AU2002361430A1 - Tetrahydrocarbozole derivatives as ligands for g-protein coupled receptors (gpcr) - Google Patents

Description

L4

CLMCS

VERIFICATION OF TRANSLATION I, Alan John SPARROW translator to RWS Group plc, of Europa House, Marsham Way, Gerrards Cross, Buckinghamshire, England, declare as follows: 1. That I am well acquainted with both the English and German languages, and 2. That the attached document is a true and correct translation made by me to the best of my knowledge and belief of: (a) The specification of International Bureau pamphlet numbered WO 03/051837 International Application No. PCT/EPO2/14344 Signature of Translator: For and on behalf of RWS Group plc Date: 5 May 2004 (No witness required) WO 03/051837 PCT/EPO2/14344 TETRAHYDROCARBAZOLE DERIVATIVES AS LIGANDS FOR G PROTEIN COUPLED RECEPTORS (GPCR) The present invention relates to novel tetrahydro 5 carbazole derivatives which are ligands of G-protein coupled receptors, and especially antagonists of gonadotropin-releasing hormone, to the preparation thereof, to the use thereof, and to the pharmaceutical compositions which include these tetrahydrocarbazole 10 derivatives. The present invention also relates to a method for treating pathological states mediated by G protein coupled receptors in a mammal, in particular a human. 15 Technical background The structural element which is common to all members of the family of G-protein coupled receptors (GPCR) is the presence of seven transmembrane alpha-helical 20 segments which are connected together by alternating intra- and extracellular loops, with the amino terminus being located on the extracellular side and the carboxy terminus being located on the intracellular side. The family of GPCRs can be divided into a plurality of 25 subfamilies (essentially family A, B and C) with further sequence homologies within these subfamilies. Since GPCRs are mainly involved in signal reception and transduction, a large number of physiological functions are influenced by them. GPCR ligands are therefore 30 potentially suitable as medicaments for the therapy and prophylaxis of a large number of pathological states. A brief survey of diseases which can be treated with GPCR ligands is given in S. Wilson et al., Pharmaceutical News 2000, 7(3) in Table 1. 35 The majority of known GPCR ligands has a peptide structure. However, peptide receptor ligands frequently have some serious disadvantages such as, for example, -2 low bioavailability and metabolic instability. This is why there has recently been an intensified search for ligands in the form of small, non-peptide molecules. A special part is played in the search for novel, non 5 peptide receptor ligands by so-called "privileged structures". These "privileged structures" are the basic molecular structures which provide ligands for a large number of different receptors. The term "privileged structures" was used for the first time by 10 Evans et al. in connection with benzodiazepine-based CCK (cholecystokinin) A antagonists from the natural product asperlicin (B.E. Evans et al., J. Med. Chem. 1988, 31, 2235). For proteases for example it has been known for some time that certain structural classes can 15 serve as inhibitors of various enzymes. Whereas descriptions in the past were in particular of mechanism-based inhibitors of various proteases, however, more recently the frequency of examples of compounds which, by reason of their three-dimensional 20 structure, fit well into the active binding region of various enzymes has increased (cf. M. Whittaker, Cur. Opin. Chem. Biol. 1998, 2, 386; A.S. Ripka et al., ibid., 441). Such "privileged structures" have already been described for GPCRs too. Examples thereof are, 25 besides the aforementioned benzodiazepines, also peptoids, 4-substituted 4-arylpiperidines, but also specific rigidized P-turn mimetics (B.A. Bunin et al., Ann. Rep. Med. Chem. 1999, 34, 267; R.N. Zuckermann et al., J. Med. Chem. 1994, 37, 2678; G.C.B. Harriman, 30 Tetrahedron Lett. 2000, 41, 8853). A review of this is to be found in A.A. Patchett et al., Ann. Rep. Med. Chem. 1999, 35, 289. The tetrahydrocarbazole derivatives of the present invention provide a further class of "privileged structures" for GPCRs. 35 Although the present invention provides ligands for GPCRs in general, the compounds provided by the present invention are suitable in particular as ligands for a particular representative of the class of GPCRs, namely - 3 gonadotropin-releasing hormone (GnRH). GnRH can be assigned to subfamily A of GPCRs (cf. U. Gether et al., Endocrine Reviews 2000, 21(1), 90). 5 GnRH is a hormone which is synthesized predominantly, but not exclusively, in mammals by nerve cells of the hypothalamus, is transported via the portal vein into the pituitary and is delivered in a controlled manner to the gonadotrophic cells. Interaction of GnRH with 10 its receptor having seven transmembrane domains stimulates the production and release of gonadotropic hormones by means of the second messenger inositol 1,4,5-trisphosphate and Ca ions. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are 15 gonadotropins released by GnRH, stimulate the production of sex steroids and gamete maturation in both sexes. In addition to GnRH (also referred to as GnRH1), there are two further forms of GnRH, namely GnRH2 and 3. 20 The GnRH receptor is used as pharmacological target in a number of disorders which depend on functioning sex hormone production, for example prostate cancer, premenopausal breast cancer, endometriosis and uterine 25 fibroids. GnRH superagonists or antagonists can be employed successfully for these disorders. A further possible indication is, in particular, male fertility control in combination with a replacement dose of androgens. 30 One advantage of GnRH antagonists compared with GnRH superagonists is their direct activity in blocking gonadotropin secretion. Superagonists initially bring about overstimulation of the pituitary, leading to 35 increased gonadotropin release and sex steroid release. This hormonal response is terminated only after a certain delay on the basis of desensitization and downregulation of GnRH receptor concentrations. It is therefore possible that GnRH superagonists, both alone - 4 and in combination with testosterone, are unable effectively to suppress sperm production in men and are thus unsuitable for male fertility control. In contrast to this, peptide GnRH antagonists, especially in 5 combination with a replacement dose of androgen, are able to induce a significant oligozoospermia in humans. However, peptide GnRH antagonists have a number of disadvantages. Thus, they have a considerably lower 10 activity as superagonists and must accordingly be administered in considerably higher dosages. In addition, their oral bioavailability is low, so that they must be administered by injection. Repeated injections in turn lead to a reduction in compliance. 15 Furthermore, the synthesis of peptide GnRH antagonists is complicated and costly by comparison with non peptide compounds. Quinoline derivatives are disclosed as non-peptide GnRH 20 antagonists for example in WO 97/14682. However, it has not been possible to date to put any non-peptide GnRH antagonists on the market. Technical problem 25 The problem on which the present invention is based is to provide novel compounds which are suitable for the treatment of GPCR-mediated pathological states and display in particular a GnRH-inhibiting (GnRH 30 antagonistic) effect. The novel GPCR ligands, preferably GnRH antagonists, ought where possible to be superior to known peptide compounds and represent an effective alternative or improvement in relation to known non-peptide compounds. The novel GPCR ligands, 35 especially GnRH antagonists, should in particular have high activity and, where possible, a high oral bioavailability. Their synthesis ought moreover to be possible simply and at minimal cost. The present invention also provides pharmaceutical compositions - 5 comprising the novel non-peptide GPCR ligands, in particular GnRH antagonists. A further problem on which the present invention is 5 based is to provide novel GPCR ligands, preferably GnRH antagonists, for use as pharmaceutical remedy and for use for producing pharmaceutical remedies, comprising the GPCR ligands, preferably GnRH antagonists. 10 In addition, it is an object of the present invention to provide a method for the treatment of GPCR-mediated pathological states, in particular for inhibiting GnRH, in a mammal, in particular a human. 15 All these problems are surprisingly solved by the provision of the novel tetrahydrocarbazole derivatives, of the pharmaceutical compositions which comprise these tetrahydrocarbazole derivatives, of the method for preparing these tetrahydrocarbazole derivatives, and of 20 the method for the treatment of GPCR-mediated pathological states, preferably for inhibition of GnRH, in a mammal, in particular a human, through administration of the tetrahydrocarbazole derivatives or the use of the tetrahydrocarbazole derivatives for 25 producing pharmaceutical remedies for the treatment of GPCR-mediated pathological states, in particular for GnRH inhibition. Summary of the invention 30 In a first aspect, the present invention provides novel tetrahydrocarbazole derivatives of the general formula (I). 35 In a second aspect, pharmaceutical compositions which comprise at least one of the novel tetrahydrocarbazole derivatives of the general formula (I) are provided.

- 6 In a third aspect, the present invention provides tetrahydrocarbazole derivatives of the general formula (I) for use as pharmaceutical remedy. 5 In a further aspect, the present invention relates to the use of a tetrahydrocarbazole derivative of the general formula (I) for producing a pharmaceutical remedy for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH. The 10 present invention likewise relates to a method for the treatment of GPCR-mediated pathological states, in particular for inhibition of GnRH, in a mammal, preferably a human, where an effective amount of a compound of the invention of the general formula (I) is 15 administered to the mammal, preferably the human, requiring such a treatment. The present invention additionally provides a method for preparing tetrahydrocarbazole derivatives of the 20 general formula (I). This method comprises for example the steps of condensation of a cyclohexanone derivative, which is tethered to a solid phase and is expediently substituted, with a suitably substituted phenylhydrazine derivative, a subsequent derivatization 25 depending on the desired structure of the final compound, and finally elimination from the solid phase and isolation of the product. Detailed description of the invention 30 In a first aspect of the present invention there is provision of novel tetrahydrocarbazole compounds of the general formula (I) -7 - 7 in which the radical R 1 is a hydrogen atom, a C 2

-C

6 alkenyl or a Ci-C 6 alkyl radical and may optionally be 5 substituted by an aryl, hetaryl radical or the group

-COOR

1 , where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of -NO 2 , -CH 3 , -CF 3 , -OCH 3 , -OCF 3 and halogen 10 atoms, and the radical R 1 is a hydrogen atom, a C 1

-C

12 alkyl, a

C

1

-C

12 aralkyl, an aryl, hetaryl radical or the group

-COCH

3 and may optionally be substituted by one substituent selected from the group consisting of 15 -CONH 2 , -COCH 3 , -COOCH 3 , -SO 2

CH

3 and aryl radicals; the radicals R 2 , R 3 , R 4 and R 5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 , -CF 3 , -OCF 3 , -NO 2 , -CN, a C 1

-C

6 alkyl, a 20 Cl-C 6 alkenyl, a C 1

-C

6 alkoxy, a C 1

-C

1 2 aralkyl, an aryl or hetaryl radical; the radical R 6 is the group -CONR 8

R

9 , -COOR 8,

-CH

2

NR

8

R

9 ,

-CH

2

R

8 , -CH 2 OR or a C 1

-C

12 alkenyl radical which is 25 optionally substituted by the radicals R 8 and R 9 , where the radicals R 8 and R 9 are each independently of one another a hydrogen atom, a Cl-C 12 alkyl, a CI-C 12 aralkyl, a C 1

-C

12 hetaralkyl, an aryl or hetaryl radical, each of which may be substituted by one or -8 more substituents selected from the group consisting of -OH, -NH 2 , -CONHR i , -COORio, -NH-C(=NH)-NH 2 and halogen atoms, where the radical R i0 is a hydrogen atom, a Ci-C 12 alkyl, 5 a C 1

-C

12 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R 1

)

2 , or where the radicals R 8 and R 9 may together form a cyclic structure which consists either exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; 10 the radical R 7 is a hydrogen atom, a Cl-C 12 alkyl, a

C

1

-C

12 alkenyl, a Cl-C 1 2 aralkyl, an aryl or hetaryl 12 13 14 14 radical, the group -NR2R , -NHCOR , -NHCONHR ,

-NHCOOR

14 or -NHSO 2

R

1 4 and may optionally be substituted 15 by one or more substituents selected from the group consisting of -OH, -NH 2 , -CONH 2 , -COOH and halogen atoms, the radicals R 12 and R 13 are each independently of one another a hydrogen atom, a C 2

-C

6 alkenyl or a Cl-C 12 20 alkyl radical and may optionally be substituted by one or more aryl or hetaryl radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -NO 2 , -CH 3 , -CF 3 , -OCH 3 , -OCF 3 and halogen atoms, 25 and the radical R 14 is a hydrogen atom, a Cl-C 12 alkyl, a

C-C

12 alkenyl, a C1-C12 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of

-NO

2 , -CH 3 , -OR 11

-CF

3 , -OCF 3 , -OH, -N(R 11 ) 2 , -OCOR 1 30 -COOH, -CONH 2 , -NHCONHR 1 , -NHCOOR 1 1 and halogen atoms; and the radicals Ra, Rb , Rc, Rd, Re and R f are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 , -CF 3 , -OCF 3 , -NO 2 , -CN, a 35 Cl-C 6 alkyl, Ci-C 6 alkoxy, an aryl or hetaryl radical; with the proviso that the compound of the general formula (I) is not selected from the group consisting of 3-amino-l, 2,3,4-tetrahydrocarbazole-3-carboxylic - 9 acid, 3-amino-6-methoxy-1,2,3,4-tetrahydrocarbazole-3 carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4 tetrahydrocarbazole-3-carboxylic acid, 3-acetamido 1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl 5 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3 carboxylate or 3-tert-butoxycarbonylamino-1,2,3,4 tetrahydrocarbazole-3-carboxylic acid. 10 One embodiment of the invention are compounds of the general formula (I) as indicated above with all the meanings indicated above for the radicals contained in (I), where the radical Ru is a heteroalkyl or a hetarylalkyl radical. 15 The basic tetrahydrocarbazole structures of those compounds which are specifically excluded above from the compounds falling within the definition of the general formula (I) were introduced by Y. Maki et al. 20 in Chem. Pharm. Bull. 1973, 21 (11), 2460-2465 and by R. Millet et al. in Letters in Peptide Science 1999, 6, 221-233. The terms indicated for explanation of the compounds of 25 the general formula (I) have in particular the following meaning: Ci-C 6 or Cl-C 12 "alkyl radical" means a branched or unbranched, cyclic or acyclic, optionally substituted 30 alkyl group having 1 to 6 or 1 to 12 carbon atoms, respectively. Representative examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n butyl, isobutyl, tert-butyl, n-pentyl, 2,2 dimethylpropyl, 3-methylbutyl, n-hexyl, n-heptyl, n 35 octyl,.. n-nonyl, n-decyl, n-undecyl and n-dodecyl groups, and cyclic groups, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl groups, 1-cyclopropyl-, 1-cyclobutyl-, 1-cyclopentyl-, 1-cyclohexyl-, 1-cycloheptylethyl-, 2-cyclopropyl-, 2- - 10 cyclobutyl-, 2-cyclopentyl-, 2-cyclohexyl-, 2 cycloheptylethyl groups and the like, but are not restricted to these. 5 C 2

-C

6 "'alkenyl radical" means a branched or unbranched, cyclic or acyclic, optionally substituted, mono- or polyunsaturated alkenyl group having 2 to 6 carbon atoms. Representative examples of such alkenyl groups include vinyl, allyl, prop-l-enyl, but-l-enyl, but-2 10 enyl, but-3-enyl, buta-1,3-dienyl, pent-l-enyl, pent-2 enyl, pent-3-enyl, pent-4-enyl, penta-1,3-dienyl, penta-1,4-dienyl, penta-2,3-dienyl, isoprenyl, hex-l enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, hexa-l,3-dienyl, hexa-l,4-dienyl, hexa-1,5-dienyl, 15 hexa-2,4-dienyl, hexa-2,5-dienyl, hexa-l,4-dienyl, hexa-l,3,5-trienyl groups and the like, but are not restricted to these.

C

2

-C

6 "alkoxy radical" means a branched or unbranched, 20 cyclic or acyclic, optionally substituted alkoxy group having 2 to 6 carbon atoms. Representative examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n pentoxy, n-hexoxy, cyclohexyloxy groups and the like, 25 but are not restricted to these.

CI-C

12 "aralkyl radical" means an alkyl radical having 1 to 12 carbon atoms which is substituted by one or more aryl radicals. Representative examples of such aralkyl 30 groups for the purposes of the present invention include benzyl, 1-phenylethyl, 1-phenylpropyl, 1 phenylbutyl, l-phenylhexyl, 1-phenyl-2-methylethyl, 1 phenyl-2-ethylethyl, l-phenyl-2,2-dimethylethyl, benzhydryl, triphenylmethyl, 2- or 3-naphthylmethyl, 2 35 phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5 phenylpentyl groups and the like, but are not restricted to these. Correspondingly, a "hetaralkyl radical" is an alkyl radical substituted by a heteroaryl radical.

- 11 "Aryl radical" means an optionally substituted mono- or polycyclic aromatic group. Representative examples of such aryl groups include phenyl, naphthyl groups and 5 the like, but are not restricted to these. The term "hetaryl radical" is identical with the term "heteroaryl radical" and represents an aryl group as defined above which includes in its structure one or 10 more heteroatoms, in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. Representative examples of such hetaryl or heteroaryl groups include unsubstituted hetaryl radicals and substituted hetaryl radicals, in particular imidazolyl, pyridyl, quinolinyl 15 groups and the like, but are not restricted to these. The term "cyclic structure" includes optionally substituted mono- or polycyclic cyclic structures with a varying number of ring members, in particular five-, 20 six- and seven-membered cyclic structures. These cyclic structures may include besides carbon atoms also one or more heteroatoms such as, in particular, nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. The cyclic structures may include saturated, but also 25 partially or completely unsaturated, structural elements. Representative examples of such cyclic structures include aza-, oxa-, thia-, phosphacyclopentane-, -cyclohexane-, -cycloheptane-, diaza-, dioxa-, dithia-, diphosphacyclopentane, 30 -cyclohexane, -cycloheptane basic cyclic structures and the like, and basic cyclic structures with mixed heteroatom exchange, but are not restricted to these. "Halogen atoms" include in particular fluorine, 35 chorine, bromine and iodine atoms, particularly preferably chlorine atoms. Reference may also be made at this point to the fact that, besides the compounds of the general formula (I), - 12 as defined above, which are mentioned per se, the present invention also encompasses physiologically tolerated derivatives or analogs, especially also salts of these compounds. 5 It may further be remarked at this point that the term "receptor ligand" or "ligand" is intended for the purposes of the present invention to designate any compound which binds in any manner to a receptor (in 10 the present invention, the receptor is a GPCR receptor, preferably a GnRH receptor) and induces either an activation, inhibition or other conceivable effect on this receptor. The term "ligand" thus includes agonists, antagonists, partial agonists/antagonists and 15 other ligands which elicit on the receptor an effect which resembles the effect of agonists, antagonists or partial agonists/antagonists. The compounds of the invention of the general formula (I) are preferably GnRH antagonists. 20 One embodiment of the present invention are novel tetrahydrocarbazole derivatives of the invention of the general formula (I) in which the radical R 7 is not a hydrogen atom when the radical R 6 is at the same time an 25 alkyl radical. A further embodiment of the present invention are compounds of the general formula (I) in which the radical R 7 is not in any case a hydrogen atom. 30 Preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are those compounds in which the radicals Ra, Rb, Rc , Rd, Re and R f are hydrogen atoms. 35 Likewise preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are those compounds in which the radical R 1 is a hydrogen atom.

- 13 Preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are additionally those compounds in which the radicals R 2 , R 3 , R and/or 5 R 5 are not hydrogen atoms. Particularly preferred compounds of the general formula (I) in this connection are those in which the radicals R 2 , R 3 , R 4 and R 5 are independently of one another methyl, chloro or methoxy radicals. Very particularly preferred compounds of the 10 general formula (I) in this connection are those in which at least the radical R 2 is not a hydrogen atom, especially the compounds phenylmethyl [(lS,2S)-1-[[[(3R)-3-[[[(S)--(aminocar bonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9 15 tetrahydro-8-methyl-lH-carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate (compound no. 150a in the examples) phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocar bonyl)-2-methylpropyl]amino]carbonyl]-6-chloro-2,3,4,9 20 tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methyl butyl]carbamate (148a), phenylmethyl [(lS,2S)-1-[[[(3R)-3-[[[(1S)-l (aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9 tetrahydro-8-methoxy-lH-carbazol-3-yl]amino]carbonyl] 25 2-methylbutyl]carbamate (147a). Preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are also those compounds in which R 6 is a hydrophobic radical which 30 includes alkyl, aryl and/or hetaryl structures and which carries a hydrogen bond donor-acceptor system at a distance of from two to four single bonds, counting from the carbon atom substituted by the radicals R 6 and

R

7 . Particularly preferred compounds of the general 35 formula (I) are those where the radical R 6 is a phenylalanylamide residue, in particular the compound phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(S)-2-amino-2 oxo-l-(phenylmethyl)ethyl]amino]carbonyl]-2,3,4,9- - 14 tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl butyl]carbamate (66), is an isoleucylamide residue, in particular the compound phenylmethyl [(IS,2S)-l-[[[(3R)-3-[[[(IS)-1 5 (aminocarbonyl)-2-methylbutyl]amino]carbonyl]-2,3,4,9 tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methyl butyl]carbamate (64), is a valyl-4-aminobenzamide residue, in particular the compound phenylmethyl [(IS,2S)-l-[[[(3R)-3-[[[(lS)-1 10 [[[4-(aminocarbonyl)phenyl]amino]carbonyl]-2-methyl propyl]amino]carbonyl]-2,3,4,9-tetrahydro-lH-carbazol 3-yl]amino]carbonyl]-2-methylbutyl]carbamate (45), is a valyl-N-methylamide residue, in particular the compound phenylmethyl [(lS,2S)-2-methyl-l-[[[(3R) 15 2,3,4,9-tetrahydro-3-[[[(1S)-2-methyl-l-[(methylamino) carbonyl]propyl]amino]carbonyl]-1H-carbazol-3 yl]amino]carbonyl]butyl]carbamate (222a), is a methyloxymethyl-4-pyridyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-O 20 (4-pyridinylmethyl)-lH-carbazole-3-methanol (287), is a carboxyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3 carboxylic acid (273), or is an ethyl propenoate radical, in particular the 25 compound ethyl 3-[2,3,4,9-tetrahydro-3-(3 phenylpropyl)-1H-carbazol-3-yl]-2-propenoate (289). Likewise particularly preferred are compounds of the general formula (I) in which the radical R 6 is a carbonylvalylamide residue, in particular the compound 30 phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(iS)-1-(aminocar bonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetra hydro-lH-carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate (58), is a carbonylthreonylamide residue, in particular the 35 compound phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(lS,2R) 1-(aminocarbonyl)-2-hydroxypropyl]amino]carbonyl] 2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate, - 15 is a cyclic carboxamide residue (such as, for example, a carbonylprolylamide radical, in particular the compound phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[(2S)-2 (aminocarbonyl)-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetra 5 hydro-1H-carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate (181a), or a carbonyloctahydroindolyl-2-carboxamide residue, in particular the compound phenylmethyl [(IS,2S)-l [[[(3R)-3-[[(2S)-2-(aminocarbonyl)octahydro-lH-indol-l 10 yl]carbonyl]-2,3,4,9-tetrahydro-lH-carbazol-3 yl]amino]lcarbonyl]l-2-methylbutyl]carbamate (190a)), is a 4-carboxamidophenylcarboxamide residue, in particular the compound phenylmethyl [(lS,2S)-l [[[(3R.)-3-[[[4-(aminocarbonyl)phenyl]amino]carbonyl] 15 2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate (62), is a methylaminomethyl-2-pyridyl radical, in particular the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N (2-pyridinylmethyl)-iH-carbazole-3-methanamine (279), 20 is a carbonylvalinol residue, in particular the compounds phenylmethyl [(lS,2S)-l-[[[(3S)-3-[[[(lS)-l (hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9 tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methyl butyl]carbamate (267b) 25 and 2,3,4,9-tetrahydro-N-[(lS)-l-(hydroxymethyl)-2 methylpropyl]-3-(3-phenylpropyl)-lH-carbazole-3 carboxamide (276) or is a methylvalinol residue, in particular the compound (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3 30 phenylpropyl)-1H-carbazol-3-yl]methyllamino]-1-butanol (284). Preferred novel tetrahydrocarbazole derivatives of the invention of general formula (I) are also compounds in 35 which R 7 is a hydrophobic radical comprising alkyl, aryl and/or hetaryl structures. Particular preference is given in this connection to compounds of the general formula (I) in which the radical R 7 is a 2,3-biphenyl propionylamino radical, in particular the compound - 16 N-[[(3R)-2,3,4,9-tetrahydro-3-[(l-oxo-2,3-diphenyl propyl)amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L aspartamide (18), is an indanoylamino radical, in particular the compound 5 (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-3 [[(2,3-dihydro-1H-inden-l-yl)carbonyl]amino]-2,3,4,9 tetrahydro-1H-carbazole-3-carboxamide (162a), is an indolylacetylamino radical, in particular the compound (3S)-N-[(iS)-1-(aminocarbonyl)-2-methyl 10 propyl]-2,3,4,9-tetrahydro-3-[(1H-indol-3-ylacetyl) amino]-1H-carbazole-3-carboxamide (164b), is a 2-naphthylacetylamino radical, in particular the compound (3S)-N-[(IS)-1-(aminocarbonyl)-2-methyl propyl]-2,3,4,9-tetrahydro-3-[(2-naphthalinylacetyl) 15 amino]-1H-carbazole-3-carboxamide (161b) or is a 3-propionylamino radical, in particular the compound N-[[(3R)-2,3,4,9-tetrahydro-3-[[(2S,3S)-3 methyl-1-oxo-2-[(1-oxo-3-phenylpropyl)amino]pentyl] amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide 20 (22). Likewise particularly preferred are compounds of the general formula (I) in which R 7 is a phenylmethyl carboxamide residue substituted on the aromatic system, in particular the compounds (3R)-N-[(1S)-1-(amino 25 carbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[(4 methylphenyl)acetyl]amino]-lH-carbazole-3-carboxamide (165a), N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9 tetrahydro-3-[[(4-methoxyphenyl)-acetyl]amino]-1H 30 carbazole-3-carboxamide (175), (3R)-N-[(iS)-1-(aminocarbonyl)-2-methylpropyll-3-[[(3 bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro-iH carbazole-3-carboxamide (96), (3R)-N-[(1S)-l-(aminocarbonyl)-2-methylpropyl]-3-[[(4 35 fluorophenyl)acetyl]lamino]-2,3,4,9-tetrahydro-lH carbazole-3-carboxamide (91), (3R)-N-[(1S)-l-(aminocarbonyl)-2-methylpropyl]l-3-[[(4 chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H carbazole-3-carboxamide (167a), - 17 is a phenylhexylamine residue, in particular the compound (3R)-N-[(iS)-1-(aminocarbonyl)-2-methyl propyl]-2,3,4,9-tetrahydro-3-[(6-phenylhexyl)amino]-1H carbazole-3-carboxamide (234a) 5 or is a phenylpropyl radical, in particular the compounds 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl propyl)-lH-carbazole-3-carboxylic acid (275) and ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-lH carbazole-3-carboxylate (272). 10 Also preferred are those novel compounds of the invention of the general formula (I) which are in the R configuration at the carbon atom substituted by the radicals R 6 and R 7 when the radicals R 6 and R 7 together 15 form an alpha-amino carboxylic acid structural element. Most preferred for the purposes of the present invention are the compounds phenylmethyl [(1S,2S)-l [[[(3R)-3-[[[(iS)-1-(aminocarbonyl)-2-methylpropyl] 20 amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-lH carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (184a), phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(lS)-1 (hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9 tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methyl 25 butyl]carbamate (267a), (2S)-l-[[(3R)-3-[[(4-chloro phenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-methoxy-lH carbazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide (189a) and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl) N-(2-pyridinylmethyl)-lH-carbazole-3-methanamine (283). 30 Further representatives of novel compounds of the invention of the general formula (I), including their preparation, are indicated in the examples. 35 The novel tetrahydrocarbazole derivatives (I) of the invention, as defined above, are ligands of GPCR and can be employed in particular for the inhibition, i.e. as antagonists, of gonadotropin-releasing hormone for example for male fertility control, for hormone -18 therapy, for the treatment of female sub- or infertility, for female contraception and for tumor control. 5 In male fertility control, the compounds of the invention bring about a reduction in spermatogenesis. Combined administration with androgens, e.g. testosterone or testosterone derivatives such as, for example, testosterone esters, is preferred. The 10 testosterone derivatives can in this case be administered for example by injection, e.g. by intra muscular depot injection. The compounds (I) of the invention can also be employed 15 where appropriate in combination with other hormones, e.g. estrogens or/and progestins, in hormone therapy, for example for the treatment of endometriosis, uterine leiomyomas and uterine fibroids. Combinations of the GnRH antagonists of the invention and tissue-selective 20 partial estrogen agonists such as Raloxifen® are particularly preferred. In addition, the compounds of the invention can be employed in hormone replacement therapy. The compounds (I) of the invention can moreover be employed to increase female fertility, for 25 example by inducing ovulation, and for the treatment of sterility. On the other hand, the novel compounds (I) of the invention are also suitable for contraception in women. 30 Thus, the GnRH antagonist of the invention can be administered on days 1 to 15 of the cycle together with estrogen, preferably with very small estrogen dosages. On days 16 to 21 of the cycle of intake, progestagen is added to the estrogen/GnRH antagonist combination. The 35 GnRH antagonist of the invention can be administered continuously throughout the cycle. It is possible in this way to reduce the hormone dosages and thus achieve a reduction in the side effects of nonphysiological hormone levels. It is additionally possible to achieve - 19 advantageous effects in women suffering from polycystic ovary syndrome and androgen-dependent disorders such as acne, seborrhea and hirsutism. An improved control of the cycle by comparison with previous administration 5 methods is also to be expected. Further indications are benign prostate hyperplasia, gonadal protection during chemotherapy, controlled ovary stimulation/assisted reproduction techniques, infantile development disorders, e.g. precocious puberty and polycystic 10 ovaries. Finally, the compounds (I) of the invention, as defined above, can also be employed for the treatment of hormone-dependent neoplastic diseases such as 15 premenopausal cancer, prostate cancer, ovarian cancer and endometrial cancer, by suppressing endogenous sex steroid hormones. The novel compounds (I) of the invention, as defined 20 above, are, as GPCR ligands, in particular GnRH antagonists, suitable for the treatment of the pathological states detailed above for administration to mammals, in particular humans, but also for veterinary medical purposes, e.g. in pets and 25 productive livestock, but also in wild animals. Administration is possible in a known manner, for example orally or non-orally, in particular topically, rectally, intravaginally, nasally or by injection or 30 implantation. Oral administration is preferred. The novel compounds (I) of the invention are converted into a form capable of administration and, where appropriate, mixed with pharmaceutically acceptable carriers or diluents. Suitable excipients and carriers 35 are described for example in Ullman's Encyclopedia of Technical Chemistry, Vol. 4 (1953), 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; H. v. Czetsch-Lindenwald, "Hilfsstoffe fEir Pharmazie und angrenzende Gebiete", Pharm. Ind. 2, 1961, 72ff; - 20 Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe ffir Pharmazie, Kosmetik und angrenzende Gebiete", Cantor KG, Aulendorf in Wurttemberg, 1971. 5 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 solution. For oral administration, the novel compounds of the invention of the general formula (I), 10 as defined above, can be combined with known and conventionally used, physiologically tolerated excipients and carriers such as, for example, gum arabic, talc, starch, sugars such as, for example, mannitol, methylcellulose, lactose, gelatin, surface 15 active agents, magnesium stearate, cyclodextrins, aqueous or nonaqueous carriers, diluents, dispersants, emulsifiers, lubricants, preservatives and flavors (e.g. essential oils). The compounds of the invention can also be dispersed in a microparticulate, e.g. nano 20 particulate, composition. Non-oral administration can take place for example by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or 25 emulsions, by means of implants or by ointments, creams or suppositories. Administration as extended-release form is also possible where appropriate. Implants may contain inert materials, e.g. biodegradable polymers or synthetic silicones such as, for example, silicone 30 rubber. Intravaginal administration is possible for example by means of pessaries. Intrauterine administration is possible for example by means of diaphragms, etc. In addition, transdermal administration, in particular by means of a formulation 35 suitable for this purpose and/or suitable means such as, for example, patches, is also provided. As already explained above, the novel compounds (I) of the invention can also be combined with other active - 21 pharmaceutical ingredients. During a combination therapy, the individual active ingredients can be administered simultaneously or separately, in particular either by the same route (e.g. orally) or by 5 separate routes (e.g. orally and as injection). They may be present and administered in identical or different amounts in a unit dose. It is also possible to apply a particular dosage regimen where this appears expedient. It is also possible in this way to combine a 10 plurality of the novel compounds (I) of the invention together. The dosage may vary within a wide range depending on the nature of the indication, the severity of the 15 disorder, the mode of administration, the age, sex, body weight and sensitivity of the subject to be treated. It is within the abilities of a skilled worker to determine a "pharmacologically effective amount" of the combined pharmaceutical composition. Unit doses of 20 from 1 gg to 100 mg, particularly preferably from 1 pg to 10 mg and most preferably from 1 gg to 1 mg, per kg of body weight of the subject to be treated are preferred. Administration can take place in a single dose or a plurality of separate dosages. 25 In a further aspect of the present invention, accordingly, the present invention also encompasses pharmaceutical compositions as described above, comprising at least one of the novel compounds (I) of 30 the invention, as defined above, and where appropriate pharmaceutically acceptable carriers and/or excipients. Preferred and particularly preferred pharmaceutical compositions are those comprising at least one of the aforementioned preferred or particularly preferred 35 novel compounds (I) of the invention, in particular the compounds mentioned by name above. In pharmaceutical compositions according to the present invention it is possible, besides the at least one compound of the general formula (I), as defined above, for other active - 22 pharmaceutical ingredients also to be present, as already described in detail above. At least one of the novel compounds (I) of the 5 invention, as defined above, is present in the pharmaceutical compositions of the invention in one of the unit doses mentioned above as preferred, particularly preferred or most preferred, specifically and preferably in an administration form which makes 10 oral administration possible. In addition, in a further aspect, the present invention provides compounds of the general formula (I) as defined above for use as pharmaceutical remedy. 15 Preferred tetrahydrocarbazole compound of the invention of the general formula (I), as defined above, for use as pharmaceutical remedy are in turn those compounds mentioned above as preferred and particularly preferred 20 compounds, in particular the preferred compounds of the invention mentioned by name, and the compounds mentioned in the examples. Concerning pharmaceutical compositions comprising 25 compounds (I) of the invention, and concerning compounds (I) of the invention for use as pharmaceutical remedy, reference may be made in relation to the possibilities for use and administration to what has already been said concerning 30 the novel compounds (I) of the invention, as defined above. In another aspect, the present invention also provides the use of at least one tetrahydrocarbazole derivative 35 of the invention of the general formula (I), as defined above, with - as defined at the outset - the tetra hydrocarbazoles disclosed in the publications by Millet et al. and Maki et al. being excluded from the meaning of the general formula (I), for producing a - 23 pharmaceutical remedy for the treatment of GPCR mediated diseases, in particular for inhibition of gonadotropin-releasing hormone (GnRH). 5 In addition, the present invention provides in a further aspect the use of at least one compound of the invention of the general formula (I) as defined above, but including the compounds previously excluded by name from the publications of Millet et al. and Maki et al., 10 namely 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3 carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4-tetra hydrocarbazole-3-carboxylic acid, 3-acetamido-1,2,3,4 tetrahydrocarbazole-3-carboxylic acid, methyl 3 15 acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3 carboxylate and 3-tert-butoxycarbonylamino-l,2,3,4 tetrahydrocarbazole-3-carboxylic acid, for producing a pharmaceutical remedy for inhibiting GnRH, preferably 20 for male fertility control, for hormone therapy, for the treatment of female sub- and infertility, for female contraception and for tumor control. Stated more clearly, the term "a compound of the general formula (I) as defined above, but including the 25 compounds excluded above by name" means a compound of the general formula (I) (1)4 - 24 in which the radical R' is a hydrogen atom, a C 2 - C 6 alkenyl or a C 1 - C 6 alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group

