AU2002361430B2 - Tetrahydrocarbozole derivatives as ligands for G-protein coupled receptors (GPCR) - Google Patents

Description

WO 03/051837 PCT/EP02/14344 TETRAHYDROCARBAZOLE DERIVATIVES AS LIGANDS FOR G- PROTEIN COUPLED RECEPTORS (GPCR) The present invention relates to novel tetrahydrocarbazole derivatives which are ligands of G-protein coupled receptors, and especially antagonists of gonadotropin-releasing hormone, to the preparation thereof, to the use thereof, and to the pharmaceutical compositions which include these tetrahydrocarbazole derivatives. The present invention also relates to a method for treating pathological states mediated by Gprotein coupled receptors in a mammal, in particular a human.

Technical background The structural element which is common to all members of the family of G-protein coupled receptors (GPCR) is the presence of seven transmembrane alpha-helical segments which are connected together by alternating intra- and extracellular loops, with the amino terminus being located on the extracellular side and the carboxy terminus being located on the intracellular side. The family of GPCRs can be divided into a plurality of subfamilies (essentially family A, B and C) with further sequence homologies within these subfamilies.

Since GPCRs are mainly involved in signal reception and transduction, a large number of physiological functions are influenced by them. GPCR ligands are therefore potentially suitable as medicaments for the therapy and prophylaxis of a large number of pathological states. A brief survey of diseases which can be treated with GPCR ligands is given in S. Wilson et al., Pharmaceutical News 2000, 7(3) in Table 1.

The majority of known GPCR ligands has a peptide structure. However, peptide receptor ligands frequently have some serious disadvantages such as, for example, 2 low bioavailability and metabolic instability. This is why there has recently been an intensified search for ligands in the form of small, non-peptide molecules. A special part is played in the search for novel, nonpeptide receptor ligands by so-called "privileged structures". These "privileged structures" are the basic molecular structures which provide ligands for a large number of different receptors. The term "privileged structures" was used for the first time by Evans et al. in connection with benzodiazepine-based CCK (cholecystokinin) A antagonists from the natural product asperlicin Evans et al., J. Med. Chem.

1988, 31, 2235). For proteases for example it has been known for some time that certain structural classes can serve as inhibitors of various enzymes. Whereas descriptions in the past were in particular of mechanism-based inhibitors of various proteases, however, more recently the frequency of examples of compounds which, by reason of their three-dimensional structure, fit well into the active binding region of various enzymes has increased (cf. M. Whittaker, Cur.

Opin. Chem. Biol. 1998, 2, 386; A.S. Ripka et al., ibid., 441). Such "privileged structures" have already been described for GPCRs too. Examples thereof are, besides the aforementioned benzodiazepines, also peptoids, 4-substituted 4-arylpiperidines, but also specific rigidized P-turn mimetics Bunin et al., Ann. Rep. Med. Chem. 1999, 34, 267; R.N. Zuckermann et al., J. Med. Chem. 1994, 37, 2678; G.C.B. Harriman, Tetrahedron Lett. 2000, 41, 8853). A review of this is to be found in A.A. Patchett et al., Ann. Rep. Med.

Chem. 1999, 35, 289. The tetrahydrocarbazole derivatives of the present invention provide a further class of "privileged structures" for GPCRs.

Although the present invention provides ligands for GPCRs in general, the compounds provided by the present invention are suitable in particular as ligands for a particular representative of the class of GPCRs, namely gonadotropin-releasing hormone receptor (GnRH receptor), GnRH receptor can be assigned to subfamily A of GPCRs (cf. U. Gether et al., Endocrine Reviews 2000, 21(1), GnRH is a hormone which is synthesized predominantly, but not exclusively, in mammals by nerve cells of the hypothalamus, is transported via the portal vein into the pituitary and is delivered in a controlled manner to the gonadotrophic cells. Interaction of GnRH with its receptor having seven transmembrane domains stimulates the production and release of gonadotropic hormones by means of the second messenger inositol 1,4,5-trisphosphate and Ca 2 ions. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which are gonadotropins released by GnRH, stimulate the production of sex steroids and gamete maturation in both sexes. In addition to GnRH (also referred to as GnRH1), there are two further forms of GnRH, namely GnRH2 and 3.

The GnRH receptor is used as pharmacological target in a number of disorders which depend on functioning sex hormone production, for example prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. GnRH superagonists or antagonists can be employed successfully for these disorders. A further possible indication is, in particular, male fertility control in combination with a replacement dose of androgens.

One advantage of GnRH antagonists compared with GnRH superagonists is their direct activity in blocking gonadotropin secretion. Superagonists initially bring about overstimulation of the pituitary, leading to increased gonadotropin release and sex steroid release.

This hormonal response is terminated only after a certain delay on the basis of desensitization and downregulation of GnRH receptor concentrations. It is therefore possible that GnRH superagonists, both alone

__M

4 and in combination with testosterone, are unable effectively to suppress sperm production in men and are thus unsuitable for male fertility control. In contrast to this, peptide GnRH antagonists, especially in combination with a replacement dose of androgen, are able to induce a significant oligozoospermia in humans.

However, peptide GnRH antagonists have a number of disadvantages. Thus, they have a considerably lower activity as superagonists and must accordingly be administered in considerably higher dosages. In addition, their oral bioavailability is low, so that they must be administered by injection. Repeated injections in turn lead to a reduction in compliance.

Furthermore, the synthesis of peptide GnRH antagonists is complicated and costly by comparison with nonpeptide compounds.

Quinoline derivatives are disclosed as non-peptide GnRH antagonists for example in WO 97/14682. However, it has not been possible to date to put any non-peptide GnRH antagonists on the market.

Technical problem The problem on which the present invention is based is to provide novel compounds which are suitable for the treatment of GPCR-mediated pathological states and display in particular a GnRH-inhibiting (GnRHantagonistic) effect. The novel GPCR ligands, preferably GnRH antagonists, ought where possible to be superior to known peptide compounds and represent an effective alternative or improvement in relation to known non-peptide compounds. The novel GPCR ligands, especially GnRH antagonists, should in particular have high activity and, where possible, a high oral bioavailability. Their synthesis ought moreover to be possible simply and at minimal cost. The present invention also provides pharmaceutical compositions N comprising the novel non-peptide GPCR ligands, in particular GnRH antagonists.

SA further problem on which the present invention is based is to provide novel GPCR ligands, preferably GnRH antagonists, for use as pharmaceutical remedy and for N use for producing pharmaceutical remedies, comprising the GPCR ligands, preferably the GnRH antagonists.

In addition, it is an object of the present invention to provide a method for the treatment of GPCR-mediated pathological states, in particular for inhibiting GnRH in a \0 mammal, in particular a human.

C All these problems are surprisingly solved by the provision of the novel S 10 tetrahydrocarbazole derivatives, of the pharmaceutical compositions which comprise these tetrahydrocarbazole derivatives, of the method for preparing these tetrahydrocarbazole derivatives, and of the method for the treatment of GPCR-mediated pathological states, preferably for inhibition of the GnRH, in a mammal, in particular a human, through administration of the tetrahydrocarbazole derivatives or the use of the tetrahydrocarbazole derivatives for producing pharmaceutical remedies for the treatment of GPCR-mediated pathological states, in particular of GnRH inhibition.

Summary of the Invention In a first aspect the present invention provides a compound of general formula (I)

R

7 R Rb Rd RR a

R

Re R 3

R

2

R(I)

in which the radical R' is a hydrogen atom, a C 2

-C

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

-CH

3

-CF

3

-OCH

3

-OCF

3 and halogen atoms, and the radical is a hydrogen atom, a Ci-C 12 alkyl, a Ci-C 1 2 aralkyl, an aryl, hetaryl radical or the group -COCH 3 and may optionally be substituted by one substituent selected from the group consisting of -CONH2, -COCH 3

-COOCH

3

-SO

2

CH

3 and aryl radicals; the radicals R 2

R

3 and R 5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2

-CF

3

-OCF

3

-NO

2 -CN, a Ci-C 6 alkyl, a

C

2

-C

6 alkenyl, a CI-C 6 alkoxy, a CI-Ci 2 aralkyl, an aryl or hetaryl radical; the radical R 4 is 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 2

-C

6 alkenyl, a C 1

-CI

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

R

9 -COOR', -CH 2

NRR

9

-CH

2

R

8

CH

2

OR

8 or a C 2

-C

1 2 alkenyl radical which is optionally substituted by the radicals R 8 and R 9 where the radicals R 8 and R 9 are each independently of one another a hydrogen atom, a Ci-Ci 2 alkyl, a Ci-C 1 2 aralkyl, a Ci-C 2 hetaralkyl, an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of-OH, -NH 2 -CONHR', -COOR'O, -NH-C(=NH)-NH 2 and halogen atoms, where the radical R' 1 is a hydrogen atom, a Ci-CI 2 alkyl, a Ci-CI 2 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R 1 2 or where the radicals R 8 and R 9 may together form a cyclic structure which consists either exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; the radical R 7 is a CI-C 12 alkyl, a C 2

-CI

2 alkenyl, a Ci-Ci 2 aralkyl, an aryl or hetaryl radical, the group -NRI2RI3, -NHCOR 14

NHCONHR

14

-NHCOOR

1 4 or -NHSO 2

R

14 and may optionally be substituted by one or more substituents selected from the group consisting of-OH, -NH 2

-CONH

2 -COOH and halogen atoms, the radicals R 1 2 and R 1 3 are each independently of one another a hydrogen atom, a

C

2

-C

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

-CH

3

-CF

3

-OCH

3

-OCF

3 and halogen atoms, and the radical R 14 is a hydrogen atom, a CI-C 12 alkyl, a C 2 -C1 2 alkenyl, a Ci-Ci2 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of-NO 2

-CH

3

-CF

3

-OCF

3

-OH,

-N(R -OCOR", -COOH, CONH 2 -NHCONHR"I, NHCOOR" and halogen atoms; and the radicals R a

R

b

R

c

R

d

R

e and RF are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2

-CF

3

-OCF

3

-NO

2 -CN, a

C

1

-C

6 alkyl, Ci-C 6 alkoxy, an aryl or hetaryl radical; with the proviso that the compound of the general formula is not selected from the group consisting of 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino- 6-methoxy- ,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-1,2,3,4-tetrahydrocarbazole-3carboxylic acid, methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate or 3-tertbutoxycarbonylamino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid.

In a second aspect the present invention provides a pharmaceutical composition comprising at least one compound according to the first aspect of the invention.

In a third aspect, the present invention provides tetrahydrocarbazole derivatives of general formula according to the first aspect of the invention for use as a pharmaceutical remedy.

In a fourth aspect, the present invention provides the use of a tetrahydrocarbazole derivative of general formula according to the first aspect of the invention for producing a pharmaceutical remedy for the treatment of GPCR-mediated pathological states.

In a fifth aspect, the present invention provides the use of a tetrahydrocarbazole derivative of general formula according to the first aspect of the invention but including the compounds specifically excluded from the first aspect for producing a pharmaceutical remedy for inhibiting GnRH.

In a sixth aspect the present invention provides a method of treating pathological states mediated by G protein-coupled receptors in a mammal, preferably a human, the method comprising administering to the mammal an effective amount of a compound of general formula according to the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention.

In a seventh aspect the present invention provides a method of inhibiting gonadotropin-releasing hormone in a mammal, preferably a human, the method comprising administering to the mammal an effective amount of a compound of general formula according to the first aspect of the invention, but including the compounds specifically excluded in the first aspect of the invention, or a pharmaceutical composition according to the second aspect of the invention.

Also disclosed herein is a method for preparing tetrahydrocarbzaole derivatives of the general formula This method comprises for example the steps of condensation of a cyclohexanone derivative, which is tethered to a solid phase and is expediently substituted, with a suitably substituted phenylhydrazine derivative, a subsequent derivatization depending on the desired structure of the final compound, and finally elimination from the solid phase and isolation of the product.

Detailed description of the invention The present invention relates to novel tetrahydrocarbazole compounds of the general formula (I)

R

7

R

6 Rd Ra R Re Rf N R 4

R

2

(I)

in which the radical R' is a hydrogen atom, a C 2

-C

6 alkenyl or a C 1

-C

6 alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group -COOR i where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of -NO 2

-CH

3 -CF3, -OCH 3

-OCF

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

-COCH

3

-COOCH

3

-SO

2

CH

3 and aryl radicals; the radicals R 2

R

3 and R 5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 -CF3, -OCF 3

-NO

2 -CN, a Ci-C 6 alkyl, a

C

2

-C

6 alkenyl, a CI-C 6 alkoxy, a CI-CI 2 aralkyl, an aryl or hetaryl radical; the radical R 4 is a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 -CF3, -OCF 3

-NO

2 -CN, a C 1

-C

6 alkyl, a C 2

-C

6 alkenyl, a Ci-CI 2 aralkyl, an aryl or hetaryl radical; the radical R 6 is the group -CONR 8

R

9

-COOR

8

-CH

2

NRR

9

-CH

2

R

8 CH20R 8 or a C 2 -C1 2 alkenyl radical which is optionally substituted by the radicals R 8 and R 9 where the radicals R 8 and R 9 are each independently of one another a hydrogen atom, a Ci-C 1 2 alkyl, a Ci-CI 2 aralkyl, a Ci-CI 2 hetaralkyl, an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of -OH, -NH 2

-CONHR

10

-COOR

10

-NH-C(=NH)-NH

2 and halogen atoms, where the radical R 10 is a hydrogen atom, a CI-C 12 alkyl, a Ci-C 12 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R")2, or where the radicals R 8 and R 9 may together form a cyclic structure which consists either exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; the radical R 7 is a Ci-C 2 alkyl, a C 2

-C

1 2 alkenyl, a Ci-C 1 2 aralkyl, an aryl or hetaryl radical, the group -NR 2 R 3

-NHCOR

4

-NHCONHR

4

-NHCOOR

14 or -NHSO 2

R

14 and may optionally be substituted by one or more substituents selected from the group consisting of -OH, -NH 2

-CONH

2 -COOH and halogen atoms, the radicals R 12 and R 13 are each independently of one another a hydrogen atom, a C 2

-C

6 alkenyl or a C 1

-C

1 2 alkyl radical and may optionally be substituted by one or more aryl or hetaryl radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -NO 2

-CH

3

-CF

3

-OCH

3

-OCF

3 and halogen atoms, and the radical R 14 is a hydrogen atom, a CI-C1 2 alkyl, a Ci-C1 2 alkenyl, a Ci-C1 2 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of

-NO

2

-CH

3

-OR

11

-CF

3

-OCF

3 -OH, -N(R 11 2

-OCOR

11 -COOH, -CONH 2

-NHCONHR

11

-NHCOOR

1 and halogen atoms; and the radicals Ra, R b

R

c

R

d

R

e and R are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2

-CF

3

-OCF

3

-NO

2 -CN, a

CI-C

6 alkyl, Ci-C 6 alkoxy, an aryl or hetaryl radical; with the proviso that the compound of the general formula is not selected from the group consisting of 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic 9 acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4tetrahydrocarbazole-3-carboxylic acid, 3-acetamido- 1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3carboxylate or 3-tert-butoxycarbonylamino-1,2,3,4tetrahydrocarbazole-3-carboxylic acid.

One embodiment of the invention are compounds of the general formula as indicated above with all the meanings indicated above for the radicals contained in where the radical R 1 is a heteroalkyl or a hetarylalkyl radical.

The basic tetrahydrocarbazole structures of those compounds which are specifically excluded above from the compounds falling within the definition of the general formula were introduced by Y. Maki et al.

in Chem. Pharm. Bull. 1973, 21 2460-2465 and by R. Millet et al. in Letters in Peptide Science 1999, 6, 221-233.

The terms indicated for explanation of the compounds of the general formula have in particular the following meaning: Ci-C 6 or Cl-C 12 "alkyl radical" means a branched or unbranched, cyclic or acyclic, optionally substituted alkyl group having 1 to 6 or 1 to 12 carbon atoms, respectively. Representative examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, tert-butyl, n-pentyl, 2,2dimethylpropyl, 3-methylbutyl, n-hexyl, n-heptyl, noctyl,.. n-nonyl, n-decyl, n-undecyl and n-dodecyl groups, and cyclic groups, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl groups, 1-cyclopropyl-, 1-cyclobutyl-, 1-cyclopentyl-, 1-cyclohexyl-, 1-cycloheptylethyl-, 2-cyclopropyl-, 2- 10 cyclobutyl-, 2-cyclopentyl-, 2-cyclohexyl-, 2cycloheptylethyl groups and the like, but are not restricted to these.

C

2

-C

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

C

2

-C

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

C

1

-C

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

11 "Aryl radical" means an optionally substituted mono- or polycyclic aromatic group. Representative examples of such aryl groups include phenyl, naphthyl groups and the like, but are not restricted to these.

The term "hetaryl radical" is identical with the term "heteroaryl radical" and represents an aryl group as defined above which includes in its structure one or more heteroatoms, in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. Representative examples of such hetaryl or heteroaryl groups include unsubstituted hetaryl radicals and substituted hetaryl radicals, in particular imidazolyl, pyridyl, quinolinyl groups and the like, but are not restricted to these.

The term "cyclic structure" includes optionally substituted mono- or polycyclic cyclic structures with a varying number of ring members, in particular five-, six- and seven-membered cyclic structures. These cyclic structures may include besides carbon atoms also one or more heteroatoms such as, in particular, nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. The cyclic structures may include saturated, but also partially or completely unsaturated, structural elements. Representative examples of such cyclic structures include aza-, oxa-, thia-, phosphacyclopentane-, -cyclohexane-, -cycloheptane-, diaza-, dioxa-, dithia-, diphosphacyclopentane, -cyclohexane, -cycloheptane basic cyclic structures and the like, and basic cyclic structures with mixed heteroatom exchange, but are not restricted to these.

"Halogen atoms" include in particular fluorine, chorine, bromine and iodine atoms, particularly preferably chlorine atoms.

Reference may also be made at this point to the fact that, besides the compounds of the general formula 12 as defined above, which are mentioned per se, the present invention also encompasses physiologically tolerated derivatives or analogs, especially also salts of these compounds.

It may further be remarked at this point that the term "receptor ligand" or "ligand" is intended for the purposes of the present invention to designate any compound which binds in any manner to a receptor (in the present invention, the receptor is a GPCR receptor, preferably a GnRH receptor) and induces either an activation, inhibition or other conceivable effect on this receptor. The term "ligand" thus includes agonists, antagonists, partial agonists/antagonists and other ligands which elicit on the receptor an effect which resembles the effect of agonists, antagonists or partial agonists/antagonists. The compounds of the invention of the general formula are preferably GnRH antagonists.

One embodiment of the present invention are novel tetrahydrocarbazole derivatives of the invention of the general formula in which the radical R 7 is not a hydrogen atom when the radical R 6 is at the same time an alkyl radical.

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

Preferred novel tetrahydrocarbazole derivatives of the invention of the general formula are those compounds in which the radicals Ra, R b

R

c Rd, Re and R f are hydrogen atoms.

Likewise preferred novel tetrahydrocarbazole derivatives of the invention of the general formula (I) are those compounds in which the radical R 1 is a hydrogen atom.

SPreferred novel tetrahydrocarbazole derivatives of the Sinvention of the general formula are additionally Sthose compounds in which the radicals R 2

R

3

R

4 and/or l 5 R 5 are not hydrogen atoms. Particularly preferred compounds of the general formula in this connection are those in which the radicals R 2

R

3

R

4 and R 5 are Sindependently of one another methyl, chloro or methoxy radicals. Very particularly preferred compounds of the C 10 general formula in this connection are those in 0 which at least the radical R 2 is not a hydrogen atom, C( especially the compounds phenylmethyl bonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9tetrahydro-8-methyl-lH-carbazol-3-yl]amino]carbonyl]-2methylbutyl]carbamate (compound no. 150a in the examples) phenylmethyl bonyl)-2-methylpropyl]amino]carbonyl]-6-chloro-2,3,4,9tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (148a), phenylmethyl (aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9tetrahydro-8-methoxy-lH-carbazol-3-yl]amino]carbonyl]- 2-methylbutyl]carbamate (147a).

Preferred novel tetrahydrocarbazole derivatives of the invention of the general formula are also those compounds in which R 6 is a hydrophobic radical which includes alkyl, aryl and/or hetaryl structures and which carries a hydrogen bond donor-acceptor system at a distance of from two to four single bonds, counting from the carbon atom substituted by the radicals R 6 and

R

7 Particularly preferred compounds of the general formula are those where the radical R 6 is a carbonylphenylalanylamide residue, in particular the compouna phenylmethyl S-[[(S)-2-amino-2oxo-l-(phenylmethyl)ethyl]amino]carbonyl]-2,3,4,9tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyllcarbarnate (66), is a carbonyl isoleucylamide residue, in particular the compound phenylmethyl (1S, 2S) -I- (aminocarbonyl) -2-methylbutyllaminolcarbonyl] -2,3,4,9tetrahydro-1H-carbazol-3-yll amino] carbonyl] -2-methylbutyllcarbamate (64), is a carbonyl valyl-4-aminobenzamide residue, in particular the compound phenylmethyl (1S, 2S)--I [3R) -l- (aiinocarbonyl) phenyl] amino] carbonyl] -2-methylpropyl] amino] carbonyl] 4, 9-tetrahydro-1H-carbazol- 3-yll amino] carbonyl] -2-methylbutyll carbamate is a carbonyl valy!-N-methylamide residue, in particular the compound phenylmethyl [(1S,2S)-2-methyl-1-[ 2,3,4,9-tetrahydro-3-[ (1S)-2-rethyl-l-[ (methylamino)carbonyllpropyllanino] carbonyl] -lH-carbazol-3yl) amino) carbonyl]butyl) carbamate (222a), is a methyloxymethyl-4-pyridyl radical, in particular the compound 2,3,4, 9-tetrahydro-3- (3-phenyipropyl) -0- (4-pyridinylmethyl)-1H-carbazole-3-nethanol (287), is a carboxyl radical, in particular the compound 2,3,4, 9-tetrahydro-3- (3-phenyipropyl) -lH-carbazole-3carboxylic acid (273), or is an ethyl propenoate radical, in particular the compound ethyl 3-[2,3,4,9-tetrahydro-3-(3phenyipropyl) -lH-carbazol-3-yl] -2-propenoate (289).

Likewise particularly preferred are compounds of the general formula in which the radical R 6 is a carbonylvalylamide residue, in particular the compound phenylmethyl bonyl)-2-methylpropyllaminolcarbonyl]-2,3,4, 9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl) -2methylbutyllcarbamate (58), is a carbonylthreonylamide residue, in particular the compound phenylinethyl (lS, 2S) 2R) 1- (aminocarbonyl) -2-hydroxypropyllIamino] carbonyl]I 2, 3 4, 9-tetrahydro-lH-carbazol-3-yl I amino] carbonyl] -2methylbutyl] carbamate, 15 is a cyclic carboxamide residue (such as, for example, a carbonylprolylanide radical, in particular the compound phenylmethyl (aminocarbonyl) -1-pyrrolidinyl] carbonyl] 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2methylbutyl] carbamate (181a), or a carbonyloctahydroindolyl-2-carboxamide residue, in particular the compound phenylmethyl [(lS,2S)-l- [[II(3R) (aminocarbonyl)octahydro-lH-indol-lyllcarbonyl]-2,3,4,9-tetrahydro-lH-carbazol-3ylllaxino] carbonyl] -2-methylbutyl] carbamate (190a)), is 4-carboxamidophenylcarboxamide residue, in particular the compound phenylmethyl [(lS,2S)-l- [HI (aminocarbonyl)phenyl] amino] carbonyl] 2,3,4,9-tetrahydro-1H-carbazol-3-yllaxninolcarbonyl]-2methylbutyllcarbamate (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 (279), is a carbonylvalinol residue, in particular the compounds phenylmethyl (hydroxymethyl) -2-methyipropyl] amino] carbonyl] -2,3,4,9tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (267b) and 2,3,4,9-tetrahydro-N-[ (lS)-l-(hydroxymethyl)-2methyipropyl] (3-phenylpropyl) -lH-carbazole-3carboxamide (276) or is a methylvalinol residue, in particular the compound (2S)-3-methyl-2-i[[[2,3,4,9-tetrahydro-3-(3phenylpropyl) -1H-carbazol-3-yllmethyll amino] -1-butanol (284).

Pref erred novel tetrahydrocarbazole derivatives of the invention of general formula are also compounds in which R 7 is a hydrophobic radical comprising alkyl, aryl and/or 'hetaryl structures. Particular preference is given in this connection to compounds of the general f ormula in which the radical R 7 is a 2,3-biphenylpropionylamino radical, in particular the compound 3,4, 9-tetrahydro-3- 3-diphelylpropyl) amino] -1H-carbazol-3-yll carbonyl] -L-valyl-Laspartamide (18), is an indanoylamino radical, in particular the compound (3 R) (1S) (aminocarbonyl) 2-methylpropyl-3 [[(2,3-dihydro-1H-inden-1-yl)carbonyl]amino]-2,3,4,9tetrahydro-lH-carbazole-3-carboxamide (162a), is an indolylacetylamino radical, in particular the IND compound (3S)-N-[(lS)-l-(aminocarbonyl)-2-methylci 10 propyl] 3,4, 9-tetrahydro-3- (lH-indol-3--ylacetyl) arino-lH-carbazole-3-carboxamide (164b), c-iis a 2 -naphthylac etyl amino radical, in particular the compound (3S) -1-(aminocarbonyl) -2-methylpropyl]-2,3,4,9-tetrahydro-3-[ (2-naphthalinylacetyl) amino] -lH-carbazole-3-carboxamide (161b) or is a 3-propionylamino radical. A further preferred compound is N-[[(3R)-2,3,4,9-tetrahydro-3-HI2S,3S)-3rethyl-l-oxo-2-[ (l-oxo-3-phenylpropyl)aminojpentyl]amino) -lH-carbazol-3-ylI carbonyl] -L-valyl-L-aspartamide (22).

