TDO2 and IDO1 inhibitors
Inventors
Pei, Zhonghua • Parr, Brendan • LIU, Wendy • Pastor, Richard • Gazzard, Lewis • Jaipuri, Firoz • Kumar, Sanjeev • POTTURI, Hima • Wu, Guoshen • Lin, Xingyu • Chu, Yanyan • Yuen, Powai
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11827639-B2
Publication Date
2023-11-28
Expiration Date
Abstract
Presently provided are inhibitors of TD02 and IDO1 and pharmaceutical compositions thereof, useful for modulating an activity of tryptophan 2,3 dioxygenase and indoleamine 2,3-dioxygenase 1; treating immunosuppression; treating a medical conditions that benefit from the inhibition of tryptophan degradation; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; and treating tumor-specific immunosuppression associated with cancer.
Core Innovation
The invention relates to substituted 5H-imidazo[5,1-a]isoindole compounds, including stereoisomers, enantiomers, diastereoisomers, racemic mixtures, stable isotopes such as deuterium, and pharmaceutically acceptable salts. The compounds are defined by formula (I) and formula (II), with a 5H-imidazo[5,1-a]isoindolyl core or imidazo[5,1-a]isoindole scaffold and aryl or heteroaryl substituents under specified substituent patterns and structural provisos.
The disclosed substituent sets include oxo, halogen, cyano, nitro, C1-6 alkyl, haloalkyl, alkyl-cyano, cycloalkyl, heterocyclyl, OR, NR2, SR, and carbonyl- and sulfonyl-containing groups, together with limitations on substitution at specified carbon positions adjacent to the core. Formula (II) further defines ring A as aryl or heteroaryl and constrains n and m to 0, 1, 2, 3 or 4.
The patent also lists specific substituted (5H-imidazo[5,1-a]isoindol-5-yl) compounds, including phenyl, fluoro, chloro, difluoroethyl, sulfonamide, benzamide, benzonitrile, methanol, and heteroaryl-substituted examples. The compounds and pharmaceutical compositions comprising the compounds with a pharmaceutically acceptable diluent, excipient, or carrier are tied to TDO2-mediated immunosuppression associated with cancer and other TDO2-associated diseases, and to modulating IDO1/TDO2 activity.
Claims Coverage
The claim coverage centers on three independent compound claim families: formula (I), formula (II), and specific enumerated substituted 5H-imidazo[5,1-a]isoindole compounds. The inventive features are the defined scaffold and substituent constraints, the proviso excluding NR2 and OH at specified positions, and the expressly named derivatives and stereochemical or salt variants. Dependent claims further cover pharmaceutical compositions and treating TDO2-mediated immunosuppression, with cancer as a narrower disease indication.
Formula (I) substituted 5H-imidazo[5,1-a]isoindole compounds
A compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R1 is aryl or heteroaryl optionally fused to aryl, heteroaryl, C3-7 cycloalkyl, or 3-7 membered heterocyclyl; R1 is substituted by one to four Ra groups selected from an enumerated set; n is 0, 1, 2, 3 or 4; each R2 is independently selected from halogen, cyano, alkyl, cycloalkyl, OR, NR2, and SR options; and each R is hydrogen or selected substituents, with a proviso excluding NR2 or OH on specified carbon positions adjacent to the 5H-imidazo[5,1-a]isoindolyl.
Formula (II) substituted 5H-imidazo[5,1-a]isoindole compounds
A compound of Formula (II), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein n and m are each 0, 1, 2, 3 or 4; each R2 is independently halogen, cyano, C1-6 alkyl, C3 cycloalkyl, haloalkyl, OR, NR2, or SR; ring A is aryl or heteroaryl; and each Ra and each R is limited to the enumerated substituent classes, including oxo, halogen, cyano, nitro, alkyl, alkyl-OR, carbonyl, sulfonyl, sulfinyl, and amide-type groups.
Specific substituted 5H-imidazo[5,1-a]isoindole compounds
A compound that is one of the specifically listed substituted 5H-imidazo[5,1-a]isoindole derivatives, including phenyl, benzamide, benzonitrile, sulfonamide, methanol, fluoro, chloro, and heteroaryl variants, or a pharmaceutically acceptable salt, or an enantiomer, diastereoisomer, racemic mixture, or stable isotope form thereof.
Treat TDO2-mediated immunosuppression by administering a TDO2-inhibiting amount
A method of treating TDO2-mediated immunosuppression associated with a disease by administering to a subject in need an effective tryptophan 2,3-dioxygenase inhibiting amount of a compound defined in the compound claims.
Cancer as the disease indication
The method wherein the disease being treated is cancer.
Pharmaceutical composition with pharmaceutically acceptable carrier components
A pharmaceutical composition comprising a compound defined in the compound claims and a pharmaceutically acceptable diluent, excipient, or carrier.
The claims are directed to substituted 5H-imidazo[5,1-a]isoindole compounds defined by formulas (I) and (II) and to specifically enumerated substituted derivatives, all with constrained substituent patterns and stereochemical or salt coverage. Dependent claims further connect these compounds to pharmaceutical compositions and to treating TDO2-mediated immunosuppression, including cancer.
Stated Advantages
Inhibiting tryptophan degradation.
Treating TDO2-mediated immunosuppression, including tumor-specific immunosuppression.
Treating IDO1/TDO2-mediated immunosuppression.
Providing treatments for cancers and other TDO2-associated diseases.
Use in combination therapy with chemotherapeutics, antivirals, IDO inhibitors, radiation therapy, and PD-1/PD-L1 pathway agents.
Enhance anti-cancer therapy efficacy.
Treat cancer-associated immunosuppression.
Documented Applications
Treating TDO2-mediated immunosuppression associated with a disease by inhibiting tryptophan 2,3-dioxygenase (TDO2).
Treating cancer via TDO2-mediated immunosuppression.
Pharmaceutical compositions comprising the compound and a pharmaceutically acceptable diluent, excipient, or carrier.
Combination therapy with chemotherapeutics, antivirals, IDO inhibitors, radiation therapy, and PD-1/PD-L1 pathway agents.
TDO2 modulation/inhibition applications for viral infection such as HIV, depression, neurodegenerative disorders, transplant rejection, and autoimmune diseases.
Modulate IDO1/TDO2 activity.
Treat IDO1/TDO2-mediated immunosuppression.
Treat diseases benefiting from inhibition of tryptophan degradation.
Enhance anti-cancer therapy efficacy.
Treat cancer-associated immunosuppression.
Interested in licensing this patent?