Pyrimidine and pyridine amine compounds and usage thereof in disease treatment
Inventors
Beaton, Graham • Tucci, Fabio • RAVULA, Satheesh • Lee, Suk Joong • Shah, Chandravadan
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11866421-B2
Publication Date
2024-01-09
Expiration Date
Abstract
Pyrimidine and Pyridine containing compounds are described herein that are enzyme p70S6K inhibitors useful in the treatment of S6K-dependent or S6K-mediated diseases and conditions, including but not limited to cancer, fibrotic metabolic and certain neurological disorders.
Core Innovation
The invention relates to pyrazole-containing compounds and salts thereof defined by a Formula I scaffold in which Ring A is a pyrazole moiety and the compound is a pyrazole-pyrimidinylamine derivative. The scaffold is defined by substituent variables including X, R_A and R_A′, R_B, L1, R_C, Ring A substituents (R_H), R_D, and further substituent groups R_E, R_F, R_G, and R_J associated with the pyrimidine or pyridine ring.
General Formula II–IX embodiments describe additional permissible substitutions for key variables including X, R_B, L1, R_C, Ring A, and the substituent groups R_E/R_F/R_G/R_H/R_J with corresponding subscript constraints for the selected structures. Preferred embodiments include specified choices such as unsubstituted pyrazolyl and particular linker L1 options together with particular settings for X/R_B/R_F.
The disclosed compounds are presented with an S6K inhibitory profile and are described in the context of compositions and S6K-selective inhibition. The document states a problem of selecting compounds having sufficient S6K inhibitory activity, including activity in intact form, and describes compounds that may lack sufficient S6K inhibition in intact form but may acquire activity through Phase I and/or Phase II metabolism.
Claims Coverage
The patent includes independent claim coverage directed to a compound of Formula I (or a salt), with dependent claims narrowing the structural scope by fixing or constraining substituent and scaffold parameters. The claim coverage also extends to compositions and S6K-selective inhibition for treating S6K-mediated disease states, and includes enumerated substituted stereochemically defined compounds within the Formula I scope.
Formula I pyrazole scaffold with defined substituent variables
A compound of Formula I (or a salt thereof) having Ring A as a pyrazole moiety and a pyrimidinylamine portion, with X, R_A and R_A′, R_B, L1, R_C, Ring A substitution, R_D, and remaining substituents R_E, R_F, R_G, and R_J defined by the provided substituent groups and constraints.
Defined pyrazole ring substitution limits
The pyrazole moiety is unsubstituted or substituted with one or two R_H substituents at its aromatic carbon atoms, where each R_H is independently selected from the listed monovalent C-linked moiety, —OH, —CN, C1-C4 alkoxy, —OC1-C4 fluoroalkyl, C1-C20 alkyl, C3-C6 cycloalkyl, C1-C4 fluoroalkyl, and halogen.
Defined remaining aromatic carbon atoms of pyrimidine or pyridine ring
The remaining aromatic carbon atom(s) of the pyrimidine or pyridine ring of formula I are unsubstituted or independently substituted by R_J, where each R_J, if present, is independently selected from the listed substituent groups.
Substituent selection constraints for R_E, R_F, and R_G
The substituents R_E, R_F, and R_G are constrained to the provided enumerated groups, including specific options for R_F and R_G and the rule that at least two adjacent R_E or R_G, if present, together define a substituted or unsubstituted C5-C6 carbocycle or heterocycle.
S6K-selective inhibition and medicament for treating S6K-mediated disease
Compositions and a medicament are provided for treating a subject with an S6K-dependent or S6K-mediated disease or condition, based on selective inhibition of S6K.
Overall, the claim set covers a Formula I chemical scaffold centered on a substituted pyrazole linked to a pyrimidinylamine framework, with defined structural and substituent constraints via variables X, R_A/R_A′, R_B, L1, R_C, R_D, R_E, R_F, R_G, and R_J. The scope also includes specific substituted stereochemically defined compounds and salts, together with compositions and treatment-oriented subject matter based on S6K-selective inhibition.
Stated Advantages
Inhibits p70S6K (S6K) for treating S6K-dependent or S6K-mediated diseases, as stated.
Provides treatment for diseases including cancer, fibrosis, metabolic disorders, and neurological disorders described as S6K-dependent or S6K-mediated.
Sufficient S6K inhibitory activity, including activity in intact form.
Compounds may acquire S6K inhibitory activity via Phase I and/or Phase II metabolism when not sufficiently active as intact entities.
Documented Applications
Treating S6K-dependent or S6K-mediated diseases, including cancer.
Treating fibrosis, including pulmonary fibrosis (IPF) and liver fibrosis, as described.
Treating metabolic disorders including obesity/diabetes-related conditions, including insulin resistance, hyperglycemia, hyperaminoacidemia, and hyperlipidemia, as described.
Treating neurological disorders including autism spectrum disorders and Fragile X syndrome, as described.
Treating a subject with an S6K-dependent or S6K-mediated disease or condition, including cancer, idiopathic fibrosis (IPF), NASH, diabetes, autism spectrum disorder, and Fragile X syndrome.
Evaluation of compounds for S6K inhibitory activity using an S6K enzymatic inhibition assay and a cell-based p70S6K inhibition assay.
Characterization of compounds by HPLC/MS using APCI MS.
Interested in licensing this patent?