CN1073103C - Compounds and compositions for treating diseases associated with tryptase activity - Google Patents

Abstract

The present invention relates to novel compounds useful as tryptase inhibitors, their pharmaceutically acceptable salts and N-oxides, their use as therapeutic drugs and processes for their preparation.

Description

Novel compounds and compositions for the treatment of diseases associated with tryptase activity

This application claims priority to prior US Application Serial No. 60/023,139, filed July 30,1996.

Field of invention:

The present invention relates to new methods and compositions for treating diseases associated with tryptase activity by administering novel tryptase inhibitors.

Description of the field:

Tryptase, the major protease secreted from human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. After a few hours of allergy, the concentration of tryptase in the blood increases (Schwartz et al., (1987) N.Eng.J.Med.316:1622-1626); Increased concentration of tryptase in the lavage fluid (Castells et al., (1988) J.Allerg.Clin.Immunol.141:563-568); After intrabronchial allergen immune challenge, the lungs of specific asthmatic patients Increased tryptase concentration in the lavage fluid. The finding that tryptase concentrations are often markedly elevated in the bronchoalveolar lavage fluid of smokers supports the hypothesis that release of the protease from activated mast cells is associated with lung destruction in smokers with emphysema. (Celenteron et al. (1988) Chest 94:119-123). In addition, tryptase appears to be a potent mitogen for fibroblasts, suggesting that tryptase may be involved in pulmonary fibrosis and is associated with interstitial lung disease (Rose et al., (1991) J.Clin.Invest.88 :493-499).

Asthma is considered an inflammatory condition (Hood et al., 1984 in Immunology, edited by Benjamin-Cummings, 2nd ed.) and is often characterized by hypersensitivity of the trachea and bronchi to immune-specific allergens and general chemical or physical stimuli. The progressive development of the reaction is characteristic. The disease involves multiple biochemical mediators in its acute and chronic phases. Hypersensitivity reactions in the endobronchial tissues of asthma are thought to result from chronic inflammatory responses that irritate and damage the epithelium lining the airway walls and promote pathological thickening of the subepithelial tissue. Bronchial biopsies of patients with mild asthma show signs of inflammation in the airway walls.

Allergic reactions to inhaled allergens can trigger inflammatory processes, for example by binding to IgE located on the cell surface, allergens can activate mast cells and basophils located in the epithelium and beneath the smooth muscle tissue. Activated mast cells release quantities of executive or primary chemical mediators (such as histamine) that carry out the inflammatory response and generate large quantities of other secondary mediators of inflammation in situ. (eg peroxides, fluid from vehicle, etc.) In addition, several macromolecules are released by mast cell loss (eg proteoglycans, tryptase, chymase, etc.).

These executive mediators from mast cells may be responsible for the early constriction of the bronchi in the asthmatic response to airborne allergens. The initial phase of the asthmatic response peaks about 15 minutes after exposure to the allergen and is generally followed by an hour or two of recovery. A further decline in respiratory function is experienced by 25-35% of patients, with this decline reaching a maximum 6-12 hours after exposure to the allergen. This late response is accompanied by an increase in the number of inflammatory cells (eg, cosinophils, neutrophils, lymphocytes, etc.) that infiltrate the bronchiolar tissue. These extravasated cells are attracted into place by the release of mast cell-derived chemoattractants and then activated later in the response. The late asthmatic response is thought to be a secondary inflammatory response mediated in part by the secretory activity of granulocytes.

Tryptase has been implicated in the degradation of neuropeptides that relax blood vessels and bronchi (Caughey et al., (1988) J. Pharmacol. Exp. Ther. 244:133-137; Franconi et al., (1988) J. Pharmacol. Exp. Ther.248:947-951; related to Tam et al. (1990) Am.J.Respir.Cell Mol.Biol.3:27-32) and regulation of bronchial response to histamine (Sekizawa et al., (1989) J . Clin. Invest. 83:175-179). These findings suggest that tryptase may augment bronchoconstriction in asthma by disrupting bronchodilation polypeptides. Tryptase cleaves the α-chain of fibrinogen and high molecular weight kininogen, suggesting that tryptase acts as a local anticoagulant like heparin. Tryptase activates prostromelysin (pro-MMP-3) and protogenase (pro-MMP-1) through MMP-3, suggesting that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Moreover, administration of tryptase inhibitors prevented the development of late airway hypersensitivity reactions in sheep induced by allergens (Clark et al., (1995) Am. J. Respir. Crit. Care Med. 152:2076-2083) and inhibited skin Direct skin reactions in allergic sheep intra-injected with allergens (Molinari et al. (1995) Amer. Physiol. Soc. 79(6):1966-1970). All of the above findings clearly indicate that tryptase inhibitors can be used as therapeutic agents in the treatment of asthma and other diseases associated with airway inflammation.

These publications, as well as other documents referred to in this application, are hereby incorporated by reference.

Summary of the invention

This application relates to compounds of formula I and their pharmaceutically acceptable salts, N-oxides, their prodrug derivatives and their protected derivatives:

I

in:

X ⁵ is C _3-14 cycloalkylene, C _3-14 heterocycloalkylene, C _6-14 arylene or C _5-14 arylene heterocyclyl;

X ⁴ and X ⁶ are independently C _0-2 alkylene;

X ¹ and X ⁹ are independently covalent bonds, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ³ )-, -N( R ³ )C(O)-, -S(O) ₂ N(R ³ )-, -N(R ³ )S(O) ₂ -, -OC(O)N(R ³ )-, -N( R ³ )C(O)O-, -N(R ³ )C(O)N(R ³ )- or -OC(O)O, wherein each R ³ is independently hydrogen, C _1-3 alkyl Or C _3-8 cycloalkyl, provided that: X ¹ and X ⁹ are not all covalent bonds;

X ³ and X ⁷ are independently -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ³ )-, -N(R ³ )C( O)-, -S(O) ₂ N(R ³ )-, -N(R ³ )S(O) ₂ -, -OC(O)N(R ³ )-, -N(R ³ )C( O)O-, -N(R ³ )C(O)N(R ³ )- or -OC(O)O-, wherein R ³ is as defined above;

X ² and X ⁸ are independently C _1-8 alkylene, C _1-8 heteroalkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ is C _0-4 alkylene Alkyl or C _3-4 heteroalkylene, and X ¹¹ is C _3-8 cycloalkylene or C _3-8 heterocycloalkylene;

R ¹ is R ⁴ -X ¹² - or R ³ -X ¹³ -, wherein

R ⁴ is amino, amidino, guanidino, 1-iminoethyl or methylamino,

X ¹² is C _4-6 alkylene, C _4-6 heteroalkylene, oxo C _4-6 heteroalkylene, oxo C _4-6 alkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ is C _3-6 cycloalkylene, C _5-6 arylene heterocyclyl, C _3-6 heterocycloalkylene or phenylene, X ¹⁴ is C _n14 alkylene, and X ¹⁶ is C _n16 alkylene, wherein n14 and n16=0, 1, 2, 3 or 4,

R is selected from the group consisting of azetidin-3-yl, benzimidazol-4-yl, benzimidazol-5-yl ^, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazole Lin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiper Pyridin-3-yl, 1-methylpiperidin-4-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, pyridin-3-yl, Pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetra Hydropyrimidin-4-yl and 1,4,5,6-tetrahydropyrimidin-5-yl and carbocyclones or their thioketone derivatives, which may be unsubstituted or replaced by one or more From halogen, hydroxyl, mercapto, C _1-8 alkyl, C _3-14 cycloalkyl, C _6-14 aryl, C _6-14 aryl C _1-4 alkyl, C _1-8 alkanoyl, C _1-8 alkyloxy, C _6-14 aryloxy, C _3-14 cycloalkyloxy, C _1-4 alkyloxy, C _1-8 alkylthio, C _3-14 ring Alkylthio, C _6-14 arylthio and -NR ⁶ R ⁷ are substituted by groups, wherein R ⁶ and R ⁷ are independently selected from hydrogen, C _1-8 alkyl, C _1-8 alkanoyl, C _3-14 cycloalkyl or C _6-14 aryl, while

X ¹³ is C _0-6 alkylene, C _2-6 heteroalkylene, oxo C _3-6 heteroalkylene, oxo C _2-6 alkylene or -X ¹⁷ -X ¹⁸ -X ¹⁹ -, wherein X ¹⁸ is the same as defined above for X ¹⁵ , X ¹⁷ is C _n17 alkylene, and X ¹⁹ is C _n19 alkylene, wherein n17 and n19=0, 1 or 2; and

R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, wherein:

R ⁸ is amino, 1-iminoethyl or methylamino,

X ²⁰ is C _4-6 alkylene, C _4-6 heteroalkylene, oxo C _4-6 heteroalkylene, oxo C _4-6 alkylene or -X ²² -X ²³ -X ²⁴ -, wherein ^X23 is as defined above for ^X15 , ^X22 is _Cn22 alkylene, and ^X24 is _Cn24 alkylene, wherein n22 and n24=0, 1, 2, 3 or 4, provided that: When R ⁸ is amino, X ²⁰ is not C _4-6 alkylene or oxo C _4-6 alkylene, and n 22 is not 1, 2, 3 or 4,

^R9 is as defined above for ^R5 , and

X ²¹ is C _0-6 alkylene, C _2-6 heteroalkylene, oxo C _3-6 heteroalkylene, oxo C _2-6 alkylene or -X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ²⁶ is the same as defined above for X ¹⁵ , X ²⁵ is C _n25 alkylene, and X ²⁷ is C _n27 alkylene, wherein n25 and n27=0, 1 or 2;

wherein each of the above-defined alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene groups may be unsubstituted or replaced by one or more selected From halogen, hydroxyl, mercapto, C _1-8 alkyl, C _3-14 cycloalkyl, C _6-14 aryl, C _6-14 aryl C _1-4 alkyl, C _1-8 alkanoyl, C _1-8 alkyloxy, C _6-14 aryloxy, C _3-14 cycloalkyloxy, C _1-4 alkyloxy, C _1-8 alkylthio, C _3-14 ring Substituted by alkylthio, C _6-14 arylthio and -NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are as defined above, provided that: at R ¹ , X ² , X ⁴ , X ⁶ There is no covalent bond between the heteroatoms contained in , X ⁸ and R ² and the heteroatoms contained in X ³ , X ⁵ , X ⁷ and X ⁹ .

ⅠA second aspect of the present invention relates to compounds of formula I and their pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof:

I

in:

X ⁴ -X ⁵ -X ⁶ together are C _2-12 alkylene or C _3-12 heteroalkylene;

X ¹ and X ⁹ are independently covalent bonds, -C(O)-, -C(O)O-, -OC(O)-, -C(O)N(R ³ )-, -N( R ³ )C(O)-, -S(O) ₂ N(R ³ )-, -N(R ³ )S(O) ₂ -, -OC(O)N(R ³ )-, -N( R ³ )C(O)O-, -N(R ³ )C(O)N(R ³ )- or -OC(O)O-, wherein each R ³ is independently hydrogen, C _1-3 alkane Group or C _3-8 cycloalkyl, provided that: X ¹ and X ⁹ are not all covalent bonds;

X ³ and X ⁷ are independently -C(O)-, -C(O)O, -OC(O)-, -C(O)N(R ³ )-, -N(R ³ )C(O )-, -S(O) ₂ N(R ³ )-, -N(R ³ )S(O) ₂ -, -OC(O)N(R ³ )-, -N(R ³ )C(O )O-, -N(R ³ )C(O)N(R ³ )-or -OC(O)O-, wherein R ³ is as defined above;

X ² and X ⁸ are independently C _1-8 alkylene, C _1-8 heteroalkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ is C _0-4 alkylene Alkyl or C _3-4 heteroalkylene, and X ¹¹ is C _3-8 cycloalkylene or C _3-8 heterocycloalkylene;

R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ -, wherein

R ⁴ is amino, amidino, guanidino, 1-iminoethyl or methylamino,

X ¹² is C _4-6 alkylene, C _4-6 heteroalkylene, oxo C _4-6 heteroalkylene, oxo C _4-6 alkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ is C _3-6 cycloalkylene, C _5-6 arylene heterocyclyl, C _3-6 heterocycloalkylene or phenylene, X ¹⁴ is C _n14 alkylene, and X ¹⁶ is C _n16 alkylene, wherein n14 and n16=0, 1, 2, 3 or 4,

R is selected from the group consisting of azetidin-3-yl, benzimidazol-4-yl, benzimidazol-5-yl ^, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2-imidazole Lin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiper Pyridin-3-yl, 1-methylpiperidin-4-yl, piperidin-3-yl, piperidin-4-yl, piperazin-1-yl, piperazin-2-yl, pyridin-3-yl , pyridin-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1,4,5,6-tetrahydropyrimidin-2-yl, 1,4,5,6- Tetrahydropyrimidin-4-yl and 1,4,5,6-tetrahydropyrimidin-5-yl and carbocyclones or their thioketone derivatives, which may be unsubstituted or replaced by one or more Selected from halogen, hydroxyl, mercapto, C _1-8 alkyl, C _3-14 cycloalkyl, C _6-14 aryl, C _6-14 aryl C _1-4 alkyl, C _1-8 alkanoyl, C _1-8 alkyloxy, C _6-14 aryloxy, C _3-14 cycloalkyloxy, C _1-4 alkyloxy, C _1-8 alkylthio, C _3-14 Cycloalkylthio, C _6-14 arylthio and -NR ⁶ R ⁷ are substituted by groups, wherein R ⁶ and R ⁷ are independently selected from hydrogen, C _1-8 alkyl, C _1-8 alkanoyl , C _3-14 cycloalkyl or C _6-14 aryl, and

X ¹³ is C _0-6 alkylene, C _2-6 heteroalkylene, oxo C _3-6 heteroalkylene, oxo C _2-6 alkylene or -X ¹⁷ -X ¹⁸ -X ¹⁹ -, wherein X ¹⁸ is the same as defined above for X ¹⁵ , X ¹⁷ is C _n17 alkylene, and X ¹⁹ is C _n19 alkylene, wherein n17 and n19=0, 1 or 2; and

R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, wherein:

R ⁸ is as defined above for R ⁴ ,

X ²⁰ is C _4-6 alkylene, C _4-6 heteroalkylene, oxo C _4-6 heteroalkylene, oxo C _4-6 alkylene or -X ²² -X ²³ -X ²⁴ -, wherein X ²³ is the same as defined above for X ¹⁵ , X ²² is C _n22 alkylene, and X ²⁴ is C _n24 alkylene, wherein n22 and n24=0, 1, 2, -3 or 4,

^R9 is as defined above for ^R5 , and

X ²¹ is C _0-6 alkylene, C _2-6 heteroalkylene, oxo C _3-6 heteroalkylene, oxo C _2-6 alkylene or -X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ²⁶ is the same as defined above for X ¹⁵ , X ²⁵ is C _n25 alkylene, and X ²⁷ is C _n27 alkylene, wherein n25 and n27=0, 1 or 2;

wherein each of the above-defined alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene groups may be unsubstituted or replaced by one or more selected From halogen, hydroxyl, mercapto, C _1-8 alkyl, C _3-14 cycloalkyl, C _6-14 aryl, C _6-14 aryl C _1-4 alkyl, C _1-8 alkanoyl, C _1-8 alkyloxy, C _6-14 aryloxy, C _3-14 cycloalkyloxy, C _1-4 alkyloxy, C _1-8 alkylthio, C _3-14 ring Substituted by alkylthio, C _6-14 arylthio and -NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are as defined above, provided that: at R ¹ , X ² , X ⁴ , X ⁶ There is no covalent bond between the heteroatoms contained in , X ⁸ and R ² and the heteroatoms contained in X ³ , X ⁵ , X ⁷ and X ⁹ .

A third aspect of the present invention is a medicament containing a compound of formula 1 or a pharmaceutically acceptable salt thereof, an N-oxide, a prodrug derivative thereof and one or more suitable excipients combination.

The fourth aspect of the present invention is a method of treating an animal disease whose pathogenesis and/or symptoms are related to tryptase activity, which method comprises a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof , N-oxide, prodrug derivative thereof is administered to the animal.

The fifth aspect of the present invention is to prepare the compound of formula I and its pharmaceutically acceptable salt, N-oxide, its prodrug derivative and its protected Derivative method.

Detailed description of the invention

definition:

Unless otherwise stated, the following terms used in the specification and claims have the following meanings:

"Alkanoyl" means a -C(O)R group, wherein R is an alkyl group as defined below containing a total of the indicated number of carbon atoms (e.g., C _1-8 alkanoyl includes formyl, acetyl, propionyl, butyl acyl, isobutyryl, crotonyl, isocrotonyl, etc.).

"Alkyl" (eg, alkyl as in alkyl, arylalkyl, alkyloxy, alkylthio) means a straight or branched, saturated or unsaturated hydrocarbon group containing the indicated number of carbon atoms (For example, C _1-8 alkyl includes methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl, 1-propenyl, iso propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methallyl, ethynyl, 1-propynyl, 2-propynyl, etc.).

"Alkylene" refers to a straight-chain saturated or unsaturated divalent hydrocarbon group containing the specified number of carbon atoms (for example, C _0-6 alkylene includes methylene (-CH ₂ -), ethylene (-( -CH ₂ -) ₂ -), ethenylene (-CH=CH-), ethynylene (-C≡C-), 2-propenylene (-CH=CH-CH ₂ -), 1- propenyl (-CH ₂ -CH=CH-), tetramethylene (-(-CH ₂ -) ₄ -), pentamethylene (-(-CH ₂ -) ₅ -) and hexamethylene ( -(-CH ₂ -) ₆ -), etc.). The term C ₀ alkylene is meant to represent a covalent bond.

"Alkoxy" means an -OR group, wherein R is an alkyl group as defined above containing the indicated number of carbon atoms (e.g., C _1-8 alkoxy includes methoxy, ethoxy, propoxy, iso propoxy, butoxy, isobutoxy, etc.).

"Alkylthio" means a -SR radical, where R is an alkyl group as defined above containing the indicated number of carbon atoms (e.g., C _1-8 alkylthio includes methylthio, ethylthio, propylthio, thiol, isopropylthio, butylthio, isobutylthio, etc.).

"Animal" includes humans, non-human mammals (eg, dogs, cats, rabbits, cows, horses, sheep, goats, pigs, deer, etc.) and non-mammals (eg, birds, etc.).

"Aryl" (as in aryl, arylalkyl, aryloxy, and arylthio) means a monocyclic or polycyclic aromatic hydrocarbon radical containing the indicated number of carbon atoms in which the free valence The carbon atom is a member of the aromatic ring and any carbocyclic ketone or its thioketone derivatives (for example, C _6-14 aryl includes phenyl, naphthyl, anthracenyl, phenanthrenyl, 1,2,3,4- tetrahydronaphthalen-5-yl, 1-oxo-1,2-dihydronaphthalen-6-yl, 1-thio-1,2-dihydronaphthalen-7-yl, etc.).

"Arylene" means a divalent monocyclic or polycyclic aromatic hydrocarbon radical containing the specified number of carbon atoms, wherein the carbon atoms containing free valences are members of the aromatic ring and any carbocyclic ketone or its thioketone derivatives (e.g. C _6-14 arylene includes 1,4-phenylene, 1,3-phenylene, 1,4-naphthylene, 2,6-naphthylene, 1,4-anthracene, 2, 6-Anthracene, 1,6-phenanthrene, 1,2,3,4-tetrahydro-5,8-naphthylene, 1-oxo-1,2-dihydro-5,7- naphthyl, 1-thio-1,2-dihydro-5,8-naphthylene, etc.).

"Aryloxy" means an -OR radical, wherein R is an aryl group as defined above containing the indicated number of carbon atoms (eg C _6-14 aryloxy includes phenoxy, naphthyloxy, anthracenyl oxygen, etc.).

"Arylthio" means a -SR radical, where R is an aryl group as defined above containing the indicated number of carbon atoms (eg C _6-14 arylthio includes phenylthio, naphthylthio, anthracene thiol, etc.).

"Cycloalkyl" (as in cycloalkyl and cycloalkyloxy) means a saturated or unsaturated monocyclic or polycyclic hydrocarbon radical containing the indicated number of carbon atoms, wherein the free valence of carbon atoms Is a non-aromatic ring and a member of any carbocyclic ketone or its thioketone derivatives (for example, C _3-14 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2, 5-cyclohexadienyl, bicyclo[2.2.2]octyl, 1,2,3,4-tetrahydronaphthalene-1-yl, oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, etc.) .

"Cycloalkylene" means a divalent saturated or unsaturated monocyclic or polycyclic group containing the specified number of carbon atoms, wherein the carbon atoms containing free valences are non-aromatic rings and any carbocyclic ketone or its thioketone derivative (for example, C _3-6 cycloalkylene includes 1,2-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,4-cyclopentylene, 1,4-cyclohexylene, 3-cyclohexene-1,2-ylidene, 2,5-cyclohexadiene-1, 4-Ylidene, 1,4-bicyclo[2.2.2]cyclooctylene, 1,2,3,4-tetrahydro-1,4-naphthylidene, 5-oxo-1,3-cycloethylene Hexyl, 2,5-dioxo-1,4-cyclohexylene, 5-thio-1,4-cyclohexylene, etc.).

"Cycloalkyloxy" means an -OR group, wherein R is a cycloalkyl group as defined above containing the indicated number of carbon atoms (eg C _3-14 cycloalkyloxy includes cyclopropyloxy, cyclobutyl oxy, cyclopentyloxy, cyclohexyloxy, etc.).

"Cycloalkylthio" means a -SR group, wherein R is a cycloalkyl group as defined above containing the indicated number of carbon atoms (for example C _3-14 cycloalkylthio includes cyclopropylthio, cyclobutyl thiol, cyclopentylthio, cyclohexylthio, etc.).

"Deprotection" refers to the removal of a protecting group after the selective reaction is complete.

"Disease" specifically includes an unhealthy physical condition of an animal or its limbs, including any unhealthy physical condition that may result from or occur incidentally to medical or veterinary treatment of an animal, a side effect of such treatment.

"Halogen" means fluorine, chlorine, bromine or iodine.

"Heteroalkylene" means that in an alkylene group as defined above, 1-5 specified carbon atoms are replaced by heteroatoms selected from N, O or S (such as azaalkylene, azaalkylene, respectively oxaalkylene and thiaalkylene) with the proviso that the O, N and S atoms contained therein do not form bonds with other heteroatoms. For example, C _3-12 heteroalkylene includes aza C ₃ -alkylene, including 3-azatrimethylene (-NHCH ₂ CH ₂ -), 2-azatrimethylene (-CH ₂ NHCH ₂ -), etc.; ω-aza-C _2-5 -alkylene, including 2-azaethylene (-NHCH ₂ -), 3-azatrimethylene, 4-azatetramethylene (-NHCH ₂ CH ₂ CH ₂ -) and 5-azapentamethylene (-NHCH ₂ CH ₂ CH ₂ CH ₂ -); oxaC ₃ -alkylene, including 3-oxatrimethylene (-OCH ₂ CH ₂ -), 2-oxa trimethylene (-CH ₂ OCH ₂ -), etc.; oxa-C ₅ -alkylene such as 3-oxa pentamethylene (-CH ₂ CH ₂ OCH ₂ CH ₂ -), etc.; thia C ₃ -alkylene, including 3-thiatrimethylene (-SCH ₂ CH ₂ -), 2-thiatrimethylene (-CH ₂ SCH ₂ -) etc.; ω-thia-C _2-4 -alkylene, including 2-thiaethylene (-SCH ₂ -), 3-thiatrimethylene and 4-thiatetramethylene (- SCH ₂ CH ₂ CH ₂ -); Diaza C ₆ alkylene, including 2,5-diazahexamethylene (-CH ₂ NHCH ₂ CH ₂ NHCH ₂ -); Azaoxa C ₆ Alkylene groups include 2-oxa-5-azahexamethylene (-CH ₂ OCH ₂ CH ₂ NHCH ₂ -) and the like.

"Heteroarylene" means that in an arylene group as defined above, 1-5 designated carbon atoms are replaced by heteroatoms selected from N, O or S (for example, C _5-6 heteroarylene, Including furylylene, thienylene, pyrrolylene, imidazolylidene, pyridinylene, etc.).

"Heterocycloalkylene" means that in a cycloalkylene group as defined above, 1-5 specified carbon atoms are replaced by heteroatoms selected from N, O or S (for example, C _3-14 heterocycloalkylene Alkyl includes 2,4-pyrrolidinylidene, 2,4-pyrrolinylidene, 2,4-imidazolinylidene, 3,5-pyrazolinylidene, 1,4-piperidinylidene, 1 , 4-piperazinylene, 2,5-quininidine, 2,5-morpholinylene, 1,3-isoindolinylene, etc.).

"Oxoheteroalkylene" means that in an alkylene group as defined above, one of the specified carbon atoms is replaced by a heteroatom selected from N, O or S, and a carbon atom adjacent to the heteroatom Substituted by a carbonyl group (C=O), such as oxoazaalkylene, oxooxaalkylene and oxothiaalkylene, respectively, provided that O, N and S contained therein Atoms do not form bonds with other heteroatoms. For example, oxoC _4-6 heteroalkylene includes oxoazepine C ₃ alkylene, including 2-aza-3-oxotrimethylene (-C(O)NHCH ₂ -), 3 -Aza-2-oxo-trimethylene (-NHC(O)CH ₂ -), etc.; oxo-oxa C ₃ alkylene, including 2-oxa-3-oxo-trimethylene (-C (O)OCH ₂ -), 3-oxa-2-oxotrimethylene (-OC(O)CH ₂ -), etc.; and thiaxo C ₃ alkylene, including 2-thia- 3-oxotrimethylene (-C(O)SCH ₂ -), 3-thia-2-oxotrimethylene (-SC(O)CH ₂ -), and the like.

"Leaving group" has the usual meaning associated with it in synthetic organic chemistry, that is, an atom or group that can be substituted under alkylation conditions, including halogen, hydroxyl, alkylsulfonyloxy (such as methylsulfonyl oxy, ethanesulfonyloxy, etc.), arylsulfonyloxy (such as benzenesulfonyloxy and p-toluenesulfonyloxy, thienyloxy), dihalophosphonyloxy, tetrahalophosphoryl Acyloxy, etc.

