HK1130062B

HK1130062B - (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives

Info

Publication number: HK1130062B
Application number: HK09110028.6A
Authority: HK
Inventors: 海因茨‧弗雷兹; 朱利安‧保泽尔; 菲利普‧理斯时
Original assignee: 埃科特莱茵药品有限公司
Priority date: 2006-08-07
Filing date: 2007-08-02
Publication date: 2012-08-17

Description

Field of the invention:

The present invention relates to (3-amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid derivatives of Formula I and their use as prostaglandin receptor modulators, most particularly as prostaglandin D₂ receptor ("DP receptor") modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation. In particular, such derivatives may be used alone or in pharmaceutical compositions for the treatment of both, chronic and acute allergic/immune diseases/disorders such as allergic asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases, such as Churg-Strauss syndrome and sinusitis, and basophil-related diseases, such as basophilic leukemia and basophilic leukocytosis, in humans and other mammals.

Background of the invention:

As a response to allergen exposure in allergic conditions, mast cells are activated and release chemotactic key mediators like histamine, thromboxane A2 (TxA2), cysteinyl leukotrienes (CysLTs) and prostaglandin D₂ (PGD₂). These mediators interact with their respective receptors and cause physiological effects such as increased vascular permeability, edema, pruritus, nasal and pulmonary congestion, bronchoconstriction, and mucus secretion. An increased vascular permeability for example, allows excessive infiltration of eosinophilic and basophilic leukocytes into the tissue and thus amplifies the allergic response.

Current treatments of allergic diseases comprise agents that can block or otherwise interrupt such interactions, e.g. anti-histamines (histamine H1 receptor antagonists), leukotriene receptor antagonists, beta-adrenergic receptor agonists, and corticosteroids. Generally, treatments with anti-histamines and leukotriene antagonists are limited in efficacy, and long-term usage of corticosteroids is associated with unwanted side effects.

PGD₂ is an agonist known to act on two G-protein-coupled receptors, the PGD₂ receptor DP1 and the recently identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor (also referred to as "DP2 receptor").

Elevated PGD₂ levels are considered to cause inflammation actions as observed in allergic diseases such as allergic rhinitis, allergic asthma, allergic conjunctivitis, atopic dermatitis and the like. Therefore, blocking the interaction of PGD₂ with its receptors is considered a useful therapeutic strategy for the treatment of such diseases.

WO 01/79169 discloses (tetrahydrocarbazol-1-yl)acetic acid derivatives as PGD₂ receptor antagonists.

GB 2388540 (Bayer AG) discloses the use of ramatroban ((3R)-3-(4-fluorobenzene-sulfonamido)-1,2,3,4-tetrahydrocarbazole-9-propionic acid), a TxA2 receptor (also referred to as "TP receptor") antagonist with additional antagonistic activity on CRTH2, for the prophylaxis and treatment of allergic diseases, such as asthma, allergic rhinitis or allergic conjunctivitis. In T. Ishizuka et al., Cardiovascular Drug Rev. 2004, 22(2), 71-90 effects of ramatroban on late-phase inflammation are described. Furthermore, oral bioavailability of ramatroban and its ability to inhibit prostaglandin D₂-induced eosinophil migration in vitro has been reported ( Journal of Pharmacology and Experimental Therapeutics, 305(1), p.347-352 (2003)).

WO 03/097598 and WO 03/097042 disclose Ramatroban analogues with CRTH2 antagonistic activity. Ulven et al, in J. Med. Chem. 2005, 48(4), 897-900 disclose further ramatroban analogues.

The compounds of the invention are structurally different from corticosteroids, anti-histamines, leukotriene antagonists or beta-adrenergic agonists.

Description of the invention:

i) The present invention relates to (3-amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid compounds of the Formula I: wherein R1, R2, R3 and R4 independently represent hydrogen, C1-5-alkyl, C1-5-alkoxy, alkenyl (especially allyl or vinyl), halogen, nitro, cyano, halo-C1-6-alkoxy, halo-C1-6-alkyl, C1-6-alkylsulfonyl, or formyl; R5 represents hydrogen, alkenyl (especially allyl or vinyl), C1-6-alkyl, cycloalkyl-C1-4-alkyl, C1-3-alkoxy-C1-4-alkyl, aryl-C1-4-alkyl, or aryloxy-C1-4-alkyl (especially R5 represents hydrogen, C1-6-alkyl, cycloalkyl-C1-4-alkyl, C1-3-alkoxy-C1-4-alkyl, aryl-C1-4-alkyl, or aryloxy-C1-4-alkyl); wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy, C1-4alkoxy, C1-4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluoromethyl); and R6 represents C1-9-alkylaminocarbonyl; C1-9-alkylaminothiocarbonyl; C1-9-alkylcarbonyl; C1-9-alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; arylaminothiocarbonyl; aryl-C1-3-alkoxy-C1-3-alkoxycarbonyl; aryl-C1-3-alkoxycarbonyl; aryl-C1-3-alkylaminocarbonyl; aryl-C1-6-alkylcarbonyl, aryl-C1-3-alkoxy-C1-3-alkylcarbonyl; arylcarbonyl; arylcarbonyl-C1-4-alkylcarbonyl; aryloxy-C1-3-alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl-C1-3-alkylcarbonyl; diaryl-C1-3-alkylcarbonyl; heterocyclylcarbonyl; heteroaryl-C1-3-alkylcarbonyl; heteroarylcarbonyl; aryl-C1-6-cycloalkylcarbonyl; cycloalkylcarbonyl; or R7-C1-4-alkylcarbonyl, wherein the bridging C1-4-alkyl group may additionally be mono-substituted with aryl or disubstituted with hydroxy, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl, C1-6-alkylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy; C1-6-alkoxy; C1-6-alkyl; C1-6-alkylsulfonyl; phenyl which is unsubstituted, mono- or di-substituted by substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl; phenyl-C1-3-alkyl, wherein the phenyl group is unsubstituted, mono- or di-substituted with substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl-C1-3-alkyl; phenoxy, wherein the phenyl group is unsubstituted, mono- or di-substituted with substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyloxy; halogen; hydroxy; halo-C1-6-alkyl; halo-C1-6-alkoxy; C1-6-alkylthio; and C1-4-alkoxycarbonylamino.
ii) In another embodiment, the invention relates to compounds of Formula I according to embodiment i), wherein R5 represents hydrogen, alkenyl (especially allyl or vinyl), or C1-6-alkyl; and R6 represents C1-9-alkylaminocarbonyl, C1-9-alkylaminothiocarbonyl, C1-9-alkylcarbonyl, C1-9-alkoxycarbonyl, arylalkenylcarbonyl, arylaminocarbonyl, arylaminothiocarbonyl, aryl-C1-3-alkoxy-C1-3-alkoxycarbonyl, aryl-C1-3-alkoxycarbonyl, aryl-C1-3-alkylaminocarbonyl, aryl-C1-3-alkylcarbonyl, aryl-C1-3-alkoxy-C1-3-alkylcarbonyl, arylcarbonyl, arylcarbonyl-C1-4-alkylcarbonyl, aryloxy-C1-3-alkylcarbonyl, arylsulfonylaminocarbonyl, cycloalkyl-C1-3-alkylcarbonyl, diaryl-C1-3-alkylcarbonyl, heterocyclylcarbonyl, heteroaryl-C1-3-alkylcarbonyl, or heteroarylcarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy; C1-6-alkoxy; C1-6-alkyl; C1-6-alkylsulfonyl; phenyl which is unsubstituted, mono- or di-substituted with substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl; phenyl-C1-3-alkyl, wherein the phenyl group is unsubstituted, mono- or di-substituted with substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl-C1-3-alkyl; phenoxy, wherein the phenyl group is unsubstituted, mono- or di-substituted with substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyloxy; halogen; hydroxy; halo-C1-6-alkyl; and halo-C1-6-alkoxy.
iii) A further embodiment of the invention relates to compounds of Formula I according to embodiment ii), wherein R1, R2, R3 and R4 independently represent hydrogen; C1-5-alkyl, especially methyl, or isopropyl; C1-5-alkoxy, especially methoxy; alkenyl, especially allyl or vinyl; halogen, especially fluoro, or chloro; halo-C1-6-alkyl, especially trifluoromethyl; or C1-6-alkylsulfonyl, especially methanesulfonyl; R5 represents hydrogen; alkenyl, especially ethenyl, or 2-propenyl; or C1-6-alkyl, especially methyl, ethyl, or propyl; and R6 represents C1-9-alkylaminocarbonyl, such as butylaminocarbonyl; C1-9-alkylcarbonyl, such as propylcarbonyl, isobutylcarbonyl, hexylcarbonyl, or nonylcarbonyl; C1-9-alkoxycarbonyl, such as propoxycarbonyl, tert-butoxycarbonyl, or isobutoxycarbonyl; arylalkenylcarbonyl, such as naphthalenylethenylcarbonyl (especially 2-naphthalen-2-yl-ethenylcarbonyl), or phenylethenylcarbonyl; arylaminocarbonyl, such as naphthalenaminocarbonyl (especially naphthalen-1-aminocarbonyl), or phenylaminocarbonyl; aryl-C1-3-alkoxy-C1-3-alkoxycarbonyl, such as benzyloxyethoxycarbonyl (especially 2-benzyloxy-ethoxycarbonyl); aryl-C1-3-alkoxycarbonyl, such as benzyloxycarbonyl; aryl-C1-3-alkylaminocarbonyl, such as benzylaminocarbonyl, or phenylethylaminocarbonyl; aryl-C1-3-alkylcarbonyl, such as phenylmethylcarbonyl, phenylethylcarbonyl (especially 2-phenylethyl-carbonyl), or naphthalenylethylcarbonyl (especially 2-naphthalen-2-yl-ethylcarbonyl); aryl-C1-3-alkoxy-C1-3-alkylcarbonyl, such as benzyloxymethyl-carbonyl; arylcarbonyl, such as phenylcarbonyl; arylcarbonyl-C1-4-alkylcarbonyl, such as phenylcarbonylethylcarbonyl (especially 2-phenylcarbonyl-ethylcarbonyl); aryloxy-C1-3-alkylcarbonyl, such as phenoxymethylcarbonyl; arylsulfonylaminocarbonyl, such as phenylsulfonylaminocarbonyl; cycloalkyl-C1-3-alkylcarbonyl, such as cyclopentylethylcarbonyl (especially 2-cyclopentylethylcarbonyl), or indanylmethylcarbonyl (especially indan-2-ylmethylcarbonyl); diaryl-C1-3-alkylcarbonyl, such as 1,2-diphenylethylcarbonyl, or 2,2-diphenylethylcarbonyl; heterocyclylcarbonyl, such as dihydroindolylcarbonyl (especially 2,3-dihydro-1H-indole-2-carbonyl); heteroaryl-C1-3-alkylcarbonyl, such as benzimidazolyl-C1-3-alkylcarbonyl (especially 2-1H-benzimidazol-2-yl-ethylcarbonyl), or indolyl-C1-3-alkylcarbonyl, such as indolylethylcarbonyl (especially 2-1H-indol-3-yl-ethylcarbonyl), or thienylmethylcarbonyl (especially 2-thienylmethylcarbonyl), or pyridinylethylcarbonyl (especially 2-(pyridin-3-yl)ethylcarbonyl); or heteroarylcarbonyl, such as indolylcarbonyl (especially 1H-indole-2-yl-carbonyl); wherein aryl (especially phenyl or naphthyl) is unsubstituted, mono- or di-substituted with (a) group(s) independently selected from C1-2-alkylendioxy (especially methylendioxy), C1-6-alkoxy (especially methoxy), C1-6-alkyl (especially methyl, ethyl, isopropyl, or tert-butyl), C1-6-alkylsulfonyl (especially methanesulfonyl), halogen (especially chloro, fluoro or bromo), hydroxy, and halo-C1-6-alkyl (especially trifluoromethyl).
iv) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to iii), wherein R1 represents hydrogen, or halogen.
v) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to iv), wherein R2 represents hydrogen, trifluoromethyl, or halogen (especially hydrogen, or halogen).
vi) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to v), wherein R3 represents hydrogen, or halogen.
vii) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to vi), wherein R4 represents hydrogen, alkenyl (especially allyl or vinyl), halogen (especially chloro or bromo), C1-6-alkylsulfonyl (especially methanesulfonyl); especially hydrogen or halogen.
viii) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to vii), wherein R1, R3 and R4 represent hydrogen.
ix) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to viii), wherein R2 represents fluoro.
x) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R5 represents hydrogen, C1-6-alkyl (especially C1-3-alkyl), cycloalkyl-C1-4-alkyl (especially cyclopropylmethyl), C1-3-alkoxy-C1-4-alkyl (especially 2-methoxyethyl), aryl-C1-4-alkyl (especially naphthylmethyl, or preferably phenyl-C2-3-alkyl), or aryloxy-C1-4-alkyl (especially phenoxyethyl); wherein aryl (especially phenyl) is unsubstituted (preferred), or mono- or di-substituted with a group independently selected from C1-2-alkylendioxy, C1-4-alkoxy, C1-4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy.
xi) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R5 represents hydrogen; C1-3-alkyl (especially methyl); cyclopropylmethyl; 2-methoxyethyl; phenyl-C2-3-alkyl; or phenoxyethyl, wherein the phenyl group is unsubstituted (preferred), or mono-substituted with a group selected from C1-2-alkylendioxy, C1-4-alkoxy, C1-4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluoromethyl).
xii) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R5 represents C1-3-alkyl (especially methyl); cyclopropylmethyl; 2-methoxyethyl; phenyl-C2-3-alkyl; or phenoxyethyl, wherein the phenyl group is unsubstituted (preferred), or mono-substituted with a group selected from C1-2-alkylendioxy, C1-4-alkoxy, C1-4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluoromethyl).
xiii) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R5 represents hydrogen, C1-3-alkyl (especially methyl), cyclopropylmethyl, or 2-methoxyethyl; especially cyclopropylmethyl, or 2-methoxyethyl.
xiv) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R5 represents hydrogen, methyl, ethyl, or n-propyl.
xv) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R5 represents hydrogen.
xvi) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R5 represents phenyl-C2-3-alkyl.
xvii) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R6 represents C1-9-alkylaminocarbonyl; C1-9-alkylcarbonyl; C1-9-alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; aryl-C1-3-alkoxy-C1-3-alkoxycarbonyl; aryl-C1-3-alkoxycarbonyl; aryl-C1-3-alkylaminocarbonyl; aryl-C1-6-alkylcarbonyl; aryl-C1-3-alkoxy-C1-3-alkylcarbonyl; arylcarbonyl; arylcarbonyl-C1-4-alkylcarbonyl; aryloxy-C1-3-alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl-C1-3-alkylcarbonyl; diaryl-C1-3-alkylcarbonyl; heterocyclylcarbonyl; heteroaryl-C1-3-alkylcarbonyl; heteroarylcarbonyl; aryl-C3-6-cycloalkylcarbonyl; cycloalkylcarbonyl; or R7-C1-4-alkylcarbonyl, wherein the bridging C1-4-alkyl group may additionally be mono-substituted with aryl, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl, C1-6-alkylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl, halogen, hydroxy, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkylthio, and C1-4-alkoxycarbonylamino.
xviii) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R6 represents aryl-C1-3-alkoxycarbonyl; aryl-C1-3-alkylaminocarbonyl; aryl-C1-6-alkylcarbonyl; aryl-C1-3-alkoxy-C1-3-alkylcarbonyl; arylcarbonyl-C1-4-alkylcarbonyl; aryloxy-C1-3-alkylcarbonyl; cycloalkyl-C1-3-alkylcarbonyl; diaryl-C1-3-alkylcarbonyl; aryl-C3-6-cycloalkylcarbonyl; or R7-C1-4-alkylcarbonyl, wherein the bridging C1-4-alkyl group may additionally be mono-substituted with aryl, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl, C1-6-alkylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl, halogen, hydroxy, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkylthio, and C1-4-alkoxycarbonylamino.
xix) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R6 represents aryl-C1-3-alkoxycarbonyl; aryl-C1-3-alkylaminocarbonyl; aryl-C1-6-alkylcarbonyl; aryloxy-C1-3-alkylcarbonyl; diaryl-C1-3-alkylcarbonyl; or R7-C1-4-alkylcarbonyl, wherein the bridging C1-4-alkyl group may additionally be mono-substituted with aryl, and R7 represents arylaminocarbonyl, or C1-6-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl, halogen, hydroxy, halo-C1-6-alkyl, halo-C1-6-alkoxy, C1-6-alkylthio, and C1-4-alkoxycarbonylamino.
xx) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R6 represents aryl-C1-2-alkoxycarbonyl; aryl-C1-2alkylaminocarbonyl; aryl-C1-4-alkylcarbonyl; aryloxy-C1-2-alkylcarbonyl; or diaryl-C2-3-alkylcarbonyl; or R7-C2-4-alkylcarbonyl, wherein the bridging C2-4-alkyl group may additionally be mono-substituted with aryl, and R7 represents arylaminocarbonyl, or C1-4-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy.
xxi) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R6 represents aryl-C1-2-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy.
xxii) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R6 represents aryl-C1-2-alkoxycarbonyl; aryl-C1-4-alkylcarbonyl; aryloxy-C1-2-alkylcarbonyl; or diaryl-C2-3-alkylcarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy.
xxiii) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxii), wherein, in case R6 represents a group which contains aryl, the aryl group is phenyl which unsubstituted, or mono- or di-substituted with a group independently selected from C1-4-alkoxy, C1-4-alkyl, halogen, and trifluoromethyl.
xxiv) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R6 represents C1-4-alkylcarbonyl (especially acetyl); or aryl-C2-4-alkylcarbonyl, wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-4-alkoxy, C1-4-alkyl, halogen, and trifluoromethyl.
xxv) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R6 represents aryl-C2-4-alkylcarbonyl, wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-4-alkoxy, C1-4-alkyl, halogen, and trifluoromethyl.
xxvi) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxv), wherein, in case R6 represents a group which contains a carbonyl group and one or more aryl moieties, said group is such that it contains a bridging group between the carbonyl group and said aryl moiety (moieties) of said R6, wherein the carbonyl moiety and at least one of the aryl moieties are directly attached to different atoms of said bridging group.
xxvii) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxv), wherein, in case R6 represents a group which contains a carbonyl group and exactly one aryl moiety, said group is such that it contains a bridging group between the carbonyl group and said aryl moiety of said R6, wherein the carbonyl moiety and the aryl moiety are directly attached to the same atom of said bridging group.
xxviii) A further embodiment of the invention relates to compounds of Formula I according to embodiment i), wherein R1 represents hydrogen, or halogen; R2 represents hydrogen, trifluoromethyl, or halogen; R3 represents hydrogen, or halogen; R4 represents hydrogen, halogen (especially chloro or bromo), or C1-6-alkylsulfonyl (especially methanesulfonyl); R5 represents hydrogen, C1-6-alkyl, cycloalkyl-C1-4-alkyl, C1-3-alkoxy-C1-4-alkyl, aryl-C1-4-alkyl, or aryloxy-C1-4-alkyl; wherein aryl is unsubstituted, mono-substituted with a group selected from trifluoromethyl; and R6 represents C1-9-alkylaminocarbonyl; C1-9-alkylcarbonyl; C1-9-alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; aryl-C1-3-alkoxy-C1-3-alkoxycarbonyl; aryl-C1-3-alkoxycarbonyl; aryl-C1-3-alkylaminocarbonyl; aryl-C1-6-alkylcarbonyl; aryl-C1-3-alkoxy-C1-3-alkylcarbonyl; arylcarbonyl; arylcarbonyl-C1-4-alkylcarbonyl; aryloxy-C1-3-alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl-C1-3-alkylcarbonyl; diaryl-C1-3-alkylcarbonyl; heterocyclylcarbonyl; heteroaryl-C1-3-alkylcarbonyl; heteroarylcarbonyl; aryl-C3-6-cycloalkylcarbonyl; cycloalkylcarbonyl; or R7-C1-4-alkylcarbonyl, wherein the bridging C1-4-alkyl group may additionally be mono-substituted with aryl or disubstituted with hydroxy, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl, C1-6-alkylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C1-2-alkylendioxy; C1-6-alkoxy; C1-6-alkyl; C1-6-alkylsufonyl; halogen; hydroxy; trifluoromethyl; trifluoromethoxy; C1-6-alkylthio; and C1-4-alkoxycarbonylamino.
xxix) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxviii), wherein the position C(3) of the tetrahydrocarbazole ring of Formula I is (S)-configurated.
xxx) A further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxviii), wherein the position C(3) of the tetrahydrocarbazole ring of Formula I is (R)-configurated.

