Heteroaryl-fused macrocyclic pyrimidine derivatives

1. A compound of formula (I):

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

R 1 is hydrogen, alkoxy, alkoxycarbonyl, alkyl, —(C═O)—NH-alkylene(NR 7 R 8 ), —(C═O)—(NR 7 R 8 ), carboxy, cyano, cyanoalkyl, cycloalkyl, fluoroalkyl, fluorocycloalkyl, hydroxyalkyl, NH 2 , —NH(acyl), —NH(alkyl), —N(alkyl) 2 , —NH(C═O)aryl, —NH-alkylene(NR 7 R 8 ), —NH(C═O)-alkylene(NR 7 R 8 ), —NR 7 (C═O)NR 7 R 8 , —NH-alkylene-heteroaryl, —NHOH, —NHOCH 3 , —O-alkylene(NR 7 R 8 ), or piperazine;

G 1 is oxygen, sulfur, S(O), S(O) 2 , NR 7 or alkylene;

G 2 is oxygen, sulfur, S(O), S(O) 2 , NR 7 , or alkylene;

wherein each carbon of the alkylene and alkylene groups of G 1 and G 2 may be optionally substituted with one or more groups selected from the group consisting of acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, alkylthio, alkynyl, amido, carboxy, cyano, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, fluorine, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, and oxo;

provided that only one of G 1 or G 2 can be oxygen, sulfur, S(O), S(O) 2 or NR 7 ;

W represents an optionally substituted heteroaryl ring selected from the group consisting of

R 2 is hydrogen, 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, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, CONR 7 R 8 , NR 7 COalkyl, —NR 7 (C═O)Oalkyl, or O-aryl;

R 3 is hydrogen, alkyl, aryl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkyl, fluorocycloalkyl, or fluorocycloalkylalky;

R 4 is hydrogen, alkoxyalkyl, alkyl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, or hydroxyalkyl;

R 5 is alkoxyalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, or hydroxyalkyl;

R 6 is hydrogen, acyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, amido, aryl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl, heteroaryl, heterocycle, hydroxy, or hydroxyalkyl;

R 7 and R 8 are each independently acyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylsulfonyl, amido, aryl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, cycloalkylalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, heteroaryl, heterocycle, hydrogen, formyl, hydroxy, or hydroxyalkyl;

A 1 is a group of structure A 2 ; wherein A 2 is:

wherein n is 1, 2, or 3; and

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, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, mercapto, and nitro;

provided that when G 1 is CH 2 or CH 2 CH 2 and G 2 is CH 2 and R 1 is NH 2 , NHalkyl, or N(alkyl) 2 , then A 1 is not a group of structure K.

2. The compound according to claim 1 wherein

G 1 is —CH 2 —;

G 2 is —CH 2 —CH 2 —; and

R 1 is NH 2 , —NH(acyl), —NH(alkyl), —N(alkyl) 2 , —NH(C═O)aryl, —NH-alkylene(NR 7 R 8 ), —NH(C═O)-alkylene(NR 7 R 8 ), —NR 7 (C═O)NR 7 R 8 , —NH-alkylene-heteroaryl, —NHOH, or —NHOCH 3 .

3. The compound according to claim 2 , wherein A 2 is

4. The compound according to claim 3 , wherein W is selected from

5. The compound according to claim 4 wherein the compound is

4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-[(3R)-3-aminopyrrolidin-1-yl]-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-furo[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

9-methyl-4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-furo[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-[(3R)-3-aminopyrrolidin-1-yl]-9-methyl-6,7-dihydro-5H-furo[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-furo[3′,2′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-[(3R)-3-aminopyrrolidin-1-yl]-8-methyl-5,6,7,8-tetrahydropyrazolo[3′,4′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

8-tert-butyl-4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-5,6,7,8-tetrahydropyrazolo[3′,4′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-8-phenyl-5,6,7,8-tetrahydropyrazolo[3′,4′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

9-bromo-4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-9-phenyl-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-[(3R)-3-aminopyrrolidin-1-yl]-6,7-dihydro-5H-pyrido[3′,2′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine;

4-[(3R)-3-aminopyrrolidin-1-yl]-10-methyl-6,7-dihydro-5H-isoxazolo[5′,4′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine; or

4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6,7-dihydro-5H-thieno[2′,3′:6,7]cyclohepta[1,2-d]pyrimidin-2-amine; or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 wherein

G 1 is —CH 2 —;

G 2 is —CH 2 —; and

R 1 is NH 2 , —NH(acyl), —NH(alkyl), —N(alkyl) 2 , —NH(C═O)aryl, —NH-alkylene(NR 7 R 8 ), —NH(C═O)-alkylene(NR 7 R 8 ), —NR 7 (C═O)NR 7 R 8 , —NH-alkylene-heteroaryl, —NHOH, or —NHOCH 3 .

7. The compound according to claim 6 , wherein A 2 is

8. The compound according to claim 7 , wherein W is a group of the formula:

9. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier.