Tricyclic spiro derivatives as CRTH2 modulators
View Patent ↗The present invention is related to the use of spiro derivatives of Formula (I) for the treatment and/or prevention of allergic diseases, inflammatory dermatoses and other diseases with an inflammatory component. Specifically, the present invention is related to the use of spiro derivatives for the modulation of CRTH2 activity.
1. A compound according to Formula (I′)
wherein:
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen, aryl and heteroaryl;
m is an integer selected from 0, 1, 2, 3 or 4;
R 2 is either C 3 -C 6 -alkyl or A; wherein
A is selected from the group consisting of A1, A2, A3, A4, A5 and A6:
with each n being an integer independently selected from 1, 2, 3 or 4; wherein
R 4 is selected from the group consisting of C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, aryl and heteroaryl;
each R 4 may optionally be substituted independently with one or more groups R 6 ;
each R 6 is independently selected from the group consisting of C 1 -C 6 -alkyl, alkoxy, alkoxycarbonyl, aryl, aryl C 1 -C 6 -alkyl, heteroaryl, substituted or unsubstituted heteroaryl C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, acylamino, nitro, sulfoxy, sulfonyl, sulfonylamine, aminosulfonyl and trihalo-C 1 -C 6 -alkyl;
R 7 is either hydrogen or C 1 -C 6 -alkyl;
R 3 is B, wherein
B is:
←(CH 2 ) n -R 5
with n being an integer independently selected from 1, 2, 3 or 4; wherein
R 5 is carboxy;
X is either CH 2 or NH;
each Y is independently either C(O) or CH 2 ; and
z is either C(O) or CHR 7 ;
as well as its geometrical isomers, optically active forms as enantiomers, diastereomers, its racemate forms, or pharmaceutically acceptable salts thereof.
2. The compounds according to claim 1 , wherein R 1 is either halogen or halo-C 1 -C 6 -alkoxy.
3. The compound according to claim 2 , wherein R 1 is halogen and m is either 1 or 2.
4. The compound according to claim 1 , wherein R 2 is A1, and n is 1.
5. The compound according to claim 1 , wherein X is CH.
6. The compound according to claim 1 , wherein X is NH.
7. The compound according to claim 1 , wherein Z is C(O).
8. A compound selecting from the group consisting of:
[5-chloro-1′-[(2-methyl-1,3-thiazol-4-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2,4-dichlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(quinolin-2-ylmethyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(4-cyanobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3-chlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3,4-dichlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(4-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(1-naphthylmethyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(3-phenoxybenzyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(4-chlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(4-methoxybenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3-methoxybenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(pyridin-2-ylmethyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-{[5-(trifluoromethyl)-2-furyl]methyl}spiro [indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(4-methylbenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-[3-(trifluoromethyl)benzyl]spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2-naphthylmethyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(1-phenylethyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(2-phenylethyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(imidazo[1,2-a]pyridin-2-ylmethyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-[(2E)-3-phenylprop-2-en-1-yl]spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-[4-(trifluoromethyl)benzyl]spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
4-(1′-benzyl-6-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)butanoic acid,
[5-chloro-1′-(2-ethoxyethyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-[2-(benzyloxy)ethyl]-5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(2-phenoxyethyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(3-phenylprop-2-yn-1-yl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
(1′-but-2-yn-1-yl-5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetic acid,
[5-chloro-1′-[(1-methyl-1H-imidazol-2-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
4-[5-chloro-1′-(4-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]butanoic acid,
4-[5-chloro-1′-(4-chlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]butanoic acid,
4-[5-chloro-2,2′,5′-trioxo-1′-[4-(trifluoromethyl)benzyl]spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]butanoic acid,
[1′-benzyl-2,2′,5′-trioxo-5-(trifluoromethoxy)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-(4-methoxybenzyl)-2,2′,5′-trioxo-5-(trifluoromethoxy)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′43-fluorobenzyl)-2,2′,5′-trioxo-5-(trifluoromethoxy)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-(2-fluorobenzyl)-2,2′,5′-trioxo-5-(trifluoromethoxy)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[2,2′,5′-trioxo-5-(trifluoromethoxy)-1′-[3-(trifluoromethyl)benzyl]spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-(1-naphthylmethyl)-2,2′,5′-trioxo-5-(trifluoromethoxy)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-(4-chlorobenzyl)-2,2′,5′-trioxo-5-(trifluoromethoxy)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-(4-fluorobenzyl)-2,2′,5′-trioxo-5-(trifluoromethoxy)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
4-[5-chloro-1′-(4-methoxybenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]butanoic acid,
