JP2005518375A - Tetrahydrocarbazole derivatives as ligands for G protein coupled receptors (GPCRs) - Google Patents

Abstract

The present invention relates to novel tetrahydrocarbazole derivatives that act as ligands for G protein-coupled receptors (GPCRs), particularly antagonists of gonadotropin releasing hormone (GnRH). The present invention also relates to a pharmaceutical composition containing the novel tetrahydrocarbazole derivative and a method for producing the derivative. The present invention further relates to the administration of tetrahydrocarbazole derivatives for the treatment of pathological conditions mediated by GPCRs, particularly for inhibition of GnRH, to mammals, particularly humans in need of such treatments, and GPCRs. It relates to the use of tetrahydrocarbazole derivatives for the manufacture of a medicament for the treatment of pathologic conditions mediated by GnRH, in particular for the inhibition of GnRH.

Description

  The present invention relates to novel tetrahydrocarbazoles which are ligands for G protein-coupled receptors, in particular antagonists of gonadotropin releasing hormone, methods for their preparation, uses thereof and pharmaceutical compositions containing these tetrahydrocarbazole derivatives. The invention also relates to a method of treating a pathological condition in a mammal, particularly a human, mediated by a G protein coupled receptor.

  A common structural element for all members of the G protein coupled receptor (GPCR) family is the presence of seven transmembrane α-helix segments, which are linked together by alternating intracellular and extracellular loops, The amino terminus is outside the cell and the carboxy terminus is inside the cell. The family of GPCRs can be divided into multiple subfamilies (substantially families A, B, and C) that further have sequence homology within these subfamilies. Since GPCRs are primarily associated with signal reception and transmission, a number of physiological functions are affected by the receptor. GPCR ligands are therefore potentially suitable as pharmaceuticals for the treatment and prevention of a number of pathological conditions. A brief survey of diseases that can be treated with GPCR ligands is shown in Table 1 of S. Wilson et al., Pharmaceutical News 2000, 7 (3).

  Most known GPCR ligands have a peptide structure. However, peptide receptor ligands often have some serious drawbacks such as low bioavailability and metabolic instability. This is why recently, research on ligands in the form of small non-peptide molecules has been enhanced. So-called “privileged structures” play a special role in research on new non-peptide receptor ligands. These “privileged structures” are the basic molecular structures that provide ligands for a large number of different receptors. The term “privileged structure” was first used by Evans et al. In connection with a benzodiazepine-based CCK (cholecystokinin) A antagonist from the natural product asperlicin (BE Evans et al., J. Med. Chem. 1988, 31, 2235). For example, with respect to proteases, it has been known for some time that defined structural classes can behave as inhibitors of various enzymes. On the other hand, previous descriptions have been particularly inhibitors based on the mechanism of various proteases, but more recently, due to their three-dimensional structure, the frequency of examples of compounds that fit well into the active binding region of various enzymes has increased. (M. Whittaker, Cur. Opin. Chem. Biol. 1998, 2, 386; AS Ripka et al., Ibid., 441). Such “privileged structures” have already been described for GPCRs. Examples include peptoids, 4-substituted 4-arylpiperidines, and immobilized β-turn mimetics in addition to the benzodiazepines described above (BA Bunin et al., Ann. Rep. Med. Chem. 1999, RN Zuckermann et al., J. Med. Chem. 19999, 34, 267; RN Zuckermann et al., J. Med. Chem. 1994, 37, 2678; GCB Harriman, Tetrahedron Lett. 2000, 41, 8853). This review can be found in A.A. Patchett et al., Ann. Rep. Med. Chem. 1999, 35, 289. The tetrahydrocarbazole derivatives of the present invention are a further class of “privileged structures” for GPCRs.

  Although the present invention generally provides ligands for GPCRs, the compounds provided by the present invention are particularly suitable as ligands for certain representatives of the GPCR class, the so-called gonadotropin releasing hormone (GnRH). GnRH is assigned to subfamily A of GPCRs (see U. Gether et al., Endocrine Reviews 2000, 21 (1), 90).

GnRH is a hormone that is synthesized, primarily but not exclusively, by hypothalamic neurons in the mammal, transported through the portal vein into the pituitary gland, and regulated and delivered to gonadotrophic cells in mammals It is. Interaction of GnRH with its receptor with a 7-transmembrane domain stimulates gonadotropin production and release by the second messenger inositol 1,4,5-trisphosphate and Ca ²⁺ ions. Luteinizing hormone (LH) and follicle stimulating hormone (FSH), gonadotropins released by GnRH, stimulate sex steroid production and gamete maturation in both genders. In addition to GnRH (also referred to as GnRH1), there are two additional forms of GnRH, namely GnRH2 and 3.

  The GnRH receptor is used as a pharmacological target in many diseases that depend on functional sex hormone production, such as prostate cancer, premenopausal breast cancer, endometriosis and uterine fibroids. GnRH superagonists or antagonists can be used effectively for the aforementioned diseases. A further possible indication is the control of male infertility, especially in combination with androgen exchange.

  One advantage of a GnRH antagonist compared to a GnRH superagonist is its direct activity in blocking gonadotropin secretion. Superagonists first cause over-stimulation of the pituitary gland and cause an increase in gonadotropin release and sex steroid release. This hormonal response only stops after a certain delay based on desensitization and down-regulation of GnRH receptor concentration. Thus, GnRH superagonists alone and in combination with testosterone cannot effectively suppress sperm production in men and are therefore unsuitable for control of male infertility. In contrast, peptide GnRH antagonists can induce significant oligospermia in humans, particularly in combination with androgen exchange administration.

  However, peptide GnRH antagonists have many disadvantages. They therefore have a considerably lower activity than superagonists and must therefore be administered at a considerably higher dose. In addition, their oral bioavailability is low, so the agonists must be administered by infusion. Moreover, repeated injection leads to a decrease in compliance. Furthermore, the synthesis of peptide GnRH antagonists is complex and expensive compared to non-peptidic compounds.

  Quinoline derivatives are disclosed, for example, as non-peptidic GnRH antagonists in WO 97/14682. However, at present it is not possible to market any non-peptidic GnRH antagonist.

Technical problems The problem underlying the present invention is to provide new compounds which are suitable for the treatment of GPCR-mediated pathological conditions and in particular exhibit GnRH inhibitory (GnRH antagonist) action. New GPCR ligands, preferably GnRH antagonists, should be superior to known peptidic compounds as much as possible and should show effective options or improvements in connection with known non-peptidic compounds. New GPCR ligands, particularly GnRH antagonists, should have particularly high activity and should have the highest possible oral bioavailability. Their synthesis should be possible more easily and at minimal cost. The present invention also provides pharmaceutical compositions containing novel non-peptidic GPCR ligands, particularly GnRH antagonists.

  A further problem underlying the present invention is the use of novel GPCR ligands, advantageously for use as pharmaceutical therapeutics and for use in producing pharmaceutical therapeutics containing GPCR ligands, preferably GnRH antagonists. Is to provide GnRH antagonists.

  Additionally, the subject of the present invention is to provide a method for treating GPCR-mediated pathological conditions in mammals, in particular humans, in particular for inhibiting GnRH.

  All the above problems are unexpectedly caused by novel tetrahydrocarbazole derivatives, pharmaceutical compositions containing these tetrahydrocarbazole derivatives, processes for the preparation of these tetrahydrocarbazole derivatives and in mammals, particularly humans, of tetrahydrocarbazole derivatives. Pharmaceutical therapeutics for treating GPCR-mediated pathological conditions by administration, advantageously for inhibiting GnRH or for treating GPCR-mediated pathological conditions, in particular for GnRH inhibition This is solved by the use of tetrahydrocarbazole derivatives to produce

SUMMARY OF THE INVENTION In a first aspect, the present invention provides novel tetrahydrocarbazole derivatives of general formula (I).

  In a second aspect, there is provided a pharmaceutical composition comprising the novel at least one tetrahydrocarbazole derivative of general formula (I).

  In a third aspect, a tetrahydrocarbazole derivative of general formula (I) is provided for use as a pharmaceutical therapeutic.

  In a further aspect, the present invention relates to the use of a tetrahydrocarbazole derivative of general formula (I) for the treatment of a GPCR-mediated pathological condition, in particular for the manufacture of a pharmaceutical therapeutic for the inhibition of GnRH. Similarly, the present invention is directed to the treatment of GPCR-mediated pathological conditions in mammals, preferably humans, particularly in the inhibition of GnRH, mammals in need of treatment with an effective amount of a compound of general formula (I). , Advantageously for administration to humans.

  Furthermore, the present invention provides a method for producing a tetrahydrocarbazole derivative of general formula (I). This method comprises, for example, a condensation step of an appropriately substituted cyclohexanone derivative connected to a stationary phase and a suitably substituted phenylhydrazine derivative, followed by derivatization depending on the desired structure of the final compound and finally Including exclusion from the stationary phase and isolation of the product.

DETAILED DESCRIPTION OF THE INVENTION In a first embodiment of the invention, a compound of general formula (I)

［式中、
基Ｒ^１は水素原子、Ｃ_２〜Ｃ_６−アルケニル基又はＣ_１〜Ｃ_６−アルキル基であり、かつ場合によりアリール基、ヘタリール基又は基−ＣＯＯＲ^１１によって置換されていてよく、その際、アリール基又はヘタリール基は−ＮＯ_２、−ＣＨ_３、−ＣＦ_３、−ＯＣＨ_３、−ＯＣＦ_３及びハロゲン原子からなる群から互いに無関係に選択された３つまでの置換基によって置換されていてよく、
基Ｒ^１１は水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基、ヘタリール基又は基−ＣＯＣＨ_３であり、かつ場合により−ＣＯＮＨ_２、−ＣＯＣＨ_３、−ＣＯＯＣＨ_３、−ＳＯ_２ＣＨ_３及びアリール基からなる群から選択される１つの置換基によって置換されていてよく、
基Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５は互いに無関係に、水素原子、ハロゲン原子、基−ＣＯＯＨ、−ＣＯＮＨ_２、−ＣＦ_３、−ＯＣＦ_３、−ＮＯ_２、−ＣＮ、Ｃ_１〜Ｃ_６−アルキル基、Ｃ_１〜Ｃ_６−アルケニル基、Ｃ_１〜Ｃ_６−アルコキシ基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基又はヘタリール基であり、
基Ｒ_６は基−ＣＯＮＲ^８Ｒ^９、−ＣＯＯＲ^８、−ＣＨ_２ＮＲ^８Ｒ^９、−ＣＨ_２Ｒ^８、−ＣＨ_２ＯＲ^８又はＣ_１〜Ｃ_１２−アルケニル基であり、前記基は場合により基Ｒ^８及びＲ^９によって置換されており、その際、基Ｒ^８及びＲ^９はそれぞれ互いに無関係に、水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アラルキル基、Ｃ_１〜Ｃ_１２−ヘテロアラルキル基、アリール基又はヘタリール基であり、前記のそれぞれは−ＯＨ、−ＮＨ_２、−ＣＯＮＨＲ^１０、−ＣＯＯＲ^１０、−ＮＨ−Ｃ（＝ＮＨ）−ＮＨ_２及びハロゲン原子からなる群から選択される１つ以上の置換基によって置換されていてよく、その際、Ｒ^１０は水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基又はヘタリール基であり、かつ基−ＣＯＮ（Ｒ^１１）_２によって場合により置換されているか、又は基Ｒ^８及びＲ^９は一緒になって、専ら炭素原子からなるか、又は炭素原子とヘテロ原子との組み合わせからなる環式構造を形成してよく、
基Ｒ^７は水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アルケニル基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基又はヘタリール基、基−ＮＲ^１２Ｒ^１３、−ＮＨＣＯＲ^１４、−ＮＨＣＯＮＨＲ^１４、−ＮＨＣＯＯＲ^１４又は−ＮＨＳＯ_２Ｒ^１４であり、かつ−ＯＨ、−ＮＨ_２、−ＣＯＮＨ_２、−ＣＯＯＨ及びハロゲン原子からなる群から選択される１つ以上の置換基によって場合により置換されていてよく、
基Ｒ^１２及びＲ^１３はそれぞれ互いに無関係に水素原子、Ｃ_２〜Ｃ_６−アルケニル基又はＣ_１〜Ｃ_１２−アルキル基であり、かつ−ＮＯ_２、−ＣＨ_３、−ＣＦ_３、−ＯＣＨ_３、−ＯＣＦ_３及びハロゲン原子からなる群から互いに無関係に選択される３つまでの置換基によって置換されていてもよい１つ以上のアリール基又はヘタリール基によって場合により置換されていてよく、
基Ｒ^１４は水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アルケニル基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基又はヘタリール基であり、前記基は−ＮＯ_２、−ＣＨ_３、−ＯＲ^１１、−ＣＦ_３、−ＯＣＦ_３、−ＯＨ、−Ｎ（Ｒ^１１）_２、−ＯＣＯＲ^１１、−ＣＯＯＨ、−ＣＯＮＨ_２、−ＮＨＣＯＮＨＲ^１１、−ＮＨＣＯＯＲ^１１及びハロゲン原子からなる群から選択される１つ以上の置換基によって場合により置換されていてよく、
かつ基Ｒ^ａ、Ｒ^ｂ、Ｒ^ｃ、Ｒ^ｄ、Ｒ^ｅ及びＲ^ｆはそれぞれ互いに無関係に水素原子、ハロゲン原子、基−ＣＯＯＨ、−ＣＯＮＨ_２、−ＣＦ_３、−ＯＣＦ_３、−ＮＯ_２、−ＣＮ、Ｃ_１〜Ｃ_６−アルキル基、Ｃ_１〜Ｃ_６−アルコキシ基、アリール基又はヘタリール基である］で表されるが、但し、一般式（Ｉ）の化合物は、３−アミノ−１，２，３，４−テトラヒドロカルバゾール−３−カルボン酸、３−アミノ−６−メトキシ−１，２，３，４−テトラヒドロカルバゾール−３−カルボン酸、３−アミノ−６−ベンジルオキシ−１，２，３，４−テトラヒドロカルバゾール−３−カルボン酸、３−アセトアミド−１，２，３，４−テトラヒドロカルバゾール−３−カルボン酸、メチル ３−アセトアミド−１，２，３，４−テトラヒドロカルバゾール−３−カルボキシレート、（−）−メンチル ３−アセトアミド−１，２，３，４−テトラヒドロカルバゾール−３−カルボキシレート又は３−ｔ−ブトキシカルボニルアミノ−１，２，３，４−テトラヒドロカルバゾール−３−カルボン酸からなる群から選択されない新規のテトラヒドロカルバゾール化合物が提供される。

[Where:
The group R ¹ is a hydrogen atom, a C ₂ -C ₆ -alkenyl group or a C ₁ -C ₆ -alkyl group and may optionally be substituted by an aryl group, a hetaryl group or a group —COOR ¹¹ , The aryl group or hetaryl group may be substituted by up to three substituents selected independently from the group consisting of —NO ₂ , —CH ₃ , —CF ₃ , —OCH ₃ , —OCF ₃ and halogen atoms. ,
The group R ¹¹ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group, a hetaryl group or a group —COCH ₃ , and optionally —CONH ₂ , —COCH ₃ , — Substituted with one substituent selected from the group consisting of COOCH ₃ , —SO ₂ CH ₃ and an aryl group,
The groups R ² , R ³ , R ⁴ and R ⁵ are independently of one another hydrogen, halogen, radicals —COOH, —CONH ₂ , —CF ₃ , —OCF ₃ , —NO ₂ , —CN, C ₁ -C. ₆ - an aralkyl group, an aryl group or hetaryl group, - an alkyl _group, C 1 -C ₆ - alkenyl _group, C 1 -C ₆ - alkoxy _group, C 1 _{-C 12}
The group R ₆ is a group —CONR ⁸ R ⁹ , —COOR ⁸ , —CH ₂ NR ⁸ R ⁹ , —CH ₂ R ⁸ , —CH ₂ OR ⁸ or a C ₁ -C ₁₂ -alkenyl group, by it is substituted by a group ^{R 8} and ^{R 9,} when the respective independently of one another radicals ^{R 8} and ^{R 9} are hydrogen _atom, C 1 _{-C 12} - alkyl _groups, C 1 _{-C 12} - aralkyl groups, C _{1 to} C ₁₂ -heteroaralkyl group, aryl group or hetaryl group, each of which is —OH, —NH ₂ , —CONHR ¹⁰ , —COOR ¹⁰ , —NH—C (═NH) —NH ₂ and a halogen atom; may be substituted by one or more substituents selected from the group consisting of, ^{where, R 10} is a hydrogen _atom, C 1 _{-C 12} - alkyl _group, C 1 _{-C 12} - aralkyl group, Ali A group or hetaryl group, and either optionally substituted by group -CON (R ¹¹⁾ _2, or a group R ⁸ and R ⁹ together, or solely composed of carbon atoms, or a carbon atom hetero It may form a cyclic structure consisting of combinations with atoms,
The group R ⁷ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -alkenyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group or a hetaryl group, a group —NR ¹² R ¹³ , —NHCOR ^14. , —NHCONHR ¹⁴ , —NHCOOR ¹⁴ or —NHSO ₂ R ¹⁴ , and optionally by one or more substituents selected from the group consisting of —OH, —NH ₂ , —CONH ₂ , —COOH and halogen atoms. May be replaced,
The groups R ¹² and R ¹³ are each independently a hydrogen atom, a C ₂ -C ₆ -alkenyl group or a C ₁ -C ₁₂ -alkyl group, and —NO ₂ , —CH ₃ , —CF ₃ , —OCH _3. Optionally substituted by one or more aryl or hetaryl groups optionally substituted by up to three substituents selected independently from the group consisting of —OCF ₃ and a halogen atom;
The group R ¹⁴ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -alkenyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group or a hetaryl group, the group being —NO ₂ , — _{^{CH 3, -OR 11, -CF 3}} , -OCF 3, -OH, -N (R 11) 2, -OCOR 11, -COOH, -CONH 2, -NHCONHR 11, a group consisting of -NHCOOR ¹¹ and a halogen atom Optionally substituted by one or more substituents selected from
And the groups R ^a , R ^b , R ^c , R ^d , R ^e and R ^f are each independently a hydrogen atom, a halogen atom, a group —COOH, —CONH ₂ , —CF ₃ , —OCF ₃ , —NO ₂ , _-CN, C 1 -C ₆ - alkyl _group, C 1 -C ₆ - alkoxy group, is represented by a is] an aryl group or hetaryl group, provided that the compound of general formula (I), 3-amino - 1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-benzyloxy-1 , 2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl 3-acetamido-1,2,3,4-te Lahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate or 3-t-butoxycarbonylamino-1,2,3,4 Novel tetrahydrocarbazole compounds are provided that are not selected from the group consisting of tetrahydrocarbazole-3-carboxylic acids.

One embodiment of the present invention has all the above-mentioned meanings for the groups contained in (I), wherein the group R ¹¹ is a heteroalkyl group or a heteroarylalkyl group as defined above ( It is a compound of I).

  The basic tetrahydrocarbazole structure of said compounds which is specifically omitted from the compounds within the definition of general formula (I) is Maki et al. In Chem. Pharm. Bull. 1973, 21 (11), 2460-2465, and R.M. Introduced in Letters in Peptide Science 1999, 6, 221-233 by Millet et al.

The terms given for the description of the compounds of general formula (I) have in particular the following meanings:
C ₁ -C ₆ - or _C 1 _{-C 12} - "alkyl group" of the branched or unbranched, cyclic or acyclic, optionally substituted, 1-6 or 1 It means an alkyl group each having 12 carbon atoms. Representative examples of such alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl group, n-hexyl group, n-heptyl group, n-octyl group, n-nonyl group, n-decyl group, n-undecyl group and n-dodecyl group, and cyclic group, especially cyclopropyl group, Cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, 1-cyclopropyl group, 1-cyclobutyl group, 1-cyclopentyl group, 1-cyclohexyl group, 1-cycloheptylethyl group, 2-cyclopropyl group, 2-cyclobutyl Groups, 2-cyclopentyl group, 2-cyclohexyl group, 2-cycloheptylethyl group, etc. Not.

C 2 _-C 6 - _"alkenyl group" is a branched or unbranched, cyclic or acyclic, when monounsaturated or having 2 to 6 carbon atoms substituted by A polyunsaturated alkenyl group is meant. Representative examples of such alkenyl groups are vinyl, allyl, prop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3. -Dienyl group, pent-1-enyl group, pent-2-enyl group, pent-3-enyl group, pent-4-enyl group, penta-1,3-dienyl group, penta-1,4-dienyl group, Penta-2,3-dienyl group, isoprenyl group, hex-1-enyl group, hex-2-enyl group, hex-3-enyl group, hex-4-enyl group, hex-5-enyl group, hexa-1 , 3-dienyl group, hexa-1,4-dienyl group, hexa-1,5-dienyl group, hexa-2,4-dienyl group, hexa-2,5-dienyl group, hexa-1,4-dienyl group A hexa-1,3,5-trienyl group, etc. , But it is not limited thereto.

C ₂ -C _6- “Alkoxy group” means a branched or unbranched, cyclic or acyclic, optionally substituted alkoxy group having 2 to 6 carbon atoms. To do. Representative examples of such alkoxy groups include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, t-butoxy group, n-pentoxy group, n-hexoxy group, cyclohexyloxy group and the like. However, it is not limited to them.

C ₁ -C ₁₂ - "aralkyl" refers to an alkyl group having 1 to 12 carbon atoms which is substituted by one or more aryl groups. Representative examples for such aralkyl groups for the purposes of the present invention are benzyl, 1-phenylethyl, 1-phenylpropyl, 1-phenylbutyl, 1-phenylhexyl, 1-phenyl-2. -Methylethyl group, 1-phenyl-2-ethylethyl group, 1-phenyl-2,2-dimethylethyl group, benzhydryl group, triphenylmethyl group, 2- or 3-naphthylmethyl group, 2-phenylethyl group, 3 -Phenylpropyl group, 4-phenylbutyl group, 5-phenylpentyl group and the like, but are not limited thereto. Correspondingly, a “heteroaralkyl group” is an alkyl group substituted by a heteroaryl group.

  “Aryl group” means an optionally substituted monocyclic or polycyclic aromatic group. Representative examples of such an aryl group include a phenyl group and a naphthyl group, but are not limited thereto.

  The term “hetaryl group” is the same as the term “heteroaryl group” and includes one or more heteroatoms, in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms, as defined above. Represents an aryl group. Representative examples of such hetaryl groups or heteroaryl groups are unsubstituted hetaryl groups and substituted hetaryl groups, particularly imidazolyl groups, pyridyl groups, quinolinyl groups, and the like, but are not limited thereto.

  The term “cyclic structure” refers to an optionally substituted cyclic structure having various numbers of ring members, especially 5-membered, 6-membered and 7-membered rings, monocyclic or polycyclic. Including. These cyclic structures may contain one or more heteroatoms in addition to carbon atoms, such as in particular nitrogen, phosphorus, oxygen, sulfur and arsenic atoms. The cyclic structure is saturated but may also contain structural elements that are partially or completely unsaturated. Representative examples of such cyclic structures are aza-, oxa-, thia-, phosphacyclopentane-, -cyclohexane-, -cycloheptane-, diaza-, dioxa-, dithia-, diphosphacyclopentane, -cyclohexane, -Including but not limited to the basic cyclic structure of cycloheptane and the like and the basic cyclic structure with mixed heteroatom exchange.

  “Halogen atoms” include in particular fluorine, chlorine, bromine and iodine atoms, particularly preferably chlorine atoms.

  In this respect, in addition to the compounds of the general formula (I) mentioned per se above, the fact that the present invention also includes physiologically tolerable derivatives or analogues of these compounds, in particular salts of these compounds. Should be referenced.

  Furthermore, in this respect, the term “receptor ligand” or “ligand” is used in any manner for the purposes of the present invention (in the present invention the receptor is a GPCR receptor, preferably a GnRH receptor). To indicate any compound that binds to and induces activation, inhibition or other possible effects on this receptor. Thus, the term “ligand” includes agonists, antagonists, partial agonists / antagonists and other ligands that manifest effects similar to those of agonists, antagonists or partial agonists / antagonists at the receptor. The compounds of general formula (I) according to the invention are advantageously GnRH antagonists.

One embodiment of the present invention is a novel tetrahydrocarbazole derivative of general formula (I) according to the present invention wherein the group R ⁷ is not hydrogen when the group R ⁶ is simultaneously an alkyl group.

A further aspect of the invention is a compound of the general formula (I) in which the group R ⁷ is in any case not a hydrogen atom.

Advantageous novel tetrahydrocarbazole derivatives of the general formula (I) according to the invention are compounds in which the radicals R ^a , R ^b , R ^c , R ^d , R ^e and R ^f are hydrogen atoms.

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

Furthermore, preferred novel tetrahydrocarbazole derivatives of the general formula (I) according to the invention are compounds in which the radicals R ² , R ³ , R ⁴ and / or R ⁵ are not hydrogen atoms. Particularly preferred compounds of the general formula (I) in this connection are those in which the radicals R ² , R ³ , R ⁴ and R ⁵ are independently of one another a methyl, chloro or methoxy group. Particularly preferred compounds of the general formula (I) in this connection are compounds in which at least the radical R ² is not a hydrogen atom, in particular the compound phenylmethyl [(1S, 2S) -1-[[[(3R) -3- [ [[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-8-methyl-1H-carbazol-3-yl] amino] carbonyl]- 2-methylbutyl] carbamate (compound number 150a in the examples),
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl-2-methylpropyl] amino] carbonyl] -6-chloro-2,3 , 4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (148a),
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-8-methoxy-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (147a)
It is.

Tetrahydrocarbazole derivative advantageous novel formula (I) of the present invention, also R ⁶ comprises an alkyl structure, an aryl structure and / or hetaryl structures and counting from the carbon atom substituted by a radical R ⁶ and R ⁷ The compound is a hydrophobic group having a hydrogen bond donor-acceptor system at a distance of 2 to 4 single bonds. Particularly advantageous compounds of the general formula (I) are those in which the radical R ⁶ is
Compounds that are phenylalanylamide residues, especially the compound phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -2-amino-2-oxo-1- ( Phenylmethyl) ethyl] amino] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (66),
Compounds that are isoleucylamide residues, especially the compound phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylbutyl] Amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (64),
Compounds that are valyl-4-aminobenzamide residues, especially the compound phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1-[[[4- (amino Carbonyl) phenyl] amino] carbonyl] -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (45) ,
Compounds that are valyl-N-methylamide residues, especially the compound phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3R) -2,3,4,9-tetrahydro-3-[[[[ (1S) -2-methyl-1-[(methylamino) carbonyl] propyl] amino] carbonyl] -1H-carbazol-3-yl] amino] carbonyl] butyl] carbamate (222a),
Compounds that are methyloxymethyl-4-pyridyl groups, especially the compound 2,3,4,9-tetrahydro-3- (3-phenylpropyl) -O- (4-pyridinylmethyl) -1H-carbazole-3-methanol (287 ),
Compounds that are carboxyl groups, especially compounds 2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylic acid (273), or compounds that are ethylpropenoate groups, especially Compound Ethyl 3- [2,3,4,9-Tetrahydro-3- (3-phenylpropyl) -1H-carbazol-3-yl] -2-propenoate (289)
It is.

Equally particularly advantageously, compounds of the general formula (I) in which the group R ⁶ is a carbonylvalylamide residue, in particular the compounds phenylmethyl [(1S, 2S) -1-[[[(3R) -3- [ [[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] Carbamate (58),
Compounds that are carbonylthreonylamide residues, especially the compound phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S, 2R) -1- (aminocarbonyl) -2- Hydroxypropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Compounds that are cyclic carboxamide residues (eg carbonylprolylamide residues), in particular the compounds phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2S) -2- ( Aminocarbonyl) -1-pyrrolidinyl] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (181a) or carbonyloctahydroindolyl-2 A compound which is a carboxamide residue, in particular the compound phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2S) -2- (aminocarbonyl) octahydro-1H-indole-1- Yl] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methyl Chill] carbamate (190a),
Compounds that are 4-carboxamide phenylcarboxamide residues, especially the compound phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[4- (aminocarbonyl) phenyl] amino] carbonyl] -2 , 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (62),
Compounds that are methylaminomethyl-2-pyridyl groups, especially the compound 2,3,4,9-tetrahydro-3- (3-phenylpropyl) -N- (2-pyridinylmethyl) -1H-carbazole-3-methanamine (279 ),
Compounds that are carbonylvalinol residues, especially the compound phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (hydroxymethyl) -2-methylpropyl] Amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (267b) and 2,3,4,9-tetrahydro-N- [ (1S) -1- (hydroxymethyl) -2-methylpropyl] -3- (3-phenylpropyl) -1H-carbazole-3-carboxamide (276) or a compound that is a methylvalinol residue, in particular a compound (2S ) -3-Methyl-2-[[[2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazol-3-yl] methyl Amino] -1-butanol (284)
It is.

The advantageous novel tetrahydrocarbazole derivative of the general formula (I) of the present invention is a compound in which R ⁷ is a hydrophobic group having an alkyl structure, an aryl structure and / or a hetaryl structure. Particular preference is given in this connection to compounds of the general formula (I) in which the group R ⁷ is a 2,3-biphenyl-propionylamino group, in particular the compounds N-[[(3R) -2,3,4,9- Tetrahydro-3-[(1-oxo-2,3-diphenylpropyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide (18),
Compounds that are indanoylamino groups, especially compounds (3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2,3-dihydro-1H-indene-1 -Yl) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide (162a),
Compounds that are indolylacetylamino groups, especially compounds (3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1H -Indol-3-ylacetyl) amino] -1H-carbazole-3-carboxamide (164b),
Compounds that are 2-naphthylacetylamino groups, especially compounds (3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[( 2-Naphthalenylacetyl) amino] -1H-carbazole-3-carboxamide (161b) or a compound which is a 3-propionylamino group, in particular the compound N-[[(3R) -2,3,4,9-tetrahydro- 3-[[(2S, 3S) -3-Methyl-1-oxo-2-[(1-oxo-3-phenylpropyl) amino] pentyl] amino] -1H-carbazol-3-yl] carbonyl] -L -Valyl-L-aspartamide (22)
It is.

Also particularly advantageously, compounds of the general formula (I) in which R ⁷ is a phenylmethylcarboxamide residue substituted in an aromatic ring system, in particular the compound (3R) -N-[(1S) -1- (amino Carbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-methylphenyl) acetyl] amino] -1H-carbazole-3-carboxamide (165a),
N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-methoxyphenyl) acetyl] amino] -1H-carbazole-3 Carboxamide (175),
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(3-bromophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide (96),
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-fluorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide (91),
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H- Carbazole-3-carboxamide (167a),
Compounds that are phenylhexylamine residues, especially compounds (3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(6 -Phenylhexyl) amino] -1H-carbazole-3-carboxamide (234a) or a compound which is a phenylpropyl residue, in particular the compound 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropiyl ) -1H-carbazole-3-carboxylic acid (275) and ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylate ( 272)
It is.

Also advantageously, the carbons substituted by the groups R ⁶ and R ⁷ of the general formula (I) according to the invention when the groups R ⁶ and R ⁷ together form an α-aminocarboxylic acid structural element. It is a novel compound having an R configuration at an atom.

Most advantageously for the purposes of the present invention the compound phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methyl Propyl] amino] carbonyl] -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (184a),
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (hydroxymethyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate (267a),
(2S) -1-[[(3R) -3-[[(4-Chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3-yl] carbonyl] -2-pyrrolidinecarboxamide (189a) and 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -N- (2-pyridinylmethyl) -1H-carbazole-3-methanamine ( 283)
It is.

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

  The novel tetrahydrocarbazole derivatives (I) of the present invention described above are ligands for GPCRs, and for example for the control of male infertility, for hormonal therapy, for the treatment of female low fertility or infertility, for female contraception and It can be used for tumor control, for inhibition of gonadotropin releasing hormone, ie as an antagonist.

  In male infertility controls, the compounds of the present invention result in reduced spermatogenesis. Administration in combination with androgens such as testosterone or testosterone derivatives such as testosterone esters is advantageous. The testosterone derivative can in this case be administered, for example, by injection, for example by intramuscular depot injection.

The compounds (I) of the present invention may also be used in combination with other hormones, such as estrogens and / or progestins, in hormonal therapy for the treatment of, for example, endometriosis, uterine fibroids and uterine fibroids. Good. The combination of a GnRH antagonist of the present invention with a tissue selective partial estrogen agonist such as raloxifene ^(R) is particularly advantageous. Additionally, the compounds of the present invention may be used in hormone exchange therapy. The compounds (I) according to the invention can furthermore be used for enhancing female fertility, for example by inducing ovulation and for the treatment of infertility.

  On the other hand, the novel compounds (I) according to the invention are also suitable for contraception in women. Thus, the GnRH antagonists of the present invention may be administered with a period of 1 to 15 days together with an estrogen, advantageously a very small dose of estrogen. On days 16-21 of the intake cycle, luteinizing hormone substances are added to the estrogen / GnRH antagonist combination. The GnRH antagonists of the invention may be administered continuously over the cycle. In this way, it is possible to reduce the hormone dose and thus reduce the side effects of non-physiological hormone levels. In addition, beneficial effects in women suffering from polycystic ovary syndrome and androgen-dependent diseases such as acne, seborrhea and hirsutism can be achieved. Improved cycle control is also expected compared to conventional dosing methods. Further instructions are benign prostatic hypertrophy, gonadal protection during chemotherapy, regulated ovarian stimulation / artificial reproduction techniques, infant developmental diseases such as premature sexual pregnancies and polycystic ovaries.

  Finally, the compound (I) of the present invention also treats hormone-dependent tumor diseases such as premenopausal cancer, prostate cancer, ovarian cancer and endometrial cancer by inhibiting endogenous steroid hormones. Can be used for

  The aforementioned novel compounds (I) of the present invention are suitable for administration to mammals, particularly humans, as GPCR ligands, particularly GnRH antagonists, for the treatment of the pathological conditions detailed above. It is also suitable for veterinary purposes, especially in pets and productive livestock as well as in wild animals.

  Administration is possible in a known manner, for example orally or parenterally, in particular topically, enterally, vaginally, nasally or by infusion or implantation. Oral administration is advantageous. The novel compound (I) of the present invention is converted into an administrable form and optionally mixed with a pharmaceutically acceptable carrier or diluent. 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), p. 918 et seq .; H. v. Czetsch-Lindenwald , "Hilfsstoffe fuer Pharmazie und angrenzende Gebiete", Pharm. Ind. 2, 1961, p. 72 et seq; Dr. HP Fiedler, "Lexikon der Hilfsstoffe fuer Pharmazie, Kosmetik und angrenzende Gebiete", Cantor KG, Aulendorf in Wuerttemberg, 971 Has been.

  Oral administration may be performed, for example, in solid form, as tablets, capsules, gel capsules, coated tablets, granules or powders, and in the form of drinking liquids. For oral administration, the novel compounds of general formula (I) according to the invention described above are known and commonly used physiologically acceptable excipients and carriers such as gum arabic, talc, starch, Sugars such as mannitol, methylcellulose, lactose, gelatin, surfactants, magnesium stearate, cyclodextrins, aqueous or non-aqueous carriers, diluents, dispersants, emulsifiers, lubricants, preservatives and flavors (eg essential oils) May be combined. The compound of the present invention may be dispersed in the form of microparticles, for example, nanoparticles.

  Parenteral administration may be effected, for example, by intravenous, subcutaneous or intramuscular injection of sterile aqueous or oily solutions, suspensions or emulsions, by implants or ointments, creams or suppositories. Administration as a delayed release form is also possible as appropriate. The implant may contain inert materials such as biodegradable polymers or synthetic silicones such as silicone rubber. Vaginal administration is possible, for example, by a pessary. Intrauterine administration is possible, for example, by a pessary. In addition, transdermal administration is also provided, particularly by means of suitable formulations and / or suitable measures, eg patches, for the purposes mentioned above.

  As already explained, the novel compound (I) of the present invention may be combined with other active pharmaceutical ingredients. During the combination therapy, the individual active ingredients may be administered simultaneously or separately, in particular by the same route (eg orally) or separate routes (eg oral and infusion). These components may be present and administered in unit doses in the same or different amounts. Certain modes of administration that may be advantageous may also be applied. Further, as described above, a plurality of the novel compounds (I) of the present invention can be combined together.

  The dose may vary within wide limits depending on the nature of the indication, the severity of the disease, the mode of administration, age, sex, weight and sensitivity of the donor to be treated. Within the abilities of those skilled in the art, a “pharmacologically effective amount” of the combined pharmaceutical composition should be defined. A unit dose of 1 μg to 100 mg, particularly preferably 1 μg to 10 mg, most preferably 1 μg to 1 mg per kg body weight of the donation to be treated is advantageous. Administration may take place in a single dose or in multiple separate doses.

  Accordingly, in a further aspect of the invention, the invention also contains said at least one compound of the invention as described above and, optionally, a pharmaceutically acceptable carrier and / or excipient. A pharmaceutical composition. Advantageous and particularly advantageous pharmaceutical compositions are those containing the abovementioned advantageous or particularly advantageous novel compounds (I) according to the invention, in particular the compounds named above. In the pharmaceutical composition according to the invention, in addition to the at least one compound of the general formula (I), other active pharmaceutical ingredients may be present as already described in detail above.

  At least one of the novel compounds (I) of the present invention as described above is in one of the unit doses mentioned above as being advantageous, particularly advantageous or most advantageous in the pharmaceutical composition of the present invention. In particular and advantageously present in dosage forms allowing oral administration.

  In addition, in a further aspect, the present invention provides a compound of general formula (I) as defined above for use as a pharmaceutical therapeutic.

  Preferred tetrahydrocarbazole compounds of the general formula (I) according to the invention for use as pharmaceutical therapeutics are also the compounds mentioned above as particularly advantageous and particularly advantageous compounds, in particular those named under the name. Preferred compounds of the invention and the compounds mentioned in the examples.

  With regard to the pharmaceutical composition containing the compound (I) of the present invention and the compound (I) of the present invention for use as a pharmaceutical therapeutic agent, it has already been mentioned with respect to the novel compound (I) of the present invention as described above. Reference will be made to the possibilities for use and administration of things.

  In another embodiment, the present invention also relates to at least one tetrahydrocarbazole derivative of the general formula (I) of the present invention described above and Millet et al. Excluded from the meaning of the general formula (I) as defined at the beginning. There is provided the use for the manufacture of a pharmaceutical therapeutic for the treatment of GPCR-mediated diseases with tetrahydrocarbazole disclosed in the literature by Maki et al., In particular for the inhibition of gonadotropin releasing hormone (GnRH).

