TWI258482B - Linear basic compounds having NK-2 antagonist activity and formulations thereof - Google Patents

Abstract

Described herein are compounds of formula (I) useful as antagonists of tachykinins in general, and in particular of neurokinin A; and the pharmaceutical formulations comprising the compounds of formula (I).

Description

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a broad range of tachykinin antagonist compounds, particularly neurokinin A, and its use as a pharmaceutical formulation. Prior Art Tachykines contain at least one of the three peptides, substance P, neurokinin A (NKA) and neurokinin B (NKB). In the field of research of tachykinin antagonists, mainly based on the agonist of substance P and other tachykinins, replacing the single or multiple amino acids of the peptide sequence of the agonist, resulting in the discovery of one or Multiple units of D-tryptophan (Regoli et al, Pharmacol. 28, 301 (1984)). However, the problem stems from the use of high molecular weight peptides in the use of pharmacology, which has the disadvantages of multiple enzymatic hydrolysis zones, low bioavailability, and rapid elimination of liver and kidneys. Therefore, it is necessary to study the smallest peptide fragments that still have antagonistic activity, so in the patent applications with the patent application number W〇9 8 3 4 9 4 9 and W〇2 0 0 1 2 9 06 6 'Study that a properly derived monocyclic or bicyclic peptide is an antagonist of neurokinin A. In addition, in the patent application Nos. W〇9519966 and WO 98452 6 2, various compounds have been disclosed as selective antagonists of substance P. However, in addition to the selectivity for the NK1 receptor, these compounds have structural properties different from those of the present invention' mainly as a group lacking a basic amine group. Further, the NK1 antagonist mentioned in the patent application No. W〇200014109, in which there is more than one α,α-di 2,528,482 substituted amino acid in the NK1 antagonist compound, and if a basic group is present, The position of the basic group is different from the position of the basic group in the compound of the present invention. Similarly, it is disclosed in the patent application No. E P 3 9 4 9 8 that a compound having N K 1 activity generally has no basic group and does not exhibit an α,α-disubstituted amino acid. Compounds having NK2 activity containing alpha, alpha-disubstituted phenylalanine (Phe) are described in Biorganic & Med. Chem. (1994), 2 (2), 101-113 (S. Boile et al.). However, the compound does not exhibit basic properties and is not similar to the structure described by formula (I). An NK1 antagonist as described in the patent application No. WO 9 4 0 4 4 4 4, which exhibits a disubstituted α-α amino acid, the structure of which is not similar to the formula (I), especially It is the place where the XI is represented by the -0-C0- group. SUMMARY OF THE INVENTION Surprisingly, it has been found that a non-peptide compound of the invention of formula (I) as defined below is shown to be effective in inhibiting tachykinin binding to ΝΚ2 receptors, and in vivo The antagonist activity of the product disclosed in the prior art patent cited above is higher. Thus, the linear compound of the formula (I) referred to in the present invention includes an α,α-disubstituted amino acid and at least one amine group capable of providing the basic character of the compound.

1258482 wherein: XI is selected from the group consisting of -NR6-CO-, -CO and -NR6-CS-; R1 is an aryl, aryl-alkyl or aryl-ethylene group comprising from 7 to 12 carbon atoms a group wherein the aryl group is selected from the group consisting of pyridine, pyridyl, thiophene, benzene, naphthalene, imidazole, diphenyl, phenyl-thiophene, and the aryl group may be independently or in one or more a C 1 -C 6 alkyl group (for example, a trifluoromethyl group) which may be substituted by not more than three fluorine atoms, and a C 1 -C 6 alkoxy group which may be substituted by not more than three fluorine atoms. (e.g., trifluoromethoxy group), OH, -NHR10, -N(R10)2, -SR10, -CONHRIO, -CORIO, -COORIO, -R9COOR10, -OR9COOR10, -R9COR10, -CONHRIO, -R9CONHR10, -NHCORIO, and a substituent of a -nitro group, wherein R10 is a fluorene or a straight or branched C1-C6 alkyl chain, and R9 is a linear or branched C1_C6 alkylene chain; or formula:

One or more c 1-C 6 alkyl groups independently selected from halogen, which may be substituted with no more than three fluorine atoms (eg, a trifluoromethyl group), may be no more than three fluorine atoms (eg, C1-C6 alkoxy group substituted by a trifluoromethoxy group, 〇H, _ NHR10, -N(R10)2, -SR10, -CONHRIO, -CORl〇, -C〇〇R1〇, - Substituted by a substituent of R9COOR10, -OR9COOR10, -R9COR10, -CONHRIO, -R9CONHR10, -NHCORIO, and -nitro, wherein R1〇 is a fluorene or a straight or branched C1-C6 alkyl chain, and R9 Is a C1-C6 alkylene chain of a linear or branched bond 1258482; wherein D is 0, S, CH2, 0-CH2 or N-R7, wherein R7 is selected from fluorene, straight or branched C1-C a group consisting of a 6 alkyl chain and a fluorenyl group R8-C0, wherein R8 is a group consisting of a group selected from the group consisting of a linear or branched C1-C6 alkyl chain; and the other R6 is selected from the group consisting of a group consisting of a linear or branched C1-C6 alkyl chain; the oxime and lanthanide are independently selected from a linear or branched C1-C6 yard chain, aryl or aryl alkane a group consisting of a base chain, wherein the aryl moiety is selected from the group consisting of benzothiophene, anthracene, pyridine, pyridyl a group consisting of benzofuran, thiophene, benzene, naphthalene, imidazole, diphenyl, and the aryl group may be independently substituted by one or more halogens and may be substituted by not more than three fluorine atoms. C1-C6 alkyl (e.g., trifluoromethyl group), may be no more than three fluorine atoms C1-C6 alkoxy (e.g., trifluoromethoxy group), 〇H, -NHR10, -N(R10)2, -SR10, -CONHRIO, -COR10, -COORIO, -R9COOR10, -OR9COOR10, -R9COR10, -CONHRIO, -R9CONHR10, -NHCOR10, and a substituent of a nitro group, wherein R10 is Η Or a chain or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene group; or a carbon atom which is bonded by ruthenium and osmium and ruthenium and osmium Forming a group having the formula (II):

Wherein the dotted line indicates a possible double bond; η and m may independently be 0, 1 or 2; R13 and R14 may be independently selected from the group consisting of H, C1-C6 alkyl chains, or R13 and R14 may be Bonding to form an aromatic group selected from the group consisting of benzothiophene, anthracene, pyridinium, fluoro-1258482, benzofuran, thiophene, benzene, naphthalene, imidazole and biphenyl. The group may be selected from one or more C 1 -C 6 alkyl groups (eg, trifluoromethyl groups) which may be substituted by no more than three fluorine atoms, and may be no more than three fluorines. A C1-C6 alkoxy group (eg, a trifluoromethoxy group) substituted with an atom, OH, -NHR10, -N(R10)2, -SR10, -CONHR10, -CORIO, -COORIO, -R9COOR10, Substituted by a substituent of -OR9COOR10, -R9COR10, -CONHRIO, -R9CONHR10, -NHCOR10, and -nitro, wherein R10 is a fluorene or a straight or branched C1-C6 alkyl chain, and R9 is a straight chain Or branched C 1-C6 alkylene chain; Χ 2 is selected from the group consisting of -C0NR6- and -CH2NR6·, wherein R6 is as defined above; R2 is selected from the group consisting of aryl-alkyl or aryl Among the ethnic groups, among them The aryl moiety is selected from the group consisting of benzothiophene, indole, pyridinium, pyridyl, benzofuran, thiophene, benzene, naphthalene, imidazole and biphenyl, and the aryl group may be one or more a C1-C6 alkane independently selected from a halogen, a C1-C6 alkyl group (e.g., a trifluoromethyl group) which may be substituted by not more than three fluorine atoms, and may be substituted by not more than three fluorine atoms. Oxyl (e.g., trifluoromethoxy group), OH, -NHR10, -N(R10)2, -SR10, -CONHRIO, -CORIO, -COORIO, -R9COOR10, -OR9COOR10, -R9COR10,-CONHRIO,- Substituted by a substituent of R9CONHR10, -NHCORIO, and -nitro, wherein RIO is H or a straight or branched C1-C6 alkyl chain, and R9 is a linear or branched C1-C6 alkylene R3 includes at least one basic amine group and may be represented by the formula: -R4 - X3- Rs wherein R4 is a group selected from the group consisting of: -C1-C6 alkylene, C5-C8 cycloalkane; An aliphatic heterocyclic ring comprising at least one atom selected from N, S and 0, and which may be substituted by one or two C1-C6 alkyl or -C0R15 groups, wherein Ri5 is selected from -NR11R12 and - a family of 0R11 In which R11 and R12 are each independently Η-based or linear or branched C 1-C 6 alkyl;

An arylalkyl or aryl group, wherein the aryl moiety is selected from the group consisting of benzothiophene, oxime D, pyridine, pyridyl, benzofuran, thiophene, benzene, naphthalene, imidazole and biphenyl. In the group, the aryl group may be unsubstituted by one or more C1-C6 alkyl groups (e.g., trifluoromethyl groups) independently selected from halogen, which may be substituted by not more than three fluorine atoms. Three fluorine atoms C PC6 alkoxy (e.g., trifluoromethoxy group), 〇Η, -NHR10, -N(R10)2, -SR10, -CONHR10, -COR10, -COORIO, -R9COOR10, -OR9COOR10 Substituted by a substituent of -R9COR10, -CONHRIO, -R9CONHR10, -NHCOR10, and -nitro, wherein R10 is a fluorene or a straight or branched C1-C6 alkyl chain, and R9 is straight or branched C1-C6 alkyl chain. Χ3 is a single bond or may be selected from the group consisting of 弋112-, -(^2_0^-, -€〇-, -〇<^2-CH20-,_0-, -NH_CO-CH2-, and -NH_CO- Or; -R4-X3• together form a -CO-CH2- group; R5 is: an aliphatic heterocyclic ring selected from the group consisting of pyroxane, decyl, morpholine, diinudidine, a group consisting of dihydropyran and 1,4-dioxa-8-azaspiro[4,5]nonane, which may be selected from one or more selected from the group consisting of C1-C6 alkyl, hydroxy Substituted by a substituent of a group consisting of methyl, -0H, cyanomethyl and C1-C6 methoxy; - azetidine, which may be substituted by a (CH2)n-R17 group, wherein R17 may a group selected from the group consisting of morpholine, acridinyl, vicinane, tetrahydropyran, and tetrahydrothiopyran; -cyclohexyl, which can be C-substituted by a C1-C6 alkyl chain, Substituted by X5-R18 group 12 1258482 group, wherein X5 is a bond or _c(Rll)(R12)., -CO-, -COCH2-, -CH2CH2- group; and R18 is selected from morpholine , consisting of pyridyl, pyridin, tetrahydropyran, tetrahydrothiopyran, cyclohexane, dioxane, I,4-dioxa-spiro(4,5)nonane and aromatic In the ethnic group Wherein the aromatic moiety is selected from the group consisting of thiophene, pyridine, furan, pyridyl, thiadiazole, thiazole and phenyl groups and the aromatic aryl group may be substituted by one or more substituents which may be substituted Selected from a C1-C6 alkyl group which includes a halogen, which may be substituted by not more than three fluorine atoms, and a C1-C6 methoxy group which may be substituted by not more than three fluorine atoms, -OH, -NHR10, -N ( R10)2 and -SR10, wherein R1〇, Ri_R12 are selected from η and a linear or branched c Κ 6 alkyl chain; - azine, which can be used as one or two C 1 -C 6 alkyl groups Substituting, and may be N-substituted by a group selected from -S02NR11R12, -(CH2)20(CH2)20H, -CH2CN, or substituted by -X4-R16, wherein X4 is a bond or may be selected from -〇: 0_, -CH2-, -C0NR6-, -COCH2 and -CO-NR6_CH2- in the group consisting of R16 is selected from the group consisting of pyroxane, morpholine, tetrahydropyran, tetrahydrofuran, dioxane, a group consisting of thiophene, pyridine, phenyl, naphthyl, diphenyl, pyrazole, oxazole, isoxazolyl and thioxanyl, which may be selected from one or more selected from the group consisting of halogens, C1-c 6 alkyl 'C 1-C 6 alkoxy, 〇H family Substituted, wherein R6, R11 and R12 are as defined above; - an amine group selected from the group consisting of -NHR11R12, -NH(CH2)m_NRllR12, an amino-tetrahydropyran, a furylmethylamino group, a group consisting of -NH(CH2)20(CH2)20H, wherein m can be from 3 to 6, and R11 and R12 are as defined above; - an amino-cycloalkyl group, which may be selected from the ring Substituted by a group of 0H and NR11R12, wherein R11 and R12 are as defined above; a cycloalkyl group, which may be substituted on the ring by a group selected from NR11R12, wherein R11 and R12 are as defined above; 13 1258482 An aryl group selected from the group consisting of thiophene, pyridinium, furan or phenyl group, which may be selected from one or more selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy Substituted with a substituent of the group consisting of 0H; a further object of the invention is a retro-inverted compound in a compound of formula (I) wherein one or more indoleamine linkages are inverted. R3 has an α,α-disubstituted amino acid and at least one amine group which is a basic compound of the reinforced compound and can be considered as a special structural property of the product of the formula (I).

