摘要:
The invention provides compounds of the Formula (I) or pharmaceutically acceptable salts thereof, wherein the variables are as described herein. The compounds or their pharmaceutically acceptable salts can inhibit the G12D mutant of Kirsten rat sarcoma (K-Ras) protein and are expected to have utility as therapeutic agents, for example, for treating cancer. The invention also provides pharmaceutical compositions which comprise compounds of Formula (I) or pharmaceutically acceptable salts thereof. The invention also relates to methods for use of the compounds or their pharmaceutically acceptable salts in the therapy and prophylaxis of cancer and for preparing pharmaceuticals for this purpose.
摘要:
Peptidomimetic macrocycles that comprise all-D configuration ?-amino acids and bind mouse double minute 2 (MDM2 aka E3 ubiquitin-protein ligase) and MDMX (aka MDM4) are described. These all-D configuration α-amino acid peptidomimetic macrocycles are protease resistant, cell permeable without inducing membrane disruption, and intracellularly activate p53 by binding MDM2 and MDMX thereby antagonizing MDM2 and MDMX binding to p53. These peptidomimetic macrocycles may be useful in anticancer therapies, particularly in combination with chemotherapy or radiation therapy.
摘要:
The invention provides compounds of general structure I: (Ar1—Ar2—Ar3-E-P(=D)R2-)nMmXnLn″. In this structure: •Ar1, Ar2 and Ar3 are aromatic groups wherein: —Ar1 and Ar3 are in a 1,3 relationship on Ar2, —each of Ar1, Ar2 and Ar3 optionally comprises one or more ring substituents of formula YR′r wherein each Y independently is absent or is O, S, B, N or Si and each R′ is independently H, halogen, alkyl, cycloalkyl, aryl or heteroaryl and r is 1, 2 or 3, where r is 1 if Y is absent or is O or S, 2 if Y is B or N and 3 if Y is Si, —Ar1, Ar2 and Ar3 are each independently carbocyclic or heterocyclic and each is independently monocyclic, bicyclic or polycyclic and each ring of each of Ar1, Ar2 and Ar3 independently has 5, 6 or 7 ring atoms; •E is absent or is selected from the group consisting of O, S, NR″, SiR″2, AsR″2 and CR″2; •M is a complexing metal; •X is selected from the group consisting of H, F, Br, CI, I, OTf, dba (dibenzylidene acetone), OC(═O)CF3 and OAc; •L is selected from the group consisting of PR″2, NR″2, OR″, SR″, SiR″3, AsR″3, alkene, alkyne, aryl and heteroaryl, each of said alkene, alkyne, aryl and heteroaryl being optionally substituted, for example with one or more halogens and/or with one or more R groups as defined herein; •each R is independently alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl or -, heteroaryl; •D is absent or is ═S or —O or —Z-linker-Z—, where each Z independently is O or NH or N-alkyl and linker is an alkyl chain of 2-5 carbon atoms in length; •each R″ is independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each other than H being optionally substituted, or R″2 is —Z-linker-Z— as defined above; and •m is 0 or 1 or 2; wherein if m is 0, n is 1, n′ and n″ are 0 and -- is absent; and if m is 1 or 2, n is 1 or 2 and n′ and n″ are integers such that the coordination sphere of M is filled, and D is absent.
摘要:
The invention provides compounds of general structure I: (Ar1—Ar2—Ar3-E-P(=D)R2-)nMmXnLn″. In this structure: •Ar1, Ar2 and Ar3 are aromatic groups wherein: —Ar1 and Ar3 are in a 1,3 relationship on Ar2, —each of Ar1, Ar2 and Ar3 optionally comprises one or more ring substituents of formula YR′r wherein each Y independently is absent or is O, S, B, N or Si and each R′ is independently H, halogen, alkyl, cycloalkyl, aryl or heteroaryl and r is 1, 2 or 3, where r is 1 if Y is absent or is O or S, 2 if Y is B or N and 3 if Y is Si, —Ar1, Ar2 and Ar3 are each independently carbocyclic or heterocyclic and each is independently monocyclic, bicyclic or polycyclic and each ring of each of Ar1, Ar2 and Ar3 independently has 5, 6 or 7 ring atoms; •E is absent or is selected from the group consisting of O, S, NR″, SiR″2, AsR″2 and CR″2; •M is a complexing metal; •X is selected from the group consisting of H, F, Br, CI, I, OTf, dba (dibenzylidene acetone), OC(═O)CF3 and OAc; •L is selected from the group consisting of PR″2, NR″2, OR″, SR″, SiR″3, AsR″3, alkene, alkyne, aryl and heteroaryl, each of said alkene, alkyne, aryl and heteroaryl being optionally substituted, for example with one or more halogens and/or with one or more R groups as defined herein; •each R is independently alkyl, cycloalkyl, heterocyclyl, heterocycloalkyl, aryl or -, heteroaryl; •D is absent or is ═S or —O or —Z-linker-Z—, where each Z independently is O or NH or N-alkyl and linker is an alkyl chain of 2-5 carbon atoms in length; •each R″ is independently H, alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each other than H being optionally substituted, or R″2 is —Z-linker-Z— as defined above; and •m is 0 or 1 or 2; wherein if m is 0, n is 1, n′ and n″ are 0 and -- is absent; and if m is 1 or 2, n is 1 or 2 and n′ and n″ are integers such that the coordination sphere of M is filled, and D is absent.
摘要:
The invention relates to isoxazolidine containing compounds that bind to bcl proteins and inhibit Bcl function. The compounds may be used for treating and modulating disorders associated with hyperproliferation, such as cancer.
摘要:
The invention relates to the preparation of amino-cyclopamines by the enzymatic transamination of a corresponding keto-cyclopamines in the presence of a cofactor and an amino donor.
摘要:
The invention relates to isoxazolidine containing compounds that bind to bcl proteins and inhibit Bcl function. The compounds may be used for treating and modulating disorders associated with hyperproliferation, such as cancer.
摘要:
The invention relates to isoxazolidine containing compounds that bind to bcl proteins and inhibit Bcl function. The compounds may be used for treating and modulating disorders associated with hyperproliferation, such as cancer.