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-11492348-B2
Publication Date
2022-11-08
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 is directed to compounds of Formula (I), including pharmaceutically acceptable salts, with a structurally variable scaffold incorporating aryl, heteroaryl, heterocycloalkyl, and cycloalkyl groups. The structure is defined by parameterized variables m, n, o, and p, each independently 0, 1, or 2, together with allowed substituent patterns on the R1-type group and on linked ring systems. The disclosed examples include morpholinophenyl, pyrimidin-2-amine, pyridazin-3-amine, and pyridin-2-amine core space linked by sulfonyl or related linkers, with hydrochloride salt forms and chiral enantiomers also described.
The scaffold further includes a linker component L selected from S(O)2, C(O), O, CH2, CF2, C(CH3)2, C(=CH2), or CRsRt, with X being O and with heteroatom patterns defined by Y1, Y2, and Y3. The claims and description specify that one of Y1, Y2, and Y3 is N and the other two are CH, together with constraints on G2 through G6 and on R3, R5, and R6. Additional constraints define Ru, Rv, Rw, and Ry, and the possibility that R7 and R8 are taken together to form CH2CH2.
The dependent formulae narrow the general Formula (I) space through Formula (II) and Formula (III), which assign specific values and patterns to X, Y1-Y3, G2-G6, and related substituent variables. Table 1 compounds are disclosed as example compounds featuring a pyrimidin-2-amine scaffold with a phenylsulfonyl-linked phenyl ring and a morpholine substituent, with variations including heteroaryl substituents and halo, alkyl, trifluoromethyl, methoxy, and trifluoromethoxy decorations. The document also includes pharmaceutical composition and treatment method aspects connected to diseases or medical conditions associated with autophagy or the PI3K-AKT-MTOR pathway.
Claims Coverage
The claim coverage centers on one broad independent claim directed to a compound of Formula (I) with extensive structural variability and explicit inclusion of pharmaceutically acceptable salts. Dependent claims refine the scaffold by fixing specific heteroatom patterns and by selecting compounds defined by Formula (II) and Formula (III), and the provided material also includes pharmaceutical composition and treatment method coverage.
Formula (I) compound scaffold with variable R1 substituents
A compound of Formula (I) wherein R1 is selected from aryl, CH=CH-aryl, heteroaryl, heterocycloalkyl, or cycloalkyl groups with m, n, o, and p each independently 0, 1, or 2, and with the allowed substituent classes on these groups defined by the claim.
Defined linker and heteroatom pattern constraints
L is selected from S(O)2, C(O), O, CH2, CF2, C(CH3)2, C(=CH2), or CRsRt; X is O; and Y1, Y2, and Y3 are constrained so that one is N and the other two are CH.
Ring-position constraints via G2 through G6
G2 is N; G3 is CR3; G4 is N; G5 is CR5; and G6 is CR6, with further constraints on R3, R5, and R6, and on Ru, Rv, Rw, and Ry.
Substituent limits for R3, R5, R6, Rv, and terminal groups
R3, R5, and R6 are each independently hydrogen, halogen, OH, alkyl, Oalkyl, haloalkyl, O-haloalkyl, or NRuRv; Ru is H or C1-4 alkyl; Rv is H, C1-4 alkyl, monocyclic cycloalkyl, C(O)C1-4 alkyl, or C(O)NRwRy; and R7 and R8 are each independently hydrogen or C1-4 alkyl, or are taken together to form CH2CH2.
Formula (II) structural narrowing
A compound defined by Formula (II), including specified values for X, Y1-Y3, G2-G6 and detailed substituent definitions for additional variables, with allowance for pharmaceutically acceptable salts.
Formula (III) structural narrowing
A compound according to Formula (III), which defines particular substituent groups and their allowed structural variations, including allowance for pharmaceutically acceptable salts.
Pharmaceutical composition with excipient
A pharmaceutical composition containing at least one compound of Formula (I) or a pharmaceutically acceptable salt together with a pharmaceutically acceptable excipient.
Treatment method for autophagy or PI3K-AKT-MTOR-linked diseases
A method of treatment for 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.
The claims define a broad Formula (I) compound space with constrained linker, heteroatom, and ring-position patterns, then narrow that space through specific heteroatom patterning and through Formula (II) and Formula (III). Additional coverage extends to pharmaceutical compositions and treatment methods linked to autophagy or the PI3K-AKT-MTOR pathway.
Stated Advantages
PI3K inhibition is stated to increase autophagy markers and cellular clearance of toxic protein aggregates.
Documented Applications
Treatment methods for diseases associated with autophagy dysregulation or PI3K-AKT-MTOR misregulation, including neurodegenerative disorders and dermatological disorders such as rosacea, acne, psoriasis, and atopic dermatitis.
PI3Kα inhibition.
mTOR assay.
pAKT pathway inhibition, including pAKT (Ser-473) inhibition.
Pharmaceutical compositions containing at least one compound of Formula (I) or a pharmaceutically acceptable salt together with a pharmaceutically acceptable excipient.
Treatment of diseases or medical conditions 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.
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