Pyrimidines as EGFR-inhibitors and methods of treating disorders
Inventors
Gray, Nathanael S. • Janne, Pasi • Choi, Hwan Geun • JANG, Jaebong
Assignees
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Publication Number
US-12331037-B2
Publication Date
2025-06-17
Expiration Date
Abstract
The application relates to a compound having Formula (I): which modulates the activity of EGFR, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which EGFR plays a role.
Core Innovation
The invention relates to compounds of Formula (I) and to pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof. The compounds are defined by specific substituent constraints, including that Z1, Z2, and Z3 are each N, and by variable groups R1 through R15 with selections such as hydrogen, alkyl, haloalkyl, amino-containing groups, halogen, alkoxy, and specified heterocycle patterns. The document also includes structural embodiments of Formula (Ia) to Formula (Ic).
The description frames the compounds as EGFR-targeting pyrimidine small-molecule inhibitors and EGFR modulators. The compounds are presented as a route to improve performance in EGFR-driven cancers and in settings involving EGFR TKI resistance, including resistance associated with EGFR T790M and other EGFR mutations. The document places the invention in the context of covalent irreversible EGFR inhibitor activity and cites comparator agents such as afatinib, WZ4002, CO-1686, and AZD9291.
In addition to the chemical compounds, the invention includes pharmaceutical compositions and methods of use. The document states that the compounds and compositions are for inhibiting EGFR and for treating or preventing EGFR- or ERBB2-associated diseases, including EGFR therapy-resistant cancers. The scope also includes therapeutic use related to resistance to EGFR-targeted therapy and formulation with a pharmaceutically acceptable carrier.
Claims Coverage
The consolidated content presents one independent claim framework defining a compound of Formula (I) and a further independent therapeutic use framework related to EGFR inhibition and EGFR- or ERBB2-associated disease. The compound claim contains multiple structural constraints across Z1-Z3 and R1-R15, while dependent claims further narrow specific substituent choices, ring-forming relationships, and structural Formula (Ic).
Formula (I) pyrimidine EGFR modulating compound class
A compound of Formula (I), or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein Z1, Z2, and Z3 are each N and R1-R15 are restricted to defined groups and size ranges, including ring-forming options for R9 and R10 with the nitrogen atom to form a 5- to 7-membered heterocycle optionally comprising additional heteroatoms and optional substitution.
Therapeutic use for EGFR or ERBB2-associated disease
A method of treating or preventing EGFR- or ERBB2-associated diseases, including EGFR therapy-resistant cancers, using the compounds or compositions described in the partial content.
R2 constrained to hydrogen
The compound of Formula (I) is further defined such that R2 is —H.
R12 hydrogen and R13 alkenyl length constraint
The compound of Formula (I) is further defined such that R12 is —H and R13 is a (C2-C6) alkenyl group.
Structural Formula (Ic) with specified variable assignments
A compound defined as having structural Formula (Ic) with specified variable definitions for X1-X6 and the corresponding R substituents, together with pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, and tautomers of that structure.
Pharmaceutical composition using the claimed compound
A pharmaceutical composition including a compound of Formula (I) and a pharmaceutically acceptable carrier.
The claim coverage centers on a structurally restricted Formula (I) compound class, including salts, hydrates, solvates, stereoisomers, and tautomers, and on therapeutic use related to EGFR inhibition and EGFR- or ERBB2-associated disease. The inventive features include the constrained substitution pattern, the requirement that Z1-Z3 are each N, the specified allowable groups and ring-forming relationships for the R-variable substituents, the structural Formula (Ic) embodiment, and the pharmaceutical composition claim.
Stated Advantages
Improves mutant selectivity.
Reduces toxicity.
Provides potent irreversible pyrimidine EGFR inhibitors.
Addresses continuing need for new potent irreversible pyrimidine EGFR inhibitors.
Enhanced potency against drug-resistant EGFR mutants compared with wild-type EGFR, expressed as up to 10,000-fold.
Covalent modification of EGFR Cys797 is described as part of the mechanism for EGFR inhibition.
Documented Applications
Treating or preventing EGFR- or ERBB2-associated diseases, including EGFR therapy-resistant cancers.
Method of inhibiting EGFR.
Method of inhibiting kinase.
Method for treating resistant to EGFR-targeted therapy.
Therapeutic use for EGFR-mediated diseases, especially cancer, including lung cancer, breast cancer, colon cancer, and prostate cancer.
Therapeutic use for inflammation-related conditions, including arthritis and systemic lupus erythematosus (SLE).
Characterization of specific example compounds using HPLC retention time, LC-MS [M+H] m/z, and 1H NMR signals, with accompanying chemical structure depictions of poly-heteroaromatic EGFR inhibitor-like scaffolds [procedural detail omitted for safety].
Downstream biochemical/biological study context referencing kinase inhibitor synthesis references, cell culture of EGFR mutant NSCLC lines, generation of drug-resistant EGFR mutant cells, and cell proliferation/clonogenic assay conditions, with Table 2 reporting cell proliferation data across mutant EGFR cell lines for WZ4002/AZD9291/Compound I-1 [procedural detail omitted for safety].
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