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WO2008017989A1 - (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives - Google Patents

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

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Publication number
WO2008017989A1
WO2008017989A1 PCT/IB2007/053046 IB2007053046W WO2008017989A1 WO 2008017989 A1 WO2008017989 A1 WO 2008017989A1 IB 2007053046 W IB2007053046 W IB 2007053046W WO 2008017989 A1 WO2008017989 A1 WO 2008017989A1
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Prior art keywords
tetrahydro
carbazol
fluoro
acetic acid
phenyl
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Application number
PCT/IB2007/053046
Other languages
French (fr)
Inventor
Heinz Fretz
Julien Pothier
Philippe Risch
Original Assignee
Actelion Pharmaceuticals Ltd
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Publication date
Priority to KR1020097004370A priority Critical patent/KR101411820B1/en
Priority to US12/376,932 priority patent/US8143304B2/en
Application filed by Actelion Pharmaceuticals Ltd filed Critical Actelion Pharmaceuticals Ltd
Priority to SI200730818T priority patent/SI2051962T1/en
Priority to PL07805287T priority patent/PL2051962T3/en
Priority to ES07805287T priority patent/ES2374321T3/en
Priority to CA2658986A priority patent/CA2658986C/en
Priority to AT07805287T priority patent/ATE530523T1/en
Priority to CN2007800292169A priority patent/CN101500996B/en
Priority to EP07805287A priority patent/EP2051962B1/en
Priority to BRPI0715179-9A priority patent/BRPI0715179A2/en
Priority to MX2009001105A priority patent/MX2009001105A/en
Priority to AU2007282949A priority patent/AU2007282949B8/en
Priority to DK07805287.5T priority patent/DK2051962T3/en
Priority to JP2009523396A priority patent/JP5220013B2/en
Priority to NZ574705A priority patent/NZ574705A/en
Publication of WO2008017989A1 publication Critical patent/WO2008017989A1/en
Priority to IL196891A priority patent/IL196891A/en
Priority to NO20090979A priority patent/NO20090979L/en
Priority to HK09110028.6A priority patent/HK1130062A1/xx
Priority to HR20120044T priority patent/HRP20120044T1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P35/00—Antineoplastic agents
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    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to (3-amino-l,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 D 2 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.
  • prostaglandin receptor modulators most particularly as prostaglandin D 2 receptor (“DP receptor”) modulators
  • 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.
  • chronic and acute allergic/immune diseases/disorders such as allergic asthma, rhinitis
  • mast cells are activated and release chemotactic key mediators like histamine, thromboxane A2 (TxA2), cysteinyl leukotrienes (CysLTs) and prostaglandin D 2 (PGD 2 ).
  • TxA2 thromboxane A2
  • CysLTs cysteinyl leukotrienes
  • PPD 2 prostaglandin D 2
  • 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 Hl receptor antagonists
  • leukotriene receptor antagonists beta-adrenergic receptor agonists
  • corticosteroids corticosteroids
  • PGD 2 is an agonist known to act on two G-protein-coupled receptors, the PGD 2 receptor DPI and the recently identified CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) receptor (also referred to as "DP2 receptor").
  • CRTH2 chemoattractant receptor-homologous molecule expressed on Th2 cells
  • Elevated PGD 2 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 PGD 2 with its receptors is considered a useful therapeutic strategy for the treatment of such diseases.
  • WO 01/79169 discloses (tetrahydrocarbazol-l-y ⁇ acetic acid derivatives as PGD 2 receptor antagonists.
  • GB 2388540 (Bayer AG) discloses the use of ramatroban ((3i?)-3-(4-fluorobenzene- sulfonamido)-l,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.
  • TP receptor also referred to as "TP receptor”
  • 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, antihistamines, leukotriene antagonists or beta-adrenergic agonists.
  • Description of the invention: i) The present invention relates to (3-amino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid compounds of the Formula I:
  • R 1 , R 2 , R 3 and R 4 independently represent hydrogen, Ci_ 5 -alkyl, Ci_ 5 -alkoxy, alkenyl (especially allyl or vinyl), halogen, nitro, cyano, halo-Ci_ 6 -alkoxy, halo-Ci_ 6 -alkyl, Ci_ 6 -alkylsulfonyl, or formyl;
  • R represents hydrogen, alkenyl (especially allyl or vinyl), Ci_ 6 -alkyl, cycloalkyl-Ci_ 4 -alkyl, Ci_ 3 -alkoxy-Ci_ 4 -alkyl, aryl-Ci_ 4 -alkyl, or aryloxy-Ci_ 4 -alkyl (especially R 5 represents hydrogen, Ci_ 6 -alkyl, cycloalkyl-Ci_ 4 -alkyl, Ci_ 3 -alkoxy-Ci_ 4 -alkyl, aryl-Ci_ 4 -alkyl, or aryloxy-Ci_ 4 -alkyl); wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_ 2 -alkylendioxy, Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluor
  • R represents Ci_ 9 -alkylaminocarbonyl; Ci_ 9 -alkylaminothiocarbonyl; Ci_ 9 -alkylcarbonyl; Ci_ 9 -alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; arylaminothiocarbonyl; aryl- C i_ 3 -alkoxy-C i_ 3 -alkoxycarbonyl; aryl-C i_ 3 -alkoxycarbonyl; aryl-Ci_ 3 -alkylaminocarbonyl; aryl-Ci_ 6 -alkylcarbonyl; aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkylcarbonyl; arylcarbonyl; arylcarbonyl- Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 3 -alkylcarbonyl; arylsulfonylaminocarbony
  • the invention relates to compounds of Formula I according to embodiment i), wherein
  • R 5 represents hydrogen, alkenyl (especially allyl or vinyl), or Ci_ 6 -alkyl
  • R 6 represents Ci_ 9 -alkylaminocarbonyl, Ci_ 9 -alkylaminothiocarbonyl, Ci_ 9 -alkylcarbonyl, Ci_ 9 -alkoxycarbonyl, arylalkenylcarbonyl, arylaminocarbonyl, arylaminothiocarbonyl, aryl- C i_ 3 -alkoxy-C i_ 3 -alkoxycarbonyl, aryl-Ci_ 3 -alkoxycarbonyl, aryl-C i_ 3 -alkylaminocarbonyl, aryl-Ci_ 3 -alkylcarbonyl, aryl-C i_ 3 -alkoxy-Ci_ 3 -alkylcarbonyl, arylcarbonyl, arylcarbonyl- Ci_ 4 -alkylcarbonyl, aryloxy-Ci_ 3 -alkylcarbonyl, arylsulfonylamino
  • R 1 , R 2 , R 3 and R 4 independently represent hydrogen; Ci_ 5 -alkyl, especially methyl, or isopropyl; Ci_ 5 -alkoxy, especially methoxy; alkenyl, especially allyl or vinyl; halogen, especially fluoro, or chloro; halo-Ci_ 6 -alkyl, especially trifluoromethyl; or Ci_ 6 -alkylsulfonyl, especially methanesulfonyl; R 5 represents hydrogen; alkenyl, especially ethenyl, or 2-propenyl; or Ci_ 6 -alkyl, especially methyl, ethyl, or propyl; and
  • R 6 represents Ci_ 9 -alkylaminocarbonyl, such as butylaminocarbonyl; Ci_ 9 -alkylcarbonyl, such as propylcarbonyl, isobutylcarbonyl, hexylcarbonyl, or nonylcarbonyl; Ci_ 9 -alkoxycarbonyl, such as propoxycarbonyl, te/t-butoxycarbonyl, or isobutoxycarbonyl; arylalkenylcarbonyl, such as naphthalenylethenylcarbonyl (especially 2-naphthalen-2-yl- ethenylcarbonyl), or phenylethenylcarbonyl; arylaminocarbonyl, such as naphthalenaminocarbonyl (especially naphthalen-1-aminocarbonyl), or phenylaminocarbonyl; aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkoxycarbonyl, such as
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to iii), wherein R 1 represents hydrogen, or halogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to iv), wherein R 2 represents hydrogen, trifluoromethyl, or halogen (especially hydrogen, or halogen).
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to v), wherein R 3 represents hydrogen, or halogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to vi), wherein R 4 represents hydrogen, alkenyl (especially allyl or vinyl), halogen (especially chloro or bromo), Ci_ 6 -alkylsulfonyl (especially methanesulfonyl); especially hydrogen or halogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to vii), wherein R 1 , R 3 and R 4 represent hydrogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to viii), wherein R 2 represents fluoro.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen, Ci_6-alkyl (especially Ci_ 3 -alkyl), cycloalkyl-Ci_ 4 -alkyl (especially cyclopropylmethyl), Ci_ 3 -alkoxy- Ci_ 4 -alkyl (especially 2-methoxyethyl), aryl-Ci_ 4 -alkyl (especially naphthylmethyl, or preferably phenyl-C 2 - 3 -alkyl), or aryloxy-Ci_ 4 -alkyl (especially phenoxy ethyl); wherein aryl (especially phenyl) is unsubstituted (preferred), or mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_4-alkyl, halogen, trifluor
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen; Ci_3-alkyl (especially methyl); cyclopropylmethyl; 2-methoxyethyl; phenyl-C 2 - 3 -alkyl; or phenoxyethyl, wherein the phenyl group is unsubstituted (preferred), or mono-substituted with a group selected from Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluoromethyl).
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents Ci_3-alkyl (especially methyl); cyclopropylmethyl; 2-methoxyethyl; phenyl-C 2 - 3 -alkyl; or phenoxyethyl, wherein the phenyl group is unsubstituted (preferred), or mono-substituted with a group selected from Ci_ 2 -alkylendioxy, Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluoromethyl).
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen, Ci_ 3 -alkyl (especially methyl), cyclopropylmethyl, or 2-methoxyethyl; especially cyclopropylmethyl, or 2-methoxyethyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen, methyl, ethyl, or n-propyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents hydrogen.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to ix), wherein R 5 represents phenyl-C2-3-alkyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents Ci_9-alkylaminocarbonyl; Ci_ 9 -alkylcarbonyl; Ci_ 9 -alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; aryl- C i_ 3 -alkoxy-C i_ 3 -alkoxycarbonyl; aryl-C i_ 3 -alkoxycarbonyl; aryl-Ci_ 3 -alkylaminocarbonyl; aryl-Ci_ 6 -alkylcarbonyl; aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkylcarbonyl; arylcarbonyl; arylcarbonyl- Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 3 -alkylcarbonyl; arylcarbony
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-
  • Ci_ 3 -alkylcarbonyl cycloalkyl-Ci_ 3 -alkylcarbonyl; diaryl-Ci_ 3 -alkylcarbonyl; aryl-
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-Ci_3-alkoxycarbonyl; aryl-Ci_ 3 -alkylaminocarbonyl; aryl-Ci_ 6 -alkylcarbonyl; aryloxy-Ci_ 3 -alkylcarbonyl; diaryl- Ci_ 3 -alkylcarbonyl; or R 7 -Ci_ 4 -alkylcarbonyl, wherein the bridging Ci_ 4 -alkyl group may additionally be mono-substituted with aryl, and R 7 represents arylaminocarbonyl, or C i_ 6 -alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-Ci_2-alkoxycarbonyl; aryl-Ci_ 2 -alkylaminocarbonyl; aryl-Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 2 -alkylcarbonyl; or diaryl-C 2 - 3 -alkylcarbonyl; or R 7 -C 2 - 4 -alkylcarbonyl, wherein the bridging C 2 - 4 -alkyl group may additionally be mono-substituted with aryl, and R 7 represents arylaminocarbonyl, or
  • C i_ 4 -alkylaminocarbonyl wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_ 2 -alkylendioxy, Ci_ 6 -alkoxy, Ci_ 6 -alkyl, Ci_ 6 -alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl- Ci_ 2 -alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_ 6 -alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-Ci_2-alkoxycarbonyl; aryl-Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 2 -alkylcarbonyl; or diaryl-C 2 - 3 -alkylcarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_ 2 -alkylendioxy, Ci_ 6 -alkoxy, Ci_ 6 -alkyl, Ci_ 6 -alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxii), wherein, in case R 6 represents a group which contains aryl, the aryl group is phenyl which unsubstituted, or mono- or di-substituted with a group independently selected from Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, and trifluoromethyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents Ci_4-alkylcarbonyl (especially acetyl); or aryl-C 2 - 4 -alkylcarbonyl, wherein aryl is unsubstituted, mono- or di- substituted with a group independently selected from Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, and trifluoromethyl.
  • R 6 represents Ci_4-alkylcarbonyl (especially acetyl); or aryl-C 2 - 4 -alkylcarbonyl, wherein aryl is unsubstituted, mono- or di- substituted with a group independently selected from Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, and trifluoromethyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) and iv) to xvi), wherein R 6 represents aryl-C 2 _ 4 -alkylcarbonyl, wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_ 4 -alkoxy, Ci_ 4 -alkyl, halogen, and trifluoromethyl.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxv), wherein, in case R 6 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 R 6 , wherein the carbonyl moiety and at least one of the aryl moieties are directly attached to different atoms of said bridging group.
  • a further embodiment of the invention relates to compounds of Formula I according to any one of embodiments i) to xxv), wherein, in case R 6 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 R 6 , wherein the carbonyl moiety and the aryl moiety are directly attached to the same atom of said bridging group.
  • a further embodiment of the invention relates to compounds of Formula I according to embodiment i), wherein R 1 represents hydrogen, or halogen;
  • R 2 represents hydrogen, trifluoromethyl, or halogen
  • R 3 represents hydrogen, or halogen
  • R 4 represents hydrogen, halogen (especially chloro or bromo), or Ci_ 6 -alkylsulfonyl
  • R 5 represents hydrogen, C ⁇ -alkyl, cycloalkyl-Ci_ 4 -alkyl, Ci_ 3 -alkoxy-Ci_ 4 -alkyl, aryl-
  • Ci_ 4 -alkyl or aryloxy-Ci_ 4 -alkyl; wherein aryl is unsubstituted, mono-substituted with a group selected from trifluoromethyl; and
  • R 6 represents Ci_ 9 -alkylaminocarbonyl; Ci_ 9 -alkylcarbonyl; Ci_ 9 -alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; aryl-C ⁇ -alkoxy-Ci-s-alkoxycarbonyl; aryl-Ci_3- alkoxycarbonyl; aryl-Ci_ 3 -alkylaminocarbonyl; aryl-Ci_ 6 -alkylcarbonyl; aryl-Ci_ 3 -alkoxy- Ci_ 3 -alkylcarbonyl; arylcarbonyl; arylcarbonyl-Ci_ 4 -alkylcarbonyl; aryloxy-Ci_ 3 - alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl-Ci.s-alkylcarbonyl; diaryl-Ci_ 3 - alkylcarbon
  • 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 (5)-configurated.
  • 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 (i?)-conf ⁇ gurated.
  • 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.
  • 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.
  • bridging group or "bridging atom” as used herein means a group or atom that is placed between two distinct moieties of the molecule.
  • bridging groups are the bridging Ci_ 6 -alkyl group in an aryl- Ci_ 6 -alkylcarbonyl group which is placed between the aryl and the carbonyl moiety; the bridging Ci_ 4 -alkyl group in an aryl-Ci_ 4 -alkyl group, which is placed between the aryl moiety and the parent molecular moiety; or the bridging Ci_ 4 -alkyl group in an R 7 -Ci_ 4 -alkylcarbonyl group which is placed between the R 7 -group and the carbonyl moiety.
  • bridging atoms is the bridging carbon atom of a methylene (-CH 2 -) 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.
  • alkyl refers to a saturated aliphatic group including a straight or branched hydrocarbon chain containing the indicated number of carbon atoms, for example Ci_ 9 -alkyl, i.e. an alkyl having 1-9 carbon atoms.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, ⁇ o-propyl, n-butyl, tert-butyl, ⁇ o-butyl (or also referred to as "2-methylpropyl"), n-pentyl (also referred to as "n-amyl”), ⁇ o-pentyl (also referred to as " ⁇ o-amyl”), n-hexyl, n-heptyl, and n-octyl.
  • Preferred are methyl, ethyl, n-propyl, ⁇ o-propyl, n-butyl, and ⁇ o-butyl.
  • Most preferred are methyl, ethyl, n-propyl, and ⁇ o-propyl.
  • a bridging Ci_ 6 -alkyl group as used in "aryl-Ci_ 6 -alkylcarbonyl" as defined for R 6 preferably means a C 2 _ 4 -alkyl group, whereby the aryl moiety and the carbonyl moiety are preferably attached to two different carbon atoms of the bridging C2-4-alkyl group.
  • Preferred examples of bridging Ci_ 6 -alkyl groups as used in R 6 being aryl-Ci_ 6 -alkylcarbonyl are ethane- 1,2-diyl, propane- 1,2-diyl, propane- 1, 3 -diyl, and 2 -methyl-propane- 1,2-diyl.
  • a bridging Ci_ 6 -alkyl group as used in "aryl-Ci_ 6 -alkylcarbonyl" as defined for R 6 means the respective Ci_6-alkyl group, whereby the aryl moiety and the carbonyl moiety preferably are attached to the same carbon atom of the bridging Ci_ 6 -alkyl group.
  • Examples of such bridging Ci_ 6 -alkyl groups as used in R 6 being aryl- Ci_ 6 -alkylcarbonyl are a methylene group (preferred) and ethane- 1,1 -diyl.
  • a bridging Ci_ 3 -alkyl group as used in "diaryl-Ci_ 3 -alkylcarbonyl" as defined for R 6 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 C 2 -3-alkyl group.
  • Preferred examples of such bridging Ci_ 3 -alkyl groups as used in R 6 being diaryl- Ci_ 3 -alkylcarbonyl are ethane- 1,2,2-triyl, and ethane- 1,1,2-triyl.
  • a bridging Ci_ 4 -alkyl group as used in "R 7 -Ci_ 4 -alkylcarbonyl, wherein the bridging Ci_ 4 -alkyl group may additionally be mono-substituted with aryl" as defined for R 6 preferably means a C 2 _ 4 -alkyl group (particularly, if the additional aryl substituent is present, it means propane- 1, 2, 3-triyl) whereby the group R 7 , the carbonyl moiety, and the aryl substituent (if present) preferably are attached to two (three, if the additional aryl substituent is present) different carbon atoms of the bridging C 2 - 4 -alkyl group.
  • Examples of bridging Ci_ 4 -alkyl groups as used in R 6 being "R 7 -Ci_ 4 -alkylcarbonyl, wherein the bridging Ci_ 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-l,3-diyl, and l-phenyl-propane-2,3- diyl; preferred are 2-phenyl-propane-l,3-diyl, and l-phenyl-propane-2,3-diyl, especially 1 -phenyl-propane-2,3-diyl.
  • a bridging Ci_ 4 -alkyl group as used in R 6 being "R 7 -Ci_ 4 -alkylcarbonyl, wherein the bridging Ci_ 4 -alkyl group may additionally be disubstituted with hydroxy" is 1 ,2-dihydroxyethane- 1 ,2-diyl.
  • R a -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.
  • Ci_ 2 -alkylendioxy refers to an -O(CH2) n O- 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.
  • alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen bridge.
  • Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexyloxy, especially methoxy.
  • alkoxycarbonyl 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.
  • R 6 representing alkoxycarbonyl preferably means n-propoxycarbonyl, and ⁇ o-butoxycarbonyl.
  • alkylcarbonyl as used herein, alone or in any combination, refers to an alkyl group attached to the parent molecular moiety through a carbonyl group.
  • alkylcarbonyl include, but are not limited to, acetyl, 1-oxopropyl, 2,2-dimethyl- 1-oxopropyl, 1-oxobutyl, and 1-oxopentyl. Further examples are l-oxo-2-methyl-butyl, and 3, 3 -dimethyl- 1-oxopropyl. Preferred are acetyl, 1-oxopropyl, 1-oxobutyl, l-oxo-2-methyl- butyl, and 3, 3 -dimethyl- 1-oxopropyl.
  • alkylsulfonyl refers to an alkyl group attached to the parent molecular moiety through a sulfonyl group.
  • alkylsulfonyl include, but are not limited to, methanesulfonyl and ethanesulfonyl, preferably methanesulfonyl.
  • 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.
  • 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.
  • 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-te/t.-butylphenyl, 4-fluorophenyl, 3 -fluorophenyl, 2-fluorophenyl, 3,4-difluorophenyl, 4-iodophenyl, 3-bromophenyl, 2-
  • arylalkenyl 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.
  • aryloxy refers to an aryl group attached to the parent molecular moiety through an oxygen bridge.
  • arylsulfonyl refers to an aryl group attached to the parent molecular moiety through a sulfonyl group.
  • carbonyl as used herein, alone or in any combination, refers to a -C(O)- group.
  • thiocarbonyl refers to a -C(S)- group.
  • cyano refers to a -C ⁇ N group.
  • cycloalkyl refers to a saturated cyclic hydrocarbon moiety containing 3-10 carbon atoms (for example C 3 _ 6 -cycloalkyl means a cycloalkyl having 3 to 6 carbon atoms), preferably a cyclopentyl or cyclohexyl radical, whereby said radicals, especially the cyclopentyl radical, may be substituted with an annellated benzene ring.
  • said benzene ring may be mono-, or di- substituted, wherein the substituent(s) are independently selected from Ci_4-alkyl, Ci_4-alkoxy, and halogen (especially Ci_4-alkoxy).
  • cycloalkyl group is used as a bridging group as for example in an "aryl-C 3 - 6 -cycloalkylcarbonyl" group as defined for R 6 , it is preferably a cyclopropane-diyl, cyclopentane-diyl or cyclohexane-diyl radical (especially cyclopropane- 1 ,2-diyl) said radical being preferably unsubstituted.
  • haloalkyl 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.
  • haloalkoxy 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.
  • heterocyclyl 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).
  • 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.
  • heteroarylalkyl 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).
  • heteroarylcarbonyl 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).
  • heteroarylamino 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).
  • heterocyclylcarbonyl 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).
  • hydroxy or "hydroxyl” as used herein, alone or in any combination, refers to an -OH group
  • nitro refers to a -NO 2 group.
  • oxy refers to an -O- group.
  • sulfonyl as used herein, alone or in any combination, refer to an -S(O) 2 - group.
  • acyl refers to groups containing a carbonyl group that is linked to a carbon atom such as Ci_ 9 -alkylcarbonyl, arylalkenylcarbonyl, aryl-Ci_ 6 -alkylcarbonyl, aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkylcarbonyl, arylcarbonyl, arylcarbonyl-Ci_ 4 -alkylcarbonyl, aryloxy- Ci_ 3 -alkylcarbonyl, cycloalkyl-Ci_ 3 -alkylcarbonyl, diaryl-Ci_ 3 -alkylcarbonyl, heterocyclylcarbonyl, heteroaryl-Ci_ 3 -alkylcarbonyl, heteroarylcarbonyl, aryl- C 3 - 6 -cycloalkylcarbonyl, cycloalkylcarbonyl, or R 7 -Ci_ 4 -alkyl
  • acylamino refers to an acyl group as described before that is linked to the parent molecular moiety through a nitrogen atom.
  • ureido refers to groups such as Ci_ 9 -alkylaminocarbonyl, arylaminocarbonyl, or aryl-Ci_ 3 -alkylaminocarbonyl that are linked to the parent molecular moiety through a nitrogen atom.
  • oxycarbonylamino refers to groups such as Ci_9-alkoxycarbonyl, aryl-Ci_ 3 -alkoxycarbonyl, or aryl-Ci_ 3 -alkoxy-Ci_ 3 -alkoxycarbonyl that are linked to the parent molecular moiety through a nitrogen atom.
