TWI246423B - Tetrahydrocarbazole derivatives as ligands for g-protein-coupled receptors (GPCR) - Google Patents

Abstract

This invention provides new tetrahydrocarbazole derivatives that act as ligands for G-protein-coupled receptors (GPCR), especially as antagonists of the gonadotropin-releasing hormone (GnRH). A pharmaceutical composition that contains these new tetrahydrocarbazole derivatives as well as a process for the production of the new tetrahydrocarbazole derivatives are also provided. Moreover, this invention relates to the administration of tetrahydrocarbazole derivatives for treating pathologic conditions that are mediated by GPCR, especially for inhibiting GnRH, in mammals, especially humans, who require such an administration, as well as the use of tetrahydrocarbazole derivatives for the production of a pharmaceutical agent for treating GPCR-mediated pathologic conditions, especially for inhibiting GnRH.

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel tetrahydrofoliate 4 derivative, a ligand for a G-protein coupled receptor, particularly an antagonist of gonadotropin releasing hormone, which is produced, Its use and pharmaceutical compositions containing such tetrahydrofuran derivatives. The invention also relates to a method of treating a pathological condition caused by a G-protein coupled receptor in a mammal, particularly a human. [Prior Art] The structural elements common to all members of the G-protein coupled receptor (GPCR) line are seven transmembrane-α-associated with each other to alter intracellular and extracellular loops. The helical segment is found to be located on the outside of the cell with the amino terminus at the inside of the cell. GPCRs can be divided into several sublines (31^€&11^1>〇 (mainly eight, 3 and (1; lines), and there are additional sequence homology in this subline. GPCRs mainly involve signal reception and transmission, so many physiological functions are affected by them. Therefore, GPCR ligands can be used to treat and prevent a variety of pathological conditions. Some diseases that can be treated with GPCR ligands are listed in S. Wilson et al., Pharmaceutical News Table 1, 2000 (3) Table 1. Most known GPCR ligands are peptide constructs. However, peptide receptor ligands often have obvious disadvantages, such as low bioavailability and metabolic instability. The search for ligands for non-peptide molecules. The so-called "privileged structures" play a special role in the search for new non-peptide receptor ligands. This 'privileged structure' is the basic molecular structure, which is A variety of different receptors are used to prepare ligands. Evans et al. first used a "privileged construct" with a CCK (cholecystosin)-A antagonist coupling derived from a natural product 82695 1246423 from benzodiazepines ( BE Evans et al., J Med·Chem· 1988, 31, 2235) ° As far as proteases are concerned, it has long been known that 'for example, some specific structures can be used as inhibitors for various g. However, it has been described in the past that the main mechanisms of various proteases are Basic inhibitors, but recently compounds have been frequently found to be easily placed in the three-way tectonic regions of various enzymes (see M. Whittaker, Cur_ Opin. Chem. Biol. 1998, 2, 386; A. S. Ripka et al., Before, 441). This kind of 'privileged structure π is also described in GPCRs. In addition to the above benzodiazepines, there are also peptoids in this case. 4-4-substituted 4-arylhexahydro-ρ P-Turn mimetic agents (B. A. Bunin et al., Ann. Rep_ Med. Chem. 1999, 34, 267; RN Zuckermann et al., J. Med. Chem. 1994, 37, 2678; GC B. Harriman, Tetrahedron Lett. 2000, 41, 8853. This report is found in AA Patchett et al., Ann. Rep. Med. Chem. 1999, 35. 289 四 The tetrahydrocarbazole derivatives of the present invention can be made into another class of "privileged structures" of GPCRs. Although the present invention generally produces ligands for GPCRs, the compounds prepared in accordance with the present invention are particularly suitable for use as ligands for certain representative GPCRs, i.e., gonadotropin-releasing hormone (GnRH). This GnRH can be classified into sublines of GPCRs (see U. Gether et al., Endocrine Reviews 2000, 21(1), 90).

GnRH is a hormone which is mainly, but not limited to, synthesized by nerve cells of the hypothalamus in a mammal, transported to the pituitary gland via the portal vein, and released in a regulated manner by gonadotropin cells. By interacting with receptors with seven transmembrane regions, GnRH stimulates the production and release of gonadotropins by the action of second messenger inositol-1,4,5-triphosphate and Ca2+ ions. 82695 -6- 1246423

GnRH released gonadotropin luteinizing hormone (LH) and follicle stimulating hormone (FSH) stimulate the production of amphoteric sterols and gamete maturation. In addition to GnRH (also known as GnRH1), there are two forms of GnRH, namely GnRH2 and 3.

The GnRH receptor is used as a pharmacological marker (pharrnacol〇gicai target) in a variety of diseases that depend on functional sex hormone production, such as prostate cancer, premenopausal breast cancer, endometriosis, and uterine fibroids. GnRH superagonists or GnRH antagonists can be successfully used in these diseases. In particular, the use of male and female hormones in combination with replacement doses of androgen may be another adaptation. An advantage of GnRH antagonists over GnRH super agonists is their immediate effect on blocking gonadotropin secretion. Super-agonists initially produce excessive stimulation of the pituitary gland, leading to the release of gonadotropins and sex steroids. This hormone response 'desenitization and down-regulation due to GnRH receptor concentration' can only be achieved after a delay. Therefore, the GnRH super agonist, whether used alone or in combination with anthrone, may not effectively inhibit the production of male sperm, and is not suitable for male fertility control. Conversely, peptide-like QnRH antagonists, especially when combined with a replacement dose of androgen, can significantly reduce spermatozoa in humans. However, peptide-like GnRH antagonists also have a number of disadvantages. When used as a super agonist, the effect is quite low, so a considerable dose must be administered. Its oral bioavailability is also low, so it must be used for injection. Repeated injections result in reduced compatibility. Furthermore, the synthesis cost of peptide-like GnRH antagonists is also costly compared to non-peptide-like compounds. W〇97/14682 discloses quinoline-derived 82695 1246423 as a non-peptide-like GnRH antagonist. But until now, no non-skin-like GnRH antagonists have been marketed. SUMMARY OF THE INVENTION The object of the present invention consists in providing a compound suitable for the treatment of pathological conditions caused by GPCR, in particular a novel compound (GnRH antagonist) having GnRH inhibition. New GPCR ligands, particularly GnRH antagonists, will go far beyond known, peptide compounds and represent improved or more known non-peptide compounds. This new GPCR ligand, especially the GnRH antagonist, is highly effective and has the highest oral bioavailability. Moreover, such compounds should be readily synthetic and as cost-effective as possible. The present invention also provides a pharmaceutical composition comprising the novel non-peptide GPCR compound, particularly a GnRH# anti-agent. The object of the present invention is to provide a novel GPCR ligand, preferably a GnRH antagonist, for use as a pharmaceutical agent or for the production of a pharmaceutical agent comprising a GPCR ligand, preferably a GnRH antagonist. Furthermore, it is an object of the present invention to provide a method for treating pathological conditions caused by GPCR, particularly GnRH, in a mammal, particularly a human. All of these objects can be surprisingly provided by the provision of a new tetrahydrocarbazole derivative-based organism, a pharmaceutical composition containing the tetrahydrozepine derivative, a method of producing such tetrahydroleaf derivatives, and a Administration of tetrahydrostilbene derivatives to treat mammals, especially humans, pathological conditions caused by GPCR, particularly methods for inhibiting GnRH, and tetrahydrocarbazole derivatives in the production of pharmaceutical agents for the treatment of pathological conditions caused by GPCRs, It is used for inhibiting GnRH. SUMMARY OF THE INVENTION In one aspect, the present invention provides novel tetrahydrophyllin derivatives of the general formula (I). In a second aspect, there is provided a pharmaceutical composition of 82695 1246423 comprising at least one novel tetrahydropurine derivative of the formula (I). The tetrahydrocarbazole derivative is used in two aspects, and the present invention provides a novel pharmaceutical agent of the general formula (I). In another aspect, the invention relates to a novel production of a tetrahydrocarbazole derivative of the formula (I)

An effective amount of the compound of the formula (I) of the present invention

GnRF milk animals, preferably for the treatment of mammals to be treated, preferably human, pathological conditions caused by GPCR, especially inhibition

The method of GnRH. Further, the present invention provides a process for producing a novel tetrahydrocarbazole derivative of the formula (1). This method includes, for example, a step of condensing a cyclohexane derivative immobilized on a solid phase and a suitable substituted phenylhydrazine derivative, followed by derivatization depending on the structure of the desired final compound, and finally from the solid phase. The mixture was cleaved and the product was isolated. [Embodiment] One aspect of the present invention provides a novel tetrahydrocarbazole compound of the formula (I)

82695 1246423 wherein the hydrogen atom is CyC6 alkenyl or c^c: 6 alkyl, and may be taken as an aryl 'heteroaryl or ?? group if desired, where the aryl or heteroaryl group may be Substituted by three substituents, the substituents are independently selected from the group consisting of _ν〇2, CI^, _CF3 ' _0CH3 ' _〇CF3 and a halogen atom, and the R11 group is a ruthenium atom, a Cl-Cl 2 fluorenyl group, Ci_Ci2 arylalkyl, aryl, heteroaryl or -CqCh3 group ' and may be substituted by a substituent selected from -C〇NH2, -COCH3, (10)CH3, -s〇2CH3 and aryl a group of constituents; -COOH C!-C6^ , -ch2oi Ci-Ci2^ R2, R3, R4 and R5 are independently of each other a hydrogen atom, a self atom, _C〇NH2, ·π3, -0CF3, _N〇2, _CN, Ci_c6 alkyl, CrC6 alkoxy, Cl-Ci2 aralkyl, aryl or heteroaryl R6 is _c〇NRV, -C00r8, _CH2Nr8r9, _CH2R8 or Cl-Cl2 alkenyl, as needed Substituted with 8 and R9 groups, wherein R8 and R9 are independently of each other a hydrogen atom, Ci_c^yl~"% fluorenyl, CVC-arylalkyl, aryl or heteroaryl, which is one or more generations Substituted The group is selected from the group consisting of _〇H, _NHy COOR '·ΝΗ_(:(=ΝΗ)_ΝΗ2& _ atoms, and this: R1. The group is a hydrogen atom, Cl-Cl2 fluorenyl group, Ci-Ci2 aryl group a aryl or heteroaryl group, and optionally substituted with a _C0N(Rn)2 group, or wherein the R8 and R9 groups together form a ring structure which may be purely a carbon atom or a carbon atom and Heteroatomic constituents; soil hydrogen atom Ci-Cu:): carboxyl group, CVC丨2 alkenyl, Ci-C12 aralkyl; I ^ & il # ^ i , -NR12R13 , .NHCOR14 , -NHCONHR14 82695 -10- 1246423 -NHCOOR14 or -NHS〇2R14, and may be substituted by one or more substituents selected from the group consisting of _0H, _NH2, -CONH2, _C〇〇H and a halogen atom, R12 and The R13 groups are independently of each other a hydrogen atom, a C2-C6 alkenyl group or a group, and are optionally substituted with one or more aryl or heteroaryl groups, which in turn may be substituted with up to three substituents, such substituents Independently selected from the group consisting of -N〇2 ' -CH3, -CF3, -OCH3 ' -〇CF3 and dentate atoms, R-based helium atom 'Ci-Ci2^-based' Ci-Ci2 alkenyl, CrCn aromatic Base, aryl or heteroaryl , which is optionally substituted with one or more substituents selected from _N02, -CH3, -OR", _cf3, _〇CF3, -OH, -N(RU)2, -〇COR&quot ;, -C00H, _c〇NH2, _NHC〇NHRll, -NHCOOR11 and a group of halogen atoms;

Ci-C: 6 alkoxy, aryl or heteroaryl; the prerequisite is that the compound of the formula (1) is not selected from the group consisting of aragonine, 2, 3, 4_

Hydrogen port bayonet sitting - 3- #酸,田备# , ^ ^ -3-carboxylic acid group.

82695 -11 - 1246423 A compound of the basic tetrahydrocarbazole structure not having the above formula and having the definition of formula (i) is from γ Maki et al. in Chem. Pharm. Bull. 1973, 21 (11), 2460- 2465 and proposed by R. Millet et al. in Letters in Peptide Science 1999, 6, 221-233. The words used to explain the compounds of formula (I) have the following specific meanings:

The Ci C6 or Ci_Ci2 fluorenyl group '' is defined as a branched or unbranched, cyclic or non-cyclic, optionally substituted alkyl group having 1 to 6 or 1 to 12 carbon atoms. Representative examples of such alkyl groups include methyl, ethyl, n-propyl, iso-propyl 'n-butyl 'iso-butyl, tert-butyl, n-pentyl, 2, 2_ Dimethylpropyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, n-nonyl-n-decyl, n-undecylalkyl and n-dodecyl Alkyl and cyclic groups 'particularly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1-cyclopropyl, 1-cyclobutyl, 1-cyclopentyl, fluorene-cyclohexyl , cycloheptylethyl, 2-cyclopropyl, 2-cyclobutyl, 2-cyclopentyl, 2-cyclohexyl, 2-cycloheptylethyl, etc., but not limited to the latter.

CrCV 'alkenyl" is defined as branched or unbranched, cyclic or non-cyclic, unsaturated, optionally having from 2 to 6 carbon atoms and one or more substituted fluorenyl groups. Representative examples include vinyl, allyl, propyl-(thyl)-but-1-enyl-but-2-yl, but-3-yl, butyl-1,3-didecyl, pentyl Alkenyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, pentyl 1,3-1,3-dienylpenta-1,4-dienylpenta-2,3- Di-diyl, isoprenyl, hexenyl, hex-2-enyl, hex-3-enyl, hexenyl, hex-5-alkenyl, hexanyl 3-alkenyl Alkenyl, hex-1,5-dilutyl, hexa-2,4-diindenyl, hexa-2,5-dienyl, hexyl-1,4-dienyl,hex-H5-trienyl Etc., 82695 -12-1246423 but not limited to the latter. c2-c6"alkoxy" means branched or unbranched 'cyclic or non-cyclic, optionally substituted alkane having 2 to 6 carbon atoms Alkoxy. Representative examples of such alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy , n-pentyloxy, positive - Hexyloxy, cyclohexyloxy, etc., but not limited to the latter. "Aralkyl" means an alkyl group having 1 to 12 carbon atoms which is substituted with - or a plurality of aryl groups. Examples of such aralkyl groups include anthracenyl, 1-phenylethyl, 1-phenylpropyl, phenylbutyl, fluorenyl-phenylhexyl, 1-phenyl-2-methylethyl, 1-phenyl-2-ethylethyl, 1-phenyl-2,2 dimethylethyl, diphenylmethyl, triphenylmethyl, 2 or 3-fluorenylmethyl, 2 phenyl Ethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, etc., but not limited to the latter. Thus, "heteroaralkyl" is a heteroaryl-substituted alkyl group. • 'Aryl' means a monocyclic or polycyclic aromatic group which is optionally substituted. Representative examples of such aryl include phenyl, naphthyl and the like, but are not limited to the latter. (hetaryl radical)" and "heteroaryl (4) (10) is called radicai)" the same = the structure of the aryl group representing the above meaning contains one or more heteroatoms, specifically: nitrogen '" dance' oxygen, sulfur and arsenic atoms. Representative examples of such heteroaryl groups include substituted heteroaryl groups and substituted heteroaryl groups, particularly imidazolyl, pyridinyl, quinolyl and the like, but are not limited thereto. The meaning of "% construction" includes the need to have a different number of ring members as needed, especially in such ring structures, except for carbon atoms, the monocyclic or polycyclic structures in which the nitrogen, phosphorus, oxygen, sulfur and arsenic atoms are replaced, *, six- and seven-membered ring structures. Also contained in one or more heteroatoms, especially such ring structures may include saturated, 82695 1246423 but also particularly fully unsaturated, structural units. Representative examples of the ring structure include nitrogen, helium, thiophene, phosphorus cyclopentane, phosphorus cyclohexane, wall ring Genghu, rat-number, one p-plug, one-scale cyclopentazone, a scale ring and two dishes. The basic ring structure such as cycloheptane and the basic ring structure in which mixed hetero atoms are exchanged, but are not limited to the latter. The 'near atom' includes fluorine, chlorine, bromine and iodine atoms, and particularly preferably a chlorine atom. It is to be noted at this point that, in addition to the compounds of the formula (1) as defined above in the art, physiologically compatible derivatives or analogs of such compounds are also included, particularly salts of such compounds. It will also be noted herein that a receptor ligand, or "ligand", which is suitable for the purposes of the present invention, refers to any receptor that is coupled to any receptor (in the present month, the genomic GPCR is doubled). Preferably, the GnRH receptor is a compound that initiates activation, inhibition or other conceivable effects at the receptor. Thus, the ligand " includes an agonist' antagonist, a partial agonist/antagonist, and other acting agonists that cause similar agitation, antagonists, partial agonists/antagonists in the reactor. The compound of the formula (1) of the present invention is preferably a (c) brittle antagonist. The novel tetrahydrofuran derivative of the formula (I) of the present invention, wherein the r7 group is not a chlorine atom, e.g., an R6 group, is an alkyl group, and is a specific embodiment of the present invention. The L form (1) hydration substance 'wherein the R7 group is not a hydrogen atom in any case is another specific embodiment of the present invention. Preferably, the novel tetrahydro 14 derivative of the formula (1) is any of its Ra, Rb,

Rc, Rd, Re and Rf are compounds of a hydrogen atom. The present invention is also preferred: & '() new tetracarbazole derivative, any compound whose Ri group 82695 - 14-1246423 is a hydrogen atom. The novel tetrahydrocarbazole derivatives of the formula (I) are preferably any of the compounds wherein R2, R, R4 and/or R5 are not hydrogen atoms. Particularly preferred in this case are any of the compounds of the formula (1) in which R2, R3, and the Han5 group are each independently methyl, chloro or methoxy. Particularly preferred in this case is any compound of the formula (1) wherein the R2 group is not a hydrogen atom, especially the following compound phenylmethyl-[(1S,2S)_W[[(3R)-3-[[[ Is)_i-(aminocarbonyl)_2_methylpropyl]amino]-carbonyl; μ2,3,4,9-tetrahydro-8-methyl-1H-indazol-3-yl]amino]carbonyl ]_2_Methylbutyl]carbamate (Compound No. in the example), phenylmethyl-[(1S,2S) small (aminocarbonylmethylpropyl)amino]-carbonyl] -6-Gas-2,3,4,9-tetrahydro-1 oxazol-3-yl]amino]carbonyl]_2-methylbutyl]aminoglycolide (148a), phenyl -[(18,28)-1-[[[(311)-3_[[[(())))))]]] , 4,9-tetrahydro-8-decyloxy-1H-carbazole-3-yl]amino]carboxy]-2-methylbutyl]carbamate (147 hearts) preferred formula of the invention (I) a novel tetrahydroanthracene derivative in which R6 is a hydrophobic group, including alkyl, aryl and/or heteroaryl structures and is calculated as two to four singles at the carbon atom substituted by the R6&R7 group. The bond is remotely bearing any compound that supplies a hydrogen bridged receptor system. Particularly preferred is a compound of the formula (]), wherein The 6 group is: phenylpropylamine mercaptoguanidino group, especially the compound phenylmethyl_[(lS,2S)-l_[[[(3R)-3-[[[(ls)-2-amino]- 2-oxo-1-(phenylmethyl)ethyl]amino]carboxy]-2,3,4,9-tetrahydro-1H-inden-3-yl]amino] 82695 -15 - 1246423 ]]-2-methylbutyl]carbamic acid @(66), isoleucido-nonylamino, especially the compound phenylmethyl [(1S, 2S) -1-[[[(311) -3-[[[(18,28)-1-(amino)yl)-methylbutyl]amino]-yl]-2,3,4,9-tetrahydro-1H-indazole- 3-yl],amino]indolyl]-2-methylbutyl]carbamate (M), amidino-4-aminobenzoic acid oxime, especially phenylmethyl -[(18,28)-1-[[[(3)-[[[[[[([([[[[[[[[[[[[[[[[[[[[[[[[[[ Propyl]amino]carbonyl]_2,3,4,9-tetrahydro-1H-indolyl-3-yl]amino]carbonyl]-2-methylbutyl]carbamate (45) ^ Aminamine methyl oxime, especially the compound phenylmethyl-[(lS,2S)-2-methyl-l-[[[(3R)-2,3,4,9_tetrahydro- 3-[[[(18)-2-Methyl-1 -[(methylamino)carbonyl]-propyl]amino]carbonyl]-1H-indazol-3-yl]amino]] Butyl]urethane (222 a), methyloxymethyl-4-pyridyl, especially the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-0-(4-pyridyl) Base)_1H_carbazole-3-methanol (287), carboxyl group, especially compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1indole-carbazole-3-carboxylic acid (^21), or ethyl acrylate group, especially the compound ethyl 3-[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1Η-oxazol-3-yl ]-2-propionic acid ester (289). Also particularly preferred compounds of the general formula (I) are those wherein the R6 group is: carbonyl amidoxime oxime amide group, especially the compound phenylmethyl-[(18,28)-1-[[[(311)-3 -[[[(18)-1-(aminocarbonyl)-2-methylpropane 82795-16- 1246423]]amino]carbonyl]-2,3,4,9-tetrahydro-1H-indazole- 3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid oxime (58), carbonyl sulfinyl guanidinoamine, especially the compound phenylmethyl-[(1S, 2S)- 1-[[[(3R)-3_[[[(1S,2R)-1-(aminocarbonyl)-2-hydroxypropyl]amino]carbonyl]-2,3,4,9-tetrahydro- 111-oxazol-3-yl]amino]-carbonyl]-2-methylbutyl]carbamate, cyclic retinoylamine (eg, exemplified propyl propylamine, especially compounds) Phenylmethyl[(lS,2S)-l-[[[(3R)-3-[[(2S)-2-(aminocarbonyl)-1-pyrrolidinyl]]yl]-2,3, 4,9-tetrahydro-1H-indazol-3-yl]amino]-carbonyl]-2-methylbutyl]carbamate (181a), or carbonyl octahydroindenyl-2-carboxylate Amidoxime, especially the compound phenylmethyl[(18,28)-1-[[[(311)-3-[[(28)-2-(aminocarbonyl)) octahydro-1^1_ 吲哚-1-yl]carbonyl]-2,3,4,9-tetrahydro-1H-indazol-3-yl]amino]carbonyl]-2-methylbutyl] Carbamate (i9〇a), 4-carboxyproguanyl phenylcarboxamide, especially the compound phenylmethyl [(lS, 2S)-l-[[[(3R)-3-[[ [4-(Aminocarbonyl)phenyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-indazol-3-yl]amino]carbonyl]_2-methylbutyl]amine Carbamate (m-), methylaminomethyl-2-acridinyl, especially the compound 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-( 2-pyridylmethyl)_1Η^carbazole-3-methaneamine izm, carbonyl guanamine group, especially compound phenylmethyl [(1§, 2§)_1_ [[[(311)-3-[ [[(18)-1-(yl)methyl)-2-methylpropyl]amino]]]],2,3,4,9-tetrahydro-1H-indazol-3-yl]amine Alkyl]carbonyl]_2-methylbutyl 82695 -17 - 1246423 benzyl]carbamate (-267b) and 2,3,4,9-tetrahydro-N-[(lS)-l-(hydroxymethyl -2-methylpropyl]-3-(3-phenylpropyl)-1 Η-indazole-3-carboxamide (X) or methyl guanamine group, especially compound (2S)-3 -methyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1«^oxazol-3-yl]methyl]amino]-1- Butanol (21 £). Preferably, the novel tetrahydrocarbazole derivative of the formula (1) of the present invention is also any compound whose R7 is a hydrophobic group, including an alkyl group, an aryl group and/or a heteroaryl group. Particularly preferred in this case are compounds of the formula (1) wherein the R7 group is: 2,3-biphenylylpropenylamine, especially the compound n-[[(3R)_ 2,3,4,9 -tetrahydro-3-[(l-oxo-2,3-diphenylpropyl)amino]-1H-indazol-3-yl]-yl]-L-nonylamino-L-aspartment Amine (ϋ), 茚St-amino group, especially compound aminocarbonyl)-2-methylpropyl]_3_[[2,3-dihydro-1H-indol-1-yl)indenyl]amino ]_2,3,4,9·tetrahydro-1H-carbazole-3-carboximine (162a), mercaptoethylamino group, especially compound (3S)_N_[(1S)-l-( ^^ylcarbonyl)-2-methylpropyl]_2,3,4,9-tetrahydro-3-([111)-indol-3-ylethyl)amino]-1H-carbazole- 3-carboxyindole (164b), 2-naphthylethylamino, especially the compound (aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3- [(2-Mercaptoethyl)amino]-1H-indazole-3-carboxamide (i61b), or 3-propenylamine, especially compound 1[[(311)_2,3, 4,9-tetrakis3-[[(2S,3S)-3-methyl-1-oxo-2-[[1]-oxy-3-ylphenyl)amino]pentyl]amino]-1H -oxazol-3-yl]carbonyl]-L-nonylamine thiol-L-associate 82695 -18- 1246423 guanamine, also particularly good for this A compound of the formula (I), wherein R7 is: a phenylmethylcarboxamide group substituted with an aromatic system, in particular a compound (3R)-N-[(lS)-l-(aminocarbonyl)-2 -Methylpropyl]_2,3,4,9-tetrahydro-3-[[(4-methylphenyl)ethinyl]amino]-1H-carbazole_3_Weiamine (165a) , ^^[(18)-1-(Amino-based)-2-methylpropyl]-2,3,4,9-tetraki-3-[[(4-methoxy)]- Ethyl]amino]·1Η-leaf olfactory-3-retinol (m), (3R)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl> 3-[[(3-bromophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-111-oxazol-3-carboxamide (96) ^ (3R)-N- [(lS)-l-(Aminocarbonyl)-2-methylpropyl]-3-[[(4-fluorophenyl)ethenyl]amino]-2,3,4,9-tetrahydro -1H-叶吐-3 - Apoein (91) ^ (3R)-N_[(lS)-l-(Aminocarbonyl)_2-methylpropyl]-3-[[(4-chlorobenzene-鲁基)Ethyl]amino]-2,3,4,9-tetrahydro-1H-yttrium-3-skin g stupid amine (167a); phenylhexylamino group, especially compound (3R)- N-[(lS)-l-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[(6-phenylhexyl)amino]-1 H _叶σ sitting-3 - rebellion 6 stupid amine (23 4a); or phenylpropyl, especially compound 6,8-Dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropyl)-1Η-indazole-3-carboxylic acid (275) and 6,8•dichloro-2 , 3,4,9-tetrahydro-3-(3-phenylpropyl)-ih-indazole-3-carboxylic acid ethyl ester (121). 82695 -19- 1246423 It is also preferred that the novel compound of the general formula (i) of the present invention is present in the R-configuration of a carbon atom, and if and in combination with a 7-group, an aminocarboxylic acid structural member, a carbon atom, is formed. It is replaced by R6 and R7. For the purposes of the present invention, the most preferred compound is phenylmethyl-[(18,28)-1-[[[(311>3-[[[(()))))) Methylpropyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-1Η-oxazol-3-yl]amino]carbonyl]-2-methylbutyl Aminoformate (j84a), phenyl f*-[(lS,2S)-l-[[[(3R)-3-[[[(())))) Methylpropyl]amino]carbonyl]_2,3,4,9-tetrachlorocarbazide: 3-amino]amino]carbonyl]-2-methylbutyl]carbamate (1^), (28)-1_[[(311)-3-[[(4-Phenylphenyl)ethinyl]amino]-2,3,4,9-tetrahydro-8-methoxy-1H-leaf吐-3-yl]carbonyl]-2-pyrrolidinecarboxamide (189a) and 6'8-chloro-2,3,4,9-tetrahydro-3_(3-phenylpropyl)_n_(2 - Pyridylmethyl)-1 - oxazole-3 - methamine (283) Other novel compounds of the formula (1) of the present invention, including their production, are illustrated in the examples. * The novel tetrahydrocarbazole derivatives of the present invention ( 1), as described above, is 〇]? (:: with ligand 'in particular for inhibition, that is, gonadotropin-releasing hormone antagonists, for example, with 10,000, force θ control, hormone therapy, such as treatment Female low birth or infertility, male contraception and right Anti-tumor. In male fertility control, the compound of the present invention reduces spermatogenesis. It is preferably administered in combination with androgen such as fluorenone or 睪 时 organism, such as 睪 旨, at this time, the guanidine derivative can be administered. By injection, for example, intramuscular retention injection, the compound of the present invention (1) can be used together with other hormones such as estrogen and / 82695 -20-1246423 or progesterone for hormones (4), for example, for treating endometriosis. , uterine leiomyoma and uterine fibroids. Particularly preferred is a coupling of a GnRH antagonist of the invention with a tissue selective partial estrogen agonist such as Ralc) xifene. Furthermore, the compounds of the invention may be used in hormone replacement therapy. The inventive compound (1) can be used to enhance female fertility, for example, by guiding ovulation to treat fertility. Conversely, the novel compound (1) of the present invention is also suitable for female contraception. Therefore, the G agonist of the present invention can be combined with an estrogen, preferably a low dose female. Hormone is given to the sputum in the first cycle of the soil for 15 days, preferably with a very low estrogen dose. In the 16th day of the administration cycle, 21 days, the progesterone is added to the estrogen antagonist. Within the combination, the GnR anti-drug of the present invention can be administered continuously throughout the fourth (four) period. This method can reduce the dose of hormones, thereby reducing the side effects caused by non-physiological hormones. In addition, it also has polycystic ovary syndrome and It is beneficial to women who rely on androgen diseases, such as acne, lipid leakage and hirsutism. It is also expected to have improved cycle monitoring compared to previous methods of administration. Other indications are benign prostatic hypertrophy, gonad protection during chemotherapy, and controlled ovarian stimulation. / Artificial reproduction techniques, infant developmental diseases, such as precocious puberty and polycystic ovary. Finally, the above-mentioned compound (I) of the present invention can also be used for the treatment of hormone-dependent tumor diseases such as pre-menopausal breast cancer, prostate cancer, ovarian cancer and endometrial cancer by inhibiting endogenous steroid hormones. The above novel compound (1) of the present invention is suitable for use as a GPCR ligand, in particular

