FGFR kinase inhibitors and pharmaceutical uses
Inventors
Patterson, Adam Vorn • Smaill, Jeffrey Bruce • Ashoorzadeh, Amir • Guise, Christopher Paul • Squire, Christopher John • Gamage, Swarnalatha Akuratiya • ABBATTISTA, Maria Rosaria • Bull, Matthew Roy • GREY, Angus Cheverton • LI, XueQiang • Ding, Ke • Ren, Xiaomei • JIANG, Shuang • Tu, Zhengchao
Assignees
Guangzhou Institute of Biomedicine and Health of CAS • Auckland Uniservices Ltd
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11192890-B2
Publication Date
2021-12-07
Expiration Date
Abstract
Fibroblast Growth Factor Receptor kinase inhibitors and prodrugs thereof of Formula (I) and their use for the treatment of hyper-proliferative diseases such as retinopathy, psoriasis, rheumatoid arthritis, osteoarthritis, septic arthritis, tumour metastasis, periodontal disease, corral ulceration, proteinuria, coronary thrombosis from atherosclerotic plaque, aneurismal aorta, dystrophobic epidermolysis bullosa, degenerative cartilage loss following traumatic joint injury, osteopenias mediated by MMP activity, tempero mandibular joint disease, and demyelating disease of the nervous system.
Core Innovation
The invention defines a compound of Formula (I) in which W is N or CH, Y is N, CH or CH2, and Z is N or C. Ar is a phenyl group substituted at the 2-position and at least one of the 3-, 5- and 6-positions with halogen, alkyl or alkoxy, and the structure includes a heterocyclic-linked radical L selected from Formulae (A)-(G). R1 is hydrogen or selected from a broad set of substituent groups, and R3 is selected from hydrogen and C1-C6 alkyl.
The chemical scope also includes a nitroarylmethyl quaternary prodrug thereof, as well as a pharmaceutically acceptable salt and a solvate of the quaternary prodrug. The document further specifies that L is attached to the heterocyclic nitrogen atom of Formula (I) and that the substitution point for R2 is defined as a point of attachment to L. This structural definition supports compound variants and stereochemical-defined embodiments enumerated in the claim set.
The document further provides biology showing in vitro FGFR1-4 kinase inhibition and cell-based anti-proliferative activity, with mechanistic studies indicating irreversible FGFR inhibition via drug washout and covalent binding. Prodrug behavior is evaluated using oxic/anoxic cytotoxicity ratios, and in vivo activity and pharmacokinetic information are described for prodrug compound 204 and related prodrugs.
Claims Coverage
The partial content provides one independent claim, defining a broad chemical scaffold via Formula (I), including nitroarylmethyl quaternary prodrugs and related salts/solvates. Main inventive structure is governed by the selections of W, Y, Z, Ar, R1, and the heterocyclic-linked radical L, with additional scope to prodrug forms.
Formula (I) compound definition
A compound of Formula (I) where W is N or CH; Y is N, CH or CH2; Z is N or C; Ar is a phenyl group substituted at the 2-position and at least one of the 3-, 5- and 6-positions with halogen, alkyl or alkoxy; R1 is hydrogen or selected from C1-C6 alkyl, C3-C6 cycloalkyl, heterocyclyl, aryl, and heteroaryl optionally substituted with hydroxy, alkyl, alkenyl, alkynyl, alkoxy, acetyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, carboxamide, alkylcarboxamide, dialkylcarboxamide, alkylsulfonyl, alkylsulfoxide, haloalkyl, haloalkoxy, amino, alkylamino, dialkylamino, morpholinyl, thiomorpholinyl, piperazinyl, N-alkylpiperazinyl, N-acetylpiperazinyl, N-alkylsulfonylpiperazinyl, pyrrolidinyl, piperidinyl, imidazolyl, or nitro; and L is a radical selected from Formulae (A)-(G) where a point of attachment is to the heterocyclic nitrogen atom of Formula (I), a point of attachment is to R2, and R3 is selected from hydrogen and C1-C6 alkyl.
Heterocyclic-linked radical L architecture
L is a radical selected from Formulae (A)-(G) where R2 is a radical of Formula (L) with R7 and R8 independently C1-C6 alkyl or may together form a non-aromatic heterocyclic ring.
Nitroarylmethyl quaternary prodrug, salt, or solvate scope
The compound is also covered as a nitroarylmethyl quaternary prodrug thereof, a pharmaceutically acceptable salt thereof, or a solvate thereof.
Overall claim coverage centers on Formula (I) heterocycle compound scaffolds defined by Ar substitution, broad R1 options, and a heterocycle-linked radical L structure from Formulae (A)-(G), with additional coverage for nitroarylmethyl quaternary prodrugs, pharmaceutically acceptable salts, and solvates.
Stated Advantages
Irreversible FGFR inhibition via drug washout and covalent binding is supported by mechanistic studies.
Prodrug behavior is evaluated using oxic/anoxic cytotoxicity ratios.
In vivo activity and pharmacokinetic information are described for prodrug compound 204 and related prodrugs.
Documented Applications
FGFR1-4 kinase inhibition and cell-based anti-proliferative activity are documented.
Prodrug oxic versus anoxic activity evaluation is documented using Hypoxic Cytotoxicity Ratio (HCR).
In vivo activity and pharmacokinetic information are documented for prodrug compound 204 and related prodrugs.
Interested in licensing this patent?