In another embodiment preferred compounds of Formula I are selected from the group consisting of:

(3S)-[3-(3,3-diphenyl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)- {3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[6-fluoro-3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-(3-isobutoxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-[6-fluoro-3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{3-[3-(4-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-(3-benzyloxycarbonylamino-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-benzyloxycarbonylamino-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; and
(3S)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid.

(3R)-{3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[6-fluoro-3-(4-oxo-4-phenyl-butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[6-fluoro-3-(2-indan-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{3-[(2,3-dihydro-1H-indole-2-carbonyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-ethyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-(3-propoxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-[6-fluoro-3-(2-p-tolyloxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-fluoro-3-[methyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[6-fluoro-3-(3-1H-indol-3-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(3-benzo[1,3]dioxol-5-yl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-fluoro-3-[ethyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[2-(4-chloro-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(2,3-diphenyl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-[6-fluoro-3-(2-phenoxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{3-[3-(3,4-difluoro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-[3-(2-benzyloxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-fluoro-3-[propyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(2-benzyloxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-(3-benzyloxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-{6-fluoro-3-[2-(4-methoxy-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{3-[3-(4-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[4-(4-bromo-phenyl)-4-oxo-butyrylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-propyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-(3-phenylacetylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-{3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-fluoro-3-[2-(4-trifluoromethyl-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-(6-fluoro-3-phenylacetylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(3-1H-benzoimidazol-2-yl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-fluoro-3-[3-(4-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[6-fluoro-3-(2-p-tolyloxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-[6-fluoro-3-(2-p-tolyl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-{3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-[3-(2-phenoxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[6-fluoro-3-(3-p-tolyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-(3-benzyloxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-[6-fluoro-3-(2-p-tolyl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-[3-(2-benzyloxy-ethoxycarbonylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[6-fluoro-3-(3-naphthalen-2-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-fluoro-3-[4-(4-methanesulfonyl-phenyl)-4-oxo-butyrylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-[3-(3-phenylsulfonyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-fluoro-3-[3-(4-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-[3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-{3-[2-(4-chloro-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-[6-fluoro-3-(3-p-tolyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-{6-fluoro-3-[3-(4-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-fluoro-3-[3-(4-hydroxy-3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-fluoro-3-[2-(3-trifluoromethyl-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-fluoro-3-[2-(4-methoxy-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{3-[2-(3-chloro-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-(3-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-{3-[2-(3,4-dichloro-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(3-isobutoxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid; and
(3S)-[6-fluoro-3-(2-phenoxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid.

(3R)-[3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(2-benzyloxy-ethoxycarbonylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(2-phenoxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-(3-propoxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-[3-(2-thiophen-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-(3-phenylacetylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-[3-(3-phenylsulfonyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(3-benzyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-[3-(3-naphthalen-1-yl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-(3-decanoylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-[6-fluoro-3-(3-naphthalen-2-yl-acryloylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{3-[2-(4-tert-butyl-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-(3-benzyloxycarbonylamino-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-benzyloxycarbonylamino-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-[6-fluoro-3-(3-pyridin-3-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-[3-(3-benzyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(3-methyl-butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(3-phenyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(3-cyclopentyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-[3-(2-thiophen-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-(3-butyrylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-(3-benzyloxycarbonylamino-8-chloro-5-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-benzyloxycarbonylamino-8-chloro-5-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-heptanoylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-[3-(3-cyclopentyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-(3-decanoylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-(3-benzoylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-[3-(3-butyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-fluoro-3-[(1H-indole-2-carbonyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-[3-(3-methyl-butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; and
(3S)-[3-(3-butyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid.

(3R)-[3-(3-Benzyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(3-Benzyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[6-Fluoro-3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-[3-(3-Benzyl-ureido)-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(3-Benzyl-ureido)-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-[8-Chloro-6-fluoro-3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[8-Chloro-6-fluoro-3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-(3-Benzyloxycarbonylamino-6-trifluoromethyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-Benzyloxycarbonylamino-6-trifluoromethyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-(3-Benzyloxycarbonylamino-8-bromo-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-Benzyloxycarbonylamino-8-bromo-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-(3-Benzyloxycarbonylamino-6-fluoro-8-vinyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-Benzyloxycarbonylamino-6-fluoro-8-vinyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-(3-Benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-Benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-Benzyloxycarbonylamino-6-fluoro-8-methyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-Benzyloxycarbonylamino-7-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(8-Allyl-3-benzyloxycarbonylamino-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3R)-(3-Benzyloxycarbonylamino-8-chloro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{3-[3-(2,4-Dimethoxy-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[6-Fluoro-3-(3-naphthalen-1-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-{6-Fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{6-Fluoro-3-[3-(2-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(2-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{6-Fluoro-3-[3-(3-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(3-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)- {6-Fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{6-Fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{6-Fluoro-3-[2-(2-methylphenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[2-(2-methylphenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(2,5-Dimethoxy-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(4-trifluoromethyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(2,6-Dichloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(2,5-Bis-trifluoromethyl-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(4-methylsulfanyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(4-iodo-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(4-isopropyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(3-trifluoromethyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(2,4-Dichloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(4-fluoro-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(3,5-Bis-trifluoromethyl-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl }-acetic acid;
(3S)-{3-[3-(4-Ethyl-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(3-iodo-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(4-methanesulfonyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(2,3-Dimethoxy-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(2-Bromo-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(3-trifluoromethoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(2,4-Dimethyl-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(3-Bromo-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-(3-tert-Butoxycarbonylamino-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[(S)-3-(4-fluoro-phenyl)-2-phenyl-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[(S)-3-(4-methoxy-phenyl)-2-phenyl-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[3-(2-fluoro-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(6-Fluoro-3-{[(2RS)-1,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{[(2RS)-8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{(2RS)-2-[(4-fluoro-phenylcarbamoyl)-methyl]-3-phenyl-propionylamino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{3-[(2RS)-2-Benzyl-3,3-dimethyl-butyrylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(6-Fluoro-3-{[(2RS)-8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{6-Fluoro-3-[3-(3-fluoro-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(6-Fluoro-3-{[(2RS)-8-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{6-Fluoro-3-[(2R)-2-methyl-3-phenyl-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(2,2-Dimethyl-3-phenyl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[6-Fluoro-3-(3-methyl-3-phenyl-butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-Fluoro-3-[(3S)-3-phenyl-butyrylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(2-Benzyloxy-acetylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid:
(3S)-[6-Fluoro-3-(4-phenyl-butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{3-[(2R,3R)-2,3-Dihydroxy-3-(2-methoxy-phenylcarbamoyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{8-Chloro-6-fluoro-3-[3-(2-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-6-fluoro-3-[3-(2-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{8-Chloro-6-fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Clhloro-6-fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{8-Chloro-6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}acetic acid;
(3S)-{8-Chloro-6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{8-Chloro-6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)- {8-Chloro-6-fluoro-3-[3-(3-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-6-fluoro-3-[3-(3-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{8-Chloro-6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-[8-Chloro-6-fluoro-3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[8-Chloro-6-fluoro-3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-{8-Chloro-6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{8-Chloro-3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-[8-Chloro-6-fluoro-3-(3-1H-indol-3-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[8-Chloro-6-fluoro-3-(3-1H-indol-3-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-{8-Chloro-3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{8-Chloro-6-fluoro-3-[2-(2-methylphenyl)-oxy-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-6-fluoro-3-[2-(2-methylphenyl)-oxy-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-[3-(3-Benzo[1,3]dioxol-5-yl-propionylamino)-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(3-Benzo[1,3]dioxol-5-yl-propionylamino)-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3R)-{8-Chloro-6-fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-6-fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{8-Chloro-3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-{8-Chloro-3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{8-Chloro-3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3R)-[8-Chloro-6-fluoro-3-(2-indan-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[8-Chloro-6-fluoro-3-(2-indan-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[6-Fluoro-3-(1-methyl-3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{3-[3-(2-Chloro-benzyl)-1-methyl-ureido]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(3-Benzyl-1-methyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(Benzyloxycarbonyl-methyl-amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
{(3S)-3-[(2-Chloro-benzyloxycarbonyl)-methyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(6-Fluoro-3-{[2-(4-methoxy-phenyl)-acetyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{methyl-[2-(4-methylphenyl)-acetyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{[2-(2-methoxy-phenyl)-acetyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{6-Fluoro-3-[(2-indan-2-yl-acetyl)-methyl-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(3-{[2-(3-Chloro-phenyl)-acetyl]-methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{methyl-[2-(3-methylphenyl)-acetyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{[2-(3-methoxy-phenyl)-acetyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-{[2-(2-Chloro-phenoxy)-acetyl]-methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-{[2-(4-Chloro-phenoxy)-acetyl]-methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{[3-(3-methoxy-phenyl)-propionyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{methyl-[2-(2-methylphenyl)-acetyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{3-[(3,3-Diphenyl-propionyl)-methyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{6-Fluoro-3-[(3-1H-indol-3-yl-propionyl)-methyl-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[(2-Benzyloxy-acetyl)-methyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[(2,3-Diphenyl-propionyl)-methyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[[3-(2-methoxy-phenyl)-propionyl]-(3-phenyl-propyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl} -acetic acid;
(3S)-{3-[Acetyl-(3-phenyl-propyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-Benzyl-(1-cyclopropylmethyl)-ureido]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(Benzyloxycarbonyl-cyclopropylmethyl-amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{3-[Cyclopropylmethyl-(3-phenyl-propionyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[Cyclopropylmethyl-((S)-2-methyl-3-phenyl-propionyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(3-{Cyclopropylmethyl-[3-(2-methoxy-phenyl)-propionyl]-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-{[2-(3-Chloro-phenoxy)-acetyl]-cyclopropylmethyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{3-[Cyclopropylmethyl-(3,3-diphenyl-propionyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[Cyclopropylmethyl-(2-naphthalen-1-yl-acetyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(3-{Benzyloxycarbonyl-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-{Acetyl-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{propionyl-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{(3-phenyl-propionyl)-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{6-Fluoro-3-[(2-phenoxy-ethyl)-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[((S)-2-methyl-3-phenyl-propionyl)-(2-phenoxy-ethyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[[3-(2-methoxy-phenyl)-propionyl]-(2-phenoxy-ethyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[Acetyl-(2-phenoxy-ethyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[3-Benzyl-1-(2-methoxy-ethyl)-ureido]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[Benzyloxycarbonyl-(2-methoxy-ethyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[(2-methoxy-ethyl)-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[(2-methoxy-ethyl)-((S)-2-methyl-3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl} -acetic acid;
(3S)-(6-Fluoro-3-{(2-methoxy-ethyl)-[3-(2-methoxy-phenyl)-propionyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{3-[[2-(3-Chloro-phenoxy)-acetyl]-(2-methoxy-ethyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[(3,3-Diphenyl-propionyl)-(2-methoxy-ethyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[(2-methoxy-ethyl)-(2-naphthalen-1-yl-acetyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(6-Fluoro-3-{[(2S)-2-methyl-3-phenyl-propionyl]-phenethyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-phenethyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-[3-(Acetyl-phenethyl-amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-Fluoro-3-[(2-naphthalen-1-yl-acetyl)-phenethyl-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[phenethyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(3-Benzyl-1-naphthalen-1-ylmethyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(Benzyloxycarbonyl-naphthalen-1-ylmethyl-amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-Fluoro-3-[naphthalen-1-ylmethyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{6-Fluoro-3-[((S)-2-methyl-3-phenyl-propionyl)-naphthalen-1-ylmethyl-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-naphthalen-1-ylmethyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-{3-[(3,3-Diphenyl-propionyl)-naphthalen-1-ylmethyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(Acetyl-naphthalen-1-ylmethyl-amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[6-Fluoro-3-(naphthalen-1-ylmethyl-propionyl-amino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{3-[(RS)-2-Benzyl-3-(2-methylphenyl)-carbamoyl-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl} -acetic acid;
(3S)-{3-[(RS)-2-Benzyl-3-(3-methoxy-phenylcarbamoyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[(RS)-2-Benzyl-3-(4-chloro-phenylcarbamoyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-{3-[(RS)-2-Benzyl-3-(4-fluoro-benzylcarbamoyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl} -acetic acid;
[(3S)-3-((RS)-2-Benzyl-3-propylcarbamoyl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[6-Fluoro-3-(3-thiophen-2-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{3-[3-(3-Chloro-isoxazol-5-yl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[6-Fluoro-3-(3-pyrimidin-2-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-{6-Fluoro-3-[3-phenyl-4-([1,3,4]thiadiazol-2-ylcarbamoyl)-butyrylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(3S)-[3-(1,3-Dibenzyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-(3-{Acetyl-[2-(2-fluoro-phenyl)-ethyl]-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-(3-{Acetyl-[2-(3-fluoro-phenyl)-ethyl]-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)-[3-(3-Benzyl-1-cyclohexylmethyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; and
(3S)-(3-{Cyclohexylmethyl-[3-(2-methoxy-phenyl)-propionyl]-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid.

Unless explicitly stated otherwise, the general terms and names used hereinbefore and hereinafter preferably have within the context of this disclosure the following meanings:

Where the plural form is used for compounds, salts, pharmaceutical compositions, diseases and the like, this is intended to mean also a single compound, salt, or the like.

Any reference to a compound of Formula I is to be understood as referring also to salts (especially pharmaceutically acceptable salts) of a compound of Formula I, as appropriate and expedient.

The term "pharmaceutically acceptable salts" refers to non-toxic, inorganic or organic acid and/or base addition salts. Reference can be made to "Salt selection for basic drugs", Int. J. Pharm. (1986), 33, 201-217.

The term "bridging group" or "bridging atom" as used herein means a group or atom that is placed between two distinct moieties of the molecule. Examples for such bridging groups are the bridging C_1-6-alkyl group in an aryl-C_1-6-alkylcarbonyl group which is placed between the aryl and the carbonyl moiety; the bridging C_1-4-alkyl group in an aryl-C_1-4-alkyl group, which is placed between the aryl moiety and the parent molecular moiety; or the bridging C_1-4-alkyl group in an R⁷-C_1-4-alkylcarbonyl group which is placed between the R⁷-group and the carbonyl moiety. An example for such bridging atoms is the bridging carbon atom of a methylene (-CH₂-) group in a benzyloxy or benzylamino group, which is placed between the phenyl ring and the oxygen atom, or the phenyl ring and the nitrogen atom, respectively.

The term "alkyl" as used herein, alone or in any combination, refers to a saturated aliphatic group including a straight or branched hydrocarbon chain containing the indicated number of carbon atoms, for example C_1-9-alkyl, i.e. an alkyl having 1-9 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, iso-butyl (or also referred to as "2-methylpropyl"), n-pentyl (also referred to as "n-amyl"), iso-pentyl (also referred to as "iso-amyl"), n-hexyl, n-heptyl, and n-octyl. Preferred are methyl, ethyl, n-propyl, iso-propyl, n-butyl, and iso-butyl. Most preferred are methyl, ethyl, n-propyl, and iso-propyl.

