# Patent

## Title
(3-amino-1,2,3,4-tetrahydro-9 H-carbazol-9-yl)-acetic acid derivatives

## Abstract

The present invention relates to (3-amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid derivatives of Formula (I) wherein R1, R2, R3, R4, R5 and R6 are as described in the description and their use as prostaglandin receptor modulators, most particularly as prostaglandin D2 receptor modulators, in the treatment of various prostaglandin-mediated diseases and disorders, to pharmaceutical compositions containing these compounds and to processes for their preparation.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the U.S. National Phase Application of International Application No. PCT/IB2007/053046, filed Aug. 2, 2007, which claims the benefit of PCT/IB2006/052723, filed Aug. 7, 2006, the disclosures of each of which is incorporated by reference.
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, C1-4-alkoxy, 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-alkylamino carbonyl; aryl-C1-6-alkylcarbonyl; aryl-C1-3-alkoxy-C1-3-alkylcarbonyl; arylcarbonyl; arylcarbonyl-C1-4-alkylcarbonyl; aryloxy-C1-3-alkylcarbonyl; aryl sulfonylamino carbonyl; 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-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-alkylamino carbonyl, 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; arylamino carbonyl, such as naphthalenaminocarbonyl (especially naphthalen-1-amino carbonyl), 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-alkylamino carbonyl; aryl-C1-6-alkylcarbonyl; aryl-C1-3-alkoxy-C1-3-alkylcarbonyl; arylcarbonyl; arylcarbonyl-C1-4-alkylcarbonyl; aryloxy-C1-3-alkylcarbonyl; aryl sulfonylamino carbonyl; cyclo alkyl-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-alkylamino carbonyl, or aryl-C1-3-alkylamino carbonyl;
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-alkylamino carbonyl, or aryl-C1-3-alkylamino carbonyl;
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-alkylamino carbonyl; 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-alkylamino carbonyl;
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-C1-2-alkylaminocarbonyl; 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-alkylamino carbonyl, or aryl-C1-3-alkylamino carbonyl;
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; 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.


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

    (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)-{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)-[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.


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

    (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.


In another embodiment preferred compounds of Formula I are 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)-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-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-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 C1-6-alkyl group in an aryl-C1-6-alkylcarbonyl group which is placed between the aryl and the carbonyl moiety; the bridging C1-4-alkyl group in an aryl-C1-4-alkyl group, which is placed between the aryl moiety and the parent molecular moiety; or the bridging C1-4-alkyl group in an R7—C1-4-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 C1-9-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, tent-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 C1-6-alkyl group as used in “aryl-C1-6-alkylcarbonyl” as defined for R6 preferably means a C2-4-alkyl group, whereby the aryl moiety and the carbonyl moiety are preferably attached to two different carbon atoms of the bridging C2-4-alkyl group. Preferred examples of bridging C1-6-alkyl groups as used in R6 being aryl-C1-6-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 C1-6-alkyl group as used in “aryl-C1-6-alkylcarbonyl” as defined for R6 means the respective C1-6-alkyl group, whereby the aryl moiety and the carbonyl moiety preferably are attached to the same carbon atom of the bridging C1-6-alkyl group. Examples of such bridging C1-6-alkyl groups as used in R6 being aryl-C1-6-alkylcarbonyl are a methylene group (preferred) and ethane-1,1-diyl.
A bridging C1-3-alkyl group as used in “diaryl-C1-3-alkylcarbonyl” as defined for R6 preferably means a C2-3-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 C2-3-alkyl group. Preferred examples of such bridging C1-3-alkyl groups as used in R6 being diaryl-C1-3-alkylcarbonyl are ethane-1,2,2-triyl, and ethane-1,1,2-triyl.
A bridging C1-4-alkyl group as used in “R7—C1-4-alkylcarbonyl, wherein the bridging C1-4-alkyl group may additionally be mono-substituted with aryl” as defined for R6 preferably means a C2-4-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 C2-4-alkyl group. Examples of bridging C1-4-alkyl groups as used in R6 being “R7—C1-4-alkylcarbonyl, wherein the bridging C1-4-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 C1-4-alkyl group as used in R6 being “R7—C1-4-alkylcarbonyl, wherein the bridging C1-4-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 (RaRbC═CRcRd). Ra—Rd 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 “C1-2-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, tent-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, 1-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-methyl-butyl, 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 C3-6-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 C1-4-alkyl, C1-4-alkoxy, and halogen (especially C1-4-alkoxy). In case the cycloalkyl group is used as a bridging group as for example in an “aryl-C3-6-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 C1-9-alkylcarbonyl, arylalkenylcarbonyl, aryl-C1-6-alkylcarbonyl, aryl-C1-3-alkoxy-C1-3-alkylcarbonyl, arylcarbonyl, arylcarbonyl-C1-4-alkylcarbonyl, aryloxy-C1-3-alkylcarbonyl, cycloalkyl-C1-3-alkylcarbonyl, diaryl-C1-3-alkylcarbonyl, heterocyclylcarbonyl, heteroaryl-C1-3-alkylcarbonyl, heteroarylcarbonyl, aryl-C3-6-cycloalkylcarbonyl, cycloalkylcarbonyl, or R7—C1-4-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 C1-9-alkylaminocarbonyl, arylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl that are linked to the parent molecular moiety through a nitrogen atom.
The term “oxycarbonylamino” as used herein refers to groups such as C1-9-alkoxycarbonyl, aryl-C1-3-alkoxycarbonyl, or aryl-C1-3-alkoxy-C1-3-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 (FLIPRTM, Molecular Devices, Sunnyvale, Calif.), 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, Colo., 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 C1-4-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 C1-4-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 C1-5-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(0), 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 are 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—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”, 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 C1-4-alkyl group may additionally be mono-substituted with aryl is obtained by treating a respective compound of Structure 8b, wherein R′ represents C1-4-alkyl, preferentially tent-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 C1-4-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
    1 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 ZQTM 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 XterraTM MS C18 column (4.6×50 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 (4.6×50 mm, 5 μm, 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 (4.6×50 mm, 5 μm, 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, 21.2×50 mm) or a Phenomenex® Gemini column (10 μm, 21.2×50 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 dimethylsulfoxide 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.