-COOR

1 1, where the aryl or hetaryl radical may be 5 substituted by up to three substituents which are selected independently of one another from the group consisting of -NO 2 , -CH 3 , -CF 3 , -OCH 3 , -OCF 3 and halogen atoms, and the radical R 11 is a hydrogen atom, a CI - C 1 2 alkyl, a 10 C 1 - C 1 2 aralkyl, an aryl, hetaryl radical or the group

-COCH

3 and may optionally be substituted by one substituent selected from the group consisting of

-CONH

2 , -COCH 3 , -COOCH 3 , -SO 2

CH

3 and aryl radicals; 15 the radicals R 2 , R 3 , R 4 and R 5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 , -CF 3 , -OCF 3 , -NO 2 , -CN, a C 1 - C 6 alkyl, a

C

1 - C 6 alkenyl, a C 1 - C 6 alkoxy, a C 1 - C1 2 aralkyl, an aryl or hetaryl radical; 20 the radical R 6 is the group -CONR R 9 , -COOR", -CH 2 NR R 9 ,

-CH

2 R , -CH 2 OR8 or a C 1 - C 12 alkenyl radical which is optionally substituted by the radicals R 8 and R 9 , where the radicals R 8 and R 9 are each independently of one 25 another a hydrogen atom, a C 1 - C 12 alkyl, a C 1 - C 12 aralkyl, a C 1 - C 1 2 hetaralkyl,. an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of -OH, -NH 2 , -CONHR 0 , -COOR 10 i , -NH-C(=NH)-NH 2 and halogen 30 atoms, where the radical R 10 is a hydrogen atom, a C 1 - C 12 alkyl, a C 1 - C 12 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R ) 2 , or where the radicals R 8 and R 9 may together form a 35 cyclic structure which consists however exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; - 25 the radical R 7 is a hydrogen atom, a C1 - C 12 alkyl, a CI - C12 alkenyl, a C 1 - C 1 2 aralkyl, an aryl or hetaryl radical, the group -NR 2 R 3 , -NHCOR 4 , -NHCONHR 14 ,

-NHCOOR

4 or -NHSO 2

R

4 and may optionally be substituted 5 by one or more substituents selected from the group consisting of -OH, -NH 2 , -CONH 2 , -COOH and halogen atoms, the radicals R 12 and R 13 are each independently of one another a hydrogen atom, a C2 - C 6 alkenyl or a C 1 - C 12 10 alkyl radical and may optionally be substituted by one or more aryl or hetaryl radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -NO 2 , -CH 3 , -CF 3 , -OCH 3 , -OCF 3 and halogen atoms, 15 and the radical R 14 is a hydrogen atom, a Ci - C 12 alkyl, a Ci - C 12 alkenyl, a C 1 - C 12 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of -NO 2 , -CH 3 , -OR 11 , -CF 3 , -OCF 3 , -OH, 20 -N(RH) 2 , -OCOR 11 , -COOH, -CONH 2 , -NHCONHR 11 , -NHCOOR 11 and halogen atoms; and the radicals Ra, Rb, Rc ,

R

d, Re and R f are each independently of one another a hydrogen atom, a halogen 25 atom, the group -COOH, -CONH 2 , -CF 3 , -OCF 3 , -NO 2 , -CN, a C1 - C6 alkyl, a C, - C6 alkoxy, an aryl or hetaryl radical. The indications already mentioned in connection with 30 the novel compounds of the invention of the general formula (I), as defined above (i.e. excluding the compound disclosed in the publications of Maki et al. and Millet et al. and mentioned above by name) have already been given above in relation to the novel 35 compounds (I) of the invention. The compounds which are preferred and particularly preferred in the use of the compounds just defined for producing a pharmaceutical remedy for inhibiting GnRH are identical to the preferred and particularly preferred compounds already -26 mentioned above in connection with the novel compounds of the invention of the general formula (I), as defined above. 5 The present invention provides in a further aspect the use of a compound (I) of the invention as defined above, but likewise including the compounds excluded by name at the outset, for male fertility control or for female contraception. Preferred and particularly 10 preferred compounds of the invention for this use are those compounds already mentioned at the outset as preferred or particularly preferred compounds of the invention of general formula (I) as defined above. 15 In addition, the present invention provides a method for male fertility control or for female contraception, comprising the administration of an amount, effective for male fertility control or for female contraception, of a compound of the invention as defined in the 20 immediately preceding paragraph, to a subject, preferably a mammal, particularly preferably a human. In another aspect, the present invention relates to a method for the treatment of pathological states 25 mediated by GPCR. The method comprises the administration of at least one compound (I) of the invention, as defined above, to a mammal, in particular a human, when such a treatment is necessary. The administration normally takes place in a 30 pharmaceutically effective amount. As already explained above in relation to the novel compounds (I) of the invention and the pharmaceutical compositions of the invention, it is the task of the expert knowledge of a skilled worker to determine a pharmaceutically 35 effective amount, depending on the specific requirements of the individual case. However, the compounds (I) of the invention are preferably administered in a unit dose of from 1 ug to 100 mg, particularly preferably from 1 gg to 10 mg and most - 27 preferably from 1 gg to 1 mg per body weight of subject to be treated. The preferred administration form is oral administration. The administration of one or more of the compounds (I) of the invention in combination 5 with at least one further active ingredient, as already explained above, is also provided. In addition, the present invention also relates to a method for inhibiting GnRH in a patient, comprising 10 administration of a pharmaceutically effective amount of a compound of the general formula (I), as defined above, but including compounds excluded by name above, to a patient requiring such a treatment. The method is preferably used in male fertility control, hormone 15 therapy, female contraception, treatment of female sub or infertility and tumor control. Finally, the present invention provides in a last aspect also a method for the production of the novel 20 tetrahydrocarbazole derivatives of the invention of the general formula (I). The method for the preparation of the compounds of the invention of the general formula (I) can be carried out in various ways, e.g. in liquid phase or as partial or complete solid-phase 25 synthesis. The choice of the suitable synthesis conditions for preparing individual representatives of compounds of the general formula (I) can be made by a skilled worker on the basis of his common general knowledge. One method of the invention for the 30 preparation of compounds of the invention of the general formula (I) is firstly described generally below. A specific variant of the method, namely a solid-phase method, is then described. For further illustration of the present invention, the examples 35 listed thereafter include numerous representatives of compounds of the general formula (I). One method for the preparation of the compounds of the invention of the general formula (I) is preferably - 28 carried out in the following way: The central tetrahydrocarbazole structure can be obtained by a Fischer indole synthesis known per se. 5 For this purpose, a suitably substituted cyclohexanone derivative provided where appropriate with protective groups is condensed with the phenylhydrazine derivative which is desired in each case and is likewise suitably substituted and provided where appropriate with 10 protective groups (e.g. as described by Britten & Lockwood, J.C.S. Perkin I 1974, 1824 or as described by Maki et al., Chem. Pharm. Bull. 1973, 21, 240). In particular, the cyclohexanone structure is substituted in positions 3,3', 5,5' and 6,6' via the radicals Ra to 15 R , and in positions 4,4' via the radicals, or where appropriate by precursors of the radicals, R 6 and R 7 . The phenylhydrazine structure is optionally substituted by the radicals R 2 to R 5 . Phenylhydrazine derivatives which are not commercially available can be prepared by 20 methods known to the skilled worker. Positional isomers which result where appropriate in the condensation of the cyclohexanone derivative and the phenylhydrazine derivative can be separated by chromatographic methods such as, for example, HPLC. 25 After the synthesis of the central tetrahydrocarbazole structure, the radical R' can be introduced by N-alkylation of the nitrogen atom in position 9 with appropriate Rl-halides with use of base (e.g. as 30 described by Pecca & Albonico, J. Med. Chem. 1977, 20, 487 or else as described by Mooradian et al., J. Med. Chem. 1970, 13, 327). The radicals R 6 and R 7 can, as already indicated above, 35 be introduced in various ways depending on their nature, which is explained in detail below. a-Aminocarboxylic acid structures in these radicals can be obtained by treating ketones with NH 4

(CO)

3 and KCN - 29 under Schotten-Baumann conditions known per se, and subsequent alkaline hydrolysis of the hydantoin which is formed (Britten & Lockwood, J.C.S. Perkin I 1974, 1824). 5 Amide residues are preferably generated using methods known per se from peptide chemistry. For this purpose, the acid component is activated with an activating reagent such as DCC or else HATU (Tetrahedron Lett. 10 1994, 35, 2279) and condensed in the presence of a base such as DIPEA and/or DMAP with the amino component. Ester residues can also be obtained by using the desired alcohols under analogous conditions. The 15 solvent used in this case is preferably anhydrous. Secondary or tertiary amide residues are obtained from primary amines either by nucleophilic substitution of alkyl halides or by reductive amination of aldehydes/ 20 ketones (e.g. J. Org. Chem. 1996, 61, 3849 or Synth. Comm. 1994, 609). Sulfonamide residues are obtained from the corresponding amides by reaction with sulfonyl 25 chlorides. Urea residues are obtained by reacting the amines with appropriate isocyanates. 30 Urethane residues can be prepared by preactivating the appropriate alcohols with carbonyldihydroxybenzo triazole ((HOBt) 2 CO) and subsequently reacted with amines (Warass et al., LIPS 1998, 5, 125). 35 Alcohols can be obtained from carboxylic esters by reduction with LiAlH 4 . Aldehyde residues are obtained from alcohol precursors by oxidation for example under Swern conditions known - 30 per se with DMSO/oxalyl chloride (Pansavath et al., Synthesis 1998, 436). Substituted amine residues are obtained by reductive 5 amination of amines with aldehydes (J. Org. Chem. 1996, 61, 3489). Ether residues can be obtained by deprotonating the alcohol precursor with a base such as NaH under 10 Williams conditions known per se and subsequently reacting with an alkyl halide. Double bonds in the radicals can be introduced by reacting an aldehyde or ketone precursor with 15 appropriate phosphonylides under Wittig conditions known per se. A solid-phase method for the preparation of compounds of the invention of formula (I) preferably includes 20 steps (a) to (d) explained in detail below: Step (a) proceeds essentially in analogy to a Fischer indole synthesis, e.g. as described by Britten & Lockwood, J.C.S. Perkin I 1974, 1824; Maki et al., 25 Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman, Tetrahedron Lett. 1996, 37, 4869 and comprises the condensation of a cyclohexanone derivative (II) which contains the group G and is tethered to a solid phase SP via a linker L suitable for forming the 30 radical

R

6 b 0

MI)

- 31 where, in the case where the radical R 7 is a hydrogen atom, a C 1 - C 12 alkyl, a C 1 - C1 2 aralkyl or a hetaryl radical, the group G is equal to the radical R 7 , and in 5 the case where the radical R 7 has another one of the meanings indicated for R 7 in formula (I), the group G is equal to a group -NH-Pg, where Pg is a protective group, with a pheny1hydrazine derivative (III) substituted by R 2 to R s 10 in the presence of an acid, preferably acetic acid, and of a metal salt, preferably ZnC1 2 . DMF is preferred as 15 solvent. The radicals R a to R f are defined as indicated above in formula (I). Certain substituents or groups may, where appropriate, also be present in protected form, in which case the protective groups are removed again by methods known per se at a suitable time during 20 the synthesis. Particularly suitable solid phase SP for the purposes of the present invention are Rink amide-resins (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard 25 et al., Int. J. Peptide Protein Res. 1982, 20, 451), Wang resins (Lu et al., J. Org. Chem. 1981, 46, 3433) or chlorotrityl-resins (Barlos et al., Int. J. Peptide Protein Res. 1991, 38, 562), where the cyclohexanone derivative (II) is to be tethered to the solid phase SP 30 by means of an (amino) carboxylic acid. Alcohol precursors of the cyclohexanone derivative (II) can be tethered by using the DHP linker (Liu & Elman, J. Org.

- 32 Chem. 1995, 60, 7712). Traceless tethering of aromatic precursors of the cyclohexanone derivative (II) to triazine resins is possible (Brase et al., Angew. Chem. Int. Ed. 1998, 37, 3413). 5 The protective group Pg which is included where appropriate in the group G and protects an a-amino group -NH 2 is preferably a "Fmoc" (9 fluorenylmethoxycarbonyl) protective group, but may 10 also be another customary amino protective group, e.g. from the series of the alkoxycarbonyl protective groups (such as, for example the "Z" (benzyloxycarbonyl) or the "Boc" (tert-butoxycarbonyl) group) or another suitable protective group, e.g. a "trityl" 15 (triphenylmethyl) protective group. The constitution of the linker L is such that appropriate derivatization (steps (b) and (c)) and workup (step (d)) result in the desired radical R 6 with 20 one of the meanings indicated above for R 6 in the final product, the tetrahydrocarbazole derivative of the general formula (I). To illustrate the constitution of the linker L, this may be explained below by way of example for the case where R 6 equals the group -CONR 8

R

9 . 25 In the case where the radical R 6 in the product of the invention of the formula (I) has the meaning -CONR 8

R

9 , firstly a compound Pg-N(R 8

)-R

9 '-COOH forming the linker L is tethered by means of an activating reagent such as 30 DCC (dicyclohexylcarbodiimide) or HATU (0-(7 azabenzotriazol-1-yl)-N,N-N',N'-tetramethyluronium hexafluorophosphate) to the solid phase SP via free amino groups of the SP, where Pg and SP have the meaning indicated above, and R 9 ' forms part of the later 35 radical R 9 . The protective group Pg is subsequently eliminated, e.g. in the case of a Fmoc protective group by means of piperidine/DMF. This results in a compound HR N-R -CONH-SP. The latter compound is then in turn reacted with a precursor of the cyclohexanone - 33 derivative (II), namely the cyclohexanone carboxylic acid (II') 0001 Rb 0 (I) Or) 5 using an activating reagent such as DCC or HATU, finally resulting in the cyclohexanone derivative (II) as defined above. The meaning of the linker L in the case just described is -CONR 8 -R 9 -CONH-SP. Any resulting 10 isomers of whatever type (enantiomers, diastereomers or positional isomers) can be fractionated - as also elsewhere during the described preparation process - in a known manner by means of HPLC. 15 The actual step (a), i.e. the condensation of the cyclohexanone derivative (II) with the substituted phenylhydrazine derivative (III) and, where appropriate, elimination of the protective group Pg in the group G by means of, for example, piperidine (in 20 the case of a Fmoc protective group) then takes place, so that a free a-amino group is produced again at this point. In the case where the radical R is the group -NHCOR 4 , 25 -NHSO 2 R , -NR 12R 13 (where R 12 and R 13 are not both hydrogen atoms), -NHCONHR 4 or -NHCOOR 14 a derivatization of the now unprotected a-amino group of the resin-bound cyclohexanone derivative (II) finally takes place in step (b), so that the various 30 alternative radicals R 7 defined above can be performed.

- 34 Depending on the nature of the desired radical R 7 in the tetrahydrocarbozole final product (I) of the invention, the procedure for this is as follows: 5 In the case where R 7 is the group -NHCOR 14 , the reaction product from step (a) is reacted with a carboxylic acid R 4 COOH in the presence of an activating reagent such as, for example, DCC or HATU and in the presence of a base such as, for example, DIPEA (diisopropyl 10 ethylamine) or DMAP (4-dimethylaminopyridine) by known processes for forming peptide linkages (cf., for example, Tetrahedron Lett. 1994, 35, 2279; alternative (i)). 15 In the case where R is a sulfonamide group -NHSO 2

R

4 , the reaction product from step (a) is reacted with a sulfonic acid derivative R 14

SO

2 X, where X is a leaving group, preferably a halogen atom, in particular a chlorine atom, in the presence of a base such as, for 20 example, DMAP or DIPEA (cf., for example, Gennari et al., EJOC 1998, 2437; alternative (ii)). In the case where R 7 is the group -NR 2

R

13 (where R 12 and

R

13 are not both hydrogen atoms), in the case where the 25 radical R 12 is a hydrogen atom, the reaction product from step (a) is reacted with a reagent R X, where X is a leaving group such as, for example, a halide atom, in particular a chloride atom, in the presence of a base such as, for example, DBU or DIPEA (cf. Green, JOC 30 1995, 60, 4287 or JOC 1996, 61, 3849) or with an aldehyde R 13 CHO in the presence of a reducing agent such as, for example, NaH/B(OAc) 3 . In the case where neither of the radicals R 12 and R 13 is a hydrogen atom, the reaction product from step (a) is a reacted with a 35 ketone R 2COR 3 in the presence of a reducing agent (cf. Ellmann et al., JOC 1997, 62, 1240 or Synth. Commun. 1994, 609; alternative (iii)). In the case where both radicals R 12 and R 13 in R equals -NR12R are hydrogen atoms, alternative (vi) below applies.

- 35 In the case where R 7 is the group -NHCONHR 4 (a urea derivative), the reaction product from step (a) is reacted with an isocyanate R 14 NCO (cf. Brown et al., 5 JACS 1997, 119, 3288; alternative (iv)). In the case where R 7 is a carbamate or urethane group

-NHCOOR

4 , the reaction product from step (a) is reacted with an alcohol HOR 14 which has been preactivated by 10 carbonyldihydroxybenzotriazole ((HOBt) 2 CO) (cf. Warass et al., LIPS 1998, 5, 125; alternative (v)). In the case where R 7 is a hydrogen atom, a Ci-C 12 alkyl, Ci-C 1 2 aralkyl, an aryl, a hetaryl radical or the group 15 -NH 2 (i.e. both radicals R 12 and R 13 in R 7 equals -NR 1 2 R 3 are hydrogen atoms), step (b) is omitted because no further derivatization is necessary (alternative (vi)). Step (c), i.e. the derivatization on the indole 20 nitrogen atom, also corresponds, in analogy to step (b) explained above, to various alternatives which are explained in detail below: For cases (i) to (v) defined above in step (b), a 25 deprotonation of the reaction product obtained in (b) takes place by means of a base such as, for example, NaH or NaHMDS and subsequent derivatization by means of a group RiX, where X is a leaving group, e.g. a halide atom, in particular a chloride atom (cf. Collini & 30 Ellingboe, Tetrahedron Lett. 1997, 38, 7963; Pecca & Albonico, J. Med. Chem. 1977, 20, 487 or Mooradian et al., J. Med. Chem. 1970, 13, 327). For case (vi) defined above in step (b), i.e. when step 35 (b) is omitted, in analogy to the above description a deprotonation of the reaction product obtained in (a) takes place by means of a base such as, for example NaH or NaHMDS and subsequent derivatization by means of a - 36 group R 1 X, where X is a leaving group, e.g. a halide atom, in particular a chloride atom. Step (d) finally substantially includes the elimination 5 of the reaction product obtained in (c) from the solid phase SP. In the case of Wang, trityl, DHP and Rink amide resins, elimination of the reaction product obtained in (c) takes place with the aid of an acid, in particular with TFA (trifluoroacetic acid). In the case 10 of an aminolytic elimination from an HMB resin, the eliminating reagent used is, for example, ammonia in methanol. The desired product is then isolated in a conventional way. 15 Exemplary embodiments of the preparation of tetrahydrocarbazole derivatives of the invention are detailed below. Examples 20 I. General synthetic methods for compounds of the invention A Coupling of carboxylic acids to the Rink amide 25 resin: 0.1 mmol of Fmoc-protected Rink amide-resin (166 mg, loading 0.6 mmol/g) are preswollen with 1.5 ml of DMF in a vessel with bottom frit for 20 min. After aspiration, 1.5 ml of 20% piperidine/DMF are added and 30 stirred for 5 min. After aspiration, a further 1.5 ml of 20% piperidine/DMF are added and stirred for 15 min. Aspiration is followed by washing four times with DMF. Then 675 gl of a 0.267 M solution of Fmoc-protected amino carboxylic acid in DMF, 675 p1 of HATU solution 35 (0.267 M in DMF) and 150 p1l of NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP are added and stirred at 40 0 C for 4 h. After aspiration, the same reagents are again added and stirred at 400C for 4 h. This is followed by aspiration and washing four times with DMF.

- 37 B Coupling of carboxylic acids to the trityl-resin: 2.98 mmol of Fmoc protected aminocarboxylic acid are dissolved in 30 ml of dry dichloromethane, mixed with 5 14.3 mmol (2.45 ml) of DIPEA and added to 2.98 mmol of 2-chlorotrityl chloride-resin (2 g, loading 1.49 mmol/g of resin). After shaking for two hours, the resin is filtered off with suction through a frit and washed three times with 20 ml of dichloromethane/MeOH/DIPEA 10 17:2:1. This is followed by washing three times with 20 ml of dichloromethane, three times with methanol and three times with 20 ml of ether and drying in vacuo. A resin with a loading of 0.5 to 1 mmol of amino carboxylic acid per g of resin is obtained. 15 C Coupling of carboxylic acids to the HMB-resin: 21.3 mmol of amino carboxylic acid and 21.3 mmol of HATU are dissolved in 60 ml of DMF and mixed with 63.9 mmol (10.9 ml) of DIPEA. After 5 minutes, 5 g of 20 polystyrene-HMB-resin (loading 0.71 mmol/g of resin) are added and shaken at RT for 5 minutes. Then 21.3 mmol (2.6 g) of DMAP are added and shaken at RT for 1 h. The resin is subsequently filtered off with suction and washed once each with 100 ml of DMF, DCM 25 and DMF. The resin is mixed with 100 ml of 10% Ac20 (acetic anhydride)/DMF/5% DMAP and shaken for 15 min. Aspiration is followed by washing three times each with 100 ml of DCM and ether and drying in vacuo. 30 D Coupling of carboxylic acids to the Wang resin: 54.6 mmol of carboxylic acid and 27.3 mmol (4.2 ml) of DIC are dissolved in 500 ml of dry DCM, and stirred at RT for 10 min. After the precipitated urea has been filtered off, the solution is evaporated to dryness and 35 the residue is dissolved in 160 ml of dry DMF. The solution is added to 4.55 mmol (5 g, loading 0.91 mmol/g of resin) of Wang resin preswollen in DMF, and 4.55 mmol (556 mg) of DMAP are added. After shaking at RT for 1.5 hours, the resin is filtered off with - 38 suction and taken up in 100 ml of 10% Ac 2 0/DMF/5% DMAP and shaken for 15 min. Aspiration is followed by washing three times each with 100 ml of DCM and ether and drying in vacuo. 5 E Coupling of an alcohol to the DHP-resin: 0.5 mmol of DHP-resin (0.5 g, loading density 1 mmol/g) are preswollen in 2 ml of dichloroethane for 15 min. To this are added 2 ml of a solution of 0.75 M 10 alcohol/0.37 M pyridinium paratoluenesulfonate and stirred at 800C for 16 h. Cooling to RT is followed by addition of 5 ml of pyridine, briefly shaking with inversion and filtration with suction. Washing is carried out twice each with 5 ml of DMF, DCM and 15 hexane. F Deprotection of a resin-bound Fmoc protective group: 1.5 ml of 20% piperidine/DMF are added to 0.1 mmol of 20 resin-bound Fmoc group and stirred for 5 min. After aspiration, 1.5 ml of 20% piperidine/DMF are again added and stirred for 15 min. Aspiration is followed by washing four times with DMF. 25 G Coupling of a carboxylic acid to resin-bound amino functions: 675 pl of a 0.267 M solution of Fmoc-protected amino carboxylic acid in DMF, 675 pl of HATU solution (0.267 M in DMF) and 150 p1l of NMM solution (2.4 M in 30 DMF) and 0.01 mmol of DMAP are added to 0.1 mmol of resin-bound amino functions and stirred at 40 0 C for 4 h. After aspiration, the same reagents are added again and stirred at 4000 for 4 h. This is followed by aspiration and washing four times with DMF. 35 H Coupling of acetic acid to resin-bound amino functions: 1.5 ml of a solution of 10% acetic anhydride in DMF are added to 0.1 mmol of resin-bound amino functions and - 39 stirred at RT for 15 min. This is followed by aspiration and washing four times with DMF. I Synthesis of tetrahydrocarbazoles starting from 5 resin-bound cyclohexanones: Before the reaction, 0.1 mmol of cyclohexanone-resin are washed twice with 2 ml of DMF and twice with 2 ml of acetic acid. Then 1 ml of DMF and 2 ml of 0.5 M hydrazine/0.5 M ZnC1 2 in acetic acid are added to the 10 resin and stirred at 7000 for 20 h. This is followed by aspiration and washing twice with 2 ml of acetic acid and 2 ml of DMF. J Synthesis of sulfonamides starting from resin 15 bound amides: The resin is washed twice with 2 ml each of DMF and DCE. 1 ml of 0.5 M sulfonyl chloride in DCE and 400 pl of 2.5 M NMM/l eq. of 0.25 M DMAP in DMF are added to 0.1 mmol of resin-bound amine. Stirring at 600C for 20 12 h is followed by aspiration and repetition of the coupling. Aspiration is followed by washing four times with 2000 ml of DMF. K Synthesis of ureas by reaction of resin-bound 25 amine with isocyanates: 2 ml of 0.5 M isocyanate in DCM are added to 0.1 mmol of resin-bound amine and stirred at RT for 18 h. Aspiration is followed by washing four times with DMF. 30 L Synthesis of carbamates by reaction of resin-bound amine with preactivated alcohols: For the preactivation, 0.4 M alcohol and 0.39 M dibenzotriazolyl carbonate and 0.39 M pyridine are stirred in DMF at 400C for 15 min. 1 mmol of resin 35 bound amine is mixed with 1 ml of preactivated alcohol, and 167 ml of 2.4 M NMM in DMF are added. Stirring at 600C for 4 h is followed by aspiration and washing four times with DMF.