A bridging C_1-6-alkyl group as used in "aryl-C_1-6-alkylcarbonyl" as defined for R⁶ preferably means a C_2-4-alkyl group, whereby the aryl moiety and the carbonyl moiety are preferably attached to two different carbon atoms of the bridging C_2-4-alkyl group. Preferred examples of bridging C_1-6-alkyl groups as used in R⁶ being aryl-C_1-6-alkylcarbonyl are ethane-1,2-diyl, propane-1,2-diyl, propane-1,3-diyl, and 2-methyl-propane-1,2-diyl. In another embodiment a bridging C_1-6-alkyl group as used in "aryl-C_1-6-alkylcarbonyl" as defined for R⁶ means the respective C_1-6-alkyl group, whereby the aryl moiety and the carbonyl moiety preferably are attached to the same carbon atom of the bridging C_1-6-alkyl group. Examples of such bridging C_1-6-alkyl groups as used in R⁶ being aryl-C_1-6-alkylcarbonyl are a methylene group (preferred) and ethane-1,1-diyl. A bridging C_1-3-alkyl group as used in "diaryl-C_1-3-alkylcarbonyl" as defined for R⁶ preferably means a C_2-3-alkyl group, whereby the carbonyl moiety and at least one of the aryl groups are preferably attached to two different carbon atoms of the bridging C_2-3-alkyl group. Preferred examples of such bridging C_1-3-alkyl groups as used in R⁶ being diaryl-C_1-3-alkylcarbonyl are ethane-1,2,2-triyl, and ethane-1,1,2-triyl. A bridging C_1-4-alkyl group as used in "R⁷-C_1-4-alkylcarbonyl, wherein the bridging C_1-4-alkyl group may additionally be mono-substituted with aryl" as defined for R⁶ preferably means a C_2-4-alkyl group (particularly, if the additional aryl substituent is present, it means propane-1,2,3-triyl) whereby the group R⁷, the carbonyl moiety. and the aryl substituent (if present) preferably are attached to two (three, if the additional aryl substituent is present) different carbon atoms of the bridging C_2-4-alkyl group. Examples of bridging C_1-4-alkyl groups as used in R⁶ being "R⁷-C_1-4-alkylcarbonyl, wherein the bridging C_1-4-alkyl group may additionally be mono-substituted with aryl" are ethane-1,2-diyl, propane-1,2-diyl, propane-1,3-diyl, 2-phenyl-propane-1,3-diyl, and 1-phenyl-propane-2,3-diyl; preferred are 2-phenyl-propane-1,3-diyl, and 1-phenyl-propane-2,3-diyl, especially 1-phenyl-propane-2,3-diyl. An example of a bridging C_1-4-alkyl group as used in R⁶ being "R⁷-C_1-4-alkylcarbonyl, wherein the bridging C_1-4-alkyl group may additionally be disubstituted with hydroxy" is 1,2-dihydroxyethane-1,2-diyl.

The term "alkenyl" as used herein, alone or in any combination, refers to a straight or branched hydrocarbon chain containing 2-7, preferably 2-4, carbon atoms with at least one carbon-carbon double bond (R_aR_bC=CR_cR_d). R_a-R_d refer to substituents, each individually and independently selected from hydrogen and alkyl. Representative examples of alkenyl include, but are not limited to, ethenyl (also referred to as "vinyl"), 2-propenyl (also referred to as "allyl"), 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl, especially ethenyl or 2-propenyl.

The term "C_1-2-alkylendioxy" as used herein, alone or in any combination, refers to an -O(CH₂)_nO- group, wherein n is 1 or 2, and wherein the oxygen atoms are attached to two adjacent carbon atoms of the parent molecular moiety, preferably the two adjacent carbon atoms of a phenyl ring.

The term "alkoxy" as used herein, alone or in any combination, refers to an alkyl group attached to the parent molecular moiety through an oxygen bridge. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexyloxy, especially methoxy.

The term "alkoxycarbonyl", as used herein, alone or in any combination, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and iso-butoxycarbonyl, especially methoxy. R⁶ representing alkoxycarbonyl preferably means n-propoxycarbonyl, and iso-butoxycarbonyl. The term "alkylcarbonyl" as used herein, alone or in any combination, refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Representative examples of alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, I -oxobutyl, and 1-oxopentyl. Further examples are 1-oxo-2-methyl-butyl, and 3,3-dimethyl-1-oxopropyl. Preferred are acetyl, 1-oxopropyl, 1-oxobutyl, 1-oxo-2-methylbutyl, and 3,3-dimethyl-1-oxopropyl.

The term "alkylsulfonyl", as used herein, alone or in any combination, refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group. Representative examples of alkylsulfonyl include, but are not limited to, methanesulfonyl and ethanesulfonyl, preferably methanesulfonyl.

The term "aminocarbonyl" (also referred to as "carbamoyl") as used herein, alone or in any combination, refers to an amino group attached to the parent molecular moiety through a carbonyl group.

The term "aryl" or "aryl group", as used herein, alone or in any combination, refers to an aromatic carbocyclic group from 6 to 14 carbon atoms having a single ring or multiple condensed rings, and preferably refers to a phenyl or naphthyl, very preferably to a phenyl group. An aryl group is preferably unsubstituted. In another embodiment the aryl group may be substituted as specifically described in the embodiments of the present invention. If an aryl group is mono- or di-substituted, preferred but not limiting examples are 4-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 2,5-bis-trifluoromethyl-phenyl, 3,5-bis-trifluoromethyl-phenyl, 3-trifluoromethoxy-phenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2,4-dichlorophenyl, 4-methylphenyl, 3-methylphenyl, 2-methylphenyl, 2,4-dimethylphenyl, 4-ethylphenyl, 4-isopropylphenyl, 4-tert.-butylphenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 3,4-difluorophenyl, 4-iodophenyl, 3-bromophenyl, 2-bromophenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 2,3-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 2-hydroxyphenyl, 4-methylthio-phenyl, 4-methanesulfonyl-phenyl, and 3-tert.-butoxycarbonylamino-phenyl.

The term "arylalkenyl", as used herein, alone or in any combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group. Representative examples of arylalkenyl include, but are not limited to, 2-phenylethenyl, 3-phenylpropen-2-yl, and 2-naphth-2-ylethenyl.

The term "aryloxy", as used herein, alone or in any combination, refers to an aryl group attached to the parent molecular moiety through an oxygen bridge.

The term "arylsulfonyl", as used herein, alone or in any combination, refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.

The term "carbonyl", as used herein, alone or in any combination, refers to a -C(O)- group.

The term "thiocarbonyl", as used herein, alone or in any combination, refers to a -C(S)-group.

The term "carboxy", as used herein, alone or in any combination, refers to a -CO₂H group.

The term "cyano", as used herein, alone or in any combination, refers to a -C≡N group.

The term "cycloalkyl", as used herein, alone or in any combination, refers to a saturated cyclic hydrocarbon moiety containing 3-10 carbon atoms (for example C_3-6-cycloalkyl means a cycloalkyl having 3 to 6 carbon atoms), preferably a cyclopentyl or cyclohexyl radical, whereby said radicals, especially the cyclopentyl radical, may be substituted with an annellated benzene ring. In another embodiment said benzene ring may be mono-, or di-substituted, wherein the substituent(s) are independently selected from C_1-4-alkyl, C_1-4-alkoxy, and halogen (especially C_1-4-alkoxy). In case the cycloalkyl group is used as a bridging group as for example in an "aryl-C_3-6-cycloalkylcarbonyl" group as defined for R⁶, it is preferably a cyclopropane-diyl, cyclopentane-diyl or cyclohexane-diyl radical (especially cyclopropane-1,2-diyl) said radical being preferably unsubstituted.

The term "formyl", as used herein, alone or in any combination, refers to a -C(O)H group.

The term "halo" or "halogen", as used herein, alone or in any combination, refers to fluorine, bromine, chlorine, or iodine, and unless specifically indicated otherwise, it refers to especially fluorine or chlorine.

The term "haloalkyl", as used herein, alone or in any combination, refers to an alkyl group having at least one hydrogen atom replaced with a halogen atom. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl, preferably trifluoromethyl.

The term "haloalkoxy", as used herein, alone or in any combination, refers to an alkoxy group having at least one hydrogen atom replaced with a halogen atom. Representative examples of haloalkoxy include, but are not limited to, chloromethoxy, 2-fluoroethoxy, trifluoromethoxy, and pentafluoroethoxy, preferably trifluoromethoxy.

The term "heterocyclyl", as used herein, alone or in any combination, refers to a monocyclic, bicyclic or polycyclic non-aromatic ring system containing up to 15 ring atoms (preferably 5 to 10 ring atoms), at least one of these being a heteroatom, preferably one to three heteroatoms, independently selected from nitrogen, oxygen or sulfur, preferably nitrogen. This ring system may be saturated, partially saturated, or unsaturated, and preferably contains one or two ring heteroatoms selected from nitrogen. Representative examples of heterocyclyl include, but are not limited to, dihydroindolyl (especially dihydroindol-2-yl) and chromane (especially chroman-3-yl).

The term "heteroaryl", as used herein, alone or in any combination, has the meaning as defined for heterocyclyl above, with the difference that the ring system is aromatic.

The term "heteroarylalkyl", as used herein, alone or in any combination, refers to a heteroaryl group attached to the parent molecular moiety through an alkyl group. Representative examples of heteroarylalkyl include, but are not limited to, thienylalkyl (especially thien-2-ylalkyl), isoxazolylalkyl (especially 3-chloro-isoxazole-5-ylalkyl), pyridylalkyl (especially pyridine-3-ylalkyl), pyrimidylalkyl (especially pyrimidine-2-ylalkyl), indolylalkyl (especially indol-3-ylalkyl), and benzoimidazolylalkyl (especially benzoimidazol-2-ylalkyl).

The term "heteroarylcarbonyl", as used herein, alone or in any combination, refers to a heteroaryl group attached to the parent molecular moiety through a carbonyl group. A representative example of heteroarylcarbonyl includes, but is not limited to, indolylcarbonyl (especially indol-2-ylcarbonyl).

The term "heteroarylamino", as used herein, alone or in any combination, refers to a heteroaryl group attached to the parent molecular moiety through an amino group. A representative example of heteroarylamino includes, thiadiazolylamino (especially 1,3,4-thiadiazol-2-yl-amino).

The term "heterocyclylcarbonyl", as used herein, alone or in any combination, refers to a heterocyclyl group attached to the parent molecular moiety through a carbonyl group. A representative example of heterocyclylcarbonyl includes, dihydroindolylcarbonyl (especially dihydroindol-2-ylcarbonyl) and chromanecarbonyl (especially chroman-3-ylcarbonyl).

The term "hydroxy" or "hydroxyl" as used herein, alone or in any combination, refers to an -OH group

The term "nitro", as used herein, alone or in any combination, refers to a -NO₂ group.

The term "oxo", as used herein, alone or in any combination, refers to an =O group.

The term "oxy", as used herein, alone or in any combination, refers to an -O- group.

The terms "sulfonyl", as used herein, alone or in any combination, refer to an -S(O)₂- group.

The term "acyl" as used herein refers to groups containing a carbonyl group that is linked to a carbon atom such as C_1-9-alkylcarbonyl, arylalkenylcarbonyl, aryl-C_1-6-alkylcarbonyl, aryl-C_1-3-alkoxy-C_1-3-alkylcarbonyl, arylcarbonyl, arylcarbonyl-C_1-4-alkylcarbonyl, aryloxy-C_1-3-alkylcarbonyl, cycloalkyl-C_1-3-alkylcarbonyl, diaryl-C_1-3-alkylcarbonyl, heterocyclylcarbonyl, heteroaryl-C_1-3-alkylcarbonyl, heteroarylcarbonyl, aryl-C_3-6-cycloalkylcarbonyl, cycloalkylcarbonyl, or R⁷-C_1-4-alkylcarbonyl groups as used in R⁶ of Formula I. In analogy, the term "acylamino" as used herein refers to an acyl group as described before that is linked to the parent molecular moiety through a nitrogen atom. The term "ureido" as used herein refers to groups such as C_1-9-alkylaminocarbonyl, arylaminocarbonyl, or aryl-C_1-3-alkylaminocarbonyl that are linked to the parent molecular moiety through a nitrogen atom. The term "oxycarbonylamino" as used herein refers to groups such as C_1-9-alkoxycarbonyl, aryl-C_1-3-alkoxycarbonyl, or aryl-C_1-3-alkoxy-C_1-3-alkoxycarbonyl that are linked to the parent molecular moiety through a nitrogen atom.

The compounds of Formula I may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond or a ring may be present in cis- (= Z-) or trans (= E-) form unless indicated otherwise. The compounds of Formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.

The compounds of the present invention have useful, in particular pharmacologically useful, properties. They bind to the CRTH2 receptor and thus modulate the effects of endogenous PGD₂. The compounds according to Formula I may be used for the preparation of a medicament, and are suitable, for the prevention and/or treatment of diseases selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising allergic asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases comprising Churg-Strauss syndrome and sinusitis, and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis, in humans and other mammals.

A compound of Formula I or a pharmaceutical composition comprising a compound of Formula I may be used for the preparation of a medicament, and is suitable, for the prevention and/or treatment of diseases selected from the group consisting of both chronic and acute allergic/immune diseases/disorders such as those mentioned in the paragraph before, such as especially allergic asthma, rhinitis, allergic rhinitis, COPD, dermatitis, inflammatory bowel disease, and rheumatoid arthritis.

In another aspect, the compounds of Formula I may be used as standard or reference compounds in tests or assays involving the modulation of the CRTH2 receptor. Such compounds could be made commercially available for use as a reference, quality standard or control, for example in pharmaceutical research when developing new assays or protocols related to CRTH2 receptor activity.

As mentioned earlier, compounds of Formula I modulate the PGD₂ activation of the CRTH2 receptor. The biological effect of such compounds may be tested in a variety of in vitro, ex vivo and in vivo assays. The ability of the compounds of Formula I to bind to the CRTH2 receptor may be measured by methods similar to those described in the literature (Arimura A. et al., J. Pharmacol. Exp. Ther. 2001, 298(2), 411-419; and Sawyer N. et al., Br. J. Pharmacol, 2002, 137, 1163-1172, respectively) and by the assays described below in the experimental part.

A functional assay with cells expressing the human CRTH2 (hCRTH2) receptor may be used to detect changes in the levels of intracellular calcium concentration following compound treatment. After addition of the compound, the cells are challenged with PGD₂. In a Fluorescent Imaging Plate Reader (FLIPR^™, Molecular Devices, Sunnyvale, California), fluorescence emission is recorded during both additions, emission peak values above base level after PGD₂ addition are exported, and normalized to low controls (no PGD₂) and high controls (no active compound). The relative values of the remaining activity are used to determine IC₅₀ values by curve fitting the data to a single site to a four-parameter logistic sigmoid dose response curve of the equation (A+((B-A)/(1+((C/x)^D)))).

The ability of the compounds to modulate PGD₂ induced changes of intracellular calcium levels via CRTH2 receptor activation may be measured by methods known to one skilled in the art or by the assay described below in the experimental part.

The present invention relates also to pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; to the use of such pharmaceutical compositions for the therapeutic, in a broader aspect of the invention also prophylactic, treatment of the diseases/disorders mentioned herein; to the compounds of Formula I, or pharmaceutically acceptable salts thereof, for use as a medicament; and to the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the prevention and/or treatment of the diseases/disorders mentioned herein.

The pharmaceutical compositions according to the invention are those for enteral administration, such as nasal, buccal, rectal, dermal or, especially oral administration, and for parenteral administration, such as intramuscular, intravenous or subcutaneous, intrasternal, intravitreal, injection or infusion, to warm-blooded animals, especially humans. Such compositions comprise an effective dose of the pharmaceutically active ingredient, alone or together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual conditions, individual pharmacokinetic data, the disease/disorder to be treated and the mode of administration.

The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of Formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

In one embodiment, the invention also relates to a method for the prevention or treatment of diseases/disorders that respond to an inhibition of the CRTH2 receptor in particular to a method for the prevention or treatment of the diseases/disorders mentioned herein, said methods comprising administering to a patient a pharmaceutically active amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

A further aspect of the invention is a process for the preparation of compounds of Formula I. Compounds according to Formula I of the present invention can be prepared according to the sequence of reactions outlined in the schemes below wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined for Formula I. Other abbreviations used are defined in the experimental section. In some instances the generic groups R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ might be incompatible with the assembly illustrated in the schemes below and, therefore, will require the use of protecting groups (PG). For example it may be necessary to protect reactive functional groups such as hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. The use of protecting groups is well known in the art (see for example "Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-Interscience, 1999). It will be assumed that such protecting groups are as necessary in place. In the following description, for example, PG, when used as amino-protecting group, preferably refers to a group such as tert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl, most preferably tert-butoxycarbonyl. Further, L refers to a leaving group, such as activated (for examples as mesylate, active ester etc.) or non-activated hydroxy, or halo, in particular chloro or bromo. Further, R and R' independently refer to a C_1-4-alkyl group, preferably ethyl or tert-butyl, whereby when R' is present R is preferably ethyl and R' is preferably tert.-butyl.

In general, all chemical transformations can be performed according to well-known standard methodologies as described in the literature, for example those described by Larock R. C. in "Comprehensive organic transformations: a guide to functional group preparations", VCH publishers, 1999, or as described in the procedures below. The compounds obtained may also be converted into pharmaceutically acceptable salts thereof in a manner known per se.

Generally, compounds of Formula I are obtained from an ester of Structure 1, wherein R represents C_1-4-alkyl, preferably ethyl, or tert-butyl, by hydrolysis of the ester group using routine procedures, for example stirring an intermediate of Structure 1 with aq. lithium, sodium or potassium hydroxide in an organic co-solvent such as an alcohol, like MeOH or EtOH; THF; acetone; MeCN; or TFA, respectively.

