
(739) Following General Procedure D, the title compound was prepared from 3-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide.
(740) .sup.1H NMR (300 MHz, acetone-d6) δ 7.89-8.04 (m, 1H), 7.69 (d, J=8.50 Hz, 1H), 7.55-7.65 (m, 2H), 7.23-7.37 (m, 1H), 6.72 (dd, J=1.90, 8.64 Hz, 1H), 3.22 (s, 3H).
Compound 207
3-chloro-N-[5-chloro-2-(methylsulfinyl)phenyl]-2-fluorobenzenesulfonamide
(741) ##STR00246##
(742) Following General Procedure C, the title compound was prepared from 3-chloro-N-[5-chloro-2-(methylthio)phenyl]-2-fluorobenzenesulfonamide.
(743) .sup.1H NMR (300 MHz, acetone-d6) δ 7.94-8.04 (m, 1H), 7.83-7.93 (m, 1H), 7.42-7.59 (m, 3H), 7.29 (dd, J=1.90, 8.35 Hz, 1H), 2.93 (s, 3H).
Compound 208
4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(744) ##STR00247##
(745) Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, 2-chloromethyl-1H-imidazole and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.
(746) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.06 (d, J=1.76 Hz, 1H), 7.89 (dd, J=2.05, 8.50 Hz, 1H), 7.63-7.78 (m, 2H), 7.45 (d, J=2.05 Hz, 1H), 7.30 (d, J=8.50 Hz, 1H), 7.14 (dd, J=2.34, 8.50 Hz, 1H), 6.73 (s, 1H), 3.83 (s, 2H).
Compound 209
4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(747) ##STR00248##
(748) Following General Procedure C, the title compound was prepared from 4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.
(749) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.18 (d, 1H), 8.03 (dd, J=1.91, 8.36 Hz, 1H), 7.72 (d, J=8.22 Hz, 1H), 7.41 (s, 2H), 7.20 (d, J=1.76 Hz, 1H), 7.06 (d, J=8.51 Hz, 1H), 6.84 (dd, J=1.91, 8.36 Hz, 1H), 4.76 (d, J=8.22 Hz, 2H).
Compound 210
4-chloro-N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(750) ##STR00249##
(751) .sup.1H NMR (600 MHz, acetone-d6) δ 8.33 (d, J=1.76 Hz, 1H), 8.18 (dd, J=1.76, 8.22 Hz, 1H), 7.70 (d, J=8.22 Hz, 1H), 7.66 (d, J=8.51 Hz, 1H), 7.58 (d, J=2.05 Hz, 1H), 7.10 (s, 2H), 6.72 (dd, J=1.91, 8.36 Hz, 1H), 4.86 (s, 2H).
Compound 211
4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(752) ##STR00250##
(753) Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, 4-chloromethyl-1H-imidazole hydrogen chloride and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.
(754) .sup.1H NMR (600 MHz, acetone-d6) δ 8.07 (d, J=2.05 Hz, 1H), 7.89-7.97 (m, 2H), 7.77 (d, J=8.51 Hz, 1H), 7.61 (d, J=2.35 Hz, 1H), 7.56 (d, J=8.22 Hz, 1H), 7.16 (dd, J=2.35, 8.22 Hz, 1H), 7.02 (s, 1H), 3.87 (s, 2H).
Compound 212
4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-3-(trifluoromethyl)benzenesulfonamide
(755) ##STR00251##
(756) Following General Procedure C, the title compound was prepared from 4-chloro-N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-3-(trifluoromethyl)benzenesulfonamide.
(757) .sup.1H NMR (600 MHz, acetone-d6) δ 8.26 (br. s., 1H), 8.17 (s, 1H), 8.08 (dd, J=1.76, 8.51 Hz, 1H), 7.82 (d, J=8.51 Hz, 1H), 7.47 (br. s., 1H), 7.38 (d, J=8.51 Hz, 1H), 7.30 (s, 1H), 7.09 (d, J=7.92 Hz, 1H), 4.48 (dd, J=2.35, 13.79 Hz, 1H), 4.20 (d, J=14.09 Hz, 1H).
Compound 213
N-{5-chloro-2-[(1H-imidazol-2-yl methyl)thio]phenyl}-1-benzofuran-2-sulfonamide
(758) ##STR00252##
(759) Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, 2-chloromethyl-1H-imidazole and 1-benzofuran-2-sulfonyl chloride.
(760) .sup.1H NMR (600 MHz, acetone-d6) δ 7.74 (d, J=7.92 Hz, 1H), 7.64 (d, J=2.35 Hz, 1H), 7.61 (d, J=8.51 Hz, 1H), 7.53 (d, J=8.51 Hz, 1H), 7.46 (td, J=1.17, 7.78 Hz, 1H), 7.41 (s, 1H), 7.33 (t, J=7.48 Hz, 1H), 7.17 (s, 2H), 7.09 (dd, J=2.35, 8.22 Hz, 1H), 4.10 (s, 2H).
Compound 214
N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(761) ##STR00253##
(762) Following General Procedure C, the title compound was prepared from N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(763) .sup.1H NMR (300 MHz, DMSO-d6) δ 7.68 (d, J=7.62 Hz, 1H), 7.51-7.61 (m, 3H), 7.41 (d, J=2.05 Hz, 1H), 7.32-7.40 (m, 1H), 7.21-7.32 (m, 1H), 7.17 (s, 1H), 6.92 (d, J=8.50 Hz, 1H), 6.74 (dd, J=1.90, 8.06 Hz, 1H), 4.89 (d, J=14.07 Hz, 1H), 4.56 (d, J=13.77 Hz, 1H).
Compound 215
N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(764) ##STR00254##
(765) Following General Procedure D, the title compound was prepared from N-{5-chloro-2-[(1H-imidazol-2-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(766) .sup.1H NMR (300 MHz, acetone-d6) δ 7.69-7.79 (m, 3H), 7.66 (s, 2H), 7.46-7.54 (m, 1H), 7.41 (s, 2H), 7.24-7.34 (m, 1H), 6.88 (dd, J=1.90, 8.64 Hz, 1H), 5.62 (s, 2H).
Compound 216
N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(767) ##STR00255##
(768) Following General Procedure C, the title compound was prepared from N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(769) .sup.1H NMR (300 MHz, acetone-d6) δ 8.34 (s, 1H), 7.75 (d, J=7.91 Hz, 1H), 7.60 (d, J=2.05 Hz, 1H), 7.47-7.56 (m, 2H), 7.43 (t, J=7.33 Hz, 1H), 7.24-7.38 (m, 3H), 7.03 (d, J=10.55 Hz, 1H), 4.58 (d, J=14.36 Hz, 1H), 4.24 (d, J=13.77 Hz, 1H)
Compound 217
N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(770) ##STR00256##
(771) Following General Procedure D, the title compound was prepared from N-{5-chloro-2-[(1H-imidazol-4-ylmethyl)thio]phenyl}-1-benzofuran-2-sulfonamide.
(772) .sup.1H NMR (300 MHz, acetone-d6) δ 8.20 (br. s., 1H), 7.66-7.81 (m, 3H), 7.35-7.53 (m, 4H), 7.23-7.35 (m, 1H), 6.95 (dd, J=2.05, 8.50 Hz, 1H), 4.87 (s, 2H).
Compound 218
N-[2-({2-[(aminocarbonyl)amino]ethyl}thio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide
(773) ##STR00257##
(774) Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, (2-chloro-ethyl)-urea and 1-benzofuran-2-sulfonyl chloride.
(775) 1H NMR (300 MHz, acetone-d6) δ 7.77 (d, J=7.91 Hz, 1H), 7.45-7.66 (m, 5H), 7.31-7.42 (m, 1H), 7.22 (dd, J=2.05, 8.50 Hz, 1H), 6.02 (br. s., 1H), 5.40 (br. s., 2H), 3.14 (q, J=6.15 Hz, 2H), 2.84 (t, J=6.45 Hz, 2H).
Compound 219
N-[2-({2-[(aminocarbonyl)amino]ethyl}sulfinyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide
(776) ##STR00258##
(777) Following General Procedure C, the title compound was prepared from N-[2-({2-[(aminocarbonyl)amino]ethyl}thio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide.
(778) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.68 (d, J=7.92 Hz, 1H), 7.54 (dd, J=5.28, 8.22 Hz, 2H), 7.42 (t, J=7.92 Hz, 1H), 7.37 (s, 1H), 7.27-7.34 (m, 2H), 7.10 (d, J=6.75 Hz, 1H), 3.58-3.67 (m, 1H), 3.44-3.53 (m, 1H), 3.36-3.43 (m, 1H), 2.98-3.09 (m, 1H).
Compound 220
N-[2-({2-[(aminocarbonyl)amino]ethyl}sulfonyl)-5-chlorophenyl]-1-benzofuran-2-sulfonamide
(779) ##STR00259##
(780) Following General Procedure D, the title compound was prepared from N-[2-({2-[(aminocarbonyl)amino]ethyl}thio)-5-chlorophenyl]-1-benzofuran-2-sulfonamide.
(781) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.85 (d, J=8.51 Hz, 1H), 7.80 (d, J=2.05 Hz, 1H), 7.77 (d, J=7.92 Hz, 1H), 7.72 (s, 1H), 7.61 (d, J=8.51 Hz, 1H), 7.52 (t, J=7.34 Hz, 1H), 7.31-7.40 (m, 2H), 3.36-3.47 (m, 4H).
Compound 221
N-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1-benzofuran-2-sulfonamide
(782) ##STR00260##
(783) Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, (3-chloro-propyl)-dimethyl-amine hydrochloride and 1-benzofuran-2-sulfonyl chloride.
(784) .sup.1H NMR (600 MHz, acetone-d6) δ 7.62-7.72 (m, 2H), 7.49 (d, J=8.22 Hz, 1H), 7.31-7.38 (m, 2H), 7.25 (t, J=7.48 Hz, 1H), 7.18 (s, 1H), 6.69 (dd, J=2.05, 8.22 Hz, 1H), 3.44 (t, J=5.58 Hz, 2H), 3.30 (s, 3H), 3.12 (s, 3H), 2.97 (t, J=6.31 Hz, 2H), 1.96-2.10 (m, 2H)
Compound 222
N-(5-chloro-2-{[3-(dimethylamino)propyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(785) ##STR00261##
(786) Following General Procedure C, the title compound was prepared from N-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(787) .sup.1H NMR (600 MHz, acetone-d6) δ 7.67 (d, J=7.92 Hz, 1H), 7.60 (d, J=1.76 Hz, 1H), 7.50 (d, J=8.22 Hz, 1H), 7.41 (d, J=8.22 Hz, 1H), 7.33 (t, J=7.92 Hz, 1H), 7.20-7.28 (m, 2H), 6.83 (dd, J=1.76, 8.22 Hz, 1H), 3.69 (ddd, J=4.99, 8.58, 13.43 Hz, 1H), 3.61 (ddd, J=4.11, 10.71, 14.23 Hz, 1H), 3.48 (ddd, J=5.58, 5.72, 13.35 Hz, 1H), 3.07-3.21 (m, 7H), 2.30-2.42 (m, 1H), 2.16-2.30 (m, 1H).
Compound 223
N-(5-chloro-2-{[3-(dimethylamino)propyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(788) ##STR00262##
(789) Following General Procedure D, the title compound was prepared from N-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(790) 1H NMR (600 MHz, acetone-d6) δ 7.63 (d, J=7.63 Hz, 1H), 7.53 (d, J=1.76 Hz, 1H), 7.48 (d, J=8.22 Hz, 1H), 7.43 (d, J=8.22 Hz, 1H), 7.30 (t, J=7.34 Hz, 1H), 7.21 (t, J=7.21 Hz, 1H), 7.17 (s, 1H), 6.74 (dd, J=2.05, 8.22 Hz, 1H), 3.60-3.69 (m, 2H), 3.36-3.48 (m, 1H), 3.20-3.33 (m, 6H), 2.90-3.01 (br. s., 1H), 2.29-2.42 (m, J=6.75 Hz, 1H), 2.08-2.21 (m, 1H).
Compound 224
N-(5-chloro-2-{[3-(dimethylnitroryl)propyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(791) ##STR00263##
(792) Following General Procedure D, the title compound was prepared from N-(5-chloro-2-{[3-(dimethylamino)propyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(793) 1H NMR (600 MHz, acetone-d6) δ 7.79 (s, 1H), 7.70 (d, J=8.51 Hz, 1H), 7.64 (d, J=7.63 Hz, 1H), 7.52 (d, J=8.51 Hz, 1H), 7.29-7.38 (m, 2H), 7.19-7.28 (m, 1H), 6.74 (d, J=8.51 Hz, 1H), 3.74-3.84 (m, 2H), 3.60-3.65 (m., 2H), 3.26 (s, 6H), 2.27-2.39 (m, 2H).
Compound 225
N-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(794) ##STR00264##
(795) Following General Procedure A, B, C, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, 5-chloromethyl-oxazolidin-2-one and 1-benzofuran-2-sulfonyl chloride.
(796) 1H NMR (600 MHz, acetone-d6) δ 7.62 (dd, J=7.92, 11.15 Hz, 1H), 7.44-7.54 (m, 2H), 7.26-7.44 (m, 3H), 7.20 (ddd, J=7.48, 7.63, 11.30 Hz, 1H), 6.87-7.05 (m, 1H), 6.51 (br. s., 1H), 4.69-5.03 (m, 1H), 3.60 (q, J=8.31 Hz, 1H), 3.45-3.55 (m, 1H), 3.23-3.45 (m, 1H), 3.06-3.17 (m, 1H).
Compound 226
N-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(797) ##STR00265##
(798) Following General Procedure D, the title compound was prepared from N-(5-chloro-2-{[(2-oxo-1,3-oxazolidin-5-yl)methyl]thio)phenyl)benzofuran-2-sulfonamide.
(799) .sup.1H NMR (600 MHz, acetone-d6) δ 7.81 (d, J=1.76 Hz, 1H), 7.68 (d, J=8.22 Hz, 2H), 7.54 (d, J=8.22 Hz, 1H), 7.29-7.40 (m, 2H), 7.22-7.29 (m, 1H), 6.79 (br. s., 1H), 6.47 (br. s., 1H), 4.94 (dt, J=6.93, 14.01 Hz, 1H), 4.17 (dd, J=5.58, 14.09 Hz, 1H), 3.96 (dd, J=6.90, 14.23 Hz, 1H), 3.65 (t, J=8.66 Hz, 1H), 3.32-3.47 (m, 1H).
Compound 227
N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide
(800) ##STR00266##
(801) Following General Procedures A and B the title compound was prepared from 2-amino-4-chloro-benzenethiol, 6-chloromethyl-1H-pyrimidine-2,4-dione and 1-benzofuran-2-sulfonyl chloride.
(802) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.72 (d, J=7.92 Hz, 1H), 7.57 (d, J=8.22 Hz, 1H), 7.45-7.51 (m, 1H), 7.44 (d, J=2.05 Hz, 1H), 7.42 (s, 1H), 7.27-7.37 (m, 2H), 7.09 (br. s., 1H), 5.05 (s, 1H), 3.64 (s, 2H).
Compound 228
N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(803) ##STR00267##
(804) Following General Procedure C, the title compound was prepared from N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(805) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.68 (d, J=7.92 Hz, 1H), 7.52 (d, J=8.51 Hz, 1H), 7.49 (d, J=8.51 Hz, 1H), 7.41 (t, J=7.92 Hz, 1H), 7.32-7.37 (m, 2H), 7.27-7.32 (m, 1H), 7.09 (d, J=8.22 Hz, 1H), 5.32 (s, 1H), 4.40 (d, J=13.21 Hz, 1H), 3.89 (d, J=12.91 Hz, 1H).
Compound 229
N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(806) ##STR00268##
(807) Following General Procedure D, the title compound was prepared from N-(5-chloro-2-{[(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)methyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(808) .sup.1H NMR (600 MHz, acetone-d6) δ 10.36 (br. s., 1H), 10.15 (br. s., 1H), 7.78 (br. s., 1H), 7.70 (d, J=8.51 Hz, 1H), 7.65 (d, J=7.92 Hz, 1H), 7.42-7.51 (m, 2H), 7.35 (t, J=7.63 Hz, 1H), 7.26 (t, J=7.48 Hz, 1H), 6.87 (d, J=6.75 Hz, 1H), 5.48 (br. s., 1H), 4.76 (br. s., 2H).
Compound 230
N-{2-[(3-aminopropyl)thio]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(809) ##STR00269##
(810) Following General Procedure F, G, the title compound was prepared from 2,2′-dithiobis(5-chloroaniline), 1-benzofuran-2-sulfonyl chloride and 3-bromo-propylamine hydrochloride.
(811) .sup.1H NMR (600 MHz, DMSO-d6) δ 8.03 (br. s., 2H), 7.69 (d, J=7.63 Hz, 1H), 7.56 (d, J=8.22 Hz, 1H), 7.37 (t, J=7.78 Hz, 1H), 7.23-7.32 (m, 2H), 7.05-7.20 (m, 2H), 6.60 (br. s., 1H), 3.03 (br. s., 2H), 2.91 (t, J=6.60 Hz, 2H), 1.74-1.92 (m, 2H).
Intermediate 38
(3-Bromo-propyl)-carbamic Acid tert-butyl Ester
(812) ##STR00270##
(813) A mixture of 3-bromo-propylamine hydrochloride (523 mg, 2.39 mmol), di-tert-butyl dicarbonate (573 mg, 2.63 mmol), NaOH (1N, 1.5 ml) in MeOH was stirred at rt overnight. The mixture was added water and extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated in vacuo. The residue was purified by column chromatography in silica gel.
(814) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 4.65 (br. s., 1H), 3.38-3.56 (m, 2H), 3.28 (d, J=5.28 Hz, 2H), 1.95-2.14 (m, 2H), 1.45 (br. s., 9H).
Compound 231
N-{2-[(3-aminopropyl)sulfinyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(815) ##STR00271##
(816) Following General Procedure F, G, C, E the title compound was prepared from 2,2′-dithiobis(5-chloroaniline), 1-benzofuran-2-sulfonyl chloride and (3-bromo-propyl)-carbamic acid tert-butyl ester.
