Tricyclic imidazole compounds as inhibitors of tryptophan hydroxylase

Patent metadata

Field	Value
Publication number	US-10189839-B2
Application number	US-201415038015-A
Country	US
Kind code	B2
Filing date	Nov 18, 2014
Priority date	Nov 19, 2013
Publication date	Jan 29, 2019
Grant date	Jan 29, 2019

Abstract

The present invention relates to compounds of the formula (I)

wherein R 1a , R 1b , R 2 , R 3 , and X are as described in the description, to their preparation, to pharmaceutically acceptable salts thereof, and to their use as pharmaceuticals, to pharmaceutical compositions containing one or more compounds of formula (I), to methods for the preparation of such compounds of formula (I), and especially to their use as TPH modulators.

First claim

The invention claimed is:

1. A compound of Formula (I)

wherein
X represents —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —S—, *—CH 2 —O—, or *—CH 2 —NR x — wherein R x represents hydrogen, —CO—(C 1-4 )alkyl, —(C 1-3 )alkyl-(C 3-6 )cycloalkyl, (C 3-6 )cycloalkyl, or —CO—(C 1-4 )alkoxy; wherein the asterisks indicate the bond attached to the imidazole ring;
R 1a and R 1b independently represent hydrogen, methyl, ethyl; or R 1a and R 1b together with the carbon atom to which they are attached to form a cyclopropyl ring;
R 2 represents aryl, or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from:
(C 1-4 )alkyl;
(C 1-4 )alkoxy;
(C 3-6 )cycloalkyl;
(C 1-3 )fluoroalkyl;
(C 1-3 )fluoroalkoxy;
halogen;
cyano;
—(CH 2 ) n —NR 21 R 22 ; wherein n represents the integer 0 or 1; and
R 21 and R 22 independently represent hydrogen or (C 1-4 )alkyl; or
R 21 and R 22 together with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated ring, wherein said ring optionally includes one ring oxygen atom;

—CO—NR 23 R 24 , wherein R 23 and R 24 independently represent hydrogen or (C 1-4 )alkyl;
—CO—NH—CN;
—NR 25 —CO—NR 26 R 27 , wherein R 25 , R 26 and R 27 independently represent hydrogen or (C 1-4 )alkyl;
—CO—(C 1-4 )alkoxy;
phenyl;
hydroxy-(C 1-4 )alkyl;
(C 1-3 )alkoxy-(C 1-4 )alkyl;
hydroxy-(C 2-4 )alkoxy; or
(C 1-3 )alkoxy-(C 2-4 )alkoxy;

R 3 represents aryl, or heteroaryl, wherein said aryl or heteroaryl independently is unsubstituted, or mono-, di-, or tri-substituted, wherein the substituents are independently selected from:
—NR 4 —Y—R 5 , wherein
R 4 represents hydrogen or (C 1-3 )alkyl; Y represents a direct bond; and R 5 represents (C 1-4 )alkyl, or (C 3-6 )cycloalky; or
R 4 represents hydrogen or (C 1-3 )alkyl; Y represents —NR Y — wherein R Y represents (C 1-3 )alkyl; and R 5 represents (C 1-4 )alkyl; or
R 4 and R 5 together with the nitrogen and the —SO 2 —Y-group to which they are attached to form a 5-, 6-, or 7-membered ring, wherein Y represents a direct bond or —NR Y — wherein R Y represents (C 1-3 )alkyl;

—CO—NR 6 R 7 , wherein R 6 and R 7 independently represent hydrogen, (C 1-4 )alkyl, or (C 3-6 )cycloalkyl;
—SO 2 —R 8 wherein R 8 represents (C 1-5 )alkyl, or —NR 81 R 82 , wherein R 81 and R 82 independently represent hydrogen or (C 1-4 )alkyl;
—(CH 2 ) m —NR 9 R 10 ; wherein m represents the integer 0 or 1; and
R 9 and R 10 independently represent hydrogen, (C 1-4 )alkyl, (C 2-3 )fluoroalkyl, hydroxy-(C 2-4 )alkyl, (C 1-4 )alkoxy-(C 2-4 )alkyl; or
R 9 and R 10 together with the nitrogen to which they are attached to form a 4-to 7-membered ring optionally including an oxygen ring atom or a group —NR 11 — wherein
R 11 represents (C 1-4 )alkyl, and wherein said ring is optionally substituted with one or two fluorine substituents;

(C 1-4 )alkyl;
(C 3-6 )cycloalkyl;
(C 1-4 )alkoxy;
(C 1-3 )fluoroalkyl;
(C 1-3 )fluoroalkoxy;
halogen;
cyano; or
5-membered heteroaryl;

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein the absolute configuration of the carbon atom carrying the substituent R 2 is as depicted in Formula (I E ):

or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 1 , wherein R 1a and R 1b both represent hydrogen;
or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 , wherein X represents —CH 2 —, —CH 2 —CH 2 —, or —S—;
or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 1 , wherein X represents —CH 2 —, —CH 2 —CH 2 —, or —S—;
or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1 , wherein R 2 represents phenyl, or 5-or 6-membered heteroaryl, wherein said phenyl or heteroaryl independently is mono-, di-, or tri-substituted, wherein the substituents are independently selected from:
(C 1-4 )alkyl;
(C 1-4 )alkoxy;
(C 3-6 )cycloalkyl;
(C 1-3 )fluoroalkyl;
(C 1-3 )fluoroalkoxy;
halogen;
cyano;
—NR 21 R 22 ; wherein
R 21 and R 22 independently represent hydrogen or (C 1-4 )alkyl; or
R 21 and R 22 together with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated ring, wherein said ring optionally contains one ring oxygen atom;

—CO—NR 23 R 24 , wherein R 23 and R 24 independently represent hydrogen or (C 1-4 )alkyl;
—NR 25 —CO—NR 26 R 27 , wherein R 25 , R 26 and R 27 independently represent hydrogen or (C 1-4 )alkyl;
—CO—(C 1-4 )alkoxy;
phenyl;
hydroxy-(C 1-4 )alkyl;
(C 1-3 )alkoxy-(C 1-4 )alkyl;
hydroxy-(C 2-4 )alkoxy; or
(C 1-3 )alkoxy-(C 2-4 )alkoxy;

or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 , wherein
R 2 represents phenyl, wherein said phenyl is mono-, di-, or tri-substituted, wherein the substituents are independently selected from:
(C 1-4 )alkyl;
(C 3-6 )cycloalkyl; or
halogen;

or R 2 represents 5-or 6-metnbered heteroaryl, wherein said heteroaryl is mono-, or di-substituted, wherein the substituents are independently selected from:
(C 1-4 )alkyl;
(C 3-6 )cycloalkyl;
(C 1-3 )fluoroalkyl; or
halogen;

or a pharmaceutically acceptable salt thereof.

8. The compound according to claim 1 , wherein R 3 represents a fragment

wherein

Z 1 and Z 2 independently represent CH or N;
R 3a represents:
—NR 4 —SO 2 —Y—R 5 , wherein
R 4 represents hydrogen or (C 1-3 )alkyl; Y represents direct bond; and R 5 represents (C 1-4 )alkyl, or (C 3-6 )cycloalkyl; or
R 4 represents hydrogen or (C 1-3 )alkyl; Y represents —NR Y — wherein R Y represents (C 1-3 )alkyl; and R 5 represents (C 1-4 )alkyl; or
R 4 and R 5 together with the nitrogen and the —SO 2 —Y-group to which they are attached to form a 5-, 6-, or 7-membered ring, wherein Y represents a direct bond or —NR Y — wherein R Y represents (C 1-3 )alkyl;

—CO—NR 6 R 7 , wherein R 6 and R 7 independently represent hydrogen, (C 1-4 )alkyl, or (C 3-6 )cycloalkyl;
—SO 2 —R 8 wherein R 8 represents (C 1-5 )alkyl, or —NR 81 R 82 , wherein R 81 and R 82 independently represent hydrogen or (C 1-4 )alkyl;
—(CH 2 ) m —NR 9 R 10 ; wherein m represents the integer 0 or 1; and R 9 and R 10 together with the nitrogen to which they are attached to form a 4- to 7-membered ring optionally including an oxygen ring atom or a group —NR 11 — wherein R 11 represents (C 1-4 )alkyl, and wherein said ring is optionally substituted with one or two fluorine substituents;
hydrogen;
halogen;
(C 1-4 )alkyl;
(C 3-6 )cycloakyl;
(C 1-3 )fluoroalkyl;
5-membered heteroaryl;
cyano; and

R 3b represents (C 1-4 )alkyl; halogen; (C 3-6 )cycloalky; or (C 1-3 )fluoroalkyl;
or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 8 , wherein Z 1 represents N and Z 2 represents CH;
or a pharmaceutically acceptable salt thereof.

10. The compound according to claim 8 , wherein R 3a represents:
—NR 41 —SO 2 —R 51 , wherein R 41 represents hydrogen; and R 51 represents (C 1-4 )alkyl or (C 3-6 )cycloalkyl; or
—NR 43 —SO 2 —R 53 , wherein R 43 and R 53 together with the n

Assignees

• Actelion Pharmaceuticals Ltd

Inventors

• Bur Daniel
• Grisostomi Corinna
• Nayler Oliver
• Remen Lubos
• Vercauteren Magali
• Welford Richard

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title