Irreversible covalent inhibitors of the GTPase K-Ras G12C

A compound of Formula I:

• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, each of which is either unsubstituted or substituted with one or more R3 groups;
• R2 is hydrogen, halogen, alkoxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, wherein each of the alkoxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl is either unsubstituted or substituted with one or more R4 groups;
• R3 is hydrogen, halogen, OR5, NR6R7, cyano, oxo, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, wherein each of the OR5, NR6R7, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl is either unsubstituted or substituted with one or more R8 groups;
• R5, R6 and R7 are independently hydrogen, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl, wherein each of the alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl or heteroaryl is either unsubstituted or substituted with one or more R9 groups;
• R4, R8 and R9 are independently hydrogen, cyano, halogen, hydroxy, alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl, wherein each of the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl is either unsubstituted or substituted with one or more R10 groups;
• each R10 is independently halogen, hydroxy, alkyl, heteroalkyl, cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl;
• and
• E is an electrophile capable of forming a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-ras G12C mutant protein and having one of the following structures:
• wherein:
• R21 is alkyl;
• R22 is CN or alkyl;
• R23 is alkyl;
• or R23 joins with R22 to form a cycloalkene or aryl ring.