"Optional" or "optionally" means that the event or condition described thereafter can or cannot occur, and that the description includes instances where the event or condition occurs and instances where it does not. For example, the term "optionally substituted with one or more groups" means that the specified group may or may not be substituted such that it falls within the scope of the invention.

"Pharmaceutically acceptable N-oxide" means a compound defined below which is pharmaceutically acceptable and possesses the desired pharmacological activity, wherein the nitrogen atom is in an oxidized state. N-oxides of compounds of formula I can be prepared by methods known to those skilled in the art.

"Oxyalkylene" means that in an alkylene group as defined above, one of the specified carbon atoms is replaced by a carbonyl (C=O), such as oxo C ₃ alkylene, including 3-oxo Trimethylene (-C(O)CH ₂ CH ₂ -) etc.

The "pathology" of a disease refers to the basic nature, etiology and development of the disease, as well as the structural and functional changes that occur during the pathogenesis.

"Pharmaceutically acceptable" refers to those that can be used to prepare pharmaceutical compositions, are generally safe, non-toxic, and have no biological or other side effects, including acceptable for veterinary and human medicine.

"Pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt as defined above which possesses the desired pharmacological activity. Such salts include combinations with inorganic acids (such as hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, etc.) or organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, p-chlorobenzenesulfonic acid, cinnamic acid, Citric acid, cyclopentanepropionic acid, 1,2-ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, caproic acid, heptanoic acid, ortho ( 4-Hydroxybenzoyl)benzoic acid, 2-hydroxyethanesulfonic acid, hydroxynaphthoic acid, lactic acid, laurylsulfonic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methanoic acid Bicyclo[2.2.2]oct-2-ene-1-carboxylic acid, 4,4′-methylene bis(3-hydroxy-2-ene-1-carboxylic acid), hexadienedioic acid, 2- Naphthalenesulfonic acid, oxalic acid, 3-phenylpropionic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, crotonic acid, tartaric acid, tert-butylacetic acid, p-toluenesulfonic acid, trimethylacetic acid, etc.) acid addition salts.

Pharmaceutically acceptable salts also include addition salts with bases which may be formed when acidic protons present are capable of reacting with inorganic or organic bases. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, trimethylamine, and the like.

"Phenylene" refers to a divalent aryl group -C ₆ H ₄ -, including 1,4-phenylene, 1,3-phenylene and the like.

"Pharmaceutically acceptable prodrug derivative" means a pharmaceutically acceptable derivative of the compound of formula I as defined above which is converted in vivo into the corresponding non-derivative of the compound of formula I form. _Such prodrugs include pyridyl groups with N _- acylation (ie, N(P) _C5H9- ), N-acylated azaalkylene groups (ie, -N(P) _CH2CH2- ), , N-acylated amino group (ie -NH ₂ (P)), N-acylated amidino group (ie -C(NP)NHP, -C(NH)NHP or -C(NP)NH ₂ ), N - acylated guanidine (i.e. -NHC(NP)NHP, -NHC(NH)NHP or -NHC(NP)NH ₂ ), wherein P is selected from -C(O)R ¹⁰ (wherein R ¹⁰ may be C _{1 -10} alkoxy or cis-2-C _1-10 alkanoyloxyphenyl vinyl), 3-C _1-10 alkanoyloxybutyryl, R ¹¹ -X ²⁸ - (wherein R ¹¹ is carboxyl , and X ²⁸ is C _1-10 alkylene) or -C(O)OCH(R ¹² )OC(O)R ¹³ (wherein R ¹² is hydrogen, C _1-10 alkyl or C _3-10 cycloalkane group, and R ¹³ is C _1-10 alkyl).

"Protecting group" has the usual meaning associated with it in synthetic organic chemistry, that is, a selective occupation of an active site in a multifunctional compound so that chemical reactions can be selectively performed on another unprotected active site. A group that is carried out and can be easily removed after the selective reaction is complete.

"Protecting reagent" refers to a reagent capable of reacting with a multifunctional compound to generate a protecting group at the active site.

A "protected derivative" of a compound or group refers to a derivative of a compound or group in which the active site is occupied by a protecting group. Protected derivatives of the compounds of formula I are themselves inhibitors of tryptase activity and are useful in the preparation of other compounds of formula I. Suitable protecting groups for reactive nitrogen atoms include t-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protecting groups (see for example T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981).

The "symptomology" of a disease refers to any morbid phenomenon or deviation from normal structure, function, or sensation experienced by a patient, and the indication, production, and signs provided by the disease.

"Therapeutically effective amount" refers to the amount needed to be administered to animals when treating a disease, which is sufficient to effectively treat the disease.

"Treatment" of a disease includes taking measures in advance for animals that have no symptoms of the disease to prevent the disease, inhibit the disease (that is, control the development of the disease) or alleviate the disease (that is, the decline of the disease).

The term "q.s." refers to the quantity needed to add sufficient to achieve the stated function (eg, to bring the solution to the desired volume, ie 100%).

The compounds of formula I and the intermediates and reaction materials used to prepare them are named according to the IUPAC nomenclature, wherein the characteristic groups used as basic groups are cited in the following descending order of priority: acids, esters, amides and amidines. Moreover, when a divalent group is described in writing in this application, the ordinal number of the prefix represents the attachment position of the group. Likewise, as far as the divalent group represented by the structural formula is concerned, the representation of the structural formula represents the linking position. For example, wherein R ¹ is 4-amidinobenzyl, X ¹ and X ⁹ are each -NHC(O)-, X ² is 1,4-piperazinylene, X ⁷ is -C(O)O-, X ⁸ is 4,1-piperidinylene, and R ² is R ⁹ -X ²¹ (wherein R ⁹ is piperidin-4-yl, and X ²¹ is 3-azatrimethylene) for the compound of formula I The following structural formula represents:

When X ³ and X ⁷ are each -C(O)O-, X ⁴ and X ⁶ are each a covalent bond, X ⁵ is cis-1,5-cyclooctylene, and P is hydrogen, the The compound is named: cis-1,5-cyclooctylene-4-(4-amidinobenzylcarbamoyl)-1-piperazinecarboxylate-4-(2-piperidin-4-ylamino Ethylcarbamoyl)-1-piperidinecarboxylate;

When X ³ and X ⁷ are each -C(O)O-, X ⁴ and X ⁶ are each a covalent bond, X ⁵ is cis-1,5-cyclooctylene, and P is 3-carboxypropane When the acyl group is present, the compound is named: 3-{4-[2-(1-{cis-5-[4-(4-amidinobenzylcarbamoyl)piperazin-1-ylcarbonyloxy]cyclo Octyloxycarbonyl}piperidin-4-ylcarbonylamino)ethylamino]piperidin-1-ylcarbonyl}propionic acid;

When X ³ is -C(O)-, X ⁷ is -C(O)O-, X ⁴ is a covalent bond, X ⁶ is methylene, X ⁵ is phenylene, and P is hydrogen, The compound is named: 4-[4-(4-amidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]benzyl-4-(2-piperidin-4-ylaminoethylcarbamoyl )-1-piperidinecarboxylate;

When each of X ³ and X ⁷ is -C(O)O-, and X ⁴ -X ⁵ -X ⁶ is 1,4-tetramethylene (ie -CH ₂ CH ₂ CH ₂ CH ₂ -), the The compounds were named: 1,4-tetramethylene-4-amidinobenzylcarbamoyl-1-piperazinecarboxylate; and

When each of X ³ and X ⁷ is -C(O)-, and X ⁴ -X ⁵ -X ⁶ is 1,4-tetramethylene (ie -CH ₂ CH ₂ CH ₂ CH ₂ -), the compound Named as: N-4-amidinobenzyl-4-{5-[4-(2-piperidin-4-ylaminoethylcarbamoyl)piperidin-1-ylcarbonyl]pentanoyl}-1 - piperazine carboxamide.

Preferred embodiments of the present invention:

Although the broadest definition of the invention is set forth in the Summary of the Invention, certain compounds of formula I are preferred. For example, a preferred compound of formula I is wherein X ⁵ is cis-1,5-cyclooctylene, X ⁴ and X ⁶ are each a covalent bond, and X ⁴ -X ⁵ -X ⁶ together are C _{4- 8} alkylene or X ⁵ is phenylene, X ⁴ and X ⁶ are C _0-1 alkylene; X ¹ and X ⁹ are each independently a covalent bond, -C(O)-, -NHC(O )-, -C(O)NH, -N(CH ₃ )C(O)- or -S(O) ₂ NH- (provided that X ¹ and X ⁹ are not all covalent bonds); X ³ and X ⁷ is independently -C(O)- or -C(O)O-; X ² and X ⁸ are independently -X ¹⁰ -X ¹¹ - (wherein X ¹⁰ is a covalent bond or methylene, and X ¹¹ is 4,1-piperidinyl or 1,4-piperazinyl); R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ , wherein R ⁴ is amidino, guanidino or methylamino, X ¹² is -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ is 1,4-phenylene or 1,4-piperidinylene, X ¹⁴ is C _n14 alkylene, and X ¹⁶ is C _n16 Alkylene, wherein n14 and n16=0, 1 or 2, R ⁵ is piperidin-4-yl, and X ¹³ is C _2-3 alkylene; and wherein R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, R ⁸ is amino, amidino, guanidino, methylamino or 1-iminoethyl, X ²⁰ is -X ²² -X ²³ -X ²⁴ , wherein X ²³ is trans-1, 4-cyclohexylene, 1,4-phenylene, 4,1-pyridinyl, 1,4-piperidinyl, X ²² is C _n22 alkylene, and X ²⁴ is C _n24 alkylene, Wherein n22 and n24=1 or 2, R ⁹ is benzimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-1-yl , 5-methylimidazol-1-yl, 1-methylpiperidin-4-yl, piperidin-4-yl, piperazin-1-yl, pyridin-3-yl, pyridin-4-yl, 1, 4,5,6-tetrahydropyrimidin-5-yl or 1,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl, and X ²¹ is C _1-6 alkylene, ω- Aza _C2-5 alkylene, 3-oxotrialkylene, ω-thia C2-4 alkylene, 3-oxo-2-azatrialkylene, 3-aza-2-oxo Trialkylene or -X ²⁵ -X ²⁶ -X ²⁷ -, where X ²⁶ is 1,4-phenylene, X ²⁵ is C _n25 alkylene, and X ²⁷ is C _n27 alkylene, where n25 and Compounds of formula I with n27=0 or 1 and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

A more preferred compound of formula I is wherein X ⁵ is cis-1,5-cyclooctylene, X ⁴ and X ⁶ are each a covalent bond or X ⁴ -X ⁵ -X ⁶ together are C _4-8 Alkylene; wherein X ¹ and X ⁹ are each independently a covalent bond, -C(O)-, -NHC(O)-, -C(O)NH or -S(O) ₂ NH- (provided : X ¹ and X ⁹ are not all covalent bonds); X ³ and X ⁷ are independently -C(O)- or -C(O)O-; X ² and X ⁸ are independently -X ¹⁰ -X ¹¹ -(where X ¹⁰ is a covalent bond or methylene, and X ¹¹ is 4,1-piperidinylene or 1,4-piperazinylene); R ¹ is R ⁴ -X ¹² -, wherein R ⁴ is amidino or guanidino, X ¹² is -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ is 1,4-phenylene or 1,4-piperidinyl, X ¹⁴ is C _n14 alkylene , and X ¹⁶ is C _n16 alkylene, wherein n14 and n16=0, 1 or 2; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, wherein R ⁸ is amino or methylamino, X ²⁰ is -X ²² -X ²³ -X ²⁴ , wherein X ²³ is trans-1-4-cyclohexylene or 1,4-phenylene, X ²² is C _n22 alkylene, and X ²⁴ is C _N24 alkylene, wherein n22 and n24=1 or 2, R ⁹ is imidazol-1-yl, imidazol-4-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, piper Pyridin-4-yl or pyridin-4-yl, and X ²¹ is a compound of formula I of C _1-5 alkylene or 3-azatrialkylene and pharmaceutically acceptable salts, N-oxides, Prodrug derivatives and protected derivatives thereof.

A particularly preferred compound of formula I is wherein X ⁵ is cis-1,5-cyclooctylene, and X ⁴ and X ⁶ are each a covalent bond; wherein X ¹ and X ⁹ are each independently -C( O)- or -NHC(O)-; wherein X ³ and X ⁷ are each -C(O)O-; X ² and X ⁸ are independently -X ¹⁰ -X ¹¹ - (wherein X ¹⁰ is a covalent bond or methylene, and X ¹¹ is 1,4-piperazinyl); R ¹ is R ⁴ -X ¹² -, wherein R ⁴ is amidino or guanidino, and X ¹² is -X ¹⁴ -X ¹⁵ -X ¹⁶ -, wherein X ¹⁵ is 1,4-phenylene, X ¹⁴ is a covalent bond, and X ¹⁶ is methylene; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ , wherein R ⁸ is amino, X ²⁰ is -X ²² -X ²³ -X ²⁴ , wherein X ²³ is trans-1,4-cyclohexylene, X ²² is a covalent bond, and X ²⁴ is methylene, R ⁹ is piper Pyridin-4-yl, and X ²¹ is ethylene or trimethylene compound of formula I and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

A particularly preferred compound of formula I is wherein X ⁴ -X ⁵ -X ⁶ together represent a C _4-8 alkylene group; X ¹ and X ⁹ are each independently -C(O)- or -NHC(O)-; X ³ and X ⁷ are independently -C(O)- or -C(O)O-; X ² and X ⁸ are independently -X ¹⁰ -X ¹¹ - (wherein X ¹⁰ is a covalent bond, and X ¹¹ is 1,4-piperazinyl); R ¹ is R ⁴ -X ¹² -, wherein R ⁴ is amidino or guanidino, and X ¹² is -X ¹⁴ -X ¹⁵ -X16-, wherein X ¹⁵ is 1 , 4-phenylene, X ¹⁴ is a covalent bond, and X ¹⁶ is methylene; and R ² is R ⁸ -X ²⁰ -, wherein R ⁸ is amidino or guanidino, and X ²⁰ is -X ²² -X ²³ -X ²⁴ , wherein X ²³ is 1,4-phenylene, X ²² is a covalent bond, and X ²⁴ is a methylene compound of formula I and its pharmaceutically acceptable salt, N-oxidation Drugs, prodrug derivatives and protected derivatives thereof. The most preferred compounds of formula I are the following compounds:

4-guanidinobenzyl-4-{7-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]-heptanoyl}-1-piperazinecarboxamide,

4-guanidinobenzyl-4-{8-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]-octanoyl}-1-piperazinecarboxamide,

4-guanidinobenzyl-4-{9-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]-nonanoyl}-1-piperazinecarboxamide,

4-amidinobenzyl-4-{7-[4-(4-amidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]-heptanoyl}-1-piperazinecarboxamide,

cis-1,5-cyclooctylene-4-(4-amidinobenzylcarbamoyl)-1-piperazinecarboxylate-4-(2-piperidin-4-ylethylcarbamoyl )-1-piperazine carboxylate,

1,5-pentamethylene-bis[4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate],

cis-1,5-Cyclooctylene-4-(4-amidinobenzylcarbamoyl)1-piperazinecarboxylate-4-(2-piperidin-4-ylethylcarbamoyl) -1-piperazine carboxylate,

cis-1,5-cyclooctylene-trans-4-(4-aminocyclohexylmethylcarbamoyl)-1-piperazinecarbamate-4-(4-guanidinobenzylcarbamoyl )-1-piperazine carboxylate,

cis-1,5-Cyclooctylene-4-(4-amidinophenylacetyl)-1-piperazinecarboxylate-4-(4-piperidin-4-ylbutyryl)-1-piper Zinc carboxylate,

1,4-Tetramethylene-bis[4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate],

cis-1,5-cyclooctylene-4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate-4-(2-piperidin-4-ylethylcarbamoyl )-1-piperazine carboxylate,

4-guanidinobenzyl-4-{6-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]-hexanoyl}-1-piperazinecarboxamide,

cis-1,5-Cyclooctylene-4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate-4-(4-piperidin-4-ylbutyryl)-1 -piperazine carboxylate,

cis-1,5-cyclooctylene-4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate-4-(2-piperidin-4-ylethylcarbamoylbutyryl )-1-piperazine carboxylate,

cis-1,5-cyclooctylene-4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate-4-(4-piperidin-4-ylbutyryl)-1-piper Zinc carboxylate,

4-guanidinobenzyl-4-{5-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]-pentanoyl}-1-piperazinecarboxamide,

3-oxa-1,5-pentamethylene-bis[4-(4-amidinophenylacetyl)piperazin-1-ylcarbonyl] and

cis-1,5-cyclooctylene-4-(4-amidinophenylacetyl)-1-piperazinecarboxylate-4-(2-piperidin-4-ylethylcarbamoyl)- 1-piperazine carboxylate

And pharmaceutically acceptable salts, N-oxides, drug prodrug derivatives and protected derivatives thereof. Pharmacology and Uses:

The compounds of the present invention are tryptase inhibitors. Such compounds of formula I are useful in the treatment of diseases, especially immune-mediated inflammation, in which tryptase activity is associated with the pathology and/or symptomology of the disease. For example, immune-mediated inflammation in which tryptase activity is associated with the pathology and/or symptomology of the disease includes asthma, allergic rhinitis, rheumatoid spondylitis, osteoarthritis, rheumatoid arthritis, rheumatoid arthritis , General arthritis, urticaria, angioedema, eczematous dermatitis, allergies, hyperproliferative skin diseases, gastric ulcers, inflammatory bowel disease, ocular conjunctivitis and adolescent conjunctivitis, inflammatory skin diseases, etc.

Suitable in vitro assays for measuring tryptase activity and compounds' inhibition thereof are known (eg, see Sturzebecher et al. (1992) Biol. Chem. Hoppe-Seyler 373:1025-1030). Typically, experiments will measure tryptase induced by hydrolysis of a polypeptide base substrate. See Example 33 below for details on the in vitro assay for assaying tryptase activity.

Suitable in vivo models of inflammation are known to those of ordinary skill in the art, for example in vivo models of asthma are known (see for example Larsen (1991) Experimental Models of Reversible Airway Obstruction. In West et al. edited by Scientific Foundations Raven Press, The Lung, New York Publishing). See Example 2 below for details on the in vitro model of asthma. In addition, inflammatory skin diseases (Walsh et al., (1995) Br.J.Pharmacol.114:1343-1350) and Armstrong et al., (1995) Prostaglandins 49:205-224), arthritis (Peacock et al., ( 1995) Cell Immunol.160:178-184 and Hourl et al., (1995) Curr.Opin.Rheumatol.7:201-205) and Gastroenterology (Anthony et al., (1995) Int.J.Exp.Pathol. 76:215-224 and Carter et al. (1995) Dig. Dis. Sci. 40:192-197) in vivo models are also known. See Example 34 below for details on the in vivo assay to measure asthmatic response. Pharmaceutical composition of the present invention:

In general, a compound of formula I may be administered in a therapeutically effective amount, either alone or in combination with another therapeutic agent, in a manner generally accepted in the art. A therapeutically effective amount can vary depending on the severity of the disease, the age and relative health of the patient, the potency of the compound being used, and other factors. For example, a therapeutically effective amount of a compound of formula I for the treatment of asthma may be in the range of 0.1 μg/kg body weight/day to 1 mg/kg body weight/day, typically 1 μg/kg body weight/day to 0.1 mg/kg body weight/day changes within the range. Thus, a therapeutically effective dose for an 80 kg asthmatic patient may be 10 μg/day to 10 mg/day, typically 0.1 mg/day to 10 mg/day.

In the treatment of asthma, other therapeutic agents that can be administered with the compound of formula I include beta-adrenergic agonists (such as albuterol, terbuterol, formoterol, fenoterol, prenaline, etc.), formazan Xanthines (such as caffeine, theophylline, aminophylline, theobromine, etc.), cromolyn (such as cromolyn, nedocromil, etc.) and corticosteroids (such as beclomethasone, triamcinolone, flurisolide, Semethasone, etc.). In general, one of ordinary skill in the art, relying on personal knowledge and the disclosure of this application, will be able to determine the therapeutically effective amount of a compound of formula I required to treat a given inflammation.

The compound of formula I can be administered in the form of a pharmaceutical composition in the following ways: oral, systemic administration (such as transdermal administration, intranasal administration or suppository administration) or parenteral administration (such as intramuscular injection, intravenous injection or subcutaneous injection). Compositions may be in the form of tablets, pills, capsules, semi-solids, powders, sustained release dosage forms, solutions, suspensions, elixirs, aerosols or other suitable forms of compositions and generally comprise a compound of formula I and at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic agents that facilitate administration and do not adversely affect the active ingredient. Such excipients may be solid, liquid, semi-solid or, in the case of aerosol compositions, excipients may be gaseous excipients generally available to those skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, maltose, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glyceryl monostearate, Sodium chloride, dry skim milk, etc. Liquid and semisolid excipients can be selected from water, ethanol, glycerol, propylene glycol and various oils, including petroleum, animal, vegetable and synthetic oils (eg peanut oil, soybean oil, mineral oil, castor oil, etc.). Preferred liquid carriers, especially for injections, include water, saline, aqueous dextrose and glycol.

Compressed gases may be used to disperse active ingredients in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, nitrogen oxide, and the like. Other suitable pharmaceutical carriers and their formulations are described in A.R. Alfonso, Remington's Pharmaceutical Sciences 1985, 17th ed., Easton, Pa.: Mack Publishing Company.

The amount of the compound of formula I used in the composition can vary widely depending on the type of formulation, size of the unit dose, type of excipients and other factors known to those skilled in the pharmaceutical art. In general, compositions of compounds of formula I for use in the treatment of asthma will contain 0.01% to 10% by weight, preferably 0.3% to 1% by weight of active ingredient, the rest being excipients. Preferably, the pharmaceutical composition is administered in a single dose for continuous treatment or randomly when relief of symptoms is particularly desired. Representative pharmaceutical formulations containing compounds of formula I are described in Example 34. Chemical:

The compound of the present invention is composed of five different small units (namely R ¹ -, -X ² -, -X ⁴ -X ⁵ -X ⁶ -, -X ⁸ - and R ² -), among which carbonyl, Formyloxy, amide, sulfonamide, carbamate, or urea linking groups (i.e. -C(O)-, -C(O)O-, -OC(O)-, -C(O)N( R ³ )-, -N(R ³ )C(O)-, -S(O) ₂ N(R ³ )-, -N(R ³ )S(O) ₂ -, -OC(O)N( R ³ )-, -N(R ³ )C(O)O-, -N(R ³ )C(O)N(R ³ )- or -OC(O)O-) linkage. Methods for forming such linking groups are known and suitable reagents are readily available (see for example March et al., Advanced Organic Chemistry, 4th Ed. (Wiley 1992); Larock, Comprehensive Organic Transformations (VCH 1989); and Furniss et al. people, Vogel's Textbook of Practical Organic Chemistry, 5th Ed.. (Longman 1989).

Small units comprising compounds of formula I can be assembled individually or into assemblies of larger small units. The following schemes are representative of methods for preparing compounds of formula I. It should be understood that compounds of formula I may be prepared by other similar methods.

Where X ⁸ is 1,4-piperazinylene or 1,4-piperidinylene, and X ⁹ is -C(O)-, -OC(O)- or -N(R ³ )C(O) - or a compound of formula I wherein X ⁸ is C _1-8 alkylene, and X ⁹ is -C(O)N(R ³ )-, -OC(O)N(R ³ )- or -N(R ³ ) The formula I compound of C(O)N(R ³ )- can be obtained by making the following formula I compound or its protected derivative 1 reacting with a compound of formula R ² -Y ⁹ -C(O)L or a protected derivative thereof (wherein L is a leaving group, Y ⁹ is a bond, -O- or -N( R ³ )-, Y ⁸ is piperazin-1-yl, piperidin-4-yl or HN(R ³ )-C _1-8 alkyl, each of R ¹ , R ² , R ³ , X ¹ , X ² , ^X3 , ^X4 , ^X5 , ^X6 and ^X7 are as defined in the Summary of the Invention), followed by (if necessary) deprotection. In addition, wherein X ⁸ is 1,4-piperazinylene or 1,4-piperidinylene, and X ⁹ is a compound of formula I of -NHC(O)- or wherein X ⁸ is C _1-8 alkylene , and X ⁹ is -NHC(O)N(R ³ )-The compound of formula I can be obtained by combining a suitable compound of formula I or its protected derivative with an isocyanate of formula R ² -NC(O) or Its protected derivatives were reacted and then (if necessary) deprotected to prepare (see Example 8 below for details).

Similarly, wherein X ² is 1,4-piperazinylene or 1,4-piperidinylene, and X ¹ is -C(O)-, -OC(O)- or -N(R ³ )C (O)- compound of formula I or wherein X ² is C _1-8 alkylene, and X ¹ is -C(O)N(R ³ )-, -OC(O)N(R ³ )- or - The formula I compound of N(R ³ )C(O)N(R ³ )- can be obtained by making the compound of the following formula 2 or its protected derivatives 2 reacting with a compound of formula R ¹ -Y ¹ -C(O)L or a protected derivative thereof (wherein L is a leaving group, Y ¹ is a bond, -O- or -N( R ³ )-, Y ² is piperazin-1-yl, piperidin-4-yl or HN(R ³ )-C _1-8 alkyl, each of R ¹ , R ² , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁹ are as defined in the Summary of the Invention), followed by (if necessary) deprotection. In addition, wherein X ² is 1,4-piperazinylene or 1,4-piperidinylene, and X ¹ is a compound of formula I of -NHC(O)- or wherein X ² is C _1-8 alkylene , and X ¹ is -NHC(O)N(R ³ )-The compound of formula I can be obtained by combining a compound of formula 2 or a protected derivative thereof with an isocyanate of formula R ¹ -NC(O) or Its protected derivatives were reacted and then (if necessary) deprotected to prepare (see Example 14(b) below for details).