TABLE 1









MS





tR [min]
Data




Formula
LC-MS
m/z


Example
Compound of Formula I
MW
Method
[M + H]+



















1
(3R)-[3-(3-Butyl-ureido)-1,2,3,4-tetrahydro-
C19H25N3O3
1.01
344.08



9H-carbazol-9-yl]-acetic acid
343.426
LC-1


2
(3R)-[3-(3-Benzyl-ureido)-1,2,3,4-tetrahydro-
C22H23N3O3
1.15
378.04



9H-carbazol-9-yl]-acetic acid
377.443
LC-1


3
(3R)-[3-(3-Phenethyl-ureido)-1,2,3,4-
C23H25N3O3
1.32
392.05



tetrahydro-9H-carbazol-9-yl]-acetic acid
391.47
LC-1


4
(3R)-[3-(3-Naphthalen-1-yl-ureido)-1,2,3,4-
C25H23N3O3
1.7
413.97



tetrahydro-9H-carbazol-9-yl]-acetic acid
413.476
LC-1


5
(3R)-[3-(3-Phenylsulfonyl-ureido)-1,2,3,4-
C21H21N3O5S
1.13
[M + Na]+



tetrahydro-9H-carbazol-9-yl]-acetic acid
427.48
LC-1
449.90


6
(3R)-(3-tert-Butoxycarbonylamino-1,2,3,4-
C19H24N2O4
1.05
[M + Na]+



tetrahydro-9H-carbazol-9-yl)-acetic acid
344.10
LC-1
367.07


7
(3R)-(3-Propoxycarbonylamino-1,2,3,4-
C18H22N2O4
1.35
331.03



tetrahydro-9H-carbazol-9-yl)-acetic acid
330.383
LC-1


8
(3R)-(3-Isobutoxycarbonylamino-1,2,3,4-
C19H24N2O4
1.69
345.03



tetrahydro-9H-carbazol-9-yl)-acetic acid
344.41
LC-1


9
(3R)-(3-Benzyloxycarbonylamino-1,2,3,4-
C22H22N2O4
1.82
[M + Na]+



tetrahydro-9H-carbazol-9-yl)-acetic acid
378.427
LC-1
400.96


10
(3R)-[3-(2-Benzyloxy-ethoxycarbonylamino)-
C24H26N2O5
1.77
[M + Na]+



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
422.479
LC-1
444.94



acid


11
(3R)-(3-Benzoylamino-1,2,3,4-tetrahydro-9H-
C21H20N2O3
1.00
349.00



carbazol-9-yl)-acetic acid
348.401
LC-2


12
(3R)-[3-(2-Phenoxy-acetylamino)-1,2,3,4-
C22H22N2O4
1.43
379.04



tetrahydro-9H-carbazol-9-yl]-acetic acid
378.427
LC-1


13
(3R)-(3-Phenylacetylamino-1,2,3,4-
C22H22N2O3
1.21
363.02



tetrahydro-9H-carbazol-9-yl)-acetic acid
362.428
LC-1


14
(3R)-[3-(2-Thiophen-2-yl-acetylamino)-
C20H20N2O3S
1.11
368.96



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
368.456
LC-1



acid


15
(3R)-[3-(3-Phenyl-propionylamino)-1,2,3,4-
C23H24N2O3
1.36
377.04



tetrahydro-9H-carbazol-9-yl]-acetic acid
376.455
LC-1


16
(3R)-[3-(2-Benzyloxy-acetylamino)-1,2,3,4-
C23H24N2O4
1.44
392.98



tetrahydro-9H-carbazol-9-yl]-acetic acid
392.454
LC-1


17
(3R)-[3-(3-Methyl-butyrylamino)-1,2,3,4-
C19H24N2O3
0.97
329.08



tetrahydro-9H-carbazol-9-yl]-acetic acid
328.411
LC-1


18
(3R)-[3-(3-Cyclopentyl-propionylamino)-
C22H28N2O3
1.77
369.07



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
368.475
LC-1



acid


19
(3R)-(3-Decanoylamino-1,2,3,4-tetrahydro-
C24H34N2O3
2.77
399.10



9H-carbazol-9-yl)-acetic acid
398.545
LC-1


20
(3S)-[3-(3-Butyl-ureido)-1,2,3,4-tetrahydro-
C19H25N3O3
0.98
344.18



9H-carbazol-9-yl]-acetic acid
343.426
LC-2


21
(3S)-[3-(3-Benzyl-ureido)-1,2,3,4-tetrahydro-
C22H23N3O3
0.99
378.18



9H-carbazol-9-yl]-acetic acid
377.443
LC-2


22
(3S)-[3-(3-Phenethyl-ureido)-1,2,3,4-
C23H25N3O3
1.01
392.17



tetrahydro-9H-carbazol-9-yl]-acetic acid
391.47
LC-2


23
(3S)-[3-(3-Phenylsulfonyl-ureido)-1,2,3,4-
C21H21N3O5S
0.99
428.05



tetrahydro-9H-carbazol-9-yl]-acetic acid
427.48
LC-2


24
(3S)-[3-(3-Phenyl-ureido)-1,2,3,4-tetrahydro-
C21H21N3O3
1.00
364.13



9H-carbazol-9-yl]-acetic acid
363.416
LC-2


25
(3S)-(3-Propoxycarbonylamino-1,2,3,4-
C18H22N2O4
1.01
331.17



tetrahydro-9H-carbazol-9-yl)-acetic acid
330.383
LC-2


26
(3S)-(3-Isobutoxycarbonylamino-1,2,3,4-
C19H24N2O4
1.04
345.15



tetrahydro-9H-carbazol-9-yl)-acetic acid
344.41
LC-2


27
(3S)-(3-Benzyloxycarbonylamino-1,2,3,4-
C22H22N2O4
1.06
379.15



tetrahydro-9H-carbazol-9-yl)-acetic acid
378.427
LC-2


28
(3S)-[3-(2-Benzyloxy-ethoxycarbonylamino)-
C24H26N2O5
1.06
423.20



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
422.479
LC-2



acid


29
(3S)-[3-(2-Phenoxy-acetylamino)-1,2,3,4-
C22H22N2O4
1.02
379.08



tetrahydro-9H-carbazol-9-yl]-acetic acid
378.427
LC-2


30
(3S)-(3-Phenylacetylamino-1,2,3,4-
C22H22N2O3
1.00
363.16



tetrahydro-9H-carbazol-9-yl)-acetic acid
362.428
LC-2


31
(3S)-[3-(2-Thiophen-2-yl-acetylamino)-
C20H20N2O3S
0.99
369.11



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
368.456
LC-2



acid


32
(3S)-[3-(3-Phenyl-propionylamino)-1,2,3,4-
C23H24N2O3
1.02
377.08



tetrahydro-9H-carbazol-9-yl]-acetic acid
376.455
LC-2


33
(3S)-[3-(2-Benzyloxy-acetylamino)-1,2,3,4-
C23H24N2O4
1.03
393.14



tetrahydro-9H-carbazol-9-yl]-acetic acid
392.454
LC-2


34
(3S)-[3-(3-Methyl-butyrylamino)-1,2,3,4-
C19H24N2O3
0.97
329.16



tetrahydro-9H-carbazol-9-yl]-acetic acid
328.411
LC-2


35
(3S)-[3-(3-Cyclopentyl-propionylamino)-
C22H28N2O3
1.01
369.18



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
368.475
LC-2



acid


36
(3S)-(3-Decanoylamino-1,2,3,4-tetrahydro-
C24H34N2O3
1.16
398.82



9H-carbazol-9-yl)-acetic acid
398.545
LC-2


37
(3S)-(3-Butyrylamino-1,2,3,4-tetrahydro-9H-
C18H22N2O3
0.94
315.18



carbazol-9-yl)-acetic acid
314.384
LC-2


38
(3S)-(3-Heptanoylamino-1,2,3,4-tetrahydro-
C21H28N2O3
1.06
357.20



9H-carbazol-9-yl)-acetic acid
356.464
LC-2


39
(3R)-[6-Fluoro-3-(2-phenoxy-acetylamino)-
C22H21N2O4F
1.04
397.16



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
396.417
LC-2



acid


40
(3R)-(6-Fluoro-3-phenylacetylamino-1,2,3,4-
C22H21N2O3F
1.01
381.16



tetrahydro-9H-carbazol-9-yl)-acetic acid
380.418
LC-2


41
(3R)-[6-Fluoro-3-(3-phenyl-propionylamino)-
C23H23N2O3F
1.03
395.22



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
394.445
LC-2



acid


42
(3R)-{3-[2-(4-Chloro-phenyl)-acetylamino]-6-
C22H20N2O3ClF
1.05
415.16



fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
414.863
LC-2



acetic acid


43
(3R)-{6-Fluoro-3-[2-(4-methoxy-phenyl)-
C23H23N2O4F
1.01
411.22



acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-
410.444
LC-2



9-yl}-acetic acid


44
(3R)-[6-Fluoro-3-(2-p-tolyl-acetylamino)-
C23H23N2O3F
1.04
395.22



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
394.445
LC-2



acid


45
(3R)-{3-[2-(3,4-Dichloro-phenyl)-
C22H19N2O3Cl2F
1.09
447.16



acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
449.308
LC-2



carbazol-9-yl}-acetic acid


46
(3R)-{3-[2-(3-Chloro-phenyl)-acetylamino]-6-
C22H20N2O3ClF
1.06
415.16



fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
414.863
LC-2



acetic acid


47
(3R)-{6-Fluoro-3-[2-(4-trifluoromethyl-phenyl)-
C23H20N2O3F4
1.08
449.17



acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-
448.415
LC-2



9-yl}-acetic acid


48
(3R)-{3-[2-(4-Chloro-phenoxy)-acetylamino]-
C22H20N2O4ClF
1.08
431.16



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
430.862
LC-2



acetic acid


49
(3R)-[6-Fluoro-3-(2-p-tolyloxy-acetylamino)-
C23H23N2O4F
1.08
411.22



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
410.444
LC-2



acid


50
(3R)-{3-[2-(2-Chloro-phenoxy)-acetylamino]-
C22H20N2O4ClF
1.07
431.16



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
430.862
LC-2



acetic acid


51
(3R)-{3-[2-(3-Chloro-phenoxy)-acetylamino]-
C22H20N2O4ClF
1.08
431.16



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
430.862
LC-2



acetic acid


52
(3R)-{6-Fluoro-3-[3-(4-methoxy-phenyl)-
C24H25N2O4F
1.03
425.28



propionylamino]-1,2,3,4-tetrahydro-9H-
424.471
LC-2



carbazol-9-yl}-acetic acid


53
(3R)-[6-Fluoro-3-(3-p-tolyl-propionylamino)-
C24H25N2O3F
1.06
409.21



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
408.472
LC-2



acid


54
(3R)-{3-[3-(4-Chloro-phenyl)-propionylamino]-
C23H22N2O3ClF
1.07
429.15



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
428.89
LC-2



acetic acid


55
(3R)-{3-[3-(2-Chloro-phenyl)-propionylamino]-
C23H22N2O3ClF
1.07
429.15



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
428.89
LC-2



acetic acid


56
(3R)-{3-[3-(3-Chloro-phenyl)-propionylamino]-
C23H22N2O3ClF
1.07
429.15



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
428.89
LC-2



acetic acid


57
(3S)-{3-[2-(4-Chloro-phenyl)-acetylamino]-6-
C22H20N2O3ClF
1.05
415.23



fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
414.863
LC-2



acetic acid


58
(3S)-{6-Fluoro-3-[2-(4-methoxy-phenyl)-
C23H23N2O4F
1.01
411.22



acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-
410.444
LC-2



9-yl}-acetic acid


59
(3S)-[6-Fluoro-3-(2-p-tolyl-acetylamino)-
C23H23N2O3F
1.01
395.15



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
394.445
LC-2



acid


60
(3S)-[6-Fluoro-3-(2-phenoxy-acetylamino)-
C22H21N2O4F
1.04
397.23



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
396.417
LC-2



acid


61
(3S)-[6-Fluoro-3-(3-phenyl-propionylamino)-
C23H23N2O3F
1.03
395.22



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
394.445
LC-2



acid


62
(3S)-{3-[2-(4-Chloro-phenoxy)-acetylamino]-
C22H20N2O4ClF
1.08
431.16



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
430.862
LC-2



acetic acid


63
(3S)-[6-Fluoro-3-(2-p-tolyloxy-acetylamino)-
C23H23N2O4F
1.07
411.22



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
410.444
LC-2



acid


64
(3S)-{6-Fluoro-3-[3-(4-methoxy-phenyl)-
C24H25N2O4F
1.03
425.21



propionylamino]-1,2,3,4-tetrahydro-9H-
424.471
LC-2



carbazol-9-yl}-acetic acid


65
(3S)-[6-Fluoro-3-(3-p-tolyl-propionylamino)-
C24H25N2O3F
1.06
409.21



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
408.472
LC-2



acid


66
(3S)-{3-[3-(4-Chloro-phenyl)-propionylamino]-
C23H22N2O3ClF
1.07
429.15



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
428.89
LC-2



acetic acid


67
(3S)-{3-[3-(2-Chloro-phenyl)-propionylamino]-
C23H22N2O3ClF
1.07
429.15



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
428.89
LC-2



acetic acid


68
(3S)-{3-[3-(3-Chloro-phenyl)-propionylamino]-
C23H22N2O3ClF
1.07
429.15



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
428.89
LC-2



acetic acid


69
(3S)-{3-[3-(3,4-Difluoro-phenyl)-
C23H21N2O3F3
1.05
431.26



propionylamino]-6-fluoro-1,2,3,4-tetrahydro-
430.425
LC-2



9H-carbazol-9-yl}-acetic acid


70
(3S)-{6-Fluoro-3-[3-(3-methoxy-phenyl)-
C24H25N2O4F
1.03
425.21



propionylamino]-1,2,3,4-tetrahydro-9H-
424.471
LC-2



carbazol-9-yl}-acetic acid


71
(3S)-{6-Fluoro-3-[3-(2-methoxy-phenyl)-
C24H25N2O4F
1.04
425.21



propionylamino]-1,2,3,4-tetrahydro-9H-
424.471
LC-2



carbazol-9-yl}-acetic acid


72
(3S)-[3-(2,3-Diphenyl-propionylamino)-6-
C29H27N2O3F
1.12
471.27



fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
470.542
LC-2



acetic acid


73
(3S)-[3-(3,3-Diphenyl-propionylamino)-6-
C29H27N2O3F
1.1
471.20



fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
470.542
LC-2



acetic acid


74
(3S)-{3-[4-(4-Bromo-phenyl)-4-oxo-
C24H22N2O4BrF
1.07
503.06



butyrylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
501.351
LC-2



carbazol-9-yl}-acetic acid


75
(3S)-[6-Fluoro-3-(4-oxo-4-phenyl-
C24H23N2O4F
1.02
423.20



butyrylamino)-1,2,3,4-tetrahydro-9H-
422.455
LC-2



carbazol-9-yl]-acetic acid


76
(3S)-{6-Fluoro-3-[4-(4-methanesulfonyl-
C25H25N2O6FS
0.97
501.19



phenyl)-4-oxo-butyrylamino]-1,2,3,4-
500.545
LC-2



tetrahydro-9H-carbazol-9-yl}-acetic acid


77
(3S)-[6-Fluoro-3-(2-indan-2-yl-acetylamino)-
C25H25N2O3F
1.07
421.19



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic
420.483
LC-2



acid


78
(3S)-{6-Fluoro-3-[3-(4-hydroxy-3-methoxy-
C24H25N2O5F
0.98
441.00



phenyl)-propionylamino]-1,2,3,4-tetrahydro-
440.47
LC-2



9H-carbazol-9-yl}-acetic acid


79
(3S)-{6-Fluoro-3-[3-(4-hydroxy-phenyl)-
C23H23N2O4F
0.97
411.02



propionylamino]-1,2,3,4-tetrahydro-9H-
410.444
LC-2



carbazol-9-yl}-acetic acid


80
(3S)-{6-Fluoro-3-[3-(3-hydroxy-phenyl)-
C23H23N2O4F
0.99
411.02



propionylamino]-1,2,3,4-tetrahydro-9H-
410.444
LC-2



carbazol-9-yl}-acetic acid


81
(3S)-{6-Fluoro-3-[3-(2-hydroxy-phenyl)-
C23H23N2O4F
1.02
411.02



propionylamino]-1,2,3,4-tetrahydro-9H-
410.444
LC-2



carbazol-9-yl}-acetic acid


82
(3S)-{3-[(2,3-Dihydro-1H-indole-2-carbonyl)-
C23H22N3O3F
1.04
408.04



amino]-6-fluoro-1,2,3,4-tetrahydro-9H-
407.444
LC-2



carbazol-9-yl}-acetic acid


83
(3S)-[6-Fluoro-3-(3-1H-indol-3-yl-
C25H24N3O3F
1.04
434.07



propionylamino)-1,2,3,4-tetrahydro-9H-
433.482
LC-2



carbazol-9-yl]-acetic acid


84
(3S)-[3-(3-1H-Benzoimidazol-2-yl-
C24H23N4O3F
0.79
435.04



propionylamino)-6-fluoro-1,2,3,4-tetrahydro-
434.47
LC-2



9H-carbazol-9-yl]-acetic acid


85
(3S)-[3-(3-Benzo[1,3]dioxol-5-yl-
C24H23N2O5F
1.04
438.99



propionylamino)-6-fluoro-1,2,3,4-tetrahydro-
438.454
LC-2



9H-carbazol-9-yl]-acetic acid


86
(3S)-{6-Fluoro-3-[(1H-indole-2-carbonyl)-
C23H20N3O3F
1.07
406.03



amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
405.428
LC-2



acetic acid


87
(3S)-[6-Fluoro-3-(3-pyridin-3-yl-
C22H22N3O3F
0.7
396.11



propionylamino)-1,2,3,4-tetrahydro-9H-
395.433
LC-3



carbazol-9-yl]-acetic acid


88
(3S)-{3-[2-(4-tert-Butyl-phenyl)-acetylamino]-
C26H29N2O3F
1.02
437.17



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
436.525
LC-3



acetic acid


89
(3S)-{6-Fluoro-3-[2-(4-trifluoromethyl-phenyl)-
C23H20N2O3F4
0.98
449.14



acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-
448.415
LC-3



9-yl}-acetic acid


90
(3S)-{6-Fluoro-3-[2-(3-trifluoromethyl-phenyl)-
C23H20N2O3F4
0.98
449.09



acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-
448.415
LC-3



9-yl}-acetic acid


91
(3S)-{6-Fluoro-3-[2-(4-trifluoromethyl-
C23H20N2O4F4
1.00
465.15



phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-
464.414
LC-3



carbazol-9-yl}-acetic acid


92
(3S)-[6-Fluoro-3-(3-naphthalen-2-yl-
C27H23N2O3F
1.01
443.07



acryloylamino)-1,2,3,4-tetrahydro-9H-
442.489
LC-3



carbazol-9-yl]-acetic acid


93
(3S)-[6-Fluoro-3-(3-naphthalen-2-yl-
C27H25N2O3F
0.99
445.15



propionylamino)-1,2,3,4-tetrahydro-9H-
444.505
LC-3



carbazol-9-yl]-acetic acid


94
(3S)-{6-Fluoro-3-[methyl-(3-phenyl-
C24H25N2O3F
0.98
409.16



propionyl)-amino]-1,2,3,4-tetrahydro-9H-
408.472
LC-3



carbazol-9-yl}-acetic acid


95
(3S)-(3-{[2-(4-Chloro-phenyl)-acetyl]-methyl-
C23H22N2O3ClF
0.99
429.10



amino}-6-fluoro-1,2,3,4-tetrahydro-9H-
428.89
LC-3



carbazol-9-yl)-acetic acid


96
(3S)-{6-Fluoro-3-[ethyl-(3-phenyl-propionyl)-
C25H27N2O3F
0.99
423.10



amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
422.498
LC-3



acetic acid


97
(3S)-(3-{[2-(4-Chloro-phenyl)-acetyl]-ethyl-
C24H24N2O3ClF
1.01
443.06



amino}-6-fluoro-1,2,3,4-tetrahydro-9H-
442.917
LC-3



carbazol-9-yl)-acetic acid


98
(3S)-{6-Fluoro-3-[propyl-(3-phenyl-propionyl)-
C26H29N2O3F
1.02
437.20



amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
436.525
LC-3



acetic acid


99
(3S)-(3-{[2-(4-Chloro-phenyl)-acetyl]-propyl-
C25H26N2O3ClF
1.03
457.21



amino}-6-fluoro-1,2,3,4-tetrahydro-9H-
456.943
LC-3



carbazol-9-yl)-acetic acid


100
(3RS)-(3-Benzyloxycarbonylamino-6-fluoro-
C22H21N2O4F
0.98
397.11



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic
396.410
LC-3



acid


101
(3RS)-(3-Benzyloxycarbonylamino-8-chloro-
C22H20N2O4ClF
1.01
431.05



6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
430.862
LC-3



acetic acid


102
(3RS)-(3-Benzyloxycarbonylamino-8-chloro-
C22H20N2O4ClF
1.01
431.04



5-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
430.862
LC-3



acetic acid









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.











TABLE 1a








tR [min]
MS Data




Formula
LCMS
m/z


Example
Compound of Formula I
MW
Method
[M + H]+



















103
(3RS)-[3-(3-Benzyl-ureido)-6-fluoro-
C22H22N3O3F
0.92
396.17



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
395.433
LC-3



acetic acid


104
(3S)-[6-Fluoro-3-(3-phenethyl-
C23H24N3O3F
0.92
410.52



ureido)-1,2,3,4-tetrahydro-9H-
409.46
LC-3



carbazol-9-yl]-acetic acid


105
(3RS)-[3-(3-Benzyl-ureido)-8-chloro-
C22H21N3O3ClF
0.95
430.07



6-fluoro-1,2,3,4-tetrahydro-9H-
429.878
LC-3



carbazol-9-yl]-acetic acid


106
(3RS)-[8-Chloro-6-fluoro-3-(3-
C23H23N3O3ClF
0.97
444.07



phenethyl-ureido)-1,2,3,4-tetrahydro-
443.905
LC-3



9H-carbazol-9-yl]-acetic acid


107
(3RS)-(3-Benzyloxycarbonylamino-6-
C23H21N2O4F3
1.02
447.25



trifluoromethyl-1,2,3,4-tetrahydro-9H-
446.424
LC-3



carbazol-9-yl)-acetic acid


108
(3RS)-(3-Benzyloxycarbonylamino-8-
C22H20N2O4BrF
1.02
474.98



bromo-6-fluoro-1,2,3,4-tetrahydro-
475.313
LC-3



9H-carbazol-9-yl)-acetic acid


109
(3RS)-(3-Benzyloxycarbonylamino-6-
C24H23N2O4F
1.01
423.15



fluoro-8-vinyl-1,2,3,4-tetrahydro-9H-
422.455
LC-3



carbazol-9-yl)-acetic acid


110
(3RS)-(3-Benzyloxycarbonylamino-6-
C23H23N2O6FS
0.95
475.15



fluoro-8-methanesulfonyl-1,2,3,4-
474.508
LC-3



tetrahydro-9H-carbazol-9-yl)-acetic



acid


111
(3S)-(3-Benzyloxycarbonylamino-6-
C23H23N2O4F
0.99
411.14



fluoro-8-methyl-1,2,3,4-tetrahydro-
410.444
LC-3



9H-carbazol-9-yl)-acetic acid


112
(3S)-(3-Benzyloxycarbonylamino-7-
C22H20N2O4ClF
1.01
431.16



chloro-6-fluoro-1,2,3,4-tetrahydro-
430.862
LC-3



9H-carbazol-9-yl)-acetic acid


113
(3S)-(8-Allyl-3-
C25H25N2O4F
1.02
437.1



benzyloxycarbonylamino-6-fluoro-
436.482
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


114
(3R)-(3-Benzyloxycarbonylamino-8-
C22H21N2O4Cl
1
413.03



chloro-1,2,3,4-tetrahydro-9H-
412.872
LC-3



carbazol-9-yl)-acetic acid


115
(3S)-{3-[3-(2,4-Dimethoxy-phenyl)-
C25H27N2O5F
0.95
455.11



propionylamino]-6-fluoro-1,2,3,4-
454.496
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


116
(3S)-[6-Fluoro-3-(3-naphthalen-1-yl-
C27H25N2O3F
0.99
445.14



propionylamino)-1,2,3,4-tetrahydro-
444.505
LC-3



9H-carbazol-9-yl]-acetic acid


117
(3RS)-{6-Fluoro-3-[2-(2-methoxy-
C23H23N2O5F
0.94
427.16



phenoxy)-acetylamino]-1,2,3,4-
426.443
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


118
(3RS)-{6-Fluoro-3-[3-(2-
C24H25N2O3F
0.97
409.08



methylphenyl)-propionylamino]-
408.472
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


119
(3RS)-{6-Fluoro-3-[3-(3-
C24H25N2O3F
0.97
409.11



methylphenyl)-propionylamino]-
408.472
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


120
(3RS)-{6-Fluoro-3-[3-(3-methoxy-
C24H25N2O4F
0.94
425.1



phenyl)-propionylamino]-1,2,3,4-
424.471
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


121
(3RS)-{6-Fluoro-3-[2-(3-methoxy-
C23H23N2O5F
0.95
427.12



phenoxy)-acetylamino]-1,2,3,4-
426.443
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


122
(3RS)-{6-Fluoro-3-[2-(2-
C23H23N2O4F
0.98
411



methylphenoxy)-acetylamino]-
410.444
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


123
(3S)-{3-[3-(2,5-Dimethoxy-phenyl)-
C25H27N2O5F
0.94
455.19



propionylamino]-6-fluoro-1,2,3,4-
454.496
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


124
(3S)-{6-Fluoro-3-[3-(4-trifluoromethyl-
C24H22N2O3F4
0.99
463.15



phenyl)-propionylamino]-1,2,3,4-
462.442
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


125
(3S)-{3-[3-(2,6-Dichloro-phenyl)-
C23H21N2O3Cl2F
0.99
463.07



propionylamino]-6-fluoro-1,2,3,4-
463.335
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


126
(3S)-{3-[3-(2,5-Bis-trifluoromethyl-
C25H21N2O3F7
1.04
530.97



phenyl)-propionylamino]-6-fluoro-
530.439
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


127
(3S)-{6-Fluoro-3-[3-(4-
C24H25N2O3FS
0.97
441.1



methylsulfanyl-phenyl)-
440.538
LC-3



propionylamino]-1,2,3,4-tetrahydro-



9H-carbazol-9-yl}-acetic acid


128
(3S)-{6-Fluoro-3-[3-(4-iodo-phenyl)-
C23H22N2O3FI
0.99
521.03



propionylamino]-1,2,3,4-tetrahydro-
520.337
LC-3



9H-carbazol-9-yl}-acetic acid


129
(3S)-{6-Fluoro-3-[3-(4-isopropyl-
C26H29N2O3F
1.01
437.17



phenyl)-propionylamino]-1,2,3,4-
436.525
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


130
(3S)-{6-Fluoro-3-[3-(3-trifluoromethyl-
C24H22N2O3F4
0.99
463.13



phenyl)-propionylamino]-1,2,3,4-
462.442
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


131
(3S)-{3-[3-(2,4-Dichloro-phenyl)-
C23H21N2O3Cl2F
1.01
463.08



propionylamino]-6-fluoro-1,2,3,4-
463.335
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


132
(3S)-{6-Fluoro-3-[3-(4-fluoro-phenyl)-
C23H22N2O3F2
0.95
413.08



propionylamino]-1,2,3,4-tetrahydro-
412.435
LC-3



9H-carbazol-9-yl}-acetic acid


133
(3S)-{3-[3-(3,5-Bis-trifluoromethyl-
C25H21N2O3F7
1.03
530.99



phenyl)-propionylamino]-6-fluoro-
530.439
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


134
(3S)-{3-[3-(4-Ethyl-phenyl)-
C25H27N2O3F
0.99
423.12



propionylamino]-6-fluoro-1,2,3,4-
422.498
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


135
(3S)-{6-Fluoro-3-[3-(3-iodo-phenyl)-
C23H22N2O3FI
0.97
521.41



propionylamino]-1,2,3,4-tetrahydro-
520.337
LC-3



9H-carbazol-9-yl}-acetic acid


136
(3S)-{6-Fluoro-3-[3-(4-
C24H25N2O5FS
0.87
473.12



methanesulfonyl-phenyl)-
472.536
LC-3



propionylamino]-1,2,3,4-tetrahydro-



9H-carbazol-9-yl}-acetic acid


137
(3S)-{3-[3-(2,3-Dimethoxy-phenyl)-
C25H27N2O5F
0.94
455.16



propionylamino]-6-fluoro-1,2,3,4-
454.496
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


138
(3S)-{3-[3-(2-Bromo-phenyl)-
C23H22N2O3BrF
0.98
474.97



propionylamino]-6-fluoro-1,2,3,4-
473.341
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


