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-11826316-B2
Publication Date
2023-11-28
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 substituted isoxazolo[5,4-b]pyridin-3-amine compounds and isoxazolo[5,4-b]pyridine(-like) amine compounds, including named members such as 5-(3-fluoro-4-methoxyphenyl)isoxazolo[5,4-b]pyridin-3-amine (25), 5-(pyridin-3-yl)isoxazolo[5,4-b]pyridin-3-amine (26), 5-(pyridin-4-yl)isoxazolo[5,4-b]pyridin-3-amine (27), 2-(3-aminoisoxazolo[5,4-b]pyridin-5-yl)phenol (28), and 4-(3-aminoisoxazolo[5,4-b]pyridin-5-yl)phenol (29). The disclosure also includes additional substituted members across the same ring system, including fluorophenyl, difluorophenyl, pyridyl, hydroxyphenyl, chlorophenyl, trifluoromethylphenyl, methoxy-substituted, thienyl, and pyrazolyl examples.
The described characterization includes yields, melting points, LCMS/HRMS, and HPLC purities for exemplified substituted isoxazolo[5,4-b]pyridin-3-amine compounds. The content further identifies specific members such as 5-(4-fluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (30), 5-(2,4-difluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (32), 5-(2,4-dichlorophenyl)isoxazolo[5,4-b]pyridin-3-amine (34), 5-(2,3,4-trichlorophenyl)isoxazolo[5,4-b]pyridin-3-amine (35), and 5-(4-(trifluoromethyl)phenyl)isoxazolo[5,4-b]pyridin-3-amine (36), along with hydroxyphenyl and methoxy-substituted variants.
The document further includes a reaction scheme narrative for making specific exemplified compounds, including compound 70 and its homologs, showing that final isoxazolo[5,4-b]pyridin-3-amine ring systems can be assembled and derivatized to yield named members 25-40 and beyond. The exemplified set for compound 70 includes 6-(4-methoxyphenyl)isoxazolo[5,4-b]pyridin-3-amine (70), as well as related members such as 6-(4-fluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (71), 6-(2,4-dichlorophenyl)isoxazolo[5,4-b]pyridin-3-amine (72), 6-(2,4-difluorophenyl)isoxazolo[5,4-b]pyridin-3-amine (73), 6-(2-thienyl)isoxazolo[5,4-b]pyridin-3-amine (74), and 6-(1-methyl-1H-pyrazol-5-yl)isoxazolo[5,4-b]pyridin-3-amine (75).
Claims Coverage
The independent claims provided are clm-00001, clm-00007, and clm-00008. Across these claims, the inventive features focus on treating cancer in a warm blooded animal by administering a pharmaceutical composition comprising a therapeutically effective amount of either a broad Formula I compound or a specified group of particular isoxazolo[5,4-b]pyridin(-like) amine compounds, together with a pharmaceutically acceptable carrier.
Treating cancer with a formula I pharmaceutical composition
A method of treating cancer in a warm blooded animal by administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, where Z is N, W is CR1, X is CR2, and Y is CR3, and where R1, R2, and R3 are each independently selected from the listed groups, together with a pharmaceutically acceptable carrier.
Treating cancer with selected substituted isoxazolo[5,4-b]pyridin(-like) amines from an enumerated group
A method of treating cancer in a warm blooded animal by administering a pharmaceutical composition comprising a therapeutically effective amount of a compound selected from the group consisting of the enumerated isoxazolo[5,4-b]pyridin-3-amine and related compounds, optionally as a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
The provided independent claims cover cancer treatment in a warm-blooded animal via administration of a pharmaceutical composition containing a therapeutically effective amount of either a Formula I compound or one of a group of specifically listed isoxazolo[5,4-b]pyridin(-like) amine derivatives, in each case optionally as pharmaceutically acceptable salts and formulated with a pharmaceutically acceptable carrier.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating cancer in a warm blooded animal, including humans.
Inhibiting IDO1, TDO, or both.
Cancer therapy combination regimens with chemotherapy, immune-modulating agents, adoptive T-cell therapy, and radiotherapy.
Inflammatory, infectious, CNS, coronary heart disease, chronic renal failure, post-anaesthesia cognitive dysfunction, female reproductive health disorders, and cataracts.
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