HUP0500014A2 - Tetrahydrocarbozole derivatives as ligands for g-protein coupled receptors (gpcr) and pharmaceutical compositions containing them - Google Patents

Abstract

The subject of the invention is compounds of the general formula (I) where R1 is a hydrogen atom, an alkenyl or alkyl group and optionally substituted with an aryl, hetaryl group or a group of the general formula -COOR11, where the aryl or hetaryl group can be substituted with up to three substituents, and the group of the general formula R11 is hydrogen atom, alkyl, aralkyl, aryl-, hetaryl group or -COCH3 group, R2, R3, R4 and R5 groups independently mean hydrogen atom, halogen atom, -COOH, -CONH2, -CF3, -OCF3, -NO2, -CN group, alkyl , alkenyl, alkoxy, aralkyl, aryl or hetaryl; the meaning of the group of the general formula R6 is a group of the general formula -CONR8R9, -COOR8, -CH2NR8R9, -CH2R8, -CH2OR8 or an alkenyl group, which may optionally be substituted with a group of the general formula R8 and R9, the group of the general formula R7 means a hydrogen atom, alkyl, alkenyl, aralkyl, aryl- vaqy hetaryl group, -NR12R13, -NHCOR14 -NHCONHR14 -NHCOOR14 or -NHSO2R14 group, the Ra, Rb, Rc, Rd, Re and Rf groups independently mean hydrogen atom, halogen atom, -COOH, -CONH2, -CF3, -OCF3, -NO2, -CN, alkyl, alkoxy, aryl or hetaryl; on the condition that certain compounds are excluded from the scope of protection. The compounds according to the invention are G-protein coupled receptor ligands. HE

Description

P05 00014

78.760/SM

S. B. G. & K.

Patent Attorney's Office H-1062 Budapest, Andrássy út 113. Telephone: 461-1000, Fax: 461-1099

PUBLICATION COPY

Tetrahydrocarbazole derivatives as ligands of G-protein coupled receptors (GPCRs) and pharmaceutical preparations containing them as active ingredients

The invention relates to novel tetrahydrocarbazole derivatives which are ligands of G-protein coupled receptors, and in particular gonadotropin releasing hormone antagonists. The invention also relates to the preparation of the compounds, their use and pharmaceutical compositions containing these tetrahydrocarbazole derivatives. The invention also relates to a method for treating pathological conditions mediated by G-protein coupled receptors in mammals, in particular humans.

Background of the invention

A common structural element in all members of the G-protein coupled receptor (GPCR) family is the presence of seven transmembrane alpha-helical segments, which are connected to each other by alternating intra- and extracellular loops, with the amino-terminus on the extracellular side and the carboxy-terminus on the intracellular side. The GPCR family can be divided into several subfamilies (these are essentially families A, B and C), with further sequence similarities within the subfamilies. Since GPCRs are mainly involved in the field of signal reception and signal transduction, they affect a large number of physiological functions. GPCR ligands therefore have potential as drugs for the prophylaxis and therapy of a large number of pathological conditions. An overview of the diseases that can be treated with GPCR ligands can be found in the following literature: S. Wilson et al., Pharmaceutical News 2000, 7(3) Table 1.

Most of the known GPCR ligands are peptide-based. However, peptide receptor ligands often have serious disadvantages, such as low bioavailability and metabolic instability. This is why there is currently an increasing search for ligands in the form of small, non-peptide molecules. A special part of this research is the search for new, non-peptide receptor ligands called privileged structures. These privileged structures are the basic molecular structures that can serve as ligands for a large number of different receptors. The term privileged structures was first used by Evans et al. in connection with the benzodiazepine-based CCK (cholecystokinin) A antagonists derived from the natural product asperlicin (B.E. Evans et al., J. Med. Chem. 1988, 31, 2235). For example, for proteases, it has been found that certain structural classes can serve as inhibitors of different enzymes. Although in the past mainly mechanism-based inhibitors of various proteases were described, nowadays there are an increasing number of compounds that, due to their three-dimensional structure, fit well into the active binding region of various enzymes (M. Whittaker, Cur. Opin. Chem. Biol. 1998, 2, 386; A.S. Ripka et al., ibid., 441). Such privileged structures have also been described for GPCRs. These include, for example, the above-mentioned benzodiazepines, peptoids, 4-substituted 4-aryl-piperidines, but also specific stiffened β-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, Tetrahedron Lett. 2000, 41, 8853). A review can be found in the following literature: A.A. Patchett et al., Ann. Rep. Med. Chem. 1999, 35, 289. The tetrahydrocarbazole derivatives of the invention represent a further class of privileged structures for GPCRs.

Although the invention relates generally to GPCR ligands, the compounds of the invention are particularly useful as ligands for specific members of the GPCR class, namely gonadotropin-releasing hormone (GnRH). GnRH is considered to be a subfamily A of GPCRs (U. Gether et al., Endocrine Reviews 2000, 21(1), 90).

GnRH is a hormone synthesized mainly, but not exclusively, by neurons in the hypothalamus of mammals and transported via the portal vein to the pituitary gland and gonadotropin cells in a regulated manner. GnRH interacts with its seven-transmembrane domain receptor to stimulate the production and release of gonadotropin hormones via the second messenger inositol 1,4,5-trisphosphate and Ca ²⁺ ions. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), the gonadotropins released by GnRH, stimulate the production of sex steroids and gamete maturation in both sexes. In addition to GnRH (also known as GnRH1), there are two other forms of GnRH, namely GnRH2 and 3.

The GnRH receptor is used as a pharmacological target for a number of disorders that depend on the functioning of sex hormone production, such as prostate cancer, premenopausal breast cancer, endometriosis, and uterine fibroids. GnRH superagonists or antagonists can be successfully used to treat these disorders. Another possible indication is mainly the regulation of male fertility, in combination with androgen replacement doses.

One advantage of GnRH antagonists compared to GnRH superagonists is their direct activity in blocking gonadotropin secretion. Superantagonists initially induce pituitary hyperstimulation, leading to increased gonadotropin and sex steroid release. This hormonal response is only inhibited after a certain delay by desensitization and downregulation of GnRH receptor concentrations. It is therefore possible that GnRH superagonists alone and in combination with testosterone are unable to effectively suppress sperm formation in men, making them unsuitable for the control of male fertility. In contrast, the peptide

GnRH antagonists, especially in combination with a replacement dose of androgen, can cause significant oligozoospermia in humans.

However, peptide GnRH antagonists have several disadvantages. Thus, they have significantly lower superagonist activity and must be administered in significantly higher doses. In addition, their oral bioavailability is low, so they must be administered by injection. However, repeated injections lead to a deterioration of doctor-patient cooperation. Furthermore, compared to non-peptide compounds, the synthesis of peptide GnRH antagonists is complicated and expensive.

Quinoline derivatives are described as non-peptide GnRH antagonists, for example, in International Patent Specification No. WO/14682. However, the origin of the appearance of non-peptide GnRH antagonists on the market is unknown.

Objective

The technical task to be solved by the invention is to develop new compounds that are suitable for the treatment of GPCR-mediated pathological conditions and in particular to demonstrate GnRH inhibitory (GnRH antagonistic) activity. The new GPCR ligands, preferably GnRH antagonists, should be as good as possible as compared to known peptide compounds and should represent an effective alternative or advantage over known non-peptide compounds. The new GPCR ligands, especially GnRH antagonists, should have a strong activity and, if possible, good oral bioavailability. Their synthesis should be as simple as possible and have minimal cost. The invention also enables the realization of pharmaceutical compositions containing new non-peptide GPCR ligands, especially GnRH antagonists.

A further object of the invention is to provide novel GPCR ligands, preferably GnRH antagonists, which are suitable for use in medicaments containing GPCR ligands, preferably GnRH antagonists, and for the production of such medicaments. In addition, the invention provides a method for treating GPCR-mediated pathological conditions, especially GnRH inhibition in mammals, especially human patients.

During our research, we have surprisingly found that the above objectives have been achieved by producing the novel tetrahydrocarbazole derivatives according to the invention and pharmaceutical compositions containing these tetrahydrocarbazole derivatives, the process for preparing the tetrahydrocarbazole derivatives, and the method for treating GPCR-mediated pathological conditions. Preferably, the administration of the tetrahydrocarbazole derivative compounds according to the invention achieves GnRH inhibition in mammals, especially human patients, thus the use of the tetrahydrocarbazole derivatives is suitable for treating GPCR-mediated pathological conditions, especially GnRH inhibition.

Summary of the invention

The invention relates to novel tetrahydrocarbazole derivatives of general formula (I).

The invention also relates to pharmaceutical compositions containing at least one novel tetrahydrocarbazole derivative of general formula (I).

The invention also relates to tetrahydrocarbazole derivatives of general formula (I) for use as medicaments.

The invention also provides the use of tetrahydrocarbazole derivatives of general formula (I) for the preparation of a medicament for the treatment of GPCR-mediated pathological conditions, in particular GnRH inhibition. The invention also provides a method for the treatment of GPCR-mediated pathological conditions, in particular GnRH inhibition, in mammals, in particular human patients, comprising administering an effective amount of a compound of general formula (I) according to the invention to a mammal, preferably a human patient, in need of such treatment.

In addition to the above, the invention also provides a process for the preparation of tetrahydrocarbazole derivatives of the general formula (I). The process comprises, for example, the following steps: condensation of a cyclohexanone derivative, which is attached to a solid phase and is preferably replaced by an appropriately substituted phenylhydrazine derivative, followed by derivatization depending on the structure of the final product, and finally recovery from the solid phase and isolation of the final product.

Detailed description of the invention.

The invention relates to novel tetrahydrocarbazole compounds of general formula (I) where R ¹ represents a hydrogen atom, an alkenyl group having 2-6 carbon atoms or an alkyl group having 16 carbon atoms and optionally substituted with an aryl, hetaryl group or a group of general formula -COOR ¹¹ , where the aryl or hetaryl group may be substituted with up to three substituents selected from the following: -N0 ₂ , -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ and halogen atom, and the R ¹¹ group represents a hydrogen atom, an alkyl group having 1-12 carbon atoms, an aralkyl group having 1-12 carbon atoms, an aryl, hetaryl group or a -COCH ₃ group, and optionally substituted with one substituent selected from the following: -CONH2, -COCH ₃ , -COOCH3,

-SO2CH3 and aryl group;

R ² , R ³ , R ⁴ and R ⁵ independently represent a hydrogen atom, a halogen atom, -COOH, -CONH ₂ , ~CF ₃ , -OCF ₃ , -NO ₂ , -CN group, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-12 aralkyl, aryl or hetaryl group;

the R ⁶ group is a group of the general formula -CONR ⁸ R ⁹ , -COOR ⁸ , -CH2NR ⁸ R ⁹ , -CH2R ⁸ , -CH ₂ OR or an alkenyl group of 1-12 carbon atoms, which may be optionally substituted by R ⁸ and R ⁹ groups, where the R ⁸ and R ⁹ groups independently represent a hydrogen atom, an alkyl of 1-12 carbon atoms, an aralkyl of 1-12 carbon atoms, a heteroaralkyl of 1-12 carbon atoms, an aryl or hetaryl group, each of which may be independently substituted by one or more substituents selected from the following: -OH, -NH2 group, -CONHR ¹⁰ , -COOR ¹⁰ group, -NH-C(=NH)-NH2 group and halogen atom, where the R ¹⁰ group is a hydrogen atom, an alkyl of 1-12 carbon atoms, an aralkyl of 1-12 carbon atoms, aralkyl, aryl or hetaryl group and optionally substituted with a group of the general formula -CON(R ^1:1 ) 2 , or where the groups R ⁸ and R ⁹ together may form a cyclic structure containing exclusively carbon atoms or a combination of carbon atoms and heteroatoms;

the R ⁷ group represents a hydrogen atom, a C 1-12 alkyl, a C 1-12 alkenyl, a C 1-12 aralkyl, aryl or hetaryl group, a group of the general formula -NR ¹² R ¹³ , -NHCOR ¹⁴ , -NHCONHR ¹⁴ , -NHCOOR ¹⁴ or -NHSO2R ¹⁴ , and may optionally be substituted with one or more substituents selected from the following: -OH, -NH2, -CONH ₂ , -COOH group and halogen atom, the R and R groups represent independently a hydrogen atom, a C 2-6 alkenyl or C 1-12 alkyl group and may optionally be substituted with one or more aryl or hetaryl groups, which in turn may be substituted with up to three substituents selected from the following: -NO ₂ , -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ group and halogen atom, and the group R ¹⁴ represents a hydrogen atom, a C 1-12 alkyl, a C 1-12 alkenyl, a C 1-12 aralkyl, aryl or hetaryl group, which may optionally be substituted with one or more substituents selected from the following: ~NO2, -CH3 group, -OR ¹¹ group, -CF3, -OCF ₃ , -OH group, -N(R ^X1 )2, -OCOR ¹¹ group, -COOH, -CONH2 group, -NHCONHR ¹¹ , -NHCOOR ¹¹ group and halogen atom;

and R ^a , R ^b , R ^c , R ^d , R ^e and R ^f are independently hydrogen, halogen, -COOH, -CONH ₂ , -CF ₃ , -OCF 3 , -NO ₂ , -CN, C 1-6 alkyl, C 1-6 alkoxy, aryl or hetaryl;

with the proviso that the following compounds are excluded from the group of compounds of general formula (I): 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic 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 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate and 3-tert-butoxycarbonylamino-1,2,3,4tetrahydrocarbazole-3-carboxylic acid.

One embodiment of the invention relates to compounds of formula (I) wherein R ¹¹ is a heteroalkyl or hetarylalkyl group and the other substituents are as defined above.

Tetrahydrocarbazole structures excluded from the compounds of formula (I) are described in the following references: Y. Maki et al. in Chem. Pharm. Bull. 1973, 21 (11), 2460-2465 and R. Millet et al., Letters in Peptide Science 1999, 6, 221-233.

The terms used in the description of the compound of general formula (I) are as follows:

The term C1-6 or C1-12 alkyl group means a branched or straight-chain, cyclic or acyclic, optionally substituted alkyl group having 1-6 or 1-12 carbon atoms, respectively. 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-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl groups, and as cyclic groups, mainly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Ι-cyclopropyl, 1-cyclobutyl, 1-cyclopentyl, 1-cyclohexyl, 1-cycloheptylethyl, 2cyclopropyl, 2-cyclobutyl, 2-cyclopentyl, 2-cyclohexyl, 2-cycloheptylethyl and the like, without limitation.

The term C2-6 alkenyl group means a branched or straight-chain, cyclic or acyclic, optionally substituted, mono- or poly-unsaturated, C2-6 alkenyl group. Examples of such alkenyl groups include, but are not limited to, vinyl, allyl, prop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, pent-1-enyl, pent-2-enyl, pent-3-enyl, pent4-enyl, penta-1,3-dienyl, penta-1,4-dienyl, penta-2,3-dienyl, isoprenyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hex-5-enyl, hexa-1,3-dienyl, hexa-1,4-dienyl, hexa-1,5-dienyl, hexa-2,4-dienyl, hexa-2,5-dienyl, hexa-1,4-dienyl, hexa-1,3,5trienyl, and the like.

The term C2-6 alkoxy group refers to a branched or straight chain, cyclic or acyclic, optionally substituted alkoxy group having 2-6 carbon atoms. Examples of such alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclohexyloxy and the like.

The term C1-12 aralkyl refers to an alkyl group having 1-12 carbon atoms substituted with one or more aryl groups. Examples of such aralkyl groups useful in the present invention include, but are not limited to, benzyl, 1-phenylethyl, 1-phenylpropyl, 1-phenylbutyl, 1-phenylhexyl, 1-phenyl-2-methylethyl, 1-phenyl-2-ethylethyl, 1-phenyl-2,2-dimethylethyl, benzhydryl, triphenylmethyl, 2- or 3-naphthylmethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, and the like. Accordingly, a hetaralkyl group refers to an alkyl group substituted with a heteroaryl group.

The term aryl group refers to an optionally substituted mono- or polycyclic aromatic group. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

The term hetaryl group is the same as the term heteroaryl group and means an aryl group as defined above, which contains one or more heteroatoms, especially nitrogen, phosphorus, oxygen, sulfur and arsenic atoms in its structure. Such hetaryl or heteroaryl groups include, but are not limited to, unsubstituted hetaryl groups and substituted hetaryl groups, especially imidazolyl, pyridyl, quinolinyl and the like.

The term cyclic structure refers to optionally substituted mono- or polycyclic cyclic structures with a variable number of ring members, such as mainly five-, six- or seven-membered cyclic structures. These cyclic structures contain, in addition to carbon atoms, one or more heteroatoms, such as mainly nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. The cyclic structures can be saturated and partially or completely unsaturated structural elements. Such cyclic structures include aza-, oxa-, thia-, phosphacyclopentane,

-cyclohexane, -cycloheptane, diaza, dioxa, dithia, diphosphacyclopentane, -cyclohexane, -cycloheptane based cyclic structures and the like, as well as these basic cyclic structures with mixed heteroatom substitution, without limitation.

The term halogen atom means fluorine, chlorine, bromine and iodine atoms, particularly preferably chlorine atoms.

In addition to the compounds of general formula (I), the scope of the invention also includes physiologically acceptable derivatives and analogues of the compounds, especially their salts.

The term receptor ligand or ligand may mean any compound which binds in any manner to a receptor (in the context of the invention the receptor is a GPCR receptor, preferably a GnRH receptor) and induces an activating, inhibitory or other conceivable effect on this receptor. The term ligand thus means agonists, antagonists, partial agonists/antagonists and other ligands which induce an effect on the receptor which is similar to an agonist, antagonist or partial agonist/antagonist effect. The compounds of the invention of general formula (I) are preferably GnRH antagonists.

According to one embodiment of the invention, the invention provides novel tetrahydrocarbazole derivatives of general formula (I) wherein the R ⁷ group is other than hydrogen when the R ⁶ group is an alkyl group.

According to another embodiment of the invention, the invention provides novel tetrahydrocarbazole derivatives of general formula (I), wherein the R ⁷ group is any of hydrogen atoms. According to another embodiment of the invention, the invention provides novel tetrahydrocarbazole derivatives of general formula (I), wherein the R ⁷ group is any of hydrogen atoms.

Preferred novel tetrahydrocarbazole derivatives according to the invention are those compounds wherein the groups R ^a , R ^b , R ^c , R ^d , R ^e and R ^f represent a hydrogen atom.

Similarly preferred novel tetrahydrocarbazole derivatives according to the invention are those compounds wherein the R ¹ group represents a hydrogen atom.

Preferred novel tetrahydrocarbazole derivatives according to the invention are also those compounds in which the groups R ² , R ³ , R ⁴ and/or R ⁵ are other than hydrogen. Particularly preferred novel tetrahydrocarbazole derivatives according to the invention are those compounds in which the groups R ² , R ³ , R ⁴ and R ⁵ are independently methyl, chlorine or methoxy. Very preferred novel tetrahydrocarbazole derivatives according to the invention are those compounds in which at least the group R ² is other than hydrogen, in particular the following compounds:

Phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-8-methyl-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (Compound 150a)

Phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2methylpropyl]amino]carbonyl]-6-chloro-2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (148a),

Phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(13)-1-(aminocarbonyl)-2methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-8-methoxy-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (147a).

Preferred tetrahydrocarbazole derivatives of the general formula (I) according to the invention are also those compounds in which R ⁶ is a hydrophobic group comprising alkyl, aryl and/or hetaryl structures and which carries a hydrogen bond donor-acceptor system, at a distance of 2-4 single bonds from the carbon atom substituted with the groups R ⁶ and R ^7. Particularly preferred compounds of the general formula (I) are those in which the group R ⁶ is a phenylalanylamide residue, such as in particular phenylmethyl [(IS,2S)-1-[[[(3R)-3

[ [ [ (IS)-2-amino-2-oxo-1-(phenylmethyl)ethyl]amino]carbonyl]2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (66), an isoleucylamide residue, such as mainly phenylmethyl [ (IS,2S)-1-[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (64), a valyl-4-aminobenzamide residue, such as mainly phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-[[[4- (aminocarbonyl)-phenyl]amino]-carbonyl]-2-methyl-propyl]-amino]-carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]carbamate (45), a valyl-N-methyl-amide residue, such as mainly phenylmethyl [(IS,2S)-2-methyl-1-[[[(3R)-2,3,4,9-tetrahydro-3-[[[(IS)-2methyl-1-[(methyl-amino)-carbonyl]-propyl]-amino]-carbonyl]-1H-carbazol-3-yl]-amino]-carbonyl]-butyl]carbamate (222a), a methyloxymethyl-4-pyridyl group, such as mainly 2,3,4,9tetrahydro-3-(3-phenylpropyl)-O-(4-pyridinylmethyl)-1H-carbazole-3-methanol (287), a carboxyl group, such as 2,3,4,9-tetrahydro-3-(3phenylpropyl)-1H-carbazole-3-carboxylic acid (273), or an ethyl propenoate group, such as ethyl 3[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazol-3-yl]-2propenoate (289).

Likewise, compounds of general formula (I) are particularly preferred where the R ⁶ group is a carbonyl valyl amide residue, such as in particular phenylmethyl [ (IS,2S)-1-[[[(3R)-3[[[(IS)-1-(aminocarbonyl)-2-methylpropyl]-amino]-carbonyl]2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate (58), a carbonyl threonyl amide residue, such as in particular phenylmethyl [ (IS,2S)-1- [ [ [ (32?) -3 - [ [ [ (IS,22?) -1-(aminocarbonyl)-2-hydroxypropyl]-amino]-carbonyl]-2,3,4,9-tetrahydro-1E-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate, a a cyclic carboxamide residue (such as a carbonyl-prolylamide group), such as, in particular, phenylmethyl [(IS,2S)-1-[[[(3R)3-[[(2S)-2-(aminocarbonyl)-1-pyrrolidinyl]-carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]carbamate (181a), or a carbonyl-octahydro-indolyl-2-carboxamide residue, such as, in particular, phenylmethyl [ (IS,2S)-1-[[[(3R)-3-[[(2S)-2-(aminocarbonyl)-octahydro-1H-indol-1-yl]-carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]carbamate (190a)), a 4-carboxamidophenylcarboxamide residue, such as mainly phenylmethyl [(IS,2S)-1-[[[(3R)—3—[[[[4-(aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]carbonyl]-2-methylbutyl]carbamate (62), a methylaminomethyl-2-pyridyl group, such as mainly

2,3,4, 9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)1H-carbazole-3-methanamine (279), a carbonyl valinol residue, such mainly phenylmethyl «««

[ (IS, 2S) -1- [ [ [ (3S) -3- [ [ [ (IS) -1-(hydroxymethyl)-2-methylpropyl]amino]-carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]carbonyl]-2-methylbutyl]-carbamate (267b) and 2,3,4,9-tetrahydro-IV-[ (IS)-1-(hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1#-carbazole-3-carboxamide (276) or a methylvalinol residue, such as (2S)-3-methyl-2[[[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazol-3-yl]methyl]-amino]-1-butanol (284) .

Preferred tetrahydrocarbazole derivatives of the general formula (I) according to the new invention are also those compounds wherein the R ⁷ group is a hydrophobic group containing alkyl, aryl and/or hetaryl structures. Particularly preferred in this respect are those compounds of general formula (I) in which the R ⁷ group is a 2,3-biphenylpropionylamino group, such as in particular N-[[(3R)-2,3,4,9-tetrahydro-3-[(1-oxo-2,3-diphenylpropyl)amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide (18), an indanoylamino group, such as in particular (3R)-N-[(1S)-1(aminocarbonyl)-2-methylpropyl]-3-[[(2,3-dihydro-1H-inden-yl)carbonyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3carboxamide (162a), an indolylacetylamino group, such as in particular (3S)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[ (1Hindol-3-ylacetyl)amino]-1H-carbazole-3-carboxamide (164b), a 2-naphthylacetylamino group, such as (3S)-N-[(IS)1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[ (2naphthalenylacetyl)amino]-1H-carbazole-3-carboxamide (161b), » * * · * ·

W 9 »·> ·* <·?·**»»* * * * » or a 3-propionylamino group, such as mainly N-[[(3R)~ 2,3,4,9-tetrahydro-3-[[(2S,3S)-3-methyl-1-oxo-2-[(1-oxo-3phenylpropyl)-amino]-pentyl]-amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide (22).