Another object of the invention is a pharmaceutically acceptable salt of a compound of formula (I) selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trifluoroacetic acid, oxalic acid, malonic acid 'maleic acid, fumaric acid, An organic or inorganic acid in the group consisting of succinic acid, tartaric acid and citric acid. A further object of the invention is the diastereomer and enantiomer of formula (I) or a mixture thereof, derived from a palmitic root or group into which the structure of formula (I) is inserted. A further object of the invention is a pharmaceutical formulation comprising a compound of formula (I) and a pharmaceutical formulation prepared using the compound for use in the treatment of a disease wherein the disease is caused by neurokinopurine.

DETAILED DESCRIPTION OF THE INVENTION A preferred compound of the invention is a compound of formula (I) wherein the residue of the amino acid of formula (III)

AxB —^ C0—

Re (III) is selected from the group of 14 1258482 consisting of an amino acid residue of the α,α-disubstituted glycine type, the α,α-disubstituted glycine type being selected from 1 -Aminocyclohexane-1.carboxylic acid (Ac6c), 1-aminocyclopentane-1-carboxylic acid (Ac5c), 1-aminocyclopent-3-ene-1-carboxylic acid (Ac5c), 1-aminoisobutyric acid, 1-aminoindan-1-carboxylic acid (Ι-Aic), 2-aminoindan-2-carboxylic acid (2-Aic), 2-aminonaphthalenecarboxylic acid (2_Atc), 2-methyl-2-ethylglycine, 2-methyl-2-isopropylglycine, 2-methyl-2-n-propylglycine, 2-methyl a group consisting of -2-(2-butyl)glycine, 2-methyl-2-isobutylglycine, 2-methyl-phenylalanine; and the remaining groups are as described above definition. Preferred compounds according to the invention are compounds of formula (I) wherein: -XI is a group of CO; R1 is an aryl or aryl-ethylene comprising from 7 to 12 carbon atoms, wherein the aryl group is selected from In a group consisting of benzene, naphthalene and biphenyl, which may be one or more independently selected from halogen, C1-C6 alkyl which may be substituted by not more than three fluorine atoms (for example, trifluoromethyl group) a group of not more than three fluorine atoms C 1-C 6 alkoxy (for example, a trifluoromethoxy group), 0H, -NHR10, -N(R10)2, _SR10, - CONHRIO, -CORIO, -COORIO, -R9COOR10, -OR9COOR10, -R9COR10, -CONHRIO, -R9CONHR10, -NHCORIO, and -nitro substituents, wherein RIO is H or a straight or branched C1-C6 alkyl chain And R9 is a linear or branched C1-C6 alkylene chain; or

The c 1-C 6 alkyl group (for example, a trifluoromethyl group) which may be independently selected from halogen, which may be substituted by not more than three fluorine atoms, may be not more than three fluorine atoms C 1 - C 6 alkoxy (for example trifluoromethoxy group), 〇^[,-]^1110, -N(R10)2, -SR10,.CONHRIO, -COR10, -COOR10, - 15 1258482 R9COOR10, Substituted by -OR9COOR10, -R9COR10, -CONHRIO, -R9CONHR10, -NHCORIO, and -nitro substituents, wherein RIO is a fluorene or a straight or branched C1-C6 alkyl chain, and R9 is straight or a branched C1-C6 alkylene chain; wherein D is 0, S or N-R7, wherein R7 is selected from a fluorene or a straight or branched C1-C6 alkyl chain and an R8-CO fluorenyl group In the group of constituents, wherein R8 is selected from the group consisting of Η or a linear or branched C1-C6 alkyl chain;

-R6 is a group consisting of a fluorene or a linear or branched C1-C6 alkyl chain; - an amino acid residue of formula (III)

(III) is an amino acid residue of the α,α-disubstituted glycine type, the type of α,α-disubstituted glycine is selected from 1-aminocyclohexane-1-carboxylic acid ( Ac6c), 1-Aminocyclopentane-1-carboxylic acid (Ac5c), 1-aminocyclopent-3-diene-1-carboxylic acid (Ac5c), 1-aminoindan-1-carboxylate Acid (l-Aic), 2-methyl-2-ethylglycine, 2-methyl-phenylalanine in a group consisting of; R2 is a phenylmethyl group, wherein the phenyl moiety can be Or two independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy and OH; -X2 is selected from -CONR6- and CH2NR6; -R3 includes at least a basic amine group, and R3 is of the formula: R4 - 乂3_ Rs 16 1258482 , wherein X4 is a bond or may be selected from the group consisting of -CH2-, -CH2-CH2- and -COCHr, and R16 is selected from the group consisting of pyridine, morpholine, tetrahydropyran, tetrahydrofuran, 1,3-dioxane, thiophene; e) an amine group selected from -NHR11R12, -NH(CH2)m- In the group consisting of NR11R12, wherein R11 and R12 and m are as defined above; 0-amino-cycloalkyl group, which may be selected from the group consisting of 0H and NR11R12 Substituting in the group, or the cycloalkyl group may be substituted by NR11R12, wherein R11 and R12 are as defined above;

g) The heteroaromatic may be selected from the group consisting of pyridine and thiazole. Among these compounds, particularly preferred ones are: XI is a -CO- group; R1 is aromatic which may be selected from biphenyl, phenyl-ethylene, zeoliyl, phenyl-warming phen, benzothiophene, benzofuran a group consisting of a C1-C6 alkyl group as an N-substituted anthracene, and may be independently selected from halogen by one, two or three, and may be substituted by not more than three fluorine atoms. Substituted in the group consisting of C 1-C 6 alkoxy, c 1-C 6 alkoxy, 0H, NHR10, and N(R10)jjf, wherein R10 is selected from η and C 1-C6 alkyl; The amino acid residue of III) is selected from the group consisting of 1-aminocyclohexane-1-carboxylic acid (Ac6c), φ 1-aminocyclopentane-1-carboxylic acid (Adc), 1-aminocyclopentane -3_ene-1-carboxylic acid (Ac5c), 1-aminoisobutyric acid, 1-aminoindan-1-carboxylic acid (1-Aic), 2·aminoindan-2-isic acid ( 2-Aic), a group consisting of 2-methyl-phenylalanine and 2-methyl-2-ethyl-aminoacetic acid; R6 is hydrazine; R2 is a phenyl-methyl group, phenyl The group may be substituted by a C1-C6 alkyl group; Χ2 is selected from -CONH- and CH2NH-; R3 includes at least one basic amine group and is represented by the following formula: 18 1258482 e) an amine group selected from NR11R12 a group consisting of -NH-(CH2)m-NRllR12, wherein R11, R12 and m are as defined above; f) an amine-cyclohexane or cyclohexane which is ring-bonded by a group of -NR11R12 Substituted wherein R11 and R12 are as defined above; g) the heteroaromatic can be represented by pyridine. Among these compounds, a more preferred compound is of formula (I) wherein: XI is a -CO- group; R1 is an aromatic group selected from the group consisting of phenyl-ethylene, naphthyl, benzothiophene and benzofuran. , may be independently selected from one, two or three halogens, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, OH, NHR 10 and N (R10) substituted by not more than three fluorine atoms Substituted in a group consisting of 2, wherein R10 is selected from the group consisting of hydrazine and a C1-C6 alkyl group; the amino acid residue of formula (III) is selected from the group consisting of 1-aminocyclohexanecarboxylic acid (Ac6c), a group consisting of 1 -aminocyclopentanyl-1 -decanoic acid (Ac 5 C); R6 is H; R2 is phenyl-methyl; X2 is -CONH-; R3 includes at least one basic amine group, And is of the formula: -R4 - X3-^5 wherein: • R4 is selected from the group consisting of -(CHyn-, wherein ^^, and the piperidinyl group may be substituted by a C1-C6 alkyl group; X3 Is a linkage or a group consisting of -C0- and -CH2-; R5 is selected from the group consisting of: a) an aliphatic heterocyclic ring selected from the group consisting of pyridine and tetrahydropyran. And may be substituted by one or more C1-C6 alkyl groups; 20 1258482

Pharmaceutically acceptable diluents and adjuvants for use in a wide range of tachykinin treatment and prevention diseases, namely neurokinin A, is a neuromodulator; for example, respiratory diseases such as asthma , allergic rhinitis and chronic obstructive bronchitis; eye diseases such as conjunctivitis; skin diseases such as allergies, contact dermatitis and psoriasis; intestinal diseases such as colonic allergy, ulcerative colitis and Crohn's disease (localized gyrus Enteritis), stomach diseases, urinary tract diseases such as cystitis and diabetes insipidus, unable to erect 'neuropathy, such as anxiety, depression and schizophrenia, cancer' autoimmune disease or AIDS-related diseases, cardiovascular disease , neuritis 'neural pain and pain treatment, especially visceral pain, inflammatory reactions such as osteoarthritis or rheumatoid arthritis. The compound of the formula (I) of the present invention as defined above can be prepared according to the methods described in the art and the book, for example, by concentration, displacement, addition or amination reduction of an amine. The following reaction formula is an example of a general route of synthesis, which can be followed by significant and appropriate changes to the substituents. In the following reaction formula, the substituents are as defined above unless otherwise specified. For example, a compound of the formula (I) can be obtained by reacting an activated carboxylic acid derivative of the formula (IV) with an intermediate compound of the formula (V) according to the following Reaction Scheme 1.

22 1258482 Reaction Scheme 1

In this example, X! = CO. Again, as an example, a compound of formula (I) can be obtained via Reaction Scheme 2, reacted according to the sequence described below: a) Derivatization of a carboxylic acid activated via formula (IV) Reaction with an amino acid of formula (VI), plus an appropriate activator and concentrate to form an oxazolinone of formula (VII); b) an oxazolinone of formula (VII) with a protecting group P The amine reaction of formula (VIII) is deprotected by techniques well known to those skilled in the art to obtain a compound of formula (IX); c) by deuteration, alkylation or amination via a suitable solvent. The final compound of formula (I) is produced.

23 1258482

B

?6 HN +

>- P (2b)

(IX)

Reaction Scheme 2 In this example, X^CO and N = 0, 1, 2. The compounds of the present invention can occur in a variety of isomeric forms, in fact 'the structure of the carbon bonded to R5 uses a specific isomer of the amino acid derivative during synthesis and is single pre-fixed, often The ground can be composed of a mixture of hard-isolated stereoisomers to form other starting products.

Thus, the compounds of the invention can be obtained via mixtures of diastereomers which can be separated by chromatography, whereas the compounds of formula (I) can be used as single enantiomers of isomers A mixture of constructs and isomers. EXAMPLES The following examples are illustrative of the compounds and methods of preparation of the present invention and are not intended to be limiting of the invention: Example ·J· 24 1258482 A white precipitate was deposited, the white precipitate was filtered and dried to give 1.44 g. (Yield = 50.5%) of (1S,2S)-N-monophenoxycarbonyldiaminecyclohexane hydrochloride compound. HPLC (Method E): Rt = 7.85 min.

