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 aryl;
• Y1 is —C(═CH2)—;
• Y2 is —NRa;
• 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 —C1-C6alkyl;
• 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 combines 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 —H;
• 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;
• and
• n is independently, at each occurrence, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.