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-11370794-B2
Publication Date
2022-06-28
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. In certain embodiments, compounds of the invention are useful for inhibiting immune response and treating diseases associated with undesirable immune response.
Core Innovation
The invention relates to compounds of formula (I), or salts or solvates thereof, defined by a heteroaromatic scaffold with positions A1 to A5, in which 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. The structure further includes indices i and j, broadly defined substituents R1, R2, R3, R2a, R3a, R4, R5 and R6, and connectivity variables U, V, W, X and Y with optional substitution by R10 and R10A.
The compounds also include defined ring-formation and take-together rules for R7, R8 and R9, including ethylene or C1-C6 alkylene formation and formation of 3-12-membered heterocyclyl or 5-10-membered heteroaryl. A specific proviso limits fused ring heteroaryl topology so that, when R8 and R9 together with the nitrogen atom form a fused ring heteroaryl comprising an aryl moiety fused to a heterocycle containing that nitrogen, the aryl moiety is not adjacent to the nitrogen atom.
The disclosure further provides explicit exclusions of named compounds, including salt or solvate forms, from the scope of formula (I). The same structural framework is used in pharmaceutical compositions and in methods for inhibiting receptor dependent response, inhibiting immune response, and treating cancer, with TLR8 and TLR9 specifically named in the receptor-dependent response context.
Claims Coverage
The independent claims collectively cover a compound of formula (I), pharmaceutical compositions comprising a pharmaceutically acceptable excipient and such compounds, and methods of inhibiting receptor dependent response, inhibiting immune response, and treating cancer. Across the claims, the main inventive features are the formula (I) scaffold with defined heteroatom placement, indices i and j, substituent and linkage variables, take-together ring-formation rules, the fused-ring heteroaryl adjacency restriction, and explicit exclusions of named compounds. The claim set also includes independent claims directed to selected named compounds.
Compound of formula (I) with constrained heteroatom pattern
A compound of formula (I), or a salt or solvate thereof, wherein A1 is C or N; A2 is CR2, N, or NR2a; A3 is CR3, N, or NR3a; A4 is N or CR4; A5 is N or CR5; provided that two, three or four of A1, A2, A3, A4, and A5 are N; and wherein dashed lines indicate partial or delocalized bonds in an aromatic ring and i and j are independently 0, 1, or 2.
Substituent and linkage variable framework
R1 is C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl, optionally substituted by R10A; each R2, R3, R3a, R4 and R5 is independently hydrogen, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, C6-C14 aryl, 5-10-membered heteroaryl, or 3-12-membered heterocyclyl, optionally substituted by R10A; R2a and R3a are likewise defined; n is 0, 1, 2, 3, or 4; U is a bond or methylene; V is a bond or C1-C2 alkylene; W is a bond or C1-C4 alkylene; and X and Y are defined as substituted carbon units.
Ring-formation rules for R7, R8 and R9
R7, R8 and R9 are defined with take-together options to form ethylene, C1-C6 alkylene, 3-12-membered heterocyclyl, or 5-10-membered heteroaryl, including the stated combinations with adjacent atoms and the nitrogen atom to which they are attached.
Fused-ring heteroaryl adjacency restriction
Provided that when R8 and R9 are taken together with the nitrogen atom to which they are attached to form a 5-10-membered heteroaryl that is a fused ring heteroaryl comprising an aryl moiety fused to a heterocycle containing the nitrogen atom, the aryl moiety is not adjacent to the nitrogen atom.
Exclusion of named compounds
Provided that the compounds are not compounds selected from a group consisting of named compounds, including salt or solvate forms.
Pharmaceutical composition with pharmaceutically acceptable excipient
A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of formula (I), or a salt or solvate thereof, with the same structural constraints and exclusions.
Method of inhibiting TLR8/TLR9 receptor dependent response
A method of inhibiting a receptor dependent response in a subject, wherein the receptor is at least one of toll-like receptor 8 (TLR8) and toll-like receptor 9 (TLR9), by administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I).
Method of inhibiting immune response
A method of inhibiting an immune response in a subject by administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I), optionally with a second therapeutic agent.
Method of treating cancer
A method of treating cancer in a subject by administering a therapeutically effective amount of a pharmaceutical composition comprising at least one compound of formula (I).
Selected named compound members
Independent claims also select specific named compound members from enumerated groups, including substituted pyrazolo[3,4-d]pyridazinyl piperidine carboxamide, methanone, acetamide, propanamide, pyrrolidine, azetidine, and piperazine-like structures, or salts or solvates thereof.
The claims center on a broad formula (I) compound class with detailed heteroatom placement, substituent and linkage definitions, ring-formation rules, and a fused-ring heteroaryl adjacency restriction, together with explicit exclusions of named compounds. Additional independent claims cover pharmaceutical compositions and therapeutic methods for inhibiting TLR8/TLR9 receptor-dependent responses, inhibiting immune response, and treating cancer, as well as claims to selected named compound members.
Stated Advantages
Inhibition of TLR8- and/or TLR9-dependent immune responses.
Treatment or amelioration of immunological disorders, including autoimmune and inflammatory diseases.
Treatment of cancer, including cancers where TLR8/9 activation is relevant.
Documented Applications
Inhibiting a receptor dependent response in a subject where the receptor is at least one of toll-like receptor 8 (TLR8) and toll-like receptor 9 (TLR9).
Inhibiting an immune response in a subject.
Treating cancer in a subject.
Treatment or amelioration of immunological disorders including autoimmune disease and inflammatory disease.
Treating cancer where TLR8/9 activation is relevant, including activated B cell type-diffuse large B cell lymphoma, Waldenstrom’s macroglobulinemia with oncogenic MYD88 mutations in cancer cells, and hepatocellular carcinoma (HCC).
Autoimmune disease examples include systemic lupus erythematosus, type I diabetes mellitus, multiple sclerosis, rheumatoid arthritis, Sjogren's syndrome, and scleroderma.
Inflammatory disease examples include inflammatory bowel disease, dermatomyositis, pancreatitis, kidney fibrosis, liver fibrosis, lung fibrosis, chronic kidney disease, alcohol-related fatty liver disease, and non-alcoholic fatty liver disease.
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