2b) Dissolve 360 mg of 1.26 mmol of la) in 10 ml of DMF and add 0.296 g of 1.29 mmol of (1R,3S)-N-t-butoxycarbonyl-3-aminocyclopentanyl Alkanecarboxylic acid, 245 mg of EDC, 173 mg of HOBt and DiPEA until the basic reaction was reached, the mixture was kept for 18 hours, then 50 ml of DCM was added, and the organic layer was 5% KHSO4 (3×50 mL), NaHCO3 (3×50) (ml), H2 〇 (3 x 5 mL) was washed and dried over anhydrous Na.sub.2SO.sub.ss.ssssssssssssssssssssssssssssssssssssssssssssssss ML of Et20 gave a white solid precipitate which afforded 440 mg (yield = 68%) product. HPLC (Method e): Rt = 15.5 min. The residue was dissolved in 10 mL of EtOAc and 20 mL of EtOAc / EtOAc. The hydrochloric acid is eaten with (1R,3S)i-aminocyclopentane-3-carboxy-N-[(lS,2S)-2-N-(phenoxycarbonyl)amino ring

Heteroic acid. HPLC (Method E): Rt = 8·9 min. 2c) 0.425 g of the product from 2b) was dissolved in 10 ml of DMF, and 1312 ^ 129 mmol of ^^(te-butoxycarbonyl)_D_phenylalanine was added, 〇.23〇克 i .29 鼋 Mo Er EDC, 0.175 g 1.29 mmol of HOBt and DiPEA until the test reaction is reached, the reaction is continued overnight, then 30 ml of DCM ' is added and 5% KHSO4 (3 x 50 ml), NaHCO3 (3x50 ml), H2 〇 (3 x 50 ml) was washed with organic layer and dried over anhydrous Na.sub.2SO.sub.sub.sub.sub.sub. ) : Rt = 11.8 minutes. In the face of the thief leg miscellaneous (four) _ stagnation can be prepared: Example 3 ΝΜΝα [Να (biphenyl _4_ carboxy-H-amino ring c-1-indenyl]-D-bengiene HlR, 3S)-3-Aminocyclopentane-1-carboxylic acid, see, trifluoroacetate ((1S, 2S)-2-aminocyclohexane) decylamine E): Rt = 10.5 min. K-aminocyclopentane-1-carboxy]-D-carboxylic acid-N-((lS,2S)-2-amino ring MS-FAB: 664.32 (M+H)+. HPLC (Method Example 4 ΝΓ {Να[Ν"(Ν-(Methyl)-D-Dyl-2-carboxyl)phenylphenylamine hydrazine H1R,3S)-3-aminocyclopentane q hexyl)decylamine trifluoroacetate MS-FAB· · 64L32 (M+H) + ◦ HPLC (Method F): shot = 4 8 minutes. Example 5 ΝΜΝα[Να[4-(methyl)cinnaphthyl sulphonyl]-ylcyclopentanyl]_d_benzene Acrylamine 醯}-(lR,3S)-3-Aminocyclopentanyl Residual Acid, _(〇s, 2S)_2-aminocyclohexyl) decylamine trifluoroacetate MS-FAB: 628.4 (M+H +. HPLC (method F): Rt = 3 37 min. Example 6 ... {, ^ (benzofuranyl carbazide-aminocyclopentane small carboxy phenyl phenyl propylamine -}-(lR, 3S)-3-Aminocyclopentan-1-carboxylic acid-n-((1S,2S)-2-aminocyclohexyl)decylamine trifluoroacetate MS-FAB: 628.3 (M+H)+ ◦ HPLC (Method E): Rt = 9.25 min. Example 7 Να[Να(4-(methyl)cinnamoyl)-(R,S)l-amine-based indane small carboxyl group]_D-phenylalanine Indoleamine-N-[(1S,3R)_3-(morpholine 1 methyl)cyclopentyl] 31 1258482 to ester disappears (take product, evaporate and use 1H-NM R analysis). The solution was divided into small volumes and extracted 25 times with 1 ml of chloroform, and 21.4 g of the dioxin produced was obtained by evaporation of the solvent. The obtained 14.79 g of the diamine was added to 175 ml of 1 M borohydride. In the THF solution, the reaction was continued for about 1 hour and was carried out under a nitrogen flow, so the temperature did not exceed 35 ° C. Once the addition was completed, the reaction mixture was heated to reflux and refluxed for 11 hours, in a drop of ice water bath. To the previously obtained solution, a solution of 4 MHC1 in 130 ml of 1,4-dioxane diluted with 100 ml of methanol was added, and the mixture was heated under reflux, and refluxed for 12 hours before being cooled to 0 - 4 °C. Obtained by filtration, 7.95 g of C-[l-(tetrahydro-pyran-4-ylmethyl)-cyclopyridine-yl]-methylamine bis-hydrogen chloride, using diploid from the mother liquor Diluted with diethyl ether to give 1.85 g of the desired product. 1H-NMR (200MHz, DMSO-d6), (ppm): 1.09-1.33 (m, 2H); 1.51-2.20 (m? 8H); 2.59-3.08 ( m? 6H); 3.09-3.58 (m5 4H); 3.76-3·91 (m, 2H); 8.18 (bromo, 3H); 10.20 (bromo, 1H). Similarly, the following amines were also prepared: <RTIgt; CDC13) 0.94 (s, 3H); 1.08-1.69 (m, 9H); 2_10 (s, 2H); 2.10-2.30 (m, 2H); 2.48-2.59 (m, 2H); 2.67-2.83 (m, 2H) ); 3.47-3.79 (m, 4H)·C-[4-mercapto-1-(4-methyl-tetraqi-03⁄4 ··4-ylmethyl V-deep _4-yl]-methylamine MS (m/z): 227.3 (MH+) C-[4-Methyl-1-(tetrahydro-pyranylmethyl)-azin-4-yl]-methylamine MS (m/z): 241.2 (MH+) 63 1258482 6-bromo-benzofuranyl-2-carboxylic acid [1-(2-phenyl-lR-{[l-(tetrahydro-pyranylmethyl)-t-butyl- ζμ曱 ] - - ] ] ] MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 69 NMR (DMS0-d6)· (except): 0.97-1.12 (m, 4H); 1·39-1·73 (m, 12H); 1·74·1·81 (m, 1H); 1.89 -1.96 (m,1H); 1.97-2.04 Ο ,2H); 2.21-2.29 (m,1H); 2.63-2.71 (m,2H); 2.79-2.92 (ni, 2H); 2.95-3.03 (m,1H) ); 3.77-3.85 (m, 2H); 4.40-4.48 (m, 1H); 7.10-7.22 (m, 5H); 7·45 (t, J = 5.7 Hz, 1H); 7.54 (d d, J 2 l·7 and 8.4 Hz, 1H); 7.67 (d, J = 〇.8 Hz, 1H) 7.79 (d, J = 8.4, 1H); 7.85 (d, J = 8.6 Hz, 1H); 7.95 (s, bromine, 1H); 8·85 (s, 1H). Example 120 6-Chloro-benzofurancarboxylic acid [1-(2-phenyl-1R-{[1_(tetrahydro-indolyl)methyl)-pyridyl-4-ylmethyl]-amine Methyl hydrazide}-ethylaminocarbamidine)-cyclopentyl]-nonylamine MS m/z: 649·3 (M+H+). HPLC (Method D): Rt = 13.00 min. 1H-NMR (DMSO-d6)· □ (other than): 〇.97-1.12〇, 4 11·42-1.73 (m, 12H); 1.74-1.81 (m, lH); 1.89-1.96 ( m,lH); 1.97-2.04 (m,2H); 2·21-2·29 (m,1H); 2.63-2.71 (m,2H); 2.79-2.92 (m,2H); 2.95-3.03 (m , 1H); 3.77-3.85 (m, 2H); 4.40-4.48 〇, 1H); 7.10-7.22 (m, 5H); 7·42 (dd, J = 1.8 and 8.4 Hz, 1H); 7.46 (t, J = 5_8 Hz, 1H); 7.66 (d, J = 0.9 Hz, 1H) 7.81-7.86 (m, 2H); 8.84 (s, 1H). Wide Example 121 5-Fluoro-benzofurancarboxylic acid [ L-(2-Phenyl]tetrahydrofuran-4-ylmethyl)-oxaridinylmethyl]-aminomethylpyridinium ethylaminocarbazide)-cyclopentyl]-nonylamine MS m/z 633.5 (M+H ). HPLC (Method D): Rt = 12.10 min. 65 1258482 1H-NMR (DMS0-d6). (except): 0.97-1.12 (m, 4H); 1.42-1.73 (m, 12H); 1·74-1·81 (m, 1H); 1.89 -1.96 (m,1H); 1.97-2.04 (πι,2H); 2.21-2.29 (m,1H); 2.63-2.71 (m,2H); 2.78-2.93 (m, 2H); 2.95-3.03 (m, 1H); 3.75-3.85 (m, 2H); 4.40-4.48 (m, 1H); 7.10-7.22 (m 5 5H)j 7.32 — 7.37 (m 1 1H); 7·46 (t, J = 5.8 Hz ' 1H); 7.60-7.66 (m, 2H); 7.71 (dd, J = 4.1 and 9.0 Hz, 1H) 7·83 (d, J = 8·6Ηζ, 1H); 8.84 (s, 1H) 〇Example 122 5-_Chloro-benzofurancarboxylic acid [1-(2-phenyl-lR-{[l-(tetrahydro-indolyl)methyl)-ytidine-4-ylmethyl]-amino Formazan}-ethylaminocarbamidine)-cyclopentyl]-nonylamine MS m/z·· 649.5 (M+H+). HPLC (Method D): Rt = 12.78 min. 1H-NMR (DMSO-d6). (except): 0.97-1.12 (m, 4H); 1.42- 1.73 (m 5 12H); 1.74-1.81 (m, 1H); 1.89-1.96 (m, 1H) ); 1.97- 2.04 (m, 2H); 2.21-2.29 (m, 1H); 2·63_2·71 (m, 2H); 2.78- 2.93 (m 5 2H); 2·95_3·03 (m, 1H) ;3.75- 4.85 (m, 1H); 7.61 (s, bromine, 1H); 7·71 (d, j = 8·8Ηζ, 1H) 7.85 (d, J = 8·6Ηζ, 1H); 7.92 (d, J 2, 1H); 8.87 (s, 1H). Example 123 5-Bromo-benzofuranyl-2-carboxylic acid [1-(2-phenyl-1R-{[1_(tetrahydro.pyranyl-4-yl)-yl)-yl-yl) ]]-Aminomethylhydrazine}-ethylaminocarbamidine)-cyclopentylamine &amp; MS m/z: 693.5 (M+H+, single isotope). HPLC (Method D) · 13 · 14 minutes. 1H-NMR (DMSO-d6). (except): 0.97-1.12 (m, 4HV ι 142-1.73 (m, 12H); 1.74-1.81 (m, 1H); 1.89-1.96 (m ^ iHv 1 h li97'2.〇4 66 1258482 (m,2H); 2·21-2·29 (m,1H); 2.63-2.71 (m,2H); 2.78-2.93

