IP Library › Granted Patent US 11,596,633
Granted Patent B2
US 11,596,633 · App. 16/810,525 · Granted Mar 7, 2023

SHP2 inhibitor compositions and methods for treating cancer

Inventors: Robert J. Nichols (Redwood City, CA); Mark A. Goldsmith (Redwood City, CA); Christopher Schulze (Redwood City, CA); Jacqueline Smith (Redwood City, CA); David E. Wildes (Redwood City, CA); Stephen Kelsey (Redwood City, CA); Mallika Singh (Redwood City, CA)
Assignee: Revolution Medicines, Inc.
A61K31/519A61P35/00A61K45/06
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Quick Facts
Patent No.
US 11,596,633
App. No.
16/810,525
Granted
Mar 7, 2023
Kind
B2
Abstract

The present invention is directed to compositions and methods of treating or preventing diseases or disorders with inhibitors of SHP2, alone, and in combination with other therapeutic agents such as RAS pathway inhibitors (e.g., MEK inhibitors); methods of establishing appropriate treatment plans for subjects based upon the expression of one or more biomarker indicative of SHP2 inhibitor sensitivity; and methods of determining sensitivity to a SHP2 inhibitor based on a phosphorylation status of SHP2.

Claims (105)

1. A method of treating a subject having a disease or disorder comprising a cell containing a mutation encoding the KRAS G12C variant, 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;

Y 1 is —S—, a direct bond, —NH—, —S(O) 2 —, —S(O) 2 —NH—, —C(═CH 2 )—, —CH—, or —S(O)—;

Y 2 is —NR a —, wherein the bond on the left side of Y 2 , as drawn, is bound to the pyrazine ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;

R 3 is combined with R a to form a 3- to 12-membered polycyclic heterocycle or a 5- to 12-membered spiroheterocycle, wherein each heterocycle or spiroheterocycle is optionally substituted with one or more —C 1 -C 6 alkyl, halogen, —OH, —OR b , —NHR b , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —(CH 2 ) n OH, —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , —CH 2 F, or ═O;

each R 1 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OH, —OR 6 , halogen, —NO 2 —, —CN, —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , 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 2 , oxo, ═O, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 2 is —NH 2 , —OR b , —CN, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, halogen, —C(O)OR b , —C 3 -C 8 cycloalkyl, 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 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

each R b is independently —H, -D, —OH, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 2 -C 6 alkenyl, —(CH 2 ) 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 —(CH 2 ) n -aryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , heterocyclyl, aryl, heteroaryl, —(CH 2 ) n OH, —C 1 -C 6 alkyl, —CF 3 , —CHF, or —CH 2 F;

R 4 is —H, -D, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —CF 2 OH, —CHFOH, —NH—NHR 5 , —NH—OR 5 , —O—NR 5 R 6 , —NHR 5 , —OR 5 , —NHC(O)R 5 , —NHC(O)NHR 5 , —NHS(O) 2 R 5 , —NHS(O) 2 NHR 5 , —S(O) 2 OH, —C(O)OR 5 , —NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n R b , —C(O)R b , —OH, —CN, —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, 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, —NH 2 , —OR b , halogen, or oxo; wherein each aryl or heteroaryl is optionally substituted with one or more —OH, —NH 2 —, or halogen;

each R 5 and R 6 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR 7 , —SR 7 , halogen, —NR 7 R 8 , —NO 2 , —CF 3 , or —CN;

each R 7 and R 8 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OR b , 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, —NH 2 , —NO, or —CN; and

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

2. 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,

Y 1 is —S—, a direct bond, —NH—, —S(O) 2 —, —S(O) 2 —NH—, —C(═CH 2 )—, —CH—, or —S(O)—,

Y 2 is —NR a —, wherein the bond on the left side of Y 2 , as drawn, is bound to the pyrazine ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;

R 3 is combined with R 1 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 —C 1 -C 6 alkyl, halogen, —OH, —OR b , —NH 2 , —NHR b , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —(CH 2 ) n OH, —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , —CH 2 F, or ═O;

each R 1 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OH, —OR 6 , halogen, —NO 2 , —CN, —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , 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 2 , oxo, ═O, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 2 is —NH, —OR b , —CN, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, halogen, —C(O)OR b , —C 3 -C 8 cycloalkyl, 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, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

each R b is independently —H, -D, —OH, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 2 -C 6 alkenyl, —(CH 2 ) 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 —(CH 2 ) n -aryl is optionally substituted with one or more —OH, halogen, —NO 2 —, oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , heterocyclyl, aryl, heteroaryl, —(CH 2 ) n OH, —C 1 -C 6 alkyl, —CF 3 , —CHF 2 , or —CH 2 F;

