Inhibitors of cyclin-dependent kinase 7 and uses thereof

Inventors

Gray, Nathanael S. • Zhang, Tinghu • Kwiatkowski, Nicholas Paul • Jiang, Jie • Hao, Mingfeng • He, Zhixiang

Assignees

Dana Farber Cancer Institute Inc

Abstract

The present disclosure provides compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. The compounds of the present disclosure are inhibitors of kinases (e.g., a cyclin-dependent kinase (CDK) (e.g., CDK7)). The compounds may be selective for inhibiting the activity of a kinase (e.g., CDK7) over certain other kinases (e.g., CDK2, CDK9, CDK12). Also provided are pharmaceutical compositions, kits, methods of use, and uses that involve the compounds. The compounds may be useful in inhibiting the activity of a kinase, down-regulating the transcription of MYC or MCL-1, inhibiting the growth of a cell, inducing apoptosis of a cell, treating a disease, and/or preventing a disease (e.g., proliferative disease, cystic fibrosis).

Core Innovation

The invention concerns compounds of Formula (I), including pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, polymorphs, co-crystals, and prodrugs. Ring A is aryl or heteroaryl, and R1 is NHC(O)CH=CH2 or L3, where L3 is a substituted or unsubstituted C1-4 hydrocarbon chain. The scaffold further includes m as 0 or 1 and L as a single bond or —C(=O)—, together with substituent options controlled by p, q, D, R9, R10, and R11.

One of R9 and R10 is hydrogen and the other is —(CH2)N(CH3)2, and R11 is substituted or unsubstituted alkyl. When p=0, D is piperidinyl or 1,2,3,4-tetrahydroisoquinolinyl, and when p=1, D is tetrahydropyranyl or tetrahydrofuryl. The disclosed compound set includes multiple variants and named exemplary compounds described as dihydropyrrolo[3,4-c]pyrazole or pyrrolo[3,4-c]pyrazole derivatives.

The compounds are described as CDK7-inhibiting compounds with binding modes in which R1 can covalently or irreversibly attach to CDK7 Cys312 or reversibly bind through noncovalent interactions. The disclosure states intended biological effects including kinase inhibition, down-regulation of MYC/MCL-1 transcription, induction of apoptosis, and inhibition of cell growth, and it includes pharmaceutical compositions and kits.

Claims Coverage

The consolidated claim coverage centers on a Formula (I) compound family with defined structural parameters. The independent claims include 5 inventive features: the Formula (I) scaffold, p-controlled D selection, fixed R9/R10 substitution, and a method for inhibiting CDK7 activity using the compound or a related pharmaceutically acceptable derivative.

Overall, the claims cover a Formula (I) compound scaffold defined by Ring A, R1, L, m, p, q, D, R9, R10, and R11, and include CDK7 inhibition by administration or contacting with an effective amount of the claimed compound or a related pharmaceutically acceptable derivative.

Stated Advantages

Documented Applications