139
(3S)-{6-Fluoro-3-[3-(3-
C24H22N2O4F4
1
479.11



trifluoromethoxy-phenyl)-
478.441
LC-3



propionylamino]-1,2,3,4-tetrahydro-



9H-carbazol-9-yl}-acetic acid


140
(3S)-{3-[3-(2,4-Dimethyl-phenyl)-
C25H27N2O3F
0.99
423.14



propionylamino]-6-fluoro-1,2,3,4-
422.498
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


141
(3S)-{3-[3-(3-Bromo-phenyl)-
C23H22N2O3BrF
0.98
474.93



propionylamino]-6-fluoro-1,2,3,4-
473.341
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


142
(3S)-{3-[3-(3-tert-
C28H32N3O5F
0.98
510.17



Butoxycarbonylamino-phenyl)-
509.576
LC-3



propionylamino]-6-fluoro-1,2,3,4-



tetrahydro-9H-carbazol-9-yl}-acetic



acid


143
(3S)-{6-Fluoro-3-[(S)-3-(4-fluoro-
C29H26N2O3F2
1.02
489.15



phenyl)-2-phenyl-propionylamino]-
488.532
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


144
(3S)-{6-Fluoro-3-[(S)-3-(4-methoxy-
C30H29N2O4F
1.01
501.16



phenyl)-2-phenyl-propionylamino]-
500.568
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


145
(3S)-{6-Fluoro-3-[3-(2-fluoro-phenyl)-
C23H22N2O3F2
0.95
413.09



propionylamino]-1,2,3,4-tetrahydro-
412.435
LC-3



9H-carbazol-9-yl}-acetic acid


146
(3S)-(6-Fluoro-3-{[(2RS)-1,2,3,4-
C25H25N2O3F
0.98
421.11



tetrahydro-naphthalene-2-carbonyl]-
420.483
LC-3



amino}-1,2,3,4-tetrahydro-9H-



carbazol-9-yl)-acetic acid


147
(3S)-(6-Fluoro-3-{[(2RS)-8-methoxy-
C26H27N2O4F
0.98
451.08



1,2,3,4-tetrahydro-naphthalene-2-
450.508
LC-3



carbonyl]-amino}-1,2,3,4-tetrahydro-



9H-carbazol-9-yl)-acetic acid


148
(3S)-(6-Fluoro-3-{(2RS)-2-[(4-fluoro-
C31H29N3O4F2
0.98
546.06



phenylcarbamoyl)-methyl]-3-phenyl-
545.584
LC-3



propionylamino}-1,2,3,4-tetrahydro-



9H-carbazol-9-yl)-acetic acid


149
(3S)-{3-[(2RS)-2-Benzyl-3,3-
C27H31N2O3F
1.02
451.12



dimethyl-butyrylamino]-6-fluoro-
450.552
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


150
(3S)-(6-Fluoro-3-{[(2RS)-8-methoxy-
C24H23N2O4F
0.95
423.11



1,2,3,4-tetrahydro-naphthalene-2-
422.455
LC-3



carbonyl]-amino}-1,2,3,4-tetrahydro-



9H-carbazol-9-yl)-acetic acid


151
(3S)-{6-Fluoro-3-[3-(3-fluoro-phenyl)-
C23H22N2O3F2
0.94
413.08



propionylamino]-1,2,3,4-tetrahydro-
412.435
LC-3



9H-carbazol-9-yl}-acetic acid


152
(3S)-(6-Fluoro-3-{[(2RS)-8-methoxy-
C24H23N2O3F
0.96
407.1



1,2,3,4-tetrahydro-naphthalene-2-
406.456
LC-3



carbonyl]-amino}-1,2,3,4-tetrahydro-



9H-carbazol-9-yl)-acetic acid


153
(3S)-{6-Fluoro-3-[(2R)-2-methyl-3-
C24H25N2O3F
0.95
409.11



phenyl-propionylamino]-1,2,3,4-
408.472
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


154
(3S)-[3-(2,2-Dimethyl-3-phenyl-
C25H27N2O3F
0.99
423.19



propionylamino)-6-fluoro-1,2,3,4-
422.498
LC-3



tetrahydro-9H-carbazol-9-yl]-acetic



acid


155
(3S)-[6-Fluoro-3-(3-methyl-3-phenyl-
C25H27N2O3F
1
423.2



butyrylamino)-1,2,3,4-tetrahydro-9H-
422.498
LC-3



carbazol-9-yl]-acetic acid


156
(3S)-{6-Fluoro-3-[(3S)-3-phenyl-
C24H25N2O3F
0.95
409.2



butyrylamino]-1,2,3,4-tetrahydro-9H-
408.472
LC-3



carbazol-9-yl}-acetic acid


157
(3S)-[3-(2-Benzyloxy-acetylamino)-6-
C23H23N2O4F
0.94
411.06



fluoro-1,2,3,4-tetrahydro-9H-
410.444
LC-3



carbazol-9-yl]-acetic acid


158
(3S)-[6-Fluoro-3-(4-phenyl-
C24H25N2O3F
0.96
409.16



butyrylamino)-1,2,3,4-tetrahydro-9H-
408.472
LC-3



carbazol-9-yl]-acetic acid


159
(3S)-{3-[(2R,3R)-2,3-Dihydroxy-3-(2-
C25H26N3O7F
0.86
500.19



methoxy-phenylcarbamoyl)-
499.493
LC-3



propionylamino]-6-fluoro-1,2,3,4-



tetrahydro-9H-carbazol-9-yl}-acetic



acid


160
(3RS)-{8-Chloro-6-fluoro-3-[3-(2-
C24H24N2O3ClF
1
443.11



methylphenyl)-propionylamino]-
442.917
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


161
(3RS)-{8-Chloro-6-fluoro-3-[2-(2-
C23H22N2O5ClF
0.98
461.18



methoxy-phenoxy)-acetylamino]-
460.888
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


162
(3RS)-{8-Chloro-6-fluoro-3-[3-(3-
C23H22N2O4ClF
0.88
445.32



hydroxy-phenyl)-propionylamino]-
444.889
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


163
(3RS)-{8-Chloro-6-fluoro-3-[3-(3-
C24H24N2O4ClF
0.98
459.04



methoxy-phenyl)-propionylamino]-
458.916
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


164
(3RS)-{8-Chloro-6-fluoro-3-[3-(3-
C24H24N2O3ClF
1.01
443.01



methylphenyl)-propionylamino]-
442.917
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


165
(3RS)-{8-Chloro-6-fluoro-3-[3-(2-
C23H22N2O4ClF
0.92
486.38



hydroxy-phenyl)-propionylamino]-
444.889
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


166
(3RS)-[8-Chloro-6-fluoro-3-(3-phenyl-
C23H22N2O3ClF
0.98
429.13



propionylamino)-1,2,3,4-tetrahydro-
428.89
LC-3



9H-carbazol-9-yl]-acetic acid


167
(3RS)-{8-Chloro-6-fluoro-3-[3-(2-
C24H24N2O4ClF
0.99
459.03



methoxy-phenyl)-propionylamino]-
458.916
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


168
(3RS)-{8-Chloro-3-[3-(3-chloro-
C23H21N2O3Cl2F
1.01
463.11



phenyl)-propionylamino]-6-fluoro-
463.335
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


169
(3RS)-[8-Chloro-6-fluoro-3-(3-1H-
C25H23N3O3ClF
0.97
468.11



indol-3-yl-propionylamino)-1,2,3,4-
467.927
LC-3



tetrahydro-9H-carbazol-9-yl]-acetic



acid


170
(3RS)-{8-Chloro-3-[2-(2-chloro-
C22H19N2O4Cl2F
1.01
465.09



phenoxy)-acetylamino]-6-fluoro-
465.307
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


171
(3RS)-{8-Chloro-6-fluoro-3-[2-(2-
C23H22N2O4ClF
1.02
445.11



methylphenyl)-oxy-acetylamino]-
444.889
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


172
(3RS)-[3-(3-Benzo[1,3]dioxol-5-yl-
C24H22N2O5ClF
0.93
473.17



propionylamino)-8-chloro-6-fluoro-
472.899
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-



acetic acid


173
(3RS)-{8-Chloro-6-fluoro-3-[2-(3-
C23H22N2O5ClF
0.99
461.09



methoxy-phenoxy)-acetylamino]-
460.888
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


174
(3RS)-{8-Chloro-3-[2-(3-chloro-
C22H19N2O4Cl2F
1.02
465



phenoxy)-acetylamino]-6-fluoro-
465.307
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


175
(3RS)-{8-Chloro-3-[3-(2-chloro-
C23H21N2O3Cl2F
1.01
463.07



phenyl)-propionylamino]-6-fluoro-
463.335
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


176
(3RS)-[8-Chloro-6-fluoro-3-(2-indan-
C25H24N2O3ClF
1.01
455.16



2-yl-acetylamino)-1,2,3,4-tetrahydro-
454.928
LC-3



9H-carbazol-9-yl]-acetic acid


177
(3S)-[6-Fluoro-3-(1-methyl-3-
C24H26N3O3F
0.98
429.13



phenethyl-ureido)-1,2,3,4-tetrahydro-
423.486
LC-3



9H-carbazol-9-yl]-acetic acid


178
(3S)-{3-[3-(2-Chloro-benzyl)-1-
C23H23N3O3ClF
0.97
444.16



methyl-ureido]-6-fluoro-1,2,3,4-
443.905
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


179
(3S)-[3-(3-Benzyl-1-methyl-ureido)-6-
C23H24N3O3F
0.94
410.12



fluoro-1,2,3,4-tetrahydro-9H-
409.46
LC-3



carbazol-9-yl]-acetic acid


180
(3S)-[3-(Benzyloxycarbonyl-methyl-
C23H23N2O4F
1.01
411.07



amino)-6-fluoro-1,2,3,4-tetrahydro-
410.444
LC-3



9H-carbazol-9-yl]-acetic acid


181
{(3S)-3-[(2-Chloro-
C23H22N2O4ClF
1.03
445.15



benzyloxycarbonyl)-methyl-amino]-6-
444.889
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


182
(3S)-(6-Fluoro-3-{[2-(4-methoxy-
C24H25N2O4F
0.95
425.19



phenyl)-acetyl]-methyl-amino}-
424.471
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


183
(3S)-(6-Fluoro-3-{methyl-[2-(4-
C24H25N2O3F
0.98
409.18



methylphenyl)-acetyl]-amino}-
408.472
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


184
(3S)-(6-Fluoro-3-{[2-(2-methoxy-
C24H25N2O4F
0.96
425.18



phenyl)-acetyl]-methyl-amino}-
424.471
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


185
(3S)-{6-Fluoro-3-[(2-indan-2-yl-
C26H27N2O3F
1.01
435.16



acetyl)-methyl-amino]-1,2,3,4-
434.509
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


186
(3S)-(3-{[2-(3-Chloro-phenyl)-acetyl]-
C23H22N2O3ClF
0.99
429.13



methyl-amino}-6-fluoro-1,2,3,4-
428.89
LC-3



tetrahydro-9H-carbazol-9-yl)-acetic



acid


187
(3S)-(6-Fluoro-3-{methyl-[2-(3-
C24H25N2O3F
0.98
409.1



methylphenyl)-acetyl]-amino}-
408.472
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


188
(3S)-(6-Fluoro-3-{[2-(3-methoxy-
C24H25N2O4F
0.95
425.08



phenyl)-acetyl]-methyl-amino}-
424.471
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


189
(3S)-(3-{[2-(2-Chloro-phenoxy)-
C23H22N2O4ClF
0.97
445.38



acetyl]-methyl-amino}-6-fluoro-
444.889
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


190
(3S)-(3-{[2-(4-Chloro-phenoxy)-
C23H22N2O4ClF
0.98
445.39



acetyl]-methyl-amino}-6-fluoro-
444.889
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


191
(3S)-(6-Fluoro-3-{[3-(3-methoxy-
C25H27N2O4F
0.96
439.47



phenyl)-propionyl]-methyl-amino}-
438.497
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


192
(3S)-(6-Fluoro-3-{methyl-[2-(2-
C24H25N2O3F
0.96
409.48



methylphenyl)-acetyl]-amino}-
408.472
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


193
(3S)-{3-[(3,3-Diphenyl-propionyl)-
C30H29N2O3F
1.02
485.52



methyl-amino]-6-fluoro-1,2,3,4-
484.569
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


194
(3S)-(6-Fluoro-3-{[3-(2-methoxy-
C25H27N2O4F
0.97
439.45



phenyl)-propionyl]-methyl-amino}-
438.497
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


195
(3S)-{6-Fluoro-3-[(3-1H-indol-3-yl-
C26H26N3O3F
0.94
448.44



propionyl)-methyl-amino]-1,2,3,4-
447.508
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


196
(3S)-{3-[(2-Benzyloxy-acetyl)-methyl-
C24H25N2O4F
0.94
425.44



amino]-6-fluoro-1,2,3,4-tetrahydro-
424.471
LC-3



9H-carbazol-9-yl}-acetic acid


197
(3S)-{3-[(2,3-Diphenyl-propionyl)-
C30H29N2O3F
1.04
485.53



methyl-amino]-6-fluoro-1,2,3,4-
484.569
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


198
(3S)-{6-Fluoro-3-[[3-(2-methoxy-
C33H35N2O4F
1.07
543.18



phenyl)-propionyl]-(3-phenyl-propyl)-
542.649
LC-3



amino]-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


199
(3S)-{3-[Acetyl-(3-phenyl-propyl)-
C25H27N2O3F
1.01
423.14



amino]-6-fluoro-1,2,3,4-tetrahydro-
422.498
LC-3



9H-carbazol-9-yl}-acetic acid


200
(3S)-{3-[3-Benzyl-(1-
C26H28N3O3F
0.99
450.2



cyclopropylmethyl)-ureido]-6-fluoro-
449.524
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


201
(3S)-[3-(Benzyloxycarbonyl-
C26H27N2O4F
1.05
451.15



cyclopropylmethyl-amino)-6-fluoro-
450.508
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-



acetic acid


202
(3S)-{3-[Cyclopropylmethyl-(3-
C27H29N2O3F
1.02
449.25



phenyl-propionyl)-amino]-6-fluoro-
448.536
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


203
(3S)-{3-[Cyclopropylmethyl-((S)-2-
C28H31N2O3F
1.03
463.27



methyl-3-phenyl-propionyl)-amino]-6-
462.563
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


204
(3S)-(3-{Cyclopropylmethyl-[3-(2-
C28H31N2O4F
1.02
479.28



methoxy-phenyl)-propionyl]-amino}-
478.562
LC-3



6-fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl)-acetic acid


205
(3S)-(3-{[2-(3-Chloro-phenoxy)-
C26H26N2O4ClF
1.03
485.2



acetyl]-cyclopropylmethyl-amino}-6-
484.953
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl)-acetic acid


206
(3S)-{3-[Cyclopropylmethyl-(3,3-
C33H33N2O3F
1.07
525.26



diphenyl-propionyl)-amino]-6-fluoro-
524.634
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


207
(3S)-{3-[Cyclopropylmethyl-(2-
C30H29N2O3F
1.04
485.26



naphthalen-1-yl-acetyl)-amino]-6-
484.569
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


208
(3S)-(3-{Benzyloxycarbonyl-[2-(4-
C31H28N2O5F4
1.15
585.14



trifluoromethyl-phenoxy)-ethyl]-
584.564
LC-3



amino}-6-fluoro-1,2,3,4-tetrahydro-



9H-carbazol-9-yl)-acetic acid


209
(3S)-(3-{Acetyl-[2-(4-trifluoromethyl-
C25H24N2O4F4
1.07
493.17



phenoxy)-ethyl]-amino}-6-fluoro-
492.468
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


210
(3S)-(6-Fluoro-3-{propionyl-[2-(4-
C26H26N2O4F4
1.08
507.18



trifluoromethyl-phenoxy)-ethyl]-
506.494
LC-3



amino}-1,2,3,4-tetrahydro-9H-



carbazol-9-yl)-acetic acid


211
(3S)-(6-Fluoro-3-{(3-phenyl-
C32H30N2O4F4
1.13
583.14



propionyl)-[2-(4-trifluoromethyl-
582.592
LC-3



phenoxy)-ethyl]-amino}-1,2,3,4-



tetrahydro-9H-carbazol-9-yl)-acetic



acid


212
(3S)-(6-Fluoro-3-{[3-(2-methoxy-
C33H32N2O5F4
1.13
613.26



phenyl)-propionyl]-[2-(4-
612.618
LC-3



trifluoromethyl-phenoxy)-ethyl]-



amino}-1,2,3,4-tetrahydro-9H-



carbazol-9-yl)-acetic acid


213
(3S)-{6-Fluoro-3-[(2-phenoxy-ethyl)-
C31H31N2O4F
1.06
515.17



(3-phenyl-propionyl)-amino]-1,2,3,4-
514.595
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


214
(3S)-{6-Fluoro-3-[((S)-2-methyl-3-
C32H33N2O4F
1.07
529.26



phenyl-propionyl)-(2-phenoxy-ethyl)-
528.622
LC-3



amino]-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


215
(3S)-{6-Fluoro-3-[[3-(2-methoxy-
C32H33N2O5F
1.06
545.25



phenyl)-propionyl]-(2-phenoxy-ethyl)-
544.621
LC-3



amino]-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


216
(3S)-{3-[Acetyl-(2-phenoxy-ethyl)-
C24H25N2O4F
0.98
425.19



amino]-6-fluoro-1,2,3,4-tetrahydro-
424.471
LC-3



9H-carbazol-9-yl}-acetic acid


217
(3S)-{3-[3-Benzyl-1-(2-methoxy-
C25H28N3O4F
0.97
454.26



ethyl)-ureido]-6-fluoro-1,2,3,4-
453.512
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