(817) .sup.1H NMR (600 MHz, acetone-d6) δ 7.78 (d, J=7.92 Hz, 1H), 7.63 (d, J=8.51 Hz, 1H), 7.54-7.59 (m, 2H), 7.46-7.52 (m, 2H), 7.32-7.40 (m, 1H), 7.21 (d, J=7.92 Hz, 1H), 4.03-4.14 (m, 1H), 3.88-4.00 (m, 1H), 3.35 (ddd, J=6.97, 7.19, 13.72 Hz, 1H), 3.10 (ddd, J=6.46, 6.60, 13.35 Hz, 1H), 2.16-2.36 (m, 2H).
Compound 232
N-{2-[(3-aminopropyl)sulfonyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide
(818) ##STR00272##
(819) Following General Procedure F, G, D, E the title compound was prepared from 2,2′-dithiobis(5-chloroaniline), 1-benzofuran-2-sulfonyl chloride and (3-bromo-propyl)-carbamic acid tert-butyl ester.
(820) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.88 (d, J=8.51 Hz, 1H), 7.79 (d, J=7.92 Hz, 1H), 7.72 (d, J=1.76 Hz, 1H), 7.68 (s, 1H), 7.61 (d, J=8.51 Hz, 1H), 7.53 (t, J=7.78 Hz, 1H), 7.40 (t, J=7.63 Hz, 1H), 7.34 (d, J=8.51 Hz, 1H), 3.47 (t, J=7.04 Hz, 2H), 3.02 (t, J=7.63 Hz, 2H), 2.06 (quin, 2H).
Compound 233
N-(5-chloro-2-{[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl]sulfinyl}phenyl)-1-benzofuran-2-sulfonamide
(821) ##STR00273##
(822) Following General Procedure A, B, C, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 5-(chloromethyl)uracil and 1-benzofuran-2-sulfonyl chloride.
(823) .sup.1H NMR (600 MHz, DMSO-d6) δ 10.99 (s, 1H), 10.75 (br. s., 1H), 7.61 (d, J=7.63 Hz, 1H), 7.51 (d, J=8.22 Hz, 1H), 7.32 (t, J=7.48 Hz, 1H), 7.16-7.27 (m, 3H), 7.01-7.10 (m, 1H), 6.86 (br. s., 1H), 6.64-6.79 (m, 1H), 4.02 (d, J=13.21 Hz, 1H), 3.85 (d, J=13.21 Hz, 1H).
Compound 234
N-(5-chloro-2-{[(2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)methyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(824) ##STR00274##
(825) Following General Procedure A, B, D, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 5-(chloromethyl)uracil and 1-benzofuran-2-sulfonyl chloride.
(826) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.69 (d, J=2.05 Hz, 1H), 7.63-7.67 (m, 2H), 7.44 (t, J=8.36 Hz, 1H), 7.32-7.39 (m, 2H), 7.27 (t, J=7.04 Hz, 1H), 7.18 (s, 1H), 6.82 (d, J=7.92 Hz, 1H), 4.70 (s, 2H).
Compound 235
N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}acetamide
(827) ##STR00275##
(828) Following General Procedure A, B, the title compound was prepared from 2-amino-4-chloro-benzenethiol, N-(4-Chloromethyl-thiazol-2-yl)-acetamide and 1-benzofuran-2-sulfonyl chloride.
(829) 1H NMR (600 MHz, CD.sub.3OD) δ 7.70 (d, J=7.92 Hz, 1H), 7.49-7.54 (m, 2H), 7.45-7.50 (m, 1H), 7.42 (s, 1H), 7.29-7.36 (m, 2H), 7.11 (dd, J=2.20, 8.36 Hz, 1H), 6.45 (s, 1H), 3.84 (s, 2H), 2.21 (s, 3H).
Compound 236
N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]-1,3-thiazol-2-yl}acetamide
(830) ##STR00276##
(831) Following General Procedure C, the title compound was prepared from N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}acetamide.
(832) .sup.1H NMR (600 MHz, acetone-d6) δ 10.93 (br. s., 1H), 7.83 (d, J=7.92 Hz, 1H), 7.80 (s, 1H), 7.62-7.67 (m, 2H), 7.49-7.58 (m, 1H), 7.39 (t, J=7.48 Hz, 1H), 7.08-7.22 (m, 2H), 6.74 (s, 1H), 4.29-4.46 (m, 2H), 2.23 (s, 3H).
Compound 237
N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]-1,3-thiazol-2-yl}acetamide
(833) ##STR00277##
(834) Following General Procedure D, the title compound was prepared from N-{4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1,3-thiazol-2-yl}acetamide.
(835) 1H NMR (600 MHz, acetone-d6) δ 10.90 (br. s., 1H), 9.65 (br. s., 1H), 7.81 (d, J=7.34 Hz, 2H), 7.75 (d, J=2.05 Hz, 1H), 7.65 (d, J=8.51 Hz, 1H), 7.60 (s., 1H), 7.51 (s., 1H), 7.38 (t, J=7.19 Hz, 1H), 7.27 (s., 1H), 6.95 (s, 1H), 4.67 (br. s., 2H), 2.21 (s, 3H).
Compound 238
N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]sulfonyl}phenyl)-1-benzofuran-2-sulfonamide
(836) ##STR00278##
(837) Following General Procedure D, the title compound (53 mg, 38%) was prepared from N-(5-chloro-2-{[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]thio}phenyl)-1-benzofuran-2-sulfonamide.
(838) 1H NMR (600 MHz, CD.sub.3OD) δ 7.79 (d, J=1.76 Hz, 1H), 7.76 (d, J=8.51 Hz, 1H), 7.67 (d, J=7.92 Hz, 1H), 7.57 (d, J=0.59 Hz, 1H), 7.37 (ddd, J=1.17, 7.19, 8.36 Hz, 1H), 7.26-7.31 (m, 1H), 7.20-7.24 (m, 1H), 7.15 (dd, J=1.76, 8.51 Hz, 1H), 3.40-3.50 (m, 2H), 2.60-2.72 (m, 2H), 2.01 (s, 6H).
Compound 239
N-{5-fluoro-2-[(3-nitrobenzyl)sulfinyl]phenyl}-1-benzofuran-2-sulfonamide
(839) ##STR00279##
(840) Following General Procedure C, the title compound (174 mg, 79%) was prepared from N-(5-fluoro-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide.
(841) 1H NMR (600 MHz, CD.sub.3OD) δ 7.98 (d, J=9.10 Hz, 1H), 7.67 (d, J=7.63 Hz, 1H), 7.49 (br. s., 1H), 7.40 (s, 1H), 7.35 (d, J=8.51 Hz, 1H), 7.26-7.32 (m, 2H), 7.21-7.26 (m, 2H), 7.12 (d, J=7.63 Hz, 1H), 6.74-6.80 (m, 1H), 6.40 (t, J=7.34 Hz, 1H), 4.52-4.64 (m, 2H).
Compound 240
N-{2-[(3-aminobenzyl)sulfinyl]-5-chlorophenyl}-2,4-difluorobenzenesulfonamide
(842) ##STR00280##
(843) Following General Procedure A, B, C, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 2,4-difluoro-benzenesulfonyl chloride.
(844) .sup.1H NMR (600 MHz, METHANOL-d.sub.4) δ 7.95 (d, J=6.16 Hz, 1H), 7.19-7.30 (m, 3H), 7.11-7.19 (m, 2H), 7.00 (t, J=7.78 Hz, 1H), 6.72 (dd, J=1.47, 7.92 Hz, 1H), 6.61 (s, 1H), 6.44 (d, J=7.04 Hz, 1H), 4.34 (d, J=12.91 Hz, 1H), 4.07 (d, J=12.90 Hz, 1H).
Compound 241
N-[5-chloro-2-(methylsulfonyl)phenyl]-4-isopropylbenzenesulfonamide
(845) ##STR00281##
(846) Following General Procedure B and D, the title compound was prepared from 5-chloro-2-(methylthio)aniline and 4-isopropyl-benzenesulfonyl chloride.
(847) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 9.13 (s, 1H), 7.80-7.85 (m, 2H), 7.71-7.76 (m, 2H), 7.34-7.39 (m, 2H), 7.16 (dd, J=2.05, 8.51 Hz, 1H), 2.95 (spt, J=6.90 Hz, 1H), 2.81 (s, 3H), 1.22 (d, J=7.04 Hz, 6H).
Compound 242
N-(5-methoxy-2-((3-nitrobenzyl)thio)phenyl)benzofuran-2-sulfonamide
(848) ##STR00282##
(849) Following General Procedure B, the title compound (406 mg, 56%) was prepared from 5-methoxy-2-((3-nitrobenzyl)thio)aniline (450 mg, 1.552 mmol) and benzofuran-2-sulfonyl chloride (335 mg, 1.552 mmol) in pyridine (5 ml).
(850) 1H NMR (600 MHz, CD.sub.3OD) δ 8.53 (dd, J=1.76, 5.87 Hz, 1H), 7.96 (ddd, J=1.03, 2.27, 8.14 Hz, 1H), 7.70 (d, J=7.92 Hz, 1H), 7.63 (t, J=1.91 Hz, 1H), 7.51 (s, 1H), 7.42 (dd, J=1.17, 8.22 Hz, 1H), 7.24-7.37 (m, 3H), 7.11 (s, 1H), 7.00 (s, 1H), 6.55 (dd, J=2.79, 8.66 Hz, 1H), 3.83 (s, 2H), 3.71 (s, 3H).
Compound 243
N-{5-chloro-2-[(1H-pyrazol-3-ylmethyl)sulfonyl]phenyl}-1-benzofuran-2-sulfonamide
(851) ##STR00283##
(852) Following General Procedure D and E, the title compound was prepared from tert-butyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}thio)methyl]-1H-pyrazole-1-carboxylate (Compound 22).
(853) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.71 (d, J=1.76 Hz, 1H), 7.66 (d, J=7.92 Hz, 1H), 7.51 (d, J=8.51 Hz, 1H), 7.31-7.43 (m, 4H), 7.24-7.29 (m, 1H), 6.79 (d, J=7.04 Hz, 1H), 5.82 (br. s., 1H), 4.99 (br. s., 2H).
Compound 244
N-{2-[(3-aminobenzyl)thio]-5-chlorophenyl}-4-chloro-2-fluorobenzenesulfonamide
(854) ##STR00284##
(855) Following General Procedure A, B, and K, the title compound was prepared from 2-amino-4-chloro-benzenethiol, 1-bromomethyl-3-nitro-benzene, and 4-chloro-2-fluoro-benzenesulfonyl chloride.
(856) .sup.1H NMR (600 MHz, CHLOROFORM-d) δ 7.84 (t, J=8.22 Hz, 1H), 7.47 (d, J=2.05 Hz, 1H), 7.25 (dt, J=1.03, 8.51 Hz, 1H), 7.17-7.22 (m, 2H), 7.04 (t, J=7.63 Hz, 1H), 6.93 (dd, J=2.35, 8.22 Hz, 1H), 6.58 (dt, J=1.17, 7.92 Hz, 1H), 6.40-6.45 (m, 2H), 3.72 (s, 2H).
Intermediate 39
2-(benzylthio)-5-chloroaniline
(857) ##STR00285##
(858) Following General Procedure A, the title compound (560 mg, 33%) was prepared from 2-amino-4-chlorobenzenethiol (1.08 g, 6.77 mmol), (bromomethyl)benzene (0.8 ml, 6.77 mmol) and K.sub.2CO.sub.3 (3.18 g, 23.04 mmol) in DMF (20 ml).
(859) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.18-7.27 (m, 3H), 7.09-7.14 (m, 2H), 7.07 (d, J=8.22 Hz, 1H), 6.69 (d, J=2.35 Hz, 1H), 6.57 (dd, J=2.35, 8.22 Hz, 1H), 4.38 (br. s., 2H), 3.85 (s, 2H).
Compound 245
N-[2-(benzylsulfanyl)-5-chlorophenyl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide
(860) ##STR00286##
(861) Following General Procedure B, the title compound (890 mg, 80%) was prepared from 2-(benzylthio)-5-chloroaniline (560 mg, 2.25 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (628 mg, 2.25 mmol).
(862) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.08 (d, J=2.35 Hz, 1H), 7.90 (dd, J=2.20, 8.36 Hz, 1H), 7.76 (s, 1H), 7.44 (d, J=2.05 Hz, 1H), 7.18-7.28 (m, 3H), 7.09-7.17 (m, 2H), 7.06 (dd, J=1.61, 7.78 Hz, 2H), 3.84 (s, 2H).
Compound 246
N-[2-(benzylsulfinyl)-5-chlorophenyl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide
(863) ##STR00287##
(864) Following General Procedure C, the title compound (246 mg, 75%) was prepared from N-[2-(benzylsulfanyl)-5-chlorophenyl]-4-chloro-3-(trifluoromethyl) benzenesulfonamide (316 mg, 0.64 mmol).
(865) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 8.25 (d, J=2.35 Hz, 1H), 8.04 (dd, J=2.05, 8.51 Hz, 1H), 7.69 (s, 1H), 7.53 (s, 1H), 7.33-7.38 (m, 1H), 7.25-7.31 (m, 2H), 6.90-7.00 (m, 3H), 6.70 (d, J=8.22 Hz, 1H), 4.30 (d, J=12.62 Hz, 1H), 4.21 (d, J=12.62 Hz, 1H).
Compound 247
N-[2-(benzylsulfonyl)-5-chlorophenyl]-4-chloro-3-(trifluoromethyl)benzenesulfonamide
(866) ##STR00288##
(867) Following General Procedure D, the title compound (286 mg, 66%) was prepared from N-[2-(benzylsulfanyl)-5-chlorophenyl]-4-chloro-3-(trifluoromethyl) benzenesulfonamide (409 mg, 0.83 mmol).
(868) .sup.1H NMR (600 MHz, acetone-d6) δ 9.23 (br. s., 1H), 8.30 (d, J=2.05 Hz, 1H), 8.21 (dd, J=2.20, 8.36 Hz, 1H), 7.97 (d, J=8.51 Hz, 1H), 7.54-7.63 (m, 2H), 7.25-7.41 (m, 4H), 7.15 (d, J=7.34 Hz, 2H), 4.63 (s, 2H).
Intermediate 40
4-Amino-3-mercaptobenzonitrile
(869) ##STR00289##
(870) A mixture of 6-cyanobenzothiazole (532 mg, 3.33 mmol) and hydrazine monohydrate (1.2 ml, 24.76 mmol) in EtOH (10 ml) was heated at 80° C. under N.sub.2 atmosphere for 2 hours. The solvent was evaporated, H.sub.2O was added to the residue, and the solution was adjusted to pH˜5-7 with AcOH. The resulting yellow precipitate was filtered and washed with H.sub.2O, dried under high vacuum to yield the title compound as yellow solid (486 mg, 97%).
(871) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.57 (d, J=1.76 Hz, 1H), 7.29 (dd, J=1.91, 8.36 Hz, 1H), 6.76 (d, J=8.51 Hz, 1H).
Intermediate 41
4-Amino-3-(benzylthio)benzonitrile
(872) ##STR00290##
(873) Following General Procedure A, the title compound (615 mg, 79%) was prepared from 4-amino-3-mercaptobenzonitrile (486 mg, 3.24 mmol), (bromomethyl)benzene (0.38 ml, 3.24 mmol) and K.sub.2CO.sub.3 (2.2 g, 16.20 mmol) in DMF (10 ml).
(874) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.30 (dd, J=1.91, 8.36 Hz, 1H), 7.25 (d, J=1.76 Hz, 1H), 7.19-7.22 (m, 3H), 7.10 (dd, J=1.61, 8.07 Hz, 2H), 6.74 (d, J=8.51 Hz, 1H), 3.91 (s, 2H).
Compound 248
N-[2-(benzylsulfanyl)-4-cyanophenyl]-1-benzofuran-2-sulfonamide
(875) ##STR00291##
(876) Following General Procedure B, the title compound (752 mg, 47%) was prepared from 4-amino-3-(benzylthio)benzonitrile (430 mg, 1.80 mmol), benzofuran-2-sulfonyl chloride (391 mg, 1.80 mmol), and DMAP (cat.) in pyridine (3 ml).
(877) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.37 (s, 1H), 7.73 (d, J=8.51 Hz, 1H), 7.67 (d, J=7.92 Hz, 1H), 7.42-7.56 (m, 4H), 7.39 (d, J=2.05 Hz, 1H), 7.29-7.35 (m, 1H), 7.17-7.18 (m, 3H), 6.93 (dd, J=2.49, 7.19 Hz, 2H), 3.84 (s, 2H).
Compound 249
N-[2-(benzylsulfinyl)-4-cyanophenyl]-1-benzofuran-2-sulfonamide
(878) ##STR00292##
(879) Following General Procedure C, the title compound (98 mg, 61%) was prepared from N-[2-(benzylsulfanyl)-4-cyanophenyl]-1-benzofuran-2-sulfonamide (156 mg, 0.37 mmol).
(880) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.62-7.70 (m, 1H), 7.56 (d, J=8.51 Hz, 1H), 7.44 (dd, J=2.20, 8.66 Hz, 1H), 7.39 (dd, J=0.73, 8.36 Hz, 1H), 7.32-7.34 (m, 1H), 7.31 (d, J=0.88 Hz, 1H), 7.22-7.29 (m, 1H), 7.15-7.22 (m, 2H), 7.04-7.11 (m, 2H), 6.94 (dd, J=1.03, 8.07 Hz, 2H), 4.48 (d, J=12.91 Hz, 1H), 4.30 (d, J=12.91 Hz, 1H).
Compound 250
N-[2-(benzylsulfonyl)-4-cyanophenyl]-1-benzofuran-2-sulfonamide
(881) ##STR00293##
(882) Following General Procedure D, the title compound (128 mg, 84%) was prepared from N-[2-(benzylsulfanyl)-4-cyanophenyl]-1-benzofuran-2-sulfonamide (142 mg, 0.34 mmol).
(883) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.78 (d, J=8.80 Hz, 1H), 7.68 (d, J=8.22 Hz, 1H), 7.62 (s., 1H), 7.49 (d, J=8.51 Hz, 1H), 7.44 (s., 1H), 7.26-7.34 (m, 3H), 7.11-7.19 (m, 1H), 6.94-7.03 (m, 2H), 6.85-6.91 (m, J=5.58 Hz, 2H), 4.76 (s., 2H).
Intermediate 42
6-(Benzylthio)-5-nitro-2,3-dihydro-1H-inden-1-one
(884) ##STR00294##
(885) Following General Procedure A, the title compound (672 mg, 79%) was prepared from 6-bromo-5-nitro-2,3-dihydro-1H-inden-1-one (1.5 g, 5.86 mmol), phenylmethanethiol (1 ml, 8.79 mmol) and K.sub.2CO.sub.3 (4.0 g, 29.29 mmol) in DMF (20 ml).