3与2当量或更多当量的一种式R¹-Y¹-C(O)L的化合物或其受保护的衍生物反应(其中L为一种离去基团，Y¹为一键、-O-或-N(R³)-,Y²和Y⁸独立地为哌嗪-1-基、哌啶-4-基或HN(R³)-C_1-8烷基，每个R¹、R²、R³、X³、X⁴、X⁵、X⁶和X⁷如发明概述中所定义)、然后(必要时)脱保护来制备。另外，其中R¹=R²,X²和/或X⁸为1,4-亚哌嗪基或1,4-亚哌啶基，X¹为-NHC(O)-和/或X⁹为-NHC(O)-的式Ⅰ化合物和/或其中X²和/或X⁸为C_1-8亚烷基，而X¹为-NHC(O)N(R³)-和/或X⁹为-NHC(O)N(R³)-的式Ⅰ化合物可以通过使下式3的化合物或其受保护的衍生物与2当量或更多当量的一种式R^1-NC(O)的异氰酸酯或其受保护的衍生物反应，然后(必要时)脱保护来制备(细节请参阅下面的实施例10)。Wherein R ¹ =R ² , X ² and/or X ⁸ are 1,4-piperazinylene or 1,4-piperidinylene, X ¹ is -C(O)-, -OC(O)- or -N(R ³ )C(O)-, and X ⁹ is a compound of formula I of -C(O)-, -OC(O)- or -N(R ³ )C(O)- and/or wherein X ² and/or X ⁸ is C _1-8 alkylene, X ¹ is -C(O)N(R ³ )-, -OC(O)N(R ³ )- or -N(R ³ )C( O)N(R ³ )-, and X ⁹ is -C(O)N(R ³ )-, -OC(O)N(R ³ )- or -N(R ³ )C(O)N(R ³ )-The compound of formula I can be obtained by making the compound of the following formula 3 or its protected derivatives:

3 react with 2 or more equivalents of a compound of formula R ¹ -Y ¹ -C(O)L or a protected derivative thereof (wherein L is a leaving group, Y ¹ is a bond, -O- or -N(R ³ )-, Y ² and Y ⁸ are independently piperazin-1-yl, piperidin-4-yl or HN(R ³ )-C _1-8 alkyl, each R ¹ , R ² , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ are as defined in the Summary of the Invention), followed by (if necessary) deprotection. In addition, wherein R ¹ =R ² , X ² and/or X ⁸ are 1,4-piperazinylene or 1,4-piperidinylene, X ¹ is -NHC(O)- and/or X ⁹ is -NHC(O)-compound of formula I and/or wherein X ² and/or X ⁸ are C _1-8 alkylene, and X ¹ is -NHC(O)N(R ³ )- and/or X ⁹ The formula I compound of -NHC(O)N(R ³ )- can be obtained by making the compound of the following formula 3 or its protected derivatives with 2 equivalents or more equivalents of a kind of formula R ^1- NC(O) Isocyanates or their protected derivatives are reacted and then (if necessary) deprotected to prepare (see Example 10 below for details).

4其中L为一种离去基团，Y¹为一键、-O-或-N(R³)-，而每个R¹、R²、R³、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸和X⁹如发明概述中所定义(细节请参阅下面的实施例20)。The compound of formula I wherein X ¹ is -N(R ³ )C(O)-, -N(R ³ )C(O)O- or -N(R ³ )C(O)N(R ³ )- can be Prepared by reacting an amine of formula R ¹ -N(R ³ )H or a protected derivative thereof with a compound of formula 4 or a protected derivative thereof:

4 wherein L is a leaving group, Y ¹ is a bond, -O- or -N(R ³ )-, and each of R ¹ , R ² , R ³ , X ² , X ³ , X ⁴ , ^X5 , ^X6 , ^X7 , ^X8 and ^X9 are as defined in the Summary of the Invention (see Example 20 below for details).

5其中L为一种离去基团，Y³为-键、-O-或-N(R³)-,Y²为哌嗪-1-基、哌啶-4-基或HN(R3)-C_1-8烷基，而每个R¹、R²、R³、X¹、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸和X⁹如发明概述中所定义(细节请参阅下面的Wherein X ² is 1,4-piperazinylene or 4,1-piperidinylene, and X ³ is -C(O)-, -OC(O)- or -C(O)N(R ³ ) - the compound of formula I or wherein X ² is C _1-8 alkylene, and X ³ is -N(R ³ )C(O)-, -N(R ³ )C(O)O- or -N( The formula I compound of R ³ )C(O)N(R ³ )- can be obtained by combining a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof with a compound of formula 5 or its The protected derivative is reacted to prepare:

5 where L is a leaving group, Y ³ is - bond, -O- or -N(R ³ )-, Y ² is piperazin-1-yl, piperidin-4-yl or HN(R3) -C _1-8 alkyl, and each R ¹ , R ² , R ³ , X ^{1 , X 2 ,} X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁹ are as in the summary of the invention defined (see below for details

Example 31).

6其中L为一种离去基团，Y³和Y⁷独立地为一键、-O-或-N(R³)、Y²为哌嗪-1-基、哌啶-4-基、HN(R³)-C_1-8烷基或HN(R³)-C_1-8杂烷基，而每个R¹、X¹、X⁴、X⁵和X⁶如发明概述中所定义(细节请参阅下面的实施例32)。Wherein X ² and X ⁸ are each 1,4-piperazinylene or 4,1-piperidinylene, and X ³ and X ⁷ are independently -C(O)-, -OC(O)- or - C(O)N(R ³ )- compound of formula I or wherein X ² and X ⁸ are each C _1-8 alkylene or C _1-8 heteroalkylene, and X ³ and X ⁷ are independently - The formula I compound of N(R ³ )C(O)-, -N(R ³ )C(O)O- or -N(R ³ )C(O)N(R ³ )- can be obtained by making 2 equivalents or Prepared by reacting more equivalents of a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof with a compound of formula 6 or a protected derivative thereof:

6 wherein L is a leaving group, Y ³ and Y ⁷ are independently a bond, -O- or -N(R ³ ), Y ² is piperazin-1-yl, piperidin-4-yl, HN(R ³ )-C _1-8 alkyl or HN(R ³ )-C _1-8 heteroalkyl, and each of R ¹ , X ¹ , X ⁴ , X ⁵ and X ⁶ is as defined in the Summary of the Invention (See Example 32 below for details).

The above-mentioned acylation reaction can be carried out by making an activated ester (such as a kind of acid chloride derivative) and a kind of suitable nucleophilic reagent in a kind of suitable organic base (such as N,N-diisopropylethylamine (DIEA ), N-methylmorpholine, etc., preferably DIEA) and a suitable solvent (such as N,N-dimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, etc.), at 20-30 ° C , typically at about 23°C for a few minutes to 24 hours to complete. Alternatively, the acylation reaction can be carried out by reacting a suitable carboxylic acid and a nucleophile in a suitable coupling agent (for example, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, etc.) and In the presence of a suitable solvent (such as DMF, etc.), the reaction is carried out at 20-30°C, typically about 23°C, for several hours to several days. The reactions and conditions under which the above-described reactions are used to prepare the compounds of formula I are descriptive, and one of ordinary skill in the art will recognize that other reaction conditions and different reaction starting materials can be used to prepare the compounds of the present invention.

Deprotection can be carried out by any means which removes the protecting group and affords the desired product in reasonable yield. A detailed description of techniques for creating and removing protecting groups can be found in T.W. greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.

In general, the starting materials and intermediates used in the preparation of compounds of formula I are commercially available or can be easily prepared by those of ordinary skill in the art. For example, intermediates useful in the preparation of compounds of formula I may be conveniently prepared by the acylation reactions described above. When multiple reaction sites are present in a reaction starting material, it is necessary to use appropriate protection chemistry to direct the reaction to the desired reaction site.

A convenient starting material for the preparation of compounds of formula I wherein X ^{and X} are each -C(O)O- is a compound of formula 7 below: 7 wherein each of X ⁴ , X ⁵ and X ⁶ is as defined in the Summary of the Invention. For example, the compound of formula 6 wherein L is chlorine can be obtained by making the corresponding diol (such as cis-1,5-cyclooctanediol, trans-1,4-cyclohexylenedimethanol, 1,4-phenylene dimethanol, etc.) with triphosgene (for details, please refer to Example 5 below).

Intermediates which are useful in the preparation of compounds of formula I and which contain an amidine group can be prepared by treating the corresponding nitrile with hydrogen chloride in ethanol followed by reaction with ammonia. Other methods for preparing compounds of formula I:

Compounds of formula I wherein ^R4 is guanidino may be prepared by reacting a corresponding compound of formula I wherein ^R4 is amino with cyanamide. The reaction can be accomplished by reacting the amine with hydrogen chloride and then reacting the purified product with excess cyanamide at about 65°C for about 2 hours (see Example 15 below for details).

A compound of formula I in the form of a pharmaceutically acceptable acid addition salt is prepared by reacting a compound of formula I in free base form with a pharmaceutically acceptable inorganic or organic acid. Alternatively, pharmaceutically acceptable base addition salts of compounds of formula I are prepared by reacting the free acid form of a compound of formula I with a pharmaceutically acceptable inorganic or organic base. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of compounds of formula I are set forth in the definitions section of this application. Alternatively, the compounds of formula I may be prepared in the form of salts using salts of the starting materials or intermediates.

Compounds of formula I in free acid or free base form may be prepared from the corresponding base or acid addition salt forms. For example, a compound of formula I in the form of an acid addition salt can be converted to the corresponding free base by treating it with a suitable base (such as ammonium hydroxide solution, sodium hydroxide solution, etc.) etc.) treatment of a compound of formula I in base addition salt form converts it to the corresponding free acid.

N-oxides of compounds of formula I can be prepared by methods known to those of ordinary skill in the art. For example, by using an oxidizing agent (such as trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, m-chloroperoxybenzoic acid, etc.) in a suitable inert organic solvent (such as a halogenated hydrocarbon such as di The N-oxides can be prepared by treating the unoxidized form of a compound of formula I in (chloromethane) at about 0°C. Alternatively, an N-oxide of a compound of formula I can be prepared from an N-oxide of a suitable reaction starting material.

By using a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide, etc.) in a suitable inert organic solvent (such as acetonitrile, ethanol, The compound of formula I in unoxidized form can be prepared from the N-oxide of the compound of formula I by treating in aqueous solution of dioxane, etc.) at 0-80°C.

Prodrug derivatives of compounds of formula I may be prepared by methods known to those of ordinary skill in the art (see, eg, Saulnier et al., (1994) Bioorganic and Medicinal Chemistry Letters. 4:1985 for details). For example, suitable prodrugs can be obtained by reacting an underivatized compound of formula I with a suitable carbamoylating agent (for example, 1,1-acyloxyalkyl carbonyl chloride, p-nitrophenyl carbonate) to prepare.

Protected derivatives of compounds of formula I can be prepared by methods known to those of ordinary skill in the art. A detailed description of techniques for creating and removing protecting groups can be found in T.W. greene, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981.

In summary, one aspect of the present invention is a process for the preparation of compounds of formula I, the process comprising:

1与一种式R²-Y⁹-C(O)L的化合物或其受保护的衍生物反应(其中L为一种离去基团，Y⁹为一键、-O-或-N(R³)-,Y⁸为哌嗪-1-基、哌啶-4-基或HN(R³)-C_1-8烷基，每个R¹、R²、R³、X¹、X²、X³、X⁴、X⁵、X⁶和X⁷如发明概述中所定义)、然后(必要时)脱保护，制得其中X⁸为1,4-亚哌嗪基或1,4-亚哌啶基，而X⁹为-C(O)-、-OC(O)-或-N(R³)C(O)-的式Ⅰ化合物或者其中X⁸为C_1-8亚烷基，而X⁹为-C(O)N(R³)-、-OC(O)N(R³)-或-NHC(O)N(R³)-的式Ⅰ化合物；(a) a compound of formula 1 or a protected derivative thereof:

1 reacting with a compound of formula R ² -Y ⁹ -C(O)L or a protected derivative thereof (wherein L is a leaving group, Y ⁹ is a bond, -O- or -N( R ³ )-, Y ⁸ is piperazin-1-yl, piperidin-4-yl or HN(R ³ )-C _1-8 alkyl, each of R ¹ , R ² , R ³ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ are as defined in the Summary of the Invention), followed by (if necessary) deprotection to obtain wherein X ⁸ is 1,4-piperazinylene or 1,4 -Piperidinylene, and X ⁹ is a compound of formula I of -C(O)-, -OC(O)- or -N(R ³ )C(O)- or wherein X ⁸ is C _1-8 alkylene group, and X ⁹ is a compound of formula I of -C(O)N(R ³ )-, -OC(O)N(R ³ )- or -NHC(O)N(R ³ )-;

(b) reacting a compound of formula 1 or a protected derivative thereof with an isocyanate of formula R ² -NC(O) or a protected derivative thereof, followed by (if necessary) deprotection, to obtain wherein X ⁸ is 1,4-piperazinyl or 1,4-piperidinyl, and X ⁹ is a compound of formula I of -NHC (O)- or wherein X ⁸ is C _1-8 alkylene, and X ⁹ A compound of formula I which is -NHC(O)N(R ³ )-;

(c) make a compound of the following formula 2 or its protected derivatives 2 reacting with a compound of formula R ¹ -Y ¹ -C(O)L or a protected derivative thereof (wherein L is a leaving group, Y ¹ is a bond, -O- or -N( R ³ )-, Y ² is piperazin-1-yl, piperidin-4-yl or HN(R ³ )-C _1-8 alkyl, and each R ¹ , R ² , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁹ are as defined in the Summary of the Invention), followed by (if necessary) deprotection to obtain wherein X ² is 1,4-piperazinylene or 1, 4-piperidinylene, and X ¹ is a compound of formula I of -C(O)-, -OC(O)- or -N(R ³ )C(O)- or wherein X ² is C _1-8 Alkyl, and X ¹ is a compound of formula I of -C(O)N(R ³ )-, -OC(O)N(R ³ )- or -NHC(O)N(R ³ )-;

(d) a compound of the following formula 3 or a protected derivative thereof: 3 react with 2 or more equivalents of a compound of formula R ¹ -Y ¹ -C(O)L or a protected derivative thereof (wherein L is a leaving group, Y ¹ is a bond, -O- or -N(R ³ )-, Y ² and Y ⁸ are independently piperazin-1-yl, piperidin-4-yl or HN(R ³ )-C _1-8 alkyl, and each R ¹ , R ² , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ , as defined in the Summary of the Invention) react, followed (if necessary) by deprotection, to produce wherein R ¹ =R ² , X ² and/or X ⁸ are 1,4-piperazinylene or 1,4-piperidinylene, X ¹ is -C(O)-, -OC(O)-, -N(R ³ )C (O)- and/or X ⁹ are -C(O)-, -OC(O)-, -N(R ³ )C(O)- compounds of formula I and/or wherein X ² and/or X ⁸ is C _1-8 alkylene, X ¹ is -C(O)N(R ³ )-, -OC(O)N(R ³ )- or -N(R ³ )C(O)N(R ³ )-, and X ⁹ is the formula I of -C(O)N(R ³ )-, -OC(O)N(R ³ )- or -N(R ³ )C(O)N(R ³ )- compound;

(f) reacting a compound of formula 3 or a protected derivative thereof with 2 equivalents or more of an isocyanate of formula R ¹ -NC(O) or a protected derivative thereof, and then (if necessary) removing Protection, wherein R ¹ = R ² , X ² and/or X ⁸ are 1,4-piperazinyl or 1,4-piperidinyl, X ¹ is -NHC(O)- and/or X ⁹ is a compound of formula I of -NHC(O)- and/or wherein X ² and/or X ⁸ are C _1-8 alkylene, and X ¹ is -NHC(O)N(R ³ )- and/or X ⁹ is a compound of formula I of -NHC(O)N(R ³ )-;

4(其中L为一种离去基团，Y¹为一键、-O-或-N(R³)-，而每个R¹、R²、R³、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸和X⁹如发明概述中所定义)反应，然后(必要时)脱保护，制得其中X¹为-N(R³)C(O)-、-N(R³)C(O)O-或-N(R³)C(O)N(R³)-的式Ⅰ化合物；(g) combining an amine of formula R ¹ -N(R ³ )H or a protected derivative thereof with a compound of formula 4 or a protected derivative thereof:

4 (where L is a leaving group, Y ¹ is a bond, -O- or -N(R ³ )-, and each R ¹ , R ² , R ³ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁹ as defined in the Summary of the Invention) reaction, followed by (if necessary) deprotection, to obtain wherein X ¹ is -N(R ³ )C(O)-, -N(R ³ )C(O)O- or -N(R ³ )C(O)N(R ³ )- compounds of formula I;

5(其中L为一种离去基团，Y³为一键、-O-或-N(R³)-,Y²为哌嗪-1-基、哌啶-4-基或HN(R³)-C_1-8烷基，而每个R¹、R²、R³、X¹、X²、X³、X⁴、X⁵、X⁶、X⁷、X⁸和X⁵如发明概述中所定义)反应，然后(必要时)脱保护，制得其中X²为1,4-亚哌嗪基或4,1-亚哌啶基，而X³为-C(O)-、-C(O)O-或C(O)N(R³)的式Ⅰ化合物，或其中X²是C_1-8亚烷基，X³是-N(R³)C(O)-、-N(R³)C(O)O-或-N(R³)C(O)N(R³)-的式Ⅰ化合物；(h) a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof and a compound of the following formula 5 or a protected derivative thereof:

5 (where L is a leaving group, Y ³ is a bond, -O- or -N(R ³ )-, Y ² is piperazin-1-yl, piperidin-4-yl or HN(R ³ )-C _1-8 alkyl, and each R ¹ , R ² , R ³ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁵ are as invented as defined in the overview), followed by (if necessary) deprotection to obtain wherein X ² is 1,4-piperazinylene or 4,1-piperidinylene and X ³ is -C(O)-, -C(O)O- or C(O)N(R ³ ) formula I compound, or wherein X ² is C _1-8 alkylene, X ³ is -N(R ³ )C(O)-, -N(R ³ )C(O)O- or -N(R ³ )C(O)N(R ³ )- compounds of formula I;

(i) 2 equivalents or more of a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof and a compound of the following formula 6 or a protected derivative thereof: 6 (where L is a leaving group, Y ³ and Y ⁷ are independently a bond, -O- or -N(R ³ )-, Y ² is piperazin-1-yl, piperidine-4- group, HN(R ³ )-C _1-8 alkyl or HN(R ³ )-C _1-8 heteroalkyl, and each of R ¹ , X ¹ , X ⁴ , X ⁵ and X ⁶ is as described in the Summary of the Invention defined) reaction, followed by (if necessary) deprotection to obtain wherein X ² and X ⁸ are each 1,4-piperazinylene or 4,1-piperidinylene, and X ³ and X ⁷ are independently -C(O)-, -C(O)O- or -C(O)N(R ³ )- compound of formula I or wherein X ² and X ⁸ are each C _1-8 alkylene or C _{1- 8} Heteroalkylene, and X ³ and X ⁷ are each independently -N(R ³ )C(O)-, -N(R ³ )C(O)O- or -N(R ³ )C(O) )N(R ³ )- compound of formula I;

(j) selectively reacting a compound of formula I wherein R is an amino group with cyanamide to prepare a compound of formula I ^{wherein R} is a guanidine group;

(k) selectively converting a compound of formula I into a pharmaceutically acceptable salt thereof;

(1) selectively converting a compound of formula I in a salt form into a non-salt form;

(m) selectively converting an unoxidized form of a compound of formula I to its pharmaceutically acceptable N-oxide;

(n) selectively converting a compound of formula I in the form of an N-oxide into its unoxidized form;

(o) selectively converting a non-derivative form of a compound of formula I into a prodrug derivative thereof;

(p) selectively converting a prodrug derivative of a compound of formula I into its non-derivative form.

In the above method, said formula I means that each of R ¹ , R ² , R ³ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ , X ⁷ , X ⁸ and X ⁹ has Formula I with the broadest definition set forth in the Summary of the Invention, and these methods are particularly applicable to preferred embodiments of the invention.

Embodiment 14-tert-butyl aminobenzylcarbamate hydrochloride

Add 4-aminobenzylamine (50.34 g, 0.412 mol) dissolved in dichloromethane (200 ml) into a 1-liter 3-necked round-bottomed flask equipped with mechanical stirring, and cool the solution to 0 ° C with 30 Di-tert-butyl carbonate (89.9 g, 0.412 mol) dissolved in dichloromethane (200 ml) was added dropwise to the above solution within minutes, and the resulting suspension was stirred at 0° C. for 2 hours to obtain an almost uniform solution. The dichloromethane solution was then washed with aqueous sodium hydroxide (1.0M, 500ml) and water (500ml), and the organic layer was dried ( _MgSO4 ), filtered and concentrated in vacuo to give a yellow oil. The oil was dissolved in ether:methanol (2:1, 225ml), and the solution was cooled to 0°C, acidified with HCl in dioxane (4.0M, 115ml, 0.412mol), mixed with ether (200ml), A thick pale yellow precipitate was obtained, which was collected by filtration, washed with diethyl ether (500ml), and dried in vacuo to obtain tert-butyl 4-aminobenzylcarbamate (100.23g, 0.387mol, yield 94%) as light yellow solid. ¹ H-NMR (300MHz,DMSO-d ₆ ):10.40-10.20(br,s,3H),7.40(tr,1H),7.30(s,4H),4.10(d,2H),1.40(s,9H ).

Example 24-guanidinobenzylcarbamate tert-butyl ester hydrochloride

Aminonitrile (100g, 2.4mol) was added to a 500mL round-bottomed flask, heated to 60-65°C until completely molten, and the tert-butyl 4-aminobenzylcarbamate hydrochloride (25.3 g, 97.8mmol.) was directly added to the liquid aminonitrile to obtain a yellow solution. The solution was stirred at 60-65°C for 2 hours, water (100ml) was added, the water mixture was cooled to room temperature, washed with diethyl ether (1L), the organic phase was back extracted with water (2X100ml), and the combined aqueous layer was washed with diethyl ether (500ml) Wash, cool in an ice-water bath, and then basify with aqueous sodium hydroxide solution (10M, 100ml) to obtain an insoluble oil that slowly crystallizes, collect the crystals by filtration, wash with water, and dry in vacuo to obtain 4-guanidinobenzylcarbamate Tert-butyl ester (18.3 g, 69.24 mmol, 70.8% yield), a colorless crystalline solid. ¹ H-NMR (300MHz, DMSO-d ₆ ): 9.70(s,1H), 7.42(tr,1H), 7.40(s,4H), 7.25(d,2H), 7.15(d,2H), 4.10( d,2H),1.40(s,9H)

Example 34-Chlorocarbonyl-1-piperazinecarboxylic acid tert-butyl ester

Dissolve triphosgene (25g, 84.2mmol) in dichloromethane (200ml), the resulting solution was cooled to 0°C, and tert-butyl 1-piperazinecarboxylate (40g, 214.8mmol) and pyridine (35ml, 432.7mmol ) dissolved in dichloromethane (100ml) was added dropwise to the solution of triphosgene, the mixture was warmed to room temperature in 30 minutes, the mixture was quenched with aqueous hydrochloric acid (0.1N, 200ml), and the aqueous (50ml), dried the combined organic phases ( _MgSO4 ) and filtered, concentrated in vacuo to give tert-butyl 4-chlorocarbonyl-1-piperazinecarboxylate (45.6g, 71.6mmol, 85% yield) as yellow solid. ¹ H-NMR (300 MHz, CDCl ₃ ): 3.70 (m, 2H), 3.60 (m, 2H), 3.50 (m, 4H), 1.50 (s, 9H).

Example 44-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylic acid tert-butyl ester trifluoroacetate

The tert-butyl 4-guanidinobenzylcarbamate (41.77g, 0.158mol) prepared in Example 2 was treated with trifluoroacetic acid (TFA, 100ml) at room temperature for 30 minutes, and the resulting almost colorless liquid was Concentrate under vacuum, triturate the residue with diethyl ether (3×400ml) and dry in vacuo to obtain a colorless foam, dissolve the residue in methanol (200ml), add DIEA (55ml, 0.32mol, according to the estimated excess TFA to determine the quantity), the mixture was cooled to 0°C, and then tert-butyl 4-chlorocarbonyl-1-piperazinecarboxylate (39.3g, 0.158mol) dissolved in dichloromethane (120ml) prepared in Example 3 was added. ), and a certain amount of DIEA (30ml) was added, the reaction mixture was warmed to room temperature, stirred for 12 hours, and concentrated in vacuo to obtain an orange oil, which was mixed with water (200ml) to obtain a thick precipitate. The precipitate was recrystallized from acetonitrile and ether to obtain tert-butyl 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate trifluoroacetate (62.0g.0.126mol, yield 80% ), as a pale yellow solid. ¹ H-NMR(300MHz,DMSO-d ₆ ):10.15(s,1H),9.10(brs,2H),7.65(s,4H),7.40(tr,1H),7.25(dd,AB,4H), 4.25(d,2H),3.55(m,4H),3.10(s,4H);

Electron spray method LRMS: calculated value (C ₁₃ H ₂₀ N ₆ O): MH ⁺ : 277.4; MH ₂ ^{+2 /2} ; 139.2;

Measured values: MH ⁺ : 277.4; MH ₂ ⁺² /2 139.3;

Example 5 cis-1,5-cyclooctylene bis(chloroformate)

Dissolve cis-1,5-cyclooctanediol (20.2g, 0.14mol) in acetonitrile (250ml), add potassium carbonate (41.4g, 0.3mol) to the mixture to obtain a suspension, and dissolve under a nitrogen atmosphere The suspension was cooled to 0°C, phosgene (1.9M, in toluene, 220ml, 0.42mol) was added dropwise within 1 hour, the suspension was warmed to room temperature, stirred for 12 hours, then 1L ether was added, and the suspension was filtered insoluble salt, concentrated. The residue was recrystallized from hexane to give cis-1,5-cyclooctylene bis(chloroformate) as a colorless crystalline solid. It was further purified by flash chromatography on silica gel using hexane:ether as eluent (10:1). ¹ H-NMR (300MHz, CDCl ₃ ): 5.00-4.85 (m, 2H), 2.20-1.60 (m, 12H).

