WO2003051837A2 - Tetrahydrocarbozole derivatives as ligands for g-protein coupled receptors (gpcr) - Google Patents

Abstract

The invention relates to novel tetrahydrocarbozole derivatives acting as ligands for G-protein coupled receptors (GPCR), especially as antagonists of gonadotropin-releasing hormone (GnRH). The invention also relates to a pharmaceutical composition containing said novel tetrahydrocarbozole derivatives, and to a method for producing the same. Furthermore, the invention relates to the administration of tetrahydrocarbozole derivatives for the treatment of pathological conditions mediated by GPCR, especially for the inhibition of GnRH, to mammals, especially humans, requiring such treatment, and to the use of tetrahydrocarbozole derivatives for producing a pharmaceutical agent for treating pathological conditions mediated by GPCR, especially for the inhibition of GnRH.

Description

 TETRAHYDROCARBAZOLE DERIVATIVES AS LIGANDS FOR G-PROTEIN COUPLED RECEPTORS (GPCR)

The present invention relates to new tetrahydrocarbazole derivatives which are ligands of G protein-coupled receptors, and in particular to gonadotropin-releasing hormone antagonists, their preparation, their use and pharmaceutical compositions comprising these tetrahydrocarbazole derivatives. The present invention also relates to a method for the treatment of disease states mediated by G protein-coupled receptors in a mammal, in particular a human.

Technical background

The structural element common to all members of the family of the G-protein coupled receptors (GPCR) is the presence of seven transmembrane alpha-helical segments which are connected to one another by alternating intra- and extracellular loops, the amino terminus being on the extracellular side and the carboxy ter inus is located on the intracellular side. The family of GPCRs can be divided into several subfamilies (mainly families A, B and C) with further sequence homologies within these subfamilies, since GPCRs are primarily involved in signal acquisition and transmission, a large number of physiological functions are influenced by you. GPCR ligands are therefore potentially medications for the therapy and prevention of a large number of disease states suitable. A brief overview of diseases treatable with GPCR ligands is given in S, Wilson et al., Pharmaceutical News 2000, 7 (3) in Table 1.

The majority of the known GPCR ligands are peptide structures. However, peptide receptor ligands often have some serious disadvantages, such as low bioavailability and metabolic instability. Therefore, ligands in the form of small, non-peptide molecules have recently been increasingly sought. So-called “privileged structures” play a special role in the search for new, non-peptide receptor ligands. These “privileged structures” are those molecular structures that provide ligands for a large number of different receptors. The term "privileged structures" was first used by Evans et al. In connection with benzodiazepine-based CCK (cholecyrtokinin) -A antagonists from the natural product asperiicin (BE Evans et al., J. Med Chem. 1988, 31 , 2235) For proteases, for example, it has long been known that certain structural classes can serve as inhibitors for various enzymes, while mechanism-based inhibitors for various proteases have been described in the past, but more and more examples of compounds have recently been found which, due to their three-dimensional structure, fit well into the active binding region of various enzymes (cf. M. Whittaker, C r. Opi. Chem. Biol. 1998, 2, 386; AS Ripka et al., ibid., 441) Such "privileged structures" have already been described in GPCRs. Examples of this are, in addition to the benzodiazepines mentioned above, peptoids, 4-substituted 4-allypiperidines, but also special rigidized ß-turn chemicals (BA Bunin et al., Arm. Rep. Med. Chem. 1999, 34, 267; RN Zuckermann et al., J. Med Chem. 1994, 37, 2678; GCB Harriman, Tetrahedron Lett. 2000, 41, 8853). An overview of this can be found in AA. Patchett et al, Ann. Rep. Med. Chem. 1999, 35, 289. The tetrahydrocarbazole derivatives according to the present invention provide a further class of “privileged structures” for GPCRs.

Although the present invention generally provides ligands for GPCR's, the compounds provided by the present invention are especially as Ligands are suitable for a specific representative of the class of GPCR's, namely the gonadotropin-releasing hormone (GnRH). The GnRH can be classified into subfamily A of the GPCR's (cf. U. Gether et al., Endocrine Reviews 2000, 21 (1), 90).

GnRH is a hormone that is predominantly, but not exclusively, synthesized in mammalian cells by hypothalamic nerve cells, transported to the pituitary gland via the portal vein and released to the gonadotrophic cells in a regulated manner. By interacting with its seven transmembrane domains, GnRH stimulates the production and release of gonadotropic hormones by means of the second messenger inositol-1, 4,5-trisphosphate and Ca ⁺ ions. The gonadotropins luteinizing hormone (LH) and follicle stimulating hormone (FSH) released by GnRH stimulate the production of sex steroids and germ cell maturation in both sexes.In addition to GnRH (also known as GnRHl), there are two other forms of GnRH, namely GnRH2 and 3.

The GnRH receptor is used as a phanacological target in a number of diseases that depend on a functioning sex homion production, for example prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. GnRH superagonists or antagonists can be successfully used in these diseases. Another possible indication is male fertility control in combination with a substitution dose of androgens.

An advantage of GnRH antagonists compared to GnRH superagonists is their immediate effectiveness in blocking gonadotropin secretion. Superagonists initially overstimulate the pituitary gland, which leads to increased gonadotropin and sex steroid releases. This hormonal response only stops after a certain delay due to desensitization and downregulation of the GnRH receptor concentrations. It is therefore possible that GnRH superagonists, both alone and in combination with testosterone, cannot effectively suppress sperm production in men and are therefore not for them suitable for male fertility control. In contrast, peptide GnRH antagonists, especially in combination with a substitution dose of androgen, are able to produce a significant oligozoospeπnie in humans

However, GnRH peptide antagonists have a number of disadvantages. They are considerably less effective than superagonists and must therefore be administered in considerably higher doses. Their oral bioavailability is also low, so that they have to be administered by injection. Repeated injections in turn lead to a reduction in compliance. In addition, the synthesis of peptide GnRH antagonists is complex and expensive compared to non-peptide compounds.

Quinoline derivatives as non-peptide GnRH antagonists are disclosed, for example, in WO 97/14682. So far, however, no non-peptide GnRH antagonists have been brought onto the market.

Technical task

The object on which the present invention is based is to provide new compounds which are suitable for the treatment of disease states mediated by GPCR and in particular have a GnRH-inhibiting (GriRH-antagonistic) action. The new GPCR ligands, preferably GnRH antagonists, should be superior to known peptide compounds if possible and should represent an effective alternative or improvement in the ratio of 2 known non-peptide compounds. The new GPCR ligands, in particular GnRH antagonists, should above all have a high potency and, if possible, a high oral bioavailability. Furthermore, they should be able to be synthesized easily and at the lowest possible cost. The present invention also provides pharmaceutical compositions containing the new non-peptide GPCR ligands, in particular GnRH antagonists.

A further object on which the present invention is based is the provision of new GPCR ligands, preferably GnRH antagonists, for use as a pharmaceutical agent or for use in the production of pharmaceutical agents, comprising the GPCR ligands, preferably GnRH antagonists, /

In addition, it is an object of the present invention to provide a method for the treatment of GPCR-mediated disease states, in particular for the inhibition of GnRH, in a mammal, in particular a human.

All of these objects are surprisingly achieved by the provision of the new tetrahydrocarbazole derivatives, the pharmaceutical compositions containing these tetrahydrocarbazole derivatives, the process for the preparation of these tetrahydrocarbazole derivatives and the process for the treatment of disease states mediated by GPCR, preferably for the inhibition of GnRH , in a mammal, in particular a human, by administration of the tetrahydrocarbazole derivatives or the use of the tetrahydrocaτbazole derivatives for the preparation pharmaceutical agent for the treatment of GPCR-mediated disease conditions, in particular for GnRH inhibition, solved.

Summary of the invention

In a first aspect, the present invention provides new tetrahydrocarbazole derivatives of the general formula (I).

In a second aspect, pharmaceutical compositions are provided which comprise at least one of the new tetrahydrocarbazole derivatives of the general formula (T).

In a third aspect, the present invention provides tetrahydrocarbazole derivatives of the general formula (T) for use as a pharmaceutical agent.

In a further aspect, the present invention relates to the use of a tetrahydrocarbazole derivative of the general formula (I) for the preparation of a pharmaceutical composition for the treatment of disease states mediated by GPCR, in particular for the inhibition of GnRH. The present invention also relates to a method for the treatment of disease states mediated by GPCR, in particular for the inhibition of GnRH in a mammal, preferably a human, an effective amount of a compound of the general formula (I) according to the invention being administered to the mammal, preferably the human, in need of such treatment.

The present invention also provides a process for the preparation of tetrahydrocarbazole derivatives of the general formula (I). This method comprises, for example, the steps of condensing an appropriately substituted cyclohexanone derivative anchored to a solid phase with a suitably substituted one Phenylhydrazine derivative, a subsequent derivatization depending on the desired structure of the end compound and finally cleavage from the solid phase and isolation of the product.

Detailed description of the invention

In a first aspect of the present invention, new tetrahydrocarbazole compounds of the general formula (I)

(I) provided wherein

the radical R ^{1 is} a hydrogen atom, a C ₂ - Ce alkenyl or a Cj - Cβ alkyl radical and can optionally be substituted by an aryl, hetaryl radical or the group -COOR ¹¹ , the aryl or hetaryl radical having up to three substituents may be substituted, which are independently selected from the group consisting of -NO ₂ , -CH ₃ , -CFs, -OCH _3, -OCF ₃ and halogen atoms and the radical R ^{11 is} a hydrogen atom, a Cj - C ₁ 2 alkyl , is a -C ₂ aralkyl, an aryl, hetaryl radical or the group -COCHs and may optionally be substituted with a substituent selected from the group consisting of -CONH2, -COCH3, -COOCH3, -SO ₂ CH3 and aryl radicals; the radicals R ² , R ³ , R ⁴ and R ^J each independently represent a hydrogen atom, a halogen atom, the group -COOH, -CONH ₂ , -CF ₃ , -OCF ₃ , -NO ₂ , -CN, ad - C _{6 are} alkyl, a - C ₆ alkenyl, a Ci - Cö alkoxy, a Ci - C12 aralkyl, an aryl or hetaryl radical;

the rest R ^fi the group -CONR ^s R ⁹ , -COOR ⁸ , -CH ₂ NR ⁸ R ⁹ , -CH ₂ R ⁸ . -CH ₂ OR ⁸ or a Ci

- C _{12 is} alkenyl, which is optionally substituted by the radicals R ^s and R ⁹ , the radicals R ⁸ and R ⁹ each independently of one another a hydrogen atom, a Ci

- C ₁₂ alkyl, a Ci - C12 aralkyl, a Ci - C12 hetaralkyl, an aryl or hetaryl radical, which can be substituted with one or more substituents, which are selected from the group consisting of -OH, -NH ₂ , -CONHR ¹⁰ , -COOR ¹⁰ , -NH-C (= NH) -NH ₂ and halogen atoms are selected group, the radical R ^{10 being} a hydrogen atom, a Ci - C ₁ 2 alkyl, a Ci - C> ₂ aralkyl, is an aryl or hetaryl radical and is optionally substituted by the group -CON (R ⁿ ) ₂ , or where the radicals R ⁸ and R ⁹ together can form an R gE structure which consists either exclusively of carbon atoms or mixed from carbon and Heteroatoms exist;

the radical R ⁷ is a hydrogen atom, a Ci - C ₁₂ alkyl, a Ci - ₂ alkenyl, a Ci - Cι _z aralkyl, an aryl or hetaryl radical, the group -NR ^l2 R ^13, -NHCOR ^14, -NHCONHR ¹⁴ , -NHCOOR ¹⁴ or NHSO2R ¹⁴ and may optionally be substituted with one or more substituents selected from the group consisting of -OH, -NH ₂ , -CONH ₂ , -COOH and halogen atoms, the radicals R ¹² and R ¹³ are each independently a hydrogen atom, a C2 - Cβ alkenyl or a Ci - C12 aikyl radical and can optionally be substituted with one or more aryl or hetaryl radicals, which in turn can be substituted with up to three substituents which are independent of one another from the group selected from -NO _{2 »} -CH ₃ , -CF3, -OCH3, -OCF ₃ and halogen atoms, and the radical R ^{14 is} a hydrogen atom, a Ci - C12 alkyl, a Ci - C ₁ 2 alkenyl ci

C12 is aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents which are selected from the group consisting of -NO ₂ , -CH ₃ , -OR ¹¹ , -CF ₃ , -OCF ₃ , -OH, -N (R ^π ) ₂ , -OCOR ¹¹ , -COOH, -CONH ₂₎ -NHCONHR ¹¹ , -NHCOOR ¹¹ and halogen atoms;

and the radicals R ^a , R, R ^fi , R ^d , R ^e and R ^f each independently represent a hydrogen atom, a halogen atom, the group -COOH, -CONH ₂ , -CF ₃ , -OCF ₃ , -NO ₂ , - CN, a Ci - Ce alkyl, C - C ₆ alkoxy, an aryl or hetaryl radical;

with the proviso that the compound of the general formula (I) does not consist of the from 3- A ino-l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-l, 2,3, 4-tetrahydrocarbazole-3-carboxylic acid, 3-am o-6-benzyloxy-l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl -3-acetamido-l, 2,3,4-tetrahydrocarbazole-3-carboxylate, (-) - menthyl-3-acetamido-l, 2,3,4-tetrahydrocarbazole-3-carboxylate or 3-tert-butoxycarbonyl-amino -l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid group is selected.

An embodiment of the invention are compounds of the general formula (I) as indicated above with all the meanings given above for the radicals contained in (I), the radical R ^{11 being} a heteroalkyl or a: hetarylalkyl radical.

The tetrahydrocarbazole structures of those compounds which are specifically excluded from the compounds falling under the definition of the general formula (I) above were described by Y. Maki et al. in Chem. Pharm. Bull. 1973, 21 (II), 2460-2465 and by R. Millet et al. in Letters in Peptide Science 1999, 6, 221-233.

The terms given to explain the compounds of the general formula (I) have in particular the following meaning:

Ci - C $ or d - C12 "alkyl radical" means a branched or unbranched, cyclic or non-cyclic, optionally substituted alkyl group having 1 to 6 or 1 to 12 carbon atoms. Representative examples of such Alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, 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 cyclic groups, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl groups, 1-cyclopropyl, 1-cyclobutyl, 1-cycloρentyl, 1-cyclohexyl, 1-cycloheptylethyl, 2-cyclopropyl, 2-cyclobutyl, 2-cyclopentyl, 2-cyclohexyl, 2-cycloheptylethyl groups and Similar ones, but are not limited to these.

Among C ₂ -. C _ö "alkenyl" a Alkenyigruppe branched or unbranched, cyclic or noncyclic, substituted or unsubstituted, mono- or poly-unsaturated is meant having 2 to 6 carbon atoms Representative examples of such alkenyl groups include vinyl, allyl, Proρ- 1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-l, 3-dienyl, pent-1-enyl, pent-2-enyl, pent 3-enyl, pent-4-enyl, penta-l, 3-dienyl, penta-l, 4-dienyl, penta-2,3-dienyl, isoprenyl, hex-1-enyl, hex -2-enyl-, hex-3-enyI-, hex-4-enyl-, hex-5-enyl, hexa-l, 3-dienyl, hexa-l, 4-dienyl, hexa- 1,5-dienyl -, Hexa-2,4-dienyl, Hexa-2,5-dienyl, Hexa-l, 4-dienyl, Hexa-1,3,5-trienyl groups and the like, but are not limited to these.

Q ₂ -C _$ "Alkoxy radical" is understood to mean a branched or unbranched, cyclic or non-cyclic, optionally substituted alkoxy group having 2 to 6 carbon atoms. Representative examples of such alkoxy groups include methoxy, etboxy, n-propoxy, iso-propoxy -, n-butoxy, iso-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclohexyloxy groups and the like, but are not limited to these.

Ci - Cj ₂ "aralkyl group" means an alkyl group with 1 to 12 carbon atoms which is substituted by one or more aryl groups. Representative examples of such aralkyl groups for the purposes of the present invention include benzyl, 1-phenylethyl, 1-phenylpropyl -, 1-phenylbutyl-, 1-phenylhexyl-, 1-phenyl-2-methylethyl-, l-phenyl-2-ethylethyl-, l-phenyl-2,2-dimethylethyl- ₃ benzhydryl-, triphenylethyl-, 2- or 3-naphthylmethyl, 2-phenylethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl groups and the like limited. Accordingly, a "hetaralkyl radical" is an alkyl radical substituted by a heteroaryl radical.

“Aryl group” means an optionally substituted mono- or polycyclic aromatic group. Representative examples of such aryl groups include, but are not limited to, phenyl, naphthyl groups and the like.

The term "hetaryl residue" is identical to the term "heteroaryl residue" and stands for an aryl group as defined above, which in its structure comprises one or more heteroatoms, in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. Representative examples of such hetaryl or heteroaryl groups include, but are not limited to, unsubstituted hetaryl groups and substituted hetaryl groups, especially idazolyl, pyridyl, quinolinyl groups and the like.

The term "ring structure" includes optionally substituted mono- or polycyclic ring structures with different numbers of ring members, but especially five-, six- and seven-membered ring structures. In addition to carbon atoms, one or more heteroatoms, such as in particular nitrogen, phosphorus, The ring structures can include saturated, but also partially or completely unsaturated structural elements. Representative examples of such ring structures include aza, oxa, thia, phosphacyclopentane, cyclohexane, cycloheptane , Diaza, dioxa, dithia, diphosphacyclopentane, cyclohexane, cycloheptane ring basic structures and the like as well as ring basic structures with mixed heteroator exchange, but are not limited to these.

“Halogen atoms” include in particular fluorine, chlorine, bromine and iodine atoms, particularly preferably chlorine atoms. At this point, it should also be pointed out that in addition to the compounds of the general formula (I) mentioned per se, as defined above, physiologically compatible derivatives or analogs, in particular also salts of these compounds, are also covered by the present invention.

Furthermore, it should be noted at this point that the term "receptor ligand" or "ligand" for the purposes of the present invention is intended to mean any compound which binds to a receptor in any way (in the present invention, the receptor is a GPCR receptor, preferably a GnRH receptor) and either triggers an activation, inhibition or other conceivable effect on this receptor. The term “ligand” thus encompasses agonists, antagonists, partial agonists / antagonists and other ligands which produce an action on the receptor which is similar to the action of agonists, antagonists or paitial agonists / antagonists. The compounds according to the invention are preferably of the general type Formula (I) antagonists of the GnRH.

One embodiment of the present invention are novel tetrahydrocarbazole derivatives according to the invention of the general formula (I) in which the radical R ^{7 is} not a hydrogen atom if the radical R ^{e is} also an alkyl radical.

A further embodiment of the present invention are compounds of the general formula (I) in which the radical R ^{7 is} in any case not a hydrogen atom.

Preferred new tetrahydrocarbazole derivatives of the general formula (I) according to the invention are those compounds in which the radicals R ^a , R, R ^c , R ^d , R * and R are hydrogen atoms.

Also preferred, new tetrahydrocarbazole derivatives of the general formula (1) according to the invention are those compounds in which the radical R ^{1 is} a hydrogen atom. Preferred new inventive tetrahydrocarbazole derivatives of the general formula (I) are also those compounds in which the radicals R ² , R ³ , R ⁴ and / or R ^{5 are} not hydrogen atoms. Those compounds of the general formula (I) in which the radicals R ² , R ³ , R ⁴ and R ^{5 are,} independently of one another, methyl, chloro or methoxy radicals are particularly preferred. Those compounds of the general formula (I) in which at least the radical R ^{2 is} not a hydrogen atom, in particular the compounds, are very particularly preferred

Phenylmethyl - [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9 -tettahydro-S-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyljcarbamate (compound no. 150 a in the examples), phenylme yl - [(lS, 2S) -l - [[[( 3R) -3 - [[[(IS) -l- (aminoc * ^ bonyl) -2-methylpropyl] amino] carbonyl] -6-cωor-2,3,4,9-tetrahydro-lH-αi-rbazole -3-yl] amino] carbonyl] -2-methylbutyl] carbamate (148a),

Phenylmemyl - [(lS, 2S) -l - [[[(3R) -3 - [[[((lS l- (am ocarbonyl) -2-methylpropyl] amino] - carbonyl] -2,3,4,9- tetrahydro-8-methoxy-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (147a).

Preferred, novel, tetrahydrocarbazole derivatives of the general

Formula (I) are also those compounds in which R ^{6 is} a radical comprising a hydrophobic alkyl, aryl and / or hetaryl structure, which is spaced two to four

Single bonds from the carbon atom substituted by the radicals R ⁶ and R ⁷ counted out carry a hydrogen bond donor acceptor system. Compounds of the general formula (I) are particularly preferred, the radical R ^{6 being} a

Phenylalanylamidrest is, in particular the compound phenylmethyl - [(1S, 2S) -1 - [[[(3R) -

3 - [[[((l S) -2-amino-2-oxo-1 - (phenylmethyl) ethyl] amino] carbonyl] -2,3,4,9-tetra-hydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (66), an isoleυcylamide residue, especially the compound phenylmethyl [(1S, 2S) -1 - [[[(3R) -

3 - [[[(IS, 2S) -1- (aminocarbonyl) -2-methylbutyl] aminoJcarbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methyl ] butyl] carbamate (64), a valyl-4-aminobenzoic acid amide residue, especially the compound phenylmethyl

[(1 S, 2S) - l - [[[(3R) -3 - [[[(l S) - 1 - [[[4- (aminocarbonyl) phenyl] amino] carbonyl] -2- methylpropyl] ammo] carbonyl] -2,3,4,9-tett-ιhydro-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (45), is a valyl-N-methylamide radical, in particular the compound phenylmethyl [(lS, 2S) -2-methyl-l - [[[(3R) -2,3,4 ₎ 9-tetrώyώo-3 - [[[(lS) -2-me ll - [(memylaπώιo ) carbonyl] -propyl] amino] carbonyl] -lH-carbazol-3-yl] an-mo] carbonyl] butyl] carbamate (I22a), is a methyloxymethyl-4-pyridyl radical, in particular the compound 2,3,4 , 9-tetrahydro-

3- (3-phenylpropyl) - (- (4-pyridinylmethyl) -IH-carbazole-3-methanol (2S7)) is a carboxyl radical, especially the compound 2,3,4,9-tetrahydro-3- (3-phenylpropyl ) -lH-carbazole-3-carboxylic acid (273), or an ethyl propenate residue, in particular the compound ethyl 3- [2,3,4,9-

Also particularly preferred are compounds of the general formula (I) in which the radical R ^{6 is} a carbonylvalylamide radical, in particular the compound phenylmethyl

[(LS, 2S) -l - [[[(3R) -3 - [[[(lS) -l- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -

2,3,4,9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (^ 8), is a carbonylthreonylamide radical, in particular the compound phenylmethyl [(1S, 2S) -1 -

[[[(3iϊ) -3 - [[[(IS, 2R) -l- (aminocarbonyl) -2-hydroxyρropyl] amino] carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3-yI ] amino] carbonyl] -2-methylbutyl] carbamate, is a cyclic carboxamide residue (such as a carbonylprolylamide residue, especially the compound phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[(2S) - 2

(aminocarbonyl) -1-pyrrolidinyl] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] - carbonyl] -2-methylbutyl] carbamate (181a) or a carbonyl octahydroindolyl-2-carboxamide residue , especially the connection

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[(2S) -2- (aminocarbonyl) octahydro-lH-indole-1-yJ] carbonyl] -2,3,4,9 -tettahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (190a)), a 4-carboxamidophenylcarboxamide radical, in particular the compound phenylmethyl

[(IS, 2S) -l - [[[(3R) -3 - [[[4- (aminocarbonyl) phenyl] amino] carbonyl] -2,3,4,9-tetrahydro-lH-carbazoI-3-yl ] amino] carbonyl] -2-raethylbutyl] carbamate (62), is a methylaminomethyl-2-pyridyl radical, in particular the compound 2,3,4,9-

Tetrahydro-3- (3-phenylpropyl) -N- (2-pyridinylmethyl) -lH-carbazole-3-methanamine (27), is a carbonylvalinol radical, in particular the compounds phenylmethyl [(1S, 2S) -1-

[[[(3S) -3 - [[[(lS) -l- (hydroxyraethyl) -2-methylproρyl] amino] carbonyl] _-2,3,4:, 9-tetrahydro-lH-carbazol-3 -yl] amino] carbonyl] -2-methylbutyl] carbamate (267b) and 2,3,4,9-tetrahydro-N - [(IS) -l- (hydroxymethyl) -2-methylρropyl] -3- (3-ρhenylproρyl) - 1H-carbazole-3-carboxamide (276) or a methylvalinol residue, in particular the compound (2S) -3-methyl-2 - [[[2,3,4,9-tetrahydro-3- (3-phenylpropyl) -IH -carbazol-3-yl] me1nyl] ammo] -l-butanol (2S4).

