EGFR kinase knockdown via electrophilically enhanced inhibitors
Provided herein are electrophilically enhanced kinase inhibitors of Formula I. Also provided herein are methods of making and utilizing the same.
1. A compound of Formula I:
wherein:
each R 1
and R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, C(═O)R 5 or C(═NR 5 ); wherein R 5 is H, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy;
each R 3 is independently H, halo, hydroxy, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heteroalkyl;
each R 4 is independently substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
W is —CH 2 —, —C═C—, O, S, or NR 1 ;
n is 1-7
Q 1 is N;
Q 2 is N;
L is A p , wherein
each A is independently NR 1 , 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 selected from:
—(CR 14 R 15 ) r —(CR 8 ═CR 8 ) q —(CR 14 R 15 ) r —
wherein
R 14 and R 15 are independently H, CN, NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or taken together are ═S, ═N —OR 11 , or ═O; wherein each R 11 is independently 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;
each R 8 is independently H, halo, hydroxy, alkoxy, cyano, nitro, S(O) 1-2 R 11 , —C(═X)YR 11 , —YC(═X)R 11 , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroalkyl, or two R 8 are taken together to form a bond;
each r is independently 0-2;
q is 1-2;
Z is —(Z 1 ) k —Z 2
Z 1 is NR 6 , 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
Z 2 is H, NR 6 2 , S(O) q R 6 , OR 6 , —C(═X)YR 6 , —Y(C═X)R 6 , 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 R 6 is independently H, halo, hydroxy, alkoxy, cyano, nitro, —C(═X)YR 7 , —YC(═X) R 7 , 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 R 7 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.
2. The compound of claim 1 wherein E is an electrophile subject to nucleophilic substitution or nucleophilic addition when contacted with a thiol or thiolate.
3. The compound of claim 1 , wherein R 1 and R 2 are independently H or substituted or unsubstituted alkyl.
4. The compound of claim 1 , wherein R 3 is H, halo, substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy.
5. The compound of claim 1 , wherein W is —CH 2 —or O.
6. The compound of claim 1 , wherein n is 1-3.
7. The compound of claim 1 , wherein E is —(C═O)—(CH═CH)—, —(CH═CH)—(C═O)—, —C(CN)═CH—, —CH═C(CN)—, —C(NO 2 )═CH—, or —CH═C(NO 2 .
8. The compound of claim 1 , wherein n is 1 or 2, and wherein one A is tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl, phenyl, cyclohexyl, cyclopentyl, pyridinyl, pyrimidinyl, piperidinyl, homopiperidinyl, pyrrolidinyl, piperazinyl, or morpholino.
9. The compound of claim 1 , wherein Z 2 is NR 6 2 , substituted or unsubstituted heteroalkyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperazinyl or a substituted or unsubstituted morpholino.
10. The compound of claim 1 , wherein R 4 is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
11. The compound of claim 1 having the Formula II:
wherein
R 3 is H, halo, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy;
R 4 is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
R 14 is H;
R 15 is H; or R 14 and R 15 taken together are ═O;
R 8a is H, lower alkyl, CN, NO 2 , or SO 2 R 11 ; and
R 8b is H, CN, NO 2 , or SO 2 R 11 .
12. The compound of claim 11 , wherein R 14 and R 15 taken together are ═O, and wherein R 8a and R 8b are H.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I:
wherein:
each R 1
and R 2 is H, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, C(═O)R 5 or C(═NR 5 ); wherein R 5 is H, hydroxy, substituted or unsubstituted alkyl or substituted or unsubstituted alkoxy;
each R 3 is independently H, halo, hydroxy, CN, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, or substituted or unsubstituted heteroalkyl;
each R 4 is independently substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocycloalkyl;
W is —CH 2 —, —C═C—, O, S, or NR 1 ;
n is 1-7
Q 1 is N;
Q 2 is N;
L is A p , wherein
each A is independently NR 1 , 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 selected from:
—(CR 14 R 15 ) r —(CR 8 ═CR 8 ) q —(CR 14 R 15 ) r —
wherein
R 14 and R 15 are independently H, CN, NO 2 , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or taken together are ═S, ═N—OR 11 , or ═O; wherein each R 11 is independently 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;
each R 8 is independently H, halo, hydroxy, alkoxy, cyano, nitro, S(O) 1-2 R 11 , —C(═X)YR 11 , —YC(═X)R 11 , substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroalkyl, or two R 8 are taken together to form a bond;
each r is independently 0-2;
q is 1-2;
Z is —(Z 1 ) k —Z 2
Z 1 is NR 6 , 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
Z 2 is H, NR 6 2 , S(O) q R 6 , OR 6 , —C(═X)YR 6 , —Y(C═X)R 6 , 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 R 6 is independently H, halo, hydroxy, alkoxy, cyano, nitro, —C(═X)YR 7 , —YC(═X) R 7 , 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 R 7 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.