CDK2 inhibitors
Inventors
Wilson, Douglas • Bifulco, JR., Neil • Brooijmans, Natasja • Kim, Joseph L. • Perola, Emanuele • Ramsden, Philip D. • Vargas, Richard • Wenglowsky, Steven Mark
Assignees
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Publication Number
US-11932648-B2
Publication Date
2024-03-19
Expiration Date
Abstract
The present disclosure provides a compound represented by structural Formula (I): or a pharmaceutically acceptable salt thereof useful for treating a cancer.
Core Innovation
This disclosure describes selective cyclin-dependent kinase 2 (CDK2) inhibitors for treating cancer. The compounds are defined by structural Formula (I) and structural Formula (Ia), together with pharmaceutically acceptable salts thereof, and include substituted pyrazolo[3,4-b]pyrazine derivatives, including pyrazolo[3,4-b]pyrazin-6-amine variants. The structures are specified through constrained choices of Ring A and Ring B and multiple substituent variables R1-R7, with enumerated allowed atom types and groups, including halo, deuterium, OH, CN, heteroaryl, and heterocyclyl fragments with defined ring sizes and heteroatom counts.
The disclosure states a need for CDK2 inhibitors used in cancer treatment with selectivity characteristics across the CDK family of kinases. CDK2 selectivity, including reduced activity relative to CDK1, is presented as functionally relevant to treatment outcomes and tolerability. The invention provides selective CDK2 inhibitor compounds in a structural framework that enables multiple embodiments via constrained definitions of Ring A, Ring B, and substituent patterns.
The disclosed examples and description content include stereodefined examples with difluoromethoxy and other substituted side chains. Example structures include cyclopropyl, oxetane, tetrahydro-2H-pyran, pyridinyl, thiazole, fluorinated, and chiral substituent motifs, with reported isolated compounds, intermediates, and analytical characterization. The content also references stereochemical resolution, enantiomeric forms, and example compounds within the claimed formula space.
Claims Coverage
Two independent claims are provided: clm-00001 and clm-00018. Each independent claim defines a pharmaceutical compound or pharmaceutically acceptable salt by a constrained multi-ring scaffold with enumerated substituent variables and ring selections; both claims include CDK2-inhibitor structure embodiments expressed through Formula (Ia) or Formula (I) and substitution ranges for the variable groups.
Formula (Ia) selective scaffold compound
A compound of Formula (Ia), or a pharmaceutically acceptable salt thereof, wherein R1, R2 (as alkyl or Ring A), and R3 are selected according to enumerated substituent options; Ring A is selected from specified ring systems; R2/R3 or their combination forms Ring B with Ring B defined as cycloalkyl or heterocyclyl; and Ra, Rb, Rc, and Rd substituent variables are selected from enumerated allowed groups with specified optional substitution patterns, including allowed ring heteroatoms and substitution-count constraints.
Formula (I) selective scaffold compound
A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1, R2 (as alkyl or Ring A), and R3 are selected according to enumerated substituent options; R2 and R3 or their combination forms Ring B with Ring B defined as cycloalkyl or heterocyclyl; Ring A is selected from specified ring systems; and Ra, Rb, Rc, and Rd along with R4 and R5 substituent variables are selected from enumerated allowed groups with specified optional substitution patterns, including allowed ring heteroatoms and substitution-count constraints.
Across clm-00001 and clm-00018, the independent claims are directed to specific Formula (Ia) and Formula (I) compound scaffolds or pharmaceutically acceptable salts defined by enumerated choices for Rings A and B and by structured substituent definitions for R1-R7, including Ra/Rb/Rc/Rd and R4/R5, with explicit constraints on ring sizes, heteroatom counts, and the number and types of optional substituents.
Stated Advantages
Enabling dosing
Reducing CDK1-mediated toxicities
Potentially improved microsomal stability/toxicity profiles
CDK2 selectivity over CDK-family kinases, notably CDK1
Treatment of cancer by administration of the selective CDK2 inhibitor compounds or salts/compositions.
Treatment of uterine cancer.
Treatment of endometrial cancer.
Treatment of breast cancer.
Treatment of ovarian cancer.
Documented Applications
Treatment of cancer by administration of the selective CDK2 inhibitor compounds or salts/compositions.
Treatment of uterine cancer.
Treatment of endometrial cancer.
Treatment of breast cancer.
Treatment of ovarian cancer.
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