Heterocyclic compounds, preparation and methods and uses thereof

A compound of Formula I, or a pharmaceutically acceptable salt thereof:

• wherein:
• X is O, NR10, S, SO2, or an optionally substituted 4 to 7 membered heterocyclic ring;
• R1 is hydrogen, optionally substituted C1-4 alkyl, or -L-R20,
• wherein L is absent or an optionally substituted C1-4 alkylene, optionally substituted C1-4 heteroalkylene, optionally substituted C3-6 carbocyclic ring, or optionally substituted 4 to 7 membered heterocyclic ring,
• wherein R20 is hydrogen, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, —NR21R22, —OR23, an optionally substituted 4 to 7 membered heterocyclyl,
• or X—R1 represents —COOH, —COOR23, —CONR21R22, —CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 cycloalkyl, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or C3-6 cycloalkyl is optionally substituted, e.g., with 1-3 groups each independently selected from F, OH, protected OH, and C1-4 alkoxy;
• wherein each of R10, R21 and R22 at each occurrence is independently hydrogen, an optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C1-4 heteroalkyl, optionally substituted C3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or a nitrogen protecting group;
• R23 at each occurrence is independently hydrogen, an optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C1-4 heteroalkyl, optionally substituted C3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or an oxygen protecting group;
• each of A1, A2, A3, A4, and A5 is independently CR30 or N,
• wherein R30 at each occurrence is independently hydrogen, F, Cl, C1-4 alkyl, or C1-4 alkoxyl;
• or R1, X, and A1 together form an optionally substituted heterocyclic or heteroaryl ring;
• R2 and R3 are each independently hydrogen, halogen, —OH, —CN, optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, optionally substituted C3-6 carbocyclic ring, optionally substituted 4 to 7 membered heterocyclic ring, or optionally substituted C1-4 alkoxy;
• Het is a 4-10 membered heterocyclic ring, optionally substituted with independently selected R4 group(s), (R4)n, wherein n is 0, 1, 2, or 3, and R4 at each occurrence is independently C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, 3 or 4 membered ring (e.g., cyclopropyl), fluorine substituted C1-4 alkyl, hydroxyl substituted C1-4 alkyl, or cyano substituted C1-4 alkyl;
• or two R4 groups can join together to form a 3-6 membered ring structure;
• U represents an electrophilic moiety capable of forming a covalent bond with a cysteine residue of a KRAS protein, e.g., a KRAS G12C mutant protein;
• R7 is hydrogen, halogen, CN, a 3-4 membered ring, (e.g., cyclopropyl), optionally substituted C1-4 alkyl, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, or optionally substituted C1-4 alkoxyl;
• and
• R8 is an optionally substituted aryl or optionally substituted heteroaryl.