Macrocyclic antagonists of the motilin receptor

1. A compound represented by the general formula (I):

or pharmaceutically acceptable salts thereof wherein:

Z 1 , Z 2 , and Z 3 are independently NR 10 , wherein R 10 is selected from the group consisting of hydrogen and lower alkyl;

R 1 is —(CH 2 ) q R 11 , wherein q is 0, 1 or 2, and R 11 is selected from the group consisting of:

wherein A 1 , A 2 , A 3 , A 4 and A 5 are each optionally present and are independently selected from the group consisting of halogen, alkyl, substituted alkyl, trifluoromethyl, hydroxy, alkoxy and nitro;

and;

B 1 , B 2 , B 3 , B 4 , B 5 and B 7 are independently NR 14a , S or O, wherein R 14a is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl and sulfonamido;

B 6 and B 8 are independently N or CH;

R 2 is hydrogen,

R 3 is selected from the group consisting of: —(CH 2 ) s CH 3 , —CH(CH 3 )(CH 2 ) t CH 3 , —(CH 2 ) u CH(CH 3 ) 2 , —C(CH 3 ) 3 , and —(CH 2 ) y —R 21 , wherein:

s is 0, 1, 2 or 3;

t is 1 or 2;

u is 0 or 1;

y is 0, 1 or 2;

R 21 is selected from the group consisting of:

wherein z1 is 1, 2, 3 or 4; and

E 1 is optionally present and selected from the group consisting of hydroxy and alkoxy;

R 4 and R 5 are each hydrogen;

R 6 is selected from the group consisting of hydrogen, —(CH 2 ) aa CH 3 , —CH 2 SCH 3 —CH 2 CH 2 SCH 3 , —(CH 2 ) bb CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 ) cc CH 3 , —(CH 2 ) dd —NR 22 R 23 , and —(CH 2 ) ee R 24 , wherein

aa is 0, 1, 2 or 3;

bb is 0 or 1;

cc is 1 or 2;

dd is 1, 2, 3 or 4;

ee is 0, 1 or 2;

R 22 and R 23 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, amido, amidino, sulfonyl and sulfonamido;

R 24 is selected from the group consisting of hydroxy, alkoxy

wherein E 2 is optionally present and is selected from the group consisting of hydroxy and alkoxy; B 9 and B 10 are independently selected from the group consisting of NR 14b , S and O, wherein R 14b is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl and sulfonamido; B 11 is selected from N and CH; and z2 is 1, 2, 3 or 4; and

X is NR 8 , wherein R 8 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl, sulfonamido and amidino;

with the provisos that when Z 1 , Z 2 and Z 3 are all NH, R 1 is:

R 2 is:

then R 3 is not:

and when Z 1 , Z 2 and Z 3 are all NH, R 1 is:

R 3 is:

then R 2 is not:

and when Z 1 , Z 2 and Z 3 are all NH, R 2 is:

and R 3 is:

then R 1 is not:

wherein Rp is hydrogen or a protecting group;

m, n 1 and p are 0; and

T is selected from the group consisting of:

wherein

U 3 is CH 2 ;

L 2 is CH or N;

L 5 is CH or N;

L 6 is CR 52 R 53 or O;

R 46 is H or CH 3 ;

R 54 , R 55 , R 56 and R 57 are independently selected from the group consisting of hydrogen and lower alkyl;

R 58 is selected from the group consisting of halogen and amidino; and

(X) is the site of a covalent bond to X in formula (I); and (Z 3 ) is the site of a covalent bond to Z 3 in formula (I).

2. The compound of claim 1 , wherein R 11 is selected from the group consisting of:

wherein R a and R b are independently selected from the group consisting of Cl, F, CF 3 , OCH 3 , OH, CH 3 and C(CH 3 ) 3 .

