Novel tetrahydrocarbazole derivatives as ligands of G-protein coupled receptors

专利摘要:

公开号:AU2008244305A1
申请号:U2008244305
申请日:2008-04-25
公开日:2008-11-06
发明作者:Silke Baasner；Eckhard Gunther；Klaus Paulini；Emmanuel Polymeropoulos；Peter Schmidt；Tilmann Schuster；Michael Teifel
申请人:Aeterna Zentaris GmbH；
IPC主号:C07K5-08

专利说明:
WO 2008/132153 PCT/EP2008/055039 Novel Tetrahydrocarbazole Derivatives as Ligands of G-protein Coupled Recep tors Description 5 Technical field The present invention relates to novel tetrahydrocarbazole derivatives as ligands of G-protein coupled receptors (GPCRs), in particular as ligands of the luteinizing hor mone releasing hormone (LHRH) receptor, processes of manufacturing thereof and 10 uses for the treatment and/or prophylaxis of physiological and/or pathophysiological conditions in mammals, in particular in humans. Prior art G-protein coupled receptors represent a superfamily of cell membrane-associated 15 receptors which play an important part in numerous biochemical and pathobiochemical processes in mammals and especially in humans. All GPCRs consist of seven hydrophobic, transmembrane alpha-helical domains which are connected together by three intracellular and three extracellular loops and have an extracellular amino terminus and an intracellular carboxy terminus. One or more heterotrimeric G proteins 20 are involved in their cellular signal transduction. Diverse physiological stimuli such as photosensitivity, taste and odor, but also fundamental processes such as metabolism, reproduction and development are mediated and controlled by them. GPCRs exist for exogenous and endogenous ligands. Peptide hormones, biogenic amines, amino acids, nucleotides, lipids, Ca 2 ,, but also photons, have inter alia been identified as 25 ligands; moreover one ligand may activate different receptors. According to a recent investigation, 367 sequences have been identified in the human genome for G-protein coupled receptors (GPCRs) with endogenous ligands (Vassilatis DK et al., PNAS 2003, 100(8): 4903-4908). Of these, 284 belong to class A, 30 50 to class B, 17 to class C and 11 to class F/S. Examples belonging to class A are the bombesin, the dopamine and the LHRH receptors, and to class B are the VIP and the calcitonin receptors. The natural ligands for numerous GPCRs are as yet unknown.
WO 2008/132153 PCT/EP2008/055039 -2 Owing to their function, GPCRs are suitable as targets for medicaments for the therapy and prevention of a large number of pathological conditions. It is speculated that about 50% of currently known targets for active ingredients are GPCRs (Fang Y et 5 al., DDT 2003, 8(16): 755-761). Thus, GPCRs play an important part in pathological processes such as, for example, pain (opioid receptor), asthma (beta2-adrenoceptor), migraine (serotonin 5-HT1 B/1D receptor), cancer (LHRH receptor), cardiovascular disorders (angiotensin receptor), metabolic disorders (GHS receptor) or depression (serotonin 5-HT1a receptor) (Pierce KL et al., Nat. Rev. Mol. Cell Biol. 2002, 3: 639 10 650). General information about GPCRs is to be found under http://www.gpcr.org. The natural ligand of this receptor, the peptide hormone LHRH, is synthesized in cells of the hypothalamus and released in pulsatile fashion from the hypothalamic neurons into the capillary plexus of the ementia mediana. In the anterior lobe of the 15 pituitary, LHRH binds to the LHRH receptors of the gonadotropic cells and stimulates certain trimeric G-proteins, which initiate a branched signal transduction cascade. The initial event is activation of phospholipase C, A 2 and/or D. This leads to an increased provision of the second messengers diacylglycerol and IP 3 , followed by Ca 2 , mobilization from intracellular pools, and activation of various subordinate protein 20 kinases. Finally, there is stimulation of the production and temporally defined pulsatile release of the gonadotropins FSH and LH. The two hormones are transported via the circulation to the target organs the testes and ovaries respectively. There they stimulate the production and release of the appropriate sex hormones. In the opposite direction there is a complex feedback mechanism by which the concentration of the sex 25 hormones formed in turn regulates the release of LH and FSH. In the male organism, LH binds to membrane receptors of the Leydig cells and stimulates testosterone biosynthesis. FSH acts via specific receptors on the Sertoli cells and assists the production of spermatozoa. In the female organism, LH binds to the LH receptors of the theca cells and activates the formation of androgen 30 synthesizing enzymes. FSH stimulates proliferation of granulosa cells of certain follicle stages via the FSH receptors thereof. The androgens which are formed are converted in the adjacent granulosa cells to the estrogens estrone and estradiol.
WO 2008/132153 PCT/EP2008/055039 -3 A number of disorders distinguished by benign or malignant tissue proliferations depend on stimulation by sex hormones such as testosterone or estradiol. Typical disorders of this type are prostate cancer and benign prostate hyperplasia (BPH) in men, and endometriosis, uterine fibroids or uterine myomas, pubertas praecox, 5 hirsutism and polycystic ovary syndrome, and breast cancer, uterine cancer, endometrial cancer, cervical cancer and ovarian cancer in women. Since its discovery in 1971 by Schally et al. (Schally A et al., Science 1971, 173: 1036-1038) more than 3000 synthetic analogues of natural LHRH have been 10 synthesized and tested. Peptide agonists such as triptorelin and leuprolide have been established for many years successfully in the therapy of gynecological disorders and cancers. However, the disadvantage of agonists is generally that they stimulate LHRH receptors in the initial phase of use and thus lead to side effects via an initial increase in the sex hormone levels. Only after downregulation of the LHRH receptor as a result 15 of this overstimulation can the superagonists display their effect. This leads to a complete reduction in the sex hormone levels and thus to pharmacological castration with all the signs and symptoms. This disadvantage is associated with the impossibility of targeted adjustment of the level of sex hormones via the dosage. Thus, therapy of diseases which do not require a total reduction of the sex hormone levels to the 20 castration level, such as, for example, benign tissue proliferations, with an agonist is not optimal for the patient. This has led to the development of peptide LHRH receptor antagonists, of which, for example, cetrorelix (Cetrotide*) has been successfully introduced for controlled 25 ovarian stimulation in the context of the treatment of female infertility. The antagonists inhibit the LHRH receptor immediately and dose-dependently, and thus lead to an immediate reduction in the plasma levels of testosterone or estradiol and progesterone. The peptide antagonists are, however, somewhat less potent than the agonists, and thus higher doses must be given. 30 Reviews of the clinical applications and the potential of LHRH agonists and antagonists are given by Millar RP et al. (Millar RP et al., British Med. Bull. 2000, 56: 761-772), Felberbaum RE et al. (Felberbaum RE et al., Mol. Cell. Endocrinology 2000, 166: 9-14) and Haviv F et al. (Haviv F et al., Integration of Pharmaceutical Discovery WO 2008/132153 PCT/EP2008/055039 -4 and Development: Case Studies, Chapter 7, ed. Borchardt et al., Plenum Press, New York 1998). Besides the treatment of malignant and benign neoplastic diseases, further possible applications are controlled ovarian stimulation in the context of in vitro 5 fertilization, fertility control (contraception), and protection from unwanted side effects of radio- or chemotherapy, the treatment of HIV infections (AIDS) and of neurological or neurodegenerative disorders such as Alzheimer's disease. Specific LHRH receptors have not only been found on pituitary cells, but also on cells in various tumors, e.g. of the breast and ovaries. These receptors might mediate a direct antiproliferative effect 10 of LHRH receptor antagonists on the tumor. The peptide LHRH receptor agonists and antagonists are mostly decapeptides whose bioavailability is inadequate for oral administration. They are typically given as solutions for injection or as depot formulation, subcutaneously or intramuscularly. This 15 application is associated with inconveniences for the patient, and the compliance suffers. In addition, synthesis of the decapeptides is complicated and costly. Compared with peptide LHRH receptor agonists and antagonists, as yet no non-peptide compound is approved and in clinical use for any of the possible 20 indications. The current state of development in the area of LHRH receptor agonists and antagonists is described in the reviews by Zhu YF et al., Expert Opin. Therap. Patents 2004, 14(2): 187-199, Zhu YF et al., Ann. Rep. Med. Chem. 2004, 39: 99-110, Tucci FC et al., Curr. Opin. Drug Discovery & Development 2004, 7(6): 832-847, Armer RE, Curr. Med. Chem. 2004, 11: 3017-3028, Chengalvala MV et al., Curr. Med. Chem 25 Anti-Cancer Agents 2003, 3: 399-410. The former publication contains a comprehensive list of the published patent specifications describing the synthesis and use of low molecular weight LHRH receptor antagonists. Among the first examples of non-peptide LHRH receptor antagonists is the 4-oxothieno[2,3-b]pyridine structure, which was described by Cho N et al. ( Cho N et 30 al., J. Med. Chem. 1998, 41: 4190-4195). Although these compounds, such as, for example, T-98475, have a high receptor affinity, their solubility in water is very poor and their bioavailability is low. Based on this lead structure, numerous further developments have been carried out, examples which may be mentioned being the WO 2008/132153 PCT/EP2008/055039 -5 publications of the international applications WO 95/28405, WO 96/24597, WO 97/14697 and WO 97/41126. The synthesis of thieno[2,3-d]pyrimidine-2,4-diones as orally available LHRH receptor antagonists is described by Sasaki S et al., (Sasaki S et al., J. Med. Chem. 2003, 46: 113-124). 5 Novel 1 -arylmethyl-5-aryl-6-methyluracils are described by Guo Z et al. (Guo Z et al., J. Med. Chem. 2004, 47: 1259-1271). The preparation of N-[(hetero)arylmethyl] benzenesulf onam ides as potent non-peptide LHRH receptor antagonists is disclosed in WO 03/078398. The patent application WO 02/11732 describes tricyclic pyrrolidines as LHRH receptor antagonists. Substituted pyridin-4-ones as LHRH receptor antagonists 10 are disclosed in WO 03/13528 and substituted 1,3,5-triazine-2,4,6-triones in WO 03/11839. The syntheses and biological activities of erythromycin A derivatives having LHRH receptor antagonistic activity is described by Randolph JT et al. (Randolph JT et al., J. Med. Chem. 2004, 47(5): 1085-1097). Selected derivatives show an oral activity on the 15 LH level in the castrated rats model. Quinoline derivatives as non-peptide LHRH antagonists are disclosed for example in WO 97/14682. Substituted 2-arylindoles are described inter alia in WO 97/21435, WO 97/21703, WO 98/55116, WO 98/55470, WO 98/55479, WO 99/21553, WO 00/04013 as LHRH receptor antagonists. Correspondingly substituted aza-2 20 arylindoles are claimed inter alia in WO 99/51231, WO 99/51596, WO 00/53178 and WO 00/53602 as LHRH receptor antagonists. Advantageous biological or biophysical data for these compounds are not disclosed. Patent EP 0 679 642 B1 describes fused heterocyclic compounds as LHRH receptor antagonists. However, a basic tetrahydrocarbazole structure is not the subject 25 matter of the invention described therein. 1,2,3,4-Tetrahydrocarbazolecarboxylic acids are described in patent EP 0 239 306 B1 as prostaglandin antagonists. An LHRH receptor antagonistic effect is neither described nor obvious. US patent US 3,970,757 discloses tetrahydrocarbazole derivatives as gastric anti 30 secretory agents. However, an LHRH receptor antagonistic effect of this type of structure is neither described nor obvious.
WO 2008/132153 PCT/EP2008/055039 -6 EP 0 603 432 B1 and US 5,708,187 describe tetrahydrocarbazole derivatives as 5 HT1 agonists inter alia for the treatment of migraine. However, an LHRH receptor antagonistic effect is neither described nor obvious. WO 2005/033099 A2 describes tetrahydrocarbazole derivatives as dipeptidyl 5 peptidase IV inhibitors. However, an LHRH receptor antagonistic effect is neither described nor obvious. There is no reference to an LHRH receptor antagonistic effect, and the disclosed structures differ from the compounds of the present invention. Davies DJ et al. describe tetrahydrocarbazole derivatives having a melatonin agonistic or antagonistic effect (Davies DJ et al., J. Med. Chem. 1998, 41: 451-467). 10 However, an LHRH receptor antagonistic effect is neither described nor obvious. Tetrahydrocarbazole derivatives are described by Shuttleworth SJ et al. as partial agonists of the neuromedin B receptor (Shuttleworth SJ et al., Bioorg. Med. Chem. Lett. 2004, 14: 3037-3042). However, an LHRH receptor antagonistic effect is neither described nor obvious. 15 Millet R et al. describe tetrahydrocarbazole derivatives as NKj/NK 2 ligands. The disclosed structures differ from the compounds of the present invention (Millet R et al., Letters in Peptide Science 1999, 6: 221-233). Moreover, an LHRH receptor antagonistic effect is neither described nor obvious. Solid-phase synthesis of 3-amino-3'-carboxytetrahydrocarbazoles described by 20 Koppitz et al. (Koppitz et al., THL 2005, 46(6): 911-914). An LHRH receptor antagonistic effect is neither described nor obvious. Tetrahydrocarbazole derivatives as peptidomimetic LHRH receptor antagonists having good receptor affinity are disclosed for example in WO 03/051837. The physicochemical and metabolic properties of these compounds do not, however, make 25 them suitable in an optimal manner for an oral dosage form. A number of publications provide an overview of the state of development of neurokinin antagonists: Giardina G et al. provide an overview of the current patent literature (Giardina G et al., IDrugs 2003, 6(8): 758-772), Leroy V et al. (Leroy V et al., Expert Opinion on 30 Investigational Drugs 2000, 9(4), 735-746) and Swain C et al. (Swain C et al., Annual Reports in Medicinal Chemistry 1999, 34: 51-60) describe the state of development relating to neurokinin receptor antagonists, while, for example, Navari RM et al. (Navari RM et al., Cancer Investigation 2004, 22(4): 569-576) describes the results of clinical WO 2008/132153 PCT/EP2008/055039 -7 studies in which NK1 receptor antagonists were employed to control chemotherapy induced emesis. Hill RG et al. describe neurokinin receptor antagonists as potential analgesics (Hill RG et al., Pain 2003, 523-530), while von Sprecher A et al. describe neurokinin 5 receptor antagonists as potential active ingredients for the therapy of inflammations and rheumatoid arthritis (Sprecher A et al., Drugs 1998, 1(1): 73-91). Millet R et al. describe tetrahydrocarbazole derivatives as NK 1
/NK
2 ligands (Millet R et al., Letters in Peptide Science 1999, 6: 221-233). The disclosed structures differ from the compounds of the present invention. 10 WO 2006/005484 discloses tetrahydrocarbozole derivatives that are said to show improved biological action and improved solubility. These tetrahydrocarbozole deriva tives act as ligands for G-protein coupled receptors, in particular LHRH receptor and NK receptors. The disclosed structures differ from the compounds of the present inven tion. 15 Description of the invention The present invention has the object to provide novel tetrahydrocarbazole deriva tives that act as ligands for G-protein coupled receptors (GPCRs). The object of the present invention has surprisingly been solved in one aspect by 20 providing tetrahydrocarbazole derivatives according to formula (1), R18 R17 R19 R16N R20 R14 R15 R13 R21 R12 R22 R1 R1 R11 W R6 / R2 N ; 6/ R10 NR R9 R8 R7 V R5m R4m R3 WO 2008/132153 PCT/EP2008/055039 -8 wherein: (A) V, W are independently from each other selected from the group consisting of: "=O, =S, =S*-O-, geminally linked H 2 "; R1, R1 * - when present - together independently form "=O, =S or =S*-O-" or are 5 independently both "hydrogen"; R2, R3 are independently from each other selected from the group consisting of: (i) ,,hydrogen, alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, het erocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, 10 CN, -CF 3 , -N 3 , -NH 2 , -NHX1, -NX2X3, -NO 2 , -OH, =O, -OCF 3 , -SH, -0
SO
3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, -P(O)(OH) 2 , C(O)-X4, -C(O)O-X5, -C(O) N H-X6, -C(O) NX7X8, -O-X9, -0(-X 1 0-O)a H (a = 1, 2, 3, 4, 5), -O(-X11 -O)b-X1 2 (b = 1, 2, 3, 4, 5), -OC(O)-X13, OC(O)-O-X1 4, -OC(O)-NHX1 5, -O-C(O)-NX1 6X1 7, 15 OP(O)(OX18)(OX19), -OSi(X20)(X21)(X22), -OS(0 2 )-X23, -NHC(O)-NH 2 , -NHC(O)-X24, -NX25C(O)-X26, -NH-C(O)-O-X27, -NH-C(O)-NH-X28, -NH-C(O)-NX29X30, -NX31-C(O)-O-X32, -NX33-C(O)-NH-X34, NX35-C(O)-NX36X37, -NHS(0 2 )-X38, -NX39S(0 2 )-X40, -S-X41, -S(O) X42, -S(0 2 )-X43, -S(0 2 )NH-X44, -S(0 2 )NX45X46, -S(0 2 )O-X47, 20 P(O)(OX48)(OX49), -Si(X50)(X51)(X52), -C(NH)-NH 2 , -C(NX53)-NH 2 , C(NH)-NHX54, -C(NH)-NX55X56, -C(NX57)-NHX58, -C(NX59) NX60X61, -NH-C(O)-NH-O-X62, -NH-C(O)-NX63-O-X64, -NX65 C(O)-NX66-O-X67, -N(-C(O)-NH-O-X68) 2 , -N(-C(O)-NX69-O-X70) 2 , N(-C(O)-NH-O-X71)(-C(O)-NX72-O-X73), -C(S)-X74, -C(S)-O-X75, 25 C(S)-NH-X76, -C(S)-NX77X78, -C(O)-NH-O-X79, -C(O)-NX80-O-X81, -C(S)-NH-O-X82, -C(S)-NX83-O-X84, -C(O)-NH-NH-X85, -C(O)-NH NX86X87, -C(O)-NX88-NX89X90, -C(S)-NH-NH-X91, -C(S)-NH NX92X93, -C(S)-NX94-NX95X96, -C(O)-C(O)-O-X97, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHX98, -C(O)-C(O)-NX99X100, -C(S)-C(O)-O-X101, 30 C(O)-C(S)-O-X 102, -C(S)-C(S)-O-X 103, -C(S)-C(O)-N H 2 , -C(S)-C(O) NHX1 04, -C(S)-C(O)-NX1 05X1 06, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHX107, -C(S)-C(S)-NX1 08X109, -C(O)-C(S)-NH 2 , -C(O)-C(S) NHX1 10, -C(O)-C(S)-NX1 11 X1 12"; WO 2008/132153 PCT/EP2008/055039 -9 wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X1 0, X11, X1 2, X1 3, X1 4, X1 5, X16,X17,X18,X19,X20,X21,X22,X23,X24,X25, X26,X27,X28,X29, X30,X31,X32,X33,X34,X35,X36,X37,X38,X39, X40,X41,X42,X43, X44,X45,X46,X47,X48,X49,X50,X51,X52,X53, X54,X55,X56,X57, 5 X58,X59,X60,X61,X62,X63,X64,X65,X66,X67, X68,X69,X70,X71, X72,X73,X74,X75,X76,X77,X78,X79,X80,X81, X82,X83,X84,X85, X86,X87,X88,X89,X90,X91,X92,X93,X94,X95, X96,X97,X98,X99, X100,X101,X102,X103,X104,X105,X106,X107, X108, X109,X110, X111, X112 are independently from each other selected from the group 10 consisting of: ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein al ternatively X7, X8 and/or X1 6, X1 7 and/or X29, X30 and/or X36, X37 and/or X45, X46 and/or X55, X56 and/or X60, X61 and/or X77, X78 and/or X86, X87 and/or X89, X90 and/or X92, X93 and/or X95, X96 and/or X99, X1 00 15 and/or X105, X106 and/or X108, X109 and/or X111, X112 and/or respec tively together can also form ,heterocyclyl"; wherein optionally above substituents of substituents group (i) can in turn independently from each other be substituted with at least one substituent, identical or different, selected from the group consisting of: 20 (ii) ,alkyl, (C 9 -C o)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycly lalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, CF 3 , -N 3 , -NH 2 , -NHX201, -NX202X203, -NO 2 , -OH, =O, -OCF 3 , -SH,
-O-SO
3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, P(O)(OH) 2 , -C(O)-X204, -C(O)O-X205, -C(O)NH-X206, 25 C(O)NX207X208, -O-X209, -O(-X21 0-O)c-H (c = 1, 2, 3, 4, 5), -O( X211-O)d-X212 (d = 1, 2, 3, 4, 5), -OC(O)-X213, -OC(O)-O-X214, OC(O)-NHX215, -O-C(O)-NX216X217, -OP(O)(OX218)(OX219), OSi(X220)(X221)(X222), -OS(0 2 )-X223, -NHC(O)-NH 2 , -NHC(O) X224, -NX225C(O)-X226, -NH-C(O)-O-X227, -NH-C(O)-NH-X228, 30 -NH-C(O)-NX229X230, -NX231-C(O)-O-X232, -NX233-C(O)-NH X234, -NX235-C(O)-NX236X237, -NHS(0 2 )-X238, -NX239S(0 2
)
X240, -S-X241, -S(O)-X242, -S(0 2 )-X243, -S(0 2 )NH-X244, S(0 2 )NX245X246, -S(0 2 )O-X247, -P(O)(OX248)(OX249), Si(X250)(X251)(X252), -C(NH)-NH 2 , -C(NX253)-NH 2 , -C(NH) 35 NHX254, -C(NH)-NX255X256, -C(NX257)-NHX258, -C(NX259)- WO 2008/132153 PCT/EP2008/055039 - 10 NX260X261, -NH-C(O)-NH-O-X262, -NH-C(O)-NX263-O-X264, NX265-C(O)-NX266-O-X267, -N(-C(O)-NH-O-X268) 2 , -N(-C(O) NX269-O-X270) 2 , -N(-C(O)-NH-O-X271)(-C(O)-NX272-0-X273), C(S)-X274, -C(S)-O-X275, -C(S)-NH-X276, -C(S)-NX277X278, 5 C(O)-NH-O-X279, -C(O)-NX280-O-X281, -C(S)-NH-O-X282, C(S)-NX283-O-X284, -C(O)-NH-NH-X285, -C(O)-NH-NX286X287, -C(O)-NX288-NX289X290, -C(S)-NH-NH-X291, -C(S)-NH NX292X293, -C(S)-NX294-NX295X296, -C(O)-C(O)-O-X297, C(O)-C(O)-NH 2 , -C(O)-C(O)-NHX298, -C(O)-C(O)-NX299X300, 10 C(S)-C(O)-O-X301, -C(O)-C(S)-O-X302, -C(S)-C(S)-O-X303, C(S)-C(O)-NH 2 , -C(S)-C(O)-NHX304, -C(S)-C(O)-NX305X306, C(S)-C(S)-NH 2 , -C(S)-C(S)-NHX307, -C(S)-C(S)-NX308X309, C(O)-C(S)-NH 2 , -C(O)-C(S)-NHX310, -C(O)-C(S)-NX31 1 X312"; wherein X201, X202, X203, X204, X205, X206, X207, X208, X209, 15 X210,X211,X212,X213,X214,X215,X216,X217,X218, X219,X220, X221,X222,X223,X224,X225,X226,X227,X228,X229, X230,X231, X232,X233,X234,X235,X236,X237,X238,X239,X240, X241,X242, X243,X244,X245,X246,X247,X248,X249,X250,X251, X252,X253, X254,X255,X256,X257,X258,X259,X260,X261,X262, X263,X264, 20 X265,X266,X267,X268,X269,X270,X271,X272,X273, X274,X275, X276,X277,X278,X279,X280,X281,X282,X283,X284, X285,X286, X287,X288,X289,X290,X291,X292,X293,X294,X295, X296,X297, X298,X299,X300,X301,X302,X303,X304,X305,X306, X307,X308, X309, X310, X311, X312 are independently from each other selected 25 from the group consisting of: ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalky lalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, het eroarylalkyl" and wherein alternatively X207, X208 and/or X216, X217 and/or X229, X230 and/or X236, X237 and/or X245, X246 and/or X255, X256 and/or X260, X261 and/or X277, X278 and/or X286, X287 and/or 30 X289, X290 and/or X292, X293 and/or X295, X296 and/or X299, X300 and/or X305, X306 and/or X308, X309 and/or X311, X312 and/or re spectively together can also form ,heterocyclyl"; wherein optionally above substituents of substituents group (ii) can in turn independently from each other be substituted with at least one sub 35 stituent, identical or different, selected from the group consisting of: WO 2008/132153 PCT/EP2008/055039 - 11 (iii) ,alkyl, (C 9 -Co)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero cyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -CI, -Br, -1, -CN, -CF 3 , -N 3 , -NH 2 , -NHX401, -NX402X403, -NO 2 , -OH, =O, OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , 5 SO 3 H, -P(O)(OH) 2 , -C(O)-X404, -C(O)O-X405, -C(O)NH-X406, C(O)NX407X408, -O-X409, -0(-X41 0-0)e-H (e = 1, 2, 3, 4, 5), O(-X41 1 -O)f-X412 (f = 1, 2, 3, 4, 5), -OC(O)-X413, -OC(O)-O X414, -OC(O)-NHX415, -O-C(O)-NX416X417, OP(O)(OX418)(OX419), -OSi(X420)(X421)(X422), -OS(0 2 )-X423, 10 -NHC(O)-NH 2 , -NHC(O)-X424, -NX425C(O)-X426, -NH-C(O) O-X427, -NH-C(O)-NH-X428, -NH-C(O)-NX429X430, -NX431 C(O)-O-X432, -NX433-C(O)-NH-X434, -NX435-C(O) NX436X437, -NHS(0 2 )-X438, -NX439S(0 2 )-X440, -S-X441, S(O)-X442, -S(0 2 )-X443, -S(02)NH-X444, -S(02)NX445X446, 15 S(0 2 )O-X447, -P(O)(OX448)(OX449), -Si(X450)(X451)(X452), C(NH)-NH 2 , -C(NX453)-NH 2 , -C(NH)-NHX454, -C(NH) NX455X456, -C(NX457)-NHX458, -C(NX459)-NX460X461, -NH C(O)-NH-O-X462, -NH-C(O)-NX463-O-X464, -NX465-C(O) NX466-O-X467, -N(-C(O)-NH-O-X468) 2 , -N(-C(O)-NX469-O 20 X470) 2 , -N(-C(O)-NH-O-X471)(-C(O)-NX472-0-X473), -C(S) X474, -C(S)-O-X475, -C(S)-NH-X476, -C(S)-NX477X478, C(O)-NH-O-X479, -C(O)-NX480-O-X481, -C(S)-NH-O-X482, C(S)-NX483-O-X484, -C(O)-NH-NH-X485, -C(O)-NH NX486X487, -C(O)-NX488-NX489X490, -C(S)-NH-NH-X491, 25 C(S)-NH-NX492X493, -C(S)-NX494-NX495X496, -C(O)-C(O) O-X497, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHX498, -C(O)-C(O) NX499X500, -C(S)-C(O)-O-X501, -C(O)-C(S)-O-X502, -C(S) C(S)-O-X503, -C(S)-C(O)-NH 2 , -C(S)-C(O)-NHX504, -C(S) C(O)-NX505X506, -C(S)-C(S)-NH 2 , -C(S)-C(S)-NHX507, -C(S) 30 C(S)-NX508X509, -C(O)-C(S)-NH 2 , -C(O)-C(S)-NHX510, -C(O) C(S)-NX51 1 X512"; wherein X401, X402, X403, X404, X405, X406, X407, X408, X409, X410, X411, X412, X413, X414, X415, X416, X417, X418, X419, X420,X421,X422,X423,X424,X425,X426,X427,X428, X429, 35 X430,X431,X432,X433,X434,X435,X436,X437,X438, X439, WO 2008/132153 PCT/EP2008/055039 - 12 X440,X441,X442,X443,X444,X445,X446,X447,X448, X449, X450,X451,X452,X453,X454,X455,X456,X457,X458, X459, X460,X461,X462,X463,X464,X465,X466,X467,X468, X469, X470,X471,X472,X473,X474,X475,X476,X477,X478, X479, 5 X480,X481,X482,X483,X484,X485,X486,X487,X488, X489, X490,X491,X492,X493,X494,X495,X496,X497,X498, X499, X500,X501,X502,X503,X504,X505,X506,X507,X508, X509, X51 0, X51 1, X512 are independently from each other selected from the group consisting of: ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylal 10 kyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, het eroarylalkyl" and wherein alternatively X407, X408 and/or X416, X417 and/or X429, X430 and/or X436, X437 and/or X445, X446 and/or X455, X456 and/or X460, X461 and/or X477, X478 and/or X486, X487 and/or X489, X490 and/or X492, X493 and/or X495, 15 X496 and/or X499, X500 and/or X505, X506 and/or X508, X509 and/or X51 1, X512 and/or respectively together can also form ,,het erocyclyl"; n independently is 0 or 1; with the first proviso that, if R1, R1 * are not present (n is 0), R2, R3 must not 20 both be "hydrogen" at the same time; with the second proviso that, if R1, R1 * are present (n is 1) and together inde pendently form "=0, =S or =S*-O-" or are independently both "hydrogen", R2, R3 must not both be "hydrogen" at the same time; with the third proviso that, if R1, R1 * are not present (n is 0), one of R2, R3 25 must not be "hydrogen" at the same time when the other one of R2, R3 is
C(=NH)-NH
2 "; with the fourth proviso that, if R1, R1* are present (n is 1) and are independ ently both "hydrogen", one of R2, R3 must not be "hydrogen" at the same time when the other one of R2, R3 is "-C(=NH)-NH 2 "; 30 with the fifth proviso that, if R1, R1 * are present (n is 1) and together independ ently form "=O" and one of R2, R3 independently is "hydrogen" and the other one of R2, R3 independently is "alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl", then the other one of R2, R3 being "alkyl, cycloalkyl, cycloalkylalkyl, WO 2008/132153 PCT/EP2008/055039 - 13 aryl, arylalkyl, heteroaryl" must be substituted with at least one substituent se lected from the group consisting of: (iv) "heterocyclyl, heterocyclylalkyl, -CF3, -N 3 , -NH 2 , -NHX600, NX601X602, -NO 2 , -OH, -OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, 5 -COOH, -S0 3 H, -P(O)(OH) 2 , -C(O)-X603, -C(O)O-X604, -C(O)NH X605, -C(O)NX606X607, -0-aryl, -0-arylalkyl, -0-heteroaryl, -0 heteroarylalkyl, -0-heterocyclyl, -0-heterocyclylalkyl, -O(-X608-O)g-H (g = 1, 2, 3, 4, 5), -O(-X609-O)h-X61 0 (h = 1, 2, 3, 4, 5), -OC(O)-X61 1, -OC(O)-O-X612, -OC(O)-NHX613, -O-C(O)-NX614X615, 10 OP(O)(OX616)(OX617), -OSi(X618)(X619)(X620), -OS(0 2 )-X621, NHC(O)-X622, -NX623C(O)-X624, -NH-C(O)-O-X625, -NH-C(O) NH-X626, -NH-C(O)-NX627X628, -NX629-C(O)-O-X630, -NX631 C(O)-NH-X632, -NX633-C(O)-NX634X635, -NHS(0 2 )-X636, NX637S(0 2 )-X638, -S-X639, -S(O)-X640, -S(0 2 )-X641, -S(0 2
)NH
15 X642, -S(0 2 )NX643X644, -S(0 2 )O-X645, -P(O)(OX646)(OX647), Si(X648)(X649)(X650), -C(NH)-NH 2 , -C(NX651)-NH 2 , -C(NH)-NHX652, -C(NH)-NX653X654, -C(NX655)-NHX656, -C(NX657)-NX658X659, NH-C(O)-NH-O-X660, -NH-C(O)-NX661-O-X662, -NX663-C(O) NX664-O-X665, -N(-C(O)-NH-O-X666) 2 , -N(-C(O)-NX667-O-X668) 2 , 20 -N(-C(O)-NH-O-X669)(-C(O)-NX670-0-X671), -C(S)-X672, -C(S) O-X673, -C(S)-NH-X674, -C(S)-NX675X676, -C(O)-NH-O-X677, C(O)-NX678-O-X679, -C(S)-NH-O-X680, -C(S)-NX681-O-X682, C(O)-NH-NH-X683, -C(O)-NH-NX684X685, -C(O)-NX686 NX687X688, -C(S)-NH-NH-X689, -C(S)-NH-NX690X691, -C(S) 25 NX692-NX693X694, -C(O)-C(O)-O-X695, -C(O)-C(O)-NH 2 , -C(O) C(O)-NHX696, -C(O)-C(O)-NX697X698, -C(S)-C(O)-O-X699, -C(O) C(S)-O-X700, -C(S)-C(S)-O-X701, -C(S)-C(O)-NH 2 , -C(S)-C(O) NHX702, -C(S)-C(O)-NX703X704, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHX705, -C(S)-C(S)-NX706X707, -C(O)-C(S)-NH 2 , -C(O)-C(S) 30 NHX708, -C(O)-C(S)-NX709X71 0"; wherein X600, X601, X602, X603, X604, X605, X606, X607, X608, X609, X610, X611, X612, X613, X614, X615, X616, X617, X618, X619, X620, X621,X622,X623,X624, X625,X626,X627,X628,X629,X630,X631, X632,X633,X634,X635, X636,X637,X638,X639,X640,X641,X642, 35 X643,X644,X645,X646, X647,X648,X649,X650,X651,X652,X653, WO 2008/132153 PCT/EP2008/055039 - 14 X654,X655,X656,X657, X658,X659,X660,X661,X662,X663,X664, X665,X666,X667,X668, X669,X670,X671,X672,X673,X674,X675, X676,X677,X678,X679, X680,X681,X682,X683,X684,X685,X686, X687,X688,X689,X690, X691,X692,X693,X694,X695,X696,X697, 5 X698,X699,X700,X701, X702,X703,X704,X705,X706,X707,X708, X709, X71 0, X71 1, X712 are independently from each other selected from the group consisting of: ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively X606, X607 and/or X614, X615 and/or X627, 10 X628 and/or X634, X635 and/or X643, X644 and/or X653, X654 and/or X658, X659 and/or X675, X676 and/or X684, X685 and/or X687, X688 and/or X690, X691 and/or X693, X694 and/or X697, X698 and/or X703, X704 and/or X706, X707 and/or X709, X71 0 and/or respectively together can also form ,heterocyclyl"; 15 with the further proviso that "-C(O)-N(alkyl) 2 , -C(O)-N(cycloalkyl) 2 , C(O)-N(cycloalkylalkyl) 2 , -C(O)-N(arylalkyl) 2 , -C(O)-N(aryl) 2 , -C(O) N(heteroaryl) 2 " are excluded from above substituents group (iv); wherein optionally the other one of R2, R3 being "alkyl, cycloalkyl, cycloalkylal kyl, aryl, arylalkyl, heteroaryl" can in turn independently from each other be ad 20 ditionally substituted with at least one substituent, identical or different, selected from above substituents group (ii); wherein optionally the other one of R2, R3 being "alkyl, cycloalkyl, cycloalkylal kyl, aryl, arylalkyl, heteroaryl" and being substituted with at least one substitu ent, identical or different, selected from above substituents group (iv) and, op 25 tionally, also (ii), can optionally be further substituted in their substituents se lected from above substituents group (iv) and, optionally, also (ii), with at least one substituent, identical or different, selected from above substituents group (iii); with the sixth proviso that, if R1, R1* are present (n is 1) and together inde 30 pendently form "=S or =S*-O" and R2, R3 are independently selected from the group consisting of "hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl", each of R2, R3 being "alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl" must be substituted with at least one substituent selected from the group consisting of: WO 2008/132153 PCT/EP2008/055039 - 15 (v) ,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -CF3, -N 3 , NH 2 , -NHX800, -NX801X802, -NO 2 , -OH, -OCF, -SH, -O-SO 3 H, OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -S0 3 H, -P(O)(OH) 2 , -C(O) X803, -C(O)O-X804, -C(O)NH-X805, -C(O)NX806X807, -0-aryl, -0 5 arylalkyl, -0-heteroaryl, -0-heteroarylalkyl, -0-heterocyclyl, -0 heterocyclylalkyl, -O(-X808-O)i-H (i = 1, 2, 3, 4, 5), -O(-X809-O)j-X810 (j = 1, 2, 3, 4, 5), -OC(O)-X811, -OC(O)-O-X812, -OC(O)-NHX813, -0 C(O)-NX814X815, -OP(O)(OX816)(OX817), -OSi(X818)(X819)(X820), OS(0 2 )-X821, -NHC(O)-X822, -NX823C(O)-X824, -NH-C(O)-O-X825, 10 NH-C(O)-NH-X826, -NH-C(O)-NX827X828, -NX829-C(O)-O-X830, NX831-C(O)-NH-X832, -NX833-C(O)-NX834X835, -NHS(0 2 )-X836, NX837S(0 2 )-X838, -S-X839, -S(O)-X840, -S(0 2 )-X841, -S(0 2
)NH
X842, -S(0 2 )NX843X844, -S(0 2 )O-X845, -P(O)(OX846)(OX847), Si(X848)(X849)(X850), -C(NH)-NH 2 , -C(NX851)-NH 2 , -C(NH)-NHX852, 15 C(NH)-NX853X854, -C(NX855)-NHX856, -C(NX857)-NX858X859, -NH C(O)-NH-O-X860, -NH-C(O)-NX861-O-X862, -NX863-C(O)-NX864 O-X865, -N(-C(O)-NH-O-X866) 2 , -N(-C(O)-NX867-O-X868) 2 , -N( C(O)-NH-O-X869)(-C(O)-NX870-O-X871), -C(S)-X872, -C(S)-O-X873, -C(S)-NH-X874, -C(S)-NX875X876, -C(O)-NH-O-X877, -C(O)-NX878 20 O-X879, -C(S)-NH-O-X880, -C(S)-NX881-O-X882, -C(O)-NH-NH X883, -C(O)-NH-NX884X885, -C(O)-NX886-NX887X888, -C(S)-NH NH-X889, -C(S)-NH-NX890X891, -C(S)-NX892-NX893X894, -C(O) C(O)-O-X895, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHX896, -C(O)-C(O) NX897X898, -C(S)-C(O)-O-X899, -C(O)-C(S)-O-X900, -C(S)-C(S)-O 25 X901, -C(S)-C(O)-NH 2 , -C(S)-C(O)-NHX902, -C(S)-C(O)-NX903X904,
-C(S)-C(S)-NH
2 , -C(S)-C(S)-NHX905, -C(S)-C(S)-NX906X907, -C(O)
C(S)-NH
2 , -C(O)-C(S)-NHX908, -C(O)-C(S)-NX909X910"; wherein X800, X801, X802, X803, X804, X805, X806, X807, X808, X809, X810, X811, X812, X813, X814, X815, X816, X817, X818, X819, X820, 30 X821,X822,X823,X824,X825,X826,X827,X828, X829, X830,X831, X832,X833,X834,X835,X836,X837,X838,X839, X840, X841,X842, X843,X844,X845,X846,X847,X848,X849,X850, X851, X852,X853, X854,X855,X856,X857,X858,X859,X860,X861, X862, X863,X864, X865,X866,X867,X868,X869,X870,X871,X872, X873, X874,X875, 35 X876,X877,X878,X879,X880,X881,X882,X883, X884, X885,X886, WO 2008/132153 PCT/EP2008/055039 - 16 X887,X888,X889,X890,X891,X892,X893,X894, X895, X896,X897, X898,X899,X900,X901,X902,X903,X904,X905, X906, X907,X908, X909, X91 0, X91 1, X912 are independently from each other selected from the group consisting of: ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, het 5 erocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively X806, X807 and/or X814, X815 and/or X827, X828 and/or X834, X835 and/or X843, X844 and/or X853, X854 and/or X858, X859 and/or X875, X876 and/or X884, X885 and/or X887, X888 and/or X890, X891 and/or X893, X894 and/or X897, X898 and/or X903, X904 10 and/or X906, X907 and/or X909, X910 and/or respectively together can also form ,heterocyclyl"; wherein optionally each of R2, R3 being "alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl" can in turn independently from each other be additionally substituted with at least one substituent, identical or different, selected from above sub 15 stituents group (ii); wherein optionally each of R2, R3 being "alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl" and being substituted with at least one substituent, identical or differ ent, selected from above substituents group (v) and, optionally, also (ii), can op tionally be further substituted in their substituents selected from above substitu 20 ents group (v) and, optionally, also (ii), with at least one substituent, identical or different, selected from above substituents group (iii); m independently is 1 or 2; R4m, R5m, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R1 9, R20, R21, R22 are independently from each other selected from the group 25 consisting of: (i) ,,hydrogen, alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, het erocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, CN, -CF 3 , -N 3 , -NH 2 , -NHX1 001, -NX1 002X1 003, -NO 2 , -OH, =O, OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, 30 P(O)(OH) 2 , -C(O)-X1004, -C(O)O-X1005, -C(O)NH-X1006, C(O)NX1007X1008, -O-X1009, -O(-X1010-O)k-H (k = 1, 2, 3, 4, 5), -O( X1011-0)|-X1012 (I = 1, 2, 3, 4, 5), -OC(O)-X1013, -OC(O)-O-X1014, OC(O)-NHX1 015, -O-C(O)-NX1016X1017, -OP(O)(OX1018)(OX1019), OSi(X1 020)(X1 021)(X1 022), -OS(O 2 )-X1 023, -NHC(O)-NH 2 , -NHC(O)- WO 2008/132153 PCT/EP2008/055039 -17 X1 024, -NX1 025C(O)-X1 026, -NH-C(O)-O-X1 027, -NH-C(O)-NH X1028, -NH-C(O)-NX1029X1030, -NX1031-C(O)-O-X1032, -NX1033 C(O)-NH-X1 034, -NX1 035-C(O)-NX1 036X1 037, -NHS(0 2 )-X1 038, NX1 039S(0 2 )-X1 040, -S-X1 041, -S(O)-X1 042, -S(0 2 )-X1 043, 5 S(0 2 )NH-X1044, -S(0 2 )NX1045X1046, -S(0 2 )O-X1 047, P(O)(OX1 048)(OX1 049), -Si(X1 050)(X1 051)(X1 052), -C(NH)-NH 2 , C(NX1 053)-NH 2 , -C(NH)-NHX1054, -C(NH)-NX1 055X1 056, C(NX1 057)-NHX1 058, -C(NX1 059)-NX1 060X1 061, -NH-C(O)-NH-O X1062, -NH-C(O)-NX1 063-O-X1064, -NX1 065-C(O)-NX1066-0 10 X1 067, -N(-C(O)-NH-O-X1 068)2, -N(-C(O)-NX1 069-O-X1 070)2, -N( C(O)-NH-O-X1 071)(-C(O)-NX1 072-O-X1 073), -C(S)-X1 074, -C(S)-O X1 075, -C(S)-NH-X1 076, -C(S)-NX1 077X1 078, -C(O)-NH-O-X1 079, C(O)-NX1 080-O-X1 081, -C(S)-NH-O-X1 082, -C(S)-NX1 083-O-X1 084, -C(O)-NH-NH-X1 085, -C(O)-NH-NX1 086X1 087, -C(O)-NX1 088 15 NX1 089X1 090, -C(S)-NH-NH-X1 091, -C(S)-NH-NX1 092X1 093, -C(S) NX1 094-NX1 095X1 096, -C(O)-C(O)-O-X1 097, -C(O)-C(O)-NH 2 , -C(O) C(O)-NHX1 098, -C(O)-C(O)-NX1 099X1 100, -C(S)-C(O)-O-X1 101, C(O)-C(S)-O-X1 102, -C(S)-C(S)-O-X1 103, -C(S)-C(O)-NH 2 , -C(S) C(O)-NHX1 104, -C(S)-C(O)-NX1 105X1 106, -C(S)-C(S)-NH 2 , -C(S) 20 C(S)-NHX1 107, -C(S)-C(S)-NX1 108X1 109, -C(O)-C(S)-NH 2 , -C(O) C(S)-NHX1 110, -C(O)-C(S)-NX1 111 X1112"; wherein X1001, X1002, X1003, X1004, X1005, X1006, X1007, X1008, X1 009, X1 010, X1011, X1012, X1 013, X1014, X1015, X1 016, X1 017, X1018, X1019, X1020, X1021, X1022, X1023, X1024, X1025, X1026, 25 X1027,X1028,X1029,X1030,X1031,X1032, X1033,X1034,X1035, X1 036, X1 037, X1038, X1039, X1 040, X1041, X1042, X1 043, X1 044, X1045, X1046, X1047, X1048, X1049, X1050, X1051, X1052, X1053, X1054, X1055,X1056, X1057, X1058, X1059, X1060, X1061, X1062, X1 063, X1 064, X1065, X1066, X1 067, X1068, X1069, X1 070, X1 071, 30 X1072,X1073,X1074,X1075,X1076,X1077, X1078,X1079,X1080, X1081, X1082, X1083, X1084, X1085, X1086, X1087, X1088, X1089, X1090, X1091, X1092, X1093, X1094, X1095, X1096, X1097, X1098, X1099, X1100, X1101, X1102, X1103, X1104, X1105,X1106, X1107, X1108, X1109, X1110, X1111, X1112 are independently from each other 35 selected from the group consisting of: ,alkyl, (C 9
-C
3 o)alkyl, cycloalkyl, WO 2008/132153 PCT/EP2008/055039 - 18 cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively X1007, X1008 and/or X1016, X1017 and/or X1029, X1030 and/or X1036, X1037 and/or X1045, X1046 and/or X1055, X1056 and/or X1060, X1061 and/or X1077, X1078 and/or 5 X1086, X1087 and/or X1089, X1090 and/or X1092, X1093 and/or X1095, X1096 and/or X1099, X1100 and/or X1105, X1106 and/or X1108, X1109 and/or X1111, X1 112 and/or respectively together can also form ,heterocy clyl"; wherein optionally above substituents of substituents group (i) can in turn 10 independently from each other be substituted with at least one substituent, identical or different, selected from the group consisting of: (ii) ,alkyl, (C 9 -Co)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycly lalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, CF 3 , -N 3 , -NH 2 , -NHX1201, -NX1202X1203, -NO 2 , -OH, =O, -OCF 3 , 15 SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, P(O)(OH) 2 , -C(O)-X1204, -C(O)O-X1205, -C(O)NH-X1206, C(O)NX1207X1208, -O-X1209, -O(-X1210O-)m-H (m = 1, 2, 3, 4, 5), -O(-X 1211-O)-X1212 (n = 1, 2, 3, 4, 5), -OC(O)-X1213, -OC(O)-O X1214, -OC(O)-NHX1215, -O-C(O)-NX1216X1217, 20 OP(O)(OX1 218)(OX1 219), -OSi(X1 220)(X1 221)(X1 222), -OS(O2) X1 223, -NHC(O)-NH 2 , -NHC(O)-X1 224, -NX1 225C(O)-X1 226, -NH C(O)-O-X1227, -NH-C(O)-NH-X1228, -NH-C(O)-NX1 229X1230, NX1 231 -C(O)-O-X1 232, -NX1 233-C(O)-NH-X1 234, -NX1 235-C(O) NX1236X1237, -NHS(0 2 )-X1238, -NX1239S(0 2 )-X1240, -S-X1241, 25 S(O)-X1 242, -S(0 2 )-X1 243, -S(0 2 )NH-X1 244, -S(0 2 )NX1 245X1 246, -S(0 2 )O-X1 247, -P(O)(OX1 248)(OX1 249), -Si(X1 250)(X1 251)(X1 252),
-C(NH)-NH
2 , -C(NX1 253)-NH 2 , -C(NH)-NHX1 254, -C(NH) NX1 255X1 256, -C(NX1 257)-NHX1 258, -C(NX1 259)-NX1 260X1 261, NH-C(O)-NH-O-X1262, -NH-C(O)-NX1 263-O-X1264, -NX1265 30 C(O)-NX1266-O-X1267, -N(-C(O)-NH-O-X1268)2, -N(-C(O) NX1 269-O-X1 270)2, -N(-C(O)-NH-O-X1 271)(-C(O)-NX1 272-0 X1 273), -C(S)-X1 274, -C(S)-O-X1 275, -C(S)-NH-X1 276, -C(S) NX1 277X1 278, -C(O)-NH-O-X1 279, -C(O)-NX1 280-O-X1 281, C(S)-NH-O-X1282, -C(S)-NX1 283-O-X1284, -C(O)-NH-NH-X1285, 35 -C(O)-N H-NX1 286X1287, -C(O)-NX1 288-NX1 289X1290, -C(S)-N H- WO 2008/132153 PCT/EP2008/055039 - 19 NH-X1 291, -C(S)-NH-NX1 292X1 293, -C(S)-NX1 294-NX1 295X1 296, -C(O)-C(O)-O-X 1297, -C(O)-C(O)-N H 2 , -C(O)-C(O)-N HX 1298, C(O)-C(O)-NX1 299X1300, -C(S)-C(O)-O-X1301, -C(O)-C(S)-O X1 302, -C(S)-C(S)-O-X1 303, -C(S)-C(O)-NH 2 , -C(S)-C(O) 5 NHX1304, -C(S)-C(O)-NX1305X1306, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHX1307, -C(S)-C(S)-NX1 308X1309, -C(O)-C(S)-NH 2 , -C(O)-C(S) NHX1310, -C(O)-C(S)-NX131 1X1312"; wherein X1201, X1 202, X1203, X1204, X1 205, X1206, X1207, X1208, X1 209, X1210, X1211, X1212, X1 213, X1214, X1215, X1 216, X1 217, 10 X1218,X1219,X1220,X1221,X1222, X1223, X1224,X1225,X1226, X1 227, X1228, X1229, X1230, X1 231, X1232, X1233, X1 234, X1 235, X1 236, X1237, X1238, X1239, X1 240, X1241, X1242, X1 243, X1 244, X1245, X1246, X1247, X1248, X1249, X1250, X1251, X1252, X1253, X1254, X1255, X1256, X1257, X1258, X1259, X1260, X1261, X1262, 15 X1263,X1264,X1265,X1266,X1267, X1268, X1269,X1270,X1271, X1272, X1273, X1274, X1275, X1276, X1277, X1278, X1279, X1280, X1281, X1282, X1283, X1284, X1285, X1286, X1287, X1288, X1289, X1290, X1291, X1292, X1293, X1294, X1295, X1296, X1297, X1298, X1299, X1300, X1301, X1302, X1303, X1304, X1305, X1306, X1307, 20 X1308, X1309, X1310, X1311, X1312 are independently from each other selected from the group consisting of: ,alkyl, (C 9
-C
30 )alkyl, cycloal kyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, het eroaryl, heteroarylalkyl" and wherein alternatively X1 207, X1 208 and/or X1 216, X1 217 and/or X1 229, X1 230 and/or X1 236, X1 237 and/or 25 X1245, X1246 and/or X1255, X1256 and/or X1260, X1261 and/or X1 277, X1 278 and/or X1 286, X1 287 and/or X1 289, X1 290 and/or X1 292, X1 293 and/or X1 295, X1 296 and/or X1 299, X1 300 and/or X1 305, X1 306 and/or X1 308, X1 309 and/or X1 311, X1 312 and/or re spectively together can also form ,heterocyclyl"; 30 wherein optionally above substituents of substituents group (ii) can in turn independently from each other be substituted with at least one sub stituent, identical or different, selected from the group consisting of: (iii) ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero cyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, WO 2008/132153 PCT/EP2008/055039 - 20 -CN, -CF 3 , -N 3 , -NH 2 , -NHX1401, -NX1402X1403, -NO 2 , -OH, =O, -OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, C(O)NH 2 , -SO 3 H, -P(O)(OH) 2 , -C(O)-X1 404, -C(O)O-X1 405, C(O)NH-X1406, -C(O)NX1407X1408, -O-X1409, -O(-X1410-O)o 5 H (o = 1, 2, 3, 4, 5), -O(-X1411-O)p-X1412 (p = 1, 2, 3, 4, 5), OC(O)-X1413, -OC(O)-O-X1414, -OC(O)-NHX1415, -0-C(O) NX1416X1417, -OP(O)(OX1418)(OX1419), OSi(X1 420)(X1 421)(X1 422), -OS(0 2 )-X1 423, -NHC(O)-NH 2 , NHC(O)-X1 424, -NX1 425C(O)-X1 426, -NH-C(O)-O-X1 427, 10 NH-C(O)-NH-X1428, -NH-C(O)-NX1 429X1430, -NX1431-C(O) O-X1432, -NX1 433-C(O)-NH-X1434, -NX1 435-C(O) NX1 436X1 437, -NHS(0 2 )-X1 438, -NX1 439S(0 2 )-X1 440, -S X1441, -S(O)-X1442, -S(0 2 )-X1443, -S(0 2 )NH-X1444, S(0 2 )NX1445X1446, -S(0 2 )O-X1447, -P(O)(OX1448)(OX1449), 15 Si(X1 450)(X1 451)(X1 452), -C(NH)-NH 2 , -C(NX1 453)-NH 2 , C(NH)-NHX1454, -C(NH)-NX1 455X1456, -C(NX1 457)-NHX1458, -C(NX1 459)-NX1 460X1461, -NH-C(O)-NH-O-X1462, -NH C(O)-NX1 463-O-X1 464, -NX1 465-C(O)-NX1 466-O-X1467, -N( C(O)-NH-O-X1468)2, -N(-C(O)-NX1469-O-X1470)2, -N(-C(O) 20 NH-O-X1471)(-C(O)-NX1 472-O-X1 473), -C(S)-X1474, -C(S) O-X1475, -C(S)-NH-X1476, -C(S)-NX1477X1478, -C(O)-NH-O X1479, -C(O)-NX1 480-O-X1481, -C(S)-N H-O-X1482, -C(S) NX 1 483-O-X 1484, -C(O)-N H-NH-X 1485, -C(O)-NH NX1 486X1 487, -C(O)-NX1 488-NX1 489X1 490, -C(S)-NH-NH 25 Xl 491, -C(S)-NH-NX1 492X1 493, -C(S)-NX1 494-NX1 495X1 496, -C(O)-C(O)-O-X 1497, -C(O)-C(O)-N H 2 , -C(O)-C(O)-N HX 1498, -C(O)-C(O)-NX1499X1500, -C(S)-C(O)-O-X1501, -C(O)-C(S) O-X1502, -C(S)-C(S)-O-X1503, -C(S)-C(O)-N H 2 , -C(S)-C(O) NHX1 504, -C(S)-C(O)-NX1 505X1 506, -C(S)-C(S)-NH 2 , -C(S) 30 C(S)-NHX1507, -C(S)-C(S)-NX1508X1509, -C(O)-C(S)-NH 2 , C(O)-C(S)-NHX1510, -C(O)-C(S)-NX1511 X1512"; wherein X1401, X1402, X1403, X1404, X1405, X1406, X1407, X1408, X1409, X1410, X1411, X1412, X1413, X1414, X1415, X1416, X1417, X1418, X1419, X1420, X1421, X1422, X1423, 35 X1424,X1425,X1426,X1427,X1428, X1429, X1430,X1431, WO 2008/132153 PCT/EP2008/055039 - 21 X1432, X1433, X1434, X1435, X1436, X1437, X1 438, X1439, X1440, X1441, X1442, X1443, X1444, X1445, X1446, X1447, X1448, X1449, X1450, X1451, X1452, X1453, X1454, X1455, X1456, X1457, X1458, X1459, X1460, X1461, X1462, X1463, 5 X1464, X1465, X1466, X1467, X1468, X1469, X1470, X1471, X1472, X1473, X1474, X1475, X1476, X1477, X1478, X1479, X1480, X1481, X1482, X1483, X1484, X1485, X1486, X1487, X1488, X1489, X1490, X1491, X1492, X1493, X1494, X1495, X1496, X1497, X1498, X1499, X1500, X1501, X1 502, X1 503, 10 X1504,X1505,X1506,X1507,X1508, X1509, X1510,X1511, X1 512 are independently from each other selected from the group consisting of: ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, hetero cyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively X1 407, X1 408 and/or X1 416, X1 417 15 and/or X1429, X1430 and/or X1436, X1437 and/or X1445, X1446 and/or X1455, X1456 and/or X1460, X1461 and/or X1477, X1478 and/or X1486, X1487 and/or X1489, X1490 and/or X1492, X1493 and/or X1495, X1496 and/or X1499, X1500 and/or X1505, X1506 and/or X1 508, X1 509 and/or X1 511, X1 512 and/or respectively to 20 gether can also form ,heterocyclyl"; or (B) V, W are independently from each other selected from the group consisting of: 25 "=O, =S, =S*-O-, geminally linked H 2 "; R1f*, R2 together independently form "heterocyclyl" or together independently form "heteroaryl"; where "heterocyclyl" and "heteroaryl" can optionally be substi tuted with at least one substituent selected from below substituents group (i); R1, R3 are independently from each other selected from the group consisting 30 of: (i) ,,hydrogen, alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, het erocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, CN, -CF 3 , -N 3 , -NH 2 , -NHZ1, -NZ2Z3, -NO 2 , -OH, =0, -OCF, -SH, -0- WO 2008/132153 PCT/EP2008/055039 - 22 SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, -P(O)(OH) 2 , C(O)-Z4, -C(O)O-Z5, -C(O)NH-Z6, -C(O)NZ7Z8, -O-Z9, -O(-Z10-O)a H (a = 1, 2, 3, 4, 5), -O(-Z1 1-O)b-Zl 2 (b = 1, 2, 3, 4, 5), -OC(O)-Z13, OC(O)-O-Z1 4, -OC(O)-NHZ1 5, -O-C(O)-NZ1 6Z1 7, 5 OP(O)(OZ1 8)(OZ1 9), -OSi(Z20)(Z21)(Z22), -OS(O 2 )-Z23, -NHC(O)-NH 2 , -NHC(O)-Z24, -NZ25C(O)-Z26, -NH-C(O)-O-Z27, -NH-C(O)-NH-Z28, -NH-C(O)-NZ29Z30, -NZ31-C(O)-O-Z32, -NZ33-C(O)-NH-Z34, NZ35-C(O)-NZ36Z37, -NHS(O 2 )-Z38, -NZ39S(O 2 )-Z40, -S-Z41, -S(O) Z42, -S(0 2 )-Z43, -S(O 2 )NH-Z44, -S(O 2 )NZ45Z46, -S(O 2 )O-Z47, 10 P(O)(OZ48)(OZ49), -Si(Z50)(Z51)(Z52), -C(NH)-NH 2 , -C(NZ53)-NH 2 , C(NH)-NHZ54, -C(NH)-NZ55Z56, -C(NZ57)-NHZ58, -C(NZ59) NZ60Z61, -NH-C(O)-NH-O-Z62, -NH-C(O)-NZ63-O-Z64, -NZ65 C(O)-NZ66-O-Z67, -N(-C(O)-NH-O-Z68) 2 , -N(-C(O)-NZ69-O-Z70) 2 , N(-C(O)-NH-O-Z71)(-C(O)-NZ72-O-Z73), -C(S)-Z74, -C(S)-O-Z75, 15 C(S)-NH-Z76, -C(S)-NZ77Z78, -C(O)-NH-O-Z79, -C(O)-NZ80-O-Z81, -C(S)-NH-O-Z82, -C(S)-NZ83-O-Z84, -C(O)-NH-NH-Z85, -C(O)-NH NZ86Z87, -C(O)-NZ88-NZ89Z90, -C(S)-NH-NH-Z91, -C(S)-NH NZ92Z93, -C(S)-NZ94-NZ95Z96, -C(O)-C(O)-O-Z97, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHZ98, -C(O)-C(O)-NZ99Z1 00, -C(S)-C(O)-O-Z1 01, 20 C(O)-C(S)-O-Z1 02, -C(S)-C(S)-O-Z1 03, -C(S)-C(O)-NH 2 , -C(S)-C(O) NHZ1 04, -C(S)-C(O)-NZ1 05Z1 06, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHZ1 07, -C(S)-C(S)-NZ1 08Z1 09, -C(O)-C(S)-NH 2 , -C(O)-C(S) NHZ1 10, -C(O)-C(S)-NZ1 11 Z1 12"; wherein Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z1 0, Z1 1, Z1 2, Z1 3, Z1 4, Z1 5, 25 Z16,Z17,Z18,Z19,Z20,Z21,Z22,Z23,Z24,Z25,Z26,Z27,Z28,Z29, Z30,Z31,Z32,Z33,Z34,Z35,Z36,Z37,Z38,Z39,Z40,Z41,Z42,Z43, Z44,Z45,Z46,Z47,Z48,Z49,Z50,Z51,Z52,Z53,Z54,Z55,Z56,Z57, Z58,Z59,Z60,Z61,Z62,Z63,Z64,Z65,Z66,Z67,Z68,Z69,Z70,Z71, Z72,Z73,Z74,Z75,Z76,Z77,Z78,Z79,Z80,Z81,Z82,Z83,Z84,Z85, 30 Z86,Z87,Z88,Z89,Z90,Z91,Z92,Z93,Z94,Z95,Z96,Z97,Z98,Z99, Z100,Z101,Z102,Z103,Z104,Z105,Z106,Z107,Z108,Z109,Z110, Z1 11, Z1 12 are independently from each other selected from the group consisting of: ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein al 35 ternatively Z7, Z8 and/or Z1 6, Z1 7 and/or Z29, Z30 and/or Z36, Z37 and/or WO 2008/132153 PCT/EP2008/055039 - 23 Z45, Z46 and/or Z55, Z56 and/or Z60, Z61 and/or Z77, Z78 and/or Z86, Z87 and/or Z89, Z90 and/or Z92, Z93 and/or Z95, Z96 and/or Z99, Z1 00 and/or Z1 05, Z1 06 and/or Z1 08, Z1 09 and/or Z1 11, Z1 12 and/or respectively to gether can also form ,heterocyclyl"; 5 wherein optionally above substituents of substituents group (i) can in turn independently from each other be substituted with at least one substituent, identical or different, selected from the group consisting of: (ii) ,alkyl, (C 9 -Co)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycly lalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, 10 CF 3 , -N 3 , -NH 2 , -NHZ201, -NZ202Z203, -NO 2 , -OH, =O, -OCF, -SH,
-O-SO
3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -S0 3 H, P(O)(OH) 2 , -C(O)-Z204, -C(O)O-Z205, -C(O)NH-Z206, C(O)NZ207Z208, -O-Z209, -O(-Z21 0-O)c-H (c = 1, 2, 3, 4, 5), -O( Z211-O)d-Z212 (d = 1, 2, 3, 4, 5), -OC(O)-Z213, -OC(O)-O-Z214, 15 OC(O)-NHZ215, -O-C(O)-NZ216Z217, -OP(O)(OZ218)(OZ219), OSi(Z220)(Z221)(Z222), -OS(0 2 )-Z223, -NHC(O)-NH 2 , -NHC(O) Z224, -NZ225C(O)-Z226, -NH-C(O)-O-Z227, -NH-C(O)-NH-Z228, NH-C(O)-NZ229Z230, -NZ231-C(O)-O-Z232, -NZ233-C(O)-NH Z234, -NZ235-C(O)-NZ236Z237, -NHS(0 2 )-Z238, -NZ239S(0 2
)
20 Z240, -S-Z241, -S(O)-Z242, -S(0 2 )-Z243, -S(0 2 )NH-Z244, S(02)NZ245Z246, -S(0 2 )O-Z247, -P(O)(OZ248)(OZ249), Si(Z250)(Z251)(Z252), -C(NH)-NH 2 , -C(NZ253)-NH 2 , -C(NH) NHZ254, -C(NH)-NZ255Z256, -C(NZ257)-NHZ258, -C(NZ259) NZ260Z261, -NH-C(O)-NH-O-Z262, -NH-C(O)-NZ263-O-Z264, 25 NZ265-C(O)-NZ266-O-Z267, -N(-C(O)-NH-O-Z268) 2 , -N(-C(O) NZ269-O-Z270) 2 , -N(-C(O)-NH-O-Z271)(-C(O)-NZ272-O-Z273), C(S)-Z274, -C(S)-O-Z275, -C(S)-NH-Z276, -C(S)-NZ277Z278, C(O)-NH-O-Z279, -C(O)-NZ280-O-Z281, -C(S)-NH-O-Z282, C(S)-NZ283-O-Z284, -C(O)-NH-NH-Z285, -C(O)-NH-NZ286Z287, 30 -C(O)-NZ288-NZ289Z290, -C(S)-NH-NH-Z291, -C(S)-NH NZ292Z293, -C(S)-NZ294-NZ295Z296, -C(O)-C(O)-O-Z297, -C(O)
C(O)-NH
2 , -C(O)-C(O)-NHZ298, -C(O)-C(O)-NZ299Z300, -C(S) C(O)-O-Z301, -C(O)-C(S)-O-Z302, -C(S)-C(S)-O-Z303, -C(S)
C(O)-NH
2 , -C(S)-C(O)-NHZ304, -C(S)-C(O)-NZ305Z306, -C(S)- WO 2008/132153 PCT/EP2008/055039 - 24 C(S)-NH 2 , -C(S)-C(S)-NHZ307, -C(S)-C(S)-NZ308Z309, -C(O)
C(S)-NH
2 , -C(O)-C(S)-NHZ31 0, -C(O)-C(S)-NZ31 1 Z312"; wherein Z201, Z202, Z203, Z204, Z205, Z206, Z207, Z208, Z209, Z210, Z211,Z212,Z213,Z214,Z215,Z216,Z217,Z218,Z219,Z220,Z221, 5 Z222,Z223,Z224,Z225,Z226,Z227,Z228,Z229,Z230,Z231,Z232, Z233,Z234,Z235,Z236,Z237,Z238,Z239,Z240,Z241,Z242,Z243, Z244,Z245,Z246,Z247,Z248,Z249,Z250,Z251,Z252,Z253,Z254, Z255,Z256,Z257,Z258,Z259,Z260,Z261,Z262,Z263,Z264,Z265, Z266,Z267,Z268,Z269,Z270,Z271,Z272,Z273,Z274,Z275,Z276, 10 Z277,Z278,Z279,Z280,Z281,Z282,Z283,Z284,Z285,Z286,Z287, Z288,Z289,Z290,Z291,Z292,Z293,Z294,Z295,Z296,Z297,Z298, Z299,Z300,Z301,Z302,Z303,Z304,Z305,Z306,Z307,Z308,Z309, Z31 0, Z31 1, Z312 are independently from each other selected from the group consisting of: ,alkyl, (C 9
-C
3 o)alkyl, cycloalkyl, cycloalkylalkyl, het 15 erocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively Z207, Z208 and/or Z216, Z217 and/or Z229, Z230 and/or Z236, Z237 and/or Z245, Z246 and/or Z255, Z256 and/or Z260, Z261 and/or Z277, Z278 and/or Z286, Z287 and/or Z289, Z290 and/or Z292, Z293 and/or Z295, Z296 and/or Z299, Z300 and/or Z305, 20 Z306 and/or Z308, Z309 and/or Z31 1, Z312 and/or respectively together can also form ,heterocyclyl"; wherein optionally above substituents of substituents group (ii) can in turn independently from each other be substituted with at least one sub stituent, identical or different, selected from the group consisting of: 25 (iii) ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero cyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, -CF 3 , -N 3 , -NH 2 , -NHZ401, -NZ402Z403, -NO 2 , -OH, =O, OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , SO 3 H, -P(O)(OH) 2 , -C(O)-Z404, -C(O)O-Z405, -C(O)NH-Z406, 30 C(O)NZ407Z408, -O-Z409, -0(-Z410-0)e-H (e = 1, 2, 3, 4, 5), O(-Z411-O)f-Z412 (f = 1, 2, 3, 4, 5), -OC(O)-Z413, -OC(O)-O Z414, -OC(O)-NHZ415, -O-C(O)-NZ416Z417, OP(O)(OZ418)(OZ419), -OSi(Z420)(Z421)(Z422), -OS(0 2 )-Z423, NHC(O)-NH 2 , -NHC(O)-Z424, -NZ425C(O)-Z426, -NH-C(O)-O- WO 2008/132153 PCT/EP2008/055039 - 25 Z427, -NH-C(O)-NH-Z428, -NH-C(O)-NZ429Z430, -NZ431 C(O)-O-Z432, -NZ433-C(O)-NH-Z434, -NZ435-C(O) NZ436Z437, -NHS(0 2 )-Z438, -NZ439S(0 2 )-Z440, -S-Z441, S(O)-Z442, -S(0 2 )-Z443, -S(0 2 )NH-Z444, -S(0 2 )NZ445Z446, 5 S(0 2 )0-Z447, -P(O)(OZ448)(OZ449), -Si(Z450)(Z451)(Z452), C(NH)-NH 2 , -C(NZ453)-NH 2 , -C(NH)-NHZ454, -C(NH) NZ455Z456, -C(NZ457)-NHZ458, -C(NZ459)-NZ460Z461, -NH C(O)-NH-O-Z462, -NH-C(O)-NZ463-O-Z464, -NZ465-C(O) NZ466-O-Z467, -N(-C(O)-NH-O-Z468) 2 , -N(-C(O)-NZ469-O 10 Z470) 2 , -N(-C(O)-NH-O-Z471)(-C(O)-NZ472-O-Z473), -C(S) Z474, -C(S)-O-Z475, -C(S)-NH-Z476, -C(S)-NZ477Z478, -C(O) NH-O-Z479, -C(O)-NZ480-O-Z481, -C(S)-NH-O-Z482, -C(S) NZ483-O-Z484, -C(O)-NH-NH-Z485, -C(O)-NH-NZ486Z487, C(O)-NZ488-NZ489Z490, -C(S)-NH-NH-Z491, -C(S)-NH 15 NZ492Z493, -C(S)-NZ494-NZ495Z496, -C(O)-C(O)-O-Z497, C(O)-C(O)-NH 2 , -C(O)-C(O)-NHZ498, -C(O)-C(O)-NZ499Z500, -C(S)-C(O)-O-Z501, -C(O)-C(S)-O-Z502, -C(S)-C(S)-O-Z503,
-C(S)-C(O)-NH
2 , -C(S)-C(O)-NHZ504, -C(S)-C(O)-NZ505Z506,
-C(S)-C(S)-NH
2 , -C(S)-C(S)-NHZ507, -C(S)-C(S)-NZ508Z509, 20 C(O)-C(S)-NH 2 , -C(O)-C(S)-NHZ510, -C(O)-C(S)-NZ51 1Z512"; wherein Z401, Z402, Z403, Z404, Z405, Z406, Z407, Z408, Z409, Z410, Z411, Z412, Z413, Z414, Z415, Z416, Z417, Z418, Z419, Z420,Z421,Z422,Z423,Z424,Z425,Z426,Z427,Z428,Z429, Z430,Z431,Z432,Z433,Z434,Z435,Z436,Z437,Z438,Z439, 25 Z440,Z441,Z442,Z443,Z444,Z445,Z446,Z447,Z448,Z449, Z450,Z451,Z452,Z453,Z454,Z455,Z456,Z457,Z458,Z459, Z460,Z461,Z462,Z463,Z464,Z465,Z466,Z467,Z468,Z469, Z470,Z471,Z472,Z473,Z474,Z475,Z476,Z477,Z478,Z479, Z480,Z481,Z482,Z483,Z484,Z485,Z486,Z487,Z488,Z489, 30 Z490,Z491,Z492,Z493,Z494,Z495,Z496,Z497,Z498,Z499, Z500,Z501,Z502,Z503,Z504,Z505,Z506,Z507,Z508,Z509, Z510, Z511, Z512 are independently from each other selected from the group consisting of: ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylal kyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, het 35 eroarylalkyl" and wherein alternatively Z407, Z408 and/or Z416, WO 2008/132153 PCT/EP2008/055039 - 26 Z417 and/or Z429, Z430 and/or Z436, Z437 and/or Z445, Z446 and/or Z455, Z456 and/or Z460, Z461 and/or Z477, Z478 and/or Z486, Z487 and/or Z489, Z490 and/or Z492, Z493 and/or Z495, Z496 and/or Z499, Z500 and/or Z505, Z506 and/or Z508, Z509 5 and/or Z51 1, Z512 and/or respectively together can also form ,,het erocyclyl"; alternatively, R1, R3 can also independently from each other be "no substitu ent"; n independently is 1; 10 m independently is 1 or 2; R4m, R5m, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R1 9, R20, R21, R22 are independently from each other selected from the group consisting of: (i) ,,hydrogen, alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, het 15 erocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -CI, -Br, -1, CN, -CF 3 , -N 3 , -NH 2 , -NHZ1 001, -NZ1 002Z1 003, -NO 2 , -OH, =0, -OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, P(O)(OH) 2 , -C(O)-Zi 004, -C(O)O-Zi 005, -C(O)NH-Z1 006, C(O)NZ1 007Z1 008, -O-Z1 009, -O(-Z1 01 0-O)k-H (k = 1, 2, 3, 4, 5), -O( 20 Zi 011-O)i-Z1012 (I = 1, 2, 3, 4, 5), -OC(O)-Z1013, -OC(O)-O-Z1014, OC(O)-NHZ1 015, -O-C(O)-NZ1 01 6Z1 017, -OP(O)(OZ1 01 8)(OZ1 019), OSi(Z1 020)(Z1 021)(Z1 022), -OS(0 2 )-Z1 023, -NHC(O)-NH 2 , -NHC(O) Z1 024, -NZ1 025C(O)-Zi 026, -NH-C(O)-O-Z1 027, -NH-C(O)-NH Z1 028, -NH-C(O)-NZ1 029Z1 030, -NZ1 031 -C(O)-O-Z1 032, -NZ1 033 25 C(O)-NH-Z1 034, -NZ1 035-C(O)-NZ1 036Z1 037, -NHS(0 2 )-Z1 038, NZ1 039S(0 2 )-Z1 040, -S-Z1 041, -S(O)-Z1 042, -S(0 2 )-Z1 043, S(0 2 )NH-Z1044, -S(0 2 )NZ1045Z1046, -S(0 2 )O-Z1047, P(O)(OZ1 048)(OZ1 049), -Si(Z1 050)(Z1 051)(Z1 052), -C(NH)-NH 2 , C(NZ1 053)-NH 2 , -C(NH)-NHZ1 054, -C(NH)-NZ1 055Z1 056, -C(NZ1 057) 30 NHZ1 058, -C(NZ1 059)-NZ1 060Z1 061, -NH-C(O)-NH-O-Z1 062, -NH C(O)-NZ1 063-O-Z1 064, -NZ1 065-C(O)-NZ1 066-O-Z1 067, -N(-C(O) NH-O-Z1 068)2, -N(-C(O)-NZ1 069-O-Z1 070)2, -N(-C(O)-NH-O Z1 071)(-C(O)-NZ1 072-O-Z1 073), -C(S)-Z1 074, -C(S)-O-Z1 075, -C(S) NH-Z1 076, -C(S)-NZ1 077Z1 078, -C(O)-NH-O-Z1 079, -C(O)-NZ1 080- WO 2008/132153 PCT/EP2008/055039 - 27 O-Z1 081, -C(S)-NH-O-Z1 082, -C(S)-NZ1 083-O-Z1 084, -C(O)-NH NH-Z1 085, -C(O)-NH-NZ1 086Z1 087, -C(O)-NZ1 088-NZ1 089Z1 090, C(S)-NH-NH-Z1 091, -C(S)-NH-NZ1 092Z1 093, -C(S)-NZ1 094 NZ1 095Z1 096, -C(O)-C(O)-O-Z1 097, -C(O)-C(O)-NH 2 , -C(O)-C(O) 5 NHZ1 098, -C(O)-C(O)-NZ1 099Z1 100, -C(S)-C(O)-O-Z1 101, -C(O) C(S)-O-Z1 102, -C(S)-C(S)-O-Z1 103, -C(S)-C(O)-NH 2 , -C(S)-C(O) NHZ1 104, -C(S)-C(O)-NZ 105Z1 106, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHZ1 107, -C(S)-C(S)-NZ 108Z1 109, -C(O)-C(S)-NH 2 , -C(O)-C(S) NHZ1 110, -C(O)-C(S)-NZ1 111 Z1 112"; 10 wherein X1001, X1002, X1003, X1004, X1005, X1006, X1007, X1008, X1 009, X1 010, X1011, X1012, X1 013, X1014, X1015, X1 016, X1 017, X1018, X1019, X1020, X1021, X1022, X1023, X1024, X1025, X1026, X1027, X1028, X1029, X1030, X1031, X1032, X1033, X1034, X1035, X1 036, X1 037, X1038, X1039, X1 040, X1041, X1042, X1 043, X1 044, 15 X1045,X1046,X1047,X1048,X1049,X1050, X1051,X1052,X1053, X1054, X1055, X1056, X1057, X1058, X1059, X1060, X1061, X1062, X1 063, X1 064, X1065, X1066, X1 067, X1068, X1069, X1 070, X1 071, X1072, X1073, X1074, X1075, X1076, X1077, X1078, X1079, X1080, X1081, X1082, X1083, X1084, X1085, X1086, X1087, X1088, X1089, 20 X1090,X1091,X1092,X1093,X1094,X1095, X1096,X1097,X1098, X1099, X1100, X1101, X1102, X1103, X1104, X1105, X1106, X1107, X1108, X1109, X1110, X1111, X1112 are independently from each other selected from the group consisting of: ,alkyl, (C 9
-C
3 o)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, 25 heteroarylalkyl" and wherein alternatively X1 007, X1 008 and/or X1 016, X1017 and/or X1029, X1030 and/or X1036, X1037 and/or X1045, X1046 and/or X1055, X1056 and/or X1060, X1061 and/or X1077, X1078 and/or X1086, X1087 and/or X1089, X1090 and/or X1092, X1093 and/or X1095, X1096 and/or X1099, X1100 and/or X1105, X1106 and/or X1108, X1109 30 and/or X1111, X1 112 and/or respectively together can also form ,heterocy clyl"; wherein optionally above substituents of substituents group (i) can in turn independently from each other be substituted with at least one substituent, identical or different, selected from the group consisting of: WO 2008/132153 PCT/EP2008/055039 - 28 (ii) ,alkyl, (C 9 -C o)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycly lalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -CI, -Br, -1, -CN, CF 3 , -N 3 , -NH 2 , -NHZ1201, -NZ1202Z1203, -NO 2 , -OH, =O, -OCF, SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, 5 P(O)(OH) 2 , -C(O)-Z1 204, -C(O)O-Z1 205, -C(O)NH-Z1 206, C(O)NZ1 207Z1 208, -O-Z1 209, -0(-Z1210-0)m-H (m = 1, 2, 3, 4, 5), O(-Z1211-0),-Z1212 (n = 1, 2, 3, 4, 5), -OC(O)-Z1 213, -OC(O)-O Z1 214, -OC(O)-NHZ1 215, -O-C(O)-NZ1 216Z1 217, OP(O)(OZ1 218)(OZ1 219), -OSi(Z1 220)(Z1 221)(Z1 222), -OS(O 2
)
10 Z1 223, -NHC(O)-NH 2 , -NHC(O)-Z1 224, -NZ1 225C(O)-Z1 226, -NH C(O)-O-Z1 227, -NH-C(O)-NH-Z1 228, -NH-C(O)-NZ1 229Z1 230, NZ1 231 -C(O)-O-Z1 232, -NZ1 233-C(O)-NH-Z1 234, -NZ1 235-C(O) NZ1 236Z1 237, -NHS(0 2 )-Z1 238, -NZ1 239S(0 2 )-Z1 240, -S-Z1 241, S(O)-Z1242, -S(0 2 )-Z1243, -S(0 2 )NH-Z1244, -S(0 2 )NZ1245Z1246, 15 S(0 2 )O-Z1 247, -P(O)(OZ1 248)(OZ1 249), -Si(Z1 250)(Z1 251)(Z1 252), C(NH)-NH 2 , -C(NZ1 253)-NH 2 , -C(NH)-NHZ1 254, -C(NH) NZ1 255Z1 256, -C(NZ1 257)-NHZ1 258, -C(NZ1 259)-NZ1 260Z1 261, NH-C(O)-NH-O-Z1 262, -NH-C(O)-NZ1 263-O-Z1 264, -NZ1 265 C(O)-NZ1 266-O-Z1 267, -N(-C(O)-NH-O-Z1 268)2, -N(-C(O) 20 NZ1 269-O-Z1 270)2, -N(-C(O)-NH-O-Z1 271)(-C(O)-NZ1 272-0 Z1 273), -C(S)-Z1 274, -C(S)-O-Z1 275, -C(S)-NH-Z1 276, -C(S) NZ1 277Z1 278, -C(O)-NH-O-Z1 279, -C(O)-NZ1 280-O-Z1 281, C(S)-NH-O-Z1 282, -C(S)-NZ1 283-O-Z1 284, -C(O)-NH-NH-Z1 285, -C(O)-NH-NZ1 286Z1 287, -C(O)-NZ1 288-NZ1 289Z1 290, -C(S)-NH 25 NH-Z1 291, -C(S)-NH-NZ1 292Z1 293, -C(S)-NZ1 294-NZ1 295Z1 296, -C(O)-C(O)-O-Z1 297, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHZ1 298, C(O)-C(O)-NZ1 299Z1 300, -C(S)-C(O)-O-Z1 301, -C(O)-C(S)-O Z1 302, -C(S)-C(S)-O-Z1 303, -C(S)-C(O)-NH 2 , -C(S)-C(O) NHZ1 304, -C(S)-C(O)-NZ1 305Z1 306, -C(S)-C(S)-NH 2 , -C(S)-C(S) 30 NHZ1 307, -C(S)-C(S)-NZ1 308Z1 309, -C(O)-C(S)-NH 2 , -C(O)-C(S) NHZ1 310, -C(O)-C(S)-NZ1311Z1312"; wherein Z1 201, Z1 202, Z1 203, Z1 204, Z1 205, Z1 206, Z1 207, Z1 208, Z1209, Z1210, Z1211, Z1212, Z1213, Z1214, Z1215, Z1216, Z1217, Z1218,Z1219,Z1220,Z1221,Z1222,Z1223,Z1224,Z1225,Z1226, 35 Z1227,Z1228,Z1229,Z1230,Z1231,Z1232,Z1233,Z1234,Z1235, WO 2008/132153 PCT/EP2008/055039 - 29 Z1236,Z1237,Z1238,Z1239,Z1240,Z1241,Z1242,Z1243,Z1244, Z1245,Z1246,Z1247,Z1248,Z1249,Z1250,Z1251,Z1252,Z1253, Z1254,Z1255,Z1256,Z1257,Z1258,Z1259,Z1260,Z1261,Z1262, Z1263,Z1264,Z1265,Z1266,Z1267,Z1268,Z1269,Z1270,Z1271, 5 Z1272,Z1273,Z1274,Z1275,Z1276,Z1277,Z1278,Z1279,Z1280, Z1281,Z1282,Z1283,Z1284,Z1285,Z1286,Z1287,Z1288,Z1289, Z1290,Z1291,Z1292,Z1293,Z1294,Z1295,Z1296,Z1297,Z1298, Z1299,Z1300,Z1301,Z1302,Z1303,Z1304,Z1305,Z1306,Z1307, Z1308, Z1309, Z1310, Z1311, Z1312 are independently from each other 10 selected from the group consisting of: ,alkyl, (C 9 -Co)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively Z1 207, Z1 208 and/or Z1 216, Z1 217 and/or Z1 229, Z1 230 and/or Z1 236, Z1 237 and/or Z1 245, Z1 246 and/or Z1 255, Z1 256 and/or Z1 260, Z1 261 and/or Z1 277, Z1 278 and/or 15 Z1 286, Z1 287 and/or Z1 289, Z1 290 and/or Z1 292, Z1 293 and/or Z1 295, Z1 296 and/or Z1 299, Z1 300 and/or Z1 305, Z1 306 and/or Z1 308, Z1 309 and/or Z1 311, Z1 312 and/or respectively together can also form ,,het erocyclyl"; wherein optionally above substituents of substituents group (ii) can in 20 turn independently from each other be substituted with at least one sub stituent, identical or different, selected from the group consisting of: (iii) ,alkyl, (C 9
-C
30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero cyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, -CF, -N 3 , -NH 2 , -NHZ1401, -NZ1402Z1403, -NO 2 , -OH, 25 =O, -OCF, -SH, -O-SOH, -OP(O)(OH) 2 , -CHO, -COOH, C(O)NH 2 , -SO 3 H, -P(O)(OH) 2 , -C(O)-Z1 404, -C(O)O-Z1 405, C(O)NH-Z1406, -C(O)NZ1407Z1408, -O-Z1409, -O(-Z1410-O) 0 H (o = 1, 2, 3, 4, 5), -O(-Z141 1-O)p-Z1 412 (p = 1, 2, 3, 4, 5), OC(O)-Z1413, -OC(O)-O-Z1414, -OC(O)-NHZ1415, -0-C(O) 30 NZ1 416Z1 417, -OP(O)(OZ1 418)(OZ1 419), OSi(Z1420)(Z1421)(Z1422), -OS(O 2 )-Z1 423, -NHC(O)-NH 2 , NHC(O)-Z1 424, -NZ1 425C(O)-Z1 426, -NH-C(O)-O-Z1 427, -NH C(O)-NH-Z1428, -NH-C(O)-NZ1429Z1430, -NZ1431-C(O)-O Z1 432, -NZ1 433-C(O)-NH-Z1 434, -NZ1 435-C(O)-NZ1 436Z1 437, 35 -NHS(0 2 )-Z1 438, -NZ1 439S(0 2 )-Z1 440, -S-Z1441, -S(O)-Z1 442, WO 2008/132153 PCT/EP2008/055039 - 30 -S(0 2 )-Z1443, -S(0 2 )NH-Z1444, -S(0 2 )NZ1445Z1446, -S(0 2
)O
Z1 447, -P(O)(OZ1 448)(OZ1 449), -Si(Z1 450)(Z1 451)(Z1 452), C(NH)-NH 2 , -C(NZ1453)-NH 2 , -C(NH)-NHZ1454, -C(NH) NZ1 455Z1 456, -C(NZ1 457)-NHZ1 458, -C(NZ1 459) 5 NZ1 460Z1 461, -NH-C(O)-NH-O-Z1 462, -NH-C(O)-NZ1 463-0 Z1 464, -NZ1 465-C(O)-NZ1 466-O-Z1 467, -N(-C(O)-NH-O Z1468)2, -N(-C(O)-NZ1469-O-Z1470)2, -N(-C(O)-NH-O Z1 471)(-C(O)-NZ1 472-O-Z1 473), -C(S)-Z1 474, -C(S)-O-Z1 475, -C(S)-NH-Z1 476, -C(S)-NZ1 477Z1 478, -C(O)-NH-O-Z1 479, 10 C(O)-NZ1 480-O-Z1 481, -C(S)-NH-O-Z1 482, -C(S)-NZ1 483-0 Z1 484, -C(O)-NH-NH-Z1 485, -C(O)-NH-NZ1 486Z1 487, -C(O) NZ1 488-NZ1 489Z1 490, -C(S)-NH-NH-Z1 491, -C(S)-NH NZ1 492Z1 493, -C(S)-NZ1 494-NZ1 495Z1 496, -C(O)-C(O)-O Z1497, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHZ1498, -C(O)-C(O) 15 NZ1 499Z1 500, -C(S)-C(O)-O-Z1 501, -C(O)-C(S)-O-Z1 502, C(S)-C(S)-O-Z1503, -C(S)-C(O)-NH 2 , -C(S)-C(O)-NHZ1504, C(S)-C(O)-NZ1 505Z1 506, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHZ1 507, -C(S)-C(S)-NZ1 508Z1 509, -C(O)-C(S)-NH 2 , -C(O) C(S)-NHZ1 510, -C(O)-C(S)-NZ1 511 Z1 512"; 20 wherein Z1401, Z1402, Z1403, Z1404, Z1405, Z1406, Z1407, Z1408, Z1409, Z1410, Z1411, Z1412, Z1413, Z1414, Z1415, Z1416, Z1417, Z1418, Z1419, Z1420, Z1421, Z1422, Z1423, Z1424, Z1425, Z1426,Z1427,Z1428,Z1429,Z1430,Z1431,Z1432,Z1433,Z1434, Z1435,Z1436,Z1437,Z1438,Z1439,Z1440,Z1441,Z1442,Z1443, 25 Z1444,Z1445,Z1446,Z1447,Z1448,Z1449,Z1450,Z1451,Z1452, Z1453,Z1454,Z1455,Z1456,Z1457,Z1458,Z1459,Z1460,Z1461, Z1462,Z1463,Z1464,Z1465,Z1466,Z1467,Z1468,Z1469,Z1470, Z1471,Z1472,Z1473,Z1474,Z1475,Z1476,Z1477,Z1478,Z1479, Z1480,Z1481,Z1482,Z1483,Z1484,Z1485,Z1486,Z1487,Z1488, 30 Z1489,Z1490,Z1491,Z1492,Z1493,Z1494,Z1495,Z1496,Z1497, Z1498,Z1499,Z15OO,Z15Ol,Z1502,Z1503,Z1504,Z15O5,Z1506, Z1 507, Z1 508, Z1 509, Z1 510, Z1 511, Z1 512 are independently from each other selected from the group consisting of: ,alkyl, (Ce
C
3 o)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, 35 aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively WO 2008/132153 PCT/EP2008/055039 - 31 Z1 407, Z1 408 and/or Z1 416, Z1 417 and/or Z1 429, Z1 430 and/or Z1436, Z1437 and/or Z1445, Z1446 and/or Z1455, Z1456 and/or Z1460, Z1461 and/or Z1477, Z1478 and/or Z1486, Z1487 and/or Z1489, Z1490 and/or Z1492, Z1493 and/or Z1495, Z1496 and/or 5 Z1 499, Z1 500 and/or Z1 505, Z1 506 and/or Z1 508, Z1 509 and/or Z1 511, Z1 512 and/or respectively together can also form ,heterocy clyl". With regard to the alternative embodiment "no substituent" for R1 and R3, it is un 10 derstood in the course of the present invention that R1 and/or R3 are not present and that the valences of the respective carbon and/or nitrogen atom, of which R1 and R3 are ligands and that are part of "heterocyclyl" or "heteroaryl", are fully used up by means of double and/or triple bonds. With regard to R1, R1* and n, it is understood in the course of the present invention 15 that if n is 0 substituents R1, R1 * and the corresponding harbouring carbon atom are not present, i.e. the nitrogen atom harbouring R2, R3 is directly attached to the carbon atom harbouring R4m, R5m. If n is 1, then one carbon atom harbouring R1, R1* is pre sent between the carbon atom harbouring R4m, R5m and the nitrogen atom harbouring R2, R3. 20 With regard to R4m, R5m, and m, it is understood in the course of the present inven tion that if m is 1, one carbon atom harbouring one radical R4m and one radical R5m is present. If m is 2, then two carbon atoms each harbouring one radical R4m and one radical R5m are present, where all four radicals R4m1, R5m1, R4m 2 , R5m 2 can independ ently from each other be identical or different. 25 In a preferred embodiment, tetrahydrocarbazole derivatives according to formula (1) are provided, where according to (A) V, W are independently "=O"; R1, R1 * together independently form "=O or =S" or are independently both "hydro 30 gen"; n is 1; m is 1 or 2; WO 2008/132153 PCT/EP2008/055039 - 32 R2 is independently selected from the group consisting of: "-NH 2 , -NH-aryl, -CO heterocyclyl, -CO-heterocyclylalkyl, -CO-heteroarylalkyl, -CO-NH heterocyclylalkyl, -NH-CO-alkyl, -NH-CO-aryl, -NH-CO-NH 2 , alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -0-alkyl", 5 where "alkyl", "cycloalkyl", "aryl", "heteroaryl" and "arylalkyl" must be independently from each other substituted with at least one substituent selected from the group consisting of: "heterocyclyl, -OH, -COOH, -N(alkyl) 2 , -P(O)(O-alkyl) 2 , -P(O)(OH) 2 , -OP(O)(O-alkyl) 2 , -OP(O)(OH) 2 , -OC(O)-alkyl, -OC(O)O-alkyl" and where "-NH aryl", "-CO-heterocyclyl", "-CO-heterocyclylalkyl", "-CO-heteroarylalkyl", "-CO 10 NH-heterocyclylalkyl", "-NH-CO-alkyl", "-NH-CO-aryl", "alkyl", "cycloalkyl", "aryl", "arylalkyl", "heterocyclyl", "heterocyclylalkyl", "heteroaryl", "heteroarylalkyl", and " O-alkyl" are optionally independently from each other (further) substituted with at least one substituent selected from the group consisting of: "alkyl, -F, -Cl, -OH, COOH, -CHO, -0-alkyl, -C(O)-alkyl, -N(alkyl) 2 , -O(-akyl-O) 2 -aky"; 15 R4m, R8 are independently "alkyl"; R3, R5m, R6, R7, R9, R11, R12, R13, R14, R15, R16, R21, R22 are independently "hydrogen"; R1 0 independently is selected from the group consisting of "-C(O)O-arylalkyl, C(O)-arylalkyl, -C(S)-arylalkyl", where "arylalkyl" is optionally substituted with at 20 least one substituent selected from the group consisting of: "-F, -Cl"; R1 7, R1 8, R1 9, R20 are independently from each other selected from the group consisting of "hydrogen, -F, -Cl, -CF 3 ". In a further preferred embodiment of the foregoing embodiment, R1, R1* are not present; 25 n is 0. In another preferred embodiment, tetrahydrocarbazole derivatives according to formula (1) are provided, where according to (A) V, W are independently "=O"; 30 n is 1; m is 1 or 2; WO 2008/132153 PCT/EP2008/055039 - 33 R1, R1 * together independently form "=O or =S" or are independently both "hydro gen"; R2 is independently selected from the group consisting of: "amino, N'-(acetyl) amino, N'-(aminocarbonyl)-amino, N'-phenyl-amino, N'-(4-hydroxy-phenyl)-amino, 5 N'-(4-methoxy-phenyl)-amino, N'-(3-hydroxy-4-methoxy-benzyl)-amino, N'-(4 hydroxy-3-methoxy-benzyl)-amino, N'-(4-hydroxy-benzoyl)-amino, 2-hydroxy-ethyl, 2-diethylamino-ethyl, 3-hydroxy-propyl, 4-hydroxy-butyl, 5-hydroxy-pentyl, 2,3,4,5,6-pentahydroxy-hexan-1-yl, 2-(3,4,5,6-tetrahydroxy)-hexanoic acid, 4-butyl phosphonic acid diethyl ester, 4-butyl-phosphonic acid, dimethylamino-acetic acid 10 4-butyl ester, carbonic acid 4-butyl ester 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl es ter, phosphoric acid mono-4-butyl ester, phosphonic acid diethyl ester 4-(2 methoxy)-phenyl ester, methoxy, ethoxy, 4-hydroxy-cyclohexyl, 4-hydroxy-phenyl, 4-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4-hydroxy-3-methoxy-phenyl, 2 hydroxy-4-methoxy-phenyl, 3-hydroxy-4-methoxy-phenyl, 2,4-dihydroxy-phenyl, 15 benzyl, 4-hydroxy-benzyl, 3-hydroxy-4-methoxy-benzyl, 2-(5-methoxy)-benzoic acid, 5-(2-methoxy)-benzoic acid, 5-(2-hydroxy)-benzoic acid, furan-2-yl-methyl, fu ran-3-yl-methyl, 2-furan-2-yl-ethyl, 2-imidazol-1-yl-ethyl, 3-imidazol-1-yl-propyl, 3 imidazol-1-yl-propionyl, 2-thiophen-2-yl-ethyl, 2-pyrazol-1-yl-ethyl, 2-(1,2,4)triazol-1 yl-ethyl, 3-(1,2,4)triazol-1 -yl-propyl, 4-(1,2,4)triazol-1 -yl-butyl, 5-methyl 20 (1 ,3,4)oxadiazol-2-yl-methyl, 2-methoxy-pyridin-4-yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, pyridin-4-yl-ethyl, 6-chloro-pyridin-3-yl-methyl, 2-pyridin-3-yl ethyl, pyrimidin-4-yl-methyl, pyrimidin-5-yl-methyl, pyrazin-2-yl-methyl, pyrrolidin-1 yl-methyl, morpholin-4-yl, morpholin-4-yl-methyl, morpholin-4-yl-ethyl, morpholin-4 yl-propyl, 3-morpholin-4-yl-propionyl, tetrahydro-pu ran-3-yl-methyl, tetrahydro 25 pu ran-4-yl-methyl, tetrahydro-pu ran-4-yl, tetrahydro-puran-4-carbonyl, 2 (tetrahydro-puran-4-yl)-ethyl, 2-(tetrahydro-puran-4-yl)-acetyl, tetrahydro-puran-4 yl-metyl-carbamoyl, 3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pu ran-2-yl, piperidin-4-yl-methyl, 1 -methyl-piperidin-4-yl-methyl, 1-formyl-piperidin-4-yl-methyl, 1 -acetyl-piperidin-4-yl-methyl"; 30 R4m, R8 are independently "1-methyl-propan-1-yl"; R3, R5m, R6, R7, R9, R11, R12, R13, R14, R15, R16, R21, R22 are independently "hydrogen"; R1 0 independently is selected from the group consisting of "benzyloxycarbonyl, 2,6-difluoro-phenyl-acetyl, 2-fluoro-phenyl-acetyl, 2-fluoro-phenyl-thioacetyl"; WO 2008/132153 PCT/EP2008/055039 - 34 R1 7, R1 8, R1 9, R20 are independently from each other selected from the group consisting of "hydrogen, -F, -Cl, -CF 3 ". In a further preferred embodiment of the foregoing embodiment, R1, R1* are not present; 5 n is 0. In a further preferred embodiment, tetrahydrocarbazole derivatives according to formula (1) are provided, where according to (B) V, W are independently "=O"; 10 n is 1; m is 1 or 2; R1f*, R2 together independently form "heteroaryl" or "heterocyclyl", where "het eroaryl" and "heterocyclyl" are optionally substituted with at least one substituent selected from the group consisting of: "alkyl, -CN, -NH 2 , =0, -C(0)0-alkyl, 15 C(O)NH 2 , -C(O)N(alkyl) 2 , -NH-C(O)-alkyl, -NH-C(O)-NH-alkyl, -NH-C(O)-NH O-alkyl, -N(C(O)-NH-O-akyl) 2 "; R1, R3 are independently "no substituent"; R4m, R8 are independently "alkyl"; R5m, R6, R7, R9, R11, R12, R13, R14, R15, R16, R21, R22 are independently "hy 20 drogen"; R1 0 independently is selected from the group consisting of "-C(0)0-arylalkyl, C(O)-arylalkyl, -C(S)-arylalkyl", where "arylalkyl" is optionally substituted with at least one substituent selected from the group consisting of: "-F, -Cl"; R1 7, R1 8, R1 9, R20 are independently from each other selected from the group 25 consisting of "hydrogen, -F, -Cl, -CF 3 ". In a yet further preferred embodiment, tetrahydrocarbazole derivatives according to formula (1) are provided, where according to (B) V, W are independently "=O"; 30 n is 1; WO 2008/132153 PCT/EP2008/055039 - 35 m is 1 or 2; R1f*, R2 together independently form "(1,3,4)oxadiazol-2-yl, 5-amino (1,3,4)oxadiazol-2-yl, 3-methyl-(1,2,4)oxadiazol-5-yl, 5-methyl-(1,3,4)oxadiazol-2-yl, 5-(1,2,4)oxadiazole-3-carboxylic acid methyl ester, 5-(1,2,4)oxadiazole-3-carboxylic 5 acid ethyl ester, 5-(1,3,4)oxadiazole-2-carboxylic acid ethyl ester, 5-oxo-4,5 dihydro-(1,3,4)-oxadiazol-2-yl, 3-carbamoyl-(1,2,4)oxadiazol-5-yl, 3 diethylcarbamoyl-(1,2,4)oxadiazol-5-yl, 5-acetylamino-(1,3,4)-oxadiazol-2-yl, 5 (1,2,4)oxadiazole-3-carboxylic acid propyl ester, 3-cyano-(1,2,4)oxadiazol-5-y, 5 (3-ethyl-ureido)-(1,3,4)oxadiazol-2-yl, 5-(3-methoxy-ureido)-(1,3,4)oxadiazol-2-yl, 5 10 [1 -(methoxy-amino-carbonyl)-3-methoxy-ureido]-(1,3,4)oxadiazol-2-yl or 1 H tetrazol-5-yl"; R1, R3 are independently "no substituent"; R4m, R8 are independently "1-methyl-propan-1-yl"; R5m, R6, R7, R9, R11, R12, R13, R14, R15, R16, R21, R22 are independently "hy 15 drogen"; R1 0 independently is selected from the group consisting of "benzyloxycarbonyl, 2,6-difluoro-phenyl-acetyl, 2-fluoro-phenyl-acetyl, 2-fluoro-phenyl-thioacetyl"; R1 7, R1 8, R1 9, R20 are independently from each other selected from the group consisting of "hydrogen, -F, -Cl, -CF 3 ". 20 In another preferred embodiment, tetrahydrocarbazole derivatives according to formula (1) and above preferred embodiments are provided that are selected from the group consisting of: Compound 1 ((S)-1-{(R)-3-[(R)-1-(5-Amino-[1,3,4]oxadiazol-2-yl)-2-methyl 25 butylcarbamoyl]-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester Ci H N 3C N O NH2 30U WO 2008/132153 PCT/EP2008/055039 - 36 Compound 2 ((S)-1 -{(S)-3-[(R)-1 -(5-Amino-[1,3,4]oxadiazol-2-yl)-2-methyl butylcarbamoyl]-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI H N / CI 5 H NH2 0 Compound 3 ((S)-1 -{(R)-6,8-Dichloro-3-[(S)-2-methyl-1 -(3-methyl [1,2,4]oxadiazol-5-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H 10 carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI N ~ HN CI H 15 Compound 4 ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-2-methyl-1 -(3-methyl [1,2,4]oxadiazol-5-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI 20 HN CI HNN H 0 Compound 5 5-((S)-1-{[(R)-3-((S)-2-Benzyloxycarbonylamino-3-methyl 25 pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester CI HN CI 0 N ,'' N 30 H O WO 2008/132153 PCT/EP2008/055039 - 37 Compound 6 5-((S)-1 -{[(S)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester 5 CI HN CI 0 O H0 Compound 7 ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-2-methyl-1 -(5-oxo-4,5-dihydro 10 [1,3,4]oxadiazol-2-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester I) - 0 N HN CI/,, 10 HNH NNH 15 H Compound 8 {(S)-1-[(R)-6,8-Dichloro-3-((S)-2-methyl-1-[1,3,4]oxadiazol-2-yl butylcarbamoyl)-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl] 2-methyl-butyll-carbamic acid benzyl ester CI 20 HN CI NN H Compound 9 {(S)-1 -[(S)-6,8-Dichloro-3-((S)-2-methyl-1 -[1,3,4]oxadiazol-2-yl 25 butylcarbamoyl)-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl] 2-methyl-butyll-carbamic acid benzyl ester CI 0 H N 0 WO 2008/132153 PCT/EP2008/055039 - 38 Compound 10 ((S)-1 -{(R)-3-[(S)-1 -(3-Carbamoyl-[1,2,4]oxadiazol-5-yl)-2 methyl-butylcarbamoyl]-6,8-dich Ioro-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI HN CI N N NH 2 H 0 Compound 11 ((S)-1 -{(S)-3-[(S)-1 -(3-Carbamoyl-[1,2,4]oxadiazol-5-yl)-2-methyl butylcarbamoyl]-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3 10 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI O 0 N H H NH HH 15 Compound 12 5-{(S)-1-[((R)-3-{(S)-2-[2-(2,6-Difluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester F F F 20 HN 0 HH 20 H - 0 0 Compound 13 5-((S)-1-{[(R)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 25 carbonyl]-amino}-2-methyl-butyl)-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester CI 0 HN ~ /CI H N N 1'!N N/N
H
300 WO 2008/132153 PCT/EP2008/055039 - 39 Compound 14 ((S)-1-{(R)-3-[(S)-1-(5-Acetylamino-[1,3,4]oxadiazol-2-yl)-2 methyl-butylcarbamoyl]-6,8-dich Ioro-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI 5 HN / CI H H N Compound 15 5-((S)-1 -{[(S)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 10 carbonyl]-amino}-2-methyl-butyl)-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester CI HN CI Ny HN 0 00 NN NN 01' N H 15 Compound 16 ((S)-1-{(S)-3-[(S)-1-(5-Acetylamino-[1,3,4]oxadiazol-2-yl)-2 methyl-butylcarbamoyl]-6,8-dich Ioro-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI 20 HN CI H 0 N 0 H H NI N Compound 17 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-2-methyl-1-(5-oxo-4,5-dihydro 25 [1,3,4]oxadiazol-2-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI HN CI oN N H Y N"N N H 30 H O WO 2008/132153 PCT/EP2008/055039 - 40 Compound 18 5-((S)-1-{[(R)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic 5 acid propyl ester HNCI HH N,kN N 0 H rN 0 10 Compound 19 5-((S)-1 -{[(S)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid propyl ester CI 15 15a H N 0 0'IN N 0 HH O Compound 20 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-1-(3-diethylcarbamoyl [1,2,4]oxadiazol-5-yl)-2-methyl-butylcarbamoyl]-2,3,4,9 20 tetrahydro-1 H-carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI HN CI 0 0 --N N ~NN N 0 H 0 25 Compound 21 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-1-(3-cyano-[1,2,4]oxadiazol-5-yl) 2-methyl-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI eHN CI 0 0 30 Ha N N H Ol WO 2008/132153 PCT/EP2008/055039 - 41 Compound 22 ((S)-1-{(S)-6,8-Dichloro-3-[(S)-1-(3-cyano-[1,2,4]oxadiazol-5-yl) 2-methyl-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI 5 HN CI H H N N K Nl 0 Compound 23 ((S)-1 -{(R)-6,8-Dichloro-3-[(S)-2-methyl-1 -(5-methyl [1,3,4]oxadiazol-2-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H 10 carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyles ter CI HN CI N H 0 15 Compound 24 ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-2-methyl-1 -(5-methyl [1,3,4]oxadiazol-2-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI 20 HN CI N O N. 0 Compound 25 5-((S)-1-{[(R)-3-((S)-2-Benzyloxycarbonylamino-3-methyl 25 pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid methyl ester CI 0H N CI 30 N N 0
H
WO 2008/132153 PCT/EP2008/055039 - 42 Compound 26 5-((S)-1 -{[(S)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid methyl ester CI 5 HN CI 5 O N O HN N H ~ N Compound 27 [(S)-1 -((R)-6,8-Dichloro-3-{(S)-1 -[5-(3-ethyl-ureido) 10 [1,3,4]oxadiazol-2-yl]-2-methyl-butylcarbamoyl}-2,3,4,9 tetrahydro-1 H-carbazol-3-ylcarbamoyl)-2-methyl-butyl]-carbam ic acid benzyl ester CI HN CI H N-N 15 H-N O He 0 -' Compound 28 5-{(S)-1-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H 20 carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester F F F HN N O H H 25 WO 2008/132153 PCT/EP2008/055039 - 43 Compound 29 5-{(S)-1-[((S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester F 5 F F HN NN 0 H F Compound 30 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 10 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[5-(3-ethyl-ureido) [1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide F F HN HN 15 F H N-N j N - H
H
0 Compound 31 (S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H 20 carbazole-3-carboxylic acid {(S)-1 -[5-(3-ethyl-ureido) [1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide F F F F HN HN F0 N--N 0 25H WO 2008/132153 PCT/EP2008/055039 - 44 Compound 32 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(5-amino-[1,3,4]oxadiazol-2 yl)-2-methyl-butyl]-amide 5 F F F HN F 0 N-N H H )-NH, TO N 10 Compound 33 F F F HN NO N 0 H O 15 Compound 34 F F F HN F 0 H N NO O 0 H 20 Compound 35 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(pyrrolidin-1 ylmethyl)-carbamoyl]-butyl}-amide 25 F F F HN F 0 0 S N ~ N N 0 H 0 H WO 2008/132153 PCT/EP2008/055039 - 45 Compound 36 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(morpholin-4 ylmethyl)-carbamoyl]-butyl}-amide F 5 F F H N N, O N N 0 H 0 H 0 Compound 37 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 10 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(morpholin-4 ylmethyl)-th iocarbamoyl]-butyl}-amide F F HN 15 F 0 S S 0 H 0 H Compound 38 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H 20 carbazole-3-carboxylic acid ((S)-1-methoxycarbamoyl-2-methyl butyl)-amide F F HN F 0 0 HiIk H ", N I 0 H 0 i H 25 WO 2008/132153 PCT/EP2008/055039 - 46 Compound 39 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(morpholine-4 carbonyl)-butyl]-amide F 5 F F HN F N O H 10 Compound 40 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-1-ethylcarbamoyl-2-methyl butyl)-amide F F F 15 HN F 0 0 O - 0 H 0 E H Compound 41 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-1-ethoxycarbamoyl-2-methyl butyl)-amide F F H 25 F 0 0 yo H 0 EH WO 2008/132153 PCT/EP2008/055039 - 47 Compound 42 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-morpholin-4-yl ethylcarbamoyl)-butyl]-amide 5 F F F F F HN F O O O 0 H EH NN NJ 1 0 10 Compound 43 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-butylcarbamoyl)-2 15 methyl-butyl]-amide F F F HN F 0 0 H H N, N OH -- 0 0 20 Compound 44 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(3-morpholin-4-yl 25 propylcarbamoyl)-butyl]-amide F F F HN O O H E H I 0 00 WO 2008/132153 PCT/EP2008/055039 - 48 Compound 45 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(1 -methyl-piperidin 5 4-ylmethyl)-carbamoyl]-butyl}-amide F F F HN F 0 0 ON I E H E H - 0 0 N 10 Compound 46 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(tetrahydro-pyran-4 15 ylmethyl)-carbamoyl]-butyl}-amide F F F HN NJ N"A NN 20 Compound 47 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(2-morpholin-4-yl 25 ethylthiocarbamoyl)-butyl]-amide F F F HN FO H H - 0 0 WO 2008/132153 PCT/EP2008/055039 - 49 Compound 48 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(1 -formyl-piperidin-4 5 ylmethyl)-carbamoyl]-2-methyl-butyl}-am ide F F F HN F O O H H ON 0 0 1* N 10 Compound 49 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(1 -acetyl-piperidin-4 15 ylmethyl)-carbamoyl]-2-methyl-butyl}-am ide F F F HN F N,, N &E H H 2000 N Compound 50 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(pyridin-4-ylmethyl) 25 carbamoyl]-butyl}-amide F F F HN O) NN YO 0
-
0
,
WO 2008/132153 PCT/EP2008/055039 - 50 Compound 51 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2-diethylamino 5 ethylcarbamoyl)-2-methyl-butyl]-amide F F F HN H H" NN N N H 0 10 Compound 52 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(tetrahydro-pyran-4 15 ylmethyl)-th iocarbamoyl]-butyl}-amide F F F HN F 0 S NK O O H H - 0 00 20 Compound 53 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy 25 butylthiocarbamoyl)-2-methyl-butyl]-amide F F F HN NJ O OH C H N vN I 0 H 0 H WO 2008/132153 PCT/EP2008/055039 - 51 Compound 54 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-morpholin-4-yl 5 ethylthiocarbamoyl)-butyl]-amide F F F HN N HN EH EH 10 Compound 55 (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino] 3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(S)-2-methyl-1 -(2-morpholin-4-yl 15 ethylcarbamoyl)-butyl]-amide CI H N F H H NH 200 Compound 56 (R) -3-1(S)-2-[2- (2- Flu oro-phenyl) -acetylam ino]-3-m ethyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl- 1-[(piperidin-4 25 ylm ethyl) -carbamoyl]-butyl}-am ide F F F H F H 0 H 0 N N 'A 0 0'' E 0
NH
WO 2008/132153 PCT/EP2008/055039 - 52 Compound 57 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2-hydroxy-ethylcarbamoyl)-2 methyl-butyl]-amide 5 F F F H N F 0 0 F H 0I HiI N "A N "A. H H H --- O 0 0 10 Compound 58 (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino] 3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid {(S)-2-methyl-1 -[(pyridin-4-ylmethyl)-carbamoyl] butyll-amide 15 CI H NF F N 0 O H N 20 Compound 59 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(5-hydroxy-pentylcarbamoyl) 2-methyl-butyl]-amide 25 F F HN F 0 0 N "' NQ N SN HOH
-
0 WO 2008/132153 PCT/EP2008/055039 - 53 Compound 60 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(pyridin-4-ylmethyl) thiocarbamoyl]-butyl}-amide 5 F F F HN N N NN - 0 0 H . 10 Compound 61 (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino] 3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(S)-2-methyl-1 -(2-morpholin-4-yl ethylthiocarbamoyl)-butyl]-amide 15 CI HN / F F O S O N N N O - 0 0 20 Compound 62 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-2-methyl-1-{[(tetrahydro-pyran 4-ylmethyl)-amino]-methyl}-butyl)-am ide 25 F FF HN H H - 00 0" WO 2008/132153 PCT/EP2008/055039 - 54 Compound 63 (4-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-butyl) phosphonic acid diethyl ester 5 F F F H F 0 0 N-, NAr - o 0 H 0 0 10 Compound 64 (4-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-butyl) phosphonic acid 15 F F F HN F 0 0 OH N~~k~ H NAN.~ &I y H 0 H OH 20 Compound 66 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(2-morpholin-4-yl ethylamino)-methyl]-butyl}-amide 25 F F HN H H r N"N
O
WO 2008/132153 PCT/EP2008/055039 - 55 Compound 67 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-phenylcarbamoyl) 2-methyl-butyl]-amide 5 F HN F 0 0 N OH yo 0 0 H 10 Compound 68 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-methoxy-phenylcarbamoyl) 2-methyl-butyl]-amide F F F 15 HN F 0 0 HIN O Compound 69 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy phenylcarbamoyl)-2-methyl-butyl]-amide F F F HN 25F 0 0 H F 0 0 6--Y ' kN"'NAN OH WO 2008/132153 PCT/EP2008/055039 - 56 Compound 70 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2,4-dihydroxy phenylcarbamoyl)-2-methyl-butyl]-amide 5 F HN F F N NOH HO F 0 0 N ' N OH F H-b 10 Compound 71 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2-hydroxy-4-methoxy phenylcarbamoyl)-2-methyl-butyl]-amide 15 F F F HN HO F 0 0 H2 H s / N N 0 20 Compound 72 (R) -3-1(S)-2-[2- (2- Flu oro-phenyl) -acetylam ino]-3-m ethyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl- 1 -(2,4,6-trimethoxy phenylcarbamoyl)-butyl]-amide F F F 25 H 0 0 WO 2008/132153 PCT/EP2008/055039 - 57 Compound 73 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy cyclohexylcarbamoyl)-2-methyl-butyl]-amide 5 F F F HN HOH 10 Compound 74 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-imidazol-1-yl propylthiocarbamoyl)-2-methyl-butyl]-amide 15 F F F HN N HH~~ N NN 20 Compound 75 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(R)-1 -(3-imidazol-1 -yl propylthiocarbamoyl)-2-methyl-butyl]-amide F F F 25 H F N N H WO 2008/132153 PCT/EP2008/055039 - 58 Compound 76 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-thiophen-2-yl ethylthiocarbamoyl)-butyl]-amide 5 F F F HN F 0 S H II H i/ E H E H - 0 0 10 Compound 77 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(pyridin-3-ylmethyl) thiocarbamoyl]-butyl}-amide 15 F F F F F HN F 0 S O N'N H HI - 0 -=1 0
--
20 Compound 78 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-3-methyl-1-(1 H-tetrazol-5-yl) butylcarbamoyl]-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl} 2-methyl-butyl)-carbamic acid benzyl ester CI CI HN HN0 25 ON HN-N 0 HN ")-N WO 2008/132153 PCT/EP2008/055039 - 59 Compound 80 5-{(S)-1-[(3-{2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester 5 F FF HN F ON 0 H 0 N - 0 H 10 Compound 81 5-{(S)-1-[((R)-3-{(R)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 15 3-carboxylic acid ethyl ester F F F HN FN N "- N 0 N, N N 00 20 Compound 82 (R)-3-{(R)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[5-(3-ethyl-ureido) 25 [1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide F F F HN F 0 6 _ H H II> N N N' "~ 0 H H Y 7 0 0 - WO 2008/132153 PCT/EP2008/055039 - 60 Compound 83 (S)-3-{(R)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[5-(3-ethyl-ureido) [1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide 5 F F F F HN 'NN F 0 N-N HN H H N O)Q> -- 0 10 Compound 85 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(2-diethylamino-ethylcarbamoyl) methyl]-amide F 15 F F HN F 0 N NN H H - 0 0 20 Compound 86 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(2-morpholin-4-yl-ethylcarbamoyl) methyl]-amide F F F 25 HN 0 / FF -- 0 0
H
WO 2008/132153 PCT/EP2008/055039 - 61 Compound 87 (S)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino] 3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid {(S)-2-methyl-1 -[(pyridin-4-ylmethyl)-carbamoyl] butyll-amide CI 5 N 10 Compound 88 (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl) thioacetylamino]-3-methyl-pentanoylamino}-2,3 ,4,9-tetrahydro 1 H-carbazole-3-carboxylic acid {(S)-2-methyl- 1-[(pyridin-4 ylmethyl)-carbamoyl]-butyl}-amide 15 CI HN / F F H 0H NJ N 0 H N 20 Compound 89 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(2-pyridin-4-yl ethylth iocarbamoyl)-butyl]-amide 25 F HN F F N' N H E H - 0 0 WO 2008/132153 PCT/EP2008/055039 - 62 Compound 90 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy cyclohexylthiocarbamoyl)-2-methyl-butyl]-amide 5 F F F HN F H 0 H S N, N OH HI0 0 H 10 Compound 91 2-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-5 methoxy-benzoic acid 15 F F F HN F 0 N H H 0 0 O OH 20 Compound 92 Phosphoric acid diethyl ester 5-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carbonyl) amino]-3-methyl-pentanoylamino}-2-methoxy-phenyl ester 25 F F F HN F 0 N~ '~'~- N .
0 - WO 2008/132153 PCT/EP2008/055039 - 63 Compound 93 Dimethylamino-acetic acid 4-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carbonyl) amino]-3-methyl-pentanoylamino}-buty ester 5 F F F HN F H H H H 0 10 Compound 94 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-benzylcarbamoyl) 2-methyl-butyl]-amide 15 F F F HN F O F 0 0 O OH 20 Compound 95 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy benzylcarbamoyl)-2-methyl-butyl]-amide 25 F FF F F HN F 0 0 N H 0 07/:" 0
OH
WO 2008/132153 PCT/EP2008/055039 - 64 Compound 96 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-3-methoxy benzylcarbamoyl)-2-methyl-butyl]-amide 5 F FF F F HN IH H 0 0 0 OH 10 Compound 97 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-methoxy phenylthiocarbamoyl)-2-methyl-butyl]-amide 15 F F F HN F 0 H N Y~~N" N~iN ~,0 yo H H 0 20 Compound 98 5-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-2 methoxy-benzoic acid 25 F F F F HN F OH H OH WO 2008/132153 PCT/EP2008/055039 - 65 Compound 99 5-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanethioylamino}-2 methoxy-benzoic acid 5 F F F F HN F N N N aOC H H OH 10 Compound 100 Carbonic acid 4-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9 tetrahydro-1 H-carbazole-3-carbonyl)-am ino]-3-methyl pentanoylamino}-butyl ester 2-[2-(2-methoxy-ethoxy)-ethoxy] 15 ethyl ester F F F HN F O 0 20 Compound 101 Phosphoric acid mono-(4-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carbonyl) amino]-3-methyl-pentanoylamino}-butyl) ester 25 F F F HN F 0 0 N N" N N O O.HH Copond1- 0hshoi 0ci moo(a()2[()31S--2(-lo WO 2008/132153 PCT/EP2008/055039 - 66 Compound 102 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-propylcarbamoyl) 2-methyl-butyl]-amide 5 F FF HN H H 10 Compound 103 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-1-benzylthiocarbamoyl-2 methyl-butyl)-amide 15 F F F rNN_ H H - 0 0 I 20 Compound 104 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(2-methoxy-pyridin-4 ylmethyl)-th iocarbamoyl]-2-methyl-butyl}-amide 25 F F F HN F S NJ k~L~kN 0 E H H N 0 0 0 WO 2008/132153 PCT/EP2008/055039 - 67 Compound 105 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(pyrimidin-5 ylmethyl)-th iocarbamoyl]-butyl}-amide 5 F FF F F HN 10 Compound 106 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1
H
carbazole-3-carboxylic acid {(S)-2-methyl- 1-[(pyrazin-2 ylmethyl)-th iocarbamoyl]-butyl}-amide 15 F F F H e HN 20 Compound 107 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1-[(6-chloro-pyridin-3-ylmethyl) thiocarbamoyl]-2-methyl-butyl}-am ide 25 F HN N C 6 1TO H
EH
WO 2008/132153 PCT/EP2008/055039 - 68 Compound 108 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-pyridin-3-yl ethylthiocarbamoyl)-butyl]-amide 5 F FF F F H N N N ~NN" H E H .- 0 0 10 Compound 109 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(pyrimidin-4 ylmethyl)-th iocarbamoyl]-butyl}-amide 15 F F F HN FS N N H H .- 0 0N 20 Compound 110 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2-imidazol-1-yl ethylthiocarbamoyl)-2-methyl-butyl]-amide 25 F FF HN N N N N N H E H - 0 0 WO 2008/132153 PCT/EP2008/055039 - 69 Compound 111 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(2-pyrazol-1 -yl ethylthiocarbamoyl)-butyl]-amide 5 F FF F F HN H EH N N N yo 0 0 10 Compound 112 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(2-[1,2,4]triazol-1 -yl ethylthiocarbamoyl)-butyl]-amide 15 F F F H N HN / F 0 s :Z N NYN" Q'KN N I H E H 20 200 Compound 113 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(3-[1,2,4]triazol-1 -yl propylthiocarbamoyl)-butyl]-amide 25 F FF F F HN H E H 6-1 0o- 0-)L N WO 2008/132153 PCT/EP2008/055039 - 70 Compound 114 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(4-[1,2,4]triazol-1 -yl butylthiocarbamoyl)-butyl]-amide 5 F FF F F HN F 9-= ON N -~ E H H 10 Compound 115 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(furan-2-ylmethyl) thiocarbamoyl]-2-methyl-butyl}-amide 15 F F F H N NJ N H H 20 Compound 116 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(furan-3-ylmethyl) thiocarbamoyl]-2-methyl-butyl}-amide 25 F FF HN Y NH -- Y 0 0 WO 2008/132153 PCT/EP2008/055039 - 71 Compound 117 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2-furan-2-yl ethylthiocarbamoyl)-2-methyl-butyl]-amide 5 F FF HN F Ics H E H 0 0 10 Compound 118 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(5-methyl [1,3,4]oxadiazol-2-ylmethyl)-thiocarbamoyl]-butyl}-amide 15 F F F HN F 0 O, N'N N ~''N" "' N 0 H H') yo 0 0 20 Compound 119 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[2-(tetrahydro-pyran 4-yl)-ethylthiocarbamoyl]-butyl}-amide 25 F F F F HN F 0 S SH-H N 0J N WO 2008/132153 PCT/EP2008/055039 - 72 Compound 120 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(tetrahydro-pyran-4 5 ylthiocarbamoyl)-butyl]-amide F F F HN F N " HiI H l i H H 10 0 0 Compound 121 5-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-2 15 hydroxy-benzoic acid F F F HN F Hii H 0 NN N"" 0 H H 0 H --- y OH 20 Compound 122 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-fluoro-4-hydroxy 25 phenylcarbamoyl)-2-methyl-butyl]-amide F F F HN F H OH Nk N 'N I I H 0 H F -F 0F WO 2008/132153 PCT/EP2008/055039 - 73 Compound 123 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy benzylthiocarbamoyl)-2-methyl-butyl]-amide 5 F F F HN F H s N 'N N < 6 - 0o 0H0 OH 10 Compound 124 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-1-hydrazinocarbonyl-2-methyl butyl)-amide F 15 F F HN F H H N N H--Y H 02 20 Compound 125 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy phenylthiocarbamoyl)-2-methyl-butyl]-amide 25 F F F HN OH F 0 S F Hii H s N N N H H O O WO 2008/132153 PCT/EP2008/055039 - 74 Compound 126 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-2-oxo-pyrrolidin-3-yl)-amide F F F 5 HN F H O N N 10 Compound 127 (S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 3 imidazol-1-yl-propyl ester F F F 15 HN F 0 F H 0 H 0 NN ~ N N O NN 0--Y H 0 20 Compound 128 (R)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 3 imidazol-1-yl-propyl ester F F F 25 H N N y F 0 H H 0 N0 NN I 0-Y H 0 WO 2008/132153 PCT/EP2008/055039 - 75 Compound 129 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-1-(4-hydroxy-benzylcarbamoyl)-2 methyl-butylcarbamoyl]-2,3,4,9-tetrahydro- 1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI CI 5 HN H H H N OH 10 Compound 130 ((S)-1-{(S)-6,8-Dichloro-3-[(S)-1-(4-hydroxy-benzylcarbamoyl)-2 methyl-butylcarbamoyl]-2,3,4,9-tetrahydro- 1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI CI HN 15 N N HI~ O H OH Compound 131 (S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid pyridin-4 ylmethyl ester F F F HN 25 F 0 0 H H N N H-I 0 0 0 WO 2008/132153 PCT/EP2008/055039 - 76 Compound 132 (R)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid pyridin-4 ylmethyl ester F 5 F F HN F H H NN N 6-:Y H 0 N 10 Compound 133 2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 2 dimethylamino-ethyl ester 15 F F F HN F H H N N N
N
20 Compound 134 (S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 3 hydroxy-4-methoxy-benzyl ester 25 F F HN F H 0 H 0 N,,Ql, N,,Jl -N"0 0 H 0 6 --- Y -- --- =OH 0 WO 2008/132153 PCT/EP2008/055039 - 77 Compound 135 (R)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 3 hydroxy-4-methoxy-benzyl ester 5 F F F HN F H H N N N H 0 OH 10 Compound 136 [(S)-1-((S)-6,8-Dichloro-3-{(S)-2-methyl-1-[(tetrahydro-pyran-4 ylmethyl)-carbamoyl]-butylcarbamoyl}-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl)-2-methyl-butyl]-carbam ic acid benzyl ester CI CI 15 HN N 0 0 H H 20 Compound 137 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1
H
carbazole-3-carboxylic acid [(S)-2-methyl-1 -(quinolin-6 ylcarbamoyl)-butyl]-amide F F F 25 HN / O Nj N F H H C H H H " WO 2008/132153 PCT/EP2008/055039 - 78 Compound 138 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(R)-2-methyl-1-(quinolin-6 ylcarbamoyl)-butyl]-amide 5 F F F H N N N N F H 0 H 0 N* " N" N N 6 - 0O H 0 H 10 Compound 139 [(S)-1-((R)-6,8-Dichloro-3-{(S)-2-methyl-1-[(tetrahydro-pyran-4 ylmethyl)-th iocarbamoyl]-butylcarbamoyl}-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl)-2-methyl-butyl]-carbam ic acid benzyl 15 ester CI CI HN H 0 H S H H H 20 Compound 140 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-1-(4-hydroxy-3-methoxy phenylcarbamoyl)-2-methyl-butylcarbamoyl]-2,3,4,9-tetrahydro 1 H-carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbam ic acid ben 25 zyl ester CI CI HN N N OH 0 OH WO 2008/132153 PCT/EP2008/055039 - 79 Compound 141 ((S)-1-{(S)-6,8-Dichloro-3-[(S)-1-(4-hydroxy-3-methoxy phenylcarbamoyl)-2-methyl-butylcarbamoyl]-2,3,4,9-tetrahydro 1 H-carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbam ic acid ben zyl ester 5 CI HN ~ OH H HO ffO H N N 0 O 0 10 Compound 142 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-2-oxo-piperidin-3-yl)-amide F HN 15 F F F H H H N Y 04 0 Compound 143 [(S)-1-((R)-6,8-Dichloro-3-{(S)-2-methyl-1-[(tetrahydro-pyran-4 20 ylmethyl)-carbamoyl]-butylcarbamoyl}-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl)-2-methyl-butyl]-carbam ic acid benzyl ester CI CI HN 25 H H )-, ON N 0
H
0 H1") WO 2008/132153 PCT/EP2008/055039 - 80 Compound 144 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(N'-phenyl hydrazinocarbonyl)-butyl]-amide 5 F F F HN F H H H N N A. 0 0 6---YO 10 Compound 145 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-3-methylsulfanyl-1 thiocarbamoyl-propyl)-amide F 15 F F HN F H H S N N H "kNH2 20 Compound 146 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(quinolin-5 ylcarbamoyl)-butyl]-amide F F F 25 HN F H 0 H 0 iji N N N N H 0 H O O- WO 2008/132153 PCT/EP2008/055039 - 81 Compound 147 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(isoquinolin-5-ylcarbamoyl)-2 methyl-butyl]-amide 5 F F F HN F H H N N N 6I -- y H 0HIN N 10 Compound 148 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(2-tetrahydro-pyran 4-yl-acetylamino)-methyl]-butyl}-amide 15 F F HN F I ~ H H N N H 0 H 20 Compound 149 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-2-methyl-1-{[(tetrahydro-pyran 4-carbonyl)-amino]-methyl}-butyl)-amide F F F 25 HN F~~ FNKN I. 0H 0
H-
WO 2008/132153 PCT/EP2008/055039 - 82 Compound 150 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(3-morpholin-4-yl propionylamino)-methyl]-butyl}-amide 5 F F F HN - 0H 0H 10 Compound 151 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(3-imidazol-1 -yl 15 propionylamino)-methyl]-2-methyl-butyl}-amide F F F HN F 0 0 N N H HN 20 Compound 152 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[3-(tetrahydro-pyran 4-ylmethyl)-ureidomethyl]-butyl}-amide 25 F F F HN F H " 0YH 0H 0 H H 6 ___ O -- , -- 0 WO 2008/132153 PCT/EP2008/055039 - 83 Compound 153 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-tetrahydro-pyran 4-yl-acetylamino)-butyl]-amide 5 F F F F H 0H H H H I 0 -- H E 0 -- 0 0 10 Compound 154 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1-[(tetrahydro-pyran-4 carbonyl)-amino]-butyl}-amide 15 F HN 20 Compound 155 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl- 1-(3-morpholin-4-yl propionylamino)-butyl]-amide F F 25 HN - FF F HF H I , 0 H N O N ' ^ ' ' ^ WO 2008/132153 PCT/EP2008/055039 - 84 Compound 156 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-imidazol-1-yl propionylamino)-2-methyl-butyl]-amide 5 F F HN I H C6 0 - 0 0 10 Compound 157 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(R)-2-methyl-1 -[3-(tetrahydro-pyran 15 4-ylmethyl)-ureido]-butyl}-amide F F F HN F H 0H H H NN N "A0 N" N N N 0 0 20 Compound 158 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((R)-2-methyl-1-{[(tetrahydro-pyran 4-ylmethyl)-carbamoyl]-methyl}-butyl)-am ide 25 F F H N F H H H I it, ~NT^N WO 2008/132153 PCT/EP2008/055039 - 85 Compound 159 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[N'-(4-hydroxy-phenyl) hydrazinocarbonyl]-2-methyl-butyl}-amide 5 F F F HN F 0 FH 0H 0 H N N N IH 0H I 6-- 0o 0OH 10 Compound 160 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[N'-(4-methoxy-phenyl) 15 hydrazinocarbonyl]-2-methyl-butyl}-amide F F F HN F 0 0 N N A 20 6 - 0Y H 0 H 0 Compound 161 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[N'-(3-hydroxy-4-methoxy 25 benzyl)-hydrazinocarbonyl]-2-methyl-butyl}-amide F F F HN F 0 0 - 0 , N N F N N OH 6 0 H 0 H WO 2008/132153 PCT/EP2008/055039 - 86 Compound 162 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[N'-(4-hydroxy-3-methoxy benzyl)-hydrazinocarbonyl]-2-methyl-butyl}-amide 5 F F F HN NFOOH F H 0 H 0 H0H N N N N 0 10 Compound 163 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(N'-acetyl-hydrazinocarbonyl) 2-methyl-butyl]-amide F F F 15 HN FO 0 F H 0H 0 H N N N -- Y 0 0 H0 Compound 164 20 F F F HN F O0 H N N N NH KH 0 0 O5H H 25 WO 2008/132153 PCT/EP2008/055039 - 87 Compound 165 (R) -3-{(S)-2-[2- (2- Flu oro-phenyl) -acetylami no]-3-m ethyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)- 1 -[N'-(4-hydroxy-benzoyl) hydrazinocarbonyl]-2-methyl-butyl}-amide 5 F F F HN/ F OH N N b-_Y 0 0 0 10 Compound Structure Chemical name F F F (R)-3-{ (S)-2-[2-(2-Fluoro HN /phenyl)-acetylamino]-3 rn methyl- pentanoylami no) 166 F H 8-trifluormethyl-2,3,4,9 NHK~ N Y N<N tetrahydro-1 H-carbazole H 0 H 3-carboxylic acid [(S)-1 6 H Y (acetylamni no-mnethyl) -2 methyl-butyl]-amide F F (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN mnethyl- pentanoylamni no)} 167 F008-trifluoromethyl-2,3,4,9 F H tetrahydro-1 H-carbazole ' N' N.NK~ 3-carboxylic acid f{(S)-1 6 -Y 0 [(3-ethyl-ureido)-m ethyl] 2-methyl-butyl}-amide FF FF (R)-3- { (S)-2-[2-(2-Fluoro HN n /ethyl- pentanoylami no)} 8-trifluoromethyl-2,3,4,9 168 F H 0H 0tetrahydro-1 H-carbazole N.~K~ NJ ,_N,,,/N 3-carboxylic acid [(S)-1 bI YO 0 (2-imidazol-1 -yI eth ylcarbamnoyl) -2-m ethyl ______________________________________________butyl]-amide WO 2008/132153 PCT/EP2008/055039 - 88 SF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} HN /8-trif luorom ethyl-2,3,4,9 169 F HH 0 tetrahydro-1 H-carbazole N N N N 3-carboxylic acid {(S)-2 H H methyl-1-[(pyrazin-2 -- YO0 ylmethyl)-carbamoyl] 'IN butyl}-amide F F F (R)-3-{ (S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN m / ethyl- pentanoylami no)} 170 F H 0 H8-trifluoromethyl-2,3,4,9 N_ A Ntetrahydro-1 H-carbazole YN"N 3-carboxylic acid 6 - H 0 HNy( ((1 S,2S)-1 -acetylamino-2 0 methyl-butyl)-amide FF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} HN /8-trifluoromethyl-2,3,4,9 171 F 0 H 0tetrahydro-1 H-carbazole H N N 0 3-carboxylic acid [(S)-1 0 N (isoquinolin-8 YO H 0I ylcarbamoyl)-2-methyl N butyl]-amide FF (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} 8-trifluoromethyl-2,3,4,9 172 F 00tetrahydro-1 H-carbazole H 3-carboxylic acid f{(S)-1 I. H H H [3-(3-hydroxy-propyl) YO 0 ureidom ethyl]-2-m ethyl butyl}-amide F F (R)-3-{ (S)-2-[2-(2-Fluoro F -~phenyl)-acetylamino]-3 IN m ethyl- pentanoylami no)} 8-trifluoromethyl-2,3,4,9 173 F H tetrahydro-1 H-carbazole NNNA N~~~N. 3-carboxylic acid f{(S)-1 H H H[(3-ethyl-thioureido) 0 m ethyl] -2-m ethyl-butyl} amide F (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} 8-trifluoromethyl-2,3,4,9 F74HF0 H 0 :- N tetrahydro-1 H-carbazole NJI, 3-carboxylic acid {(S)-2 H 0 N H N methyl-i -[(3-pyridin-4-yI YO H H Hureido)-methyl]-butyl} amide WO 2008/132153 PCT/EP2008/055039 - 89 FFFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} HN /8-trif luorom ethyl-2,3,4,9 175~ F H 0 H 0 H tetrahydro-1 H-carbazole N N N. 3-carboxylic acid {(S)-2 N I.0 E H 0H NN methyl-1 -[3-(l1H-tetrazol 6 --- Y H 0 N-N 5-yI) -pro pylcarbamoyl] butyl}-amide FFFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylamni no)} HN /8-trifluoromethyl-2,3,4,9 176 F H 0 H 0 H tetrahydro-l H-carbazole N,,, YN N 3-carboxylic acid {(S)-2 H" 0 'IH methyl-i -[(1 H-tetrazol-5 - 0 N- ylmethyl)-carbamoyl] butyl}-amide FFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} HN /8-trifluoromethyl-2,3,4,9 177 F H 0 H 0 Ntetrahydro-1 H-carbazole N N N 3-carboxylic acid f{(S)-1 H 0 NzzN [(2-tert-butyl-2H-tetrazol -~ 05-ylm ethyl) -carbamoyl] -2 methyl-butyll-amide F (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 H .- m ethyl- pentanoylami no)} N / 8-trifluoromethyl-2,3,4,9 178 F H H 0 NH tetrahydro-1 H-carbazole N ~w~.s N,,-kN- N 3-carboxylic acid [(S)-1 E H b = (2-tert-butyl-2H-tetrazol-5 ylcarbamoyl)-2-methyl butyl]-amide FFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylamni no)} HN /8-trifluoromethyl-2,3,4,9 179F H0 H - erhdo1Hcraoe F H 0 H 0 tetahyro-1i Hacidrbaole N" N N (1-cartboxylic acid [(S)- I ~. 0 H 0 H 1-etbtl- -erzl5 6HY ylcarbamoyl)-2-methyl butyl]-amide FF (R)-3-{ (S)-2-[2-(2-Fluoro F ~-phenyl)-acetylamino]-3 H N m ethyl- pentanoylami no)} 8-trifluoromethyl-2,3,4,9 180 F H0 H tetrahydro-1 H-carbazole HJI U , 3-carboxylic acid {(S)-2 6EY H 0 H methyl-i -[(2-pyridin-4-yI acetylamino)-m ethyl] ____ ___ __ ___________________________________butyl}-amide WO 2008/132153 PCT/EP2008/055039 - 90 F (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} HN /8-trifluoromethyl-2,3,4,9 181 F H 0 H 0tetrahydro-1 H-carbazole N~-N~ w N S N 3-carboxylic acid {(S)-2 I: E H 0N methyl-1 -[2-(l1-methyl-1 H b ___ O H N-Ntetrazol-5-ylsu Ifanyl) ethylcarbamoyl]-butyl} amide F F F (R)-3-{ (S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} 182 F 08-trifluoromethyl-2,3,4,9 H H tetrahydro-1 H-carbazole NA " 3-carboxylic acid [(1 S,2S) I -. Y 0 0 ON 2-methyl-1 -(2-pyridin-4-y acetylamino)-butyl]-amide FFFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} HN ~ /8-trifluoromethyl-2,3,4,9 183 F H 0 H 0 tetrahydro-1 H-carbazole NJ , N3-carboxylic acid (S)-2 H 0 H methyl-1 -[(pyrimidin-5 N ylmethyl)-carbamoyl] butyl}-amide F F F HN/ 184 F H 0 H Np=N SH 0 H FFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} HN ~ /8-trifluoromethyl-2,3,4,9 185 F H 0 H 0 N=N tetrahydro-1 H-carbazole N~J~ N ~KNN N 3-carboxylic acid [(S)-2 YO E H 0 E H methyl-1 -(2-tetrazol-1 -y ethylcarbamoyl)-butyl] amide F Ff()2[( )3f()2[-2 F Fluoro-phenyl) F acetylamino]-3-m ethyl HN pentanoylamino}-8 186 F H 0 0trif luoromethyl-2,3,4,9
N
1 1 A 0H tetrahydro-1 H-carbazole ~Ni N~N 0 3-carbonyl)-amino]-3 6 _ H 0 H methyl-pentyl}-carbamic acid tetrahydro-pyran-4-y _______________________________________________ester WO 2008/132153 PCT/EP2008/055039 - 91 F F F F f{(S)-2-[((R)-3-{ (S)-2-[2-(2 F ~Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8 187 F H trifluoromethyl-2,3,4,9 N, tetrahydro-1 H-carbazole N 0O 3-carbonyl)-amino]-3 methyl-pentyl}-carbamic acid methyl ester 1 -tert-butyl-4-(3-{(S)-2 F F [((R)-3-{(S)-2-[2-(2-fluoro F F F phenyl)-acetylamino]-3 HN 0methyl-pentanoylamino} 18 0 8-trifluoromethyl-2,3,4,9 tetrahydro-1H-carbazole 3-carbonyl)-amino]-3 N N methyl-pentanoylamino} propyl)-4H-tetrazol-1 -ium; Trifluoro-acetate F (R)-3-{(S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 methyl-pentanoylamino} 189 8-trifluoromethyl-2,3,4,9 9F H 0 H 0 tetrahydro-1 H-carbazole N N K 3-carboxylic acid [(S)-2 0 N H 0 Hmethyl-1-(3-tetrazol-1-yl N N propylcarbamoyl)-butyl] amide F F (R)-3-{(S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 methyl-pentanoylamino} 8-trifluoromethyl-2,3,4,9 190 F H 0 H 0 tetrahydro-1 H-carbazole SN N3-carboxylic acid [(S)-2 S00Hmethyl-1-(3-pyridin-4 0 N ylmethyl-ureidomethyl) butyl]-amide F F F HN 191 F H H O S H 0 H ~N N' I FFFF (R)-3- { (S)-2-[2-(2-Fluoro F Fphenyl)-acetylamino]-3 HN /mehlpnaolmn 192 8-trifluoromethyl-2,3,4,9 F1H02 0 N4J, tetrahydro-1 H-carbazole F H 0H H N ' N N'(3 3-carboxylic acid [(S)-2 I O H 0 H H methyl-1-(1H-tetrazol-5 ylcarbamoyl)-butyl]-amide WO 2008/132153 PCT/EP2008/055039 - 92 F (R)-3-{(S)-2 F F [(Bicyclo[4.2.0]octa 1(6),2,4-triene-7 carbonyl)-amino]-3 193 H 0 H methyl-pentanoylamino} N N~ 8-trifluoromethyl-2,3,4,9 H NH 2 tetrahydro-1 H-carbazole (15 0 0 3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{(S)-2-[2-(2-Chloro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino} 194 C8-trifluoromethyl-2,3,4,9 H 0 H Stetrahydro-1 H-carbazole N N 3-carboxylic acid ((S)-2 N H2 0 H 0 methyl-1-thiocarbamoyl butyl)-amide F (R)-3-{(S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 methyl-pentanoylamino} HN 8-trifluoromethyl-2,3,4,9 F1H9H N=N tetrahydro-1 H-carbazole N 3-carboxylic acid [(S)-2 I E H H methyl-1 -(4-tetrazol-1 -yl butylcarbamoyl)-butyl] amide F F F (R)-3-((S)-3-Methyl-2 phenylacetylamino HN /pentanoylamino)-8 196 0trifluoromethyl-2,3,4,9 H Stetrahydro-1 H-carbazole N NNH 3-carboxylic acid ((S)-2 0 H 0 methyl-1-thiocarbamoyl butyl)-amide F (R)-3-{(S)-2-[2-(2-Fluoro F F -phenyl)-acetylamino]-3 HN methyl-pentanoylamino} 8-trifluoromethyl-2,3,4,9 197 F H 0 H 0 tetrahydro-1H-carbazole N ~3-carboxylic acid ((S)-2 H 0 H Omethyl-1 -{[(morpholine-4 6 _ 0 <0 carbonyl)-amino]-methyl} butyl)-amide F R)-3-{(S)-2-[2-(2-Fluoro F F -phenyl)-acetylamino]-3 HN methyl-pentanoylamino} 8-trifluoromethyl-2,3,4,9 198 F H H 0 0~o tetrahydro-1 H-carbazole NJ N k3-carboxylic acid ((S)-2 I H 0 H H methyl-1 -{[3-(tetrahydro pyran-4-yl)-ureido] methyl}-butyl)-amide WO 2008/132153 PCT/EP2008/055039 - 93 FFFF (R)-3-{ (S)-3-Methyl-2-[2 F (2-trifluoromethyl-phenyl) HN / acetylamino] HN / pentanoylamino}-8 199 FF 19F H 0 H S trifluoromethyl-2,3,4,9 N NQN~ Nl.jKN tetrahydro-1 H-carbazole FN" NH H 3-carboxylic acid ((S)-2 methyl-i -thiocarbamnoyl butyl)-amide F (R)-3-[(S)-3-Methyl-2-(2 Ft omethyl-2-phenyl HN /propionylamino) pentanoylamino]-8 200 H 0 H s trifluoromethyl-2,3,4,9 Nj N N tetrahydro-1 H-carbazole 3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F (R)-3-[(S)-2-[2-(2-Fluoro F ~ phenyl)-acetylamino]-3 HN methyl-pentanoylamino N 8 -trifluoromethyl-2,3,4,9 201 F00 tetrahydro-1 H-carbazole H NH2 N N--kNJ-N N 3-carboxylic acid ((S)-2 methyl-1-[3-(2-pyridin-4 YO H Z- yI-ethyl)-ureidomethyl] butyll-amide F F F (R)-3-[(S)-3-Methyl-2-((S) 2-phenyl-propionylamino) HN pentanoylamino]-8 202 0 8trifluoromethyl-2,3,4,9
>
1 H tetrahydro-1 H-carbazole N"' ':) NH3-carboxylic acid {(S)-2 S0 H 0 2methyl-1-thiocarbanoyl butyl)-amide F F F (R)-3-[(S)-3-Methyl-2-((R) 2-phenyl-propionylamino) HN /pentanoylamino]-8 trifluoromethyl-2,3,4,9 H 0 H 'S tetrahydro-1 H-carbazole N N~ 3-carboxylic acid ((S)-2 0 H 0 2 methyl-1-thiocarbamoyl butyl)-amide F (R)-3-(S)-2-[2-(2-Fluoro 2-phenyl)-acetylamino]-3 methyl-pentanoylamino 8-trifluoromethyl-2,3,4,9 204 F 0 0 tetrahydro-1 H-carbazole H H - 3-carboxylic acid [(S)-2 0 H (methanesulfonylamino methyl)-2-methyl-butyl] amide WO 2008/132153 PCT/EP2008/055039 - 94 F (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 F m methyl- pentanoylami no)} HN "'8-trif luorom ethyl-2,3,4,9 205 F H tetrahydro-1 H-carbazole NHJN~ No H 3-carboxylic acid [(S)-2 H"H N N methyl-1 -(3-pyridin-4 6 - H 0 H H N ylmethyl th iou rei dom ethyl) -butyl] amide FF (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 F m ethyl- pentanoylami no)} N "'/8-trifluoromethyl-2,3,4,9 206 F H 0 tetrahydro-l H-carbazole N H s3-carboxylic acid {(S)-2 H 0 N N methyl-i -[3-(tetrahydro 6 -Y 0 H H 0 pyran-4-ylm ethyl) thioureidomethyl]-butyl} amide FF F (R)-3-[(S)-3-Methyl-2-((R) 2-phenyl-butyrylamino) HN /pentanoylamino]-8 207 0strifluoromethyl-2,3,4,9 H 0 H Stetrahydro-1 H-carbazole N N". N"'UNH 23-carboxylic acid ((S)-2 0 0 0 methyl-1 -thiocarbamoyl butyl)-amide FF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m I ethyl- pentanoylami no)} 8-trifluoromethyl-2,3,4,9 208 F H 0 H 0 tetrahydro-1 H-carbazole N~~N w N 0 3-carboxylic acid ((S)-2 H N Nmethyl-1 -{3-[2-(tetrahydro 0 0IY H H pyran-4-yI)-ethyl] ureidomethyl}-butyl) amide F F R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN methyl-pentanoylamino} 8-trifluoromethyl-2,3,4,9 209 F H ~ H 0 ro tetrahydro-1 H-carbazole NJ)k NN%"N 3-carboxylic acid {(S)-2 I ~. 0 H H Hmethyl-i -[3-(2-morpholin 6 -A- 04-yI-ethyl)-ureidom ethyl] ____ ___ __ ___________________________________butyl}-amide WO 2008/132153 PCT/EP2008/055039 - 95 F F F (R)-3-{ (S)-2-[2-(2-Fluoro HN phenyl)-acetylamino]-3 HNm ethyl- pentanoylami no)} 210 F 0 s8-trifluoromethyl-2,3,4,9 H H tetrahydro-1 H-carbazole N N N "' 3-carboxylic acid ((S)-1 6 - H H benzylthiocarbamoyl-2 methyl-butyl)-amide FFF (R)-3- (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN m ethyl- pentanoylami no)} 211 F H 0 H8-trifluoromethyl-2,3,4,9 211 H 0 N tetrahydro-1 H-carbazole & Y HQN~ N NH 3-carboxylic acid [(S)-l (3-hydroxy propylcarbamoyl)-2 methyl-butyl]-amide F F F (R)-3-{ (S)-2-[2-(2-Fluoro HN /phenyl)-acetylamino]-3 F 0 m ethyl- pentanoylamni no)} 212 F H H08-trifluoromethyl-2,3,4,9 NH tetrahydro-1 H-carbazole YO H0 3-carboxylic acid ((S)-2 oxo-azepan-3-yI)-amide F F F (R)-3-{ (S)-2-[2-(2-Fluoro HN phenyl)-acetylamino]-4 HN /methylsulfanyl 23F H0 Hsbutyrylamino}-8 Nj N NNH trifluoromethyl-2,3,4,9 H" -A H tetrahydro-1 H-carbazole 6 --Y H 03-carboxylic acid ((S)-2 S", methyl-i -thiocarbamoyl butyl)-amide F F F (R)-3-{ (S)-2-[2-(2-Fluoro HN phenyl)-acetylamino]-3 HNm ethyl- pentanoylamni no)} 24F H 8-trifluoromethyl-2,3,4,9 214Hl tetrahydro-1 H-carbazole 'I:KN' N:- NH 2 3-carboxylic acid ((R)-1 SH 0 carbamoyl-2 S methylsulfanyl-ethyl) amide WO 2008/132153 PCT/EP2008/055039 - 96 F F F (R)-3-{(R)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methylsulfanyl 215 F H spropionylamino}-8 N HI trifluoromethyl-2,3,4,9 "A~'N" - H tetrahydro-1 H-carbazole O 3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN / methyl-pentanoylamino} 8-trifluoromethyl-2,3,4,9 216 F 0j H S tetrahydro-1 H-carbazole N N" N_), N 0 K3-carboxylic acid {(S)-1 O H H -N [(2-methoxy-pyridin-4 ylmethyl)-thiocarbamoyl] 2-methyl-butyl}-amide F F F (R)-3-{(R)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN - HN /thiophen-2-yI 217 propionylamino-8 N17 Htrifluoromethyl-2,3,4,9 tetrahydro-1 H-carbazole H H0 3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-((S)-2-{[2-(2-Fluoro phenyl)-acetyl]-methyl HN /amino}-3-methyl F H S pentanoylamino)-8 218 H J trifluoromethyl-2,3,4,9 tetrahydro-1 H-carbazole O H23-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{(S)-2-[2-(2-Fluoro H N /phenyl)-acetylamino]-3 methyl-pentanoylamino} F H 0 H 08-trifluoromethyl-2,3,4,9 2 N N-N' 0 tetrahydro-1 H-carbazole I - 0 H 0 H ~3-carboxylic acid [(S)-2 methyl-1 -(morpholin-4 ylcarbamoyl)-butyl]-amide WO 2008/132153 PCT/EP2008/055039 -97 F F (R)-3-((S)-2-{[2-(2-Fluoro phenyl)-acetyl]-methyl amino}-3-methyl 0F H 0pentanoylamino)-8 220~ H N trifluoromethyl-2,3,4,9 N N NH2 tetrahydro-1 H-carbazole 63-carboxylic acid ((S)-l carbamoyl-2-methyl butyl)-amide F F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 methyl-pentanoylamino} 221 F H 8-trifluoromethyl-2,3,4,9 NN, N N) Q tetrahydro-1 H-carbazole N" "kN-No H H3-carboxylic acid [(S)-2 methyl-1 -(piperidin-1 ylcarbamoyl)-butyl]-amide F F F F (R)-3-{(S)-2-[3-(2-Fluoro HN p / phenyl)-ureido]-3-methyl pentanoylamino}-8 222 F H HH S trifluoromethyl-2,3,4,9 Stetrahydro-1 H-carbazole H 2 3-carboxylic acid ((S)-2 0 ~ 0 methyl-1-thiocarbamoyl butyl)-amide F F FF (R)-3-{(S)-2-[3-(2-Fluoro HN / benzyl)-ureido]-3-methyl pentanoylamino}-8 223 FH s trifluoromethyl-2,3,4,9 H NNY NNN tetrahydro-1 H-carbazole H 2 3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide Carbonic acid 4-{(S)-2 [((R)-3-{(S)-2-[2-(2-fluoro F F Fphenyl)-acetylamino]-3 /N methyl-pentanoylamino} F 08-trifluoromethyl-2,3,4,9 224 HO Ntetrahydro-1 H-carbazole o- H 0 H 0 3-carbonyl)-amino]-3 methyl-pentanoylamino} butyl ester 2-[2-(2 methoxy-ethoxy)-ethoxy] ethyl ester WO 2008/132153 PCT/EP2008/055039 - 98 F (R)-3-{(S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 methyl-pentanoylamino} HN /8-trifluoromethyl-2,3,4,9 225 F H H 0tetrahydro-1 H-carbazole Nj NYNNI 3-carboxylic acid [(S)-2 H 0 H methyl-1 -(N'-methyl-N' phenyl hydrazinocarbonyl)-butyl] amide F F F F(R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN methyl-pentanoylamino} F 0 08-trifluoromethyl-2,3,4,9 226 KFtetrahydro-1 H-carbazole 226 N H N F & IT H 0 3-carboxylic acid {(S)-1 [N'-(4-fluoro-benzoyl) hydrazinocarbonyl]-2 methyl-butyl}-amide F F (R)-3-((S)-2-{[1 -(2-Fluoro phenyl) HN /cyclopentanecarbonyl] amino}-3-methyl 227 H H 0 H S pentanoylamino)-8 N N~ trifluoromethyl-2,3,4,9 270 H 2 tetrahydro-1 H-carbazole 3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F FR)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino} F 8-trifluoromethyl-2,3,4,9 228 F H 0 H0 - tetrahydro-1 H-carbazole N,_k~' N N F 3-carboxylic acid {(S)-1 O O ' H H [N'-(2,4-difluoro-phenyl) hydrazinocarbonyl]-2 methyl-butyl}-amide F F F F(R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN / methyl-pentanoylamino} 8-trifluoromethyl-2,3,4,9 229 H 0 0 tetrahydro-1 H-carbazole H H 3-carboxylic acid ((S)-2 methyl-1 phenoxycarbamoyl-butyl) amide WO 2008/132153 PCT/EP2008/055039 - 99 F F F (R)-3-[(S)-3-Methyl-2-(2 HN /pyridin-3-yl-acetylamino) pentanoylamino]-8 230 HS trifluoromethyl-2,3,4,9 N.<kN N" H tetrahydro-1 H-carbazole HN 2 3-carboxylic acid ((S)-2 N methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-[(S)-3-Methyl-2-(2 HN /pyridin-2-yl-acetylamino) pentanoylamino]-8 231 HH s trifluoromethyl-2,3,4,9 NK N", tetrahydro-1 H-carbazole H 2 3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F 3-f{(S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN methyl-pentanoylamino HN /8-trifluoromethyl-2,3,4,9 232 F 0 tetrahydro-1 H-carbazole H 0 H 3-carboxylic acid (S)-2 N- methyl-1 -[N'-(pyridine-4 0 HO 0 H 1 N carbonyl) hydrazinocarbonyl]-butyl} amide F F F HN 233 F H 0 H 0I 0I 23 FN N-N N' H H H H F F F F F 3-{(S)-2-[3-(4-Fluoro HN / benzyl)-ureido]-3-methyl pentanoylamino}-8 234 FH 0 trifluoromethyl-2,3,4,9 N_, N N 2 tetrahydro-1 H-carbazole H 03-carboxylic acid ((S)-2 0 0methyl-1-thiocarbamoyl butyl)-amide WO 2008/132153 PCT/EP2008/055039 -100 F FF 3-f{(S)-2-[3-(3-Fluoro FHN /benzyl) -u rei do]-3-m ethyl F pentanoylamino}-8 235 H trifluoromethyl-2,3,4,9 6 -N <~IN N tetrahydro-1 H-carbazole Hr =- 3-carboxylic acid ((S)-2 0 0 methyl-1 -thiocarbamoyl butyl)-amide F F FF (R)-3-[(S)-3-Methyl-2-(2 H N /pyridin-4-yI-acetylamino) pentanoylamino]-8 236 H 0 H strif luoromethyl-2,3,4,9 N~AKN~ N~).~NHtetrahydro-1 H-carbazole N 0 H 0 23-carboxylic acid ((S)-2 0 methyl-i -thiocarbamoyl butyl)-amide F F F (R)-3-{ (S)-3-Methyl-2-[3 H N /(3-methyl-benzyl)-ureido] pentanoylamino}-8 237 H H 0 H s trif luoromethyl-2,3,4,9 N, N N H tetrahydro-1 H-carbazole yI 2 3-carboxylic acid ((S)-2 0 0 -methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{ (S)-3-Methyl-2-[3 HN /(4-methyl-benzyl)-ureido] pentanoylamino}-8 238 H H 0o s trif luoromethyl-2,3,4,9 NN N tetrahydro-1 H-carbazole - H -carboxylic acid ((S)-2 methyl-i -thiocarbamoyl butyl)-amide F F (R)-3-{ (S)-2-[3-(4 Methoxy-benzyl)-ureido] HN /3-methyl 2390 pentanoylamino}-8 29H H H trif luoromethyl-2,3,4,9 O-O ." N Ntetrahydro-1 H-carbazole 0 H 03-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl butyl)-amide WO 2008/132153 PCT/EP2008/055039 -101 F F (R)-3-{ (S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN m / ethyl- pentanoylamni no)} 8-trifluoromethyl-2,3,4,9 240 F H 0 H "0 tetrahydro-1 H-carbazole N N" NN 3-carboxylic acid f{(S)-1l z 0-H 0 H /[N'-(3-methoxy-benzoyl) o hydrazinocarbonyl]-2 methyl-butyll-amid F F (R)-3-{ (S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN m / ethyl- pentanoylami no)} "N 8-trifluoromethyl-2,3,4,9 241 F H 0 H 0 0 tetrahydro-l H-carbazole 0 3-carboxylic acdf(S)-1l ' N N" )N-N ai -H H H [N'-(furan-2-carbonyl) Z 00 hydrazinocarbonyl]-2 methyl-butyl}-amide F F (R)-3-{ (S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 H N m / ethyl- pentanoylami no)} 242 F0 C 08-trifluoromethyl-2,3,4,9 24 H tetrahydro-l H-carbazole NIA>p N-N ~ 3-carboxylic acid [(S)-l o H ~hydrazinocarbonyI)-2 methyl-butyl]-amide F F F (R)-3-{ (S)-2-[2-(2-Fluoro phenyl)-2-hydroxy HN /acetylamnino]-3-m ethyl 23F OH H pentanoylamino}-8 24 HN H IK trifluoromethyl-2,3,4,9 H A 2 tetrahydro-l H-carbazole 6 -11 YO3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl butyl)-amide FF F (R)-3-{ (S)-2-[3-(2-Fluoro benzyl) -u rei do]-3-m ethyl HN /pentanoylamino}-8 ,F 00 trifluoromethyl-2,3,4,9 244 HHA H H tetrahydro-1 H-carbazole
H
0 N 3croyi acid [(S)-2 hydrazinocarbonyl)-butyl] amide WO 2008/132153 PCT/EP2008/055039 -102 F F(R)-3-{(S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN / methyl-pentanoylamino} 8-trifluoromethyl-2,3,4,9 245H tetrahydro-1 H-carbazole N, . ~ > N /3-carboxylic acid [(S)-2 H 0 iH methyl-1-(N'-pyridin-2-yl hydrazinocarbonyl)-butyl] amide F F (R)-3-[(S)-3-Methyl-2-(2 oxo-2-phenyl HN /acetylamino) pentanoylamino]-8 246 H 0 H trifluoromethyl-2,3,4,9 H 0 NH 2 tetrahydro-1H-carbazole C o H 3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F {(S)-2-Methyl-1-[(R)-3 ((S)-2-methyl-1 thiocarbamoyl butylcarbamoyl)-8 247 H O . Hk Strifluoromethyl-2,3,4,9 N -:tetrahydro-1 H-carbazol-3 H2 0 o ylcarbamoyl]-butyl} carbamic acid benzyl es ter F F F (R)-3-{(S)-2-[3-(3 Methoxy-benzyl)-ureido] HN /3-methyl pentanoylamino}-8 248 Hs trifluoromethyl-2,3,4,9 N NN tetrahydro-1 H-carbazole H 2 3-carboxylic acid ((S)-2 0 0methyl-1-thiocarbamoyl butyl)-am ide F F F F(R)-3-{(2S,3S)-2-[2-(2 H -Fluoro-phenyl) N /acetylamino]-3-methyl 9 Fpentanoylamino}-8 249 Htrifluoromethyl-2,3,4,9 N', N tetrahydro-1 H-carbazole li 0 X ' 0 3-carboxylic acid [(1S,2S) 2-methyl-1 -(4-phenyl thiazol-2-yl)-butyl]-amide WO 2008/132153 PCT/EP2008/055039 -103 F F F F(R)-3-{(2S,3S)-2-[2-(2 Fluoro-phenyl) HN /acetylamino]-3-methyl pentanoylamino}-8 250 F H 0 H 'Strifluoromethyl-2,3,4,9 N~. N Q C/ O tetrahydro-1 H-carbazole 0 N 3-carboxylic acid {(1 S,2S)-1 -[4-(4-methoxy phenyl)-thiazol-2-yl]-2 methyl-butyl}-ami F F F 2-{(1R,2S)-1-[((R)-3 {(2S,3S)-2-[2-(2-Fluoro HN /phenyl)-acetylamino]-3 methyl-pentanoylamino} 251 F H 0 H8-trifluoromethyl-2,3,4,9 NK~ N 0tetrahydro-1 H-carbazole O N2O 3-carbonyl)-amino]-2 methyl-butyl}-thiazole-4 carboxylic acid ethyl ester F (R)-3-{(2S,3S)-2-[2-(2 Fluoro-phenyl) HN /acetylamino]-3-methyl pentanoylamino}-8 252 F H0 S F trifluoromethyl-2,3,4,9 ~ tetrahydro-1 H-carbazole IN F3-carboxylic acid [(1S,2S) 2-methyl-1 -(4 trifluoromethyl-thiazol-2 yl)-butyl]-amide F F F (R)-3-{(2S,3S)-2-[2-(2 Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8 253 F H 0 trifluoromethyl-2,3,4,9 N> ~ N"' N N tetrahydro-1 H-carbazole OI N N - 0 03-carboxylic acid [(1S,2S) 1-(4-ethyl-thiazol-2-yl)-2 methyl-butyl]-amide F (R)-3-{(2S,3S)-2-[2-(2 F F Fluoro-phenyl) HN /acetylamino]-3-methyl pentanoylamino}-8 254 F H trifluoromethyl-2,3,4,9 N tetrahydro-1 H-carbazole 4 ~3-carboxylic acid [(1 S,2S) 1-(4-tert-butyl-thiazol-2 yl)-2-methyl-butyl]-amide WO 2008/132153 PCT/EP2008/055039 - 104 F (R)-3-{(2S,3S)-2-[2-(2 F F Fluoro-phenyl) H acetylamino]-3-methyl N /pentanoylamino}-8 S0 OHtrifluoromethyl-2,3,4,9 255 F H tetrahydro-1 H-carbazole N TN F F 3-carboxylic acid [(1 S,2S) O H 0 ... 1-(4-hydroxy-4 trifluoromethyl-4,5 dihydro-thiazol-2-yl)-2 methyl-butyll-amide F F F F2-{(1S,2S)-1-[((R)-3 {(2S,3S)-2-[2-(2-Fluoro HN /phenyl)-acetylamino]-3 methyl-pentanoylamino} 256 F 0 OH 8-trifluoromethyl-2,3,4,9 H tetrahydro-1 H-carbazole N o 3-carbonyl)-amino]-2 O 0 methyl-butyl}-thiazole-4 I carboxylic acid F F F F(R)-3-{(S)-2-[3-(3 Methoxy-phenyl) HN /propionylamino]-3-methyl pentanoylamino}-8 257 0s trifluoromethyl-2,3,4,9 Hjj N"' N NH 2tetrahydro-1 H-carbazole H 23-carboxylic acid ((S)-2 0 methyl-1-thiocarbamoyl butyl)-amide F 2-{(1 S,2S)-1 -[((R)-3 F F f{(2S,3S)-2-[3-(2-Fluoro HN / benzyl)-ureido]-3-methyl pentanoylamino}-8 258 0H HS 0-trifluoromethyl-2,3,4,9 Stetrahydro-1 H-carbazole F' 3-carbonyl)-amino]-2 methyl-butyl}-thiazole-4 carboxylic acid ethyl ester F F F 2-{(1S,2S)-1-[((R)-3 {(2S,3S)-2-[3-(4-Methoxy HN / benzyl)-ureido]-3-methyl 259 'N 0pentanoylamino}-8 trifluoromethyl-2,3,4,9 tetrahydro-1 H-carbazole ) H3-carbonyl)-amino]-2 methyl-butyl}-thiazole-4 carboxylic acid ethyl ester WO 2008/132153 PCT/EP2008/055039 -105 F F F F2-{(1S,2S)-1-[((R)-3 {(2S,3S)-2-[3-(4-Methoxy HN / benzyl)-ureido]-3-methyl pentanoylamino}-8 260 0 s OH trifluoromethyl-2,3,4,9 N N ~tetrahydro-1 H-carbazole )N 0 3-carbonyl)-amino]-2 07 methyl-butyl}-thiazole-4 carboxylic acid F F (R)-3-{(2S,3S)-2-[2-(2 Fluoro-phenyl) HN /acetylamino]-3-methyl pentanoylamino}-8 261 O S NH 2 trifluoromethyl-2,3,4,9 H> N).A~~ ~ Ntetrahydro-1 H-carbazole 0- )3-carboxylic acid [(1S,2S) 1-(4-carbamoyl-thiazol-2 yl)-2-methyl-butyl]-amide F 2-{(1 S,2S)-1 -[((R)-3 F F f{(2S,3S)-2-[3-(2-Fluoro HN /benzyl)-thioureido]-3 methyl-pentanoylamino} 262 H H0 H S 08-trifluoromethyl-2,3,4,9 Stetrahydro-1 H-carbazole F H3-carbonyl)-amino]-2 methyl-butyl}-thiazole-4 carboxylic acid ethyl ester F (R)-3-{(2S,3S)-2-[3-(2 F F Fluoro-benzyl)-thioureido] 3-methyl pentanoylamino}-8 263 H H 0 H S NH 2 trifluoromethyl-2,3,4,9 N N ~N tetrahydro-1 H-carbazole F H 0 3-carboxylic acid [(1S,2S) 1-(4-carbamoyl-thiazol-2 yl)-2-methyl-butyl]-amide (R)-3-{(2S,3S)-2-[3-(2 F F Fluoro-benzyl)-thioureido] 3-methyl HN /pentanoylamino}-8 264 HH 0 C Strifluoromethyl-2,3,4,9 tetrahydro-1 H-carbazole 26 NH 2 3-carboxylic acid FH0((1 S,2S)-2-methyl-1 thiocarbamoyl-butyl) amide WO 2008/132153 PCT/EP2008/055039 -106 F (R)-3-{(S)-2-[2-(3 Methoxy-phenyl) HN /acetylamino]-3-methyl pentanoylamino}-8 265 0trifluoromethyl-2,3,4,9 H H Stetrahydro-1 H-carbazole JN~. N H2 3-carboxylic acid ((S)-2 H N methyl-1 -thiocarbamoyl butyl)-amide F (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 H - HO 0 ethyl-pentanoylamino NF F_ 8-trifluoromethyl-2,3,4,9 26 Ftetrahydro-1 H-carbazole 3-carboxylic acid {(S)-2 methyl-1-[(tetrahydro H S thiopyran-4-ylmethyl) carbamoyl]-butyl}-amide For the avoidance of doubt, if chemical name and chemical structure of the above illustrated compounds do not correspond by mistake, the chemical structure is regarded to unambigously define the compound. 5 All the above generically or explicitly disclosed tetrahydrocarbazole derivatives, in cluding preferred subsets/embodiments of formula (1) and Compounds 1 to 266, are hereinafter referred to as compounds of the (present) invention. 10 The terms indicated for explanation of the above compounds of the invention al ways, unless indicated otherwise in the description or in the claims, have the following meanings: The term "unsubstituted" means that the corresponding radical, group or moiety has no substituents. 15 The term "substituted" means that the corresponding radical, group or moiety has one or more substituents. Where a radical has a plurality of substituents, and a selec tion of various substituents is specified, the substituents are selected independently of one another and do not need to be identical. The term "alkyl" for the purposes of this invention refers to acyclic saturated or un 20 saturated hydrocarbon radicals which may be branched or straight-chain and have 1 to 8 carbon atoms, i.e. C- 8 -alkanyls, C 2
-
8 -alkenyls and C 2
-
8 -alkynyls. Alkenyls have at WO 2008/132153 PCT/EP2008/055039 -107 least one C-C double bond and alkynyls at least one C-C triple bond. Alkynyls may additionally also have at least one C-C double bond. Examples of suitable alkyl radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, 2- or 3-methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n 5 heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl, n octadecyl, n-icosanyl, n-docosanyl, ethylenyl (vinyl), propenyl (-CH 2
CH=CH
2 ; -CH=CH
CH
3 , -C(=CH 2
)-CH
3 ), butenyl, pentenyl, hexenyl, heptenyl, octenyl, octadienyl, octade cenyl, octadec-9-enyl, icosenyl, icos-11-enyl, (Z)-icos-11-enyl, docosnyl, docos-13 enyl, (Z)-docos-13-enyl, ethynyl, propynyl (-CH 2 -CECH, -CEC-CH 3 ), butynyl, pentynyl, 10 hexynyl, heptynyl, octynyl, The term "(C 9
-C
3 o)alkyl" for the purposes of this invention refers to acyclic saturated or unsaturated hydrocarbon radicals which may be branched or straight-chain and have 9 to 30 carbon atoms, i.e. C 9
-
3 o-alkanyls, C 9
-
30 -alkenyls and C 9
-
30 -alkynyls. C9-3o Alkenyls have at least one C-C double bond and C 9
-
30 -alkynyls at least one C-C triple 15 bond. C 9
-
30 -Alkynyls may additionally also have at least one C-C double bond. Exam ples of suitable (C 9
-C
30 )alkyl radicals are tetradecyl, hexadecyl, octadecyl, eicosanyl, cis-13-docosenyl (erucyl), trans-13-docosenyl (brassidyl), cis-15-tetracosenyl (ner vonyl) and trans-1 5-tetracosenyl. The term "cycloalkyl" for the purposes of this invention refers to saturated and par 20 tially unsaturated non-aromatic cyclic hydrocarbon groups/radicals, having 1 to 3 rings, that contain 3 to 20, preferably 3 to 12, most preferably 3 to 8 carbon atoms. The cycloalkyl radical may also be part of a bi- or polycyclic system, where, for example, the cycloalkyl radical is fused to an aryl, heteroaryl or heterocyclyl radical as defined herein by any possible and desired ring member(s). The bonding to the compounds of 25 the general formula (1) can be effected via any possible ring member of the cycloalkyl radical. Examples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopen tyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclohexenyl, cyclopentenyl and cyclooctadienyl. The term "heterocyclyl" for the purposes of this invention refers to a mono- or poly 30 cyclic system of 3 to 20, preferably 5 or 6 to 14 ring atoms comprising carbon atoms and 1, 2, 3, 4, or 5 heteroatoms, in particular nitrogen, oxygen and/or sulfur which are identical or different. The cyclic system may be saturated, mono- or polyunsaturated but may not be aromatic. In the case of a cyclic system consisting of at least two rings the rings may be fused or spiro- or otherwise connected. Such "heterocyclyl" radicals WO 2008/132153 PCT/EP2008/055039 -108 can be linked via any ring member. The term "heterocyclyl" also includes systems in which the heterocycle is part of a bi- or polycyclic saturated, partially unsaturated and/or aromatic system, such as where the heterocycle is fused to an "aryl", "cycloal kyl", "heteroaryl" or "heterocyclyl" group as defined herein via any desired and possible 5 ring member of the heterocycyl radical. The bonding to the compounds of the general formula (1) can be effected via any possible ring member of the heterocycyl radical. Examples of suitable "heterocyclyl" radicals are pyrrolidinyl, thiapyrrolidinyl, piperidinyl, piperazinyl, oxapiperazinyl, oxapiperidinyl, oxadiazolyl, tetrahydrofuryl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl, morpholinyl, tetrahydrothiophenyl, dihydropyranyl. 10 The term "aryl" for the purposes of this invention refers to aromatic hydrocarbon systems having 3 to 14, preferably 5 to 14, more preferably 6 to 14 carbon atoms. The term "aryl" also includes systems in which the aromatic cycle is part of a bi- or poly cyclic saturated, partially unsaturated and/or aromatic system, such as where the aro matic cycle is fused to an "aryl", "cycloalkyl", "heteroaryl" or "heterocyclyl" group as 15 defined herein via any desired and possible ring member of the aryl radical. The bond ing to the compounds of the general formula (1) can be effected via any possible ring member of the aryl radical. Examples of suitable "aryl" radicals are phenyl, biphenyl, naphthyl and anthracenyl, but likewise indanyl, indenyl, or 1,2,3,4-tetrahydronaphthyl. The term "heteroaryl" for the purposes of this invention refers to a 3 to 14, prefera 20 bly 5 to 14, more preferably 5-, 6- or 7-membered cyclic aromatic hydrocarbon radical which comprises at least 1, where appropriate also 2, 3, 4 or 5 heteroatoms, preferably nitrogen, oxygen and/or sulfur, where the heteroatoms are identical or different. The number of nitrogen atoms is preferably 0, 1, 2, or 3, and that of the oxygen and sulfur atoms is independently 0 or 1. The term "heteroaryl" also includes systems in which the 25 aromatic cycle is part of a bi- or polycyclic saturated, partially unsaturated and/or aro matic system, such as where the aromatic cycle is fused to an "aryl", "cycloalkyl", "het eroaryl" or "heterocyclyl" group as defined herein via any desired and possible ring member of the heteroaryl radical. The bonding to the compounds of the general for mula (1) can be effected via any possible ring member of the heteroaryl radical. Exam 30 ples of suitable "heteroaryl" are pyrrolyl, thienyl, furyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, quinolinyl, isoquinolinyl, imidazolyl, triazolyl, triazinyl, tetrazolyl, phthalazinyl, indazolyl, indolizinyl, quinoxalinyl, quinazolinyl, pteridinyl, carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl, acridinyl.
WO 2008/132153 PCT/EP2008/055039 -109 For the purposes of the present invention, the terms "alkyl-cycloalkyl", "cycloalkylal kyl", "alkyl-heterocyclyl", "heterocyclylalkyl", "alkyl-aryl", "arylalkyl", "alkyl-heteroaryl" and "heteroarylalkyl" mean that alkyl, cycloalkyl, heterocycl, aryl and heteroaryl are each as defined above, and the cycloalkyl, heterocyclyl, aryl and heteroaryl radical is 5 bonded to the compounds of the general formula (1) via an alkyl radical, preferably Cj
C
8 -alkyl radical, more preferably Cl-C 4 -alkyl radical. The term "halogen", "halogen atom" or "halogen substituent" (Hal-) for the purposes of this invention refers to one, where appropriate, a plurality of fluorine (F, fluoro), bro mine (Br, bromo), chlorine (Cl, chloro), or iodine (1, iodo) atoms. The designations "di 10 halogen", "trihalogen" and "perhalogen" refer respectively to two, three and four sub stituents, where each substituent can be selected independently from the group con sisting of fluorine, chlorine, bromine and iodine. "Halogen" preferably means a fluorine, chlorine or bromine atom. 15 All stereoisomers of the compounds of the invention are contemplated, either in a mixture or in pure or substantially pure form. The compounds of the invention can have asymmetric centers at any of the carbon atoms. Consequently, they can exist in the form of their racemates, in the form of the pure enantiomers and/or diastereomers or in the form of mixtures of these enantiomers and/or diastereomers. The mixtures may 20 have any desired mixing ratio of the stereoisomers. Thus, for example, the compounds of the invention which have one or more centers of chirality and which occur as racemates or as diastereomer mixtures can be fraction ated by methods known per se into their optical pure isomers, i.e. enantiomers or di astereomers. The separation of the compounds of the invention can take place by col 25 umn separation on chiral or nonchiral phases or by recrystallization from an optionally optically active solvent or with use of an optically active acid or base or by derivatiza tion with an optically active reagent such as, for example, an optically active alcohol, and subsequent elimination of the radical. The compounds of the invention may be present in the form of their double bond 30 isomers as "pure" E or Z isomers, or in the form of mixtures of these double bond iso mers. Where possible, the compounds of the invention may be in the form of the tautom ers.
WO 2008/132153 PCT/EP2008/055039 -110 It is likewise possible for the compounds of the invention to be in the form of any desired prodrugs such as, for example, esters, carbonates, carbamates, ureas, amides or phosphates, in which cases the actually biologically active form is released only through metabolism. Any compound that can be converted in vivo to provide the bioac 5 tive agent (i.e. compounds of the invention) is a prodrug within the scope and spirit of the invention. Various forms of prodrugs are well known in the art and are described for instance in: (i) Wermuth CG et al., Chapter 31: 671-696, The Practice of Medicinal Chemistry, 10 Academic Press 1996; (ii) Bundgaard H, Design of Prodrugs, Elsevier 1985; and (iii) Bundgaard H, Chapter 5: 131-191, A Textbook of Drug Design and Develop ment, Harwood Academic Publishers 1991. Said references are incorporated herein by reference. 15 It is further known that chemical substances are converted in the body into metabo lites which may where appropriate likewise elicit the desired biological effect - in some circumstances even in more pronounced form. Any biologically active compound that was converted in vivo by metabolism from any of the compounds of the invention is a metabolite within the scope and spirit of the 20 invention. The compounds of the invention can, if they have a sufficiently basic group such as, for example, a secondary or tertiary amine, be converted with inorganic and organic acids into salts. The pharmaceutically acceptable salts of the compounds of the inven 25 tion are preferably formed with hydrochloric acid, hydrobromic acid, iodic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, p-toluenesulfonic acid, carbonic acid, for mic acid, acetic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, malonic acid, maleic acid, succinic acid, tartaric acid, racemic acid, malic acid, embonic acid, man delic acid, fumaric acid, lactic acid, citric acid, taurocholic acid, glutaric acid, stearic 30 acid, glutamic acid or aspartic acid. The salts which are formed are, inter alia, hydro chlorides, chlorided, hydrobromides, bromides, iodides, sulfates, phosphates, methanesulfonates, tosylates, carbonates, bicarbonates, formates, acetates, sulfoace tates, triflates, oxalates, malonates, maleates, succinates, tartrates, malates, embon- WO 2008/132153 PCT/EP2008/055039 -111 ates, mandelates, fumarates, lactates, citrates, glutarates, stearates, aspartates and glutamates. The stoichiometry of the salts formed from the compounds of the invention may moreover be an integral or non-integral multiple of one. The compounds of the invention can, if they contain a sufficiently acidic group such 5 as, for example, the carboxy, sulfonic acid, phosphoric acid or a phenolic group, be converted with inorganic and organic bases into their physiologically tolerated salts. Examples of suitable inorganic bases are ammonium, sodium hydroxide, potassium hydroxide, calcium hydroxide, and of organic bases are ethanolamine, diethanolamine, triethanolamine, ethylenediamine, t-butylamine, t-octylamine, dehydroabietylamine, 10 cyclohexylamine, dibenzylethylene-diamine and lysine. The stoichiometry of the salts formed from the compounds of the invention can moreover be an integral or non integral multiple of one. It is likewise possible for the compounds of the invention to be in the form of their solvates and, in particular, hydrates which can be obtained for example by crystalliza 15 tion from a solvent or from aqueous solution. It is moreover possible for one, two, three or any number of solvate or water molecules to combine with the compounds of the invention to give solvates and hydrates. It is known that chemical substances form solids which exist in different order states which are referred to as polymorphic forms or modifications. The various modifications 20 of a polymorphic substance may differ greatly in their physical properties. The com pounds of the invention can exist in various polymorphic forms and certain modifica tions may moreover be metastable. All these polymorphic forms of the compounds are to be regarded as belonging to the invention. 25 According to a further aspect, the object of the invention has surprisingly been solved by providing a process for manufacturing the compounds of the invention. The tetrahydrocarbazole derivatives (compounds of the invention) as illustrated herein are ligands of G-protein coupled receptors (GPCRs). 30 Thus, the aforementioned compounds of the invention are suitable for the treatment and/or prophylaxis of physiological and/or pathological conditions mediated by G protein coupled receptors or physiological and/or pathological conditions which can be WO 2008/132153 PCT/EP2008/055039 -112 influenced by modulation of these receptors, and thus prevented, treated and/or allevi ated. For the purpose of the present invention, the term "treatment" is also intended to in clude prophylactic treatment or alleviation. 5 The term "(GPCR) receptor ligand" or "ligand" is intended to refer for the purposes of the present invention to every compound which binds in any way to a receptor (the receptors in the present invention being GPCR receptors) and induces activation, inhi bition and/or another conceivable effect at this receptor. The term "(GPCR) receptor 10 ligand" or "ligand" thus includes agonists, antagonists, partial agonists/antagonists, inverse agonists and other ligands which cause an effect at the receptor which is simi lar to the effect of agonists, antagonists, partial agonists/antagonists or inverse ago nists. The term "modulation" or "modulated" is intended to refer for the purposes of the 15 present invention to as follows: "activation, partial activation, inhibition, partial inhibi tion". In this case, it is within the specialist knowledge of the average person skilled in the art to measure and determine such activation, partial activation, inhibition, partial inhibition by means of the usual methods of measurement and determination. Thus, a partial activation can be measured and determined in relation to a complete activation; 20 likewise, a partial inhibition in relation to a complete inhibition. The terms "inhibiting, inhibition and/or retardation" are intended to refer for the pur poses of the present invention to as follows: "partial or complete inhibiting, inhibition and/or retardation". In this case, it is within the specialist knowledge of the average person skilled in the art to measure and determine such inhibiting, inhibition, and/or 25 retardation by means of the usual methods of measurement and determination. Thus, a partial inhibiting, inhibition and/or retardation, for example, can be measured and de termined in relation to a complete inhibiting, inhibition and/or retardation. The compounds of the invention being ligands of GPCR receptors are surprisingly 30 characterized by a strong binding affinity to such receptors, preferably to the GnRH/LHRH receptor, compared to known prior art compounds. Due to their surprisingly strong receptor binding, the compounds of the invention can be advantageously administered at lower doses compared to other less potent WO 2008/132153 PCT/EP2008/055039 -113 binders while still achieving equivalent or even superior desired biological effects. In addition, such a dose reduction may advantageously lead to less or even no medicinal adverse effects. Further, the high binding specificity of the compounds of the invention may translate into a decrease of undesired side effects on its own regardless of the 5 dose applied. The compounds of the invention being ligands of GPCR receptors are surprisingly characterized by a strong inhibition of luteinizing hormone (LH) secretion, which is at least equivalent or even superior to that of known prior art compounds. In addition, the compounds of the invention being ligands of GPCR receptors sur 10 prisingly show more advantageous hormone suppression. Thus, for example, in the treatment of endometriosis or uterine myomas in women, a reliable, therapeutically effective and controlled reduction in the estradiol level may be achieved without chemi cal castration being brought about and hormone withdrawal manifestation which are disadvantageous for the patients recurring. In the treatment of benign prostate hyper 15 plasia (BPH) in men, for example, a pronounced, deeper and/or longer-lasting reduc tion in the testosterone level may be achieved, but likewise without reaching the castra tion level and/or causing disadvantageous hormone withdrawal manifestations. Furthermore, the compounds of the invention, being of non-peptidic nature, are re sistant to degradation by enzymes of the gastro-intestinal tract. Hence, they offer the 20 advantage to be given by oral route. They surprisingly display an improved metabolic stability, in particular microsomal stability, an improved solubility, in particular in acidic milieus such as gastric juice, and/or an improved bioavailability. Hence, again an ad vantageous dose reduction may be achievable which may cause less or even no ad verse medicinal effects. 25 The compounds of the invention, being characterized by novel C-terminus modifica tions, advantageously show improved receptor binding affinity, improved metabolic stability as well as improved solubility, each and all of which are supposed to be attrib utable to the novel C-terminus modifications. 30 According to a further aspect, the object of the invention has surprisingly been solved by providing the compounds of the present invention or pharmaceutical compo sitions as described herein for use as a medicament.
WO 2008/132153 PCT/EP2008/055039 - 114 According to another aspect, the object of the present invention has surprisingly been solved by providing the use of the compounds of the invention or pharmaceutical compositions as described herein for the manufacture of a medicament for the treat ment and/or prophylaxis of physiological and/or pathological conditions mediated by 5 G-protein coupled receptors or of physiological and/or pathological conditions which can be treated by modulation of these receptors. Likewise, corresponding medica ments comprising at least one compound of the invention or at least one pharmaceuti cal composition as described herein for use in the treatment and/or prophylaxis of physiological and/or pathological conditions mediated by G-protein coupled receptors 10 or of physiological and/or pathological conditions which can be treated by modulation of these receptors are also comprised by the present invention. In a preferred embodiment, these G-protein coupled receptors are selected from the group consisting of "GnRH receptor, LHRH receptor, neurokinin family receptor, NK, receptor, NK 2 receptor". Particularly preferred is the GnRH/LHRH receptor. 15 As illustrated supra, the compounds of the invention can acts as modulators of these GPCR receptors. In a preferred embodiment, the compounds of the invention act as GnRH receptor antagonists, LHRH receptor antagonists, NK, receptor antagonists and/or NK 2 receptor antagonists. Most preferably, the compounds of the invention are antagonists of the GnRH/LHRH receptor. 20 The compounds of the invention and pharmaceutical compositions as described herein can be administered for the treatment and/or prophylaxis of physiological and/or pathological conditions mediated by G-protein coupled receptors or physiological and/or pathological conditions which can be influenced by modulation of these recep tors. 25 For the purpose of the present invention, all physiological and/or pathological condi tions are intended to be comprised that are known to be mediated by G-protein coupled receptors or that are known to be able to be influenced by modulation of these recep tors. Preferably, these conditions are benign and malignant neoplastic diseases, male 30 fertility control, hormone therapy, hormone replacement therapy, controlled ovarian stimulation (COS) in the context of in-vitro fertilization (IVF), female sub- and infertility, female contraception, nausea and vomiting, for example as a consequence of emeto genic chemotherapy, pain, inflammations, rheumatic and arthritic pathological condi tions as well as the following conditions: chronic pain, panic disorder, disturbances of WO 2008/132153 PCT/EP2008/055039 -115 mood and sleep, depression, fibromyalgia, post-traumatic stress disorder, tension headache, migraine headache, anxiety, generalized anxiety disorder, bowel syndrome, irritable bowel sysndrome, stress-induced hypertension, asthma, emesis, cough, cysti tis of the bladder, pancreatitis, atopic dermatitis (refer to Rupniak NM, Chapter 4.3: 5 Substance P (NK1 receptor) antagonists, in Steckler T, Kalin NH, Reul JMHM (Eds.) Handbook of Stress and Brain, Vol. 15, 2005; Duffy RA, Expert Opin. Emerg. Drugs 2004, 9(1):9-21). Hormone therapy in this connection includes, inter alia, the treatment of endome triosis, uterine leiomyomas, uterine fibroids and benign prostate hyperplasia (BPH). In 10 male fertility control, the compounds of the invention bring about a reduction in sper matogenesis. Combined administration with androgens, e.g. testosterone or testoster one derivatives, such as, for example, testosterone esters, is preferred. The testoster one derivatives can in this case be administered for example by injection, e.g. by in tramuscular depot injection. 15 Female hormone therapy in this connection includes, inter alia, for example, the treatment of benign hormone-dependent disorders such as endometriosis, uterine fi broids, uterine myomas (uterine leiomyomas), endometrium hyperplasia, dysmenor rhea, and dysfunctional uterine bleeding (menorrhagia, metrorrhagia), where appropri ate in combination with other hormones, e.g. estrogens or/and progestins. Particularly 20 preferred are combinations of the LHRH receptor antagonists of the invention and tis sue-selective partial estrogen agonists, such as raloxifene*. The compounds of the invention can also be employed in hormone replacement therapy, for example for treating hot flushes, in the control of female fertility, for exam ple by switching off the endogenous hormone cycle for controlled induction of ovulation 25 (controlled ovarian stimulation, COS), and for the treatment of sterility within the scope of assisted reproduction techniques (ART) such as in-vitro fertilization (IVF), as well as in female contraception. Thus, an LHRH receptor antagonist of the invention can be administered on days 1 to 15 of the female cycle together with estrogen, preferably with very low estrogen dos 30 ages. On days 16 to 21 of the cycle of intake, progestagen is added to the combination of estrogen and LHRH receptor antagonist. The LHRH receptor antagonist of the in vention can be administered continuously throughout the cycle. It is possible in this way to achieve a reduction in the hormone dosage and thus a reduction in the side effects of non-physiological hormone levels. It is additionally possible to achieve advantageous WO 2008/132153 PCT/EP2008/055039 -116 effects in women suffering from polycystic ovary syndrome and androgen-dependent disorders, such as acne, seborrhea and hirsutism. An improved cycle control compared with previous administration methods is also to be expected. Further preferred conditions that can be treated and/or prevented by administering 5 the compounds of the invention or pharmaceutical compositions as described herein are malignant hormone-dependent tumor diseases, such as premenopausal breast cancer, prostate cancer, ovarian cancer, uterine cancer, cervical cancer and endo metrial cancer, benign prostate hyperplasia (BPH), gonadal protection during chemo therapy, developmental disturbances in early childhood, e.g. pubertas praecox, HIV 10 infections or AIDS, neurological or neurodegenerative disorders, ARC (AIDS related complex), Kaposi sarcoma, tumors originating in the brain and/or nervous system and/or meninges (refer to WO 99/01764), dementia and Alzheimer's disease. In a further preferred embodiment, the physiological and/or pathological conditions 15 are selected from the group consisting of: "benign tumor diseases, malignant tumor diseases, male fertility control, hormone therapy, hormone replacement therapy, fe male sub- or infertility, controlled ovarian stimulation in in vitro fertilization (COS/ART), female contraception, side effects due to chemotherapy, prostate cancer, breast can cer, uterine cancer, endometrial cancer, cervical cancer, ovarian cancer, benign pros 20 tate hyperplasia (BPH), endometriosis, uterine fibroids, uterine myomas, endometrium hyperplasia, dysmenorrhoea, dysfunctional uterine bleeding (menorrhagia, metror rhagia), pubertas praecox, hirsutism, polycystic ovary syndrome, hormone-dependent tumor diseases, HIV infections or AIDS, neurological or neurodegenerative disorders, ARC (AIDS related complex), Kaposi sarcoma, tumors originating from the brain and/or 25 nervous system and/or meninges, dementia, Alzheimer's disease, nausea, vomiting, pain, inflammations, such as appendicitis, arteritis, arthritis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis, con junctivitis, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, endocardi tis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, 30 gastritis, gastroenteritis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, uveitis, vaginitis, vascu- WO 2008/132153 PCT/EP2008/055039 -117 litis, vulvitis but also asthma, irritable bowel syndrome and cystitis of the bladder, chronic inflammations, acute inflammations, rheumatic and arthritic pathological states, such as arthritis, rheumatoid arthritis, lupus erythematosus, Sj6gren's syndrome, scleroderma (systemic sclerosis), dermatomyositis, polychondritis, polymyositis, 5 polymyalgia rheumatica, osteoarthritis (arthrosis), septic arthritis, fibromyalgia, gout, pseudogout, spondyloarthropathies, ankylosing spondylitis, reactive arthritis (Reiter's syndrome), psoriatic arthropathy, enteropathic spondylitis, reactive arthropathy, vascu litis, polyarteritis nodosa, Henoch-Sch6nlein purpura, serum sickness, Wegener's granulomatosis, giant cell arteritis, temporal arteritis, Takayasu's arteritis, Behget's 10 syndrome, Kawasaki's disease (mucocutaneous lymph node syndrome) and Buerger's disease (thromboangiitis obliterans), chronic pain, panic disorder, disturbances of mood and sleep, depression, fibromyalgia, post-traumatic stress disorder, tension headache, migraine headache, anxiety, generalized anxiety disorder, bowel syndrome, irritable bowel sysndrome, stress-induced hypertension, asthma, emesis, cough, cysti 15 tis of the bladder, pancreatitis and/or atopic dermatitis. Likewise, corresponding medicaments comprising at least one compound of the in vention or at least one pharmaceutical composition as described herein for use in the treatment and/or prophylaxis of the herein disclosed physiological and/or pathological 20 conditions are also comprised by the present invention. As illustrated supra, the compounds of the invention are ligands of GPCR re ceptors. They can be administered to various mammalian species, including human, for the treatment and/or prophylaxis of physiological and/or pathological conditions in such mammals. 25 For the purpose of the present invention, all mammalian species are regarded as being comprised. Preferably, such mammals are selected from the group consisting of "human, domestic animals, cattle, livestock, pets, cow, sheep, pig, goat, horse, pony, donkey, hinny, mule, hare, rabbit, cat, dog, guinea pig, hamster, rat, mouse". More preferably, such mammals are human. 30 In a further aspect of the present invention, the compounds of the invention or pharmaceutical compositions as described herein are used in combination with at least one additional pharmacologically active substance.
WO 2008/132153 PCT/EP2008/055039 -118 Such additional pharmacologically active substance may be other compounds of the present invention and/or other suitable therapeutic agents useful in the treatment and/or prophylaxis of the aforementioned physiological and/or pathological conditions. The additional pharmacologically active substance may be an antagonist of GPCRs 5 and/or an agonist of GPCRs depending on the purpose of the combined use. Selection and combination of the additional pharmacologically active substance(s) can be easily performed by the skilled artisan on the basis of his expert knowledge and depending on the purpose of the combined use and physiological and/or pathological conditions tar geted. 10 In a preferred embodiment, the compounds of the invention or pharmaceutical compositions as described herein are used for the treatment and/or prophylaxis of the aforementioned physiological and/or pathological conditions in the form of a medica ment, where such medicament comprises at least one additional pharmacologically 15 active substance. In another preferred embodiment, the compounds of the invention or pharmaceuti cal compositions as described herein are used for the treatment and/or prophylaxis of the aforementioned physiological and/or pathological conditions in the form of a me dicament, where the medicament is applied before and/or during and/or after treatment 20 with at least one additional pharmacologically active substance. In a further preferred embodiment, the additional pharmacologically active sub stance being selected from the group consisting of: "androgens, estrogens, progestins, progestagens, selective estrogen receptor modulator (SERM), selective androgen receptor modulator (SARM), receptor-type tyrosine kinase inhibitor, 5alpha-reductase 25 inhibitors, 5alpha-reductase 1 inhibitors, 5alpha-reductase 2 inhibitors, alpha-receptor inhibitors (alpha blockers), alphal-adrenergic receptor antagonists, aromatase inhibitors, lyase inhibitors, GnRH/LHRH receptor agonists, GnRH/LHRH receptor antagonists, NK, receptors antagonists, NK 2 receptors antagonists, NK, receptors agonists, NK 2 receptors agonists". 30 In a yet further preferred embodiment, the additional pharmacologically active sub stance being selected from the group consisting of: "testosterone, oestradiol, oestriol, oestrone, progesterone, raloxifene {[2-(4-hydroxyphenyl)-6-hydrobenzo[b]thien-3-yl][4 (2-(1-piperidinyl)ethoxy)phenyl]-methanone; Chemical Abstract Services Registry No. 84449-90-11, arzoxifene [2-(4-methoxypheny)-3-[4-[2-(1 -piperidinyl)ethoxy]phenoxy]- WO 2008/132153 PCT/EP2008/055039 -119 Benzo[b]thiophene-6-ol, Chemical Abstract Services Registry No. 182133-25-1], laso foxifene [5,6,7,8-tetrahydro-6-phenyl-5-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]-(5R,6S)- 2 Naphthalenol, Chemical Abstract Services Registry No. 180916-16-9], ospemifene {2 [4-[(1Z)-4-chloro-1,2-diphenyl-1-buten-1-yl]phenoxy]-Ethanol, Chemical Abstract Ser 5 vices Registry No. 128607-22-71, TSE-424 {1-[[4-[2-(hexahydro-1 H-azepin-1 yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-1H-Indol-5-ol acetate (1:1), Chemical Abstract Services Registry No. 198481-33-31, HMR-3339, SERM-3339, SPC 8490, HM-101 {2-[2-[4-[(1Z)-4-chloro-1,2-diphenyl-1-buten-1-yl]phenoxy]ethoxy] Ethanol, Chemical Abstract Services Registry No. 341524-89-81, bazedoxifene (WAY 10 140424) {1-[[4-[2-(hexahydro-1 H-azepin-1 -yl)ethoxy]phenyl]methyl]-2-(4 hydroxyphenyl)-3-methyl-1 H-Indol-5-ol, Chemical Abstract Services Registry No. 198481-32-21, flutamide {2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]- Propanamide, Chemical Abstract Services Registry No. 13311-84-71, casodex {N-[4-cyano-3 (trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-Propanamide, 15 Chemical Abstract Services Registry No. 90357-06-51, nilutamide {5,5-dimethyl-3-[4 nitro-3-(trifluoromethyl)phenyl]-2,4-Imidazolidinedione, Chemical Abstract Services Registry No. 63612-50-01, tamoxifen {2-[4-[(1Z)-1,2-diphenyl-1-buten-1-yl]phenoxy] N,N-dimethyl-Ethanamine, Chemical Abstract Services Registry No. 10540-29-11, ful vestrant {7-[9-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]nonyl]-, (7alpha,1 7beta)-Estra 20 1,3,5(10)-triene-3,17-diol, Chemical Abstract Services Registry No. 129453-61-81, fi nasteride {N-(1 ,1 -dimethylethyl)-2,4a,4b,5,6,6 a, 7,8,9,9a,9b,10,11,11 a-tetradecahydro 4a,6a-dimethyl-2-oxo-(4aR,4bS,6aS,7S,9aS,9bS, 11 aR)-1 H-Indeno[5,4-f]quinoline-7 carboxamide, Chemical Abstract Services Registry No. 98319-26-71, dutasteride {N [2,5-bis(trifluoromethyl)phenyl]-2,4a,4b,5,6,6a,7,8,9,9a,9b, 10,11,11 a-tetradecahydro 25 4a,6a-dimethyl-2-oxo-(4aR,4bS,6aS,7S,9aS,9bS, 11 aR)-1 H-Indeno[5,4-f]quinoline-7 carboxamide, Chemical Abstract Services Registry No. 164656-23-91, izonsteride {8 [(4-ethyl-2-benzothiazolyl)thio]-1,4,4a,5,6,1 Ob-hexahydro-4,1 Ob-dimethyl-(4aR,1 ObR) (9CI) Benzo[f]quinolin-3(2H)-one, Chemical Abstract Services Registry No. 176975-26 11, epristeride {17-[[(1,1 -dimethylethyl)amino]carbonyl]-(1 7beta)- Androsta-3,5-diene-3 30 carboxylic acid, Chemical Abstract Services Registry No. 119169-78-71, tamsulosin {5 [(2R)-2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-2-methoxy-Benzenesulfonamide, Chemical Abstract Services Registry No. 106133-20-41, prazosin {[4-(4-amino-6,7 dimethoxy-2-quinazolinyl)-1 -piperazinyl]-2-furanyl-Methanone, Chemical Abstract Ser vices Registry No. 19216-56-91, terazosin {[4-(4-amino-6,7-dimethoxy-2-quinazolinyl) 35 1 -piperazinyl](tetrahydro-2-furanyl)-methanone, Chemical Abstract Services Registry WO 2008/132153 PCT/EP2008/055039 -120 No. 63590-64-71, doxazosin {[4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-1 piperazinyl](2,3-dihydro-1,4-benzodioxin-2-yl)-Methanone, Chemical Abstract Services Registry No. 74191-85-81, silodosin {2,3-dihydro-1-(3-hydroxypropyl)-5-[(2R)-2-[[2-[2 (2,2,2-trifluoroethoxy)phenoxy]ethyl]amino]propyl]-1 H-Indole-7-carboxamide, Chemical 5 Abstract Services Registry No. 160970-54-71, alfuzosin {N-[3-[(4-amino-6,7-dimethoxy 2-quinazolinyl)methylamino]propyl]tetrahydro-2-Furancarboxamide, Chemical Abstract Services Registry No. 81403-80-71, anastrozole {alpha1,alpha1,alpha3,alpha3 tetramethyl-5-(1 H-1,2,4-triazol-1 -ylmethyl)-1,3-Benzenediacetonitrile, Chemical Ab stract Services Registry No. 120511-73-11, letrozole {4,4'-(1 H-1,2,4-triazol-1 10 ylmethylene)bis-Benzonitrile, Chemical Abstract Services Registry No. 112809-51-51, finrozole {4-[(1 R,2S)-3-(4-fluorophenyl)-2-hydroxy-1 -(1 H-1,2,4-triazol-1-yl)propyl] Benzonitrile, Chemical Abstract Services Registry No. 160146-17-81, exemestane {6 methylene- Androsta-1,4-diene-3,17-dione, Chemical Abstract Services Registry No. 107868-30-41, gefitinib {N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(4 15 morpholinyl)propoxy]-4-Quinazolinamine, Chemical Abstract Services Registry No. 184475-35-21, imatinib {4-[(4-methyl-1 -piperazinyl)methyl]-N-[4-methyl-3-[[4-(3 pyridinyl)-2-pyrimidinyl]amino]phenyl]-Benzamide, Chemical Abstract Services Registry No. 152459-95-5}, semaxanib {3-[(3,5-dimethyl-1 H-pyrrol-2-yl)methylene]-1,3-dihydro (3Z)-2H-lndol-2-one, Chemical Abstract Services Registry No. 194413-58-61, SU-6668 20 {5-[(1,2-dihydro-2-oxo-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1 H-Pyrrole-3-propanoic acid, Chemical Abstract Services Registry No. 252916-29-31, SU-1 01 {5-methyl-N-[4 (trifluoromethyl)phenyl]-4-Isoxazolecarboxamide, Chemical Abstract Services Registry No. 75706-12-61, CI-1033 {N-[4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(4 morpholinyl)propoxy]-6-quinazolinyl]-2-Propenamide hydrochloride (1:2), Chemical 25 Abstract Services Registry No. 289499-45-21, E-6006 {N,N-dimethyl-2-[(1-methyl-1H pyrazol-5-yl)-2-thienylmethoxy]-eEthanamine, Chemical Abstract Services Registry No. 247046-52-21, R-1 16301 {4-[(2R,4S)-1 -[3,5-bis(trifluoromethyl)benzoyl]-2 (phenylmethyl)-4-piperidinyl]-N-(2,6-dimethylphenyl)-1 -piperazineacetamide with hy droxy-(S)-Butanedioic acid (1:1), Chemical Abstract Services Registry No. 257888-24 30 7}, aprepitant {5-[[(2R,3S)-2-[(1 R)-1 -[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4 fluorophenyl)-4-morpholinyl]methyl]-1,2-dihydro-3H-1,2,4-Triazol-3-one, Chemical Ab stract Services Registry No. 170729-80-31, GW-2016, ZD-4794, BL-1 832, BL-1833, GW-597599, GW-679769, KRP-103, TKA-457, L-758298, L-760735, L-759274, NIP 530, CJ-1 7493, R-1 124, ezlopitant {2-(diphenylmethyl)-N-[[2-methoxy-5-(1 35 methylethyl)phenyl]methyl]-(2S,3S)-1-Azabicyclo[2.2.2]octan-3-amine, Chemical Ab- WO 2008/132153 PCT/EP2008/055039 -121 stract Services Registry No. 147116-64-11, CP-1 22721 {N-[[2-methoxy-5 (trifluoromethoxy)phenyl]methyl]-2-phenyl-(2S,3S)-3-Piperidinamine, Chemical Abstract Services Registry No. 145742-28-51, PD-154075 {[(i R)-1-(1 H-indol-3-ylmethyl)-1 methyl-2-oxo-2-[[(1 S)-1 -phenylethyl]amino]ethyl]-Carbamic acid 2-benzofuranylmethyl 5 ester, Chemical Abstract Services Registry No. 158991-23-21, CP-96345 {2 (diphenylmethyl)-N-[(2-methoxyphenyl)methyl]-(2S,3S)-1 -Azabicyclo[2.2.2]octan-3 amine, Chemical Abstract Services Registry No. 132746-60-21, R-673 {N,alpha,alpha trimethyl-N-[4-(2-methylphenyl)-2-(4-methyl-1 -piperazinyl)-5-pyrimidinyl]-3,5 bis(trifluoromethyl)- Benzeneacetam ide, Chemical Abstract Services Registry No. 10 311340-66-61, SSR 240600 {1-[2-[(2R)-4-[[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4 dichlorophenyl)-2-morpholinyl]ethyl]-alpha,alpha-dimethyl-4-Piperidineacetamide, Chemical Abstract Services Registry No. 537034-22-31, MK-0869 {5-[[(2R,3S)-2-[(1 R) 1-[3,5-bis(trifluoromethyl)phenyl]ethoxy]-3-(4-fluorophenyl)-4-morpholinyl]methyl]-1,2 dihydro-3H-1,2,4-Triazol-3-one, Chemical Abstract Services Registry No. 170729-80 15 31, SR 140333 {1-[2-[(3S)-3-(3,4-dichlorophenyl)-1 -[[3-(1 -methylethoxy)phenyl]acetyl] 3-piperidinyl]ethyl]-4-phenyl-1 -Azoniabicyclo[2.2.2]octane, Chemical Abstract Services Registry No. 155418-05-61, CP-99,994 {(2R,3R)-N-[(2-methoxyphenyl)methyl]-2 phenyl-3-Piperidinamine dihydrochloride, Chemical Abstract Services Registry No. 872726-33-51, NKP-608 {N-[(2R,4S)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[(4 20 chlorophenyl)methyl]-4-piperidinyl]-4-Quinolinecarboxamide, Chemical Abstract Ser vices Registry No. 177707-12-9}, TAK-637 {7-[[3,5-bis(trifluoromethyl)phenyl]methyl] 8,9,10,11 -tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]Diazocino[2, 1 g][1,7]naphthyridine-6,13-dione, Chemical Abstract Services Registry No. 217185-75 61, MEN-1 1467 {N-[(1 S,2R)-2-[[(2R)-2-[methyl[(4-methylphenyl)acetyl]amino]-3-(2 25 naphthalenyl)-1 -oxopropyl]amino]cyclohexyl]-1 H-Indole-3-carboxamide, Chemical Ab stract Services Registry No. 214487-46-41, GR 73632 {N-(5-amino-1-oxopentyl)-L phenylalanyl-L-phenylalanyl-L-prolyl-N-methyl-L-leucyl-L-Methioninamide, Chemical Abstract Services Registry No. 133156-06-61, phenoxybenzamine {N-(2-chloroethyl)-N (1 -methyl-2-phenoxyethyl)-Benzenemethanamine, Chemical Abstract Services Regis 30 try No. 59-96-11, sildenafil {5-[2-ethoxy-5-[(4-methyl-1-piperazinyl)sulfonyl]phenyl]-1,6 dihydro-1-methyl-3-propyl-7H-Pyrazolo[4,3-d]pyrimidin-7-one, Chemical Abstract Ser vices Registry No. 139755-83-21, bicalutamide {N-[4-cyano-3-(trifluoromethyl)phenyl]-3 [(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-Propanamide, Chemical Abstract Ser vices Registry No. 90357-06-51, cyproterone acetate {(1 beta,2beta)- 1 7-(acetyloxy)-6 35 chloro-1,2-dihydro-3'H-Cyclopropa[1,2]pregna-1,4,6-triene-3,20-dione, Chemical Ab- WO 2008/132153 PCT/EP2008/055039 -122 stract Services Registry No. 427-51-01, ketoconazole {1-[4-[4-[[(2R,4S)-2-(2,4 dichlorophenyl)-2-(1 H-imidazol-1 -ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1 piperazinyl]-Ethanone, Chemical Abstract Services Registry No. 65277-42-11, aminoglutethimide {3-(4-aminophenyl)-3-ethyl-2,6-Piperidinedione, Chemical Abstract 5 Services Registry No. 125-84-81, danazol {(17alpha)-Pregna-2,4-dien-20-yno[2,3 d]isoxazol-1 7-ol, Chemical Abstract Services Registry No. 17230-88-51". According to a further aspect of the present invention, the object of the invention has surprisingly been achieved by providing a kit comprising a pharmacologically active 10 amount of at least one compound of the invention and/or at least one pharmaceutical composition as described herein and a pharmacologically active amount of at least one further pharmacologically active substance as defined herein. The compounds of the present invention and/or where appropriate additional phar 15 macologically active substances or pharmaceutical compositions as described herein can be administered in a known manner. The route of administration may thereby be any route which effectively transports the active compound to the appropriate or de sired site of action, for example orally or non-orally, in particular topically, transdermally, pulmonary, rectally, intravaginally, nasally or parenteral or by implanta 20 tion. Oral administration is preferred. The compounds of the present invention and/or where appropriate additional phar macologically active substances or pharmaceutical compositions as described herein can be administered as liquid, semisolid and solid medicinal forms. This takes place in the manner suitable in each case in the form of aerosols, powders, dusting powders 25 and epipastics, tablets including coated tablets, emulsions, foams, solutions, suspen sions, gels, ointments, pastes, pills, pastilles, capsules or suppositories. They can be administered in a suitable dosage form to the skin, epicutaneously as solution, suspen sion, emulsion, foam, ointment, paste or plaster; via the oral and lingual mucosa, buc cally, lingually or sublingually as tablet, pastille, coated tablet, linctus or gargle; via the 30 gastric and intestinal mucosa, enterally as tablet, coated tablet, capsule, solution, sus pension or emulsion; via the rectal mucosa, rectally as suppository, rectal capsule or ointment; via the nasal mucosa, nasally as drops, ointments or spray; via the bronchial and alveolar epithelium, by the pulmonary route or by inhalation as aerosol or inhalant; via the conjunctiva, conjunctivally as eyedrops, eye ointment, eye tablets, lamellae or WO 2008/132153 PCT/EP2008/055039 -123 eye lotion; via the mucosa of the genital organs, intravaginally as vaginal suppositories, ointments and douche, by the intrauterine route as uterine pessary; via the urinary tract, intraurethrally as irrigation, ointment or bougie; into an artery, intraarterially as injection; into a vein, intravenously as injection or infusion; into the skin, intracutane 5 ously as injection or implant; under the skin, subcutaneously as injection or implant; into the muscle, intramuscularly as injection or implant; into the abdominal cavity, in traperitoneally as injection or infusion. As already explained above, the compounds of the invention can also be combined with other pharmaceutically active substances. It is possible for the purpose of a 10 combination therapy to administer the individual active ingredients simultaneously or separately, in particular either by the same route (for example orally) or by separate routes (for example orally and as injection). They may be present and administered in identical or different amounts in a unit dose. It is also possible to use a particular dosage regimen when this appears appropriate. It is also possible in this way to 15 combine a plurality of the novel compounds according to the invention with one another. The compounds of the invention and/or where appropriate additional pharmacologi cally active substances are converted into a form which can be administered and are mixed where appropriate with pharmaceutically acceptable carriers and/or auxiliaries 20 and/or diluents. Suitable excipients and carriers are described for example in Zanowiak P, Ullmann's Encyclopedia of Industrial Chemistry 2005, Pharmaceutical Dosage Forms, 1-33; Spiegel AJ et al., Journal of Pharmaceutical Sciences 1963, 52: 917-927; Czetsch-Lindenwald H, Pharm. Ind. 1961, 2: 72-74; Fiedler HP, Lexikon der Hilfsstoffe fOr Pharmazie, Kosmetik and angrenzende Gebiete 2002, Editio Cantor Verlag, p65 25 68. Oral administration can take place for example in solid form as tablet, capsule, gel capsule, coated tablet, granulation or powder, but also in the form of a drinkable solu tion or emulsion. The compounds of the invention can for oral administration be com bined with known and ordinarily used, physiologically acceptable auxiliaries and carri 30 ers, such as, for example, gum arabic, talc, starch, sugars such as, for example, man nitol, methylcellulose, lactose, gelatin, surface-active agents, magnesium stearate, cyclodextrins, aqueous or nonaqueous carriers, diluents, dispersants, emulsifiers, lu bricants, preservatives and flavorings (e.g. essential oils). The compounds of the inven tion can also be dispersed in a microparticulate, e.g. nanoparticulate, composition.
WO 2008/132153 PCT/EP2008/055039 - 124 Non-oral administration can take place for example by intravenous, subcutaneous, intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by means of implants or by ointments, creams or suppositories. Administration as sus tained release form is also possible where appropriate. Implants may comprise inert 5 materials, e.g. biodegradable polymers or synthetic silicones such as, for example, silicone rubber. Intravaginal administration is possible for example by means of vaginal rings. Intrauterine administration is possible for example by means of diaphragms or other suitable intrauterine devices. Transdermal administration is additionally provided, in particular by means of a formulation suitable for this purpose and/or suitable means 10 such as, for example, patches. The dosage may vary within a wide range depending on type and/or severity of the disease, physiological and/or pathological condition, the mode of administration, the age, gender, bodyweight and sensitivity of the subject to be treated. It is within the abil ity of a skilled worker to determine a "pharmacologically effective amount" of a com 15 pound of the invention and/or additional pharmacologically active substance. Admini stration can take place in a single dose or a plurality of separate dosages. A suitable unit dose is, for example, from 0.001 mg to 100 mg of the active ingredi ent, i.e. at least one compound of the invention and, where appropriate, at least one additional pharmacologically active substance, per kg of a patient's bodyweight. 20 In another aspect, the present invention relates to a pharmaceutical composition comprising a pharmacologically active amount of at least one compound of the inven tion, preferably a compound of the invention selected from the group consisting of: compound 1,2,3,4,5, 6,7,8,9,10,11,12,13,14,15,16,17,18,19, 20, 21, 22, 23, 25 24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 80, 81, 82, 83, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,100,101,102,103,104,105,106,107,108,109,110,111,112,113, 114,115,116,117,118,119,120,121,122,123,124,125,126,127,128,129,130, 30 131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147, 148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164, 165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181, 182,183,184,185,186,187,188,189,190,191,192,193,194,195,196,197,198, 199,200,201,202,203,204,205,206,207,208,209,210,211,212,213,214,215, WO 2008/132153 PCT/EP2008/055039 -125 216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232, 233,234,235,236,237,238,239,240,241,242,243,244,245,246,247,248,249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265 and/or compound 266. 5 In a further aspect, such a pharmaceutical composition additionally comprises at least one pharmaceutically acceptable carrier and/or auxiliary and/or comprises at least one further pharmacologically active substance. In a preferred embodiment, such further pharmacologically active substance is se 10 lected from the group consisting of: "androgens, estrogens, progestins, progestagens, selective estrogen receptor modulator (SERM), selective androgen receptor modulator (SARM), receptor-type tyrosine kinase inhibitor, 5alpha-reductase inhibitors, 5alpha reductase 1 inhibitors, 5alpha-reductase 2 inhibitors, alpha-receptor inhibitors (alpha blockers), alphal -adrenergic receptor antagonists, aromatase inhibitors, lyase 15 inhibitors, GnRH/LHRH receptor agonists, GnRH/LHRH receptor antagonists, NK, receptors antagonists, NK 2 receptors antagonists, NK, receptors agonists, NK 2 receptors agonists" and preferably is selected from the group consisting of: "testoster one, oestradiol, oestriol, oestrone, progesterone, raloxifene, arzoxifene, lasofoxifene, ospemifene, TSE-424, HMR-3339, SERM-3339, SPC-8490, HM-1 01, bazedoxifene 20 (WAY 140424), flutamide, casodex, nilutamide, tamoxifen, fulvestrant, finasteride, du tasteride, izonsteride, epristeride, tamsulosin, prazosin, terazosin, doxazosin, silodosin, alfuzosin, anastrozole, letrozole, finrozole, exemestane, gefitinib, imatinib, semaxanib, SU-6668, SU-101, CI-1033, E-6006, R-116301, aprepitant, GW-2016, ZD-4794, BL 1832, BL-1833, GW-597599, GW-679769, KRP-103, TKA-457, L-758298, L-760735, L 25 759274, NIP-530, CJ-17493, R-1 124, ezlopitant, CP-122721, PD-154075, CP-96345, R-673, SSR 240600, MK-0869, SR 140333, CP-99,994, NKP-608, TAK-637, MEN 11467, GR 73632, phenoxybenzamine, sildenafil, bicalutamide, cyproterone acetate, ketoconazole, aminoglutethimide, danazol". 30 Concerning the pharmaceutical compositions of the invention, at least one of the compounds of the invention is present in a pharmacologically effective amount, pref erably in a unit dose, e.g. the aforementioned unit dose, specifically and preferably in an administration form which makes oral administration possible. Furthermore, refer- WO 2008/132153 PCT/EP2008/055039 -126 ence may be made to that already said in connection with the possible uses and ad ministrations of the compounds of the invention.
WO 2008/132153 PCT/EP2008/055039 -127 Chemical synthesis: General methods for synthesizing the embodiments of the invention The compounds of the invention can be prepared for example in the following way: 5 Firstly, the compounds of the invention can be synthesized by preparing the de picted central tetrahydrocarbazole structure R18 R17 R19 R16, N R20 R14 R15 R21 R12 R22 R13 0
H
2 N HO where this optionally protected tetrahydrocarbazole structure already contains the required substituents where appropriate as precursors or in protected form. 10 The central tetrahydrocarbazole structure is obtainable, for example, by a Fischer indole synthesis, known per se. For this purpose, a suitably substituted cyclohexanone derivative which is provided where appropriate with protective groups is condensed with the particular desired phenylhydrazine derivative which is likewise suitably substi 15 tuted and, where appropriate, provided with protective groups (e.g. as described by Britten & Lockwood, J. Chem. Soc. Perkin Trans. / 1974, 1824 or Maki et al., Chem. Pharm. Bull. 1973, 21, 240). The cyclohexane structure is substituted in the 4,4' posi tion by the radicals -COOH and -NH 2 or where appropriate by the (protected) precur sors thereof. The phenylhydrazine structure is substituted where appropriate by the 20 radicals R1 7 to R20. Phenylhydrazine derivatives which are not commercially available can be prepared by processes known to the skilled worker. Positional isomers resulting where appropriate in the condensation of the cyclohexanone derivative and the phenylhydrazine derivative can be separated by chromatographic methods such as, for example, HPLC.
WO 2008/132153 PCT/EP2008/055039 -128 The derivatization of the terahydocarbazole unit can in principle be achieved in various ways known to the skilled worker, and as indicated for example in WO 03/051837 or in WO 2006/005484. The embodiments of the invention or intermediates thereof were synthesized either 5 by conventional liquid phase synthesis in solution (see below) or else wholly or partly on a solid phase as described in WO 2006/005484. The synthesis of relevant building blocks like tert-butyl ((S)-1-carbamoyl-2 methylbutyl)carbamate (Boc-Ile-NH 2 ), tert-butyl ((S)-2-methyl-1 -thiocarbamoylbutyl) carbamate (Boc-Ile thioamide), (S)-2-amino-3-methylpentanamide (H-Ile thioamide), 10 (R/S)-3-((S)-2-benzyloxycarbonylamino-3-methylpentanoylamino)-6,8-dichloro-2,3,4,9 tetrahydro-1 H-carbazole-3-carboxylic acid (Z-(S)-Ile-(R/S)-(6,8-CI)-Thc-OH) and the synthesis of C-terminal substituted amides in solution as exemplified by the synthesis of (S)-2-{[(R/S)-3-((S)-2-benzyloxycarbonylamino-3-methylpentanoylamino)-6,8 dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3-carbonyl]amino}-3-methylpentanoic acid 15 ((S)-Z-Ile-(R/S)-(6,8-CI)-Thc-(S)-Ile-OH) + R1-NH-R2 has been described in WO 2006/005484, Purification of the crude reaction products (i.e. mixtures of diastereoisomers) by semipreparative HPLC 20 Analytical and semipreparative HPLC systems from Shimadzu; column 250-50, LiChrospher@ 100, RP18 (12 pm) from Merck; flow rate 60 ml/min. Eluents: A = 970 ml of water + 30 ml of ACN + 1 ml of TFA B = 300 ml of water + 700 ml of ACN + 1 ml of TFA UV detector 220 nm. 25 All products were isolated by gradient elution. The crude products are dissolved in eluent B (DMF added for products of low solu bility) and purified in portions on the column (e.g. dissolve 500 mg of crude product in 15 ml of B and separate in one portion). The separation conditions in this case depend on the peptide sequence and nature and amount of the impurities and are established 30 experimentally beforehand on the analytical column. A typical gradient is: 60% B-1 00% B in 30 minutes.
WO 2008/132153 PCT/EP2008/055039 -129 If the crude products are mixtures of diastereomers, they are separated by this method. The isolated fractions are checked by analytical HPLC. ACN and TFA are removed in a rotary evaporator, and the remaining aqueous concentrate is lyophilized. 5 The compounds of the present invention were prepared as indicated below .The analytical characterization of the compounds of the invention took place by 1 H-NMR spectroscopy and/or mass spectrometry. The chemicals and solvents employed were obtained commercially from usual suppliers (Acros, Avocado, Aldrich, Bachem, Fluka, Lancaster, Maybridge, Merck, 10 Sigma, TCl etc.) or synthesized by processes known to the skilled worker. For the exemplary embodiments indicated below, chiral building blocks were usu ally employed in enantiopure form. In the case of the tetrahydrocarbazole precursor, the racemic building block was employed. Final products were purified by semiprepara tive HPLC and characterized in the form of the pure diastereomers. 15 WO 2008/132153 PCT/EP2008/055039 -130 List of abbreviations used: e.g. for example DBU 1,8-diazabicyclo[5.4.0]undec-7-ene HOBt 1 -hydroxybenzotriazole 5 Fmoc 9-fluoroenylmethoxycarbonyl Boc tert-butyloxycarbonyl Z benzyloxycarbonyl Z-CI benzyloxycarbonyl chloride Boc 2 O di-tert-butyl dicarbonate 10 Bzl benzyl AA amino acid EDT 1,2-ethanedithiol DEAD diethyl azodicarboxylate DIC N,N'-diisopropylcarbodiimide 15 DCC N,N'-dicyclohexylcarbodiimide HATU N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate HOAt 1 -hydroxy-7-azabenzotriazole PyBop (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophos 20 phate OSu N-hydroxysuccinimidyl DIPEA diisopropylethylamine DMAP N,N'-dimethylaminopyridine DBU 1,8-diazabicyclo[5.4.0]undec-7-ene 25 NMM N-methylmorpholine TFA trifluoroacetic acid DCM dichloromethane WO 2008/132153 PCT/EP2008/055039 -131 DMF N,N'-dimethylformamide DMA N,N'-dimetylacetamide ACN acetonitrile THF tetrahydrofuran 5 Me methyl MeOH methanol Lawesson's reagent 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide Thc 3-amino-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid 10 Ala alanine(yl) Val valine(yl) lie isoleucine(yl) Leu leucine(yl) GIn glutamine(yl) 15 Asn asparagine(yl) Tyr tyrosine(yl) hTyr homo-tyrosine(yl) Arg arginine(yl) Lys lysine(yl) 20 RT room temperature m.p. melting point ml milliliter min minute h hour 25 ELISA enzyme linked immunosorbent assay HEPES N-(2-hydroxyethyl)piperazine-N'-2-ethanesulfonic acid DMEM Dulbecco's modified Eagles medium WO 2008/132153 PCT/EP2008/055039 -132 RIA radio immuno assay LHRH luteinizing hormone releasing hormone LH luteinizing hormone NK1 neurokinin 1 5 NK2 neurokinin 2 PG protecting group Brief description of the drawings 10 Figure 1 depicts the results [area-under-the-curve (AUC)] of the pharmacokinetic study according to IV) of the example section for compound 52 of the invention and prior art compound WO 2006/005484 - substance 76. The results are indicative for the respective bioavailability. Figure 2 depicts the mean plasma testosterone concentration (ng/mL) over time 15 upon administration of compound 54 (TFA salt) of the invention. The compounds of the invention were named using the AutoNom 2000 software (ISIS TM/ Draw 2.5; MDL). 20 The contents of all cited references and patents are hereby incorporated by refer ence in their entirety. The invention is explained in more detail by means of the follow ing examples without, however, being restricted thereto.
WO 2008/132153 PCT/EP2008/055039 -133 Examples 1) Synthesis and physicochemical characterization of selected compounds of the invention 5 Examples 1 and 2: ((S)-1-{(R)-3-[(R)-1-(5-Amino-[1,3,4]oxadiazol-2-yl)-2-methyl-butylcarbamoyl]-6,8 dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester (1) and ((S)-1 -{(R)-3-[(R)-1 -(5-Amino-[1,3,4]oxadiazol-2-yl)-2-methyl 10 butylcarbamoyl]-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl}-2-methyl butyl)-carbamic acid benzyl ester (2) 0.200 g (0.37 mmol) of (R/S)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid, 0.104 15 g (0.37 mmol) of (S)-1-(5-amino-[1,3,4]oxadiazol-2-yl)-2-methyl-butyl-ammonium trifluoro-acetate, 0.139 g (0.37 mmol) of HATU and 0.4 mL (2.35 mmol) of DIPEA were heated in 5 mL of DMF in a microwave at 110 C and 100 watt for 5 min. The reaction solution was separated on a preparative HPLC column. 20 Compound 1: Yield: 0.056 g (20% of theory). "H-NMR (DMSO-d 6 , 600 MHz): 6 = 11.36 (s, 1 H); 7.76 (s, 1 H); 7.68 (d, 1 H); 7.41 (s, 1H); 7.22-7.37 (m, 6H); 7.14 (s, 1H); 7.02 (s, 2H); 5.02 (d, 1 H); 4.87 (dd, 1 H); 4.80 (d, 1 H); 3.81 (dd, 1 H); 2.98 (d, 1 H); 2.86 (d, 1 H); 2.75-2.82 (m, 2H); 2.56-2.61 (m, 1 H); 25 2.11-2.18 (m, 1H); 1.90-1.96 (m, 1H); 1.56-1.63 (m, 1H); 1.44-1.51 (m, 1H); 1.30-1.37 (m, 1 H); 1.11-1.18 (m, 1H); 0.99-1.07 (m, 1H); 0.78-0.85 (m, 6H); 0.75 (d, 3H); 0.72 (t, 3H) ppm. ESI-MS: found: 698.5 (M+H+); calculated: 697 g/mol. 30 WO 2008/132153 PCT/EP2008/055039 -134 Compound 2: Yield: 0.035 g (13% of theory). "H-NMR (DMSO-d 6 , 600 MHz): 6 = 11.26 (s, 1 H); 8.04 (s, 1 H); 7.64 (d, 1 H); 7.44 (d, 1 H); 7.30-7.39 (m, 6H); 7.11 (s, 1 H); 6.98 (s, 2H); 5.07 (d, 1 H); 4.98 (d, 1 H); 4.86 (dd, 5 1H); 3.77 (dd, 1H); 3.53 (d, 1H); 3.07 (d, 1H); 2.95-3.03 (m, 1H); 2.74 (dd, 1H); 2.21 2.27 (m, 1 H); 2.04-2.11 (m, 1 H); 1.95-2.00 (m, 1 H); 1.44-1.51 (m, 1 H); 1.35-1.41 (m, 1 H); 1.08-1.20 (m, 2H); 0.84 (d, 3H); 0.81 (t, 3H); 0.72-0.80 (m, 1 H); 0.48 (d, 3H); 0.33 (t, 3H) ppm. ESI-MS: found: 698.5 (M+H+); calculated: 697 g/mol. 10 By the above procedure, the following compounds were also prepared: Examples 3 and 4: ((S)-1 -{(R)-6,8-Dichloro-3-[(S)-2-methyl-1 -(3-methyl-[1,2,4]oxadiazol-5-yl) 15 butylcarbamoyl]-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl}-2-methyl-butyl) carbamic acid benzyl ester and ((S)-1-{(S)-6,8-Dichloro-3-[(S)-2-methyl-1-(3-methyl [1,2,4]oxadiazol-5-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl} 2-methyl-butyl)-carbamic acid benzyl ester 20 Compound 3: "H-NMR (DMSO-d 6 , 600 MHz): 6 = 11.36 (s, 1 H); 7.92 (d, 1 H), 7.80 (s, 1 H); 7.40 (s, 1H); 7.23-7.36 (m, 6H); 7.14 (s, 1H); 5.00-5.08 (m, 2 H), 4.79 (d, 1H), 3.84 (dd, 1H) 2.99 (d, 1H), 2.88 (d, 1H), 2.73-2.82 (m, 2H), 2.55-2.64 (m, 1 H), 2.35 (s, 3H), 2.12 2.18 (m, 1H), 1.99-2.05 (m, 1H), 1.57-1.63 (m, 1 H), 1.41-1.49 (m, 1H), 1.30-1.37 (m, 25 1H), 1.14-1.22 (m, 1H), 0.99-1.07 (m, 1H), 0.81 (t, 3H), 0.78 (d, 3H), 0.76 (d, 3H), 0.72 (t, 3H) ppm. ESI-MS: found: 697.3 (M+H+); calculated: 696 g/mol. 30 WO 2008/132153 PCT/EP2008/055039 -135 Compound 4: "H-NMR (DMSO-d 6 , 600 MHz): 6 = 11.26 (s, 1 H); 8.08 (s, 1 H); 7.86 (d, 1 H); 7.45 (d, 1H); 7.30-7.39 (m, 6H); 7.12 (s, 1H); 5.02-5.09 (m, 2H); 4.96 (d, 1H); 3.80 (dd, 1H); 3.54 (d, 1 H); 3.05 (d, 1 H); 2.96-3.03 (m, 1 H); 2.79 (dd, 1 H); 2.34 (s, 3H); 2.22-2.26 (m, 5 1H); 2.03-2.11 (m, 2H); 1.42-1.49 (m, 1 H); 1.36-1.42 (m, 1 H); 1.08-1.23 (m, 2H); 0.79 0.84 (m, 6H); 0.71-0.79 (m, 1H); 0.48 (d, 3H); 0.35 (t, 3H) ppm. ESI-MS: found: 697.4 (M+H+); calculated: 696 g/mol. Data on further exemplary embodiments are compiled in Table 1 below: 10 Table 1: Further exemplary embodiments with MS data Compound Name (Autonom) cas). (fund) 5-((S)-1 -{[(R)-3-((S)-2 Benzyloxycarbonylamino-3 methyl-pentanoylamino)-6,8 5 dichloro-2,3,4,9-tetrahydro-1 H- 754.0 755.6 carbazole-3-carbonyl]-amino}-2 methyl-butyl)-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester 5-((S)-1 -{[(S)-3-((S)-2 Benzyloxycarbonylamino-3 methyl-pentanoylamino)-6,8 6 dichloro-2,3,4,9-tetrahydro-1 H- 754.0 755.3 carbazole-3-carbonyl]-amino}-2 methyl-butyl)-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-2 methyl-1 -(5-oxo-4,5-dihydro [1,3,4]oxadiazol-2-yl) 7 butylcarbamoyl]-2,3,4,9- 698.0 699.5 tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl) carbamic acid benzyl ester {(S)-1 -[(R)-6,8-Dichloro-3-((S) 2-methyl-1 -[1,3,4]oxadiazol-2-yl 8 butylcarbamoyl)-2,3,4,9- 682.0 683.4 tetrahydro-1 H-carbazol-3 ylcarbamoyl]-2-methyl-butyl} carbamic acid benzyl ester WO 2008/132153 PCT/EP2008/055039 -136 {(S)-1 -[(S)-6,8-Dichloro-3-((S)-2 methyl-1 -[1,3,4]oxadiazol-2-y 9 butylcarbamoyl)-2,3,4,9- 682.0 683.4 tetrahydro-1 H-carbazol-3 ylcarbamoyl]-2-methyl-butyl} carbamic acid benzyl ester ((S)-1 -{(R)-3-[(S)-1-(3 Carbamoyl-[1,2,4]oxadiazol-5 yl)-2-methyl-butylcarbamoyl] 10 6,8-dichloro-2,3,4,9-tetrahydro- 725.0 726.2 1 H-carbazol-3-ylcarbamoyl}-2 methyl-butyl)-carbamic acid benzyl ester ((S)-1 -{(S)-3-[(S)-1 -(3 Carbamoyl-[1,2,4]oxadiazol-5 yl)-2-methyl-butylcarbamoyl] 11 6,8-dichloro-2,3,4,9-tetrahydro- 725.0 726.3 1 H-carbazol-3-ylcarbamoyl}-2 methyl-butyl)-carbamic acid benzyl ester 5-{(S)-1 -[((R)-3-{(S)-2-[2-(2,6 Difluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 12 trifluoromethyl-2,3,4,9- 774.0 775.2 tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl butyl}-[1,2,4]oxadiazole-3 carboxylic acid ethyl ester 5-((S)-1 -{[(R)-3-((S)-2 Benzyloxycarbonylamino-3 methyl-pentanoylamino)-6,8 13 dichloro-2,3,4,9-tetrahydro-1 H- 754.0 755.3 carbazole-3-carbonyl]-amino}-2 methyl-butyl)-[1,3,4]oxadiazole 2-carboxylic acid ethyl ester ((S)-1 -{(R)-3-[(S)-1-(5 Acetylamino-[1,3,4]oxadiazol-2 yl)-2-methyl-butylcarbamoyl] 14 6,8-dichloro-2,3,4,9-tetrahydro- 739.0 740.2 1 H-carbazol-3-ylcarbamoyl}-2 methyl-butyl)-carbamic acid benzyl ester 5-((S)-1 -{[(S)-3-((S)-2 Benzyloxycarbonylamino-3 methyl-pentanoylamino)-6,8 15 dichloro-2,3,4,9-tetrahydro-1 H- 754.0 755.3 carbazole-3-carbonyl]-amino}-2 methyl-butyl)-[1,3,4]oxadiazole 2-carboxylic acid ethyl ester WO 2008/132153 PCT/EP2008/055039 -137 ((S)-1 -{(S)-3-[(S)-1 -(5 Acetylamino-[1,3,4]oxadiazol-2 yl)-2-methyl-butylcarbamoyl] 16 6,8-dichloro-2,3,4,9-tetrahydro- 739.0 740.3 1 H-carbazol-3-ylcarbamoyl}-2 methyl-butyl)-carbamic acid benzyl ester ((S)-1 -{(R)-6,8-Dichloro-3-[(S) 2-methyl-1 -(5-oxo-4,5-dihydro [1,3,4]oxadiazol-2-yl) 17 butylcarbamoyl]-2,3,4,9- 698.0 699.3 tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl) carbamic acid benzyl ester 5-((S)-1 -{[(R)-3-((S)-2 Benzyloxycarbonylamino-3 methyl-pentanoylamino)-6,8 18 dichloro-2,3,4,9-tetrahydro-1H- 768.0 769.5 carbazole-3-carbonyl]-amino}-2 methyl-butyl)-[1,2,4]oxadiazole 3-carboxylic acid propyl ester 5-((S)-1 -{[(S)-3-((S)-2 Benzyloxycarbonylamino-3 methyl-pentanoylamino)-6,8 19 dichloro-2,3,4,9-tetrahydro-1H- 768.0 769.5 carbazole-3-carbonyl]-amino}-2 methyl-butyl)-[1,2,4]oxadiazole 3-carboxylic acid propyl ester ((S)-1 -{(R)-6,8-Dichloro-3-[(S) 1-(3-diethylcarbamoyl [1,2,4]oxadiazol-5-yl)-2-methyl 20 butylcarbamoyl]-2,3,4,9- 781.0 782.7 tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl) carbamic acid benzyl ester ((S)-1 -{(R)-6,8-Dichloro-3-[(S) 1-(3-cyano-[1,2,4]oxadiazol-5 21 yl)-2-methyl-butylcarbamoyl]- 707.0 708.5 2,3,4,9-tetrahydro-1 H-carbazol 3-ylcarbamoyl}-2-methyl-butyl) carbamic acid benzyl ester ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-1 (3-cyano-[1,2,4]oxadiazol-5-yl) 22 2-methyl-butylcarbamoyl]- 707.0 708.5 2,3,4,9-tetrahydro-1 H-carbazol 3-ylcarbamoyl}-2-methyl-butyl) carbamic acid benzyl ester WO 2008/132153 PCT/EP2008/055039 -138 ((S)-1 -{(R)-6,8-Dichloro-3-[(S) 2-methyl-1 -(5-methyl [1,3,4]oxadiazol-2-yl) 23 butylcarbamoyl]-2,3,4,9- 696.0 697.4 tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl) carbamic acid benzylester ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-2 methyl-1 -(5-methyl [1,3,4]oxadiazol-2-yl) 24 butylcarbamoyl]-2,3,4,9- 696.0 697.4 tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl) carbamic acid benzyl ester 5-((S)-1 -{[(R)-3-((S)-2 Benzyloxycarbonylamino-3 methyl-pentanoylamino)-6,8 25 dichloro-2,3,4,9-tetrahydro-1 H- 740.0 741.4 carbazole-3-carbonyl]-amino}-2 methyl-butyl)-[1,2,4]oxadiazole 3-carboxylic acid methyl ester 5-((S)-1 -{[(S)-3-((S)-2 Benzyloxycarbonylamino-3 methyl-pentanoylamino)-6,8 26 dichloro-2,3,4,9-tetrahydro-1 H- 740.0 741.4 carbazole-3-carbonyl]-amino}-2 methyl-butyl)-[1,2,4]oxadiazole 3-carboxylic acid methyl ester [(S)-i -((R)-6,8-Dichloro-3-{(S) 1-[5-(3-ethyl-ureido) [1,3,4]oxadiazol-2-yl]-2-methyl 27 butylcarbamoyl}-2,3,4,9- 768.0 769.2 tetrahydro-1 H-carbazol-3 ylcarbamoyl)-2-methyl-butyl] carbamic acid benzyl ester 5-{(S)-i -[((R)-3-{(S)-2-[2-(2 Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 28 trifluoromethyl-2,3,4,9- 756.0 758.0 tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl butyl}-[1,2,4]oxadiazole-3 carboxylic acid ethyl ester 5-{(S)-1-[((S)-3-{(S)-2-[2-(2 Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 29 trifluoromethyl-2,3,4,9- 756.0 757.5 tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl butyl}-[1,2,4]oxadiazole-3 carboxylic acid ethyl ester WO 2008/132153 PCT/EP2008/055039 -139 (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8 30 trifluoromethyl-2,3,4,9- 770.0 771.6 tetrahydro-1 H-carbazole-3 carboxylic acid {(S)-1-[5-(3 ethyl-ureido)-[1,3,4]oxadiazol-2 yl]-2-methyl-butyl}-amide (S)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8 31 trifluoromethyl-2,3,4,9- 770.0 771.5 tetrahydro-1 H-carbazole-3 carboxylic acid {(S)-1-[5-(3 ethyl-ureido)-[1,3,4]oxadiazol-2 yl]-2-methyl-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8 32 trifluoromethyl-2,3,4,9- 699.0 700.4 tetrahydro-1 H-carbazole-3 carboxylic acid [(S)-1-(5-amino [1,3,4]oxadiazol-2-yl)-2-methyl butyl]-amide 33 Name not generated by 772.0 773.7 AutoNom 34 Name not generated by 845.0 846.4 AutoNom 5-{(S)-1 -[(3-{2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8 80 trifluoromethyl-2,3,4,9- 756.0 757.4 tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl butyl}-[1,2,4]oxadiazole-3 carboxylic acid ethyl ester 5-{(S)-1-[((R)-3-{(R)-2-[2-(2 Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 81 trifluoromethyl-2,3,4,9- 756.0 757.4 tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl butyl}-[1,2,4]oxadiazole-3 carboxylic acid ethyl ester WO 2008/132153 PCT/EP2008/055039 - 140 (R)-3-{(R)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8 82 trifluoromethyl-2,3,4,9- 770.0 771.6 tetrahydro-1 H-carbazole-3 carboxylic acid {(S)-1-[5-(3 ethyl-ureido)-[1,3,4]oxadiazol-2 yl]-2-methyl-butyl}-amide (S)-3-{(R)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8 83 trifluoromethyl-2,3,4,9- 770.0 771.6 tetrahydro-1 H-carbazole-3 carboxylic acid {(S)-1-[5-(3 ethyl-ureido)-[1,3,4]oxadiazol-2 yl]-2-methyl-butyl}-amid The embodiments presented in Table 1 were synthesized according to the following general reaction scheme: R3 HN O--[sgN] H 0 H 2 N [C,N] R1 N OH + R4 O R 2 O coupling reagent -R3 HN O 0O--[N] R1 N[C,N] i N R4 0 R2 O 5 The definition of the R radicals shown in the above reaction scheme and further herein disclosed general reaction schemes corresponds to the substituents (e.g. R radicals) defined above in connection with the general formula (1) and preferred sub sets/embodiments. For the avoidance of doubt, the R radicals shown in the above re 10 action scheme and further herein disclosed general reaction schemes can be identical, but do not need to be identical with the substituents (e.g. R radicals) defined above in WO 2008/132153 PCT/EP2008/055039 -141 connection with the general formula (1) and preferred subsets/embodiments. The indi vidual assignment can be accomplished in a simple manner by the person skilled in the art on the basis of his or her average technical knowledge. 5 The building blocks (intermediates) were prepared from commercially available starting materials according to WO 06/005484 and the literature citated herein. The oxadiazole building blocks were synthesized according the following literature: 1) Houben-Weyl Vol. E8c: 409. 2) Houben-Weyl Vol. E8d: 189. 10 3) J. Org. Chem. 1995, 60: 3112. Compound 35: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid {(S)-2-methyl- 1 15 [(pyrrolidin-1 -ylmethyl)-carbamoyl]-butyl}-amide 0.500 g (0.76 mmol) of (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid ((S)-1-carbamoyl-2-methyl-butyl)-amide (described in WO 2006/005484) and 0.5 mL 20 (6.68) of formaldehyde (37 % in water) were suspended in 20 mL methanol. After 30 min 65 mg (0.91 mmol) of pyrrolidine were added and the reaction mixture was heated under reflux for 5 h. The solvents were removed under vaccum and the residue purified by chromatography. Yield: 0.220 g (39% of theory). 25 'H-NMR (DMSO-d 6 , 600 MHz): 6 = 11.13 (s, 1H); 8.16 (s, 1H); 8.11 (d, 1H); 7.86 (s, 1H); 7.60 (d, 1H); 7.34 (d, 1H); 7.19-7.27 (m, 3H); 7.06-7.12 (m, 3 H); 4.11-4.20 (m, 3 H); 3.95 (dd, 1 H); 3.52 (d, 1 H); 3.30 (d, 1 H); 3.04 (d, 1 H); 2.96 (d, 1 H); 2.82 (dd, 1 H); 2.60-2.67 (m, 2H); 2.52-2.53 (m, 4H); 2.12-2.17 (m, 1H); 1.62-1.69 (m, 6H); 1.34-1.38 (m, 2H); 0.98-1.05 (m, 2H); 0.80 (d, 3H); 0.76-0.78 (m, 6H); 0.72 (t, 3H) ppm. 30 ESI-MS: found: 743.4 (M+H+); calculated: 742 g/mol.
WO 2008/132153 PCT/EP2008/055039 - 142 The described procedure can be based on carboxamides or on thioamides as starting materials. By the above procedure, but with morpholine instead of pyrrolidine the foll wing compounds were also prepared: 5 Compound 36: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid {(S)-2-methyl- 1 [(morpholin-4-ylmethyl)-carbamoyl]-butyl}-amide 10 "H-NMR (DMSO-d 6 , 600 MHz): 8 = 11.13 (s, 1H); 8.10-8.14 (m, 2H); 7.86 (s, 1 H); 7.62 (d, 1 H); 7.34 (d, 1 H); 7.19-7.27 (m, 3H); 7.07-7.12 (m, 3 H); 4.17-4.20 (m, 2 H); 4.01 (dd, 1H); 3.83 (dd, 1 H); 3.51-3.55 (m, 5H); 3.31 (d, 1H); 3.05 (d, 1H); 2.97 (d, 1H); 2.82 (dd, 1H); 2.60-2.68 (m, 2H); 2.39-2.45 (m, 4H); 2.12-2.17 (m, 1H); 1.69-1.70 (m, 1H); 1.62-1.63 (m, 1 H); 1.32-1.39 (m, 2H); 1.00-1.06 (m, 2H); 0.75-0.81 (m, 9H); 0.72 (t, 3H) 15 ppm. ESI-MS: found: 759.4 (M+H+); calculated: 758 g/mol. Compound 37: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 20 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid {(S)-2-methyl- 1 [(morpholin-4-ylmethyl)-thiocarbamoyl]-butyl}-amide "H-NMR (DMSO-d 6 , 600 MHz): 8 = 11.14 (s, 1H); 10.20 (s, 1 H); 8.01 (d, 1H); 7.86 (s, 1H); 7.59 (d, 1 H); 7.34 (d, 1 H); 7.31 (d, 1 H); 7.24-7.27 (m, 1H); 7.19 (t, 1H); 7.06-7.12 25 (m, 3 H); 4.60 (dd, 1 H); 4.52 (dd, 1 H); 4.32 (dd, 1 H); 4.21 (dd, 1 H), 3.55-3.57 (m, 4H); 3.49 (d, 1 H); 3.27 (d, 1 H); 3.04 (d, 1 H); 2.91 (d, 1 H); 2.81 (dd, 1 H); 2.68 (dd, 1 H); 2.53 2.62 (m, 5H); 2.11-2.15 (m, 1H); 1.75-1.78 (m, 1 H); 1.63-1.64 (m, 1H); 1.45-1.48 (m, 1 H); 1.34-1.38 (m, 1 H); 1.00-1.07 (m, 2H); 0.81 (d, 3H); 0.76-0.78 (m, 6H); 0.73 (t, 3H) ppm. 30 ESI-MS: found: 775.4 (M+H+); calculated: 774 g/mol.
WO 2008/132153 PCT/EP2008/055039 -143 Compound 38: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid ((S)- 1 methoxycarbamoyl-2-methyl-butyl)-amide 5 0.500 g (0.91 mmol) of (R/S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid (synthesized in according to WO 2006/005484), 0.521 g (1.37 mmol) of HATU and 2.0 mL (11.76 mmol) of DIPEA were dissolved in DMF and stirred for 30 min at room tem 10 perature. 0.220 g (1.37 mmol) of (S)-2-Amino-3-methyl-pentanoic acid methoxy-amide were added and the reaction mixture and heated at 110 C for 3 h. The solvent was removed under vaccum and the residue was purified by high performance liquid chro matography. 15 Yield: 0.177 g (28% of theory). "H-NMR (DMSO-d 6 , 600 MHz): 6=11.15 (s, 1H); 11.12 (s, 1H), 8.07 (d, 1H), 7.86 (s, 1H); 7.64 (d, 1 H); 7.34 (d, 1 H); 7.19-7.23 (m, 3H); 7.07-7.12 (m, 3 H); 4.17 (dd, 1H), 4.01 (dd, 1 H); 3.57 (s, 3H); 3.51 (d, 1 H), 3.28 (d, 1 H); 3.02 (d, 1 H); 2.94 (d, 1 H); 2.81 (d, 1 H); 2.67-2.74 (m, 1H); 2.57-2.63 (m, 1 H); 2.11-2.17 (m, 1 H); 1.61-1.68 (m, 2H); 20 1.32-1.40 (m, 2H); 0.98-1.07 (m, 2H); 0.77-0.81 (m, 9H); 0.72 (t, 3H) ppm. ESI-MS: found: 690.4 (M+H+); calculated: 689 g/mol. Accordign to the procedure described for the synthesis of compound 38, the following compounds were also prepared: 25 Compound 39: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid [(S)-2-methyl- 1 (morpholine-4-carbonyl)-butyl]-amide 30 WO 2008/132153 PCT/EP2008/055039 -144 "H-NMR (DMSO-d 6 , 600 MHz): 8 = 11.12 (s, 1H); 7.98 (d, 1 H); 7.82 (s, 1H); 7.64 (d, 1H); 7.32-7.35 (m, 2H); 7.18-7.26 (m, 2H); 7.05-7.12 (m, 3 H); 4.64 (dd, 1H); 4.22 (m, 1 H); 3.44-3.57 (m, 9H); 3.23 (d, 1 H); 3.00 (d, 1 H); 2.94 (d, 1 H); 2.81 (dd, 1 H); 2.72 (dd, 1H), 2.60 (d, 1H); 2.13-2.18 (m, 1H); 1.75-1.76 (m, 1H); 1.60-1.61 (m, 1H); 1.33-1.39 5 (m, 2H); 0.97-1.05 (m, 2H); 0.83 (d, 3H), 0.76-0.79 (m, 6H); 0.73 (t, 3H) ppm. ESI-MS: found: 730.5 (M+H+); calculated: 729 g/mol. Compound 41: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 10 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid ((S)- 1 ethoxycarbamoyl-2-methyl-butyl)-amide "H-NMR (DMSO-d 6 , 600 MHz): I= 11.12 (s, 1H); 11.03 (s, 1H), 8.06 (d, 1H), 7.86 (s, 1H); 7.63 (d, 1 H); 7.34 (d, 1 H); 7.20-7.26 (m, 3H); 7.06-7.12 (m, 3 H); 4.18 (dd, 1H), 15 4.03 (dd, 1 H); 3.78 (q, 2H); 3.51 (d, 1H), 3.29 (d, 1 H); 3.02 (d, 1H); 2.94 (d, 1H); 2.81 (d, 1 H); 2.69 (d, 1 H); 2.54-2.62 (m, 1H); 2.12-2.17 (m, 1 H); 1.61-1.67 (m, 2H); 1.33 1.39 (m, 2H); 1.14 (t, 3H); 0.99-1.07 (m, 2H); 0.77-0.89 (m, 9H); 0.73 (t, 3H) ppm. ESI-MS: found: 704.3 (M+H+); calculated: 703 g/mol. 20 Compound 42: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid [(S)-2-methyl-1 -(2 morpholin-4-yl-ethylcarbamoyl)-butyl]-amide 25 'H-NMR (DMSO-d 6 , 600 MHz): 6 = 11.12 (s, 1H); 8.10 (d, 1H); 7.85 (s, 1H); 7.78 (s, 1H); 7.62 (d, 1H); 7.34 (d, 1H); 7.23-7.27 (m, 1H); 7.18-7.20 (m, 2H); 7.06-7.11 (m, 3 H); 4.13-4.17 (m, 2 H); 3.46-3.56 (m, 5H), 3.24-3.30 (m, 2H); 3.10-3.17 (m, 1H); 2.97 3.04 (m, 2H); 2.81 (dd, 1H); 2.57-2.67 (m, 2H); 2.28-2.47 (m, 5H); 2.1 -2.15 (m, 1H); 1.61-1.67 (m, 2H); 1.30-1.38 (m, 2H); 0.98-1.06 (m, 2H); 0.85-0.87 (m, 1 H); 0.75-0.80 30 (m, 9H); 0.71 (t, 3H) ppm. ESI-MS: found: 773.3 (M+H+); calculated: 772 g/mol.
WO 2008/132153 PCT/EP2008/055039 -145 Compound 43: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid [(S)-1 -(4-hydroxy butylcarbamoyl)-2-methyl-butyl]-amide 5 "H-NMR (DMSO-d 6 , 600 MHz): 6=11.12 (s, 1H); 8.12 (d, 1H); 7.93 (s, 1H); 7.71 (t, 1H); 7.64 (d, 1 H); 7.34 (d, 1 H); 7.23-7.27 (m, 1 H); 7.16-7.20 (m, 2H); 7.06-7.12 (m, 3 H); 4.39-4.40 (m, 1 H); 4.12-4.20 (m, 2 H); 3.50 (d, 1 H); 3.37-3.40 (m, 2H); 3.29 (d, 1 H); 2.96-3.12 (m, 4H); 2.82 (dd, 1H); 2.60-2.67 (m, 2H); 2.11-2.16 (m, 1H); 1.62-1.67 (m, 10 2H); 1.30-1.44 (m, 6H); 0.97-1.06 (m, 2H); 0.75-0.78 (m, 9H); 0.71 (t, 3H) ppm. ESI-MS: found: 732.6 (M+H+); calculated: 731 g/mol. Compound 44: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 15 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid [(S)-2-methyl-1 -(3 morpholin-4-yl-propylcarbamoyl)-butyl]-amide "H-NMR (DMSO-d 6 , 600 MHz): 8 = 11.12 (s, 1H); 8.12 (d, 1 H); 7.81 (s, 1H); 7.79 (s, 1H); 7.62 (d, 1H); 7.34 (d, 1H); 7.23-7.26 (m, 1H); 7.16-7.21 (m, 2H); 7.06-7.12 (m, 3 20 H); 4.11-4.16 (m, 2 H); 3.53-3.59 (m, 4H); 3.50 (d, 1H); 3.29 (d, 1H); 3.09-3.14 (m, 1H); 2.98-3.06 (m, 3H); 2.82 (dd, 1H); 2.61-2.65 (m, 2H); 2.25-2.45 (m, 5H); 2.12-2.15 (m, 1H); 1.54-1.68 (m, 4H); 1.32-1.35 (m, 2H); 0.98-1.04 (m, 2H); 0.81-0.88 (m, 1H); 0.74 0.78 (m, 9H); 0.71 (t, 3H) ppm. ESI-MS: found: 787.7 (M+H+); calculated: 786 g/mol. 25 Data on further exemplary embodiments synthesized according or in analogy to com pound 38 are compiled in Table 2 below: 30 WO 2008/132153 PCT/EP2008/055039 - 146 Table 2: Further exemplary embodiments with MS data Compound Name (Autonom) cas). (fund) (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 45 2,3,4,9-tetrahydro-1 H-carbazole-3- 770.0 771.8 carboxylic acid {(S)-2-methyl-1-[(1 methyl-piperidin-4-ylmethyl) carbamoyl]-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 46 2,3,4,9-tetrahydro-1 H-carbazole-3- 757.0 758.7 carboxylic acid {(S)-2-methyl- 1 [(tetrahydro-pyran-4-ylmethy) carbamoyl]-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 47 2,3,4,9-tetrahydro-1 H-carbazole-3- 788.0 789.7 carboxylic acid [(S)-2-methyl-1-(2 morpholin-4-yl-ethylthiocarbamoyl) butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 48 2,3,4,9-tetrahydro-1 H-carbazole-3- 784.0 785.5 carboxylic acid {(S)-1 -[(1 -formyl piperidin-4-ylmethyl)-carbamoyl]-2 methyl-butyll-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 49 2,3,4,9-tetrahydro-1 H-carbazole-3- 798.0 799.7 carboxylic acid {(S)-1 -[(1 -acetyl piperidin-4-ylmethyl)-carbamoyl]-2 methyl-butyll-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 50 2,3,4,9-tetrahydro-1 H-carbazole-3- 750.0 751.6 carboxylic acid {(S)-2-methyl- 1 [(pyridin-4-ylmethyl)-carbamoyl] butyll-amide 5 WO 2008/132153 PCT/EP2008/055039 -147 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 51 2,3,4,9-tetrahydro-1 H-carbazole-3- 758.0 759.4 carboxylic acid [(S)-1-(2 diethylamino-ethylcarbamoyl)-2 methyl-butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 52 2,3,4,9-tetrahydro-1 H-carbazole-3- 773.0 774.7 carboxylic acid {(S)-2-methyl- 1 [(tetrahydro-pyran-4-ylmethyl) thiocarbamoyl]-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 53 2,3,4,9-tetrahydro-1 H-carbazole-3- 747.0 748.7 carboxylic acid [(S)-1-(4-hydroxy butylthiocarbamoyl)-2-methyl-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 54 2,3,4,9-tetrahydro-1 H-carbazole-3- 788.0 789.6 carboxylic acid [(S)-2-methyl-1-(2 morpholin-4-yl-ethylthiocarbamoyl) butyl]-amide (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2 fluoro-phenyl)-acetylamino]-3-methyl 55 pentanoylamino}-2,3,4,9-tetrahydro- 756.0 757.6 1 H-carbazole-3-carboxylic acid [(S) 2-methyl-1 -(2-morpholin-4-yl ethylcarbamoyl)-butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 56 2,3,4,9-tetrahydro-1 H-carbazole-3- 756.0 757.7 carboxylic acid {(S)-2-methyl- 1 [(piperidin-4-ylmethyl)-carbamoyl] butyll-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 57 2,3,4,9-tetrahydro-1 H-carbazole-3- 703.0 704.5 carboxylic acid [(S)-1-(2-hydroxy ethylcarbamoyl)-2-methyl-butyl] amide WO 2008/132153 PCT/EP2008/055039 -148 (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2 fluoro-phenyl)-acetylamino]-3-methyl 58 pentanoylamino}-2,3,4,9-tetrahydro- 734.0 735.5 1 H-carbazole-3-carboxylic acid {(S) 2-methyl-1 -[(pyridin-4-ylmethyl) carbamoyl]-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 59 2,3,4,9-tetrahydro-1 H-carbazole-3- 745.0 746.6 carboxylic acid [(S)-1-(5-hydroxy pentylcarbamoyl)-2-methyl-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 60 2,3,4,9-tetrahydro-1 H-carbazole-3- 766.0 767.3 carboxylic acid {(S)-2-methyl- 1 [(pyridin-4-ylmethyl)-thiocarbamoyl] butyll-amide (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2 fluoro-phenyl)-acetylamino]-3-methyl 61 pentanoylamino}-2,3,4,9-tetrahydro- 772.0 773.6 1 H-carbazole-3-carboxylic acid [(S) 2-methyl-1 -(2-morpholin-4-yl ethylthiocarbamoyl)-butyl]-amide (4-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 63 2,3,4,9-tetrahydro-1 H-carbazole-3- 851.0 852.6 carbonyl)-amino]-3-methyl pentanoylamino}-butyl)-phosphonic acid diethyl ester (4-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 64 2,3,4,9-tetrahydro-1 H-carbazole-3- 795.0 796.6 carbonyl)-amino]-3-methyl pentanoylamino}-butyl)-phosphonic acid (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 67 2,3,4,9-tetrahydro-1 H-carbazole-3- 751.0 752.4 carboxylic acid [(S)-1-(4-hydroxy phenylcarbamoyl)-2-methyl-butyl] amide WO 2008/132153 PCT/EP2008/055039 -149 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 68 2,3,4,9-tetrahydro-1 H-carbazole-3- 765.0 766.5 carboxylic acid [(S)-1-(4-methoxy phenylcarbamoyl)-2-methyl-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 69 2,3,4,9-tetrahydro-1 H-carbazole-3- 781.0 782.5 carboxylic acid [(S)-1-(3-hydroxy-4 methoxy-phenylcarbamoyl)-2-methyl butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 70 2,3,4,9-tetrahydro-1 H-carbazole-3- 767.0 768.4 carboxylic acid [(S)-1-(2,4-dihydroxy phenylcarbamoyl)-2-methyl-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 71 2,3,4,9-tetrahydro-1 H-carbazole-3- 781.0 782.5 carboxylic acid [(S)-1-(2-hydroxy-4 methoxy-phenylcarbamoyl)-2-methyl butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 72 2,3,4,9-tetrahydro-1 H-carbazole-3- 825.0 826.5 carboxylic acid [(S)-2-methyl-1-(2,4,6 trimethoxy-phenylcarbamoyl)-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 73 2,3,4,9-tetrahydro-1 H-carbazole-3- 757.0 758.6 carboxylic acid [(S)-1-(4-hydroxy cyclohexylcarbamoyl)-2-methyl-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 74 2,3,4,9-tetrahydro-1 H-carbazole-3- 783.0 784.4 carboxylic acid [(S)-1-(3-imidazol-1 yl-propylthiocarbamoyl)-2-methyl butyl]-amide WO 2008/132153 PCT/EP2008/055039 -150 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 75 2,3,4,9-tetrahydro-1 H-carbazole-3- 783.0 784.4 carboxylic acid [(R)-1-(3-imidazol-1 yl-propylthiocarbamoyl)-2-methyl butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 76 2,3,4,9-tetrahydro-1 H-carbazole-3- 785.0 786.3 carboxylic acid [(S)-2-methyl-1-(2 thiophen-2-yl-ethylthiocarbamoyl) butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 77 2,3,4,9-tetrahydro-1 H-carbazole-3- 766.0 767.3 carboxylic acid {(S)-2-methyl- 1 [(pyridin-3-ylmethyl)-thiocarbamoyl] butyll-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl 85 pentanoylamino}-8-trifluoromethyl- 702.0 703.4 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(2-diethylamino ethylcarbamoyl)-methyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl 86 pentanoylamino}-8-trifluoromethyl- 716.0 717.4 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(2-morpholin-4-yI ethylcarbamoyl)-methyl]-amide (S)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2 fluoro-phenyl)-acetylamino]-3-methyl 87 pentanoylamino}-2,3,4,9-tetrahydro- 734.0 735.5 1 H-carbazole-3-carboxylic acid {(S) 2-methyl-1 -[(pyridin-4-ylmethyl) carbamoyl]-butyl}-amide (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2 fluoro-phenyl)-thioacetylamino]-3 88 methyl-pentanoylamino}-2,3,4,9- 750.0 751 .5 tetrahydro-1 H-carbazole-3-carboxylic acid {(S)-2-methyl-1-[(pyridin-4 ylmethyl)-carbamoyl]-butyl}-amide WO 2008/132153 PCT/EP2008/055039 -151 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 89 2,3,4,9-tetrahydro-1 H-carbazole-3- 780.0 781.4 carboxylic acid [(S)-2-methyl-1-(2 pyridin-4-yl-ethylthiocarbamoyl) butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 90 2,3,4,9-tetrahydro-1 