DNA alkylating agents
Provided herein are compounds of formula I: wherein the variables are defined herein, processes of making them, and methods of treating cancer comprising administering such compounds.
1. A compound of formula I:
or a pharmaceutically acceptable salt, or a solvate of each thereof, wherein
X 10 is O, S, SO, or SO 2 ;
A is C 6 -C 10 aryl, 5-15 membered heteroaryl, or —N═CR 1 R 2 ;
each R 1 and R 2 independently is hydrogen, - 13 CN, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, ether, —CONR 13 R 14 , or —NR 13 COR 14 ;
each X and Z independently is hydrogen or C 1 -C 6 alkyl;
Y is hydrogen, halo, or C 1 -C 6 alkyl;
R is hydrogen or C 1 -C 6 alkyl;
each R 13 and R 14 independently is hydrogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4-15 membered heterocycle, 5-15 membered heteroaryl, or ether;
T is OP(Z 1 )(NHCH 2 CH 2 Cl) 2 , OP(Z 1 )(NHCH 2 CH 2 Br) 2 , OP(Z 1 )(NH 2 )(N(CH 2 CH 2 X 1 ) 2 ), OP(Z 1 )(N(CH 2 ) 2 ) 2 , or OP(Z 1 )(N(CH 2 CH 2 C 1 ) 2 ) 2 , wherein Z 1 is O or S, and X 1 is C 1 , Br, or OMs; and
wherein the alkyl, cycloalkyl, aryl, heterocycle, heteroaryl, ether groups are optionally substituted.
2. The compound of claim 1 , wherein T is OP(O)(N(CH 2 CH 2 )) 2 , OP(O)(NHCH 2 CH 2 Cl) 2 , OP(O)(NHCH 2 CH 2 Br) 2 , or OP(O)(NH 2 )(N(CH 2 CH 2 Cl) 2 ).
3. The compound of claim 1 , wherein A is optionally substituted C 6 -C 10 aryl.
4. The compound of claim 3 , wherein A is optionally substituted phenyl.
5. The compound of claim 1 , wherein A is optionally substituted 5-15 membered heteroaryl.
6. The compound of claim 5 , wherein A is optionally substituted pyridyl.
7. The compound of claim 1 , wherein A is —N═CR 1 R 2 where R 1 and R 2 are defined as in claim 1 .
8. The compound of claim 1 , wherein R is methyl.
9. The compound of claim 1 , wherein the compound is
10. A pharmaceutically acceptable composition comprising a compound of claim 1 and at least a pharmaceutically acceptable excipient or carrier.
11. A process of making the compound of formula I of claim 1 comprising contacting a compound of formula II:
wherein L is a leaving group, and the remaining variables are defined as in claim 1 , with a compound of formula III:
wherein X 10 is defined as in claim 1 , and optionally a base, to provide a compound of formula I.