-40 M Synthesis of N-alkylamines by N-alkylation of resin-bound amines with alkyl halides and catalytic KI: 1 ml of 0.5 M halide/0.05 M KI in DMF and 416 il of 2.4 M DIPEA in DNF are added to 0.1 mmol of resin-bound 5 amine and stirred at 90 0 C for 12 h. After aspiration, the resin is washed four times with 2 ml of DMF. N N-alkylation of resin-bound indole nitrogens with halide/NaH in DMF: 10 1 ml of DMF and 0.5 mmol of NaH (55% suspension in oil) are added to 0.1 mmol of resin-bound amine. After stirring at RT for 30 min, 1 ml of 0.5 M halide in DMF are added and stirred at 45 0 C for 8 h. This is followed by aspiration and washing twice each with 2 ml of 15 methanol, DMF, methanol and DMF. 0 Elimination from the Wang, trityl, DHP, Rink amide-resin: 2 ml of 95% TFA/5% H20 solution are added to 0.1 mmol of 20 resin and shaken at RT for 3 h. The resin is then filtered off and washed with a further 2 ml of TFA. The combined TFA solutions are evaporated to dryness and afford the crude products. 25 P Aminolytic elimination from the HMB-resin: 2 ml of DMF and 2 ml of 7 M NH 3 in methanol are added to 0.1 mmol of resin and shaken at RT for 18 h. The resin is then filtered off and washed with DMF. The combined solutions are evaporated to dryness and afford the 30 crude product. Preparation of required starting compounds: 3-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]-2,3,4,9 35 tetrahydro-lH-carbazole-3-carboxylic acid 1 38.4 mmol (6.0 g) of 4,4-ethylenedioxycyclohexanone and 39.8 mmol (4.3 g) of phenylhydrazine are dissolved separately in 50 ml and 10 ml, respectively, of water, - 41 and then mixed. The milky emulsion resulting after stirring for 10 min is extracted five times with ethyl acetate, dried with MgS0 4 and evaporated to dryness. Yield: 9.2 g of orange oil. 5 9.2 g of the unpurified phenylhydrazone are dissolved in 240 ml of toluene at RT, and 4.9 g of freshly ground ZnC1 2 are added. After refluxing with a water trap for 90 min, most of the toluene is distilled off, an excess 10 of 2 N NaOH is added, and the mixture is extracted three times with ethyl acetate. The extract is washed with brine and dried with MgSO 4 , and the solvent is distilled off. The remaining black oil is purified on silica gel with ethyl acetate/hexane 1:9. Yield: 2.7 g 15 of beige solid. 11.6 mmol (2.7 g) of 1,2,4,9-tetrahydrospiro[3H carbazole-3,2'-[1,3]dioxolane] and 640 mg of p toluenesulfonic acid are taken up in 70 ml of acetone 20 and stirred at RT for 2.5 h. The solution is added to NaHCO 3 solution, extracted with ethyl acetate, washed with brine, dried with MgSO 4 and concentrated. 2.13 g of red-brown solid remain. Recrystallization from ether results in 1.1 g of beige-colored solid. 25 60.2 mmol (11.1 g) of 1,2,4,9-tetrahydrospiro-3H carbazol-3-one, 8.3 g of KCN and 22.0 g of (NH 4

)

2 C0 3 are heated in 550 ml of 60% ethanol in an autoclave at 80 0 C for 3 h. After cooling to room temperature, the 30 reaction mixture is added to ice-water, and the precipitated solid is filtered off. Yield: 10.1 g of gray solid. 44.2 mmol (11.3 g) of 1,2,4,9-tetrahydrospiro[3H 35 carbazole-3,4'-imidazolidine]-2',5'-dione is heated with 62 g of Ba(OH) 2 x 8 H 2 0 in 145 ml of H 2 0 at 150 0 C for 13 h. After cooling to room temperature, the viscous mass is mixed with 37 g of (NH 4

)

2 C0 3 with stirring and heated at 100 0 C for 30 min. Cooling to - 42 room temperature is followed by filtration, washing with water and evaporation of the filtrate to dryness. Yield: 7.7 g of beige solid. 5 26 mmol (5.8 g) of 3-amino-2,3,4,9-tetrahydro-lH carbazole-3-carboxylic acid in 26 ml of 1 N NaOH and 26 mmol (8.76 g) of Fmoc-ONSu in 28 ml of acetonitrile are combined at room temperature and diluted with 130 ml of acetonitrile/H 2 0 1:1. After two hours, the pH 10 is readjusted to 9 with NEt 3 (1.5 ml) and the mixture is stirred at room temperature overnight. Then a further 6.3 g (18.7 mmol) of Fmoc-0NSu dissolved in 19 ml of acetonitrile are added, and stirring is continued for two hours while controlling the pH. Removal of the 15 acetonitrile by distillation is followed by acidification with 0.01 M HCI and extraction with ethyl acetate. The extract is washed until neutral, dried with Na 2

SO

4 and evaporated to dryness in a rotary evaporator. Recrystallization takes place from 20 ether/hexane. Yield: 10.7 g. 1H NMR (d 6 DMSO): 8 = 2.07 ppm (m, 1H); 2.50 (m, 1H); 2.70 (bs; 2H); 3.04 (q, 2H); 4.17 (m, 2H); 4.28 (m, 2H); 6.92 (tr, 2H); 6.99 (tr, 2H); 7.23 (tr, 2H); 7.24 25 7.35 (m, 3H); 7.38 (tr, 2H); 7.62 (s, 1H); 7.68 (dd, 2H); 7.87 (d, 2H); 10.71 (s, 1H). Melting point: 119 0 C Fractionation into the two enantiomers takes place by chiral HPLC. 30 (R)-3-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino] 2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid la tR = 6.4 min (Chiralcel OD 10 pm LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) 35 (S)-3-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino] 2,3,4,9-tetrahydro-lH-carbazole-3-carboxylic acid lb tR = 7.5 min (Chiralcel OD 10 pm LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) - 43 1 - [ [ (9H-Fluoren-9-ylmethoxy)carbonyl]amino] -4-oxocyclo hexanecarboxylic acid 2 320 mmol (50 g) of 4,4-ethylenedioxycyclohexanone are 5 suspended in 800 ml of 50% EtOH, and 1500 mmol (144.5 g) of (NH 4

)

2 C0 3 and 640 mmol (41.7 g) of KCN are added. After stirring at 60 0 C for 5 h, the ethanol is removed in vacuo, and the aqueous residue after cooling with ice is filtered off, washed with water and dried. 10 Yield: 72.4 g of 4,4-1,4-dioxa-9,11-diazadi spiro[4.2.4.2]tetradecane-10,12-dione. 295 mmol (66.8 g) of 4,4-1,4-dioxa-9,11-diazadi spirol[4.2.4.2]tetradecane-10,12-dione and 826 mmol 15 (260.6 g) of Ba(OH) 2 x 8 H 2 0 are stirred in 2.5 1 at 1500C in an autoclave for 6 h. After cooling to room temperature, 1032 mmol (99.2 g of (NH4) 2 C0 3 are added to the solution and stirred at 60 0 C for 1 h. The suspension is filtered and washed, and the filtrate is 20 lyophilized. The residue is recrystallized from

H

2 0/MeOH. Yield: 45.4 g of 8-amino-1,4-dioxa spiro[4,5]decane-8-carboxylic acid. 213 mmol (42.9 g) of 8-amino-l,4-dioxaspiro[4,5]decane 25 8-carboxylic acid in 213 ml of 1 N NaOH and 213 mmol (71.9 g) of Fmoc-ONSu in 240 ml of acetonitrile are combined and diluted with 1000 ml of acetonitrile/H 2 0 1:1. Adjustment of the pH to 9 is followed by stirring at room temperature overnight. Removal of the 30 acetonitrile in a rotary evaporator is followed by acidification with 0.01 M HCI and extraction with ethyl acetate. The extract is washed until neutral, dried with Na 2

SO

4 and evaporated to dryness. The residue is recrystallized from ethyl acetate/hexane. Yield: 79.0 g 35 of 8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-l, 4 dioxaspiro[4,5]decane-8-carboxylic acid. 187 rnmol (79 g) of 8-[[(9H-fluoren-9-ylmethoxy) carbonyl]amino-l,4-dioxaspiro[4,5]decane-8-carboxylic - 44 acid are taken up in 3.5 1 of acetone/0.1 M HC1 1:1 and stirred at room temperature for 4 h. The acetone is stripped off in a rotary evaporator, and the precipitated product is filtered off, washed with water 5 and dried. Yield: 68.7 g of 2. 1H NMR (d 6 DMSO): 6 = 1.52-1.73 (m, 4H); 1.82-2.14 (m, 4H); 4.27 (m, 3H); 7.85 (tr, 2H); 7.42 (tr, 2H); 7.67 (s, 1H); 7.75 (d, 2H); 7.91 (d, 2H) 10 Melting point: 157oC 4-Oxocyclohexanecarboxylic acid 3 20 mmol (3.4 g) of ethyl 4-oxocyclohexanecarboxylate are suspended in 40 ml of 2% H 2 S0 4 and stirred at 900C 15 for 2 h. This is followed by extraction four times with ethyl acetate, drying with Na 2

SO

4 and removal of the solvent. Recrystallization from ether/hexane affords 2.9 g of white solid 3. 20 'H NMR (d 6 DMSO): 6 = 1.72 (m, 2H); 2.08-2.18 (m, 2H); 2.19-2.47 (m, 4H); 2.72 (m, 1H); 12.23 (bs, 1H). 4-Chloro-3-[[(phenylamino)carbonyl]amino]benzeneacetic acid 4 25 18.55 nmmnol (2.21 g) of SOC1 2 are slowly added to 18.55 mmol (4 g) of 4-chloro-3-nitrobenzeneacetic acid in 50 ml of MeOH while cooling in ice and stirring. After stirring for 30 min, the mixture is allowed to warm to RT and a further 3.71 mmol (0.44 g) of SOC1 2 are 30 added. Stirring overnight is followed by heating to reflux for 30 min. Stripping off the solvent is followed by recrystallization from ether/hexane. Yield: 3.43 g of methyl 4-chloro-3-nitrobenzeneacetate as yellowish solid. 35 13.07 mmol (3.0 g) of methyl 4-chloro-3 nitrobenzeneacetate and 198.8 mmol (13.0 g) of Zn dust are heated to reflux in 500 ml of MeOH for 10 min. Then, under reflux, 13 ml of conc. HCl are added - 45 dropwise, and refluxing is continued for 30 min. The suspension is filtered hot, the methanol is distilled off, and the residue is adjusted to pH 14 with a NaHCO 3 solution. Extraction with ethyl acetate, drying with 5 Na 2

SO

4 and removal of the solvent by distillation affords 2.3 g of methyl 3-amino-4-chlorobenzeneacetate as beige solid. 2.08 mmol (415 mg) of methyl 3-amino-4 10 chlorobenzeneacetate are dissolved in 40 ml of DCM and, at 0 0 C, 0.83 mmol (246.3 mg) of triphosgene and 0.6 ml of pyridine are added. After stirring at 0 0 C for one hour, 10.4 mmol (1.11 g) of benzylamine are added, and stirring is continued at room temperature overnight. 15 Extraction is carried out with DCM/H 2 0, the organic phase is dried, and the solvent is removed. Yield: 727 mg of methyl 4-chloro-3-[[(phenylamino) carbonyl]amino]benzeneacetate. 20 2.98 mmol (990 mg) of methyl 4-chloro-3-[[(phenyl amino)carbonyl]amino]benzeneacetate are taken up in 10 ml of methanol, and 6 mmol of 1 N NaOH are added. After stirring at RT for 2 h, the methanol is distilled off and the residue is acidified to pH 2-3 with 1 M 25 HCl. Extraction is carried out with ethyl acetate, and drying with Na 2

SO

4 , and the solvent is removed. Recrystallization takes place from boiling isopropanol. Yield: 830 mg of white solid 4. 30 1 H NMR (d 6 DMSO): 6 = 3.57 (s, 2H); 6.92 (d, 1H); 6.99 (tr, 1H); 7.35-7.50 (m, SH); 8.10 (s, 1H); 8.30 (s, 1H); 9.42 (s, 1H); 12.40 (bs, 1H). 4-Chloro-3-[[[ (phenylmethyl)amino]carbonyl]amino] 35 benzeneacetic acid 5 2.08 mmol (415 mg) of methyl 3-amino-4 chlorobenzeneacetate are mixed with 10.4 mmol (969 mg) of aniline as described under 4.) and worked up analogously. Yield: 662 mg of solid.

I

- 46 For the ester cleavage, 2.47 mmol (790 mg) of methyl 4 chloro-3 [[[(phenylmethyl)amino]carbonyl]amino]benzeneacetate 5 are hydrolyzed with 1 N Na0H in analogy to the above method. The product 5 is obtained without recrystallization. Yield: 693 mg of yellowish solid. ES-MS: 319 (M+H ) 10 4-Chloro-3-[[(4-pyridinylamino)carbonyl]amino] benzeneacetic acid 6 2.08 mmol (415 mg) of methyl 3-amino-4 chlorobenzeneacetate are mixed with 10.4 mmol (979 mg) of 4-aminopyridine as described under 4.) and worked up 15 analogously. Yield: 664 mg of solid. For the ester cleavage, 2.63 mmol (840 mg) of methyl 4 chloro-3-[[(4-pyridinylamino)carbonyl]amino] benzeneacetate are hydrolyzed with 1 N NaOH in analogy 20 to the above method. The product 6 is obtained without recrystallization. Yield: 481 mg of yellowish solid. H NMR (d 6 DMSO): 6 = 3.57 (s, 2H); 6.94 (d, 1H); 7.40 (m, 3H); 8.05 (s, 1H); 8.35 (d, 2H); 8.50 (s, 1H); 9.92 25 (s, 1H); 12.40 (bs, 1H) 4-Chloro-3-[[(2-pyridinylamino)carbonyl]amino] benzeneacetic acid 7 2.08 mmol (415 mg) of methyl 3-amino-4 30 chlorobenzeneacetate are mixed with 10.4 mmol (979 mg) of 2-aminopyridine as described under 4.) and worked up analogously. Yield: 617 mg of solid. For the ester cleavage, 2.47 mmol (790 mg) of methyl 4 35 chloro-3-[[(2 pyridinylamino)carbonyl]amino]benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product 7 is obtained without recrystallization. Yield: 693 mg of yellowish solid.

- 47 1 H NMR (d 6 DMSO): 8 = 3.59 (s, 2H); 6.94 (dd, 1H); 7.03 (dd, 1H); 7.22 (d, 1H); 7.42 (d, 1H); 7.78 (dtr, 1H); 8.29 (m, 2H); 10.02 (s, 1H); 11.82 (bs, 1H); 12.50 (s, 5 1H). II. Examples of compounds (I) of the invention Example 1: 10 0.3 mnmol (42.6 mg) of 4-oxocyclohexanecarboxylic acid are dissolved in 1 ml of acetic acid and added to a suspension of 0.3 mmol (43.3 g) of phenylhydrazine hydrochloride and 0.3 mmol (40.0 mg) of ZnC1 2 in 1 ml of acetic acid. Stirring at 70 0 C for 20 h is followed by 15 dilution with 20 ml of water and extraction with ethyl acetate. The ethyl acetate phase is washed with water, dried over Na 2

SO

4 and evaporated to dryness. Yield: 65.6 mg (100%) of white solid. 20 Name Number Mfnd Mcalc 2,3,4,9-Tetrahydro-lH-carbazole 3-carboxylic acid 8 215 215.2507 The column headings (name, number of the compound, Mfnd 25 (measured molecular mass), Mcaic (calculated molecular mass)) which are introduced here also apply to the following examples and are therefore not repeated again. 30 Example 2: Synthesis takes place on the 0.2 mmol scale by methods A, I and O. 2,3,4,9-Tetrahydro-1H-carbazole 35 3-carboxamide 9 214 214.2666 - 48 Example 3: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, I and 0. 5 N- (IS) -1- (Aminocarbonyl)-2-methyl propyl] - (3S)-2,3,4,9-tetrahydro-1H carbazole-3-carboxamide 10a 314 313.3987 N- [(IS) -1- (Aminocarbonyl)-2-methyl 10 propyl]-(3R)-2,3,4,9-tetrahydro-1H carbazole-3-carboxamide 10b 314 313.3987 N-(2-Amino-2-oxoethyl)-2,3,4,9 tetrahydro-1H-carbazole-3 15 carboxamide 11 271 271.3183 Example 4: Synthesis takes place on the 0.2 mmol scale by methods D, F, G, F, G, I and O. 20 N-[(3S)-(2,3,4,9-Tetrahydro-1H carbazol-3-yl)carbonyl] -L-valyl-L glutamine 12a 442 442.513 25 N-[ (3R)-(2,3,4,9-Tetrahydro-1H carbazol-3-yl)carbonyl] -L-valyl-L glutamine, Isomer B 12b 442 442.513 Example 5: 30 Synthesis takes place on the 0.2 mmol scale by methods D, F, G, I, F and O: N-[ [(3S)-3-Amino-2,3,4,9-tetrahydro 1H-carbazol-3-yl)carbonyl] -L 35 alanine 13 301 301.3441 Example 6: 0.1 mmol of carboxylic acid, 0.1 mmol of HOBt and 0.15 mmol of amine component are dissolved in 15 ml of - 49 dry DMF (also THF, DCM), and, while cooling in ice and stirring, 0.5 minmol of NMM is added. After about 15 min, 0.15 mmol of EDCI x HC1 is added, and the mixture is stirred for one hour, warmed to room temperature and 5 stirred overnight. For workup, the solvent is stripped off, and the product is dissolved in ethyl acetate and washed twice each with 0.1 N HC1 and saturated NaCl solution. Drying and stripping off the solvent are followed if necessary by recrystallization. 10 9H-Fluoren-9-ylmethyl [ (3S) -3- [[[(4 bromophenyl)methyl] amino]carbonyl 2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbamate 14 620 620.5439 15 Methyl N- [ [ (3S)-3- [ [ (9H-fluoren-9-yl methoxy)carbonyl] amino]-2,3,4,9 tetrahydro-1H-carbazol-3-yl]carbonyl] L-alaninate 15 537 537.6129 20 Example 7: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, G, F, G and O.

- 50 N-[(3R)-34((2,53}2-I(9H-Fbxoren.9- 18 779 77.9178 ylmetiioxy)carbonyIlano]-3-methy1-l oxopentyl~amno]-2,3A9-?etrahYdro-1ff-cara 1-3 yl]carbonyl]-1-valyl-L-aspartmide N.{((3S-3-[(2S,3S)-2-[f(9H-Fluocu-9k- 779 T97 Yhncthoxy)carboaYljamino]-3-methyl-l oxopeatyIammuo]-Z3A9-ttrhydo-lf~cabzo-3. y!]oarbonyll--lyl-L-asL ramdo -ff(3R)-ZA9-TeMkydr-3-f(-OXO-Z3- it- 651 850.7758 dipbMYPropyamin]-lH-bazol-3-yoaionyl-.L valyl-L-Waartamide N-[((3S*2,3,4,9-Tehrhydro-3-((I-OXO-23- 19 51 050.7758 diphe-nylpropiAn=Ino-H-carbaZ-.3-ycxbo11]-valy. L-aspatmude, homer A N4[(3S)-2,3,4,9-TetabYdr.3-4(1.OXO-2,3- 651 650.778 diphenylptopyl)amino-H-carbazol-3-ycaboiy-L-valy L-aspartamide, Isomer B A-((3S-2,3A49-TcUahYdr-3- [(2S3~-3-mthyjI o'o-2- Li 88 687.8371 [(] -oxo-3-phenylproDpyfaminopentylaminollIHcarbazol. 3-yl]carbonylj.L-valyl-L-aspartamide - 51 -I N-[[(3R)-Z,3,4,9-Tctydro-3 -[[(2S,3S-3-methy- -oxo-2- Z? 8 687.8371 (1-oxo-3-pheylpropyl~amino]peltyl]amino]-lH-Carbazol 3-yI~carbonyl]-Laval-l~aspartamide N4[(3-S)-2 7 3,4,9-Tetmhydro-34((2S)-l-oxo-2- 23 648 647.7289 [((ph ymethioxy)cabonayIaminolpropyl]ammoII. cubazol-3-yI~carbonyl]-L-valyl-L-aupartamide N-[[(3R1-,3,4,-Tehydro-3[(2)--oxo-2- 24 M48 647.7289 [(pbeoylmthoxyX~abony1]aminolpropy1W23inoPcatbazol -3-yI]cubonyl]-L-valyl-L-aspaztanmide JVa3)234,-etyr- -[(S3)3rahJj o 8826 681.75U7 2-fflphenylmethoxY)Carbonylaminopentylamino]-1IH cax1bazoI -3-yI]carbonyl]-L-alanyl4-aspartamide N-U3023 9T a* -- 12.S--ehlloo M 647 848.784 2-fl(phenylmethnx)cbonyjamino]pntylaino]-1Hf carbazl -3-.yljcabonyl-l-valyl-L-alaniiimide N-[[(3S)-7.,3,4,-Tdrhydo.3-[[(2S,S)-3-mety1-1-oxo-2- 7 WO 8898M9 fl(phenylmnethox)carbonyl]aminojpexty~amino]-1H. carbazol -3-yljcarbony]-D-valyl-L-apartamid8 NV-ff(3R)-2,3,49-TctahYdr-3-[(2S,3S)-3-niethyl-1-oxo- 28 no0 689.8003 24[(.heny~methoxy)caronyiamino~penty1]arino-H carbazol -3-yl]carbonYl}.D-valYl-L-aspartamide N-C31)-Z,3,4,9-Tedrakydro-3-1((2S,3S)3-methy1-l-oxo- Le- 890 88093m 24[(phenylmetboxy)vabonyllamino]pentyl~amino]-Ili cairbitzol -3 -yllcarbonyj-L-valyl-D-aspartamide N4[(3S)-2,%49-Tendro-3ff(23S)-3-methy-1-oro-2,- 20 800 688.8093 [(phyen)arbonyamino)peltylJamino4IH carbazol -3-yllcrbonyl]-L-vlyl-t-asprtamide )9Y{(3)-2,3A49-TewAhydro-34[(2S,3S)-3-methy1-i-oxo-2- n w62 881755 [[(phenytmethox)carbonyllamino]pentyljaminoj-IH =abawl 3y]carbnyL-any-L.aspartamde NV-[(3,S)2,3,49-Tetahydro-3-f(pheaylarcetyamino]-lH- 32 851 550.8514 carbazol -3-yIlcarbonlyl]-L-Valyl-L-aspartamide NV4E(3R)-2,3A49-Tetrahydro-3-(-oxo-3- M3 575 574.6782 phenylpropyl)amino]-IH-caxbazol,3-ycarbonyl]-L-valyl L-aspartamide N-[[(3S)-2,3,4,9-Tetrahydro-3-[(1-oDXO.3- a4 675 674.67a2 phenylpropyl)amino]-IH-cabazol.-3-yI]carbonyl]-L-valyl L-aSpartamide - 52 N-[3S 2 3,4,9-Tetrhydro-3{[(2S3)-3.methy1-l-oxo-2- M 647 64784 [[Ehmethoxy)cbylamiopntfaMio]-IHf carbazo! .- 3-yl]Carbonyfl--va~yI-L-aLahniaide N4U(3R)-2,3,4,9-Ttahdr-3-J'lIAen yfy)aminoJ-1H- M8 56 560.6514 Mabazol -3-ylcarbonyl)-L-valyl-L-apartamide N-[[(3P2,3,4,9-Ttrahydro-3-[XI-oxo-4- 21 69 588.705 phenylbutyl~amino]-1H1-cabazol -3-yi]cabonyl]--vagyl L-aspar~mide N4[(3S-34,9'-Tetkhdro-3-t(1-oxO-4- 38 589 588.705 phenylbutyl~amino]-I*-carbazol -3-yljcarbonyl]-L-valyl L-apartamide N-[(3PR)-3-R(DiPhnYhaeialifOJ-2,3A49-tethYdr- 9 837 86%.749 I R-cazbwzl -3-yflcarony-vay-I.aspartaride N-l3)3[Dpolctlai)2349ehdo 4M 637 W68.749) 1H-carbazol -3-YiloabonYl]-L-vslYl-Lata~mide N-[t(3R-Z23A49-TetahYdro-3-E(1-oxo-2- Ll 676 574.6782 phcnylpropyl)awino-lH-carbazo -3 yloarbonyUl-L-vaiy! L-aspartmide, Isomer A N-[f(3R)-Z3,4,9-Tetnydro-3-[(3.methyl-i-oxo-2- 2 617 616.758M phenylpentyl)aminoN-H-carbazl -3-y4]cabony1I-L-a~yl L-aapartamnide, homer B N4[(S)Z3,,-Tihydro-3(3-lebyl--ox-2- 43 S17 616.7688 phenylpentyl)amino]-IH-mabazol -3-yljvarbonylLvalyl ILpatamide, Isomer A N-U[(3S-2,3A49-TerhYdro-3-(3-netyl-I-oxo-2- a4 617 616.7588 pbenylpcrrtyl)amino]-lH-carbazol -3-yljcarbonyl]-L-valyl-t.. asarTaMide Isomer B Phesylmetbyl [(1s,2s)14[(3R)-3-ff[Is)-14ft4- 0- 895 694.8284 (a~mrbonyphny]ammocarbonylj-2 matylpropyl]mno]crny-3,4,9-teftAlydro-H cabazol -3-yl]axinolcarbonyl]-2-metbylbutyllcarbaniate Phenybiebyl [0 S,2S)-14[[(3S)-3-flI(I S)-I -I: 14- As 8OM 694.8284 (aminocarbonyl)phftnyllaminojcarbonyl]-2 metbylpropyl~amino~carbonyU)-23,4,9-tcfraydro-lH cuabao-3-y1Iaminojcarbony11-2-rnetiylbutyl]cubtuate - 53 N-fl(3S)-2,3,4,9-Teahydro3.[X3-methy1-1-OX0-2- 47 603 602.7318 phenylbutyj)amino]-1H-carbzo-3-yllcarbnyl-L-valy-L aspartamide, Isomer A N-FJ(3S)-2,3A49-TetrahYdro-3-[(3-methYl-1-axo-2- OR 603 802731 phenlbuty))aminD)-lH-ca~bazol .3-yllcarbonyl]-L-valyl-L aspaTwidec, Isomer B N-j(3R)-2,3,49-Texaydio-3-[(3-methl-I-oxo-2- ! 6M 6M273111 phonylbut~mn-xbazol.3-y]bonl]-L-vayl-L aspartamide Phenylmethyl ((S2)I[(S.3MI)I(I4 0 715 714.9025 (aznioc~xbonyfylohxylmethyllarimoloarbonyl] 2 metylpropyIlamnowcurbny-2.,3A4,-erydro-1H carbmzo -3.yllaminolcarbony)J-2-mcthylibu~ityl mara te N1-f[(3R,)-23A49-Tetrahydw-34j(3 - 51 6M3 6M748 pheaoyphenylactylamino]-IH-carbazoI .. 3-Yl]carbony1].. L-valyl-L-aspartamide "N-[[(3S)-2Z3,49-Tetahydko-3-[[(3- 52 853 W52.748 phenoxyphenyl)acetyllamino].IH-cazl-3-y]carbonyl] L-valyl-L-aspartaraidc Phenylmethyl [(IS,2s)1-[II(3R)-3-UI(IS)-1-Ugf3- 53 709 70B.855 (ammln yl ehyl]methyarbo] nyl-2 methYlPrOPYI]aminojcarbonYl]-2,3A49-terAhYdro-IR carbazol.-3-ylaminolcabonyl-2-mehylbutylAcabamate, Phenylmethyl PA ,S--((S-3fAl)1Ifp 709 708.6=8 (=ambn~hymtymiomoyl2 methylpropyl]aminojcabonyl]-2Z3,4,9-tetahydro- 11 cubazol -3-.y]amno]carbouy}.2metybutylcarbamate (3PR)-N-II(l S)-1-(Aminocarbony-2-meylpopy-23,4,9- 55 608 607.7509 tetrhydro-3-[[(2R)-l-oxo-2-[(l-oxo-3 phenylpropyl)amin]-3.pbe-nylpropyoamino)-IH-cabaoe 3-carboxamide N-[[(3S)-2,3,4,9.Tetrahydro-3-{QI-oxo-2- ER6576 574.6782 pheniylpropylrNmino]-1H-carbazol -3-yljcaxbonyl]-L-valyl-L aspaftamide Phenlylniethyl (1S,2S)-J-[jf(3R)-3-I(C(1S)-1.{[I[4- 57 715 714.9025 (aminocabonyl~cclohtexYllmethiytlaminolcarbonyl]-2 methiyipropy1]amino]carbonyfl-2),3,49-te"rhydro-1H carbazol -3-yl~amiriolcarbonyl]-2-rnethylbutyllcabamate - 54 Example 8: Synthesis takes place on the 0.2 minol scale by methods A, F, G, F, G and 0. PhenylniethYl ((I S,2S).149l(3R)-3-I(1QS)-1- ~56 5575 (anocarbony-2-et~ropyjamino]carbonyl-,3,4,9. tetrahydro-1fl-crbazu1 -3-31]aznino]ceorbonyl]-2 MtumtYl~carbamae N-[f(3S)-341:(9*i-Fluorea-9-ylmethoxy)cabonyljaminojl- 66 604.759 2,3,4,9-tetrahydro-H-cibazo.3-yJcarboiy]-l-valyl-L aspanamtiidc N.[[(3pYQ-3-fl(9H-ulorei-.ylMethoXy)CMbony1,MinoJ- 6O 665 e84.75a 2,3,4,94ebd1Dr-1H-crbazoI -- yl)carbonyl]-L-valyl.

aspartamide Phenylietyl [(IS,2*)14ff(3S)-3-Qf(AS)-1- 11 57 575.7059 (aminocbony-2-.mehyropyl]anminolcarbony1J-2,3,4,9 tetrhydrolH-crbzl-3-yiaminocarbouy]-2 metbylbuylloarbamate Phenylmethyl [(S2)1[l3~--a-62 w9 59.6963 (axninocarbonyl~henyllaminolcarbonyl}.2,3,4,9.etraydro IH-carbazol-3-yl]amino~cabouyl]-2-methylblztyl]carbamae Pheeyt ~f((SS.IA(3S-4[4- g W96 595.6m8 (amiocabozny~phtwyJamnooabony13-2Z3)4,9-tetrhydro lH-cadbaol -3-yjamiolcabonyJ.2-mehyTbzzy1]otbamate PheymehylS2--I[3)3f(SS4 6_ 590 689.7327 (naoarbonyrD-2-mhybty]amiiobonyI..