Likewise particularly preferred are compounds of the general formula in which R 7 is a phenylmethylcarboxamide residue substituted on the aromatic system, in particular the compounds (3R)-N-[(1S)-l-(aninocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[ rnethylphenyl) acetyl] amino] -lH-carbazole-3-carboxamide (165a), N-[(1S)-l--(aminocarbonyl)-2-methylpropyl]-2,3, 4 ,9tetrahydro-3- [(4-methoxyphenyl) -acetyllaminol -lHcarbazole-3-carboxamide (175), (3R) -1-(aminocarbonyl) -2-methylpropyll bromophenyl)acetyllamino] 3,4,9-tetrahydro-lHcarbazole-3-carboxamide (96), (3R) -1-(aminocarbonyl) -2-methylpropyl] fluorophenyl)acetyllamino]-2,3,4, 9-tetrahydro-lHcarbazole-3-carboxamide (91), (3R) -1-(aminocarbonyl) -2-methylpropyl] chlorophenyl)acetylllamino] 9-tetrahydro-lHcarbazole-3-carboxamide (167a), 17 is a phenylhexylamine residue, in particular the compound (3R)-N-[(S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[(6-phenylhexyl)amino]-1Hcarbazole-3-carboxamide (234a) or is a phenylpropyl radical, in particular the compounds 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-lH-carbazole-3-carboxylic acid (275) and ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1Hcarbazole-3-carboxylate (272).

Also preferred are those novel compounds of the invention of the general formula which are in the R configuration at the carbon atom substituted by the radicals R 6 and R 7 when the radicals R 6 and R 7 together form an alpha-amino carboxylic acid structural element.

Most preferred for the purposes of the present invention are the compounds phenylmethyl [(1S,2S)-1- [[[(3R)-3-[[[(1S)-1-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-lHcarbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (184a), phenylmethyl (hydroxymethyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9tetrahydro-lH-carbazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (267a), phenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-methoxy-lHcarbazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide (189a) and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)- N-(2-pyridinylmethyl)-lH-carbazole-3-methanamine (283).

Further representatives of novel compounds of the invention of the general formula including their preparation, are indicated in the examples.

The novel tetrahydrocarbazole derivatives of the invention, as defined above, are ligands of GPCR and can be employed in particular for the inhibition, i.e.

as antagonists, of gonadotropin-releasing hormone for example for male fertility control, for hormone 18 therapy, for the treatment of female sub- or infertility, for female contraception and for tumor control.

In male fertility control, the compounds of the invention bring about a reduction in spermatogenesis.

Combined administration with androgens, e.g.

testosterone or testosterone derivatives such as, for example, testosterone esters, is preferred. The testosterone derivatives can in this case be administered for example by injection, e.g. by intramuscular depot injection.

The compounds of the invention can also be employed where appropriate in combination with other hormones, e.g. estrogens or/and progestins, in hormone therapy, for example for the treatment of endometriosis, uterine leiomyomas and uterine fibroids. Combinations of the GnRH antagonists of the invention and tissue-selective partial estrogen agonists such as Raloxifen® are particularly preferred. In addition, the compounds of the invention can be employed in hormone replacement therapy. The compounds of the invention can moreover be employed to increase female fertility, for example by inducing ovulation, and for the treatment of sterility.

On the other hand, the novel compounds of the invention are also suitable for contraception in women.

Thus, the GnRH antagonist of the invention can be administered on days 1 to 15 of the cycle together with estrogen, preferably with very small estrogen dosages.

On days 16 to 21 of the cycle of intake, progestagen is added to the estrogen/GnRH antagonist combination. The GnRH antagonist of the invention can be administered continuously throughout the cycle. It is possible in this way to reduce the hormone dosages and thus achieve a reduction in the side effects of nonphysiological hormone levels. It is additionally possible to achieve 19 advantageous effects in women suffering from polycystic ovary syndrome and androgen-dependent disorders such as acne, seborrhea and hirsutism. An improved control of the cycle by comparison with previous administration methods is also to be expected. Further indications are benign prostate hyperplasia, gonadal protection during chemotherapy, controlled ovary stimulation/assisted reproduction techniques, infantile development disorders, e.g. precocious puberty and polycystic ovaries.

Finally, the compounds of the invention, as defined above, can also be employed for the treatment of hormone-dependent neoplastic diseases such as premenopausal cancer, prostate cancer, ovarian cancer and endometrial cancer, by suppressing endogenous sex steroid hormones.

The novel compounds of the invention, as defined above, are, as GPCR ligands, in particular GnRH antagonists, suitable for the treatment of the pathological states detailed above for administration to mammals, in particular humans, but also for veterinary medical purposes, e.g. in pets and productive livestock, but also in wild animals.

Administration is possible in a known manner, for example orally or non-orally, in particular topically, rectally, intravaginally, nasally or by injection or implantation. Oral administration is preferred. The novel compounds of the invention are converted into a form capable of administration and, where appropriate, mixed with pharmaceutically acceptable carriers or diluents. Suitable excipients and carriers are described for example in Ullman's Encyclopedia of Technical Chemistry, Vol. 4 (1953), 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; H. v.

Czetsch-Lindenwald, "Hilfsstoffe fir Pharmazie und angrenzende Gebiete", Pharm. Ind. 2, 1961, 72ff; 20 Dr. H.P. Fiedler, "Lexikon der Hilfsstoffe ffr Pharmazie, Kosmetik und angrenzende Gebiete", Cantor KG, Aulendorf in Wirttemberg, 1971.

Oral administration can take place for example in solid form as tablet, capsule, gel capsule, coated tablet, granulation or powder, but also in the form of a drinkable solution. For oral administration, the novel compounds of the invention of the general formula as defined above, can be combined with known and conventionally used, physiologically tolerated excipients and carriers such as, for example, gum arabic, talc, starch, sugars such as, for example, mannitol, methylcellulose, lactose, gelatin, surfaceactive agents, magnesium stearate, cyclodextrins, aqueous or nonaqueous carriers, diluents, dispersants, emulsifiers, lubricants, preservatives and flavors essential oils). The compounds of the invention can also be dispersed in a microparticulate, e.g. nanoparticulate, composition.

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. Administration as extended-release form is also possible where appropriate. Implants may contain inert materials, e.g. biodegradable polymers or synthetic silicones such as, for example, silicone rubber. Intravaginal administration is possible for example by means of pessaries. Intrauterine administration is possible for example by means of diaphragms, etc. In addition, transdermal administration, in particular by means of a formulation suitable for this purpose and/or suitable means such as, for example, patches, is also provided.

As already explained above, the novel compounds of the invention can also be combined with other active 21 pharmaceutical ingredients. During a combination therapy, the individual active ingredients can be administered simultaneously or separately, in particular either by the same route orally) or by separate routes orally and as injection). They may be present and administered in identical or different amounts in a unit dose. It is also possible to apply a particular dosage regimen where this appears expedient. It is also possible in this way to combine a plurality of the novel compounds of the invention together.

The dosage may vary within a wide range depending on the nature of the indication, the severity of the disorder, the mode of administration, the age, sex, body weight and sensitivity of the subject to be treated. It is within the abilities of a skilled worker to determine a "pharmacologically effective amount" of the combined pharmaceutical composition. Unit doses of from 1 gg to 100 mg, particularly preferably from 1 g to 10 mg and most preferably from 1 pg to 1 mg, per kg of body weight of the subject to be treated are preferred. Administration can take place in a single dose or a plurality of separate dosages.

In a further aspect of the present invention, accordingly, the present invention also encompasses pharmaceutical compositions as described above, comprising at least one of the novel compounds of the invention, as defined above, and where appropriate pharmaceutically acceptable carriers and/or excipients.

Preferred and particularly preferred pharmaceutical compositions are those comprising at least one of the aforementioned preferred or particularly preferred novel compounds of the invention, in particular the compounds mentioned by name above. In pharmaceutical compositions according to the present invention it is possible, besides the at least one compound of the general formula as defined above, for other active 22 pharmaceutical ingredients also to be present, as already described in detail above.

At least one of the novel compounds of the invention, as defined above, is present in the pharmaceutical compositions of the invention in one of the unit doses mentioned above as preferred, particularly preferred or most preferred, specifically and preferably in an administration form which makes oral administration possible.

In addition, in a further aspect, the present invention provides compounds of the general formula as defined above for use as pharmaceutical remedy.

Preferred tetrahydrocarbazole compound of the invention of the general formula as defined above, for use as pharmaceutical remedy are in turn those compounds mentioned above as preferred and particularly preferred compounds, in particular the preferred compounds of the invention mentioned by name, and the compounds mentioned in the examples.

Concerning pharmaceutical compositions comprising compounds of the invention, and concerning compounds of the invention for use as pharmaceutical remedy, reference may be made in relation to the possibilities for use and administration to what has already been said concerning the novel compounds of the invention, as defined above.

In another aspect, the present invention also provides the use of at least one tetrahydrocarbazole derivative of the invention of the general formula as defined above, with as defined at the outset the tetrahydrocarbazoles disclosed in the publications by Millet et al. and Maki et al. being excluded from the meaning of the general formula for producing a 23 pharmaceutical remedy for the treatment of GPCRmediated diseases, in particular for inhibition of gonadotropin-releasing hormone (GnRH).

In addition, the present invention provides in a further aspect the use of at least one compound of the invention of the general formula as defined above, but including the compounds previously excluded by name from the publications of Millet et al. and Maki et al., namely 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-l,2,3,4-tetrahydrocarbazole-3carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-1,2,3,4tetrahydrocarbazole-3-carboxylic acid, methyl 3acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-l,2,3,4-tetrahydrocarbazole-3carboxylate and 3-tert-butoxycarbonylamino-l,2,3,4tetrahydrocarbazole-3-carboxylic acid, for producing a pharmaceutical remedy for inhibiting GnRH, preferably for male fertility control, for hormone therapy, for the treatment of female sub- and infertility, for female contraception and for tumor control. Stated more clearly, the term "a compound of the general formula as defined above, but including the compounds excluded above by name" means a compound of the general formula (I) 24 in which the radical R 1 is a hydrogen atom, a C 2

C

6 alkenyl or a C 1

C

6 alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group

-COOR

1 1, where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of -NO 2

-CH

3 -CF3, -OCH 3

-OCF

3 and halogen atoms, and the radical R 11 is a hydrogen atom, a CI C 1 2 alkyl, a

C

1

C

1 2 aralkyl, an aryl, hetaryl radical or the group

-COCH

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

-CONH

2

-COCH

3

-COOCH

3 -S0 2

CH

3 and aryl radicals; the radicals R 2

R

3

R

4 and R 5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2

-CF

3

-OCF

3

-NO

2 -CN, a C 1

C

6 alkyl, a

C

1

C

6 alkenyl, a C 1 Cs alkoxy, a C 1 C12 aralkyl, an aryl or hetaryl radical; the radical R 6 is the group -CONR R 9 -COOR, -CH 2 NR R 9

-CH

2

R

8

-CH

2 0R 8 or a C 1

C

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

C

12 alkyl, a C 1

C

12 aralkyl, a C 1

C

12 hetaralkyl,. an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of -OH, -NH 2

-CONHR

10

-COOR

10

-NH-C(=NH)-NH

2 and halogen atoms, where the radical R 10 is a hydrogen atom, a C 1

C

12 alkyl, a C 1

C

12 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R 1 2 or where the radicals R 8 and R 9 may together form a cyclic structure which consists however exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; 25 the radical R 7 is a hydrogen atom, a C1 C 12 alkyl, a C1 C12 alkenyl, a C 1

C

12 aralkyl, an aryl or hetaryl radical, the group -NR 12

R

3

-NHCOR

1

-NHCONHR

14

-NHCOOR

14 or -NHSO 2

R

14 and may optionally be substituted by one or more substituents selected from the group consisting of -OH, -NH 2

-CONH

2 -COOH and halogen atoms, the radicals R 12 and R 13 are each independently of one another a hydrogen atom, a C2 C 6 alkenyl or a C 1

C

12 alkyl radical and may optionally be substituted by one or more aryl or hetaryl radicals which in turn may be substituted by up to three substituents selected independently of one another from the group consisting of -NO 2

-CH

3

-CF

3

-OCH

3

-OCF

3 and halogen atoms, and the radical R 14 is a hydrogen atom, a Ci C 12 alkyl, a Ci C 12 alkenyl, a C 1

C

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

-CH

3

-OR

11

-CF

3

-OCF

3

-OH,

-N(R

1 2

-OCOR

11 -COOH, -CONH2, -NHCONHR 11

-NHCOOR

11 and halogen atoms; and the radicals Ra, Rb, R c

R

d Re and R f are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2

-CF

3

-OCF

3

-NO

2 -CN, a C1 C6 alkyl, a Ci C6 alkoxy, an aryl or hetaryl radical.

The indications already mentioned in connection with the novel compounds of the invention of the general formula as defined above excluding the compound disclosed in the publications of Maki et al.

and Millet et al. and mentioned above by name) have already been given above in relation to the novel compounds of the invention. The compounds which are preferred and particularly preferred in the use of the compounds just defined for producing a pharmaceutical remedy for inhibiting GnRH are identical to the preferred and particularly preferred compounds already 0 26 mentioned above in connection with the novel compounds of the invention of the general formula as defined above.

The present invention provides in a further aspect the use of a compound of the invention as defined above, but likewise including the compounds excluded by name at the outset, for male fertility control or for female contraception. Preferred and particularly preferred compounds of the invention for this use are those compounds already mentioned at the outset as preferred or particularly preferred compounds of the invention of general formula as defined above.

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

In another aspect, the present invention relates to a method for the treatment of pathological states mediated by GPCR. The method comprises the administration of at least one compound of the invention, as defined above, to a mammal, in particular a human, when such a treatment is necessary. The administration normally takes place in a pharmaceutically effective amount. As already explained above in relation to the novel compounds of the invention and the pharmaceutical compositions of the invention, it is the task of the expert knowledge of a skilled worker to determine a pharmaceutically effective amount, depending on the specific requirements of the individual case. However, the compounds of the invention are preferably administered in a unit dose of from 1 ug to 100 mg, particularly preferably from 1 gg to 10 mg and most 27 preferably from 1 gg to 1 mg per body weight of subject to be treated. The preferred administration form is oral administration. The administration of one or more of the compounds of the invention in combination with at least one further active ingredient, as already explained above, is also provided.

In addition, the present invention also relates to a method for inhibiting GnRH in a patient, comprising administration of a pharmaceutically effective amount of a compound of the general formula as defined above, but including compounds excluded by name above, to a patient requiring such a treatment. The method is preferably used in male fertility control, hormone therapy, female contraception, treatment of female subor infertility and tumor control.

Finally, the present invention provides in a last aspect also a method for the production of the novel tetrahydrocarbazole derivatives of the invention of the general formula The method for the preparation of the compounds of the invention of the general formula can be carried out in various ways, e.g. in liquid phase or as partial or complete solid-phase synthesis. The choice of the suitable synthesis conditions for preparing individual representatives of compounds of the general formula can be made by a skilled worker on the basis of his common general knowledge. One method of the invention for the preparation of compounds of the invention of the general formula is firstly described generally below. A specific variant of the method, namely a solid-phase method, is then described. For further illustration of the present invention, the examples listed thereafter include numerous representatives of compounds of the general formula One method for the preparation of the compounds of the invention of the general formula is preferably 28 carried out in the following way: The central tetrahydrocarbazole structure can be obtained by a Fischer indole synthesis known per se.

For this purpose, a suitably substituted cyclohexanone derivative provided where appropriate with protective groups is condensed with the phenylhydrazine derivative which is desired in each case and is likewise suitably substituted and provided where appropriate with protective groups as described by Britten Lockwood, J.C.S. Perkin I 1974, 1824 or as described by Maki et al., Chem. Pharm. Bull. 1973, 21, 240). In particular, the cyclohexanone structure is substituted in positions 5,5' and 6,6' via the radicals Ra to

R

f and in positions 4,4' via the radicals, or where appropriate by precursors of the radicals, R 6 and R 7 The phenylhydrazine structure is optionally substituted by the radicals R 2 to R 5 Phenylhydrazine derivatives which are not commercially available can be prepared by methods known to the skilled worker. Positional isomers which result where appropriate in the condensation of the cyclohexanone derivative and the phenylhydrazine derivative can be separated by chromatographic methods such as, for example, HPLC.

After the synthesis of the central tetrahydrocarbazole structure, the radical R 1 can be introduced by N-alkylation of the nitrogen atom in position 9 with appropriate R 1 -halides with use of base as described by Pecca Albonico, J. Med. Chem. 1977, 487 or else as described by Mooradian et al., J. Med.

Chem. 1970, 13, 327).

The radicals R 6 and R 7 can, as already indicated above, be introduced in various ways depending on their nature, which is explained in detail below.

a-Aminocarboxylic acid structures in these radicals can be obtained by treating ketones with NH 4

(CO)

3 and KCN 29 under Schotten-Baumann conditions known per se, and subsequent alkaline hydrolysis of the hydantoin which is formed (Britten Lockwood, J.C.S. Perkin I 1974, 1824).

Amide residues are preferably generated using methods known per se from peptide chemistry. For this purpose, the acid component is activated with an activating reagent such as DCC or else HATU (Tetrahedron Lett.

1994, 35, 2279) and condensed in the presence of a base such as DIPEA and/or DMAP with the amino component.

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

Secondary or tertiary amide residues are obtained from primary amines either by nucleophilic substitution of alkyl halides or by reductive amination of aldehydes/ ketones J. Org. Chem. 1996, 61, 3849 or Synth.

Comm. 1994, 609).

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

Urea residues are obtained by reacting the amines with appropriate isocyanates.

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

Alcohols can be obtained from carboxylic esters by reduction with LiAlH 4 Aldehyde residues are obtained from alcohol precursors by oxidation for example under Swern conditions known

"I/

30 per se with DMSO/oxalyl chloride (Pansavath et al., Synthesis 1998, 436).

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

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

Double bonds in the radicals can be introduced by reacting an aldehyde or ketone precursor with appropriate phosphonylides under Wittig conditions known per se.

A solid-phase method for the preparation of compounds of the invention of formula preferably includes steps to explained in detail below: Step proceeds essentially in analogy to a Fischer indole synthesis, e.g. as described by Britten Lockwood, J.C.S. Perkin I 1974, 1824; Maki et al., Chem. Pharm. Bull. 1973, 21, 240 or Hutchins Chapman, Tetrahedron Lett. 1996, 37, 4869 and comprises the condensation of a cyclohexanone derivative (II) which contains the group G and is tethered to a solid phase SP via a linker L suitable for forming the radical R 6 31 where, in the case where the radical R 7 is a hydrogen atom, a Ci C 12 alkyl, a C, C1 2 aralkyl or a hetaryl radical, the group G is equal to the radical R 7 and in the case where the radical R 7 has another one of the meanings indicated for R 7 in formula the group G is equal to a group -NH-Pg, where Pg is a protective group, with a phenylhydrazine derivative (III) substituted by R 2 to R in the presence of an acid, preferably acetic acid, and of a metal salt, preferably ZnCl 2 DMF is preferred as solvent. The radicals R 8 to R f are defined as indicated above in formula Certain substituents or groups may, where appropriate, also be present in protected form, in which case the protective groups are removed again by methods known per se at a suitable time during the synthesis.

Particularly suitable solid phase SP for the purposes of the present invention are Rink amide-resins (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB resins (Sheppard et al., Int. J. Peptide Protein Res. 1982, 20, 451), Wang resins (Lu et al., J. Org. Chem. 1981, 46, 3433) or chlorotrityl-resins (Barlos et al., Int. J. Peptide Protein Res. 1991, 38, 562), where the cyclohexanone derivative (II) is to be tethered to the solid phase SP by means of an (amino) carboxylic acid. Alcohol precursors of the cyclohexanone derivative (II) can be tethered by using the DHP linker (Liu Elman, J. Org.

32 Chem. 1995, 60, 7712). Traceless tethering of aromatic precursors of the cyclohexanone derivative (II) to triazine resins is possible (Brase et al., Angew. Chem.

Int. Ed. 1998, 37, 3413).

The protective group Pg which is included where appropriate in the group G and protects an a-amino group -NH 2 is preferably a "Fmoc" (9fluorenylmethoxycarbonyl) protective group, but may also be another customary amino protective group, e.g.

from the series of the alkoxycarbonyl protective groups (such as, for example the (benzyloxycarbonyl) or the "Boc" (tert-butoxycarbonyl) group) or another suitable protective group, e.g. a "trityl" (triphenylmethyl) protective group.

The constitution of the linker L is such that appropriate derivatization (steps and and workup (step result in the desired radical R 6 with one of the meanings indicated above for R 6 in the final product, the tetrahydrocarbazole derivative of the general formula To illustrate the constitution of the linker L, this may be explained below by way of example for the case where R 6 equals the group -CONRR 9 In the case where the radical R 6 in the product of the invention of the formula has the meaning -CONRR 9 firstly a compound Pg-N(R 8

)-R

9 '-COOH forming the linker L is tethered by means of an activating reagent such as DCC (dicyclohexylcarbodiimide) or HATU azabenzotriazol-1-yl)-N,N-N',N'-tetramethyluronium hexafluorophosphate) to the solid phase SP via free amino groups of the SP, where Pg and SP have the meaning indicated above, and R 9 forms part of the later radical R 9 The protective group Pg is subsequently eliminated, e.g. in the case of a Fmoc protective group by means of piperidine/DMF. This results in a compound HR N-R -CONH-SP. The latter compound is then in turn reacted with a precursor of the cyclohexanone 33 derivative namely the cyclohexanone carboxylic acid (II') 0 Or) (In) using an activating reagent such as DCC or HATU, finally resulting in the cyclohexanone derivative (II) as defined above. The meaning of the linker L in the case just described is -CONR -R 9 -CONH-SP. Any resulting isomers of whatever type (enantiomers, diastereomers or positional isomers) can be fractionated as also elsewhere during the described preparation process in a known manner by means of HPLC.

The actual step i.e. the condensation of the cyclohexanone derivative (II) with the substituted phenylhydrazine derivative (III) and, where appropriate, elimination of the protective group Pg in the group G by means of, for example, piperidine (in the case of a Fmoc protective group) then takes place, so that a free a-amino group is produced again at this point.

In the case where the radical R 7 is the group -NHCOR 14

-NHS

2

R

14 -NR2R 13 (where R 12 and R 13 are not both hydrogen atoms), -NHCONHR 14 or -NHCOOR 14 a derivatization of the now unprotected a-amino group of the resin-bound cyclohexanone derivative (II) finally takes place in step so that the various alternative radicals R 7 defined above can be performed.

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

R

14 the reaction product from step is reacted with a sulfonic acid derivative R 14

SO

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

R

13 (where R 12 and

R

13 are not both hydrogen atoms), in the case where the radical R 12 is a hydrogen atom, the reaction product from step is reacted with a reagent R 13 X, where X is a leaving group such as, for example, a halide atom, in particular a chloride atom, in the presence of a base such as, for example, DBU or DIPEA (cf. Green, JOC 1995, 60, 4287 or JOC 1996, 61, 3849) or with an aldehyde R 13 CHO in the presence of a reducing agent such as, for example, NaH/B(OAc) 3 In the case where neither of the radicals R 12 and R 13 is a hydrogen atom, the reaction product from step is a reacted with a ketone R2COR in the presence of a reducing agent (cf.

Ellmann et al., JOC 1997, 62, 1240 or Synth. Commun.

1994, 609; alternative In the case where both radicals R 12 and R 13 in R 7 equals -NRR 13 are hydrogen atoms, alternative (vi) below applies.

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

-NHCOOR

14 the reaction product from step is reacted with an alcohol HOR 14 which has been preactivated by carbonyldihydroxybenzotriazole ((HOBt)2CO) (cf. Warass et al., LIPS 1998, 5, 125; alternative In the case where R 7 is a hydrogen atom, a Ci-C 12 alkyl, Ci-C 12 aralkyl, an aryl, a hetaryl radical or the group

-NH

2 both radicals R 12 and R 13 in R 7 equals -NRI 2

R

1 3 are hydrogen atoms), step is omitted because no further derivatization is necessary (alternative Step i.e. the derivatization on the indole nitrogen atom, also corresponds, in analogy to step (b) explained above, to various alternatives which are explained in detail below: For cases to defined above in step a deprotonation of the reaction product obtained in (b) takes place by means of a base such as, for example, NaH or NaHMDS and subsequent derivatization by means of a group R 1 X, where X is a leaving group, e.g. a halide atom, in particular a chloride atom (cf. Collini Ellingboe, Tetrahedron Lett. 1997, 38, 7963; Pecca Albonico, J. Med. Chem. 1977, 20, 487 or Mooradian et al., J. Med. Chem. 1970, 13, 327).

For case (vi) defined above in step i.e. when step is omitted, in analogy to the above description a deprotonation of the reaction product obtained in (a) takes place by means of a base such as, for example NaH or NaHMDS and subsequent derivatization by means of a

I

36 group R 1 X, where X is a leaving group, e.g. a halide atom, in particular a chloride atom.

Step finally substantially includes the elimination of the reaction product obtained in from the solid phase SP. In the case of Wang, trityl, DHP and Rink amide resins, elimination of the reaction product obtained in takes place with the aid of an acid, in particular with TFA (trifluoroacetic acid). In the case of an aminolytic elimination from an HMB resin, the eliminating reagent used is, for example, ammonia in methanol. The desired product is then isolated in a conventional way.

Exemplary embodiments of the preparation of tetrahydrocarbazole derivatives of the invention are detailed below.

Examples I. General synthetic methods for compounds of the invention A Coupling of carboxylic acids to the Rink amideresin: 0.1 mmol of Fmoc-protected Rink amide-resin (166 mg, loading 0.6 mmol/g) are preswollen with 1.5 ml of DMF in a vessel with bottom frit for 20 min. After aspiration, 1.5 ml of 20% piperidine/DMF are added and stirred for 5 min. After aspiration, a further 1.5 ml of 20% piperidine/DMF are added and stirred for 15 min.

Aspiration is followed by washing four times with DMF.

Then 675 gl of a 0.267 M solution of Fmoc-protected amino carboxylic acid in DMF, 675 gl of HATU solution (0.267 M in DMF) and 150 1l of NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP are added and stirred at 400C for 4 h. After aspiration, the same reagents are again added and stirred at 400C for 4 h. This is followed by aspiration and washing four times with DMF.

37 B Coupling of carboxylic acids to the trityl-resin: 2.98 mmol of Fmoc protected aminocarboxylic acid are dissolved in 30 ml of dry dichloromethane, mixed with 14.3 mmol (2.45 ml) of DIPEA and added to 2.98 mmol of 2-chlorotrityl chloride-resin (2 g, loading 1.49 mmol/g of resin). After shaking for two hours, the resin is filtered off with suction through a frit and washed three times with 20 ml of dichloromethane/MeOH/DIPEA 17:2:1. This is followed by washing three times with ml of dichloromethane, three times with methanol and three times with 20 ml of ether and drying in vacuo. A resin with a loading of 0.5 to 1 mmol of amino carboxylic acid per g of resin is obtained.