GnRH antagonists are administered to mammals, particularly humans, to treat the above mentioned pathologies, and are also suitable for veterinary medicines, such as animals for breeding and animals, but are also suitable for use in wild animals. , 七丁 can be known by known methods, such as oral or parenteral administration, especially 82695 -21 - 1246423 is administered locally, rectally, intravaginally, nasally or by injection or implantation. It is preferably administered orally. The novel compound (I) of the present invention can be formulated into a administrable form and, if necessary, mixed with a pharmaceutically compatible carrier or diluent. Suitable adjuvants and carriers can be found in Ullmann's Encyclopedia of Technical Chemistry,

Vol. 4, (1 953), 1-39; Journal of Pharmaceutical Sciences, Vol. 52 (1963), 918 ff; published by Czetsch-Lindenwald, '’Hilfsstoffe fur

Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]'' ; Pharm. Ind. 2,1961,72 ff ; Dr. Η. P. Fiedler, '丨Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants For Pharmaceutics, Cosmetics and Related Fields], ', Cantor, K. G., Aulendorf in Wurttemberg, 1971. Oral administration can be accomplished, for example, in solid form such as ingots, capsules, gelatin capsules, coated ingots, granules or granules, but can also be accomplished in the form of a drinkable solution. For oral administration, the above novel compound of the general formula (I) of the present invention can be used together with known physiologically compatible adjuvants and carriers which are often used, such as acacia, talc, starch, sugars such as mannitol, methyl. Cellulose, lactose, gelatin, surfactant 'magnesium stearate, cyclodextrin, aqueous or non-aqueous carrier, diluent, dispersant, emulsifier, lubricant, preservative and flavoring substance (such as ether oil). The compounds of the invention may also be dispersed in microparticles, such as nanoparticulate compositions. Non-oral administration can be accomplished, for example, by intravenous, subcutaneous or intramuscular injection of a sterile aqueous or oily solution, suspension or emulsion, or by implantation or by cream, cream or stopper. It can also be given as a timed release. The implant may contain an inert material such as a biodegradable polymer or a synthetic oxime such as oxime 82695-22-1246423 alkane rubber. Intravaginal administration can, for example, be completed by a haze ring. It can be given in the uterus, for example, by the interval. In addition, it can also be administered transdermally, especially with formulations suitable for the process and/or suitable means such as hydrazine. As described above, the novel compound (1) of the present invention can also be used in combination with other pharmaceutically active agents. Within the scope of combination therapy, the individual active ingredients may be administered simultaneously or separately, in particular by the same route (e.g., orally) or by a different route (e.g., by oral and injection). These active ingredients may be administered in the same or different amounts in a unit dose. Special dosing regimens can also be used when needed. In this way, several novel compounds (I) of the present invention can also be mixed with each other. The dosage may vary widely depending on the indication, the severity of the disease, the mode of administration, the age, sex, weight and sensitivity of the patient. The "pharmacologically effective amount" of a mixed pharmaceutical composition will depend on the skill of the skilled artisan. In the unit dose, the patient's mother weight is 1 microgram to 1 〇 0 mg, and particularly preferably 1 microgram to 1 gram, preferably 1 microgram to 1 milligram. Administration can be done in individual doses or in divided doses. Accordingly, the present invention also encompasses the above pharmaceutical composition comprising at least one of the above novel compounds (I) of the present invention, and optionally a pharmaceutically compatible carrier and/or adjuvant. A preferred pharmaceutical composition is any of the above: a composition of the above novel compound of the invention, particularly the above-described aliquot. In the pharmaceutical composition of the present invention, in addition to at least one of the compounds of the above formula (I), there may be additional pharmaceutically active ingredients, as described above. In the pharmaceutical composition of the present invention, in one of the above preferred, particularly preferred or preferred unit dosage forms, especially in a dosage form for oral administration, comprising 82695-23-2346423 at least one compound of the invention G). Further, another H of the present invention provides a compound of the formula (1).如上| As described above, the preferred four-hearted compound of the formula (1) of the present invention is also a preferred compound, particularly a preferred compound as described above and in the following examples.曰 For the compound (1) of the present invention for use in a pharmaceutical composition and the compound (1) for use as a medical agent, please refer to the note concerning the above novel compound (1) of the present invention: and the possible use and administration method. In addition, the invention also provides at least one of the formula (1) tetrachloro-flavor (four) organisms of the invention, which has the definitions as described above, and thus defines the tetrahydro-salt saliva disclosed by MiUet et al. and Maki et in the publication. Included in the definition of formula (1) 'in the preparation of a pharmaceutical agent for the treatment of diseases associated with GpCR, in particular: gonadotropin-releasing hormone (GnRHU material.), in force-million, the invention provides at least one The compound of the present formula (1) as defined above, but also includes the compound excreted in the publication by et al et al et al., i.e., 3-amino-i, 2, 3, 4·4 Hydrogen μ-3 oleic acid/3-Amino-6-methoxy-1,2,3,4-tetrahydroyelt-3 oleic acid, 3-amino-6-lower base-1,2 , 3,4-tetrahydroanthracene _3_acid, 3_ethylamino-1,2,3〆-tetrahydroindole small acid, methyl-3-acetamido], 2, 3,4_four-leaf leaf H-recodile's (-)-methyl-3_acetamido-1,2,3,4-tetrahydrocarbazole, oxime, and -butoxycarbonyl- Amino-indole, 2,3,4-tetrahydrocarbazole_3_carboxylic acid, in: a pharmaceutical agent to inhibit GnRH, preferably for male fertility control, for hormone therapy, female lower pregnancy And infertility, for female contraception and treatment of itching 82795 -24-1246423. More clearly, ''the above formula (I) compound, but also includes the above-mentioned compounds excreted'' means the formula ( I) Compound

Wherein the R1 group is a hydrogen atom, C^C:6 alkenyl or Cl_C6 alkyl, and may be optionally substituted with an aryl group, a heteroaryl group or a -COOR11 group, wherein the aryl or heteroaryl group may be up to three Substituted by a substituent, the substituents are independently selected from the group consisting of _n〇2, -CH3, -CF3, _OCH3'-OCF3 and a halogen atom, and the R11 group is a hydrogen atom, a CVCk alkyl group, a Cl_Ci2 aralkyl group , aryl, heteroaryl or -COCH; group ' and may be substituted by a substituent selected from the group consisting of -CONH2, -COCH3, -C00CH3, -so2ch3 and aryl; R 'R 'R and R groups are independent of each other. JL is a hydrogen atom, a halogen atom, _c〇〇H, -CONH2, -CF3, -OCF3, -no2, -CN, c"c6 alkyl, 匕心稀' C"C6 alkane An oxy group, a Ci-Ci2 aralkyl group, an aryl group or a heteroaryl group; the R6 group is, C〇NR8R9, -CO〇R8, -CH2NR8R9, -CH2R8, -CH2OR8 or a C1-C12 group, which is optionally 8 and R9-substituted, 82695 -25 - 1246423 wherein R8 and R9 are independently of each other a hydrogen atom, c, butyl kc12fe, Ci-Ci2 aryl-CVCn heteroarylalkyl, aryl or heteroaryl, And α has one or more Substituted by a substituent, these substituents are selected from the group consisting of _〇H, _NH2, _e (3NHRi% -COORW '- atoms, where R10 is a hydrogen atom, CVCq alkyl, cc 匕 12 vol a aryl group, an aryl group or a heteroaryl group, and optionally substituted with a _CON(Ru) 2 group, or wherein Rm together form a ring structure which may be purely composed of a dish atom or a carbon atom and a hetero atom Composition; R7 group is a hydrogen atom, a Cl-Cl2 alkyl group, a Cl_Ci2 fluorenyl group, a fluorene group, an aryl group, an aryl group or a heteroaryl group, -NR12R13, -NHCOR14, _NHec)NHRl4, -NHC00R14 or - deleted from 4, and It may be substituted with one or more substituents, and the substituents are independently selected from the group consisting of _〇H, -NH2, _c〇NH2, and a halogen atom, and the R12 and R13 groups are independently a hydrogen atom, CrQ olefin. Or a Ci-Ci2 alkyl group, and optionally substituted with one or more aryl or heteroaryl groups, which in turn may be substituted with two substituents independently selected from _νό2, _ch3,- a group consisting of CF3, -0Ch3, _OCf3 and a halogen atom, the R14 group being a hydrogen atom 'CVC12 alkyl group, cVCu cation group, CVCid alkyl group, aryl group or heteroaryl group, Optionally substituted with one or more substituents selected from -N02, -OR11, -CFV -〇CF3, -0H -N(RU)2 ' -OCOR", /οοΗ,_c〇Nh2 , -NHC0NHRii: a group consisting of -NHCOOR11 and a South atom;

Ha ' Hb ' ' Rd ' Re and "each is a hydrogen atom, a halogen atom, -COOH, -CONH2, -CF3, _〇Cf3, _N〇2, -CN, Ci_C6 alkyl 82695 -26- 1246423 alkoxy , aryl or heteroaryl. Indications relating to the above novel compounds of the general formula (1) of the present invention (i.e., compounds which have been removed from the publications previously disclosed in Maki et al. and Millet et al.) have been found in the present invention. The novel compound (I) is provided in the reference. Preferred and particularly preferred compounds, such as the above compounds, are used in the preparation of a pharmaceutical agent for inhibiting GnRH, and are preferred compounds of the novel compound of the above formula (1) of the present invention and The present invention provides the above-mentioned compound (1) of the present invention, but also includes the use of a compound excluding the name, for use in male birth control or female contraception. Preferred compounds of the present invention for use herein and The particularly preferred compound is a preferred or particularly preferred compound of the above formula (1) of the present invention as described above. Further, the present invention provides a method for male birth control or female contraception, which comprises administering to a subject, preferably a mammal. , Particularly preferred is a human, effective control of male fertility or a contraceptive amount of a compound of the present invention. In another aspect, the present invention relates to a method for treating a pathological condition caused by gpcr, and the method comprises administering a mammal in need of such treatment, in particular It is a human at least π sigma (I). This administration is generally carried out in a pharmaceutically effective amount. As described in the foregoing (four) new compound (1) of the present invention and the pharmaceutical composition of the present invention, it is necessary to know by its skill. Ρ know 4 to determine the effective ΐ required for individual cases. However, the compound of the present invention (1) j 疋 is 1 microgram to 100 milligrams in the early position of the sword, especially preferably 1 microgram to 1 〇 券 日 from the day ^,,, preferably疋 1 μg to 1 mg / body weight to the patient in the oral therapy. Preferably, the sputum is given in a manner of 疋,. to the mouth. The ice may be one or more compounds of the invention (1) 盥s 7 . One other active ingredient is combined into the butyl, which has been as described above. 82695-27-2746423 Further, the present invention is also directed to a method of inhibiting GnRH in a patient which comprises administering a pharmaceutically effective amount of a compound of the above formula (1), but also to administer a compound excluding the above-mentioned name to a patient in need of treatment. This method is preferably used for male fertility, steroid therapy, female contraception, treatment of female pregnancy or infertility and anti-tumor. In a final aspect, the invention also provides a process for producing a novel tetrahydrogen derivative of the formula (I) of the invention. The process for the production of the novel tetrahydrocarbazole derivatives of the formula (I) according to the invention can be carried out in various ways, for example in the liquid phase or in part or all of the solid phase synthesis: suitable synthesis for the production of individual representative compounds of the formula (I) The selection of conditions can be accomplished with the general technical knowledge of the skilled artisan. Next, the process for producing the compound of the formula (1) of the present invention will be described in a general manner. Then describe the specific process of change, the solid phase process. To further illustrate the invention, various representative compounds of formula (1) are seen in the examples below. The process for producing the compound of the formula (I) of the present invention is preferably carried out as follows: A central tetrahydrocarbazole skeleton is obtained by Fischer-indole synthesis known in the art. After completion, a suitable protected cyclohexanone derivative-protected group is condensed with a suitably protected phenyl hydrazine derivative which is also suitably substituted in each case (for example according to Britten & Lockwood, J. c. S. Perkin I 1974 1824 or according to Maki et al., Chem. Pharm· Bull· 1973 21 240). Specifically, the cyclohexanone skeleton is substituted at the positions 3, 3, 5, 5, and 6, 6 at a position 1 to a group and at the 4, 4' position with a group R6 and R7 or, if desired, The precursor is replaced. The benzoquinone skeleton is substituted with an R4R5 group as needed. The commercially available derivatives which are not commercially available can be obtained by methods known to those skilled in the art. The positional isomer obtained by condensing the cyclohexanone derivative and the phenylhydrazine derivative is separated by a dark method, 82695-28-2846423, for example, HPLC. After synthesis of the central tetrahydrogen leaf-biting skeleton, the R1 group can be introduced by a N-alkylation of the corresponding R1-halide with a nitrogen atom at the 9-position (for example, according to Pecca & Albonico, J. Med. Chem. 1977, 20,487 or also according to Mooradian et al., J. Med. Chem. 1970, 13, 327). The R6 and R7 groups, as described above, vary depending on their type and are introduced in different ways, as will be described in more detail below. In these groups, the α-amino carboxylic acid structure can be treated by NH4(CO)3 and KCN under the Schotten-Baumann conditions known in the art, and then the resulting carbendazole is hydrolyzed. (Britten & Lockwood, J. C. S. Perkin I 1974, 1824) The guanamine group is preferably prepared by peptide chemistry known in the art. At this time, the acid component is activated with an activator such as DCC or HATU (Tetrahedron Lett. 1994, 35, 2279) and condensed with the amine component in the presence of a test such as DIPEA and/or DMAP. The ester group can be prepared from the desired alcohol according to similar conditions. The solvent used in this case is preferably anhydrous. The secondary or tertiary amine group is prepared by nucleophilic substitution of the primary amine alkyl iS complex or reductive amination of the aldehyde/ketone (eg J. 〇rg. Chem. 1996, 61, 3849 or Synth· Comm· 1994, 609). The sulfonamide group is prepared by reacting the corresponding amine with sulfonium chloride. Urea groups are prepared by reacting an amine with the corresponding isocyanate.

The urethane group is prepared by first reacting the corresponding alcohol with carbonyl dihydroxybenzotriazole ((HOBt) 2CO) and then reacting with an amine (Warass et al., LIPS 82695 -29-1246423 1998, 5, 125). The alcohol can be obtained by reduction of a carboxylic acid ester with LiAlH4. The aldehyde group can be prepared by oxidation of the alcohol precursor with DMSO/grass chloride, for example under Swern conditions known in the art (Pansavath et al., Synthesis 1998, 436). The substituted amine group can be obtained by reductive amination of an amine with an aldehyde (J. Org. Chem. 1996, 61, 3849). The ether group can be obtained by subjecting an alcohol precursor to deprotonation by, for example, NaH under the Williams conditions known in the art, and then reacting with an alkyl dentate. The double bond in the group can be introduced by reaction of the aldehyde or ketone precursor with the corresponding phosphine compound under Wittig conditions known in the art. The solid phase process for producing the compound of the formula (I) of the present invention preferably comprises the steps (a) to (d), which are described in detail below:

Step (a) is primarily similar to Fischer-4丨嗓 synthesis, for example according to Britten & Lockwood, JCS Perkin I 1974, 1824; Maki et al.? Chem. Pharm. Bull. 1973, 21, 240 or Hutchins & Chapman, The method of Tetrahedron Lett. 1996, 3 7, 4869, which comprises a cyclohexanone derivative (II) suitable for the formation of an R6 group via a linker L to a solid phase SP, 82695 -30-1246423 wherein When the R7 group is a hydrogen atom, a q-Cu alkyl group, a Ci-Cu# alkyl group or a heteroaryl group, the G group is equal to R7, and when the R7 group is different from the definition of R7 in the formula (I), the G group is The group is equal to the -NH-Pg group, wherein Pg represents a protecting group and a phenyl anthracene derivative (III) substituted with R2 to R5

(ΠΙ) Condensation in the presence of an acid, preferably acetic acid, and a metal salt, preferably ZnCl. The solvent is preferably DMF. The definition of Ra to R/ is as described in the above formula (I). Some substituents or groups may optionally be in protected form, and such protecting groups may be removed in the process at a suitable time according to methods known in the art. For the purposes of the present invention, Rinkgi amine resin (Rink, Tetrahedron Lett. 1989, 28, 3787), HMB Tree (Sheppard et al, Int. Peptide Protein Res. 1982, 20, 451), Wang resin (1^) 61&1.,1.0.(:1^111· 1981,46,3433) or chlorotrityl-based resin for &1*1〇36131.,1 plus.1·Peptide Protein Res·1991,38 , 562) is a suitable solid phase SP if the cyclohexanone derivative (II) is to be immobilized on the solid phase SP by (amino-)carboxylic acid. When the alcohol precursor of the cyclohexanone derivative (II) is to be immobilized, a DHP linker can be used (Liu & Elman, J. 〇rg. Chem. 1995, 60, 7712). The aromatic compound precursor of the cyclohexanone derivative (II) can be immobilized on the triterpene resin in a 'scratch-free' manner (Brase et al., Angew. Chem. Int. Ed. 1998, 37, 3413). 〇82695 -31 - 1246423 Preferably, the Pg protecting group contained in the G group and protecting the α-amino group-NH2 is preferably a SnFm〇c"(9-fluorenylmethoxycarbonyl) protecting group, but it is also generally used. Other amine protecting groups, for example, are alkoxycarbonyl protecting groups (e.g., (wherein oxycarbonyl) or "Boc" (tris-butoxycarbonyl) or other suitable protecting group such as ''trityl The protective group of (trityl). The structure of the linker L is defined by the above R6 after the corresponding derivatization (steps (3) and (c)) and the final product (step (d)). The desired R6 group is a derivative of the formula (1) tetrahydroanthracene derivative. When the structure of the linker L is described, when R6 is equal to the -conr8r9 group, the R6 group of the product of the formula (1) of the present invention has _C〇NR8R9. In the sense, the compound Pg-N(R8)-R9, which forms the linker L, is first activated with an activating reagent such as Dcc (dicyclohexylcarbodiimide). HATU (7) <7_nitrobenzoxazolyl)-N,N,Nf,N'-tetramethylphosphonium hexafluorophosphate) is immobilized on the solid phase SP via a free amine group of sp, wherein "and SP The meaning is as described above, R9, forming part of the subsequent R9 group. The protecting group Pg is then cleaved, for example, by cleavage of the Fmoc protecting group with hexapyridine/DMF. The compound CONH-SP is prepared, and the latter compound and ring are prepared. A ketone derivative (π), a cyclohexanonecarboxylic acid (ruthenium) precursor.

G\ /COOH X /Rb 82695 -32 - 1246423 The above cyclohexanone derivative (II) is obtained by reacting with an activator such as DCC or HATU. The meaning of the linker L is the same as that of the aforementioned -CONR8-R9'-CONH-SP. Any type of isomer (enantiomer, non-mirrored stereoisomer or positional isomer) which is sometimes produced, as well as the isomers produced in the other steps described above, can be separated by HPLC using known methods. The actual step (a), that is, the condensation of the cyclohexanone derivative (II), is carried out by using the substituted phenylhydrazine derivative (III), and cleaving the G group by, for example, hexahydropyridine (when the Fmoc protecting group) The protecting group Pg in this case, in turn, can produce a free α-amino group. If the R7 group is -NHCOR14, -NHS02R14, -NR12R13 (wherein R12 and R13 are not simultaneously a hydrogen atom), -NHCONHR14 or -NHCOOR14 groups, and finally cyclohexanone bonded to the resin in step (b) The newly formed unprotected α-amine group of the derivative (II) is derivatized to form various aforementioned different R7 groups. Depending on the type of R7 group required for the tetrahydrocarbazole end product (1) of the present invention, the procedure is as follows: when R7 is a -NHCOR14 group, the final product of step (a) and the carboxylic acid - R14C〇OH are used as an activator. , for example, in the presence of DCC or HATU, and in the presence of a base such as DIPEA (diisopropylethylamine) or DMAP (4-dimethylaminophyllophosphonate), known to form peptide bonds Method (see, for example, Tetrahedron Lett. 1994, 35, 2279; Alternative (i)). When R7 is sulfonamide-NHS02R14, the reaction product of step (a) is reacted with a sulfonic acid derivative R14S〇2X wherein X is a leaving group, preferably a halogen atom, especially a chlorine atom, in the presence of a base such as Reaction in the presence of DMAP or DIPEA (see, for example, Gennari et al., EJOC 1998, 2437; Alternative (ii)) 〇82695 -33 - 1246423 where R7 is a -NR12R13 group (wherein Ri2 and not simultaneously a hydrogen atom) And when R12 is a hydrogen atom, the reaction product of step (a) is reacted with reagent r13x, wherein X is a leaving group, preferably a functional atom, especially a chlorine atom, in the presence of a base such as DBU or DIPEA. The next reaction (see, for example, j〇c 1995, 60, 4287 or JOC 1996, 61, 3849), or reacted with the acid r^cho in the presence of a reducing agent such as, for example, NAH/B(OAc)3. When neither Ri2 nor Rn is a hydrogen atom, the reaction product ketone R12c〇R13 in step (4) is reacted in the presence of a reducing agent (refer to Ellmann et al., JOC 1997, 62, 1240 or Synth.

Commun· 1994, 609; Alternative (iii)). When r7 is equal to -NRi2Ri3 and both R12 and R13 are hydrogen atoms, the following alternative (vi) is used. When R7 is -NHCONHR14 (urea derivative), the reaction product of the step is reacted with isocyanine R14NCO (refer to Brown et al., JACS 1997 119 3288; Alternative (iv)). The r7 is a carbamate or In the urethane-NHCOOR14 group, the reaction product of step (a) is reacted with an alcohol HOR which is first activated with carbonyl dihydroxybenzotriazole ((HOBt) 2c) (cf. Warass et al., LIPS 1998, 5 125;

Alternative (v)) ° where R7 is a hydrogen atom, a cvcu alkyl group, an even aralkyl group, an aryl group, a heteroaryl group or a group 2 (ie, R7 is equal to _nr12r13, and both r12 and R13 are hydrogen atoms) When the name is gone to step (b), because it does not need to be further evolved (aiternative. Similar to step (b) above, step (C), that is, the derivation of the nitrogen atom of the ruthenium, also corresponds to each of the other methods detailed below: In the above (1) to (V) precision of the above step (b), the product obtained by (b) is deprotonated with a base such as, for example, NaH or NaHMD, and then subjected to R1X group derivation 82695 -34 - 1246423. Wherein oxime is a leaving group, such as a halogen atom, especially a chlorine atom (see Collini & Ellingboe, Tetrahedron Lett. 1997, 38, 7963; Pecca & Albonico, J. Med. Chem. 1997, 20, 487 or Mooradian Et al·, J·

Med·Chem. 1970, 13, 327). In the case of (vi) described in the above step (b), if step (b) is omitted, the deprotonation reaction is carried out in a similar manner to the above method using a base such as NaH or NaHMDS (a), and then the R^X group is used. Derivatized, wherein X is a leaving group, such as a halogen atom, especially a chlorine atom. 10 Finally, step (d) mainly comprises cleavage of the reaction product obtained in (c) from the solid phase SP. For example, Wang, trityl, DHP and Rink amide resins are used, and (c) the cleavage of the obtained reaction product is carried out by means of an acid, particularly TFA (trifluoroacetic acid). For example, HMB resin undergoes amine-based decomposition and cleavage, using ammonia in methanol as a cracking agent. The desired product is then isolated by general method. Specific examples for producing the tetrahydrocarbazole derivatives of the present invention are described below. EXAMPLE 1. General Synthetic Method of the Compound of the Invention - A. Coupling a Carboxylic Acid to a Rink Amidyl Resin Resin: A 1 mmol of Fmoc-protected Rinkamide resin (166 mg, concentration 0.6 mmol/g ) Pre-soaked with 1.5 ml of DMF for 20 minutes in a glass bottom reactor. After aspiration, add 1 · 5 ml of 20% hexahydropyridine / DMF and stir for 5 minutes.

After aspirating, 1.5 ml of 20% hexahydropyridine/DMF was added and stirred for 15 minutes. Then add 675 μl of a 0.267 F solution of Fmoc-protected aminocarboxylic acid in DMF, 675 μl of HATU solution (0.267 Μ in DMF) and 150 μl of hydrazine solution (2·4 Μ in DMF). And 0.01 mmol of DMAP, stirred at 40 ° C 82695 -35-1246423 for 4 hours. After aspirating, the same reagent was added and stirred at 40 ° C for 4 hours. Then aspirate and wash four times with DMF. B. Coupling the carboxylic acid to the trityl-resin resin: 2.98 mmol of Fmoc-protected aminocarboxylic acid was dissolved in 30 ml of anhydrous dichloromethane and mixed with 14.3 mmol (2.45 ml) of DIPEA. Within 2.98 millimoles of 2-chlorotriphenylmethyl-based resin (2 grams, 1.49 millimoles per gram of resin). After shaking for 2 hours, the resin was aspirated with glass and washed three times with 20 ml of dichloromethane/MeOH/DIPEA 17:2:1. It was then washed three times with 20 ml of methylene chloride, three times with methanol, three times with 20 ml of ether and dried in vacuo. A resin having a concentration of 0.5 to 1 mmol of aminocarboxylic acid per gram of resin was obtained. C. Coupling of the carboxylic acid to the HMB resin: 21.3 mmol of the amino acid and 21.3 mmol of HATU were dissolved in 60 ml of DMF and mixed with 63.9 mmol (10.9 ml) of DIPEA. After 5 minutes, 5 g of polystyrene-HMB resin (concentration: 0.71 mmol/g resin) was added and shaken at room temperature for 5 minutes. Then 21.3 millimolar (2.6 grams) of DMAP was added and shaken at room temperature for 1 hour. The resin was then aspirated and washed once with 100 ml of DMF, DCM and DMF. The resin was mixed with 100 ml of 10% Ac20 (acetic anhydride) / DMF / 5% DMAP and shaken for 15 minutes. After aspirating, it was washed three times with 100 ml of DCM and ether, and it was vacuum dried. D. Coupling the carboxylic acid to Wang resin: 54.6 mmol of carboxylic acid and 27.3 mmoles (4.2 ml) of DIC were dissolved in 500 ml of anhydrous DCM and stirred at room temperature for 10 min. After the precipitated urea was filtered off, the solution was evaporated to dryness and the residue was dissolved in 160 ml of anhydrous DMF. This solution was added to 4.55 mmol (5 g, 0.91 mmol/g resin) Wang resin 82695 -36-1246423. This resin line was immersed in DMF and with 4.55 millimolar (556 mg) DMAP. mixing. After shaking at room temperature for 1.5 hours, the tree was aspirated and dissolved in 100 ml of 10% Ac20/DMF/5% DMAP and shaken for 15 minutes. After aspirating, it was washed three times with 100 ml of DCM and ether, and dried under vacuum. E. Coupling the alcohol to the DHP resin: 0.5 mmol of DHP resin (0.5 g, concentration density 1 mmol/g) was pre-soaked in 2 ml of dichloroethane for 15 minutes. A solution of 2 ml of 0.75 sterol/0.37 Μp-pyridinium sulfonate was added and stirred at 80 ° C for 16 hours. After cooling to room temperature, add 5 ml of pyridine, shake briefly and aspirate. Wash twice with 5 ml of DMF, DCM and hexane. F. Protective removal of resin bonded Fmoc protecting groups: 1.5 ml of 20% hexahydropyridine/DMF was added to 0.1 mmol of resin bonded Fmoc groups for 5 minutes. After aspiration, add 1.5 ml of 20% hexahydrate to the DMF/DMF and stir for 15 minutes. Wash out four times with DMF after aspiration. G. Coupling the carboxylic acid to the resin-bonded amine function: 675 μl of a solution of 0.267 F of Fmoc-protected aminocarboxylic acid in DMF, 675 μl of HATU solution (0.267 M in DMF) and 150 A microliter of NMM solution (2.4 Torr in DMF) and 0.01 mmol of DMAP were added to 0.1 mmol of resin bonded amino function and stirred at 40 °C for 4 hours. After aspirating, the same reagent was added and stirred at 40 ° C for 4 hours. Then aspirate and wash four times with DMF. H. Coupling of acetic acid to resin-bonded amine function: A solution of 1.5 ml of 10% acetic anhydride in DMF was added to 0.1 mmol of the resin bonded amino function and stirred at room temperature for 15 minutes. Then aspirate and wash four times with DMF. 82695 -37- 1246423 I ·Synthesis of tetrazole with resin-bonded cyclohexanol! Sit: Before the reaction, wash 0.1 mM earring hexanone resin twice with 2 ml of DMF and wash with 2 ml of acetic acid. Two times. Then, a solution of 丨ml of DMF and 2 ml of 0.5 M 肼/0.5 M ZnCl2 in acetic acid was added to the resin, and the mixture was stirred at 70 ° C for 20 hours. Then, it was aspirated and washed twice with 2 ml of acetic acid and 2 ml of DMF. J. Starting with a resin-bonded awake amine. The amine was washed twice with 2 ml of DMF and DCE. Here, 0. 1 millimolar resin bonded amine was added with 1 ml of 0.5 M DC of diacetyl chloride in DCE and 2·5 Μ NMM/1 equivalent of 0·25 M DMAP in 400 μl of DMF. After stirring at 60 ° C for 12 hours, aspirate and repeat the coupling. After aspiration, wash four times with 2000 ml of DMF. K. Synthesis of urea by reaction of resin-bonded amine with isocyanate: A solution of 2 ml of 0.5 Å isocyanate in DCM was added to 0.1 mmol of resin-bonded amine, and stirred at room temperature for 18 hours. Then aspirate and wash four times with DMF.

L. Resin-bonded amine reacts with pre-activated alcohol to synthesize urethane. · Pre-activated, 0.4 Μ alcohol and 0·39 Μ dibenzotriazole carbonate and 〇·39 Μ pyridine Stir at 40 ° C for 15 minutes in DMF. A 1 mM resin-bonded amine was mixed with 1 ml of pre-activated alcohol, and 167 ml of a 24 Torr solution of hydrazine in DMF was added. After stirring at 6 ° C for 4 hours, it was aspirated and washed four times with DMF. M. Synthesis of N-alkylamine by resin-bonded amine with alkyl halide and catalyst alkylation: 1 ml of 〇·5 Μ halide in DMF/0.05 Μ KI and 416 μl 82695 - 38-1246423 2.4 DIPEA in hydrazine DMF was added to 0.1 mmol of resin-bonded amine and stirred at 90 ° C for 12 hours. After aspiration, the resin was washed four times with 2 ml of DMF. N. N-alkylation of resin-bonded ruthenium nitrogen with a halide/NaH in DMF: Know 1 liter DMF and 0.5 mM NaH (5 5% oil suspension) 0 · 1 耄 More resin bonded amine. After stirring at room temperature for 3 minutes, add 0.5 ml of the halide in the DMF of 0. 5 Torr at 45. (3 stirring for 8 hours. Then aspirate, wash twice with 2 ml of methanol, DMF, methanol and DMF. O. Wang, tribendyl, DHP and Rink amide resin cleavage: 2 ml 95% TFA/ A 5% H2 hydrazine solution was added to ο mM resin and shaken for 3 hours at room temperature. The resin was then filtered off and washed with 2 mL of TFA. The combined TFA solution was evaporated to dryness to give crude product. Amino-based decomposition cracking of Shuyue: Add 23⁄4 liters of DMF and 7 M Μ]% in 2 ml of methanol to 〇1 mmol of the resin, shake at room temperature for 18 hours, then filter out the resin, using DMF The mixture is evaporated to dryness to give the crude product.

3 [[(9H % 9_ylmethoxy)carbonyl]amino]2,3,4,9-tetrahydro-old_indole-3-carboxylic acid I will be 38.4 millimolar (6·m) 4. Heart ethylene dioxycyclohexanone and 39·8 millimolar (4.3 g) phenylhydrazine are dissolved in 5 ml of water or 1 ml of water, respectively, and mixed. After stirring for 1 minute, the resulting milky emulsion was extracted five times with ethyl acetate, dried over MgSO4, and evaporated to dryness. Yield: 9.2 g of orange oil. 9.2 g of unpurified phenyl hydrazine was dissolved in 24 ml of toluene at room temperature, and mixed with 46.9 g of ZnCU freshly ground in 82695 - 39-1246423. After refluxing for 9 minutes in a water separator, most of the toluene was distilled off and mixed with an excess of 2N NaOH, and extracted three times with ethyl acetate. The extract was washed with brine, dried over MgSO.sub. The resulting black oil was purified on cerium oxide gel using ethyl acetate / hexanes: 9 . Yield: 2.7 g of a beige solid. 11.6 millimolar (2.7 g) 1,2,4,9-tetrahydrospiro[3H-carbazole-3,2*-[1,3]di-p-sinter] and 640 mg p-toluene continued The acid was dissolved in 70 ml of propylene® and stirred at room temperature for 2.5 hours. This solution was added to a NaHC〇3 solution, extracted with ethyl acetate, washed with brine, dried with EtOAc, and evaporated. It gave 2.13 g of a reddish brown solid. Recrystallization from ether gave 1 · 1 g of a beige solid. Will be 60.23⁄4 mol (11.1 g) 1,2,4,9-tetrahydrospiro- 3H-leaf-3-one, 83 g KCN and 22.0 g (NH4) 2 C 〇3 at 80 C in 550 ml 60% Heat in ethanol for 3 hours in an autoclave. After cooling to room temperature, the reaction mixture was added to ice water and the solid was filtered. Yield: 1 〇 · 1 g of a gray solid. 44.23⁄4 mol (11.3 g) 1,2,4,9-tetrahydrospiro[3H-leaf-3,4,-misoporphyrin-2],5f-diketone and 62 g Ba(OH) 2 x 8 H20 was heated to 145 C for 13 hours in 145 ml of water. After cooling to room temperature, the viscous material was mixed with 37 g of (NH 4 ) 2 C 〇 3 while stirring and heating to 10 ° C for 30 minutes. After cooling to room temperature, it was filtered, washed with water and the filtrate was evaporated to dry. Yield: 7·7 g of beige solid. 26 mM (5.8 g) of 3-amino-2,3,4,9-tetrahydro-1H-leaf-3-carboxylic acid in 26 ml of 1 N NaOH and 26 mM in 28 ml of acetonitrile Ears (8.76 g) Fmoc-ONSu was mixed at room temperature and diluted with 130 ml of acetonitrile/H 2 〇1 :1. After two hours, the pH was adjusted to 9 (1.5 mL) with NEt3 and stirred at room temperature overnight. 82695 -40 - 1246423 Then 6.3 g (18.7 mmol) of Fmoc-ONSu dissolved in 19 ml of acetonitrile was added and stirred for another two hours while monitoring the pH. After distilling off acetonitrile, it was acidified with 0.01 M EtOAc and ethyl acetate. The extract was washed to neutrality, dried over Na 2 S 4 and centrifuged to dryness. Recrystallization from ether/hexane. Yield: 1〇.7 g. lH-NMR (d6-DMSO): 5-2. 〇7 ppm (m? 1H); 2.50 (m5 1H); 2.70 (bs; 2H); 3.04 (q, 2H); 4.17 (m? 2H); 4.28 (m5 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 Separated into diastereomers by palm hplc. (R) -3-[[(9H-芴-9-ylmethoxy)carbonyl]amino]_2,3,4,9-tetrahydro-1H-indazole-3-deoxalate] tR=6.4 min (Chiralcel OD 10 μιη LC50 250x4.6 cm, burned / isopropanol 75 : 25, 80 ml / min) (S) -3-[[(9H_^冬基methoxy) 基基]amino]- 2,3,4,9_tetrahydro-1Η-咔吐-3 - tartrate edge tR=7.5 minutes (Chiralcel OD 10 μηι of LC50 250x4.6 cm, hexane/isopropanol 75: 25, 80 ml/ Min) 1-[[(9HU-ylmethoxy)-yl]amino]> 4-oxocyclohexanecarboxylic acid 2 320 mM (50 g) 4,4-ethylenedioxycyclohexane It was suspended in 8 〇 0 ml of 50% EtOH and mixed with 1500 mM (144.5 g) (NH4) 2C03 and 640 mM (41.7 g) KCN. After stirring at 60 ° C for 5 hours, B 82695 -41 - 1246423 alcohol was removed in vacuo, and after cooling, the aqueous residue was filtered, washed with water and dried. Yield: 72.4 g of 4,4-1,4-diindole-9,1 diazane disulfide [4.2.4.2] fourteen post-burning -1 0,1 2 -dioxin. 295 millimoles (66.8 grams) of 4,4-1,4-dioxa-9,11-diazaspiro[4.2.4.2] tetradecane-10,12-dione and 826 millimolar ( 260.6 g) Ba(OH)2 X 8H20 was stirred in a dust boiler at 150 ° C for 6 hours at 2.5 °C. After cooling to room temperature, 1032 mmol (99.2 g) of (NH 4 ) 2 CO 3 was added to the solution and stirred at 60 ° C for one hour. The suspension was filtered, washed again and the filtrate was lyophilized. The residue was recrystallized from H2 /MeOH. Yield: 45.4 g of 8-amino-1,4-dioxaspiro[4,5]nonane-8-carboxylic acid. 213 millimoles (42.9 grams) of 8-amino-1,4-dioxaspiro[4,5]nonane-8-carboxylic acid in 213 ml of IN NaOH and 213 millimoles in 240 ml of acetone ( 71.9 g) Fmoc-ONSu was mixed and diluted with 1 ml of acetonitrile/H20 1 :1. After the pH reached 9, the mixture was stirred at room temperature overnight. After removing the acetonitrile by a rotary evaporator, it was acidified with 〇·〇1 M HCl and extracted with ethyl acetate. The extract was washed until neutral, dried over NajO4 and evaporated to dryness. The residue was recrystallized from ethyl acetate /hexane. Yield: 79.0 g of 8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino-indole, diterpenoid [4,5]decane-8-rebel acid. 187 mmol (79 g) of 8-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino-1,4·dioxaspiro[4,5]decane-8-carboxylic acid Stir at room temperature for 4 hours in 3.5 liters of acetone / ο"M HC1 1 :1. After removing the acetone by a cyclone evaporator, the precipitated product was filtered, washed with water and dried. Yield: 68.7 g 2 ^-NMR (d6-DMSO): 5 = 1.52-1.73 (m5 4H); 1.82-2.14 (m5 4H); 4.27 (m, 3H); 7.85 (tr, 2H); , 2H); 7.67 (s,1H); 7.75 (d,2H); 7.91 (d,2H) 82695 -42- 1246423 Melting point: 157 ° C 4-oxocyclohexanecarboxylic acid i 203⁄4 mol (3.4 g The 4-oxocyclohexanol acid ethyl ester was suspended in 4 liters of 2% ΗΑ〇4 and stirred at 90 ° C for 2 hours. It was then extracted four times with ethyl acetate and dried over NajCU to remove solvent. Recrystallization from ether/hexane gave 2.9 g of white solid. ^-NMR (d6.DMSO): 5 = 1.72 (m5 2H); 2.08-2.18 (m5 2H); 2.19-2.47 (m? 4H); 2.72 (m: 1H); 12.23 (bs; 1H) 4-chloro -3-[[(phenylamino)carbonyl]amino]phenylacetic acid was added 18.553⁄4 mol (2.21 g) of SOCh slowly added to 5 liters of MeOH within 18.55 millimolar (4.克) 4-chloro-3-nitrophenylacetic acid while stirring. After stirring for 30 minutes, it was allowed to warm to room temperature, and 371 mmol (〇·44 g) of SOCh was added. After stirring overnight, reflux for 3 minutes. After removal of the solvent, it was recrystallized from ether / hexane. Yield: 3.43 g of methyl 4-chloro-3-nitrophenylacetate as a yellow solid. 13.073⁄4 mol (3.0 g) of methyl-4-[3-chloro-3-nitrophenylacetate and 1988 Mox (13.0 g) of Zn powder were refluxed in 500 ml of MeOH for 1 min. Then, 13 φ liter of concentrated HCl was added dropwise under reflux, followed by reflux for 30 minutes. The suspension was filtered while hot, and methanol was distilled off, and the solution was made with NaHC 3; It was extracted with ethyl acetate, dried over NajCU, and then evaporated to give diethyl ether (3 g) of ethyl 3-amino-4-chlorophenylacetate as a beige solid. 2.08 mmol (415 mg) of methyl 3-amino-4-chlorophenylacetate was dissolved in 40 ml of DCM at 0 ° C with 0.83 mmol (246·3 mg) of triphosgene and hydrazine. Mix 6 ml of pyridine. 〇t: After stirring for one hour, add 1 〇 4 mmol (111 g) of 82695 -43 - 1246423 of the lower amine and continue stirring at room temperature overnight. The solvent was removed by extraction with hydrazine (::]^/]9 [2 ,, organic = dried. Yield: π mg of methyl 4n [[(phenylamino))]amino]phenylacetate. ~ 2.98 mmol (990 mg of chloro-3-[[(phenylamino)carbonyl]amino]ammonium acetate) is dissolved in 10 ml of methanol and mixed with 6 mM 1NNa〇H. After stirring for 2 hours, the residue was evaporated to dryness eluting with EtOAc EtOAc (EtOAc) · 83 〇 mg white solid. H-NMR (d6-DMSO): 5 = 3.57 (s5 2H); 6.92 (d5 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-ox-3-[[[(phenylmethyl)amino]carbonyl) Amino] phenylacetate oxime 2.08 mmol (415 mg) of methyl 3-amino-4-phenylphenylacetate was mixed with 1 〇. 4 mmol (969 mg) of aniline and treated as described in 4) Yield: 662 mg solids. For ester cleavage, 2,47 mmol (790 mg) of 4-chloro-3-[[[(phenylmethyl)amino]] ]amine Methyl phenylacetate was saponified with IN NaOH to give product 5 without recrystallization. Yield: 693 mg of a yellow solid. ES-MS: 319 (M+H+) 4 - s. Aminoamino)phenylacetic acid 6 2.08 mmol (415 mg) of methyl 3-amino-4-chlorophenylacetate with 1 〇.4 mmol (979 mg) of 4-amino The pyridine was mixed and treated as described in 4). Yield: 664 mg solid. For ester cleavage, in a manner similar to the above, 2.63 mmol (840 mg) of 4-82695-44-1246423 gas-3-[[(4-p-decylamino)carboxy]amino]phenylacetate The ester is Μ &0H. If you get the product, you don't have to recrystallize. Yield: 4 8 1 mg yellow solid bone #. ^-NMR (d6-DMSO): 5 = 3.57 (s? 2H); 6.94 (d? iH); 7A 〇 (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-pyridylamino)carbonyl]amino]phenylacetic acid i will be 2.083⁄4 mol (4153⁄4 g) 3-Amino-4-chlorophenylacetic acid formazan was mixed with 1 4 4 mmol (979 mg) of 2-aminopyridine to be treated in a manner similar to that described in 4). Yield: 617 mg solid. For ester cleavage, 2.47 mmol (79 mg) of 4-chloro-3-[[(2-pyridylamino)carbonyl]amino]phenylacetic acid methyl ester as in Na〇H was used in the same manner as above. Interested. The product Z is obtained without recrystallization. Yield: 693 mg of a yellow solid. ^-NMR (d6-DMSO): 5 = 3.59 (s? 2H); 6.94 (dd5 1H); 7.03 (dd? 1H); 7.22 (d, 1H); 7.42 (d, 1H); 7.78 (dtr, 1H) 8:29 (m, 2H); 10.02 (s, 1H); 11.82 (bs, 1H); 12.50 (s, 1H). II. Example of Compound (I) of the Invention Example 1 : Dissolving 〇·3 mmol (42.6 mg) of 4-oxocyclohexanecarboxylic acid in 1 ml of acetic acid' plus 0.33⁄4 mol (43.3 mg) of phenyl Hydrazine hydrochloride and ο"mole (4〇.〇^*) ZnCl3 in a suspension of 13⁄4 liters of acetic acid. After stirring for 2 hours at 7 Torr, it was diluted with 20 mL of water and extracted with ethyl acetate. The ethyl acetate phase was washed with water and dried over NajCU and evaporated to dryness. Yield: 65 6 mg (1%) white solid. 82695 -45- 1246423 Name_NumberΜ(10)f_MCaic 2,3,4,9-Tetrahydro-1H-咔口坐-3-Resin 8 215 215.2507 The headings of the above columns are also used in the following examples (name, compound number; Mgef (measured molecular mass), Mcalc (calculated molecular mass), will not be repeated later. Example 2: Synthesis according to method A, I and hydrazine at 0.2 millimolar scale. 2,3,4,9-tetrahydrogen -1H-carbazole, 3-carboxylic acid decylamine Example 3: 9 214 214.2666 Synthesis according to methods A, F, G, I and 0 at 0.2 millimolar ο N-[(lS)-l-(aminocarbonyl) )-2-methylpropyl]-(3S)-2,3,4,9-tetrahydro-1H-indazole-3-carboxamide 10a 314 313.3987 N-[(1S)-1_(aminocarbonyl) )-2-methylpropyl H3R)-2,3,4,9_tetrazo-111-port bayonet-3_complexed Yue'an 10b 314 313.3987 N-(2-Amino-2-oxo B Base)-2,3,4,9-tetrahydro-1 沁咔 坐 -3- 驴 驴 实例 实例 Example 4 : Π 271 271.3183 〇 · 2 millimeter scale according to method D, F, G, F, G , I and 0 synthesis. N-[(3S)-(2,3,4,9-tetrahydro-1H-carbazole-3-yl)carbonyl]-L-sentamine S basket base amine test group 12a 442 442.513 N-[(3SM2, 3,4,9-tetrahydro-1H-indazol-3-yl)carbonyl] 12b 442 442.513 -L-dominylamine-based amine, isomer B Example 5: according to the method of 0.2 millimolar D, F, G, I, F and Ο synthesis. 82695 -46- 1246423 N_[[(3S)-3-Amino-2,3,4,9-tetrahydro·1Η-叶峻-3- π 301 301.3441 】]carbonyl]-L-alanine Example 6 : Dissolve 〇·1 mmol of carboxylic acid, 0.1 mmol of HOBt and 0.15 mmol of the amine in 15 ml of anhydrous DMF (or THF, DCM), add 毫·5 mmol of NMM, and take an ice bath. Cool and stir. After 1 5 minutes, add 1.5 mM EDC1 X HCl, stir for an additional hour, warm to room temperature and continue stirring overnight. After the recovery, the solvent was removed, and the product was dissolved in ethyl acetate and washed twice with 0.1N HCl and saturated NaCl. After the solvent is removed, it is recrystallized if necessary. 9H-indoleylmethyl[(3S)-H[[(4-bromophenyl)-methyl 14 62〇6205439 yl]amino]carbonyl]_2,3,4,9-tetrahydro-111-carbazole -3-yl]carbamate N-[[(3S)_3-[[(9H-indoleylmethoxy)carboxy]amine u 537 537.6129 yl]_2,3,4,9-tetrahydro- Methyl oxazol-3-yl]carbonyl]cardiacyanate Example 7: Synthesis according to methods A, F, G, F, G, F, G and 0 on a 0.2 millimolar scale. N_[[(3R)-3_[[(2S,3S)-2-[[(9H-芴-9-yloxy ash 779 777.9178))-postyl]amino]methyl-1-oxo Amino]] 2,3,4,9-tetrahydro-1Η-carbazolyl]carbonyl]-L-nonylamine thiol-L-aspartate N-[[(3S)-3-[ [(2S,3S)_2-[[(9H-芴-9-ylmethoxy)jj 779 777.9178)-carbonyl]amino]methylmethyloxypentyl]amine 82695 -47-1246423 base]-2, 3,4,9-tetrahydro-1oxazol-3-yl]carbonyl]indole-decylamine-L-aspartate from [[(3 幻-2,3,4,9-tetrahydro) -3-[(1-oxo-2,3-diphenyl 18 651 650.7758 propyl)amino HH-indazol-3-yl]carbonyl]-L-nonylamine thiol-L-aspartate [[(33)-2,3,4,9-tetrahydro_3-[(1-oxo-2,3-diphenyl 19 651 650.7758 propyl)amino]-1Η-oxazol-3-yl ]carbonyl]-L-proline-L-aspartic acid amine, isomer A bucket [[(38>2,3,4,9-tetrahydro-3-[(1-oxo-2,3) -diphenyl 20 651 650.7758 propyl)amino HH-carbazol-3-yl]carbonyl]-L-decylamine indole-L-aspartate, isomer B 砵[[(38)- 2,3,4,9-tetrahydro_3-[[(23,38)-methyl-1- 21 688 687.8371 Oxygen 2 -[(1-oxo-3-phenylpropyl)amino]penta Amino]-1H-leaf-3 -yl] 基基]-L- decylamine-L_aspartate gt ;1-[[(311)-2,3,4,9-tetrahydro-3,[[(28,38)-methyl-1- 22 688 687.8371 Oxygen 2_[(1-oxo-3-benzene) Propyl)amino]pentyl]amino]-1H-indazol-3-yl]carbonyl]-L-nonylamine decyl-L-aspartamide 仏[[(38)-2,3, 4,9-tetrahydro-3-[[(23)小氧- 23 648 647.7289 2-[[(phenylmethoxy)carbonyl]amino]propyl]amino]]-1H-indazole-3- ]]carbonyl]-L-Amidinoindolyl-L-aspartate 1[[(311)-2,3,4,9-tetrahydro-3-[[(23) Oxygen- 24 648 647.7289 82695 -48- 1246423 2-[[(Phenylmethoxy)carbonyl]amino]propyl]amino]-1H-anthracepin-3-yl]-yl]-L-ampicylamine-L-Day Winter oxime N-[[(3R)-2,3,4,9-tetrahydro-3-[[(2S,3S)-3-methyl-p-oxy-2-[[(phenylphenyl) )carbonyl]amino]pentyl]amino]-1Η-oxazol-3-yl]carbonyl]-L-alaninyl-L-aspartate!^-[[(311)-2,3, 4,9-tetrahydro-3-[[(28,38)-3-methyl-l-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amino]- 1Η-oxazol-3-yl]carbonyl]-L-nonylamine decyl-L-alanamine amide 1[[(33)_2,3,4,9-tetrahydro-3-[[(28,38) 3-Methyl-p--1-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amino]-1Η-oxazol-3-yl]carbonyl]-D-decylamine醯基-L- Winter guanamine team [[(3 illus-2,3,4,9-tetrahydro-3-[[(23,38)-3-methyl silk-1-oxo-2-[[(phenyl methoxy) Alkyl)carbonyl]amino]pentyl]amino]-1Η-carbazoleyl]carbonyl] amidoxime-L-aspartamide N-[[(3R)-2,3,4,9- Tetrahydro-3-[[(2S,3S))methyl-1-indolyl 1[[(phenylmethoxy)carbonyl]amino]pentyl]amino]-1Η-oxazol-3-yl ]carbonyl]-L-Amidoxime-D-aspartamide from [[(38)-2,3,4,9-tetrahydro-3-[[(28,33)-3-methylhydrazine] 662 661.7557 647 646.7844 690 690 690 690 689.8093 689.8093 689.8093 689.8093 82695 -49-1246423-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amino]-1H-carbazole- 3-yl]carbonyl]-L-amidoxime-D-aspartame 汴[[(33)-2,3,4,9-tetrahydro-3-[[(28,33)-3_ Methyl 31 662 661.7557 small oxygen 2_[[(phenylmethoxy)carbonyl]amino]pentyl]amino]]-3-yl] cyclyl]-L-alanine-L-aspartate Amine N-[[(3S)-2,3,4,9-tetrahydro-3-[(phenylethenyl)amine 32 651 560.6514 yl]-1H-indazol-3-yl]carbonyl]-L - amidoxime-L-aspartamide N-[[(3R)-2,3,4,9-tetrahydro-3-[(l-oxo-3-phenylpropan 33 575 574.6782)) ]]-1Η-oxazol-3-yl]carbonyl]-L-decylamine --L-aspartate group [[(38)-2,3,4,9-tetrahydro_3-[(1-oxo-3-phenylpropan 34 575 574.6782))]amino]- Oxazol-3-yl]carbonyl]-L-decylamine-L-aspartic acid amine [[(33)-2,3,4,9-tetrahydro-3-[[(28,38)) -3-methyl 35 647 646.7844 -1-oxy-2_[[(phenylmethoxy) yl]amino]pentyl]amino]-1Η-oxazol-3-yl]carbonyl]-L- Amidoxime-L-alanamine N-[[(3R)-2,3,4,9-tetrahydro-3-[(phenylethenyl)amine 36 561 560.6514 yl]-1H-carbazole -3-yl]carbonyl]-L-amidoxime-L-aspartamide N-[[(3R)-2,3,4,9·tetrahydro_3-[(1-oxo-4-) Phenyl butyl 37 589 588.705 82695 -50- 1246423 yl)amino]-1 Η-oxazol-3-yl]carbonyl]-L-nonylamine decyl-L-aspartate N-[[(3S)- 2,3,4,9-tetrahydro-3-[(l-oxo-4-phenylbutan 38 589 588.705)amino HH-indazol-3-yl]carbonyl]-L-nonylamine thiol- L-aspartate N-[[(3R)-3-[(diphenylethenyl)amino]- 39 637 % 636.749 ^ 2,3,4,9-tetrahydro-1H-carbazole- 3-yl]carbonyl]cardiacamine-indenyl-L-aspartame N-[[(3S)-3-[(diphenylethenyl)amino]- 40 637 • 636.749 2,3, 4,9-tetrahydro-carbazole group]carbonyl]-L-nonylamine sulfhydryl-L-aspartate group [[ (3)-2,3,4,9-tetrahydro-3-[(1-oxo-2-phenylpropanyl 41 575 574.6782 yl)amino]-1 Η-咔 -3- -3-yl] fluorenyl] -L-Amidoxime-L-aspartate, isomer A 1[[(31〇-2,3,4,9-tetrahydro-3-[(3-methyl-1-oxo-) 2- 42 617 616.7586 Phenylpentyl)amine HH-indazoles]carbonyl]Centresamine decyl aspartame, isomer B 1[[(38)-2,3,4,9- Tetrahydro-3-[(3-methyl-1-oxo-2-43 617 • 616.7586 r phenylpentyl)amino]-1H-carbazole group]carbonyl]cardiacamine-L-day Winter amide, isomer A ]^-[[(38)-2,3,4,9-tetrahydro-3-[(3-methyl-1-oxo-2-44 617 % 616.7586 phenyl pentyl) Amino]-1 Η-carbazole group] carbonyl] heart, guanamine group-L-aspartate, isomer B [(lS, 2S)-H[[(3R)-3-[ [[(lS)-H[[4-(amino 45 695 694.8284 82695 -51 - 1246423 carbonyl)phenyl]amino]carbonyl]-2-methylpropyl]amino]carbonyl]-2,3, Benzyl 4,9-tetrahydro-1oxazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamate [(lS,2S)-l-[[[(3S)) -3-[[[(1S)-H[[4-(amino)carbonyl)phenyl]amino]carbonyl]-2-methylpropyl]amino]carbonyl]-2,3,4,9 -tetrahydro-1 team carbazole group]amino]carbonyl]-2-methylbutyl] Benzyl carbamate 讣[[(33)-2,3,4,9-tetrahydro-3-([3-methyl-1-oxo-2-47phenylphenyl))-amine HH-carbazole 3-yl]carbonyl]-L-amidoxime-L-aspartate, isomer A 泮[[(38)-2,3,4,9-tetrahydro-3-[(3- Methyl small oxygen winter 48 phenyl butyl) amine HH-indazol-3-yl]carbonyl]-L-decyl fluorenyl-L-aspartate, isomer B 1^-[[(311 -2,3,4,9-tetrahydro-3-[(3-methyl-1-oxo-2-49phenylbutyl)amino HH-carbazole-3-yl]carbonyl]-L- Amine-tested by the test amine [(lS,2S)-l-[[[(3S)-3-[[[(())]] Amino]carbonyl]-2-methylpropyl]amino]carbonyl]_2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl]-2-methyl Benzyl] benzyl carbamic acid N-[[(3R)-2,3,4,9-tetrahydro-3-[[(3-phenoxyphenyl)51 ethoxy]amino]- 1H-carbazoleyl]carbonyl]cardiacamine-L-aspartate 695 694.8284 603 602.7318 603 602.7318 603 602.7318 715 714.9026 653 652.748 82695 -52- 1246423 652.748 Bucket [[(38)-2,3, 4,9-tetrahydro-3-[[(3-phenoxyphenyl)52 653 acetaminophen]amino]-1H-yel-3-yl] amidyl]-L-amine L-aspartic I amide 708.8552 [(lS, 2S )-l-[[[(3R)-3-[[[(())]]]]]] Propyl] 708.8552 Amino] Amino] 2,3,4,9·tetrahydro_11"1_咔嗤-3-yl]amino]carbonyl]_2-methylbutyl]carbamic acid benzoic acid Ester [(lS,2S)-H[[(3S)-3-[[[(lS)-l-[[[[3-(amino][([[[[[ Carbonyl]-2-methylpropyl]amino]carbonyl]_2,3,4,9-tetrahydro-1H-indazol-3-yl]amino]carboxy]-2-methylbutyl]amino Benzyl formate 607.7509 (3R)_N-[( 1 S)_ 1 -(aminocarbonyl)-2_methylpropyl]· 55 608 2,3,4,9-tetrachloro-3-[[(2R )-l-oxy-2-[(l-oxo-3-phenylpropyl)amino]-3-phenylpropyl]amino]-1H- saponin-3 rebellion 1 amine amine 574.6782 team [ [(33)-2,3,4,9-tetrahydro_3-[(1-oxo-2-phenylpropan-reverse 575-yl)amino HH-carbazole group]carbonyl]cardiacamine thiol- L-aspartate decylamine 714.9026 [(lS,2S)-l-[[[(3R)-3-[[[(())]]] Methyl]amino]carbonyl]-2-methylpropyl]amino]carbonyl]_2,3,4,9-tetrahydro-1H-indazol-3-yl]amino]carbonyl]methanol Benzyl carbazate § Example 8 82695 -53-1246423 based on 0.23⁄4 ohm scale Method a, ρ1, G, F, G and Ο synthesis. [(lS,2S)-l-[[[(3R)-3-[[[(lS)-H-aminocarbonyl)) 2-methylpropyl]amino]carbonyl]_2,3,4,9· Tetrahydro-1H-carbazole group]amino]carbonyl]-2,methylbutyl] benzyl carbamate 58 576 575.7059 N-[[(3S)-H[(9H-芴冬基methoxy) Alkyl]carbonyl]amino]_2,3,4,9-tetrahydro-1!1_carbazole-3-yl]carbonyl]cardiacamine-L-aspartate 59 665 664.759 N-[[ (3R)-H[(9H-carbomethoxy)carbonyl]amino]-2,3,4,9·tetrahydro-1H-carbazole group]carbonyl]-L-nonylamine fluorenyl _L- Aspartame 60 665 664.759 [(lS,2S)-H[[(3S)-3-[[[(lS)-l-(aminocarbonyl)-2-methylpropyl]amino]carbonyl] -2,3,4,9-tetrahydro-1H-carbazoleyl]amino]carbonyl]methanolyl]aminobenzyl benzoate 61 576 575.7059 [(is,2s)-h[[( 3r)-h[[4_(Aminocarbonyl)phenyl]amino]]]]]],3,4,9-tetrahydro-1H-ylide-3-yl]amino]]]]]] Methyl butyl] carbamic acid phenyl ester 62 596 595.6963 [(is, 2s)_i-[[[(3s)-h[[4-(aminocarbonyl)phenyl]]amino]carbonyl]_2,3 ,4,9_tetrahydro-1 oxazol-3-yl]amino] cyano]-2-methylbutyl]carbamic acid benzoquinone 63 596 595.6963 [(lS,2S)-l_[ [[(3R)-3-[[[(1S, 2S) H-(Aminocarbonyl)_2.methylbutyl]amino]Anthracene]-2,3,4,9-tetrahydro-1H-leaf _3_yl]Amino]Alkyl]-:2 ·Methylbutyl] 64 590 589.7327 82695 -54-1246423 Benzyl carbazide [(lS,2S)-H[[(3S)-3-[[[(lS,2S)-l-〇^SI Benzyl-2-methylbutyl]amino]carbonyl]-2,3,4,9·tetrahydro-1H-carbazole each]amino]carbonyl]methylbutyl] benzyl carbamate [(lS,2S)-l-[[[(3R)-3-[[[(()))]]]]]]]]]]]] -2,3,4,9-tetrahydro-1H-indazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester [(lS,2S)-l_[[ [(3S)-3-[[[(lS)-2-amino-2-oxo-1-(phenylmethyl)ethyl]amino]carbonyl]-2,3,4,9-tetra -1H-leaf sitting _3-yl]amino] benzyl]-2-methylbutyl] carbamic acid benzyl ester (3R)-N-[(1 S)-1 -(aminocarbonyl) -2-methylpropyl]-2,3,4,9-tetrahydro-3-[(l-oxo-2-phenylpropyl)amino]-1H-indazole-3-treazone [ (lS,2S)-l-[[[(3S)-H[[[3-(aminocarbonyl)phenyl]methyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H -carbazole _3_yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester [(lS,2S)-H[[(3R)-3-[[[[3-( Aminocarbonyl)benzene Methyl]amino]carbonyl]-2,3,4,9-tetrahydro-1oxazolyl]amino]carbonyl]_2-methylbutyl]carbamic acid phenylmethyl ester 65 590 589.7327 66 623 623.7499 67 623 623.7499 68 460 460.5748 69 610 609.7231 70 610 609.7231

