Phenyl derivatives, their manufacture and use as pharmaceutical agents

1. A Compound of the formula

and enantiomers and pharmaceutically acceptable salts or esters thereof, wherein

X 1 is O, S, CH 2

R 1 is hydrogen or C 1-7 -alkyl;

R 2 is hydrogen or C 1-7 -alkyl,

or, if X 1 is CH 2 , R 2 is hydrogen, C 1-7 -alkyl or C 1-7 -alkoxy;

R 3 is hydrogen or C 1-7 -alkyl;

R 4 and R 8 independently from each other are selected from the group consisting of hydrogen, C 1-7 -alkyl,

C 3-7 -cycloalkyl, halogen, C 1-7 -alkoxy-C 1-7 -alkyl, C 2-7 -alkenyl, C 2-7 -alkinyl, fluoro-C 1-7 -alkyl, cyano-C 1-7 -alkyl or cyano;

R 5 , R 6 and R 7 independently from each other are selected from the group consisting of hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, halogen, C 1-7 -alkoxy-C 1-7 -alkyl, C 2-7 -alkenyl, C 2-7 -alkinyl, fluoro-C 1-7 -alkyl, cyano-C 1-7 -alkyl or cyano;

and one of R 5 , R 6 and R 7 is

wherein

X 2 is selected from the group consisting of S, O, NR 9 , (CH 2 ) p NR 9 CO, or (CH 2 ) p CONR 9 ,

R 9 is selected from the group consisting of hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, fluoro-C 1-7 -alkyl, hydroxy-C 2-7 -alkyl, or C 1-7 -alkoxy-C 2-7 -alkyl;

Y 1 , Y 2 , Y 3 and Y 4 are N or C—R 12 , and 1 or 2 of Y 1 , Y 2 , Y 3 and Y 4 are N and the other ones are C—R 12 ;

R 10 is C 1-7 -alkyl, C 3-7 -cycloalkyl, fluoro-C 1-7 -alkyl, or C 1-7 -alkoxy-C 1-7 -alkyl;

R 11 is hydrogen, C 1-7 -alkyl, C 1-7 -alkoxy-C 1-7 -alkyl;

R 12 independently from each other is selected from the group consisting of hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, fluoro-C 1-7 -alkyl, C 1-7 -alkoxy-C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, C 1-7 -alkylthio-C 1-7 -alkyl, carboxy-C 1-7 -alkoxy-C 1-7 -alkyl, carboxy, carboxy-C 1-7 -alkyl, mono- or di-C 1-7 -alkyl-amino-C 1-7 -alkyl, C 1-7 -alkanoyl-C 1-7 -alkyl, C 2-7 -alkenyl, and C 2-7 -alkinyl;

R 13 is aryl or heteroaryl;

m is 0 or 1, n is 0, 1, 2 or 3, and p is 0, 1 or 2, and the sum of m, n and p is 1, 2, 3 or 4;

provided that compounds of formula I are excluded, wherein

X 1 is O, R 2 and R 3 are hydrogen,

R 6 is equal to

X 2 is O or S, and m is 0.

2. The Compound of claim 1 , wherein

X 2 is NR 9 , (CH 2 ) p NR 9 CO or (CH 2 ) p CONR 9 ,

R 9 is hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, fluoro-C 1-7 -alkyl, hydroxy-C 2-7 -alkyl, or

C 1-7 -alkoxy-C 2-7 -alkyl; and p is 0, 1 or 2.

3. The Compound of claim 2 , wherein X 2 is NR 9 , and R 9 is hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, fluoro-C 1-7 -alkyl, hydroxy-C 2-7 -alkyl, or C 1-7 -alkoxy-C 2-7 -alkyl.

4. The Compound of claim 1 , wherein

X 2 is (CH 2 ) p NR 9 CO, or (CH 2 ) p CONR 9 ,

R 9 is hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, fluoro-C 1-7 -alkyl, hydroxy-C 2-7 -alkyl, or C 1-7 -alkoxy-C 2-7 -alkyl; and p is 0, 1 or 2.

5. The Compound of claim 4 , wherein R 9 is C 1-7 -alkyl.

6. The Compound of claim 2 , wherein said compound is selected from the group consisting of

(2-(3-methoxy-propyl)-4-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-amino}-phenoxy)-acetic acid,

[rac]-[2-methyl-4-(methyl-{1-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-yl]-butyl}-amino)-phenoxy]-acetic acid,

(4-{[6-(4-chloro-phenyl)-pyridin-3-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid, 2-methyl-2-[3-(methyl-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-phenoxy]-propionic acid, and

(4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethyl]-methyl-amino}-2-methyl-phenoxy)-acetic acid.