218
(3S)-{3-[Benzyloxycarbonyl-(2-
C25H27N2O5F
0.97
454.26



methoxy-ethyl)-amino]-6-fluoro-
454.496
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


219
(3S)-{6-Fluoro-3-[(2-methoxy-ethyl)-
C26H29N2O4F
0.98
453.25



(3-phenyl-propionyl)-amino]-1,2,3,4-
452.524
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


220
(3S)-{6-Fluoro-3-[(2-methoxy-ethyl)-
C27H31N2O4F
1
467.18



((S)-2-methyl-3-phenyl-propionyl)-
466.551
LC-3



amino]-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


221
(3S)-(6-Fluoro-3-{(2-methoxy-ethyl)-
C27H31N2O5F
0.98
483.19



[3-(2-methoxy-phenyl)-propionyl]-
482.55
LC-3



amino}-1,2,3,4-tetrahydro-9H-



carbazol-9-yl)-acetic acid


222
(3S)-{3-[[2-(3-Chloro-phenoxy)-
C25H26N2O5ClF
1
489.17



acetyl]-(2-methoxy-ethyl)-amino]-6-
488.941
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


223
(3S)-{3-[(3,3-Diphenyl-propionyl)-(2-
C32H33N2O4F
1.04
529.28



methoxy-ethyl)-amino]-6-fluoro-
528.622
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


224
(3S)-{6-Fluoro-3-[(2-methoxy-ethyl)-
C29H29N2O4F
1.01
489.24



(2-naphthalen-1-yl-acetyl)-amino]-
488.557
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl}-



acetic acid


225
(3S)-(6-Fluoro-3-{[(2S)-2-methyl-3-
C32H33N2O3F
1.07
513.27



phenyl-propionyl]-phenethyl-amino}-
512.623
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


226
(3S)-(6-Fluoro-3-{[3-(2-methoxy-
C32H33N2O4F
1.06
529.27



phenyl)-propionyl]-phenethyl-amino}-
528.622
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl)-



acetic acid


227
(3S)-[3-(Acetyl-phenethyl-amino)-6-
C24H25N2O3F
0.98
409.16



fluoro-1,2,3,4-tetrahydro-9H-
408.472
LC-3



carbazol-9-yl]-acetic acid


228
(3S)-{6-Fluoro-3-[(2-naphthalen-1-yl-
C34H31N2O3F
1.08
535.27



acetyl)-phenethyl-amino]-1,2,3,4-
534.629
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


229
(3S)-{6-Fluoro-3-[phenethyl-(3-
C31H31N2O3F
1.06
499.2



phenyl-propionyl)-amino]-1,2,3,4-
498.596
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


230
(3S)-[3-(3-Benzyl-1-naphthalen-1-
C33H30N3O3F
1.05
536.25



ylmethyl-ureido)-6-fluoro-1,2,3,4-
535.617
LC-3



tetrahydro-9H-carbazol-9-yl]-acetic



acid


231
(3S)-[3-(Benzyloxycarbonyl-
C33H29N2O4F
1.09
537.24



naphthalen-1-ylmethyl-amino)-6-
536.601
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl]-acetic acid


232
(3S)-{6-Fluoro-3-[naphthalen-1-
C34H31N2O3F
1.07
535.25



ylmethyl-(3-phenyl-propionyl)-
534.629
LC-3



amino]-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


233
(3S)-{6-Fluoro-3-[((S)-2-methyl-3-
C35H33N2O3F
1.09
549.26



phenyl-propionyl)-naphthalen-1-
548.656
LC-3



ylmethyl-amino]-1,2,3,4-tetrahydro-



9H-carbazol-9-yl}-acetic acid


234
(3S)-(6-Fluoro-3-{[3-(2-methoxy-
C35H33N2O4F
1.07
565.26



phenyl)-propionyl]-naphthalen-1-
564.655
LC-3



ylmethyl-amino}-1,2,3,4-tetrahydro-



9H-carbazol-9-yl)-acetic acid


235
(3S)-{3-[(3,3-Diphenyl-propionyl)-
C40H35N2O3F
1.11
611.21



naphthalen-1-ylmethyl-amino]-6-
610.727
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


236
(3S)-[3-(Acetyl-naphthalen-1-
C27H25N2O3F
1
445.24



ylmethyl-amino)-6-fluoro-1,2,3,4-
444.505
LC-3



tetrahydro-9H-carbazol-9-yl]-acetic



acid


237
(3S)-[6-Fluoro-3-(naphthalen-1-
C28H27N2O3F
1.01
459.15



ylmethyl-propionyl-amino)-1,2,3,4-
458.531
LC-3



tetrahydro-9H-carbazol-9-yl]-acetic



acid


238
(3S)-{3-[(RS)-2-Benzyl-3-(2-
C32H32N3O4F
0.97
542.22



methylphenyl)-carbamoyl-
541.621
LC-3



propionylamino]-6-fluoro-1,2,3,4-



tetrahydro-9H-carbazol-9-yl}-acetic



acid


239
(3S)-{3-[(RS)-2-Benzyl-3-(3-
C32H32N3O5F
0.97
558.24



methoxy-phenylcarbamoyl)-
557.620
LC-3



propionylamino]-6-fluoro-1,2,3,4-



tetrahydro-9H-carbazol-9-yl}-acetic



acid


240
(3S)-{3-[(RS)-2-Benzyl-3-(4-chloro-
C31H29N3O4ClF
1.01
562.09



phenylcarbamoyl)-propionylamino]-6-
562.039
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


241
(3S)-{3-[(RS)-2-Benzyl-3-(4-fluoro-
C32H31N3O4F2
0.96
560.21



benzylcarbamoyl)-propionylamino]-6-
559.611
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


242
[(3S)-3-((RS)-2-Benzyl-3-
C28H32N3O4F
0.91
494.25



propylcarbamoyl-propionylamino)-6-
493.577
LC-3



fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl]-acetic acid


243
(3S)-[6-Fluoro-3-(3-thiophen-2-yl-
C21H21FN2O3S
0.93
400.61



propionylamino)-1,2,3,4-tetrahydro-
400.47
LC-3



9H-carbazol-9-yl]-acetic acid


244
(3S)-{3-[3-(3-Chloro-isoxazol-5-yl)-
C20H19ClFN3O4
0.91
420.09



propionylamino]-6-fluoro-1,2,3,4-
419.83
LC-3



tetrahydro-9H-carbazol-9-yl}-acetic



acid


245
(3S)-[6-Fluoro-3-(3-pyrimidin-2-yl-
C21H21FN4O3
0.8
397.11



propionylamino)-1,2,3,4-tetrahydro-
396.41
LC-3



9H-carbazol-9-yl]-acetic acid


246
(3S)-{6-Fluoro-3-[3-phenyl-4-
C27H26FN5O4S
0.87
536.14



([1,3,4]thiadiazol-2-ylcarbamoyl)-
535.59
LC-3



butyrylamino]-1,2,3,4-tetrahydro-9H-



carbazol-9-yl}-acetic acid


247
(3S)-[3-(1,3-Dibenzyl-ureido)-6-
C29H28FN3O3
1.02
486.22



fluoro-1,2,3,4-tetrahydro-9H-
485.55
LC.3



carbazol-9-yl]-acetic acid


248
(3S)-(3-{Acetyl-[2-(2-fluoro-phenyl)-
C24H24F2N2O3
0.99
427.07



ethyl]-amino}-6-fluoro-1,2,3,4-
426.46
LC-3



tetrahydro-9H-carbazol-9-yl)-acetic



acid


249
(3S)-(3-{Acetyl-[2-(3-fluoro-phenyl)-
C24H24F2N2O3
0.99
427.07



ethyl]-amino}-6-fluoro-1,2,3,4-
426.46
LC-3



tetrahydro-9H-carbazol-9-yl)-acetic



acid


250
(3S)-[3-(3-Benzyl-1-
C29H34N3O3F
1.06
492.26



cyclohexylmethyl-ureido)-6-fluoro-
491.605
LC-3



1,2,3,4-tetrahydro-9H-carbazol-9-yl]-



acetic acid


251
(3S)-(3-{Cyclohexylmethyl-[3-(2-
C31H37N2O4F
1.10
521.25



methoxy-phenyl)-propionyl]-amino}-
520.643
LC-3



6-fluoro-1,2,3,4-tetrahydro-9H-



carbazol-9-yl)-acetic acid









Synthesis of Precursors and Intermediates
General Methods for the Synthesis of Intermediates of Structure 1




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. 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-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.










TABLE 2





Intermediates of Structure 1:

tR [min]



Ethyl [3-ureido-1,2,3,4-tetrahydro-9H-
Formula
LC-MS
MS Data


carbazol-9-yl]-acetate derivatives
MW
Method
m/z [M + H]+


















Ethyl (3R)-[3-(3-butyl-ureido)-1,2,3,4-
C21H29N3O3
1.1
372.05


tetrahydro-9H-carbazol-9-yl]-acetate
371.47
LC-2


Ethyl (3R)-[3-(3-benzyl-ureido)-1,2,3,4-
C24H27N3O3
1.99
406.06


tetrahydro-9H-carbazol-9-yl]-acetate
405.496
LC-1


Ethyl (3R)-[3-(3-phenethyl-ureido)-
C25H29N3O3
2.15
420.04


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
419.523
LC-1


acetate


Ethyl (3R)-[3-(3-naphthalen-1-yl-ureido)-
C27H27N3O3
1.19
441.95


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
441.52
LC-2


acetate


Ethyl (3R)-[3-(3-phenylsulfonyl-ureido)-
C23H25N3O5S
1.96
454.1


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
455.534
LC-1


acetate


Ethyl (3S)-[3-(3-butyl-ureido)-1,2,3,4-
C21H29N3O3
1.08
372.16


tetrahydro-9H-carbazol-9-yl]-acetate
371.479
LC-2


Ethyl (3S)-[3-(3-benzyl-ureido)-1,2,3,4-
C24H27N3O3
1.1
406.16


tetrahydro-9H-carbazol-9-yl]-acetate
405.496
LC-2


Ethyl (3S)-[3-(3-phenethyl-ureido)-1,2,3,4-
C25H29N3O3
1.12
420.15


tetrahydro-9H-carbazol-9-yl]-acetate
419.523
LC-2


Ethyl (3S)-[3-(3-phenylsulfonyl-ureido)-
C23H25N3O5S
1.09
454.16


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
455.534
LC-2


acetate


Ethyl (3S)-[3-(3-phenyl-ureido)-1,2,3,4-
C23H25N3O3
1.11
392.17


tetrahydro-9H-carbazol-9-yl]-acetate
391.47
LC-2









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.








TABLE 2a





Intermediates of Structure 1:



Ethyl [3-ureido-1,2,3,4-tetrahydro-9H-
Formula


carbazol-9-yl]-acetate derivatives
MW







Ethyl (3RS)-[3-(3-benzyl-ureido)-6-fluoro-1,2,3,4-
C25H28FN3O3


tetrahydro-9H-carbazol-9-yl]-acetate
437.51


Ethyl (3S)-[6-fluoro-3-(3-phenethyl-ureido)-
C25H28N3O3F


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
437.51


Ethyl (3RS)-[3-(3-benzyl-ureido)-8-chloro-6-
C24H25ClFN3O3


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
457.93


acetate


Ethyl (3RS)-[8-chloro-6-fluoro-3-(3-phenethyl-
C25H27ClFN3O3


ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
471.95


acetate


Ethyl (3S)-[6-fluoro-3-(1-methyl-3-phenethyl-
C26H30FN3O3


ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
451.53


acetate


Ethyl (3S)-{3-[3-(2-chloro-benzyl)-1-methyl-
C25H27ClFN3O3


ureido]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
471.95


9-yl}-acetate


Ethyl (3S)-[3-(3-benzyl-1-methyl-ureido)-6-fluoro-
C25H28FN3O3


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
437.51


Ethyl (3S)-{3-[3-benzyl-(1-cyclopropylmethyl)-
C28H32FN3O3


ureido]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
477.57


9-yl}-acetate


Ethyl (3S)-{3-[3-benzyl-1-(2-methoxy-ethyl)-
C27H32FN3O4


ureido]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
481.56


9-yl}-acetate


Ethyl (3S)-[3-(3-benzyl-1-cyclohexylmethyl-
C31H37N3O3F


ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
519.655


9-yl]-acetate


Ethyl (3S)-[3-(1,3-Dibenzyl-ureido)-6-fluoro-
C29H28FN3O3


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
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.










TABLE 3





Intermediates of Structure 1:





Ethyl (3-oxycarbonylamino-1,2,3,4-

tR [min]


tetrahydro-9H-carbazol-9-yl)-acetate
Formula
LC-MS
MS Data


derivatives
MW
Method
m/z







Ethyl (3R)-(3-propoxycarbonylamino-
C20H26N2O4
1.14
380.98 [M + Na]+


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate
358.436
LC-2


Ethyl (3R)-(3-isobutoxycarbonylamino-
C21H28N2O4
1.20
395.04 [M + Na]+


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate
372.463
LC-2


Ethyl (3R)-(3-benzyloxycarbonylamino-
C24H26N2O4
1.17
407.02 [M + H]+


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
406.48
LC-2


acetate


Ethyl (3R)-[3-(2-benzyloxy-
C26H30N2O5
1.17
473.01 [M + Na]+


ethoxycarbonylamino)-1,2,3,4-
450.533
LC-2


tetrahydro-9H-carbazol-9-yl]-acetate


Ethyl (3S)-(3-propoxycarbonylamino-
C20H26N2O4
1.12
381.09 [M + Na]+


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
358.436
LC-2


acetate


Ethyl (3S)-(3-isobutoxycarbonylamino-
C21H28N2O4
1.15
373.13 [M + H]+


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
372.463
LC-2


acetate


Ethyl (3S)-(3-benzyloxycarbonylamino-
C24H26N2O4
1.16
 407.2 [M + H]+


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate
406.48
LC-2


Ethyl (3S)-[3-(2-benzyloxy-
C26H30N2O5
1.17
473.14 [M + Na]+


ethoxycarbonylamino)-1,2,3,4-
450.533
LC-2


tetrahydro-9H-carbazol-9-yl]-acetate









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.








TABLE 3a





Intermediates of Structure 1:



Ethyl (3-oxycarbonylamino-1,2,3,4-tetrahydro-
Formula


9H-carbazol-9-yl)-acetate derivatives
MW







Ethyl (3RS)-(3-benzyloxycarbonylamino-6-
C25H25N2O4F3


trifluoromethyl-1,2,3,4-tetrahydro-9H-carbazol-9-
474.478


yl)-acetate


Ethyl (3RS)-(3-benzyloxycarbonylamino-8-
C24H24N2O4BrF


bromo-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-
503.367


yl)-acetate


Ethyl (3RS)-(3-benzyloxycarbonylamino-6-fluoro-
C26H27N2O4F


8-vinyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
450.508


acetate


Ethyl (3RS)-(3-benzyloxycarbonylamino-6-fluoro-
C25H27N2O6FS


8-methanesulfonyl-1,2,3,4-tetrahydro-9H-
502.561


carbazol-9-yl)-acetate


Ethyl (3S)-(3-benzyloxycarbonylamino-6-fluoro-8-
C25H27N2O4F


methyl-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
438.497


acetate


Ethyl (3S)-(3-benzyloxycarbonylamino-7-chloro-
C24H24ClFN2O4


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
458.91


acetate


Ethyl (3S)-(8-allyl-3-benzyloxycarbonylamino-6-
C27H29N2O4F


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
464.535


acetate


Ethyl (3R)-(3-benzyloxycarbonylamino-8-chloro-
C24H25N2O4Cl


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate
440.926


Ethyl (3S)-[3-(benzyloxycarbonyl-methyl-amino)-
C25H27N2O4F


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
438.494


acetate


Ethyl {(3S)-3-[(2-chloro-benzyloxycarbonyl)-
C25H26N2O4ClF


methyl-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-
472.939


carbazol-9-yl}-acetate


Ethyl (3S)-[3-(benzyloxycarbonyl-
C28H31N2O4F


cyclopropylmethyl-amino)-6-fluoro-1,2,3,4-
478.558


tetrahydro-9H-carbazol-9-yl]-acetate


Ethyl (3S)-(3-{benzyloxycarbonyl-[2-(4-
C33H32N2O5F4


trifluoromethyl-phenoxy)-ethyl]-amino}-6-fluoro-
612.614


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-{3-[benzyloxycarbonyl-(2-methoxy-
C27H31N2O5F


ethyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-9H-
482.546


carbazol-9-yl}-acetate









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 preparative 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.