82695 -55- 1246423 [(lS,2S)-H[[(3S)-3-[[[[[4-(aminocarbonyl)cyclohexyl] 615 yl]methyl]amino]carbonyl]-2,3 ,4,9-tetrahydro-1H-carbazoleyl]amino]carbonyl]methylenemethyl]aminobenzoic acid benzyl ester [(lS,2S)-l-[[[(3R)-3_[ [[[4-(Aminocarbonyl)cyclohexan] 615-yl]methyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazolyl]amino]carbonyl]methyl butyl Phenylmethyl carbazide [(lS,2S)-l-[[[(3S)-3-[[[3-(amino)carbonyl)phenyl]73 596 methyl]amino]carbonyl]- 2,3,4,9-tetrahydro-111-carbazole-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester [(lS,2S)-H[[( 3R)-3-[[[3_(aminocarbonyl)phenyl]μ 596 methyl]amino]carbonyl]-2,3,4,9-tetrahydro-1Η-carbazole-3·yl]amino group Benzyl carbonyl]-2-methylbutyl]carbamic acid benzyl ester [(lS,2S)-l-[[[(3S)-3-[[[(()))) - 75 610 phenylethyl]amino]carbonyl]_2,3,4,9-tetrahydro-1H-indazolyl]amino]carbonyl]_2-methylbutyl]carbamic acid benzyl ester [ (lS,2S)-l-[[[(3S)-3-[[[(lR)-Amino-2-oxo-1-76 610 phenylethyl]amino]carbonyl]-2,3, 4,9-tetrahydro-1H-carbazole-3-yl]amino]carbonyl]methylbutyl]carbamic acid benzoic acid 615.7705 615.7705 595.6963 595.6963 609.7231 609.7231 82695 -56- 1246423 [(lS,2S)-l-[[[(3R)-3-[[(2-amino-2-oxo-1-phenylethyl)amino) Carbonyl]-2,3,4,9-tetrahydro-1H-indazol-3-yl]amino] benzyl] 2-methylbutyl] carbamic acid benzyl ester, isomer A 77 609 609.7231 [(lS,2S)-l-[[[(3R)-3-[[(2-amino-2-yloxyphenyl)amino]carbonyl]_2,3,4,9_tetrahydro -1H-carbazol-3-yl]amino] benzyl]-2-methylbutyl]carbamic acid benzyl ester, isomer B 78 609 609.7231 (31〇-from [(13)-1- (aminocarbonyl)-2-methylpropyl]- 2,3,4,9-tetrahydro-3-[[(3_#-phenylphenyl)ethinyl]amino]-1H-carbazole Carboxylamidine 79 462 462.547 (3R)-H[[3_(Ethyloxy)phenyl]ethinyl]amino]-N-[(l S)-l-(aminocarbonyl)-2- Methylpropyl]-2,3,4,9-tetrahydro-1H-indazole-3-indolylamine%0 504 504.5838 3-[2-[[3R)-3-[[[(l()) -l-(Aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1oxazol-3-yl]amino]-2-oxo Phenyl-3-3⁄4-based phenylacetate 81 597 596.6804 (3R)-N-[(lS)-l-(amino-based)_2-methylpropyl]~ 2,3,4,9 -tetrazole-3-[(罗至基phenyl乙酉盈基)月安基]-1H-叶唆-3 - Rebel g-amine 82 462 462.547 (3R)-N-[(lS)-l-(Amino-based)-2-methylpropyl]_ H [(4-Bromophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-1H-leaf 17-spin-3 - Rebel S-salt S3 525 525.4441 (3R)-N-[( 1 S)-l-(Aminocarbonyl)-2-methylpropyl]- 84 481 480.9931 82695 -57- 1246423 3-[[(2-Chlorophenyl)ethinyl]amino]-2,3 ,4,9-tetrahydro-1H-indazole-3-carboxamide (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-85 497 496.9921 3- [[(3-chloro-4-hydroxyphenyl)ethinyl]amino]-2,3,4,9-tetrahydro-1H-indazole-3-carboxamide (3R)_3-[[[ 4-(Ethyloxy)each chlorophenyl]acetamidine 539 539.0289 base]amino]-N-[(1S) small (aminocarbonyl)_2-methylpropyl]-2,3,4 , 9-tetrachloro-111-port bayonet sitting -3- tacrolein (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]· 87 481 480.5371 3-[[(3-Fluoro-4)hydroxyphenyl)ethinyl]amino]_ 2,3,4,9-tetrahydro-1H-indazole-3-carboxamide (3R)-3- [[[4-(Ethyloxy)-3-fluorophenyl]acetamidine 88 523 522.5739 yl]amino]-N-[(lS)-l-(aminocarbonyl)-2-methylpropane -2,3,4,9-tetrahydro-111-indazole-3-carboxamide (3R)-N-[( 1S)-1 -(amino 2-methylpropyl]- 89 492 491.5451 2,3,4,9-tetrahydro-3·[[(4-nitrophenyl)ethenyl]amino]-1Η-carbazole- 3-Carboxyguanamine (3R)-N-[( 1 S)-l-(aminocarbonyl)-2-methylpropyl]- 90 515 515.4382 3-[[(2,4-dichlorophenyl) Ethyl]amino]-2,3,4,9-tetrahydro-3-1H-leadol-3-desperamine (3R)-N-[(lS)-l-(aminocarbonyl) winter Methylpropyl]- 91 464 464.5381 3_[[(4-fluorophenyl)ethinyl]amino]_2,3,4,9-tetrahydro-3 -1H-leaf-3 -retinamide 3R)-N-[(1 S) small (aminocarbonyl)-2-methylpropyl]- 92 462 462.547 82695 -58- 1246423 2,3,4,9-tetrahydro-3-[[(4 -hydroxyphenyl)ethinyl]amino]-1H-indazole-3-carboxamide (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl] - 93 525 525.4441 3-[[(2-Bromophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-3-1H-oxime-3-islanamine (3R)- N-[(1 S)-l-(Aminocarbonyl)-2-methylpropyl]- 94 491 491.5451 2,3,4,9-tetrahydro-3-[[(2-nitrophenyl) Ethyl]amino]-1H- saponin-3-destinyl (3R)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]- 95 491 491.5451 2 ,3,4,9-tetrahydro-3-[[(3-nitrophenyl)ethinyl]amino]-1H-indazole-3-carboxamide (3R)-N-[(1S) -1_( Aminocarbonyl)-2-methylpropyl]- 96 525 525.4441 3-[[(3-Bromophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-1H-carbazole -3-Rebelamine (3R)-N-[( 1S)-1 -(Aminocarbonyl)-2-methylpropyl]- 97 499 498.9832 3-[[(2_chloro-4-fluorophenyl) Ethyl]amino]-2,3,4,9-tetrahydro-1H-indazole-3-rebelamine (3R)-N-[(1 S)-l-(aminocarbonyl)- 2-methylpropyl]- 98 523 522.6456 3-[([1.1f-Biphenyl]-4-ylethyl)amino]-2,3,4,9-tetrahydro-1H-咔吐- 3-Read J-Amine (3R)-N-[( 1S)-1-(Aminocarbonyl)-2-methylpropyl]- 99 475 474.6016 3-[[(3,5-Dimethylphenyl) Ethyl]amino]-2,3,4,9-tetrahydro-1H_咔 坐 妾 妾 妾 ( ( (3R)-N-[(lS)-l-(amino-based )-2-methylpropyl]- 100 490 490.557 82695 -59- 1246423 3-[(1,3-benzodioxol-5-ylethylidene)amino]-2,3,4, 9-tetrahydro-1H-indazole-3-carboxamide (3R)-N-[( 1 S)-l-(aminocarbonyl)-2-methylpropyl]- 101 481 480.9931 3-[[ (3-chlorophenyl)ethylidene]amino]_2,3,4,9-tetrahydro-1H-yellow-3-amine (3R)-N-[(1 S)-l-( Aminocarbonyl)-2-methylpropyl]- 102 461 460.5748 2,3,4,9-tetrahydro-3-[[(3-methylphenyl)ethinyl]amino]-1Η- Oxazole-3-carboxamide (3R)-N-[( 1 S)-l-(aminocarbonyl)-2-methylpropyl]- 103 464 464.5381 H[(2-fluorophenyl)ethenyl Amino]-2,3,4,9-tetrahydro-1H-indazole-3-carboxamide (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methyl Propyl]-104 461 460.5748 2,3,4,9-tetrahydro-3-[[(2-methylphenyl)ethyl]amino]-1H-indazole-3-carboxamide (3R )-N-[(1 S)-l-(amino-based)-2-methylpropyl]_ 105 489 488.6284 2,3,4,9-tetrahydro-3-[[[4-(1 -methylethyl)phenyl]ethinyl]amino HH-indazole-3-carboxamide (3R)-N-[( 1 S)-l-(aminocarbonyl)-2-methylpropane Base]-106 490 489.6165 H[[4_(Dimethylamino)phenyl]ethinyl]amino]-2,3,4,9-tetrahydro-1H-indazole each carboxamide (3R) -N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]- 107 524 524.6388 2,3,4,9-tetrahydro-3-[[[4-(methyl continued Phenyl)phenyl]ethinyl]amino]-1Η-carbazole-3-carboxamide (3R)-N-[(1S)-1 -(aminocarbonyl)-2-methylpropyl] - 108 478 478.5649 82695 -60- 1246423 3-[[(3-Fluoro-4-methylphenyl)ethinyl]amino]- 2,3,4,9-tetraaza-11^_ mouth Sitting -3- township resurrection Shengyue 5 Example 9: According to method B, F, G, F, G, F, G at 0.2 millimeter scale Billion synthesis. N-[[(3R)_2,3,4,9-tetrahydro:[[(2S,3S), 3-methyl 691 690.7934 -1-oxo-2-[[(phenylmethoxy)carbonyl) Amino]pentyl]amino]-1Η-oxazol-3-yl]carbonyl]-L-nonylamine thiol-L-aspartate [[(38)-2,3,4,9 -tetrahydro-3-[[(28,33)-3_methyl 691 690.7934 -1-oxy-2_[[(phenylmethoxy)carbonyl]amino]]pentyl]amino]-1Η- Oxazol-3-yl]carbonyl]-L-guanidinium-L-aspartame Example 10: according to methods A, F, G, F, G, F, G, and 〇 synthesis. N-[[(3R)-3-[[(2S,3S)-2-(Ethylamino)-3-methyl 598 597.7127 yloxyoxy]amino]-2,3,4,9 -tetrahydro-111-leaf-3-yl]-based]-L-leucine-L-aspartate N-[[(3S)-3-[[(2S,3S)-2- (Ethylamino)-3-methyl 598 597.7127 yl-I-oxopentyl]amino]-2,3,4,9-tetrazo-1H·leaf-3-yl] L-Dysamine Azure Aspartic Acid N-[[(3R)-3-[[(2R,3R)-2-(Ethylamino)]carbamate 598 597.7127 yloxyoxypentyl]amine ]-2,3,4,9-tetrahydro-11·!- 82695 -61 - 1246423 oxazol-3-yl]carbonyl]-L-nonylamine thiol-L-aspartate N_[[(3S )-3-[[(2R,3R)-2-(ethinylamino)-3-methyl </ br> benzyl-1- oxypentyl]amino]-2,3,4,9-tetrahydro- 1H-carbazol-3-yl]carbonyl]-L_decylamine-L-aspartamide Example 11 : According to methods A, F, G, F, G, F on a 0.2 millimolar scale. N_[[(3R)-3-(Ethylamino)-2,3,4,9-tetrahydrom 484 -1 Η-oxazol-3-yl]carbonyl]-L-nonylamine fluorenyl heart Asparagine N-[[(3S)-3-(acetamidoamino)-2,3,4,9-tetra-rat 116 484 -1H-indazol-3-yl]carbonyl]-L-decylamine Mercapto-L-aspartate N-[[(3S)_3-(ethylhydrazino)-2,3,4,9-tetrahydro 112 484 1H-indazol-3-yl]carbonyl]- D-Amidoxime-based indoleamide 597.7127, 11 and 0 in 484.5538 484.5538 484.5538 N-[[(3S)-3-(ethinylamino)-2,3,4,9-tetrahydroin 484 -1H-carbazole group]carbonyl]-L-decylamine-yl-D-day 484.5538 Winter oxime Example 1 2: Synthesis according to methods A, F, G and hydrazine on a 0.2 millimolar scale. [(lS,2S)-l-[[[(3R)-3-(aminocarbonyl)-2,3,4,9- 119 476 tetrahydro-1H-indazoles]amino]carbonyl]- Phenylmethyl 2-methylbutyl]carbamate 476.5738 82695 -62- 1246423 Phenylmethyl[(lS,2S)-l-[[[(3S)-3-(aminocarbyl 476 476.5738) -2,3,4,9_tetranitro-1!1-leaf-3-yl]amino] cyano]-2-methylbutyl]carbamate Example 1 3 : to 0.2 mmol The ear scale is synthesized according to methods A, F, G, F, G, F, G, F, G and 〇. Team [[(311)-2,3,4,9-tetrahydro-3-[[(28)-1-oxo-2-121 722 721.8543 [G-oxo-propyl)amino]-3- Phenylpropyl]amino]-1H-indazol-3-yl]carbonyl]-L-nonylamine decyl-L-aspartame &amp;[[(311)-2,3,4,9- Tetrahydro-3-[[(211,311)-3-methyltan 688 687.8371 oxy-2_[(1-oxo-3-phenylpropyl)amino]pentyl]amine HH-carbazole group ]Carbonyl]Hetaamine-L-aspartate Example 14: Synthesis according to methods D, ρ, G, F, G and oxime on a 毫 2 mM scale. N-[[(3R)-2,3,4,9-tetrahydro-3-[[(2S,3S)-3-methylindole 577 576.69 -1· Oxygen: [[(phenylmethoxy)) Amino]amyl]amyl]amino HH-carbazole-3-yl]carbonyl]cardinic acid, N-[[(3R)-2,3,4,9-tetrahydro-3-[[ (2S)-3-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amine HH-carbazole group]carbonyl]cardamine, N_[ [(3S)-2,3,4,9-tetrahydro-3-[[(2S,3S)-3-methylindole 577 576.69 small oxygen 2_[[(()) ]pentyl] 82695 -63 - 1246423 Amino]-1Η-oxazol-3-yl]carbonyl]-L-proline acid Example 1 5 : according to methods C, F, G, F, on a 0.2 millimolar scale Synthesis of G, F, G and P. N-[[(3S,3S)-2-[[(1,1-dimethylethoxy) 125 656 655.7921)carbonyl]amino group ]:methylammonioethoxy]amino]-2,3,4,9-tetrahydro-1H-indazol-3-yl]carbonyl]-L-nonylamine decyl-L-aspartate 1 6 : Synthesized according to methods A, F, G, F, G, F and hydrazine at 0.2 millimolar scale. N_[[(3S)-3-Amino-2,3,4,9-tetrahydro-1 Carbazole-3- 126 442 442.517 base]-l-]-L-sentamine-L-aspartic amine N-[[(3R)_3-amino-2,3,4,9-tetrahydro -1 carbazole-3- 127 442 442.517 base] aid base]-L - serotonin-L-aspartate (3S)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]- buried 441 441.5725 3-[[(2S,3S )-2-amino-3-methyl-1-oxopentyl]amino]-2,3,4,9-tetrahydro-1oxazol-3-carboxamide Instance 1 7 : 0.2 m The molar scale is synthesized according to the methods D, F, G, F, G, F, Η and Ο. N-[[(3S)-3-(ethinylamino)-2,3,4,9-tetrahydrogen Plastic 485 485.5379 -1H-carbazol-3-yl]carbonyl]-L-nonylamine decyl-L-aspartamide Example 1 8 : 82695 -64 - 1246423 According to Method A, F, on a 0.2 millimolar scale G, F, Η and 0 are synthesized. (3R)-3-(Ethylene fluorenyl)-N-[(lS)-2-monthan, 2-oxo 130 418 418.4944 -1-(phenyl Ethyl]ethyl]-2,3,4,9-tetrahydro-1H-indazole-3-tereic acid amine (3S)-3-(ethidylamino)-N-[(lS)-2- Amino-2-oxo 131 418 418.4944 -1-(phenylmethyl)ethyl]-2,3,4,9-tetrahydro-leaf sitting-3-indolyl-8-amine Example 19: at 0.2 mmol The scale is synthesized according to methods B, F, 0 and 0. (3S)_2,3,4,9-tetrahydro-3-[[(2S,3S)-3-methyl-1-oxo 132 478 477.5579 -2-[[(phenylmethoxy)carbonyl]amine ]]pentyl]amino]-1H-indazole-3-carboxylic acid Example 20: Synthesis of 0 (3S)_3-[[[(2) according to methods B, F, G, F and 0 at 0.2 millimolar scale ,2-diphenylethyl)amino]ethinyl] 134 468 467.5661 Amino]-2,3,4,9-tetrahydro-111-indazole-3-carboxylic acid Example 2 1 : 0.2 m The molar scale is synthesized according to methods A, F, G, F, Η and 0. (3S)-3-(ethenylamino)-N-H3-(aminocarbonyl)benzene 135 404.4676 yl]methyl]-2,3,4,9-tetrahydro-1H-carbazole-3 - Carboxylamamine (3S)-3-(ethenylamino)-N-[[4-(aminocarbonyl) ring 136 410 410.515 hexyl]methyl]-2,3,4,9-tetrahydro- 1H-indazole-3-carboxamide (3R)-3-(ethinylamino)-N-[[4-(aminocarbonyl) ring 137 410 410.515

