Cyclin-dependent kinase 7 (CDK7) non-covalent inhibitors

Inventors

Mevellec, Laurence Anne • COUPA ép. DESCAMPS, Sophie • Adelinet, Christiphe Denis Pascal • Ligny, Yannick Aimé Eddy • Meyer, Christophe • Stansfield, Ian

Assignees

Janssen Pharmaceutica NV • Janssen Cilag SAS

Abstract

The invention relates to pharmaceutical compounds of formula (I) and pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds as inhibitors of cyclin-dependent kinase 7 (CDK7) and to their use in the treatment of diseases, e.g. cancer.

Core Innovation

The invention relates to compounds of formula (Va) or (Vb), including tautomeric forms, stereochemically isomeric forms, isotopically labeled forms, and pharmaceutically acceptable salts or solvates thereof. The compounds are defined by variables including R2, R5a, R5b, R6a, R6b, R7a, R7b, R8, A, R9, R10, n, and p, with permitted options including haloC1-6alkyl, C1-6alkoxy, cycloalkyl, phenyl, monocyclic heterocyclyl, heteroaryl, spiro-C3-6cycloalkyl, and spiro-monocyclic heterocyclyl containing at least one heteroatom that is N, O or S. Certain substituent pairs can form C3-6cycloalkyl, including cyclopropyl, together with the carbon atom to which they are bound.

The compounds are described as CDK7 inhibitor compounds and as agents for modulating or inhibiting CDK7 activity by contacting CDK7 protein, or a portion thereof, with the compound. The disclosure links CDK7 activity to proliferation and cancer biology, and it frames the compounds for therapeutic and prophylactic use in diseases mediated by CDK7, with particular emphasis on proliferative diseases including cancer. The description also includes pharmaceutical compositions comprising the compounds.

The disclosure further presents stereochemically isomeric and isotopically labeled chiral compounds within the same structural family, including deuterated motifs and distinct stereochemical variants. The set includes measured optical rotation values and characterization of isolated stereochemical and isotopic forms. Example compound sets are described with cyclohexyl/aryl fused cores, heteroaromatic substituents, and halogen variants such as Cl and F.

Claims Coverage

Independent claim coverage centers on a broad compound family of formula (Va) or (Vb), including tautomeric, stereochemically isomeric, isotopically labeled, and pharmaceutically acceptable salt or solvate forms. The claim family also includes CDK7-directed use claims and claim refinements to specific structural constraints. Four main inventive features are repeatedly supported across the input items.

Overall, claim coverage is anchored by a broad structural genus of formula (Va)/(Vb) with explicit inclusion of tautomeric, stereoisomeric, isotopically labeled, salt, and solvate forms, and it is functionally directed to CDK7 modulation or inhibition and treatment of cancers with elevated or abnormal CDK7 activity.

Stated Advantages

Documented Applications