Lactam glycogen phosphorylase inhibitors and method of use

A pharmaceutical composition that inhibits the enzyme glycogen phosphorylase comprising a compound of formula I

• 70
• wherein
• W is a bicyclic hetroaryl of the structure
• 71
• X is —O—, —S—, —SO2—, —CHR5—, —CHR50—, —CHR5S—, —CHR5SO2—, —CHR5CO— or —CH2CHR5—;
• Y is a bond or —CHR6—;
• Z is an aryl or heteroaryl group of the following structure:
• 72
• A is —CH— or —N—;
• B is —O— or —S—;
• R1 is hydrogen, alkyl, aryl or alkenyl;
• R2 is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or alkenyl;
• R3 and R4 are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy;
• R5 and R6 are each independently hydrogen, alkyl, aryl, alkenyl, CN, CN4R9A (tetrazole), CO2R9A, CONR9AR9B or CONR9AOR9B;
• R7 and R8 are each independently hydrogen, halo, trifluoromethyl, cyano, hydroxy, a hydrogen bonding group, alkyl, alkoxy, aryl, arylalkyl, heteroarylalkyl, aryloxy or alkenyl;
• and
• R9A and R9B are independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R9A and R9B may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups,
• wherein when R1, R2, R5, R6, R7 and R8 are alkyl, aryl, alkenyl, arylalkyl, heteroarylalkyl, alkoxy or aryloxy, R1, R2, R5, R6, R7 and R8 may each independently be substituted with 1 to 3 hydrogen bonding groups;
• with the proviso that compounds of formula I exclude compounds of the following structure:
• 3-chloro-5-[N-(4-oxo-2,3,4,5-tetrahydrobenz[1,5] thiazepin-3-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole;
• 2,3-dichloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole;
• 2-chloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;
• 2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;
• 2-chloro-5-[N-(3-oxo-2,3,4,5-tetrahydro-1H-benz[2]azepin-4-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

A method of inhibiting the enzyme glycogen phosphorylase which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of compound of formula I

• 77
• wherein
• W is a bicyclic hetroaryl of the structure
• 78
• X is —O—, —S—, —SO2—, —CHR5—, —CHR5O—, —CHR5S—, —CHR5SO2—, —CHR5CO— or —CH2CHR5—;
• Y is a bond or —CHR6—;
• Z is an aryl or heteroaryl group of the following structure:
• 79
• A is —CH— or —N—;
• B is —O— or —S—;
• R1 is hydrogen, alkyl, aryl or alkenyl;
• R2 is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or alkenyl;
• R3 and R4 are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy;
• R5 and R6 are each independently hydrogen, alkyl, aryl, alkenyl, CN, CN4R9A (tetrazole), CO2R9A, CONR9AR9B or CONR9AOR9B;
• R7 and R8 are each independently hydrogen, halo, trifluoromethyl, cyano, hydroxy, a hydrogen bonding group, alkyl, alkoxy, aryl, arylalkyl, heteroarylalkyl, aryloxy or alkenyl;
• and
• R9A and R9B are independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R9A and R9B may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups,
• wherein when R1, R2, R5, R6, R7 and R8 are alkyl, aryl, alkenyl, arylalkyl, heteroarylalkyl, alkoxy or aryloxy, R1, R2, R5, R6, R7 and R8 may each independently be substituted with 1 to 3 hydrogen bonding groups;
• with the proviso that compounds of formula I exclude compounds of the following structure:
• 3-chloro-5-[N-(4-oxo-2,3,4,5-tetrahydrobenz[1,5]thiazepin-3-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole;
• 2,3-dichloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-4H-thieno[3,2-b]pyrrole;
• 2-chloro-5-[N-(2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;
• 2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole;
• 2-chloro-5-[N-(3-oxo-2,3,4,5-tetrahydro-1H-benz[2]azepin-4-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.