METHODS OF AFFECTING GASTROINTESTINAL TRANSIT AND GASTRIC EMPTYING, AND COMPOUNDS USEFUL THEREIN

1 . A method of slowing gastrointestinal motility in a patient, which comprises inhibiting peripheral tryptophan hydroxylase in the patient without causing an adverse effect associated with the lowering of serotonin levels in the central nervous system.

2 . A method of slowing gastrointestinal motility in a patient, which comprises administering to the patient an effective amount of a potent TPH1 inhibitor of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

A is optionally substituted cycloalkyl, aryl, or heterocycle;

X is a bond, —O—, —S—, —C(O)—, —C(R 4 )═, ═C(R 4 )—, —C(R 3 R 4 )—, —C(R 4 )═C(R 4 )—, —C≡C—, —N(R 5 )—, —N(R 5 )C(O)N(R 5 )—, —C(R 3 R 4 )N(R 5 )—, —N(R 5 )C(R 3 R 4 )—, —ONC(R 3 )—, —C(R 3 )NO—, —C(R 3 R 4 )O—, —OC(R 3 R 4 )—, —S(O 2 )—, —S(O 2 )N(R 5 )—, —N(R 5 )S(O 2 )—, —C(R 3 R 4 )S(O 2 )—, or —S(O 2 )C(R 3 R 4 )—;

D is optionally substituted aryl or heterocycle;

R 1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;

R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl;

each R 5 is independently hydrogen or optionally substituted alkyl or aryl; and

n is 0-3.

3 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

4 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

wherein:

A is optionally substituted cycloalkyl, aryl, or heterocycle;

X is a bond, —O—, —S—, —C(O)—, —C(R 4 )═, ═C(R 4 )—, —C(R 3 R 4 )—, —C(R 4 )═C(R 4 )—, —C≡C—, —N(R 5 )—, —N(R 5 )C(O)N(R 5 )—, —C(R 3 R 4 )N(R 5 )—, —N(R 5 )C(R 3 R 4 )—, —ONC(R 3 )—, —C(R 3 )NO—, —C(R 3 R 4 )O—, —OC(R 3 R 4 )—, —S(O 2 )—, —S(O 2 )N(R 5 )—, —N(R 5 )S(O 2 )—, —C(R 3 R 4 )S(O 2 )—, or —S(O 2 )C(R 3 R 4 )—;

D is optionally substituted aryl or heterocycle;

E is optionally substituted aryl or heterocycle;

R 1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 3 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl;

R 4 is hydrogen, alkoxy, amino, cyano, halogen, hydroxyl, or optionally substituted alkyl or aryl;

R 5 is hydrogen or optionally substituted alkyl or aryl; and

n is 0-3.

5 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

6 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

wherein: each of A 1 and A 2 is independently a monocyclic optionally substituted cycloalkyl, aryl, or heterocycle.

7 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

8 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

9 . The method of claim 2 , wherein the potent TPH1 inhibitor is:

wherein:

each of Z 1 , Z 2 , Z 3 , and Z 4 is independently N or CR 6 ;

each R 6 is independently hydrogen, cyano, halogen, OR 7 , NR 8 R 9 , amino, hydroxyl, or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 8 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

m is 1-4.

10 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

11 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

12 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

wherein:

each of Z′ 1 , Z′ 2 , and Z′ 3 is independently N, NH, S, O or CR 6 ;

each R 6 is independently amino, cyano, halogen, hydrogen, OR 7 , SR 7 , NR 8 R 9 , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 7 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 8 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 9 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

p is 1-3.

13 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

14 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

15 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

wherein:

each of Z″ 1 , Z″ 2 , Z″ 3 , and Z″ 4 is independently N or CR 10 ;

each R 10 is independently amino, cyano, halogen, hydrogen, OR 11 , SR 11 , NR 12 R 13 , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 11 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

each R 13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle.

16 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

17 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

18 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

wherein:

each of Z″ 1 , Z″ 2 , Z″ 3 , and Z″ 4 is independently N or CR 10 ;

each R 10 is independently amino, cyano, halogen, hydrogen, OR 11 , SR 11 , NR 12 R 13 , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 11 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 12 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

each R 13 is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle.

19 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

20 . The method of claim 2 , wherein the potent TPH1 inhibitor is of the formula:

21 . A method of slowing gastrointestinal motility in a patient, which comprises administering to the patient an effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

A 2 is optionally substituted cycloalkyl, aryl, or heterocycle;

R 1 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 2 is hydrogen or optionally substituted alkyl, alkyl-aryl, alkyl-heterocycle, aryl, or heterocycle;

R 10 is independently amino, cyano, halogen, hydrogen, OR 11 , SR 11 , NR 12 R 13 , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R 14 is independently amino, halogen, hydrogen, C(O)R A , OR A , NR B R C , S(O 2 )R A , or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R A is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R B is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle;

each R C is independently hydrogen or optionally substituted alkyl, alkyl-aryl or alkyl-heterocycle; and

m is 1-4.