Combinations of retinaldehyde dehydrogenase 1 (raldh1) inhibitors and immunostimulators and methods using same

A method of treating, preventing, and/or ameliorating a solid tumor in a subject in need thereof, the method comprising administering to the subject a pharmaceutically effective amount of:

• (a) at least one immunostimulator;
• and
• (b) a retinaldehyde dehydrogenase 1 (RALDH1) inhibitor, wherein the RALDH1 inhibitor is selected from the group consisting of:
• (i) a compound of formula (I), or a salt, solvate, prodrug, stereoisomer, tautomer, or isotopologue thereof:
• wherein:
• R1a is selected from the group consisting of optionally substituted C2-C8 heterocyclyl, optionally substituted phenyl, and optionally substituted C5-C8 cycloalkenyl,
• wherein each optional substituent in R1a is independently selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, OH, N(Ra)(Rb), NO2, CN, C(═O)Ra, C(═O)N(Ra)(Rb), S(═O)2Ra, S(═O)2N(Ra)(Rb), and N(Ra)C(═O)Rb,
• wherein each optional substituent is optionally substituted with at least one substituent selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, halogen, CN, and NO2, and
• wherein two vicinal or geminal optional substituents in R1a may combine with the atoms to which they are bound to form a C2-C8 heterocyclyl or C3-C8 cycloalkyl;
• R1b and R1c, if present, are each independently selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, halogen, OH, N(Ra)(Rb), NO2, and CN;
• each occurrence of R2 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C3 haloalkoxy, C1-C6 hydroxyalkyl, halogen, NO2, and CN;
• R3 is selected from the group consisting of optionally substituted C2-C8 heterocyclyl, optionally substituted phenyl, N(Ra)(optionally substituted C3-C8 cycloalkyl), and N(Ra)(optionally substituted C2-C8 heterocyclyl),
• wherein each optional substituent in R3 is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, OH, N(Ra)(Rb), NO2, CN, C(═O)Ra, C(═O)N(Ra)(Rb), S(═O)2Ra, S(═O)2N(Ra)(Rb), and N(Ra)C(═O)Rb;
• A is selected from the group consisting of optionally substituted C6-C10 aryl and optionally substituted C2-C8 heterocyclyl,
• wherein each optional substituent in A is independently selected from the group consisting of C1-C6 alkyl, C1-C6 alkoxy, C1-C6 hydroxyalkyl, halogen, OH, N(Ra)(R), NO2, CN, C(═O)Ra, C(═O)N(Ra)(Rb), S(═O)2Ra, S(═O)2N(Ra)(Rb), and N(Ra)C(═O)Rb;
• L is selected from the group consisting of —CH2—, —C(═O)—, and —S(═O)2—;
• X is selected from the group consisting of N and CR1c;
• n is an integer selected from the group consisting of 0, 1, 2, 3, and 4;
• and
• each occurrence of Ra, Rb, and Rc is independently selected from the group consisting of H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and C2-C8 heterocyclyl;
• and
• (ii) a compound selected from the group consisting of:
• 1-benzylindoline-2,3-dione;
• ethyl 2-((4-oxo-3-(3-(pyrrolidin-1-yl)propyl)-3,4-dihydrobenzo[4,5]thieno[3,2-d]pyrimidin-2-yl)thio)acetate;
• 2-((2-(sec-butyl)-3-oxo-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)thio)-N-(o-tolyl)butanamide;
• and
• 8-((4-(cyclopropanecarbonyl)piperazin-1-yl)methyl)-7-isopentyl-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione;
• or a salt, solvate, prodrug, stereoisomer, tautomer, or isotopologue thereof.