Tryptophan Hydroxylase Inhibitors for the Treatment of Cancer

1 . A method of inhibiting the growth of a tumor that overexpresses THP, which comprises contacting the tumor with a compound 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.

2 . A method of inhibiting the growth of a tumor that produces serotonin, which comprises contacting the tumor with a compound 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 tumor is not a carcinoid tumor.

4 . A compound of the formula:

or a pharmaceutically acceptable salt thereof, for use in treating cancer, 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.

5 . The use of claim 4 , wherein the cancer is breast cancer.

6 . The use of claim 4 , wherein the cancer is cholangiocarcinoma.

7 . The use of claim 4 , wherein the cancer is a neuroendocrine tumor.

8 . The use of claim 7 , wherein the neuroendocrine tumor is not a carcinoid tumor.

9 . The use of claim 4 , wherein the cancer is prostate cancer.

10 . The use of claim 4 , wherein the compound is of the formula:

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

11 . The use of claim 10 , wherein the compound 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.

12 . The use of claim 11 , wherein the compound is of the formula:

wherein:

A 2 is optionally substituted heterocycle;

R 10 is 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 14 is independently 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;

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

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

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

m is 1-4.

13 . The use of claim 12 , wherein A 2 is optionally substituted pyrazole.

14 . The use of claim 12 , wherein R 1 is hydrogen.

15 . The use of claim 12 , wherein R 10 is amino.