Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use as ATR kinase inhibitors
Inventors
Crane, Sheldon N. • Truong, Vouy Linh • ABDOLI, Abbas • TRUCHON, Jean-François • Black, Cameron • DORICH, Stéphane • FADER, LEE • LANOIX, Stéphanie • Jones, Paul • St-Onge, Miguel • PICARD, Audrey • LACBAY, Cyrus M.
Assignees
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Publication Number
US-12264155-B2
Publication Date
2025-04-01
Expiration Date
Abstract
Disclosed are compounds and pharmaceutically acceptable salts thereof that may be used in the treatment of subjects in need thereof. The compounds disclosed herein may be inhibitors of Ataxia-telangiectasia and RAD-3-related protein kinase (ATR). Also disclosed are pharmaceutical compositions containing the compounds or pharmaceutically acceptable salts thereof and methods of their preparation and use.
Core Innovation
The invention relates to compounds of formula (I), or pharmaceutically acceptable salts thereof, defined by a double bond or a single bond segment and variable substituents Y, R1-R6, Q, and X. The core structure includes extensive optional substitution across alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, and sulfur-containing substituent motifs, and the provided examples show a closely related compound scaffold featuring a fused polycyclic heteroaromatic core, a phenolic OH, and heterocyclic or heteroaryl substituents.
The disclosed structural scope includes R2 as optionally substituted C2-9 heterocyclyl, C1-6 alkyl, C3-8 cycloalkyl, C2-9 heterocyclyl C1-6 alkyl, C6-10 aryl, C1-9 heteroaryl, C1-9 heteroaryl C1-6 alkyl, halogen, and nitrogen- or oxygen- or sulfur-containing substituent forms such as —N(R5)2, —OR5, —CON(R6)2, —SO2N(R6)2, —SO2R5A, and —Q-R5B. R3 is optionally substituted C1-9 heteroaryl, while R4, R5, R5A, R5B, R6, Q, and X are further defined by the stated option sets, including hydrogen or halogen for X.
The examples vary across halogen and fluoro substituents, sulfur-containing groups, terminal aryl heterocycles, nitrogen-containing heterocycles, cycloalkyl ring substituents, and stereodefined chemical structures, including examples with a chiral center labeled (R). The provided content also identifies a class of compounds as ATR kinase inhibitor candidates and includes formula variants and subsets, including compounds of formulas (II), (IA), (IA-a), (IB), (IB-a), (IC), (IC-a), (ID), and (ID-a).
Claims Coverage
The consolidated claim coverage includes the broad independent structural claim for formula (I) compounds and the ATR kinase inhibition method claim. Across the provided items, the independent inventive features are the formula (I) scaffold with extensive substituent options, and the use of the claimed compound to inhibit ATR kinase activity in ATR-expressing cells.
Formula (I) compound class with variable substituent framework
A compound of formula (I), or a pharmaceutically acceptable salt thereof, with a double bond or a single bond segment and independently defined Y, R1-R6, Q, and X groups, including the stated heterocyclyl, cycloalkyl, aryl, heteroaryl, halogen, hydrogen, and sulfur-containing substituent options.
R2 substituent framework defining heterocyclyl, aryl, heteroaryl, and sulfonyl motifs
R2 is selected from optionally substituted C2-9 heterocyclyl, C1-6 alkyl, C3-8 cycloalkyl, C2-9 heterocyclyl C1-6 alkyl, C6-10 aryl, C1-9 heteroaryl, C1-9 heteroaryl C1-6 alkyl, halogen, —N(R5)2, —OR5, —CON(R6)2, —SO2N(R6)2, —SO2R5A, or -Q-R5B.
R3 and linked terminal substituent options
R3 is optionally substituted C1-9 heteroaryl; R5 is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted C6-10 aryl, optionally substituted C1-9 heteroaryl, or —SO2R5A; R5A is optionally substituted C1-6 alkyl, C3-8 cycloalkyl, or C6-10 aryl; R5B includes hydroxyl, optionally substituted alkyl, aryl, heteroaryl, —N(R5)2, —CON(R6)2, —SO2N(R6)2, —SO2R5A, or optionally substituted alkoxy; and R6 is independently hydrogen, optionally substituted C1-6 alkyl, C2-6 alkoxyalkyl, C6-10 aryl C1-6 alkyl, C6-10 aryl, C3-8 cycloalkyl, or C1-9 heteroaryl, with optional ring formation to form an optionally substituted C2-9 heterocyclyl.
Q and X backbone and terminal options
Q is optionally substituted C2-9 heterocyclylene, optionally substituted C3-8 cycloalkylene, optionally substituted C1-9 heteroarylene, or optionally substituted C6-10 arylene; X is hydrogen or halogen.
ATR kinase inhibition by contacting a cell
Inhibiting ATR kinase activity in a cell that expresses ATR kinase by contacting the cell with the compound of claim 1.
The claim coverage is centered on a broad formula (I) chemical class with extensive, explicitly enumerated substituent options, together with a method claim for inhibiting ATR kinase activity in ATR-expressing cells by contacting them with the claimed compound.
Stated Advantages
Inhibits ATR kinase activity.
ATR inhibitory activity is reported as IC50 values in a HeLa S3 whole-cell assay.
Mass confirmation data are reported as MS (+ESI) [M+1] masses for the exemplary compounds.
Treats diseases or conditions characterized by cell hyperproliferation, including cancer.
Documented Applications
Inhibiting ATR kinase activity in a cell that expresses ATR kinase by contacting the cell with the compound of claim 1.
ATR inhibitory activity measurement in a HeLa S3 whole-cell assay for exemplary compounds.
Treatment of diseases or conditions characterized by cell hyperproliferation, including broad cancer types such as carcinoma, sarcoma, leukemia, and melanoma.
Treatment including additional cancer categories explicitly listed: non-Hodgkin lymphoma, Hodgkin's disease, and pre-malignant condition.
A pharmaceutical composition comprising the compounds, including compositions isotopically enriched in deuterium.
Therapeutic use as ATR kinase inhibitors, including patient selection for ATR-inhibitor sensitivity.
Cancer treatment.
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