Preferred new tetrahydrocarbazole derivatives according to the invention of the general

Formula (I) are also those compounds in which R ^{7 is} a residue comprising a hydrophobic alkyl, aryl and / or etaryl structure. Are particularly preferred

Compounds of the general formula (I) in which the radical R ^{7 is} a 2,3-

Biphenylpropionylamino radical, in particular the compound N - [[(3R) -2,3,4,9-

Tetrahydro-3 - [(l-oxo-2,3-diphenylpropyl) amino] - lH-carbazol-3-yl] carbonylj-L-valyl-L-aspartamide (18), is an indanoylamino radical, in particular the compound (3R) N - [(1S) -1-

(Am ocarbonyl) -2-methylρropyl] -3 - [[(2,3-dihydro-lΗ-inden-l-yl) carbonyl] amino] ^

2,3,4,9-tetrahydro-lH-carbazol-3-caτboxamid (162a), is an indolylacetylamino radical, in particular the compound (3S) -N - [(1S) -1-

(Aminocarbonyl) -2-memylpropyl] -2,3,4,9-tetrahydro-3 - [(1H-indole-3 "ylacetyl) amino] - 1H-carbazole-3-carboxamide (164b), which is a 2-naphthylacetylamino residue , especially the compound (3S) -N - [(1S) -1-

(Aminoc.u-bonyl) -2-methylpropyI] -2,3,4,9-tetrahydro-3 - [(2-naphthalmy ^] acetyl) amino] - 1H-carbazole-3-carboxamide (161b) or a 3- Is propionylamino radical, especially the compound N - [[(3Ä) -2,3,4,9-

Teiτahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2 - [(l-oxo-3-ρhenylproρyl) amino] ρentyl] amino] - lH-carbazol-3-yl] carbonyl] - L-valyl-L-aspartamide (22).

Compounds of the general formula (I) in which

R ^{7 is} a phenylmethylcarboxamide radical substituted on the aromatic system, in particular the compounds (3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -

2, 3, 4,9-tetrahydro-3 - [[(4-methylphenyl) acetyl] amino] - 1 Η-carbazole-3-carboxamide (165a), N - [(IS) -l- (ammocarbonyl) -2-methylpropyl] -2,3,4,9-tetr dro-3 - [[(4-methoxyphenyl) acetyl] amino] -lH-carbazole-3- carboxamide (175),

(3R) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(3-bromophenyl) acetyl] amino] -

2,3,4,9-tettahydro-lH-carbazole-3-carboxamide (6),

(3R) -N - [(lS) -l- (Ammocarbonyl) -2-methylpropyl] -3 - [[(4-fluorophenyl) acetyl] amino] -

2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide (91),

(3R) -N - [(lS) -l- (Ammocarbonyl) -2-memylpropyl] -3 - [[(4-cωorphenyl) acetyl] amino] -

2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide (167a), is a phenylhexylamine radical, in particular the compound (3R) -N - [(1S) -1-

(Aminocarbonyl) -2-methylpropyl] -2,3,4,9-tettahydro-3 - [(6-phenyexyl) amino] -IH-carbazole-3-carboxamide (234a) or a phenylpropyl radical, especially the compounds 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -lH-carbazole-3-carboxylic acid (275) and ethyl-6,8-dϊchloro-

2,3,4,9-tetrahvdro-3- (3-phenylpropyl) -IH-carbazole-3-carboxylate (272).

Also preferred are those new compounds of the general formula (I) according to the invention which are present in the R configuration on the carbon atom substituted by the radicals R ⁶ and R ⁷ , provided that the radicals R ⁶ and R ⁷ together form an alpha- aminocarboxylic acid structural element ,

Most preferred for the purposes of the present invention are the compounds phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6,8-dichloro-2,3,4 ₇ 9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (184a), phenylmethyl [(IS, 2S) -l - [[[(3R) -3- [[[(1 S) - l- (hydroxymethyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3 "yl ] amino] carbonyl] -2-methylbutyl] carbamate (267a), (2S) -l - [[(3R) -3 - [[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro -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) -IH-carbazole-3-methanamine (283). Further representatives of new compounds of the general formula (I) according to the invention, including their preparation, are given in the examples.

The new tetrahydrocarbazole derivatives (T) according to the invention, as defined above, are ligands of GPCR and can in particular be used for inhibition, i.e. can be used as antagonists of the gonadotropin-releasing hormone, for example for male fertility control, for hormone therapy, for the treatment of female sub- or mertility, for female contraception and for combating tumors

In male fertility control, the compounds of the invention reduce spermatogenesis. Combined administration with androgens, e.g. Testosterone or testosterone derivatives, such as testosterone esters. The administration of the testosterone derivatives can, for example, by injection, e.g. by intramuscular depot injection.

In hormone therapy, for example for the treatment of endometriosis, uterine leiomyomas and uterine fibroids, the compounds (I) according to the invention can optionally be used in combination with other hormones, for example estrogens and / or progestins. Combinations of the GnRH antagonists according to the invention and tissue-selective partial estrogen agonists such as Raloxifene ^® are particularly preferred. In addition, the compounds according to the invention can be used in hormone replacement therapy. Furthermore, the compounds (I) according to the invention can be used to increase female fertility, for example by inducing ovulation, and to treat sterility.

On the other hand, the new compounds (I) according to the invention are also suitable for contraception in women. Thus, the GnRH antagonist according to the invention can be administered on days 1 to 15 of the cycle together with estrogen, preferably with very low estrogen doses. Progestagen of the estrogen-GnRH 'antagonist combination is added on days 16 to 21 of the intake cycle. The GnRH antagonist according to the invention can be used continuously over the entire cycle be administered. In this way, a reduction in hormone doses and thus a reduction in the side effects of unphysiological hormone levels can be achieved. Furthermore, advantageous effects can be achieved in women who suffer from polycystic ovary syndrome and androgen-dependent diseases such as acne, seborrhea and hirsutism. Improved cycle control over previous administration methods is also to be expected. Other indications are benign prostatic hyperplasia, gonadal protection during chemotherapy, controlled ovarian timulation / artificial reproduction techniques, early childhood developmental disorders, e.g. puberty praecox and polycystic ovaries.

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

The new compounds (I) according to the invention, as defined above, are available as GPCR ligands, in particular GnRH antagonists, for the treatment of the disease states listed above for administration to mammals, in particular humans, but also for veterinary purposes, e.g. suitable for domestic and farm animals, but also for 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 new compounds (I) according to the invention are brought into a form suitable for administration and, if appropriate, mixed with pharmaceutically acceptable carriers or diluents. Suitable auxiliaries and carriers are described, for example, in Ullman's E cyclopedia of Technical Chemistry, Vol. 4, (1953), 1-39; J rnal of Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; H. v. Czetsch-Lindenwald, “Auxiliaries for pharmacy and neighboring areas ¹¹ ; Pharm. Ind 2, 1961, 72ff; Dr. HP Fiedler,, Jüexikon der excipients for pharmacy, Cosmetics and adjacent areas ", Cantor KG, Aulendorf in Württemberg, 1971.

Oral administration can take place, for example, in solid form as a tablet, capsule, gel capsule, dragee, granulate or powder, but also in the form of a drinkable solution. For oral administration, the new compounds of the general formula (I) according to the invention, as defined above, can be combined with known and commonly used, physiologically compatible auxiliaries and excipients, such as, for example, Gum arabic, talc, starch, sugar such as Mannitol, methyl cellulose, lactose, gelatin, surfactants, magnesium stearate, cyclodextrins, aqueous or non-aqueous vehicles, diluents, dispersants, emulsifiers, lubricants, preservatives and flavors (e.g. essential oils). The compounds according to the invention can also be used in a microparticulate, e.g. dispersed nanoparticulate composition.

The non-oral administration can take place, for example, by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by means of implants or by ointments, creams or suppositories. If necessary, it can also be administered as a slow-release form. Implants can contain inert materials, e.g. biodegradable polymers or synthetic silicones such as Silicone rubber. Intravaginal administration can e.g. by means of vaginal rings. Intrauterine administration can e.g. using diaphragms etc. In addition, transdermal administration, in particular by means of a suitable formulation and / or suitable agents such as e.g. Plasters, provided

As already explained above, the new compounds (I) according to the invention can also be combined with other active pharmaceutical ingredients. In the context of combination therapy, the individual active ingredients can be administered simultaneously or separately, either in the same way (for example orally) or in separate ways (for example, orally and as an injection). They can be present or administered in the same or different amounts in a unit dose. It a certain dosage regimen can also be used, if this seems appropriate. In this way, several of the new compounds (I) according to the invention can also be combined with one another.

The dosage can vary within a wide range depending on the type of indication, the severity of the disease, the type of administration, the age, gender, body weight and the sensitivity of the subject to be treated. It corresponds to the skill of a person skilled in the art to determine a “pharmacologically effective amount” of the combined pharmaceutical composition. Preferred doses are from 1 μg to 100 mg, particularly preferably from 1 μg to 10 mg and most preferably from 1 μg to 1 mg per kg Body weight of the subject to be treated and can be administered in a single dose or multiple separate doses

Accordingly, in a further aspect of the present invention, pharmaceutical compositions as described above, comprising at least one of the new compounds (I) according to the invention, as defined above, and optionally pharmaceutically acceptable carriers and / or auxiliaries, are also covered by the present invention. Preferred and particularly preferred pharmaceutical compositions are those which comprise at least one of the abovementioned preferred or particularly preferred new compounds (I) according to the invention, in particular the abovementioned compounds. In addition to the at least one compound of the general formula (I), as defined above, other pharmaceutical active ingredients can also be present in pharmaceutical compositions according to the present invention, as already detailed above.

In the pharmaceutical compositions according to the invention, at least one of the new compounds (I) according to the invention, as defined above, is present in one of the preferred, particularly preferred or most preferred unit doses mentioned above, preferably in a form of administration which enables oral administration. In addition, the present invention provides in a further aspect compounds of the general formula (I) as defined above for use as a pharmaceutical agent.

Preferred tetrahydrocarbazole compounds according to the invention of the general formula (I), as defined above, for use as pharmaceutical agents are, in turn, those compounds which have been mentioned above as preferred and particularly preferred compounds, in particular the preferred compounds according to the invention mentioned by name and those mentioned in the examples Links.

With regard to pharmaceutical compositions comprising compounds (I) according to the invention and with regard to the compounds (I) according to the invention for use as pharmaceutical compositions, reference is made to what has already been said regarding the new compounds (I) according to the invention, as defined above, with regard to use and administration options.

In another aspect, the present invention also provides the use of at least one tetrahydrocarbazole derivative according to the invention of the general formula (I) as defined above, wherein - as initially defined - the in the publications by Millet et al. and Maki et al. disclosed tetrahydrocarbazoles are excluded from the meaning of the general formula (I), for the preparation of a pharmaceutical composition for the treatment of GPCR-mediated diseases, in particular for the inhibition of the gonadotropin-releasing hormone (GnRH).

In addition, the present invention provides in a further aspect the use of at least one compound according to the invention of the general formula (I) as defined above, but including the compounds from the publications by Millet et al. and Maki et al., namely 3-amino-l ^^^ - tetr-ώydrocarbazoW-carboxylic acid, 3-ammo-6-methoxy-l, 2,3,4-tetra-hydrocarbazole-3-carboxylic acid, 3-amino- 6-benzyloxy-l ₁ 2,3,4-tetrahydro-carbazole-3- carboxylic acid, 3-acetamido-I, 2 _s 3 _? 4-tetrahydrocarbazole-3-carboxylic acid, methyl-3-acetamido-l, 2,3,4-tetrahydrocarbazole-3-carboxylate, (-) - menthyl-3-acetamido-l, 2,3,4-tetrahydrocarbazole-3- carboxylate and 3-tert-butoxycarbonyl-amino-l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid, for the production of a pharmaceutical agent for the inhibition of GnRH, preferably for male fertility control, for hormone therapy, for the treatment of female sub- and infertility, for female contraception and for tumor control, ready More clearly said, the term "a compound of the general formula (I) as defined above, but including the compounds excluded by name above" means a compound of the general formula (I)

(D where:

the radical R ^{1 is} a hydrogen atom, a C ₂ - C alkenyl or a Ci - C ₆ alkyl radical and can optionally be substituted with an aryl, hetaryl radical or the group -COOR ¹¹ , the aryl or hetaryl radical with up to three substituents can be substituted, which are independently selected from the group consisting of -NO2, -CH ₃ , -CF3, -OCHs, -OCF ₃ and halogen atoms and the radical R ^{11 is} a hydrogen atom, a Ci - C ₁₂ alkyl, is a Ci - C _J2 aralkyl, an aryl, hetaryl or the group -COCH ₃ and optionally with one of those from -CONH _2; -COCH3, -CθOCH ₃ , -SO2CH3 and aryl groups consisting of selected substituents may be substituted; the radicals R ² , R ³ , R ⁴ and R ^s each independently represent a hydrogen atom, a halogen atom, the group -COOH, -CONH ₂ , -CF ₃ , -OCF ₃ , -NO ₂ , -CN, a Ci - C ₆ alkyl, a C "- C _Ö alkenyl, a

- Cg are alkoxy, a Ci - C1 ₂ aralkyl, an aryl or hetaryl radical;

the radical R ^{6 is} the group -CONR ⁸ R ⁹ , -COOR ⁸ , -CH ₂ NRV, -CH ₂ R ⁸ , -CH ₂ OR ⁸ or a Ci

- C ₁ 2 is alkenyl, which is optionally substituted by the radicals R ⁵ and R ⁹ , the radicals R ^s and R ⁹ each independently of one another a hydrogen atom, a Ci

- Cπ alkyl, a Ci - C ₁₂ aralkyl, a Ci - C _{] 2} hetaralkyl, an aryl or hetaryl radical, which can be substituted with one or more substituents, which from the from -OH, -NH2, - group consisting CONHR ^10, COOR ^10, -NH-C (= NH) -NH2 and halogen atoms are selected, where the radical R ^J0 a hydrogen atom, a Ci - C ₁ 2 alkyl, a Ci - C12 aralkyl, an aryl, - or hetaryl radical and is optionally substituted by the group -CON (R ⁿ ) ₂ , or wherein the radicals R ⁸ and R ⁹ together can form a ring structure which consists either exclusively of carbon atoms or mixed of carbon and heteroatoms;

the radical R ^{7 is} a hydrogen atom, a d - C1 alkyl, a Ci - Cι ₂ alkenyl, a Ci - C ₁₂ aralkyl, an aryl or hetaryl radical, the group -NR ¹² R ¹³ , -NHCOR ¹⁴ , -NHCONHR ¹⁴ , -NHCOOR ¹⁴ or -NHSO ₂ R ¹⁴ and may optionally be substituted with one or more substituents selected from the group consisting of -OH, -NH ₂ , -CONH ₂ , -COOH and halogen atoms, the radicals R ¹² and R ¹³ are each independently a hydrogen atom, a C ₂ -Cg alkenyl or a Ci - C12 alkyl radical and can optionally be substituted by one or more aryl or hetaryl radicals, which in turn can be substituted by up to three substituents which are independently selected from the group consisting of -NO ₂ , -CH ₃ , «CF3, -OCH3, -OCFj and halogen atoms, and the radical R ^{14 is} a hydrogen atom, a Ci - Cι ₂ alkyl, a Cj - C ₁₂ alkenyl a Ci

- C12 is aralkyl, an aryl or hetaryl radical, optionally with one or can be substituted by a plurality of substituents which are selected from the group consisting of -NO ₂ , -CH ₃ , -OR ¹¹ , -CF3, -OCF ₃ , -OH, -N (R ^H ) ₂ , -OCOR ^u , -COOH, -CONH ₂ , -NHCONHR ¹¹ , -NHCOOR ¹¹ and halogen atoms;

and the radicals R ^a , R ^b , R ^c , R ^d , R ^fl and R ^f independently of one another each represent a hydrogen atom, a halogen atom, the group -COOH, -CONH _2? -CF ₃ , -OCF ₃ , -NO ₂ , -CN, a Ci - Cδ alkyl, Ci - Ce alkoxy, an aryl or hetaryl radical.

The indications already mentioned in connection with the new compounds of the general formula (I) according to the invention as defined above (ie excluding the compounds mentioned by name above and disclosed in the publications by Maki et al. And Millet et al.) Have already been mentioned given above in relation to the new compounds (I) according to the invention. The preferred and particularly preferred compounds which are preferred and particularly preferred in the use of the compounds just defined for the preparation of a pharmaceutical composition for inhibiting GnRH are identical to those preferred and already mentioned above in connection with the new compounds of the general formula (I) according to the invention as defined above particularly preferred associations.

In a further aspect, the present invention provides the use of a compound (T) according to the invention as defined above, but also including the compounds excluded by name at the outset, for male fertility control or for female contraception. Preferred and particularly preferred compounds according to the invention for this use are those compounds which have already been mentioned at the beginning as preferred or particularly preferred compounds of the general formula (I) as defined above.

In addition, the present invention provides a method of male fertility control or female contraception comprising administering male fertility control or female Contraceptive effective amount of a compound of the invention as defined in the immediately preceding paragraph to a subject, preferably a mammal, particularly preferably a human.

In another aspect, the present invention relates to a method for treating GPCR-mediated disease states. The method comprises the administration of at least one compound (I) according to the invention, as defined above, to a mammal, in particular a human, in which such treatment is required. Administration is usually in a pharmaceutically effective amount. As already explained above in relation to the new compounds (I) according to the invention and the pharmaceutical compositions according to the invention, it is the specialist knowledge of a person skilled in the art to determine a pharmaceutically effective amount, depending on the special requirements of the individual case. However, the compounds (I) according to the invention are preferably administered in a unit dose of 1 μg to 100 mg, particularly preferably from 1 μg to 10 mg and most preferably from 1 μg to 1 mg per body weight to be treated. The preferred mode of administration is oral administration. It is also intended to administer one or more of the compounds (I) according to the invention in combination with at least one further active ingredient, as already explained above.

Furthermore, the present invention also relates to a method for inhibiting GnRH in a patient, comprising administering to a patient who has a pharmaceutically effective amount of a compound of the general formula (I) as defined above, but including the compounds excluded by name above such treatment is needed. The method is preferably used in male fertility control, hormone therapy, female contraception, treatment of female sub- or infertility and tumor control. Finally, in a last aspect, the present invention also provides a process for the preparation of the novel tetrahydrocarbazole derivatives of the general formula (I) according to the invention. The process for the preparation of the compounds of the general formula (I) according to the invention can be carried out in various ways, for example in the liquid phase or as partial or complete solid-phase synthesis. The choice of suitable synthesis conditions for the preparation of individual representatives of compounds of the general formula (I) can be made by a person skilled in the art on the basis of his general specialist knowledge. A process according to the invention for the preparation of compounds of the general formula (I) according to the invention is first described below. A specific variant of the process, namely a solid phase process, is then described. To further illustrate the present invention, numerous examples of compounds of the general formula (I) can be found in the examples listed thereafter.

A process for the preparation of the compounds of the general formula (I) according to the invention is preferably carried out as follows:

The central tetrahydrocarbazole skeleton is accessible through a known Fischer indole synthesis. For this purpose, a suitably substituted and optionally protected cyclohexanone derivative is condensed with the respectively desired, also appropriately substituted and optionally protected phenylhydrazine derivative (e.g. according to Brjtten & Lockwood, JCS Perkinl 1914, 1824 or according to Maki et al., Chem. Ph rm.Bull. 1973, 21, 240). In particular, the cyclohexanone skeleton is in the positions 3.3 ', 5.5' and 6.6 'by the radicals R ^a to R ^f and in the positions 4.4' by the radicals or, if appropriate, by precursors of the radicals R ⁶ and R ⁷ substituted. The phenylhydrazine structure is optionally substituted by the radicals R ^z to R ⁵ . Phenylhydrazine derivatives which are not commercially available can be prepared by methods known to the person skilled in the art. Optionally, positional isomers formed during the condensation of the cyclohexanone derivative and the phenylhydrazine derivative can be separated by chroraatographic methods such as HPLC. After the synthesis of the central tetrahydrocarbazole skeleton, the radical R ^{1 can be} obtained by N-alkylation of the nitrogen atom in the 9-position with corresponding R ^ halides using base (for example according to Pecca & Albonico, J. Med Chem. 1977, 20, 487 or also according to Mooradian et al., J. Med Chem. 1970, 13, 327).

The radicals R ^o and R ⁷ can, as already indicated above, be introduced in different ways depending on their type, which is explained in more detail below.

α-Aminocarboxylic acid structures in these residues are accessible by treatment of ketones with NH4 (CO) ₃ and KCN under known Schotten-Baumann conditions and subsequent alkaline hydrolysis of the hydantoin formed (Britten & Lockwood, J.CÄ PerkinI 1974, 1824).

Amide residues are preferably generated using methods known per se from peptide chemistry. For this purpose, the acid component with an activating reagent such as DCC or HATU {Tetrahedron L & tt. 1994, 35, 2279) activated and condensed with the amino component in the presence of a base such as DIPEA and / or DMAP.

Ester residues can be obtained under analogous conditions using the desired alcohols. The solvent used here is preferably anhydrous.

Secondary or tertiary amine residues are obtained from primary amines either by nucleophilic substitution of alkyl halides or by reductive amination of aldehydes / ketones (e.g. J. Org. Chem. 1996, 61, 3849 or Synth. Comm, 1994, 609).

Sulfonamide residues are obtained from the corresponding amines by reaction with sulfonic acid chlorides.

Residues of urea are obtained if the amines are reacted with appropriate isocyanates. Urethane residues can be produced by preactivating corresponding alcohols with carbonyldihydroxybenzotriazole ((HOBt) ₂ CO) and then reacting them with amines (Warass et al., UPS 1998, 5, 125).

Alcohols are accessible from carboxylic acid esters by reduction with LiAlΗ.

Aldehyde residues are obtained from alcohol precursors by, for example, oxidizing with DMSO / oxalyl chloride under known Swern conditions (Pansavath et al., Synthesis 1998, 436),

Substituted amine residues are obtained by reductive amination of amines with aldehydes (J. Org. Chem. 1996, 61, 3849).

Ether residues can be obtained by deprotonating the alcohol precursor with a base such as NaH under known Williams conditions and then reacting it with an alkyl halide.

Double bonds in the radicals can be introduced by reacting an aldehyde or ketone precursor with corresponding phosphonylidene in accordance with Wittig conditions known per se.

A solid phase process for the preparation of compounds of the formula (I) according to the invention preferably comprises the steps (a) to (d) explained in more detail below:

Step (a) proceeds essentially analogously to a Fischer indole synthesis z, B. according to Britten & Lockwood, JCS Perkin 1 1914, 1824; Maki et al “Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman, Tetrahedron Lett. 1996, 37, 4869 and comprises the condensation of a cyclohexanone derivative (IT) containing group G and anchored to a solid phase SP via a linker L suitable for forming the rest * 6.

(H)

where in the event that the R ⁷ radical is a hydrogen atom, a C 1 -C ₂ alkyl, a C 1 -C ₁₂ aralkyl or a hetaryl radical, the group G is the same as the R ⁷ radical, and in the event that the R ⁷ has another of the meanings given for R ⁷ in formula (I), the group G is a group -NH-Pg, where Pg is a protective group, with a phenylhydrazine derivative (III) substituted by R ² to R ⁵

(III)

in the presence of an acid, preferably acetic acid, and a metal salt, preferably ZnCl ₂ . DMF is preferred as the solvent. The radicals R ^a to R ^f are defined as indicated above in formula (1). Certain substituents or groups can optionally also be present in protected form, the protective groups being removed again at a suitable point in time during the synthesis by processes which are known per se.

For the purposes of the present invention, the solid phase SP is, in particular, rinkamide resins (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard et al., Int. 1 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) if the cyclohexanone derivative (II) is to be anchored to the solid phase SP by means of an (amino) carboxylic acid. The DHP-Li ker (Liu & Elman, J. Org. Chem. 1995, 60, 7712) can be used to anchor alcohol precursors of the cyclohexanone derivative (II); aromatic precursors of the cyclohexanone derivative (II) can be “traceless” Triazine resins (Bräse et al ,, Angew. Chem. Int. Ed. 1998, 37, 3413) can be anchored.

The protective group Pg which is optionally included in group G and which protects an -amino group -NH ₂ is preferably an “Fmoc” (9-fluorenylmethoxycarbonyl) protective group, but can also be another common amino protective group, for example from the series of alkoxycarbonyl protective groups (such as, for example, the “Z” (benzyloxycarbonyl) - or the “Boc” (tert-butoxycarbonyl) group) or another suitable protective group, for example a “trityl” (triphenylmethyl) protective group.

The linker L is such that after corresponding derivatization (steps (b) and (c)) and workup (step (d)) in the end product, the tetrahydrocarbazole derivative of the general formula (I), the desired R ^δ with one of the above for R ⁶ indicated meanings results. To illustrate the nature of the linker L, this is subsequently explained by way of example for the case that R ^{6 is} equal to the group -CONR ⁸ R ⁹ .

In the event that the radical R ^{δ in} the product of the formula (I) according to the invention has the meaning -CONR ^a R ⁹ , a compound Pg-N (R ^Ä ) -R ^{9 '} -COOH which forms the linker L is first obtained by means of an activation reagent such as DCC (dicyciohexylcarbodiimide) or HATU (O- (7-azabenzotriazol-l-yl) -N, N-N ', N'-tetramethyluronium hexafluorophosphate) anchored to the solid phase SP via free amino groups of the SP, with Pg and SP the above Have meaning and R ^{9 '} forms part of the later radical R ⁹ . The protective group Pg is then split off, for example in the case of an Fmoc protective group using piperidine DMF. from that results in a connection HR ⁸ NR ⁹ -CONH-SP. The latter compound is now with a precursor of the cyclohexanone derivative (II), namely the cyclohexanone carboxylic acid (IT)

(IF)

again using an activation reagent such as DCC or HATU, which ultimately results in the cyclohexanone derivative (11) as defined above. The linker L has the meaning -CONR ⁸ -R ^{9 '} -CONH-SP for the case just described. Any resulting isomers of any kind (enantiomers, diastereomers or positional isomers) can be separated in a known manner by means of HPLC, as at other points in the production process described.

Then the actual step (a) takes place, i.e. the condensation of the cyclohexanone derivative (π) with the substituted phenylhydrazine derivative (HI) and, if appropriate, cleavage of the protective group Pg in group G by means of e.g. Piperidine (in the case of an Fmoc protective group), so that a free α-amino group is formed again at this point.

In the event that the radical R ^{7 is} the group -NHCOR ¹⁴ , -NHSOaR ¹⁴ , -NR ¹² R ¹³ (where R ¹² and R ^{13 are} not simultaneously hydrogen atoms), -NHCONHR ¹⁴ or -NHCOOR ¹⁴ , in step ( b) finally derivatization of the now unprotected α-amino group of the resin-bound cyclohexanone derivative (II) takes place, so that the various alternative radicals R ⁷ defined above can be formed. Depending on the nature of the desired R ⁷ radical in the tetrahydrocarbazole end product (I) according to the invention, the procedure is as follows:

In the event that R ^{7 is} the group -NHCOR ¹⁴ , the reaction product from step (a) with a carboxylic acid R ¹⁴ COOH in the presence of an activation reagent such as DCC or HATU and in the presence of a base such as DΪPEA (diisopropylethylamine) or DMAP (4-dimethylaminopyridine) implemented according to known methods for forming peptide bonds (see, for example, Tetrahedron Leu. 1994, 35, 2279; alternative (i)),

In the event that R ^{7 is} a sulfonamide group -NHSO ₂ R ¹⁴ , the reaction product from step (a) with a sulfonic acid derivative R ¹⁴ Sθ2X, where X is a leaving group, preferably a halogen atom, in particular a chlorine atom, in the presence of a base such as e.g. implemented DMAP or DIPEA (see e.g. Gennari et al., E OC 1998, 2437; alternative (ii)).

In the event that R ^{7 is} the group -NR ¹² R ¹³ (where R ¹² and R ^{13 are} not simultaneously hydrogen atoms), in the event that the radical R ^{12 is} a hydrogen atom, the reaction product from step (a) with a reagent R ¹³ X, where X is a leaving group such as a halide atom, in particular a chloride atom, in the presence of a base ie DBU or DIPEA (cf. Green, JOC 1995, 60, 4287 or JOC 1996, 61, 3849) or reacted with an aldehyde R ¹³ CHO in the presence of a reducing agent such as NaH B (OAc) 3. In the event that none of the radicals R ¹² and R ^{13 is} a hydrogen atom, the reaction product from step (a) is reacted with a ketone R ¹² COR ¹³ in the presence of a reducing agent (cf. Ellmann et al., JOC 1997, 62, 1240 or Synth Commun. 1994, 609; Alternative (iii)). In the event that in R ⁷ is -NR ¹² R ¹³ both radicals R ¹² and R ^{13 are} hydrogen atoms, the following alternative (vi) applies,

In the event that R ^{7 is} the group -NHCONHR ¹⁴ (a urea derivative), the reaction product from step (a) is reacted with an isocyanate R ¹⁴ NC0 (cf. Brown et al, JΛCS 1997, 119, 288; alternative (iv )). In the event that R ^{7 is} a carbamate or urethane group -NHCOOR ¹⁴ , the reaction product from step (a) is reacted with an alcohol HÖR ¹⁴ preactivated by carbonyldihydroxybenzotriazole ((HOBt) ₂ CO) (cf. Warass et al., LIPS 1998, 5, 125; Alternative (v)).

In the event that R ^{7 is} a hydrogen atom, a Ci - Cι ₂ alkyl, a Ci - C12 aralkyl, an aryl, a hetaryl radical or the group -NH ₂ (ie in R ⁷ is -NR ¹² R ¹³ both Residues R ¹² and R ^{13 are} hydrogen atoms), step (b) is omitted since no further derivatization is necessary (alternative (vi)).

Analogous to step (b) explained above, step (c) also corresponds, i.e. the derivatization on the indole nitrogen atom, various alternatives, which are explained in more detail below:

For cases (i) to (v) defined above in step (b), deprotonation of the reaction product obtained in (b) takes place using a base such as e.g. NaH or NaHMDS and subsequent derivatization using a group R'X, where X is a leaving group, e.g. a halide atom, in particular a chloride atom, is taking place (cf. Collini & Ellingboe, Tetrahedron Leti. 1997, 8, 7963; Pecca & Albonico, J. Med. Chem. 1917, 20, 487 or Mooradian et al., J. Med Chem. 1970, 13, 327).

For the case (vi) defined in step (b) above, ie if step (b) has been omitted, a deprotonation of the reaction product obtained in (a) by means of a base such as NaH or NaHMDS and a subsequent derivatization takes place analogously to that described above by means of a group K ¹ X, where X is a leaving group, for example a halide atom, in particular a chloride atom.

Finally, step (d) essentially comprises the cleavage of the reaction product obtained in (c) from the solid phase SP. In the case of Wang, Trityl, DHP and Rinkamid resin the cleavage of the reaction product obtained in (c) takes place with the help an acid, especially with TFA (trifluoroacetic acid) instead. In the case of an aminolytic cleavage from an HMB resin, ammonia in methanol, for example, is used as the cleavage reagent. The desired product is then isolated in the usual way.

Exemplary embodiments for the preparation of tetrahydrocarbazole derivatives according to the invention are listed below.

Examples

I. General synthesis instructions for compounds according to the invention

A Coupling of C rbonsäkuten to the Rink amide resin:

0.1 mmol F oc-protected Rink amide resin (166 mg, loading 0.6 mmol / g) are in a vessel with a frit bottom with 1.5 ml DMF for 20 min. pre-swollen. After suction, 1.5 ml of 20% piperidine DMF are added and 5 min. touched. After suction, another 1.5 ml of 20% piperidine DMF are added and the mixture is stirred for 15 min. After suction, washing four times with DMF. Then 675 μl of a 0.267 M solution of Fmoc-protected ammo-carboxylic acid in DMF, 675 μl of HATU solution (0.267 M in DMF) and 150 μl of NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP are added and Stirred at 40 ° C for 4 h. After aspiration, the same reagents are added again and the mixture is stirred at 40 ^° C. for 4 h. It is then suctioned off and washed four times with DMF.

B Coupling of carboxylic acids to the trityl resin:

2.98 mmol of Fmoc-protected amino carboxylic acid are dried in 30 ml

Dissolved dichloromethane, mixed with 14.3 mmol (2.45 ml) DIPEA and to 2.98 mmol 2- Chlorotrityl chloride resin (2 g, loading 1.49 mmol / g resin) added. After shaking for two hours, the resin is sucked off through a frit and washed three times with 20 ml dichloromethane / MeOH DIPEA 17: 2: 1. The mixture is then washed three times with 20 ml of dichloroethane, three times with methanol and three times with 20 ml of ether and dried in vacuo. A resin is obtained with a loading of 0.5 to 1 mmol of amino carboxylic acid per g of resin.

C Coupling of carboxylic acids to the HMB-H ri

21.3 mmol of amino carboxylic acid and 21.3 mmol of HATU are dissolved in 60 ml of DMF and 63.9 mmol (10.9 ml) of DIPEA are added. After 5 minutes, 5 g of polystyrene-HMB resin (loading 0.71 mmol / g resin) are added and shaken at RT for 5 minutes. Then 21.3 mmol (2.6 g) DMAP are added and shaken at RT for 1 h. The resin is then suctioned off and washed once with 100 ml of DMF, DCM and DMF. The resin is mixed with 100 ml of 10% AC2O (acetic anhydride) DMF / 5% DMAP and 15 min. shaken. After suction, the mixture is washed three times with 100 ml of DCM and ether and dried in vacuo.

D Coupling of carboxylic acids to the W ng resin:

54.6 mmol carboxylic acid and 27.3 mmol (4.2 ml) DIC are dissolved in 500 ml dry DCM and 10 min. stirred at RT. After filtering off the precipitated urea, the solution is evaporated to dryness and the residue is dissolved in 160 ml of dry DMF. The solution is added to 4.55 mmol (5 g, loading 0.91 mmol / g resin) in Wang resin pre-swollen in DMF and mixed with 4.55 mmol (556 mg) DMAP. After shaking for 1.5 hours at RT, the resin is filtered off and taken up in 100 ml of 10% Ac ₂ O / DMF / 5% DMAP and 15 min. shaken. After suction, the mixture is washed three times with 100 ml of DCM and ether and dried in vacuo.

E Coupling an alcohol to the DHP resin: 0.5 mmol DHP resin (0.5 g, loading density 1 mmol / g) are 15 min. pre-swollen in 2 ml dichloroethane. 2 ml of a solution of 0.75 M alcohol, 0.37 M pyridmium paratoluenesulfonate are added and the mixture is stirred at 80 ° C. for 16 h. After cooling to RT, 5 ml of pyridine are added, briefly shaken and suction filtered. It is washed twice with 5 ml of DMF, DCM and hexane.

F Protection of a resin-bound Fmoc protective group:

1.5 ml of 20% piperidine / DMF are added to 0.1 mmol of resin-bound Fmoc group and 5 min. touched. After suction, another 1.5 ml of 20%

Piperidine DMF added and 15 min. touched. After suction, washing four times with DMF.

G Coupling a carboxylic acid to resin-bound amino functions:

675 μl of a 0.267 M solution of Fmoc-protected amino carboxylic acid in DMF, 675 μl

HATU solution (0.267 M in DMF) and 150 μl NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP are added to 0.1 mmol of resin-bound amino functions and the mixture is stirred at 40 ° C. for 4 h. After aspiration, the same reagents are added again and the mixture is stirred at 40 ° C. for 4 h. It is then suctioned off and washed four times with DMF.

H Coupling of acetic acid to resin-bound amino functions: 1.5 ml of a solution of 10% acetic anhydride in DMF are added to 0.1 mmol of resin-bound amino functions and stirred at RT for 15 min. It is then suctioned off and washed four times with DMF.

I Synthesis of tetrahydrocarbazoles from resin-bound cyclohexanones: Before the reaction, 0.1 mmol of cyclohexanone resin is washed twice with 2 ml of DMF and twice with 2 ml of acetic acid. Then 1 ml DMF and 2 ml 0.5 M hydrazine / 0.5 M ZnCl ₂ in acetic acid are added to the resin and stirred at 70 ° C for 20 h. It is then suctioned off and washed twice with 2 ml of acetic acid and 2 ml of DMF.

J Synthesis of sulfonamides starting from resin-bound amides:

The resin is washed twice with 2 ml DMF and DCE. 1 ml of 0.5 M sulfonic acid chloride in DCE and 400 μl of 2.5 are added to 0.1 mmol of resin-bound amine

M NMM / 1 eq. Pour 0.25 M DMAP into DMF. After stirring at 60 ° C. for 12 h, the product is filtered off with suction and the coupling is repeated. After aspiration, it is washed four times with 2000 ml of DMF.

K Synthesis of ureas by reaction of resin-bound amine with isocyanates: 2 ml of 0.5 M isocyanate in DCM are added to 0.1 mmol of resin-bound amine and stirred at RT for 18 h. After vacuuming, it is washed four more times with DMF.

L Synthesis of carbamates by reaction of resin-bound amine with preactivated alcohols:

For preactivation, 0.4 M alcohol and 0.39 M dibenzotriazolyl carbonate and 0.39 M pyridine in DMF are stirred at 40 ° C. for 15 minutes. 1 mmol of resin-bound amine is mixed with 1 ml of preactivated alcohol and 167 ml of 2.4 M NMM in DMF are added. After 4 hours of stirring at 60 ° C., the product is filtered off with suction and washed four times with DMF

M Synthesis of N-alkytamines by N-alkylation of resin-bound amines with alkyl halides and catalytic AI: 1 ml of 0.5 M halide / 0.05 M KI in DMF and 416 μl of 2.4 M DIPEA in DMF are added to 0.1 mmol of resin-bound amine and the mixture is stirred at 90 ° C. for 12 h. After suction, the resin is washed four times with 2 ml of DMF.

N N-Alkylation of resin-bound indole nitrogen with halide / NoH in DMF: 1 ml DMF and 0.5 mmol NaH (55% suspension in oil) are added to 0.1 mmol resin-bound amine. After 30 min. Stirring at RT, 1 ml of 0.5 M halide in DMF are added and the mixture is stirred at 45 ° C. for 8 h. It is then suctioned off and washed twice with 2 ml of methanol, DMF, methanol and DMF.

O Splitting from Wdng, Trityl, DHP, Rink amide resin:

2 ml of a 95% TFA / 5% H ₂ O solution are added to 0.1 mmol resin and shaken at RT for 3 h. The resin is then filtered off and washed with a further 2 ml of TFA.

The combined TFA solutions are evaporated to dryness and deliver the raw ones

Products.

P Aminolytic cleavage from HMB-Har∑:

2 ml of DMF and 2 ml of 7 M NH ₃ in methanol are added to 0.1 mmol of resin and shaken at RT for 18 h. The resin is then filtered off and washed with DMF. The combined solutions are evaporated to dryness and provide the crude product.

Presentation of required output connections:

3 - [[(9H-Ftuoren-9-ylmethoxy) carbonyl] amino] -2, 3, 4, 9-ieirahydro-lH-carbazole-3-carboxylic acid 1 38.4 mmol (6.0 g) of 4,4-ethylenedioxycyclohexanone and 39.8 mmol (4.3 g) of phenylhydrazine are dissolved separately in 50 ml and 10 ml of water, respectively, and then mixed. After 10 min. The resulting milky emulsion is extracted five times with ethyl acetate, dried with MgSO 4 and evaporated to dryness. Yield: 9.2 g of orange oil.

9.2 g of the unpurified phenylhydrazone are dissolved in 240 ml of toluene at RT, and 4.9 g of freshly ground ZnCl _{2 are} added. After 90 min. Most of the toluene is distilled off at reflux on the water separator, an excess of 2 N NaOH is added and the mixture is extracted three times with ethyl acetate. The extract is washed with brine, dried with MgSO ₄ and the solvent is distilled off. The remaining black oil is purified on silica gel with ethyl acetate / hexane 1: 9. Yield: 2.7 g of beige solid.

11.6 mmol (2.7 g) l, 2,4,9-tetrahydrospiro [3H-carba2ol-3,2 '- [1,3] dioxolane] and 640 mg p-toluenesulfonic acid are taken up in 70 ml acetone and 2 , 5 h at RT. The solution is poured onto NaHCO 3 solution, extracted with ethyl acetate, washed with brine, dried with MgSO ₄ and concentrated. This leaves 2.13 g of red-brown solid. After recrystallization from ether, 1.1 g of a beige solid are obtained.

60.2 mmol (11.1 g) l, 2,4,9-tetrahydrospiro-3H-carbazol-3-one, 8.3 g KCN and 22.0 g NH4) 2CO ₃ are dissolved in 550 ml 60% ethanol 3 h heated in an autoclave at 80 ° C. After cooling to room temperature, the reaction mixture is poured onto ice water and the precipitated solid is filtered off. Yield: 10.1 g of gray solid.

44.2 mmol (11.3 g) l ^^^ - TetrahydrospiropH-carbazol-S ^ '- imidazolidinj ^' ^ '- dione is mixed with 62 g Ba (OH) ₂ X 8 H ₂ O in 145 ml H ₂ O Heated to 150 ° C for 13 h. After cooling to room temperature, 37 g of (NH ₄ ) 2CO _{3 are} added to the viscous mass with stirring and 30 min. heated to 100 ° C. After cooling to room temperature, the mixture is filtered off, washed with water and the filtrate is evaporated to dryness. Yield: 7.7 g of beige solid. 26 mmol (5.8 g) 3-amino-2,3,4,9-tetrahydro-lH-carbazole-3-carboxylic acid in 26 ml 1 N NaOH and 26 mmol (8.76 g) Fmoc-ONSu in 28 ml Acetonitrile are combined at room temperature and diluted 1: 1 with 130 ml acetonitiil / HϊO. After two hours the pH is adjusted to 9 (1.5 ml) with NEts and stirred overnight at room temperature. Then a further 6.3 g (18.7 mmol) of Fmoc-ONSu dissolved in 19 ml of acetonitrile are added and the mixture is stirred for a further two hours under pH control. After the acetonitrile has been removed by distillation, it is acidified with 0.01 M HCl and extracted with ethyl acetate. The extract is washed neutral, dried with N ₂ SO ₄ and evaporated to dryness. UrncrystalUsation is made from ether hexane. Yield: 10.7 g.

1H-NMR (d ⁶ -DMSO): ö = 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).

Mp: 11 ° C

The two enantiomers are separated by chiral HPLC.

(R) -3-ff (9H-fluoren-9-ylmeϊhoxy) carbonylJaminoJ-2, 3, 4, 9-tetrahydro-1H-carbazole-3 ~ carboxylic acid la ts. = 6.4 min (Chiralcel OD 10 μm LC50 250 x 4.6 cm, hexane / isopropanol 75:25, 80 ml / min)

(S) -3 ~ [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -2, 3, 4, 9-tetrahydro-lH-carbazole-3-carboxylic acid 1b t _R = 7.5 min (Chiralcel OD 10 μm LC50 250 x 4.6 cm, hexane / isopropanol 75:25, 80 ml / min)

1 - [[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] -4-oxocyclohexane carboxylic acid 2320 mmol (50 g) 4,4-ethylenedioxycyclohexanone are suspended in 800 ml 50% EtOH and with 1500 mmol (144.5 g ) (BU ^ COs and 640 mmol (41.7 g) KCN. After 5 h stirring at 60 ° C the ethanol is removed in vacuo and the after cooling, the aqueous residue was filtered off with ice, washed with water and dried, yield: 72.4 g of 4,4-l, 4-dioxa-9, l l-diazadispiro [4.2.4.2] tetradecane-10,12-dione.

295 mmol (66.8 g) 4,4-l, 4-dioxa-9, ll-diazadispiro [4.2.4.2] tetradecane-10,12-dione and 826 mmol (260.6 g) Ba (OH) ₂ x 8 H ₂ 0 are stirred in 2.5 1 in an autoclave at 150 ° C. for 6 h. After cooling to room temperature, 1032 mmol (99.2 g (NIL ^ COa) are added to the solution and the mixture is stirred for one hour at 60 ° C. The suspension is filtered, washed and the filtrate is lyophilized. The residue is recrystallized from H ₂ O MeOH. Yield : 45.4 g of S-amino-1,4-dioxaspno [4,5] decane-8-carboxylic acid.

213 mmol (42.9 g) 8-amino-l, 4-dioxaspiro [4,5] decane-8-carboxylic acid in 213 ml 1N NaOH and 213 mmol (71.9 g) Fmoc-ONSu in 240 ml acetonitrile combined and diluted 1: 1 with 1000 ml of acetonitrile H ₂ O. After adjusting the pH to 9, the mixture is stirred at room temperature overnight. After removal of the acetonitrile on a rotary evaporator, it is acidified with 0.01 M HC1 and extracted with ethyl acetate. The extract is washed neutral, dried with Na ₂ SO ₄ and evaporated to dryness. The residue is recrystallized from ethyl acetate / hexane. Yield: 79.0 g of 8 - [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -l, 4-dioxaspiro [4,5] decane-8-carboxylic acid.

187 mmol (79 g) 8 - [[(9H-fluoren-9-ylme1-hoxy) c ^ bonyl] amino] -l, 4-diθxaspiro [4,5] decane-8-carboxylic acid are dissolved in 3.5 l acetone / 0.1 M HC1 1: 1 and stirred for 4 h at room temperature. The acetone is removed on a rotary evaporator and the precipitated product is filtered off, washed with water and dried. Yield: 68.7 g 2.

1H 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) mp: 157 ° C 4-oxocyclohexane carboxylic acid 3

20 mmol (3.4 g) of 4-oxocyclohexane carboxylic acid ethyl ester are suspended in 40 ml of 2% H ₂ SO4 and stirred at 90 ° C. for ₂ hours. Then it is extracted 4 times with ethyl acetate, dried with Na ₂ SO ₄ and freed from the solvent. Recrystallization takes place from ether / hexane and yields 2.9 g of white solid 3.