H-carbazole-3- 773.0 775.0 carboxylic acid [(S)-1-(4-hydroxy cyclohexylthiocarbamoyl)-2-methyl butyl]-amide 2-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 91 2,3,4,9-tetrahydro-1 H-carbazole-3- 809.0 810.5 carbonyl)-amino]-3-methyl pentanoylamino}-5-methoxy-benzoic acid Phosphoric acid diethyl ester 5-{(S) 2-[((R)-3-{(S)-2-[2-(2-fluoro-phenyl) acetylamino]-3-methyl 92 pentanoylamino}-8-trifluoromethyl- 917.0 918.5 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-3-methyl pentanoylamino}-2-methoxy-pheny ester Dimethylamino-acetic acid 4-{(S)-2 [((R)-3-{(S)-2-[2-(2-fluoro-phenyl) acetylamino]-3-methyl 93 pentanoylamino}-8-trifluoromethyl- 816.0 816.9 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-3-methyl pentanoylaminol-butyl ester (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 94 2,3,4,9-tetrahydro-1 H-carbazole-3- 765.0 766.5 carboxylic acid [(S)-1-(4-hydroxy benzylcarbamoyl)-2-methyl-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 95 2,3,4,9-tetrahydro-1 H-carbazole-3- 795.0 796.7 carboxylic acid [(S)-1-(3-hydroxy-4 methoxy-benzylcarbamoyl)-2-methyl butyl]-amide WO 2008/132153 PCT/EP2008/055039 -152 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 96 2,3,4,9-tetrahydro-1 H-carbazole-3- 795.0 796.7 carboxylic acid [(S)-1-(4-hydroxy-3 methoxy-benzylcarbamoyl)-2-methyl butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 97 2,3,4,9-tetrahydro-1 H-carbazole-3- 781.0 782.4 carboxylic acid [(S)-1-(4-methoxy phenylthiocarbamoyl)-2-methyl-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 102 2,3,4,9-tetrahydro-1 H-carbazole-3- 717.0 718.3 carboxylic acid [(S)-1-(3-hydroxy propylcarbamoyl)-2-methyl-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 103 2,3,4,9-tetrahydro-1 H-carbazole-3- 765.0 766.3 carboxylic acid ((S)-1 benzylthiocarbamoyl-2-methyl-butyl) amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 107 2,3,4,9-tetrahydro-1 H-carbazole-3- 800.0 801.3 carboxylic acid {(S)-1-[(6-chloro pyridin-3-ylmethyl)-thiocarbamoyl]-2 methyl-butyll-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 108 2,3,4,9-tetrahydro-1 H-carbazole-3- 780.0 781.5 carboxylic acid [(S)-2-methyl-1-(2 pyridin-3-yI-ethylthiocarbamoyl) butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 109 2,3,4,9-tetrahydro-1 H-carbazole-3- 767.0 768,4 carboxylic acid {(S)-2-methyl- 1 [(pyrimidin-4-ylmethyl) thiocarbamoyl]-butyl}-amide WO 2008/132153 PCT/EP2008/055039 -153 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylam ino]-3-m ethyl pentan oylam ino}-8-triflIu oro methyl 110 2,3,4,9-tetrahydro-1 H-carbazole-3- 769.0 carboxylic acid [(S)-1 -(2-imidazo-1 yI-ethylth iocarbamoyl) -2-m ethyl __________ butyl]-am ide_____ (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylam ino]-3-m ethyl pentanoylamino}-8-trifluoromethyl 111 2,3,4,9-tetrahydro-1 H-carbazole-3- 769.0 carboxylic acid [(S)-2-methyl- 1-(2 pyrazol- 1 -yI-ethylthiocarbamoyl) __________ butyl]-am ide_____ (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylam ino]-3-m ethyl pentanoylamino}-8-trifluoromethyl 112 2,3,4,9-tetrahydro-1 H-carbazole-3- 770.0 771 ,6 carboxylic acid [(S)-2-methyl- 1-(2 [1 ,2,4]triazol- 1 -yI-ethylthiocarbamoyl) __________ butyl]-am ide_____ 5-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 121 2,3,4,9-tetrahydro-1 H-carbazole-3- 795.0 796.7 carbonyl) -am ino]-3-m ethyl pentanoylam ino}-2-hydroxy-benzoic ___________ acid _____ (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylam ino]-3-m ethyl pentanoylamino}-8-trifluoromethyl 122 2,3,4,9-tetrahydro-1 H-carbazole-3- 769.0 770.5 carboxyl ic acid [(S)- 1-(3-fluoro-4 hydroxy-ph enylcarbam oyl) -2-m ethyl __________ butyl]-am ide_____ (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylam ino]-3-m ethyl pentanoylamino}-8-trifluoromethyl 123 2,3,4,9-tetrahydro-1 H-carbazole-3- 811.0 812.4 carboxylic acid [(S)-1 -(3-hydroxy-4 methoxy-benzylth iocarbamoyl)-2 __________ methyl-butyl]-am ide_____ (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylam ino]-3-m ethyl pentanoylamino}-8-trifluoromethyl 124 2,3,4,9-tetrahydro-1 H-carbazole-3- 674.0 675.4 carboxyl ic acid ((S) -1 hydrazinocarbonyl-2-methyl-butyl) __________ amide_____ WO 2008/132153 PCT/EP2008/055039 -154 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 125 2,3,4,9-tetrahydro-1 H-carbazole-3- 797.0 798.6 carboxylic acid [(S)-1-(3-hydroxy-4 methoxy-phenylthiocarbamoyl)-2 methyl-butyl]-amide (S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl 127 pentanoylamino}-8-trifluoromethyl- 768.0 769.3 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-3-methyl-pentanoic acid 3-imidazol-1-yl-propyl ester (R)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl 128 pentanoylamino}-8-trifluoromethyl- 768.0 769.5 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-3-methyl-pentanoic acid 3-imidazol-1-yl-propyl ester ((S)-1 -{(R)-6,8-Dichloro-3-[(S)-1 -(4 hydroxy-benzylcarbamoyl)-2-methyl 129 butylcarbamoyl]-2,3,4,9-tetrahydro- 763.0 764.6 1 H-carbazol-3-ylcarbamoyl}-2 methyl-butyl)-carbamic acid benzyl ester ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-1 -(4 hydroxy-benzylcarbamoyl)-2-methyl 130 butylcarbamoyl]-2,3,4,9-tetrahydro- 763.0 764.6 1 H-carbazol-3-ylcarbamoyl}-2 methyl-butyl)-carbamic acid benzyl ester (S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl 131 pentanoylamino}-8-trifluoromethyl- 751 .0 752.5 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-3-methyl-pentanoic acid pyridin-4-ylmethyl ester (R)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl 132 pentanoylamino}-8-trifluoromethyl- 751 .0 752.5 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-3-methyl-pentanoic acid pyridin-4-ylmethyl ester 2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl 133 pentanoylamino}-8-trifluoromethyl- 732.0 732.7 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-3-methyl-pentanoic acid 2-dimethylamino-ethyl ester WO 2008/132153 PCT/EP2008/055039 -155 (S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 134 2,3,4,9-tetrahydro-1 H-carbazole-3- 796.0 797.6 carbonyl)-amino]-3-methyl-pentanoic acid 3-hydroxy-4-methoxy-benzyl ester (R)-2-[((R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 135 2,3,4,9-tetrahydro-1 H-carbazole-3- 796.0 797.5 carbonyl)-amino]-3-methyl-pentanoic acid 3-hydroxy-4-methoxy-benzyl ester [(S)-1 -((S)-6,8-Dichloro-3-{(S)-2 methyl-1 -[(tetrahydro-pyran-4 ylmethyl)-carbamoyl] 136 butylcarbamoyl}-2,3,4,9-tetrahydro- 755.0 756.6 1 H-carbazol-3-ylcarbamoyl)-2 methyl-butyl]-carbamic acid benzyl ester (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl 137 pentanoylamino}-8-trifluoromethyl- 786.0 787.5 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(S)-2-methyl-1 (quinolin-6-ylcarbamoyl)-butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl 138 pentanoylamino}-8-trifluoromethyl- 786.0 787.7 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(R)-2-methyl-1 (quinolin-6-ylcarbamoyl)-butyl]-amide [(S)-1 -((R)-6,8-Dichloro-3-{(S)-2 methyl-1 -[(tetrahydro-pyran-4 ylmethyl)-thiocarbamoyl] 139 butylcarbamoyl}-2,3,4,9-tetrahydro- 771.0 772.6 1 H-carbazol-3-ylcarbamoyl)-2 methyl-butyl]-carbamic acid benzyl ester ((S)-1 -{(R)-6,8-Dichloro-3-[(S)-1 -(4 hydroxy-3-methoxy phenylcarbamoyl)-2-methyl 140 butylcarbamoyl]-2,3,4,9-tetrahydro- 779.0 780.7 1 H-carbazol-3-ylcarbamoyl}-2 methyl-butyl)-carbamic acid benzyl ester WO 2008/132153 PCT/EP2008/055039 -156 ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-1 -(4 hydroxy-3-methoxy phenylcarbamoyl)-2-methyl 141 butylcarbamoyl]-2,3,4,9-tetrahydro- 779.0 780.6 1 H-carbazol-3-ylcarbamoyl}-2 methyl-butyl)-carbamic acid benzyl ester [(S)-1 -((R)-6,8-Dichloro-3-{(S)-2 methyl-1 -[(tetrahydro-pyran-4 ylmethyl)-carbamoyl] 143 butylcarbamoyl}-2,3,4,9-tetrahydro- 755.0 756.7 1 H-carbazol-3-ylcarbamoyl)-2 methyl-butyl]-carbamic acid benzyl ester (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 144 2,3,4,9-tetrahydro-1 H-carbazole-3- 750.0 751.6 carboxylic acid [(S)-2-methyl-1-(N' phenyl-hydrazinocarbonyl)-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl 145 pentanoylamino}-8-trifluoromethyl- 693.0 694.4 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-3-methylsulfanyl 1 -thiocarbamoyl-propyl)-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl 146 pentanoylamino}-8-trifluoromethyl- 786.0 787.6 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(S)-2-methyl-1 (quinolin-5-ylcarbamoyl)-butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl 147 pentanoylamino}-8-trifluoromethyl- 786.0 787.6 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(S)-1-(isoquinolin-5 ylcarbamoyl)-2-methyl-butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 148 8-trifluoromethyl-2,3,4,9-tetrahydro-1H 771,0 772,8 carbazole-3-carboxylic acid {(S)-2 methyl-1 -[(2-tetrahydro-pyran-4-yl acetylamino)-methyll-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 149 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 757,0 758,7 carbazole-3-carboxylic acid ((S)-2 methyl-1 -{[(tetrahydro-pyran-4-carbonyl) amino]-methyl}-butyl)-amide WO 2008/132153 PCT/EP2008/055039 -157 (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 152 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 786,0 787,4 carbazole-3-carboxylic acid {(S)-2 methyl-i -[3-(tetrahydro-pyran-4 ylmethyl)-ureidomethyl]-butyl}-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 153 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 75, 783 carbazole-3-carboxylic acid [(S)-2-methyl- 75,78, 1 -(2-tetrahydro-pyran-4-yI-acetylamino) butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 157 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 772,0 carbazole-3-carboxylic acid {(R)-2 methyl-i -[3-(tetrahydro-pyran-4 ylmethyl)-ureido]-butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 158 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 771,0 772,6 carbazole-3-carboxylic acid ((R)-2 methyl-i -{[(tetrahydro-pyran-4-ylmethyl) carbamoyl]-m ethyl) -butyl) -am ide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 160 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 78, carbazole-3-carboxylic acid f{(S)-1 -[N'-(4- 78, methoxy-phenyl)-hydrazinocarbonyl]-2 methyl-butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 163 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 716,0 carbazole-3-carboxylic acid [(S)-1 -(N' acetyl- hydrazinocarbonyl)-2-m ethyl butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 164 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 717,0 carbazole-3-carboxylic acid [(S)-1 -(N' aminocarbonyl-hydrazinocarbonyl)-2 methyl-butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 165 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 79, carbazole-3-carboxylic acid {(S)-1 -[N'-(4- 79, hydroxy-benzoyl)-hydrazinocarbonyl]-2 methyl-butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 166 8-trifluormethyl-2,3,4,9-tetrahydro-1 H- 687,0 688,5 carbazole-3-carboxylic acid [(S)-1 (acetylam ino-m ethyl) -2-m eth yl-butyl] amide WO 2008/132153 PCT/EP2008/055039 -158 (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 167 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 716,0 717,6 carbazole-3-carboxylic acid f{(S)-1-[(3 ethyl-u re ido) -m ethyl] -2-m eth yl-butyl} amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 168 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 753,0 754,6 carbazole-3-carboxylic acid [(S)-l-(2 imidazol-1 -yI-ethylcarbamoyl)-2-methyl butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 169 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 751,0 752,6 carbazole-3-carboxylic acid {(S)-2 methyl-i j[(pyrazi n-2-ylm ethyl) carbamoyl]-butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 170 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 673,0 674,4 carbazole-3-carboxylic acid ((1 S,2S)-1 acetylamino-2-methyl-butyl)-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 171 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 786,0 787,6 carbazole-3-carboxylic acid [(S)-1 (isoquinolin-8-ylcarbamoyl)-2-methyl butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 172 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 74, 779 carbazole-3-carboxylic acid f{(S)-1 -[3-(3- 74,779 hydroxy-propyl) -u reidom ethyl]-2-m ethyl butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 173 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 73, 737 carbazole-3-carboxylic acid f{(S)-1-[(3- 730 737 ethyl-thioureido)-methyl]-2-methyl-butyl} ____________ amide____ ________ (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 174 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 765,0 766,6 carbazo Ie-3-carboxylic acid { (S)-2 methyl-i -[(3-pyridin-4-yI-ureido)-m ethyl] butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 175 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 769,0 770,3 carbazo Ie-3-carboxylic acid { (S)-2 methyl-i -[3-(1 H-tetrazol-5-yI) propylcarbamoyl]-butyl}-am ide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) 176 acetylamino]-3-methyl-pentanoylamino}- 741,0 742,6 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazo Ie-3-carboxylic acid { (S)-2- ______ WO 2008/132153 PCT/EP2008/055039 -159 methyl-1 -[(1 H-tetrazol-5-ylmethyl) carbamoyl]-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 177 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 797,0 798,5 carbazole-3-carboxylic acid {(S)-1-[(2 tert-butyl-2H-tetrazo l-5-ylm ethyl) carbamoyl]-2-methyl-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 178 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 783,0 784,4 carbazole-3-carboxylic acid [(S)-1-(2-tert butyl-2H-tetrazol-5-ylcarbamoyl)-2 methyl-butyll-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 179 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 783,0 784,5 carbazole-3-carboxylic acid [(S)-1 -(1 -tert butyl-1 H-tetrazol-5-ylcarbamoyl)-2 methyl-butyll-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 180 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 764,0 765,6 carbazole-3-carboxylic acid {(S)-2 methyl-1 -[(2-pyridin-4-yl-acetylamino) methyl]-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 181 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 801,0 802,3 carbazole-3-carboxylic acid {(S)-2 methyl-1 -[2-(1 -methyl-1 H-tetrazol-5 ylsulfanyl)-ethylcarbamoyl]-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 182 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 750,0 751,6 carbazole-3-carboxylic acid [(1 S,2S)-2 methyl-1 -(2-pyridin-4-yl-acetylamino) butyll-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 183 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 751,0 752,4 carbazole-3-carboxylic acid (S)-2-methyl 1 -[(pyrimidin-5-ylmethyl)-carbamoyl] butyl}-amide 184 865,0 866,5 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 185 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 755,0 756,6 carbazole-3-carboxylic acid [(S)-2-methyl 1-(2-tetrazol-1 -yl-ethylcarbamoyl)-butyl] amide WO 2008/132153 PCT/EP2008/055039 -160 {(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 186 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 773,0 774,4 carbazole-3-carbonyl)-amino]-3-methyl- ' ' pentyl}-carbamic acid tetrahydro-pyran-4 y ester {(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 187 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 703,0 704,4 carbazole-3-carbonyl)-amino]-3-methyl pentyl}-carbamic acid methyl ester 1 -tert-butyl-4-(3-{(S)-2-[((R)-3-{(S)-2-[2 (2-fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 188 2,3,4,9-tetrahydro-1 H-carbazole-3- 826,0 826,4 carbonyl)-amino]-3-methyl pentanoylamino}-propyl)-4H-tetrazol-1 ium; Trifluoro-acetate (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 189 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 769,0 770,2 carbazole-3-carboxylic acid [(S)-2-methyl 1-(3-tetrazol-1 -yl-propylcarbamoyl)-butyl] amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 190 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 779,0 780,6 carbazole-3-carboxylic acid [(S)-2-methyl 1 -(3-pyridin-4-ylmethyl-ureidomethyl) butyll-amide 191 972,0 973,5 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 192 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 727,0 728,3 carbazole-3-carboxylic acid [(S)-2-methyl 1 -(1 H-tetrazol-5-ylcarbamoyl)-butyl] amide (R)-3-{(S)-2-[(Bicyclo[4.2.0]octa-1 (6),2,4 triene-7-carbonyl)-amino]-3-methyl 193 pentanoylamino}-8-trifluoromethyl- 669,0 670,4 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-2-methyl-1 thiocarbamoyl-butyl)-amide (R)-3-{(S)-2-[2-(2-Chloro-phenyl) acetylamino]-3-methyl-pentanoylamino} 194 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 691,0 692,4 carbazole-3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl-butyl)-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 195 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 783,0 784,4 carbazole-3-carboxylic acid [(S)-2-methyl 1-(4-tetrazol-1 -yl-butylcarbamoyl)-butyl] amide WO 2008/132153 PCT/EP2008/055039 -161 (R)-3-((S)-3-Methyl-2-phenylacetylamino pentanoyl am ino) -8-trif luoro methyl 196 2,3,4,9-tetrahydro-1 H-carbazole-3- 657,0 658,3 carboxylic acid ((S)-2-methyl-1 thiocarbamoyl-butyl)-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 197 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 758,0 759,4 carbazole-3-carboxylic acid ((S)-2 methyl-i -{[(morpholine-4-carbonyl) aminol-methyll-butyl)-amide R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 198 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 772,0 773,4 carbazole-3-carboxylic acid ((S)-2 methyl-i -{[3-(tetrahydro-pyran-4-y) u reidol -m ethyl) -butyl) -am ide (R)-3-{ (S)-3-Methyl-2-[2-(2 trif luoromethyl-phenyl)-acetylamino] 199 pentanoylamino}-8-trif luoromethyl- 725,0 726,5 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-2-methyl-1 thiocarbamoyl-butyl)-amide (R)-3-[(S)-3-Methyl-2-(2-methyl-2-phenyl propionylamino)-pentanoylamino]-8 200 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 685,0 686,5 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl-butyl)-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 201 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 79, 744 carbazole-3-carboxylic acid {(S)-2- 79, 744 methyl-i -[3-(2-pyridin-4-yI-ethyl) ureidomethyl]-butyll-amide (R)-3-[(S)-3-Methyl-2-((S)-2-phenyl propionylamino)-pentanoylamino]-8 202 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 671 ,0 672,3 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl-butyl)-amide (R)-3-[(S)-3-Methyl-2-((R)-2-phenyl propionylamino)-pentanoylamino]-8 203 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 671 ,0 672,4 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl-butyl)-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 204 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 723,0 724,3 carbazole-3-carboxylic acid [(S)-i (m ethan esu Ifonyl am ino-m ethyl) -2-m ethyl butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 205 8-trifluoromethyl-2,3,4,9-tetrahydro-i H- 79, 766 carbazole-3-carboxylic acid [(S)-2-methyl- 79,766 1 -(3-pyridi n-4-ylm ethyl -th iou reidom ethyl) ___________ butyl]-amide______ ______ WO 2008/132153 PCT/EP2008/055039 -162 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 206 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 802,0 803,3 carbazole-3-carboxylic acid {(S)-2 methyl-1 -[3-(tetrahydro-pyran-4 ylmethyl)-thioureidomethyll-butyl}-amide (R)-3-[(S)-3-Methyl-2-((R)-2-phenyl butyrylamino)-pentanoylamino]-8 207 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 685,0 686,4 carbazole-3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl-butyl)-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 208 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 800,0 801,3 carbazole-3-carboxylic acid ((S)-2 methyl-1 -{3-[2-(tetrahydro-pyran-4-yl) ethyl]-ureidomethyl}-butyl)-amide R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 209 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 801 ,0 802,3 carbazole-3-carboxylic acid {(S)-2 methyl-1 -[3-(2-morpholin-4-yl-ethyl) ureidomethyll-butyl}-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 210 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 765,0 766,3 carbazole-3-carboxylic acid ((S)-1 benzylthiocarbamoyl-2-methyl-butyl) amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 211 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 717,0 718,3 carbazole-3-carboxylic acid [(S)-1-(3 hydroxy-propylcarbamoyl)-2-methyl butyl]-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 212 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 657,0 658,3 carbazole-3-carboxylic acid ((S)-2-oxo azepan-3-yl)-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-4-methylsulfanyl 213 butyrylamino}-8-trifluoromethyl-2,3,4,9 693,0 694,5 tetrahydro-1 H-carbazole-3-carboxylic acid ((S)-2-methyl-1-thiocarbamoyl-butyl) amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 214 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 663,0 664,4 carbazole-3-carboxylic acid ((R)-1 carbamoyl-2-methylsulfanyl-ethyl)-amide (R)-3-{(R)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methylsulfanyl 215 propionylamino}-8-trifluoromethyl-2,3,4,9 679,0 6804 tetrahydro-1 H-carbazole-3-carboxylic ' acid ((S)-2-methyl-1-thiocarbamoyl-butyl) amide WO 2008/132153 PCT/EP2008/055039 -163 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 216 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 796,0 797,6 carbazole-3-carboxylic acid {(S)-1 -[(2 methoxy-pyridin-4-ylmethyl) thiocarbamoyl]-2-methyl-butyl}-amide (R)-3-{(R)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-thiophen-2-yl 217 propionylamino}-8-trifluoromethyl-2,3,4,9 715,0 716,5 tetrahydro-1 H-carbazole-3-carboxylic acid ((S)-2-methyl-1-thiocarbamoyl-butyl) amide (R)-3-((S)-2-{[2-(2-Fluoro-phenyl)-acetyl] methyl-amino}-3-methyl 218 pentanoylamino)-8-trifluoromethyl- 689,0 690,6 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-2-methyl-1 thiocarbamoyl-butyl)-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 219 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 744,0 745,8 carbazole-3-carboxylic acid [(S)-2-methyl 1 -(morpholin-4-ylcarbamoyl)-butyll-amide (R)-3-((S)-2-{[2-(2-Fluoro-phenyl)-acetyl] methyl-amino}-3-methyl 220 pentanoylamino)-8-trifluoromethyl- 673,0 674,7 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-1-carbamoyl-2 methyl-butyl)-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 221 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 742,0 743,3 carbazole-3-carboxylic acid [(S)-2-methyl 1 -(piperidin-1 -ylcarbamoyl)-butyl-amide (R)-3-{(S)-2-[3-(2-Fluoro-phenyl)-ureido] 3-methyl-pentanoylamino}-8 222 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 676,0 677,5 carbazole-3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl-butyl)-amide (R)-3-{(S)-2-[3-(2-Fluoro-benzyl)-ureido] 3-methyl-pentanoylamino}-8 223 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 690,0 691,8 carbazole-3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl-butyl)-amide Carbonic acid 4-{(S)-2-[((R)-3-{(S)-2-[2 (2-fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl 224 2,3,4,9-tetrahydro-1 H-carbazole-3- 921,0 922,6 carbonyl)-amino]-3-methyl pentanoylamino}-butyl ester 2-[2-(2 methoxy-ethoxy)-ethoxy]-ethyl ester (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 225 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 764,0 765,6 carbazole-3-carboxylic acid [(S)-2-methyl 1 -(N'-methyl-N'-phenyl hydrazinocarbonyl)-butyll-amide WO 2008/132153 PCT/EP2008/055039 - 164 (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 226 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 79, 776 carbazole-3-carboxylic acid f{(S)-1 -[N'-(4- 79,77, fluoro-benzoyl)-hydrazinocarbonyl]-2 methyl-butyll-amide (R)-3-((S)-2-{[i -(2-Fluoro-phenyl) cyclopentanecarbonyl]-amino}-3-methyl 227 pentanoyl am ino) -8-trif luoro methyl- 729,0 730,6 2,3,4,9-tetrahydro-i H-carbazole-3 carboxylic acid ((S)-2-methyl-i thiocarbamoyl-butyl)-amide R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 228 8-trifluoromethyl-2,3,4,9-tetrahydro-i H- 786,0 787,6 carbazole-3-carboxylic acid {(S)-i-[N' (2,4-difluoro-phenyl)-hydrazinocarbonyl] 2-methyl-butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 229 8-trifluoromethyl-2,3,4,9-tetrahydro-i H- 751 ,0 752,6 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -phenoxycarbamoyl-butyl)-amide (R)-3-[(S)-3-Methyl-2-(2-pyridin-3-y acetylamino)-pentanoylamino]-8 230 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 658,0 659,5 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl-butyl)-amide (R)-3-[(S)-3-Methyl-2-(2-pyridin-2-y acetylamino)-pentanoylamino]-8 231 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 658,0 659,5 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl-butyl)-amide 3-f{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 232 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 779,0 780,5 carbazo Ie-3-carboxylic acid { (S)-2 methyl-i -[N'-(pyridine-4-carbonyl) hydrazinocarbonyl]-butyll-amide 233 793,0 794,7 3-f{(S)-2-[3-(4-Fluoro-benzyl)-ureido]-3 m ethyl-pentanoyl am ino)-8-trif luorom ethyl 234 2,3,4,9-tetrahydro-1 H-carbazole-3- 690,0 691 ,5 carboxylic acid ((S)-2-methyl-l thiocarbamoyl-butyl)-amide 3-f{(S)-2-[3-(3-Fluoro-benzyl)-ureido]-3 m ethyl-pentanoyl am ino)-8-trif luorom ethyl 235 2,3,4,9-tetrahydro-1 H-carbazole-3- 690,0 691 ,6 carboxylic acid ((S)-2-methyl-l thiocarbamoyl-butyl)-amide WO 2008/132153 PCT/EP2008/055039 -165 (R)-3-[(S)-3-Methyl-2-(2-pyridin-4-y acetylamino)-pentanoylamino]-8 236 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 658,0 659,6 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl-butyl)-amide (R)-3-{ (S) -3- Methyl -2-[3- (3- methyl benzyl)-ureido]-pentanoylamino}-8 237 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 686,0 687,6 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl-butyl)-amide (R)-3-{ (S) -3- Methyl -2-[3- (4- methyl benzyl)-ureido]-pentanoylamino}-8 238 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 686,0 687,5 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl-butyl)-amide (R)-3-{ (S)-2-[3-(4-Methoxy-benzyl) ureido]-3-methyl-pentanoylamino}-8 239 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 702,0 703,5 carbazo Ie-3-carboxylic acid ((S)-2 methyl-i -thiocarbamoyl-butyl)-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 240 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 80, 896 carbazole-3-carboxylic acid f{(S)-1i-[N'-(3- 80,896 methoxy-benzoyl)-hydrazinocarbonyl]-2 methyl-butyll-amid (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 241 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 768,0 769,4 carbazole-3-carboxylic acid {(S)-l-[N' (f uran -2-carbonyl) -hydrazi nocarbonyl]-2 methyl-butyl}-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 242 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 778,0 779,7 carbazole-3-carboxylic acid [(S)-l -(N' benzoyl-hydrazinocarbonyl) -2-m ethyl butyll-amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl)-2 hydroxy-acetylamino]-3-methyl 243 pentanoyl am ino)}-8-trif luoro methyl- 691 ,0 692,5 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-2-methyl-l thiocarbamoyl-butyl)-amide (R)-3-{ (S)-2-[3-(2-Fluoro-benzyl)-ureido] 3-methyl-pentanoylaminol-8 244 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 76, 764 carbazole-3-carboxylic acid [(S)-2-methyl- 76,764 1 -(N'-phenyl-hydrazinocarbonyl)-butyl] amide (R)-3-{ (S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 245 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 75, 722 carbazole-3-carboxylic acid [(S)-2-methyl- 71, 5, 1 -(N'-pyridin-2-yl-hydrazinocarbonyl) ___________ butyll-amide______ ______ WO 2008/132153 PCT/EP2008/055039 -166 (R)-3-[(S)-3-Methyl-2-(2-oxo-2-phenyl acetylamino)-pentanoylamino]-8 246 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 671,0 672,4 carbazole-3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl-butyl)-amide {(S)-2-Methyl-1 -[(R)-3-((S)-2-methyl-1 thiocarbamoyl-butylcarbamoyl)-8 247 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 673,0 674,4 carbazol-3-ylcarbamoyl]-butyl}-carbamic acid benzyl ester (R)-3-{(S)-2-[3-(3-Methoxy-benzyl) ureido]-3-methyl-pentanoylamino}-8 248 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 702,0 703,6 carbazole-3-carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl-butyl)-am ide (R)-3-{(2S,3S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 249 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 775,0 776,2 carbazole-3-carboxylic acid [(1 S,2S)-2 methyl-1 -(4-phenyl-thiazol-2-yl)-butyl] amide (R)-3-{(2S,3S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 250 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 805,0 806,3 carbazole-3-carboxylic acid {(1S,2S)-1-[4 (4-methoxy-phenyl)-thiazol-2-yl]-2 methyl-butyl}-ami 2-{(1 R,2S)-1 -[((R)-3-{(2S,3S)-2-[2-(2 Fluoro-phenyl)-acetylamino]-3-methyl 251 pentanoylamino}-8-trifluoromethyl- 771 ,0 772,2 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl-butyl}-thiazole 4-carboxylic acid ethyl ester (R)-3-{(2S,3S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 252 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 767,0 768,3 carbazole-3-carboxylic acid [(1 S,2S)-2 methyl-1 -(4-trifluoromethyl-thiazol-2-yl) butyll-amide (R)-3-{(2S,3S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 253 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 727,0 728,0 carbazole-3-carboxylic acid [(1 S,2S)-1 -(4 ethyl-thiazol-2-yl)-2-methyl-butyll-amide (R)-3-{(2S,3S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 254 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 755,0 756,2 carbazole-3-carboxylic acid [(1 S,2S)-1-(4 tert-butyl-thiazol-2-yl)-2-methyl-butyl] amide (R)-3-{(2S,3S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 255 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 785,0 786,3 carbazole-3-carboxylic acid [(1 S,2S)-1-(4 hydroxy-4-trifluoromethyl-4,5-dihydro thiazol-2-yl)-2-methyl-butyll-amide WO 2008/132153 PCT/EP2008/055039 -167 2-f{(1 S,2S)-1 -[((R)-3-{ (2S,3S)-2-[2-(2 Fluoro-phenyl)-acetylamino]-3-methyl 256 pentanoyl am ino)}-8-trif luoro methyl- 743,0 744,2 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl-butyl}-thiazole 4-carboxylic acid (R)-3-{ (S)-2-[3-(3-Methoxy-phenyl) propionylamino]-3-m ethyl 257 pentanoylamino}-8-trif luoromethyl- 701 ,0 702,5 2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-2-methyl-1 thiocarbamoyl-butyl)-amide 2-f{(1 S,2S)-1 -[((R)-3-{ (2S,3S)-2-[3-(2 Fluoro-benzyl)-ureido]-3-methyl 258 pentanoyl am ino)}-8-trif luoro methyl- 786,0 787,6 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl-butyl}-thiazole 4-carboxylic acid ethyl ester 2-f{(1 S,2S)-1 -[((R)-3-{ (2S,3S)-2-[3-(4 Meth oxy-be nzyl) -u reido]-3- methyl 259 pentanoyl am ino)}-8-trif luoro methyl- 798,0 799,3 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl-butyl}-thiazole 4-carboxylic acid ethyl ester 2-f{(1 S,2S)-1 -[((R)-3-{ (2S,3S)-2-[3-(4 Meth oxy-be nzyl) -u reido]-3- methyl 260 pentanoyl am ino)}-8-trif luoro methyl- 770,0 771 ,3 2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl-butyl}-thiazole 4-carboxylic acid (R)-3-{ (2S,3S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 261 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 74, 735 carbazole-3-carboxylic acid [(1 S,2S)-1 -(4 720 4, carbamoyl-thiazol-2-y)-2-methyl-butyl] amide 2-f{(1 S,2S)-1 -[((R)-3-{ (2S,3S)-2-[3-(2 Fluoro-benzyl)-thioureido]-3-m ethyl 262 pentanoyl am ino)}-8-trif luoro methyl- 80, 833 2,3,4,9-tetrahydro-1 H-carbazole-3- 820 833 carbonyl)-amino]-2-methyl-butyl}-thiazole 4-carboxylic acid ethyl ester (R)-3-{ (2S,3S)-2-[3-(2-Fluoro-benzyl) thioureido]-3-methyl-pentanoylamino}-8 263 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 73, 745 carbazole-3-carboxylic acid [(1 S,2S)-1 -(4- 73,745 carbamoyl-thiazol-2-y)-2-methyl-butyl] amide (R)-3-{ (2S,3S)-2-[3-(2-Fluoro-benzyl) thioureido]-3-methyl-pentanoylamino}-8 264 trifluoromethyl-2,3,4,9-tetrahydro-1 H- 706,0 707,3 carbazole-3-carboxylic acid ((1 S,2S)-2 methyl-i -thiocarbamoyl-butyl)-amide (R)-3-{ (S)-2-[2-(3-Methoxy-phenyl) 265 acetylamino]-3-methyl-pentanoylamino}- 687,0 688,5 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazo le-3-carboxylic acid ((S)-2- ______ WO 2008/132153 PCT/EP2008/055039 -168 methyl-1 -thiocarbamoyl-butyl)-amide (R)-3-{(S)-2-[2-(2-Fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino} 266 8-trifluoromethyl-2,3,4,9-tetrahydro-1 H- 773,0 774,5 carbazole-3-carboxylic acid {(S)-2 methyl-1 -[(tetrahydro-thiopyran-4 ylmethyl)-carbamoyl]-butyl}-amide The presented embodiments were synthesized according to the following, well known, general reaction scheme: S R4
H
2 N N - R3 HN / [OS, H 2 coupling reagent H2N H 0 H2 [O,N]-R4 R1 N N OH 0 R2 O coupling reagent H2N ,R5 R3 H coupling reagent HN n =0,1 [OS, H 2 ] H 0 H R1 N N [O,N]-R4 - R3 0 R2 O HN 0 H - R3 R1 N N R5 HN ~~< N nN 0 R2 H H O H 0, H 5 R4 n=0,1 R1 N N N 0 R2 o 5 The definition of the R radicals shown in the above reaction scheme and further herein disclosed general reaction schemes corresponds to the substituents (e.g. R radicals) WO 2008/132153 PCT/EP2008/055039 -169 defined above in connection with the general formula (1) and preferred sub sets/embodiments. For the avoidance of doubt, the R radicals shown in the above re action scheme and further herein disclosed general reaction schemes can be identical, but do not need to be identical with the substituents (e.g. R radicals) defined above in 5 connection with the general formula (1) and preferred subsets/embodiments. The indi vidual assignment can be accomplished in a simple manner by the person skilled in the art on the basis of his or her average technical knowledge. The building blocks (intermediates) were synthesized from commercially available 10 starting materials in analogy to well known literature procedures. Amino acids with thiazole-C-termini were synthesized according to D.F.W. Cross et al. (J. Chem. Soc. 1963, 2143-2150) or R. Houssin et al. (J. Org. Chem. 1985, 50, 2787 2788) from the corresponding amino acid thioamide and alpha-halogen ketone deriva tives. 15 Hydrazide or substituted thioamide building blocks were synthesized from commer cially available starting materials in analogy to well known literature procedures out lined in the following reaction schemes: 0S 0 H 0 Lawesson's H STFA HN R H H2N-R6 tB NR6reagent t-Bu 'N K RN t-t-BuONu N N H OSU N H R4 R5 0 4R 0 R4 R5 H 0 R4 R5 R6 = H H N R7 1)2) H0H Hq 0 t-BuO N R7t-Bu N 0 R4 R5 0 R TFA 1
H
2 N R7 R4 R5H t-BuO N R6 TFA H2N R6 20 0 R4 R5 R4 R 5 H 1) US 2 908 688 (Hoffmann-La Roche 1958). Ekegren et al J. Med. Chem. 2006; 1828 - 1832.
WO 2008/132153 PCT/EP2008/055039 - 170 2) Brain et al: J. Org. Chem. 1997, 62: 3808. The definition of the R radicals shown in the above reaction scheme and further herein disclosed general reaction schemes corresponds to the substituents (e.g. R radicals) 5 defined above in connection with the general formula (1) and preferred sub sets/embodiments. For the avoidance of doubt, the R radicals shown in the above re action scheme and further herein disclosed general reaction schemes can be identical, but do not need to be identical with the substituents (e.g. R radicals) defined above in connection with the general formula (1) and preferred subsets/embodiments. The indi 10 vidual assignment can be accomplished in a simple manner by the person skilled in the art on the basis of his or her average technical knowledge. Synthesis of ester derivatized building blocks from protected amino acids and alcohols in analogy to well known standard procedures: 15 0 0 t HO-R6 t-BuO N R6 TFA H 2 N R6 t-BuO. N "HY0X10 SCoupling R4 R5 R4 R5 0 R4" R5 reagent The definition of the R radicals shown in the above reaction scheme and further herein disclosed general reaction schemes corresponds to the substituents (e.g. R radicals) 20 defined above in connection with the general formula (1) and preferred sub sets/embodiments. For the avoidance of doubt, the R radicals shown in the above re action scheme and further herein disclosed general reaction schemes can be identical, but do not need to be identical with the substituents (e.g. R radicals) defined above in connection with the general formula (1) and preferred subsets/embodiments. The indi 25 vidual assignment can be accomplished in a simple manner by the person skilled in the art on the basis of his or her average technical knowledge. Synthesis of diamino building blocks from protected amides in analogy to well known standard procedures: WO 2008/132153 PCT/EP2008/055039 -171 0 trifluoroacetic 2' O anhydride H H RaNi H PG N2PG-N CN NH3- PG'N NH,
NH
2 2) R4 R5 R4 R5 R4 R5 bis(trifluoroacetoxy) iododbenzene H PG' N
NH
2 R4 R5 1) a. Louden et al. J. Org. Chem. 1984, 42: 4272. b. Guerlavais et al. J. Med. Chem. 2003, 46: 1191. 2) Boeijen et al. Eur. J. Org. Chem. 1999: 2127. 5 The definition of the R radicals shown in the above reaction scheme and further herein disclosed general reaction schemes corresponds to the substituents (e.g. R radicals) defined above in connection with the general formula (1) and preferred sub sets/embodiments. For the avoidance of doubt, the R radicals shown in the above re 10 action scheme and further herein disclosed general reaction schemes can be identical, but do not need to be identical with the substituents (e.g. R radicals) defined above in connection with the general formula (1) and preferred subsets/embodiments. The indi vidual assignment can be accomplished in a simple manner by the person skilled in the art on the basis of his or her average technical knowledge. 15 These diamino building blocks were further modified according to well known standard procedures: 20 WO 2008/132153 PCT/EP2008/055039 - 172 R6 R7 O R6 R7 s
H
2 N R8 H 2 N R4 R5 R4 R5 deprotection Ideprotection H R6 R7 O Lawesson's H R6 R7 s o PG'N, N A 8 reagent t-BuO N N k R8 CI R8 R4 R5 o R4 R 5 H R6 NH2 C.R8 HR NR7 protection, R6 R7R PG' n 114 2). PG'N n NJL~ 0 -- ------- N~K R4 R5 R8-NCO R4 R5 H R4 R5 H or R8-NCS [0, S] HR R7 R6 R7 I PG R8 deprotection H2N R8 R4 R5 H H R4 R5 H H n = 0,1 PG = Protecting group The definition of the R radicals shown in the above reaction scheme and further herein disclosed general reaction schemes corresponds to the substituents (e.g. R radicals) 5 defined above in connection with the general formula (1) and preferred sub sets/embodiments. For the avoidance of doubt, the R radicals shown in the above re action scheme and further herein disclosed general reaction schemes can be identical, but do not need to be identical with the substituents (e.g. R radicals) defined above in connection with the general formula (1) and preferred subsets/embodiments. The indi 10 vidual assignment can be accomplished in a simple manner by the person skilled in the art on the basis of his or her average technical knowledge. Compound 62: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 15 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid ((S)-2-methyl-1 {[(tetrahydro-pyran-4-ylmethyl)-amino]-methyl}-butyl)-am ide 0.050 g (0.06 mmol) of (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid WO 2008/132153 PCT/EP2008/055039 -173 {(S)-2-methyl-1 -[(tetrahydro-pyran-4-ylmethyl)-thiocarbamoyl]-butyl}-amide were dis solved in 7 mL of THF/Methanol (1 : 1). 0.123 g (0.52 mmol) of nickel(II)chloride hexa hydrate were added at room temperature. The mixture was stirred for 10 min at this temperature. At 0 0C 0.059 g (1.55 mmol) sodium borhydrate were added. Stirring was 5 continued for 18 h at room temperature. The mixture was filtered over silica gel and the silica gel layer was washed with MeOH. The filtrate and washes were combined, con centrated and the residue purified by HPLC. Yield: 0.030 g (62% of theory). 10 'H-NMR (DMSO-d 6 , 600 MHz): 8 = 11.08 (s, 1H); 8.26 (bs, 1H); 7.72 (bs, 1H); 7.58 (d, 1H); 7.34 (d, 1 H); 7.21-7.31 (m, 2H); 7.05-7.14 (m, 4H); 3.94 (t, 1H); 3.75-3.86 (m, 3H); 3.56 (d, 1H); 3.37-3.46 (m, 2H); 3.01-3.13 (m, 2H); 2.82 (d, 2H); 2.70 (m, 1 H); 2.14 (m, 1H); 1.57-1.70 (m, 3H); 1.27-1.42 (m, 3H); 1.13-1.20 (m, 2H); 1.01 (sept, 2H); 0.79 (t, 3H); 0.74 (d, 3H); 0.72 (d, 3H); 0.69 (t, 3H) ppm. 15 ESI-MS: found: 744.6 (M+H+); calculated: 743 g/mol. According to the procedure described for the synthesis of compound 62, the following compound was also prepared: 20 Compound 66: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(2 morpholin-4-yl-ethylamino)-methyl]-butyl}-amide 25 "H-NMR (DMSO-d 6 , 600 MHz): 8 = 11.11 (s, 1H); 8.37 (d, 2H); 7.99 (s, 1H); 7.58 (d, 2H); 7.35 (d, 2H); 7.28-7.32 (m, 2H); 7.24 (d, 2H); 7.13-7.17 (m, 2H); 7.11 (t, 1H); 3.91 4.00 (m, 3H); 3.63 (d, 1H); 3.54 (d, 1H); 3.15-3.23 (m , 2H); 3.03 (t, 1H); 2.92 (t, 2H); 2.81 (bs, 1H); 2.12 (m, 1H); 1.64 (m, 1 H); 1.23- 1.43 (m, 4H); 1.03 (m, 1 H); 0.79 (t, 3H); 30 0.76(d, 3H); 0.70-0.73 (m, 6H) ppm. ESI-MS: found: 759.5 (M+H+); calculated: 758 g/mol.
WO 2008/132153 PCT/EP2008/055039 -174 Compound 78: ((S)-1 -{(R)-6,8-Dichloro-3-[(S)-3-methyl-1 -(1 H-tetrazol-5-yl)-butylcarbamoyl]-2,3,4,9 tetrahydro-1 H-carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester 5 0.122 g (0.19 mmol) of {(S)-1 -[(R)-6,8-Dichloro-3-((S)-1 -cyano-3-methyl butylcarbamoyl)-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl]-2-methyl-butyl} carbamic acid benzyl ester synthesized according to 84 (see below), 0.028 g (0.44 mmol) of sodium azide and 0.026 (0.48 mmol) of ammonium chloride were heated in 2 10 mL of DMF in a microwave at 110 C and 100 watt for 6 h. The reaction solution was separated on a preparative HPLC column. Yield: 0.035 g (26% of theory). "H-NMR (DMSO-d 6 , 600 MHz): 8 = 15.98 (bs, 1H); 11.35 (s, 1H); 7.88 (bs, 1H); 7.85 (s, 15 1H); 7.38 (s, 1H); 7.26 (d, 2H); 7.29-7.35 (m, 4H); 7.15 (s, 1H); 5.29 (q, 1H); 5.03 (d, 1H); 4.83 (d, 1H); 3.81 (t, 1H); 2.98 (d, 1H); 2.86 (d, 1H); 2.79 (dd, 1H); 2.73 (dd, 1H); 2.57 (m, 1H); 2.15 (m, 1H); 1.75-1.84 (m, 2H); 1.57-1.65 (m, 2H); 1.35 (m, 1H); 1.04 (m, 1 H); 0.86 (t, 6H); 0.76 (d, 3H); 0.73 (t, 3H) ppm. ESI-MS: found: 683.6 (M+H+); calculated: 682 g/mol. 20 Compound 84: (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid ((S)-1 -cyano-2 methyl-butyl)-amide 25 1.649 g (2.50 mmol) of (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxylic acid ((S)-1-carbamoyl-2-methyl-butyl)-amide were dissolved in 10 mL of pyridine. At 0 0C 0.70 mL (5.0 mmol) of trifluoroacetic anhydrate were added and the mixture was stirred 30 for 20 h at room temperature. The reaction mixture was concentrated and the residue purified by HPLC WO 2008/132153 PCT/EP2008/055039 -175 Yield: 0.530 g (54% of theory). "H-NMR (DMSO-d 6 , 600 MHz): 8 = 11.12 (s, 1H); 8.24 (d, 1 H); 8.20 (d, 1 H); 7.95 (s, 1H); 7.68 (d, 1 H); 7.34 (d, 1 H); 7.26-7.29 (m, 2H); 7.09-7.15 (m, 3H); 4.56 (t, 1H); 4.08 5 (t, 1 H); 3.58 (d, 1 H); 3.41 (d, 1 H); 3.03 (d, 1 H); 3.96(d; 1 H); 2.82 (dd, 1 H); 2.70 (dd, 1H); 2.60 (m, 1H); 2.16 (m, 1H); 1.74 (m, 1H); 1.63 (m, 1H); 1.35-1.41 (m, 2H); 0.98 1.12 (m, 3H); 0.91 (d, 3H); 0.77-0.80 (m, 6H); 0.74 (t, 3H) ppm. ESI-MS: found: 642.4 (M+H+); calculated: 641 g/mol. 10 WO 2008/132153 PCT/EP2008/055039 - 176 II) LHRH-Receptor Binding Assay For LHRH receptor binding studies, an assay system using alpha T3-1 cell line with endogenous GnRH receptor expression was employed (Windle et al., Mol.Endocrinol. 5 1990, 4(4): 597-603). lodinated cetrorelix was used as a tracer with about 80% of peptide capable of specific receptor association. For displacement binding assays, the cells were incubated with approximately 200pM [1251] cetrorelix and different concentrations of unlabeled test compounds as 10 competitor. The cell suspension in binding medium was layered on top of sili con/paraffin oil, incubated for 60 min at 370C and separated by centrifugation. The tips of the tubes containing the cell pellet were cut off, subsequently cell pellet and super natant were analyzed by gamma-radiation analysis. The amount of unspecific binding was determined by including unlabeled cetrorelix 15 at 1 pM final concentration and was typically 5 10% of total binding. IC50 values were calculated by using the GraphPad Prism analysis program (GraphPad Software Inc.). Table 3 shows the receptor binding data (absolute / normalized) of selected com pounds of the invention in comparison with pertinent prior art examples. From the experimental data presented in the table it is evident that the selected 20 compounds of the invention show an up to 529% higher receptor binding affinity compared to the pertinent prior art examples. 25 30 WO 2008/132153 PCT/EP2008/055039 -177 Table 3 - LHRH rezeptor-binding assay - EC 50 values for selected compounds Compounds EC 50 [nM] Normalized Affinity compound 52 17 218% compound 54 15 247% (TFA salt) compound 60 15 247% compound 69 7 529% compound 71 9 411% compound 74 15 247% compound 118 13 285% compound 178 10 370% WO 2006/005484
-
37 100% substance 75 WO 2006/005484
-
38 97% substance 76 WO 2006/005484
-
39 95% substance 66 WO 2006/005484
-
151 25% substance 67 WO 2006/005484 - 179 21% substance 7 5 WO 2008/132153 PCT/EP2008/055039 -178 Ill) Metabolic Stability Testing in Liver Microsomes Subcellular fractions of different tissues can be prepared easily by ultracentrifuga tion. Most commonly these are prepared from the liver of animals and human donors to 5 gain information about the potential hepatic clearance of compounds (first-pass elimi nation of drugs). Human or animal (e.g. dog, mouse, rat) subcellular fraction like liver microsomes, or possibly the fraction called S9 have therefore become a very com monly and widely used as an in vitro model to investigate mainly cytochrome P450 dependent phase I (but also phase 1l) metabolism that takes place in the liver. As en 10 zymatic activities are stable during a prolonged storage of the microsomes (at -80 0C), microsomes do not need to be freshly prepared and are commercially available. In order to reflect the standard proportion of the enzymes in human and animal liv ers, liver microsomes are usually pooled from a number of species of the same sex (or mixed-gender). By supplementing the liver microsomes with relevant cofactors and 15 other components it is possible to investigate and distinguish between CYPs, flavin containing monooxygenase (FMO) and UDP-glucuronosyltransferase (UGT) activities. Selected compounds of the invention were tested for their stability in mixed-gender human liver microsomes and compared to pertinent prior art compounds. Under the test conditions applied (1 mg microsomal protein/mL, initial concentration 20 of 10 pM, and incubation for 60 minutes at 370C) the following normalized results were obtained. Table 4 shows the normalized microsomal stability of selected compounds of the invention in comparison with pertinent prior art examples. From the experimental data presented in the table it is evident that the selected 25 compounds of the invention show an up to 1948% higher microsomal stability com pared to the pertinent prior art examples. 30 WO 2008/132153 PCT/EP2008/055039 -179 Table 4 - Normalized microsomal stability for selected compounds Compounds Normalized microsomal stability compound 52 178% compound 167 274% compound 31 276% compound 173 285% compound 239 307% compound 219 452% compound 114 537% compound 54 611% compound 73 624% compound 190 665% compound 36 774% compound 205 800% compound 251 1033% compound 69 1041% compound 244 1096% compound 256 1194% compound 258 1215% compound 164 1230% compound 188 1259% compound 137 1296% WO 2008/132153 PCT/EP2008/055039 -180 compound 242 1322% compound 236 1328% compound 183 1350% compound 144 1352% compound 250 1491% compound 249 1580% compound 74 1889% compound 230 1948% WO 2006/005484
-
100% substance 7 WO 2006/005484
-
93% substance 68 WO 2006/005484
-
61% substance 76 WO 2008/132153 PCT/EP2008/055039 -181 IV) Pharmacokinetic study Adult male Wistar rats weighing 278-290 g (Janvier, France) were used in the study. Animals were housed in a temperature-controlled room (20-24 0C) and main 5 tained in a 12h light/1 2h dark cycle. Food and water were available ad libitum. For surgery, rats were anaesthetised with a ketamine (90 mg/kg)/ xylazine (10 mg/kg) mixture, and cannulated with silicone tubing via the right jugular vein. Prior to the first blood sampling, animals were connected to a counterbalanced system and tubing to perform blood sampling in the freely moving rat. 10 Separate stock solutions (5 mg/ml) of compound 52 of the invention and prior art substance WO 2006/005484 - substance 76 were prepared in Solutol HS 15/PEG300 (3:1). The whole process was performed under constant stirring. Half of the volume of the vehicle was added first. After sonication (5 minutes), the second half of the vehicle was added and the vials were again sonicated. All the solutions were clear and free of 15 particles or agglomerates. Immediately before application, the dosing mixture was prepared by adding equal volumes of the stock solutions to end up with a final concentration of 1 mg/ml for each compound. The mixture was applied orally to rats with an application volume of 5 ml/kg. 20 Blood samples (200 pl) were taken 1 hour before application and 1, 2, 4, 6, 8, 12 and 24 hours after. They were centrifuged at 650 g for 10 minutes at 40C and then the plasma was harvested and kept at -200C until LC/MS analysis. The following results displayed in table 5 were obtained. Figure 1 depicts the area under-the-curve (AUC) which is indicative for bioavailability of the compounds. As can 25 be seen from table 5 and figure 1, compared to the pertinent prior art substance com pound 52 of the invention shows a more than 300% higher AUC indicative for a higher bioavailability. 30 WO 2008/132153 PCT/EP2008/055039 -182 Table 5 - Results of the pharmacokinetic study Compound 52 WO 2006/005484 substance 76 Dose (mg/kg) 5 5 Cmax obs 38.2 12.5 (ng/ml) tmax obs (h) 4.0 4.0 AUC0-tz 305.9 96.2 (ng*h/ml) 5 WO 2008/132153 PCT/EP2008/055039 -183 V) Testosterone suppression experiment Male Wistar rats weighing 248-296 g (Janvier, France) were used in the present study. Animals were housed in a temperature-controlled room (20-22 0C) and main 5 tained in a 12h light/1 2h dark cycle. Food and water were available ad libitum. Rats were anaesthetised with a ketamine (135mg/kg)/ xylazine (10mg/kg) mixture, and cannulated with silicone tubing via the right jugular vein. Prior to the first blood sampling, animals were connected to a counterbalanced system and tubing, to perform blood sampling in the freely moving rat. 10 The dosing solutions were prepared immediately before application. The po solu tion was obtained by dissolving the compound 54 (TFA salt) of the invention in Solutol HS15/PEG300 (3:1). A group of control rats was applied with the po vehicle (5 ml/kg) and the compound 54 of the invention. A baseline of testosterone level was established by two blood sam 15 ples taken at -1 and Oh. At time 0 (0h), the compound was applied and blood samples (200 pl) were taken 1, 2, 4, 6, 8, 12, and 24h post-dose after po. The blood samples were collected in heparinized tubes and stored on ice. They were centrifuged at 3000 g (10 min, 40C). Plasma was harvested and kept at -20C until being assayed. 20 The concentrations of testosterone in the rat plasma samples were determined us ing the Testosterone ELISA (EIA-1 559) from DRG Instruments according to the manu facturer's instructions. This assay is based on the competition between unlabeled tes tosterone from the sample and a fixed amount of horse-radish peroxidase conjugated testosterone for the binding sites of a monoclonal testosterone antibody bound to the 25 plate. In detail, 25 pl/well of blank, standards (in duplicate) and samples (in singula) without special pre-treatment were added to the microtiter plate. After 1 h of incubation together with 200 pl/well of enzyme conjugate, the plate was washed 3 times with wash buffer, provided with the kit. For the colour reaction, 200 pl of substrate solution were added to each well. The reaction was stopped after 15 min by adding 100 pl of stop 30 solution (0.5 M H 2
SO
4 ) to each well. The plate was read within the next 30 min with a Spectramax Plus (Molecular Devices) at 450 nm. The concentration of testosterone in the samples was calculated from the standard curve and is inversely proportional to the optical density measured.
WO 2008/132153 PCT/EP2008/055039 -184 Due to the pulsatile release of testosterone in intact rats, two pre-treatment sam ples were collected to establish baseline values prior the administration of the com pound. For data analysis, the pre-treatment time points (-1 and Oh) were averaged. A paired t-test (SigmaStat software; SPSS; Erkrath, Germany) was performed to deter 5 mine whether or not the treatment had an effect. This repeated measure procedure is used to test differences of testosterone levels in the same individual before and after treatment. The pre-treatment mean value was compared to the testosterone levels measured after application. Figure 2 shows the achieved testosterone suppression for the administration of 10 compound 54 (TFA salt) of the invention.