(m, 2H); 2.95-3.03 (m, 1H); 3.75-3.84 (m, 2H); 4.40-4.48 (m, 1H); 7.11-7.21 (m, 5H); 7.44 (t, J = 5.8 Hz , 1H); 7.58-7.69 (m ' 3H) 7.85 (d, J = 8.6Hz, 1H); 8.06 (d, J = 2.0 ^ 1H); 8.87 (s, 1H) 〇 Example 124 7_ 特-丁-Benzofuranyl-2-carboxylic acid [l-(2-phenyl(tetrahydro-pyranylmethyl)-pyridin-4-ylmethyl]-aminomethylpyridinium ethylamino) _Cyclopentyl decylamine MS m/z: 671.6 (M+H+). HPLC (Method D): Rt = 15.16 min. Example 125 6-Methyl-benzofurancarboxylic acid [1-(2-phenyl-1R_{[1•(tetrahydrofuran-cardylmethyl)-? D-methyl]-amino group A醢}-Ethylaminocarbamidine)-cyclopentylbuminamine MS m/z: 629.5 (M+H+). HPLC (Method D): Rt = 12.69 min. Example 126 5-Methyl-benzofurancarboxylic acid [1-(2-phenyltetrahydro-P-pyranylmethyl)-thromid-4-ylmethyl]-aminomethylpyridinium ethylamino Formamidine)-cyclopentyl]-enzyme amine MS m/z: 629.5 (M+H+). HPLC (Method D): Rt = 12.66 min. 1H-NMR (DMSO-d6)·□ (except): 0.97-1.12 (m, 4H); lA2^ 1.73 (m, 12H); 1.74-1.81 (m, 1H); 1.89-1.96 (m ^ lH); l·97-2.04 (m, 2H); 2.21-2.29 (m, 1H); 2.44 (s, 3H) 2.63-2.71, 2H); 2.78-2.93 (m, 2H); 2.95-3.03 (m , 1H); 3.75-3.84 (m , 2H); 4.40-4.48 (m, 1H); 7.11-7.21 (m ^ 5H); 7.29-7.33 , 1H) 7.49 (t, J = 5.7 Hz, 1H); 7.53 -7.60 (m, 3H); 7·86 (d , J = 8.5 Hz, 1H); 8.76 (s, 1H). Example 127 67 1258482 2·28 (m, 1H); 2.45 (s, 3H); 2.67-2.73 (m, 2H); 2.79-2.87 (m, 1H); 2.88-3.00 (m, 2H); 1-3.20 (m, 1H) Hz,1H); 7.84 (d,J = 8.6 5 1H); 7.95- 7.98 (m,1H); 8.00-8.04 (m,1H); 8.27 (s,1H); 8.89 (s, 1H). Example 142 1-Methyl-111-11 cited|]-[2-(2-phenyl-1-{[1 ft-(tetrahydro-heptan-4-ylmethyl)) - Pyridylmethyl]-aminomethylhydrazine}-ethylaminocarbamidine)-cyclopentyl]-guanamine Example 143 7-Chloro-1-methyl-1Η-〇5丨 竣 [ [ lR-(2-Phenyl-1-{[1-(tetrahydro-D-pyranylmethyl)-pyridin-4-ylmethyl]-aminomethylpyridinium ethylaminopyridinylcyclopentyl]- Indoleamine Example 144

5-Chloromethyl-benzofuranyl-2-carboxylic acid [lR-(2-phenyl-1-{[1-(tetrahydro-pyranylmethyl)-piperidine-4-ylmethyl) ]-Aminomethylhydrazine}•Ethylaminomethylhydrazine)-cyclopentyl]-decylamine Example 145 6-Diethylamino-benzofuranyl-2-carboxylic acid [1-(2-Benzene) (tetrahydro-p-pyranyl-4-ylmethyl)-n-pyridylmethyl]-aminocarboxamidomethylaminocarboxamidine)-cyclopentyl]-nonylamine MS m/z: 686.4 (M +H+). HPLC (Method d): Rt = 8.76 min. Example 146 methoxy-benzofuranyl-2-carboxylic acid [1-(2-phenyl small {[1R_(tetrahydro deanylmethyl)-pyridin-4-ylmethyl]-amine)醯 醯 乙基 乙基 乙基 乙基 乙基 乙基 乙基 MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS HPLC (Method D): Rt = u 98 min. Example 147 72 1258482 5-Isylethylamino-benzopyranyl-2-residual acid [1-(2_本基-1-{[1R-(tetragas-pyrenepyran-4-yl) Methyl)-acridin-4-ylmethyl]-aminomethylhydrazide}-ethylaminocarbamidine)-cyclopentyl]-nonylamine MS m/z: 686.6 (M+H+). HPLC (Method D): Rt = 8.58 min. Example 148 3,5,6-Trimethyl-benzofuranyl-2-carboxylic acid [1-(2-phenyl-1-{[1R-(tetrahydro-pyran-4-ylmethyl)) -cyclohex-4-ylmethyl]-aminomethylhydrazine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine Example 149 Naphthalene-2-carboxylic acid [1-(2-phenyl-) 1-{[1R-(tetrahydropyran-4-yl-methyl)-oxaridin-4-ylmethyl]-aminomethylhydrazine}-ethylamine hydrazide)-cyclopentyl]-guanamine MS m/z: 639·5 (Μ+Η+). HPLC (Method D): Rt = 13.14 min. Example 150 5-Bromo-naphthalene-2·carboxylic acid [1-(2·Phenyl-1-{[1R-(tetrahydro-pyran-4-ylmethyl)-n-ylidine_4_yl) Aminomethylhydrazine}-ethylaminomethylhydrazine)-cyclopentyl]-nonylamine MS m/z: 703.4 (M+H+, single isotope). HPLC (Method D): Rt = 13.5 3 min. Example 151 Naphthalene-2-carboxylic acid [1-(2-phenyl-1R-{[1_(tetrahydro-pyran-4-ylmethyl)-cyclopyridine-4-ylmethyl]-amino)醯}_Ethylaminomethylhydrazine)-cyclopentyl]-nonylamine MS m/z: 625.5 (M+H+). HPLC (Method D) Rt = 12.29 min. 1H-NMR (DMSO-d6). δ (other than): 0.94-1.07 (m, 4H); 1.43-1.72 (m, 12H); 1.76-1.83 (m, 1H); 1.90-2.00 (m ^ 3H); 2.25-2.34 (m, 1H); 2.55-2.63 (m, 2H); 2.82-2.90 (m, 2H); 2.94-3.01 (m, 1H); 3.74-3.83 (m, 2H); 3.91 ( s, 3H); 4.42-4.49

(m, 1H); 7.10-7.21 (m, 5H); 7.23-7.27 (m, 1H); 7.52 (t, J 73 1258482 6-bromo-naphthalene-2-carboxylic acid [l-(l(R)) -{[4-Methyl small (tetrahydrofuranylmethylidridin-4-ylmethyl)-aminomethylhydrazine}-2-phenyl-ethylaminocarbamidine)-cyclopentyl] - 醯amine' using the C-[4-methyl-1-(tetrahydro-indolyl-4-ylmethyl)-n-yl-4-yl]-methylamine prepared as described in Example 117a) MS (m/z): 717.4 (isotopic diagram of MH+, Br). HPLC (method a): Rt = 4.16 min.

Mobile phase: A = H20 + 0.1% TFA; B = MeCN + 0.1% TFA

Method A Columns · ZorbaxTM SB-18, 3·5 μιη, 10〇A (50 x 4.6 mm) Washing solution step concentration: 6.5 minutes from A/B = 95/5 to A/B =: 5/95 +1 minute isocratic flow rate: 3 ml/min λ=220, 270 nm.

Method B Column: PlatinumTM RP-18, 3 μιη, 10 〇Α (33 χ 7 mm) Rinse solution step concentration: Α/Β=95/5 to Α/Β=5/95 for 6.5 minutes +1 Minute with solvent flow rate: 3 ml / min λ = 220, 270 nm.

Method C Column: JupiterTM C18, 5 μιη (250 χ 4.6 mm) Washing solution step concentration: from Α/Β=85/15 to Α/Β=5/95 for 20 minutes Flow rate: 1 ml/min λ=210 Nm.

Method D 75 1258482 Evaluate the antagonist activity of the N K-2 receptor, and the analysis of the ΝΚ-2 antagonist by a test of linkage and function has been described in the literature.

In particular, the affinity of the compounds of the invention for the human ΝΚ-2 receptor is assessed via a one-click assay using a Chinese hamster ovary (CHO) cell membrane transfected with the human ileum Κ2 receptor&apos; [125 I ]NKA (Amersham, radioactive activity 2 〇 OCi / millimolar) radiation adhesive, the concentration of ΙΟΟρΜ used in competition research. The test of the quality of the test is in the range from 〇.〇ln]y^fj1〇nM 'at the incubation time (30 minutes' 20. The end time of the sputum, the sample is filtered and the radioactivity is detected using the Gamma counter. Some of the compounds of formula (I) are shown in Table I and indicate the affinity of human N K-2 receptors:

Table I Compound pKi Compound pKi Example 1 9.2 Example 2 9.8 Example 3 9.6 Example 4 9.8 Example 5 9.7 Example 6 9.7 Example 7 9.9 Example 8 9.6 Example 9 8.8 Example 10 9.3 Example 11 8.7 Example 12 9.5 Example 13 9.0 Example 14 9.9 Example 15 10.0 Example 16 9.3 Example 17 8.6 Example 18 9.1 Example 19 8.9 Example 20 9.1 Example 21 9.6 Example 22 9.2 Example 23 8.7 Example 24 9.1 77 1258482 Example 25 9.6 Example 26 10.3 Example 27 10.2 Example 28 10.3 Example 30 10.0 Example 31 10.1 Example 32 8.9 Example 33 9.2 Example 34 8.9 Example 36 10.6 Example 37 10.9 Example 38 9.5 Example 40 8.9 Example 41 8.8 Example 42 8.3 Example 44 9.1 Example 45 8.3 Example 47 8.6 Example 48 9.4 Example 49 8.6 Example 50 9.4 Example 51 9.1 Example 52 8.7 Example 53 8.6 Example 54 8.5 Example 55 9.0 Example 56 8.8 Example 57 9.9 Example 58 8.5 Example 60 9.0 Example 61 9.0 Example 62 8.7 Example 63 9.2 Example 64 9.1 Example 65 9.0 Example 67 8.7 Example 68 8.9 Example 69 10.2 Example 70 8.8 Example 71 9.6 Example 72 10.0 Example 73 9.3 Example 74 9.3 Example 75 8.7 Example 76 9.0 Example 77 9.1 Example 78 9.0 Example 79 10.2 Example 80 9.6 Example 81 10.1 Example 82 10.0 Example 84 9.5

78 1258482 Example 87 8.9 Example 88 9.1 Example 89 9.9 Example 91 9.0 Example 93 10.1 Example 94 9.2 Example 95 8.8 Example 96 10.0 Example 97 10.7 Example 99 9.5 Example 1〇1 8.9 Example 102 9.3 Example 103 8.9 Example 104 9.3 Example 104 9.5 Example 108 10.1 Example 109 10.0 Example 111 9.7 Example 114 8.8 Example 115 8.5 Example 116 9.5 Example 117 10.3 Example 118 9.5 Example 119 9.6 Example 120 9.5 Example 121 9.3 Example 122 10.0 Example 123 10.0 Example 124 10.0 Example 125 9.6 Example 126 9.8 Example 127 10.1 Example 128 9.9 Example 129 10.3 Example 130 10.3 Example 131 10.4 Example 132 10.5 Example 133 10.2 Example 134 10.2 Example 135 9.8 Example 136 10.2 Example 137 10.1 Example 13 8 9.8 Example 139 10.1 Example 141 9.6 Example 145 9.3 Example 146 9.4 Example 147 9.2 Example 148 9.5 Example 149 9.9 Example 151 8.9 Example 152 9.9 79 1258482, urethritis, nephritis, inability to erect; - cancer condition, Immune disease or disease associated with AIDS; - neurological disorders such as anxiety, depression, schizophrenia, dementia, epilepsy, Bajindui's disease, Alzheimer's disease, drug and alcohol addiction, alcoholism, chorea, nerve Degenerative diseases and physical diseases such as stress; • Treatment of pain, especially visceral pain, neuritis, neuralgia; - cardiovascular diseases such as high blood pressure, edema, thrombosis, colic, vasospasm; - inflammation, such as Arthritis, rheumatoid arthritis.

