3,3′-spiroindolinone derivatives
There are provided compounds of the formula or a pharmaceutically acceptable salt or ester thereof wherein X, Y, W, W′, V, V′, V″, R 1 , R 2 and R 3 are as herein described. The compounds have utility as antiproliferative agents, especially, as anticancer agents.
1. A compound of the formula
wherein
X is Cl,
Y is hydrogen,
V is F or Cl,
V′ is hydrogen or F,
V″ is hydrogen,
W is Cl,
W′ is hydrogen,
R 1 and R 2 are methyl or ethyl,
or R 1 and R 2 may link to form a cyclic structure selected from a substituted or unsubstituted cycloalkyl
R 3 is NHS(═O) 2 R″,
R′, R″ is selected independently from the group consisting of lower alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl
and the pharmaceutically acceptable salts and esters and enantiomers thereof.
2. A compound selected from the group consisting of
chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
chiral (2′R, 3R, 4′S)-6-chloro-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-2′-(5-chloro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro2-(1-ethoxycarbonyl-1-propyl-butoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
chiral (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(2-cyclopropanesulfonylamino-1,1-dimethyl-2-oxo-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one and
racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-cyclobutoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one.
3. A compound selected from the group consisting of
racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(2-methoxycarbonyl-methoxy)-phenyl]-2′-[5-difluoro-2-methyl-phenyl]-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1 H)-one,
racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(4,5-difluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
racemic (2′R, 3R, 4′S)-6-chloro-4′-[5-chloro-4-fluoro-2-methoxy-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1 H)-one,
racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5,6-difluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-4-fluoro-2-(1-methoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one,
racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxylcarbamoyl-1-methyl-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one and
racemic (2′S, 3S, 4′R)-6-chloro-4′-[5-chloro-2-(1-methoxylcarbamoyl-1-ethyl-propoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-6′-thioxo spiro[3H-indole-3,3′-piperidine]-2(1H)-one.
4. A pharmaceutical composition comprising a compound of the formula
wherein
X is Cl,
Y is hydrogen,
V is F or Cl,
V′ is hydrogen,
V″ is hydrogen or F,
W is Cl,
W is hydrogen,
R 1 and R 2 are methyl or ethyl,
R 3 is NHS(═O) 2 R″,
R′, R″ is selected independently from the group consisting of lower alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl
and the pharmaceutically acceptable salts and esters and enantiomers thereof together with a pharmaceutically acceptable excipient or carrier.