Kinase inhibitors and uses thereof
Inventors
de Vicente Fidalgo, Javier • Estrada, Anthony A. • Feng, Jianwen A. • Fox, Brian • Francini, Cinzia Maria • Hale, Christopher R. H. • Hu, Cheng • Leslie, Colin Philip • Osipov, Maksim • Serra, Elena • Sweeney, Zachary K. • Thottumkara, Arun
Assignees
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Publication Number
US-12129263-B2
Publication Date
2024-10-29
Expiration Date
Abstract
The present disclosure relates generally to compounds and compositions, intermediates, processes for their preparation, and their use as kinase inhibitors.
Core Innovation
The invention relates to compounds according to Formula I, or pharmaceutically acceptable salts, solvate, prodrug, isotopic analog, or isomer thereof, defined by variable positions W1, W2, W3, W4, Y, and Z together with extensive substituent definitions for R1a, R1b, R1c, R2a, R2b, R3a, R3b, R4a, R4b, R5, R6, R7, and R8 and related subgroups. The compound space permits multiple halogen, cyano, hydroxyl, alkyl, alkoxy, heterocyclyl, aryl, and heteroaryl substituent classes, and includes carbonyl-containing and nitrile-containing groups. A key conditional structural constraint applies when W2 is CR7, in which case either W4 is C—CN or R1a is not hydrogen and R1b and R1c together form a piperidin-4-yl ring substituted by (R5)n, with n being 1-9.
The definitions also allow alternative constructions in which R1b and R1c together form C3-10 cycloalkyl or 4- to 12-membered heterocyclyl, or R1a, R1b, and R1c together form C5-10 cycloalkyl or 6- to 8-membered heterocyclyl, or R1a is absent and R1b and R1c together form C6-10 aryl or 5- to 12-membered heteroaryl. The disclosure further includes selected specific benzoxazepin-based compounds and related pyrido[3,4-f][1,4]oxazepine or tetrahydropyrido[3,4-f][1,4]oxazepine structures. These explicitly named compounds include carbonitrile or carbonyl variants, fluorinated, chloro, bromo, and methoxy substituted members, and structures incorporating piperidyl, pyrimidinyl, and related heteroaryl moieties.
Claims Coverage
The consolidated claim coverage includes two independent claim themes: one broad Formula I compound class with a conditional W2=CR7 restriction and extensive substituent definitions, and one selection claim covering explicitly listed benzoxazepin-based compounds. In total, the merged coverage reflects 8 inventive features.
Formula I compound with conditional W2=CR7 constraint
A compound according to Formula I, or a pharmaceutically acceptable salt, isotopic analog, or isomer thereof, wherein W1, W2, W3, and W4 are defined, Y is CR4aR4b, Z is O, and when W2 is CR7 then either W4 is C—CN or R1a is not hydrogen and R1b and R1c together form a piperidin-4-yl ring substituted by (R5)n, with n being 1-9.
Extensive substituent definitions across W, Y, Z, and R groups
The compound includes Y as CR4aR4b and Z as O, with detailed definitions for R1a, R1b, R1c, R2a, R2b, R3a, R3b, R4a, R4b, R5 and its subgroups, R6 and its subgroups, R7 and its subgroups, and R8 and its subgroups, covering halogen, cyano, hydroxyl, alkyl, alkoxy, heterocyclyl, aryl, and heteroaryl options.
Alternative constructions from R1 groups
R1b and R1c may together form C3-10 cycloalkyl or 4- to 12-membered heterocyclyl, R1a, R1b, and R1c may together form C5-10 cycloalkyl or 6- to 8-membered heterocyclyl, or R1a may be absent and R1b and R1c may together form C6-10 aryl or 5- to 12-membered heteroaryl.
Selected benzoxazepin-based compounds
A compound, or a pharmaceutically acceptable salt, solvate, prodrug, isotopic analog, or isomer thereof, selected from an explicitly listed set of named benzoxazepin-based structures.
Carbonitrile and carbonyl functionalized benzoxazepines
The selected compounds include benzoxazepine-9-carbonitrile members and carbonyl-containing members such as butan-1-one, propan-1-one, and methanone variants attached to the benzoxazepine core.
Halogen and methoxy substituted benzoxazepine cores
The selected structures include fluoro, chloro, bromo, and methoxy substitution on the benzoxazepine scaffold.
Fluorinated carbonyl substituent patterns
The selected compounds include difluoro and trifluoro patterns on carbonyl-substituted side chains.
Heteroaryl and piperidyl carbonyl-linked moieties
Some selected compounds incorporate pyrimidinyl and piperidyl carbonyl-linked moieties, including 5-fluoropyrimidin-2-yl and piperidine-4-carbonyl or methanone variants.
Overall, the claim coverage is centered on a broad Formula I scaffold with a conditional W2=CR7 limitation and extensive substituent definitions, together with a separate selection claim listing specific benzoxazepin-derived compounds and their salt, solvate, prodrug, isotopic analog, or isomer forms.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a RIPK1-mediated disease or disorder by administering a therapeutically effective amount of a compound according to the claims; ulcerative colitis and psoriasis are explicitly listed.
A pharmaceutical composition including a compound according to the claims together with a pharmaceutically acceptable excipient.
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