Lactam glycogen phosphorylase inhibitors and method of use

1. A compound of formula I

wherein

W is a bicyclic heteroaryl of the structure

X is —CHR 5 —;

Y is a bond;

Z is selected from

A is —CH— or —N—;

B is —O— or —S—;

R 1 is hydrogen, alkyl, aryl or alkenyl;

R 2 is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or alkenyl;

R 3 and R 4 are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy;

R 5 and R 6 are each independently hydrogen, alkyl, aryl, alkenyl, CN, CN 4 R 9A (tetrazole), CO 2 R 9A , CONR 9A R 9B or CONR 9A OR 9B ;

R 7 and R 8 are each independently hydrogen, halo, trifluoromethyl, cyano, hydroxy, a hydrogen bonding group, alkyl, alkoxy, aryl, arylalkyl, heteroarylalkyl, aryloxy or alkenyl; and

R 9A and R 9B are independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R 9A and R 9B 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 R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are alkyl, aryl, alkenyl, arylalkyl, heteroarylalkyl, alkoxy or aryloxy, R 1 , R 2 , R 5 , R 6 , R 7 and R 8 may each independently be substituted with 1 to 3 hydrogen bonding groups;

where R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9A or R 9B is a hydrogen bonding group, the hydrogen bonding group is independently selected from the group consisting of OR 9A , OCO 2 R 10 , OCONR 9A R 9B , CN, NO 2 , CN 4 R 9A (tetrazole) COCF 3 , COR 9A CO 2 R 9A , CONR 9A R 9B , CONR 9A OR 9B , C(NR 9A )NR 9B R 9C , CONR 9A SO 2 R 9B , SOR 10 , SO 2 R 10 , SO 3 H, SO 2 NR 9A R 9B , SO 2 NR 9A COR 9B , SO 2 NR 9A CONR 9B R 9C , POR 9A R 9B , PO 2 R 9A R 9B , PO 3 R 9A R 9B , PO 2 R 9A NR 9B R 9C , NR 9A R 9B , NR 9A COR 9B , NR 9A C(NR 9B )R 9C , NR 9A CO 2 R 9B , NR 9A CONR 9B R 9C , NR 9A C(NR 9B )NR 9C R 9D , NR 9A SO 2 R 9B , NR 9A CONR 9B SO 2 R 9C , NR 9A SO 2 NR 9B R 9C , NR 9A POR 9B R 9C , NR 9A PO 2 R 9B R 9C , NR 9A PO 3 R 9B R 9C and NR 9A PO 2 R 9B NR 9C R 9D ; wherein

R 9C and R 9D are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and

R 10 is independently alkyl, arylalkyl, heteroarylalkyl, or aryl;

wherein R 9A , R 9B , R 9C R 9D or R 10 may further be substituted with one to three additional hydrogen bonding groups as defined above;

and wherein

two of R 9A , R 9B , R 9C or R 9D within the same hydrogen bonding group as defined above may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups as defined above;

with the proviso that compounds of formula I exclude compounds of the following structures:

1-t-butoxycarbonylmethyl-3-(carbonyl-2-indolyl)aminodihydrocarbostyril;

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; and

2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

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

wherein

W is a bicyclic hetroaryl of the structure

X is —CHR 5 —;

Y is a bond;

Z is selected from

A is —CH— or —N—;

B is —O— or —S—;

R 1 is hydrogen, alkyl, aryl or alkenyl;

R 2 is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or alkenyl;

R 3 and R 4 are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy;

R 5 and R 6 are each independently hydrogen, alkyl, aryl, alkenyl, CN, CN 4 R 9A (tetrazole), CO 2 R 9A , CONR 9A R 9B or CONR 9A OR 9B ;

R 7 and R 8 are each independently hydrogen, halo, trifluoromethyl, cyano, hydroxy, a hydrogen bonding group, alkyl, alkoxy, aryl, arylalkyl, heteroarylalkyl, aryloxy or alkenyl; and

