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-10888567-B2
Publication Date
2021-01-12
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 disclosure describes 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine and pharmaceutically acceptable salts thereof within the structural framework of isoxazolo[5,4-b]pyridin-3-amine and closely related substituted isoxazolo analogs. Representative characterization is provided for substituted members of this family, including halogenated, methyl- and phenyl-substituted variants and additional aromatic or heteroaryl substituted members.
The material also describes substituted isoxazolo[5,4-b]pyridin-3-amine derivatives and related intermediates, including 6-(2-Thienyl)isoxazolo[5,4-b]pyridin-3-amine, (1-Methyl-1H-pyrazol-5-yl)isoxazolo[5,4-b]pyridin-3-amine, and ether/alkylation analogs such as 6-(3-(Dimethylamino)propoxy)isoxazolo[5,4-b]pyridin-3-amine, 6-(2-(Dimethylamino)ethoxy)isoxazolo[5,4-b]pyridin-3-amine, and 6-(2-Morpholinoethoxy)isoxazolo[5,4-b]pyridin-3-amine.
The disclosure further includes related isoxazolo[5,4-d]pyrimidin-3-amine and isoxazolo[5,4-b]quinolin-3-amine members, and variants such as carboxylate and diamine derivatives explicitly enumerated in the compound lists. The invention also presents 3-aminoisoxazolopyridine compounds of Formula I as inhibitors of IDO1 and/or TDO, and states that the compounds are used to treat cancer and to modulate tumor-related immunity.
Claims Coverage
The provided claim set contains three independent claims. Across these claims, the coverage is defined by one specific compound and two overlapping selected-compound lists of substituted isoxazolo[5,4-b]pyridin-3-amine(-type) structures, each with optional pharmaceutically acceptable salts.
6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine or a pharmaceutically acceptable salt
The claim covers 6-chloro-5-fluoroisoxazolo[5,4-b]pyridin-3-amine, including any pharmaceutically acceptable salt thereof.
Selected substituted isoxazolo[5,4-b]pyridin-3-amine and related variants with pharmaceutically acceptable salts
The claim covers a compound selected from a specified list of substituted isoxazolo[5,4-b]pyridin-3-amine structures and related carboxylate/diamine variants, or a pharmaceutically acceptable salt thereof.
Selected substituted isoxazolo[5,4-b]pyridin-3-amine(-type) structures with pharmaceutically acceptable salts
The claim covers a compound selected from a specified list of substituted isoxazolo[5,4-b]pyridin-3-amine structures and related carboxylate/diamine variants, or a pharmaceutically acceptable salt thereof.
Across the independent claims, the inventive coverage is the selection of explicitly enumerated substituted isoxazolo[5,4-b]pyridin-3-amine(-type) compounds, including specific halogenated examples, with optional pharmaceutically acceptable salt forms.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Cancer therapy, including monotherapy or combination with chemotherapeutics.
Combination with immune checkpoint modulators, including CTLA4 and PD-1 antibodies.
Anti-cancer vaccines.
Adoptive T-cell therapies.
Radiotherapy.
Inflammatory disorders.
Infectious disorders.
CNS disorders.
Female reproductive disorders.
Cardiovascular disorders.
Renal disorders.
Post-anaesthesia cognitive disorders.
Cataracts.
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