  • 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 PGD 2 .
  • 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-Str
  • 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.
  • 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.
  • 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.
  • compounds of Formula I modulate the PGD 2 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 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 PGD 2 . In a Fluorescent Imaging Plate Reader (FLIPRTM, Molecular Devices, Sunnyvale, California), fluorescence emission is recorded during both additions, emission peak values above base level after PGD 2 addition are exported, and normalized to low controls (no PGD 2 ) and high controls (no active compound).
  • FLIPRTM Fluorescent Imaging Plate Reader
  • 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)/(l+((C/x) ⁇ D)))).
  • the ability of the compounds to modulate PGD 2 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.
  • 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.
  • compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of Formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.
  • 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 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined for Formula I. Other abbreviations used are defined in the experimental section. In some instances the generic groups R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 might be incompatible with the assembly illustrated in the schemes below and, therefore, will require the use of protecting groups (PG).
  • PG protecting groups
  • PG when used as amino-protecting group, preferably refers to a group such as tert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl, most preferably tert- butoxycarbonyl.
  • 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.
  • R and R' independently refer to a Ci_ 4 -alkyl group, preferably ethyl or tert-hvXyl, whereby when R is present R is preferably ethyl and R' is preferably tert. -hvXyX.
  • compounds of Formula I are obtained from an ester of Structure 1, wherein R represents Ci_4-alkyl, preferably ethyl, or tert-bv ⁇ yl, 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 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-R 6 , wherein R 6 is as defined for Formula I and L is a leaving group as defined before.
  • R 6 transferring reagent of Structure L-R 6 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 R 6 in the presence of a base, such as Et 3 N, DIEA, JV-ethyl-morpholine, TV-methylpiperidine, or pyridine, in a suitable solvent, such as THF, or DCM.
  • a base such as Et 3 N, DIEA, JV-ethyl-morpholine, TV-methylpiperidine, or pyridine
  • 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.
  • a coupling reagent such as DCC, diisopropylcarbodiimide, HATU and the like
  • 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.
  • intermediates of Structure 1, wherein R 4 represents an Ci_ 5 -alkyl, allyl, vinyl, or a methanesulfonyl group is obtained by reacting intermediates of Structure 2c wherein R 4 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 K 2 CO 3 , in the presence of a palladium catalyst such as tetr ⁇ Hs(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 6O 0 C and 130
  • a substituent R 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.
  • a reducing agent such as sodium triacetoxyborohydride
  • a base such as DIEA
  • an intermediate of Structure 2a wherein R 5 is not hydrogen, is obtained from an intermediate of Structure 2b via a sulfonamide of Structure 3a.
  • an intermediate of Structure 2b is reacted with/?-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, ⁇ /-dimethyl-aminopyridine, to afford the desired sulfonamide of Structure 3a.
  • the sulfonamide of Structure 3a is easily alkylated with the respective commercially available or well known alkylating agent R 5 -L, with K 2 CO 3 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. Pena et al, Tetrahedron Lett. 2005, 46, 2783-2787).
  • a methyl group is introduced by reaction of a sulfonamide of Structure 3a either with methyl iodide or with diazomethane dissolved in diethylether.
  • 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.
  • a thiol such as thiophenol, or thioacetic acid
  • 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.
  • the PG is a group such as tert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl, most preferably te/t-butoxycarbonyl.
  • An intermediate of Structure 2c is generated by reacting an intermediate of Structure 4 with a compound of Formula L-CH 2 CO 2 R 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.
  • a base such as cesium carbonate, sodium hydride, potassium tert-butanolate or the like
  • 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.
  • the compound of Formula L-CH 2 CO 2 R is ethyl bromoacetate.
  • 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.
  • a coupling reagent such as DCC, diisopropylcarbodiimide, ⁇ ATU or the like
  • a compound of Structure 8a wherein the bridging Ci_ 4 -alkyl group may additionally be mono-substituted with aryl is obtained by treating a respective compound of Structure 8b, wherein R' represents Ci_4-alkyl, preferentially tert-butyl, as a protecting group, with reaction with TFA in DCM or hydrochloric acid in an organic solvent, such as dioxane, diethylether, AcOEt, or the like, at room temperature.
  • R represents Ci_4-alkyl
  • 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 Ci_ 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 Et 3 N, DIEA, or the like, in a solvent such as DCM or DMF.
  • a coupling reagent such as DCC, diisopropylcarbodiimide, HATU, or the like
  • a base such as Et 3 N, DIEA, or the like
  • 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 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 ⁇ m) column, a Daicel ChiralCel OD-H (5-10 ⁇ m) column, or a Daicel ChiralPak IA (10 ⁇ m) or AD-H (5 ⁇ m) column.
  • Typical conditions of chiral HPLC are an isocratic mixture of eluent A (EtOH, in presence or absence of an amine such as Et 3 N, diethylamine) and eluent B (hexane), at a flow rate of 0.8 to 150 mL/min.
  • EtOH EtOH
  • eluent B hexane
  • 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-I 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).
  • - LC-2 Analytical HPLC on a Zorbax ® SB-AQ column (4.6x50 mm, 5 ⁇ m, 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.
  • 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.
  • 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.
  • Table 1 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 Example Compound of Formula I Formula t R [min] MS
  • Table 2a Listed in Table 2a below are further ethyl [3-ureido-l,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 Listed in Table 2a below are further ethyl [3-ureido-l,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.
  • 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 T ⁇ F 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 0 C.
  • the mixture is stirred at rt for 1 h, or overnight, then sat. NaHCO 3 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-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 is obtained with >50% yield and is either used as such in the next step or purified by prepaprative ⁇ PLC to give the pure ethyl (3-acylamino-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 with 13 to 95% yield.
  • Table 4 Listed in Table 4 below are crude ethyl (3-acylamino-l,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
  • Table 4a Listed in Table 4a below are further ethyl (3-acylamino-l,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 Listed in Table 4a below are further ethyl (3-acylamino-l,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.

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Abstract

The present invention relates to (3-amino-l,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.

Description

(3-Amino-1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic Acid Derivatives
Field of the invention:
The present invention relates to (3-amino-l,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 Hl 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 DPI 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-l-y^acetic acid derivatives as PGD2 receptor antagonists.
GB 2388540 (Bayer AG) discloses the use of ramatroban ((3i?)-3-(4-fluorobenzene- sulfonamido)-l,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, antihistamines, leukotriene antagonists or beta-adrenergic agonists. Description of the invention: i) The present invention relates to (3-amino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid compounds of the Formula I:
Figure imgf000004_0001
wherein
R1, R2, R3 and R4 independently represent hydrogen, Ci_5-alkyl, Ci_5-alkoxy, alkenyl (especially allyl or vinyl), halogen, nitro, cyano, halo-Ci_6-alkoxy, halo-Ci_6-alkyl, Ci_6-alkylsulfonyl, or formyl;
R represents hydrogen, alkenyl (especially allyl or vinyl), Ci_6-alkyl, cycloalkyl-Ci_4-alkyl, Ci_3-alkoxy-Ci_4-alkyl, aryl-Ci_4-alkyl, or aryloxy-Ci_4-alkyl (especially R5 represents hydrogen, Ci_6-alkyl, cycloalkyl-Ci_4-alkyl, Ci_3-alkoxy-Ci_4-alkyl, aryl-Ci_4-alkyl, or aryloxy-Ci_4-alkyl); wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy (especially trifluoromethyl); and
R represents Ci_9-alkylaminocarbonyl; Ci_9-alkylaminothiocarbonyl; Ci_9-alkylcarbonyl; Ci_9-alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; arylaminothiocarbonyl; aryl- C i_3-alkoxy-C i_3-alkoxycarbonyl; aryl-C i_3-alkoxycarbonyl; aryl-Ci_3-alkylaminocarbonyl; aryl-Ci_6-alkylcarbonyl; aryl-Ci_3-alkoxy-Ci_3-alkylcarbonyl; arylcarbonyl; arylcarbonyl- Ci_4-alkylcarbonyl; aryloxy-Ci_3-alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl- Ci_3-alkylcarbonyl; diaryl-Ci_3-alkylcarbonyl; heterocyclylcarbonyl; heteroaryl- Ci_3-alkylcarbonyl; heteroarylcarbonyl; aryl-C3_6-cycloalkylcarbonyl; cycloalkylcarbonyl; or R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_4-alkyl group may additionally be mono- substituted with aryl or disubstituted with hydroxy, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl, Ci_6-alkylaminocarbonyl, or aryl-Ci_3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy; Ci_6-alkoxy; Ci_6-alkyl; Ci_6-alkylsulfonyl; phenyl which is unsubstituted, mono- or di-substituted by substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl; phenyl-Ci_3-alkyl, wherein the phenyl group is unsubstituted, mono- or di-substituted with substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl-Ci_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-Ci_6-alkyl; halo-Ci_6-alkoxy; Ci_6-alkylthio; and Ci_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 Ci_6-alkyl; and
R6 represents Ci_9-alkylaminocarbonyl, Ci_9-alkylaminothiocarbonyl, Ci_9-alkylcarbonyl, Ci_9-alkoxycarbonyl, arylalkenylcarbonyl, arylaminocarbonyl, arylaminothiocarbonyl, aryl- C i_3-alkoxy-C i_3-alkoxycarbonyl, aryl-Ci_3-alkoxycarbonyl, aryl-C i_3-alkylaminocarbonyl, aryl-Ci_3-alkylcarbonyl, aryl-C i_3-alkoxy-Ci_3-alkylcarbonyl, arylcarbonyl, arylcarbonyl- Ci_4-alkylcarbonyl, aryloxy-Ci_3-alkylcarbonyl, arylsulfonylaminocarbonyl, cycloalkyl- Ci_3-alkylcarbonyl, diaryl-Ci_3-alkylcarbonyl, heterocyclylcarbonyl, heteroaryl- Ci_3-alkylcarbonyl, or heteroarylcarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy; Ci_6-alkoxy; Ci_6-alkyl; Ci_6-alkylsulfonyl; phenyl which is unsubstituted, mono- or di-substituted with substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl; phenyl-Ci_3-alkyl, wherein the phenyl group is unsubstituted, mono- or di-substituted with substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl-Ci_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-Ci_6-alkyl; and halo-Ci_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; Ci_5-alkyl, especially methyl, or isopropyl; Ci_5-alkoxy, especially methoxy; alkenyl, especially allyl or vinyl; halogen, especially fluoro, or chloro; halo-Ci_6-alkyl, especially trifluoromethyl; or Ci_6-alkylsulfonyl, especially methanesulfonyl; R5 represents hydrogen; alkenyl, especially ethenyl, or 2-propenyl; or Ci_6-alkyl, especially methyl, ethyl, or propyl; and
R6 represents Ci_9-alkylaminocarbonyl, such as butylaminocarbonyl; Ci_9-alkylcarbonyl, such as propylcarbonyl, isobutylcarbonyl, hexylcarbonyl, or nonylcarbonyl; Ci_9-alkoxycarbonyl, such as propoxycarbonyl, te/t-butoxycarbonyl, or isobutoxycarbonyl; arylalkenylcarbonyl, such as naphthalenylethenylcarbonyl (especially 2-naphthalen-2-yl- ethenylcarbonyl), or phenylethenylcarbonyl; arylaminocarbonyl, such as naphthalenaminocarbonyl (especially naphthalen-1-aminocarbonyl), or phenylaminocarbonyl; aryl-Ci_3-alkoxy-Ci_3-alkoxycarbonyl, such as benzyloxyethoxycarbonyl (especially 2-benzyloxy-ethoxycarbonyl); aryl- Ci_3-alkoxycarbonyl, such as benzyloxycarbonyl; aryl-Ci_3-alkylaminocarbonyl, such as benzylaminocarbonyl, or phenylethylaminocarbonyl; aryl-Ci_3-alkylcarbonyl, such as phenylmethylcarbonyl, phenylethylcarbonyl (especially 2-phenylethyl-carbonyl), or naphthalenylethylcarbonyl (especially 2-naphthalen-2-yl-ethylcarbonyl); aryl-Ci_3-alkoxy- Ci_3-alkylcarbonyl, such as benzyloxymethyl-carbonyl; arylcarbonyl, such as phenylcarbonyl; arylcarbonyl-Ci_4-alkylcarbonyl, such as phenylcarbonylethylcarbonyl (especially 2-phenylcarbonyl-ethylcarbonyl); aryloxy-Ci_3-alkylcarbonyl, such as phenoxymethylcarbonyl; arylsulfonylaminocarbonyl, such as phenylsulfonylaminocarbonyl; cycloalkyl-Ci_3-alkylcarbonyl, such as cyclopentylethylcarbonyl (especially 2-cyclopentylethylcarbonyl), or indanylmethylcarbonyl (especially indan- 2-ylmethylcarbonyl); diaryl-Ci_3-alkylcarbonyl, such as 1 ,2-diphenylethylcarbonyl, or 2,2-diphenylethylcarbonyl; heterocyclylcarbonyl, such as dihydroindolylcarbonyl (especially 2,3-dihydro-lH-indole-2-carbonyl); heteroaryl-Ci_3-alkylcarbonyl, such as benzimidazolyl-Ci_3-alkylcarbonyl (especially 2-lH-benzimidazol-2-yl-ethylcarbonyl), or indolyl-Ci_3-alkylcarbonyl, such as indolylethylcarbonyl (especially 2-lH-indol-3-yl- ethylcarbonyl), or thienylmethylcarbonyl (especially 2-thienylmethylcarbonyl), or pyridinylethylcarbonyl (especially 2-(pyridin-3-yl)ethylcarbonyl); or heteroarylcarbonyl, such as indolylcarbonyl (especially lH-indole-2-yl-carbonyl); wherein aryl (especially phenyl or naphthyl) is unsubstituted, mono- or di-substituted with (a) group(s) independently selected from Ci_2-alkylendioxy (especially methylendioxy), Ci_6-alkoxy (especially methoxy), Ci_6-alkyl (especially methyl, ethyl, isopropyl, or tert- butyl), Ci_6-alkylsulfonyl (especially methanesulfonyl), halogen (especially chloro, fluoro or bromo), hydroxy, and halo-Ci_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), Ci_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, Ci_6-alkyl (especially Ci_3-alkyl), cycloalkyl-Ci_4-alkyl (especially cyclopropylmethyl), Ci_3-alkoxy- Ci_4-alkyl (especially 2-methoxyethyl), aryl-Ci_4-alkyl (especially naphthylmethyl, or preferably phenyl-C2-3-alkyl), or aryloxy-Ci_4-alkyl (especially phenoxy ethyl); wherein aryl (especially phenyl) is unsubstituted (preferred), or mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_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; Ci_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 Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_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 Ci_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 Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_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, Ci_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 Ci_9-alkylaminocarbonyl; Ci_9-alkylcarbonyl; Ci_9-alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; aryl- C i_3-alkoxy-C i_3-alkoxycarbonyl; aryl-C i_3-alkoxycarbonyl; aryl-Ci_3-alkylaminocarbonyl; aryl-Ci_6-alkylcarbonyl; aryl-Ci_3-alkoxy-Ci_3-alkylcarbonyl; arylcarbonyl; arylcarbonyl- Ci_4-alkylcarbonyl; aryloxy-Ci_3-alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl- Ci_3-alkylcarbonyl; diaryl-Ci_3-alkylcarbonyl; heterocyclylcarbonyl; heteroaryl- Ci_3-alkylcarbonyl; heteroarylcarbonyl; aryl-C3_6-cycloalkylcarbonyl; cycloalkylcarbonyl; or R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_4-alkyl group may additionally be mono- substituted with aryl, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl, Ci_6-alkylaminocarbonyl, or aryl-C i_3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_6-alkylsulfonyl, halogen, hydroxy, halo- Ci_6-alkyl, halo-Ci_6-alkoxy, Ci_6-alkylthio, and Ci_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-
Ci_3-alkoxycarbonyl; aryl-C i_3-alkylaminocarbonyl; aryl-Ci_6-alkylcarbonyl; aryl-
C i_3-alkoxy-C i_3-alkylcarbonyl; arylcarbonyl-C i_4-alkylcarbonyl; aryloxy-
Ci_3-alkylcarbonyl; cycloalkyl-Ci_3-alkylcarbonyl; diaryl-Ci_3-alkylcarbonyl; aryl-
C3-6-cycloalkylcarbonyl; or R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_4-alkyl group may additionally be mono-substituted with aryl, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl,
Ci_6-alkylaminocarbonyl, or aryl-C i_3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_6-alkylsulfonyl, halogen, hydroxy, halo- Ci_6-alkyl, halo-Ci_6-alkoxy, Ci_6-alkylthio, and Ci_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-Ci_3-alkoxycarbonyl; aryl-Ci_3-alkylaminocarbonyl; aryl-Ci_6-alkylcarbonyl; aryloxy-Ci_3-alkylcarbonyl; diaryl- Ci_3-alkylcarbonyl; or R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_4-alkyl group may additionally be mono-substituted with aryl, and R7 represents arylaminocarbonyl, or C i_6-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_6-alkylsulfonyl, halogen, hydroxy, halo- Ci_6-alkyl, halo-Ci_6-alkoxy, Ci_6-alkylthio, and Ci_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-Ci_2-alkoxycarbonyl; aryl-Ci_2-alkylaminocarbonyl; aryl-Ci_4-alkylcarbonyl; aryloxy-Ci_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
C i_4-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_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- Ci_2-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_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-Ci_2-alkoxycarbonyl; aryl-Ci_4-alkylcarbonyl; aryloxy-Ci_2-alkylcarbonyl; or diaryl-C2-3-alkylcarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_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 Ci_4-alkoxy, Ci_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 Ci_4-alkylcarbonyl (especially acetyl); or aryl-C2-4-alkylcarbonyl, wherein aryl is unsubstituted, mono- or di- substituted with a group independently selected from Ci_4-alkoxy, Ci_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 Ci_4-alkoxy, Ci_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 Ci_6-alkylsulfonyl
(especially methanesulfonyl);
R5 represents hydrogen, C^-alkyl, cycloalkyl-Ci_4-alkyl, Ci_3-alkoxy-Ci_4-alkyl, aryl-
Ci_4-alkyl, or aryloxy-Ci_4-alkyl; wherein aryl is unsubstituted, mono-substituted with a group selected from trifluoromethyl; and
R6 represents Ci_9-alkylaminocarbonyl; Ci_9-alkylcarbonyl; Ci_9-alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; aryl-C^-alkoxy-Ci-s-alkoxycarbonyl; aryl-Ci_3- alkoxycarbonyl; aryl-Ci_3-alkylaminocarbonyl; aryl-Ci_6-alkylcarbonyl; aryl-Ci_3-alkoxy- Ci_3-alkylcarbonyl; arylcarbonyl; arylcarbonyl-Ci_4-alkylcarbonyl; aryloxy-Ci_3- alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl-Ci.s-alkylcarbonyl; diaryl-Ci_3- alkylcarbonyl; heterocyclylcarbonyl; heteroaryl-Ci_3-alkylcarbonyl; heteroarylcarbonyl; aryl-C3_6-cycloalkylcarbonyl; cycloalkylcarbonyl; or R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_4-alkyl group may additionally be mono-substituted with aryl or disubstituted with hydroxy, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl,
Ci_6-alkylaminocarbonyl, or aryl-Ci_3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy; Ci_6-alkoxy; Ci_6-alkyl; Ci_6-alkylsulfonyl; halogen; hydroxy; trifluoromethyl; trifluoromethoxy; Ci_6-alkylthio; and Ci_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 (5)-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 (i?)-confϊgurated.
