Inhibitors of the ras oncoprotein, methods of making and methods of use thereof

A compound selected from a compound of Formula (I),

• and
• salts and esters thereof, wherein
• R1 is a monovalent H, carboxy, nitro, sulfo, halogen, aryl, cycloalkyl, heterocyclyl, heteroaryl, —(C1-C3)alkyl-aryl, —(C1-C3)alkyl-cycloalkyl, —(C1-C3)alkyl-heterocyclyl, —(C1-C3)alkyl-heteroaryl, C1-C8alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C1-C7 alkoxy, optionally substituted with halogen, hydroxy, C1-C5 alkyl, C1-C4 alkoxy, methanoly, carboxy, nitro, cyano, amino, carbamoyl, ethynyl, —CF3, —CF2CF3, —OCF3, —OCF2CF3, or sulfo;
• X1 is bivalent —(NH)—, —(CH2)—, —(NHCH2)—, —(CH2NH)—, —(C2H4)—, —(C2H2)—, —(C2)—, —O—, —O—(CH2)—, —(CH2)—O—, —S—, —S—(CH2)—, or —(CH2)—S—, optionally substituted with halogen, hydroxy, —Rx, methanoly, carboxy, nitro, cyano, amino, carbamoyl, ethynyl, —CF3, —CF2CF3, —OCF3, —OCF2CF3, or sulfo;
• Rx is C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C1-C7 alkoxy, optionally substituted with halogen, hydroxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, methanoly, carboxy, nitro, cyano, amino, carbamoyl, ethynyl, —CF3, —CF2CF3, —OCF3, —OCF2CF3, or sulfo;
• R2 is aryl, cycloalkyl, heterocyclyl, heteroaryl, —(C1-C3)alkyl-aryl, —(C1-C3)alkyl-cycloalkyl, —(C1-C3)alkyl-heterocyclyl, or —(C1-C3)alkyl-heteroaryl, which is substituted with —SO2—R3, —(C═O)—R3, and optionally further substituted with halogen, hydroxy, C1-C16 alkyl, C2-C16 alkenyl, C2-C16 alkynyl, C1-C15 alkoxy, methanoly, carboxy, nitro, cyano, amino, carbamoyl, ethynyl, —CF3, —CF2CF3, —OCF3, —OCF2CF3, sulfo, —SO2—R3, —(C═O)—R3, or —O—R3;
• R3 is-NRaRb, aryl, cycloalkyl, heterocyclyl, heteroaryl, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, or C1-C6 alkoxy, optionally substituted with halogen, hydroxy, C1-C5 alkyl, C1-C4 alkoxy, methanoly, carboxy, nitro, cyano, amino, carbamoyl, ethynyl, —CF3, —CF2CF3, —OCF3, —OCF2CF3, or sulfo;
• Ra is monovalent H, aryl, cycloalkyl, heterocyclyl, heteroaryl, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, or C1-C6 alkoxy, optionally substituted with halogen, hydroxy, C1-C8alkyl, C1-C4 alkoxy, methanoly, carboxy, nitro, cyano, amino, carbamoyl, ethynyl, —CF3, —CF2CF3, —OCF3, —OCF2CF3, or sulfo;
• and
• Rb is monovalent H, aryl, cycloalkyl, heterocyclyl, heteroaryl, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, or C1-C6 alkoxy, which H, aryl, cycloalkyl, heterocyclyl, heteroaryl, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, or C1-C6 alkoxy optionally substituted with halogen, hydroxy, C1-C5 alkyl, C1-C4 alkoxy, methanoly, carboxy, nitro, cyano, amino, carbamoyl, ethynyl, —CF3, —CF2CF3, —OCF3, —OCF2CF3, or sulfo;
• wherein
• if R2 comprises substitutions chosen from methanoly, carboxy, amino, C1-C16 alkyl, C2-C16 alkenyl, C2-C16 alkynyl, or C1-C15 alkoxy, then each substituent may be independently and optionally substituted with halogen, hydroxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, methanoly, carboxy, nitro, cyano, amino, —NH(C1-C4 alkyl), —N(C1-C4 alkyl) (C1-C4 alkyl), carbamoyl, ethynyl, —CF3, —CF2CF3, —OCF3, —OCF2CF3, sulfo, or —Rc;
• and
• Rc may be the same or different for each choice, and may be —CO—OCH3, —CO—NRfRg, —SO2—NRfRg, —NRfRg, —NH—CO—CH3, —NH—CO—NRfRg, —NH—CO—OCH3, aryl, cycloalkyl, heterocyclyl, heteroaryl, 5-7 membered monocyclic heterocyclyl, 5-7 membered monocyclic heteroaryl, tetrazolyl, triazolyl, imidazolyl, pyrrolyl, pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, pyridyl, pyrazinyl, pyrimidinyl, thienyl, furyl, pyranyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridazinyl, furazanyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, or pyrazolinyl, optionally substituted with halogen, hydroxy, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 alkoxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, methanoly, carboxy, nitro, cyano, amino, carbamoyl, ethynyl, —CF3, —CF2CF3, —OCF3, —OCF2CF3, or sulfo;
• Rf may be the same or different for each choice and may be H or C1-C4 alkyl;
• Rg may be the same or different for each choice and may be H or C1-C4 alkyl;
• and the compound is not