(886) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.56 (s, 1H), 7.52 (s, 1H), 7.41-7.47 (m, 2H), 7.35-7.39 (m, 2H), 7.30-7.35 (m, 1H), 4.26 (s, 2H), 3.13-3.22 (m, 2H), 2.74-2.82 (m, 2H).
Intermediate 43
5-Amino-6-(benzylthio)-2,3-dihydro-1H-inden-1-one
(887) ##STR00295##
(888) Following General Procedure L, the title compound (370 mg, 61%) was prepared from 6-(benzylthio)-5-nitro-2,3-dihydro-1H-inden-1-one (670 mg, 2.24 mmol).
(889) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.18-7.30 (m, 6H), 7.04 (s, 1H), 4.05 (s, 2H), 2.92-2.97 (m, 2H), 2.62-2.68 (m, 2H).
Compound 251
N-[6-(benzylsulfanyl)-1-oxo-2,3-dihydro-1H-inden-5-yl]-1-benzofuran-2-sulfonamide
(890) ##STR00296##
(891) Following General Procedure B, the title compound (752 mg, 47%) was prepared from 5-Amino-6-(benzylthio)-2,3-dihydro-1H-inden-1-one (463 mg, 1.72 mmol) and benzofuran-2-sulfonyl chloride (371 mg, 1.72 mmol) in pyridine (3 ml).
(892) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.90 (s, 1H), 7.85 (s, 1H), 7.61-7.70 (m, 1H), 7.42-7.50 (m, 3H), 7.29-7.36 (m, 1H), 7.20-7.24 (m, 3H), 6.98-7.06 (m, 2H), 3.94 (s, 2H), 2.90-2.98 (m, 2H), 2.61-2.68 (m, 2H).
Compound 252
N-[6-(benzylsulfinyl)-1-oxo-2,3-dihydro-1H-inden-5-yl]-1-benzofuran-2-sulfonamide
(893) ##STR00297##
(894) Following General Procedure C, the title compound (99 mg, 61%) was prepared from N-[6-(benzylsulfanyl)-1-oxo-2,3-dihydro-1H-inden-5-yl]-1-benzofuran-2-sulfonamide (143 mg, 0.32 mmol).
(895) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 7.69 (s, 1H), 7.59 (s, 1H), 7.29-7.42 (m, 3H), 7.09-7.27 (m, 5H), 6.96 (d, J=7.63 Hz, 2H), 4.38 (d, J=12.91 Hz, 1H), 4.18 (d, J=12.91 Hz, 1H), 2.80-2.95 (m, J=4.99 Hz, 2H), 2.51-2.66 (m, 2H).
Compound 253
N-[6-(benzylsulfonyl)-1-oxo-2,3-dihydro-1H-inden-5-yl]-1-benzofuran-2-sulfonamide
(896) ##STR00298##
(897) Following General Procedure D, the title compound (92 mg, 63%) was prepared from N-[6-(benzylsulfanyl)-1-oxo-2,3-dihydro-1H-inden-5-yl]-1-benzofuran-2-sulfonamide (137 mg, 0.31 mmol).
(898) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.05 (s, 1H), 7.71 (dt, J=1.03, 7.92 Hz, 1H), 7.65 (d, J=0.88 Hz, 1H), 7.60 (s, 1H), 7.48-7.53 (m, 1H), 7.41-7.47 (m, 1H), 7.29-7.37 (m, 2H), 7.19-7.28 (m, 2H), 7.03 (d, J=7.04 Hz, 2H), 4.43 (s, 2H), 2.90-3.07 (m, 2H), 2.63-2.78 (m, 2H).
Intermediate 44
Methyl 4-(((2-amino-4-chlorophenyl)thio)methyl)benzoate
(899) ##STR00299##
(900) Following General Procedure A, the title compound (2.2 g, 88%) was prepared from 2-amino-4-chlorobenzenethiol (1.3 g, 8.14 mmol), methyl 4-(bromomethyl)benzoate (1.86 g, 8.14 mmol) and K.sub.2CO.sub.3 (5.6 g, 40.73 mmol) in DMF (20 ml).
(901) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.89 (d, J=8.22 Hz, 2H), 7.13 (d, J=8.22 Hz, 2H), 6.99 (d, J=8.22 Hz, 1H), 6.67 (d, J=2.35 Hz, 1H), 6.53 (dd, J=2.05, 8.22 Hz, 1H), 4.30 (br. s., 2H), 3.89 (s, 3H), 3.85 (s, 2H)
Compound 254
Methyl 4-(((4-chloro-2-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)phenyl)thio)methyl)benzoate
(902) ##STR00300##
(903) Following General Procedure B, the title compound (635 mg, 66%) was prepared from 4-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (535 mg, 1.74 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (486 mg, 1.74 mmol) in pyridine (5 ml).
(904) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.11 (d, J=2.35 Hz, 1H), 7.91 (d, J=8.51 Hz, 2H), 7.82 (dd, J=2.35, 8.51 Hz, 1H), 7.64 (b.s, 1H), 7.59 (d, J=8.51 Hz, 1H), 7.53 (d, J=2.05 Hz, 1H), 7.01-7.06 (m, 3H), 6.95 (dd, J=2.20, 8.36 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 2H).
General Procedure Q
Compound 255
4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic Acid
(905) ##STR00301##
(906) A mixture of methyl 4-(((4-chloro-2-(4-chloro-3-(trifluoromethyl)phenylsulfonamido) phenyl) thio) methyl) benzoate (635 mg, 1.155 mmol), NaOH (5M, 2 ml) in MeOH (10 ml) was stirred at room temperature overnight. The solvent was removed and the residue was diluted with water, acidified with 10% HCl. The mixture was extracted with EtOAc (2×20 ml). The combined organic layer was washed with brine and concentrated under vacuum. The desire product was purified by MPLC (50% to 100% EtOAc/Hexane).
(907) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.12 (d, J=2.05 Hz, 1H), 7.98 (d, J=8.22 Hz, 2H), 7.84 (dd, J=2.35, 8.51 Hz, 1H), 7.66 (s, 1H), 7.61 (d, J=8.51 Hz, 1H), 7.54 (d, J=2.35 Hz, 1H), 7.05-7.08 (m, 3H), 6.96 (dd, J=2.20, 8.36 Hz, 1H), 3.78 (s, 2H).
Compound 256
4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic Acid
(908) ##STR00302##
(909) Following General Procedure C, the title compound (179 mg, 86%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl) benzoic acid (203 mg, 0.38 mmol).
(910) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.21 (d, J=2.05 Hz, 1H), 8.01 (d, J=2.35 Hz, 1H), 7.98 (d, J=8.22 Hz, 2H), 7.74 (d, J=8.51 Hz, 1H), 7.21 (s, 1H), 7.13-7.16 (m, 4H), 7.06 (d, J=8.22 Hz, 1H), 4.37 (d, J=12.91 Hz, 1H), 4.27 (d, J=12.91 Hz, 1H).
Compound 257
4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic Acid
(911) ##STR00303##
(912) Following General Procedure D, the title compound (170 mg, 79%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl) benzoic acid (203 mg, 0.38 mmol).
(913) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.20 (d, J=2.05 Hz, 1H), 7.97 (dd, J=2.20, 8.36 Hz, 1H), 7.91 (d, J=8.22 Hz, 2H), 7.65 (d, J=8.51 Hz, 1H), 7.44 (d, J=2.05 Hz, 1H), 7.32 (d, J=8.80 Hz, 1H), 7.07 (d, J=7.92 Hz, 2H), 6.97 (d, J=9.68 Hz, 1H), 4.38 (s, 2H).
General Procedure R
Compound 258
tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino) phenyl]sulfanyl}methyl)phenyl]carbonyl}amino)acetate
(914) ##STR00304##
(915) A mixture of 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl) benzoic acid (98 mg, 0.18 mmol), glycine t-butyl ester (36 mg, 0.27 mmol), 4-methyl morpholine (60 μl, 0.55 mmol) and EDC (53 mg, 0.27 mmol) in DMF (3 ml) was stirred at room temperature overnight. The reaction was quenched with water and extracted with EtOAc (2×5 ml). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (30%-100% EtOAc in hexane) to afford the title compound (92 mg, 78%).
(916) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.10 (d, J=2.05 Hz, 1H), 7.81 (dd, J=2.20, 8.36 Hz, 1H), 7.67 (d, J=8.22 Hz, 2H), 7.59 (d, J=8.51 Hz, 1H), 7.48 (d, J=2.35 Hz, 1H), 6.98-7.08 (m, 3H), 6.94 (dd, J=2.05, 8.22 Hz, 1H), 6.69 (t, J=4.55 Hz, 1H), 4.10 (d, J=4.99 Hz, 2H), 3.74 (s, 2H), 1.48 (s, 9H).
Compound 259
tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)phenyl]carbonyl}amino)acetate
(917) ##STR00305##
(918) Following General Procedure R, the title compound (98 mg, 81%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid (100 mg, 0.18 mmol).
(919) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.21 (d, J=1.76 Hz, 1H), 7.97 (dd, J=1.91, 8.36 Hz, 1H), 7.61 (d, J=7.92 Hz, 2H), 7.57 (d, J=8.51 Hz, 1H), 7.38 (d, J=1.47 Hz, 1H), 6.90 (d, J=7.63 Hz, 2H), 6.74-6.83 (m, 2H), 4.25 (d, J=12.62 Hz, 1H), 4.06-4.13 (m, 3H), 1.47 (s, 9H).
Compound 260
tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)phenyl]carbonyl}amino)acetate
(920) ##STR00306##
(921) Following General Procedure R, the title compound (92 mg, 64%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid (119 mg, 0.21 mmol).
(922) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.21 (d, J=1.47 Hz, 1H), 7.98 (d, J=8.22 Hz, 1H), 7.41-7.53 (m, 3H), 7.36 (br. s., 1H), 7.17 (d, J=8.51 Hz, 1H), 6.81 (t, J=4.99 Hz, 1H), 6.71 (d, J=7.63 Hz, 2H), 6.53 (dd, J=1.76, 8.51 Hz, 1H), 4.47 (br. s., 2H), 4.02 (d, J=4.99 Hz, 2H), 1.43 (s, 9H).
General Procedure S
Compound 261
({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)phenyl]carbonyl}amino)acetic Acid
(923) ##STR00307##
(924) A mixture of tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino) phenyl]sulfanyl}methyl)phenyl]carbonyl}amino)acetate (90 mg, 0.14 mmol) in formic acid (2 ml) was stirred at room temperature overnight. Formic acid was removed under vacuum and the desired product (72 mg, 88%) was re-crystallized from 10% MeOH in CH.sub.2Cl.sub.2.
(925) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.10 (d, J=2.05 Hz, 1H), 7.91 (dd, J=2.05, 8.51 Hz, 1H), 7.71-7.81 (m, 3H), 7.41 (s, 1H), 7.19 (d, J=8.22 Hz, 2H), 7.08-7.17 (m, 2H), 4.05 (br. s., 2H), 3.92 (s, 2H).
Compound 262
({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)phenyl]carbonyl}amino)acetic Acid
(926) ##STR00308##
(927) Following General Procedure S, the title compound (58 mg, 70%) was prepared from tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)phenyl]carbonyl}amino) acetate (90 mg, 0.14 mmol).
(928) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.13 (d, J=2.05 Hz, 1H), 8.02 (dd, J=2.20, 8.36 Hz, 1H), 7.84 (d, J=8.51 Hz, 1H), 7.76 (d, J=8.22 Hz, 2H), 7.12-7.30 (m, 4H), 7.03 (s, 1H), 4.46 (d, J=12.91 Hz, 1H), 4.24 (d, J=12.91 Hz, 1H), 4.08 (s, 2H).
Compound 263
({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino) phenyl]sulfonyl}methyl)phenyl]carbonyl}amino)acetic Acid
(929) ##STR00309##
(930) Following General Procedure S, the title compound (60 mg, 73%) was prepared from tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl) phenyl]carbonyl}amino)acetate (89 mg, 0.13 mmol).
(931) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.36 (s, 1H), 8.10-8.21 (m, 2H), 7.72 (d, J=8.22 Hz, 2H), 7.45-7.53 (m, 1H), 7.38 (d, J=8.51 Hz, 1H), 7.35 (d, J=8.22 Hz, 2H), 6.73 (s., 1H), 4.97 (s, 2H), 4.05 (s, 2H).
Intermediate 45
Methyl 3-(((2-amino-4-chlorophenyl)thio)methyl)benzoate
(932) ##STR00310##
(933) Following General Procedure A, the title compound (1.4 g, 42%) was prepared from 2-amino-4-chlorobenzenethiol (1.7 g, 10.90 mmol), methyl 3-(bromomethyl)benzoate (2.5 g, 10.90 mmol) and K.sub.2CO.sub.3 (7.5 g, 54.50 mmol) in DMF (30 ml).
(934) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 7.88 (dt, J=1.47, 7.63 Hz, 1H), 7.78 (t, J=1.76 Hz, 1H), 7.26-7.33 (m, 1H), 6.97-7.05 (m, 2H), 6.70 (d, J=2.35 Hz, 1H), 6.67 (d, J=2.05 Hz, 1H), 4.32 (br.s., 2H), 3.89 (s, 3H), 3.87 (s, 2H).
Compound 264
Methyl 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate
(935) ##STR00311##
(936) Following General Procedure B, the title compound (1.65 g, 65%) was prepared from methyl 3-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (1.41 g, 4.59 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.28 g, 4.59 mmol) in pyridine (10 ml).
(937) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 8.10 (d, J=2.05 Hz, 1H), 7.92 (d, J=7.92 Hz, 1H), 7.83 (dd, J=2.20, 8.36 Hz, 1H), 7.65 (br.s, 1H), 7.60 (d, J=8.51 Hz, 1H), 7.54 (d, J=2.05 Hz, 1H), 7.25-7.39 (m, 2H), 7.14 (d, J=7.04 Hz, 1H), 7.08 (s, 1H), 6.96 (dd, J=2.20, 8.36 Hz, 1H), 3.90 (s, 3H), 3.77 (s, 2H).
Compound 265
methyl 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoate
(938) ##STR00312##
(939) Following General Procedure C, the title compound (36 mg, 88%) was prepared from Methyl 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate (40 mg, 0.07 mmol).
(940) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.11 (d, J=2.05 Hz, 1H), 8.02 (dd, J=2.20, 8.36 Hz, 1H), 7.91-7.97 (m, 1H), 7.86 (d, J=8.22 Hz, 2H), 7.57 (br.s, 1H), 7.37-7.42 (m, 1H), 7.32 (d, J=7.92 Hz, 1H), 7.20-7.28 (m, 2H), 7.01 (d, J=1.47 Hz, 1H), 4.43 (d, J=13.20 Hz, 1H), 4.23 (d, J=13.20 Hz, 1H), 3.87 (s, 3H).
Compound 266
methyl 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino) phenyl]sulfonyl}methyl)benzoate
(941) ##STR00313##
(942) Following General Procedure D, the title compound (61 mg, 89%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl) benzoic acid (65 mg, 0.12 mmol).
(943) .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.26 (d, J=1.76 Hz, 1H), 8.14 (dd, J=2.35, 8.22 Hz, 1H), 7.93 (d, J=7.92 Hz, 1H), 7.84-7.90 (m, 2H), 7.76 (s, 1H), 7.38-7.48 (m, 3H), 7.38 (d, J=2.05 Hz, 1H), 7.11 (br. s., 1H), 4.95 (s, 2H), 3.82 (s, 3H).
Compound 267
3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic Acid
(944) ##STR00314##
(945) Following General Procedure Q, the title compound (1.2 g, 75%) was prepared from methyl 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate (1.65 g, 3 mmol).
(946) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.08 (d, J=2.05 Hz, 1H), 7.92 (dd, J=2.35, 8.51 Hz, 1H), 7.88 (d, J=7.63 Hz, 1H), 7.73-7.79 (m, 2H), 7.44 (d, J=2.35 Hz, 1H), 7.27-7.38 (m, 2H), 7.10-7.18 (m, 2H), 3.91 (s, 2H).
Compound 268
3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic Acid
(947) ##STR00315##
(948) Following General Procedure D, the title compound (74 mg, 64%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (109 mg, 0.20 mmol).
(949) .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 8.24 (d, J=2.35 Hz, 1H), 8.11 (dd, J=2.05, 8.51 Hz, 1H), 7.92 (d, J=8.51 Hz, 1H), 7.85 (d, J=7.63 Hz, 1H), 7.74-7.79 (m, 1H), 7.46 (d, J=8.51 Hz, 1H), 7.27-7.41 (m, 3H), 7.17 (s, 1H), 4.90 (s, 2H).
Compound 269
3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic Acid
(950) ##STR00316##
(951) Following General Procedure C, the title compound (30 mg, 21%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (140 mg, 0.26 mmol).
(952) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.24 (d, J=2.35 Hz, 1H), 8.09 (d, J=7.92 Hz, 1H), 8.02 (dd, J=2.35, 8.51 Hz, 1H), 7.63-7.68 (m, 2H), 7.55 (d, J=1.76 Hz, 1H), 7.39-7.46 (m, 1H), 7.25 (s, 1H), 6.95 (dd, J=1.91, 8.36 Hz, 1H), 6.72 (d, J=8.22 Hz, 1H), 4.23-4.38 (m, 2H).
Compound 270
3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide
(953) ##STR00317##
(954) Following General Procedure R, the title compound (388 mg, 80%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (411 mg, 0.77 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.15 ml, 1.15 mmol), EDC (294 mg, 1.53 mmol) and DMAP (cat.) in DMF (10 ml).
(955) .sup.1H NMR (600 MHz, CDCl.sub.3) δ 8.22 (t, J=4.99 Hz, 1H), 8.05 (d, J=2.05 Hz, 1H), 7.53-7.74 (m, 3H), 7.41 (d, J=8.51 Hz, 1H), 7.37 (d, J=2.35 Hz, 1H), 7.21 (d, J=7.92 Hz, 1H), 7.09-7.18 (m, 1H), 6.93 (d, J=8.51 Hz, 1H), 6.78 (dd, J=2.20, 8.36 Hz, 1H), 3.80 (s, 2H), 3.75 (q, J=5.48 Hz, 2H), 3.21 (t, J=5.43 Hz, 2H), 3.09 (br. s., 4H), 1.77-1.88 (m, 4H).