1H NMR (d ⁶ -DMSO): δ = 1.72 (m, 2H); 2.08-2.18 (m; 2H); 2.19-2.47 (m, 4H); 2.72 (m; 1H); 12.23 (bs; 1H)

4 - chloro-3 - [[(phenylamino) carbonylJamino] benzene acetic acid 4

18.55 mmol (2.21 g) SOCl _{2 are} slowly added to 18.55 mmol (4 g) 4-chloro-3-nitrobenzeneacetic acid in 50 ml MeOH with ice cooling and stirring. After 30 min. Stirring is allowed to warm to RT and a further 3.71 mmol (0.44 g) SOCl ₂ are added. After stirring overnight, 30 min. heated to reflux. After the solvent has been stripped off, the residue is recrystallized from ether / hexane. Yield: 3.43 g of methyl 4-chloro-3-nitrobenzene acetate as a yellowish solid,

13.07 mmol (3.0 g) of methyl 4-chloro-3-nitrobenzeneacetate and 198.8 mmol (13.0 g) of Zn dust are dissolved in 500 ml of MeOH for 10 min. heated to reflux. Then 13 ml of HCl conc. added dropwise and another 30 min. refluxed. The suspension is filtered hot, the methanol is distilled off and the residue is adjusted to pH 14 with NaHCO ₃ solution. Extraction with ethyl acetate, drying with Na ₂ Sθ and distillation of the solvent gives 2.3 g of methyl 3-amino-4-chlorobenzene acetate as 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 one hour at 0 ° C., 10.4 mmol (1.11 g) of benzylarain are added and stirring is continued overnight at room temperature. It is extracted with DCM / H ₂ O and dried the organic phase and frees from the solvent. Yield: 727 mg of methyl 4-chloro-3 - [[(phenylamino) carbonyl] amino] benzene acetate.

2.98 mmol (990 mg) methyl 4-chloro-3 - [[(ρhenylamino) carbonyl] amino] benzene acetate are taken up in 10 ml methanol and mixed with 6 mmol IN NaOH. After stirring at RT for 2 h, the methanol is distilled off and the residue is acidified to pH 2-3 with 1 M HCl. It is extracted with ethyl acetate, dried with Na ₂ SO ₄ and freed from the solvent. Recrystallization takes place from boiling isopropanol. Yield: 830 mg of white solid 4.

1H NMR (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'Chlor-3 - (([henylmethyl) amino] carbonyl] amino] benzene acetic acid 5 2.08 mmol (415 mg) methyl 3-amino-4-chlorobenzene acetate are described as under 4.) with 10.4 mmol (969 mg ) Aniline added and worked up analogously. Yield: 662 mg of solid.

For ester cleavage, 2.47 mmol (790 mg) of methyl 4-chloro- ³ - [[[(plιenylmethyl) amino] carbonyl] amino] benzene acetate are saponified with 1 N NaOH, analogously to the above procedure. The product 5 is obtained without recrystallization. Yield: 693 mg of yellowish solid, ES-MS: 3l9 (M + H)

4-chloro-3-ff (4-pyridinylamino) carbonyl] aminoJbenzenacetic acid 6 2.08 mmol (415 mg) methyl 3-amino-4-chlorobenzene acetate are described as under 4.) with 10.4 mmol (979 mg) 4- Aminopyridine added and worked up analogously. Yield: 664 mg of solid. For the ester cleavage, 2.63 mmol (840 mg) of methyl 4-chloro-3 - [[(4-pyridinylamino) carbonyl] amino] benzene acetate are saponified with IN NaOH analogously to the above procedure. The product

6 is obtained without recrystallization. Yield: 481 mg of yellowish solid.

1H 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] benzoacetic acid 7 2.08 mmol (415 mg) methyl 3-amino-4-chlorobenzene acetate are described as under 4.) with 10.4 mmol (979 mg ) 2-aminopyridine added and worked up analogously. Yield: 617 mg solid.

For ester cleavage, 2.47 mmol (790 mg) of methyl 4-chloro-3 - [[(2-pyridmylamino) carbonyl] aminθ] benzene acetate are saponified with 1 N NaOH, analogously to the above procedure. The product

7 is obtained without primary crystallization. Yield: 693 mg of yellowish solid.

1H-NMR (d ^β -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 Compounds (I) According to the Invention

Example 1:

0.3 mmol (42.6 mg) 4-oxocyclohexane carboxylic acid are dissolved in 1 ml acetic acid and a suspension of 0.3 mmol (43.3 mg) phenylhydrazine hydrochloride and 0.3 mmol (40.0 mg) ZnCl ₂ in 1 given ml of acetic acid. After stirring at 70 ° C. for 20 h, the mixture is diluted with 20 ml of water and extracted with ethyl acetate. The ethyl acetate phase is with water washed, dried over Na ₂ SO ₄ and evaporated to dryness, yield: 65.6 mg (100%) white solid.

Name Nimmier Mgg Mr.d

2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid β 215 215.2507

The column labeling introduced here (name, number of the compound, M _{& f} (determined molecular mass), M _ca (calculated molecular mass)) also applies to the following examples, which is therefore no longer repeated.

Example 2:

The synthesis is carried out on a 0.2 mmol scale according to instructions A, I and O.

2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 2 214 214.2668

Example 3:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I and O.

N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] - (3S) - ιo 314 313.3987

2,3,4,9-tetrahydro-lH-carbazol-3-carboxamide

^ [(^^ - ^ (Aminocarbony ^^ - ethylpro ylj-ζSi?) - lob 31 313.39Ö7

2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide N- (2-Amino-2-oxoethyl) -2,3,4,9 "tetrahydro-1H-11 2 ⁷ 1 271, ³ 1 ⁸³ carbazole-3-carboxamide

Example 4:

The synthesis takes place on a 0.2 mmol scale according to the regulations D, F, G, F, G, I and O.

N - [(3S) - (2,3,4,9-tetrahydro-lH-carbazol-3-yl) carbonyI] - - 12 * "42 442 ^{, 5} 1 ³ valyl-L-glutamine

N - [(3R) - (2,3,4,9-tetrahydro-lH-carbazol-3-yl) carbonyl] - 12b 442 442 ^{, 5} 13 L-vaJyl-t-glutamine, isomer B

Example 5:

The synthesis takes place on a 0.2 mmol scale according to the regulations D, F, G, I, F and O:

N - [[(3 ^ -3-Ammo-2 _? 3,4,9-tetrahydro-lH-carbazol-3- 3 301 301.3441 yl] carbonyl] - -alanine

Example 6:

Dissolve 0.1 mmol carboxylic acid, 0.1 mmol HOBt and 0.15 mmol amine component in 15 ml dry DMF (also THF, DCM) and add 0.5 mmol NMM while cooling with ice and stirring. After about 15 min. 0.15 mmol EDCI x HCl are added, the mixture is stirred for one hour, warmed to room temperature and stirred overnight. For working up, the solvent is drawn off, the product is dissolved in ethyl acetate and each washed twice with 0.1 N HCl and saturated NaCl solution. After drying and stripping off the solvent, the product is recrystallized if necessary.

9H-fluoren-9-ylmethyl [(3S) -3 - [[[(4- 34 620 620.5439 bromρhenyl) methyl] amino] carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3- yl] carbamate

Methyl N - [[(3S) -3 - [[(9H-fluoren-9- 35 537 537.6129 ylmemoxy) carbonyl] an-ino] -2,3,4,9-tetrahydro-lH-carbazole-3- yl] carbonyl] -L-aIaninat

Example 7:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, G, F, G and O.

N - [[(3R) -3 - [[(2S, 3S) -2 - [[(9H-fluorene-9-1 * 779 777.9176 ylmethoxy) carbonyl] amino] -3-methyl-l-oxopentyI] amino] -2,3,4,9-tetrahydro-lH-carba2; ol-3-yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3S) -3 - [[(2S, 3S) -2 - [[(9H-fluorene-9-31 779 777.9178 yImethoxy) carbonyl] amino] -3-methyl-l-oxopentyl] amino ] -2,3,4,9-tetrahydro-lH-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

N * - [[(3R) -2,3,4,9-tetr * hydro-3 - [(l-oxo-2,3- 31 651 650.7758 diρhenylpropyl) amino] -lH-carbazol-3-yl ] carbonyl] -L-valyl- -aspartamide

N - [[(3S) -2,3,4,9-tetrahydro-3 - [(l-oxo-2,3- 19 651 650.7758 diphenylρroρyl) amino] -lH-carbazol-3-yl] carbonyI] -L-valyl- L-aspartamide, isomer A

N - [[(3S) -2,3,4,9-tetrahydro-3 - [(l-oxo-2,3- 651 650.7758 diphenylpropyl) aminoJ-lH-carbazol-3-yl] carbonyl] - - valyl-L-aspartamide, isomer B

N - [[(3S 2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-µoxo-2- 21 688 ₆ 87, B371

[(L-oxo-3-phenylpropyl) amino] pentyl] amino] -lH-carbazoI-

3-yl] carbonyl] -L-valyl-L-aspartamide N - [[(3R) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2- 22 688 687.8371

[(L-oxo-S-phenyl-propyl ^ anDinolpentylJaminol-lH-carbazol--

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

N - [[(3S) -2,3,4,9-tetrahydro-3 - [[(2S) -l-oxo-2- 23 648 647.7239

[[(phenylmethoxy) c ^ bonyl] aminio] propyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3R) -2,3,4,9-Tetrahydro-3 - [[(2S) -l-oxo-2 4648 ⁶ 47.7289

[[(henylmethoxy) carbonyl] am o] propyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

^ [[(S ^^^^^ - Tetrahydro-St ^ S ^ SJ-S ^ met yl-l-oxo- 25 ⁶⁶ 2 ⁶⁶ 1,7557

2 - [[(phenylmethoxy) carbonyl] amino3pentyl] amino] -IH-carba2ol-3-yI] carbonyl] -L-alanyl- aspartamide

N - [[(3i?) - 2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2 ^{6 6} 4 ⁶ 4 ⁶ , ⁷⁸ 44

2 - [[(phenylmethoxy) carbonyllamino] pentyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valyl- -alaninamide

N - [[(3S) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2- 27 690 689.8093

[[(phenylmethoxy) carbonyl] amino] pentyl] amino] -IH-carbazol-3-yl] carbonyl] -D-valyl-L-aspartamide

N - [[(3R) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2g 690 689.8093

2 - [[(phenylmethoxy) carbonyl] amino] pentyl] amino] -lH-carbazol-3-yl] carbonyl] -D-valyl- aspartamide

N - [[(3R) -2,3,4,9-tetrahydro-3 - [[(2S, 3 ^ -3-methyl-l-oxo-29 890 689.8093

2 - [[(phenylmethoxy) carbonyl] amino] pentyl] amino] -lH-carbazol-3-yl] carbonyl] -) L-valyl-D-aspartamide

N - [[(3S) -2 ₅ 3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo- ^2-3 ° 690 689.8093

[[(phenylmetboxy) carbonyl] amino] pentyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valyl-r> aspartaraid

N - [[(3S) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2- 662 661.7557

[[(phenylmethoxy) carbonyl] araino] pentyl] amino] -lH-carbazol-3-yl] carbonyI] -i, -a nyl- -aspartamide

N-1 [(3S) -2,3,4,9-tetrahydro-3 - [(phenylacetyl) amino] -lH-32 651 560.6514 carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3 -2,3,4,9-tetrahydro-3 - [(l-oxo-3- 33 575 574.6782 phenylpropyl) amino] - lH-carbazol-3 -yl] carbonyl] -L- valyl

L-aspartamide

N - [[(3S) -2,3,4,9-tetrahydro-3 - [(l-oxo-3- 34 575 574.6782 phenylpropyl) amino] -lH-carbazol-3-yl] carbonyl] -L -valyl- L-aspartamide N - [[(3S) -2,3,4,9-tetrahydro-3 - [[(2S, 3S 3-methyl-l-oxo-2-S 647 646.7844

[[(phenylmethoxy) carbonyl] amino] pentyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valyl-L-alaninamide

Ν - [[(3R) -2,3,4,9-tetrahydro-3 - [(phenylacetyl) amino] -lH- 3§ 561 560.6514 carbazol-3-yl] carbonyl] -L-valyl-L- aspartamide

N - [[(3R) -2,3,4,9-tetrahydro-3 - [(l-oxo-4-2Z 589 588,705 phenylbutyl) amino] -lH-carbazol-3-yl] carbonyl] -L-valyl -

L-aspartamide

N - [[(3S) -2,3,4 ₅ 9-tetrahydro-3 - [(l-oxo-4- ∞ 589 5Θ8,705 phenylbutyl) amino] -lH-carbazol-3-yl] carbonyl] -L -valyl-

L-aspartamide

N - [[(3R) -3 - [(Diphenylacetyl) amino] -2,3,4,9-tetrahydro-lH-carbazol 636.749 £ ^637-3-yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3S) -3 - [(Oiphenylacetyl) amino] -2,3,4,9-tetrahydro-40 637 636.749 lH-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3R) -2,3,4,9-tetrahydro-3 - [(l-oxo-2- ü 575 574.6782 phenylpropyl) ammo] -lH-carbazol-3-yl] carbonyl] -L -vaIyl-

L-aspartamide, isomer A

N - [[(3R) -2,3,4,9-tetrahydro-3 - [(3-methyl-l-oxo-2- 61 ^β i7 616.7586 phenylpentyl) amino] -IH-carbazol-3-yl ] carbonyl] -L-valyl

L-aspartamide, isomer B

N - [[(3S) -2,3,4,9-tetrahydro-3 - [(3-methyl-l-oxo-2- 43 617 616.75B6 phenylpentyl) amino] -IH-carbazol-3-yl] carbonyl ] -L-valyl

L-aspartamide, isomer A

N - [[(3S) -2,3,4,9-tetrahydro-3 - [(3-methyH-oxo-2- -M 617 616.7586 phenylpentyl) amino] -IH-carbazol-3-yl] carbonyl ] -L-valyl-L-aspartamide, isomer B

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[((IS) -l - [([4- 45 695 694.8284

(aminocarbonyl) phenyl] araino] carbonyl] -2-methylpropyl] amino] carbonyl] -2.3 ₅ 4,9-tetrahydro-lH-carbazol-3-yl] aminoϊcarbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IS) -l - [[[4- 46 595 694.8284

(aminocarbonyl) phenyl] amino] carbonyl] -2-ethylpropyπaminolcarbonylJ ^^^^ - tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate N - [[(3S) -2,3,4,9-tetrahydro-3 - [(3-methyl-l-oxo-2- * L ⁶⁰ 3 602.7318 phenylbutyl) amino] -IH-carbazole-3- yl] carbonyl] -L-valyl "L-aspartamide, isomer A

N - [[(3S) -2,3,4,9-tetrahydro-3 - [(3-methyl-l-oxo-2- 38. ⁶ 03 602.7318 phenylbutyl) amino] -IH-carbazole-3- yl] carbonyl] -L-valyl-L-aspartamide, isomer B

N - [[(3R) -2,3,4,9-tetrahydro-3 - [(3-methyl-l-oxo-2- 49 603 602.7318 phenyl ibutyl) amino] -lH-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

Phenylmethyl [(lS, 2S) -l - [[[(3S) -3 - [[[(lS) -l - ([[[4- §o 715 714.9026

(ammocaxbonyl) cyclohexyl] methyl] amino] carbonyl] -2-methyroρyl] amino] carbonyl] -2,3,4, -tetrahydro-1H-c-urbazole "3-yl] aminoϊcarbonyl] -2-methylbutyl] carbamate

N - [[(3R) -2,3,4,9-tetrahydro-3 - [[(3- §1 653 652,749 phenoxypheny ^ acetyπammol-1H-carbazol-S-yllcarbonyl] -

L-valyl-L-aspartamide

N - [[(3S) -2,3,4,9-tetrahydro-3 - [[(3- 52 653 652,748 phenoxyphenyl) acetyl] amino] -lH-carbazol-3-yl] carbonyl] -

L-valyl-L-aspartamide

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[((IS) -l - [[[[3 -s 709 708.3552

(aminocarbonyl) phenyl] methyl] amino] carbonyl] -2-me propyl] amino] carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3-yl] amino] carbonylj-2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -I - [[[(3S) -3 - [[((IS) -l - [[[[3- 54 709 708.8552

(aminocarbonyl) phenyl] methyl3amino] carbonyl] -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-lH-carba2ol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyI] -2,3,4,9-! ^β o ^β 607.7509 tetrahydro-3 - [[(2R l-oxo-2 - [(l-oxo-3-phenylpropyl) amino] -3-phenylpropyl] amino] - 1 H-carbazole-

3-carboxamide

N - [[(3S) -2,3,4,9-tetrahydro-3 - [(ϊ-oxo-2- 56 575 574.6782 ρhenyIproρyl) amino] - 1 H-carbazol-3-yl] carbonyi] - L-valyl-L-aspartamide

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[[(lS) -l - [[r [4- 57 715 714,9Ü26

(aminocarbonyl) cyclohexylϊmethyl] amino] c _- rbonyy-2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate Example 8:

The synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, F, G and O,

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[((IS) -l- 58 576 576.7059

(aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-caτbazol-3-yl3amino] carbonyl] -2-methylbutyl] carbamate

N - [[(3S) -3 - [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] - 5! 665 664.759

^ S ^^ - tetranydro-lH-carbazol-S-yllcarbonyll-L-valyl-L-aspartamide

N - [[(3R) -3 - [[(9H-fluoren-9-ylmethoxy) carbonyl] amino] - §2 6 ⁶ 5 664.759

2,3,4,9-teixahydro-lH-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IS) -l- ^§ 1 576 575.7059

(aminocarbonyl) -2-methylpropyl] ajnino] carbonyl] -2,3 _> 4,9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[4- §2 596 595.6963

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

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[4- 63 596 595.6963

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

Phenylmethyl [(1S, 2S) -1 - [[[(3R) -3 [[[(1S, 2S> -1- ⁵⁹⁰ 289.7327

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

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IS, 2S) -l- 590 589.7327

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

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -2-amino-2-oxo §§ 623 623.7499 1 - (phenylmethyl) ethyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IS) -2-amino-2-oxo-1-SZ 623 623.7499

(phenylmethyl) ethyl] aminojcarbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- 460 460,5748 tetrahydro-3 - [(l-oxo-2-phenylpropyl) amino] -lH-carbazole-3-carboxamide

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[3- -.2 610 609.7231

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

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[[3- ZQ 610 609.7231

(aminocarbonyl) phenyl] methyl] aminθ] carbonyl] -2,3,4,9-tetrahydro-1H-C ^ bazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(lS, 2S) -l - [[[(3S 3 - [[[[4- ZI eis 615.7705

(Aminocarbonyl) cyclohexyljmethyl] amino] carbonyl] -

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

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[[4- U 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) -l - [[((3S 3 - [[[3- U 596 595.6963

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

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[3- Z4 596 595.6963

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

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IS) -2-amino-2-oxo-1-5 610 609.7231 phenylethyl] amino] carbonyl] -2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IR) -2-amino-2-oxo Z§ 610 609.7231 1 -phenylethyl] amino] carbonyl] -2 , 3,4,9-tetrahydro-1H-carba2θl-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[(2-amino-2-oxo-l- ZZ 609 609.7231 phenylethyaminoJcarbonylϊ ^^^^ - tetrahydro-lH-carbazol- 3-yl] amino] carbonyl] -2-methylbutyl] carbamate, Isomer A

Phenylmethyl [(IS, 2S) -l - [[((3R) ~ 3 - [[(2-amino-2-oxo-l-Z | 609 609.7231 phenylethyl) amino] c _- rbonyl] -2,3, 4,9-tetrahydro-'lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbaraate, isomer B

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- T 4 ⁶ 2 462,547 tetrahydro-3 - [[(3-hydroxyρhenyl) acetyl] amino] -lH-carbazole-3-carboxamide

(3R) -3 - [[[3- (acetyloxy) phenyl] acetyl] amino] -N - [(IS) -l- 504 504.5838

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

3- [2 - [[(3R) -3 - [[[(IS) -l- (aminocarbonyl) -2- 51 597 596.6804 methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-lH- carbazol-3 "yl] amino] -2-oxoethyl] phenyl 3-hydroxybenzene acetate

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- §2 462 462.547 tetrahydro-3 - [(hydroxyphenylacetyl) am o] -lH-carbazole- 3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] "3 - [[(4- & 525 525,4441 bromophenyl) acetyl] amino] -2,3,4,9-tetrahydro -lH-carbazole

3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(2- 1 481 480.9931 chIo henyl) acetyl] ammo] -2,3,4,9- tetrahydro-lH-carbazole

3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyI] -3 - [[(3- §5 97 496.9921 chloro-4-hydroxyρhenyl) acetyl] amino] -2,3, 4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -3 - [[[4- (acetyloxy) -3-chlorophenyl] acetyl] amino] -N- ∞ 539 539.0289

[(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(3- IZ 481 480.5371 fluoro-4-hydroxyρhenyl) acetyl] amino] -2,3,4 , 9-tetrahydro-1H-carbazole-3-carboxamide (3R) -3 - [[[4- (acetyloxy) -3-üuorphenyl] acetyl] amino] -. N- 22 ^{523 5} 22 ^{, 5} 73 ⁹

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

(3R) -N - [(IS) -l- (Aπιinocarbonyl) -2-methylpropyl] -2 _J 3,4,9- § .. 4 ⁹ 2 491,5451 tetrahydro-3 - [[(4-nitrophenyl) acetyl] amino] -IH-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(2,4- 90 515 515.4382 dichloipheny ^ acetyyaminol ^^^^ - tetrahydro-lH-carbazole- 3-carboxamide

(3R> N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- -ü 64 464.5381 fluθJ ^ henyI) acetyl] amino] -2.3.4 _s 9 -tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-22,462,462,547 tetrahychO-3 - [[(4-hydroxyphenyl) acetyl] amino] -lH carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(2- 525 525.4441 bromophenyl) acetyl] amino] -2,3,4,9-tetrahydro-lH- carbazole

3-carboxamide

(3R) -N - [(IS 1 - (aminocarbonyl) -2-methylpropyl] -2,3,4,9- B * 491 4Θ1,64S1 tetrahydro-3 - [[(2-mtrophenyl) acetyl] aruino] - 1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- 22 4 ⁹ 1 491,5451 tetrahydro-3 - [[(3-nitrophenyl) acetyl] amino] - 1H-carbazole-3 - carboxamide

(3R) -N - [(IS> l- (aminocarbonyl) -2-methylpropyl] -3 - [[(3-! § 525 525,4441 bromophenyl) acetyl] amino] -2,3,4,9-tetrahydro -lH'Carbazol-

3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(2- SZ 499 498.9832 chloro-4-fluorophenyl) acetyl] amino] -2,3,4 , 9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [([I ₇ 1'-22 523 522.6456 biρhenyl] -4-ylacetyl) amino] -2 ₇ 3 , 4,9-tetrahydro-lH-carbazole

3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(3,5- ∞ 475 474,6016 dimethylphenyl) acetyl] amino] -2,3,4,9 -tetrahydro-1H-carbazole-3-carboxamide (3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [(1,3-322,490,490,557 benzodioxol-5-ylacetyl) amino] -2,3,4,9 -tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(3-. L 481 480,9931 chlorophenyl) acetyl] ammo] -2,3,4,9- tet r ιhydro-ΪH-carbazole

3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- 322,461,460,5748 tetrahydro-3 - [[(3-methylphenyl) acetyl] amino] -lH-carbazole

3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(2- 322 464 464.5381 fluorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-lH -carbazoI-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- 32 * 461 460,5748 tetrahydro-3 - [[(2-memylphenyl) acetyl] amino ] -lH-carbazole

3-carboxamide

(3R) -N - [(IS) -Camino carbonyl) -2-methylpropyl] -2,3,4,9- 125 489 488,6284 tetrahydro-3 - [[[4- (l-methylethyl) phenyl] acetyl] amino] -IH-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[[4- 302 490 489.6165

(dimemylamino) phenyl] acetyl] an ino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- 32Z 5 4 524,6388 telrahydro-3 - [[[4- (methylsulfonyl) ρhenyl] acetyl] amino] -IH-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(3- 322 479 478.5649 fluoro-4-methylphenyl) acetyl] amino] -2,3,4 , 9-tetrahydro-1H-carbazole-3-carboxamide

Example 9:

The synthesis is carried out on a 0.2 mmol scale according to the regulations B, F, G, F, G, F, G and O.