82695 -65- 1246423 hexyl]methyl]-2,3,4,9-tetrahydro-1 oxazole _3-carboxyguanamine (3S)-3-(ethylideneamino)-N-[( lS)-2-Amino-2-oxygen 404 404.4676 Small phenylethyl]-2,3,4,9-tetrahydro-111-oxazol-3-carboxamide Azide Example 22: According to Examples 18 and 6 The synthesis was carried out at a scale of 0.2 millimolar. [(lS,2S)-l-[[[(3R)-3-[(ethylamino)carbonyl]-2,3,4,9-tetrahydro-1oxazol-3-yl]amino) ] carbonyl] 2 -methylbutyl] phenyl carbazate 139 505 504.6274 [(lS, 2S)-2-methyl-1_[[[(3 幻-2,3,4,9-tetrahydro- 4-[[(l-methylethyl)amino]carbonyl]-1H-indazol-3-yl]amino]carbonyl]butyl]aminocarbamic acid benzyl ester 140 519 518.6542 [(lS, 2S) -2-Methyl small [[[(311)-2,3,4,9-tetrahydro-3-[[(2-methylpropyl)amino]carbonyl]-1]-indazol-3-yl) Amido]carbonyl]butyl]aminobenzoic acid benzyl ester 141 533 532.681 [(1 S,2S)-H[[(3R)-3-[[(2,2-dimethylpropyl)amino) ]]carbonyl]_2,3,4,9·tetrahydro-1H-indazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 142 547 546.7078 [(lS, 2S -2-methyl-1_[[[(311)-2,3,4,9-tetrahydro-[(phenylamino)carbonyl]-1Η-oxazol-3-yl]amino]carbonyl] Benzyl] benzyl carbazate 143 553 552.6714 [(1S, 2S &gt; 2_methyl small [[[(311)-2,3,4,9-tetrahydro-3_[[(phenylmethyl))amine Benzyl]carbonyl]-1H-carbazole-3- 144 567 566.6982 82695 -66- 1246423 benzyl]amino]carbonyl]butyl]amino phthalic acid benzyl ester [(1 S,2S)-2-methyl small [[[(31〇-2,3 ,4,9-tetrahydro-3-[[(2-phenylethyl)amino]-yl]-1H-ylide-3-yl]amino] benzyl]butyl]aminobenzoic acid phenylhydrazine Ester 145 581 580.725 [(1 S,2S)-2-methyl small [[[(311)-2,3,4,9-tetrahydro-3-[[(phenylphenyl)amino]] ]-1H-yttrium-3-yl]amino]carbonyl]butyl]aminobenzoic acid benzyl ester Example 23: 146 595 594.7518 According to A, F, G, I, F, G and 0, the method is 0.2 Synthesis at millimolar scale. [(lS,2S)-l-[[[(m)-3_[[[(lS)-l-(aminocarbonyl)) 2-methylpropyl]amino]] -2,3,4,9-tetrahydro-methoxy-1H-carbazoleyl]amino]carbonyl]-2-mercaptobutyl]aminobenzoic acid benzyl ester 147a 606 605.7317 [(lS, 2S)-l-[[[(3S)-3-[[[(lS)-l-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-2,3,4,9-tetra Hydrogen methoxy-1H-carbazole each]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 147b 606 605.7317 [(lS,2S)-l-[[[(3R) -3-[[[(lS)-l-(aminocarbonyl)_2.methylpropyl]amino]carbonyl]-6-chloro-2,3,4,9-tetrahydro-1H-indazole Benzo]amino]carbonyl]methylenemethyl]aminobenzoic acid benzyl ester 148a 610 610.151 [(lS,2S)-H[[(3S)-3-[[[(lS)-l-(amino Carbonyl 148b 610 610.151 yl) 2 -methylpropyl]amino]carbonyl]-6-chloro-2,3,4,9- 82695 -67- 1246423 tetrahydro-1H-indazole-3-yl]amino]carbonyl Benzylmethyl butyl] benzyl carbazide [(lS, 2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl)))) Amino]carbonyl]each chloro-2,3,4,9-tetrazo-1H-carbazoleyl]amino]carbonyl]methylenemethyl]aminobenzoic acid benzyl ester 180a 610 610.151 [(lS , 2S)-l-[[[(3S)-3-[[[(1S)-l-(aminocarbonyl)))))]]]]]]] , 4,9_tetrahydro-1H-leaf sitting on the base]amino]]]]]_methylbutyl] carbamic acid benzyl ester 180b 610 610.151 [(1S,2S)-1-[[[ 3R) each [[[(1S)小(aminocarbonyl)_2_methylpropyl]amino]]] 2,3,4,9·tetrahydro(trifluoromethyl)-1Η-carbazole Benzoyl]carbonyl]-2-methylbutyl]aminobenzoate 149a 644 643.703 [(lS,2S)-l-[[[(3S)-3-[[[(lS)) L-(Aminocarbonyl)_2-methylpropyl]amino]carbonyl]-2,3,4,9·tetrahydro_8-(trifluoromethyl)-1Η-carbazole]amino]carbonyl] Methylbutyl]carbamic acid benzoquinone 149b 644 643.703 [(lS,2S)-H[[(3R)-3-[[[(lSH-(aminocarbonyl)))) Amino]carbonyl]-2,3,4,9·tetrahydromethyl-1H-17carbandyl 3-yl]amino]indenyl]_2•methylbutyl]carbamic acid benzyl ester 150a 590 589.7327 [(lS,2S)-l_[[[(3S)-3-[[[(lSH-(aminoalkyl)-2-methylpropyl]amino]]]] 2,3 , 4,9_tetrahydro 150b 590 589.7327 82695 -68- 1246423 each methyl-1H-indazoleyl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester [(lS, 2S )-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl)-2-methylpropyl]amino]carbonyl] 2,3,4,9-tetrahydro- 5-methyl-1H_carbazoleyl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 151a 590 589.7327 [(lS,2S)_H[[(3SKH[[(lS) -l-(aminocarbonyl)_2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydrofurylmethyl-1H-carbazoleyl]amino]carbonyl]-2- Methyl butyl] phenyl carbamate 151b 590 589.7327 [(1S,2S)-l-[[[(3R)-3-[[[(()))) Propyl]amino]carbonyl]-2,3,4,9·tetrahydro-7-methyl-1H-feptidyl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 151c 590 589.7327 [(lS,2S)-l_[[[(3S)-3-[[[(lS)-l-(aminocarbonyl)_2)methylpropyl]amino]carbonyl ]-2,3,4,9-tetrahydromethyl-1H-carbazole each]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 151d 590 589.7327 [(1S, 2S) -1-[[[(3R)_3-[[[(1S)-H-aminocarbonyl)·2·methylpropyl]amino]carbonyl]-5-chloro-2,3,4,9-tetra Hydrogen-1H-indolozole]amino]carbonyl]:methylbutyl]carbamic acid benzyl ester 152a 610 610.151 [(lS,2S)-l-[[[(3S)-3-[[[ (lS) small (aminocarbonyl): methylpropyl]amino]carbonyl]-7-chloro-2,3,4,9-152b 610 610.151 82695 -69- 1246423 tetrahydro-1H-indazole Amino]carbonyl]_2-methylbutyl]carbamic acid benzyl ester [(lS,2S)-l-[[[(3R)-3-[[[(lS))) ))2-methylpropyl]amino]carbonyl]-7-chloro-2,3,4,9-tetrahydro-1H-carbazole group]amino]carbonyl]-2-methylbutyl] Benzoyl carbazide 152c 610 610.151 (m)-3-[[[(l S)-l-(aminocarbonyl)-2-methylpropyl]-amino]carbonyl]-2,3,4 ,9-tetrahydro-[[(28,33)-3-methyl-1-oxo-2-[[(phenylmethoxy)carbonyl]amino]pentyl]amino]-1Η-carbazole -8-carboxylic acid 153a 620 619.7149 (3S)-H[[(1 S)-l-(aminocarbonyl)-2-methylpropyl]-amino]carbonyl]-2,3,4,9- Tetrahydro[[(23,33)-3-methyl-1-oxo- 2-[[(phenylmethoxy)indolyl]amino]pentyl]amino]-1H- saponin-8-acid 153b 620 619.7149 [(1S,2S)-H[[(3R)- 3_[[[(1S)-H-aminocarbonyl)-2-methylpropyl]methyl]amino]carbonyl]-6-fluoro-2,3,4,9-tetrahydro.oxazol-3-yl Amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 154a 593 593.696 [(1S,2S)-H[[(3S)-3_[[[(1S)-K-aminocarbonyl) _2_Methylpropyl]methyl]amino]carbonyl]-6-fluoro-2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl]_2_methylbutyl Benzyl carbazate 154b 593 593.696 [(1S,2S)-1-[[[(3R)-3_[[[(1S) s(amino) yl)) ]基基]-2,3,4,9_tetrahydrogen 155a 605 605.7317 82695 -70- 1246423 each methoxy-1H-carbazole group]amino]carbonyl]-2-methylbutyl]amino group Benzyl formate [(lS,2S)-H[[(3S)-3-[[[(lS)-l-(aminocarbonyl)_2-methylpropyl]amino]carboxy]-2,3 ,4,9-tetrahydromethoxy-1H-carbazole each]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 155b 605 605.7317 m [(lS,2S)-l- [[[(3R)-3-[[[(()))))] ke-lH-carbazole Benzo]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 156a 589 589.7327 • [(lS,2S)-H[[(3S)-3-[[[(lS)-l- (aminocarbonyl)_2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydromethyl-1H- thiazolyl]amino]carbonyl]-2-methylbutyl Phenyl methacrylate 156b 589 589.7327 [(lS,2S)-l_[[[(3R)-3_[[[(lS)-l-(aminocarbonyl)) 2-methylpropyl]amino) ]carboxy]· 2,3,4,9·tetrahydro•6_nitro-1H-carbazoleyl]amino]carbonyl]methylenemethyl]aminobenzoic acid benzyl ester 157a 621 620.703 • [( lS,2S)_l_[[[(3S)-3-[[[(lS)-l-(aminocarbonyl)-2-methylpropyl]amino]]]],,,,,,,,,,,,,,,,, -tetrahydro-nitro-1H-carbazoleyl]amino]carbonyl]methylenemethyl]aminobenzoic acid benzyl ester 157b 621 620.703 [(lS,2S)-H[[(3R)-3- [[[(lS)-l-(aminocarbonyl)_4_[(aminoiminomethyl)amino]butyl]amino] 158 633 632.7616 82695 -71 - 1246423 carbonyl]-2,3,4 , 9-tetrahydro-1H-carbazoleyl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester (3R)-N-[(1 S)-l-(aminocarbonyl) &gt;2-Methylpropyl]- 159a 2.3.4.9- Tetrahydro-3-[(3w ratio ethyl)amino]-1H-咔-3-carboxyguanamine (3S)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]- 15% 2.3.4.9-tetrahydro-3-[(3 Qiao Ethylamino)amino]-1H-leaf-3-actual amine (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]-160a 2.3 .4.9- Tetrahydro-3-[(l-naphthylethyl)amino]-1H-leaf-3-carboxamide (3S)-N-[(lS)-l-(aminocarbyl) -2-methylpropyl]-160b 2.3.4.9- Four mouse-3-[(l-naphthyl)amino]-1H-anthracene-3-acid amine (3R)-N- [(lS)-l-(Amino-postyl)-2-methylpropyl]-161a 2.3.4.9- Tetrahydro-3-[(2-mercaptoethyl)amino]-1H-leaf -3- complex g-amine (3S)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]- to the side 2.3.4.9-tetrahydro-3-[(2- Naphthylethyl)amino]-1H-leaf-sit-3 - retinoid (3R)-N-[(lS)-l-(amino)yl-2-methylpropyl]- 162a二鼠-1H-印-1-yl) 基基]amino]_ 2.3.4.9-tetrahydro-1H-carbazole-3_carboxamide (3S)-N-[(1 S)-l-( Aminocarbonyl)-2-methylpropyl]-brain 447 447.5361 447 447.5361 496 496.6078 496 496.6078 496 496.6078 496 496.6078 472 472.5858 472 472.5858 82695 -72- 1246423 3-[[2,3-diazo-1H-print -1-yl) ethyl]amino]-2,3,4,9-tetrahydro-1H-carbazole Amine (3R)-N-[(lS)-l-(aminocarbonyl&gt;2-methylpropyl]-163a 436 436.5132 2,3,4,9-tetrahydro-3-[(1Η-imidazole- 4-ylethyl hydrazino)amino]-1H-indazole-3-carboxamide (3S)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]-163b 436 436.5132 2,3,4,9-Tetrahydro-3-[(1Η-isopropyl-tetra-4-ylethyl)amino]-1H-carbazole_3_carboxamide (3R)-N- [(1 S)-l-(Aminocarbonyl)-2-methylpropyl]- 164a 486 485.5849 2,3,4,9-tetrahydro-3-[(1Η-吲哚-3-ylethane) Amino]-1H-indazole-3-carboxamide (3S)-N-[(1 S) small (aminocarbonyl)-2-methylpropyl]- 164b 486 485.5849 2,3,4 ,9-tetrahydro-3-[(1Η-indol-3-ylethyl)amino]-1Η-indazole-3-carboxamide (3R)-N-[(1 S)-l -(aminocarbonyl)-2-methylpropyl]- 165a 461 460.5748 2,3,4,9-tetrahydro-3-[[(4-methylphenyl)ethinyl]amino]-1H -carbazole each carboguanamine (3S)-N-[(1 S)-l-(aminocarbonyl&gt;2-methylpropyl]-165b 461 460.5748 2,3,4,9-tetrahydro-3 -[[(4-methylphenyl)ethyl)amino]-1H-leaf-3-retest amine (3R)-N-[(1 S)-l-(aminocarbonyl)-2 -methylpropyl]- 166a 515 514.5451 2,3,4,9-tetrahydro-3-[[[4-(trifluoromethyl)phenyl]ethenyl]amine ]]-Η-carbazole-3-carboxamide (3S)-N-[(1S)-1 -(aminocarbonyl)-2-methylpropyl]- 166b 515 514.5451 82695 -73 - 1246423 2 ,3,4,9-tetrahydro-3-[[[4-(trimethylene)phenyl]acetate]amino]_1H-indazole-3-carboxamide (3R)-N-[( 1 S)-l-(Aminocarbonyl)-2-methylpropyl]- 167a 481 480.9931 3-[[(4-Chlorophenyl)ethinyl]amino]_2,3,4,9_4 Hydrogen-1 Fan Yejun-3-Rebellion @ Stupid Amine (3S)-N-[(1 S)-l-(Aminocarbonyl&gt;2-Methylpropyl)- 167b 481 480.9931 3-[[(4 -chlorophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-1H-leaf-3-carboxyguanamine (3S)-N-[(1S)-1 -(amine Carboxycarbonyl)-2-methylpropyl]- 168a 515 514.5451 2,3,4,9-tetrahydro-3-[[[3-trifluoromethyl]phenyl]acetamidinyl]amino]-1H -carbazole-3-carboxamide (3R)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]- 168b 515 514.5451 2,3,4,9-tetrahydro- 3-[[[3-Trifluoromethyl]phenyl]ethenyl]amino HH-indazole-3-carboxamide (3R)-N-[(1 S) small (aminocarbonyl)-2 -methylpropyl]- 169a 465 464.5381 H[(3-fluorophenyl)ethinyl]amino]_2,3,4,9-tetrahydro(3S)-N-[(1 S)-1- (aminocarbonyl)-2-methylpropyl]- 169b 465 464.5381 H[(3-fluorophenyl)ethenyl]amine Base]-2,3,4,9-tetrahydro-1H-leaf-3-carboxylic acid amine (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl ]- 170a 477 476.5738 2,3,4,9-tetrahydro-3-[[(3-methoxyphenyl)ethenyl]amino]-1H-leaf _3-rebel S-amine (3 S)-N- [(1S)-1-(aminocarbonyl)-2-methylpropyl]- 170b 477 476.5738 82695 -74- 1246423 2,3,4,9-tetrahydro-3-[[( 3-methoxyphenyl)ethylidene]amino]-1Η-carbazole-3-carboxamide (3R)-N-[(1S) small (aminocarbonyl)-2-methylpropyl] - 171a 477 476.5738 2,3,4,9-tetrahydro-3-[[(2-methoxyphenyl)acetoxy]amino]1H-indazole-3-carboxamide (3S)-N -[( 1S)-1 -(aminocarbonyl)-2-methylpropyl]- 171b 477 476.5738 2,3,4,9-tetrahydro-3-[[(2-methoxyphenyl))醯基] Amino]1H-叶峻_3 -竣g-Amin (3R)-N-[(lS)-l-(Amino-based)-2-methylpropyl]- 172a 479 478.5649 3- [[3-(4-Fluorophenyl)-1-oxopropyl]amino]-2,3,4,9-tetrahydro-1H-leaf-3-indoleamine (3S)-N-[ (lS)-l-(Amino-based)-2-methylpropyl]_172b 479 478.5649 3-[[3-(4-Fluorophenyl)oxypropyl]amino]_2,3,4 ,9_tetrahydro-1H-indazole-3-decylamine (3R)-N-[(lS)-l-(amino-based)-2-methylpropyl]_ 173a 497 496.5 55 3-[[3_(3,4-Difluorophenyl)oxypropyl]amino]-2,3,4,9-tetrahydro-1H-port bayonet-3, several amines (3 S)-N-[( 1S)-1 -(Aminocarbonyl)-2-methylpropyl]- 173b 497 496.555 3-[[3-(3,4-difluorophenyl)-1 oxypropyl Amino] 2,3,4,9-tetrahydro·1Η-mouth kougui-3_carboxamide (3R)-N-[(1 S)-;K-aminocarbonyl)-2-A Propyl]- 174a 593 592.6057 3-[[3-[3,4-bis(trifluoromethyl)phenyl]-1-oxopropyl]amino]-2,3,4,9-tetrahydro -1 carbazole carboxamide (3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]- 174b 593 592.6057 82695 -75 - 1246423 3-[[3- [3,4-bis(trifluoromethyl)phenyl]oxypropyl]amino]-2,3,4,9-tetrahydro-1H-indazole-3-carboxamide N-[(lS )-l-(aminocarbonyl&gt;2-methylpropyl]-175 477 476.5738 2,3,4,9-tetrahydro-3-[[(4-methoxyphenyl)ethenyl]amine Base]_1H-carbazole-3-carboxamide (3R)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]- 176a 491 490.6006 2,3,4,9- Tetrahydro-3-[[3-(4-methoxyphenyl)-1-oxypropyl]amino]-1Η-indazole-3-carboxamide (3S)-N-[( 1S) -1 -(aminocarbonyl)-2-methylpropyl]- 176b 491 490.6006 2,3,4,9-tetrahydro-3-[[3-(4-methoxyphenyl)-1- Propyl]amino]-1Η-carbazole-3-carboxamide (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]- 177a 491 490.6006 2, 3,4,9-tetrahydro-3-[[3-(2-methoxyphenyl)oxypropyl]amino]-1Η-carbazole-3-carboxamide (3S)-N-[ (1 S)_l-(Aminocarbonyl)-2-methylpropyl]- 177b 491 490.6006 2,3,4,9-Tetraam-3-([3-(2-methoxyphenyl)- 1-Lactylpropyl]amino]-1Η-indazole-3-carboxamide (3R)-N-[(1 S)-1-(aminocarbonyl)-2-methylpropyl]- 178a 500 499.6117 2,3,4,9-tetrahydro-3-[[3-(1Η-indol-3-yl)-1-oxopropyl]amino; carbazole carboxamide (3S)-N -[( 1 S&gt; 1 -(aminocarbonyl)-2-methylpropyl]- 178b 500 499.6117 2,3,4,9-tetrahydro-3-[[3-(1Η-啕哚-3- ))-1-oxopropyl]amino]-1Η-carbazole-3-carboxamide (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl] - 179a 503 502.6552 82695 -76- 1246423 2.3.4.9- Tetrahydro-3-[(l-oxo-6-phenylhexyl)amino]-1H-indazole-3-carboxamide (3S)-N- [(1 S)-l-(Aminocarbonyl)-2_methylpropyl]- 17% 2.3.4.9- Four mouse-3-[(1-oxo-6-t-m-hexyl)hydanto]-1H -carbazole-3-carboxamide [(lS,2S)-l-[[[(3R)-3-[[(2S)-2-(aminocarbonyl 181a)))) Base] 2,3,4,9-tetrazo-111- thiazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester [(lS, 2S )-l_[[[(3S)-3-[[(2S)-2-(aminocarbonyl 181byl)-1] pyrrolidinyl]carbonyl]-2,3,4,9_tetrahydro-111- Benzyl-3-oxa]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester [(1S,2S) small [[[(3R)-3-[[[(lS)) -(Aminocarbonyl succinyl)_2_mercaptopropyl]amino]carbonyl]-7,8-dichloro, 2,3,4,9-tetrahydro.oxazol-3-yl]amino] Benzyl carbonyl]-2-methylbutyl]carbamate [(lS,2S)-l-[[[(3S)-3-[[[(lS))-l-(aminocarbonyl 182b)) -2-methylpropyl]amino]carbonyl]-7 mustard dichloro-2,3,4,9-tetrahydro.oxazol-3-yl]amino]carbonyl]-2-methylbutyl] Benzyl carbazide [(lS,2S)-l-[[[(3R)-3-[[[(lS)-l-(indolyl I 183a)))) Carbonyl]-2,3,4,9-tetrahydro-5,8-dimethyl-1H-indazol-3-yl]amino]carbonyl]-2- 503 502.6552 574 574 645 604 573.6901 573.6901 644.5961 644.5961 603.7595 82695 -77- 1246423 benzyl mercaptobutyl] carbazide [(1S, 2S) small [[[(3S)-3-[[[(()))) Methylpropyl]aminomercapto]-2,3,4,9·tetrahydro -5,8-Dimethyl-1H-indazol-3-yl]amino]carbonyl]: methyl butyl] phenyl carbamate 183b 604 603.7595 [(lS,2S)-l-[[[ (3R)-3-[[[(lS)-l-(Amino plexyl)-2-methylpropyl]aminocarbonyl]_6,8-dichloro»2,3,4,9_4 Hydrogen. carbazole _3_yl]amino]carbonyl]methylbutyl]carbamic acid benzyl ester 184a 645 644.5961 [(1S,2S)-H[[(3S)_3-[[[(1S)) H Aminocarbonyl)_2-methylpropyl]amino]carbonyl]-6,8_di-gas-2,3,4,9-tetrahydro-11'1-portalin-3-yl]amine Benzene]·2-methylbutyl]methyl carbamic acid benzyl ester 184b 645 644.5961 [(1S,2S)-H[[(3R)_3-[[[(1S)-H-aminocarbonyl)- 2-methylpropyl]amino]carbonyl]-6-di-2,3,4,9-tetrahydro-1H-carbazole-1-yl]amino]carbonyl]-2-methylbutyl]carbamic acid Benzene methyl ester 185a 655 654.602 [(lS,2S)-H[[(3S)-3-[[[(lS))-l-(aminocarbonyl)-2-methylpropyl]amino]] yl]- 6-Bromo-2,3,4,9-tetrahydro-1H-leazol-1yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 185b 655 654.602 (3R)-N- [( 1S)-nonylaminocarbonyl]-2-methylpropyl]-3-[[(4-chlorophenyl)ethinyl]amino]_2,3,4,9-tetrahydro-8- methoxy-1H-叶峻-3-瘦amine 186a 511 511.0189 82695 •78- 1246423 (3S)-N-[(1 S)-l-(Aminocarbonyl)-2-methylpropyl]- 186b 3_[[(4-chlorophenyl)ethenyl]amine Base]_2,3,4,9-tetrahydro-8-methoxy-1H-indazole-3-carboxamide [(lS,2S)-l-[[[(3R)-3-[[[ (lR)-2-Amino-l-[(4- 187a chlorophenyl)methyl]-2-oxoethyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-indole Benzyl-3-yl]amino]carbonyl]methylbutyl]carbamic acid benzyl ester [(lS,2S)-l-[[[(3S)-3-[[[(l))) Base-l-[(4- 187b chlorophenyl)methyl]-2:oxyethyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-indazol-3-yl]amine Benzyl]carbonyl]-glycolylbutyl]carbamic acid benzyl ester [(lS,2S)-l_[[[3-[[(3-amino-3-oxypropyl)amino]carbano]]- 2,3,4,9-tetrahydro-1-oxazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester (2S)-H[(3R)-3 -[[(4-chlorophenyl)ethinyl]amine 189a]]-2,3,4,9-tetrahydro-8-methoxy-111-oxazol-3-yl] fluorenyl]-2 -External 1: Luoxian, a few g of amine (2S)-H[(3S)-3-[[(4-chlorophenyl)ethinyl]amine 18% base]-2,3,4,9-four Hydrogen-8-methoxy-1oxazol-3-yl]carbonyl]-2-pyrrolidinecarboxamide [(lS,2S)-l-[[[(3R)-3-[[(2S) -2-(aminocarbonyl) 190a octahydro-1H-indole哚-1-yl]carbonyl]-2,3,4,9-tetrahydro-1H-indazol-3-yl]amino]carbonyl]-2-methylbutyl]benzyl benzoate 511 511.0189 658 658 548 509 509 628 658.195 658.195 547.6523 509.0031 509.0031 627.7815 82695 •79- 1246423 [(1S,2S) small [[[(3S)-3-[[(2S)-2-(aminocarbonyl) octahydro-1H) -吲哚-1-yl]carbonyl]-2,3,4,9-tetrahydro-1H-carbazole-m-yl]amino]carbonyl]-m-methylbutyl] phenyl carbamic acid 190b 628 627.7815 [ (lS,2S)-l-[[[(3S,4R)-3-[((2S,4R)-2-(aminocarbonylhydroxy-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetra Hydrogen-1H-carbazoleyl]amino]carbonyl]methylenemethyl]aminobenzoic acid benzyl ester 191a 590 589.6891 [(lS,2S)-l-[[[(3S)-3-[[ 2S,4R)-2-(Aminocarbonyl)-4-hydroxy-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetrahydro-1H-indazoleyl]amino]carbonyl]- Benzyl 2-methylbutyl]carbamate 191b 590 589.6891 [(lS,2S)-l-[[[(3R)-3-[[[(lS,2R)-l-(aminocarbonyl)) _2•Hydroxypropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-indazole each]amino]carbonyl]·2-methylbutyl] benzyl carbamate 291a 578 577.6781 [(lS,2S)-l-[[[(3S)-3-[[[(lS,2R)-l_ (aminocarbonyl)_2_light propyl]amino]carbonyl]_ 2,3,4,9-tetrahydro-1H-carbazole group]amino]carbonyl]methylbutyl] carbamic acid benzene Methyl ester 291b 578 577.6781 [(1 S,2S)-l-[[[(3S)-3-[[(2-amino-2-oxyethyl)amino]carbonyl]-2,3,4, 9-tetrahydro-1H-indazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzoate 292 534 533.6255 [(is,2s)-h[[3-[[ [2-(Aminocarbonyl)phenyl]amino] 192 596 595.6963 82695 -80 - 1246423 carbonyl]-2,3,4,9-tetrahydro-1 oxazol-3-yl]amino]carbonyl]- Benzyl 2-methylbutyl]carbamate (3R)-N-[( 1S)-1 -(Aminocarbonyl)-2-methylpropyl]--3-[[[4-chloro- 3-[[(4-pyridylamino)-carbonyl]amino]phenyl]-ethenyl]amino]-2,3,4,9-tetrahydro-1H-咔峻-3-复IS Amine (3S)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]-•3_[[4·chloro-3-[[(4-pyridylamino)) -carbonyl]amino]phenyl]-ethenyl]amino]-2,3,4,9-tetraindole-1oxazol-3-carboxyguanamine (3R)-N_[(1 S)- 1-(Aminocarbonyl)-2-methylpropyl]--3-[[[4-chloro_3_[[(phenylamino)]carboxy]amino]phenyl]-ethenyl]amine Base]-2,3,4,9-tetraar-1H_indazole-3-carboxamide (3S)-N-[(1S)-1 - (aminocarbonyl)-2-methylpropyl]--3_[[[4-chloro-3_[[(phenylamino)-yl]amino]phenyl]-ethinyl]amino] -2,3,4,9-tetrahydro-1 oxazol-3-carboxamide (3R)-N-[( 1S)-1 ·(aminomercapto)-2-methylpropyl]- -H[[4-chloro-3-[[[(phenylmethyl)amino]]carboxy]amino]phenyl]-ethinyl]amino]_2,3,4,9-tetrahydro- 11·!- Ye. 3-O-decylamine (3S)-N-[(1 S)_l-(aminocarbonyl)-2-methylpropyl]-H[[4-chloroindole[[(phenylmethyl) Amino]-carboxy]amine 193a 616 616.119 193b 616 616.119 194a 615 615.13 194b 615 615.13 195a 629 629.157 195b 629 629.157

82695 -81- 1246423 base]phenyl]-ethinyl]amino]-2,3,4,9-tetrahydro-1«:-carbazole-3-carboxamide (3R)-N-[( 1S)-1 -(Aminocarbonyl)-2-methylpropyl]- 196a 616 616.119 Each [[[4-chloro][[(2-p-butylamino)]amino]phenyl] Ethyl]amino]_2,3,4,9-tetrahydro-1oxazol-3-carboxamide (3S)-N- [(1S)-1 -(aminocarbonyl)-2 -Methylpropyl]- 196b 616 616.119 Chlorine [[(2- 淀 胺 胺 yl)]]]]]]]]]]]]]]]]]]]]]]]] Hydrogen-1H-indazole-3-carboxamide Azide 24: Synthesis according to the A, F, G, I, F, oxime and 0 methods on a 0.2 millimolar scale. (3R)-3-(Ethylamino)-N-[(l S)-l-(aminocarbonyl 197a 400 400.4762)·2-methylpropyl]-2,3,4,9- Tetrahydro-8-methoxy-1H-indazole-3-carboxamide (3S)-3-(ethenylamino)-N-[(lS)-l-(aminocarbonyl 197b 400 400.4762 -2·methylpropyl]-2,3,4,9-tetrahydro-8-methoxy-1H-leaf-3-indoleamine 3-(ethenylamino)-N-[ (lS) small (aminocarbonyl)-2-198 405 404.8955 methylpropyl]-6-chloro-2,3,4,9-tetrahydro-1oxazol-3-carboxamide-3 (B Mercaptoamine)-N-[(lS)-l-(aminocarbonyl)_2_ 199 769 768.9544 methylpropyl]-2,3,4,9-tetrahydro-5-methyl-1H-carbazole 82695 -82- 1246423 -3-Acidamine 3-(ethenylamino)-N-[(lS)-l-(aminocarbonyl)-2-200methylpropyl]-2,3, 4,9-tetrahydro-8-methyl-1H-indazole-3-indoline 3-(ethylideneamino)-N-[(lS)-l-(aminocarbonyl)-2- 201 Methylpropyl]-5-chloro-2,3,4,9-tetrahydro-1 oxazol-3-carboxycarboxamide 3-(ethenylamino)-N-[(lS)-l -(aminocarbonyl)-2-202methylpropyl]-7-chloro:2,3,4,9-tetrahydro-1H-indazole-3-carboxamide (3R)-3-(acetamidine Amino)-N-[(lS)-l-(aminocarbonyl203a group&gt;2-methylpropyl]-6-fluoro-2,3,4,9-tetrahydro-1H-咔峻- 3-test (3S)-3-(Ethylamino)-N-[(lS)-l-(aminocarbonyl203b)-2-methylpropyl]-6_gas-2,3,4,9 - four mice-11^~ thiazol-3-carboxyguanamine (3R)-3-(ethenylamino)-N-[(lS)-l-(aminocarbonyl204a)-2-methyl Propyl]-2,3,4,9-tetrahydro-6-methoxy-1H-indazole-3-anthraquinone (3S)-3-(ethylideneamino)-N-[(lS )_l-(Aminocarbonyl 204b-yl)-2-methylpropyl]-2,3,4,9-tetra-rat-6-methoxy-1H-indazole-3-indoleamine (3R)- 3-(Ethylamino group: hN-[(lS)-l-(aminocarbonyl 205a)-2-methylpropyl]-2,3,4,9-tetrazo-6-methyl- 11^- 769 768.9544 810 809.7911 810 388 809.7911 388.4405 388 388.4405 400 400.4762 400 400.4762 384 384.4772