  Additionally, the present invention provides, in a further aspect, compounds previously excluded by the names from Millet et al. And Maki et al., Ie 3-amino-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid. 3-amino-6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-benzyloxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido- 1,2,3,4-tetrahydrocarbazole-3-carboxylate and 3-t-butoxycarbonylamino- Of at least one compound of the general formula (I) according to the invention as defined above, for inhibiting GnRH, preferably for the control of male infertility, including 2,3,4-tetrahydrocarbazole-3-carboxylic acid Thus, it provides use for manufacturing pharmaceutical therapeutics for hormonal therapy, for the treatment of low fertility and infertility in women, for contraception in women, and for tumor control. More specifically, the term “a compound of the above general formula (I) including a compound excluded by name” is defined by the general formula (I)

［式中、
基Ｒ^１は水素原子、Ｃ_２〜Ｃ_６−アルケニル基又はＣ_１〜Ｃ_６−アルキル基であり、かつアリール基、ヘタリール基又は基−ＣＯＯＲ^１１によって場合により置換されていてよく、その際、アリール基又はヘタリール基は、−ＮＯ_２、−ＣＨ_３、−ＣＦ_３、−ＯＣＨ_３、−ＯＣＦ_３及びハロゲン原子からなる群から互いに無関係に選択された３つまでの置換基によって置換されていてよく、かつ
基Ｒ^１１は水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基、ヘタリール基又は基−ＣＯＣＨ_３であり、かつ−ＣＯＮＨ_２、−ＣＯＣＨ_３、−ＣＯＯＣＨ_３、−ＳＯ_２ＣＨ_３及びアリール基からなる群から選択される１つの置換基によって場合により置換されていてよく、
基Ｒ^２、Ｒ^３、Ｒ^４及びＲ^５はそれぞれ互いに無関係に、水素原子、ハロゲン原子、基−ＣＯＯＨ、−ＣＯＮＨ_２、−ＣＦ_３、−ＯＣＦ_３、−ＮＯ_２、−ＣＮ、Ｃ_１〜Ｃ_６−アルキル基、Ｃ_１〜Ｃ_６−アルケニル基、Ｃ_１〜Ｃ_６−アルコキシ基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基又はヘタリール基であり、
基Ｒ^６は基−ＣＯＮＲ^８Ｒ^９、−ＣＯＯＲ^８、−ＣＨ_２ＮＲ^８Ｒ^９、−ＣＨ_２Ｒ^８、−ＣＨ_２ＯＲ^８又はＲ^８及びＲ^９によって場合により置換されているＣ_１〜Ｃ_１２−アルケニル基であり、その際、基Ｒ^８及びＲ^９はそれぞれ互いに無関係に水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アラルキル基、Ｃ_１〜Ｃ_１２−ヘテロアラルキル基、アリール基又はヘタリール基であり、前記基のそれぞれは−ＯＨ、−ＮＨ_２、−ＣＯＮＨＲ^１０、−ＣＯＯＲ^１０、−ＮＨ−Ｃ（＝ＮＨ）−ＮＨ_２及びハロゲン原子からなる群から選択される１つ以上の置換基によって置換されていてよく、
その際、基Ｒ^１０は水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基又はヘタリール基であり、かつ基−ＣＯＮ（Ｒ^１１）_２によって場合により置換されていてよいか、又は基Ｒ^８及びＲ^９は一緒になって、専ら炭素原子からなるか、又は炭素原子及びヘテロ原子の組み合わせからなる環式構造を形成してよく、
基Ｒ^７は水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アルケニル基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基又はヘタリール基、基−ＮＲ^１２Ｒ^１３、−ＮＨＣＯＲ^１４、−ＮＨＣＯＮＨＲ^１４、−ＮＨＣＯＯＲ^１４又は−ＮＨＳＯ_２Ｒ^１４であり、かつ−ＯＨ、−ＮＨ_２、−ＣＯＮＨ_２、−ＣＯＯＨ及びハロゲン原子からなる群から選択される１つ以上の置換基によって場合により置換されていてよく、
基Ｒ^１２及びＲ^１３はそれぞれ互いに無関係に水素原子、Ｃ_２〜Ｃ_６−アルケニル基又はＣ_１〜Ｃ_１２−アルキル基であり、かつ−ＮＯ_２、−ＣＨ_３、−ＣＦ_３、−ＯＣＨ_３、−ＯＣＦ_３及びハロゲン原子からなる群から互いに無関係に選択される３つまでの置換基によって置換されていてもよい１つ以上のアリール基又はヘタリール基によって場合により置換されていてよく、
かつ基Ｒ^１４は水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アルケニル基、Ｃ_１〜Ｃ_１２−アラルキル基、アリール基又はヘタリール基であり、前記基は、−ＮＯ_２、−ＣＨ_３、−ＯＲ^１１、−ＣＦ_３、−ＯＣＦ_３、−ＯＨ、−Ｎ（Ｒ^１１）_２、−ＯＣＯＲ^１１、−ＣＯＯＨ、−ＣＯＮＨ_２、−ＮＨＣＯＮＨＲ^１１、−ＮＨＣＯＯＲ^１１及びハロゲン原子からなる群から選択される１つ以上の置換基によって場合により置換されていてよく、かつ
基Ｒ^ａ、Ｒ^ｂ、Ｒ^ｃ、Ｒ^ｄ、Ｒ^ｅ及びＲ^ｆはそれぞれ互いに無関係に水素原子、ハロゲン原子、基−ＣＯＯＨ、−ＣＯＮＨ_２、−ＣＦ_３、−ＯＣＦ_３、−ＮＯ_２、−ＣＮ、Ｃ_１〜Ｃ_６−アルキル基、Ｃ_１〜Ｃ_６−アルコキシ基、アリール基又はヘタリール基である］の化合物を意味する。

[Where:
The group R ¹ is a hydrogen atom, a C ₂ -C ₆ -alkenyl group or a C ₁ -C ₆ -alkyl group and may be optionally substituted by an aryl group, a hetaryl group or a group —COOR ¹¹ , The aryl group or hetaryl group is substituted with up to three substituents selected independently from the group consisting of —NO ₂ , —CH ₃ , —CF ₃ , —OCH ₃ , —OCF ₃ and a halogen atom. And the group R ¹¹ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group, a hetaryl group or a group —COCH ₃ , and —CONH ₂ , —COCH ₃ , Optionally substituted by one substituent selected from the group consisting of —COOCH ₃ , —SO ₂ CH ₃ and an aryl group,
The groups R ² , R ³ , R ⁴ and R ⁵ are independently of each other a hydrogen atom, a halogen atom, a group —COOH, —CONH ₂ , —CF ₃ , —OCF ₃ , —NO ₂ , —CN, C _1- A C ₆ -alkyl group, a C ₁ -C ₆ -alkenyl group, a C ₁ -C ₆ -alkoxy group, a C ₁ -C ₁₂ -aralkyl group, an aryl group or a hetaryl group,
Group ^{R 6} is a group ^{-CONR 8 R 9, -COOR 8,} -CH 2 NR 8 R 9, -CH 2 R 8, C 1 ~ which is optionally substituted by _-CH 2 OR ⁸ or ^{R 8} and ^{R 9} A C ₁₂ -alkenyl group, wherein the groups R ⁸ and R ⁹ are independently of one another a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -aralkyl group, a C ₁ -C ₁₂ -hetero. An aralkyl group, an aryl group, or a hetaryl group, each of the groups selected from the group consisting of —OH, —NH ₂ , —CONHR ¹⁰ , —COOR ¹⁰ , —NH—C (═NH) —NH _2, and a halogen atom. One or more substituents may be substituted,
In that case, the group R ¹⁰ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group or a hetaryl group and is optionally substituted by the group —CON (R ¹¹ ) ₂ . Or the groups R ⁸ and R ⁹ together may form a cyclic structure consisting exclusively of carbon atoms or a combination of carbon atoms and heteroatoms,
The group R ⁷ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -alkenyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group or a hetaryl group, a group —NR ¹² R ¹³ , —NHCOR ^14. , —NHCONHR ¹⁴ , —NHCOOR ¹⁴ or —NHSO ₂ R ¹⁴ , and optionally by one or more substituents selected from the group consisting of —OH, —NH ₂ , —CONH ₂ , —COOH and halogen atoms. May be replaced,
The groups R ¹² and R ¹³ are each independently a hydrogen atom, a C ₂ -C ₆ -alkenyl group or a C ₁ -C ₁₂ -alkyl group, and —NO ₂ , —CH ₃ , —CF ₃ , —OCH _3. Optionally substituted by one or more aryl or hetaryl groups optionally substituted by up to three substituents selected independently from the group consisting of —OCF ₃ and a halogen atom;
And the group R ¹⁴ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -alkenyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group or a hetaryl group, and the group is —NO ₂ , —CH ₃ , —OR ¹¹ , —CF ₃ , —OCF ₃ , —OH, —N (R ¹¹ ) ₂ , —OCOR ¹¹ , —COOH, —CONH ₂ , —NHCONHR ¹¹ , —NHCOOR ¹¹ and a halogen atom Optionally substituted by one or more substituents selected from the group consisting of, and the groups R ^a , R ^b , R ^c , R ^d , R ^e and R ^f are each independently a hydrogen atom, halogen atom , group _{-COOH, -CONH 2, -CF 3,} -OCF 3, -NO 2, -CN, C 1 ~C 6 - alkyl _group, C 1 -C ₆ - alkoxy group, and an aryl group It means a compound of the hetaryl is a group.

  The instructions given above for the novel compounds of general formula (I) of the present invention described above (ie excluding those compounds disclosed in Maki et al. And Millet et al. And named above by name) are the novel compounds of the present invention. Already mentioned above for (I). Advantageous and particularly advantageous compounds in the use of compounds defined exactly for the manufacture of pharmaceutical therapeutics for the inhibition of GnRH are related to the novel compounds of the general formula (I) according to the invention described above. Already identical to the abovementioned advantageous and particularly advantageous compounds.

  The invention provides, in a further aspect, the use of a compound (I), as previously described, which is also excluded at the beginning by name, for male infertility control or female contraception. The compounds of the invention for this use which are advantageous and particularly advantageous are those which have already been mentioned as compounds of the invention of the general formula (I) already preferred and particularly advantageous at the beginning.

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

  In another embodiment, the present invention relates to a method for the treatment of pathological conditions mediated by GPCRs. The method comprises administering at least one compound (I) of the present invention as described above to a mammal, particularly a human, when such treatment is required. The administration is usually performed in a pharmaceutically effective amount. As already explained above in connection with the novel compound (I) of the present invention and the pharmaceutical composition of the present invention, a pharmaceutically effective amount is defined depending on the specific requirements of the individual case. This is within the abilities of those skilled in the art. However, the compounds (I) according to the invention are preferably administered in unit doses of 1 μg to 100 mg, particularly preferably 1 μg to 10 mg, particularly preferably 1 μg to 1 mg per kg body weight of the donor to be treated. The The preferred dosage form is oral administration. It is also provided to administer one or more compounds (I) according to the invention in combination with at least one further active ingredient already described above.

  Additionally, the present invention also provides for a GnRH in a patient comprising administering to a patient in need of such treatment a pharmaceutically effective amount of a compound comprising a compound as defined above but excluded by name. It relates to a method for inhibition. The method is advantageously used in male infertility control, hormonal therapy, female contraception, female low conception or infertility treatment and tumor control.

  Finally, the present invention provides, in the last aspect, and a process for the preparation of the novel tetrahydrocarbazole derivatives of general formula (I) according to the invention. The process for the preparation of the compounds of general formula (I) according to the invention can be carried out in various ways, for example in the liquid phase or as a partial or complete solid phase synthesis. The selection of suitable synthesis conditions for the preparation of the individual representatives of the compounds of general formula (I) can be made by those skilled in the art based on their general general knowledge. The process according to the invention for the compounds of general formula (I) according to the invention is first generally described below. A particular variation, namely the solid phase method, will now be described. For further explanation of the invention, the examples listed below contain a number of representatives of compounds of general formula (I).

One process for the preparation of the compounds of general formula (I) according to the invention is advantageously carried out as follows:
The central tetrahydrocarbazole structure can be obtained by a Fischer indole synthesis known per se. For this purpose, an appropriately substituted cyclohexanone derivative with an appropriate protecting group is desirable in each case and is likewise condensed with an appropriately substituted phenyl hydrazine derivative with an appropriate protecting group (for example Britten). & Lockwood, JCS Perkin I 1974, 1824 or by Maki et al., Chem. Pharm. Bull. 1973, 21, 240). In particular, the cyclohexanone structure is substituted by groups R ^{a to} R ^f at the 3,3 ′, 5,5 ′ and 6,6 ′ positions, and the groups R ⁶ and R ⁷ or, if appropriate, the groups at the 4,4 ′ positions. Is replaced by a precursor of The phenylhydrazine structure is optionally substituted by groups R ^{2 to} R ⁵ . Non-commercial phenylhydrazine derivatives can be prepared by methods known to those skilled in the art. Where appropriate, the regioisomers formed in the condensation of cyclohexanone and phenylhydrazine derivatives can be resolved by chromatographic methods such as HPLC.

After synthesis of the central tetrahydrocarbazole structure, the group R ¹ may be introduced using a base with an appropriate R ¹ -halide by N-alkylation of the 9-position nitrogen atom (eg Pecca & Albonico, J. Med. Chem. 1977, 20, 487 or Mooradian et al., J. Med. Chem. 1970, 13, 327).

The groups R ⁶ and R ⁷ can be introduced in various ways as described below, depending on their nature, as already indicated above.

The α-aminocarboxylic acid structure in these groups is obtained by treating the ketone with NH ⁴ (CO) ₃ and KCN under Schotten-Baumann conditions known per se and subsequently by alkaline hydrolysis of the hydantoin formed. (Britten & Lockwood, JCS 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 HATU (Tetrahedron Lett. 1994, 35, 2279) and condensed with the amino component in the presence of a base such as DIPEA and / or DMAP. Let

  The ester residue can also be obtained by using the desired alcohol under similar conditions. The solvent used in this case is preferably an anhydride.

  Secondary or tertiary amide residues are obtained from primary amines either by nucleophilic substitution of alkyl halides or by reductive amination of aldehydes / ketones (eg 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 reaction of amines with suitable isocyanates.

Urethane residues can be prepared by preactivation of the appropriate alcohol with carbonyldihydroxybenzotriazole ((HOBt) ₂ CO) and may subsequently be reacted with an amine (Warass et al., LIPS 1998, 5, 125).

The alcohol can be obtained from the carboxylic acid ester by reduction with LiAlH ₄ .

  Aldehyde residues can be obtained from alcohol precursors, for example by oxidation with DMSO / oxalyl chloride under known Schwern conditions (Pansavath et al., Synthesis 1998, 436).

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

  The ether residue can be obtained by deprotonating the alcohol precursor with a base, for example NaH, under William conditions known per se, and subsequently reacting with an alkyl halide.

  Double bonds in the group can be introduced by reacting an aldehyde or ketone precursor with an appropriate phosphonylide under known Wittig conditions.

  The solid phase process for the preparation of the compounds of formula (I) according to the invention advantageously comprises steps (a) to (d) which are explained in detail below.

Step (a) is substantially described by Britten & Lockwood, JCS Perkin I 1974, 1824; Maki et al., Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman, Tetrahedron Lett. 1996, 37, 4869 Proceeds as analogously to Fischer's indole synthesis and contains the group G and the solid phase SP contains the group R ⁶

［式中、
基Ｒ^７が水素原子、Ｃ_１〜Ｃ_１２−アルキル基、Ｃ_１〜Ｃ_１２−アラルキル基又はヘタリール基である場合においては、基Ｇは基Ｒ^７と同一であり、かつ
基Ｒ^７が式（Ｉ）中のＲ^７に関して示される意味の別の意味を有する場合においては、基Ｇは基−ＮＨ−Ｐｇと同一であり、その際、Ｐｇは保護基である］を形成するために適当なリンカーＬを介してつながれているシクロヘキサノン誘導体（ＩＩ）と、Ｒ^２〜Ｒ^５によって置換されたフェニルヒドラジン誘導体（ＩＩＩ）

[Where:
Group ^{R 7} is a hydrogen _atom, C 1 _{-C 12} - alkyl _group, C 1 _{-C 12} - In the case of an aralkyl group or hetaryl group, group G is the same as group ^{R 7,} and ^{R 7} radical has the formula In the case of having another meaning of the meaning indicated for R ^{7 in} (I), the group G is identical to the group —NH—Pg, where Pg is a protecting group] Cyclohexanone derivative (II) connected through a simple linker L and phenylhydrazine derivative (III) substituted by R ^{2 to} R ⁵

との、酸、有利には酢酸及び金属塩、有利にはＺｎＣｌ_２の存在下での縮合を含む。ＤＭＦは溶剤として有利である。基Ｒ^ａ〜Ｒ^ｆは式（Ｉ）中に前記に示されるように定義される。一定の置換基又は基は、適宜、保護された形で存在してよく、その場合に、保護基は自体公知の方法によって再び合成の間の適当な時間で取り除かれる。

And condensation in the presence of an acid, preferably acetic acid and a metal salt, preferably ZnCl ₂ . DMF is advantageous as a solvent. The groups R ^{a to} R ^f are defined as indicated above in formula (I). Certain substituents or groups may optionally be present in protected form, in which case the protecting groups are again removed at a suitable time during the synthesis by methods known per se.

  Particularly suitable solid phase SPs for the purposes of the present invention are Rink amide resin (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB resin (Sheppard et al., Int. J. Peptide Protein Res. 1982, 20, 451), Wang resin (Lu et al., J. Org. Chem. 1981, 46, 3433) or chlorotrityl resin (Barlos et al., Int. J. Peptide Protein Res. 1991, 38, 562), At that time, the cyclohexanone derivative (II) should be linked to the solid phase SP by (amino) carboxylic acid. The alcohol precursor of the cyclohexanone derivative (II) may be linked by a DHP linker (Liu & Elman, J. Org. Chem. 1995, 60, 7712). Traceless linking of the aromatic precursor of the cyclohexanone derivative (II) to the triazine resin is possible (Braese et al., Angew. Chem. Int. Ed. 1998, 37, 3413).

The protecting group Pg, optionally contained in the group G and protecting the α-amino group —NH ₂ , is preferably the “Fmoc” (9-fluorenylmethoxycarbonyl) protecting group, An amino protecting group such as a series of alkoxycarbonyl protecting groups (eg "Z" (benzyloxycarbonyl) or "Boc" (t-butoxycarbonyl) group) or another suitable protecting group such as "trityl" (triphenylmethyl) ) May be a protecting group.

Linker L is suitable for derivatization (steps (b) and (c)) and workup (step (d)) as defined above for R ⁶ in the tetrahydrocarbazole derivative of general formula (I) in the final product. The configuration results in the desired group R ⁶ having one. In order to explain the structure of the linker L, this will be described below as an example where R ⁶ is a group —CONR ⁸ R ⁹ .

In the case where the group R ⁶ in the product of the formula (I) according to the invention means —CONR ⁸ R ⁹ , first the Pg—N (R ⁸ ) —R ^{9 ′} —COOH which forms the linker L is the activating reagent Release of SP to solid phase SP, for example by DCC (dicyclohexylcarbodiimide) or HATU (O- (7-azabenzotriazol-1-yl) -N, N-N ', N'-tetramethyluronium hexafluorophosphate) Connected via an amino group, where Pg and SP have the meanings given above and R ^{9 '} forms part of the subsequent group R ⁹ . The protecting group Pg is subsequently removed, for example with piperidine / DMF in the case of the Fmoc protecting group. Thereby, the compound of HR < ⁸ > NR < ^{9 '} >-CONH-SP is obtained. The compound is then precursor of cyclohexanone derivative (II), ie cyclohexanone carboxylic acid (II ′)

と、活性化試薬、例えばＤＣＣ又はＨＡＴＵを使用して反応させ、最終的に前記のシクロヘキサノン誘導体（ＩＩ）が得られる。前記の場合のリンカーＬは−ＣＯＮＲ^８−Ｒ^９′−ＣＯＮＨ−ＳＰを意味する。如何なる型の任意の生じる異性体（エナンチオマー、ジアステレオマー又は位置異性体）を、記載される製造方法の間のどこでも、公知のようにＨＰＣＬによって分別できる。

And an activating reagent such as DCC or HATU, and finally the cyclohexanone derivative (II) is obtained. Linker L in the case of the means ^{-CONR 8 -R 9 '-CONH-SP} . Any type of any resulting isomers (enantiomers, diastereomers or regioisomers) can be fractionated by HPCL as is known everywhere during the described production process.

  Protecting group Pg in group G by virtual step (a), ie condensation of cyclohexanone derivative (II) with substituted phenylhydrazine derivative (III) and, for example, piperidine (in the case of Fmoc protecting group) Is eliminated, so that a free α-amino group is once again formed at this point.

In the case where the group R ⁷ is a group —NHCOR ¹⁴ , —NHSO ₂ R ¹⁴ , —NR ¹² R ¹³ (wherein R ¹² and R ¹³ are not both hydrogen atoms), —NHCONHR ¹⁴ or —NHCOOR ¹⁴ Since the derivatization of the currently unprotected α-amino group of the cyclohexanone derivative (II) bound to the resin is finally carried out in step (b), the various selective groups R ⁷ described above can be carried out.

Depending on the nature of the desired group R ⁷ in the final product tetrahydrocarbazole (I) 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 (a) is reacted in the presence of carboxylic acid R ¹⁴ COOH and an activating reagent such as DCC or HATU and a base such as DIPEA (diisopropylethylamine). Alternatively, the reaction is performed by a known method for forming a peptide bond in the presence of DMAP (4-dimethylaminopyridine) (see, for example, Tetrahedron Lett. 1994, 35, 2279; option (i)).

In the case where R ⁷ is a sulfonamide group —NHSO ₂ R ¹⁴ , the reaction product from step (a) is converted to the sulfonic acid derivative R ¹⁴ SO ₂ X, wherein X is a leaving group, preferably a halide. Atoms, in particular chloride atoms], in the presence of a base, such as DMAP or DIPEA (see for example Gennari et al., EJOC 1998, 2437; see option (ii)).

When R ⁷ is a group —NR ¹² R ¹³ (wherein R ¹² and R ¹³ are not both hydrogen atoms) and the group R ¹² is a hydrogen atom, the reaction product from step (a) is Reagent R ¹³ X wherein X is a leaving group such as a halide atom, in particular a chloride atom, and a base such as DBU or DIPEA (Green, JOC 1995, 60, 4287 or JOC 1996, 61, 3849 In the presence of aldehyde R ¹³ CHO and a reducing agent such as NaH / B (OAc) ₃ . In the case where neither of the groups R ¹² and R ¹³ is a hydrogen atom, the reaction product from step (a) is converted to ketone R ¹² COR ¹³ and a reducing agent (Ellmann et al., JOC 1997, 62, 1240 or Synth. Commun. 1994, 609; see option (iii)). In the case where R ⁷ is —NR ¹² R ¹³ and both groups R ¹² and R ¹³ are both hydrogen, the following option (vi) applies.

In the case where R ⁷ is a group —NHCONHR ¹⁴ (urea derivative), the reaction product from step (a) is reacted with an isocyanate R ¹⁴ NCO (Brown et al., JACS 1997, 119, 3288; option (iv) checking).

In the case where R ⁷ is a carbamate group or a urethane group —NHCOOR ¹⁴ , the reaction product from step (a) is reacted with an alcohol HOR ¹⁴ preactivated by carbonyldihydroxybenzotriazole ((HOBt) ₂ CO). (See Warass et al., LIPS 1998, 5, 125 ,; option (v)).

R ⁷ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group, a hetaryl group or a group —NH ₂ (ie, R ⁷ is —NR ¹² R ¹³ , In the case where the radicals R ¹² and R ¹³ are hydrogen atoms, step (b) is omitted (option (vi)) since no further derivatization is necessary.

  Step (c), ie, derivatization with an indole nitrogen atom, corresponds to the various options described below, as in step (b) described above.

In the above cases (i) to (v) in step (b), the deprotonation of the reaction product obtained in (b) is carried out with a base, such as NaH or NaHMDS, followed by the group R ¹ X [wherein X is a leaving group such as a halide atom, in particular a chloride atom] (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 the above case (vi) in step (b), ie when step (b) is omitted, as described above, the deprotonation of the reaction product obtained in (a) is a base, for example Carried out with NaH or NaHMDS and subsequently derivatized with the group R ¹ X, wherein X is a leaving group, for example a halide atom, in particular a chloride atom.

  Substantially finally, step (d) comprises desorbing the reaction product obtained in (c) from the solid phase SP. In the case of Wang resin, trityl resin, DHP resin and Rink amide resin, elimination of the reaction product obtained in (c) is performed using an acid, particularly TFA (trifluoroacetic acid). In the case of aminolytic desorption from the HMB resin, the desorption reagent used is, for example, ammonia in methanol. The desired product is then isolated by conventional methods.

  Embodiments of the production of the tetrahydrocarbazole derivative of the present invention are illustrated in detail below.

Example I.1. General Synthetic Methods for Compounds of the Invention A Coupling of carboxylic acid to Rink amide resin:
0.1 mmol Fmoc protected Rink amide resin (166 mg, load 0.6 mmol / g) is pre-swelled with 1.5 ml DMF for 20 minutes in a vessel with a bottom frit. After aspiration, 1.5 ml of 20% piperidine / DMF is added and stirred for 5 minutes. After aspiration, add an additional 1.5 ml of 20% piperidine / DMF and stir for 15 minutes. Following aspiration, wash 4 times with DMF. Then 675 μl of 0.267 M solution of Fmoc protected aminocarboxylic acid in DMF, 675 μl of HATU solution (0.267 M in DMF) and 150 μl of NMM solution (2.4 M in DMF) and 0.01 mmol DMAP And stir at 40 ° C. for 4 hours. After aspiration, the same reagent is added again and stirred at 40 ° C. for 4 hours. This is followed by aspiration and washing 4 times with DMF.

B Coupling of carboxylic acid to trityl resin:
2.98 mmol Fmoc protected aminocarboxylic acid was dissolved in 30 ml anhydrous dichloromethane, mixed with 14.3 mmol (2.45 ml) DIPEA and 2.98 mmol 2-chlorotrityl chloride resin ( 2 g, load 1.49 mmol / g (resin)). After shaking for 2 hours, the resin is filtered off with suction through a frit and washed 3 times with 20 ml of dichloromethane / MeOH / DIPEA 17: 2: 1. This is followed by washing 3 times with 20 ml of dichloromethane, 3 times with methanol and 3 times with 20 ml of ether and drying in vacuo. A resin having an aminocarboxylic acid loading of 0.5 to 1 mmol per gram of resin is obtained.

Coupling of C carboxylic acid to HMB resin:
21.3 mmol aminocarboxylic acid and 21.3 mmol HATU are dissolved in 60 ml DMF and mixed with 63.9 mmol (10.9 ml) DIPEA. After 5 minutes, 5 g of polystyrene-HMB resin (load 0.71 mmol / g (resin)) is added and shaken for 5 minutes at room temperature. Then 21.3 mmol (2.6 g) of DMAP is added and shaken for 1 hour at room temperature. The resin is subsequently filtered off with suction and washed once with 100 ml each of DMF, DCM and DMF. The resin is mixed with 100 ml of 10% Ac ₂ O (acetic anhydride) / DMF / 5% DMAP and shaken for 15 minutes. Following aspiration, it is washed 3 times with 100 ml DCM and ether each and dried in vacuo.

D Coupling of carboxylic acid to Wang resin:
54.6 mmol of carboxylic acid and 27.3 mmol (4.2 ml) of DIC are dissolved in 500 ml of anhydrous DCM and stirred at room temperature for 10 minutes. After filtering off the precipitated urea, the solution is evaporated to dryness and the residue is dissolved in 160 ml of anhydrous DMF. The solution is added to 4.55 mmol (5 g, loading 0.91 mmol / g (resin)) Wang resin pre-swelled in DMF and 4.55 mmol (556 mg) DMAP is added. After shaking for 1.5 hours at room temperature, the resin is filtered off with suction and taken up in 100 ml of 10% Ac ₂ O / DMF / 5% DMAP and shaken for 15 minutes. Following aspiration, it is washed 3 times with 100 ml DCM and ether each and dried in vacuo.

E Coupling of alcohol to DHP resin:
0.5 mmol DHP resin (0.5 g, loading density 1 mmol / g) is pre-swelled in 2 ml dichloroethane for 15 minutes. To this is added 2 ml of a 0.75 M alcohol / 0.37 M pyridinium paratoluenesulfonate solution and stirred at 80 ° C. for 16 hours. Following cooling to room temperature, 5 ml of pyridine is added, reversed gently and shaken and filtered with suction. Washing is performed twice with 5 ml each of DMF, DCM and hexane.

Deprotection of the Fmoc protecting group attached to the F resin:
1.5 ml of 20% piperidine / DMF is added to the Fmoc group bound to 0.1 mmole resin and stirred for 5 minutes. After aspiration, 1.5 ml of 20% piperidine / DMF is added again and stirred for 15 minutes. Following aspiration, wash 4 times with DMF.

G Coupling of a carboxylic acid with an amino function attached to the resin:
675 μl of 0.267 M Fmoc protected aminocarboxylic acid solution in DMF, 675 μl of HATU solution (0.267 M in DMF) and 150 μl of NMM solution (2.4 M in DMF) and 0.01 mmol of DMAP is added to the amino function bound to 0.1 mmol resin and stirred at 40 ° C. for 4 hours. After aspiration, the same reagent is added again and stirred at 40 ° C. for 4 hours. This is followed by aspiration and washing 4 times with DMF.

H Coupling of acetic acid with resin-attached amino function:
A solution of 1.5 ml 10% acetic anhydride in DMF is added to the amino functionality bound to 0.1 mmol resin and stirred for 15 minutes at room temperature. This is followed by aspiration and washing 4 times with DMF.

I Synthesis of tetrahydrocarbazole starting from chlorohexanone bound to a resin:
Prior to the reaction, 0.1 mmol of cyclohexanone resin is washed twice with 2 ml of DMF and twice with 2 ml of acetic acid. Then 1 ml of 0.5 M hydrazine / 0.5 M ZnCl ₂ in 1 ml DMF and 2 ml acetic acid is added to the resin and stirred at 70 ° C. for 20 hours. This is followed by washing twice with 2 ml acetic acid and 2 ml DMF.

Synthesis of sulfonamides starting from amides bound to J resin:
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 μl of 2.5 M NMM / 1 equivalent of 0.25 M DMAP in DMF are added to 0.1 mmol resin bound amine. Following agitation for 12 hours at 60 ° C., aspiration and coupling are repeated. Following aspiration, wash 4 times with 2000 ml DMF.

Synthesis of urea by reaction of amine and isocyanate bound to K resin:
2 ml of 0.5M isocyanate in DCM is added to 0.1 mmol resin bound amine and stirred at room temperature for 18 hours. Following aspiration, wash 4 times with DMF.

Synthesis of carbamate by reaction of amine bound to L resin with preactivated alcohol:
For preactivation, 0.4 M alcohol and 0.39 M dibenzotriazolyl carbonate and 0.39 M pyridine are stirred in DMF at 40 ° C. for 15 minutes. The amine bound to 1 mmol of resin is mixed with 1 ml of preactivated alcohol and 167 ml of 2.4 M NMM in DMF is added. Following agitation for 4 hours at 60 ° C., aspiration and washing 4 times with DMF.

Synthesis of N-alkylamines by N-alkylation of amines bound to M resin with alkyl halides and catalytic KI:
1 ml of 0.5 M halide / 0.05 M KI in DMF and 416 μl of 2.4 M DIPEA in DMF are added to 0.1 mmol resin bound amine and at 90 ° C. for 12 hours. Stir. After aspiration, the resin is washed with 2 ml DMF for 4 hours.

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

Desorption from O Wang resin, trityl resin, DHP resin, Rink amide resin:
2 ml of 95% TFA / 5% H ₂ O solution is added to 0.1 mmol resin and shaken at room temperature for 3 hours. The resin is then filtered off and washed with a further 2 ml of TFA. The combined TFA solution is evaporated to dryness and the crude product is obtained.

Aminolytic elimination from PHMB resin:
2 ml of DMF and 2 ml of 7M NH ₃ in methanol are added to 0.1 mmol of resin and stirred at room temperature for 18 hours. The resin is then filtered off and washed with DMF. The combined solution is evaporated to dryness and the crude product is obtained.

Preparation of the necessary starting compounds:
3-[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid 1
38.4 mmol (6.0 g) 4,4-ethylenedioxycyclohexanone and 39.8 mmol (4.3 g) phenylhydrazine are dissolved separately in 50 ml and 10 ml water, respectively, and then mixed. The milky emulsion obtained after 10 minutes of stirring is extracted 5 times with ethyl acetate, dried over MgSO ₄ and evaporated to dryness.

Yield: phenylhydrazone of crude orange oil 9.2g of 9.2g were dissolved at room temperature in toluene in 240 ml, and adding ZnCl ₂ newly grinding of 4.9 g. After refluxing in a water trap for 90 minutes, most of the toluene is distilled off, excess 2N NaOH is added and the mixture is extracted three times with ethyl acetate. The extract is washed with brine and dried over MgSO ₄ and the solvent is evaporated. The remaining black oil is purified on silica gel using ethyl acetate / hexane 1: 9.

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

60.2 mmol (11.1 g) of 1,2,4,9- tetrahydrospiro -3H- carbazol-3-one, of 8.3 g KCN and 22.0g of _{(NH 4)} 60 to 2 CO ₃ in 550ml Heat in 80% autoclaving in 80% ethanol for 3 hours. 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) 1,2,4,9-tetrahydrospiro [3H-carbazole-3,4'-imidazolidine] -2 ', 5'-dione Is heated together with 62 g Ba (OH) ₂ × 8H ₂ O in 145 ml H ₂ O at 150 ° C. for 13 hours. After cooling to room temperature, the viscous material is mixed with 37 g (NH ₄ ) ₂ CO ₃ with stirring and heated at 100 ° C. for 30 minutes. Following cooling to room temperature, it is filtered, washed with water and the filtrate is evaporated to dryness.

Yield: 7.7 g beige solid 26 mmol (5.8 g) 3-amino-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid in 26 ml 1N NaOH and 28 ml 26 mmol (8.76 g) Fmoc-ONSu in acetonitrile are combined at room temperature and diluted with 130 ml acetonitrile / H ₂ O 1: 1. After 2 hours, the pH is readjusted to 9 with NEt ₃ (1.5 ml) and the mixture is stirred overnight at room temperature. An additional 6.3 g (18.7 mmol) of Fmoc-ONSu dissolved in 19 ml of acetonitrile is then added and stirring is continued for 2 hours during pH adjustment. Following removal of acetonitrile by distillation, it is acidified with 0.01 M HCl and extracted with ethyl acetate. The extract is washed until neutral, dried over Na ₂ SO ₄ and evaporated to dryness in a rotary evaporator. Recrystallize from ether / hexane.

Yield: 10.7g
¹ H NMR (d ⁶ DMSO): δ = 2.07 ppm (m, 1H); 2.50 (m, 1H); 2.70 (bs; 2H); 3.04 (q, 2H); 4.17 (M, 2H); 4.28 (m, 2H); 6.92 (tr, 2H); 6.99 (tr, 2H); 7.23 (tr, 2H); 7.24-7.35 ( m, 3H); 7.38 (tr, 2H); 7.62 (s, 1H); 7.68 (dd, 2H); 7.87 (d, 2H); 10.71 (s, 1H)
Melting point: 119 ° C
Fractionation into two enantiomers by chiral HPLC.

(R) -3-[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid 1a
t _R = 6.4 min (Chiral Cell OD 10 μm LC50 250 × 4.6 cm, hexane / isopropanol 75:25, 80 ml / min)
(S) -3-[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid 1b
t _R = 7.5 min (Chiral Cell OD 10 μm LC50 250 × 4.6 cm, hexane / isopropanol 75:25, 80 ml / min)
1-[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] -4-oxocyclohexanecarboxylic acid 2
320 mmol (50 g) 4,4-ethylenedioxycyclohexanone was suspended in 800 ml 50% EtOH and 1500 mmol (144.5 g) (NH ₄ ) ₂ CO ₃ and 640 mmol (41.7 g). ) KCN. After stirring for 5 hours at 60 ° C., 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 4,4-1,4-dioxa-9,11-diazadispiro [4.2.4.2] tetradecane-10,12-dione 295 mmol (66.8 g) 4,4-1 , 4-Dioxa-9,11-diazadispiro [4.2.4.2] tetradecane-10,12-dione and 826 mmol (260.6 g) Ba (OH) ₂ × 8H ₂ O in 2.5 liters 150 Stir for 6 hours in an autoclave at ° C. After cooling to room temperature, 1032 mmol (99.2 g of (NH ₄ ) ₂ CO ₃ is added to the solution and stirred for 1 hour at 60 ° C. The suspension is filtered and washed and the The filtrate is lyophilized and the residue is recrystallized from H ₂ O / 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-1,4-dioxaspiro in 213 ml of 1N NaOH Combine [4,5] decane-8-carboxylic acid and 213 mmol (71.9 g) Fmoc-ONSu in 240 ml acetonitrile and dilute with 1000 ml acetonitrile / H ₂ O 1: 1. Stir overnight at room temperature following adjusting the pH to 9. Following removal of acetonitrile in a rotary evaporator, it is acidified with 0.01 M HCl and extracted with ethyl acetate. The extract is washed until neutral, dried over Na ₂ SO ₄ and evaporated to dryness. The residue is recrystallized from ethyl acetate / hexane.

Yield: 79.0 g of 8-[[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -1,4-dioxaspiro [4,5] decane-8-carboxylic acid 187 mmol (79 g) of 8-[[ (9H-Fluoren-9-ylmethoxy) carbonyl] amino-1,4-dioxaspiro [4,5] decane-8-carboxylic acid is taken up in 3.5 l acetone / 0.1 M HCl 1: 1 and at room temperature Stir for 4 hours. Acetone is removed by stripping in a rotary evaporator and the precipitated product is filtered off, washed with water and dried.

Yield: 68.7 g of compound 2.
¹ H NMR (d ⁶ DMSO): δ = 1.52-1.73 (m, 4H); 1.82-2.14 (m, 4H); 4.27 (m, 3H); 7.85 ( tr, 2H); 7.42 (tr, 2H); 7.67 (s, 1H); 7.75 (d, 2H); 7.91 (d, 2H)
Melting point: 157 ° C
4-Oxocyclohexanecarboxylic acid 3
20 mmol (3.4 g) of ethyl 4-oxocyclohexanecarboxylate are suspended in 40 ml of 2% H ₂ SO ₄ and stirred at 90 ° C. for 2 hours. This is followed by extraction with ethyl acetate for 4 hours, drying with Na ₂ SO ₄ and removal of the solvent. Recrystallization from ether / hexane gives 2.9 g of white solid 3.
¹ H NMR (d ⁶ DMSO): δ = 1.72 (m, 2H); 2.08-2.18 (m, 2H); 2.19-2.47 (m, 4H); 2.72 ( m, 1H); 12.23 (bs, 1H)
4-chloro-3-[[(phenylamino) carbonyl] amino] benzeneacetic acid 4
18.55 mmol (2.21 g) SOCl ₂ is slowly added to 18.55 mmol (4 g) 4-chloro-3-nitrobenzeneacetic acid in 50 ml MeOH with ice cooling and stirring. After stirring for 30 minutes, the mixture is allowed to warm to room temperature and an additional 3.71 mmol (0.44 g) of SOCl ₂ is added. Following stirring overnight, heat to reflux for 30 minutes. Following removal of the solvent by stripping, it is recrystallized from ether / hexane.

Yield: 3.43 g of methyl 4-chloro-3-nitrobenzeneacetate 13.07 mmol (3.0 g) of methyl 4-chloro-3-nitrobenzeneacetate as a yellowish solid and 198.8 mmol (13.0 g) Of Zn powder is heated to reflux in 500 ml of MeOH for 10 minutes. Then, under reflux, 13 ml of concentrated HCl are added dropwise and reflux is continued for 30 minutes. The suspension is filtered hot, the methanol is distilled off and the residue is adjusted to pH 14 with NaHCO ₃ solution. Extraction with ethyl acetate, drying over Na ₂ SO ₄ and removal of the solvent by distillation gives 2.3 g of methyl 3-amino-4-chlorobenzene acetate as a beige solid.

2.08 mmol (415 mg) methyl 3-amino-4-chlorobenzeneacetate is dissolved in 40 ml DCM and 0.83 mmol (246.3 mg) triphosgene and 0.6 ml pyridine are added at 0 ° C. . After stirring for 1 hour at 0 ° C., 10.4 mmol (1.11 g) of benzylamine is added and stirring is continued overnight at room temperature. Extraction with DCM / H ₂ O, 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 Is taken up in 10 ml of methanol and 6 mmol of 1N NaOH are added. After stirring for 2 hours at room temperature, the methanol is distilled off and the residue is acidified to pH 2-3 with 1M HCl. Extraction with ethyl acetate and drying over Na ₂ SO ₄ and removal of the solvent. Recrystallization is performed from boiling isopropanol.

Yield: 830 mg of white solid 4
¹ H NMR (d ⁶ DMSO): δ = 3.57 (s, 2H); 6.92 (d, 1H); 6.99 (tr, 1H); 7.35-7.50 (m, 3H) 8.10 (s, 1H); 8.30 (s, 1H); 9.42 (s, 1H); 12.40 (bs, 1H);
4-Chloro-3-[[[(phenylmethyl) amino] carbonyl] amino] benzeneacetic acid 5
2.08 mmol (415 mg) of methyl 3-amino-4-chlorobenzeneacetate is mixed with 10.4 mmol (969 mg) of the aniline described as 4 and worked up in the same way.

Yield: 662 mg of solid For ester degradation, 2.47 mmol (790 mg) of methyl 4-chloro-3-[[[(phenylmethyl) amino] carbonyl] amino] benzeneacetate with 1N NaOH as described above. Hydrolyze in the same way. Product 5 is obtained without recrystallization.

Yield: 693 mg of yellowish solid ES-MS: 319 (M + H ^< + ^> )
4-Chloro-3-[[(4-pyridinylamino) carbonyl] amino] benzeneacetic acid 6
2.08 mmol (415 mg) of methyl 3-amino-4-chlorobenzeneacetate is mixed with 10.4 mmol (979 mg) of 4-aminopyridine described as 4 and worked up in the same way.

Yield: 664 mg of solid For ester degradation 2.63 mmol (840 mg) of methyl 4-chloro-3-[[(4-pyridinylamino) carbonyl] amino] benzeneacetate with 1N NaOH as above. Hydrolyzes. The product 6 is obtained without recrystallization.

Yield: 481 mg of yellowish solid
¹ H NMR (d ⁶ DMSO): δ = 3.57 (s, 2H); 6.94 (d, 1H); 7.40 (m, 3H); 8.05 (s, 1H); 8.35 (D, 2H); 8.50 (s, 1H); 9.92 (s, 1H); 12.40 (bs, 1H)
4-Chloro-3-[[(2-pyridinylamino) carbonyl] amino] benzeneacetic acid 7
2.08 mmol (415 mg) of methyl 3-amino-4-chlorobenzeneacetate is mixed with 10.4 mmol (979 mg) of 2-aminopyridine described as 4 and worked up in the same way.

Yield: 617 mg of solid For ester degradation, 2.47 mmol (790 mg) of methyl 4-chloro-3-[[(2-pyridinylamino) carbonyl] amino] benzeneacetate with 1N NaOH as in the previous method. Hydrolyzes. Product 7 is obtained without recrystallization.

Yield: 693 mg of yellowish solid
¹ H NMR (d ⁶ DMSO): δ = 3.59 (s, 2H); (dd, 1H); 7.03 (dd, 1H); 7.22 (d, 1H); 7.42 (d, 7.78 (dtr, 1H); 8.29 (m, 2H); 10.02 (s, 1H); 11.82 (bs, 1H); 12.50 (s, 1H)
II. Examples of Compound (I) of the Invention Example 1:
0.3 mmol (42.6 mg) 4-oxocyclohexanecarboxylic acid was dissolved in 1 ml acetic acid and 0.3 mmol (43.3 g) phenylhydrazine hydrochloride and 0.3 mmol in 1 ml acetic acid. It added to a suspension of ZnCl ₂ in (40.0 mg). Following stirring for 20 hours at 70 ° C., it is diluted with 20 ml of water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried over Na ₂ SO ₄ and evaporated to dryness.