In another embodiment preferred compounds of Formula I are selected from the group consisting of:
(35)-[3-(3,3-diphenyl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-{3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-[6-fluoro-3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-(3-isobutoxycarbonylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (3i?)-[6-fluoro-3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{3-[3-(4-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-(3-benzyloxycarbonylamino-6-fluoro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (35)-(3-benzyloxycarbonylamino-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; and
(35)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-fluoro-l,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:
(3i?)-{3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-[6-fluoro-3-(4-oxo-4-phenyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(35)-[6-fluoro-3-(2-indan-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-{3-[(2,3-dihydro-lH-indole-2-carbonyl)-amino]-6-fiuoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-(3-{[2-(4-chloro-phenyl)-acetyl]-ethyl-amino}-6-fiuoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (3i?)-(3-propoxycarbonylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-[6-fluoro-3-(2-/?-tolyloxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{6-fluoro-3-[methyl-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3S)-[6-fluoro-3-(3-lH-indol-3-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(35)-[3-(3-benzo[l,3]dioxol-5-yl-propionylamino)-6-fluoro-l,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;
(35)-{3-[2-(4-chloro-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(35)-[3-(2,3-diphenyl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[6-fluoro-3-(2-phenoxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{3-[3-(3,4-difluoro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-[3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-[3-(2-benzyloxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-{6-fluoro-3-[propyl-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-[3-(2-benzyloxy-acetylamino)-l ,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-(3-benzyloxycarbonylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-{6-fluoro-3-[2-(4-methoxy-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{3-[3-(4-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[4-(4-bromo-phenyl)-4-oxo-butyrylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-(3-{[2-(4-chloro-phenyl)-acetyl]-propyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(3i?)-(3-phenylacetylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-{3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-fluoro-3-[2-(4-trifluoromethyl-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-(6-fluoro-3-phenylacetylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-[3-(3-lH-benzoimidazol-2-yl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid;
(35)-{6-fluoro-3-[3-(4-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-[6-fluoro-3-(2-/?-tolyloxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[6-fluoro-3-(2-/?-tolyl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-{3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (3i?)-[3-(2-phenoxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[6-fluoro-3-(3-/?-tolyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-(3-benzyloxycarbonylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-[6-fluoro-3-(2-/?-tolyl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-[3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-[3-(2-benzyloxy-ethoxycarbonylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-[6-fluoro-3-(3-naphthalen-2-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(35)-{6-fluoro-3-[4-(4-methanesulfonyl-phenyl)-4-oxo-butyrylamino]-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid; (35)-(3-{[2-(4-chloro-phenyl)-acetyl]-methyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-[3-(3-phenylsulfonyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{6-fluoro-3-[3-(4-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol- 9-yl} -acetic acid;
(3i?)-[3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-{3-[2-(4-chloro-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(3i?)-[6-fluoro-3-(3-/?-tolyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-{6-fluoro-3-[3-(4-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-{6-fluoro-3-[3-(4-hydroxy-3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid; (35)-{6-fluoro-3-[2-(3-trifluoromethyl-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-fluoro-3-[2-(4-methoxy-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{3-[2-(3-chloro-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(35)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-(3-tert-butoxycarbonylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-{3-[2-(3,4-dichloro-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-(3-isobutoxycarbonylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid; and
(35)-[6-fluoro-3-(2-phenoxy-acetylamino)-l,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:
(3i?)-[3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-[3-(2-benzyloxy-ethoxycarbonylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3S)-[3-(2-phenoxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-(3-propoxycarbonylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (35)-[3-(2-thiophen-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-(3-phenylacetylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-[3-(3-phenylsulfonyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-benzyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[3-(3-naphthalen-l-yl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-(3-decanoylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-[6-fluoro-3-(3-naphthalen-2-yl-acryloylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(35)-{3-[2-(4-fert-butyl-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (3i?)-(3-benzyloxycarbonylamino-8-chloro-6-fluoro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-benzyloxycarbonylamino-8-chloro-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-[6-fluoro-3-(3-pyridin-3-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(3i?)-[3-(3-benzyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-methyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-[3-(3-phenyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-cyclopentyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[3-(2-thiophen-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-(3-butyrylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-(3-benzyloxycarbonylamino-8-chloro-5-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-benzyloxycarbonylamino-8-chloro-5-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-heptanoylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (3i?)-[3-(3-cyclopentyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-(3-decanoylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (3i?)-(3-benzoylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (3i?)-[3-(3-butyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-{6-fluoro-3-[(lH-indole-2-carbonyl)-amino]-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(3i?)-[3-(3-methyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; and (35)-[3-(3-butyl-ureido)-l,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:
(3i?)-[3-(3-Benzyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-Benzyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[6-Fluoro-3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-[3-(3-Benzyl-ureido)-8-chloro-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-Benzyl-ureido)-8-chloro-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[8-Chloro-6-fluoro-3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[8-Chloro-6-fluoro-3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-6-trifluoromethyl- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)- acetic acid; (35)-(3-Benzyloxycarbonylamino-6-trifluoromethyl-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-8-bromo-6-fluoro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-Benzyloxycarbonylamino-8-bromo-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-6-fluoro-8-vinyl- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)- acetic acid; (35)-(3-Benzyloxycarbonylamino-6-fluoro-8-vinyl-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl- 1 ,2,3 ,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (35)-(3-Benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(3-Benzyloxycarbonylamino-6-fluoro-8-methyl-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-Benzyloxycarbonylamino-7-chloro-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(8-Allyl-3-benzyloxycarbonylamino-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-8-chloro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (35)-{3-[3-(2,4-Dimethoxy-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-[6-Fluoro-3-(3-naphthalen-l-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(3i?)-{6-Fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{6-Fluoro-3-[3-(2-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-{6-Fluoro-3-[3-(2-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{6-Fluoro-3-[3-(3-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(3-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{6-Fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid; (35)-{6-Fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(3i?)-{6-Fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-{6-Fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{6-Fluoro-3-[2-(2-methylphenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[2-(2-methylphenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[3-(2,5-Dimethoxy-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(4-trifluoromethyl-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{3-[3-(2,6-Dichloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[3-(2,5-Bis-trifluoromethyl-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(4-methylsulfanyl-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(4-iodo-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(4-isopropyl-phenyl)-propionylamino]-l,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;
(35)-{3-[3-(2,4-Dichloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(4-fluoro-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[3-(3,5-Bis-trifluoromethyl-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid; (35)-{3-[3-(4-Ethyl-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(3-iodo-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-{6-Fluoro-3-[3-(4-methanesulfonyl-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[3-(2,3-Dimethoxy-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[3-(2-Bromo-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(3-trifluoromethoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[3-(2,4-Dimethyl-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{3-[3-(3-Bromo-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[3-(3-fert-Butoxycarbonylamino-phenyl)-propionylamino]-6-fluoro-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[(5)-3-(4-fluoro-phenyl)-2-phenyl-propionylamino]-l,2,3,4-tetrahydro- 9H-carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[(5)-3-(4-methoxy-phenyl)-2-phenyl-propionylamino]-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(2-fluoro-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-(6-Fluoro-3-{[(2i?5)-l,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{[(2i?5)-8-methoxy-l,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{(2i?5)-2-[(4-fluoro-phenylcarbamoyl)-methyl]-3-phenyl- propionylamino}-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{3-[(2i?5)-2-Benzyl-3,3-dimethyl-butyrylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-(6-Fluoro-3-{[(2i?5)-8-methoxy-l,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[3-(3-fluoro-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-(6-Fluoro-3-{[(2i?5)-8-methoxy-l,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[(2i?)-2-methyl-3-phenyl-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-[3-(2,2-Dimethyl-3-phenyl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol- 9-yl] -acetic acid;
(35)-[6-Fluoro-3-(3-methyl-3-phenyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(3S)- {6-Fluoro-3-[(35)-3-phenyl-butyrylamino]-l,2,3,4-tetrahydro-9H-carbazol-9-yl} -acetic acid; (35)-[3-(2-Benzyloxy-acetylamino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[6-Fluoro-3-(4-phenyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{3-[(2i?,3i?)-2,3-Dihydroxy-3-(2-methoxy-phenylcarbamoyl)-propionylamino]-6- fluoro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl} -acetic acid; (3i?)-{8-Chloro-6-fluoro-3-[3-(2-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[3-(2-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{8-Chloro-6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{8-Chloro-6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(3-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{8-Chloro-6-fluoro-3-[3-(3-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-[8-Chloro-6-fluoro-3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9- yl] -acetic acid;
(35)-[8-Chloro-6-fluoro-3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid; (3i?)-{8-Chloro-6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-[8-Chloro-6-fluoro-3-(3-7H-indol-3-yl-propionylamino)-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid; (35)-[8-Chloro-6-fluoro-3-(3-ii/-indol-3-yl-propionylamino)-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid;
(3i?)-{8-Chloro-3-[2-(2-chloro-ρhenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[2-(2-methylphenyl)-oxy-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{8-Chloro-6-fluoro-3-[2-(2-methylphenyl)-oxy-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-[3-(3-Benzo[l,3]dioxol-5-yl-propionylamino)-8-chloro-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl] -acetic acid; (35)-[3-(3-Benzo[l,3]dioxol-5-yl-propionylamino)-8-chloro-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl] -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-3-[2-(3-chloro-ρhenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (3i?)-{8-Chloro-3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-[8-Chloro-6-fluoro-3-(2-indan-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9- yl] -acetic acid;
(35)-[8-Chloro-6-fluoro-3-(2-indan-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(3^-[6-Fluoro-3-(l-methyl-3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-{3-[3-(2-Chloro-benzyl)-l-methyl-ureido]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-[3-(3-Benzyl-l-methyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(Benzyloxycarbonyl-methyl-amino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
{(35)-3-[(2-Chloro-benzyloxycarbonyl)-methyl-amino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-(6-Fluoro-3-{[2-(4-methoxy-phenyl)-acetyl]-methyl-amino}-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{methyl-[2-(4-methylphenyl)-acetyl]-amino}-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (35)-(6-Fluoro-3-{[2-(2-methoxy-phenyl)-acetyl]-methyl-amino}-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[(2-indan-2-yl-acetyl)-methyl-amino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-(3-{[2-(3-Chloro-phenyl)-acetyl]-methyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3 - {methyl- [2-(3 -methylphenyl)-acetyl] -amino }- 1 ,2,3 ,4-tetrahy dro-9H- carbazol-9-yl)-acetic acid;
(3iS)-(6-Fluoro-3 - { [2-(3 -methoxy-phenyl)-acetyl] -methyl-amino } - 1 ,2,3 ,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (35)-(3-{[2-(2-Chloro-phenoxy)-acetyl]-methyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(3-{[2-(4-Chloro-phenoxy)-acetyl]-methyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3 - { [3 -(3 -methoxy-phenyl)-propiony 1] -methyl-amino } - 1 ,2,3 ,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{methyl-[2-(2-methylphenyl)-acetyl]-amino}-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-{3-[(3,3-Diphenyl-propionyl)-methyl-amino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid; (35)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-methyl-amino}-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[(3-7H-indol-3-yl-propionyl)-methyl-amino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[(2-Benzyloxy-acetyl)-methyl-amino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[(2,3-Diphenyl-propionyl)-methyl-amino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid; (35)-{6-Fluoro-3-[[3-(2-methoxy-phenyl)-propionyl]-(3-phenyl-propyl)-amino]-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{3-[Acetyl-(3-phenyl-propyl)-amino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid; (35)-{3-[3-Benzyl-(l-cyclopropylmethyl)-ureido]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-[3-(Benzyloxycarbonyl-cyclopropylmethyl-amino)-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid;
(35)-{3-[Cyclopropylmethyl-(3-phenyl-propionyl)-amino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[Cyclopropylmethyl-((5)-2-methyl-3-phenyl-propionyl)-amino]-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-(3-{Cyclopropylmethyl-[3-(2-methoxy-phenyl)-propionyl]-amino}-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid; (35)-(3-{[2-(3-Chloro-phenoxy)-acetyl]-cyclopropylmethyl-amino}-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{3-[Cyclopropylmethyl-(3,3-diphenyl-propionyl)-amino]-6-fluoro-l,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;
(3^-(3-{Benzyloxycarbonyl-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-6-fluoro-
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(3 - {Acetyl- [2-(4-trifluoromethyl-phenoxy)-ethyl] -amino } -6-fluoro- 1 ,2,3 ,4-tetrahydro-
9H-carbazol-9-yl)-acetic acid; (35)-(6-Fluoro-3-{propionyl-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3 - {(3 -phenyl-propionyl)- [2-(4-trifluoromethyl-phenoxy)-ethyl] -amino } -
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-[2-(4-trifluoromethyl-phenoxy)- ethyl]-amino}-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[(2-phenoxy-ethyl)-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{6-Fluoro-3-[((S)-2-methyl-3-phenyl-propionyl)-(2-phenoxy-ethyl)-amino]-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[[3-(2-methoxy-phenyl)-propionyl]-(2-phenoxy-ethyl)-amino]-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid; (35)-{3-[Acetyl-(2-phenoxy-ethyl)-amino]-6-fluoro-l,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;
(35)-{3-[Benzyloxycarbonyl-(2-methoxy-ethyl)-amino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[(2-methoxy-ethyl)-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3S)- {6-Fluoro-3-[(2-methoxy-ethyl)-((S)-2-methyl-3-phenyl-propionyl)-amino]-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid; (3iS)-(6-Fluoro-3- {(2 -methoxy-ethyl)-[3-(2-methoxy-phenyl)-propionyl]-amino} -1,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{3-[[2-(3-Chloro-phenoxy)-acetyl]-(2-methoxy-ethyl)-amino]-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{3-[(3,3-Diphenyl-propionyl)-(2-methoxy-ethyl)-amino]-6-fluoro-l,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;
(35)-(6-Fluoro-3-{[(25)-2-methyl-3-phenyl-propionyl]-phenethyl-amino}-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid; (35)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-phenethyl-amino}-l,2,3,4-tetrahydro-
9H-carbazol-9-yl)-acetic acid;
(35)-[3-(Acetyl-phenethyl-amino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{6-Fluoro-3-[(2-naphthalen-l-yl-acetyl)-phenethyl-amino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[phenethyl-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid; (35)-[3-(3-Benzyl-l-naphthalen-l-ylmethyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid;
(35)-[3-(Benzyloxycarbonyl-naphthalen-l-ylmethyl-amino)-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid; (35)- {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 - [((5)-2-methyl-3 -phenyl-propionyl)-naphthalen- 1 -ylmethyl-amino] -
1, 2,3, 4-tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-(6-Fluoro-3 - { [3 -(2-methoxy-phenyl)-propionyl] -naphthalen- 1 -ylmethyl-amino } - l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{3-[(3,3-Diphenyl-propionyl)-naphthalen-l-ylmethyl-amino]-6-fluoro-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-[3-(Acetyl-naphthalen-l-ylmethyl-amino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl] -acetic acid; (3iS)-[6-Fluoro-3-(naphthalen- 1 -ylmethyl-propionyl-amino)- 1 ,2,3 ,4-tetrahydro-9H-carbazol-
9-yl] -acetic acid;
(35)-{3-[(i?5)-2-Benzyl-3-(2-methylphenyl)-carbamoyl-propionylamino]-6-fluoro-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{3-[(i?5)-2-Benzyl-3-(3-methoxy-phenylcarbamoyl)-propionylamino]-6-fluoro-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{3-[(i?5)-2-Benzyl-3-(4-chloro-phenylcarbamoyl)-propionylamino]-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{3-[(i?5)-2-Benzyl-3-(4-fluoro-benzylcarbamoyl)-propionylamino]-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid; [(35)-3-((i?5)-2-Benzyl-3-propylcarbamoyl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl] -acetic acid;
(35)-[6-Fluoro-3-(3-thiophen-2-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(35)-{3-[3-(3-Chloro-isoxazol-5-yl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3^-[6-Fluoro-3-(3-pyrimidin-2-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid; (35)-{6-Fluoro-3-[3-phenyl-4-([l,3,4]thiadiazol-2-ylcarbamoyl)-butyrylamino]-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-[3-(l,3-Dibenzyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-(3-{Acetyl-[2-(2-fluoro-phenyl)-ethyl]-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(3-{Acetyl-[2-(3-fluoro-phenyl)-ethyl]-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-[3-(3-Benzyl-l-cyclohexylmethyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl] -acetic acid; and (3iS)-(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 Ci_6-alkyl group in an aryl- Ci_6-alkylcarbonyl group which is placed between the aryl and the carbonyl moiety; the bridging Ci_4-alkyl group in an aryl-Ci_4-alkyl group, which is placed between the aryl moiety and the parent molecular moiety; or the bridging Ci_4-alkyl group in an R7-Ci_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 Ci_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, ώo-propyl, n-butyl, tert-butyl, ώo-butyl (or also referred to as "2-methylpropyl"), n-pentyl (also referred to as "n-amyl"), ώo-pentyl (also referred to as "ώo-amyl"), n-hexyl, n-heptyl, and n-octyl. Preferred are methyl, ethyl, n-propyl, ώo-propyl, n-butyl, and ώo-butyl. Most preferred are methyl, ethyl, n-propyl, and ώo-propyl.
A bridging Ci_6-alkyl group as used in "aryl-Ci_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 Ci_6-alkyl groups as used in R6 being aryl-Ci_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 Ci_6-alkyl group as used in "aryl-Ci_6-alkylcarbonyl" as defined for R6 means the respective Ci_6-alkyl group, whereby the aryl moiety and the carbonyl moiety preferably are attached to the same carbon atom of the bridging Ci_6-alkyl group. Examples of such bridging Ci_6-alkyl groups as used in R6 being aryl- Ci_6-alkylcarbonyl are a methylene group (preferred) and ethane- 1,1 -diyl. A bridging Ci_3-alkyl group as used in "diaryl-Ci_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 Ci_3-alkyl groups as used in R6 being diaryl- Ci_3-alkylcarbonyl are ethane- 1,2,2-triyl, and ethane- 1,1,2-triyl. A bridging Ci_4-alkyl group as used in "R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_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 Ci_4-alkyl groups as used in R6 being "R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_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-l,3-diyl, and l-phenyl-propane-2,3- diyl; preferred are 2-phenyl-propane-l,3-diyl, and l-phenyl-propane-2,3-diyl, especially 1 -phenyl-propane-2,3-diyl.
An example of a bridging Ci_4-alkyl group as used in R6 being "R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_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 "Ci_2-alkylendioxy" as used herein, alone or in any combination, refers to an -O(CH2)nO- group, wherein n is 1 or 2, and wherein the oxygen atoms are attached to two adjacent carbon atoms of the parent molecular moiety, preferably the two adjacent carbon atoms of a phenyl ring.
The term "alkoxy" as used herein, alone or in any combination, refers to an alkyl group attached to the parent molecular moiety through an oxygen bridge. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentoxy, and hexyloxy, especially methoxy.
The term "alkoxycarbonyl", as used herein, alone or in any combination, refers to an alkoxy group attached to the parent molecular moiety through a carbonyl group. Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and iso-butoxycarbonyl, especially methoxy. R6 representing alkoxycarbonyl preferably means n-propoxycarbonyl, and ώo-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 l-oxo-2-methyl-butyl, and 3, 3 -dimethyl- 1-oxopropyl. Preferred are acetyl, 1-oxopropyl, 1-oxobutyl, l-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-te/t.-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 S-te/t.-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 Ci_4-alkyl, Ci_4-alkoxy, and halogen (especially Ci_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 =0 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 Ci_9-alkylcarbonyl, arylalkenylcarbonyl, aryl-Ci_6-alkylcarbonyl, aryl-Ci_3-alkoxy-Ci_3-alkylcarbonyl, arylcarbonyl, arylcarbonyl-Ci_4-alkylcarbonyl, aryloxy- Ci_3-alkylcarbonyl, cycloalkyl-Ci_3-alkylcarbonyl, diaryl-Ci_3-alkylcarbonyl, heterocyclylcarbonyl, heteroaryl-Ci_3-alkylcarbonyl, heteroarylcarbonyl, aryl- C3-6-cycloalkylcarbonyl, cycloalkylcarbonyl, or R7-Ci_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 Ci_9-alkylaminocarbonyl, arylaminocarbonyl, or aryl-Ci_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 Ci_9-alkoxycarbonyl, aryl-Ci_3-alkoxycarbonyl, or aryl-Ci_3-alkoxy-Ci_3-alkoxycarbonyl that are linked to the parent molecular moiety through a nitrogen atom.
The compounds of Formula I may contain one or more stereogenic or asymmetric centers, such as one or more asymmetric carbon atoms. Substituents at a double bond or a ring may be present in cis- (= Z-) or trans (= E-) form unless indicated otherwise. The compounds of Formula I may thus be present as mixtures of stereoisomers or preferably as pure stereoisomers. Mixtures of stereoisomers may be separated in a manner known to a person skilled in the art.
The compounds of the present invention have useful, in particular pharmacologically useful, properties. They bind to the CRTH2 receptor and thus modulate the effects of endogenous PGD2. The compounds according to Formula I may be used for the preparation of a medicament, and are suitable, for the prevention and/or treatment of diseases selected from the group consisting of chronic and acute allergic/immune diseases/disorders, comprising allergic asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease (COPD), dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia- reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases comprising Churg-Strauss syndrome and sinusitis, and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis, in humans and other mammals. A compound of Formula I or a pharmaceutical composition comprising a compound of Formula I may be used for the preparation of a medicament, and is suitable, for the prevention and/or treatment of diseases selected from the group consisting of both chronic and acute allergic/immune diseases/disorders such as those mentioned in the paragraph before, such as especially allergic asthma, rhinitis, allergic rhinitis, COPD, dermatitis, inflammatory bowel disease, and rheumatoid arthritis.
In another aspect, the compounds of Formula I may be used as standard or reference compounds in tests or assays involving the modulation of the CRTH2 receptor. Such compounds could be made commercially available for use as a reference, quality standard or control, for example in pharmaceutical research when developing new assays or protocols related to CRTH2 receptor activity.
As mentioned earlier, compounds of Formula I modulate the PGD2 activation of the CRTH2 receptor. The biological effect of such compounds may be tested in a variety of in vitro, ex vivo and in vivo assays. The ability of the compounds of Formula I to bind to the CRTH2 receptor may be measured by methods similar to those described in the literature (Arimura
A. et al, J. Pharmacol. Exp. Ther. 2001, 298(2), 411-419; and Sawyer N. et al, Br. J.
Pharmacol, 2002, 137, 1163-1172, respectively) and by the assays described below in the experimental part.
A functional assay with cells expressing the human CRTH2 (hCRTH2) receptor may be used to detect changes in the levels of intracellular calcium concentration following compound treatment. After addition of the compound, the cells are challenged with PGD2. In a Fluorescent Imaging Plate Reader (FLIPR™, Molecular Devices, Sunnyvale, California), fluorescence emission is recorded during both additions, emission peak values above base level after PGD2 addition are exported, and normalized to low controls (no PGD2) and high controls (no active compound). The relative values of the remaining activity are used to determine IC50 values by curve fitting the data to a single site to a four- parameter logistic sigmoid dose response curve of the equation (A+((B-A)/(l+((C/x)ΛD)))).
The ability of the compounds to modulate PGD2 induced changes of intracellular calcium levels via CRTH2 receptor activation may be measured by methods known to one skilled in the art or by the assay described below in the experimental part.
The present invention relates also to pharmaceutical compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier; to the use of such pharmaceutical compositions for the therapeutic, in a broader aspect of the invention also prophylactic, treatment of the diseases/disorders mentioned herein; to the compounds of Formula I, or pharmaceutically acceptable salts thereof, for use as a medicament; and to the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the prevention and/or treatment of the diseases/disorders mentioned herein.
The pharmaceutical compositions according to the invention are those for enteral administration, such as nasal, buccal, rectal, dermal or, especially oral administration, and for parenteral administration, such as intramuscular, intravenous or subcutaneous, intrasternal, intravitreal, injection or infusion, to warm-blooded animals, especially humans. Such compositions comprise an effective dose of the pharmaceutically active ingredient, alone or together with a pharmaceutically acceptable carrier. The dosage of the active ingredient depends on the species of warm-blooded animal, the body weight, the age and the individual conditions, individual pharmacokinetic data, the disease/disorder to be treated and the mode of administration.
The production of the pharmaceutical compositions can be effected in a manner which will be familiar to any person skilled in the art (see for example Mark Gibson, Editor, Pharmaceutical Preformulation and Formulation, IHS Health Group, Englewood, CO, USA, 2001; Remington, The Science and Practice of Pharmacy, 20th Edition, Philadelphia College of Pharmacy and Science) by bringing the described compounds of Formula I or their pharmaceutically acceptable salts, optionally in combination with other therapeutically valuable substances, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants. In one embodiment, the invention also relates to a method for the prevention or treatment of diseases/disorders that respond to an inhibition of the CRTH2 receptor in particular to a method for the prevention or treatment of the diseases/disorders mentioned herein, said methods comprising administering to a patient a pharmaceutically active amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A further aspect of the invention is a process for the preparation of compounds of Formula I. Compounds according to Formula I of the present invention can be prepared according to the sequence of reactions outlined in the schemes below wherein R1, R2, R3, R4, R5, R6 and R7 are as defined for Formula I. Other abbreviations used are defined in the experimental section. In some instances the generic groups R1, R2, R3, R4, R5, R6 and R7 might be incompatible with the assembly illustrated in the schemes below and, therefore, will require the use of protecting groups (PG). For example it may be necessary to protect reactive functional groups such as hydroxy, amino, imino, thio or carboxy groups, where these are desired in the final product, to avoid their unwanted participation in the reactions. The use of protecting groups is well known in the art (see for example "Protective Groups in Organic Synthesis", T.W. Greene, P.G.M. Wuts, Wiley-Interscience, 1999). It will be assumed that such protecting groups are as necessary in place. In the following description, for example, PG, when used as amino-protecting group, preferably refers to a group such as tert-butoxycarbonyl, benzyloxycarbonyl, or allyloxycarbonyl, most preferably tert- butoxycarbonyl. Further, L refers to a leaving group, such as activated (for examples as mesylate, active ester etc.) or non-activated hydroxy, or halo, in particular chloro or bromo. Further, R and R' independently refer to a Ci_4-alkyl group, preferably ethyl or tert-hvXyl, whereby when R is present R is preferably ethyl and R' is preferably tert. -hvXyX.
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 Ci_4-alkyl, preferably ethyl, or tert-bvΛyl, 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.
Figure imgf000040_0001
Structure 1, wherein R represents Ci_4-alkyl
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, JV-ethyl-morpholine, TV-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.
Figure imgf000041_0001
Structure 2a: R5 ≠ H 2c 2b: R5= H
In a specific case, intermediates of Structure 1, wherein R4 represents an Ci_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 tetrαHs(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 6O0C and 1300C.
A substituent R 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/?-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,Λ/-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. Pena 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.
Figure imgf000042_0001
Structure 3a, wherein R5 represents H
3b, wherein R5 ≠ H
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 te/t-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.
Figure imgf000043_0001
Structure 4
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.
Figure imgf000043_0002
Structure
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.
Figure imgf000043_0003
Structure
Both, the (R)- and the (5)-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 (3i?5)-(3-amino-l,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 (3i?)-(3-tert-butoxycarbonylamino-l,2,3,4-tetrahydro- 9H-carbazol-9-yl)-acetate is described in WO 03/097598.
Figure imgf000044_0001
Structure 8a, wherein R' represents Η and R represents Ci_4-alkyl 8b, wherein R and R independently represent Ci_4-alkyl
In a particular case, a compound of Structure 1, wherein R6 represents "R7-Ci_4- alkylcarbonyl, wherein the bridging Ci_4-alkyl group may additionally be mono-substituted with aryl, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl, C1-6- alkylaminocarbonyl, or aryl-Ci_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, ΗATU 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 Ci_4-alkyl group may additionally be mono-substituted with aryl is obtained by treating a respective compound of Structure 8b, wherein R' represents Ci_4-alkyl, preferentially tert-butyl, as a protecting group, with reaction with TFA in DCM or hydrochloric acid in an organic solvent, such as dioxane, diethylether, AcOEt, or the like, at room temperature.
Figure imgf000044_0002
Structure 9, wherein R represents Ci_4-alkyl 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 Ci_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 l,8-Diazabicyclo[5.4.0]undec-7-ene
DCC 1 ,3-Dicyclohexylcarbodiimide
DCM Dichloromethane
DIEA JV,Λ/-Diisopropylethylamine
DMAP Λf,Λ/-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- lH-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 JV-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 tic 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 (0C). Unless otherwise indicated, the reactions take place at room temperature (rt).
In mixtures, relations of parts of solvent or eluent or reagent mixtures in liquid form are given as volume relations (v/v), unless indicated otherwise.
Analytical HPLC conditions as used in the Examples below: HPLC/MS analyses are performed on a Waters 2795 Alliance HPLC instrument, equipped with a Waters 996 Photodiode Array Detector and a Micromass ZQ™ Waters mass spectrometer (electron spray ionization), detection at 200-400 nm (LC-I 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-I : Analytical HPLC on a Xterra™ MS C18 column (4.6x50 mm, 5 μm, Waters); Linear gradient of water/ 0.06% formic acid (A) and MeCN/ 0.06% formic acid (B) from 5% to 95% B over 1 min; flow rate 3 ml/min, detection at 215 nm.
- LC-2: Analytical HPLC on a Zorbax® SB-AQ column (4.6x50 mm, 5μm, Agilent); Linear gradient of water/ 0.06% formic acid (A) and MeCN/ 0.06% formic acid (B) from 5% to 95% B over 1 min; flow rate 3 ml/min, detection at 215 nm.
- LC-3: Analytical HPLC on a Zorbax® SB-AQ column (4.6x50 mm, 5μm, Agilent); Linear gradient of water/ 0.05% TFA (A) and MeCN (B) from 5% to 95% B over 1 min; flow rate 4.5 ml/min, detection at 215 nm.
Preparative HPLC/MS purifications are performed on a Waters HPLC system, equipped with a Waters 600 controller, a Waters 2767 sample manager, a Waters 996 Photodiode Array Detector, and a Micromass ZQTM Waters mass spectrometer (electron spray ionization), detection at 200-400 nm, using a Zorbax® PrepHT SB. Aq (5 μm, 21.2x50 mm) or a Phenomenex® Gemini column (10 μm, 21.2x50 mm), with a linear gradient of water/ 0.02% formic acid (A) and MeCN/ 0.02% formic acid (B) over 5 min; flow rate 4 ml/min, detection at 215 nm.
1H NMR spectra are recorded either on a Varian Mercury 300VX FT-NMR spectrometer or on a Bruker Advance II 400 spectometer. Chemical shifts (S) are reported in parts per million (ppm) relative to proton resonances resulting from incomplete deuteration of the NMR solvent, e.g. for dimetylsulfoxide S(Il) 2.49 ppm, for chloroform S(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. IN LiOH or IN 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 Example Compound of Formula I Formula tR [min] MS
MW LC-MS Data
Method m/z
[M+H]+
(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
(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
(3R)-[3-(3-Phenethyl-ureido)-1 ,2,3,4- C23H25N3O3 1.32 392.05 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 391.47 LC- 1 (3R)-[3-(3-Naphthalen-1-yl-ureido)-1 ,2,3,4- C25H23N3O3 1.7 413.97 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 413.476 LC- 1 (3R)-[3-(3-Phenylsulfonyl-ureido)-1 ,2,3,4- C21 H21 N3O5S 1.13 [M+Na]+ tetrahydro-9/-/-carbazol-9-yl]-acetic acid 427.48 LC- 1 449.90 (3R)-(3-te/t-Butoxycarbonylamino-1 ,2,3,4- C19H24N2O4 1.05 [M+Na]+ tetrahydro-9/-/-carbazol-9-yl)-acetic acid 344.10 LC- 1 367.07 (3R)-(3-Propoxycarbonylamino-1 ,2,3,4- C18H22N2O4 1.35 331.03 tetrahydro-9/-/-carbazol-9-yl)-acetic acid 330.383 LC- 1 (3R)-(3-lsobutoxycarbonylamino-1 ,2,3,4- C19H24N2O4 1.69 345.03 tetrahydro-9/-/-carbazol-9-yl)-acetic acid 344.41 LC- 1 (3R)-(3-Benzyloxycarbonylamino-1 ,2,3,4- C22H22N2O4 1.82 [M+Na]+ tetrahydro-9/-/-carbazol-9-yl)-acetic acid 378.427 LC- 1 400.96 (3R)-[3-(2-Benzyloxy-ethoxycarbonylamino)- C24H26N2O5 1.77 [M+Na]+ 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 422.479 LC- 1 444.94 acid (3R)-(3-Benzoylamino-1 ,2,3,4-tetrahydro-9/-/- C21 H20N2O3 1.00 349.00 carbazol-9-yl)-acetic acid 348.401 LC-2 (3R)-[3-(2-Phenoxy-acetylamino)-1 ,2,3,4- C22H22N2O4 1.43 379.04 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 378.427 LC- 1 (3R)-(3-Phenylacetylamino-1 ,2,3,4- C22H22N2O3 1.21 363.02 tetrahydro-9/-/-carbazol-9-yl)-acetic acid 362.428 LC- 1 (3R)-[3-(2-Thiophen-2-yl-acetylamino)- C20H20N2O3S 1.11 368.96 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 368.456 LC- 1 acid (3R)-[3-(3-Phenyl-propionylamino)-1 ,2,3,4- C23H24N2O3 1.36 377.04 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 376.455 LC- 1 (3R)-[3-(2-Benzyloxy-acetylamino)-1 ,2,3,4- C23H24N2O4 1.44 392.98 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 392.454 LC- 1 (3R)-[3-(3-Methyl-butyrylamino)-1 ,2,3,4- C19H24N2O3 0.97 329.08 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 328.41 1 LC- 1 (3R)-[3-(3-Cyclopentyl-propionylamino)- C22H28N2O3 1.77 369.07 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 368.475 LC- 1 acid (3R)-(3-Decanoylamino-1 ,2,3,4-tetrahydro- C24H34N2O3 2.77 399.10 9H-carbazol-9-yl)-acetic acid 398.545 LC- 1 (3S)-[3-(3-Butyl-ureido)-1 ,2,3,4-tetrahydro- C19H25N3O3 0.98 344.18 9/-/-carbazol-9-yl]-acetic acid 343.426 LC-2 (3S)-[3-(3-Benzyl-ureido)-1 ,2,3,4-tetrahydro- C22H23N3O3 0.99 378.18 9/-/-carbazol-9-yl]-acetic acid 377.443 LC-2 (3S)-[3-(3-Phenethyl-ureido)-1 ,2,3,4- C23H25N3O3 1.01 392.17 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 391.47 LC-2 (3S)-[3-(3-Phenylsulfonyl-ureido)-1 ,2,3,4- C21 H21 N3O5S 0.99 428.05 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 427.48 LC-2 (3S)-[3-(3-Phenyl-ureido)-1 ,2,3,4-tetrahydro- C21 H21 N3O3 1.00 364.13 9/-/-carbazol-9-yl]-acetic acid 363.416 LC-2 (3S)-(3-Propoxycarbonylamino-1 ,2,3,4- C18H22N2O4 1.01 331.17 tetrahydro-9/-/-carbazol-9-yl)-acetic acid 330.383 LC-2 (3S)-(3-lsobutoxycarbonylamino-1 ,2,3,4- C19H24N2O4 1.04 345.15 tetrahydro-9/-/-carbazol-9-yl)-acetic acid 344.41 LC-2 (3S)-(3-Benzyloxycarbonylamino-1 ,2,3,4- C22H22N2O4 1.06 379.15 tetrahydro-9/-/-carbazol-9-yl)-acetic acid 378.427 LC-2 (3S)-[3-(2-Benzyloxy-ethoxycarbonylamino)- C24H26N2O5 1.06 423.20 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 422.479 LC-2 acid (3S)-[3-(2-Phenoxy-acetylamino)-1 ,2,3,4- C22H22N2O4 1.02 379.08 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 378.427 LC-2 (3S)-(3-Phenylacetylamino-1 ,2,3,4- C22H22N2O3 1.00 363.16 tetrahydro-9/-/-carbazol-9-yl)-acetic acid 362.428 LC-2 (3S)-[3-(2-Thiophen-2-yl-acetylamino)- C20H20N2O3S 0.99 369.1 1 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 368.456 LC-2 acid (3S)-[3-(3-Phenyl-propionylamino)-1 ,2,3,4- C23H24N2O3 1.02 377.08 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 376.455 LC-2 (3S)-[3-(2-Benzyloxy-acetylamino)-1 ,2,3,4- C23H24N2O4 1.03 393.14 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 392.454 LC-2 (3S)-[3-(3-Methyl-butyrylamino)-1 ,2,3,4- C19H24N2O3 0.97 329.16 tetrahydro-9/-/-carbazol-9-yl]-acetic acid 328.41 1 LC-2 (3S)-[3-(3-Cyclopentyl-propionylamino)- C22H28N2O3 1.01 369.18 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 368.475 LC-2 acid (3S)-(3-Decanoylamino-1 ,2,3,4-tetrahydro- C24H34N2O3 1.16 398.82 9/-/-carbazol-9-yl)-acetic acid 398.545 LC-2 (3S)-(3-Butyrylamino-1 ,2,3,4-tetrahydro-9H- C18H22N2O3 0.94 315.18 carbazol-9-yl)-acetic acid 314.384 LC-2 (3S)-(3-Heptanoylamino-1 ,2,3,4-tetrahydro- C21 H28N2O3 1.06 357.20 9/-/-carbazol-9-yl)-acetic acid 356.464 LC-2 (3R)-[6-Fluoro-3-(2-phenoxy-acetylamino)- C22H21 N2O4F 1.04 397.16 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 396.417 LC-2 acid (3R)-(6-Fluoro-3-phenylacetylamino-1 ,2,3,4- C22H21 N2O3F 1.01 381.16 tetrahydro-9/-/-carbazol-9-yl)-acetic acid 380.418 LC-2 (3R)-[6-Fluoro-3-(3-phenyl-propionylamino)- C23H23N2O3F 1.03 395.22 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 394.445 LC-2 acid (3R)-{3-[2-(4-Chloro-phenyl)-acetylamino]-6- C22H20N2O3CIF 1.05 415.16 fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 414.863 LC-2 acetic acid (3R)-{6-Fluoro-3-[2-(4-methoxy-phenyl)- C23H23N2O4F 1.01 411.22 acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 410.444 LC-2 9-yl}-acetic acid (3R)-[6-Fluoro-3-(2-p-tolyl-acetylamino)- C23H23N2O3F 1.04 395.22 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 394.445 LC-2 acid (3R)-{3-[2-(3,4-Dichloro-phenyl)- C22H19N2O3CI2F 1.09 447.16 acetylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 449.308 LC-2 carbazol-9-yl}-acetic acid (3R)-{3-[2-(3-Chloro-phenyl)-acetylamino]-6- C22H20N2O3CIF 1.06 415.16 fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 414.863 LC-2 acetic acid (3R)-{6-Fluoro-3-[2-(4-trifluoromethyl-phenyl)- C23H20N2O3F4 1.08 449.17 acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 448.415 LC-2 9-yl}-acetic acid (3R)-{3-[2-(4-Chloro-phenoxy)-acetylamino]- C22H20N2O4CIF 1.08 431.16 6-fluoro-1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- 430.862 LC-2 acetic acid (3R)-[6-Fluoro-3-(2-p-tolyloxy-acetylamino)- C23H23N2O4F 1.08 411.22 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 410.444 LC-2 acid (3R)-{3-[2-(2-Chloro-phenoxy)-acetylamino]- C22H20N2O4CIF 1.07 431.16 6-fluoro-1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- 430.862 LC-2 acetic acid (3R)-{3-[2-(3-Chloro-phenoxy)-acetylamino]- C22H20N2O4CIF 1.08 431.16 6-fluoro-1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- 430.862 LC-2 acetic acid (3R)-{6-Fluoro-3-[3-(4-methoxy-phenyl)- C24H25N2O4F 1.03 425.28 propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 424.471 LC-2 carbazol-9-yl}-acetic acid (3R)-[6-Fluoro-3-(3-p-tolyl-propionylamino)- C24H25N2O3F 1.06 409.21 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 408.472 LC-2 acid (3R)-{3-[3-(4-Chloro-phenyl)-propionylamino]- C23H22N2O3CIF 1.07 429.15 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 428.89 LC-2 acetic acid (3R)-{3-[3-(2-Chloro-phenyl)-propionylamino]- C23H22N2O3CIF 1.07 429.15 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 428.89 LC-2 acetic acid (3R)-{3-[3-(3-Chloro-phenyl)-propionylamino]- C23H22N2O3CIF 1.07 429.15 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 428.89 LC-2 acetic acid (3S)-{3-[2-(4-Chloro-phenyl)-acetylamino]-6- C22H20N2O3CIF 1.05 415.23 fluoro-1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- 414.863 LC-2 acetic acid (3S)-{6-Fluoro-3-[2-(4-methoxy-phenyl)- C23H23N2O4F 1.01 411.22 acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 410.444 LC-2 9-yl}-acetic acid (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 (3S)-[6-Fluoro-3-(2-phenoxy-acetylamino)- C22H21 N2O4F 1.04 397.23 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 396.417 LC-2 acid (3S)-[6-Fluoro-3-(3-phenyl-propionylamino)- C23H23N2O3F 1.03 395.22 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 394.445 LC-2 acid (3S)-{3-[2-(4-Chloro-phenoxy)-acetylamino]- C22H20N2O4CIF 1.08 431.16 6-fluoro-1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- 430.862 LC-2 acetic acid (3S)-[6-Fluoro-3-(2-p-tolyloxy-acetylamino)- C23H23N2O4F 1.07 411.22 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 410.444 LC-2 acid (3S)-{6-Fluoro-3-[3-(4-methoxy-phenyl)- C24H25N2O4F 1.03 425.21 propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 424.471 LC-2 carbazol-9-yl}-acetic acid (3S)-[6-Fluoro-3-(3-p-tolyl-propionylamino)- C24H25N2O3F 1.06 409.21 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetic 408.472 LC-2 acid (3S)-{3-[3-(4-Chloro-phenyl)-propionylamino]- C23H22N2O3CIF 1.07 429.15 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 428.89 LC-2 acetic acid (3S)-{3-[3-(2-Chloro-phenyl)-propionylamino]- C23H22N2O3CIF 1.07 429.15 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 428.89 LC-2 acetic acid (3S)-{3-[3-(3-Chloro-phenyl)-propionylamino]- C23H22N2O3CIF 1.07 429.15 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 428.89 LC-2 acetic acid (3S)-{3-[3-(3,4-Difluoro-phenyl)- C23H21 N2O3F3 1.05 431.26 propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro- 430.425 LC-2 9/-/-carbazol-9-yl}-acetic acid (3S)-{6-Fluoro-3-[3-(3-methoxy-phenyl)- C24H25N2O4F 1.03 425.21 propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 424.471 LC-2 carbazol-9-yl}-acetic acid (3S)-{6-Fluoro-3-[3-(2-methoxy-phenyl)- C24H25N2O4F 1.04 425.21 propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/-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-9/-/-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-9/-/- 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-9/-/- 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-9/-/-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-9/-/-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 9/-/-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-9/-/- 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-9/-/- 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-9/-/- 410.444 LC-2 carbazol-9-yl}-acetic acid
82 (3S)-{3-[(2,3-Dihydro-1 H-indole-2-carbonyl)- C23H22N3O3F 1.04 408.04 amino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 407.444 LC-2 carbazol-9-yl}-acetic acid
83 (3S)-[6-Fluoro-3-(3-1 H-indol-3-yl- C25H24N3O3F 1.04 434.07 propionylamino)-1 ,2,3,4-tetrahydro-9/-/- 433.482 LC-2 carbazol-9-yl]-acetic acid 84 (3S)-[3-(3-1 H-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 9/-/-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-9/-/-carbazol-9-yl}- 405.428 LC-2 acetic acid
87 (3S)-[6-Fluoro-3-(3-pyridin-3-yl- C22H22N3O3F 0.7 396.1 1 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-9/-/-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-9/-/-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-9/-/- 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- C23H22N2O3CIF 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-9/-/-carbazol-9-yl}- 422.498 LC-3 acetic acid
97 (3S)-(3-{[2-(4-Chloro-phenyl)-acetyl]-ethyl- C24H24N2O3CIF 1.01 443.06 amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/-carbazol-9-yl}- 436.525 LC-3 acetic acid
99 (3S)-(3-{[2-(4-Chloro-phenyl)-acetyl]-propyl- C25H26N2O3CIF 1.03 457.21 amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 456.943 LC-3 carbazol-9-yl)-acetic acid
100 (3RS)-(3-Benzyloxycarbonylamino-6-fluoro- C22H21 N2O4F 0.98 397.1 1 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)-acetic 396.410 LC-3 acid
101 (3RS)-(3-Benzyloxycarbonylamino-8-chloro- C22H20N2O4CIF 1.01 431.05 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)- 430.862 LC-3 acetic acid
102 (3RS)-(3-Benzyloxycarbonylamino-8-chloro- C22H20N2O4CIF 1.01 431.04 5-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)- 430.862 LC-3 acetic acid
Listed in Table Ia 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 Ia Example Compound of Formula I Formula tR [min] MS Data
MW LCMS m/z
Method [M+H]+
103 (3RS)-[3-(3-Benzyl-ureido)-6-fluoro- C22H22N3O3F 0.92 396.17 1 ,2,3,4-tetrahydro-9/-/-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-9/-/- 409.46 LC-3 carbazol-9-yl]-acetic acid 105 (3RS)-[3-(3-Benzyl-ureido)-8-chloro- C22H21 N3O3CIF 0.95 430.07 6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 429.878 LC-3 carbazol-9-yl]-acetic acid
106 (3/?S)-[8-Chloro-6-fluoro-3-(3- C23H23N3O3CIF 0.97 444.07 phenethyl-ureido)-1 ,2,3,4-tetrahydro- 443.905 LC-3 9/-/-carbazol-9-yl]-acetic acid
107 (3RS)-(3-Benzyloxycarbonylamino-6- C23H21 N2O4F3 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 9/-/-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-9/-/-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 9/-/-carbazol-9-yl)-acetic acid
112 (3S)-(3-Benzyloxycarbonylamino-7- C22H20N2O4CIF 1.01 431.16 chloro-6-fluoro-1 ,2,3,4-tetrahydro- 430.862 LC-3 9/-/-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- C22H21 N2O4CI 1 413 .03 chloro-1 ,2,3,4-tetrahydro-9/-/- 412.872 LC-3 carbazol-9-yl)-acetic acid
115 (3S)-{3-[3-(2,4-Dimethoxy-phenyl)- C25H27N2O5F 0.95 455 .1 1 propionylamino]-6-fluoro-1 , 2,3,4- 454.496 LC-3 tetrahydro-9/-/-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-9/-/-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 0.97 409.1 1 methylphenyl)-propionylamino]- 408.472 LC-3
1 ,2,3,4-tetrahydro-9/-/-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-9/-/-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-9/-/-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-9/-/-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-9/-/-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-9/-/-carbazol-9-yl}-acetic acid 125 (3S)-{3-[3-(2,6-Dichloro-phenyl)- C23H21 N2O3CI2F 0.99 463.07 propionylamino]-6-fluoro-1 , 2,3,4- 463.335 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetic acid
126 (3S)-{3-[3-(2,5-Bis-trifluoromethyl- C25H21 N2O3F7 1.04 530. 97 phenyl)-propionylamino]-6-fluoro- 530.439 LC-3
1 ,2,3,4-tetrahydro-9/-/-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-
9/-/-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-9/-/-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-9/-/-carbazol-9-yl}-acetic acid
131 (3S)-{3-[3-(2,4-Dichloro-phenyl)- C23H21 N2O3CI2F 1.01 463. 08 propionylamino]-6-fluoro-1 , 2,3,4- 463.335 LC-3 tetrahydro-9/-/-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
9/-/-carbazol-9-yl}-acetic acid
133 (3S)-{3-[3-(3,5-Bis-trifluoromethyl- C25H21 N2O3F7 1.03 530. 99 phenyl)-propionylamino]-6-fluoro- 530.439 LC-3
1 ,2,3,4-tetrahydro-9/-/-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-9/-/-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-
9/-/-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-9/-/-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-9/-/-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-9/-/-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-9/-/-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-9/-/-carbazol-9-yl}-acetic acid
143 (3S)-{6-Fluoro-3-[(S)-3-(4-fluoro- C29H26N2O3F2 1.02 phenyl)-2-phenyl-propionylamino]- 488.532 LC-3 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid (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-9/-/-carbazol-9-yl}- acetic acid (3S)-{6-Fluoro-3-[3-(2-fluoro-phenyl)- C23H22N2O3F2 0.95 413.09 propionylamino]-1 ,2,3,4-tetrahydro- 412.435 LC-3 9/-/-carbazol-9-yl}-acetic acid (3S)-(6-Fluoro-3-{[(2RS)-1 ,2,3,4- C25H25N2O3F 0.98 421.1 1 tetrahydro-naphthalene-2-carbonyl]- 420.483 LC-3 amino}-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl)-acetic acid (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- 9/-/-carbazol-9-yl)-acetic acid (3S)-(6-Fluoro-3-{(2RS)-2-[(4-fluoro- C31 H29N3O4F2 0.98 546.06 phenylcarbamoyl)-methyl]-3-phenyl- 545.584 LC-3 propionylamino}-1 ,2,3,4-tetrahydro- 9H-carbazol-9-yl)-acetic acid (3S)-{3-[(2RS)-2-Benzyl-3,3- C27H31 N2O3F 1.02 451.12 dimethyl-butyrylamino]-6-fluoro- 450.552 LC-3 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid (3S)-(6-Fluoro-3-{[(2RS)-8-methoxy- C24H23N2O4F 0.95 423.1 1 1 ,2,3,4-tetrahydro-naphthalene-2- 422.455 LC-3 carbonyl]-amino}-1 ,2,3,4-tetrahydro- 9/-/-carbazol-9-yl)-acetic acid (3S)-{6-Fluoro-3-[3-(3-fluoro-phenyl)- C23H22N2O3F2 0.94 413.08 propionylamino]-1 ,2,3,4-tetrahydro- 412.435 LC-3 9/-/-carbazol-9-yl}-acetic acid (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- 9/-/-carbazol-9-yl)-acetic acid 153 (3S)-{6-Fluoro-3-[(2R)-2-methyl-3- C24H25N2O3F 0.95 409.1 1 phenyl-propionylamino]-1 ,2,3,4- 408.472 LC-3 tetrahydro-9/-/-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-9/-/-carbazol-9-yl]-acetic acid
155 (3S)-[6-Fluoro-3-(3-methyl-3-phenyl- C25H27N2O3F 1 423 .2 butyrylamino)-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/- 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-9/-/- 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-9/-/- 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-9/-/-carbazol-9-yl}-acetic acid
160 (3RS)-{8-Chloro-6-fluoro-3-[3-(2- C24H24N2O3CIF 1 443. 1 1 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- C23H22N2O5CIF 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-fluoiO-3-[3-(3- C23H22N2O4CIF 0.88 445. 32 hydroxy-phenyl)-propionylamino]- 444.889 LC-3
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- acetic acid
(3RS)-{8-Chloro-6-fluoro-3-[3-(3- C24H24N2O4CIF 0.98 459.04 methoxy-phenyl)-propionylamino]- 458.916 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- acetic acid (3RS)-{8-Chloro-6-fluoro-3-[3-(3- C24H24N2O3CIF 1.01 443.01 methylphenyl)-propionylamino]- 442.917 LC-3 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid (3RS)-{8-Chloro-6-fluoro-3-[3-(2- C23H22N2O4CIF 0.92 486.38 hydroxy-phenyl)-propionylamino]- 444.889 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- acetic acid (3RS)-[8-Chloro-6-fluoro-3-(3-phenyl- C23H22N2O3CIF 0.98 429.13 propionylamino)-1 ,2,3,4-tetrahydro- 428.89 LC-3 9H-carbazol-9-yl]-acetic acid (3RS)-{8-Chloro-6-fluoro-3-[3-(2- C24H24N2O4CIF 0.99 459.03 methoxy-phenyl)-propionylamino]- 458.916 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- acetic acid (3RSHS-ChIOrO-S-[S-(S-ChIOrO- C23H21 N2O3CI2F 1.01 463.1 1 phenyl)-propionylamino]-6-fluoro- 463.335 LC-3 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid (3RS)-[8-Chloro-6-fluoro-3-(3-7H- C25H23N3O3CIF 0.97 468.1 1 indol-3-yl-propionylamino)-1 ,2,3,4- 467.927 LC-3 tetrahydro-9/-/-carbazol-9-yl]-acetic acid (3RS)-{8-Chloro-3-[2-(2-chloro- C22H19N2O4CI2F 1.01 465.09 phenoxy)-acetylamino]-6-fluoro- 465.307 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- acetic acid (3RS)-{8-Chloro-6-fluoro-3-[2-(2- C23H22N2O4CIF 1.02 445.1 1 methylphenyl)-oxy-acetylamino]- 444.889 LC-3 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid
(3/?S)-[3-(3-Benzo[1 ,3]dioxol-5-yl- C24H22N2O5CIF 0.93 473.17 propionylamino)-8-chloro-6-fluoro- 472.899 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]- acetic acid (3RS)-{8-Chloro-6-fluoro-3-[2-(3- C23H22N2O5CIF 0.99 461.09 methoxy-phenoxy)-acetylamino]- 460.888 LC-3 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid (3RS)-{8-Chloro-3-[2-(3-chloro- C22H19N2O4CI2F 1.02 465 phenoxy)-acetylamino]-6-fluoro- 465.307 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- acetic acid (3RS)-{8-Chloro-3-[3-(2-chloro- C23H21 N2O3CI2F 1.01 463.07 phenyl)-propionylamino]-6-fluoro- 463.335 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- acetic acid (3RS)-[8-Chloro-6-fluoro-3-(2-indan- C25H24N2O3CIF 1.01 455.16 2-yl-acetylamino)-1 ,2,3,4-tetrahydro- 454.928 LC-3 9/-/-carbazol-9-yl]-acetic acid (3S;-[6-Fluoro-3-(1-methyl-3- C24H26N3O3F 0.98 429.13 phenethyl-ureido)-1 ,2,3,4-tetrahydro- 423.486 LC-3 9/-/-carbazol-9-yl]-acetic acid (3S)-{3-[3-(2-Chloro-benzyl)-1- C23H23N3O3CIF 0.97 444.16 methyl-ureido]-6-fluoro-1 ,2,3,4- 443.905 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetic acid (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 (3S)-[3-(Benzyloxycarbonyl-methyl- C23H23N2O4F 1.01 411.07 amino)-6-fluoro-1 ,2,3,4-tetrahydro- 410.444 LC-3 9/-/-carbazol-9-yl]-acetic acid {(3S)-3-[(2-Chloro- C23H22N2O4CIF 1.03 445.15 benzyloxycarbonyl)-methyl-amino]-6- 444.889 LC-3 fluoro-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl}-acetic acid
(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-9/-/-carbazol-9-yl)- acetic acid
(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
(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-9/-/-carbazol-9-yl)- acetic acid
(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-9/-/-carbazol-9-yl}-acetic acid
(3S)-(3-{[2-(3-Chloro-phenyl)-acetyl]- C23H22N2O3CIF 0.99 429.13 methyl-amino}-6-fluoro-1 ,2,3,4- 428.89 LC-3 tetrahydro-9/-/-carbazol-9-yl)-acetic acid
(3S)-(6-Fluoro-3-{methyl-[2-(3- C24H25N2O3F 0.98 409.1 methylphenyl)-acetyl]-amino}- 408.472 LC-3
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)- acetic acid
(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-9/-/-carbazol-9-yl)- acetic acid
(3S)-(3-{[2-(2-Chloro-phenoxy)- C23H22N2O4CIF 0.97 445.38 acetyl]-methyl-amino}-6-fluoro- 444.889 LC-3
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid
(3S)-(3-{[2-(4-Chloro-phenoxy)- C23H22N2O4CIF 0.98 445.39 acetyl]-methyl-amino}-6-fluoro- 444.889 LC-3 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid
(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-9/-/-carbazol-9-yl)- acetic acid
(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
(3S)-{3-[(3,3-Diphenyl-propionyl)- C30H29N2O3F 1.02 485.52 methyl-amino]-6-fluoro-1 ,2,3,4- 484.569 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetic acid
(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-9/-/-carbazol-9-yl)- acetic acid
(3S)-{6-Fluoro-3-[(3-7H-indol-3-yl- C26H26N3O3F 0.94 448.44 propionyl)-methyl-amino]-1 , 2,3,4- 447.508 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetic acid
(3S)-{3-[(2-Benzyloxy-acetyl)-methyl- C24H25N2O4F 0.94 425.44 amino]-6-fluoro-1 ,2,3,4-tetrahydro- 424.471 LC-3
9/-/-carbazol-9-yl}-acetic acid
(3S)-{3-[(2,3-Diphenyl-propionyl)- C30H29N2O3F 1.04 485.53 methyl-amino]-6-fluoro-1 ,2,3,4- 484.569 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetic acid
(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-9/-/- carbazol-9-yl}-acetic acid
(3S)-{3-[Acetyl-(3-phenyl-propyl)- C25H27N2O3F 1.01 423.14 amino]-6-fluoro-1 ,2,3,4-tetrahydro- 422.498 LC-3
9/-/-carbazol-9-yl}-acetic acid (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 (3S)-[3-(Benzyloxycarbonyl- C26H27N2O4F 1.05 451.15 cyclopropylmethyl-amino)-6-fluoro- 450.508 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]- acetic acid (3S)-{3-[Cyclopropylmethyl-(3- C27H29N2O3F 1.02 449.25 phenyl-propionyl)-amino]-6-fluoro- 448.536 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- acetic acid (3S)-{3-[Cyclopropylmethyl-((S)-2- C28H31 N2O3F 1.03 463.27 methyl-3-phenyl-propionyl)-amino]-6- 462.563 LC-3 fluoro-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl}-acetic acid (3S)-(3-{Cyclopropylmethyl-[3-(2- C28H31 N2O4F 1.02 479.28 methoxy-phenyl)-propionyl]-amino}- 478.562 LC-3 6-fluoro-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl)-acetic acid (3S)-(3-{[2-(3-Chloro-phenoxy)- C26H26N2O4CIF 1.03 485.2 acetyll-cyclopropylmethyl-aminoj-θ- 484.953 LC-3 fluoro-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl)-acetic acid (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 (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-9/-/- carbazol-9-yl}-acetic acid (3Sj-(3-{Benzyloxycarbonyl-[2-(4- C31 H28N2O5F4 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 (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 (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-9/-/- carbazol-9-yl)-acetic acid (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-9/-/-carbazol-9-yl)-acetic acid (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-9/-/- carbazol-9-yl)-acetic acid (3S)-{6-Fluoro-3-[(2-phenoxy-ethyl)- C31 H31 N2O4F 1.06 515.17 (3-phenyl-propionyl)-amino]-1 , 2,3,4- 514.595 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetic acid (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-9/-/- carbazol-9-yl}-acetic acid (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-9/-/- carbazol-9-yl}-acetic acid (3S)-{3-[Acetyl-(2-phenoxy-ethyl)- C24H25N2O4F 0.98 425.19 amino]-6-fluoro-1 ,2,3,4-tetrahydro- 424.471 LC-3 9/-/-carbazol-9-yl}-acetic acid (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-9/-/-carbazol-9-yl}-acetic acid
(3S)-{3-[Benzyloxycarbonyl-(2- C25H27N2O5F 0.97 454.26 methoxy-ethyl)-amino]-6-fluoro- 454.496 LC-3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- acetic acid (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-9/-/-carbazol-9-yl}-acetic acid (3S)-{6-Fluoro-3-[(2-methoxy-ethyl)- C27H31 N2O4F 1 467.18 ((S)-2-methyl-3-phenyl-propionyl)- 466.551 LC-3 amino]-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl}-acetic acid (3S)-(6-Fluoro-3-{(2-methoxy-ethyl)- C27H31 N2O5F 0.98 483.19 [3-(2-methoxy-phenyl)-propionyl]- 482.55 LC-3 amino}-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl)-acetic acid (3S)-{3-[[2-(3-Chloro-phenoxy)- C25H26N2O5CIF 1 489.17 acetyl]-(2-methoxy-ethyl)-amino]-6- 488.941 LC-3 fluoro-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl}-acetic acid (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-9/-/-carbazol-9-yl}- acetic acid (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-9/-/-carbazol-9-yl}- acetic acid (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 (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
(3S)-[3-(Acetyl-phenethyl-amino)-6- C24H25N2O3F 0.98 409.16 fluoro-1 ,2,3,4-tetrahydro-9/-/- 408.472 LC-3 carbazol-9-yl]-acetic acid
(3S)-{6-Fluoro-3-[(2-naphthalen-1-yl- C34H31 N2O3F 1.08 535.27 acetyl)-phenethyl-amino]-1 ,2,3,4- 534.629 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetic acid
(3S)-{6-Fluoro-3-[phenethyl-(3- C31 H31 N2O3F 1.06 499.2 phenyl-propionyl)-amino]-1 , 2,3,4- 498.596 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetic acid
(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-9/-/-carbazol-9-yl]-acetic acid
(3S)-[3-(Benzyloxycarbonyl- C33H29N2O4F 1.09 537.24 naphthalen-1-ylmethyl-amino)-6- 536.601 LC-3 fluoro-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl]-acetic acid
(3S)-{6-Fluoro-3-[naphthalen-1- C34H31 N2O3F 1.07 535.25 ylmethyl-(3-phenyl-propionyl)- 534.629 LC-3 amino]-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl}-acetic acid
(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
(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
(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-9/-/- 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-9/-/-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-9/-/-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-9/-/-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-9/-/-carbazol-9-yl}-acetic acid
240 (3S)-{3-[(RS)-2-Benzyl-3-(4-chloro- C31 H29N3O4CIF 1.01 562.09 phenylcarbamoyl)-propionylamino]-6- 562.039 LC-3 fluoro-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl}-acetic acid
241 (3S)-{3-[(RS)-2-Benzyl-3-(4-fluoro- C32H31 N3O4F2 0.96 560.21 benzylcarbamoyl)-propionylamino]-6- 559.61 1 LC-3 fluoro-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/- carbazol-9-yl]-acetic acid
243 (3S)-[6-Fluoro-3-(3-thiophen-2-yl- C21 H21 FN2O3S 0.93 400.61 propionylamino)-1 ,2,3,4-tetrahydro- 400.47 LC-3
9/-/-carbazol-9-yl]-acetic acid 244 (3S)-{3-[3-(3-Chloro-isoxazol-5-yl)- C20H19CIFN3O4 0.91 420.09 propionylamino]-6-fluoro-1 , 2,3,4- 419.83 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetic acid
245 (3S;-[6-Fluoro-3-(3-pyrimidin-2-yl- C21 H21 FN4O3 0.8 397.1 1 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-9/-/- carbazol-9-yl}-acetic acid
247 (3S)-[3-(1 ,3-Dibenzyl-ureido)-6- C29H28FN3O3 1.02 486.22 fluoro-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/-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-9/-/-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- C31 H37N2O4F 1.10 521.25 methoxy-phenyl)-propionyl]-amino}- 520.643 LC-3
6-fluoro-1 ,2,3,4-tetrahydro-9/-/- carbazol-9-yl)-acetic acid Synthesis of Precursors and Intermediates:
General Methods for the synthesis of intermediates of Structure 1:
Figure imgf000074_0001
Structure 1, wherein R represents Ci_4-alkyl
1 ) Λ/-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 00C 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-l,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-l,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 : Formula tR [min] MS Data
Ethyl [3-ureido-1 ,2,3,4-tetrahydro-9H- MW LC-MS m/z carbazol-9-yl]-acetate derivatives Method [M+H]+
Ethyl (3R)-[3-(3-butyl-ureido)-1 ,2,3,4- C21 H29N3O3 1.1 tetrahydro-9/-/-carbazol-9-yl]-acetate 371.47 LC-2
Ethyl (3R)-[3-(3-benzyl-ureido)-1 ,2,3,4- C24H27N3O3 1.99 tetrahydro-9/-/-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 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl]- 441.95
441.52 LC-2 acetate
Ethyl (3R)-[3-(3-phenylsulfonyl-ureido)-
C23H25N3O5S 1.96 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl]- 454.1
455.534 LC-1 acetate
Ethyl (3S)-[3-(3-butyl-ureido)-1 ,2,3,4- C21 H29N3O3 1.08 tetrahydro-9/-/-carbazol-9-yl]-acetate 371.479 LC-2
Ethyl (3S)-[3-(3-benzyl-ureido)-1 ,2,3,4- C24H27N3O3 1.1
406.16 tetrahydro-9/-/-carbazol-9-yl]-acetate 405.496 LC-2
Ethyl (3S)-[3-(3-phenethyl-ureido)-1 ,2,3,4- C25H29N3O3 1.12 tetrahydro-9/-/-carbazol-9-yl]-acetate 419.523 LC-2
Ethyl (3S)-[3-(3-phenylsulfonyl-ureido)-
C23H25N3O5S 1.09 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl]- 454.16
455.534 LC-2 acetate
Ethyl (3S)-[3-(3-phenyl-ureido)-1 ,2,3,4- C23H25N3O3 1.11 tetrahydro-9/-/-carbazol-9-yl]-acetate 391.47 LC-2
Listed in Table 2a below are further ethyl [3-ureido-l,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 : Formula
Ethyl [3-ureido-1 ,2,3,4-tetrahydro-9Η- MW carbazol-9-yl]-acetate derivatives
Ethyl (3RS)-[3-(3-benzyl-ureido)-6-fluoro-1 ,2,3,4- C25Η28FN3O3 tetrahydro-9/-/-carbazol-9-yl]-acetate 437.51
Ethyl (3S)-[6-fluoro-3-(3-phenethyl-ureido)- C25H28N3O3F 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetate 437.51 Ethyl (3RS)-[3-(3-benzyl-ureido)-8-chloro-6-
C24H25CIFN3O3 fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]- 457.93 acetate
Ethyl (3RS)-[8-chloro-6-fluoro-3-(3-phenethyl-
C25H27CIFN3O3 ureido)-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]- 471.95 acetate
Ethyl (3S)-[6-fluoro-3-(1 -methyl-3-phenethyl-
C26H30FN3O3 ureido)-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]- 451.53 acetate
Ethyl (3S)-{3-[3-(2-chloro-benzyl)-1 -methyl-
C25H27CIFN3O3 ureido]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-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-9/-/-carbazol- 477.57
9-yl}-acetate
Ethyl (3S)-{3-[3-benzyl-1-(2-methoxy-ethyl)-
C27H32FN3O4 ureido]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 481.56
9-yl}-acetate
Ethyl (3S)-[3-(3-benzyl-1-cyclohexylmethyl-
C31 H37N3O3F ureido)-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 519.655
9-yl]-acetate
Ethyl (3S)-[3-(1 ,3-Dibenzyl-ureido)-6-fluoro- C29H28FN3O3 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetate 513.60
ZL Reaction of intermediates of Structure 2a or 2b with chloroformates:
The appropriate chloro formate (neat) and a catalytical amount of DMAP is added to a 00C 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-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 is obtained by preparative ΗPLC with 5 to 96% yield.
Listed in Table 3 below are ethyl (S-oxycarbonylamino-l^^^-tetrahydro-QH-carbazol-Q- 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 : Formula tR [min] MS Data
Ethyl (3-oxycarbonylamino-1 ,2,3,4- MW LC-MS m/z tetrahydro-9Η-carbazol-9-yl)-acetate Method derivatives
Ethyl (3R)-(3-propoxycarbonylamino-
C20Η26N2O4 1.14 380.98
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)-
358.436 LC-2 [M+Na]+ acetate
Ethyl (3R)-(3-isobutoxycarbonylamino-
C21 H28N2O4 1.20 395.04
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)-
372.463 LC-2 [M+Na]+ acetate
Ethyl (3R)-(3-benzyloxycarbonylamino-
C24Η26N2O4 1.17 407.02
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)- 406.48 LC-2 [M+H]+ acetate
Ethyl (3R)-[3-(2-benzyloxy-
C26H30N2O5 1.17 473.01 ethoxycarbonylamino)-1 ,2,3,4-
450.533 LC-2 [M+Na]+ tetrahydro-9/-/-carbazol-9-yl]-acetate
Ethyl (3S)-(3-propoxycarbonylamino-
C20H26N2O4 1.12 381.09
1 ,2,3,4-tetrahydro-9Η-carbazol-9-yl)-
358.436 LC-2 [M+Na]+ acetate
Ethyl (3S)-(3-isobutoxycarbonylamino-
C21 H28N2O4 1.15 373.13
1 ,2,3,4-tetrahydro-9Η-carbazol-9-yl)-
372.463 LC-2 [M+H]+ acetate
Ethyl (3S)-(3-benzyloxycarbonylamino-
C24H26N2O4 1.16 407.2
1 ,2,3,4-tetrahydro-9Η-carbazol-9-yl)- 406.48 LC-2 [M+H]+ acetate Ethyl (3S)-[3-(2-benzyloxy-
C26H30N2O5 1.17 473.14 ethoxycarbonylamino)-1 ,2,3,4-
450.533 LC-2 [M+Na]+ tetrahydro-9/-/-carbazol-9-yl]-acetate
Listed in Table 3a below are further ethyl (3-oxycarbonylamino-l,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 : Formula
Ethyl (3-oxycarbonylamino-1,2,3,4-tetrahydro- MW
9Η-carbazol-9-yl)-acetate derivatives
Ethyl (3RS)-(3-benzyloxycarbonylamino-6-
C25Η25N2O4F3 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-
C24H24CIFN2O4 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- C24H25N2O4CI 1 ,2,3,4-tetrahydro-9/-/-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)-
C25H26N2O4CIF methyl-amino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 472.939 carbazol-9-yl}-acetate
Ethyl (3Sj-[3-(benzyloxycarbonyl-
C28H31 N2O4F cyclopropylmethyl-amino)-6-fluoro-1 ,2,3,4- 478.558 tetrahydro-9/-/-carbazol-9-yl]-acetate
Ethyl (3S)-(3-{benzyloxycarbonyl-[2-(4-
C33H32N2O5F4 trifluoromethyl-phenoxy)-ethyl]-amino}-6-fluoro- 612.614
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)-acetate
Ethyl (3S)-{3-[benzyloxycarbonyl-(2-methoxy-
C27H31 N2O5F ethyl)-amino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 482.546 carbazol-9-yl}-acetate
3) Λ/-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 00C, 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-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetate derivative of Structure 1 is isolated by preparative ΗPLC 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 TΗF 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 00C. 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-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetate derivative of Structure 1 is obtained with >50% yield and is either used as such in the next step or purified by prepaprative ΗPLC to give the pure ethyl (3-acylamino-l,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-l,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 : Formula tR [min] MS Data
Ethyl (3-acylamino-1 ,2,3,4-tetrahydro-9Η- MW LC-MS m/z carbazol-9-yl)-acetate derivatives Method [M+H]+
Ethyl (3R)-(3-benzoylamino-1 ,2,3,4-tetrahydro-9Η- C23Η24N2O3 1.11 399.00 carbazol-9-yl)-acetate 376.455 LC-2 [M+Na]+
Ethyl (3R)-[3-(2-phenoxy-acetylamino)-1 ,2,3,4- C24H26N2O4 1.13 428.93 tetrahydro-9/-/-carbazol-9-yl]-acetate 406.48 LC-2 [M+Na]+
Ethyl (3R)-(3-phenylacetylamino-1 , 2,3,4- C24H26N2O3 1.1 1 412.97 tetrahydro-9/-/-carbazol-9-yl)-acetate 390.481 LC-2 [M+Na]+
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 tetrahydro-9/-/-carbazol-9-yl]-acetate 404.508 LC-2 [M+Na]+
Ethyl (3R)-[3-(2-benzyloxy-acetylamino)-1 , 2,3,4- C25H28N2O4 1.14
421.07 tetrahydro-9/-/-carbazol-9-yl]-acetate 420.507 LC-2
Ethyl (3R)-[3-(3-methyl-butyrylamino)-1 ,2,3,4- C21 H28N2O3 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-9/-/-carbazol-9-yl]-acetate 396.529 LC-2
Ethyl (3R)-(3-decanoylamino-1 ,2,3,4-tetrahydro- C26H38N2O3 1.28 449.01
9H-carbazol-9-yl)-acetate 426.599 LC-2 [M+Na]+ Ethyl (3S)-[3-(2-phenoxy-acetylamino)-1 ,2,3,4- C24H26N2O4 1.03
407.23 tetrahydro-9/-/-carbazol-9-yl]-acetate 406.48 LC-2
Ethyl (3S)-(3-phenylacetylamino-1 , 2,3,4- C24H26N2O3 1.1 tetrahydro-9/-/-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 tetrahydro-9/-/-carbazol-9-yl]-acetate 404.508 LC-2
Ethyl (3S)-[3-(2-benzyloxy-acetylamino)-1 , 2,3,4- C25H28N2O4 1.14 tetrahydro-9/-/-carbazol-9-yl]-acetate 420.507 LC-2
Ethyl (3S)-[3-(3-methyl-butyrylamino)-1 ,2,3,4- C21 H28N2O3 1.1
357.13 tetrahydro-9/-/-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
9H-carbazol-9-yl)-acetate 426.599 LC-2
Ethyl (3S)-(3-butyrylamino-1 ,2,3,4-tetrahydro-9H- C20H26N2O3 1.07 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-9/-/-carbazol-9-yl)-acetate 408.472 LC-2
Ethyl (3R)-[6-Fluoro-3-(3-phenyl-propionylamino)- C25H27N2O3F 1.15
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetate 422.498 LC-2
Ethyl (3R)-{3-[2-(4-Chloro-phenyl)-acetylamino]-6- C24H24N2O3CIF 1.18 fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}-acetate 442.917 LC-2
Ethyl (3R)-{6-fluoro-3-[2-(4-methoxy-phenyl)-
C25H27N2O4F 1.12 acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 439.2
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]-C24H23N2O3CI2F 1.18 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- C24H24N2O3CIF 1.16
443.28 fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}-acetate 442.917 LC-2
Ethyl (3R)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-
C25H24N2O3F4 1.17 acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 477.29
476.469 LC-2 acetate
Ethyl (3R)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6- C24H24N2O4CIF 1.18 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- C24H24N2O4CIF 1.17 fluoro-1 , 2,3,4-tetrahydro-9H-carbazol-9-yl}-acetate 458.916 LC-2
Ethyl (3R)-{3-[2-(3-chloro-phenoxy)-acetylamino]-6- C24H24N2O4CIF 1.18 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 propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 453.26
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-9/-/-carbazol-9-yl]-acetate 436.525 LC-2
Ethyl (3/?)-{3-[3-(4-chloro-phenyl)-propionylamino]-
C25H26N2O3CIF 1.18 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 457.2
456.943 LC-2 acetate
Ethyl (3/?)-{3-[3-(2-chloro-phenyl)-propionylamino]-
C25H26N2O3CIF 1.18 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 457.2
456.943 LC-2 acetate
Ethyl (3/?)-{3-[3-(3-chloro-phenyl)-propionylamino]-
C25H26N2O3CIF 1.17 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 457.2
456.943 LC-2 acetate
Ethyl (3S)-{3-[2-(4-chloro-phenyl)-acetylamino]-6- C24H24N2O3CIF 1.15
443.21 fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}-acetate 442.917 LC-2
Ethyl (3S)-{6-fluoro-3-[2-(4-methoxy-phenyl)-
C25H27N2O4F 1.12 acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 439.33
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-9/-/-carbazol-9-yl]-acetate 422.498 LC-2
Ethyl (3S)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6- C24H24N2O4CIF 1.17 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 propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 453.33
452.524 LC-2 yl}-acetate
Ethyl (3S)-[6-fluoro-3-(3-p-tolyl-propionylamino)- C26H29N2O3F 1.17 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate 436.525 LC-2
Ethyl (3S)-{3-[3-(4-chloro-phenyl)-propionylamino]-
C25H26N2O3CIF 1.17 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 457.27
456.943 LC-2 acetate
Ethyl (3S)-{3-[3-(2-chloro-phenyl)-propionylaminol-
C25H26N2O3CIF 1.17 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 457.27
456.943 LC-2 acetate
Ethyl (3S)-{3-[3-(3-chloro-phenyl)-propionylaminol-
C25H26N2O3CIF 1.18 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 457.27
456.943 LC-2 acetate
Ethyl (3S)-{3-[3-(3,4-difluoro-phenyl)-
C25H25N2O3F3 1.17 propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 459.28
458.479 LC-2 carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(3-methoxy-phenyl)-
C26H29N2O4F 1.14 propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 453.33
452.524 LC-2 yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(2-methoxy-phenyl)-
C26H29N2O4F 1.16 propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 453.33
452.524 LC-2 yl}-acetate
Ethyl (3S)-[3-(2,3-diphenyl-propionylamino)-6- C31 H31 N2O3F 1.21 fluoro-1 ,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetate 498.596 LC-2
Ethyl (3S)-[3-(3,3-diphenyl-propionylamino)-6- C31 H31 N2O3F 1.2 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 butyrylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 531 .25
529.404 LC-2 carbazol-9-yl}-acetate
Ethyl (3S)-[6-fluoro-3-(4-oxo-4-phenyl-
C26H27N2O4F 1.12 butyrylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]- 451 .25
450.508 LC-2 acetate
Ethyl (3S)-{6-Fluoro-3-[4-(4-methanesulfonyl-
C27H29N2O6FS 1.07 phenyl)-4-oxo-butyrylamino]-1 ,2,3,4-tetrahydro-9/-/- 529.31
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 phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 469.04
468.52 LC-3 carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(4-hydroxy-phenyl)-
C25H27FN2O4 1.07 propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 439.06
438.49 LC-3 yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(3-hydroxy-phenyl)-
C25H27FN2O5 1.08 propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 439.06
439.49 LC-3 yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(2-hydroxy-phenyl)-
C25H27FN2O6 n. d. propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- n. d.
