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, hydrate, solvate, stereoisomer, or tautomer thereof,
• wherein:
• ring A is 5- to 12-membered cycloalkyl, 5- to 12-membered heterocycloalkyl, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl, wherein the 5- to 12-membered cycloalkyl, 5- to 12-membered heterocycloalkyl, 5- to 12-membered aryl, or 5- to 12-membered heteroaryl is monocyclic or polycyclic;
• each R1 is independently H, D, halogen, CN, NO2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C(O)R5, C(O)NR5R6, C(O)OR5, NR5R6, NR5C(O)R6, NR5S(O)R6, NR5S(O)NR5R6, NR5S(O)2R6, NR5S(O)2NR5R6, OR6, ═O, SR5, S(O)R5, S(O)NR5R6, S(O)2R5, S(O)2NR5R6, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, monocyclic heterocyclyl, polycyclic heterocyclyl, spiroheterocyclyl, or heteroaryl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, monocyclic heterocyclyl, polycyclic heterocyclyl, spiroheterocyclyl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of CN, NO2, R5, NR5R6, NR5S(O)R6, NR5S(O)NR5R6, NR5S(O)2R6, NR5S(O)2NR5R6, OR5, ═O, SR5, S(O)R5, S(O)NR5R6, S(O)2R5, S(O)2NR5R6, heterocyclyl, aryl, and heteroaryl;
• Y1 is —S—, —S(O)—, or —S(O)2—;
• R2 is F, Br, I, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OH, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, heterocyclyl, aryl, or heteroaryl;
• wherein the heterocyclyl or heteroaryl contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, S, O, and P;
• wherein the heterocyclyl or heteroaryl is not attached via a nitrogen heteroatom;
• and
• wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, CN, NO2, R5, NR5R6, NR5S(O)R6, NR5S(O)NR5R6, NR5S(O)2R6, NR5S(O)2NR5R6, OR5, SR5, S(O)R5, S(O)NR5R6, S(O)2R5, S(O)2NR5R6, heterocyclyl, aryl, and heteroaryl;
• Y2 is —NRa—;
• Ra is H, D, C1-C6 alkyl, —(CH2)naryl, OH, C3-C8 cycloalkyl, or 3- to 12-membered heterocyclyl, wherein the C1-C6 alkyl or C3-C8 cycloalkyl is optionally substituted with one or more NH2 substituents;
• R3 is C1-C6 alkyl, —(CH2)nRb, C3-C8 cycloalkyl, monocyclic 3- to 12-membered heterocyclyl, polycyclic 3- to 12-membered heterocyclyl, or 5- to 12-membered spiroheterocyclyl, wherein the C1-C6 alkyl, C3-C8 cycloalkyl, monocyclic 3- to 12-membered heterocyclyl, polycyclic 3- to 12-membered heterocyclyl, or 5- to 12-membered spiroheterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of C1-C6 alkyl, (CH2)nOH, NHRb, ORb, heterocyclyl, and spiroheterocyclyl;
• or
• Ra and R3, taken together with the nitrogen atom to which they are attached, form a monocyclic 3- to 12-membered heterocyclyl, polycyclic 3- to 12-membered heterocyclyl, or 5- to 12-membered spiroheterocyclyl, wherein the monocyclic 3- to 12-membered heterocyclyl, polycyclic 3- to 12-membered heterocyclyl, or 5- to 12-membered spiroheterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6 alkyl, CH2F, CHF2, CF3, (CH2)nNH2, (CH2)nOH, C(O)NHRb, C(O)NH(CH2)nC(O)ORb, C(O)ORb, NHRb, NHC(O)ORb, ORb, ═O, heterocyclyl, and heteroaryl;
• R4 is H, D, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, CHFOH, CF2OH, C(O)Rb, C(O)NR5R6, C(O)NH(CH2)nRb, C(O)OR5, NH2, NH(CH2)nOH, NHC(O)R5, NHC(O)NHR5, NHNHR5, NHOR5, NHS(O)2R5, NHS(O)2NHR5, OH, ONR5R6, S(O)2NR5R6, S(O)2OH, C3-C8 cycloalkyl, heterocyclyl, or aryl;
• wherein the heterocyclyl contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, S, O, and P;
• wherein the C1-C6 alkyl, C3-C8 cycloalkyl, or heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NH2, ORb, and ═O;
• and
• wherein the aryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, NH2, and OH;
• each Rb is independently H, D, C1-C6 alkyl, —(CH2)naryl, C2-C6 alkenyl, OH, C3-C8 cycloalkyl, heterocyclyl, or heteroaryl;
• wherein each heterocyclyl and heteroaryl independently contains 1, 2, 3, 4, or 5 heteroatoms independently selected from the group consisting of N, S, O, and P;
• and
• wherein each C1-C6 alkyl, aryl portion of —(CH2)naryl, C2-C6 alkenyl, C3-C8 cycloalkyl, heterocyclyl, and heteroaryl is optionally and independently substituted with one or more substituents independently selected from the group consisting of halogen, R5, CH2F, CHF2, —(CH2)nOH, C(O)NR5R6, NR5R6, NR5C(O)R6, NR5S(O)R6, NR5S(O)NR5R6, NR5S(O)2R6, NR5S(O)2NR5R6, OR5, ═O, SR5, S(O)R5, S(O)NR5R6, S(O)2R5, S(O)2NR5R6, aryl, and heteroaryl;
• each RS is independently H, D, CN, NO2, C1-C6 alkyl, CF3, C2-C6 alkenyl, C2-C6 alkynyl, NR7R8, OR7, SR7, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, monocyclic 3- to 12-membered heterocyclyl, or polycyclic 3- to 12-membered heterocyclyl;
• each R6 is independently H, D, halogen, CN, NO2, C1-C6 alkyl, CF3, C2-C6 alkenyl, C2-C6 alkynyl, NR7R8, OR7, SR7, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, monocyclic 3- to 12-membered heterocyclyl, or polycyclic 3- to 12-membered heterocyclyl;
• each R7 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ORb, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, monocyclic 3- to 12-membered heterocyclyl, or polycyclic 3- to 12-membered heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, monocyclic 3- to 12-membered heterocyclyl, and polycyclic 3- to 12-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of CN, NO2, NH2, OH, and SH;
• each R8 is independently H, D, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, ORb, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, monocyclic 3- to 12-membered heterocyclyl, or polycyclic 3- to 12-membered heterocyclyl, wherein each C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C4-C8 cycloalkenyl, monocyclic 3- to 12-membered heterocyclyl, and polycyclic 3- to 12-membered heterocyclyl is optionally and independently substituted with one or more substituents independently selected from the group consisting of CN, NO2, NH2, OH, and SH;
• each m is independently 1, 2, 3, 4, 5, or 6;
• and
• each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.