R 4 is —H, -D, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —CF 2 OH, —CHFOH, —NH—NHR 5 , —NH—OR 5 , —O—NR 5 R 6 , —NHR 5 , —OR 5 , —NHC(O)R 5 , —NHC(O)NHR 5 , —NHS(O) 2 R 5 , —NHS(O) 2 NHR 5 , —S(O) 2 OH, —C(O)OR 5 , —NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n R b , —C(O)R b , —NH 2 , —OH, —CN, —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, 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, —OR b , halogen, or oxo; wherein each aryl or heteroaryl is optionally substituted with one or more —OH, —NH 2 , or halogen;

each R 5 and R 6 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR 7 , —SR 7 , halogen, —NR 7 R 8 , —NO 2 , —CF 3 , or —CN;

each R 7 and R 8 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OR b , 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 2 , or —CN; and

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

3. The method of claim 2 , wherein the RAS pathway mutation is selected from a KRAS mutation, an NRAS mutation, a SOS mutation, a BRAF Class III mutation, a Class I MEK1 mutation, a Class II MEK1 mutation, and an NF1 mutation.

4. 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 KRAS G12C mutant, a KRAS Gl2D mutant, a KRAS G12S mutant, or a KRAS G12V 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;

Y 1 is —S—, a direct bond, —NH—, —S(O) 2 —, —S(O) 2 —NH—, —C(═CH 2 )—, —CH—, or —S(O)—;

Y 2 is —NR a —, wherein the bond on the left side of Y 2 , as drawn, is bound to the pyrazine ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;

R 3 is combined with R a 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 —C 1 -C 6 alkyl, halogen, —OH, —OR b , —NH 2 , —NHR b , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —(CH 2 ) n OH, —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , —CH 2 F, or ═O;

each R 1 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OH, —OR 6 , halogen, —NO 2 , —CN, —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , 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, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 2 is —NH 2 , —OR b , —CN, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, halogen, —C(O)OR b , —C 3 -C 8 cycloalkyl, 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 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

each R b is independently —H, -D, —OH, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 2 -C 6 alkenyl, —(CH 2 ) 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 —(CH 2 ) n -aryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , heterocyclyl, aryl, heteroaryl, —(CH 2 ) n OH, —C 1 -C 6 alkyl, —CHF 2 , or —CH 2 F;

R 4 is —H, -D, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —CF 2 OH, —CHFOH, —NH—NHR 5 , —NH—OR 5 , —O—NR 5 R 6 , —NHR 5 , —OR 5 , —NHC(O)R 5 , —NHC(O)NHR 5 , —NHS(O) 2 R 5 , —NHS(O) 2 NHR 5 , —S(O) 2 OH, —C(O)OR 5 , —NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n R b , —C(O)R b , —NH 2 , —OH, —CN, —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, 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, —NH 2 , —OR b , halogen, or oxo; wherein each aryl or heteroaryl is optionally substituted with one or more —OH, —NH 2 , or halogen;

each R 5 and R 6 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR 7 , —SR 7 , halogen, —NR 7 R 8 , —CF, or —CN;

each R 7 and R 8 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OR b , 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.

5. A method for treating a subject having a tumor comprising:

(a) determining whether a biological sample obtained from the subject is classified as an NF1 LOF mutant; and

(b) administering to the subject an inhibitor of SHP2 if the biological sample is classified as an NF1 LoF 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;

Y 1 is —S—, a direct bond, —NH—, —S(O) 2 —, —S(O) 2 —NH—, —C(═CH 2 )—, —CH—, or —S(O)—;

Y 2 is —NR a —, wherein the bond on the left side of Y 2 , as drawn, is bound to the pyrazine ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;

R 3 is combined with R 1 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 —C 1 -C 6 alkyl, halogen, —OH, —OR b , —NH 2 , —NHR b , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —(CH 2 ) n OH, —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , —CH 2 F, or ═O;

each R 1 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OH, —OR 6 , halogen, —NO 2 , —CN, —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , 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, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 2 is —NH 2 , —OR b , —CN, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, halogen, —C(O)OR b , —C 3 -C 8 cycloalkyl, 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 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

each R b is independently —H, -D, —OH, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 2 -C 6 alkenyl, —(CH 2 ) 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 —(CH 2 ) n -aryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , heterocyclyl, aryl, heteroaryl, —(CH 2 ) n OH, —C 1 -C 6 alkyl, —CF 3 , —CHF 2 , or —CH 2 F;