R 9A and R 9B are independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R 9A and R 9B 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 R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are alkyl, aryl, alkenyl, arylalkyl, heteroarylalkyl, alkoxy or aryloxy, R 1 , R 2 , R 5 , R 6 , R 7 and R 8 may each independently be substituted with 1 to 3 hydrogen bonding groups;

where R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9A or R 9B is a hydrogen bonding group, the hydrogen bonding group is independently selected from the group consisting of OR 9A , OCO 2 R 10 , OCONR 9A R 9B , CN, NO 2 , CN 4 R 9A (tetrazole), COCF 3 , COR 9A , CO 2 R 9A , CONR 9A R 9B , CONR 9A OR 9B , C(NR 9A )NR 9B R 9C , CONR 9A SO 2 R 9B , SOR 10 , SO 2 R 10 , SO 3 H, SO 2 NR 9A R 9B , SO 2 NR 9A COR 9B , SO 2 NR 9A CONR 9B R 9C , POR 9A R 9B , PO 2 R 9A R 9B , PO 3 R 9A R 9B , PO 2 R 9A NR 9B R 9C , NR 9A R 9B , NR 9A COR 9B , NR 9A C(NR 9B )R 9C , NR 9A CO 2 R 9B , NR 9A CONR 9B R 9C , NR 9A C(NR 9B )NR 9C R 9D , NR 9A SO 2 R 9B , NR 9A CONR 9B SO 2 R 9C , NR 9A SO 2 NR 9B R 9C , NR 9A POR 9B R 9C , NR 9A PO 2 R 9B R 9C , NR 9A PO 3 R 9B R 9C and NR 9A PO 2 R 9B NR 9C R 9D ; wherein

R 9C and R 9D are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and

R 10 is independently alkyl, arylalkyl, heteroarylalkyl, or aryl;

wherein R 9A , R 9B , R 9C R 9D or R 10 may further be substituted with one to three additional hydrogen bonding groups as defined above;

and wherein

two of R 9A , R 9B , R 9C or R 9D within the same hydrogen bonding group as defined above may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups as defined above;

with the proviso that compounds of formula I exclude compounds of the following structures:

1-t-butoxycarbonylmethyl-3-(carbonyl-2-indolyl)aminodihydrocarbostyril;

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; and

2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.

3. The pharmaceutical composition of claim 2 wherein

R 1 is hydrogen;

Z is

 and

W is

4. The pharmaceutical composition of claim 2 wherein:

Z is

5. The pharmaceutical composition of claim 2 wherein: W is 5-chloroindol-2-yl.

6. The pharmaceutical composition of claim 2 wherein: R 5 or R 6 is CO 2 H.

7. The pharmaceutical composition of claim 2 wherein the compound of formula I is selected from:

3-(5-chloroindole-2-carbonylamino)-5-methoxy-3,4-dihydrocarbostyril;

3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-1-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-1-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-1-(2-hydroxyethyl)-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-1-aminocarbonylmethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-1-aminocarbonylmethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(R)-3-(5-chloroindole-2-carbonylamino)-1-methyl-3,4-dihydrocarbostyril;

(S)-3-(5-chloroindole-2-carbonylamino)-1-methyl-3,4-dihydrocarbostyril;

(S)-1-allyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(S)-3-(5-chloroindole-2-carbonylamino)-1-cyanomethyl-3,4-dihydrocarbostyril;

(R)-3-(5-chloroindole-2-carbonylamino)-1-cyanomethyl-3,4-dihydrocarbostyril;

3-(indole-2-carbonylamino)-3,4-dihydrocarbostyril;

(3R* ,4S*)-4-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(3R* ,4R*)-4-carbomethoxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril;

(3R* ,4S*)-4-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril-trans racemate;

(3R* ,4S*)-4-carboxymethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril-trans homochiral isomers; and

4-benzylaminocarbonylmethyl-3-(5-chloroindole-2-carbonylamino)-3,4-dihydrocarbostyril.

