Certain chemical entities, compositions, and methods
Inventors
Qian, Xiangping • Zhu, Yong-Liang
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10947201-B2
Publication Date
2021-03-16
Expiration Date
Abstract
Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.
Core Innovation
The invention is directed to a compound having a specified chemical formula, or a pharmaceutically acceptable salt thereof, defined by positional variables including X or X10 as aryl or heteroaryl, R3, R4, R5, and R6 independently hydrogen, cyano, fluoro, or chloro, and R34, R35, R36, R37, and R38 independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkyl, optionally substituted amino, or E. At least one of R34, R35, R36, R37, and R38 is E, and E is defined as an electrophilic group capable of covalent bond formation with cysteine or a nucleophile.
The substituted alkoxy and substituted amino groups are defined by constrained structural forms, including O-(substituted alkyl) and NHRd or NRdRe, with substituted alkyl and substituted heterocycloalkyl further limited to selected substituents under defined size and substitution constraints. The scaffold also includes Q independently hydrogen, cyano, or halo, m as 0, 1, or 2, and additional variable positions and linker elements described for the general compound family.
The disclosed subject matter is also presented as substituted quinazoline-based acrylamide compounds and related acrylamide derivative frameworks, including quinazolin-2-yl motifs, an anilide/acrylamide linkage, and varied aryl or heteroaryl substituents. Example compounds include piperazine, piperidine, pyrrolidine, morpholine, and azetidinyl-containing substituents, as well as fluorinated and chlorinated aryl or pyridyl groups.
The patent places these compounds in a pharmaceutical and therapeutic context for cancer and EGFR-mediated disorders. It describes treatment frameworks in which a therapeutically effective amount of the compound or a pharmaceutically acceptable salt is administered, and one method includes determining whether an EGFR mutation is present in an isolated biological sample before administration.
Claims Coverage
The consolidated independent-claim coverage is directed to a formula-defined compound, or pharmaceutically acceptable salt thereof, with one electrophilic substituent E required among the specified variable positions. Across the combined claims material, the main inventive features are the constrained formula variables, the placement and definition of E, the restricted substitution rules for alkoxy, amino, alkyl, and heterocycloalkyl groups, and therapeutic administration for EGFR-mediated disorders.
Formula-defined compound with constrained variable positions
A compound having a specified chemical formula, or a pharmaceutically acceptable salt thereof, wherein X or X10 is aryl or heteroaryl; R3, R4, R5, and R6 are independently hydrogen, cyano, fluoro, or chloro; R34, R35, R36, R37, and R38 are independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted heterocycloalkyloxy, optionally substituted heterocycloalkyl, optionally substituted amino, or E; Q is independently hydrogen, cyano, or halo; and m is 0, 1, or 2.
Electrophilic group E present at least once
E is defined as an electrophilic group capable of covalent bond formation with cysteine or a nucleophile, and at least one of R34, R35, R36, R37, and R38 is E.
Restricted substitution patterns for alkoxy, amino, alkyl, and heterocycloalkyl groups
Each substituted alkoxy is O-(substituted alkyl), each substituted amino is NHRd or NRdRe, and substituted alkyl and substituted heterocycloalkyl are limited to substitution with defined groups under the stated size and substitution constraints.
Quinazoline-based acrylamide derivative embodiments
The claim material also includes specific N-(...)-substituted phenyl acrylamide derivative embodiments featuring quinazolin-2-yl or quinazoline motifs and various substituted fluorophenyl, chlorophenyl, fluoropyridin, or chloropyridin groups plus different amino or oxy substituents.
Therapeutic administration for an EGFR-mediated disorder
A method for treating an EGFR-mediated disorder in a subject by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
EGFR mutation presence-guided administration
A method for treating a disorder in a subject by determining whether an EGFR mutation is present in an isolated biological sample and, if present, administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
Packaged pharmaceutical composition for cancer treatment
A packaged pharmaceutical composition including the pharmaceutical composition and instructions for using it to treat a subject with cancer.
The claim coverage centers on a chemically defined compound family with tightly constrained substituent variables and a required electrophilic E substituent among the designated positions. The merged claim scope also includes quinazoline-based acrylamide derivative embodiments, the same limited substitution rules for the alkyl and heterocycloalkyl framework, and therapeutic, mutation-guided, and packaged-use claims for cancer and EGFR-mediated disorders.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating cancer by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
Treating an EGFR-mediated disorder in a subject by administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
Determining whether an EGFR mutation is present in an isolated biological sample and, if present, administering a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof.
A packaged pharmaceutical composition including instructions for using it to treat a subject with cancer.
Kinase inhibition activity against BTK and EGFR, including EGFR L858R and EGFR L858R/T790M mutants.
Cancer cell growth inhibition activity.
Treating a subject with cancer using a packaged pharmaceutical composition.
Interested in licensing this patent?