Substituted pyrimidine derivatives

1. A compound of formula (I):

or a pharmaceutically acceptable, salt, ester, or amide thereof, wherein

p is 1;

q is 0;

r is 0; and

X is O;

v and w are single or double bonds; with the proviso that w can be a single or a double bond when p is 1;

R 1 is selected from hydrogen, —(C═O)—NH-alkylene(NR 13 R 14 ), —(C═O)—(NR 13 R 14 ), NH 2 , —NH(acyl), —NH(alkyl), —N(alkyl) 2 , —NH-alkylene-heteroaryl, —NH-alkylene(NR 13 R 14 ), —NH(C═O)-alkylene(NR 13 R 14 ), —NH(C═O)aryl, —NR 13 (C═O)NR 13 R 14 , —NHOH, —NHOCH 3 , —O-alkylene(NR 13 R 14 ), alkoxy, alkoxycarbonyl, alkyl, carboxy, cyano, cyanoalkyl, cycloalkyl, fluoroalkyl, fluorocycloalkyl, hydroxyalkyl, and piperazine;

R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are each independently selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkyl, alkylsulfonyl, alkylthio, alkynyl, amido, aryl, carboxy, cyano, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl, halogen, heteroaryl, heterocycle, hydrogen, hydroxy, hydroxyalkyl, mercapto, nitro, C(O)NR 13 R 14 , NR 11 COalkyl, —NR 13 R 14 , —N(R 13 )SO 2 (R 14 ), —O-aryl, —O-heteroaryl, —S-aryl, and —SO 2 (NR 13 R 14 );

R 2 and R 4 together with the atom they are attached may form a ring, alternatively, any two of R 2 , R 4 , R 6 , and R 8 that are on non-adjacent carbon atoms, may optionally be taken together to form a bridge selected from —CH═CH—, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, or —CH 2 CH 2 CH 2 CH 2 CH 2 —;

R 11 is selected from alkoxyalkyl, alkyl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, hydrogen, and hydroxyalkyl;

R 12 is selected from the group consisting of alkoxyalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, and hydroxyalkyl;

R 13 and R 14 are each independently selected from acyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, amido, aryl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl, heteroaryl, heterocycle, hydrogen, hydroxy, and hydroxyalkyl;

A 1 is a group of structure A 2 or A 3

wherein A 2 is

and A 3 is selected from

wherein G 1 is O, S, S(O), or S(O) 2 ;

n is 1,2, or 3;

m is 0,1, or 2;

wherein each carbon atom of groups A 1 may be optionally substituted with one or more groups selected from acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, alkylthio, alkynyl, amido, carboxy, cyano, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, fluorine, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl, hydroxy, hydroxyalkyl, mercapto, and nitro.

2. The compound of claim 1 , wherein R 1 is selected from hydrogen, NH 2 , NHOH, —NHOCH 3 , fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, hydroxyalkyl, cyano, and alkoxy.

3. The compound of claim 1 , wherein

v is a double bond;

w is a single bond;

R 2 and R 4 form a ring; and

R 3 and R 5 are hydrogen.

4. The compound of claim 3 , wherein R 1 is NH 2 .

5. The compound of claim 4 , wherein A 1 is a group of the formula

6. The compound of claim 1 , wherein

v is a double bond;

w is a double bond;

R 2 and R 4 form a ring; and

R 3 and R 5 are hydrogen.

7. The compound of claim 6 , wherein R 1 is NH 2 .

8. The compound of claim 7 , wherein A 1 is a group of the formula

9. The compound of claim 1 , wherein the compound is:

4-piperazin-1-yl-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;

4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;

(7aS,11aS)-4-piperazin-1-yl-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;

(7aR,11aR)-4-piperazin-1-yl-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;

4-(4-methyl-1,4-diazepan-1-yl)-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;

4-(4-methylpiperazin-1-yl)-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;

4-[(3R)-3-aminopyrrolidin-1-yl]-7a,8,9,10,11,11a-hexahydro[1]benzofuro[2,3-h]quinazolin-2-amine;

4-[(1R,5S)-3,6-diazabicyclo[3.2.0]hept-6-yl]-7a,8,9,10,11,11a-hexahydro[1]benzofuro[2,3-h]quinazolin-2-amine;

4-(1,4-diazepan-1-yl)-5,6,7a,8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine;

4-(4-isopropyl-1,4-diazepan-1-yl)-5,6,7a, 8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine; and

4-(4-cyclobutyl-1,4-diazepan-1-yl)-5,6,7a, 8,9,10,11,11a-octahydro[1]benzofuro[2,3-h]quinazolin-2-amine.

10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.