C Coupling of carboxylic acids to the HMB-resin: 21.3 mmol of amino carboxylic acid and 21.3 mmol of HATU are dissolved in 60 ml of DMF and mixed with 63.9 mmol (10.9 ml) of DIPEA. After 5 minutes, 5 g of polystyrene-HMB-resin (loading 0.71 mmol/g of resin) are added and shaken at RT for 5 minutes. Then 21.3 mmol (2.6 g) of DMAP are added and shaken at RT for 1 h. The resin is subsequently filtered off with suction and washed once each with 100 ml of DMF, DCM and DMF. The resin is mixed with 100 ml of 10% (acetic anhydride)/DMF/5% DMAP and shaken for 15 min.

Aspiration is followed by washing three times each with 100 ml of DCM and ether and drying in vacuo.

D Coupling of carboxylic acids to the Wang resin: 54.6 mmol of carboxylic acid and 27.3 mmol (4.2 ml) of DIC are dissolved in 500 ml of dry DCM, and stirred at RT for 10 min. After the precipitated urea has been filtered off, the solution is evaporated to dryness and the residue is dissolved in 160 ml of dry DMF. The solution is added to 4.55 mmol (5 g, loading 0.91 mmol/g of resin) of Wang resin preswollen in DMF, and 4.55 mmol (556 mg) of DMAP are added. After shaking at RT for 1.5 hours, the resin is filtered off with 38 suction and taken up in 100 ml of 10% Ac 2 0/DMF/5% DMAP and shaken for 15 min. Aspiration is followed by washing three times each with 100 ml of DCM and ether and drying in vacuo.

E Coupling of an alcohol to the DHP-resin: mmol of DHP-resin (0.5 g, loading density 1 mmol/g) are preswollen in 2 ml of dichloroethane for 15 min. To this are added 2 ml of a solution of 0.75 M alcohol/0.37 M pyridinium paratoluenesulfonate and stirred at 800°C for 16 h. Cooling to RT is followed by addition of 5 ml of pyridine, briefly shaking with inversion and filtration with suction. Washing is carried out twice each with 5 ml of DMF, DCM and hexane.

F Deprotection of a resin-bound Fmoc protective group: ml of 20% piperidine/DMF are added to 0.1 mmol of resin-bound Fmoc group and stirred for 5 min. After aspiration, 1.5 ml of 20% piperidine/DMF are again added and stirred for 15 min. Aspiration is followed by washing four times with DMF.

G Coupling of a carboxylic acid to resin-bound amino functions: 675 pl of a 0.267 M solution of Fmoc-protected amino carboxylic acid in DMF, 675 pl of HATU solution (0.267 M in DMF) and 150 1l of 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 stirred at 40 0 C for 4 h. After aspiration, the same reagents are added again and stirred at 400°C for 4 h. This is followed by aspiration and washing four times with DMF.

H Coupling of acetic acid to resin-bound amino functions: ml of a solution of 10% acetic anhydride in DMF are added to 0.1 mmol of resin-bound amino functions and 39 stirred at RT for 15 min. This is followed by aspiration and washing four times with DMF.

I Synthesis of tetrahydrocarbazoles starting from resin-bound cyclohexanones: Before the reaction, 0.1 mmol of cyclohexanone-resin are washed twice with 2 ml of DMF and twice with 2 ml of acetic acid. Then 1 ml of DMF and 2 ml of 0.5 M M ZnC1 2 in acetic acid are added to the resin and stirred at 700C for 20 h. This is followed by aspiration and washing twice with 2 ml of acetic acid and 2 ml of DMF.

J Synthesis of sulfonamides starting from resinbound amides: The resin is washed twice with 2 ml each of DMF and DCE. 1 ml of 0.5 M sulfonyl chloride in DCE and 400 il of 2.5 M NMM/1 eq. of 0.25 M DMAP in DMF are added to 0.1 mmol of resin-bound amine. Stirring at 600C for 12 h is followed by aspiration and repetition of the coupling. Aspiration is followed by washing four times with 2000 ml of DMF.

K Synthesis of ureas by reaction of resin-bound amine with isocyanates: 2 ml of 0.5 M isocyanate in DCM are added to 0.1 mmol of resin-bound amine and stirred at RT for 18 h.

Aspiration is followed by washing four times with DMF.

L Synthesis of carbamates by reaction of resin-bound amine with preactivated alcohols: For the preactivation, 0.4 M alcohol and 0.39 M dibenzotriazolyl carbonate and 0.39 M pyridine are stirred in DMF at 400C for 15 min. 1 mmol of resinbound amine is mixed with 1 ml of preactivated alcohol, and 167 ml of 2.4 M NMM in DMF are added. Stirring at 600C for 4 h is followed by aspiration and washing four times with DMF.

40 M Synthesis of N-alkylamines by N-alkylation of resin-bound amines with alkyl halides and catalytic KI: 1 ml of 0.5 M halide/0.05 M KI in DMF and 416 il of 2.4 M DIPEA in DMF are added to 0.1 mmol of resin-bound amine and stirred at 90 0 C for 12 h. After aspiration, the resin is washed four times with 2 ml of DMF.

N N-alkylation of resin-bound indole nitrogens with halide/NaH in DMF: 1 ml of DMF and 0.5 mmol of NaH (55% suspension in oil) are added to 0.1 mmol of resin-bound amine. After stirring at RT for 30 min, 1 ml of 0.5 M halide in DMF are added and stirred at 45 0 C for 8 h. This is followed by aspiration and washing twice each with 2 ml of methanol, DMF, methanol and DMF.

0 Elimination from the Wang, trityl, DHP, Rink amide-resin: 2 ml of 95% TFA/5% H20 solution are added to 0.1 mmol of resin and shaken at RT for 3 h. The resin is then filtered off and washed with a further 2 ml of TFA. The combined TFA solutions are evaporated to dryness and afford the crude products.

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

Preparation of required starting compounds: 3-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]-2,3,4,9tetrahydro-lH-carbazole-3-carboxylic acid 1 38.4 mmol (6.0 g) of 4,4-ethylenedioxycyclohexanone and 39.8 mmol (4.3 g) of phenylhydrazine are dissolved separately in 50 ml and 10 ml, respectively, of water, 41 and then mixed. The milky emulsion resulting after stirring for 10 min is extracted five times with ethyl acetate, dried with MgS0 4 and evaporated to dryness.

Yield: 9.2 g of orange oil.

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 refluxing with a water trap for min, most of the toluene is distilled off, an excess of 2 N NaOH is added, and the mixture is extracted three times with ethyl acetate. The extract is washed with brine and dried with MgS0 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) of 1,2,4,9-tetrahydrospiro[3Hcarbazole-3,2'-[1,3]dioxolane] and 640 mg of ptoluenesulfonic acid are taken up in 70 ml of acetone and stirred at RT for 2.5 h. The solution is added to NaHCO 3 solution, extracted with ethyl acetate, washed with brine, dried with MgS0 4 and concentrated. 2.13 g of red-brown solid remain. Recrystallization from ether results in 1.1 g of beige-colored solid.

60.2 mmol (11.1 g) of 1,2,4,9-tetrahydrospiro-3Hcarbazol-3-one, 8.3 g of KCN and 22.0 g of (NH 4 2 C0 3 are heated in 550 ml of 60% ethanol in an autoclave at 80 0

C

for 3 h. After cooling to room temperature, the reaction mixture is added to ice-water, and the precipitated solid is filtered off. Yield: 10.1 g of gray solid.

44.2 mmol (11.3 g) of 1,2,4,9-tetrahydrospiro[3Hcarbazole-3,4'-imidazolidine]-2',5'-dione is heated with 62 g of Ba(OH) 2 x 8 H 2 0 in 145 ml of H 2 0 at 150 0

C

for 13 h. After cooling to room temperature, the viscous mass is mixed with 37 g of (NH4) 2 C0 3 with stirring and heated at 100 0 C for 30 min. Cooling to 42 room temperature is followed by filtration, washing with water and evaporation of the filtrate to dryness.

Yield: 7.7 g of beige solid.

26 mmol (5.8 g) of 3-amino-2,3,4,9-tetrahydro-lHcarbazole-3-carboxylic acid in 26 ml of 1 N NaOH and 26 mmol (8.76 g) of Fmoc-ONSu in 28 ml of acetonitrile are combined at room temperature and diluted with 130 ml of acetonitrile/H 2 0 1:1. After two hours, the pH is readjusted to 9 with NEt 3 (1.5 ml) and the mixture is stirred at room temperature overnight. Then a further 6.3 g (18.7 mmol) of Fmoc-ONSu dissolved in 19 ml of acetonitrile are added, and stirring is continued for two hours while controlling the pH. Removal of the acetonitrile by distillation is followed by acidification with 0.01 M HCI and extraction with ethyl acetate. The extract is washed until neutral, dried with Na 2 S0 4 and evaporated to dryness in a rotary evaporator. Recrystallization takes place from ether/hexane. Yield: 10.7 g.

1H NMR (d 6 DMSO): 8 2.07 ppm 1H); 2.50 1H); 2.70 (bs; 2H) 3.04 2H); 4.17 2H); 4.28 (m, 2H); 6.92 (tr, 2H); 6.99 (tr, 2H); 7.23 (tr, 2H); 7.24- 7.35 3H) 7.38 (tr, 2H) 7.62 1H) 7.68 (dd, 2H); 7.87 2H); 10.71 1H).

Melting point: 119 0

C

Fractionation into the two enantiomers takes place by chiral HPLC.

(R)-3-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]- 2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid la tR 6.4 min (Chiralcel OD 10 pm LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) (S)-3-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]- 2,3,4,9-tetrahydro-lH-carbazole-3-carboxylic acid lb tR 7.5 min (Chiralcel OD 10 pm LC50 250 x 4.6 cm, hexane/isopropanol 75:25, 80 ml/min) 43 1-[[(9H-Fluoren-9-ylmethoxy)carbonyl]amino]-4-oxocyclohexanecarboxylic acid 2 320 mmol (50 g) of 4,4-ethylenedioxycyclohexanone are suspended in 800 ml of 50% EtOH, and 1500 mmol (144.5 g) of (NH 4 2 C0 3 and 640 mmol (41.7 g) of KCN are added. After stirring at 60 0 C for 5 h, the ethanol is removed in vacuo, and the aqueous residue after cooling with ice is filtered off, washed with water and dried.

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

295 mmol (66.8 g) of 4,4-1,4-dioxa-9,11-diazadispiro[4.2.4.2]tetradecane-10,12-dione and 826 mmol (260.6 g) of Ba(OH) 2 x 8 H 2 0 are stirred in 2.5 1 at 1500C in an autoclave for 6 h. After cooling to room temperature, 1032 mmol (99.2 g of (NH4) 2

CO

3 are added to the solution and stirred at 60 0 C for 1 h. The suspension is filtered and washed, and the filtrate is lyophilized. The residue is recrystallized from

H

2 0/MeOH. Yield: 45.4 g of 8-amino-1,4-dioxaspiro[4,5]decane-8-carboxylic acid.

213 mmol (42.9 g) of 8-amino-l,4-dioxaspiro[4,5]decane- 8-carboxylic acid in 213 ml of 1 N NaOH and 213 mmol (71.9 g) of Fmoc-ONSu in 240 ml of acetonitrile are combined and diluted with 1000 ml of acetonitrile/H 2 0 1:1. Adjustment of the pH to 9 is followed by stirring at room temperature overnight. Removal of the acetonitrile in a rotary evaporator is followed by acidification with 0.01 M HC1 and extraction with ethyl acetate. The extract is washed until neutral, dried with Na 2 S0 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,4dioxaspiro[4,5]decane-8-carboxylic acid.

187 mmol (79 g) of 8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino-l,4-dioxaspiro[4,5]decane-8-carboxylic M M M 44 acid are taken up in 3.5 1 of acetone/0.1 M HC1 1:1 and stirred at room temperature for 4 h. The acetone is stripped off in a rotary evaporator, and the precipitated product is filtered off, washed with water and dried. Yield: 68.7 g of 2.

1H NMR (d 6 DMSO): 6 1.52-1.73 4H); 1.82-2.14 (m, 4H); 4.27 3H); 7.85 (tr, 2H); 7.42 (tr, 2H); 7.67 1H); 7.75 2H); 7.91 2H) Melting point: 157°C 4-Oxocyclohexanecarboxylic acid 3 mmol (3.4 g) of ethyl 4-oxocyclohexanecarboxylate are suspended in 40 ml of 2% H 2 S0 4 and stirred at 90 0

C

for 2 h. This is followed by extraction four times with ethyl acetate, drying with Na 2

SO

4 and removal of the solvent. Recrystallization from ether/hexane affords 2.9 g of white solid 3.

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

4-Chloro-3-[[(phenylamino) carbonyl]amino]benzeneacetic acid 4 18.55 mmol (2.21 g) of SOC1 2 are slowly added to 18.55 mmol (4 g) of 4-chloro-3-nitrobenzeneacetic acid in 50 ml of MeOH while cooling in ice and stirring.

After stirring for 30 min, the mixture is allowed to warm to RT and a further 3.71 mmol (0.44 g) of SOC1 2 are added. Stirring overnight is followed by heating to reflux for 30 min. Stripping off the solvent is followed by recrystallization from ether/hexane.

Yield: 3.43 g of methyl 4-chloro-3-nitrobenzeneacetate as yellowish solid.

13.07 mmol (3.0 g) of methyl 4-chloro-3nitrobenzeneacetate and 198.8 mmol (13.0 g) of Zn dust are heated to reflux in 500 ml of MeOH for 10 min.

Then, under reflux, 13 ml of conc. HCl are added 45 dropwise, and refluxing is continued for 30 min. The suspension is filtered hot, the methanol is distilled off, and the residue is adjusted to pH 14 with a NaHCO 3 solution. Extraction with ethyl acetate, drying with Na 2

SO

4 and removal of the solvent by distillation affords 2.3 g of methyl 3-amino-4-chlorobenzeneacetate as beige solid.

2.08 mmol (415 mg) of methyl 3-amino-4chlorobenzeneacetate are dissolved in 40 ml of DCM and, at 0°C, 0.83 mmol (246.3 mg) of triphosgene and 0.6 ml of pyridine are added. After stirring at 0°C for one hour, 10.4 mmol (1.11 g) of benzylamine are added, and stirring is continued at room temperature overnight.

Extraction is carried out with DCM/H 2 0, the organic phase is dried, and the solvent is removed.

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

2.98 mmol (990 mg) of methyl 4-chloro-3-[[(phenylamino)carbonyl]amino]benzeneacetate are taken up in ml of methanol, and 6 mmol of 1 N NaOH are added.

After stirring at RT for 2 h, the methanol is distilled off and the residue is acidified to pH 2-3 with 1 M HCl. Extraction is carried out with ethyl acetate, and drying with Na 2

SO

4 and the solvent is removed.

Recrystallization takes place from boiling isopropanol.

Yield: 830 mg of white solid 4.

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

4-Chloro-3-[ (phenylmethyl) amino]carbonyl amino] benzeneacetic acid 2.08 mmol (415 mg) of methyl 3-amino-4chlorobenzeneacetate are mixed with 10.4 mmol (969 mg) of aniline as described under and worked up analogously. Yield: 662 mg of solid.

46 For the ester cleavage, 2.47 mmol (790 mg) of methyl 4chloro-3- [[[(phenylmethyl)amino]carbonyl]amino]benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product 5 is obtained without recrystallization. Yield: 693 mg of yellowish solid.

ES-MS: 319 4-Chloro-3- (4-pyridinylamino) carbonyl] amino] benzeneacetic acid 6 2.08 mmol (415 mg) of methyl 3-amino-4chlorobenzeneacetate are mixed with 10.4 mmol (979 mg) of 4-aminopyridine as described under and worked up analogously. Yield: 664 mg of solid.

For the ester cleavage, 2.63 mmol (840 mg) of methyl 4chloro-3-[[(4-pyridinylamino)carbonyl]amino] benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product 6 is obtained without recrystallization. Yield: 481 mg of yellowish solid.

H NMR (d 6 DMSO): 6 3.57 2H); 6.94 1H); 7.40 3H); 8.05 1H); 8.35 2H); 8.50 1H); 9.92 1H); 12.40 (bs, 1H) 4-Chloro-3-[[(2-pyridinylamino)carbonyl]amino] benzeneacetic acid 7 2.08 mmol (415 mg) of methyl 3-amino-4chlorobenzeneacetate are mixed with 10.4 mmol (979 mg) of 2-aminopyridine as described under and worked up analogously. Yield: 617 mg of solid.

For the ester cleavage, 2.47 mmol (790 mg) of methyl 4chloro-3-[[(2pyridinylamino)carbonyl]amino]benzeneacetate are hydrolyzed with 1 N NaOH in analogy to the above method. The product 7 is obtained without recrystallization. Yield: 693 mg of yellowish solid.

47 1 H NMR (d 6 DMSO): 8 3.59 2H); 6.94 (dd, 1H); 7.03 (dd, 1H); 7.22 1H); 7.42 1H); 7.78 (dtr, 1H); 8.29 2H); 10.02 1H); 11.82 (bs, 1H); 12.50 (s, 1H).

II. Examples of compounds of the invention Example 1: 0.3 mmol (42.6 mg) of 4-oxocyclohexanecarboxylic acid are dissolved in 1 ml of acetic acid and added to a suspension of 0.3 mmol (43.3 g) of phenylhydrazine hydrochloride and 0.3 mmol (40.0 mg) of ZnCl2 in 1 ml of acetic acid. Stirring at 70 0 C for 20 h is followed by dilution with 20 ml of water and extraction with ethyl acetate. The ethyl acetate phase is washed with water, dried over Na 2 S0 4 and evaporated to dryness. Yield: 65.6 mg (100%) of white solid.

Name Number Mfnd Mcalc 2,3,4,9-Tetrahydro-lH-carbazole- 3-carboxylic acid 8 215 215.2507 The column headings (name, number of the compound, Mfnd (measured molecular mass), Mcaic (calculated molecular mass)) which are introduced here also apply to the following examples and are therefore not repeated again.

Example 2: Synthesis takes place on the 0.2 mmol scale by methods A, I and 0.

2,3,4,9-Tetrahydro-1H-carbazole- 3-carboxamide 9 214 214.2666 11, 48 Example 3:- Synthesis takes place on the 0.2 mol scale by methods A, F, G, I and 0.

N- -1-(Aminocarbonyl) -2-methyl propyl] 9-tetrahydro-1Hcarbazole-3 -carboxamide N- -1-(Aminocarbonyl) -2-methyl propyl]-(3R)-2,3,4,9-tetrahydro-1Hcarbazole-3 -carboxamide N- (2-Amino-2-oxoethyl) -2,3,4,9tetrahydro-1H-carbazole-3 carboxamide 10a 314 313.3987 lob 11 314 313.3987 271 271.3183 scale- by methods Example 4: Synthesis takes place on the 0.2 rmcl D, F, G, F, G, I and 0.

(3S)-(2,3,4,9-Tetrahydro-1Hcarbazol-3-yl) carbonyl] -L-valyl-Lglutamine (3R)-(2,3,4,9-Tetrahydro-1Hcarbazol-3-yl) carbonyl] -L-valyl-Lglutaxnine, Isomer B 12a 442 442.513 12b 442 442.513 Exampl e Synthesis takes place on the 0. 2 rnmol scale by methods D, F, G, I, F and 0: [(3S)-3-Amino-2,3,4,9-tetrahydro- 1H-carbazol-3-yl) carbonyl] -Lalanine 301 301.3441 Example 6: 0.1 mmol of carboxylic acid, 0.1 mmnol of HOBt and 0. 15 mmcl of amine component are dissolved in 15 ml of 49 dry DMF (also THF, DCM), and, while cooling in ice and stirring, 0.5 mmol of NMM is added. After about 15 min, 0.15 mmol of EDCI x HC1 is added, and the mixture is stirred for one hour, warmed to room temperature and stirred overnight. For workup, the solvent is stripped off, and the product is dissolved in ethyl acetate and washed twice each with 0.1 N HC1 and saturated NaCl solution. Drying and stripping off the solvent are followed if necessary by recrystallization.

9H-Fluoren-9-ylmethyl bromophenyl)methyl]amino]carbonyl]- 2,3,4,9-tetrahydro-lH-carbazol-3-yl] carbamate Methyl N-[[(3S)-3-[[(9H-fluoren-9-yl methoxy)carbonyl]amino]-2,3,4,9tetrahydro-1H-carbazol-3-yl]carbonyl]- L-alaninate 620 620.5439 15 537 537.6129 Example 7: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, G, F, G and 0.

50 N-[3R)-34([(2S35)-2-(9H-Fkzoren-9ylmetiioxy)carbonyIlano]-3-methy1-loxopentyl~amno]-2,3A9-?etrahYdro-1ff-cara 1-3yl]carbonyl]-L-wvayl-L-aspartmide N-[a(3S)-3-ff(2S3s)-2-[f(9H-Fluotcu-9- Yhncthoxy)carboaYljamino]-3-methyl-loxopeatyIamino]-Z3A9-ttrhydo-Hcabzo-3.

y!]oarbonyll--lyl-L-asL ramdc -ff(3R)-3,49-TetMkydr-3-f(1-OooZ3dipbMYPropyamin]-lH-bazol-3-yoaionyl-.Lvalyl-L-Waartamide N.{((3S*2,3,4,9-Tehirhydro-3-((I-oxo-2,3diphe-nylprop I~a no-H-carbaZ-.3-ycxbo11]-valy.

L-aspwlAttde, hsomer A N-[[(3S)-2,3,4,9-TetabYdr.3[(F-oxo-2,3diphenylptopyl)amino-H-carbazol-3-ycaboiy-L-valy- L-apwtanide, Isomer B N-[[(3S-2,3A49-TeUhYdro-3-[[(3)-3-methyI-I 0'co-2- [(I-oxo-3-phenylproDpy~aminolpentylIamino3-lH-cabazo.

3-yl]carbonylj.L-valyl-L-aspartamide 10 770 777.9178 779 777.0178 a 651 650.7758 15 51 050.7758 S 651 650.778 6i 88 687.8371 51 N-[(3R)-2,3,4,9-Tctydro-3 -[[(2S,3S)3-methy-j -oxo-2- (1-oxo-3-phenylpropyl~aminolpeltyl]amino]-LH-carbazol- 3.yI~carbonyl]-Laval-l~aspartamide N4[(3B)-23,4,9-Tedrahydro-34((2S)-I-Oxo-2nymethioxy)carbonyI~amino]Propyllammo]-1IKcarbazol-3-yI~carbonyl]-L-valyl-L-aspartamide N-[[(3R1-,3,4,-Tehydro-3[(2)--oxo-2- [((pbeymthoxy)bn~ minopropyW22ino]catbazol -3-yI]cubonyl]-L-valyl-L-aspaztanmide JVg3)2349Ttyr--[(S3)3rehlloo 2-ff(jenylmtoxy)crbonylaminopentylamino]-1ffcax1bazoI -3-yI]cabonyl]-L-alanyl4,-apartamide N-U30239Tuh~--1(s3)3mty--o 2-fl(phenylmethnx)cbonyjamino]pnylAniino]-1Hcarbmzo -3-yljcabonyl-L-valyl-L-alaniaids N-[[(3S)-7.,3,4,-Tlrhydo-3-R2,S)-3-metby-1-oxo-2fl(phenylmnethox)carbonyl]aminojpexty~amino]-1Hcarbazol -3-y1JcarbonyUj-D-valyl-L-aspartamide NV-ff(3R)-2,3,49-Tetahydr-3-((2s,3s)-3-niethyl-1-oxo- 2-[(hesnyeoxy)caonylaminopentyl]amino}4IHcarbazol -3-yl]carbonyl}.D-valyl-L-aspartamide N-([(31R)-Z3,4,9-Tedrakydro-3-[((2S3S)3-methyl-l-oxo- 241(phenylmetboxy~varbonyllaminolpentyllamino)-IHcairbatzol -3 -yllcarbonyl-L-valyl-D-aspartamide N4[(3S)-23A9-ThYdro-3ff(2aS3S)-3-methy-I -oxo-2-- [[(pheyle)carbonylmino)petylamino)-lIcarbazol -3-yllrbonyl-Lvlyl-t-aspartamide )#-[(3S)-2,3A49-TewAhYdro-34[(2S3S-3-methy1-l-oxo>-2- [[(phenytmethox)carbonyllaminolpentyljaminoj-IH =abaw-3-y]carbnyL-any-L-~aspartamde NV-[(3,ST)2,3A49-Tetahydro-3-f(pheaylacetyIamino]-lHcarbazol -3-ylcarbonyl}.Lr-valyl-L-asparlamide N4E(3R)-23A49-Tetrahydro-3-(-oxo-3phenylpropyl)amino]-IH-carbazol 3-yl~carbonyl]-L-valyl- L-aspartamide N4[(3S)-2,3,4,9-Tetrahydro-3-[(1-oxro-3phenylpropyl)amino]-IH-cabazol.-3-yI]carbonyl]-L-valyl- L-aSpartamide Z? 688 687.8371 23 648 647.7289 24 648 647.7289 P 882 681.75U7 26 647 648.7844 27 690 68.809 28 no0 689.8003 Le 890 689.609 30 690 689.8093 n1 662 681.7557 32 851 560.8514 M3 575 574.6782 a4 575 674.67a2 52 N-[3S 2 3,4,9-Tetrhydro-3[(aS)-3.methy1-1-oxo-2carbazol -3-yl]carbonyl)-l-valyI-L-aLaninamide N-U(3R) 2,3,4,9.-Teahydro-3-pIoeylacety)aminoJ-1Hmabazol -3-ylcarbonyl)L-valyl-L-wpatamide N-I(3P2,3,4,9-Terhydro-3-(I-oxo4phenylbutyl~amino]-1H1-cabazol -3-yi]cabony]-L-vagyl- L-aspam~mide N4[(3S-34,9'-Tetkhdro-3-t(1-oxo-4phenylbutyl~amino]-I*-carbazol3-yljcarboyl]L-valyl- L-apatamide N-f(3PR)-3-[(iPhnYkaoeyianinoJ-2,3A49-tethYdr- I 1-cazbwzl -3-yflcarony-vay-I~aspartaride N-fl(3S-341ohy1cy)ami -23,49emhydro- 1H-carazol -3-yiloabonyl]-L-valyl-Lasartmide N-[t(3R)-2.3A49-TetrahYdro-3-E(1-oxo-2phcnylpropyl)amino-lH-carbaz -3-yloarbonyU-L-valy!- L-aspartmide, Isomer A N4(C(3R)Z3,4,9-Tetnydro-3-[(3-methyl-l-oxo-2phenylpentyl)anonqIH-carbazl -3-y4]cabony1I-L-a~yl- L-aapartamnide, Isomer B N-ffl3S)-,3,4,-Trahydro-3[(3-iebyl-l-oxo-2phenylpentyl)amino]-IH-mabazol -3-yljvarbonyl]-L-valyl- ILpatamide, Isomer A N-([(3S)-2,349-TerhYdro-3-(3-netYl--o-2phenylpcrrtyl)amino]-1H-mabazol -3-yljcarbonyl]-L-valyl-t..

asTamide, Isomer B Phevylmetbyl [(1s,2s)14[(3R)-3-ffRIIs-4ft4- (ammocarbony~phnylamo~carbonyljmatypropy]mno]crny-3,4,9eftAiydro-Hcabaz&l.3-yl]azino)carbonyl]-2-metbylbutyl]carbaniate Phenybiebyl S,2S)-14[[(3S)-34U[(I S-I-[[14- (aminocarbonyl)phftnyllaminojcarbonyl]-2methylpropyljamfiflojcbonyl)-2,3,4,9-tctrahydro-lHoubazoI-3-y1]aminolcarbony11-2-rnetiylbutyflcubunate 35 647 646.7844 38 581 560.6514 21 589 588.705 38 589 588.70 19 637 636.749 42 637 838.749 g1 676 574.5782 42 617 616.7586 43 617 616.7688 44 617 616.7588 6 95 694.8284 As 8OM 694.8284 53 N-fl(3S)-2,3,4,9-Teahydro3.[X3-methy1-1-OX0-2phenylbutyj)amino]-1H-carbzo-3-yl]carbnyl-L-valyl-Laspartamide, Isomer A N-[[(3S)-2,34,9-TetrahYdro-3-[(3-methYl-1-axo-2phenlbuty))aminD)-lH-ca~bazol -3-yl]carbonylLvalyl-Laxpwan~idp, Isomer B N-rj(3R)-2,3,A9-Texayd~o-3-[(3-methy-l-oxo-2phonylbutmn-xbazol.3-y]bonl]-L-vayl-Laspartamide Phenylmethyl (azniocubonyfylohxylmethyllarimoloarbonyl] 2metylpropylamnowcurbny-2.,3A4,erydr-Y*carbmzo -3.yllaminolcarbony)J-2-mcthylibu~itylrnae N-II(3)-2,3A49-Tetrahydz-34[(3 pheaoyphenylactyllaino]-IH-carbazoI 3-Yl]carbonyl]..

