Pyridinyloxy- and phenyloxy-pyrazolyl compounds

Patent metadata

Field	Value
Publication number	US-9790217-B2
Application number	US-201715498977-A
Country	US
Kind code	B2
Filing date	Apr 27, 2017
Priority date	Oct 31, 2014
Publication date	Oct 17, 2017
Grant date	Oct 17, 2017

Abstract

The invention provides novel compounds having the general formula (I)

wherein R 1 , R 2 and n are as described herein, compositions including the compounds and methods of using the compounds.

First claim

We claim:

1. A compound of formula (I) wherein

R 1 is substituted phenyl or substituted pyridinyl, wherein substituted phenyl and substituted pyridinyl are substituted with one to three substituents independently selected from cyano, halogen, haloalkyl, alkoxy and alkyl;
R 2 is a ring system selected from group A, B, C, D, E, F, G and H:

R 3 and R 7 are independently selected from H, alkyl, alkoxy, halogen, haloalkoxy, carboxy, alkoxycarbonyl, optionally substituted phenylalkoxy, optionally substituted heteroarylalkoxy, optionally substituted heteroarylalkyl, optionally substituted heteroaryloxyalkyl or optionally substituted heterocycloalkoxy, wherein the optionally substituted moieties are substituted with one to three substituents independently selected from alkyl or halogen;
R 4 is (i) H, (ii) hydroxy, (iii) hydroxyalkyl, (iv) alkoxy, (v) alkoxycarbonyl, (vi) halogen, (vii) phenylalkoxy, (viii) heterocycloalkylcarbonyl optionally substituted by one to three substituents independently selected from alkylcarbonyl, alkylsulfonyl or hydroxyalkyl, (ix) heteroarylalkoxy optionally substituted by one to three substituents independently selected from alkyl and halogen, (x) heteroaryloxyalkyl optionally substituted by one to three halogen(s), (xi) heteroarylalkyl optionally substituted by one to three substituents hydroxy, (xii) heterocycloalkoxy optionally substituted by one to three alkylcarbonyl, or (xiii) heterocycloalkylalkyl optionally substituted by one to three substituents independently selected from halogen and hydroxyalkyl;
R 6 is H or halogen;
R 5 is H, halogen, alkoxy, alkylsulfonyl, alkylsulfanyl or haloalkyl;
R 8 is alkyl or phenylalkyl;
R 9 is H, alkylcarbonyl or heteroarylcarbonyl optionally substituted by one to three alkyl groups;
n is zero, 1 or 2; or
a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 is phenyl substituted with substituted with one to three substituents independently selected from cyano and halogen.

3. The compound according to claim 1 wherein R 2 is a ring system selected from group A, B, C, D, E and F.

4. The compound according to claim 3 , wherein R 2 is a ring system selected from group A, B and C.

5. The compound according claim 4 wherein one of R 2 is the ring system group A.

6. The compound according to claim 1 wherein n is zero.

7. The compound according claim 1 wherein R 7 is H.

8. The compound according to claim 1 wherein R 3 is H, alkoxy, halogen, haloalkoxy or heteroarylalkoxy optionally independently substituted with one to three alkyl substituents.

9. The compound according to claim 1 , wherein R 4 is H, hydroxy, heteroarylalkoxy or heterocycloalkylalkyl.

10. The compound according to claim 1 , wherein R 4 is H.

11. The compound according to claim 1 wherein R 5 is H.

12. The compound according to claim 1 wherein R 6 is H.

13. The compound according to claim 1 wherein R 7 is H.

14. The compound of claim 1 wherein R 3 is H, alkoxy, halogen, haloalkoxy or heteroarylalkoxy optionally independently substituted with one to three alkyl substituents, and R 4 , R 5 , R 6 and R 7 are hydrogen.