An intermediate of Structure 1 is obtained by reacting an intermediate of Structure 2a or 2b, or a salt thereof, such as the hydrochloride salt, with a reagent of Formula L-R⁶, wherein R⁶ is as defined for Formula I and L is a leaving group as defined before. R⁶ transferring reagent of Structure L-R⁶ may be a chloroformate; or an acyl halide, preferably an acid chloride, or acid bromide, used as such; or generated in situ from the corresponding commercially available or well known carboxylic acid with an activating reagent, such as a halogenating reagent under conditions known to a skilled person, preferably by means of oxalyl chloride or phosphorous oxychloride; or an acyl anhydride, transferring R⁶ in the presence of a base, such as Et₃N, DIEA, N-ethyl-morpholine, N-methylpiperidine, or pyridine, in a suitable solvent, such as THF, or DCM.

In another aspect, an intermediate of Structure 2a or 2b is condensed with a commercially available or well known carboxylic acid in the presence of a coupling reagent, such as DCC, diisopropylcarbodiimide, HATU and the like, in the presence of a base described hereinabove, to form an intermediate of Structure 1.

In a further aspect, an intermediate of Structure 2a or 2b is reacted with a commercially available isocyanate or isothiocyanate in the presence of a base to form an intermediate of Structure 1.

In a specific case, intermediates of Structure 1, wherein R⁴ represents an C_1-5-alkyl, allyl, vinyl, or a methanesulfonyl group, is obtained by reacting intermediates of Structure 2c wherein R⁴ represents halogen, preferably I or Br, or a methanesulfonyloxy, or a toluenesulfonyloxy group, with reagents such as tetramethyltin, allyltributyltin, a complex of vinylboronic anhydride and pyridine together with a base, such as K₂CO₃, in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(O), or the like, or sodium methanesulfinate in the presence of copper (I) iodide, respectively, in a polar aprotic solvent such as DMF, or DME, or NMP, at a temperature between 60°C and 130°C.

A substituent R⁵ in an intermediate of Structure 2a is obtained by reacting an intermediate of Structure 2b with the respective aldehyde in a solvent such as DCM or the like in presence of a reducing agent, such as sodium triacetoxyborohydride, and a base, such as DIEA.

Alternatively, an intermediate of Structure 2a, wherein R⁵ is not hydrogen, is obtained from an intermediate of Structure 2b via a sulfonamide of Structure 3a. First, an intermediate of Structure 2b is reacted with p-nitrobenzenesulfonyl chloride in a solvent such as DCM, THF or another suitable organic solvent, in the presence of a base, such as DIEA, with or without a catalytic amount of N,N-dimethyl-aminopyridine, to afford the desired sulfonamide of Structure 3a. In a second step, in order to afford a sulfonamide of Structure 3b, the sulfonamide of Structure 3a is easily alkylated with the respective commercially available or well known alkylating agent R⁵-L, with K₂CO₃ or any other suitable base, in an organic solvent, such as toluene, preferably in the presence of a phase transfer agent, such as tetrabutylammonium bromide in accordance to a procedure described in the literature (C. Peña et al., Tetrahedron Lett. 2005, 46, 2783-2787). Specifically, a methyl group is introduced by reaction of a sulfonamide of Structure 3a either with methyl iodide or with diazomethane dissolved in diethylether. Subsequently, the sulfonamide of Structure 3b is treated in a typical procedure according to S.C. Miller and coworker (J. Am. Chem. Soc. 1997, 119, 2301-2302) with a thiol, such as thiophenol, or thioacetic acid, in the presence of a base, such as DBU or the like, in a suitable organic solvent, such as DMF, to remove the sulfonamido group, furnishing an intermediate of Structure 2a.

An intermediate of Structure 2b is obtained after removal of the protective group (PG) from an intermediate of Structure 2c, applying reaction conditions known to a skilled person. Preferably, the PG is a group such as tert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl, most preferably tert-butoxycarbonyl.

An intermediate of Structure 2c is generated by reacting an intermediate of Structure 4 with a compound of Formula L-CH₂CO₂R wherein R and L are as defined before, in the presence of a base, such as cesium carbonate, sodium hydride, potassium tert-butanolate or the like, in a suitable solvent, such as acetone, MeCN, THF or dioxane. Suitable L is a leaving group such as halo, in particular bromo or chloro; mesyloxy or tosyloxy. Preferably, the compound of Formula L-CH₂CO₂R is ethyl bromoacetate.

An intermediate of Structure 4, with PG as described hereinabove, is obtained in a Fischer-type indole synthesis according to the literature (J. D. Ha et al., Bulletin of the Korean Soc. Chem. 2004, 25, 1784-1790): reaction of a commercially available or well known hydrazine of Structure 5 (either as a free base or as a salt) and a cyclohexanone of Structure 6, which is commercially available or whose synthesis is as described in the above mentioned literature, furnishes the desired intermediate of Structure 4 as a racemate.

In another aspect, an intermediate of Structure 4 is obtained through protection of the amino group in a tetrahydrocarbazol-3-ylamine of Structure 7 with a hereinabove described PG applying methods known to a skilled person.

Both, the (R)- and the (S)-enantiomer of starting tetrahydrocarbazol-3-ylamine of Structure 7 arc obtained in a stereospecific reaction following a procedure described in literature (Rosentreter U. et al., Arzneim.-Forsch. 1989, 39(12), 1519-1521; and EP 0242518 ).

A synthesis of racemic ethyl (3RS)-(3-amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate hydrochloride is described in the literature (Ulven, T.; Kostenis, E. J. Med. Chem. 2005, 48, 897-900).

A stereoselective synthesis of methyl (3R)-(3-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate is described in WO 03/097598 .

In a particular case, a compound of Structure 1, wherein R⁶ represents "R⁷-C_1-4-alkylcarbonyl, wherein the bridging C_1-4-alkyl group may additionally be mono-substituted with aryl, and R⁷ represents arylaminocarbonyl, heteroarylaminocarbonyl, C_1-6-alkylaminocarbonyl, or aryl-C_1-3-alkylaminocarbonyl", is obtained by reaction of the respective compound of Structure 8a with the respective amine, in the presence of a coupling reagent, such as DCC, diisopropylcarbodiimide, HATU or the like, in the presence Et₃N, DIEA, or the like, in a solvent such as DCM or DMF.

A compound of Structure 8a wherein the bridging C_1-4-alkyl group may additionally be mono-substituted with aryl is obtained by treating a respective compound of Structure 8b, wherein R' represents C_1-4-alkyl, preferentially tert-butyl, as a protecting group, with reaction with TFA in DCM or hydrochloric acid in an organic solvent, such as dioxane, diethylether, AcOEt, or the like, at room temperature.

A compound of Structure 8b, is obtained by reacting a compound of Structure 2a or 2b with the corresponding compound of Structure 9, wherein the bridging C_1-4-alkyl group may additionally be mono-substituted with aryl, which are commercially available or synthesized according to well known methods such as enolate alkylation (see for example: J. Org. Chem. 1986, 51(6), 938-940), in the presence of a coupling reagent, such as DCC, diisopropylcarbodiimide, HATU, or the like, in the presence of a base such as Et₃N, DIEA, or the like, in a solvent such as DCM or DMF.

Whenever the compounds of Formula I are obtained in the form of mixtures of enantiomers, the enantiomers can be separated using methods known to the one skilled in the art: e.g. by formation and separation of diastereomeric salts or by HPLC over a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 µm) column, a Daicel ChiralCel OD-H (5-10 µm) column, or a Daicel ChiralPak IA (10 µm) or AD-H (5 µm) column. Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as Et₃N, diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.

Experimental section: Abbreviations (as used herein):

AcOEt: Ethyl acetate
AcOH: Acetic acid
aq.: aqueous
Bdg: Binding
BSA: Bovine Serum Albumin
CC: Column chromatography on silica gel
DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCC: 1,3-Dicyclohexylcarbodiimide
DCM: Dichloromethane
DIEA: N,N-Diisopropylethylamine
DMAP: N,N-Dimethyl-4-aminopyridine
DME: Dimethoxyethane
DMF: Dimethylformamide
DMSO: Dimethylsulfoxide
EDTA: Ethylene Diamine Tetraacetic Acid
ESI-MS: Electrospray Ionization Mass Spectroscopy
Et3N: Triethylamine
FC: Flash chromatography on silica gel
h: hour(s)
HATU: O-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
HPLC: High Performance Liquid Chromatography
I: liter(s)
LC-MS: Liquid Chromatography - Mass Spectroscopy
Me: Methyl
MeCN: Acetonitrile
MeI: Methyl iodide
MeOH: Methanol
mesyl: Methanesulfonyl
Meth.: Method
min: minute(s)
MS: Mass Spectroscopy
MW: Molecular Weight
N: Normality of solution
NaBH(OAc)3: Sodium triacetoxyborohydride
NMP: N-Methylpyrrolidinone
org.: organic
PBS: Phosphate Buffered Saline
PG: Protecting Group
PGD2: Prostaglandin D2
PMSF: Phenylmethylsulfonyl fluoride
rt: room temperature
s: second(s)
sat.: saturated
subst.: substituted
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
tlc: thin layer chromatography
tosyl: Toluenesulfonyl
tR: retention time
Tris: Tris-(hydroxymethyl)aminomethane buffer

Chemistry General remarks

All solvents and reagents are used as obtained from commercial sources unless otherwise indicated.

Temperatures are indicated in degrees Celsius (°C). Unless otherwise indicated, the reactions take place at room temperature (rt).

In mixtures, relations of parts of solvent or eluent or reagent mixtures in liquid form are given as volume relations (v/v), unless indicated otherwise.

Analytical HPLC conditions as used in the Examples below:

HPLC/MS analyses are performed on a Waters 2795 Alliance HPLC instrument, equipped with a Waters 996 Photodiode Array Detector and a Micromass ZQ™ Waters mass spectrometer (electron spray ionization), detection at 200-400 nm (LC-1 and LC-2), or on a Agilent 1100 system, equipped with a Dionex P580 binary pump, a Dionex PDA-100 Photodiode Array Detector and a Finnigan AQA mass spectrometer (LC-3).

The LC retention times are obtained using the following elution conditions:

LC-1: Analytical HPLC on a Xterra™ MS C18 column (4.6x50 mm, 5 µm, Waters); Linear gradient of water/ 0.06% formic acid (A) and MeCN/ 0.06% formic acid (B) from 5% to 95% B over 1 min; flow rate 3 ml/min, detection at 215 nm.
LC-2: Analytical HPLC on a Zorbax® SB-AQ column (4.6x50 mm, 5µm, Agilent); Linear gradient of water/ 0.06% formic acid (A) and MeCN/ 0.06% formic acid (B) from 5% to 95% B over 1 min; flow rate 3 ml/min, detection at 215 nm.
LC-3: Analytical HPLC on a Zorbax® SB-AQ column (4.6x50 mm, 5µm, Agilent); Linear gradient of water/ 0.05% TFA (A) and MeCN (B) from 5% to 95% B over 1 min; flow rate 4.5 ml/min, detection at 215 nm.

Preparative HPLC/MS purifications are performed on a Waters HPLC system, equipped with a Waters 600 controller, a Waters 2767 sample manager, a Waters 996 Photodiode Array Detector, and a Micromass ZQTM Waters mass spectrometer (electron spray ionization), detection at 200-400 nm, using a Zorbax® PrepHT SB.Aq (5 µm, 21.2x50 mm) or a Phenomenex® Gemini column (10 µm, 21.2x50 mm), with a linear gradient of water/0.02% formic acid (A) and MeCN/ 0.02% formic acid (B) over 5 min; flow rate 4 ml/min, detection at 215 nm.

¹H NMR spectra are recorded either on a Varian Mercury 300VX FT-NMR spectrometer or on a Bruker Advance II 400 spectometer. Chemical shifts (δ) are reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for dimetylsulfoxide δ(H) 2.49 ppm, for chloroform δ(H) 7.24 ppm, and the abbreviations s, d, t, q, m and br refer to singlet, doublet, triplet, quartet, multiplet, and broad, respectively.

Synthesis of Compounds of Formula I:

The following examples illustrate the preparation of pharmacologically active compounds of the invention but do not at all limit the scope thereof. First the synthesis of Example compounds is described, followed by the description of the synthesis of intermediates and starting materials. Whenever used in the experimental part, generic Structures 1 to 9 refer to the Structures described in preceeding general description of the preparation of compounds of Formula I.

General method for saponification of intermediates of Structure 1:

Aq. 1N LiOH or 1N NaOH (1 ml, 1 mmol) is added to a stirred solution of the appropriate compound of Structure 1 (0.105 mmol) in THF (1 ml) and the resulting biphasic mixture is continued to stir overnight. DCM (2 ml) and AcOH (1 ml), or 2N HCl, are added to the reaction mixture. The aq. layer, obtained after phase separation, is extracted three times with DCM (1 ml). The combined org. phases are washed with brine and dried over Na₂SO₄ and the solvent is evaporated. Purification is performed by CC with a 1:1 mixture of AcOEt/heptane containing 1% AcOH, or by preparative HPLC to give the desired compound of Formula I in 6 to 98% yield.

Listed in Table 1 below are examples of compounds of Formula I, prepared according to the above-mentioned method with the corresponding compound of Structure 1 as starting material.


C19H25N303	1.01	344.08
343.426	LC-1
C22H23N303	1.15	378.04
377.443	LC-1
C23H25N303	1.32	392.05
391.47	LC-1
C25H23N303	1.7	413.97
413.476	LC-1
C21H21N305S	1.13
427.48	LC-1	449.90
C19H24N204	1.05
344.10	LC-1	367.07
C18H22N204	1.35	331.03
330.383	LC-1
C19H24N204	1.69	345.03
344.41	LC-1
C22H22N204	1.82
378.427	LC-1	400.96
C24H26N205	1.77
422.479	LC-1	444.94
C21H20N2O3	1.00	349.00
348.401	LC-2
C22H22N204	1.43	379.04
378.427	LC-1
C22H22N203	1.21	363.02
362.428	LC-1
C20H20N2O3S	1.11	368.96
368.456	LC-1
C23H24N203	1.36	377.04
376.455	LC-1
C23H24N204	1.44	392.98
392.454	LC-1
C19H24N203	0.97	329.08
328.411	LC-1
C22H28N203	1.77	369.07
368.475	LC-1
C24H34N203	2.77	399.10
398.545	LC-1
C19H25N303	0.98	344.18
343.426	LC-2
C22H23N303	0.99	378.18
377.443	LC-2
C23H25N303	1.01	392.17
391.47	LC-2
C21H21N3O5S	0.99	428.05
427.48	LC-2
C21H21N3O3	1.00	364.13
363.416	LC-2
C18H22N204	1.01	331.17
330.383	LC-2
C19H24N204	1.04	345.15
344.41	LC-2
C22H22N204	1.06	379.15
378.427	LC-2
C24H26N205	1.06	423.20
422.479	LC-2
C22H22N204	1.02	379.08
378.427	LC-2
C22H22N203	1.00	363.16
362.428	LC-2
C20H20N2O3S	0.99	369.11
368.456	LC-2
C23H24N203	1.02	377.08
376.455	LC-2
C23H24N204	1.03	393.14
392.454	LC-2
C19H24N2O3	0.97	329.16
323.411	LC-2
C22H28N203	1.01	369.18
368.475	LC-2
C24H34N203	1.16	398.82
398.545	LC-2
C18H22N203	0.94	315.18
314.384	LC-2
C21H28N203	1.06	357.20
356.464	LC-2
C22H21N204F	1.04	397.16
396.417	LC-2
C22H21N2O3F	1.01	381.16
380.418	LC-2
C23H23N203F	1.03	395.22
394.445	LC-2
C22H20N2O3ClF	1.05	415.16
414.863	LC-2
C23H23N204F	1.01	411.22
410.444	LC-2
C23H23N203F	1.04	395.22
394.445	LC-2
C22H19N2O3Cl2F	1.09	447.16
449.308	LC-2
C22H20N2O3ClF	1.06	415.16
414.863	LC-2
C23H20N2O3F4	1.08	449.17
448.415	LC-2
C22H20N2O4ClF	1.08	431.16
430.862	LC-2
C23H23N204F	1.08	411.22
410.444	LC-2
C22H20N2O4ClF	1.07	431.16
430.862	LC-2
C22H20N2O4ClF	1.08	431.16
430.862	LC-2
C24H25N204F	1.03	425.28
424.471	LC-2
C24H25N203F	1.06	409.21
408.472	LC-2
C23H22N2O3ClF	1.07	429.15
428.89	LC-2
C23H22N2O3ClF	1.07	429.15
428.89	LC-2
C23H22N2O3ClF	1.07	429.15
428.89	LC-2
C22H20N2O3ClF	1.05	415.23
414.863	LC-2
C23H23N204F	1.01	411.22
410.444	LC-2
C23H23N203F	1.01	395.15
394.445	LC-2
C22H21N204F	1.04	397.23
396.417	LC-2
C23H23N203F	1.03	395.22
394.445	LC-2
C22H20N2O4ClF	1.08	431.16
430.862	LC-2
C23H23N204F	1.07	411.22
410.444	LC-2
C24H25N204F	1.03	425.21
424.471	LC-2
C24H25N203F	1.06	409.21
408.472	LC-2
C23H22N2O3ClF	1.07	429.15
428.89	LC-2
C23H22N2O3ClF	1.07	429.15
428.89	LC-2
C23H22N2O3ClF	1.07	429.15
428.89	LC-2
C23H21N203F3	1.05	431.26
430.425	LC-2
C24H25N204F	1.03	425.21
424.471	LC-2
C24H25N204F	1.04	425.21
424.471	LC-2
C29H27N203F	1.12	471.27
470.542	LC-2
C29H27N203F	1.1	471.20
470.542	LC-2
C24H22N204BrF	1.07	503.06
501.351	LC-2
C24H23N204F	1.02	423.20
422.455	LC-2
C25H25N206FS	0.97	501.19
500.545	LC-2
C25H25N203F	1.07	421.19
420.483	LC-2
C24H25N205F	0.98	441.00
440.47	LC-2
C23H23N204F	0.97	411.02
410.444	LC-2
C23H23N204F	0.99	411.02
410.444	LC-2
C23H23N204F	1.02	411.02
410.444	LC-2
C23H22N303F	1.04	408.04
407.444	LC-2
C25H24N303F	1.04	434.07
433.482	LC-2
C24H23N403F	0.79	435.04
434.47	LC-2
C24H23N205F	1.04	438.99
438.454	LC-2
C23H20N3O3F	1.07	406.03
405.428	LC-2
C22H22N303F	0.7	396.11
395.433	LC-3
C26H29N203F	1.02	437.17
436.525	LC-3
C23H20N2O3F4	0.98	449.14
448.415	LC-3
C23H20N2O3F4	0.98	449.09
448.415	LC-3
C23H20N2O4F4	1.00	465.15
464.414	LC-3
C27H23N203F	1.01	443.07
442.489	LC-3
C27H25N203F	0.99	445.15
444.505	LC-3
C24H25N203F	0.98	409.16
408.472	LC-3
C23H22N2O3ClF	0.99	429.10
428.89	LC-3
C25H27N203F	0.99	423.10
422.498	LC-3
C24H24N2O3ClF	1.01	443.06
442.917	LC-3
C26H29N203F	1.02	437.20
436.525	LC-3
C25H26N2O3ClF	1.03	457.21
456.943	LC-3
C22H21 N204F	0.98	397.11
396.410	LC-3
C22H20N2O4ClF	1.01	431.05
430.862	LC-3
C22H20N2O4ClF	1.01	431.04
430.862	LC-3

Listed in Table 1a below are further compounds of Formula I, prepared according to the abovementioned general method with the corresponding compound of Structure 1 as starting material.


