Compounds and compositions for treating conditions associated with STING activity
Inventors
Venkatraman, Shankar • Katz, Jason • Roush, William R. • Seidel, Hans Martin
Assignees
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Publication Number
US-12503436-B2
Publication Date
2025-12-23
Expiration Date
Abstract
This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit (e.g., antagonize) Stimulator of Interferon Genes (STING). Said chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) STING activation (e.g., STING signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also features compositions containing the same as well as methods of using and making the same.
Core Innovation
The invention relates to compounds of Formula (I), including pharmaceutically acceptable salts or tautomers, defined by constrained linker and ring selections. The compound definition uses L1-L5 and the binary parameters a1-a5 to determine the presence of linkage segments, restricts allowable combinations to prevent prohibited heteroatom-heteroatom bonds, and defines Q1 as -Rg with a five-membered heteroaryl ring and a six-membered aryl or heteroaryl ring.
The structural scope further includes selected N-(indolyl) acetamide, amide, and carbamide compounds and specific single-compound embodiments, including trans-3-hydroxy-1-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl) cyclobutane-1-carboxamide, N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide, N-(5-((1R,2S,3R)-2-methyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide, N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)acetamide, and 1-(methoxymethyl)-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl) cyclopropane-1-carboxamide. Related disclosed structures include substituted indole or fused heteroaryl cores, ether linkers, cyclobutoxy, cyclopropane, and cyclobutane motifs, and fluorinated substituents including trifluoromethyl and difluoromethyl patterns.
The patent further links the claimed compounds to STING-related use contexts. It states methods that contact STING to inhibit STING activity and methods for treating a disease, disorder, or condition associated with STING by administering an effective amount to a subject in need thereof, with examples including cancer, type I interferonopathies, Aicardi-Goutières Syndrome (AGS), systemic lupus erythematosus, rheumatoid arthritis, amyotrophic lateral sclerosis, and Parkinson’s disease.
Claims Coverage
The provided material includes a broad Formula (I) compound claim, selected compound claims, and specific single-compound claims, together with STING inhibition and STING-associated disease-treatment use claims. The inventive features across the independent claims are: a constrained Formula (I) scaffold; selected N-(indolyl) acetamide, amide, and carbamide compounds; specific named indole-based single compounds; and use of the claimed compounds to inhibit STING activity and treat STING-associated diseases.
Constrained formula (I) compound structure
A compound of Formula (I), or a pharmaceutically acceptable salt or tautomer thereof, wherein L1-L5 are assembled with binary parameters a1-a5 subject to presence constraints, L1/L3/L5 are selected from —O—, —N(H)—, —N(Rd)—, S(O)0-2, and —C(=O)—, L2 and L4 are selected from straight-chain alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, heterocyclylene, or heterocycloalkenylene moieties subject to connectivity restrictions, Q1 is -Rg, X1 and X2 define a five-membered heteroaryl ring, and Y1-Y3 define a six-membered aryl or heteroaryl ring with additional bonding and attachment constraints.
Selected N-(indolyl) acetamide, amide, and carbamide compounds
A compound selected from the group consisting of specific N-(indol-3-yl) acetamide, amide, and carbamide structures, optionally as a pharmaceutically acceptable salt thereof.
Trans-3-hydroxy-1-methyl indole cyclobutane-1-carboxamide scaffold
A compound of the following structure: trans-3-hydroxy-1-methyl-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl) cyclobutane-1-carboxamide.
Trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy indole acetamide scaffold
A compound of the following structure: N-(5-(trans-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide.
1R,2S,3R cyclobutoxy indole acetamide scaffold
A compound of the following structure: N-(5-((1R,2S,3R)-2-methyl-3-(4-(trifluoromethyl)phenyl)cyclobutoxy)-1H-indol-3-yl)acetamide.
Trifluoromethyl phenethoxy indole acetamide scaffold
A compound of the following structure: N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl)acetamide.
Methoxymethyl cyclopropane-1-carboxamide indole scaffold
A compound of the following structure: 1-(methoxymethyl)-N-(5-(4-(trifluoromethyl)phenethoxy)-1H-indol-3-yl) cyclopropane-1-carboxamide.
Inhibiting STING activity by contacting STING
A method that inhibits STING activity by contacting STING with the claimed compound or a pharmaceutically acceptable salt thereof.
Treating STING-associated diseases by administering an effective amount
A method of treating a disease, disorder, or condition associated with STING by administering an effective amount of the claimed compound or a pharmaceutically acceptable salt to a subject in need thereof.
The claim coverage centers on a broad Formula (I) scaffold with extensive linker, ring, and bonding constraints, plus selected and specifically named indole-based acetamide, amide, and carbamide compounds. The claim set further includes use claims for inhibiting STING activity by contacting STING and for treating STING-associated diseases by administering an effective amount.
Stated Advantages
Inhibiting STING activity by contacting STING.
Treating a disease, disorder, or condition associated with STING.
Pharmaceutical compositions are provided that include the claimed compounds.
Inhibits STING pathway activation as indicated by EC50 classification in Table BA.
Documented Applications
Inhibiting STING activity by contacting STING with the compound or a pharmaceutically acceptable salt thereof.
Treating a disease, disorder, or condition associated with STING by administering an effective amount of the compound or a pharmaceutically acceptable salt to a subject in need thereof.
Cancer.
Type I interferonopathies.
Aicardi-Goutières Syndrome (AGS).
Systemic lupus erythematosus.
Rheumatoid arthritis.
Amyotrophic lateral sclerosis.
Parkinson’s disease.
STING pathway luciferase reporter readout with THP1-Dual® KO-IFNAR2 cells using 2’3’cGAMP stimulation, with EC50 classification and varying degrees of STING pathway activation inhibition by the listed compounds.
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