82695 -83 - 1246423 Oxazol-3-Respiratory Amine (3S)-3-(Ethylamino)-N-[(lS)-l-(Aminocarbonyl)-2-methylpropyl]- 2,3,4,9-tetrahydro-6-methyl-1H-leaf-3-ylideamine 205b 384 384.4772 (3R)-3-(ethylideneamino)-N-[(lS)- L-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-carbazole _3- 酉 酉 206 206 206 206a 370 370.4504 (3S)-3-(乙醯Amino)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-indazole-3 -carboxamide 205b 370 370.4504 (3R)-3-(Ethylamino)-N-[(l S)-l-(aminocarbonyl)-2-methylpropyl]-7,8-dichloro-2,3 ,4,9-tetrahydro-1H-leaf-3-branched amine 207a 439 439.3406 (3S)-3-(ethenylamino)-N-[(lS)-l-(aminocarbonyl)- 2-methylpropyl]-7,8-dichloro-2,3,4,9-tetrahydro-1H-indazole-3-rebelamine 207b 439 439.3406 (3R)-3-(ethinylamine -N-[(lS) small (aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetraindole-5,8-dimethyl-1H-indazole-3- Rebel amine 208a 399 398.504 (3S)-3-(ethylideneamino)-N-[(lS) small (aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetra Hydrogen-5,8-dimethyl-1H-indole-4-ol decylamine 208b 399 398.504 (3R)-3-(ethylideneamino)-N-[(lS )-l-(Aminocarbonyl)-2-methylpropyl]-6,8-dichloro-2,3,4,9-tetrahydro 209a 439 439.3406 82695 -84- 1246423 -1 Η-port bayonet Sit-3 - Rebel-amine C3S)-3-(ethenylamino)-N-[(lSH-(aminocarbonyl)_2-methylpropyl]-6,8-dichloro-2,3 , 4,9-tetrahydro-1H-indazole-3-carboxamide amide Example 25: 209b 439 439.3406 According to the A, F, G, I, F, G, F and 〇 methods on a 〇 2 mM scale Synthesis (3R)-3_[[(2S)-2_Amino-5-[(aminoiminomethyl)amino]-1-oxopentyl]amino]-N-[(lSH- (Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-111-oxazol-3-carboxyguanamine 210a 485 484.6014 (3S)-3-[[(2S)- 2-Amino-5-[(aminoiminomethyl)amino]methoxypentyl]amino]-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl ]-2,3,4,9-tetrahydro-1H-carbazole-3-succinylamine 210b 485 484.6014 (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methyl Propyl]-2,3,4,9-tetrahydro-3-[[[[2-(l-hexahydrop-decyl)ethyl]amino]] yl]amino]-1H- YE Jun-3-skinny amine 211a 497 496.652 (3S)-N-[(1 S) small (aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3 -[[[[2-(1·6 t/pyridinyl)ethyl]amino]]]indenyl] Amino]-1Η-carbazole-3-carboxamide 211b 497 496.652 (311)-&gt;^[(18)-1_(aminocarbonyl)_2-methylpropyl]-2,3,4,9 -tetrahydro-3-[[[[2-(1Η-indol-3-yl)ethyl]amino]]]indolyl]amino]-1 oxime-carbazole each carboxamide 212a 529 528.6534 82695 -85 - 1246423 (3S)-N-[(1 S)小(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[[[2-(1Η·· -?丨哚-3-yl)ethyl]amino]ethinyl]amino]-1Η-carbazole-3-carboxyguanamine 212b 529 528.6534 (3R)-N-[(1 S)-l- (aminocarbonyl)-2-methylpropyl]-3_[[[(1,3_benzodioxopentamethyl)amino]ethinyl]amino]-2,3,4, 9-tetrahydro-1H-indazole each carboxamide 213a 520 519.5987 (3S)-N-[(lS)_l-(aminocarbonyl)-2-methylpropyl]-3-[[[(1, 3-benzodioxopenta-5-ylmethyl)amino]ethylidene]amino]_2,3,4,9-tetrahydro-loxazol-3-carboxamide 213b 520 519.5987 ( 3R)-N-[(1S)-1 ·(Aminocarbonyl)-2-methylpropyl]-3-[[[(2,2-diphenylethyl)amino]]indolyl]amine ]],2,3,4,9-tetrahydro-1 oxazole each carboguanamine 214a 566 565.7141 (3 S)-N-[( 1S)-1 -(aminocarbonyl)_2-methylpropyl ]-3-[[[(2, diphenylethyl)amino]]]indenyl]amino] -2,3,4,9-tetrahydro-1H-carbazole-3,carboxamide 214b 566 565.7141 (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropane -2,3,4,9-tetrahydro-3-[[[[2-[methyl(phenylmethyl)amino]ethyl]-amino]]]indenyl]amino]-1H -carbazole-3-carboxamide 215a 533 532.685 (3S)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro -3-[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[[ 1246423 Carboxylamidine Example 26: Synthesis according to the A, F, G, I, F, G, F, Η and 0 methods at 0.2 millimolar scale. Η[[Ethyl][2-(l-hexahydropyridinyl)ethyl]ethenyl]amino]-indole-[(1S)-1 -(aminocarbonyl)_2-methylpropyl]- 2,3,4,9-tetrahydro-111-leaf sitting-3-desperamine 216 539 538.6888 (3R)-3-[[[[[[[[[[[[[[ Ethyl]-amino]ethinyl]amino]-N-[(lS)-l-(aminocarbonyl)·2-methylpropyl]-2,3,4,9-tetrahydro- 1H-咔唆-3-inferior amine 217a 575 574.7217 (3S)-3-[[[Ethyl][2_[methyl(phenylmethyl)amino]ethyl]-amino]ethinyl] Amino]-N-[(l S)-l-(amino-based)-2-methylpropyl]-2,3,4,9-tetrazo-1H-leaf-3-indenylamine 217b 575 574.7217 (3R)-3-[[[Ethyl][2,2-diphenylethyl]amino]ethyl]amino]HN-[(lS)-l-(aminocarbonyl) -2-methylpropyl]-2,3,4,9·tetrahydro-1H-indazole-3-carboxamide 218a 608 607.7509 (3S)-3-[[[[Ethyl][2,2- Diphenylethyl]amino]ethynyl]amino]-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro -1H-Lepto-3-Azoline 218b 608 607.7509 (3R)-3-[[[Ethyl][1,3-benzodioxopenta-5-ylmethyl]amino]ethenyl ]-Amino]-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetra -1H-咔219a 562 561.6355 82695 -87- 1246423 -3--3-Bake Amine (3S)-3-[[[Ethyl][1,3-benzodioxopenta-5-ylmethyl]amine Ethyl]ethylamino]-amino]-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-1H-indazole- 3-Carboxyguanamine (3R)-3-[[[Ethyl][2-(1Η-indol-3-yl)ethyl]amino]ethyl]-amino]~1^-[(18 )-1-(amino-based)-2-methylpropyl]-2,3,4,9-tetrahydro-1 oxazol-3- benzylamine (3S)-3-[[[ Ethyl fluorenyl [2-(1Η-(9) 哚-3-yl)ethyl]amino]]]]]]]]]]]]]]]]]]] 2-methylpropyl]-2,3,4,9-tetrahydro-1H-indazole-3-carboxamide 3-[[(2S)-2-(ethinylamino)-5-[ (2-Aminoiminomethyl)amino H-oxopentyl]amino]-N-[(1S)-1-(amino-based)-2-methylpropyl]-2,3, 4,9-four gas-1H_ 21% 562 561.6355 220a 571 570.6902 220b 571 570.6902 221 527 526.6382

Ye Jun-3-Resinamide Example 27: Synthesis according to C, F, G, I, F, G and P methods at 0.2 millimolar scale 0 [(lS, 2S)-2-methyl-l-[ [[(3R)-2,3,4,9-tetrahydro-3_ 222a 589 589.7327 [[[(1 S)-2-methyl-2-[(methylamino)carbonyl]-propyl]amine Benzyl]carbonyl]-1 Η-oxazol-3-yl]amino]carbonyl]-butyl]aminobenzoic acid phenyl ester 82695 -88 - 1246423 [(1S,2S&gt;2-methyl_l-[[[ (3S)-2,3,4,9-tetrahydro-3-222b 589 589.7327 [[[(1S) Wintermethyl-2_[(methylamino)carbonyl]-propyl]amino]carbonyl]- 1 Η-oxazol-3-yl]amino]carbonyl]-butyl]aminobenzoic acid benzyl ester Example 28: Synthesis according to A, F, G, I, F, J and 0 methods at 0.2 millimolar scale (3R)-N-[(1 S)-l-(Aminocarbonyl)-2-methylpropyl]-3_[[(4-chlorophenyl)sulfonyl]amino]-2,3 ,4,9_tetrahydro-1H-leaf^shen-3 - decylamine 223a 503 503.0203 (3S)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]-3 -[[(4-chlorophenyl)sulfonyl]amino]_2,3,4,9-tetrahydro-1 凡叶吐-3-致@篮胺223b 503 503.0203 (3R)-N-[( 1 S)-1 -(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrazole-3-[(methyl phenyl)amino]-1H- leaf spit 3-reacid amine 22 4a 407 406.5044 (3S)-N-[(lS)-l-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrazole-3-([(methyl acid group) )月安基]-1H- Bite-3-Bound amine 224b 407 406.5044 (3R)-N-[(1 S)-l-(Aminocarbonyl)-2-methylpropyl]-2,3 , 4,9-tetra-rat-3-[(phenyl fluorescein)-based acetaminophen-1H_ mouth card. Sodium-3-acid amine 225a 469 468.5752 (3S)-N-[(lS)-l-( Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrazole-3-[(phenylindolyl)amino]-1H- 225b 469 468.5752 82695 -89- 1246423 Sodium-3-treacoamine 483 482.602 483 482.602 (3R)-N-[( 1S)-1 -(Aminocarbonyl)-2-methylpropyl]-226a 2.3.4.9- Tetrahydro-3-[[ (phenylmethyl)-g-amino]-amino]-1H-leaf 17 sitting-3-reposted S-amine (3S)-N-[(1 S)-1-(aminocarbonyl)-2_methyl Propyl]-226b 2.3.4.9- Tetrahydro-3-[[(phenylmethyl)methyl]amino]-1H-leaf 17 sitting-3-treazone Example 29: According to A, F, G , I, F, L and oxime methods are synthesized on a scale of 0.2 millimolar. [[3R)_3_[[[(1 S)-l_(aminocarbonyl)-2-methylpropyl]227a amino]carbonyl) ]_2,3,4,9-Tetrahydro-111-oxazol-3-yl]aminobenzoic acid 3-phenylpropyl ester [(3S)-3-[[[(lS)-l-(amino) )-2-methylpropyl]227b Amino]carbonyl]-2,3,4,9-tetrahydro-111-oxazol-3-yl]carbamic acid 3-phenylpropanoid [(3R)-3_[[[(lS)-l- (amino group)~2_methylpropyl]228a amino]carbonyl]-2,3,4,9-tetrahydro-1H-indazol-3-yl]carbamic acid benzyl ester [(3S) _3_[[[(1S)_1_(aminocarbonyl)-2-methylpropyl]228b amino]carbonyl]-2,3,4,9-tetrahydro-111-oxazol-3-yl]amino Benzyl formate [(3R)-3-[[[(lS)-l-(aminocarbonyl)_2_methylpropyl]229a Amino]]]],3,4,9-tetrazole- 1H-leaf-3-yl]amine 491 490.6006 491 490.6006 463 462.547 463 462.547 449 448.5202 82695 -90- 1246423 phenyl carbamate [(3S)-3-[[[(l()))))) 2-methylpropyl]22 at 449 448.5202 Amino]carbonyl]-2,3,4,9-tetrahydro-1oxazol-3-yl]carbamic acid phenyl ester Example 30: According to A, F, The G, I, F, hydrazine and hydrazine methods were synthesized as 0 (3R)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]-2,3 on a 0.2 millimolar scale. 4,9_Tetrahydro-3-[[(4-nitrophenyl)methyl]amino]-1H-leaf-3 - Rebel Stiltamine 230a 464 463.5351 (3S)-N-[(lS) -l-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrachloro-3-[[(4-nitrophenyl)methyl]hydanto]_ 1H- Xanthene 230b 464 463.5351 (3R)-N-[(1 S)-l-(Aminocarbonyl)-2-methylpropyl]-3-(ethylamino)-2,3,4,9-tetrazo -111-Lepto-3-treazone 231a 356 356.4672 (3S)-N-[(1 S)-l-(Aminocarbonyl)-2-methylpropyl]-3-(ethylamino) -2,3,4,9-tetrahydro-1-indazole-3-carboxamide 231b 356 356.4672 (3R)-N-[(1S) small (aminocarbonyl)-2-methylpropyl]- 2,3,4,9-Tetrahydro-3-[(2-phenylethyl)amino]-1H-indole-3-carboximine 232a 433 432.5648 (3S)-N-[(lS)- L-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[(2-phenylethyl)amino]-1H-咔232b 433 432.5648 82695 - 91 - 1246423 wow-3- complex S-amine (3R)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3 -[(3-phenylpropyl)amino HH-oxime-3-indoleamine 233a 447 446.5916 (3 S)-N-[( 1S)-1 -(Aminocarbonyl)-2-methylpropane Base]-2,3,4,9-tetrahydro-3-[(3-phenylpropyl)amino]-1H-indole 17 sitting-3-retest amine 233b 447 446.5916 (3R)-N-[ (1 S)-l-(Aminocarbonyl)-2-methylpropyl]-3-[bis(3-phenylpropyl)amino]_2,3,4,9-tetrahydro-11·! - carbazole-3-carboxamide 233c 565 564.7696 (3R)-N-[( 1 S)-l-(aminocarbonyl)-2-methylpropyl]-2,3,4,9- Tetrahydro-3-[(6-phenylhexyl)amino]-1H-indazole-3-rebelamine 234a 489 488.672 (3S)-N-[(1 S) small (aminocarbonyl)-2- Methylpropyl]-2,3,4,9-tetrazole-3-[(6-phenylhexyl)amino]] 1H-leaf ol-3 - retinoid 234b 489 488.672 (3R)-N- [(lS)-l-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[(l-methylethyl)amino]-1H-leaf吐-3-carboxychiral amine 235a 370 370.494 (3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9 _tetrazole-3- [(1·Methylethyl)amino]-1Η-叶峻-3-竣g-amine 235b 370 370.494 (3R)-N-[(1 S)-l-(Aminocarbonyl)-2-A Propyl]-2,3,4,9-tetrahydro-3-([1-methylpropyl)amino]- 236a 385 384.5208 82695 -92- 1246423 1H-leaf-3-treazone 3S)-N-[(1 S)-l-(Aminocarbonyl)-2-methylpropyl]- 236b 385 384.5208 2,3,4,9-tetrahydro-3-[(l-methylpropane) Amino]-1H-yellow-3 -3⁄4 amine (3R)-N-[(1 S) small (aminocarbonyl)-2-methylpropyl]- 237a 399 398.5476 2,3,4, 9-tetrahydro-3-[(3-methylbutyl)amino]-1H-fema-3-cyclosylamine (3S)-N-[(1S)-1 -(aminocarbonyl)- 2-methylpropyl]-237b 399 398.5476 2,3,4,9_tetrahydro:3-[(3-methylbutyl)amino] -1H-carbazole-3-carboxamide (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]- 238a 342 342.4404 2,3,4,9- Tetrahydro-3-(3•methylamino)-1Η-carbazole-3-amine 1 (3S)-N-[(1 S)-l-(aminocarbonyl&gt;2-methylpropane Base]- 238b 342 342.4404 2,3,4,9-tetrahydro-3_(3-methylamino)-1Η-carbazole-3-carboxamide (3R)-N-[(1 S) small ( Aminocarbonyl)-2-methylpropyl]- 238c 356 356.4672 3-(Dimethylamino)-2,3,4,9-tetrahydro-111-oxazole-3-skin@amine S)-N-[( 1S)-1 -(Aminocarbonyl)-2-methylpropyl]- 238d 356 356.4672 3-(Dimethylamino)-2,3,4,9-tetra- 1H-Yangjun-3-Halamine Example 3 1 : According to the A, F, G, I, F, K and 0 methods, 82,695-93 - 1246423 were formed at a 0.2 mm molar scale. (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]-239a 2.3.4.9-tetrahydro-3-[[(aminoamino)amino] -1H-leaf-3-indenylamine (3S&gt;N-[(1 S&gt;l-(aminocarbonyl)-2-methylpropyl]-239b 2.3.4.9-tetrahydro-3-[[( Methylamino)indolyl]amino]-old-leaf-3-derived oxime (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl] · 240a 2.3.4.9- Tetrahydro-3-[[(phenylamino)carboxy]amino]-1H-indazole-3-carboxamide (3S)_N-[(1 S)-l-(amine Carboxycarbonyl)-2-methylpropyl]-240b 2.3.4.9-tetrazole-3-[[(phenyl)]-yl]]]]]]] 3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]- 241a 2.3.4.9-tetrahydro-3-[[[(phenylmethyl)amino]carboxyl Amino]-1H-leaf-3-oxoamine (3S)-N-[(1S)-1-(aminocarbonyl)-2-methylpropyl]-241b 2.3.4.9-tetrahydro- 3-[[[(phenyl)amino)]]]]]]]]]]]H]-carbazole-3-carboximine (3R)-N-[(1 S)-l-(aminocarbonyl) -2-methylpropyl]- 242a 253.4.9- Tetrazo-3,[[[(2-phenylethyl)]]]]]]]]]]]] Amine (3S)-N_[(lS)-l-(aminocarbonyl)-2-methylpropyl]- 242b 2.3.4.9-tetrazole-3-[[[(2-phenylethyl)) Anji] number base] 385 385.4653 385 448 448 462 462 476 476 385.4653 447.5361 447.5361 461.5629 461.5629 475.5897 475.5897 82695 -94- 1246423 Amino]-1Η-carbazole-3-carboxamide (3R)-N-[(lS )-l-(Aminocarbonyl)_2-methylpropyl]-3-[[(cyclohexylamino)carbonyl]amino]-2,3,4,9-tetrahydro-1H-indazole-3 - Carboxylamamine 243a 454 453.5835 (3S)-N-[(1S)-1 -(Aminocarbonyl)-2-methylpropyl]-3.[[(cyclohexylamino)carbonyl]amino] -2,3,4,9-tetrahydro-1 fluorene-3-carboxime 243b 454 453.5835 (3R)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl -2,3,4,9-tetrahydro-3-[[[(l-methylethyl)amino]carboxy]amino]]] oxime-carbazole carboxamide 244a 414 413.5189 (3S)- N-[(lS)-l-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[[(l-methylethyl)amino]] Carboxy]amino]-1Η-carbazole-3-carboxamide 244b 414 413.5189 (3R)-N-[(1S)-1 -(aminocarbonyl)-2-methylpropyl]-2,3, 4,9-tetrahydro-3-[[[(l-methylpropyl)amino]carbonyl]amino]-1H-indazole-3-carboxamide 245a 428 427.5457 (3S)-N-[( 1 S)-l-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[[(l-methylpropyl)amino]carboxy]amine base] -1H-carbazole-3-carboxamide 245b 428 427.5457 (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]-2,3,4,9- Tetrahydro-3-[[[[(lR)-l-phenylethyl]amino]carbonyl]amino HH-indazole-3-carboxamide 246a 476 475.5897 (3S)-N-[(1 S )-l-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[[[(l()))]]]]]] 476 475.5897 82695 -95-1246423 carbonyl]amino HH-indazole-3-carboxamide (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl]-3 -[[[(4-chlorophenyl)amino]carbonyl]amino]-2,3,4,9-tetrahydro-1H-indazole-3-carboxamide 247a 482 481.9812 (3S)-N- [(lS)-l-(Aminocarbonyl)-2-methylpropyl]-3_[[[(4-chlorophenyl)amino]carbonyl]amino]-2,3,4,9-tetra Hydrogen-1H-indazole-3-carboxamide 247b 482 481.9812 (3R)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]-2,3,4,9- Tetrahydro-3-[[[[(())]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]] 1 S)-l-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3-[[[[(l())))] ]carbonyl]amino]-1H-indazole-3-carboxamide Azide Example 32: 248b 476 475.5897 Based on A, F, G, I, F, G, N and Ο Square-law to carry out 2 mmol scale synthesis. (3R)-3-[[[(l S)-l-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]]phenylphenyl)ethinyl]amino]-1,2, 3,4-tetrahydro-9H-leaf-9-acetic acid ethyl 249a 567 567.0825 (3S)-3-[[[(l S)-l-(aminocarbonyl)-2-methylpropyl]amine Substrate]-3_[[(4-murophenyl)ethyl s phenyl]amino]** 1,2,3,4-tetrahydro-9 oxime-carbazole-9-ethyl acetate 249b 567 567.0825 (3R)-N-[( 1S)· 1 -(Aminocarbonyl)-2-methylpropyl]-3-[[(4-chlorophenyl)ethinyl]amino]-2,3, 4,9-tetrahydro 250a 599 599.1711 82695 -96- 1246423 -9-(3-phenylpropyl)-1 oxime-carbazole-3-carboxamide (3S)-N-[(1S) small (amine Carboxyl)-2-methylpropyl]-250b 3-[[(4-chlorophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-9-(3-phenyl Propyl)-1Η-carbazole-3-carboxamide (3R)-3-[[[(lS)-l-(aminocarbonyl)-2-methylpropyl]251a-amino]carbonyl]- 3-[[(4-chlorophenyl)ethyl)amino]_1,2,3,4_tetrahydro-9Η-carbazole-9-acetate (3S)-3-[[[(l S)-l-(aminocarbonyl&gt;2-methylpropyl]-25ibamino]carbonyl]-3-[[(4-chlorophenyl)ethinyl]amino]-1,2,3 , 4-tetrahydro-9Η-carbazole-9-acetic acid hydrazine (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl] 252a -3_[[( 4-chlorophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-9-(3-methylbutyl)-1 oxime-carbazole _3_carboxamide (3S)- N-[(lS)-l-(amino-based)-2-methylpropyl] 252b-H[(4-phenylphenyl)ethinyl]amino]-2,3,4,9_ Tetrahydro-9-(3-methylbutyl)-1H-indazole-3-carboxamide (3R)-N-[(1 S)-1 -(aminocarbonyl&gt;2-methylpropyl ] 253a -H[(4-chlorophenyl)ethinyl]amino]-2,3,4,9·tetrahydro-9-(4-pyridylmethyl)-1Η-carbazole-3-carboxylate Indoleamine (3S)-N-[(1 S)-l-(aminocarbonyl)_2-methylpropyl] Yiying_3_[[(4-chlorophenyl)ethinyl]amino]_2, 3,4,9_tetrahydro-9-(4-ρ-decylmethyl)-1Η-叶峻-3-Rebel S (Acryl) carbonyl (3R)-N-[(1S)-1-(aminocarbonyl) -2-methylpropyl] carbaryl [[(4-chlorophenyl)ethinyl]amino]-2,3,4,9-tetrahydro 599 599.1711 539 539.0289 539 551 551 572 572 572 539.0289 551.1271 551.1271 572.1056 572.1056 572.1056 82695 -97- 1246423 -9-(3-Pyridylmethyl)-1Η-indazole-3-carboxamide (3S)-N-[(1 S)-l-(aminocarbonyl) -2-methylpropyl]-3-[[(4-chlorophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-9-(3-pyridylmethyl)- 1Η-叶咬-3-carboxyguanamine 254b 572 572.1056 (3R)-N-[(1S) small (amino carbonyl )-2-methylpropyl]-3-[[(4-chlorophenyl)ethinyl]amino]_2,3,4,9-tetrahydro-9-(2-naphthymethyl-seat- 3-Fushen Luanan 255a 621 621.1773 (3S)-N-[(1 S)-l-(Aminocarbonyl)-2-methylpropyl]-3-[[(4-chlorophenyl)acetamidine] Amino]-,,,,,,,,,,,,, S)-l-(Aminocarbonyl)-2-methylpropyl][[(4-chlorophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-9-( 2-Methylpropyl)-1Η-indazole-3-carboxamide 256a 537 537.1003 (3 S)-N-[(1S)-1-(Aminocarbonyl)-2-methylpropyl] -3 -[[(4-chlorophenyl)ethyl)amino]-2,3,4,9-tetrahydro-9-(2-methylpropyl)-1Η-indazole-3-carboxamide 256b 537 537.1003 (3R)-N-[(1S)Small (aminocarbonyl)-2-methylpropyl]-3-[[(4-chlorophenyl)ethinyl]amino]-2,3 ,4,9-tetrahydro-9-(2-phenylethyl)-1Η-indazole-3-carboxamide 257a 585 585.1443 (3 S)-N-[( 1S)-1-(aminocarbonyl) )-2-methylpropyl]-3-[[(4-chlorophenyl)ethinyl]amino]-2,3,4,9-tetrahydro-9-(2-phenylethyl) -1Η-carbazole-3-carboxamide 257b 585 585.1443 (3R)-N-[(1 S)-l-(aminocarbonyl)-2-methylpropyl] _3_[[(4-chlorophenyl) ) Amino] phenethyl- 258a 509 509.0467 82695 -98- 1246423 2.3.4.9- tetrahydro-1H-indazole-3-carboxamide (3S)-N-[(1S) small (aminocarbonyl) -2-methylpropyl] Yiying-3 - [[(4-chlorophenyl)ethyl)amino]-9-ethyl- 2.3.4.9-tetrahydro-1H-indazole-3-carboxylate Indoleamine (3R)-N-[(lS)-l-(aminocarbonyl&gt;2-methylpropyl]--3-[[(4-chlorophenyl)ethinyl]amino] Cyclohexylmethyl)-2,3,4,9-tetrahydro-111-oxazol-3-carboxamide (3S)-N-[(lS)-l-(amino-based)-2-A Propyl] 259b _3-[[(4-chlorophenyl)ethyl)amino]-9-(cyclohexylmethyl)-2,3,4,9-tetrahydro-1 oxazole-3 - Carboxylamamine (3R)-N-[(lS)-l-(amino)yl-2-methylpropyl] 260a -3-[[(4-chlorophenyl)ethyl)amino ]-9-[(2,6·Difluorophenyl)methyl]-2,3,4,9-tetrahydro-1Η-carbazole-3-carboxamide (3S)-N-[(1 S )-l-(Aminocarbonyl)-2-methylpropyl] 260b -3-[[(4-chlorophenyl)ethinyl]amino]-9-[(2,6-diphenyl) )methyl]-2,3,4,9-tetrahydro-1H-indazole-3-carboxamide 509 509.0467 577 577.1649 577 577.1649 607 607.0977 607 607.0977 Example 33: According to A, F, G, I, F, Η, N and Ο methods, synthesized at 0.2 millimolar scale. (3R)-3-(Ethylamino)-N-[(lS)-l-(aminocarbonyl and b 489 488.6284)-2-methylpropyl]-2,3,4,9- Tetrahydro-9-(3-phenylpropyl)-1Η-indazole-3-carboxamide 82682695 -99-1246423 (3S)-3-(ethenylamino)-N-[(lS)-l -(Aminocarbonyl sulfhydryl)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(3-phenylpropyl)-1Η-叶峻-3- decylamine (3R)-3-(Ethylamino)-N-[(lS)-l-(aminocarbonyl 262a)-2-methylpropyl]-2,3,4,9-tetrahydro- 9-(3-Methylbutyl)-1Η-leaf 17 is taken from -3-decylamine (3S)-3-(ethenylamino)-N-[(lS)-; K-aminocarbonyl hydrazine 2-methylpropyl]_2,3,4,9-tetrahydro-9-(3-methylbutyl)-1H-indazole-3-carboxamide (3R)-3-(B Hydrazinyl)-N-[[[(lS)-l-(aminocarbonyl 263a)-2-methylpropyl]-2,3,4,9-tetraaza-9-(2_na Methyl)-1Η-carbazole-3-carboxamide (3S)-3-(ethenylamino)-N-[[[(lS)-l-(aminocarbonyl 263b))-2 Propyl]-2,3,4,9-tetrahydro-9-(2-mercaptomethyl)-1Η-indazole-3-carboxamide 3-(ethylideneamino)-N-[ (lS)-l-(Aminocarbonyl)-2- 264methylpropyl]-2,3,4,9-tetrahydro-9-(1-indolylmethyl)-1H-leaf-3- Rebel amine 3-(ethylideneamino)-N-[(lS) small (aminocarbonyl)-2- 265 Propyl]-9-(cyclohexylmethyl)-2,3,4,9-tetrahydro-1H-indazole-3-treazone (3R)-3-(ethylamino)-N-[ (lS)-l-(Amino-based 266a)-2-methylpropyl]-2,3,4,9-tetrahydro-9-(2-methylpropyl)-1H-lead-3 - complex S-amine 489 488.6284 441 441 511 511 511 467 427 440.5844 440.5844 510.6346 510.6346 510.6346 466.6222 426.5576 82695 -100- 1246423 (3S&gt;3-(ethylideneamino)-N-[(lS)-l-(amine Radical thiophene 427 426.5576 base)-2-methylpropyl]-2,3,4,9-tetrahydro-9·(2-methylpropyl)-1Η-17 kawake-3-retinoin Example 34: The synthesis was carried out according to the D, F, G, I, F, 〇 method on a 0.2 milliohm scale and then coupled according to Example 6. [(lS,2S)-H[[(3R)-3-[[[(1S))] (hydroxyl 563 562.7068)-2-methylpropyl]amino]carbonyl]_2,3,4, 9_tetrahydro-1H-leaf sitting _3_yl]amino] benzyl]_2-methylbutyl] benzyl carbamate [(lS,2S)-l-[[[(3S)- 3_[[[(lS)-l-(hydroxy hydroxy 563 562.7068 yl)-2-methylpropyl]amino]carbonyl]·2,3,4,9_tetrahydro-1 Η-carbazole-3 -yl]amino]carbonyl]·2-methylbutyl] phenyl carbazate Example 35 : 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-111-oxime Azole_3-carboxylic acid ethyl vinegar 268 10 mmol (1.6 ml) of ethyl 4-oxocycloalkanoate, 25 mmol (1.4 ml) of glycol and 10 micromoles pTsOH in water separator in water The mixture was refluxed for 24 hours in toluene. The solvent was removed and dissolved in ethyl acetate / water. The organic phase is washed with water, dried and evaporated to dryness. The product was distilled in a bulb at 120 ° C under high vacuum at 0.03 mbar. Yield: 1.52 g of 4-ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate 85 μl of diisopropylamine in 500 μl of dry THF at -20 ° C in argon The mixture was added dropwise to 0.6 mmol of 1.6 butyl butyllithium in heptane and stirred at 82,695 - 101 - 1246423 for 10 minutes. After cooling to -70 ° C, add 毫·5 mmol (107 mg in 200 μl of dry THF, let it rise to within 1 hour, stir for another 3 minutes. Cool to -7 (after TC) Add 300 μl of 〇·7 mmol (1 〇 6 μl) of 1-bromo-3-phenylpropanone in anhydrous THF, stir for another 3 minutes, allow to warm to room temperature, and stir for an additional hour. The organic phase was carefully treated with a saturated ΝΗβΙ solution and a η-hexane mixed stone, and 1 〇 was removed for 4 liters. It was washed with water from the organic phase. After filtration through Whatman filter, it was evaporated to dryness. Yield: 165 mg 8- (3-Phenylpropyl)-i,4-dioxaspiro[4.5]decane tetamine ethyl ester 12 Lithium. 6 mM (200 mg) 22 liters dissolved in 25 ml of acetone / 0.1 μ HC1 The mixture was stirred at 50 ° C for 48 hours with a catalytic amount of pTsOH in 1 : 1. Acetone was removed in a cyclone evaporator, and the product was filtered, washed with water and dried. Yield: 156 mg 4-oxo-8- Ethyl (3-phenylpropyl)cyclohexanecarboxylate 271. Separated as phenylhydrazine as described in Example 1. Evaporation to give HPLC yield: 65 mg of 2,3,4,9·tetrahydro- 3·(3-Phenylpropyl)-1Η-carbazole-3-carboxylic acid ethyl m 268 〇ES-MS : 362(M+H+ In a similar manner, 2,4-dichlorophenylhydrazine was used to prepare 80 mg of 6,8-dichloro 2 ' 3,4,9 -tetrasole-3 ·( 3 -propenylpropyl)_ 1Η - mouth card Jun-3 - acid oxime 272. ES-MS: 430 (Μ + Η +) Example 36: 2,3,4,9-tetrahydro-3-(3-phenylpropyl V1H-carbazole-3- #酸273 3.94 mmol (1.31 g) of 269 in 50 ml of methanol and 30 ml of 50% sodium hydroxide solution was stirred at 60 ° C for 4 hours. Acidified with dilute HC1, using ether extract 82695 -102-1246423 Drying with NaJO4 and evaporating, yield 1 2 g (85%) of white solid, 8-(3-d-propylpropyl)-1,4-dioxaspiro[4.5]decane-8-carboxylate m and m were deprotected with HC1 and then reacted with phenylhydrazine. Evaporation and preparation of HPL C: Yield: mg 273. ES-MS: 334 (M+H+) 2,4-Dichlorophenyl hydrazine to give 39 mg of 6,8-dichloro 2.3.4.9-tetrahydro-3-(3_winterpropyl octazone-3-acid 275. ES-MS: 478 ( M+H+) Example 37: 2.3.4.9- Tetrahydro-N-[(lS)-l-(hydroxymethyl)_2-methylpropylbu- 3-(3-phenylpropyl)-1 - oxazole- 3-Carboxyguanamine 276 will be 0.66 mmol (200 mg in a similar manner to Example 6 with i · 5 equivalents of decylamine Alcohol reaction. 277 mg of white solid 仏[(13)-1-(light methyl)_2_methylpropyl]-8-(3-phenylpropyl)-1,4-dioxaspiro[4·5]癸 醯 醯 277 277 277 277 277 〇 277 277 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 After evaporation and preparative HPLC treatment: Yield: 15 mg ES-MS: 418 (M+H+) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 25 mg 68-chloro-2,3,4 9-tetrahydro-N-[(lS)_l-(hydroxymethyl)-2-methylpropyl]_3_(3_phenylpropyl)-1Η-carbazole-3-carboxy 酉 278 〇ES- MS: 486 (M+H+) 82695 - 103 1246423 Example 3 8 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-pyridylmethyl)-lH- Carbazole-3-methaneamine A solution of 54 ml of 1 μL of LiAlH4 in dry THF was added to a solution of 18 mM (6 g) 270 in 250 mL of anhydrous THF under argon at room temperature. After refluxing for 3 hours, it was carefully hydrolyzed with 300 mL of saturated NH4Cl solution and mixed with 250 mL of ether. The aluminum salt was filtered off and washed with ether. The ether phase was dried over Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. 5.86 mmol (1.7 g) of 2 hydrazine was dissolved in 60 ml of anhydrous DCM and 20 ml of anhydrous DMSO. Carefully add 44 millimolar (6.1 milliliters) of TEA at room temperature under nitrogen, followed by 17.6 millimoles (2.8 grams) of the S03-pyridine complex and stir for one hour. It was then mixed with 200 ml of a saturated NH4Cl solution and extracted with 150 ml of ether. The ether phase was dried over Naj.sub.4 and evaporated to give &lt;RTI ID=0.0&gt;&gt;&gt;&gt;&gt; 0.719 耄 molar sodium borohydride was added to 359.359 mmol (1 〇 3 耄) Zhao Zhao and 0.359. mM (37 ml) 2-pyridylmethane in 2.5 ml 1, In a mixture of 2-dichloroethane. The mixture was stirred at room temperature for 3 hours. It was mixed with a saturated NaHC〇3 solution and extracted with ether. The ether extract was dried and evaporated to give 101 mg (76%) of white solid N-[8-(3-phenylpropyl-17 snail[4.5] oxime-8-yl]-2-indole Amine 282. Then, as described in 2_Z1, it will be first deprotected with HCl and then deuterated with phenyl hydrazine. After evaporation and preparative HPLC, the yield is 71 mg 279. 82695 -104 - 1246423 ES-MS : 410 (M+H+) 54 mg of 6,8-dichloro-2,3,4,9-tetrahydro-3-(3-phenylpropene) was prepared in a similar manner using 2,4- phenylindole. Base)_;^-(2-峨 基 基 methyl)_1^_叶口坐-3-甲院胺283 〇ES-MS ·· 478(M+H+) Example 39 : (2S)-3-甲Benzyl-2-[[[2,3,4,9-tetrahydro-3-(3-phenyl))]11-carbazole-3-yl]methyl]-amino]_1_butanol will be 0.368 mmol The ear (106 mg) was dissolved in 1.5 ml of anhydrous methanol with 0.368 mmol (38 mg) of the amino alcohol and stirred at room temperature for 3 minutes. After cooling, add 0.557 mmol (21 mg) of NaBEU. Stir at room temperature for 1 hour. Add 0.4373⁄4 mol (25 μl) of sour acid' and mix at pH 6 for 2 hours.

The NaHC〇3 solution was mixed and extracted with ether. The organic phase was dried and evaporated with EtOAc (EtOAc) EtOAc (EtOAc) Yield after evaporation and preparative HPLC: 18 mg white solid. ES-MS: 405 (M+H+) obtained in a similar manner using 2,4-dichlorophenylhydrazine to give 17 mg (2S)-2-[[[6,8-dichloro-2,3,4,9 -tetrahydro-3-(3-phenylpropyl)-1Η-ylide-3-yl]methyl]amino]-3-methyl-butanol 286 〇ES-MS : 473(M+H+) Example 40 2,3,4,9-Tetrahydro-3-(3-phenylpropyl)-indole-(4-pyridylmethyl)-l-indazole-3-methanol 287 82695-105- 1246423 0.689 millimolar NaH (55% suspension in mineral oil) was added to a solution of 0.344 millimolar (100 mg) in 1 mL of anhydrous DMF under hydrazine. Allow to warm to room temperature and stir for 30 minutes. 1377 mmol of 4_(chloromethyl)pyridine was added and stirred at 95-1 00 ° C overnight. After cooling to room temperature, it was hydrolyzed with 2 ml of water and extracted with ether. The LM was dried and evaporated to give a crude oil (yield: 115 mg) which was then deprotected as described for m and m and (5). After evaporation and preparative HPLC: Yield: 14 mg of white solids: ESI: 411 (M+H+) Example 41: 3-[2,3,4,9-tetrahydro-3-(3-phenylpropane Ethylzol-3_yl]_2_ethyl acrylate 289 0.347 mmoles of ruthenium. 5 ml of Norne (d) solution was added dropwise to 0.378 mmol (triphenylphosphinyl) ethyl acetate under ice cooling.丨ml of the solution in pure thf. After the addition, let it rise to room temperature, stir for 2 days, hydrolyze with water and extract with ether, dry with NajO4, filter off phosphine oxide and impurities, and evaporate to remove solvent. Yield: 80. Ethyl 3-[8-(3-phenylpropyl)_M_ snail [45] 癸_8_ yl]-2-propionate acetate 290. Then, as 270 and 2 Ί l/jf, the protection is described. After evaporation and preparative HPLC treatment, yield: 9 mg of white solid ES-MS: 388 (M+H+) ~~ In addition, the compound of the formula (I) of the present invention is 293^$300, 302, according to A, F, G, F, (^0 method preparation, compound Ying ^ according to B, F, G, F, G and 〇 method, compound ^ is according to 82695 -106-1246423 G, Prepared by F, G, F, L and 〇, on a scale of 0.2 millimolar. Compound name number MFn d Mdd [(lS,2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6, 4-Difluoro 2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 293 612 611.6861 [(lS , 2S)-l-[[[(3S)_3-[[[(())]]] 2,3,4,9-tetrahydro.oxazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 294 620 619.7585 [(1S,2S)-1-[ [[(3R) Each [[[(lS,2S)-l-(aminocarbonyl)_2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9- Benzene tetrahydro-111-oxazol-3-yl]amino]indenyl]-2-methylbutyl]carbamic acid 295 659 658.6229 [(lS,2S)-l-[[[(3R) -3-[[[(lS)-l-(aminocarbonyl)-3_methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-1H - oxazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 296 659 658.6229 [(lS,2S)-l-[[[(3R)-3-[[ [(lS)-l_(Amino |yl)-2-cyclohexylethyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro.oxazol-3-yl Amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 297 699 698.6875 [(lS,2S)-l-[[[(3R) -3-[[[(())))]]]]] Name No. MFnd Mcid -2,3,4,9-tetrahydro-1carbazoleyl]amino]carbonyl]_2-methylbutyl]carbamic acid benzyl ester [(lS,2SH-[[[ (3R)_3-[[[(lS)_l-(aminocarbonyl)-3-phenylpropyl]amino]carbonyl]_6,8-dichloro-2,3,4,9-tetrahydro-111 - oxazol-3-yl]amino]carbonyl]methylbutyl]carbamic acid benzyl ester 299 707 706.6669 [(1S,2S)-H[[(3R)-3_[[[(1S)-K Aminocarbonyl)_2-methylbutyl]amino]anthracene]di-gas-2,3,4,9-tetrahydro-1:»-oxazol-3-yl]amino]carbonyl]-2- Benzyl cyclomethylamino] carbamic acid 300 685 684.6607 [(1S, 2S) small [[[(3S))3-[[[(1S,2S)-1-(carboxy)_2_methylbutyl]] Amino]carbonyl]-M-dichloro-2,3,4,9-tetrahydro-1carbazole-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 301 660 659.607 [(lS)-l-[[[(3S)-3_[[[(lS,2S)-l-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]_6,8 -Dichloro-2,3,4,9-tetrahydro-1H-carbazoleyl]amino]carbonyl]-2-(4-hydroxyphenyl)-ethyl]carbamic acid benzoquinone 302 709 708.6391 [(lS)-H[[(3R)-3-[[[(lS,2S)-l-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-6,8-di Chloro-2,3,4,9-tetrazo-1H-mouth bayonet-3-yl]yetyl]-3-yl(4-hydroxyphenyl)-propyl]carbamic acid benzoate Ester 303 723 722.6659 [(lS)-l-[[[(3R)-3-[[[(lS,2S)-l-(aminocarbonyl 304 707 706.6669 82695 -108-1246423 compound name number MFnd Mcid base) Winter methyl butyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-1-oxazol-3-yl]amino]carbonyl]-3-phenylpropane Benzyl carbamic acid benzyl ester [(lS)-l_[[[(3R)-3-[[[(())]]] -6,8-Dichloro, 2,3,4,9-tetrahydro-1H-indazol-3-yl]amino]carbonyl]methylbenzyl butyl]carbamic acid 305 659 658.6229 [( 1S)-H[[(3R)-H[[(1S)-1_(aminocarbonyl)-3-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4, Benzyl 9-tetrahydro-1H-carbazole-3-yl]amino]carbonyl]- 3-methylbutyl]carbamate 306 659 658.6229 III. GnRH antagonism of compound (I) according to the invention Test material: Buserelin was purchased from Welding (Frankfurt/Main, Germany). This compound was labeled with 1251 using the gas amine T-method and Na125I (4000 Curie/mole; Amersham-Buchler, Germany). The labeled material was purified by reverse phase HPLC on a Spherisorb ODS II column (250 X 4 mm, particle size 3 μm) with 50% acetonitrile / 0.15% trifluoroacetic acid at a flow rate of 毫升5 ml/min. The specific activity is 2000 Curie/mole. All other chemicals are of the highest purity commercially available. Cell culture: αΤ3-1 cells (Bilezikjian et al., Mol. Endocrinol 5 (1991), 347-3 5 5) containing penicillin (100 IU/ml), streptomycin (〇.; [毫82695] -109 - 1246423 g/ml) and glutamine (0.01 mol/L) and 丨0. /. Fetal bovine serum (Fcs; PAA Laboratories, Coelbe, Germany) was cultured in DMEM medium (Gibco-BRL, Eggenstein-Leopoldshafen, Germany) in a plastic culture dish (Nimc, 245 x 245 x 20 mm). Ch〇-3 cells (Schmid et al., J. Biol. Chem. 275 (2000), 9193-9200) were cultured under the same conditions using only Hams F 12 medium (Gibco-BRL). Ten confluent cell culture dishes were rinsed twice with 50 ml of phosphate buffered saline solution (pBS). The cells were scraped into 5 ml of pbs with a squeegee, and the cells were pelleted by a laboratory centrifuge (Heraeus) at 800 rpm for 1 minute. The cell pellet was then suspended in 5 ml of 〇25 mol/liter sucrose/0·01 mol/liter diethanolamine, pH 7.4. The cells were chilled/dried in an ice bath and thawed at room temperature, and the cells were lysed three times in this cycle. The lysate was centrifuged at 900 rpm for 1 minute and the precipitate was discarded. The supernatant was centrifuged at 18 rpm for 3 minutes using a s〇rvaU SS34 rotator. Pellet (cell membrane) was suspended in 5 ml of identification buffer (0.25 m/L sucrose, 〇·〇1 mol/L3 triethanolamine, pH 7.5, 丨mg/ml egg albumin) to 200 μl with Potters The whole is stored at _2 ° ° C. Proteins were determined according to the Bradford method (Anal Biochem. 72 (1976), 248-254) 〇 Receptor Identification Competition curve coupling studies were performed in three sets. The test sample contains 6 microliters of cell membrane suspension (10 μg of αΤ3-1 cell protein, 4 μg of CHO3 cell protein), 2 μl of microliter 1251_labeled buserelin (1〇〇, 〇〇〇Ipm/competition curve sample) , 1,500 to 200, 〇〇〇Ipm saturation test) and 2 〇 microliter test buffer or test a liquid 4 solution. The test compound is dissolved in distilled water or 5 ethanol. Serial dilution with 82695 -110-1246423 test buffer (5x1 (T6 mol/L to 5x1 0·12 m/L). In the presence of excess unlabeled buserelin (l (T6 mol/L)) The non-specific coupling was determined. The test sample was incubated at room temperature for 30 minutes. The bonded and free-form ligands were separated by filtration using an Amicon 10x receiver (Whatman GF/C-filter, 2.5 cm diameter), using 5 ml 0.02 Mo Ears/liter Tris/HCl, pH 7.4, washed twice. The filter was wetted with 0.3% polyethyleneimine (Serva; Heidelberg, Germany) for 30 minutes to reduce non-specific coupling. The radioactivity collected by the filter was 5- Channel γ-counter (Wallac-LKB 1470 Wizard) determination The following table lists the IC5 enthalpy values of the compounds prepared above. Example of compound name hGnRH-receptor Ca2+ release human number ic5〇[M1 ic5〇IM1 1^[[( 311)-2,3,4,9-tetrahydro-3-[(1-oxo-2,3-diphenylpropyl)amino]-1Η-oxazol-3-yl]carbonyl]-L- Amidoxime-L-aspartate 18 0.0000009 0.000005 (3 S)-N- [(1S)-1-(aminocarbonyl)-2-methylpropyl]-2,3,4,9- Tetrahydro-3-[(1Η^1哚-3-ylethyl)aminopurine-carbazole Carboxyguanamine 164b 0.000006 0.0000065 (3 S)-N-[( 1S)-1 -(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro each [(2-荇Ethylamino)amino]-1H-leaf ternary oleylamine 161b 0.0000037 0.0000036 1[[(311)-2,3,4,9-tetrazole-3-[[(23,33)- 3-Methyl-1-oxo-2-[[1-lac-3-phenylpropyl)-amino]pentyl]amino]-1H-indazol-3-yl]carbonyl]-L-indole Amine 醯 22 0.000002 0.000001 82695 -111 - 1246423 Compound name example hGnRH-receptor Ca 2+ release human number ic5 〇 IM1 ICsnCMl ke-L-aspartate [(18,28)-1-[[[(311)- 3-[[[(18,28&gt;&gt;1-(amino-based)-2-methylbutyl]amino]-carbonyl]-2,3,4,9-tetrahydro-1H-carbazolyl ]Amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 64 0.0000017 0.0000015 [(lS,2S)-l_[[[(3R)-3-[[[(1))] [[4-(Aminocarbonyl)phenyl]amino]carbonyl]-2-methylpropyl]amino] 基基]_2,3,4,9_tetrahydro-111_叶口坐-3_ Benzyl]amino]methylbutyl]carbamic acid phenylmethyl ester 45 0.0000003 0.000001 [(lS,2S)-2-methyl small [[[(311)-2,3,4,9-four Hydrogen-3_[[[(1 S)-2·methyl-1-[(methylamino)carboxy]propyl]amino]carbonyl]-1Η-carbazole group] Amino]carbonyl]butyl]-carbamic acid benzyl ester 222a 0.0000025 0.000003 [(lS,2S)-H[[(3R)-3-[[[(lS)-l-(aminocarbonyl)-2 -methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-pyrazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzoate Ester 58 〇.〇〇〇〇〇〇3 〇.〇〇〇〇〇〇37 [(lS,2S)-l-[[(3R)-3-[[(2S)-2-(Aminocarbonyl) )-1-pyrrolidinyl]carbonyl]-2,3,4,9-tetrahydro-1carbazoleyl]amino]carbonyl]methylenemethylbutyl]carbamic acid benzyl ester 181a 〇.〇 〇〇〇〇〇7 0.000003 [(1S,2S)-H[[(3R)-3_[[(2S)-2-(aminocarbonyl) 190a 0.000002 〇.〇〇〇〇〇〇5 82695 -112 - 1246423 Compound name example hGnRH-receptor Ca2+ release human number IC5〇IMl iCsoIMl 八风τ1Η·Ί卜朵-1-基][基基]-2,3,4,9-tetrazo-1H-leaf sitting Amino]methyl butyl] benzyl carbamic acid 2,3,4,9-tetrahydro-3-(3-phenylpropyl)-N-(2-p aryl amide Base)-1Η-carbazole-3-methaneamine 279 0.000002 0.000003 (2S)-3-methyl-2-[[2,3,4,9-tetrahydro-3-(3-phenylpropyl) -1Η-ρ卡咬_3·基]Methyl]-amino]-1-butanol 284 0.000007 0.000007 N-[(lS)-l-(Amino)-2-methylpropyl]·* 2,3,4,9-tetrahydro-3-[[(4-methoxyphenyl)- Ethyl HH-carbazole-3-carboxamide 175 0.000008 0.0000018 (3R)-N-[(1 S)-1-(Aminocarbonyl)-2-methylpropyl] _3·[[ (3_Bromophenyl)ethinyl]-amino]-2,3,4,9-tetrahydro-1Η-carbazole-3-carboxamide 96 0.000004 0.000003 (3R)-N-[(1 S )-l-(Aminocarbonyl)_2-methylpropyl]-3-[[(4-fluorophenyl)ethyl]amino]_2,3,4,9-tetrahydro-1H-leaf Jun-3-Resinamine 91 0.0000024 0.000002 (3R)-N-[(1 S)-l-(Aminocarbonyl)_2-methylpropyl]-3-[[(4-chlorophenyl)acetamidine] ]]-amino]-2,3,4,9-tetrahydro-1 H_p card ol-3 - rebellious g-amine 167a 0.000001 0.0000026 (3R)-N-[(1 S)_ 1-(aminocarbonyl) )-2-methylpropyl]-2,3,4,9-tetrahydro-3-[(6-phenylhexyl)amino]-11·!-Yejun-3-treazone 234a 0.000009 0.000001 1246423 Compound name example hGnRH-receptor Ca2+ release human number ic5〇IM1 ic5〇IMI [(1S,2S) small [[[(3R)-3-[[[((s)))) _Methylpropyl]amino]-mercapto]_2,3,4,9-tetrahydro-8-methyl-1H- thiazolyl]amino]carbonyl]_2-methylbutyl]aminocarboxylic acid Benzyl methyl ester 150a 〇.〇〇〇〇〇〇11 〇.〇〇〇〇〇〇28 [(lS,2S)-l-[[[(3R)-3-[[[(lS) small (aminocarbonyl)_2 _Methylpropyl]amino]-carbonyl]·6_chloro-2,3,4,9-tetrahydro-1 oxazol-3-yl]amino]carbonyl]-2·methylbutyl]amine Benzoic acid benzoquinone 148a 〇.〇〇〇〇〇〇08 〇.〇〇〇〇〇〇14 [(lS,2S)-H[[(3R)-3-[[[(lSH-(amino) Carbonyl)-2-methylpropyl]amino]-yl]-2,3,4,9-tetrahydro-methoxy-1H-carbazoleyl]amino]carbonyl]methylbutyl]amine Benzoic acid benzoquinone 147a 〇.〇〇〇〇〇〇076 〇.〇〇〇〇〇〇25 [(lS,2S)-l-[[[(3R)-3-[[[(l() -l-(aminocarbonyl)_2.methylpropyl]amino]-carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-1H-anthracene 3-yl]amino group j Benzyl carbonyl]methylene methyl butyl urethane 184a 〇.〇〇〇〇〇〇015 〇.〇〇〇〇〇〇045 [(lS,2S)_l-[[[(3R)-3- [[[(lS)_l-(hydroxymethyl)_2-methylpropyl]amino]carbonyl]-2,3,4,9-tetrahydro-1H-carbazole-3-yl]amino]carbonyl Benzyl-2-methylbutyl]carbamate 267a 〇.〇〇〇〇〇〇4 〇.〇〇〇〇〇〇5 (2S)_H[C3R)-3-[[(4-chloro) Phenyl) ]]-amino]-2,3,4,9-tetrazo-8-decyloxy-1H-leaf sitting-3- 189a 〇.〇〇〇〇〇〇7 0.0000005 82695 -114- 1246423 Compound name _ Example hGnRH-receptor Ca2+ release human number ic5〇IM1 ic5〇IM1 base]carbonyl]-2-pyrazine rebate amine 6,8-dichloro-2,3,4,9-tetrahydro ice (3 -Phenylpropyl)-indole-(2-ρ ratio decylmethyl)-1Η^ bayonet sitting-3-methylamine 283 0.000001 0.000003 Compounds 293 to 306 were tested according to the following methods: Receptor coupling identification material · 125I-Triptorelin [_125l-(D)_Trp6-GnRH] was purchased from Biotrend Company (Cologne, Germany). The specific activity in each case was 2.13 Curie/mole. Other chemicals are the highest quality commercially available. Cell culture: Puncture LTK, cells (ATCC No. CCL-1.3) in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (100 IU/mL), streptomycin (〇·1 mg/ml) and valley Amine amide (0.01 mol / liter) and 10% fetal bovine serum (FCS; Invitrogen Life Technologies,