Yield: 65.6 mg (100%) white solid Name: 2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid Number: 8
M _{actual measurement value} : 215
M _{calculated value} : 215.2507
The item headings introduced here (name, compound number, M _{measured value} (measured molecular weight), M _{calculated value} (calculated molecular weight)) are also applied to the following examples. Therefore, it does not repeat.

Example 2:
The synthesis is carried out by methods A, I and O on a scale of 0.2 mmol.

2,3,4,9-Tetrahydro-1H-carbazole-3-carboxamide 9
214
214.2666
Example 3:
The synthesis is carried out by methods A, F, G, I and O on a 0.2 mmol scale.

N-[(1S) -1- (aminocarbonyl) -2-methylpropyl]-(3S) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 10a
314
313.3987
N-[(1S) -1- (aminocarbonyl) -2-methylpropyl]-(3R) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 10b
314
313.3987
N- (2-amino-2-oxoethyl) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 11
271
271.3183
Example 4:
The synthesis is carried out by methods D, F, G, F, G, I and O on a scale of 0.2 mmol.

N-[(3S)-(2,3,4,9-tetrahydro-1H-carbazol-3-yl) carbonyl] -L-valyl-L-glutamine 12a
442
442.513
N-[(3R)-(2,3,4,9-tetrahydro-1H-carbazol-3-yl) carbonyl] -L-valyl-L-glutamine, isomer B
12b
442
442.513
Example 5:
The synthesis is carried out by methods D, F, G, I, F and O on a scale of 0.2 mmol.

N-[[(3S) -3-Amino-2,3,4,9-tetrahydro-1H-carbazol-3-yl) carbonyl] -L-alanine 13
301
301.3441
Example 6:
0.1 mmol carboxylic acid, 0.1 mmol HOBt and 0.15 mmol amine component were dissolved in 15 ml anhydrous DMF (also THF, DCM) and 0.5 ml with ice cooling and stirring. Add mmol NMM. After about 15 minutes, 0.15 mmol of EDCI × HCl is added and the mixture is stirred for 1 hour, warmed to room temperature and stirred overnight. For workup, the solvent is removed by stripping and the product is dissolved in ethyl acetate and washed twice with 0.1 N HCl and NaCl saturated solutions, respectively. Following drying of the solvent and stripping removal, recrystallization is performed as necessary.

9H-Fluoren-9-ylmethyl [(3S) -3-[[[(4-bromophenyl) methyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbamate 14
620
620.5439
Methyl N-[[(3S) -3-[[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L- Alaninate 15
537
537.6129
Example 7:
The synthesis is carried out by methods A, F, G, F, G, F, G and O on a 0.2 mmol scale.

N-[[(3R) -3-[[(2S, 3S) -2-[[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -3-methyl-1-oxopentyl] amino] -2, 3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 16
779
777.9178
N-[[(3S) -3-[[(2S, 3S) -2-[[(9H-fluoren-9-ylmethoxy) carbonyl] amino] -3-methyl-1-oxopentyl] amino] -2, 3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 17
779
777.9178
N-[[(3R) -2,3,4,9-tetrahydro-3-[(1-oxo-2,3-diphenylpropyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl -L-Aspartamide 18
651
650.7758
N-[[(3S) -2,3,4,9-tetrahydro-3-[(1-oxo-2,3-diphenylpropyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl -L-aspartamide, isomer A
19
651
650.7758
N-[[(3S) -2,3,4,9-tetrahydro-3-[(1-oxo-2,3-diphenylpropyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl -L-aspartamide, isomer B
20
651
650.7758
N-[[(3S) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[(1-oxo-3-phenylpropyl) amino ] Pentyl] amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 21
688
687.8371
N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[(1-oxo-3-phenylpropyl) amino ] Pentyl] amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 22
688
687.8371
N-[[(3S) -2,3,4,9-tetrahydro-3-[[(2S) -1-oxo-2-[[(phenylmethoxy) carbonyl] amino] propyl] amino] -1H-carbazole -3-yl] carbonyl] -L-valyl-L-aspartamide 23
648
647.7289
N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S) -1-oxo-2-[[(phenylmethoxy) carbonyl] amino] propyl] amino] -1H-carbazole -3-yl] carbonyl] -L-valyl-L-aspartamide 24
648
647.7289
N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -L-alanyl-L-aspartamide 25
662
6611.7557
N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-alaninamide 26
647
6466.7844
N-[[(3S) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -D-valyl-L-aspartamide 27
690
689.8093
N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -D-valyl-L-aspartamide 28
690
689.8093
N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-D-aspartamide 29
690
689.8093
N-[[(3S) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-D-aspartamide 30
690
689.8093
N-[[(3S) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -L-alanyl-L-aspartamide 31
662
6611.7557
N-[[(3S) -2,3,4,9-tetrahydro-3-[(phenylacetyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 32
651
560.6514
N-[[(3R) -2,3,4,9-tetrahydro-3-[(1-oxo-3-phenylpropyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L -Aspartamide 33
575
574.6782
N-[[(3S) -2,3,4,9-tetrahydro-3-[(1-oxo-3-phenylpropyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L -Aspartamide 34
575
574.6782
N-[[(3S) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-alaninamide 35
647
6466.7844
N-[[(3R) -2,3,4,9-tetrahydro-3-[(phenylacetyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 36
561
560.6514
N-[[(3R) -2,3,4,9-tetrahydro-3-[(1-oxo-4-phenylbutyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L -Aspartamide 37
589
588.705
N-[[(3S) -2,3,4,9-tetrahydro-3-[(1-oxo-4-phenylbutyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L -Aspartamide 38
589
588.705
N-[[(3R) -3-[(diphenylacetyl) amino] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 39
637
636.749
N-[[(3S) -3-[(diphenylacetyl) amino] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 40
637
636.749
N-[[(3R) -2,3,4,9-tetrahydro-3-[(1-oxo-2-phenylpropyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L -Aspartamide, isomer A
41
575
574.6782
N-[[(3R) -2,3,4,9-tetrahydro-3-[(3-methyl-1-oxo-2-phenylpentyl) amino] -1H-carbazol-3-yl] carbonyl] -L -Valyl-L-aspartamide, isomer B
42
617
616.7586
N-[[(3S) -2,3,4,9-tetrahydro-3-[(3-methyl-1-oxo-2-phenylpentyl) amino] -1H-carbazol-3-yl] carbonyl] -L -Valyl-L-aspartamide, isomer A
43
617
616.7586
N-[[(3S) -2,3,4,9-tetrahydro-3-[(3-methyl-1-oxo-2-phenylpentyl) amino] -1H-carbazol-3-yl] carbonyl] -L -Valyl-L-aspartamide, isomer B
44
617
616.7586
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1-[[[4- (aminocarbonyl) phenyl] amino] carbonyl] -2-methylpropyl] Amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 45
695
694.8284
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1-[[[4- (aminocarbonyl) phenyl] amino] carbonyl] -2-methylpropyl] Amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 46
695
694.8284
N-[[(3S) -2,3,4,9-tetrahydro-3-[(3-methyl-1-oxo-2-phenylbutyl) amino] -1H-carbazol-3-yl] carbonyl] -L -Valyl-L-aspartamide, isomer A
47
603
602.7318
N-[[(3S) -2,3,4,9-tetrahydro-3-[(3-methyl-1-oxo-2-phenylbutyl) amino] -1H-carbazol-3-yl] carbonyl] -L -Valyl-L-aspartamide, isomer B
48
603
602.7318
N-[[(3R) -2,3,4,9-tetrahydro-3-[(3-methyl-1-oxo-2-phenylbutyl) amino] -1H-carbazol-3-yl] carbonyl] -L -Valyl-L-aspartamide 49
603
602.7318
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1-[[[[4- (aminocarbonyl) cyclohexyl] methyl] amino] carbonyl] -2- Methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 50
715
714.9026
N-[[(3R) -2,3,4,9-tetrahydro-3-[[(3-phenoxyphenyl) acetyl] amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L- Aspartamide 51
653
652.748
N-[[(3S) -2,3,4,9-tetrahydro-3-[[(3-phenoxyphenyl) acetyl] amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L- Aspartamide 52
653
652.748
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1-[[[[3- (aminocarbonyl) phenyl] methyl] amino] carbonyl] -2- Methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 53
709
708.8552
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1-[[[[3- (aminocarbonyl) phenyl] methyl] amino] carbonyl] -2- Methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 54
709
708.8552
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(2R) -1-oxo-2-[( 1-oxo-3-phenylpropyl) amino] -3-phenylpropyl] amino] -1H-carbazole-3-carboxamide 55
608
6077.7509
N-[[(3S) -2,3,4,9-tetrahydro-3-[(1-oxo-2-phenylpropyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L -Aspartamide 56
575
574.6782
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1-[[[[4- (aminocarbonyl) cyclohexyl] methyl] amino] carbonyl] -2- Methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 57
715
714.9026
Example 8:
The synthesis is carried out by methods A, F, G, F, G and O on a scale of 0.2 mmol.

Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-Tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 58
576
575.7059
N-[[(3S) -3-[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl -L-Aspartamide 59
665
664.759
N-[[(3R) -3-[[(9H-Fluoren-9-ylmethoxy) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl -L-Aspartamide 60
665
664.759
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-Tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 61
576
575.7059
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[4- (aminocarbonyl) phenyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazole- 3-yl] amino] carbonyl] -2-methylbutyl] carbamate 62
596
595.6963
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[4- (aminocarbonyl) phenyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazole- 3-yl] amino] carbonyl] -2-methylbutyl] carbamate 63
596
595.6963
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S, 2S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -2,3,4 , 9-Tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 64
590
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S, 2S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -2,3,4 , 9-Tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 65
590
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -2-amino-2-oxo-1- (phenylmethyl) ethyl] amino] carbonyl] -2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 66
623
623.7499
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -2-amino-2-oxo-1- (phenylmethyl) ethyl] amino] carbonyl] -2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 67
623
623.7499
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1-oxo-2-phenylpropyl) amino]- 1H-carbazole-3-carboxamide 68
460
460.5748
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[[3- (aminocarbonyl) phenyl] methyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H -Carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 69
610
609.7231
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[[3- (aminocarbonyl) phenyl] methyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H -Carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 70
610
609.7231
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[[4- (aminocarbonyl) cyclohexyl] methyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H -Carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 71
615
615.7705
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[[4- (aminocarbonyl) cyclohexyl] methyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H -Carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 72
615
615.7705
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[3- (aminocarbonyl) phenyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazole- 3-yl] amino] carbonyl] -2-methylbutyl] carbamate 73
596
595.6963
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3- (aminocarbonyl) phenyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino ] Carbonyl] -2-methylbutyl] carbamate 74
596
595.6963
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -2-amino-2-oxo-1-phenylethyl] amino] carbonyl] -2,3,4 , 9-Tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 75
610
609.7231
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1R) -2-amino-2-oxo-1-phenylethyl] amino] carbonyl] -2,3,4 , 9-Tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 76
810
609.7231
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2-amino-2-oxo-1-phenylethyl) amino] carbonyl] -2,3,4,9-tetrahydro -1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate, isomer A
77
609
609.7231
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2-amino-2-oxo-1-phenylethyl) amino] carbonyl] -2,3,4,9-tetrahydro -1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate, isomer B
78
609
609.7231
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(3-hydroxyphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide 79
462
462.547
(3R) -3-[[[3- (Acetyloxy) phenyl] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9- Tetrahydro-1H-carbazole-3-carboxamide 80
504
504.5838
3- [2-[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazole -3-yl] amino] -2-oxoethyl] phenyl-3-hydroxybenzeneacetate 81
597
596.6804
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(hydroxyphenylacetyl) amino] -1H-carbazole-3 -Carboxamide 82
462
462.547
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-bromophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide 83
525
525.4441
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H- Carbazole-3-carboxamide 84
481
480.9931
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(3-chloro-4-hydroxyphenyl) acetyl] amino] -2,3,4,9 -Tetrahydro-1H-carbazole-3-carboxamide 85
497
496.99921
(3R) -3-[[[4- (Acetyloxy) -3-chlorophenyl] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4 , 9-Tetrahydro-1H-carbazole-3-carboxamide 86
539
539.00289
(3R) -N-[(1S) -1- (Aminocarbonyl) -2-methylpropyl] -3-[[(3-fluoro-4-hydroxyphenyl) acetyl] amino] -2,3,4,9 -Tetrahydro-1H-carbazole-3-carboxamide 87
481
480.5371
(3R) -3-[[[4- (Acetyloxy) -3-fluorophenyl] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3 4,9-Tetrahydro-1H-carbazole-3-carboxamide 88
523
522.5739
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-nitrophenyl) acetyl] amino] -1H -Carbazole-3-carboxamide 89
492
491.5451
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2,4-dichlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro- 1H-carbazole-3-carboxamide 90
515
515.4382
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-fluorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide 91
464
464.5381
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-hydroxyphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide 92
462
462.547
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2-bromophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide 93
525
525.4441
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(2-nitrophenyl) acetyl] amino] -1H -Carbazole-3-carboxamide 94
491
491.5451
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(3-nitrophenyl) acetyl] amino] -1H -Carbazole-3-carboxamide 95
491
491.5451
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(3-bromophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide 96
525
525.4441
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2-chloro-4-fluorophenyl) acetyl] amino] -2,3,4,9 -Tetrahydro-1H-carbazole-3-carboxamide 97
499
498.9832
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[([1,1′-biphenyl] -4-ylacetyl) amino] -2,3,4, 9-Tetrahydro-1H-carbazole-3-carboxamide 98
523
522.456
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(3,5-dimethylphenyl) acetyl] amino] -2,3,4,9-tetrahydro -1H-carbazole-3-carboxamide 99
475
4744.6016
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[(1,3-benzodioxol-5-ylacetyl) amino] -2,3,4 9-Tetrahydro-1H-carbazole-3-carboxamide 100
490
490.557
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(3-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H- Carbazole-3-carboxamide 101
481
480.9931
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(3-methylphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide 102
461
460.5748
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2-fluorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide 103
464
464.5381
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(2-methylphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide 104
461
460.5748
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[4- (1-methylethyl) phenyl] acetyl Amino] -1H-carbazole-3-carboxamide 105
489
488.6284
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[4- (dimethylamino) phenyl] acetyl] amino] -2,3,4,9- Tetrahydro-1H-carbazole-3-carboxamide 106
490
489.6165
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[4- (methylsulfonyl) phenyl] acetyl] amino ] -1H-carbazole-3-carboxamide 107
524
524.6388
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(3-fluoro-4-methylphenyl) acetyl] amino] -2,3,4,9 -Tetrahydro-1H-carbazole-3-carboxamide 108
478
478.5649
Example 9:
The synthesis is carried out by methods B, F, G, F, G, F, G and O on a 0.2 mmol scale.

N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-asparagine 109
691
690.7934
N-[[(3S) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-asparagine 110
691
690.7934
Example 10:
The synthesis is carried out by methods A, F, G, F, G, F, G, F, H and O on a 0.2 mmol scale.

N-[[(3R) -3-[[(2S, 3S) -2- (acetylamino) -3-methyl-1-oxopentyl] amino] -2,3,4,9-tetrahydro-1H-carbazole -3-yl] carbonyl] -L-valyl-L-aspartamide 111
598
597.7127
N-[[(3S) -3-[[(2S, 3S) -2- (acetylamino) -3-methyl-1-oxopentyl] amino] -2,3,4,9-tetrahydro-1H-carbazole -3-yl] carbonyl] -L-valyl-L-aspartamide 112
598
597.7127
N-[[(3R) -3-[[(2R, 3R) -2- (acetylamino) -3-methyl-1-oxopentyl] amino] -2,3,4,9-tetrahydro-1H-carbazole -3-yl] carbonyl] -L-valyl-L-aspartamide 113
598
597.7127
N-[[(3S) -3-[[(2R, 3R) -2- (acetylamino) -3-methyl-1-oxopentyl] amino] -2,3,4,9-tetrahydro-1H-carbazole -3-yl] carbonyl] -L-valyl-L-aspartamide 114
598
597.7127
Example 11:
The synthesis is carried out by methods A, F, G, F, G, F, H and O on a scale of 0.2 mmol.

N-[[(3R) -3- (acetylamino) -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 115
484
484.5538
N-[[(3S) -3- (acetylamino) -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 116
484
484.5538
N-[[(3S) -3- (acetylamino) -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -D-valyl-L-aspartamide 117
484
484.5538
N-[[(3S) -3- (acetylamino) -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-D-aspartamide 118
484
484.5539
Example 12:
The synthesis is carried out by methods A, F, G and O on a 0.2 mmol scale.

Phenylmethyl [(1S, 2S) -1-[[[(3R) -3- (aminocarbonyl) -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2- Methylbutyl] carbamate 119
476
476.5738
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3- (aminocarbonyl) -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2- Methylbutyl] carbamate 120
476
476.5738
Example 13:
The synthesis is carried out by methods A, F, G, F, G, F, G, F, G and O on a 0.2 mmol scale.

N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S) -1-oxo-2-[(1-oxo-3-phenylpropyl) amino] -3-phenylpropyl Amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 121
722
721.8543
N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2R, 3R) -3-methyl-1-oxo-2-[(1-oxo-3-phenylpropyl) amino ] Pentyl] amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 122
688
687.8371
Example 14:
The synthesis is carried out by methods D, F, G, F, G and O on a scale of 0.2 mmol.

N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl-L-valine, N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S) -3-methyl-1-oxo -2-[[(Phenylmethoxy) carbonyl] amino] pentyl] amino] -1H-carbazol-3-yl] carbonyl] -L-valine 123
577
576.69
N-[[(3S) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] Amino] -1H-carbazol-3-yl] carbonyl-L-valine 124
577
576.69
Example 15:
The synthesis is performed by methods C, F, G, F, G, F, G and P on a 0.2 mmol scale.

N-[[(3R) -3-[[(2S, 3S) -2-[[(1,1-dimethylethoxy) carbonyl] amino] -3-methyl-1-oxopentyl] amino] -2,3 , 4,9-Tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 125
656
655.7921
Example 16:
The synthesis is carried out by methods A, F, G, F, G, F and O on a scale of 0.2 mmol.

N-[[(3S) -3-Amino-2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 126
442
442.517
N-[[(3R) -3-Amino-2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide 127
442
442.517
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2S, 3S) -2-amino-3-methyl-1-oxopentyl] amino]- 2,3,4,9-Tetrahydro-1H-carbazole-3-carboxamide 128
441
441.5725
Example 17:
The synthesis is performed by methods D, F, G, F, G, F, H and O on a 0.2 mmol scale.

N-[[(3S) -3- (acetylamino) -2,3,4,9-tetrahydro-1H-carbazol-3-yl] carbonyl] -L-valyl-L-asparagine 129
485
485.5379
Example 18:
The synthesis is carried out by methods A, F, G, F, H and O on a 0.2 mmol scale.

(3R) -3- (acetylamino) -N-[(1S) -2-amino-2-oxo-1- (phenylmethyl) ethyl] -2,3,4,9-tetrahydro-1H-carbazole-3 Carboxamide 130
418
418.4944
(3S) -3- (acetylamino) -N-[(1S) -2-amino-2-oxo-1- (phenylmethyl) ethyl] -2,3,4,9-tetrahydro-1H-carbazole-3 Carboxamide 131
418
418.4944
Example 19:
The synthesis is carried out by methods B, F, G and O on a 0.2 mmol scale.

(3S) -2,3,4,9-Tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] amino] -1H -Carbazole-3-carboxylic acid 132
478
477.5579
Example 20:
The synthesis is carried out by methods B, F, G, F and O on a scale of 0.2 mmol.

(3S) -3-[[[(2,2-Diphenylethyl) amino] acetyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid 134
468
467.5661
Example 21:
The synthesis is carried out by methods A, F, G, F, H and O on a 0.2 mmol scale.

(3S) -3- (acetylamino) -N-[[3- (aminocarbonyl) phenyl] methyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 135
404
404.4676
(3S) -3- (acetylamino) -N-[[4- (aminocarbonyl) cyclohexyl] methyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 136
410
410.515
(3R) -3- (acetylamino) -N-[[4- (aminocarbonyl) cyclohexyl] methyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 137
410
410.515
(3S) -3- (acetylamino) -N-[(1S) -2-amino-2-oxo-1-phenylethyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 138
404
404.4676
Example 22:
The synthesis is carried out according to Examples 18 and 6 on a 0.2 mmol scale.

Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[(ethylamino) carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-Methylbutyl] carbamate 139
505
504.6274
Phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3R) -2,3,4,9-tetrahydro-3-[[(1-methylethyl) amino] carbonyl] -1H-carbazole -3-yl] amino] carbonyl] butyl] carbamate 140
519
518.6542
Phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3R) -2,3,4,9-tetrahydro-3-[[(2-methylpropyl) amino] carbonyl] -1H-carbazole -3-yl] amino] carbonyl] butyl] carbamate 141
533
532.681
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2,2-dimethylpropyl) amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazole-3 -Yl] amino] carbonyl] -2-methylbutyl] carbamate 142
547
546.7078
Phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3R) -2,3,4,9-tetrahydro-3-[(phenylamino) carbonyl] -1H-carbazol-3-yl] Amino] carbonyl] butyl] carbamate 143
553
552.6714
Phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3R) -2,3,4,9-tetrahydro-3-[[(phenylmethyl) amino] carbonyl] -1H-carbazole-3 -Yl] amino] carbonyl] butyl] carbamate 144
567
566.66982
Phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3R) -2,3,4,9-tetrahydro-3-[[(2-phenylethyl) amino] carbonyl] -1H-carbazole -3-yl] amino] carbonyl] butyl] carbamate 145
581
580.725
Phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3R) -2,3,4,9-tetrahydro-3-[[(3-phenylpropyl) amino] carbonyl] -1H-carbazole -3-yl] amino] carbonyl] butyl] carbamate 146
595
594.7518
Example 23:
The synthesis is carried out by methods A, F, G, I, F, G and O on a 0.2 mmol scale.

Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-8-methoxy-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
147a
606
605.7317
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-8-methoxy-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
147b
606
605.7317
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6-chloro-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
148a
610
610.151
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6-chloro-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
148b
610
610.151
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -8-chloro-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
180a
610
610.151
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -8-chloro-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
180b
610
610.151
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-Tetrahydro-8- (trifluoromethyl) -1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
149a
644
643.703
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-8- (trifluoromethyl) -1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
149b
644
643.703
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-8-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
150a
590
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-8-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
150b
590
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-5-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
151a
590
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-5-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
151b
590
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-7-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
151c
590
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-7-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
151d
590
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -5-chloro-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
152a
610
610.151
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -7-chloro-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
152b
610
610.151
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -7-chloro-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
152c
610
610.151
(3R) -3-[[[(1S) -1- (Aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-3-[[(2S, 3S)- 3-Methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] amino] -1H-carbazole-8-carboxylic acid
153a
620
619.7149
(3S) -3-[[[(1S) -1- (Aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-3-[[(2S, 3S)- 3-Methyl-1-oxo-2-[[(phenylmethoxy) carbonyl] amino] pentyl] amino] -1H-carbazole-8-carboxylic acid
153b
620
619.7149
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6-fluoro-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
154a
593
593.696
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6-fluoro-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
154b
593
593.696
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-6-methoxy-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
155a
605
605.7317
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-6-methoxy-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
155b
605
605.7317
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-6-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
156a
589
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-6-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
156b
589
589.7327
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-6-nitro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
157a
621
620.703
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-6-nitro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
157b
621
620.703
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -4-[(aminoiminomethyl) amino] butyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
158
633
632.7616
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(3-pyridinylacetyl) amino] -1H- Carbazole-3-carboxamide
159a
447
447.5361
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(3-pyridinylacetyl) amino] -1H- Carbazole-3-carboxamide
159b
447
447.5361
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1-naphthalenylacetyl) amino] -1H- Carbazole-3-carboxamide
160a
496
496.6078
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1-naphthalenylacetyl) amino] -1H- Carbazole-3-carboxamide
160b
496
496.6078
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(2-naphthalenylacetyl) amino] -1H- Carbazole-3-carboxamide
161a
496
496.6078
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(2-naphthalenylacetyl) amino] -1H- Carbazole-3-carboxamide
161b
496
496.6078
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2,3-dihydro-1H-inden-1-yl) carbonyl] amino] -2, 3,4,9-tetrahydro-1H-carbazole-3-carboxamide
162a
472
472.5858
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2,3-dihydro-1H-inden-1-yl) carbonyl] amino] -2, 3,4,9-tetrahydro-1H-carbazole-3-carboxamide
162b
472
472.5858
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1H-imidazol-4-ylacetyl) amino] -1H -Carbazole-3-carboxamide
163a
436
436.5132
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1H-imidazol-4-ylacetyl) amino] -1H -Carbazole-3-carboxamide
163b
436
436.5132
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1H-indol-3-ylacetyl) amino] -1H -Carbazole-3-carboxamide
164a
486
485.5849
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1H-indol-3-ylacetyl) amino] -1H -Carbazole-3-carboxamide
164b
486
485.5849
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-methylphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide
165a
461
460.5748
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-methylphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide
165b
461
460.5748
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[4- (trifluoromethyl) phenyl] acetyl] Amino] -1H-carbazole-3-carboxamide
166a
515
514.5451
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[4- (trifluoromethyl) phenyl] acetyl] Amino] -1H-carbazole-3-carboxamide
166b
515
514.5451
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H- Carbazole-3-carboxamide
167a
481
480.9931
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H- Carbazole-3-carboxamide
167b
481
480.9931
(3S) -N-[(1S)-(Aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[3- (trifluoromethyl) phenyl] acetyl] amino] -1H-carbazole-3-carboxamide
168a
515
514.5451
(3R) -N-[(1S)-(Aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[3- (trifluoromethyl) phenyl] acetyl] amino] -1H-carbazole-3-carboxamide
168b
515
514.5451
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(3-fluorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide
169a
465
464.5381
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(3-fluorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide
169b
465
464.5381
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(3-methoxyphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide
170a
477
476.5738
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(3-methoxyphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide
170b
477
476.5738
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(2-methoxyphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide
171a
477
476.5738
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(2-methoxyphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide
171b
477
476.5738
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[3- (4-fluorophenyl) -1-oxopropyl] amino-2,3,4, 9-Tetrahydro-1H-carbazole-3-carboxamide
172a
479
478.5649
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[3- (4-fluorophenyl) -1-oxopropyl] amino-2,3,4, 9-Tetrahydro-1H-carbazole-3-carboxamide
172b
479
478.5649
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[3- (3,4-difluorophenyl) -1-oxopropyl] amino] -2,3 , 4,9-Tetrahydro-1H-carbazole-3-carboxamide
173a
497
496.5555
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[3- (3,4-difluorophenyl) -1-oxopropyl] amino] -2,3 , 4,9-Tetrahydro-1H-carbazole-3-carboxamide
173b
497
496.5555
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[3- [3,4-bis (trifluoromethyl) phenyl] -1-oxopropyl] amino ] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
174a
593
592.6605
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[3- [3,4-bis (trifluoromethyl) phenyl] -1-oxopropyl] amino ] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
174b
593
592.6605
N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-methoxyphenyl) acetyl] amino] -1H-carbazole-3 -Carboxamide
175
477
476.5738
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[3- (4-methoxyphenyl) -1-oxo Propyl] amino] -1H-carbazole-3-carboxamide
176a
491
490.6006
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[3- (4-methoxyphenyl) -1-oxo Propyl] amino] -1H-carbazole-3-carboxamide
176b
491
490.6006
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[3- (2-methoxyphenyl) -1-oxo Propyl] amino] -1H-carbazole-3-carboxamide
177a
491
490.6006
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[3- (2-methoxyphenyl) -1-oxo Propyl] amino] -1H-carbazole-3-carboxamide
177b
491
490.6006
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[3- (1H-indol-3-yl)- 1-oxopropyl] amino] -1H-carbazole-3-carboxamide
178a
500
499.6117
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[3- (1H-indol-3-yl)- 1-oxopropyl] amino] -1H-carbazole-3-carboxamide
178b
500
499.6117
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1-oxo-6-phenylhexyl) amino]- 1H-carbazole-3-carboxamide
179a
503
502.6655
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1-oxo-6-phenylhexyl) amino]- 1H-carbazole-3-carboxamide
179b
503
502.6655
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2S) -2- (aminocarbonyl) -1-pyrrolidinyl] carbonyl] -2,3,4,9-tetrahydro- 1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
181a
574
573.6901
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[(2S) -2- (aminocarbonyl) -1-pyrrolidinyl] carbonyl] -2,3,4,9-tetrahydro- 1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
181b
574
573.6901
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -7,8-dichloro- 2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
182a
645
644.5961
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -7,8-dichloro- 2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
182b
645
644.5961
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-5,8-dimethyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
183a
604
6033.7595
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4, 9-tetrahydro-5,8-dimethyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
183b
604
6033.7595
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6,8-dichloro- 2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
184a
645
644.5961
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6,8-dichloro- 2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
184b
645
644.5961
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6-bromo-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
185a
655
654.602
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6-bromo-2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
185b
655
654.602
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-8- Methoxy-1H-carbazole-3-carboxamide
186a
511
511.0189
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-8- Methoxy-1H-carbazole-3-carboxamide
186b
511
511.0189
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1R) -2-amino-1-[(4-chlorophenyl) methyl] -2-oxoethyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
187a
658
658.195
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1R) -2-amino-1-[(4-chlorophenyl) methyl] -2-oxoethyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
187b
658
658.195
Phenylmethyl [(1S, 2S) -1-[[[3-[[(3-amino-3-oxopropyl) amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl ] Amino] carbonyl] -2-methylbutyl] carbamate
188
548
547.6523
(2S) -1-[[(3R) -3-[[(4-Chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3-yl] carbonyl] -2-pyrrolidinecarboxamide
189a
509
509.0031
(2S) -1-[[(3S) -3-[[(4-Chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3-yl] carbonyl] -2-pyrrolidinecarboxamide
189b
509
509.0031
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2S) -2- (aminocarbonyl) octahydro-1H-indol-1-yl] carbonyl] -2,3,4 , 9-Tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
190a
628
627.7815
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[(2S) -2- (aminocarbonyl) octahydro-1H-indol-1-yl] carbonyl] -2,3,4 , 9-Tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
190b
628
627.7815
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2S, 4R) -2- (aminocarbonyl) -4-hydroxy-1-pyrrolidinyl] carbonyl] -2,3 4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
191a
590
589.6891
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[(2S, 4R) -2- (aminocarbonyl) -4-hydroxy-1-pyrrolidinyl] carbonyl] -2,3 4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
191b
590
589.6891
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S, 2R) -1- (aminocarbonyl) -2-hydroxypropyl] amino] carbonyl] -2,3 4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
291a
578
577.6781
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S, 2R) -1- (aminocarbonyl) -2-hydroxypropyl] amino] carbonyl] -2,3 4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate
291b
578
577.6781
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[(2-amino-2-oxoethyl) amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazole- 3-yl] amino] carbonyl] -2-methylbutyl] carbamate
292
534
533.6255
Phenylmethyl [(1S, 2S) -1-[[[3-[[[2- (aminocarbonyl) phenyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] Amino] carbonyl] -2-methylbutyl] carbamate
192
596
595.6963
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[4-chloro-3-[[(4-pyridinylamino) carbonyl] amino] phenyl] acetyl] Amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
193a
616
616.119
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[4-chloro-3-[[(4-pyridinylamino) carbonyl] amino] phenyl] acetyl] Amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
193b
616
616.119
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[4-chloro-3-[[(phenylamino) carbonyl] amino] phenyl] acetyl] amino ] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
194a
615
615.13
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[4-chloro-3-[[(phenylamino) carbonyl] amino] phenyl] acetyl] amino ] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
194b
615
615.13
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[4-chloro-3-[[[(phenylmethyl) amino] carbonyl] amino] phenyl] Acetyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
195a
629
629.157
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[4-chloro-3-[[[(phenylmethyl) amino] carbonyl] amino] phenyl] Acetyl] amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
195b
629
629.157
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[4-chloro-3-[[(2-pyridinylamino) carbonyl] amino] phenyl] acetyl] Amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
196a
616
616.119
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[4-chloro-3-[[(2-pyridinylamino) carbonyl] amino] phenyl] acetyl] Amino] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide
196b
616
616.119
Example 24:
The synthesis is carried out by methods A, F, G, I, F, H and O on a 0.2 mmol scale.

(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-8-methoxy-1H-carbazole-3 Carboxamide 197a
400
400.4762
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-8-methoxy-1H-carbazole-3 -Carboxamide 197b
400
400.4762
3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -6-chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 198
405
404.8555
3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-5-methyl-1H-carbazole-3-carboxamide 199
769
768. 9544
3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-8-methyl-1H-carbazole-3-carboxamide 200
768. 9544
3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -5-chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 201
610
609.7911
3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -7-chloro-2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 202
610
609.7911
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3 -Carboxamide 203a
388
388.4405
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -6-fluoro-2,3,4,9-tetrahydro-1H-carbazole-3 -Carboxamide 203b
388
388.4405
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-6-methoxy-1H-carbazole-3 -Carboxamide 204a
400
400.4762
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-6-methoxy-1H-carbazole-3 -Carboxamide 204b
400
400.4762
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-6-methyl-1H-carbazole-3 -Carboxamide 205a
384
384.4772
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-6-methyl-1H-carbazole-3 -Carboxamide 205b
384
384.4772
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 206a
370
370.4504
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 206b
370
370.4504
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -7,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole -3-carboxamide 207a
439
439.3406
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -7,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole -3-carboxamide 207b
439
439.3406
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-5,8-dimethyl-1H-carbazole -3-carboxamide 208a
399
398.504
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-5,8-dimethyl-1H-carbazole -3-carboxamide 208b
399
398.504
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole -3-Carboxamide 209a
439
439.3406
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -6,8-dichloro-2,3,4,9-tetrahydro-1H-carbazole -3-Carboxamide 209b
439
439.3406
Example 25:
The synthesis is carried out by methods A, F, G, I, F, G, F and O on a 0.2 mmol scale.

(3R) -3-[[(2S) -2-amino-5-[(aminoiminomethyl) amino] -1-oxopentyl] amino] -N-[(1S) -1- (aminocarbonyl) -2 -Methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 210a
485
484.6014
(3S) -3-[[(2S) -2-amino-5-[(aminoiminomethyl) amino] -1-oxopentyl] amino] -N-[(1S) -1- (aminocarbonyl) -2 -Methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 210b
485
484.6014
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[2- (1-piperidinyl) ethyl] amino Acetyl] amino] -1H-carbazole-3-carboxamide 211a
497
496.652
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[2- (1-piperidinyl) ethyl] amino Acetyl] amino] -1H-carbazole-3-carboxamide 211b
497
496.652
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[2- (1H-indol-3-yl ) Ethyl] amino] acetyl] amino] -1H-carbazole-3-carboxamide 212a
529
528.6534
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[2- (1H-indol-3-yl ) Ethyl] amino] acetyl] amino] -1H-carbazole-3-carboxamide 212b
529
528.6534
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[(1,3-benzodioxol-5-ylmethyl) amino] acetyl] amino]- 2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 213a
520
519.5987
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[(1,3-benzodioxol-5-ylmethyl) amino] acetyl] amino]- 2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 213b
520
519.5987
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[(2,2-diphenylethyl) amino] acetyl] amino] -2,3,4, 9-Tetrahydro-1H-carbazole-3-carboxamide 214a
566
565.141
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[(2,2-diphenylethyl) amino] acetyl] amino] -2,3,4, 9-Tetrahydro-1H-carbazole-3-carboxamide 214b
566
565.141
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[2- [methyl (phenylmethyl) amino] Ethyl] amino] acetyl] amino] -1H-carbazole-3-carboxamide 215a
533
532.685
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[2- [methyl (phenylmethyl) amino] Ethyl] amino] acetyl] amino] -1H-carbazole-3-carboxamide 215b
533
532.685
Example 26:
The synthesis is performed by methods A, F, G, I, F, G, F, H and O on a 0.2 mmol scale.

3-[[[Acetyl [2- (1-piperidinyl) ethyl] amino] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9 -Tetrahydro-1H-carbazole-3-carboxamide 216
539
538.6888
(3R) -3-[[[Acetyl [2- [methyl (phenylmethyl) amino] ethyl] amino] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl]- 2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 217a
575
574.7217
(3S) -3-[[[Acetyl [2- [methyl (phenylmethyl) amino] ethyl] amino] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl]- 2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 217b
575
574.7217
(3R) -3-[[[Acetyl (2,2-diphenylethyl) amino] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4 , 9-Tetrahydro-1H-carbazole-3-carboxamide 218a
608
6077.7509
(3S) -3-[[[Acetyl (2,2-diphenylethyl) amino] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4 , 9-Tetrahydro-1H-carbazole-3-carboxamide 218b
608
6077.7509
(3R) -3-[[[Acetyl (1,3-benzodioxol-5-ylmethyl) amino] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 219a
562
561.6355
(3S) -3-[[[Acetyl (1,3-benzodioxol-5-ylmethyl) amino] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 219b
562
561.6355
(3R) -3-[[[Acetyl [2- (1H-indol-3-yl) ethyl] amino] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 220a
571
570.6902
(3S) -3-[[[Acetyl [2- (1H-indol-3-yl) ethyl] amino] acetyl] amino] -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 220b
571
570.6902
3-[[(2S) -2- (acetylamino) -5-[(aminoiminomethyl) amino] -1-oxopentyl] amino] -N-[(1S) -1- (aminocarbonyl) -2- Methylpropyl] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 221
527
526.6382
Example 27:
The synthesis is carried out by methods C, F, G, I, F, G and P on a 0.2 mmol scale.

Phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3R) -2,3,4,9-tetrahydro-3-[[[(1S) -2-methyl-1-[(methyl Amino) carbonyl] propyl] amino] carbonyl] -1H-carbazol-3-yl] amino] carbonyl] butyl] carbamate 222a
589
589.7327
Phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3S) -2,3,4,9-tetrahydro-3-[[[(1S) -2-methyl-1-[(methyl Amino) carbonyl] propyl] amino] carbonyl] -1H-carbazol-3-yl] amino] carbonyl] butyl] carbamate 222b
589
589.7327
Example 28:
The synthesis is carried out by methods A, F, G, I, F, J and O on a 0.2 mmol scale.

(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) sulfonyl] amino] -2,3,4,9-tetrahydro-1H- Carbazole-3-carboxamide 223a
503
503.0203
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) sulfonyl] amino] -2,3,4,9-tetrahydro-1H- Carbazole-3-carboxamide 223b
503
503.0203
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(methylsulfonyl) amino] -1H-carbazole-3- Carboxamide 224a
407
406.5044
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(methylsulfonyl) amino] -1H-carbazole-3- Carboxamide 224b
407
406.5044
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(phenylsulfonyl) amino] -1H-carbazole-3- Carboxamide 225a
469
468.5752
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(phenylsulfonyl) amino] -1H-carbazole-3- Carboxamide 225b
469
468.5752
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(phenylmethyl) sulfonyl] amino] -1H-carbazole -3-carboxamide 226a
483
482.602
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(phenylmethyl) sulfonyl] amino] -1H-carbazole -3-carboxamide 226b
483
482.602
Example 29:
The synthesis is carried out by methods A, F, G, I, F, L and O on a 0.2 mmol scale.

3-Phenylpropyl [(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazole-3 -Yl] carbamate 227a
491
490.6006
3-Phenylpropyl [(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazole-3 -Yl] carbamate 227b
491
490.6006
Phenylmethyl [(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl Carbamate 228a
463
462.547
Phenylmethyl [(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl Carbamate 228b
463
462.547
Phenyl [(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] Carbamate 229a
449
448.5202
Phenyl [(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] Carbamate 229b
449
448.5202
Example 30
The synthesis is carried out by methods A, F, G, I, F, M and O on a 0.2 mmol scale.

(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-nitrophenyl) methyl] amino] -1H -Carbazole-3-carboxamide 230a
464
463.5351
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-nitrophenyl) methyl] amino] -1H -Carbazole-3-carboxamide 230b
464
463.5351
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3- (ethylamino) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 231a
356
356.4672
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3- (ethylamino) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 231b
356
356.4672
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(2-phenylethyl) amino] -1H-carbazole- 3-Carboxamide 232a
433
432.5648
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(2-phenylethyl) amino] -1H-carbazole- 3-Carboxamide 232b
433
432.5648
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(3-phenylpropyl) amino] -1H-carbazole- 3-Carboxamide 233a
447
446.5916
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(3-phenylpropyl) amino] -1H-carbazole- 3-Carboxamide 233b
447
446.5916
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3- [bis (3-phenylpropyl) amino] -2,3,4,9-tetrahydro-1H-carbazole -3-carboxamide 233c
565
564.7696
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(6-phenylhexyl) amino] -1H-carbazole- 3-Carboxamide 234a
489
488.672
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(6-phenylhexyl) amino] -1H-carbazole- 3-Carboxamide 234b
489
488.672
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1-methylethyl) amino] -1H-carbazole- 3-Carboxamide 235a
370
370.494
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1-methylethyl) amino] -1H-carbazole- 3-Carboxamide 235b
370
370.494
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1-methylpropyl) amino] -1H-carbazole- 3-Carboxamide 236a
385
384.5208
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1-methylpropyl) amino] -1H-carbazole- 3-Carboxamide 236b
385
384.5208
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(3-methylbutyl) amino] -1H-carbazole-3 Carboxamide 237a
399
398.5476
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(3-methylbutyl) amino] -1H-carbazole-3 Carboxamide 237b
399
398.5476
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3- (methylamino) -1H-carbazole-3-carboxamide 238a
342
342.4404
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3- (methylamino) -1H-carbazole-3-carboxamide 238b
342
342.4404
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3- (dimethylamino) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 238c
356
356.4672
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3- (dimethylamino) -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 238d
356
356.4672
Example 31
The synthesis is carried out by methods A, F, G, I, F, K and O on a 0.2 mmol scale.

