Macrocycles for use in treating disease
Inventors
ROGERS, Evan W. • Ung, Jane • Nguyen, Vivian • Zhai, Dayong • Deng, Wei • CUI, Jingrong J.
Assignees
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Publication Number
US-11634433-B2
Publication Date
2023-04-25
Expiration Date
Abstract
The present disclosure relates to certain chiral diaryl macrocyclic derivatives, pharmaceutical compositions containing them, and methods of using them to treat cancer.
Core Innovation
The invention provides compounds of formula I, including chiral diaryl macrocyclic derivatives and pharmaceutically acceptable salts thereof. The compounds are defined by extensive substitution patterns for R1 and R2, R3 and R3′, R4 and R5, and R6 and R7, with allowable groups including hydrogen, deuterium, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, cycloalkyl, heterocycloalkyl, mono- or bicyclic heteroaryl, and multiple oxygen-, nitrogen-, phosphorus-, and sulfur-containing substituents.
The formula I framework further specifies optional substitution rules and structural options in which R3 and R3′ are independently selected, including the possibility that R3 and R3′ taken together with the carbon atom they are attached to form a C3-C6 cycloalkyl. The definitions for R4 and R5 include a broad list of substituent types, while R6 is selected from hydrogen, deuterium, or C1-C6 alkyl and R7 is selected from hydrogen or deuterium.
The patent describes these compounds as agents for treating cancer by inhibiting ALK receptor tyrosine kinase activity. It focuses on ALK and ALK fusion proteins, including EML4-ALK and NPM-ALK, and references ALK resistance mutations such as solvent-front and compound mutations, while also mentioning a selectivity aim over FGFRs.
The document additionally scopes the invention to pharmaceutical compositions comprising the compound of formula I, or a pharmaceutically acceptable salt thereof, together with optional at least one diluent, carrier, or excipient.
Claims Coverage
Independent claim coverage in the provided material centers on compounds of formula I with extensive substituent options and pharmaceutically acceptable salts, with additional claim scope extending to a pharmaceutical composition. The inventive coverage is centered on 2 grouped features in the provided material.
Compounds of formula I as chiral diaryl macrocyclic derivatives
A compound of the formula I wherein the substituent variables are defined by extensive enumerated options, including optional substitution patterns, and including a pharmaceutically acceptable salt thereof.
Pharmaceutical composition including a formula I compound
A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and optionally at least one diluent, carrier or excipient.
The provided material supports coverage anchored by compounds of formula I with extensive substituent flexibility and optional pharmaceutically acceptable salts. The claim scope also extends to a pharmaceutical composition comprising the formula I compound or salt, with optional diluent, carrier, or excipient.
Stated Advantages
Selectivity over FGFRs.
Targets ALK receptor tyrosine kinase activity in cancer, including ALK fusion proteins and ALK resistance mutations.
Biochemical kinase inhibition against ALK and mutant ALKs is reported with IC50 values below 10 nM for compounds 1 and 2 [procedural detail omitted for safety].
In vivo xenograft efficacy is reported with tumor growth inhibition/regression versus lorlatinib [procedural detail omitted for safety].
In vivo pharmacodynamic immunoblotting is reported to show reduced ALK phosphorylation [procedural detail omitted for safety].
Documented Applications
Treating cancer by inhibiting ALK receptor tyrosine kinase activity, including ALK fusion proteins and contexts involving ALK resistance mutations.
Use in described xenograft tumor model evaluation with references to ALK phosphorylation/inhibition and body-weight monitoring.
Biochemical kinase inhibition assays against ALK and mutant ALKs (including mutant ALKs) for compounds 1 and 2 [procedural detail omitted for safety].
Cell proliferation assays in ALK/EML4-ALK and other fusion-positive Ba/F3, KM12, and KG-1 models [procedural detail omitted for safety].
Evaluation of solubility at pH 7.4 and liver microsomal stability via intrinsic clearance [procedural detail omitted for safety].
Mouse pharmacokinetics and related in vivo measurements [procedural detail omitted for safety].
Subcutaneous xenograft efficacy with tumor growth inhibition/regression and comparison to lorlatinib [procedural detail omitted for safety].
In vivo pharmacodynamic immunoblotting showing reduced ALK phosphorylation [procedural detail omitted for safety].
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