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-11787813-B2
Publication Date
2023-10-17
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 invention relates to a method of treating cancer in a patient by administering a therapeutically effective amount of a compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof. The compounds are defined by multiple variable substituents including X1 and X2, R1 and R2, R3, X11 and X12, R5 and R5′, R6 and R7, and additional substituent positions such as R23, R24, R25, R27, R31a, R31b, R32a, and R32b. The substituent options are restricted to specified choices including hydrogen, halo, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, and specified aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl ring-forming options.
The disclosed compounds include pyrazolo[3,4-d]pyrimidine-based structures and related named compounds, including specific substituted pyrazolo[3,4-d]pyrimidine derivatives and a group of listed named compounds for administration in cancer treatment. Representative structures include benzyl-linked pyrazolo[3,4-d]pyrimidine compounds with imidazolyl, pyrazolyl, triazolyl, and other heteroaryl substituents, together with pharmaceutically acceptable salts or solvates. The treatment context is described as cancer treatment in a patient using therapeutically effective amounts of these defined compounds.
Claims Coverage
The provided material includes multiple independent claims directed to treating cancer by administering a therapeutically effective amount of a Formula I compound, or a pharmaceutically acceptable salt or solvate, and one independent claim directed to a defined group of specific named compounds. Across the independent claims, the inventive features center on the Formula I structural framework, its restricted substituent selections, and the selection of enumerated pyrazolo[3,4-d]pyrimidine-containing compounds.
Cancer treatment by administering a Formula I compound
A method of treating cancer in a patient by administering a therapeutically effective amount of 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 limited to the stated substituent sets and ring-forming options.
Formula I compounds with X1 and X2 selected from N and CR2
A method of treating cancer in a patient by administering a therapeutically effective amount of a compound having Formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 and X2 are independently selected from N and CR2 and the remaining substituent positions are defined by the recited structural and substituent limitations.
Selected named pyrazolo[3,4-d]pyrimidine compounds for cancer treatment
A method of treating cancer in a patient by administering a therapeutically effective amount of a compound selected from a group consisting of enumerated named pyrazolo[3,4-d]pyrimidine-containing compounds, or a pharmaceutically acceptable salt or solvate thereof.
The claim coverage is directed to cancer treatment methods that administer therapeutically effective amounts of Formula I compounds with detailed substituent restrictions and, in one independent claim, a defined group of named pyrazolo[3,4-d]pyrimidine-containing compounds.
Stated Advantages
Increased USP1-inhibitor sensitivity in p53-mutant cancers.
Increased LISP/USP1 inhibitor sensitivity in BRCA-mutant cancers.
USP1 is required for viability of a subset of ovarian and breast cancer cell lines.
Rad18 mRNA/protein levels correlate with sensitivity to USP1 loss/inhibition.
Rad18 deletion can rescue effects of USP1 deletion.
Documented Applications
Treating cancer in a patient by administering a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or solvate thereof.
Treating USP1-mediated disorders by USP1 inhibition, including cancer.
Treating cancer with genetic or pathway contexts including p53 loss-of-function, BRCA1 and BRCA2 mutation or deficiency, PARP inhibitor resistant or refractory cancers, homologous recombination deficiency, DNA damage repair pathway deficiency, ATM mutation or deficiency, and triple negative breast cancer.
Long-term proliferation and colony formation assays correlating sensitivity with p53, BRCA1/BRCA2, and ATM mutation context.
ADME solubility screening and liver microsomal stability screening of example compounds.
CRISPR-Cas9 gene depletion showing USP1 required for viability of a subset of ovarian and breast cancer cell lines.
Selecting patients or tumors based on elevated RAD18 levels.
Forming pharmaceutical compositions and kits that include the USP1 inhibitor compound or salts/solvates.
Treating cancer in a patient by administering therapeutically effective amounts of selected named pyrazolo[3,4-d]pyrimidine-containing compounds or pharmaceutically acceptable salts or solvates.
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