(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(methylamino) carbonyl] amino] -1H-carbazole -3-carboxamide 239a
385
385.4653
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(methylamino) carbonyl] amino] -1H-carbazole -3-carboxamide 239b
385
385.4653
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(phenylamino) carbonyl] amino] -1H-carbazole -3-carboxamide 240a
448
447.5361
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(phenylamino) carbonyl] amino] -1H-carbazole -3-carboxamide 240b
448
447.5361
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[(phenylmethyl) amino] carbonyl] amino]- 1H-carbazole-3-carboxamide 241a
462
461.5629
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[(phenylmethyl) amino] carbonyl] amino]- 1H-carbazole-3-carboxamide 241b
462
461.5629
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[(2-phenylethyl) amino] carbonyl] amino ] -1H-carbazole-3-carboxamide 242a
476
475.5897
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[(2-phenylethyl) amino] carbonyl] amino ] -1H-carbazole-3-carboxamide 242b
476
475.5897
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(cyclohexylamino) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazole -3-carboxamide 243a
454
453.5835
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(cyclohexylamino) carbonyl] amino] -2,3,4,9-tetrahydro-1H-carbazole -3-carboxamide 243b
454
453.5835
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[(1-methylethyl) amino] carbonyl] amino ] -1H-carbazole-3-carboxamide 244a
414
413.5189
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[(1-methylethyl) amino] carbonyl] amino ] -1H-carbazole-3-carboxamide 244b
414
413.5189
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[(1-methylpropyl) amino] carbonyl] amino ] -1H-carbazole-3-carboxamide 245a
428
427.5457
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[(1-methylpropyl) amino] carbonyl] amino ] -1H-carbazole-3-carboxamide 245b
428
427.5457
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[(1R) -1-phenylethyl] amino ] Carbonyl] amino] -1H-carbazole-3-carboxamide 246a
476
475.5897
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[(1R) -1-phenylethyl] amino ] Carbonyl] amino] -1H-carbazole-3-carboxamide 246b
476
475.5897
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[(4-chlorophenyl) amino] carbonyl] amino] -2,3,4,9-tetrahydro -1H-carbazole-3-carboxamide 247a
482
481.9812
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[[(4-chlorophenyl) amino] carbonyl] amino] -2,3,4,9-tetrahydro -1H-carbazole-3-carboxamide 247b
482
481.9812
(3R) -N-[(1S) -1- (Aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[(1S) -1-phenylethyl] amino ] Carbonyl] amino] -1H-carbazole-3-carboxamide 248a
476
475.5897
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[[[(1S) -1-phenylethyl] amino ] Carbonyl] amino] -1H-carbazole-3-carboxamide 248b
476
475.5897
Example 32:
The synthesis is carried out by methods A, F, G, I, F, G, N and O on a 0.2 mmol scale.

Ethyl (3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -3-[[(4-chlorophenyl) acetyl] amino] -1,2,3 , 4-Tetrahydro-9H-carbazole-9-acetate 249a
567
5677.0825
Ethyl (3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -3-[[(4-chlorophenyl) acetyl] amino] -1,2,3 , 4-Tetrahydro-9H-carbazole-9-acetate 249b
567
5677.0825
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (3-Phenylpropyl) -1H-carbazole-3-carboxamide 250a
599
599.1711
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (3-Phenylpropyl) -1H-carbazole-3-carboxamide 250b
599
599.1711
(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -3-[[(4-chlorophenyl) acetyl] amino] -1,2,3 4-Tetrahydro-9H-carbazole-9-acetic acid 251a
539
539.00289
(3S) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -3-[[(4-chlorophenyl) acetyl] amino] -1,2,3 4-Tetrahydro-9H-carbazole-9-acetic acid 251b
539
539.00289
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (3-Methylbutyl) -1H-carbazole-3-carboxamide 252a
551
551.1271
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (3-Methylbutyl) -1H-carbazole-3-carboxamide 252b
551
551.1271
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (4-Pyridinylmethyl) -1H-carbazole-3-carboxamide 253a
572
572.1056
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (4-Pyridinylmethyl) -1H-carbazole-3-carboxamide 253b
572
572.1056
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (3-Pyridinylmethyl) -1H-carbazole-3-carboxamide 254a
572
572.1056
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (3-Pyridinylmethyl) -1H-carbazole-3-carboxamide 254b
572
572.1056
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (2-Naphthalenylmethyl) -1H-carbazole-3-carboxamide 255a
621
621.1773
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (2-Naphthalenylmethyl) -1H-carbazole-3-carboxamide 255b
621
621.1773
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (2-Methylpropyl) -1H-carbazole-3-carboxamide 256a
537
537.1003
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (2-Methylpropyl) -1H-carbazole-3-carboxamide 256b
537
537.1003
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (2-Phenylethyl) -1H-carbazole-3-carboxamide 257a
585
585.1443
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-9- (2-Phenylethyl) -1H-carbazole-3-carboxamide 257b
585
585.1443
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -9-ethyl-2,3,4,9- Tetrahydro-1H-carbazole-3-carboxamide 258a
509
509.0467
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -9-ethyl-2,3,4,9- Tetrahydro-1H-carbazole-3-carboxamide 258b
509
509.0467
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -9- (cyclohexylmethyl) -2,3,4 , 9-Tetrahydro-1H-carbazole-3-carboxamide 259a
577
577.1649
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -9- (cyclohexylmethyl) -2,3,4 , 9-Tetrahydro-1H-carbazole-3-carboxamide 259b
577
577.1649
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -9-[(2,6-difluorophenyl) methyl ] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 260a
607
607.0977
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -9-[(2,6-difluorophenyl) methyl ] -2,3,4,9-tetrahydro-1H-carbazole-3-carboxamide 260b
607
607.0977
Example 33:
The synthesis is carried out by methods A, F, G, I, F, H, N and O on a 0.2 mmol scale.

(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-9- (3-phenylpropyl)- 1H-carbazole-3-carboxamide 261a
489
488.6284
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-9- (3-phenylpropyl)- 1H-carbazole-3-carboxamide 261b
489
488.6284
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-9- (3-methylbutyl) -1H -Carbazole-3-carboxamide 262a
441
440.5844
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-9- (3-methylbutyl) -1H -Carbazole-3-carboxamide 262b
441
440.5844
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-9- (2-naphthalenylmethyl) ) -1H-carbazole-3-carboxamide 263a
511
510.6346
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-9- (2-naphthalenylmethyl) ) -1H-carbazole-3-carboxamide 263b
511
510.6346
3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-9- (1-naphthalenylmethyl) -1H- Carbazole-3-carboxamide 264
511
510.6346
3- (Acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -9- (cyclohexylmethyl) -2,3,4,9-tetrahydro-1H-carbazole-3- Carboxamide 265
467
466.6222
(3R) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-9- (2-methylpropyl)- 1H-carbazole-3-carboxamide 266a
427
426.5576
(3S) -3- (acetylamino) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-9- (2-methylpropyl)- 1H-carbazole-3-carboxamide 266b
427
426.5576
Example 34:
The synthesis is carried out on a 0.2 mmol scale by methods D, F, G, I, F, O and subsequent coupling according to Example 6.

Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (hydroxymethyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 267a
563
562.7068
Phenylmethyl [(1S, 2S) -1-[[[(3S)-[[[(1S) -1- (hydroxymethyl) -2-methylpropyl] amino] carbonyl] -2,3,4,9- Tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate 267b
563
562.7068
Example 35:
Ethyl 2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylate 268
10 mmol (1.6 ml) of ethyl 4-oxocyclohexanecarboxylate, 25 mmol (1.4 ml) of glycol and 10 μmol of pTsOH are refluxed in anhydrous toluene using a water trap for 24 hours. The solvent is removed and the residue is taken up in ethyl acetate / water. The organic phase is washed with water, dried and evaporated to dryness. The product is distilled in a bulb apparatus at 120 ° C. and 0.03 mbar under high vacuum.

Yield: 1.52 g of 4-ethyl 1,4-dioxaspiro [4,5] decane-8-carboxylate 269
85 μl of diisopropylamine in 500 μl of anhydrous THF are added dropwise to 0.6 mmol of a 1.6 molar butyllithium solution in heptane at −20 ° C. under argon and then stirred for 10 minutes. After cooling to −70 ° C., 269 compounds in 0.5 mmol (107 mg) of 200 μl anhydrous THF are added dropwise, allowing to reach 0 ° C. over 1 hour and stirring for a further 30 minutes. After cooling to −70 ° C., 0.7 mmol (106 μl) of 1-bromo-3-phenylpropane in 300 μl of anhydrous THF is added and the mixture is stirred for 30 minutes. Allow to reach room temperature and then stir for 1 hour. Carefully by the addition of saturated _NH 4 Cl solution and n- hexane in the organic phase, it is stirred for 10 minutes. The organic phase is separated and washed with water. Following filtration through a Whatman filter, it is evaporated to dryness.

Yield: 165 mg of ethyl 8- (3-phenylpropyl) -1,4-dioxaspiro [4,5] decane-8-carboxylate 270
0.6 mmol (200 mg) of 270 compounds are taken up in 25 ml of acetone / 0.1 M HCl 1: 1 and stirred for 48 hours at 50 ° C. with a catalytic amount of pTsOH. 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
Indolization is carried out using phenylhydrazine as described in Example 1.

Yield after distillation and fractional HPLC: 65 mg ethyl 2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylate 268
ES-MS: 362 (M + H ⁺ )
80 mg of ethyl 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylate 272 using 2,4-dichlorophenylhydrazine as well To manufacture.

ES-MS: 430 (M + H ⁺ )
Example 36:
2,3,4,9-Tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylic acid 273
3.94 mmol (1.31 g) 269 compounds are stirred for 4 hours at 60 ° C. in 50 ml methanol and 30 ml 50% sodium hydroxide solution. The mixture is acidified with dilute HCl and extracted with ether. It was dried over Na ₂ SO _4, and evaporated to a white solid 8- (3-phenylpropyl) -1,4-dioxaspiro [4,5] decane-8-carboxylic acid 1.02 g (85%) 274 is obtained.

  65 mg of 274 compound is first deprotected with HCl and then reacted with phenylhydrazine as described for compounds 270 and 271 for indolization.

Yield after evaporation and fractional HPLC: 15 mg of 273 compounds ES-MS: 334 (M + H ^< + ^> )
39 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylic acid 275 is prepared analogously using 2,4-dichlorophenylhydrazine .

ES-MS: 478 (M + H ⁺ )
Example 37:
2,3,4,9-Tetrahydro-N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -3- (3-phenylpropyl) -1H-carbazole-3-carboxamide 276
0.66 mmol (200 mg) of 274 compounds are reacted with 1.5 equivalents of valinol as in Example 6. 277 mg of white solid N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -8- (3-phenylpropyl) -1,4-dioxaspiro [4,5] -decane-8-carboxamide 277 is obtained.

0.3 mmol (117 mg) of 277 compounds are then first deprotected with HCl and subsequently reacted with phenylhydrazine as described for compounds 270 and 271 for indolization. Yield after evaporation and fractional HPLC: 15 mg of 276 compounds ES-MS: 418 (M + H ^< + ^> )
25 mg of 6,8-dichloro-2,3,4,9-tetrahydro-N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -3- (3-phenylpropyl) -1H-carbazole -3-Carboxamide 278 is prepared analogously using 2,4-dichlorophenylhydrazine.

ES-MS: 486 (M + H ⁺ )
Example 38:
2,3,4,9-Tetrahydro-3- (3-phenylpropyl) -N- (2-pyridinylmethyl) -1H-carbazole-3-methanamine 279
54 ml of a 1M LiAlH ₄ solution in anhydrous THF is added to a solution of 18 mmol (6 g) 270 compounds in 250 ml of anhydrous THF at room temperature under argon. After heating at reflux for 3 hours, careful hydrolysis is carried out with 300 ml of saturated NH ₄ Cl solution and 250 ml of ether are added. The aluminum salt is filtered off and washed with ether. The ether phase was dried over Na ₂ SO ₄ and the solvent was evaporated, yielding 3.4 g of 8- (3-phenylpropyl) -1,4-dioxaspiro [4,5] decane-8-methanol 280. It is done.

5.86 mmol (1.7 g) 280 compounds are dissolved in 60 ml anhydrous DCM and 20 ml anhydrous DMSO. Under nitrogen at room temperature, first 44 mmol (6.1 ml) of TEA are added, then 17.6 mmol (2.8 g) of SO ₃ -pyridine complex are carefully added and the mixture is stirred for 1 hour. . Subsequently 200 ml of saturated NH ₄ Cl solution are added and extraction is carried out with 150 ml of ether. By drying the ether phase with Na ₂ SO ₄ and evaporating the solvent, 1.9 g of 8- (3-phenylpropyl) -1,4-dioxaspiro [4,5] decane-8-carbaldehyde 281 was obtained. Obtained as a colorless oil.

0.719 mmol of sodium triacetoxyborohydride was added to 0.359 mmol (103 mg) of 281 compound and 0.359 mmol (37 ml) of 2-pyridinemethanamine in 2.5 ml of 1,2-dichloroethane. Add to mixture. The mixture is stirred under N ₂ at room temperature for 3 hours. Saturated NaHCO ₃ solution is added and the mixture is extracted with ether. 101 mg (76%) of white solid N- [8- (3-phenylpropyl) -1,4-dioxaspiro [4,5] dec-8-yl] -2-pyridine by drying and evaporating the extract Methanamine 282 is obtained.

Subsequently 101 mg of 282 compounds are first deprotected with HCl and then reacted with phenylhydrazine as described for compounds 270 and 271 for indolization. Yield after evaporation and fractional HPLC: 71 mg of 279 compounds ES-MS: 410 (M + H ^< + ^> )
54 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -N- (2-pyridinylmethyl) -1H-carbazole-3-methanamine 283 was prepared in the same manner Prepared using dichlorophenylhydrazine.

ES-MS: 478 (M + H ⁺ )
Example 39:
(2S) -3-Methyl-2-[[[2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazol-3-yl] methyl] amino] -1-butanol 284
0.368 mmol (106 mg) 281 compound and 0.368 mmol (38 mg) valinol are dissolved in 1.5 ml anhydrous methanol and stirred at room temperature for 30 min. After cooling to 0 ° C., 0.557 mmol (21 mg) NaBH ₄ is added and stirred for 1 hour at room temperature. 0.437 mmol (25 μl) acetic acid is added and stirring is continued at pH 6 for 2 hours. Saturated NaHCO ₃ solution is added and the mixture is extracted with ether. The organic phase is dried over Na ₂ SO ₄ and evaporated to give 106 mg (77%) of a colorless oil for 270 and 271 compounds.

Deprotection and indolization is then performed as described for compounds 270 and 271. Yield after evaporation and fractional HPLC: 18 mg of white solid 284
ES-MS: 405 (M + H ⁺ )
17 mg of (2S) -2-[[[6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazol-3-yl] methyl] amino] -3 -Methyl-1-butanol 286 is prepared analogously using 2,4-dichlorophenylhydrazine.

ES-MS: 473 (M + H ⁺ )
Example 40:
2,3,4,9-Tetrahydro-3- (3-phenylpropyl) -O- (4-pyridinylmethyl) -1H-carbazole-3-methanol 287
0.689 mmol NaH (as a 55% suspension in mineral oil) is added to a solution of 0.344 mmol (100 mg) 280 compounds in 10 ml anhydrous DMF at 0 ° C. under N ₂ atmosphere. The mixture is allowed to reach room temperature and stirred for 30 minutes. 1.377 mmol of 4- (chloromethyl) pyridine is added and the mixture is stirred at 95-100 ° C. overnight. Following cooling to room temperature, it is hydrolyzed with 2 ml of water and extracted with ether. Drying and evaporation of the solvent gives 115 mg of a yellow oil 288.

Deprotection and indolization is then performed as described for compounds 270 and 271. Yield after evaporation and fractional HPLC: 14 mg of white solid 287
ES-MS: 411 (M + H ⁺ )
Example 41:
Ethyl 3- [2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazol-3-yl] -2-propenoate 289
0.347 mmol 281 compound in 0.5 ml THF is added dropwise to a solution of 0.378 mmol ethyl (triphenylphosphoranylidene) acetate in 1 ml anhydrous THF while cooling in ice. . After the addition is complete, the mixture is allowed to warm to room temperature and stirred for another 2 days. It is then hydrolyzed with water and extracted with ether. Na ₂ SO ₄ is used for drying, phosphane oxide and desiccant are filtered off and the solvent is removed. Yield: 80% ethyl 3- [8- (3-phenylpropyl) -1,4-dioxaspiro [4,5] dec-8-yl] -2-propenoate 290
Deprotection and indolization is then performed as described for compounds 270 and 271.

Yield after evaporation and fractional HPLC: 9 mg of white solid 289
ES-MS: 388 (M + H ⁺ )
In addition, the compounds of the numbers 293 to 300, 302 and 304 to 306 encompassed by the general formula (I) are obtained by methods A, F, G, F, G and O on a scale of 0.2 mmol, and the compounds 301 is obtained by methods B, F, G, F, G and O and compound 303 is obtained by methods A, F, G, F, G, F, L and O.

III Supporting the GnRH-antagonist effect of compound (I) of the invention Materials:
Buzzellin is obtained from Welding (Frankfurt / Main, Germany). And that the ^Na 125 I using the chloramine T method the compound with ¹²⁵ I (4000Ci / mmol; Amersham - Bufura, Brunn shoe Vic, Germany) labeled with. The labeled material was purified by reverse phase HPLC on a Spherisorb ODS II column (250 × 4 mm, particle size 3 μm) by elution with 50% acetonitrile / 0.15% trifluoroacetic acid at a flow rate of 0.5 ml / min. To do. The specific activity is 2000 Ci / mmol.

  All other chemicals are obtained from commercial sources with the highest obtainable purity.

Cell culture:
αT3-1 cells (Bilezikjian et al., Mol. Endocrinol 5 (1991), 347-355) were transformed into penicillin (100 IU / ml), streptomycin (0.1 mg / ml) and glutamine (0.01 mol / l). ) And 10% calf serum (FCS; PAA Laboratories, Coelbe, Germany) in DMEM medium (Gibco-BRL, Eggenstein-Lepoldshafen, Germany) in plastic tissue culture plates (Nunc, 245 × 245 × 20 mm) Incubate above. CHO-3 cells (Schmid et al., J. Biol. Chem. 275 (2000), 9193-9200) are cultured under the same conditions except that Ham's F12 medium (Gibco-BRL) is used.

  Ten confluent cell culture plates are washed twice with 50 ml phosphate buffered saline (PBS). These cells are replanted in 5 ml PBS by scraping with a rubber policeman and pelleted by centrifugation at 800 rpm for 10 minutes 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 a dry ice / ethanol bath and thawing at room temperature. The lysate is centrifuged at 900 rpm for 10 minutes and the precipitate is discarded. The supernatant is centrifuged for 30 minutes at 18000 rpm in a Sorvall SS34 rotor. The pellet (cell membrane) was suspended in a potter in 5 ml assay buffer (0.25 mol / l sucrose, 0.01 mol / l triethanolamine, pH 7.5, 1 mg / ml ovalbumin). Turbid and store 200 μl aliquots at −20 ° C. Protein is measured by the method of Bradford (Anal. Biochem. 72 (1976), 248-254).