C22H22N303F	0.92	396.17
395.433	LC-3
C23H24N303F	0.92	410.52
409.46	LC-3
C22H21N3O3ClF	0.95	430.07
429.878	LC-3
C23H23N3O3ClF	0.97	444.07
443.905	LC-3
C23H21N204F3	1.02	447.25
446.424	LC-3
C22H20N2O4BrF	1.02	474.98
475.313	LC-3
C24H23N204F	1.01	423.15
422.455	LC-3
C23H23N206FS	0.95	475.15
474.508	LC-3
C23H23N204F	0.99	411.14
410.444	LC-3
C22H20N2O4ClF	1.01	431.16
430.862	LC-3
C25H25N204F	1.02	437.1
436.482	LC-3
C22H21N2O4Cl	1	413.03
412.872	LC-3
C25H27N205F	0.95	455.11
454.496	LC-3
C27H25N203F	0.99	445.14
444.505	LC-3
C23H23N205F	0.94	427.16
426.443	LC-3
C24H25N203F	0.97	409.08
408.472	LC-3
C24H25N203F	0.97	409.11
408.472	LC-3
C24H25N204F	0.94	425.1
424.471	LC-3
C23H23N205F	0.95	427.12
426.443	LC-3
C23H23N204F	0.98	411
410.444	LC-3
C25H27N205F	0.94	455.19
454.496	LC-3
C24H22N203F4	0.99	463.15
462.442	LC-3
C23H21N2O3Cl2F	0.99	463.07
463.335	LC-3
C25H21 N203F7	1.04	530.97
530.439	LC-3
C24H25N203FS	0.97	441.1
440.538	LC-3
C23H22N2O3FI	0.99	521.03
520.337	LC-3
C26H29N203F	1.01	437.17
436.525	LC-3
C24H22N203F4	0.99	463.13
462.442	LC-3
C23H21N2O3Cl2F	1.01	463.08
463.335	LC-3
C23H22N203F2	0.95	413.08
412.435	LC-3
C25H21N203F7	1.03	530.99
530.439	LC-3
C25H27N203F	0.99	423.12
422.498	LC-3
C23H22N2O3FI	0.97	521.41
520.337	LC-3
C24H25N205FS	0.87	473.12
472.536	LC-3
C25H27N205F	0.94	455.16
454.496	LC-3
C23H22N203BrF	0.98	474.97
473.341	LC-3
C24H22N204F4	1	479.11
478.441	LC-3
C25H27N203F	0.99	423.14
422.498	LC-3
C23H22N203BrF	0.98	474.93
473.341	LC-3
C28H32N305F	0.98	510.17
509.576	LC-3
C29H26N203F2	1.02	489.15
488.532	LC-3
C30H29N204F	1.01	501.16
500.568	LC-3
C23H22N203F2	0.95	413.09
412.435	LC-3
C25H25N203F	0.98	421.11
420.483	LC-3
C26H27N204F	0.98	451.08
450.508	LC-3
C31H29N304F2	0.98	546.06
545.584	LC-3
C27H31N203F	1.02	451.12
450.552	LC-3
C24H23N204F	0.95	423.11
422.455	LC-3
C23H22N203F2	0.94	413.08
412.435	LC-3
C24H23N203F	0.96	407.1
406.456	LC-3
C24H25N203F	0.95	409.11
408.472	LC-3
C25H27N203F	0.99	423.19
422.498	LC-3
C25H27N203F	1	423.2
422.498	LC-3
C24H25N203F	0.95	409.2
408.472	LC-3
C23H23N204F	0.94	411.06
410.444	LC-3
C24H25N203F	0.96	409.16
408.472	LC-3
C25H26N307F	0.86	500.19
499.493	LC-3
C24H24N2O3ClF	1	443.11
442.917	LC-3
C23H22N2O5ClF	0.98	461.18
460.888	LC-3
C23H22N2O4ClF	0.88	445.32
444.889	LC-3
C24H24N2O4ClF	0.98	459.04
458.916	LC-3
C24H24N2O3ClF	1.01	443.01
442.917	LC-3
C23H22N2O4ClF	0.92	486.38
444.889	LC-3
C23H22N2O3ClF	0.98	429.13
428.89	LC-3
C24H24N2O4ClF	0.99	459.03
458.916	LC-3
C23H21N2O3Cl2F	1.01	463.11
463.335	LC-3
C25H23N3O3ClF	0.97	468.11
467.927	LC-3
C22H19N2O4Cl2F	1.01	465.09
465.307	LC-3
C23H22N2O4ClF	1.02	445.11
444.889	LC-3
C24H22N2O5ClF	0.93	473.17
472.899	LC-3
C23H22N2O5ClF	0.99	461.09
460.888	LC-3
C22H19N2O4Cl2F	1.02	465
465.307	LC-3
C23H21N2O3Cl2F	1.01	463.07
463.335	LC-3
C25H24N2O3ClF	1.01	455.16
454.928	LC-3
C24H26N3O3F	0.98	429.13
423.486	LC-3
C23H23N3O3ClF	0.97	444.16
443.905	LC-3
C23H24N3O3F	0.94	410.12
409.46	LC-3
C23H23N2O4F	1.01	411.07
410.444	LC-3
C23H22N2O4ClF	1.03	445.15
444.889	LC-3
C24H25N2O4F	0.95	425.19
424.471	LC-3
C24H25N2O3F	0.98	409.18
408.472	LC-3
C24H25N2O4F	0.96	425.18
424.471	LC-3
C26H27N2O3F	1.01	435.16
434.509	LC-3
C23H22N2O3ClF	0.99	429.13
428.89	LC-3
C24H25N2O3F	0.98	409.1
408.472	LC-3
C24H25N2O4F	0.95	425.08
424.471	LC-3
C23H22N2O4ClF	0.97	445.38
444.889	LC-3
C23H22N2O4ClF	0.98	445.39
444.889	LC-3
C25H27N2O4F	0.96	439.47
438.497	LC-3
C24H25N2O3F	0.96	409.48
408.472	LC-3
C30H29N2O3F	1.02	485.52
484.569	LC-3
C25H27N2O4F	0.97	439.45
438.497	LC-3
C26H26N3O3F	0.94	448.44
447.508	LC-3
C24H25N2O4F	0.94	425.44
424.471	LC-3
C30H29N2O3F	1.04	485.53
484.569	LC-3
C33H35N2O4F	1.07	543.18
542.649	LC-3
C25H27N2O3F	1.01	423.14
422.498	LC-3
C26H28N3O3F	0.99	450.2
449.524	LC-3
C26H27N2O4F	1.05	451.15
450.508	LC-3
C27H29N2O3F	1.02	449.25
448.536	LC-3
C28H31N2O3F	1.03	463.27
462.563	LC-3
C28H31N2O4F	1.02	479.28
478.562	LC-3
C26H26N2O4ClF	1.03	485.2
484.953	LC-3
C33H33N2O3F	1.07	525.26
524.634	LC-3
C30H29N2O3F	1.04	485.26
484.569	LC-3
C31H28N2O5F4	1.15	585.14
584.564	LC-3
C25H24N2O4F4	1.07	493.17
492.468	LC-3
C26H26N2O4F4	1.08	507.18
506.494	LC-3
C32H30N2O4F4	1.13	583.14
582.592	LC-3
C33H32N2O5F4	1.13	613.26
612.618	LC-3
C31H31N2O4F	1.06	515.17
514.595	LC-3
C32H33N2O4F	1.07	529.26
528.622	LC-3
C32H33N2O5F	1.06	545.25
544.621	LC-3
C24H25N2O4F	0.98	425.19
424.471	LC-3
C25H28N3O4F	0.97	454.26
453.512	LC-3
C25H27N205F	0.97	454.26
454.496	LC-3
C26H29N204F	0.98	453.25
452.524	LC-3
C27H31N204F	1	467.18
466.551	LC-3
C27H31 N205F	0.98	483.19
482.55	LC-3
C25H26N2O5ClF	1	489.17
488.941	LC-3
C32H33N204F	1.04	529.28
528.622	LC-3
C29H29N204F	1.01	489.24
488.557	LC-3
C32H33N203F	1.07	513.27
512.623	LC-3
C32H33N204F	1.06	529.27
528.622	LC-3
C24H25N203F	0.98	409.16
408.472	LC-3
C34H31 N203F	1.08	535.27
534.629	LC-3
C31H31N2O3F	1.06	499.2
498.596	LC-3
C33H30N303F	1.05	536.25
535.617	LC-3
C33H29N204F	1.09	537.24
536.601	LC-3
C34H31 N203F	1.07	535.25
534.629	LC-3
C35H33N203F	1.09	549.26
548.656	LC-3
C35H33N204F	1.07	565.26
564.655	LC-3
C40H35N203F	1.11	611.21
610.727	LC-3
C27H25N203F	1	445.24
444.505	LC-3
C28H27N203F	1.01	459.15
458.531	LC-3
C32H32N304F	0.97	542.22
541.621	LC-3
C32H32N305F	0.97	558.24
557.620	LC-3
C31H29N3O4ClF	1.01	562.09
562.039	LC-3
C32H31N304F2	0.96	560.21
559.611	LC-3
C28H32N304F	0.91	494.25
493.577	LC-3
C21H21FN203S	0.93	400.61
400.47	LC-3
C20H19ClFN3O4	0.91	420.09
419.83	LC-3
C21H21FN4O3	0.8	397.11
396.41	LC-3
C27H26FN504S	0.87	536.14
535.59	LC-3
C29H28FN303	1.02	486.22
485.55	LC.3
C24H24F2N203	0.99	427.07
426.46	LC-3
C24H24F2N203	0.99	427.07
426.46	LC-3
C29H34N303F	1.06	492.26
491.605	LC-3
C31H37N204F	1.10	521.25
520.643	LC-3

Synthesis of Precursors and Intermediates: General Methods for the synthesis of intermediates of Structure 1:

Structure 1, wherein R represents C_1-4-alkyl

1) N-Carbamoylation of an intermediate of Structure 2a or 2b:

The appropriate isocyanate (0.132 mmol) and a catalytical amount of DMAP are added to a 0°C cold solution of a hydrochloride of the appropriate intermediate of Structure 2a or 2b (0.11 mmol) and Et₃N (0.034 ml, 0.242 mmol) in DCM (2 ml). The reaction mixture is stirred at rt overnight. Then, a 1:4 mixture (1 ml) of sat. NaHC₃ solution and H₂O is added. After phase separation, the aq. layer is extracted three times with DCM. The combined org. phases are washed with 10% citric acid. The solvent is evaporated and the pure [3-ureido-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate derivative of Structure 1 is obtained by preparative HPLC with 8 to 98% yield.

Listed in Table 2 below are ethyl [3-ureido-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate derivatives of Structure 1, prepared according to the above mentioned method, with the corresponding compound of Structure 2a or 2b as starting material.


C21H29N303	1.1	372.05
371.47	LC-2	372.05
C24H27N303	1.99	406.06
405.496	LC-1	406.06
C25H29N303	2.15	420.04
419.523	LC-1	420.04
C27H27N303	1.19	441.95
441.52	LC-2	441.95
C23H25N305S	1.96	454.1
455.534	LC-1	454.1
C21H29N303	1.08	372.16
371.479	LC-2	372.16
C24H27N303	1.1	406.16
405.496	LC-2	406.16
C25H29N303	1.12	420.15
419.523	LC-2	420.15
C23H25N305S	1.09	454.16
455.534	LC-2	454.16
C23H25N303	1.11	392.17
391.47	LC-2	392.17

Listed in Table 2a below are further ethyl [3-ureido-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate derivatives of Structure 1, prepared according to the above mentioned method, with the corresponding compound of Structure 2a or 2b as starting material.


	C25H28FN303
	437.51

	C25H28N303F
	437.51
	C24H25ClFN3O3
	457.93

	C25H27ClFN3O3
	471.95

	C26H30FN303
	451.53

	C25H27ClFN3O3
	471.95

	C25H28FN303
	437.51

	C28H32FN303
	477.57

	C27H32FN304
	481.56

	C31H37N3O3F
	519.655

	C29H28FN303
	513.60

2) Reaction of intermediates of Structure 2a or 2b with chloroformates:

The appropriate chloroformate (neat) and a catalytical amount of DMAP is added to a 0°C cold solution of a hydrochloride of the appropriate intermediate of Structure 2a or 2b (0.132 mmol) and Et₃N (0.034 ml, 0.242 mmol) in DCM (2 ml). The reaction mixture is stirred at rt overnight. Then, a 1:4 mixture (1 ml) of sat. NaHCO₃ solution and H₂O is added. After phase separation, the aq. layer is extracted three times with DCM. The combined org. phases are washed with 10% citric acid. The solvent is evaporated and the pure (3-oxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 is obtained by preparative HPLC with 5 to 96% yield.

Listed in Table 3 below are ethyl (3-oxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivatives of Structure 1, prepared according to the above mentioned method, with the corresponding compound of Structure 2a or 2b as starting material.


C20H26N204	1.14	380.98
358.436	LC-2
C21H28N204	1.20	395.04
372.463	LC-2
C24H26N204	1.17	407.02
406.48	LC-2
C26H30N205	1.17	473.01
450.533	LC-2
C20H26N204	1.12	381.09
358.436	LC-2
C21H28N204	1.15	373.13
372.463	LC-2
C24H26N204	1.16	407.2
406.48	LC-2
C26H30N205	1.17	473.14
450.533	LC-2

Listed in Table 3a below are further ethyl (3-oxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivatives of Structure 1, prepared according to the above mentioned method, with the corresponding intermediate of Structure 2a or 2b as starting material.


	C25H25N204F3
	474.478
	C24H24N204BrF
	503.367
	C26H27N204F
	450.508
	C25H27N206FS
	502.561
	C25H27N204F
	438.497
	C24H24ClFN2O4
	458.91
	C27H29N2O4F
	464.535
	C24H25N2O4Cl
	440.926
	C25H27N204F
	438.494
	C25H26N2O4ClF
	472.939
	C28H31N204F
	478.558
	C33H32N205F4
	612.614
	C27H31N205F
	482.546

3) N-Acylation of an intermediate of Structure 2a or 2b: Method (A)

The appropriate acid chloride (0.132 mmol) and a catalytical amount of DMAP are added to a stirred solution of a hydrochloride of the appropriate intermediate of Structure 2a or 2b (0.11 mmol) and Et₃N (0.034 ml, 0.242 mmol) in DCM (2 ml) at 0°C, and the resulting reaction mixture is kept stirring at rt overnight. Then, a (1:4) mixture (1 ml) of sat. NaHCO₃ and H₂O is added. After phase separation, the aq. layer is extracted three times with DCM, and the combined org. layers are washed with 10% citric acid to remove DMAP. The solvent is evaporated and the pure ethyl (3-acylamido-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 is isolated by preparative HPLC in 10 to 95 % yield.

Method (B)

A solution of a hydrochloride of the appropriate intermediate of Structure 2a or 2b (0.075 mmol) and DIEA (0.15 mmol) in a 4:1 mixture (2 ml) of dry DMF and THF is added dropwise to a stirred solution of the appropriate carboxylic acid (0.113 mmol), HATU (0.15 mmol) and DIEA (0.15 mmol) in a 4:1 mixture (2 ml) of dry DMF and THF at 0°C. The mixture is stirred at rt for 1 h, or overnight, then sat. NaHCO₃ solution is added. After phase separation, the aq. layer is extracted three times with DCM. The combined org. phases are evaporated. The crude ethyl (3-acylamido-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 is obtained with >50% yield and is either used as such in the next step or purified by prepaprative HPLC to give the pure ethyl (3-acylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 with 13 to 95% yield.

Listed in Table 4 below are crude ethyl (3-acylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivatives of Structure 1, prepared according to the above mentioned methods (A) or (B), with the corresponding intermediate of Structure 2a or 2b as starting material.


