Discovery of covalent egfr inhibitor through cysteine 775

A compound of Formula A-I:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• X is O, S, NH, CH2, or a bond;
• 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, 3-10 membered heterocycloalkenyl, and 6-11 membered bicyclic ring;
• each R1 is independently selected from the group consisting of H, ═O, halo, CN, OR7, NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-N(R7)2, C1-C6 alkyl-OH, N(R7)2, NHC(O) R7, C(O)N(R7)2, NHC(O)N(R7)2, NS(O)(C1-C6 alkyl)2, NS(NH)(C1-C6 alkyl)2, NS(NC1-C6 alkyl) (C1-C6 alkyl)2, SO2N(R7)2, NHSO2R7, OC(O)N(R7)2, NHC(O)OR7, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkenyl, and 4-10 membered heterocycloalkenyl;
• q is 1, 2, or 3;
• R3 and R3a are each independently selected from the group consisting of H, halo, CN, C1-C6 alkyl, C1-C6 alkoxy, NH2, NH(C1-C6 alkyl), and N(C1-C6 alkyl)2, wherein C1-C6 alkyl is optionally substituted one, two, or three times with R9;
• alternatively, R3 and R3a optionally combine to form C3-C10 cycloalkyl or 3-10 membered heterocycloalkyl;
• n is 0, 1, or 2;
• R4 is selected from the group consisting of H, C1-C6 alkyl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C6-C10 aryl, and 5-10 membered heteroaryl, wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with one or two R8;
• R5 is selected from the group consisting of H, C1-C6 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkenyl, and 3-10 membered heterocycloalkenyl, 6-11 membered bicyclic ring, wherein 3-10 membered heterocycloalkyl, 6-11 membered bicyclic ring, C6-C10 aryl, and 5-10 membered heteroaryl are each optionally substituted with one, two, or three R5a;
• each R5a is independently selected from the group consisting of ═O, 3-10 membered heterocycloalkyl, O-3-10 membered heterocycloalkyl, halo, NS(O)(C1-C6 alkyl)2, NS(NH)(C1-C6 alkyl)2, NS(NC1-C6 alkyl) (C1-C6 alkyl)2, SO2C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy, and C3-C10 cycloalkyl, wherein 3-10 membered heterocycloalkyl, O-3-10 membered heterocycloalkyl, C1-C6 alkyl, and C1-C6 alkoxy are optionally substituted with one, two, or three R5aa;
• each R5aa is independently selected from the group consisting of ═O, C1-C6 alkyl, C1-C6 haloalkyl, halo, CN, OH, SO2C1-C6 alkyl, NH2, N(H)(C1-C6 alkyl), N(C1-C6 alkyl)2, SO2NH2, SO2N(H)(C1-C6 alkyl), SO2N(C1-C6 alkyl)2, and 3-10 membered heterocycloalkyl, wherein 3-10 membered heterocycloalkyl is optionally substituted with one or two C1-C6 alkyl or SO2C1-C6 alkyl;
• R6 is selected from the group consisting of H, halo, CN, OR7, NO2, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkyl-N(R7)2, C1-C6 alkyl-OH, N(R7)2, NHC(O) R7, C(O)N(R7)2, NHC(O)N(R7)2, SO2N(R7)2, NHSO2R7, OC(O)N(R7)2, NHC(O)OR7, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkenyl, and 4-10 membered heterocycloalkenyl;
• each R7 is independently selected from the group consisting of H, OH, halo, C1-C6 alkyl, C6-C10 aryl, 5-10 membered heteroaryl, C3-C10 cycloalkyl, and 3-10 membered heterocycloalkyl;
• each R8 is independently selected from halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C10 cycloalkyl, 3-10 membered heterocycloalkyl, O-3-10 membered heterocycloalkyl, C6-C10 aryl, 5-10 membered heteroaryl, OH, CN, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, C1-C6 alkyl-OH, C(O)C1-C6 alkyl-OH, SO2C1-C6 alkyl, SO2C3-C6 cycloalkyl, C(O)C1-C6 alkyl, C(O)NHC1-C6 alkyl, NHC(O)C1-C6 alkyl, SO2NH2, SO2NH(C1-C6 alkyl), SO2NH(C3-C6 cycloalkyl), SO2N(C1-C6 alkyl)2, SO2N(C3-C6 cycloalkyl)2, NHSO2 (C1-C6 alkyl), and NHSO2 (C3-C10 cycloalkyl), wherein C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered heterocycloalkyl, O-3-10 membered heterocycloalkyl, NH(C1-C6 alkyl), and N(C1-C6 alkyl)2 are optionally substituted with one or two R8a;
• R8a is selected from C1-C6 alkyl, C1-C6 alkoxy, OH, NH2, NH(C1-C6 alkyl), N(C1-C6 alkyl)2, and 3-10 membered heterocycloalkyl, wherein 3-10 membered heterocycloalkyl is optionally substituted with one or two C1-C6 alkyl and C1-C6 alkoxy;
• each R9 is independently selected from the group consisting of halo, CN, OH, C1-C6 alkyl, OC1-C6 alkoxy, NH2, NH(C1-C6 alkyl), and N(C1-C6 alkyl)2;
• R2 is selected from the group consisting of:
• L3 is a bond, —NH—, —N(C1-C4 alkyl)-, or C1-C4 alkylene, optionally wherein one or more carbons 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, C2-C6 alkenyl, C2-C6 alkynyl, 3-8 membered cycloalkyl, 3-12 membered heterocycloalkyl, 6-10 membered aryl, 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, form a 3-8 membered cycloalkyl or 4-7 membered heterocycloalkyl, both of which are optionally substituted with one, two, or three R9;
• L4 is a bond or C1-C6 alkyl optionally substituted with one, two, or three R9;
• each of RE1, RE2, RE3, and RE4 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 and 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;
• RE6 is hydrogen, C1-C6 alkyl, or a nitrogen protecting group;
• each Y is independently O, S, CH2, or NRE7;
• RE7 is hydrogen, C1-C6 alkyl, or a nitrogen protecting group;
• 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;
• and
• z is 1, 2, or 3.