Inhibitors of tryptophan dioxygenases (IDO1 and TDO) and their use in therapy
Inventors
Palmer, Brian Desmond • Ching, Lai-Ming
Assignees
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Publication Number
US-11414428-B2
Publication Date
2022-08-16
Expiration Date
Abstract
Pharmaceutical compositions comprising 3-aminoisoxazolopyridine compounds of the Formula I having IDO1 and/or TDO inhibitory activity are described, where W is CR1, N or N-oxide; X is CR2, N or N-oxide; Y is CR3, N or N-oxide; Z is CR4, N or N-oxide; and at least one of W, X, Y, and Z is N or N-oxide; and R9 and R10 are as defined. Also described are methods of using such compounds in the treatment of various conditions, such as cancer.
Core Innovation
The invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, based on an isoxazolopyridine ring system in which W, X, Y, and Z are CR and/or N, including N-oxides, with at least one of W, X, Y, and Z being N or N-oxide. The compounds include extensive substitution patterns defined by independently selected groups R1, R2, R3, and R4 and additional substituent variables, together with ring formation options and optional substitution of aryl, heteroaryl, and cyclic groups as specified.
The Formula I genus explicitly incorporates carbonyl-linked functionalities at the 3-position, including 3-position ureas and thioureas, carbamates and thiocarbamates, amides and thioamides, and sulfonamides. The provided description further specifies synthetic routes to these 3-position carbonyl-linked functionalities by methods using isocyanate and isothiocyanate, chloroformate and chlorothioformate, activated carboxylic acid coupling, and sulfonyl chloride.
The provided therapeutic context states that Formula I compounds inhibit IDO1 and/or TDO for cancer immunotherapy. The document further states potential broader use including inflammatory, infectious, CNS, and other indications, and describes pharmaceutical compositions comprising Formula I compounds.
Claims Coverage
The partial content provides one independent compound claim and one independent method-of-treatment claim, with the method claim including a biological target inhibition feature. The compound claim contains the principal structural genus through Formula I and extensive substitution definitions, with additional dependent claims narrowing the genus.
Compounds of formula I
A compound of Formula I or a pharmaceutically acceptable salt thereof, wherein W, X, Y, and Z are CR or N or N-oxide, with at least one of W, X, Y, and Z being N or N-oxide, and wherein R1, R2, R3, and R4 and additional substituent variables are each independently selected from the defined groups and options, with specified provisos and excluded examples.
Inhibiting IDO1 and/or TDO for treatment
A method for treating cancer or other specified conditions by administering to a warm-blooded animal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the method involves inhibiting IDO1 and/or TDO.
Overall, coverage centers on the Formula I structural genus with defined W/X/Y/Z heteroatom placement and extensive allowed substituent patterns, and a treatment method that uses the compounds to inhibit IDO1 and/or TDO in the treatment of cancer and other specified conditions.
Stated Advantages
Inhibits IDO1 and/or TDO for therapeutic treatment.
The compounds are stated to inhibit IDO1 and/or TDO for cancer immunotherapy.
The provided content states potential broader inflammatory, infectious, CNS, and other indications.
Documented Applications
Medicaments and treatment methods for cancer by administering a Formula I compound to a warm-blooded animal with IDO1 and/or TDO inhibition.
Therapeutic treatment contexts described include inflammatory condition, infectious disease, central nervous system disease or disorder, coronary heart disease, chronic renal failure, post anaesthesia cognitive dysfunction, a condition or disorder relating to female reproductive health, and cataracts.
Combination approaches described include combination with chemotherapeutics, immune-modulating agents such as anti-cancer vaccines and immune checkpoint proteins CTLA4 and PD1, adoptive T cell immunotherapy including CAR-T, and radiotherapy.
Cancer immunotherapy using Formula I compounds that inhibit IDO1 and/or TDO.
Other indications stated as inflammatory, infectious, CNS, and other indications.
Pharmaceutical compositions comprising Formula I compounds.
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