Inhibitors of cyclin-dependent kinases
Inventors
Kanouni, Toufike • Arnold, Lee • Kaldor, Stephen W. • Murphy, Eric A.
Assignees
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Publication Number
US-11447493-B2
Publication Date
2022-09-20
Expiration Date
Abstract
Provided herein are inhibitors of cyclin-dependent kinases (CDKs), pharmaceutical compositions comprising said compounds, and methods for using said compounds for the treatment of diseases.
Core Innovation
The invention relates to compounds, or pharmaceutically acceptable salts or solvates thereof, defined by Formula (I), Formula (II), Formula (III), and Formula (IV) structural frameworks. The disclosed compounds are CDK inhibitory heteroaromatic compounds and include quinazoline or isoquinoline-derived heteroaromatic structures, related fused heterocycles such as pyrido[2,3-d]pyrimidin and benzo[b][1,4]oxazin, and variable substituent patterns including E, G, L, q, n, m, X, Y, R1-R5, R11, and R15-R18.
The compounds are described as stereodefined and enumerated in selected examples, including (R)-configured structures and additional stereochemical descriptors where stated. The examples include quinazolin-2-ylamino and isoquinolin-3-ylamino motifs linked through carbonyl-containing piperidine, pyrrolidine, or azetidine frameworks to phenyl acrylamide, enamide, propiolamide-like, but-2-enamide, butanamide, ethenesulfonamide, and ynamide functional patterns, with substituent variation such as fluoro, chloro, methoxy, methyl, methyl sulfonyl, cyano, and related analogs.
The disclosure also includes modified CDK12 or CDK13 polypeptides corresponding to Formula (IV) structural substituent patterns, as well as pharmaceutical composition and therapeutic-use embodiments. Therapeutic-use embodiments include cancer and neoplastic disease, breast cancer, colorectal cancer, ovarian cancer, pancreatic cancer, prostate cancer, lung cancer, and myotonic dystrophy type 1, and the compounds are further described in isotopically enriched forms including deuterated variants.
Claims Coverage
The consolidated claim coverage includes broad Formula (I) compound claims and narrower enumerated compound claims, together with a method claim for CDK inhibition. In total, the merged set covers the defined heteroaromatic chemical space through structural variables and selected compound lists, plus one functional inhibition use claim.
Formula (I) heteroaromatic CDK inhibitory compound
A compound, or pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (I), with defined selections for E, G, L, q, n, m, X, Y, R1-R5, R11, and R15-R18.
Defined substituent group Y with R15-R18 options
A Formula (I) compound in which Y is selected from the listed group options and R15, R16, R17, and R18 are independently selected from the stated substituent classes and related groups.
Enumerated stereodefined heteroaryl acrylamide/enamide/propiolamide-like compounds
A compound, or pharmaceutically acceptable salt or solvate thereof, selected from enumerated (R)-configured quinazoline/isoquinoline and related fused heterocycle structures bearing acrylamide, enamide, propiolamide-like, but-2-enamide, butanamide, ethenesulfonamide, or ynamide motifs.
Quinazolin-2-ylamino or isoquinolin-3-ylamino carbonyl-linked scaffold
Selected compounds in which a quinazolin-2-ylamino or isoquinolin-3-ylamino unit is linked through a carbonyl-containing piperidine, pyrrolidine, or azetidine framework to a substituted phenyl warhead.
CDK2/CDK7/CDK12 enzyme inhibition by contacting
A method for inhibiting CDK2, CDK7, and/or CDK12 enzymes by contacting them with the claimed compound.
The claim coverage centers on Formula (I) heteroaromatic CDK inhibitory compounds defined by extensive substituent and ring-parameter variables, a selected Y group with R15-R18 options, and enumerated stereodefined quinazoline/isoquinoline-related compounds bearing carbonyl-linked heterocyclic scaffolds and acrylamide/enamide/propiolamide-like motifs. The consolidated set also includes a method for inhibiting CDK2/CDK7/CDK12 enzymes by contacting them with the claimed compound.
Stated Advantages
Inhibiting CDK2, CDK7, and/or CDK12 enzymes.
Improved metabolic stability
Improved efficacy
Extended duration of action
Documented Applications
A method for inhibiting CDK2, CDK7, and/or CDK12 enzymes by contacting them with the claimed compound.
Pharmaceutical compositions comprising a compound of Formula (I) or Formula (II) and a pharmaceutically acceptable excipient.
Methods of treating disease by administering a compound of Formula (I) or Formula (II), with cancer optionally included as a disease context.
IC50 profiling of kinase targets CDK12, CDK2, and CDK7 using thiol-containing and thiol-free radiometric kinase assays.
Pharmaceutical composition and therapeutic-use embodiments.
Cancer and neoplastic disease.
Breast cancer.
Colorectal cancer.
Ovarian cancer.
Pancreatic cancer.
Prostate cancer.
Lung cancer.
Myotonic dystrophy type 1.
Oral capsule.
Solution for injection.
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