8. The pharmaceutical composition of claim 2 further comprising a pharmaceutically acceptable carrier.

9. A method for treating or delaying the progression of diabetes, hyperglycemia, obesity, or glucose intolerance which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of the pharmaceutical composition as defined in claim 2 .

10. A method of inhibiting the enzyme glycogen phosphorylase to treat or delay the progression of diabetes, hyperglycemia, obesity, or glucose intolerance, which comprises administering to a mammalian patient in need of treatment a therapeutically effective amount of the pharmaceutical composition as defined in claim 1 comprising a compound of formula I

wherein

W is a bicyclic hetroaryl of the structure

X is—CHR 5 —;

Y is a bond;

Z is selected from

A is —CH— or —N—;

B is —O— or —S—;

R 1 is hydrogen, alkyl, aryl or alkenyl;

R 2 is hydrogen, alkyl, aryl, arylalkyl, heteroarylalkyl or alkenyl;

R 3 and R 4 are each independently hydrogen, halo, trifluoromethyl, cyano, alkyl or alkoxy;

R 5 and R 6 are each independently hydrogen, alkyl, aryl, alkenyl, CN, CN 4 R 9A (tetrazole), CO 2 R 9A , CONR 9A R 9B or CONR 9A OR 9B ;

R 7 and R 8 are each independently hydrogen, halo, trifluoromethyl, cyano, hydroxy, a hydrogen bonding group, alkyl, alkoxy, aryl, arylalkyl, heteroarylalkyl, aryloxy or alkenyl; and

R 9A and R 9B are independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl, or R 9A and R 9B 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 R 1 , R 2 , R 5 , R 6 , R 7 and R 8 are alkyl, aryl, alkenyl, arylalkyl, heteroarylalkyl, alkoxy or aryloxy, R 1 , R 2 , R 5 , R 6 , R 7 and R 8 may each independently be substituted with 1 to 3 hydrogen bonding groups;

where R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9A or R 9B is a hydrogen bonding group, the hydrogen bonding group is independently selected from the group consisting of OR 9A , OCO 2 R 10 , OCONR 9A R 9B , CN, NO 2 , CN 4 R 9A (tetrazole) COCF 3 , COR 9A , CO 2 R 9A , CONR 9A R 9B , CONR 9A OR 9B , C(NR 9A )NR 9B R 9C , CONR 9A SO 2 R 9B , SOR 10 , SO 2 R 10 , SO 3 H, SO 2 NR 9A R 9B , SO 2 NR 9A COR 9B , SO 2 NR 9A CONR 9B R 9C , POR 9A R 9B , PO 2 R 9A R 9B , PO 3 R 9A R 9B , PO 2 R 9A NR 9B R 9C , NR 9A R 9B , NR 9A COR 9B , NR 9A C(NR 9B )R 9C , NR 9A CO 2 R 9B , NR 9A CONR 9B R 9C , NR 9A C(NR 9B )NR 9C R 9D , NR 9A SO 2 R 9B , NR 9A CONR 9B SO 2 R 9C , NR 9A SO 2 NR 9B R 9C , NR 9A POR 9B R 9C , NR 9A PO 2 R 9B R 9C , NR 9A PO 3 R 9B R 9C and NR 9A PO 2 R 9B NR 9C R 9D ; wherein

R 9C and R 9D are each independently hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl; and

R 10 is independently alkyl, arylalkyl, heteroarylalkyl, or aryl;

wherein R 9A , R 9B , R 9C R 9D or R 10 may further be substituted with one to three additional hydrogen bonding groups as defined above;

and wherein

two of R 9A , R 9B , R 9C or R 9D within the same hydrogen bonding group as defined above may optionally be cyclized together to form a ring, wherein said ring may further be substituted with one to three additional hydrogen bonding groups as defined above;

with the proviso that compounds of formula I exclude compounds of the following structures:

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; and

2-chloro-5-[N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinol-3-yl)carbamoyl]-6H-thieno[2,3-b]pyrrole.