3 4,9 tcuhydro-H-cabazo-3-yaino]carboiiyI]-2 methylbutft~arbamate Ph~enylmethyl [(1 S,2S>4{([[(3S)-3-( (1S,2S).1- 065 90 589.7327 (aminocarbonyl)-2-methybutyl]aminoicabonyl].2,3,9 tetrahydro-IH-caxbazol -3-yl~aminoJcarbonyl}.2 mctbylbuty))caxbamate Phenyhmethyl [(I S,2S)1 *1I[(3R)-3-Mj(I S)-2-amio.2oxro 66 M2 2.7499 1-(Phenytrnethyl)ethyl]aminolcarbonyl]-2,3,49-tetrahydro 1H-mrzol- 3 -aui]cabony-2-ethybuty]carbamate -55 Phenylmethyl [(S,2S)-1-EU(3S)..3-[[R1IS)-2-anino-2-oxo-I- 67 623 623.7499 (pkiylmethyr1)einao]carbonyI]-2,3,A9tetrahydo 1H-.carbazo] -3-yllamino]caxbonyll-2-melhylbutyl]carbamate (3,)-N-[K1S)-I-(norbon2-mehylpropyJ.23A49- M 480 4W0.6748 tdtrahydro-34(-"o-2-phenyprpyfamiio]Hcbaoe:3 carboxmide Phenylmethyl. [(1 S,2S)--J(3 S)-3-[ff[3- 6a 810 6M9.7231 (ainobouyl phenYlmethylamiolabonYl-2,3A49. tetrabydro-ll-carbazol -3-yljaminojc~kbOI3yl].2. methylbutyllcarbamate Pbenymethyl [QlS,2S)-1-UJ(3R)-3-[[[[3- 70 810 609.7231 (amiocaroY)J lmeioAarmo~bon y -2,3,4,9 tetrAhydo-IH-carbazl -3-yI]aminD~cabonyl]-2 methylbutylcarbamate P~ih ne~yl (1S,2S)-1-E(E(3 S)-34J[J4- U 615 615.7706 (amnocabo yclDheylmetyljamnocarbony] 23A9-tetraiYdro-IH-car wzl - 3 -Yl1aminolcarbonyl}2 methylbutylcabauiate Phenyimethyl (S.2S)-1-[f[(3R)-34E4- 2 6156 1~5.705 (ami obonyIrcyclohexyAmethyljamikocdonyl]. 2,3,4,9.tetrahydro-IH-carbazo -3.yljamiaojcarbonyi]-2 metylbutyquiabaxnate Pbenlmetbyl [(lS,2S)-I-U(3S)-3-ff[3- 7 s 59 W9.696 (ammocabolyI)pheiyIjamino]arbony1.2,39twrydro. 1H-carbazol - 3 -yIjamin]coq-2-methybuy]cabne Phenyim ethyl [(IS,2S)-1-U[(3R)-3-[ff3- Z4 5e 5sS.0AM (am rbonyl)pheiyl]arnio)ca tonyl]-2 3,49.teiahydro. IH-carbazol -3yaiocroy]2mbluylabmt Flienylmethyl [(1 S,2S)-1-1 (3S)-3-[[g(1S)-2ajno2oxo-l-. Z5- 610 809.7231 phenylehfylaninolcarbonyl]-2,3,4,9Aetrahydro1H =abazol - 3 -yflaminojcarbonyl]-2-mthylbutyllcarbamaie Phenyirnethyl [(I S,2S)--[((3S)-3[((R)2auoD2-OXD. 76 810 609.7231 I-phenythyIami]arbony]-23,49tetahydw..H cabao - 3 -yl]ano]caboy-2mejylbuty]uamate Phenylmethyl [(I S,2S)-1-(([(3R)-3-f ((2..amino--2..oxo.. HZ 509 609.7231 phenylethyl)amino]cabonyl-2.3,4,9-.tthydro-IH. carbazoi.3-y~amino]carbony]-2-methylbutyI~carbamte, - 56-/ Isomer A Pbeuylmelliyl [(I S,2-1-Uj(3R)-3-R2ano-2-Oo-1- Z- 0 9 809.7231 pheaylethiy1aminoDvaxbny]-2 3 3,94emrahYdro-1H oarbazol-3-yIlamino]cbony1-2-metylbutyllcarbamate, Isomer 1B (3R,)N4(1)-Amkocbony)-2-nthypropyI]-23,4,9- Z! 482 46Z'47 terhydxo-3-[f3-hydroxyphcnyi)aoetyl]amino]-IH carbazole-3-carboxmde (3R)-3 -j[3-(Accbao)pheny]aety1j an~jno]-N-[WS)-1- 12 04 604.5838 (aminoxiboyl)-2-merhylpropyI]-2,3,4,9-tetrahydro-1B carbazole-3-carboxumide 34(2-ff(3R)-3-fl[(IS)-.-(Amiuon rbnyl)-2- 81 597 56.6804 methy Propy1]aminocrbonY!j-2,A9-temhYdr0-IH carbazol-3-y~mIfoJ-2-oxoethi54phflyl 3 hydroxybenzeacftate (3R>.N4[(S1-(4Amiocarbonyl)-2-methylpropyl]-2Z3A9- 82 462 4OZ547 teUhy-3[(hydroxheyacety)amiw1-1H-carbazle-3 carbaxamide (3R)-N-(S)1-(Aminocarbony)2-methylprop1J--[[(4- La M2 2,4441 bromphenyl~acetyl~amino]-2,3A49-teuahydro-I1I-cabazole 3-.carboxa,:nde (3R:)-N-(l)-1-(Aminobnyl2-methylpropyfl-3-a(2- -M 481 480.9931 chlorpheactlio-249teftahydro-IH-carbaole 3-caboxamide (3R)-N-[(1S)-1-(Amiaocabonyl)-2-mthylpopyl]-3-[[(3- !1 497 498,9921 chor4hydrxyphenyaty]amino-23,49-terabdro IH-wabazole-3-carboxaraide (3R> 34[[4-(Aceox)3-cblorpenljcetylamio]-N- 86 639 6w8.O28 [(I S)-I-(aminocarbonyID-2-methylpropyl]-2,3,4,9 tetrahydro-IR-mabazole -3-carboxamide _ (3P19-N4{Q S)-l -(Aminocarbonyl)-2-methylpropyl]-3-1[(3- 67481 480.5371 fluor-4-hydroxhenyaetyl]amino]-Z23A9-ttrahYdro-1H carbazle .3-carboxamide - 57 -I (3)3R4Atliy--loohn~(tq m]N M8 523 =22S739 [(1S)-1-(aminowbonyl-2-3iehylpropyIJ-2.3A49' tetrakydrodIH-carbazol -3-caboxamide (3R)-N-[(IS)-1.(Aminocaronyl)-2-methylpropyl]-2,3,4,9- . 2 492 491.401 tcydr-3-(4mkropheyacetamol HcabazoI -3 caboxamide (3R) -N-[(IS--(Awinoabon92-methyprop1]-3-1[(2,4- 90 515 515.4382 diblorophenyl~acetyl]amiao]-Z,3,9-terbydro-1H carbazol-3-catboxwmdeo (3R)-N-(I S)- -(Aminocrbouiy)-2-methypropy)-3-[((4- 91 484 4M4.5381 tuoroPhmyD1]amno-239-&ahYdro-IH-arbzo1-3 carboxamide (3R,)-N4Q(lS)4-(Aninocaboyf-2-methY]PropyO-Z3A9- 21 4w2 4M2.47 tetraiiydr-3-[(4hxypheny)aceyijampiuoJ]ffl carbazol -3-carhoxamide (3PR)-N-[(IS)-<Aninoarboy)-2-metbylproDPyl-.[(2- M m2 M254441 bromophenyfjaetyl]amno]-3,4,9-ttmhydro-1H-carbazol 3-carboxarnide (3R)-N-[(1S)1-(AminocarbonY])-2-methY]ProyI.349- 1 491 491 tehydr,-3-[(2-iphenyacaamino]{.cabaoi-3 carboxamide Q3R)-N-[(I S)-1-(AminocrbonyD-2-methypropyJ-.,3,4,9- 9M 491 491.5451 tecraydro-3-[[(3-nitrophwmyIacet)]aino]-1H-carbazo-3 carboxainide (3R)-N-I(1 S).-(Amcarby)-2mehypropyp-34j{3 96 62 526.4441 bromopheny1)aco1amino]-Z3,4,9-ttrahydro-1UH-abazo 3-caiboxamide (3B)-4(1S)--(Aiwy1)-2-mthypropi-3{fi(2- PI 4W 498.9M ebloro-fluoroPhenYlacetYaiino-2,39-esxlrdro-1H carbazo]-3-.arboxamide (3t)-N4(ISI-(Anorb ny)-2-mehyprpy]-3[([ 1 ,1'. 5M645 biphenyl]-4-ylacetyl~aninoJ-23,4,9-terAhydro-ffl-carlazoI 3-caiboxamide (3R)-N-(] S)-l -(AmilocarbonYl)-2-methylpropyl].3.[((3,5- 22 475 474.0010 die thylphenyI)acetyl]3amino]-2,3,4,9-terahydro-1H.. curbazol-3-caxboxamide -58 (3R,)-N-[(18)-1.{AMiko~abony1)-2-mehy~propyI)-[(I,3- 100- 49D 400.567 benzodioxol-S-ylacotyl)8mino]-2,3,4,9-tthydro-IH carbazol -3-maboxamide (3R-N-[(IS)-1-A~fm rony)-2-metby~propy]-3-[[(3- IM 481 480.9931 chloroPhenYt~aCety]aminloJ-2,3A49-et ra o-1H-crbazo1 3.varboxamide (3K)-N-[(I S)-1-(Aminocaronyl)-2-methiYlPropyl-2,3,49- 102 461 40.574, thydr-3fl(3-mthyphn1)ce4ylamino]-H..cabazo! 3-carbou~mide (3R9-N-[(l I 4(AminoaboyI)-2-mtbyIpopyI.34I2 103 484 484,5381 fluoropheny1)ac;M4]amino-23,4,9-ttriiydo-1H-carbazoI-3 carboxaudde tebyo-3(2mthypiy)act1Aino-H-abazol 3-carboxamide (3P)-N-[(1S)-I{(Aminoarbon)-2methylpropyl}.Z3A49- 105 49 488.6M8 tetruydro-34E[4-1-methylgthyl Phenyllacetyljamino]-1H carbaxl -3.carboxamide (3R)N-(S)-I-(Auocabonyl)-2-methylropyl)-3-fl(4- 106 490 489.616S (diniethy~mino)phenyl)acetj43amino]-2,3,4,9-torahydro I H-carbazol -3-caxboxaznide (3R)-N-(IS)--(Amuocboyl-2-mthylproyl-23,4,9- 1-07 524 624.6388 =hydro-3{ff4-(metbyhifnyophenyllaccyI~nmino]-IH marazl -3-caboxmde (3)-N-[(1 S)-1-(Aminocabouyf)-2-melhiylpropylj-3-(f(3. 10_8 478 478.64W flu -methyilphenyl cetyl]amino]-.3,49-tmWayro-l{ carbazol -3-carboxamide Exampl e 9: Synthesis takes place on the 0.2 mrmol scale by methods B, F, G, F, G, F, G and 0. 5 N-[[X3R)-2,3,4,9-Tetrahydro-3-((28S3S)-3-methyl-l-oxo-2- L±29 6 91 690.7934 (((phenylmethoxy)carbonuy~aminiolpentyl]ariijo].1H. cabao-3-yI]-L-vanyllva-L-aspaaine N-i (3 S)-%349-TetrhYdro-3-(2S,3S)3-mety-l-oxo-2- 110 691 690.7934 [[fphenylmethoxy)osrbiyl]aininolpentyllamino]-1H carbazol -3-yl]carbonyl]-L-valyl-L-aspaigine - 59 Example 10: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, G, F, G, F, H and 0. N-[[(3)-3-[[(2S,3S)-(Acetylamino)-3-methyl-1- 111 59 597.7127 oxopentyl]amino]-2,3,4,9-tetrahydro-IH-carbazol-3 yl]carbonyl]-I,-valyl-b-aspamtamide N-I(3S)-3-[[(2S,3S)-2-(Aetylamiz)-3-methyl-l- 112 598 597.7127 oxopentyl]amino]-Z,3,4,94trahydro-IH-carbazol-3 yl]carbonyl-L-valyl-D-asparamide N-[[(3R)-3-[[(2R,3R)-2-(Acetyamino)-3-methyl-1- J 5 s8 697.7127 oxopentyl]amino]-2,3,4,9-tetrahydro-IH-carbazol.-3 yl]carbonyl]-L-valyl-L-aspartamide N-[[(3S)-3-[[4(2R,3)-2-(Acetylamino}-3-methyl-l- j14 598 597.7127 oxopentyl]amino]-2,3,4,9-tetrahydro-1H.-carbazol-3.

yl]carbonyl)-L-valyl-L-aspartamide 5 Example 11: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, G, F, H and O. 10 N-[[(3R)-3-(Acetylamino)-2,3,4,9-terahydro-IH.carbazol.-3-. 115 484 484.5538 yl]carbonyl]-L-valyl-L-aspartamide N-[[(3S)-3-(Acetylamino)-2,3,4,9-tetrahydro-IH-,oabazol -3-. 1_18 484 484.5538 yl]carbonyl)-Lvalyl-L-aspartamide N-[[(3S)-3-(Acetylazino)-2,3,4,9-tetrahydro-lH-carbazol-3- i1 484 484.55ss3a yl]carbonylj-D-valyl-L-aspartamide N-[[(3S)-3-(Acetylamino)-2,3,4,9-tetrahydro-1H-carbazoI-3.- 11B 454 484.ss538 yl]oarbonyl]-L-valyl-D-asparamide Example 12: 15 Synthesis takes place on the 0.2 mmol scale by methods A, F, G and 0.

- 60 pbe~ylmetLiyl [(1S,2S)4-(3R)-3(minocazonyl)-2,3A49- 119 478 476.673 tetrabydw-fl-abazoI -3-yIlamino]carbonyJ}2 methylbutyijoaramate Phenylmethyl [(IS,2S)-I.{U[(3S)-3-(aminocazbony)-Z3,4,9- 120 478 470 738 tetmbydro-IH-caibzo -3.yI1amin01wabonyl-2 methylbutylcarbamatc Example 13: Synthesis takes place on the 0.2 mmol scale by methods 5 A, F, G, F, G, F, G, F, G and 0. N-IIX3R)-2Z3,4,9g-TtAhdrO-34(2S)--OXO-2{(1-oxro-3- 121 722 721.8543 phenylpropyl)aminoj-3-phenypoylamino]-IH-carbazol 3-ylcaronyl)-L-valyl-L-aspartamide N-fl(3R)-2,34-T hYdro-3-4((2R,3R)-3-methy-l-oxo-2,- M o6n Mu7837 [(I -oxo-3-pheriylpropylominolpentyl]amino]-IR-eabazol. 3-y1Jcai1onyI]-L-v81yl-L-aspatamide Example 14: 10 Synthesis takes place on the 0.2 mcl scale by methods D, F, G, F, G and 0. N4(3)-2,3.4,9-TtraYdro-3lI(2S3S)-3-mehYl-.oxo-2-. M3 $77 676.69 [L(pnylmetY)bonyUamino]pely1amiJo]-1H cabazoI .3.yIjoarbcmyl}.L-valin, N-[(3R)-Z34,9 Tetrahydro-3-([(2S)-3-nwthyl-1-oxo -2 [[(phenylmetbioxy)carbony1]amino]pemyt3]amino]4IH carbazol -3-yl]wabouyl].L,-valinc N-[((3$)-2,3,4,9-Tetahydro-3-U(2S,3S)-3-methyl-1-oxo-2- J124 57 67a.69 [[(phcnylmethioxy)earbony]umiwopenty~ainino]-IH carbazoI-3-yl~carbonyl]-L-valine 15 Example 15: Synthesis takes place on the 0.2 rmmcl scale by methods C, F, G, F, G, F, G and P - 61 N-[[(3R)-3-[((2S,3S)-2-f[[(1, I - 12 656 655.7921 Dimethylethoxy)oarbonyl]amino]-3-methyl-1 oxopentyl]amino]-2,3,4,94etrahydro-H-carbazol-3 yl]carbonylJ-L-valyl-L-aspartamide Example 16: Synthesis takes place on the 0.2 mmol scale by methods 5 A, F, G, F, G, F and 0. N-[[(3S)-3-Amino-2,3,4,9-tctrahydro-lH.cabazol-3- 126 442 442.617 yl]carbonyl]-L-valyl-L-aspartamide N-[l(3R)-3-Amino-2,3,4,9-tetrahydro-I-carbazol-3. Z 442 442.517 yl]carbonyl]-L-valyl-L.aspartamide (3S)-N-[(1S)-I-(Aminocarbonyl)-2-methylpropyl).

3 . 18 441 441.5725

[((

2 S,3S}-2-amino-3-methyl-I-oxopentyamino]2,3,4,9-.. tetrahydro-IH-carbazole-3-carboxamide Example 17: 10 Synthesis takes place on the 0.2 mmol scale by methods D, F, G, F, G, F, H and O. N-[[(3S)-3-(Aetylamno)-2,3,4,9-tetrahydro.-1H-carbazol-3- 29 485 4s65.5379 yl]carbonyl)]-L-valyl-L-asparagine 15 Example 18: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, H and O. (3R)-3-(Acetylamino-N-[(1)-2-amino-2-oxo.-1. 130 418 418.4944 (phenylmethyl)ethyl-2,3,4,9-teahydro-IH-carbazol-3 carboxamide (3S)-3-(Acetylamino)-N-[(IS)-2-amino-2-oxo-1.- 131 418 418.4944 (phenylmethyl)ethyl]-2,3,4,9-tetrahydro-IH-carbazol;3 carboxamide - 62 Example 19: Synthesis takes place on the 0.2 mmol scale by methods B, F, G and 0. (3S)-.2,3,4,9-Tetrahydro-3-[[(2S,3S)-3-methyl-l-oxo-2- 132 478 4T77,Ss [[(phenylmethoxy)carbonyl]amino]pentyI]amino]-IH carbazole-3-carboxylic acid 5 Example 20: Synthesis takes place on the 0.2 mmol scale by methods B, F, G, F and 0. (3S)-3-[[[(2,2.Diphbnylethyl)amino]acetyl]amino]-2,3,4,9- 134 468 467,5661 tetrahydro-iH-carbazole-3-carboxylic acid 10 Example 21: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, H and O. 15 (3S)-3-(Acetylamino)-N-[3- 135 404 404.4676 (aminocarbony)phenyl]methyl}-2,3,4,9-tetxahydro-1H carbazole-3-carboxamide (3S)-3-(Acetylamino)-N-4- _13_ 410 410.515 (ainocabonycyclohexyl]methyl-2,3,4,9-terahydro-lH carbazole-3-carboxamide (3R)-3-(Acetylamino)-N-4[4. 137 410 410.515 (aminocarboexyI)yohcxyl]methyl]-2,3,4,9-tetahydro-IH varbazole-3-carboxamide (3S)-3-(Acetylamino)-N-[(IS)-2-amino-2-oxo-l- 13_8 404 404.4678 pheuylethyl]-Z,3,4,9-tetrahydro-IH-carbazole-3-carboxamide Example 22: Synthesis takes place on the 0.2 mmol scale in 20 accordance with Examples 18 and 6.

- 63 Phentylmethyl [(1S,2S-I-[[[(3R)-3[(ethykamiiio)cabonyI]- mA 505 146274 2,3,4,9-teraydro-III-cabazl-3ylamiolvwbonyl]-2 tnetliylbutyllcarbamae Phenylmethyl [(I S,2S)-2-vwfthyl-1I-fE([(3P)-2,3,4,9- I14l Sig 51f.654 tetraliydro-341[(1-methylethyloaminolcarbonyl]-lH-carbazol 3-yIjaminOJ~wbonyIbuty1]cabamate Phenylmetby [(IS,28)-2-meth1.--l(3R)-Z,3,4.9- 141 M33 532.68 tetrhydro-34[(2-methylpropyl~amino]carbouyl].IH carbazol -3-yl]amiuojoabonyl]jbuycarbamate Phenethyl [(1 S,2S)-t.{[[[(3R)-3.{[(2,2- 142 547 546.7078 dimethylpropyl)aminiojoarbonyl]-23,4,9-tetrahydro-1H oarbaol -3.yIlaininolcarbony1]-2-maethylbutyl]cabarnate Phenylmethyl [(1S,2S)-2-niethyl-l-a[(3R)-Z3.4,9- 143 553 552.6714 tetra11ydro-3-[(pbenylamino)carbony1]-1H-carbazol-3 yIjaminojcarbonyI~butyljcarbamate Phenylmethyl [(1 S,2S)-2-rnethy1-l-(E((3R)Z3A9- 144 567 W8.6982 terhYdo-3-EphenYlmethYlamino)carbonylj-1H-cabazol 3-y13aimino]carbonyIjbuty1]varbamate Phenylmetbyl [(I1S,2S)2-nlethyfl.[((3R)-Z3,4,9- 145 651 580.725 tetrahydro-3-[[(2-phenylethyl)aninojcrbonyl]-I H-carbazol 3-yl]axnino]carbonyl~butyl]carbamate PhenylmOthy [(1 S,2S)-2-methYl-I-fff (3R)-3,4,9- LE $ 5694.7510 tetrahydro-3-(f(3-phenylpropyl)aniinocarbonyl-lrn Carbazol -3-yllamino]Garbonyllbutyl~carbamate Example 23: 5 Synthesis takes place on the 0.2 mmol scale by methods A, F, G, I, F, G and 0.

- 64 PhenuYlmethyl [( S,2S)-14 f(3R).3-flI(1*1-- 147 600 80.7317 (aminocaboyl)-2-methyipropyljamino]cubonyl]-2,3,4,9 tctrAhydro-8-methox-1H-cabazol -3-yljsmisiojcarbonyl]-2 methylbutyllcmbamate Phenylmethyl f(IS,2S)-1-Mfl3S)-34IT(i1)1- 14Th 806 605.7317 (aminorcy -2-methyp y~aim n]rb ny]-2,34,9 teM yr-mt.1Hc ybI. lyawinoylamcony.2 methylbutyijoarbamate Phenylmathyl (I S,28)-l I (3R)-3-{[(lS)- I- ldaa 610 61aa.1 (am ofny1)-2-nmctylpropyIlaminolcarbony].6cboro 2,3,4,9-tetahydro-II--carbzo -3-yIjamnDnocarbonylj-2. methylbvrtyllcarbamte (aminocarbonyl)-2-methylpropylamino]cabonyll-..choro 2.3,4,9-tetrahroD-lll-baol-3-y]zuino)carbonyl]-2 mothylbuty1]oarbamate (ainocarbonylO-2-methylpropylano)mbonyJ..chlaby 2,3,4,9-tetrahydro-fl{-orbazol-3-yl]amfino]carbonyfl-2 Taethylbutyi]carbainate -65 Phenylmthyl 1802)1[[3)3[[( )1 Sb 810 M1.151 (aMnom ety-7hylopyl]aninomoij g~djox 2,3,4,9-tetrabydro-ffl-caibzo -3-ylJamino~carbonylj-2 methylbutyllcarbamaie Phenylmdhiyl E(IS,2)-1{fl(3PR)-34ff(1S)-l- 49a 644 843.703 (a inoca bOnl)-2-methYlPropyljazinocarbonylj2 349 terAydr&uoromeyf}.IH-abi~o1.3 y1Jaino]mabony].2-mehylbuy1Jcabamate Phenylmethyl [(1S,2*>14[(3S)3-g[fQS)-I. 149b 844 843.703 (amiovmbony1)-2-mepropyUamo~cabony}.23,4, tetrahydro-Sudfoomey)..IHc 1 -. 3. yIjamino]oncyl-2mehybuty]cmbamat Pbenylmethyl ((I S,28141(3R:)-3-[ff (1S)..- 10.5 589.7327 (amnOcbonY)-2-mYlPrOPYadolabony1I-.3, 9 tet-hydro-S-methyl-1Hcabazob3y]miro3cbony.2 methylbutyijoarbamatu PhenylmetMy [(1S,2S)-1-[[[(3S)-3-aIS)-l- 15Gb 560 589.7327 (anoarbony-2-metiypropy1]aminOlCarboy1-234 tetmydrD-8-methyI4Hcrao13-YIaminO]crbny]-2 methiylbutyllcarbamate Phenybnethyl [(ISA2)-.E[((31Q3-(ff(1S).1. Isla 590 589.7327 (aino 2 .. meth ylpartoyllCM bony1I.Z34 te'Yd 5-iethy..rnarbazoI.3-yl]aniko]boy].

2 . znethylbutyl~caibamate. Phenylmethyl [(lS,2s)-l.{[[(3S)-3{ftlS).I. 15b 890 689.7327 (aminocrboDnyI)-2.mehylpropy1amoJmrboDnyl]23, 49 methylbutylgcarbarnaft Pheuyhnethyl ((IS-2S)-I-LRf(3R,)-34Ua~s)-1.. 151c 590 689.7327 (aminOobwY1)-2..mthY)propyaminocabonyti.234 9 methiylbutylcarbainate - 66 Phenylmethyl (S,2S)-141(3S).3-1f((JS)-I- I51d 590 597327 (arinobonYl-methYlPropyljaminocarbonYl-2,3A49 tctrahydro-7-mehyl-U-cub=1o-3yljamino]cabony]-2 rnethylbutyljcarbamate Phenylinethyl [(lS2S)-1-ll(3KQ-3-I(S)-l- 152s 610 610.151 (amioboniyI)- dypropyl moarb onyS-c~oo-. 2,,4,9teraydro-H-carbazol3-y]amino]any].2 methylbutylicarbamate Pheoiylmethy1 (S2)1{I3S--l )I 162b 610 61 0.151 (ainobol)-2-meylpropyomiocbony]-7.cioro 2,349-cwahYdro-ffl-cabazol -3-Yljamiuojvarbnylj2 methiylbutylJcarbamt (aminboy)-2-mro rpyamino] bony]-c~oro 2,3A49.emahYdO-IH-abzo-3-YJlaminolcarbonYl}.2 inetiiylbutyllcarbamate (3PR)-3-fl[(1S)-I-(Amnocarbony)-2- _1 U3 020 619,7149 methylpropyllaminojcarbonylJ-2,3,9-tehydro-3 [[(2S,3S),-.3methy1-l-oxo-2 [peylethoxy)rbonyamino]pentyJamino]-H onbaole -8-carboxylic acid (3S)-3-[[t(1S)-I-(Aninocaxbonyl)-2 ,IS~ 620 610,7149 uithYlprOPyl]aminoloabonyIJ-3A4,tetrahydro-3 [((23 mhyl-l-oxo-2 [ihnehoy)carbonyaminoetyl]amiino11lH carbazole-8-carboxylic acid Phenyirnethyl [(I S,2S)-I-[ff(31R)-3-[ff(1S).- 1"A 593 593.690 (amlinocobonyl)-2-niethylpropyl~aminocrbonyll-6fuo.ro 2,3,4)9-tetrahydro-1H-mArbazl -3-y1]arako]oa~bonyl]-2 inetbylbutyfloarbaate Phenyimethyl Y( S,2S)-149f(3S)-3-((S1- 1,54b 593 59$.690 (aminocbony-mehylppyamocbonyl]-6-fluoro 2 ,3,4,9-tetraIhydro-1H-carbazo1-3-yI]minocarbony] metbylbutyl~carbamate Phenylmethyl ((I S,2S)-1.{([(3R)-3.{(f(I S)-I- 156. 60$ 605.7317 (a~m o aoYl)-2-methYlpropyllazuinolcarbouyl]-2,3A9, tetrahYdro-6-methoXY-IH-carbazol -3-yllaminolcarbonyll-2 methylbutyl]carbaniate 67 -I Phnymthl[QIS,2S)-l.{[[(3S)-3-1[(1S)-1- 155b W 60 067317 (aminocarbonyl) -2-mtiylpropyJainojcrbony]-23,4,9 tetrahydxo-methoxy-1H-carbaol -3-yI~anmino]carbony1]-2 rnethylbutyI~cabamate Piieaylmethyl [(ISX2)-l-[ff(3?)-3.{[(1 )1 - lis-a a89 689.7327 (aminocaronyf)-2-methylpropyI]aminoloabony]-2,3,4,9 tcmhydro-6-mty-lH-abzo1-3-yI]amino]caboiiy)]2-. metbylbutyUcarbamate Phenylmethyl [(1S,2S)-14J1f(3S)-3.{f[(1S)-l- Its. b a89 50.7w (aminocbny-2mthypopyoaino]=abonyl]-2,3,4,9 terahyro-&methy-1H-cubazol -3-yflaminolcarboyl]-2 mothfibutylqcaibamate (nicarboy-2-ethpropyUamino]caboxyoJ-23,49 teahydro--Diro-lH-arazo-3-yaminocrbouyl]-2 methylbutyllearbaxnate PhenYlmethyl [(IB,2S)1-fff(3S)-3fl(IS)-1. 167b 621 M2.703 (arnoboM]-ylpropaino] bonyl.,3,4,9 tetrahydo-6-ntr-lH-carbazl.3-y~aminojcarbonylj-2 methiylbutyflearbamate Phenylmnethyl (I S,2S)-1-[[(3R)-3-[:(1 S)-1- Ise 633 832.7818 (ainowabDoyl-4 [(aminOimino~methYl~azinObuYl~Rn~jinolcarbonyf]-2,3,.49 tehydro-fl abazol-3-yamino]erbony4]-2 umethylbutytcarbainate (3R,)-N-[QIS)4-(AminOvabnyl)2-Methylpropyl]-2,3,4,9- 1600 447 447.5361 tetruYdr-34(3-PYridiYlminoj -U-abzle-3 carboxmide (3S)-N-[(IS)-1-(Azriiorarbony)-2-methylpropy1).2,3,4,9- 159b 447 447.6361 tebA-ydro-3-[(3-pyriiyacety)amxino]-1H-ca~azoe-3 caiboxamide tetrahydr-34(1-nhtaenycety)amino]-IH-carbazole-3 carboxamide - 68 (3S>-N-[(1 S)-I-(Aniinocabonyl)-2-metbylpropyl]-2,3,49- 11_0 496 496.6078 tetrabydro-3-[(1-naphthalenylaety))axnino]4IH-carbazole-3 carboxamide (3R)-N-[((S)-H-AMinacabon-2-metbypropy]-2,3,4,9- 11a 498 498 1 607e teuhydro-3-[(2-ahfteayacety)aniuio]-IH-cbo~le caboxamide (3S)-N-I(I ).-AmiuocabonyI)-2-MethylpropyI]-2,3,49- I61b 498 496,6D78 terahydro-3-[2-naphb ayactyamio]-H-ai1azoe -3 carboxamide (3R)-N4(1S>-I-(AxniocabonYl)-2-metbylPropyl-34[(Z3- .I!2I 472 472.58W8 dhYdrO-1H-inden-1-yl~cadoyljmino-2,3A49-ttrahYdro IH-carbazole -3-carboxamide (3$).-.(l S)-1-(AMiwobonyl)-2-Mclhylpropyl].3-([(2,3- 162b 472 472.G85 dgyr-Hidn1y~by~dl2349tU&do IH-varbazole -3-carboxamide (3R)-.N[(lS>-(Aminocabony)-2-mthylpropyl]-2,3,4,9- 163a 438 43&65132 tehydro-3(H-iidazol-yacety)anoH-czbazale 3-maboxamide (3S)-N-E(1 S)-1-(Aliincarbonyl)-2-methylpropylj-2,3,4,9- .13b 436 438.5132 tetrahydro-34-[midz -4-ylacey1)amio]-IH-carbazole 3-varboxamide (3R)-N-[(1S)-1-(Amnocrbony)-2-metylpropyi3-Z3,4,9- A84a 48W 485.584 tethYdro-3-(1-indO1-3YiactY1)rnino-IH-carbazole -3 carboxamide (3S-N-(1*-1-(AmOcbony)-2-m~hlpropy1]-2,3,4,9- 1Mb 488 486.6849 tetlahydro-3-4(1H-indo-3-)4aceylamin9]-1H-carbazole 3 carboxamide (3R)-N-[(I S)-l -(Aninocabonyl-2-metbylpropylj-2,3,4.9- WOe 461 480.5748 tchYdD [(4-me-thylPhenYl)acetYlmino-I-cabazole.

