Macrocyclic Benzofused Pyrimidine Derivatives

A compound of formula (I):

• or a pharmaceutically acceptable, salt, ester, amide, or prodrug thereof, wherein:
• G1 is selected from oxygen, sulfur, S(O), S(O)2, NR8 and alkylene;
• G2 is selected from oxygen, sulfur, S(O), S(O)2, NR8, and alkylene wherein each carbon of the alkylene and methylene groups of G1 and G2 may be optionally substituted with one or more groups selected from alkyl, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, fluorine, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, and oxo;
• provided that when G1 is oxygen, sulfur, S(O), S(O)2 or NR8, G2 is alkylene;
• provided that when G2 is oxygen, sulfur, S(O), S(O)2, or NR8 G1 is alkylene;
• R1 is selected from H, NH2, —NH(acyl), —NH(alkyl), —N(alkyl)2, —NH(C═O)aryl, —NH-alkylene(NR8R9), —NH(C═O)-alkylene(NR8R9), —NR8(C═O)NR8R9, —NH—alkylene-heteroaryl, —NHOH, —NHOCH3, —O-alkylene(NR8R9), alkyl, piperazine, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, hydroxyalkyl, cyano, alkoxycarbonyl, carboxy, —(C═O)—(NR8R9), —(C═O)—NH-alkylene(NR8R9), and alkoxy;
• R2, R3, R4, R5, are each independently selected from hydrogen, alkyl, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, aryl, heteroaryl, heterocycle, O-aryl, O-heteroaryl, S-aryl, CONR8R9, NR8COalkyl, NR8(C═O)Oalkyl, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, —NR8R9, -carbonyl(NR8R9), —SO2 (NR8R9), and N(R8)SO2(R9);
• R3 and R4 taken together with the carbon atoms to which each is attached form a ring, wherein R3 and R4 taken together are —CH2CH2CH2—, —CH2CH2CH2CH2—, or —CH2OCH2—;
• R6 is selected from hydrogen, alkyl, fluoroalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, and alkylfluorocycloalkyl;
• R7 is selected from fluoroalkyl, hydroxyalkyl, alkoxyalkyl, fluorocycloalkyl, and alkylfluorocycloalkyl;
• R8 and R9 each are each independently selected from hydrogen, alkyl, fluoroalkyl, cycloalkyl, cyanoalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, aryl, heteroaryl, heterocycle, acyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, amido, formyl, hydroxy, and hydroxyalkyl;
• A1 is a group of structure A2 or A3;
• wherein A2 is selected from
• and A3 is selected from
• wherein G3 is O, S, S(O), S(O)2;
• n is 1, 2, or 3;
• m is 0, 1, or 2;
• wherein each carbon atom of groups A1 may be optionally substituted with one or more groups selected from alkyl, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, fluorine, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio;
• provided that when G1 is CH2 and G2 is selected from CH2, CH2CH2, oxygen or sulfur and R1 is selected from NH2, NHalkyl, or alkyl, then A1 is not a group of structure K;
• and further provided that when G1 is CH2CH2 and G2 is CH2 and R1 is selected from NH2, NHalkyl, or alkyl, then A1 is not a group of structure K.