Example 6 cis-1,5-cyclooctylene chloroformate 4-tert-butoxycarbonyl-1-piperazinecarboxylate

The cis-1,5-cyclooctylene bis(chloroformate) (1.91g, 7.1mmol) prepared in Example 5 dissolved in dichloromethane (25ml) was added dropwise to dichloromethane ( In a mixture of tert-butyl-1-piperazinecarboxylate (1.3g, 7.1mmol) and DIEA (1.3g, 7.1mmol) in 25ml), the mixture was stirred at room temperature for 15 minutes, treated with 0.1M aqueous hydrochloric acid, and dried in dichloromethane layer (MgSO ₄ ), filtered and concentrated, and the residue was purified by flash chromatography on silica gel using diethyl ether and hexane as eluents to give cis-1,5-cyclooctylene chloroformate 4-tert-butoxycarbonyl - 1-Piperazinecarboxylate (660 mg, 1.6 mmol. Yield 22%). ¹ H-NMR(300MHz, CDCl ₃ ):5.00-4.90(m,1H),4.80-4.70(m,1H),3.40(s,8H),2.05-1.40(m,12H),1.40(s,9H ).

Example 7 cis-1,5-cyclooctylene-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-tert-butoxycarbonyl-1-piperazinecarboxylate

Treat tert-butyl 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate trifluoroacetate (383.7 g, 1.06 g) prepared in Example 4 with pure trifluoroacetic acid (1 ml) at room temperature mmol) for 10 minutes, the mixture was concentrated in vacuo to obtain a colorless oil, the oil was dissolved in water (15ml), and 5M aqueous sodium hydroxide solution was added dropwise to adjust the pH to 7-8. cis-1,5-cyclooctylene chloroformate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (444.7mg, 1.06mmol) prepared in Example 6 was added to the above aqueous solution, and 1M Aqueous sodium hydroxide solution continued to adjust the pH until there was no change in pH and the mixture was concentrated in vacuo to remove most of the THF, then diethyl ether (5 mL) and 5M aqueous sodium hydroxide (enough to adjust the pH to 14) were added to give a thick white suspension . The suspension was allowed to stand at room temperature for 15-30 minutes, then the precipitate was collected by filtration and washed with water (2X15ml). Vacuum drying obtains cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (527mg , 0.82 mmol, yield 77%), as a colorless solid.

¹ H-NMR (300MHz, DMSO-d ₆ ): 7.05(d,2H),7.00(tr,1H),6.70(d,2H),5.10(br,3H),4.65(m,2H),4.15( d,2H), 3.30(s,16H), 1.90-1.40(m,12H), 1.40(s,9H).

Example 8 Cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarbamate 4(2-piperidin-4-ylethylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate (compound 1)

The compound of formula (I) is prepared as follows, wherein R ¹ is 4-guanidinobenzyl, R ² is 2-piperidin-4-ylethyl, X ¹ and X ⁹ are each -NHC(O)-, X ² and X ⁸ are each 1,4-piperazinylene, X ³ and X ⁷ are each -C(O)O-, X ⁴ and X ⁶ are each a covalent bond, X ⁵ is cis-1, 5-Cyclooctylene.

Cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-tert-butoxycarbonyl-1-piperazinecarboxylate prepared in Example 7 (818mg, 1.24mmol) was treated with pure TFA (2ml) for 10 minutes, the mixture was concentrated in vacuo to give a colorless oil, the residue was triturated with ether (2X10ml) and dried in vacuo to give a colorless foam. The residue was then dissolved in DMF (2ml), DIEA (700ml, 4.0mmol) and tert-butyl 4-(2-isocyanoethyl)-1-piperidinecarboxylate (3.2ml, 0.39M, DMF medium, 1.25mmol), the mixture was stirred for 12 hours, concentrated in vacuo, the residue was triturated with water (2X, 5ml), dried in vacuo to give a yellow solid, the solid was treated with TFA (2ml), the mixture was concentrated in vacuo, the residue was dissolved in water , purified from the aqueous mixture by preparative reverse-phase HPLC to give cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(2 -piperidin-4-ylethylcarbamoyl)-1-piperazinecarboxylate as an amorphous colorless solid. Plasma Absorption LRMS: Calculated for (C ₃₅ H ₅₅ N ₁₀ O ₆ ): MH ⁺ : 712.9; Found MH ⁺ : 713.2.

According to the method for embodiment 8, use different raw materials, prepare following formula (I) compound:

cis-1,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate Ester (Compound 2); Calculated for (C ₃₅ H ₅₀ N ₁₀ O ₆ ): MH ⁺ : 707.9, Found MH ⁺ : 707.7;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-piperidinylmethylcarbamoyl)-1-piperazine Formate (Compound 3); Calculated for (C ₃₄ H ₅₃ N ₁₀ O ₆ ): MH ⁺ : 698.9, Found MH ⁺ : 699.7;

cis-1,5-cyclooctylene 4-(trans-4-aminocyclohexylmethylcarbamoyl)-1-piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-1- Piperazine carboxylate (Compound 4); Calculated (C ₃₅ H ₅₅ N ₁₀ O ₆ ): MH ⁺ : 712.9, Found MH ⁺ : 713.6;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 3-piperidin-4-ylpropylcarbamoyl-1-piperazinecarbamate Ester (Compound 5); Calculated (C ₃₆ H ₅₈ N ₁₀ O ₆ ): MH ⁺ : 727.9, Found MH ⁺ : 727.9;

4-[4-(2-Piperidin-4-ylethylcarbamoyl)piperazin-1-ylcarbonyl]benzyl 4(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate (Compound 6); Calculated for (C ₃₄ H ₄₈ N ₁₀ O ₅ ): MH ⁺ : 677.8, Found MH ⁺ : 677.6;

4-[4-(3-Piperidin-4-ylpropylcarbamoyl)piperazin-1-ylcarbonyl]benzyl 4(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate (Compound 7); Calculated for (C ₃₅ H ₅₀ N ₁₀ O ₅ ): MH ⁺ : 691.9, Found MH ⁺ : 691.5;

4-[4-(4-Piperidin-4-ylbutylcarbamoyl)piperazin-1-ylcarbonyl]benzyl 4(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate (Compound 8); Calculated for (C ₃₆ H ₅₂ N ₁₀ O ₅ ): MH ⁺ : 705.9, Found MH ⁺ : 705.9;

4-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]benzyl 4(2-piperidin-4-ylethylcarbamoyl)-1-piperazinecarboxylate (Compound 9); Calculated for (C ₃₄ H ₄₈ N ₁₀ O ₅ ): MH ⁺ : 677.8, Found MH ⁺ .677.7;

4-[4-(4-Guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]benzyl 4(3-piperidin-4-ylpropylcarbamoyl)-1-piperazinecarboxylate (Compound 10); Calculated for (C ₃₅ H ₅₀ N ₁₀ O ₅ ): MH ⁺ : 691.9, Found MH ⁺ : 691.3;

4-[4-(2-piperidin-4-ylethylcarbamoyl)piperazin-1-ylcarbonylmethyl]benzyl 4(4-guanidinobenzylcarbamoyl)-1-piperazine Ester (Compound 11); Calculated (C ₃₅ H ₅₀ N ₁₀ O ₅ ): MH ⁺ : 691.9, Found MH ⁺ : 692.1;

4-[4-(3-piperidin-4-ylpropylcarbamoyl)piperazin-1-ylcarbonylmethyl]benzyl 4(4-guanidinobenzylcarbamoyl)-1-piperazine Ester (Compound 12); Calculated for (C ₃₆ H ₅₂ N ₁₀ O ₅ ): MH ⁺ : 705.9, Found MH ⁺ : 705.6;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-methylaminomethylbenzylcarbamoyl)-1- Piperazine carboxylate (Compound 13); Calculated for (C ₃₇ H ₅₄ N ₁₀ O ₆ ): MH ⁺ : 735.9, Found MH ⁺ : 735.7;

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4-(2-piperidin-4-ylethylcarbamoyl)-1-piper Mezincarboxylate (Compound 14); Calculated (C ₃₅ H ₅₅ N ₉ O ₆ ): MH ⁺ : 698.9, Found MH ⁺ : 698.2;

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4-(3-piperidin-4-ylpropylcarbamoyl)-1-piper Oxyzinecarboxylate (Compound 15); Calculated (C ₃₆ H ₅₇ N ₂ O ₆ ): MH ⁺ : 712.9, Found MH ⁺ : 712.3;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-imidazol-1-ylbutylcarbamoyl)-1- Piperazine carboxylate (Compound 16); Calculated for (C ₃₅ H ₅₃ N ₁₁ O ₆ ): MH ⁺ : 724.9, Found MH ⁺ : 724.5;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarbamate 4-(4-imidazolin-2-ylaminobutylcarbamoyl)- 1-Piperazinecarboxylate (Compound 17); Calculated (C ₃₅ H ₅₆ N ₁₂ O ₆ ): MH ⁺ : 741.9, Found MH ⁺ : 741.7;

cis-1,5-cyclooctylene 4-(trans-4-aminocyclohexylmethylcarbamoyl)-1-piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-1- Piperazine carboxylate (Compound 18); Calculated (C ₃₅ H ₅₆ N ₁₀ O ₆ ): MH ⁺ : 713.9, Found MH ⁺ : 714.1;

cis-1,5-cyclooctylene 2-(1-tert-butyryloxymethoxycarbonylpiperidin-4-yl)ethylcarbamoyl-1-piperazinecarboxylate 4-(4-guanidino Benzylcarbamoyl)-1-piperazinecarboxylate (Compound 19); Calculated for (C ₄₂ H ₆₆ N ₁₀ O ₁₀ ): MH ⁺ : 872.1, Found MH ⁺ : 871.8;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-[2-(1-methylpiperidin-4-yl)ethyl Carbamoyl]-1-piperazinecarboxylate (Compound 20); Calculated for (C ₃₆ H ₅₈ N ₁₀ O ₆ ): MH ₂ ⁺ : 364.0, Found MH ₂ ⁺ /2: 364.3;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(3-imidazol-2-ylaminopropylcarbamoyl)-1 - piperazine carboxylate (compound 21); calcd (C ₃₄ H ₅₄ N ₁₂ O ₆ ): MH ⁺ : 727.9, found MH ⁺ : 728.0;

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4-[1-(1-iminoethyl)piperidin-4-yl Methylcarbamoyl]-1-piperazinecarboxylate (Compound 22); Calculated for (C ₃₆ H ₅₇ N ₁₁ O ₆ ): MH ⁺ : 740.9, Found MH ⁺ : 740.5;

cis-1,5-cyclooctylene 4-(4-guanidinobenzoylaminomethyl)-1-piperidinecarboxylate 4-(2-piperidin-4-ylethylcarbamoyl)-1 - piperazine carboxylate (compound 23); calcd (C ₃₆ H ₅₇ N ₉ O ₆ ): MH ⁺ : 712.9, found MH ⁺ : 711.6;

cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-1-piperazinecarboxylate 2-(1-methoxycarbonylpiperidin-4-yl)ethylaminomethyl Acyl-1-piperazinecarboxylate (Compound 24); Calculated for (C ₃₇ H ₅₇ N ₉ O ₈ ): MH ⁺ : 756.9, Found MH ⁺ : 756.7;

3{4-[2-(4-{cis-5-[4-(4-amidinobenzylaminomethyl)piperazin-1-ylcarbonyloxy]cyclooctyloxycarbonyl}piperazine-1- (C ₃₉ H ₆₀ N ₉ O ₉ ): MH ⁺ : 799.0, Found MH ⁺ : 798.6;

According to Example 8, with active ester instead of isocyanate, the following compound of formula I was prepared:

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-imidazol-4-ylacetyl-1-piperazinecarboxylate (compound 26); Calculated (C ₃₂ H ₄₆ N ₁₀ O ₆ ): MH ⁺ : 667.8, Found MH ⁺ : 667.7;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(E-3-imidazol-4-ylacryloyl)-1-piper Oxyzinecarboxylate (Compound 27); Calculated for (C ₃₃ H ₄₆ N ₁₀ O ₆ ): MH ⁺ : 679.9, Found MH ⁺ : 679.8;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazine carboxylate 4-(3-imidazol-4-ylpropionyl)-1-piperazine Ester (Compound 28); Calculated (C ₃₃ H ₄₈ N ₁₀ O ₆ ): MH ⁺ : 681.8, Found MH ⁺ : 681.7;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazine carboxylate 4-(5-imidazol-4-ylpentanoyl)-1-piperazine Ester (Compound 29); Calculated (C ₃₅ H ₅₂ N ₁₀ O ₆ ): MH ⁺ : 709.9, Found MH ⁺ : 709.5;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazine carboxylate 4-(6-imidazol-4-ylhexanoyl)-1-piperazine Ester (Compound 30); Calcd. (C ₃₆ H ₅₄ N ₁₀ O ₆ ): MH ⁺ : 723.9, Found MH ⁺ : 723.4;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-imidazol-1-ylmethylphenylacetyl)-1 - piperazine carboxylate (compound 31); calcd (C ₃₉ H ₅₂ N ₁₀ O ₆ ): MH ⁺ : 757.9, found MH ⁺ : 757.2;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-imidazol-1-ylmethylbenzoyl)-1- Piperazine carboxylate (Compound 32); Calcd. (C ₃₈ H ₅₀ N ₁₀ O ₆ ): MH ⁺ : 743.9, Found MH ⁺ : 743.7;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(3-imidazol-4-ylmethylbenzoyl)-1- Piperazine carboxylate (Compound 33); Calcd. (C ₃₈ H ₅₀ N ₁₀ O ₆ ): MH ⁺ : 743.9, Found MH ⁺ : 743.6;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylaminomethyl)-1-piperazinecarboxylate 4-(7-imidazol-1-ylheptanoyl)-1-piperazine Ester (Compound 34); Calculated for (C ₃₇ H ₅₆ N ₁₀ O ₆ ): MH ⁺ : 737.9, Found MH ⁺ : 737.6;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-[6-(methylimidazol-1-yl)hexanoyl]-1 - piperazine carboxylate (compound 35); calcd (C ₃₇ H ₅₆ N ₁₀ O ₆ ): MH ⁺ : 737.9, found MH ⁺ : 737.3;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-imidazol-1-ylphenoxyacetyl)-1- Piperazine carboxylate (Compound 36); Calculated for (C ₃₈ H ₅₀ N ₁₀ O ₇ ): MH ⁺ : 759.9, Found MH ⁺ : 759.3;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-[6-(4-methylimidazol-1-yl)hexanoyl] -1-piperazinecarboxylate and cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate;

4-[6-(5-Methylimidazol-1-yl)hexanoyl]-1-piperazinecarboxylate, mixture (compound 37); calculated for (C ₃₇ H ₅₆ N ₁₀ O ₆ ): MH ⁺ : 737.9, found MH ⁺ : 738.2;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-piperidin-4-ylbutyryl)-1-piperazine Formate (Compound 38); Calculated for (C ₃₆ H ₅₇ N ₉ O ₆ ): MH ⁺ : 712.9, Found MH ⁺ : 712.4;

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4-(4-piperidin-4-ylbutyryl)-1-piperazine Ester (Compound 39); Calculated (C ₃₆ H ₅₆ N ₈ O ₆ ): MH ⁺ : 697.9, Found MH ⁺ : 697.5;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(2-piperidin-4-ylethyl)(methyl)amino Formyl-1-piperazinecarboxylate (Compound 40); Calculated for (C ₃₆ H ₅₈ N ₁₀ O ₆ ): MH ⁺ : 727.9, Found MH ⁺ : 727.6;

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4-(2-piperidin-4-ylethyl)(methyl)aminomethyl Acyl-1-piperazinecarboxylate (Compound 41); Calculated for (C ₃₆ H ₅₇ N ₉ O ₆ ): MH ⁺ : 712.9, Found MH ⁺ : 712.7;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(2-piperidin-4-ylethoxycarbonyl)-1-piper Mezincarboxylate (Compound 42); Calcd. (C ₃₅ H ₅₅ N ₉ O ₇ ): MH ⁺ : 714.9, Found MH ⁺ : 714.5;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylaminomethyl)-1-piperazinecarboxylate 4-(4-imidazol-1-ylphenylacetyl)-1-piperazine Mezincarboxylate (Compound 43); Calculated (C ₃₈ H ₅₀ N ₁₀ O ₆ ): MH ⁺ : 743.9, Found MH ⁺ : 743.6;

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4-(6-imidazol-1-ylhexanoyl)-1-piperazinecarboxylate Ester (Compound 44); Calcd. (C ₃₆ H ₅₃ N ₉ O ₆ ): MH ⁺ : 708.9, Found MH ⁺ : 708.8;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylaminomethyl)-1-piperazinecarboxylate 4-(3-pyridin-4-ylthiopropionyl)-1-piper Oxyzinecarboxylate (Compound 45); Calculated (C ₃₅ H ₄₉ N ₉ O ₆ ): MH ⁺ : 724.9, Found MH ⁺ : 724.4;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbonyl)-1-piperazinecarboxylate 4-pyridin-4-ylthioacetyl-1-piperazinecarboxylate (compound 46); Calculated (C ₃₄ H ₄₇ N ₉ O ₆ ): MH ⁺ : 710.9, Found MH ⁺ : 710.8;

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4-(3-pyridin-4-ylthiopropionyl)-1-piperazine Formate (Compound 47); Calculated for (C ₃₅ H ₄₈ N ₈ O ₆ ): MH ⁺ : 709.9, Found MH ⁺ : 709.3;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazine carboxylate 4-(6-imidazol-4-ylhexanoyl)-1-piperazine Ester (Compound 48); Calculated for (C ₃₆ H ₅₄ N ₁₀ O ₆ ): MH ⁺ : 723.9, Found MH ⁺ : 723.5;

cis-1,5-cyclooctylene 4-(4-benzimidazol-6-ylcarbonyl)-1-piperazinecarboxylate 4-(guanidinobenzylcarbamoyl)-1-piperazinecarboxylate Ester (Compound 49); Calcd. (C ₃₅ H ₄₇ N ₁₀ O ₆ ): MH ⁺ : 703.8, Found MH ⁺ : 703.4;

cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(6-imidazol-1-ylhexanoyl)-1-piperazine Ester (Compound 50); Calculated (C ₃₆ H ₅₃ N ₉ O ₆ ): MH ⁺ : 708.9, Found MH ⁺ : 708.6;

cis-1,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)-1-piperazinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-1-piperidine Formate (Compound 51); Calculated for (C ₃₇ H ₅₄ N ₈ O ₆ ): MH ⁺ : 707.9, Found MH ⁺ : 707.5;

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-1-piperazinecarboxylate Ester (Compound 52); Calcd. (C ₃₅ H ₅₂ N ₁₀ O ₆ ): MH ⁺ : 708.9, Found MH ⁺ : 708.4;

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4-pyridin-4-ylcarbamoylacetyl-1-piperazinecarboxylate (Compound 53); Calculated for (C ₃₅ H ₄₇ N ₉ O ₇ ): MH ⁺ : 706.8, Found MH ⁺ : 706.3;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(3-pyridin-4-ylaminopropionyl)-1-piperazine Formate (Compound 54); Calculated for (C ₃₅ H ₅₀ N ₁₀ O ₆ ): MH ⁺ : 707.9, Found MH ⁺ : 707.3;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 3-[pyridin-4-yl(tert-butoxycarbonyl)amino]propionyl- 1-Piperazinecarboxylate (Compound 55); Calculated for (C ₄₀ H ₅₈ N ₁₀ O ₈ ): MH ₂ ²⁺ /2: 404.5, Found MH ₂ ^{2+ /2} : 404.2;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(3-piperazin-1-ylcarbonylpropionyl)-1-piper Oxyzinecarboxylate (Compound 56); Calculated (C ₃₅ H ₅₄ N ₁₀ O ₇ ): MH ⁺ : 727.9, Found MH ⁺ : 727.5;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-piperidin-1-ylcarbonylaminoacetyl-1-piperazinecarboxylate Ester (Compound 57); Calculated for (C ₃₅ H ₅₄ N ₁₀ O ₇ ): MH ⁺ : 727.9, Found MH ⁺ : 727.5;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(imidazol-4-ylpentanoyl)-1-piperazinecarboxylate (Compound 58); Calculated for (C ₃₅ H ₅₂ N ₁₀ O ₆ ): MH ⁺ : 708.9, Found MH ⁺ : 709.4;

cis-1,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)-1-piperazinecarboxylate 4-(3-piperazin-1-ylcarbonylpropionyl)-1- Piperazine carboxylate (Compound 59); Calculated (C ₃₆ H ₅₄ N ₈ O ₇ ): MH ⁺ : 711.9, Found MH ⁺ : 711.4;

cis-1,5-cyclooctylene 4-(4-amidinobenzoylaminomethyl)-1-piperazinecarboxylate 4-piperidin-4-ylcarbonylaminoacetyl-1-piperazine Ester (Compound 60); Calculated (C ₃₆ H ₅₄ N ₈ O ₇ ): MH ⁺ : 711.9, Found MH ⁺ : 711.4;

cis-1,5-cyclooctylene 4-[3-(2-aminopyrimidin-5-yl)propionyl]-1-piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)- 1-Piperazinecarboxylate (Compound 61); Calculated for (C ₃₄ H ₄₉ N ₁₁ O ₆ ): MH ⁺ : 708.8, Found MH ⁺ : 708.4;

cis-1,5-cyclooctylene 4-[3-(6-aminopyridin-3-yl)propionyl]-1-piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)- 1-Piperazinecarboxylate (Compound 62); Calculated for (C ₃₅ H ₅₀ N ₁₀ O ₆ ): MH ⁺ : 707.8, Found MH ⁺ : 707.4;

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-[4-(4-pyridine-4-thio)butyryl]-1 - piperazine carboxylate (compound 63); calcd (C ₃₆ H ₅₁ N ₉ O ₆ ): MH ⁺ : 738.9, found MH ⁺ : 738.4;

cis-1,5-cyclooctylene 4-[3-(2-amino-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)propionyl]-1- Piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl-1-piperazinecarboxylate (Compound 64); Calculated for (C ₃₄ H ₄₈ N ₁₀ O ₈ ): MH ⁺ : 725.8, found MH ⁺ :725.2;

cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(4-piperidin-4-ylbutyryl)-1-piperazine Formate (Compound 65); Calculated for (C ₃₆ H ₅₆ N ₈ O ₆ ): MH ⁺ : 697.9, Found MH ⁺ : 697.4;

cis-1,5-cyclooctylene 4-(4-amidinobenzylaminomethyl)-1-piperidinecarboxylate 4-(4-piperidin-4-ylbutyryl)-1-piperazine Formate (Compound 66); Calculated for (C ₃₇ H ₅₇ N ₇ O ₆ ): MH ⁺ : 696.9, Found MH ⁺ : 696.4;

cis-1,5-cyclooctylene 4-(1-amidinopiperidin-4-ylacetyl)-1-piperidinecarboxylate 4-(6-imidazol-1-ylhexanoyl)-1- Piperazine carboxylate (Compound 67); Calculated (C ₃₅ H ₅₇ N ₉ O ₆ ): MH ⁺ : 700.9, Found MH ⁺ : 700.5;

cis-1,5-Cyclooctylene 4-(1-amidino-4-piperidinylacetyl)-1-piperazinecarboxylate 4-(4-piperidin-4-ylbutyryl)-1 - piperazine carboxylate (compound 68); calcd (C ₃₅ H ₆₀ N ₉ O ₆ ): MH ⁺ : 689.9, found MH ⁺ : 689.4;

cis-1,5-Cyclooctylene 4-(1-amidino-4-piperidinylacetyl)-1-piperazinecarboxylate 4-(6-imidazol-1-ylhexanoyl)-1- Piperazine carboxylate (Compound 69); Calculated (C ₃₅ H ₅₇ N ₉ O ₆ ): MH ⁺ : 700.9, Found MH ⁺ : 700.4;

cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-1-piperazine Ester (Compound 70); Calculated for (C ₃₆ H ₅₃ N ₉ O ₆ ): MH ⁺ 708.9, Found MH ⁺ : 708.4;

cis-1,5-cyclooctylene 4-(4-amidinobenzoyl)-1-piperidinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-1-piperazinecarboxylate (Compound 71); Calculated for (C ₃₇ H ₅₄ N ₈ O ₆ ): MH ⁺ : 709.9, Found MH ⁺ : 707.4;

cis-1,5-cyclooctylene 4-(4-amidinophenylacetyl)-1-piperazinecarboxylate 4-(6-imidazol-1-ylhexanoyl)-1-piperazinecarboxylate Ester (Compound 72); Calculated for (C ₃₆ H ₅₂ N ₈ O ₆ ): MH ⁺ 693.9, Found MH ⁺ : 693.4;

cis-1,5-cyclooctylene 4-(4-amidinophenylacetyl)-1-piperazinecarboxylate 4-(4-piperidin-4-ylbutyryl)-1-piperazine Ester (Compound 73); Calculated for (C ₃₆ H ₅₅ N ₇ O ₆ ): MH ⁺ : 682.9, Found MH ⁺ : 682.4;

cis-1,5-cyclooctylene 4-(4-amidinophenylacetyl)-1-piperazinecarboxylate 4-(6-imidazol-4-ylhexanoyl)-1-piperazinecarboxylate Ester (Compound 74); Calculated for (C ₃₆ H ₅₂ N ₈ O ₆ ): MH ⁺ : 693.9, Found MH ⁺ : 693.4;

cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-[4-(2-(1-tert-butylcarbonyloxymethoxy (C ₄₃ H ₆₅ N ₉ O ₁₀ ): MH ⁺ : 857.0, found MH ⁺ :856.6;

Example 9 cis-1,5-cyclooctylene bis(4-tert-butoxycarbonyl-1-piperazinecarboxylate)

The cis-1,5-cyclooctylene bis(chloroformate) (3.69g, 13.7mmol) and DIEA (7.2ml, 41mmol) prepared in Example 5 were dissolved in DMF (25ml), and -1 - tert-butyl piperazinecarboxylate (5.1 g, 27.4 mmol), the mixture was stirred at room temperature for 12 hours, then concentrated in vacuo to give a semi-solid residue. The residue was partitioned between dichloromethane (50ml) and water (50ml), the dichloromethane layer was washed with 0.1N aqueous hydrochloric acid (2X, 25ml), dried ( _MgSO4 ) and filtered, concentrated in vacuo to give cis-1, 5-Cyclooctylene bis(4-tert-butoxycarbonyl-1-piperazinecarboxylate), an amorphous solid. ¹ H-NMR (300MHz, CDCl ₃ ): 4.80 (m, 2H), 3.40 (brs, 16H), 2.00-1.40 (m, 12H), 1.40 (s, 18H).

