Benzimidazole-proline derivatives

Patent metadata

Field	Value
Publication number	US-11040966-B2
Application number	US-201916405797-A
Country	US
Kind code	B2
Filing date	May 7, 2019
Priority date	Jun 4, 2012
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

Abstract

The present invention relates to compounds of the formula (II)wherein Ar1, R1, R2, R3, R4a, R4b and (R5)n 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 (II), and especially to their use as orexin receptor antagonists.

First claim

The invention claimed is:

1. A compound of the formula (II); wherein the absolute configuration is as depicted in formula (II):

wherein
Ar 1 represents
phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted; wherein
one of said substituents is attached in ortho-position to the point of attachment of Ar 1 to the rest of the molecule; wherein said ortho substituent is phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy;
or said ortho substituent is benzo[1,3]dioxolyl, or 2-(3-methoxy-phenyl)-ethynyl;
and the other of said substituents of said group Ar 1 , if present, is/are independently selected from (C 1-4 )alkyl; (C 1-4 )alkoxy; (C 3-6 )cycloalkyl; halogen; cyano;
(C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; —NR 10 R 11 , wherein R 10 and R 11 independently represent hydrogen or (C 1-4 )alkyl, or R 10 and R 11 together with the nitrogen to which they are attached to form a pyrrolidine ring; unsubstituted pyridinyl; and phenyl which is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, cyano, and halogen;

one of R 2 and R 3 represents hydrogen, and the other represents hydrogen or (C 1-4 )alkyl; and

one of R 4a and R 4b represents hydrogen, and the other represents hydrogen, (C 1-4 )alkoxy, or halogen; or R 4a and R 4b together represent a group H 2 C═; or both R 4a and R 4b represent fluorine;
wherein, in case R 3 is different from hydrogen, both R 4a and R 4b represent hydrogen;
R 1 represents hydrogen, (C 1-4 )alkyl, (C 3-6 )cycloalkyl-(CH 2 )—, (C 2-3 )fluoroalkyl, or (C 1-4 )alkoxy-(C 2-4 )alkyl; and
(R 5 ) n represents one to three optional substituents independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-4 )alkyl-thio-, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 1-3 )fluoroalkyl-thio-, hydroxy-(C 1-4 )alkyl-, (C 1-4 )alkoxy-carbonyl-, nitro, hydroxy, and cyano; or (R 5 ) n represents a group —O—CH 2 —CH 2 —O—; or (R 5 ) n represents a fused phenyl group which, together with the benzimidazole moiety to which it is fused to, forms a 1H-naphtho[2,3-d]imidazol-2-yl group;

with the exception of
[(S)-2-(1H-benzimidazol-2-yl)-1-pyrrolidinyl][2-(1H-pyrazol-1-yl)phenyl]-methanone;
[(S)-2-(1H-benzimidazol-2-yl)-1-pyrrolidinyl][5-(2,5-dimethyl-1H-pyrrol-1-yl)-1-methyl-1H-pyrazol-4-yl]-methanone;
[(S)-2-(1H-benzimidazol-2-yl)-1-pyrrolidinyl][1,1′-biphenyl]-2-yl-methanone;
[(S)-2-(6-methyl-1H-benzimidazol-2-yl)-pyrrolidin-1-yl][3-phenyl-isoxazol-4-yl]-methanone;
[(S)-2-(1H-imidazol-2-yl)phenyl][2-(6-methyl-1H-benzimidazol-2-yl)-pyrrolidin-1-yl]-methanone;
[(S)-2-(6-methyl-1H-benzimidazol-2-yl)-pyrrolidin-1-yl][3-(thien-2-yl)-1H-pyrazol-4-yl]-methanone;
[(S)-2-(6-methyl-1H-benzimidazol-2-yl)-pyrrolidin-1-yl][3-phenyl-1H-pyrazol-4-yl]-methanone;
[(S)-2-(1H-benzimidazol-2-yl)-pyrrolidin-1-yl][3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl]-methanone;
[(S)-2-(1H-benzimidazol-2-yl)-pyrrolidin-1-yl][1-(2-fluorophenyl)-5-(1H-pyrrol-1-yl)-1H-pyrazol-4-yl]-methanone; and
[(S)-2-(5-Chloro-4-methyl-1H-benzoimidazol-2-yl)-2-methyl-pyrrolidin-1-yl]-(5-methoxy-2-[1,2,3]triazol-2-yl-phenyl)-methanone;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 ; wherein
one of R 2 and R 3 represents hydrogen, and the other represents hydrogen or methyl; and
R 4a and R 4b represent hydrogen; or R 4a represents methoxy or fluorine, and R 4b represents hydrogen; or R 4a and R 4b together represent a group H 2 C═; wherein, in case R 3 is methyl, both R 4a and R 4b represent hydrogen;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 ; wherein
R 2 represents hydrogen or methyl; and R 3 , R 4a and R 4b represent hydrogen;

