Bicyclic pyridine compositions and methods of using the same for cancer therapy
Inventors
Roninson, Igor B. • Chen, Mengqian • Li, Jing • Liang, Jiaxin • Zhang, Li • McInnes, Campbell
Assignees
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Publication Number
US-11572369-B2
Publication Date
2023-02-07
Expiration Date
Abstract
Disclosed herein are bicyclic pyridines, such as thienopyridine, pyrrolopyridine, furopyridine compounds, and methods for treating cancers.
Core Innovation
The invention relates to bicyclic pyridine compounds, including thienopyridine, pyrrolopyridine, or furopyridine derivatives, defined by a Formula 1 structure with variable heteroatom/linker selections. In Formula 1, Q is sulfur, —NH—, or oxygen, and X is —(CH2)n— with n selected from 0, 1, or 2. The scaffold includes substituent variability at R4, R3, R2, and R1, with conditional restrictions that depend on whether Q is sulfur or not.
A central aspect of the compounds is the use of deuterated or undeuterated substituents for R1, including deuterated hydroxyl, deuterated carboxy, deuterated or undeuterated amino, deuterated or undeuterated amido, and deuterated or undeuterated sulfonamide. The framework also includes saturated or unsaturated, branched or unbranched, substituted or unsubstituted deuterated or undeuterated C1–C6 alkyl and deuterated or undeuterated C1–C6 alkoxyl selections. The claim language further distinguishes R1 options when Q is sulfur versus when at least one of Q is not sulfur.
The described compounds are CDK8/CDK19-selective inhibitors intended for cancer therapy, and the patent document further provides synthetic examples preparing substituted benzamide/thieno[2,3-b]pyridine/cyanopyridine derivatives bearing a 1,4-diazepane moiety. The examples include coupling and protection/deprotection, substitution using halogenated and cyanopyridine building blocks, functional group modifications, hydrolysis to carboxy intermediates, and formation of carboxamide derivatives.
Claims Coverage
The provided content includes independent claims directed to a Formula 1 compound and to a method for treatment of cancer by administering a therapeutically effective amount of a Formula 1 compound. The core coverage centers on Formula 1 bicyclic pyridine compounds with conditional structural selections involving Q, X, R4, R3, R2, and R1, including deuterated or undeuterated R1 options that vary with Q.
Formula 1 compound with conditional Q-dependent substituent sets including deuterated R1
A compound of Formula 1 wherein Q is selected from sulfur, —NH—, or oxygen; X is selected from —(CH2)n— and n is selected from 0, 1, or 2; R4 is hydrogen or a C1–C6 alkyl group; R3 and R2 are selected from hydrogen, cyano, halo, amino, amido, or sulfonamido; and R1 is selected from specific deuterated or undeuterated substituent options with conditional restrictions depending on whether Q is sulfur or not.
Treatment method by administering a therapeutically effective amount of a Formula 1 compound
A method for treatment of a subject having a cancer, comprising administering a therapeutically effective amount of a compound of Formula 1 having the specified selections for Q, X, n, R4, R3, and R2, with R1 limited to hydrogen, cyano, and deuterated or undeuterated hydroxyl, carboxy, halo, amino, amido, sulfonamide, C1–C6 alkyl, or C1–C6 alkoxyl options.
Across the independent claims, the core inventive coverage is directed to Formula 1 bicyclic pyridine compounds with specified heteroatom/linker selections and tightly constrained substituent sets, including deuterated or undeuterated R1 choices that vary with the selection of Q, and to cancer treatment by administering a therapeutically effective amount of such compounds.
Stated Advantages
Improved pharmacokinetics, as described for deuterated analogs, including reported high AUC and slow clearance.
Strong selectivity shifts observed in kinome profiling with deuteration.
Tumor efficacy reported in vivo across multiple cancer contexts, including prostate cancer variants, metastatic TNBC, and leukemia (AML xenograft growth inhibition).
Documented Applications
Treatment of cancer, including prostate cancer (including CRPC/PSA suppression), metastatic TNBC, and leukemia including acute myeloid leukemia (AML) with xenograft growth inhibition reported.
Synthetic examples preparing substituted benzamide/thieno[2,3-b]pyridine/cyanopyridine derivatives bearing a 1,4-diazepane moiety, including characterization of at least one carboxamide intermediate by ESI-MS and 1H/13C NMR.
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