IP Library › Granted Patent US 9,981,926

Granted Patent B2

US 9,981,926 · App. 15/104,729 · Granted May 29, 2018

Heteroaryl butanoic acid derivatives

Inventors: Birgit Bollbuck (Munich, DE); Christian Markert (Riehen, CH); Wolfgang Miltz (Basel, CH); Till Roehn (Zurich, CH)

Assignee: Novartis AG

C07D257/04 A61K31/41 A61K31/415 A61K31/422 A61K31/428 A61K31/4245 A61K31/4439 A61K45/06 C07D231/12 C07D271/10 C07D401/12 C07D413/12 C07D417/12

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Quick Facts

Patent No.: US 9,981,926
App. No.: 15/104,729
Granted: May 29, 2018
Kind: B2

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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.

Claims (195)

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

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-difluorophenoxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;

(S)-3-amino-4-(5-(4-(p-tolyloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;

(R)-3-amino-4-(5-(4-(4-fluorophenoxy) phenyl)-1,3,4-oxadiazol-2-yl)butanoic acid;

(R)-3-amino-4-(5-(4-(4-chlorophenoxy) phenyl)-1,3,4-oxadiazol-2-yl)butanoic acid;

(R)-3-amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butanoic acid;

(R)-3-amino-4-(3-(4-(4-chlorophenoxy)phenyl)-1,2,4-oxadiazol-5-yl)butanamide;

(S)-3-amino-4-(4-(4-(4-chlorophenoxy)phenyl)-1H-pyrazol-1-yl)butanoic acid;

and

(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid.

12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

13. A combination comprising a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof and one or more therapeutically active co-agents.

14. The pharmaceutical composition of claim 12 , wherein the compound is

(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-(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;

(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl))-2H-tetrazol-2-yl)butanoic acid,

or a pharmaceutically acceptable salt thereof.

15. The combination of claim 13 , wherein the compound is

(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-(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;

(S)-3-amino-4-(5-(4-((5-chloro-3-fluoropyridin-2-yl)oxy)phenyl)-2H-tetrazol-2-yl)butanoic acid,

or a pharmaceutically acceptable salt thereof.

16. The pharmaceutical composition of claim 12 , wherein the compound is

(R)-3-amino-4-(5-(4-(benzo[d]thiazol-2-yloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;

(S)-3-amino-4-(5-(4-(benzo[d]thiazol-2-yloxy)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,

or a pharmaceutically acceptable salt thereof.

17. The combination of claim 13 , wherein the compound is

(R)-3-amino-4-(5-(4-(benzo[d]thiazol-2-yloxy)phenyl)-2H-tetrazol-2-yl)butanoic acid;

(S)-3-amino-4-(5-(4-(benzo[d]thiazol-2-yloxy)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,

or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition of claim 12 , wherein the compound is