440.49 LC-3 yl}-acetate
Ethyl (3S)-{3-[(2,3-dihydro-1 H-indole-2-carbonyl)-
C25H26FN3O3 1.14 amino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 436.08
435.49 LC-3 yl}-acetate
Ethyl (3S)-[6-fluoro-3-(3-1 H-indol-3-yl-
C27H28FN3O3 1.15 propionylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 462.05
461.53 LC-3 yl]-acetate
Ethyl (3S)-[3-(3-1 H-benzoimidazol-2-yl-
C26H27FN4O3 0.86 propionylamino)-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 463.09
462.52 LC-3 carbazol-9-yl]-acetate
Ethyl (3S)-[3-(3-benzo[1 ,3]dioxol-5-yl-
C26H27FN2O5 1.15 propionylamino)-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 467.03
466.5 LC-3 carbazol-9-yl]-acetate Ethyl (3S)-{6-fluoro-3-[(1 H-indole-2-carbonyl)-
C25H24FN3O3 n. d. amino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- n. d.
433.47 LC-3 acetate
Ethyl (3S)-[6-fluoro-3-(3-pyridin-3-yl-
C24H26FN3O3 n. d. propionylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- n. d.
423.48 LC-3. yl]-acetate
Ethyl (3S)-{3-[2-(4-te/t-butyl-phenyl)-acetylamino]-
C28H33FN2O3 n. d. 6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- n. d.
464.57 LC-3 acetate
Ethyl (3S)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-
C25H24F4N2O3 n. d. acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- n. d.
476.46 LC-3 acetate
Ethyl (3S)-{6-fluoro-3-[2-(3-trifluoromethyl-phenyl)-
C25H24F4N2O3 1.26 acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 477.04
476.46 LC-2 acetate
Ethyl (3S)-{6-fluoro-3-[2-(4-trifluoromethyl-
C25H24F4N2O4 n. d. phenoxy)-acetylamino]-1 ,2,3,4-tetrahydro-9/-/- n. d.
492.46 LC-3. carbazol-9-yl}-acetate
Ethyl (3S)-[6-fluoro-3-(3-naphthalen-2-yl-
C29H27FN2O3 1.29 acryloylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 471.05
470.53 LC-2 yl]-acetate
Ethyl (3S)-[6-fluoro-3-(3-naphthalen-2-yl-
C29H29FN2O3 1.27 propionylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 473.08
472.55 LC-2 yl]-acetate
Ethyl (3S)-{6-fluoro-3-[methyl-(3-phenyl-propionyl)-
C26H29FN2O3 1.08 amino]- 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 437.28
436.52 LC-3 acetate
Ethyl (3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-methyl-
C25H26CIFN2O3 1.09 amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 473.08
456.94 LC-3 yl)-acetate
Ethyl (3S)-{6-fluoro-3-[ethyl-(3-phenyl-propionyl)-
C27H31 FN2O3 1.09 amino]- 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 451.23
450.55 LC-3 acetate
Ethyl (3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-ethyl-
C26H28CIFN2O3 1.1 amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 471.22
470.96 LC-3 yl)-acetate Ethyl (3S)-{6-fluoro-3-[propyl-(3-phenyl-propionyl)-
C28H33FN2O3 1.1 1 amino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 465.:
464.57 LC-3 acetate
Ethyl (3S)-(3-{[2-(4-chloro-phenyl)-acetyl]-propyl-
C27H30CIFN2O 1.12 amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 485.:
484.99 LC-3 yl)-acetate
Listed in Table 4a below are further ethyl (3-acylamino-l,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 : Formula
Ethyl (3-acylamino-1 ,2,3,4-tetrahydro-9Η- MW carbazol-9-yl)-acetate derivatives
Ethyl (3S)-{3-[3-(2,4-dimethoxy-phenyl)-
C27Η31 N2O5F propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 482.546 carbazol-9-yl}-acetate
Ethyl (3S)-[6-fluoro-3-(3-naphthalen-1 -yl-
C29H29N2O3F propionylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol- 472.555
9-yl]-acetate
Ethyl (3RS)-{6-fluoro-3-[2-(2-methoxy-phenoxy)-
C25H27N2O5F acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 454.493 yl}-acetate
Ethyl (3RS)-{6-fluoro-3-[3-(2-methylphenyl)-
C26H29N2O3F propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 436.522
9-yl}-acetate
Ethyl (3RS)-{6-fluoro-3-[3-(3-methylphenyl)-
C26H29N2O3F propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 436.522
9-yl}-acetate
Ethyl (3RS)-{6-fluoro-3-[3-(3-methoxy-phenyl)-
C26H29N2O4F propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 452.521
9-yl}-acetate Ethyl (3RS)-{6-fluoro-3-[2-(3-methoxy-phenoxy)-
C25H27N2O5F acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 454.493 yl}-acetate
Ethyl (3RS)-{6-fluoro-3-[2-(2-methylphenoxy)-
C25H27N2O4F acetylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 438.494 yl}-acetate
Ethyl (3S)-{3-[3-(2,5-dimethoxy-phenyl)-
C22H31 N2O5F propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 482.546 carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(4-trifluoromethyl-
C26H26N2O3F4 phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 490.492 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[3-(2,6-dichloro-phenyl)-
C25H25N2O3CI2F propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 491.385 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[3-(2,5-bis-trifluoromethyl-phenyl)-
C27H25N2O3F7 propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 558.489 carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(4-methylsulfanyl-
C26H29N2O3FS phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 468.588 carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(4-iodo-phenyl)-
C25H26N2O3FI propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 548.387
9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(4-isopropyl-phenyl)-
C28H33N2O3F propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 464.575
9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(3-trifluoromethyl-
C26H26N2O3F4 phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 490.492 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[3-(2,4-dichloro-phenyl)-
C25H25N2O3CI2F propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 491.385 carbazol-9-yl}-acetate Ethyl (3S)-{6-fluoro-3-[3-(4-fluoro-phenyl)-
C25H26N2O3F2 propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 440.485
9-yl}-acetate
Ethyl (3S)-{3-[3-(3,5-bis-trifluoromethyl-phenyl)-
C27H25N2O3F7 propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 558.489 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[3-(4-ethyl-phenyl)-
C27H31 N2O3F propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 450.548 carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(3-iodo-phenyl)-
C25H26N2O3FI propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 548.387
9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(4-methanesulfonyl-
C26H29N2O5FS phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 500.586 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[3-(2,3-dimethoxy-phenyl)-
C27H31 N2O5F propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 482.546 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[3-(2-bromo-phenyl)-
C25H26N2O3BrF propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 501.391 carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(3-trifluoromethoxy-
C26H26N2O4F4 phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 506.491 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[3-(2,4-dimethyl-phenyl)-
C27H31 N2O3F propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 450.548 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[3-(3-bromo-phenyl)-
C25H26N2O3BrF propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 501.391 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[3-(3-te/t-butoxycarbonylamino-
C30H36N3O5F phenyl)-propionylamino]-6-fluoro-1 , 2,3,4- 537.626 tetrahydro-9/-/-carbazol-9-yl}-acetate Ethyl (3S)-{6-fluoro-3-[(S)-3-(4-fluoro-phenyl)-2-
C31 H30N2O3F2 phenyl-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/- 528.618 carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[3-(2-fluoro-phenyl)-
C25H26N2O3F2 propionylamino]-1 ,2,3,4-tetrahydro-9/-/-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-9/-/-carbazol-9-yl)-acetate
Ethyl (3S)-(6-fluoro-3-{[(2RS)-8-methoxy-
1 ,2,3,4-tetrahydro-naphthalene-2-carbonyl]- C28H31 N2O4F amino}-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)- 478.558 acetate
Ethyl (3S)-(6-fluoro-3-{(2RS)-2-[(4-fluoro- phenylcarbamoyl)-methyl]-3-phenyl- C33H33N3O4F2 propionylamino}-1 ,2,3,4-tetrahydro-9/-/-carbazol- 573.634
9-yl)-acetate
Ethyl (3S)-{3-[(2RS)-2-benzyl-3,3-dimethyl-
C29H35N2O3F butyrylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 478.602 carbazol-9-yl}-acetate
Ethyl (3S)-(3-{[(3RS)-chroman-3-carbonyl]-
C26H27N2O4F amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 450.505
9-yl)-acetate
Ethyl (3S)-{6-fluoro-3-[3-(3-fluoro-phenyl)-
C25H26N2O3F2 propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 440.485
9-yl}-acetate
Ethyl (3S)-(6-fluoro-3-{[(1 R,2R)-2-phenyl-
C26H27N2O3F cyclopropanecarbonyl]-amino}-1 ,2,3,4- 434.506 tetrahydro-9/-/-carbazol-9-yl)-acetate Ethyl (3S)-{6-fluoro-3-[(2R)-2-methyl-3-phenyl-
C26H29N2O3F propionylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol- 436.522
9-yl}-acetate
Ethyl (3S)-[3-(2,2-dimethyl-3-phenyl- C27H31 N2O3F propionylamino)-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 450.552 carbazol-9-yl]-acetate 450.548
Ethyl (3S)-[6-fluoro-3-(3-methyl-3-phenyl-
C27H31 N2O3F butyrylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 450.548 yl]-acetate
Ethyl (3S)-{6-fluoro-3-[(3S)-3-phenyl-
C26H29N2O3F butyrylamino]-1 ,2,3,4-tetrahydro-9/-/-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-9/-/-carbazol-9-yl]-acetate 436.522
Ethyl (3S)-{3-[(2R,3R)-2,3-dihydroxy-3-(2- methoxy-phenylcarbamoyl)-propionylamino]-6- C27H30N3O7F fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 527.543 acetate
Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(2-
C26H28N2O3CIF methylphenyl)-propionylamino]-1 , 2,3,4- 470.967 tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl (3RS)-{8-chloro-6-fluoro-3-[2-(2-methoxy-
C25H26N2O5CIF phenoxy)-acetylamino]-1 ,2,3,4-tetrahydro-9/-/- 488.938 carbazol-9-yl}-acetate
Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(3-hydroxy-
C25H26N2O4CIF phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 472.939 carbazol-9-yl}-acetate Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(3-methoxy-
C26H28N2O4CIF phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 486.966 carbazol-9-yl}-acetate
Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(3-
C22H28N2O3CIF methylphenyl)-propionylamino]-1 ,2,3,4- 470.967 tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(2-hydroxy-
C25H26N2O4CIF phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 472.939 carbazol-9-yl}-acetate
Ethyl (3RS)-[8-chloro-6-fluoro-3-(3-phenyl-
C25H26N2O3CIF propionylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol- 456.94
9-yl]-acetate
Ethyl (3RS)-{8-chloro-6-fluoro-3-[3-(2-methoxy-
C26H28N2O4CIF phenyl)-propionylamino]-1 ,2,3,4-tetrahydro-9/-/- 486.966 carbazol-9-yl}-acetate
Ethyl (3RS)-{8-chloro-3-[3-(3-chloro-phenyl)-
C25H25N2O3CI2F propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 491.385 carbazol-9-yl}-acetate
Ethyl (SRSJ-p-chloro-β-fluoro-S-CS- W-indol-3-
C27H27N3O3CIF yl-propionylamino)-1 ,2,3,4-tetrahydro-9/-/- 495.977 carbazol-9-yl]-acetate
Ethyl (3RS)-{8-chloro-3-[2-(2-chloro-phenoxy)-
C24H23N2O4CI2F acetylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 493.357 carbazol-9-yl}-acetate
Ethyl (3RS)-{8-chloro-6-fluoro-3-[2-(2-
C25H26N2O4CIF methylphenyl)-oxy-acetylamino]-1 , 2,3,4- 472.939 tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl (3RS)-[3-(3-benzo[1 ,3]dioxol-5-yl-
C26H26N2O5CIF propionylamino)-8-chloro-6-fluoro-1 , 2,3,4- 500.949 tetrahydro-9/-/-carbazol-9-yl]-acetate
Ethyl (3RS)-{8-chloro-6-fluoro-3-[2-(3-methoxy-
C25H26N2O5CIF phenoxy)-acetylamino]-1 ,2,3,4-tetrahydro-9/-/- 488.938 carbazol-9-yl}-acetate Ethyl (3RS)-{8-chloro-3-[2-(3-chloro-phenoxy)-
C24H23N2O4CI2F acetylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 493.357 carbazol-9-yl}-acetate
Ethyl (3RS)-{8-chloro-3-[3-(2-chloro-phenyl)-
C25H25N2O3CI2F propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 491.385 carbazol-9-yl}-acetate
Ethyl (3RS)-[8-chloro-6-fluoro-3-(2-indan-2-yl-
C27H28N2O3CIF acetylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 482.978 yl]-acetate
Ethyl (3S)-(6-fluoro-3-{[2-(4-methoxy-phenyl)-
C26H29N2O4F acetyl]-methyl-amino}-1 ,2,3,4-tetrahydro-9/-/- 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
9/-/-carbazol-9-yl)-acetate
Ethyl (3S)-(6-fluoro-3-{[2-(2-methoxy-phenyl)-
C26H29N2O4F acetyl]-methyl-amino}-1 ,2,3,4-tetrahydro-9/-/- 452.521 carbazol-9-yl)-acetate
Ethyl (3S)-{6-fluoro-3-[(2-indan-2-yl-acetyl)-
C28H31 N2O3F methyl-amino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 462.559 yl}-acetate
Ethyl (3S)-(3-{[2-(3-chloro-phenyl)-acetyl]-
C25H26N2O3CIF methyl-amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/- 452.521 carbazol-9-yl)-acetate
Ethyl (3S)-(3-{[2-(2-chloro-phenoxy)-acetyl]-
C25H26N2O4CIF methyl-amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 472.939 carbazol-9-yl)-acetate Ethyl (3S)-(3-{[2-(4-chloro-phenoxy)-acetyl]-
C25H26N2O4CIF methyl-amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 472.939 carbazol-9-yl)-acetate
Ethyl (3S;-(6-fluoro-3-{[3-(3-methoxy-phenyl)-
C27H31 N2O4F propionyl]-methyl-amino}-1 ,2,3,4-tetrahydro-9/-/- 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
9/-/-carbazol-9-yl)-acetate
Ethyl (3S)-{3-[(3,3-diphenyl-propionyl)-methyl-
C32H33N2O3F amino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 512.619
9-yl}-acetate
Ethyl (3S)-(6-fluoro-3-{[3-(2-methoxy-phenyl)-
C27H31 N2O4F propionyl]-methyl-amino}-1 ,2,3,4-tetrahydro-9/-/- 466.547 carbazol-9-yl)-acetate
Ethyl (3S)-{6-fluoro-3-[(3-1 H-indol-3-yl-
C28H30N3O3F propionyl)-methyl-amino]-1 ,2,3,4-tetrahydro-9/-/- 475.558 carbazol-9-yl}-acetate
Ethyl (3S)-{3-[(2-benzyloxy-acetyl)-methyl-
C26H29N2O4F amino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 452.521
9-yl}-acetate
Ethyl (3S)-{3-[(2,3-diphenyl-propionyl)-methyl-
C32H33N2O3F amino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-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-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-{3-[acetyl-(3-phenyl-propyl)-amino]-6-
C27H31 N2O3F fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 450.548 acetate
Ethyl (3S)-{3-[cyclopropylmethyl-(3-phenyl-
C29H33N2O3F propionyl)-amino]-6-fluoro-1 ,2,3,4-tetrahydro- 476.586
9/-/-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-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-(3-{cyclopropylmethyl-[3-(2-methoxy-
C30H35N2O4F phenyl)-propionyl]-amino}-6-fluoro-1 , 2,3,4- 506.612 tetrahydro-9/-/-carbazol-9-yl)-acetate
Ethyl (3S)-(3-{[2-(3-chloro-phenoxy)-acetyl]-
C28H30N2O4CIF cyclopropylmethyl-amino}-6-fluoro-1 , 2,3,4- 513.003 tetrahydro-9/-/-carbazol-9-yl)-acetate
Ethyl (3S;-{3-[cyclopropylmethyl-(3,3-diphenyl-
C35H37N2O3F propionyl)-amino]-6-fluoro-1 ,2,3,4-tetrahydro- 552.684
9/-/-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-9/-/-carbazol-9-yl)-acetate
Ethyl (3S)-(6-fluoro-3-{propionyl-[2-(4-
C28H30N2O4F4 trifluoromethyl-phenoxy)-ethyl]-amino}-1 ,2,3,4- 534.544 tetrahydro-9/-/-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-9/-/-carbazol-9-yl)-acetate
Ethyl (3S)-(6-fluoro-3-{[3-(2-methoxy-phenyl)- propionyl]-[2-(4-trifluoromethyl-phenoxy)-ethyl]- C35H36N2O5F4 amino}-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)- 640.668 acetate
Ethyl (3S)-{6-fluoro-3-[(2-phenoxy-ethyl)-(3-
C33H35N2O4F phenyl-propionyl)-amino]-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/-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-9/-/-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-9/-/- 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-9/-/-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-9/-/-carbazol-9-yl)-acetate
Ethyl (3S)-{3-[[2-(3-chloro-phenoxy )-acetyl]-(2-
C27H30N2O5CIF methoxy-ethyl)-amino]-6-fluoro-1 , 2,3,4- 516.991 tetrahydro-9/-/-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-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[(2-methoxy-ethyl)-(2-
C31 H33N2O4F naphthalen-1-yl-acetyl)-amino]-1 , 2,3,4- 516.607 tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-(6-fluoro-3-{[(2S)-2-methyl-3-phenyl- propionyl]-phenethyl-amino}-1 ,2,3,4-tetrahydro- C34H37N2O3F 9/-/-carbazol-9-yl)-acetate 540.673
Ethyl (3S)-(6-fluoro-3-{[3-(2-methoxy-phenyl)-
C34H37N2O4F propionyl]-phenethyl-amino}-1 ,2,3,4-tetrahydro- 556.672
9/-/-carbazol-9-yl)-acetate Ethyl (3S)-[3-(acetyl-phenethyl-amino)-6-fluoro- C26H29N2O3F 1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetate 436.522
Ethyl (3S)-{6-fluoro-3-[(2-naphthalen-1-yl-
C36H35N2O3F acetyl)-phenethyl-amino]-1 ,2,3,4-tetrahydro-9/-/- 562.679 carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[phenethyl-(3-phenyl-
C33H35N2O3F propionyl)-amino]-1 ,2,3,4-tetrahydro-9/-/- 526.646 carbazol-9-yl}-acetate
Ethyl (3S)-[3-(3-benzyl-1 -naphthalen-1 -ylmethyl-
C35H34N3O3F ureido)-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 563.667
9-yl]-acetate
Ethyl (3S)-[3-(benzyloxycarbonyl-naphthalen-1 -
C35H31 N2O4F ylmethyl-amino)-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 564.651 carbazol-9-yl]-acetate
Ethyl (3S)-{6-fluoro-3-[naphthalen-1-ylmethyl-(3-
C36H35N2O3F phenyl-propionyl)-amino]-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/-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-9/-/-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-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-[3-(acetyl-naphthalen-1 -ylmethyl-
C29H29N2O3F amino)-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 472.555
9-yl]-acetate
Ethyl (3S)-[6-fluoro-3-(naphthalen-1 -ylmethyl-
C30H31 N2O3F propionyl-amino)-1 ,2,3,4-tetrahydro-9/-/- 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-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-[6-fluoro-3-(3-thiophen-2-yl-
C23H25FN2O3S propionylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol- 428.012
9-yl]-acetate
Ethyl (3S)-{3-[3-(3-chloro-isoxazol-5-yl)-
C22H23CIFN3O4 propionylamino]-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 447.88 carbazol-9-yl}-acetate
Ethyl (3Sj-[6-Fluoro-3-(3-pyrimidin-2-yl-
C23H25FN4O3 propionylamino)-1 ,2,3,4-tetrahydro-9/-/-carbazol- 424.46
9-yl]-acetate
Ethyl (3S)-(3-{acetyl-[2-(2-fluoro-phenyl)-ethyl]-
C26H28F2N2O3 amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 454.51
9-yl)-acetate
Ethyl (3S)-(3-{acetyl-[2-(3-fluoro-phenyl)-ethyl]-
C26H28F2N2O3 amino}-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 454.51
9-yl)-acetate
Ethyl (3S)-(3-{cyclohexylmethyl-[3-(2-methoxy-
C33H41 N2O4F phenyl)-propionyl]-amino}-6-fluoro-1 , 2,3,4- 548.693 tetrahydro-9/-/-carbazol-9-yl)-acetate
General Method for the Preparation of Intermediates of Structure 1 , wherein R4 represents Cr-fi-alkyl or allyl
To a stirred and degassed solution of an appropriately protected ethyl (3-amino-8-bromo- l,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 tetraCi_5-alkyltin or allyltrialkyltin, respectively (0.22 mmol, 1.1 eq.). The reaction mixture is allowed to stir overnight at 1100C. 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-Ci_5-alkyl-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetate derivative or ethyl (3-amino-8-allyl-l,2,3,4-tetrahydro-9H-carbazol- 9-yl)-acetate derivative of Structure 1, respectively.