Tf 81

Claims (1)

12584« 曰修(更)本本本本本本本本本本本专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利 专利Amino group, Wherein: XI is a group of -C0-; R1 is a group selected from the group consisting of biphenyl, phenyl-ethylene, naphthyl, phenyl-thiophene, benzothiophene, benzofuran, and anthracene a group of groups which may be N-substituted by a C 1 -C 6 alkyl group which may be independently selected from C 1 -C 6 alkane which may be substituted by halogen and may be substituted by not more than three fluorine atoms. Substituted by a group of a group consisting of C 1-C 6 alkoxy, OH, NHR10, and N(R10)2, wherein R10 is selected from the group consisting of fluorene and a C1-C6 alkyl group; The amino acid residue is selected from the group consisting of 1-aminocyclohexane-1-carboxylic acid (Ac6c), 1-aminocyclopentane-1-carboxylic acid (Ac5c), 1-aminocyclopentan-3- Alkenyl-1-carboxylic acid (Ac5c) '1-Amine-based sultan-1-decanoic acid (1-Aic) '2-Methyl-methacrylic acid, and 2-methyl-2-ethyl-glycine The group formed; R6 is Η ; (in) 82 1258482 The amino acid residue is a residue of the α,α-disubstituted glycine type selected from the group consisting of 1·aminocyclohexane-1-carboxylic acid (Ac6c), 1-aminocyclopentane-1 _carboxylic acid (Ac5c), 1-aminocyclopent-3-ene-1-carboxylic acid (Ac5c), amine indane small carboxylic acid (1-Aic), 2-methyl-2-ethylglycolamine a group consisting of acid '2-methyl-phenylalanine; R2 is a phenyl-methyl group having a phenyl group which may be substituted by a C1-C6 alkyl group; X2 is selected from -C〇NH, CH2NH-; R3 includes at least one basic amine group having the formula: -R4 - X3-R5 wherein: -R4 is selected from the group consisting of: η is from -1 to 3 -(CH2)n a group selected from the group consisting of a cyclopentene and a cyclohexene C5-C8 cycloalkylene group, and an aliphatic heterocyclic ring selected from the group consisting of a steep base and a piperazine, which may be one or two C ΙΟ 6 alkyl substituted; -χ3 is a bond or a group selected from -CO-, -CH2-, -CH2-CH2· and -ΝΗ_CO-; -R5 is selected from: a) aliphatic heterocycle , which is selected from the group consisting of pyridinyl, pyridin, morpholine, diazepane, tetrahydropyran, and M-dioxa-8-azaspiro[4,5]nonane , may be substituted by one or two groups selected from C 1-C 6 alkyl, C 1-C 6 alkoxy, OH, and cyanomethyl; b) azetidine, which is one (CH2) Substituting the n_Ri7 group, wherein R17 is tetrahydro 83 1258482 pyran; C) phenothyridinyl, which may be C-substituted by a c 1-C6 alkyl group and substituted by a group of X5-R18, wherein X5 is a bond or a group selected from -C(R11)(R12)-, -C0-, -CH2CH2-, and -COCH2-, and R18 is selected from the group consisting of thiophene, tetrahydropyran, tetrahydrogen a group of thiapyran, pyridin, cyclohexane, cyclopentane, and 1,3-dioxane, which may be selected from one or more selected from the group consisting of C 1-C6 alkyl, -NHR10 and -N (R10) Substituted by a group of 2, wherein RIO, R11 and R12 are C 1 -C 6 moieties selected from the group consisting of hydrazine and a straight or branched chain; d) pyridazine, which may be substituted by one or two C 1 -C 6 alkanes The group is C-substituted and may be N-substituted by a group selected from the group consisting of -CH2CN_ and X4-R16, wherein X4 is a bond or selected from -CH2- and -COCH2-, and R16 is selected from a group consisting of thiophene, thiophene, tetrahydrofuran, morpholine, tetrahydrofuran, and 1,3-dioxane; e) an amine group selected from NR11R12 And -NH-(CH2)m-NRllR12, wherein R11, R12 and m are as defined above; 0-amino-cyclohexane or cyclohexane, which may be substituted on the ring by a -NR11R12 group, wherein R11 and R12 Is as defined above; g) Heteroaromatic, which can be represented by pyridine. 2. A compound of the formula (I) according to claim 1 wherein XI is a group of -C0-; R1 is selected from the group consisting of phenyl-ethylene, naphthyl, benzothiophene, and benzofuran. The aromatic group of the group may be one, two or three independently selected from the group consisting of halogen, c 1-C6 alkyl group substituted by not more than three fluorine atoms, C 1-C6 alkoxy group, OH, Substituting NHR10, and N(R10)2, wherein R10 is selected from Η and C1-C6 alkyl; the amino acid residue of formula (III) is selected from 1-aminocyclohexane-1 - carboxylic acid (Ac6c), with 1-aminocyclopentan-1-hydroxy acid (Ac5c); 84 1258482 R6 is hydrazine; R2 is phenyl-methyl; Χ2 is -CONH-; R3 includes at least one The amine group 'is the following group: ~ R4 - Χ3- R5 wherein: -R4 is selected from -(CH2)n- wherein η is from 1 to 3, and can be substituted by a C1-C6 alkyl group X3 is a bond or a group selected from -C0- and -CH2-; R5 is selected from the group consisting of: a) an aliphatic heterocyclic ring selected from the group consisting of hexyl and tetrahydropyran Substituted by one or more C1-C6 alkyl groups; b) a propylidene group which may be C-substituted by a C1-C6 alkyl group which is X5-R18-based Substituted by a group wherein X5 is a bond or a group selected from _C(R11)(R12)- and -C0-, and R18 is selected from the group consisting of tetrahydropyran, cyclohexane, and 1,3- a group of dioxane, which may be substituted by one or more groups selected from the group consisting of C 1-C 6 alkyl, -NHR10, and -N(R10)2, wherein RIO, R11, and R12 are selected from fluorene. And a linear or branched C C C 6 alkyl group; c) a pyridazine which may be C-substituted by one or two C1-C 6 alkyl groups and may be substituted by a group of X4-R16, Wherein Χ4 is -CH2-, and R16 is selected from the group consisting of tetrahydropyran and 1,3-dihydroalkane. 3. A compound of the formula (I) according to claim 1 wherein the compound is defined by the formula: Να[Να(benzo[b]phenylthio-2-ylcarbonyl)-1-aminocyclopentanyl Alkyl-1-carbonyl]-D-phenylalanine-N-[3(morpholin-4-yl)propyl]decylamine (1R,3S)-acid-Nr {&gt;^[^(benzo Phenylthio-2-yl-carbonyl)-1-aminocyclopentane- 85 1258482 1-carboxy]-D-phenylalanine}-3-aminocyclopentane-1-carboxy-N-[(lS , 2S)-2-aminocyclohexyl]decylamine Ντ {Να [Να (biphenyl-4-ylcarboxy)-1-aminocyclopentane_1_carboxy]-D-phenylalanine}-( lR,3S)-3-Aminocyclopentane-1-carboxylic acid-N-((lS,2S)-2-aminocyclohexyl)decylamine trifluoroacetate ΝΜΝα [N"(N-(methyl吲哚-2-ylcarboxy)-1 -aminocyclopentane-1-carboxy]-D-phenylpropylamine oxime MlR, 3S)-3-aminocyclopentane-1-carboxylic acid-N-( (lS,2S)-2-aminocyclohexyl)decylamine trifluoroacetate NT {Να[『[4-(methyl)cinnamoyl]-1-aminocyclopentan-1-carboxy]_D- Phenylalanine}-(lR,3S)_3-Amine ί 戊 院 -1- 竣 --N-((lS,2S)-2-Amino- oxime) guanamine trifluoroacetate ΝΜΝα [ Ν"(benzofuranyl-2-ylcarboxylate ))-1-aminocyclopentane-1-carboxy]-D-phenylpropylamine 醯}-(lR,3S)-3-aminocyclopentane-1-carboxylic acid-N-((lS,2S )-2-aminocyclohexyl)guanamine trifluoroacetate [Να(4-(methyl)cinnamoyl)-(R,S)1-aminoindan-1-carboxy]-D-phenyl Indoleamine-N-[(lS,;3R)-3_(morpholinomethyl)cyclopentyl] ΝΜΝα [N"(benzo[b]phenylthio-2-ylcarbonyl)-1-amine Cyclopentane-1-carboxy]-D-phenylpropylamine 醯}-(lR,3S)-3-Aminocyclopentane-1-carboxylic acid-N-((lS,2S)-2-dimethyl Aminocyclohexyl)decalamine hydrogen chloride N,[Μ(benzo[b]phenylthio-2-ylcarbonyl)monoaminecyclopentan-1-carboxy]-D-4-methyl-phenylpropylamine }_(1&,38)-3-Aminopyrazine-1-indolic acid-1^-(18,28)-2- _.methylaminocyclohexyl)decylamine hydrogen chloride [N"( 4-methyl-cinnamonyl)-1-aminocyclopentane-1-carboxy]-D-phenylpropylamine 醯}-(lR,3S)-3-aminocyclopentane-1-carboxylic acid- N-((lS,2S)-2-dimethylaminocyclohexyl)decylamine hydrogen chloride NT {N" [N"(benzofuranyl-2-ylcarboxy)-1-aminocyclopentane- 1-carboxy]-D-benzene 86 1258482 propyl alanine (1 R, 3S)-3-amine ί 抚 院-1 - decanoic acid-N- (( 1 S,2S)-2-_*methylaminocyclohexyl)decylamine hydrogen chloride ΝΜΝα [&gt;T (biphenyl-4-ylcarbonyl)-1-aminocyclopentane-1-carboxyl] -D-phenylpropylamine oxime}-(1 尺,38)-3-aminocyclopentane-1-carboxylic acid-N-((lS,2S)-2-dimethylaminocyclohexyl) decylamine Hydrogen chloride {Μ[N"(N-(methyl)indol-2-ylcarboxy)-1-aminocyclopentane-1-carboxy]-D-phenylpropylamine 醯}-(lR,3S)- 3-aminocyclopentane-1-carboxylic acid-N-((lS,2S)-2-dimethylaminocyclohexyl)decylamine hydrogen chloride salt NT {N" [N"(benzo[b]benzene Thio-2-ylcarbonyl)-(R)-a-methyl.