15. The compound according to claim 1 wherein R 2 is C or D and R 9 is heteroarylcarbonyl substituted by one alkyl.

16. The compound according to claim 1 which compound is selected from the group consisting of:
4-(4-Chlorophenoxy)-5-(2,3-difluorophenyl)-1H-pyrazole;
3-(4-Chlorophenyl)-4-(4-methoxyphenoxy)-1H-pyrazole;
4-(4-Chlorophenoxy)-3-(4-chlorophenyl)-1H-pyrazole;
4-(4-Chlorophenoxy)-3-(2-methoxyphenyl)-1H-pyrazole;
4-(4-Chlorophenoxy)-3-(2,4-dimethoxyphenyl)-1H-pyrazole;
4-(4-Chlorophenoxy)-5-(2-chlorophenyl)-1H-pyrazole;
4-(4-Chlorophenoxy)-5-[2-(trifluoromethoxy)phenyl]-1H-pyrazole;
4-(4-Chlorophenoxy)-5-[2-(difluoromethoxy)phenyl]-1H-pyrazole;
4-(4-Chlorophenoxy)-5-(2-fluorophenyl)-1H-pyrazole;
3-(5-Chloro-2-methoxyphenyl)-4-(4-chlorophenoxy)-1H-pyrazole;
5-(4-Chloro-2-fluorophenyl)-4-(4-chlorophenoxy)-1H-pyrazole;
4-(4-Chlorophenoxy)-5-(4-methylsulfonylphenyl)-1H-pyrazole;
4-(4-Chlorophenoxy)-5-[2-fluoro-4-(trifluoromethyl)phenyl]-1H-pyrazole;
4-(4-Chlorophenoxy)-5-[4-(trifluoromethyl)phenyl]-1H-pyrazole;
4-(4-Chlorophenoxy)-5-(2,4-difluorophenyl)-1H-pyrazole;
5-(4-Methylsulfonylphenyl)-4-[4-(trifluoromethyl)phenoxy]-1H-pyrazole;
5-(2-Chloro-4-methyl sulfanylphenyl)-4-(4-chlorophenoxy)-1H-pyrazole;
4-[[5-(4-Methylsulfonylphenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
2-Chloro-5-[[5-(2-chlorophenyl)-1H-pyrazol-4-yl]oxy]pyridine;
5-[[5-(2-Chlorophenyl)-1H-pyrazol-4-yl]oxy]-2-methylpyridine;
2-[[5-(2,4-Dichlorophenyl)-1H-pyrazol-4-yl]oxy]-6-fluoropyridine;
2-[[3-(2,4-Dichlorophenyl)-1H-pyrazol-4-yl]oxy]-6-methylpyridine;
5-(2-Chlorophenyl)-4-[4-(trifluoromethyl)phenoxy]-1H-pyrazole;
4-(4-Chloro-2-fluorophenoxy)-5-(2-chlorophenyl)-1H-pyrazole;
4-[[5-(2-Chlorophenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[5-(2-Chloro-4-methylsulfanylphenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
5-(4-Chloro-2-fluorophenyl)-4-[4-(trifluoromethyl)phenoxy]-1H-pyrazole;
4-[[5-(2-Chlorophenyl)-1H-pyrazol-4-yl]oxy]-3-fluorobenzonitrile;
4-[[5-(2,3-Difluorophenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[5-(3-Chloro-2-fluorophenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
5-(3-Chloro-2-fluorophenyl)-4-(4-chlorophenoxy)-1H-pyrazole;
4-[[5-(3-Chlorophenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
Methyl 3-[4-(4-cyanophenoxy)-1H-pyrazol-3-yl]benzoate;
5-(2-Chloro-3-fluorophenyl)-4-(4-chlorophenoxy)-1H-pyrazole;
4-[[5-(2-Chloro-3-fluorophenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[5-(3-Phenylmethoxyphenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[5-(2-Chloropyridin-4-yl)-1H-pyrazol-4-yl]oxy]benzonitrile;
Methyl 3-[4-(4-cyano-2-fluorophenoxy)-1H-pyrazol-3-yl]benzoate;
Ethyl 2-[4-(4-cyanophenoxy)-1H-pyrazol-3-yl]benzoate;
2-[4-(4-Cyanophenoxy)-1H-pyrazol-3-yl]benzoic acid;
4-[[5-(2-Phenylmethoxyphenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
5-(2-Chloro-4-methylsulfonylphenyl)-4-(4-chlorophenoxy)-1H-pyrazole;
4-[[5-(2-Chloro-4-methylsulfonylphenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-(4-Acetylpiperazine-1-carbonyl)phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-(Morpholine-4-carbonyl)phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-(4-Methylsulfonylpiperazine-1-carbonyl)phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-[3-(Hydroxymethyl)azetidine-1-carbonyl]phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-(3-Hydroxyphenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-(Hydroxymethyl)phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-(Pyridin-2-ylmethoxy)phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-(Pyridin-3-ylmethoxy)phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-[(3-Methyl-1,2-oxazol-5-yl)methoxy]phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-[(3-Methyltriazol-4-yl)methoxy]phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-(Pyridin-4-ylmethoxy)phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-[(2-Chloropyridin-4-yl)methoxy]phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-[3-[(1-Methylpyrazol-4-yl)methoxy]phenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
(rac)-4-[[3-(3-Pyrrolidin-3-yloxyphenyl)-1H-pyrazol-4-yl]oxy]benzonitrile;
(rac)-4-[[3-[3-(1-Acetylpyrrolidin-3-yl)oxyphenyl]-1H-pyrazol-4-yl]oxy]benzonitrile;
4-[[3-(3-Butoxyphenyl)-1H-pyrazol-4-yl]o

Assignees

• Hoffmann La Roche

Inventors

• Aebi Johannes
• Amrein Kurt
• Hornsperger Benoit
• Kuhn Bernd
• Li Dongbo
• Liu Yongfu
• Maerki Hans P
• Martin Rainer E
• Mayweg Alexander V
• Tan Xuefei
• Wang Lisha
• Wu Jun

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/42

  for decreasing, blocking or antagonising the activity of mineralocorticosteroids · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P13/12

  of the kidneys · CPC title