Compound 271
3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide
(956) ##STR00318##
(957) Following General Procedure D, the title compound (42 mg, 28%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide (144 mg, 0.23 mmol).
(958) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.22 (d, J=2.34 Hz, 1H), 8.06 (dd, J=1.90, 8.06 Hz, 1H), 7.67-7.81 (m, 3H), 7.21-7.38 (m, 2H), 7.18 (d, J=2.05 Hz, 1H), 6.99 (d, J=8.20 Hz, 1H), 6.72 (dd, J=2.05, 8.20 Hz, 1H), 4.53 (d, J=12.89 Hz, 1H), 4.23 (d, J=13.19 Hz, 1H), 3.90-4.00 (m, 2H), 3.58-3.85 (m, 6H), 2.08-2.39 (m, 4H).
Compound 272
3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide
(959) ##STR00319##
(960) Following General Procedure R, the title compound (17 mg, 19%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid (76 mg, 0.14 mmol), 2-(pyrrolidin-1-yl)ethanamine (26 μl, 0.21 mmol), EDC (53 mg, 0.28 mmol) and DMAP (cat.) in DMF (2 ml).
(961) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.20 (d, J=2.05 Hz, 1H), 8.05 (dd, J=2.20, 8.35 Hz, 1H), 7.97 (s, 1H), 7.80-7.86 (m, 1H), 7.71 (d, J=8.21 Hz, 1H), 7.23-7.47 (m, 2H), 7.16 (d, J=1.76 Hz, 1H), 7.12 (d, J=8.20 Hz, 1H), 6.76 (dd, J=1.90, 8.35 Hz, 1H), 4.60 (d, J=12.89 Hz, 1H), 4.13 (d, J=13.19 Hz, 1H), 3.65-3.84 (m, 2H), 3.34-3.59 (m, 6H), 1.95-2.21 (m, 4H).
Compound 273
3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide
(962) ##STR00320##
(963) Following General Procedure D, the title compound (63 mg, 40%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide (144 mg, 0.23 mmol).
(964) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.38 (d, J=2.05 Hz, 1H), 8.20 (dd, J=2.05, 8.21 Hz, 1H), 7.92 (s, 1H), 7.75 (d, J=7.62 Hz, 1H), 7.69 (d, J=8.50 Hz, 1H), 7.21-7.50 (m, 4H), 6.58 (dd, J=2.05, 8.50 Hz, 1H), 5.00 (s, 2H), 3.88-4.03 (m, 2H), 3.52-3.87 (m, 6H), 1.93-2.45 (m, 4H).
Compound 274
3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide
(965) ##STR00321##
(966) Following General Procedure R, the title compound (21 mg, 49%) was prepared from 3-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid (48 mg, 0.085 mmol), 2-(pyrrolidin-1-yl)ethanamine (16 μl, 0.13 mmol), EDC (32 mg, 0.17 mmol) and DMAP (cat.) in DMF (2 ml).
(967) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.36 (s, 1H), 8.12-8.25 (m, 2H), 7.83 (d, J=7.91 Hz, 1H), 7.72 (d, J=8.50 Hz, 1H), 7.57 (d, J=6.74 Hz, 1H), 7.49 (d, J=8.50 Hz, 1H), 7.43 (d, J=7.62 Hz, 1H), 7.29 (d, J=1.76 Hz, 1H), 6.58-6.70 (m, 1H), 5.01 (s, 2H), 3.76 (t, J=5.57 Hz, 2H), 3.39-3.58 (m, 6H), 2.02-2.10 (m, 4H).
Compound 275
4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide
(968) ##STR00322##
(969) Following General Procedure R, the title compound (345 mg, 71%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (410 mg, 0.765 mmol), 2-(pyrrolidin-1-yl)ethanamine (0.15 ml, 1.15 mmol), EDC (293 mg, 1.53 mmol) and DMAP (cat.) in DMF (5 ml).
(970) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.96-8.05 (m, 1H), 7.69-7.76 (m, 1H), 7.63 (d, J=8.51 Hz, 2H), 7.46-7.54 (m, 1H), 7.31-7.38 (m, 1H), 6.98 (d, J=8.22 Hz, 2H), 6.91-6.96 (m, 1H), 6.83-6.90 (m, 1H), 3.70 (s, 2H), 3.46 (t, J=6.02 Hz, 2H), 2.63-2.73 (m, 2H), 2.51-2.62 (m, 4H), 1.62-1.81 (m, 4H).
Compound 276
4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide
(971) ##STR00323##
(972) Following General Procedure D, the title compound (52 mg, 40%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide (126 mg, 0.20 mmol).
(973) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.11 (d, J=1.76 Hz, 1H), 7.86 (d, J=7.62 Hz, 1H), 7.72 (d, J=8.21 Hz, 2H), 7.29-7.49 (m, 3H), 7.20 (d, J=8.20 Hz, 2H), 7.08-7.16 (m, 1H), 3.87-4.03 (m, 4H), 3.44-3.80 (m, 6H), 2.26-2.48 (m, 2H), 2.00-2.22 (m, 2H).
Compound 277
4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide
(974) ##STR00324##
(975) Following General Procedure D, the title compound (53 mg, 40%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide (126 mg, 0.20 mmol).
(976) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.23 (d, J=1.76 Hz, 1H), 8.06 (dd, J=1.90, 8.35 Hz, 1H), 7.61-7.78 (m, 3H), 7.27 (s, 1H), 7.09 (d, J=8.20 Hz, 2H), 6.92 (d, J=8.50 Hz, 1H), 6.70 (dd, J=1.90, 8.35 Hz, 1H), 4.47 (d, J=12.89 Hz, 1H), 4.26 (d, J=12.89 Hz, 1H), 3.83-3.97 (m, 2H), 3.50-3.81 (m, 6H), 2.00-2.43 (m, 4H).
Compound 278
4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide
(977) ##STR00325##
(978) Following General Procedure L, the title compound (55 mg, 81%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide (70 mg, 0.11 mmol).
(979) .sup.1H NMR (600 MHz, CD.sub.3OD) δ 8.23 (d, J=2.05 Hz, 1H), 8.06 (dd, J=2.05, 8.22 Hz, 1H), 7.69-7.71 (m, 4H), 7.27 (d, J=2.05 Hz, 1H), 7.11 (d, J=8.22 Hz, 2H), 6.90 (d, J=8.51 Hz, 1H), 6.67 (dd, J=2.05, 8.22 Hz, 1H), 4.47 (d, J=12.91 Hz, 1H), 4.29 (s, 1H), 3.72 (t, J=5.72 Hz, 2H), 3.35-3.56 (m, 6H), 2.03-2.21 (m, 4H).
Compound 279
4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide
(980) ##STR00326##
(981) Following General Procedure D, the title compound (97 mg, 69%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide (130 mg, 0.21 mmol).
(982) .sup.1H NMR (600 MHz, acetone-d6) δ 8.41 (d, J=2.05 Hz, 1H), 8.19-8.29 (m, 1H), 7.95 (s, 1H), 7.57-7.75 (m, 3H), 7.34 (d, J=8.51 Hz, 1H), 7.26 (d, J=8.22 Hz, 2H), 6.47 (dd, J=2.05, 8.51 Hz, 1H), 4.96 (s, 2H), 3.87-4.01 (m, 2H), 3.65-3.80 (m, 4H), 3.53-3.64 (m, 2H), 2.24-2.39 (m, 2H), 2.07-2.16 (m, 2H).
Compound 280
4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)-N-[2-(pyrrolidin-1-yl)ethyl]benzamide
(983) ##STR00327##
(984) Following General Procedure L, the title compound (59 mg, 92%) was prepared from 4-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)-N-[2-(1-oxidopyrrolidin-1-yl)ethyl]benzamide (66 mg, 0.10 mmol).
(985) .sup.1H NMR (600 MHz, acetone-d6) δ 8.27 (d, J=2.05 Hz, 1H), 8.24 (t, J=5.72 Hz, 1H), 8.09 (dd, J=2.05, 8.22 Hz, 1H), 7.60-7.65 (m, 3H), 7.48 (d, J=2.05 Hz, 1H), 7.26 (d, J=8.51 Hz, 1H), 7.15 (d, J=8.51 Hz, 2H), 6.42 (dd, J=2.05, 8.51 Hz, 1H), 4.72 (s, 2H), 3.64-3.81 (m, 2H), 3.43-3.59 (m, 6H), 1.93-2.05 (m, 4H).
Intermediate 46
Methyl 2-(((2-amino-4-chlorophenyl)thio)methyl)benzoate
(986) ##STR00328##
(987) Following General Procedure A, the title compound (1.6 g, 84%) was prepared from 2-amino-4-chlorobenzenethiol (969 mg, 6.06 mmol), methyl 2-(bromomethyl)benzoate (1.4 g, 6.11 mmol) and K.sub.2CO.sub.3 (4.2 g, 30.55 mmol) in DMF (50 ml).
(988) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.90 (dd, J=1.47, 7.63 Hz, 1H), 7.27-7.41 (m, 2H), 6.95-7.01 (m, 2H), 6.67 (s, 1H), 6.48-6.56 (m, 1H), 4.41 (br. s., 2H), 4.27 (s, 2H), 3.88 (s, 3H).
Compound 281
Methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate
(989) ##STR00329##
(990) Following General Procedure B, the title compound (936 mg, 37%) was prepared from methyl 2-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (1.41 g, 4.56 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.3 g, 4.56 mmol) in pyridine (10 ml).
(991) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.12 (d, J=1.76 Hz, 1H), 7.86-8.00 (m, 2H), 7.76 (d, J=8.50 Hz, 1H), 7.50 (d, J=1.76 Hz, 1H), 7.27-7.45 (m, 2H), 6.94-7.18 (m, 3H), 4.21 (s, 2H), 3.86 (s, 3H).
Compound 282
2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic Acid
(992) ##STR00330##
(993) Following General Procedure Q, the title compound (405 mg, 94%) was prepared from methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino) phenyl]sulfanyl}methyl)benzoate (444 mg, 0.81 mmol).
(994) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.08 (d, J=1.47 Hz, 1H), 7.82-8.01 (m, 2H), 7.75 (d, J=8.20 Hz, 1H), 7.49 (d, J=2.05 Hz, 1H), 7.27-7.38 (m, 2H), 7.20 (d, J=8.50 Hz, 1H), 7.04-7.15 (m, 1H), 6.88-6.99 (m, 1H), 4.21 (s, 2H).
Compound 283
Methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoate
(995) ##STR00331##
(996) Following General Procedure C, the title compound (88 mg, 71%) was prepared from methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate (120 mg, 0.22 mmol).
(997) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.12 (d, J=2.05 Hz, 1H), 7.90-8.06 (m, 2H), 7.83 (d, J=8.50 Hz, 1H), 7.38-7.54 (m, 2H), 6.97-7.35 (m, 4H), 4.61-4.82 (m, 2H), 3.83 (s, 3H).
Compound 284
2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic Acid
(998) ##STR00332##
(999) Following General Procedure Q, the title compound (30 mg, 23%) was prepared from methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoate (128 mg, 0.24 mmol).
(1000) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.12-8.28 (m, 2H), 8.00 (d, J=8.21 Hz, 1H), 7.57-7.68 (m, 2H), 7.50 (t, J=5.71 Hz, 2H), 7.03-7.24 (m, 3H), 4.80 (d, J=11.43 Hz, 1H), 4.44 (d, J=11.14 Hz, 1H).
Compound 285
Methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoate
(1001) ##STR00333##
(1002) Following General Procedure D, the title compound (88 mg, 78%) was prepared from methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate (107 mg, 0.20 mmol).
(1003) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 8.30 (d, J=2.05 Hz, 1H), 8.07-8.20 (m, 1H), 7.94 (d, J=8.50 Hz, 1H), 7.81 (d, J=6.74 Hz, 1H), 7.35-7.58 (m, 3H), 7.29-7.24 (m, 3H), 5.28 (s, 2H), 3.70 (s, 3H).
Compound 286
2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic Acid
(1004) ##STR00334##
(1005) Following General Procedure Q, the title compound (67 mg, 50%) was prepared from methyl 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoate (125 mg, 0.23 mmol).
(1006) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.41 (d, J=2.05 Hz, 1H), 8.30 (dd, J=2.05, 8.50 Hz, 1H), 7.76 (dd, J=1.03, 7.77 Hz, 1H), 7.76 (dd, J=1.03, 7.77 Hz, 1H), 7.68 (d, J=8.50 Hz, 1H), 7.52 (d, J=8.50 Hz, 1H), 7.29 (td, J=1.17, 7.62 Hz, 1H), 7.16 (td, J=1.47, 7.47 Hz, 1H), 7.00 (d, J=7.62 Hz, 1H), 6.67 (dd, J=1.90, 8.64 Hz, 1H), 5.31 (s, 2H).
Compound 287
2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzamide
(1007) ##STR00335##
(1008) A mixture of 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (156 mg, 0.29 mmol), HOBT (59 mg, 0.44 mmol), EDC (84 mg, 0.44 mmol), and NH.sub.3—H.sub.2O (28-30% NH.sub.3 basis, 2×4 ml, excess) in DMF (3 ml) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (40˜100% EtOAc in hexane) to yield the title compound (69 mg, 45%).
(1009) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.09 (d, J=2.05 Hz, 1H), 7.97 (s, 1H), 7.94 (dd, J=2.34, 8.50 Hz, 1H), 7.75 (d, J=8.50 Hz, 1H), 7.48-7.53 (m, 1H), 7.44 (d, J=2.34 Hz, 1H), 7.22-7.34 (m, 3H), 7.09 (dd, J=2.34, 8.50 Hz, 1H), 6.90-6.99 (m, 1H), 4.10 (s, 2H).
Compound 288
2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N,N-dimethylbenzamide
(1010) ##STR00336##
(1011) A mixture of 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (304 mg, 0.57 mmol), DMAP (138 mg, 1.13 mmol), EDC (217 mg, 1.13 mmol), and dimethylamine hydrochloride (93 mg, 1.13 mmol) in CH.sub.2Cl.sub.2 (3 ml) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0˜30% EtOAc in hexane) to yield the title compound (122 mg, 38%).
(1012) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 8.21 (d, J=2.05 Hz, 1H), 7.84 (dd, J=2.20, 8.35 Hz, 1H), 7.52 (d, J=8.50 Hz, 1H), 7.45 (d, J=2.34 Hz, 1H), 7.33 (d, J=8.20 Hz, 1H), 7.16-7.27 (m, 2H), 7.10 (td, J=2.05, 7.18 Hz, 1H), 7.03 (dd, J=2.34, 8.50 Hz, 1H), 6.74 (d, J=7.33 Hz, 1H), 3.77 (s, 2H), 3.18 (s, 3H), 2.85 (s, 3H).
Compound 289
2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)-N-ethylbenzamide
(1013) ##STR00337##
(1014) A mixture of 2-({[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid (394 mg, 0.74 mmol), HOBT (199 mg, 1.47 mmol), EDC (211 mg, 1.47 mmol), ethylamine hydrochloride (119 mg, 1.47 mmol) in DMF (3 ml) was stirred at room temperature overnight. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0-30% EtOAc in hexane) to yield the title compound (100 mg, 24%).
(1015) .sup.1H NMR (300 MHz, acetone-d6) δ 8.29 (d, J=2.05 Hz, 1H), 8.10 (dd, J=2.34, 8.50 Hz, 1H), 7.87 (d, J=8.50 Hz, 1H), 7.75 (br. s., 1H), 7.43-7.52 (m, 3H), 7.22-7.34 (m, 2H), 7.14 (dd, J=2.20, 8.35 Hz, 1H), 7.03-7.10 (m, 1H), 4.17 (s, 2H), 3.50 (qd, J=5.86, 7.23 Hz, 2H), 1.25 (t, J=7.18 Hz, 3H).
Intermediate 47
3-Bromo-N,N-diethylpropanamide
(1016) ##STR00338##
(1017) A mixture of 3-bromopropanoyl chloride (1.0 g, 5.8 mmol) and diethylamine (1.9 g, 26 mmol) in THF (20 ml) was stirred at 0° C. for 30 min, the resulting white solid was filtered and the filtrate was concentrated to give a crude oil which was used in the next reaction without further purification.
(1018) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 3.67 (t, J=7.18 Hz, 2H), 3.39 (q, J=7.13 Hz, 2H), 3.31 (q, J=7.33 Hz, 2H), 2.89 (t, J=7.18 Hz, 2H), 1.19 (t, J=7.18 Hz, 3H), 1.12 (t, J=7.18 Hz, 3H).
Intermediate 48
3-((2-amino-4-chlorophenyl)thio)-N,N-diethylpropanamide
(1019) ##STR00339##
(1020) Following General Procedure A, the title compound (1.0 g, 88%) was prepared from 2-amino-4-chlorobenzenethiol (660 mg, 4.13 mmol), crude 3-bromo-N,N-diethylpropanamide (860 mg, 6.60 mmol) and K.sub.2CO.sub.3 (2.9 g, 20.67 mmol) in DMF (20 ml).
(1021) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 7.28 (d, J=8.20 Hz, 1H), 6.70 (d, J=2.34 Hz, 1H), 6.62 (dd, J=2.20, 8.06 Hz, 1H), 4.55 (br. s., 2H), 3.36 (q, J=7.03 Hz, 2H), 3.22 (q, J=7.33 Hz, 2H), 3.02 (t, J=7.18 Hz, 2H), 2.52 (t, J=7.18 Hz, 2H), 0.99-1.18 (m, 6H).
Compound 290
3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N,N-diethylpropanamide
(1022) ##STR00340##
(1023) Following General Procedure B, the title compound (999 mg, 85%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-N,N-diethylpropanamide (635 mg, 2.22 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (619 mg, 2.22 mmol) in pyridine (6 ml).
(1024) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 8.25 (d, J=1.76 Hz, 1H), 7.86 (dd, J=2.34, 8.50 Hz, 1H), 7.70 (s, 1H), 7.54 (d, J=8.21 Hz, 1H), 7.39 (d, J=8.50 Hz, 1H), 7.05 (dd, J=2.34, 8.20 Hz, 1H), 3.48 (q, J=7.03 Hz, 2H), 3.28 (q, J=7.23 Hz, 2H), 2.88 (t, J=6.30 Hz, 2H), 2.47 (t, J=6.30 Hz, 2H), 0.97-1.29 (m, 6H).