权利要求:
Claims (8)
[1] 1. Tetrahydrocarbazole derivative according to formula (1) R18 R17 R19 R16,N R20 R14 R15 R13 R21 R12 R22 * R1 R1 R11 W R6 / R2 N ; 6/ R10 NR R9 R8 R7 V R5m R4m R3 wherein: (A) V, W are independently from each other selected from the group consisting of: "=O, =S, =S*-O-, geminally linked H 2 "; 10 R1, R1 * -when present - together independently form "=O, =S or =S*-O-" or are independently both "hydrogen"; R2, R3 are independently from each other selected from the group consisting of: (i) ,,hydrogen, alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, het 15 erocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -CI, -Br, -1, CN, -CF 3 , -N 3 , -NH 2 , -NHX1, -NX2X3, -NO 2 , -OH, =O, -OCF 3 , -SH, -0 SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, -P(O)(OH) 2 , C(O)-X4, -C(O)O-X5, -C(O)N H-X6, -C(O)NX7X8, -O-X9, -O(-X10-0)a H (a = 1, 2, 3, 4, 5), -O(-X11-0)b-X12 (b = 1, 2, 3, 4, 5), -OC(O)-X13, 20 OC(O)-O-X14, -OC(O)-NHX15, -O-C(O)-NX16X17, - WO 2008/132153 PCT/EP2008/055039 -186 OP(O)(OX18)(OX19), -OSi(X20)(X21)(X22), -OS(0 2 )-X23, -NHC(O)-NH 2 , -NHC(O)-X24, -NX25C(O)-X26, -NH-C(O)-O-X27, -NH-C(O)-NH-X28, -NH-C(O)-NX29X30, -NX31-C(O)-O-X32, -NX33-C(O)-NH-X34, NX35-C(O)-NX36X37, -NHS(0 2 )-X38, -NX39S(0 2 )-X40, -S-X41, -S(O) 5 X42, -S(0 2 )-X43, -S(0 2 )NH-X44, -S(0 2 )NX45X46, -S(0 2 )O-X47, P(O)(OX48)(OX49), -Si(X50)(X51)(X52), -C(NH)-NH 2 , -C(NX53)-NH 2 , C(NH)-NHX54, -C(NH)-NX55X56, -C(NX57)-NHX58, -C(NX59) NX60X61, -NH-C(O)-NH-O-X62, -NH-C(O)-NX63-0-X64, -NX65 C(O)-NX66-0-X67, -N(-C(O)-NH-O-X68) 2 , -N(-C(O)-NX69-0-X70) 2 , 10 N(-C(O)-NH-O-X71)(-C(O)-NX72-O-X73), -C(S)-X74, -C(S)-O-X75, C(S)-NH-X76, -C(S)-NX77X78, -C(O)-NH-O-X79, -C(O)-NX80-0-X81, -C(S)-NH-O-X82, -C(S)-NX83-0-X84, -C(O)-NH-NH-X85, -C(O)-NH NX86X87, -C(O)-NX88-NX89X90, -C(S)-NH-NH-X91, -C(S)-NH NX92X93, -C(S)-NX94-NX95X96, -C(O)-C(O)-O-X97, -C(O)-C(O)-NH 2 , 15 -C(O)-C(O)-NHX98, -C(O)-C(O)-NX99X100, -C(S)-C(O)-O-X 101, C(O)-C(S)-O-X 102, -C(S)-C(S)-O-X 103, -C(S)-C(O)-N H 2 , -C(S)-C(O) NHX1 04, -C(S)-C(O)-NX1 05X1 06, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHX107, -C(S)-C(S)-NX1 08X109, -C(O)-C(S)-NH 2 , -C(O)-C(S) NHX 110, -C(O)-C(S)-NX 111 X 112"; 20 wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X1 0, X11, X1 2, X1 3, X1 4, X15, X16,X17,X18,X19,X20,X21,X22,X23,X24,X25,X26,X27,X28,X29, X30,X31,X32,X33,X34,X35,X36,X37,X38,X39,X40,X41,X42,X43, X44,X45,X46,X47,X48,X49,X50,X51,X52,X53,X54,X55,X56,X57, X58,X59,X60,X61,X62,X63,X64,X65,X66,X67,X68,X69,X70,X71, 25 X72,X73,X74,X75,X76,X77,X78,X79,X80,X81,X82,X83,X84,X85, X86,X87,X88,X89,X90,X91,X92,X93,X94,X95,X96,X97,X98,X99, X100,X1O1,X102,X103,X104,X105,X106,X107,X108, X109,X11O, X111, X112 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, 30 heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein al ternatively X7, X8 and/or X1 6, X1 7 and/or X29, X30 and/or X36, X37 and/or X45, X46 and/or X55, X56 and/or X60, X61 and/or X77, X78 and/or X86, X87 and/or X89, X90 and/or X92, X93 and/or X95, X96 and/or X99, X1 00 and/or X1 05, X1 06 and/or X108, X1 09 and/or X111, X112 and/or respec 35 tively together can also form ,heterocyclyl"; WO 2008/132153 PCT/EP2008/055039 -187 wherein optionally above substituents of substituents group (i) can in turn independently from each other be substituted with at least one substituent, identical or different, selected from the group consisting of: (ii) ,alkyl, (C 9 -C 3 o)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycly 5 lalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, CF 3 , -N 3 , -NH 2 , -NHX201, -NX202X203, -NO 2 , -OH, =0, -OCF 3 , -SH, -O-SOH, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, P(O)(OH) 2 , -C(O)-X204, -C(O)O-X205, -C(O)NH-X206, C(O)NX207X208, -O-X209, -O(-X21 O-O)c-H (c = 1, 2, 3, 4, 5), -O( 10 X211-O)d-X212 (d = 1, 2, 3, 4, 5), -OC(O)-X213, -OC(O)-O-X214, OC(O)-NHX215, -O-C(O)-NX216X217, -OP(O)(OX218)(OX219), OSi(X220)(X221)(X222), -OS(0 2 )-X223, -NHC(O)-NH 2 , -NHC(O) X224, -NX225C(O)-X226, -NH-C(O)-O-X227, -NH-C(O)-NH-X228, -NH-C(O)-NX229X230, -NX231-C(O)-O-X232, -NX233-C(O)-NH 15 X234, -NX235-C(O)-NX236X237, -NHS(O 2 )-X238, -NX239S(O 2 ) X240, -S-X241, -S(O)-X242, -S(O 2 )-X243, -S(O 2 )NH-X244, S(0 2 )NX245X246, -S(O 2 )O-X247, -P(O)(OX248)(OX249), Si(X250)(X251)(X252), -C(NH)-NH 2 , -C(NX253)-NH 2 , -C(NH) NHX254, -C(NH)-NX255X256, -C(NX257)-NHX258, -C(NX259) 20 NX260X261, -NH-C(O)-NH-O-X262, -NH-C(O)-NX263-O-X264, NX265-C(O)-NX266-0-X267, -N(-C(O)-NH-O-X268) 2 , -N(-C(O) NX269-O-X270) 2 , -N(-C(O)-NH-O-X271)(-C(O)-NX272-0-X273), C(S)-X274, -C(S)-O-X275, -C(S)-NH-X276, -C(S)-NX277X278, C(O)-NH-O-X279, -C(O)-NX280-0-X281, -C(S)-NH-O-X282, 25 C(S)-NX283-0-X284, -C(O)-NH-NH-X285, -C(O)-NH-NX286X287, -C(O)-NX288-NX289X290, -C(S)-NH-NH-X291, -C(S)-NH NX292X293, -C(S)-NX294-NX295X296, -C(O)-C(O)-O-X297, C(O)-C(O)-NH 2 , -C(O)-C(O)-NHX298, -C(O)-C(O)-NX299X300, C(S)-C(O)-O-X301, -C(O)-C(S)-O-X302, -C(S)-C(S)-O-X303, 30 C(S)-C(O)-NH 2 , -C(S)-C(O)-NHX304, -C(S)-C(O)-NX305X306, C(S)-C(S)-NH 2 , -C(S)-C(S)-NHX307, -C(S)-C(S)-NX308X309, C(O)-C(S)-NH 2 , -C(O)-C(S)-NHX31 0, -C(O)-C(S)-NX31 1 X312"; wherein X201, X202, X203, X204, X205, X206, X207, X208, X209, X210, X211, X212, X213, X214, X215, X216, X217, X218, X219, X220, 35 X221,X222,X223,X224,X225,X226,X227,X228,X229, X230,X231, WO 2008/132153 PCT/EP2008/055039 -188 X232,X233,X234,X235,X236,X237,X238,X239,X240, X241,X242, X243,X244,X245,X246,X247,X248,X249,X250,X251, X252,X253, X254,X255,X256,X257,X258,X259,X260,X261,X262, X263,X264, X265,X266,X267,X268,X269,X270,X271,X272,X273, X274,X275, 5 X276,X277,X278,X279,X280,X281,X282,X283,X284, X285,X286, X287,X288,X289,X290,X291,X292,X293,X294,X295, X296,X297, X298,X299,X300,X301,X302,X303,X304,X305,X306, X307,X308, X309, X31 0, X31 1, X312 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalky 10 lalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, het eroarylalkyl" and wherein alternatively X207, X208 and/or X216, X217 and/or X229, X230 and/or X236, X237 and/or X245, X246 and/or X255, X256 and/or X260, X261 and/or X277, X278 and/or X286, X287 and/or X289, X290 and/or X292, X293 and/or X295, X296 and/or X299, X300 15 and/or X305, X306 and/or X308, X309 and/or X31 1, X312 and/or re spectively together can also form ,heterocyclyl"; wherein optionally above substituents of substituents group (ii) can in turn independently from each other be substituted with at least one sub stituent, identical or different, selected from the group consisting of: 20 (iii) ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero cyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, -CF 3 , -N 3 , -NH 2 , -NHX401, -NX402X403, -NO 2 , -OH, =O, OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , SO 3 H, -P(O)(OH) 2 , -C(O)-X404, -C(O)O-X405, -C(O)NH-X406, 25 C(O)NX407X408, -O-X409, -0(-X41 0-0)e-H (e = 1, 2, 3, 4, 5), O(-X41 1-O)f-X412 (f = 1, 2, 3, 4, 5), -OC(O)-X413, -OC(O)-O X414, -OC(O)-NHX415, -O-C(O)-NX416X417, OP(O)(OX418)(OX419), -OSi(X420)(X421)(X422), -OS(O 2 )-X423, -NHC(O)-NH 2 , -NHC(O)-X424, -NX425C(O)-X426, -NH-C(O) 30 O-X427, -N H-C(O)-N H-X428, -N H-C(O)-NX429X430, -NX43 1 C(O)-O-X432, -NX433-C(O)-NH-X434, -NX435-C(O) NX436X437, -NHS(0 2 )-X438, -NX439S(0 2 )-X440, -S-X441, S(O)-X442, -S(0 2 )-X443, -S(0 2 )N H-X444, -S(0 2 )NX445X446, S(0 2 )O-X447, -P(O)(OX448)(OX449), -Si(X450)(X451)(X452), 35 C(NH)-NH 2 , -C(NX453)-NH 2 , -C(NH)-NHX454, -C(NH)- WO 2008/132153 PCT/EP2008/055039 -189 NX455X456, -C(NX457)-N HX458, -C(NX459)-NX460X461, -NH C(O)-N H-O-X462, -NH-C(O)-NX463-0-X464, -NX465-C(O) NX466-0-X467, -N(-C(O)-N H-O-X468) 2 , -N(-C(O)-NX469-0 X470) 2 , -N(-C(O)-N H-O-X471)(-C(O)-NX472-O-X473), -C(S) 5 X474, -C(S)-O-X475, -C(S)-NH-X476, -C(S)-NX477X478, C(O)-NH-O-X479, -C(O)-NX480-0-X481, -C(S)-NH-O-X482, C(S)-NX483-0-X484, -C(O)-NH-NH-X485, -C(O)-NH NX486X487, -C(O)-NX488-NX489X490, -C(S)-NH-NH-X491, C(S)-NH-NX492X493, -C(S)-NX494-NX495X496, -C(O)-C(O) 10 O-X497, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHX498, -C(O)-C(O) NX499X500, -C(S)-C(O)-O-X501, -C(O)-C(S)-O-X502, -C(S) C(S)-O-X503, -C(S)-C(O)-NH 2 , -C(S)-C(O)-NHX504, -C(S) C(O)-NX505X506, -C(S)-C(S)-NH 2 , -C(S)-C(S)-NHX507, -C(S) C(S)-NX508X509, -C(O)-C(S)-NH 2 , -C(O)-C(S)-NHX510, -C(O) 15 C(S)-NX51 1X512"; wherein X401, X402, X403, X404, X405, X406, X407, X408, X409, X410, X411, X412, X413, X414, X415, X416, X417, X418, X419, X420,X421,X422,X423,X424,X425,X426,X427,X428, X429, X430,X431,X432,X433,X434,X435,X436,X437,X438, X439, 20 X440,X441,X442,X443,X444,X445,X446,X447,X448, X449, X450,X451,X452,X453,X454,X455,X456,X457,X458, X459, X460,X461,X462,X463,X464,X465,X466,X467,X468, X469, X470,X471,X472,X473,X474,X475,X476,X477,X478, X479, X480,X481,X482,X483,X484,X485,X486,X487,X488, X489, 25 X490,X491,X492,X493,X494,X495,X496,X497,X498, X499, X500,X501,X502,X503,X504,X505,X506,X507,X508, X509, X510, X511, X512 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylal kyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, het 30 eroarylalkyl" and wherein alternatively X407, X408 and/or X416, X417 and/or X429, X430 and/or X436, X437 and/or X445, X446 and/or X455, X456 and/or X460, X461 and/or X477, X478 and/or X486, X487 and/or X489, X490 and/or X492, X493 and/or X495, X496 and/or X499, X500 and/or X505, X506 and/or X508, X509 WO 2008/132153 PCT/EP2008/055039 -190 and/or X51 1, X512 and/or respectively together can also form ,,het erocyclyl"; n independently is 0 or 1; with the first proviso that, if R1, R1 * are not present (n is 0), R2, R3 must not 5 both be "hydrogen" at the same time; with the second proviso that, if R1, R1 * are present (n is 1) and together inde pendently form "=0, =S or =S*-O-" or are independently both "hydrogen", R2, R3 must not both be "hydrogen" at the same time; with the third proviso that, if R1, R1 * are not present (n is 0), one of R2, R3 10 must not be "hydrogen" at the same time when the other one of R2, R3 is C(=NH)-NH 2 "; with the fourth proviso that, if R1, R1* are present (n is 1) and are independ ently both "hydrogen", one of R2, R3 must not be "hydrogen" at the same time when the other one of R2, R3 is "-C(=NH)-NH 2 "; 15 with the fifth proviso that, if R1, R1 * are present (n is 1) and together independ ently form "=O" and one of R2, R3 independently is "hydrogen" and the other one of R2, R3 independently is "alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl", then the other one of R2, R3 being "alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl" must be substituted with at least one substituent se 20 lected from the group consisting of: (iv) "heterocyclyl, heterocyclylalkyl, -CF3, -N 3 , -NH 2 , -NHX600, NX601X602, -NO 2 , -OH, -OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -SO 3 H, -P(O)(OH) 2 , -C(O)-X603, -C(O)O-X604, -C(O)NH X605, -C(O)NX606X607, -0-aryl, -0-arylalkyl, -0-heteroaryl, -0 25 heteroarylalkyl, -0-heterocyclyl, -0-heterocyclylalkyl, -O(-X608-O)g-H (g = 1, 2, 3, 4, 5), -O(-X609-O)h-X610 (h = 1, 2, 3, 4, 5), -OC(O)-X611, -OC(O)-O-X612, -OC(O)-NHX613, -O-C(O)-NX614X615, OP(O)(OX616)(OX617), -OSi(X618)(X619)(X620), -OS(0 2 )-X621, NHC(O)-X622, -NX623C(O)-X624, -NH-C(O)-O-X625, -NH-C(O) 30 NH-X626, -NH-C(O)-NX627X628, -NX629-C(O)-O-X630, -NX631 C(O)-NH-X632, -NX633-C(O)-NX634X635, -NHS(0 2 )-X636, NX637S(0 2 )-X638, -S-X639, -S(O)-X640, -S(0 2 )-X641, -S(0 2 )NH X642, -S(0 2 )NX643X644, -S(0 2 )O-X645, -P(O)(OX646)(OX647), - WO 2008/132153 PCT/EP2008/055039 -191 Si(X648)(X649)(X650), -C(NH)-NH 2 , -C(NX651)-NH 2 , -C(NH)-NHX652, -C(NH)-NX653X654, -C(NX655)-NHX656, -C(NX657)-NX658X659, N H-C(O)-N H-O-X660, -N H-C(O)-NX661 -O-X662, -NX663-C(O) NX664-0-X665, -N(-C(O)-NH-O-X666) 2 , -N(-C(O)-NX667-0-X668) 2 , 5 -N(-C(O)-NH-O-X669)(-C(O)-NX670-0-X671), -C(S)-X672, -C(S) O-X673, -C(S)-NH-X674, -C(S)-NX675X676, -C(O)-NH-O-X677, C(O)-NX678-0-X679, -C(S)-NH-O-X680, -C(S)-NX681-0-X682, C(O)-NH-NH-X683, -C(O)-NH-NX684X685, -C(O)-NX686 NX687X688, -C(S)-NH-NH-X689, -C(S)-NH-NX690X691, -C(S) 10 NX692-NX693X694, -C(O)-C(O)-O-X695, -C(O)-C(O)-NH 2 , -C(O) C(O)-NHX696, -C(O)-C(O)-NX697X698, -C(S)-C(O)-O-X699, -C(O) C(S)-O-X700, -C(S)-C(S)-O-X701, -C(S)-C(O)-NH 2 , -C(S)-C(O) NHX702, -C(S)-C(O)-NX703X704, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHX705, -C(S)-C(S)-NX706X707, -C(O)-C(S)-NH 2 , -C(O)-C(S) 15 NHX708, -C(O)-C(S)-NX709X71 0"; wherein X600, X601, X602, X603, X604, X605, X606, X607, X608, X609, X610, X611, X612, X613, X614, X615, X616, X617, X618, X619, X620, X621,X622,X623,X624, X625,X626,X627,X628, X629,X630,X631, X632,X633,X634,X635, X636,X637,X638,X639, X640,X641,X642, 20 X643,X644,X645,X646, X647,X648,X649,X650, X651,X652,X653, X654,X655,X656,X657, X658,X659,X660,X661, X662,X663,X664, X665,X666,X667,X668, X669,X670,X671,X672, X673,X674,X675, X676,X677,X678,X679, X680,X681,X682,X683, X684,X685,X686, X687,X688,X689,X690, X691,X692,X693,X694, X695,X696,X697, 25 X698,X699,X700,X701, X702,X703,X704,X705, X706,X707,X708, X709, X710, X711, X712 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively X606, X607 and/or X614, X615 and/or X627, 30 X628 and/or X634, X635 and/or X643, X644 and/or X653, X654 and/or X658, X659 and/or X675, X676 and/or X684, X685 and/or X687, X688 and/or X690, X691 and/or X693, X694 and/or X697, X698 and/or X703, X704 and/or X706, X707 and/or X709, X71 0 and/or respectively together can also form ,heterocyclyl"; WO 2008/132153 PCT/EP2008/055039 -192 with the further proviso that "-C(O)-N(alkyl) 2 , -C(O)-N(cycloalkyl) 2 , C(O)-N(cycloalkylalkyl) 2 , -C(O)-N(arylalkyl) 2 , -C(O)-N(aryl) 2 , -C(O) N(heteroaryl) 2 " are excluded from above substituents group (iv); wherein optionally the other one of R2, R3 being "alkyl, cycloalkyl, cycloalkylal 5 kyl, aryl, arylalkyl, heteroaryl" can in turn independently from each other be ad ditionally substituted with at least one substituent, identical or different, selected from above substituents group (ii); wherein optionally the other one of R2, R3 being "alkyl, cycloalkyl, cycloalkylal kyl, aryl, arylalkyl, heteroaryl" and being substituted with at least one substitu 10 ent, identical or different, selected from above substituents group (iv) and, op tionally, also (ii), can optionally be further substituted in their substituents se lected from above substituents group (iv) and, optionally, also (ii), with at least one substituent, identical or different, selected from above substituents group (iii); 15 with the sixth proviso that, if R1, R1* are present (n is 1) and together inde pendently form "=S or =S*-O" and R2, R3 are independently selected from the group consisting of "hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl", each of R2, R3 being "alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl" must be substituted with at least one substituent selected from the group consisting of: 20 (v) ,heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -CF3, -N 3 , NH 2 , -NHX800, -NX801X802, -NO 2 , -OH, -OCF 3 , -SH, -O-SO 3 H, OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, -P(O)(OH) 2 , -C(O) X803, -C(O)O-X804, -C(O)NH-X805, -C(O)NX806X807, -0-aryl, -0 arylalkyl, -0-heteroaryl, -0-heteroarylalkyl, -0-heterocyclyl, -0 25 heterocyclylalkyl, -O(-X808-0)i-H (i = 1, 2, 3, 4, 5), -O(-X809-O)j-X810 (j = 1, 2, 3, 4, 5), -OC(O)-X811, -OC(O)-O-X812, -OC(O)-NHX813, -0 C(O)-NX814X815, -OP(O)(OX816)(OX817), -OSi(X818)(X819)(X820), OS(0 2 )-X821, -NHC(O)-X822, -NX823C(O)-X824, -NH-C(O)-O-X825, NH-C(O)-NH-X826, -NH-C(O)-NX827X828, -NX829-C(O)-O-X830, 30 NX831-C(O)-NH-X832, -NX833-C(O)-NX834X835, -NHS(0 2 )-X836, NX837S(0 2 )-X838, -S-X839, -S(O)-X840, -S(0 2 )-X841, -S(0 2 )NH X842, -S(0 2 )NX843X844, -S(0 2 )O-X845, -P(O)(OX846)(OX847), Si(X848)(X849)(X850), -C(NH)-NH 2 , -C(NX851)-NH 2 , -C(NH)-NHX852, C(NH)-NX853X854, -C(NX855)-NHX856, -C(NX857)-NX858X859, -NH- WO 2008/132153 PCT/EP2008/055039 -193 C(O)-NH-O-X860, -NH-C(O)-NX861-0-X862, -NX863-C(O)-NX864 O-X865, -N(-C(O)-NH-O-X866) 2 , -N(-C(O)-NX867-0-X868) 2 , -N( C(O)-NH-O-X869)(-C(O)-NX870-0-X871), -C(S)-X872, -C(S)-O-X873, -C(S)-NH-X874, -C(S)-NX875X876, -C(O)-NH-O-X877, -C(O)-NX878 5 O-X879, -C(S)-NH-O-X880, -C(S)-NX881-0-X882, -C(O)-NH-NH X883, -C(O)-NH-NX884X885, -C(O)-NX886-NX887X888, -C(S)-NH NH-X889, -C(S)-NH-NX890X891, -C(S)-NX892-NX893X894, -C(O) C(O)-O-X895, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHX896, -C(O)-C(O) NX897X898, -C(S)-C(O)-O-X899, -C(O)-C(S)-O-X900, -C(S)-C(S)-O 10 X901, -C(S)-C(O)-NH 2 , -C(S)-C(O)-NHX902, -C(S)-C(O)-NX903X904, -C(S)-C(S)-NH 2 , -C(S)-C(S)-NHX905, -C(S)-C(S)-NX906X907, -C(O) C(S)-N H 2 , -C(O)-C(S)-N HX908, -C(O)-C(S)-NX909X91 0"; wherein X800, X801, X802, X803, X804, X805, X806, X807, X808, X809, X810, X811, X812, X813, X814, X815, X816, X817, X818, X819, X820, 15 X821,X822,X823,X824,X825,X826,X827,X828,X829, X830,X831, X832,X833,X834,X835,X836,X837,X838,X839,X840, X841,X842, X843,X844,X845,X846,X847,X848,X849,X850,X851, X852,X853, X854,X855,X856,X857,X858,X859,X860,X861,X862, X863,X864, X865,X866,X867,X868,X869,X870,X871,X872,X873, X874,X875, 20 X876,X877,X878,X879,X880,X881,X882,X883,X884, X885,X886, X887,X888,X889,X890,X891,X892,X893,X894,X895, X896,X897, X898,X899,X900,X901,X902,X903,X904,X905,X906, X907,X908, X909, X910, X911, X912 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, het 25 erocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively X806, X807 and/or X814, X815 and/or X827, X828 and/or X834, X835 and/or X843, X844 and/or X853, X854 and/or X858, X859 and/or X875, X876 and/or X884, X885 and/or X887, X888 and/or X890, X891 and/or X893, X894 and/or X897, X898 and/or X903, X904 30 and/or X906, X907 and/or X909, X910 and/or respectively together can also form ,heterocyclyl"; wherein optionally each of R2, R3 being "alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl" can in turn independently from each other be additionally substituted with at least one substituent, identical or different, selected from above sub 35 stituents group (ii); WO 2008/132153 PCT/EP2008/055039 -194 wherein optionally each of R2, R3 being "alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl" and being substituted with at least one substituent, identical or differ ent, selected from above substituents group (v) and, optionally, also (ii), can op tionally be further substituted in their substituents selected from above substitu 5 ents group (v) and, optionally, also (ii), with at least one substituent, identical or different, selected from above substituents group (iii); m independently is 1 or 2; R4m, R5m, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R1 9, R20, R21, R22 are independently from each other selected from the group 10 consisting of: (i) ,,hydrogen, alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, het erocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, CN, -CF 3 , -N 3 , -NH 2 , -NHX1 001, -NX1 002X1 003, -NO 2 , -OH, =O, OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, 15 P(O)(OH) 2 , -C(O)-X1004, -C(O)O-X1005, -C(O)NH-X1006, C(O)NX1 007X1 008, -O-X1 009, -O(-X1 01 0-O)k-H (k = 1, 2, 3, 4, 5), -O( X1011-O)i-X1012 (I = 1, 2, 3, 4, 5), -OC(O)-X1013, -OC(O)-O-X1014, OC(O)-NHX1 015, -O-C(O)-NX1016X1017, -OP(O)(OX1018)(OX1019), OSi(X1 020)(X1 021)(X1 022), -OS(O 2 )-X1 023, -NHC(O)-NH 2 , -NHC(O) 20 X1 024, -NX1 025C(O)-X1 026, -NH-C(O)-O-X1 027, -NH-C(O)-NH X1028, -NH-C(O)-NX1029X1030, -NX1031-C(O)-O-X1032, -NX1033 C(O)-NH-X1 034, -NX1 035-C(O)-NX1 036X1 037, -NHS(0 2 )-X1 038, NX1 039S(0 2 )-X1 040, -S-X1 041, -S(O)-X1 042, -S(0 2 )-X1 043, S(0 2 )NH-X1044, -S(0 2 )NX1045X1046, -S(0 2 )O-X1 047, 25 P(O)(OX1 048)(OX1 049), -Si(X1 050)(X1 051)(X1 052), -C(NH)-NH 2 , C(NX1 053)-NH 2 , -C(NH)-NHX1 054, -C(NH)-NX1 055X1 056, C(NX1 057)-NHX1 058, -C(NX1 059)-NX1 060X1 061, -NH-C(O)-NH-O X1 062, -NH-C(O)-NX1063-0-X1 064, -NX1065-C(O)-NX1066-0 X1 067, -N(-C(O)-NH-O-X1 068)2, -N(-C(O)-NX1 069-0-X1 070)2, -N( 30 C(O)-NH-O-X1 071)(-C(O)-NX1 072-0-X1 073), -C(S)-X1 074, -C(S)-O X1 075, -C(S)-NH-X1 076, -C(S)-NX1 077X1 078, -C(O)-NH-O-X1 079, C(O)-NX1 080-0-X1 081, -C(S)-NH-O-X1 082, -C(S)-NX1 083-0-X1 084, -C(O)-NH-NH-X1 085, -C(O)-NH-NX1 086X1 087, -C(O)-NX1 088 NX1 089X1 090, -C(S)-NH-NH-X1 091, -C(S)-NH-NX1 092X1 093, -C(S)- WO 2008/132153 PCT/EP2008/055039 -195 NX1 094-NX1 095X1 096, -C(O)-C(O)-O-X1 097, -C(O)-C(O)-NH 2 , -C(O) C(O)-NHX1 098, -C(O)-C(O)-NX1 099X1 100, -C(S)-C(O)-O-X1 101, C(O)-C(S)-O-X1 102, -C(S)-C(S)-O-X1 103, -C(S)-C(O)-NH 2 , -C(S) C(O)-NHX1 104, -C(S)-C(O)-NX 105X1 106, -C(S)-C(S)-NH 2 , -C(S) 5 C(S)-NHX1 107, -C(S)-C(S)-NX 108X1 109, -C(O)-C(S)-NH 2 , -C(O) C(S)-NHX1 110, -C(O)-C(S)-NX1 11 1X1i112"; wherein X1001, X1002, X1003, X1004, X1005, X1006, X1007, X1008, X1 009, X1 010, X1011, X1012, X1 013, X1014, X1015, X1 016, X1 017, X1018, X1019, X1020, X1021, X1022, X1023, X1024, X1025, X1026, 10 X1027,X1028,X1029,X1030,X1031,X1032, X1033,X1034,X1035, X1 036, X1 037, X1038, X1039, X1 040, X1041, X1042, X1 043, X1 044, X1045, X1046, X1047, X1048, X1049, X1050, X1051, X1052, X1053, X1054, X1055, X1056, X1057, X1058, X1059, X1060, X1061, X1062, X1 063, X1 064, X1065, X1066, X1 067, X1068, X1069, X1 070, X1 071, 15 X1072,X1073,X1074,X1075,X1076,X1077, X1078,X1079,X1080, X1081, X1082, X1083, X1084, X1085, X1086, X1087, X1088, X1089, X1090, X1091, X1092, X1093, X1094, X1095, X1096, X1097, X1098, X1099, X1100, X1101, X1102, X1103, X1104, X1105, X1106, X1107, X1 108, X1 109, X1 110, X1111, X1 112 are independently from each other 20 selected from the group consisting of: ,alkyl, (C 9 -C 3 o)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively X1 007, X1 008 and/or X1 016, X1017 and/or X1029, X1030 and/or X1036, X1037 and/or X1045, X1046 and/or X1 055, X1056 and/or X1 060, X1061 and/or X1077, X1078 and/or 25 X1086, X1087 and/or X1089, X1090 and/or X1092, X1093 and/or X1095, X1096 and/or X1099, X1100 and/or X1105, X1106 and/or X1108, X1109 and/or X1111, X1 112 and/or respectively together can also form ,heterocy clyl"; wherein optionally above substituents of substituents group (i) can in turn 30 independently from each other be substituted with at least one substituent, identical or different, selected from the group consisting of: (ii) ,alkyl, (C 9 -C 3 o)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycly lalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, CF 3 , -N 3 , -NH 2 , -NHX1201, -NX1202X1203, -NO 2 , -OH, =0, -OCF 3 , - WO 2008/132153 PCT/EP2008/055039 -196 SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, P(O)(OH) 2 , -C(O)-X1204, -C(O)O-X1205, -C(O)NH-X1206, C(O)NX1 207X1 208, -O-X1 209, -0(-X1 21 0-0)m-H (m = 1, 2, 3, 4, 5), -O(-X1 211-0),-X1 212 (n = 1, 2, 3, 4, 5), -OC(O)-X1 213, -OC(O)-O 5 X1214, -OC(O)-NHX1215, -O-C(O)-NX1216X1217, OP(O)(OX1 218)(OX1 219), -OSi(X1 220)(X1 221)(X1 222), -OS(0 2 ) Xl 223, -NHC(O)-NH 2 , -NHC(O)-X1 224, -NX1 225C(O)-X1 226, -NH C(O)-O-X1227, -NH-C(O)-NH-X1228, -NH-C(O)-NX1 229X1230, NX1231-C(O)-O-X1232, -NX1233-C(O)-NH-X1234, -NX1235-C(O) 10 NX1 236X1 237, -NHS(0 2 )-X1 238, -NX1 239S(0 2 )-X1 240, -S-X1241, S(O)-X1 242, -S(0 2 )-X1 243, -S(0 2 )NH-X1 244, -S(0 2 )NX1 245X1 246, -S(0 2 )0-X1 247, -P(O)(0X1 248)(0X1 249), -Si(X1 250)(X1 251)(X1 252), -C(NH)-NH 2 , -C(NX1 253)-N H 2 , -C(NH)-NHX1254, -C(N H) NX1255X1256, -C(NX1257)-NHX1258, -C(NX1259)-NX1260X1261, 15 NH-C(O)-NH-O-X1262, -NH-C(O)-NX1 263-0-X1264, -NX1265 C(O)-NX1 266-0-X1267, -N(-C(O)-N H-O-X1268)2, -N(-C(O) NX1 269-0-X1 270)2, -N(-C(O)-NH-O-X1 271)(-C(O)-NX1 272-0 Xl 273), -C(S)-X1 274, -C(S)-O-X1 275, -C(S)-NH-X1 276, -C(S) NX1 277X1 278, -C(O)-NH-O-X1 279, -C(O)-NX1 280-0-X1 281, 20 C(S)-NH-O-X1 282, -C(S)-NX1 283-0-X1 284, -C(O)-NH-NH-X1 285, -C(O)-NH-NX1 286X1287, -C(O)-NX1 288-NX1 289X1290, -C(S)-NH NH-X1 291, -C(S)-NH-NX1 292X1 293, -C(S)-NX1 294-NX1 295X1 296, -C(O)-C(O)-O-X1297, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHX1298, C(O)-C(O)-NX1 299X1 300, -C(S)-C(O)-O-X1 301, -C(O)-C(S)-O 25 Xl 302, -C(S)-C(S)-O-X1 303, -C(S)-C(O)-NH 2 , -C(S)-C(O) NHX1304, -C(S)-C(O)-NX1305X1306, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHX1307, -C(S)-C(S)-NX1308X1309, -C(O)-C(S)-NH 2 , -C(O)-C(S) NHX1 310, -C(O)-C(S)-NX1311X1312"; wherein X1201, X1202, X1203, X1204, X1205, X1206, X1207, X1208, 30 Xl 209, X1210, X1211, X1212, Xl 213, X1214, X1215, Xl 216, Xl 217, X1218, X1219, X1220, X1221, X1222, X1223, X1224, X1225, X1226, X1227, X1228, X1229, X1230, X1231, X1232, X1233, X1234, X1235, X1236, X1237, X1238, X1239, X1240, X1241, X1242, X1243, X1244, X1245, X1246, X1247, X1248, X1249, X1250, X1251, X1252, X1253, 35 X1254,X1255,X1256,X1257,X1258, X1259, X1260,X1261,X1262, WO 2008/132153 PCT/EP2008/055039 -197 X1263, X1264, X1265, X1266, X1267, X1268, X1269, X1270, X1271, X1272, X1273, X1274, X1275, X1276, X1277, X1278, X1279, X1280, X1281, X1282, X1283, X1284, X1285, X1286, X1287, X1288, X1289, X1290, X1291, X1292, X1293, X1294, X1295, X1296, X1297, X1298, 5 X1299,X1300,X1301,X1302,X1303, X1304, X1305,X1306,X1307, X1 308, X1 309, X1 310, X1 311, X1 312 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 30 )alkyl, cycloal kyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, het eroaryl, heteroarylalkyl" and wherein alternatively X1 207, X1 208 and/or 10 X1216, X1217 and/or X1229, X1230 and/or X1236, X1237 and/or X1245, X1246 and/or X1255, X1256 and/or X1260, X1261 and/or X1277, X1278 and/or X1286, X1287 and/or X1289, X1290 and/or X1292, X1293 and/or X1295, X1296 and/or X1299, X1300 and/or X1305, X1306 and/or X1308, X1309 and/or X1311, X1312 and/or re 15 spectively together can also form ,heterocyclyl"; wherein optionally above substituents of substituents group (ii) can in turn independently from each other be substituted with at least one sub stituent, identical or different, selected from the group consisting of: (iii) ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero 20 cyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, -CF 3 , -N 3 , -NH 2 , -NHX1401, -NX1402X1403, -NO 2 , -OH, =0, -OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, C(O)NH 2 , -SO 3 H, -P(O)(OH) 2 , -C(O)-X1 404, -C(O)O-X1 405, C(O)NH-X1406, -C(O)NX1407X1408, -O-X1409, -O(-X1410-O) 0 25 H (o = 1, 2, 3, 4, 5), -O(-X1411-O)p-X1412 (p = 1, 2, 3, 4, 5), OC(O)-X1413, -OC(O)-O-X1414, -OC(O)-NHX1415, -0-C(O) NX1416X1417, -OP(O)(OX1418)(OX1419), OSi(X1420)(X1421)(X1422), -OS(O 2 )-X1423, -NHC(O)-NH 2 , NHC(O)-Xl424, -NX1425C(O)-X1426, -NH-C(O)-O-Xl427, 30 NH-C(O)-NH-Xl428, -NH-C(O)-NX1429X1430, -NX1431-C(O) O-X1432, -NX1433-C(O)-NH-X1434, -NX1435-C(O) NX1 436X1 437, -NHS(0 2 )-Xl 438, -NX1 439S(0 2 )-Xl 440, -S X1441, -S(O)-X1442, -S(0 2 )-X1443, -S(0 2 )NH-X1444, S(0 2 )NX1445X1446, -S(0 2 )O-X1447, -P(O)(OX1448)(OX1449), 35 Si(X1450)(X1451)(X1452), -C(NH)-NH 2 , -C(NX1453)-NH 2 , - WO 2008/132153 PCT/EP2008/055039 -198 C(NH)-NHX1454, -C(NH)-NX1 455X1456, -C(NX1 457)-NHX1458, -C(NX1 459)-NX1 460X1461, -NH-C(O)-NH-O-X1462, -NH C(O)-NX1 463-0-X1 464, -NX1 465-C(O)-NX1 466-0-X1 467, -N( C(O)-N H-O-X1468)2, -N(-C(O)-NX1469-0-X1470)2, -N(-C(O) 5 NH-O-X1471)(-C(O)-NX1472-O-X1473), -C(S)-X1474, -C(S) O-X1475, -C(S)-NH-X1476, -C(S)-NX1477X1478, -C(O)-NH-O X1479, -C(O)-NX1480-0-X1481, -C(S)-NH-O-X1482, -C(S) NX1483-0-X1484, -C(O)-NH-NH-X1485, -C(O)-NH NX1486X1487, -C(O)-NX1488-NX1489X1490, -C(S)-NH-NH 10 X1491, -C(S)-NH-NX1492X1493, -C(S)-NX1494-NX1495X1496, -C(O)-C(O)-O-X1497, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHX1498, -C(O)-C(O)-NX1499X1500, -C(S)-C(O)-O-X1501, -C(O)-C(S) O-X1502, -C(S)-C(S)-O-X1503, -C(S)-C(O)-NH 2 , -C(S)-C(O) NHX1504, -C(S)-C(O)-NX1505X1506, -C(S)-C(S)-NH 2 , -C(S) 15 C(S)-NHX1507, -C(S)-C(S)-NX1508X1509, -C(O)-C(S)-NH 2 , C(O)-C(S)-NHX1510, -C(O)-C(S)-NX1511X1512"; wherein X1401, X1402, X1403, X1404, X1405, X1406, X1407, X1408, X1409, X1410, X1411, X1412, X1413, X1414, X1415, X1416, X1417, X1418, X1419, X1420, X1421, X1422, X1423, 20 X1424,X1425,X1426,X1427,X1428, X1429,X1430,X1431, X1432, X1433, X1434, X1435, X1436, X1437, X1438, X1439, X1440, X1441, X1442, X1443, X1444, X1445, X1446, X1447, X1448, X1449, X1450, X1451, X1452, X1453, X1454, X1455, X1456, X1457, X1458, X1459, X1460, X1461, X1462, X1463, 25 X1464, X1465, X1466, X1467, X1468, X1469, X1470, X1471, X1472, X1473, X1474, X1475, X1476, X1477, X1478, X1479, X1480, X1481, X1482, X1483, X1484, X1485, X1486, X1487, X1488, X1489, X1490, X1491, X1492, X1493, X1494, X1495, X1496, X1497, X1498, X1499, X1500, X1501, X1502, X1 503, 30 X1504,X1505,X1506,X1507,X1508, X1509,X1510,X1511, X1 512 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, hetero cyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively X1 407, X1 408 and/or X1 416, X1 417 35 and/or X1429, X1430 and/or X1436, X1437 and/or X1445, X1446 WO 2008/132153 PCT/EP2008/055039 -199 and/or X1455, X1456 and/or X1460, X1461 and/or X1477, X1478 and/or X1486, X1487 and/or X1489, X1490 and/or X1492, X1493 and/or X1495, X1496 and/or X1499, X1500 and/or X1505, X1506 and/or X1 508, X1 509 and/or X1 511, X1 512 and/or respectively to 5 gether can also form ,heterocyclyl"; or (B) V, W are independently from each other selected from the group consisting of: 10 "=O, =S, =S*-O-, geminally linked H 2 "; R1 *, R2 together independently form "heterocyclyl" or together independently form "heteroaryl"; where "heterocyclyl" and "heteroaryl" can optionally be substi tuted with at least one substituent selected from below substituents group (i); R1, R3 are independently from each other selected from the group consisting 15 of: (i) ,,hydrogen, alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, het erocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, CN, -CF 3 , -N 3 , -NH 2 , -NHZ1, -NZ2Z3, -NO 2 , -OH, =O, -OCF 3 , -SH, -0 SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, -P(O)(OH) 2 , 20 C(O)-Z4, -C(O)O-Z5, -C(O)NH-Z6, -C(O)NZ7Z8, -O-Z9, -O(-Z10-0)a H (a = 1, 2, 3, 4, 5), -O(-Z1 1-O)b-Zl2 (b = 1, 2, 3, 4, 5), -OC(O)-Z13, OC(O)-O-Z1 4, -OC(O)-NHZ1 5, -O-C(O)-NZ1 6Z1 7, OP(O)(OZ1 8)(OZ1 9), -OSi(Z20)(Z21)(Z22), -OS(0 2 )-Z23, -NHC(O)-NH 2 , -NHC(O)-Z24, -NZ25C(O)-Z26, -NH-C(O)-O-Z27, -NH-C(O)-NH-Z28, 25 -NH-C(O)-NZ29Z30, -NZ31-C(O)-O-Z32, -NZ33-C(O)-NH-Z34, NZ35-C(O)-NZ36Z37, -NHS(0 2 )-Z38, -NZ39S(0 2 )-Z40, -S-Z41, -S(O) Z42, -S(0 2 )-Z43, -S(0 2 )NH-Z44, -S(0 2 )NZ45Z46, -S(0 2 )O-Z47, P(O)(OZ48)(OZ49), -Si(Z50)(Z51)(Z52), -C(NH)-NH 2 , -C(NZ53)-NH 2 , C(NH)-NHZ54, -C(NH)-NZ55Z56, -C(NZ57)-NHZ58, -C(NZ59) 30 NZ60Z61, -NH-C(O)-NH-O-Z62, -NH-C(O)-NZ63-O-Z64, -NZ65 C(O)-NZ66-O-Z67, -N(-C(O)-NH-O-Z68) 2 , -N(-C(O)-NZ69-O-Z70) 2 , N(-C(O)-NH-O-Z71)(-C(O)-NZ72-O-Z73), -C(S)-Z74, -C(S)-O-Z75, C(S)-NH-Z76, -C(S)-NZ77Z78, -C(O)-NH-O-Z79, -C(O)-NZ80-O-Z81, WO 2008/132153 PCT/EP2008/055039 - 200 -C(S)-NH-O-Z82, -C(S)-NZ83-O-Z84, -C(O)-NH-NH-Z85, -C(O)-NH NZ86Z87, -C(O)-NZ88-NZ89Z90, -C(S)-NH-NH-Z91, -C(S)-NH NZ92Z93, -C(S)-NZ94-NZ95Z96, -C(O)-C(O)-O-Z97, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHZ98, -C(O)-C(O)-NZ99Z1 00, -C(S)-C(O)-O-Z1 01, 5 C(O)-C(S)-O-Z1 02, -C(S)-C(S)-O-Z1 03, -C(S)-C(O)-N H 2 , -C(S)-C(O) NHZ1 04, -C(S)-C(O)-NZ1 05Z1 06, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHZ1 07, -C(S)-C(S)-NZ1 08Z1 09, -C(O)-C(S)-NH 2 , -C(O)-C(S) NHZ1 10, -C(O)-C(S)-NZ1 11 Z1 12"; wherein Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z1 0, Z1 1, Z1 2, Z1 3, Z1 4, Z1 5, 10 Z16,Z17,Z18,Z19,Z20,Z21,Z22,Z23,Z24,Z25,Z26,Z27,Z28,Z29, Z30,Z31,Z32,Z33,Z34,Z35,Z36,Z37,Z38,Z39,Z40,Z41,Z42,Z43, Z44,Z45,Z46,Z47,Z48,Z49,Z50,Z51,Z52,Z53,Z54,Z55,Z56,Z57, Z58,Z59,Z60,Z61,Z62,Z63,Z64,Z65,Z66,Z67,Z68,Z69,Z70,Z71, Z72,Z73,Z74,Z75,Z76,Z77,Z78,Z79,Z80,Z81,Z82,Z83,Z84,Z85, 15 Z86,Z87,Z88,Z89,Z90,Z91,Z92,Z93,Z94,Z95,Z96,Z97,Z98,Z99, Z100,Z1Ol,Z102,Z103,Z104,Z1O5,Z106,Z107,Z108,Z109,Z110, Z1 11, Z1 12 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein al 20 ternatively Z7, Z8 and/or Z1 6, Z1 7 and/or Z29, Z30 and/or Z36, Z37 and/or Z45, Z46 and/or Z55, Z56 and/or Z60, Z61 and/or Z77, Z78 and/or Z86, Z87 and/or Z89, Z90 and/or Z92, Z93 and/or Z95, Z96 and/or Z99, Z1 00 and/or Z1 05, Z1 06 and/or Z1 08, Z1 09 and/or Z1 11, Z1 12 and/or respectively to gether can also form ,heterocyclyl"; 25 wherein optionally above substituents of substituents group (i) can in turn independently from each other be substituted with at least one substituent, identical or different, selected from the group consisting of: (ii) ,alkyl, (C 9 -Co)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycly lalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, 30 CF 3 , -N 3 , -NH 2 , -NHZ201, -NZ202Z203, -NO 2 , -OH, =O, -OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -S0 3 H, P(O)(OH) 2 , -C(O)-Z204, -C(O)O-Z205, -C(O)NH-Z206, C(O)NZ207Z208, -O-Z209, -O(-Z21 0-O)c-H (c = 1, 2, 3, 4, 5), -O( Z21 1 -O)d-Z212 (d = 1, 2, 3, 4, 5), -OC(O)-Z213, -OC(O)-O-Z214, - WO 2008/132153 PCT/EP2008/055039 - 201 OC(O)-NHZ215, -O-C(O)-NZ216Z217, -OP(O)(OZ218)(OZ219), OSi(Z220)(Z221)(Z222), -OS(0 2 )-Z223, -NHC(O)-NH 2 , -NHC(O) Z224, -NZ225C(O)-Z226, -NH-C(O)-O-Z227, -NH-C(O)-NH-Z228, NH-C(O)-NZ229Z230, -NZ231-C(O)-O-Z232, -NZ233-C(O)-NH 5 Z234, -NZ235-C(O)-NZ236Z237, -NHS(0 2 )-Z238, -NZ239S(0 2 ) Z240, -S-Z241, -S(O)-Z242, -S(0 2 )-Z243, -S(0 2 )NH-Z244, S(0 2 )NZ245Z246, -S(0 2 )O-Z247, -P(O)(OZ248)(OZ249), Si(Z250)(Z251)(Z252), -C(NH)-NH 2 , -C(NZ253)-NH 2 , -C(NH) NHZ254, -C(NH)-NZ255Z256, -C(NZ257)-NHZ258, -C(NZ259) 10 NZ260Z261, -NH-C(O)-NH-O-Z262, -NH-C(O)-NZ263-O-Z264, NZ265-C(O)-NZ266-O-Z267, -N(-C(O)-NH-O-Z268) 2 , -N(-C(O) NZ269-O-Z270) 2 , -N(-C(O)-NH-O-Z271)(-C(O)-NZ272-O-Z273), C(S)-Z274, -C(S)-O-Z275, -C(S)-NH-Z276, -C(S)-NZ277Z278, C(O)-NH-O-Z279, -C(O)-NZ280-O-Z281, -C(S)-NH-O-Z282, 15 C(S)-NZ283-O-Z284, -C(O)-NH-NH-Z285, -C(O)-NH-NZ286Z287, -C(O)-NZ288-NZ289Z290, -C(S)-NH-NH-Z291, -C(S)-NH NZ292Z293, -C(S)-NZ294-NZ295Z296, -C(O)-C(O)-O-Z297, -C(O) C(O)-NH 2 , -C(O)-C(O)-NHZ298, -C(O)-C(O)-NZ299Z300, -C(S) C(O)-O-Z301, -C(O)-C(S)-O-Z302, -C(S)-C(S)-O-Z303, -C(S) 20 C(O)-NH 2 , -C(S)-C(O)-NHZ304, -C(S)-C(O)-NZ305Z306, -C(S) C(S)-NH 2 , -C(S)-C(S)-NHZ307, -C(S)-C(S)-NZ308Z309, -C(O) C(S)-N H 2 , -C(O)-C(S)-N HZ31 0, -C(O)-C(S)-NZ31 1 Z312"; wherein Z201, Z202, Z203, Z204, Z205, Z206, Z207, Z208, Z209, Z210, Z211,Z212,Z213,Z214,Z215,Z216,Z217,Z218,Z219,Z220,Z221, 25 Z222,Z223,Z224,Z225,Z226,Z227,Z228,Z229,Z230,Z231,Z232, Z233,Z234,Z235,Z236,Z237,Z238,Z239,Z240,Z241,Z242,Z243, Z244,Z245,Z246,Z247,Z248,Z249,Z250,Z251,Z252,Z253,Z254, Z255,Z256,Z257,Z258,Z259,Z260,Z261,Z262,Z263,Z264,Z265, Z266,Z267,Z268,Z269,Z270,Z271,Z272,Z273,Z274,Z275,Z276, 30 Z277,Z278,Z279,Z280,Z281,Z282,Z283,Z284,Z285,Z286,Z287, Z288,Z289,Z290,Z291,Z292,Z293,Z294,Z295,Z296,Z297,Z298, Z299,Z300,Z301,Z302,Z303,Z304,Z305,Z306,Z307,Z308,Z309, Z31 0, Z31 1, Z312 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 3 o)alkyl, cycloalkyl, cycloalkylalkyl, het 35 erocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" WO 2008/132153 PCT/EP2008/055039 - 202 and wherein alternatively Z207, Z208 and/or Z216, Z217 and/or Z229, Z230 and/or Z236, Z237 and/or Z245, Z246 and/or Z255, Z256 and/or Z260, Z261 and/or Z277, Z278 and/or Z286, Z287 and/or Z289, Z290 and/or Z292, Z293 and/or Z295, Z296 and/or Z299, Z300 and/or Z305, 5 Z306 and/or Z308, Z309 and/or Z31 1, Z312 and/or respectively together can also form ,heterocyclyl"; wherein optionally above substituents of substituents group (ii) can in turn independently from each other be substituted with at least one sub stituent, identical or different, selected from the group consisting of: 10 (iii) ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero cyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, -CF 3 , -N 3 , -NH 2 , -NHZ401, -NZ402Z403, -NO 2 , -OH, =O, OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , SO 3 H, -P(O)(OH) 2 , -C(O)-Z404, -C(O)O-Z405, -C(O)NH-Z406, 15 C(O)NZ407Z408, -O-Z409, -0(-Z410-0)e-H (e = 1, 2, 3, 4, 5), O(-Z41 1-O)f-Z412 (f = 1, 2, 3, 4, 5), -OC(O)-Z413, -OC(O)-O Z414, -OC(O)-NHZ415, -O-C(O)-NZ416Z417, OP(O)(OZ418)(OZ419), -OSi(Z420)(Z421)(Z422), -OS(0 2 )-Z423, NHC(O)-NH 2 , -NHC(O)-Z424, -NZ425C(O)-Z426, -NH-C(O)-O 20 Z427, -NH-C(O)-NH-Z428, -NH-C(O)-NZ429Z430, -NZ431 C(O)-O-Z432, -NZ433-C(O)-NH-Z434, -NZ435-C(O) NZ436Z437, -NHS(0 2 )-Z438, -NZ439S(0 2 )-Z440, -S-Z441, S(O)-Z442, -S(0 2 )-Z443, -S(0 2 )NH-Z444, -S(0 2 )NZ445Z446, S(0 2 )O-Z447, -P(O)(OZ448)(OZ449), -Si(Z450)(Z451)(Z452), 25 C(NH)-NH 2 , -C(NZ453)-NH 2 , -C(NH)-NHZ454, -C(NH) NZ455Z456, -C(NZ457)-NHZ458, -C(NZ459)-NZ460Z461, -NH C(O)-NH-O-Z462, -NH-C(O)-NZ463-O-Z464, -NZ465-C(O) NZ466-O-Z467, -N(-C(O)-NH-O-Z468) 2 , -N(-C(O)-NZ469-0 Z470) 2 , -N(-C(O)-N H-O-Z471)(-C(O)-NZ472-O-Z473), -C(S) 30 Z474, -C(S)-O-Z475, -C(S)-NH-Z476, -C(S)-NZ477Z478, -C(O) NH-O-Z479, -C(O)-NZ480-O-Z481, -C(S)-NH-O-Z482, -C(S) NZ483-O-Z484, -C(O)-NH-NH-Z485, -C(O)-NH-NZ486Z487, C(O)-NZ488-NZ489Z490, -C(S)-NH-NH-Z491, -C(S)-NH NZ492Z493, -C(S)-NZ494-NZ495Z496, -C(O)-C(O)-O-Z497, 35 C(O)-C(O)-NH 2 , -C(O)-C(O)-NHZ498, -C(O)-C(O)-NZ499Z500, WO 2008/132153 PCT/EP2008/055039 - 203 -C(S)-C(O)-O-Z501, -C(O)-C(S)-O-Z502, -C(S)-C(S)-O-Z503, -C(S)-C(O)-NH 2 , -C(S)-C(O)-NHZ504, -C(S)-C(O)-NZ505Z506, -C(S)-C(S)-NH 2 , -C(S)-C(S)-NHZ507, -C(S)-C(S)-NZ508Z509, C(O)-C(S)-NH 2 , -C(O)-C(S)-NHZ51 0, -C(O)-C(S)-NZ51 1 Z512"; 5 wherein Z401, Z402, Z403, Z404, Z405, Z406, Z407, Z408, Z409, Z410, Z411, Z412, Z413, Z414, Z415, Z416, Z417, Z418, Z419, Z420,Z421,Z422,Z423,Z424,Z425,Z426,Z427,Z428,Z429, Z430,Z431,Z432,Z433,Z434,Z435,Z436,Z437,Z438,Z439, Z440,Z441,Z442,Z443,Z444,Z445,Z446,Z447,Z448,Z449, 10 Z450,Z451,Z452,Z453,Z454,Z455,Z456,Z457,Z458,Z459, Z460,Z461,Z462,Z463,Z464,Z465,Z466,Z467,Z468,Z469, Z470,Z471,Z472,Z473,Z474,Z475,Z476,Z477,Z478,Z479, Z480,Z481,Z482,Z483,Z484,Z485,Z486,Z487,Z488,Z489, Z490,Z491,Z492,Z493,Z494,Z495,Z496,Z497,Z498,Z499, 15 Z500,Z501,Z502,Z503,Z504,Z505,Z506,Z507,Z508,Z509, Z51 0, Z51 1, Z512 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylal kyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, het eroarylalkyl" and wherein alternatively Z407, Z408 and/or Z416, 20 Z417 and/or Z429, Z430 and/or Z436, Z437 and/or Z445, Z446 and/or Z455, Z456 and/or Z460, Z461 and/or Z477, Z478 and/or Z486, Z487 and/or Z489, Z490 and/or Z492, Z493 and/or Z495, Z496 and/or Z499, Z500 and/or Z505, Z506 and/or Z508, Z509 and/or Z51 1, Z512 and/or respectively together can also form ,,het 25 erocyclyl"; alternatively, R1, R3 can also independently from each other be "no substitu ent"; n independently is 1; m independently is 1 or 2; 30 R4m, R5m, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R1 9, R20, R21, R22 are independently from each other selected from the group consisting of: WO 2008/132153 PCT/EP2008/055039 - 204 (i) ,,hydrogen, alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, het erocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -CI, -Br, -1, CN, -CF 3 , -N 3 , -NH 2 , -NHZ1 001, -NZ1 002Z1 003, -NO 2 , -OH, =O, -OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, 5 P(O)(OH) 2 , -C(O)-Z1 004, -C(O)O-Z1 005, -C(O)NH-Z1 006, C(O)NZ1 007Z1 008, -O-Z1 009, -O(-Z1 01 0-O)k-H (k = 1, 2, 3, 4, 5), -O( Zi 011-O)i-Z1012 (I = 1, 2, 3, 4, 5), -OC(O)-Z1013, -OC(O)-O-Z1014, OC(O)-NHZ1 015, -O-C(O)-NZ1 01 6Z1 017, -OP(O)(OZ1 01 8)(OZ1 019), OSi(Z1 020)(Z1 021)(Z1 022), -OS(0 2 )-Z1 023, -NHC(O)-NH 2 , -NHC(O) 10 Z1 024, -NZ1 025C(O)-Z1 026, -NH-C(O)-O-Z1 027, -NH-C(O)-NH Z1 028, -NH-C(O)-NZ1 029Z1 030, -NZ1 031 -C(O)-O-Z1 032, -NZ1 033 C(O)-N H-Z1 034, -NZ1 035-C(O)-NZ1 036Z1 037, -NHS(0 2 )-Z1 038, NZ1 039S(0 2 )-Z1 040, -S-Z1 041, -S(O)-Z1 042, -S(0 2 )-Z1 043, S(0 2 )NH-Z1044, -S(0 2 )NZ1045Z1046, -S(0 2 )O-Z1047, 15 P(O)(OZ1 048)(OZ1 049), -Si(Z1 050)(Z1 051)(Z1 052), -C(NH)-NH 2 , C(NZ1 053)-NH 2 , -C(NH)-NHZ1 054, -C(NH)-NZ1 055Z1 056, -C(NZ1 057) NHZ1 058, -C(NZ1 059)-NZ1 060Z1 061, -NH-C(O)-NH-O-Z1 062, -NH C(O)-NZ1 063-0-Z1 064, -NZ1 065-C(O)-NZ1 066-0-Z1 067, -N(-C(O) NH-O-Z1068)2, -N(-C(O)-NZ1069-0-Z1070)2, -N(-C(O)-NH-O 20 Z1 071)(-C(O)-NZ1 072-0-Z1 073), -C(S)-Z1 074, -C(S)-O-Z1 075, -C(S) NH-Z1 076, -C(S)-NZ1 077Z1 078, -C(O)-NH-O-Z1 079, -C(O)-NZ1 080 0-Z1 081, -C(S)-NH-O-Z1 082, -C(S)-NZ1 083-0-Z1 084, -C(O)-NH NH-Z1 085, -C(O)-NH-NZ1 086Z1 087, -C(O)-NZ1 088-NZ1 089Z1 090, C(S)-NH-NH-Z1 091, -C(S)-NH-NZ1 092Z1 093, -C(S)-NZ1 094 25 NZ1095Z1096, -C(O)-C(O)-O-Z1097, -C(O)-C(O)-NH 2 , -C(O)-C(O) NHZ1 098, -C(O)-C(O)-NZ1 099Z1 100, -C(S)-C(O)-O-Z1 101, -C(O) C(S)-O-Z1 102, -C(S)-C(S)-O-Z1 103, -C(S)-C(O)-NH 2 , -C(S)-C(O) NHZ1 104, -C(S)-C(O)-NZ1 105Z1 106, -C(S)-C(S)-NH 2 , -C(S)-C(S) NHZ1 107, -C(S)-C(S)-NZ1 108Z1 109, -C(O)-C(S)-NH 2 , -C(O)-C(S) 30 NHZ1 110, -C(O)-C(S)-NZ1111 Zl 112"; wherein X1001, X1002, X1003, X1004, X1005, X1006, X1007, X1008, Xl 009, Xl 010, X1011, X1012, Xl 013, X1014, X1015, Xl 016, Xl 017, X1018, X1019, X1020, X1021, X1022, X1023, X1024, X1025, X1026, X1027, X1028, X1029, X1030, X1031, X1032, X1033, X1034, X1035, 35 X1036,X1037,X1038,X1039,X1040,X1041, X1042,X1043,X1044, WO 2008/132153 PCT/EP2008/055039 - 205 X1045, X1046, X1047, X1048, X1049, X1050, X1051, X1052, X1053, X1054, X1055, X1056, X1057, X1058, X1059, X1060, X1061, X1062, X1 063, X1 064, X1065, X1066, X1 067, X1068, X1069, X1 070, X1 071, X1072, X1073, X1074, X1075, X1076, X1077, X1078, X1079, X1080, 5 X1081,X1082,X1083,X1084,X1085,X1086, X1087,X1088,X1089, X1090, X1091, X1092, X1093, X1094, X1095, X1096, X1097, X1098, X1099, X1100, X1101, X1102, X1103, X1104, X1105, X1106, X1107, X1108, X1109, X1110, X1111, X1112 are independently from each other selected from the group consisting of: ,alkyl, (C 9 -Co)alkyl, cycloalkyl, 10 cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively X1 007, X1 008 and/or X1 016, X1017 and/or X1029, X1030 and/or X1036, X1037 and/or X1045, X1046 and/or X1 055, X1056 and/or X1 060, X1061 and/or X1077, X1078 and/or X1086, X1087 and/or X1089, X1090 and/or X1092, X1093 and/or X1095, 15 X1096 and/or X1099, X1100 and/or X1105, X1106 and/or X1108, X1109 and/or X1111, X1 112 and/or respectively together can also form ,heterocy clyl"; wherein optionally above substituents of substituents group (i) can in turn independently from each other be substituted with at least one substituent, 20 identical or different, selected from the group consisting of: (ii) ,alkyl, (C 9 -Co)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycly lalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, CF 3 , -N 3 , -NH 2 , -NHZ1 201, -NZ1 202Z1 203, -NO 2 , -OH, =O, -OCF 3 , SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, -C(O)NH 2 , -SO 3 H, 25 P(O)(OH) 2 , -C(O)-Z1 204, -C(O)O-Z1 205, -C(O)NH-Z1 206, C(O)NZ1 207Z1 208, -O-Z1 209, -0(-Z1210-0)m-H (m = 1, 2, 3, 4, 5), O(-Z1211-0)-Z1212 (n = 1, 2, 3, 4, 5), -OC(O)-Z1 213, -OC(O)-O Z1214, -OC(O)-NHZ1215, -O-C(O)-NZ1216Z1217, OP(O)(OZ1 218)(OZ1 219), -OSi(Z1 220)(Z1 221)(Z1 222), -OS(0 2 ) 30 Z1 223, -NHC(O)-NH 2 , -NHC(O)-Z1 224, -NZ1 225C(O)-Z1 226, -NH C(O)-O-Z1 227, -NH-C(O)-NH-Z1 228, -NH-C(O)-NZ1 229Z1 230, NZ1 231 -C(O)-O-Z1 232, -NZ1 233-C(O)-N H-Z1 234, -NZ1 235-C(O) NZ1 236Z1 237, -NHS(0 2 )-Z1 238, -NZ1 239S(0 2 )-Z1 240, -S-Z1 241, S(O)-Z1242, -S(0 2 )-Z1243, -S(0 2 )NH-Z1244, -S(0 2 )NZ1245Z1246, 35 S(0 2 )O-Z1 247, -P(O)(OZ1 248)(OZ1 249), -Si(Z1 250)(Z1 251)(Z1 252), - WO 2008/132153 PCT/EP2008/055039 - 206 C(NH)-NH 2 , -C(NZ1 253)-NH 2 , -C(NH)-NHZ1 254, -C(NH) NZ1 255Z1 256, -C(NZ1 257)-NHZ1 258, -C(NZ1 259)-NZ1 260Z1 261, NH-C(O)-NH-O-Z1 262, -NH-C(O)-NZ1 263-0-Z1 264, -NZ1 265 C(O)-NZ1266-0-Z1267, -N(-C(O)-NH-O-Z1268)2, -N(-C(O) 5 NZ1 269-0-Z1 270)2, -N(-C(O)-NH-O-Z1 271)(-C(O)-NZ1 272-0 Z1 273), -C(S)-Z1 274, -C(S)-O-Z1 275, -C(S)-NH-Z1 276, -C(S) NZ1 277Z1 278, -C(O)-NH-O-Z1 279, -C(O)-NZ1 280-0-Z1 281, C(S)-NH-O-Z1 282, -C(S)-NZ1 283-0-Z1 284, -C(O)-NH-NH-Z1 285, -C(O)-N H-NZ1 286Z1 287, -C(O)-NZ1 288-NZ1 289Z1 290, -C(S)-N H 10 NH-Z1 291, -C(S)-NH-NZ1 292Z1 293, -C(S)-NZ1 294-NZ1 295Z1 296, -C(O)-C(O)-O-Z1 297, -C(O)-C(O)-N H 2 , -C(O)-C(O)-N HZ1 298, C(O)-C(O)-NZ1 299Z1 300, -C(S)-C(O)-O-Z1 301, -C(O)-C(S)-O Z1 302, -C(S)-C(S)-O-Z1 303, -C(S)-C(O)-N H 2 , -C(S)-C(O) NHZ1 304, -C(S)-C(O)-NZ1 305Z1 306, -C(S)-C(S)-NH 2 , -C(S)-C(S) 15 NHZ1 307, -C(S)-C(S)-NZ1 308Z1 309, -C(O)-C(S)-NH 2 , -C(O)-C(S) NHZ1 310, -C(O)-C(S)-NZ1311Z1312"; wherein Z1 201, Z1 202, Z1 203, Z1 204, Z1 205, Z1 206, Z1 207, Z1 208, Z1209,Z1210,Z1211,Z1212,Z1213,Z1214,Z1215,Z1216,Z1217, Z1218,Z1219,Z1220,Z1221,Z1222,Z1223,Z1224,Z1225,Z1226, 20 Z1227,Z1228,Z1229,Z1230,Z1231,Z1232,Z1233,Z1234,Z1235, Z1236,Z1237,Z1238,Z1239,Z1240,Z1241,Z1242,Z1243,Z1244, Z1245,Z1246,Z1247,Z1248,Z1249,Z1250,Z1251,Z1252,Z1253, Z1254,Z1255,Z1256,Z1257,Z1258,Z1259,Z1260,Z1261,Z1262, Z1263,Z1264,Z1265,Z1266,Z1267,Z1268,Z1269,Z1270,Z1271, 25 Z1272,Z1273,Z1274,Z1275,Z1276,Z1277,Z1278,Z1279,Z1280, Z1281,Z1282,Z1283,Z1284,Z1285,Z1286,Z1287,Z1288,Z1289, Z1290,Z1291,Z1292,Z1293,Z1294,Z1295,Z1296,Z1297,Z1298, Z1299,Z1300,Z1301,Z1302,Z1303,Z1304,Z1305,Z1306,Z1307, Z1308, Z1309, Z1310, Z1311, Z1312 are independently from each other 30 selected from the group consisting of: ,alkyl, (C 9 -C 3 o)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively Z1 207, Z1 208 and/or Z1 216, Z1 217 and/or Z1 229, Z1 230 and/or Z1 236, Z1 237 and/or Z1 245, Z1 246 and/or Z1 255, Z1 256 and/or Z1 260, Z1 261 and/or Z1 277, Z1 278 and/or 35 Z1 286, Z1 287 and/or Z1 289, Z1 290 and/or Z1 292, Z1 293 and/or Z1 295, WO 2008/132153 PCT/EP2008/055039 - 207 Z1 296 and/or Z1 299, Z1 300 and/or Z1 305, Z1 306 and/or Z1 308, Z1 309 and/or Z1 311, Z1 312 and/or respectively together can also form ,,het erocyclyl"; wherein optionally above substituents of substituents group (ii) can in 5 turn independently from each other be substituted with at least one sub stituent, identical or different, selected from the group consisting of: (iii) ,alkyl, (C 9 -C 30 )alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, hetero cyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, -F, -Cl, -Br, -1, -CN, -CF 3 , -N 3 , -NH 2 , -NHZ1401, -NZ1402Z1403, -NO 2 , -OH, 10 =0, -OCF 3 , -SH, -O-SO 3 H, -OP(O)(OH) 2 , -CHO, -COOH, C(O)NH 2 , -SO 3 H, -P(O)(OH) 2 , -C(O)-Z1 404, -C(O)O-Z1 405, C(O)NH-Z1 406, -C(O)NZ1 407Z1 408, -O-Z1 409, -O(-Z1 410-0)o H (o = 1, 2, 3, 4, 5), -O(-Z141 1-O)p-Z1412 (p = 1, 2, 3, 4, 5), OC(O)-Z1413, -OC(O)-O-Z1414, -OC(O)-NHZ1415, -0-C(O) 15 NZ1416Z1417, -OP(O)(OZ1418)(OZ1419), OSi(Z1420)(Z1421)(Z1422), -OS(0 2 )-Z1423, -NHC(O)-NH 2 , NHC(O)-Z1424, -NZ1425C(O)-Z1426, -NH-C(O)-O-Z1427, -NH C(O)-NH-Z1 428, -NH-C(O)-NZ1 429Z1 430, -NZ1 431 -C(O)-O Z1 432, -NZ1 433-C(O)-NH-Z1 434, -NZ1 435-C(O)-NZ1 436Z1 437, 20 -NHS(0 2 )-Z1438, -NZ1439S(O 2 )-Z1440, -S-Z1441, -S(O)-Z1442, -S(0 2 )-Z1 443, -S(0 2 )NH-Z1 444, -S(0 2 )NZ1 445Z1 446, -S(0 2 )O Z1447, -P(O)(OZ1448)(OZ1449), -Si(Z1450)(Z1451)(Z1452), C(NH)-NH 2 , -C(NZ1453)-NH 2 , -C(NH)-NHZ1454, -C(NH) NZ1 455Z1 456, -C(NZ1 457)-NHZ1 458, -C(NZ1 459) 25 NZ1460Z1461, -NH-C(O)-NH-O-Z1462, -NH-C(O)-NZ1463-0 Z1 464, -NZ1 465-C(O)-NZ1 466-0-Z1 467, -N(-C(O)-NH-O Z1468)2, -N(-C(O)-NZ1469-0-Z1470)2, -N(-C(O)-NH-O Z1 471)(-C(O)-NZ1 472-0-Z1 473), -C(S)-Z1 474, -C(S)-O-Z1 475, -C(S)-NH-Z1476, -C(S)-NZ1477Z1478, -C(O)-NH-O-Z1479, 30 C(O)-NZ1 480-0-Z1 481, -C(S)-NH-O-Z1 482, -C(S)-NZ1 483-0 Z1484, -C(O)-NH-NH-Z1485, -C(O)-NH-NZ1486Z1487, -C(O) NZ1488-NZ1489Z1490, -C(S)-NH-NH-Z1491, -C(S)-NH NZ1 492Z1 493, -C(S)-NZ1 494-NZ1 495Z1 496, -C(O)-C(O)-O Z1497, -C(O)-C(O)-NH 2 , -C(O)-C(O)-NHZ1498, -C(0)-C(0) 35 NZ1 499Z1 500, -C(S)-C(O)-O-Z1 501, -C(O)-C(S)-O-Z1 502, - WO 2008/132153 PCT/EP2008/055039 - 208 C(S)-C(S)-O-Z1503, -C(S)-C(O)-NH 2 , -C(S)-C(O)-NHZ1504, C(S)-C(O)-NZ1 505Z1 506, -C(S)-C(S)-N H 2 , -C(S)-C(S) NHZ1 507, -C(S)-C(S)-NZ1 508Z1 509, -C(O)-C(S)-NH 2 , -C(O) C(S)-NHZ1510, -C(O)-C(S)-NZ151 1Z1512"; 5 wherein Z1401, Z1402, Z1403, Z1404, Z1405, Z1406, Z1407, Z1408, Z1409, Z1410, Z1411, Z1412, Z1413, Z1414, Z1415, Z1416, Z1417, Z1418, Z1419, Z1420, Z1421, Z1422, Z1423, Z1424, Z1425, Z1426,Z1427,Z1428,Z1429,Z1430,Z1431,Z1432,Z1433,Z1434, Z1435,Z1436,Z1437,Z1438,Z1439,Z1440,Z1441,Z1442,Z1443, 10 Z1444,Z1445,Z1446,Z1447,Z1448,Z1449,Z1450,Z1451,Z1452, Z1453,Z1454,Z1455,Z1456,Z1457,Z1458,Z1459,Z1460,Z1461, Z1462,Z1463,Z1464,Z1465,Z1466,Z1467,Z1468,Z1469,Z1470, Z1471,Z1472,Z1473,Z1474,Z1475,Z1476,Z1477,Z1478,Z1479, Z1480,Z1481,Z1482,Z1483,Z1484,Z1485,Z1486,Z1487,Z1488, 15 Z1489,Z1490,Z1491,Z1492,Z1493,Z1494,Z1495,Z1496,Z1497, Z1498,Z1499,Z1500,Z15Ol,Z1502,Z1503,Z1504,Z15O5,Z1506, Z1 507, Z1 508, Z1 509, Z1 510, Z1 511, Z1 512 are independently from each other selected from the group consisting of: ,alkyl, (Ce C 3 o)alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, 20 aryl, arylalkyl, heteroaryl, heteroarylalkyl" and wherein alternatively Z1 407, Z1 408 and/or Z1 416, Z1 417 and/or Z1 429, Z1 430 and/or Z1436, Z1437 and/or Z1445, Z1446 and/or Z1455, Z1456 and/or Z1460, Z1461 and/or Z1477, Z1478 and/or Z1486, Z1487 and/or Z1489, Z1490 and/or Z1492, Z1493 and/or Z1495, Z1496 and/or 25 Z1 499, Z1 500 and/or Z1 505, Z1 506 and/or Z1 508, Z1 509 and/or Z1 511, Z1 512 and/or respectively together can also form ,heterocy clyl".
[2] 2. Tetrahydrocarbazole derivative according to formula (1) as claimed in claim 1, 30 where according to (A) V, W are independently "=O"; R1, R1 * together independently form "=O or =S" or are independently both "hydro gen"; WO 2008/132153 PCT/EP2008/055039 - 209 n is 1; m is 1 or 2; R2 is independently selected from the group consisting of: "-NH 2 , -NH-aryl, -CO heterocyclyl, -CO-heterocyclylalkyl, -CO-heteroarylalkyl, -CO-NH 5 heterocyclylalkyl, -NH-CO-alkyl, -NH-CO-aryl, -NH-CO-NH 2 , alkyl, cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, -0-alkyl", where "alkyl", "cycloalkyl", "aryl", "heteroaryl" and "arylalkyl" must be independently from each other substituted with at least one substituent selected from the group consisting of: "heterocyclyl, -OH, -COOH, -N(alkyl) 2 , -P(O)(O-alkyl) 2 , -P(O)(OH) 2 , 10 -OP(O)(O-alkyl) 2 , -OP(O)(OH) 2 , -OC(O)-alkyl, -OC(O)O-alkyl" and where "-NH aryl", "-CO-heterocyclyl", "-CO-heterocyclylalkyl", "-CO-heteroarylalkyl", "-CO NH-heterocyclylalkyl", "-NH-CO-alkyl", "-NH-CO-aryl", "alkyl", "cycloalkyl", "aryl", "arylalkyl", "heterocyclyl", "heterocyclylalkyl", "heteroaryl", "heteroarylalkyl", and " O-alkyl" are optionally independently from each other (further) substituted with at 15 least one substituent selected from the group consisting of: "alkyl, -F, -Cl, -OH, COOH, -CHO, -0-alkyl, -C(O)-alkyl, -N(alkyl) 2 , -O(-alkyl-O) 2 -alkyl"; R4m, R8 are independently "alkyl"; R3, R5m, R6, R7, R9, R11, R12, R13, R14, R15, R16, R21, R22 are independently "hydrogen"; 20 R10 independently is selected from the group consisting of "-C(O)O-arylalkyl, C(O)-arylalkyl, -C(S)-arylalkyl", where "arylalkyl" is optionally substituted with at least one substituent selected from the group consisting of: "-F, -Cl"; R1 7, R1 8, R1 9, R20 are independently from each other selected from the group consisting of "hydrogen, -F, -Cl, -CF 3 ". 25
[3] 3. Tetrahydrocarbazole derivative according to formula (1) as claimed in claim 2, where R1, R1* are not present; n is 0. 30 WO 2008/132153 PCT/EP2008/055039 - 210 4. Tetrahydrocarbazole derivative according to formula (1) as claimed in any of claims 1 to 3, where according to (A) V, W are independently "=O"; n is 1; 5 m is 1 or 2; R1, R1 * together independently form "=O or =S" or are independently both "hydro gen"; R2 is independently selected from the group consisting of: "amino, N'-(acetyl) amino, N'-(aminocarbonyl)-amino, N'-phenyl-amino, N'-(4-hydroxy-phenyl)-amino, 10 N'-(4-methoxy-phenyl)-amino, N'-(3-hydroxy-4-methoxy-benzyl)-amino, N'-(4 hydroxy-3-methoxy-benzyl)-amino, N'-(4-hydroxy-benzoyl)-amino, 2-hydroxy-ethyl, 2-diethylamino-ethyl, 3-hydroxy-propyl, 4-hydroxy-butyl, 5-hydroxy-pentyl, 2,3,4,5,6-pentahydroxy-hexan-1-yl, 2-(3,4,5,6-tetrahydroxy)-hexanoic acid, 4-butyl phosphonic acid diethyl ester, 4-butyl-phosphonic acid, dimethylamino-acetic acid 15 4-butyl ester, carbonic acid 4-butyl ester 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethyl es ter, phosphoric acid mono-4-butyl ester, phosphonic acid diethyl ester 4-(2 methoxy)-phenyl ester, methoxy, ethoxy, 4-hydroxy-cyclohexyl, 4-hydroxy-phenyl,
[4] 4-methoxy-phenyl, 3-fluoro-4-hydroxy-phenyl, 4-hydroxy-3-methoxy-phenyl, 2 hydroxy-4-methoxy-phenyl, 3-hydroxy-4-methoxy-phenyl, 2,4-dihydroxy-phenyl, 20 benzyl, 4-hydroxy-benzyl, 3-hydroxy-4-methoxy-benzyl, 2-(5-methoxy)-benzoic acid, 5-(2-methoxy)-benzoic acid, 5-(2-hydroxy)-benzoic acid, furan-2-yl-methyl, fu ran-3-yl-methyl, 2-furan-2-yl-ethyl, 2-imidazol-1-yl-ethyl, 3-imidazol-1-yl-propyl, 3 imidazol-1-yl-propionyl, 2-thiophen-2-yl-ethyl, 2-pyrazol-1-yl-ethyl, 2-(1,2,4)triazol-1 yl-ethyl, 3-(1,2,4)triazol-1 -yl-propyl, 4-(1,2,4)triazol-1 -yl-butyl, 5-methyl 25 (1 ,3,4)oxadiazol-2-yl-methyl, 2-methoxy-pyridin-4-yl-methyl, pyridin-3-yl-methyl, pyridin-4-yl-methyl, pyridin-4-yl-ethyl, 6-chloro-pyridin-3-yl-methyl, 2-pyridin-3-yl ethyl, pyrimidin-4-yl-methyl, pyrimidin-5-yl-methyl, pyrazin-2-yl-methyl, pyrrolidin-1 yl-methyl, morpholin-4-yl, morpholin-4-yl-methyl, morpholin-4-yl-ethyl, morpholin-4 yl-propyl, 3-morpholin-4-yl-propionyl, tetrahydro-puran-3-yl-methyl, tetrahydro 30 pu ran-4-yl-methyl, tetrahydro-puran-4-yl, tetrahydro-puran-4-carbonyl, 2 (tetrahydro-puran-4-yl)-ethyl, 2-(tetrahydro-puran-4-yl)-acetyl, tetrahydro-puran-4 yl-metyl-carbamoyl, 3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pu ran-2-yl, piperidin-4-yl-methyl, 1-methyl-piperidin-4-yl-methyl, 1-formyl-piperidin-4-yl-methyl, 1 -acetyl-piperidin-4-yl-methyl"; WO 2008/132153 PCT/EP2008/055039 -211 R4m, R8 are independently "1 -methyl-propan-1 -yl"; R3, R5m, R6, R7, R9, R11, R12, R13, R14, R15, R16, R21, R22 are independently "hydrogen"; R10 independently is selected from the group consisting of "benzyloxycarbonyl, 5 2,6-difluoro-phenyl-acetyl, 2-fluoro-phenyl-acetyl, 2-fluoro-phenyl-thioacetyl"; R1 7, R1 8, R1 9, R20 are independently from each other selected from the group consisting of "hydrogen, -F, -Cl, -CF 3 ".
[5] 5. Tetrahydrocarbazole derivative according to formula (1) as claimed in claim 4, 10 where R1, R1* are not present; n is 0.
[6] 6. Tetrahydrocarbazole derivative according to formula (1) as claimed in claim 1, 15 where according to (B) V, W are independently "=O"; n is 1; m is 1 or 2; R1 *, R2 together independently form "heteroaryl" or "heterocyclyl", where "het 20 eroaryl" and "heterocyclyl" are optionally substituted with at least one substituent selected from the group consisting of: "alkyl, -CN, -NH 2 , =0, -C(0)0-alkyl, C(O)NH 2 , -C(O)N(alkyl) 2 , -NH-C(O)-alkyl, -NH-C(O)-NH-alkyl, -NH-C(O)-NH 0-alkyl, -N(C(O)-NH-O-alkyl) 2 "; R1, R3 are independently "no substituent"; 25 R4m, R8 are independently "alkyl"; R5m, R6, R7, R9, R1 1, R1 2, R1 3, R1 4, R1 5, R1 6, R21, R22 are independently "hy drogen"; R10 independently is selected from the group consisting of "-C(0)0-arylalkyl, C(O)-arylalkyl, -C(S)-arylalkyl", where "arylalkyl" is optionally substituted with at 30 least one substituent selected from the group consisting of: "-F, -Cl"; WO 2008/132153 PCT/EP2008/055039 -212 R1 7, R1 8, R1 9, R20 are independently from each other selected from the group consisting of "hydrogen, -F, -Cl, -CF 3 ".