4-[5-chloro-1′-(2-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]butanoic acid,
4-[5-chloro-1′-(2-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]butanoic acid,
[(3S)-1′-benzyl-5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[(3R)-1′-benzyl-5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[6-chloro-1′-(2-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[6-chloro-1′-(3-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[6-chloro-1′-(4-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
4-[5-chloro-2,2′,5′-trioxo-1′-(2-phenylethyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]butanoic acid,
[5-chloro-1′-(3,5-dichlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(4-phenoxybenzyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2-methoxybenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[4-(methylsulfonyl)benzyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-[4-(aminocarbonyl)benzyl]-5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3-cyanobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(5-methylisoxazol-3-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-(1,3-benzothiazol-2-ylmethyl)-5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(5-chloro-2-thienyl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(5-chloro-1,2,4-thiadiazol-3-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-[(2-phenyl-1,3-thiazol-4-yl)methyl]spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2-chloro-4-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2,5-dichlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-[4-(acetylamino)benzyl]-5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(6-chloropyridin-3-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(1H-indol-3-ylmethyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(5-chloro-2-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(1,3-thiazol-4-ylmethyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(4-chloropyridin-3-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(pyridin-3-ylmethyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(3,5-dimethylisoxazol-4-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[1′-[(5-tert-butyl-1,2,4-oxadiazol-3-yl)methyl]-5-chloro-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(5-cyclopropyl-1,3,4-thiadiazol-2-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(4,6-dichloropyridin-3-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-(2-thienylmethyl)spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(3,4-dimethoxypyridin-2-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(isoquinolin-1-ylmethyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-2,2′,5′-trioxo-1′-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]spiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
(3R)-[5-chloro-1′-(3-chlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
(3S)-[5-chloro-1′-(3-chlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
(3R)-[5-chloro-1′-(3-methoxybenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
(3S)-[5-chloro-1′-(3-methoxybenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2,4-difluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(1,3-oxazol-2-ylmethyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(4-methoxy-3-methylpyridin-2-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-{[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-{[5-(4-methoxyphenyl)-1,2,4-oxadiazol-3-yl]methyl}-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(1-methyl-1H-1,2,3-benzotriazol-5-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3-furylmethyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2-chloro-5-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2,5-difluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2,3-difluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3,5-difluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3,4-difluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(1-methyl-1H-benzimidazol-2-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3-fluoro-4-methoxybenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(3-chloro-5-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-[(3-methyl-5-phenylisoxazol-4-yl)methyl]-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-{[2-(3-chlorophenyl)-1,3-thiazol-4-yl]methyl}-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5′-chloro-1-(5-chloro-2-fluorobenzyl)-2,2′,5-trioxospiro[imidazolidine-4,3′-indol]-1′(2′H)-yl]acetic acid,
[5′-chloro-1-[(5-methyl-3-phenylisoxazol-4-yl)methyl]-2,2′,5-trioxospiro[imidazolidine-4,3′-indol]-1′(2′H)-yl]acetic acid,
(1-benzyl-5′-chloro-2,2′,5-trioxospiro[imidazolidine-4,3′-indol]-1′(2′H)-yl)acetic acid,
[5′-chloro-1-(2-fluorobenzyl)-2,2′,5-trioxospiro[imidazolidine-4,3′-indol]-1′(2′H)-yl]acetic acid,
(3R)-[5-chloro-1′-(2-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
(3S)-[5-chloro-1′-(2-fluorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
(3S)-[5-chloro-1′-(2-fluoro-5-chlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
(3R)-[5-chloro-1′-(2-fluoro-5-chlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
(1′-benzyl-5-chloro-2,5′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetic acid,
[5-chloro-1′-[(3-methyl-5-phenylisoxazol-4-yl)methyl]-2,5′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid,
[5-chloro-1′-(2-fluorobenzyl)-2,5′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid, and
[5-chloro-1′-(5-chloro-2-fluorobenzyl)-2,5-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl]acetic acid.