Compound 291
3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}-N,N-diethylpropanamide
(1025) ##STR00341##
(1026) Following General Procedure C, the title compound (272 mg, 61%) was prepared from 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N,N-diethylpropanamide (430 mg, 0.81 mmol).
(1027) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.21 (d, J=2.05 Hz, 1H), 7.89 (dd, J=2.05, 8.50 Hz, 1H), 7.67 (d, J=1.76 Hz, 1H), 7.58 (d, J=8.50 Hz, 1H), 7.47 (d, J=8.50 Hz, 1H), 7.21 (dd, J=1.90, 8.35 Hz, 1H), 3.44 (q, J=7.23 Hz, 2H), 3.33 (q, J=7.03 Hz, 2H), 3.12-3.25 (m, 1H), 2.95-3.08 (m, 1H), 2.85-2.94 (m, 1H), 2.64-2.77 (m, 1H), 1.11-1.24 (m, 6H)
Compound 292
3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}-N,N-diethylpropanamide
(1028) ##STR00342##
(1029) Following General Procedure D, the title compound (300 mg, 79%) was prepared from 3-{[4-chloro-2-({[4-chloro-3-(trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}-N,N-diethylpropanamide (357 mg, 0.68 mmol).
(1030) .sup.1H NMR (300 MHz, CDCl.sub.3) δ 8.26 (d, J=2.34 Hz, 1H), 8.01 (dd, J=2.34, 8.50 Hz, 1H), 7.70-7.78 (m, 2H), 7.65 (d, J=8.50 Hz, 1H), 7.18 (dd, J=1.90, 8.64 Hz, 1H), 3.43 (t, J=6.89 Hz, 2H), 3.24-3.39 (m, 4H), 2.79 (t, J=7.03 Hz, 2H), 1.19 (t, J=7.18 Hz, 3H), 1.08 (t, J=7.03 Hz, 3H).
Intermediate 49
3-((2-amino-4-chlorophenyl)thio)-1-(pyrrolidin-1-yl)propan-1-one
(1031) ##STR00343##
(1032) To a solution of K.sub.2CO.sub.3 (3.6 g, 26 mmol) in THF (20 ml) was added pyrrolidine (2.1 ml, 26 mmol) at room temperature, then the mixture was cooled to −78° C. and 3-bromopropanoyl chloride (1.0 g, 5.83 mmol) was added slowly. After it was stirred for 30 min, 2-amino-4-chlorobenzenethiol (837 mg, 5.24 mmol) was added to the mixture and the reaction was stirred at room temperature for 3 hours. The mixture was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0˜30% EtOAc in hexane) to yield the title compound (760 mg, 46%).
(1033) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 7.28 (d, J=8.21 Hz, 1H), 6.70 (d, J=2.34 Hz, 1H), 6.61 (dd, J=2.34, 8.21 Hz, 1H), 4.58 (br. s., 2H), 3.45 (t, J=6.74 Hz, 2H), 3.32 (t, J=6.74 Hz, 2H), 3.02 (t, J=7.03 Hz, 2H), 2.47 (t, J=7.03 Hz, 2H), 1.76-2.01 (m, 4H).
Compound 293
4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1-yl)propyl]sulfanyl}phenyl)-3-(trifluoromethyl)benzenesulfonamide
(1034) ##STR00344##
(1035) Following General Procedure B, the title compound (242 mg, 17%) was prepared from 3-((2-amino-4-chlorophenyl)thio)-1-(pyrrolidin-1-yl)propan-1-one (758 mg, 2.67 mmol) and 4-chloro-3-(trifluoromethyl)benzene-1-sulfonyl chloride (745 mg, 2.67 mmol) in pyridine (10 ml).
(1036) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 9.52 (br. s., 1H), 8.25 (d, J=2.05 Hz, 1H), 7.87 (dd, J=2.20, 8.35 Hz, 1H), 7.67 (d, J=2.34 Hz, 1H), 7.54 (d, J=8.21 Hz, 1H), 7.37 (s, 1H), 7.04 (dd, J=2.20, 8.35 Hz, 1H), 3.56 (t, J=6.89 Hz, 2H), 3.35 (t, J=6.74 Hz, 2H), 2.88 (t, J=6.15 Hz, 2H), 2.40 (t, J=6.30 Hz, 2H), 1.75-2.08 (m, 4H).
Compound 294
4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1-yl)propyl]sulfinyl}phenyl)-3-(trifluoromethyl)benzenesulfonamide
(1037) ##STR00345##
(1038) Following General Procedure C, the title compound (91 mg, 78%) was prepared from 4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1-yl)propyl]sulfanyl}phenyl)-3-(trifluoromethyl)benzenesulfonamide (113 mg, 0.21 mmol).
(1039) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.12 (d, J=2.05 Hz, 1H), 7.98 (dd, J=2.05, 8.50 Hz, 1H), 7.78 (d, J=8.50 Hz, 1H), 7.64 (d, J=8.50 Hz, 1H), 7.33 (dd, J=1.90, 8.35 Hz, 1H), 7.26 (d, J=2.05 Hz, 1H), 3.26-3.55 (m, 5H), 3.07-3.22 (m, 1H), 2.71-2.87 (m, 1H), 2.50-2.69 (m, 1H), 1.82-2.05 (m, 4H).
Compound 295
4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1-yl)propyl]sulfonyl}phenyl)-3-(trifluoromethyl)benzenesulfonamide
(1040) ##STR00346##
(1041) Following General Procedure D, the title compound (76 mg, 94%) was prepared from 4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1-yl)propyl]sulfanyl}phenyl)-3-(trifluoromethyl)benzenesulfonamide (68 mg, 0.13 mmol).
(1042) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.30 (d, J=2.05 Hz, 1H), 8.12 (dd, J=2.20, 8.35 Hz, 1H), 7.61-7.72 (m, 2H), 7.48 (d, J=2.05 Hz, 1H), 6.75 (dd, J=2.05, 8.50 Hz, 1H), 3.93 (t, J=7.62 Hz, 2H), 3.34-3.46 (m, 4H), 2.63 (t, J=7.62 Hz, 2H), 1.72-2.04 (m, 4H).
Compound 296
Methyl 2-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)benzoate
(1043) ##STR00347##
(1044) Following General Procedure B, the title compound (277 mg, 58%) was prepared from methyl 2-(((2-amino-4-chlorophenyl)thio)methyl)benzoate (300 mg, 0.98 mmol) and benzofuran-2-sulfonyl chloride (211 mg, 0.98 mmol) in pyridine (3 ml).
(1045) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.85 (dd, J=3.81, 5.57 Hz, 1H), 7.66-7.77 (m, 1H), 7.54 (d, J=2.05 Hz, 1H), 7.41-7.52 (m, 3H), 7.30-7.39 (m, 1H), 7.21-7.29 (m, 2H), 6.97-7.12 (m, 2H), 6.81 (dd, J=3.52, 5.57 Hz, 1H), 4.22 (s, 2H), 3.84 (s, 3H).
Compound 297
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]benzoic Acid
(1046) ##STR00348##
(1047) Following General Procedure Q, the title compound (247 mg, 92%) was prepared from Methyl 2-(((2-(benzofuran-2-sulfonamido)-4-chlorophenyl)thio)methyl)benzoate (277 mg, 0.57 mmol).
(1048) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.89 (dd, J=1.76, 7.33 Hz, 1H), 7.72 (ddd, J=1.03, 1.17, 7.77 Hz, 1H), 7.53 (d, J=2.34 Hz, 1H), 7.50-7.52 (m, 1H), 7.48 (dd, J=1.17, 7.03 Hz, 1H), 7.46 (d, J=0.88 Hz, 1H), 7.31-7.37 (m, 1H), 7.17-7.29 (m, 2H), 7.09-7.14 (m, 1H), 6.97-7.07 (m, 1H), 6.70 (dd, J=1.61, 7.18 Hz, 1H), 4.23 (s, 2H).
Compound 298
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]benzoic Acid
(1049) ##STR00349##
(1050) Following General Procedure C, the title compound (78 mg, 92%) was prepared from 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]benzoic acid (82 mg, 0.17 mmol).
(1051) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.96-8.09 (m, 1H), 7.73 (d, J=7.91 Hz, 1H), 7.28-7.62 (m, 7H), 7.13-7.26 (m, 2H), 6.87-6.99 (m, 1H), 4.77 (d, J=12.31 Hz, 1H), 4.67 (d, J=12.31 Hz, 1H).
Compound 299
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]benzoic Acid
(1052) ##STR00350##
(1053) Following General Procedure D, the title compound (68 mg, 83%) was prepared from 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]benzoic acid (77 mg, 0.16 mmol).
(1054) .sup.1H NMR (300 MHz, acetone-d6) δ 7.98-8.06 (m, 1H), 7.81-7.86 (m, 2H), 7.80 (d, J=2.05 Hz, 1H), 7.60-7.65 (m, 1H), 7.45-7.56 (m, 4H), 7.35-7.43 (m, 1H), 7.14-7.31 (m, 2H), 5.32 (s, 2H).
Intermediate 50
2-amino-4-fluorobenzenethiol
(1055) ##STR00351##
(1056) Following General Procedure K, the title compound (1.4 g, 84%) was prepared from 5-fluoro-2-methylbenzo[d]thiazole (1.8 g, 10.8 mmol).
(1057) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 6.83 (dd, J=5.42, 8.06 Hz, 1H), 6.22-6.36 (m, 2H).
Intermediate 51
methyl 2-(((2-amino-4-fluorophenyl)thio)methyl)benzoate
(1058) ##STR00352##
(1059) Following General Procedure A, the title compound (1.8 g, 60%) was prepared from 2-amino-4-fluorobenzenethiol (1.4 g, 9.79 mmol) and methyl 2-(bromomethyl)benzoate (2.2 g, 9.79 mmol), K.sub.2CO.sub.3 (4.0 g, 29.4 mmol) in DMF (50 ml).
(1060) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.83 (dd, J=1.76, 7.33 Hz, 1H), 7.30 (td, J=1.76, 6.74 Hz, 2H), 6.97 (dd, J=1.61, 7.18 Hz, 1H), 6.86 (dd, J=6.45, 8.50 Hz, 1H), 6.42 (dd, J=2.64, 11.14 Hz, 1H), 6.13 (td, J=2.64, 8.50 Hz, 1H), 4.24 (s, 2H), 3.86 (s, 3H).
Compound 300
methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate
(1061) ##STR00353##
(1062) Following General Procedure B, the title compound (1.6 g, 55%) was prepared from methyl 2-(((2-amino-4-fluorophenyl)thio)methyl)benzoate (1.8 g, 6.19 mmol) and benzofuran-2-sulfonyl chloride (1.3 g, 6.19 mmol) in pyridine (10 ml).
(1063) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.80-7.89 (m, 1H), 7.72 (d, J=7.62 Hz, 1H), 7.42-7.57 (m, 3H), 7.30-7.39 (m, 2H), 7.19-7.28 (m, 2H), 7.10 (dd, J=6.30, 8.64 Hz, 1H), 6.66-6.78 (m, 2H), 4.18 (s, 2H), 3.85 (s, 3H).
Compound 301
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoic Acid
(1064) ##STR00354##
(1065) Following General Procedure Q, the title compound (130 mg, 99%) was prepared from methyl 2-(((2-(benzofuran-2-sulfonamido)-4-fluorophenyl)thio)methyl)benzoate (137 mg, 0.29 mmol).
(1066) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.91 (dd, J=1.61, 7.47 Hz, 1H), 7.70 (d, J=7.91 Hz, 1H), 7.04-7.55 (m, 8H), 6.73 (td, J=2.78, 8.42 Hz, 1H), 6.56-6.66 (m, 1H), 4.19 (s, 2H).
Compound 302
methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoate
(1067) ##STR00355##
(1068) Following General Procedure C, the title compound (416 mg, 85%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate (476 mg, 1.01 mmol).
(1069) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.92-8.00 (m, 1H), 7.75 (d, J=7.91 Hz, 1H), 7.31-7.64 (m, 6H), 7.26 (dd, J=2.34, 10.26 Hz, 1H), 7.16 (dd, J=5.86, 8.79 Hz, 1H), 6.93-7.01 (m, 2H), 4.82 (d, J=12.31 Hz, 1H), 4.70 (d, J=12.31 Hz, 1H), 3.85 (s, 3H).
Compound 303
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoic Acid
(1070) ##STR00356##
(1071) Following General Procedure Q, the title compound (276 mg, 90%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoate (315 mg, 0.65 mmol).
(1072) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 8.05 (dd, J=1.76, 7.33 Hz, 1H), 7.74 (d, J=7.91 Hz, 1H), 7.27-7.66 (m, 7H), 7.20 (dd, J=6.15, 8.79 Hz, 1H), 6.78-7.02 (m, 2H), 4.63-4.80 (m, 2H).
Compound 304
methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoate
(1073) ##STR00357##
(1074) Following General Procedure D, the title compound (386 mg, 86%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate (422 mg, 0.90 mmol).
(1075) .sup.1H NMR (300 MHz, DMSO-d.sub.6) δ 7.71-7.82 (m, 3H), 7.65 (d, J=8.20 Hz, 1H), 7.27-7.52 (m, 6H), 7.15 (d, J=7.33 Hz, 1H), 6.89 (t, J=8.20 Hz, 1H), 5.33 (s, 2H), 3.72 (s, 3H).
Compound 305
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoic Acid
(1076) ##STR00358##
(1077) Following General Procedure Q, the title compound (254 mg, 94%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoate (278 mg, 0.55 mmol).
(1078) .sup.1H NMR (300 MHz, CD.sub.3OD) δ 7.91 (d, J=9.08 Hz, 1H), 7.76 (d, J=7.91 Hz, 1H), 7.72 (s, 1H), 7.45-7.61 (m, 4H), 7.31-7.43 (m, 3H), 7.08 (d, J=8.79 Hz, 1H), 6.83-6.97 (m, 1H), 5.19 (s, 2H).
Intermediate 52
methyl 3-(((2-amino-4-fluorophenyl)thio)methyl)benzoate
(1079) ##STR00359##
(1080) Following General Procedure A, the title compound (750 mg, 88%) was prepared from 2-amino-4-fluorobenzenethiol (417 mg, 2.92 mmol) and methyl 3-(bromomethyl)benzoate (666 mg, 2.92 mmol), K.sub.2CO.sub.3 (1.21 g, 8.75 mmol) in DMF (10 ml).
(1081) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.89 (d, J=7.92 Hz, 1H), 7.80 (s, 1H), 7.28-7.32 (m, 1H), 7.22-7.25 (m, 1H), 7.06 (dd, J=6.46, 8.51 Hz, 1H), 6.39 (dd, J=2.64, 10.56 Hz, 1H), 6.29 (td, J=2.64, 8.51 Hz, 1H), 4.41 (br. s., 2H), 3.91 (s, 3H), 3.86 (s, 2H).
Compound 306
methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate
(1082) ##STR00360##
(1083) Following General Procedure B, the title compound (601 mg, 50%) was prepared from methyl 3-(((2-amino-4-fluorophenyl)thio)methyl)benzoate (750 mg, 2.58 mmol) and benzofuran-2-sulfonyl chloride (556 mg, 2.58 mmol) in pyridine (5 ml).
(1084) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 8.23 (s, 1H), 7.86 (dt, J=1.36, 7.85 Hz, 1H), 7.62-7.70 (m, 2H), 7.50 (d, J=0.88 Hz, 1H), 7.46-7.49 (m, 1H), 7.39-7.46 (m, 2H), 7.32 (ddd, J=1.03, 7.12, 8.00 Hz, 1H), 7.22-7.26 (m, 1H), 7.02-7.10 (m, 2H), 6.57-6.63 (m, 1H), 3.88 (s, 3H), 3.79 (s, 2H).
Compound 307
3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoic Acid
(1085) ##STR00361##
(1086) Following General Procedure Q, the title compound (223 mg, 79%) was prepared from methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate (291 mg, 0.62 mmol).
(1087) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 8.23 (s, 1H), 7.91 (ddd, J=1.32, 1.47, 7.78 Hz, 1H), 7.64-7.70 (m, 2H), 7.51 (d, J=1.17 Hz, 1H), 7.47-7.50 (m, 1H), 7.40-7.45 (m, 2H), 7.32 (ddd, J=1.03, 7.12, 8.00 Hz, 1H), 7.28 (t, J=7.78 Hz, 1H), 7.12 (d, J=7.92 Hz, 1H), 7.08 (dd, J=6.16, 8.80 Hz, 1H), 6.56-6.66 (m, 1H), 3.80 (s, 2H).
Compound 308
methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoate
(1088) ##STR00362##
(1089) Following General Procedure C, the title compound (120 mg, 96%) was prepared methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate (120 mg, 0.26 mmol).
(1090) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 10.92 (br. s., 1H), 7.94 (d, J=7.92 Hz, 1H), 7.68 (d, J=7.63 Hz, 1H), 7.56-7.60 (m, 1H), 7.44-7.48 (m, 1H), 7.36-7.42 (m, 2H), 7.27-7.33 (m, 2H), 7.26 (t, J=3.81 Hz, 1H), 7.10 (d, J=7.63 Hz, 1H), 6.72 (dd, J=5.72, 8.66 Hz, 1H), 6.60 (td, J=2.05, 8.07 Hz, 1H), 4.44 (d, J=12.62 Hz, 1H), 4.31 (d, J=12.62 Hz, 1H), 3.86 (s, 3H).
Compound 309
3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoic Acid
(1091) ##STR00363##
(1092) Following General Procedure Q, the title compound (33 mg, 48%) was prepared from methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoate (74 mg, 0.15 mmol).
(1093) .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.82 (d, J=7.34 Hz, 1H), 7.76 (d, J=7.92 Hz, 1H), 7.68 (d, J=7.92 Hz, 1H), 7.59-7.64 (m, 2H), 7.50 (t, J=7.78 Hz, 1H), 7.32-7.38 (m, 2H), 7.08-7.26 (m, 3H), 7.00 (dd, J=2.05, 10.27 Hz, 1H), 4.39 (d, J=12.91 Hz, 1H), 4.08 (d, J=12.91 Hz, 1H).
Compound 310
methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoate
(1094) ##STR00364##
(1095) Following General Procedure D, the title compound (125 mg, 94%) was prepared from methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate (125 mg, 0.27 mmol).