Example 10 cis-1,5-cyclooctylenebis[4-(2-piperidin-4-ylethylcarbamoyl)-1-piperazinecarboxylate] (compound 76)

Compounds of formula I are prepared as follows, wherein R ^and R are ^each 2-piperidin-4-ylethyl, X ^{and X} are each -NHC(O)-, X ^{and X} are each 1 , 4-piperazinylene, each of X ³ and X ⁷ is -C(O)O, each of X ⁴ and X ⁶ is a covalent bond, and X ⁵ is cis-1,5-cyclooctylene.

cis-1,5-cyclooctylene bis(4-tert-butoxycarbonyl-1-piperazinecarboxylate) (47.9 mg, 0.088 mmol) prepared in Example 9 was treated with pure TFA (1 ml) for 10 minutes, A colorless oil was obtained, the mixture was concentrated in vacuo, the residue was triturated with ether (2X, 5ml) and dried repeatedly in vacuo to give an amorphous solid. The solid residue was dissolved in DMF (5ml) and DIEA (100ml, 0.5mmol), and tert-butyl 4-(2-isocyanatoethyl)-1-piperidinecarboxylate (460ml, 0.39M, In DMF, 0.18 mmol), the mixture was stirred for 12 hours, concentrated in vacuo, the residue was triturated with water (2X, 5 mL), and dried in vacuo to give a yellow oil. The solid was treated with TFA (2 ml), the mixture was concentrated in vacuo, the residue was dissolved in water, purified from the aqueous mixture by preparative reverse phase HPLC, and lyophilized to give cis-1,5-cyclooctylenebis[4-( 2-piperidin-4-ylethylcarbamoyl)-1-piperazinecarboxylate], a colorless amorphous solid. Electron spray method LRMS: calculated value (C ₃₄ H ₆₀ N ₈ O ₆ ): MH ⁺ : 677.9, measured value MH ⁺ : 677.6;

According to the method of Example 10, different raw materials were used to obtain cis-1,5-cyclooctylene bis[4-(4-methylaminomethylbenzylcarbamoyl)-1-piperazinecarboxylate] (Compound 77). Calculated (C ₃₈ H ₅₆ N ₈ O ₆ ): MH ⁺ : 721.9, Found MH ⁺ : 721.7;

According to Example 10, the following compound of formula I is obtained by using active ester instead of isocyanate:

cis-1,5-cyclooctylenebis[4-(4-piperidin-4-ylbutyryl)-1-piperazinecarboxylate] (Compound 78). Calculated (C ₃₆ H ₆₂ N ₆ O ₆ ): MH ⁺ : 675.9, Found MH ⁺ : 675.6;

p-Methylenephenylene bis[4-(4-piperidin-4-ylbutyryl)-1-piperazinecarboxylate]. (Compound 79) Calculated (C ₃₆ H ₅₆ N ₆ O ₆ ): MH ⁺ : 669.9, Found MH ⁺ : 669.4;

Example 11 tert-butyl 4-(3-imidazol-1-ylpropylcarbamoyl)-1-piperazinecarboxylate

Dissolve tert-butyl 4-chlorocarbonyl-1-piperazinecarboxylate (188mg, 0.76mmol) prepared in Example 3 in dichloromethane (10ml), add DIEA (150ml, 0.86mmol), and add 1- (3-Aminopropyl)imidazole (100ml, 0.84mmol), the mixture was stirred for 12 hours, dichloromethane (10ml) was added to the mixture, the organic layer was washed with water (1X, 10ml), dried (MgSO ₄ ) and filtered, concentrated tert-Butyl 4-(3-imidazol-1-ylpropylcarbamoyl)-1-piperazinecarboxylate (230 mg, 0.68 mmol, 90% yield) was obtained as a colorless oil. ¹ H-NMR (300MHz, DMSO-d ₆ ): 7.60(s,1H), 7.20(s,1H), 6.85(s,1H), 6.60(tr,1H), 3.95(tr,2H), 3.30( s,8H), 3.00(q,2H), 1.80(m,2H), 1.40(s,9H). Example 12 tert-butyl 4-aminomethyl-1-phenylcarbamate hydrochloride

4-aminobenzylamine (5.56g, 45.6mmol) was added to water (45ml), citric acid (9.63g, 50mmol) was added to the solution, and di-tert-butyl carbonate (9.94g, 45.5 mmol), the mixture was stirred at room temperature for 48 hours to obtain a yellow suspension. The suspension was filtered, the aqueous solution was basified with excess solid sodium carbonate, extracted with ethyl acetate (3X, 35ml), the combined extracts were washed with saturated aqueous sodium chloride solution, dried ( _MgSO4 ), filtered and concentrated in vacuo to give a white solid, The solid was dissolved in methanol (30ml) and the solution was acidified with HCl in dioxane (4M, 8.4ml, 33.6mmol) and diethyl ether (100ml) was added to give a suspension which was isolated by filtration and dried in vacuo to give 4- Aminomethyl-1-phenylcarbamate tert-butyl hydrochloride (7.2 g, 27.8 mmol, 61% yield) as a colorless solid. ¹ H-NMR (300 MHz, DMSO-d ₆ ): 9.43 (s, 1H), 8.20 (brs, 3H), 7.40 (dd, AB, 4H), 3.92 (m, 2H), 1.50 (s, 9H).

Example 13 tert-butyl 4-isocyanatomethyl-1-phenylcarbamate

Dissolve the tert-butyl 4-aminomethyl-1-phenylcarbamate hydrochloride (3.39g, 13.1mmol) prepared in Example 12 in dichloromethane (120ml) at 0°C, add pyridine (4.3ml , 53mmol) and triphosgene (1.3g, 4.4mmol), the mixture was warmed to room temperature in 30 minutes, and aqueous hydrochloric acid (0.5N, 100ml) was added. The organic phase was dried (MgSO ₄ ), filtered, and concentrated to give tert-butyl 4-isocyanatomethyl-1-phenylcarbamate (2.7 g, 11 mmol, 84% yield) as a yellow solid. ¹ H-NMR (300 MHz, CDCl ₃ ): 7.29 (dd AB, 4H), 6.55 (brs, 1H), 4.40 (s, 2H), 1.55 (s, 9H).

Example 14 cis-1,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-1-piperazinecarbamate 4-(3-imidazol-1-ylpropylcarbamoyl)- 1-piperazine carboxylate (compound 80)

The compound of formula I is prepared as follows, wherein R ¹ is 4-aminobenzyl, R ² is 3-imidazol-1-ylpropyl, X ¹ and X ⁹ are each -NHC(O)-, X ² and X ⁸ are each One is 1,4-piperazinyl, each of X ³ and X ⁷ is -C(O)O, each of X ⁴ and X ⁶ is a covalent bond, and X ⁵ is cis-1,5-cyclooctene base.

10 Minutes, the mixture was concentrated in vacuo, the residue was dissolved in dichloromethane (10ml), excess DIEA (1.0ml) was added to the solution, and the solution prepared in Example 6 was dissolved in dichloromethane (5ml). -1,5-Cyclooctylene chloroformate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (279mg, 0.67mmol), the mixture was stirred for 1 hour, then dichloromethane (10ml) was added, organic The layer was washed with saturated aqueous sodium bicarbonate (1X, 10ml), dried ( _MgSO4 ) and filtered, concentrated to give crude cis-1,5-cyclooctylene 4-(3-imidazol-1-ylpropylaminomethyl Acyl)-1-piperazinecarboxylate tert-butoxycarbonyl-1-piperazinecarboxylate adduct, colorless foam

(b) Treat the product prepared in part (a) with pure TFA (1ml) for 10 minutes, concentrate the mixture in vacuo, dissolve the residue in DMF (10ml), add excess DIEA (1.5ml) and 4 - tert-butyl isocyanatomethyl-1-phenylcarbamate (165mg, 0.67mmol), the mixture was stirred for 12 hours, concentrated in vacuo, the residue was treated with pure TFA, the mixture was concentrated in vacuo, the residue was dissolved in water (15ml), The aqueous solution was extracted with diethyl ether (1X, 15ml), and the aqueous phase was basified with 1.0M aqueous sodium hydroxide solution, then extracted with dichloromethane, dried with dichloromethane (MgSO ₄ ), filtered, and concentrated in vacuo to give cis-1,5- Cyclooctylene 4-(4-aminobenzylcarbamoyl)-1-piperazinecarboxylate 4-(3-imidazol-1-ylpropylcarbamoyl)-1-piperazinecarboxylate, for Colorless foam. ¹ H-NMR (300MHz, CDCl ₃ ): 7.45(,4H),7.10(d,2H),7.05(s,1H),6.90(s,1H),6.60(d,2H),4.85-4.70(m ,4H), 4.30(d,2H), 4.00(tr,2H), 3.50-3.30(m,18H), 2.00(m,2H), 1.90-1.50(m,12H).

According to the method of Example 14, using different raw materials, the following compound of formula I was obtained:

cis-1,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-1-piperazinecarboxylate 4-(2-pyridin-4-ylethylcarbamoyl)-1-piper Zinc carboxylate (compound 81);

cis-1,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-1-piperazinecarboxylate 4-(3-piperidin-4-ylpropyl)-1-piperidinylmethyl ester (compound 82); and

cis-1,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-1-piperazine carboxylate 4-(4-piperidin-4-ylbutyl)-1-piperazine Ester (compound 83); Example 15 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(3-imidazole-1- propylcarbamoyl)-1-piperazinecarboxylate (compound 84)

The compound of formula I is prepared as follows, wherein R ¹ is 4-guanidinobenzyl, R ² is 3-imidazol-1-ylpropyl, X ¹ and X ⁹ are each -NHC(O)-, X ² and X ⁸ Each is 1,4-piperazinyl, each of X ³ and X ⁷ is -C(O)O-, each of X ⁴ and X ⁶ is a covalent bond, and X ⁵ is cis-1,5-ylidene Cyclooctyl.

The cis-1,5-cyclooctylene 4-(4-aminobenzylcarbamoyl)-1-piperazinecarboxylate 4-(3-imidazol-1-ylpropylaminomethyl) prepared in Example 14 Acyl)-1-piperazinecarboxylate was dissolved in methanol, diethyl ether and excess HCl (4M in dioxane) were added, the compound was concentrated and dried in vacuo, an excess of cyanamide (1.0 g) was added, and the mixture was heated at 65 °C for 2 hours to obtain a yellow solution. The mixture was cooled to room temperature, triturated with diethyl ether (3X, 10 mL), and the insoluble residue was dissolved in water and purified from the aqueous mixture by preparative reverse-phase HPLC to give cis-1,5-cyclooctylene 4-(4- Guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(3-imidazol-1-ylpropylcarbamoyl)-1-piperazinecarboxylate, a colorless amorphous solid. Electrospray method, LRMS: Calculated for (C ₃₄ H ₅₁ N ₁₁ O ₆ ) MH ⁺ : 710.9: Found MH ⁺ : 710.6.

According to the method of Example 15, using different raw materials, the following compound of formula I was obtained:

cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-(2-pyridin-1-ylethylcarbamoyl)-1- Piperazine carboxylate (Compound 85); Calcd. (C ₃₅ H ₅₀ N ₁₀ O ₆ ) MH ⁺ : 707.9; Found MH ⁺ : 707.6.

Cis-1,5-cyclooctylene 3-piperidin-4-ylpropyl-1-piperazinecarboxylate 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate ( Compound 86); and

Cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 4-piperidin-4-ylbutyl-1-piperidinecarboxylate ( Compound 87); Calcd. for (C ₃₇ H ₆₀ N ₈ O ₅ ) MH ⁺ : 697.9; Found MH ⁺ : 697.7. Example 16 cis-1,5-cyclooctylene chloroformate 4-benzyloxycarbonyl-1-piperazinecarboxylate

At 0°C, 1-piperazinecarboxylic acid benzyl ester (1.0g, 4.53mmol, 1.0eq) and DIEA (0.88ml, 4.98mmol, 1.1eq) dissolved in dichloromethane (25ml) were added dropwise to the In the cis-1,5-cyclooctylene bis(chloroformate) (1.2 g, 4.53 mmol, 1.0 equivalent) dissolved in dichloromethane (25 ml) prepared in Example 5, the reaction mixture was stirred for 22 hours, While warming to room temperature, the mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid and saturated aqueous sodium chloride, the organic layer was dried over sodium sulfate and concentrated, and the residue was purified by flash column chromatography with 20% and 30% ethyl acetate in hexane was eluted to give cis-1,5-cyclooctyl chloroformate 4-benzyloxycarbonyl-1-piperazinecarboxylate (0.81g, 1.81mmool, 40 %), as a yellow oil. IR: 2939(s), 2863(m), 1770(s), 1732(s), 1696(s); ¹ H-NMR (300MHz, CDCl ₃ ): 7.35(s, 5H), 5.15(s, 2H ), 4.95(m,1H), 4.75(m,1H), 3.45(s,8H), 1.50-2.05(m,12H).

Example 171-[cis-5-(4-benzyloxycarbonylpiperazin-1-ylcarbonyloxy)cyclooctyloxycarbonyl]-4-piperidinecarboxylic acid

Add iso-3-piperidinecarboxylic acid (75 mg, 0.58 mmol, 1.1 eq) and DIEA (0.23 ml, 1.33 mmol, 2.5 eq) to the cis -1,5-Cyclooctylene chloroformate 4-benzyloxycarbonyl-1-piperazinecarboxylate (0.24g, 0.53mmol, 1.0eq), a white suspension was obtained, and the suspension was stirred for 18 hours, While warming to room temperature, the reaction mixture was partitioned between dichloromethane and 0.05N aqueous hydrochloric acid, and the organic phase was concentrated to give 1-[cis-5-(4-benzyloxycarbonylpiperazin-1-ylcarbonyloxy)cyclooctyl oxycarbonyl]-4-piperidinecarboxylic acid (0.36 g) as a colorless oil. ¹ HNMR(300MHz, CDCl ₃ ):7.35(s,5H),5.15(s,2H),4.75(m,2H),3.90(m,1H),3.45(s,8H),2.75(m,1H) ,2.50(m,3H),1.50-1.90(m,16H).

Example 18 cis-1,5-cyclooctylene 4-benzyloxycarbonyl-1-piperazinecarboxylate 4[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl] -1-piperidinecarboxylate

1-Hydroxybenzotriazole (80mg.58.3mmol, 1.1 equivalent), tert-(2-aminoethyl)-1-piperidinecarboxylic acid tert-butyl ester hydrochloride (0.14g, 0.53mmol, 1.0 equivalent) and 4-methylmorpholine (0.15ml, 1.33mmol, 2.5eq) were added to the crude 1-[cis-5-(4-benzyloxycarbonylpiperazine- In 1-ylcarbonyloxy)cyclooctyloxycarbonyl]-4-piperidinecarboxylic acid (0.36g, 0.53mmol, 1.0eq), 1-(3-dimethylaminopropyl)-3 -Ethylcarbodiimide hydrochloride (0.13g, 0.66mmol, 1.25 equivalents) was added to the reaction mixture, the solution was stirred at 0°C for 1.5 hours, and at 23°C for 3 days, the reaction mixture was dichloromethane, 0.05N Partition between aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water (2 parts) and saturated aqueous sodium chloride, dry the organic phase (MgSO ₄ ), concentrate, and purify from the residue by flash column chromatography with 3% methanol Eluted with dichloromethane solution to give cis-1,5-cyclooctylene 4-benzyloxycarbonyl-1-piperazinecarboxylate 4[2-(1-tert-butoxycarbonylpiperidin-4-yl) Ethylcarbamoyl]-1-piperidinecarboxylate (0.15g0.2mmol, 37%, in two steps), as yellow bag oil. ¹ HNMR(300MHz, CDCl ₃ ):7.35(s,5H),5.15(s,2H),4.80(m,2H),4.10(m,4H),3.45(m,10H),3.30(m,2H) , 2.70(m,2H), 1.50-1.90(m,23H), 1.45(s,9H); Electron spray: LRMS: Calculated (C ₄₀ H ₆₂ N ₅ O ₉ )(MH ⁺ ):756.97; Measured value 757.0.

Example 19 cis-1,5-cyclooctylene 1-piperazinecarboxylate 4[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl 1-1-piperidinylmethyl Ester

Ethanol (3ml) was added to the cis-1,5-cyclooctylene 4-benzyloxycarbonyl-1-piperazinecarboxylate 4[2-(1-tert-butoxycarbonyl) prepared in Example 18 under a nitrogen atmosphere Piperidin-4-yl) ethylcarbamoyl]-1-piperazinecarboxylate (0.15g, 0.20mmol, 1.0 equivalent), was added to 5% palladium/carbon (75mg, 0.50wt equivalent), and the mixture was Stir under hydrogen atmosphere (1 atm) and 23 ℃ for 17 hours, put the reaction mixture under nitrogen atmosphere, and filter. -tert-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]-1-piperidinecarboxylate (110mg, 0.18mmol, 90%,), a colorless oil. ¹ HNMR (300MHz, CDCl ₃ ): 5.5(m, 1H), 4.9(m, 2H), 4.75(m, 1H), 4.1(m, 4H), 3.45(m, 4H), 3.25(m, 2H) ,2.60-2.85(m,8H),2.10(m,1H),1.50-1.95(m,23H),1.45(s,9H); Electron Spray: LRMS: Calculated (C ₃₂ H ₅₆ N ₅ O ₇ ) (MH ⁺ ): 622.83; found 622.7. Example 20 cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl-l-piperazinecarbamate 4(2-piperidin-4-ylethylcarbamoyl]- 1-piperidinecarboxylate (compound 88)

The compound of formula I is prepared as follows, wherein R ¹ is 4-guanidinobenzyl, R ² is 2-piperidin-4-ylethyl, X ¹ and X ⁹ are each -NHC(O)-, X ² is 1 , 4-piperazinylene, X ⁸ is 4,1-piperidinylene, X ³ and X ⁷ are each -C(O)O-, X ⁴ and X ⁶ are each a covalent bond, X ⁵ is cis-1,5-cyclooctylene.

Triphosgene (30mg, 0.10mmol, 0.58eq) and pyridine (30ml, 0.39mmol, 2.1eq) were added to the cis-1,5- Cyclooctylene 1-piperazinecarboxylate 4[2-(1-tert-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]-1-piperazinecarboxylate (0.11g, 0.18mmol, 1.0 equiv), the reaction mixture was stirred at 0°C for 3 hours, the mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid and saturated aqueous sodium chloride, the organic phase was dried (MgSO ₄ ), and concentrated to give a brown oily residue. To the residue was added 4-guanidinobenzylamine hydrochloride (43 mg, 0.20 mmol, 1.1 equiv) and DIEA (0.16 ml, 0.90 mmol, 5.0 equiv) dissolved in DMF (2 ml) to obtain a suspension, which was The suspension was stirred at 23°C for 18.5 hours, the residue was dissolved in 50% TFA in dichloromethane (4 ml), the mixture was stirred at 23°C for 45 minutes, the reaction mixture was concentrated, the residue was triturated with ether, dried in vacuo, and prepared with Purified from the residue by precise reverse-phase HPLC and lyophilized to give cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl-1-piperazinecarboxylate 4(2-piperazine Pyridin-4-ylethylcarbamoyl]-1-piperidinecarboxylate as a colorless amorphous solid. Electron spray, LRMS: Calculated for (C ₃₆ H ₅₈ N ₉ O ₆ )(MH ⁺ ): 712.91 , measured value: 712.8.

According to Example 20, using different starting materials, the following compound of formula I was prepared:

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4(3-imidazol-4-ylpropylcarbamoyl]-1-piperazine Formate (compound 89), calculated for (C ₃₄ H ₅₀ N ₁₀ O ₆ ): MH ⁺ : 695.9, found: MH ⁺ : 695.4.

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4(2-imidazol-4-ylethylcarbamoyl]-1-piperazine Formate (compound 90), calculated for (C ₃₃ H ₄₈ N ₁₀ O ₆ ): MH ⁺ : 681.3, found: MH ⁺ : 680.9.

cis-1.5-Cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4(3-imidazol-1-ylpropylcarbamoyl]-1-piperazinecarboxylate Ester (compound 91), calculated for (C ₃₄ H ₅₀ N ₁₀ O ₆ ): MH ⁺ : 695.9, found: MH ⁺ : 694.9.

cis-1,5-cyclooctylene 4-(4-guanidinophenylacetyl)-1-piperazinecarboxylate 4(4-imidazol-1-ylbutylcarbamoyl]-1-piperazine Formate (compound 92), calculated for (C ₃₅ H ₅₃ N ₁₀ O ₆ ): MH ⁺ : 709.9, found: MH ⁺ : 709.4.

cis-1,5-cyclooctylene 4-(4-guanidinobenzylacetyl)-1-piperazinecarboxylate 4(3-imidazol-1-ylpropylcarbamoyl]-1-piperazine Formate (compound 93), calculated for (C ₃₅ H ₅₁ N ₁₀ O ₆ ): MH ⁺ : 709.9, found: MH ⁺ : 710.4.

Example 21 3-piperidin-4-yl propionate hydrochloride

4-Pyridine acrylate hydrochloride (12.0g, 64.4mmol) and 13.7g platinum oxide were suspended in acetic acid (80ml), hydrogenated at 50-60psi for 12 hours, the mixture was diluted with water, filtered through a Celite pad, and the solid was water (200ml), the combined filtrate and wash water were concentrated in vacuo to give a white solid, the solid was suspended in a small amount of methanol, the mixture was diluted with ether (200ml), the particulate was isolated by filtration, washed with ether and hexane, and air dried to give 3- Piperidin 4-ylpropion hydrochloride (11.3g, 58.1mmol, 90%), as a colorless solid H ¹ NMR (300MHz, MDSO-d ₆ ): 8.75(br,s,2H), 3.15(d, 2H), 2.75(t,1H), 2.2(t,2H), 1.75(d,2H), 1.45(t,2H), 1.25(br,q,2H).

Example 223-(1-tert-butoxycarbonylpiperidin-4-yl)propionic acid

Dissolve 3-piperidine-4-propionic acid (5.07g, 26.2mmol) prepared in Example 21 in 2NNaOH (40ml, 80mmol), add THF (40ml) and di(tert-butyl)carbonate (6.21g, 28.4mmol) ), the suspension was obtained, the suspension was stirred for 22 hours, diluted with water, concentrated in vacuo, the residue was washed with diethyl ether (2X, 100ml), the aqueous phase was acidified to pH2-3 with 1.0N KHSO ₄ aqueous solution, and washed with ethyl acetate (3X , 200ml), the combined organic phases were washed with brine, dried (MgSO ₄ ), and concentrated in vacuo to obtain 3-[4-(1-tert-butoxycarbonyl)-4-piperidine]propionic acid (6.21g, 24.1 mmol, 92%), a colorless oil that crystallized on standing. H ¹ NMR (300MHz, CDCl ₃ ): 4.10(br,d,2H), 2.65(br,t,2H), 2.35(t,2H), 1.70-.50(m,3H), 1.45(s,9H ),1.20-0.95(m,2H).

Example 234-Benzyloxycarbonyl-1-piperazinecarboxylic acid tert-butyl ester

tert-Butyl-1-piperazinecarboxylate (2.01g, 10.8mmol) and DIEA (2.0ml , 1.48g, 11.5mmol), the mixture was stirred for 42 hours, partitioned between ethyl acetate and 0.5N KHSO ₄ , the aqueous phase was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried (MgSO ₄ ) and Concentrate and purify from the residue by silica gel chromatography (ethyl acetate:hexane, 1:3) to give tert-butyl 4-benzyloxycarbonyl-1-piperazinecarboxylate (3.33 g, 10.4 mmol, 96%) , is a colorless solid. H ¹ NMR (300 MHz, CDCl ₃ ): 7.35 (b, s, 5H), 5.13 (s, 2H), 3.55-3.25 (m, 8H), 1.45 (s, 9H).