Likewise, compounds of general formula (I) in which the R ⁷ substituent is a phenylmethylcarboxamide residue substituted on the aromatic system are particularly preferred, such as (3R)-N-[(IS)-1-(aminocarbonyl)-2methylpropyl]-2,3,4,9-tetrahydro-3-[[(4-methylphenyl)acetyl]amino]-1H-carbazole-3-carboxamide (165a), N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro3-[[(4-methoxyphenyl)acetyl]amino]-1H-carbazole-3-carboxamide (175), (3R)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(3-bromophenyl)acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3carboxamide (96), (3R)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(4-fluorophenyl)acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3carboxamide (91), (3R)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(4-chlorophenyl)acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3carboxamide (167a), a phenylhexylamine residue, such a compound is mainly found in (3R)-N[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3[(6-phenylhexyl)amino]-1H-carbazole-3-carboxamide (234a) or a phenylpropyl group, such as

6,8-dichloro,··. ·'·: .··» <*·, ·**» . % »*i .·· · . ’· ·>'·<* >-* w *

2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylic acid (275) and ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylate (272).

Also preferred are those novel compounds of general formula (I) according to the invention which have the R configuration on the carbon atom substituted with the R ⁶ and R ⁷ groups, when the R ⁶ and R ⁷ groups together form an alpha-aminocarboxylic acid structural element.

The following compounds are most preferred:

phenylmethyl [ (IS, 2S) -1- [ [ [ (3R) -3- [ [ [ (IS) -1-(aminocarbonyl.)-2methylpropyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydrolH-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (184a) , phenylmethyl [ (IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(hydroxymethyl)-2-methylpropyl]-amino]carbonyl]-2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate 267a), (2S) —1-[[(3R)-3-[[(4-chlorophenyl)acetyl]amino]-2,3,4,9tetrahydro-8-methoxy-1H-carbazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide (189a) and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)-1H-carbazole-3-methanamine (283).

Further representatives of the novel compounds of general formula (I) according to the invention and their preparation are illustrated in the examples.

The novel tetrahydrocarbazole derivatives of the general formula (I) according to the invention are GPCR ligands and can be used mainly as antagonists for inhibiting gonadotropin-releasing hormone, for example for regulating male fertility, hormone therapy, treating female infertility, female contraception and tumor control.

In the case of male fertility regulation, the compounds of the invention cause a decrease in spermatogenesis. Combined administration with androgens, such as testosterone or testosterone esters, is preferred. In such cases, the testosterone derivatives can be administered, for example, by injection, such as intramuscular depot injection.

The compounds of formula (I) according to the invention can be used in combination with other hormones, such as estrogens and/or progestins, in hormone therapy, for example for the treatment of endometriosis, uterine leiomyomas and uterine fibroids. The combination of GnRH antagonists according to the invention and tissue-selective partial estrogen agonists, such as Raloxifene, is particularly advantageous. In addition, the compounds of the invention can also be used in hormone replacement therapy. The compounds of formula (I) according to the invention can be used, for example, to increase female fertility by inducing ovulation, and can also be used to treat infertility.

The novel compounds of general formula (I) according to the invention are also suitable for contraception in women. Thus, the GnRH antagonists according to the invention can be administered together with estrogen on days 1-15 of the cycle, preferably with very low estrogen doses. On days 16-21 of the cycle, a progestogen is added to the estrogen/GnRH antagonist combination. The GnRH antagonists according to the invention can also be administered continuously during the cycle. In this way, it is possible to reduce the hormone doses and thus the side effects of non-physiological hormone levels. In addition, the compounds according to the invention can achieve beneficial effects in women with polycystic ovary syndrome and androgen-dependent disorders such as acne, seborrhea and hirsutism. Compared to the methods known so far, the compounds according to the invention are expected to achieve better cycle regulation. Additional indications for use include benign prostatic hyperplasia, gonadal protection during chemotherapy, controlled ovarian stimulation/assisted reproductive methods, childhood developmental disorders such as precocious puberty and polycystic ovaries.

Finally, the compounds of general formula (I) according to the invention can also be used for the treatment of hormone-dependent cancer diseases, such as premenopausal cancer, prostate cancer, ovarian cancer and endometrial cancer, by suppressing endogenous sex steroid hormones.

The novel compounds of general formula (I) according to the invention, as GPCR ligands, especially GnRH antagonists, are suitable for the treatment of the above-mentioned pathological conditions when administered to mammals, especially human patients, but can also be used in veterinary cases, such as in the treatment of pets and productive domestic animals, as well as wild animals.

Administration can be carried out in a known manner, for example orally or non-orally, in particular topically, rectally, intravaginally, nasally or by injection or implantation. Oral administration is preferred. The novel compounds of formula (I) according to the invention can be formulated for administration and, where appropriate, mixed with pharmaceutically acceptable carriers or diluents. Suitable excipients and carriers include, for example, those described in the following publications: 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 für Farmazie und angrenzende Gebiete", Farm. Ind. 2, 1961, 72ff; Dr. H.P. Fiedler, Lexikon der Hilfsstoffe fur Farmazie, Kosmetik und angrenzende Gebiete, Cantor KG, Aulendorf in Württemberg, 1971.

Oral administration can be in solid form, such as tablets, capsules, gel capsules, coated tablets, granules or powders, but also in the form of a drinkable solution. For oral administration, the compounds of formula (I) according to the invention can be mixed with known and commonly used, physiologically tolerable excipients and carriers, such as gum arabic, talc, starch, sugars, such as mannitol, methylcellulose, lactose, gelatin, surfactants, magnesium stearate, cyclodextrins, aqueous or non-aqueous carriers, diluents, dispersants, emulsifiers, lubricants, preservatives and flavoring agents, such as essential oils. The compounds of the invention can also be dispersed in a microparticulate, such as nanoparticulate composition.

Non-oral administration can be, for example, in the form of intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, or in the form of implants, or ointments, creams or suppositories. If appropriate, administration of sustained-release forms is also possible. The implants can contain inert materials, such as biodegradable polymers or synthetic silicones, such as silicone rubber. Intravaginal administration is possible, for example, by means of pessaries, intrauterine administration can be carried out, for example, by means of diaphragms, etc. Transdermal administration is possible in particular by means of preparations suitable for this purpose and/or, for example, by means of patches.

As previously described, the novel compounds of formula (I) according to the invention can also be combined with other active pharmaceutical ingredients. In the case of combination therapy, the individual active ingredients can be administered simultaneously or separately, this can be done by the same route, for example orally, or by different routes, for example orally and by injection. In a unit dose, the active ingredients can be present and administered in the same or different amounts. Where appropriate, a specific dosage range can also be used. It is also possible to combine several novel compounds of formula (I) according to the invention in this way.

The dosage may vary within a wide range, depending on the nature of the indication, the severity of the disorder, the route of administration, the age, sex, body weight and sensitivity of the patient. It is within the skill of the art to determine the pharmacologically effective amount of the combined pharmaceutical composition. Preferred unit dosages, based on the body weight in kg of the patient to be treated, are doses in the range of 1 pg to 100 mg, more preferably 1 pg to 10 mg, and most preferably 1 pg to 1 mg. The administration may be in a single dose or in several separate doses.

According to a further embodiment of the invention, the invention also includes the pharmaceutical compositions described above, which contain at least one novel compound of the general formula (I) according to the invention, where possible, in addition to pharmaceutically acceptable carriers and/or excipients. Preferred and particularly preferred pharmaceutical compositions are those which contain at least one preferred or particularly preferred novel compound of the general formula (I) according to the invention, in particular the compounds designated by the specific names above. In the pharmaceutical compositions according to the invention, in addition to the at least one compound of the general formula (I), other active, pharmaceutically acceptable ingredients may also be present, as already described in detail above.

At least one novel compound of general formula (I) according to the invention is present in the preferred pharmaceutical compositions according to the invention described above, which can be administered preferably in an oral administration form.

In addition to the above, according to a further embodiment of the invention, the use of compounds of general formula (I) as a medicine is also included within the scope of the invention.

Among the tetrahydrocarbazole compounds of the general formula (I), those compounds designated by specific names above and described in the examples are preferred and particularly preferred for use as a medicine.

Among pharmaceutical compositions containing compounds of general formula (I) and compounds of general formula (I) for use as a medicine, preferred are compounds advantageous in terms of use and administration.

According to another embodiment of the invention, the scope of the invention includes the use of at least one tetrahydrocarbazole derivative of general formula (I) as described above together with tetrahydrocarbazoles described in the literatures of Millet et al. and Maki et al. described at the beginning of the description, which are excluded from the scope of compounds of general formula (I), for the treatment of GPCR-mediated diseases, in particular for the preparation of a medicament for inhibiting gonadotropin-releasing hormone (GnRH).

In addition to the above, according to a further embodiment of the invention, the scope of the invention includes the use of at least one compound of general formula (I) according to the invention, but including the compounds previously excluded from the scope of protection of the Millet et al. and Maki et al. literatures, namely 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic 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 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate and The use of 3-tert-butoxycarbonylamino-1,2,3,4-tetrahydrocarbazole-3carboxylic acid for inhibiting GnRH, preferably for regulating male fertility, hormone therapy, treating female infertility, female contraception and tumor control in the manufacture of a medicament. In particular, the term "compound of formula (I)" as described above, but including the compounds excluded above, means compounds of formula (I)

(I) wherein R ¹ is hydrogen, C 2-6 alkenyl or C 1-6 alkyl, and optionally substituted with an aryl, hetaryl, or -COOR ¹¹ group, wherein the aryl or hetaryl group is substituted with up to three substituents independently selected from the following: -N0 ₂ , -CH ₃ , -CF ₃ , -OCH ₃ , -OCF ₃ and halogen, and R ¹¹ is hydrogen, C 1-12 alkyl, C 1-12 aralkyl, aryl, hetaryl, or -COCH ₃ and optionally substituted with a substituent selected from the following: -CONH ₂ , -COCH ₃ , -COOCH 3 , -SO ₂ CH ₃ and aryl;

R ² , R ³ , R ⁴ and R ⁵ are independently hydrogen, halogen, -COOH, -CONH ₂ , -CF ₃ , -OCF 3 , -NO 2 , -CN, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-12 aralkyl, aryl or hetaryl;

the R ⁶ group means a group of the general formula -CONR ⁸ R ⁹ , -COOR ⁸ , -CH2NR ⁸ R ⁹ , -CH2R ⁸ , -CH ₂ OR ⁸ or a group of 1-12 carbon atoms, which may optionally be substituted by a group of the general formula R ⁸ and R ⁹ ' PQ, where the groups of the general formula R and R independently mean a hydrogen atom, a C 1-12 alkyl, C 1-12 aralkyl, C 1-12 hetaralkyl, aryl or hetaryl group, each of which may be substituted by one or more substituents selected from the following: -OH, -NH ₂ group, -CONHR ¹⁰ ,

-COOR ¹⁰ group, -NH-C(=NH)-NH ₂ group and halogen atom, where R ¹⁰ group means hydrogen atom, alkyl of 1-12 carbon atoms, aralkyl of 1-12 carbon atoms, aryl or hetaryl group, and optionally may be substituted with -CON(R ¹¹ ) ₂ group, or where R ⁸ and R ⁹ groups together may form a cyclic structure consisting mainly of carbon atoms or a combination of carbon atoms and heteroatoms;

the R ⁷ group represents a hydrogen atom, a C 1-12 alkyl, a C 1-12 alkenyl, a C 1-12 aralkyl, aryl or hetaryl group, a group of the general formula -NR ¹² R ¹³ , -NHCOR ¹⁴ , -NHCONHR ¹⁴ , -NHCOOR ¹⁴ or -NHSO2R ¹⁴ , and may optionally be substituted with one or more substituents selected from the following: -OH, -NH2, -CONH ₂ , -COOH group, halogen atom, the R ¹² and R ¹³ groups independently represent a hydrogen atom, a C 2-6 alkenyl or C 1-12 alkyl group, and may optionally be substituted with one or more aryl or hetaryl groups, which in turn may be substituted with up to three substituents independently selected from the following: -NO ₂ , -CH ₃ , -CF ₃ , -OCH 3 , -OCF 3 group and halogen atom, and the R ¹⁴ group represents a hydrogen atom, a C 1-12 alkyl, a C 1-12 alkenyl, a C 1-12 aralkyl, aryl or hetaryl group, which may optionally be substituted with one or more substituents selected from the following: -N0 ₂ , -CH ₃ , -OR ¹¹ , -CF ₃ , -OCF ₃ , -OH group,

-N(R ^1:1 ) 2 , -OCOR ¹¹ , -COOH, -CONH ₂ , -NHCONHR ¹¹ , -NHCOOR ¹¹ and halogen;

and R ^a , R ^b , R ^c , R ^d , R ^e and R ^f are independently hydrogen, halogen, -COOH, -CONH ₂ , -CF ₃ , -OCF 3 , -NO 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy, aryl or hetaryl.

The indications of the novel compounds of general formula (I) according to the invention (except for the compounds described in the literatures of Maki et al. and Millet et al. and specifically named above), the compounds which can be used advantageously and particularly advantageously in the preparation of medicaments for GnRH inhibition, have been described above.

According to a further embodiment of the invention, the invention includes the use of the compounds of formula (I) as defined above, together with the compounds specifically excluded above, for the control of male fertility or for female contraception. Preferred and particularly preferred compounds of the invention for this use are the compounds of formula (I) as described above.

In addition to the above, the invention also provides a method for controlling male fertility or female contraception by administering to a patient, especially a mammal, especially a human patient, an amount of a compound of the invention as defined in the immediately preceding paragraph that is effective for controlling male fertility or female contraception.

In a further aspect, the invention provides a method for treating GPCR-mediated pathological conditions by administering at least one compound of formula (I) as defined above to a mammal, especially a human patient, in need of such treatment. The administration is generally in a therapeutically effective amount. As already explained above, it is within the skill of the art to determine the therapeutically effective amount, taking into account the specific requirements of the individual case. The compounds of formula (I) according to the invention are preferably administered in the following unit doses: unit doses of between 1 pg and 100 mg, particularly preferably between 1 pg and 10 mg, most preferably between 1 pg and 1 mg, based on the body weight of the patient to be treated. Oral administration is preferred. The administration of one or more compounds of formula (I) according to the invention in combination with at least one further active substance is also possible.

In addition to the above, the invention also provides a method for inhibiting GnRH by administering to a patient in need of such treatment a therapeutically effective amount of a compound of the invention of general formula (I), wherein the compound of general formula (I) of the invention is any of the above, but including those specifically excluded by name. The method is preferably used for male fertility control, hormone therapy, female contraception, treatment of female infertility and infertility, and tumor control.

Finally, the invention also provides a process for the preparation of the novel tetrahydrocarbazole derivatives of the general formula (I) according to the invention. The preparation of the compounds of the general formula (I) can be carried out in various ways, such as in liquid phase or by partial or total solid phase synthesis. The selection of suitable synthesis conditions is the task of the skilled person based on the knowledge required for the preparation of a specific representative of the compounds of the general formula (I). Below, a general method for the preparation of the compounds of the general formula (I) is first described, and then a specific process variant, the solid phase method, is described. The compounds of the general formula (I) according to the invention are further illustrated by examples in which the compounds are designated by specific names.

The compounds of formula (I) according to the invention are preferably prepared as follows:

The central tetrahydrocarbazole structure can be obtained by a Fischer indole synthesis known per se. The procedure is to condense an optionally protected, suitably substituted cyclohexanone derivative with an optionally protected, suitably substituted phenylhydrazine derivative, for example as described in the following literatures: Britten & Lockwood, JCS Perkin I 1974, 1824; Maki et al., Chem. Farm. Bull. 1973, 21, 240. The cyclohexanone structure is mainly substituted at the 3,3', 5,5' and 6,6' positions by the groups R ^a —> R ^f , and at the 4,4' positions by the groups R ⁶ and R ⁷ , or where possible, by precursors of these groups. The phenylhydrazine structure is optionally substituted at the R ² —> R ⁵ groups. Phenylhydrazine derivatives that are not commercially available can be prepared in a known manner. The positional isomers that may be formed by condensation of the cyclohexanone derivative and the phenylhydrazine derivative can be separated by chromatographic methods, such as high-pressure liquid chromatography (HPLC).

After synthesis of the central tetrahydrocarbazole structure, the R ¹ group can be introduced by N-alkylation of the nitrogen atom at position 9, with a suitable R ¹ halide in the presence of a base, for example, as described in the following references: Pecca & Albonico, J. Med. Chem. 1977, 20, 487 or Mooradian et al., J. Med. Chem. 1970, 13, 327.

The groups R ⁶ and R ⁷ , as already indicated, can be introduced in various ways depending on the nature of the groups, the reactions being described in detail below.

In these groups, the α-aminocarboxylic acid structures can be obtained by treating ketones with ammonium carbonate (NH ₄ (CO) ₃ ) and potassium cyanide (KCN) in a known manner under Schotten-Baumann conditions, and subjecting the resulting hydantoin to alkaline hydrolysis. (Britten & Lockwood, J'.CS Perkin I 1974, 1824) .

Amide residues are preferably generated in a known manner, using methods known in peptide chemistry. For this purpose, the acid component is activated with an activating reagent, such as 1,3-dicyclohexylcarbodiimide or O-(7-azabenzotriazol-1-yl)N,N,Ν',Ν'-tetramethyluronium hexafluorophosphate (Tetrahedron Lett. 1994, 35, 2279) and condensed with the amino component in the presence of a base, such as diisopropylethylamine (DIPEA) and/or 4-dimethylaminopyridine (DMAP).

Ester residues can also be obtained using the desired alcohols under analogous conditions. The solvent used in this case is preferably anhydrous.

Secondary or tertiary amide residues are obtained from primary amides by nucleophilic substitution of alkyl halides or by reductive amination of aldehydes/ketones (e.g. J. Org. Chem. 1996, 61, 3849 or Synt. Com. 1994, 609).

Sulfonamide residues are obtained from the corresponding amides by reaction with sulfonyl chlorides.

Urea residues are prepared by reacting amines with appropriate isocyanates.

Urethane residues can be prepared by reacting the appropriate alcohols with carbonyldihydroxybenzotriazole ((HOBt) ₂ CO) followed by amines (Warass et al., LIPS 1998, 5, 125).

Alcohols can be obtained from carboxylic acid esters by reacting them with lithium aluminum hydride (LiAlH ₄ ).

Aldehyde residues are obtained from alcohol precursors by oxidation, for example by oxidation carried out in a known manner under Swern conditions with the aid of dimethyl sulfoxide (DMSO)/oxalyl chloride (Pansavat et al., Syntesis 1998, 436).

Substituted amine residues are obtained by reductive amination of amines with aldehydes (J. Org. Chem. 1996, 61, 3489).

Ether residues can be obtained by deprotonating an alcohol precursor, in a manner known per se, with a base, such as sodium hydride (NaH), under Williams conditions, and then reacting the mixture with an alkali halide.

Double bonds can be introduced into the groups by reacting an aldehyde or ketone precursor with appropriate phosphonilides in a manner known per se, under Wittig conditions.

A solid phase preparation process for the compounds of general formula (I) according to the invention is described by a detailed description of steps (a)-(d) below:

Step (a) is practically analogous to a Fischer indole synthesis, such as those described in the following literatures: Britten & Lockwood, JCS Perkin I 1974, 1824; Maki et al., Chern. Farm. Bull. 1973, 21, 240, Hutchins & Chapman, Tetrahedron Lett. 1996, 37, 4869. In step (a), a cyclohexanone derivative of general formula (II) bound to an SP solid phase via a linking group L containing the group G and suitable for forming the group R ⁶

where, in the case where the R ⁷ group represents a hydrogen atom, an alkyl group of 1-12 carbon atoms, an aralkyl group of 1-12 carbon atoms or a hetaryl group, the G group has the same meaning as the R ⁷ group, and in the case where the R ⁷ group has another meaning as given in the meaning of the R ⁷ group in the general formula (I), the G group has the same meaning as the group of the general formula -NH-Pg, where Pg represents a protecting group, with a phenylhydrazine derivative of the general formula (III) containing R ² —> R ⁵ substituents

(UI) is condensed in the presence of an acid, preferably acetic acid, or a metal salt, preferably zinc chloride (ZnCl ₂ ). The use of dimethylformamide (DMF) as solvent is preferred. The meanings of the groups R ^a —> R ^f are as given above for general formula (I). Where possible, certain substituents or groups may also be present in protected form, in which case the protecting groups are removed in a known manner at an appropriate time, at an appropriate point in the synthesis.

Particularly preferred SP solid phases for use in the process of the invention are the following: Rink amide resins (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard 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 of general formula (II) is bound to the SP solid phase by means of an (amino)carboxylic acid. The alcohol precursors of the cyclohexanone derivatives of general formula (II) can be linked to the SP solid phase using 3,4-dihydro-2Hpyran (DHP) linking compounds (linkers) (Liu & Elman, J. Org. Chem. 1995, 60,

7712). Traceless coupling of aromatic precursors of cyclohexanone derivatives of general formula (II) to triazine resins is possible (Bráse et al., Angew. Chem. Int. Ed. 1998, 37, 3413).

The protecting group Pg, which is optionally located within the G group and protects an _-NH2 α-amino group, is preferably an Fmoc (9-fluorenylmethoxycarbonyl) protecting group, but may also be another conventional amino protecting group, such as an alkoxycarbonyl protecting group (such as the Z (benzyloxycarbonyl) or Boc (tert-butoxycarbonyl) group) or another suitable protecting group, such as the trityl (triphenylmethyl) protecting group.

The composition of the linker L is such that after appropriate substitution (steps (b) and (c)) and processing (step (d)) the desired R ⁶ group is obtained, the meaning of which is one of those given above for the meaning of R ⁶ in the final product tetrahydrocarbazole derivatives of general formula (I). The composition of the linker L is illustrated below by the example where R ⁶ is a group of general formula -CONR ⁸ R ⁹ .

In the case where the R ⁶ group in the final product of formula (I) according to the invention is a group of the general formula -CONR ⁸ R ⁹ , to form the linking group L, a compound of the general formula Pg-N (R ⁸ )-R ⁹ '-COOH is first attached to the SP solid phase via the free amino group of SP with the help of an activating reagent, such as DCC (dicyclohexylcarbodiimide) or HATU (0-(7azabenzotriazol-1-yl)-N,N-N',Ν'-tetramethyluronium hexafluoro40 phosphate), where Pg and SP are as defined above and R ⁹ ' is part of the subsequent R ⁹ group. The Pg protecting group is then removed, for example in the case of an Fmoc protecting group with the help of piperidine/dimethylformamide (DMF). This results in a compound of the general formula HR ⁸ NR ⁹ '-CONH-SP. This latter compound can then be reacted with a cyclohexanone derivative precursor compound of general formula (II), more specifically with a cyclohexanone carboxylic acid of general formula (II')

(Π') with the aid of an activating reagent such as DCC or HATU, finally producing the cyclohexanone derivative of general formula (II) as described above. The linking group L means in the above-described case a group of general formula -CONR ⁸ -R ⁹ '-CONH-SP. Any type of isomer (enantiomers, diastereomers or positional isomers) obtained can be fractionated by high-pressure liquid chromatography (HPLC) in a known manner, at any step of the described preparation process.

The actual step (a), i.e. the condensation of the cyclohexanone of general formula (II) with the substituted phenylhydrazine derivative of general formula (III) and, optionally, the removal of the Pg protecting group in the G group, for example using piperidine (in the case of an Fmoc protecting group), proceeds in such a way that a free α-amino group is again formed at this point.

In the case where the R ⁷ group is a group of the general formula -NHCOR ¹⁴ , -NHSO2R ¹⁴ , -NR ¹² R ¹³ (wherein R ¹² and R ¹³ are other than hydrogen), -NHCONHR ¹⁴ or -NHCOOR ¹⁴ , the now unprotected a-amino group of the cyclohexanone derivative of the general formula (II) bound to the resin is converted in step (b) in such a way that various alternative R ⁷ groups as described above can be formed.

Depending on the nature of the desired R ⁷ group formed in the target tetrahydrocarbazole compound of general formula (I), the preparation process thereof may be as follows:

In the case where R ⁷ is a group of the general formula -NHCOR ¹⁴ , the reaction product of step (a) was reacted with a carboxylic acid of the general formula R ¹⁴ COOH in the presence of an activating reagent, such as 1,3-dicyclohexylcarbodiimide (DCC) or O-(7-azabenzotriazol-1-yl)-N,N,Ν',Ν'-tetramethyluronium hexafluorophosphate (HATU) and a base, such as diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP), according to known methods used in the formation of peptide bonds (see, for example, Tetrahedron Lett. 1994, 35, 2279; alternative (i)).

