2,3-dihydrobenzofuran-5YL compounds as DYRK kinase inhibitors
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Publication Number
US-10005769-B2
Publication Date
2018-06-26
Expiration Date
Abstract
The present invention relates to compounds of below Formula (I), physiologically functional derivatives or salts thereof, where the groups R1, R2, R3, R4, RA, X1, and A, as well as the variables n, m and p are detailed further herein.In another aspect, the present invention provides methods for their preparation, their medical use and pharmaceutical compositions comprising said compounds, physiologically functional derivatives, solvates or salts thereof.
Core Innovation
The invention relates to compounds of formula (I) and pharmaceutically acceptable derivatives, solvates or salts thereof. The compounds are characterized by a 2,3-dihydrobenzofuran moiety with an X1-azol moiety attached at the 5- or 6-position, together with integer parameters n, m and p, variable substituents R1, R2, R3 and R4, and a monocyclic or bicyclic heteroaromatic ring system A having 5 to 10 ring atoms.
X1 is selected from NRn, O and S, and Rn is selected from H and the listed alkyl, aralkyl, haloalkyl, haloalkoxy, OH, alkoxy, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, CONH2, CONH(R′), CO(R′), COH, COO(R′), COOH and SO2R′ groups. A is a monocyclic or bicyclic heteroaromatic ring system having at least one N atom and optional additional heteroatoms selected from O, S and N, with exclusions that A is not pyridine substituted by heterocycloalkyl and is not a pyrazole substituted with CONH2.
The pharmaceutically acceptable derivatives are specified as compounds of formula I in which a carboxylic acid group is derivatized into an ester, a hydroxyl group is derivatized into an ester, a carboxylic acid is derivatized into an amide, an amine is derivatized into an amide, or a hydroxyl group is derivatized into a phosphate ester. Exemplary compounds are reported as thiazole-4-carboxamide derivatives, including 2-(2,3-dihydrobenzofuran-5-yl)-thiazole-4-carboxamide derivatives and 2-(2,3-dihydro-1-benzofuran-5-yl)-1,3-thiazole-4-carboxamide derivatives.
The disclosed compounds are described in a therapeutic cancer context and are associated with DYRK kinase inhibitors and hedgehog/GLI signaling concepts. The partial content further reports biological evaluation, including DYRK1B kinase assay results, Hedgehog signaling pathway inhibition using a Gli-Reporter assay, and a xenograft assay.
Claims Coverage
The consolidated claim coverage centers on compounds of formula (I) and related pharmaceutically acceptable derivatives, solvates and salts, with the key inventive scaffold being a 2,3-dihydrobenzofuran moiety bearing an X1-azol moiety at the 5- or 6-position. The coverage includes defined integer parameters, variable substituent sets, the heteroaromatic ring system A, derivative definitions, and a method-of-treatment feature.
2,3-Dihydrobenzofuran with 5- or 6-position X1-azol attachment
A compound of formula (I) or a pharmaceutically acceptable derivative, solvate or salt thereof, wherein the X1-azol moiety is attached at the 5- or 6-position of the 2,3-dihydrobenzofuran moiety.
Defined integer parameters and variable substituents
n is an integer from 0 to 2, m is an integer from 0 to 3, p is an integer from 0 to 2, and R1, R2, R3 and R4 are independently selected from defined substituent groups.
X1, Rn and heteroaromatic ring system A
X1 is independently selected from NRn, O and S; Rn is independently selected from defined substituent options; A is a monocyclic or bicyclic heteroaromatic ring system having 5 to 10 ring atoms, at least one N atom, optionally additional O, S and N heteroatoms, and remaining ring atoms being carbon atoms.
Heteroaromatic ring system A exclusions
A is not pyridine substituted by heterocycloalkyl and A is not a pyrazole substituted with —CONH2.
Pharmaceutically acceptable derivative by specified derivatization
A carboxylic acid group is derivatized into an ester, a hydroxyl group is derivatized into an ester, a carboxylic acid is derivatized into an amide, an amine is derivatized into an amide, or a hydroxyl group is derivatized into a phosphate ester.
Method of treating a subject
A method for treating a subject by administering an effective amount of the compound for a listed set of medical conditions, wherein the treatment alleviates the condition, stops its progression, or partially heals it.
The claims are directed to formula (I) compounds defined by the 2,3-dihydrobenzofuran/X1-azol scaffold, integer-controlled substitution, and a constrained heteroaromatic ring system A, together with expressly defined pharmaceutically acceptable derivatives. The provided material also includes a treatment method tied to the compounds and listed medical conditions.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment or prevention of multiple cancers, including breast, esophagus, gastrointestinal tract, gastro-intestinal stromal tumors, pancreas, prostate, biliary tract, bladder, basal cell carcinoma, medulloblastoma, rhabdomyosarcoma, glioma, small-cell lung cancer, oral squamous cell carcinoma, melanoma, colorectal cancer, non-small cell lung cancer, osteosarcoma, glioblastoma, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, acute myeloid leukemia, ovarian cancer, meningioma, and liver cancer.
Biological activity testing against DYRK1B, with assay results and IC50 values reported for exemplary compounds.
Hedgehog signaling pathway inhibition using a Gli-Reporter assay and a xenograft assay.
Xenograft tumor-volume comparison in a xenograft context, including compound example 5 versus vehicle control with L3.6pl cancer cells in Foxn1nu/nu nude mice.
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