L-valyl-L-aspartamide 3 9-Tecahydro-3-[f (3phenoxyphenyl)acetyllamino].IH-cazl-3-y]carbonyl- L-valyl-L-Wsartaraidc Phenylmethyl [(IS,2s)1-[ff(3R)-3-UI(IS)-1-Ugf3- (ammln yl ehylamnhyarbo] nyl-2methYlPrOPYI]aminojcarbonYl]-2,3A49-terAhYdro-IRcarbazol -3-yilaminolcabonyl-2-mehylbutyflcabanmate Phenylmethyl methylpropyl]aminojcabonyl]-2Z3,4,9-tetrahydro- 11cubazol -3-.y]amno]carouy.2metylbutylcrbamate S)-1 (Aminocarbonyf)-2-mehlpropy]-2,3,4,9tetruhydro-3-[[(2R)-I-oxo,-2-[(l-oxo-3phenylpropyl)amin]-3.pbe-nylpropyIoaino)-IH-cabale- 3-carboxamide N-[[(3S)-2,3,4,9.Tetrahydro-3-{QI-oxo-2pheniylpropylrNmino]-1H-carbazol -3-yljcaxbonyl]-L-vayl-Laspatamide (aminocazbonyl)cyclohexYllmethytlaminolcarbonyl]-2methyipropy1]amino]carbonyfl-2),3,49-te"rhydro-1Hcarbazol -3-yl~aminolcarbonyl]-2-rnethylbutyllcabamate !R 603 602.7318 S 603 802731 9 603 6M27318 50 715 714.9025 51 653 6M2748 52 853 652.748 53 709 70B.855 PA 709 708.85= 55 608 607.7509 E6 676 674.8782 57 715 714.9026 54 Example 8: Synthesis takes place on the 0.2 inmol scale by methods A, F, G, F, G and 0.

Phenylniethyl S,2S).149l(3R)-3-I(IS)-1- (anocarbony-2-ethypropyjaminocarbonyJ-2,3,4,9tetrahydro-1fl-mubazu1 -3-y1znmo]cearbonyl]-2- MetumtYl~oarbmae N-[f(3S)-3-(t(9*i-Fluorea-9-ylmethoxy)cabonyljamino- 2,3,4,9-tetrahydro-H-cibazOI.3-y1JcabO~Y1]I-dY-L-1b aspananiide N-[[(3YQ)-3-fl(9H-Fhzormi-9ylmethoxy)cvbony]aminOJ- 2,3,4,94daro-H-crbaI -3.yl)oarbonyl]--valyl-Laspartamide Phenylniethyl[(S2)1f(S3-(S-- (aminocabony)2..methyopropyllanino]carbony1]-3,4,9tetrhydrolH-cafbozl-3-Iaminolcarbouy]-2metbylbuyllcarbamate (axninocarbonyl~henyllamiaolcarbonyl}.2,3,4,9.etraydro- IH-carbazol-3-yl]amino~carbouyl)-2-methylbiztylfcabamae Pheeymtf((SS)IA[(3S)-3J[4- (amiocaboxyi)phtny1Jaminooabony1-2Z3)4,94trathydrolH-caraol -3-yijamiolcabonyJ.2-mehyrhbzzy1]oatbaatc Phenylmethyl (S2)1[[(R34(S2)- (nanocrbonyl-2-mhyby]amiocarbonyll.34,9tcuhydro-H-cabazo-3-yaino]carboiiyI]-2methylbutyltarbamate phenylmethyl (1S,2S).1- (aminocarbonyl)-2-mthylbutylaminocxbonyl].2,3,4,9tetrahYdro-IH-caxbazol -3-yllaminoJcarboDYl)-2mcthylbuty))caxbamate 1-(phenytrnethyl)ethyl]amino]carbonyl]-2,3,49-ttrahydr- 1H-mrzol- 3 -yjaino]carbony]-2-ethybuty]carbamate 11 676 .575.7069 aI 665 604.759 6e 665 64.75a 11 M7 575.7059 62 w9 56.6963 W356 595.6983 6_ 590 689.7327 65 590 589.7327 623 823.7499 55 Phenylmethyl [(S,2S)-1-EU(3S)..3-[[R1IS)-2-anino-2-oxo-I- (pkiylmethyr1)eIammolcarbonyI}.2,3,A9ttrhydro- 1H-.carbazo] -3-yllamino]caxbonyll-2-methylbuty]carbanlate S)-I.{Anoarbonl)2-mehylpropy].Z3A49tdtrahydro-34(1I2-phenypopy~mino]Hcboe 3carboxmide Phenylmethyl. S,2S)--jJ(3 (aminocabouy phenyllmethyl~amiolazbonYl-2,3A4,9.

tetraydro-ll-carbazol .3-yljaminojc~kbomyl].2.

methylbutyllcarbamate Phenymethyl [(IS,2S)-1-M(3R)-3-[ffl3- (amiocary~Jmme&Aminolmy1 l-2,3,4,9tetrAhydo-IH-carbazl -3-yI~aminD~cabonyl]-2methylbutylcarbwmate P~ih ne~yl (1S,2S)-1-E(E(3 S)-34J[J4- (amnocaboyycldheylmetyljamnocarbony]- 23A9-tetraiYdro-IH-car wzl 3 -ylaino3=abonyI]-a methylbutylcabauiate Phenyimethyl S,2S)-1-ff[(3R)-34Ff4- (ami obonyIrcyclohexUmethyljamikocdonyl].

2,3,4,9.tetrahydro-IH-carbazo -3.yljaminojcarbonyi]-2methylbutyquiabaxnate Pbenlmetbyl [(S,2S)-I-JU(3S)-3-ff[3- (azmOcabOnYI)Phi~iYlamino]arbony1..,3A49.tetrydro.

1H-cabazol 3 -yilaminDicronyJ-2-methylb4yIcrbamnwe Phenyim ethyl [(IS,2S)-1-U[(3R)-3-[ff3- (arnocrbonyphey]ao)tonyl23,4,..teax.ro.

IH-carbazol .3yaiocroy]2mbluylabmt phenylehfylaminolcarbonyl]-2,3,4,9AetrahydrolH- =abazol 3 -yflaminojcarbonyl]-2-mthylbutyllcarbamate I-phenyletbyIlamino]varbony1]-23,4,9-taydro.1H carbazol 3 -yl]aminojoabonyl}.2-methylbutyl]carbamate Phenylmethyl ((2..amino--2..oxo.

phenylethyl)aminolcabonyl-2.3,4,9.tthydro-IH.

carbazoi.3-ylaminolcarbony]-2-methylbutyI~carbamte, 67 623 n23.7499 !0 460 4M0.6748 8a 810 6M9.7231 70 810 609.7231 71 615 615.7706 72 615 815.7706 D~ 69w W9.Sm Z4 596 585.63 610 W09.7231 76 810 609.7231 HZ 509 609.7231 56 Isomer A ?beuylmethyl S2)-1-([(3R)-34((2-amino-2-oxo-lphenylethiy1aminojvaxbny1]- 3 3,94emrahYdro-1Hcarbazol-3-yIlamino]cbony}.2-metybutyllcarbamate, Isomer 1B (3pR)N4(1)-Amocbony)-2-nthylpropyI]-23,4,9terhyxo-3-1[f3-hydroxyphcnyi)aoetyl]amino]-IHcarbazole-3-carboxmde (3R,)-3-f[[3-(Acbo)pheny]aeyjan~jo]-N-[S)-I- (aminoxiboyl)-2-merhylpropyI]-2,3,4,9-tetrahydro-1Bcarbazole-3-carboxumide methy Propy1]aminocrbonY!j-2,A9-temhYdr0-IHcarbazol-3-y~aIfo-2-xoethi54phflyl 3hydroxybe=Meacftate (3R>.N4[(IS)-1-(Aminocarbonyl)-2-methylpropyl]-23,49teUhydr3-[(hydroxhyacety)amiw1-1H-carbazole-3carboxamide (3R)-N-((IS)-1-(Aminocarbonyl)-2-methylpropylj-[[(4bromphenyl~acetyl~amino]-2,3A49-teuahydro-Ifl-cabazole- 3-.carboxa,:nde (3R:)-N-(l)-1-(Aminobnyl2-methylpropyfl-3-a(2chlorpheactlio-249tftaydro-IH-carbaole- 3-vaboxamide (3R)-N-[(1S)-1-(Amiaocabonyl)-2-methylpopyrj-3-[[(3chlor4hydrpheny~aetyamio-23,49-terabdro- IH-carbazole-3-cazboxarmide (3R>-3-4[4-(Acey~ox)-3-cbloropheny1acety1Jamino]-N- I (aminocabonyI)-2-methylpropyl]-2,3,4,9tetrahydro-1I-abazole -3-carboxamide S)-l-(Aminocarbonyl)-2-methylpropyl]-3-1[(3fluor-4-hydroxyhenyI~acety]mino]-Z3A94tcrahYdro-IHcarbmzle .3-carboxamide Le M09 609.7231 Z! 482 462,547 P-2 504 604.583M 81 597 696.8804 82 462 462.647 La M. 554441 -M 481 480.9931 85 497 496,9921 88 639 639028 67 481 480.5371 57 [(1S)-1-(aminooabonyl-2-niehylpropyIJ-2.3A49'tetrakydrodIH-carbazol -3-caboxamide (3R)-N-[(IS)-1.(Aminocaronyl)-2-methylpropyl]}2,3,4,9tcy ~dr-3(4-ni phenyacety4]amol H-carazoI -3caboyamide (3R)-N-[(IS)-I-(Amiinocabony92-mthypropy]p-[[(2,4dioblorophenyloactyl]amiao]-Z,3,4tradro-1Hcarbazol-3-catboxwmdeo fluorophonyD1]t~amno-239-trahydro-IH-arbazo-3carboxamide (3R)-N-(1S)--(AmincaboYf-2-mhY]PrOPY1]-2,A9teryd-3[(4-hoy pheny)aceyijamioJlIcarbazol -3-carhoxamide 1 inoarboyl)-2-meLihylproDPyl-.[(2bromophenyfoaoetyl]amno]-3,4,9-temhydro-IH-carbazol- 3-carboxarnide- (3R)-N-[(1S)I-(AminocarbonYI)-2-methY]ProyI.3A49tyd-3-(2-iophyIacyamino]-{.cabazol3carboxmide Q3R)-N-[(I S)-l-(Amincarboy-2-methylpropy1J-2,3,4,9teydro-3-[[(3-nitrophyacet4amno]-IH-crbzo-3carboxainide (3R)-N-(IS)--(Acarbny)-2-methyipropyp-34i3brornopheny1)coty1]amino]-Z3,4,9-ttrahydro-1UH-abazo1- 3-caboxamide eblDo-fluoPhenY1)acetylaiino-2,39e~rdrO-Hcarbazo]-3-.arboxamide (3t)-N-(IS-1-(Aminocarbony)--methypmpyU-3-[[1 1 biphenyl]-4-ylatcetyl~aninoJ-23,4,9-terAhydro-IH-caxbazol 3-carboximide S)-I-(AmilocarbonYl)-2-mnethylpropyl}.3.[((3,5dimethylphenyl)acetyl]lamino]-2,3,4,9-tetrahydro-Hcarbazol -3-caxboxamide =22S739 89 492 491.546 90 515 515.4382 91 484 464.5381 21 462 482.547 M3 W5 M254441 94 491 491.6451 9M 491 491.5451 96 62 525.4441 PI 499 498.983 98 623 56.456 99 475 474.0010 58 benzodioxol-S-ylactyl)8hrzno]-2,3,4,9-tthydro-IHcarbazol -3-=aboxamide S)-1-(Aminoarbonyl-2metypropyJ-23,4,9oboohoYDr-3.fl(3 mctyihny1)ece,4A9mio-H bazo- 3-carboxamide S)4I(Amnocony)-2-mbiYlPrOPYI4(2 tetmhro-3ny1[c(3-miylnyo4,9tylrair-1H-carbazoI-3 3carboxamide (3R -N-[RI S)-I -(Aminocabony1)-2-methy~propyIj-3 4,9 tBuoroph34I(2cq]metypiylj2,avcltahyo-H-carbazDI-3 3carboxude (3P.*N-[(lS)-I-(Azmioarbony)-2-methypoy1.Z3,4,9tetrhydro-3-fl[(-mthylcthyl)ahenylAceylino]- 1Ubzocab3 u--carboxamide (3R)-N-(S)-I-(Auilocabonyl)-2-mehylpropyl)-23-fl4 (dtekyro1 1-mtlghypheny1)ceylainJ2,,4tlahyo- Ica ol -3cabonide (3R)N-[(IS)--(muoabuyI)-2-mthlropyJ-23-,4-9 ydrd~o-3ff4y(mebyhuAfonynoheny3accyI-tminoJ-2 Icarbal 3-caboxamide S)-l-(Aminocabouyf)-2-methiylpropylj-3-(f(3flor4-methy~lpheny~acetyl]amino]-.3,A9-ttrahyro-li{carbazol -3-carboxamide 100 49D 400.567 101 481 480.9931 102 461 460.5748 103 464 464,5381 104 461 460.674B 105 489 488.6284 1068 490 489.616S 1071 524 624.8388 108 478 478.684 Exampl e 9: Synthesis takes place on the 0.2 mnol scale by methods B, F, G, F, G, F, G and 0.

N-[[X3R)-2,3,4,9--Teraydro-3-((28S3S-3-methy-i-oxo-2- [((jhenylmethoxy)carbonyaminopenty]aruino]-1Hcrai-3-YIltb]- -,vay-L-asparaine 690.7934 N-i (3 S)-2%349 -TetahYdro-3-(2S,3S)-3-mety-l-oxo-2- [[fphenylmethoxy)osrbiyl]ain'nolpenylamino]-1Hcarbazol -3-yl]carbouyl]-L-valyl-L-aspaigine 110 691 690.7934 59 Example Synthesis takes place on the 0. 2 inmol scale by methods A, F, G, F, G, F, G, F, H and 0.

N-E(3P)-3-[(2S,3S)2-(AcetylaMimo)-3-methyl-Ioxopemiy1]amino]-2,3A49-tetrahydro-iH-carbamo1-3yJ]carbonyl]-L-valyl-L-aspattamide N-f(3S)-3-[(S,3S)-2-(AvetylamI )-3-methyl-loxopentyl]amino]-Z3,4,94etralydro-IH-caiawl -3yl]carbonyl}.L-vzlyl-D~asparaamide oxopcntyljaminD]-2,3,4,9-tctrahdro-IH-cabazol.3yl]carbonyl]-L-vayl-L-aspartamide N-E[(3S)-341[(2R3R,-2-(Acatymino.3-mctlkyl-I.

oxoPentyIlaminD]-2,3,49-te~abiydo-1H-carbazoi3.

yl]carbonyl}l--valyl-L-aspartaniide 111 598 597.7127 112 598 597.7127 JL3 598 697.7127 114 598 597.7127 Exampl e 11 Synthesis takes place on the 0. 2 nimol scale by methods A, F, G, F, G, F, H and 0.

N-U(3R)-3-Acetymino)-2,3,4,9tUrahydro-IH-carbazoi-3yI]carbonyl]-l-valyl-L-aspartamide N-ll(3S)-3-(Ace*ylamino)-23A9terhYdro-IHvwirbazol y1JcaronyI)-L-v~1yI-L-aspartanide N.{[[(3S)-3-(Ac~tylino)-2,3,4,9-tetrahydro-lH-oabazol-3yI]oazbonylj-D-valyl-L-aspartamide -3-(Acetylaxnino)-2,3,4,9-terahdro-1H.carbazol-3yl]coarbonyl]-l-valyl-D-aspartarde 115 484 11-8 484 11-7 484 II B 484 484.5538 484.5538 484.0538 484.5538 Exampl e 12: Synthesis takes place on the 0. 2 nimol scale by methods A, F, G and 0.

60 pbe~ylmetliyl [(1S,2S)4-fl(3R)-3.(aminocazonyl)-2349- 119 478 476.673 tetrabydw-fl-abazoI -3-yIlamino]carbonyJ}2mcthylbutylcarbamate Phenylmethyl [(IS,2S)-I{UI(3S)-3-(aminocazbonl)-Z3,4,9- 120 478 4705n73 tetmbydro-IH-caibzo -3.yI1amin01Mabonyl-2methylbutylcarbamatc Example 13: Synthesis takes place on the 0.2 rrmol scale by methods A, F, G, F, G, F, G, F, G and 0.

N-fl(3R)-23,4,9g-Tcznhydro-34(2s)--Oxo-2{(1-oxro-3phenylpropyl)aminoj-3-phenylpoylamino]-IH-carbazol- 3-yicarbonyl)-L-valyI-L-aspatamide N-1J(3R,)-23A49-Tctrahydro-3-4((2R,3R)-3-mnethyl-l-oxo-2ox-3-phenylpropyaminopenty]amiao]-1f-bazo1- 3-y1cai1ony]-l-v81y-L-aspatamide 121 722 721.8543 M on 887.8371 Example 14: Synthesis takes place on the 0.2 mmcl scale by methods D, F, G, F, G and 0.

N4[(3R) -2,3,4,9-Traydo-3E[(2s,3s)-3-mehYl-1-oxo-2- [(peylmetxy)cabonyUamno]pnt1amiJo]-1H.

carbazoI .3.yljoarbcmyl}.-"a, N-[(3R)-Z349- Tetrahydro-3-([(2S)-3-methyl-l-oxo -2- [[(phenylmettboxy)cabony1]amino]pemyt3]amino]4IHcarbazol -3-yl~cabouyl]-L-valinc N-[((3$)-2,3,4,9-Tetahydro-3-U(2S,3S)3-met1y1-l-oxo-2- [[(phcnylmethioxy)earbony]umiwopenty~aiio]-IHcarbazoI-3-yl~carbonyl]-L-valine m2 $77 678.09 124 57 670.69 Exanp~le Synthesis takes place on the 0.2 rmnol scale by methods C, F, G, F, G, F, G and P 61 N-I[(3P)-3-(((2S.3S)-2-ffl(L I Dimethylethoxy)Garbonyllamio]-3-methyl-1- OxoPcutY1]amino-2v3A494trahYdro-H-carbao1-3.

Yl~carbonyl]-L-valyI L-aspartamide 125 6M~ 655.7921 Example 16: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, G, F and 0.

yl]carbonyi]-L-valyl-L-aspartamide yljcabonyl]-L-valyl-L-aspartamjde (3S)-N-(S)4I-(Amnocrbony).2-methylpopyl].

3 [(2S,3S)-2-amin-3-mety-l-xooPeiYamio}2 3 A9 terhdoI-abzl--abxmd 126 442 442.617 19 442 442.517 128 441 441.5725 Example 17: Synthesis takes place on the 0.2 mmol scale by methods D, F, G, F, G, F, H and 0.

N-rI(3S--Aotylamino) -2 ,3,9-tetrhdro1H-Garbazo1-3- 129 485 y1]cubon1-L-valy] L-aspaagmne 465.5370 Example 18: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, F, H and 0.

(3R)-3-(Acetyamino)-N-[(1S)2-amio-2-oxco-1.

(jphenylmethyl)ethy1)-23,4,9-tetrahydro-lH-cabzo1.3caiboxaniide (phenylmethy~ethy1]-2,3,4,9-tetahydro-1H-carbazo.3carboxamide 130 418 418.4944 131 418 418.4944 62 Exampl e 19: Synthesis takes place on the 0.2 inmol scale by methods B, F, G and 0.

(3S).Z3,4,9-TerAhydo-3-[(2S3S)-3-met31y1-l-oxo-2- [[(pheylmeoxy)abonyamino]pentyJamino]-IHcarbazole-3-carboxyic acid Example Synthesis takes place on the 0.2 rmnol B, F, G, F and 0.

(3S)-3-[[[(2,2-Dipbenylethyl)aifinolacetyljmioj-2,3,4,9tetrabydro-1R-carbazole carboxylic acid Example 21: Synthesis takes place on the 0.2 mmol A, F, G, F, H and 0.

(3S)-3-(Acetyaino)-N4[f3- (aminooabonYEOPhnY13ieYIIy-2,3,4Ctexado-1Hcarbazole--arbxamide (3S)-3-(Acetylamno)-N-Et4- (anocany~ohelmhyj-394,9euhydro-lHcaiibazole-3-varboxamide (3X)-3-(AcetyI&MinO)-N114- (ami~oohxYICO~metIy]~-2-39-teahdro1Hvarbazole-3-caiboxamide (3S)-3-(Acetylamiuo)-IX[IS)-2-amino-2-oxo-lpheuiethtyI]-7,3,4,9-tetrahydro-IH-cubazole -3-carboxamide 132 478 477556M scale by methods 13_4 468 467,5661 scale by methods 135 404 404.4676 13-S 410 410.515 13_7 410 410.515 138 404 404.4670 Example 22: Synthesis takes place on the 0.2 inmol scale in accordance with Examples 18 and 6.

63 2,3,4,9-tetaydro-IR-carbazol-3yla omia~ bonyl]-2tnetliylbutyllcarbamae Phenylmethyl S,2S)-2-vwfthyi-1I-ff [(3P)-Z3,4,9tetrahiydro-341[(1-methyletbyIoamino]carbonyl]-H-carbazol- 3-yIjaminoJ~abonyllbuty1]carbamate Phenylmetby [(IS,28)-2-meth1.--l(3R)-Z,3,4.9tetrhydro-34(2-methylpropy~amino]carbouyI].1Hcarbazol -3-yl~ammi~uojbonyl]jbuycarbamate Phenylmethyl dimethylpropyl)aminiojoarbonyl]-23,4,9-tetrahydro-1H- =abawol -3.yllaifinolcarbonyl]-2-maethlbutyl]cabarate Phenylmethyl [(1S,2S)-2-methyl-I-a[(3R)-Z3,4,9tetrahydro-3-(penylamino)carbony]-H-carbazol-3yIjaminojcarbonyI~butyljcarbamate Phenylmethyl S,2S)-2-rnethyl-l-Qh1(3R>.Z34,9terhydro-3-E[phenylmethyl)amino)carbonyl]-1H-cabazol- 3-yljaniino]oarbonyljbutyl]vabamate Phenylmetbyl [(I1S,2S)2-nlethyfl.[((3R)-2,3,4,9tetrahdro-3-[[(2-phenylethyl)aniinocarbonyl]-IH-carbazol 3-yl]axnino]carbonyl~butyl]carbamate Phenylmathy S,2S)2-methyl-I-[ff 3R-Z3,4,9tetrahydro-3-(f(3-phenylpropyl)aniinocarbonyl]-1ncaibazol -3-yllamino]Garbonylbutycarbamate In 505 504.6274 142 S1g 519.654 141 M33 532.68 142 547 546.7078 143 553 52.714 144 567 W8.6982 1456 681 580.725 iAN 585 594.7510 Exam~ple 23: Synthesis takes place on the 0.2 rnmol scale by methods A, F, G, I, F, G and 0.

m 64 PhenuYlmethyl S2S)-14f(3R).3-flI(1*- (aminocaboyl)-2-methypropyjamino]cubonyl]-2,3,4,9teahyro--ietoxy-lH-obazol -3-yljamiiiojcarbonyl]-2methylbutyllcarbanme (aminorcay-2-methylopy~amin]erony]-2,3,4,9teM yr-mt.1Hc ybI. ryawinoylamconyl.2.

methylbutyijoarbamate Phenylmethyl (IS,2S)- I I (am &ubony1)-2-nmchylpropyIlamino]carbonyl]-6cbaro- 2,3,4,9-tetydro-II--carbzo -3-yIjamnDnocarbonylj-2.

methylbvrtyjcarbamate Phenylmcthyl (tS2s)-1-fl((3s)-34J((1I (aininocarbony)-2-methylpropylaiino]abonyll-6.choro- 2.3,4,9-tetrahyroD-lll-bazol-3-y]amino)carbonyl]-2mothylbutyl]cuobamate (ainocarbony)-2-methylpropyIlan-dojabony}.schJory- 2 3,4,9-tetrahydro-fl{-orbazol,-3-yl]amfino]carbonyl]-2- Taethylbuty]carbainate 1j478 0 0571 14Th O0N 805.7317 124da 610 610.151 .3Aqk 610 810.151 1500 sIO 810.151 65 Phenylmthyl )1 (mnovfn2methylopyl1ainino~ijrjo xc]-dd.o 2,3,4,9-tetrabydro-ffl-caibzo -3-ylJaminolearbonyfl-2methylbutyl~carbamaie Phenylmdhiyl [(IS,2S)-1-[f(3PR)-34ff(lsy.I- (anOcabOnyl)-2-ethYlPropyjaminocarbonyl}.2,3A49tetrAydr&Uoromeyf}.IH-abimo1.3 y1Jaino]mabony].2-mehylbuy1oaibamate Phenylmethyl [(1S,2*1[(3S)34ffQIS)-4.