R 4 is —H, -D, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —CF 2 OH, —CHFOH, —NH—NHR 5 , —NH—OR 5 , —O—NR 5 R 6 , —NHR 5 , —OR 5 , —NHC(O)R 5 , —NHC(O)NHR 5 , —NHS(O) 2 R 5 , —NHS(O) 2 NHR 5 , —S(O) 2 OH, —C(O)OR 5 , —NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n R b , —C(O)R b , —NH 2 , —OH, —CN, —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, 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, —NH 2 , —OR b , halogen, or oxo; wherein each aryl or heteroaryl is optionally substituted with one or more —OH, —NH 2 , or halogen;

each R 5 and R 6 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR′, —SR′, halogen, —NR 7 R 8 , —NO 2 , —CF 3 , or —CN;

each R 7 and R 8 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OR b , 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, —NH 2 , —NO 2 , or —CN; and

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

6. 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;

Y 1 is —S—, a direct bond, —NH—, —S(O) 2 —, —S(O) 2 —NH—, —C(═CH 2 )—, —CH—, or —S(O)—;

Y 2 is —NR a —, wherein the bond on the left side of Y 2 , as drawn, is bound to the pyrazine ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;

R 3 is combined with R a 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 —C 1 -C 6 alkyl, halogen, —OH, —OR b , —NHR b , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —(CH 2 ) n OH, —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , —CH 2 F, or ═O;

each R 1 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OH, — 0 R 6 , halogen, —NO 2 —, —CN, —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , 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 2 , oxo, ═O, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 2 is —NH 2 , —OR b , —CN, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, halogen, —C(O)OR b , —C 3 -C 8 cycloalkyl, 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 2 , oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

each R b is independently —H, -D, —OH, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 2 -C 6 alkenyl, —(CH 2 ) 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 —(CH 2 ) n -aryl is optionally substituted with one or more —OH, halogen, —NO, oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , heterocyclyl, aryl, heteroaryl, —(CH 2 ) n OH, —C 1 -C 6 alkyl, —CF 3 , —CHF 2 , or —CH 2 F,

R 4 is —H, -D, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —CF 2 OH, —CHFOH, —NH—NHR 5 , —NH—OR 5 , —O—NR 5 R 6 , —NHR 5 , —OR 5 , —NHC(O)R 5 , —NHC(O)NHR 5 , —NHS(O) 2 R 5 , —NHS(O) 2 NHR 5 , —S(O) 2 OH, —C(O)OR 5 , —NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n R b , —C(O)R b , —NH 2 , —OH, —CN, —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, 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, —NH 2 , —OR b , halogen, or oxo; wherein each aryl or heteroaryl is optionally substituted with one or more —OH, —NH 2 , or halogen;

each R 5 and R 6 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR 7 , —SR 7 , halogen, —NR 7 R 8 , —NO 2 , —CF 3 , or —CN;

each R 7 and R 8 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OR b , 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, —NH 2 , —NO 2 , or —CN, and

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

7. 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;

Y 1 is —S—, a direct bond, —NH—, —S(O) 2 —, —S(O) 2 —NH—, —C(═CH 2 )—, —CH—, or —S(O)—;

Y 2 is —NR a —, wherein the bond on the left side of Y 2 , as drawn, is bound to the pyrazine ring and the bond on the right side of the Y 2 moiety, as drawn, is bound to R 3 ;

R 3 is combined with R 1 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 —C 1 -C 6 alkyl, halogen, —OH, —OR b , —NH 2 , —NHR b , heteroaryl, heterocyclyl, —(CH 2 ) n NH 2 , —(CH 2 ) n OH, —COOR b , —CONHR b , —CONH(CH 2 ) n COOR b , —NHCOOR b , —CF 3 , —CHF 2 , —CH 2 F, or ═O;

each R 1 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OH, —OR 6 , halogen, —NO 2 , —CN, —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)R 5 , —CO 2 R 5 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , 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 2 , oxo, ═O, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl;

R 2 is —NH 2 , —OR b , —CN, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, halogen, —C(O)OR b , —C 3 -C 8 cycloalkyl, 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, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , heterocycle, aryl, or heteroaryl; and wherein the heterocyclyl or heteroaryl is not attached via a nitrogen atom;

each R b is independently —H, -D, —OH, —C 1 -C 6 alkyl, —C 3 -C 8 cycloalkyl, —C 2 -C 6 alkenyl, —(CH 2 ) 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 —(CH 2 ) n -aryl is optionally substituted with one or more —OH, halogen, —NO, oxo, —CN, —R 5 , —OR 5 , —NR 5 R 6 , —SR 5 , —S(O) 2 NR 5 R 6 , —S(O) 2 R 5 , —NR 5 S(O) 2 NR 5 R 6 , —NR 5 S(O) 2 R 6 , —S(O)NR 5 R 6 , —S(O)R 5 , —NR 5 S(O)NR 5 R 6 , —NR 5 S(O)R 6 , —C(O)NR 5 R 6 , —NR 5 C(O)R 6 , heterocyclyl, aryl, heteroaryl, —(CH 2 ) n OH, —C 1 -C 6 alkyl, —CF 3 , —CHF 2 , or —CH 2 F;

