Substituted pyrazolopyrimidines and substituted purines and their use as ubiquitin-specific-processing protease 1 (USP1) inhibitors
Inventors
Brenneman, Jehrod Burnett • KRALL, Elsa Beyer • Schlabach, Michael • WYLIE, Andrew Alistair
Assignees
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Publication Number
US-11485736-B2
Publication Date
2022-11-01
Expiration Date
Abstract
The present disclosure provides compounds having Formula I: and the pharmaceutically acceptable salts and solvates thereof, wherein X1, X2, X11, X12, R1, R3, R5, R5′, R6, and R7 are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I to inhibit a USP1 protein and/or to treat a disorder responsive to the inhibition of USP1 proteins and USP1 activity. Compounds of the present disclosure are especially useful for treating cancer.
Core Innovation
The disclosure provides compounds having Formula I, or pharmaceutically acceptable salts or solvates thereof, with multiple variable substituents. X1 and X2 are independently selected from N and CR2, X11 and X12 are independently selected from N and CH, and R1, R2, and R3 are defined by broad hydrogen, halo, cyano, optionally substituted alkyl, alkenyl, alkynyl, aryl, and heteroaryl selections.
Further substitution variability is provided through R5, R5′, R6, R7, R23, R24, R25, R27, R31a, R31b, R32a, and R32b, with selections that include hydrogen, optionally substituted alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, haloalkoxy, hydroxyalkyl, cyano, halo, sulfonamido, carbonyl- and sulfonyl-containing groups, and optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, and alkyl-linked variants. The claim language also allows R5 and R5′ to be taken together to form optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, or spiroheterocycloalkyl rings.
The document further includes enumerated substituted pyrazolo[3,4-d]pyrimidine compounds, including benzyl-linked imidazole, pyrazole, and triazole variants bearing fluorinated substituents such as trifluoromethyl and difluoromethyl. Analytical characterization is reported for multiple named compounds and intermediates, including LC-MS and 1H NMR, and the content also describes preparation of common intermediates and related heterocyclic intermediates.
Claims Coverage
Independent claims identified across the input cover Formula I compounds and one enumerated group of specific pyrazolo[3,4-d]pyrimidine compounds. The Formula I claims are defined by extensive substituent-variable selections, and the enumerated claim covers specific named heterocyclic members in salt or solvate form.
Formula I compound with variable substituents
A compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof, with R1 and R2 independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R3 selected from optionally substituted phenyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl, or optionally substituted pyrazolyl; X11 and X12 independently selected from N and CH; and R5, R5′, R6, R7, R23, R24, R25, R27, R31a, R31b, R32a, and R32b selected from the specified group lists, including ring-forming options where R5 and R5′ taken together form an optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or spiro ring.
Formula I compound with X1/X2 selection and broad ring-forming options
A compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 and X2 are independently selected from N and CR2; R1 and R2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl; R3 is selected from the specified aryl and heteroaryl ring classes; X11 and X12 are independently selected from N and CH; and R5 and R5′ are selected from the defined group lists with the option that they are taken together to form optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or spiro rings.
Formula I compound with R5 restricted to heteroaryl classes
A compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 and X2 are independently selected from N and CR2, R1 and R2 are independently selected from hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted alkynyl, R3 is selected from the specified aryl and heteroaryl ring classes, X11 and X12 are independently selected from N and CH, and R5 is selected from optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl, or optionally substituted tetrazolyl.
Enumerated pyrazolo[3,4-d]pyrimidine compounds
A compound selected from the group consisting of multiple specifically named heterocyclic structures based on pyrazolo[3,4-d]pyrimidine, including benzyl-linked imidazole, pyrazole, and triazole substituents with trifluoromethyl or difluoromethyl motifs, and including pharmaceutically acceptable salts or solvates thereof.
The independent claim coverage centers on Formula I compounds with extensive, explicitly defined substituent-variable ranges and ring-forming relationships for R5 and R5′, together with an enumerated claim directed to specific substituted pyrazolo[3,4-d]pyrimidine compounds in salt or solvate form.
Stated Advantages
Inhibition of USP1 in a Ub-Rho deubiquitinating assay with an IC50 less than about 1 μM (Example 26).
Provides LC-MS and 1H NMR characterization for described intermediates and products, including reported m/z values.
Compounds act as USP1 protein inhibitors in animals and are intended for treatment of USP1-mediated diseases, notably cancers.
Documented Applications
Treating cancer via USP1 inhibition, including diagnostic/patient-selection concepts associated with p53 mutation status and RAD18 elevated protein or mRNA levels.
Use/kit concepts including medicament use, pharmaceutical compositions comprising the compound and a pharmaceutically acceptable carrier, and kits with diagnostic agents.
Targeting cancers based on p53, BRCA1/BRCA2, ATM mutations or deficiencies, and/or elevated RAD18 levels.
A kit concept including RAD18 detection.
Treatment of USP1-mediated diseases, notably cancers.
Analytical characterization and structure support for chlorinated, CF3-containing heteroaryl compounds using LC-MS m/z values and 1H-NMR chemical shifts, together with structure images.
Preparation of common intermediates and subsequent intermediates, including coupling/functionalization of imidazole and benzaldehyde building blocks and formation of a fused pyrazolo[3,4-d]pyrimidine core.
USP1 inhibitor sensitivity in cancer cell lines, including correlations with p53 mutation status, BRCA mutation status, and possibly ATM mutations.
CRISPR-Cas9 dropout screens indicating that USP1 is required for viability of a subset of ovarian and breast cancer lines.
Rad18 mRNA levels and Rad18 protein expression correlating with sensitivity to USP1 loss, and Rad18 deletion rescuing viability loss caused by USP1 deletion in ES2 cells.
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