Intermediates of Structure 1 wherein R4 represents Ci_5-alkyl or allyl: Ethyl (35)-(3-benzyloxycarbonylamino-6-fluoro-8-methyl-l,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+Η]+.
Ethyl (35)-(3-benzyloxycarbonylamino-6-fluoro-8-allyl-l,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+Η]+.
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-l,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-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetate derivatives of Structure 1.
Intermediate of Structure 1 wherein R4 represents vinyl:
Ethyl (35)-(3-benzyloxycarbonylamino-6-fluoro-8-vinyl-l,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+Η]+.
General Method for the Preparation of Intermediates of Structure 1 wherein R4 represents
Figure imgf000098_0001
A solution of an appropriately protected ethyl (3-amino-8-bromo-l,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 methanesulfmate (129 mg, 1.073 mmol, 4.5 eq.) in degassed NMP (5 ml) is heated under inert atmosphere at 1400C 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-l,2,3,4-tetrahydro- 9H-carbazol-9-yl)-acetate derivative of Structure 1.
Intermediate of Structure 1 wherein R4 represents Ci_6-alkylsulfonyl:
Ethyl (3i?5)-(3-benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl-l,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+Η]+.
General Methods for the Preparation of Intermediates of Structure 2a:
R5
Nh
R1
OR
Structure 2a : R5 ≠ H
2b : R5= H
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-tetrahvdro-9/-/-carbazol-9-yll-acetate derivative of Structure 3a:
A catalytical amount of DMAP and /?-nitrobenzenesulfonyl chloride (223 mg, 1.01 mmol) are added to an ice cold stirred solution of the appropriate (3-amino-l,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 (35)-[6-fluoro-3-(4-nitro-benzenesulfonylamino)- l,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+Η]+.
Step B) Λ/-Substitution of a 4-nitro-benzenesulfonamide intermediate of Structure 3a to yield intermediates of Structure 3b:
Following a procedure described in the literature (Peiia, 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 700C for 30 min before adding the corresponding alkylating agent R5 -L (0.841 mmol). The reaction mixture is continued to stir at 700C 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
Intermediates of Structure 3b Formula tR [min] MS Data
MW Meth. m/z [M+H]+
Ethyl (3S)-{6-fluoro-3-[methyl-(4-nitro-
C23H24N3O6F 1.09 benzenesulfonyl)-amino]-1 ,2,3,4-tetrahydro- 490.05
489.52 (LC-3)
9H-carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[ethyl-(4-nitro-
C24H26N3O6FS 1.1 1 benzenesulfonyl)-amino]-1 ,2,3,4-tetrahydro- 504.15
503.549 LC-3
9H-carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[propyl-(4-nitro-
C25H28N3O6FS 1.13 benzenesulfonyl)-amino]-1 ,2,3,4-tetrahydro- 518.23
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
Intermediates of Structure 3b Formula tR [min] MS Data
MW Method m/z
[M+H]+
Ethyl (3S)-{6-fluoro-3-[(4-nitro-
C31 H32N3O6FS 1.16 benzenesulfonyl)-(3-phenyl-propyl)-amino]- 594.12
593.674 LC-3
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl (3S){-3-[cyclopropylmethyl-(4-nitro-
C26H28N3O6FS 1.12 benzenesulfonyl)-amino]-6-fluoro-1 ,2,3,4- 530.02
529.587 LC-3 tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-(6-fluoro-3-{(4-nitro- benzenesulfonyl)-[2-(3-trifluoromethyl- C31 H29N3O7F4S 1.17
664.17 phenoxy)-ethyl]-amino}-1 ,2,3,4-tetrahydro-9/-/- 663.643 LC-3 carbazol-9-yl)-acetate
Ethyl (3S)-{6-fluoro-3-[(4-nitro-
C30H30N3O7FS 1.14 benzenesulfonyl)-(2-phenoxy-ethyl)-amino]- 596.18
595.646 LC-3
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-{6-fluoro-3-[(2-methoxy-ethyl)-(4-
C25H28N3O7FS 1.09 nitro-benzenesulfonyl)-amino]-1 , 2,3,4- 534.16
533.575 LC-3 tetrahydro-9/-/-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 tic 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.
Intermediates of Structure 2a Formula tR [min] MS Data
MW Method m/z [M+H]+
Ethyl (3S)-(6-fluoro-3-methylamino-1 ,2,3,4- C17H21 FN2O2 0.76
305.19 tetrahydro-9/-/-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-9/-/-carbazol-9-yl)-acetate 332.41 LC-3
Table 6
Listed in Table 6a below are further intermediates of Structure 2a, prepared according to the abovementioned method. Table 6a
Intermediates of Structure 2a Formula tR [mm] MS Data
MW LC-MS m/z
Method [M+H]+
Ethyl (3S)-[6-fluoro-3-(3-phenyl-propylamino)- C25H29N2O2F 0.91
409.15
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetate 408.515 LC-3
Ethyl (3S)-[3-(cyclopropylmethyl-amino)-6-
C20H25N2O2F 0.82 fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]- 345.18 344.428 LC-3 acetate
Ethyl (3S)-{6-fluoro-3-[2-(4-trifluoromethyl-
C25H26N2O3F4 0.95 phenoxy)-ethylamino]-1 ,2,3,4-tetrahydro-9/-/- 479.07 478.484 LC-3 carbazol-9-yl}-acetate
Ethyl (3S)-[6-fluoro-3-(2-phenoxy-ethylamino)- C24H27N2O3F 0.88
41 1.10
1 ,2,3,4-tetrahydro-9/-/-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-9/-/-carbazol-9-yl]-acetate 348.417 LC-3
Method (B)
To a stirred suspension of an appropriate ethyl (3-amino-l,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
Intermediates of Structure 2a Formula tR [min] MS Data
MW LC-MS m/z
Method [M+H]+
Ethyl (3S)-(6-fluoro-3-phenethylamino-1 ,2,3,4- C24H27N2O2F 0.88
395.18 tetrahydro-9/-/-carbazol-9-yl)-acetate 394.488 LC-3
Ethyl (3S)-{6-fluoro-3-[(naphthalen-1 -ylmethyl)-
C27H27N2O2F 0.91 amino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}- 431.22 430.521 LC-3 acetate
Ethyl (3S)-(3-benzylamino-6-fluoro-1 ,2,3,4- C23H25N2O2F 0.89
381.16 tetrahydro-9/-/-carbazol-9-yl)-acetate 380.461 LC-3
Ethyl (3S)-{6-fluoro-3-[2-(2-fluoro-phenyl)-
C24H26N2O2F2 0.88 ethylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 413.14 412.478 LC-3 yl}-acetate
Ethyl (3S)-{6-fluoro-3-[2-(3-fluoro-phenyl)-
C24H26N2O2F2 0.88 ethylamino]-1 ,2,3,4-tetrahydro-9/-/-carbazol-9- 413.14 412.478 LC-3 yl}-acetate
Ethyl (3S)-[3-(cyclohexylmethyl-amino)-6-fluoro- CC2233HH3311 NN22OO22FF 0.88
387.20
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl]-acetate 386.509 LC-3 General Procedures for the Preparation of Intermediates of Structure 2b:
Figure imgf000104_0001
Structure 2b 2c
Cleavage of PG= terf-butoxycarbonyl
To a stirred solution of an ethyl (3-tert-butoxycarbonylamino-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetate derivative of Structure 2c (1.61 mmol) in TΗF (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
Intermediates of Structure 2b Formula tR [min] MS Data
MW Method m/z [M+H]+ (parent)
Ethyl (3R)-(3-amino-1 ,2,3,4-tetrahydro-9Η- C16Η21 N2O2CI 0.74
273.16 carbazol-9-yl)-acetate hydrochloride 308.807 LC-2
Ethyl (3S)-(3-amino-1 ,2,3,4-tetrahydro-9H- C16H21 N2O2CI 0.74
273.16 carbazol-9-yl)-acetate hydrochloride 308.807 LC-2
Ethyl (3R)-(3-amino-6-fluoro-1 ,2,3,4-
C16H20CIFN2O2 0.74 tetrahydro-9H-carbazol-9-yl)-acetate 291.15 326.79 LC-2 hydrochloride
Ethyl (3S)-(3-amino-6-fluoro-1 ,2,3,4-
C16H20N2O2CIF 0.73 tetrahydro-9H-carbazol-9-yl)-acetate 291.11 326.79 LC-2 hydrochloride Cleavage of PG= benzyloxycarbonyl
To a stirred solution of an ethyl (3-benzyloxycarbonylamino-l,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 Ih 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
Intermediates of Structure 2b Formula tR [min] MS Data
MW LC-MS m/z
Method [M+H]+
Ethyl (3RS)-(3-amino-8-chloro-6-fluoro-1 ,2,3,4- C16H19N2O2CI2F 0.78
325.05 tetrahydro-carbazol-9-yl)-acetate hydrochloride 361.243 LC-3
Ethyl (3RS)-(3-amino-6-fluoro-1 ,2,3,4- C20H19N2O2F 1.02
339.12 tetrahydro-carbazol-9-yl)-acetate hydrochloride 338.381 LC-3
General Method for the Synthesis of Intermediates of Structure 2c:
Figure imgf000105_0001
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 (600C) 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 6O0C 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
Intermediates of Structure 2c Formula tR [min] MS Data
MW LC-MS m/z
Method [M+Na]+ or [M+H]+
Ethyl (3R)-(3-tert-
C21 H28N2O4 1.15 butoxycarbonylamino-1 ,2,3,4- 394.95
372.463 LC-2 tetrahydro-9/-/-carbazol-9-yl)-acetate
Ethyl (3S)-(3-tert-
C21 H28N2O4 1.15 butoxycarbonylamino-1 ,2,3,4- 395.15
372.463 LC-2 tetrahydro-9/-/-carbazol-9-yl)-acetate
Ethyl {3R)-{3-tert- butoxycarbonylamino-6-fluoro- C21 H27FN2O4 1.15
413.09 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)- 390.45 LC-2 acetate
Ethyl (3S)-(3-tert- butoxycarbonylamino-6-fluoro- C21 H27FN2O4 1.16
413.09 1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)- 390.45 LC-2 acetate
Ethyl {3RS)-{3- benzyloxycarbonylamino-δ-chloro-δ- C24H24N2O4CIF 1.11
458.99 fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 458.916 LC-3
9-yl)-acetate
Ethyl (3RS)-(3-
C24H25N2O4F 1.06 benzyloxycarbonylamino-6-fluoro- 425.22
424.47 LC-3
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)- acetate
Ethyl (3/?S)-(3- benzyloxycarbonylamino-δ-chloro-θ- C24H24N2O4CIF 1.11
459.05 fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 458.916 LC-3
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
Intermediates of Structure 2c Formula tR [min] MS Data
MW LC-MS m/z [M+H]+
Method
Ethyl (3RS)-(3-benzyloxycarbonylamino-6-
C25H25N2O4F3 1.1 1 trifluoromethyl-1 ,2,3,4-tetrahydro-9/-/-carbazol- 475.14
474.478 LC-3
9-yl)-acetate
Ethyl (3RS)-(3-benzyloxycarbonylamino-8-
C24H24N2O4BrF 1.1 1 bromo-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol- 505.11
503.367 LC-3
9-yl)-acetate
Ethyl (3S)-(3-benzyloxycarbonylamino-7-
C24H24CIFN2O4 not not chloro-6-fluoro-1 ,2,3,4-tetrahydro-9/-/-carbazol-
458.91 determined determined
9-yl)-acetate
Ethyl (3R)-(3-benzyloxycarbonylamino-8-
C24H25N2O4CI 1.1 chloro-1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl)- 441.07
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 at., Bulletin of the Korean Soc. Chem. 2004, 25, 1784-1790). Table 9
Intermediates of Structure 4 Formula tR [min] MS Data
MW Method m/z [M+H]+
(3RS)-(8-Chloro-5-fluoro-2,3,4,9-
C20H18N2O2CIF 1.07 tetrahydro-1 H-carbazol-3-yl)- 373.03
372.825 LC-3 carbamic acid benzyl ester (3RS)-(8-Chloro-6-fluoro-2,3,4,9-
C20H18N2O2CIF 1.06 tetrahydro-1 H-carbazol-3-yl)- 372.99
372.825 LC-3 carbamic acid benzyl ester
(3RS)-(6-Fluoro-2,3,4,9-tetrahydro-
C20H19N2O2F 1.02 IH-carbazol-S-yh-carbamic acid 339.12
338.38 LC-3 benzyl ester
Listed in Table 9a below are further intermediates of Structure 4, prepared according to the abovementioned procedure. Table 9a
Intermediates of Structure 4 Formula tR [min] MS Data
MW Method m/z
[M+H]+
(3RS)-(6-Trifluoromethyl-2,3,4,9-
C21 H19N2O2F3 1.07 tetrahydro-1 H-carbazol-3-yl )- 389.08 388.388 LC-3 carbamic acid benzyl ester (3RS)-(8-Bromo-6-fluoro-2,3,4,9-
C20H18N2O2BrF 1.07 tetrahydro-1 H-carbazol-3-yl )- 417.03 417.277 LC-3 carbamic acid benzyl ester (3RS)-(7-Chloro-6-fluoro-2,3,4,9-
C20H18N2O2CIF 1.05 tetrahydro-1 H-carbazol-3-yl )- 373.07 372.825 LC-3 carbamic acid benzyl ester (3R)-(8-Chloro-2,3,4,9-tetrahydro-
C20H19N2O2CI 1.05 1 H-carbazol-3-yl)-carbamic acid 355.11 354.836 LC-3 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, 1.5eq.) and DIEA (0.048 ml, 0.280 mmol, 3 eq.) in 0.5 ml (DMF/THF 4:1) is added a solution of an intermediate of Structure 8a in 0.5 ml (DMF/THF 4:1). The reaction mixture is stirred for 2Oh, then diluted with DCM and sat. NaHCO3 solution. After stirring for an additional Ih, 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
Intermediates of Structure 1 starting from Formula tR [min] MS Data intermediates of Structure 8a MW LC-MS m/z
Method [M+H]+
Ethyl (3S)-{3-[(RS)-2-benzyl-3-(2- methylbenzyl)-carbamoyl-propionylamino]-6- C34H36FN3O4 1.06
570.21 fluoro-1 ,2,3,4-tetrahydro-9H-carbazol-9-yl}- 569.67 LC-3 acetate
Ethyl (3S)-{3-[(RS)-2-benzyl-3-(3-methoxy-
C34H36FN3O5 1.06 phenylcarbamoyl)-propionylamino]-6-fluoro- 586.21 585.67 LC-3
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-{3-[(RS)-2-benzyl-3-(4-chloro-
C33H33CIFN3O4 1.09 phenylcarbamoyl)-propionylamino]-6-fluoro- 590.2 590.08 LC-3
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl (3S)-{3-[(RS)-2-benzyl-3-(4-fluoro-
C34H35F2N3O4 1.05 benzylcarbamoyl)-propionylamino]-6-fluoro- 588.25 587.66 LC-3
1 ,2,3,4-tetrahydro-9/-/-carbazol-9-yl}-acetate
Ethyl [(3S)-3-((RS)-2-benzyl-3-propylcarbamoyl-
C30H36FN3O4 1 propionylamino)-6-fluoro-1 ,2,3,4-tetrahydro-9/-/- 522.26 521.62 LC-3 carbazol-9-yl]-acetate
General Method for the Preparation of Intermediates of Structure 8a from intermediates of Structure 8b
Figure imgf000110_0001
Structure 8a, wherein R' represents H and R represents Ci_4-alkyl 8b, wherein R and R independently represent Ci_4-alkyl
A solution of an intermediate of Structure 8b (0.54 mmol) and TFA (0.8 ml, 10 mmol, 20 eq.) in DCM (8 ml) is stirred for 2.5h. The volatiles are removed under reduced pressure to yield an intermediate of Structure 8a.
Intermediate of Structure 8a: 3-benzyl-Λ/-(9-ethoxycarbonylmethyl-6-fluoro-2,3,4,9- tetrahydro-lH-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 Ci_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-iH-carbazol-3-yl)- succinamic acid tert-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+Η]+.
Starting materials:
Starting materials of Structure 4:
(3i?)-(2,3,4,9-tetrahydro-lH-carbazol-3-yl)-carbamic acid 1,1-dimethylethyl ester,
(35)-(2,3,4,9-tetrahydro-lH-carbazol-3-yl)-carbamic acid 1,1-dimethylethyl ester, (3i?)-(6-fluoro-2,3,4,9-tetrahydro-lH-carbazol-3-yl)-carbamic acid 1,1-dimethylethyl ester, and
(35)-(6-fluoro-2,3,4,9-tetrahydro-lH-carbazol-3-yl)-carbamic acid 1,1-dimethylethyl ester; as well as
Starting materials of Structure 7: (3i?)-(2,3,4,9-tetrahydro-lH-carbazol-3-ylamine),
(35)-(2,3,4,9-tetrahydro-lH-carbazol-3-ylamine),
(3i?)-(6-fluoro-2,3,4,9-tetrahydro-lH-carbazol-3-ylamine), and
(35)-(6-fiuoro-2,3,4,9-tetrahydro-lH-carbazol-3-ylamine), are prepared according to literature procedures (Rosentreter U. et ah, 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
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
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 -800C. 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 -200C.
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, 220O00 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 unspecifϊc 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
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Intracellular calcium mobilization assay (FLIPR):
Cells (ΗEK-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 λex=488 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)ΛD)))) and to calculate the IC50 values.

Claims

Claims:
1. A compound of Formula I :
Figure imgf000120_0001
wherein
R1, R2, R3 and R4 independently represent hydrogen, Ci_5-alkyl, Ci_5-alkoxy, alkenyl, halogen, nitro, cyano, halo-Ci_6-alkoxy, halo-Ci_6-alkyl, Ci_6-alkylsulfonyl, or formyl;
R5 represents hydrogen, alkenyl, Ci_6-alkyl, cycloalkyl-Ci_4-alkyl, Ci_3-alkoxy-Ci_4-alkyl, aryl-Ci_4-alkyl, or aryloxy-Ci_4-alkyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy; and
R6 represents Ci_9-alkylaminocarbonyl; Ci_9-alkylaminothiocarbonyl; Ci_9-alkylcarbonyl; Ci_9-alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; arylaminothiocarbonyl; aryl- C i_3-alkoxy-C i_3-alkoxycarbonyl; aryl-C i_3-alkoxycarbonyl; aryl-Ci_3-alkylaminocarbonyl; aryl-Ci_6-alkylcarbonyl; aryl-Ci_3-alkoxy-Ci_3-alkylcarbonyl; arylcarbonyl; arylcarbonyl- Ci_4-alkylcarbonyl; aryloxy-Ci_3-alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl- Ci_3-alkylcarbonyl; diaryl-Ci_3-alkylcarbonyl; heterocyclylcarbonyl; heteroaryl- Ci_3-alkylcarbonyl; heteroarylcarbonyl; aryl-C3_6-cycloalkylcarbonyl; cycloalkylcarbonyl; or R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_4-alkyl group may additionally be mono- substituted with aryl or disubstituted with hydroxy, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl, Ci_6-alkylaminocarbonyl, or aryl-Ci_3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy; Ci_6-alkoxy; Ci_6-alkyl; Ci_6-alkylsulfonyl; phenyl which is unsubstituted, mono- or di-substituted by substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl; phenyl-Ci_3-alkyl, wherein the phenyl group is unsubstituted, mono- or di-substituted with substituents independently selected from halogen, trifluoromethyl, methoxy and methyl; naphthyl-Ci_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-Ci_6-alkyl; halo-Ci_6-alkoxy; Ci_6-alkylthio; and Ci_4-alkoxycarbonylamino; or a salt of such a compound.
2. A compound according to claim 1, wherein R1, R3 and R4 represent hydrogen; or a salt of such a compound.
3. A compound according to claim 1 or 2, wherein R2 represents hydrogen, trifluoromethyl, or halogen; or a salt of such a compound.
4. A compound according to any one of claims 1 to 3, wherein R5 represents hydrogen; Ci_3-alkyl; cyclopropylmethyl; 2-methoxyethyl; phenyl-C2-3-alkyl; or phenoxyethyl, wherein the phenyl group is unsubstituted, or mono-substituted with a group selected from Ci_2-alkylendioxy, Ci_4-alkoxy, Ci_4-alkyl, halogen, trifluoromethyl, and trifluoromethoxy; or a salt of such a compound.
5. A compound according to any one of claims 1 to 4, wherein R6 represents Ci_g- alkylaminocarbonyl; Ci_9-alkylcarbonyl; Ci_9-alkoxycarbonyl; arylalkenylcarbonyl; arylaminocarbonyl; aryl-Ci_3-alkoxy-Ci_3-alkoxycarbonyl; aryl-Ci_3-alkoxycarbonyl; aryl- Ci_3-alkylaminocarbonyl; aryl-Ci_6-alkylcarbonyl; aryl-Ci_3-alkoxy-Ci_3-alkylcarbonyl; arylcarbonyl; arylcarbonyl-C^-alkylcarbonyl; aryloxy-C^-alkylcarbonyl; arylsulfonylaminocarbonyl; cycloalkyl-C^-alkylcarbonyl; diaryl-Ci_3-alkylcarbonyl; heterocyclylcarbonyl; heteroaryl-C^-alkylcarbonyl; heteroarylcarbonyl; aryl- C3-6-cycloalkylcarbonyl; cycloalkylcarbonyl; or R7-Ci_4-alkylcarbonyl, wherein the bridging Ci_4-alkyl group may additionally be mono-substituted with aryl, and R7 represents arylaminocarbonyl, heteroarylaminocarbonyl, Ci_6-alkylaminocarbonyl, or aryl- C i_3-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_6-alkylsulfonyl, halogen, hydroxy, halo- Ci_6-alkyl, halo-Ci_6-alkoxy, Ci_6-alkylthio, and Ci_4-alkoxycarbonylamino; or a salt of such a compound.