N - [[(3R) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-me% l-l-oxo-2- 322 691 690.7934

[[(phenylmethoxy) caxbonyl] amino] pentyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valyl-L-asparagine N - [[(3S) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2- 312 ⁶ 91 690.7934

[[(phenylmethoxy) carbonyl] aminθ] pentyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valyl-L-asparagme

Example 10:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, G, F, G, F,

Dog O.

N - [[(3R) -3 - [[(2S, 3S) -2- (acetylamino) -3-methyl-1- 331 598 597.7127 oxopentyl] amino] -2,3,4,9-tetrahydro- 1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3S) -3 - [[(2S, 3S) -2- (acetylamino) -3-methyl-l- 332 598 597.7127 o ^χ opentyl] amko] -2,3,4,9- tetrahydro-lH-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3R) -3- |; [(2R, 3R) -2- (acetylammo) -3-methyl-l-332 598 597.7127 oxopentyl] amino] -2,3,4,9-tetrahydro-lH -carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3S) -3 - [[(2R, 3R) -2- (AcetyIamino) -3-methyl-1-- 1 598 597.7127 oxopentyl] amino] -2,3,4,9-t ^ rahydro-lH-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

Example 11:

The synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, F, G, F, H and O.

N - [[(3R) -3- (acetylamino) -2,3,4,9-tetrahydro-lH-carbazole-3- 332 484 484.5538 yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3S) -3- (acetylamino) -2,3,4,9-tetrahydro-lH-carbazol-3- 484 434.5538 yl] carbonyl] -L-valyl-L-asρartamide N - [[(3S) -3- (Acetylaroino) -2,3,4,9-tetrahydro-lH-carbazole-3- ± LZ 484 484.553B yl] carbonyl] -D-valyl-L-aspartamide

N - [[(3S) -3- (acetylamino) -2,3,4,9-tetrahydro-1H-carbazole-3-HS 484 484.5539 yl] carbonyl] -L-valyl-D-aspartamide

Example 12:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G and O.

Phenylmethyl [(IS, 2SH - [[[(3R) -3- (aminocarbonyi) -2,3,4,9- 312 476 476,5738 tetrahydro-lH-carbazol-3-yI] am o] carbonyl] 2- methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3- (aminocarbonyl) -2,3,4,9- 47 ^β 476,5738 tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Example 13:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, G, F, G, F, G and O.

N - [[(3R) -2,3,4,9-tetrahydro-3 - [[(2S) -l-oxo-2 - [(l-oxo-3- 321 722 721.8543 phenylpropyl) amino] -3 - ρhenylpropyl] amino] - 1 H-carbazole-3-yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3R) -2,3,4 ₃ 9-tetrahydro-3 - [[(2R, 3R) -3-methyl-l-oxo-2- 122 688 687.8371

[(L-oxo-3-phenylproρyI) amino] penty]] amino] -lH-carbazole

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

Example 14:

The synthesis is carried out on a 0.2 mmol scale according to the regulations D, F, G, F, G and O. N - [[(3R) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l ^ oxo-2- 322 577 576.69

[[(phenylmethoxy) carbonyl] amino] pentyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valJn, N - [[(3R) -2,3,4,9-

Tetrahydro-3 - [[(2S) -3-methyl-l-oxo-2-

[[(phenylmethoxy) carbonyl] amino] pentyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valine

N - [[(3S) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2- 32fl 577 576.69

[[(phenymιemoxy) carbonyl] an _- o] ρentyl] amino] -lH-carbazol-3-yl] carbonyl] -L-valine

Example 15:

The synthesis is carried out on a 0.2 mmol scale in accordance with the instructions C, F, G, F, G, F, G and P.

N - [[(3R) -3 - [[(2S, 3S) -2 - [[(l, l- 325 656 655.7921

Dimethylethoxy) carbonyl] amino] -3-me-l-l-oxopen1yl] amino] -2,3,4,9-tetrahydro-lH-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide

Example 16:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, G, F and O.

N - [[(3S) -3-amino-2,3,4,9-tetrahydro-lH-carbazole-3- 1 6 442 442,517 yl] carbonyl] -L-valyl-L-aspartamide

N - [[(3R) -3-Ammo-2,3,4,9-tetrahydro-lH-carbazole-3-HZ 442 442,517 yl] carbonyl] -L-valyl-L-aspartamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3- 121 441 441.5725

[[(2S, 3S) -2-amino-3-methyl-l-oxoentyl] amino] -2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide Example 17:

The synthesis is carried out on a 0.2 mmol scale according to the regulations D, F, G, F, G, F, H and O.

N - [[(3S) -3- (acetylamino) -2,3,4,9-tetrahydro-lH-carbazole-3- 122 485 485.5379 yI] carbonyl] -L-vaIyl-L-asparagine

Example 18:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, H and O.

(3R) -3- (Acetylamino) -N - [(IS) -2-amino-2-oxo-1- 130 418 418.4944

(phenylmethyl) ethyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -3- (Acetylamino) -N - [(IS) -2-amino-2-oxo-1- 321 418 418.4944

(phenylmethyl) ethyl] -2,3,4,9-teιrahydro-1H-carbazole-3-carboxamide

Example 19:

The synthesis takes place on a 0.2 mmol scale according to the regulations B, F, G and O.

(3S) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2- 322 478 477.5579

[[(phenylmethoxy) carbonyl] amino] pentyl] amino] -lH-carbazoI-3-carboxylic acid

Example 20:

The synthesis is carried out on a 0.2 mmol scale according to the regulations B, F, G, F and O.

(3S) -3 - [[[(2,2-diphenylethyl) amino] acetyl] amino] -2,3,4,9- 324 468 467,5661 tetrahydro-1H-carbazole-3-carboxylic acid Example 21:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, F, H and O.

(3S) -3- (Acetylamino) -N - [[3- m 04 404.4676

(aminocarbonyl) phenyl] methyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -3- (Acetylamino) -N - [[4- I 410 410.515

(aminocarbonyl) cyclohexyl] methyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -3- (Acetylamino) -N - [[4- 32Z 410 410.515

(aminocarbonyl) cyclohexyl] methyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -3- (Acetylamino) -N - [(IS) -2-amino-2-oxo-1- 122 404 404.4676 phenylethyl] -2,3,4,9-tetrahydro-1H-carbazole-3 -carboxamide

Example 22:

The synthesis is carried out on a 0.2 mmol scale according to Examples 18 and 6.

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [(ethylamino) carbonyl] - l2a 505 504.6274

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

Phenylmethyl [(lS, 2S) -2-methyl-l - [[[(3R) -2,3,4,9- 14S 519 518,6542 tetrahydro-3 - [[(l-methylethyl) amino] carbonyl] - lH-carbazole

3-yl] amino] carbonyl] butyl] carbamate

Phenylmethyl [(IS, 2S) -2-methyl-l - [[[(3R) -2,3,4,9- 341 533 532,681 tetrahydro-3 - [[(2-methylρropyl) amino] carbonyI] -lH- carbazol-3-yl] amino] carbonyl] butyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[(2,2-3,547,546,7078 dimethylpropyl) amino] carbonyl] -2,3,4,9-tetrahydro-lH carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate Phenylmethyl [(IS, 2S) -2-methyl-1 - [[[(3R) -2,3,4,9- 342 553 552.6714 tetrahydro-3 - [(phenylamino) carbonyl] -IH-carbazo-3 - yl] amino] carbonyl] butyl] carbamate

Phenylmethyl [(IS, 2S) -2-methyl-1 - [[[(3R) -2,3,4,9-144,567,566,6982 tetrahydro-3 - [[(ρhenylmethyl) amino carbonyl] -IH-carbazole "

3-yl] ammo] carbonyl] butyl] carbamate

Phenylmethyl [(IS, 2S) -2-methyl-l - [[[(3R) -2,3,4,9- 34 ⁵ 581 58DJ25 te1xahydro-3 - [[(2-phenylemyl) aminoϊcarbonyl] -lH-carbazole -

3-yl] amino] carbonyl] butyl] carbamate

Phenylmethyl [(IS, 2S) -2-methyl-I - [[[(3R) -2,3,4,9- 42 595 594.7518 tetrahydro-3 - [[(3-phenylpropyl) amino] carbonyl] - 1H-carbazol-3-ylϊamino] carbonyl] butyl] carbamate

Example 23:

The synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, I, F, G and O.

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- - Zs 606 605.7317

(anunocarbonyl) -2-methy) propyl] amino] carbonyl] -2,3,4,9-te1xahydro-8-methoxy-lH-carbazol-3-yl] amino3carbonyl] -2 "methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[((IS) -l- J47b eos 605.7317

(ammocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-telrahydro-8-methoxy-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[((IS) -l- 1 ** 2,610 610,151

(ar ^Q inocarbonyl) -2-methylpropyl] amino] carbonyl] -6-chloro

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

Phenylmethyl [(IS _? 2S) -l - [[[(3S) -3 - [[[(IS) -l- J k 610 610.151

(Aminocarbonyl) -2-methylρropyl] amino] carbonyl] -6-chloro-

2,3,4 _J 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyljcarbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- 2P 610 610,151

(Aminocarbonyl) -2-methylpropyl] amino] carbonyl] -8-chloro-

2 ₃ 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-raethylbutyl] carbamate Phenylmethyl [(1S, 2S) -1 - [[[(3S 3 - [[[(1S) -1- -32PJ- 610 610,151

(Aminocarbonyl) -2-methylpropyl] amino] carbonyl] -8-chloro-

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

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[[(lS) -l- -14§ä ⁶ 44 843J0 ³

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

Phenylmethyl [(1S, 2S) -1 - [[[(3S 3 - [[[(1S) -1- .142b 644 643.703

(aminocarbony ^^ - methylpropyljaminojcarbonyl] ^^^^ - tetrahydro-8- (trifluoromethyl) -lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[[(lS) -l- -12O- 590 589.7327

(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 - [[[(3S) -3 - [[((IS) -l-isob 590 589.7327

(aminocarbonyl) -2-meylpropyl] 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) -l- J-ia 590 589.7327

(Aninocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-5-methyl-1H-carbazol-3-yl] amino] carbonyl3-2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IS) -l- J23J2 590 589.7327

(aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-5-methyl-1H-carbazol-3-yI] amino] carbonyl] -2-methylbutyljcarbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[((IS) -l- 515 590 589.7327

(aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3 _} 4,9-tetrahydro-7-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyljcarbamate Phenylmethyl [(lS, 2S) -l - [[[(3S) -3 - [[[(lS) -l- l§lύ 590 589.7327

(aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-7-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- J52a eio 610.151

(Aminocarbonyl) -2-methylpropyI] amino] carbonyl] -5-chloro-

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

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[((IS) -l- J52b 610 610, 151

(An.inocarbonyl) -2-methylpropyl] amino] carbonyl] -7-chloro-

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

Phenylmethyl [(1S, 2S) -1 - [[[(3R 3 - [[[(1S) -1- J22S 610 610, 151

(Aminocarbonyl) -2-methylpropyl] amino] carbonyl] -7-chloro-

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

(3R) -3 - [[[(IS) -l- (aminocarbonyl) -2- JS 620 619.7149 methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-3-

[[(2S, 3S) -3-methyl-l-oxo-2-

[[(ρhenylmethoxy) carbonyl] amino] pentyl] amino] -lH-carbazole-8-carboxylic acid

(3S) -3 - [[[(IS) -l- (aminocarbonyl) -2- 53b 620 619.7149 methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-3-

[[(2S, 3 S 3-methyl-l-oxo-2-

Ϊ [^ henylmεinoxy) carbonyl] aιmno] ρentyl] amino] -1H-carbazole-S-carboxylic acid

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[((IS) -l-J54a 593 593,696

(Aminocarbonyl) -2-methylproρyl] araino] carbonyl] -6-fluoro-

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

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[((IS) -l- 54i> 593 593,696

(Aminocarbonyl) -2-methyIpropyl] amino] carbonyl] -6-fluoro-

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

Phenylmethyl [(! S, 2S) -l - [[[(3R) -3 - [[[(lS) -l- 55a 605 605.7317

(aminocarbonyl) -2-methylpropyl] araino] carbonyl] -2,3,4,9-tetrahydro-6-methoxy-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[((IS) -l- -352! »6 ^{05 605} , 7317

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

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- 1 $ 589 ⁵⁸⁹ , 7327

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

Phenylmethyl [(1S, 2S) -1 - [[[(3S) -3 ^ [[[(1S) -1- -Sgb 589 589.7327

(aminocarbonyό ^ -methylpropyljaminojcarbonyl] ^^^^ - te1xahydro-6-methyl-lH-caτbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- -! 5Z§ 621 620J03

(aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-te1ιahydro-6-nitro-lH-carbazo-3-yl3amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[((IS) -l- 621 620.703

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

Phenylmethyl [(! S, 2S) -l - [[[(3R) -3 - [[[(lS) -l- ™ * 633 632.7616

(Aminocarbonyl) -4-

[(an-inoimmome yl) amino] butyl] amino] carbonyI] -2,3,4,9-tetrahydro-lH-carba-ole-S-yπaminoicarbonyl] ^ - methylbutyl] carbamate

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- Δ§ 47 447,5361 tetrahydro-3 - [(3-pyridinylacetyl) amino] -lH carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- -12-.J- 447 447,5361 tetrahydro-3 - [(3-pyridinylacetyl) amino] - 1 H-carbazole-3 - carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- -122§ 496 496,6078 tetrahydro-3 - [(l-naphthalinylacetyl) amino] - 1H-carbazole-3 "carboxamide (3S) -N - [(IS) -l- (aminocarbonyl) "2-methylpropyl] -2,3,4,9- -12PJ- 496,496,6078 tetrahydro-3 - [(l-naphthalinylacety]) amino] -H carbazole-3-carboxamide

carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyI] -2,3,4,9- J b 496 496,6078 tetrahydro-3 - [(2-naphthalinylacetyl) amino] -lH -carba2θl-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(2,3- Δ $ M 472 472.5858 dihydro-lH-inden-l-yl) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(2,3- J ^β gb 472 472,5858 dιhyό ^ o-lH-inden-l-yl) c rbonyl] amino] -2,3,4 ₅ 9-tetrahydro-lH-carbazole-3-carboamide

(3R) -N - [(IS l- (aminocarbonyl) -2-methylpropyl] -2 _s 3,4,9- -123a 436 436,5132 tetxahydro-S- ^ lH-in- dazo -ylacety aminol-lH- carbazole

3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- J ^ 436 436.5132 tetrahydro-3 - [(lH-imidazol-4-ylacetyl) amino] -lH-carbazole

3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- -12 a 486 485,5849 tetrahydro-3 - [(lH-indol-3-ylacetyl ) amüιo] -lH-carbazole-3-caiboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- J24! _ 48 © 485,5849 telxahydro-3 - [(lH-indole-3- ylac «tyI) amin9] -lH-carbazole-3-carboxa id

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- J2§H 461 460,5748 tetrahydro-3 - [[(4-methylphenyl) acetyl3amino] -lH-carbazole

3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- J- 461 460,5748 tetr.ιhydro-3 - [[(4-methylphenyl) acetyl ] amino] -lH-carbazoI-

3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- ¹ 6 ⁸ * a ⁵ 15 514.5451 tetrahydro-3 - [[[4- ( trifluoromethyl) phenyl] acetyl] amino] -lH-carbazole-3-carboxamide (3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- JG b 515 514,5451 tetrahydro-3 - [[[4- (trifluomiomethyl) phenyl] acetyl] a ino] -lH-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- 2ZS 481 480.9931 chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro -lH-carbazole

3-carboxamide

(3S) -N - ((IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- 2Zi- 481 480.9931 chlorophenyl) acetyl] amino] -2,3,4,9- tetrahydro-lH-carbazole

3-carboxamide

(3S) -N - [(IS) -l- (aninocarbonyl) -2-methylpropyl] -2,3,4,9- -322a 515 514.5451 tetrahydro-3 - [[[3- (trifluoromethyl) phenyl] acetyl] amino] -IH-carba201-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2.3.4 _J 9-22J2 515 514.5451 tetrahydro-3 - [[[3- (trifluoromethyl) ρhenyl] acetyl ] amino] - 1 H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3- [|; (3- J 2Ü 465 464.5381 fluo henyl) acetyl] amino] -2,3,4, 9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -N - [(IS) -HAminocarbonyl) -2-methylρropyl] -3 - [[(3- .122.2 465 464.5381 fluoropheny]) acetyl] amino] -2,3,4,9-tetrahydro- 1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- JZ2a 477 476,5738 tetrahydro-3 - [[(3-methoxyphenyl) acetyl] amino] -lH-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2 ₁ 3,4,9-1,0b 477 476.5738 tetrahydro-3 - [[(3-methoxyphenyl) acetyl] amino] - 1H-carbazole-3-carbo xamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- JZlü 477 476,5738 tetrahydro-3 - [[(2-methoxyphenyl) acetyl] amino] lH-carbazoI-

3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2.3 _? 4,9- -IBib 477 476,5738 tetrahydro-3 - [[(2-methoxyphenyl) acetyl] amino] 1H-carbazole-3-carboxamide-

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylρropyl] -3 - [[3- (4- 172a 479 478.5649 rluorophenyl) -l-oxopropyl3amino] -2,3,4, 9-tetrahydro-1H-carbazole-3-carboxamide (3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[3- (4- J 2 ^b 479 478.5649 fluorophenyl) -l-oxopropyl] amino] -2, 3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[3- -1Z39 497 496.555

(3,4-difluorophenyl) -l-oxopropyl] amino] -2,3,4,9-tetrahydro-lH-carbazoϊ-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3-i; i; 3- JT b 497 496.555

(3,4-difluorophenyl) -l-oxopropyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[3- -3Z4i ⁵⁹ 3 592.6057

[3,4-bis (trifluoromethyl) phenyl] -l-oxopropyl] amino] -2,3,4,9-tetrahydro-lH-carbazoI-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[3- JZ4b 593 592.6057

P ^ -bisÖrifluoimethy phenylj-l-oxopropylJanώio] ^^^^ - tetrahydro-lH-carbazole-3-carboxamide

N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2 ₅ 3,4,9-1Z5 477 476,5738 tetrahydro-3 - [[(4-methoxyphenyl) acetyl] amino] -lH-carbazole -3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- JZ ^β § 491 490,6006 tetrahydro-3 - [[3- (4-methoxyphenyl) -l-oxopropyl] amino] - 1H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- 1 ⁶ 491 490.6006 teirahydro-3 - [[3- (4-memoxyphenyl) - l-oxopropyl] amino] - 1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (arainocarbonyl) -2-methylpropyl] -2,3,4,9- JZZa 491 490,6006 tetrahydro-3 - [[3- (2-methoxyphenyl) -l -oxopropyl] amino] - 1H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- 1 b 491 490,6008 tetrahydro-3 - [[3- (2-methoxyphenyl) - l-oxopropyl] amino] -

1 H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- -178a 500 499,6117 tetrahydro-3 - [[3- (lH-indole-3 -yl) -l-oxoproρyl] amino] -lH-carbazole-3-carboxamid

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- ^i7Bb 500 499,6117 tetrahydro-3 - [[3- (lH-indole-3- yl l-oxopropyl] amino] -lH-carbazole-3-carboxamide (3R) -N - [(lS) -l- (aminocarbonyl) -2-methylρropyl] -2,3,4,9- -1Z9§ 503 502,6552 tetra ydro-3 - [(l-oxo-6- phenylhexyl) amino] -IH-carbazoI-3-carboxamide

(3S) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4 ₃ 9- JZ ^ li 503 502.6552 tetrahydro-3 - [(l-oxo-6-phenylhexyl) amino] -IH-carbazole-3-carboxamide

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[(2S) -2-23ii 574 573.6901

(aminocarbonyl) -l-pyrrolidϊnyl] carbonyI] -2,3,4,9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[(2S) -2- Ak 574 573.6901

(aminocarbonyl) -l-ρyπOlidinyl] carbonyl] -2,3,4,9-telxahydro-lH-carbazol-3-yl] amino] carbonyI] -2-methylbutyl3carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[((IS) -l- -322a 645 644.5961

(aminocarbonyl) -2-methylpropyl] amino3carbonyl] -7, S-dichloro-2,3,4,9-tetrahydrσ-1H-carbazol-3-yl3ammo3carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IS) -l- -122 ^b 645 644.5961

(aminocarbonyl) -2-methylpropyl] amino3carbonyl] -7,8-dichloro-2,3,4,9-tetrahydro-lH-c-ιrba-sol-3-yl] amino] carbonyl3-2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- 233 604 603.7595

(aminocarbonyl) -2-methylpropyl3amino] carbonyJ3-2,3,4,9-tetrahydro-5,8-dimethyl-lH-carbazol-3-yl] amino3carbθnyl] - 2-methylbutyl3carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[[(IS) -l- -i§3b 004 603.7595

(aminocarbonyl) "2-methylpropyl3amino3carbonyl3-2,3,4,9-tetrahydro-5,8-dimethyl-1H-carba_2θI-3-yl3amino] carbonyl] - 2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[((IS) -l- J2 a 645 644.5961

(aminocarbonyl) -2-methylpropyl3amino3carbonyl3-6,8-dichloro-2,3,4,9-tetrahydro-lH-carbazol-3-yl3amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS _> 2S) -l - [[[(3S) -3 - [[((S) -l- J © 5 644.5961

(aminocarbonyl) -2-methylpropyl3amino3carbonyl3-6,8-dichloro-2,3,4,9-tetrahydrσ-1H-carbazol-3-yl] amino] carbonyI] -2-methylbutyl] carbamate Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- Δ2 & L 655 654,602

(Aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6-bromo-

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

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[((IS) -l- er 655 654.602

(Aminocarbonyl) -2-methylpropyl3amino] carbonyl] -6-bromo-

2,3,4,9-tetrahydro-lH-carbazol-3-yl3amino3carbonyl3-2-methylbutyljcarbamate

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- 22≤ sn 511.0189 chlorophenyl) ace1yl] ajnino] -2,3,4,9- tetrahydro-8-methoxy-1H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[(4- 22.2 511 511.0189 chlorophenyl) acetyl3amino] -2,3,4,9-tetrahydro-8- methoxy-1H-carbazole-3-carboxamide

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[[(lR) -2-amino-l - [(4- J2Za 658 658.195 chlorophenyl) methyl3-2-oxoethyl3amino] carbonyl] - 2,3,4,9-tetrahydro-lH-carbazol-3-yl3amino3carbθnyl3-2-methylbutyljcarbamate

Phenylmethyl [(lS, 2S) -l - [[[(3S) -3 - [[[(lR) -2-amino-l - [(4- -3271. 658 658,195 chloτphenyl) methyl] -2-oxoethyl] amino3carbonyl3-2,3,4,9-tetrahydro-1H-carbazol-3-yl3ammo] carbonyl3-2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[3 - [[(3-amino-3- 322 546 547.6523 oxopropyl) amino3carbonyl3-2,3,4, -tetrahydro-IH-carbazoI-3-y) 3aπύno3carbonyl3-2-methylDutyl3carbamat

