Covalent EGFR inhibitors and methods of use thereof

A compound of Formula I:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• is an optional double bond;
• X is O, S, or NH;
• A is selected from the group consisting of C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkenyl, and 3-10 membered heterocycloalkenyl;
• B is selected from the group consisting of C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkenyl, and 3-10 membered heterocycloalkenyl;
• R1 is selected from the group consisting of H, halo, OH, NH2, CN, NO2, C1-6 alkyl, NH(C1-6 alkyl), N(C1-6 alkyl)2, C1-6 haloalkyl, C1-6 alkoxy, C(O)-C1-C6 alkyl, C(O)NH2, C(O)NH-C1-C6 alkyl, C1-C6 alkyl-OH, P(O)(C1-C6 alkyl)2, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl, wherein C1-6 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl are each optionally substituted with Ra;
• R4 is selected from the group consisting of H, halo, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NH(C1-6 alkyl), N(C1-6 alkyl)2, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkyl-OH, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl;
• R5 is selected from the group consisting of H, halo, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NH(C1-6 alkyl), N(C1-6 alkyl)2, C1-6 haloalkyl, C1-6 alkoxy, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl;
• each R4′, R6, R6′, R7, R7, R8, R8′, R9, and R9′is independently selected from the group consisting of H, halo, OH, NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NH(C1-6 alkyl), N(C1-6 alkyl)2, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkyl-OH, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl;
• wherein aryl, heteroaryl, cycloalkyl, and heterocycloalkyl are each optionally substituted with C1-3 alkyl;
• Ra is selected from the group consisting of C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl all of which are optionally substituted with C1-3 alkyl;
• R2 is selected from the group consisting of:
• L3 is a bond, -NH-, or C1-C4 alkylene, optionally wherein one or more carbon is independently replaced with —C(O)—, —O—, —S—, —NRL3a—, —NRL3aC(O)—, —C(O)NRL3a—, —SC(O)—, —C(O)S—, —OC(O)—, —C(O)O—, —NRL3aC(S)—, —C(S)NRL3a—, trans—CRL3b═CRL3b—, cis—CRL3b═CRL3b—, —C≡C—, —S(O)—, —S(O)O—, —OS(O)—, —S(O)NRL3a—, —NRL3aS(O)—, —S(O)2, —S(O)2O—, —OS(O)2—, —S(O)2NRL3a—, or —NRL3aS(O)2—;
• RL3a is hydrogen, C1-C6 alkyl optionally substituted with R9, or a nitrogen protecting group;
• RL3b is independently, at each occurrence, selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2C6 alkenyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered ary;, and 5-8 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three R9;
• or, alternatively, two RL3b groups, together with the atoms to which they are attached, from a 3-8membered cycloalkyl or 4-7 membered heterocycloalkyl, both of which are optionally substituted with one, two, or three R9;
• each of RE1, RE2, and RE3 is independently selected from the group consisting of hydrogen, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-12 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-12 membered aryl, and 5-12 membered heteroaryl, CN, CH2OREE, CH2N(REE)2, CH2SREE, OREE, N(REE)2, SREE, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three R9;
• or, alternatively, RE1 and RE3, or RE2 and RE3, or RE1 ad RE2 are joined to form 3-8 membered cycloalkyl or 4-7 membered heterocycloalkyl, both of which are optionally substituted with one, two, or three R9;
• each REE is independently selected from the group consisting of hydrogen, C1-C6 alkyl C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, 6-10 membered aryl, and 5-10 membered heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three R9;
• or, alternatively, two REE groups, together with the atom to which they are attached, form 4-7 membered heterocycloalkyl;
• each Y is independently O, S, CH2, or NRE7;
• RE7 is hydrogen or C1-C6 alkyl;
• each R9 is independently selected from the group consisting of halo, OH, NH2;
• NH(C1-C6 alkyl), and N(C1-C6 alkyl)2;
• a is 0, 1, or 2;
• n is 0, 1, or 2.