Galpha12 inhibitors and methods using same

A method of treating, preventing, and/or ameliorating an airway disease in a subject, the method comprising administering to the subject at least one selected from the group consisting of:

• (a) a compound of formula (I), or a salt, solvate, prodrug, stereoisomer, isotopologue, or tautomer thereof, or any mixtures thereof:
• wherein:
• A1 is selected from the group consisting of optionally substituted phenyl and optionally substituted C1-C10 heterocyclyl;
• A2 is selected from the group consisting of optionally substituted phenyl, optionally substituted C1-C10 heterocyclyl, and NH(optionally substituted C2-C8 heterocyclyl);
• B is selected from the group consisting of
• L1 is selected from the group consisting of a bond, —NR4—, —O—, and optionally substituted C1-C3 alkylenyl;
• L2 is selected from the group consisting of a bond, —C(═O)—, —C(═O)O—, —C(═O)(optionally substituted C1-C3 alkylenyl)-, and optionally substituted C1-C3 alkylenyl;
• X is selected from the group consisting of —O— and —C(R5a)(R5b)—,
• Y1 and Y2 are each independently selected from the group consisting of N and CR6,
• wherein Y1 and Y2 cannot be both N, and
• wherein if X is O, then Y1 is CR6;
• Z1 is selected from the group consisting of CR7a and N, Z2 is selected from the group consisting of CR7b and N, Z3 is selected from the group consisting of CR7c and N, and Z4 is selected from the group consisting of CR7d and N,
• wherein 0-2 selected from the group consisting of Z1, Z2, Z3, and Z4 are N;
• R1a, R1b, R2a, R2b, R3a, and R3b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, and halogen;
• R4 is selected from the group consisting of H and optionally substituted C1-C6 alkyl;
• R5a and R5b are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, and halogen;
• R6 is selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, and halogen;
• R7a, R7b, R7c, and R7d are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 alkoxy, optionally substituted phenyl, optionally substituted C2-C8 heterocyclyl, halogen, CN, NO2, ORa, N(Ra)(Rb), C(═O)Ra, C(═O)ORa, OC(═O)Ra, C(═O)N(Ra)(Rb), S(═O)2N(Ra)(Rb), NRaC(═O)Rb, and NRaS(═O)2Rb,
• wherein two vicinal substituents selected from the group consisting of R7a, R7b, R7c, and R7d can combine with the atoms to which they are bound to form an optionally substituted phenyl or optionally substituted C2-C8 heterocyclyl;
• Ra and Rb are each independently selected from the group consisting of H, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted benzyl, optionally substituted phenyl, and optionally substituted C2-C8 heterocyclyl;
• * indicates a bond between A1 and L1;
• ** indicates a bond between B and Y1;
• and
• *** indicates a bond between Y2 and L2;
• (b) a compound selected from the group consisting of:
• 2-(4-(2-(3,4-dimethylphenyl)acetyl)morpholin-2-yl)-N-(2-hydroxyethyl)quinoline-4-carboxamide;
• N-(2-hydroxyethyl)-2-(4-((1-methyl-1H-indol-3-yl)methyl)morpholin-2-yl)quinoline-4-carboxamide;
• N-(2-methoxyethyl)-2-(4-phenethylmorpholin-2-yl)quinoline-4-carboxamide;
• 2-(4-((1H-indol-5-yl)methyl)morpholin-2-yl)-N-(2-hydroxyethyl)-N-methylquinoline-4-carboxamide;
• 2-(4-benzoylmorpholin-2-yl)-N-isobutylquinoline-4-carboxamide;
• N-isopropyl-2-(4-(quinolin-4-ylmethyl)morpholin-2-yl)quinoline-4-carboxamide;
• N-methyl-2-(4-((3-phenyl-1H-pyrazol-4-yl)methyl)morpholin-2-yl)quinoline-4-carboxamide;
• 1-(1′-(2-(2-fluorophenyl)acetyl)-[2,4′-bipiperidin]-1-yl)-3-(1H-indazol-1-yl)propan-1-one;
• 2-(4-(2-(4-fluorophenyl)acetyl)morpholin-2-yl)-N-isobutylquinoline-4-carboxamide;
• 2-(4-((1H-indol-5-yl)methyl)morpholin-2-yl)-N-(2-methoxyethyl)quinoline-4-carboxamide;
• N-(2-hydroxyethyl)-2-(4-(quinolin-6-ylmethyl)morpholin-2-yl)quinoline-4-carboxamide
• N-isobutyl-2-(4-(2-phenylacetyl)morpholin-2-yl)quinoline-4-carboxamide;
• 3-(6-(4-(4,6-dimethylpyrimidin-2-yl)morpholin-2-yl)pyridin-3-yl)propenamide;
• N,N-dimethyl-2-(2-(pyridin-2-yl)morpholino)acetamide;
• 3-(1H-indazol-1-yl)-1-(2-(5-(4-methoxybenzyl)pyridin-2-yl)pyrrolidin-1-yl)propan-1-one;
• 1-(2-(6-(3-fluorobenzyl)pyrazin-2-yl)pyrrolidin-1-yl)-3-(1H-indazol-1-yl)propan-1-one;
• 4-(3-(1H-indazol-1-yl)propanoyl)-3-(3-(pyridin-4-yl)benzyl)piperazin-2-one;
• (2-(6-(dimethylamino)pyridin-2-yl)morpholino)(5-methylpyridin-3-yl)methanone;
• 1-(2-(pyrazin-2-yl)morpholino)-2-(pyridin-3-yl)ethan-1-one;
• and
• N-(2-hydroxyethyl)-N-methyl-2-(morpholin-2-yl)quinoline-4-carboxamide;
• or a salt, solvate, prodrug, stereoisomer, isotopologue, or tautomer thereof, or any mixtures thereof.