[7] 7. Tetrahydrocarbazole derivative according to formula (1) as claimed in any of claims 5 1 and 6, where according to (B) V, W are independently "=O"; n is 1; m is 1 or 2; R1 *, R2 together independently form "(1,3,4)oxadiazol-2-yl, 5-amino 10 (1,3,4)oxadiazol-2-yl, 3-methyl-(1,2,4)oxadiazol-5-yl, 5-methyl-(1,3,4)oxadiazol-2-yl, 5-(1,2,4)oxadiazole-3-carboxylic acid methyl ester, 5-(1,2,4)oxadiazole-3-carboxylic acid ethyl ester, 5-(1,3,4)oxadiazole-2-carboxylic acid ethyl ester, 5-oxo-4,5 dihydro-(1,3,4)-oxadiazol-2-yl, 3-carbamoyl-(1,2,4)oxadiazol-5-yl, 3 diethylcarbamoyl-(1,2,4)oxadiazol-5-yl, 5-acetylamino-(1,3,4)-oxadiazol-2-yl, 5 15 (1,2,4)oxadiazole-3-carboxylic acid propyl ester, 3-cyano-(1,2,4)oxadiazol-5-yl, 5 (3-ethyl-ureido)-(1,3,4)oxadiazol-2-yl, 5-(3-methoxy-ureido)-(1,3,4)oxadiazol-2-yl, 5 [1 -(methoxy-amino-carbonyl)-3-methoxy-ureido]-(1,3,4)oxadiazol-2-yl or 1 H tetrazol-5-yl"; R1, R3 are independently "no substituent"; 20 R4m, R8 are independently "1 -methyl-propan-1 -yl"; R5m, R6, R7, R9, R1 1, R1 2, R1 3, R1 4, R1 5, R1 6, R21, R22 are independently "hy drogen"; R10 independently is selected from the group consisting of "benzyloxycarbonyl, 2,6-difluoro-phenyl-acetyl, 2-fluoro-phenyl-acetyl, 2-fluoro-phenyl-thioacetyl"; 25 R1 7, R1 8, R1 9, R20 are independently from each other selected from the group consisting of "hydrogen, -F, -Cl, -CF 3 ". 30 WO 2008/132153 PCT/EP2008/055039 - 213 8. Tetrahydrocarbazole derivative according to any of claims 1 to 7 selected from the group consisting of: Compound 1 ((S)-1-{(R)-3-[(R)-1-(5-Amino-[1,3,4]oxadiazol-2-yl)-2-methyl butylcarbamoyl]-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3 5 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI / CI H 0 H N 0 10 Compound 2 ((S)-1 -{(S)-3-[(R)-1 -(5-Amino-[1,3,4]oxadiazol-2-yl)-2-methyl butylcarbamoyl]-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI H - 15 N CI O H NH2 Compound 3 ((S)-1 -{(R)-6,8-Dichloro-3-[(S)-2-methyl-1 -(3-methyl 20 [1,2,4]oxadiazol-5-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI N HN CI 25 HT:N.,' H O WO 2008/132153 PCT/EP2008/055039 -214 Compound 4 ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-2-methyl-1 -(3-methyl [1,2,4]oxadiazol-5-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI 5 HN CI H N H Compound 5 5-((S)-1-{[(R)-3-((S)-2-Benzyloxycarbonylamino-3-methyl 10 pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester CI HN CI 15 H Compound 6 5-((S)-1 -{[(S)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 20 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid ethyl ester CI HN g CI 0 H 25 0 WO 2008/132153 PCT/EP2008/055039 - 215 Compound 7 ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-2-methyl-1 -(5-oxo-4,5-dihydro [1,3,4]oxadiazol-2-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester 5 HN C I 0 Y 0 H H4 H N , N NH N - 0 -" Compound 8 {(S)-1-[(R)-6,8-Dichloro-3-((S)-2-methyl-1-[1,3,4]oxadiazol-2-yl 10 butylcarbamoyl)-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl] 2-methyl-butyll-carbamic acid benzyl ester CI HN ~ /CI 0 0 H 15 Compound 9 {(S)-1 -[(S)-6,8-Dichloro-3-((S)-2-methyl-1 -[1,3,4]oxadiazol-2-yl butylcarbamoyl)-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl] 2-methyl-butyll-carbamic acid benzyl ester CI HN / CI 20 HN 0 Compound 10 ((S)-1 -{(R)-3-[(S)-1 -(3-Carbamoyl-[1,2,4]oxadiazol-5-yl)-2 methyl-butylcarbamoyl]-6,8-dich Ioro-2,3,4,9-tetrahydro- 1 H 25 carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI HN CI H H N H N NH O WO 2008/132153 PCT/EP2008/055039 - 216 Compound 11 ((S)-1 -{(S)-3-[(S)-1 -(3-Carbamoyl-[1,2,4]oxadiazol-5-yl)-2-methyl butylcarbamoyl]-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester HN CI 5 oH H N NH, Compound 12 5-{(S)-1-[((R)-3-{(S)-2-[2-(2,6-Difluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H 10 carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester F F F HN NH N N ~N 0 H - 0 0 15 Compound 13 5-((S)-1-{[(R)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester CI 20 H0 HN C I o o N' N H 0 Compound 14 ((S)-1-{(R)-3-[(S)-1-(5-Acetylamino-[1,3,4]oxadiazol-2-yl)-2 25 methyl-butylcarbamoyl]-6,8-dich Ioro-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester Cl HN C H NT X N 0 NN H 30 WO 2008/132153 PCT/EP2008/055039 -217 Compound 15 5-((S)-1 -{[(S)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,3,4]oxadiazole-2-carboxylic acid ethyl ester CI 5 NHN- oi HN CI H H N 0 Compound 16 ((S)-1-{(S)-3-[(S)-1-(5-Acetylamino-[1,3,4]oxadiazol-2-yl)-2 10 methyl-butylcarbamoyl]-6,8-dich Ioro-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI HN CI H H N o o 15 H H H H - 0 Compound 17 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-2-methyl-1-(5-oxo-4,5-dihydro [1,3,4]oxadiazol-2-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl 20 ester CI HN / CI 0 0 0 0 0 NH T- N N H 25 Compound 18 5-((S)-1-{[(R)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid propyl ester HN CI 30 o o--N N" 0C~K HN.~J N, N N 0 H KN0 WO 2008/132153 PCT/EP2008/055039 - 218 Compound 19 5-((S)-1 -{[(S)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid propyl ester CI 5 HN CI Qa, H H Compound 20 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-1-(3-diethylcarbamoyl 10 [1,2,4]oxadiazol-5-yl)-2-methyl-butylcarbamoyl]-2,3,4,9 tetrahydro-1 H-carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI N HN CI / O H O-.N N HN 'N N N 0 15 H O Compound 21 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-1-(3-cyano-[1,2,4]oxadiazol-5-yl) 2-methyl-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester 20 CI eHN CI N" N H O Compound 22 ((S)-1-{(S)-6,8-Dichloro-3-[(S)-1-(3-cyano-[1,2,4]oxadiazol-5-yl) 25 2-methyl-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI HN CI 00 H H N H O WO 2008/132153 PCT/EP2008/055039 - 219 Compound 23 ((S)-1 -{(R)-6,8-Dichloro-3-[(S)-2-methyl-1 -(5-methyl [1,3,4]oxadiazol-2-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyles ter C, 5 HN CI E H 1 ON O H 0 Compound 24 ((S)-1 -{(S)-6,8-Dichloro-3-[(S)-2-methyl-1 -(5-methyl 10 [1,3,4]oxadiazol-2-yl)-butylcarbamoyl]-2,3,4,9-tetrahydro-1 H carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI HN CI ON-N o 0N O H 15 Compound 25 5-((S)-1-{[(R)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic 20 acid methyl ester CI o o -H CI N 0 H 25 Compound 26 5-((S)-1 -{[(S)-3-((S)-2-Benzyloxycarbonylamino-3-methyl pentanoylamino)-6,8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 carbonyl]-amino}-2-methyl-butyl)-[1,2,4]oxadiazole-3-carboxylic acid methyl ester CI HN CI 30 0 0 H N 0 H 0 WO 2008/132153 PCT/EP2008/055039 - 220 Compound 27 [(S)-1 -((R)-6,8-Dichloro-3-{(S)-1 -[5-(3-ethyl-ureido) [1,3,4]oxadiazol-2-yl]-2-methyl-butylcarbamoyl}-2,3,4,9 tetrahydro-1 H-carbazol-3-ylcarbamoyl)-2-methyl-butyl]-carbam ic acid benzyl ester 5 -. HN CI HN O, N O HN N O H= 0 - ' 10 Compound 28 5-{(S)-1-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester F F F HN 15 Ni H I~~~ ~ "'1: 0 YO H O Compound 29 5-{(S)-1-[((S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 20 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester F F F HN 25 H - 0 H 0 K WO 2008/132153 PCT/EP2008/055039 - 221 Compound 30 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[5-(3-ethyl-ureido) [1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide F 5 F F HN F HI'N)_ H F O N N --N H 6---YO - 0 ) 0 10 Compound 31 (S)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[5-(3-ethyl-ureido) [1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide F F 15 HN HN F 0 N-N Hi HN I -N N'- H qH Compound 32 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(5-amino-[1,3,4]oxadiazol-2 yl)-2-methyl-butyl]-amide F F F HN/ 25 F H NH NI F yo HI 0E WO 2008/132153 PCT/EP2008/055039 - 222 Compound 33 F F F HN F J N,,- NN 0 NN 0 5 Compound 34 F F F HN O F O N-N H -4; H 0 ~ 100 N-0" H Compound 35 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(pyrrolidin-1 15 ylmethyl)-carbamoyl]-butyl}-amide F F F H N HNN N - H HE 20 Compound 36 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(morpholin-4 ylmethyl)-carbamoyl]-butyl}-amide F 25 F F HN F0 N N N 0 H WO 2008/132153 PCT/EP2008/055039 - 223 Compound 37 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(morpholin-4 ylmethyl)-th iocarbamoyl]-butyl}-amide 5 F F HN 10 Compound 38 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)- 1-methoxycarbamoyl-2-methyl butyl)-amide F F F 15 HN N N N I . E H 0 E H Compound 39 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl- 1 -(morpholine-4 carbonyl)-butyl]-amide F F F HN 25 25 )N" N"'~ 0 0 H H ) Com oun 3 (R -- j()--[2(2-Fl or-peny) aceyla i o]3- ety0 WO 2008/132153 PCT/EP2008/055039 - 224 Compound 40 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-1-ethylcarbamoyl-2-methyl butyl)-amide 5 F F F HN F O 0 N IN H 0 H 10 Compound 41 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-1-ethoxycarbamoyl-2-methyl butyl)-amide F F 15 H F HO H FN N H 0 H Compound 42 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-morpholin-4-yl ethylcarbamoyl)-butyl]-amide F F F HN 25 H H H - 0 0 WO 2008/132153 PCT/EP2008/055039 - 225 Compound 43 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-butylcarbamoyl)-2 methyl-butyl]-amide 5 F F F HN F 0 0 H e H O - 0 0 10 Compound 44 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(3-morpholin-4-yl propylcarbamoyl)-butyl]-amide 15 F F F H N O O 6 H J H 0 I 0 00H-00 20 Compound 45 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(1 -methyl-piperidin 4-ylmethyl)-carbamoyl]-butyl}-amide F F F 25 HN F 0 0 O,. N I e H HA .- 0 0 N WO 2008/132153 PCT/EP2008/055039 - 226 Compound 46 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(tetrahydro-pyran-4 ylmethyl)-carbamoyl]-butyl}-amide 5 F F F HN F 0 0 H H - 0-o 0 0 10 Compound 47 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-morpholin-4-yl ethylthiocarbamoyl)-butyl]-amide 15 F F F F HN 20 Compound 48 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)- 1-[(1 -formyl-piperidin-4 ylmethyl)-carbamoyl]-2-methyl-butyl}-am ide F F F 25 H N N H H -- 0 0N 20 Copound48 (R -3-(S)-2[2-(2 Flu ro-penyl)-acetlarin ]3mehl penanolamnol8-rifuormetyl-,34,9tetahyro- 0 WO 2008/132153 PCT/EP2008/055039 - 227 Compound 49 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(1 -acetyl-piperidin-4 ylmethyl)-carbamoyl]-2-methyl-butyl}-am ide 5 F F F HN H H H O N 10 Compound 50 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(pyridin-4-ylmethyl) carbamoyl]-butyl}-amide 15 F F HN F O O N N YO- 0 " 0 kzz, 20 Compound 51 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2-diethylamino ethylcarbamoyl)-2-methyl-butyl]-amide F F F 25 HN O 0 O, NN 0 H H 0 0 WO 2008/132153 PCT/EP2008/055039 - 228 Compound 52 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(tetrahydro-pyran-4 ylmethyl)-th iocarbamoyl]-butyl}-amide 5 F F F HN F 0 H S E H E H 6- 0 0O 10 Compound 53 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy butylthiocarbamoyl)-2-methyl-butyl]-amide 15 F HN F O H F H H H H N N N, __OH - O H O = H 20 Compound 54 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-morpholin-4-yl ethylthiocarbamoyl)-butyl]-amide F F F 25 HN F sO E H H 0 0 WO 2008/132153 PCT/EP2008/055039 - 229 Compound 55 (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino] 3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(S)-2-methyl-1 -(2-morpholin-4-yl ethylcarbamoyl)-butyl]-amide 5 C, H N ~ )~NH H N 10 100 Compound 56 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(piperidin-4 ylmethyl)-carbamoyl]-butyl}-amide 15 F F F HN F 0 0 NH N N 'C H 6 - O H OH0NH 20 Compound 57 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2-hydroxy-ethylcarbamoyl)-2 methyl-butyl]-amide F F F H H F 0 0H WO 2008/132153 PCT/EP2008/055039 - 230 Compound 58 (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino] 3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid {(S)-2-methyl- 1 -[(pyridin-4-ylmethyl)-carbamoyl] butyll-amide 5 0I HN NN F H 0 HHI 0 0 N 10 Compound 59 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(5-hydroxy-pentylcarbamoyl) 2-methyl-butyl]-amide F 15 F F HN F 0 0 H HO N 0 H 20 Compound 60 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(pyridin-4-ylmethyl) thiocarbamoyl]-butyl}-amide F F F 25 HN H N -- 0" 0 '.N WO 2008/132153 PCT/EP2008/055039 - 231 Compound 61 (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino] 3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid [(S)-2-methyl-1 -(2-morpholin-4-yl ethylthiocarbamoyl)-butyl]-amide 5 CI HN / F F O S O NN NJ N. IE H E H - 0 0 10 Compound 62 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-2-methyl-1 -{[(tetrahydro-pyran 4-ylmethyl)-amino]-methyl}-butyl)-amide 15 F FF HN methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-butyl) phosphonic acid diethyl ester F F F 25 H F 0 0O N N 25 O WO 2008/132153 PCT/EP2008/055039 - 232 Compound 64 (4-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-butyl) phosphonic acid 5 F F F HN F 0 0 OH H H H HO y~O - 0 0 10 Compound 66 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(2-morpholin-4-yl ethylamino)-methyl]-butyl}-amide 15 F F HN NN F H H0 6-11YO 20 Compound 67 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-phenylcarbamoyl) 2-methyl-butyl]-amide 25 F HN F 0 0 N OH S 0 WO 2008/132153 PCT/EP2008/055039 - 233 Compound 68 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-methoxy-phenylcarbamoyl) 2-methyl-butyl]-amide F 5 F F H F 00 HH I N N N O / o 10 Compound 69 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy phenylcarbamoyl)-2-methyl-butyl]-amide F F F 15 HN/ F 0 0 H HT 0 yo N NA /N~ 0 0 OOH 20 Compound 70 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2,4-dihydroxy phenylcarbamoyl)-2-methyl-butyl]-amide F 25 F F HN HO0 N N OH K o H WO 2008/132153 PCT/EP2008/055039 - 234 Compound 71 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(2-hydroxy-4-methoxy phenylcarbamoyl)-2-methyl-butyl]-amide 5 F FF H HO F 0 0 15 H N >N' NL AN 0 F / 0 10 Compound 72 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl--(2,4,6-trimethoxy phenylcarbamoyl)-butyl]-amide F F F 15 / HH H OH 0 20 Compound 73 (R) -3-1(S)-2-[2-(2- Flu oro-phenyl) -acetylamin o]-3-m ethyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-l1-(4-hydroxy cyclohexylcarbamoyl)-2-methyl-butyl]-amide F F F 25 HN / F 0N ~ 0 H H~ WO 2008/132153 PCT/EP2008/055039 - 235 Compound 74 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-im idazol-1-yl propylthiocarbamoyl)-2-methyl-butyl]-amide 5 F F F HN 10 Compound 75 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(R)- 1-(3-imidazol- 1-yl propyith iocarbamoyl)-2-methyl-butyl]-am ide F F F 15 HN N N N Compound 76 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-thiophen-2-yl ethylthiocarbamoyl)-butyl]-amide F F F 25 HN H HiI E H N H- -N - 0 0N WO 2008/132153 PCT/EP2008/055039 - 236 Compound 77 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(pyridin-3-ylmethyl) thiocarbamoyl]-butyl}-amide 5 F F F HN F 0N N N'IN '," H H -^ 0 0 H 10 Compound 78 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-3-methyl-1-(1 H-tetrazol-5-yl) butylcarbamoyl]-2,3,4,9-tetrahydro-1 H-carbazol-3-ylcarbamoyl} 2-methyl-butyl)-carbamic acid benzyl ester CI CI HN 15 o0 N N 0 HN--N HN N Y Compound 80 5-{(S)-1-[(3-{2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester F F F HN F 0 25 H, , HN N N N o - o H0 WO 2008/132153 PCT/EP2008/055039 - 237 Compound 81 5-{(S)-l-[((R)-3-{(R)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-2-methyl-butyl}-[1,2,4]oxadiazole 3-carboxylic acid ethyl ester F 5 F F HN F -N 0 H 0 H o H 0, 10 Compound 82 (R)-3-{(R)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[5-(3-ethyl-ureido) [1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide 15 F F H F 0 N--N H N 0 N' ) 6__ H e E 0 0 20 Compound 83 (S)-3-{(R)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[5-(3-ethyl-ureido) 25 [1,3,4]oxadiazol-2-yl]-2-methyl-butyl}-amide F F F H HN NI N,)> H WO 2008/132153 PCT/EP2008/055039 - 238 Compound 85 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(2-diethylamino-ethylcarbamoyl) methyl]-amide 5 F F F N HN N FF H H - 0 0 10 Compound 86 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(2-morpholin-4-yl-ethylcarbamoyl) methyl]-amide F 15 F F HN N N INN -- Y 0 0 H 20 Compound 87 (S)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl)-acetylamino] 3-methyl-pentanoylamino}-2,3,4,9-tetrahydro-1 H-carbazole-3 carboxylic acid {(S)-2-methyl- 1 -[(pyridin-4-ylmethyl)-carbamoyl] butyll-amide CI H N /F 25 F H H o 0 -N WO 2008/132153 PCT/EP2008/055039 - 239 Compound 88 (R)-8-Chloro-6-fluoro-3-{(S)-2-[2-(2-fluoro-phenyl) thioacetylamino]-3-methyl-pentanoylamino}-2,3,4,9-tetrahydro 1 H-carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(pyridin-4 ylmethyl)-carbamoyl]-butyl}-amide 5 CI HN / F F F H 0H 0 N H H H 10 Compound 89 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-pyridin-4-yl ethylthiocarbamoyl)-butyl]-amide 15 F F HN F0 NH H H 0 H 20 Compound 90 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy cyclohexylthiocarbamoyl)-2-methyl-butyl]-amide F F F 25 HN F H N S K), . N / OH Y 0 I 0 H WO 2008/132153 PCT/EP2008/055039 - 240 Compound 91 2-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-5 methoxy-benzoic acid 5 F HN F 0 O 0 OH 10 Compound 92 Phosphoric acid diethyl ester 5-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carbonyl) amino]-3-methyl-pentanoylamino}-2-methoxy-phenyl ester 15 F F 0 F N. N F H N 20 Compound 93 Dimethylamino-acetic acid 4-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carbonyl) amino]-3-methyl-pentanoylamino}-butyl ester F F F 25 HN F 0 O I H E H - 0 00 WO 2008/132153 PCT/EP2008/055039 - 241 Compound 94 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-benzylcarbamoyl) 2-methyl-butyl]-amide 5 F F F HN F O F 0 0 N N 6I _ H H H, S0 0 O 10 Compound 95 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy benzylcarbamoyl)-2-methyl-butyl]-amide 15 F FF F F HN F 0 0 N H - 0' OH 20 Compound 96 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-hydroxy-3-methoxy benzylcarbamoyl)-2-methyl-butyl]-amide F F F 25 HN F HH I H HI 0 -- 0 0 OH WO 2008/132153 PCT/EP2008/055039 - 242 Compound 97 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(4-methoxy phenylthiocarbamoyl)-2-methyl-butyl]-amide 5 F F F HN N N '"'N' N- &~0 yo H H 0 10 Compound 98 5-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-2 methoxy-benzoic acid 15 F F F F HN F 0 0 HO 0 OH 20 Compound 99 5-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanethioylamino}-2 methoxy-benzoic acid F F F 25 HN F OH N N H H ~ 00 OH) WO 2008/132153 PCT/EP2008/055039 - 243 Compound 100 Carbonic acid 4-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro-phenyl) acetylamino]-3-methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9 tetrahydro-1 H-carbazole-3-carbonyl)-am ino]-3-methyl pentanoylamino}-butyl ester 2-[2-(2-methoxy-ethoxy)-ethoxy] 5 ethyl ester F HN F O O N N O O O ,HY HH II 0 0 0 10 Compound 101 Phosphoric acid mono-(4-{(S)-2-[((R)-3-{(S)-2-[2-(2-fluoro phenyl)-acetylamino]-3-methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9-tetrahydro-1 H-carbazole-3-carbonyl) amino]-3-methyl-pentanoylamino}-butyl) ester 15 F FF HN F 0 0 H H HE H I"0 NN N Y N'-'O' ,OHH Y 0 1 0 ")0 20 Compound 102 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-propylcarbamoyl) 2-methyl-butyl]-amide F F F 25 HN HN OH N 0 H 0 WO 2008/132153 PCT/EP2008/055039 - 244 Compound 103 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-1-benzylthiocarbamoyl-2 methyl-butyl)-amide 5 F F F 6__YH_ _HN N__/ N 10 Compound 104 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(2-methoxy-pyridin-4 ylmethyl)-th iocarbamoyl]-2-methyl-butyl}-am ide 15 F F F HN F H C HS NkJ ~ K~N 0 IE H H N - 0 0 20 Compound 105 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(pyrimidin-5 ylmethyl)-th iocarbamoyl]-butyl}-amide F F F 25 HN F0 N j HH 0 N WO 2008/132153 PCT/EP2008/055039 - 245 Compound 106 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(pyrazin-2 ylmethyl)-th iocarbamoyl]-butyl}-amide 5 F F F F NjH HN 10 Compound 107 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(6-chloro-pyridin-3-ylmethyl) thiocarbamoyl]-2-methyl-butyl}-amide 15 F FF HN 20 Compound 108 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl- 1-(2-pyridin-3-yl ethylth iocarbamoyl)-butyl]-amide F F F 25 HN / N C 20~~~~~~ Copon 10 R-3jS--2(-Fuoopey)-ctlmi ]3mehl 25 H H WO 2008/132153 PCT/EP2008/055039 - 246 Compound 109 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(pyrimidin-4 ylmethyl)-th iocarbamoyl]-butyl}-amide 5 F F F HN 10 Compound 110 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)- 1-(2-im idazol- 1-yl ethylth iocarbamoyl)-2-methyl-butyl]-amide 15 F F FF F H N N HN N N H H" C 20 Compound 111 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-pyrazol-1-yl ethylthiocarbamoyl)-butyl]-amide F F F 25 HN/ N N H E H - 0 0 WO 2008/132153 PCT/EP2008/055039 - 247 Compound 112 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(2-[1,2,4]triazol-1-yl ethylthiocarbamoyl)-butyl]-amide 5 F F F HN 'NN F 0 s N:Z N N I H E H 10 100 Compound 113 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(3-[1,2,4]triazol-1-yl propylthiocarbamoyl)-butyl]-amide 15 F FF F F HN NN H E H yo 0") 0-1L N 20 Compound 114 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1 -(4-[1,2,4]triazol-1-yl butylthiocarbamoyl)-butyl]-amide F F F 25 HN N% ~- H H WO 2008/132153 PCT/EP2008/055039 - 248 Compound 115 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(furan-2-ylmethyl) thiocarbamoyl]-2-methyl-butyl}-amide 5 F F F HN Nj N.~ Nk H H 100 100 Compound 116 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(furan-3-ylmethyl) thiocarbamoyl]-2-methyl-butyl}-amide 15 F FF HN 20 Compound 117 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)- 1-(2-furan-2-yl ethylth iocarbamoyl)-2-methyl-butyl]-amide F F F 25 HN 0 F 0 F S FH 0 H n 0 0*'0 WO 2008/132153 PCT/EP2008/055039 - 249 Compound 118 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(5-methyl [1,3,4]oxadiazol-2-ylmethyl)-thiocarbamoyl]-butyl}-amide 5 F F F HN F 0 N N 0 'EK HN yo0 0 N'N 10 Compound 119 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[2-(tetrahydro-pyran 4-yl)-ethylthiocarbamoyl]-butyl}-amide 15 F F HN F 0 S Hi H - 0 0 20 Compound 120 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(tetrahydro-pyran-4 ylthiocarbamoyl)-butyl]-amide 25 F F F HN F N N H H WO 2008/132153 PCT/EP2008/055039 - 250 Compound 121 5-{(S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3 methyl-pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoylamino}-2 hydroxy-benzoic acid 5 F FF F F HN N. N N'N N" 0 IH 0H -o OH 10 Compound 122 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-fluoro-4-hydroxy phenylcarbamoyl)-2-methyl-butyl]-amide 15 F F F HN F H 0 ~ OH N N..I~ -aI I H 0 H F NFO - o 00 20 Compound 123 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy benzylthiocarbamoyl)-2-methyl-butyl]-amide F 25 F F HN F H H S NJN" N N H 0 H OH WO 2008/132153 PCT/EP2008/055039 - 251 Compound 124 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-1-hydrazinocarbonyl-2-methyl butyl)-amide F 5 F F HN F H H N N H--y H 02 10 Compound 125 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-hydroxy-4-methoxy phenylthiocarbamoyl)-2-methyl-butyl]-amide 15 F F F HN OH F 0 S 0 H H N N N N H H O2O 20 Compound 126 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-2-oxo-pyrrolidin-3-yl)-amide F F F 25 HN F H O N N NH 6 --- YO H WO 2008/132153 PCT/EP2008/055039 - 252 Compound 127 (S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 3 imidazol-1-yl-propyl ester 5 F FF F F HN / F H 0 H 0 H NH I--Y H 0 10 Compound 128 (R)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 3 imidazol-1-yl-propyl ester 15 F F F HN F 0 F H 0 H 0 N N w~ N O NN 20 Compound 129 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-1-(4-hydroxy-benzylcarbamoyl)-2 methyl-butylcarbamoyl]-2,3,4,9-tetrahydro- 1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI CI 25 HN H 0 H 0 S ON N' NNN S H N 0 H 0 O ' aOH WO 2008/132153 PCT/EP2008/055039 - 253 Compound 130 ((S)-1-{(S)-6,8-Dichloro-3-[(S)-1-(4-hydroxy-benzylcarbamoyl)-2 methyl-butylcarbamoyl]-2,3,4,9-tetrahydro- 1 H-carbazol-3 ylcarbamoyl}-2-methyl-butyl)-carbamic acid benzyl ester CI CI 5 HN H O N ,, N H H OH 10 Compound 131 (S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid pyridin-4 ylmethyl ester F F F 15 HN F 0 0 H H N N N H 0 0 0 20 Compound 132 (R)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid pyridin-4 ylmethyl ester F F F 25 HN F H H O N 6-:Y H 0 N WO 2008/132153 PCT/EP2008/055039 - 254 Compound 133 2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 2 dimethylamino-ethyl ester 5 F F F HN F H H N N I - 10 Compound 134 (S)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 3 hydroxy-4-methoxy-benzyl ester 15 F FF HN F H 0 H 0 N 0 0 H 0 OH 20 Compound 135 (R)-2-[((R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carbonyl)-amino]-3-methyl-pentanoic acid 3 hydroxy-4-methoxy-benzyl ester F F F 25 HN F H H N N N H 00 OH1 WO 2008/132153 PCT/EP2008/055039 - 255 Compound 136 [(S)-1-((S)-6,8-Dichloro-3-{(S)-2-methyl-1-[(tetrahydro-pyran-4 ylmethyl)-carbamoyl]-butylcarbamoyl}-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl)-2-methyl-butyl]-carbam ic acid benzyl ester CI CI 5 HN I- H H ON N H NH 10 Compound 137 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(quinolin-6 ylcarbamoyl)-butyl]-amide F F F 15 HN / N F H H NN N N I~ ~H H Compound 138 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(R)-2-methyl-1 -(quinolin-6 ylcarbamoyl)-butyl]-amide F F F HN 25 N H H 0 Y N N"~ N N I 0 H 0 H WO 2008/132153 PCT/EP2008/055039 - 256 Compound 139 [(S)-1-((R)-6,8-Dichloro-3-{(S)-2-methyl-1-[(tetrahydro-pyran-4 ylmethyl)-th iocarbamoyl]-butylcarbamoyl}-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl)-2-methyl-butyl]-carbam ic acid benzyl ester 5 CI HN H 0 H S ()-,0 N N N * N YH H 10 Compound 140 ((S)-1-{(R)-6,8-Dichloro-3-[(S)-1-(4-hydroxy-3-methoxy phenylcarbamoyl)-2-methyl-butylcarbamoyl]-2,3,4,9-tetrahydro 1 H-carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbam ic acid ben zyl ester 15 CI CI HN 200 20 Compound 141 ((S)-1-{(S)-6,8-Dichloro-3-[(S)-1-(4-hydroxy-3-methoxy phenylcarbamoyl)-2-methyl-butylcarbamoyl]-2,3,4,9-tetrahydro 1 H-carbazol-3-ylcarbamoyl}-2-methyl-butyl)-carbam ic acid ben zyl ester 25 CI CI HN O OH H fN N4 0 Y H H WO 2008/132153 PCT/EP2008/055039 - 257 Compound 142 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-2-oxo-piperidin-3-yl)-amide F F F 5 HN F H H N N , ~ N,,,,, t N H H N 10 Compound 143 [(S)-1-((R)-6,8-Dichloro-3-{(S)-2-methyl-1-[(tetrahydro-pyran-4 ylmethyl)-carbamoyl]-butylcarbamoyl}-2,3,4,9-tetrahydro- 1 H carbazol-3-ylcarbamoyl)-2-methyl-butyl]-carbam ic acid benzyl ester CI CI 15 HN H 0 H 0 0 ',0 N,)," NA S Y H 0 H 0 20 Compound 144 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(N'-phenyl hydrazinocarbonyl)-butyl]-amide F F F 25 HN F H H H N N NO N 0 0 WO 2008/132153 PCT/EP2008/055039 - 258 Compound 145 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-3-methylsulfanyl-1 thiocarbamoyl-propyl)-amide F 5 F F HN F H H S N N H N)'NNH2 10 Compound 146 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(quinolin-5 ylcarbamoyl)-butyl]-amide F F F 15 HN F H H 6 yN NN N N H 0 H 20 Compound 147 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(isoquinolin-5-ylcarbamoyl)-2 methyl-butyl]-amide F F F 25 HN / F H H N N N H y N N WO 2008/132153 PCT/EP2008/055039 - 259 Compound 148 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(2-tetrahydro-pyran 4-yl-acetylamino)-methyl]-butyl}-amide 5 F F F HN 0 0 N N'" H 0 H 10 Compound 149 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((S)-2-methyl-1 -{[(tetrahydro-pyran 4-carbonyl)-amino]-methyl}-butyl)-amide F F F 15 HN F H 0 H~~ 0 I. 0 H 0H 0 H 0 Compound 150 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(3-morpholin-4-yl propionylamino)-methyl]-butyl}-amide F F F HN 25 F H 0H 0 0 H H I~.0 H 00 WO 2008/132153 PCT/EP2008/055039 - 260 Compound 151 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[(3-imidazol-1-yl propionylamino)-methyl]-2-methyl-butyl}-amide 5 F F HN F 0~ H 0 N 10 Compound 152 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[3-(tetrahydro-pyran 4-ylmethyl)-ureidomethyl]-butyl}-amide F F 15 HN IH 0 H H -"-1 0 20 Compound 153 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(2-tetrahydro-pyran 4-yl-acetylamino)-butyl]-amide F F F 25 HN F H 0H H H F 0---0 00 WO 2008/132153 PCT/EP2008/055039 - 261 Compound 154 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-2-methyl-1 -[(tetrahydro-pyran-4 carbonyl)-amino]-butyl}-amide 5 F F F F HN F H 0 _ H H 0 0 -1 10 Compound 155 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-2-methyl-1-(3-morpholin-4-yl propionylamino)-butyl]-amide F F F 15 HN F H H H 0 > N N N N' o N I H -- ,0 0 0 Compound 156 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(3-im idazol-1-yl propionylamino)-2-methyl-butyl]-amide F F F HN 25 N N N I H - 0 -, 0 -, 0 WO 2008/132153 PCT/EP2008/055039 - 262 Compound 157 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(R)-2-methyl-1 -[3-(tetrahydro-pyran 4-ylmethyl)-ureido]-butyl}-amide 5 F F HN F N0 F H"Y H H H H0 0 O 0 10 Compound 158 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid ((R)-2-methyl-1-{[(tetrahydro-pyran 4-ylmethyl)-carbamoyl]-methyl}-butyl)-am ide F F F 15 HN F Hi , H H N N-_- N K H YO O Compound 159 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[N'-(4-hydroxy-phenyl) hydrazinocarbonyl]-2-methyl-butyl}-amide F F F 25 HN F 0 H H H N N N b 0 0 OH WO 2008/132153 PCT/EP2008/055039 - 263 Compound 160 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[N'-(4-methoxy-phenyl) hydrazinocarbonyl]-2-methyl-butyl}-amide 5 F F F HN F 0 H 0 H O0 10 Compound 161 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[N'-(3-hydroxy-4-methoxy benzyl)-hydrazinocarbonyl]-2-methyl-butyl}-amide 15 F F F HN F H 0 H 0 H~ O' NN ~ N N N OH 6 O H H 20 Compound 162 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[N'-(4-hydroxy-3-methoxy benzyl)-hydrazinocarbonyl]-2-methyl-butyl}-amide 25 F F F HN NO OH N, N ) N "-J N 0 IH 0 H WO 2008/132153 PCT/EP2008/055039 - 264 Compound 163 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid [(S)-1-(N'-acetyl-hydrazinocarbonyl) 2-methyl-butyl]-amide F 5 F F HN FO 0 F H 0C_-H 0 H N N - o 0 0 10 Compound 164 F F F HN F H H 15 N N N NH N O H H Compound 165 (R)-3-{(S)-2-[2-(2-Fluoro-phenyl)-acetylamino]-3-methyl 20 pentanoylamino}-8-trifluoromethyl-2,3,4,9-tetrahydro-1 H carbazole-3-carboxylic acid {(S)-1 -[N'-(4-hydroxy-benzoyl) hydrazinocarbonyl]-2-methyl-butyl}-amide F F F HN 25 OH N N H H -- Y 0 0 H0 WO 2008/132153 PCT/EP2008/055039 - 265 Compound Structure Chemical name F F F (R)-3-{ (S)-2-[2-(2-Fluoro HN /phenyl)-acetylamino]-3 _- D methyl-pentanoylamino}-8 166 F 0 H 0trifluormethyl-2,3,4,9 HN tetrahydro-1 H-carbazole-3 N~jk "''N NH carboxylic acid [(S)-1 I yo (acetylamino-methyl)-2 methyl-butyl]-amide F F (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 167 F00trifluoromethyl-2,3,4,9 F H Ctetrahydro-1 H-carbazole-3 NNJkN N N 'N J N'.- carboxylic acid f{(S)-1-[(3 yo H H H ethyl-ureido)-methyl]-2 methyl-butyl}-amide FFF (R)-3-{ (S)-2-[2-(2-Fluoro HN /methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 168 F H 0H tetrahydro-1 H-carbazole-3 N N N NK 6 carboxylic acid [(S)-1 -(2 H imidazol-1 -yI ethylcarbamoyl)-2-methyl butyl]-amide FFFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 HN /trifluoromethyl-2,3,4,9 169 F H 0H 0tetrahydro-1 H-carbazole-3 N N..- N carboxylic acid {(S)-2 H H methyl-i -[(pyrazin-2 -- yo ylmethyl)-carbamoyl] N butyl}-amide F F F (R)-3-{ (S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 170 F H - trifluoromethyl-2,3,4,9 N"Y j )J tetrahydro-1 H-carbazole-3 0 N H N carboxylic acid ((1 S,2S)-1 H 0 HNy.< acetylamino-2-m ethyl 0 butyl)-amide WO 2008/132153 PCT/EP2008/055039 - 266 F (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 HN /trif luorom ethyl-2,3,4,9 171 F H 0 H 0 tetrahydro-1 H-carbazole-3 H H carboxylic acid [(S)-1 H~>N 0H (isoquinolin-8 H__Y ylcarbamoyl)-2-methyl N butyl]-amide FF (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 172 F 00tetrahydro-1 H-carbazole-3 H' carboxylic acid f{(S)-1 -[3 (3-hydroxy-propyl) YO H 0 H Hureidom ethyl]-2-m ethyl butyl}-amide F (R)-3-{ (S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN_ methyl-pentanoylamino}-8 173 F0strifluoromethyl-2,3,4,9 F H 9 tetrahydro-1 H-carbazole-3 N~A~ N carboxylic acid f{(S)-1-[(3 S 0 H 0 H Hethyl-thioureido)-methyl]-2 methyl-butyl}-amide F (R)-3-{ (S)-2-[2-(2-Fluoro F hnlactlmn]3 F phnl-ctlmn] HN methyl-pentanoylamino}-8 HN trifluoromethyl-2,3,4,9 174HF0 H 0 -N tetrahydro-1 H-carbazole-3 ~ N~..N N ~ I carboxylic acid {(S)-2 0 H 0 E H Hmethyl-1-[(3-pyridin-4-y & YO H H H ~ u re ido) -m et hyl] -bu tyl} amide FFFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 HN /trifluoromethyl-2,3,4,9 175 F H 0 H 0 H tetrahydro-1 H-carbazole-3 H H N. carboxylic acid {(S)-2 N~JN~ ehl- [3( -ttaNl5 6 -- H 0 H N-N yI)-propylcarbamoyl] butyl}-amide FFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 HN /trifluoromethyl-2,3,4,9 176 F H 0 H 0 H tetrahydro-1 H-carbazole-3 NKN N carboxylic acid {(S)-2 0 0 HI0 methyl-i -[(1 H-tetrazol-5 6 -- Y H H N-Nylmethyl)-carbamoyl] _________ ___________________________________butyl}-amide WO 2008/132153 PCT/EP2008/055039 - 267 FFFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 HN ~ /trif luorom ethyl-2,3,4,9 177 F H 0 H 0 ,tetrahydro-1 H-carbazole-3 N N N < carboxylic acid f{(S)-1-[(2 N:H:NN tert-butyl-2H-tetrazol-5 --- H ylm ethyl)-carbamoyl]-2 methyl-butyl}-amide F (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 H -methyl-pentanoylamino}-8 N /trifluoromethyl-2,3,4,9 178 F H 0 H N, tetrahydro-1 H-carbazole-3 N N,,A, Ncarboxylic acid [(S)-1 -(2 E H o H HN=N etbtl2-erzl5 ylcarbamoyl)-2-methyl butyl]-amide FFFF (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 HN /trifluoromethyl-2,3,4,9 179 F H0 H 0 N tetrahydro-1 H-carbazole-3 'N ~N~ ,Ncarboxylic acid [(S)-1 -(l1 N" ~ Y N N tert-butyl-1 H-tetrazol-5 6H-y ylcarbamoyl)-2-methyl butyl]-amide FF (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 H N methyl-pentanoylamino}-8 HN trifluoromethyl-2,3,4,9 180 F H H o tetrahydro-1 H-carbazole-3 H carboxylic acid {(S)-2 6 -- O H H methyl-1 -[(2-pyridin-4-y acetylamino)-m ethyl] butyl}-amide F (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 HN /trifluoromethyl-2,3,4,9 181 F H 0 H 0 tetrahydro-1 H-carbazole-3 N -kN N N.lNN carboxylic acid {(S)-2 0 H 0 H N-~ methyl-1 -[2-(l1-methyl-1 H & YO o Ntetrazol-5-ylsu Ifanyl) ethylcarbamoyl]-butyll amide F F F (R)-3-{ (S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 182 F trifluoromethyl-2,3,4,9 HH H tetrahydro-1 H-carbazole-3 NA " carboxylic acid [(1 S,2S)-2 6 0 H 0 0 N methyl-1 -(2-pyridin-4-y acetylamino)-butyl]-amide WO 2008/132153 PCT/EP2008/055039 - 268 F F(R)-3-{(S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 183 F H 0 H 0 tetrahydro-1 H-carbazole-3 N- N N NNz carboxylic acid (S)-2 H H Imethyl-1 -[(pyrimidin-5 N ylmethyl)-carbamoyl] butyl}-amide F F F HN 184 F H O NHN H O H F (R)-3-{(S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 185 F H 0 H o N=N tetrahydro-1 H-carbazole-3 N N N carboxylic acid [(S)-2 H 0H methyl-1-(2-tetrazol-1-yl ethylcarbamoyl)-butyl] amide F F F F f{(S)-2-[((R)-3-{ (S)-2-[2-(2 F ~Fluoro-phenyl) HN acetylamino]-3-methyl pentanoylamino}-8 F trifluoromethyl-2,3,4,9 H H tetrahydro-1 H-carbazole-3 H -N---N ~carbonyl)-amino]-3-methyl H pentyl}-carbamic acid tetrahydro-pyran-4-yl ester F F F F f{(S)-2-[((R)-3-{ (S)-2-[2-(2 F ~Fluoro-phenyl) HN acetylamino]-3-methyl pentanoylamino}-8 187 F H 0 H trifluoromethyl-2,3,4,9 k N tetrahydro-1 H-carbazole-3 NN 0carbonyl)-amino]-3-methyl pentyl}-carbamic acid me thyl ester 1 -tert-butyl-4-(3-{(S)-2 F F F [((R)-3-{(S)-2-[2-(2-fluoro F F F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 188 F H 0trifluoromethyl-2,3,4,9 H0tetrahydro-1 H-carbazole-3 N N carbonyl)-amino]-3-methyl N N pentanoylamino}-propyl) 4H-tetrazol-1-ium; Trifluo ro-acetate WO 2008/132153 PCT/EP2008/055039 - 269 F (R)-3-{ (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 HN /trifluoromethyl-2,3,4,9 19F H 0 H 0 tetrahydro-1 H-carbazole-3 N N carboxylic acid [(S)-2 H 0 H /N methyl-1 -(3-tetrazol-1 -y N=N propylcarbamoyl)-butyl] amide F F (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 HN /trifluoromethyl-2,3,4,9 190 F H ~ H 0 tetrahydro-1 H-carbazole-3 NJ N N N carboxylic acid [(S)-2 r HN oH" methyl-1 -(3-pyridin-4 6 -- lA H 0 H L , N ylm et hyl-u rei dom et hyl) butyl]-amide F F F HN 191 F H H 0N ~~ 0 0 H 0 SFFF (R)-3- (S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 192 o -trif luorom ethyl-2,3,4,9 F H 0 H 0tetrahydro-1 H-carbazole-3 [(SN-N N...kp~N~ N' carboxylic acid ()2 0 Ey H 0 E H H methyl-1 -(l1H-tetrazol-5 ylcarbamoyl)-butyl]-amide F (R)-3-{ (S)-2 F F [(Bicyclo[4.2.O]octa HN 1 (6) ,2,4-triene-7-carbonyl) HN /amino]-3-methyl 193 H 0 H Spentanoylamino}-8 NjN"N N~I trifluoromethyl-2,3,4,9 H" 0 ~H 2 tetrahydro-1 H-carbazole-3 11yo H carboxylic acid ((S)-2 methyl-i -thiocarbamoyl butyl)-amide F F F (R)-3-{ (S)-2-[2-(2-Chloro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 194 Cl0strif luoromethyl-2,3,4,9 CI H 0 H Stetrahydro-1 H-carbazole-3 N N" NAt.N carboxylic acid ((S)-2 -6 0 EH 02methyl-i -thiocarbamoyl butyl)-amide WO 2008/132153 PCT/EP2008/055039 - 270 F (R)-3-{(S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 HN /trifluoromethyl-2,3,4,9 F H 00N tetrahydro-1 H-carbazole-3 N N N carboxylic acid [(S)-2 0 H Hmethyl-1 -(4-tetrazol-1 -yl butylcarbamoyl)-butyl] amide F F (R)-3-((S)-3-Methyl-2 phenylacetylamino HN /pentanoylamino)-8 196 0trifluoromethyl-2,3,4,9 0 H tetrahydro-1 H-carbazole-3 ,,YNN N~ H carboxylic acid ((S)-2 0 H 0 E 2methyl-1 -thiocarbamoyl butyl)-amide F (R)-3-{(S)-2-[2-(2-Fluoro F F ~phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 197 F H0tetrahydro-1 H-carbazole-3 0 H,, carboxylic acid ((S)-2 HHmethyl-1 -{[(morpholine-4 S -"'I carbonyl)-amino]-methyl} butyl)-amide F R)-3-{(S)-2-[2-(2-Fluoro F F -phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 198 F H 0 H 0 0 tetrahydro-1 H-carbazole-3 N J'm, N N, carboxylic acid ((S)-2 S0 H 0 H H methyl-1 -{[3-(tetrahydro pyran-4-yl)-ureido] methyl}-butyl)-amide FF FF (R)-3- { (S)-3-Methyl-2-[2-(2 F F tilooehlpey) HN acetylamino] 199 F F F H 0 N s trifluoromethyl-2,3,4,9 N__ H~~ 1 1 N H A tetrahydro-i H-carbazole-3 0 H 2 carboxylic acid ((S)-2 0 methyl-i -thiocarbamoyl butyl)-amide F (R)-3-[(S)-3-Methyl-2-(2 FiFmethyl-2-phenyl HN /propionylamino) pentanoylamino]-8 200 H0 s trifluoromethyl-2,3,4,9 N ~ N N tetrahydro-1 H-carbazole-3 H 0 carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide WO 2008/132153 PCT/EP2008/055039 - 271 FF (R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 F N_ methyl-pentanoylamino-8 HNiN trif luorom ethyl-2,3,4,9 F phenyl)-aioetylamino HN melpentanoylamino]-8 202 0trifluoromethyl-2,3,4,9 H 0 Stetrahydro-1 H-carbazole-3 N' carboxylic acid ((S)-2 0 H methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-[(S)-3-Methyl-2-((R) 2-phenyl-propionylamino) HN /pentanoylamino]-8 trifluoromethyl-2,3,4,9 0 H 'S tetrahydro-1 H-carbazole-3 yN) N >carboxylic acid ((S)-2 0 0 H 0 methyl-1 -thiocarbamoyl butyl)-amide F (R)-3-(S)-2-[2-(2-Fluoro 2-phenyl)-acetylamino]-3 methyl-pentanoylamino-8 trifluoromethyl-2,3,4,9 204 F H tetrahydro-1 H-carbazole-3 N carboxylic acid ((S)-2 N --- NH2 So H H (methanesulfonylamino methyl)-2-methyl-butyl] amide F (R)-3-{(S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 205 F H 0 - H tetrahydro-1 H-carbazole-3 6 -N..N N, )carboxylic acid [(S)-2 " N O N ON 0 H H N N N" methyl-i -(3-pyridin-4 ylmethyl-thioureidomethyl) butyl]-amide F (R)-3-{(S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 F -methyl-pentanoylamino}-8 "' trifluoromethyl-2,3,4,9 206 F H 0 tetrahydro-1 H-carbazole-3 N H s carboxylic acid [(S)-2 E H N N methyl-1 -[3-(tetrahydro 0 0 H H 0 C pyran-4-ylm ethyl) thioureidomethyl]-butyl butl]-amide WO 2008/132153 PCT/EP2008/055039 - 272 FF F (R)-3-[(S)-3-Methyl-2-((R) 2-phenyl-butyrylamino) HN /pentanoylamino]-8 207 0strifluoromethyl-2,3,4,9 H H Stetrahydro-l H-carbazole-3 N" Nlz)NH carboxylic acid ((S)-2 -H 0 methyl-i -thiocarbamoyl butyl)-amide FF (R)-3-{ (S)-2-[2-(2-Fluoro F -phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 208 F H 0 H 0tetrahydro-1 H-carbazole-3 N,,'~ N )j carboxylic acid ((S)-2 0 EH 0 4N methyl-1 -{3-[2-(tetrahydro 6 - 0 H H pyran-4-yI)-ethyl] ureidomethyl}-butyl)-amide F F R)-3-{ (S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 209 F H 0 H 0 ro tetrahydro-1 H-carbazole-3 Nj N k .-. ,N.), carboxylic acid {(S)-2 0 H H Hmethyl-1 -[3-(2-morpholin 6 --- O H H H4-yI-ethyl)-ureidomethyl] butyll-amide F F F (R)-3-{ (S)-2-[2-(2-Fluoro HN phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 210 F 0 trifluoromethyl-2,3,4,9 H H tetrahydro-1 H-carbazole-3 N I N carboxylic acid ((S)-1 6 H H benzylthiocarbamoyl-2 methyl-butyl)-amide FF F (R)-3-{ (S)-2-[2-(2-Fluoro HN phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 211 F H 0 H trifluoromethyl-2,3,4,9 ~ N ttayr-1 H-carbazole-3 I -. 0 H 0 -1H carboxylic acid [(S)-l -(3 hydroxy-propylcarbamoyl) 2-methyl-butyl]-amide WO 2008/132153 PCT/EP2008/055039 - 273 F F F (R)-3-{(S)-2-[2-(2-Fluoro HN /phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 212 H H 0 trifluoromethyl-2,3,4,9 22 NH tetrahydro-1 H-carbazole-3 6 H carboxylic acid ((S)-2-oxo azepan-3-yl)-amide F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-4 methylsulfanyl 3F H S butyrylamino}-8 213 H31Htrifluoromethyl-2,3,4,9 N -NH 2 tetrahydro-1 H-carbazole-3 H carboxylic acid ((S)-2 Ss methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 F H 0 trifluoromethyl-2,3,4,9 21 Htetrahydro-1 H-carbazole-3 N "-:NH 2 carboxylic acid ((R)-1 o 0 carbamoyl-2 methylsulfanyl-ethyl) amide F F F (R)-3-{(R)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methylsulfanyl propionylamino}-8 215 H 0 Strifluoromethyl-2,3,4,9 1 N N NH2 tetrahydro-1 H-carbazole-3 0 carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 216 F H s tetrahydro-1 H-carbazole-3 SN N carboxylic acid {(S)-1-[(2 H Nr methoxy-pyridin-4 ylmethyl)-thiocarbamoyl]-2 methyl-butyl}-amide WO 2008/132153 PCT/EP2008/055039 - 274 F F F (R)-3-{(R)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /thiophen-2-yl propionylamino}-8 217 H trifluoromethyl-2,3,4,9 N FN H 2 tetrahydro-1 H-carbazole-3 NH H 2 carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F (R)-3-((S)-2-{[2-(2-Fluoro phenyl)-acetyl]-methyl HN /amino}-3-methyl 218 F pentanoylamino)-8 218 ~ H trifluoromethyl-2,3,4,9 tetrahydro-1 H-carbazole-3 H 2 carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{(S)-2-[2-(2-Fluoro HN phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 F O O rfurmehl2349 219 N N N- O H H0H_/ 6--yo carboxylic acid [(S)-2 methyl-i -(morpholin-4 ylcarbamoyl)-butyl]-amide F F (R)-3-((S)-2-{[2-(2-Fluoro phenyl)-acetyl]-methyl HN /amino}-3-methyl metylpentanoylamino)-8 220 H trifluoromethyl-2,3,4,9 tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-2 carbamoyl-2-methyl-butyl) amide F F F (R)-3-((S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 methyl-pentanoylamino-8 221 F H 0 H trifluoromethyl-2,3,4,9 tetrahydro-1 H-carbazole-3 H carboxylic acid [(S)-2 ylcarbamoyl)-butyl]-amide WO 2008/132153 PCT/EP2008/055039 - 275 F F F F (R)-3-{(S)-2-[3-(2-Fluoro HN p / phenyl)-ureido]-3-methyl pentanoylamino}-8 222 F HH S trifluoromethyl-2,3,4,9 Stetrahydro-1 H-carbazole-3
[8] 222-'J' N N H2ttayr NH 2 carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F FF (R)-3-{(S)-2-[3-(2-Fluoro HN /benzyl)-ureido]-3-methyl F pentanoylamino}-8 223 H H 0 H strifluoromethyl-2,3,4,9 C N Ntetrahydro-1 H-carbazole-3 o H carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide Carbonic acid 4-{(S)-2 F [((R)-3-{(S)-2-[2-(2-fluoro F F phenyl)-acetylamino]-3 / methyl-pentanoylamino}-8 224 H 0 H 0trifluoromethyl-2,3,4,9 224H H tetrahydro-1 H-carbazole-3 carbonyl)-amino]-3-methyl pentanoylamino}-butyl ester 2-[2-(2-methoxy ethoxy)-ethoxy]-ethyl ester F F(R)-3-{(S)-2-[2-(2-Fluoro F phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 225 F 0 H 0Ltetrahydro-1 H-carbazole-3 NjN N, 2 I N'N carboxylic acid [(S)-2 H H methyl-1-(N'-methyl-N' phenyl-hydrazinocarbonyl) butyl]-amide F F F F(R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN methyl-pentanoylamino}-8 F H 0 H '0 0 trifluoromethyl-2,3,4,9 N N F tetrahydro-1 H-carbazole-3 226 tetrHydF 0 H 0 H H carboxylic acid {(S)-1 -[N' (4-fluoro-benzoyl) hydrazinocarbonyl]-2 methyl-butyl}-amide WO 2008/132153 PCT/EP2008/055039 - 276 F F F (R)-3-((S)-2-{[1 -(2-Fluoro phenyl) HN /cyclopentanecarbonyl] amino}-3-methyl 227 H H 0 H S pentanoylamino)-8 N. 1 NK trifluoromethyl-2,3,4,9 227HNH2 tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F FR)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 F trifluoromethyl-2,3,4,9 28F H Hi H tetrahydro-1 H-carbazole-3 N,_Qk~ NjKN / F carboxylic acid {(S)-1 -[N' H H N F (2,4-difluoro-phenyl) hydrazinocarbonyl]-2 methyl-butyl}-amide F F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 F 0 trifluoromethyl-2,3,4,9 N NQ, 0tetrahydro-1 H-carbazole-3 carboxylic acid ((S)-2 methyl-1 phenoxycarbamoyl-butyl) amide F F F (R)-3-[(S)-3-Methyl-2-(2 HN /pyridin-3-yl-acetylamino) pentanoylamino]-8 230 H0 s trifluoromethyl-2,3,4,9 W'L >tetrahydro-1 H-carbazole-3 H 2 carboxylic acid ((S)-2 N" H methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-[(S)-3-Methyl-2-(2 HN /pyridin-2-yl-acetylamino) pentanoylamino]-8 2u1 H 0 s Ntrifluoromethyl-2,3,4,9 23 ' H2tetrahydro-1 H-carbazole-3 H 2 carboxylic acid ((S)-2 ~N 0 0methyl-1 -thiocarbamoyl butyl)-amide WO 2008/132153 PCT/EP2008/055039 - 277 F 3-{(S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 232 F 0tetrahydro-1 H-carbazole-3 H H ~ carboxylic acid {(S)-2 N N-N methyl-1-[N'-(pyridine-4 O H 0 HN H--yo 'N carbonyl) hydrazinocarbonyl]-butyl} amide F F F HN 233 F 0 0 6 - H H H H - 0 0 F F FF 3-{(S)-2-[3-(4-Fluoro HN /benzyl)-ureido]-3-methyl pentanoylamino}-8 F 0 trifluoromethyl-2,3,4,9 23 H HN. l Ntetrahydro-1 H-carbazole-3 H -carboxylic acid ((S)-2 0 0 methyl-1 -thiocarbamoyl butyl)-amide F F F F F 3-{(S)-2-[3-(3-Fluoro benzyl)-ureido]-3-methyl F Hpentanoylamino}-8 235 H H0 H trifluoromethyl-2,3,4,9 ,,NK)N N K tetrahydro-1 H-carbazole-3 NH 2 carboxylic acid ((S)-2 0 - 0methyl-1 -thiocarbamoyl butyl)-amide F F F F F (R)-3-[(S)-3-Methyl-2-(2 HN /pyridin-4-yl-acetylamino) pentanoylamino]-8 236 H 0 H s trifluoromethyl-2,3,4,9 N KNH tetrahydro-1 H-carbazole-3 N O NH2 H 0 carboxylic acid ((S)-2 0 - 0methyl-1 -thiocarbamoyl butyl)-amide WO 2008/132153 PCT/EP2008/055039 - 278 F F F (R)-3-{(S)-3-Methyl-2-[3-(3 HN /methyl-benzyl)-ureido] pentanoylamino}-8 237 H HH 0 H strifluoromethyl-2,3,4,9 ~N H tetrahydro-1 H-carbazole-3 0 carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{(S)-3-Methyl-2-[3-(4 HN /methyl-benzyl)-ureido] pentanoylamino}-8 238 HH s trifluoromethyl-2,3,4,9 NN N N, ,~~ tetrahydro-1 H-carbazole-3 0 H carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F FF (R)-3-{(S)-2-[3-(4-Methoxy HN /benzyl)-ureido]-3-methyl pentanoylamino}-8 239 1H H H trifluoromethyl-2,3,4,9 N N N tetrahydro-1 H-carbazole-3 H carboxylic acid ((S)-2 0 0 methyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 240 F H 0 H 0o tetrahydro-1 H-carbazole-3 N NN. H carboxylic acid {(S)-1 -[N' 0 H 0 H (3-methoxy-benzoyl) 0 - hydrazinocarbonyl]-2 methyl-butyl}-amid F F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 241 F H 0 0o 0 0tetrahydro-1 H-carbazole-3 N NN carboxylic acid {(S)-1 -[N' H H H (furan-2-carbonyl) 0 0 Ohydrazinocarbonyl]-2 methyl-butyl}-amide WO 2008/132153 PCT/EP2008/055039 - 279 F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 242 F 0 H0tetrahydro-1 H-carbazole-3 N~J N-N -carboxylic acid [(S)-1-(N' H 0 H benzoyl 00 hydrazinocarbonyl)-2 methyl-butyl]-amide F F (R)-3-{(S)-2-[2-(2-Fluoro phenyl)-2-hydroxy acetylamino]-3-methyl 43F OH H pentanoylamino}-8 trifluoromethyl-2,3,4,9 4 N2 tetrahydro-1 H-carbazole-3 '-- 0 carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide F F F F(R)-3-{(S)-2-[3-(2-Fluoro benzyl)-ureido]-3-methyl HN /pentanoylamino}-8 F 0trifluoromethyl-2,3,4,9 244 HH H H tetrahydro-1 H-carbazole-3 Ncarboxylic acid [(S)-2 methyl-1-(N'-phenyl hydrazinocarbonyl)-butyl] amide F (R)-3-{(S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 trifluoromethyl-2,3,4,9 245 F H 0 tetrahydro-1 H-carbazole-3 N / Ncarboxylic acid [(S)-2 H 0 H methyl-1 -(N'-pyridin-2-yl hydrazinocarbonyl)-butyl] amide F F F (R)-3-[(S)-3-Methyl-2-(2 oxo-2-phenyl HN /acetylamino) pentanoylamino]-8 246 0 H H trifluoromethyl-2,3,4,9 NN, N NH N 0 Htetrahydro-1 H-carbazole-3 o O O carboxylic acid ((S)-2 methyl-1 -thiocarbamoyl butyl)-amide WO 2008/132153 PCT/EP2008/055039 - 280 F F F {(S)-2-Methyl-1 -[(R)-3-((S) HN /2-methyl-1 -thiocarbamoyl butylcarbamoyl)-8 247 H H Strifluoromethyl-2,3,4,9 N2 tetrahydro-1 H-carbazol-3 H2 0 0 ylcarbamoyl]-butyl} carbamic acid benzyl ester F F F (R)-3-{(S)-2-[3-(3-Methoxy benzyl)-ureido]-3-methyl HN /pentanoylamino}-8 trifluoromethyl-2,3,4,9 8H H H.tetrahydro-1 H-carbazole-3 2 NH2 carboxylic acid ((S)-2 N H 0 methyl-1 -thiocarbamoyl butyl)-am ide F F F F(R)-3-{(2S,3S)-2-[2-(2 H Fluoro-phenyl) N /acetylamino]-3-methyl pentanoylamino}-8 249 trifluoromethyl-2,3,4,9 N N tetrahydro-1 H-carbazole-3 carboxylic acid [(1 S,2S)-2 methyl-1 -(4-phenyl-thiazol 2-yl)-butyl]-amide F F F F(R)-3-{(2S,3S)-2-[2-(2 Fluoro-phenyl) HN /acetylamino]-3-methyl pentanoylamino}-8 5 Ftrifluoromethyl-2,3,4,9 250 F H0 HS N NN / tetrahydro-1 H-carbazole-3 0Y 0 carboxylic acid {(1S,2S)-1 [4-(4-methoxy-phenyl) thiazol-2-yl]-2-methyl butyl}-ami F F F 2-{(1R,2S)-1-[((R)-3 {(2S,3S)-2-[2-(2-Fluoro HN /phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 251 F H 0 H >- trifluoromethyl-2,3,4,9 0 0 " N 0tetrahydro-1H-carbazole-3 YO ~carbon yl) -am ino]-2-m et hyl butyl}-thiazole-4-carboxylic acid ethyl ester WO 2008/132153 PCT/EP2008/055039 - 281 F F F (R)-3-{ (2S,3S)-2-[2-(2 Fluoro-phenyl) HN /acetylam ino]-3-m ethyl F pentanoylamino}-8 252 F H 0 H strif luorom ethyl-2,3,4,9 N" N F F tetrahydro-1 H-carbazole-3 . ~ H carboxylic acid [(1 S,2S)-2 yo methyl-i -(4-trifluoromethyl 1 1 thiazol-2-yI)-butyl]-amide F F F (R)-3-{ (2S,3S)-2-[2-(2 HN Fluoro-phenyl) HN /acetylam ino]-3-m ethyl F 0 spentanoylamino}-8 253 H H I t r iflIu oro me t hyI- 2,3,4,9 )N ' N", N tetrahydro-1 H-carbazole-3 - o 0 0 carboxylic acid [(1 S,2S)-1 1 1 (4-ethyl-thiazol-2-yI)-2 methyl-butyl]-amide FF F (R)-3-{ (2S,3S)-2-[2-(2 F F Fluoro-phenyl) HN /acetylam ino]-3-m ethyl pentanoylamino}-8 254 F H trif luoromethyl-2,3,4,9 N. i tetrahydro-1 H-carbazole-3 H carboxylN acid [(1 S,2S)-1 I methyl-butyl]-amide F (R)-3-{ (2S,3S)-2-[2-(2 F F Fluoro-phenyl) H acetylam ino]-3-m ethyl N /pentanoylamino}-8 25F H Q OHF trif luoromethyl-2,3,4,9 255I.Q tetrahydro-1 H-carbazole-3 N N F carboxylic acid [(1 S,2S)-1 1N FF 0OD. H~ 0 (4-hydroxy-4 1 1 trifluoromethyl-4,5-dihydro thiazol-2-yI)-2-methyl butyll-amide F F 2-f{(1 S,2S)-l -[((R)-3 F f{(2S,3S)-2-[2-(2-Fluoro HN /phenyl)-acetylamino]-3 methyl-pentanoylamino}-8 256 F H0 Hs OH trifluoromethyl-2,3,4,9 ii ~ ii ~'tetrahydro-1 H-carbazole-3 A<14 ' N 0 carbon yl) -am ino]-2-m et hyl 6z 02, 0-,, butyl}-thiazole-4-carboxylic _________________________ Iacid WO 2008/132153 PCT/EP2008/055039 - 282 F F F (R)-3-{ (S)-2-[3-(3-Methoxy phenyl)-propionylamino]-3 HN H / methyl-pentanoylamino}-8 257 0strif luorom ethyl-2,3,4,9 HI H [Itetrahydro-l H-carbazole-3 ':')N" N :'<NH carboxylic acid ((S)-2 0 H 0methyl-i -thiocarbamoyl butyl)-amide F 2-f{(1 S,2S)-l -[((R)-3 F F f{(2S,3S)-2-[3-(2-Fluoro HN benzyl)-ureido]-3-methyl / pentanoylamino}-8 258 H H H SJ trifluoromethyl-2,3,4,9 NN , te1hyr-1 H-carbazole-3 F 0) O carbon yl) -am ino]-2-m et hyl F 0 butyl}-thiazole-4-carboxylic acid ethyl ester FF F 2-f{(1 S,2S)-1 -[((R)-3 { (2S,3S)-2-[3-(4-Methoxy HN /benzyl)-ureido]-3-methyl 259 0-/pentanoylamino}-8 259H H0 trif luoromethyl-2,3,4,9 N~NNL~ 0 0tetrahydro-1 H-carbazole-3 Y 0 carbon yl) -am ino]-2-m et hyl 0 butyll-thiazole-4-carboxylic 1 acid ethyl ester FF F 2-f{(1 S,2S)-1 -[((R)-3 HN /benzyl)-ureido]-3-methyl pentanoylamino}-8 260 H H 0 S OH trif luoromethyl-2,3,4,9 N N o N "Ltetrahydro-1 H-carbazole-3 Y H 0 ~carbon yl) -am ino]-2-m et hyl 0 butyl}-thiazole-4-carboxylic acid FF F (R)-3-{ (2S,3S)-2-[2-(2 Fluoro-phenyl) HN /acetylam ino]-3-m ethyl pentanoylamino}-8 261 F H 0 H NH 2 trifluoromethyl-2,3,4,9 N~k~N N 0 tetrahydro-1 H-carbazole-3 0 0 2.carboxylic acid [(1 S,2S)-1 1 1 (4-carbamoyl-thiazol-2-yl) 2-methyl-butyl]-amide WO 2008/132153 PCT/EP2008/055039 - 283 F 2-{(1 S,2S)-1 -[((R)-3 F F f{(2S,3S)-2-[3-(2-Fluoro HN benzyl)-thioureido]-3 methyl-pentanoylamino}-8 262 H H0 H S 0trifluoromethyl-2,3,4,9 Ntetrahydro-1 H-carbazole-3 carbonyl)-amino]-2-methyl butyl}-thiazole-4-carboxylic acid ethyl ester F F F F(R)-3-{(2S,3S)-2-[3-(2 Fluoro-benzyl)-thioureido] HN /3-methyl-pentanoylamino} 263 0 S NH8-trifluoromethyl-2,3,4,9 H H H tetrahydro-1 H-carbazole-3 . N N' N N 0 carboxylic acid [(1S,2S)-1 F S 0- O (4-carbamoyl-thiazol-2-yl) 2-methyl-butyl]-amide F F (R)-3-{(2S,3S)-2-[3-(2 Fluoro-benzyl)-thioureido] HN 3-methyl-pentanoylamino} 264 0 / 8-trifluoromethyl-2,3,4,9 HHII H Stetrahydro-1 H-carbazole-3 2 NH 2 carboxylic acid ((1 S,2S)-2 F 0, omethyl-1 -thiocarbamoyl butyl)-amide F F F (R)-3-{(S)-2-[2-(3-Methoxy phenyl)-acetylamino]-3 HN /methyl-pentanoylamino}-8 265 trifluoromethyl-2,3,4,9 H 0 H S tetrahydro-1 H-carbazole-3 o NA '0 N~ H carboxylic acid ((S)-2 H 2 methyl-1 -thiocarbamoyl butyl)-amide F (R)-3-{(S)-2-[2-(2-Fluoro F F phenyl)-acetylamino]-3 H HO 0 methyl-pentanoylamino}-8 266/ F trifluoromethyl-2,3,4,9 26 Ftetrahydro-1 H-carbazole-3 H e H carboxylic acid {(S)-2 N methyl-1-[(tetrahydro cthiopyran-4-ylmethyl) carbamoyl]-butyl}-amide WO 2008/132153 PCT/EP2008/055039 - 284 9. Process for manufacturing a tetrahydrocarbazole derivative as claimed in any of claims 1 to 8. 10. Pharmaceutical composition comprising a pharmaceutically active amount of at 5 least one compound as claimed in any of claims 1 to 8. 11. Pharmaceutical composition as claimed in claim 10, where the at least one com pound is present in a unit dose of from 0.001 mg to 100 mg per kg of body weight of the patient. 10 12. Pharmaceutical composition as claimed in any of claims 10 to 11, where the com position additionally comprises at least one pharmaceutically acceptable carrier and/or auxiliary. 15 13. Pharmaceutical composition as claimed in any of claims 10 to 12, where the com position additionally comprises at least one further pharmacologically active sub stance. 14. Pharmaceutical composition as claimed in claim 13, where the further pharmaco 20 logically active substance is selected from the group consisting of: "androgens, es trogens, progestins, progestagens, selective estrogen receptor modulator (SERM), selective androgen receptor modulator (SARM), receptor-type tyrosine kinase inhibitor, 5alpha-reductase inhibitors, 5alpha-reductase 1 inhibitors, 5alpha reductase 2 inhibitors, alpha-receptor inhibitors (alpha blockers), alphal-adrenergic 25 receptor antagonists, aromatase inhibitors, lyase inhibitors, GnRH/LHRH receptor agonists, GnRH/LHRH receptor antagonists, NK, receptors antagonists, NK 2 receptors antagonists, NK, receptors agonists, NK 2 receptors agonists". 15. Pharmaceutical composition as claimed in claim 14, where the further pharmaco 30 logically active substance is selected from the group consisting of: "testosterone, oestradiol, oestriol, oestrone, progesterone, raloxifene, arzoxifene, lasofoxifene, WO 2008/132153 PCT/EP2008/055039 - 285 ospemifene, TSE-424, HMR-3339, SERM-3339, SPC-8490, HM-101, bazedoxifene (WAY 140424), flutamide, casodex, nilutamide, tamoxifen, fulvestrant, finasteride, dutasteride, izonsteride, epristeride, tamsulosin, prazosin, terazosin, doxazosin, si lodosin, alfuzosin, anastrozole, letrozole, finrozole, exemestane, gefitinib, imatinib, 5 semaxanib, SU-6668, SU-101, CI-1033, E-6006, R-116301, aprepitant, GW-2016, ZD-4794, BL-1832, BL-1833, GW-597599, GW-679769, KRP-103, TKA-457, L 758298, L-760735, L-759274, NIP-530, CJ-17493, R-1124, ezlopitant, CP-122721, PD-154075, CP-96345, R-673, SSR 240600, MK-0869, SR 140333, CP-99,994, NKP-608, TAK-637, MEN-11467, GR 73632, phenoxybenzamine, sildenafil, bicalu 10 tamide, cyproterone acetate, ketoconazole, aminoglutethimide, danazol". 16. Tetrahydrocarbazole derivative according to any of claims 1 to 8 or pharmaceutical composition according to any of claims 10 to 15 for use as a medicament. 15 17. Use of a tetrahydrocarbazole derivative according to any of claims 1 to 8 or a pharmaceutical composition according to any of claims 10 to 15 for the manufac ture of a medicament for the treatment and/or prophylaxis of physiological and/or pathological conditions mediated by G-protein coupled receptors or of physiological and/or pathological conditions which can be treated by modulation of these recep 20 tors. 18. The use as claimed in claim 17, where the G-protein coupled receptors are se lected from the group consisting of "GnRH receptor, LHRH receptor, neurokinin family receptor, NK, receptor, NK 2 receptor". 25 19. The use as claimed in any of claims 17 to 18, where the tetrahydrocarbazole de rivative as claimed in any of claims 1 to 8 acts as a GnRH receptor antagonist, LHRH receptor antagonist, NK, receptor antagonist and/or NK 2 receptor antagonist. 30 20. The use as claimed in any of claims 17 to 19, where the physiological and/or patho logical conditions are selected from the group consisting of: "benign tumor dis eases, malignant tumor diseases, male fertility control, hormone therapy, hormone WO 2008/132153 PCT/EP2008/055039 - 286 replacement therapy, female sub- or infertility, controlled ovarian stimulation in in vi tro fertilization (COS/ART), female contraception, side effects due to chemother apy, prostate cancer, breast cancer, uterine cancer, endometrial cancer, cervical cancer, ovarian cancer, benign prostate hyperplasia (BPH), endometriosis, uterine 5 fibroids, uterine myomas, endometrium hyperplasia, dysmenorrhoea, dysfunctional uterine bleeding (menorrhagia, metrorrhagia), pubertas praecox, hirsutism, polycys tic ovary syndrome, hormone-dependent tumor diseases, HIV infections or AIDS, neurological or neurodegenerative disorders, ARC (AIDS related complex), Kaposi sarcoma, tumors originating from the brain and/or nervous system and/or men 10 inges, dementia, Alzheimer's disease, nausea, vomiting, pain, inflammations, chronic inflammations, acute inflammations, rheumatic and arthritic pathological states, chronic pain, panic disorder, disturbances of mood and sleep, depression, fibromyalgia, post-traumatic stress disorder, tension headache, migraine headache, anxiety, generalized anxiety disorder, bowel syndrome, irritable bowel sysndrome, 15 stress-induced hypertension, asthma, emesis, cough, cystitis of the bladder, pan creatitis and/or atopic dermatitis". 21. The use according to any of claims 17 to 20, where the medicament additionally comprises at least one further pharmacologically active substance. 20 22. The use according to any of claims 17 to 20, where the medicament is adminis tered before and/or during and/or after the treatment with at least one further phar macologically active substance. 25 23. The use according to any of claims 21 to 22, where the further pharmacologically active substance is selected from the group consisting of: "androgens, estrogens, progestins, progestagens, selective estrogen receptor modulator (SERM), selective androgen receptor modulator (SARM), receptor-type tyrosine kinase inhibitor, 5alpha-reductase inhibitors, 5alpha-reductase 1 inhibitors, 5alpha-reductase 2 30 inhibitors, alpha-receptor inhibitors (alpha blockers), alphal-adrenergic receptor antagonists, aromatase inhibitors, lyase inhibitors, GnRH/LHRH receptor agonists, GnRH/LHRH receptor antagonists, NK, receptors antagonists, NK 2 receptors antagonists, NK, receptors agonists, NK 2 receptors agonists". WO 2008/132153 PCT/EP2008/055039 - 287 24. The use according to claim 23, where the further pharmacologically active sub stance is selected from the group consisting of: "testosterone, oestradiol, oestriol, oestrone, progesterone, raloxifene, arzoxifene, lasofoxifene, ospemifene, TSE-424, 5 HMR-3339, SERM-3339, SPC-8490, HM-101, bazedoxifene (WAY 140424), flu tamide, casodex, nilutamide, tamoxifen, fulvestrant, finasteride, dutasteride, izon steride, epristeride, tamsulosin, prazosin, terazosin, doxazosin, silodosin, alfuzosin, anastrozole, letrozole, finrozole, exemestane, gefitinib, imatinib, semaxanib, SU 6668, SU-101, CI-1033, E-6006, R-116301, aprepitant, GW-2016, ZD-4794, BL 10 1832, BL-1833, GW-597599, GW-679769, KRP-103, TKA-457, L-758298, L 760735, L-759274, NIP-530, CJ-1 7493, R-1124, ezlopitant, CP-122721, PD 154075, CP-96345, R-673, SSR 240600, MK-0869, SR 140333, CP-99,994, NKP 608, TAK-637, MEN-1 1467, GR 73632, phenoxybenzamine, sildenafil, bicalu tamide, cyproterone acetate, ketoconazole, aminoglutethimide, danazol". 15 25. Kit comprising a pharmacologically active amount of at least one tetrahydrocarba zole derivative as claimed in any of claims 1 to 8 and/or at least one pharmaceuti cal composition as claimed in any of claims 10 to 15 and a pharmacologically active amount of at least one further pharmacologically active substance as claimed in 20 any of claims 23 to 24.