C23H24N203	1.11	399.00
376.455	LC-2
C24H26N204	1.13	428.93
406.48	LC-2
C24H26N203	1.11	412.97
390.481	LC-2
C22H24N203S	1.09	396.98
396.51	LC-2	396.98
C25H28N203	1.13	427.03
404.508	LC-2
C25H28N204	1.14	421.07
420.507	LC-2	421.07
C21H28N2O3	1.09	357.1
356.464	LC-2	357.1
C24H32N203	1.17	397.05
396.529	LC-2	397.05
C26H38N203	1.28	449.01
426.599	LC-2
C24H26N204	1.03	407.23
406.48	LC-2	407.23
C24H26N203	1.1	391.13
390.481	LC-2	391.13
C22H24N203S	1.1	397
396.51	LC-2	397
C25H28N203	1.13	405.12
404.508	LC-2	405.12
C25H28N204	1.14	421.09
420.507	LC-2	421.09
C21H28N203	1.1	357.13
356.464	LC-2	357.13
C24H32N203	1.18	397.16
396.529	LC-2	397.16
C26H38N203	1.15	427.32
426.599	LC-2	427.32
C20H26N203	1.07	343.15
342.437	LC-2	343.15
C23H32N203	1.18	385.18
384.518	LC-2	385.18
C24H25N204F	1.15	425.28
424.471	LC-2	425.28
C24H25N203F	1.12	409.28
408.472	LC-2	409.28
C25H27N203F	1.15	423.27
422.498	LC-2	423.27
C24H24N2O3ClF	1.18	443.21
442.917	LC-2	443.21
C25H27N204F	1.12	439.2
438.497	LC-2	439.2
C25H27N203F	1.14	423.34
422.498	LC-2	423.34
C24H23N2O3Cl2F	1.18	477.22
477.362	LC-2	477.22
C24H24N2O3ClF	1.16	443.28
442.917	LC-2	443.28
C25H24N203F4	1.17	477.29
476.469	LC-2	477.29
C24H24N2O4ClF	1.18	459.28
458.916	LC-2	459.28
C25H27N204F	1.18	439.27
438.497	LC-2	439.27
C24H24N2O4ClF	1.17	459.21
458.916	LC-2	459.21
C24H24N2O4ClF	1.18	459.21
458.916	LC-2	459.21
C26H29N204F	1.14	453.26
452.524	LC-2	453.26
C26H29N203F	1.17	437.26
436.525	LC-2	437.26
C25H26N2O3ClF	1.18	457.2
456.943	LC-2	457.2
C25H26N2O3ClF	1.18	457.2
456.943	LC-2	457.2
C25H26N2O3ClF	1.17	457.2
456.943	LC-2	457.2
C24H24N2O3ClF	1.15	443.21
442.917	LC-2	443.21
C25H27N204F	1.12	439.33
438.497	LC-2	439.33
C25H27N203F	1.15	423.27
422.498	LC-2	423.27
C24H25N204F	1.15	425.28
424.471	LC-2	425.28
C25H27N203F	1.14	423.27
422.498	LC-2	423.27
C24H24N2O4ClF	1.17	459.21
458.916	LC-2	459.21
C25H27N204F	1.18	439.27
438.497	LC-2	439.27
C26H29N204F	1.14	453.33
452.524	LC-2	453.33
C26H29N203F	1.17	437.33
436.525	LC-2	437.33
C25H26N2O3ClF	1.17	457.27
456.943	LC-2	457.27
C25H26N2O3ClF	1.17	457.27
456.943	LC-2	457.27
C25H26N2O3ClF	1.18	457.27
456.943	LC-2	457.27
C25H25N203F3	1.17	459.28
458.479	LC-2	459.28
C26H29N204F	1.14	453.33
452.524	LC-2	453.33
C26H29N204F	1.16	453.33
452.524	LC-2	453.33
C31H31N2O3F	1.21	499.39
498.596	LC-2	499.39
C31H31N2O3F	1.2	499.39
498.596	LC-2	499.39
C26H26N2O4BrF	1.17	531.25
529.404	LC-2	531.25
C26H27N204F	1.12	451.25
450.508	LC-2	451.25
C27H29N2O6FS	1.07	529.31
528.599	LC-2	529.31
C27H29N203F	1.18	449.31
448.536	LC-2	449.31
C26H29FN205	1.08	469.04
468.52	LC-3	469.04
C25H27FN204	1.07	439.06
438.49	LC-3	439.06
C25H27FN205	1.08	439.06
439.49	LC-3	439.06
C25H27FN206	n. d.	n. d.
440.49	LC-3	n. d.
C25H26FN303	1.14	436.08
435.49	LC-3	436.08
C27H28FN303	1.15	462.05
461.53	LC-3	462.05
C26H27FN403	0.86	463.09
462.52	LC-3	463.09
C26H27FN205	1.15	467.03
466.5	LC-3	467.03
C25H24FN303	n. d.	n. d.
433.47	LC-3	n. d.
C24H26FN303	n. d.	n. d.
423.48	LC-3.	n. d.
C28H33FN203	n. d.	n. d.
464.57	LC-3	n. d.
C25H24F4N203	n. d.	n. d.
476.46	LC-3	n. d.
C25H24F4N203	1.26	477.04
476.46	LC-2	477.04
C25H24F4N204	n. d.	n. d.
492.46	LC-3.	n. d.
C29H27FN203	1.29	471.05
470.53	LC-2	471.05
C29H29FN203	1.27	473.08
472.55	LC-2	473.08
C26H29FN203	1.08	437.28
436.52	LC-3	437.28
C25H26ClFN2O3	1.09	473.08
456.94	LC-3	473.08
C27H31FN203	1.09	451.23
450.55	LC-3	451.23
C26H28ClFN2O3	1.1	471.22
470.96	LC-3	471.22
C28H33FN203	1.11	465.23
464.57	LC-3	465.23
C27H30ClFN2O	1.12	485.20
484.99	LC-3	485.20

Listed in Table 4a below are further ethyl (3-acylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivatives of Structure 1, prepared according to the above mentioned methods (A) or (B), with the corresponding intermediate of Structure 2a or 2b as starting material.


	C27H31 N205F
	482.546
	C29H29N203F
	472.555
	C25H27N205F
	454.493
	C26H29N203F
	436.522
	C26H29N203F
	436.522
	C26H29N204F
	452.521
	C25H27N205F
	454.493
	C25H27N204F
	438.494
	C22H31 N205F
	482.546
	C26H26N203F4
	490.492
	C25H25N2O3Cl2F
	491.385
	C27H25N203F7
	558.489
	C26H29N203FS
	468.588
	C25H26N2O3FI
	548.387
	C28H33N203F
	464.575
	C26H26N203F4
	490.492
	C25H25N2O3Cl2F
	491.385
	C25H26N203F2
	440.485
	C27H25N203F7
	558.489
	C27H31N2O3F
	450.548
	C25H26N2O3FI
	548.387
	C26H29N205FS
	500.586
	C27H31 N205F
	482.546
	C25H26N203BrF
	501.391
	C26H26N204F4
	506.491
	C27H31N203F
	450.548
	C25H26N203BrF
	501.391
	C30H36N305F
	537.626
	C31H30N203F2
	516.582
	C32H33N204F
	528.618
	C25H26N203F2
	440.485
	C27H29N203F
	448.533
	C28H31N2O4F
	478.558
	C33H33N304F2
	573.634
	C29H35N203F
	478.602
	C26H27N204F
	450.505
	C25H26N203F2
	440.485
	C26H27N203F
	434.506
	C26H29N203F
	436.522
	C27H31N2O3F
	450.552
	450.548
	C27H31 N203F
	450.548
	C26H29N203F
	436.522
	C25H27N204F
	438.494
	C26H29N203F
	436.522
	C27H30N307F
	527.543
	C26H28N2O3ClF
	470.967
	C25H26N2O5ClF
	488.938
	C25H26N2O4ClF
	472.939
	C26H28N2O4ClF
	486.966
	C22H28N2O3ClF
	470.967
	C25H26N2O4ClF
	472.939
	C25H26N2O3ClF
	456.94
	C26H28N2O4ClF
	486.966
	C25H25N2O3Cl2F
	491.385
	C27H27N3O3ClF
	495.977
	C24H23N2O4Cl2F
	493.357
	C25H26N2O4ClF
	472.939
	C26H26N2O5ClF
	500.949
	C25H26N2O5ClF
	488.938
	C24H23N2O4Cl2F
	493.357
	C25H25N2O3Cl2F
	491.385
	C27H28N2O3ClF
	482.978
	C26H29N204F
	452.521
	C22H29N203F
	436.522
	C26H29N204F
	452.521
	C28H31 N203F
	462.559
	C25H26N2O3ClF
	456.94
	C26H29N203F
	436.522
	C26H29N204F
	452.521
	C25H26N2O4ClF
	472.939
	C25H26N2O4ClF
	472.939
	C27H31N2O4F
	466.547
	C26H29N203F
	436.522
	C32H33N203F
	512.619
	C27H31N204F
	466.547
	C28H30N303F
	475.558
	C26H29N204F
	452.521
	C32H33N203F
	512.619
	C35H39N204F
	570.699
	C27H31N203F
	450.548
	C29H33N203F
	476.586
	C30H35N2O3F
	490.613
	C30H35N2O4F
	506.612
	C28H30N2O4ClF
	513.003
	C35H37N2O3F
	552.684
	C32H33N2O3F
	512.619
	C27H28N2O4F4
	520.518
	C28H30N2O4F4
	534.544
	C34H34N2O4F4
	610.642
	C35H36N2O5F4
	640.668
	C33H35N2O4F
	542.645
	C34H37N204F
	556.672
	C34H37N2O5F
	572.671
	C26H29N2O4F
	452.521
	C28H33N2O4F
	480.574
	C29H35N2O4F
	494.601
	C29H35N2O5F
	510.6
	C27H30N2O5ClF
	516.991
	C34H37N2O4F
	556.672
	C31H33N2O4F
	516.607
	C34H37N2O3F
	540.673
	C34H37N2O4F
	556.672
	C26H29N2O3F
	436.522
	C36H35N2O3F
	562.679
	C33H35N2O3F
	526.646
	C35H34N3O3F
	563.667
	C35H31N2O4F
	564.651
	C36H35N2O3F
	562.679
	C37H37N2O3F
	576.706
	C37H37N2O4F
	592.705
	C42H39N2O3F
	638.777
	C29H29N2O3F
	472.555
	C30H31N2O3F
	486.581
	C29H30FN5O4S
	563.64
	C23H25FN2O3S
	428.012
	C22H23ClFN3O4
	447.88
	C23H25FN4O3
	424.46
	C26H28F2N2O3
	454.51
	C26H28F2N2O3
	454.51
	C33H41N2O4F
	548.693

General Method for the Preparation of Intermediates of Structure 1, wherein R ⁴ represents C _1-5 -alkyl or allyl

To a stirred and degassed solution of an appropriately protected ethyl (3-amino-8-bromo-1,2,3,4-tetrahydro-9Hcarbazol-9-yl)-acetate derivative of Structure 2c (0.2 mmol) and Pd(PPh₃)₄ (0.02 mmol, 0.1 eq.) in dry DMF (1.5 ml) is added under inert atmosphere the appropriate tetraC_1-5-alkyltin or allyltrialkyltin, respectively (0.22 mmol, 1.1 eq.). The reaction mixture is allowed to stir overnight at 110°C. After cooling to rt, acetonitrile (1 ml) and heptane (1 ml) are added. The acetonitrile-DMF phase is washed three times with heptane. Water is then added and the resulting aq. phase is extracted twice with AcOEt. The combined org. phases arc washed with brine and dried over Na₂SO₄. Evaporation of the solvent in vaccuo yields the protected ethyl (3-amino-8-C_1-5-alkyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative or ethyl (3-amino-8-allyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1, respectively.

Intermediates of Structure 1 wherein R⁴ represents C_1-5-alkyl or allyl:

Ethyl (3S)-(3-benzyloxycarbonylamino-6-fluoro-8-methyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate is obtained in quantative yield as a yellow oil. tR = 1.09 min (LC-3), ESI-MS (pos.): m/z 439.15 [M+H]+.
Ethyl (3S)-(3-benzyloxycarbonylamino-6-fluoro-8-allyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate is obtained in quantative yield as a yellow oil. tR = 1.11 min (LC-3), ESI-MS (pos.): m/z 465.22 [M+H]+.

General Method for the Preparation of Intermediates of Structure 1 wherein R ⁴ represents vinyl

A suspension of an appropriately protected ethyl (3-amino-8-bromo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (0.4 mmol), vinylboronic anhydride pyridine complex (0.22 mmol, 0.56 eq.), Pd(PPh₃)₄ (23 mg, 0.02 mmol, 0.05 eq.), and K₂CO₃ (55 mg, 0.4 mmol, 1 eq.) in 1 ml (DME/ H₂O) is stirred for 4 h at reflux. Water is added and the resulting aq. phase is extracted three times with AcOEt. The combined org. phases are dried over Na₂SO₄, filtered and concentrated in vaccuo. The crude product is purified by FC (heptane / AcOEt, 3:1) to yield protected ethyl (3-amino-8-vinyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivatives of Structure 1.

Intermediate of Structure 1 wherein R⁴ represents vinyl:

Ethyl (3S)-(3-benzyloxycarbonylamino-6-fluoro-8-vinyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate is obtained in 87% yield as a white solid. tR = 1.11 min (LC-3), ESI-MS (pos.): m/z 451.19 [M+H]+.

General Method for the Preparation of Intermediates of Structure 1 wherein R ⁴ represents C _1-6 -alkylsulfonyl

A solution of an appropriately protected ethyl (3-amino-8-bromo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (0.238 mmol), cuprous iodide (204 mg, 1.073 mmol, 4.5 eq.) and sodium methanesulfinate (129 mg, 1.073 mmol, 4.5 eq.) in degassed NMP (5 ml) is heated under inert atmosphere at 140°C overnight. Then, the mixture is diluted with heptane (5 ml) and AcOEt (5 ml) and filtered over a pad of silica gel with AcOEt as eluent. The solvent is removed in vaccuo and the residue dissolved in AcOEt and H₂O. The phases are separated and the aq. phase is extracted twice with AcOEt. The combined org. phases are washed with brine and H₂O, dried over Na₂SO₄ and concentrated in vacuuo to yield the corresponding ethyl (3-amino-8-methanesulfonyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1.

Intermediate of Structure 1 wherein R⁴ represents C_1-6-alkylsulfonyl:

Ethyl (3RS)-(3-benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate is obtained in quantitative yield as a brown solid. tR = 1.04 min (LC-3), ESI-MS (pos.): m/z 503.12 [M+H]+.

General Methods for the Preparation of Intermediates of Structure 2a:

Method (A) Step A) 4-Nitro-benzenesulfonylation of an intermediate of Structure 2b to yield an ethyl [3-(4-nitro-benzenesulfonylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate derivative of Structure 3a:

A catalytical amount of DMAP and p-nitrobenzenesulfonyl chloride (223 mg, 1.01 mmol) arc added to an ice cold stirred solution of the appropriate (3-amino-1,2,3,4-tetrahydro-9H carbazol-9-yl)-acetate derivative hydrochloride of Structure 2b (0.92 mmol) and pyridine (0.96 ml, 11.9 mmol) in DCM. The reaction mixture is allowed to warm up to rt and is continued to stir overnight. The reaction is then quenched by addition of H₂O and sat. NaHCO₃ solution. After phase separation the aq. phase is extracted with DCM. The combined org. phases are dried over Na₂SO₄, filtered, and the solvent is evaporated to dryness. The crude product is filtered through a plug of silica gel (heptane/AcOEt, 2:1) to give the desired intermediate of Structure 3a.

Intermediate of Structure 3a: Ethyl (3S)-[6-fluoro-3-(4-nitro-benzenesulfonylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate is obtained in 71% yield as a yellow solid: t_R = 1.05 min (LC-3), ESI-MS (pos.): m/z 476.12 [M+H]⁺.

Step B) N-Substitution of a 4-nitro-benzenesulfonamide intermediate of Structure 3a to yield intermediates of Structure 3b:

Following a procedure described in the literature (Peña, C. et al. Tetrahedron Lett. 2005, 46, 2783-2787), a stirred suspension of the appropriate intermediate of Structure 3a (0.21 mmol), K₂CO₃ (291 mg, 2.1 mmol) and tetrabutylammonium bromide (6.78 mg, 0.021 mmol) in toluene (2 ml) is heated at 70°C for 30 min before adding the corresponding alkylating agent R⁵ -L (0.841 mmol). The reaction mixture is continued to stir at 70°C overnight, cooled to rt, and treated with sat. NH₄Cl solution. After phase separation, the aq. layer is extracted three times with DCM. The combined org. phases are dried over Na₂SO₄, filtered, and the solvent evaporated to dryness, affording the corresponding intermediate of Structure 3b in quantitative yield.

Listed in Table 5 below are intermediates of Structure 3b, prepared according to the above-mentioned method.


C23H24N306F	1.09	490.05
489.52	(LC-3)	490.05
C24H26N3O6FS	1.11	504.15
503.549	LC-3	504.15
C25H28N3O6FS	1.13	518.23
517.576	LC-3	518.23

Listed in Table 5a below are further intermediates of Structure 3b, prepared according to the above-mentioned method.


C31H32N3O6FS	1.16	594.12
593.674	LC-3	594.12
C26H28N3O6FS	1.12	530.02
529.587	LC-3	530.02
C31H29N3O7F4S	1.17	664.17
663.643	LC-3	664.17
C30H30N3O7FS	1.14	596.18
595.646	LC-3	596.18
C25H28N3O7FS	1.09	534.16
533.575	LC-3	534.16

Step C) Cleavage of the 4-nitro-benzenesulfonyl group to yield an intermediate of Structure 2a:

In analogy to the literature (Miller, S. C.; Scanlan, T. S. J. Am. Chem. Soc. 1997, 119, 2301-2302), mercaptoacetic acid (0.019 ml, 0.267 mmol) and DBU (0.081 ml, 0.53 mmol) are added to a stirred solution of an intermediate of Structure 3b (0.179 mmol) in dry DMF (2 ml). The reaction mixture is allowed to stir overnight, then, at rt, sat. Na₂CO₃ solution, H₂O and DCM are added. After phase separation, the org. layer is extracted twice with sat. Na₂CO₃ solution, and twice with H₂O. The combined org. phases are washed with brine and dried over Na₂SO₄. After filtration, the solvent is evaporated and the residue is purified by preparative tlc on silica gel (DCM/MeOH/NH₄OH, 90:10:1) to give the desired intermediate of Structure 2a in 30-40% yield.