In the case where R ⁷ is a sulfonamide group of the general formula -NHSO2R ¹⁴ , the reaction product of step (a) is reacted with a sulfonic acid derivative of the general formula R ¹⁴ SO2X , where X is a leaving group, preferably a halogen atom, especially a chlorine atom, in the presence of a base, such as diisopropylethylamine (DIPEA) or 4-dimethylaminopyridine (DMAP) (see, for example, Gennari et al., EJOC 1998, 2437; alternative (ii)) In the case where R ⁷ is a group of the general formula -NR ¹² R ¹³ (where R ¹² and R ¹³ are different from hydrogen), in the case where R ¹² is hydrogen, the reaction product of step (a) is reacted with a reagent of the general formula R ¹³ X , where X is a leaving group, for example, The reaction is carried out in the presence of a halogen atom, especially a chlorine atom, a base such as 1,8-diazabicyclo[5.4.0]undec-ene (DBU) or diisopropylethylamine (DIPEA) (see, for example, Green, JOC 1995, 60, 4287 or JOC 1996, 61, 3849) or an aldehyde of the general formula R ¹³ CHO in the presence of a reducing agent such as sodium hydride/boron triacetate (NaH/B (OAc) ₃ ). In the case where neither of R ¹² and R ¹³ is hydrogen, the reaction product of step (a) is reacted with a ketone of the general formula R COR in the presence of a reducing agent (see Ellmann et al., JOC 1997, 62, 1240 or Synt. Commun. 1994, 609; alternative (iii)). In the case where R ⁷ = -NR ¹² R ¹³ is hydrogen, alternative step (vi) below is used.

In the case where R ⁷ is a group of the general formula -NHCONHR ¹⁴ (a urea derivative), the reaction product of step (a) is reacted with an isocyanate of the general formula R ¹⁴ NCO (see Brown et al., JACS 1997, 119, 3288;

alternative (arc)).

In the case where R ⁷ is a carbamate or urethane group of the general formula -NHCOOR ¹⁴ , the reaction product of step (a) can be reacted with an alcohol of the general formula HOR ¹⁴ , previously preactivated with carbonyldihydroxybenzotriazole ((HOBt) ₂ CO) (see Warass et al., LIPS 1998, 5, 125;

alternative (v)).

In the case where R ⁷ is hydrogen, C 1-12 alkyl, C 1-12 aralkyl, aryl, hetaryl, or -NH ₂ (i.e., R ¹² and R ¹³ are hydrogen in the formula R ⁷ = -NR ¹² R ¹³ ), step (b) is omitted since no further transformation is required (alternative (vi)).

Step (c), i.e. the transformation at the indole nitrogen atom, can also be carried out in analogy to step (b) according to different analogies, detailed below:

In the cases (i) to (v) described above in step (b), the reaction product obtained in step (b) is deprotonated in the presence of a base, such as sodium hydride (NaH) or NaHMDS, and is subsequently converted by means of a group of the general formula R ¹ X, where X is a leaving group, such as a halogen atom, especially a chlorine atom (see Collini & Ellingboe, Tetrahedron Lett. 1997, 38, 7963; Pecca & Albonico, J. Med. Chem. 1911, 20, 487 or Mooradian et al., J. Med. Chem. 1970, 13, 327).

In case (vi) defined in step (b) above, i.e., if step (b) is omitted, in analogy to the above description, the reaction product obtained in step (a) is deprotonated with a base, such as sodium hydride (NaH) or NaHMDS, followed by conversion with a group of the general formula R ¹ X, where X is a leaving group, such as a halogen atom, especially a chlorine atom.

Finally, step (d) essentially involves the elimination of the reaction product obtained in step (c) from the SP solid phase. In the case of Wang, trityl, 3,4-dihydro-2H-pyran (DHP) and Rink amide resins, the elimination of the reaction product obtained in step (c) from the SP solid phase is carried out with the aid of an acid, such as trifluoroacetic acid (TEA). In the case of aminolytic elimination from 3,4-dihydro-2H-pyran (HMB) resin, the eliminating reagent used is, for example, ammonia in methanol. The desired product is then isolated in a known manner.

The preparation of the tetrahydrocarbazole derivatives of the invention is illustrated in detail in the following examples.

Examples

I. General synthetic methods for the preparation of the compounds of the invention

Coupling of Carboxylic Acids to Ränk Amide Resin:

0.1 mmol of Fmoc-protected Rink amide resin (166 mg, loading 0.6 mmol/g) was pre-swollen with 1.5 ml of dimethylformamide (DMF) in a reaction vessel equipped with a bottom stirrer for 20 minutes. After suction, 1.5 ml of 20% piperidine/dimethylformamide was added and stirred for 5 minutes. After suction, another 1.5 ml of 20% piperidine/dimethylformamide was added to the resin and stirred for 15 minutes, and after suction, washed four times with dimethylformamide. Then 675 μΐ of 0.267 M dimethylformamide Fmoc-protected amino carboxylic acid solution, 675 μΐ of O-(7-azabicyclotriazol-1-yl)-N,N,Ν',N'tetramethyluronium hexafluorophosphate (HATU) solution (0.267 M solution in dimethylformamide) and 150 μΐ of NMM solution (2.4 M solution in DMF) and 0.01 mmol of 4-dimethylaminopyridine (DMAP) are added and stirred at 40°C for 4 hours. After suction, the same reagents are added to the resin again and stirred at 40°C for 4 hours. Then suction and washing with dimethylformamide are performed four times.

B Coupling of carboxylic acids to trityl resin:

2.98 mmol of Fmoc-protected aminocarboxylic acid are dissolved in 30 ml of dry dichloromethane, mixed with 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 resin). After shaking for two times, the resin is filtered off with suction and washed three times with 20 ml of a 17:2:1 mixture of dichloromethane/methanoldiisopropylethylamine. It is then washed three times with 20 ml of dichloromethane, three times with methanol, and three times with 20 ml of ether, and then dried in vacuo. In this way, a resin with a loading of 0.5-1 mmol of aminocarboxylic acid/g resin is obtained.

C Coupling of carboxylic acids to HMB resin:

21.3 mmol of aminocarboxylic acid and 21.3 mmol of O-(7azabenzotriazol-1-yl)-N,N,Ν',N'-tetramethyluronium hexafluorophosphate (HATU) were dissolved in 60 ml of dimethylformamide and then mixed with 63.9 mmol (10.9 ml) of diisopropylethylamine (DIPEA). After 5 minutes, 5 g of polystyrene HMB resin (loading 0.71 mmol/g resin) were added and shaken for 5 minutes at room temperature. Subsequently, 21.3 mmol (2.6 g) of 4-dimethylaminopyridine (DMAP) were added and shaken for 1 hour at room temperature. The resin was then filtered off with suction and washed once with 100 ml of dimethylformamide, dichloromethane (DCM) and dimethylformamide. The resin is then mixed with 100 ml of a 10% acetic anhydride (Ac ₂ O)/dimethylformamide/5% 4-dimethylaminopyridine (DMAP) mixture and shaken for 15 minutes.

After suction filtration, it is washed three times with 100 ml each of dichloromethane (DCM) and ether and dried in vacuo.

D Coupling of carboxylic acids to Wang resin:

54.6 mmol of carboxylic acid and 27.3 mmol (4.2 ml) of DIC were dissolved in 500 ml of dry dichloromethane and stirred at room temperature for 10 minutes. After the precipitated urea was filtered off, the solution was evaporated to dryness and the residue was dissolved in 160 ml of dry dimethylformamide. The resulting solution was added to 4.55 mmol (5 g, loading 0.91 mmol/g resin) of Wang resin pre-swollen in dimethylformamide and 4.55 mmol (556 mg) of 4-dimethylaminopyridine (DMAP) were added. After shaking at room temperature for 1.5 hours, the resin is filtered off with suction, taken up in 100 ml of 10% acetic anhydride/dimethylformamide/5% 4-dimethylaminopyridine and shaken for 15 minutes. After suction, it is washed three times with 100 ml each of dichloromethane (DCM) and ether, and then dried in vacuo.

E Coupling of alcohol to DHP (3,4-dihydro-2H-pyridine) resin:

0.5 mmol of DHP resin (0.5 g, packing density 1 mmol/g) was pre-swollen in 2 ml of dichloroethane for 15 min. 2 ml of a 0.75 molar alcohol/0.37 molar pyridinium para-toluenesulfonate solution were added and stirred at 80°C for 16 h. After cooling to room temperature, 5 ml of pyridine was added, shaken briefly and filtered with suction. The mixture was then washed twice with 5 ml each of dimethylformamide, dichloromethane (DCM) and hexane.

F Removal of resin-bound Fmoc protecting group:

1.5 ml of 20% piperidine/dimethylformamide mixture is added to 0.1 mmol of resin-bound Fmoc group and stirred for 5 minutes. After suctioning off, 1.5 ml of 20% piperidine/dimethylformamide mixture is added again and stirred for 15 minutes. After suctioning off, wash four times with dimethylformamide.

G Coupling of carboxylic acid to resin-bound amino functional groups:

675 μΐ 0.267 M solution of Fmoc-protected aminocarboxylic acid in dimethylformamide, 675 μΐ O-(7azabenzotriazol-1-yl)-N,N,Ν',N'-tetramethyluronium hexafluorophosphate (HATU) in dimethylformamide (0.267 M), 150 μΐ N-methylmorpholine (NMM) solution (2.4 M solution in dimethylformamide) and 0.01 mmol 4-dimethylaminopyridine (DMAP) are added to 0.1 mmol resin-bound amino functions and stirred at 40°C for 4 hours. After suction, the same reagents are added again and stirred at 40°C for 4 hours. Then, suction is removed and washed four times with dimethylformamide.

H Coupling of acetic acid to resin-bound amino functions:

1.5 ml of 10% acetic anhydride solution in dimethylformamide is added

0.1 mmol of resin-bound amino functions and stirred at room temperature for 15 minutes. Then filtered off with suction and washed four times with dimethylformamide.

I Synthesis of tetrahydrocarbazoles starting from resin-bound cyclohexanones:

Before the reaction, 0.1 mmol of cyclohexanone resin was washed twice with 2 ml of dimethylformamide and twice with 2 ml of acetic acid. Subsequently, 1 ml of dimethylformamide and 2 ml of a 0.5 M hydrazine/0.5 M zinc chloride (ZnCl ₂ ) mixture in acetic acid were added to the resin and stirred at 70°C for 20 hours. Then, the mixture was filtered off with suction and washed twice with 2 ml of acetic acid and twice with 2 ml of dimethylformamide.

J Synthesis of sulfonamides starting from resin-bound amides:

The resin is washed twice with 2 ml each of dimethylformamide and dichloroethane (DCE). 1 ml of 0.5 M sulfonyl chloride in dichloroethane (DCE) and 400 μΐ of 2.5 M N-methylmorpholine (NMM)/1 equivalent of 0.25 M 4-dimethylaminopyridine (DMAP) in dimethylformamide are added to 0.1 mmol of resin-bound amine. After stirring at 60°C for 12 hours, the mixture is filtered off with suction and the coupling is repeated. After filtration, the mixture is washed four times with 2000 ml of dimethylformamide.

K Synthesis of ureas by the reaction of resin-bound amine and isocyanates:

1 ml of 0.5 M isocyanate in dimethylformamide is added to 0.1 mmol of resin-bound amine and stirred at room temperature for 18 hours. After suction filtration, the mixture is washed four times with dimethylformamide.

L Synthesis of carbamates by reacting resin-bound amines and preactivated alcohols:

For preactivation, 0.4 M alcohol, 0.39 M dibenzotriazolyl carbonate and 0.39 M pyridine were mixed in dimethylformamide at 40 °C for 15 min. 1 mmol of resin-bound amine was mixed with 1 ml of preactivated alcohol and 167 ml of 2.4 M N-methylmorpholine (NMM) in dimethylformamide were added. The mixture was stirred at 60 °C for 4 h, then filtered off with suction and washed four times with dimethylformamide.

Synthesis of N-alkylamines M by N-alkylation of resin-bound amines using alkyl halides and catalytic amounts of potassium iodide (KI):

mL of a 0.5 M halide/0.05 M potassium iodide mixture in dimethylformamide and 416 μΐ of 2.4 M diisopropylethylamine (DIPEA) in dimethylformamide are added to 0.1 mmol of resin-bound amine and stirred at 90°C for 12 hours. After suction filtration, the resin is washed four times with 2 ml of dimethyl formamide.

N N-Alkylation of resin-bound indole nitrogens using halide/sodium hydride in dimethylformamide:

ml of dimethylformamide and 0.5 mmol of sodium hydride (NaH) (55% oil suspension) are added to 0.1 mmol of resin-bound amine. After stirring at room temperature for 30 minutes, 1 ml of 0.5 molar halide in dimethylformamide is added and the mixture is stirred at 45°C for 8 hours. This is followed by suction filtration and washing twice with 2 ml each of methanol, dimethylformamide, methanol and dimethylformamide.

Elimination from Wang, trityl, DHP (3 _r 4-dihydro-2H-pyran), Rink amide resin:

1 mL of 95% trifluoroacetic acid (TEA)/5% water was added to 0.1 mmol of the resin and shaken at room temperature for 3 h. The resin was then filtered and washed with an additional 2 mL of trifluoroacetic acid. The combined trifluoroacetic acid solutions were evaporated to dryness to give the crude products.

P Aminolytic elimination from HMB resin:

1 ml of dimethylformamide and 2 ml of 7 M ammonia in methanol are added to 0.1 mmol of the resin and shaken at room temperature for 18 hours. The resin is then filtered off and bound with dimethylformamide. The combined solutions are evaporated to dryness to give the crude product.

Preparation of starting materials:

3-[[(9H--Fluorene--9-yl-methoxy)-carbonyl]-aminoJ-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid 1

38.4 mmol (6.0 g) of 4,4-ethylenedioxycyclohexanone and 39.8 mmol (4.3 g) of phenylhydrazine were dissolved separately in 50 ml and 10 ml of water, respectively, and mixed. The resulting milky emulsion was extracted five times with ethyl acetate, dried over magnesium sulfate (MgSO ₄ ) and evaporated to dryness. Yield: 9.2 g of orange oil.

9.2 g of crude phenylhydrazone was dissolved in 240 ml of toluene at room temperature and 4.9 g of freshly ground zinc chloride (ZnCl ₂ ) was added. After refluxing for 90 min with a water trap, most of the toluene was distilled off and excess 2 M sodium hydroxide (NaOH) was added, and the mixture was extracted three times with ethyl acetate. The extract was washed with saturated sodium chloride solution and dried over magnesium sulfate, and the solvent was distilled off. The remaining brown oil was purified on silica gel with ethyl acetate/hexane (1:9). Yield: 2.7 g of beige solid.

11.6 mmol (2.7 g) of 1,2,4,9-tetrahydrospiro[3H-carbazole3,2'-[1,3]-dioxolane] and 640 mg of p-toluenesulfonic acid are taken up in 70 ml of acetone and stirred at room temperature for 2.5 hours. The solution is added to a sodium bicarbonate (NaHCO ₃ ) solution, extracted with ethyl acetate, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. 2.13 g of a reddish-brown solid remains. Recrystallization from ether gives 1.1 g of a beige solid.

60.2 mmol (11.1 g) of 1,2,4,9-tetrahydrospiro-3H-carbazol-3-one, 8.3 g of potassium cyanide (KCN) and 22.0 g of ammonium carbonate ((NH ₄ ) ₂ CO ₃ ) in 550 ml of 60% ethanol were heated at 80°C in an autoclave for 3 hours. After cooling to room temperature, the reaction mixture was added to ice water and the precipitated solid was filtered off. Yield: 10.1 g of a grey solid.

44.2 mmol (11.3 g) of 1,2,4,9-tetrahydrospiro[3Hcarbazole-3,4'-imidazolidine]-2' , 5' -dione was heated with 62 g of barium hydroxide (Ba(OH) ₂ x 8 H ₂ O) in 145 ml of water at 150°C for 13 hours. After cooling to room temperature, the viscous mass was mixed with 37 g of ammonium carbonate ((NH ₄ ) ₂ CO ₃ ) and heated at 100°C for 30 minutes. After cooling to room temperature and filtering, the filtrate was washed with water and evaporated to dryness. Yield: 7.7 g of a beige solid.

mmol (5.8 g) of 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid in 26 ml of 1 M sodium hydroxide solution and 26 mmol (8.76 g) of Fmoc-ONSu in 28 ml of acetonitrile were mixed at room temperature and diluted with 130 ml of a 1:1 acetonitrile/water mixture. Two hours later, the pH was adjusted to 9 with 1.5 ml of triethylamine (NEt ₃ ) and the mixture was stirred overnight at room temperature. Subsequently, a further 6.3 g (18.7 mmol) of Fmoc-ONSu dissolved in 19 ml of acetonitrile was added and stirring was continued for two hours while monitoring the pH. After removal of the acetonitrile by distillation and acidification with 0.01 M hydrochloric acid, the mixture is extracted with ethyl acetate. The extract is washed until neutral, dried over sodium sulfate and evaporated to dryness in a rotary evaporator. It is then recrystallized from ether/hexane.

Production: 10.7 g.

NMR (d ⁶ DMSO): δ = 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); 7.24-7.35 (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°C

The separation of the two enantiomers is performed by chiral HPLC.

(R)-3-[[ (9H-Fluoren-9-yl-methoxy)-carbonyl]-amino]-2,3,4,9tetrahydro-1H-carbazole-3-carboxylic acid la t _R = 6.4 min (Chiralcel OD 10 pm LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) (S)-3~[[(9H-Fluoren-9-yl-methoxy)-carbonyl]-amino]-2,3,4,9tetrahydro-1H-carbazole-3-carboxylic acid lb t _R 7.5 min (Chiralcel OD 10 pm LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) l-[[(9H-Fluoren-9-yl-methoxy)-carbonyl]-amino]-4-oxocyclohexanecarboxylic acid 2

320 mmol (50 g) of 4, 4-ethylenedioxycyclohexanone are suspended in 800 ml of 50% ethanol and 1500 mmol (144.5 g) of ammonium carbonate ((NH ₄ ) ₂ CO ₃ ) and 640 mmol (41.7 g) of potassium cyanide (KCN) are added. After stirring at 60°C for 5 hours, the ethanol is removed in vacuo and the aqueous residue is filtered off after cooling in ice, washed with water and dried.

Yield: 72.4 g of 4,4-1,4-dioxa-9,11-diazadispiro[4.2.4.2]tetradecane-10,12-dione.

In a 2.5 L autoclave, 295 mmol (66.8 g) of 4,4-1,4-dioxa9,11-diazadispiro[4.2.4.2]-tetradecane-10,12-dione and 826 ml (260.6 g) of barium hydroxide (Ba(OH) ₂ x 8 H ₂ O) were stirred at 150°C for 6 hours. After cooling to room temperature, 1032 mmol (99.2 g) of ammonium carbonate ((NH ₄ ) ₂ CO ₃ ) was added to the solution and stirred at 60°C for 1 hour. The suspension was filtered and washed, and the filtrate was lyophilized. The residue was recrystallized from water/methanol.

Yield: 45.4 g of 8-amino-1,4-dioxaspiro[4,5]-decane-8-carboxylic acid.

213 mmol (42.9 g) of 8-amino-1,4-dioxaspiro[4,5]-decane-8-carboxylic acid in 213 ml of 1M sodium hydroxide and 213 mmol (71.9 g) of Fmoc-ONSu in 240 ml of acetonitrile were mixed and diluted with 1000 ml of a 1:1 acetonitrile/water. The pH was adjusted to 9 and the mixture was stirred overnight. The acetonitrile was removed in a rotary evaporator, acidified with 0.01 M hydrochloric acid and extracted with ethyl acetate. The extract was washed until neutral, dried over sodium sulfate (Na ₂ SO ₄ ) and evaporated to dryness. The residue was recrystallized from ethyl acetate/hexane. Yield: 79.0 g of 8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1,4-dioxaspiro[4,5]decane-8-carboxylic acid.

187 mmol (79 g) of 8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino-1,4-dioxaspiro[4,5]-decane-8-carboxylic acid are taken up in 3.5 l of acetone/0.1 M hydrochloric acid in a 1:1 ratio and stirred at room temperature for four hours. The acetone is evaporated off in a rotary evaporator and the precipitated product is filtered, washed with water and dried. Yield: 68.7 g of 2.

^X H NMR (d ⁶ DMSO): δ = 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).

Melting point: 157°C

4-Oxocyclohexanecarboxylic acid 3 mmol (3.4 g) of ethyl 4-oxocyclohexanecarboxylate was suspended in 40 ml of 2% sulfuric acid (H ₂ SO ₄ ) and stirred at 90°C for 2 hours. The mixture was then extracted four times with ethyl acetate, dried over sodium sulfate (Na ₂ SO ₄ ) and the solvent was removed. After recrystallization from ether/hexane, 2.9 g of white solid 3 were obtained.

¹ H NMR (d ⁶ DMSO): δ = 1.72 (m, 2H); 2.08-2.18 (m, 2H); 2.192.47 (m, 4H); 2.72 (m, 1H); 12.23 (bs, 1H).

4-Chloro-3-[[(phenylamino)carbonyl]amino]benzeneacetic acid 4

18.55 mmol (2.21 g) of thionyl chloride (SOC1 ₂ ) was added slowly to a solution of 18.55 mmol (4 g) of 4-chloro-3-nitrobenzeneacetic acid in 50 ml of methanol under ice-cooling and stirring. After stirring for 30 min, the mixture was allowed to warm to room temperature, and then an additional 3.71 mmol (0.44 g) of thionyl chloride was added. After stirring overnight, the mixture was refluxed for 30 min. The solvent was evaporated and the residue was recrystallized from ether/hexane.

Production: 3.43% methyl 4-chloro-3-nitrobenzeneacetate is obtained as a yellowish solid.

13.07 mmol (3.0 g) of methyl 4-chloro-3-nitrobenzene acetate and 198.8 mmol (13.0 g) of zinc powder are heated in 500 ml of methanol under reflux for 10 minutes. Subsequently, 13 ml of concentrated hydrochloric acid are added dropwise under reflux and the refluxing is continued for 30 minutes. Then the suspension is filtered, the methanol is distilled off and the pH of the residue is adjusted to 14 with sodium hydrogen carbonate (NaHCO ₃ ) solution. Subsequently, it is extracted with ethyl acetate, dried over sodium sulfate (Na ₂ SO ₄ ) and after removing the solvent, 2.3 g of methyl 3-amino-4-chlorobenzene acetate is obtained in the form of a beige solid.

2.08 mmol (415 mg) of methyl 3-amino-4-chlorobenzene acetate are dissolved in 40 ml of DCM and 0.83 mmol (246.3 mg) of triphosgene and 0.6 ml of pyridine are added at 0°C. After stirring for 1 hour at 0°C, 10.4 mmol (1.11 g) of benzylamine are added and stirring is continued at room temperature overnight. Extraction is carried out with a dichloromethane (DCM)/water mixture, the organic phase is dried and the solvent is evaporated.

Yield: 727 mg of methyl 4-chloro-3-[[(phenylamino)carbonyl]amino]benzeneacetate.

2.98 mmol (990 mg) of methyl 4-chloro-3-[[(phenylamino)carbonyl]amino]benzene acetate are taken up in 10 ml of methanol and 6 mmol of 1 M sodium hydroxide are added. After stirring at room temperature for 2 hours, the methanol is distilled off and the residue is acidified to pH=2-3 with 1 M hydrochloric acid. Extraction is carried out with ethyl acetate, then drying over sodium sulfate (Na ₂ SO ₄ ) and the solvent is removed. After recrystallization from hot isopropanol, the yield is: 830 mg of white solid 4.

¹ HNMR (d ⁶ DMSO): δ = 3.57 (s, 2H); 6.92 (d, 1H); 6.99 (tr, 1H); 7.35-7.50 (m, 3H); 8.10 (s, 1H); 8.30 (s, 1H); 9.42 (s, 1H); 12.40 (bs, 1H).

4-Chloro-3-[[[(phenylmethyl)amino]carbonyl]amino]benzoacetic 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 above in point 4. The work-up is also carried out in an analogous manner.

Yield: 662 mg of solid.

For the ester cleavage, 2.47 mmol (790 mg) of methyl 4-chloro-3-[[[(phenylmethyl)amino]carbonyl]amino]benzeneacetate was hydrolyzed with 1 M sodium hydroxide as described above. The product 5 was obtained without recrystallization.

Yield: 693 mg of yellowish solid.

ES-MS: 319 (M+H ⁺ )

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, proceeding as described above under point 4. The work-up is also carried out in an analogous manner.

Yield: 664 mg of solid.

For the ester cleavage, 2.63 mmol (840 mg) of methyl 4-chloro-3-[[(4-pyridinylamino)carbonyl]amino]benzeneacetate was hydrolyzed with 1 M sodium hydroxide in an analogous manner to the above. The product 6 was obtained without recrystallization.

Yield: 481 mg of yellowish solid.

NMR (d ⁶ DMSO): δ = 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 (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-chlorobenzeneacetate are mixed with 10.4 mmol (979 mg) of 2-aminopyridine according to point 4.) and the work-up is carried out analogously.

Yield: 617 mg of solid.