(aMinovbony1-2-meypropyUanjo~cbony2}.3A9tetrahydro-Sudoromey)IHcrbzoI3 yIjamino]Qncyl-2mehybuty]cmbamate Pbenylmethyl S.2*141(3R1)-3-[ff[(1 sy1- (aminOCabOnY)-2-mYlPropyflnocrbny1].3,49 tethydro-S-methyl-1Hcabazob3y]miro3cbony .2 methylbutyljcarbamatu (a ino rbonyD)-2-met~lypropyl~aminolcarbonuyl-2 3,4,9methiylbutyljcarbamate (ao 2 oy-2mcthy lroy1]ntirojbonyI. teydr 5-iethy-)HnarzoI3-yllani~ocoy].

2 znethylbutyl~caibamate Phenylmethyl (aminocrbony)--mehylpropy1amo~carbefnl]1}2349 methylbutylgcaxbarnaft (amlinocarbny)2-mehypropyain~ar~bonyli2,3, 4 9 meffiylbutylcarbainate I80b 810 610.151 49a 644 043.703 149b 844 843.703 150a 5w 589.7327 560 589.7327 Isla 590 589.7327 I51b $90 689.7327 151c 590 689.7327 66 Phenylmethyl (1S,2S)-14[(3S).3-[f((JIS)-I- (arinobonYl-methYlPropyljaminocrbonYl-2,3A49tctrahydro-7-mehyl-U-cub=1o-3yljamino]carbony]-2rnethylbutyljcarbamate Phenylinethyl [(lS2S)-4[[(3KQ-3-f(1S)-l-.

(amiobonyi pro poaminomcarbony.S-c~oto- 2,,4,9teraydro-H-carbazol3-y1]amin]any].2methylbutylicarbamate (ainobol)-2-mthpropyomiocbony]-7.cliloro- Z3,49-cwahYdro-ffl-Cabazol -3-YljamiuojvarbnYlj2methylbutyl~oarbamt (aminaoy)-2-meypropyaino]bonyl]?-c~oro 2,3A49.emahYdO-IH-abazl-3-YJlaminolcarbonYl}.2inetilbutyllcarbamat methiylpropyllaminojcarbonylJ-2,3A49-tetrahydro-3- [[(2S,3S),-.3methyl-1-oxo-2- [peylethoxy)rbyainopentyamino]-Honbaole -8-carboxylic acid (3S) -3-[[IIt(S)I-(Aninocaxbonyl)-2 ufiYlpOPyl1aminoloabonyIJ-23A4,tetrahYdro-3mhyl-l-oxo-2- [ihnehoy)arbonyaminobpetyl]anmino11lHcarbazole-8-carboxylic acid (anioenyl)-2-cthylpropyailarbonYll-6-huoro- 2,3,4)9-tetrahydro-1H-mArbazl -3-y1]arako]oa~bonyl]-2umethylbutyflearbamate (aminocbony-mehylppyamnocarbonyl]-6-fluoro- 2 ,3,4,9-tetrahydro-!H-carbazol-3-yljuninojcarbnyl]-2metbylbutyl~carbamate Phenylmethyl (Oa OcaxnYl)-2-methYlpropyllazuinolcarbouyl]-2,3A9,tetrahYdro-6-methoXY-IH-carbazol -3-yllaminolcarbonyll-2methylbutyl]carbaniate I51d 590 589.7327 152s 610 610.151 162b 810 610.151 152C 810 610.161 U3 620 819,7149 IS~ 620 610,7149 1"A3 593 593.690 134b 593 MUM69 -155. 6s 605.7317 67 Phenylmethyl (aminocarbonyl) -2-meftylpropyJainojcarbony]-23,4,9tetrahydxo.-methoxy-1H-carbazol -3-yI~anmino]carbony1]-2.

rnethylbutyIcabamate Piieaylmethyl )1 (aminocarbonyi)-2-methylpropyI]aminoloabony]-2,3,4,9tcmhydro-6-mety-lH-abmzo -3-yI]amino]caboiiyD2-.

metbylbutyUcarbamate Phenylmethyl S,2S)-1.{ff (3S)-341(1S)-l- (aminocbny-2mthypopyoaino]=abonyl]-34,9terahyro-&methy-1H-cubazol -3-yflaminolcarboyl]-2mothfibutylqcaibamate Phenylmethyl (nicarboy-2-eth~ropyUamino]carboxnyoJ-23,49teahydro--Diro-lH-arazo-3-yaminocarouyl]-2methylbutyllearbaxnate Phnylmethyl [1B28--f( )3f( )i (arnoboprop mylpraminjv o]onyl.,3,4,9tetrahydo-6-ntr-lH-carbzl.3-yamnojcarbonylj-2methiylbutyflearbamate Phenylmnethyl (I S)-1- (ainowabDoyl-4- [(aminOiminomethYl~azinOlbutyljaninolcarbonyf]-2,3,.4,9tehydro-fl abazol-3-yamino]erbony4]-2umethylbutytcarbainate (3R,)-N-[(1S)4I-(AminOvabnyl)2-Methylpropyl]-2,3,4,9tetruYdr-34(3-PYridiYlminoj -U-abzle-3carboxmide (3S)-N-[(IS)-1-(Aznor-arbonyl)-2-methylpropyl).2,3,4,9tea-aydro-3-[(3-pyridiyacety)amxino]4IH-cabazoe-3carboxamide S)-1.{AnioocarbonY1)-2-methylpropy1].2,3,4,9tetrahydr-34(1-nhtbaenycety)amino]-IHcarbaole-3carboxainide 15b W0S 60.7317 is-a 689 689.7327 Its.b 689 58".7w2 -J7 821 620.703 167b 621 620.703 158 633 832.7818 1600 447 447.5361 159b 447 447.5361 180a 495 496.6078 68 S)-I-(Aniinocarbonyl)-2-Metbylpropyl]-2,3,49tetrabydro-3-[Q-naphthalenylaoety))axnino]-4H-carbazole-3carboxamide (3R-N-E(lS)-N-Aminocabon-2-metbylpropyll-2,3,A9teuhydro-3-[(2-ahtbaeayacety)amiu]-IH-cbolecaboxamid..

(3S)-N-I(I I-(AminocazboyI)-2-methylpropyI]-2,3,A9.

terahydro-3-[2-naphtaenyaceyIDaino-lH-caazole -3carboxamide (3R,)-N4(1S>-I-(AxniOcabOnYl)-2-metbYlPrOPYl]-34[(Z3dihydro-1H-inden-l-yl)caduyjminoj-2,3A49-tetrahYdro- IH-carbazole -3-carboxamide dhiydro-lH-inden-1I)abOnyIw-2.3,4,9-teUrahydro,- IH-varbazole -3-carboxamide (3R,)-N[I(IS>4-(Aminocabol)-2-meylpropyl]-2,3,4,9tehydro-3-(Hmidazol-4-ylacetarno)H-czbazole 3-carboxamide (3 S)-N-1 S)-1 -(AminocarbonYl)-2-MethYlprvPYlJ-23A49tetahYdrO-34-[lidzo-4-aetY1)aino]-IH-carbazle 3-varboxamide (3R)-N-[(1S)-1-(Amnocrbony)-2,metylpropy3-3,4,9 tetiihydro-3(1-indO1-3YiactY1aninJ-IH-carbazole -3carboxamide (3S)-N-1(1*-1-(AmOcrbonY1)-2-m~hPrOPY1]-2,3,A,9tbetahydro-34(1H-indo-3-y4aceylamin9]-1H-cabazole -3carboxamide (3R)-N-I(1 S)-l -(Axninocabonyl)2-metbylpropyl-2,3,4.9tdhydr -1(4-methheylhn)acetylmino-R-crbazoe.

3-caxboxamide (3S)-.(tS)-1-(Amnocbonyl)-2-methylpropyl]-2,3,4,9tetrahYdro-3.f[(4-methYlPheyaYety]aminol]flcabazole.

3-carboxamide (3R)-N-I(1 S)-1-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9.

tctraydro-3-[([4-(trifluoromethyl)phenyl]acetyi]amino}.1carbazole-.3-carboxamide 1-0b 4 96 496.6078 IB_18 498 161b 498 .162a 472 162b 472 498,M078 496,6D78 472.68W8 472.GM5 lla 438 43&65132 163b 438 184a 4W8 1Mb 488 Iisa .461 438.5132 485.5849 485.6849 460.6748 165b 481 460.6748 166a 615 614.6451 69 (3S)-N-I(1 S)-1(AminocAxbonY1)-2-methYlPropyI]-2,3,4,9- 166b btahdro-3-[[4-tifuoromethylphenyllaoy]amino].1H.

carbazole -3-caboxaniide (3R)-N-[(1S)-I-(AiinocabnYi)-2-methypropyJ-3-[[(4- 1672 ceiorophenyI~acetyamino]23,3A94etahydr-o-1H-carbazole 3-carboxamide (3S)-H-tS)-1-(AminOcbOnY1)-mehYlrOPyI)-34(+ XU cbloropheny1acetyI]amino]-2,3A4teruhYdru..rajbazole 3-cazboxamide (3S)N40(IS-1-(Aminocbouyl>.2-meIthyprop 3 ,9 1sla tewdro-3-ff(3-(tri~oromehy1)phenyIlacety1]amino]-iHmabazole -3-carboxamide (3R)-N-i[(1S)-I-(AmiDOcabouYf)-2-metYlpropyJ.2,3,4,9- 168b tdmW-34-(fuoromehyl)phnyjaety]mino]-1Hcarbazole .3-carboxamide S)-1-(Aminocarbonyl2-methylpropyl]-3-[[(3- 169* fluorOPhny~actY[]aminO]-2,3,49-teramiYdro-1Ii-cabale -3carboiamide (3S)-N,-(1S)--(Aminoaboy)2-methypopyl..3r3, 169b iuoxtophenYlDactlamino]-23A49-tetabdo4H-cabazle -3carboxamide (3R)-N-t(IS)--(AminocabonYl)-2-methylpopy-2,3,4,9- i2Q.

tetahy(3-[thc toypheny ce~amino-IHcarbazole-3-carboxmdc 615 514.6451 481 460.993 481 4B0.9931 514.S451 514.6451 464.631 464.6381 477 476a5M3 (35)-N-(IS)-1-(Amiuochzbonyl)-2-mcthylpropyl)-2,3,4,9ttbydro-3R-inetmhxyhey)actylamino)-rncaibaole -3-carbommide -(Amioaboyl2-methypropy}2A3,4,9.

tethydro3(2-mepchenyl)aceylamino] n-varbazole.- 3-carboxamide- S)-1-(Aminocarbonyl)-2-methylpropyl)..z3,4,9terhydro-3-(-metoxypheylaety3amino]1IH-carbazol c.

3-carboxamide- 170b 47673B 1712 477 476.573B 171b 477 470.5M3 (3R)-Nf(IS-(AMinocabo.nyl methyIpoy3f3( 172 479 fluorophanl)-l-OXopropyl~amino]-2,3,4,9-tetaydro-1 III carbazole -3-carboxamide 476.5649 70 (3S)-N-11S)-1.(AminocaboDnyl)72-methylpropyI]-3-[[3-(4fluorophenyl)-l-oxopropy]amino]-2,3,4,9texaydro-1Hcarbazole -3-maboxamide (3R)-NM(1S)--(Amnoabnyl)-2-mthylpropyU-3-E[3- (3,4-difuorophenyl)-l-oxopropyl~amino-23A9-etahYdrco- IH-carbazole -3-maboxamide (3S)-N-[(1S)--(AinocabonyD-2-mehylpropy1J-3-U3- (3,4iiuoopheny)l-I.0op1p]amo-2,3,4,94drhydo- IH-mt~azole.3-cazoxmde (3 S) I (Aminocarbonyf)-2-mehylpropyW]3.{f3 [3,4-EWi(tifluoromethyl)pheny1l-l-aopropyIlamino]-2,3,4,9tetrahydr-H-mabmzot -3-carboxamide (3S).N4(IS)--(Aminoaboyl-2-mtlproyl]-3-13 [s,4-bfluiuorometby)pheny]--'oprpy]amino]-2,3,4,9tetrahydro-1H-=abazole -3-carboxaniide N-RI *)1-(Aminocarony)-2-m11tI1ylp~pYI-Z3,4,9tethydro-3[1(4-methoxypbeyl)cetl]amino]-lHcarbmzle'.3-carboxamide (3P)-N-E(1S)-1-(Aminovaboyl)-2-mnethylpropyll-2.3,4)9tahdo-34j[3-(4-methoxyphenyl)-l-or-opropyl]amino]fl{-mabazole -3-ceooxude (3S)-N[(S)-I-(Amnobonyr)-2-methylpropyl-2,3A49'thydro-343-(4mhxYphenI-OxOPrOPYIIam- IH-carbazole .3-carboxaniide (3R)-N4(IS)-I-(AiinoabonY1)-2-mthYlPrOPYI]2 A349tty413-(:2-m foxyphnyl)-I- ppylamino]lH-carbazoe-3-maroxariide (38-N-(-1-(Aiuoabnyl)-2-metylpropyl]-2,3,4,9tehydro-3(32-methoxypnyl)-l-xoropyjaziuo]- 1iH-vabazole 3-cazboxamide (3R)-N-r(1s)..(Aminocaboayi)-2,methylpropyI]-2.3,4,9tetrahydro,-34(3-(1H-iudol-3-yl)-l-oxopropyl]amino]-1Hcarbazole -3-carboxaide (3S)N-[(lS)-l-(Aminocarbonyl)-2-methylpropyl]-2 3,4,9tetrahydro-3-1[3-(Hli-indoI-3-yl) -l-oxopropyIaino3-1lHcarbazole .3-caboxmide 72b 479 478.5649 17'3a 497 496.555 .1L-b 497 490.5M5 .746 93 692.805 14b 693 592.605 175 477 4?6.5M~ -176-A 491 490.08 176b 491 490.600 -Meh 491 490.6=0 .17f 491 490.800 1784 600 499.6117 AMD 600 499.6117 71 (3R)-N-[(1S)-.(AminocabonyI>-2-methylpropylj..23,4,9.

caiboxainide (3S}-N-(1S)--(Amzocarbony1)-2-methylpropyI-2,3,4,9tetraJydro-3-[(l-ox~o-6-phcayhexy)amino].1H-caijzI -3carboxamide Phonylmthyl B,2S)-1-ffl(3R)-3-[[(2S)-2- (aminocabony1)-l-pyroidlzmyI]carbonyIJ-2,3,4,9teftrabydro-IH-carbzc-3-y]aminolcarbony1..2methylbutyijoabaate.

(amnMon1-YIdiny] c arbon]234,9teu-hydro-H-abzo-3-y]minocaboy]-2xnethylbutyl~abammt Phenylmethyl

I-

(am nocarbonyl)-2-methylpropyIJaxinokcarbeyI]4',s.

dic~oro-2,3A49-tetrahdro-1H-carbazoI -3yllaminoloarbonyl-)-2-niethylbutyflcarbaxnate (arninocarbonyl)-2-mctpropyl]amino]cabory]-7,8.

dichloro-23,4,94etx-aydro-IH-carbazo1 -3yl]amocabonyl]-2-methylbutyl]oarbamnate PhenyImethyl S,2S)-14-ff(3R)-3.r[( (aminymbthYD-pro~pyIpyamiiolbony)-239-.

te-ydro-5,9direthy4-IH-arbaZDI -3-yIqaminojwbony}j 2-metbylbutlcabamate Phenyhnethyl

S)-I.

(amiocabOrnY)-2-mebYlpropyljaminolcarbvuy11Z23.49tetzhydro-58-dimethy1-m-oa61iao.3.y]amino]carbonyl].

2-metthylbutyl]carbama Phenylmethyl (X1S,2S)-1-Q(3RL)3-(ff(1S)-4- (aminovabony)-2-methylpropylamiio]caibonyl..6,&.

diohlorov-2,3,4,9-tetrabydro..IH-carbz1 -3yI]aminovarbonyl]-2-metylbutyllvarbamate PhenYlmethyl S,2S)-14U(3 S)-I- (ainoabonyrj?-2-meffi~propy~aminolcabonyl].6,..

dichloro-2,3,4,9-tetrahydro-1H-oarbazol.3 yI]amino]c-arbonyl]-2-methylbuty1carbamate A? 9a 603 179b 503 502-6552 5028552 .1818 574 57.690 Ml~k 574 573.89m l82a 845 644.6961 182b W4 644.6961 1832 604 603.7M9 -163b 804 0037595 lUg 646 644.6081 -LOO 645 644.6901 72 Phenylmethyl [(IS,2S)-1.{a[(3R)-.34fl(I S)-1- (aminocabnyI)-2-mnethylproy]aminolcarbony1Jl-bromo.

2,3,49-tetrahydfo-1H-=ab ol -3-yIlaniiwo~oarboiiy1]-2methylbutyIcwt1amate Phenylznetkyl f(3S)-34[(1 S)-1- (aminocab2-p eorlyl)aminobonyl]-6-broio- 2,3,49.tetrahydro-E-ozbazoI -3-yl~aminojcarbonylj-2mehylbutyijearbanate (Amrbony}.2-Meppy1-3f((4chlcropeyao]-2ain3,4,9-t rahydro-etoxy.

IH-cwtiw.-3-abtxnid (3S)-N-(1S)-(Amnocabony)-2-mthyApopyJ-3-[(cbloropbenyloacetyllamiiioJ-2,3,4,9-tetaydro-4-metboxy IH-caxbazole-3-carboxaxdde 'Phenybn~etbyl [(1S,ZS)-[(3R)3f[(R)-2-axnnod4-(4cborophenyi)mIJy-2-ozocthy~aminojsboyl-2,3,4,9te~dro-Hcro-3-y]a n carbony4]-2methylbutyijoarbamate dd1OrPheaYI)methY1]-2-OxOethy1]aminOlcarbOnYl]-23A49.

timydro-IH-cazl-.3-yi]amino]oabonyl]-2methylbutyI]carbamae orcopropyl am noarbo 3n-2,3,49-te bYdro. 1H.uarbazol- 3-yljamino]crboyl-2-metbylbutyl~cabamate (2S)-I-ft(3.-34(4-cbiloopheny~acetAlmino.49tahydro-8-methoxy-lIH-carbazol-3-yl]carbollyl]-2pyrrolidinecarboxamide (2S)-I-[((3S)-3-ff(4-Cblor-ophenyl)acctynaminoj-2,3A49tetrahydro-8-mehoxy-1H-oarbazol-3-ylcarbonyl]-2pyrrolidbiecarboxamide Phemyliethyl S,2S)-1-(fl(3L)-3-t[(2s)-2- (am nocarbonyl)octahydro. 1H-indol-1PyI~carbonyl]-2,3A49tetrahydro-U{-carbazol -3-yljamlnq)cmbonyi]2.

methylbiityljoarbamate 1 Wa 855 654.602 .18-9b 6WS 654.602 1eft 511 511.0189 186b 511 511.0189 .JM t e 6 558.195 187b 658 6M.195 188 64S 647.0523 I1304 509 509,0031 _t9b 509.0031 19021 626 627.7815 73 Phenylmiethyl (I S,2S)-llt((3 S)-34[(2S)-2- (aminocarbonY1)OCtWYdro-1H-indo--Y1]carbOinYI]-2,3A49terAhydro-.IH-carbazo1 -3-yl]aminolcarbonyU-2methylbutylqcabamate Pheaylxnethyl (I S,2S)-i -gj(3)-3-f [(2-SAE)2- (anm oaroy)-4-hydroxy--pyodiny]carbonyI]- 2,3,4,-totrahYdro-1H-ca~alo -3-Yllaminocarbouyl]-2methy~butyI)carbamate Phenylmethyl [(IS,2S)-I (ammoboy)--hdroxy--prroidiny4]crboy1)- 72)3A49-tetcahYdro-1H-carbazol-3-Y1]aminolcarbouYI]-2methylbutyl~cadbaae (amno~nyl)-2hydroxypropylamino]arboyl]-2,3,4,9tetrahydro-1H-vmbarol-3-yljaminojcarbonyfl-2methylbuty~cwbamate (=uinonyI J)-2-hydxy proy amino]cabny12,3,4,9tetrahydro-JH-carbazol -3.yi]aminojcarbonylj-2methylbutyl]carbamate Phenylmethyl 2S)-1-a((3 1 S)3-[[(2-amiuo-2oocthyl)amino]carbonyl3-2,3,4,9-tetahydro-1H-oarbazol -3yi]aminojabonyl]-2-nehylbutycArmbamate Phenylmethyl r(IS,2s)-11f3-f[2- (aminocabony~phenyl]azuinocabor1y]-234,9 etrahdo- I H-abazol -3-y]aroinolcabonyl-2-methylbuticarbamate (3R)--(IS)--(Anoarbony-2methypropyl]3-l(4.

chloro-3-[[(4-pyiidinylaniino)- =oyl]aMino]phenyljacetyl]amino]-23,4,9tetahydo- IH-cuxbazoe--caboxamiide S)-.1-Ainocarbo3y)-2-metbylpropy]-3-[[4chloro-3-[II(4pyidinylmino)azbonyaiuo]phenyl]acetyllamino]- 2,3,4 9-tetrahydro-1H-caxbazole-3-cuxboxamide (3R)-N4(1 S)-I.(Aminoarony)-2-mthypropy]-3{[[4chloro-3-[[(phenyamino)caronYiaiw-3PhenylactYlamim.,]2,3A9-trahYdrO-.

IH-carbazol.e-3-carboxamide (3S)-bl.{(1S)-l-(Anmocarbonyl)-2-methylpropyl.3-[[f4.

190b 828 627.7815 1910 590 589.891 191b 590 589.6891 MR1 578 577.6701 291b 677.6781- 292 634 633.625 598 595.86m 193R 618 615.119 .LO3b 618 616.119 194a 815 615.13 194b 615 61S.13 74 cbloro-3-[[(phenylamino)cabony]amino]phnyl]acetyamino]2,3,49terayro- IH-cabamk-3-cuboxamidc (3PR)-N-[(ISM--(AmnocarbnYI)-2-netbYlPwOpyI-34fJ4vb~oro,-3.(ftbeqy~methyI)aminqjcmbony1]axninDpIbnylacety!JsminG334,94etrhydro- (3 S)-1-(Axoiuovabmy1)-2-mehylpropyI]-3-fl[4c~ro3-[[[(phny~mty)3minocabonylJamino]phenyl~acety1aminoJ-2,3A4,-emYdro-1H-cabazole-3coiboxamide (3R,)-N-[(1S)-1-(Aminocabonyr)-2-methyipropy}.3-[[[4cdloro-3-[(2-pyidinylamno)czbozu4]amino]pbenyljacatlamino]-2 1 3.4,9-teWalydro-IR-cabazolce-3carboxumdec (3SN-(1*-(Ainobony-2-mtypropl-3-[(4chloro-3-([(2-pyridinykahio)crbowyi]qmin pho-yflaetyJaminol-,3,4,9thydr-H-cabazol-3-carboxmide -195a O2n Q9.157 A6Gb M2 M2.157 _198M 616 618.119 196b 619 B18.119 Example 24: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, I, F, H and 0.

(3R)-3-(Aetin) -N-[(1S)-1-(aminocabonyI)-2methylpropyiJ-2,3A49-tetahYdro.8methOXY-IH-carbazoI -3carboxamide (3S)-3-(Aoetyamino)N4(S)-1(aminoabonyQ-2mhYlPrOPYlj-2349-ttahYdr--methoxcy-1H-carazol -3carboxamide 3-(Acetylamino)-N-((IS)-1-(amniocarbonyl)-2methylpropylj-6-cloro-2,34,9-tetahydxo-1H-carbazole-3carboxamide 3-(ACetylamino)-N-j(IS)-1-(amiriocarbonyl)-2mnebylpropyl-2,4,9-tydro-5-ethyl-IH-crazole-3carbwmmnide 197a 400 400.47M2 AM7 400 400.4762 198 403 404.8M5 199 759 788.9544 75 3-(Acetylmino)-N-[(S-1aminoarbony)methylpropy]]-2,3,4,9-tetrabydro-8-methyl-lH-carbazole -3caiboxamide methylpropylJ-.5-coro-2,3,49-tewraydro-I1I-cabazole-3caiboxamide 3-(Aceybwano)-N-[(IS)--(aiiooaboy)-2mcthypropy)-7-Ioro-2.,3,4,9tmhydro-1H-carbazoo-3coboxamide methylpropy1]-6-fliuoro -23,4,9-tetrahydro-lH-carbazole -3carboxamide (3S)3-(Acetylmino)-N-IXI S)I-(zinocarbonyI.)-2methylpxopyl3-6.fluoro-23A49-teraydro-IH-varbazole -3carboxamide (3R)-3-(Avetylamino)-N-((IS)-1-(aminocarbonyi)-2 mnhylpropyI]-3,4,9tcraydro--methoxy-1H-carbazoe -3carboumaide (3S)-3-(Acetylamino)-N-[(1 S)-1-(amincicabonuyl)-2methylprop34-2,A9teuraihYdro-6-methoxy-1H-cmamole -3carboxarnide (3R)-3-(Acetylamino)-N-[(1S)-1-(aminocarboyl)-2miethYlPropY1]-2 1 3A49-tet-ahYdo-6-Methy-IH-cerba2zok -3carboxamide 200 769 768.9544 201 810 609.7'911 QZ 810 809.7911 388 385.4405 203bk 3M8 388.4405 .22Aa 400 400.4762 204b 400.4762 205a 384 384.4772 (3S)-(Acetylamiiio)-N-[(IS)-1-(aminocarbonyl)-2- .Z~k 384 384.4772 thyiprop31]-2Z3A49-tctraydro-6-xn~zhy-]H-carbazole -3carboxamide (3R)-3-(Acetykamio) -N-[(1S>-I-(aminocarbonyl).2- 206a 370 370.4504 methylpropy1-2,3A9-telrahydro1H-carbazo1l -3-caxboxandde (3S)-3-(Acetylaxino)-N-((IS)-I-(aminovrbnyl)-2- -906 370 370.4504 methylprvpyfl-2,3,4,9-tctrahydro-1H-caibazle -3-carboxamide (3R,)-3-(Acetylamino) -N-[(1S)-1-(arinocarbonyl)-2- -207a 439 439.3406 methylpropyl]-7,8-dichoro-2,3,4,9.4etrahydro-IH-carbazole -3carboxamideI 76 (3S)-3-(Acelmino)-N(S)-I-(an ocarbOny>.2 -207b 439 mehylpropYl-7.8-dCbloro23,4,tetrahydry.IH.vwbazole -3carboxamide 439.3406 (3R)-3-(Acc-tylamino)-N-[fQ S)--(auxouabonyl)-2- 28 nethylpropyl-2,3,4,9-tetabydro-58-dimthyl-H-cabazole 3-carboxmnide (3S)-3-(Acetyamino)-N4(S)1-(rinocrbnl)-2- A methylpropyl]-,4,94traYdr-58-dimcthyl4IH-abazole 3-carboxamide (3R)-3-(Alatymino)-N-[(IS)--(anoabonyl)-2- 22 methYlPropyl]-6,8didioro2,3A4,teayo-1H-cmbazole -3carboxamide (3S>-3-(Acet~4aino)-N-[(1S)-(aminocabny)- Mb ~ethylpropyl]-6,S-didro-2349-eahydro-I H-carbazol e -3cad~oxmide 390 39.504 399 39E.604 439 439.8408 439.3406 Example Synthesis takes place on the 0.2 inmol scale by methods A, F, G, I, F, G, F and 0.