Listed in Table 6 below are intermediates of Structure 2a, prepared according to the above-mentioned method.


C17H21FN2O2	0.76	305.19
304.36	LC-3	305.19
C18H23FN2O2	0.78	319.14
318.39	LC-3	319.14
C19H25FN2O2	0.81	333.15
332.41	LC-3	333.15

Listed in Table 6a below are further intermediates of Structure 2a, prepared according to the abovementioned method.


C25H29N2O2F	0.91	409.15
408.515	LC-3	409.15
C20H25N2O2F	0.82	345.18
344.428	LC-3	345.18
C25H26N2O3F4	0.95	479.07
478.484	LC-3	479.07
C24H27N2O3F	0.88	411.10
410.487	LC-3	411.10
C19H25N2O3F	0.77	349.15
348.417	LC-3	349.15

Method (B)

To a stirred suspension of an appropriate ethyl (3-amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative hydrochloride of Structure 2b (0.73 mmol) and DIEA (0.769 mmol, 0.132 ml, 1.05 eq.) and the corresponding aldehyde (0.806 mmol, 1.1 eq.) in DCM (10 ml) is added NaBH(OAc)₃ (1.62 mmol, 2.2 eq.). The reaction mixture is stirred overnight and diluted with DCM and sat. NaHCO₃ solution. The resulting aq. phase is extracted three times with DCM. The combined org. phases are dried over Na₂SO₄, filtered, and the solvent is evaporated to dryness. The crude product is purified by flash-chromatography on silica gel (DCM/MeOH, 95:5) to give the desired intermediate of Structure 2a in 66 to 95% yield.

Listed in Table 6b below are intermediates of Structure 2a, prepared according to the abovementioned method.


C24H27N2O2F	0.88	395.18
394.488	LC-3	395.18
C27H27N2O2F	0.91	431.22
430.521	LC-3	431.22
C23H25N2O2F	0.89	381.16
380.461	LC-3	381.16
C24H26N2O2F2	0.88	413.14
412.478	LC-3	413.14
C24H26N2O2F2	0.88	413.14
412.478	LC-3	413.14
C23H31N2O2F	0.88	387.20
386.509	LC-3	387.20

General Procedures for the Preparation of Intermediates of Structure 2b:

Cleavage of PG= tert-butoxycarbonyl

To a stirred solution of an ethyl (3-tert-butoxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (1.61 mmol) in THF (4 ml) is added 2N HCl (2 ml) in diethylether, or in AcOEt. The reaction mixture is stirred overnight, and the formed precipitate is filtered off, rinsed with diethylether and dried to give the desired intermediate of Structure 2b as a white solid in quantitative yield.

Listed in Table 7 below are intermediates of Structure 2b, prepared according to the above-mentioned method, with corresponding intermediate of Structure 2c as starting material.


C16H21N2O2Cl	0.74	273.16
308.807	LC-2	273.16
C16H21N2O2Cl	0.74	273.16
308.807	LC-2	273.16
C16H20ClFN2O2	0.74	291.15
326.79	LC-2	291.15
C16H20N2O2ClF	0.73	291.11
326.79	LC-2	291.11

Cleavage of PG= benzyloxycarbonyl

To a stirred solution of an ethyl (3-benzyloxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (7.58 mmol) in AcOH (85 ml) and EtOH (20 ml) is added Pd /C (806 mg, 0.76 mmol, 0.1 eq.). The reaction mixture is stirred for 1h under a H₂ atmosphere then diluted with DCM and filtered over a plug of celite. A solution of 4M HCl in dioxane (30 ml, 10 eq.) is added to the filtrate and the solvents are removed in vaccuo to give an intermediate of Structure 2b.

Listed in Table 7a below are further intermediates of Structure 2b, prepared according to the above-mentioned methods, with the corresponding intermediate of Structure 2c as starting material.


C16H19N2O2Cl2F	0.78	325.05
361.243	LC-3	325.05
C20H19N2O2F	1.02	339.12
338.381	LC-3	339.12

General Method for the Synthesis of Intermediates of Structure 2c:

Alkylation of an intermediate of Structure 4:

A solution of e.g. ethyl bromoacetate (1.25 ml, 11.25 mmol) in dry DMF (20 ml) is added dropwise to a heated (60°C) solution of an intermediate of Structure 4 (10.22 mmol) and Cs₂CO₃ (9.99 g, 30.67 mmol) in dry DMF (50 ml) over a period of 15 min. The resulting suspension is continued to stir at 60°C for 1 h, or overnight. After cooled to rt, the reaction mixture is filtered and washed with DCM. The DCM is evaporated and the residue is partitioned between AcOEt and H₂O. The aq. layer is extracted three times with AcOEt. The combined org. layers are washed with H₂O and brine, dried over MgSO₄ and filtered. The solvent is evaporated and the solid residue is purified by FC with a continuous gradient of eluents from AcOEt/ heptane 1:99 to 1:1 to give the desired intermediate of Structure 2c in 40 to 80% yield.

Listed in Table below are intermediates of Structure 2c, prepared according to the above-mentioned method, starting from corresponding intermediate of Structure 4.


C21H28N2O4	1.15	394.95
372.463	LC-2	394.95
C21H28N2O4	1.15	395.15
372.463	LC-2	395.15
C21H27FN2O4	1.15	413.09
390.45	LC-2	413.09
C21H27FN2O4	1.16	413.09
390.45	LC-2	413.09
C24H24N2O4ClF	1.11	458.99
458.916	LC-3	458.99
C24H25N2O4F	1.06	425.22
424.47	LC-3	425.22
C24H24N2O4ClF	1.11	459.05
458.916	LC-3	459.05

Listed in Table 8a below are further intermediates of Structure 2c, prepared according to the above-mentioned method, starting from corresponding intermediate of Structure 4.


C25H25N2O4F3	1.11	475.14
474.478	LC-3	475.14
C24H24N2O4BrF	1.11	505.11
503.367	LC-3	505.11
C24H24ClFN2O4	not determined	not determined
458.91	not determined	not determined
C24H25N2O4Cl	1.1	441.07
440.926	LC-3	441.07

Listed in Table 9 below are intermediates of Structure 4, prepared in analogy to the procedure described in the literature (Ha, J. D. et al., Bulletin of the Korean Soc. Chem. 2004, 25, 1784-1790).


C20H18N2O2ClF	1.07	373.03
372.825	LC-3	373.03
C20H18N2O2ClF	1.06	372.99
372.825	LC-3	372.99
C20H19N2O2F	1.02	339.12
338.38	LC-3	339.12

Listed in Table 9a below are further intermediates of Structure 4, prepared according to the abovementioned procedure.


C21H19N2O2F3	1.07	389.08
388.388	LC-3	389.08
C20H18N2O2BrF	1.07	417.03
417.277	LC-3	417.03
C20H18N2O2ClF	1.05	373.07
372.825	LC-3	373.07
C20H19N2O2Cl	1.05	355.11
354.836	LC-3	355.11

General Method for the Preparation of Intermediates of Structure 1 from intermediates of Structure 8a

To a solution of the respective amine (0.140 mmol, 1.5 eq.), HATU (0.140 mmol, 1.5eq.) and DIEA (0.048 ml, 0.280 mmol, 3 eq.) in 0.5 ml (DMF/THF 4:1) is added a solution of an intermediate of Structure 8a in 0.5 ml (DMF/THF 4:1). The reaction mixture is stirred for 24h, then diluted with DCM and sat. NaHCO₃ solution. After stirring for an additional 1h, H₂O is added and the org. phase is separated. The aq. phase is extracted with DCM, the combined org. extracts are concentrated under a stream of air to yield the desired crude intermediate of Structure 1.

Listed in Table 10 below are intermediates of Structure 1, prepared according to the abovementioned method with corresponding intermediate of Structure 8a as starting material.


C34H36FN3O4	1.06	570.21
569.67	LC-3	570.21
C34H36FN3O5	1.06	586.21
585.67	LC-3	586.21
C33H33ClFN3O4	1.09	590.2
590.08	LC-3	590.2
C34H35F2N3O4	1.05	588.25
587.66	LC-3	588.25
C30H36FN3O4	1	522.26
521.62	LC-3	522.26

General Method for the Preparation of Intermediates of Structure 8a from intermediates of Structure 8b

A solution of an intermediate of Structure 8b (0.54 mmol) and TFA (0.8 ml, 10 mmol, 20 eq.) in DCM (8 ml) is stirred for 2.5h. The volatiles are removed under reduced pressure to yield an intermediate of Structure 8a.

Intermediate of Structure 8a: 3-benzyl-N-(9-ethoxycarbonylmethyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-succinamic acid is quantitative yield as light brown foam. t_R = 0.97 min (LC-3), ESI-MS (pos.): m/z 481.22 [M+H]⁺.

General Method for the Preparation of Intermediates of Structure 8b from intermediates of Structure 2a or 2b

A solution of an appropriate intermediate of Structure 2a or 2b (2.16 mmol), an appropriate C_1-4alkanedicarboxylic acid mono-ester of Structure 9 (4.05 mmol, 1.9 eq.), DIEA (1.5 ml, 8.65 mmol, 4 eq.) and HATU (1.64 g, 4.32 mmol, 2 eq.) in 10 ml (DMF / THF, 4:1) is stirred overnight. The reaction mixture is diluted with AcOEt and sat. NaHCO₃. The aq. phase is extracted twice with AcOEt. The combined org. extracts are washed with brine, dried over MgSO₄, and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel with a gradient of heptane/AcOEt to yield the desired intermediate of Structure 8b.

Intermediate of Structure 8b:

3-Benzyl-N-(9-ethoxycarbonylmethyl-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-succinamic acid tert-butyl ester is obtained in 25% yield as an orange oil: t_R = 1.10 min (LC-3), ESI-MS (pos.): m/z 537.28 [M+H]⁺.

Starting materials: Starting materials of Structure 4:

(3R)-(2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid 1,1-dimethylethyl ester,
(3S)-(2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid 1,1-dimethylethyl ester,
(3R)-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid 1,1-dimethylethyl ester, and
(3S)-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carbamic acid 1,1-dimethylethyl ester;

as well as Starting materials of Structure 7:

(3R)-(2,3,4,9-tetrahydro-1H-carbazol-3-ylamine),
(3S)-(2,3,4,9-tetrahydro-1H-carbazol-3-ylamine),
(3R)-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine), and
(3S)-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-ylamine),

are prepared according to literature procedures (Rosentreter U. et al., Arzneim.-Forsch. 1989, 39(12), 1519-1521); EP 0242518 ; Ha J. D. et al., Bulletin of the Korean Soc. Chem. 2004, 25, 1784-1790; WO 03/033099 ). Starting materials of Structure 9:

Starting materials of Structure 9 are commercially available or synthesized according to well known methods (see for example: J. Org. Chem. 1986, 51(6), 938-940).

NMR data of selected compounds are given in Table 11 below.

Compound	Chemical shifts (δ) in parts per million (ppm)	Solvent


1.19 (d, 6 H), 1.73 (m, 1 H), 1.97 (m, 1 H), 2.38 (t, 2 H), 2.36-2.45 (m, 1H), 2.70 (m, 2 H), 2.80 (t, 2H), 2.82-2.90 (m, 2H), 4.01 (m, 1 H), 4.87 (m, 2 H), 6.88 (dt, 1 H), 7.01 (m, 4 H), 7.33 (dd, 1 H), 7.93 (d, 1 H), 12.90 (bs, 1H)
1.59 (m, 0.5 H), 1.74 (m, 1 H), 1.91 (m, 0.5 H), 2.32 (m, 2 H), 2.68 (m, 4 H), 2.90 (m, 1 H), 3.08 (m, 1 H), 3.57 (m, 1 H), 3.95 (m, 1 H), 4.84 (m, 2 H), 6.87 (m, 1 H), 6.97 (d, 0.5 H), 7.10 (m, 2.5 H), 7.21 (m, 3 H), 7.30 (m, 3 H), 7.60 (m, 2 H), 7.97 (t, 1 H), 9.99 (d, 1 H), 13.00 (br.s, 1H)
0.26 (m, 2 H), 0.47 (d, 2 H), 1.07 (m, 1 H), 2.05 (m, 1 H), 2.18 (m, 1 H), 2.82 (m, 2H), 3.21 (d, 2 H), 4.10 (m, 1 H), 4.88 (s, 2 H), 5.14 (s, 2 H), 6.88 (t, 1 H), 7.19 (d, 1 H), 7.45 (m, 6 H), 12.90 (br.s, 1H).
2.06 (m, 2 H), 2.77 (m, 6 H), 3.29 (m, 2 H), 3.45 (m, 3 H), 4.08 (dd, 1 H), 4.88 (m, 2 H), 5.13 (s, 2 H), 6.89 (m, 1 H), 7.16 (m, 1 H), 7.34 (m, 6 H), 13.00 (br. s, 1H).
1.93 (dd, 1 H), 2.09 (m, 1 H), 2.75 (m, 8 H), 3.66 (m, 3 H), 3.77 (m, 2 H), 4.13 (m, 3 H), 4.90 (m, 2 H), 6.90 (m, 6 H), 7.17 (m, 3 H), 7.33 (m, 3 H), 12.90 (br. s, 1H)
1.93 (m, 2 H), 2.70-3.08 (m, 8 H), 4.41 (m, 0.5 H), 4.86 (m, 2.5 H), 5.05 (m, 2 H), 6.87 (m, 1 H), 7.04 (m, 2 H), 7.19 (m, 3 H), 7.35 (m, 3 H), 7.56 (m, 3 H), 7.83 (m, 1 H), 7.97 (m, 1 H), 8.15 (m, 1 H), 13.00 (br.s, 1H).

Biological assays: Preparation of hCRTH2 receptor membranes and radioligand binding assay:

Preparation of the membranes and radioligand binding assays are performed according to known procedures (e.g. Sawyer N. et al., Br. J. Pharmacol. 2002, 137, 1163-1172). A clonal HEK 293 cell line, expressing high level of recombinant hCRTH2 receptor, is selected for the preparation of membranes. Cells are detached from culture plates in 5 ml buffer A per plate (5 mM Tris, pH 7.4, 1 mM MgCl₂, 0.1 mM PMSF, 0.1 mM phenanthroline) using a police rubber and transferred into centrifugation tubes and frozen at -80°C. After thawing, the cells are centrifuged at 500 g for 5 min and then resuspended in buffer A. Cells are then fragmented by homogenization with a Polytron cell homogenizer for 30 s. The membrane fragments are collected by centrifugation at 3000 g for 40 min and resuspended in buffer B (50 mM Tris, pH 7.4, 25 mM MgCl₂, 250 mM saccharose) and aliquots are stored at -20°C.

Binding assay is performed in a total volume of 250 µl. In each well, 75 µl buffer C (50 mM Tris, pH 7.4, 100 mM NaCl, 1 mM EDTA, 0.1% BSA (protease free), 0.01 % NaN₃) is mixed with 50 µl {³H}-PGD₂ (2.5 nM, 220'000 dpm/well, Amersham Biosciences, TRK734), 100 µl CRTH2 membranes to give 80 µg per well, and 25 µl of test compound in buffer C containing 1% DMSO. For unspecific binding, PGD₂ is added to the reaction mixture at 1 µM final concentration. This binding assay mix is incubated at rt for 90 min and then filtered through a GF/C filter plate. The filter is washed three times with ice cold binding buffer C. Then, Microscint-40 (Packard, 40 µl/well) is added and the receptor bound radioactivity is quantified by scintillation counting in a "TopCount" benchtop microplate scintillation counter (Packard).

Results for ligand binding to the hCRTH2 receptor:

Antagonistic activities (IC₅₀ values) of compounds of Formula I are in the range of 0.1 to 10000 nM with respect to the hCRTH2 receptor (preferred compounds: < 1000 nM, more preferred compounds: < 100 nM, most preferred compounds: < 10 nM). IC₅₀ values of 242 from 251 exemplified compounds (9 IC₅₀ values being not available) are in the range of 0.4-2050 nM with an average of 97 nM with respect to the hCRTH2 receptor. Antagonistic activities of selected compounds are displayed in Table 12.



2
4
6
6
6
9
11
14
15
15
16
16
18
21
26
33
39
47
57
60
61
72
84
93
117
147
152
297
400
488
824
896

Intracellular calcium mobilization assay (FLIPR):

Cells (HEK-293), stably expressing the hCRTH2 receptor under the control of the cytomegalovirus promotor from a single insertion of the expression vector pcDNA5 (Invitrogen), are grown to confluency in DMEM (low glucose, Gibco) medium supplemented with 10% fetal calf serum (Bioconcept, Switzerland) under standard mammalian cell culture conditions (37°C in a humidified atmosphere of 5% CO₂). Cells are detached from culture dishes using a dissociation buffer (0.02% EDTA in PBS, Gibco) for 1 min, and collected by centrifugation at 200 g at rt for 5 min in assay buffer (equal parts of Hank's BSS (HBSS, Bioconcept) and DMEM (low glucose, without phenol red, Gibco)). After incubation for 45 min (37°C and 5% CO₂) in the presence of 1 µM Fluo-4 and 0.04% Pluronic F-127 (both Molecular Probes), and 20 mM HEPES (Gibco) in assay buffer, the cells are washed with and resuspended in assay buffer, then seeded onto 384-well FLIPR assay plates (Greiner) at 50,000 cells in 66 µl per well, and sedimented by centrifugation. Stock solutions of test compounds are made up at a concentration of 10 mM in DMSO, and serially diluted in assay buffer to concentrations required for inhibition dose response curves. Prostaglandin D₂ (Biomol, Plymouth Meeting, PA) is used as an agonist.