or a pharmaceutically acceptable salt thereof.

4. A compound according to claim 1 ; which is also a compound of the formula (V); wherein the absolute configuration is as depicted in formula (V):

wherein
Ar 1 represents
phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di-, or tri-substituted; wherein
one of said substituents is attached in ortho-position to the point of attachment of Ar 1 to the rest of the molecule; wherein said ortho substituent is phenyl or 5- or 6-membered heteroaryl; wherein said phenyl or 5- or 6-membered heteroaryl substituent is independently unsubstituted, mono-, di-, or tri-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, cyano, (C 1-3 )fluoroalkyl, and (C 1-3 )fluoroalkoxy;
or said ortho substituent is benzo[1,3]dioxolyl;
and the other of said substituents of said group Ar 1 , if present, is/are independently selected from (C 1-4 )alkyl; (C 1-4 )alkoxy; (C 3-6 )cycloalkyl; halogen; cyano; (C 1-3 )fluoroalkyl; (C 1-3 )fluoroalkoxy; NR 10 R 11 , wherein R 10 and R 11 independently represent hydrogen or (C 1-4 )alkyl, or R 10 and R 11 together with the nitrogen to which they are attached to form a pyrrolidine ring; unsubstituted pyridinyl; and phenyl which is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, cyano, and halogen;

R 1 represents hydrogen, (C 1-4 )alkyl, (C 3-6 )cycloalkyl-(CH 2 )—, (C 2-3 )fluoroalkyl, or (C 1-4 )alkoxy-(C 2-4 )alkyl; and
(R 5 ) n represents one to three optional substituents independently selected from (C 1-4 )alkyl, (C 1-4 )alkoxy, halogen, (C 1-4 )alkyl-thio-, (C 1-3 )fluoroalkyl, (C 1-3 )fluoroalkoxy, (C 1-3 )fluoroalkyl-thio-, hydroxy-(C 1-4 )alkyl-, (C 1-4 )alkoxy-carbonyl-, nitro, hydroxy, and cyano;
or (R 5 ) n represents a group —O—CH 2 —CH 2 —O—;

or a pharmaceutically acceptable salt thereof.

5. A compound according to claim 4 ; wherein
the fragment

represents a fragment

wherein
R 1 represents hydrogen; and
R 14 , R 15 , R 16 and R 17 together represent one or two substituents; wherein
one of R 15 and R 16 represents methyl, methoxy, fluorine, chlorine, bromine, trifluoromethyl, or trifluoromethoxy;
one of R 14 and R 17 , or the remaining of R 15 and R 16 , represents hydrogen, methyl, methoxy, fluorine, or chlorine;
and the remaining of R 14 , R 15 , R 16 and R 17 represent hydrogen;

and
Ar 1 is a group independently selected from one of the following groups A, B, C, D, and E:

or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 3 ; wherein the fragment

represents a fragment

Assignees

• Idorsia Pharmaceuticals Ltd

Inventors

• Boss Christoph
• Brotschi Christine
• Gude Markus
• Heidmann Bibia
• Sifferlen Thierry
• Williams Jodi

Classifications

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title