2,5-disubstituted 3-methyl pyrazines and 2,5,6-trisubstituted 3-methyl pyrazines as allosteric SHP2 inhibitors

A compound of Formula I-W:

• or a pharmaceutically acceptable salt, solvate, hydrate, or tautomer thereof, wherein:
• A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12-membered polycyclic;
• Y1 is —S— or a direct bond;
• Y2 is —NRa—, —(CRa2)m—, —C(O)—, —C(Ra)2NH—, —(CRa2)mO—, —C(O)N(Ra)—, —N(Ra)C(O)—, —S(O)2N(Ra)—, —N(Ra)S(O)2—, —N(Ra)C(O)N(Ra)—, —N(Ra)C(S)N(Ra)—, —C(O)O—, —OC(O)—, —OC(O)N(Ra)—, —N(Ra)C(O)O—, —C(O)N(Ra)O—, —N(Ra)C(S)—, —C(S)N(Ra)—, or —OC(O)O—;
• wherein the bond on the left side of Y2, as drawn, is bound to the pyrazine ring and the bond on the right side of the Y2 moiety, as drawn, is bound to R3;
• R1 is independently, at each occurrence, —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —OH, —OR6, halogen, —NO2, —CN, —NR5R6, —SR5, —S(O)2NR5R6, —S(O)2R5, —NR5S(O)2NR5R6, —NR5S(O)2R6, —S(O)NR5R6, —S(O)R5, —NR5S(O)NR5R6, —NR5S(O)R6, —C(O)R5, —CO2R5, —C(O)NR5R6, —NR5C(O)R6, monocyclic or polycyclic heterocyclyl, spiroheterocyclyl, heteroaryl, or oxo, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, spiroheterocyclyl, or heteroaryl is optionally substituted with one or more —OH, —NO2, oxo, —CN, —R5, —OR5, —NR5R6, —SR5, —S(O)2NR5R6, —S(O)2R5, —NR5S(O)2NR5R6, —NR5S(O)2R6, —S(O)NR5R6, —S(O)R5, —NR5S(O)NR5R6, —NR5S(O)R6, heterocycle, aryl, or heteroaryl;
• R2 is independently —OH, —CN, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, F, Br, I, —C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O;
• wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO2, —CN, —R5, —OR5, —NR5R6, —SR5, —S(O)2NR5R6, —S(O)2R5, —NR5S(O)2NR5R6, —NR5S(O)2R6, —S(O)NR5R6, —S(O)R5, —NR5S(O)NR5R6, —NR5S(O)R6, heterocycle, aryl, or heteroaryl;
• and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
• Ra is independently, at each occurrence, —H, -D, —OH, —C3-C8cycloalkyl, —C1-C6alkyl, 3- to 12-membered heterocyclyl, or —(CH2)n-aryl, wherein each alkyl or cycloalkyl is optionally substituted with one or more —NH2, or wherein 2 Ra, together with the carbon atom to which they are both attached, can combine to form a 3- to 8-membered cycloalkyl;
• Rb is independently, at each occurrence, —H, -D, —OH, —C1-C6alkyl, —C3-C8cycloalkyl, —C2-C6alkenyl, —(CH2)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O;
• wherein each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or —(CH2)n-aryl is optionally substituted with one or more —OH, halogen, —NO2, oxo, —CN, —R5, —OR5, —NR5R6, —SR5, —S(O)2NR5R6, —S(O)2R5, —NR5S(O)2NR5R6, —NR5S(O)2R6, —S(O)NR5R6, —S(O)R5, —NR5S(O)NR5R6, —NR5S(O)R6, —C(O)NR5R6, —NR5C(O)R6, heterocycle, aryl, heteroaryl, —(CH2)nOH, —C1-C6alkyl, —CF3, —CHF2, or —CH2F;
• R3 is independently —H, —C1-C6alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5- to 12-membered spiroheterocycle, C3-C8cycloalkyl, or —(CH2)n—Rb, wherein each alkyl, spiroheterocycle, heterocycle, or cycloalkyl is optionally substituted with one or more —C1-C6alkyl, —OH, —NH2, —ORb, —NHRb, —(CH2)nOH, heterocyclyl, or spiroheterocyclyl;
• or
• R3 can combine with Ra to form a 3- to 12-membered monocyclic or polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more —C1-C6alkyl, halogen, —OH, —ORb, —NH2, —NHRb, heteroaryl, heterocyclyl, —(CH2)nNH2, —(CH2)nOH, —COORb, —CONHRb, —CONH(CH2)nCOORb, —NHCOORb, —CF3, —CHF2, —CH2F, or ═O;
• R4 is independently —H, -D, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6hydroxyalkyl, —CF2OH, —CHFOH, —NH—NHR5, —NH—OR5, —O—NR5R6, —NHC(O)R5, —NHC(O)NHR5, —NHS(O)2R5, —NHS(O)2NHR5, —S(O)2OH, —C(O)OR5, —NH(CH2)nOH, —C(O)NH(CH2)nOH, —C(O)NH(CH2)nRb, —C(O)Rb, —NH2, —OH, —C(O)NR5R6, —S(O)2NR5R6, C3-C8cycloalkyl, aryl, or heterocyclyl containing 1-5 heteroatoms selected from the group consisting of N, S, P, and O, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more —OH, —NH2, —ORb, halogen, or oxo;
• wherein each aryl is optionally substituted with one or more —OH, —NH2, or halogen;
• or
• Ra and R4, together with the atom or atoms to which they are attached, can combine to form a monocyclic or polycyclic C3-C12cycloalkyl or a monocyclic or polycyclic 3- to 12-membered heterocycle, wherein the cycloalkyl or heterocycle is optionally substituted with oxo;
• wherein the heterocycle optionally comprises —S(O)2— in the heterocycle;
• R5 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR7, —SR7, —NR7R8, —NO2, —CF3, or —CN;
• R6 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocycle, —OR7, —SR7, halogen, —NR7R8, —NO2, —CF3, or —CN;
• R7 and R8 are independently, at each occurrence, —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —ORb, or a monocyclic or polycyclic 3- to 12-membered heterocycle, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more —OH, —SH, —NH2, —NO2, or —CN;
• m is independently, at each occurrence, 1, 2, 3, 4, 5 or 6;
• and
• n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.