Pyrimidine and pyridine amine compounds and usage thereof in disease treatment
Inventors
Beaton, Graham • Tucci, Fabio • RAVULA, Satheesh • Lee, Suk Joong • Shah, Chandravadan
Assignees
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Publication Number
US-12234224-B2
Publication Date
2025-02-25
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 is directed to a method for treating a S6K-dependent or S6K-mediated disease or condition in a subject by administering an effective amount of a compound or a pharmaceutically acceptable salt thereof. The compound is defined by a Formula I structure incorporating a pyrazole moiety and a pyrimidine or pyridine ring, with defined substituent variables including X, R1A, R1A′, R1B, L1, R1C, Ring A, and the remaining aromatic carbon atom(s) substituted or unsubstituted by RJ.
In Formula I, X is selected as N or a substituted or unsubstituted carbon atom, Ring A is a pyrazole moiety with RH substituents, and the substituent parameters are limited to enumerated groups for each variable, including substituted phenyl, C5–C6 heteroaryl, aryl, heteroaryl, alkylene, cycloalkylene, heterocycloalkylene, halogen, alkyl, fluoroalkyl, alkoxy, cycloalkyl, and related functional groups. The structure further constrains the remaining aromatic carbon atom(s) of the pyrimidine or pyridine ring to be unsubstituted or independently substituted by RJ options.
The disclosure includes broad permitted variability for the aryl or heteroaryl substituent R^B and the aryl or heteroaryl substituent R^C, together with a broad allowable set of linker L^1 types. The detailed description also includes numerous stereoisomeric and structural analogs built on a shared pyrazole–pyrimidine scaffold with aryl substitutions, together with embodiments including pharmaceutically acceptable salts.
Claims Coverage
The claim coverage centers on one core structural formula with multiple inventive structural elements, including X, R1A/R1A′, R1B, L1, R1C, Ring A pyrazole, and the substitution rules for the remaining aromatic carbon atom(s) and RJ, together with treatment-by-administration and pharmaceutically acceptable salts. Across the claim set, there are three merged inventive features.
Treatment of S6K-dependent or S6K-mediated disease by Formula I administration
A method for treating a S6K-dependent or S6K-mediated disease or condition in a subject by administering an effective amount of a compound, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula I.
Formula I pyrazole–pyrimidine or pyridine scaffold
The administered compound has the structure of Formula I with a pyrazole moiety (Ring A), a pyrimidine or pyridine ring, and defined variables including X, R1A, R1A′, R1B, L1, R1C, and RJ, with the remaining aromatic carbon atom(s) unsubstituted or independently substituted.
Enumerated substituent options for structural variables
The structure is limited by enumerated substituent options for Ring A RH substituents and for variables such as R1A, R1A′, R1B, L1, R1C, and RJ, including dependent refinements that select particular L1 and RF options and, in at least one refinement, R^G = −CF3.
Overall, the claim coverage requires the therapeutic method to use a Formula I compound or pharmaceutically acceptable salt with fixed scaffold elements: the pyrazole Ring A, the pyrimidine or pyridine core, and defined substitution at X, R1A, R1A′, R1B, L1, R1C, and RJ.
Stated Advantages
Compounds lacking initial S6K inhibitory activity can acquire activity via in vivo metabolism (Phase I/II).
Documented Applications
Treating a S6K-dependent or S6K-mediated disease or condition in a subject using a Formula I compound, including pharmaceutically acceptable salts.
S6K-dependent disease or condition selected from diabetes and diabetic complications, organ fibrosis, liver disease, or autism spectrum disorders.
S6K-mediated disease or condition limited to nonalcoholic steatohepatitis (NASH) or Fragile X syndrome.
Treating S6K-dependent or S6K-mediated diseases or conditions in a subject, including cancer, pulmonary fibrosis, idiopathic pulmonary fibrosis, obesity, diabetes, NASH, liver fibrosis, liver cancer, insulin resistance, hyperglycemia, hyperaminoacidemia, hyperlipidemia, autism spectrum disorders, and Fragile X syndrome.
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