3-carboxamide (3S)-.(tS)-1-(AMinocebonyl)-2-miethylpropyl]-2,3,4,9- 165b 481 480.6748 tetrahydro-3.f[(4-methylpheayl*aceylamimoi]lcabaole. 3-carboxamide (3R}.N-Il S)-1-(Arninocarbony1)-2-methylpropy1]-2,3,4,9- Ag-6a 615 614.651 tctraydro-3-[([4-(trifluoromethyl)phenyllacetyi]amino]-1H carbazole-.3-carboxamide -69 (3S)-N-[(1 S)-1-(AminocabonY1)-2-methYlPropyI].2,3,4,9- I66b 615 514.6451 btahdro-3-[[4-tifuoromethylphenylaoy]amino].1H. carbazDOl -3-caboxaniide (3R)-N-[(1S)-I-(AminocarbonYl)-2-methiylpropyl].3[(4- 67a 481 480.993 c~iorophenyI~acetyamino]23,3A94etahydlro..1H-carbazole . 3-carboxamide (3S)-tIS-1-(AminOcboAY1)-mehYlrOPyI)-34(+4 16gTh 481 4B0.9931 cbloropheny1acety]amin]-2,3A49erhydru..rn.arbazole. 3-cazboxamide (3S)N-[(IS)-1{(AmitnocarbODV2-metbLYIprOPYQ-2.349- Isl 61,5 514.5451 =dro-3-ff(3-(tri~oromehy1)phenyIlaccty1]amino]-iH mabazole -3-carboxamide (3R)-N-i[(1S)-I-(AmiDOcabouYf)-2-metbYlpropyIJ-2,3,4,9- 168b 515 614.5451 tdrW -3-rwneiuThy mpenfyijaeey]amiyl=no]-H carbazol e .3-carboxamide (3R)-N-(lS)-1-(Aninocabony1-mehylpropy]-3-(((3- 189a 465 464.5311 fluorOPhnYDt~aeY]aiwnO]-2,3A49-terahYdro-l-abale -3 carboiamide (3S)-N-(1S)-1-(AMnOarbOaYi)2-MethYiPrpfOl..f3..[(- 169b 485 484.6381 fiuoxophenYlDactlamino]-23A49-tetabdo4H-cabazle .3.. carboxamide (3R)-N-t(IS)--(AminocabonYl).2-methylpopyU..2,3,4,9. i2Q. 477 478a5M3 teta(( o3-[thc toyphe ny ce~amino-IH. carbazole-3-carboxmdc (35)N-IXIS)-1-(AmiuochzbonYl)-2-mcthYlPrOPYl)-2,3,4,9.- 17_b 477 476.5738 ttbydro-34[-inehxyheny)actylamino)-rn caibaole -3-carbommide (3R-)-N[(S)-I-(Amioboyi..2-mehyprpyJ.3,4,9. 1712 477 476.5738 tehmYdrO34(2-mepbaynY aCetyIJaminoI IH.cabazole.

3carboxramide. (3SYNI,-[(1 S)-1 (Aminocarbonyl)-2-methylpropyl)..z3,4,9- 171b 477 470.573B terhydro-3[(2-methoxypheylaety13avinoD]1H-cabazole.

3-carboxamide (3R,)-N-((IS-1-(AMinocazbOnYl)-2-Methylpropyii.34r(344. 1726 479 478.5649 fluoPhenYl)-l-OxOpropy~ainn]-2,3,4,9-teraydro-1 III carbazole -3-carboxamide - 70 - (3S)_N_1-11xxbAin~onY1 )2-Methypropy]3-[3-(4- 17b 479 478-5649 fluorophenyl)-l-oxopropy]amino]-2,3,4,9txydro-1H carbazole -3-maboxamide (3R$'4-[(IS)--(Amnocarbo l)-2-methylpropyU-3-[[3- 173a 497 496 55 (3,4-difuoroDphenyl)-l-oxopropyl~amino-23A9-etahydrco IH-carbazole -3-caiboxamide (3S)-N-[(1S)-I-AinocabonyD-2-mehylpropy1J-3-U3- _ULb 497 49065M (3,4iiuophenyl)l-o7op1py]amno-2,3,4,94etrydo IH-mt~azole.3-cazoxmde (3 R)-'N-[XI S)- I (Aminocarbonyf)-2-methylpropy]34f3 - 746 93 692.805 [3,4-.b(trifluoromethylphenylj-l-aoppyl]amino]-2,3,49 tetrahdr-Hcabmzot -3-carboxamide (3S).N-[(IS)-1-(Aminocaboyl-2-mtlprol]-3-1t3- 14b 693 592.805 [3,4-bis(tzifluorometbyI)phenyfl-l-o'opvpy]amino]-2,3,4,9 tetrahydro-1H-=abazole -3-carboxaniide N-RI *)1-(Aminocarony)-2-meitI1ylp~pYI-Z3,4,9- 175 477 47Cl5M tethydro-3[(4-methoxypbeyl)cetl]amino]-lH carbmzle -3-carboxamide (3P.)-N-[(l S)- I-(Aminovrboyl)-2-mnetlpropyll-2.3,4,9- 176a 491 490.8M0 tahdo-34j[3-(4-methoxyphenyl)-l-or-opropyl]amin~oj fl{-=abazole -3-ceooxude (3 S)-N-[(l S)-I-(Aminocabony).2-methylpropyl]-2,3,4,9- 176b 491 490.600 thydro-343-(4mhxyphenl-xOPrOPYlIamD IH-carbazole .3-carboxaniide (3R)-N-((IS)--(AinoabonY1)-2-mthYlPrOPYI]Z,,49- JMA 491 490.500 teuy-341 [3-(2-m oxyphnyl)-I-x propylamino] lH-carbazole -3-carboxaride (35 N4(1 S)-(Amiuocabonyl)-2-Methylpropyl]-2,3,4,9- .1U 491 490.800 tehydro-3(32-methoxyphnyl)-oprpylaziuo] 1iH-cabazoe -3-carboxamide (3R)-N-r(1s)-1.(AMinO~abonyi)-2,MethylpropyI]-2,3,4,9- _178a 500 499.6117 tetrahydro,-3-[[3-(1H-iudol-3-yl)-l-oxopropyl]amino]-1H carbazole -3-carboxaide (3S)-N-[(ls)-I.-(AminocarbonYl)-2-metylPropyl]-2,3A49- AMD 600 499.6117. tetrahydro-3-1[3-(Hli-indoI-3-yl) -l-oxopr~opyI]aino3-1lH carbazole .3-caboxmide - 71 -I (3R)-N-[(1S)-(AmnomcarbonyI)-2-methylpropyiJ23,4,9. A? 9a 6 03 502.6s52 caiboxainide (3S)-N-(1S)-(Amzocarbony1)-2-methylpropy1]-2,3,4,9- 179b 503 5028552 tetra~ydro-3-[(l-ox~o-6-phcaylhexyI)aminoJ.1H-cai zI -3 carboxamide Phonylmthyl [(1 ,S)-1-ff[(3R)-3-[[(2S)-2- 1818l 674 57.590 (amino~abony1)-l-pyroidlzmyI]carbonyIJ-2,3,4,9 teftrabydro-IH-carbzc-3-y]aminolcarbony1..2 methylbutyijoabaate. Plhonyimethy1 [(I 5,2S)-l(3 S)-34(((2S)-2- Mk 574 573.890 (aminobon -pymid inyl]c~rbony]234,9 teu-hydro-H-abzo-3-y]minocaboy]-2 xnethylbutyl~abammt Phenylmethyl [(I S,2S)-U[f(3P)-3-f(1S*)I- lB2a 645 844.6961 (am nw-bc oy)-2methypropyIJaxinokarbey]4',s. dich~owa-23A49-tetrahdro-1H-carbazoI -3 yllamoloarbonyl)-2-niethylbutyflcarbaxnate Phpenylmethyl [(I S,28)- 1 a(3 S)-3 -[[IS)- I- 182b W4 4s.6961 (arninocarbonyl)-2-mctpropyl]amino]carbornyl]-7,8. dichloro-23,4,94etx-aydro-IH-carbazo1 -3 yl]amocabonyl]-2-methylbutyl]oarbamnate PhenyImethyl [I1S,2S)-I -fI((3R)-3.E[(l S).4- 1832 604 603.7M9 (aminymbthYD-pmro rpyI)m i olrbony)-23A49. te-ydro-5,9direthy4-IH-arbaZDI -3-yIqaminojwbony}j 2-metbylbutlcabamate Phonyhnethyl

-

,s--D3S.-E(S-.183b 004 0037595 (amlocabOrnY)-2-mebYlpropyljaminolcarbvuy11Z23,49 tefhydo-5-dimethy4H-arbzol3y]aino]cabonyI]. 2-metthylbutyl]carbama Phenylmethyl (X1S,2S)--Q(3RL)3-(ff(1S)-l lUg- 646 644.6901 (aminovarbony)-2-methylpropyl~aMiz'Io(carbnyl].6,8 diohlorov-2,3,4,9-tetrabydro..IH-carbaz1 -3 yIjaminoorbonyl]-2-mediylbutyllvarbanate PhenYlmethyl [(IS,2S).14U(3S).3.a[((IS)-l- _84b 645 644.6901 (aminocabonyrj-2-meffi~propyrainolgcaibonyl].6,8. dichloro-2,3,4,9-tetrahydro-1H-oarbazol.3 yI]ainino]c-arbonyU-2-methylbuty1carbamate -72 Phenylmethyl [(IS,2S)-1.{a[(3R)--4f(IS)-1. 1 Wa 855 654.602 (aminocarbony)-2-methylpropy]aminocarbonyJl-brozna. 2,349-tetrahyro-H-orbaol -3-yI~amwo~moaxoy] metbylbutyJca1bamate Phenylznetkyl (S,2*)-M f(3S)-34II1S)-. .18-9b 6WS 654.602 (aminocarmoe -2ylp ropyl)am o arboyl-6-bromo 2,3,49.tetrahydro-E-ozbazoI -3-yl~aminojcarbonylj-2 mehylbutyijearbanate (3R-N[(S)- (AaOny}.2mehytopy1-3f((4- 18BM 511 611.0189 cbloropbyn~tya2ino4,9-thydro-iehoxy.

1H-caibiw1e3-mazbxmid (3S)-N-[(1S)-(Amnoabony)-2-mcthipwpyJ-3-[(4.- 186b 511 511.0189 cbloropbenyoacetyllanhinoJ-2,3,4,9-tetydo-8-metboxy IH-caxbazole-3-carbouaide PhenybnetbYl [(1SZS)-(3R)3f[(R-2-axnnod4-(4- .i-1M 5 5.151 cb~oropheny1)medhlJ-2-owcthyamimolvabonyl]-2,3,4,9 te~dro-Hcro- 3--y1 ]n carbony4]-2 methylbutyl~oaxbamate Pheriyimethyl r(Is,2S)-]4(3S)-3-ff [QP)-2-amin-1r(4- 117b 658 65.195 dilorOPheaY)methYl]-2-oxoethyllaminOjcarbOnYl]-23,49. timydro-IH-cwbazol-.3-yi]amino]oabonyl]-2 methylbutyI]carbamae Pbei,-ylmethy1 [(1S,2S)-1-MI3-E[ (34amino-3- 188 64S 647.0523 orcopropyl am noarbo 3n-2,3,49-te bYdro. 1H.uarbazol 3-yljamino]crboyl-2-metbylbutyl~cabamae (2S)-I4[(31-)..34[(4-cbiloropheny1)acetyAtmino.49- I1304 509 509,0031 tahydro-8-methoxy-lIH-carbazol-3-yl]carbollyl]-2 pyrrolidinecarboxumide (2S)..I-[((3S)-3ff(4-Cboropheny)acty]amino]-2,3A9,- -1-0b 509 509-0031 tetrahydro-8-methox-1H-oarbazol-3-ylcarbonyl]-2 pyrrolidiiecarboxamide Phemyliethyl [(1 S2S)-1-f[f(31L)-3-t[(2S)-2- Iso 62 827.7815 (aminOCarbonYl)OctahYdro1H-indo1-ycarbonyJ.2,3A49 tetrahydro-IH-carbazl -3-yljamlno)varbonyi]2. me~hylbiityljoarbamate - 73 -I Phenylmiethyl (I S,2S)-llt((3 S)-34[(2S)-2- 190b 628 627.7815 (aminocarbony1)Octaydro-1H-mdo--y]carbonyl]-2,3A49 terAhydro-.IH-carbazo1 -3-yl]aminolcarbonyU-2 methylbutylqcabamate Pheaylxnethyl (I S,2S)-i.{fl(3R)-3-f [(2-SAE)2- 1910 ago 589.8881 (anm arboniy9-4-ydroxy--pyohidiny]carbonyI] 2,3,4,-totrahYdro-1H-ca~alo -3-Yllaminojcarbouyl]-2 methylbutyI)carbamate Phenylmethyl [(IS,2S)-14ff(3S)3-1(2S4R)-2- 191b 590 589.6891 (ammoboy)--hdroxy--prroidiny4]crboy1) 723A49-ttcahYdr-H-carbazol-3-Y1]aminolcarbouYI]-2 methylbutyl~cadbaae Phenylmethyl 1(16,2*-[U1I(3R)-3-Ui(IS,2*).- MRl 578 577.6701 (amno~nyl)-2hydroxypropylamino]arboyl]-2,3,4,9 tetrahydro-1H-vmbarol-3-yljaMino]carbonyfl-2 methylbuty~cwbamate Phenylmethyl [(1S,21J((3)-3f(S2)-1- 291b 578 677.5781 (=uino~nyI)-2-hydoy propylamio]abny1-2,3,4,9 tetrahydro-JH-carbazol -3.yi]amino]carbonylj-2 methylbutyl]carbamate Phenylmethyl [(IS, 2S)-1-a(3*)3-U[(2-aniuo-2- 22 534 633.625 oxothy)amino]carbonyI3-2,3,4,9-tetahydro-H-arbzo -3 yi]aminojabonyl]-2-nehylbutycArmbamate Phenylmethyl r(IS,2s)-11113-f[2- 192 59s 9586 (aminocronyI~phenyl]azuinolcabory]-234,9 etrahdo I H-carbaol -3-y]aroinolcarbnl-2-methylbuyvArbamate (3R)-N-(S)-I-(Aminocarbon!-2-methypropy}.3-[4 193R 618D S1U.119 chloro-3-[[(4-pyiidinylaniino) =oyl]amiDD]phenyljacetyl]amino]-2,3,4,9tetahydro IH-carbazoe-3-caboxamiide (3S)-N-[(I S)..1(A!nocarboltyl)-2-methylpropyl]-3{[[4. 193b 618 616.119 chloro-3-[I(4 pyidinylmino)azbonyjamiuo]phenyl]acetyllamino] 2,3,4 9-tetrahydro-1H-caxbazole-3-cuxboxamide (3R,)-N4(l S)-l (AMinor-arbonyl)-2-Methylpropyl]-3-{jj4- 194a 615 615.13 chloro-3-[[(penyamino) caronYiamiw-3PhenylacYlamim,]2,3A9-trahydro. IH-carbazoloe-3-carboxamide (3S)-N-[(1S)-l-(Amocrbony)-2-methypropyl]-3-[[(4. 194b 615 61S.13 - 74 cbloro-3-[[(phenylamino) cabony]amino]phnyl]acetyjamino]-2,3,49terayro IH-cabamk-3-cuboxamidc (3R)-N-[(IS)- 1-(AminorbonyI)-2-lnetbylPrOPY1]-34([4- -195a 529 629157 vb~oro,-3.(ftbeqy1methyI)aminqj cmbony1]aminD~pIboylacety!JsMinG334,9-tetraydo (3 S)-N-( S)-1-(Axoiuovabmy1)-2-mehylpropyI]-3-fl[4- AS5b M2 M2.157 choo3-[[[(Phny~mty)3inocabonylJamino] phenyl~acety13aminoJ-23A4-e~bYdro -1H-carbazolecaiboxamide (3R-)-N-[(1S)-1-(Aminocabonyl)-2-methyipropyl]-34ff4- -18; 61 618.119 cbloro-3.{((2-pyiidinylamino)cazboul]Rmino] pbenyljacatljamino]-2,3.4,9-te~raydro.-IH-cabazoc-3 caiboxumdet Q *)N-(1 )1-(Amnocarbony1)-2-metyipropy]-3-[((4 196b 616 818.11.9 chloro-3.{[(2-pydnybamio)crbonyi]ammo~nJph,,nyjjayj] aminol-Z3A4hYdr-H-cabazol-3-abmide Example 24: Synthesis takes place on the 0.2 mrmol scale by methods 5 A, F, G, I, F, H and 0. (3R)-3-(Aety in)-N-[(1S)-1-(aminocabonyI)-2- 197a 400 400.4762 methylprop~iJ-Z,3A49-tetahYdro.8methoXY-IH-carbazoI -3 carboxamide (3S)-3-(Aoetylamino-N((IS).1-aminocabony)-2- 197 400 400.4762 mthYlProplJ-2 8 .3,49-tetahYdro--Methoxy-1H-carazol -3 carboxamide 3-(Acetylaino)-N-((IS)-1-(anocarbonyl)-2- 198 405 404.8M5 raethylpropyI]-6-diloro-2,3 2 4,9-tetrahydxo-1H-carbAzoe-3 carboxamide 3-(Acletylamino) -N-j(IS)-1-(amiriocarbonyl)-2- 199 759 788.9544 mnebylpropyl-2,,4,9-tehydro-5-methyl-IH-carbazole-3 carbwmmnide - 75 3-(Acetylmino)-N-[(S-1aminoarbony- 200 769 768.9544 methylpropy]]-2,3,4,94-trabydro-8-methyl-lH-carbazole -3 caiboxamide 3-(Acetymino)-N-[(1S)1-(amnocazixmyl)-2- ~ 2 610 609.7911 methylpropylJ-.5-coro-2,3,49-tewraydro-I1I-carbazole -3 caiboxazmde 3-(Aeyano)-N-[(IS)--(axiiooabol)-2- w~ 810 809.7911. mcthypropy)-7-Ioro-2.,3,4,9tmhydro-1H-cmaraok-3 coboxamide (3R)-.3-(Aoetylamino)-N-[(1S)-I-(aminocaibonyl)-2- 2M 38 388.44M5 methylpropy1]-6-fliuoro-23,4,9-tetrahydro-lH-carbazole -3 carboxaide (3S)3-(Acymno)-N((1S)-I-(aninocarbonyl)-2- 203bk 3M 38M.4405 metylpropy1].6.fluoro-23A49-eraydro-IH-varbazoieo -3 carboxamide (3R)-3-(Avetylamino)-N-((IS)-1-(aminocarbonyi)-2 .22d& 400 400.4M8 nietlpropy2,,4,9y~dr methoxy--crbzoe -3 carboxamide (3S)-3-(AcetaMio)-N-(IS)--(amncicabonyl)-2- 204 400 400.4762 mwhylpropy4j-2,3A9tealYdro-6-methoy-H-mamzQO -3 carboxaxnide (3R,)-3-(Acetylamino)-N-[(1S)-1-(aminocarbonyl)2- 205a 384 384.4772 miethylPropy1]-23A49-tet-.hYdo-6-methy-IH-cerba2zok -3 caboxamide (3S)-3-(Acetylamiiio)-N-[(IS)-1-(aminocarbonyl)-2- .Z~k 384 384.4772 thylpropy1]-2Z3A49-tctraydr-6-nWzhy-]H-carbazole -3 carboxamide (3R)-3-(Acetykamino)-N-[(1S>-I-(aminocarbonyl).2- 206a 370 370.4504 methylpropy]-2,3,A9-telrahydro.H-arbazol -3-carboxanmide (3S)-3-(Acetylaxnino)-N-((IS)-I-(aminovbnyl)-2- -906 370 370.4504 methylprvpyfl-2,3,4,9-tctrahydro-1H-caiimaoe -3-carboxa-mide (3R,)-3-(AceBtylamino)-N-[(1S)-1-(aninocabonuyl)-2- -207a 439 439.3406 methylpropyl]-7,8-dichloro-2,3,4,9-tetrahydro-IH-carbazole -3 carboxamide - 76 (3S)-3-(Azemino)-N(S)-I-(amocarbOny.2 -207b 439 439.3406 mehylpropYl-7.8-dCbloro23,4,tetrahydry.IH.vwbazole -3 carboxamide (3K)-3-(Acetyaxniuo)-N-((I S)-1-(arainocarbonyl)-2- M0a 390 39.504 nethYlPrOPYl]-2,3,4,9-twtahydro-58-dimethyl-1H-carbazle 3-catboxanmide (3S)-3-(Acetyamino)-N4(1S).-(rinocrbnl)-2- .9Fik 399 39ELS04 methylPropyl]-2,3,4,9-tetrahydro-5,8-dimcthyl4IH-cabazole 3-caroxamide (3R)-3-(Acetylamino)-N-[(IS)--(anocabonyl)-2m 2024 439 439.8408 methYlPropyl]-6,8-didiloro2,3A4,taYdro-1H-cobazole -3 carboxamide (3S>-3-(Acef4amino)-N-[(1S)-(aminocarbonyf)- Mb 43W 439.3408 m~ethylpropy1-6,S-didro-2,349-eahydro-I H-carbazo e -3 cad~oxmide Example 25: Synthesis takes place on the 0.2 mmol scale by methods 5 A, F, G, I, F, G, F and 0. (3R)-3-[(2S)-2-AMinO-4-(ninoiMiiOMethy~ami no-l- 210a 405 484.8014 oxop1y]amino]-N-IS)-I-amiocabony-2 miethylpropyJ-2,3A494etahydro-IH-carbazole -3-cadwxnide (3S)-3-[[(2S)-2.Ai=bo-S4(a~min iwmethy)aMioJ..1 210b 40$ 484.6014 oxopentyl]amino]-N4(1 S)-ami11ocarbo~yl)-2 methypopy1l-2,3A494aydro-H-abaole-3-caeboxmide (3R)-N-ff(1S)- I (Aminoc1Iio1-2-mehypropy3-2,3,4,9. _211Ia 497 498.652 tthydo3-[2.(pipridiny~ethylamno]aCetY1]aMIno] IH-carbazole-3-caboxamide (3S)-N-[(1S-.(Aminocarbonyl)-Z-mehiylpropyl}.3,4,9.. Z&1 497 498.852 tetrahydro-3-[[t2{1-pipridiy)t]y1Iaminolaoty]minoj UI-ceibazole-3-carboxamide (3R)-N{(S)-I-(AmnOcarbony).2-meypropy].39 2-8 52n 525.5534 uetahydro-3{[J2-(IH-indoi-3 yl)e.hy]amno]actIamio-lU-arbazole-3-vaiboxamide - 77 (3S)-N-[(lS)-1(Aminocarbonyl)2metylpropyl}.2,3,4,9- 212b 529 528.6534 tetrahydro-3.{[(((2-(1H-indoI-3 yl)ethy]aminolacetyllamino]-1H..carbazole-3-carboxamide (3R)-N-IS)I-(Aminocarbonyl)-2-methylpropyfl-3-[fl(13- 21an 520 519.6987 benzodioxol-5-ylmethyl)amiii]acezyl]amino]-2,3,4,9 tetrahydr-ffi-wbazol-3-aroxaid (3S)-N-f(1 S)-.1-(Aminocarbouyl)-2-methylpropyl]-3-ff((i,3. 213b 52W 619.5987 benzodioxol--5-ylmthy~aminoaetlano-3A49 tetrahydo-1H-carbazole.3-carboxamide diheuylehyaminoace~mino34crAhYdrO-IH carbazole-3-carboxamide (3S)-N-E(IS) -1.(AMinocarboayl)-2-inethylpropyl]-3-ff((2,2- IM4b 868 505.7141 diphenylediyI~amiolacety1jamibo].2,3A49-trahydro4IH carbazole-3-carboxamide (3RL)-N-[(t$--(Annobony)-2-mthy*wpy]-Z3,4,9- 2150 63w M3685 tetrahydro-3-1E1 [metblenyhuyI oaminominoyacety]am~tylio] IH-caxbazole-3-carboxamide (3S)-N-IS)-1.(Aminocabonyl)-2-methylpropyl].2,3,4,9- 215b 533 53268 tdrhydro-3(((Z [methyl(phenylmthyoamino]elyl~aminoacetyl]amino] 1H-carbazole-3-carboxarnide Example 26: Synthesis takes place on the 0.2 inmol scale by methods 5 A, F, G, I, F, G, F, H and 0. 3-[IIAcetyl[2-(1.piperidiny1)ethyl]amino]acetyl]amino]-N- 216 5M 538.88 (I S)-l-(azniocarbony1)-2-methylpropyI]-2.3,4,9 tetahydro-H-cabazok-3-caboxamide (3R,)-3.{[fAcctyl[2- .11_-/ 676 674.7217 [metbyl(phenylmehyl)aminoetiyljaminolacetyljaminoj.N [(I S)-N-ainomaronYI)-2-methylpopyl]2,3,4,9 tetrahydro.-lfl.carbazole-3-cabaxmidc - 78 (3S)-3-[[[AcetyI[2- Mb12 575 574.7217 [methyl(phenylmethyIoamino]ethyllamacety1]ammInoN ((IS}-I -(aminocarbonyl)-2.-rethylpropylj-2,3,A9 tetirahydro-1H-cabazo1e-3-caroxamide (3R)-3-flIAcetyl(2,2-diphenylethyl)auiiioacetynaminoj-N- 218a 8108 607.7509 [(1S)-1-(ammooarbonyl2-methYlPrOPy]23,49 ttrydro-lHbazoe-3cboamIde (3&)-3-[Acvtyi(2,2-dihenylothy1)amino~acetyllaminoJ-N- _23 110 607.7M0 [(1 S)-1-(aminocarbonyr)-2-methylpropylj2,3,4,9 teydroIH-cabazoe-3-arbomide (3R)-3-f[AcetyI(1,3-benzodioxot-5- _219 W82 561.6355 ylmetf)aminolacety]amino]-N-[(I S)-(aminocarbon)* 2-mthylpopyU-23,4,94eur-bydro-1H-crbazoIG3 cwrboxamide (3S)-3-fAoetyI1,3bezodioxco1-5- &19b M6 6.65 2-metby4propyi]-2,349-tctzuhydroD-1H-cabazole!-3 carboxamide (3R)-3-I([Acetyl[2{1IHndoI-3- 220a 571 b7.6 yI)ethyi~aminojacetyl]aminol-N-[(I S)-I -(amino ewtonyl)-2 mef~poy]239ttadr-Hcral--~bx~d (3S)-34[ffAceqyi[2-(IH-indol.3- 220b 571 570.6902 yl)ethyl]aminolacetyl]amino]-N-[(l8). I.(aminooaronl)-2 mehylpyI2,4,9-tahyd-IH-cazoe3carboxamicle 34t(2S)-2-(Acetyaio)-5[(aminoimomehy)niuo]-l- ZL1 627 826382 oxntyamo-N-E()-(amoarbony)-2 mehylpropyl-2,349tt-ahydro-I-cabe-3-vboxamide Example 27: Synthesis takes place on the 0. 2 irmol scale by methods 5 C, F, G, I, F, G and P. Phenylmetbl [(I S,2S)-2-methyl-14j[[(3R)-34,9. 2U28 689 689.7w2 tetrahydro-3{II(LIS)-2-methyl-I [(mnethylamino)carbonyI]propyl3amiao]copy]-1IH carbaol-3-yl]aminolcarbonyflbutyl]oabamate Phenyltuethyl [(1S,2S)-2-methyil--E[(38) -2,3,4,9- 222b 689 689.73V7 tetrahydro-34f(I S)-2-methyl-I [(me-thylamino)carbonyljpropyl]aniino]oarbonyU-1H c-abazol-3-y1]anilo~carbonyI]butyl]carbamate Example 28: -7 Synthesis takes place on the 0. 2 rrml scale by methods A, F, G, I, F, J and 0. (3R)-N4[(S)-I-(Aminocaony)-2-meypro~ij-3-[[(4- 223 503 603.0203 chlorophcnyasufonuy1]mino]-2,3,4,9-tetmhydro..IH carbazol-3-carboxamWd (3S)-N4-(IS)-l.{Arnoomny-2-mehylpropy]-3-[(4- 223b~ 03 603.0203 dieomphcnylmsfonyamiuo]-,3,4,9-tetrahydro-IH carbazole-3-carboxamide (3R)4I(S)--(AminOI)-2-methYlPropyI.3A49- 224A 407 405044 trhyd-3-f (metbylsulfony1)amino]-III-cazbazolc.3 carbomimide (3S-Nq()--(Amiobo Y1)-2-mey IPropy1]-2,3A4,- -94b 407 46504 tetahdro-3-[(mcthy~m~fny~amino]-1H-carbazole-3 carboxamide (3R-)-N-[(IS)--Aminocabonyl)-2-methylpropyl].2,3,49- A2so 4w9 408.5752 teto-3-[(pheny fonyl)ain]-IH-crbazole43. carboxaniide (3S)-N*-(S)-I-(Ai1wcarbny1)2mtr ~ roy]2349 2M~ 469 488.S762 tetrahydro-3-[(pheny~sufonyl ain)-lH-cabazoc-3 caeboxamide (3RY-N{(IS)--(Az ainronYl)-2-methYlpropyl}.23A49 226a 483 482602 teerhydro-3-[(phmenyfony1]amino]-l-erbtzoe 3-varboxamide (3S)-N.{[(IS)-I4(Aminovarbonyl)-2-metylpropyl-2,3,4,9. _22r-b 4183 4V2.802 tehydro-34[(Phnymethy)sulfony1]amino]4IHcaxbzole. 3-carboxamide 5 Example 29: Synthesis takes place on the 0.2 mmcl scale by methods A, F, G, I, F, L and 0.

