Substituted 2,3-dihydro-1H-benzo[a]pyrano[2,3-c]phenazines as anti-angiogenic and anti-cancer agents

1. A compound of formula (Ia):

and pharmaceutically acceptable salts thereof, wherein

R 1 and R 2 are each, independently, H, halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, amino, alkylamino, dialkylamino, aryl, arylalkyl, heteroaryl, heterocyclyl, nitro, cyano, carboxy, or amido;

R 3 and R 4 are each, independently, H, halogen, hydroxy, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C1-C6 alkoxycarbonyl, amino, alkylamino, aryl, arylalkyl, heteroaryl, heterocyclyl, nitro, cyano, carboxy, or amido;

X is selected from the group consisting of —COOR 5 , —CONHR 6 , —CONR 6 R 7 , —C(O)R 8 , and —C(═NOH)R 9 ;

R 5 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl groups is optionally substituted with one or more group(s) selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy and halogen;

R 6 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl groups is optionally substituted with one or more group(s) selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halogen and hydroxy(C1-C4 alkyl);

R 7 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl groups is optionally substituted with one or more group(s) selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halogen and aryl; or R 7 is C1-C6 alkoxy; or R 7 is —CHR 10 R 11 , wherein R 10 is aryl or heteroaryl and R 11 is —C(O)NHR 12 , wherein R 12 is C1-C6 alkyl or cycloalkyl; or R 7 and R 6 are taken together to form together with the nitrogen atom they are attached to a 5- or 6-membered cycloalkyl or a 5- or 6-membered heterocyclyl ring, the latter cycloalkyl or heterocyclyl rings being optionally substituted with one or more group(s) selected from the group consisting of C1-C4 alkyl, hydroxy, aryl and aralkyl;

R 8 is C1-C6 alkyl, C2-C6 alkenyl, cycloalkyl, heterocyclyl, aryl, arylalkynyl or heteroaryl, wherein each of said cycloalkyl, heterocyclyl, aryl, arylalkynyl or heteroaryl groups is optionally substituted with one or more group(s) selected from the group consisting of halogen, C1-C6 haloalkyl, C1-C6 alkoxy, aryl-C1-C2 alkoxy optionally substituted by one or more group(s) selected from halogen, and C1-C4 alkylsulfonylamino;

R 9 is C1-C6 alkyl, C2-C6 alkenyl, cycloalkyl, heterocyclyl, aryl, arylalkynyl or heteroaryl, wherein each of the cycloalkyl, heterocyclyl, aryl, arylalkynyl or heteroaryl groups is optionally substituted with one or more group(s) selected from the group consisting of C1-C6 haloalkyl and C1-C6 alkoxy;

R 14 and R 15 are independently selected from H, C1-C4 alkyl, C2-C6 alkenyl, hydroxy, halo, alkoxy, amino, alkylamino, nitro, cyano, carboxy, or amido; and

R 16 and R 17 are independently selected from H, C1-C4 alkyl, C2-C6 alkenyl, or hydroxy.

2. The compound according to claim 1 , having the formula (Ia-2)

and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 , having the formula (Ie-1), formula (Ie-2), formula (Ie-3), formula (Ie-4), formula (Ie-5), or formula (Ie-6):

and pharmaceutically acceptable salts thereof,

wherein Y 4 is O, S, —CHOH or N—R 20 and R 20 is C1-C6 alkyl, 6-membered aryl, or 6-membered aralkyl.

4. The compound according to claim 1 and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , R 3 , and R 4 are each H.

5. The compound according to claim 1 selected from the group consisting of:

6. A medicament comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier, diluent, excipient and/or adjuvant.