Receptor assay:
Binding studies on competition plots are performed in triplicate. Test samples were 60 μl cell membrane suspension (10 μg protein for αT3-1-cells or 40 μg protein for CHO3 cells), 20 μl ¹²⁵ I-labeled buzerelin (100,000 ipm per sample for saturation plots and saturation test) 1 to 200,000 ipm) and 20 μl of test buffer or test compound solution. Test compounds are dissolved in distilled water or 50% ethanol. Serial dilutions (5 × 10 ⁻⁶ mol / l to 5 × 10 ⁻¹² mol / l) are made in the test buffer. Nonspecific binding is measured in the presence of excess unlabeled buzerelin (10 ⁻⁶ mol / l). The test sample is incubated for 30 minutes at room temperature. Bound and free ligand are separated by filtration (Whatman GF / C filter, 2.5 cm diameter) using an Amicon 10x recovery apparatus and with 5 ml 0.02 mol / l Tris / HCl, pH 7.4. Wash twice. The filter is moistened with 0.3% polyethyleneimine (Serva, Heidelberg, Germany) for 30 minutes to reduce non-specific binding. The radioactivity retained in the filter is measured in a 5-channel gamma counter (Wallac-LKB 1470 Wizard).

The IC ₅₀ values obtained for such advantageous compounds are given in the table below.

  Compounds numbered 293-306 are tested by the method shown below.

Receptor binding assay Materials:
¹²⁵ I-triptorelin [ ¹²⁵ I- (D) -Trp6-GnRH] is obtained from Biotrend (Cologne, Germany). The specific activity is 2.13 Ci / mmol in each case. All other chemicals are obtained with the highest purity available from commercial sources.

Cell culture:
Transfected LTK 'cells (ATCC number CCL-1.3) were treated with penicillin (100 IU / ml), streptomycin (0.1 mg / ml) and glutamine (0.01 mol / l) and 10% Incubate on plastic tissue culture plates (Nunc, Germany, 245 × 245 × 20 mm) in DMEM medium (Invitrogen Life Technologies, Germany) with calf serum (FCS; Invitrogen Life Technologies, Germany).

test:
The 80% confluent cell culture plate is washed twice with 50 ml phosphate buffered saline (PBS) and then detached with 0.01 M EDTA solution. The cells are pelleted by centrifuging at 200 × g for 5 minutes in a laboratory centrifuge (Kendro, Germany). The cell pellet was added to 3 ml of binding medium (DMEM; 10 mM Hepes; 0.5% BSA; 0.1% NaN ₃ ; 1 g / l bacitracin (newly added, stock solution 100 times); 0.1 g / l SBTI (freshly added, stock solution 1000 times)) and cell counts are measured by trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted with a binding medium to a concentration of 5 × 10 ⁵ cells / 0.05 ml.

Binding studies for competition plots are performed in duplicate. The test substance is used as a 10 mM DMSO solution. They are diluted with binding medium to 4 times the final concentration used. 25 μl substance dilution is mixed with 25 μl tracer solution ( ¹²⁵ I-triptorelin). The tracer concentration is adjusted to about 50000 cpm (measured in Cobra II, gamma counter (PE Liefe Science, Germany)) in a final reaction volume of 100 μl.

200 μl of silicone / liquid paraffin mixture (84%: 16%) is introduced into a 650 μl conical tube (Roth, Germany). 50 μl of the cell suspension is pipetted there, followed by 50 μl of the test substance / tracer mixture. The tube is capped and incubated for 60 minutes at 37 ° C. with vertical rotation in an incubator. After incubation, the samples centrifuge (Kendro, Germany) and centrifuged at 900rpm in so continue to shock frozen in liquid N _2. Chips with cell pellets are cut and transferred into prepared counting vials (Roth, Germany). The conical tube residue with the remaining supernatant is also transferred into a counting vial. The measurement is carried out in a gamma counter over 1 minute / sample.

  Sample evaluation was performed using GraphPad Prism (GraphPad Software Inc., USA) after subtraction of non-specific binding (excess unlabeled ligand, 1 μm) after calculation of specific binding compared to untreated cells. carry out.

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

Cell culture :
Functional studies were performed using stably transfected LTK cells (ATCC number CCL-1.3) with heterologous expression of GnRH receptor and cAMP responsive elements and CMV minimal promoter driven luciferase reporter gene To do.

  The cells have penicillin (100 IU / ml), streptomycin (0.1 mg / ml) and glutamine (0.01 mol / l) and 10% calf serum (FCS; Invitrogen Life Technologies, Germany) Incubate on plastic tissue culture plates (Nunc, Germany, 245 × 245 × 20 mm) in DMEM medium (Invitrogen Life Technologies, Germany).

Exam :
80% confluent cell culture plates are washed twice with 50 ml phosphate buffered saline (PBS) and then detached with trypsin EDTA solution (Invitrogen Life Technologies, Germany). These cells are pelleted by centrifugation at 200 × g for 5 minutes in a laboratory centrifuge (Kendro, Germany). The cell pellet was treated with penicillin (100 IU / ml), streptomycin (0.1 mg / ml) and glutamine (0.01 mol / l) and 10% calf serum (FCS; Invitrogen Life Technologies, Germany). Resuspend in 3 ml of assay medium (Invitrogen Life Technologies, Germany) and count the cell count by trypan blue staining in a Neubauer counting chamber. The cell suspension is adjusted to a concentration of 1 × 10 ⁴ cells / 100 μl using assay medium. The cells are mounted on white 96 well microtiter plates (Costar, Germany) and incubated for 18 hours in an incubator.

For carrying out the test, the test substance is diluted in assay medium as a 10 mM DMSO solution to 6 times the final concentration used. 25 μl of test substance is added to 100 μl of cells and incubated for 60 minutes at 37 ° C., 5% CO ₂ .

Triptorelin (D-Trp6-GnRH) / rolipram solution (6 nM / 6 μM) is then added followed by another 6 hours incubation at 37 ° C., 5% CO ₂ .

  Following incubation, 50 μl of lysis / detection buffer (LucLite, PE Life Science) is added and measurements are taken in a Lumistar luminometer (BMG Labtechnologies GmbH, Germany).

  Sample evaluation was performed using GraphPad Prism (GraphPad Software Inc., USA) or optionally OMMM (Accelrys, Germany) after subtraction of unstimulated controls after calculation of inhibition compared to untreated stimulated cells. To implement.

The EC ₅₀ values obtained for compounds 293-306 are shown in the table below.

Claims (32)

Formula (I)

[Where:
The group R ¹ is a hydrogen atom, a C ₂ -C ₆ -alkenyl group or a C ₁ -C ₆ -alkyl group and may be substituted by an aryl group, a hetaryl group or a group —COOR ¹¹ , in which case the aryl group Or the hetaryl group may be substituted by up to three substituents independently selected from the group consisting of —NO ₂ , —CH ₃ , —CF ₃ , —OCH ₃ , —OCF ₃ and a halogen atom,
The group R ¹¹ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group, a hetaryl group or a group —COCH ₃ , and —CONH ₂ , —COCH ₃ , —COOCH ₃ may be substituted by one substituent selected from the group consisting of -SO ₂ CH _3, and aryl groups,
The groups R ² , R ³ , R ⁴ and R ⁵ are independently of one another hydrogen, halogen, radicals —COOH, —CONH ₂ , —CF ₃ , —OCF ₃ , —NO ₂ , —CN, C ₁ -C. ₆ - an aralkyl group, an aryl group or hetaryl group, - an alkyl _group, C 1 -C ₆ - alkenyl _group, C 1 -C ₆ - alkoxy _group, C 1 _{-C 12}
The group R ₆ is a group —CONR ⁸ R ⁹ , —COOR ⁸ , —CH ₂ NR ⁸ R ⁹ , —CH ₂ R ⁸ , —CH ₂ OR ⁸ or a C _{1 to} C ₁₂ -alkenyl group, which group R ⁸ and R ⁹ may be substituted, in which case the groups R ⁸ and R ⁹ are, independently of one another, a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -aralkyl group, C ₁ -C ₁₂ - heteroaralkyl group, an aryl group or hetaryl group, each of _said ^{-OH, -NH 2, -CONHR 10,} -COOR 10, from -NH-C (= NH) -NH 2 and halogen atoms made it may be substituted by one or more substituents selected from the group, ^{where, R 10} is a hydrogen _atom, C 1 _{-C 12} - alkyl _group, C 1 _{-C 12} - aralkyl group, an aryl group It is a hetaryl group and may be substituted by a group -CON (R ¹¹⁾ _2, or a group R ⁸ and R ⁹ together, or solely of carbon atoms, or a carbon atom and a hetero atom A cyclic structure consisting of a combination may be formed,
The group R ⁷ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -alkenyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group or a hetaryl group, a group —NR ¹² R ¹³ , —NHCOR ^14. , -NHCONHR ¹⁴ , -NHCOOR ¹⁴ or -NHSO ₂ R ¹⁴ and substituted by one or more substituents selected from the group consisting of -OH, -NH ₂ , -CONH ₂ , -COOH and a halogen atom You can,
The groups R ¹² and R ¹³ are each independently a hydrogen atom, a C ₂ -C ₆ -alkenyl group or a C ₁ -C ₁₂ -alkyl group, and —NO ₂ , —CH ₃ , —CF ₃ , —OCH _3. , —OCF ₃ and a halogen atom, optionally substituted by one or more aryl or hetaryl groups optionally substituted by up to three substituents selected independently of each other, R ¹⁴ is a hydrogen atom, a C ₁ -C ₁₂ -alkyl group, a C ₁ -C ₁₂ -alkenyl group, a C ₁ -C ₁₂ -aralkyl group, an aryl group or a hetaryl group, the groups being —NO ₂ , —CH ₃ , —OR ¹¹ , —CF ₃ , —OCF ₃ , —OH, —N (R ¹¹ ) ₂ , —OCOR ¹¹ , —COOH, —CONH ₂ , —NHCONHR ¹¹ , May be substituted by one or more substituents selected from the group consisting of -NHCOOR ¹¹ and halogen atoms,
And the groups R ^a , R ^b , R ^c , R ^d , R ^e and R ^f are each independently a hydrogen atom, a halogen atom, a group —COOH, —CONH ₂ , —CF ₃ , —OCF ₃ , —NO ₂ , _-CN, C 1 -C ₆ - alkyl _group, C 1 -C ₆ - alkoxy group, is represented by a is] an aryl group or hetaryl group, provided that the compound of general formula (I), 3-amino - 1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-methoxy-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-amino-6-benzyloxy-1 , 2,3,4-tetrahydrocarbazole-3-carboxylic acid, 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, methyl 3-acetamido-1,2,3,4-te Lahydrocarbazole-3-carboxylate, (-)-menthyl 3-acetamido-1,2,3,4-tetrahydrocarbazole-3-carboxylate or 3-t-butoxycarbonylamino-1,2,3,4 A compound not selected from the group consisting of tetrahydrocarbazole-3-carboxylic acid. The compound according to claim 1, wherein the groups R ^a , R ^b , R ^c , R ^d , R ^e and R ^f are hydrogen atoms. The compound according to claim 1 or 2, wherein the group R ¹ is a hydrogen atom. Group ^{R 2,} R 3, ^{R 4} and / or ^{R 5} is not hydrogen atom, the compound of any one of claims 1 to 3. Group ^{R 2,} R 3, ^{R 4} and ^{R 5} independently of one another radical _-CH 3, is -Cl or -OCH _3, claim 4 compounds described.   Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-8-methyl-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate, phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[[ (1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6-chloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2- Methylbutyl] carbamate and phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbo Le] -2,3,4,9-tetrahydro-8-methoxy -1H- carbazol-3-yl] amino] carbonyl] -2-methylbutyl] is selected from the group consisting of carbamate 6. The compound of claim 5, wherein. R ⁶ is an alkyl structure, an aryl structure and / or comprises a hetaryl structures and hydrogen bond donor at a distance of the single bonds of 2-4 counting from the carbon atom substituted by a radical R ⁶ and R ⁷ - hydrophobic with an acceptor system A compound that is a functional group. The group R ⁶ is a phenylalanylamide residue, isoleucylamide residue, valyl-4-aminobenzamide residue, valyl-N-methylamide residue, methyloxymethyl-4-pyridyl group, carboxyl group, ethylprop Noate residue, carbonylvalylamide residue, carbonylthreonylamide residue, cyclic carboxamide residue, 4-carboxamide phenylcarboxamide residue, methylaminomethyl-2-pyridyl group, carbonylvalinol residue and methylvalyl residue 8. A compound according to claim 7, wherein the compound is selected from the group consisting of nor residues. Compound is
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -2-amino-2-oxo-1- (phenylmethyl) ethyl] amino] carbonyl] -2, 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S, 2S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -2,3,4 , 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1-[[[4- (aminocarbonyl) phenyl] amino] carbonyl] -2-methylpropyl] Amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -2-methyl-1-[[[(3R) -2,3,4,9-tetrahydro-3-[[[(1S) -2-methyl-1-[(methyl Amino) carbonyl] propyl] amino] carbonyl] -1H-carbazol-3-yl] amino] carbonyl] butyl] carbamate,
2,3,4,9-tetrahydro-3- (3-phenylpropyl) -O- (4-pyridinylmethyl) -1H-carbazole-3-methanol,
2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylic acid,
Ethyl 3- [2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazol-3-yl] -2-propenoate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S, 2R) -1- (aminocarbonyl) -2-hydroxypropyl] amino] carbonyl] -2,3 4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2S) -2- (aminocarbonyl) -1-pyrrolidinyl] carbonyl] -2,3,4,9-tetrahydro- 1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[(2S) -2- (aminocarbonyl) octahydro-1H-indol-1-yl] carbonyl] -2,3,4 , 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate),
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[4- (aminocarbonyl) phenyl] amino] carbonyl] -2,3,4,9-tetrahydro-1H-carbazole- 3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
2,3,4,9-tetrahydro-3- (3-phenylpropyl) -N- (2-pyridinylmethyl) -1H-carbazole-3-methanamine,
Phenylmethyl [(1S, 2S) -1-[[[(3S) -3-[[[(1S) -1- (hydroxymethyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
2,3,4,9-tetrahydro-N-[(1S) -1- (hydroxymethyl) -2-methylpropyl] -3- (3-phenylpropyl) -1H-carbazole-3-carboxamide and (2S) -3-Methyl-2-[[[2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazol-3-yl] methyl] amino] -1-butanol 9. The compound of claim 8, wherein The compound according to any one of claims 1 to 5, 7 or 8, wherein R ⁷ is a hydrophobic group having an alkyl structure, an aryl structure and / or a hetaryl structure. A phenylmethylcarboxamide residue in which the group R ⁷ is substituted in a 2,3-biphenylpropionylamino group, indanoylamino group, indolylacetylamino group, 2-naphthylacetylamino group, 3-propionylamino group, aromatic ring system 11. A compound according to claim 10, selected from the group consisting of: a phenylhexylamine residue and a phenylpropyl group. Compound is
N-[[(3R) -2,3,4,9-tetrahydro-3-[(1-oxo-2,3-diphenylpropyl) amino] -1H-carbazol-3-yl] carbonyl] -L-valyl -L-aspartamide,
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(2,3-dihydro-1H-inden-1-yl) carbonyl] amino] -2, 3,4,9-tetrahydro-1H-carbazole-3-carboxamide,
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(1H-indol-3-ylacetyl) amino] -1H -Carbazole-3-carboxamide,
(3S) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(2-naphthalenylacetyl) amino] -1H- Carbazole-3-carboxamide,
N-[[(3R) -2,3,4,9-tetrahydro-3-[[(2S, 3S) -3-methyl-1-oxo-2-[(1-oxo-3-phenylpropyl) amino ] Pentyl] amino] -1H-carbazol-3-yl] carbonyl] -L-valyl-L-aspartamide,
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-methylphenyl) acetyl] amino] -1H -Carbazole-3-carboxamide,
N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[[(4-methoxyphenyl) acetyl] amino] -1H-carbazole-3 -Carboxamide,
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(3-bromophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide,
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-fluorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H -Carbazole-3-carboxamide,
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -3-[[(4-chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-1H- Carbazole-3-carboxamide,
(3R) -N-[(1S) -1- (aminocarbonyl) -2-methylpropyl] -2,3,4,9-tetrahydro-3-[(6-phenylhexyl) amino] -1H-carbazole- 3-carboxamide,
6,8-Dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -1H-carbazole-3-carboxylic acid and ethyl 6,8-dichloro-2,3,4,9-tetrahydro 12. A compound according to claim 11 selected from the group consisting of -3- (3-phenylpropyl) -1H-carbazole-3-carboxylate. Compound, when the group R ⁶ and R ⁷ form a turned with α- amino acid structural elements together, in the R configuration at the carbon atom substituted by a radical R ⁶ and R ^7, claim 1 5 , 7, 8, 10 or 11. Compound is
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6,8-dichloro- 2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (hydroxymethyl) -2-methylpropyl] amino] carbonyl] -2,3,4 9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
(2S) -1-[[[(3R) -3-[[(4-Chlorophenyl) acetyl] amino] -2,3,4,9-tetrahydro-8-methoxy-1H-carbazol-3-yl] carbonyl ] A group consisting of 2-pyrrolidinecarboxamide and 6,8-dichloro-2,3,4,9-tetrahydro-3- (3-phenylpropyl) -N- (2-pyridinylmethyl) -1H-carbazole-3-methanamine 2. A compound according to claim 1 selected from.   A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 14.   16. The pharmaceutical composition according to claim 15, wherein the compound is present in a unit dose of 1 [mu] g to 100 mg per kg patient body weight.   17. A pharmaceutical composition according to claim 15 or 16, wherein the compound is present in the composition in combination with at least one further active pharmaceutical ingredient and / or a pharmaceutically acceptable carrier.   15. A process for producing a compound according to any one of claims 1-14.   15. A compound according to any one of claims 1 to 14 for use as a pharmaceutical therapeutic.   15. Use of a compound according to any one of claims 1 to 14 for the manufacture of a pharmaceutical therapeutic for the treatment of pathological conditions mediated by G protein coupled receptors.   Use of a compound comprising a compound as claimed in claim 1 but specifically excluded in claim 1 for the manufacture of a pharmaceutical therapeutic for inhibiting gonadotropin releasing hormone.   22. Use according to claim 20 or 21 in the control of male infertility, hormonal therapy, the treatment of female low conception or infertility, female contraception and tumor control.   Use of a compound comprising a compound as claimed in claim 1 but specifically excluded in claim 1 for the control of male infertility or female contraception. Compound is
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylpropyl] amino] carbonyl] -6,8-difluoro- 2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S, 2S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -8-methoxy-2 , 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S, 2S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -6,8-dichloro -2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -3-methylbutyl] amino] carbonyl] -6,8-dichloro-2 , 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-cyclohexylethyl] amino] carbonyl] -6,8-dichloro- 2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2,2-dimethylpropyl] amino] carbonyl] -6,8- Dichloro-2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -3-phenylpropyl] amino] carbonyl] -6,8-dichloro- 2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -6,8-dichloro-2 , 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-cyclohexylmethyl] carbamate,
Phenylmethyl [(1S, 2S) -1-[[[(3R) -3-[[[(1S, 2S) -1- (carboxy) -2-methylbutyl] amino] carbonyl] -6,8-dichloro- 2,3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2-methylbutyl] carbamate,
Phenylmethyl [(1S) -1-[[[(3R) -3-[[[(1S, 2S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -6,8-dichloro-2 , 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -2- (4-hydroxyphenyl) ethyl] carbamate,
Phenylmethyl [(1S) -1-[[[(3R) -3-[[[(1S, 2S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -6,8-dichloro-2 , 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -3- (4-hydroxyphenyl) propyl] carbamate,
Phenylmethyl [(1S) -1-[[[(3R) -3-[[[(1S, 2S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -6,8-dichloro-2 , 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -3-phenylpropyl] carbamate,
Phenylmethyl [(1S) -1-[[[(3R) -3-[[[(1S, 2S) -1- (aminocarbonyl) -2-methylbutyl] amino] carbonyl] -6,8-dichloro-2 , 3,4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -3-methylbutyl] carbamate,
Phenylmethyl [(1S) -1-[[[(3R) -3-[[[(1S) -1- (aminocarbonyl) -3-methylbutyl] amino] carbonyl] -6,8-dichloro-2,3 The compound of claim 1 selected from the group consisting of, 4,9-tetrahydro-1H-carbazol-3-yl] amino] carbonyl] -3-methylbutyl] carbamate.   25. A pharmaceutical composition comprising at least one compound according to claim 24.   26. The pharmaceutical composition of claim 25, wherein the compound is present in a unit dose of 1 [mu] g to 100 mg per kg patient body weight.   27. A pharmaceutical composition according to claim 25 or 26, wherein the compound is present in the composition in combination with at least one further active pharmaceutical ingredient and / or a pharmaceutically acceptable carrier.   A method for producing the compound of claim 24.   25. A compound according to claim 24 for use as a pharmaceutical therapeutic.   25. Use of a compound according to claim 24 for the manufacture of a pharmaceutical therapeutic for the treatment of a pathological condition mediated by a G protein coupled receptor.   25. Use of a compound according to claim 24 for the manufacture of a pharmaceutical therapeutic for inhibiting gonadotropin releasing hormone.   32. Use according to claim 30 or 31 in the control of male infertility, hormonal therapy, the treatment of female low conception or infertility, female contraception and tumor control.