For the ester cleavage, 2.47 mmol (790 mg) of methyl 4-chloro-3-[[(2-pyridinylamino)carbonyl]amino]benzeneacetate was hydrolyzed with 1 M sodium hydroxide as above. The product 7 was obtained without recrystallization. Yield: 693 of a yellowish solid.

NMR (d ⁶ DMSO): δ = 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, 1H).

II. Examples of the preparation of compounds of general formula (I) according to the invention

1. Example:

0.3 mmol (42.6 mg) of 4-oxo-cyclohexanecarboxylic acid was 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 zinc chloride (ZnCl ₂ ) in 1 ml of acetic acid. After stirring at 70°C for 20 hours, the mixture was diluted with 20 ml of water and extracted with ethyl acetate. The ethyl acetate phase was washed with water, dried over sodium sulfate and evaporated to dryness.

Yield: 65.6 mg (100%) of white solid.

Compound name Compound number M _measured M _calculated

2,3,4,9-Tetrahydro-1H-carbazole3-carboxylic acid 8 215 215.2507

In the examples below, the above table heading (compound name, compound number, M _measured (measured molecular weight), M _calculated (calculated molecular weight) is used.

Example:

The synthesis is carried out on a 0.2 mmol scale, following methods A, I and O.

2,3,4,9-Tetrahydro-1H-carbazole-3-carboxamide

214 214.2666

3. Example:

The synthesis is carried out on a 0.2 mmol scale, following methods A, F, G, I and 0.

N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-(3S)-2,3,4,9-tetrahydro-1Hcarbazole-3-carboxamide 10a 314 313.3987

N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-(3R)-2,3,4,9-tetrahydrolicarbazole-3-carboxamide 10b 314 313.3987

N-(2-Amino-2-oxo-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 11 271 271.3183

4. Example:

The synthesis was carried out on a 0.2 mmol scale, following methods D, F, G, F, G, I and O.

N-['(3S)-(2,3,4,9-Tetrahydro-1Hcarbazol-3-yl)carbonyl]-L-valyl-Lglutamine 12a 442 442,513

N-[(3A)-(2,3,4,9-Tetrahydro-1Hcarbazol-3-yl)carbonyl]-L-valyl-Lglutamine, B Isomer 12b 442 442,513

5. Example:

The synthesis is carried out on a 0.2 mmol scale, with D, F, G, I,

Using methods F and O:

N-[[(3S)-3-Amino-2,3,4,9-tetrahydrolH-carbazol-3-yl)-carbonyl]-Lalanine 13 301 301.3441

6. Example:

0.1 mmol of carboxylic acid, 0.1 mmol of butyl alcohol (HOBt) and 0.15 mmol of the amine component are dissolved in 15 ml of dry dimethylformamide (or tetrahydrofuran (THF), dichloromethane (DOM)) and 0.5 mmol of NMM are added while cooling with ice and stirring. After about 15 minutes, 0.15 mmol of EDCI x HCl are added and the mixture is warmed to room temperature and stirred overnight. For work-up, the solvent is evaporated and the product is dissolved in ethyl acetate and washed twice with 0.1 M hydrochloric acid and saturated sodium chloride solution. After drying and evaporation of the solvent, recrystallization is carried out if desired.

9H-Fluoren-9-ylmethyl[(3S)-3-[[[(4bromophenyl)methyl]amino]carbonyl]2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbamate 14. 620 620.5439

Methyl N-[[(3S)-3-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-2,3,4,9tetrahydro-1H-carbazol-3-yl]carbonyl]L-alanine 15,537,537.6129

7. Example:

The synthesis was carried out on a 0.2 mmol scale following methods A, F, G, F, G, F, G and O.

N-[[(3R)-3-[[(2S,3S)-2-[[9H-Fluoren-9- 16 779 777.9178 -yl-methoxy)-carbonyl]-amino]-3-methyl-1-oxo-pentyl]-amino]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbonyl]-L-valyl-L-aspartamide N— [ [ (3S) —3—[[(2S,3S) —2—[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]-3-methyl-1-oxopentyl]amino]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide 17 779 777.9178 N-[[(3R)-2,3,4-Tetrahydro-3-[(1-oxo-2,3-diphenylpropyl)amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide 18 651 650.7758 N-[[(3S)-2,3,4,9-Tetrahydro-3-[(1-oxo-2,3-diphenylpropyl)amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide, A isomer 19 651 650.7758 N-[[(3S)-2,3,4,9-Tetrahydro-3-[(1-oxo-2,3-diphenylpropyl)amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide, B isomer 20 651 650.7758 N-[[(33)-2,3,4,9-Tetrahydro-3- -[[(2S,3S)-3-methyl-1-oxo-2-[(1-oxo-3- phenylpropyl)amino]-1H-carbazol-3-yl]- -carbonyl]-L-valyl-L-aspartamide 21 688 687.8371 N-[[(3R)-2,3,4,9-Tetrahydro-3- -[[(23,3S)-3-methyl-1-oxo-2-[(l-oxo-3- -phenyl-propyl)-amino]-pentyl]-amino]- -1H-carbazol-3-yl]carbonyl]-L-valyl-L- 22 688 687.8371

aspartamide

N- [ [ (3S)-2,3,4,9-Tetrahydro-3- [ [ (2S)-1- 23

-oxo-2-[[(phenyl-methoxy)carbonyl]amino]propyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide

N-[[(3R)-2,3,4,9-Tetrahydro-3-[[(2S)-1- 24

-oxo-2-[[(phenylmethoxy)carbonyl]amino]propyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide

N-[[(3R)-2,3,4,9-Tetrahydro-3-25

-[[(2S,3S)-3-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amino]-1H-carbazol-3-yl]carbonyl]-L-alanyl-L-aspartamide

N-[[(3R)-2,3,4,9-Tetrahydro-3-2_6

-[[(2S,3S)-3-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-alanine amide

N-[[(3S)-2,3,4,9-Tetrahydro-3-27

-[[(2S,3S)-3-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]-amino]-pentyl]-amino]-1H-carbazol-3-yl]-carbonyl]-D-valyl-L-aspartamide

N-[[(3S)-2,3,4,9-Tetrahydro-3-2_8

-[[(2S,3S)-3-methyl-1-oxo-2-[[(phenyl-

-methoxy)carbonyl]amino]pentyl]-

-amino]-1H-carbazol-3-yl]carbonyl]-D-

-valyl-L-aspartamide

N-[[(3R)-2,3,4,9-Tetrahydro-3-2 9

648 647.7289

648 647.7289

662 661.7557

647 646.7844

690 689.8093

690 689.8093

690 689.8093

-[[(2S,3S)-3-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-D-aspartamide

N-[[(33)-2,3,4,9-Tetrahydro-3- 30 690 689.8093 - [ [ (2S,3S)-3-methyl-1-oxo-2-[[(phenyl- -methoxy)carbonyl]amino]pentyl]- -amino]-1H-carbazol-3-yl]carbonyl]-L- -valyl-D-aspartamide N-[[(33)-2,3,4,9-Tetrahydro-3- 31 662 661.7557 -[[(2S,33)-3-methyl-1-oxo-2-[[(phenyl- -methoxy)carbonyl]amino]pentyl]- -amino]-1H-carbazol-3-yl]carbonyl]-L- -alanyl-L-aspartamide N- [ [(33)-2,3,4,9-Tetrahydro-3-[(phenyl- 32 651 560.6514 -acetyl)-amino]-1H-carbazol-3-yl]- -carbonyl]-L-valyl-L-aspartamide N-[[(3R)-2,3,4,9-Tetrahydro-3-[(1-oxo- 33 575 574.6782 -3-phenylpropyl)amino]-1H-carbazole-3- -yl]carbonyl]-L-valyl-L-aspartamide N-[[(33)-2,3,4,9-Tetrahydro-3-[(1-oxo- 34 575 574.6782 -3-phenylpropyl)amino]-1H-carbazole-3- -yl]carbonyl]-L-valyl-L-aspartamide N- [ [ (33)-2,3,4,9-Tetrahydro-3- 36 647 646.7844 -[[(23,33)-3-methyl-1-oxo-2-[[(phenyl- -methoxy)carbonyl]amino]pentyl]- -amino]-1H-carbazol-3-yl]carbonyl]-L- -valyl-L-alanine amide N-[[(3R)-2,3,4,9-Tetrahydro-3-[(1-oxo- 37 589 588,705 -4-phenylbutyl)amino]-1H-carbazol-3- -yl]carbonyl]-L-valyl-L-aspartamide N—[[(33)—2,3,4,9-Tetrahydro-3-[(1-oxo- 38 589 588,705 -4-phenyl-butyl)-amino]-1H-carbazole-3- -yl]-carbonyl]-L-valyl-L-aspartamide N-[[(3R)-3-[(Diphenylacetyl)amino]- 39 637 636,749

-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbonyl]-L-valyl-L-aspartamide

N- [ [3S)-3- [ (Diphenylacetyl)amino]- 40 637 636,749 -2,3,4,9-tetrahydro-1H-carbazol-3-yl]- -carbonyl]-L-valyl-L-aspartamide N-[[(3R)-2,3,4,9-Tetrahydro-3-[(1-oxo- 41 575 574.6782 -2-phenylpropyl)amino]-1H-carbazole-3- -yl]carbonyl]-L-valyl-L-aspartamide, A isomer N-[[(3R)-2,3,4,9-Tetrahydro-3-[(3- 42 617 616.7586 -methyl-1-oxo-2-phenylpentyl)-amino]-1H- -carbazol-3-yl]-carbonyl]-L-valyl-L- -aspartamide, B isomer N-[[(3S)-2,3,4,9-Tetrahydro-3-[(3- 43 617- 616.7588 -methyl-1-oxo-2-phenylpentyl)-amino]-1H- -carbazol-3-yl]-carbonyl]-L-valyl-L- -aspartamide, A isomer N-[[(3S)-2,3,4,9-Tetrahydro-3-[ (3- 44 617 616.7586 -methyl-1-oxo-2-phenyl-pentyl)-amino]-1H- -carbazol-3-yl]carbonyl]-L-valyl-L- -aspartamide, B isomer Phenylmethyl-[(IS,2S)-1-[[[(3R)-3- 45 695 694.8284 —[[[(IS)—1—[[[4-(aminocarbonyl·)- -phenyl]-amino]-carbonyl]-2-methyl- -propyl]-amino]-carbonyl]-2,3,4,9- -tetrahydro-1H-carbazol-3-yl]-amino]- -carbonyl]-2-methyl-butyl]-carbamate Phenylmethyl-[(IS,2S)-1-[[[(3S)-3- 46 695 694.8284 — [[[(IS)—1—[[[4-(aminocarbonyl)- -phenyl]-amino]-carbonyl]-2-methyl- -propyl]-amino]-carbonyl]-2,3,4,9- -tetrahydro-1H-carbazol-3-yl]-amino]- -carbonyl]-2-methyl-butyl]-carbamate

Ν-[[(3S)-2,3,4,9-Tetrahydro-3-[(3- 47 603 602.7318 -methyl-1-oxo-2-phenylbutyl)-amino]-1H- -carbazol-3-yl]-carbonyl]-L-valyl-L- -aspartamide, A isomer N-[[(3S)-2,3,4,9-Tetrahydro-3-[(3- 48 603 602.7318 -methyl-1-oxo-2-phenyl-butyl)-amino]-1H- -carbazol-3-yl]carbonyl]-L-valyl-Laspartamide, B isomer N-[[(3R)-2,3,4,9-Tetrahydro-3-[(3- 49 603 602.7318 -methyl-1-oxo-2-phenyl-butyl)-amino]-1H- -carbazol-3-yl]-carbonyl]-L-valyl-L- -aspartamide Phenyl-methyl-[(IS,2S)-1- [ [ [(3S)-3- 50 715 714.9026 — [[[(IS)-1-[[[[4-(aminocarbonyl)cyclohexyl]methyl]amino]carbonyl]-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate N-[[(3R)-2,3,4,9-Tetrahydro-3-[[(3- 51 653 652,748 -phenoxyphenyl)acetyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide N-[[(3S)-2,3,4,9-Tetrahydro-3-[[(3- 52 653 652,748 -phenoxy-phenyl)-acetyl]-amino]-1H- -carbazol-3-yl]carbonyl]-L-valyl-L- - aspartamide Phenylmethyl-[(IS,2S)-1-[[[(3R)-3- 53 709 708.8552 -[[[(1S)-1-[[[[3-(aminocarbonyl)- -phenyl]-methyl]-amino]-carbonyl]-2- -methylpropyl]amino]carbonyl]- -2,3,4,9-tetrahydro-1H-carbazol-3-yl]- -amino]carbonyl]-2-methylbutyl]-

-carbamate

Phenylmethyl-[(IS,2S)-1-[[[(3S)-3- —[[[(IS)—1—[[[[3-(aminocarbonyl)phenyl]methyl]amino]carbonyl]-2-methyl- 54 709 708.8552 -propyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 55 608 607.7509 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[(2R)-1-oxo-2-[(1-oxo-3-phenylpropyl)amino]-3-phenylpropyl]amino]-1H-carbazole-3-carboxamide N- [ [(33)-2,3,4,9-Tetrahydro-3-[(1-1- 56 575 574.6782 -oxo-2-phenylpropyl)-amino]-1H- -carbazol-3-yl]carbonyl]-L-valyl-L- - aspartamide Phenylmethyl-[(IS,2S)-1-[[[(3R)-3- 57 715 714.9026 - [ [ [ (IS)-1-[[[[4-(aminocarbonyl)cyclohexyl]methyl]amino]carbonyl]-2-methylpropyl]amino]carbonyl]- -2,3,4,9-tetrahydro-1H-carbazol-3-yl]- -amino]carbonyl]-2-methylbutyl]- -carbamate Example 8: The synthesis was carried out on a 0.2 mmol scale using A, F, G, F, G and O methods are carried out. Phenylmethyl-[(IS,2S)-1-[[[(3R)-3- 58 576 575.7059 - [[[(IS)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate N-[[(3S)-3-[[(9H-Fluoren-9-yl-methoxy)- 59 665 664,759

-carbonyl]-amino]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbonyl]-L-valyl-L71

-aspartamide

N-[[(3R)-3-[[(9H-Fluoren-9-yl-methoxy)- 60 665 664,759 -carbonyl]-amino]-2,3,4,9-tetrahydro- -1H-carbazol-3-yl]-carbonyl]-L-valyl-L- -aspartamide Phenylmethyl-[(IS,2S)-1-[ [[(3S)-3- 61 576 575.7059 - [ [ [(IS)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS,2S)-1-[[[(3R)-3-[[[4- 62 596 595.6963 -(aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS,2S)-1-[[[(3S)-3-[[[4- 63 596 595.6963 -(aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS,2S)-1-[[[(3R)-3- 64 590 589.7327 [[[(IS,2S)-1-(aminocarbonyl)-2-methylbutyl]-amino]-carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate Phenylmethyl-[(IS,2S)-1-[[[(3S)-3- 65 590 589.7327 -[[[(IS,2S)-1-(aminocarbonyl)-2-methyl- -butyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS,2S)-1-[[[(3R)-3- 66 623 623.7499 — [[[(IS)-2-amino-2-oxo-1-(phenylmethyl) -

-ethyl]-amino]-carbonyl]-2,3, 4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]-carbamate

Phenylmethyl-[(1S,2S)-1-[ [ [ (3S)-3- 67 623 623.7499 -[[[(IS)-2-amino-2-oxo-1-(phenylmethyl)ethyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 68 460 460.5748 tal -propyl] -2,3,4,9-tetrahydro-3-[(1- -oxo-2-phenyl-propyl)-amino]-1H-carbazole-3-carboxamide Phenylmethyl-[(IS,2S)-1-[[[(3S)-3-[[[[3- 69 610 609.7231 -(aminocarbonyl)phenyl]methyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS,2S)-1-[[[(3R)-3-[[[[3- 70 610 609.7231 -(aminocarbonyl)phenyl]methyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS,2S)-1-[[[(3S)-3-[ [ [ [4- 71 615 615.7705 -(aminocarbonyl)cyclohexyl]methyl]- -amino]carbonyl]-2,3,4,9-tetrahydro- -1H-carbazol-3-yl]amino]carbonyl]-2- -methylbutyl]carbamate Phenylmethyl-[(IS,2S)-1-[[[(3R)-3-[[[[4- 72 615 615.7705 -(aminocarbonyl)cyclohexyl]methyl]- -amino]carbonyl]-2,3,4,9-tetrahydro- -1H-carbazol-3-yl]amino]carbonyl]-2- -methylbutyl]carbamate Phenylmethyl-[(IS,2S)-1-[[[(3S)-3-[[[3- 73 596 595.6963

-(aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-ylamino]carbonyl]-2-methylbutyl]73

-carbamate

Phenylmethyl-[(2S, 2S)-1-[[[(3R)-3-[[[3- 74

-(aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl- [ (IS, 2S) -1- [ [ [ (3S) -3- 75

-[[[(IS)-2-amino-2-oxo-1-phenylethyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS,2S)-1-[[[(3S)-3- 7 6

-[[[(IR)-2-amino-2-oxo-1-phenylethyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS,2S)-1-[[[(3R)-3-[[(2- 77

-amino-2-oxo-1-phenylethyl)amino]carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]carbonyl]-2-methylbutyl]carbamate, A isomer

Phenylmethyl-[(IS,2S)-1-[[[(3R)-3-[[(2- 78

-amino-2-oxo-1-phenylethyl)amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate, B isomer (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 7 9 ethylpropyl]-2,3,4,9-tetrahydro-3-[[(3-hydroxyphenyl)-acetyl]-amino]-1H-carbazole-3-carboxamide (3R)-3 - [ [ [3 - (Acetyloxy) -phenyl] -ace- 8 0 ethyl]-amino]-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

596 595.6963

610 609.7231

610 609.7231

609 609.7231

609 609.7231

462 462,547

504 504.5838

3-[2-[[(3R)-3-[[[(IS)-1-(Aminocarbo- 81 597 596.6804 [(nyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]-2-oxoethyl]phenyl-3-hydroxybenzene acetate (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[(hydroxyphenylacetyl)amino]-1H-carbazole-3-carboxamide 82 462 462,547 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[(4-bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 83 525 525.4441 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[(2-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 84 461 480.9931 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[(3-chloro-4-hydroxyphenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 85 497 496.9921 (3R)-3-[[[4-(Acetyloxy)-3-chlorophenyl]acetyl]amino]-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 86 539 539.0269 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[(3-fluoro-4-hydroxyphenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 87 481 480.5371 (3R)-3-[[[4-(Acetyloxy)-3-fluoro- nyl]-acetyl]-amino]-N-[(IS)-1-(amino- 88 523 522.5739

-carbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-ΙΗ-carbazole-3-carboxamide

(3R)-N-[(IS)-1-(Aminocarbonyl)-2-methyl-propyl]-2,3,4,9-tetrahydro-3-[[[4-nitrophenyl)acetyl]amino]-1H-carbazole-3-carboxamide 89 492 491.5451 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[(2,4-dichlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 90 515 515.4382 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[(4-fluorophenyl)acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 91 464 464.5381 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[(4-hydroxyphenyl)acetyl]amino]-1H-carbazole-3-carboxamide 92 462 462,547 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[(2-bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 93 525 . 525.4441 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[(2-nitrophenyl)acetyl]amino]-1H-carbazole-3-carboxamide 94 491 491.5451 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[ (3-nitrophenyl)acetyl]amino]-1H-carbazole-3-carboxamide 95 491 491.5451 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methyl-propyl]-3-[[(3-bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole- 96 525 525.4441

-3-carboxamide

(3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 97 499 498.9832 ethylpropyl]-3-[[(2-chloro-4-fluorophenyl)- -acetyl]-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 98 523 522.6456 ethylpropyl]-3-[([1,1'-biphenyl]-4-yl- -acetyl)-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3R)-N-[(1S)-1-(Aminocarbonyl)-2-me- 99 475 474.6016 tyl-propyl]-3-[[(3,5-dimethylphenyl)- -acetyl]-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 100 490 490,557 ethylpropyl]-3-[(1,3-benzo-dioxol-5-yl- -acetyl)-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 101 481 480.9931 -methylpropyl]-3-[[(3-chlorophenyl)- -acetyl]-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3R)-N-[(1S)-1-(Aminocarbonyl)-2- 102 461 460.5748 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[(3-methylphenyl)acetyl]amino]-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 103 464 464.5381 -methyl]-3-[[(2-fluorophenyl)acetyl]- -amino]-2,3,4,9-tetrahydro-1H-carbazole- -3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 104 461 460.5748

-methylpropyl]-2,3,4,9-tetrahydro-3-

-[[(2-methylphenyl)acetyl]amino]-1H-

-carbazole-3-carboxamide

(3R)-N-[(1S)-1-(Aminocarbonyl)-2- 105 489 488.6289 -methylpropyl]-2,3,4,9-tetrahydro-3- [ [[4-(1-methylethyl)phenyl]acetyl]amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[[4-(dimethylamino)phenyl]-acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 106 490 489.6165 (3R)-N-[(13)-1-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[[4-(methylsulfonyl)phenyl]acetyl]amino]-1H-carbazole-3-carboxamide 107 524 524.6388 (3R) -N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[(3-fluoro-4-methylphenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide Example 9: 108 478 478.5649 The synthesis is carried out on a 0.2 mmol scale following methods B, F. G, F, G, F, G and 0 N-[[(3R)-2,3,4,9-Tetrahydro-3- -[[(2S,3S)-3-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-asparagine 109 691 690.7934 N-[[(3R)-2,3,4,9-Tetrahydro-3- -[[(2S,3S)-3-methyl-1-oxo-2-[[(phenyl- -methoxy)carbonyl]amino]pentyl]- -amino]-1H-carbazol-3-yl]carbonyl]-L- 110 691 690.7934

-valyl-L-asparagine

Example 10

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, F, G, F, G, F, H and 0.

N-[[(3R)-3-[[(2S,3S)-2-(Acetylamino)- 111 598 597.7127

-3-methyl-1-oxo-pentyl]-amino]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbonyl] -L-valyl-L-aspartamide

N-[[(3S)-3-[[ (2S,3S)-2-(Acetylamino)- 112 598 597.7127

-3-methyl-1-oxo-pentyl]-amino]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbonyl] -L-valyl-L-aspartamide

N-[[(3R)-3-[[(2R,3R)-2-(Acetylamino)- 113 598 597.7127

-3-methyl-1-oxo-pentyl]-amino]-2,3,4,9-

-tetrahydro-1H-carbazol-3-yl]-carbonyl]-L-valyl-L-aspartamide

N-[[(3S)-3-[[(2R,3R)-2-(Acetylamino)- 114 598 597.7127

-3-methyl-1-oxo-pentyl]-amino]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbonyl] -L-valyl-L-aspartamide

Example 11

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, F, G, F, H and O.

N-[[(3R)-3-(Acetylamino)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide

N-[[(3S)-3-(Acetylamino)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide

N-[[(3R)-3-(Acetylamino)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbonyl]-D-valyl-L-aspartamide

N-[[(3S)-3-(Acetylamino)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbonyl]-L-valyl-D-aspartamide

484 484.5538

484 484.5538

Example 12:

The synthesis is carried out on a 0.2 mmol scale following the procedure in A. F, G, and 0 methods Phenylmethyl-[(IS,2S)-1-[[[(3R)-3-(ami- 119 474 476, 5738 ( Phenylmethyl-[(1S,2S)-1-[[[(3S)-3-(aminocarbonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate 120 476 476.5738 Example 13 The synthesis was carried out on a 0.2 mmol scale using A, F, G, F, G, F, G, F, G and we drive by following 0 methods finally. N-[[3R)-2,3,4,9-Tetrahydro-3-[[(2S)-1-oxo-2-[(1-oxo-3-phenylpropyl)amino]-3-phenylpropyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide 121 722 421.6543 N-[[(3R)-2,3,4,9-Tetrahydro-3- 122 688 687.8371

-[[(2R,3R)-3-methyl-1-oxo-2-[(1-oxo-3-phenylpropyl)-amino]-pentyl]-amino]-1H-carbazol-3-yl]-carbonyl]-L-valyl-L-aspartamide

Example 14:

The synthesis is carried out on a 0.2 mmol scale following methods D, F, G, F, G, and 0.

N-[[(3R)-2,3,4,9-Tetrahydro-3- 123,577,576.69

-[[(2S,3S)-3-methyl-1-oxo-2-[[(phenyl-

-methoxy)carbonyl]amino]pentyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valine, N-[ [ (3R)-2,3,4,9-Tetrahydro-3-[[(2S)-3-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valine

N-[[(3S)-2,3,4,9-Tetrahydro-3- 124,577,576.69

-[[(2S,3S)-3-methyl-1-oxo-2-[[(phenyl-

-methoxy)carbonyl]amino]pentyl]amino]-1H-carbazol-3-yl]carbonyl]-L-valine

Example 15

The synthesis is carried out on a 0.2 mmol scale following methods C, F, G, F, G, F, G and P.

