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, halo, 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, C 1 -C 6 alkyl, or C 6 -C 10 aryl;
R 2 and R 3 are independently hydrogen or halo;
R 4 is hydrogen, halo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, or C 6 -C 10 aryl,
R 5 , R 7 , R 9 , R 12 , and R 15 independently are 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;
R 6 and R 10 independently are hydrogen or halo;
R 8 is hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or 5-15 membered heteroaryl;
each R 11 independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, or C 6 -C 10 aryl;
R 13 , R 14 , R 16 , and R 17 are independently hydrogen, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkyny, or C 1 -C 6 alkoxy;
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 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.
8 . The compound of claim 1 of formula:
9 . The compound of claim 1 of formula:
10 . The compound of claim 1 of formula:
11 . The compound of claim 1 of formula:
12 . The compound of claim 1 of formula:
13 . The compound of claim 8 , wherein R 8 is hydrogen.
14 . The compound of claim 8 , wherein R 8 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl.
15 . The compound of 8 , wherein R 9 is optionally substituted C 1 -C 6 alkyl.
16 . The compound of claim 9 , wherein R 7 is optionally substituted C 1 -C 6 alkyl.
17 . The compound of claim 10 , wherein R 12 is optionally substituted C 1 -C 6 alkyl.
18 . The compound of claim 11 , wherein R 15 is optionally substituted C 1 -C 6 alkyl.
19 . The compound of claim 3 , wherein R 5 is a non-hydrogen substituent.
20 . 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.
21 . A pharmaceutical composition comprising the compound of claim 1 and at least one pharmaceutically acceptable excipient.
22 . A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .