Modulators of eukaryotic initiation factor 2

A compound of Formula A:

• or a pharmaceutically acceptable salt, isotopically enriched analog, stereoisomer, mixture of stereoisomers or prodrug thereof, wherein:
• A and B are independently C3-10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, provided that at least one of A or B is C3-10 cycloalkyl;
• X is C or N;
• C is cycloalkyl when X is C or heterocyclyl when X is N;
• L1 is —NR9C(O)CH2O—, —C(O)NR9CH2O—, a heteroalkylene optionally substituted with one to six R5, or L1 is a heterocyclyl or heteroaryl, each of which is optionally substituted with one to six R13;
• provided that when C is a bicyclo[1.1.1]pentane or bicyclo[2.1.1]hexane, then L1 is —NR9C(O)CH2O— or —C(O)NR9CH2O— and L2 is a bond;
• L2 is a bond or a C1-2 alkylene optionally substituted with one to four R5;
• n is 0, 1, 2, 3, 4, 5, or 6;
• p is 0, 1, 2, 3, 4, 5, 6, 7, or 8;
• q is 0, 1, 2, 3, 4, 5, or 6;
• s is 0 or 1;
• R1 is hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl or heterocyclyl, each of which, other than hydrogen, is optionally substituted with one to six R11;
• each R2 is independently halo, cyano, —NR6R7, hydroxyl, oxo, —C(O)OR6, —OC(O)NR6R7, —C(O)NR6R7, —NR6C(O)R7, C1-12 alkoxy, C1-12 haloalkoxy, C1-12 alkyl, C1-12 haloalkyl, heteroaryl, heterocyclyl, and cycloalkyl, wherein each of heterocyclyl, heteroaryl, and cycloalkyl are independently optionally substituted with one to six cyano, halo, C1-12 alkyl, or C1-12 haloalkyl, or two R2 on non-adjacent ring atoms together form a bond, C1-13 alkylene optionally substituted with one to six R5, or C1-2 heteroalkylene optionally substituted with one to four R5, provided that when C is cyclobutyl then R2 is not oxo;
• each R5 is independently halo, C1-6 alkyl or C1-6 haloalkyl;
• R3 and R4 are independently R11;
• each R11 is independently halo, cyano, nitro, oxo, —OR6, —SR6, —SF5, —NR6R7, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R6, —C(O)OR6, —OC(O)OR6, —OC(O)R6, —C(O)NR6R7, —OC(O)NR6R7, —NR6C(O)NR7R8, —S(O)1-2R6, —S(O)1-2NR6, —NR6S(O)1-2R7, —NR6S(O)1-2NR7R8, —NR6C(O)R7 or —NR6C(O)OR7, wherein each C1-12 alkyl, C2-12alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl of R11 is independently optionally substituted with one to six R12;
• each of R6, R7, and R8 is independently hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R20, —C(O)OR20, —C(O)NR20R21, —S(O)1-2R20 or —S(O)1-2NR20, wherein each C1-12alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl of R6, R7, and R8 is independently optionally substituted with one to six R12;
• or
• two of R6, R7, and R8 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to six halo, or C1-12 alkyl independently optionally substituted by one to six oxo, halo, hydroxyl or amino;
• R9 is independently hydrogen or C1-12 alkyl optionally substituted with one to six halo;
• each R12 is independently halo, cyano, nitro, oxo, —OR30, —SR30, —SF5, —NR30R31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R30, —C(O)OR30, —OC(O)OR30, —OC(O)R30, —C(O)NR30R31, —OC(O)NR30R31, —NR30C(O)NR30R31, —S(O)1-2R30, —S(O)1-2NR30, —NR30S(O)1-2R31, —NR30S(O)1-2NR30R31, —NR30C(O)R31 or —NR30C(═O)OR31, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl of R12 is independently optionally substituted with one to six halo or C1-12 alkyl independently optionally substituted by one to six oxo, halo, hydroxyl or amino;
• each R13 is independently halo, cyano, nitro, oxo, —OR30, —SR30, —SF5, —NR30R31, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)R30, —C(O)OR30, —OC(O)OR30, —OC(O)R30, —C(O)NR30R31, —OC(O)NR30R31, —NR30C(O)NR30R31, —S(O)1-2R30, —S(O)1-2NR30, —NR30S(O)1-2R31, —NR30S(O)1-2NR30R31, —NR30C(O)R31 or —NR30C(═O)OR31, wherein each C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, C3-10 cycloalkyl, heterocyclyl, aryl and heteroaryl of R13 is independently optionally substituted with one to six halo or C1-12 alkyl independently optionally substituted by one to six oxo, halo, hydroxyl or amino;
• each R20 and R21 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to six oxo, halo, hydroxyl or amino;
• or
• R20 and R21 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one to six halo or C1-12 alkyl independently optionally substituted by one to six oxo, halo, hydroxyl or amino;
• and
• each R30 and R31 is independently hydrogen or C1-12 alkyl independently optionally substituted with one to six oxo, halo, hydroxyl or amino;
• or R30 and R31 are taken together with the atoms to which they are attached to form heterocyclyl independently optionally substituted by one or to six halo or C1-12 alkyl independently optionally substituted by one to six oxo, halo, hydroxyl or amino;
• provided that:
• the compound is not -(4-chloro-2-methylphenoxy)-N-[1-(5-cyclopropyl-1H-pyrazol-3-yl)-4-piperidinyl]-acetamide or N-[1-(5-cyclopropyl-1H-pyrazol-3-yl)-4-piperidinyl]-2-phenoxy-acetamide;
• and when s is 0, two of R2 on non-adjacent ring atoms together form a bond, C1-3 alkylene optionally substituted with one to six R5, or C1-2 heteroalkylene optionally substituted with one to four R5.