(2S) -l - [[(3R) -3 - [[(4-chlorophenyl) acetyl3amino3-2,3,4,9- S 509 509,0031 tetrahydro-8-methoxy-lH-carbazol-3-yl3carbonyl3- 2-pyrrolidine carboxamide

(2S) -l - [[(3S) -3 - [[(4-chlorophenyl) acetyl] amino] -2,3,4,9- -122.2 509 509.0031 tetrahydro-8-methoxy-1H-carbazole- 3-yl3carbonyl] -2-pyrrolidinecarboxamide

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[(2S) -2- J22a 628 627.7815

(aminocarbonyl) octahydro-lH-indol-l-yl] carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3-yl3-amino3carbonyl3-2-methylbutyljcarbamate Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[(2S) -2- J2 b 628 627.7815

(aminocarbonyl) octahydro-lH-indol-l-yl3carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -2-methylbutylcarbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[(2S, 4R) -2- Jul 590 589.6891

(ammocarbonyl) -4-hydroxy-1-pyrrolidinyljcarbonyl] - 2,3,4,9-tetrahydro-1H-carbazol-3-yl3amino] carbonyl] -2-methylbutyl3carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[(2S, 4R) -2- J2U. 590 589.6891

(aminocarbonyl) -4-hydroxy-1-pyrrolidinyl3carbonyl] - 2,3,4,9-tetrahydro-lH-carbazoI-3-yI3amino] carbonyl3-2-methylbutyl] carbamate

Phenylmethyl [(! S, 2S) -l - [[[(3R) -3 - [[[(lS, 2R) -l- 223a 578 577.6781

(ammocarbonyl) -2-hydroxypropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yI] amino] carbonyl3-2-methylbutyljcarbamate

Phenylmethyl [(IS, 25) -l - [[[(3S) -3 - [[[(IS, 2R) -l-Z9ib 578 577.6781

(aminocarbonyl) -2-hydroxyρroρyl] amino] carbonyl] -2,3,4,9-tetrabydro-1H-c bazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[(2-amino-2- 222 534 533.6255 oxoeώyl) amino] carbonyl3-2,3,4,9-tetrahydro-lH-carbazole -3- yl] amino3carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[3 - [[[2- 192 596 595.6963

(aminocarbonyl) phenyl3amino] carbonyi] -2,3,4,9-tetrahydro-lΗ-carbazol-3-yl] amino] carbonyI] -2-methylbutyl3carbamate

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[[4-93a 616 616,119 c or-3 - [[(4-pyridinylamino) carbonyl] amino] phenyl3acetyl ] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3-r [[4- ^193b 616 616.119 chloro-3 - [[(4-pyridinylanioino) carbonyl] amino] phenyl] acetyl3amino] - 2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[[4- 94a 615 615.13 chloro-3 - ([(phenylamino) - carbonyl3amino] phenyl3acetyl3amino] -2, 3,4,9-tetrahydro-1 H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyI] -3 - [[[4- ¹⁹ b 615 615.13 chloro-3 - [[(phenylamino) - carbonyl3amino3phenyl3acetyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[[4- -I i 629 629,157 chloro-3 - [([(phenylmethyl) amino3-carbonyl] amino] phenyl ] acetyI3amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[[4- JÜäb 629 629,157 chloro-3 - [[((phenylmeyl) amino] carbonyl] amino] "phenyl ] acetyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[[4- - 223 616 ^β ι ^β .119 c or-3-i [(2-pyridinylamino) carbonyl3amino3-phenyl] acetyl3amino3-2 ₅ 3,4,9-tetrahydro-lH-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[[4- 22fe 616 ^β ι ^β , nβ cWor-3 - [[(2-pyridinylamino) carDonyl3amino] phenyl] acetyl3-amino3-2,3,4, 9-tetrahydro-1 H-carbazole-3-carboxamide

Example 24:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, H and O.

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyI) -2- -U-Za 400 400.4762 methylρropyl3-2.3, 4, 9-tetrahydro-8-methoxy-1 H-carbazole-3 - carboxamide

(3S) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- ü-Zfe 400 400.4762 methylρroρyl] -2,3,4,9-tetrahydro-8-methoxy-1H carbazole-3-carboxamide

3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- 198 405 404.8955 methylpropylJ-6-chloro-2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide

3- (Acety ^] amino) -N - [(IS) -l- (aminocarbonyl) -2- 199 769 768.9544 methylpropyl] -2,3,4,9-tetrahydro-5-methyl-1H-carbazole-3 - carboxamide 3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- 22Q 769 768.9544 methylpropyl3-2,3,4,9-tetrahydro-8-methyl-1H-carbazole-3-carboxamide

3- (Acetylamino) -N - [(IS) -l- (ammocarbonyl) -2- 221 810 809.7911 meώylpropyl] -5-chloro-2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide

3- (Acetylamino) -N - [(IS) -l- (ammocarbonyl) -2- 202 Bio 809.7911 methylρroρyl] -7-chloro-2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- 203a 388 388.4405 methylpropyl3-6-fluoro-2,3,4,9-tetrahydro-lH-carbazole- 3-carboxamide

(3S) -3- (Acetylaraino) -N - [(lS) -l- (aminocarbonyl) -2- 203b 388 388.4405 methylpropyl3-6-fluoro-2,3,4,9-tetrahydro-lH-carbazole- 3-carboxamide

(3R) -3- (Acetylamino) -N - [(lS) -l- (aminocarbonyl) -2- 24S 400 400.4762 methylpropyl3-2.3 ₃ 4,9-tetrahydro-6-methoxy-lH-carbazole- 3-carboxamide

(3S) -3- (AcetyIamino) -N - [(IS) -l- (aminocarbonyl) -2- .224b 400 400.4762 methylpropyl3-2,3,4,9-tetrahydro-6-methoxy-lH-carbazole -3-carboxamide

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- 205a 384 384.4772 methylpropyl] -2,3,4,9-tetrahydro-6-methyl-1H-carbazole -3-carboxamide

(3S) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- -205b 384 384.4772 methylpropyl3-2,3,4,9-tetrahydro-6-methyl-1H-carbazole -3-carboxamide

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- -2223 3 0 370.4504 methylρropyl] -2,3,4,9-tetrahydro-lH-carbazole-3 -carboxamide

(3S) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- 206b 370 370.4504 methylpropyl3-2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- -207a 439 439.3406 methylpropyl3-7,8-dichloro-2,3,4 _? 9-tetrahydro-lH-carba5: ol-3-carboxamide (3S) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyI) -2-. 9 b 439 439.3406 methylpropyl3-7.8-dichloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- -202a 399 398.504 methylpropyl] -2,3,4,9-tetrahydro-5,8-dimethyl-lH- carbazole

3-carboxamide

(3S) -3- (acetylamino) -N - [(lS) -l- (aminocarbonyl) -2- - 22b 399 398.504 methylpropyl] -2,3,4,9-tetrahydro-5,8-dimethyl-lH- carbazole

3-carboxamide

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- .222a 439 439.3406 methylpropyl3-6, 8-dichloro-2,3,4,9-tetrahydro-1 H-carbazole-3 - carboxamide

(3S) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- -209 439 439.3406 methylρroρyl] -6, 8-dichloro-2 _} 3,4,9-tetrahydro- 1 H-carbazole-3-carboxamide

Example 25:

The synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, I, F, G, F and

O.

(3R) -3 - [[(2S) -2-Ammo-5 - [(ammoiminomethyl) amino3-l- 32i 485 484.6014 o ^χ opentyl3amino3-N - [(lS) - 1 - (aminocarbonyl) -2 - methylpropylJ ^^^^ - tetrahydro-lH-carbazole-S-carboxamide

(3S) -3 - [[(2S) -2-Amino-5 - [(aminoiminomethyl) ammo] -l- -232 ^b 485 484.6014 oxopentyl3amino] -N - [(lS) -l - (aminocarbonyI) -2 - methylρropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(lS) -l- (aminocarbonyl) -2-methylρroρyl] -2,3,4,9-211a 497 496,652 tetrahydro-3 - [[[[2- (l-piperidinyl) ethyI3amino] acetyl] amino3-1H-carbazole-3-carboxamide

(3S) -N - [(lS) -l- (aminocarbonyl) -2-methyIpropyl3-2,3,4,9- ^211b 497 496.652 tetrahydro-3 - [[[|; 2- (l-piρeridinyl) ethyl3amino] acetyl3amino3-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- -212a 529,528,6534 tetrahydro-3 - [[[[2- (lH-indole- 3-yl) ethyl] amino] acetyl] amino] -IH-carbazole-3-carboxamide (3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- -2321. 529 52 ⁸ , 6534 tetrahydro-3 - [[[[2- (1H-indol-3-yl) ethyl3amino3acetyl] amino3-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[[((1,3-232 ^a 520 519.5987 benzodioxol-5-ylmethyl) amino] acetyl] amino] - 2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[[((1,3,220,519,5987 benzodioxol-5-ylmethyl) amino] acetyl] amino3-2 , 3,4, 9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[[(2,2- 22 5Θ6 565,7141 diphenyle yl) am o3acetyl3ammo3-2,3,4,9- tetrahydro-1H-carbazole-3-carboxamide

(3S) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[[(2,2- -ü-fe 566 565.7141 diphenyle l) arnino3acetyl] amino3-2,3, 4,9-tetrahydro-lH-carbazole-3-carboxaπιid

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- .2323 533 532,685 tetrahydro-3 - [[[[2-

[Memyl (phenylmethyl) amino] ethyl] amino3acetyl] amino] -

1 H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- .2 5 533 532,685 tetrahydro-3 - [[[[2-

[raethylhenylmemyl) amino3ethyI] amino] acetyl] amino] - 1H-carbazole-3-carboxamide

Example 26:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, G, F, H and O.

3 - [[[Acetyl [2- (l-ρiρeridinyl) ethylJamino3acetyl] amino3-N- 216 539 538.6883 [(1 S) - 1 - (aminocarbonyl) -2-methylρropyl] -2, 3, 4, 9- tetrahydro-lH-carbazol-3-carboxamide

(3R) -3 - [[[Acetyl [2- .217a. 575 574.7217

[methyl (phenylmethyl) amino] ethyl3amino3acetyl] amino] -N- ϊ (IS) -l- (aminocarbony]) - 2-methylpropyl3-2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide (3S) -3 - [[[Acetyl [2-2W> 575 574.7217

[me yl (phenylmethyl) ammo] ethyl3amino] acetyl] amino] -N- [(1 S) - 1 - (aminocarbonyl) -2-methylρroρyl] -2,3, 4, 9-tetrahydro-lH-carbazol-3- carboxamide

(3R) -3 - [[[acetyl (2,2-diphenylethyl) amino] acetyl3amino] -N- -2323 608 607.7509 [(1 S) - 1 - (aminocarbonyl) -2-methylpropyl] -2.3 , 4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -3 - [[[AcetyI (2,2-diphenylethyl) amino] acetyl] araino3-N- ^ 3 h 608 607.7509

[(IS) -l- (aminocarbonyl) -2-methylpropyI3-2,3,4,9-tetrahydro-1 H-carbazole-3-carboxamide

(3R) -3 - [[[AcetyI (1,3-benzodioxol-5- 219a 562 561.6355 ylmethyl) ammo3acetyl3aιnmo3-N - [(IS) -l- (aminocarbonyl) -

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

(3S) -3 - [[[Acetyl (l, 3-benzodtoxol-5- 3 b 562 561.6355 ylmethyl) amino] acetyl] amino] -N - [(l S) -l - (aminocarbonyl) - 2- methylpropyl3-2,3,4,9-tetrahydro-lH-carbazole-3-carboxamide

(3R) -3 - [[[Acetyl [2- (1H-indole-3-22S 571 570.6902 yl) ethyl] ammo] acetyl] amino] -N - [(IS) -I- (aminocarbonyl) -2 - methylρropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -3 - [[[AcetyI [2- (lH-indol-3- .220b 571 570.6902 yl) ethyl] amino3acetyl3amino3-N - [(lS) -l- (aminocarbonyl) -2-methylρropyl3-2 , 3,4,9-tetrahydro-lH-carbazol-3-carboxamide

3 - [[(2S) -2- (Acetylannno) -5 - [(aminoiminomethyl) amino3-1-221,527,526.6382 oxopentyl] amino3-N - [(IS) - 1 - (aminocarbonyl) -2-methylpropy ! 3-2,3,4, 9-tetrahydro-1H-carbazole-3-carboxamide

Example 27:

The synthesis is carried out on a 0.2 mmol scale according to the instructions C, F, G, I, F, G and P.

Phenylmethyl [(lS, 2S) -2-methyl-l - [[[(3R) -2,3,4,9-222a 589 589,7327 tetrahydro-3 - [[[(lS) -2-methyl- l-

[(methylamino) carbonyl] propyl3amino] carbonyl] -lH-carbazol-3-yl3amino3carbonyl3butyl] carbamate Phenylmethyl [(IS, 2S) -2-methyl-1 - [[[(3S) -2,3,4,9-222 ^{b 589} 589.7327 tetrahydro-3 - [[[(1S) -2-methyl -l- [(methylamino) carbonyl] propyl] aminojcarbonyl] -1H-carbazol-3-yl3aminoJcarbonyl3butyl] carbamate

Example 28:

The synthesis takes place on the 0.2 mmol scale in accordance with the regulations A, F, G, I, F, J and O.

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[(4- -22 3 ⁵ 03 503.0203 chlorophenyl) sulfonyl3amino] -2,3,4,9-tetrahydro -lH-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-meüιylpropyl] -3 - [[(4- -223J- 503 503.0203 chlorophenyl) sulfonyl3amino] -2,3,4,9-tetrahydro-lH carbazole-3-carboxamide

(3R) -N - [(IS) -l- (Aminocarbθnyl) -2-methylpropyl3-2,3,4,9- -224a 407 406,5044 tetrahydro-3 - [(methyisulfonyl) amino] -lH-carbazole- 3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyI3-2,3,4,9- .224b 407 406,5044 tetrahydro-3 - [(methylsulfonyl) amino] -lH-carbazole- 3-carboxamide

(3R) -N - [(IS) -l- (AminocarbonyI) -2-methylpropyl] -2,3,4,9- -2223 469 468,5752 tetrahydro-3 - [(phenylsulfonyl) amino3-lH-carbazole- 3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- - ⁵ 1,469,466,5752 tetrahydro-3 - [(phenylsulfonyl) amino3-lH- carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylρroρyl] -2,3,4,9- -226a 483 482,602 tetrahydro-3 - [[(phenylmethyl) sulfonyl] amino] -lH- carbazole

3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4 _; 9-. ⁶⁴⁸³ 482.602 tetrahydro-3 - [[(phenylmethyl) sulfonyl3amino3-lH-carbazole

3-carboxamide Example 29:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, L and O.

3-phenylpropyl [(3R) -3 - [[[(lS) -l- (aminocarbonyl) -2- -22Z§ 491 490.6006 methylρroρyl] arnino3carbonyl3-2,3,4,9-tetrahydro-lH-carbazole- 3-yl] carbamate

3 "phenylpropyl [(3S) -3 - [[[(IS) -l- (aminocarbonyl) -2- 27b 491 490.6006 memylρropyl3amino3carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3-yl ] carbamate

Phenylmethyl [(3R) -3 - [[[(IS) -l- (aminocarbonyl) -2- M 463 462,547 me ylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3- yl3carbamat

Phenylmethyl [(3 S) -3 - [[[(IS) -l- (aminocarbonyl) -2- -22ab 463 462,547 methylpropyl3amino] carbonyI] -2,3,4,9-tetrahydro-lH-carbazol-3 -yl ] carbamate

Phenyl [(3R) -3 - [[[(IS) -l- (aminocarbony)) - 2- 223 49 448.5202 methylρropyI] amino3carbonyl3-2,3,4,9-tetrahydro-lH-carbazol-3 -yl ] carbamate

Phenyl [(3S) -3 - [[[(IS) -l- (aminocarbonyl) -2- .2220 449 448.5202 methylpropyl3amino] carbonyl3-2,3,4,9-tetrahydro-lH-carbazoI-3-yl3carbamate

Example 30:

The synthesis takes place on a 0.2 mmol scale according to the regulations A, F, G, I, F, M and

O.

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylρropyl] -2,3,4,9- | θa 464 463,5351 tetrahydro-3 - [[(4-nitrophenyl) methyl3amino] - 1H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- 230b 464 463,5351 tetrahydro-3 - [[(4-nitrophenyl) methyl] amino] - 1H-carbazole-3-carboxamide

(3R) -N - [(IS 1- (aminocarbonyl) -2-methylpropyl3-3- _23ia 356 356.4672

(Ethylamino) -2,3,4,9-tetrahydro-lH-carbazol-3-carboxamide (3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3-.-Ä-ü »356 356.4672

(Ethylamino) -2,3,4,9-tetrahydro-lH-carbazol-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- & 433 432,5648 tetrahydro-3 - [(2-ρhenylethyl) amino3-lH-carba2ol -3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- .232b 433 432,5648 tetrahydro-3 - [(2-phenylethyl) amino] -lH -carbazole - 3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- -223a 447 446,5916 tetrahydro-3 - [(3-phenylpropyl) amino] -lH- carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9-23b 447 446,5916 tetrahydro-3 - [(3-phenylpropyl) amino] -lH-carbazole -3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3- [bis (3- - 33c 565 564.7696 phenylpropyl) amino] -2,3,4,9-tetrahydro- 1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- - 34a 489 488,672 tetrahydro-3 - [(6-phenylhexyl) amino] -IH-carbazole -3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- .234b 489 488,672 tetrahydro-3 - [(6-phenylhexyl) amino] -lH-carbazole- 3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- - 35s 370 370,494 tetrahydro-3 - [(l-methylethyl) amino] -IH-carbazole -3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- - 25,370,370,494 tetrahydro-3 - [(l-methylethyl) amino] -IH-carbazoI -3-carboxamide

(3R) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- 23 ^β a SΘÖ 384,5208 tetrahydro-3 - [(l-methylρropyl) amino3-lH- carbazole-3-carboxamide

(3S) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- 236b 385 384,5208 tetrahydro-3 - [(l-methylpropyl) amino3-lH-carbazole- 3-carboxamide (3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2.3 ₎ 4.9-2Za 399 398.5476 tetrahydro-3 - [(3-methylbutyl) amino3-lH-carbazole -3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- Zk 399 398,5476 tetrahydro-3 - [(3-memylbutyl) amino3-1H-carbazole -3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- ∞M 342 342,4404 tetrahydτo-3- (methylamino) -lH-carbazole-3- carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- -22 ^8b 342 342,4404 tetrahydro-3 - (memylamino) - 1 H-carbazole-3 -carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3- -23Bc 356 356.4672

(dimethylamino) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3- ^ 2Sd 356 356.4672

(dimethylamino) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

Example 31:

The synthesis is carried out in 0.2 mmol scale according to the rules A, F, G, I, F, K, and _O.

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- 39a 385 385,4653 tetrahydro-3 - [[(memylamino) carbonyl] amino] -lH- carbazole

3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- 239b 385 385,4653 tetrahydro-3 - [[(methylamino) carbonyl3amino3-1H-carbazole-

3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyJ) -2-methylpropyl3-2.3 _] 4.9-24 ⁰ a 448 447.5361 tetrahydro-3 - [[(phenylamino) carbonyI] amino] - lH-carbazole

3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2.3 _] 4.9-240b 44a 447.5361 tetrahydro-3 - [[(phenylIamino) carbonyl3amino3-lH-carbazole-

3-carboxamide (3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9-, 2 1a. 462 461.5629 tetrahydro-3 - [[[(phenylmethyl) amino3carbonyl3amino] -lH-carba2θl-3-carboxamide

(3S) -N - [(IS) -l- (AminocarbonyI) -2-methylpropyl3 ^ 2,3,4,9- -241b 462,461,5629 tetrahydro-3 - [[[(phenylmethyfyam ojcarbonyljaminoj- 1 H-carbazoI -3-carboxamide

(3R> N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- -242a 476 475,5897 tetrahydro-3 - [[[(2-phenylethyl) amino] carbonyl3amino ] -lH-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- -242b 476 475,5897 tetrahydro-3 - [[[(2-phenylethyl) amino3carbonyl] amino ] -H-carbazole-3-carboxamide

(3R) -N - [(IS 1- (aminocarbonyl) -2-methylpropyl3-3- -242a 454 453.5835

[[(cyclohexylam o) carbonyl] amino3-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (Ainocarbonyl) -2-methylpropyl3-3- 42fe 454 453.5835

[[(cyclohexylan _- mo) carbonyl] amino3-2,3,4,9-tetrahydro-1H-carbazoI-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- -244a 414 413,5189 tetrahydro-3 - [[[(1-methylethyl) amino3carbonyl3amino] -lH-carbazole-3-carboxamide

(3S) -N - [(lS) -l ~ (aminocarbonyl) -2-methylpropyl3-2,3,4,9- 44b 414 413,5189 tetrahydro-3 - [[[(l-methylethyl) araino] carbonyl3amino] -lH-carbazole-3-carboxamide

(3R) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- -245a 42 ^β 427,5457 tetrahydro-3 - [[[(l-methylpropyl) aιnino] carbonyl3amino] -

1 H-carbazole-3-carboxamide

(3S) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9- 245b 428 427,5457 tetrahydro-3 - [[[(l-methylpropyI) amino3carbonyl3amino] -

1 H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- -246a 476 475,5897 tetr-dιyατo-3 - [[[[(lR) - l-ρhenylethyl3amino] carbonyl] amino3-1H-carbazole-3-carboxamide

(3S) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- -246b 476 475,5897 tetrahydro-3 - [[[[(lR) -l- phenylethyl] amino3carbonyl] amino] - 1H-carbazole-3-carboxamide (3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[[(4- -24Za 4 ⁸ 2 481 ^, 9812 chloroenyl) amino3carbonyl3amino] -2.3, 4.9 -tetrahy dro- 1 H-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[[((4- Ik 482 481.9812 chlθhenyl) amino3carbonyl] amino3-2,3,4,9- tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- 2 & Ά 476,475,5897 te1xahyo ^ o-3 - [[[[(IS) -l -phenyleώyl3amino] carbonyl3amino3- 1H-carbazole-3-carboxamide

(3S) -N - [(lS) -l- (Aminocarbθnyl) -2-methylpropyl] -2,3,4,9- -24§b 47S 475,5897 tetrahydro-3 - ([[[(l S) - l-phenyle yI] am o3carbonyl] amino] - lH-carbazole-3-carboxamide

Example 32:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, G, N and

O.

Ethyl (3R) -3 - [[[(IS) -l- (aminocarbonyl) -2- J49a 567 567.0825 ethylpropyl] amino3carboήyl] -3 - [[(4-chloroenyl) acetyl] amino] -l, 2 _: 3,4-tetrahydro-9H-carbazole-9-acetate

Ethyl (3S) -3 - [[[(IS) -l- (aminocarbonyl) -2-. 9b 567 567.0825 roethylpropyl] amino3carbonyl3-3 - [[(4-chlorophenyl) acetyl3amino] -l, 2,3,4-tetrahydro-9H-carbazole-

9-acetate

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- - ^S 0a 599 599.1711 c orρhenyl) acetyl3amino3-2,3,4,9-tetrahydro -9- (3-phenylpropyl) -lH-carba.zol-3-carboxamide

(3S) -N - [(IS) -l- (Anώιocaτbonyl) -2-methylpropyl3-3 - [[(4- 25 b 599 599.1711 c orphenyl) acetyI] amino} -2,3,4,9- tetrahydro-9- (3-phenylpropyl) - 1H-carbazole-3-carboxamide

(3R) -3 - [[[(IS) -l- (aminocarbonyl) -2- 5ia 539 539.0239 methylpropyl3amino3carbonyl3-3 - [[(4-chlorophenyI) acetyl3amino3-l, 2 _> 3,4-tetrahydro-9H -carbazol-

9-acetic acid (3S) -3 - [[[(IS) -l- (aminocarbonyl) -2- sib ⁵³⁹ 539.0289 methylpropyl] amino] carbonyl3-3 - [[(4-chlorophenyl) acetyl3 amino] - 1, 2.3 , 4-tetrahydro-9H-carbazole

9-acetic acid

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[(4- .2 ⁵ 23 ⁵⁵ 1 551.1271 cMorphenyl) acetyl] amino] -2,3,4,9- tetrahydro-9- (3-methylbutyl) -IH-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- -2 _- 2! 55 ^{1 55} 1.1271 chlorophenyl) acetyl3amino3-2.3.4 , 9-tetrahydro-9- (3-methylbutyl) -IH-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- -253a 57 ² 572,1056 chlorophenyl) acetyl] ammo3-2,3,4,9- tetrahydro-9- (4-pyridinylmethyl) -IH-carbazole-3-carboxamide

(3S) -N "[(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- -223b 5 ⁷ 2 572, i05 ^β chlorophenyl) acetyl3ammo3-2,3,4,9- tetrahydro-9- (4-pyridinylmethyl) -lH-carba2θl-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- -254a 5 ⁷ 2 572.1056

CϊWoιphenyl) acetyl] amino3-2,3,4,9-tetrahydro-9- (3-pyridinylmethyl) -lH-carbazoI-3-carboxamide

(3S) -N - [(IS) -l- (arainocarbonyl) -2-methylpropyl3-3 - [[(4- - ^{5 b} 5 ⁷ 2 572,1056 chlorophenyl) acetyl] amino] -2,3,4, 9-tetrahydro-9- (3-pyridinylmethyl) -IH-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- .25 ⁵ a 621 821.1773 chlorophenyl) acetyl] amino3-2,3,4,9 -tetrahydro-9- (2-naphthalinylmethyl) -lH-carbazole-3-carboxamide

(3S) -N - [(lS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- 2§ ^§ k 621 621,1773 chlorophenyl) acetyl3amino] -2,3,4,9- tetrahydro-9- (2-naphthaIinylmethyϊ) -lH-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbony ^] ) -2-methylpropyl3-3 - [[(4- 256a 537 537,1003 chlorophenyl) acetyl3amino] -2,3,4,9-tetrahydro-9 "(2-methylpropyl) -IH-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- ^25β b 5 ³ 7 537,1003 chlorophenyl) acetyl3amino] -2,3,4,9- tetrahydro-9- (2-methylpropyl) -lH-carbazole-3-carboxamate

( ³ ) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- 257a 585 585.1443 chlorophenyl) acetyl] araino] -2,3,4,9-tetrahydro -9- (2-phenylethyl) -IH-carbazole-3-carboxamide (3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - {[(4- .257b 585 585.1443 chlorophenyl) acetyl] amino3-2,3,4,9-tetrahydro-9 - (2-phenylethyl) -lH-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- M 509 509.0467 chlorophenyl) acetyl3amino] -9-ethyl-2,3,4,9-tetrahydro -lH-carbazole-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- -2ä§b 509 509.0467 chlorophenyl) acetyl] araino] -9-ethyl-2, 3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- 2 3 577 577,1649 chlorophenyl) acetyl3amino3-9- (cycloheτcylmethyl) -2,3,4 , 9-tetrahydro-lH-carba2θl-3-carboxamide

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[(4- -2§§b 577 577,1649 chloroenyl) acetyl3amino] -9- (cyclohexylmethyl) -2 , 3,4,9-tetrahydro-1H-carbazole-3-carboxamide

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(4- 22S 607 607.0977 chlorophenyl) acetyl3amino] -9 - [(2,6-difluorophenyl) methyl3-

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

(3S) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[(4- .220b 607 607.0977 chlorophenyl) acetyl] amino] -9 - [(2,6-difluorophenyl ) methyl3-

2,3,4,9-tetrahydro-lH-carbazol-3-carboxamide

Example 33:

The synthesis is carried out on a 0.2 mmol scale according to the regulations A, F, G, I, F, H, N and O.

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- 261 a 489 488.6284 methylpropy ⁾ ] -2,3,4,9-tetrahydro-9- (3- phenylpropyl) -lH-carbazole-3-carboxamide

(3S) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- J ^ b 489 488.6284 methylpropyl] -2,3,4,9-tetrahydro-9- (3- phenylpropyl) -lH-carbazole-3-carboxamide

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- .2223 441 440.5844 methylpropyl3-2,3,4,9-tetrahydro-9- (3-methy! butyl) -lH-carb azole-3-carboxamide (3S) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- -2226 441 440.5844 methylpropyl3-2,3,4,9-tetrahydro-9- (3-methylbutyl) -lH-carbazole-3-carboxamide

(3R) -3- (acetylamino) -N - [(lS) -l- (aminocarbonyl) -2- -2S a en 510.6346 methylpropyl] -2,3,4,9-tetrahydro-9- (2- Naρhthalinylmethyl) - 1H-carbazole-3-carboxamide

(3S) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- 221.511 510.6346 methylpropyl] -2,3,4,9-tetrahydro-9- (2-naphthalinylmethyl ) - 1H-carbazole-3-carboxamide

3- (acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- 224 511 510.6346 methylpropyl3-2,3,4,9-tetrahydro-9- (l-naphthalinylmethyl) - lH-carbazole- 3-carboxamide

3- (AcetyIamino) -N - [(IS) -l- (aminocarbonyl) -2- 222 6 4 ^56, 6222 methylpropyl] -9- (cyclohexylimethyl) -2 _> 3,4,9-tetrahydro-lH-carbazole- 3-carboxamide

(3R) -3- (Acetylamino) -N - [(IS) -l- (aminocarbonyl) -2- .2223 427 426.5576 methylpropyl] -2.3 _J 4,9-tetrahydro-9- (2-methylpropyl ) -lH-carbazole-3-carboxamide

(S) -3- (AcetyIamino) -N - [(IS) -l- (aminocarbonyl) -2- 2 427 426.5576 methylρropyl] -2,3,4,9-tetrahydro-9- (2-methylpropyl) -lH-carbazole-3-carboxamide

Example 34:

The synthesis is carried out on a 0.2 mmol scale according to the regulations D, F, G, I, F, O and subsequent coupling according to Example 6.

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[((IS) -l- 22Za 563 562.7068

(hydroxymethyi) -2-methylpropyl3amino3carbonyl] -2,3,4,9-tetrahydro-lH-carbazol-3-yl] amino3carbonyJ] -2-methylbutyrjcarbamate

Phenylmethyl [(IS, 2S) -l - [[[(3S) -3 - [[f (IS) -l- 22Zi_ 563 562.7068

(hydroxymethyl) -2-methylpropyl] amino3carbonyl3-2,3,4,9-tetrahydro-1H-carbazol-3 -yl3amino3carbonyl] -2-methylbutyljcarbamate Example 35:

Ethyl 2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylate 268

10 mmol (1.6 ml) of ethyl 4-oxocyclohexane carboxylate, 25 mmol (1.4 ml) of glycol and 10 μmol of pTsOH are refluxed in dry toluene on a water separator for 24 h. The solvent is removed and the residue is taken up in ethyl acetate / water. The organic phase is washed with water, dried and evaporated to dryness. The product is distilled in a high vacuum at 120 ° C and 0.03 mbar in the Kugelrohr still. Yield: 1.52 g of 4-ethyl 1,4-dioxaspiro [4,5-decane-8-carboxylate 269.

85 μl of diisopropylamine in 500 μl of dry THF are added dropwise to 0.6 mmol of a 1.6 molar solution of butyllithium in heptane at −20 ° C. under argon and 10 min. stirred. After cooling to ~ 70 ° C., 0.5 mmol (107 mg) of 269 in 200 μl of dry THF are added dropwise, the mixture is brought to 0 ° C. in the course of an hour and the mixture is stirred for a further 30 min. After cooling to -70 * C, 0.7 mmol (106 μl) l-bromo-3-phenylpropane in 300 μl dry THF are added and 30 min. stirred. The mixture is allowed to come to RT and stirred for a further 1 hour. Saturated NFL.C1 solution and n-hexane are carefully added to the organic phase and the mixture is stirred for 10 minutes. The organic phase is separated and washed with water. After filtration through a Whatman filter, the mixture is evaporated to dryness.

Yield: 165 mg of ethyl 8- (3-ρhenyIpropyl) -l, 4-dioxasρiro [4,5] decane-8-carboxylate 270.

0.6 mmol (200 mg) 270 are taken up in 25 ml acetone / 0.1 M HCl 1: 1 and stirred with catalytic amounts of pTsOH at 50 ° C. for 48 h. The acetone is removed on a rotary evaporator and the precipitated product is filtered off, washed with water and dried. Yield: 156 mg of ethyl 4-oxo-8- (3-phenylpropyl) cyclohexane carboxylate 271.

The indolization is carried out as described in Example 1 with phenylhydrazine. Yield after evaporation and preparative HPLC: 65 mg of ethyl 2,3,4,9-tetrahydro-3- (3-phenylpropyl) -lH-carbazole-3-carboxyla 268,

ES-MS: 362 (M + Η *)

Analogously, 80 mg of ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylate 272 is prepared using 2,4-dichlorophenylhydrazine.

ES-MS: 430 (M + Η ¹

Example 36:

2,3,4,9-tetrahydro-3- (3-ρhenyIpropyl) - 1H-carbazole-3-carboxylic acid 273

3.94 mmol (1.31 g) 269 are stirred in 50 ml of methanol and 30 ml of 50% sodium hydroxide solution at 60 ° C. for 4 h. It is acidified with dilute ΗC1 and extracted with ether. Drying with Na ₂ SO ₄ and evaporation yields 1.02 g (85%) of white solid 8- (3-phenylρropyl) -1,4-dioxaspiro [4,53decane-8-carboxylic acid 274.

65 mg 274 are first deprotected with ΗC1 as described for 270 and 271 and then reacted with phenylhydrazine for indolization. Yield after evaporation and preparative ΗPLC: 15 mg 273.

ES-MS: 334 (M + Ef)

Analogously, using 2,4-dichlorophenylhydrazine, 39 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylic acid 275 are prepared.

ES-MS: 478 (M + tf ^" ) Example 37:

2,3,4,9-tetrahydro-N - [(IS) -l- (hydroxymethyl) -2-me% lpropyl] -3- (3-ρhenylpropyl) -lH-carbazole-3-carboxamide 276

0.66 mmol (200 mg) 274 are reacted with 1.5 equivalents of valinol analogously to Example 6. 277 mg of white solid N - [(IS) -1- (hydroxymethyl) -2- methypropyl3-8- (3-phenylpropyl) -1,4-dioxaspiro [4 ₃ 5] decane-8-carboxamide 227 are obtained.

Then, as described for 270 and 271, 0.3 mmol (117 mg) 277 are first deprotected with HCl and then reacted with phenylhydrazine for indolization. Yield after evaporation and preparative HPLC: 15 mg 276.

ES-MS: 418 (M + H ^)

Analogously, using 2,4-dichlorophenylhydrazine, 25 mg of 6,8-dichloro-

2,3,4,9-tetrahydro-N - [(IS) -l- (hydroxymethyl) -2-methylpropyl] -3- (3-phenylpropyl) -lH-carbazole-3-carboxamide 278.

ES-MS: 486 (M + H ⁺ )

Example 38:

2,3,4,9-tetrahydro-3- (3-phenylpropyl) -N- (2-pyridinylmethyl) -lH-carbazole-3-methanamine 279 54 ml of a 1 M solution of LLAIH4 in dry THF are carefully added to a solution of 18 mmol (6 g) 270 in 250 ml of dry THF under argon at room temperature. After heating to reflux for 3 h, it is carefully hydrolyzed with 300 ml of saturated NH 4 Cl solution and mixed with 250 ml of ether. The aluminum salts are filtered off and washed with ether. Drying the ether phase with Na ₂ SO ₄ and evaporation of the solvent yield 3.4 g of S- (3-phenylpropyl) -1,4-dioxaspiro [4,5] decane-8-methanol 280.

5.86 mmol (1.7 g) 280 are dissolved in 60 ml dry DCM and 20 ml dry DMSO. 44 mmol (6.1 ml) of TEA and then carefully 17.6 mmol (2.8 g) of S03-pyridine complex are added under nitrogen at room temperature and the mixture is stirred for one hour. 200 ml of saturated NH 4 Cl solution are then added and the mixture is extracted with 150 ml of ether. Drying the ether phase with NajSO and evaporation of the solvent yield 1.9 g of 8- (3-phenylpropyl) -1,4-dioxaspiro [4,53decane-8-carbaldehyde 281 as a colorless oil.

0.719 mmol of sodium triacetoxyborohydride are added to a mixture of 0.359 mmol (103 mg) of 281 and 0.359 mmol (37 ml) of 2-pyridinemethanamine in 2.5 ml of 1,2-dichloroethane. The mixture is stirred under N _{2 for} 3 h at room temperature. Saturated NaHCO ₃ solution is added and the mixture is extracted with ether. The dried and evaporated ether extract provides 101 mg (76%) of white solid N- [8- (3-phenylpropyl) -1,4-dioxaspiro [4,5] dec-8-yl] -2-pyridine methanamine 282.

Then, as described for 270 and 271, 101 mg 282 are first deprotected with HCl and then reacted with phenylhydrazine for indolization, yield after evaporation and preparative HPLC: 71 mg 279.

ES-MS: 410 (M + H *)

Analogously, using 2,4-dichlorophenylhydrazine, 54 mg of 6,8-dichloro-

2,3,4,9-tetrahydro-3- (3-phenylpropyl) -N- (2-ρyridinylmethyl) -lH-carbazole-3-methanamine 283. ES-MS: 478 (M + H)

Example 39:

(2 ^ -3-Methyl-2 - [[[2,3,4,9-tetrahydro-3- (3-phenylpropyl) -IH-carbazol-3-yl] methyl] - amino] -I-butanol 284

0.368 mmol (106 mg) 281 and 0.368 mmol (38 mg) valinol are dissolved in 1.5 ml dry methanol and 30 min. stirred at room temperature. After cooling to 0 ° C., 0.557 mmol (21 mg) NaBHj are added and the mixture is stirred at room temperature for 1 hour. 0.437 mmol (25 μl) of acetic acid are added and the mixture is stirred at pH 6 for a further 2 h. Saturated NaHCO 3 solution is added and the mixture is extracted with ether. Drying the organic phase with Na ₂ SO ₄ and evaporation yields 106 mg (77%) colorless oil for 270 and 271,

Then, as described for 270 and 271, deprotection and indolization are carried out. Yield after evaporation and preparative HPLC: 18 mg white solid 284. ES-MS: 405 (M + H ⁴ )

Analogously, using 2,4-dichlorophenylhydrazine, 17 mg (2S) -2 - [[[6, S-

Dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -lH-carbazol-3-yl] methyl] amino3-3-methyl-1-butanol 286. ES-MS: 473 (M + H ⁺ )

Example 40: 2,3,4,9-tetrahydro-3- (3-phenylpropyl) -O- (4-pyridinylmethyl) -IH-carbazole-3-methanol

287 0.689 mmol NaH (as a 55% suspension in mineral oil) are added to a solution of 0.344 mmol (100 mg) 280 in 10 ml dry DMF at 0 ° C under a Nu atmosphere. The mixture is allowed to come to room temperature and stirred for 30 minutes. to. 1.377 mmol of 4- (chloromethyl) pyridine are added and the mixture is stirred at 95-100 ° C. overnight. After cooling to room temperature, it is hydrolyzed with 2 ml of water and extracted with ether. Drying the LM and evaporation provides 115 mg of yellow oil 288.

Then, as described for 270 and 271, deprotection and indolization are carried out. Yield after evaporation and preparative HPLC: 14 mg white solid 287. ES-MS: 411 (M + H ⁴ )

Example 41:

Ethyl 3- [2,3,4,9-tetrahydro-3- (3-phenylpropyl) -IH-carbazol-3-yl3-2-propenoate 2S9

0.347 mmol of 281 in 0.5 ml of THF are added dropwise to a solution of 0.378 mmol of ethyl (triρhenyphosphoranylidene) acetate in 1 ml of absolute THF with ice cooling. When the addition is complete, the mixture is allowed to warm to room temperature and stirred for a further 2 days. It is then hydrolyzed with water and extracted with ether. It is dried with N ₂ Sθ4, filtered off phosphine oxide and drying agent and freed from the solvent. Yield 80% ethyl 3- [8- (3-phenylpropyl) - ^] , 4-dioxaspiro [4,5] dec-8-yl3-2-propenoate 290.

Then, as described for 270 and 271, deprotection and indolization are carried out. Yield after evaporation and preparative HPLC: 9 mg white solid 289. ES-MS; 388 (M + H ^* )

Furthermore, the compounds Nos. 293 to 300, 302 and 304 to 306 according to the invention falling under the general formula (I) according to the regulations A, F, G, F, G and O, the connection 301 according to the regulations B, F, G, F, G and O and the connection 303 according to the regulations A, F, G, F, G, F, L and O on a 0.2 mmol scale receive.

DI detection of the GnRH-antagonistic activity of compounds (I) according to the invention

Materials:

Buserelin is purchased from Welding (Frankfurt / Main, Germany). The compound is ^labeled with ¹²⁵ I using the chloramine T method and Na ¹² I (4000 Ci / mmol; Amersham-Buchler, Braunschweig, Germany). The marked substance is purified by reverse phase HPLC on a Spherisorb ODS H column (250 x 4 mm, particle size 3 μm) by means of marriage 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 are sourced from commercial sources to the highest degree of purity available.

Cell Culture:

Alpha T3-1 cells (Bilezikjian et. Al., Mol Endocrinol 5 (1991), 347-355) are in DMEM medium (Gibco-BRL, Eggenstein-Leopoldshafen, Germany) with penicillin (100 IU / ml), streptomycin (0.1 mg / ml) and glutamine (0.01 mol 1) and 10% fetal calf serum (FCS PAA Laboratories, Coelbe, Germany) on plastic tissue culture plates (Nunc, 245 x 245 x 20 mm). CHO-3-ZelIen (Schmid et ^al., J. Biol. Chem. 275 (2000), 9193-9200) are cultivated under identical conditions, except that Ha 's F12 medium (Gibco-BRL) is used ,

10 confluent cell culture plates are rinsed twice with 50 ml of phosphate-buffered saline (PBS). The cells are harvested by scraping with a rubber scraper in 5 ml of PBS and sedimented by centrifugation at 800 rpm for 10 min in a laboratory centrifuge (Heraeus). The cell pellet is resuspended in 5 ml of 0.25 mol / 1 sucrose / 0.01 mol / 1 triethanolamine, pH 7.4. The cells are lysed by freezing in dry ice / ethanol bath and thawing at room temperature for three cycles. The lysate is centrifuged at 900 rpm for 10 min and the sediment is discarded. The supernatant is centrifuged at 18,000 rpm in a Sorvall SS34 rotor for 30 minutes. The pellet (cell membranes) is suspended by pottem in 5 ml assay buffer (0.25 mol / 1 sucrose, 0.01 mol / 1 triethanolamine, pH 7.5, 1 mg / m) ovalbumin) and stored in 200 μl aliquots at -20 ° C. Protein determination is carried out using the Bradford method (Anal. Biochem, 72: 248-254 (1976).

Receptor assay:

Binding tests for competition curves are carried out as triplicates. A test sample contains 60 μl cell membrane suspension (10 μg protein for αT3-1 cells or 40 μg protein for CH03 lines), 20 μl ¹²⁵ I labeled buserelin (100,000 Ipm per sample for competition curves and between 1,500 and 200,000 Ipm for saturation experiments) and 20 μl TestpufFer or test connection solution. The test compounds are dissolved in distilled water or 50% ethanol. Serial dilutions (5 x 10 "* mol / 1 to 5 x 10 ^{" 12} mol / 1) are made in test buffer. The non-specific binding is determined in the presence of an excess of unlabeled buserelin IG ⁶ mol / 1). The test samples are incubated for 30 min at room temperature. Bound and free ligand are separated by filtration (Whatman GF / C filter 2.5 cm diameter) using an Amicon 10x collecting device and washed twice with 5 ml 0.02 mol / 1 Tris / HCl, pH 7.4. The filters are moistened with 0.3% polyethyleneimine (Serva; Heidelberg, Germany) for 30 min in order to reduce the non-specific binding. The radioactivity retained by the filters is determined in a 5-channel gamma counter (Wallac-LKB 1470 Wizard) ,

The table below shows the IC 50 values obtained for the preferred compounds as defined above

The compounds of numbers 293 to 306 are tested according to the methods given below;

Receptor Binding Assay

Materials: ²³ I-TriptoreIin [ ¹²⁵ I- (D) -Trp6-GnRΗj is obtained from Biotrend (Kö, Germany). The specific activity is 2.13 Ci / mmol. All other

Chemicals are obtained from commercial sources in the highest degree of purity available.

Cell Culture:

Transferred LTK ^" cells (ATCC No. CCL-1.3) are in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (1001.U./ml), streptomycin (0.1 mg / ml) and giutamine (0.01 mol 1) and 10% fetal calf serum (FCS; Invitrogen Life Technologies, Germany) on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 mm).

Testuπg:

80% confluent cell culture plates are washed twice with 50 ml of phosphate-buffered saline (PBS) and then removed with 0.01M EDTA solution. The cells are pelleted by centrifugation at 200xg for 5 min in a laboratory centrifuge (Kendro, Germany). The cell pellet is resuspended in 3 ml binding medium (DMEM; lOmM Hepes; 0.5% BSA; 0.1% NaN ₃ ; lg / 1 bacitracin (add fresh, stick 100x); O.lg / 1 SBTI (add fresh, stick lOOOx) and determine the cell number by means of trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted to a concentration of 5x10 ⁵ Z / 0.05 ml with binding medium.

Binding tests for competition curves are carried out as duplicates. The test substances are used as 10mm DMSO solutions. They are diluted to 4 times the final concentration with binding medium. 25 μl of the substance dilution are mixed with 25 μl tracer solution ( ^I2ϊ I-triptorelin). The concentration of tracer is set to approximately SOOOOcpm (measured in the Cobra H, γ-counter, PE Liefe Science, Germany) in the final reaction volume of 100 μl. 200μl silicone / Pa afϊnöl mixture (84%: 16%) are placed in 650μl pointed bottom tubes (Roth, Germany). 50μl of the cell suspension are pipetted onto it, followed by 50μl of the test substance / tracer mixture. The tubes are closed and incubated for 60 min at 37 ° C. in an incubator overhead. After incubation, the samples are centrifuged in a centrifuge (Kendro, Germany) at 900 rpm and then snap frozen in liquid N. The tip with the cell pellet is cut off and transferred to prepared counting tubes (Roth, Germany). The remaining pointed bottom tube with the remaining supernatant is also transferred to a counting tube. The measurement takes place in the γ-counter for 1min / sample.

Evaluation of the samples takes place after calculation of the specific binding compared with untreated cells, after subtraction of the nonspecific binding (excess unlabeled ligand, 1 uM) by means of GraphPad Prism (GraphPad Software, _{Inc., USA).} Functional reporter geassay

Materials;

All chemicals are sourced from commercial sources to the highest degree of purity available.