TABLE 4





Intermediates of Structure 1:

tR [min]
MS Data


Ethyl (3-acylamino-1,2,3,4-tetrahydro-9H-
Formula
LC-MS
m/z


carbazol-9-yl)-acetate derivatives
MW
Method
[M + H]+







Ethyl (3R)-(3-benzoylamino-1,2,3,4-tetrahydro-9H-
C23H24N2O3
1.11
399.00 [M + Na]+


carbazol-9-yl)-acetate
376.455
LC-2


Ethyl (3R)-[3-(2-phenoxy-acetylamino)-1,2,3,4-
C24H26N2O4
1.13
428.93 [M + Na]+


tetrahydro-9H-carbazol-9-yl]-acetate
406.48
LC-2


Ethyl (3R)-(3-phenylacetylamino-1,2,3,4-
C24H26N2O3
1.11
412.97 [M + Na]+


tetrahydro-9H-carbazol-9-yl)-acetate
390.481
LC-2


Ethyl (3R)-[3-(2-thiophen-2-yl-acetylamino)-1,2,3,4-
C22H24N2O3S
1.09
396.98


tetrahydro-9H-carbazol-9-yl]-acetate
396.51
LC-2


Ethyl (3R)-[3-(3-phenyl-propionylamino)-1,2,3,4-
C25H28N2O3
1.13
427.03 [M + Na]+


tetrahydro-9H-carbazol-9-yl]-acetate
404.508
LC-2


Ethyl (3R)-[3-(2-benzyloxy-acetylamino)-1,2,3,4-
C25H28N2O4
1.14
421.07


tetrahydro-9H-carbazol-9-yl]-acetate
420.507
LC-2


Ethyl (3R)-[3-(3-methyl-butyrylamino)-1,2,3,4-
C21H28N2O3
1.09
357.1


tetrahydro-9H-carbazol-9-yl]-acetate
356.464
LC-2


Ethyl (3R)-[3-(3-cyclopentyl-propionylamino)-
C24H32N2O3
1.17
397.05


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
396.529
LC-2


Ethyl (3R)-(3-decanoylamino-1,2,3,4-tetrahydro-
C26H38N2O3
1.28
449.01 [M + Na]+


9H-carbazol-9-yl)-acetate
426.599
LC-2


Ethyl (3S)-[3-(2-phenoxy-acetylamino)-1,2,3,4-
C24H26N2O4
1.03
407.23


tetrahydro-9H-carbazol-9-yl]-acetate
406.48
LC-2


Ethyl (3S)-(3-phenylacetylamino-1,2,3,4-
C24H26N2O3
1.1
391.13


tetrahydro-9H-carbazol-9-yl)-acetate
390.481
LC-2


Ethyl (3S)-[3-(2-thiophen-2-yl-acetylamino)-1,2,3,4-
C22H24N2O3S
1.1
397


tetrahydro-9H-carbazol-9-yl]-acetate
396.51
LC-2


Ethyl (3S)-[3-(3-phenyl-propionylamino)-1,2,3,4-
C25H28N2O3
1.13
405.12


tetrahydro-9H-carbazol-9-yl]-acetate
404.508
LC-2


Ethyl (3S)-[3-(2-benzyloxy-acetylamino)-1,2,3,4-
C25H28N2O4
1.14
421.09


tetrahydro-9H-carbazol-9-yl]-acetate
420.507
LC-2


Ethyl (3S)-[3-(3-methyl-butyrylamino)-1,2,3,4-
C21H28N2O3
1.1
357.13


tetrahydro-9H-carbazol-9-yl]-acetate
356.464
LC-2


Ethyl (3S)-[3-(3-cyclopentyl-propionylamino)-
C24H32N2O3
1.18
397.16


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
396.529
LC-2


Ethyl (3S)-(3-decanoylamino-1,2,3,4-tetrahydro-
C26H38N2O3
1.15
427.32


9H-carbazol-9-yl)-acetate
426.599
LC-2


Ethyl (3S)-(3-butyrylamino-1,2,3,4-tetrahydro-9H-
C20H26N2O3
1.07
343.15


carbazol-9-yl)-acetate
342.437
LC-2


Ethyl (3S)-(3-heptanoylamino-1,2,3,4-tetrahydro-
C23H32N2O3
1.18
385.18


9H-carbazol-9-yl)-acetate
384.518
LC-2


Ethyl (3R)-[6-fluoro-3-(2-phenoxy-acetylamino)-
C24H25N2O4F
1.15
425.28


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
424.471
LC-2


Ethyl (3R)-(6-fluoro-3-phenylacetylamino-1,2,3,4-
C24H25N2O3F
1.12
409.28


tetrahydro-9H-carbazol-9-yl)-acetate
408.472
LC-2


Ethyl (3R)-[6-Fluoro-3-(3-phenyl-propionylamino)-
C25H27N2O3F
1.15
423.27


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
422.498
LC-2


Ethyl (3R)-{3-[2-(4-Chloro-phenyl)-acetylamino]-6-
C24H24N2O3ClF
1.18
443.21


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate
442.917
LC-2


Ethyl (3R)-{6-fluoro-3-[2-(4-methoxy-phenyl)-
C25H27N2O4F
1.12
439.2


acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
438.497
LC-2


acetate


Ethyl (3R)-[6-fluoro-3-(2-p-tolyl-acetylamino)-
C25H27N2O3F
1.14
423.34


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
422.498
LC-2


Ethyl (3R)-{3-[2-(3,4-dichloro-phenyl)-acetylamino]-
C24H23N2O3Cl2F
1.18
477.22


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
477.362
LC-2


acetate


Ethyl (3R)-{3-[2-(3-chloro-phenyl)-acetylamino]-6-
C24H24N2O3ClF
1.16
443.28


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate
442.917
LC-2


Ethyl (3R)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-
C25H24N2O3F4
1.17
477.29


acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
476.469
LC-2


acetate


Ethyl (3R)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-
C24H24N2O4ClF
1.18
459.28


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate
458.916
LC-2


Ethyl (3R)-[6-fluoro-3-(2-p-tolyloxy-acetylamino)-
C25H27N2O4F
1.18
439.27


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
438.497
LC-2


Ethyl (3R)-{3-[2-(2-chloro-phenoxy)-acetylamino]-6-
C24H24N2O4ClF
1.17
459.21


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate
458.916
LC-2


Ethyl (3R)-{3-[2-(3-chloro-phenoxy)-acetylamino]-6-
C24H24N2O4ClF
1.18
459.21


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate
458.916
LC-2


Ethyl (3R)-{6-fluoro-3-[3-(4-methoxy-phenyl)-
C26H29N2O4F
1.14
453.26


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
452.524
LC-2


yl}-acetate


Ethyl (3R)-[6-fluoro-3-(3-p-tolyl-propionylamino)-
C26H29N2O3F
1.17
437.26


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
436.525
LC-2


Ethyl (3R)-{3-[3-(4-chloro-phenyl)-propionylamino]-
C25H26N2O3ClF
1.18
457.2


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
456.943
LC-2


acetate


Ethyl (3R)-{3-[3-(2-chloro-phenyl)-propionylamino]-
C25H26N2O3ClF
1.18
457.2


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
456.943
LC-2


acetate


Ethyl (3R)-{3-[3-(3-chloro-phenyl)-propionylamino]-
C25H26N2O3ClF
1.17
457.2


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
456.943
LC-2


acetate


Ethyl (3S)-{3-[2-(4-chloro-phenyl)-acetylamino]-6-
C24H24N2O3ClF
1.15
443.21


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate
442.917
LC-2


Ethyl (3S)-{6-fluoro-3-[2-(4-methoxy-phenyl)-
C25H27N2O4F
1.12
439.33


acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
438.497
LC-2


acetate


Ethyl (3S)-[6-fluoro-3-(2-p-tolyl-acetylamino)-
C25H27N2O3F
1.15
423.27


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
422.498
LC-2


Ethyl (3S)-[6-fluoro-3-(2-phenoxy-acetylamino)-
C24H25N2O4F
1.15
425.28


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
424.471
LC-2


Ethyl (3S)-[6-fluoro-3-(3-phenyl-propionylamino)-
C25H27N2O3F
1.14
423.27


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
422.498
LC-2


Ethyl (3S)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-
C24H24N2O4ClF
1.17
459.21


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate
458.916
LC-2


Ethyl (3S)-[6-fluoro-3-(2-p-tolyloxy-acetylamino)-
C25H27N2O4F
1.18
439.27


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
438.497
LC-2


Ethyl (3S)-{6-fluoro-3-[3-(4-methoxy-phenyl)-
C26H29N2O4F
1.14
453.33


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
452.524
LC-2


yl}-acetate


Ethyl (3S)-[6-fluoro-3-(3-p-tolyl-propionylamino)-
C26H29N2O3F
1.17
437.33


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
436.525
LC-2


Ethyl (3S)-{3-[3-(4-chloro-phenyl)-propionylamino]-
C25H26N2O3ClF
1.17
457.27


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
456.943
LC-2


acetate


Ethyl (3S)-{3-[3-(2-chloro-phenyl)-propionylamino]-
C25H26N2O3ClF
1.17
457.27


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
456.943
LC-2


acetate


Ethyl (3S)-{3-[3-(3-chloro-phenyl)-propionylamino]-
C25H26N2O3ClF
1.18
457.27


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
456.943
LC-2


acetate


Ethyl (3S)-{3-[3-(3,4-difluoro-phenyl)-
C25H25N2O3F3
1.17
459.28


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
458.479
LC-2


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(3-methoxy-phenyl)-
C26H29N2O4F
1.14
453.33


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
452.524
LC-2


yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(2-methoxy-phenyl)-
C26H29N2O4F
1.16
453.33


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
452.524
LC-2


yl}-acetate


Ethyl (3S)-[3-(2,3-diphenyl-propionylamino)-6-
C31H31N2O3F
1.21
499.39


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
498.596
LC-2


Ethyl (3S)-[3-(3,3-diphenyl-propionylamino)-6-
C31H31N2O3F
1.2
499.39


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
498.596
LC-2


Ethyl (3S)-{3-[4-(4-bromo-phenyl)-4-oxo-
C26H26N2O4BrF
1.17
531.25


butyrylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
529.404
LC-2


carbazol-9-yl}-acetate


Ethyl (3S)-[6-fluoro-3-(4-oxo-4-phenyl-
C26H27N2O4F
1.12
451.25


butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
450.508
LC-2


acetate


Ethyl (3S)-{6-Fluoro-3-[4-(4-methanesulfonyl-
C27H29N2O6FS
1.07
529.31


phenyl)-4-oxo-butyrylamino]-1,2,3,4-tetrahydro-9H-
528.599
LC-2


carbazol-9-yl}-acetate


Ethyl (3S)-[6-fluoro-3-(2-indan-2-yl-acetylamino)-
C27H29N2O3F
1.18
449.31


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
448.536
LC-2


Ethyl (3S)-{6-fluoro-3-[3-(4-hydroxy-3-methoxy-
C26H29FN2O5
1.08
469.04


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
468.52
LC-3


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(4-hydroxy-phenyl)-
C25H27FN2O4
1.07
439.06


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
438.49
LC-3


yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(3-hydroxy-phenyl)-
C25H27FN2O5
1.08
439.06


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
439.49
LC-3


yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(2-hydroxy-phenyl)-
C25H27FN2O6
n.d.
n.d.


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
440.49
LC-3


yl}-acetate


Ethyl (3S)-{3-[(2,3-dihydro-1H-indole-2-carbonyl)-
C25H26FN3O3
1.14
436.08


amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-
435.49
LC-3


yl}-acetate


Ethyl (3S)-[6-fluoro-3-(3-1H-indol-3-yl-
C27H28FN3O3
1.15
462.05


propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-
461.53
LC-3


yl]-acetate


Ethyl (3S)-[3-(3-1H-benzoimidazol-2-yl-
C26H27FN4O3
0.86
463.09


propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-
462.52
LC-3


carbazol-9-yl]-acetate


Ethyl (3S)-[3-(3-benzo[1,3]dioxol-5-yl-
C26H27FN2O5
1.15
467.03


propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-
466.5
LC-3


carbazol-9-yl]-acetate


Ethyl (3S)-{6-fluoro-3-[(1H-indole-2-carbonyl)-
C25H24FN3O3
n.d.
n.d.


amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
433.47
LC-3


acetate


Ethyl (3S)-[6-fluoro-3-(3-pyridin-3-yl-
C24H26FN3O3
n.d.
n.d.


propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-
423.48
LC-3.


yl]-acetate


Ethyl (3S)-{3-[2-(4-tert-butyl-phenyl)-acetylamino]-
C28H33FN2O3
n.d.
n.d.


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
464.57
LC-3


acetate


Ethyl (3S)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-
C25H24F4N2O3
n.d.
n.d.


acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
476.46
LC-3


acetate


Ethyl (3S)-{6-fluoro-3-[2-(3-trifluoromethyl-phenyl)-
C25H24F4N2O3
1.26
477.04


acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
476.46
LC-2


acetate


Ethyl (3S)-{6-fluoro-3-[2-(4-trifluoromethyl-
C25H24F4N2O4
n.d.
n.d.


phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-
492.46
LC-3.


carbazol-9-yl}-acetate


Ethyl (3S)-[6-fluoro-3-(3-naphthalen-2-yl-
C29H27FN2O3
1.29
471.05


acryloylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-
470.53
LC-2


yl]-acetate


Ethyl (3S)-[6-fluoro-3-(3-naphthalen-2-yl-
C29H29FN2O3
1.27
473.08


propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-
472.55
LC-2


yl]-acetate


Ethyl (3S)-{6-fluoro-3-[methyl-(3-phenyl-propionyl)-
C26H29FN2O3
1.08
437.28


amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
436.52
LC-3


acetate


Ethyl (3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-methyl-
C25H26ClFN2O3
1.09
473.08


amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-
456.94
LC-3


yl)-acetate


Ethyl (3S)-{6-fluoro-3-[ethyl-(3-phenyl-propionyl)-
C27H31FN2O3
1.09
451.23


amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
450.55
LC-3


acetate


Ethyl (3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-ethyl-
C26H28ClFN2O3
1.1
471.22


amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-
470.96
LC-3


yl)-acetate


Ethyl (3S)-{6-fluoro-3-[propyl-(3-phenyl-propionyl)-
C28H33FN2O3
1.11
465.23


amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
464.57
LC-3


acetate


Ethyl (3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-propyl-
C27H30ClFN2O
1.12
485.20


amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-
484.99
LC-3


yl)-acetate









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.








TABLE 4a





Intermediates of Structure 1:



Ethyl (3-acylamino-1,2,3,4-tetrahydro-9H-
Formula


carbazol-9-yl)-acetate derivatives
MW







(3S)-{3-[3-(2,4-dimethoxy-phenyl)-
C27H31N2O5F


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
482.546


carbazol-9-yl}-acetate


Ethyl (3S)-[6-fluoro-3-(3-naphthalen-1-yl-
C29H29N2O3F


propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-
472.555


9-yl]-acetate


Ethyl (3RS)-{6-fluoro-3-[2-(2-methoxy-phenoxy)-
C25H27N2O5F


acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
454.493


yl}-acetate


Ethyl (3RS)-{6-fluoro-3-[3-(2-methylphenyl)-
C26H29N2O3F


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
436.522


9-yl}-acetate


Ethyl (3RS)-{6-fluoro-3-[3-(3-methylphenyl)-
C26H29N2O3F


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
436.522


9-yl}-acetate


Ethyl (3RS)-{6-fluoro-3-[3-(3-methoxy-phenyl)-
C26H29N2O4F


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
452.521


9-yl}-acetate


Ethyl (3RS)-{6-fluoro-3-[2-(3-methoxy-phenoxy)-
C25H27N2O5F


acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
454.493


yl}-acetate


Ethyl (3RS)-{6-fluoro-3-[2-(2-methylphenoxy)-
C25H27N2O4F


acetylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
438.494


yl}-acetate


Ethyl (3S)-{3-[3-(2,5-dimethoxy-phenyl)-
C22H31N2O5F


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
482.546


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(4-trifluoromethyl-
C26H26N2O3F4


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
490.492


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[3-(2,6-dichloro-phenyl)-
C25H25N2O3Cl2F


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
491.385


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[3-(2,5-bis-trifluoromethyl-phenyl)-
C27H25N2O3F7


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
558.489


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(4-methylsulfanyl-
C26H29N2O3FS


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
468.588


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(4-iodo-phenyl)-
C25H26N2O3FI


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
548.387


9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(4-isopropyl-phenyl)-
C28H33N2O3F


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
464.575


9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(3-trifluoromethyl-
C26H26N2O3F4


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
490.492


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[3-(2,4-dichloro-phenyl)-
C25H25N2O3Cl2F


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
491.385


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(4-fluoro-phenyl)-
C25H26N2O3F2


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
440.485


9-yl}-acetate


Ethyl (3S)-{3-[3-(3,5-bis-trifluoromethyl-phenyl)-
C27H25N2O3F7


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
558.489


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[3-(4-ethyl-phenyl)-
C27H31N2O3F


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
450.548


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(3-iodo-phenyl)-
C25H26N2O3FI


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
548.387


9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(4-methanesulfonyl-
C26H29N2O5FS


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
500.586


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[3-(2,3-dimethoxy-phenyl)-
C27H31N2O5F


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
482.546


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[3-(2-bromo-phenyl)-
C25H26N2O3BrF


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
501.391


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(3-trifluoromethoxy-
C26H26N2O4F4


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
506.491


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[3-(2,4-dimethyl-phenyl)-
C27H31N2O3F


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
450.548


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[3-(3-bromo-phenyl)-
C25H26N2O3BrF


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
501.391


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[3-(3-tert-butoxycarbonylamino-
C30H36N3O5F


phenyl)-propionylamino]-6-fluoro-1,2,3,4-
537.626


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[(S)-3-(4-fluoro-phenyl)-2-
C31H30N2O3F2


phenyl-propionylamino]-1,2,3,4-tetrahydro-9H-
516.582


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[(S)-3-(4-methoxy-phenyl)-
C32H33N2O4F


2-phenyl-propionylamino]-1,2,3,4-tetrahydro-9H-
528.618


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[3-(2-fluoro-phenyl)-
C25H26N2O3F2


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
440.485


9-yl}-acetate


Ethyl (3S)-(6-fluoro-3-{[(2RS)-1,2,3,4-tetrahydro-
C27H29N2O3F


naphthalene-2-carbonyl]-amino}-1,2,3,4-
448.533


tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{[(2RS)-8-methoxy-
C28H31N2O4F


1,2,3,4-tetrahydro-naphthalene-2-carbonyl]-
478.558


amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-


acetate


Ethyl (3S)-(6-fluoro-3-{(2RS)-2-[(4-fluoro-
C33H33N3O4F2


phenylcarbamoyl)-methyl]-3-phenyl-
573.634


propionylamino}-1,2,3,4-tetrahydro-9H-carbazol-


9-yl)-acetate


Ethyl (3S)-{3-[(2RS)-2-benzyl-3,3-dimethyl-
C29H35N2O3F


butyrylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
478.602


carbazol-9-yl}-acetate


Ethyl (3S)-(3-{[(3RS)-chroman-3-carbonyl]-
C26H27N2O4F


amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
450.505


9-yl)-acetate


Ethyl (3S)-{6-fluoro-3-[3-(3-fluoro-phenyl)-
C25H26N2O3F2


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
440.485


9-yl}-acetate


Ethyl (3S)-(6-fluoro-3-{[(1R,2R)-2-phenyl-
C26H27N2O3F


cyclopropanecarbonyl]-amino}-1,2,3,4-
434.506


tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-{6-fluoro-3-[(2R)-2-methyl-3-phenyl-
C26H29N2O3F


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-
436.522


9-yl}-acetate


Ethyl (3S)-[3-(2,2-dimethyl-3-phenyl-
C27H31N2O3F


propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-
450.552


carbazol-9-yl]-acetate
450.548


Ethyl (3S)-[6-fluoro-3-(3-methyl-3-phenyl-
C27H31N2O3F


butyrylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-
450.548


yl]-acetate


Ethyl (3S)-{6-fluoro-3-[(3S)-3-phenyl-
C26H29N2O3F


butyrylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
436.522


yl}-acetate


Ethyl (3S)-[3-(2-benzyloxy-acetylamino)-6-
C25H27N2O4F


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
438.494


acetate


Ethyl (3S)-[6-fluoro-3-(4-phenyl-butyrylamino)-
C26H29N2O3F


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
436.522


Ethyl (3S)-{3-[(2R,3R)-2,3-dihydroxy-3-(2-
C27H30N3O7F


methoxy-phenylcarbamoyl)-propionylamino]-6-
527.543


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-


acetate


Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(2-
C26H28N2O3ClF


methylphenyl)-propionylamino]-1,2,3,4-
470.967


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3RS)-{8-chloro-6-fluoro-3-[2-(2-methoxy-
C25H26N2O5ClF


phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-
488.938


carbazol-9-yl}-acetate


Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(3-hydroxy-
C25H26N2O4ClF


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
472.939


carbazol-9-yl}-acetate


Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(3-methoxy-
C26H28N2O4ClF


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
486.966


carbazol-9-yl}-acetate


Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(3-
C22H28N2O3ClF


methylphenyl)-propionylamino]-1,2,3,4-
470.967


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(2-hydroxy-
C25H26N2O4ClF


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
472.939


carbazol-9-yl}-acetate


Ethyl (3RS)-[8-chloro-6-fluoro-3-(3-phenyl-
C25H26N2O3ClF


propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-
456.94


9-yl]-acetate


Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(2-methoxy-
C26H28N2O4ClF


phenyl)-propionylamino]-1,2,3,4-tetrahydro-9H-
486.966


carbazol-9-yl}-acetate


Ethyl (3RS)-{8-chloro-3-[3-(3-chloro-phenyl)-
C25H25N2O3Cl2F


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
491.385


carbazol-9-yl}-acetate


Ethyl (3RS)-[8-chloro-6-fluoro-3-(3-1H-indol-3-
C27H27N3O3ClF


yl-propionylamino)-1,2,3,4-tetrahydro-9H-
495.977


carbazol-9-yl]-acetate


Ethyl (3RS)-{8-chloro-3-[2-(2-chloro-phenoxy)-
C24H23N2O4Cl2F


acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
493.357


carbazol-9-yl}-acetate


Ethyl (3RS)-{8-chloro-6-fluoro-3-[2-(2-
C25H26N2O4ClF


methylphenyl)-oxy-acetylamino]-1,2,3,4-
472.939


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3RS)-[3-(3-benzo[1,3]dioxol-5-yl-
C26H26N2O5ClF


propionylamino)-8-chloro-6-fluoro-1,2,3,4-
500.949


tetrahydro-9H-carbazol-9-yl]-acetate


Ethyl (3RS)-{8-chloro-6-fluoro-3-[2-(3-methoxy-
C25H26N2O5ClF


phenoxy)-acetylamino]-1,2,3,4-tetrahydro-9H-
488.938


carbazol-9-yl}-acetate


Ethyl (3RS)-{8-chloro-3-[2-(3-chloro-phenoxy)-
C24H23N2O4Cl2F


acetylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
493.357


carbazol-9-yl}-acetate


Ethyl (3RS)-{8-chloro-3-[3-(2-chloro-phenyl)-
C25H25N2O3Cl2F


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
491.385


carbazol-9-yl}-acetate


Ethyl (3RS)-[8-chloro-6-fluoro-3-(2-indan-2-yl-
C27H28N2O3ClF


acetylamino)-1,2,3,4-tetrahydro-9H-carbazol-9-
482.978


yl]-acetate


Ethyl (3S)-(6-fluoro-3-{[2-(4-methoxy-phenyl)-
C26H29N2O4F


acetyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-
452.521


carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{methyl-[2-(4-
C22H29N2O3F


methylphenyl)-acetyl]-amino}-1,2,3,4-tetrahydro-
436.522


9H-carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{[2-(2-methoxy-phenyl)-
C26H29N2O4F


acetyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-
452.521


carbazol-9-yl)-acetate


Ethyl (3S)-{6-fluoro-3-[(2-indan-2-yl-acetyl)-
C28H31N2O3F


methyl-amino]-1,2,3,4-tetrahydro-9H-carbazol-9-
462.559


yl}-acetate


Ethyl (3S)-(3-{[2-(3-chloro-phenyl)-acetyl]-
C25H26N2O3ClF


methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-
456.94


carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{methyl-[2-(3-
C26H29N2O3F


methylphenyl)-acetyl]-amino}-1,2,3,4-tetrahydro-
436.522


9H-carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{[2-(3-methoxy-phenyl)-
C26H29N2O4F


acetyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-
452.521


carbazol-9-yl)-acetate


Ethyl (3S)-(3-{[2-(2-chloro-phenoxy)-acetyl]-
C25H26N2O4ClF


methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-
472.939


carbazol-9-yl)-acetate


Ethyl (3S)-(3-{[2-(4-chloro-phenoxy)-acetyl]-
C25H26N2O4ClF


methyl-amino}-6-fluoro-1,2,3,4-tetrahydro-9H-
472.939


carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{[3-(3-methoxy-phenyl)-
C27H31N2O4F


propionyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-
466.547


carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{methyl-[2-(2-
C26H29N2O3F


methylphenyl)-acetyl]-amino}-1,2,3,4-tetrahydro
436.522


9H-carbazol-9-yl)-acetate


Ethyl (3S)-{3-[(3,3-diphenyl-propionyl)-methyl-
C32H33N2O3F


amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
512.619


9-yl}-acetate


Ethyl (3S)-(6-fluoro-3-{[3-(2-methoxy-phenyl)-
C27H31N2O4F


propionyl]-methyl-amino}-1,2,3,4-tetrahydro-9H-
466.547


carbazol-9-yl)-acetate


Ethyl (3S)-{6-fluoro-3-[(3-1H-indol-3-yl-
C28H30N3O3F


propionyl)-methyl-amino]-1,2,3,4-tetrahydro-9H-
475.558


carbazol-9-yl}-acetate


Ethyl (3S)-{3-[(2-benzyloxy-acetyl)-methyl-
C26H29N2O4F


amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
452.521


9-yl}-acetate


Ethyl (3S)-{3-[(2,3-diphenyl-propionyl)-methyl-
C32H33N2O3F


amino]-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
512.619


9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[[3-(2-methoxy-phenyl)-
C35H39N2O4F


propionyl]-(3-phenyl-propyl)-amino]-1,2,3,4-
570.699


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-{3-[acetyl-(3-phenyl-propyl)-amino]-6-
C27H31N2O3F


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
450.548


acetate


Ethyl (3S)-{3-[cyclopropylmethyl-(3-phenyl-
C29H33N2O3F


propionyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-
476.586


9H-carbazol-9-yl}-acetate


Ethyl (3S)-{3-[cyclopropylmethyl-((S)-2-methyl-
C30H35N2O3F


3-phenyl-propionyl)-amino]-6-fluoro-1,2,3,4-
490.613


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-(3-{cyclopropylmethyl-[3-(2-methoxy-
C30H35N2O4F


phenyl)-propionyl]-amino}-6-fluoro-1,2,3,4-
506.612


tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-(3-{[2-(3-chloro-phenoxy)-acetyl]-
C28H30N2O4ClF


cyclopropylmethyl-amino}-6-fluoro-1,2,3,4-
513.003


tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-{3-[cyclopropylmethyl-(3,3-diphenyl-
C35H37N2O3F


propionyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-
552.684


9H-carbazol-9-yl}-acetate


Ethyl (3S)-{3-[cyclopropylmethyl-(2-naphthalen-
C32H33N2O3F


1-yl-acetyl)-amino]-6-fluoro-1,2,3,4-tetrahydro-
512.619


9H-carbazol-9-yl}-acetate


Ethyl (3S)-(3-{acetyl-[2-(4-trifluoromethyl-
C27H28N2O4F4


phenoxy)-ethyl]-amino}-6-fluoro-1,2,3,4-
520.518


tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{propionyl-[2-(4-
C28H30N2O4F4


trifluoromethyl-phenoxy)-ethyl]-amino}-1,2,3,4-
534.544


tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{(3-phenyl-propionyl)-[2-
C34H34N2O4F4


(4-trifluoromethyl-phenoxy)-ethyl]-amino}-
610.642


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{[3-(2-methoxy-phenyl)-
C35H36N2O5F4


propionyl]-[2-(4-trifluoromethyl-phenoxy)-ethyl]-
640.668


amino}-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-


acetate


Ethyl (3S)-{6-fluoro-3-[(2-phenoxy-ethyl)-(3-
C33H35N2O4F


phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-
542.645


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[((S)-2-methyl-3-phenyl-
C34H37N2O4F


propionyl)-(2-phenoxy-ethyl)-amino]-1,2,3,4-
556.672


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[[3-(2-methoxy-phenyl)-
C34H37N2O5F


propionyl]-(2-phenoxy-ethyl)-amino]-1,2,3,4-
572.671


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-{3-[acetyl-(2-phenoxy-ethyl)-amino]-
C26H29N2O4F


6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
452.521


acetate


Ethyl (3S)-{6-fluoro-3-[(2-methoxy-ethyl)-(3-
C28H33N2O4F


phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-
480.574


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[(2-methoxy-ethyl)-((S)-2-
C29H35N2O4F


methyl-3-phenyl-propionyl)-amino]-1,2,3,4-
494.601


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-(6-fluoro-3-{(2-methoxy-ethyl)-[3-(2-
C29H35N2O5F


methoxy-phenyl)-propionyl]-amino}-1,2,3,4-
510.6


tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-{3-[[2-(3-chloro-phenoxy)-acetyl]-(2-
C27H30N2O5ClF


methoxy-ethyl)-amino]-6-fluoro-1,2,3,4-
516.991


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-{3-[(3,3-diphenyl-propionyl)-(2-
C34H37N2O4F


methoxy-ethyl)-amino]-6-fluoro-1,2,3,4-
556.672


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[(2-methoxy-ethyl)-(2-
C31H33N2O4F


naphthalen-1-yl-acetyl)-amino]-1,2,3,4-
516.607


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-(6-fluoro-3-{[(2S)-2-methyl-3-phenyl-
C34H37N2O3F


propionyl]-phenethyl-amino}-1,2,3,4-tetrahydro-
540.673


9H-carbazol-9-yl)-acetate


Ethyl (3S)-(6-fluoro-3-{[3-(2-methoxy-phenyl)-
C34H37N2O4F


propionyl]-phenethyl-amino}-1,2,3,4-tetrahydro-
556.672


9H-carbazol-9-yl)-acetate


Ethyl (3S)-[3-(acetyl-phenethyl-amino)-6-fluoro-
C26H29N2O3F


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
436.522


Ethyl (3S)-{6-fluoro-3-[(2-naphthalen-1-yl-
C36H35N2O3F


acetyl)-phenethyl-amino]-1,2,3,4-tetrahydro-9H-
562.679


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[phenethyl-(3-phenyl-
C33H35N2O3F


propionyl)-amino]-1,2,3,4-tetrahydro-9H-
526.646


carbazol-9-yl}-acetate


Ethyl (3S)-[3-(3-benzyl-1-naphthalen-1-ylmethyl-
C35H34N3O3F


ureido)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
563.667


9-yl]-acetate


Ethyl (3S)-[3-(benzyloxycarbonyl-naphthalen-1-
C35H31N2O4F


ylmethyl-amino)-6-fluoro-1,2,3,4-tetrahydro-9H-
564.651


carbazol-9-yl]-acetate


Ethyl (3S)-{6-fluoro-3-[naphthalen-1-ylmethyl-(3-
C36H35N2O3F


phenyl-propionyl)-amino]-1,2,3,4-tetrahydro-9H-
562.679


carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[((S)-2-methyl-3-phenyl-
C37H37N2O3F


propionyl)-naphthalen-1-ylmethyl-amino]-
576.706


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-(6-fluoro-3-{[3-(2-methoxy-phenyl)-
C37H37N2O4F


propionyl]-naphthalen-1-ylmethyl-amino}-
592.705


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-{3-[(3,3-diphenyl-propionyl)-
C42H39N2O3F


naphthalen-1-ylmethyl-amino]-6-fluoro-1,2,3,4-
638.777


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-[3-(acetyl-naphthalen-1-ylmethyl-
C29H29N2O3F


amino)-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
472.555


9-yl]-acetate


Ethyl (3S)-[6-fluoro-3-(naphthalen-1-ylmethyl-
C30H31N2O3F


propionyl-amino)-1,2,3,4-tetrahydro-9H-
486.581


carbazol-9-yl]-acetate


Ethyl (3S)-{6-fluoro-3-[3-phenyl-4-
C29H30FN5O4S


([1,3,4]thiadiazol-2-ylcarbamoyl)-butyrylamino]-
563.64


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-[6-fluoro-3-(3-thiophen-2-yl-
C23H25FN2O3S


propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-
428.012


9-yl]-acetate


Ethyl (3S)-{3-[3-(3-chloro-isoxazol-5-yl)-
C22H23ClFN3O4


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-
447.88


carbazol-9-yl}-acetate


Ethyl (3S)-[6-Fluoro-3-(3-pyrimidin-2-yl-
C23H25FN4O3


propionylamino)-1,2,3,4-tetrahydro-9H-carbazol-
424.46


9-yl]-acetate


Ethyl (3S)-(3-{acetyl-[2-(2-fluoro-phenyl)-ethyl]-
C26H28F2N2O3


amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
454.51


9-yl)-acetate


Ethyl (3S)-(3-{acetyl-[2-(3-fluoro-phenyl)-ethyl]-
C26H28F2N2O3


amino}-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
454.51


9-yl)-acetate


Ethyl (3S)-(3-{cyclohexylmethyl-[3-(2-methoxy-
C33H41N2O4F


phenyl)-propionyl]-amino}-6-fluoro-1,2,3,4-
548.693


tetrahydro-9H-carbazol-9-yl)-acetate









General Method for the Preparation of Intermediates of Structure 1, Wherein R4 Represents C1-5-Alkyl or Allyl

To a stirred and degassed solution of an appropriately protected ethyl (3-amino-8-bromo-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 2c (0.2 mmol) and Pd(PPh3)4 (0.02 mmol, 0.1 eq.) in dry DMF (1.5 ml) is added under inert atmosphere the appropriate tetraC1-5-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 are washed with brine and dried over Na2SO4. Evaporation of the solvent in vaccuo yields the protected ethyl (3-amino-8-C1-5-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 C1-5-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 R4 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 R4 Represents C1-6-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 C1-6-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) are 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: tR=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.










TABLE 5






Formula
tR [min]
MS Data


Intermediates of Structure 3b
MW
Meth.
m/z [M + H]+







Ethyl (3S)-{6-fluoro-3-[methyl-(4-nitro-
C23H24N3O6F
1.09
490.05


benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-
489.52 
(LC-3)


9H-carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[ethyl-(4-nitro-
C24H26N3O6FS
1.11
504.15


benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-
503.549
LC-3


9H-carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[propyl-(4-nitro-
C25H28N3O6FS
1.13
518.23


benzenesulfonyl)-amino]-1,2,3,4-tetrahydro-
517.576
LC-3


9H-carbazol-9-yl}-acetate









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










TABLE 5a








MS Data



Formula
tR [min]
m/z


Intermediates of Structure 3b
MW
Method
[M + H]+







Ethyl (3S)-{6-fluoro-3-[(4-nitro-
C31H32N3O6FS
1.16
594.12


benzenesulfonyl)-(3-phenyl-propyl)-amino]-
593.674
LC-3


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S){-3-[cyclopropylmethyl-(4-nitro-
C26H28N3O6FS
1.12
530.02


benzenesulfonyl)-amino]-6-fluoro-1,2,3,4-
529.587
LC-3


tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-(6-fluoro-3-{(4-nitro-
C31H29N3O7F4S
1.17
664.17


benzenesulfonyl)-[2-(3-trifluoromethyl-
663.643
LC-3


phenoxy)-ethyl]-amino}-1,2,3,4-tetrahydro-9H-


carbazol-9-yl)-acetate


Ethyl (3S)-{6-fluoro-3-[(4-nitro-
C30H30N3O7FS
1.14
596.18


benzenesulfonyl)-(2-phenoxy-ethyl)-amino]-
595.646
LC-3


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-{6-fluoro-3-[(2-methoxy-ethyl)-(4-
C25H28N3O7FS
1.09
534.16


nitro-benzenesulfonyl)-amino]-1,2,3,4-
533.575
LC-3


tetrahydro-9H-carbazol-9-yl}-acetate









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.