(3R)-3-[(2S)-2-Anino-.{(xnnoimiiomthy)aino-loxop1t]amio]-N-IS)-I-amioabony)-2mnethylpropy1J-2.A494etahydro-IH-cabazoe -3-cad~mxmide (3S)-3-[(2S)-2A=Io-S4(a~miniu methy)aMioJ-1oxopentyl]amino]-N4(1 S)-ami1oarbo~yl)-2methypopy1l-2,3A94mydro-Harbazoe-3-arboxatide I (Aminocaony1)-2-methypropy3-2,3,4,9 tthydro3-[[2-(Iperidinyedy]amo]aCetY1]xIno}.] IH-carbazole-3-caboxamide (3S)-N-[(IS)-1.(Anminca nyl)-7,mehiylpropy}.3,4,9.

tetrahydro-3-[[a2-(1-piperidiniyjethy1Iaminolacty]amino}.

UI-carbazole-3-caboxamide 210a 405 484.6014 210b 405 484.6014 _211Ia 497 498.652 MI-h 497 498.832 -N.{(1S)-I-(AMInoarony)-2-methylpropy1]..Z3A,9 uetahydro-3{[J2-(IH-indoI-3yl)ethyl]amno]actIan~o-lU-abazole-3-caiboxamide 28 W2 525.5534 77 (3S)-N-[(lS)-1(Aminocarbonyl)-2-metylpropyl..2,3,4,9tetrahydro-3.{[(((2-(1H-indol-3yl)ethy]amino]acetyl)amino]-1H-carbazole-3-carboxamide (3R)-N-I S-(Amnocarbonyl)-2-methy4propyl-3-[f([(13benzodioxol-5-ylmethyl)amiiio]acezyl]amino]-2,3,4,9tetrahydr-Hcbazol-3-crboxamide S)-1-(AmimcarbouyWY2-mcthylpropyl]-3{f((i,3benzodioxol-5-ylmthyaminoaetylano-3A49tetrahydo-1H-carbazole.3-carboxamide dipheuylehyaino]ace~mino3,9-ttAYdro-IHcarbazole-3-carboxamide (3S)-N-E(IS)-1.(Amnocarbay)-2-nethylpropyJ-3.{ff(Z2 diPhenYledaYI)aiolacetY1]amino].2,3A49-trahydro4-Hcarbazole-3-carboxamide (3R,)-N-[(t$--(Annobony)-2-mthy*wy1-Z3,4,9tetrahydro-3-flJ1- [metby(phenyliz hyoaminolethylamino]ac-etyflao]- IH-caxbazole-3-carboxamide (3S)--II S)-I -(Aminocarbonyl)-2-methylpropy]2,3,4,9tetnhydro-3-((((Z- [methyl(phenylmethyloamino]etbylaminoacetyl]amino]- 1H-carbazole-3-carboxamide 212b 529 528.6534 213a 520 21M1 52" 619.698U mos5s8 214b 668 2150 633 216b 53 62.8 Example 26: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, I, F, G, F, H and 0.

3-[IIAcetyl[2-(1-piperidiny1)ethyl]amino]acetyl]amino-N- (I S)-l-(apiinocarbony1)-2-methylpropyI]-2.3,4,9tetahydro-IHcarbazo-3-rcaboxamide (3R,)-3-[ftAcctyl[2- [metbyl(phenylmethiyI)amino~ethyI~amino]acetyanmo]-N- S)-ainomarony)-2-methylpropyl]2,3,4,9tetrahydro.-lfl.carbazole-3-caxbaxamidc 638.8888 217u*/ 676 674.72V7 78 (3S)-3-[[[AcetyI[2- [methyl(phenylmethyIoamino]ethyllamacety1]amino]-N- -(aminocarbonyl)-2.-rethylpropylj-2Z3,4,9tetirahydro-1H-cabazo1e-3-caroxamide (3R)-3-(IIAcetyl(2,2-diphnylethy)aviiioactyJamino-N- [(1S)4 -(am nomcaronl)2-methYlPrOPy]23,49ttrydro-lHbazoe-3cboamIde (3&)-3-[Acvtyi(2 2-dihenyothy)annoacetyllaminoJ-N- S)-1-(aminocarbonyr)-2-methylpropylj2,3,4,9teydroIH-cabazoe-3-arbomide (3R)-3-f[AcetyI(1,3-benzdioxot-5ymet)aminojacety]amino]-N-[(I S)4-(aminocarboeyl)- 2-mthylpopyU-23,4,94eurAbydro-H-crbzoI-3ocrboxumida Mbi~ 575 574.7217 218a 808 218b 808 607.7509 807.750 219u 562 561-.855 (3S)-3-fAoetyI1,3bezOdioI-5- 119b ylmethy1)aminolacetyl]azinoj-N-(1S)-(minocrby)- 2-.methb4propy1-2,349-tctzuhydro-1H-cabazole-.3carboxamide (3R)-3-I([AcetyI2.{1H-indoI-3- 220a yI)ethyigaminojacetyl]aminol-N-[(I S)-I -(aminocitonyl)-2mef~poy]239tm~r-Hcral--~bx~d (3S)-34[ffAcetyI[2-(IH-indol.3- 220b yl)etbhyl]aminolacetyl]amino]-N-[(l8). I.(aminooaronl)-2mehylproI2,4,9trahydo-IH-cbazo-3ctarbmide 3-ff(2S)-2-(Acetylanmino)-5-[(aminoiiuomethyl)aninoJ-l. z~i oxntyamo]-N-(I)--(amoarbony)-2methylpropyl-23A9-tetrahydro-1I-crel-3-.vrboxamide 571 570.690M 571 627 570.6902 8.6382.

Example 27: Synthesis takes place on the 0. 2 nrmol scale by methods C, F, G, I, F, G and P.

Phenylmebyl S,2S)-2-methyl-14j[[(3R)-34,9.

tetrahydro-3{II(IS)-2-methyl-l- [(mnethylamino)carbonyIlpropyl3amiao]copyl]-1IHcarbazol-3-yl]aminolcabonyflbutyl]oabaniate Phenyiuethyl [(1S,2S)-2-methyil--E[(38)-2,3,4,9tetrahydro-34ff(i S)-2-methyl-I- [(rnethylamino)carbonylJpropyl]aniinoloabonyU-lHcarbazo-3-y1amino]carbonyi]buty1jcarbamate MI 689 S89.7327 222b 689 689.7827 79 Example 28: Synthesis takes place on the 0. 2 rrml A, F, G, I, F, J and 0.

(3R)-N4[(1S) -1-(Aminocabonyl)-2-mehylpropyij-3-[[(4chlorophcnyasufonuy1]mino-,3,4,9-tetmhydro.IHcarbazol-3-carboxamWd (3S)-N4-(IS)-l.(Ariioarbny)-2-methylpropy]-3.{[(4dieomphcnylosufony~amiuo]-2,3,4,9-tetrahydro-IHcarbmzle-3-carboimide terhyd-3-f (metbylsulfony1)amino]-III-cazazolc.3carbomimide (3S-N-[(1-1-(Amiobony)-2-methyproPY1]-2,3A49tetrahydro-3-[(mcthy~m~fny~amino]-1H-carbazole-3carboxamide (3R)-N-[(IS)-1-(Aminocabonyl)-2-methylpropyl].2,3,4,9tetdro-3 -[(phenyu fony)amino]-H-carazole3 carboxaniide (3S)-N4-[IS)-I-(Amnocarbny)-2-mthypropy]-2,3,4,9thyd3-[(phenyLfnyl in)-H-abaole.3caeboxamide (3RY N{(IS)--(AzfmocarbonYl)-2-methylpropy}.23A49 teerhydro-3-[(phenyimfoy1afo]amino]-l tarb zoe.

3-varboxamide (3S)-N.{[(IS)-I4Aminocabonyl)-2-metylpropyl]-2,3,4,9.

tebhydro-3[(phenymethy)sulfonyl]amino]4IHcaitzole.

3-carboxamide scale by methods 223 603 603.0M0 223b 503 603.0203 224a 401 4M56044 224b 407 406.5044 2250 4W 406.575 .M 469 488.S762 226a 483 482.602 226b 482.802 Example 29: Synthesis takes place on the 0. 2 mmcl scale by methods A, F, G, I, F, L and 0.

80 3-Phenylpropyl ((3R)-3-[[[(1S)-1.(azninocarbojyl)-2methylpropyl]anmino]carbonyl]-2,3A,9-etrahydro-lHcarbazole-3-yIlcarbamate 3-Phenyipropyl )1(mncroy)2 methylpropyljawino]cabonyl]-7Z34terAhYdjro-IIIcarbazoi-3-yl~carbamatc Phenylmethyl -(minoabnyDj-2mnetylpropyljaminojcarbouy]-Z3A49-tetrahydro-1Hoarbazol-3-yl~carbamnle Phenylmethyl [3S)-3-IE(1S)-1-(aminocarbonyl)-2ethylpropylJamixno]Qarbony1]-2,%4,9ktctrahydro-1H.

carb=zo-3-yIlcarbamate Phenyl [(3R)-34[(1S)-1-(=kmnoarbon))-2methYlPrOPYI]aminolcarbouyU-7Z3A494otrhYdro-1Hmabazol-3-yl]=abamato Phenyl I-(aminocarbonyl)-2mnethyIpropylJaminolcarbonyO-2,3,4,9-tetrahydro-IHcarbazol-3-yl]cubamat Za 491 490.8008 491 490.800 _228a 483 462547 _228b 483 482-547 .M 448 448.5202 229b 449 448.5202 Example Synthesis takes place on the 0.2 mmol scale by methods A, F, G, I, F, M and 0.

(3R) -N-{(IS)-I-(Aminocarbonyl)-2-methylpropy]-2,349- 230* 484 .483.5351 tetrahYdrO-34(f(4-nitropltenymethiyllamino)-1H-cabazole-3- Carboxainide (3S)-N4I(ls)-l-(AminocrbOnY1)-2-methYlPrOP41]-2,34,9- Mh0 4N4 483.6351 tdaydro..3-fj(4-nitrophenyl~mtyllamiinO}.IH-carbazole-3carboxamide (3P,)-N4(l S>.1-(Aniinoc-arbonyl)-2-methylpropyl]-3- 231 a 356 356.4M7 (ethylanio)-2,3A4-eahYdro-IH-carbaote-3-carboanide 81 (3 S)-l.{Aminocarbonyl)-2-methylpropyl]-3- (ethylamino)-2,3,4,9-tetuhydro-LH-carbazole-3-carboxamide (3R)-N-[(IS)-1-(Aminocarbonyl)2-maethylpropyll-2,3,49tetrhydro-3-[(2-phenylet)3yf~ainol-Ui-carbaole-3carboxamide (3S)-N{(S)--(Ainoabony)-2-me1ylpropy]-2,3,4,9tetmhdro-3-((2-phenylethylominoj-IH-carbzol-3carbownide S)-l-(Anocarbnyl-2mehylpropyl]2,3,4,9te-hydro-3-[(3-phenylpropyl)amino]-IH-carazole.-3carboxanide (3S)-N-(1--(Aninocabony)-2-metby~ropy1J-2,3,4,9.

tetrahydro-34(3-phenylpropyl)aminoj-IH-carbazole-3caiboxmide (3R)-N-[(lS)-1-(Aminocadxmyl)-2-methylpropylJ-3-[bis(3phenylopy)amuio]-2,4,9-tetaydro-ITJ-cabazolc-3carboxaniide (3R)-N-[(IS)-1-(Aminoc-arbonyl)-2-mnethylpropyi]-2,3,49tetrahYd-34(6ylhexYlhl)MinoIH-crbazole-3carboxamide (3S)-N(S)-(Amincabowl)--metbylpropyl]-2,3,4,9terahydro-3-(6phenyhexy)aiino]-H-carbazole-3carboxainide (3R)-N4I(IS--(AitOabonl)2-metylropyl]-2,349thydro-3(1-mhyethy)aio]-IR-abale-3carboxumde -(Aminoeaboriyl)-2-methylpropyl]-2,3,4,9tathydro-3[(-methyethy)aino]-IH-caibaoe-3carboxamide -(Aminocarboniyl)-2-methypropy]-23,49twtahydro-3{(-etbylpropylaminoJ-H-carbzoe-3carboxamide S}-I-(Aminmoabny)-2-nethylpropy1]2,3.4,9tetahydr-34(1-methylpropyl)amino]-IH-earbazole-.3carboxamide -231 b 3w6 358.4672 23 2a 4325848 432.5848 _232b 433 _M32 447 46.591> 233b 447 44U.918 50C 65 584.7698 234a 489 488.672 234b 489 488.672 2350 370 370-404 235b 370 37a.494 236a 385 3"4.5208 236b 385 384.5208 82 -1-(AmiziocarbanyI)-2-methylpropy1)A3,4,9.

tdtraydro-3-[(3-methybuty)aino-lH-cabazole-3carboxamide S)-I -(AmiocarboDy)-2methypropyA.2,349tetrahydro-3-[(3-methylbu1)amino]-H-arazoe-3carboxamide (3R)-N-[(1S)-I-(Amnocarbonyl-2-methiylpiropylj2,3,A9tetmdro-3-(etyluAmix)-R-ebaolc-3caboxamide (3S)-N-E[(IS)-1-(Aminocabonyl)-2-uitylpropyl]-2Z3,4,9tehar-3-(mhylamin)-Hcbazole-3-aboanide (3R)-N-[(1S)--(Amnoabonyl.2-methypoyU-3- (dimethylamino)-2,3A49-tetrahydro-IH-carbazole-3- Carboxamide M3a 399 398.5478 237b 399 398.5478 .ft 3M2 3aZ4404 238b M42 342-4404 _238c M5 358.487 (38 N4QIS)--(Amnocabony)-2-melpropyI]-3- 236 M5 355.4M7 (dimethyl w -3,49-to ydro-1H-carbazolo-3carboxamide Example 31: Synthesis takes place on the 0.2 rnmol scale by methods A, F, G, I, F, K and 0.

238amnouoy2-elrpy]234- 385 385.4853 tetrabydro-3fl(ethybamino)carnyIlamioJ-iE-carbazoie.

3-carboxauiide (3S)-N-[(IS)I-(Aminocabnyl)-2-metbylpropyl]-2,3,,9.

tnrhydro-3J(metyamino)carbonyl]amino].1H-arbzoce 3-carboxamide (3R)-N-{(1S)-1-(AzmiaonyJ)-2-rnethylpropyl]-23,4,91tetrahydro-3-[[(phenylamio)abonyl]mino]-n-axazole- 3-caboxamide (3S)N-[(S)--(Amziocaronyl)-2-methylpropy]-2,34,9tdhydro-3-ftphenylino~e bny]amino]-H carbzoe.

3-carboxamide Mb 385 385.4853 240a 448 447.638 _40b 448 447.5361 83 (3R)-N-[(IS)-1-(Aminocarbonyl)-2-methylpropyll-2,3,4,9ttrhydro-3.{[(phenylmethyl)aminolcarbonylgamino]- 11carbazole:-3-carboxamide.

(3S)-N-(1S*-I-Aminocarbony)-2-metlpropylJ-2!3,4,9tetrahydr-3-[pheylrethy)aminolcarboyIamino-I*carbazole-3-varboxamide S)-1-(AiuinovarbonyI)-2-methylpropyl]-Z23,4,9tdhydro3E[(2-phnyletylainooubnyl~amino]-IHcarbazolo-3-caiboxamide (3S)-N-[(1S)-1-(Aminocabonyl)-2-methylpropyl]-2,.3,4,9te~ra1ydro-3[U(2-phenylcthiyI~amio]carbony13amino]-IHcarbazole!3-carboxumddc (3R)-N'{(IB)4.(Aninocrbny)-2-metbylpropyl]-3- [[(cyclohezylamino)carbony!]amiino]-2,3A49-tetrhYdro-lHciubazole-3-carboxamide (3S)-N-4(1S)-1-(Aniiocazibonyl)-2-znethylpropyl]-3fl(ccohl,cyianoim~cony~anmino)-2,3,4,9-tetahydro-1Hcarbazole-3-maboxamide (3R) -N-((IS)-1-(Amiocarbonyl)-2-methylpropylJ-2,3,4,9twiahydro-3-4(((1-metbylethypamio)crbony1]9mino]-1Hcarbazole-3-carboxarnide (3S)-N-[(1S)-1.{Aminocarbonyl)-2-metlpropyl]..2,34,9tahydro-3M(-mehylehyamino]cabonyl3aminoJ-Icarbazole-3-carboxamide (3R)-N-(1S)-1-(Amrocarbaiyl)-2-.ethylpropy1}-.3,4,9terhydro-34ff (1-ma Wpropyl)aino]carbnyllanmino]- IH-carbazol-3-mazoxamide (3S)-N-(S)--(Aninoarbony)-2-methylpropy]-23,4,9temydro-3U(1-MCthyppyaMin]carbnyl]xno- 1H-carbazole-3-carboxamide (3R)-N-[RIS>4l-(Aminocarbonyl)-2-mcthylpropyll-2,3,4,9tetrahydro-3-t1R)--penyethyl]aminocarbony]amino]- IH-carbazole-3--caboxamide (3S)-N-[(1S)-1-(Amnoaon)-2-methypropyl-21,3A49tetrhydro-34tr(R)--phenylethyIlminocarbonyl]ano]- IH-caibazolc-3-carboxaxndd -4412 482 401.62M 241b 462 461.562 ,2A28 478 475.5897 ,2-42b 478 475.6097 .ft 454 453.583 243b 454 453.5 24a~ 414 413.5189 2M 414 413.5189 _24bO 428 427.545 245b 428 427.5457 246a 476 475.5897 246b 478 475.5897 84 (3R)-N-[QlS)-l-(Amxwoarbony)-2-methylpopy]-3 -ffjjf{ chlorpheny)amino)crbony]aino-2,3,94eYdr-lH carbazole-3-carboxaaiide (3S)i-N-[(IS)-1-(Amin cb yl).2metbylpyjl:34r(4 c~iorophenYtDainolcarbonllamiznJ.-2,3A49ter YdroIHcarbazole-3-oarboxamide (3R)-N-[(S)--(Aminocrbon)2-methypopyI-23,49tetrhydro-3-(Ef(l$)-l-pyletbyaioabonyl]ano]- IHrbazole-3-carboxamide (3S)-N.[(S>-1-(Aminocabony>.z-methylpropy].2,3,49teraydro 3 yleiA]amirabo y]mio].

1H-carbazole-3-cadboxamide 2472 482 481.9812 247b 482 481.9812 .20a 478 475.5897 245b& 476 475.5W9 Example 32: Synthesis takes place on the 0.2 mmol scale by methods A, F, G, I, F, G, N and 0.

Wty S)-1.{aminocabMny)-2methyipropyl~amino]caboiiyl]-3-[[(4vhlorophenylaylano-,3temhydr-9H-caitazolc..

9-acetate Ethy (3S)-3-fI((1*)1-(aminoaxoyl)-2miethylpropyl3amhio]cwabonyl3-3-fl(4chlorophenyacetyla~no]-lA,4-tmydro9H-aiazok.., 9-acetat (3R)-N-E(WS)-1-(Aminocarbonyl)-2-mehiylpropyl]-3-[[(4.

c~iorophmny1)acetylamino]-2,3A94trhYdro-9-03phenylpropyH- Ifcarbaoe3-cboxamide lI)I(mo Wil2mfilrpI--(4 cehoropheny1)aceyl~amino334-eftrahYdro-9-($phenylpropylH-1arb zolc-3-crboxamide (3R)-3-[[[(lS)-l-(Amniitocarbonyl)-2metliylpro>pyliaminoloarbonyl]-3-[[(4cblorophenylcdeyllamino]-1,2,3,4-tetmhydro-911-carbazole- 9- acetic acid 24ft W8 667.0825 29b 587 567.0825 260a 59W 699.1711 250b 599 699.1711 2Z18 539 639.0289 85 (3S)-[f(LS)-1.(Aminocazbonyl)-2- 251b 539 639,0289 methylpropyl]axninco]caxbonyl]-3-[[(4cbloxophenyl)acety amino]-I1,2,3,4-tetrahydro-911-carbazob.- 9- acetic acid S)-1-(AMinocarbonyl).2-Methylpropylj-34([(4 2M9* 551 651.1271 chlor oplienyl~actyl~amino]-2,3,49-tetahdro-9-(3mebylbutyl)-1YH-varbazole-3-carboxamdc (3S)-N-[(IS)-1(Aminocarbonyl)-2-mthypropy!-[(4- 2Mk 561 551.1271 c1oroPhenYIbacetYIlarniao]-2:3A4tahYdro-9-(3mebylbutyl)-1H-carbazole-3-caboxarnde (3R)-N-[(1S)-1-(Amincarb y}.2-mthypropIJ3-[(4- .ZVa 67 n 721066 4btorophenyI~acetyIamino]-2,3,4,9-terahydroi-9-(4pyidiulmethyl)-I-crbazol-3-aroxnmide (3 S) (A m mo rbony)-2 -methylpropy)3 1-63b 572 52105 chlorophenyl)aoetyl]amino]-2,3,4,9-tetrahydro-9-(4.

pyxidinylmethy1)-1H-carbazoke-3-cauboanmide (3R-)-N.{QIS)--(Aninoob4-2- cthylpropy-3-[[(4- 8A 57n 5721056 dhoropheny)acctyIamino)-2,3,4,9-tetra1ydro-9-(3pyridinylmethyl)-1H-crbazol-3-arboxaide 1-(Aninocabo!y)-2-methypropy]-3{[(4. 'A4b 872 572.10 diloxophenyloacetyljamino]-:2 34,9tctaydro.-(3.

pyridinylmethyl)-1H-,ao~lc-3-caboxamidc (3R-)-N-[(IS-I-(Aminoabony)-2-etylpropyfl.34[(4. Ma5 621 821.1773 chgoropheny~)acety1)amino]-2,3,4,9-etrahydro.9-(, uaphtanymhy)-I-abazoe-3-crboxmjdc (3S)-N-[(1S)--(AmnocabonyI-2-wetylppl]-3-[(4. 25Gb 621 621.1773 .chorophenyl~acetyl]aminoj.23,4,9-tetrathydro-9-.

lnaptnylmethyl)-H-carbol3cboxnjde (3P1Q-N-[(I S)-l.(AminOcabony)-2-methylpmopyl].3-[((4- 2,-668 537 537.1003 chloropJhenyIbacetyIlaminoJ-2,3,4,9-tei~ydro-9.<2micthyoropyl)-1H-ceArazole -3-caxboxamide (3S)-N-(1S-1-(Anfocbony)-2-ncdiylpropyNl..g-(4- -256b 537 6537.100 chloTopbenyI)acetyl~axmo]-Z,3,4,9-terahydro-9.{2.

methylpropyl)-lii-carbzoc-3-v-arboxaidcI (3R)-N-[(1S)--(Armocarbony)-2-xothy]propyI13.{((4. 257a 665 5.1443 choropherny1acety1]amino]-2,3,4,9-tetrahydro9<-2phenYIlikly1-IH-cadb~azole-3-carboxamide 86 (Amiloabony)-2-methylpropylj-3-r[(4cblorophenyl)acetyaniio]-,3A4-etrahYdro.9-(2phenylethyl)-lH-carazle-3-caboxamide (3R)-N-[(IS)-1-(Amnombony-2-methylpropyl]-3[((4chiorophenyl~acetylgamiiio]-9-cthyl-2,3,4,9-terahydro.IH.

carbawkl-3-caboxamide dilorophenyl)acetylamino]-9ety-2,3,4,9-ttraiydro-IiiaubazoIv-3-carboxanmide (3R-)-N-[(1S)--(Amiomrbo 2-mtlybpopj4-3p1(4chophenyaotyamno-9c ohemy)-2,34,9tetray&64-H aaole-3.curoxmde choropeoacamino-9-Iohx hy)239 tcmraydrb-IHica zoe-3-crboxamidc chlorophenyl)acetygamino]-9((2,,6difluorophenyl)metbYl] 2,%,4,tab offaazoloe3*carboxamide (3S)-N-R1IS)-1.{Amino aboy)-2-methyproyl1.t3-rr(4 choophmo]-9.{(26u9-(2,Morop1ei y)mt]- 2,3,4,9-tctrahy'dr6 -W-cabazole-3-carbtxmife- 25T US5 585.1443 268 609 M09.0467 268b 509 509.487 -M9A 677 MANS84 .M 577 677.1549 07 SU7M077 260b 807 607.0977 Example 33: Synthesis takes place on the 0.2 nimol scale by methods A, F, G, I, F, H, N and 0.