- 80 3-Phenylpropyl [(3R)-3-[[[(IS)-1-(aminocarbonyl)-2- .ma 491 490.800 methylpropylamino]carbonyl]-2,3A,9-tetrahydro-1H carbazole-3-yl]carbamate 3-Pbenylpropyl [(3 4)-3-[[(1S)-1-(aminocarbonyl)-2. a 491 490.6000 methylpropylamino]oarbonyl]-23,4,9-tetrahydro-IH carbazoI-3-ylcarbamate Phenylmethyl [(3R)-3-[[[(S)-1-(aminocarbonyl)-2- _ 43 462.547 methylpropyl]amino]carbouyl]-2,3,4,9-tetrahydro-lH carbazol-3-yl]carbamatc Phenylmethyl [(3S)-3-[E(18)-1-(aminocarbonyl)-2- .22b 43 42.547 wethy1propyl]amino]carbonyj-2,3,4,9-tetrahydro-1H. carbazol-3-yl~carbamate Phenyl [(3R)-3[[[(1S)--(aminocarbony))-2- .8 449 448.5202 methylpropyl]amino]carboyl]-23,4,94trahydro-1H carbazol-3-yl]carbamate Phonyl [(3 )-3-[[[(1S)-1-(aminocarbonyl)-2- 229b 449 448.5202 methylIpropyl]aminolcarbonyl-2,3,4,9-tetrahydro-IH carbazol-3-y]carbamate Example 30: Synthesis takes place on the 0.2 mmol scale by methods 5 A, F, G, I, F, M and 0. (3R)-N-[(IS)-I-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9- 230s 464 483.5351 tetrahydro-3-[[(4-nitrophenyl)methyl]amino)-1H-carbazole-3 carboxamide (3S)-N-[(1s)-1-(Aminocarbonyl)-2-methylpropyl]-2,34,9- 2b 44 483.6351 terahydro-3-[[(4-nitrophenyl)methylaminoblH-carbazole-3 carboxamide (3P,)-N4(1 S).1-(Aminocarbonyl)-2-methylpropyl]-3- 231 356 356.4872 (ethylamino)-2,3,4,9-tetrahydro-IH-carbazole-3-carboxamide 81 -1 (3 S)-N-[(l S)-l.{Aminocarbonyl)-2-methylpropyl]-3- -231b 3w0 358.4672 (ethylamino)-2,3,4,9-tetuhydro-LH-carbazole-3-carboxamide (3R)-N-[(IS-1-(Aminocarbonyl)2-methylpropyll-2,3A49- ~-22 4n 464 tetrhydro-3-[(2-phenylet)3yf~ainol-Ui-carbaole-3 carboxamide (3S)-N{(1S)--(Ainoabony)-2-me1ylpropyU-23,4,9- _232b 433 432.S640 tetmhdro-3-((2-phenylethylominoj-IH-carbzol-3 carbownaide (3p,-N-[(1S)-1-(AMnocaronyl)-2mehy~propyI].2,3,4,9- _M32 447 446.591w tuhydro-3-[(3-phonylpropyl)amino]-IH-carazole.-3 carboxanude (3S)-N-(1*--(Aninocabony)-2-metby~ropy1J-2,3,4,9.. 233b 447 44"6916 tetrahydro-4(3-phenylpropyl)amino*IH-cbazole-3 caiboxmide (3R)-N-[(lS)-1-(Aminocadxmyl)-2-methylpropylJ-3-[bis(3- -03- 55 564.76W8 phenylropyl)amino]-23,4,9-tetaydro-IHi-cabazole-3 carboxaniide (3R)-N-[(ls)-1-(Aminocarbonyl)-2-mnethiylpropyi-2,3,49- 234a 489 4m8.672 tetrahYdr-34(6-henYlhxy)MInJH-crbazole-3 carboxamaide (3S)-N(S)--(Amincabowl)-2-methylpropyl]-2,3,4,9- 234b 489 488.672 terahydro-3-(6pnyhexy)aiino]-H-carbazole-3 carboxainide (3R)-N4[(IS--(Aioabonl)2methylropyl]-2,349- ZM 3 TO 370-404 tdhydro-3(1-mhyethy)aio]-R-abaole-3 carboxumde (3S)-N-[(IS)- (Aminoeaboriyl)-2-methYlpropyl]-2,3,4,9- 235b 370 370.44 tahydro-3-(-methylthyl)amiuo]-IH-aazle-3 carboxamide (3R)-N-[(IS)-I-(Aminocarbonlyl)-2-methylpropyl]-2,3,4,9. 236a 385 38.520 twtahydro-3{(-mtylpropylamino-H-cabzoe-3 carboxmi~de (3S)-N-[(l S)-l -(AminocabnYI)-2-nethylpropyl}-2,3.4,9- -736b 385 384.5208 tetahydr-34(1-mehylpropyl)aminio]-iH-erbazole-.3 carboxamide - 82 (3k)-N-( S)-1-(AmiziocarbanyI)-2-methylpropy1)A3,4,9. 237a 399 :398.5478 tetrahydro-3-[(3-methybuty)amino-lH-cabazole-3 carboxamide (3S).N-[(1 S)- I (Aminocarbonyl)-2.methy~propyl].2,3,4,9- AM7 309 398.5478 tetrahydro-3{[(3-methylbu1)amino]-H-arazoe-3 carboxamide (3R)-N-[(1S)I-(Amnoarboyl-2-mehiylpropyJ-2,3,4,9- _2M 342 34Z.4404 tetmdro-3-(ntyluAmix)-R-ebaolc-3caxboxamide (3S)-N-E(IS)-1-(Aminocabony1)-2-uietiylpropy1]-2Z3,4,9- 238b - 3244D4 te-3hr-(mymnr)-1H -lHr bazole-3- boanide (3P)-N-[(1S)--(Anoabon*)2-methy~poyU-3- _238c 35W 358.487 (dimethiylamino)-2 1 3A49-etbydo-IH-carbazole-3 (38 N4(IS$--(Amioazoy)-2-metlpropyI]-3- 236 M5 356.4M7 (dimethyl w)-3,49-to ydro-1H-carbazolo-3 carboxamide Example 31: Synthesis takes place on the 0.2 rnmol scale by methods 5 A, F, G, I, F, K and 0. (3R)-N-[(I S)-1-(Aminoca11nyo2-mthyprpy]-23,4,9- &3_0 386 385.4853 tetabydro-3fl(ethyamino)carbonyllamio]-1E-carbazole. 3-carboxauiide (3S)-N-[(IS)I-(Aminocabnyl)-2-metbyhpropyfl-2,3,4,9. Zuk W8 385.4853 tdeyr-34J(metbylamino)carbony]amino]-H-arbzoce 3-carboxaxnide (3R)-N-[(1S)-1-(AzzknocrbonYJ)-2-rnethypropyl]-23,4,9. 2404 448 447.6381 tetrahydro-3-[[(phenylamino)cabonyl]ammno]-rn-aibazole 3-caboxamide (3S)-N-[(lS)-1-(Amnocaronyl)-2-methylpropyl]-2,3,4,9. 40b 448 447.5351 tthydro-3-ftphenynieobny1ain ino]-Hcarbaole 3-carboxamide -83 (3R)-N-[(IS)-1-(Aminocrbonyl)-2-methylpropyll-2,3,4,9- _4412 482 401.562 ttrhydro-3.{[(phenylmethyl)aminolcarbonylgamino]. 111 carbazole-3-carboxamide. (3S)-N4(1S)-I-(AMinocarbony)-2-metiylpropylJ-23,4,9- 241b 462 461.5M2 tetrahydro3IIUpheylethyominolcarboylamino 1H carbazole-3-varboxamide (3R)-N4[(l S)-1-(AiuinovarbonyI).2-Methylpropy1]-Z23,4,9- - 22a 478 475.5887 tdhydro-3-f [(2-phnyletylarnnooubnyl~amino]-dH carbazolo-3-caiboxamide (3S)-N-[(1 S)-1-(Aminocabonyl)-2-methylpropyl]-2,3,4,9- .2_42b 478 475.5587 te~ra1ydro-3[U(2-phenylcthiyI~amio]carbony13amino]-IH carbaZole--arboxumddc (3PR)-N4(B)4.(Aninocrbny)-2-metbylpropyl]-3- -2.f 454 453.6=3 [[(cyclohexylamizno)carbony1]amiiio]-2,3A49-tetrahYdro-lH ciubazole-3-carboxamide (3S)-N-4(1S)-1-(Aniiocazibonyl)-2-znethylpropyl]-3- 243b 484 453.5 fl(ccohwyamino)carbonyvamino)-2,3,4,9-tetahydro-1H carbazole-3-Garboxamide (3R)-N-((IS)-l-(Amino~aboy)-2-mthylpropyJ-!2,3A49- 244 414 413.6189 twiahydro-3-4(-ntIethypamio)crbony1]smino]-1H carbazole-3-carboxarnide (3S)-N-[(1S)-1.{Aminocarbonyl)2-metypropy1}.2,3A9- IM4 414 413.5189 tahydro-3-M(-mehyl-hyoacino]caxboniyl3arninod-IH ceibazole-3-carboxamide (3)-N-(1S)-1-(Anrocabiyl)-2-methylpropy1)-2,3,4,9- -24bA 4211 427.545 terhydro-34ff(1-mathylpropyl)aimno]rny1]anmino] 1fl-carbazolt-3-mazoxamide (3S)-N-(S)--(Aninoarbony)-2-methylpropy]-23,4,9- 245b 428 427.5457 tetrabydro-3-(U(I-mcthylpopyoamino]varbonyl]xnnoJ 1H-carbazole-3-carboxamide (3R)-N-[RIS>4.(Aminocrony)-2-mchylpropy]-2,3,4,9- 246a 478 475.5897 tetrahydro3-UR1R)-1-penylcthyl]aminocarbonyl]amino] IH-carbazole-3-carboxamide (3S)-N-[(1S)-1-(Aminocaony)-2-meypropyl-2 ,3A49- 246b 478 475.5897 tetrhydro-34tr()--phenylethyzlminocabonyl]aio] IH-caibazolc-3-carboxaxnidd - 84 (3pR)-N-[QS)-l-(Amkwiocbony)-2-methylpropyi}. 3-4(gt. _=ah 482 481.9812 chloropheny)amino)crbony1aminoJ-2,3,494ernjYdro..l; carbazole-3-carboxaaiide (3~--(Sl(momoy).-typpj-4f4 AM 482 481.9812 cWilophenYtDainOlcarboylaminJ.-2,3A494etr'AYdro..IH carbazole-3-oarboxamide (3R)-N-[(1S)-1-(Aminocarbony2methypropy]..2,3,4,9. A-83 478 475-597 tetrhydro-3-(Ef(l$)-l-penyletbyaiioabonyl]amiao] IHrb azole-3-carboxamide (3S)-N-{(lS)4-(Amnocabony.Z-Methylpropyl].2,3,4,9. 248b 478 475.589 tetaydro 3 -[W (lS)-ble Aamoovarbon y]amio] 1H-carbazole-3-cadboxarnide Example 32: Synthesis takes place on the 0.2 nimol scale by methods 5 A, F, G, I, F, G, N and 0. Wty (3R)-3.{[((l S)-1.{amino cny)-2- 24ft W8 667.0825 mthyipropyl~amio]caboiyl]-3-[( chlorophenyloacetylano-,34-ethydro-9H-citazol.. 9-acetate Ethy (3S)-3-fI((IS)--(amjnocaboyl)-2- 29b 587 567.0825 miethylpropy13amho]cwabonyl3-3-f(4 chlorophenypacetylano]-lA,4-tydro9H-aiazok.., 9-acetate (3R)-N-f(lS)-1-(Aminocaronyl)-2mehiylpropy]-3-[[(4 260a 6W9 6991J711 c~iorophmny1)acetylamino]-2,3A94trhYdro-9-03 phenylpropyl)-lH-crbazole=-3-cboxamide (3) lI)I(mo 'oil2mfilr 250b 599 599.1711 cehoropheny1)acedylamino3-23 4-etahydro-9-( phenylpropyl)yAH- ar~zoe-3-carboxamide (3R)-3-[[[(lS)-l-(Amniitocarbonyl)-2- 2Z18 539 639.0289 metiylpro>pyllaminoloarbonyl-3-[(4 clorophenylAztyllamino]-1,2,3,4-tetrhydiro-911-carbazole 9- acetic acid -85 (3S)-[f(LS)-1.(Aminocarbonyl)-2- 251b 539 639,0289 methylpropyl]axninco]caxbonyl]-3-[[(4 cbloxophenyl)acety amino]-I1,2,3,4-tetrahydro-911-carbazobe 9-acetic acid (3PR)-N-[(I S)-1-(Aminocnanyl).2-methylpropylj-34((4 2M9* 551 651.1271 chlor oplienyl~actyl~amino]-2,3,494trahdro-9-(3 mebylbutyl)-1YH-varbazole-3-carboxamdc (3S)-N-[(IS)-1.(Aminocarbonyl)-mthypopy!--[(4- 2Mk 561 551.1271 c1oroPhenYIbacetYIlarniao]-2:3A4,tahYdro-9-(3 mebylbutyl)-1H-carbazole-3-caboxarnde (3R)-N-[(1S)-1-(Amincarbyl-2-mcthylpropyl-3-[(4- .ZVa 67 n 721066 4btorophenyI~acetyIamino]-2,3,4,9-terahydroi-9-(4 pyidiulmethyl)-I-crbazol-3-aroxmide (3 S)-N4 (I S) -- (A mocarbony)-2 -methypropy]3 - [(4- A§3b 572 572105 chlorophenyl)aoetyl]amino]-2,3,4,9-tetrahydro-9-( 4 pyxidinylmethy1)-1H-carbazoke-3-cauboanide (3---(S--Aioabn3)2mtypoy--[4 l84a 672 5721056 dhoropheny)acctIamino)-2,3,4,9-tetra1ydro-9-(3 pytidinylmethyl)-1H-carbazolc-3-carboxamide (3S)-N-[(1S) 1-(Aninocabo!y)-2-methypropy]-3{[(4. 'A4b S72 57210 diloxophenyloacetyljamino]-:2 34,9tctaydro.-(3. pyridinylmethyl)-1H-,ao~lc-3-caboxamidc (3R)-N-[(IS)-I{Aminocbony)-2-etylpropyfl3..fl(4. Ma5 621 821.1773 chgoropheny~)acety1)amino]-2,3,4,9-etrahydro.9-(, uaphtanymhy)-I-abazoe-3-crboxmjdc (3S)-N-[(1S)-1-(AmnocabonyI)-2-wethylpropyl]-3-[(4. 255b 621 621.1773 .chorophenyl~acetyl]aminoj.23,4,9-tetrathydro-9-. lnaptnylmethyl)-H-carbol3cboxnjde (3P1Q-N-[(I S)-l.(AminOcabonyl)-2-meth~ylpmopyl].3-[((4 .ZQ 2566 37 537.1003 chlorophenyIbacetyljaminoJ-2,3,4,9-eI~ydro-.<2 oicthy1ropyl)-1H-carbazole-3-cazboxamide

(

3 S)-N-(1S-1-(Anfocbony)-2-mdiylpropyNl..g-(4- -256b 537 6537.100 chloTopbenyI)acetyl~axmo]-Z,3,4,9-terahydro-9.{2 nletllylpropyfr-H-arazoc-3-arboxaidc (3R)-N-[(1S)--(Armocarbony)-2-xothy]propyI3134((4. 257a 555 5M~.1443 choropherny1acety1]amino]-2,3,49-tetrahydro9<-2. phenYIlikl)1}IH-cad'azole-3-carboxamide -86 (3S)-N-[(1)-1-(Amiloabony)-2-methylpropylj-3-r[(4- M5T US 685.1443 cbloropheny)acetyaniio-2,3A4-etrahYdro.9-(2 phenayiethy1)-lH-crbzoe-3-maboxamide (3R-N-[(IS)-1-(Amnocboy)-2-methylpropyl]-3.((4. 268a 609 609.0467 CWhIOophenyl~acetlamio-9-cthyl-2,3,4,9-ttrahydro-IH carbazole-3-caboxamide (3 S)-N-[(l )-I -(Aminocarbny).-Mehylpopy1},3-f,4 298b 60 500467 dilorophenyl)acetyl]amino-9ety-2,3,4,9-tetraiydro-III caubazoIv-3-carboxanmide (3R-)-N-[(1S)--(Amino arb2-me~lybpiopl-3p1(47- M&69 577 677184 chkophenyaOetylamno-9Oclohemyo)-2,34,9 tetrydrd-1H arbaole-3.caboxaride (3S)-N{)14- 1(Amicarboy)2-metpropy3.{g4- ME 57 677.16,49 chOrOPheacetginO-9-h ,oeymethyI239 tctrahydro-IHcarbazole-3-carboxamdc (3R)-N-(S)-1-(m~AyI) 2 methyproy..3f[g4. M80 507 6UL977 chlorophenyl)ac-ety]amino]-9(2,6-diiuoroph I )methy1 2,%,4,tabdoffaaz~e3-*carboXaide (3S)-N-R1IS)-1-(Amino aboy)2-methypropyl1.t3-rr(1- 260b 807 607.0977 choophm -9-[(26o] op-[2eiMorphy1 )mt ] 2,3,4,9--tctahydro -1-carbazole-3-catonxmidec Example 33: Synthesis takes place on the 0.2 inmol scale by methods 5 A, F, G, I, F, H, N and 0. (3R)-3-(Acetylamino)-N-[(1S)4-(aminocabonyl)-2- M1a 489 408.624 methylpropyJJ-2,3A49-tcurahYdro-9-(3-phonylpropy1)-1H carbazole -3-carboxamide (3S)-3-(Acetylamino)-N-[(1S)-1-(aminocarboayl)-2- 261b 489 488.6284 methylpropyl]-2,3,4,9-teUrahydro-9(3-phenylpropyl)- II caiibuzola-3-caxboxamide (3R,)-3-(Acetylamino)-N-C((S)4.-(aminocaitonyl)-2- 262a 441 440.5844 inethylpropyll-23,4.9-tetahydro-9.(3-methiylbutyl)-1H carbazole-3-carboxamide - 87 (3S)-3-(Acetylamino)-N-[(1S)-1-(aminocarbonyl)-2- .Th 441 440.844 methylpropyl]-2,3,4,9-tehydro-9-(3-methylbutyl)-H carbazole-3-carboxam ide (3R)-3-(Acetylanino)-N-[(1S)-1-(aminocarbonyl}-2- 2a 11 5lo.sae methylpropl]-2,3,4,9-tetrahydro-9-(2-napithalenylmethyl) 1IH-carbazole-3-carboxamide (3S)-3-(Aclamino)-N-[(IS)-1-(aminocarbonyl)-2- .2Mb 511 510.634 mdhylpl 3,4,9-te4bydr-9-(2-naphalnylmethyl) 1H-carbazole-3-carboxamide 3-(Acetylamino)-N-[(15)-I-(aminocarbonyi)-2- 284 Sit 610.64 methylpopy1-234,9-trhydro-941-aphth enymethyl) 1H-carbazole-3-carboxamide 3-(Acylamino)N-[(S)-1-(aminocabony)-2- 5 4U 4M.222 mOthypropy]-9-(cyclboxylmethyl)-2,3,4,9-terrahydro-11 carbuzole-3-carboxamide (3R)-3-(Acetylamino)-N-[(IS)-I-(aminoarbonyl)2- 288a 427 426.576 methyIpropyI-2,34,9-terrahydro-9-(2-methylpropyl)-H carbazole-3-carboxamide (3S)-3-(Acetylamino)-N-[(IS)-1-(aminocarbony)-2- .26b 427 426.5578 metpropyl]-2,3,4,9 ahydro-9-(2-mehylpropyl)-IH carbazole-3-carboxamide Example 34: Synthesis takes place on the 0.2 mmol scale by methods 5 D, F, G, I, F, 0 and subsequent coupling in accordance with Example 6. Phenylmethyl [(IS,2S)4-[[[(3R)-3-[[[(1s)-1- 2 a 83 62.70sa (hydroxymethyl)-2-methylpropyllaminotcarbonyf]-23,4,9 tetrahydro-1H-carbazol-3-yl]amino]carbonyl}-2 methylbutylcarbamate Phenylmethyl [(1S,2S)-1-[[(3S)-34[(IS)-1- 9Zb 56 562.7068 (hYdromethYl)-2-methylProPyl]amino]carbonyl]-2,3,4,9 teahydro-1H-arbazol-3-yl]aino]oarbanyl]-2 methylbutyl]oarbamate 10 Example 35: Ethyl 2,3,4, 9-tetrahydro-3- (3-phenylpropyl) -1H carbazole-3-carboxylate 268 10 mmol (1.6 ml) of ethyl 4-oxocyclohexanecarboxylate, 15 25 mmol (1.4 ml) of glycol and 10 pmol of pTsOH are - 88 refluxed in dry toluene with a water trap for 24 h. The solvent is removed and the residue is taken up in ethyl acetate/water. The organic phase is washed with water, dried and evaporated to dryness. The product is 5 distilled in a Kugelrohr apparatus under high vacuum at 120 0 C and 0.03 mbar. Yield: 1.52 g of 4-ethyl 1,4-dioxaspiro[4,5]decane-8 carboxylate 269. 10 85 pl of diisopropylamine in 500 p1l of dry THF are added dropwise to 0.6 mmol of a 1.6 molar solution of butyllithium in heptane at -20 0 C under argon and then stirred for 10 min. After cooling to -70 0 C, 0.5 mmol (107 mg) of 269 in 200 pl of dry THF are added 15 dropwise, allowed to reach 0 0 C over the course of one hour and stirred for a further 30 min. After cooling to -700C, 0.7 mmol (106 p1l) of 1-bromo-3-phenylpropane in 300 p1 of dry THF are added, and the mixture is stirred for 30 min. It is allowed to reach RT and then stirred 20 for 1 hour. The saturated NH 4 C1 solution and n-hexane are cautiously added to the organic phase, which is stirred for 10 min. The organic phase is separated and washed with water. Filtration through a Whatman filter is followed by evaporation to dryness. 25 Yield: 165 mg of ethyl 8-(3-phenylpropyl)-l,4 dioxaspiro[4,5]decane-8-carboxylate 270. 0.6 mmol (200 mg) of 270 are taken up in 25 ml of acetone/0.1 M HC1 1:1 and stirred with catalytic 30 amounts of pTsOH at 50 0 C for 48 h. The acetone is stripped off in a rotary evaporator, and the precipitated product is filtered off, washed with water and dried. Yield: 156 mg of ethyl 4-oxo-8-(3-phenylpropyl)cyclo 35 hexanecarboxylate 271. The indolization takes place as described in Example 1 using phenylhydrazine.

- 89 Yield after evaporation and preparative HPLC: 65 mg of ethyl 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-lH carbazole-3-carboxylate 268. 5 ES-MS: 362 (M+H+) 80 mg of ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3 phenylpropyl)-lH-carbazole-3-carboxylate 272 are prepared analogously using 2,4-dichlorophenylhydrazine. 10 ES-MS: 430 (M+H ) Example 36: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-lH-carbazole-3 15 carboxylic acid 273 3.94 mmol (1.31 g) of 269 are stirred in 50 ml of methanol and 30 ml of 50% sodium hydroxide solution at 60 0 C for 4 h. The mixture is acidified with dilute HC1 20 and extracted with ether. Drying with Na 2

SO

4 and evaporation affords 1.02 g (85%) of white solid 8-(3 phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid 274. 25 65 mg of 274 are first deprotected with HC1 and then reacted with phenylhydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparative HPLC: 15 mg of 273. 30 ES-MS: 334 (M+H') 39 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl propyl)-lH-carbazole-3-carboxylic acid 275 are prepared 35 analogously using 2,4-dichlorophenylhydrazine. ES-MS: 478 (M+H +) Example 37: - 90 2,3,4,9-Tetrahydro-N-[(lS)-1l-(hydroxymethyl)-2 methylpropyl]-3-(3-phenylpropyl)-1H-carbazole-3 carboxamide 276 5 0.66 mmol (200 mg) of 274 are reacted with 1.5 equivalents of valinol in analogy to Example 6. 277 mg of white solid N-[(1S)-1-(hydroxymethyl)-2 methylpropyl]-8-(3-phenylpropyl)-1,4-dioxaspiro[4,5] decane-8-carboxamide 277 are obtained. 10 Then 0.3 mmol (117 mg) of 277 are first deprotected with HCI and subsequently reacted with pheny1hydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparative HPLC: 15 mg of 15 276. ES-MS: 418 (M+H +) 25 mg of 6,8-dichloro-2,3,4,9-tetrahydro-N-[(1S)-1 20 (hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1H carbazole-3-carboxamide 278 are prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 486 (M+H ) 25 Example 38: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinyl methyl)-1H-carbazole-3-methanamine 279 30 54 ml of a 1 M solution of LiAlH 4 in dry THF are cautiously added to a solution of 18 mmol (6 g) of 270 in 250 ml of dry THF under argon at room temperature. After heating to reflux for 3 h, cautious hydrolysis is carried out with 300 ml of saturated NH 4 Cl solution, and 35 250 ml of ether are added. The aluminum salts are filtered off and washed with ether. Drying of the ether phase with Na 2

SO

4 and evaporation of the solvent afford 3.4 g of 8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]decane 8-methanol 280.

- 91 5.86 mmol (1.7 g) of 280 are dissolved in 60 ml of dry DCM and 20 ml of dry DMSO. Under nitrogen at room temperature, firstly 44 mmol (6.1 ml) of TEA and then 5 cautiously 17.6 mmol (2.8 g) of S0 3 -pyridine complex are added, and the mixture is stirred for one hour. Subsequently 200 ml of saturated NH 4 Cl solution are added and extraction is carried out with 150 ml of ether. Drying of the ether phase with Na 2

SO

4 and 10 evaporation of the solvent afford 1.9 g of 8-(3 phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carbaldehyde 281 as colorless oil. 0.719 mmol of sodium triacetoxyborohydride are added to 15 a mixture of 0.359 mmol (103 mg) of 281 and 0.359 mmol (37 ml) of 2-pyridinemethanamine in 2.5 ml of 1,2 dichloroethane. The mixture is stirred under N 2 at room temperature for 3 h. Saturated NaHCO 3 solution is added, and the mixture is extracted with ether. The dried and 20 evaporated ether extract affords 101 mg (76%) of white solid N-[8-(3-phenylpropyl)-l,4-dioxaspiro[4,5]dec-8 yl]-2-pyridinemethanamine 282. Subsequently, 101 mg of 282 are first deprotected with 25 HC1 and then reacted with phenylhydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparation HPLC: 71 mg of 279. ES-MS: 410 (M+H ) 54 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl 30 propyl)-N-(2-pyridinylmethyl)-iH-carbazole-3 methanamine 283 are prepared analogously using 2,4 dichlorophenylhydrazine. ES-MS: 478 (M+H ) 35 Example 39: (2S)-3-Methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenyl propyl)-lH-carbazol-3-yl]methyl]amino]-1-butanol 284 - 92 0.368 mmol (106 mg) of 281 and 0.368 mmol (38 mg) of valinol are dissolved in 1.5 ml of dry methanol and stirred at room temperature for 30 min. After cooling to 0 0 C, 0.557 mmol (21 mg) of NaBH 4 are added and 5 stirred at room temperature for 1 h. 0.437 mmol (25 pl) of acetic acid is added, and stirring is continued at pH 6 for 2 h. Saturated NaHCO 3 solution is added, and the mixture is extracted with ether. Drying of the organic phase with Na 2

SO

4 and evaporation affords 106 mg 10 (77%) of colorless oil for 270 and 271. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 18 mg of white solid 284. 15 ES-MS: 405 (M+H ) 17 mg of (2S)-2-[[[6,8-dichloro-2,3,4,9-tetrahydro-3 (3-phenylpropyl)-lH-carbazol-3-yl]methyl]amino]-3 methyl-l-butanol 286 are prepared analogously using 20 2,4-dichlorophenylhydrazine. ES-MS: 473 (M+H') Example 40: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-O-(4-pyridinyl 25 methyl)-1H-carbazole-3-methanol 287 0.689 mnmol of NaH (as 55% suspension in mineral oil) are added to a solution of 0.344 mmol (100 mg) of 280 in 10 ml of dry DMF at 0 0 C under an N 2 atmosphere. The 30 mixture is allowed to reach room temperature and is stirred for 30 min. 1.377 mmol of 4 (chloromethyl)pyridine are added, and the mixture is stirred at 95-1000C overnight. Cooling to room temperature is followed by hydrolysis with 2 ml of 35 water and extraction with ether. Drying of the solvent and evaporation affords 115 mg of yellow oil 288.

- 93 Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 14 mg of white solid 287. ES-MS: 411 (M+H ) 5 Example 41: Ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H carbazol-3-yl]-2-propenoate 289 10 0.347 mmol of 281 in 0.5 ml of THF are added dropwise to a solution of 0.378 mmol of ethyl (triphenylphosphoranylidene)acetate in 1 ml of absolute THF while cooling in ice. After the addition is complete, the mixture is allowed to warm to room 15 temperature and is stirred for a further 2 days. It is then hydrolyzed with water and extracted with ether. Na 2

SO

4 is used for drying, phosphane oxide and desiccant are filtered off, and the solvent is removed. Yield 80% of ethyl 3-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec 20 8-yl]-2-propenoate 290. Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 9 mg of 25 white solid 289. ES-MS: 388 (M+H +) In addition, the compounds of the invention Nos. 293 to 300, 302 and 304 to 306, which are covered by the 30 general formula (I), are obtained on the 0.2 mmol scale by methods A, F, G, F, G and O, the compound 301 by methods B, F, G, F, G and O, and the compound 303 by methods A, F, G, F, G, F, L and O.

- 94 Compound name Number Mfnd Mcalc Phenylmethyl [(1S,2S)-1-[[[(3R)-3- 293 612 611.6861 [[[(iS)-1-(aminocarbonyl)-2 methylpropyl]amino]carbonyl]-6,8 difluoro-2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S,2S)-1-[[[(3R)-3- 294 620 619.7585 [[[(1S,2S)-1-(aminocarbonyl)-2 methylbutyl]lamino]carbonyl]-8 methoxy-2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S,2S)-1-[[[(3R)-3- 295 659 658.6229 [[[(1S,2S)-1-(aminocarbonyl)-2 methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S,2S)-1-[[[(3R)-3- 296 659 658.6229 [[[(iS)-1-(aminocarbonyl)-3 methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S,2S)-1-[[[(3R)-3- 297 699 698.6875 [[[(IS)-1-(aminocarbonyl)-2 cyclohexylethyl]amino]carbonyl] 6,8-dichloro-2,3,4,9-tetrahydro iH-carbazol-3-yl]amino]carbonyl] 2-methylbutyl]carbamate Phenylmethyl [(1S,2S)-1-[[[(3R)-3- 298 659 658.6229 [[[(1S)-1-(aminocarbonyl)-2,2 dimethylpropyl]amino]carbonyl] 6,8-dichloro-2,3,4,9-tetrahydro 1H-carbazol-3-yl]amino]carbonyl] 2-methylbutyl]carbamate Phenylmethyl [(1S,2S)-1-[[[(3R)-3- 299 707 706.6669 [[[(iS)-1-(aminocarbonyl)-3 phenylpropyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(IS,2S)-1-[[[(3R)-3- 300 685 684.6607 [[[(iS)-1-(aminocarbonyl)-2 methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl]-2 cyclohexylmethyl]carbamate - 95 Phenylmethyl [(1S,2S)-1-[[[(3R)-3- 301 660 659.607 [[[(iS,2S)-1-(carboxy)-2 methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S)-1-[[[(3R)-3- 302 709 708.6391 [[[(1S,2S)-1-(aminocarbonyl)-2 methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl]-2 (4-hydroxyphenyl)ethyl]carbamate Phenylmethyl [(1S)-l-[[[(3R)-3- 303 723 722.6659 [[[(iS,2S)-1-(aminocarbonyl)-2 methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1iH carbazol-3-yl]amino]carbonyl]-3 (4-hydroxyphenyl)propyl]carbamate Phenylmethyl [(1S)-1-[[[(3R)-3- 304 707 706.6669 [[[(iS,2S)-1-(aminocarbonyl)-2 methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-lH carbazol-3-yl]amino])carbonyl]-3 phenylpropyl]carbamate Phenylmethyl [(1S)-1-[[[(3R)-3- 305 659 658.6229 [[[(iS,2S)-1-(aminocarbonyl)-2 methylbutyl]lamino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-iH carbazol-3-yl]amino]carbonyl]-3 methylbutyl]carbamate Phenylmethyl [(1S)-1-[[[(3R)-3- 306 659 658.6229 [[[(1S)-1-(aminocarbonyl)-3 methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl]-3 methylbutyl]carbamate III Demonstration of the GnRH-antagonistic effect of compounds (I) of the invention 5 Materials: Buserelin is purchased from Welding (Frankfurt/Main, Germany). The compound is labeled with 1251 by using the chloramine T method and Na125I (4000 Ci/mmol; Amersham Buchler, Brunswick, Germany). The labeled substance is 10 purified by reverse phase HPLC on a Spherisorb ODS II column (250 x 4 mm, particle size 3 pm) by elution with 50% acetonitrile/0.15% trifluoroacetic acid at a flow rate of 0.5 ml/min. The specific activity is 2000 Ci/mmol.