Cell Culture:

Stable transfected, GnRH receptor-bearing LTK cells (ATCC No. CCL-1.3), with heterologous expression of cAMP responsive elements and a CMV minimal promoter-driven lucäferase reporter gene are used for the Durcl-conducting functional tests.

The cells are in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (1001.U./ml), streptomycin (0.1 mg ml) and glutamine (0.01 mol / l) and 10% fetal calf serum (FCS ; Invitrogen Life Technologies, Germany) cultivated on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 mm).

testing:

80% confluent cell culture plates are washed twice with 50 ml of phosphate-buffered saline (PBS) and then removed with trypsin EDTA solution (Invitrogen Life Technologies, Germany). The cells are pelleted by centrifuge at 200xg for 5min in a laboratory centrifuge (Kendro, Germany). The cell pellet is in 3 ml assay medium (Invitrogen Life Technologies, Germany) with penicillin (100 IU / l), streptomycin (0.1 rag ml) and glutamine (0.01 mol / l) and 10% fetal calf serum (FCS; Invitrogen Life Technolgies, Germany) and the cell count was determined by trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted to a concentration of 1 × 10 ⁴ Z / 100 μl with assay medium. The cells are exposed on white 96-well microtiter plates (Costar, Germany) and incubated for 18 hours in the incubator. To carry out the test, test substances are diluted as 10 mm DMSO solutions in assay medium to 6 times the final concentration used. 25 μl of the test substance are added to 100 μl cells and incubated for 60 min at 37 ° C., 5% CO ₂ . This is followed by the addition of triptorelin (D-Trp6-GnRH) / Rolipram solution (6nM / 6μM) and a new incubation for 6h at 37 ° C, 5% CO ₂ .

After incubation, 50μl lysis / detection buffer (LucLite, PE Life Science) is added and the measurement is carried out in the Lumistar Luminometer (BMG Labtechnologies GmbH, Germany),

The samples are evaluated after calculation of the inhibition compared to untreated stimulated cells, after subtracting the non-stimulated control, using GraphPad Prism (GraphPad Software, Inc., USA) or alternatively using OMMM (Accelrys, Germany) software.

The table below shows the EC ₅₀ values obtained for compounds 293 to 306.

Claims

1, compound of the general formula (I)

(D woπn

the radical R ^{1 is} a hydrogen atom, a C - Cς alkenyl or a Ci - C _& alkyl radical and can optionally be substituted by an aryl, hetaryl radical or the group -COOR ¹¹ , the aryl or hetaryl radical having up to three substituents may be substituted, which are independently selected from the group consisting of -NO ₂ , -CH3, -CF ₃ , -OCH ₃ , -OCF ₃ and halogen atoms and the radical R ^{n is} a hydrogen atom, a Ci - C ₂ alkyl, is a Ci - C ₁₂ aralkyl, an aryl, hetaryl radical or the group -COCH3 and optionally substituted with a substituent selected from the group consisting of -CONH ₂ , -COCH ₃ , -COOCH ₃ , - O ₂ CH3 and aryl radicals can;

the radicals R ² , R, R ⁴ and R ⁵ are each independently a hydrogen atom, a halogen atom, the group -COOH, -CONH ₂ , -CF ₃ , -OCF ₃ , -NO ₂ , -CN, a C _i - C _{6 are} alkyl, a Ct - C _ö alkenyl, a Ci - C ₆ alkoxy, a Ci - C ₃₂ aralkyl, an aryl or hetaryl radical; the radical R ° is the group -CONR ^a R ⁹ , -COOR ⁸ , -CH ₂ NR ⁸ R ⁹ , -CH ₂ R ⁸ , -CHaOR ⁸ or a Cj - C ₁₂ alkenyl radical which may be combined with the radicals R ^B and R ^{9 is} substituted, the radicals R ⁸ and R ⁹ each independently being a hydrogen atom, a Cj - C ₁₂ alkyl, a Ci - C _u aralkyl, a Ci - C _w hetaralkyl, an aryl or

Are hetaryl radicals which can be substituted by one or more substituents selected from the group consisting of -OH, -NH ₂ , -CONHR ¹⁰ , -COOR ¹⁰ , -NH-C (-NH) -NH ₂ and halogen atoms, wherein the radical R ^{10 is} a hydrogen atom, a Ci - C ₁₂ alkyl, a Cj - Cπ

Aralkyl, an aryl or hetaryl radical and optionally with the group

-C0N (R ^u ) _{2 is} substituted, or wherein the radicals R and R ⁹ together can form a ring structure which either consists exclusively of carbon atoms or mixed

There are carbon and heteroatoms;

the radical R ^{7 is} a hydrogen atom, a Ci - C _J2 alkyl, a Ci - C12 alkenyl, a Ci - C ₁₂ aralkyl, an aryl or hetaryl radical, the group -NR ^I2 R ¹³ , -NHCOR ¹⁴ , -NHCONHR ¹⁴ , -NHCOOR ¹⁴ or -NHSO ₂ R ¹⁴ and may optionally be substituted with one or more substituents selected from the group consisting of -OH, -NH ₂ , -CONH2, -COOH and halogen atoms, the radicals R ¹² and R ¹³ are each independently a hydrogen atom, a Ca - C ₆ alkenyl or a Ci - C12 alkyl radical and can optionally be substituted by one or more aryl or hetaryl radicals, which in turn can be substituted by up to three substituents which are independent are selected from the group consisting of -NO ₂ , -CH ₃ , -CF3, -OCH3, -OCF3 and halogen atoms, and the radical R ^{14 is} a hydrogen atom, a Ci - C ₁₂ alkyl, a Ci - C «alkenyl is a Ci - C _{] 2} aralkyl, an aryl or hetaryl radical, which may have an ode r can be substituted by several substituents which are selected from the group consisting of -NO ₂ , -CH ₃ , -OR ¹¹ , -CF ₃ , -OCF ₃ , -OH, -N (R ⁿ ) ₂ , -OCOR ⁿ , -COOH, -CONH ₂ , -NHCONHR ¹¹ , -NHCOOR ¹¹ and halogen atoms;

and the radicals R ^a , R ^h , R °, R ^d , R ^B and R ¹ each independently represent a hydrogen atom, a halogen atom, the group -COOH, -CONH ₂ , -CF ₃ , -0CF ₃ , -NO2, - CN, a Cj - C ₆ alkyl, Ci - CÖ alkoxy, an aryl or hetaryl radical.

with the proviso that the compound of the general formula (I) is not derived from the 3-amino-l, 2,3,4-tetrahydrocarbazo-3-carboxylic acid, 3-amino-6 ~ methoxy-l, 2,3,4 ~ tetra-hydrocarbazole-3-carboxylic acid, 3-amino-6-benzyloxy-l, 2,3,4-tetrahydro-carbazoI-3-carboxylic acid, 3-acetamido-l, 2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl -3-acetamido-l, 2,3,4-tetrahydrocarbazole-3-carboxylate, (-) - menthyl-3-acetamido-l, 2,3 _? 4-tetrahydrocarbazoI-3-carboxylate or 3-tert-butoxycarbonyl-an _- ol, 2,3,4-tetiahydrocarbazole-3-carboxylic acid group is selected.

2. A compound according to claim 1, wherein the radicals *, R ^b , R ^c , R ^d , R ^β and R ^{f are} hydrogen atoms.

3. A compound according to claim I or 2, wherein the radical R ^{1 is} a hydrogen atom.

4. A compound according to any one of claims 1 to 3, wherein the radicals R ² , R ³ ₄ R ⁴ and or R ^{s are} not hydrogen atoms.

5. A compound according to claim 4, wherein the radicals R ² , R ³ , R ⁴ and R ^{5 are} independently the group -CH ₃₎ -CI or -OCH ₃ .

6. The compound of claim 5, wherein the compound from the Phenylmethyl - [(IS _J 2S) -l - [[[(3R) -3 - [[[(IS) -l- (arainocarbonyl) -2-methylpropyl3amino] carbonyl] -2,3,4,9-tetrahydro- 8-methyl-1H-carbazol-3-yl] amino3carbonyl] -2-methylbutyl] carbamate,

Phenylmethyl - [(lS, 2S) -l - [[[(3R) -3 - [[[(lS) -l- (aminocarbonyl) -2- me lpropyl] amino3carbonyl3-6-cWor-2,3,4, 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate, and

PhenylmethyI - [(lS, 2S) -l - [[[(3R) -3 - [[[(lS) -l- (aminocarbonyl) -2-methyropropyl] amino3carbonyl] -2,3,4,9-tetrahydro- 8-methoxy-1H-carbazol-3-yl) amino3carbonyl3-2-methylbutyl3carbamate group is selected.

7. A compound according to any one of claims 1 to 5, wherein the radical R ^{ö is} a hydrophobic alkyl, aryl and / or hetaryl structure radical which is substituted by the radicals R ⁶ and R ⁷ at a distance of two to four single bonds Carbon atom counted from a hydrogen bond donor acceptor system.

8. A compound according to claim 7, wherein the radical R ^ß from that of a phenylalanylamide radical, an isoleucylamide radical, a valyl-4-aminobenzoic acid radical, a valyl-N-methylamide radical, a methyloxymethyl-4-pyridyl radical, a carboxyl radical, an ethyl propenate radical, a carbonylvalylamide radical , a carbonylthreonylamide group, a cyclic carboxamide group, a 4-carboxamidophenylcarboxamide group, a methylaminomethyl-2-pyridyl group, a carbonylvalinol group and a methylvalinol group.

9. A compound according to claim 8, wherein the compound from the phenylmethyl - [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -2-amino-2-oxo-l- (pheny ^] nαethyl) ethyl3am o] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl3amiπo] carbonyl] -2-methylbutyl] carbamate, Phenylmethyl - [(lS, 2S) -l - [[[(3R) -3- |; [[(lS ₁ 2S) -l- (aminocarbonyl) -2-methylbutyl3amino] carbonyl] -2,3,4,9 tetrahydro-IH-carbazol-3-yl] amino3-carbonyl] -2-methylbutyl-carbamate,

Phenylmemyl - [(lS, 2S) -l - [[[(3R) -3 - [[[(lS) -l - [[[4- (aminocarbonyl) - phenyllammoJcarbonyy ^ -mel-hylpropy ^ aminojcarbonylj ^ S ^^ tetrahydro-lH-carbazol-3-yl3amino3carbonyl3-2-methylbutyl] carbamate,

Phenylmethyl - [(IS, 2S) -2-methyl-1 - [[[(3R) -2,3,4,9-tetrahydro-3 - [[[(IS) -2-methyl-1 - [(methylamino ) carbonyl3propyl3amino] carbonyl] -lH-carbazol-3-yl3amino3carbonyl] butyl3carbamate,

2,3,4,9-tetrahydro-3- (3-phenylpropyl) -O- (4-ρyridinylmethyl) -li- ^' -carbazoI-3-methanoL

2,3,4,9-tetrahyro-3- (3-phenylpropyl) -lH-carbazole-3-carboxylic acid,

Ethyl-3- [2,3,4,9-tetrahydro-3- (3-ρhenylpropyl) -lH-carbazol-3-yl] -2-propenoate,

Phenylmethyl - [(IS, 2S) -l - [[((3R) -3 - [[[(IS) -l- (ammocarbonyl) -2-methylpropyl] amino] carbonyl3-2,3,4,9-tetrahydro -lH-carbazol-3-yl] amino3carbonyl] -2-methylbutyl3carbamate,

Phenylmethyl [{IS S} - l - [[[(3R) -3 - [[[((lS, 2R l- (aminocarbonyl) -2-hydroxypropyl] amino3carbonyl] -2,3,4,9-tetrahydro-lH- carbazol-3-yl] amino] carbonyl3-2-raethylbutyl3carbamate,

Phenylmethyl - [(lS, 2S) -l - [[[(3R) -3 - [[(2S) -2- (aminocarbonyl) -l- ρyrtθhdinyl] carbonyl3-2,3,4,9-tetrahydro-lH- carbazol-3-yl3amino] carbonyl3-2-methylbutyl] carbamate,

Phenylmethyl - [(lS, 2S) -l - [[[(3R) -3 - [[(2S) -2- (aminocarbonyl) octahydro-lH-indole

1 -yl] carbonyl3-2,3,4,9-tetrahydro-lH-caτbazol-3 -yl] amino] carbonyl3-2-methylbutyl] carbamate),

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[[4- (aminocarbonyl) phenyI] amino3carbonyl3-

2,3,4,9-tetiahydro-lH-carbazol-3-yl3aminσ] carbonyl3-2-methylbutyl3carbamate _?

2,3,4,9-tetrahydro-3- (3-ρhenylpropyl) -N- (2-pyridinylmethyl) -lH-carbazole-3-methane Phenylmethyl - [(lS, 2S) -l - [[[(3S) -3 - [[[(lS) -l- (hydroxymethyl) -2-methylpropyl3amjno] carbonyl] -2,3,4,9-tetrahydro- 1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl-3-carbamate,

2,3,4,9-tetrahydro-N - [(IS) "1- (hydroxymethyl) -2-methylρroρyl] -3- (3-phenylpropyl) -1H-carbazole-3-carboxamide and

(2 ^ -3-Methyl-2 - [[[2,3,4,9-tetrahydro-3- (3-phenylρroρyl) -lH-carbazol-3-yl] methyl3amino3-l-butanol is selected.

, A compound according to any one of claims 1 to 5, 7 or 8, wherein the radical R ^{7 is} a radical comprising alkyl, aryl and / or hetaryl structures.

, A compound according to claim 10, wherein the R. ⁷ radical consists of a 2,3-biphenylpropionylamino radical, an indanoylamino radical, an indolylacetylamino radical, a 2-naphthylacetylamino radical, a 3-propionylamino radical, a phenylmethylcarboxamide radical substituted on the aromatic system, a phenylhexylpropyl radical and a phenylhexylamine radical existing group is selected.

, Connection according to claim 11, wherein the connection from the

N - [[(3R) -2,3,4,9-tetr.ιhydro-3 - [(l-oxo-2,3-ό phenylpropyl) ammo3-lH-carb '^ 3-ylJcarbonyl3-L-valyl- L-aspaιtamid,

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-3 - [[(2,3-dihydro-lH-inden-l-yl) carbonyl3amino] -2,3,4,9 -tetrahydro-lH-carbazole-3-carboxanid, (3S) -N - [(lS) -l- (ammocarbonyl) -2-methylρropyl] -2,3,4,9-tetrahydro-3 - [(lH-indole -3-ylacetyl) amino3- 1 H-carbazole-3-carboxamide,

(3S) -N - [(lS) -l- (ammocarbonyl) -2-methylρroρyl] -2,3,4,9-tetrahydro-3 - [(2-naphthalinylacetyl) amino3-lH-carbazole-3-carboxaraid, N - [[(3R) -2,3,4,9-tetrahydro-3 - [[(2S, 3S) -3-methyl-l-oxo-2 - [(l-oxo-3-phenyI-propyl) amino3ρentyl3arnino3-1H-carbazol-3-yl] carbonyl] -L-valyl- -asρartamide, (3R) -N - [(IS1- (aminocarbonyl) -2-methylpropyI] -2,3,4,9-tetrahydro-3 - [[(4-methylρhenyl) acetyl] amino3-lH-carbazole-3-carboxamide .

N - [(IS) -l- (aminocarbonyl) -2-methylpropyl3-2,3,4,9-tetrahydro-3 - [[(4-methoxyphenyl) acetyl3amino] -lH-carbazole-3-carboxamide,

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylpropyl] -3 - [[(3-bromophenyl) acetyl3-aminol ^^^^ - tetrahydro-lH-carbazole-S-carboxamide,

(3R) ~ N - [(1 S> 1 - (aminocarbonyl) -2-methylpropyl] -3 - [[(4-fluorophenyl) acetyl3-amino3-2,3,4,9-tetrahydro-1H-carbazole-3 -carboχamid,

(3R) -N - [(IS) -l- (aminocarbonyl) -2-methylρropyI3-3 - [[(4-chlorophenyl) acetyl3-amino] -2,3,4,9-tetrahydro-lH-carbazole-3 carboxamide,

(3R) -N - [(IS 1- (aminocarbonyl) -2-methylpropyl] -2 _J 3,4,9-tetrahydro-3 - [(6-phenylhexyl) amino3-1H-carbazole-3-carboxamide

6,8-dichloro-2,3,4,9-teixahydro-3- (3-phenylpropyl) -lH- ^ rba _- : ol-3-carboxylic acid and

Ethyl-6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -lH-carbazole-3-carboxylate group is selected.

13. A compound according to any one of claims 1 to 5, 7, 8, 10 or 11, wherein the compound is present in the R-configuration on the carbon substituted by the radicals R ⁶ and R ⁷ , provided that the radicals R ⁶ and R ⁷ together Form alpha-amino carboxylic acid structural element.

14. The compound of claim 1, wherein the compound from the phenylmethyl - [(lS, 2S) -l - [[[(3R) -3 - [[[(lS) -l- (aminocarbonyl) -2-methylpropyl3amino] carbonyl] -6,8-dichloro-2,3,4,9-tetrahydro-lΗ-carbazol-3-yl3arnino3carbonyl] -2-methy ^] butyl3carbamate,

Phenylmethyl - [(IS, 2S) -l - [[[(3R) -3- [|; [(IS) -l- (hydroxymethyl) -2-methylpropyl] - araino] carbonyl] -2,3,4, 9-tetrahydro-lH-carbazol-3-yl] amino3carbonyl3-2-methylbutyricarbamate, (2S) -l - [[(3R) -3 - [[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3-yl3carbonyl] -2 -pyrrolidine carboxamide and 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -N- (2-pyridmyImethyl) -lH-carbazole-3-methanamine group is selected.

15. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 14.

16. The pharmaceutical composition according to claim 15, wherein the compound is present in a unit dose of 1 μg to 100 mg per kg of body weight of a patient.

17. A pharmaceutical composition according to claim 15 or 16, wherein the compound is present in combination with at least one further pharmaceutical active ingredient and / or pharmaceutically acceptable carrier in the composition.

18. A method for producing a compound according to any one of claims 1 to 14.

19. A compound according to any one of claims 1 to 14, for use as a pharmaceutical agent.

20. Use of a compound according to any one of claims 1 to 14, for the manufacture of a pharmaceutical composition for the treatment of disease states mediated by G protein-coupled receptors.

21. Use of a compound as defined in claim 1, but including the compounds excluded by name in claim 1, for the preparation a pharmaceutical agent for inhibiting the gonadotropin releasing hormone.

22. Use according to claim 20 or 21 in male fertility control, in hormone therapy, treatment of female sub- or infertility, female contraception and tumor control.

23. Use of a compound as defined in claim 1, but including compounds excluded by name in claim 1, for male fertility control or for female contraception.

24. The compound of claim 1, wherein the compound from the phenylmethyl [(IS, 2S 1 - [[[(3R) -3 - [[[((IS 1- (aminocarbonyl 2-methylpropyl] ammo3 carbonyl] -6.8- difluoro-2,3,4,9-tetrahydro-1H-carba2θl-3-yljamino] carbonyl] -2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS, 2S) -l- (aminocarbonyl) -2-methylbutyl3araino] carbonyl] -8-methoxy-2,3,4 , 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methyl! Butyl] carbamate

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[[(lS, 2S) -l- (aminocarbonyl) -2-memylbutyI] am o3carbonyl3-6, S-dicMor-2,3 , 4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl3-2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- (aminocarbonyl) -3-methylbutyl] amino] carbonyl3-6,8-dichloro-2,3, 4,9-tetrahydro-1H-carbazoJ-3-yl] amino] carbonyl3-2-methylbutyljcarbamate

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[[(lS) -l- (aminocarbonyl) -2-cyclohexylethyl3amino3carbonyl] -6,8-dichloro-2,3,4,9 -tetrahydro-1H-carbazoI-3-yl] amino3carbonyl3-2-methylbutyl3carbamate

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[[(l S) -I- (aminocarbonyl) -2 _! 2-dimethylpropyl] amino3carbonyl] -6,8-dichloro-2,3,4,9-tetrahydro-1H-carba2θl-3-yl] amino] carbonyl] -2-methyl ^] butyl] carbarate Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- (aminocarbonyl) -3-phenylpropyl] amino] carbonyl] -6,8-dichloro-2,3 , 4,9-tetrahydro-1H-carbazol-3-yl] amino3carbonyl3-2-methylbutyl] carbamate

Phenylmethyl [(IS, 2S) -l - [[[(3R) -3 - [[[(IS) -l- (aminocarbonyl) -2-methylbutyl] amino] carbonyl3-6,8-dichloro-2,3, 4,9-tetrahydro-1H-carbazol-3-yl] amino3carbonyl] -2-cyclohexylmethyl] carbamate

Phenylmethyl [(lS, 2S) -l - [[[(3R) -3 - [[[(l S, 2S) -l- (carbθ y) -2-methylbutyl3amino] carbonyl3-6,8-dichloro-2, 3,4,9-tetrahydro-lH-carbazol-3-yI] amino3carbonyI] -2-methylbutyl3carbamate

Phenylmethyl [(1 S) -1 - [[[(3R 3 - [[[(1 S, 2S) - 1 - (aminocarbonyl) -2-methylbutyl] amino] carbonylJ-6,8-dichloro-2,3, 4,9-tetrahydro-lH-carbazol-3-yl3amino] carbonyl3-2- (4-hydroxyphenyl) ethyl 3carbamate

Phenylmethyl [(IS) -l - [[[(3R) -3 - [[[(IS, 2S) -l- (aminocarbonyl) -2-methylbutyl] amino3carbonyl] -6,8-dichloro-2,3,4 , 9-tetrahydro-1H-carbazol-3-yI] amino] carbonyI] -3- (4-hydroxyphenyl) propyl 3 carbamate

Phenylmethyl [(1 S) -l - [[[(3R) -3 - [[[(lS, 2S) -l- (aminocarbonyl) -2-methylbutyl] axnino] carbonyl3-6,8-dichloro-2 ₅ 3 , 4 ₃ 9-tetrahydro-lH-carbazol-3-yl3amino3carbonyl3-3-phenylpropyl3carbamate

Phenylmethyl [(1 S) -l - [[[(3R) -3 - [[[(1 S, 2S) - 1 - (aminocarbonyl) -2-methylbutyl] amino3carbonyl3-6,8-dichloro-2,3, 4,9-tetrahydro-1H-carbazol-3-yl3ammo] carbonyl] -3-methylbutyljcarbamate

Phenylmethyl [(IS) -l - [[[(3R> 3 - [[((IS) -l- (aminocarbonyl) -3-methylbutyI] amino3carbonyI3-6,8-dichloro-2,3,4,9-tetrahydro -IH-carbazol-3-yl] amino] carbonyl3-3-methylbutyl] carbamate

existing group is selected.

25. A pharmaceutical composition comprising at least one compound according to claim 24.

26. The pharmaceutical composition according to claim 25, wherein the compound is present in a unit dose of 1 μg to 100 mg per kg of body weight of a patient.

27. Pharmaceutical composition according to claim 25 or 26, wherein the compound is present in combination with at least one further pharmaceutical active ingredient and or pharmaceutically acceptable carrier in the composition.

28. A method for producing a compound according to claim 24.

29. A compound according to claim 24, for use as a pharmaceutical agent,

30. Use of a compound according to claim 24, for the manufacture of a pharmaceutical composition for the treatment of disease states mediated by G protein-coupled receptors.

31. Use of a compound according to claim 24 for the preparation of a pharmaceutical agent for inhibiting the gonadotropin-releasing hormone.

32. Use according to claim 30 or 31 in male fertility control, in hormone therapy, treatment of female sub- or infertility, female contraception and tumor control.