Pyridazinyl-thiazolecarboxamide compound
Inventors
Watanabe, Hideyuki • Seki, Yohei • Okuyama, Keiichiro • Kurosawa, Kazuo • Ikeda, Osamu • Tomiyama, Hiroshi • Iwai, Yoshinori • Nakamura, Akihiko • Miyasaka, Kozo
Assignees
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Publication Number
US-12227517-B2
Publication Date
2025-02-18
Expiration Date
Abstract
A compound useful as an active ingredient of a pharmaceutical composition for treatment of cancer related to activation of immune cells or cancer having resistance to anti-PD-1 antibody/anti-PD-L1 antibody therapy is provided.The present inventors have conducted studies on a compound useful as an active ingredient of a pharmaceutical composition for treatment of cancer related to activation of immune cells or cancer having resistance to anti-PD-1 antibody/anti-PD-L1 antibody therapy, and found that a pyridazinyl-thiazolecarboxamide compound has DGK ξ (DGKzeta) inhibitory effect, leading to completion of the present invention. The pyridazinyl-thiazolecarboxamide compound of the present invention has DGK ξ inhibitory effect, and can be used as a therapeutic agent for treatment of cancer related to activation of immune cells or cancer having resistance to anti-PD-1 antibody/anti-PD-L1 antibody therapy.
Core Innovation
The invention relates to compounds of formula (I) and salts thereof, defined by variable substituent groups R1, R2, R3, and R4, together with a linker L and heteroatom or replacement options X, Y, Ra, Rb, Rc, Rd, and indices m and n. The definition includes multiple allowed forms for R1 and R3, including phenyl, cycloalkyl, pyridyl, pyrazolyl, and pyrrolidinyl optionally substituted with groups such as C1-6 alkyl, halogeno-C1-6 alkyl, C3-5 cycloalkyl, O-(C1-6 alkyl), cyano, nitro, methanesulphonyl, and halogen. L is a bond, CO, SO2, O, or NH, while X is CH2, O, or N-methyl and Y is CH2 or O.
The described embodiments include specific chemical structures within the formula (I) framework, showing variations such as fluorine, CF3, nitro versus amino, piperidine or pyrrolidine-type ring systems, Boc-protected amines, aryl ether-linked heterocycle cores, stereochemical wedges, and salt forms including hydrochloride, fumarate, and mono[(2E)-but-2-enedioate] representations. The examples and tables support the claimed structural variability across the disclosed scaffold.
The invention positions this compound family as DGKζ inhibitory compounds. Dependent coverage links the compounds to cancer treatment contexts involving immune-cell activation and resistance to anti-PD-1/anti-PD-L1 therapy, including non-small cell lung cancer, mismatch repair-deficient bowel cancer, and melanoma.
Claims Coverage
The independent claim coverage is centered on a broad formula (I) compound or salt with extensive substituent definitions. Across the provided claims, there are 3 recurring inventive feature groups: the formula (I) scaffold, DGKζ inhibitory activity, and cancer-treatment use in immune-cell activation or anti-PD-1/anti-PD-L1 resistance contexts.
Formula (I) compound and salts
A compound of formula (I) or a salt thereof, wherein R1 is a group of formula (i), (ii), (iii), (iv) or (v), R2 is selected from the stated alkyl, cycloalkyl, alkoxy, methanesulphonyl, halogeno-alkyl, or halogen options, R3 is selected from optionally substituted phenyl, cycloalkyl, pyridyl, pyrazolyl, or pyrrolidinyl groups, R4 is H or F, L is a bond, CO, SO2, O or NH, X is CH2, O or N-methyl, Y is CH2 or O, Ra is H or methyl, Rb is H, methyl, ethyl or —(CH2)2O—CH3, Rc is H, methyl or oxetanyl, Rd is H, methyl, —(CH2)2OH, —(CH2)2O—CH3 or oxetanyl, and m and n are 1 or 2.
Diacylglycerol kinase ζ inhibitory activity
A compound (or a salt thereof) defined by the formula (I) framework is specified to have Diacylglycerol kinase ζ inhibitory activity.
Treating cancers involving immune-cell activation or resistance to anti-PD-1/anti-PD-L1 therapy
A method of treating cancer by administering an effective amount of a compound (or a salt thereof), for cancers involving immune cell activation or resistance to anti-PD-1 and/or anti-PD-L1 therapy, including non-small cell lung cancer, mismatch repair-deficient bowel cancer, or melanoma.
The claim coverage centers on the formula (I) chemical definition with broad substituent and linker variability, and further narrows to DGKζ inhibitory activity and treatment of specified cancers in immune-activation or anti-PD-1/anti-PD-L1 resistance settings.
Stated Advantages
Inhibits Diacylglycerol kinase ζ.
Treats cancers involving immune cell activation or resistance to anti-PD-1/anti-PD-L1 therapy.
Enables use in the indicated cancer immunotherapy setting involving DGKζ inhibitory effect and immune-cell activation-related cancers with anti-PD-1/anti-PD-L1 resistance (primary or acquired).
Documented Applications
Use in cancer treatment by administering the compound or salt to a subject for cancers involving immune cell activation or resistance to anti-PD-1/anti-PD-L1 therapy, including non-small cell lung cancer, mismatch repair-deficient bowel cancer, or melanoma.
Use in pharmaceutical compositions to treat cancer involving immune-cell activation and/or resistance to anti-PD-1 or anti-PD-L1 therapy.
Treatment of cancers related to activation of immune cells, including cancers with primary or acquired resistance to anti-PD-1/anti-PD-L1 antibody therapy.
Treatment of non-small cell lung cancer, mismatch repair-deficient bowel cancer, or melanoma.
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