- 96 All other chemicals are purchased from commercial source in the highest available purity. 5 Cell culture: Alpha T3-1 cells (Bilezikjian et al., Mol. Endocrinol 5 (1991), 347-355) are cultivated in DMEM medium (Gibco BRL, Eggenstein-Lepoldshafen, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine 10 (0.01 mol/l) and 10% fetal calf serum (FCS; PAA Laboratories, Coelbe, Germany) on plastic tissue culture plates (Nunc, 245 x 245 x 20 mm). CHO-3 cells (Schmid et al., J. Biol. Chem. 275 (2000), 9193-9200) are cultivated under identical conditions apart from 15 the use of Ham's F12 medium (Gibco-BRL). 10 confluent cell culture plates are washed twice with 50 ml of phosphate-buffered saline (PBS). The cells are harvested by scraping off with a rubber policeman into 20 5 ml of PBS and sedimented by centrifugation at 800 rpm for 10 min in a laboratory centrifuge (Heraeus). The cell pellet is resuspended in 5 ml of 0.25 mol/l sucrose/0.01 mol/l triethanolamine, pH 7.4. The cells are lysed by three cycles of freezing in dry 25 ice/ethanol bath and thawing at room temperature. The lysate is centrifuged at 900 rpm for 10 min, and the J sediment is discarded. The supernatant is centrifuged at 18 000 rpm in a Sorvall SS34 rotor for 30 min. The pellet (cell membranes) is suspended in 5 ml of assay 30 buffer (0.25 mol/l sucrose, 0.01 mol/l triethanolamine, pH 7.5, 1 mg/ml ovalbumin) in a Potter, and stored in 200 .l aliquots at -20 0 C. Protein is determined by the method of Bradford (Anal. Biochem. 72 (1976), 248-254). 35 Receptor assay: Binding studies for competition plots are carried out as triplicates. A test sample contains 60 il of cell membrane suspension (10 4g of protein for aT3-l-cells or 40 pg of protein for CHO3 cells), 20 pl of 125I - 97 labeled Buserelin (100 000 ipm per sample for competition plots and between 1500 and 200 000 ipm for saturation experiments) and 20 pl of test buffer or test compound solution. The test compounds are 5 dissolved in distilled water or 50% ethanol. Serial dilutions (5 x 10 -6 mol/l to 5 x 10

-

12 mol/l) are prepared in test buffer. The nonspecific binding is determined in the presence of an excess of an unlabeled Buserelin (10 -6 mol/l). The test samples are incubated 10 at room temperature for 30 min. Bound and free ligand are separated by filtration (Whatman GF/C filter 2.5 cm diameter) using an Amicon 10x collecting apparatus and washed twice with 5 ml of 0.02 mol/l Tris/HCl, pH 7.4. The filters are moistened with 0.3% polyethyleneimine 15 (Serva, Heidelberg, Germany) for 30 min in order to reduce the nonspecific binding. The radioactivity retained by the filters is determined in a 5-channel gamma counter (Wallac-LKB 1470 Wizard). 20 The IC 50 values obtained for the preferred compounds, as defined above, are indicated in the table which follows. Compound Name Example hGnRH Ca + release No. receptor human IC 50 ICso 0 M] [ [M] N-[[(3R)-2,3,4,9-Tetrahydro-3- 18 0.0000009 0.000005 [(1-oxo-2,3-diphenylpropyl) amino] -lH-carbazol-3-yl] carbonyl] -L-valyl-L aspartamide (3S)-N-[(1S)-l-(Amino- 164b 0.000006 0.0000065 carbonyl)-2-methylpropyl] 2,3,4,.9-tetrahydro-3-[ (1H indol-3-ylacetyl)amino] -1H carbazole-3-carboxamide (3S)-N-[(lS)-l-(Amino- 161b 0.0000037 0.0000036 carbonyl)-2-methylpropyl] 2,3,4,9-tetrahydro-3-[(2 naphthalinylacetyl)amino] -1H carbazole-3-carboxamide - 98 N-[[(3R)-2,3,4,9-Tetrahydro-3- 22 0.000002 0.000001 [[(2S,3S)-3-methyl-1-oxo-2 [(1-oxo-3-phenylpropyl)amino] pentyl]amino]-1H-carbazol-3 yl]carbonyl]-L-valyl-L aspartamnide Phenylmethyl [(1S,2S)-1- 64 0.0000017 0.0000015 [ [(3R)-3-[ [[ (1S,2S) -- -(amino carbonyl)-2-methylbutyl] amino]carbonyl]-2,3,4,9 tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2-methyl butyl]carbamate Phenylmethyl [(1S,2S)-1- 45 0.0000003 0.000001 [[[(3R)-3-[[[(1S)-1-[[[4 (aminocarbonyl)phenyl]amino] carbonyl]-2-methylpropyl] amino]carbonyl]-2,3,4,9 tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S,2S)-2- 222a 0.0000025 0.000003 methyl-1-[[[(3R)-2,3,4,9 tetrahydro-3-[[[(IS)-2-methyl 1-[(methylamino)carbonyl] propyl]amino]carbonyl]-1H carbazol-3-yl]amino]carbonyl] butyl]carbamate Phenylmethyl [(1S,2S)-1- 58 0.0000003 0.00000037 [[[(3R)-3-[[[(1S)-1-(amino carbonyl)-2-methylpropyll amino]carbonyl]-2,3,4,9 tetrahydro-l1H-carbazol-3 yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S,2S)-1- 181a 0.0000007 0.000003 [[[(3R)-3-[[(2S)-2-(amino carbonyl)-1-pyrrolidinyl] carbonyl]-2,3,4,9-tetrahydro 1H-carbazol-3-yl]amino] carbonyl]-2-methylbutyl] carbamate Phenylmethyl [(1S,2S)-1- 190a 0.000002 0.0000005 [[(3R)-3-[[(2S)-2-(amino carbonyl)octahydro-1H-indol-1 yl]carbonyl]-2,3,4,9 tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2 methylbutyl]carbamate 2,3,4,9-Tetrahydro-3-(3- 279 0.000002 0.000003 phenylpropyl)-N-(2-pyridinyl methyl)-1H-carbazole-3 methanamine - 99 (2S)-3-Methyl-2-[[[2,3,4,9- 284 0.000007 0.000007 tetrahydro-3-(3-phenylpropyl 1H-carbazol-3-yl]methyl] amino]-1-butanol N-[(1S)-1-(Aminocarbonyl)-2- 175 0.000008 0.0000018 methylpropyl]-2,3,4,9 tetrahydro-3- [ [ (4-methoxy phenyl)acetyl] amino-1H carbazole- 3 -carboxamide (3R)-N-[(1S)-1-(Amino- 96 0.000004 0.000003 carbonyl)-2-methylpropyl] -3 S[ (3-bromophenyl)acetyl] amino]-2,3,4,9-tetrahydro-1H carbazole-3-carboxamide (3R)-N-[(1S)-1-(Amino- 91 0.0000024 0.000002 carbonyl)-2-methylpropyl] -3 [[(4-fluorophenyl)acetyl] amino] -2,3,4,9-tetrahydro-1H carbazole-3-carboxamide (3R)-N-[(1S)-1-(Amino- 167a 0.000001 0.0000026 carbonyl)-2-methylpropyl] -3 [[(4-chlorophenyl)acetyll] amino]-2,3,4,9-tetrahydro-1H carbazole-3-carboxamide (3R)-N-[(1S)-1-(Amino- 234a 0.000009 0.000001 carbonyl)-2-methylpropyl] 2,3,4,9-tetrahydro-3-[(6 phenylhexyl)amino] - 1H carbazole-3-carboxamide Phenylmethyl [(1S,2S)-1- 150a 0.00000011 0.00000028 [[[(3R)-3-[[[(1S)-1-(amino carbonyl)-2-methylpropyl] amino]carbonyl]-2,3,4,9 tetrahydro-8-methyl - 1H carbazol-3-yl] amino] carbonyl] 2-methylbutyl] carbamate Phenylmethyl [(1S,2S)-1- 148a 0.00000008 0.00000014 [[[(3R)-3-[[ (1S)-1-(amino carbonyl)-2-methylpropyll] amino]carbonyl]-6-chloro 2,3,4,9-tetrahydro-1H carbazol-3-yll]amino] carbonyl] 2-methylbutyl] carbamate Phenylmethyl [(1S,2S)-1- 147a 0.000000076 0.00000025 [[[(3R)-3-[[[(1S)-1-(amino carbonyl) -2-methylpropyl] amino]lcarbonyl]-2,3,4,9 tetrahydro- 8 -methoxy- 1H carbazol-3-yl]amino] carbonyl] 2-methylbutyl] carbamate - 100 Phenylmethyl [(1S,2S)-1- 184a 0.000000015 0.000000045 [[[(3R)-3-[[[(1S)-1-(amino carbonyl)-2-methylpropyl] amino]carbonyl]-6,8-dichloro 2,3,4,9-tetrahydro-1H carbazol-3-yl]amino]carbonyl] 2-methylbutyl]carbamate Phenylmethyl [(1S,2S)-1- 267a 0.0000004 0.0000005 [[[(3R)-3- [[ (1S)-1-(hydroxy methyl) -2-methylpropyll]amino] carbonyl] -2,3,4,9-tetrahydro 1H-carbazol-3-yl]amino] carbonyl]-2-methylbutyl] carbamate (2S)-1-[[(3R)-3-[[(4-Chloro- 189a 0.0000007 0.0000005 phenyl)acetyl]amino]-2,3,4,9 tetrahydro-8-methoxy-1H carbazol-3-yl]carbonyl]l-2 pyrrolidine carboxamide _ 6,8-Dichloro-2,3,4,9-tetra- 283 0.000001 0.000003 hydro-3-(3-phenylpropyl)-N-(2 pyridinylmethyl)-1H-carbazole 3-methanamine The compounds of numbers 293 to 306 are tested by the methods indicated below: 5 Receptor binding assay Materials: 125 1-Triptorelin [125I- (D)-Trp6-GnRH] is purchased from Biotrend (Cologne, Germany). The specific activity is 10 in each case 2.13 Ci/mmol. All other chemicals are purchased from commercial sources in the highest purity available. Cell culture: 15 Transfected LTK' cells (ATCC No. CCL-1.3) are cultivated in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/l) and 10% fetal calf serum (FCS; Invitrogen Life 20 Technologies, Germany) on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 munm).

- 101 Testing: 80% confluent cell culture plates ate washed twice with 50 ml of phosphate-buffered saline (PBS) and then detached with 0.01 M EDTA solution. The cells are 5 pelleted by centrifugation at 200xg for 5 min in a laboratory centrifuge (Kendro, Germany). The cell pellet is resuspended in 3 ml of binding medium (DMEM; 10 mM Hepes; 0.5% BSA; 0.1% NaN 3 ; 1 g/l Bacitracin (add fresh, stock 100x); 0.1 g/l SBTI (add fresh, stock 10 1000x) and the cell count is determined by Trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted with binding medium to a concentration of 5 x 10 5 cells/0.05 ml. Binding studies for competition plots are carried out 15 as duplicates. The test substances are employed as 10 mM DMSO solutions. They are diluted to 4 times the final concentration employed with binding medium. 25 pl of the substance dilution are mixed with 25 gl of tracer solution (1 25 1-triptorelin). The tracer 20 concentration is adjusted to approx. 50 000 cpm (measured in a Cobra II, y counter, PE Liefe Science, Germany) in the final reaction volume of 100 jl. 200 gi of silicone/liquid paraffin mixture (84%:16%) are introduced into 650 pl conical tubes (Roth, 25 Germany). 50 pl of the cell suspension are pipetted thereon, followed by 50 il of the test substance/tracer mixture. The tubes are capped and incubated with vertical rotation in an incubator at 370C for 60 min. After incubation, the samples are centrifuged in a 30 centrifuge (Kendro, Germany) at 900 rpm and subsequently shock-frozen in liquid N 2 . The tip with the cell pellet is cut off and transferred into prepared counting vials (Roth, Germany). The remainder of the conical tube with the remaining supernatant is likewise 35 transferred into a counting vial. The measurement takes place in a y counter for 1 min/sample. Evaluation of the samples takes place after calculation of the specific binding compared with untreated cells, after subtraction of the nonspecific binding (excess of - 102 unlabeled ligand, 1 pm) by means of GraphPad Prism (GraphPad Software Inc., USA). Functional reporter gene assay 5 Materials: All chemicals are purchased from commercial sources in the highest purity available. 10 Cell culture: Stably transfected LTK cells (ATCC No. CCL-1.3) which harbor the GnRH receptor and have heterologous expression of cAMP-responsive elements and a CMV minimal promoter-driven luciferase reporter gene are 15 employed to carry out functional investigations. The cells are cultivated in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/l) and 10% fetal calf serum (FCS; Invitrogen 20 Life Technologies, Germany) on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 mm). Testing: 80% confluent cell culture plates are washed twice with 25 50 ml of phosphate-buffered saline (PBS) and then detached with trypsin EDTA solution (Invitrogen Life Technologies, Germany). The cells are pelleted by centrifugation at 200xg for 5 min in a laboratory centrifuge (Kendro, Germany). The cell pellet is 30 resuspended in 3 ml of assay medium (Invitrogen Life Technologies, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/l) and 10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany), and the cell count is 35 determined by Trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted to a concentration of 1x10 4 cells/100 p.l with assay medium. The cells are set out on white 96-well microtiter - 103 plates (Costar, Germany) and incubated in an incubator for 18 h. To carry out the test, test substances are diluted as 5 10 mM DMSO solutions in assay medium to 6 times the final concentration employed. 25 pl of the test substance are added to 100 Ipl of cells and incubated at 37 0 C, 5% CO 2 for 60 min. Triptorelin (D-Trp6-GnRH)/Rolipram solution (6 nM/6 pM) 10 is then added, followed by incubation again at 37 0 C, 5%

CO

2 for 6 h. Incubation is followed by addition of 50 pl of lysis/detection buffer (LucLite, PE Life Science) and measurement in a Lumistar luminometer (BMG 15 Labtechnologies GmbH, Germany). Evaluation of the samples takes place after calculation of the inhibition compared with untreated stimulated cells, after subtraction of the unstimulated control, by means of GraphPad Prism (GraphPad Software Inc., 20 USA) or alternatively by means of OMMM (Accelrys, Germany) software. The ECs 5 o values obtained for compounds 293 to 306 are indicated in the table below. 25 Compound Name Example Functional Human binding No. human EC 50 triptorelin [M] ECs 50 (M] Phenylmethyl [(1S,2S)-1- 293 0.000000762 0.000000332 [[[(3R) -3-[[[(1S)-I (aminocarbonyl)-2-methyl propyl] amino] carbonyl] 6,8-difluoro-2,3,4,9 tetrahydro-lH-carbazol-3 yl]amino]carbonyl]-2 methylbutyl] carbamate Phenylmethyl [(1S,2S)-1- 294 0.000000089 0.000000036 [[[(3R)-3-[ [[ (lS,2S)-1 (aminocarbonyl)-2-methyl butyl] amino] carbonyl]-8 methoxy-2,3,4,9-tetra hydro-1H-carbazol-3 yl)aamino]carbonyl] -2 methylbutyl] carbamate - 104 Phenylmethyl [(1S,2S)-1- 295 0.000000007 0.000000018 [[[(3R)-3-[[[(1S,2S)-l (aminocarbonyl)-2-methyl butyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetra hydro-1H-carbazol-3 yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S,2S)-1- 296 0.000000014 0.000000022 [[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-3-methyl butyl]lamino]carbonyl]-6,8 dichloro-2,3,4,9-tetra hydro-1H-carbazol-3 yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S,2S)-1- 297 0.000000284 0.000000482 [[[(3R)-3-[[[(IS)-I (aminocarbonyl)-2-cyclo hexylethyl]amino]carbonyl] -6,8-dichloro-2,3,4,9 tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S,2S)-1- 298 0.000000288 [[[(3R)-3-[[[(IS)-1 (aminocarbonyl)-2,2 dimethylpropyl]amino] carbonyl]-6,8-dichloro 2,3,4,9-tetrahydro-1H carbazol-3-yl]amino] carbonyl]-2-methylbutyl] carbamate Phenylmethyl [(1S,2S)-1- 299 0.000001497 0.000001307 [[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-3-phenyl propyl]amino]carbonyl] 6,8-dichloro-2,3,4,9 tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(IS,2S)-1- 300 0.000000017 0.000000023 [[[ (3R)-3-[ [[ (1S)-1 (aminocarbonyl)-2-methyl butyl]lamino]carbonyl]-6,8 dichloro-2,3,4,9-tetra hydro-1H-carbazol-3-yl] amino]carbonyl]-2-cyclo hexylmethyl]carbamate - 105 Phenylmethyl [(1S,2S)-1- 301 0.000000176 0.000000538 [[[(3R)-3-[[[(1S,2S)-1 (carboxy)-2-methylbutyl] amino]carbonyl]-6,8 dichloro-2,3,4,9-tetra hydro-1H-carbazol-3 yl]amino]carbonyl]-2 methylbutyl]carbamate Phenylmethyl [(1S)-1- 302 0.000000324 0.000000475 [[[(3R)-3-[[[(1S,2S)-1 (aminocarbonyl)-2-methyl butyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetra hydro-1H-carbazol-3-yl] amino]carbonyl]-2-(4 hydroxyphenyl)ethyl] carbamate Phenylmethyl [(1S)-1- 303 0.000000021 [[[(3R)-3-[[[(1S,2S)-1 (aminocarbonyl)-2-methyl butyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetra hydro-lH-carbazol-3-yl] amino]carbonyl]-3-(4 hydroxyphenyl)propyl] carbamate Phenylmethyl [(1S)-1- 304 0.000000018 0.000000038 [[[(3R)-3-[[[(1S,2S)-1 (aminocarbonyl)-2-methyl butyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetra hydro-lH-carbazol-3-yl] amino]carbonyl]-3-phenyl propyl]carbamate Phenylmethyl [(1S)-1- 305 0.000000056 [[[(3R)-3-[[[(1S,2S)-1 (aminocarbonyl)-2-methyl butyl]lamino]lcarbonyl]-6,8 dichloro-2,3,4,9-tetra hydro-lH-carbazol-3-yl] amino]carbonyl]-3-methyl butyl]carbamate Phenylmethyl [(1S)-1- 306 0.000000077 [[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-3-methyl butyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetra hydro-1H-carbazol-3-yl] amino]carbonyl]-3-methyl butyl]carbamate WO 03/051837 - 106 - PCT/EPO2/14344 CLAIMS 1. A compound of the general formula (I) q 7 5 in which the radical R' is a hydrogen atom, a C 2

-C

6 alkenyl 10 or a C 1 -C6 alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group -COOR 1 , where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another 15 from the group consisting of -NO 2 , -CH 3 , -CF 3 ,

-OCH

3 , -OCF 3 and halogen atoms, and the radical R" is a hydrogen atom, a C1-C12 alkyl, a CI-C 12 aralkyl, an aryl, hetaryl radical or the group -COCH 3 and may optionally be substituted by 20 one substituent selected from the group consisting of -CONH 2 , -COCH 3 , -COOCH 3 , -S0 2

CH

3 and aryl radicals; the radicals R 2 , R 3 , R and R 5 are each 25 independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 , -CF 3 , -OCF 3 ,

-NO

2 , -CN, a C 1

-C

6 alkyl, a C 1

-C

6 alkenyl, a CI-C6 - 107 alkoxy, a C 1

-C

12 aralkyl, an aryl or hetaryl radical; the radical R is the group -CONR R 9 , -COOR, 5 -CH 2 NR R , -CH 2

R

8 , -CH 2 OR or a CI-C 1 2 alkenyl radical which is optionally substituted by the radicals R 8 and R 9 , where the radicals R 8 and R 9 are each independently of one another a hydrogen atom, a Ci-C 12 alkyl, a 10 Ci-C 12 aralkyl, a CI-C 12 hetaralkyl, an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of -OH, -NH 2 , -CONHR i o, -COOR i ,

-NH-C(=NH)-NH

2 and halogen atoms, 15 where the radical R 10 is a hydrogen atom, a Cl-C 12 alkyl, a Ci-C 12 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON (R 11 ) 2, or where the radicals R 8 and R 9 may together form a 20 cyclic structure which consists either exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; the radical R 7 is a hydrogen atom, a Ci-C 12 alkyl, a 25 Cl-C 12 alkenyl, a Cl-C 12 aralkyl, an aryl or hetaryl radical, the group -NR 12 R 3 , -NHCOR 4 , -NHCONHR 14 ,

-NHCOOR

14 or -NHSO 2

R

14 and may optionally be substituted by one or more substituents selected from the group consisting of -OH, -NH 2 , -CONH 2 , 30 -COOH and halogen atoms, the radicals R 12 and R 13 are each independently of one another a hydrogen atom, a C 2

-C

6 alkenyl or a Ci-C 12 alkyl radical and may optionally be substituted by one or more aryl or hetaryl 35 radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -NO 2 , -CH 3 ,

-CF

3 , -OCH 3 , -OCF 3 and halogen atoms, - 108 and the radical R 14 is a hydrogen atom, a Cl-C 12 alkyl, a C1-C 12 alkenyl, a C 1

-C

12 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected 5 from the group consisting of -NO 2 , -CH 3 , -OR n ,

-CF

3 , -OCF 3 , -OH, -N(R 1 1

)

2 , -OCOR 11 , -COOH, -CONH 2 ,

-NHCONHR

1 , -NHCOOR and halogen atoms; and the radicals Ra, R b , R', R d , Re and R are each 10 independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 , -CF 3 , -OCF 3 ,

-NO

2 , -CN, a C 1

-C

6 alkyl, Cl-C 6 alkoxy, an aryl or hetaryl radical; 15 with the proviso that the compound of the general formula (I) is not selected from the group consisting of 3-amino-l,2,3,4-tetrahydrocarbazole 3-carboxylic acid, 3-amino-6-methoxy-l,2,3,4 tetrahydrocarbazole-3-carboxylic acid, 3-amino-6 20 benzyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-l,2,3,4-tetrahydrocarbazole-3 carboxylic acid, methyl 3-acetamido-l,2,3,4 tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3 acetamido-l,2,3,4-tetrahydrocarbazole-3-carbox 25 ylate or 3-tert-butoxycarbonylamino-l,2,3,4-tetra hydrocarbazole-3-carboxylic acid. 2. The compound as claimed in claim 1, where the radicals Ra, Rb, Rc, Rd, Re and R f are hydrogen 30 atoms. 3. The compound as claimed in claim 1 or 2, where the radical R 1 is a hydrogen atom. 35 4. The compound as claimed in any of claims 1 to 3, where the radicals R , R , R' and/or R s are not hydrogen atoms.

- 109 5. The compound as claimed in claim 4, where the 2 3 45 radicals R 2 , R , R and R 5 are independently of one another the group -CH 3 , -Cl or -OCH 3 . 5 6. The compound as claimed in claim 5, where the compound is selected from the group consisting of phenylmethyl [(lS,2S)-1-[[[(3R)-3-[[[(lS)-1 (aminocarbonyl)-2-methylpropyl]amino]carbonyl] 2,3,4,9-tetrahydro-8-methyl-1H-carbazol-3 10 yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl- [ (lS,2S) -- [ [ [(3R)-3-[[[(IS)-1 (aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6 chloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2-methylbutyl]carbamate, and 15 phenylmethyl [(lS,2S)-1-[[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-2-methylpropyl]amino]carbonyl] 2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3 yl]amino]carbonyl]-2-methylbutyl]carbamate. 20 7. The compound as claimed in any of claims 1 to 5, where the radical R 6 is a hydrophobic radical which includes alkyl, aryl and/or hetaryl structures and which carries a hydrogen bond donor-acceptor system at a distance of from two to four single 25 bonds, counting from the carbon atom substituted by the radicals R 6 and R . 8. The compound as claimed in claim 7, where the radical R is selected from the group consisting of 30 a phenylalanylamide residue, an isoleucylamide residue, a valyl-4-aminobenzamide residue, a valyl-N-methylamide residue, a methyloxymethyl-4 pyridyl radical, a carboxyl radical, an ethyl propenoate residue, a carbonylvalylamide residue, 35 a carbonylthreonylamide residue, a cyclic carboxamide residue, a 4-carboxamidophenyl carboxamide residue, a methylaminomethyl-2-pyridyl radical, a carbonylvalinol residue and a methylvalinol residue.

- 110 9. The compound as claimed in claim 8, where the compound is selected from the group consisting of phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(lS)-2-amino 5 2-oxo-1- (phenylmethyl)ethyl]amino]carbonyl] 2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino] carbonyl] -2-methylbutyl] carbamate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S,2S)-1 (aminocarbonyl)-2-methylbutyl] amino] carbonyl] 10 2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino] carbonyl] -2-methylbutyl] carbamate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(lS)-1-[[[4 (aminocarbonyl)phenyl] amino]carbonyl]-2 methylpropyl]aminol]carbonyl] -2,3,4,9-tetrahydro 15 1H-carbazol-3-yl] amino] carbonyl] -2 methylbutyl] carbamate, phenylmethyl [(1S,2S)-2-methyl-1-[[[(3R)-2,3,4,9 tetrahydro-3-[[[ (lS)-2-methyl-l- [ (methylamino) carbonyl ] propyl] amino] carbonyl] -lH-carbazol-3 20 yl]amino]carbonyl]butyl] carbamate, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-O-(4 pyridinylmethyl) -1H-carbazole-3-methanol, 2,3,4,9-tetrahydro-3- (3-phenylpropyl) -lH carbazole-3-carboxylic acid, 25 ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H carbazol-3-yl] -2-propenoate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(lS)-l (aminocarbonyl)-2-methylpropyl] amino)]carbonyl] 2,3,4,9-tetrahydro-lH-carbazol-3-yl] amino] 30 carbonyl] -2-methylbutyl]carbamate, phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(1S,2R)-1 (aminocarbonyl)-2-hydroxypropyll]aminol]carbonyl] 2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino] carbonyl] -2-methylbutyl] carbamate, 35 phenylmethyl [(lS,2S)-1-[[[(3R)-3-[[(2S)- 2 (aminocarbonyl)-l-pyrrolidinyl]carbonyl] -2,3,4,9 tetrahydro-1H-carbazol-3-yl]amino]carbonyl] -2 methylbutyl] carbamate, - ill phenylmethyl [(1S,2S)-l-[[[(3R)-3-[[(2S)-2 (aminocarbonyl)octahydro-1H-indol-1-yl]carbonyl] 2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino] carbonyl] -2-methylbutyl] carbamate), 5 phenylmethyl [(1S,2S)-l-[[[(3R)-3-[[[4 (aminocarbonyl)phenyl] amino]carbonyl]-2,3,4,9 tetrahydro-1H-carbazol-3-yl] amino]carbonyl]-2 methylbutyl] carbamate, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2 10 pyridinylmethyl) -1H-carbazole-3-methanamine, phenylmethyl [ (1S,2S)-1-[ [ (3S)-3- [ [ [ (1S)-1 (hydroxymethyl)-2-methylpropyl] aminol] carbonyl] 2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino] carbonyl] -2-methylbutyl]carbamate, 15 2,3,4,9-tetrahydro-N-[ (1S) -1- (hydroxymethyl)-2 methylpropyl] -3-(3-phenylpropyl) -1H-carbazole-3 carboxamide and (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3 phenylpropyl) -lH-carbazol-3-yl]methyl] amino] -1 20 butanol. 10. The compound as claimed in any of claims 1 to 5, 7 or 8, where the radical R 7 is a hydrophobic radical including alkyl, aryl and/or hetaryl structures. 25 11. The compound as claimed in claim 10, where the radical R 7 is selected from the group consisting of a 2,3-biphenylpropionylamino radical, an indanoylamino radical, an indolylacetylamino 30 radical, a 2-naphthylacetylamino radical, a 3 propionylamino radical, a phenylmethylcarboxamide residue which is substituted on the aromatic system, a phenylhexylamine residue and a phenylpropyl radical. 35 12. The compound as claimed in claim 11, where the compound is selected from the group consisting of - 112 N-[[(3R)-2,3,4,9-tetrahydro-3-[(1-oxo-2,3 diphenylpropyl)amino]-1H-carbazol-3-yl]carbonyl] L-valyl-L-aspartamide, (3R)-N-[(1S)-l-(aminocarbonyl)-2-methylpropyl]-3 5 [[(2,3-dihydro-1H-inden-1-yl)carbonyl]amino] 2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide, (3S)-N-[(iS)-1-(aminocarbonyl)-2-methylpropyll 2,3,4,9-tetrahydro-3-[l(1H-indol-3-ylacetyl)amino] 1H-carbazole-3-carboxamide, 10 (3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl] 2,3,4,9-tetrahydro-3-[(2-naphthalinylacetyl) amino]-iH-carbazole-3-carboxamide, N-[[(3R)-2,3,4,9-tetrahydro-3-[[(2S,3S)-3-methyl 1-oxo-2-[(1-oxo-3-phenylpropyl)amino]pentyl] 15 amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L aspartamide, (3R)-N-[(iS)-1-(aminocarbonyl)-2-methylpropyl] 2,3,4,9-tetrahydro-3-[[(4-methylphenyl)acetyl] amino]-iH-carbazole-3-carboxamide, 20 N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9 tetrahydro-3-[[(4-methoxyphenyl)acetyl]amino]-1H carbazole-3-carboxamide, (3R)-N-[(1S)-l-(aminocarbonyl)-2-methylpropyl]-3 [[(3-bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro 25 1H-carbazole-3-carboxamide, (3R)-N-[(iS)-1-(aminocarbonyl)-2-methylpropyl]-3 [[(4-fluorophenyl)acetyl]amino]-2,3,4,9 tetrahydro-IH-carbazole-3-carboxamide, (3R)-N-[(iS)-1-(aminocarbonyl)-2-methylpropyl]-3 30 [[(4-chlorophenyl)acetyl]amino]-2,3,4,9 tetrahydro-iH-carbazole-3-carboxamide, (3R)-N-[(1S)-l-(aminocarbonyl)-2-methylpropyl] 2,3,4,9-tetrahydro-3-[(6-phenylhexyl)amino]-1H carbazole-3-carboxamide, 35 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl propyl)-lH-carbazole-3-carboxylic acid and ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3 phenylpropyl)-1H-carbazole-3-carboxylate.