A FLIPR384 instrument (Molecular Devices) is operated according to the manufacturer's standard instructions, adding 4 µl of test compound dissolved at 10 mM in DMSO and diluted prior to the experiment in assay buffer to obtain the desired final concentration. 10 µl of 80 nM prostaglandin D₂ (Biomol, Plymouth Meeting, PA) in assay buffer, supplemented with 0.8% bovine serum albumin (fatty acid content <0.02%, Sigma), is then added to obtain a final concentration of 10 nM and 0.1%, respectively. Changes in fluorescence are monitored before and after the addition of test compounds at λ_ex=488 nm and λ_em=540 nm. Emission peak values above base level after prostaglandin D₂ addition are exported after base line subtraction. Values are normalized to high-level control (no test compound added) after subtraction of base line value (no prostaglandin D₂ added). The program XLlfit 3.0 (IDBS) is used to fit the data to a single site dose response curve of the equation (A+((B-A)/(1+((C/x)^D)))) and to calculate the IC₅₀ values.

Claims

A compound of Formula I: wherein R¹, R², R³ and R⁴ independently represent hydrogen, C_1-5-alkyl, C_1-5-alkoxy, alkenyl, halogen, nitro, cyano, halo-C_1-6-alkoxy, halo-C_1-6-alkyl, C_1-6-alkylsulfonyl, or formyl; R⁵ represents hydrogen, alkenyl, C_1-6-alkyl, cycloalkyl-C_1-4-alkyl, C_1-3-alkoxy-C_1-4-alkyl, aryl-C_1-4-alkyl, or aryloxy-C_1-4-alkyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C_1-2-alkylendioxy, C_1-4-alkoxy, C_1-4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy; and R⁶ represents aryl-C_1-3-alkoxy-C_1-3-alkoxycarbonyl; aryl-C_1-3-alkoxycarbonyl; aryl-C_1-3-alkylaminocarbonyl; aryl-C_1-6-alkylcarbonyl; aryl-C_1-3-alkoxy-C_1-3-alkylcarbonyl; arylcarbonyl-C_1-4-alkylcarbonyl; aryloxy-C_1-3-alkylcarbonyl; cycloalkyl-C_1-3-alkylcarbonyl; diaryl-C_1-3-alkylcarbonyl; heteroaryl-C_1-3-alkylcarbonyl; aryl-C_3-6-cycloalkylcarbonyl; or R⁷-C_1-4-alkylcarbonyl, wherein the bridging C_1-4-alkyl group may additionally be mono-substituted with aryl, and R⁷ represents arylaminocarbonyl, heteroarylaminocarbonyl, C_1-6-alkylaminocarbonyl, or aryl-C_1-3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C_1-2-alkylendioxy, C_1-6-alkoxy, C_1-6-alkyl, C_1-6-alkylsulfonyl, halogen, hydroxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, C_1-6-alkylthio, and C_1-4-alkoxycarbonylamino. or a salt of such a compound.
A compound according to claim 1, wherein R¹, R³ and R⁴ represent hydrogen; or a salt of such a compound.
A compound according to claim 1 or 2, wherein R² represents hydrogen, trifluoromethyl, or halogen; or a salt of such a compound.
A compound according to any one of claims 1 to 3, wherein R⁵ represents hydrogen; C_1-3-alkyl; cyclopropylmethyl; 2-methoxyethyl; phenyt-C_2-3-alkyl; or phenoxyethyl, wherein the phenyl group is unsubstituted, or mono-substituted with a group selected from C_1-2-alkylendioxy, C_1-4-alkoxy, C_1-4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy; or a salt of such a compound.
A compound according to any one of claims 1 to 3, wherein R⁵ represents hydrogen, methyl, ethyl, or n-propyl; or a salt of such a compound.
A compound according to any one of claims 1 to 5, wherein R⁶ represents aryl-C_1-3-alkoxycarbonyl; aryl-C_1-3-alkylaminocarbonyl; aryl-C_1-6-alkylcarbonyl; aryl-C_1-3-alkoxy-C_1-3-alkylcarbonyl; arylcarbonyl-C_1-4-alkylcarbonyl; aryloxy-C_1-3-alkylcarbonyl; cycloalkyl-C_1-3-alkylcarbonyl; diaryl-C_1-3-alkylcarbonyl; aryl-C_3-6-cycloalkylcarbonyl; or R⁷-C_1-4-alkylcarbonyl, wherein the bridging C_1-4-alkyl group may additionally be mono-substituted with aryl, and R⁷ represents arylaminocarbonyl, heteroarylaminocarbonyl, C_1-6-alkylaminocarbonyl, or aryl-C_1-3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C_1-2-alkylendioxy, C_1-6-alkoxy, C_1-6-alkyl, C_1-6-alkylsulfonyl, halogen, hydroxy, halo-C_1-6-alkyl, halo-C_1-6-alkoxy, C_1-6-alkylthio, and C_1-4-alkoxycarbonylamino; or a salt of such a compound.
A compound according to any one of claims 1 to 5, wherein R⁶ represents aryl-C_1-2-alkoxycarbonyl; aryl-C_1-2-alkylaminocarbonyl; aryl-C_1-4-alkylcarbonyl; aryloxy-C_1-2-alkylcarbonyl; or diaryl-C_2-3-alkylcarbonyl; or R⁷-C_2-4-alkylcarbonyl, wherein the bridging C_2-4-alkyl group may additionally be mono-substituted with aryl, and R⁷ represents arylaminocarbonyl, or C_1-4-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C_1-2-alkylendioxy, C_1-6-alkoxy, C_1-6-alkyl, C_1-6-alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy; or a salt of such a compound.
A compound according to any one of claims 1 to 5, wherein R⁶ represents aryl-C_2-4-alkylcarbonyl, wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from C_1-4-alkoxy, C_1-4-alkyl, halogen, and trifluoromethyl; or a salt of such a compound.
A compound according to any one of claims 1 to 7, wherein, in case R⁶ represents a group which contains a carbonyl group and one or more aryl moieties, said group is such that it contains a bridging group between the carbonyl group and said aryl moiety (moieties) of said R⁶, wherein the carbonyl moiety and at least one of the aryl moieties are directly attached to different atoms of said bridging group; or a salt of such a compound.
A compound according to claim 1 selected from the group consisting of:
(3S)-[3-(3,3-diphenyl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[6-fluoro-3 -(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3 ,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-[6-fluoro-3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{3-[3-(4-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-(3-benzyloxycarbonylamino-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-benzyloxycarbonylamino-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[6-fluoro-3-(4-oxo-4-phenyl-butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[6-fluoro-3-(2-indan-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-ethyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3R)-[6-fluoro-3-(2-p-tolyloxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{6-fluoro-3-[methyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[6-fluoro-3-(3-1H-indol-3-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(3-benzo[1,3]dioxol-5-yl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{6-fluoro-3-[ethyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[2-(4-chloro-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(2,3-diphenyl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-[6-fluoro-3-(2-phenoxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{3-[3-(3,4-difluoro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-[3-(2-benzyloxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-fluoro-3-[propyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(2-benzyloxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-(3-benzyloxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3R)-{6-fluoro-3-[2-(4-methoxy-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{3-[3-(4-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[4-(4-bromo-phenyl)-4-oxo-butyrylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-propyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3R)-(3-phenylacetylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3R)-{3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-fluoro-3-[2-(4-trifluoromethyl-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-(6-fluoro-3-phenylacetylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(3-1H-benzoimidazol-2-yl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{6-fluoro-3-[3-(4-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[6-fluoro-3-(2-p-tolyloxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-[6-fluoro-3-(2-p-tolyl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-[3-(2-phenoxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[6-fluoro-3-(3-p-tolyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-(3-benzyloxycarbonylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-[6-fluoro-3-(2-p-tolyl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-[3-(2-benzyloxy-ethoxycarbonylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[6-fluoro-3-(3-naphthalen-2-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{6-fluoro-3-[4-(4-methanesulfonyl-phenyl)-4-oxo-butyrylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{6-fluoro-3-[3-(4-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-[3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{3-[2-(4-chloro-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-[6-fluoro-3-(3-p-tolyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{6-fluoro-3-[3-(4-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-fluoro-3-[3-(4-hydroxy-3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-fluoro-3-[2-(3-trifluoromethyl-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-fluoro-3-[2-(4-methoxy-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{3-[2-(3-chloro-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{3-[2-(3,4-dichloro-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[6-fluoro-3-(2-phenoxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-[3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(2-benzyloxy-ethoxycarbonylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(2-phenoxy-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(2-thiophen-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-(3-phenylacetylamino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-[3-(3-benzyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{3-[2-(4-tert-butyl-phenyl)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-(3-benzyloxycarbonylamino-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-benzyloxycarbonylamino-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-[6-fluoro-3-(3-pyridin-3-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-[3-(3-benzyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(3-cyclopentyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-[3-(2-thiophen-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-(3-benzyloxycarbonylamino-8-chloro-5-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-benzyloxycarbonylamino-8-chloro-5-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; and

(3R)-[3-(3-cyclopentyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
or a salt of such a compound.
A compound according to claim 1 selected from the group consisting of:
(3R)-[3-(3-Benzyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(3-Benzyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[6-Fluoro-3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-[3-(3-Benzyl-ureido)-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(3-Benzyl-ureido)-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-[8-Chloro-6-fluoro-3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[8-Chloro-6-fluoro-3-(3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-(3-Benzyloxycarbonylamino-6-trifluoromethyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-Benzyloxycarbonylamino-6-trifluoromethyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3R)-(3-Benzyloxycarbonylamino-8-bromo-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-Benzyloxycarbonylamino-8-bromo-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3R)-(3-Benzyloxycarbonylamino-6-fluoro-8-vinyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-Benzyloxycarbonylamino-6-fluoro-8-vinyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3R)-(3-Benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-Benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-Benzyloxycarbonylamino-6-fluoro-8-methyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-Benzyloxycarbonylamino-7-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(8-Allyl-3-benzyloxycarbonylamino-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3R)-(3-Benzyloxycarbonylamino-8-chloro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{3-[3-(2,4-Dimethoxy-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[6-Fluoro-3-(3-naphthalen-1-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{6-Fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{6-Fluoro-3-[3-(2-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(2-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{6-Fluoro-3-[3-(3-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(3-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{6-Fluoro-3-[3-(3-methoxy-phenyl)-propionylmnino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{6-Fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{6-Fluoro-3-[2-(2-methylphenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[2-(2-methylphenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(2,5-Dimethoxy-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(4-trifluoromethyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(2,6-Dichloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(2,5-Bis-trifluoromethyl-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(4-methylsulfanyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(4-iodo-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(4-isopropyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(3-trifluoromethyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(2,4-Dichloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(4-fluoro-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(3,5-Bis-trifluoromethyl-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(4-Ethyl-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(3-iodo-phenyl)-propionylaminol-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(4-methanesulfonyl-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(2,3-Dimethoxy-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(2-Bromo-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(3-trifluoromethoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(2,4-Dimethyl-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(3-Bromo-phenyl)-propionylamino]-6fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-(3-tert-Butoxycarbonylamino-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[(S)-3-(4-fluoro-phenyl)-2-phenyl-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[(S)-3-(4-methoxy-phenyl)-2-phenyl-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(2-fluoro-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-(6-Fluoro-3-{(2RS)-2-[(4-fluoro-phenylcarbamoyl)-methyl]-3-phenyl-propionylamino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{3-[(2RS)-2-Benzyl-3,3-dimethyl-butyrylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[3-(3-fluoro-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[(2R)-2-methyl-3-phenyl-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(2,2-Dimethyl-3-phenyl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[6-Fluoro-3-(3-methyl-3-phenyl-butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{6-Fluoro-3-[(3S)-3-phenyl-butyrylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(2-Benzyloxy-acetylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[6-Fluoro-3-(4-phenyl-butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{8-Chloro-6-fluoro-3-[3-(2-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-6-fluoro-3-[3-(2-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{8-Chloro-6-fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-6-fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)- {8-Chloro-6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{8-Chloro-6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{8-Chloro-6-fluoro-3-[3-(3-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-6-fluoro-3-[3-(3-methylphenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{8-Chloro-6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-[8-Chloro-6-fluoro-3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[8-Chloro-6-fluoro-3-(3-phenyl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{8-Chloro-6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{8-Chloro-3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-[8-Chloro-6-fluoro-3-(3-1H-indol-3-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[8-Chloro-6-fluoro-3-(3-1H-indol-3-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{8-Chloro-3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{8-Chloro-6-fluoro-3-[2-(2-methylphenyl)-oxy-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-6-fluoro-3-[2-(2-methylphenyl)-oxy-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-[3-(3-Benzo[1,3]dioxol-5-yl-propionylamino)-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(3-Benzo[1,3]dioxol-5-yl-propionylamino)-8-chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3R)-{8-Chloro-6-fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-6-fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{8-Chloro-3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-{8-Chloro-3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{8-Chloro-3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3R)-[8-Chloro-6-fluoro-3-(2-indan-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[8-Chloro-6-fluoro-3-(2-indan-2-yl-acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[6-Fluoro-3-(1-methyl-3-phenethyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{3-[3-(2-Chloro-benzyl)-1-methyl-ureido]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(3-Benzyl-1-methyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(Benzyloxycarbonyl-methyl-amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

{(3S)-3-[(2-Chloro-benzyloxycarbonyl)-methyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-(6-Fluoro-3-{[2-(4-methoxy-phenyl)-acetyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(6-Fluoro-3-{methyl-[2-(4-methylphenyl)-acetyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(6-Fluoro-3-{[2-(2-methoxy-phenyl)-acetyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{6-Fluoro-3-[(2-indan-2-yl-acetyl)-methyl-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-(3-{[2-(3-Chloro-phenyl)-acetyl]-methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(6-Fluoro-3-{methyl-[2-(3-methylphenyl)-acetyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(6-Fluoro-3-{[2-(3-methoxy-phenyl)-acetyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-{[2-(2-Chloro-phenoxy)-acetyl]-methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-{[2-(4-Chloro-phenoxy)-acetyl]-methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(6-Fluoro-3-{[3-(3-methoxy-phenyl)-propionyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(6-Fluoro-3-{methyl-[2-(2-methylphenyl)-acetyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{3-[(3,3-Diphenyl-propionyl)-methyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{6-Fluoro-3-[(3-1H-indol-3-yl-propionyl)-methyl-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[(2-Benzyloxy-acetyl)-methyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[(2,3-Diphenyl-propionyl)-methyl-aminol-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[[3-(2-methoxy-phenyl)-propionyl]-(3-phenyl-propyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-Benzyl-(1-cyclopropylmethyl)-ureido]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(Benzyloxycarbonyl-cyclopropylmethyl-amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{3-[Cyclopropylmethyl-(3-phenyl-propionyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[Cyclopropylmethyl-((S)-2-methyl-3-phenyl-propionyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl} -acetic acid;

(3S)-(3-{Cyclopropylmethyl-[3-(2-methoxy-phenyl)-propionyl]-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(3-{[2-(3-Chloro-phenoxy)-acetyl]-cyclopropylmethyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{3-[Cyclopropylmethyl-(3,3-diphenyl-propionyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[Cyclopropylmethyl-(2-naphthalen-1-yl-acetyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-(3-{Benzyloxycarbonyl-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(6-Fluoro-3-{(3-phenyl-propionyl)-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{6-Fluoro-3-[(2-phenoxy-ethyl)-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[((S)-2-methyl-3-phenyl-propionyl)-(2-phenoxy-ethyl)amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[[3-(2-methoxy-phenyl)-propionyl]-(2-phenoxy-ethyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[3-Benzyl-1-(2-methoxy-ethyl)-ureido]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[Benzyloxycarbonyl-(2-methoxy-ethyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[(2-methoxy-ethyl)-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[(2-methoxy-ethyl)-((S)-2-methyl-3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl} -acetic acid;

(3S)-(6-Fluoro-3-{(2-methoxy-ethyl)-[3-(2-methoxy-phenyl)-propionyl]-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{3-[[2-(3-Chloro-phenoxy)-acetyl]-(2-methoxy-ethyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[(3,3-Diphenyl-propionyl)-(2-methoxy-ethyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[(2-methoxy-ethyl)-(2-naphthalen-1-yl-acetyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-(6-Fluoro-3-{[(2S)-2-methyl-3-phenyl-propionyl]-phenethyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-phenethyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{6-Fluoro-3-[(2-naphthalen-1-yl-acetyl)-phenethyl-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[phenethyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(3-Benzyl-1-naphthalen-1-ylmethyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(Benzyloxycarbonyl-naphthalen-1-ylmethyl-amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{6-Fluoro-3-[naphthalen-1-ylmethyl-(3-phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{6-Fluoro-3-[((S)-2-methyl-3-phenyl-propionyl)-naphthalen-1-ylmethyl-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-naphthalen-1-ylmethyl-amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;

(3S)-{3-[(3,3-Diphenyl-propionyl)-naphthalen-1-ylmethyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[(RS)-2-Benzyl-3-(2-methylphenyl)-carbamoyl-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{-[(RS)-2-Benzyl-3-(3-methoxy-phenylcarbamoyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[(RS)-2-Benzyl-3-(4-chloro-phenylcarbamoyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-{3-[(RS)-2-Benzyl-3-(4-fluoro-benzylcarbamoyl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

[(3S)-3-((RS)-2-Benzyl-3-propylcarbamoyl-propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[6-Fluoro-3-(3-thiophen-2-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{3-[3-(3-Chloro-isoxazol-5-yl)-propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[6-Fluoro-3-(3-pyrimidin-2-yl-propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-{6-Fluoro-3-[3-phenyl-4-([1,3,4]thiadiazol-2-ylcarbamoyl)-butyrylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;

(3S)-[3-(1,3-Dibenzyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

(3S)-[3-(3-Benzyl-1-cyclohexylmethyl-ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; and

(3S)-(3-{Cyclohexylmethyl-[3-(2-methoxy-phenyl)-propionyl]-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
or a salt of such a compound.
A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for use as a medicament.
Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of chronic and acute allergic/immune diseases/disorders, comprising allergic asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease, dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases comprising Churg-Strauss syndrome and sinusitis, and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.