α-ethylglycine 醯]-D_phenylpropylamine 醯}-(lR,3S)-3-aminocyclopentane-1- Carboxylic acid-N-((lS,2S)-2-aminocyclohexyl)decylamine trifluoroacetate NMNa [Na(4-methylcinnamonyl)-(R)-a-methyl-a-B Glycine 醯]-D-phenylpropylamine 醯}-(lR,3S)-3-aminocyclopentane-1-carboxylic acid-N-((lS,2S)-2-aminocyclohexyl)indole Amine trifluoroacetate {Na [&gt;T (biphenyl-4-carboxy)-1-aminocyclopentane-1-carboxy]-R-3(4(methyl)phenyl)propylamine 醯}-( lR,3S)-3-Aminocyclopentane-1-carboxylic acid-N-((lS,2S)-2-aminocyclohexyl)decylamine hydrogen chloride salt N7 {Να [Na(N-(methyl)D)-2-ylcarboxy)-1-aminocyclopentane-1-carboxy]-R-3-(4.methyl)phenyl)propylamine 醯HlR, 3S --3-aminocyclopentane-1-carboxylic acid-N-((1S,2S)-2-aminocyclohexyl)decylamine hydrogen chloride {Μ [N"(4-(methyl)cinnamyl) )-1-aminocyclopentane-1-carboxy]-R-3[4-methyl)phenyl]propylamine -}-(lR,3S)-3-aminocyclopentane-1-carboxylic acid- N-((lS,2S)-2-aminocyclohexyl)decylamine hydrogen chloride Na[Na(benzo[b]phenylthio-2-yl-carbonyl)monoaminecyclohexane-1-carboxy]_D Phenylalanine-N-{3-[bis(n-butyl)amino]propyl}decylamine Na[Na(benzo[b]phenylthio-2-ylcarbonyl)-1-amino Cyclohexane-1-carboxy]-D-phenylpropanyl 87 1258482 Amino acid-N-[3(morpholine-4-yl)propyl]proline -3-cis-N7 {Να [N"( Benzo[b]phenylthio-2-ylcarbonyl)-1-aminocyclohexane-1-carboxy]phenylalanine}aminocyclohexane-1-carboxy-N-((lR,2S)- 2-Aminocyclohexyl)guanamine NT (benzo[b]phenylthio-2-ylcarbonyl)-1.aminocyclohexane-1-carboxy]-D-phenylpropylamine 醯}-3-cis -Aminocyclohexane-1-carboxylic acid-N-(5-aminopentyl)-decylamine trifluoroacetate Να[Να(benzo[b]phenylthio-2-ylcarbonyl -l-(R)-amino------1-carboxy]-D-phenylalanine-N-[3(?indol-4-yl)propyl]decylamine Να[Να(benzo[b][b Phenylthio-2-ylcarbonyl)_1·aminocyclopentane-1-carboxy]-L-phenylpropanylamine-N-[3(morpholine-4-yl)propyl]decylamine (1R) ,3S)acid-3-N7 {N" (benzo[b]phenylthio-2-ylcarbonyl)-1-aminocyclohexane-1-carboxy]-D-phenylalanine}aminocyclopentane alkyl-1-carboxy-N-(lS,2R)-2-aminocyclohexyl)proline -3-cis-NT {N" [N"(benzo[b]phenylthio-2-ylcarbonyl )-1-aminocyclopentane-1-carboxy]-L-phenylalanine}aminocyclohexane-1-carboxy-N-(2-cis-aminocyclohexyl) decylamine N7 {N "(Benzo[b]phenylthio-2-ylcarbonyl)-1-aminocyclohexane-1-carboxy]-D-phenylφ-propylalanine} - (L-(4R)Amino-cephaline -N-( 1R,2R)-Amino- succinyl) acid -3- cis-indole 7 {Ν" [Ν"(benzo[b]phenylthio-2-ylcarbonyl)-1-amine Cyclohexane-1-carboxy]-D-phenylalanine}_Aminocyclohexane-1-carboxy-N-[(lS,2S)-2-aminocyclohexyl]proline -3- cis -NT {N" [N"(Benzo[b]phenylthio-2-ylcarbonyl)-1-aminocyclopentane-1-carboxy]-D-phenylalanine} Aminocyclohexane- 1-carboxy-N-[ (lS,2R)-2-dimethylaminocyclohexyl]proline -3-cis-NT {Ν" [Να (benzo[b]phenylthio-2-ylcarbonyl)-1-amine Cyclopentane-1- 88 1258482 carboxy]-D-phenylalanine}aminocyclohexane-1-carboxy-N-[(1S,2R)-aminocyclohexyl]proline _3_cis _Ντ [Να (benzo[b]phenylthio-2-ylcarbonyl)-1-aminocyclopentane-1-carboxy]-D-phenylalanine}aminocyclohexane-1-carboxy-N -[(1S,2S)-aminocyclohexyl] amidoxime α[Να(benzo[b]phenylthio-2-ylcarbonyl)-1-aminocyclopentane_1_carboxy]-D_phenyl Indoleamine-N-[(lS,;3R)-3-(4-(methyl)pyrazine-1-yl)methyl)cyclopentyl] Να[Να(benzo[b]phenylsulfonate- 2-ylcarbonyl)-1-aminocyclopentane-1_carboxy]-D_phenylalanine decylamine-N-[(lS,:3R)-3-(4-(methyl)-on-azine- 1_yl)carbonyl)cyclopentaneΝα[Να(benzo[b]phenylthio-2-ylcarbonyl)-Da-methylphenylalanine]-D-phenylalanine-N-[3_( Phytyl)propyl]proline--3-cis-Na[Na(benzo[b]phenylsulfan-2-ylcarbonyl)-1-aminocyclohexane-1-carboxy]-D-phenyl Alanine}aminocyclohexane-1-carboxy-N-((lR,2S)-2-methylaminocyclohexyl) decylamine Na[Na(benzo[b]benzene) -2-ylcarbonyl)-1-aminocyclopentane·1-carboxy]-D-phenylalanine}-L-(4R)amino-proline-indole-(2-cis-amine Cyclohexyl)guanamine (1R,3S) acid-3-Ν7 {Να [Μ(benzo[b]phenylthio-2-ylcarbonyl)_1_aminocyclopentane-1-carboxy]-D-benzene Alanine}Aminocyclopentane-1-carboxyindole-(2-cis-aminocyclohexyl)guanamine (lS,3R)_l-N{Na[Na(benzo[b]phenylsulfonate- 2-ylcarbonyl)monoaminocyclopentane-1-carboxy]-D-phenylalanine}-3-{[lS-((2S)-aminocyclohexyl)amino]methyl}amino ring Pentanoic acid-3-cis-N{Na[Na(benzo[b]phenylthio-2-ylcarbonyl)-1-aminocyclopentane-1-carboxy]-D-phenylalanine}amine基ί哀院-1-骏-N-((lR,2S)-2-_^Methylaminocyclohexyl)decylamine (1R,3S) acid-3-N{Na[Na(benzo[ b] phenylthio-2-ylcarbonyl) small amine cyclohexane_1_ 89 1258482 carboxy]-D-phenylalanine}aminocyclopentane small carboxy-N-((1R,2R)2-amino group Cyclohexyl)guanamine biphenyl-4_decanoic acid, {1-[1-(3-morphin-4-yl-propylaminomethyl)-2-(R)-phenyl-ethylamino Formamidine]-cyclopentyl}-melamine benzofuran-2-carboxylic acid, {1-[1-(3-morpholinyl)propylaminocarboxamidine)-2_(R)_phenyl- Aminoaminocarbamyl]cyclopentyldiamine benzo[b]thiophene-2-carboxylic acid, methyl-{1-[1-(3-morpholin-4-yl-propylaminocarbamidine) -2(R)-phenyl-ethylaminocarbamyl]-cyclohexyldiguanamine 1-[3-(3,4-dichlorophenyl)-acrylamide]-cyclopentanecarboxylic acid, [1-(3_morpholinyl-propylaminomethylhydrazine)-2-(R)-phenyl-ethyl]-nonylamine benzo[b]thiophene-2-carboxylic acid {l-[lR -(3-morpholin-4-yl-propylaminocarbamyl)-2-phenyl-ethylaminomethylcarbazide]-cyclopent-3-enyl}-nonylamine 1-methyl-111-吲哚_2_carboxylic acid, {1-[1_(3-morpholinyl-propylaminocarbazide)_2_(R)-phenyl-ethylaminocarboxamidine; μcyclopentyldibenzamide And [b]thiophene-2-carboxylic acid (1-{1-[3-(2,6-dimethyl-morpholin-4-yl)-propylaminocarbamidine]-2-(R)- Phenyl-ethylaminomethylhydrazide}-cyclohexyl)-guanamine 1H-indole I carboxylic acid, {i-KL morpholine_4_yl-propylaminocarbamidine)_2_(R)_phenyl - ethylaminomethionine]-cyclopentyl}-nonylamine 1-[3_(3,4-dibromophenyl)propenylamine]-cyclopentanecarboxylic acid [1-(3·morpholine) _4·yl-propylaminocarbamidine)-2-(R)·phenyl-ethyl]-nonylamine 5-phenyl-thiophene-2-carboxylic acid, {ΐ·[ι_(3-morpholine) _4_yl-propylaminocarbamidine)-2-(R)- Phenyl-ethylaminomethylformamidine]-cyclopentyldiamine benzo[b]thiophene-2-carboxylic acid, (1-{1(R)_[3-(4-methyl-[1, 4] Diazepam-1-yl)-propylaminomethylhydrazide]phenylethylaminocarbazide cyclopentyl)-guanamine trifluoroacetate benzo[b]_phen-2-carboxylic acid (1_ {1(rH3_(4_methoxy-piperidine "- propylpropylaminocarbazide]-2-phenyl-ethylaminocarbamylcyclopentyl)-decylamine trifluoroacetate 1258482 benzo[ b] porphin-2-carboxylic acid (i) 1-(r)-[3-(4-hydroxy, pyridine small)-propylaminocarboxamidine]-2-phenylethylaminocarbazide Cyclopentyl)-nonylaminobenzo[b]porphin-2-carboxylic acid (1-{i(r)-[3-(1,4-dioxaza-spiro[4.5]癸-8-) Base l·propylaminocarbazide&gt;2-phenyl-ethylaminomethylpyridylcyclopentyl)-guanamine trifluoroacetate benzo[b]porphin-2-carboxylic acid (hwrhw-cis Formula - dimethyl hydrazine _ι_yl) _3_ oxidized-propylaminomethyl hydrazide]-2-phenyl-ethylaminomethyl hydrazide}-cyclopentyl)-guanamine trifluoroacetate benzo [ b] porphin·2_carboxylic acid (i_{1(R)-[3-oxidized_3_(4·pyridin-2-yl-doxazin-1-yl)-propylaminocarbamidine]-2- Phenyl-ethylaminomethylhydrazine}-cyclopentyl)-guanamine bromo, naphthalene 4 carboxylic acid (l-{l(R)-[3- Oxidation_3_(4-pyridin-2-ylindol-1-yl)propylaminocarbazin]-2-phenyl-ethylaminomethylpyridylcyclopentyl)-guanamine trifluoroacetate 6 _Bromo-benzo[b]thiophene-2-carboxylic acid (l-{l(R)-[3_oxidized_3-(4-pyridyl-piperazin-1-yl)-propylamino) Formamidine]-2-phenyl-ethylaminocarbamyl}}cyclopentyl l-decylamine benzo[b]porphincarboxylic acid [l-(i(R)-{3-oxidation_3_[4_ (tetrahydro-pyranylmethyl)-pyridazin-1-yl]-propylaminocarbazin}-2-phenyl-ethylaminocarbamidine)-cyclopentyl]-decylamine trifluoroacetic acid Salt benzo[b]pyrrole-2-decanoic acid [1-(1(foot)-{3-oxidized-3-[4-(tetragas-pyrenepyran-4-yl)-_qin_1_ ] _ 胺 胺 -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- 1(11)-[3-(4-[1,3]dioxane_5-ylmethyl-piperidin-1-yl)-3-oxo-propylaminomethylhydrazine]_2_phenyl- Ethylaminomethylpyridylcyclopentyl)-decylamine trifluoroacetate benzo[b]porphin-2-carboxylic acid [1-(1())_{[1-(1-amino-ring) Pentanecarbonyl) oxa-4-ylmethyl]-aminoformamidine}-2-phenyl-ethylaminocarbamidine)-cyclopentyl]-nonylamine benzo[b]thiophene-2-indole Acid [l-(i(R)-{3-oxidized-3-[4-(tetrahydrogen) -furan_2(R)-ylmethyl 91 1258482 ))-pyridazin-1-yl]-propylaminocarbazide 2_phenyl-ethylaminocarbamidine)-cyclopentyl]-decylamine Trifluoroacetate benzo[b]thiophene-2-carboxylic acid (l-{l(R)-[3_(4-cyanomethyl-pyrazine small))_3_oxidation_propylaminomethylhydrazine] -2-phenyl-ethylaminomethylcarbazide}-cyclopentyl)-guanamine benzo[b]thiophene-2·carboxylic acid {1-[2_phenyl-1(R)-(1-pyridine Methylmethionine _4_ylaminocarbamidine)-ethylaminocarbamyl]-cyclopentyl}-nonylamine trifluoroacetate benzo[b]thiophene-2-carboxylic acid [1-(2 -phenyl-l(R)-{l-[2-(tetrahydro-indolyl-4-yl)-ethyl]-ytidine-4-ylaminocarboxamidine}-ethylaminocarbamidine )-cyclopentyl]-nonylamine trifluoroacetate bromo-naphthalenecarboxylic acid (1_{1(R)-[(1-ethyl-acridin-4-ylmethyl)-aminocarboxamidine]_ 2-phenyl-ethylaminomethylpyridinium cyclopentyl)-guanamine benzo[b]thiophene-2-carboxylic acid {1-[2-phenyl-l(R)-({l-[2 -(tetrahydro-indolyl-4(yl)-ethyl]-piperidin-4-ylmethyl}-aminocarboxamidine)-ethylaminocarbamidine]-cyclopentylguanamine benzo[ b] thiophene-2-carboxylic acid (1-{1(R)_[(1-cyclohexyl-undyridin-4-ylmethyl)-aminocarboxamidine]-2-phenyl-ethylamine Amidoxime Benzo[b]thiophene-2·carboxylic acid [1-(2_phenyl-l(R)-{[l-(tetrahydro-thiopyran-4-yl)_? steep_ 4-ylmethyl] -aminomethamid ethylaminoglyoxime)-cyclopentyl]-decylamine trifluoroacetate benzo[b]porphin-2-carboxylic acid [1-(2-phenyl-1(R)-{ [1·(tetrahydro-thiopyran-4-ylmethyl)-dhen-4-ylmethyl]-aminomethylhydrazine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine l- ((E)-3-p-tolyl-propenylamine)_cyclopentanecarboxylic acid {2_phenyl-1(R)_[(1_phenylsulfonyl-2-ylmethyl-piperidine-4 -ylmethyl)-aminomethylhydrazine]-ethyl}-decylamine trifluoroacetate 6-bromo-naphthalene-2-carboxylic acid (1) 2-phenyl-l(R)-[2-( L-Pyroxane-2(S)-ylmethyl, steep-4-yl)-ethylaminocarbamidine]-ethylaminomethylpyridylcyclopentyl)-decylamine trifluoroacetate -naphthalene-2-carboxylic acid (1_{2_phenyl-l(R)-[()-pyridyl-indolylmethyl)-aminocarboxamidine&gt; ethylaminomethylhydrazine}-cyclopentyl) - amidoxime 3-?