7. The Compound of claim 4 , wherein said compound is selected from the group consisting of

2-methyl-2-(3-{methyl-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylmethyl]-carbamoyl}-phenoxy)-propionic acid,

2-[3-([}2-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-acetyl}-methyl-amino)-phenoxy]-2-methyl-propionic acid,

2-methyl-2-[3-(methyl-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetyl}-amino)-5-trifluoromethyl-phenoxy]-propionic acid,

2-[4-({[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid, and

2-methyl-2-(4-{[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-ylcarbamoyl]-methyl}-phenoxy)-propionic acid.

8. The Compound of claim 4 , wherein said compound is selected from the group consisting of

2-[3-chloro-4-({[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-2-methyl-propionic acid,

2-methyl-2-[4-({[4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-phenoxy]-propionic acid; and

2-(4-{[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylcarbamoyl]-methyl}-phenoxy)-2-methyl-propionic acid.

9. The Compound of claim 1 , wherein X 1 and X 2 are O and R 2 is C 1-7 -alkyl.

10. The Compound of claim 1 , wherein X 1 and X 2 are O and R 2 and R 3 are C 1-7 -alkyl.

11. The Compound of claim 10 , wherein said compound is selected from the group consisting of

2-methyl-2-{2-methyl-4-[2-methyl-6-(3-trifluoromethyl-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid,

2-methyl-2-{2-methyl-4-[6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid, and

2-{4-[4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid.

12. The Compound of claim 10 , wherein said compound is selected from the group consisting of

2-methyl-2-{2-methyl-4-[2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-phenoxy}-propionic acid,

2-{4-[4-cyclopropyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid, and

2-{4-[4-(2-methoxy-ethyl)-6-methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid.

13. The Compound of claim 10 , wherein said compound is selected from the group consisting of

2-{4-[2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid,

2-{4-[4-methoxymethyl-6-methyl-2-(3-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy-2-methyl-phenoxy}-2-methyl-propionic acid,

2-{4-[2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid,

2-{4-[4-methoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid,

2-{4-[2-cyclopropyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid, and

2-{4-[4-methoxymethyl-2-(4-trifluoromethoxy-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy}-2-methyl-propionic acid.

14. The Compound of claim 1 , wherein X 1 and X 2 are O and m is 1.

15. The Compound of claim 14 , wherein said compound is selected from the group consisting of

[rac]-(4-{1-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethoxy}-2-methyl-phenoxy)-acetic acid, and

[rac]-(4-{1-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-butoxy}-2-methyl-phenoxy)-acetic acid.

16. The Compound of claim 1 , wherein X 1 is S.

17. The Compound of claim 16 , wherein said compound is selected from the group consisting of

[rac]-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-phenylsulfanyl)-acetic acid, and

[rac]-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-butoxy}-phenylsulfanyl)-acetic acid.

18. The Compound of claim 1 , wherein X 1 is O, X 2 is S and m is 1.

19. The Compound of claim 18 , wherein said compound is selected from the group consisting of

[rac]-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethylsulfanyl}-phenoxy)-acetic acid, and

[rac]-(4-{1-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-yl]-ethylsulfanyl}-2-methyl-phenoxy)-acetic acid.

20. The Compound of claim 1 , wherein R 13 is unsubstituted phenyl or phenyl substituted with one to three groups selected from C 1-7 -alkyl, C 1-7 -alkoxy, halogen, fluoro-C 1-7 -alkyl, fluoro-C 1-7 -alkoxy and cyano.

21. The Compound of claim 20 , wherein R 13 is unsubstituted phenyl or phenyl substituted with one to three groups selected from C 1-7 -alkyl, C 1-7 -alkoxy, halogen, fluoro-C 1-7 -alkyl and cyano.

22. The Compound of claim 21 , wherein R 13 is phenyl substituted with halogen or fluoro-C 1-7 -alkyl.

23. The Compound of claim 20 , wherein R13 is phenyl substituted with fluoro-C 1-7 -alkoxy.

24. The Compound of claim 23 , wherein R 1 is hydrogen.

25. The Compound of claim 1 , wherein R 3 is C 1-7 -alkyl.

26. The Compound of claim 1 , wherein 2 of Y 1 , Y 2 , Y 3 and Y 4 are N and the other ones are C—R 12 .

27. A process for the manufacture of a compound of claim 1 , which process comprises

a) reacting a compound of formula

wherein R 1 is C 1-7 -alkyl, R 2 to R 8 are as defined as in claim 1 and one of R 5 , R 6 or R 7 is selected from —OH, —SH or —NHR 9 , wherein R 9 is as defined in claim 1 , with a compound of formula

wherein Y 1 to Y 4 , R 10 , R 11 , R 13 , m and n are as defined in claim 1 and R 14 is —OH, —Cl, —Br, —I or another leaving group, to obtain a compound of formula

wherein one of R 5 , R 6 and R 7 is

and wherein X 2 is O, S or —NR 9 , R 1 is C 1-7 -alkyl and X 1 , Y 1 to Y 4 , R 2 to R 13 and m and n are as defined in claim 1 ,

