Compounds and compositions as modulators of TLR signaling
Inventors
Natala, Srinivasa Reddy • Wrasidlo, Wolfgang J. • Stocking, Emily M.
Assignees
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Publication Number
US-11299487-B2
Publication Date
2022-04-12
Expiration Date
Abstract
The present disclosure relates to substituted aryl and heteroaryl compounds, pharmaceutical compositions comprising such compounds, and use of such compounds in methods of treatment or in medicaments for treatment of inflammatory diseases and certain neurological disorders that are related to inflammatory signaling processes, including but not limited to misfolded proteins.
Core Innovation
The invention relates to compounds of Formula (A), including tautomers and pharmaceutically acceptable salts of any of the foregoing. The compounds are defined by fixed substituents R1 as —OH, R2 as —C(O)H, and R3 as C1-C6 alkoxy or halogen, with G1 and G2 each CH and the ring indicated as aromatic. The structural framework further defines Y1-Y5 with allowed atom choices and limits on how many of Y1-Y5 may be S or O and how many may be N or NH.
The Formula (A) scaffold further constrains R7 as H or C1-C6 alkyl, n as 0, 1, 2, or 3, and R4 as indicating that the ring is saturated, partially unsaturated, or fully unsaturated. The linkage variables G3-G6 are defined as CH(X1-R6a), C(X1-R6a), N, N(X1-R6a), S, or O, with G7 as N, C, or CH, and X1-X4 each independently absent. The variable m is 1-6.
R6a, R6b, R6c, and R6d are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo, —OH, —NRpRq, aryl, heterocyclyl, heteroaryl, —C1-C6 alkyl-heterocyclyl, —OC(O)-heterocyclyl, —C(O)Rh, —S(O)2NRw1Rw2, —S(O)2Ry, or —NRz1S(O)2Rz2, with further rules for permitted substitution on alkyl, alkoxy, aryl, heteroaryl, and heterocyclyl moieties. The patent also provides an alternative ring-forming condition in which R6c and R6d, taken together with the attached carbon atoms, form a 6-membered aryl, 6-membered heterocyclyl, or 6-membered heteroaryl ring, each independently unsubstituted or substituted.
Claims Coverage
The claim set centers on one independent compound claim for Formula (A) and dependent claims that narrow substituent choices, fix a quantitative parameter, define additional G-variable patterns, and add a pharmaceutical composition. In total, the claims emphasize the Formula (A) scaffold and its constrained substituent architecture, with the main inventive features focused on the specific R, Y, G, X, n, m, and R6 variable definitions.
Formula (A) compound with constrained substituent pattern
A compound of Formula (A), or a tautomer, or a pharmaceutically acceptable salt, wherein R1 is —OH, R2 is —C(O)H, R3 is C1-C6 alkoxy or halogen, G1 and G2 are each CH, Y1 is C or N, Y2 is CH, N, NH, S, or O, Y3 is C or N, Y4 is CH, N, NH, S, or O, Y5 is CR7, N, NH, S, or O, with limits on the number of S or O and N or NH among Y1-Y5, R7 is H or C1-C6 alkyl, n is 0, 1, 2, or 3, and R4 indicates that the ring is saturated, partially unsaturated, or fully unsaturated.
G3-G7 framework with absent X1-X4 flags
G3 is CH(X1-R6a), C(X1-R6a), N, N(X1-R6a), S, or O; G4 is CH(X2-R6b), C(X2-R6b), N, N(X2-R6b), S, or O; G5 is CH(X3-R6c), C(X3-R6c), N, N(X3-R6c), S, or O; G6 is CH(X4-R6d), C(X4-R6d), N, N(X4-R6d), S, or O; G7 is N, C, or CH; X1, X2, X3, and X4 are each independently absent; and m is 1-6.
Enumerated substituent classes for R6a-R6d
R6a, R6b, R6c, and R6d are each independently hydrogen, C1-C6 alkyl, C1-C6 alkoxy, halo, —OH, —NRpRq, aryl, heterocyclyl, heteroaryl, —C1-C6 alkyl-heterocyclyl, —OC(O)-heterocyclyl, —C(O)Rh, —S(O)2NRw1Rw2, —S(O)2Ry, or —NRz1S(O)2Rz2, with specified substitution rules for the listed moieties.
Alternative 6-membered ring formation from R6c and R6d
G5 is CH(X3-R6c) or C(X3-R6c), G6 is CH(X4-R6d) or C(X4-R6d), and R6c and R6d are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, 6-membered heterocyclyl, or 6-membered heteroaryl ring, each independently unsubstituted or substituted.
Pharmaceutical composition comprising the claimed compound
A pharmaceutical composition comprising at least one compound of Formula (A), including a tautomer or a pharmaceutically acceptable salt, optionally together with a pharmaceutically acceptable excipient.
The claims cover Formula (A) compounds defined by fixed R1, R2, and R3 assignments, controlled Y1-Y5 heteroatom patterns, and a detailed G3-G7 linkage architecture with X1-X4 absent and m in the range 1-6. Dependent claims further narrow R3, fix n, specify G3-G7 patterns, enumerate allowed R6 substituent classes, provide an alternative 6-membered ring-forming mode for R6c and R6d, and include a pharmaceutical composition comprising the claimed compounds.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating inflammatory diseases and neurological disorders using TLR2/TLR9 inflammatory-signaling modulation.
Treating diseases linked to TLR2 heterodimerization and/or TLR9 inhibition.
Interfering with TLR2 heterodimerization in vitro, ex vivo, and in vivo.
Therapeutic context includes misfolded-protein related conditions, including alpha-synuclein (aSyn), linked to pro-inflammatory signaling.
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