Egfr kinase knockdown via electrophilically enhanced inhibitors

A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I:

• wherein:
• each R1
• and R2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, C(═O)R5 or C(═NR5);
• wherein R5 is H, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy;
• each R3 is independently H, halo, hydroxy, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heteroalkyl;
• each R4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
• W is —CH2—, —C═C—, O, S, or NR1;
• n is 1-7
• Q1 is N or CR3;
• Q2 is N or CR3;
• L is Ap, wherein
• each A is independently NR1, S(O)q, O, C(═X)Y, Y(C═X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
• wherein each q is independently 0-2;
• p is 0-5;
• E is an electrophile;
• Z is -(Z1)k-Z2 or is absent,
• Z1 is NR6, O, C(═X)Y, Y(C═X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl
• Z2 is H, NR62, S(O)qR6, OR6, —C(═X)YR6, —Y(C═X)R6, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
• each R6 is independently H, halo, hydroxy, alkoxy, cyano, nitro, —C(═X)YR7, —YC(═X)R7, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl, wherein R7 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl;
• k is 0-4;
• each X is independently S or O;
• each Y is independently S or O;
• or a pharmaceutically acceptable salt thereof;
• and a pharmaceutically acceptable carrier.

A method of treating a disorder mediated by a cysteine containing kinase comprising administering to an individual in need thereof a therapeutically effective amount of a compound of Formula I:

• wherein:
• each R1
• and R2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, C(═O)R5 or C(═NR5);
• wherein R5 is H, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy;
• each R3 is independently H, halo, hydroxy, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heteroalkyl;
• each R4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
• W is —CH2—, —C═C—, O, S, or NR1;
• n is 1-7
• Q1 is N or CR3;
• Q2 is N or CR3;
• L is Ap, wherein
• each A is independently NR1, S(O)q, O, C(═X)Y, Y(C═X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
• wherein each q is independently 0-2;
• p is 0-5;
• E is an electrophile;
• Z is -(Z1)k-Z2 or is absent,
• Z1 is NR6, O, C(═X)Y, Y(C═X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl
• Z2 is H, NR62, S(O)qR6, OR6, —C(═X)YR6, —Y(C═X)R6, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
• each R6 is independently H, halo, hydroxy, alkoxy, cyano, nitro, —C(═X)YR7, —YC(═X)R7, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl, wherein R7 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl;
• k is 0-4;
• each X is independently S or O;
• each Y is independently S or O;
• or a pharmaceutically acceptable salt thereof.

A method of binding a cysteine containing kinase to a compound of Formula I comprising contacting the kinase with the compound of Formula I, wherein the compound of Formula I has the structure:

• wherein:
• each R1
• and R2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, C(═O)R5 or C(═NR5);
• wherein R5 is H, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy;
• each R3 is independently H, halo, hydroxy, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heteroalkyl;
• each R4 is independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
• W is —CH2—, —C═C—, O, S, or NR1;
• n is 1-7
• Q1 is N or CR3;
• Q2 is N or CR3;
• L is Ap, wherein
• each A is independently NR1, S(O)q, O, C(═X)Y, Y(C═X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
• wherein each q is independently 0-2;
• p is 0-5;
• E is an electrophile;
• Z is -(Z1)k-Z2 or is absent,
• Z1 is NR6, O, C(═X)Y, Y(C═X), substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl
• Z2 is H, NR62, S(O)qR6, OR6, —C(═X)YR6, —Y(C═X)R6, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
• each R6 is independently H, halo, hydroxy, alkoxy, cyano, nitro, —C(═X)YR7, —YC(═X)R7, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl, wherein R7 is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroalkyl;
• k is 0-4;
• each X is independently S or O;
• each Y is independently S or O;
• or a pharmaceutically acceptable salt thereof.