SHP2 inhibitor compositions and methods for treating cancer

A method of treating a subject having a disease or disorder associated with a RAS pathway mutation in a cell of the subject that renders the cell at least partially dependent on signaling flux through SHP2, comprising providing to the subject an inhibitor of SHP2, wherein the inhibitor of SHP2 is a compound of Formula I-V2:

• or a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein:
• A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12-membered polycyclic,
• Y1 is —S—, a direct bond, —NH—, —S(O)2—, —S(O)2—NH—, —C(═CH2)—, —CH—, or —S(O)—,
• 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;
• R3 is combined with R1 to form a 3- to 12-membered polycyclic heterocyclyl or a 5- to 12-membered spiroheterocyclyl, wherein each heterocyclyl or spiroheterocyclyl 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;
• each R1 is independently —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, halogen, —NO2, oxo, ═O, —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 —NH, —ORb, —CN, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, halogen, —C(O)ORb, —C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO, 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;
• and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
• each Rb is independently —H, -D, —OH, —C1-C6alkyl, —C3-C8cycloalkyl, —C2-C6alkenyl, —(CH2)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, cycloalkyl, alkenyl, heterocyclyl, 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, heterocyclyl, aryl, heteroaryl, —(CH2)nOH, —C1-C6alkyl, —CF3, —CHF2, or —CH2F;
• R4 is —H, -D, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6hydroxyalkyl, —CF2OH, —CHFOH, —NH—NHR5, —NH—OR5, —O—NR5R6, —NHR5, —OR5, —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, —CN, —C(O)NR5R6, —S(O)2NR5R6, C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O, wherein each alkyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more —OH, —ORb, halogen, or oxo;
• wherein each aryl or heteroaryl is optionally substituted with one or more —OH, —NH2, or halogen;
• each R5 and R6 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR7, —SR7, halogen, —NR7R8, —NO2, —CF3, or —CN;
• each R7 and R8 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —ORb, or a monocyclic or polycyclic 3-to 12-membered heterocyclyl, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more —OH, —SH, —NO2, or —CN;
• and
• each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

A method for treating a subject having a tumor comprising:

• (a) determining whether a biological sample obtained from the subject is classified as a KRAS mutant;
• and
• (b) administering to the subject an inhibitor of SHP2 if the biological sample is classified as a KRASG12C mutant, a KRASGl2D mutant, a KRASG12S mutant, or a KRASG12V mutant, wherein the inhibitor of SHP2 is a compound of Formula I-V2:
• or a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein:
• A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12-membered polycyclic;
• Y1 is —S—, a direct bond, —NH—, —S(O)2—, —S(O)2—NH—, —C(═CH2)—, —CH—, or —S(O)—;
• 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;
• R3 is combined with Ra to form a 3- to 12-membered polycyclic heterocyclyl or a 5- to 12-membered spiroheterocyclyl, wherein each heterocyclyl or spiroheterocyclyl 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;
• each R1 is independently —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, halogen, —NO, oxo, ═O, —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 —NH2, —ORb, —CN, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, halogen, —C(O)ORb, —C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl 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, heterocycle, aryl, or heteroaryl;
• and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
• each Rb is independently —H, -D, —OH, —C1-C6alkyl, —C3-C8cycloalkyl, —C2-C6alkenyl, —(CH2)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, cycloalkyl, alkenyl, heterocyclyl, 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, heterocyclyl, aryl, heteroaryl, —(CH2)nOH, —C1-C6alkyl, —CHF2, or —CH2F;
• R4 is —H, -D, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6hydroxyalkyl, —CF2OH, —CHFOH, —NH—NHR5, —NH—OR5, —O—NR5R6, —NHR5, —OR5, —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, —CN, —C(O)NR5R6, —S(O)2NR5R6, C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from 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 or heteroaryl is optionally substituted with one or more —OH, —NH2, or halogen;
• each R5 and R6 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR7, —SR7, halogen, —NR7R8, —CF, or —CN;
• each R7 and R8 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —ORb, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more —OH, —SH, —NO, or —CN;
• and
• each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

A method for treating a subject having a tumor comprising:

• (a) determining whether a biological sample obtained from the subject is classified as an NF1LOF mutant;
• and
• (b) administering to the subject an inhibitor of SHP2 if the biological sample is classified as an NF1LoF mutant,
• wherein the inhibitor of SHP2 is a compound of Formula I-V2:
• or a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein:
• A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12-membered polycyclic;
• Y1 is —S—, a direct bond, —NH—, —S(O)2—, —S(O)2—NH—, —C(═CH2)—, —CH—, or —S(O)—;
• 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;
• R3 is combined with R1 to form a 3- to 12-membered polycyclic heterocyclyl or a 5- to 12-membered spiroheterocyclyl, wherein each heterocyclyl or spiroheterocyclyl 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;
• each R1 is independently —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, halogen, —NO, oxo, ═O, —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 —NH2, —ORb, —CN, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, halogen, —C(O)ORb, —C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl 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, heterocycle, aryl, or heteroaryl;
• and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
• each Rb is independently —H, -D, —OH, —C1-C6alkyl, —C3-C8cycloalkyl, —C2-C6alkenyl, —(CH2)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, cycloalkyl, alkenyl, heterocyclyl, 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, heterocyclyl, aryl, heteroaryl, —(CH2)nOH, —C1-C6alkyl, —CF3, —CHF2, or —CH2F;
• R4 is —H, -D, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6hydroxyalkyl, —CF2OH, —CHFOH, —NH—NHR5, —NH—OR5, —O—NR5R6, —NHR5, —OR5, —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, —CN, —C(O)NR5R6, —S(O)2NR5R6, C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from 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 or heteroaryl is optionally substituted with one or more —OH, —NH2, or halogen;
• each R5 and R6 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR′, —SR′, halogen, —NR7R8, —NO2, —CF3, or —CN;
• each R7 and R8 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —ORb, or a monocyclic or polycyclic 3-to 12-membered heterocyclyl, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more —OH, —SH, —NH2, —NO2, or —CN;
• and
• each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

A method for treating a subject having a tumor comprising:

• (a) determining whether a biological sample obtained from the subject is classified as a Class 3 BRAF mutant;
• and
• (b) administering to the subject an inhibitor of SHP2 if the biological sample is classified as a Class 3 BRAF mutant,
• wherein the inhibitor of SHP2 is a compound of Formula I-V2:
• or a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein:
• A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12-membered polycyclic;
• Y1 is —S—, a direct bond, —NH—, —S(O)2—, —S(O)2—NH—, —C(═CH2)—, —CH—, or —S(O)—;
• 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;
• R3 is combined with Ra to form a 3- to 12-membered polycyclic heterocyclyl or a 5- to 12-membered spiroheterocyclyl, wherein each heterocyclyl or spiroheterocyclyl is optionally substituted with one or more —C1-C6alkyl, halogen, —OH, —ORb, —NHRb, heteroaryl, heterocyclyl, —(CH2)nNH2, —(CH2)nOH, —COORb, —CONHRb, —CONH(CH2)nCOORb, —NHCOORb, —CF3, —CHF2, —CH2F, or ═O;
• each R1 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —OH, —0R6, 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, halogen, —NO2, oxo, ═O, —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 —NH2, —ORb, —CN, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, halogen, —C(O)ORb, —C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl 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, heterocycle, aryl, or heteroaryl;
• and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
• each Rb is independently —H, -D, —OH, —C1-C6alkyl, —C3-C8cycloalkyl, —C2-C6alkenyl, —(CH2)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, cycloalkyl, alkenyl, heterocyclyl, heteroaryl, or —(CH2)n-aryl is optionally substituted with one or more —OH, halogen, —NO, 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, heterocyclyl, aryl, heteroaryl, —(CH2)nOH, —C1-C6alkyl, —CF3, —CHF2, or —CH2F,
• R4 is —H, -D, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6hydroxyalkyl, —CF2OH, —CHFOH, —NH—NHR5, —NH—OR5, —O—NR5R6, —NHR5, —OR5, —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, —CN, —C(O)NR5R6, —S(O)2NR5R6, C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from 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 or heteroaryl is optionally substituted with one or more —OH, —NH2, or halogen;
• each R5 and R6 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR7, —SR7, halogen, —NR7R8, —NO2, —CF3, or —CN;
• each R7 and R8 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —ORb, or a monocyclic or polycyclic 3- to 12-membered heterocyclyl, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more —OH, —SH, —NH2, —NO2, or —CN, and
• each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

A method for treating or preventing drug resistance in a subject receiving administration of a RAS pathway inhibitor, comprising administering to the subject an inhibitor of SHP2, wherein the inhibitor of SHP2 is a compound of Formula I-V2:

• or a pharmaceutically acceptable salt and/or stereoisomer thereof, wherein:
• A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are 5- to 12-membered monocyclic or 5- to 12-membered polycyclic;
• Y1 is —S—, a direct bond, —NH—, —S(O)2—, —S(O)2—NH—, —C(═CH2)—, —CH—, or —S(O)—;
• 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;
• R3 is combined with R1 to form a 3- to 12-membered polycyclic heterocyclyl or a 5- to 12-membered spiroheterocyclyl, wherein each heterocyclyl or spiroheterocyclyl 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;
• each R1 is independently —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, halogen, —NO2, oxo, ═O, —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 —NH2, —ORb, —CN, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, halogen, —C(O)ORb, —C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO, 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;
• and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;
• each Rb is independently —H, -D, —OH, —C1-C6alkyl, —C3-C8cycloalkyl, —C2-C6alkenyl, —(CH2)n-aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O;
• wherein each alkyl, cycloalkyl, alkenyl, heterocyclyl, heteroaryl, or —(CH2)n-aryl is optionally substituted with one or more —OH, halogen, —NO, 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, heterocyclyl, aryl, heteroaryl, —(CH2)nOH, —C1-C6alkyl, —CF3, —CHF2, or —CH2F;
• R4 is —H, -D, —C1-C6alkyl, —C1-C6haloalkyl, —C1-C6hydroxyalkyl, —CF2OH, —CHFOH, —NH—NHR5, —NH—OR5, —O—NR5R6, —NHR5, —OR5, —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, —CN, —C(O)NR5R6, —S(O)2NR5R6, C3-C8cycloalkyl, aryl, heterocyclyl containing 1-5 heteroatoms selected from N, S, P, and O, or heteroaryl containing 1-5 heteroatoms selected from 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 or heteroaryl is optionally substituted with one or more —OH, —NH2, or halogen;
• each R5 and R6 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR7, —SR7, halogen, —NR7R8, —NO2, —CF3, or —CN;
• each R7 and R8 is independently —H, -D, —C1-C6alkyl, —C2-C6alkenyl, —C4-C8cycloalkenyl, —C2-C6alkynyl, —C3-C8cycloalkyl, —ORb, or a monocyclic or polycyclic 3-to 12-membered heterocyclyl, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocyclyl is optionally substituted with one or more —OH, —SH, —NH2, —NO2, or —CN;
• and
• each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.