N-[[(3R)-3-[[2S,3S)-2-[[(1,1-Dimethyl- 125 656 655.7921

-ethoxy)-carbonyl]-amino]-3-methyl-1-oxo-pentyl]-amino]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-carbonyl]-L-valyl-L-aspartamide

Example 16:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, F, G, F, and O.

Ν-[[ (3S)-3-Amino-2,3,4,9-tetrahydro-1H- 126,442,442,517

-carbazol-3-yl]-carbonyl]-L-valyl-L-aspartamide

N-[[(3R)-3-Amino-2,3,4,9-tetrahydro-1H- 127,442,442,517

-carbazol-3-yl]carbonyl]-L-valyl-L-aspartamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 128 441 441.5725 ethylpropyl]-3-[[(2S,3S)-2-amino-3-methyl-1-oxo-pentyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

Example 17:

The synthesis is carried out on a 0.2 mmol scale following methods D, F, G, F, G, F, H and O.

N-[[(3S)-3-(Acetylamino)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbonyl]-L-valyl-L-asparagine

Example 18:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, F, H and 0.

(3R)-3-(Acetylamino)-N-[(IS)-2-amino- 130 418 418.4944

-2-oxo-1-(phenylmethyl)ethyl]-2,3,4,9-

-tetrahydro-1H-carbazol-3-carboxamide (3S)-3-(Acetylamino)-N-[(IS)-2-amino- 131 418 418.4944

-2-oxo-1-(phenylmethyl)ethyl]-2,3,4,9-

-tetrahydro-1H-carbazole-3-carboxamide

Example 19:

The synthesis is carried out on a 0.2 mmol scale following methods B, F, G, and 0.

(3S)-2,3,4,9-Tetrahydro-3-[[(2S,3S)-3- 132 478 477.5579

-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]-amino]-pentyl]amino]-1H-carbazole-3-carboxylic acid

Example 20:

The synthesis is carried out on a 0.2 mmol scale following methods B, F, G, F, and O.

(3S)-3-[[[(2,2-Diphenylethyl)amino]- 134 468 467.5661

-acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid

Example 21:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, F, H and 0.

(3S)-3-(Acetylamino)-N-[[3-(aminocarbonyl)-phenyl]methyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S)-3-(Acetylamino)-N-[[4-(aminocarbonyl) 136 410 410,515 bonyl)-cyclohexyl]-methyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3R)-3-(Acetylamino)-N-[[4-(aminocarb- 137 410 410,515 bonyl)-cyclohexyl]-methyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S)-3-(Acetylamino)-N-[(IS)-2-amino- 138 404 404.4676

-2-oxo-1-phenylethyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

Example 22:

The synthesis was carried out on a 0.2 mmol scale following the procedure of Examples 18 and 6.

Phenylmethyl-[(IS,2S)-1-[[[(3R)-3- 139 505 504.6274 [(ethylamino)carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS,2S)-2-methyl-1-[[[(3R)- 140 519 518.6542 -2,3,4,9-tetrahydro-3-[[(1-methylethyl)- -amino]carbonyl]-1H-carbazol-3-yl]- -amino]carbonyl]-butyl]carbamate Phenylmethyl-[(IS, 2S)-2-methyl-1-[[[(3R)- 141 533 532,681 -2,3,4,9-tetrahydro-3-[[(2-methylpropyl)amino]carbonyl]-1H-carbazol-3-yl]amino]carbonyl]butyl]carbamate Phenylmethyl-[(IS,2S)-l-[[[(3R)-3-[[(2,2- 141 547 546, 7078 -dimethylpropyl)-amino]carbonyl]- -2,3,4,9-tetrahydro-1H-carbazol-3-yl]- - amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl 1-[(IS,2S)-2-methyl-1-[[[ (3R)- 143 553 552.6714 -2,3,4,9-tetrahydro-2-[(phenylamino)- -carbonyl]-1H-carbazol-3-yl]-amino]- - carbonyl]butyl]carbamate Phenylmethyl-[(1S,2S)-2-methyl-1-[[[(3R)- 144 567 566.6982 -2, 3, 4,9-tetrahydro-3-[[(phenylmethyl)amino]carbonyl]-1H-carbazol-3-yl]amino]carbonyl]-butyl]carbamate Phenylmethyl-[(IS, 2S)-2-methyl-1-[[[(3R)- 145 581 580,725

-2,3,4,9-tetrahydro-3-[[(2-phenylethyl)amino]carbonyl]-1H-carbazol-3-yl]amino]carbonyl]butyl]carbamate

Phenylmethyl-[(IS, 2S)-2-methyl-1-[[[ (3R) - 146 595 594.7518

-2,3,4,9-tetrahydro-3-[[(3-phenylpropyl)amino]carbonyl]-1H-carbazol-3-yl]amino]carbonyl]butyl]carbamate

Example 23:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, I, F, G and 0.

Phenylmethyl-[(IS, 2S )-1-[[[ ( 3R )-3-[[[ (IS) - 147a 606 605.7317

-1-aminocarbonyl)-2-methylpropyl]-

-amino]-carbonyl]-2,3,4,9-tetrahydro-8-

-methoxy-1H-carbazol-3-yl]-amino]-carbonyl]-methyl-butyl]-carbamate

Phenylmethyl-[(1S,2S)-1-[[[(3S)-3[[[(1S)-1- 147b 606 605,7317

-(aminocarbonyl)-2-methylpropyl]-amino]-carbonyl]-2,3,4,9-tetrahydro-8-

-Methoxy-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]-carbamate

Phenylmethyl-[(IS, 2S)-1-[[[ (3R)-3-[[[ (IS) - 148a 610 610,151

-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS, 2S)-1-[[[(3S)-3-[[[(1S) - 148b 610 610,151

-1-(aminocarbonyl)-2-methylpropyl]-

- amino]-carbonyl]-6-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]-carbamate

Phenylmethyl-[(IS, 2S)-!-[[[ (3R)-3-[[[ (IS)

180a 610 610,151

-1-(aminocarbonyl)-2-methylpropyl]-

- amino]carbonyl]-8-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS, 2S)-1-[[[(3S)-3-[[[(1S) - 180b 610 610,151

-1-(aminocarbonyl)-2-methylpropyl]-

- amino]-carbonyl]-8-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]-carbamate

Phenylmethyl-[(1S,2S)-1-[[[(3R)-3-[[[(1S)- 149a 644 643, 703

-1-(aminocarbonyl)2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-8-(trifluoromethyl)-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS, 2S)-1-[[[ (3S)-3-[[[ (IS) - 149b 644 643,703

-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-8-

-(trifluoromethyl)-1H-carbazol-3-yl]-

- amino]-carbon 1]-2-methyl-butyl]-carbamate

Phenylmethyl-[(IS, 2S)-!-[[[ (3R)-3-[[[ (IS) - 150a 590 589, 7327

-1-(aminocarbonyl)-2-methylpropyl]

-amino]carbonyl]-2,3,4,9-tetrahydro-8-methyl-1H-carbazol-3-yl]amino]carbonyl]methylbutyl]carbamate

Phenylmethyl-[ (IS, 2S) -!-[[[ (3S) -3—[[[ (IS) - 150b 590 589.7327 -1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-8-methyl-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS, 2S)-l-[[[(3R)-3-[[[(IS)- 151a 590 589.7327 -1-(aminocarbonyl)-2-methylpropyl]- -amino]-carbonyl]-2,3,4, 9-tetrahydro-5- -methyl-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]-carbamate Phenylmethyl-[(IS, 2S)-1-[[[(3S)-3-[[[(IS)- 151b 590 589.7327 -1-(aminocarbonyl)-2-methylpropyl]- -amino]carbonyl]-2,3,4,9-tetrahydro-5- -methyl-1H-carbazol-3-yl]-amino]- carbo- nyl]-2-methyl-butyl]carbamate Phenylmethyl-[(IS, 2S)-1-[[[(3R)-3-[[[(1S)- 151c 590 589.7327 -1-(aminocarbonyl)-2-methylpropyl]- -amino]-carbonyl]-2,3, 4,9-tetrahydro-7- -methyl-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate Phenylmethyl-[ (IS, 2S) -!-[[[ (3S) -3-[[[ (IS) - 151d 590 589.7327 -1-(Aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-7-methyl-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS, 2S)-!-[[[ (3R)-3-[[[ (IS)- 152a 610 610,151

-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-5-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS,2S)-1-[[[(3S)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-7-chloro-2,3,4,9-tetra- hydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS, 2S)-l-[[[(3R)-3-[[[(IS)- 152b 152c 610 610 610,151 610,151 -1-(aminocarbonyl)-2-methylpropyl]- - amino]-carbonyl]-7-chloro-2,3,4,9-tetrahydro-1H-carbazole-3-yl]-amino]-carbonyl]-2-methyl-butyl]-carbamate (3R) - 3-[[[ (IS) -1- (Aminocarbonyl) -2- 153a 620 619.7149 -methyl-propyl]-amino]-carbonyl]-2,3,4,9- -tetrahydro-3-[[ (2S, 3S)-3-methyl-1-oxo-2- -[[ (phenylmethoxy)-carbonyl]-amino]-pen- tyl]-amino]-1H-carbazole-8-carboxylic acid (3S) —3—[[[ (IS) —1 — (Aminocarbonyl) -2- 153b 620 619.7149 -methyl-propyl]-amino]-carbonyl]-2,3,4,9- -tetrahydro-3-[[ (2S, 3S)-3-methyl-1-oxo-2-[[ (phenylmethoxy)-carbonyl]-amino]-pentyl]-amino]-1H-carbazole-8-carboxylic acid Phenylmethyl-[(IS, 2S)-1-[[[(3R)-3-[[[(IS)- 154a 593 593,696 -1-(Aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6-fluoro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(1S,2S) — 1—[[[ (3S) — 3—[[[ (IS) — 154b 593 593,696

-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6-fluoro-2,3,4, 9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS, 2s)-l-[[[(3R)-3-[[[(IS)- 155a 605 605.7317 -1-(aminocarbonyl)-2-methylpropyl]-amino]-carbonyl]-2,3, 4,9-tetrahydro-6- -methoxy- 1H-carbazol -3- yl]-amino]-carbonyl] -2-methylbutyl]-carbamate Phenylmethyl-[(lS,2S) -1-[[[(3S) -3-[[[ (IS) - 155b 605 605.7317 -1-(aminocarbonyl)-2-methylpropyl]- -amino]-carbonyl]-2,3,4,9-tetrahydro-6- -methoxy-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(1S,2S)-1-[[[(3R)-3-[[[ (IS)- 156a 589 589.7327 -1-(aminocarbonyl)-2-methylpropyl]-amino]-carbonyl]-2 ,3,4,9-tetrahydro-6- -methyl-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]-carbamate Phenylmethyl-[(1S,2S)-1-[[[(3S)-3-[[[(IS)- 156b 589 589.7327 -1-(aminocarbonyl)-2-methylpropyl]- -amino]carbonyl]-2,3,4,9-tetrahydro-6- -methyl-1H-carbazol-3-yl]-amino]-carbo- nyl]-2-methyl-butyl]carbamate Phenylmethyl-[(IS, 2S)-!-[[[(3R)-3-[[[(IS)- 157a 621 620,703 -1-(aminocarbonyl)-2-methylpropyl]- -amino]carbonyl]-2,3,4, 9-tetrahydro-6- -nitro-ΙΗ-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]-carbamate Phenylmethyl-[(IS, 2S)-!-[[[(3S)-3-[[[(IS)- 157b 621 620,703

-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-6-nitro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-4-[(aminoiminomethyl)amino]butyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate 158 633 632.7616 (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 159a 447 447.5361 -methylpropyl]-2,3,4,9-tetrahydro-3-[ (3- -pyridinylacetyl)-amino]-1H-carbazole- -3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 159b 447 447.5361 ethylpropyl]-2,3,4,9-tetrahydro-3-[(3- -pyridinylacetyl)-amino]-1H-carbazole- -3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 160a 496 496.6078 ethylpropyl]-2,3,4,9-tetrahydro-3-[(1- -naphthalenylacetyl)-amino]-1H-carbazole- -3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2-me- 160b 496 496.6078 ethylpropyl]-2,3,4,9-tetrahydro-3-[ (1- -naphthalenylacetyl)-amino]-1H-carbazole- -3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 161a 496 496.6078 ethylpropyl]-2,3,4,9-tetrahydro-3-[ (2- -naphthalenyl-acetyl)-amino]-1H-carbazole- -3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2- 161b 496 496.6078

-methylpropyl]-2,3,4,9-tetrahydro-3-[(2-naphthalenylacetyl)amino]-1H-carbazole-3-carboxamide

(3R)-N-[(1S)-1-(Aminocarbonyl)-2- 162a 472 472.5858 -methyl-propyl]-3-[[ (2,3-dihydro-1H-inden-1-yl)-carbonyl]-amino]-2,3,4,9-tetrahydro-ΙΗ-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 162b 472 472.5858 -methylpropyl]-3-[[ (2,3-dihydro-1H-inden-1-yl)-carbonyl]-amino]-2,3,4,9- -tetrahydro-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 163a 436 436.5132 -methylpropyl]-2,3,4,9-tetrahydro-2- -[ (1H-imidazol-4-yl-acetyl)-amino]-1H- -carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 163b 436 436.5132 -methylpropyl]-2, 3,4,9-tetrahydro-3- -[ (1H-imidazol-4-yl-acetyl)-amino]-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 164a 486 485.5849 -methylpropyl]-2,3,4,9-tetrahydro-3- -[ (1H-indol-3-ylacetyl)amino]-1H- -carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 164b 486 485.5849 -methylpropyl]-2,3,4,9-tetrahydro-[(1H-indol-3-yl-acetyl)-amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 165a 461 460.5748 -methylpropyl]-2, 3,4, 9-tetrahydro-3- -[[ (4-methylphenyl)-acetyl]-amino]-1H- -carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 165b 461 460.5748

-methyl-propyl]-2,3,4,9-tetrahydro-3-[[(4-methyl-phenyl)-acetyl]-amino]-1H91

-carbazole-3-carboxamide

(3R)-N-[(IS)-1-(Aminocarbonyl)-2- 166a 515 514.5451 -methylpropyl]-2,3,4,9-tetrahydro-3-[[[4- - (trifluoromethyl) -phenyl]-acetyl]-amino]- -1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 166b 515 514.5451 -methylpropyl]-2,3,4,9-tetrahydro-3-[[[4- - (trifluoromethyl) -phenyl]-acetyl]-amino]- -1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 167a 481 480.9931 -methylpropyl]-3-[[(4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2- 167b 481 480.9931 -methylpropyl]-3-[[ (4-chlorophenyl)- -acetyl]-amino]-2,3,4 , 9-tetrahydro-1H- -carbazole-3-carboxamide (3S)-N-[ (IS)-1-(Aminocarbonyl)-2- 168a 515 514.5451 -methylpropyl]-2,3,4,9-tetrahydro-3-[[[3- (trifluoromethyl) -phenyl]-acetyl]-amino]- -1H-carbazole-3-carboxamide (3R) -N-[(IS)-1-(Aminocarbonyl)-2- 168b 515 514.5451 -methylpropyl]-2,3,4,9-tetrahydro-3-[[[3-(trifluoromethyl)-phenyl]-acetyl]-amino]- -1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 169a 465 464.5381

-methyl-propyl]-3-[[(3-fluorophenyl)-acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -N-[ (IS) -1-(Aminocarbonyl)-2- 169b 465 464.5381 -methylpropyl]-3-[[ (3-fluorophenyl)- -acetyl]-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 170a 477 476.5738 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[ (3-methoxyphenyl)-acetyl]-amino]-1H- -carbazole-3-carboxamide (3S) -N-[ (IS) -1-(Aminocarbonyl)-2- 170b 477 476.5738 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[ (3-methoxyphenyl)-acetyl]-amino]-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 171a 477 476.5738 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[ (2-methoxyphenyl)-acetyl]-amino]-1H- -carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 171b 477 476.5738 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[ (2-methoxyphenyl)-acetyl]-amino]-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 172a 479 476.5649 -methylproyl]-3-[[3-(4-fluorophenyl)-1- -oxo-propyl]-amino]-2,3,4,9-tetrahydro- -1H-carbazole-3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2- 172b 479 476.5649 -methylpropyl]-3-[[3-(4-fluorophenyl)-1-oxopropyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3R)-N-[(1S)-1-(Aminocarbonyl)-2- 173a 497 496,555

-methyl-propyl]-3-[[3-(3,4-difluoro-phenyl)-1-oxo-propyl]-amino]-2,3,4 , 993

-tetrahydro-ΙΗ-carbazole-3-carboxamide

(3S)-N-[(IS)-1-(Aminocarbonyl)-2- 173b 497 496,555 -methylpropyl]-3-[[3-(3,4-difluoro- -phenyl)-1-oxo-propyl]-amino]-2,3,4,9- -tetrahydro-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 174a 593 592.6057 -methylpropyl]-3-[[3-[3, 4-bis (trifluoro- -methyl) -phenyl]-1-oxo-propyl]-amino]- -2,3,4,9-tetrahydro-1H-carbazole-3- -carboxamide ( 3S) -N-[(IS) -1-(Aminocarbonyl) -2- 174b 593 592.6057 -methylpropyl]-3-[[3-[3,4-bis (trifluoro- -methyl)-phenyl]-1-oxo-propyl]-amino]- -2,3,4,9-tetrahydro-1H-carbazole-3- -carboxamide N-[(IS)-1-(Aminocarbonyl)-2-methyl- 175 477 476.5738 -propyl]-2,3,4,9-tetrahydro-3-[[ ( 4- -methoxyphenyl)-acetyl]-amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 176a 491 490.6006 -methylpropyl]-2, 3,4,9-tetrahydro-3-[[3- - (4-Methoxyphenyl)-1-oxo-propyl]-amino]- -1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 176b 491 490.6006 -methylpropyl]-2,3,4,9-tetrahydro-3-[[3- - (4-Methoxyphenyl)-1-oxo-propyl]-amino]- -1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 177a 491 490.6006

-methyl-propyl]-2,3,4,9-tetrahydro-3-[[3-(2-methoxy-phenyl)-1-oxo-propyl]-amino]-1H-carbazole-3-carboxamide

(3S)-N-[(1S)-1-(Aminocarbonyl)-2- 177b 491 490.6006 -methylpropyl]-2,3,4,9-tetrahydro-3-[[3- -(2-Methoxyphenyl)-1-oxo-propyl]-amino]- -1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 178a 500 499.6117 -methylpropyl]-2,3,4,9-tet rahydro-3-[[3- -(1H-indol-3-yl)-1-oxo-propyl]-amino]- -1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 178b 500 499.6117 -methylpropyl]-2,3,4,9-tet rahydro-3-[[3- -(1H-indol-3-yl)-1-oxo-propyl]-amino]- -1H-carbazole-3-carboxamide (3R)-N-[(IS)1-(Aminocarbonyl)-2-methyl- 179a 503 502.6552 -propyl]-2,3,4,9-tetrahydro-3-[(1-oxo-6- -phenylhexyl)amino]-1H-carbazole-3- -carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 179b 503 502.6552 -methylpropyl]-2,3,4,9-tet rahydro-3-[ (1- -oxo-6-phenylhexyl)-amino]-1H-carbazole- -3-carboxamide Phenylmethyl-[(IS,2S)-!-[[[(3R)-3-[[(2S)- 181a 574 573.6901 -2-(aminocarbonyl)-1-pyrrolidinyl]- -carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate Phenylmethyl-[(IS, 2S)-!-[[[(3S)-3-[[(2S)- 181b 574 573.6901

-2-(aminocarbonyl)-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(1S,2S)-1-[[[(3R)-3-[[[ (IS)- 182a 645 644.5961 -1-(aminocarbonyl)-2-methylpropyl]-amino]-carbonyl]-7,8-dichloro-2,3,4,9- -tetrahydro-1H-carbazol-3-yl]-amino]- -carbonyl]-2 -methyl-butyl]-carbamate Phenylmethyl-[(1S, 2S) -!-[[[ ( 3S) -3-[[[ (IS) - 182b 645 644.5961 -1-(aminocarbonyl)-2-methylpropyl]- -amino]carbonyl]-7,8-dichloro-2,3,4,9- -tetrahydro-1H-carbazol-3-yl]-amino]- -carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[ (IS, 2S) -!-[[[ (3R) — 3—[[[ (IS) - 183a 604 603.7595 -1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-5,8-dimethyl-ΙΗ-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS, 2S)-l-[[[(3S)-3-[[[(IS)- 183b 604 603.7595 -1-(aminocarbonyl)-2-methylpropyl]- -amino]carbonyl]-2,3,4,9-tetrahydro- -5,8-dimethyl-1H-carbazol-3-yl]-amino]- - carbonyl]-2-methyl-butyl]-carbamate Phenyl-methyl-[ (IS, 2S) -l-[[[ (3R) -3-[[[ (IS) - 184a 645 644.5961 -1-(aminocarbonyl)-2-methylpropyl]- -amino]carbonyl]-6, 8-dichloro-2,3,4,9- -tetrahydro-1H-carbazol-3-yl]-amino]- -carbonyl]-2 -methyl-butyl]carbamate Phenylmethyl-[(IS, 2S)-!-[[[(3S)-3-[[[(IS)- 184b 645 644.5961

-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS, 2S)-!-[[[(3R)-3-[[[ (IS)- -1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbo- 185a 655 654,602 nyl]-2-methyl-butyl]-carbamate Phenylmethyl-[ (IS, 2S) -1-[[[(3S) -3-[[[ (IS) - 185b 655 654,602 -1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6-bromo-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbo- nyl]-2-methylbutyl]carbamate (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 186a 511 511.0189 ethylpropyl]-3-[[ (4-chlorophenyl)-acetyl]- -amino]-2,3,4,9-tetrahydro-8-methoxy-1H- -carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 186b 511 511.0189 -methylpropyl]-3-[[(4-chlorophenyl)- -acetyl]-amino]-2, 3, 4, 9-tetrahydro-8- -methoxy-1H-carbazole-3-carboxamide Phenylmethyl-[(IS, 2S)-1-[[[(3R)-3-[[[(IR)- 187a 658 658,195 -2-amino-1-[(4-chlorophenyl)methyl]-2-oxo- -ethyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methyl-butyl]carbamate Phenylmethyl-[(IS, 2S)-1-[[[[[(3S)-3-[[[(IR)- 187b 658 658,195

-2-amino-1-[(4-chlorophenyl)methyl]-2-oxoethyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS, 2S)-1-[[[3-[[ (3-amino-3- 188 548 547.6523 -oxo-propyl) -amino]-carbonyl]-2,3,4,9- -tetrahydro-1H-carbazol-3-yl]-amino]- -carbonyl]-2-methyl-butyl]-carbamate (2S) -1-[[ (3R) - 3-[[ (4-Chloro-phenyl) -acetyl]- 189a 509 509.0031 -amino]-2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3-yl]-carbon! 1]-2-pyrrole idine carboxamide (2S) — 1—[[ (3S)-3-[[ (4-Chlorophenyl)-acetyl]- 189b 509 509.0031 -amino]-2,3,4,9-tetrahydro-8-methoxy-1H- -carbazol-3-yl]carbonyl]-2-pyrrolidine- -carboxamide Phenylmethyl-[(IS, 2S)-!-[[[ (3R)-3-[[(2S)- 190a 628 627.7815 -2-(aminocarbonyl)-octahydro-1H-indol- -1-yl]-carbonyl]-2,3,4,9-tetrahydro-1H- -carbazol-3-yl]-amino]-carbonyl]-2- -methyl-butyl]-carbamate Phenylmethyl-[ (IS, 2S) -1 -[[[ (3S) -3-[[ (2S) - 190b 628 627.7815 -2-(aminocarbonyl)-octahydro-1H-indole- -1-yl]carbonyl]-2,3,4,9-tetrahydro-1H- -carbazol-3-yl]-amino]-carbonyl]-2- -methylbutyl]carbamate Phenylmethyl-[(1S,2S)-1-[[[(3R)-3- 191a 590 589.6891