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同族专利:

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EP1988098A1|2008-11-05|

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引用文献:

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公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

DZ2769A1|1998-04-17|2003-12-01|Lilly Co Eli|Substituted tricyclics.|

---

RU2207340C2|2001-08-10|2003-06-27|Ципла Лтд.|Method for preparing 1,2,3,9-tetrahydro-9-methyl-3-[methyl]-4h-carbazole-4-one or its pharmaceutically acceptable salts|

---

CA2468880A1|2001-12-14|2003-06-26|Zentaris Gmbh|Tetrahydrocarbazole derivatives as ligands for g-protein coupled receptors |

---

DE102004033902A1|2004-07-14|2006-02-16|Zentaris Gmbh|New tetrahydrocarbazole compounds are neurokinin-1 receptor antagonists useful to treat or prevent e.g. pubertas praecox, hirsutism, polycystic ovary syndrome, hormone dependent neoplastic diseases and Alzheimer's disease|EP2095818A1|2008-02-29|2009-09-02|AEterna Zentaris GmbH|Use of LHRH antagonists at non-castrating doses|

---

CA2823665A1|2011-01-04|2012-07-12|Novartis Ag|Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration |

---

US8748470B2|2011-03-17|2014-06-10|The University Of Chicago|Methods for treating ovarian cancer by inhibiting fatty acid binding proteins|

---

CN102139107B|2011-03-23|2012-10-03|浙江理工大学|Anticancer effect of antagonist of neurokinin receptor|

---

CN103142593B|2011-03-23|2014-07-16|浙江理工大学|Application of neurokinin receptor 2 antagonist to treatment of leukemia|

---

US10806740B2|2012-06-18|2020-10-20|Therapeuticsmd, Inc.|Natural combination hormone replacement formulations and therapies|

---

US10537581B2|2012-12-21|2020-01-21|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|

---

US20130338122A1|2012-06-18|2013-12-19|Therapeuticsmd, Inc.|Transdermal hormone replacement therapies|

---

US9301920B2|2012-06-18|2016-04-05|Therapeuticsmd, Inc.|Natural combination hormone replacement formulations and therapies|

---

MX365818B|2011-11-23|2019-05-30|Therapeuticsmd Inc|Natural combination hormone replacement formulations and therapies.|

---

US20150196640A1|2012-06-18|2015-07-16|Therapeuticsmd, Inc.|Progesterone formulations having a desirable pk profile|

---

US10806697B2|2012-12-21|2020-10-20|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|

---

US10568891B2|2012-12-21|2020-02-25|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|

---

US10471072B2|2012-12-21|2019-11-12|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|

---

US11246875B2|2012-12-21|2022-02-15|Therapeuticsmd, Inc.|Vaginal inserted estradiol pharmaceutical compositions and methods|

---

WO2014002051A2|2012-06-28|2014-01-03|Novartis Ag|Complement pathway modulators and uses thereof|

---

CN104379579B|2012-06-28|2017-03-08|诺华股份有限公司|Pyrrolidin derivatives and its purposes as complement pathway regulator|

---

JP6155332B2|2012-06-28|2017-06-28|ノバルティス アーゲー|Pyrrolidine derivatives and their use as complement pathway regulators|

---

CN104640855B|2012-06-28|2017-08-29|诺华股份有限公司|Complement is by way of conditioning agent and application thereof|

---

EP2867224B1|2012-06-28|2017-07-26|Novartis AG|Pyrrolidine derivatives and their use as complement pathway modulators|

---

WO2014009833A2|2012-07-12|2014-01-16|Novartis Ag|Complement pathway modulators and uses thereof|

---

CN103864754B|2012-12-10|2016-12-21|中国科学院上海药物研究所|Five-membered azole heterocycle compound and preparation method thereof, pharmaceutical composition and purposes|

---

US9180091B2|2012-12-21|2015-11-10|Therapeuticsmd, Inc.|Soluble estradiol capsule for vaginal insertion|

---

WO2014130932A2|2013-02-25|2014-08-28|Novartis Ag|Novel androgen receptor mutation|

---

EP3145489A1|2014-05-22|2017-03-29|TherapeuticsMD, Inc.|Natural combination hormone replacement formulations and therapies|

---

CN106794175B|2014-06-12|2020-06-09|西达-赛奈医疗中心|Compositions for treating cancer|

---

US10328087B2|2015-07-23|2019-06-25|Therapeuticsmd, Inc.|Formulations for solubilizing hormones|

---

CA3020153A1|2016-04-01|2017-10-05|Therapeuticsmd, Inc.|Steroid hormone pharmaceutical composition|

---

US10286077B2|2016-04-01|2019-05-14|Therapeuticsmd, Inc.|Steroid hormone compositions in medium chain oils|

---

WO2017205582A1|2016-05-27|2017-11-30|Forsyth Dental Infirmary For Children|Compositions and methods of treating cancer using lipid agonists and receptors thereof|

---

TR201819936A2|2018-12-20|2020-07-21|Hacettepe Ueniversitesi|UNIQUE AND NEXT GENERATION INHIBITOR COMPOUNDS SPECIFIC TO GST P1 ENZYME|

---

WO2021067600A1|2019-10-03|2021-04-08|Caren Pharmaceuticals, Inc.|Combination hormone formulations and therapies|

法律状态:
2013-11-28| FGA| Letters patent sealed or granted (standard patent)|

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2015-11-19| MK14| Patent ceased section 143(a) (annual fees not paid) or expired|

优先权:

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申请号 | 申请日 | 专利标题

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US91442407P| true| 2007-04-27|2007-04-27||

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EP07107094A|EP1988098A1|2007-04-27|2007-04-27|Novel Tetrahydrocarbazole Derivatives as Ligands of G-protein Coupled Receptors|

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US60/914,424||2007-04-27||

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EP07107094.0||2007-04-27||

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PCT/EP2008/055039|WO2008132153A1|2007-04-27|2008-04-25|Novel tetrahydrocarbazole derivatives as ligands of g-protein coupled receptors|

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