TABLE 6






Formula
tR [min]
MS Data


Intermediates of Structure 2a
MW
Method
m/z [M + H]+







Ethyl (3S)-(6-fluoro-3-methylamino-1,2,3,4-
C17H21FN2O2
0.76
305.19


tetrahydro-9H-carbazol-9-yl)-acetate
304.36
LC-3


Ethyl (3S)-(6-fluoro-3-ethylamino-1,2,3,4-
C18H23FN2O2
0.78
319.14


tetrahydro-9H-carbazol-9-yl)-acetate
318.39
LC-3


Ethyl (3S)-(6-fluoro-3-propylamino-1,2,3,4-
C19H25FN2O2
0.81
333.15


tetrahydro-9H-carbazol-9-yl)-acetate
332.41
LC-3









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










TABLE 6a







tR [min]
MS Data



Formula
LC-MS
m/z


Intermediates of Structure 2a
MW
Method
[M + H]+







Ethyl (3S)-[6-fluoro-3-(3-phenyl-propylamino)-
C25H29N2O2F
0.91
409.15


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
408.515
LC-3


Ethyl (3S)-[3-(cyclopropylmethyl-amino)-6-
C20H25N2O2F
0.82
345.18


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-
344.428
LC-3


acetate


Ethyl (3S)-{6-fluoro-3-[2-(4-trifluoromethyl-
C25H26N2O3F4
0.95
479.07


phenoxy)-ethylamino]-1,2,3,4-tetrahydro-9H-
478.484
LC-3


carbazol-9-yl}-acetate


Ethyl (3S)-[6-fluoro-3-(2-phenoxy-ethylamino)-
C24H27N2O3F
0.88
411.10


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
410.487
LC-3


Ethyl (3S)-[6-fluoro-3-(2-methoxy-ethylamino)-
C19H25N2O3F
0.77
349.15


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
348.417
LC-3









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.










TABLE 6b







tR [min]
MS Data



Formula
LC-MS
m/z


Intermediates of Structure 2a
MW
Method
[M + H]+







Ethyl (3S)-(6-fluoro-3-phenethylamino-1,2,3,4-
C24H27N2O2F
0.88
395.18


tetrahydro-9H-carbazol-9-yl)-acetate
394.488
LC-3


Ethyl (3S)-{6-fluoro-3-[(naphthalen-1-ylmethyl)-
C27H27N2O2F
0.91
431.22


amino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-
430.521
LC-3


acetate


Ethyl (3S)-(3-benzylamino-6-fluoro-1,2,3,4-
C23H25N2O2F
0.89
381.16


tetrahydro-9H-carbazol-9-yl)-acetate
380.461
LC-3


Ethyl (3S)-{6-fluoro-3-[2-(2-fluoro-phenyl)-
C24H26N2O2F2
0.88
413.14


ethylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
412.478
LC-3


yl}-acetate


Ethyl (3S)-{6-fluoro-3-[2-(3-fluoro-phenyl)-
C24H26N2O2F2
0.88
413.14


ethylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-
412.478
LC-3


yl}-acetate


Ethyl (3S)-[3-(cyclohexylmethyl-amino)-6-fluoro-
C23H31N2O2F
0.88
387.20


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate
386.509
LC-3









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.










TABLE 7








MS Data



Formula
tR [min]
m/z [M + H]+


Intermediates of Structure 2b
MW
Method
(parent)







Ethyl (3R)-(3-amino-1,2,3,4-tetrahydro-9H-
C16H21N2O2Cl
0.74
273.16


carbazol-9-yl)-acetate hydrochloride
308.807
LC-2


Ethyl (3S)-(3-amino-1,2,3,4-tetrahydro-9H-
C16H21N2O2Cl
0.74
273.16


carbazol-9-yl)-acetate hydrochloride
308.807
LC-2


Ethyl (3R)-(3-amino-6-fluoro-1,2,3,4-
C16H20ClFN2O2
0.74
291.15


tetrahydro-9H-carbazol-9-yl)-acetate
326.79 
LC-2


hydrochloride


Ethyl (3S)-(3-amino-6-fluoro-1,2,3,4-
C16H20N2O2ClF
0.73
291.11


tetrahydro-9H-carbazol-9-yl)-acetate
326.79 
LC-2


hydrochloride









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 1 h 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.










TABLE 7a







tR [min]
MS Data



Formula
LC-MS
m/z


Intermediates of Structure 2b
MW
Method
[M + H]+







Ethyl (3RS)-(3-amino-8-
C16H19N2O2Cl2F
0.78
325.05


chloro-6-fluoro-1,2,3,4-
361.243
LC-3


tetrahydro-carbazol-9-yl)-


acetate hydrochloride


Ethyl (3RS)-(3-amino-6-
C20H19N2O2F
1.02
339.12


fluoro-1,2,3,4-tetrahydro-
338.381
LC-3


carbazol-9-yl)-acetate


hydrochloride









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










TABLE 8







tR 
MS Data m/z



Formula
[min] LC-MS
[M + Na]+


Intermediates of Structure 2c
MW
Method
or [M + H]+







Ethyl (3R)-(3-tert-
C21H28N2O4
1.15
394.95


butoxycarbonylamino-1,2,3,4-
372.463
LC-2


tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3S)-(3-tert-
C21H28N2O4
1.15
395.15


butoxycarbonylamino-1,2,3,4-
372.463
LC-2


tetrahydro-9H-carbazol-9-yl)-acetate


Ethyl (3R)-(3-tert-
C21H27FN2O4
1.15
413.09


butoxycarbonylamino-6-fluoro-
390.45 
LC-2


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-


acetate


Ethyl (3S)-(3-tert-
C21H27FN2O4
1.16
413.09


butoxycarbonylamino-6-fluoro-
390.45 
LC-2


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-


acetate


Ethyl (3RS)-(3-
C24H24N2O4ClF
1.11
458.99


benzyloxycarbonylamino-8-chloro-5-
458.916
LC-3


fluoro-1,2,3,4-tetrahydro-9H-carbazol-


9-yl)-acetate


Ethyl (3RS)-(3-
C24H25N2O4F
1.06
425.22


benzyloxycarbonylamino-6-fluoro-
424.47 
LC-3


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-


acetate


Ethyl (3RS)-(3-
C24H24N2O4ClF
1.11
459.05


benzyloxycarbonylamino-8-chloro-6-
458.916
LC-3


fluoro-1,2,3,4-tetrahydro-9H-carbazol-


9-yl)-acetate









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.










TABLE 8a







tR [min]




Formula
LC-MS
MS Data


Intermediates of Structure 2c
MW
Method
m/z [M + H]+







Ethyl (3RS)-(3-benzyloxycarbonylamino-6-
C25H25N2O4F3
1.11
475.14


trifluoromethyl-1,2,3,4-tetrahydro-9H-carbazol-
474.478
LC-3


9-yl)-acetate


Ethyl (3RS)-(3-benzyloxycarbonylamino-8-
C24H24N2O4BrF
1.11
505.11


bromo-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
503.367
LC-3


9-yl)-acetate


Ethyl (3S)-(3-benzyloxycarbonylamino-7-
C24H24ClFN2O4
not
not


chloro-6-fluoro-1,2,3,4-tetrahydro-9H-carbazol-
458.91 
determined
determined


9-yl)-acetate


Ethyl (3R)-(3-benzyloxycarbonylamino-8-
C24H25N2O4Cl
1.1 
441.07


chloro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-
440.926
LC-3


acetate









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).










TABLE 9








MS Data



Formula
tR [min]
m/z


Intermediates of Structure 4
MW
Method
[M + H]+







(3RS)-(8-Chloro-5-fluoro-
C20H18N2O2ClF
1.07
373.03


2,3,4,9-tetrahydro-1H-carbazol-
372.825
LC-3


3-yl)-carbamic acid benzyl ester


(3RS)-(8-Chloro-6-fluoro-
C20H18N2O2ClF
1.06
372.99


2,3,4,9-tetrahydro-1H-carbazol-
372.825
LC-3


3-yl)-carbamic acid benzyl ester


(3RS)-(6-Fluoro-2,3,4,9-
C20H19N2O2F
1.02
339.12


tetrahydro-1H-carbazol-3-yl)-
338.38 
LC-3


carbamic acid benzyl ester









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










TABLE 9a








MS Data



Formula
tR [min]
m/z


Intermediates of Structure 4
MW
Method
[M + H]+







(3RS)-(6-Trifluoromethyl-
C21H19N2O2F3
1.07
389.08


2,3,4,9-tetrahydro-1H-carbazol-
388.388
LC-3


3-yl)-carbamic acid benzyl ester


(3RS)-(8-Bromo-6-fluoro-
C20H18N2O2BrF
1.07
417.03


2,3,4,9-tetrahydro-1H-carbazol-
417.277
LC-3


3-yl)-carbamic acid benzyl ester


(3RS)-(7-Chloro-6-fluoro-
C20H18N2O2ClF
1.05
373.07


2,3,4,9-tetrahydro-1H-carbazol-
372.825
LC-3


3-yl)-carbamic acid benzyl ester


(3R)-(8-Chloro-2,3,4,9-
C20H19N2O2Cl
1.05
355.11


tetrahydro-1H-carbazol-3-yl)-
354.836
LC-3


carbamic acid benzyl ester









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, 1.5 eq.) 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 20 h, then diluted with DCM and sat. NaHCO3 solution. After stirring for an additional 1 h, 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.










TABLE 10







tR [min]
MS Data


Intermediates of Structure 1 starting from
Formula
LC-MS
m/z


intermediates of Structure 8a
MW
Method
[M + H]+







Ethyl (3S)-{3-[(RS)-2-benzyl-3-(2-
C34H36FN3O4
1.06
570.21


methylbenzyl)-carbamoyl-propionylamino]-6-
569.67
LC-3


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-


acetate


Ethyl (3S)-{3-[(RS)-2-benzyl-3-(3-methoxy-
C34H36FN3O5
1.06
586.21


phenylcarbamoyl)-propionylamino]-6-fluoro-
585.67
LC-3


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-{3-[(RS)-2-benzyl-3-(4-chloro-
C33H33ClFN3O4
1.09
590.2


phenylcarbamoyl)-propionylamino]-6-fluoro-
590.08
LC-3


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl (3S)-{3-[(RS)-2-benzyl-3-(4-fluoro-
C34H35F2N3O4
1.05
588.25


benzylcarbamoyl)-propionylamino]-6-fluoro-
587.66
LC-3


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate


Ethyl [(3S)-3-((RS)-2-benzyl-3-propylcarbamoyl-
C30H36FN3O4
1
522.26


propionylamino)-6-fluoro-1,2,3,4-tetrahydro-9H-
521.62
LC-3


carbazol-9-yl]-acetate









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 2.5 h. 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. tR=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 C1-4alkanedicarboxylic 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 tent-butyl ester is obtained in 25% yield as an orange oil: tR=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)-carb amic acid 1,1-dimethylethyl ester,
    (3R)-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carb amic acid 1,1-dimethylethyl ester, and
    (3S)-(6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-carb amic 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.









TABLE 11





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







(3S)-[3-(3-Cyclopentyl-
0.99 (br.s, 2H), 1.41-1.64 (m, 9H), 1.98 (m, 2H),
CDCl3


propionylamino)-1,2,3,4-
2.06 (t, 2H), 2.48-2.72 (m, 4H), 2.99 (m, 1H),


tetrahydro-9H-carbazol-9-
4.33 (m, 1H), 4.63 (s, 2H), 6.03 (d, 1H),


yl]-acetic acid
6.94-7.14 (m, 3H), 7.32 (d, 2H).


(3RS)-[3-(3-Benzyl-
1.78 (m, 1H), 2.02 (m, 1H), 2.48 (m, 1H),
DMSO-


ureido)-6-fluoro-1,2,3,4-
2.69 (m, 2H), 2.92 (dd, 1H), 3.93 (m, 1H), 4.23 (m, 2H),
d6


tetrahydro-9H-carbazol-9-
4.86 (d, 2H), 6.09 (d, 1H), 6.30 (t, 1H),


yl]-acetic acid
6.88 (td, 1H), 7.15 (dd, 1H), 7.24 (m, 3H), 7.32 (m, 3H)


(3S)-{6-Fluoro-3-[3-(4-
1.19 (d, 6H), 1.73 (m, 1H), 1.97 (m, 1H),
DMSO-


isopropyl-phenyl)-
2.38 (t, 2H), 2.36-2.45 (m, 1H), 2.70 (m, 2H), 2.80 (t,
d6


propionylamino]-1,2,3,4-
2H), 2.82-2.90 (m, 2H), 4.01 (m, 1H), 4.87 (m, 2H),


tetrahydro-9H-carbazol-9-
6.88 (dt, 1H), 7.01 (m, 4H), 7.33 (dd, 1H),


yl}-acetic acid
7.93 (d, 1H), 12.90 (bs, 1H)


(3S)-(6-Fluoro-3-{(2RS)-2-
1.59 (m, 0.5H), 1.74 (m, 1H), 1.91 (m, 0.5H),
DMSO-


[(4-fluoro-
2.32 (m, 2H), 2.68 (m, 4H), 2.90 (m, 1H),
d6


phenylcarbamoyl)-methyl]-
3.08 (m, 1H), 3.57 (m, 1H), 3.95 (m, 1H), 4.84 (m, 2H),


3-phenyl-propionylamino}-
6.87 (m, 1H), 6.97 (d, 0.5H), 7.10 (m, 2.5H),


1,2,3,4-tetrahydro-9H-
7.21 (m, 3H), 7.30 (m, 3H), 7.60 (m, 2H),


carbazol-9-yl)-acetic acid
7.97 (t, 1H), 9.99 (d, 1H), 13.00 (br.s, 1H)


(3S)-[3-
0.26 (m, 2H), 0.47 (d, 2H), 1.07 (m, 1H),
DMSO-


(Benzyloxycarbonyl-
2.05 (m, 1H), 2.18 (m, 1H), 2.82 (m, 2H), 3.21 (d, 2H),
d6


cyclopropylmethyl-amino)-
4.10 (m, 1H), 4.88 (s, 2H), 5.14 (s, 2H),


6-fluoro-1,2,3,4-
6.88 (t, 1H), 7.19 (d, 1H), 7.45 (m, 6H),


tetrahydro-9H-carbazol-9-
12.90 (br.s, 1H).


yl]-acetic acid


(3S)-{3-
2.06 (m, 2H), 2.77 (m, 6H), 3.29 (m, 2H),
DMSO-


[Benzyloxycarbonyl-(2-
3.45 (m, 3H), 4.08 (dd, 1H), 4.88 (m, 2H), 5.13 (s, 2H),
d6


methoxy-ethyl)-amino]-6-
6.89 (m, 1H), 7.16 (m, 1H), 7.34 (m, 6H),


fluoro-1,2,3,4-tetrahydro-
13.00 (br. s, 1H).


9H-carbazol-9-yl}-acetic


acid


(3S)-{6-Fluoro-3-[[3-(2-
1.93 (dd, 1H), 2.09 (m, 1H), 2.75 (m, 8H),
DMSO-


methoxy-phenyl)-
3.66 (m, 3H), 3.77 (m, 2H), 4.13 (m, 3H), 4.90 (m, 2H),
d6


propionyl]-(2-phenoxy-
6.90 (m, 6H), 7.17 (m, 3H), 7.33 (m, 3H),


ethyl)-amino]-1,2,3,4-
12.90 (br. s, 1H)


tetrahydro-9H-carbazol-9-


yl}-acetic acid


(3S)-{6-Fluoro-3-
1.93 (m, 2H), 2.70-3.08 (m, 8H), 4.41 (m, 0.5H),
DMSO-


[naphthalen-1-ylmethyl-(3-
4.86 (m, 2.5H), 5.05 (m, 2H), 6.87 (m, 1H),
d6


phenyl-propionyl)-amino]-
7.04 (m, 2H), 7.19 (m, 3H), 7.35 (m, 3H),


1,2,3,4-tetrahydro-9H-
7.56 (m, 3H), 7.83 (m, 1H), 7.97 (m, 1H), 8.15 (m, 1H),


carbazol-9-yl}-acetic acid
13.00 (br.s, 1H).


(3RS)-(3-
1.76 (m, 1H), 2.05 (m, 1H), 2.48 (m, 1H),
DMSO-


Benzyloxycarbonylamino-
2.68 (m, 1H), 2.75 (t, 1H), 2.93 (d, 1H), 3.77 (m, 1H),
d6


6-fluoro-1,2,3,4-
4.85 (s, 2H), 5.05 (s, 2H), 6.87 (dt, 1H), 7.14 (dd,


tetrahydro-9H-carbazol-9-
1H), 7.29-7.38 (m, 5H), 7.46 (m, 1H).


yl)-acetic acid


(3S)-Ethyl [3-(3-butyl-
0.86 (t, 3H), 1.20 (t, 3H), 1.31 (m, 2H), 1.42 (m,
DMSO-


ureido)-1,2,3,4-tetrahydro-
2H), 2.06 (m, 2H), 2.64 (dd, 1H), 2.70 (m, 2H),
d6


9H-carbazol-9-yl]-acetate
3.03-3.10 (m, 3H), 4.18 (q, 2H), 4.28 (m, 1H),



4.71 (s, 2H), 7.04-7.21 (m, 3H), 7.45 (d, 1H).