9. A compound according to Formula (I),
as well as its geometrical isomers, its optically active forms as enantiomers, diastereomers and its racemate forms, and tautomers, or a pharmaceutically acceptable salts thereof, wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen, aryl and heteroaryl;
m is an integer selected from 0, 1, 2, 3 or 4;
R 2 is either C 1 -C 6 -alkyl or A;
R 3 is B;
R 4 is selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, aryl, heteroaryl, sulfonylamine, amine, halo-C 1 -C 6 -alkyl, hydroxylamine and hydroxyl; wherein each R 4 may be substituted independently with one or more groups R 6 ;
R 5 is carboxy;
R 6 is selected from the group consisting of C 1 -C 6 -alkyl, alkoxy, alkoxycarbonyl, aryl, aryl C 1 -C 6 -alkyl, heteroaryl, heteroaryl C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, carboxyl, cyano, halogen, hydroxy, amino, amino carbonyl, nitro, sulfoxy, sulfonyl, sulfonamide and trihalo-C 1 -C 6 -alkyl;
R 7 is either hydrogen or C 1 -C 6 -alkyl;
A is selected from the group consisting of A1, A2, A3, A4, A5 and A6:
wherein each n is an integer independently selected from 0, 1, 2, 3, 4;
B is:
←(CH 2 ) n -R 5 ;
wherein n is an integer selected from 1, 2, 3 or 4
T is CH;
each Y is independently either C(O), or CH2;
X is either CH 2 or NH; and
z is either C(O) or CHHR 7 .
10. The compound according to claim 9 , wherein R 1 is either halogen or halo-C 1 -C 6 -alkoxy.
11. The compound according to claim 10 , wherein R 1 is halogen.
12. The compound according to claim 9 , wherein R 2 is A1, and n is 1.
13. The compound according to claim 9 , wherein R 2 is A5, and n is 2.
14. The compound according to claim 9 , wherein R 4 is either aryl or heteroaryl.
15. The compound according to claim 9 , wherein R 3 is B, and n is either 1 or 3.
16. A method for treating allergic disease, inflammatory dermatoses, rheumatoid arthritis, inflammatory bowel disease and multiple sclerosis comprising administering to a subject a compound, wherein said compound is a modulator of CRTH2 activity, according to Formula (I):
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen, aryl and heteroaryl;
m is an integer selected from 0, 1, 2, 3 or 4;
R 2 is either C 1 -C 6 -alkyl or A;
R 3 is either C 1 -C 6 -alkyl or B;
R 4 is selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, aryl, heteroaryl, sulfonylamine, amine, halo-C 1 -C 6 -alkyl, hydroxylamine and hydroxyl; wherein each R 4 may be substituted independently with one or more groups R 6 ;
R 5 is carboxy;
R 6 is selected from the group consisting of C 1 -C 6 -alkyl, alkoxy, alkoxycarbonyl, aryl, aryl C 1 -C 6 -alkyl, heteroaryl, heteroaryl C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, carboxyl, cyano, halogen, hydroxy, amino, amino carbonyl, nitro, sulfoxy, sulfonyl, sulfonamide and trihalo-C 1 -C 6 -alkyl;
R 7 is either hydrogen or C 1 -C 6 -alkyl;
A is selected from the group consisting of A1, A2, A3, A4, A5 and A6:
wherein each n is an integer independently selected from 0, 1, 2, 3 or 4;
B is:
←(CH 2 ) n -R 5 ;
wherein n is an integer selected from 1, 2, 3 or 4
T is CH;
each Y is independently either C(O), or CH2;
X is either CH 2 or NH; and
z is either C(O) or CHR 7 ;
as well as geometrical isomers, enantiomers, diastereomers, racemate forms and pharmaceutically acceptable salts of said compounds for the preparation of a medicament.
17. The method according to claim 16 , wherein said allergic disease is selected from the group consisting of allergic asthma, allergic rhinitis, allergic conjunctivitis, systemic anaphylaxis or hypersensitivity responses.
18. The method according to claim 16 , wherein said inflammatory dermatosis is selected from the group consisting of atopic dermatitis, contact hypersensitivity, allergic contact dermatitis, chronic urticaria/chronic, idiopathic/autoimmune urticaria, drug-induced exanthems, photodermatosis or polymorphous light eruption and myositis.
