Tri-substituted aryl and heteroaryl derivatives as modulators of PI3-kinase and autophagy pathways
Inventors
Stocking, Emily M. • Wrasidlo, Wolfgang J.
Assignees
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Publication Number
US-12049462-B2
Publication Date
2024-07-30
Expiration Date
Abstract
The present disclosure relates to tri-substituted aryl and heteroaryl derivatives. pharmaceutical compositions containing them, and methods of using them, including methods for modulating autophagy or preventing, reversing, slowing or inhibiting the PI3K-AKT-MTOR pathway, and methods of treating diseases that are associated with autophagy or the PI3K-AKT-MTOR pathway.
Core Innovation
The invention relates to compounds of Formula (I), Formula (II), and Formula (III), including pharmaceutically acceptable salts. The compounds are defined by extensive structural constraints on R1, linker L, X, Y1-Y3, G2-G6, and related substituents, with permitted scope including aryl, heteroaryl, heterocycloalkyl, and cycloalkyl variants with limited substitution patterns.
Additional structural constraints define linker and ring patterns, including L being absent or selected from S(O)2, C(O), O, CH2, CF2, C(CH3)2, C(≃CH2), or CRsRt, while X is O and the disclosed claim sets fix the heteroatom pattern across the scaffold. The examples include substituted pyrimidin-2-amine compounds, sulfonyl-linked aryl or heteroaryl fragments, morpholine-bearing aryl or pyrimidinyl sulfonyl analogs, azetidine or other cyclic amine variants, and substituted phenyl, benzyl, pyridine, pyrimidine, and related heteroaryl motifs.
The patent further states that the compounds modulate the PI3K-AKT-MTOR pathway and activate autophagy. It links these compounds to inhibition of PI3K-AKT-MTOR activity, including AKT/mTOR phosphorylation, PI3K pathway activity, increased autophagy markers, cellular clearance of toxic aggregates, PI3Kα ATP→ADP conversion, mTOR kinase activity, and loss of pAKT.
Claims Coverage
The consolidated claim coverage centers on Formula (I) compounds with extensive structural parameter constraints, together with Formula (II) and Formula (III) definitions where present in the provided excerpts. Independent claim features focus on variable R1 frameworks, permitted Rx substitution, fixed scaffold variables such as L and X, and defined heteroatom patterns across Y1-Y3 and G2-G6. The provided excerpts also include treatment claims and a pharmaceutical composition claim.
Formula (I) compound with variable R1 framework and substituent constraints
A compound of Formula (I) wherein R1 is selected from aryl, CH2-aryl or CH=CH-aryl, heteroaryl, heterocycloalkyl, or cycloalkyl variants, with m, n, o, and p each independently 0, 1, or 2; each ring system in R1 is unsubstituted or substituted with one or two Rx substituents defined by the permitted substituent list; and the scope includes the stated substituent restrictions for Ra-Rh and related groups.
Formula (I) scaffold parameters including L, X, and ring-atom constraints
L is absent or selected from S(O)2, C(O), O, CH2, CF2, C(CH3)2, C(≃CH2), or CRsRt; X is O; Y1, Y2, and Y3 are each CH or follow the stated narrower pattern; G2 is N; G3 is CR3; G4 is N; G5 is CR5; and G6 is CR6, with the further stated options for R3, R5, R6, Ru, Rv, R7, and R8.
Formula (I) compound with R6 as NRuRv
A compound of Formula (I) or a pharmaceutically acceptable salt thereof in which R6 is NRuRv.
Formula (I) compound with L as S(O)2
A compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein L is S(O)2.
Formula (I) compound with L absent
A compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein L is absent.
Formula (III) compound
The compound is a compound of Formula (III), with specified substituent definitions and variable constraints, and may be a pharmaceutically acceptable salt thereof.
Treating a disease linked to autophagy or the PI3K-AKT-MTOR pathway
A method of treating a disease or medical condition linked to autophagy or the PI3K-AKT-MTOR pathway by administering an effective amount of at least one compound of Formula (I) or a pharmaceutically acceptable salt thereof.
Pharmaceutical composition containing a Formula (I) compound
A pharmaceutical composition containing at least one Formula (I) compound or pharmaceutically acceptable salt together with a pharmaceutically acceptable excipient.
Overall, the claim coverage defines a structurally constrained Formula (I) compound family, with additional dependent refinements for the linker L, the heteroatom pattern, and specific substituent choices such as R6 as NRuRv. The provided excerpts also extend to Formula (III) coverage, to treatment claims targeting autophagy or the PI3K-AKT-MTOR pathway, and to a pharmaceutical composition containing a Formula (I) compound and an excipient.
Stated Advantages
Inhibits PI3K-AKT-mTOR activity, including AKT/mTOR phosphorylation.
Increases autophagy markers.
Increases cellular clearance of toxic aggregates.
Reports biological activity associated with PI3K-pathway inhibition, including PI3Kα ATP→ADP conversion, mTOR kinase activity, and loss of pAKT.
Documented Applications
Treating diseases or medical conditions associated with autophagy or the PI3K-AKT-MTOR pathway.
Neurodegenerative disorders including Alzheimer’s disease and Parkinson’s disease.
Cancers.
Infections.
Dermatological disorders including rosacea, atopic dermatitis, acne, and psoriasis.
Methods of treating a disease or medical condition linked to autophagy or the PI3K-AKT-MTOR pathway by administering an effective amount of at least one Formula (I) compound or a pharmaceutically acceptable salt to a subject.
A pharmaceutical composition containing at least one Formula (I) compound or pharmaceutically acceptable salt together with a pharmaceutically acceptable excipient.
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