-[[(2R,4R)-2-(aminocarbonyl)-4-hydroxy-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl-[(IS, 2S)-1-[[[(3S)-3- -[[(2S, 4R)2-(aminocarbonyl)-4-hydroxy- 191b 590 589.6891 -1-pyrrolidinyl]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate Phenylmethyl-[(IS,2S)-l-[[[(3R)-3- 291a 578 577.6781 -[[[ (IS, 2R)-1-(aminocarbonyl)-2-hydroxypropyl]amino]carbonyl]-2,3,4,9-tetrahydro-ΙΗ-carbazol-3-yl]amino]carbonyl]-2-methyl 1 -butyl·]carbamate Phenylmethyl-[(IS,2S)-!-[[[(3S)-3- 2 91b 578 577.6781 —[[[ (1S, 2R) — 1 — (aminocarbonyl) -2-hydroxypropyl]-amino]-carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2 -methyl-butyl]-carbamate Phenylmethyl-[(IS, 2S) -1-[[[ (3S) -3-[[ (2- 292 534 533.6255 -amino-2-oxoethyl)-amino]-carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl 1]-2-methyl-butyl-1]-carbamate Phenylmethyl-[ (IS, 2S) — 1—[[[3 — [[[2 — (amino- 192 596 595.6963 -carbonyl)-phenyl]-amino]-carbonyl]- -2,3,4,9-tetrahydro-1H-carbazol-3-yl]- - amino]-carbonyl]-2-methylbutyl]-carbamate (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 193a 616 616,119

-methyl-propyl]-3-[[[4-chloro-3-[[ (4-pyridinyl-amino)-carbonyl]-amino]-phenyl]-acetyl]-amino]-2, 3, 4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S)-N-[(IS)-1-(Aminocarbonyl)-2- -methylpropyl]-3-[[[4-chloro-3-[[ (4-pyridi- 193b 616 616,119 nylamino)carbonyl]amino]phenyl]- -acetyl]-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3R) -N-[ (IS) -1- (Amino - carbon 1) -2- 194a 615 615.13 -methyl-propyl]-3-[[[4-chloro-3-[[ (phenyl- -amino)-carbonyl]-amino]-phenyl]-acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide ( 3S )-N-[ (IS)-1-(Amino-carbon 1)-2- 194'b 615 615.13 -methyl-propyl]-3-[[[4-chloro-3-[[ (phenyl- -amino)-carbonyl]-amino]-phenyl]-acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide ( 3R ) -N-[ (IS) —T — (Amino-carbon 1)-2- 195a 629 629,157 -methyl-propyl]-3-[[[4-chloro-3-[[[ (phenyl- -methyl)-amino]-carbonyl]-amino]-phenyl]-acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Amino-carbonyl)-2- 195b 629 629,157 -methylpropyl]-3-[[[4-chloro-3-[[[ (phenyl- -methyl)-amino]-carbonyl]-amino]-phenyl]-acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide ( 3R )-N-[ (IS )-1-(Amino-carbon 1)-2- 196a 616 616,119

-methyl-propyl]-3-[[[4-chloro-3-[[ (2-pyridinyl-amino)-carbonyl]-amino]~

- phenyl] - acetyl]-amino]-2,3,4, 9-tetrahydro-1H-carbazole-3-carboxamide

100 (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 196b 616 616,119

-methyl-propyl]-3-[[[4-chloro-3-[[ (2-pyridinyl-amino)-carbonyl]-amino]-phenyl]~

-acetyl]-amino]-2,3, 4,9-tetrahydro-1H-carbazole-3-carboxamide

Example 4:

The synthesis is carried out on a 0.2 mmol scale following methods A, F. , G, I, F, H and 0 (3R)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-2,3,4,9- -tetrahydro-8-methoxy-1H-carbazole-3- -carboxamide 197a 400 400.4762 (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-2,3,4,9- -tetrahydro-8-methoxy-1H-carbazole-3- -carboxamide 197b 400 400.4762 3-(Acetylamino)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-6-chloro-2, 3,4,9-tetrahydro-1H-carbazole-3-carboxamide 198 405 404.8955 3-(Acetylamino)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-5-methyl-1H-carbazole-3-carboxamide 199 769 768.9544 3-(Acetylamino)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-8-methyl-1H-carbazole-3-carboxamide 200 769 768.9544 3-(Acetylamino)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-5-chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 201 810 809.7911 3- (Acetylamino) -N-[(IS) -1- (aminocarbonyl) -2-methylpropyl]-7-chloro-2,3,4,9- 202 810 809.7911

101

-tetrahydro-1H-carbazole-3-carboxamide

(3R)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl)-2-methylpropyl]-6-fluoro- -2,3,4,9-tetrahydro-1H-carbazole-3- -carboxamide 203a 388 388.4405 (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-6-fluoro- -2,3,4,9-tetrahydro-1H-carbazole-3- -carboxamide 203b 388 388.4405 (3R)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-2,3,4,9- -tetrahydro-6-methoxy-1H-carbazo1-3- -carboxamide 204a 400 400.4762 (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- 204b 400 400.4762 -carbonyl) -2-methylpropyl]-2,3,4,9- -tetrahydro-6-methoxy-1H-carbazo1-3- -carboxamide (3R)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-2,3,4,9- -tetrahydro-6-methyl-1H-carbazole-3- -carboxamide 205a 384 384.4772 (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- 205b 384 384.4772 -carbonyl) -2-methylpropyl]-2,3,4,9- -tetrahydro-6-methyl-1H-carbazole-3- -carboxamide (3R)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-2,3,4,9- -tetrahydro-1H-carbazole-3-carboxamide 206a 370 370.4504 (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- 206b 370 370.4504

-carbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

102

(3R)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-7,8-dichloro- -2,3,4,9-tetrahydro-1H-carbazole-3- -carboxamide 207a 439 439.3406 (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-7,8-dichloro- -2,3,4,9-tetrahydro-1H-carbazole-3- -carboxamide 207b 439 439.3406 (3R)-3-(Acetylamino)-N-[(IS)-1-(amino- 208a 399 398,504 -carbonyl)-2-methylpropyl]-2,3,4,9- -tetrahydro-5,8-dimethyl-1H-carbazole-3- -carboxamide (3S)-3-(Acetylamino)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9- -tetrahydro-5,8-dimethyl-1H-carbazole-3- -carboxamide 208b 399 398,504 (3R)-3-(Acetylamino)-N-[(IS)-1-(amino- 209a 439 439.3406 -carbonyl) -2-methylpropyl]-6, 8-dichloro- -2,3,4,9-tetrahydro-1H-carbazole-3- -carboxamide (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-6, 8-dichloro- -2,3,4,9-tetrahydro-1H-carbazole-3- 209b 439 439.3406

-carboxamide

Example 25:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, I, F, and O.

103

(3R) — 3—[[ (2S)-2-Amino-4-[(amino-imino- 210a 465 484.6014 -methyl)-amino]-1-oxo-pentyl]-amino]-N- -[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S) — 3-[[ (2S) -2-Amino-5-[ (amino-imino- 210b 485 484.6014 -methyl)-amino]-1-oxo-pentyl]-amino]-N- -[ (1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 211a 497 496,652 -methylpropyl]-2, 3, 4,9-tetrahydro-3- -[[[[2-(1-piperidinyl)-ethyl]-amino]- -acetyl]amino]-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 211b 497 496,652 ethylpropyl]-2,3,4,9-tetrahydro-3-[[[[2- -(1-piperidinyl)-ethyl]-amino]-acetyl]- -amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 212a 529 528.6534 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[[[2-(1H-indol-3-yl)-ethyl]-amino]- -a cetyl]amino]-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 212b 529 528.6534 ethylpropyl]-2,3,4,9-tetrahydro-3-[[[[2-(1H-indol-3-yl)-ethyl]-amino]-acetyl·]- -amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 213a 520 519.5987 -methyl-propyl]-3-[[[ (1, 3-benzodioxo 1-5-

-ylmethyl)-amino]-acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3104

-carboxamide

(3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 213b 520 519.5987 ethylpropyl]-3-[[[ (1,3-benzo-dioxol-5-yl- -methyl)-amino]-acetyl]-amino]-2,3,4,9- -tetrahydro-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 214a 586 565.7141 tylpropyl]-3-[[[(2,2-diphenylethyl)-amino]-acetyl]-amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2- 214b 565 565.7141 -methylpropyl]-3-[[[ (2,2-diphenylethyl)- -amino]-acetyl]-amino]-2,3,4, 9-tetra- hydro-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 215a 533 532,685 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[[[2-[methyl-(phenylmethyl)-amino]-ethyl]- -amino]-acetyl]-amino]-1H-carbazole-3- -carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2- 215b 533 532,685

-methyl-propyl]-2,3,4,9-tetrahydro-3~[[[[2-[methyl-(phenylmethyl)-amino]-ethyl]-amino]-acet i 1]-amino]-1H-carbazole-3-carboxamide

Example 26

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, I, F, G, F, H and .

105

3-[[[Acetyl-[2-(1-piperidinyl)-ethyl]- -amino]-acetyl]-amino]-N-[(IS)-1-(amino- -carbonyl) -2-methoxypropyl]-2,3,4,9- -tetrahydro-1H-carbazole-3-carboxamide 216 539 538.6888 (3R)-3-[[[Acetyl-[2-[methyl-(phenylmethyl)- 217a 575 574.7217 -amino]-ethyl]-amino]-acetyl]-amino]-N- -[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide ( 3S )-3-[[[Acetyl-[2-[methyl-(phenylmethyl]- 217b 575 574.7217 - amino]-ethyl]-amino]-acetyl]-amino]-N- -[ (1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3R)-3-[[[Acetyl-(2,2-diphenylethyl)- 218a 608 607.7509 -amino]-acetyl]-amino]-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S)-3-[[[Acetyl-(2,2-diphenylethyl)- 218b 608 607.7509 -amino]-acetyl]-amino]-N-[(IS)-1-(amino- -carbonyl) -2-methylpropyl]-2,3,4,9- -tetrahydro-1H-carbazole-3-carboxamide (3R)-3-[[[Acetyl-(1,3-benzodioxol-5-yl- 219a 562 561.6355 -methyl) -amino]-acetyl]-amino]-N-[(IS) -1- -(aminocarbonyl) -2-methylpropyl]- -2,3, 4, 9-tetrahydro-1H-carbazole-3- -carboxamide ( 3S) -3-[[[Acetyl-(1,3-benzodioxol-5-yl- 219b 562 561.6355

-methyl)-amino]-acetyl]-amino]-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9 tetrahydro-1H-carbazole-3106

-carboxamide (3R)-3-[[[Acetyl-[2-(1H-indol-3-yl) - 220a 571 570, 6902

- et i 1]-amino]-acetyl]-amino]-N-[(IS)-1-

-(aminocarbonyl)-2-methylpropyl]-

- 2,3,4,9-tetrahydro-1H-carbazole-3~

-carboxamide (3S)-3-[[[Acetyl-[1H-indol-3-yl)-ethyl]- 220b 571 570, 6902

- amino]-acetyl]-amino]-N-[(IS)-1-(amino-

-carbonyl)-2-methylpropyl]-2,3,4,9-

-tetrahydro-1H-carbazole-3-carboxamide

3-[[ (2S)-2-(Acetylamino)-5-[ (amino- 221 527 526, 6382

-imino-methyl)-amino]-1-oxo-pentyl]-

- amino]-N-[(IS)-1-(aminocarbonyl)-2-

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

-carbazole-3-carboxamide

Example 27:

The synthesis is carried out on a 0.2 mmol scale following methods C, F, G, I, F, G and P.

Phenylmethyl-[(IS, 2S)-2-methyl-1-[[[ (3R) - 222a 589 589.7327

- 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)-2-methyl-1-[[[ (3S) - 222b 589 589.7327

- 2, 3, 4, 9-tetrahydro-3-[[[ (IS)-2-methyl-1-

[(methylamino)carbonyl]propyl]amino]carbonyl]-1H-carbazol-3-yl]aminocarbonyl]butyl]carbamate

107

Example 8:

Synthesis of Ά is carried out on a 0.2 mmol scale following methods A, F, G, I, F, J and 0.

(3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 223a 503 503.0203 ethylpropyl]-3-[[(4-chlorophenyl)sulfonyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2- 223b 506 503.0203 -methylpropyl]-3-[[ (4-chlorophenyl)sulfonyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3R)-N-[(1S)-1-(Aminocarbonyl)-2- 224a 407 406.5044 -methylpropyl]-2,3,4,9-tetrahydro-2- -[ (methylsulfonyl)-amino]-1H-carbazole- -3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 224b 407 406.5044 -methylpropyl]-2, 3, 4, 9-tetrahydro-3- -[ (methylsulfonyl)-amino]-1H-carbazole- -3-carboxamide (3R)-N-[(1S)-1-(Aminocarbonyl)-2- 225a 469 468.5762 -methylpropyl]-2,3,4,9-tetrahydro-2- -[(phenylsulfonyl)amino]-1H-carbazole- -3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 225b 469 468.5752 -methylpropyl]-2,3,4,9-tetrahydro-3- -[ (phenylsulfonyl)-amino]-1H-carbazole- -3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 226a 463 482,602

-methylpropyl]-2,3,4,9-tetrahydro-3-[[(phenylmethyl)sulfonyl]amino]-1H108

-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[(phenylmethyl]sulfonyl]amino]-1H-carbazole-3-carboxamide

226b 483 482,602

Example 29:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, I, F, L and O.

3-Phenylpropyl[ (3R)-3-[[[ (IS)-1-(amino- 227a 491 490.6006 -carbonyl)-2-methyl-1-propyl]-amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]carbamate 3-Phenylpropyl-[(3S)-3-[[[(IS)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazole- 227b 491 490.6006 -3-yl]-carbamate Phenylmethyl-[(3R)-3-[[[(IS)-1-(amino- -carbonyl)-2-methyl-1-propyl]-amino]-car- bonyl]-2,3,4,9-tetrahydro-1H-carbazole- 228a 463 462,547 -3-yl·]-carbamate Phenylmethyl-[(3S)-3-[[[(IS)-1-(amino- -carbonyl)-2-methyl-propyl]-amino]-carbonyl]-2,3,4,9-tetrahydro-1H-carbazole-3- 228b 463 462,547 -il]-carbamate Phenyl-[(3R)-3-[[[(IS)-1-(aminocarbonyl)- -2-methylpropyl]amino]carbonyl]- -2,3,4,9-tetrahydro-1H-carbazol-3-yl]- 229a 449 448.5202

-carbamate

109

Phenyl-[(3S)-3-[[[(1S)-1-(aminocarbonyl) - 22 9b 449 448.5202

-2-methylpropyl]amino]carbonyl]-

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

Example 30:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, I, F, M and 0.

( 3R )-N-[ (IS)-1-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[ ( 4-

-nitrophenyl)-methyl]-amino]-1H-carbazole- -3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 230b 464 463.5351 ethylpropyl]-2,3,4,9-tetrahydro-3-[[(4-nitrophenyl)methyl]amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 231a 356 356.4672 tylpropyl]-3-(ethylamino)-2,3,4,9- -tetrahydro-1H-carbazol-3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2-me- 231b 356 356.4672 tylpropyl]-3-(ethylamino)-2,3,4,9- -tetrahydro-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 232a 433 432.5648 ethylpropyl]-2,3,4,9-tetrahydro-3-[ (2- -phenylethyl)amino]-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 232b 433 432.5648

tylpropyl]-2,3,4,9-tetrahydro-3-[(2-phenylethyl)amino]-1H-carbazole-3

-carboxamide

110

(3R)-N-[(IS)-1-(Aminocarbonyl)-2- 233a 447 446, 5916

-methylpropyl]-2, 3,4,9-tetrahydro-3-[ (3-

-phenylpropyl)-amino]-1H-carbazole-3-

-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 233b 447 446, 5916

-methylpropyl]-2, 3,4,9-tetrahydro-3-[ (3-

- phenylpropyl) - amino]- 1H-carbazole -3-

-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 233c 565 564.7696

- methylpropyl]-3-(bis(3-phenylpropyl)-

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

-3-carboxamide

(3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 234a 489 488,672 ethylpropyl]-2,3,4,9-tetrahydro-3-[(6- -phenylhexyl)-amino]-1H-carbazole-3- -carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 234b 489 488,672 ethylpropyl]-2,3,4,9-tetrahydro-3-[(6- -phenylhexyl)-amino]-1H-carbazole-3- -carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 235a 370 370,494 ethylpropyl]-2,3,4,9-tetrahydro-3-[(1- -methylethyl)-amino]- 1H-carbazo 1-3- -carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 235b 370 370,494 -methylpropyl]-2, 3, 4, 9-tetrahydro-3-[ (1- -methylethyl)-amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 236a 385 384.5208

-methylpropyl]-2,3,4,9-tetrahydro-3-[(1-methylpropyl)amino]-1H-carbazole-3111

-carboxamide

( 3S )-N-[(IS)-1-(Aminocarbonyl)-2-me- 236b 385 384.5208 ethylpropyl]-2,3,4,9-tetrahydro-3-[ (1- -methylpropyl)-amino]-1H-carbazole-3- -carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 237a 399 398.5476 -methylpropyl]-2,3,4,9-tetrahydro-3-] (3- -methyl-butyl)-amino]- 1H-carbazole-3- -carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 237b 399 398.5476 -methylpropyl]-2,3,4,9-tetrahydro-3-[ (3- -methyl-butyl)-amino]-1H-carbazole-3- -carboxamide (3R)—N—[(IS)-1-(Aminocarbonyl)-2- -methylpropyl]-2, 3, 4,9-tetrahydro-3- -(methylamino)-1H-carbazole-3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2- 238a 342 343.4404 238b 342 342.4404 -methylpropyl]-2,3,4,9-tetrahydro-3- - (methylamino)-1H-carbazole-3-carboxamide (3R)-N-[(1S)-1-(Aminocarbonyl)-2- 238c 356 356.4672 -methylpropyl]-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide ( 3S )-N-[ (IS)-1-(Aminocarbonyl)-2- 238d 356 356.4672 -methylpropyl]-3-(dimethylamino)- -2,3,4,9-tetrahydro-1H-carbazole-3- -carboxamide

Example 31:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, I, F, K and 0.

112

(3R)-N-[(IS)-1-(Aminocarbonyl)-2- 239a 385 385.4653 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[ (methylamino)carbonyl]amino]-1H- -carbazole-3-carboxamide ( 3S )-N-[(1S)-1-(Aminocarbonyl)-2- 239b 385 385.4653 -methylpropyl]-2, 3, 4,9-tetrahydro-3- -[[ (methylamino)carbonyl]amino]-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 240a 448 447.5361 -methylpropyl]-2,3,4,9-tetrahydro-3-[[(phenylamino)carbonyl]amino]-1H-carbazole-3-carboxamide ( 3S )-N-[(IS)-1-(Aminocarbonyl)-2- 240b 448 447.5361 -methylpropyl]-2, 3, 4,9-tetrahydro-3- -[[(phenylamino)carbonyl]amino]-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 241a 462 461.5629 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[[ (phenylmethyl)-amino]-carbonyl]- - amino]-1H-carbazole-3-carboxamide ( 3S )-N-[(IS)-1-(Aminocarbonyl)-2- 241b 462 461.5629 -methylpropyl]-2, 3, 4, 9-tetrahydro-3- -[[[ (phenylmethyl)-amino]-carbonyl]~ - amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 242a 47 6 475.5897

-methylpropyl]-2,3,4,9-tetrahydro-3-[[[(2-phenylethyl)-amino]-carbonyl]-amino]-1H-carbazole-3-carboxamide

113

(3S) -N-[ (IS) -1-(Aminocarbonyl)-2- 242b 476 475.5897 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[[ (2-phenylethyl)-amino]-carbonyl]- - amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2- 243a 454 453.5835 -methylpropyl]-3-[[ (cyclohexylamino) - -carbonyl]-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 243b 454 453.5835 -methylpropyl]-3-[[ (cyclohexylamino) - -carbonyl]-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3R)-N-[(IS)-1-(aminocarbonyl)-2- 244a 414 413.5189 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[[ (1-methylethyl)-amino]carbonyl]~ - amino]-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 244b 414 413.5189 -methylpropyl]-2, 3, 4, 9-tetrahydro-3- -[[[ (1-methylethyl)-amino]-carbonyl]- - amino]-1H-carbazole-3-carboxamide (3R)-N-[(1S)-1-(Aminocarbonyl)-2- 245a 428 427.5457 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[[ (1-methylpropyl)-amino]-carbonyl]-amino]-1H-carbazole-3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2- 245b 428 427.5457

-methyl-propyl]-2,3,4,9-tetrahydro-3-[[[(1-methyl-propyl)-amino]-carbonyl]-amino]-1H-carbazo 1-3-carboxamide

114

(3R)-N-[(1S)-1-(Aminocarbonyl)-2- 246a 476 475.5897 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[[[ (ÍR)-1-phenylethyl]-amino]-carbonyl]- -amino-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 246b 476 475.5897 -methylpropyl]-2, 3,4, 9-tetrahydro-3- -[[[[ (ÍR)-1-phenylethyl]-amino]-carbonyl]- - amino]-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 247a 482 481.9812 ethylpropyl]-3-[[[ (4-chlorophenyl)-amino]- -carbonyl]-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 247b 482 481.9812 ethylpropyl]-3-[[[ (4-chlorophenyl)-amino]- -carbonyl]-amino]-2,3,4,9-tetrahydro-1H- -carbazole-3-carboxamide (3R) -N-[ (IS)— 1 —(Aminocarbonyl)-2-me- 248a 476 475.5897 tylpropyl]-2,3,4,9-tetrahydro-3- -[[[[ (IS)-1-phenylethyl]amino]carbonyl]~ -amino]-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2- 248b 476 475.5897 -methylpropyl]-2,3,4,9-tetrahydro-3- -[[[[ (IS)-1-phenylethyl]-amino]-carbonyl]- -amino]-1H-carbazole-3-carboxamide

example:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, I, F, G, N and O.

115

Ethyl-(3R)-3-[[[(IS)-1-(aminocarbonyl)- 249a 5 6.7 567.0825 -2-methyl-propyl]-amino]-carbonyl]-3-[[(4- -chloro-phenyl)-acetyl]-amino]-1,2,3,4- -tetrahydro-9H-carbazole-9-acetate Ethyl-(3S)-3-[[[(IS)-1-(aminocarbonyl)- 24 9b 567 567.0825 -2-methyl-propyl]-amino]-carbon 1]—3—[[ (4- -chlorophenyl)-acetyl]-amino]-1, 2,3,4- -tetrahydro-9H-carbazole-9-acetate (3R)-N-[(IS)-1-(aminocarbonyl)-2-me- 250a 599 599.1711 tylpropyl]-3-[[ (4-chlorophenyl)-acetyl]- -amino]-2,3,4,9-tetrahydro-9-(3-phenyl- -propyl)-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 250b 599 599.1711 ethylpropyl]-3-[[ (4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-9-(3-phenylpropyl)-1H-carbazole-3-carboxamide (3R) —3—[[[ (IS) -1- (Aminocarbonyl) -2- 251a 539 636.0289 [methyl]-propyl]-amino]-carbonyl]-3-[[(4chlorophenyl)-acetyl]-amino]-1,2,3,4tetrahydro-9H-carbazole-9-acetic acid (3S) — 3—[[[ (IS) -1- (Aminocarbonyl) -2- 251b 539 539.0289 -methyl-propyl]-amino]-carbonyl]-3-[[ (4- -chloro-phenyl) -acetyl]-amino]-1, 2,3,4- -tetrahydro-9H-carbazole-9-acetic acid (3R)—N-[(IS)-1-(Amino-carbonyl)-2-me- 252a 551 551.1271 ethyl-propyl]-3-[[(4-chloro-phenyl)-acetyl]-amino]-2,3,4,9-tetrahydro-9-(3-methyl-butyl)-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Amino-carbonyl)-2-me- 252b 551 551.1271

tyl-proyl]-3-[[ (4-chlorophenyl) -acetyl]-amino]-2,3, 4,9-tetrahydro-9-(3-methyl116

-butyl)-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 253a 572 572.1056 ethylpropyl]-3-[[(4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-(4-pyridinylmethyl)-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-me- 253b 572 572.1058 ethylpropyl]-3-[[ (4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-9-(4-pyridinylmethyl)-1H-carbazole-3-carboxamide (3R)—N—[ (IS)-1-(Aminocarbonyl)-2-me- 254a 572 572.1056 tylproyl]-3-[[(4-chlorophenyl)-acetyl]-amino]-2,3,4,9-tetrahydro-9-(3-pyridinylmethyl)-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-methyl- 254b 572 572.1056 -propyl]-3-[[ (4-chlorophenyl)-acetyl]-amino]-2,3,4,9-tetrahydro-9-(3-pyridinylmethyl)-1H-carbazole-3-carboxamide (3R)-N-[ (IS)-1-(Aminocarbonyl)-2-me- 255a 621 621.1773 ethyl-propyl]-3-[[ (4-chlorophenyl)-acetyl]-amino]-2,3,4,9-tetrahydro-9-(2-naphthalenylmethyl)-1H-carbazole-3-carboxamide (3S) -N-[(IS)-1-(Aminocarbonyl)-2-me- 255b 621 621.1773 ethylpropyl]-3-[[ (4-chlorophenyl)-acet1]-amino]-2,3,4,9-tetrahydro-9-(2-naphthalenylmethyl9-1H-carbazole-3-carboxamide ( 3R )-N-[ (IS)-1-(Aminocarbonyl)-2-me- 256a 537 537.1003

propyl]-3[[(4-chlorophenyl)acetyl]amino]-2,3,49-tetrahydro-9-(2-methylpropyl)-1H-carbazole-3-carboxamide

117

(3S)-N-[(1S)-1-(Aminocarbonyl)-2-me- 256b 537 537.1003 ethylpropyl]-3-[[ (4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-9-(2-methylpropyl)-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 257a 585 585.1443 ethyl-propyl]-3-[[ (4-chlorophenyl)-acetyl]-amino]-2,3, 4, 9-tetrahydro-9-(2-phenylethyl)-1H-carbazole-3-carboxamide (3S) -N-[(1S)-1-(Aminocarbonyl)-2-methyl- 257b 585 585.1443 ethylpropyl]-3-[[(4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-9-(2-phenylethyl)-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 258a 509 509.0467 ethylpropyl]-3-[[ (4-chlorophenyl)-acetyl]-amino]-9-ethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S)-N-[(1S)-1-(Aminocarbonyl)-2- 258b 509 509.0467 -methylpropyl]-3-[[(4-chlorophenyl)acetyl]amino]-9-ethyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)2-methyl- 259a 577 577.1649 -propyl]-3-[[ (4-chlorophenyl) -acetyl]- - amino]-9-(cyclohexylmethyl)-2,3,4,9- -tetrahydro-1H-carbazole-3-carboxamide (3S) -N-[ (IS)-1-(Aminocarbonyl)-2-methyl- 259b 577 577.1649

propyl]-3-[[(4-chlorophenyl)acetyl]amino]-9-(cyclohexylmethyl)-2,3,4,9

-tetrahydro-1H-carbazole-3-carboxamide

118 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-me- 2 60a 607 607.0977 tylpropyl]-3-[[ (4-chlorophenyl)-acetyl]-

-amino]-9-[(2,6-difluorophenyl)methyl]-

-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-3-[[(4-chlorophenyl)acetyl]-

-amino]-9-[(2,6-difluorophenyl)-methyl]-

-2,3,4,9-te trahydro-1H-carbazole-3-

-carboxamide

Example 33:

The synthesis is carried out on a 0.2 mmol scale following methods A, F, G, I, F, Η, N and 0.

