Dihydrofolate reductase inhibitors
View Patent ↗The present disclosure provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein R 5 , R 6 and Z are as described herein. The disclosure also provides pharmaceutical compositions thereof; and methods for inhibiting DHFR activity; and methods for treating cell proliferative diseases, autoimmune disease, inflammatory disease or bacterial, fungal or parasitic infection by administering a compound of Formula I.
1. A compound having the structure
wherein
Z is a seven to 10-membered heteroaryl ring comprising 0-4 heteroatoms independently selected from the group consisting of N, O, and S;
when two rings comprise the seven to 10-membered heteroaryl ring, the two rings are heteroaromatic;
R represents one or more moieties independently selected from the group consisting of H, halo, lower alkyl, lower alkoxy, CF 3 , amino, CN, CO 2 CH 3 , optionally-substituted aryl, and optionally-substituted heterocyclyl;
R 5 is selected from the group consisting of H, halo, lower alkyl, and lower alkoxy;
R 6 is selected from the group consisting of H, halo, lower alkyl, lower alkoxy, CF 3 , 5-membered heteroarylmethylene, and amino; and pharmaceutically acceptable salts and solvates thereof.
2. The compound of claim 1 , wherein Z is selected from the group consisting of optionally-substituted isoquinoline, benzofuran, benzothiophene, indole, pyrrolopyridine, imidazopyridine, indazole benzimidazole, benzothiazole, quinoline, and benzotriazole.
3. The compound of claim 2 , wherein Z is optionally-substituted benzimidazole.
4. The compound of claim 1 , wherein R is selected from the group consisting of halo, optionally-substituted lower alkyl, lower alkoxy, and heterocyclyl.
5. The compound of claim 1 , wherein R is selected from the group consisting of Me, Et, i-Pr, Cl, F, MeO, cyano, and CF 3.
6. The compound of claim 1 , wherein R is an optionally-substituted heteroaryl group.
7. The compound of claim 1 , wherein R 5 and R 6 are independently selected from the group consisting of F, Cl, lower alkyl, OMe, CF 3 , NMe 2 , and imidazolylmethyl.
8. The compound of claim 1 , where the compound is
7-(5,6-dimethyl-2-(pyridin-2-yl)-1H-benzo[d]-imidazol-1-yl)quinazoline-2,4-diamine.
9. The compound of claim 1 , where the compound is
7-[5,6-dimethyl-2-(thiazol-2-yl)-1H-benzo[d]-imidazol-1-yl]quinazoline-2,4-diamine.
10. The compound of claim 1 , where the compound is
7-(5,6-dimethoxy-2-(thiazol-2-yl)-1H-benzo[d]imidazo-1-yl)quinazoline-2,4-diamine.
11. The compound of claim 1 , where the compound is
7-(2-(furan-2-yl)-5,6-dimethoxy-1H-benzo[d]-imidazol-1-yl)quinazoline-2,4-diamine.
12. The compound of claim 1 , where the compound is
7-(5,6-dimethyl-2-(thiophen-2-yl)-1H-benzo[d]-imidazol-1-yl)quinazoline-2,4-diamine.
13. The compound of claim 1 , where the seven to 10-membered heteroaryl ring is an eight to 10-membered heteroaryl ring.
14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier.
15. A method of impeding growth of a bacterium by exposing the bacterium to a compound of claim 1 .