Macrocyclic pyrimidine derivatives

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein

G 1 is C 3 -alkylene;

G 2 is C 1 -alkylene;

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

G 4 is a bond;

R 1 is NH 2 , —NH(acyl), —NH(alkyl), —N(alkyl) 2 , —NH(C═O)aryl, —NH-alkylene(NR 8 R 9 ), —NH(C═O)-alkylene(NR 8 R 9 ), —NR 8 (C═O)NR 8 R 9 , —NH-alkylene-heteroaryl, —NHOH, or —NHOCH 3 ;

R 6 at each occurrence is independently hydrogen, alkoxyalkyl, alkyl, alkylcycloalkyl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, or hydroxyalkyl;

R 7 is alkoxyalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, or hydroxyalkyl;

R 8 and R 9 at each occurrence are independently hydrogen, acyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcycloalkyl, alkylsulfonyl, amido, aryl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl, heteroaryl, heterocycle, hydroxy, or hydroxyalkyl;

R 10 is independently hydrogen, acyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcycloalkyl, alkylsulfonyl, amido, aryl, arylalkyl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl, heteroaryl, heterocycle, hydroxy, or hydroxyalkyl;

R 11 is independently hydrogen, acyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcycloalkyl, alkylsulfonyl, amido, aryl, arylalkyl, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl, heteroaryl, heterocycle, hydroxy, or hydroxyalkyl;

A 1 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, alkylcycloalkyl, alkylsulfonyl, alkylthio, alkynyl, amido, carboxy, cyano, cyanoalkyl, cycloalkoxyalkyl, cycloalkyl, fluoro, fluoroalkoxy, fluoroalkyl, fluorocycloalkyl, fluorocycloalkylalkyl, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, and nitro.

2. The compound of claim 1 , wherein R 1 is NHOH, or —NHOCH 3 .

3. The compound of claim 1 , wherein R 1 is NH n , —NHCH 3 , —NH(C═O)CH 3 , —NH(C═O)phenyl, —NH(C═O)NHCH 3 , —NH(C═O)CH 2 NH 2 , —NH(C═O)CH 2 NHCH 3 , —NH(C═O)CH 2 N(CH 3 ) 2 , —NH(C═O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 (pyridin-3-yl), —NHCH 2 (imidazol-4-yl), or —NHCH 2 CH 2 N(CH 3 ) 2 .

4. The compound of claim 1 , wherein G 1 is CH 2 CH 2 CH 2 —.

5. The compound of claim 1 , wherein G 2 is —CH 2 —.

6. The compound of claim 1 , wherein A 1 is a group of the formula:

7. The compound of claim 1 , wherein R 10 is hydrogen and R 11 is aryl or heteroaryl.

8. The compound of claim 1 , wherein R 10 and R 11 are both alkyl or alkoxy.

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

(R)-4-(3-aminopyrrolidin-1-yl)-9,9-dimethyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;

9,9-dimethyl-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;

(R)-4-(3-aminopyrrolidin-1-yl)-9,9-diethyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;

(R)-4-(3-aminopyrrolidin-1-yl)-9,9-dibenzyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;

4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;

9-(2-methylpyridin-4-yl)-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;

methyl 5-(2-amino-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-9-yl)nicotinate;

5-(2-amino-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-9-yl)nicotinic acid;

4-((R)-3-(methylamino)pyrrolidin-1-yl)-9-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;

4-(3-(methylamino)azetidin-1-yl)-9-phenyl-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;

9-phenyl-4-(piperazin-1-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine;

9-phenyl-(4-tetrahydro-1H-pyrrolo[3,4-b]pyridine-6(2H,7H,7aH)-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine; or

9-phenyl-4-((4aR,7aR)-tetrahydro-1H-pyrrolo[3,4-b]pyridin-6 (2H,7H,7aH)-yl)-6,7,8,9-tetrahydro-5H-cyclohepta[d]pyrimidin-2-amine.

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