Pyrimidines and variants thereof, and uses therefor
The present disclosure provides pyrimidine compounds of Formula 1 and uses thereof, for example, for the potential treatment of diseases associated with P2X purinergic receptors: In certain aspects, the present disclosure provides P2X3 and/or P2X2/3 antagonists which are useful, for example, for the potential treatment of visceral organ, cardiovascular and pain-related diseases, conditions and disorders.
1. A compound of Formula 1:
or a pharmaceutically acceptable salt thereof, wherein:
W is selected from O, S and NH;
X 1 is N or CR 2 ;
X 2 is CR 3 ;
X 3 is CR 4 ;
X 4 is CR 5 ;
X 5 is N or CR 6 , provided, however, when X 1 is CR 2 , W is not O;
Y is —NR d R e , wherein one of R d and R e is hydrogen, and the other is selected from hydrogen and C 1-12 -alkyl;
D is absent;
R 1 is selected from C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, C 3-12 -cycloalkyl, C 3-12 -cycloalkenyl, C 1-12 -haloalkyl, and C 1-12 -hydroxyalkyl;
R 2 , R 3 , and R 4 are each independently selected from hydrogen, C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, amino, halo, amido, C 1-12 -haloalkyl, C 1-12 -alkoxy, hydroxy, C 1-12 -haloalkoxy, nitro, C 1-12 -hydroxyalkyl, C 2-12 -alkoxyalkyl, C 1-12 -hydroxyalkoxy, C 3-12 -alkynylalkoxy, C 1-12 -alkylsulfonyl, C 5-12 -arylsulfonyl, cyano, C 6-12 -aryl, C 5-12 -heteroaryl, C 3-12 -heterocyclyl, C 4-12 -heterocyclylalkoxy, C 6-12 -aryloxy, C 5-12 -heteroaryloxy, C 7-12 -arylalkyloxy, C 6-12 -heteroaralkyloxy, optionally substituted phenoxy, —(CH 2 ) m —(Z) n —(CO)—R f and —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n′ —R f , where m, n and n′ are each independently 0 or 1;
R 5 is selected from hydrogen, C 1-12 -alkyl, C 2-12 -alkenyl, C 2-12 -alkynyl, amino, amido, C 1-12 -haloalkyl, C 1-12 -alkoxy, hydroxy, C 1-12 -haloalkoxy, nitro, C 1-12 -hydroxyalkyl, C 2-12 -alkoxyalkyl, C 1-12 -hydroxyalkoxy, C 3-12 -alkynylalkoxy, C 1-12 -alkylsulfonyl, C 5-12 -arylsulfonyl, cyano, C 6-12 -aryl, C 5-12 -heteroaryl, C 3-12 -heterocyclyl, C 4-12 -heterocyclylalkoxy, C 6-12 -aryloxy, C 5-12 -heteroaryloxy, C 7-12 -arylalkyloxy, C 6-12 -heteroaralkyloxy, optionally substituted phenoxy, —(CH 2 ) m —(Z) n —(CO)—R f and —(CH 2 ) m —(Z) n —SO 2 —(NR g ) n′ —R f , where m, n and n′ are each independently 0 or 1;
Z is O or NR g ;
R f is selected from hydrogen, C 1-12 -alkyl, hydroxy, C 1-12 -alkoxy, amino, C 1-12 -hydroxyalkyl and C 2-12 -alkoxyalkyl;
each R g is independently selected from hydrogen and C 1-12 -alkyl;
R 6 is hydrogen; and
R 7 is hydrogen.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is CR 2 and W is S, providing compounds of Formula 1a as follows:
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 1 is N, providing compounds of Formula 1b, as follows:
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 5 is N, providing compounds of Formula 1l, as follows:
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein X 5 is CR 6 , providing compounds of Formula 1m, as follows
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is O.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is S.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W is NH.
9. The compound of claim 1 of Formula 2, or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is selected from C 1-12 -alkyl, C 2-12 -alkenyl, C 3-12 -cycloalkyl, and C 3-12 -cycloalkenyl.
10. The compound of claim 1 of Formula 3, or a pharmaceutically acceptable salt thereof:
11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from:
12. A composition which comprises an inert carrier and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.