3. The compound of claim 1 wherein m, n and p are 0; X, Z 1 , Z 2 and Z 3 are NH; and R 2 , R 4 and R 5 are hydrogen, represented by formula (III):

4. The compound of claim 1 selected from the group consisting of:

5. A compound represented by the general formula (I):

or pharmaceutically acceptable salts thereof wherein:

Z 1 , Z 2 , and Z 3 are independently NR 10 , wherein R 10 is selected from the group consisting of hydrogen and lower alkyl;

R 1 is —(CH 2 ) q R 11 , wherein q is 0, 1 or 2, and R 11 is selected from the group consisting of:

wherein A 1 , A 2 and A 3 are each optionally present and are independently selected from the group consisting of halogen, alkyl, substituted alkyl, trifluoromethyl, hydroxy, alkoxy and nitro;

B 1 , B 2 , B 3 , B 4 , B 5 and B 7 are independently NR 14a , S or O, wherein R 14a is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl and sulfonamido;

B 6 and B 8 are independently N or CH;

R 2 is hydrogen;

R 3 is selected from the group consisting of: —(CH 2 ) s CH 3 , —CH(CH 3 )(CH 2 ) t CH 3 , —(CH 2 ) u CH(CH 3 ) 2 , —C(CH 3 ) 3 , and —(CH 2 ) y —R 21 , wherein:

s is 0, 1, 2 or 3;

t is lor 2;

u is 0 or 1;

y is 0, 1 or 2;

R 21 is selected from the group consisting of:

wherein z1 is 1, 2, 3 or 4; and

E 1 is optionally present and selected from the group consisting of hydroxy and alkoxy;

R 4 and R 5 are each hydrogen;

R 6 is each independently selected from the group consisting of hydrogen, —(CH 2 ) aa CH 3 , —CH 2 SCH 3 , —CH 2 CH 2 SCH 3 , —(CH 2 ) bb CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 ) cc CH 3 , —(CH 2 ) dd —NR 22 R 23 , and —(CH 2 ) ee R 24 , wherein

aa is 0, 1, 2 or 3;

bb is 0 or 1;

cc is 1 or 2;

dd is 1, 2, 3 or 4;

ee is 0, 1 or 2;

R 22 and R 23 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, amido, amidino, sulfonyl and sulfonamido;

R 24 is selected from the group consisting of hydroxy, alkoxy

wherein E 2 is optionally present and is selected from the group consisting of hydroxy and alkoxy; B 9 and B 10 are independently selected from the group consisting of NR 14b , S and O, wherein R 14b is selected from the group consisting of hydrogen, alkyl, substituted alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl and sulfonamido; B 11 is selected from the group consisting of N and CH; and Z2 is 1, 2, 3 or 4; and

X is NR 8 , wherein R 8 is selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, formyl, acyl, carboxyalkyl, carboxyaryl, amido, sulfonyl, sulfonamido and amidino;

with the provisos that when Z 1 , Z 2 and Z 3 are all NH, R 1 is:

R 2 is:

then R 3 is not:

and when Z 1 , Z 2 and Z 3 are all NH, R 1 is:

R 3 is:

then R 2 is not:

and when Z 1 , Z 2 and Z 3 are all NH, R 2 is:

and R 3 is:

then R 1 is not:

wherein Rp is hydrogen or a protecting group;

m, n, and p are 0; and

T is selected from the group consisting of:

wherein R 30 and R 31 are independently selected from the group consisting of hydrogen and methyl; and (X) is the site of a covalent bond to X in formula (I); and (Z 3 ) is the site of a covalent bond to Z 3 in formula (I).

6. A pharmaceutical composition comprising:

(a) a compound of claim 1 ; and

(b) a pharmaceutically acceptable carrier.

7. A pharmaceutical composition, comprising:

(a) a compound of claim 4 ; and

(b) a pharmaceutically acceptable carrier.

8. A pharmaceutical composition, comprising:

(c) a compound of claim 5 ; and

(d) a pharmaceutically acceptable carrier.

9. A method of treating a gastrointestinal disorder associated with the motilin receptor or motility dysfunction in humans or other mammals comprising administering a therapeutically effective amount of a compound of claim 1 .

10. A method of treating a gastrointestinal disorder associated with hyperotility or hypermotilinemia in humans or other mammals comprising administering a therapeutically effective amount of a compound of claim 1 .

11. A method of treating irritable bowel syndrome or dyspepsia in humans or other mammals, comprising administering a therapeutically effective amount of a compound of claim 1 .

12. A method of treating Crohn's disease, gastroesophogeal reflux disorders, ulcerative colitis, pancreatitis, infantile hypertrophic pyloric stenosis, carcinoid syndrome, malabsorption syndrome, diarrhea, atrophic colitis or gastritis, gastrointestinal dumping syndrome, postgastroenterectomy syndrome or celiac disease in humans or other mammals comprising administering a therapeutically effective amount of a compound of claim 1 .