Toll-like receptor antagonist compounds and methods of use
Inventors
Candia, III, Albert Frederick • Beresis, Richard Thomas • Coffman, Robert L.
Assignees
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Publication Number
US-11827641-B2
Publication Date
2023-11-28
Expiration Date
Abstract
The invention relates to compounds of formula (I): or a salt or solvate thereof, wherein the variables are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are antagonists of toll-like receptors such as TLR7, TLR8 and/or TLR9 that are useful for inhibiting immune response and treating diseases associated with undesirable immune response.
Core Innovation
The invention relates to a method of treating or ameliorating an autoimmune disease or disorder by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof. The method is directed to autoimmune diseases or disorders of the skin, heart, liver, endocrine glands, digestive system, blood, connective tissue, muscle, nervous system, eye, or inner ear.
Formula (I) is exhaustively defined by structural variables including A1 through A5, values for i and j, and multiple substituent and ring-forming groups. A1 is C or N; A2 is CR2, N, or NR2a; A3 is CR3, N, or NR3a; A4 is N or CR4; and A5 is N or CR5, with two, three, or four of A1, A2, A3, A4, and A5 being N, and dashed lines indicating partial or delocalized bonds in an aromatic ring.
The structural definition further includes U, V, W, X, and Y as bonds or alkylene/linker units with optional substitution, together with R1, R2, R3, R3a, R4, R5, R6, R7, R8, R9, R10, and R10A. The invention also includes the constraint that when R8 and R9 form a fused ring heteroaryl comprising an aryl moiety fused to a heterocycle containing the nitrogen atom, the aryl moiety is not adjacent to that nitrogen atom.
Claims Coverage
The consolidated claim coverage centers on one independent method claim. It contains a single therapeutic use feature and a broadly defined compound of formula (I), with detailed structural limitations across the A1-A5 aromatic framework, i and j values, linker variables, substituent definitions, and a fused-ring heteroaryl positional restriction.
Autoimmune treatment by administering formula (I) compounds
A method of treating or ameliorating an autoimmune disease or disorder of the skin, heart, liver, endocrine glands, digestive system, blood, connective tissue, muscle, nervous system, eye, or inner ear by administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
A1-A5 aromatic framework with partial or delocalized bonds
A1 is C or N; A2 is CR2, N, or NR2a; A3 is CR3 or CR30, N, or NR3a; A4 is N or CR4; A5 is N or CR5; two, three, or four of A1, A2, A3, A4, and A5 are N; and dashed lines indicate partial or delocalized bonds in an aromatic ring.
i and j ring-position constraints
i and j are independently 0, 1, or 2.
Defined substituent and ring-forming variables
R1 is C1-C6 alkyl, C3-C5 cycloalkyl, C6-C14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl, with optional substitution by R10A; each of R2, R3, R3a, R4, and R5 is independently hydrogen, halogen, C1-C6 alkyl, C3-C5 cycloalkyl, C6-C14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl with optional substitution by R10A; and U, V, W, X, and Y are bonds or alkylene/linker units as defined.
R7-R9 ring formation and fused-ring heteroaryl constraint
R7, R8, and R9 include cases where groups are taken together to form ethylene, C1-C6 alkylene, 3-12-membered heterocyclyl, or 5-10-membered heteroaryl; and when R8 and R9 are taken together with the nitrogen atom to form a fused ring heteroaryl comprising an aryl moiety fused to a heterocycle containing that nitrogen atom, the aryl moiety is not adjacent to the nitrogen atom.
The claim coverage is anchored in a method of treating or ameliorating autoimmune disease or disorder using a therapeutically effective amount of a compound of formula (I). The inventive scope is defined by the A1-A5 scaffold, i and j, extensive R-group and linker definitions, and the fused-ring heteroaryl adjacency restriction.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating or ameliorating an autoimmune disease or disorder of the skin, heart, liver, endocrine glands, digestive system, blood, connective tissue, muscle, nervous system, eye, or inner ear by administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.
Autoimmune skin diseases including alopecia areata, autoimmune urticaria, dermatitis herpetiformis, pemphigus vulgaris, psoriasis, and systemic scleroderma.
Combination therapy with an additional therapeutic agent chosen from a nonsteroidal anti-inflammatory drug, a corticosteroid, an antimalarial drug, an immunosuppressive drug, and a biologic.
Administration by oral, mucosal, intramuscular, subcutaneous, intravenous, topical, or transdermal routes.
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