(1096) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 9.44 (br. s., 1H), 7.98 (dd, J=1.17, 7.63 Hz, 1H), 7.70 (d, J=7.92 Hz, 1H), 7.60 (s, 1H), 7.58 (s, 1H), 7.54 (dd, J=2.20, 10.42 Hz, 1H), 7.41-7.49 (m, 3H), 7.29-7.36 (m, 2H), 7.17 (d, J=7.63 Hz, 1H), 6.68-6.79 (m, 1H), 4.37 (s, 2H), 3.86 (s, 3H).
Compound 311
3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoic Acid
(1097) ##STR00365##
(1098) Following General Procedure Q, the title compound (87 mg, 94%) was prepared from methyl 3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoate (94 mg, 0.19 mmol).
(1099) .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.81 (td, J=1.61, 4.47 Hz, 1H), 7.73-7.78 (m, 2H), 7.60-7.66 (m, 2H), 7.51-7.57 (m, 1H), 7.45 (t, J=7.78 Hz, 1H), 7.34 (t, J=7.48 Hz, 1H), 7.29-7.31 (m, 2H), 7.27 (dd, J=2.49, 11.59 Hz, 1H), 6.91 (s, 1H), 4.93 (s, 2H).
Intermediate 53
methyl 4-(((2-amino-4-fluorophenyl)thio)methyl)benzoate
(1100) ##STR00366##
(1101) Following General Procedure A, the title compound (873 mg, 94%) was prepared from 2-amino-4-fluorobenzenethiol (456 mg, 3.19 mmol) and methyl 4-(bromomethyl)benzoate (731 mg, 3.19 mmol), K.sub.2CO.sub.3 (1.32 g, 9.58 mmol) in DMF (20 ml).
(1102) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.89 (d, J=8.22 Hz, 2H), 7.12 (d, J=8.22 Hz, 2H), 7.03 (dd, J=6.46, 8.51 Hz, 1H), 6.38 (dd, J=2.64, 10.56 Hz, 1H), 6.27 (td, J=2.64, 8.51 Hz, 1H), 4.36 (br. s., 2H), 3.90 (s, 3H), 3.83 (s, 2H).
Compound 312
methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate
(1103) ##STR00367##
(1104) Following General Procedure B, the title compound (929 mg, 66%) was prepared from methyl 4-(((2-amino-4-fluorophenyl)thio)methyl)benzoate (873 g, 2.99 mmol) and benzofuran-2-sulfonyl chloride (646 mg, 2.99 mmol) in pyridine (5 ml).
(1105) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 8.25 (br. s., 1H), 7.80-7.88 (m, 2H), 7.68 (dt, J=1.03, 7.92 Hz, 1H), 7.51 (d, J=1.17 Hz, 1H), 7.39-7.49 (m, 3H), 7.31-7.35 (m, 1H), 7.01 (dd, J=6.16, 8.51 Hz, 1H), 6.96 (d, J=8.22 Hz, 2H), 6.49-6.63 (m, 1H), 3.89 (s, 3H), 3.77 (s, 2H).
Compound 313
4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoic Acid
(1106) ##STR00368##
(1107) Following General Procedure Q, the title compound (516 mg, 86%) was prepared from methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate (620 mg, 1.32 mmol).
(1108) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 8.25 (s, 1H), 7.91 (d, J=8.51 Hz, 2H), 7.69 (s, 1H), 7.40-7.54 (m, 4H), 7.33 (dd, J=0.88, 14.97 Hz, 1H), 7.03 (dd, J=6.16, 8.51 Hz, 1H), 6.99 (d, J=8.51 Hz, 2H), 6.60 (td, J=2.64, 8.22 Hz, 1H), 3.79 (s, 2H).
Compound 314
methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoate
(1109) ##STR00369##
(1110) Following General Procedure C, the title compound (55 mg, 44%) was prepared from methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate (120 mg, 0.26 mmol).
(1111) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 10.83 (br. s., 1H), 7.21-7.92 (m, 8H), 6.90 (s, 2H), 6.60 (s, 1H), 6.50 (s, 1H), 4.16-4.61 (m, 2H), 3.82 (s, 3H).
Compound 315
4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoic Acid
(1112) ##STR00370##
(1113) Following General Procedure Q, the title compound (48 mg, 100%) was prepared from methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfinyl)methyl]benzoate (50 mg, 0.103 mmol).
(1114) .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.74-7.80 (m, 3H), 7.69 (d, J=8.51 Hz, 1H), 7.62 (s, 1H), 7.50 (t, J=7.63 Hz, 1H), 7.37 (t, J=7.48 Hz, 1H), 7.19-7.25 (m, 1H), 7.09-7.15 (m, 1H), 7.07 (d, J=7.63 Hz, 2H), 6.99 (d, J=10.27 Hz, 1H), 4.39 (d, J=12.91 Hz, 1H), 4.11 (d, J=12.91 Hz, 1H).
Compound 316
methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoate
(1115) ##STR00371##
(1116) Following General Procedure D, the title compound (92 mg, 71%) was prepared from methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfanyl)methyl]benzoate (121 mg, 0.26 mmol).
(1117) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.88 (d, J=8.22 Hz, 2H), 7.71 (d, J=7.92 Hz, 1H), 7.61 (s, 1H), 7.52-7.57 (m, 1H), 7.42-7.51 (m, 2H), 7.31-7.40 (m, 2H), 7.03 (d, J=8.22 Hz, 2H), 6.67-6.76 (m, 1H), 4.39 (s, 2H), 3.90 (s, 3H).
Compound 317
4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoic Acid
(1118) ##STR00372##
(1119) Following General Procedure Q, the title compound (80 mg, 91%) was prepared from methyl 4-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-fluorophenyl}sulfonyl)methyl]benzoate (90 mg, 0.179 mmol).
(1120) .sup.1H NMR (600 MHz, DMSO-d.sub.6) δ 7.77 (d, J=7.92 Hz, 1H), 7.74 (d, J=8.22 Hz, 2H), 7.66 (s, 1H), 7.64 (d, J=8.51 Hz, 1H), 7.50-7.53 (m, 1H), 7.46 (t, J=7.78 Hz, 1H), 7.35 (t, J=7.63 Hz, 1H), 7.25-7.31 (m, 1H), 7.20 (d, J=8.22 Hz, 2H), 6.80-6.96 (m, 1H), 4.93 (s, 2H).
Intermediate 54
Methyl 2-(((2-aminophenyl)thio)methyl)benzoate
(1121) ##STR00373##
(1122) Following General Procedure A, the title compound (1.7 g, 74%) was prepared from 2-aminobenzenethiol (1.1 g, 8.47 mmol), methyl 2-(bromomethyl)benzoate (1.9 g, 8.47 mmol), and K.sub.2CO.sub.3 (3.5 g, 25.4 mmol) in DMF (50 ml).
(1123) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 7.90 (dd, J=1.90, 7.18 Hz, 1H), 7.22-7.35 (m, 2H), 7.07-7.12 (m, 2H), 6.94-7.01 (m, 1H), 6.68 (d, J=7.62 Hz, 1H), 6.57 (td, J=1.17, 7.47 Hz, 1H), 4.33 (br. s., 2H), 4.30 (s, 2H), 3.88 (s, 3H).
Compound 318
methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfanyl)methyl]benzoate
(1124) ##STR00374##
(1125) Following General Procedure B, the title compound (803 mg, 74%) was prepared from methyl 2-(((2-aminophenyl)thio)methyl)benzoate (652 mg, 2.39 mmol) and benzofuran-2-sulfonyl chloride (816 mg, 3.78 mmol) in pyridine (10 ml).
(1126) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 8.36 (s, 1H), 7.89-8.02 (m, 1H), 7.63 (t, J=7.62 Hz, 2H), 7.36-7.49 (m, 3H), 7.24-7.33 (m, 4H), 7.20 (dd, J=1.32, 7.77 Hz, 1H), 6.86-7.00 (m, 1H), 6.79 (d, J=5.86 Hz, 1H), 4.25 (s, 2H), 3.93 (s, 3H).
Compound 319
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfanyl)methyl]benzoic Acid
(1127) ##STR00375##
(1128) Following General Procedure Q, the title compound (220 mg, 99%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfanyl)methyl]benzoate (227 mg, 0.50 mmol).
(1129) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 8.52 (s, 1H), 8.03-8.17 (m, 1H), 7.64 (dd, J=8.06, 13.63 Hz, 2H), 7.17-7.52 (m, 8H), 6.91-7.01 (m, 1H), 6.83-6.90 (m, 1H), 4.29 (s, 2H).
Compound 320
methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfinyl)methyl]benzoate
(1130) ##STR00376##
(1131) Following General Procedure C, the title compound (182 mg, 77%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfanyl)methyl]benzoate (228 mg, 0.50 mmol).
(1132) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 7.99-8.15 (m, 1H), 7.76 (dd, J=0.88, 8.50 Hz, 1H), 7.58-7.67 (m, 1H), 7.48 (d, J=0.88 Hz, 1H), 7.33-7.45 (m, 5H), 7.21-7.30 (m, 1H), 7.14-7.20 (m, 1H), 6.99-7.12 (m, 2H), 4.82 (d, J=11.72 Hz, 1H), 4.57 (d, J=12.01 Hz, 1H), 3.91 (s, 3H).
Compound 321
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfinyl)methyl]benzoic Acid
(1133) ##STR00377##
(1134) Following General Procedure Q, the title compound (145 mg, 96%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfinyl)methyl]benzoate (155 mg, 0.33 mmol).
(1135) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 10.37 (br.s, 1H), 8.11-8.26 (m, 1H), 7.76 (d, J=8.50 Hz, 1H), 7.64 (d, J=7.62 Hz, 1H), 7.35-7.52 (m, 4H), 7.23-7.33 (m, 4H), 7.06-7.18 (m, 2H), 4.88 (d, J=12.01 Hz, 1H), 4.52 (d, J=12.01 Hz, 1H).
Compound 322
methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfonyl)methyl]benzoate
(1136) ##STR00378##
(1137) Following General Procedure D, the title compound (201 mg, 63%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfanyl)methyl]benzoate (300 mg, 0.66 mmol).
(1138) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 7.85-7.94 (m, 1H), 7.76 (d, J=8.50 Hz, 1H), 7.65 (d, J=7.62 Hz, 1H), 7.35-7.57 (m, 7H), 7.24-7.33 (m, 1H), 7.10-7.18 (m, 1H), 6.98-7.08 (m, 1H), 5.10 (s, 2H), 3.75 (s, 3H).
Compound 323
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfonyl)methyl]benzoic Acid
(1139) ##STR00379##
(1140) Following General Procedure Q, the title compound (154 mg, 87%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]phenyl}sulfonyl)methyl]benzoate (182 mg, 0.38 mmol).
(1141) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 8.06 (dd, J=1.76, 7.33 Hz, 1H), 7.77 (d, J=8.50 Hz, 1H), 7.67 (d, J=7.33 Hz, 1H), 7.39-7.60 (m, 7H), 7.28-7.37 (m, 2H), 7.03-7.14 (m, 1H), 5.13 (s, 2H).
Intermediate 55
Methyl 2-(((4-methyl-2-nitrophenyl)thio)methyl)benzoate
(1142) ##STR00380##
(1143) To a solution of 1-fluoro-4-methyl-2-nitrobenzene (1.35 g, 8.70 mmol) in DMF (20 ml) was added Na.sub.2S.9H.sub.2O (2.09 g, 8.70 mmol) and the reaction was stirred at room temperature for 16 hours, then methyl 2-(bromomethyl)benzoate (1.99 g, 8.70 mmol) and K.sub.2CO.sub.3 (6.0 g, 43.52 mmol) was added and the reaction was continued for 3 hours, diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0˜20% EtOAc in hexane) to yield the title compound (741 mg, 27%).
(1144) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.91-8.02 (m, 2H), 7.42-7.52 (m, 2H), 7.29-7.39 (m, 3H), 4.66 (s, 2H), 3.90 (s, 3H), 2.39 (s, 3H).
Intermediate 56
Methyl 2-(((2-amino-4-methylphenyl)thio)methyl)benzoate
(1145) ##STR00381##
(1146) Following General Procedure L, the title compound (567 mg, 85%) was prepared from methyl 2-(((4-methyl-2-nitrophenyl)thio)methyl)benzoate (741 mg, 2.34 mmol), Zn (3.7 g, 58.44 mmol) and saturated aqueous NH.sub.4Cl (1 ml) in MeOH (20 ml).
(1147) .sup.1H NMR (300 MHz, CDCL.sub.3) δ 7.90 (d, J=7.62 Hz, 1H), 7.22-7.38 (m, 2H), 6.99 (d, J=7.91 Hz, 2H), 6.53 (s, 1H), 6.40 (d, J=7.62 Hz, 1H), 4.26 (s, 2H), 3.88 (s, 3H), 2.23 (s, 3H).
Compound 324
Methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfanyl)methyl]benzoate
(1148) ##STR00382##
(1149) Following General Procedure B, the title compound (688 mg, 75%) was prepared from methyl 2-(((2-amino-4-methylphenyl)thio)methyl)benzoate (567 mg, 1.98 mmol) and benzofuran-2-sulfonyl chloride (854 mg, 3.96 mmol) in pyridine (10 ml).
(1150) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 8.33 (s, 1H), 7.94-7.97 (m, 1H), 7.60-7.64 (m, 1H), 7.45-7.48 (m, 2H), 7.38-7.42 (m, 1H), 7.38 (d, J=0.9 Hz, 1H), 7.24-7.32 (m, 3H), 7.07 (d, J=7.63 Hz, 1H), 6.78-6.83 (m, 1H), 6.70-6.76 (m, 1H), 4.20 (s, 2H), 3.93 (s, 3H), 2.31 (s, 3H).
Compound 325
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfanyl)methyl]benzoic Acid
(1151) ##STR00383##
(1152) Following General Procedure Q, the title compound (250 mg, 98%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfanyl)methyl]benzoate (262 mg, 0.56 mmol).
(1153) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 8.09-8.12 (m, 1H), 7.61-7.63 (m, 1H), 7.50 (d, J=0.88 Hz, 1H), 7.46 (dq, J=0.88, 8.51 Hz, 1H), 7.33-7.42 (m, 4H), 7.25-7.30 (m, 1H), 7.17 (d, J=7.92 Hz, 1H), 6.94 (dd, J=1.76, 7.34 Hz, 1H), 6.78 (ddd, J=0.88, 1.91, 7.78 Hz, 1H), 4.24 (s, 2H), 2.32 (s, 3H).
Compound 326
Methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfinyl)methyl]benzoate
(1154) ##STR00384##
(1155) Following General Procedure C, the title compound (162 mg, 94%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfanyl)methyl]benzoate (167 mg, 0.36 mmol).
(1156) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 10.62 (br. s., 1H), 8.07 (dd, J=1.61, 7.48 Hz, 1H), 7.65 (d, J=7.92 Hz, 1H), 7.59 (s, 1H), 7.49 (d, J=0.88 Hz, 1H), 7.37-7.47 (m, 4H), 7.27-7.31 (m, 1H), 7.15 (dd, J=1.61, 7.19 Hz, 1H), 7.07 (d, J=7.92 Hz, 1H), 6.88 (dd, J=0.73, 7.78 Hz, 1H), 4.81 (d, J=11.74 Hz, 1H), 4.55 (d, J=12.03 Hz, 1H), 3.93 (s, 3H), 2.37 (s, 3H).
Compound 327
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfinyl)methyl]benzoic Acid
(1157) ##STR00385##
(1158) Following General Procedure Q, the title compound (120 mg, 88%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfinyl)methyl]benzoate (140 mg, 0.29 mmol).
(1159) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 10.48 (br. s., 1H), 8.14-8.20 (m, 1H), 7.66 (d, J=7.92 Hz, 1H), 7.58 (s, 1H), 7.50 (d, J=0.88 Hz, 1H), 7.43-7.49 (m, 3H), 7.37-7.42 (m, 1H), 7.28-7.34 (m, 1H), 7.00-7.14 (m, 2H), 6.90 (dd, J=0.88, 7.92 Hz, 1H), 4.82 (d, J=12.03 Hz, 1H), 4.67 (d, J=12.03 Hz, 1H), 2.37 (s, 3H).
Compound 328
Methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfonyl)methyl]benzoate
(1160) ##STR00386##
(1161) Following General Procedure D, the title compound (166 mg, 93%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfanyl)methyl]benzoate (168 mg, 0.36 mmol).
(1162) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 7.90-7.93 (m, 1H), 7.66 (d, J=7.63 Hz, 1H), 7.57 (s, 1H), 7.53 (d, J=0.59 Hz, 1H), 7.48 (dd, J=0.59, 8.51 Hz, 1H), 7.38-7.44 (m, 3H), 7.35 (d, J=7.92 Hz, 1H), 7.28-7.32 (m, 1H), 7.11-7.18 (m, 1H), 6.86 (dd, J=0.59, 8.22 Hz, 1H), 5.07 (s, 2H), 3.77 (s, 3H), 2.37 (s, 3H).
Compound 329
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfonyl)methyl]benzoic Acid
(1163) ##STR00387##
(1164) Following General Procedure Q, the title compound (117 mg, 86%) was prepared from methyl 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-methylphenyl}sulfonyl)methyl]benzoate (140 mg, 0.29 mmol).
(1165) .sup.1H NMR (600 MHz, CDCL.sub.3) δ 9.43 (s, 1H), 8.09 (dd, J=1.47, 7.63 Hz, 1H), 7.69 (d, J=7.92 Hz, 1H), 7.40-7.59 (m, 7H), 7.30-7.36 (m, 1H), 7.23-7.29 (m, 1H), 6.91 (d, J=7.92 Hz, 1H), 5.11 (s, 2H), 2.38 (s, 3H).
Compound 330
N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]phenyl}acetamide
(1166) ##STR00388##
(1167) To a solution of N-{2-[(3-aminobenzyl)sulfanyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide (440 mg, 0.90 mmol) in CH.sub.2Cl.sub.2 (10 ml) was added acetyl chloride (71 μl, 0.99 mmol), pyridine (180 μl, 2.25 mmol), and catalytic amount of DMAP. The reaction was stirred at room temperature for 2 hours, diluted with 1M HCl, and extracted with CH.sub.2Cl.sub.2. The organic layer was dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-10% EtOAc in hexane) to yield the title compound (330 mg, 68%).