- 113 13. The compound as claimed in any of claims 1 to 5, 7, 8, 10 or 11, where the compound is in the R configuration at the carbon atom substituted by the radicals R 6 and R 7 when the radicals R 6 and R 7 5 together form an alpha-amino carboxylic acid structural element. 14. The compound as claimed in claim 1, where the compound is selected from the group consisting of 10 phenylmethyl [(lS,2S)-1-[[[(3R)-3-[[[(lS)-1 (aminocarbonyl)-2-methylpropyl]amino]carbonyl] 6; 8-dichloro-2,3,4,9-tetrahydro-lH-carbazol-3 yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(1S,2S)-l-[[[(3R)-3-[[[(1S)-1 15 (hydroxymethyl)-2-methylpropyllamino]carbonyll 2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino] carbonyl]-2-methylbutyl]carbamate, (2S)-1-[[[(3R)-3-[[(4-chlorophenyl)acetyl]amino] 2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3 20 yl]carbonyl]-2-pyrrolidinecarboxamide and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl propyl)-N-(2-pyridinylmethyl)-lH-carbazole-3 methanamine. 25 15. A pharmaceutical composition comprising at least one compound as claimed in any of claims 1 to 14. 16. The pharmaceutical composition as claimed in claim 15, where the compound is present in a unit dose 30 of from 1 pg to 100 mg per kg of a patient's body weight. 17. The pharmaceutical composition as claimed in claim 15 or 16, where the compound is present in 35 combination with at least one further active pharmaceutical ingredient and/or pharmaceutically acceptable carrier in the composition.

- 114 18. A method for preparing a compound as claimed in any of claims 1 to 14. 19. The compound as claimed in any of claims 1 to 14, 5 for use as pharmaceutical remedy. 20. The use of a compound as claimed in any of claims 1 to 14 for producing a pharmaceutical remedy for the treatment of pathological states mediated by G 10 protein-coupled receptors. 21. The use of a compound as defined in claim 1, but including the compounds specifically excluded in claim 1, for producing a pharmaceutical remedy for 15 inhibiting gonadotropin-releasing hormone. 22. The use as claimed in claim 20 or 21 in male fertility control, in hormone therapy, treatment of female subfertility or infertility, female 20 contraception and tumor control. 23. The use of a compound as defined in claim 1, but including the compounds specifically excluded in claim 1, for male fertility control or for female 25 contraception. 24. The compound as claimed in claim 1, where the compound is selected from the group consisting of phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(lS)-l 30 (aminocarbonyl)-2-methylpropyl]amino]carbonyl] 6,8-difluoro-2,3,4,9-tetrahydro-lH-carbazol-3 yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(lS,2S)-l (aminocarbonyl)-2-methylbutyl]lamino]carbonyl]-8 35 methoxy-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(lS,2S)-l-[[[(3R)-3-[[[(lS,2S)-l (aminocarbonyl)-2-methylbutyl]amino]carbonyl]-6,8- - 115 dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]l-2-methylbutyl]carbamate, phenylmethyl [(1S,2S)-l-[[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-3-methylbutyl]amino]carbonyl]-6,8 5 dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-2-cyclohexylethyl]amino]carbonyl] 6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 10 yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-2,2-dimethylpropyl]amino] carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-1H carbazol-3-yl]lamino]carbonyl]l-2-methylbutyl] 15 carbamate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-3-phenylpropyl]amino]carbonyl] 6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2-methylbutyl]carbamate, 20 phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-2-methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2-cyclohexylmethyl]carbamate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(1S,2S)-1 25 (carboxy)-2-methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl ((1S)-1-[[[(3R)-3-[[[(1S,2S)-1 (aminocarbonyl)-2-methylbutyl]amino]carbonyl]-6,8 30 dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-2-(4-hydroxyphenyl)ethyl] carbamate, phenylmethyl [(1S)-1-[[[(3R)-3-[[[(1S,2S)-1 (aminocarbonyl)-2-methylbutyl]amino]carbonyl]-6,8 35 dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-3-(4-hydroxyphenyl)propyl] carbamate, phenylmethyl [(1S)-1-[[[(3R)-3-[[[(1S,2S)-1 (aminocarbonyl)-2-methylbutyl]amino]carbonyl]-6,8- - 116 dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-3-phenylpropyl]carbamate, phenylmethyl [(1S)-l-[[[(3R)-3-[[[(1S,2S)-1 (aminocarbonyl)-2-methylbutyl]amino]carbonyl]-6,8 5 dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 yl]amino]carbonyl]-3-methylbutyl]carbamate, phenylmethyl [(1S)-1-[[[(3R)-3-[[[(1S)-1 (aminocarbonyl)-3-methylbutyl]amino]carbonyl]-6,8 dichloro-2,3,4,9-tetrahydro-1H-carbazol-3 10 yl]amino]carbonyl]-3-methylbutyl]carbamate. 25. A pharmaceutical composition comprising at least one compound as claimed in claim 24. 15 26. The pharmaceutical composition as claimed in claim 25, where the compound is present in a unit dose of from 1 gg to 100 mg per kg of a patient's body weight. 20 27. The pharmaceutical composition as claimed in claim 25 or 26, where the compound is present in combination with at least one further active pharmaceutical ingredient and/or pharmaceutically acceptable carrier in the composition. 25 28. A method for preparing a compound as claimed in claim 24. 29. The compound as claimed in claim 24, for use as 30 pharmaceutical remedy. 30. The use of a compound as claimed in claim 24 for producing a pharmaceutical remedy for the treatment of pathological states mediated by G 35 protein-coupled receptors. 31. The use of a compound as claimed in claim 24 for producing a pharmaceutical remedy for inhibiting gonadotropin-releasing hormone.

- 117 32. The use as claimed in claim 30 or 31 in male fertility control, in hormone therapy, treatment of female subfertility or infertility, female contraception and tumor control.

Claims (32)

1. Verbindung der allgemeinen Formel (I) R7 R o Re"Rb R Ra 5 FRO Ra R4 RI RR3 (1) won der Rest R' ein Wasserstoffatom, ein C 2 - C6 Alkenyl- oder ein Ct - Ca Alkylrest ist und gegebenenfalls mit einem Aryl-, Hetarylrest oder der CGruppe -COOR 1 substituiert sein kann, wobei der Aryl- oder Hetarylrest mit bis zu drei Substituenten substituiert sein kann, die unabhangig voneinander aus tier aus -NO 2 , -CH 3 , -CF 3 , -OCH3, -OCF 3 und Halogenatomen bestehenden Gruppe ausgewihlt sind und der Rest R 1 ein Wasserstoffatom, ein C, - C Alkyl-, ein C1 - Cl2 Aralkyl-, ein Aryl-, Hetarykrest oder die Gruppe -COCH ist und gegebenenfalls mit einem aus der aus -CONH 2 , -COCHa, -COOCH, -SO 2 CH3 und Arylresten bestehenden Gruppe ausgewahlten Substituenten substituiert sein kann; die Reste R2, R 3 , R 4 und R unabhaingig voueinander jeweils ein Wasserstoffatonm, ein Halogenatom, die Gruppe -COOH, -CONH 2 , -CF 3 , -OCF 3 , -NO 2 , -CN, ein C, - C6 Alkyl-, ein Ct - C Alkenyl-, ein C, - C6 Alkoxy-, ein C - CQ2 Aralkyl-, ein Aryl- oder Hetarylrest sind; WO 03/051837 PCT/EPO2/14344 104 der Rest RK die Grppe -CONR R 9 , -COOR 8 , -CH2NRR 9 , -CH 2 R', -CH O R oder ein C) - C 1 2 Alkenyirest ist, der gegebenenfalls mit den Resten R' und R? substituiert ist, wobei die Reste R' und R? unabhaingig voneinander jeweils ein Wasserstoffatom, ein C 1 - C12 Alkyl-, ein Cl - C12 Aralkyl-, ein Cj - C,2 Hetaralkyl-, ein Aryl- oder Hetarylrest sind, welche mit einem oder mehreren Substituenten substituiert sein kbnnen, die aus der aus -OH, -NH 2 , -CONHIR', -COOR!o, -NH-C(--NH)-NH2 und Halogenatomen bestehenden Gruppe ausgewshlt sind, wobei der Rest KRo ein Wasserstoffatom, ein C - C 12 Alkyl-, ein C, - C12 Aralkyl-, ein Aryl- oder Hetarylrest ist und gegebenenfalls wit der Gruppe -CON(R") 2 substituiert ist, oder wobei die Reste R! und R 9 zusammes eine Ringstrmktur ausbilden kbnnen, die entweder ausschlie0lich aus Kohlenstoffatomen oder germischt aus Kohlenstoff- und Heteroatomen besteht; der Rest R 7 ein Wasserstoffatom, ein Ci - C12 Alkyl-, ein Ci - C 12 Alkenyl-, ein CI - C12 Aralkyl-, ein Aryl- oder Hetarylrest, die Gruppe -NRzR 3 , -NHCOR t4 , -NTHCONHR 4 , -NHCOOR' 4 oder -NHSO2RW ist uand gegebenenfalls mit einem oder mehreren Substituenten substituiert sein kann, die aus der aus -OH, -NH 2 , -CONH 2 , -COOH und Halogenatomen bestehenden Gruppe ausgewahlt werden, die Reste R 2 und R, 3 unabbangig voneinander jeweils ein Wasserstoffatom, ein C2 - C6 Alkenyl- oder ein Cl - C 12 Alkylrest siud und gegebenenfalls mit einem oder mehreren Aryl- oder Hetarylresten substituiert sein k6unen, welche ihrerseits mit bis zu drei Substituenten substituiert sein k6nnen, die untabhangig voneinanrder aus der aus -NO 2 , -CH3, -CF 3 , -OCH, -OCF 3 und Halogenatomen bestehenden GCruppe ausgewthlt sind, und der Rest R1 4 ein Wasserstoffatom, ein C, - CI2 Alkyl-, ein C, - 012 Alkenyl-, ein C - Cz Aralkyl-, ein Aryl- oder Hetarylrest ist, der gegebenenfalls mit einem oder mehreren Substituenten substituiert sein karu, die aUs der aus -NO 2 , -CH 3 , WO 03/051837 PCT/EPO2/14344 105 -OR", -CF 3 , -OCIF3, -OH, -N(') 2 , -0C0R 3 1 , -COOH, -. CONH 2 , -NHCONIR" -NHCOOI! 1 und Iialogenatomen besteheaden Gruppe ausgewahlt sind; und die Reste R%,R~ R, W R und R unabhdngig voneinander jeweils ein Wasserstoffatoni eiin Halogenatom, die Cmuppe -COOKI -CONH 2 , -CF 3 , -OCF 3 , ~-NQ 2 , .- CN, ein C 1 - C 6 Alkyl-, Ct - Q5 Alkoxy-, ein Aryl- oder Hetaryirest sind. xnit der MaBgabe, dass die Verbindung der ailgemneinen Formel (I) nicht aus der aus 3 -Amino- 1,2,3A4-tetrahydrocarbazol-3 -carbonsaure, 3-Axnino-6-niethoaxy 1.2,3,4-tea-hydrocarbazo-3-carbonsgiure, 3-Amino-6-benzyloxy-1,2,3,4 tetrahydro-carbazo-3-carbonsaIure, 3-Acetamido-1 ,2,3,4-tetrahydtocarbazol-3 carbonsaure, Methy1-3-acetamido-1,2,3,4-tetrahydroarbazol-3-caiboxylat (-) Menthyl-3-acetainido-I ,2,3,4-tetrahydrocarbazol-3-carboxylat oder 3-tert Butoxycarbonyl-axnino-1 ,2,3,4-tetrahydrocarbazol-3-earbonsaure bestehenden Gruppe ausgewAblt ist.

2. Verbindung geiB Anspruch 1, wobei die Reste W~, Rb, r 0 , R , R! und R Wasserstoffatome sind.

3. Verbindung gemaJ3 Anspruch I odor 2, wobei der Rest R' ein Wasserstoffatom ist.

4. Verbindung gemdJ einem der Auspruche 1 bis 3, wobei die Reste R 2 , R!, R 4 und/oder R keine Wasserstoffatome sind.

S. Verbindung geniaLf Anspruch 4, wobei die Reate W~, R 3 , R 4 und R 5 unabhiingig voneinander die Gruppa -CH9, -CI oder -OCL1 3 sind.

6. Verbindung gemrJ3 Anspruch 5, wobei die Verbindung aus der aus WO 03/051837 PCT/EPO2/14344 106 Phenylmethyl-[(l S,2S)-l -[[[(3R)-3..{rt(1 $)-I -(aminocarbonyl)-2 methylpropyI~amino~carbony1]-2,3,4,9-tetrahydro-8-nethy=1E-curbazol-3 yllaminojcabonyl]-2-methylbutyl]-carbamat, Phenylmethyl-[(1 S,2S)-l -[E(3R)-3-[[[(l S)-l -(aminocarbonyl)-2 methylpropyl1amino~carbonyl]-6-ch~or-2,3,4,9-tetrahydio-Iflcarbazo-3-yl]am noJ-carbonay1]-2-methylbuty1]carbamat, und Phenylruethyl-[(1 S,2S)-1 -[[[(3R)-3-[[[( 1 S)-I -(auninocarbonyl)-2 maethylpropyl]arino]carbonyI]-2,3,4,9-tetrahydro-8-methoxy-1H-carbazo-3 yljami no]carbonyl]-2-methylbutyl]carbamat bestehenden Gruppe ausgewilhlt ist.

7. Verbindung gemliB eiuexn der Anspriche 1 bis 5, wobel der Rest R 6 ein hydrophober Alkyl-, Aryl- und/oder Hetaryistrukturen umfassender Rest ist, dler im Abstand von zwei bis vier Einfachbindungen von dein darch die Reste R 6 unci IC7 substituierten Kohienstoffatom aus geziihit ein Wasserstoftbracken-Donor Akzeptorsystem Mrgt

8. Verbindung gemRSl Ansprach 7, wobei der Rest W 6 aus der aus exne Phenylalanylainidrest, einern Isoleucylanidrest, einexn Valyl-4 atninobenzoes~urcamidrest, eiuem ValyL-N-methylamidrest, einem Methyloxymethyl-4-pyridylrest, einarn Carboxyirest, eiem Propensiureethylesterres, einemn Carbonylvalylamidrest, einem Carbonyltbreonylamidrest einern zyklischen Carboxamidrest, einen 4 Carboxamidophenylcarboxamidrest, einem Methylarninomethyl-2-pyridylrest, einern Carbonylvalinoirest und einemn Methylvalinoirest bestehenden Gruppe ausgewShlt ist.

9. Verbindung gemOJ Anspruch 8, wobei die Verbindung aus der- aus Phenylmethyl-[(1 S,2S)- 1 -if[(3R)-3-[[[(1 S)-2-amnino-2-oxo (phenyl tnethyl)ethyl]amino]-carbonyl]-2,3 ,4,9-tetrahydro- 1H-cax-bazol-3 yliminojcarbonyll-2-methylbutylj-carbamrat, WO 03/051837 PCT/EPO2/14344 107 Phenyhnuethyl-[(1 S,28)- 1-[[[(3R)-3 -(LI(1 S,2S)-I-(aminocarbonyl)-,2 methylbuty1]amino]carbony1]-2,3,4,9-4etrahydro- IH-carbazol-3 -ylJ aminio] carbonylj-2-inethylbutyljcarbamat, Phenylniethyl-[(1 S,2S)- I-[[[(3 R)-3-[([(l S)-1 4[[4-(aminocarbonyl)-. phenyl] amino] carbonyl]-2-methylpropyl] amino] carborxyI]-2,3,4,9-tetrahiydro- IH carbazol-3-yllaminolcarbonyl]-2-methylbutyl]carbamat, Phenylmethyl-[(1 S,2S)-2-methyl-1 -[[[(3R)-2,3,4,9-tetrahydra-3 -[[[(I S)-2-methyl 14(xnethylaiio)crbony1]propyl]aminolcarbony1-IH-cabazol-3 yl]etmino]carbonyl]butyl]carbamat, .2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-O-(4-pyridinylriety)- lH-carbazol-3 methanol, 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-1H-carbazo--arbonsaiure, EthyI-3-[2,3,4,9-tetrahydro-3-(3-phenylpropy1)- 1H-c-arbazol-3-yl]-2-propenoat, Phenylniethyl-[(1 S,2S)-l -[[[(3RL)-3-[[[(1 S)-1 -(amiriocarbonyl)-2 methylpropy1JaminolcarbonyIJ-2,3,4,9-tetrahydro-1 H-carbazol-3 yllamino]carbonyl]-2-methylbutyllcarbamat Phenylmethyl [(1S,2 1 S)- I-L[(3R)-3-[[[( IS,2R)I-(aminocarbonyl)-2 hydroxypropyl]amino]cabonyl]-2,3,4,9-ttrahydro-H-cabazo-3 yl]amirio]carbonyl]-2-nethylbutyllcarbamat, Phenylmetliyl-[( 1 ,2S)- 1-[[[(3R)-3-[[(2S)-2-(aminocarbony1)-l pyrrolidinyl] carbony1]-2,3,4,9-tetrahydro-1lI-carbazo-3-y]amino]carbony]-2 xnethylbutyl]carbamat, PhenylmethylF{(1S,2S)-1 -[[[(3R)-3-[[(2S)-2-(aminocabony)octahydro-H-inol. 1 -y1]carbonyl]p2,3,4,9-tetrahydro-lH-carbazol-3 -yl] aminolcarbo-nyl]-2 niethylbutyl]oarbamat), Phenylniethyl [(1S,2S)- I-[[[( 3 R)- 3 -[[[4-(aminocarbony)phenyL]aminocabony) 2,3,4,9-tetahydro- IH-carbazo1-3-y1]amino]carbony11-2-methylbutyIlcarbamat, 2,4,9-Ttrahydro33phenypropy)-N-(2-pyridinyhmethy). H-carbazo1-3 inethanamin, WO 03/05 1837 PCT/EPO2/14344 108 Phenylmethyl-[(l S,25)-I -[[[(3 S)-3 -[[[(I 5)-i -(hydroxymnetbyl)-2 xnethylpropyl]aniino]oarbonyl)-2,3,4,9-tetrahydro-1H-earbazol-3 y1]amino~carbony]-2-methybutyljcarbaxnat, 2,3 ,4,9-Tetrahydro-N-[(lSy.I -(hydroxymethyl)-2-rnethylpropylj-3-(3 phenylpropyl)-WH-carbazob-3-carboxamnid mad (2S)-3-Methyl-2-[[2,3,4,9-tetrahydt'o-3-(3-phenylpropyl)-JH-carbazol-3 yl]methyllamino]-1-butanol bestehenden Grxuppe ausgewahlt ist.

10. Verbindung gemiii cinem der Ansprflche I bis 5, 7 oder 8, wobei dier Rest R7 ein hydrophober Alkyl-, Aryl- und/oder Hetaryistrukturen umfassender Rest ist.

11, Verbindung gemai3 Anspruch 10, wobei der Rest Bk 7 aus der aus eiuem 2,3 Biphenyipropionylaininorest, eiuem Ludanoylaminoret, einemn Judo lylacetylaminorest, einem 2-Naplithylacetylaminorest, einem 3 Propionylarninorest, einlem am aroxnatischen Systemn substituie-teni Phenylmethylcaboxamidrest, cinem Phenyihexylaminrest und einem Phenyipropyirest besteheniden Gruppe ausgewahlt ist.

12, Verbindung gemal Anspruch 11, wobei die Verbindung aus der aus N-[[(3Rj)2,3,4,9-Tewrahydro-3-[QI-oxo-2,3 -diphenyipropyl)amino]-1ft-carbazol. 3 -yIjcarbony1]-L-valy1-L-aspamiid, (3R)-N-[( 1 S)- 1-(Aminocarbony])-2-methylpropyl]-3-ff(2,3-duhydro- lll-inden-1 yl)carbonyl]amino]-2,3 ,4.9-tetrahydro- 1H-carbazol-3-carboxainid, (3 S)-N-[(1 S)- 1-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3{( H indol-3 -ylacetyl)amino]- 1H-carbazol-3-cm-boxanid, (3 S)-N-(I 5)-i -(Amnocarbonyl)-2-rnethylpropyl]-2,3,4,9-tetrahydro.3.r(z twphthalinylacetyl)amino]- iH-carbazol-3-carboxanid, NV-[[(3R)-2,3 ,4,9-Tetrahydro-3-[[(2S,33)-3-naethyl-l -oxo-2-[(1 -oxo-3-phenyl propyi)arninolpentyl] amino]- 1H-carbazol-3 -yl) caib onyl]-L-vaiyl-L-aspartamid, WO 03/05 1837 PCT/EPO2/14344 109 (3R)-N-[(1 5)- 1-(Axinocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3 -[[(4 rnethylphenyl)avetyllamino)-1H-carbazol-3-carboxamid, N-[(1 S)-l-(Aminooarboayl)-2-methylpropylj-2,3,4,9-Aetrahydro-34((4-mthoxy phenyl)-acetyljamtinoj-1H-carbazol-3-cacboxamid, (3R)-NJ[(1 5)-i -(Axninocarbonyl)-2-mnethylpropyl]-3-ffC(3-bromphenyl)aeetylj ammno]-2,3,4,9-tetrahydro- lH-oarbazol-3-carboxaxid, (3R)-N-[(1 S}- I-(Aminocarbonyl)-2-methylpropyl]-3-[[(4-fluorphenyl)acetyip amino]-2,3,4,9-tetrahydro- 1H-oarbazol-3-caxboxanid, (3R)-N-L(1 5)-i -(Aminoear-bonyl)-2-methylpropyl]-3-[r(4-elilorphenyl)aoetyl] ammno]-2,3,4,9-tetrahydro- lH-carbazo1-3-carboxamid, (3R,)-N-[(1 5)-I -(Aminoearbonyl)-2-methylpropylj-2,3,4,9-tetrahydro-3-[(6 phenyihexyl)amninoj-1H-carbazol-3 -carboxamid 6,8-Dichlor-2,3,4,9-tetrahydro-3-(3-phenylpropyl)- 1H-earbazol-3-oarbonsaure und Ethyl-6, 8-dicblor-2,3 ,4,9-tetrahydro-3-(3-phenylpropyl)-1R-carbazol-3 carboxylat bestehenden Gnippe ausgewahit ist.

13. Verbindung gemafl einern der Anspriicbe 1 bis 5, 7, 8, 10 odor 11, wobti die Verbindung an demi durch die Reste R 6 und R! substituierten Kohienstoffatom in R-Konfiguration vorliegt, sofern die Reste 1(6 und R7 gemeinsam emn alpha Amninocarbonsaiure-Strukturelement bifden.

14, Verbindung gema3 Anspruch 1, wobei die Verbindung aus der aus Phenyhnethyi-[(l 5,25)-I -[[[(3R)-3-[[[(l S)- I-(aininocarbonyl)-2 methylpropyllanino]carbonyl]-6, S-dichlor-2,3,4,9-tetrahydro- IH-carbazol-3 yllamino]carbonyl]-2-methy]-butyllcarbanat, Phenyhnethyl-[(I 5,2S)- 1-[[[(3R)-3-[[[(1 5)-I -(hydroxymethyl)-2-inethylpropyl]. anuno]carbonyl]-2,3,4,9-tetrahydro- 1H-carbazol-3 -yl]amino]carbonyl]-2 methylbutylicarbaxuat, WO 03/051837 PCT/EPO2/14344 110 (2S)- 1-[[(3R)-3-[[(4-Chlorphenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-methoxy 1H-carbazol-3-yl]carbonyl]-2-pyrrolidincarboxamid und 6,8-Dichlor-2,3,4,9-tetrahydro-3-(3-pheny1propyl)-N-(2-pyridinylmethyl)- 11 carbazol-3-methanamin bestehenden Gruppe ausgewithlt ist.

15. Pharmazeutische Zusammensetzung, umfassend mindestens eine Verbindung gemBl einem der AnsprOche 1 bis 14.

16. Pharmazeutische Zusammensetzung gemi3 Anspruoh 15, wobei die Verbindung in ciner Einheitsdosis von 1 pg his 100 mg pro kg Kbrpergewicht eines Patienten vorliegt.

17. Pharmazeutische Zusammensetzung gemA8 Anspruch 15 oder 16, wobei die Verbindung in Kombination mit mindestens einem weiteren pharmazeutischen Wirkstoff und/oder pharmazeutisch vertriglichen Tragerstoff in der Zusammensetzung vorliegt.

18. Verfabren zur Herstellung einer Verbindung gema3 einem der Anspriache 1 his 14.

19. Verbindung gemiB einem der Anspriche 1 bis 14, zur Verwendung als pharmazeutisches Mittel.

20. Verwendung einer Verbindung gemaB einem der Ansprfiche 1 bis 14, zur Herstellung eines pharmazeutischen Mittels zur Behandlung von durch G-Protein gekoppelte Rezeptoren vermittelten Krankheitszustanden.

21. Verwendung einer Verbindung wie in Anspruch 1 defmiert, jedoch einschlielich der in Anspruch 1 uamentlich ausgenommenen Verbindungen, zur Herstellung WO 03/051837 PCT/EPO2/14344 eines pharnazeutischen Mittels zur Irihbierung des Cionadotropin-freisetzenden Hormons

22. Verwendung gemkJ3 Ansprueh 20 oder 21 in der mannihen Fertilitatskontrolle, in der Hlormontherapie, Behandlurig von weiblicher Sub- oder Infbrtilit&t, weiblichen Empfdngnisverhfitung und Tumorbekk.npfung,

23, Verwendung einer Verbindung wie in Anspruch 1 definiert, jedocli einschlieBlich der in Anspru~ch 1 namentlich ausgenomimenen Verbindungen, zur mannlichen Ferittskontrolle oder zur weiblichen Empfangnisverhitng.

24, Verbindung gema13 Anspruch 1, wobei die Verbindung aus der aus Phenylmethyl [(1 S,2S)- 1-Ij[(3R)-3-((1S)- 1 -arinocarbony)-2 methylpropyl)amino]carbonyl]-6, B-difluor-2,3,4,9-tetrahydro-H-carbazol-3 yl]aminolcarbony1]-2-methylbuty1lcarbamat Phenyixuethyl [(1 S,2S)-1 -[[[(3R)-3-[[[(1 S,2S)- 1-(aminocarbonyl)-2 methylbutyl]arnino]carbonyl]-8-methoxy-2349tetrahydro 1H-carbazol-3 y1]amino]car-bonyl]-2-metbylbuty1]carbamat Phenylinethyl [(1 S,2S)- 1-[[[(3R)-3-[[[(1 S,2S)- 1-(aminocarbonyl)-2 mehluy~mnl~roy]68dclo-,,,-erhdol-abzl3 yI]aniinolcarbonyl]-2-methybLityl]rarbamat Phenylmethyl [(1 S,2S)-1 -[[[(3R)-3-fl[I 1)-I-(aninocarbonyl)-3 methylbuty1]amino~carbonyl]-6,S-dichlor-2,3,4, 9-tetralhydro- 1H-carbazo)-3 y1]aminolcrbonyl]-2-methylbuty1]carbamat Phenylmethyl [(1 S,2S)- I -I[(3R,)-3-[[t(1 S)- l-(axninocarbonyl)-2 cyclohexylethy1]aminoJcabony)-6, S-dichlor-2,3,4,9-tetxahydro-lH-carbazol3 yl]aminolcarbonyll-2-methylbutyllcarbamat Phenylmethyl [(I S,2S)-1 -[[[(3R)-3-([[(] S)- I -(amino carbony])-2,2 dimethylpropyl]amino]carbony3-6, 8-dichlor-2,3,4, 9-tetrahydro-1 Wcarbazol-3 yljainolcarbonyl]-2-methylbutyl]cabanaat WO 03/051837 PCT/EPO2/14344 112 Phenylmetthyl [(1 S,2S)-l1-[[[(3k)-3-[[((1 S)- 1-(aminocarbo~y1)-3. phenylpropyl] amino]carbonyl]-6, 8-dicblor-2,3,4,9-tetahydro- IH-carbazol-3 y1]amino]carbony1]-2-methylbutyl]carbarmat Phenylmethyl [(1 S,2S)- 1-[[[(3R)-3-[[[(1 $)- 1-(aininocarbony1)-2 methylbutyl]aniino]carbonyl]-6, 8-dichlor-2,3,4,9-tetrahydro- 1H-carbazo1-3 yl]aminolcarbonayl]-2-cyclohexyIrmethy1]carbinfit Phenylmnethyl [(1IS-1-II3)3IL( S,2S)- 1 -(carboxy)-2 yl]amino]carbonyl]-2-methylbutyllcarbaniat Phenylmetbyl [(1 S)-1-[[(3R)-3-[[[(1 S,2S)- I-(axninocarbonyl)-2 mehluylmn~abnl-,-iho-,,,-erhdoI-abzl3 yl]amino]cr-bony1]-2-(4-hydroxyphenyI)ethyl]carbamat Phenylmnethyl [(I S)- 1[(3)-[(1S,2S)- 1 -(aminocarbonyl)-2 methylbutyl]amino~carbony]-6, 8-dichlor-2,3,4,9-tetrahydro-IH-carbazol-3 yIlamino]carbonylI-3-(4-hydroxypheny1)propyl]carbamat Phenylmethyl (IS)- 1-[[[(3R)-3-[[[(1 S,28)-l1-(ainnocar-bonyl)-2 methylbutyl]aminolcarbonyl]-6,8-dichlor-2,3,4, 9-etrahydro-IH-cabazol-3 yllamino]carbony]-3-phenylpropylJcajbamat Phenylmethiyl [(1 S)-1 -[I[(3R)-3-lI[(1 S,2S)-1 -(aminocarbonyl)-2 methybutyl]aminolcarbonyl]-6, 8-dichlor-2,3,4, 9-tetahydro-1IH-carbazol-3 yllarnino]earbonyl]-3-methylbutyl]carbamat methylbuty1]amino~carbonyIJ-6,8-dichlor-2,3,49terahydro1lH-cabazol3 yl~atnino]roarbonyl]-3-miethylbutylleabamat bestehenden Gruppe ausgewahit ist.

25. Pharmazeutische Zusammensetzung,,, umfassend mindestens eine Verbindung gemAJ3 Anspruch 24. WO 03/051837 PCT/EPO2/14344 113

26. Pharmazeutische Zusammnensetzung gemB Anspruch 25, wobei die Verbindung in einer Einheitsdosis von I pg bis 100 mg pro kg Kbrpergewicht eines Patienten vorliegt.

27. Pharmazeutische Zusammensetzung gem Anspruch 25 oder 26, wobei die Verbindung in Kombination mit mindestens einem weiteren pharmazeutischen Wirkstoff und/oder pharmazeutisch vertraglichen Tragerstoff in der Zusanmmensetzung vorliegt.

28. Verfahren zur Herstellung einer Verbindung gemaiB Anspruch 24.

29. Verbindung gemiB Auspruch 24, zur Verwendung als pharmazeutisehes MitteL

30. Verwendung einer Verbindung gem Anspruch 24, zur Herstellung eines pharmnazeutischen Mittels zur Behandlung von durh (G-Protein gekoppelte Rezeptoren vermittelten Krankheitszustiinden

31. Verwendung einer Verbindung gem3 Anspruch 24, zur Herstellung eines pharmazeutischen Mittels zur Inhibierung des Gonadotropin-freisetzenden Hormons.

32. Verwendung gemB Anspruch 30 oder 31 in der miinulichen Fertilitatskontrolle, in der Hormontherapie, Behandlung von weiblicher Sub- oder Infertilittt, weiblichen Empfangnisverhitung und TumorbekLmpfung.