(3R)-3-(Acetylamino)-N-[(IS)-1-(amino- 261a 489 488.6284 -carbonyl) -2-methylpropyl]-2,3,4,9- -tetrahydro-9-(3-phenylpropyl)-1H-carbazole-3-carboxamide (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- 261b 489 488.6284 -carbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(3-phenylpropyl)-1H-carbazole-3-carboxamide (3R)-3-(Acetylamino)-N-[(IS)-1-(amino- 262a 441 440.5844 -carbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(3-methylbutyl)-1H-carbazole-3-carboxamide (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- 262b 441 440.5844

-carbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(3-methylbutyl)-1H-carbazole-3-carboxamide

119

(3R)-3-(Acetylamino)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(2-naphthalenylmethyl)-1H-carbazole-3-carboxamide 263a 511 510.6346 (3S)-3-(Acetylamino)-N-[(IS)-1-(amino- 263b 511 510.6346 -carbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(2-naphthalenylmethyl)-1H-carbazole-3-carboxamide 3-(Acetylamino)-N-[(IS)-1-(amino-arm- 264 511 510.6346 bonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(1-naphthalenylmethyl)-1H-carbazole-3-carboxamide 3-(Acetylamino)-N-[(IS)-1-(amino- 265 467 466.6222 bonyl)-2-methylpropyl]-9-(cyclohexyl- -methyl)-2,3,4,9-tetrahydro-1H-carbazole- -3-carboxamide (3R)-3-(Acetylamino)-N-[(IS)-1-(amino- 266a 427 426.5576 -carbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(2-methylpropyl)-1H-carbazole-3-carboxamide (3S)-3-(Acetylamino)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(2-methylpropyl)-1H-carbazole-3-carboxamide 266b 427 426.5576

Example 34:

The synthesis was carried out on a 0.2 mmol scale according to methods D, F, G, I, F, 0 and then by coupling according to Example 6.

120 .........

Phenylmethyl-[(IS, 2S)-1-[[[ (3R)-3-[[[ (IS) - 267a 563 462.7068

-1-(hydroxymethyl)-2-methyl-propyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methyl-butyl]carbamate

Phenylmethyl~[ (IS, 2S)-1-[[[ (3S)-3-[[[ (IS) - 287b 563 562,7068

-1-(hydroxymethyl)-2-methylpropyl]-amino]-carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate

35. Example:

Ethyl 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3carboxylate 268 mmol (1.6 ml) ethyl 4-oxocyclohexanecarboxylate, 25 mmol (1.4 ml) glycol and 10 μιηοΐ pTsOH are boiled in dry toluene under reflux with a water trap for 24 hours. 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 distilled off in a kugelrohr apparatus under high vacuum at 120°C and 0.03 mbar.

Yield: 1.52 g 4-ethyl 1,4-dioxaspiro[4,5]-decane-8-carboxylate

269.

121

85 μΐ diisopropylamine was added dropwise to a solution of 0.6 mmol of 1.6 M butyllithium in heptane (500 μΐ dry tetrahydrofuran) at -20 °C under argon and stirred for 10 min. After cooling to -70 °C, 0.5 mmol (107 mg) of compound 269 was added dropwise in 200 μΐ dry tetrahydrofuran, allowed to warm to 0 °C over 1 h and stirred for a further 30 min. After cooling to -70 °C, 0.7 mmol (106 μΐ) l-bromo-3phenylpropane was added in 300 μΐ dry tetrahydrofuran and the mixture was stirred for 30 min. After cooling to -70 °C, 0.7 mmol (106 μΐ) of l-bromo-3phenylpropane was added to the mixture in 300 μΐ dry tetrahydrofuran and the mixture was stirred for 1 h. After this, it was allowed to warm to room temperature and stirred for 30 min. Saturated ammonium chloride NH ₄ Cl) solution and n-hexane were carefully added to the organic phase, which was stirred for 10 minutes. The organic phase was separated and washed with water. After filtration through a Whatman filter, the mixture was evaporated to dryness. Production: 165 mg of ethyl 8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carboxylate 270. 0.6 mmol (200 mg) of compound 270 was taken up in 25 ml of acetone/0.1 M hydrochloric acid 1:1 and stirred at 50°C with a catalytic amount of pTsOH for 48 hours. The acetone was removed with suction in a rotary evaporator and the precipitated product was filtered off, washed with water and dried. Yield: 156 mg of ethyl 4-oxo-8-(3-phenylpropyl)cyclohexanecarboxylate 271.

122

The indolization is carried out according to Example 1 using phenylhydrazine.

Yield: after evaporation and preparative HPLC: 65 mg of ethyl 2,3,4,9tetrahydro-3-(3-phenyl+propyl)-1H-carbazole-3-carboxylate 268.

ES-MS: 362 (M+H ⁺ )

Analogously, 80 mg of ethyl 6,8-dichloro-2,3,4,9tetrahydro-3-(3-phenylpropyl)-1E-carbazole-3-carboxylate No. 272 were prepared using 2,4-dichlorophenylhydrazine.

ES-MS: 430 (M+H ⁺ )

36. Example:

2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylic acid 273 3.94 mmol (1.31 g) of compound 269 in 50 ml of methanol and 50 ml of 50% sodium hydroxide solution were stirred at 60°C for 4 h. The mixture was acidified with dilute hydrochloric acid and extracted with ether. After drying over sodium sulfate (Na ₂ SO ₄ ) and evaporation, 1.02 g (85%) of 8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]-decane-8-carboxylic acid 274 was obtained as a white solid.

mg of compound 274 was first deprotected with hydrochloric acid and then reacted with phenylhydrazine to perform the indolization, proceeding as described for compounds 270 and 271.

Yield after evaporation and preparative HPLC: 15 mg of compound 273. ES-MS: 334 (M+H ⁺ )

123 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1-carbazole-3-carboxylic acid No. 275 were prepared analogously using 2,4-dichlorophenylhydrazine.

ES-MS: 478 (M+H ⁺ )

37. Example:

2,3,4,9-Tetrahydro-N-[(IS)-1-(hydroxymethyl)-2-methylpropyl]-3(3-phenylpropyl)-1-carbazole-3-carboxamide 276

0.66 mmol (200 mg) of compound 274 was reacted with 1.5 equivalents of valine in a manner analogous to that described in Example 6. 277 mg of white solid N-[(IS)-1-(hydroxymethyl)-2-methylpropyl]-8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]-decane-8-carboxamide 277 were obtained.

Subsequently, 0.3 mmol (117 mg) of compound 277 was first deprotected with hydrochloric acid and then reacted with phenylhydrazine to perform the indolization, as described for compounds 270 and 271. Production: after evaporation and preparative HPLC: 15 276. ES-MS: 418 (M+H ⁺ ) mg 278 6,8-dichloro-2,3,4,9-tetrahydro-N-[(IS)-1-(hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1H-carbazole3-carboxamide was prepared analogously using 2,4-dichlorophenyl hydrazine.

ES-MS: 486 (M+H ⁺ )

124

38. Example:

2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)-15carbazole-3-methanamine 279 ml of a 1 molar solution of lithium aluminum hydride (LiAlH ₄ ) in dry tetrahydrofuran was carefully added to a solution of 18 mmol (6 g) of compound 270 in 250 ml of dry tetrahydrofuran under argon at room temperature. After heating under reflux for 3 hours, careful hydrolysis was carried out with 300 ml of saturated ammonium chloride (NH ₄ C1) solution and 250 ml of ether were added. The aluminum salts were filtered off and washed with ether. After drying the ether phase over sodium sulfate and evaporating the solvent, 3.4 g of 8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]-decane-8-methanol 280 are obtained.

Compound 280 (5.86 mmol, 1.7 g) was dissolved in 60 mL of dry dichloromethane (DCM) and 20 mL of dry dimethylformamide (DMSO). Under nitrogen atmosphere at room temperature, first 44 mmol (6.1 mL) of triethylamine (TEA) was added, then 17.6 mmol (2.8 g) of _SO3 -pyridine complex was carefully added, and the mixture was stirred for one hour. Subsequently, 200 mL of saturated ammonium chloride (NH4Cl) solution was added to the mixture and extraction was carried out with 150 mL of ether. After drying the ethereal phase over sodium sulfate ( _Na2SO4 ) and evaporating the solvent, 1.9 g of 8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]-decane-8-carbaldehyde 281 was obtained as a colorless oil.

Sodium triacetoxyborohydride (0.719 mmol) was added to a mixture of 0.359 mmol (103 mg) of compound 281 and 0.359 mmol (37 mL) of pyridinemethanamine 2125 in 2.5 mL of 1,2-dichloroethane. The reaction mixture was stirred under nitrogen at room temperature for 3 h. Saturated sodium bicarbonate (NaHCO ₃ ) was added and the mixture was extracted with ether. The dried and concentrated ethereal extract gave 101 mg (76%) of N-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]-dec-8-yl]-2-pyridinemethanamine 282 as a white solid.

Subsequently, 101 mg of compound 282 was first deprotected with hydrochloric acid and then reacted with phenylhydrazine to perform the indolization, as described for compounds 270 and 271. Yield after evaporation and preparative HPLC: 71 mg of compound 279. ES-MS: 410 (M+H ⁺ ) mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)-1H-carbazole-3-methanamine 283 was prepared analogously using 2,4-dichlorophenylhydrazine. ES-MS: 478 (M+H ⁺ )

39. Example:

(2 S)-3-Methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1Hcarbazol-3-yl]methyl]amino]-1-butanol 284

0.368 mmol (106 mg) of compound 281 and 0.368 mmol (38 mg) of valine were dissolved in 1.5 ml of dry methanol and stirred at room temperature for 30 min. After cooling to 0°C, 0.557 mmol (21 mg) of sodium borohydride (NaBH ₄ ) was added and stirred at room temperature for 1 h. Then 0.437 mmol

126 (25 μΐ) acetic acid was added and stirring was continued at pH=6 for another 2 h. Saturated sodium bicarbonate (NaHCO ₃ ) solution was then added and the mixture was extracted with ether. After drying the organic phase over sodium sulfate (Na ₂ SO ₄ ) and evaporation, 106 mg (77%) of compounds 270 and 271 were obtained as colorless oils.

Deprotection and indolization are then performed as described for compounds 270 and 271.

Yield: after evaporation and preparative HPLC: 18 mg of compound 284 as a white solid.

ES-MS: 405 (M+H ⁺ ) mg of (25)-2-[[[6,8-dichloro-2,3,4,9-tetrahydro-3(3-phenylpropyl)-1H-carbazol-3-yl]methyl]amino]-3-methyl-1-butanol No. 286 was prepared analogously using 2,4-dichlorophenylhydrazine.

ES-MS: 473 (M+H ⁺ )

40. Example:

2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-O-(4-pyridinylmethyl)-1Hcarbazole-3-methanol 287

0.689 mmol. sodium hydride (NaH, 55% suspension in mineral oil) was added to a solution of 0.344 mmol (100 mg) of compound 280 in 10 mL of dry dimethylformamide (DMF) at 0°C under nitrogen (N ₂ ). The mixture was allowed to warm to room temperature and stirred for 30 min. 1.377 mmol. 4-(chloromethyl)pyridine was then added and the

127 mixture was stirred at 95-100°C overnight. After cooling to room temperature, hydrolysis with 2 ml of water, extraction with ether was carried out. After drying and evaporation of the solvent, 115 mg of compound 288 was obtained as a yellow oil.

Deprotection and indolization are then performed as described above for compounds 270 and 271.

Yield: after evaporation and preparative HPLC: 14 mg of compound 287 as a white solid.

ES-MS: 411 (M+H ⁺ )

41. Example:

Ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1,H-carbazol-3yl]-2-propenoate 289

Compound 281 (0.347 mmol) in 0.5 ml of tetrahydrofuran (THE) was added dropwise to a solution of ethyl (triphenylphosphoranylidene) acetate (0.378 mmol) in 1 ml of absolute tetrahydrofuran under ice-cooling. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for another 2 days. It was then hydrolyzed with water and extracted with ether. The mixture was dried over sodium sulfate (Na ₂ SO ₄ ) using phosphane oxide as a drying agent, filtered, and the solvent was removed.

Yield: 80% ethyl 3-[8-(3-phenylpropyl)-1, 4-dioxaspiro[4,5]dec-8-yl]-2-propenoate 290.

128

Deprotection and indolization were then performed as described above for compounds 270 and 271.

Yield: after evaporation and preparative HPLC: 9 mg of compound 289 as a white solid.

ES-MS: 388 (M+H ⁺ )

In addition to the above, compounds 293-300, 302 and 304-306 belonging to the group of compounds of general formula (I) were prepared in 0.2 mmol scale by methods A, F, G, F, G and 0, compound 301 by methods B, F, G, F, G and O, and compound 303 by methods A, F, G, F, G, F, L and 0.

129

Compound name Number Found Mcalculated Phenylmethyl [(1S,2S)-1- [[[(3R)-3- [ [ [ [ (IS)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6,8-difluoro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate 293 612 611.6861 Phenylmethyl [ (IS,23)-1- [[[ (3R)-3- [ [ [ (1S,2S)-1-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-8-methoxy2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate 294 620 619.7585 Phenylmethyl [(1S,2S)-1- [[[(3R)-3-[[[(IS,2S)-1-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate 295 659 658.6229 Phenylmethyl [(1S,2S)-1- 296 659 658.6229

[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-3-methylbutyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

130 Phenylmethyl [(1S,2S)-1- 297 699 698.6875

[[[(3R)-3- [ [ [(IS)-1-(aminocarbonyl)-2-cyclohexylethyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 298 659 658.6229

[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2,2-dimethylpropyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 299 707 706.6669

[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-3-phenylpropyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl[(IS,2S)-1-[[[(3R)- 300 685 684,6607

3-[[[(IS)-1-(aminocarbonyl) 2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-cyclohexylmethyl]carbamate

131 Phenylmethyl [(1S,2S)-1- 301

[[[(3R)-3-[[[(1S,2S)-1(carboxy)-2-methylbutyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl] carbamate

Phenylmethyl [(IS)-1-[[[(3R)-3- 302 [[[(IS,2S)-1-(aminocarbonyl)2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-(4-hydroxyphenyl)ethyl]carbamate

Phenylmethyl [(IS)-1-[[[(3R)-3- 303

[[[(IS, 2S)-1-(aminocarbonyl)2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-3-(4-hydroxyphenyl)propyl]carbamate

Phenylmethyl [(IS)-1-[[[(3R)-3- 304 [[[(IS,23)-1-(aminocarbonyl) 2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-3-phenylpropyl]carbamate

Phenylmethyl [ (IS)-1-[ [ [ ( 3R)-3- 305

[[[(13,23)-1-(aminocarbonyl) 2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-3-methylbutyl]carbamate

660 659,607

709 708.6391

723 722.6659

707 706.6669

659 658.6229

132 Phenylmethyl [(IS)-1-[[[(3R)-3- 306 659 658.6229

[[[(IS)-1-(aminocarbonyl)-3methylbutyl]-amino]-carbonyl]6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]carbonyl]-3-methylbutyl]carbamate

III Proof of the GnRH antagonistic effect of the compounds of general formula (I) according to the invention

Materials:

Buserelin (Welding, Frankfurt/Main, Germany) was labeled with J ¹²⁵ using the chloramine T method and J ¹²⁵ Na (4000 Ci/mmol; AmershamBuchler, Brunswick, Germany). The labeled material was purified by reverse-phase HPLC on a Sferizorb ODS II column (250 x 4 mm, particle size: 3 μιη) eluting with 50% acetonitrile/0.15% trifluoroacetic acid,

at a flow rate of 0.5 ml/min. The specific activity is 2000 Ci/mmol.

All other chemicals were obtained from commercial sources, in the highest possible purity.

Cell culture:

Alpha T3-1 cells (Bilezikjian et al., Mol. Endocrinol 5 (1991), 347-355) were cultured in DMEM medium (Gibco-BRL,

Eggenstein-Lepoldshafen, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml), glutamine (0.01 mol/l) and 10% fetal calf serum (FCS; PAA Laboratories, Coelbe,

Germany) on plastic tissue culture plates (Nunc,

133

245 x 245 x 20 mm). CHO-3 cells (Schmid et al., J. Biol.

Chem. 275 (2000), 9193-9200) were cultured under identical conditions, with the difference that Ham's F12 medium (GibcoBRL) was used.

A cell culture plate with confluent cultures was washed twice with 50 ml of phosphate-buffered saline (PBS). The cells were collected by scraping into 5 ml of phosphate-buffered saline (PBS) with a rubber scraper and sedimented by centrifugation at 800 rpm in a laboratory centrifuge (Heraeus). The cell pellet was resuspended in 5 ml of 0.25 mol/l sucrose/0.01 mol/l triethanolamine, pH 7.4. The cells were then lysed in three freeze-thaw cycles in a dry ice/ethanol bath and thawed at room temperature. The lysate was centrifuged at 900 rpm for 10 min and the sediment discarded. The supernatant was centrifuged at 18,000 rpm in a Sorvall SS34 rotor for 30 min. The pellet (cell membranes) was suspended in 5 ml assay buffer (0.25 mol/l sucrose, 0.01 mol/l triethanolamine, pH= 7.5, 1 mg/ml ovalbumin) in a Potter jar and 200 μΐ aliquots were stored at -20°C. Protein was determined by the method of Bradford (Anal. Biochem. 72 (1976), 248-254). Receptor assay:

To obtain competition curves, binding assays were performed in triplicate. A test sample contained 60 μΐ cell membrane suspension (10 μρ protein for CCT3-1134 cells or 40 μρ protein for CHO3 cells), 20 μΐ J ¹²⁵ labeled Buserelin (100,000 ipm/sample for competition curves and 1500 to 200,000 ipm for saturation experiments) and 20 μΐ test buffer or test compound solution. Test compounds were dissolved in distilled water or 50% ethanol. Serial dilutions (5 x 10 ⁶ mol/1 —> 5 x 10~ ¹² mol/1) were prepared in test buffer. Non-specific binding was determined in the presence of an excess of unlabeled Buserelin (10“ ⁶ mol/l). The test samples were incubated at room temperature for 30 minutes. Bound and free ligands were separated by filtration (Whatman GF/C filter 2.5 cm diameter) using an Amicon lOx collector and washed twice with 5 ml of 0.02 mol/l Tris/HCl, pH= 7.4. The filtrates were wetted with 0.3% polyethyleneimine (Serva, Heidelberg, Germany) for 30 minutes to reduce non-specific binding. The radioactivity retained by the filters was determined using a 5-channel gamma counter (Wallac-LKB 1470 Wizard).

The IC ₅₀ values determined for the preferred compounds defined above are shown in the table below.

135

Compound name

N-[[(3R)-2,3,4,9Tetrahydro-3-[(1-oxo-2,3diphenylpropyl)amino]-1Hcarbazol-3-yl]carbonyl]-Lvalyl-L-aspartamide (33)-N-[(IS)-1-(Aminocarbonyl) -2-methylpropyl]2,3,4,9-tetrahydro-3-[(1Hindol-3-ylacetyl)amino]1H-carbazole-3-carboxamide (3S)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]2,3,4,9-tetrahydro-3-[(2naphthalenylacetyl)amino]1H-carbazole-3-carboxamide N-[[(3R)-2,3,4,9Tetrahydro-3- [ [ (2S, 3S)-3methyl-l-oxo-2-[(l-oxo-3phenyl-propyl) amino]pentyl]amino]-1H-carbazol3-yl]carbonyl]-L-valyl-L-aspartamide

Phenylmethyl [(1S,2S)-1[[[(3R)-3-[[[(1S,2S)-1-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Example hGnRH Ca2 ⁺ number receptor liberate _IC50 [M] human IC ₅₀ [M] 18 0.0000009 0.000005 164b 0.000006 0.0000065 161b 0.0000037 0.0000036 22 0.000002 0.000001 64 0.0000017 0.0000015

Phenylmethyl [(1S,2S)-1[[[(3R)-3-[ [[ (IS)-1- [ [[4(aminocarbonyl)phenyl]amino]carbonyl]-2-methylpropyl]-amino]carbonyl]2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-2methyl-1-[[[(3R)-2,3,4,9tetrahydro-3-[[[(IS)-2methyl-1-[(methylamino)carbonyl]propyl]amino]carbonyl]-1H-carbazol-3yl]amino]carbonyl]butyl]carbamate

Phenylmethyl [(1S,2S)-1[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3yl]amino]carbonyl]-2methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1[[[(3R)-3-[[(2S)-2-(aminocarbonyl)-1-pyrrolidinyl]-carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3yl]amino]carbonyl]-2methylbutyl]carbamate Phenylmethyl [(1S,2S)-1[[[(3R)-3-[[(2S)-2-(aminocarbonyl)octahydro-1Hindol-1-yl]carbonyl]2,3,4,9-tetrahydro-1H-

136 45 0.0000003 0.000001 222a 0.0000025 0.000003 58 0.0000003 0.00000037 181a 0.0000007 0.000003 190a 0.000002 0.0000005

137

[carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate 2,3,4,9-Tetrahydro-3-(3phenylpropyl)-N-(2pyridinylmethyl)-1Hcarbazole-3-methanamine 279 0.000002 0.000003 (23)-3-Methyl-2-[[[2,3,4,9- 284 0.000007 0.000007 tetrahydro-3-(3-phenyl- propyl-1H-carbazol-3-yl]- methyl]amino]-1-butanol N—[(IS)-1-(Aminocarbonyl)- 175 0.000008 0.0000018 2-methylpropyl]-2,3,4,9tetrahydro-3-[[(4-methoxyphenyl)acetyl]-amino-1Hcarbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]3-[[(3-bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro1H-carbazole-3-carboxamide 96 0.000004 0.000003 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl]3-[[(4-fluorophenyl)acetyl]amino]-2,3,4,9-tetrahydro1H-carbazole-3-carboxamide 91 0.0000024 0.000002 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyl] 3-[[ (4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro1H-carbazole-3-carboxamide 167a 0.000001 0.0000026 (3R)-N-[(IS)-1-(Amino- 234a 0.000009 0.000001

carbonyl)-2-methylpropyl] 2,3,4,9-tetrahydro-3-[(6phenylhexyl)amino]-1Hcarbazole-3-carboxamide

138 Phenylmethyl [(1S,2S)-1- 150a

[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9tetrahydro-8-methyl-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 148a

[[[(3R)-3-[[[(13)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6-chloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 147a

[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9tetrahydro-8-methoxy-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(13,23)-1- 184a

[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6,8dichloro-2,3,4,9-tetrahydro1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 267a

[[[(3R)— 3— [ [ [(13)-1(hydroxymethyl)-2-methylpropyl]-amino]-carbonyl]0.00000011 0.00000028

0.00000008 0.00000014

0.000000076 0.00000025

0.000000015 0.000000045

0.0000004 0.0000005

139

2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]carbonyl]-2-methyl-butyl]carbamate (2S)-1-[[(3R)-3-[ [ (4-Chloro- 189a phenyl)-acetyl]-amino]2,3,4,9-tetrahydro-8methoxy-1H-carbazol-3-yl]carbonyl]-2-pyrrolidine carboxamide

6, 8-Dichloro-2,3,4,9-tetra- 283 hydro-3-(3-phenylpropyl)-N(2-pyridinylmethyl)-1/7carbazole-3-methanamine

0.0000007 0.0000005

0.000001 0.000003

Compounds 293 - 306 were tested using the following methods:

Receptor binding assay

Materials:

AJ ¹²⁵ -Triptorelin [ J ¹²⁵ - (D) -Trp6-GnRH] was purchased from Biotrend (Cologne, Germany). The specific activity was 2.13 Ci/mmol in all cases. All other chemicals were purchased commercially in the highest possible purity.