6. A compound according to any one of claims 1 to 4, wherein R6 represents aryl- Ci_2-alkoxycarbonyl; aryl-Ci_2-alkylaminocarbonyl; aryl-Ci_4-alkylcarbonyl; aryloxy- Ci_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 Ci_4-alkylaminocarbonyl; wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_2-alkylendioxy, Ci_6-alkoxy, Ci_6-alkyl, Ci_6-alkylsulfonyl, halogen, hydroxy, trifluoromethyl, and trifluoromethoxy; or a salt of such a compound.
7. A compound according to any one of claims 1 to 6, wherein, in case R6 represents a group which contains a carbonyl group and one or more aryl moieties, said group is such that it contains a bridging group between the carbonyl group and said aryl moiety (moieties) of said R6, wherein the carbonyl moiety and at least one of the aryl moieties are directly attached to different atoms of said bridging group; or a salt of such a compound.
8. A compound according to any one of claims 1 to 3, wherein
R6 represents Ci_4-alkylcarbonyl; or aryl-C2-4-alkylcarbonyl, wherein aryl is unsubstituted, mono- or di-substituted with a group independently selected from Ci_4-alkoxy, Ci_4-alkyl, halogen, and trifluoromethyl; and R5 represents phenyl-C2_3-alkyl; or a salt of such a compound.
9. A compound according to claim 1 selected from the group consisting of:
(35)-[3-(3,3-diphenyl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-{3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-[6-fluoro-3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-{3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-(3-isobutoxycarbonylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-[6-fluoro-3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-{3-[3-(4-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-(3-benzyloxycarbonylamino-6-fluoro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(3-benzyloxycarbonylamino-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{3-[2-(4-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(3i?)-{3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-[6-fiuoro-3-(4-oxo-4-phenyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(35)-[6-fluoro-3-(2-indan-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{3-[(2,3-dihydro-lH-indole-2-carbonyl)-amino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-(3-{[2-(4-chloro-phenyl)-acetyl]-ethyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(3i?)-(3-propoxycarbonylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (3i?)-[6-fluoro-3-(2-/?-tolyloxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{6-fluoro-3-[methyl-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (3S)-[6-fluoro-3-(3-lH-indol-3-yl-propionylamino)-l,2,3,4-tetrahydro-9Η-carbazol-9-yl]- acetic acid;
(35)-[3-(3-benzo[l,3]dioxol-5-yl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-
9-yl] -acetic acid;
(35)-{6-fluoro-3-[ethyl-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(35)-{3-[2-(4-chloro-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(35)-[3-(2,3-diphenyl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-[6-fluoro-3-(2-phenoxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{3-[3-(3,4-difluoro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-[3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[3-(2-benzyloxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-{6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-{6-fluoro-3-[propyl-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-[3-(2-benzyloxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-(3-benzyloxycarbonylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-{6-fluoro-3-[2-(4-methoxy-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{3-[3-(4-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-{3-[4-(4-bromo-phenyl)-4-oxo-butyrylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-(3-{[2-(4-chloro-phenyl)-acetyl]-propyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (3i?)-(3-phenylacetylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-{3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-fluoro-3-[2-(4-trifluoromethyl-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-(6-fluoro-3-phenylacetylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-[3-(3-lH-benzoimidazol-2-yl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid;
(35)-{6-fluoro-3-[3-(4-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-[6-fluoro-3-(2-/?-tolyloxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-[6-fluoro-3-(2-/?-tolyl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-{3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-[3-(2-phenoxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[6-fluoro-3-(3-/?-tolyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-(3-benzyloxycarbonylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-[6-fluoro-3-(2-/?-tolyl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-[3-(2-benzyloxy-ethoxycarbonylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[6-fluoro-3-(3-naphthalen-2-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid; (35)-{6-fluoro-3-[4-(4-methanesulfonyl-phenyl)-4-oxo-butyrylamino]-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid;
(35)-(3-{[2-(4-chloro-phenyl)-acetyl]-methyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (35)-[3-(3-phenylsulfonyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{6-fluoro-3-[3-(4-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(3i?)-[3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-{3-[2-(4-chloro-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(3i?)-[6-fluoro-3-(3-/?-tolyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-{6-fluoro-3-[3-(4-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol- 9-yl} -acetic acid;
(35)-{6-fluoro-3-[3-(4-hydroxy-3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid;
(35)-{6-fluoro-3-[2-(3-trifluoromethyl-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{6-fluoro-3-[2-(4-methoxy-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{3-[2-(3-chloro-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(35)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-(3-tert-butoxycarbonylamino- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-{3-[2-(3,4-dichloro-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-(3-isobutoxycarbonylamino-l,2,3,4-tetrahydro-9Η-carbazol-9-yl)-acetic acid; (35)-{6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-[6-fluoro-3-(2-phenoxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(2-benzyloxy-ethoxycarbonylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(2-phenoxy-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-(3-propoxycarbonylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-[3-(2-thiophen-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-(3-phenylacetylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-[3-(3-phenylsulfonyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-benzyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[3-(3-naphthalen-l-yl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-(3-decanoylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-[6-fluoro-3-(3-naphthalen-2-yl-acryloylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(35)-{3-[2-(4-tert-butyl-phenyl)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (3i?)-(3-benzyloxycarbonylamino-8-chloro-6-fluoro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-benzyloxycarbonylamino-8-chloro-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-[6-fluoro-3-(3-pyridin-3-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(3i?)-[3-(3-benzyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-methyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-{6-fluoro-3-[2-(4-trifluoromethyl-phenyl)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-[3-(3-phenyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-cyclopentyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[3-(2-thiophen-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-(3-butyrylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-(3-benzyloxycarbonylamino-8-chloro-5-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-benzyloxycarbonylamino-8-chloro-5-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-heptanoylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-[3-(3-cyclopentyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-(3-decanoylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-(3-benzoylamino-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3i?)-[3-(3-butyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-{6-fluoro-3-[(lH-indole-2-carbonyl)-amino]-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid;
(3i?)-[3-(3-methyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-[3-(3-butyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; or a salt of such a compound.
10. A compound according to claim 1 selected from the group consisting of:
(3i?)-[3-(3-Benzyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-Benzyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-[6-Fluoro-3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-[3-(3-Benzyl-ureido)-8-chloro-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[3-(3-Benzyl-ureido)-8-chloro-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (3i?)-[8-Chloro-6-fluoro-3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[8-Chloro-6-fluoro-3-(3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-6-trifluoromethyl- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-Benzyloxycarbonylamino-6-trifluoromethyl-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-8-bromo-6-fluoro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)- acetic acid; (35)-(3-Benzyloxycarbonylamino-8-bromo-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-6-fluoro-8-vinyl- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(3-Benzyloxycarbonylamino-6-fluoro-8-vinyl-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl- 1 ,2,3 ,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (35)-(3-Benzyloxycarbonylamino-6-fluoro-8-methanesulfonyl-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(3-Benzyloxycarbonylamino-6-fluoro-8-methyl-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid; (35)-(3-Benzyloxycarbonylamino-7-chloro-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(35)-(8-Allyl-3-benzyloxycarbonylamino-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl)- acetic acid;
(3i?)-(3-Benzyloxycarbonylamino-8-chloro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{3-[3-(2,4-Dimethoxy-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-[6-Fluoro-3-(3-naphthalen-l-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid; (3i?)-{6-Fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{6-Fluoro-3-[3-(2-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(2-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{6-Fluoro-3-[3-(3-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-{6-Fluoro-3-[3-(3-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{6-Fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol- 9-yl} -acetic acid;
(3i?)-{6-Fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-{6-Fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(3i?)-{6-Fluoro-3-[2-(2-methylphenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-{6-Fluoro-3-[2-(2-methylphenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[3-(2,5-Dimethoxy-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(4-trifluoromethyl-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[3-(2,6-Dichloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[3-(2,5-Bis-trifluoromethyl-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid; (35)-{6-Fluoro-3-[3-(4-methylsulfanyl-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(4-iodo-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(4-isopropyl-phenyl)-propionylamino]-l,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;
(35)-{3-[3-(2,4-Dichloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{6-Fluoro-3-[3-(4-fluoro-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[3-(3,5-Bis-trifluoromethyl-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid;
(35)-{3-[3-(4-Ethyl-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(3-iodo-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-{6-Fluoro-3-[3-(4-methanesulfonyl-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[3-(2,3-Dimethoxy-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{3-[3-(2-Bromo-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(3-trifluoromethoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[3-(2,4-Dimethyl-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[3-(3-Bromo-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[3-(3-fert-Butoxycarbonylamino-phenyl)-propionylamino]-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid; (35)-{6-Fluoro-3-[(5)-3-(4-fluoro-phenyl)-2-phenyl-propionylamino]-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[(5)-3-(4-methoxy-phenyl)-2-phenyl-propionylamino]-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[3-(2-fluoro-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-(6-Fluoro-3-{[(2i?5)-l,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{[(2i?5)-8-methoxy-l,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (35)-(6-Fluoro-3-{(2i?5)-2-[(4-fluoro-phenylcarbamoyl)-methyl]-3-phenyl- propionylamino}-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{3-[(2i?5)-2-Benzyl-3,3-dimethyl-butyrylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-(6-Fluoro-3-{[(2i?5)-8-methoxy-l,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}- l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[3-(3-fluoro-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (35)-(6-Fluoro-3-{[(2i?5)-8-methoxy-l,2,3,4-tetrahydro-naphthalene-2-carbonyl]-amino}-
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[(2i?)-2-methyl-3-phenyl-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-[3-(2,2-Dimethyl-3-phenyl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-
9-yl] -acetic acid;
(35)-[6-Fluoro-3-(3-methyl-3-phenyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(35)-{6-Fluoro-3-[(35)-3-phenyl-butyrylamino]-l,2,3,4-tetrahydro-9H-carbazol-9-yl}-acetic acid;
(35)-[3-(2-Benzyloxy-acetylamino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-[6-Fluoro-3-(4-phenyl-butyrylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{3-[(2i?,3i?)-2,3-Dihydroxy-3-(2-methoxy-phenylcarbamoyl)-propionylamino]-6- fluoro- 1 ,2,3 ,4-tetrahydro-9H-carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(2-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[3-(2-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (3i?)-{8-Chloro-6-fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[2-(2-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[3-(3-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{8-Chloro-6-fluoro-3-[3-(3-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(3-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{8-Chloro-6-fluoro-3-[3-(3-methylphenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{8-Chloro-6-fluoro-3-[3-(2-hydroxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-[8-Chloro-6-fluoro-3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9- yl] -acetic acid;
(35)-[8-Chloro-6-fluoro-3-(3-phenyl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[3-(2-methoxy-phenyl)-propionylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (3i?)-{8-Chloro-3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-3-[3-(3-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-[8-Chloro-6-fluoro-3-(3-7H-indol-3-yl-propionylamino)-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid;
(35)-[8-Chloro-6-fluoro-3-(3-ii/-indol-3-yl-propionylamino)-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid;
(3i?)-{8-Chloro-3-[2-(2-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{8-Chloro-3-[2-(2-chloro-ρhenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[2-(2-methylphenyl)-oxy-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-6-fluoro-3-[2-(2-methylphenyl)-oxy-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-[3-(3-Benzo[l,3]dioxol-5-yl-propionylamino)-8-chloro-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl] -acetic acid; (35)-[3-(3-Benzo[l,3]dioxol-5-yl-propionylamino)-8-chloro-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl] -acetic acid;
(3i?)-{8-Chloro-6-fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{8-Chloro-6-fluoro-3-[2-(3-methoxy-phenoxy)-acetylamino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-3-[2-(3-chloro-phenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-3-[2-(3-chloro-ρhenoxy)-acetylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3i?)-{8-Chloro-3-[3-(2-chloro-ρhenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{8-Chloro-3-[3-(2-chloro-phenyl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (3i?)-[8-Chloro-6-fluoro-3-(2-indan-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9- yl] -acetic acid;
(35)-[8-Chloro-6-fluoro-3-(2-indan-2-yl-acetylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(3^-[6-Fluoro-3-(l-methyl-3-phenethyl-ureido)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-{3-[3-(2-Chloro-benzyl)-l-methyl-ureido]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-[3-(3-Benzyl-l-methyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-[3-(Benzyloxycarbonyl-methyl-amino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
{(35)-3-[(2-Chloro-benzyloxycarbonyl)-methyl-amino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-(6-Fluoro-3-{[2-(4-methoxy-phenyl)-acetyl]-methyl-amino}-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{methyl-[2-(4-methylphenyl)-acetyl]-amino}-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (S^-Cό-Fluoro-S-ICl^l-methoxy-pheny^-acety^-methyl-aminol-l^^^-tetrahydro-QH- carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[(2-indan-2-yl-acetyl)-methyl-amino]-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid; (S^-CS-IP^S-Chloro-phenyO-acety^-methyl-aminol-β-fluoro-l^^^-tetrahydro-QH- carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3 - {methyl- [2-(3 -methylphenyl)-acetyl] -amino }- 1 ,2,3 ,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3 - { [2-(3 -methoxy-phenyl)-acetyl] -methyl-amino } - 1 ,2,3 ,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(3-{[2-(2-Chloro-phenoxy)-acetyl]-methyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(3-{[2-(4-Chloro-phenoxy)-acetyl]-methyl-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (35)-(6-Fluoro-3 - { [3 -(3 -methoxy-phenyl)-propiony 1] -methyl-amino } - 1 ,2,3 ,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{methyl-[2-(2-methylphenyl)-acetyl]-amino}-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-{3-[(3,3-Diphenyl-propionyl)-methyl-amino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol- 9-yl} -acetic acid;
(3iS)-(6-Fluoro-3 - { [3 -(2-methoxy-phenyl)-propiony 1] -methyl-amino } - 1 ,2,3 ,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[(3-7H-indol-3-yl-propionyl)-methyl-amino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid; (35)-{3-[(2-Benzyloxy-acetyl)-methyl-amino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl} -acetic acid;
(35)-{3-[(2,3-Diphenyl-propionyl)-methyl-amino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-{6-Fluoro-3-[[3-(2-methoxy-phenyl)-propionyl]-(3-phenyl-propyl)-amino]-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{3-[Acetyl-(3-phenyl-propyl)-amino]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl}- acetic acid; (35)-{3-[3-Benzyl-(l-cyclopropylmethyl)-ureido]-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-[3-(Benzyloxycarbonyl-cyclopropylmethyl-amino)-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid; (35)-{3-[Cyclopropylmethyl-(3-phenyl-propionyl)-amino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{3-[Cyclopropylmethyl-((5)-2-methyl-3-phenyl-propionyl)-amino]-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-(3-{Cyclopropylmethyl-[3-(2-methoxy-phenyl)-propionyl]-amino}-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(3-{[2-(3-Chloro-phenoxy)-acetyl]-cyclopropylmethyl-amino}-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{3-[Cyclopropylmethyl-(3,3-diphenyl-propionyl)-amino]-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid; (35)- {3-[Cyclopropylmethyl-(2-naphthalen- 1 -yl-acetyl)-amino]-6-fluoro- 1 ,2,3,4-tetrahydro-
9H-carbazol-9-yl} -acetic acid;
(3^-(3-{Benzyloxycarbonyl-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-6-fluoro-
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3iS)-(3 - {Acetyl- [2-(4-trifluoromethyl-phenoxy)-ethyl] -amino } -6-fluoro- 1 ,2,3 ,4-tetrahydro- 9H-carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{propionyl-[2-(4-trifluoromethyl-phenoxy)-ethyl]-amino}-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3 - {(3 -phenyl-propionyl)- [2-(4-trifluoromethyl-phenoxy)-ethyl] -amino } -
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid; (35)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-[2-(4-trifluoromethyl-phenoxy)- ethyl]-amino}-l,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{6-Fluoro-3-[(2-phenoxy-ethyl)-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[((S)-2-methyl-3-phenyl-propionyl)-(2-phenoxy-ethyl)-amino]-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(3S)- {6-Fluoro-3-[[3-(2-methoxy-phenyl)-propionyl]-(2-phenoxy-ethyl)-amino]-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid; (35)-{3-[Acetyl-(2-phenoxy-ethyl)-amino]-6-fluoro-l,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; (35)-{3-[Benzyloxycarbonyl-(2-methoxy-ethyl)-amino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[(2-methoxy-ethyl)-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[(2-methoxy-ethyl)-((S)-2-methyl-3-phenyl-propionyl)-amino]-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-(6-Fluoro-3-{(2-methoxy-ethyl)-[3-(2-methoxy-phenyl)-propionyl]-amino}-l, 2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(3S)- {3-[[2-(3-Chloro-phenoxy)-acetyl]-(2-methoxy-ethyl)-amino]-6-fluoro-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid; (35)-{3-[(3,3-Diphenyl-propionyl)-(2-methoxy-ethyl)-amino]-6-fluoro-l,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;
(35)-(6-Fluoro-3-{[(25)-2-methyl-3-phenyl-propionyl]-phenethyl-amino}-l,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-(6-Fluoro-3-{[3-(2-methoxy-phenyl)-propionyl]-phenethyl-amino}-l,2,3,4-tetrahydro-
9H-carbazol-9-yl)-acetic acid;
(35)-[3-(Acetyl-phenethyl-amino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid; (35)-{6-Fluoro-3-[(2-naphthalen-l-yl-acetyl)-phenethyl-amino]-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(35)-{6-Fluoro-3-[phenethyl-(3-phenyl-propionyl)-amino]-l,2,3,4-tetrahydro-9H-carbazol-
9-yl} -acetic acid;
(35)-[3-(3-Benzyl-l-naphthalen-l-ylmethyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl] -acetic acid;
(35)-[3-(Benzyloxycarbonyl-naphthalen-l-ylmethyl-amino)-6-fluoro-l,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 - [((5)-2-methyl-3 -phenyl-propionyl)-naphthalen- 1 -ylmethyl-amino] -
1, 2,3, 4-tetrahydro-9H-carbazol-9-yl} -acetic acid; (3iS)-(6-Fluoro-3 - { [3 -(2-methoxy-phenyl)-propionyl] -naphthalen- 1 -ylmethyl-amino } -
1 ,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid;
(35)-{3-[(3,3-Diphenyl-propionyl)-naphthalen-l-ylmethyl-amino]-6-fluoro-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-[3-(Acetyl-naphthalen-l-ylmethyl-amino)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl] -acetic acid;
(35)-[6-Fluoro-3-(naphthalen-l-ylmethyl-propionyl-amino)-l,2,3,4-tetrahydro-9H-carbazol-
9-yl] -acetic acid;
(3S)- {3-[(i?5)-2-Benzyl-3-(2-methylphenyl)-carbamoyl-propionylamino]-6-fluoro- 1,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid; (3S)- {3-[(i?5)-2-Benzyl-3-(3-methoxy-phenylcarbamoyl)-propionylamino]-6-fluoro- 1,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{3-[(i?5)-2-Benzyl-3-(4-chloro-phenylcarbamoyl)-propionylamino]-6-fluoro-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-{3-[(i?5)-2-Benzyl-3-(4-fluoro-benzylcarbamoyl)-propionylamino]-6-fluoro-l, 2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
[(35)-3-((i?5)-2-Benzyl-3-propylcarbamoyl-propionylamino)-6-fluoro-l,2,3,4-tetrahydro-
9H-carbazol-9-yl] -acetic acid;
(35)-[6-Fluoro-3-(3-thiophen-2-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid; (35)-{3-[3-(3-Chloro-isoxazol-5-yl)-propionylamino]-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl} -acetic acid;
(3^-[6-Fluoro-3-(3-pyrimidin-2-yl-propionylamino)-l,2,3,4-tetrahydro-9H-carbazol-9-yl]- acetic acid;
(35)-{6-Fluoro-3-[3-phenyl-4-([l,3,4]thiadiazol-2-ylcarbamoyl)-butyrylamino]-l,2,3,4- tetrahydro-9H-carbazol-9-yl} -acetic acid;
(35)-[3-(l,3-Dibenzyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9-yl]-acetic acid;
(35)-(3-{Acetyl-[2-(2-fluoro-phenyl)-ethyl]-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid; (35)-(3-{Acetyl-[2-(3-fluoro-phenyl)-ethyl]-amino}-6-fluoro-l,2,3,4-tetrahydro-9H- carbazol-9-yl)-acetic acid;
(35)-[3-(3-Benzyl-l-cyclohexylmethyl-ureido)-6-fluoro-l,2,3,4-tetrahydro-9H-carbazol-9- yl] -acetic acid; and (35)-(3-{Cyclohexylmethyl-[3-(2-methoxy-phenyl)-propionyl]-amino}-6-fluoro- 1,2,3,4- tetrahydro-9H-carbazol-9-yl)-acetic acid; or a salt of such a compound.
11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
12. A compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 11, for use as a medicament.
13. Use of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention and/or treatment of chronic and acute allergic/immune diseases/disorders, comprising allergic asthma, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease, dermatitis, inflammatory bowel disease, rheumatoid arthritis, allergic nephritis, conjunctivitis, atopic dermatitis, bronchial asthma, food allergy, systemic mast cell disorders, anaphylactic shock, urticaria, eczema, itching, inflammation, ischemia-reperfusion injury, cerebrovascular disorders, pleuritis, ulcerative colitis, eosinophil-related diseases comprising Churg-Strauss syndrome and sinusitis, and basophil-related diseases, comprising basophilic leukemia and basophilic leukocytosis.
PCT/IB2007/053046 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives WO2008017989A1 (en)

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MX2009001105A MX2009001105A (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives.
BRPI0715179-9A BRPI0715179A2 (en) 2006-08-07 2007-08-02 compound, pharmaceutical composition and use of a compound
AU2007282949A AU2007282949B8 (en) 2006-08-07 2007-08-02 (3-Amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl)-acetic acid derivatives
US12/376,932 US8143304B2 (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9 H-carbazol-9-yl)-acetic acid derivatives
ES07805287T ES2374321T3 (en) 2006-08-07 2007-08-02 ACID DERIVATIVES (3-AMINO-1,2,3,4-TETRAHIDRO-9H-CARBAZOL-9-IL) -ACETIC.
CA2658986A CA2658986C (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives
AT07805287T ATE530523T1 (en) 2006-08-07 2007-08-02 (3-AMINO-1,2,3,4-TETRAHYDRO-9H-CARBAZOL-9-YL)-ACETIC ACID DERIVATIVES
CN2007800292169A CN101500996B (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives
EP07805287A EP2051962B1 (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives
KR1020097004370A KR101411820B1 (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives
PL07805287T PL2051962T3 (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives
SI200730818T SI2051962T1 (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives
DK07805287.5T DK2051962T3 (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl) acetic acid derivatives
JP2009523396A JP5220013B2 (en) 2006-08-07 2007-08-02 (3-Amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl) -acetic acid derivative
NZ574705A NZ574705A (en) 2006-08-07 2007-08-02 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives
IL196891A IL196891A (en) 2006-08-07 2009-02-04 (3-amino-1,2,3,4-tetrahydro-9h-carbazol--9-yl)-acetic acid derivatives, pharmaceutical compositions containing them and their use in the preparation of medicaments
NO20090979A NO20090979L (en) 2006-08-07 2009-03-04 (3-amino-1,2,3,4-tetrahydro-9H-carbazol-9-yl) acetic acid
HK09110028.6A HK1130062A1 (en) 2006-08-07 2009-10-28
HR20120044T HRP20120044T1 (en) 2006-08-07 2012-01-13 (3-amino-1,2,3,4-tetrahydro-9h-carbazol-9-yl)-acetic acid derivatives

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