-tolyl-acrylamide-cyclopentanecarboxylic acid (2-phenyl-l(R)-{2-[l-(tetrahydro-92 1258482 喃 _4_ 甲甲Base)-piperidin-4-yl]-ethylaminocarbamyl}-ethyl)-guanamine trifluoroacetic acid m rrrL benzo[b] pheno-carboxylic acid (1-{1(R)_[2 -(1-cyanomethyl·n-din-4-yl )-ethylaminomethylhydrazine]-2-phenyl-ethylaminocarbamyl}-cyclopentyl)-guanamine trifluoroacetate benzo[b]thiophene-2-carboxylic acid dioxane_5 _ylmethyl-octyl-4-ylmethyl)-aminoformamidine]-2-phenyl-ethylaminomethylhydrazide}-cyclopentyl)-guanamine trifluoroacetate benzo[b] Thiophenecarboxylic acid (1-{1(R)-[(1-[1,3]dioxan-2-ylmethyl-acridinyl-4-ylmethyl)-aminomethylhydrazine]-2-phenyl -ethylaminomethylpyridylcyclopentyl)-nonylamine 5-chloro-benzofuranyl-2.carboxylic acid [1-(2-phenyl-l(R)-{[l-(tetrahydro-) Pyran-4-yl)-acridin-4-ylmethyl]-aminoformamidine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine 5-chloro-benzofuranyl-2- Carboxylic acid [1-(2-phenyl-l(R)_{[l-(tetrahydropyran-4-yl)-pyridin-4-ylmethyl]-aminocarbazide}-ethylamino Formamidine)_cyclopentyl]_guanamine benzo[b]thiophenecarboxylic acid [1-(1(R)-benzyl-2]2-[l-(phenylsulfan-2-yl-indenyl) _ 啶 -4- 4-yl]-ethylamino}-ethylaminocarbamidine)-cyclopentyl]-decylamine trifluoroacetate benzo[b]thiophenecarboxylic acid [1-(1(R) -{[1-(1-Amino-cyclohexanecarbonylpyridinyl-4-ylmethyl)-female-branched}-2-phenyl-ethylaminomethyl-)-cyclopentyl]-bristamine Difluoroacetate bromo-naphthalene 1 carboxylic acid [1 _(2_Phenyl-l(RH2-[l-([]tt-carbane-2(S)-carbonyl), pyridine-4-yl]-ethylaminocarbamidine}-ethylaminocarbamidine )-cyclopentyl]-nonylamine 6-bromo-naphthoquinone[1-(2_phenyl-1(尺)_{2-[1-([]瞎院-2(尺)- Base)_? steep-4_yl]-ethylaminomethylcarbazide}-ethylaminocarbamidine)-cyclopentyl]-guanamine benzo[b-phen-2-carboxylic acid [1-(2 • Phenyl·1(Κ)·{2_[4-(phenylthiol-yl)indolyl-1-yl]-ethylaminopyridin}-ethylaminomethylhydrazine)-cyclopentyl ]]-nonylamine chloro-benzofuranyl residual acid {l-[lR-(3·morpholin-4-yl-propylaminocarboxamidine)_2_phenyl-ethylaminomethylhydrazine]-cyclopentyl }}-decylamine 93 1258482 5-Chloro-benzo[b]thiophene-2-carboxylic acid {l-[lR-(3-morpholin-4-yl-propylaminocarboxamidine)-2-phenyl -ethylaminomethylhydrazine]-cyclopentylbudecamide 5-bromo-benzofuranyl-2-carboxylic acid {l-[lR-(3-?咐-4-yl-propylamino)醯)- 2-Phenyl-ethylaminomethylhydrazine]-cyclopentyl}-nonylamine 6-chloro-benz[b]porphin-2-decanoic acid {l-[lR-(3-? -4-yl-propylaminomethyl-)-2-phenyl-ethylaminomethylhydrazide]-cyclopentyl}-nonylamine 6-methoxy-benzo[b]thiophene-2-carboxylic acid { L-[lR-(3-morpholin-4-yl-propylaminocarbamidine) -2-phenyl-ethylaminocarbamyl]-cyclopentyl}-nonylamine 4-chlorobenzo[b]thiophene-2-carboxylic acid {1-[111-(3_morpholin-4-yl) -propylaminomethylhydrazine)-2-phenyl-ethylaminomethyl]]cyclopentyl}-bristamine 6-bromo-benzo[b]thiophene-2-carboxylic acid {l_[lR- (3-morpholin-4-yl-propylaminocarbamidine)·2-Phenyl-ethylaminocarbamic acid]-cyclopentyl}-bristamine 6-bromo-benzo[b]thiophene-2 -carboxylic acid {1_[1R_(3_morpholin-4-yl-propylaminocarbazide)-2-phenyl-ethylaminocarbamidine]-cyclohexylamine 5·Rear-1-A -1-1H-丨唯-2·竣酸{l-[lR-(3-morphin-4-yl-propylaminomethyl)-2-phenyl-ethylaminocarbamidine]-cyclopentyl }--nonylamine 6-gas-1-methyl-1H-P _2-竣 竣 { {1-[1 R-(3 -?咐-4-yl-propylaminomethyl)-2 -phenyl-ethylaminocarboxylic acid]- 哀 戊 pentyl}-acid amine 7-methyl-benzo[b]thiophene-2-carboxylic acid {l-[lR-(3-morpholin-4-yl- Propylaminocarbazide)-2-phenyl-ethylaminomethyl]-cyclopentyl}-bristamine 5-methyl-benzofuran-2-carboxylic acid {l-[lR-(3 -morpholin-4-yl-propylaminocarbazide)- 2-phenyl-ethylaminocarbamic acid]-cyclopentyl}-bristamine 1,5-monomethyl-111_11 卩 卩 -2_ Tannin {1-[1 foot _(3-?咐-4- -propylaminocarboxylic acid)- 2-phenyl-ethylaminocarbamyl]-cyclopentyl}-nonylamine 6-amino-benzo[b]warm phen-2-carboxylic acid {l-[lR -(3-morpholin-4-yl-propylaminocarbamidine)- 2-phenyl-ethylaminocarbamidine]-cyclopentyl decylamine 94 1258482 6,7-dichloro-benzo[ b] thiophene-2-carboxylic acid {1-[1R_(3-?咐I-propyl-propylaminocarboxamidine)-2-phenyl-ethylaminocarboxamidine]-cyclopentyl}-decylamine 5 _-Butyl-benzofurancarboxylic acid [1-(2•phenyl-lR-{[l-(tetrahydro-pyranylmethyl)-pyridylmethyl]-aminomethylpyridinium ethyl) Aminomethyl hydrazide)-cyclopentyl]-nonylamine 6-iodo-benzo[b] warm phen-2-carboxylic acid [1-(2_phenyl-1R-{[1_(tetrahydro-pyran)_ 4_ylmethyl)-peptidin-4-ylmethyl]-aminomethylhydrazide}-ethylaminocarbamidine)-cyclopentyl]-nonylamine 7-bromo-benzo[b] warm phenanthrene 2-carboxylic acid [1-(2-phenyl-1R-{[1·(tetrahydro-pyran-4-ylmethyl)-pyridin-4-ylmethyl]-aminocarboxamidine}- Ethylaminopyridinium)-cyclopentyl]-nonylamine 7-iodobenzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-lR-{[l-(tetrahydro-pyran) -4-ylmethyl)-cyridin-4-ylmethyl]-aminoformamidine}-ethylaminomethylhydrazinecyclopentyl]-nonylamine 7-methyl-benzo[b]thiophene-2 ·Residual acid [1-(2·phenyl) -1[-{[1_(tetrahydro-0-pyranyl-4-ylmethyl)-acridin-4-ylmethyl]-aminocarboxamidine}-ethylaminocarbamyl)-cyclopentyl] -decylamine 7·trifluoromethyl-benzo[b]thiophene-2-carboxylic acid [1·(2-phenyl-1R-{[1_(tetrahydro-pyranylmethyldonidin-4-yl) Methyl]-aminomethylpyridinium ethylaminocarbazide)-cyclopentyl]-nonylamine 7-chlorobenzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1_ (tetrahydro-pyran-4-ylmethyl)-n-butyl-4-ylmethyl]-aminocarboxamidine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine benzofuranyl _ 2-carboxylic acid [1-(2-phenyl-1-{[1R-(tetrahydro-pyranylmethyl)piperidin-4-ylmethyl]-aminomethylpyridinium ethylaminocarbamidine) _cyclopentyl]-nonylamine 1_methyl-1H-indole-2-carboxylic acid [1-(2-phenyl small {[1R-(tetrahydro.pyran-4-ylmethyl)) piperidine _4-ylmethyl]-aminomethylhydrazine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine 7-chloro-1-methyl-1HH2-decanoic acid [lR-(2-phenyl) -1-{[1-(tetrahydro-P-pyran-4-ylmethyl)-oxaridin-4-ylmethyl]-aminomethylhydrazine}-ethylaminocarbamidine)-cyclopentyl] - indoleamine 5-chloro-3-methyl-benzofurancarboxylic acid [1R_(2-phenyl-; 1-{[1-(tetrahydro-pyran-4-ylmethyl)-piperidine- 4-ylmethyl]-aminoformamidine}-ethylamino group A )-cyclopentyl]-oxime 1258482 Amine 5-methoxy-benzofuranyl-2-carboxylic acid [1-(2-phenyl-1-{[1R-(tetrahydro-pyranylmethyl)) -piperidin-4-ylmethyl]-aminomethylpyridinium ethylaminocarbazide)-cyclopentyl]-nonylamine 3,5,6-dimethyl-benzofuranyl-2-decanoic acid [1 -(2-phenyl-1-{[1R&quot;·(tetraki-D-pyran-4-ylmethyl)-piperidin-4-ylmethyl]-aminocarboxamidine}-ethylamino group A醯)-cyclopentyl]-nonylamine 5-bromo-naphthalenecarboxylic acid [丨#-phenyl small {[1R-(tetrahydro-pyran-4-ylmethyl)-pyridin-4-yl) ]]-aminomethylhydrazine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine naphthalenecarboxylic acid [1-(2-phenyl-lR-{[l-(tetrahydro-pyran-4) -ylmethylbupyridylmethyl]-aminomethylpyridinium ethylamino)-cyclopentyl]-nonylamine benzo[b]thiophenecarboxylic acid [1-(2-phenyl-i(R) )-{[i_(tetrahydro-pyran-4-ylmethyl)-azetidin-3-ylmethyl]-aminoformamidine}-ethylaminocarbamidine)-cyclopentyl]_醯amine. 