and optionally hydrolysing the ester group to obtain a compound of formula I, wherein R 1 is hydrogen;

or, alternatively,

b) reacting a compound of formula

wherein R 1 is C 1-7 -alkyl, R 2 to R 8 are as defined as in claim 1 and one of R 5 , R 6 or R 7 is —(CH 2 ) p —NHR 9 , wherein R 9 and p are as defined in claim 1 , with a compound of formula

wherein Y 1 to Y 4 , R 10 , R 11 , R 13 , m and n are as defined in claim 1 , to obtain a compound of formula

wherein one of R 5 , R 6 and R 7 is

and wherein X 2 is —(CH 2 ) p —NR 9 CO—, R 1 is C 1-7 -alkyl and X 1 , Y 1 to Y 4 , R 2 to R 13 and m, n and p are as defined in claim 1 ,

and optionally hydrolysing the ester group to obtain a compound of formula I, wherein R 1 is hydrogen;

or, alternatively,

c) reacting a compound of formula

wherein R 1 is C 1-7 -alkyl, R 2 to R 8 are as defined as in claim 1 and one of R 5 , R 6 or R 7 is —(CH 2 ) p —COOH, and p is defined as in claim 1 , with a compound of formula

wherein Y 1 to Y 4 , R 9 , R 10 , R 11 , R 13 , m and n are as defined in claim 1 , to obtain a compound of formula

wherein one of R 5 , R 6 and R 7 is

and wherein X 2 is —(CH 2 ) p —CONR 9 , R 1 is C 1-7 -alkyl and X 1 , Y 1 to Y 4 , R 2 to R 13 and m, n and p are as defined in claim 1 ,

and optionally hydrolysing the ester group to obtain a compound of formula I, wherein R 1 is hydrogen.

28. A pharmaceutical composition which comprises a compound of the formula

and enantiomers and pharmaceutically acceptable salts and esters thereof, wherein

X 1 is O, S, CH 2

R 1 is hydrogen or C 1-7 -alkyl;

R 2 is hydrogen or C 1-7 -alkyl, or, if X 1 is CH 2 , R 2 is hydrogen, C 1-7 -alkyl or C 1-7 -alkoxy;

R 3 is hydrogen or C 1-7 -alkyl;

R 4 and R 8 independently from each other are selected from the group consisting of hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, halogen, C 1-7 -alkoxy-C 1-7 -alkyl, C 2-7 -alkenyl, C 2-7 -alkinyl, fluoro-C 1-7 -alkyl, cyano-C 1-7 -alkyl or cyano;

R 5 , R 6 and R 7 independently from each other are selected from the group consisting of hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, halogen, C 1-7 -alkoxy-C 1-7 -alkyl, C 2-7 -alkenyl, C 2-7 -alkinyl, fluoro-C 1-7 -alkyl, cyano-C 1-7 -alkyl or cyano;

and one of R 5 , R 6 and R 7 is

wherein

X 2 is selected from the group consisting of S, O, NR 9 , (CH 2 ) p NR 9 CO, or (CH 2 ) p CONR 9 ,

R 9 is selected from the group consisting of hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, fluoro-C 1-7 -alkyl, hydroxy-C 2-7 -alkyl, or C 1-7 -alkoxy-C 2-7 -alkyl;

Y 1 , Y 2 , Y 3 and Y 4 are N or C—R 12 , and 1 or 2 of Y 1 , Y 2 , Y 3 and Y 4 are N and the other ones are

R 10 is C 1-7 -alkyl, C 3-7 -cycloalkyl, fluoro-C 1-7 -alkyl, or C 1-7 -alkoxy-C 1-7 -alkyl;

R 11 is hydrogen, C 1-7 -alkyl, C 1-7 -alkoxy-C 1-7 -alkyl;

R 12 independently from each other in each occurance is selected from the group consisting of hydrogen, C 1-7 -alkyl, C 3-7 -cycloalkyl, fluoro-C 1-7 -aklyl, C 1-7 -alkoxy-C 1-7 -alkyl, hydroxy-C 1-7 -alkyl, C 1-7 -alkylthio-C 1-7 -alkyl, carboxy-C 1-7 -alkoxy-C 1-7 -alkyl, carboxy, carboxy-C 1-7 -alkyl, mono- or di-C 1-7 -alkyl-amino-C 1-7 -alkyl, C 1-7 -alkanoyl-C 1-7 -alkyl, C 2-7 -alkenyl, and C 2-7 -alkinyl;

R 13 is aryl or heteroaryl;

m is 0 or 1, n is 0, 1, 2 or 3, and p is 0, 1 or 2, and the sum of m, n and p is 1, 2, 3 or 4;

provided that compounds of formula I are excluded, wherein

X 1 is O, R 2 and R 3 are hydrogen,

R 6 is equal to

X 2 is O or S, and m is 0 together with a pharmaceutically acceptable carrier or excipient.