Germany) Cultured on plastic tissue culture dishes (Nunc, Germany, 245 x 245 x 20 mm). Test: The 80% confluent cell culture dish was rinsed twice with 50 ml of phosphate buffered saline (PBS) and dissolved as 〇.〇1 M EDTA solution as follows. The cells were pelleted by centrifugation on a X-well chamber centrifuge (Kendro, Germany) for 5 minutes. The cell pellet was suspended in 3 ml of coupling medium (DMEM; 1 0 82695 -115 - 1246423 mM Hepes; 0.5% BSA; 0.1% NaN3; 1 g / liter of bacitracin (new addition, storage ΙΟΟχ); 0.1 g / liter In SBTI (new addition, storage ΙΟΟΟχ), the cells were counted by trypan blue staining in the Neubauer counting chamber. The cell suspension was set at 5xl05Z/0.05 ml with the coupling medium. The competition curve coupling test was performed in two. The test substance was 1 〇. Use with millimolar DMSO solution. Dilute to 4x of final concentration in coupling medium. Mix 25 μl of material dilution with 25 μl of tracer solution (125I-tripto; relin). Tracker concentration is set at 100 μl Final reaction volume of approximately 50,000 cpm (Cobra II, gamma counter, PE Liefe Science, Germany) 200 200 μl of decane/paraffin mixture (84%: 16%) was introduced into a 650 μl bit of bottom tube (Roth) , Germany), titrate 50 microliters of cell suspension, and then titrate 50 μl of test substance / tracer mixture. Seal the tube and incubate at 37 ° C for 60 minutes in a top-rotating incubator. After culturing, use a centrifuge (Ken Dro, Germany) The sample was centrifuged at 900 rpm and then frozen in liquid N2. One end of the cell pellet was excised and inserted into the prepared counting tube (Roth, Germany). There is a little remaining supernatant. The bottom tube was also inserted into the counter tube. Each sample was counted for 1 minute with a gamma counter. Removal of UN specific bond by GraphPad Prism (GraphPad Software Inc., USA) (excess unlabeled ligand) After 1 micromolar, the count specific binding was compared to the untreated cells to evaluate the sample. Functional Receptor Gene Identification Materials: All chemicals were commercially available of the highest quality. 82695 -116- 1246423 Cell Culture Substance: For functional assays, use steadily, puncture LTK cells with GnRH receptor (ATCC No. CCL-1.3), heterologous expression with cAMP-related elements, and CMV minimal promoter to luciferase Reporter gene. Cells were in DMEM medium (Invitrogen Life Technologies, Germany) with penicillin (100 IU/ml), streptomycin (0.1 mg/ml) and amidoxime (0.01 mol/L) and 10 % fetal bovine serum (FCS; Invitrogen Life Technologies, Germany) was cultured on plastic tissue culture dishes (Nunc, Germany, 245 X 245 X 20 mm). Test: 80% confluent cell culture plates were washed twice with 50 ml of phosphate buffered saline (PBS) and then dissolved with trypsin EDTA solution (Invitrogen Life Technologies, Germany). The cells were pelleted by centrifugation at 200 xg for 5 minutes in a laboratory centrifuge (Kendro, Germany). The cell pellet was then suspended in 3 ml of identification medium (Invitrogen Life Technologies, Germany) containing penicillin (100 IU/ml), streptomycin (0.1 mg/ml) and glutamine (0.01 mol/L). And 10% fetal bovine serum (FCS; Invitrogen Life Technologies, Germany), cells were counted by trypan blue staining in a Neubauer counting chamber. This cell suspension was set at a concentration of lxl 〇 4Z/100 microliters using an identification medium. The cells were then placed on a white 96-concave microtiter dish (Costar, Germany) and cultured in an incubator for 18 hours. During the test, the test substance was diluted to 10 mM DMSO solution in the identification medium to a final concentration of 6x. Twenty microliters of the test substance was added to 100 μl of the cells, and cultured at 37 ° C for 60 minutes, 5 ° / 〇 C 〇 2 . Then add triptorelin 82695 -117- 1246423 (D-Trp6-GnRH) / Rolipram solution (6 nanomoles / 6 micromoles), and then incubated at 37 ° C for 6 hours, 5% CO 2 . After the incubation, 50 μl of dissolution/assay buffer (LucLite, PE Life Science) was added and assayed in a Lumistar luminometer (BNG Labtechnologies GmbH, Germany). After removal of the unstimulated controls, inhibition and comparison of untreated stimulated cells were calculated, and samples were evaluated by GraphPad Prism (GraphPad Software Inc., USA) or with 〇MMM (Accelrys, Germany) Software. The following table lists the EC5 values of compounds 293 to 306. 名称 compound name example number functional human ec5 〇 IMI human coupling Triptorelin EC50IMI [(lS, 2S)-l-[[[(3R)-3-[[[(l() -l-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6,8-difluoro-2,3,4,9-tetrahydro-1^1-leaf sitting-3- Benzyl]-2-methylbutyl]carbamic acid benzyl ester 293 〇.〇〇〇〇〇〇762 〇.〇〇〇〇〇〇332 [(1S,2S)-1- [[[(3R)_3-[[[(1S,2SH-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-8-methoxy-2,3,4,9-tetra Hydrogen-1H-indazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 294 〇.〇〇〇〇〇〇089 〇.〇〇〇〇〇〇036 [ (lS,2S)-l-[[[(3R)-3-[[[(lS,2S)-l-(aminobenzyl)-2-methylbutyl]amino]] yl]-6 ,8·Dichloro-2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester 295 〇.〇〇 〇〇〇〇007 〇.〇〇〇〇〇〇018 1246423 Compound name Juyan example number functional person EC50IMI human coupling Triptorelin ECsn "Ml [(lS,2S)-l-[[[(3R)-3-[[[ (lS)-l-(aminocarbonyl)methylbenzyl]amino]carbonyl Benzyl]-hydrazine-dichloro-2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carboxy]-2-methylbutyl]carbamic acid benzyl ester 296 〇. 〇〇〇〇〇〇014 〇.〇〇〇〇〇〇022 [(lS,2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl)_2_ Cyclohexylethyl]amino]carbonyl]_6,8-dichloro-2,3,4,9-tetrahydro-11-oxazol-3-yl]amino]carbonyl]-2-methylbutyl Benzyl carbazate 297 〇.〇〇〇〇〇〇284 〇.〇〇〇〇〇〇482 [(lS,2S)-l_[[[(3R)-3-[[[(1) Aminocarbonyl)-2,2-dimethylpropyl]amino]carbonyl]-6,8-dichloro, 2,3,4,9-tetrahydro.oxazol-3-yl]amino]carbonyl ]-2-methylbutyl]carbamic acid benzyl ester 298 〇.〇〇〇〇〇〇288 [(1S,2S) small [[[(3R)-3_[[[(1S)-1_(amine Carbonyl)-3-phenylpropyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-1: «-oxazol-3-yl]amino]carbonyl ]-2-methylbutyl]carbamic acid benzyl ester 299 0.000001497 0.000001307 [(lS,2S)-l-[[[(3RKH[[(lS)-l-(aminocarbonyl)))] Benzyl]amino]-6,8-dichloro-2,3,4,9-tetrahydro-1 oxazolyl]amino]carbonyl]-2-cyclohexylmethyl]aminocarbamic acid benzene Methyl ester 300 〇.〇〇 〇〇〇017 〇.〇〇〇〇〇〇023 [(lS,2S)-l-[[[(3R)-3-[[[(lS,2S)-l-(Rebel 301 〇.〇〇〇 〇〇〇176 〇.〇〇〇〇〇〇538 82695 -119- 1246423 Compound m Example number Functional human ECsoIMI Human coupling Triptorelin ec5〇[M1 base)-2·Methylbutyl]amino]]yl]-6 ,8_digas-2,3,4,9-tetrahydro-111-leafyl-3-yl]amino] benzyl]-2-methylbutyl]carbamic acid benzyl ester [(lS )-l-[[[(3R)-3-[[[(lS,2SH-(aminocarbonyl)) 2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3, 4,9-tetrahydro-1H-port succinyl-3-yl]amino]carbonyl]-2-(4-hydroxyphenyl)ethyl]carbamic acid benzoate 302 〇.〇〇〇〇〇 〇324 〇.〇〇〇〇〇〇475 [(lS)-H[[(3R)-3-[[[(lS,2SH-(aminocarbonyl))))]]]]]] 6,8-Dichloro-2,3,4,9-tetrahydro-111-flan-3-yl]amino]pyrimidin]-3-(4-hydroxyphenyl)propyl]aminocarboxylic acid Benzene 303 〇.〇〇〇〇〇〇021 [(lS)-l-[[[(3S)-3-[[[(lS,2S)-l-(aminocarbonyl)-2-methyl) Butyl]amino]carbonyl]digas-2,3,4,9,tetrahydro-111-oxazol-3-yl]amino]carbonyl]-3-phenylpropyl]amino Benzene methacrylate 304 〇.〇〇〇〇〇〇018 〇.〇〇〇〇〇〇038 [(lS)-l_[[[(3R)-3-[[[(lS,2S)-l-(( Aminocarbonyl)_2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-1H-leaf--3-yl]amino]carbonyl] Benzyl methyl butyl] carbamic acid 305 〇.〇〇〇〇〇〇056 [(lS)-H[[(3R)-3-[[[(lS)-l-(aminocarbonyl)) -3-methylbutyl]amino]carbonyl]dichloro 306 〇.〇〇〇〇〇〇077 82695 -120- 1246423 Compound name example number functional human ec5〇IM1 human coupling Triptorelin EC50IMI -2,3,4, 9-tetrahydro-1H-indazol-3-yl]amino]] benzyl]-3-methylbutyl]carbamic acid phenyl ester 82695 121 -

Claims (1)

Wen Yuming's patent spine replacement (September 94) Pickup, patent application scope: L A compound of formula (I) The R1 group is a hydrogen atom, a CrC6 alkenyl group or a Cl_C6 alkyl group, and may be optionally substituted with an aryl group, a heteroaryl group or a -COOR11 group, where the aryl or heteroaryl group may be substituted by up to three substituents, These substituents are independently selected from the group consisting of 7 02 ' _CH 3 ' _CF 3 ' _ 〇 CH 3 ' 〇 〇 with 3 and _ atoms, and wherein the R group is a hydrogen atom, a Ci-Cu alkyl group, a cvc 12 aralkyl group, An aryl, heteroaryl or -cocH; group, and may be substituted by a substituent selected from the group consisting of -CONH2, -COCH3, _cooch3, _so2ch3 and aryl; R2, R3, ! And the R5 groups are independently of each other a hydrogen atom, a halogen atom, -COOH, -CONH2, -CF3, -〇CF3, -N02, -CN, (VC6 alkyl or cardio-alkoxy; R6 group is -CONR8R9, -COOR8, -ch2nr8r9, -ch2r8 or -CH2OR8, 1246423 wherein R8 and R9 are independently of each other a hydrogen atom, a Cl-Cl2 alkyl group, a Ci_Ci2 arylalkyl group, a Ci-Ci2 heteroarylalkyl group, an aryl group or a heteroaryl group. , which is substituted with one or more substituents selected from the group consisting of -〇H,_nh2, -CONHR10, -COOR10, -NH-C(=NH)-NH2 and a halogen atom, Wherein the R10 group is a hydrogen atom, a CVCu alkyl group, a CVCu aralkyl group, an aryl group or a heteroaryl group, and is optionally substituted with a -CON(Ru)2 group, or wherein the R8 and R9 groups together form a ring Constructed, the ring may be composed purely of carbon atoms or consisting of carbon atoms and heteroatoms selected from the group consisting of N, hydrazine and S; R7 groups are hydrogen atoms, q-Cu alkyl groups, Cl-C12 aralkyls a aryl, aryl or heteroaryl group, _NR12R13, -NHCOR14, -NHCONHR14, -NHCOOR14 or -NHS〇2R14, and may be substituted by one or more substituents selected from -OH, -NH2, _CONH2, a group consisting of -COOH and a functional atom, the R12 and R13 groups are each independently a hydrogen atom or a Ci_Ci2 alkyl group, and are optionally substituted with one or more aryl or heteroaryl groups, and up to three Substituted by a substituent, the substituents are independently selected from the group consisting of -N〇2, -CH3, _CF3, -OCH3, -OCF3 and a halogen atom, and the R-based squirrel atom 'C1-C12 alkyl' Ci_Ci2 aryl group An aryl or heteroaryl group which is optionally substituted with one or more substituents selected from the group consisting of Ν02, -CH3, -OR11, -CF3, -〇CF3, -0H, -N ( a group of RU)2, -OCOR11'-COOH, -CONH2, -NHCONHR11, -NHCOOR11 and a halogen atom; 82695-940930.doc -2 - 1246423 halogen atom, Ci-C6 alkyl group and Ra, Rb, Re, Rd, Re and Rf are each independently a halogen atom, -cooh, -CONh2, _Cf3, _〇Cf3, ·Ν〇2,_CN 4C "C6 alkoxy; preconditions are that the compound of formula (1) is not selected from a 3-amino group - tetrahydrofuran-3-sodium acid, 3_amino-m-methoxy-U2,3, tetrachlorinated salicin, '% carboxylic acid' 3-amino-6-benzyloxy-i, 2 , 3,4-tetrahydrocarbazole _3_carboxylic acid, 3· Amine amino 1,2,3,4·tetrahydroindole-3·carboxylic acid, methyl-3-3-acetamido-1,2,3,4-tetrahydrocarbazole-3·carboxylate , 十)·f-based _3_acetamido-1'2,3,4-tetrahydrocarbazole _3·carboxylate or 3-tris-butoxycarbonyl-amino-1,2, A group consisting of 3,4_tetrahydrocarbazole _3·carboxylic acid. 2. A compound according to the first aspect of the patent application, wherein Ra, Rb, RC, Rd, Re and R/ are hydrogen atoms. 3. A compound according to claim 1 or 2, wherein the base is a nitrogen atom. 4. The compound according to claim 1 or 2, wherein the r2, r3, r4 and/or R5 groups are not hydrogen atoms. 5. A compound according to item 4 of the patent application, wherein the R2, r3, R4&amp;R5 groups are independently -CH3, -C1 or -OCH3 groups. 6. A compound according to item 5 of the patent application, wherein the compound is selected from the group consisting of [(lS, 2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl))- 2_Methylpropyl]amino]]indolyl]_2,3,4,9-tetrahydro-8-methyl-111-yttrium-3-yl]amino]rocarbyl]-2-methyl Phenyl benzyl carbamic acid benzyl ester, [(lS, 2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl)-2-mercaptopropyl]] Amino]^yl]-6-chloro-2,3,4,9-tetrahydro-indole-yttrium _3.yl]amino]-rocon charcoal 82695-940930.doc 1246423 base&gt;2-methyl Butyl]carbamate benzoate, and [(lS,2S)-l-[[[(3R)-3-[[[(lS))-l-(aminocarbonyl)-2-mercaptopropyl Amino]carbonyl]-2,3,4,9-tetrahydro-8-methoxy-111-oxazol-3-yl]amino]carbonyl]-2-mercaptobutyl]aminopurine a group of acid benzyl esters. 7. The compound according to claim 1 or 2, wherein the R6 group is selected from the group consisting of phenylpropylamine decylamino, isalamine decylamino, amidino-4-aminobenzoic acid Amidino, amidinomethylaminoamine, methyloxymethyl-4 - ρ thiol, thiol, ethyl propionate, green chloroamine, amine, carbonyl Amidoxime, cyclic carboxylamido, 4-carboxyguanidinophenylcarboxamide, methylaminomethyl-2-pyridyl, carbonylguanamine, and methylguanamine a group consisting of alcohol groups. 8. A compound according to claim 7 wherein the compound is selected from the group consisting of [(lS,2S)-l-[[[(3R)-3-[[[(lS))) 1-(phenylmethyl)ethyl]amino]-carbonyl]-2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl]-2-mercaptobutyl Benzyl]-amino benzyl decanoate, [(lS, 2S)-l-[[[(3S)-3-[[[(lS,2S)-l-(aminocarbonyl)-2-methyl) Butyl]amino]]yl]-2,3,4,9-tetrahydro-1H-11carbin-3-yl]amino] stilbene] methyl butyl] carbamic acid benzyl ester, [ (18,28)-1-[[[(3&amp;)-3-[[[(18)-1-[[[4-(aminocarbonyl)-phenyl]amino]carbonyl]-2-yl) Benzyl]amino]carbonyl]-2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester, [(1S,2S)_2-Methyl-1-[[[(311)-2,3,4,9-tetrahydro-3_[[[(())))) Amino)carbonyl]propyl]amino]carbonyl]-1H-indazol-3-yl]amino]carbonyl]butyl]aminocarbamic acid benzyl ester, 82695-940930.doc 1246423 2,3,4, 9-tetrahydro-3-(3-phenylpropyl)-0-(4-12 ratio thiol)_ιΗ-叶β sit-3 -methanol, 2.3.4.9-tetrahydro- 3-(3- Phenylpropyl)-indole-leaf-3-weilic acid, 3-[2, Ethyl 3,4,9-tetrahydro-3-(3-phenylpropyl)_1-carbazole-3-yl]-2-propenoate, [(lS,2S)-l_[[[(3R)) _3_[[[(lS)_l-(aminocarbonyl)-2-mercaptopropyl]amino]carbonyl]-2,3,4,9-tetrahydro·1Η-oxazol-3-yl]amino Benzyl carbonyl]-2-methylbutyl]carbamic acid benzyl ester, [(lS,2S)-l-[[[(3R)-3-[[[(lS,2R)-l-(amino) Carbonyl)-2-hydroxypropyl]amino]carbonyl]-2,3,4,9-tetrahydro-lH-indazol-3-yl]amino]carbonyl]-2-methylbutyl]amino Methyl formate, [(lS,2S)-l-[[[(3R)-3-[[(2S)_2-(aminocarbonyl)pyrrolidinyl]carbonyl]-2,3,4,9 - tetrahydro-111-oxazol-3-yl]amino]carbonyl]-2-methylbutyl] benzyl carbamate, [(lS,2S)_l_[[[(3R)-3_[[ (2S)-2-(Aminocarbonyl) octahydro-1H-indol-1-yl]carbonyl]-2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl ]-2-methylbutyl]amino phthalic acid benzyl ester, [(lS,2S)-l-[[[(3R)-3-[[[4-(amino)phenyl)amine] Benzyl]carboyl]-2,3,4,9-tetrahydro-1H-indazole-3-yl]amino]carbonyl]-2-mercaptobutyl] benzyl carbamate, 2.3.4.9 - Tetrahydro-3-(3)phenylpropyl)-indole (2-pyridylmethyl-indazole-3-methaneamine, [( lS,2S)_l-[[[(3S)-3-[[[(lS)-l-(hydroxymethyl)-2-mercaptopropyl]amino]]]]]]] 9-tetrahydro-1H-yttrium-3-yl]amino]]yl] 曱82695-940930.doc 1246423 phenyl butyl carbamate, 2,3,4,9_tetrahydro-N- [(lS)-l-(hydroxymethyl)-2-methylpropyl]-3-(3-phenylpropyl)_1H-indazole·3_carboxamide and (2S)-3-methyl- 2-[[[2,3,4,9-tetrahydro-3_(3-phenylpropyl)-111-oxazol-3-yl]methyl]amino]-1-butanol, group. 9. A compound according to the invention of claim i, 5 or 8, wherein the R7 group is selected from the group consisting of 2,3-biphenylpropionylamino, cholesterylamino, chiral decylamine a group consisting of 2-mercaptoethylamino, 3-propenylamino (which is substituted on an aromatic system), phenylhexylamino and phenylpropyl. The compound according to claim 9 wherein the compound is selected from the group consisting of N-[[(3R)-2,3,4,9-tetrahydro_3_[(1_oxy-2,3-diphenyl) Propyl)amino]-1H-yttrium-3-yl]yl]-L-sensylamine-branched aspartame, (3R)-N-[(lS)_l-(amine-based) 2_mercaptopropyl b 3·[[(2,3-dihydro-1仏茚-1-yl)carbonyl]amino]-2,3,4,9-tetrahydro-111_carbazole_3 - entamamine, (38)-&gt; 1-[(18)-1-(amino)-2-methylpropyl]_2,3,4,9-tetrahydro-3-[(1Η -4丨嗓-3-ylethylidene]amino]-1Η-yttrium-3-treazone, (38)_&gt;1-[(18)-1-(aminosyl)_2- Methylpropyl]_2,3,4,9-tetrahydro-3-[(2-mercaptoethyl)amino]_1Η-carbazole_3_carboxamide, N-[[(3R)- 2,3,4,9-tetrahydro 3_[[(2S,3S)-3-methyloxy-2-((1-oxo-3-phenyl)amino]pentyl]amino] -1H-yttrium-3-yl]weiki]-L-sodium sulphate-L-aspartic acid amine (3)_&gt;1-[(18)_1-(aminosyl)- 2-methylpropyl]_2,3,4,9-tetrahydro-3-[[(4-methylphenyl)acetoxy]amino]-1H-leaf β-s--3-ggamine, 82695 -940930.doc -6 - 1246423 N-[(lS)-l-(Aminocarbonyl)-2-methylpropyl]-2,3,4,9-tetrahydro-3_ [ [(4-methoxy-phenyl)-ethinyl]amino MH-carbazole carboxamide, (3R)-N-[(lS)-l-(aminocarbonyl)·2-methylpropane Base]_3_[[(3-bromophenyl)ethinyl]•amino]-2,3,4,9-tetrahydro-1oxazol-3-carboxamide, (3R)_N-[( 1 S)-l_(Aminocarbonyl)-2.methylpropyl&quot;-[[(influenza)]ethinyl]amino]-2,3,4,9-tetrahydro-1H-indole Oxazole-3-carboxamide, (3R)-N-[(lS)-l-(aminocarbonyl)-2-methylpropyl]-3_[[(4-phenylphenyl)ethyl]- Amino]-2,3,4,9-tetraqi_1^1-leaf saliva_3_slow|basinamine, (3R)-N-[(lS)-l-(aminocarbonyl)-2- Methylpropyl]-2,3,4,9-tetrahydro-3·[(6-phenylhexyl)amino]-1H-indazole-3_carboxamide, 6.8-dichloro-2,3 , 4,9-tetrahydro-3-(3-phenylpropyl)_1;^-leaf 11 sitting _3_acid and 6.8-digas-2,3,4,9-tetrahydro_3-( a group consisting of 3-phenylpropyl)_1{^-leaf-3-ethyl citrate. 11. A compound according to claim 1, 2, 5, 6 or 1 wherein the compound is a carbon atom in the R-configuration, if R6 and R7 together form an alpha-amino carboxylic acid structural element. , substituted with R6 and R7 groups. 12. The compound according to claim 1, wherein the compound is selected from the group consisting of [(lS, 2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl)) 2-methylpropyl]amino]carbonyl]-6,8-dioxa-2,3,4,9-tetrahydro-1indole-indazol-3-yl]amino]]yl]-2-indole Benzo-butyl] benzyl carbamate, [(1S, 2S)-1-[[[(3r)-3-[[[(1S)-1-(hydroxymethylmethylpropyl]) Benzyl]-2,3,4,9-tetrahydro-1H_lead α-3-yl]amino]carbophenyl]-2-mercaptobutyl]aminobenzoic acid benzyl ester, 82695 -940930.doc 1246423 (2S)-l-[[(3R)-3-[[(4-Chlorophenyl)ethinyl]amino) 2,3,4,9-tetrahydro-8-methoxy -1H-indazol-3-yl]carbonyl]-2-pyrrolidinium carboxamide and 6,8-dione.,7^tetrahydro-:(i)-phenylpropylb^^pyridinylpyridyl Methyl)-1Η-flavored salivyl-3-methylamine, a group formed. 13. 14. 15. 16. 17. 18. 19. 20. A pharmaceutical composition as a ligand for a G protein-coupled receptor ((3!&gt;(:11), which contains at least one according to the scope of the patent application The pharmaceutical composition according to any one of claims 1 to 12, wherein the amount of the compound in the unit dose is from 1 μg to 100 mg/kg of the patient's body weight according to claim 13 of the patent application. A pharmaceutical composition wherein the compound is co-present in the composition with at least one other pharmaceutically active ingredient and/or a pharmaceutically compatible carrier. According to the compound of claim 2 or 2, it is provided as a G protein. A pharmaceutical agent for the ligand of a coupled receptor (GPCR). Use of a compound according to any one of claims 12 to 12 for the manufacture of a medicament for the treatment of a disease caused by a G-protein coupled receptor. A use of a compound as defined in the scope of the patent application (but including the excluded compounds listed in claim 1) for the production of a pharmaceutical agent for inhibiting gonadotropin-releasing hormone. The application of the scope of the patent application No. 17 or 18 for male reproductive control 'hormone therapy' for the treatment of female low birth or non-fertility, female contraception and treatment of cancer. A compound defined by the scope of patent application (1 (but includes申82695-940930.doc 1246423 Please refer to the exclusion of compounds listed in item 1 of the patent scope for the manufacture of pharmaceutical preparations for male birth control or for female contraception. 21· The compound according to the scope of claim 1 wherein the compound is Free [(lS,2S)-l-[[[(3R)-3-[[[(lS)-l-(aminocarbonyl)-2-methylpropyl]amino]carbonyl]-6, 8_Difluoro-2,3,4,9-tetrahydro-1H-indazol-3-yl]amino]]]yl]-2-methylbutyl]carbamic acid benzyl ester, [(lS, 2S)-l-[[[(3S)-3-[[[(lS,2S)-l-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-8-methoxy- 2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl]-2-mercaptobutyl]amino phthalic acid benzyl ester, [(lS, 2S)-l- [[[(3R)-3-[[[(lS,2S)-l-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]_6,8-dichloro-2,3,4 ,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl]-2.methylbutyl]amino group Benzyl ester, [(1S,2S)-1-[[[(3S)-1_[[[(1S)-1)(aminocarbonyl)-3.methylbutyl]amino]carbonyl]-6, 8-dihydro-2,3,4,9-tetrahydro-1^1_oxazol-3-yl]amino]carbonyl]-2-methylbutyl]carbamic acid benzyl ester, [(lS , 2S)-l-[[[(3R)-3-[[[(()))]]]]]]]]]]]]]] ,3,4,9-tetrahydro-111_oxazol-3-yl]amino] benzyl]-2-methylbutyl]carbamic acid benzoquinone g, [(lS, 2S)-l- [[[(3R)-3-[[[(()))))) 4,9-tetrahydro-1H-indazol-3-yl]amino]weiki]-2-methylbutyl]amino phthalic acid benzoquinone g, [(lS, 2S)_l-[[[ (3R)-3-[[[(lS)_l-(aminocarbonyl)_3_phenylpropyl]amino]carbonyl]-6,8-dichloro-2,3,4,9·tetrahydro- 1H-indazol-3-yl]amino]carbonyl]-2-methylbutyl]aminophenyl phthalate, 82695-940930.doc -9- 1246423 [(lS,2S)-l-[[ [(3R)-3-[[[(lS)-l-(aminocarbonyl)-2-methylbutyl]amino]carbonyl]-6,8·di 2,3,4,9- Benzene tetrahydro-111-oxazol-3-yl]amino]carbonyl]-2-cyclohexylmethyl]aminocarboxylate, [(lS,2S)-l-[[[(3R)-3- [[[(lS 2S)-l-(carboxy)-2-methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-111_carbazole-3-yl]amine Benzyl]carbonyl]-2-methylbutyl]carbamic acid benzyl ester, [(lS)-l-[[[(3R)-3-[[[(lS,2S)-l-(aminocarbonyl) )-2-methylbutyl]amino]carbonyl]·6,8-dioxa-2,3,4,9-tetrahydro-1^1-carbazole-3-yl]amino]carbonyl]- Benzyl 2-(4-hydroxyphenyl)ethyl]carbamate, [(lS)-l-[[[(3R)-3-[[[(lS,2S)-l-(aminocarbonyl) )_2_Methylbutyl]amino]carbonyl]-6,8-dichloro-2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]carbonyl]-3-(4) -Hydroxyphenyl)propyl]carbamic acid benzyl ester, [(lS)-l-[[[(3S)-3-[[[(lS,2S)-l.(aminocarbonyl)-2-) Methylbutyl]amino]carbonyl]-6,8-dioxa-2,3,4,9-tetrahydro-111-oxazol-3-yl]amino]rocarbyl]-3-phenyl Phenyl]aminobenzyl phthalate, [(lS)-l-[[[(3R)-3-[[[(lS,2S)-l-(aminocarbonyl)-2-methylbutyl) Amino]carbonyl]-6,8-dioxa-2,3,4,9-tetrahydro-111-carbazole-3-yl]amino]carbonyl]-3-methylbutyl]carbamic acid Benzene g, [(lS)-l-[[[(3R)-3-[[[(l))))]]]]]] _ two gas a group consisting of -2,3,4,9-tetrahydro-1H-indazol-3-yl]amino]]yl]-3-methylbutyl]amino phthalic acid benzoquinone. 22. The pharmaceutical composition according to claim 13 of the patent application, wherein the compound is as defined in claim 21 of the scope of the patent application. 82 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 The pharmaceutical composition according to claim 22 or 23, wherein the compound is co-present in the composition with at least one other pharmaceutically active ingredient and/or a pharmaceutically compatible carrier. 25. A compound according to claim 21, which is a pharmaceutical agent for use as a ligand for a G protein coupled receptor (GPCR). 26. It is very suspected that the scope of patents is 27. The use of the disease caused by &amp; protein coupled receptors. = The use of a compound according to claim 21 of the patent application for the production of a medicament for inhibiting gonadotropin-releasing hormone. 28. According to the use of Section 26 or 27 of the scope of the patent application, it is controlled by hormone therapy to treat women with low or no fertility treatment of tumors. For male reproduction, female contraception and 82695-940930.doc