(3S)-Ethyl (3-
0.93 (t, 3H), 1.24 (t, 3H), 1.63 (m, 2H),
CDCl3


propoxycarbonylamino-
2.03-2.14 (m, 2H), 2.65 (dd, 1H), 2.77 (t, 2H), 3.12 (dd,


1,2,3,4-tetrahydro-9H-
1H), 4.02 (t, 2H), 4.20 (m, 4H), 4.72 (s, 2H),


carbazol-9-yl)-acetate
7.07-7.14 (m, 1H,H), 7.17 (m, 2H), 7.44 (d, 1H).


(3S)-Ethyl [3-(2-phenoxy-
1.24 (t, 3H), 2.04 (m, 1H), 2.17 (m, 1H),
CDCl3


acetylamino)-1,2,3,4-
2.60-2.86 (m, 3H), 3.15 (dd, 1H), 4.20 (q, 2H),


tetrahydro-9H-carbazol-9-
4.53 (m, 1H), 4.49 (s, 2H), 4.72 (s, 2H), 6.71 (d, 1H),


yl]-acetate
6.90 (s, 2H), 7.02-7.27 (m, 6H), 7.45 (d, 1H).


(3R)-Ethyl (3-tert-
1.25 (t, 3H), 1.45 (s, 9H), 1.99 (m, 1H), 2.12 (m,
CDCl3


butoxycarbonylamino-
1H), 2.63 (dd, 1H,), 2.75 (m, 2H), 3.09 (dd, 1H),


1,2,3,4-tetrahydro-9H-
4.16 (m, 1H), 4.21 (d, 2H), 4.72 (s, 2H), 7.18 (m,


carbazol-9-yl)-acetate
3H), 7.45 (d, 1H).


(3R)-Ethyl {6-fluoro-3-[2-
1.24 (t, 3H), 2.04 (m, 2H), 2.60 (m, 2H), 2.70 (dt,
CDCl3


(4-trifluoromethyl-phenyl)-
1H), 3.01 (dd, 1H), 3.54 (s, 2H), 4.19 (q, 2H),


acetylamino]-1,2,3,4-
4.43 (m, 1H), 4.66 (s, 2H), 5.58 (d, 1H), 6.88 (dt,


tetrahydro-9H-carbazol-9-
1H), 7.06 (m, 2H), 7.27 (m, 1H), 7.39 (d, 2H),


yl}-acetate
7.54 (d, 2H).


(3RS)-Ethyl (3-
1.18 (t, 3H), 1.76 (m, 1H), 2.03 (m, 1H), 2.46 (m,
DMSO-


benzyloxycarbonylamino-
1H), 2.63-2.80 (m, 2H), 2.90 (dd, 1H), 3.75 (m,
d6


8-chloro-6-fluoro-1,2,3,4-
1H), 4.14 (q, 2H), 5.03 (s, 2H), 5.15 (s, 2H),


tetrahydro-9H-carbazol-9-
7.01 (dd, 1H), 7.19 (dd, 1H), 7.27-7.36 (m, 5), 7.45 (d,


yl)-acetate
1H).


(3S)-Ethyl [6-fluoro-3-(4-
1.28 (t, 3H), 2.07 (dd, 2H), 2.54 (dd, 1H), 2.73 (t,
CDCl3


nitro-
2H), 2.87 (dd, 1H), 3.94 (m, 1H), 4.21 (d, 2H),


benzenesulfonylamino)-
4.68 (s, 2H), 4.90 (d, 1H), 6.85-6.94 (m, 2H),


1,2,3,4-tetrahydro-9H-
7.06 (dd, 1H), 8.03 (d, 1H), 8.30 (d, 1H).


carbazol-9-yl]-acetate


(3S)-Ethyl {6-fluoro-3-
1.27 (t, 3H), 1.85 (m, 1H), 2.01 (m, 1H), 2.65 (dd,
CDCl3


[methyl-(4-nitro-
1H), 2.75-2.82 (m, 3H), 2.94 (s, 3H), 4.20 (d,


benzenesulfonyl)-amino]-
2H), 4.36 (m, 1H), 4.67 (s, 2H), 6.90 (dt, 1H),


1,2,3,4-tetrahydro-9H-
6.97 (dd, 1H), 7.06 (dd, 1H), 8.03 (d, 1H), 8.37 (d,


carbazol-9-yl}-acetate
1H).


(3RS)-(8-Chloro-6-fluoro-
1.76 (m, 1H), 1.99 (m, 1H), 2.48 (m, 1H),
DMSO-


2,3,4,9-tetrahydro-1H-
2.74-2.93 (m, 3H), 3.80 (m, 1H), 5.03 (s, 2H), 7.00 (dd,
d6


carbazol-3-yl)-carbamic
1H), 7.10 (dd, 1H), 7.28-7.36 (m, 5H), 7.43 (d,


acid benzyl ester
1H), 11.10 (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.








TABLE 12






hCRTH2 Bdg


Compound
IC50 (nM)
















(3S)-[3-(3,3-Diphenyl-propionylamino)-6-fluoro-1,2,3,4-
2


tetrahydro-9H-carbazol-9-yl]-acetic acid


(3S)-(3-{Acetyl-[2-(2-fluoro-phenyl)-ethyl]-amino}-6-
4


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid


(3S)-(6-Fluoro-3-{(2-methoxy-ethyl)-[3-(2-methoxy-
6


phenyl)-propionyl]-amino}-1,2,3,4-tetrahydro-9H-


carbazol-9-yl)-acetic acid


(3S)-{3-[(RS)-2-Benzyl-3-(3-methoxy-
6


phenylcarbamoyl)-propionylamino]-6-fluoro-1,2,3,4-


tetrahydro-9H-carbazol-9-yl}-acetic acid


(3S)-[3-(3-Benzyl-1-cyclohexylmethyl-ureido)-6-fluoro-
6


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid


(3S)-{3-[2-(4-Chloro-phenoxy)-acetylamino]-6-fluoro-
9


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid


(3S)-{3-[(2,3-Dihydro-1H-indole-2-carbonyl)-amino]-6-
11


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid


(3S)-{6-Fluoro-3-[3-(4-methylsulfanyl-phenyl)-
14


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-


acetic acid


(3S)-{3-[3-(2,5-Bis-trifluoromethyl-phenyl)-
15


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-


carbazol-9-yl}-acetic acid


(3S)-[3-(3-Benzo[1,3]dioxol-5-yl-propionylamino)-6-
15


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid


(3S)-{6-Fluoro-3-[ethyl-(3-phenyl-propionyl)-amino]-
16


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid


(3S)-{3-[3-(2,4-Dichloro-phenyl)-propionylamino]-6-
16


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid


(3S)-(6-Fluoro-3-{[(2RS)-8-methoxy-1,2,3,4-tetrahydro-
18


naphthalene-2-carbonyl]-amino}-1,2,3,4-tetrahydro-9H-


carbazol-9-yl)-acetic acid


(3S)-{6-Fluoro-3-[((S)-2-methyl-3-phenyl-propionyl)-(2-
21


phenoxy-ethyl)-amino]-1,2,3,4-tetrahydro-9H-carbazol-


9-yl}-acetic acid


(3RS)-(3-Benzyloxycarbonylamino-6-trifluoromethyl-
26


1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid


(3S)-{6-Fluoro-3-[3-(2-hydroxy-phenyl)-
33


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-


acetic acid


(3R)-{3-[3-(3-Chloro-phenyl)-propionylamino]-6-
39


fluoro-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid


(3S)-{6-Fluoro-3-[3-(3-trifluoromethoxy-phenyl)-
47


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-


acetic acid


(3RS)-[8-Chloro-6-fluoro-3-(3-phenyl-propionylamino)-
57


1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid


(3S)-{3-[(2-Benzyloxy-acetyl)-methyl-amino]-6-fluoro-
60


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid


(3R)-[6-Fluoro-3-(3-p-tolyl-propionylamino)-1,2,3,4-
61


tetrahydro-9H-carbazol-9-yl]-acetic acid


(3S)-{6-Fluoro-3-[3-(4-methanesulfonyl-phenyl)-
72


propionylamino]-1,2,3,4-tetrahydro-9H-carbazol-9-yl}-


acetic acid


(3S)-(3-Isobutoxycarbonylamino-1,2,3,4-tetrahydro-9H-
84


carbazol-9-yl)-acetic acid


(3S)-{3-[3-(3-tert-Butoxycarbonylamino-phenyl)-
93


propionylamino]-6-fluoro-1,2,3,4-tetrahydro-9H-


carbazol-9-yl}-acetic acid


(3S)-[3-(2-Benzyloxy-ethoxycarbonylamino)-1,2,3,4-
117


tetrahydro-9H-carbazol-9-yl]-acetic acid


(3R)-[3-(3-Phenylsulfonyl-ureido)-1,2,3,4-tetrahydro-
147


9H-carbazol-9-yl]-acetic acid


(3R)-[3-(3-Naphthalen-1-yl-ureido)-1,2,3,4-tetrahydro-
152


9H-carbazol-9-yl]-acetic acid


(3R)-[3-(2-Thiophen-2-yl-acetylamino)-1,2,3,4-
297


tetrahydro-9H-carbazol-9-yl]-acetic acid


(3R)-[3-(3-Cyclopentyl-propionylamino)-1,2,3,4-
400


tetrahydro-9H-carbazol-9-yl]-acetic acid


(3R)-(3-Benzoylamino-1,2,3,4-tetrahydro-9H-carbazol-
488


9-yl)-acetic acid


(3S)-{6-Fluoro-3-[(1H-indole-2-carbonyl)-amino]-
824


1,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid


(3S)-[3-(3-Butyl-ureido)-1,2,3,4-tetrahydro-9H-
896


carbazol-9-yl]-acetic acid









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 λex488 nm and λem=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

1. A compound of Formula I:




wherein
R1, R2, R3 and R4 are independently hydrogen, C1-5-alkyl, C1-5-alkoxy, alkenyl, halogen, nitro, cyano, halo-C1-6-alkoxy, halo-C1-6-alkyl, C1-6-alkylsulfonyl, or formyl;
R5 is a hydrogen, alkenyl, C1-6-alkyl, cycloalkyl-C1-4-alkyl, C1-3-alkoxy-C1-4-alkyl, aryl-C1-4-alkyl, or aryloxy-C1-4-alkyl; wherein the aryl is unsubstituted, mono- or di-substituted by C1-2-alkylendioxy, C1-4-alkoxy, C1-4-alkyl, halogen, trifluoromethyl, or trifluoromethoxy; and
R6 is a 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-C3-6-cycloalkylcarbonyl; cycloalkylcarbonyl; or R7—C1-4-alkylcarbonyl wherein the bridging C1-4-alkyl group of the R7—C1-4-alkylcarbonyl may additionally be mono-substituted with an aryl or disubstituted with a hydroxy, and wherein R7 is an arylaminocarbonyl, heteroarylaminocarbonyl, C1-6-alkylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl;
further wherein the aryl is unsubstituted, mono- or di-substituted with a C1-2-alkylendioxy; C1-6-alkoxy; C1-6-alkyl; C1-6-alkylsulfonyl; phenyl which is unsubstituted, mono- or di-substituted by a halogen, trifluoromethyl, methoxy or methyl; naphthyl; phenyl-C1-3-alkyl, wherein the phenyl group is unsubstituted, mono- or di-substituted independently with a halogen, trifluoromethyl, methoxy or methyl; naphthyl-C1-3-alkyl; phenoxy, wherein the phenyl group is unsubstituted, mono- or di-substituted independently with a halogen, trifluoromethyl, methoxy or methyl; naphthyloxy; halogen; hydroxy; halo-C1-6-alkyl; halo-C1-6-alkoxy; C1-6-alkylthio; or C1-4-alkoxycarbonylamino;

or a salt thereof.

2. The compound according to claim 1, wherein R1, R3 and R4 are hydrogen; or a salt thereof.

3. The compound according to claim 1, wherein R2 is a hydrogen, trifluoromethyl, or halogen;
or a salt thereof.

4. The compound according to claim 1, wherein R5 is a hydrogen; C1-3-alkyl; cyclopropylmethyl; 2-methoxyethyl; phenyl-C2-3-alkyl; or phenoxyethyl,
wherein the phenyl group is unsubstituted or mono-substituted with C1-2-alkylendioxy, C1-4-alkoxy, C1-4-alkyl, halogen, trifluoromethyl, or trifluoromethoxy;
or a salt thereof.

5. The compound according to claim 1, wherein R6 is a 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 of the R7—C1-4-alkylcarbonyl may additionally be mono-substituted with aryl, and R7 is an arylaminocarbonyl, heteroarylaminocarbonyl, C1-6-alkylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl;
further wherein the aryl is unsubstituted, mono- or di-substituted independently with a C1-2-alkylendioxy, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl, halogen, hydroxy, halo-C1-6-alkyl, halo-C1-5-alkoxy, C1-6-alkylthio, or C1-4-alkoxycarbonylamino;
or a salt thereof.

6. The compound according to claim 1, wherein R6 is an aryl-C1-2-alkoxycarbonyl; aryl-C1-2-alkylaminocarbonyl; aryl-C1-4-alkylcarbonyl; aryloxy-C1-2-alkylcarbonyl; 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 is an arylaminocarbonyl or C1-4-alkylaminocarbonyl;
further wherein the aryl is unsubstituted, mono- or di-substituted independently with a C1-2-alkylendioxy, C1-6-alkoxy, C1-6-alkyl, C1-6-alkylsulfonyl, halogen, hydroxy, trifluoromethyl, or trifluoromethoxy;
or a salt thereof.

7. The compound according to claim 1, wherein,
if R6 is a group comprising a carbonyl group and one or more aryl moieties,
then R6 comprises a bridging group between said carbonyl group and said one or more aryl moieties, further wherein said carbonyl moiety and at least one of said one or more aryl moieties are directly attached to different atoms of said bridging group;

or a salt thereof.

8. The compound according to claim 1, wherein
R6 is a C1-4-alkylcarbonyl or aryl-C2-4-alkylcarbonyl, wherein the aryl is unsubstituted, mono- or di-substituted independently with a C1-4-alkoxy, C1-4-alkyl, halogen, or trifluoromethyl; and
R5 is a phenyl-C2-3-alkyl;
or a salt thereof.

9. The compound according to claim 1, wherein the compound is
(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;
(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-phenyl acetylamino-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)-[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;
(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;
(3R)-{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; or
(3S)-[3-(3-butyl-ureido)-1,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;

or a salt thereof.

10. The compound according to claim 1, wherein the compound is:
(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-Benzyloxylcarbonylamino-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;
(3R)-{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-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;
(3R)-[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; or
(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 thereof.

11. A pharmaceutical composition, comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

12. A medicament, comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. A method of antagonizing a CRTH2 receptor, comprising the step of administering an effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

14. The method of claim 13, wherein said patient has a disease or disorder that comprises 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, an eosinophil-related disease, or a basophil-related disease.

15. The method of claim 14, wherein said patient has an eosinophil-related disease comprising Churg-Strauss syndrome or sinusitis.

16. The method of claim 14, wherein said patient has a basophil-related disease comprising basophilic leukemia or basophilic leukocytosis.

17. The compound according to claim 1, wherein
R5 is hydrogen, methyl, ethyl, or n-propyl;
or a salt thereof.

18. The compound according to claim 2, wherein
R5 is hydrogen, methyl, ethyl, or n-propyl;
or a salt thereof.

19. The compound according to claim 1, wherein R6 is 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 of the R7—C1-4-alkylcarbonyl may additionally be mono-substituted with an aryl, and wherein R7 is an arylaminocarbonyl, heteroarylaminocarbonyl, C1-6-alkylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl; further wherein the aryl is unsubstituted, mono- or di-substituted with a 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, or C1-4-alkoxycarbonylamino;
or a salt thereof.

20. The compound according to claim 17, wherein R6 is 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 of the R7—C1-4-alkylcarbonyl may additionally be mono-substituted with an aryl, and wherein R7 is an arylaminocarbonyl, heteroarylaminocarbonyl, C1-6-alkylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl; further wherein the aryl is unsubstituted, mono- or di-substituted with a 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, or C1-4-alkoxycarbonylamino;
or a salt thereof.

21. The compound according to claim 18, wherein R6 is 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 of the R7—C1-4-alkylcarbonyl may additionally be mono-substituted with an aryl, and wherein R7 is an arylaminocarbonyl, heteroarylaminocarbonyl, C1-6-alkylaminocarbonyl, or aryl-C1-3-alkylaminocarbonyl; further wherein the aryl is unsubstituted, mono- or di-substituted with a 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, or C1-4-alkoxycarbonylamino;
or a salt thereof.

22. The compound according to claim 1, wherein R6 represents C1-9-alkylaminocarbonyl; C1-9-alkylcarbonyl; or C1-9-alkoxycarbonyl;
or a salt thereof.

23. The compound according to claim 2, wherein R6 represents C1-9-alkylaminocarbonyl; C1-9-alkylcarbonyl; or C1-9-alkoxycarbonyl;
or a salt thereof.