Aziridine containing DNA alkylating agents
Provided herein are compounds of formula (I)-(VI): wherein the variables are defined herein, processes of making them, and methods of treating cancer comprising administering such compounds.
1. A compound selected from:
or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of each thereof, wherein
R 1 is hydrogen, —N 3 , CN, NR 21 R 22 , —OR 23 , —SO 2 (C 1 -C 6 alkyl), C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether;
each R 21 and R 22 independently is hydrogen, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or —SO 2 (C 1 -C 6 alkyl); or R 21 and R 22 together with the nitrogen atom they are bonded to form a 4-15 membered heterocycle or a 5-15 membered heteroaryl;
R 23 is hydrogen or C 1 -C 6 alkyl;
R 2 is hydrogen or halo;
R 3 is hydrogen;
R 4 is hydrogen, halo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, or C 6 -C 10 aryl,
R 5 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl; or R 4 and R 5 together with the intervening carbon atoms between them form a C 5 -C 6 cycloalkyl ring;
wherein the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocycle, heteroaryl, alkoxy and ether groups are optionally substituted.
2. The compound of claim 1 of formula:
3. The compound of claim 2 , wherein R 1 is a non-hydrogen substituent, R 2 and R 3 are hydrogen, and R 4 is hydrogen or halo, or R 4 and R 5 together form a 5 membered cycloalkyl group.
4. The compound of claim 3 , wherein R 4 is hydrogen.
5. The compound of claim 3 , wherein R 4 is halo.
6. The compound of claim 3 , wherein R 4 is fluoro.
7. The compound of claim 3 , wherein R 1 is NR 21 R 22 , wherein each R 21 and R 22 independently is hydrogen, hydroxy, C 1 -C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroayl, or —SO 2 (C 1 -C 6 alkyl); or R 21 and R 22 together with the nitrogen atom they are bonded to form a 4-15 membered heterocycle or a 5-15 membered heteroaryl.
8. The compound of claim 3 , wherein R 5 is a non-hydrogen substituent.
9. The compound of claim 3 , wherein R 1 is a non-hydrogen substituent; R 2 and R 3 are hydrogen, and R 4 is hydrogen or halo, and R 5 is optionally substituted C 1 -C 6 alkyl.
10. A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.
11. A method of inhibiting the growth of the tumor comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .