Abstract: The invention relates to a method of identifying selective covalently binding inhibitors by using a reversibly inhibiting scaffolds modified by a warhead comprising a fast-reacting Michael acceptor moiety and a linker of different length, determining kinact, and replacing the warhead of the covalently binding inhibitor with the highest kinact by a warhead comprising a moderately reacting Michael acceptor.

Abstract: Kinase-targeted covalent inhibitors are usually irreversibly targeting noncatalytic cysteines in the ATP-binding site. These compounds are designed by directly introducing an electrophile on a reversible-inhibitor scaffold. Our invention relates to novel triazine compounds, containing chemical reactive groups (warheads), targeting a solvent exposed cysteine at >10 ? from the core reversible inhibitor. A variety of novel linkers have been designed and used to link the warhead with the reversible scaffold. We disclose a novel chemical space for drug-like covalent modifiers of phosphoinositide 3-kinase alpha (PI3K?), an enzyme frequently altered in human malignancies. The invention relates to novel covalent inhibitors showing higher in vitro affinity, cellular potency and improved metabolic stability (rat liver microsomes).

Abstract: Our invention relates to novel triazine compounds, containing chemical reactive groups (warheads) and behaving as reversible and irreversible covalent inhibitors. Linkers have been introduced to target a solvent exposed, distal cysteine at >10 ? from the core reversible inhibitor. Different exit vectors have been investigated to modulate inhibitor intrinsic reactivity and efficiency in covalent bond formation. We disclose novel, optimized covalent modifiers of phosphoinositide 3-kinase alpha (PI3K?), an enzyme frequently altered in human malignancies. The compounds of the invention could be exploited as therapeutic agents and chemical probes useful for the investigation of the role of PI3K isoforms in cancer and metabolism, and for treatment of PI3K?-driven cancers and malformations.

Abstract: The invention relates to novel phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR) and PI3K-related kinase (PIKKs) inhibitor compounds of formula (I), wherein X1, X2 and X3 are N or CH, with the proviso that at least two of X1, X2 and X3 are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

Abstract: The invention relates to novel phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR) and PI3K-related kinase (PIKKs) inhibitor compounds of formula (I), wherein X1, X2 and X3 are N or CH, with the proviso that at least two of X1, X2 and X3 are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

Abstract: The invention relates to novel phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR) and PI3K-related kinase (PIKKs) inhibitor compounds of formula (I), wherein X1, X2 and X3 are N or CH, with the proviso that at least two of X1, X2 and X3 are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

Abstract: The invention relates to novel phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR) and PI3k-related kinase (PIKKs) inhibitor compounds of formula (I), wherein X1, X2 and X3 are N or CH, with the proviso that at least two of X1, X2 and X3 are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

Abstract: The invention relates to novel phosphoinositide 3-kinase (PI3k), mammalian target of rapamycin (mTOR) and PI3k-related kinase (PIKKs) inhibitor compounds of formula (I), wherein X1, X2 and X3 are N or CH, with the proviso that at least two of X1, X2 and X3 are N; Y is N or CH, These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

Abstract: The invention relates to novel phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor compounds of formula (I) and (II), which are conformationally restricted, and for which the meaning of the substituents are listed in the description. Preferred compounds are those wherein X isoxygen, R1 is morpholino and R2 is substituted phenyl or heteroaryl. These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

Abstract: The invention relates to novel phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor compounds of formula (I) and (II), which are conformationally restricted, and for which the meaning of the substituents are listed in the description. Preferred compounds are those wherein X isoxygen, R1 is morpholino and R2 is substituted phenyl or heteroaryl. These compounds are useful, either alone or in combination with further therapeutic agents, for treating disorders mediated by lipid kinases.

Abstract: The invention relates to novel therapeutic agents and diagnostic probes. The invention also relates to phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor triazine-, pyrimidine- and pyridine-based compounds^ Formula (I), their stereoisomers, geometric isomers, tautomers, solvates, metabolites, N-oxide derivatives, pharmaceutically acceptable salts, and prodrugs thereof compositions of the new compounds; either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, for treating disorders mediated by lipid kinases. •Methods of using compounds of Formula (I) for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

Abstract: The invention relates to new triazines (G=Q=U are N), pyrimidines (two out of G, Q and U are N), and pyridopyrimidines (one of G and U together with R2 forms an anullated pyridine ring) of formula (I) carrying a spirocyclic substituent, wherein E1 is CR4 or N; X1 is CHR4, CH2CH2, NR4, NR4?0, or O; and the other substituents are as defined in the specification. The compounds inhibit phosphoinositide 3-kinase (PI3K), mammalian target of rapamycin (mTOR), DNA-PK and ATM kinase, and may be used as therapeutic agents or diagnostic probes. The invention also relates to methods of using the compounds for treatment of associated pathological conditions.

Abstract: The invention relates to compounds of formula (I) R1 is methyl, n-hexyl, aminoethyl, methylaminoethyl, ethylaminoethyl, dimethylaminoethyl, acryloylaminoethyl, methacryloylaminoethyl, methoxyethyl, ethoxyethyl, d-C4-alkyl-sulfonyl, acryloyl, or methacryloyl; or R1 is aminoethyl, acryloyl or acryloylaminoethyl carrying a linker and a tag, and R2 and R3, independently of each other, are hydrogen or CrC4-alkyl, or R2 and R3 together form a methylene or an ethylene bridge; and tautomers, solvates and pharmaceutically acceptable salts thereof. These compounds are effective in preventing or treating a disease or disorder modulated by PI3 kinases and/or mTOR, in particular treating a hyperproliferative disorder.

Abstract: The invention relates to novel therapeutic agents and diagnostic probes. The invention also relates to phosphoinositide 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitor triazine-, pyrimidine- and pyridine-based compounds? Formula (I), their stereoisomers, geometric isomers, tautomers, solvates, metabolites, N-oxide derivatives, pharmaceutically acceptable salts, and prodrugs thereof compositions of the new compounds; either alone or in combination with at least one additional therapeutic agent, with a pharmaceutically acceptable carrier; and uses of the new compounds, either alone or in combination with at least one additional therapeutic agent, for treating disorders mediated by lipid kinases. •Methods of using compounds of Formula (I) for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

Abstract: The present invention describes novel methods, assays and kits for identifying and/or quantifying Aminoglycoside Binding Molecules (ABMs), enzymes modifying such molecules, and compounds modulating the interaction between ABMs and either enzymes or aminoglycosides, by exploiting the scintillation proximity effect. The invention, which makes use of aminoglycoside-coated scintillating supports, can be adapted to high throughput screening formats.

Abstract: The present invention describes novel methods, assays and kits for identifying and/or quantifying Aminoglycoside Binding Molecules (ABMs), enzymes modifying such molecules, and compounds modulating the interaction between ABMs and either enzymes or aminoglycosides, by exploiting the scintillation proximity effect. The invention, which makes use of aminoglycoside-coated scintillating supports, can be adapted to high throughput screening formats.