Spiroindolinone derivatives
AssigneeHoffmann-La Roche Inc.
InventorsQingjie Ding, Nan Jiang, Song Yang, Jing Zhang, Zhuming Zhang
Life of this patent
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Abstract
There are provided compounds of the formula and pharmaceutically acceptable salts and esters thereof wherein W, V, X, Y, A, R and R′ are as described herein. The compounds are useful as anticancer agents.
Claims22
A compound of the formula
- wherein
- X is CI, F or Br
- R is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of:
- W is selected from the group consisting of F, CI, Br, I, methyl, ethyl, cyclopropyl, cyano, methoxy, hydroxymethyl, COOMe, ethynyl, CF3, vinyl, isopropenyl, 1-propynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 3-trifluoroethynyl, phenyl, 2-furany, 2-thiophenyl and 4-thiazolyl,
- Y is hydrogen, F, CI or Me,
- V is hydrogen, F, CI or methyl,
- A is selected from the group consisting of O and NH,
- n=1, 2 or 3,
- R′ is selected from the group consisting of heterocycle, substituted heterocyle, heteroaryl, substitluted heteroaryl, aryl, substituted aryl, substituted cycloalkyl, and CR1R2C(═O)NR3R4 wherein
- R1, R2 are hydrogen or lower alkyl,
- or may independently link to form a cyclic structure selected from a substituted or unsubstituted cycloalkyl and
- R3, R4 are independently selected from the group consisting of hydrogen, lower alkyl, aryl, lower alkenyl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl with the proviso that R3, R4 are not both hydrogen,
- or R3/R4 may independently link to form a cyclic structure selected from a substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or a substituted or unsubstituted heterocycle
- and the pharmaceutically acceptable salts and esters thereof.
A pharmaceutical composition comprising a compound of the formula
- wherein
- X is CI, F or Br
- R is a substituted phenyl or substituted heteroaryl with the substituted phenyl or substituted heteroaryl selected from group consisting of:
- W is selected from the group consisting of F, CI, Br, I, methyl, ethyl, cyclopropyl, cyano, methoxy, hydroxymethyl, COOMe, ethynyl, CF3, vinyl, isopropenyl, 1-propynyl, 3-methyl-1-butynyl, 3,3-dimethyl-1-butynyl, 3-trifluoroethynyl, phenyl, 2-furany, 2-thiophenyl and 4-thiazolyl,
- Y is hydrogen, F, CI or Me,
- V is hydrogen, F, CI or methyl,
- A is selected from the group consisting of O and NH,
- n =1, 2 or 3
- R′ is selected from the group consisting of heterocycle, substituted heterocyle, heteroaryl, substitluted heteroaryl, aryl, substituted aryl, substituted cycloalkyl and
- CR1R2C(═O)NR3R4 wherein
- R1, R2 are hydrogen or lower alkyl,
- or may independently link to form a cyclic structure selected from a substituted or unsubstituted cycloalkyl and
- R3, R4 are independently selected from the group consisting of hydrogen, lower alkyl, arid, lower alkenyl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl with the proviso that R3, R4 are not both hydrogen,
- or R3/R4 may independently link to form a cyclic
- structure selected from a substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl or a substituted or unsubstituted heterocycle and the pharmaceutically acceptable salts and esters thereof together with a pharmaceutically acceptable carrier or excipient.
A compound selected from the group consisting of racemic(2′R,3R,4′S)-6-chloro-2′-(5-chloro-2-imidazol-1-yl-phenyl)-4′-(3-chlorophenyl) spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione, racemic(2′R,3′R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(2-thiophenyl)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione, chiral (2′R, 3′R, 4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-(2-furanyl)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione, racemic(2′R,3′R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-(2-hydroxy-ethoxy)-5-phenyl-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione, racemic(2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-iodo-phenyl]spiro[3H-indole-3,3′-piperidine]-2,6′-dione, racemic(2′R,3′R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[5-(2-furanyl)-2-hydroxy-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione, racemic(2′R,3′R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-(2-thiofuranyl)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione, racemic(2′R,3′R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-phenyl]-phenyl-spiro[3H-indole-3,3′-piperidine]-2,6′-dione, racemic(2′R,3′R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-(2-thiazolyl)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione and racemic(2′R,3′R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-[2-hydroxy-5-(2-thiazolyl)-phenyl]-spiro[3H-indole-3,3′-piperidine]-2,6′-dione.
Dependencies are inferred from the claim text.