Substituted coumarins and quinolines and analogs as activators of caspases and inducers of apoptosis and the use thereof

A compound of Formula IIA:

• 34
• or a pharmaceutically acceptable salt or pro drug thereof, wherein:
• X is O, S, halo or NR6, wherein R6 is hydrogen or optionally substituted alkyl or aryl;
• Y is CN, COR7, CO2R7 or CONRxRy, wherein R7, Rx and Ry are independently hydrogen, C1-10 alkyl, halolkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl;
• or Rx and Ry are taken together with the nitrogen to which they are attached to form a heterocycle;
• Z is O, S, halo, NR8, or NCOR8, wherein R8 is independently H, C1-4 alkyl or aryl;
• A is optionally substituted and is aryl, heteroaryl, saturated carbocyclic, partially saturated carbocylic, saturated heterocyclic, partially saturated heterocyclic, arylalkyl or heteroarylalkyl;
• and
• R1-R4 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, C1-10 alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, methylenedioxy, carbonylamido or alkylthiol;
• or
• R1 and R2, or R2 and R3, or R3 and R4, taken together with the atoms to which they are attached form an aryl, heteroaryl, partially saturated carbocyclic or partially saturated heterocyclic group, wherein said group is optionally substituted.

A compound selected from the group consisting of:

• 3-Cyano-7-methoxy-4-(3-bromo-4,5-dimethoxyphenyl)-2-oxo-2H-chromene;
• 3-Cyano-7-methoxy-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene;
• 3-Cyano-4-(3-methoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-4-phenyl-quinolin-1H-2-one;
• 3-Cyano-7-methoxy-4-(3-methoxy-phenyl)quinolin-1H-2-one;
• 7-Chloro-3-cyano-4-(3-methoxyphenyl)-quinolin-1H-2-one;
• 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methoxy-quinolin-1H-2-one;
• 3-Cyano-2-imino-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-2-imino-7-methyl-4-(5-methyl-pyridin-3-yl)-2H-pyrrolo[2,3-h]chromene;
• 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-7-methyl-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-4-(5-methyl-pyridin-3-yl)-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-4-(5-methyl-pyridin-3-yl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 4-(3,5-Dimethoxyphenyl)-3-cyano-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-4-(3-methoxy-phenyl)-7-methoxy-2-oxo-2H-chromene;
• 7-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-2-oxo-2H-chromene;
• 2-Amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-5,6-dihydro-benzo[h]quinoline;
• 4-(3-Bromo-4,5-dimethoxyphenyl)-3-cyano-7,8-dihydro-8,8-dimethyl-2-oxo-2H-furo[3,2-h]chromene;
• 3-Cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxyphenyl)-2-oxo-2H-chromene;
• 7-Amino-3-cyano-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene;
• 3-Cyano-7-dimethylamino-4-(3,5-dimethoxyphenyl)-2-oxo-2H-chromene;
• 3-Cyano-4-(2,5-dimethoxyphenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 4-(3-Bromo-4,5-dimethoxy-phenyl)-3-cyano-7-methylamino-2-oxo-2H-chromene;
• 7-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-2H-chromene;
• 7-Bromo-4-(3 -bromo-4,5-dimethoxy-phenyl)-3-cyano-2-imino-2H-chromene;
• 4-(3-Bromo-4,5-dimethoxy-phenyl)-7-chloro-3-cyano-2-oxo-2H-chromene;
• 4-(3-Bromo-4,5-dimethoxy-phenyl)-7-chloro-3-cyano-2-imino-2H-chromene;
• 2-Imino-3-cyano-7-methoxy-4-(3′-methoxy-phenyl)-2H-thiochromene;
• 2-Imino-3-cyano-7-dimethylamino-4-(3-bromo-4,5-dimethoxy-phenyl)-2H-chromene;
• 3-Cyano-2-imino-7-methyl-4-(3-nitro-phenyl)-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-2-imino-7-methyl-4-(3,4,5-trimethoxy-phenyl)-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-4-(3,5-dimethoxy-phenyl)-2-imino-7-methyl-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-2-imino-4-(3-methoxy-4,5-methylenedioxyphenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-2-imino-4-(3-methoxy-phenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-2-imino-4-(3-bromophenyl)-7-methyl-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-7-methyl-4-(3-nitro-phenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-4-(3,5-dimethoxy-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-4-(3-methoxy-4,5-methylenedioxyphenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-4-(3-methoxy-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene;
• 3-Cyano-4-(3-bromo-phenyl)-7-methyl-2-oxo-2H-pyrrolo[2,3-h]chromene;
• and
• 3-Cyano-7-methyl-4-(3,4,5-trimethoxy-phenyl)-2-oxo-2H-pyrrolo[2,3-h]chromene.

A process for the preparation of a compound having Formula III:

• 37
• wherein Y is CN, COR7, CO2R7 or CONRxRy, wherein R7, Rx and Ry are independently hydrogen, C1-10 alkyl, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl or aminoalkyl;
• or Rx and Ry are taken together with the nitrogen to which they are attached to form a heterocycle;
• A is optionally substituted and is aryl, heteroaryl, saturated carbocyclic, partially saturated carbocylic, saturated heterocyclic, partially saturated heterocyclic, arylalkyl or heteroarylalkyl;
• and
• R1-R4 are independently hydrogen, halo, haloalkyl, aryl, fused aryl, carbocyclic, a heterocyclic group, a heteroaryl group, C1-10 alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, carbocycloalkyl, heterocycloalkyl, hydroxyalkyl, aminoalkyl, carboxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, methylenedioxy, carbonylamido or alkylthiol;
• or
• R1 and R2, or R2 and R3, or R3 and R4, taken together with the atoms to which they are attached, form an aryl, heteroaryl, partially saturated carbocyclic or partially saturated heterocyclic group, wherein said group is optionally substituted;
• the process comprising reacting a 2-aminobenzopyran having the formula:
• 38
• with an oxidant in an organic solvent to produce a 2-imino-2H-chromene of Formula IV:
• 39
• contacting said 2-imino-2H-chromene with an aqueous acid, and isolating the product of Formula III.