Inhibitors of tryptophan dioxygenases (IDO1 and TDO) and their use in therapy
Inventors
Palmer, Brian Desmond • Ching, Lai Ming • Gamage, Swarnalatha Akuratiya
Assignees
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Publication Number
US-12508268-B2
Publication Date
2025-12-30
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 3-aminoisoxazolopyridine compounds of Formula I, including pharmaceutically acceptable salts, and pharmaceutical compositions containing a compound of Formula I with defined substituent options. The compositions include a pharmaceutically acceptable carrier, and the substituent definitions specify that at least one of W, X, Y, Z is N or N-oxide, with R9 and R10 being H.
The pharmaceutical compositions and combination kits further include one or more additional agents selected from chemotherapeutic agents for treating cancer and immune-modulating agents. The immune-modulating agents include anti-cancer vaccines, immune checkpoint modulators such as CTLA4 and PD1, and chimeric antigen receptor T cells (CAR T / CART cells), and the document also describes combination regimens that involve radiotherapy.
The invention also encompasses therapeutic use in warm-blooded animals, including methods of treating cancer by administering a therapeutically effective amount of a Formula I compound or a pharmaceutically acceptable salt. The document further describes a broad set of enumerated example compounds of Formula I and related substituted isoxazolo/pyridine(aza)amine derivatives, together with analytical characterization data for multiple substituted compounds.
Claims Coverage
The independent claims cover pharmaceutical compositions and kits centered on Formula I 3-aminoisoxazolopyridine compounds, or specified subsets and named species, formulated with pharmaceutically acceptable carriers and, in combination claims, additional agents comprising chemotherapeutic agents and immune-modulating agents. Across the set, the inventive features include defined Formula I substituent limitations, selected enumerated compound groups, and co-administration of additional agents.
Formula I composition with defined substituent scope and carrier plus chemotherapeutic and immune-modulating agents
A pharmaceutical combination or kit comprising a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof with defined Z, W, X, Y and R-group substituent selections, a pharmaceutically acceptable carrier, and one or more additional agents selected from chemotherapeutic agents for treating cancer and immune-modulating agents.
Named isoxazolo[pyridine] amine composition with carrier
A pharmaceutical composition comprising a compound selected from the group consisting of substituted isoxazolo[pyridine] amines listed in the claim, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Composition with constrained Formula I substituents and carrier
A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof wherein Z is N, W is CR1, X is CR2, and Y is CR3; R1 is H; R2 and R3 are each independently halogen, or one of R2 and R3 is H and the other of R2 and R3 is —CF3, —CHF2, —OCF3, or —OCHF2; and R9 and R10 are each H; and a pharmaceutically acceptable carrier.
Cancer treatment method in warm-blooded animals using constrained Formula I compound
A method of treating cancer in a warm-blooded animal comprising administering to the animal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof wherein Z is N, W is CR1, X is CR2, and Y is CR3; R1 is H; R2 and R3 are each independently halogen, or one of R2 and R3 is H and the other of R2 and R3 is —CF3, —CHF2, —OCF3, or —OCHF2; and R9 and R10 are each H.
Kit with specified isoxazolo[pyridine] amine group plus chemotherapeutic and immune-modulating agents
A pharmaceutical combination or kit comprising (a) a pharmaceutical composition comprising a compound selected from the group consisting of substituted isoxazolo[pyridine] amines listed in the claim, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; and (b) one or more additional agents selected from chemotherapeutic agents for treating cancer and immune-modulating agents.
Overall, the independent claims provide coverage for pharmaceutical compositions and combination kits built around Formula I 3-aminoisoxazolopyridine compounds, including specified substituent patterns and enumerated named compound sets, formulated with pharmaceutically acceptable carriers and, where recited, combined with chemotherapeutic agents and immune-modulating agents. One independent claim set also covers a warm-blooded animal cancer treatment method by administering a therapeutically effective amount of a constrained Formula I compound.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating cancer in a warm blooded animal by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.
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