Heteroaryl butanoic acid derivatives

Patent metadata

Field	Value
Publication number	US-9981926-B2
Application number	US-201415104729-A
Country	US
Kind code	B2
Filing date	Dec 18, 2014
Priority date	Dec 20, 2013
Publication date	May 29, 2018
Grant date	May 29, 2018

Abstract

The present invention describes novel heteroaryl butanoic acid derivatives that are good drug candidates especially with regard to leukotriene A4 hydrolase (LTA4H). The present invention also relates to pharmaceutical compositions comprising said novel heteroaryl butanoic acid derivatives, methods of using said compounds in the treatment of various diseases and disorders, and processes for preparing the said novel compounds.

First claim

The invention claimed is:

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof;

wherein,
R1 is OH or NH 2 ;
Y is O, S or CH 2 ;
X1, X2, X3 and X4 are N; or
X1, X2, X3 and X4 are selected from N, NH, C, CH and O with the proviso that at least two of X1, X2, X3 or X4 are N or NH;

R2 is C 1 -C 6 alkyl optionally substituted by phenyl; C 3 -C 6 cycloalkyl; phenyl optionally being substituted by halogen, cyano, C 1 -C 6 alkyl optionally substituted by halogen, C 1 -C 6 alkoxy, or a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O and S; or a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O and S, said heteroaryl being optionally substituted by halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof; wherein
R1 is OH or NH 2 ;
Y is O;
X1, X2, X3 and X4 are selected from N, NH, C, CH and O with the proviso that at least two of X1, X2, X3 or X4 are N or NH; and
R2 is phenyl optionally being substituted by halogen, cyano, C 1 -C 6 alkyl optionally substituted by halogen, C 1 -C 6 alkoxy, or a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O and S; or
R2 is a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O and S said heteroaryl being optionally substituted by halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is attached in the para-position of the phenyl moiety.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Y is attached in the meta-position of the phenyl moiety.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof; wherein
R1 is OH or NH 2 ;
Y is CH 2 ; X1, X2, X3 and X4 are N; and
R2 is C 1 -C 6 alkyl optionally substituted by phenyl; or C 3 -C 6 cycloalkyl.

6. The compound of claim 1 which is a compound of formula (II) or a pharmaceutically acceptable salt thereof,

wherein
R1 is OH or NH 2 ;
R2 is C 1 -C 6 alkyl optionally substituted by phenyl; C 3 -C 6 cycloalkyl; phenyl optionally being substituted by halogen, cyano, C 1 -C 6 alkyl optionally substituted by halogen, C 1 -C 6 alkoxy, or a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O and S; or a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O and S said heteroaryl being optionally substituted by halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen, and
Y is O, S or CH 2 .

7. The compound of claim 1 which is a compound of formula (III) or a pharmaceutically acceptable salt thereof,

wherein
R1 is OH or NH 2 ;
R2 is C 1 -C 6 alkyl optionally substituted by phenyl; C 3 -C 6 cycloalkyl; phenyl optionally being substituted by halogen, cyano, C 1 -C 6 alkyl optionally substituted by halogen, C 1 -C 6 alkoxy, or a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O and S; or a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O and S said heteroaryl being optionally substituted by halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen, and
Y is O, S or CH 2 .

8. The compound of claim 1 which is a compound of formula (IV) or a pharmaceutically acceptable salt thereof,

wherein
R1 is OH or NH 2 ;
R2 is C 1 -C 6 alkyl optionally substituted by phenyl; C 3 -C 6 cycloalkyl; phenyl optionally being substituted by halogen, cyano, C 1 -C 6 alkyl optionally substituted by halogen, C 1 -C 6 alkoxy, or a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O and S; or a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O and S said heteroaryl being optionally substituted by halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen, and
Y is O, S or CH 2 .

9. The compound in accordance to claim 1 , which is a compound of formula (V) or a pharmaceutically acceptable salt thereof;

wherein
R1 is OH or NH 2 ;
R2 is C 1 -C 6 alkyl optionally substituted by phenyl; C 3 -C 6 cycloalkyl; phenyl optionally being substituted by halogen, cyano, C 1 -C 6 alkyl optionally substituted by halogen, C 1 -C 6 alkoxy, or a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O and S; or a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O and S said heteroaryl being optionally substituted by halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen, and
Y is O, S or CH 2 ; or

wherein
R1 is OH;
Y is O; and
R2 is phenyl optionally being substituted by halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy; or
R2 is a 5-10 membered mono- or bicyclic heteroaryl containing 1 to 4 heteroatoms selected from N, O and S said heteroaryl being optionally substituted by halogen, cyano or C 1 -C 6 alkyl optionally substituted by halogen.

10. The compound in accordance to claim 9 , or a pharmaceutically acceptable salt thereof; wherein
R1 is OH;
Y is O; and
R2 is a pyridyl ring being optionally substituted by cyano or halogen.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
(R)-3-amino-4-(5-(4-(benzo[d]thiazol-2-yloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-((5-chloropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-(4-(oxazol-2-yl)-phenoxy)phenyl)-2H-tetrazol-2-yl)-butanoic acid;
(R)-3-amino-4-(5-(3-(4-chlorophenoxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-(4-fluorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-(3-chloro-4-fluorophenoxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(S)-3-amino-4-(5-(3-phenoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;
(S)-3-amino-4-(5-(4-(benzo[d]thiazol-2-yloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(S)-3-amino-4-(5-(4-(4-chlorophenoxy)-phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(3-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-phenethoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-(benzyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(3-(benzyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-butoxyphenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-(pentyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(3-(benzo[d]thiazol-2-yloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;
(R)-3-amino-4-(5-(3-(3,5-diflu

Assignees

• Bollbuck Birgit
• Markert Christian
• Miltz Wolfgang
• Roehn Till
• Novartis Ag

Inventors

• Bollbuck Birgit
• Markert Christian
• Miltz Wolfgang
• Roehn Till

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title