(1168) 1H NMR (CHLOROFORM-d) δ 8.10 (s, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.62 (d, J=2.1 Hz, 1H), 7.28-7.53 (m, 6H), 7.25 (s, 1H), 7.07-7.18 (m, 2H), 6.92 (dd, J=8.2, 2.1 Hz, 1H), 6.66 (d, J=7.6 Hz, 1H), 3.75 (s, 2H), 2.15 (s, 3H).
Compound 331
N-(2-{[3-(acetylamino)benzyl]sulfanyl}-5-chlorophenyl)-N-(1-benzofuran-2-ylsulfonyl)acetamide
(1169) ##STR00389##
(1170) To a solution of N-{2-[(3-aminobenzyl)sulfanyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide (440 mg, 0.90 mmol) in CH.sub.2Cl.sub.2 (10 ml) was added acetyl chloride (71 μl, 0.99 mmol), pyridine (180 μl, 2.25 mmol), and catalytic amount of DMAP. The reaction was stirred at room temperature for 2 hours, diluted with 1M HCl, and extracted with CH.sub.2Cl.sub.2. The organic layer was dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (5-10% EtOAc in hexane) to yield the title compound (69 mg, 13%).
(1171) 1H NMR (CHLOROFORM-d) δ 7.70-7.77 (m, 2H), 7.57-7.64 (m, 1H), 7.32-7.57 (m, 7H), 7.17-7.29 (m, 2H), 7.01 (d, J=7.9 Hz, 1H), 4.10 (s, 2H), 2.14 (s, 3H), 2.01 (s, 3H).
Compound 332
N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfanyl)phenyl]-1-benzofuran-2-sulfonamide
(1172) ##STR00390##
(1173) To a solution of N-{2-[(3-aminobenzyl)sulfanyl]-5-chlorophenyl}-1-benzofuran-2-sulfonamide (440 mg, 0.90 mmol) in pyridine (4 ml) was added methanesulfonyl chloride (70 μl, 0.90 mmol). The reaction was stirred at room temperature for 2 hours and was concentrated, diluted with 1 M HCl, and extracted with EtOAc. The organic layer was dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (4% EtOAc in hexane) to yield the title compound (344 mg, 67%).
(1174) 1H NMR (CHLOROFORM-d) δ 8.03 (br. s., 1H), 7.68 (d, J=7.9 Hz, 1H), 7.61 (d, J=2.1 Hz, 1H), 7.40-7.55 (m, 3H), 7.30-7.37 (m, 1H), 7.15-7.23 (m, 2H), 7.06-7.13 (m, 1H), 6.94 (dd, J=8.4, 2.2 Hz, 1H), 6.77-6.84 (m, 2H), 6.70 (s, 1H), 3.78 (s, 2H), 2.95 (s, 3H).
Compound 333
N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)methyl]phenyl}acetamide
(1175) ##STR00391##
(1176) To a solution of N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]phenyl}acetamide (105 mg, 0.216 mmol) in CH.sub.2Cl.sub.2 (3 ml) was added mCPBA (52 mg, ˜0.216 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was directly loaded onto Celite and purified by flash column chromatography on silica gel (50-100% EtOAc in hexane) to yield the title compound (55 mg, 51%).
(1177) 1H NMR (METHANOL-d4) δ 7.76 (d, J=7.9 Hz, 1H), 7.57-7.65 (m, 1H), 7.45-7.56 (m, 3H), 7.33-7.41 (m, 1H), 7.23-7.33 (m, 4H), 7.18 (t, J=7.8 Hz, 1H), 6.77 (d, J=7.3 Hz, 1H), 4.32 (d, J=12.9 Hz, 1H), 4.10 (d, J=12.9 Hz, 1H), 2.10 (s, 3H).
Compound 334
N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)methyl]phenyl}acetamide
(1178) ##STR00392##
(1179) To a solution of N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)methyl]phenyl}acetamide (145 mg, 0.298 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (179 mg, ˜0.744 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was directly loaded onto Celite and purified by flash column chromatography on silica gel (30-100% EtOAc in hexane) to yield the title compound (154 mg, 100%).
(1180) 1H NMR (CHLOROFORM-d) δ 9.34 (br. s., 1H), 7.76 (d, J=1.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.42-7.61 (m, 5H), 7.30-7.39 (m, 2H), 7.22-7.28 (m, 1H), 7.18 (t, J=7.9 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.68 (d, J=7.6 Hz, 1H), 4.31 (s, 2H), 2.15 (s, 3H).
Compound 335
N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfinyl)phenyl]-1-benzofuran-2-sulfonamide
(1181) ##STR00393##
(1182) To a solution of N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfanyl)phenyl]-1-benzofuran-2-sulfonamide (124 mg, 0.237 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (57 mg, ˜0.237 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was directly loaded onto Celite and purified by flash column chromatography on silica gel (50-100% EtOAc in hexane) to yield the title compound (78 mg, 61%).
(1183) 1H NMR (METHANOL-d4) δ 7.75 (d, J=7.3 Hz, 1H), 7.55-7.62 (m, 1H), 7.45-7.53 (m, 2H), 7.32-7.40 (m, 1H), 7.24-7.29 (m, 1H), 7.14-7.24 (m, 4H), 6.99 (s, 1H), 6.78-6.86 (m, 1H), 4.38 (d, J=13.2 Hz, 1H), 4.15 (d, J=12.9 Hz, 1H), 2.91 (s, 3H).
Compound 336
N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfonyl)phenyl]-1-benzofuran-2-sulfonamide
(1184) ##STR00394##
(1185) To a solution of N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfanyl)phenyl]-1-benzofuran-2-sulfonamide (134 mg, 0.256 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (154 mg, ˜0.641 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction mixture was directly loaded onto Celite and purified by flash column chromatography on silica gel (30-100% EtOAc in hexane) to yield the title compound (140 mg, 99%).
(1186) 1H NMR (METHANOL-d4) δ 7.77 (d, J=7.9 Hz, 1H), 7.68-7.74 (m, 2H), 7.44-7.60 (m, 3H), 7.32-7.40 (m, 1H), 7.18-7.24 (m, 1H), 7.11-7.17 (m, 2H), 6.96 (s, 1H), 6.73-6.81 (m, 1H), 4.51 (s, 2H), 2.88 (s, 3H).
Compound 337
({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)acetic Acid
(1187) ##STR00395##
(1188) To a solution of N,N′-[dithiobis(5-chloro-2,1-phenylene)]bis(1-benzofuran-2-sulfonamide) (300 mg, 0.44 mmol) in CH.sub.2Cl.sub.2 (5 ml) and dioxane (5 ml) was added saturated aqueous NaHCO.sub.3 (5 ml), polymer-bound triphenylphosphine (˜3 mmol/g triphenylphosphine loading, 0.44 g, 1.32 mmol), and 2-bromoacetic acid (65 μl, 0.88 mmol). The reaction was stirred at room temperature for 4 hours and was filtered, extracted with EtOAc (×2). The aqueous layer was acidified with HCl, extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (50-100% EtOAc in hexane) to yield the title compound (144 mg, 41%).
(1189) 1H NMR (METHANOL-d4) δ 7.70 (dt, J=7.9, 1.0 Hz, 1H), 7.53-7.58 (m, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.47-7.49 (m, 1H), 7.44-7.46 (m, 1H), 7.41 (d, J=0.9 Hz, 1H), 7.30-7.37 (m, 1H), 7.18 (dd, J=8.5, 2.3 Hz, 1H), 3.47 (s, 2H).
Compound 338
({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)acetic Acid
(1190) ##STR00396##
(1191) To a solution of ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)acetic acid (44 mg, 0.11 mmol) in CH.sub.2Cl.sub.2 (2 ml) and acetonitrile (2 ml) was added mCPBA (27 mg, ˜0.11 mmol). The reaction was stirred at room temperature for 4 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane, then 20-30% MeOH in EtOAc) followed by PTLC (25% MeOH in EtOAc) to yield the title compound (34 mg, 74%).
(1192) 1H NMR (CHLOROFORM-d) δ 7.72 (br. s., 1H), 7.66 (d, J=7.9 Hz, 1H), 7.52 (br. s., 2H), 7.45 (t, J=7.5 Hz, 1H), 7.36 (br. s., 1H), 7.32 (t, J=7.3 Hz, 1H), 7.14 (d, J=7.3 Hz, 1H), 4.24 (br. s., 1H), 3.96 (br. s., 1H).
Compound 339
({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)acetic Acid
(1193) ##STR00397##
(1194) To a solution of ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)acetic acid (38 mg, 0.095 mmol) in CH.sub.2Cl.sub.2 (2 ml) and acetonitrile (2 ml) was added mCPBA (57 mg, ˜0.24 mmol). The reaction was stirred at room temperature for 4 hours and additional mCPBA (34 mg, ˜0.14 mmol) was added. The reaction was continued for 2 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane, then 20% MeOH in EtOAc) followed by PTLC (25% MeOH in EtOAc) to yield the title compound (22 mg, 54%).
(1195) 1H NMR (CHLOROFORM-d) δ 7.79 (br. s., 2H), 7.66 (d, J=7.3 Hz, 1H), 7.55 (br. s., 1H), 7.47-7.53 (m, 1H), 7.41-7.46 (m, 1H), 7.31 (t, J=6.9 Hz, 1H), 7.11-7.19 (m, 1H), 4.22 (br. s., 2H).
Intermediate 57
(1196) ##STR00398##
(1197) To a solution of 2,2′-dithiobis(5-chloroaniline) (CAS 29124-55-8)(1.27 g, 4.0 mmol) in DMF (20 ml) was added methyl acrylate (0.72 ml, 8.0 mmol), K.sub.2CO.sub.3 (1.1 g, 8.0 mmol), and sodium hydroxymethanesulfinate dihydrate (Rongalite, CAS 6035-47-8) (2.5 g, 16 mmol). The reaction was stirred at room temperature for 15 minutes, diluted with H.sub.2O, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-20% EtOAc in hexane) to yield methyl 3-((2-amino-4-chlorophenyl)thio)propanoate (1.5 g, 76%).
(1198) 1H NMR (CHLOROFORM-d) δ 7.29 (d, J=8.2 Hz, 1H), 6.72 (d, J=2.3 Hz, 1H), 6.65 (dd, J=8.2, 2.1 Hz, 1H), 4.49 (br. s., 2H), 3.67 (s, 3H), 2.95 (t, J=7.2 Hz, 2H), 2.54 (t, J=7.2 Hz, 2H).
Compound 340
methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate
(1199) ##STR00399##
(1200) To a solution of methyl 3-((2-amino-4-chlorophenyl)thio)propanoate (412 mg, 1.67 mmol) in pyridine (2 ml) was added 1-benzofuran-2-sulfonyl chloride (363 mg, 1.67 mmol). The reaction was stirred at room temperature for 72 hours, diluted with EtOAc and extracted with HCl, brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo.
(1201) The residue was purified by column chromatography on silica gel (10-20% EtOAc in hexane) to yield the title compound (373 mg, 52%).
(1202) 1H NMR (CHLOROFORM-d) δ 8.32 (s, 1H), 7.72 (dd, J=1.9, 1.3 Hz, 1H), 7.67 (dd, J=7.9, 0.6 Hz, 1H), 7.49-7.54 (m, 2H), 7.44-7.48 (m, 1H), 7.39 (dd, J=8.4, 1.3 Hz, 1H), 7.33 (t, J=7.5 Hz, 1H), 7.03 (ddd, J=8.4, 2.2, 1.2 Hz, 1H), 3.69 (s, 3H), 2.91 (t, J=7.0 Hz, 2H), 2.46 (t, J=7.0 Hz, 2H).
Compound 341
3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoic Acid
(1203) ##STR00400##
(1204) To a solution of methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate (125 mg, 0.29 mmol) in THF (3 ml) was added a solution of LiOH.H.sub.2O (25 mg, 0.59 mmol) in H.sub.2O (1 ml). The reaction was stirred at room temperature for 1 hour, acidified with 1M HCl, and was extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was triturated with MeOH to yield the title compound (102 mg, 84%).
(1205) 1H NMR (DMSO-d6) δ 10.53 (br. s., 2H), 7.75 (d, J=7.9 Hz, 1H), 7.70 (dd, J=8.5, 0.6 Hz, 1H), 7.48-7.54 (m, 2H), 7.29-7.40 (m, 3H), 7.09 (d, J=2.1 Hz, 1H), 2.88 (t, J=7.3 Hz, 2H), 2.20 (t, J=7.3 Hz, 2H).
Compound 342
methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfinyl)propanoate
(1206) ##STR00401##
(1207) To a solution of methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate (181 mg, 0.43 mmol) in CH.sub.2Cl.sub.2 (4 ml) was added mCPBA (153 mg, ˜0.64 mmol). The reaction was stirred at room temperature for 1 hour, diluted with EtOAc, extracted with saturated aqueous NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25-100% EtOAc in hexane, then 10% MeOH in CH.sub.2Cl.sub.2) to yield the title compound (87 mg, 46%).
(1208) 1H NMR (METHANOL-d4) δ 7.70-7.73 (m, 1H), 7.56-7.60 (m, 2H), 7.47 (ddd, J=8.5, 7.2, 1.3 Hz, 1H), 7.41 (d, J=0.9 Hz, 1H), 7.32-7.36 (m, 2H), 7.27 (dd, J=8.4, 1.9 Hz, 1H), 3.59 (s, 3H), 3.40 (ddd, J=13.6, 8.1, 7.0 Hz, 1H), 3.25-3.30 (m, 1H), 2.66-2.73 (m, 1H), 2.49-2.56 (m, 1H).
Compound 343
methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfonyl)propanoate
(1209) ##STR00402##
(1210) To a solution of methyl 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4-chlorophenyl}sulfanyl)propanoate (181 mg, 0.43 mmol) in CH.sub.2Cl.sub.2 (4 ml) was added mCPBA (153 mg, ˜0.64 mmol). The reaction was stirred at room temperature for 1 hour, diluted with EtOAc, extracted with saturated aqueous NaHCO.sub.3 and brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (25-100% EtOAc in hexane, then 10% MeOH in CH.sub.2Cl.sub.2) to yield the title compound (75 mg, 38%).
(1211) 1H NMR (METHANOL-d4) δ 7.76-7.81 (m, 2H), 7.74 (d, J=7.9 Hz, 1H), 7.65 (br. s., 1H), 7.58 (d, J=8.5 Hz, 1H), 7.48 (t, J=7.8 Hz, 1H), 7.35 (t, J=7.5 Hz, 1H), 7.23 (br. s., 1H), 3.66 (br. s., 2H), 3.54 (s, 3H), 2.65 (t, J=7.2 Hz, 2H).
Intermediate 58
N,N′-(disulfanediylbis(3-chloro-6,1-phenylene))bis(4-chloro-2-fluorobenzenesulfonamide)
(1212) ##STR00403##
(1213) To a solution of 2,2′-dithiobis(5-chloroaniline) (CAS 29124-55-8)(0.83 g, 2.6 mmol) in pyridine (5 ml) was added 4-chloro-2-fluorobenzene-1-sulfonyl chloride (1.20 g, 5.2 mmol) and the reaction was stirred at room temperature for 16 hours. Additional 4-chloro-2-fluorobenzene-1-sulfonyl chloride (1.20 g, 5.2 mmol) was added, and the reaction was stirred for 6 hours. The mixture was concentrated in vacuo and the resulting solid was washed with saturated aqueous Na.sub.2CO.sub.3 (×3), H.sub.2O (×3), and dried to give 2.4 g sandy solid, which was taken in methanol (50 ml) and was treated with 4M NaOH (5.5 ml) at 100° C. for 15 min, cooled to room temperature, quenched slowly with 1M HCl with stirring and cooling to pH 7-8. The volume of the resulting suspension was reduced in vacuo, followed by extraction with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (5-40% EtOAc in hexane) to yield the title compound (0.81 g, 44%).
Compound 344
methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate
(1214) ##STR00404##
(1215) To a solution of N,N′-(disulfanediylbis(3-chloro-6,1-phenylene))bis(4-chloro-2-fluorobenzenesulfonamide) (650 mg, 0.93 mmol) in CH.sub.2Cl.sub.2 (10 ml) and dioxane (10 ml) was added saturated aqueous NaHCO.sub.3 (10 ml), polymer-bound triphenylphosphine (˜3 mmol/g triphenylphosphine loading, 0.93 g, 2.79 mmol), methyl 3-bromopropanoate (0.20 ml, 1.86 mmol). The reaction was stirred at room temperature for 2 hours and was diluted with EtOAc, filtered, and washed with saturated aqueous NH.sub.4Cl, brine, dried over Na.sub.2SO.sub.4, and concentrated. The residue was purified by column chromatography on silica gel (5-20% ethyl acetate in hexane) to yield the title compound as a pale yellow solid (626 mg, 77%).
(1216) 1H NMR (CHLOROFORM-d) δ 8.30 (s, 1H), 7.89 (dd, J=8.4, 7.8 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.41 (d, J=8.2 Hz, 1H), 7.24-7.31 (m, 1H), 7.20 (dd, J=9.7, 2.1 Hz, 1H), 6.98-7.05 (m, 1H), 3.72 (s, 3H), 2.94 (t, J=7.0 Hz, 2H), 2.51 (t, J=7.0 Hz, 2H).
Compound 345
3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic Acid
(1217) ##STR00405##
(1218) To a solution of methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate (545 mg, 1.24 mmol) in THF (10 ml) was added a solution of LiOH.H.sub.2O (104 mg, 2.48 mmol) in H.sub.2O (2 ml). The reaction was stirred at room temperature for 1.5 hours, acidified with 1M HCl, and was extracted with EtOAc (×2). The combined organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated. The crude product was triturated with CH.sub.2Cl.sub.2, filtered, rinsed with H.sub.2O, and dried to yield the title compound as beige solid (500 mg, 95%).
(1219) 1H NMR (METHANOL-d4) δ 7.78 (t, J=8.2 Hz, 1H), 7.37-7.48 (m, 3H), 7.34 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.5, 2.3 Hz, 1H), 2.94 (t, J=7.2 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H).
Compound 346
methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]propanoate
(1220) ##STR00406##
(1221) To a solution of methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate (173 mg, 0.39 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (142 mg, ˜0.59 mmol). The reaction was stirred at room temperature for 1 hour, and was directly loaded on Celite, purified by flash column chromatography on silica gel (30-70% EtOAc in hexane) to yield the title compound (130 mg, 73%).
