Substituted dihydrobenzoxazinones, dihydroquinolones, and methods of their use and synthesis
Disclosed are dihydrobenzoxazinone compounds, dihydroquinolone compounds, and methods of their synthesis. The disclosed compounds may be prepared by reacting a benzoxazinedione compound and a ketone compound in the presence of an N-heterocyclic carbine (NHC) catalyst to perform a NHC-catalyzed decarboxylative cycloaddition. The disclosed compounds may be utilized to treat diseases and disorders associated with the biological activity of dihydrobenzoxazinone compounds and dihydroquinolone compounds.
1. A compound of the following formula or a salt or hydrate thereof:
wherein:
R 1 is selected from alkyl, alkoxy, carboxyalkyl, haloalkyl, and amino;
R 2 is selected from cycloalkyl, aryl, heteroaryl, which optionally is substituted at one or more positions with a substituent selected from alkyl, alkoxy, halo, haloalkyl, and amino;
R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and amino;
X is selected from O and CH 2 ; and
Z is selected from O and CH 2 .
2. The compound of claim 1 , wherein R 1 is trifluoroalkyl.
3. The compound of claim 1 , wherein R 2 is phenyl.
4. The compound of claim 1 , wherein R 2 is thiophene.
5. The compound of claim 1 , wherein R 2 is aryl substituted at one more positions with a substituent selected from alkyl, alkoxy, halo, and haloalkyl.
6. The compound of claim 5 , wherein R 2 is ortho-substituted, meta-substituted, di-meta-substituted, or para-substituted.
7. The compound of claim 1 , wherein at least one of R 3 , R 4 , R 5 , and R 6 is bromo.
8. The compound of claim 1 , wherein at least one of R 3 , R 4 , R 5 , and R 6 is fluoro.
9. The compound of claim 1 , wherein at least one of R 3 , R 4 , R 5 , and R 6 , is chloro.
10. The compound of claim 1 , wherein at least one of R 3 , R 4 , R 5 , and R 6 is methoxy.
11. The compound of claim 1 , wherein at least one of R 3 , R 4 , R 5 , and R 6 is methyl.
12. The compound of claim 1 , wherein R 3 is hydrogen.
13. The compound of claim 1 , wherein R 6 is hydrogen.
14. The compound of claim 1 , having a formula:
15. The compound of claim 1 , wherein the compound has a formula selected from the group consisting of:
16. An enantiomerically pure composition comprising the compound of claim 1 .
17. A racemic mixture of compounds comprising the compound of claim 1 ,
wherein the compound represents at least about 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% of the racemic mixture of compounds.
18. A pharmaceutical composition comprising: (a) an effective amount of the compound of claim 1 ; and (b) at least one of a carrier, excipient, or diluent.
19. A method of synthesizing any of the compounds of claim 1 , the method comprising reacting:
(a) a compound of a formula
wherein:
R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, alkyl, alkoxy, halo, haloalkyl, and amino; and
(b) a compound of a formula
wherein:
R 1 is selected from alkyl, carboxyalkyl, and haloalkyl;
R 2 is selected from cycloalkyl, aryl, and heteroaryl, which optionally is substituted at one or more positions with a substituent selected from alkyl, alkoxy, halo, haloalkyl, and amino; wherein the compound (a) and the compound (b) are reacted in the presence of an N-heterocyclic carbene (NHC) catalyst to perform a NHC-catalyzed decarboxylative cycloaddition.