Cell culture:

Transfected LTK' cells (ATCC No. CCL-1.3) were cultured in DMEM medium (Invitrogen Life Technologies, Germany) supplemented with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml), glutamine (0.01 mol/l) and 10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany)

140 on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 mm).

Examination:

Cell culture plates at 80% confluence were washed twice with 50 ml phosphate-buffered saline (PBS) and then separated with 0.01 M EDTA solution. Cells were pelleted by centrifugation at 200g for 5 min in a laboratory centrifuge (Kendro, Germany). The cell pellet was resuspended in 3 ml of binding medium (DMEM; 10 mM Hepes; 0.5% BSA; 0.1% NaN ₃ ; 1 g/l Bacitracin (fresh stock solution at 100-fold dilution); 0.1 g/l SBTI (fresh stock solution at 1000-fold dilution) and the cell number was determined by Trypan blue staining in a Neubauer counting chamber. The cell suspension was adjusted to a concentration of 5 x 10 ⁵ cells/0.05 ml with binding medium.

Binding assays were performed in duplicate to obtain competition curves. The test substances were used as 10 mM DMSO solutions. The solutions were diluted fourfold with binding medium. 25 μΐ of the diluted substance was mixed with 25 μΐ of tracer solution (J ¹²⁵ triptorelin). In a final reaction volume of 100 μΐ, the tracer concentration was adjusted to approximately 50,000 cpm (measured with a Cobra II, γ counter, PE Liefe Science, Germany).

200 μΐ of silicone/liquid paraffin mixture (84%:16%) was placed in 650 μΐ conical tubes (Rőt, Germany). 50 μΐ cells

141 suspension, followed by 50 μΐ of the test substance/trace mixture were pipetted into the tubes. The tubes were sealed and incubated in an incubator with vertical rotation at 37 °C for 60 minutes. After incubation, they were centrifuged in a centrifuge (Kendro, Germany) at 900 rpm and then flash-frozen in liquid nitrogen. The tip of the cell pellet was cut off and placed in prepared counting vials (Rőt, Germany). The remainder of the conical tube was also placed in a counting vial together with the remainder of the supernatant. The measurement was performed in a γ counter at a rate of 1 min/sample.

Samples were evaluated after calculating specific binding, compared to untreated cells, after subtracting non-specific binding (excess unlabeled ligand, 1 pm), using GrafPad Prism (GrafPad Software Inc., USA).

Functional reporter gene assay

Materials:

All chemicals were obtained commercially in the highest possible purity.

Cell culture:

Stably transfected LTK cells (ATCC number: CCL-1.3) carrying the GnRH receptor and heterologous expression of cAMP-responsive elements and a CMV minimal promoter-driven luciferase reporter gene were used to perform functional assays.

142

Cells were cultured in DMEM medium (Invitrogen Life Technologies, Germany) supplemented with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml), glutamine (0.01 mol/l) and 10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany) on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 mm).

Examination:

Plates containing 80% confluent cell cultures were washed twice with 50 ml of phosphate-buffered saline (PBS) and then detached with trypsin EDTA solution (Invitrogen Life Technologies, Germany). The cells were pelleted by centrifugation at 200g for 5 min in a laboratory centrifuge (Kendro, Germany). The cell pellet was resuspended in 3 ml of assay medium (Invitrogen Life Technologies, Germany) supplemented with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml), glutamine (0.01 mol/l), and 10% fetal calf serum (FCS, Invitrogen Life Technologies,

Germany) and the cell number was determined by Trypan blue staining in a Neubauer counting chamber. The concentration of the cell suspension was adjusted to 1xlO ⁴ cells/100 μΐ with measurement medium. The cells were plated in white 96-well microtiter plates (Costar, Germany) and incubated in an incubator for 18 hours.

To perform the test, the test substances were diluted into 10 mM DMSO solutions, diluted six-fold in assay medium.

143 μΐ test material was added to 100 μΐ cells and incubated at 37°C in a 5% CO ₂ atmosphere for 60 minutes.

After this, Triptorelin (D-Trp6-GnRH)/Rolipram solution (6 nM/6 μΜ) was added and then incubated again at 37°C, in a 5% CO ₂ atmosphere, for 6 hours.

After incubation, 50 μΐ of lysis/detection buffer (LucLite, PE Life Science) was added and measured in a Lumistar luminometer (BMG Labtechnologies GmbH, Germany).

Samples were evaluated after calculating the inhibition, compared to untreated stimulated cells, after subtracting the unstimulated control, using a GrafPad Prism (GrafPad Software Inc., USA) or OMMM (Accelrys, Germany) software.

The EC ₅₀ values for compounds 293-306 can be seen in the table below.

Compound name

144

Example Functional Human binding number, human EC ₅₀ triptorelin

[M] _EC50 [M]

Phenylmethyl [(1S,2S)-1- 293

[[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2methylpropyl]amino]carbonyl]-6,8-difluoro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 294

[[[(3R)-3-[[[(1S,2S)-1-(aminocarbonyl)-2methylbutyl]-amino]carbonyl]-8-methoxy2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

0.000000762 0.000000332

0.000000089 0.000000036

Phenylmethyl [(1S,2S)-1- 295

[ [ [ (3R)-3-[[[(1S,2S) -1(aminocarbonyl)-2methylbutyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 296

[[[(3R)-3-[[[(1S)-1(aminocarbonyl)-3methylbutyl]amino]0.000000007

0.000000014

0.000000018

0.000000022 « * . · ···; • · · · · «

145 carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]-amino]carbonyl]-2-methylbutyl]-carbamate

Phenylmethyl [(1S,2S)-1- 297 0.000000284 0.000000482

[[[(3R)-3-[[[(IS)-1(aminocarbonyl)-2cyclohexylethyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 298 0.000000288

[[[(3R)-3-[[[(IS)-1(aminocarbonyl)-2,2dimethylpropyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 299 0.000001497 0.000001307

[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-3-phenylpropyl]-amino]carbonyl] 6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]carbonyl]-2-methylbutyl]carbamate

Phenylmethyl [(1S,2S)-1- 300 0.000000017 0.000000023

[[[(3R)-3-[[[(IS)-1(aminocarbonyl)-2methylbutyl]amino]carbonyl]-6,8-dichloro• * .··. ···; ··· · · ·

146 2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-cyclohexylmethyl]carbamate

Phenylmethyl [(1S,2S)-1- 301 0.000000176 0.000000538

[[[(3R)-3-[[[(1S,2S)-1(carboxy)-2-methylbutyl]-amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]-amino]carbonyl]-2-methylbutyl]-carbamate

Phenylmethyl [(1S)-1- 302 0.000000324 0.000000475

[[[(3R)-3-[[[(1S,2S) -1(aminocarbonyl)-2methylbutyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-(4-hydroxyphenyl)ethyl]carbamate

Phenylmethyl [(1S)-1- 303 0.000000021

[[[(3R)-3-[[[(1S,2S)-1(aminocarbonyl)-2-methylbutyl]amino]carbonyl]6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-3-(4-hydroxyphenyl)propyl]carbamate

Phenylmethyl [(1S)-1- 304 0.000000018 0.000000038

[[[(3R)-3-[[[(1S,2S)-1-(aminocarbonyl)-2methylbutyl]amino]carbonyl]-6,8-dichloro147

2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-3-phenylpropyl]carbamate

Phenylmethyl [(1S)-1- 305 0.000000056

[[[(3R)-3-[[[(1S,2S)-1(aminocarbonyl)-2methylbutyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-3-methylbutyl]carbamate

Phenylmethyl [(1S)-1- 306 0.000000077

[[[(3R)-3-[[[(IS)-1(aminocarbonyl)-3methylbutyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-3-methylbutyl]carbamate

Claims (32)

148 PATENT CLAIMS Compounds of general formula (I) wherein the group of general formula R ¹ represents a hydrogen atom, a C 2-6 alkenyl or C 1-6 alkyl group and optionally substituted with an aryl, hetaryl group or a group of general formula -COOR ¹¹ , wherein the aryl or hetaryl group may be substituted with up to three substituents, which may be independently selected from the following: -N0 ₂ , -CH 3 , -CF 3 , -OCH ₃ , -OCF 3 group and halogen atom, and the group of general formula R ¹¹ represents a hydrogen atom, a C 1-12 alkyl, a C 1-12 aralkyl, aryl, hetaryl group or -COCH ₃ group, and optionally substituted with a substituent selected from the following: -CONH ₂ , -COCH ₃ , -COOCH 3 , -SO ₂ CH ₃ and aryl group; 149 R ² , R ³ , R ⁴ and R ⁵ are independently hydrogen, halogen, -COOH, -CONH ₂ , -CF ₃ , -OCF 3 , -NO ₂ , -CN, C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkoxy, C 1-12 aralkyl, aryl or hetaryl; the group of general formula R ⁶ means a group of general formula -CONR ⁸ R ⁹ , -COOR ⁸ , -CH2NR ⁸ R ⁹ , -CH2R ⁸ , -CH2OR ⁸ or a group of general formula 1-12 alkenyl group, which may be optionally substituted by groups of general formula R ⁸ and R ⁹ , where the groups of general formula R ⁸ and R ⁹ independently mean a hydrogen atom, a C 1-12 alkyl, a C 1-12 aralkyl, a C 1-12 hetaralkyl, aryl or hetaryl group, each of which may be substituted by one or more substituents selected from the following: -OH, -NH ₂ group, -CONHR ¹⁰ , -COOR ¹⁰ group, -NH-C(=NH)-NH ₂ group and halogen atom, where the group of general formula R ¹⁰ means a hydrogen atom, C1-12 alkyl, C1-12 aralkyl, aryl or hetaryl and optionally substituted with -CON(R ¹¹ ) ₂ , or where R and R together can form a cyclic structure which is either »·*» 150 carbon atoms, or a combination of carbon atoms and heteroatoms; the group of general formula R ⁷ represents a hydrogen atom, C 1-12 alkyl, C 1-12 alkenyl, C 1-12 aralkyl, aryl or hetaryl group, -NR ¹² R ¹³ , -NHCOR ¹⁴ , -NHCONHR ¹⁴ , -NHCOOR ¹⁴ or -NHSO2R ¹⁴ and optionally substituted with one or more substituents selected from the following group: -OH, -NH2, -CONH ₂ , -COOH group and halogen atom, the groups of general formula R and R independently represent a hydrogen atom, a C2-6 alkenyl or C1-12 alkyl group and optionally substituted with one or more aryl or hetaryl groups, which in turn may be substituted with up to three substituents, which may be independently selected from the following: -NO ₂ , -CH ₃ , -CF ₃ , -OCH 3 , -OCF ₃ group and halogen atom, and the group of general formula R ¹⁴ represents a hydrogen atom, a C1-12 alkyl, C1-12 alkyl alkenyl, aralkyl of 1-12 carbon atoms, aryl or hetaryl group, which may optionally be substituted with one or more substituents selected from the following: -NO2, -CH3, -OR ¹¹ , -CF3, -OCF ₃ , -OH group, -N(R ¹¹ )2, -OCOR ¹¹ group, -COOH, -CONH2 group, -NHCONHR ¹¹ , -NHCOOR ¹¹ group and halogen atom; and R ^a , R ^b , R ^c , R ^d , R ^e and R ^f are independently hydrogen, halogen, -COOH, -CONH ₂ , -CF ₃ , -OCF 3 , -NO ₂ , -CN, C 1-6 alkyl, C 1-6 alkoxy, aryl or hetaryl; with the proviso that the following compounds are excluded from the group of compounds of general formula (I): 3-amino1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl 3-acetamido1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate and 3-tert-butoxycarbonylamino-1,2,3,4 tetrahydrocarbazole-3-carboxylic acid. 2. Compounds according to claim 1, wherein R ^a , R ^b , R ^c , R ^d , R ^e and R ^f are hydrogen. 3. Compounds according to claims 1 or 2, wherein the group R ¹ represents a hydrogen atom. 4. Compounds according to any one of claims 1-3, wherein R ² , R ³ , R ⁴ and/or R ⁵ are other than hydrogen. 152 5. Compounds according to claim 4, wherein R ² , R ³ , R ⁴ and R ⁵ are independently -CH ₃ , -Cl or -OCH ₃ . 6. The following compounds according to claim 5: phenylmethyl [ (IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2-methylpropyl]-amino]-carbonyl]-2,3,4,9-tetrahydro-8-methyl-1H-carbazol-3-yl]-amino]-carbonyl]-2-methyl-butyl]-carbamate, phenylmethyl-[(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2-methyl-propyl]-amino]-carbonyl]-6-chloro-2,3,4,9tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate, and phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2-methyl-propyl]-amino]-carbonyl]-2-methylbutyl]-carbamate. -2-Methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate. 7. Compounds according to any one of claims 1-5, wherein the R group is a hydrophobic group comprising alkyl, aryl and/or hetaryl structures and which carries a hydrogen bond donor-acceptor system at a distance of two to four single bonds from the carbon atom substituted with the R ⁶ and R ⁷ groups. 8. Compounds according to claim 7, wherein the R ⁶ group is a phenylalanylamide residue, an isoleucylamide residue, a valyl-4-aminobenzamide residue, a valyl-N-methylamide residue, a methyloxymethyl-4-pyridyl group, a carboxyl group, an ethylpropenoate residue, a carbonylvalylamide residue, a carbonylthreonylamide residue. 153 residue, a cyclic carboxamide residue, a 4-carboxamidophenylcarboxamide residue, a methylaminomethyl-2-pyridyl group, a carbonylvaline residue or a methylvaline residue. 9. The compounds according to claim 8 are the following: phenylmethyl [(IS, 2S)-1-[[[(3R)-3-[[[(IS)-2-amino-2-oxo-l(phenylmethyl)ethyl]amino]carbonyl]-2,3,4,9-tetrahydrolH-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl [ (IS, 2S)-1-[[[(3R)-3-[[[(IS, 2S)-1-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-2,3,4,9tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(IS, 2S)-1-[[[(3R)-3-[[[(IS)-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 [(IS, 2S)-2-methyl-1-[[[(3R)-2,3,4,9-tetrahydro3-[[[(IS)-2-methyl-1-[(methylamino)carbonyl]propyl]amino]carbonyl]-1H-carbazol-3-yl]amino]carbonyl]butyl]carbamate, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-0-(4-pyridinylmethyl)-1H-carbazole-3-methanol, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3carboxylic acid, ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazol-3-yl]-2-propenoate 154 Phenylmethyl [(IS,2S)-1-[[ [(3R)-3-[[[(IS)-1-(aminocarbonyl)-2-methyl-propyl]-amino]-carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]carbamate, Phenylmethyl [(IS, 2S)-1-[[[(3R) -3-[[[(IS,2R)-1-(aminocarbonyl)-2-hydroxypropyl]amino]carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]-carbamate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[(2S)-2-(aminocarbonyl) -1-pyrrolidinyl]carbonyl]-2,3,4,9-tetrahydro-1Hcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl [(IS,2S)-1-[[[(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 ), phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[4-(amino-carbonyl) phenyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]carbonyl]-2-methylbutyl]carbamate, 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)-1H-carbazole-3-methanamine, phenylmethyl [(IS,2S)-1-[[[(3S)-3-[[[(IS)-1-(hydroxymethyl)-2-methylpropyl]-amino]-carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate, 2,3,4,9-tetrahydro-77-[(IS)-1-(hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)-1H-carbazole-3-carboxamide and 155 (2S)-3-methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenylpropyl) 1H-carbazol-3-yl]methyl]amino]-1-butanol. 10. Compounds according to claims 1-5, 7 or 8, wherein the group R ⁷ represents a hydrophobic group, including alkyl, aryl and/or hetaryl structures. 11. Compounds according to claim 10, wherein the R ⁷ group represents a 2,3-biphenylpropionylamino group, an indanoylamino group, an indolylacetylamino group, a 2-naphthylacetylamino group, a 3-propionylamino group, a phenylmethylcarboxamide residue substituted on the aromatic system, a phenylhexylamine residue or a phenylpropyl group. 12. The compounds of claim 11, which are: 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-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-3-[[(2,3dihydro-1H-inden-1-yl)carbonyl]amino]-2,3,4,9tetrahydro-1H-carbazole-3-carboxamide, (3S)-N-[ (IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9tetrahydro-3-[(1H-indol-3-ylacetyl)amino]-1H-carbazole-3carboxamide, (3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9tetrahydro-3-[(2-naphthalenylacetyl)amino]-1H-carbazole-3carboxamide, 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, • ·* · *· ·· Μ ·· 156 (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9tetrahydro-3-[[(4-methylphenyl)acetyl]amino]-1H-carbazole-3-carboxamide, N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9tetrahydro-3-[[(4-methoxyphenyl)acetyl]amino]-1Hcarbazole-3-carboxamide, (3R)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-3-[[ (3bromophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide, (3R)-N-[ (IS)-1-(aminocarbonyl)-2-methylpropyl]-3-[[ (4fluorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1Hcarbazole-3-carboxamide, (3R)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-3-[ (4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide, (3R)-N-[(IS)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9tetrahydro-3-[(6-phenylhexyl)amino]-1H-carbazole-3-carboxamide, 6, 8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylic acid and ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylate. 13. Compounds according to any one of claims 1-5, 7, 8, 10 or 11, wherein the compound has the R configuration on the carbon atom substituted with R ⁶ and R ⁷ groups when R ⁶ and R ⁷ groups together form structural elements of an alpha-amino carboxylic acid. ► ··>···· ♦·<· ·· »· w ·· 157 14. The compounds according to claim 1 are: phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2-methylpropyl]-amino]-carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2methylbutyl]-carbamate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(IS)-1-(hydroxymethyl)-2-methylpropyl]-amino]-carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate, (2S)-1-[[[(3R)-3-[[(4-chlorophenyl)acetyl]amino]-2,3,4,9tetrahydro-8-methoxy-1H-carbazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)-1H-carbazole-3-methanamine. 15. A pharmaceutical composition comprising at least one compound according to claims 1-14. A compound according to any one of claims 1 to 10. 16. A pharmaceutical composition according to claim 15, comprising a unit dose of compound in the range of 1 pg to 100 mg per kg of patient weight. 17. A pharmaceutical composition according to claim 15 or 16, wherein the compound is present in combination with at least one further active pharmaceutical ingredient and/or a pharmaceutically acceptable carrier. 18. A process for preparing a compound according to claims 1-14. 19. Compounds according to claims 1-14 for use as a medicament. • · ··· ·· • · · · · · · ··*· ·* ·· a*· ·< 158 20. Use of the compounds according to claims 1-14 for the preparation of medicaments suitable for the treatment of pathological conditions associated with Gprotein coupled receptors. 21. Use of the compounds of claim 1, including but not limited to compounds excluded in claim 1, for the manufacture of a medicament for inhibiting gonadotropin releasing hormone. 22. Use according to claim 20 or 21 for the preparation of a medicament for use in male fertility regulation, hormone therapy, treatment of female reduced fertility or infertility, female contraception and tumor control. 23. Use of the compounds of claim 1, including but not limited to compounds excluded in claim 1, for the manufacture of a medicament for the control of male fertility or for female contraception. 24. The compounds according to claim 1 are the following: phenylmethyl [ (IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2-methyl-propyl]-amino]-carbonyl]-6,8-difluoro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2methyl-butyl]-carbamate, phenylmethyl [ (IS,2S)-1-[ [ [ (3R)-3-[[[(IS,2S)-1-(aminocarbonyl)-2-methyl-butyl]-amino]-carbonyl]-8-methoxy2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2methyl-butyl]-carbamate, phenylmethyl [(1S,2S)-1-[[[(3R)-3-[[[(IS,2S)-1-(aminocarbonyl)-2-methyl-butyl]-carbamate -2-methyl-butyl]-amino]-carbonyl]-6,8-dichloro- * * · · ·') ··**· *' ·< · · * *> 159 2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2methyl-butyl]-carbamate, phenylmethyl [(1S,2S)-1-[[[(3R) — 3 —[[[[(IS) —1— (aminocarbonyl) -3-methyl-butyl]-amino]-carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2methyl-butyl]-carbamate, phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[[(IS)-1-(aminocarbonyl) -2-cyclohexyl-ethyl]-amino]-carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2methyl-butyl]-carbamate, phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-2,2-dimethylpropyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2methylbutyl]carbamate, phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl)-3-phenylpropyl]amino]carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]amino]carbonyl]-2methylbutyl]carbamate, phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(IS)-1-(aminocarbonyl) -2-methyl-butyl]-amino]-carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2cyclohexylmethyl]-carbamate, phenylmethyl [(IS,2S)-1-[[[(3R)-3-[[[(IS,2S)-1-(carboxy)-2methyl-butyl]-amino]-carbonyl]-6,8-dichloro-2,3,4,9tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2-methylbutyl]-carbamate, _w ' V · ♦.* 160 phenylmethyl [(IS)-1-[[[(3R)-3-[[[(IS,2S)-1-(aminocarbonyl)-2-methyl-butyl]-amino]-carbonyl]-6, 8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-2(4-hydroxy-phenyl)-ethyl]-carbamate, phenylmethyl [(IS)-1-[[[(3R)-3-[[[(IS,2S)-1-(aminocarbonyl)-2-methyl-butyl]-amino]-carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-3(4-hydroxy-phenyl)-propyl]-carbamate, phenylmethyl [(IS)-1-[[[(3R)-3-[[[(IS,2S)-1-(aminocarbonyl)-2-methyl-butyl]-amino]-carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-3(4-hydroxy-phenyl)-propyl]-carbamate, -2-methyl-butyl]-amino]-carbonyl]-6, 8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-3phenyl-propyl]-carbamate, phenyl-methyl [(IS)-1-[[[(3R)-3-[[[(IS,2S)-1-(aminocarbonyl)-2-methyl-butyl]-amino]-carbonyl]-6,8-dichloro2,3,4,9-tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-3methyl-butyl]-carbamate, phenyl-methyl [(IS)-1- [ [ [ (3R)-3-[[[[(IS)-1-(aminocarbonyl)3-methyl-butyl]-amino]-carbonyl]-6,8-dichloro-2,3,4,9tetrahydro-1H-carbazol-3-yl]-amino]-carbonyl]-3methyl-butyl]-carbamate -carbamate. 25. A pharmaceutical composition comprising at least one compound according to claim 24. 26. A pharmaceutical composition according to claim 25, comprising 1 μg to 100 mg of compound per unit dose, based on the patient's body weight in kg. 27. A pharmaceutical composition according to claims 25 or 26, which comprises the active ingredient in combination with at least one further active ingredient. 161 in combination with a pharmacological ingredient and/or a pharmaceutically acceptable carrier. 28. A process for preparing the compounds of claim 24. 29. Compounds according to claim 24 for use as a medicament. 30. Use of the compounds of claim 24 for the preparation of a medicament for the treatment of pathological conditions mediated by G protein-coupled receptors. 31. Use of the compounds according to claim 24 for the preparation of a medicament for inhibiting gonadotropin-releasing hormone. 32. Use of the compounds according to claims 30 or 31 for the preparation of a medicament for the regulation of male fertility, for hormone therapy, for the treatment of female reduced fertility or infertility, for female contraception and for tumor control. The authorized person Mária Somlai, patent attorney Member of i.B.G. & K Patent Attorneys Office H-1062 Budapest, Andrássy Street 113. Phone: 461-1000 Fax: 461-1099 JÍUU VT ^/