(3R)-3-(Acetylamino)-N-[(1S)4-<aminocaronyl)-2nethiYlpropyij-2,3,49-tetrahYdro-9-(3-phonylpropyl)-1Hcarbazole -3-carboxamide (3S)-3-(Acetylamino)-N-[(1S)-1-(aminocarboayl)-2methylpropyl]-2,3,4,9-teUrahydro-9-(3-phenypropyl).1Ucaiibuzola-3-maboxamide (3R,)-3-(Acetylamxino)-N-C((S)4.-(aminocarbonyl)-2inethylpropyll-23,4.9-teraydro-9.(3-methiylbutyl)-1Hcarbazole-3-carboxamide ILIA 489 488.6294 261b 489 488.6284 262p 441 440.6844 87 (3S)-3-(Acetyaino)-N-(S)-(amnoarbonyi)-z..

methylprpy]-2,3A49-thrydro-9-(3-methylbuty)-uH carbazole-3-carbaxaaide (3R)--(Acey~ino)-N-[(1S)-minoczbonyl)-2mehfylprop34}.Z3,4,9-tetrhydr-9-(2nplhalenymethy) IH-mabazole-3-carboxamide (S-3-(Acmno)-N-[(S)-1-(aminocarboy9-2mdbYllr-Z3,4,9-e4byd2.nap halenym thy)- 1H-carbazole-3-carboxanide 3-(Actylamino)-N.{(1S)-I-(aninocarbonyf)2methyipropy1-Z,3A49thYdro-9<1xmthenybethy) 1U-cazibazole-3-carboxaide 3-(Ayluno)-N-[(S--(amincionyr)-2mOfth~rOPY1]-9-cobxYmeiYI)-2,349-ttruydro-lHoarbuzole-3-arboxaniide methY]OPYI-2,3A49-teuraYdro-9-(2-mt1ylpropy1)4Hvarbazole-3-carboxmide.

(3S)-3-(Aceyamino)-N-[(S)--(minoabonyDy.2medlypropyl]-2,3,4,9-twahydro-9-(2-metlylpropyl).4ncarbazole-3-carboxamide 262b 441 440.6844 2_03 811 510.634 -M3b 511 510.6M4 28 511 610.6348 288a 427 428.0576 6b 427 426.5576 Example 34: Synthesis takes place on the 0.2 mmol scale by methods D, F, G, I, F, 0 and subsequent coupling in accordance with Example 6.

Phenylmethyl(1S.2S)-1-[[[(3R,)-3-[[(IS)-- (hydra ~methyl)-2-methylropyllaxinolcarony]-2,3A49.

teurahydro-lH-carbazoI--yllamitolarbonyJ.2methylbuty1)carbamate Phenylmethyl (1S,2S)-1-ftIX3S)-34fj(1S)-l- (hYdro~methYl)4.nethYlPrOPYl]aminolcabonylj-2,3,9 t-Ahydro-H-mabazol-3yainx]Qarbaonyl..2 zuethylbutyl]oadbanAte 267a 583 62.708 IM7 M6 5627068 Example Ethyl 9-tetrahydro-3- (3-phenyipropyl) -1Hcarbazole-3-carboxylate 268 mrnol (1.6 ml) of ethyl 4-oxocyclohexanecarboxylate, 25 inmol (1.4 ml) of glycol and 10 pmol of pTsOH are 88 refluxed in dry toluene with a water trap for 24 h. The solvent is removed and the residue is taken up in ethyl acetate/water. The organic phase is washed with water, dried and evaporated to dryness. The product is distilled in a Kugelrohr apparatus under high vacuum at 120 0 C and 0.03 mbar.

Yield: 1.52 g of 4-ethyl 1,4-dioxaspiro[4,5]decane-8carboxylate 269.

85 il of diisopropylamine in 500 pg of dry THF are added dropwise to 0.6 mmol of a 1.6 molar solution of butyllithium in heptane at -20 0 C under argon and then stirred for 10 min. After cooling to -70 0 C, 0.5 mmol (107 mg) of 269 in 200 p of dry THF are added dropwise, allowed to reach 0°C over the course of one hour and stirred for a further 30 min. After cooling to 0.7 mmol (106 pl) of 1-bromo-3-phenylpropane in 300 p1 of dry THF are added, and the mixture is stirred for 30 min. It is allowed to reach RT and then stirred for 1 hour. The saturated NH 4 C1 solution and n-hexane are cautiously added to the organic phase, which is stirred for 10 min. The organic phase is separated and washed with water. Filtration through a Whatman filter is followed by evaporation to dryness.

Yield: 165 mg of ethyl 8-(3-phenylpropyl)-1,4dioxaspiro[4,5]decane-8-carboxylate 270.

0.6 mmol (200 mg) of 270 are taken up in 25 ml of acetone/0.1 M HC1 1:1 and stirred with catalytic amounts of pTsOH at 50 0 C for 48 h. The acetone is stripped off in a rotary evaporator, and the precipitated product is filtered off, washed with water and dried.

Yield: 156 mg of ethyl 4-oxo-8-(3-phenylpropyl)cyclohexanecarboxylate 271.

The indolization takes place as described in Example 1 using phenylhydrazine.

89 Yield after evaporation and preparative HPLC: 65 mg of ethyl 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1Hcarbazole-3-carboxylate 268.

ES-MS: 362 mg of ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3-(3phenylpropyl)-lH-carbazole-3-carboxylate 272 are prepared analogously using 2,4-dichlorophenylhydrazine.

ES-MS: 430 (M+H) Example 36: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-lH-carbazole-3carboxylic acid 273 3.94 mmol (1.31 g) of 269 are stirred in 50 ml of methanol and 30 ml of 50% sodium hydroxide solution at 0 C for 4 h. The mixture is acidified with dilute HC1 and extracted with ether. Drying with Na 2

SO

4 and evaporation affords 1.02 g of white solid 8-(3phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid 274.

65 mg of 274 are first deprotected with HC1 and then reacted with phenylhydrazine for the indolization as described for 270 and 271.

Yield after evaporation and preparative HPLC: 15 mg of 273.

ES-MS: 334 39 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1H-carbazole-3-carboxylic acid 275 are prepared analogously using 2,4-dichlorophenylhydrazine.

ES-MS: 478 (M+H Example 37: 90 2,3,4,9-Tetrahydro-N-[(1S)-l-(hydroxymethyl)-2methylpropyl]-3-(3-phenylpropyl)-1H-carbazole-3carboxamide 276 0.66 mmol (200 mg) of 274 are reacted with equivalents of valinol in analogy to Example 6. 277 mg of white solid N-[(1S)-1-(hydroxymethyl)-2methylpropyl]-8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carboxamide 277 are obtained.

Then 0.3 mmol (117 mg) of 277 are first deprotected with HC1 and subsequently reacted with phenylhydrazine for the indolization as described for 270 and 271.

Yield after evaporation and preparative HPLC: 15 mg of 276.

ES-MS: 418 (M+H mg of 6,8-dichloro-2,3,4,9-tetrahydro-N-[(1S)-1- (hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl) -1Hcarbazole-3-carboxamide 278 are prepared analogously using 2,4-dichlorophenylhydrazine.

ES-MS: 486 Example 38: 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl)-1H-carbazole-3-methanamine 279 54 ml of a 1 M solution of LiAlH 4 in dry THF are cautiously added to a solution of 18 mmol (6 g) of 270 in 250 ml of dry THF under argon at room temperature.

After heating to reflux for 3 h, cautious hydrolysis is carried out with 300 ml of saturated NH 4 C1 solution, and 250 ml of ether are added. The aluminum salts are filtered off and washed with ether. Drying of the ether phase with Na 2

SO

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

91 5.86 mmol (1.7 g) of 280 are dissolved in 60 ml of dry DCM and 20 ml of dry DMSO. Under nitrogen at room temperature, firstly 44 mmol (6.1 ml) of TEA and then cautiously 17.6 mmol (2.8 g) of S0 3 -pyridine complex are added, and the mixture is stirred for one hour.

Subsequently 200 ml of saturated NH 4 C1 solution are added and extraction is carried out with 150 ml of ether. Drying of the ether phase with Na 2 S0 4 and evaporation of the solvent afford 1.9 g of 8-(3phenylpropyl)-1,4-dioxaspiro[4,5]decane-8-carbaldehyde 281 as 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 1,2dichloroethane. The mixture is stirred under N 2 at room temperature for 3 h. Saturated NaHC03 solution is added, and the mixture is extracted with ether. The dried and evaporated ether extract affords 101 mg of white solid N-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec-8yl]-2-pyridinemethanamine 282.

Subsequently, 101 mg of 282 are first deprotected with HC1 and then reacted with phenylhydrazine for the indolization as described for 270 and 271. Yield after evaporation and preparation HPLC: 71 mg of 279.

ES-MS: 410 54 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridinylmethyl) -H-carbazole-3methanamine 283 are prepared analogously using 2,4dichlorophenylhydrazine.

ES-MS: 478 (M+H Example 39: (2S)-3-Methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-lH-carbazol-3-yl]methyl]amino]-1-butanol 284 92 0.368 mmol (106 mg) of 281 and 0.368 mmol (38 mg) of valinol are dissolved in 1.5 ml of dry methanol and stirred at room temperature for 30 min. After cooling to 0°C, 0.557 mmol (21 mg) of NaBH 4 are added and stirred at room temperature for 1 h. 0.437 mmol (25 pl) of acetic acid is added, and stirring is continued at pH 6 for 2 h. Saturated NaHCO 3 solution is added, and the mixture is extracted with ether. Drying of .the organic phase with Na 2 S0 4 and evaporation affords 106 mg of colorless oil for 270 and 271.

Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 18 mg of white solid 284.

ES-MS: 405 17 mg of (2S)-2-[[[6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl)-1H-carbazol-3-yl]methyl]amino]-3methyl-l-butanol 286 are prepared analogously using 2,4-dichlorophenylhydrazine.

ES-MS: 473 Example 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-O-(4-pyridinylmethyl)-1H-carbazole-3-methanol 287 0.689 mmol of NaH (as 55% suspension in mineral oil) are added to a solution of 0.344 mmol (100 mg) of 280 in 10 ml of dry DMF at 0°C under an N 2 atmosphere. The mixture is allowed to reach room temperature and is stirred for 30 min. 1.377 mmol of 4- (chloromethyl)pyridine are added, and the mixture is stirred at 95-1000C overnight. Cooling to room temperature is followed by hydrolysis with 2 ml of water and extraction with ether. Drying of the solvent and evaporation affords 115 mg of yellow oil 288.

93 Deprotection and indolization are then carried out as described for 270 and 271. Yield after evaporation and preparative HPLC: 14 mg of white solid 287.

ES-MS: 411 (M+H Example 41: Ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1Hcarbazol-3-yl]-2-propenoate 289 0.347 mmol of 281 in 0.5 ml of THF are added dropwise to a solution of 0.378 mmol of ethyl (triphenylphosphoranylidene)acetate in 1 ml of absolute THF while cooling in ice. After the addition is complete, the mixture is allowed to warm to room temperature and is stirred for a further 2 days. It is then hydrolyzed with water and extracted with ether.

Na 2

SO

4 is used for drying, phosphane oxide and desiccant are filtered off, and the solvent is removed. Yield of ethyl 3-[8-(3-phenylpropyl)-1,4-dioxaspiro[4,5]dec- 8-yl]-2-propenoate 290.

Deprotection and indolization are then carried out as described for 270 and 271.

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

ES-MS: 388 (M+H In addition, the compounds of the invention Nos. 293 to 300, 302 and 304 to 306, which are covered by the general formula are obtained on the 0.2 mmol scale by methods A, F, G, F, G and 0, the compound 301 by methods B, F, G, F, G and 0, and the compound 303 by methods A, F, G, F, G, F, L and 0.

94 Compound name Number Mfnd Mcaic Phenylmethyl 293 612 611.6861 [L -1-(aminocarbonyl) -2methyipropyl] amino] carbonyl] -6,8difluoro-2, 3,4, 9-tetrahydro-1Hcarbazol-3-yl] amino] carbonyl] -2methylbutyl] carbamate____ Phenylmethyl (1S, 2S)-_1-HI (3R) 294 620 619.7585 [[[(1S,2S)-1-(aminocarbonyl)-2methylbutyl] amino] carbonyl] -8methoxy-2, 3,4, 9-tetrahydro-1Hcarbazol-3-yl] amino] carbonyl] -2methylbutyl] carbamate________ Phenyimethyl 295 659 658.6229 [[I(1S,2S)-1-(aminocarbonyl)-2methylbutyl] amino] carbonyl] -6,8dichloro-2, 3,4, 9-tetrahydro-lHcarbazol-3-yllamino] carbonyl] -2methyibutyl] carbamate____ Phenylmethyl (1S, 296 659 658.6229 [I -1-(aminocarbonyl) -3methylbutyll amino] carbonyl] -6,8dichloro-2, 3,4, 9-tetrahydro-1Hcarbazol-3-yllamino]carbonyl] -2methylbutyl] carbamate Phenylmethyl 297 699 698.6875 -1-(aminocarbonyl) -2cyclohexylethyllamino] carbonyl] 6, 8-dichloro-2, 3,4, 9-tetrahydro- IH-carbazol-3-yl] amino] carbonyl] 2 -methyibutyl] carbamate Phenylmethyl 298 659 658.6229 H (1S)-1-(aminocarbonyl)-2,2dimethyipropyl] amino] carbonyl] 6, 8-dichioro-2, 3,4, 9-tetrahydro- 1H-carbazol-3-yl] amino]carbonyl] 2 -methyibutyl] carbamate_________ Phenylmethyl 299 707 706.6669 -1-(aminocarbonyl) -3phenyipropyl] amino] carbonyl] -6,8dichloro-2, 3,4, 9-tetrahydro-1Hcarbazol-3-yilaminolcarbonyl] -2methylbutyl] carbamate_________ Phenylmethyl 300 685 684.6607 -1-(aminocarbonyl) -2methyibutyl ]amino] carbonyl]-6,8dichloro-2 9-tetrahydro-lHcarbazol-3-yi] amino] carbonyl] -2cyciohexylmethyl] carbainate 95 Phenylmethyl 301 660 659.607 2S)-1- (carboxy) -2methylbutyl] amino] carbonyl] 8dichloro-2, 3,4, 9-tetrahydro-1Hcarbazol-3-yl] amino] carbonyl] -2methylbutyl] carbainate Phenylmethyl 302 709 708.6391 [LI 1S,2S)-1-(aminocarbonyl)-2methylbutyl] amino] carbonyl] -6,8dichloro-2 9-tetrahydro-1Hcarbazol-3-yl] amino] carbonyl] -2- (4-hydroxyphenyl) ethyl] carbamate Phenylmethyl 303 723 722.6659 (aminocarbonyl) -2methylbutyl] amino] carbonyl] -6,8dichloro-2, 3,4, 9-tetrahydro-Icarbazol-3-yl]amino] carbonyl] -3- (4 -hydroxyphenyl) propyl] carbamate Phenylmethyl 304 707 706.6669 2S)-1- (aminocarbonyl) -2methylbutyl] amino] carbonyl] -6,8dichloro-2 9-tetrahydro-lHcarbazol-3-yl] amino] carbonyl] -3phenyipropyl] carbamate____ Phenylmethyl 305 659 658.6229 2S) (aminocarbonyl) -2methylbutyl] amino] carbonyl] -6,8dichloro-2 9-tetrahydro-iNcarbazol-3-yl] amino] carbonyl] -3methylbutyl] carbamate Phenyimethyl 306 659 658.6229 (aiinocarbonyl) -3methylbutyllaminolcarbonyl] -6,8dichloro-2 9-tetrahydro-1Hcarbazol-3-yl] amino] carbonyl] -3methylbutyl] carbamate_________ III Demonstration of the GnRH-antagonistic effect of compounds of the invention materials: Buserelin is purchased from Welding (Frankfurt/Main, Germany). The compound is labeled with 1251 by using the chioramine T method and N1251 (4000 C i/mmol; Amersham- Buchier, Brunswick, Germany). The labeled substance is purified by reverse phase HPLC on a Spherisorb ODS II column (250 x 4 mm, particle size 3 pm) by elution with acetonitrile/0.15% trifluoroacetic acid at a flow rate of 0.5 mi/mmn.

2000 Ci/mmol.

The specific activity

_M

96 All other chemicals are purchased from commercial source in the highest available purity.

Cell culture: Alpha T3-1 cells (Bilezikjian et al., Mol. Endocrinol (1991), 347-355) are cultivated in DMEM medium (Gibco- BRL, Eggenstein-Lepoldshafen, Germany) with penicillin (100 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 cells (Schmid et al., J. Biol. Chem. 275 (2000), 9193-9200) are cultivated under identical conditions apart from the use of Ham's F12 medium (Gibco-BRL).

confluent cell culture plates are washed twice with ml of phosphate-buffered saline (PBS). The cells are harvested by scraping off with a rubber policeman into 5 ml of PBS and sedimented by centrifugation at 800 rpm for 10 min in a laboratory centrifuge (Heraeus). The cell pellet is resuspended in 5 ml of 0.25 mol/l sucrose/0.01 mol/l triethanolamine, pH 7.4. The cells are lysed by three cycles of freezing in dry ice/ethanol bath and thawing at room temperature. The lysate is centrifuged at 900 rpm for 10 min, and the J sediment is discarded. The supernatant is centrifuged at 18 000 rpm in a Sorvall SS34 rotor for 30 min. The pellet (cell membranes) is suspended in 5 ml of assay buffer (0.25 mol/l sucrose, 0.01 mol/l triethanolamine, pH 7.5, 1 mg/ml ovalbumin) in a Potter, and stored in 200 .l aliquots at -20 0 C. Protein is determined by the method of Bradford (Anal. Biochem. 72 (1976), 248-254).

Receptor assay: Binding studies for competition plots are carried out as triplicates. A test sample contains 60 il of cell membrane suspension (10 ig of protein for aT3-l-cells or 40 pg of protein for CHO3 cells), 20 il of 125I N 4 97 labeled Buserelin (100 000 ipm per sample for competition plots and between 1500 and 200 000 ipm for saturation experiments) and 20 il of test buffer or test compound solution. The test compounds are dissolved in distilled water or 50% ethanol. Serial dilutions (5 x 10 6 mol/l to 5 x 10 12 mol/1) are prepared in test buffer. The nonspecific binding is determined in the presence of an excess of an unlabeled Buserelin (10 6 mol/1). The test samples are incubated at room temperature for 30 min. Bound and free ligand are separated by filtration (Whatman GF/C filter 2.5 cm diameter) using an Amicon 10x collecting apparatus and washed twice with 5 ml of 0.02 mol/l Tris/HCl, pH 7.4.

The filters are moistened with 0.3% polyethyleneimine (Serva, Heidelberg, Germany) for 30 min in order to reduce the nonspecific binding. The radioactivity retained by the filters is determined in a gamma counter (Wallac-LKB 1470 Wizard).

The IC 50 values obtained for the preferred compounds, as defined above, are indicated in the table which follows.

Compound Name Example hGnRH Ca 2 release No. receptor human IC 50 ICso [M]

[M]

N-[[(3R)-2,3,4,9-Tetrahydro-3- 18 0.0000009 0.000005 [(l-oxo-2,3-diphenylpropyl)amino] -lH-carbazol-3-yl] carbonyl]-L-valyl-Laspartamide (3S)-N-[(1S)-1-(Amino- 164b 0.000006 0.0000065 carbonyl)-2-methylpropyl]- 2,3,4,9-tetrahydro-3-[(1Hindol-3-ylacetyl)amino] -1Hcarbazole-3-carboxamide (3S)-N-[(lS)-1-(Amino- 161b 0.0000037 0.0000036 carbonyl)-2-methylpropyl]- 2,3,4,9-tetrahydro-3-[(2naphthalinylacetyl)amino]-1Hcarbazole-3-carboxamide 98 N-[[(3R)-2,3..4,9-Tetrahydro-3- 22 0.000002 0.000001 [f(2S, 3S) -3-methyl-1-oxo-2- [(1-oxo-3-phenylpropyl)amino] pentyl] amino] -1H-carbazol-3yl] carbonyl] -L-valyl-Laspartainide_____ Phenylmethyl 64 0.0000017 0.0000015 ft (aminocarbonyl) -2-methylbutyl] aininolcarbonyl]-2, 3,4,9tetrahydro-1H-carbazol-3 yl] amino] carbonyl] -2-methylbutyl] carbamate Phenylmethyl 45 0.0000003 0.000001 (aminocarbonyl)phenyl] amino] carbonyl] -2-methyipropyl] amino] carbonyl] -2,3,4,9tetrahydro-1H-carbazol-3 ylJ amino] carbonyl] -2methylbutyl] carbainate Phenylmethyl 222a 0.0000025 0.000003 methyl-1-[ ft(3R)-2,3,4,9tetrahydro-3- -2-methyl- 1- [(methylainino) carbonyl] propyl] amino] carbonyl] Hcarbazol-3-yl] amino] carbonyl] butyl] carbamate Phenylmethyl 58 0.0000003 0.00000037 [ft (3R)-3-[[E(lS)-1-(aminocarbonyl) -2-methyipropyl] amino] carbonyl] -2,3,4,9tetrahydro- 1H-carbazol -3yl] amino] carbonyl] -2methylbutyl] carbainate Phenylmethyl 181a 0.0000007 0.000003 carbonyl) -1-pyrrolidinyl] carbonyl] 9-tetrahydro- 1H-carbazol-3-yllamino] carbonyl] -2-methylbutyl] carbamate Phenyimethyl 190a 0.000002 0.0000005 [ft (3R) (aminocarbonyl) octahydro-1H-indol-1yllcarbonyl]-2,3,4,9tetrahydro-1H-carbazol-3 yl]aminolcarbonyi] -2methylbutyl] carbamate______ 2,3,4,9-Tetrahydro-3-(3- 279 0.000002 0.000003 phenyipropyl) (2-pyridinylmethyl) -1H-carbazole-3methanainine 99- (2S)-3-Methyl-2-[[[2,3,4,9- 284 0.000007 0.000007 tetrahydro-3- (3-phenyipropyl- 1H-carbazol-3-yllmethyl] amino] N-[(1S)-l-(Aminocarbonyl)-2- 175 0.000008 0.0000018 methylpropylL]-2,3,4, 9tetrahydro-3- [(4-methoxyphenyl) acetyl] amino-1Hcarbazole- 3-carboxamide (3R)-N-[(lS)-1-(Amino- 96 0.000004 0.000003 carbonyl) -2-methyipropyl] -3- I[[(3-bronophenyl)acetyl]amino] 9-tetrahydro-1Hcarbazole-3 -carboxamide (3R)-N-[(1S)-1-(Axnino- 91 0.0000024 0.000002 carbonyl) -2-methyipropyl] -3- [[(4-fluorophenyl)acetyl]amino] 9-tetrahydro-1Hcarbazole-3 -carboxamide (3R)-N-[(1S)-1-(Amino- 167a 0.000001 0.0000026 carbonyl) -2-methyipropyl] -3- I I(4-chlorophenyl)acetyllamino] 9-tetrahydro-1Hcarbazole-3 -carboxainide 234a 0.000009 0.000001 carbonyl) -2-methyipropyl] 2,3,4,9-tetrahydro-3-[ (6phenyihexyl) amino] Hcarbazole-3 -carboxamide Phenylmethyl 150a 0.00000011 0.00000028 carbonyl) -2-methyipropyl] amino] carbonyl] -2,3,4,9tetrahydro- 8-methyl Hcarbazol-3-yl] amino] carbonyl] 2 -methylbutyl] carbamate Phenylmethyl 148a 0.00000008 0.00000014 (1S)-l-(aminocarbonyl) -2-methyipropyl] amino] carbonyl] -6-chioro- 2,3,4, 9-tetrahydro-1Hcarbazol-3-yllamino] carbonyl] 2 -iethylbutyl] carbainate Phenylmethyl 147a 0.000000076 0.00000025 carbonyl) -2-methyipropyl] aminolcarbonyl] -2,3,4,9tetrahydro- 8-methoxy- 1Hcarbazol-3-yl]amino] carbonyl] 2 -methylbutyl] 100 Phenylmethyl 184a 0.000000015 0.000000045 [[(1S)-1-(aminocarbonyl) -2-methyipropyl] amino] carbonyl] 8-dichioro- 2,3,4, 9-tetrahydro-llcarbazol-3-yl] amino] carbonyl] 2 -methylbutyl] carbamate Phenylmethyl 267a 0.0000004 0.0000005 1S)-1-(hydroxymethyl) -2-methyipropyllamino] carbonyl] 9-tetrahydro- 1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbainate 189a 0.0000007 0.0000005 phenyl) acetyl] amino] -2,3,4,9tetrahydro-8 -methoxy-1Hcarbazol-3-yl] carbonyl] -2pyrrol idine carboxamide______ 6,8-Dichloro-2,3,4,9-tetra- 283 0.000001 0.000003 hydro-3- (3-phenyipropyl) (2pyridinylmethyl) -1H-carbazole- 3-me thanamine The compounds of numbers 293 methods indicated below: to 306 are tested by the Receptor binding assay materials: -Triptorelin [1 25 _-(D)-Trp6-GnRH] is purchased from Biotrend (Cologne, Germany). The specific activity is in each case 2.13 Ci/mmol. All other chemicals are purchased from commercial sources in the highest purity available.

Cell culture: Transfected LTK' cells (ATCC No. CCL-l.3) are cultivated in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/l) and fetal calf serum (FCS; Invitrogen Life Technologies, Germany) on plastic tissue culture plates (Nunc, Germany, 245 x 245 x 20 mm).

101 Testing: confluent cell culture plates ate washed twice with ml of phosphate-buffered saline (PBS) and then detached with 0.01 M 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 of binding medium (DMEM; mM Hepes; 0.5% BSA; 0.1% NaN 3 1 g/l Bacitracin (add fresh, stock 100x); 0.1 g/l SBTI (add fresh, stock 1000x) and the cell count is determined by Trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted with binding medium to a concentration of 5 x 10 5 cells/0.05 ml.

Binding studies for competition plots are carried out as duplicates. The test substances are employed as mM DMSO solutions. They are diluted to 4 times the final concentration employed with binding medium. 25 tl of the substance dilution are mixed with 25 il of tracer solution (1 25 I-triptorelin). The tracer concentration is adjusted to approx. 50 000 cpm (measured in a Cobra II, y counter, PE Liefe Science, Germany) in the final reaction volume of 100 l.