Example 241-Benzyl piperazinecarboxylate hydrochloride

Suspend tert-butyl 4-benzyloxycarbonyl-1-piperazinecarboxylate (1.01 g, 3.16 mmol) prepared in Example 23 in 4 ml of ethyl acetate, cool the suspension in an ice-water bath, add 4N HCl (12 ml, dissolve In 1,4-dioxane), a solution was obtained. The solution was stirred on an ice bath for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether (76ml) to obtain a precipitate, which was separated by filtration and washed with diethyl ether Washing and drying in vacuo gave benzyl 1-piperazinecarboxylate hydrochloride (740 mg, 2.78 mmol, 88%) as a colorless solid. H ¹ NMR (300 MHz, DMSO-d ₆ ): 9.25 (brs, 2H), 7.33 (s, 5H), 5.06 (s, 2H), 3.58 (brs, 4H), 3.04 (t, 4H). Example 254-[2-(4-Benzyloxycarbonylpiperazin-1-ylcarbonylamino)ethyl]-1-pyridinecarboxylic acid tert-butyl ester

3-[4-(1-tert-butoxycarbonyl)-4-piperidinyl]propionic acid (2.16g, 8.4mmol) prepared in Example 22 was dissolved in anhydrous benzene (28ml) and triethylamine (1.35 ml, 951mg, 9.40mmol) and diphenylphosphoryl azide (2.05ml, 2.62g, 9.53mmol), the reaction mixture was gradually heated to reflux and maintained at reflux for 3.5 hours, the mixture was cooled to room temperature, and then added dropwise to Example 24 A suspension of 1-piperazinecarboxylate benzyl hydrochloride (2.44 g, 9.19 mmol) and triethylamine (1.40 ml) in anhydrous dichloromethane (10 ml) was prepared and the reaction mixture was stirred for 43 hours , diluted with ethyl acetate and 0.5N KHSO ₄ , the organic phase was washed with water, aqueous sodium bicarbonate and brine, dried (Na ₂ SO ₄ ) and concentrated, and the residue was purified by silica gel chromatography (first with 4:1 ethyl acetate-hexane, then pure diethyl ether) to give tert-butyl 4-[2-(4-benzyloxycarbonylpiperazin-1-ylcarbonylamino)ethyl]-1-piperidinecarboxylate (3.84 g , 8.1 mmol, 96%) as a white solid. H ¹ NMR(300MHz,CDCl ₃ ):7.35(s,5H),5.15(s,2H),4.50(brt,,1H),4.05(brs,2H)3.55-3.45(m,4H),3.40-3.30 (m,4H), 3.25(q,2H), 2.65(t,2H), 1.70(s,2H), 1.45(s,11H), 1.20-1.00(m,2H).

Example 26 cis-1,5-cyclooctylene chloroformate 4-[2-(4-tert-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]-1-piperazinecarboxylic acid ester

tert-butyl 4-[2-(4-benzyloxycarbonylpiperazin-1-ylcarbonylamino)ethyl]-1-piperazinecarboxylate (2.03g, 4.28mmol) prepared in Example 25 and 10% A suspension of palladium/charcoal (570 mg) dissolved in ethanol (19 ml) was hydrogenated overnight at atmospheric pressure, the reaction mixture was filtered, the catalyst was washed with ethanol, the filtrate and washings were concentrated in vacuo, and the residue was dissolved in dichloromethane (30 ml) ,, was treated with DIEA (500ml), and the solution was added dropwise to the cis-1,5-cyclooctylene bis(chloroformate) dissolved in ice-cooled methylene chloride (75ml) prepared in Example 5 ( 4.15 g, 15.4 mmol), the reaction mixture was stirred overnight, diluted with 0.5N KHSO ₄ and dichloromethane, the aqueous phase was extracted with dichloromethane, the combined organic phases were washed with brine, dried (MgSO ₄ ) and concentrated, and washed with Purification from the residue by silica gel chromatography (first with 3:1 ethyl acetate-hexane, then with pure ethyl acetate) gave cis-1,5-cyclooctylene chloroformate 4-[2 -(4-tert-butoxycarbonylpiperidin-4-yl)ethylcarbamoyl]-1-piperazinecarboxylate (1.02g, 1.8mmol, 42%), as light yellow oil. ¹ H-NMR(300MHz, CDCl ₃ ):5.00-4.90(m,1H),4.85-4.75(m,1H),4.35(brt,1H),4.05(brd,2H),3.50-3.40(m,4H ), 3.35-3.30(m,4H), 3.25(q,2H), 2.65(t,2H), 2.05-1.55(m,17H), 1.40(s,9H), 1.25-1.00(m,2H).

Example 274-cyanophenylacetic acid

Dissolve 2-(4-cyanophenyl)ethanol (5.00g, 34.0mmol) in acetone (140ml) and cool to 10-15°C, add CrO ₃ dissolved in aqueous sulfuric acid dropwise, and keep the internal temperature at 30 Below ℃, until the orange color does not disappear, a suspension is obtained. The suspension was stirred for 45 minutes and filtered, the solid was washed with acetone (150ml), the combined filtrate and washings were stirred with 2-propanol (20ml) for 30 minutes, the mixture was filtered, the filtrate was concentrated in vacuo, and the residue was dissolved in ethyl acetate , the solution was washed with 0.5NKHSO ₄ , water and brine, concentrated, the residue was dissolved in dichloromethane, the solution was treated with sodium hydroxide (1.56 g) dissolved in water (100 ml), and the aqueous phase was treated with dichloromethane , acidified to pH 1-2 with concentrated hydrochloric acid to obtain a precipitate, which was washed with water, air-dried, and vacuum-dried to give 4-cyanophenylacetic acid (3.36g, 20.7mmol, 61%) as a white powder. ¹ H-NMR (300 MHz, CDCl ₃ ): 7.63 (d, 2H), 7.40 (d, 2H), 3.72 (s, 2H).

Example 28 tert-butyl 4-(4-cyanophenylacetyl)-1-piperazinecarboxylate

Suspend the mixture of 4-cyanophenylacetic acid (890mg, 5.52mmol), dichloroethane (1.16g, 6.07mmol) and 1-hydroxybenzotriazole hydrate (820mg, 6.07mmol) prepared in Example 27 To the resulting homogeneous solution in THF (18ml) was added tert-butyl-piperazinecarboxylate (1.04g, 5.60mmol) and DIEA, the solution was concentrated in vacuo, the residue was treated with 0.2N _KHSO4 , the mixture was filtered, The solid was collected, washed with water, and dried in vacuo to afford tert-butyl 4-(4-cyanophenylacetyl)-1-piperazinecarboxylate (1.68 g, 5.1 mmol, 92%) as a solid. ¹ H-NMR (300MHz, CDCl ₃ ): 7.70(d,2H),7.35(d,2H),3.80(s,2H),3.70-3.60(m,2H),3.45-3.30(m,6H), 1.40(s,9H). Example 294-[4-(N-hydroxyamidino)phenylacetyl]-1-piperazinecarboxylic acid tert-butyl ester

With hydroxylamine hydrochloride (461mg, 6.63mmol) and triethylamine (924ml, 671mg, 6.63mmol) process the 4-(4-cyanophenylacetyl group prepared in Example 28) dissolved in absolute ethanol (10ml) )-1-tert-butyl piperazinecarboxylate (1.68g, 5.1mmol), the mixture was heated to reflux for 3.5 hours, cooled to room temperature, concentrated in vacuo, the residue was dissolved in ethanol, filtered, and the filtrate was cooled overnight to obtain a crystalline product, which was filtered The crystals were separated, washed with cold ethanol, and air-dried to obtain tert-butyl 4·[4-(N-hydroxyamidino)phenylacetyl]·1-piperazinecarboxylate (1.62g, 4.5mmol, 88%).

¹ H-NMR (300MHz, DMSO-d ₆ ): 9.60(s, 1H), 7.60(d, 2H), 7.20(d, 2H), 5.75(s, 2H), 3.70(s, 2H), 3.40( brs,4H), 3.25(brs,4H), 1.40(s,9H).

Example 304-piperazin-1-ylcarbonylmethylbenzamidine bis(trifluoroacetate)

tert-butyl 4-[4-(N-hydroxyamidino)phenylacetyl]-1-piperazinecarboxylate (653 mg, 1.81 mmol) prepared in Example 29 and 10% palladium/carbon (200 mg) were suspended in In acetic acid (12ml), hydrogen gas was passed into the suspension overnight, the reaction mixture was filtered, the catalyst was washed with acetic acid, the combined filtrate and washings were concentrated in vacuo, the residue was dissolved in TFA, the solution was allowed to stand for 1 hour, and the residue was concentrated in vacuo. The product was co-evaporated from a mixture of dichloromethane and methanol, then suspended in ether, and the particles were collected by filtration and dried to give 4-piperazin-1-ylcarbonylmethylbenzamidine bis(trifluoroacetate) (1.04g, 1.81mmol, 100%), as a white solid. ¹ H-NMR (300MHz, DMSO-d ₆ ): 9.30(d,4H), 9.15(brs,2H), 7.70(d,2H), 7.40(d,2H), 3.85(s,2H), 3.65( brd, 4H), 4.20-3.90 (m, 4H).

Example 31 cis-1,5-cyclooctylene 4-(4-amidinophenylacetyl)-1-piperazinecarboxylate 4(2-piperidin-4-ylethylcarbamoyl]- 1-piperazine carboxylate (compound 94)

The compound of formula I is prepared as follows, wherein R ¹ is 4-amidinobenzyl, R ² is 2-piperidin-4-ylethyl, X ¹ and X ⁹ are each -NHC(O)-, X ² and X ⁸ each is 1,4-piperazinylene, each of X ³ and X ⁷ is -C(O)O-, each of X ⁴ and X ⁶ is a covalent bond, and X ⁵ is cis-1,5- Cyclooctylene.

The 4-piperazin-1-ylcarbonylmethylbenzamidine bis(trifluoroacetate) (80 mg, 0.17 mmol) prepared in Example 30 was dissolved in DMF (1.0 ml), and the solution was treated with DIEA (150 ml), Add cis-1,5-cyclooctylene chloroformate 4-[2-(4-tert-butoxycarbonylpiperazin-1-yl)ethyl prepared in Example 26 dissolved in DMF (1.0ml) Carbamoyl]-1-piperazinecarboxylate (100 mg), the mixture was stirred overnight, concentrated in vacuo, the residue was dissolved in dichloromethane and TFA (1:1), the mixture was concentrated in vacuo, the residue was triturated with ether , giving a foamy residue. Purification from the residue by preparative reverse-phase HPLC and lyophilization of the purified fractions afforded cis-1,5-cyclooctylidene 4-(4-amidinophenylacetyl)-1-piperazinecarboxylic acid Ester 4(2-piperidin-4-ylethylcarbamoyl _] -1-piperazinecarboxylate as a _colorless solid. Electron spray: LRMS: _Calcd . for ( _C35H54N8O8 )MH ⁺ : 683.9; MH ₂ ⁺² /2: 342.5; Found: MH ⁺ : 683.8; MH ₂ ^{+2 /2} : 342.3.

According to the method of Example 31, using different starting materials, the following compound of formula I was prepared:

cis-1,5-cyclooctylene 4-(1-amidinopiperidin-4-ylacetyl)-1-piperazinecarboxylate 4(2-piperidin-4-ylethylcarbamoyl] -1-piperazinecarboxylate (Compound 95); Calculated (C ₃₄ H ₅₉ N ₉ O ₆ ) MH ⁺ : 690.9; Found: MH ⁺ : 690.6;

cis-1,5-cyclooctylene 4-(4-amidinobenzoylaminoethyl)-1-piperidinecarboxylate 4(2-piperidin-4-ylethyl)carbamoyl]- 1-Piperazinecarboxylate (Compound 96); Calcd. (C ₃₆ H ₅₆ N ₈ O ₆ ) MH ⁺ : 697.9; Found: MH ⁺ : 697.7;

cis-1,5-cyclooctylene 4-(4-amidinobenzylcarbamoyl)-1-piperazinecarboxylate 4(2-piperidin-4-ylethylcarbamoyl]-1- Piperazine carboxylate (Compound 97); Calcd. (C ₃₅ H ₅₅ N ₉ O ₆ ) MH ⁺ : 698.9; Found: MH ⁺ : 698.7;

cis-1,5-cyclooctylene 4-(4-amidinobenzenesulfonylaminomethyl)-1-piperidinecarboxylate 4(2-piperidin-4-ylethylcarbamoyl]-1 - piperazine carboxylate (Compound 98); Calcd. (C ₃₅ H ₅₆ N ₈ O ₇ ) MH ⁺ : 733.9; Found: MH ⁺ : 733.4;

cis-1,5-cyclooctylene 4-[2-(1-amidinopiperidin4-yl)ethylcarbamoyl]-1-piperazinecarboxylate 4(2-piperidin-4-yl Ethylcarbamoyl]-1-piperazinecarboxylate (Compound 99); Calculated for (C ₃₅ H ₆₂ N ₁₀ O ₆ ) MH ⁺ : 719.9; Found: MH ⁺ : 719.5;

cis-1,5-cyclooctylene 4-(4-amidinophenylcarbamoylmethyl)-1-piperidinecarboxylate 4(2-piperidin-4-ylethylcarbamoyl]- 1-Piperazinecarboxylate (Compound 100); Calcd. (C ₃₆ H ₅₆ N ₈ O ₆ ) MH ⁺ : 697.9; Found: MH ⁺ : 695.6;

cis-1,5-cyclooctylene 4-(4-N-methoxycarbonylamidinobenzylcarbamoyl)-1-piperazinecarboxylate 4(2-piperidin-4-ylethylaminomethyl Acyl]-1-piperazinecarboxylate (Compound 101); Calculated for (C ₃₇ H ₅₇ N ₉ O ₈ ) MH ⁺ : 756.9; Found: MH ⁺ : 756.4;

Cis-1,5-cyclooctylene 4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate 3-piperidin-4-ylpropyl-1-piperidinecarboxylate ( Compound 102); Calcd. for (C ₃₆ H ₅₈ N ₈ O ₅ ) MH ⁺ : 683.9; Found: MH ⁺ : 683.3.

Example 321,5-pentamethylenebis[4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate] (compound 103)

Compounds of formula I are prepared as follows, wherein R ^{and R} are each 4-guanidinobenzyl, X ^{and X} are each -NHC(O)-, X ^{and X} are each 1,4- Piperazinyl, X ³ and X ⁷ are each -C(O)O-, X ⁴ -X ⁶ -X ⁵ together are 1,5-pentamethylene.

4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate tert-butyl trifluoroacetate (306 mg, 0.62 mmol) was treated with neat trifluoroacetic acid (1 ml) for 10 minutes at room temperature, A colorless homogeneous solution was obtained. The liquid was concentrated and the oily residue was triturated with ether (3X 10ml) and dried in vacuo to give a colorless foam. The deprotected piperazine salt was dissolved in DMF (2.5ml), followed by the addition of diisopropylethylamine (0.5ml, 3.1mmol) and 1,5-n-pentylene bis(chloroformate) (70mg , 0.31mmol), the mixture was stirred at room temperature for 1 hour, the reaction mixture was concentrated, the residue was triturated with diethyl ether (3X10ml), dried in vacuo, the crude product was dissolved in water (5ml), purified by preparative reverse-phase HPLC, and freeze-dried to give 1,5 - Pentamethylenebis[4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate], a colorless amorphous solid. Electrospray: LRMS: Calculated for ( _C33H48N12O6 )MH ⁺ _{: 709.8} ; _Found : 709.3.

Following the procedure of Example 32, using different starting materials, the following compound of formula I was prepared.

1,5-Tetramethylenebis[4-(4-guanidinobenzylcarbamoyl)-1-piperazinecarboxylate] (compound 104), calculated for (C ₃₂ H ₄₆ N ₁₂ O ₆ )MH ⁺ : 695.8; measured value: MH ⁺ : 695.8;

4-guanidinobenzyl

4-{5-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]pentanoyl}-1-piperazinecarboxamide, (compound 105), calculated (C ₃₂ H ₄₆ N ₁₂ O ₆ ) MH ⁺ : 663.8; Measured value: MH ⁺ : 663.4;

4-guanidinobenzyl

4-{6-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]hexanoyl}-1-piperazinecarboxamide, (compound 106), calculated (C ₃₃ H ₄₈ N ₁₂ O ₄ ) MH ⁺ : 677.8; Measured value: MH ⁺ : 677.4;

4-guanidinobenzyl

4-{7-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]heptanoyl}-1-piperazinecarboxamide, (compound 107), calculated (C ₃₄ H ₅₀ N ₁₂ O ₄ ) MH ⁺ : 691.9; Measured value: MH ⁺ : 691.5;

4-guanidinobenzyl

4-{8-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]octanoyl}-1-piperazinecarboxamide, (compound 108), calculated (C ₃₇ H ₅₇ N ₉ O ₈ ) MH ⁺ : 756.9; Measured value: MH ⁺ : 756.4;

4-guanidinobenzyl

4-{9-[4-(4-guanidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]nonanoyl}-1-piperazinecarboxamide, (compound 109), calculated (C ₃₆ H ₅₄ N ₁₂ O ₄ ) MH ⁺ : 719.9; Measured value: MH ⁺ : 719.5;

4-Amidinobenzyl

4-{7-[4-(4-Amidinobenzylcarbamoyl)piperazin-1-ylcarbonyl]heptanoyl}-1-piperazinecarboxamide, (compound 110), calculated (C ₃₄ H ₄₈ N ₁₀ O ₄ ) MH ⁺ : 661.8; Measured value: MH ⁺ : 661.3:

1,5-Pentamethylenebis[4-(4-guanidinophenylacetyl)piperazin-1-ylcarbonyl], (compound 111), calculated for (C ₃₃ H ₄₆ N ₁₀ O ₄ ), MH ⁺ : 647.8; measured value: MH ⁺ : 647.3;

1,6-Hexamethylenebis[4-(4-guanidinophenylacetyl)piperazin-1-ylcarbonyl], (compound 112), calculated for (C ₃₄ H ₄₈ N ₁₀ O ₄ ), MH ⁺ : 661.8; measured value: MH ⁺ : 661;

1,7-Heptamethylenebis[4-(4-guanidinophenylacetyl)piperazin-1-ylcarbonyl], (compound 113), calculated for (C ₃₅ H ₅₀ N ₁₀ O ₄ ), MH ⁺ : 675.9; measured value: MH ⁺ : 675.4;

3-Oxa-1,5-pentamethylenebis[4-(4-guanidinophenylacetyl)piperazin-1-ylcarbonyl], (compound 114), calculated (C ₃₂ H ₄₄ N ₁₀ O ₇ ), MH ⁺ : 681.8; measured value: MH ⁺ : 681.4;

Example 33 In vitro inhibition test of tryptase

Dissolved in Tris buffer (composed of: NaCl, 100mM; Tris, 50mM; 2-[N-morpholine]ethanesulfonic acid, 2.5mM, CaCl ₂ , 0.5mM; DMSO, 10%; glycerol, 5%; Human tryptase (15 μg/ml) and test compounds (various concentrations) in polyoxyethylene sorbitan monolaurate (Tween-20), 0.05%; heparin, 25 ng/ml; pH 8.2) at room temperature After incubation for 1 hour at 90°C, Tosyl-Gly-Pro-Lys-p-nitroaniline was added to give a final concentration of the assay mixture of 0.5 mM, the substrate was hydrolyzed, and spectroscopic measurements were performed for 5 minutes (405 nm), using standard mathematical models from the enzyme Apparent inhibition constants (Ki) were calculated from progression curves.

Human tryptase can be obtained from human lung and skin tissue samples (see, for example, Smith et al. (1984) J. Biol. Chem. 59; 11046-11051; Braganza et al. (1991) Biochem 30: 4997-5007) and human columnar cells Purified strains are also commercially available (eg, ICNBiomedicals, Irvine California; Athens Research and Technology, Athens Georgia). Porcine intestinal mucosal heparin and Tosyl-Gly-Pro-Lys-p-nitroaniline are available from Sigma Chemical Company.

According to the method described in the present application or the method known to those skilled in the art, the compound of the following formula I was prepared and tested for its inhibitory activity against tryptase.

Compound 1, K _i =0.003 μM; Compound 2, K _i =0.8 μM; Compound 3, K _i =0.07 μM; Compound 4, K _i =0.001 μM; Compound 5, K _i =0.2 μM; Compound 6, K _i Compound 7, K _i =0.3 μM; Compound 8, K _i =4 μM; Compound 9, K _i =0.4 μM; Compound 10, K _i =1 μM; Compound 11, K _i =0.09 μM; Compound 12, K _i = 0.2 μM; Compound 13, K _i =0.02 μM; Compound 14, K _i =0.004 μM; Compound 15, K _i =0.5 μM; Compound 16, K i =0.9 μM; Compound 17, K _i =1 μM _; Compound 18, K _i =0.08 μM; Compound 19, K _i =1.2 μM; Compound 20, K _i =3.4 μM; Compound 21, K _i =0.5 μM; Compound 22, K _i =0.2 μM; Compound 23, K _i = Compound 24, K _i =0.3 μM; Compound 25, K _i =0.002 μM; Compound 26, K _i =19 μM; Compound 27, K _i =2 μM; Compound 28, K _i =4 μM; Compound 29, K _i = 1 μM; Compound 30, K _i =0.031 μM; Compound 31, K _i =1 μM; Compound 32, K _i =2 μM; Compound 33, K _i =1 μM; Compound 34, K _i =3 μM; Compound 35, K _i =0.8 μM; Compound 36, K _i =0.6 μM; Compound 37, K _i =0.07 μM; Compound 38, K _i =0.004 μM; Compound 39, K _i =0.004 μM; Compound 40, K _i =4 μM; Compound 41, K Compound 42, K _i =0.02 μM; Compound 43, K _i =0.4 μM; Compound 44, K _i =0.02 μM; Compound 45, K _i =0.08 μM; Compound 46, K _i = ₁ μM; Compound 47, K _i =0.3 μM; Compound 48, K _i =0.09 μM; Compound 49, K _i =2 μM; Compound 50, K _i =0.08 μM; Compound 51, K _i =1 μM; Compound 52, K _i =0.04 μM Compound 53, K _i =6 μM; Compound 54, K _i =0.1 μM; Compound 55, K _i =2 μM; Compound 56, K _i =10 μM; Compound 57, K _i =2 μM; Compound 58, K _i =0.1 μM Compound 59, K _i =0.5 μM; Compound 60, K _i =5 μM; Compound 61, K _i =41 μM; Compound 62, K _i =0.2 μM; Compound 63, K _i =2 μM; Compound 64, K _i =1 μM Compound 65, K _i =0.001 μM; Compound 66, K _i =0.02 μM; Compound 67, K _i =3 μM; Compound 68, K _i =0.04 μM; Compound 69, K _i =0.5 μM; Compound 70, K _i Compound 71, K _i =0.8 μM; Compound 72, K _i =0.1 μM; Compound 73, K _i =0.002 μM; Compound 74, K _i =0.04 μM; Compound 75, K _i =0.01 μM; Compound 76, K _i =0.1 μM; Compound 77, K _i =6 μM; Compound 78, K _i =0.1 μM; Compound 79, K _i =1 μM; Compound 84, K _i =0.06 μM; Compound 85, K _i =0.9 μM Compound 86, K _i =0.08 μM; Compound 87, K _i =0.05 μM; Compound 88, K _i =0.1 μM; Compound 89, K _i =0.1 μM; Compound 90, K _i =1 μM; Compound 91, K _i Compound 92, K _i =0.1 μM; Compound 93, K _i =0.02 μM; Compound 94, K _i =0.007 μM; Compound 95, K _i =0.02 μM; Compound 96, K _i =0.02 μM; Compound 97, K _i =0.0009 μM; Compound 98, K _i =0.03 μM; Compound 99, K _i =0.05 μM; Compound 100, K _i =0.009 μM; Compound 101, K _i =0.04 μM; Compound 102, K _i = Compound 103, K _i =0.001 μM; Compound 104, K _i =0.003 μM; Compound 105, K _i =0.04 μM; Compound 106, K _i =0.004 μM; Compound 107, K _i =0.0001 μM; Compound 108 , K _i =0.0005 μM; Compound 109, K _i =0.0007 μM; Compound 110, K _i =0.0008 μM; Compound 111, K _i =0.3 μM; Compound 112, K _i =0.09 μM; Compound 113, K _i =0.005 μM; compound 114, K _i =0.058 μM.

Example 33 In vitro test of asthma

Transgenic sheep with double responder characteristics (i.e. exhibiting early and late bronchoconstriction) were challenged with antigen (e.g. Ascaris suum) with test compound and vehicle 0.5 h before antigen challenge and 4 and 24 h after antigen challenge. The above-mentioned sheep were administered by inhalation of aerosol spray. Specific lung resistance ( _SRL ) was monitored by esophageal balloon catheter prior to treatment with the first test compound or vehicle and every 0.5-1 hour thereafter.

Additionally, tracheal reactivity is monitored with test compound and vehicle administration 1-2 days prior to antigen challenge and 24 hours after antigen challenge. For the present application, airway reactivity was defined as the cumulative dose of carbachol required to increase SRL by 400% (PC ₄₀₀ ). 0-30 respiratory units of 1% carbachol (10 mg in 1 mL PBS) were administered by aerosol inhalation until a PC ₄₀₀ value was obtained at a 400% increase in SRL.

Sheep dosed with vehicle exhibited early bronchoconstriction 0-4 hours after antigen challenge and late bronchoconstriction 4 to more than 8 hours after antigen challenge. Additionally vehicle treated sheep showed hyperresponsiveness to carbachol (ie a 60% decrease in _PC400 values was observed).

Sheep treated with tryptase inhibitors did not show late bronchoconstriction (ie, SR _L remained at basal levels 4-8 hours after antigen challenge), and sheep treated with tryptase inhibitors did not show response to ammonium chloride Acylcholine hyperresponsiveness.