4. A compound of the formula (I) according to claim 1 or 2, wherein the compound is defined by the following formula: / benzo[b]thiophene Icarboxylic acid (1_{2_phenyl-wrhh tetrahydro- Pyranyl-ylmethyl)-propandidin-4-ylaminocarbamidine]-ethylaminomethylpyridylcyclopentyl)-guanamine trifluoroacetate benzo[b]thiophene-2-carboxylic acid [l-(l(R)-{2-[(l-Amino-cyclohexanecarbonyl)-amino]-ethylaminocarbamyl}-2-phenyl-ethylaminocarbamidine)_ Cyclopentyl]-nonylamine 6-bromo-benzo[b]thiophene Icarboxylic acid phenyl-1(R)_{[1-(tetrahydro-pyranylmethyl)-oxaridin-4-yl Methyl]-aminomethylpyridinium ethylaminocarbazide)-cyclopentylguanamine trifluoroacetate benzo[b]thiophene Icarboxylic acid-isopropyl-cylinyl+ylmethylamine-based brewing]- 2-Phenyl-ethylaminoformamidine cyclopentylguanamine benzo[b]thiophenecarboxylic acid κι phenyl (tetrahydro-p-pyranylmethyl)-disindol-4-ylmethyl]-amine醯 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 乙基 环 环 环 环 环 环 环 环 环 环 环 环 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1-基)_口所96 1258482 pyridine-4-ylmethyl]-aminomethylpyridinium ethylaminocarbazide)-cyclopentyl]-nonylamine benzo[b]thiophenecarboxylic acid [1-(2-phenyl _l(R) -{[l-(tetrahydro-D-pyrano-4-yl)-piperidine-4-ylmethyl]-aminomethylpyridinium ethylaminocarbazide)-cyclopentyl]-nonylamine l-(3 -Ep-tolyl-acrylamide)-cyclopentanecarboxylic acid (2-phenyl-l(R)-{[l-(tetrahydro-pyran-4-ylmethyl)-pyridinylmethyl) ]-Aminomethyl hydrazide ethyl)-decylamine trifluoroacetate benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-l(R)-{2-[l-(tetrahydro) -pyran-4-ylmethyl)-acridin-4-yl]-ethylaminocarbamyl}-ethylaminocarbamidine)-cyclopentyl]-nonylamine trifluoroacetate瞳 竣 竣 [1-(2·Phenyl-1 (R)- {2_[ 1 _(tetrazine-fluorenyl _4_yl)·卩卩定· _心基]-ethylamino Hyperthyroid}}-ethylaminopyridinium)-cyclopentyl]-nonylamine trifluoroacetate salt-naphthoic acid [1-(2-phenyl-1(R)- {[ 1 -( four gas ·卩比喃-4·-yl)-卩卩定·4_ylmethyl]-aminomethylhydrazine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine 6·bromo-naphthalenecarboxylic acid (Mi(R)-[(l-[l,3]dioxan-5-ylmethyl-acridinylmethyl)-aminocarboxamidine]-2-phenyl-ethylaminocarbamidine} -cyclopentyl)-nonylamine chloro-benzofurancarboxylic acid (1-{1(R)-[(1-[1,3]dioxan-5-ylmethyl?-yl-methyl) )-Aminomethylhydrazine]-2-phenyl- Aminoaminocarbazide}-cyclopentyl)-nonylamine 6·bromo-naphthalenecarboxylic acid [Hl(RH[l-(l-aminocyclohexanecarbonyl)-pyridinyl-4) carbazyl l ·Aminomethylhydrazine}-2-phenyl-ethylaminocarbamidine)-cyclopentyl]-nonylamine iodine-naphthalene-2-carboxylic acid [1-(2-phenyl-1R-{[1_(( Tetrahydropyran-4-ylmethyl)-pyridinyl-4-ylmethyl]-aminoformamidine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine 6-methoxy-naphthalene- 2-carboxylic acid [1-(2-phenyl-lR_{[l-(tetrahydro-D-pyran-4-ylmethyl)-p-pyridyl-phenylmethyl]-aminomethylpyridinium ethylamino)醯)-cyclopentyl]-guanamine bromobenzofuran-2-carboxylic acid [1-(2-phenyl-lR-{[l-(tetrahydro-pyranyl)methyl l·peri Pyridin-4-ylmethyl]-aminoformamidine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine chloro-benzofuranyl-2-carboxylic acid [1-(2-phenyl) -1R-{[1_(tetrahydro-pyran-4-ylmethyl 97 1258482 )-oxazin-4-ylmethyl]-aminocarbazide}-ethylaminomethylhydrazine)-cyclopentyl] - indoleamine fluoro-benzofuranyl-2- decanoic acid [1_(2_phenyl]R-{[le(tetrahydro-indolyl-4-indolyl)-oxazin-4-ylmethyl ]-Aminomethylhydrazine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine 5-chloro-benzofuranyl-2-carboxylic acid [1_(2_phenyl qR-Ui•(tetrahydrogen) _卩比喃_ Methyl)-piperidin-4-ylmethyl]-aminoformamidine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine 5-bromo-benzofuranyl-2-carboxylic acid [1_(2·Phenyl^[{[Bu(tetrahydro-p-pyrene-pyranyl-yl)methyl)-pyridine-4-yl-methyl]-aminocarboxamidine}-ethylaminocarbamidine)-ring戊基]-Amidoxime-butyl-benzofurancarboxylic acid [1_(2_phenyl-1R-{[1•(tetrahydro-indolebi-4)-methyl)-piperidine- 4-ylmethyl]-aminomethylpyridinium ethylaminocarbazide)-cyclopentyldiamine methyl-benzofuranyl residual acid [1-(2-phenyl) (tetrahydro-P-pyranyl) Methyl)-piperidin-4-ylmethyl]-aminomethylpyridinium ethylaminocarbazide)-cyclopentyl&gt;nonylamine 5-methyl-benzofuranyl-2-carboxylic acid [1_(2 _Phenyl-1R-{[1_(tetrahydro.pyran-4-ylmethyl)-piperidin-4-ylmethyl]-aminocarbazide}-ethylaminomethylhydrazine)-cyclopentyl] - decylamine % iodine-benzofuranyl 2 -carboxylic acid [1_(2_phenyl·(tetrahydro-indolyl-4-ylmethyl)-piperidin-4-ylmethyl]-amino Hyperthymidine}_ethylaminocarbamidine)-cyclopentyl]-nonylamine 6-chloro-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1_(four Hydrogen-p-pyrano-4-ylmethyl l-piperidin-4-ylmethyl]-aminocarbazide}-ethylaminocarbamidine-cyclopentane ]_醯amine 6-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid [1-(2-phenyl-1R-{[1·(tetrahydro-indolepyran-4-ylmethyl) )-Butidine-4-ylmethyl]-aminocarbazide}-ethylaminocarbamidine&gt;cyclopentyl]-nonylamine 6-methoxy-benzo[b]thiophene-2-carboxylic acid [1-(2-Phenyl-1R-{[1_(tetrahydro-indolyl-4-ylmethyl)-n-pyridylmethyl]-aminomethylhydrazine}•Ethylaminomethylhydrazine)_ Cyclopentyl]-nonylamine·5-methyl-benzo[b]thiophene Icarboxylic acid [1-(2-phenyl-iR-{[1•(tetrahydro-0)pyranylmethyl)啶 -4--4-ylmethyl]-aminomethyl hydrazide}•ethylaminocarbamidine)-cyclopentyl decylamine 6-methyl-benzo[b]thiophene-2-indole[1-( 2_Phenyl-(8)(1)-(10)hydrogen--ylmethyl 98 1258482 yl)-n-pyridylmethyl]-aminoformamidine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine 6- Fluoro-benzo[b]nonphenecarboxylic acid [1-(2-phenyltetrahydro.pyranyl-4-ylmethyl)-naphthyridin-4-ylmethyl]-aminoformamidine}-ethylamine Basement 醯)_cyclopentyl decylamine 6_diethylamino-benzofurancarboxylic acid [1-(2-phenyl-1-{[1R_(10)hydrogen-pyranylmethyl)-benzidine 4--4-methyl]-aminomethamid ethylaminoglyoxime)-cyclopentyl]-nonylamine 5-diethylamino-benzofuranyl_2 Carboxylic acid [1_(2_phenyl small {[1R-(tetrahydro-indolyl)-4-ylmethyl)-n-yl-4-ylmethyl]-aminocarboxamidine}-ethylamino醯)_cyclopentyl> guanamine naphthalene 1 carboxylic acid [1-(2-phenyl(tetrahydro-pyran-4-yl)methyl)- pyridine]-methyl-1-aminomethyl}- Ethylaminopyridinium)-cyclopentyl]-nonylamine bromo-naphthalenecarboxylic acid [l-(l(R)-{[l-(4-methyl-tetrahydro-pyran-4-yl) Methyl)-piperidin-4-ylmethyl]-aminomethylhydrazine}_2_phenyl-ethylaminocarbamidine)-cyclopentylamine 6-bromo-naphthalene-2-carboxylic acid L-(l(R)_{[l-(5-Ethyl-[I,3]di-butanylmethyl)-?11-decylmethyl]-aminomethylhydrazine}-2-phenyl- Ethylaminopyridinium)-cyclopentyl]-decylamine, bromo-naphthalenecarboxylic acid [l-(l(R)-{[4-methyl-1-(4-methyl-tetrahydro-) Pyran-4-ylmethyl)-oxaridin-4-ylmethyl]-aminoformamidine}_2_phenyl-ethylaminocarbamidine)-cyclopentylguanamine, 6-bromo-naphthalene _2_carboxylic acid [l-(l(R)-{[4-methyl small(tetrahydro-D-pyanylmethyl)-piperacylmethyl]-aminomethylhydrazine}-2-benzene Base-ethylaminocarbamidine)-cyclopentyl]-guanamine. 5. A compound defined by the formula: benzo[b]warm phen-2-carboxylic acid, [H1-aminomethyl-2-(R)-phenyl-ethylaminocarbamidine)-ring Hexyl]-melamine benzo[b]thiophene:carboxylic acid {i-pphenyl_1(κ)-(piperidine I-aminoamidoxime)-ethylaminocarbamidine]-cyclopentyldiphenyl Amine benzo[b] warm phen-2-carboxylic acid (1_{2_phenyl) (RH(pyridinyl-4-methyl-methyl)-aminomethylhydrazine 99 1258482]-ethylaminomethylhydrazine} _cyclopentyl)-guanamine benzo[b]thiophene-2-carboxylic acid {1-[2-phenyl-URH2??D疋I-ethyl-ethylaminocarbamidine)-ethylaminoformamidine ]-cyclopentyl}-nonylamine trifluoroacetate benzo[b]thiophene-2-carboxylic acid [H2-phenyltetrahydropyran-4-ylmethyl)·D D-l-yl]- Ethylaminomethylhydrazine}-ethylaminocarbamidine)-cyclopentyl]-nonylamine trifluoroacetate. 6. The use of a compound of formula (1) as claimed in claim 5 is for the preparation of a treatment for respiratory diseases such as asthma and allergic rhinitis; eye diseases such as conjunctivitis; skin diseases such as allergies With contact dermatitis 'and psoriasis' intestinal diseases such as colon allergy, ulcerative colitis and Chron disease, stomach diseases, urinary tract diseases such as cystitis and urinary tract can not erect, nerve Central system diseases such as anxiety 'frustration and schizophrenia 'cancer' autoimmune disease or AIDS-related diseases, cardiovascular disease, neuritis, neuralgia and treatment of pain, visceral pain, inflammatory response 'such as osteoarthritis or rheumatism A pharmaceutical formulation for arthritis. A pharmaceutical composition comprising at least one compound of the formula (I) according to any one of claims 1 to 4 or a mixture thereof as an active element. 8. The pharmaceutical composition according to item 7 of the patent application, further comprising a pharmaceutically acceptable diluent and an auxiliary. 9_ The pharmaceutical composition of claim 7 or 8 for the treatment of respiratory diseases such as asthma and allergic rhinitis; eye diseases such as conjunctivitis; skin diseases such as allergies and contact dermatitis, and Psoriasis, intestinal diseases such as colon allergy, ulcerative colitis and Chron disease, stomach diseases, urinary tract diseases, such as bladder bronchi and diabetes insipidus, unable to erect, nervous system diseases such as anxiety , depression and schizophrenia, cancer, autoimmune disease or AIDS 100 1258482 related diseases, cardiovascular disease, neuritis, neuralgia and treatment of pain, visceral pain, inflammatory response, such as osteoarthritis or rheumatoid arthritis. 101