R 4 is —H, -D, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 hydroxyalkyl, —CF 2 OH, —CHFOH, —NH—NHR 5 , —NH—OR 5 , —O—NR 5 R 6 , —NHR 5 , —OR 5 , —NHC(O)R 5 , —NHC(O)NHR 5 , —NHS(O) 2 R 5 , —NHS(O) 2 NHR 5 , —S(O) 2 OH, —C(O)OR 5 , —NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n OH, —C(O)NH(CH 2 ) n R b , —C(O)R b , —NH 2 , —OH, —CN, —C(O)NR 5 R 6 , —S(O) 2 NR 5 R 6 , C 3 -C 8 cycloalkyl, 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, —NH 2 , —OR b , halogen, or oxo; wherein each aryl or heteroaryl is optionally substituted with one or more —OH, —NH 2 , or halogen;

each R 5 and R 6 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, a monocyclic or polycyclic 3- to 12-membered heterocyclyl, —OR 7 , —SR 7 , halogen, —NR 7 R 8 , —NO 2 , —CF 3 , or —CN;

each R 7 and R 8 is independently —H, -D, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —OR b , 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, —NH 2 , —NO 2 , or —CN; and

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.

8. The method of any one of the preceding claim 1 , 2 , 3 , 4 , 5 , 6 , or 7 , wherein the inhibitor of SHP2 is selected from:

(i) Compound A having the structure:

(ii) Compound B having the structure:

and

(iii) the compound of the following structure:

9. The method of claim 1 , wherein the inhibitor of SHP2 is:

10. The method of claim 2 , wherein the inhibitor of SHP2 is:

11. The method of claim 4 , wherein the inhibitor of SHP2 is:

12. The method of claim 5 , wherein the inhibitor of SHP2 is:

13. The method of claim 6 , wherein the inhibitor of SHP2 is:

14. The method of claim 7 , wherein the inhibitor of SHP2 is:

15. The method of claim 1 , wherein the inhibitor of SHP2 is selected from a compound of Formula I-V2 wherein Y 1 is —S— or a direct bond, or a pharmaceutically acceptable salt and/or stereoisomer thereof.

16. The method of claim 2 , wherein the inhibitor of SHP2 is selected from a compound of Formula I-V2 wherein Y 1 is —S— or a direct bond, or a pharmaceutically acceptable salt and/or stereoisomer thereof.

17. The method of claim 4 , wherein the inhibitor of SHP2 is selected from a compound of Formula I-V2 wherein Y 1 is —S— or a direct bond, or a pharmaceutically acceptable salt and/or stereoisomer thereof.

18. The method of claim 5 , wherein the inhibitor of SHP2 is selected from a compound of Formula I-V2 wherein Y 1 is —S— or a direct bond, or a pharmaceutically acceptable salt and/or stereoisomer thereof.

19. The method of claim 6 , wherein the inhibitor of SHP2 is selected from a compound of Formula I-V2 wherein Y 1 is —S— or a direct bond, or a pharmaceutically acceptable salt and/or stereoisomer thereof.

20. The method of claim 7 , wherein the inhibitor of SHP2 is selected from a compound of Formula I-V2 wherein Y 1 is —S— or a direct bond, or a pharmaceutically acceptable salt and/or stereoisomer thereof.

21. The method of claim 3 , wherein the RAS pathway mutation is a KRAS mutation.

Assignments (2)
SECURITY INTEREST Recorded Jun 25, 2025
From: REVOLUTION MEDICINES, INC.
To: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS AGENT
Reel/Frame 071721/0025 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 1, 2020
From: NICHOLS, ROBERT J.; GOLDSMITH, MARK A.; SCHULZE, CHRISTOPHER; SMITH, JACQUELINE; WILDES, DAVID E.; KELSEY, STEPHEN; SINGH, MALLIKA
To: REVOLUTION MEDICINES, INC.
Reel/Frame 053966/0837 →
Continuity (6)
Continuation PCTUS2018049744 · Sep 6, 2018
Provisional Application 62681001 · Jun 5, 2018
Provisional Application 62653831 · Apr 6, 2018
Provisional Application 62558255 · Sep 13, 2017
Provisional Application 62555400 · Sep 7, 2017
Related Publication 20200368238A1 · Nov 26, 2020