Example 34 Typical Medicaments Containing Compounds of Formula I

Oral preparations

Formula I compound 10-100mg

Citric Acid Monohydrate 105mg

Sodium Hydroxide 18mg

flavoring agent

Add enough water to 100mL

                               

Formula I compound 0.1-10mg

Sufficient glucose monohydrate to achieve isotonicity

Citric acid monohydrate 1.05mg

Sodium Hydroxide 0.18mg

Add enough water for injection to 1.0mL

Tablets

Compound of formula Ⅰ 1%

Microcrystalline Cellulose 73%

Stearic acid 25%

Colloidal silicon dioxide 1%

Claims (44)

1. the compound of a formula I and pharmacy acceptable salt thereof and N-oxide compound: I

Wherein:

X ⁵Be C _3-14Cycloalkylidene, C _3-14Inferior Heterocyclylalkyl, C _6-14Arylidene or C _5-14Inferior aromatic heterocyclic;

X ⁴And X ⁶Be C independently of each other _0-2Alkylidene group;

X ¹And X ⁹Be independently of each other covalent linkage ,-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O-,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein each R ³Be hydrogen, C independently _1-3Alkyl or C _3-8Cycloalkyl, condition is: X ¹And X ⁹Not covalent linkage entirely;

X ³And X ⁷Be independently-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O-,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein R ³As defined above;

X ²And X ⁸Be C independently _1-8Alkylidene group, C _1-8Inferior assorted alkyl ,-X ¹⁰-X ¹¹-or-X ¹¹-X ¹⁰-, X wherein ¹⁰Be C _0-4Alkylidene group or C _3-4Inferior assorted alkyl, and X ¹¹Be C _3-8Cycloalkylidene or C _3-8Inferior Heterocyclylalkyl;

R ¹Be R ⁴-X ¹²-or R ⁵-X ¹³-, wherein

R ⁴Be amino, amidino groups, guanidine radicals, 1-imino-ethyl or methylamino,

X ¹²Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ¹⁴-X ¹⁵-X ¹⁶-, X wherein ¹⁵Be C _3-6Cycloalkylidene, C _5-6Inferior aromatic heterocyclic, C _3-6Inferior Heterocyclylalkyl or phenylene, X ¹⁴Be C _N14Alkylidene group, and X ¹⁶Be C _N16Alkylidene group, wherein n14 and n16=0,1,2,3 or 4,

R ⁵Be selected from azetidin-3-base, benzoglyoxaline-4-base, benzoglyoxaline-5-base, imidazoles-1-base, imidazoles-2-base, imidazol-4 yl, 2-tetrahydroglyoxaline-2-base, 2-tetrahydroglyoxaline-3-base, glyoxal ethyline-1-base, 4-methylimidazole-1-base, 5-Methylimidazole-1-base, 1-methyl piperidine-3-base, 1-methyl piperidine-4-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base, piperazine-2-base, pyridin-3-yl, pyridin-4-yl, pyrimidine-4-base, pyrimidine-5-base, tetramethyleneimine-3-base, 1,4,5,6-tetrahydropyrimidine-2-base, 1,4,5,6-tetrahydropyrimidine-4-base and 1,4,5,6-tetrahydropyrimidine-5-base and carbocyclic ring ketone or its sulfo-ketone derivatives, this group can be unsubstituted or by one or more halogens that are selected from, hydroxyl, sulfydryl, C _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷Be independently selected from hydrogen, C _1-8Alkyl, C _1-8Alkyloyl, C _3-14Cycloalkyl or C _6-14Aryl, and

X ¹³Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ¹⁷-X ¹⁸-X ¹⁹-, X wherein ¹⁸With above-mentioned X ¹⁵Definition identical, X ¹⁷Be C _N17Alkylidene group, and X ¹⁹Be C _N19Alkylidene group, wherein n17 and n19=0,1 or 2; And

R ²Be R ⁸-X ₂₀-or R ⁹-X ²¹-, wherein:

R ⁸Be amino, 1-imino-ethyl or methylamino,

X ²⁰Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ²²-X ²³-X ²⁴-, X wherein ²³With above-mentioned X ¹⁵Definition identical, X ²²Be C _N22Alkylidene group, and X ²⁴Be C _N24Alkylidene group, wherein n22 and n24=0,1,2,3 or 4, condition is: work as R ⁸When being amino, X ²⁰Not C _4-6Alkylidene group or oxo C _4-6Alkylidene group, and n22 is not 1,2,3 or 4,

R ⁹With above-mentioned R ⁵Definition identical, and

X ²¹Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ²⁵-X ²⁶-X ²⁷-, X wherein ²⁶With above-mentioned X ¹⁵Definition identical, X ²⁵Be C _N25Alkylidene group, and X ²⁷Be C _N27Alkylidene group, wherein n25 and n27=0,1 or 2;

Wherein the alkylidene group of each above-mentioned definition, cycloalkylidene, inferior assorted alkyl, inferior Heterocyclylalkyl, phenylene, arylidene and inferior heteroaryl can be unsubstituted or by one or more halogen, hydroxyl, sulfydryl, C of being selected from _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷As defined above, condition is: at R ¹, X ², X ⁴, X ⁶, X ⁸And R ²In contained heteroatoms and X ³, X ⁵, X ⁷And X ⁹In do not have covalent linkage between the contained heteroatoms.

2. the compound of claim 1 and pharmacy acceptable salt thereof and N-oxide compound, wherein:

X ⁵Be cis-1, the inferior ring of 5-octyl group, X ⁴And X ⁶Respectively be that a covalent linkage or X5 are phenylene, X ⁴And X ⁶Be C _0-1Alkylidene group;

X ¹And X ⁹Be independently of one another a covalent linkage ,-C (O)-,-NHC (O)-,-C (O) NH ,-N (CH ₃) C (O)-or-S (O) ₂NH-;

X ³And X ⁷Be independently-C (O)-or-C (O) O-;

X ²And X ⁸Be independently-X ¹⁰-X ¹¹-, wherein

X ¹⁰Be a covalent linkage or methylene radical, and

X ¹¹Be 4,1-piperidylidene or 1, the inferior piperazinyl of 4-;

R ¹Be R ⁴-X ¹²-or R ⁵-X ¹³, wherein

R ⁴Be amidino groups, guanidine radicals or methylamino,

X ¹²For-X ¹⁴-X ¹⁵-X ¹⁶-, X wherein ¹⁵Be 1,4-phenylene or 1,4-piperidylidene, X ¹⁴Be C _N14Alkylidene group, and X ¹⁶Be C _N16Alkylidene group, wherein n14 and n16=0,1 or 2,

R ⁵Be piperidin-4-yl, and

X ¹³Be C _2-3Alkylidene group; And

R ²Be R ⁸-X ²⁰-or R ⁹-X ²¹-, wherein

R ⁸Be amino, methylamino or 1-imino-ethyl,

X ²⁰For-X ²²-X ²³-X ²⁴, X wherein ²³Be anti-form-1,4-cyclohexylidene, 1,4-phenylene, 4,1-pyridylidene, 1,4-piperidylidene, X ²²Be C _N22Alkylidene group, and X ²⁴Be C _N24Alkylidene group, wherein n22 and n24=1 or 2,

R ⁹Be benzoglyoxaline-5-base, imidazoles-1-base, imidazol-4 yl, 2-tetrahydroglyoxaline-2-base, 4-methylimidazole-1-base, 5-Methylimidazole-1-base, 1-methyl piperidine-4-base, piperidin-4-yl, piperazine-1-base, pyridin-3-yl, pyridin-4-yl, 1,4,5,6-tetrahydropyrimidine-5-base or 1,4,5,6-tetrahydrochysene-2-dioxo pyrimidine-5-base, and

X ²¹Be C _1-6Alkylidene group, ω-azepine C _2-5Alkylidene group, 2-azepine-3-oxo trimethylene, 3-azepine-2-oxo trimethylene, 3-oxo trimethylene, ω-thia-C _2-4Alkylidene group or-X ²⁵-X ²⁶-X ²⁷-, X wherein ²⁶Be 1,4-phenylene, X ²⁵Be C _N25Alkylidene group, and X ²⁷Be C _N27Alkylidene group, wherein n25 and n27=0 or 1.

3. the compound of claim 2 and pharmacy acceptable salt thereof and N-oxide compound, wherein

X ⁵Be cis-1, the inferior ring of 5-octyl group, X ⁴And X ⁶It respectively is a covalent linkage; X ¹And X ⁹Be independently of one another a covalent linkage ,-C (O)-,-NHC (O)-,-C (O) NH or-S (O) ₂NH-; X ³And X ⁷Be independently-C (O)-or-C (O) O-; R ¹Be R ⁴-X ¹²-, R wherein ⁴Be amidino groups or guanidine radicals; And R ²Be R ⁸-X ²⁰-or R ⁹-X ²¹-, R wherein ⁸Be amino or methylamino, X ²³Be anti-form-1,4-cyclohexylidene or 1,4-phenylene, R ⁹Be imidazoles-1-base, imidazol-4 yl, 4-methylimidazole-1-base, 5-Methylimidazole-1-base, piperidin-4-yl or pyridin-4-yl, and X ²¹Be C _1-5Alkylidene group or 3-azepine three alkylidene groups.

4. the compound of claim 3 and pharmacy acceptable salt thereof and N-oxide compound, wherein

X ¹And X ⁹Be independently of one another-C (O)-or-NHC (O)-; X ³And X ⁷Respectively be-C (O) O-; X ²And X ⁸Be independently-X ¹⁰-X ¹¹-, X wherein ¹⁰Be covalent linkage, and X ¹¹Be 1, the inferior piperazinyl of 4-; R ¹Be R ⁴-X ¹²-, R wherein ⁴Be amidino groups or guanidine radicals, and X ¹²For-X ¹⁴-X ¹⁵-X ¹⁶-, X wherein ¹⁵Be 1,4-phenylene, X ¹⁴Be a covalent linkage, and X ¹⁶Be methylene radical; And R ²Be R ⁸-X ²⁰-or R ⁹-X ²¹-, R wherein ⁸Be amino, X ²⁰For-X ²²-X ²³-X ²⁴, X wherein ²³Be anti-form-1,4-cyclohexylidene, X ²²Be a covalent linkage, and X ²⁴Be methylene radical, R ⁹Be piperidin-4-yl, and X ²¹Be ethylidene or trimethylene.

5. the compound of claim 4, wherein X ¹And X ⁹Respectively do for oneself-NHC (O)-, R ¹Be 4-amidino benzyl R ²For 2-piperidin-4-yl ethyl is a cis-1, the inferior ring of 5-octyl group-4-(4-amidino benzyl formamyl)-1-piperazinecarboxylic acid ester-4-(2-piperidin-4-yl ethylamino formyl radical)-1-piperazinecarboxylic acid ester and pharmacy acceptable salt and N-oxide compound.

6. the compound of claim 4, wherein X ¹For-NHC (O)-, X ⁹For-C (O)-, R ¹Be 4-amidino benzyl R ²For 3-piperidin-4-yl propyl group is a cis-1, the inferior ring of 5-octyl group-4-(4-amidino benzyl formamyl)-1-piperazinecarboxylic acid ester-4-(4-piperidin-4-yl butyryl radicals)-1-piperazinecarboxylic acid ester and pharmacy acceptable salt and N-oxide compound.

7. the compound of claim 4, wherein X ¹And X ⁹Respectively do for oneself-NHC (O)-, R ¹Be 4-guanidine radicals benzyl R ²For trans-4-aminocyclohexyl methyl is a cis-1, the inferior ring of 5-octyl group-trans-4-(4-aminocyclohexyl methylamino formyl radical)-1-piperazinecarboxylic acid ester-4-(4-guanidine radicals benzylamino formyl radical)-1-piperazinecarboxylic acid ester and pharmacy acceptable salt and N-oxide compound.

8. the compound of claim 4, wherein X ¹And X ⁹Respectively do for oneself-C (O)-, R ¹Be 4-aminobenzyl R ²For 3-piperidin-4-yl propyl group is a cis-1, the inferior ring of 5-octyl group-4-(4-amidino groups phenylacetyl)-1-piperazinecarboxylic acid ester-4-(4-piperidin-4-yl butyryl radicals)-1-piperazinecarboxylic acid ester and pharmacy acceptable salt and N-oxide compound.

9. the compound of claim 4, wherein X ¹And X ⁹Respectively do for oneself-NHC (O)-, R ¹Be 4-guanidine radicals benzyl R ²For 2-piperidin-4-yl ethyl is a cis-1, the inferior ring of 5-octyl group-4-(4-guanidine radicals benzylamino formyl radical)-1-piperazinecarboxylic acid ester-4-(2-piperidin-4-yl ethylamino formyl radical)-1-piperazinecarboxylic acid ester and pharmacy acceptable salt and N-oxide compound.

10. the compound of claim 4, wherein X ¹For-NHC (O)-, X ⁹For-C (O)-, R ¹Be 4-guanidine radicals benzyl R ²For 3-piperidin-4-yl propyl group is a cis-1, the inferior ring of 5-octyl group-4-(4-guanidine radicals benzylamino formyl radical)-1-piperazinecarboxylic acid ester-4-(4-piperidin-4-yl butyryl radicals)-1-piperazinecarboxylic acid ester and pharmacy acceptable salt and N-oxide compound.

11. the compound of claim 4, wherein X ¹For-C (O)-, X ⁹For-NHC (O)-, R ¹Be 4-guanidine radicals benzyl R ²For 2-piperidin-4-yl ethyl is a cis-1, the inferior ring of 5-octyl group-4-(4-guanidine radicals phenylacetyl)-1-piperazinecarboxylic acid ester-4-(2-piperidin-4-yl ethylamino formyl radical)-1-piperazinecarboxylic acid ester and pharmacy acceptable salt and N-oxide compound.

12. the compound of claim 4, wherein X ¹And X ⁹Respectively do for oneself-C (O)-, R ¹Be 4-guanidine radicals benzyl R ²For 3-piperidin-4-yl propyl group is a cis-1, the inferior ring of 5-octyl group-4-(4-guanidine radicals phenylacetyl)-1-piperazinecarboxylic acid ester-4-(4-piperidin-4-yl butyryl radicals)-1-piperazinecarboxylic acid ester and pharmacy acceptable salt and N-oxide compound.

13. the compound of claim 4, wherein X ¹For-C (O)-, X ⁹For-NHC (O)-, R ¹Be 4-amidino benzyl R ²For 2-piperidin-4-yl ethyl is a cis-1, the inferior ring of 5-octyl group-4-(4-amidino groups phenylacetyl)-1-piperazinecarboxylic acid ester-4-(2-piperidin-4-yl ethylamino formyl radical)-1-piperazinecarboxylic acid ester and pharmacy acceptable salt and N-oxide compound.

14. one kind contains the compound of the claim 1 for the treatment of significant quantity and a kind of pharmaceutical composition of pharmaceutically acceptable vehicle.

15. one kind is used for preparing application at the medicine of the active relevant Animal diseases of its pathology of treatment and/or symptomology and tryptase with the compound in the following formula I or its pharmacy acceptable salt or N-oxide compound, comprises with the following formula I compound for the treatment of significant quantity or its pharmacy acceptable salt or N-oxide compound carrying out administration: I

Wherein:

X ⁵Be C _3-14Cycloalkylidene, C _3-14Inferior Heterocyclylalkyl, C _6-14Arylidene or C _5-14Inferior aromatic heterocyclic;

X ⁴And X ⁶Be C independently of each other _0-2Alkylidene group;

X ¹And X ³Be independently of each other covalent linkage ,-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O-,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein each R ³Be hydrogen, C independently _1-3Alkyl or C _3-8Cycloalkyl;

X ⁷And X ⁹Be independently-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O-,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein R ³As defined above;

X ²And X ⁸Be C independently _1-8Alkylidene group, C _1-8Inferior assorted alkyl ,-X ¹⁰-X ¹¹-or-X ¹¹-X ¹⁰-, X wherein ¹⁰Be C _0-4Alkylidene group or C _3-4Inferior assorted alkyl, and X ¹¹Be C _3-8Cycloalkylidene or C _3-8Inferior Heterocyclylalkyl;

R ¹Be R ⁴-X ¹²-or R ³-X ¹³-, wherein

R ⁴Be amino, amidino groups, guanidine radicals, 1-imino-ethyl or methylamino,

X ¹²Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ¹⁴-X ¹⁵-X ¹⁶-, X wherein ¹⁵Be C _3-6Cycloalkylidene, C _5-6Inferior aromatic heterocyclic, C _3-6Inferior Heterocyclylalkyl or phenylene, X ¹⁴Be C _N14Alkylidene group, and X ¹⁶Be C _N16Alkylidene group, wherein n14 and n16=0,1,2,3 or 4,

R ⁵Be selected from azetidin-3-base, benzoglyoxaline-4-base, benzoglyoxaline-5-base, imidazoles-1-base, imidazoles-2-base, imidazol-4 yl, 2-tetrahydroglyoxaline-2-base, 2-tetrahydroglyoxaline-3-base, glyoxal ethyline-1-base, 4-methylimidazole-1-base, 5-Methylimidazole-1-base, 1-methyl piperidine-3-base, 1-methyl piperidine-4-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base, piperazine-2-base, pyridin-3-yl, pyridin-4-yl, pyrimidine-4-base, pyrimidine-5-base, tetramethyleneimine-3-base, 1,4,5,6-tetrahydropyrimidine-2-base, 1,4,5,6-tetrahydropyrimidine-4-base and 1,4,5,6-tetrahydropyrimidine-5-base and carbocyclic ring ketone or its sulfo-ketone derivatives, this group can be unsubstituted or by one or more halogens that are selected from, hydroxyl, sulfydryl, C _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷Be independently selected from hydrogen, C _1-8Alkyl, C _1-8Alkyloyl, C _3-14Cycloalkyl or C _6-14Aryl, and

X ¹³Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ¹⁷-X ¹⁸-X ¹⁹-, X wherein ¹⁸With above-mentioned X ¹⁵Definition identical, X ¹⁷Be C _N17Alkylidene group, and X ¹⁹Be C _N19Alkylidene group, wherein n17 and n19=0,1 or 2; And

R ²Be R ⁸-X ²⁰-or R ⁹-X ²¹-, wherein:

R ⁸Be amino, 1-imino-ethyl or methylamino,

X ²⁰Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ²²-X ²³-X ²⁴-, X wherein ²³With above-mentioned X ¹⁵Definition identical, X ²²Be C _N22Alkylidene group, and X ²⁴Be C _N24Alkylidene group, wherein n22 and n24=0,1,2,3 or 4, condition is: work as R ⁸When being amino, X ²⁰Not C _4-6Alkylidene group or oxo C _4-6Alkylidene group, and n22 is not 1,2,3 or 4,

R ⁹With above-mentioned R ⁵Definition identical, and

X ²¹Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ²⁵-X ²⁶-X ²⁷-, X wherein ²⁶With above-mentioned X ¹⁵Definition identical, X ²⁵Be C _N25Alkylidene group, and X ²⁷Be C _N27Alkylidene group, wherein n25 and n27=0,1 or 2;

Wherein the alkylidene group of each above-mentioned definition, cycloalkylidene, inferior assorted alkyl, inferior Heterocyclylalkyl, phenylene, arylidene and inferior heteroaryl can be unsubstituted or by one or more halogen, hydroxyl, sulfydryl, C of being selected from _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷As defined above, condition is: at R ¹, X ², X ⁴, X ⁶, X ⁸And R ²In contained heteroatoms and X ³, X ⁵, X ⁷And X ⁹In do not have covalent linkage between the contained heteroatoms.

16. the application of claim 15, wherein said disease be selected from asthma, allergic rhinitis, rheumatic spondylitis, osteoarthritis, air permeability sacroiliitis, rheumatic arthritis, general sacroiliitis, urticaria, angioedema, eczematoid dermatitis, allergy, hyperplasia dermatoses, stomach ulcer, inflammatory bowel, eye conjunctivitis and pubescence conjunctivitis, inflammatory skin disease.

17. the application of claim 16, wherein said disease is an asthma.

18. the application of claim 17, compound wherein pharmaceutically acceptable be applicable to as the aerosolized carrier of inhalation administration in administration.

19. the application of claim 18, compound wherein merges administration with beta-adrenaline excitant, methyl xanthine, cromoglycate or the reflunomide of treatment significant quantity.

20. the application of claim 19, wherein beta-adrenaline excitant is selected from salbutamol, terbutaline, formoterol, Partusisten and prenaline, methyl xanthine is selected from caffeine, theophylline, aminophylline and Theobromine, cromoglycate is selected from Cromoglycic Acid and nedocromil, and reflunomide is selected from beclometasone, triamcinolone, flurisolide and dexamethasone.

21. the application of claim 16, wherein said disease is rheumatoid arthritis or conjunctivitis.

22. the application of claim 21, the administration in the carrier of pharmaceutically acceptable suitable topical of compound wherein.

23. compound and the pharmacy acceptable salt and the N-oxide compound of the formula I described in the claim 1:

I

Wherein:

X ⁴-X ⁵-X ⁶Be C together _2-12Alkylidene group or C _2-12Inferior assorted alkyl;

X ¹And X ⁹Be independently of each other covalent linkage ,-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O-,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein each R ³Be hydrogen, C independently _1-3Alkyl or C _3-8Cycloalkyl, condition is: X ¹And X ⁹Not covalent linkage entirely;

X ³And X ⁷Be independently-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O-,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein R ³As defined above;

X ²And X ⁸Be C independently _1-8Alkylidene group, C _1-8Inferior assorted alkyl ,-X ¹⁰-X ¹¹-or-X ¹¹-X ¹⁰-, X wherein ¹⁰Be C _0-4Alkylidene group or C _3-4Inferior assorted alkyl, and X ¹¹Be C _3-8Cycloalkylidene or C _3-8Inferior Heterocyclylalkyl;

R ¹Be R ⁴-X ¹²-or R ⁵-X ¹³-, wherein

R ⁴Be amino, amidino groups, guanidine radicals, 1-imino-ethyl or methylamino,

X ¹²Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ¹⁴-X ¹⁵-X ¹⁶-, X wherein ¹⁵Be C _3-6Cycloalkylidene, C _5-6Inferior aromatic heterocyclic, C _3-6Inferior Heterocyclylalkyl or phenylene, X ¹⁴Be C _N14Alkylidene group, and X ¹⁶Be C _N16Alkylidene group, wherein n14 and n16=0,1,2,3 or 4,

R ⁵Be selected from azetidin-3-base, benzoglyoxaline-4-base, benzoglyoxaline-5-base, imidazoles-1-base, imidazoles-2-base, imidazol-4 yl, 2-tetrahydroglyoxaline-2-base, 2-tetrahydroglyoxaline-3-base, glyoxal ethyline-1-base, 4-methylimidazole-1-base, 5-Methylimidazole-1-base, 1-methyl piperidine-3-base, 1-methyl piperidine-4-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base, piperazine-2-base, pyridin-3-yl, pyridin-4-yl, pyrimidine-4-base, pyrimidine-5-base, tetramethyleneimine-3-base, 1,4,5,6-tetrahydropyrimidine-2-base, 1,4,5,6-tetrahydropyrimidine-4-base and 1,4,5,6-tetrahydropyrimidine-5-base and carbocyclic ring ketone or its sulfo-ketone derivatives, this group can be unsubstituted or by one or more halogens that are selected from, hydroxyl, sulfydryl, C _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷Be independently selected from hydrogen, C _1-8Alkyl, C _1-8Alkyloyl, C _3-14Cycloalkyl or C _6-14Aryl, and

X ¹³Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ¹⁷-X ¹⁸-X ¹⁹-, X wherein ¹⁸With above-mentioned X ¹⁵Definition identical, X ¹⁷Be C _N17Alkylidene group, and X ¹⁹Be C _N19Alkylidene group, wherein n17 and n19=0,1 or 2; And R ²Be R ⁸-X ²⁰-or R ⁹-X ²¹-, wherein:

R ⁸With above-mentioned R ⁴Definition identical,

X ²⁰Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ²²-X ²³-X ²⁴-, X wherein ²³With above-mentioned X ¹⁵Definition identical, X ²²Be C _N22Alkylidene group, and X ²⁴Be C _N24Alkylidene group, wherein n22 and n24=0,1,2,3 or 4,

R ⁹With above-mentioned R ⁵Definition identical, and

X ²¹Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ²⁵-X ²⁶-X ²⁷-, X wherein ²⁶With above-mentioned X ¹⁵Definition identical, X ²⁵Be C _N25Alkylidene group, and X ²⁷Be C _N27Alkylidene group, wherein n25 and n27=0,1 or 2;

Wherein the alkylidene group of each above-mentioned definition, cycloalkylidene, inferior assorted alkyl, inferior Heterocyclylalkyl, phenylene, arylidene and inferior heteroaryl can be unsubstituted or by one or more halogen, hydroxyl, sulfydryl, C of being selected from _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷As defined above, condition is: at R ¹, X ², X ⁴, X ⁶, X ⁸And R ²In contained heteroatoms and X ³, X ⁵, X ⁷And X ⁹In do not have covalent linkage between the contained heteroatoms.

24. the compound of claim 23 and pharmacy acceptable salt thereof and N-oxide compound, wherein:

X ⁴-X ⁵-X ⁶Be C together _2-10Alkylidene group or C _3-10Inferior assorted alkyl;

X ¹And X ⁹Be independently of each other covalent linkage ,-C (O)-,-NHC (O)-,-C (O) NH-,-N (CH ₃) C (O)-or-S (O) ₂NH-;

X ³And X ⁷Be independently-C (O)-or-C (O) O-;

X ²And X ⁸Be independently-X ¹⁰-X ¹¹-, X wherein ¹⁰Be a covalent linkage or methylene radical, and X ¹¹Be 4,1-piperidylidene or 1, the inferior piperazinyl of 4-;

R ¹Be R ⁴-X ¹²-or R ⁵-X ¹³-, wherein

R ⁴Be amidino groups, guanidine radicals or methylamino,

X ¹²Be-X ¹⁴-X ¹⁵-X ¹⁶-, X wherein ¹⁵Be 1,4-phenylene or 1,4-piperidylidene, X ¹⁴Be C _N14Alkylidene group, and X ¹⁶Be C _N16Alkylidene group, wherein n14 and n16=0,1 or 2,

R ⁵Be piperidin-4-yl, and

X ¹³Be C _2-3Alkylidene group; And

R ²Be R ⁸-X ²⁰-or R ⁹-X ²¹-, wherein:

R ⁸Be amino, amidino groups, guanidine radicals, methylamino or 1-imino-ethyl,

X ²⁰For-X ²²-X ²³-X ²⁴-, X wherein ²³Be anti-form-1,4-cyclohexylidene, 1,4-phenylene, 4,1-pyridylidene, 1,4-piperidylidene, X ²²Be C _N22Alkylidene group, and X ²⁴Be C _N24Alkylidene group, wherein n22 and n24=1 or 2,

R ⁹Be benzoglyoxaline-5-base, imidazoles-1-base, imidazol-4 yl, 2-tetrahydroglyoxaline-2-base, 4-methylimidazole-1-base, 5-Methylimidazole-1-base, 1-methyl piperidine-4-base, piperidin-4-yl, piperazine-1-base, pyridin-3-yl, pyridin-4-yl, 1,4,5,6-tetrahydropyrimidine-5-base or 1,4,5,6-tetrahydrochysene-2-dioxo pyrimidine-5-base, and

X ²¹Be C _1-6Alkylidene group, ω-azepine C _2-5Alkylidene group, 2-azepine-3-oxo three alkylidene groups, 3-azepine-2-oxo trimethylene, 3-oxo trimethylene, ω-thia-C _2-4Alkylidene group or-X ²⁵-X ²⁶-X ²⁷-, X wherein ²⁶Be 1,4-phenylene, X ²⁵Be C _N25Alkylidene group, and X ²⁷Be C _N27Alkylidene group, wherein n25 and n27=0 or 1.