19. A pharmaceutical composition containing at least one compound according to claim 1 or 9 and a pharmaceutically acceptable carrier, diluent or excipient thereof.
20. Process for the manufacture of the compound of Formula (I′) wherein intermediate II:
where:
R 3 is (CH 2 )n-CO 2 R wherein R is either C 1 -C 6 -alkyl or benzyl and n is an integer selected from 1, 2, 3 or 4;
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen, aryl and heteroaryl;
R 2 is either C 3 -C 6 -alkyl or A; wherein
A is selected from the group consisting of A1, A2, A3, A4, A5 and A6:
with each n being an integer independently selected from 1, 2, 3 or 4; wherein
R 4 is selected from the group consisting of C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, aryl and heteroaryl; each R 4 may optionally be substituted independently with one or more groups R 6 ; each R 6 is independently selected from the group consisting of C 1 -C 6 -alkyl, alkoxy, alkoxycarbonyl, aryl, aryl C 1 -C 6 -alkyl, heteroaryl, substituted or unsubstituted heteroaryl C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, acylamino, nitro, sulfoxy, sulfonyl, sulfonylamine, aminosulfonyl and trihalo-C 1 -C 6 -alkyl;
R 7 is either hydrogen or C 1 -C 6 -alkyl;
X is either CH 2 or NH;
each Y is independently either C(O) or CH 2 ; and
z is either C(O) or CHR 7 ; is hydrolized under conditions such that Formula I′ is formed:
where:
R 3 is (CH 2 )n-CO 2 H wherein n is an integer selected from 1,2,3 of 4;
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen, aryl and heteroaryl;
m is an integer selected from 0, 1, 2, 3 or 4;
R 2 is either C 3 -C 6 -alkyl or A; wherein
A is selected from the group consisting of A1, A2, A3, A4, A5 and A6:
with each n being an integer independently selected from 1, 2, 3 or 4; wherein
R 4 is selected from the group consisting of C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, aryl and heteroaryl; each R 4 may optionally be substituted independently with one or more groups R 6 ; each R 6 is independently selected from the group consisting of C 1 -C 6 -alkyl, alkoxy, alkoxycarbonyl, aryl, aryl C 1 -C 6 -alkyl, heteroaryl, substituted or unsubstituted heteroaryl C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, acylamino, nitro, sulfoxy, sulfonyl, sulfonylamine, aminosulfonyl and trihalo-C 1 -C 6 -alkyl;
R 7 is either hydrogen or C 1 -C 6 -alkyl;
X is either CH 2 or NH;
each Y is independently either C(O) or CH 2 ; and
z is either C(O) or CHR 7 .
21. The process according to claim 20 , wherein said intermediate II:
is formed by means of an alkylation of intermediate III:
where:
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen, aryl and heteroaryl;
R 2 is either C 3 -C 6 -alkyl or A; wherein:
A is selected from the group consisting of A1, A2, A3, A4, A5 and A6:
with each n being an integer independently selected from 1, 2, 3 or 4; wherein
R 4 is selected from the group consisting of C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, aryl and heteroaryl;
each R 4 may optionally be substituted independently with one or more groups R 6 ;
each R 6 is independently selected from the group consisting of C 1 -C 6 -alkyl, alkoxy, alkoxycarbonyl, aryl, aryl C 1 -C 6 -alkyl, heteroaryl, substituted or unsubstituted heteroaryl C 1 -C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -heterocycloalkyl, carboxyl, cyano, halogen, hydroxy, amino, aminocarbonyl, acylamino, nitro, sulfoxy, sulfonyl, sulfonylamine, aminosulfonyl and trihalo-C 1 -C 6 -alkyl;
R 7 is either hydrogen or C 1 -C 6 -alkyl;
X is either CH 2 or NH;
each Y is independently either C(O) or CH 2 ; and
z is either C(O) or CHR 7 .
22. The process according to claim 20 wherein said intermediate II:
is formed by means of an alkylation of intermediate IV:
where:
R 1 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkyl, halo-C 1 -C 6 -alkoxy, halogen, aryl and heteroaryl;
R 3 is B, wherein
B is:
←(CH 2 ) n -R 5
with n being an integer independently selected from 1, 2, 3 or 4; wherein
R 5 is carboxy;
X is either CH 2 or NH;
each Y is independently either C(O) or CH 2 ; and
z is either C(O) or CHR 7 .