(1222) 1H NMR (acetone) δ 8.02 (t, J=8.2 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.24-7.45 (m, 2H), 6.83 (br. s., 1H), 3.72 (t, J=7.3 Hz, 2H), 3.61 (s, 3H), 2.64 (t, J=7.3 Hz, 2H).
Compound 347
methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]propanoate
(1223) ##STR00407##
(1224) To a solution of methyl 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate (173 mg, 0.39 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (142 mg, ˜0.59 mmol). The reaction was stirred at room temperature for 1 hour, and was directly loaded on Celite, purified by flash column chromatography on silica gel (30-70% EtOAc in hexane) to yield the title compound (40 mg, 22%).
(1225) 1H NMR (METHANOL-d4) δ 7.82 (t, J=8.1 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.37-7.56 (m, 3H), 7.21 (d, J=1.8 Hz, 1H), 3.65 (s, 3H), 3.33-3.42 (m, 1H), 3.13-3.25 (m, 1H), 2.57-2.86 (m, 2H).
Compound 348
3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]propanoic Acid
(1226) ##STR00408##
(1227) To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid (160 mg, 0.38 mmol) in CH.sub.2Cl.sub.2 (5 ml) and acetone (5 ml) was added mCPBA (136 mg, ˜0.56 mmol). The reaction was stirred at room temperature for 2 hours, and additional mCPBA (91 mg, ˜0.38 mmol) was added. The reaction was continued for 1 hour, and was directly loaded on Celite, purified by flash column chromatography on silica gel (30-100% EtOAc in hexane) to yield the title compound (101 mg, 59%).
(1228) 1H NMR (DMSO-d6) δ 7.85 (t, J=8.2 Hz, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.55 (d, J=9.1 Hz, 1H), 7.35-7.44 (m, 2H), 7.09 (br. s., 1H), 3.70 (t, J=7.5 Hz, 2H), 2.43 (t, J=7.5 Hz, 2H).
Compound 349
3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]propanoic Acid
(1229) ##STR00409##
(1230) To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid (91 mg, 0.21 mmol) in CH.sub.2Cl.sub.2 (2 ml) and acetone (2 ml) was added mCPBA (50 mg, ˜0.21 mmol). The reaction was stirred at room temperature for 1 hour and was concentrated. The solid residue was rinsed with Et.sub.2O to yield the title compound (88 mg, 94%).
(1231) 1H NMR (DMSO-d6) δ 11.94 (br. s., 1H), 7.71-7.78 (m, 2H), 7.67 (d, J=8.2 Hz, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.46 (dd, J=8.4, 1.9 Hz, 1H), 7.09 (d, J=2.1 Hz, 1H), 3.21 (ddd, J=13.4, 8.9, 6.5 Hz, 1H), 2.94-3.01 (m, 1H), 2.54 (ddd, J=16.8, 8.9, 6.3 Hz, 1H), 2.30-2.39 (m, 1H).
Compound 350
3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]-N-ethyl-N-methylpropanamide
(1232) ##STR00410##
(1233) To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid (297 mg, 0.70 mmol) in DMF (2 ml) was added EDC.HCl (148 mg, 0.77 mmol), HOBT.H.sub.2O (104 mg, 0.77 mmol), and N-methylethanamine (0.30 ml, 3.5 mmol). The reaction was stirred at room temperature for 16 hours, diluted with 1 M HCl, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-40% EtOAc in hexane) to yield the title compound (269 mg, 83%) as a mixture of amide bond cis-trans isomers.
(1234) 1H NMR (METHANOL-d4) δ 7.74-7.81 (m, 1H), 7.38-7.45 (m, 3H), 7.34 (ddd, J=8.4, 2.0, 0.7 Hz, 1H), 7.15-7.20 (m, 1H), 3.34-3.46 (m, 2H), 2.89-3.02 (m, 5H), 2.54 (2×t, J=10.3, 7.0 Hz, 2H), 1.11 (2×t, J=8.6, 7.3 Hz, 3H).
Compound 351
3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]-N-ethyl-N-methylpropanamide
(1235) ##STR00411##
(1236) To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]-N-ethyl-N-methylpropanamide (119 mg, 0.256 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (61 mg, ˜0.26 mmol). The reaction was stirred at room temperature for 1 hour and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane, then 10% MeOH in CH.sub.2Cl.sub.2) to yield the title compound (53 mg, 43%) as a mixture of amide bond cis-trans isomers.
(1237) 1H NMR (METHANOL-d4) δ 7.82 (t, J=8.1 Hz, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.36-7.52 (m, 3H), 7.32 (d, J=2.1 Hz, 1H), 3.34-3.45 (m, 2H), 3.23-3.28 (m, 1H), 3.09-3.21 (m, 1H), 2.90-3.03 (m, 3H), 2.66-2.90 (m, 2H), 1.05-1.22 (m, 3H).
Compound 352
3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]-N-ethyl-N-methylpropanamide
(1238) ##STR00412##
(1239) To a solution of 3-[(4-chloro-2-{[(4-chloro-2-fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]-N-ethyl-N-methylpropanamide (96 mg, 0.21 mmol) in CH.sub.2Cl.sub.2 (5 ml) was added mCPBA (124 mg, ˜0.52 mmol). The reaction was stirred at room temperature for 1 hour and was concentrated. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexane) to yield the title compound (98 mg, 95%) as a mixture of amide bond cis-trans isomers.
(1240) 1H NMR (METHANOL-d4) δ 8.00 (t, J=8.2 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.8 Hz, 1H), 7.39-7.49 (m, 2H), 7.23 (d, J=8.2 Hz, 1H), 3.61 (td, J=6.8, 3.1 Hz, 2H), 3.32-3.42 (m, 2H), 2.74-3.01 (m, 5H), 1.01-1.19 (m, 3H).
Intermediate 59
methyl 2-(((5-chloro-2-nitrophenyl)thio)methyl)benzoate
(1241) ##STR00413##
(1242) To a solution of 4-chloro-2-fluoro-1-nitrobenzene (352 mg, 2.0 mmol) in dioxane (3 ml) was added a solution of Na.sub.2S.9H.sub.2O (960 mg, 4.0 mmol) in H.sub.2O (3 ml) and the reaction was stirred at room temperature for 30 minutes, then methyl 2-(bromomethyl)benzoate (458 mg, 2.0 mmol) and K.sub.2CO.sub.3 (345 mg, 2.5 mmol) was added and the reaction was continued for 2 hours, diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (0˜10% EtOAc in hexane) to yield the title compound (199 mg, 29%).
(1243) 1H NMR (CHLOROFORM-d) δ 8.16 (d, J=8.8 Hz, 1H), 8.01 (dd, J=7.3, 0.9 Hz, 1H), 7.47-7.52 (m, 3H), 7.39 (ddd, J=8.1, 5.8, 2.8 Hz, 1H), 7.20 (dd, J=8.9, 2.2 Hz, 1H), 4.69 (s, 2H), 3.91 (s, 3H).
Intermediate 60
methyl 2-(((2-amino-5-chlorophenyl)thio)methyl)benzoate
(1244) ##STR00414##
(1245) Following General Procedure L, the title compound (158 mg, crude) was prepared from methyl 2-(((5-chloro-2-nitrophenyl)thio)methyl)benzoate (163 mg, 0.48 mmol), Zn (780 mg, 12.0 mmol) and saturated aqueous NH.sub.4Cl (10 ml) in MeOH (5 ml) and THF (5 ml). The crude product was used in the next reaction without further purification.
Compound 353
methyl 2-(((2-(benzofuran-2-sulfonamido)-5-chlorophenyl)thio)methyl)benzoate
(1246) ##STR00415##
(1247) Following General Procedure B, the title compound (65 mg, 28%) was prepared from methyl 2-(((2-amino-5-chlorophenyl)thio)methyl)benzoate (150 mg, crude) and benzofuran-2-sulfonyl chloride (104 mg, 0.48 mmol) in pyridine (3 ml).
(1248) 1H NMR (CHLOROFORM-d) δ 8.27 (s, 1H), 7.95-8.03 (m, 1H), 7.56-7.66 (m, 2H), 7.35-7.50 (m, 3H), 7.16-7.35 (m, 5H), 6.80-6.89 (m, 1H), 4.27 (s, 2H), 3.94 (s, 3H).
Compound 354
2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-5-chlorophenyl}sulfanyl)methyl]benzoic Acid
(1249) ##STR00416##
(1250) Following General Procedure Q, the title compound (48 mg, 96%) was prepared from methyl 2-(((2-(benzofuran-2-sulfonamido)-5-chlorophenyl)thio)methyl)benzoate (51 mg, 0.11 mmol).
(1251) 1H NMR (METHANOL-d4) δ 7.92 (dd, J=7.6, 1.5 Hz, 1H), 7.71 (dt, J=7.9, 1.0 Hz, 1H), 7.51-7.54 (m, 1H), 7.45-7.49 (m, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.38 (d, J=1.2 Hz, 1H), 7.34 (ddd, J=7.9, 7.0, 0.9 Hz, 1H), 7.20-7.30 (m, 3H), 7.12 (d, J=2.6 Hz, 1H), 6.74 (dd, J=7.3, 1.2 Hz, 1H), 4.27 (s, 2H).
Biological Data
(1252) HEK-Gqi5 cells stably expressing CCR2 were cultured in DMEM high glucose, 10% FBS, 1% PSA, 400 μg/ml geneticin and 50 μg/ml hygromycin. Appropriate positive control chemokines (MCP-1, MIP1A or RANTES) was used as the positive control agonist for screening compound-induced calcium activity assayed on the FLIPR.sup.Tetra. The drug plates were prepared in 384-well microplates using the EP3 and the MultiPROBE robotic liquid handling systems. Compounds were synthesized and tested for CCR2 activity.
(1253) Table 1 shows activity at CCR2 receptor (IC.sub.50) nM
(1254) TABLE-US-00001 TABLE 1 CCR2 CCR2 % Compound Name IC50 (nM) ANTAGONISM N-[2-(benzylsulfanyl)-5-chlorophenyl]-4- 1284 68 chloro-3- (trifluoromethyl)benzenesulfonamide N-[2-(benzylsulfinyl)-5-chlorophenyl]-4- 493 77 chloro-3- (trifluoromethyl)benzenesulfonamide N-[2-(benzylsulfonyl)-5-chlorophenyl]-4- 538 71 chloro-3- (trifluoromethyl)benzenesulfonamide N-[2-(benzylsulfanyl)-4-cyanophenyl]-1- 604 79 benzofuran-2-sulfonamide N-[2-(benzylsulfinyl)-4-cyanophenyl]-1- 1030 94 benzofuran-2-sulfonamide N-[2-(benzylsulfonyl)-4-cyanophenyl]-1- 888 96 benzofuran-2-sulfonamide N-[6-(benzylsulfinyl)-1-oxo-2,3-dihydro-1H- nd 73 inden-5-yl]-1-benzofuran-2-sulfonamide N-[6-(benzylsulfonyl)-1-oxo-2,3-dihydro-1H- 2242 45 inden-5-yl]-1-benzofuran-2-sulfonamide 4-({[4-chloro-2-({[4-chloro-3- 255 102 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid 4-({[4-chloro-2-({[4-chloro-3- 2105 23 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3- 657 43 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)phenyl]carbonyl}amino)acetate tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3- nd 93 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)phenyl]carbonyl}amino)acetate tert-butyl ({[4-({[4-chloro-2-({[4-chloro-3- 2662 77 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)phenyl]carbonyl}amino)acetate ({[4-({[4-chloro-2-({[4-chloro-3- nd 75 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)phenyl]carbonyl}amino)acetic acid ({[4-({[4-chloro-2-({[4-chloro-3- nd 24 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)phenyl]carbonyl}amino)acetic acid methyl 3-({[4-chloro-2-({[4-chloro-3- 1359 57 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate methyl 3-({[4-chloro-2-({[4-chloro-3- 3108 93 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoate methyl 3-({[4-chloro-2-({[4-chloro-3- 2973 55 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoate 3-({[4-chloro-2-({[4-chloro-3- 56 102 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid 3-({[4-chloro-2-({[4-chloro-3- 1578 101 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid 3-({[4-chloro-2-({[4-chloro-3- nd 89 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid 3-({[4-chloro-2-({[4-chloro-3- 2170 97 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)- N-[2-(pyrrolidin-1- yl)ethyl]benzamide 3-({[4-chloro-2-({[4-chloro-3- 910 105 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)- N-[2-(pyrrolidin-1- yl)ethyl]benzamide 3-({[4-chloro-2-({[4-chloro-3- nd 51 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)- N-[2-(1-oxidopyrrolidin-1- yl)ethyl]benzamide 3-({[4-chloro-2-({[4-chloro-3- 817 110 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)- N-[2-(pyrrolidin-1- yl)ethyl]benzamide 4-({[4-chloro-2-({[4-chloro-3- 2316 75 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)- N-[2-(pyrrolidin-1- yl)ethyl]benzamide 4-({[4-chloro-2-({[4-chloro-3- nd 31 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)- N-[2-(1-oxidopyrrolidin-1- yl)ethyl]benzamide 4-({[4-chloro-2-({[4-chloro-3- 1426 85 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)- N-[2-(pyrrolidin-1- yl)ethyl]benzamide methyl 2-({[4-chloro-2-({[4-chloro-3- 2383 88 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoate 2-({[4-chloro-2-({[4-chloro-3- 79 99 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzoic acid methyl 2-({[4-chloro-2-({[4-chloro-3- 274 101 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoate 2-({[4-chloro-2-({[4-chloro-3- 853 99 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}methyl)benzoic acid methyl 2-({[4-chloro-2-({[4-chloro-3- 515 82 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoate 2-({[4-chloro-2-({[4-chloro-3- nd 105 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}methyl)benzoic acid 2-({[4-chloro-2-({[4-chloro-3- 167 88 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)benzamide 2-({[4-chloro-2-({[4-chloro-3- 171 71 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)- N,N-dimethylbenzamide 2-({[4-chloro-2-({[4-chloro-3- 149 92 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfanyl}methyl)- N-ethylbenzamide 3-{[4-chloro-2-({[4-chloro-3- 1687 56 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfinyl}- N,N-diethylpropanamide 3-{[4-chloro-2-({[4-chloro-3- 1861 61 (trifluoromethyl)phenyl]sulfonyl}amino)phenyl]sulfonyl}- N,N-diethylpropanamide 4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1- 2287 60 yl)propyl]sulfanyl}phenyl)-3- (trifluoromethyl)benzenesulfonamide 4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1- 1663 72 yl)propyl]sulfinyl}phenyl)-3- (trifluoromethyl)benzenesulfonamide 4-chloro-N-(5-chloro-2-{[3-oxo-3-(pyrrolidin-1- nd 58 yl)propyl]sulfonyl}phenyl)-3- (trifluoromethyl)benzenesulfonamide 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 7 101 chlorophenyl}sulfanyl)methyl]benzoic acid 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 806 98 chlorophenyl}sulfinyl)methyl]benzoic acid 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- nd 96 chlorophenyl}sulfonyl)methyl]benzoic acid methyl 2-[({2-[(1-benzofuran-2- 272 93 ylsulfonyl)amino]-4- fluorophenyl}sulfanyl)methyl]benzoate 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 11 99 fluorophenyl}sulfanyl)methyl]benzoic acid methyl 2-[({2-[(1-benzofuran-2- 140 91 ylsulfonyl)amino]-4- fluorophenyl}sulfinyl)methyl]benzoate 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 1849 92 fluorophenyl}sulfinyl)methyl]benzoic acid methyl 2-[({2-[(1-benzofuran-2- 41 90 ylsulfonyl)amino]-4- fluorophenyl}sulfonyl)methyl]benzoate 2-[({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 2471 89 fluorophenyl}sulfonyl)methyl]benzoic acid N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]- 379 96 4- chlorophenyl}sulfanyl)methyl]phenyl}acetamide N-(2-{[3-(acetylamino)benzyl]sulfanyl}-5- 1605 73 chlorophenyl)-N-(1-benzofuran-2- ylsulfonyl)acetamide N-[5-chloro-2-({3- 1277 90 [(methylsulfonyl)amino]benzyl}sulfanyl)phenyl]- 1-benzofuran-2-sulfonamide N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]- nd 95 4- chlorophenyl}sulfinyl)methyl]phenyl}acetamide N-{3-[({2-[(1-benzofuran-2-ylsulfonyl)amino]- 854 100 4- chlorophenyl}sulfonyl)methyl]phenyl}acetamide N-[5-chloro-2-({3- 2422 77 [(methylsulfonyl)amino]benzyl}sulfinyl)phenyl]- 1-benzofuran-2-sulfonamide N-[5-chloro-2-({3- 6570 91 [(methylsulfonyl)amino]benzyl}sulfonyl)phenyl]- 1-benzofuran-2-sulfonamide ({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 484 95 chlorophenyl}sulfanyl)acetic acid methyl 3-({2-[(1-benzofuran-2- 864 91 ylsulfonyl)amino]-4- chlorophenyl}sulfanyl)propanoate 3-({2-[(1-benzofuran-2-ylsulfonyl)amino]-4- 46 99 chlorophenyl}sulfanyl)propanoic acid methyl 3-({2-[(1-benzofuran-2- 217 99 ylsulfonyl)amino]-4- chlorophenyl}sulfinyl)propanoate methyl 3-({2-[(1-benzofuran-2- 225 96 ylsulfonyl)amino]-4- chlorophenyl}sulfonyl)propanoate methyl 3-[(4-chloro-2-{[(4-chloro-2- 995 79 fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoate 3-[(4-chloro-2-{[(4-chloro-2- 129 102 fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]propanoic acid methyl 3-[(4-chloro-2-{[(4-chloro-2- 212 82 fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]propanoate methyl 3-[(4-chloro-2-{[(4-chloro-2- 98 93 fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]propanoate 3-[(4-chloro-2-{[(4-chloro-2- nd 90 fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]propanoic acid 3-[(4-chloro-2-{[(4-chloro-2- nd 83 fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]propanoic acid 3-[(4-chloro-2-{[(4-chloro-2- nd 49 fluorophenyl)sulfonyl]amino}phenyl)sulfanyl]- N-ethyl-N-methylpropanamide 3-[(4-chloro-2-{[(4-chloro-2- 7523 89 fluorophenyl)sulfonyl]amino}phenyl)sulfinyl]- N-ethyl-N-methylpropanamide 3-[(4-chloro-2-{[(4-chloro-2- 2262 87 fluorophenyl)sulfonyl]amino}phenyl)sulfonyl]- N-ethyl-N-methylpropanamide nd: Not determined.