25. the compound of claim 24 and pharmacy acceptable salt thereof and N-oxide compound, wherein:

X ⁴-X ⁵-X ⁶Be C together _4-8Alkylidene group or C _4-10Inferior assorted alkyl;

X ¹And X ⁹Be independently of each other covalent linkage ,-C (O)-,-NHC (O)-,-C (O) NH-or-S (O) ₂NH-;

X ³And X ⁷Be independently-C (O)-or-C (O) O-;

R ¹Be R ⁴-X ¹²-, R wherein ⁴Be amidino groups or guanidine radicals, and

R ²Be R ⁸-X ²⁰-or R ⁹-X ²¹-, wherein:

R ⁸Be amino, amidino groups, guanidine radicals or methylamino,

X ²³Be anti-form-1,4-cyclohexylidene or 1, the 4-phenylene,

R ⁹Be imidazoles-1-base, imidazol-4 yl, 4-methylimidazole-1-base, 5-Methylimidazole-1-base, piperidin-4-yl or pyridin-4-yl, and

X ²¹Be C _1-5Alkylidene group or 3-azepine trimethylene.

26. the compound of claim 25 and pharmacy acceptable salt thereof and N-oxide compound, wherein:

X ¹And X ⁹Be independently of each other-C (O)-or-NHC (O)-;

X ³And X ⁷Be independently-C (O)-or-C (O) O-;

X ²And X ⁸Respectively be-X ¹⁰-X ¹¹-, X wherein ¹⁰Be a covalent linkage, and X ¹¹Be 1, the inferior piperazinyl of 4-;

R ¹Be R ⁴-X ¹²-, R wherein ⁴Be amidino groups or guanidine radicals, and X ¹²Be-X ¹⁴-X ¹⁵-X ¹⁶-, X wherein ¹⁵Be 1,4-phenylene, X ¹⁴Be a covalent linkage, and X ¹⁶Be methylene radical, and

R ²Be R ⁸-X ²⁰-, R wherein ⁸Be amidino groups or guanidine radicals, and X ²⁰For-X ²²-X ²³-X ²⁴-, X wherein ²³Be 1,4-phenylene, X ²²Be a covalent linkage, and X ²⁴Be methylene radical.

27. the compound of claim 26, wherein X ⁴-X ⁵-X ⁶Be hexa-methylene together, X ¹And X ⁹Respectively be-NHC (O)-, X ³And X ⁷Respectively be-C (O)-, and R ¹And R ²Be 4-guanidine radicals benzyl-4-{7-[4-(4-guanidine radicals benzylamino formyl radical) piperazine-1-base carbonyl respectively for 4-guanidine radicals benzyl]-oenanthyl }-1-piperazine carboxamides and pharmacy acceptable salt and N-oxide compound.

28. the compound of claim 26, wherein X ⁴-X ⁵-X ⁶Be heptamethylene together, X ¹And X ⁹Respectively be-NHC (O)-, X ³And X ⁷Respectively be-C (O)-, and R ¹And R ²Be 4-guanidine radicals benzyl-4-{8-[4-(4-guanidine radicals benzylamino formyl radical) piperazine-1-base carbonyl respectively for 4-guanidine radicals benzyl]-capryloyl }-1-piperazine carboxamides and pharmacy acceptable salt and N-oxide compound.

29. the compound of claim 26, wherein X ⁴-X ⁵-X ⁶Be eight methylene radical together, X ¹And X ⁹Respectively be-NHC (O)-, X ³And X ⁷Respectively be-C (O)-, and R ¹And R ²Be 4-guanidine radicals benzyl-4-{9-[4-(4-guanidine radicals benzylamino formyl radical) piperazine-1-base carbonyl respectively for 4-guanidine radicals benzyl]-nonanoyl }-1-piperazine carboxamides and pharmacy acceptable salt and N-oxide compound.

30. the compound of claim 26, wherein X ⁴-X ⁵-X ⁶Be hexa-methylene together, X ¹And X ⁹Respectively be-NHC (O)-, X ³And X ⁷Respectively be-C (O)-, and R ¹And R ²Each 4-amidino benzyl is 4-amidino benzyl-4-{7-[4-(4-amidino benzyl formamyl) piperazine-1-base carbonyl]-oenanthyl }-1-piperazine carboxamides and pharmacy acceptable salt and N-oxide compound.

31. the compound of claim 26, wherein X ⁴-X ⁵-X ⁶Be pentamethylene together, X ¹And X ⁹Respectively be-NHC (O)-, X ³And X ⁷Respectively be-C (O) O-, and R ¹And R ²Respectively be that 4-guanidine radicals benzyl is 1,5-pentamethylene-two [4-(4-guanidine radicals benzylamino formyl radical) 1-piperazinecarboxylic acid ester] and pharmacy acceptable salt and N-oxide compound.

32. the compound of claim 26, wherein X ⁴-X ⁵-X ⁶Be tetramethylene together, X ¹And X ⁹Respectively be-NHC (O)-, X ⁹And X ⁷Respectively be-C (O) O-, and R ¹And R ²Respectively be that 4-guanidine radicals benzyl is 1,5-tetramethylene-two [4-(4-guanidine radicals benzylamino formyl radical) 1-piperazinecarboxylic acid ester] and pharmacy acceptable salt and N-oxide compound.

33. the compound of claim 26, wherein X ⁴-X ⁵-X ⁶Be pentamethylene together, X ¹And X ⁹Respectively be-NHC (O)-, X ³And X ⁷Respectively be-C (O)-, and R ¹And R ²Be 4-guanidine radicals benzyl-4-{6-[4-(4-amidino benzyl formamyl) piperazine-1-base carbonyl respectively for 4-guanidine radicals benzyl]-caproyl }-1-piperazine carboxamides and pharmacy acceptable salt and N-oxide compound.

34. the compound of claim 26, wherein X ⁴-X ⁵-X ⁶Be 3-oxa-tetramethylene together, X ¹And X ⁹Respectively be-C (O)-, X ³And X ⁷Respectively be-C (O)-, and R ¹And R ²Respectively be the 4-amidino benzyl, i.e. 3-oxa--1,5-pentamethylene-two [4-(4-guanidine radicals phenylacetyl) piperazine-1-base carbonyl] and pharmacy acceptable salt and N-oxide compound.

35. one kind contains a kind of compound of the claim 23 for the treatment of significant quantity and a kind of pharmaceutical composition of pharmaceutically acceptable vehicle.

36. one kind is used for preparing application at the medicine of the active relevant Animal diseases of its pathology of treatment and/or symptomology and tryptase with the compound in the following formula I or its pharmacy acceptable salt or N-oxide compound, comprises with the following formula I compound for the treatment of significant quantity or its pharmacy acceptable salt or N-oxide compound to this animals administer:

I

Wherein:

X ⁴-X ⁵-X ⁶Be C together _2-12Alkylidene group or C _3-12Inferior assorted alkyl;

X ¹And X ⁹Be independently of each other covalent linkage ,-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O-,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein each R ³Be hydrogen, C independently _1-3Alkyl or C _3-8Cycloalkyl, condition is: X ¹And X ⁹Not covalent linkage entirely;

X ³And X ⁷Be independently-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O-,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein R ³As defined above;

X ²And X ⁸Be C independently _1-8Alkylidene group, C _1-8Inferior assorted alkyl ,-X ¹⁰-X ¹¹-or-X ¹¹-X ¹⁰-, X wherein ¹⁰Be C _0-4Alkylidene group or C _3-4Inferior assorted alkyl, and X ¹¹Be C _3-8Cycloalkylidene or C _3-8Inferior Heterocyclylalkyl;

R ¹Be R ⁴-X ¹²-or R ⁵-X ¹³-, wherein

R ⁴Be amino, amidino groups, guanidine radicals, 1-imino-ethyl or methylamino,

X ¹²Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ¹⁴-X ¹⁵-X ¹⁶-, X wherein ¹⁵Be C _3-6Cycloalkylidene, C _5-6Inferior aromatic heterocyclic, C _3-6Inferior Heterocyclylalkyl or phenylene, X ¹⁴Be C _N14Alkylidene group, and X ¹⁶Be C _N16Alkylidene group, wherein n14 and n16=0,1,2,3 or 4,

R ⁵Be selected from azetidin-3-base, benzoglyoxaline-4-base, benzoglyoxaline-5-base, imidazoles-1-base, imidazoles-2-base, imidazol-4 yl, 2-tetrahydroglyoxaline-2-base, 2-tetrahydroglyoxaline-3-base, glyoxal ethyline-1-base, 4-methylimidazole-1-base, 5-Methylimidazole-1-base, 1-methyl piperidine-3-base, 1-methyl piperidine-4-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base, piperazine-2-base, pyridin-3-yl, pyridin-4-yl, pyrimidine-4-base, pyrimidine-5-base, tetramethyleneimine-3-base, 1,4,5,6-tetrahydropyrimidine-2-base, 1,4,5,6-tetrahydropyrimidine-4-base and 1,4,5,6-tetrahydropyrimidine-5-base and any carbocyclic ring ketone or its sulfo-ketone derivatives, this group can be unsubstituted or by one or more halogens that are selected from, hydroxyl, sulfydryl, C _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷Be independently selected from hydrogen, C _1-8Alkyl, C _1-8Alkyloyl, C _3-14Cycloalkyl or C _6-4Aryl, and

X ¹³Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ¹⁷-X ¹⁸-X ¹⁹-, X wherein ¹⁸With above-mentioned X ¹⁵Definition identical, X ¹⁷Be C _N17Alkylidene group, and X ¹⁹Be C _N19Alkylidene group, wherein n17 and n19=0,1 or 2; And

R ²Be R ⁸-X ²⁰-or R ⁹-X ²¹-, wherein:

R ⁸With above-mentioned R ⁴Definition identical,

X ²⁰Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ²²-X ²³-X ²⁴-, X wherein ²³With above-mentioned X ¹⁵Definition identical, X ²²Be C _N22Alkylidene group, and X ²⁴Be C _N24Alkylidene group, wherein n22 and n24=0,1,2,3 or 4,

R ⁹With above-mentioned R ⁵Definition identical, and

X ²¹Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ²⁵-X ²⁶-X ²⁷-, X wherein ²⁶With above-mentioned X ¹⁵Definition identical, X ²⁵Be C _N25Alkylidene group, and X ²⁷Be C _N27Alkylidene group, wherein n25 and n27=0,1 or 2;

Wherein the alkylidene group of each above-mentioned definition, cycloalkylidene, inferior assorted alkyl, inferior Heterocyclylalkyl, phenylene, arylidene and inferior heteroaryl can be unsubstituted or by one or more halogen, hydroxyl, sulfydryl, C of being selected from _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷As defined above, condition is: at R ¹, X ², X ⁴, X ⁶, X ⁸And R ²In contained heteroatoms and X ³, X ⁵, X ⁷And X ⁹In do not have covalent linkage between the contained heteroatoms.

37. the application of claim 36, wherein said disease be selected from asthma, allergic rhinitis, rheumatic spondylitis, osteoarthritis, air permeability sacroiliitis, rheumatic arthritis, general sacroiliitis, urticaria, angioedema, eczematoid dermatitis, allergy, hyperplasia dermatoses, stomach ulcer, inflammatory bowel, eye conjunctivitis and pubescence conjunctivitis, inflammatory skin disease.

38. the application of claim 37, wherein said disease is an asthma.

39. the application of claim 38, pharmaceutical composition wherein comprise a kind of treat significant quantity, be dissolved in the pharmaceutically acceptable aerosolized carrier, be applicable to formula I compound as the inhalation administration.

40. the application of claim 39, pharmaceutical composition wherein also comprise a kind of beta-adrenaline excitant, methyl xanthine, cromoglycate or reflunomide for the treatment of significant quantity.

41. the application of claim 40, wherein beta-adrenaline excitant is selected from salbutamol, terbutaline, formoterol, Partusisten and prenaline, methyl xanthine is selected from caffeine, theophylline, aminophylline and Theobromine, cromoglycate is selected from Cromoglycic Acid and nedocromil, and reflunomide is selected from beclometasone, triamcinolone, flurisolide and dexamethasone.

42. the application of claim 37, wherein said disease is rheumatoid arthritis or conjunctivitis.

43. the application of claim 42, pharmaceutical composition wherein comprise a kind of treat significant quantity, be dissolved in formula I compound in the pharmaceutically acceptable carrier, that be applicable to the epidermis administration.

44. the method for a preparation and pharmacy acceptable salt and N-oxide compound: I

Wherein:

X ⁵Be C _3-14Cycloalkylidene, C _3-14Inferior Heterocyclylalkyl, C _6-14Arylidene or C _5-14Inferior aromatic heterocyclic;

X ⁴And X ⁶Be C independently of each other _0-2Alkylidene group or X ⁴-X ⁵-X ⁶Be C together _2-12Alkylidene group or C _3-12Inferior assorted alkyl;

X ¹And X ⁹Be independently of each other covalent linkage ,-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O ,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein each R ³Be hydrogen, C independently _1-3Alkyl or C _3-8Cycloalkyl, condition is: X ¹And X ⁹Not covalent linkage entirely;

X ³And X ⁷Be independently-C (O)-,-C (O) O-,-OC (O)-,-C (O) N (R ³)-,-N (R ³) C (O)-,-S (O) ₂N (R ³)-,-N (R ³) S (O) ₂-,-OC (O) N (R ³)-,-N (R ³) C (O) O-,-N (R ³) C (O) N (R ³)-or-OC (O) O-, wherein R ³As defined above;

X ²And X ⁸Be C independently _1-8Alkylidene group, C _1-8Inferior assorted alkyl ,-X ¹⁰-X ¹¹-or-X ¹¹-X ¹⁰-, X wherein ¹⁰Be C _0-4Alkylidene group or C _3-4Inferior assorted alkyl, and X ¹¹Be C _3-8Cycloalkylidene or C _3-8Inferior Heterocyclylalkyl;

R ¹Be R ⁴-X ¹²-or R ³-X ¹³-, wherein

R ⁴Be amino, amidino groups, guanidine radicals, 1-imino-ethyl or methylamino,

X ¹²Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ¹⁴-X ¹⁵-X ¹⁶-, X wherein ¹⁵Be C _3-6Cycloalkylidene, C _5-6Inferior aromatic heterocyclic, C _3-6Inferior Heterocyclylalkyl or phenylene, X ¹⁴Be C _N14Alkylidene group, and X ¹⁶Be C _N16Alkylidene group, wherein n14 and n16=0,1,2,3 or 4,

R ⁵Be selected from azetidin-3-base, benzoglyoxaline-4-base, benzoglyoxaline-5-base, imidazoles-1-base, imidazoles-2-base, imidazol-4 yl, 2-tetrahydroglyoxaline-2-base, 2-tetrahydroglyoxaline-3-base, glyoxal ethyline-1-base, 4-methylimidazole-1-base, 5-Methylimidazole-1-base, 1-methyl piperidine-3-base, 1-methyl piperidine-4-base, piperidines-3-base, piperidin-4-yl, piperazine-1-base, piperazine-2-base, pyridin-3-yl, pyridin-4-yl, pyrimidine-4-base, pyrimidine-5-base, tetramethyleneimine-3-base, 1,4,5,6-tetrahydropyrimidine-2-base, 1,4,5,6-tetrahydropyrimidine-4-base and 1,4,5,6-tetrahydropyrimidine-5-base and carbocyclic ring ketone or its sulfo-ketone derivatives, this group can be unsubstituted or by one or more halogens that are selected from, hydroxyl, sulfydryl, C _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷Be independently selected from hydrogen, C _1-8Alkyl, C _1-8Alkyloyl, C _3-14Cycloalkyl or C _6-14Aryl, and

X ¹³Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ¹⁷-X ¹⁸-X ¹⁹-, X wherein ¹⁸With above-mentioned X ¹⁵Definition identical, X ¹⁷Be C _N17Alkylidene group, and X ¹⁹Be C _N19Alkylidene group, wherein n17 and n19=0,1 or 2; And

R ²Be R ⁸-X ²⁰-or R ⁹-X ²¹-, wherein:

R ⁸Be amino, 1-imino-ethyl or methylamino,

X ²⁰Be C _4-6Alkylidene group, C _4-6Inferior assorted alkyl, oxo C _4-6Inferior assorted alkyl, oxo C _4-6Alkylidene group or-X ²²-X ²³-X ²⁴-, X wherein ²³With above-mentioned X ¹⁵Definition identical, X ²²Be C _N22Alkylidene group, and X ²⁴Be C _N24Alkylidene group, wherein n22 and n24=0,1,2,3 or 4, condition is: work as R ⁸When being amino, X ²⁰Not C _4-6Alkylidene group or oxo C _4-6Alkylidene group, and n22 is not 1,2,3 or 4,

R ⁹With above-mentioned R ⁵Definition identical, and

X ²¹Be C _0-6Alkylidene group, C _2-6Inferior assorted alkyl, oxo C _3-6Inferior assorted alkyl, oxo C _2-6Alkylidene group or-X ²⁵-X ²⁶-X ²⁷-, X wherein ²⁶With above-mentioned X ¹⁵Definition identical, X ²⁵Be C _N25Alkylidene group, and X ²⁷Be C _N27Alkylidene group, wherein n25 and n27=0,1 or 2;

Wherein the alkylidene group of each above-mentioned definition, cycloalkylidene, inferior assorted alkyl, inferior Heterocyclylalkyl, phenylene, arylidene and inferior heteroaryl can be unsubstituted or by one or more halogen, hydroxyl, sulfydryl, C of being selected from _1-8Alkyl, C _3-14Cycloalkyl, C _6-14Aryl, C _6-14Aryl C _1-4Alkyl, C _1-8Alkyloyl, C _1-8Alkyl oxy, C _6-14Aryloxy, C _3-14Cycloalkyl oxy, C _1-4Alkyl oxy, C _1-8Alkyl sulfenyl, C _3-14Cycloalkyl sulfenyl, C _6-14Artyl sulfo and-NR ⁶R ⁷Group replace R wherein ⁶And R ⁷As defined above, condition is: at R ¹, X ², X ⁴, X ⁶, X ⁸And R ²In contained heteroatoms and X ³, X ⁵, X ⁷And X ⁹In do not have covalent linkage between the contained heteroatoms.This method comprises:

(a) make a kind of compound of formula 1: 1

With a kind of formula R ²-Y ⁹The compound reaction of-C (O) L, wherein L is a kind of leavings group, Y ⁹Be a key ,-O-or-N (R ³)-, Y ⁸Be piperazine-1-base, piperidin-4-yl or HN (R ³)-C _1-8Alkyl, each R ¹, R ², R ³, X ¹, X ², X ³, X ⁴, X ⁵, X ⁶And X ⁷Such as in the summary of the invention definition, deprotection in case of necessity makes wherein X then ⁸Be 1, the inferior piperazinyl or 1 of 4-, 4-piperidylidene, and X ⁹For-C (O)-,-OC (O)-or-N (R ³) C (O)-formula I compound or X wherein ⁸Be C _1-8Alkylidene group, and X ⁹For-C (O) N (R ³)-,-OC (O) N (R ³)-or-NHC (O) N (R ³)-formula I compound;

(b) make a kind of compound and formula R of formula 1 ²The isocyanate reaction of-NC (O), deprotection in case of necessity makes wherein X then ⁸Be 1, the inferior piperazinyl or 1 of 4-, 4-piperidylidene, and X ⁹For-NHC (O)-formula I compound or X wherein ⁸Be C _1-8Alkylidene group, and X ⁹For-NHC (O) N (R ³)-formula I compound;

(c) make a kind of compound of following formula 2 2

With a kind of formula R ¹-Y ¹The compound reaction of-C (O) L, wherein L is a kind of leavings group, Y ¹Be a key ,-O-or-N (R ³)-, Y ²Be piperazine-1-base, piperidin-4-yl or HN (R ³)-C _1-8Alkyl, and each R ¹, R ², R ³, X ³, X ⁵, X ⁵, X ⁶, X ⁷, X ⁸And X ⁹Such as in the summary of the invention definition, deprotection in case of necessity makes wherein X then ²Be 1, the inferior piperazinyl or 1 of 4-, 4-piperidylidene, and X ¹For-C (O)-,-OC (O)-or-N (R ³) C (O)-formula I compound or X wherein ²Be C _1-8Alkylidene group, and X ¹For-C (O) N (R ³)-,-OC (O) N (R ³)-or-NHC (O) N (R ³)-formula I compound;

(d) make the compound of following formula 3:

3

With 2 equivalents or how normal a kind of formula R ¹-Y ¹The compound reaction of-C (O) L, wherein L is a kind of leavings group, Y ¹Be a key ,-O-or-N (R ³)-, Y ²And Y ⁸Be piperazine-1-base, piperidin-4-yl or HN (R independently ³)-C _1-8Alkyl, and each R ¹, R ², R ³, X ³, X ⁴, X ⁵, X ⁶And X ⁷Such as in the summary of the invention definition, deprotection in case of necessity makes wherein R then ¹=R ², X ²And/or X ⁸Be 1, the inferior piperazinyl or 1 of 4-, 4-piperidylidene, X ¹For-C (O)-,-OC (O)-,-N (R ³) C (O)-and/or X ⁹For-C (O)-,-OC (O)-,-N (R ³) C (O)-formula I compound and/or X wherein ²And/or X ⁸Be C _1-8Alkylidene group, X ¹For-C (O) N (R ³)-,-OC (O) N (R ³)-or-N (R ³) C (O) N (R ³)-, and X ⁹For-C (O) N (R ³)-,-OC (O) N (R ³)-or-N (R ³) C (O) N (R ³)-formula I compound;

(f) make compound and 2 equivalents or how normal a kind of formula R of formula 3 ¹The isocyanate reaction of-NC (O), deprotection in case of necessity makes wherein R then ¹=R ², X ²And/or X ⁸Be 1, the inferior piperazinyl or 1 of 4-, 4-piperidylidene, X ¹For-NHC (O)-and/or X ⁹For-NHC (O)-formula I compound and/or X wherein ²And/or X ⁸Be C _1-8Alkylidene group, and X ¹For-NHC (O) N (R ³)-and/or X ⁹For-NHC (O) N (R ³)-formula I compound;

(g) make a kind of formula R ¹-N (R ³) amine of H and the reaction of the compound of a kind of following formula 4:

4

Wherein L is a kind of leavings group, Y ¹Be a key ,-O-or-N (R ³)-, and each R ¹, R ², R ³, X ², X ³, X ⁴, X ⁵, X ⁶, X ⁷, X ⁸And X ⁹Such as in the summary of the invention definition,

Deprotection in case of necessity makes wherein X then ¹For-N (R ³) C (O)-,-N (R ³) C (O) O-or-N (R ³) C (O) N (R ³)-formula I compound;

(h) make a kind of formula R ¹-X ¹-Y ²Compound and the reaction of the compound of a kind of following formula 5: 5

Wherein L is a kind of leavings group, Y ³Be a key ,-O-or-N (R ³)-, Y ²Be piperazine-1-base, piperidin-4-yl or HN (R ³)-C _1-8Alkyl, and each R ¹, R ², R ³, X ¹, X ², X ³, X ⁴, X ⁵, X ⁶, X ⁷, X ⁸And X ⁹Such as in the summary of the invention definition,

Deprotection in case of necessity makes wherein X then ²Be 1, the inferior piperazinyl or 4 of 4-, 1-piperidylidene, and X ³For-C (O) ,-C (O) O-or C (O) N (R ³) formula I compound, X wherein ²Be C _1-8Alkylidene group and X ³Be-N (R ³) C (O)-,-N (R ³) C (O) O-or-NHC (O) N (R ³)-formula I compound;

(i) make 2 equivalents or how normal a kind of formula R ¹-X ¹-Y ²Compound and the reaction of the compound of a kind of following formula 6:

6

Wherein L is a kind of leavings group, Y ³And Y ⁷Be independently a key ,-O-or-N (R ³)-, Y ²Be piperazine-1-base, piperidin-4-yl, HN (R ³)-C _1-8Alkyl or HN (R ³)-C _1-8Assorted alkyl, and each R ¹, X ¹, X ⁴, X ⁵And X ⁶Such as in the summary of the invention definition,

Deprotection in case of necessity makes wherein X then ²And X ⁸Respectively do for oneself 1, the inferior piperazinyl or 4 of 4-, 1-piperidylidene, and X ³And X ⁷Be independently-C (O)-,-C (O) O-or-C (O) N (R ³)-formula I compound or X wherein ²And X ⁸C respectively does for oneself _1-8Alkylidene group or C _1-8Inferior assorted alkyl, and X ³And X ⁷Be independently of one another-N (R ³) C (O)-,-N (R ³) C (O) O-or-N (R ³) C (O) N (R ³)-formula I compound;

(j) optionally make a kind of wherein R ⁴Formula I compound and cyanamide reaction for amino prepare wherein R ⁴Formula I compound for guanidine radicals;

(k) optionally a kind of formula I compound is changed into its pharmacy acceptable salt;

(l) optionally a kind of formula I compound of salt form is changed into salt-independent shape;

(m) optionally a kind of formula I compound of not oxidised form is changed into its pharmaceutically acceptable N-oxide compound;

(n) optionally a kind of formula I compound of N-oxide form is changed into its not oxidised form;

(o) optionally its non-derivative form of a kind of formula I compound change into prodrug derivatives and

(p) optionally a kind of prodrug derivatives of formula I compound is changed into its non-derivative form.