200 gl of silicone/liquid paraffin mixture (84%:16%) are introduced into 650 gl conical tubes (Roth, Germany). 50 g1 of the cell suspension are pipetted thereon, followed by 50 ul of the test substance/tracer mixture. The tubes are capped and incubated with vertical rotation in an incubator at 370C for 60 min.

After, incubation, the samples are centrifuged in a centrifuge (Kendro, Germany) at 900 rpm and subsequently shock-frozen in liquid N 2 The tip with the cell pellet is cut off and transferred into prepared counting vials (Roth, Germany). The remainder of the conical tube with the remaining supernatant is likewise transferred into a counting vial. The measurement takes place in a y counter for 1 min/sample.

Evaluation of the samples takes place after calculation of the specific binding compared with untreated cells, after subtraction of the nonspecific binding (excess of 102 unlabeled ligand, 1 pm) by means of GraphPad Prism (GraphPad Software Inc., USA).

Functional reporter gene assay Materials: All chemicals are purchased from commercial sources in the highest purity available.

Cell culture: Stably transfected LTK cells (ATCC No. CCL-1.3) which harbor the GnRH receptor and have heterologous expression of cAMP-responsive elements and a CMV minimal promoter-driven luciferase reporter gene are employed to carry out functional investigations.

The cells are cultivated in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (100 streptomycin (0.1 mg/ml) and glutamine (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).

Testing: confluent cell culture plates are washed twice with 50 ml of phosphate-buffered saline (PBS) and then detached with trypsin EDTA solution (Invitrogen Life Technologies, Germany). The cells are pelleted by centrifugation at 200xg for 5 min in a laboratory centrifuge (Kendro, Germany). The cell pellet is resuspended in 3 ml of assay medium (Invitrogen Life Technologies, Germany) with penicillin (100 I.U./ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/1) and fetal calf serum (FCS; Invitrogen Life Technologies, Germany), and the cell count is determined by Trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted to a concentration of 1x10 4 cells/100 ul with assay medium.

The cells are set out on white 96-well microtiter 103 plates (Costar, Germany) and incubated in an incubator for 18 h.

To carry out the test, test substances are diluted as 10 mM DMSO solutions in assay medium to 6 times the final concentration employed. 25 pl of the test substance are added to 100 Ip of cells and incubated at 37 0 C, 5% C02 for 60 min.

Triptorelin (D-Trp6-GnRH)/Rolipram solution (6 nM/6 pM) is then added, followed by incubation again at 37 0 C,

CO

2 for 6 h.

Incubation is followed by addition of 50 pl of lysis/detection buffer (LucLite, PE Life Science) and measurement in a Lumistar luminometer (BMG Labtechnologies GmbH, Germany).

Evaluation of the samples takes place after calculation of the inhibition compared with untreated stimulated cells, after subtraction of the unstimulated control, by means of GraphPad Prism (GraphPad Software Inc., USA) or alternatively by means of OMMM (Accelrys, Germany) software.

The ECso values obtained for compounds 293 to 306 are indicated in the table below.

Compound Name Example Functional Human binding No. human EC 50 triptorelin ECo 0

[M]

Phenylmethyl 293 0.000000762 0.000000332 (aminocarbonyl)-2-methylpropyl]amino]carbonyl]- 6,8-difluoro-2,3,4,9tetrahydro-lH-carbazol-3yl]amino]carbonyl]-2methylbutyl] carbamate Phenylmethyl 294 0.000000089 0.000000036 (aminocarbonyl)-2-methylbutyl]amino]carbonyl]-8methoxy-2,3,4,9-tetrahydro-1H-carbazol-3yl]amino]carbonyl]-2methylbutyl]carbamate -104- Phenylmethyl 295 0.000000007 0.000000018 (aminocarbonyl) -2-methyl butyl] amino] carbonyl] 8dichloro-2 9-tetrahydro-1H-carbazol-3 yl] amino] carbonyl] -2methylbutyl] Phenylmethyl 296 0.000000014 0.000000022 (aminocarbonyl) -3-methylbutyl] amino] carbonyl] 8dichloro-2 ,3,4 ,9-tetrahydro- 1H-carbazol-3 yl] amino] carbonyl] -2methylbutyl] Phenylmethyl 297 0.000000284 0.000000482 (aminocarbonyl) -2-cyclohexylethyl Jamino] carbonyl] 8-dichloro-2,3,4, 9tetrahydro-1H-carbazol-3 yl] amino] carbonyl] -2methylbutyl] carbamate Phenylmethyl 298 0.000000288 (aminocarbonyl) -2,2dimethyipropyl] amino] carbonyl] 8-dichioro- 2,3,4, 9-tetrahydro-1Hcarbazol-3-yl]amino] carbonyl] -2-methylbutyl] carbamate Phenylmethyl 299 0-000001497 0.000001307 (1S)-1- (aminocarbonyl) -3 -phenyl propyl] amino] carbonyl] 6,8-dichloro-2,3,4,9tetrahydro-1H-carbazol-3 yl] amino] carbonyl] -2methylbutyl] carbamate Phenylmethyl 300 0.000000017 0.000000023 [lLil(3R)-3-[[Li(1S)-1- (aminocarbonyl) -2-methylbutyllamino] carbonyl] 8dichloro-2, 3,4, 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-cyclohexylmethyl] 105 Phenylmethyl 301 0.000000176 0.000000538 [EL (carboxy) -2-methylbutyl] amino]carbonyl] -6,8dichloro-2, 3,4, 9-tetrahydro-1H-carbazol-3 yl] amino] carbonyl] -2methylbutyl 1carbainate Phenylmethyl 302 0.000000324 0.000600475 (1S,2S)-1- (aminocarbonyl) -2 -methylbutyll]amino] carbonyl]-6,8dichloro-2, 3,4, 9-tetrahydro-1H-carbazol-3-yl] aininojcarbonyl] (4hydroxyphenyl) ethyl] carbama te Phenylmethyl 303 0.000000021 C3R)-3-[[U(1S,2S)-1- (aminocarbonyl) -2-methylbutyl]axnino]carbonyl] -6,8dichloro-2,3,4, 9-tetrahydro-lH-carbazol-3-yl] amino]carbonyl]-3- (4hydroxyphenyl )propyl] carbamate Phenylmethyl 304 0.000000018 0.000000038 (aminocarbonyl) -2-methylbutyllaminolcarbonyl] -6,8dichloro-2, 3,4, 9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -3-phenylpropyl Icarbamate________ Phenylmethyl 305 0.000000056 (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -6,8dichloro-2, 3 9-tetrahydro-lH-carbazol-3-yl] amino] carbonyl] -3-methylbutyl] carbamate Phenylmethyl 306 0.000000077 (aminocarbonyl) -3-methylbutyl ]amino] carbonyl] -6,8dichloro-2, 3,4, 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -3-methylbutyl) carbamate

Claims (23)

1. A compound of the general formula (I) R 7 R 6 Rb Re Rb Rd Ra R Re R' N R4 R 3 R 2 R (I) in which the radical R' is a hydrogen atom, a C 2 -C 6 alkenyl or a CI-C 6 alkyl radical and may optionally be substituted by an aryl, hetaryl radical or the group -COOR", where the aryl or hetaryl radical may be substituted by up to three substituents which are selected independently of one another from the group consisting of -NO 2 -CH 3 -CF 3 -OCH 3 -OCF 3 and halogen atoms, and the radical R" is a hydrogen atom, a CI-C 2 alkyl, a Ci-C 1 2 aralkyl, an aryl, hetaryl radical or the group -COCH 3 and may optionally be substituted by one substituent selected from the group consisting of -CONH 2 -COCH 3 -COOCH 3 -SO 2 CH 3 and aryl radicals; the radicals R 2 R 3 and R 5 are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 -CF 3 -OCF 3 -NO 2 -CN, a CI-C 6 alkyl, a C 2 -C 6 alkenyl, a CI-C 6 alkoxy, a CI-C 2 aralkyl, an aryl or hetaryl radical; the radical R 4 is 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 2 -C 6 alkenyl, a CI-C 1 2 aralkyl, an aryl or hetaryl radical; the radical R 6 is the group -CONR8 R, -COOR 8 -CH 2 NR8R 9 -CH 2 R 8 CH 2 0R 8 or a C 2 -C 1 2 alkenyl radical which is optionally substituted by the radicals R and R 9 where the radicals R 8 and R 9 are each independently of one another a hydrogen atom, a Ci-C 12 alkyl, a Ci-C 12 aralkyl, a Ci-C 12 hetaralkyl, an aryl or hetaryl radical, each of which may be substituted by one or more substituents selected from the group consisting of-OH, -NH 2 -CONHR' 1 -COORo 1 -NH-C(=NH)-NH 2 and halogen atoms, where the radical R' 1 is a hydrogen atom, a CI-C 12 alkyl, a Ci-C 1 2 aralkyl, an aryl or hetaryl radical and is optionally substituted by the group -CON(R' )2, or where the radicals R 8 and R 9 may together form a cyclic structure which consists either exclusively of carbon atoms or a combination of carbon atoms and heteroatoms; AH21(834816 1) AAK S107 C, the radical R is a C 1 -CI 2 alkyl, a C 2 -C 12 alkenyl, a Ci-C 2 aralkyl, an aryl or hetaryl Sradical, the group -NR2R 1 3 -NHCOR 14 NHCONHR 1 4 -NHCOOR 14 or -NHSO 2 R 1 4 and may optionally be substituted by one or more substituents selected from the group CN consisting of-OH, -NH 2 -CONH2, -COOH and halogen atoms, the radicals R 12 and R 13 are each independently of one another a hydrogen atom, a c C 2 -C 6 alkenyl or a Ci-Ci 2 alkyl radical and may optionally be substituted by one or more aryl or hetaryl radicals which in turn may be substituted by up to three substituents c selected independently of one another from the group consisting of -NO 2 -CH 3 -CF 3 -OCH 3 -OCF 3 and halogen atoms, and the radical R 14 is a hydrogen atom, a Ci-C 12 alkyl, a C 2 -C 1 2 alkenyl, a CI-C 12 aralkyl, an aryl or hetaryl radical which may optionally be substituted by one or more substituents selected from the group consisting of-NO 2 -CH 3 -CF 3 -OCF 3 -OH, 2 -OCOR", -COOH, CONH 2 -NHCONHR", NHCOOR" and halogen atoms; and the radicals Ra, Rb, R c Rd, Re and R f are each independently of one another a hydrogen atom, a halogen atom, the group -COOH, -CONH 2 -CF 3 -OCF 3 -NO 2 -CN, a Ci-C 6 alkyl, Ci-C 6 alkoxy, an aryl or hetaryl radical; with the proviso that the compound of the general formula is not selected from the group consisting of 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-

6-methoxy- ,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4- tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-1,2,3,4-tetrahydrocarbazole-3- carboxylic acid, methyl 3-acetamido- 1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido- 1,2,3,4-tetrahydrocarbazole-3-carboxylate or 3-tert- butoxycarbonylamino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid. 2. The compound as claimed in claim 1, where the radicals Ra, R b R c R, R and R f are hydrogen atoms. 3. The compound as claimed in claim 1 or 2, where the radical R' is a hydrogen atom. 4. The compound as claimed in any one of claims 1 to 3, where the radicals R R 3 R 4 and/or R 5 are not hydrogen atoms. 5. The compound as claimed in claim 4, where the radicals R2 R R and R 5 are independently of one another the group -CH 3 -Cl or -OCH 3 AH21(8348161) AAK 108 6. The compound as claimed in claim 5, where the compound is selected from the group consisting of phenylmethyl IS)- I-(aminocarbonyl)-2- methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-8-methyl- 1 H-carbazol-3- yl]amino]carbonyl]-2-methylbutyllcarbamate, phenylmethyl-[( 15,2S)- 1 IS)- 1 -(aminocarbonyl)-2-methylpropyl] amino] carbonyl] -6-chloro-2,3 ,4,9-tetrahydro- I H- carbazol -3 -yl ]am ino] carbonyl -meth ylbutyl] carbam atc, and phenylmethyl S,2S)- 1- I -(aminocarbonyl)-2-methylpropyl]amiino]carbonyl]-2,3 ,4,9-tetrahydro-

8-methioxy- 1H-carbazol-3 -yl]am-ino]carbonyl]-2-methylbutyllcarbamnate. 7. The compound as claimed in any one of claims I to 5, where the radical R 6 is selected from the group consisting of a carbonylphenylalanylamide residue, a carbonylisoleucylamide residue, a carbonyl valyl-4-aminobenzamide residue, a carbonylvalyl-N-methylamide residue, a methylox ymnethyl -4-pyri dyl radical, a carboxyl radical, an ethyl propenoate residue, a carbonylvalylamide residue, a carbonylthreonylamide residue, a cyclic carboxamide residue, a 4-carboxamidophenyl- carboxamide residue, a methylaminomethyl-2-pyridyl radical, a carbonylvalinol residue and a methylvalinol residue. A] 121(834816_1) AAK 8. The compound as claimed in claim 7, where the compound is selected from the group consisting of phenylmethyl 2-oxo-l- (phenylmethyl) ethyl) amino) carbonyl] 2,3,4, 9-tetrahycdro-1H-carbazol--3-yljamino]- carbonyl] -2 -methylbutyl] carbarnate, phenylmethyl (aminocarbonyl) -2 -methylbutyl ]amino) carbonyl] 2, 3,4, 9-tetrahydro- 1H-carbazol- 3 -yl Iamino) carbonyl] -2-methylbutyl] carbamate, phenylmethyl (arinocarbonyl) phenyl )amino] carbonyl]1 -2 methylpropyl Iamino Jcarbonyl]) 3, 4, 9-tetrahydro- 1H-carbazol-3 -yl ]amino ]carbonyl inethylbutyl Icarbamate, phenylmethyl [(lS,2S)-2-methyl-l-[[[(3R)-2,3,4,9- tetrahydro-3- -2-methyl-i- [(methylamino) carbonyllpropyl] amino] carbonyl] -1H-carbazol-3- yl]amino] carbonyi]butyl] carbamate, 2, 3,4, 9-tetrahydro-3- (3-phenyipropyl) (4- pyridinylmethyl) -1H-carbazole-3-methanol, 2, 3,4, 9 -tetrahydro- 3- (3 -phenyipropyl) -lH- carbazole-3-carboxylic acid, ethyl 3-12,3,4,9-tetrahydro-3-(3-phenylpropyl)-lH- carbazol-3-yl] -2-propenoate, phenyimethyl (aminocarbonyl) -2-methyipropyl] amino] carbonyl] 2, 3,4, 9 -tetrahydro-i1H- carbazoi1- 3-ylI] amino] carbonyl] -2-methylbutyilcarbamate, phenylmethyl (aminocarbonyl) -2-hydroxypropyl] amino] carbonyl] 2,3,4, 9-tetrahydro-lH-carbazol-3-yilamino] carbonyl] -2-methyibutyl] carbamate, phenylmethyl (ami nocarbolyl1) -1I- pyrro1i diinyl Icarboiyl1) 3, 4,9 tetrahydro -lIH -carba zoi1- 3-yl1] ani n o] carbony] -2 methylbutyl]I carbamzate, phenylmethyl [HIS, 2S)-1- 2S) -2- (arinocarbonyl) octahydro-lH-indol-1-yl] carbonyl] 2, 3, 4,9-tetrahydro-1H-carbazol-3- yl I amino]I carbonyl -2--methylbutyl carbamate) phenylmethyl 2S) (3R) (aminocarbonyl) phenyl]I amino carbonyl 3, 4, 9 tetrahydro-1IH-carba zol 3-yl]amino Icarbonl) -2 methylbutyl] carbamate, 2, 3,4, 9-tetrahydro-3- (3-phenyipropyl) (2- pyridinylmethyl) -l1H- carbazole- 3 -methananine, phenylmethyl (1S, 2S) C3S) -1- (hydroxymethyl) -2-methyipropyl] amino] carbonyl] 2,3,4,9-tetrahydro-H-carbazol-3-ylamifl- carbonyl] -2-methylbutyl] carbamate, 2, 3, 4,9-tetrahydro-N- (1S) -1-(hydrox-yrethyl) -2- methyipropyl] (3-phenyipropyl) -1H-carbazole-3- carboxamide and (2S) -3-methyl-2- 3,4,9-tetrahydro3- 3- phenyipropyl) -lH-carbazol-3-yljrnethyll amino] -1- butanol.

9. The compound as claimed in any one of claims I to 5 or 7, wherein the radical R 7 is selected from the group consisting of a 2,3-biphenyipropionylamino radical, an indanoylamino radical, an indolylacetylamino radical, a 2-naphthylacetylamino radical, a 3- propionylamino radical, a phenylmethylcarboxamide residue which is substituted on the aromatic system, a phenyihexylamine residue and a phenyipropyl radical. The compound as claimed in claim 9, where the compound is selected from the group consisting of N- (3R) 3,4, 9-tetrahydro-3- (1-oxo-2, 3- diphenyipropyl) amino) -1H-carbazol-3-yl] carbonyl] L-valyl-L-aspartanide, (3R) (iS) -1I- (arninocarbonyl) -2 -methyipropyl]1 -3 l[t(2,3-dihydro-1H-inden-1-yl)carbonyllamino)- 2, 3,4, 9-tetrahydro-1H-carbazole-3-carboxamide, (3S) (iS) (aminocarbonyl) -2-methyipropyl] 2, 3, 4,9-tetrahydro-3- [(lH-indol-3-ylacetyl) amino] 1H--carbazole-3-carboxamide, (3S) (1S) -1-(aminocarbonyl) -2-methylpropyl] 2,3, 4, 9-tetrahydro-3- (2 -naphthalIinylacetyl) amino) -1H--carbazole-3-carboxanide, (3R) (iS) (aminocarbonyl) -2-methyipropyll]- 2, 3, 4,9-tetrahydro-3-[ f 4 -methyiphenyl) acetyl- amino] -lH--carbazole-3-carboxamide, N- f (lS) -l-(aminocarbonyl) -2-methylpropyi234,9 tetrahydro-3- [If 4 -methoxyphenyl) acetyl) amino] -lii- carbazole-3 -carboxamide, (3R) (IS) (aminocarbonyl) -2-methyipropyl] -3- f1[ 3 -bromophenyi) acetyl]Iamino)-2, 3, 4, 9tetrahydro- 1H-carbazole-3 -carboxamide, (3R) (iS) (arninocarbonyl) -2-methyipropyl] -3- [4-f luorophenyl) acetyllamino]-2, 3,4, 9- tetrahydro-1H-carbazole-3 -carboxamide, (3R) (iS) (aminocarbonyi) -2-methylpropyly -3- 4 -chlorophenyl) acetyl) amino)j 3,4, 9- tetrahydro-1H-carbazole-3-carboxamide, (3R) (IS) (aminocarbonyl) -2-methyipropyl) 2, 3, 4, 9 -tetrahydro- 3- (6 -phenyihexyi) amino]-1H- carbazole-3-carboxamide, 6,8-dichloro-2, 3, 4,9-tetrahydro-3- (3-phenyl- propyl) -lH-carbazole-3--carboxylic acid and ethyl 6,8-dichloro-2,3,4,9-tetraaydro3(3- phienyipropyl) -lH-carbazole-3-carboxylate.

11. The compound N-[[3R)-2,3,4,9-tetrahydro-3-[[(2S,3S)-3-methyl-l-oxo-2-[(1- oxo-3-phenylpropyl)amino]pentyl]-amino]- 1H-carbazole-3-yl]carbonyl]-L-valyl-L- aspartamide.

12. The compound as claimed in any one of claims 1 to 5, 7 or 9, where the compound is in the R configuration at the carbon atom substituted by the radicals R 6 and R 7 when the radicals R 6 and R 7 are each part of an alpha-amino carboxylic acid structural element.

13. The compound as claimed in claim 1, where the compound is selected from the group consisting of phenylmethyl S,2S)-1 -(aminocarbonyl)-2-methylpropyl]- amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro- 1H-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate, phenylmethyl 1-(hydroxymethyl)-2-methylpropyl]- amino]-carbonyl]-2,3,4,9-tetrahydro- 1 H-carbazol-3-yl]amino]carbonyl]-2- methylbutyl]carbamate, (2S)-1-[[[(3R)-3-[[(4-chlorophenyl)acetyl]amino]-2,3,4,9-tetrahydro-8-methoxy- 1H-carbazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide, and 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenyl-propyl)-N-(2-pyridinylmethyl)-IH- carbazole-3-methanamine.

14. A compound of general as defined in claim 1, substantially as hereinbefore described with reference to any one of the Examples. A pharmaceutical composition comprising at least one compound as claimed in any one of claims 1 to 14.

16. The pharmaceutical composition as claimed in claim 15, where the compound is present in a unit dose of from 1 pg to 100 mg per kg of a patient's body weight.

17. The pharmaceutical composition as claimed in claim 15 or 16, where the compound is present in combination with at least one further active pharmaceutical ingredient and/or pharmaceutically acceptable carrier in the composition. A1121(8348161) AAK

18. A process for preparing a compound of general formula as defined in claim 1, substantially as hereinbefore described with reference to any one of the examples.

19. The compound as claimed in any of claims 1 to 14, for use as pharmaceutical remedy. The use of a compound as claimed in any one of claims 1 to 14 for producing a pharmaceutical remedy for the treatment of pathological states mediated by G protein-coupled receptors.

21. The use of a compound as defined in claim 1, but including the compounds specifically excluded in claim 1, for producing a pharmaceutical remedy for inhibiting gonadotropin-releasing hormone.

22. The use as claimed in claim 20 or 21 in male fertility control, in hormone therapy, treatment of female subfertility or infertility, female contraception and tumor control.

23. The use of a compound as defined in claim 1, but including the compounds specifically excluded in claim 1, for male fertility control or for female contraception.

24. The compound as claimed in claim 1, where the compound is selected from the group consisting of phenylmethyl (aminocarbonyl) -2-methylpropyl] amino] carbonyl] 6,8-difluoro-2,3,4,9-tetrahydro-1H-carbazol-3- yl]amino]carbonyl]-2-methylbutyl]carbamate, phenylmethyl (aminocarbonyl) -2-methylbutyl] amino carbonyl methoxy-2,3,4,9-tetrahydro-lH-carbazol-3- yl]amino] carbonyl]-2-methylbutyl ]carbamate, phenylmethyl (S,2S)-1- (ami nocarbonyl)-2-methylbutyl] amino]carbonyl 1 -6,8- dichloro-2, 3,4, 9-tetrahydro-1H-carbazol-3- yl] amino] carbonyl] -2-methylbutyl] carbamate, phenyimethyl (1S, 3-U[(1S) -1- (arinocarbonyl) -3-methylbutyllamino] carbonyl] -6,8- dichloro-2, 3,4, 9-tetrahydro--1H-carbazol-3- yl] a-mino] carbonyl] -2--methylbutyl] carbamate, phenylmethyl (aminocarbonyl) -2-cyclohexylethyl] amino] carbonyl] 6, 8-dichloro-2, 3,4, 9-tetrahydro-1H-carbazol-3- yl] amino] carbonyl] -2-methylbutyl] carbamate, phenyirnethyl (aminocarbonyl) 2-dimethyipropyll amino I- carbonyl] 8-dichloro-2, 3,4, 9-tetrahydro-1H- carbazol-3-yl Iamino] carbonyl] -2-methylbutyl] carbamate, phenylmethyl (arinocarbonyl) -3-phenyipropyl] amino] carbonyl] 6, 8-dichloro-2, 3,4, 9-tetrahydro-1H-carbazol-3- yl] amino] carbonyl] -2-methylbutyl] carbamate, phenylmethyl (aminocarbonyl) -2-methylbutyllamino] carbonyl] -6,8- dichloro-2, 3,4, 9-tetrahydro-lH-carbazol-3- yl] amino] carbonyl] -2-cyclohexylmethyl] carbamate, phenylmethyl (carboxy) -2-methylbutyllamino] carbonyl] -6,8- dichloro-2, 3,4, 9-tetrahydro-1H-carbazol-3- yl] amino] carbonyl] -2-methylbutyl] carbamate, phenylmethyl (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -6,8- dichloro-2,3,4, 9-tetrahydro-lH-carbazol-3- yl] amino] carbonyl] (4-hydroxyphenyl) ethyl] carbamate, phenylmethyl (aminocarbonyl) -2-methylbutyll amino] carbonyl] 8- dichloro-2,3,4,9-tetrahydro-1H-carbazol-3- yl]aminolcarbonyl]-3- (4-hydroxyphenyl)propyl]- carbamate, phenylmethyl (aminocarbonyl) -2-methylbutyllamino] carbonyl] -6,8- 115 dichloro-2,3,4,9-tetrahydro- H-carbazol-3-yl]amino]carbonyl]-3- phenylpropyl]carbamate, phenylmethyl S,2S)-1 -(aminocarbonyl)- 2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro- 1H-carbazol-3- yl]amino]carbonyl]-3-methylbutyl]carbamate, phenylmethyl (aminocarbonyl)-3-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro- H- carbazol-3-yl]amino]carbonyl]-3-methylbutyl]carbamate. A pharmaceutical composition comprising at least one compound as claimed in claim 24.

26. The pharmaceutical composition as claimed in claim 25, where the compound is present in a unit dose of from 1 g to 100 mg per kg of a patient's body weight.

27. The pharmaceutical composition as claimed in claim 25 or 26, where the compound is present in combination with at least one further active pharmaceutical ingredient and/or pharmaceutically acceptable carrier in the composition.

28. The compound as claimed in claim 24, for use as a pharmaceutical remedy.

29. The use of a compound as claimed in claim 24 for producing a pharmaceutical remedy for the treatment of pathological states mediated by G protein-coupled receptors. The use of a compound as claimed in claim 24 for producing a pharmaceutical remedy for inhibiting gonadotropin-releasing hormone.

31. The use as claimed in claim 29 or 30 in male fertility control, in hormone therapy, treatment of female subfertility or infertility, female contraception and tumor control.

32. A method of treating pathological states mediated by G protein-coupled receptors in a mammal, the method comprising administering to the mammal an effective amount of a compound according to any one of claims 1 to 14 or 24, or a pharmaceutical composition according to any one of claims 15 to 17, or 25 to 27.

33. A method of inhibiting gonadotropin-releasing hormone in a mammal, the method comprising administering to the mammal an effective amount of a compound according to any one of claims 1 to 14 or 24, but including the compounds specifically excluded in claim 1, or a pharmaceutical composition according to any one of claims to 17, or 25 to 27. Dated 21 August, 2007 Zentaris GmbH Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON