SI9720047A - Novel compounds and compositions for treating diseases associated with tryptase activity - Google Patents

Abstract

The present invention relates to novel compounds which are tryptase inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.

Description

NEW COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF THE DISEASE RELATED TO THE OPERATION OF TRIPTASE

This application relates to the U.S. Provisional Application No. 60 / 023,139, filed July 30, 1996.

FIELD OF THE INVENTION

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

Area description:

Tryptase, the predominant protease that is secreted by human mast cells, is thought to be involved in neuropeptide processing and tissue inflammation. Tryptase concentrations are increased in the bloodstream for several hours following anaphylaxis (Schwartz et al. (1987) N. Eng. J. Med. 316: 1622-1626), increased in the nasal and pulmonary leaching fluid of atopic subjects, following the challenge. with specific antigens (Castells et al. (1988) J. AHerg. CHn. Immunol. 141: 563-568) and are elevated in the pulmonary lavage fluid of atopic asthmatics after challenge with endobronchial allergens. Smokers often have marked increases in tryptase levels of the bronchoalveolar lavage fluid; a finding that provides some support for the hypothesis that the release of proteinase from activated mast cells could contribute to lung destruction in smoker emphysema. (Celenteron et al. (1988) Chest 94: 119-123). In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting that it is implicated in pulmonary fibrosis and interstitial lung disease (Ross et al. (1991) J. din. Invest. 88: 493-499).

Asthma has been identified as an inflammatory disorder (Hood eta /. (1984) in Benjamin-Cummings, ed. Immunology 2nd ed.) And is often characterized by the progressive development of excessive susceptibility of the trachea and bronchi to immunospecific allergens and generalized chemical or physical stimuli. Multiple biochemical mediators are involved in the disease in both acute and chronic stages. Excessive susceptibility of bronchiolar tissue to asthmatics is considered to be the result of chronic inflammatory reactions that irritate and damage

-2The epithelium lining the airway wall and accelerating pathological swelling of underlying tissue. Bronchial biopsies in patients with mild asthma only have features of inflammation in the airway wall.

Allergic responses to inhaled allergens can initiate an inflammatory sequence. For example, allergens can activate mast cells and basophils present in epithelium and underlying smooth muscle tissue by binding IgE located on the cell surface. Activated mast cells release a large number of preformed or primary chemical mediators (eg, histamine) of the inflammatory response and generate many other secondary inflammatory mediators (eg, superoxide, lipid-derived mediators, etc.) in situ. In addition, various large molecules (eg, proteoglycans, tryptase, chymase, etc.) are released by mast cell degranulation.

The release of these preformed mast cell mediators likely explains the early bronchiolar constriction in the asthmatic reaction to airborne allergens. The early phase of the asthmatic reaction culminates approximately fifteen minutes after exposure to the allergen and is generally followed by recovery over the next one or two hours. Five to twenty to five and thirty percent of the patient population experiences a further decline in respiratory function, which is increased to a maximum of six to twelve hours after exposure. This late reaction phase is accompanied by a marked increase in the number of inflammatory cells (eg eosinophils, neutrophils, lymphocytes, etc.) infiltrating bronchiolar tissue. The release of mast cell-derived chemotactic agents attracts infiltrating cells to the site and then become activated during the late reaction phase. The late asthmatic response is thought to be a secondary inflammatory reaction caused in part by the secretory activity of granulocytes.

Tryptase has been implicated in the degradation of vasodilatory and bronchorelaxant neuropeptides (Caughey et al. (1988) J. Pharmacol. Exp. Ther. 244: 133-137; Franconi etat. (1988) J. Pharmacol. Exp. Ther. 248: 947-951; and Tam et ai. (1990) Am. J. Respir. Whole Mol. Biol. 3: 27-32) and modulation of bronchial susceptibility to histamine (Sekizawa et ai. (1989) J. Ciin. invest. 83: 175-179 ). These findings suggest that tryptase might increase bronchoconstriction in asthma by destroying bronchodilator peptides. Tryptase cleaves fibrinogen α-chains and high molecular weight kininogen, suggesting that tryptase works together with heparin as a topical anticoagulant. Tryptase activates prostromelysin

-3 (pro-MMP-3) and procollagenase (pro-MMP-1) by MMP-3, suggesting that tryptase is involved in tissue inflammation and remodeling and joint destruction in rheumatoid arthritis. Administration of a tryptase inhibitor further protects against the development of late and airway hyperresponsiveness in allergen-induced sheep (Clark etak (1995) Am. J. Respir. Crit. Charms Med. 152: 2076-2083) and inhibits the immediate cutaneous response to intradermal allergen injection. in allergic sheep (Molinari et al. (1995). Amer. Physiok Soc. 79 (6): 1966-1970). All of the findings described above clearly demonstrate the usefulness of tryptase inhibitors as therapeutic agents in the treatment of asthma and other disorders associated with inflammation of the respiratory tract.

The descriptions of these and other documents referenced throughout this application are incorporated herein by reference.

SUMMARY OF THE INVENTION

This application relates to a compound of Formula I:

r'-x'-x ² -x ³ -xV ^ X ⁵ r ² -x ⁹ -x ⁸ -x ⁷ -x ⁶ ^ in which:

X is ⁵ (C _{3. 14)} cycloalkylene, hetero (C _{3. 14)} cycloalkylene, (C _{6. 14)} arylene or hetero (C _{5. 14)} arylene;

X ⁴ and X ⁶ are independently (C _{o. 2)} alkylene;

X ¹ and X ⁹ are independently covalent bond, -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 ³ is independently hydrogen, (C ₁ .gjalkil or (C _{3. 8)} cycloalkyl, with the proviso that X ¹ and X ⁹ are not both 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;

-4X ² and X ⁸ are independently (C _8) alkyl, hetero (C1 _8) alkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ (C0. ₄₎ alkylene or hetero (C _{3. 4)} alkylene and X ¹¹ is (C _{3. 8)} cycloalkyl or hetero (C _{3. 8)} cycloalkylene;

R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ -, in which:

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

X ¹² is (C ₄ , ₆ ) alkylene, hetero (C ₄ ; ₆ ) alkylene _and heterooxo (C ₄ , ₆ ) alkylene, oxo (C ₄ , ₆ ) alkylene, or -X ¹⁴ -X ¹⁵ -X ¹⁶ -, v wherein X ^{15 is} (C3.6) cycloalkylene, hetero (C5.6) arylene, hetero (C3-6) cycloalkylene or phenylene, X ¹⁴ is (C 14-14) alkylene and X ¹⁶ is (C _16-16 ) alkylene, the sum of which is n14inn16 O , 1,2, 3 or 4,

R ⁵ is a group selected from the following, such as: azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2- imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-3-yl, 1-methylpiperid- 4-yl, piperid-3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-ii, 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 any carbocyclic ketone or thioketone derivative thereof, wherein this group is optionally substituted by one or more radicals selected from the following, such as: halo, hydroxy, mercapto, (C1-3) alkyl, (C3.14) cycloalkyl, (C6 .14) aryl, (C6.14) aryl (C1-4) alkyl, (C1-6alkanoyl, (C1-8) alkyloxy, (C6.14) aryloxy, (C3.14) cycloalkyloxy, (C4-4) alkyloxy. , (C 1-6 alkylthio, (C 3 14) cycloalkylthio, (C 6-14) arylthio and -NR ⁸ R ⁷ , wherein R ⁶ and R ^{7 are} not depending selected from the following such as: hydrogen, (C1_ ₈₎ alkyl, (C ^ gjaikanoil, (C _{3. 14)} cycloalkyl or (C _{6. 14)} aryl, and

X ¹³ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.6) alkylene, or -X ¹⁷ -X ¹⁸ -X ¹⁹ -, wherein X ¹⁸ , as defined above for X ¹⁵ , X ¹⁷ is (Cn ¹⁷ ) alkylene and X ¹⁹ is (C _{n 19} ) alkylene, wherein the sum of n 17 and n 19 is 0, 1 or 2; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, in which:

^R8 is amino, 1-iminoethyl or methylamino,

X ²⁰ is (C4.6) alkylene, hetero (C4.6) alkylene, heterooxo (C4.6) alkylene, oxo (C4.6) alkylene or -X ²² -X ²³ -X ²⁴ -, wherein X ²³ , as defined above for X ¹⁵ , X ²² is (Cn ²² ) alkylene and X ²⁴ is (Cn ²⁴ ) alkylene, wherein the sum of n ^{22 and} n ²⁴ is 0, 1, 2, 3 or 4, with the proviso that when R ⁸ amino, then X ²⁰ is not (C4_ ₆₎ alkylene or oxa (C _{4. 6)} alkylene and n22 is not 1, 2, 3 or 4,

R ⁹ is as defined above for R ⁵ and

-5X ²¹ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3-6) alkylene, oxo (C2.6) alkylene, or -X ²⁵ -X ²⁸ -X ²⁷ -, wherein X is ²⁶ , as defined above for X ¹⁵ , X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (C _{n 27} ) alkylene, wherein the sum of n 25 and n 27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene as defined above is optionally substituted by one or more radicals selected from the following, such as: halo, hydroxy, mercapto, (C 1-6 alkyl) _{(C3. 14)} cycloalkyl, (C _{6. 14)} aryl, (C ₆ _ ₁₄₎ aryl (C., _ ₄₎ alkyl, (C ^ gjalkanoil, _{(C1. 8)} alkyloxy, (C _{6. 14)} aryloxy, (C _{3. 14)} cycloalkyloxy, (C ₁ _ ₄₎ alkyloxy, (C ₁ _ ₈₎ atkiltio, (C _{3. 14)} cycloalkylthio, (C _{6. 14)} arylthio, and -NR ⁶ R ^7, wherein R ⁶ and R ⁷ are as defined above, with the proviso that the covalent bonds do not occur between the heteroatoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any hetero atoms contained in X ³ , X ⁵ , X ⁷ and X ⁹ ; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

Another aspect of this application relates to a compound of Formula I:

r'-x'-X ² -X ³ -X ⁴ / ^χ5 r ² -x ⁹ -x ⁸ -x ⁷ -x ⁶ in which:

X ⁴ -X ⁵ -X ⁶ together are (C _{2nd 12)} alkylene or hetero (C _{3. 12)} alkylene;

X ¹ and X ⁹ are independently covalent bond, -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) CO-, -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 ³ is independently hydrogen, (C_ ₃₎ alkyl or (C _{3. 8)} cycloalkyl , with the proviso that X ¹ and X ⁹ are not both 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) 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 ³ is as defined above;

X ² and X ⁸ are independently (C, _ ₈₎ alkylene, heterofC ^ _ ₈₎ alkylene, -X ¹⁰ -X ¹¹ - or

-X ¹¹ -X ¹⁰ -, wherein X ¹⁰ (C0.4) alkylene or hetero (C3-4) alkylene and X ¹¹ is (C3. ₈₎ cycloalkylene or hetero _{(C3. 8)} cycloalkylene;

-6R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ -, in which:

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

X ¹² is (C ₄ _ ₆₎ alkyl, hetero (C _{4. 6)} alkylene, heterooxo (C _{4. 6)} alkylene, oxo (C _{4. 6)} alkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ - in wherein X ^{15 is} (C3.6) cycloalkylene, hetero (C5.6) arylene, hetero (C3.6) cycloalkylene or phenylene, X ¹⁴ is (Cn14) alkylene and X ¹⁶ is ( _C16 ) alkylene, sum n14 and n16 O, 1,2, 3 or 4,

R ⁵ is a group selected from the following, such as: azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl,

2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-3-yl, 1 - methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidine- 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 any carbocyclic ketone or thioketone derivative thereof, wherein this group is optionally substituted by one or more radicals chosen from halo, hydroxy, mercapto, (C, _{first 8)} alkyl, (C ₃ _ ₁₄₎ cycloalkyl, (C _{6. 14)} aryl, (C _{6. 14)} aryl (C _{first 4)} alkyl, (C, _{first 8)} alkanoyl, (C _ ₈₎ alkyloxy, (C _{6. 14)} aryloxy, (C _{3. 14)} cycloalkyloxy, (C _{first 4)} alkyloxy, (C ^ gjalkiltio, (C _{3. 14)} cycloalkylthio, (C _{6. 14)} arylthio, and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ is independently selected from the following such as: hydrogen, (C ₁ _ ₈₎ alkyl, (C, _{first 8)} alkanoyl, (C _{3. 14)} cycloalkyl or (C ₆ . ₁₄ ) aryl and

X ¹³ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.6) alkylene or -Χ ¹⁷ -Χ ^1θ -Χ ^1θ -, wherein X ¹⁸ is as defined above for X ^15, X ¹⁷ is (Cn17) alkylene and X ¹⁹ is (C _N19) alkylene, wherein the sum nl7 and nl9 0, 1 or 2; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, in which:

R ⁸ is as defined above for R ⁴ ,

X ²⁰ is (C4.6) alkylene, hetero (C4.6) alkylene, heterooxo (C4.6) alkylene, oxo (C4.6) alkylene or -X ²² -X ²³ -X ²⁴ -, wherein X ²³ , as defined above for X ¹⁵ , X ²² is (Cn ²² ) alkylene and X ²⁴ is (C _n ²⁴ ) alkylene, wherein the sum of n ²² and n ²⁴ is 0, 1, 2, 3 or 4,

R ⁹ is as defined above for R ⁵ and

X ²¹ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.6) alkylene or -X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ²⁶ , as defined above for X ¹⁵ , X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (C _{n 27} ) arylene, wherein the sum of n 25 and n 27 is 0, 1 or 2; wherein each is alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene,

-7fenilen, arylene and heteroarylene, as defined above, optionally substituted by one or more radicals chosen from halo, hydroxy, mercapto, (C ₁ _ ₈₎ alkyl, (C _{3. 14)} cycloalkyl, (C _{6. 14)} aryl, (Cg_ ₁₄₎ aryl (C., _ ₄₎ alkyl, (C ^ alkanoyl, (C, _ 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 ⁸ R ⁷ wherein R ⁶ and R ^7, such as as defined above, with the proviso that the covalent bonds do not occur between the heteroatoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any hetero atoms contained in X ³ , X ⁵ , X ⁷ and X ⁹ ; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

A third aspect of the present invention is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt, AAoxide or prodrug derivative thereof, in admixture with one or more suitable excipients.

A fourth aspect of the present invention is a method of treating a disease in an animal in which the action of tryptase contributes to the pathology and / or symptomatology of the disease, the method comprising administering to the animal a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt, ΛΖ-oxide or prodrug derivative of these.

A fifth aspect of the present invention is a process for the preparation of compounds of Formula I and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof, as explained in the Detailed Description of the Invention.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

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

Alkanoyl means the radical -C (O) R, wherein R is alkyl, as defined below, having generally the indicated number of carbon atoms (e.g., (C 1-6 alkanoyl includes radicals formyl, acetyl, propionyl, butyryl, isobutyryl, crotonoyl) , isocrotonyl, etc.).

-8 “Alkyl, as in alkyl, arylalkyl, alkyloxy, alkylthio, means a straight or branched, saturated or unsaturated hydrocarbon radical having a specified number of carbon atoms (e.g., (C alkyl includes methyl, ethyl, propyl, isopropyl, butyl, se / r-butyl, isobutyl, tert-butyl, vinyl, allyl,

1- propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl, 1-propynyl,

2- propynyl, etc.).

"Alkylene" means a straight, saturated or unsaturated hydrocarbon divalent radical having the number of carbon atoms (eg., (C _{is 0. 6)} alkylene includes methylene (-CH ₂ -), ethylene (- (CH _{2) 2} -), vinylene (-CH: CH-), ethinylene (-CC-), 2-propylene (-CH: CH * CH ₂ -), 1-propylene (-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.

'Alkyloxy' means a radical -OR, wherein R is alkyl, as defined above, having the indicated number of carbon atoms (e.g., (C ₄ , ₈ ) alkyloxy includes the radicals methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, etc.).

'Alkylthio' means a radical -SR, wherein R is alkyl, as defined above, having the indicated number of carbon atoms (e.g., (C ₁ , ₈ ) alkylthio includes the radicals methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, etc.).

'Animal' includes humans, non-human mammals (eg dogs, cats, rabbits, cattle, horses, sheep, goats, pigs, game, etc.) and non-mammals (eg birds, etc.).

Aryl, as in aryl, arylalkyl, aryloxy and arylthio, means an aromatic monocyclic or polycyclic hydrocarbon radical containing a specified number of carbon atoms, wherein the free valence carbon atom is a member of the aromatic ring, and any carbocyclic ketone or thioketone derivative (these eg., (C _{6. 14)} aryl include phenyl, naphthyl, anthracenyl, phenanthrenyl, 1,2,3,4-tetrahydronaphthalen-5-yl, l-oxo-1,2-dihydronaphth-6-yl, 1-thioxo -1,2-dihydronaphth-7-yl, etc.).

'Arylene' means an aromatic monocyclic or polycyclic hydrocarbon bivalent radical containing a specified number of carbon atoms, wherein the free valence carbon atoms are members of an aromatic ring, and any carbocyclic ketone or thioketone derivative thereof (e.g., (C ₆ . ₁₄ ) arylene includes 1,4-phenylene, 1,3-phenylene,

-91.4- Naphthylene, 2,6-naphthylene, 1,4-anthracenylene, 2,6-anthracenylene, 1,6-phenanthrenylene,, 2,3,4-tetra-hydro-5,8-naphthylene, 1-oxo- 1,2-dihydro-5,7-naphthylene, 1-thioxo-1,2-dihydro-5,8-naphthylene, etc.).

"Aryloxy" means the radical -OR, wherein R is aryl, as defined above, having the number of carbon atoms (eg. (C _{6. 14)} aryloxy includes the radicals phenoxy, naphthyloxy, anthracenyloxy, etc.)..

"Arylthio" means the radical -SR, wherein R is aryl, as defined above, having the number of carbon atoms (eg., (C _{6. 14)} arylthio includes the radicals phenylthio, naphthylthio, anthracenylthio, etc.).

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

'Cycloalkylene' means a saturated or unsaturated, monocyclic or polycyclic hydrocarbon bivalent radical containing a specified number of carbon atoms, wherein the free valence carbon atoms are members of a non-aromatic ring, and any carbocyclic ketone and thioketone derivative thereof (eg. C ₃ _ ₆₎ cikloalkiien includes 1,2-cyclopropylene, 1,2-cyclobutylene, 1,3-cyclobutylene, 1,2-cyclopentylene, 1,3-cyclopentylene, 1,4-cyclopentylene,

1,4-cyclohexylene, 3-cyclohexen-1,2-ylene, 2,5-cyclohexadiene-1,4-ylene,

1,4-bicyclo [2.2.2] octylene, 1,2,3,4-tetrahydro-1,4-naphthylene, 5-oxo-1,3-cyclohexylene,

2.5-dioxo-1,4-cyclohexylene, 5-thioxo-1,4-cyclohexylene, etc.).

"Cycloalkyloxy" means a radical -OR, wherein R is cycloalkyl, as defined above, having the number of carbon atoms (eg., A (C ₃ _ ₁₄₎ eikloalkiioksi includes the radicals cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, etc.).

'Cycloalkylthio' means the radical -OR, wherein R is cycloalkyl as defined above having

-10navedeno number of carbon atoms (eg., (C _{3. 14)} cycloalkylthio includes the radicals cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.).

Removal of protection 'refers to the removal of any protecting groups present after a selective reaction has been carried out.

'Disease' specifically includes any unhealthy condition of an animal or part of it and includes an unhealthy condition that may be caused by the medical or veterinary therapy used in that animal or which occurs in that therapy, ie, the 'side effects' of such therapy .

'Halo' means fluoro, chloro, bromo or iodo.

Heteroalkylene means alkylene as defined above, wherein 1 to 5 of the aforementioned carbon atoms are replaced by a heteroatom selected from the following, such as: N, O or S (e.g. azaalkylene, oxaalkylene and thiaalkylene, singly), with reservation, that the oxygen, nitrogen, and sulfur atoms contained within do not form bonds with other heteroatoms. For example, hetero (C _{3. 12)} alkylene is meant to encompass aza _(C3) alkylene which includes

3- Azatrimethylene (-NHCH ₂ CH ₂ -), 2-Azatrimethylene (-CH ₂ »NH'CH ₂ -), etc .; o-aza (C _{2nd 5)} alkylene which includes 2-azaetilen (-NH-CH ₂ -), 3-azatrimethylene, 4-azatetramethylene (-NH-CH ₂ 'CH _2' CH ₂ -) and 5-azapentamethylene (-NH * CH ₂ * CH ₂ 'CH ₂ * CH ₂ -); oxa (C ₃ ) alkylene including 3-oxatrimethylene (-O * CH ₂ »CH ₂ -), 2-oxatrimethylene (-CH ₂ * O * CH ₂ -), etc .; oxa (C ₅ ) alkylene, such as e.g. 3-oxapentamethylene (-CH ₂ «CH ₂ * O * CH ₂ * CH ₂ -), etc .; thia (C ₃ ) alkylene which includes 3-thiatrimethylene (-S »CH ₂ 'CH ₂ -), 2-thiatrimethylene (-CH ₂ * S * CH ₂ -), etc .; o-thia (C _{2nd 4)} alkylene which includes 2-tiaetilen (-NH-CH ₂ -), 3-thiatrimethylene and

4- thiatetramethylene (-S-CH ₂ * CH ₂ 'CH ₂ -); diaza (C ₆ ) alkylene including

2,5-diazahexamethylene (-CH ₂ * NH »CH ₂ * CH ₂ « NH »CH ₂ -); azoxy (C ₆ ) alkylene which includes 2, -oxa-5-azahexamethylene (-CH ₂ * O * CH ₂ * CH ₂ * NH * CH ₂ -); etc.

"Heteroarylene" means arylene, as defined above, wherein 1 to 5 of the carbon atoms indicated are replaced by a heteroatom selected from the following such as: N, O, or S (eg., A hetero _{(C5. 6)} arylene includes furylene, thienylene, pyrrolylene, imidazolylene, pyridylene, etc.).

-11Heterocikloalkilen means cycloalkylene, as defined above, wherein 1 to 5 of the carbon atoms indicated are replaced by a heteroatom selected from the following such as: N, O, or S (eg., A hetero (C _{3. 14)} includes cikloalkiien 2 , 4-pyrrolidinylene,

2,4-pyrrolinylene, 2,4-imidazolinylene, 2,4-imidazolinylene, 3,5-pyrazolinylene, 1,4-piperidylene,

1.4- piperazinylene, 2,5-quinuclidinylene, 2,5-morpholinylene, 1,3-isoindolinylene, etc.).

Heterooxalkylene means alkylene as defined above, wherein one of the indicated numbers of carbon atoms is replaced by a heteroatom selected from the following: N, O or S and a carbon atom adjacent to the heteroatom is replaced by a carbonyl group (C = O) e.g. azooxoalkylene, oxaoxoalkylene and thiaoxoalkylene, respectively, with the proviso that the oxygen, nitrogen and sulfur atoms contained within do not form bonds with other heteroatoms. For example, heterooxo (C _{4. 6)} alkylene is meant to encompass azaoxo (C ₃₎ alkylene which includes 2-aza-3-oxotrimethylene (-C (O) * NH * CH ₂ -),

3-aza-2-oxotrimethylene (-NH * C (O) * CH ₂ -), etc .; oxaoxo (C ₃ ) alkylene including

2-oxa-3-oxotrimethylene (-C (O) O * CH ₂ -), 3-oxa-2-oxotrimethylene (-O * C (O) * CH ₂ -), etc .; and thiaxo (C ₃ ) arylene, including 2-thia-3-oxotrimethylene (-C * (O) 'S-CH ₂ -),

3- thia-2-oxotrimethylene (-S * C (O) * CH ₂ -), etc.

A prominent group has a meaning conventionally associated with it in synthetic organic chemistry, i.e., an atom or a group which can be cleaved under alkylation conditions and includes halogen, hydroxy, alkylsulfonyloxy (e.g., mesyloxy, ethanesulfonyloxy, etc.), arylsulfonyloxy (e.g., benzenesulfonyloxy and tosyloxy, thienyloxy), dihalophosphinoyloxy, tetrahalophosphoxy and the like.

Optional or optional means that the event or circumstance described later may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not occur. For example, the phrase optionally substituted by one or more radicals means that the group to which it refers may or may not be substituted to fall within the scope of the present invention.

Pharmaceutically acceptable / V-oxide means a compound in which the nitrogen is in an oxidized state (i.e., O-N), which is pharmaceutically acceptable as defined below and which has the desired pharmacological effect. The V-oxides of the compounds of Formula I can be prepared by methods known to one of ordinary skill in the art.

-12Oxoalkylene means alkylene as defined above, wherein one of the indicated numbers of carbon atoms is replaced by a carbonyl group (C = O), e.g., oxo (C ₃ ) alkylene includes 3-oxotrimethylene (-C (O) CH ₂ «CH ₂ -), etc.

'Pathology * of disease means the essential nature, causes and development of disease, as well as the structural and functional changes that result from disease processes.

Pharmaceutically acceptable 'means that which is useful in the preparation of a pharmaceutical composition, which is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes what is acceptable for veterinary and human pharmaceutical use.

'Pharmaceutically acceptable salts' means salts which are pharmaceutically acceptable as defined above and which have the desired pharmacological effect. Such salts include acid addition salts formed with inorganic acids such as e.g. hydrobromic acid, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid and the like; or with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphrasulfonic acid, p-chlorobenzene-sulfonic acid, cinnamic acid, citric acid, cyclopentanpropionic acid, 1,2-ethanedisulfonic acid, ethoxy sulfonic acid, ethoxy sulfonic acid, ethoxy sulfonic acid acid, gluconic acid, glutamic acid, glycolic acid, hexanoic acid, heptanoic acid, h? - (4-hydroxybenzoyl) benzoic acid, 2-hydroxyethanesulfonic acid, hydroxynaphthoic acid, lactic acid, lauryl acid, lauryl acid, lauryl acid, lauryl acid acid, almond acid, methanesulfonic acid, 4-methylbicyclo [2.2.2] oct-2-ene 1-carboxylic acid, 4,4'-methylenebis (3-hydroxy-2-ene-1-carboxylic acid), muconic acid, 2-naphthalenesulfonic acid, oxalic acid, 3-phenylpropionic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, tartaric acid, tertiary butylacetic acid saliva, /> toluenesulfonic acid, trimethylacetic acid and the like.

Pharmaceutically acceptable salts also include base addition salts which may be formed when acidic protons are present 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

-13bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine and the like.

Phenylene means a bivalent aromatic radical -C ₆ H ₄ - and includes 1,4-phenylene, 1,3-phenylene and the like.

Pharmaceutically acceptable prodrug derivatives' means derivatives of compounds of Formula I that are pharmaceutically acceptable as defined above and which are converted in vivo to the corresponding non-derivatized form of a compound of Formula I. Such prodrugs include compounds of Formula I having / V-acylated piperidyl (i.e., N (P) C ₅ H _g -), / V-acylated azaalkylene, (e.g. -N (P) * CH ₂ CH ₂ -), / V-acylated amino (i.e., -NH ₂ (P )), / V-acylated amidino, (i.e., -C (NP) -NHP, -C (NH) -NHP or -C (NP) -NH ₂ ), / V-acylated guanidino (i.e., -NHC (NP ) * NHP, -NH * C (NH) »NHP or -NH» C (NP) »NH ₂ ) groups in which P is a group selected from the following, such as: -C (O) R ¹⁰ , v wherein R ¹⁰ may be (C 1-6 alkyloxy or c / Ls-2- (C 1 O) alkanoyloxyphenylvinyl, 3- (C 1 O) alkanoyloxybutyryl, R ¹¹ -X ²⁸ - wherein R ^{11 is} carboxy and X ²⁸ is (Οη_ ₁₀ ) alkylene or -C (O) * O * CH (R ¹² ) * O * C (O) R ¹³ , wherein R ^{12 is} hydrogen, (C 1-10) alkyl or (C 3,10) cycloalkyl and R ¹³ is (C _1-10 > alkyl.

A protecting group has the meaning conventionally associated with it in synthetic organic chemistry, that is, a group that selectively blocks one reactive site in a multifunctional compound so that a chemical reaction can be carried out selectively at another unprotected reactive site and that can be easily removed when the selective reaction is complete.

Protective agent means an agent that will react with a multifunctional compound to create a protecting group in the reactive site.

Protected derivatives means, when referring to a compound or group, a derivative of a compound or group in which the reactive site is blocked or sites are blocked by protecting groups. Protected derivatives of Formula I are active tryptase inhibitors and are useful in the preparation of other compounds of Formula I. Suitable protecting groups for reactive nitrogen atoms include tert-butoxycarbonyl, benzyloxycarbonyl and any other suitable amino protecting groups (e.g., see TW Greene , Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981).

-14Symptomatology of a disease means any pathological phenomenon or deviation from normal in a patient's structure, function or feeling that is characteristic of the disease, their effect and the indications that they provide.

Therapeutically effective amount means that which is sufficient when given to an animal for the treatment of a disease to carry out such treatment of the disease.

Treating or treating a disease involves preventing the disease from occurring in an animal that may be predisposed to the disease but is not yet presenting or showing symptoms of the disease, inhibiting the disease (i.e., holding back its development) or facilitating the disease (i.e., causing disease regression) .

Q.s. means adding a sufficient amount to achieve the stated purpose, e.g., to bring the solution to the desired volume (i.e., 100%).

The compounds of Formula I and the intermediates and starting materials used in their preparation are named in accordance with the lUPAC nomenclature rules, in which the characteristic groups have a declining priority for citation as essential groups, as follows: acids, esters, amides and amidines. Referring further to a bivalent radical with a written description, the arrangement of numerical prefixes for the purposes of this Application is the orientation of its connection. Similarly, when referring to a bivalent radical of a formula, the orientation of the bond indicates the way in which the formula is presented. For example, a compound of Formula I 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-piperidylene and R ² is R ⁹ -X ²¹ , wherein R ^{9 is} piperid-4-yl and X ²¹ is 3-azatrimethylene, is illustrated by the following formula:

NH

-15this compound is called:

cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- (2-piperid-4-ylaminoethylcarbamoyl) -1-piperidinecarboxylate, if X ³ and X ^{7 are} each -C (O) O-, X ⁴ and X ⁶ are each covalent bond, X ⁵ is c / s-1 , 5-cyclooctylene and P is hydrogen;

3- {4- [2- (1- {cZs-5- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyloxy] cyclooxyloxycarbonyl} piperid-4-ylcarbonylamino) ethylamino] piperid-1-ylcarbonyl} propionic acid, if X ³ and X ^{7 are} each -C (O) O-, X ⁴ and X ⁶ are each covalent bond, X ⁵ is c / 5-1,5-cyclooctylene and P is 3-carboxypropionyl;

4- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] benzyl 4- (2-piperid-4-ylaminoethylcarbamoyl) -1-piperadinecarboxylate if X is ³ -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;

1,4-tetramethylene 4-amidinobenzylcarbamoyl-1-piperazinecarboxylate if X ³ and X ^{7 are} each -C (O) O- and X ⁴ -X ⁵ -X ⁶ is 1,4-tetramethylene (i.e., -CH ₂ * CH ₂ -CH ₂ -CH ₂ -); and N-4-amidinobenzyl-4- {5- [4- (2-piperid-4-ylaminoethylcarbamoyl) piperid-1-ylcarbonyl] valeryl} -1-piperazinecarboxamide if X ³ and X ^{7 are} each -C (O ) - and X ⁴ -X ⁵ -X ⁶ is

1.4- tetramethylene (ie, -CH ₂ * CH ₂ * CH ₂ * CH ₂ -).

Current preferred embodiments:

While the broadest definition of the present invention is explained in the Summary of the Invention, certain compounds of Formula I are preferred. For example, preferred compounds of Formula I are those wherein X is ⁵ c / s-1,5-cyclooctylene and X ⁴ and X ⁶ are each a covalent bond. X ⁴ -X ⁵ -X ⁶ together are (C 4, 8) alkylene or X ^{5 is} 1,4-phenylene and X ⁴ and X ⁶ are (Co_ ₁ ) alkylene; X ¹ and X ² are independently covalent bond, -C (O) -, -NHC (O) -, -C (O) NH-, -N (CH ₃ ) C (O) - or -S (O) ₂ NH-, with the proviso that X ¹ and X ⁹ are not both 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 -, wherein X ^{10 is a} covalent bond or methylene and X ¹¹ is 4,1-piperidylene or 1,4-piperazinylene; 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-piperidylene, X ¹⁴ is (Cn14) alkylene and X ¹⁶ is (Cn16) alkylene, wherein the sum of n14 and n16 is 0, 1 or 2, R ⁵ is piperid-4-yl and X ¹³ is (C2.3) alkylene; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, wherein R ^{8 is} amino, amidino, guanidino, methylamino or 1-iminoethyl, X ²⁰ is -X ²² -X ²³ -X ²⁴ -, v wherein X ^{23 is} frans-1,4-cyclohexyene, 1,4-phenylene, 4,1-pyridiniene, 1,4-piperidylene, X ²² is (Cn ²² ) alkylene and X ²⁴ is (C _n ²⁴ ) alkylene, wherein the sum of n22 and n24 is 1 or 2, R ⁹ is benzoimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-1-yl,

-165-methylimidazol-1-yl, 1-methylpiperid-4-yl, piperid-4-yl, piperazin-1-yl, pyrid-3-yl, pyrid-4-yl,

1,4,5,6-tetrahydropyrimidine-5-yl or 1,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl, and X ²¹ is a (C ₁₆₎ alkyl, O-aza (C _{2nd 5)} alkylene, 3-oxotrimethylene, o-thia (C _{2nd 4)} alkylene, 3-oxo-2-azatrimethylene, 3-aza-2-oxotrimethylene or -X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ²⁶

1,4-phenylene, X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (Cn ²⁷ ) alkylene, wherein the sum of n25 and n27 is O or 1; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives, and protected derivatives thereof.

More preferred compounds of Formula I are those wherein X ^{5 is} c / s-1,5-cyclooctylene and X ⁴ and X ⁶ are each covalent bond or X ⁴ -X ⁵ -X ⁶ together are (C4.8) alkylene ; X ¹ and X ⁹ are independently covalent bond -C (O) -, -NHC (O) -, -C (O) NH- or -S (O) 2NH-, with the proviso that X ¹ and X ⁹ are not both 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 -, wherein X ^{10 is a} covalent bond or methylene and X ¹¹ is 4,1-piperidylene or 1,4-piperazinylene; 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 or 1,4-piperidylene, X ¹⁴ is (Cn ¹⁴ ) alkylene and X ¹⁶ is (Cn ¹⁶ ) alkylene, wherein the sum of n 14 and n 16 is 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-), 4-cyclohexylene or 1,4-phenylene, X ²² is (Cn ²² ) alkylene and X ¹⁶ is (Cn ²⁴ ) alkylene, wherein the sum of n ²² and n 24 is 1 or 2, R ⁹ is imidazol-1-yl, imidazol-4- or, 4-methylimidazol-1-yl,

5-methylimidazol-1-yl, piperid-4-yl or pyrid-4-yl, and X ²¹ is (C ₁ _ ₅₎ alkylene or 3-azatrimethylene; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

Particularly preferred compounds of Formula I are those wherein X ^{5 is} cis-), 5-cyclooctylene and X ⁴ and X ⁶ are each a covalent bond; X ¹ and X ⁹ are independently -C (O) - or -NHC (O) -; 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 and X ¹¹ is 1,4-piperazinylene; 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-), 4- cyclohexylene, X ²² is a covalent bond and X ²⁴ is methylene, R ⁹ is piperid-4-yl and X ²¹ is ethylene or three methylene; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

Particularly preferred compounds of Formula I are those wherein X ⁴ -X ⁵ -X ^{8 are} together

-17 (C ₄ _ ₈₎ alkylene; X ¹ and X ⁹ are 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 each -X ¹⁰ -X ¹¹ -, in which X ^{10 is a} covalent bond and X ¹¹ is

1.4- piperazinylene; R ¹ is R ⁴ -X ¹² -, wherein R 1 is amidino or guanidino and X ¹² is -X ¹⁴ -X ¹⁵ -X ¹⁸ -, wherein X ^{5 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

1.4-phenylene, X ²² is a covalent bond and X ²⁴ is methylene; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

The most preferred compounds of Formula I are the following:

4-guanidinobenzyl 4- {7- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonylheptanoyl} -1-piperazinecarboxamide;

4-guanidinobenzyl

4- {8- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyloctanoyl} 1-piperazinecarboxamide;

4-guanidinobenzyl 4- {9- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonylnanoanoyl} -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-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate;

1,5-pentamethylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate]; cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate;

cis-1,5-cyclooctylene / 3 S-4- (4-aminocyclohexylmethylcarbamoyl) 1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate; cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate

4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate;

1,4-tetramethylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate]; cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate;

4-guanidinobenzyl

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

-18c / s-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate;

cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-44ylethylcarbamoyl) -1-piperazinecarboxylate;

cis-T, 5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate;

4-guanidinobenzyl

4- {5- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] valeryl} 1-piperazinecarboxamide;

3-Oxa-1,5-pentamethylene di [4- (4-guanidinophenylacetyl) piperazin-1-yl carbon and I]; and cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate

4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof.

Pharmacology and utility:

The compounds of the present invention are tryptase inhibitors. As such, the compounds of Formula I are useful for the treatment of diseases, especially immune-induced inflammatory diseases, in which the action of tryptase is involved in the pathology and / or symptomatology of the disease. For example, immune-induced inflammatory diseases in which the function of tryptase is involved in their pathology and / or symptomatology include asthma, allergic rhinitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczema, eczema, anaphylaxis, hyperproliferative skin disease, peptic ulcers, inflammatory bowel disease, ocular and spring conjunctivitis, inflammatory skin conditions and the like.

Suitable in vitro assays for measuring the action of tryptase and its inhibition by compounds are known (e.g., see Sturzebecher et ai. (1992) Biol. Chem. Hoppe-Seyier 373: 1025-1030). Typically, tryptase-induced hydrolysis of the peptide base substrate will be measured by the test. For further details of the in vitro assay for measuring tryptase function, see Example 33, below.

Suitable in vivo models of inflammation are known to those of ordinary skill in the art. For example, in vivo models for asthma are known (e.g., see Larsen (1991) Experimenta! Modeis of

-19Reversible Airway Obstruction, m ·. West et al., Eds. The Lung: Scientific Foundations, Raven Press, New York). For further details of the in vitro asthma model, see Example 2, below. In vivo models of inflammatory skin conditions (VValsh etat (1995) Br. J. Pharmacoi. 114: 1343-1350; and Armstrong et al. (1995) Prostagiandins 49: 205-224) and arthritic conditions (Peacock etat. 1995 ) CeliImmunot 160: 178-184; and Houri etat (1995) Curr. Opin. Rheumatot 7: 201-205) and gastrointestinal diseases (Anthony et ai (1995) / nt. J. Exp. Pathot 76: 215-224; and Carter et at (1995) Dig. Dis. Set 40: 192-197). For further details of the in vivo test for measuring asthmatic responses, see Example 34, below.

Administration and pharmaceutical compositions:

In general, the compounds of Formula I will be administered in therapeutically effective amounts by any of the usual and acceptable methods known in the art, either individually or in combination with another therapeutic agent. The therapeutically effective amount may vary widely depending on the severity of the disease, the age and relative health of the subject, the efficacy of the compound used, and other factors. For example, the therapeutically effective amounts of a compound of Formula I for the treatment of asthma may vary from 0.1 micrograms per kilogram body weight (pg / kg) per day to 1 milligrams per kilogram body weight (mg / kg) per day, typically 1 pg / kg. kg / day to 0.1 mg / kg / day. Therefore, a therapeutically effective amount for an asthmatic human patient of 80 kg may vary from 10 pg / day to 10 mg / day, typically 0.1 mg / day to 10 mg / day.

Therapeutic agents that may be useful for administration in combination with the compounds of Formula I in the treatment of asthma include β-adrenergic agonists (e.g., albuterol, terbutaline, formoterol, phenoterol, prenalin, and the like), methylxanthines (e.g., caffeine, theophylline, aminophylline) , theobromine, and the like), chromoglycates (e.g., cromolin, necromyl, and the like), and corticosteroids (e.g., beclomethasone, triamcinolone, flurisolid, dexamethasone, and the like). Generally, the average person skilled in the art, based on personal knowledge and the description of this application, will be able to determine a therapeutically effective amount of a compound of Formula I for the treatment of a given inflammatory disease.

The compounds of Formula I may be administered as pharmaceutical compositions by one of the following routes:

-20oral, systemic (eg transdermal, intranasal or suppository) or parenterally (eg intramuscular, intravenous or subcutaneous). The compositions may take the form of tablets, pills, capsules, semi-solids, powders, prolonged release preparations, solutions, suspensions, elixirs, aerosols, or any other suitable composition, and generally consist of a compound of Formula I, in combination with at least one pharmaceutical acceptable excipients. Acceptable excipients are non-toxic, assist in administration and do not adversely affect the therapeutic utility of the active substance. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, a gaseous excipient that is generally available to one skilled in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semi-solid excipients can be selected from the following, such as: water, ethanol, glycerol, propylene glycol and various oils, including petroleum, animal, vegetable or synthetic origin (eg peanut oil, soybean oil, mineral oil, sesame oil, etc.) .). Preferred liquid carriers, especially for injectable solutions, include water, salt solution in water, aqueous dextrose and glycols.

Compressed gases can be used to spray the active substance in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, nitrous oxide, etc. Other suitable pharmaceutical carriers and preparations thereof are described in A.R. Alfonso Remington's Pharmaceutics! Sciences 1985, 17th Edition, Easton, Pa .: Cat Publishing Company.

The amount of a compound of Formula I in the composition may vary widely depending on the type of preparation, the size of the single dose, the type of excipients and other factors known to those of skill in the pharmaceutical sciences. In general, the composition of the compound of Formula I for the treatment of asthma will comprise from 0.01 wt. % to 10 wt. %, preferably 0.3 wt. % to 1 wt. % of the active substance with the remainder being the excipient or excipients. Preferably, the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in the form of a single dose ad libitum if symptomatic relief is explicitly required. Typical pharmaceutical compositions containing a compound of Formula I are described

-21v Example 35.

Chemistry:

The compounds of this invention are composed of five distinct subunits (i.e., R ¹ -, -X ² -, -Χ ⁴ -Χ ⁵ -Χ ^θ -, X ⁸ and R ² -), these subunits being linked by carbonyl, formyloxy, amide, sulfonamide, carbamate or urea bonds (i.e., -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-). Methods for forming such linking groups are known and suitable reagents are readily obtainable (e.g., see March, Advanced Organic Chemistry, 4th Edition (Wiley 1992); Larock, Comprehensive Organic Transformations (VCH 1989); and Furniss et al. , Vogebs Textbook of Practicai Organic Chemistry, 5th edition, (Longman 1989).

Subunits comprising compounds of Formula I (may be assembled individually or as larger combinations of subunits. The following reaction schemes are typical processes for the preparation of compounds of Formula I. It is understood that compounds of Formula I may be prepared by other analogous methods.

Compounds of Formula I in which X ^{8 is} 1,4-piperazinylene or 1,4-piperidium and X ⁹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) - , or wherein X is ⁸ (C.,. ₈ ) alkylene and X ⁹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) - may be prepared by reacting a compound of Formula 1:

κ'-χ'-χυχ ^ χ ⁴ .

Υ ⁸ -χ ⁷ .χ ⁶ ′ or a protected derivative thereof, with a compound of formula R ² -Y ⁹ -C (O) L, or a protected derivative thereof, wherein L is a protruding group, Y ⁹ is a bond, -O- or -N (R ³⁾ -, Y ⁸ is a piperazin-1-yl, piperid-4-yl or HN (R ³⁾ - (C, _{first 8)} alkyl, respectively, and each of R ^1, R ² , R ³ , X ¹ , X ² , X ³

X ⁴ , X ⁵ , X ⁶ and X ⁷ is as defined in the Summary of the Invention and then by deprotection,

-22 when necessary. Alternatively, compounds of Formula I in which X ^{8 is} 1,4-piperazinylene or t, 4-piperidylene and X ⁹ is -NHC (O) -, or in which X ^{8 is} (C, ₈ ) alkylene and X ⁹ is -NHC (O) N (R ³ ) -, can be prepared by reacting a suitable compound of Formula 1 or a protected derivative thereof, with an isocyanate of formula R ² -NC (O) or a protected derivative thereof and then by removing the protection when necessary (see Example 8 below for further details).

In an analogous manner, compounds of Formula I in which X ^{2 is} 1,4-piperazinylene or 1,4-piperidylene and X ¹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) -, or in which X is ² (C ₁ _g) alkylene and X ¹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ A) C (O) N (R ³ ) - may be prepared by reacting a compound of Formula 2:

Y ² -X ³ -x <

R ² -X ⁹ -X ⁸ -X ⁷ -X ⁶ or a protected derivative thereof, with a compound of the 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, piperid-4-yl or HN (R ³ ) - (C 1-8) alkyl, singly, 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 and then by deprotection when necessary. Alternatively, compounds of Formula I in which X ^{2 is} 1,4-piperazinylene or 1,4-piperidylene and X ¹ is -NHC (O) -, or in which X ^{2 is} (C-, _8) alkylene and X ¹ is -NHC (O) N (R ³ ) -, can be prepared by reacting a compound of formula 2 or a protected derivative thereof, with an isocyanate of formula R ¹ -NC (O) or a protected derivative thereof, and then removing the protection when necessary (see Example 14 (b) below for further details).

Compounds of Formula I wherein R ^{1 is} equal to R ² ; X ² and / or X ⁸ is 1,4-piperazinylene or 1,4-piperidylene; X ¹ is -C (O) -, -OC (O) -, or -N (R ³ ) C (O) -; and X ⁹ is -C (O) -, -OC (O) - or -N (R ³⁾ C (O) - and / or in which X ² and / or X ⁸ _(d C, 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 -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) -, can be prepared by reacting the compound with Formula 3:

-23Y ² -X ³ -XV / ^χ5

Υ * -Χ ^7- z ⁶ or a protected derivative thereof, with 2 or more mole 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, piperid-4-yl or HN (R ³ ) - (C 1-8) alkyl and each R ¹ , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ are as defined in the Summary of the Invention and thereafter by deprotection when necessary. Alternatively, compounds of Formula I in which R ^{1 is} equal to R ² ; X ² and / or X ⁸ is 1,4-piperazinylene or 1,4-piperidylene; X ¹ is -NHC (O) - and / or X ⁹ is -NHC (O) - and / or in which X ² and / or X ⁸ (C 1 _ ₈ ) is a (kilen and X ¹ is -NHC ( O) N (R ³ ) - and / or X ⁹ is -NHC (O) N (R ³ ) - may be prepared by reacting a compound of Formula 3 or a protected derivative thereof with two or more mole equivalents of an isocyanate of Formula R ¹ -NC (O) or a protected derivative thereof, and then deprotecting when necessary (see Example 10 below for further details).

Compounds 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 ) -, may 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:

LC (O) -Y'-X ² -X ³ -X ⁴ r ² -x ⁹ -x * -x ⁷ -x ⁶ 'or some protected derivative, in which L is a prominent group, Y ¹ is a bond, - 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 is as defined in the Summary of the Invention (see Example 20 below for further details).

Compounds of Formula I in which X ^{2 is} 1,4-piperazinyl or 4,1-piperidylene and X ³ is -C (O) -,

-24-C (0) 0- or -C (O) N (R ³⁾ - or in which X ² (C ₁ _ ₈₎ alkylene and X ³ 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 a compound of formula R ¹ -X ¹ -Y ² or a protected derivative of which, with a compound of Formula 5:

LC (O> Y ³ -XY ^ X ⁵ r ² -x ⁹ -x ⁸ -x ⁷ -x ^{& /} f

or a protected derivative thereof, in which L is a prominent group, Y ³ is a bond, -O- or -N (R ³ ) -, Y ² is piperazin-1-yl, piperid-4-yl or HN ( R ³⁾ - (C, _{first 8)} alkyl, respectively, and each of R ^1, R ^2, R ^3, X ^1, X ^2, X ^3, X ^4, X ^{5, Χ} θ, X ^7, X ⁸ and X ⁹ is as defined in the Summary of the Invention (see Example 31 below for further details).

Compounds of Formula I wherein X ² and X ^{8 are} each 1,4-piperazinylene or 4,1-piperidylene and X ³ and X ⁷ are independently -C (O) -, -C (O) O- or -C (O) N (R ³ ) -, or in which X ² and X ^{8 are} each (C ₁ - ₈ ) alkyl or hetero (C 1 - ₈ ) alkylene and X ³ and X ⁷ are independently -N (R ³ ) C (O) -, -N (R ³ ) C (O) Oali -N (R ³ ) C (O) N (R ³ ) -, can be prepared by reacting two or more molar equivalents of a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof, with a compound of Formula 6:

LC (O) -Y ³ -X%

LC (O) Y ⁷ -X ⁶ or a protected derivative thereof, wherein L is a prominent group, Y ³ and Y ⁷ are independently a bond, -O- or -N (R ³ ) -, Y ² is piperazine -1-yl, piperid-4-yl, HN (R ³ ) - (C 1-8) alkyl or HN (R ³ ) -hetero (C _1-8 ) alkyl, singly, and each 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 further details).

The acylation reactions described above can be performed by reacting one

-25activated ester (e.g. acid chloride derivative) and a suitable nucleophile in the presence of a suitable organic base (e.g., / V, / V-diisopropylethylamine (DIEA), / V-methylmorpholine, etc., preferably DIEA) and a suitable solvent (e.g. / V, N-Adimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane, etc.) at 20 to 30 ° C, typically at about 23 ° C, minutes to 24 hours. Alternatively, acylation may be accomplished by reacting a suitable carboxylic acid and a nucleophile in the presence of a suitable coupling reagent (e.g. 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, etc.) and a suitable solvent (e.g. DMF, etc.) at 20 up to 30 ° C, typically at about 23 ° C, for several hours to several days. The reactions described above for the preparation of compounds of Formula I and the conditions for carrying out the reactions are illustrative, and one of ordinary skill in the art will appreciate that other reaction conditions can be applied and that different starting materials may be used to prepare the compounds of this invention.

Removal of the protection may be effected by any means which removes the protecting group and gives the desired product in reasonable yield. A detailed description of the techniques that can be used to form protecting groups and remove them can be found in T.W. Greene, Protective Groups in Organic Synthesis by John Wiley & Sons, Inc. 1981.

Generally, starting materials useful in the preparation of Formula I compounds and intermediates are usable in the preparation of Formula I compounds commercially available or can be readily prepared by one of ordinary skill in the art. For example, intermediates useful in the preparation of compounds of Formula I are suitably prepared by the acylation reactions described above. Where necessary, suitable protective chemistry is used to direct the reaction to the desired reactive site, when multiple reactive sites are present in the starting materials.

A suitable starting material for the preparation of compounds of Formula I in which X ³ and X ^{7 are} each -C (O) O- is a compound of Formula 7:

LC (O) -O-XV ^ X ⁵ ι / χομο-χ ⁶ in which each X ⁴ , X ⁵ and X ⁶ is as defined in the Summary of the Invention. For example, compounds of

-26Formulos 6 in which L is chloro can be prepared by reacting some suitable diol (e.g. cis-1,5-cyclooctanediol, trans-1,4-cyclohexylenedimethanol, 1,4-phenylenedimethanol, etc.) with triphosgene (for for further details see Example 5, below).

Intermediates useful in the preparation of compounds of Formula I in which such an intermediate contains an amidine group can be prepared by treating the corresponding nitrile with hydrogen chloride in ethanol and then reacting with ammonia.

Additional procedures for the preparation of compounds of Formula I:

Compounds of Formula I in which R ^{4 is} guanidino can be prepared by reacting the corresponding compound of Formula I wherein R ^{4 is} amino with cyanamide. The reaction is carried out by treating the amine with hydrogen chloride and then reacting it with undiluted cyanamide excess at about 65 ° C for about two hours (for further details see Example 15, below).

The compounds of Formula I may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base forms of a compound of Formula I with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable base addition salts of the compounds of Formula I may be prepared by reacting the free acid forms of the compounds of Formula I with pharmaceutically acceptable inorganic or organic bases. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of compounds of Formula I are shown in the definitions section of this application. Alternatively, salt forms of the compounds of Formula I may be prepared using salts of starting materials or intermediates.

Forms of the free acid or free base of compounds of Formula I may be prepared from a suitable form of a base addition salt or an acid addition salt. For example, compounds of Formula I in the form of an acid addition salt may be converted to a suitable free base by treatment with a suitable base (e.g. ammonium hydroxide solution, sodium hydroxide, etc.). Compounds of Formula I in the form of a base addition salt may be converted to the corresponding free acid by treatment with some suitable acid (eg hydrochloric acid, etc.).

The V-oxides of compounds of Formula I can be prepared by methods known to the average

-27 expert. For example, / V-oxides may be prepared by treating some non-oxidized form of a compound of Formula I with some oxidizing agent (e.g., trifluoro-peracetic acid, permaleic acid, perbenzoic acid, peracetic acid, / non-chloroperoxybenzoic acid, etc.) in appropriate an organic solvent (eg, some halogenated hydrocarbon such as methylene chloride) at about 0 ° C. Alternatively, the N-oxides of the compounds of Formula I may be prepared from the N-oxide of the corresponding starting material.

Compounds of Formula I in non-oxidized form may be prepared from / V-oxides of compounds of Formula I by treatment with a reducing agent (eg sulfur, sulfur dioxide, triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.). ) in a suitable inert organic solvent (eg acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 ° C.

The prodrug derivatives of compounds of Formula I can be prepared by methods known to one of ordinary skill in the art (e.g., for further details, see Saulnier et al (1994), Bioorganic and Medicine Chemistry Letters. 4: 1985). Suitable prodrugs may be prepared, for example, by reacting a non-derivatized compound of Formula I with a suitable carbamylating agent (e.g. 1,1-acyloxyalkylcarbon chloride, para-nitrophenyl carbonate, etc.).

Protected derivatives of compounds of Formula I can be made using agents known to one of ordinary skill in the art. A detailed description of the techniques applicable to the formation of protecting groups and their removal can be found in T.W. Greene, Protective Groups in Organic Synthesis by 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:

(a) reacting a compound of Formula 1:

And γ2 v3 γ4

X

-28 or a protected derivative thereof, with a compound of the 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 a piperazin-1-yl, piperid-4-yl or HN (R ³⁾ - (C, _{first 8)} alkyl, respectively, and each of R ^1, R ^2, R ^3, X ^1, X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ is as defined in the Summary of the Invention and then deprotection when necessary to prepare a compound of Formula I in which X ⁸

1,4-piperazinylene or 1,4-piperidylene and X ⁹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) -, or in which X ⁸ (C ₁ _ ₈ ) alkylene and X ⁹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) -;

(b) reacting a compound of Formula I or a protected derivative thereof, with an isocyanate of Formula R ² -NC (O), or a protected derivative thereof, and then deprotecting, where necessary, to prepare a compound of Formula I , in which X ⁸

1,4-piperazinylene or 1,4-piperidylene and X is a ^9-NHC (O) -, or wherein X ⁸ (C ₁ _g) alkylene and X is a ^9-NHC (O) N (R ³⁾ -;

(c) reacting a compound of Formula 2:

Υ ^ Χ'-Χ ⁴ ·

X ^J

R ² -X ⁹ -X * -X ⁷ -X ⁶ 'or a protected derivative thereof, with a compound of the formula R ¹ -Y ¹ -C (O) L or a protected derivative thereof, in which L is a leaving group Y ¹ is a bond, -O- or -N (R ³⁾ -, Y ² is piperazin-1-yl, piperid-4-yl or HN (R ³⁾ - (C ₁ _ ₈₎ alkyl, respectively, 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 and then deprotect when necessary to prepare a compound of Formula I wherein X is ²

1,4-piperazinylene or 1,4-piperidylene and X ¹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) -, or in which X ² (C _{1 8} ) alkylene and X ¹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) -;

(d) reacting a compound of Formula 2 or a protected derivative thereof, with an isocyanate of formula R ¹ -NC (O), or with a protected derivative thereof, and then deprotecting when necessary to prepare a compound of Formula I, in which X ²

1,4-piperazinylene or 1,4-piperidylene and ^X1 is -NHC (O) -, or wherein X ² (C ₁ _g) alkylene and ^X1 is -NHC (O) N (R ³⁾ -;

(e) reacting a compound of Formula 3;

-29Υ ² -Χ ³ -χΝ> ⁵

Υ * -Χ ⁷ -Χ ⁶ or a protected derivative thereof, with 2 or more molar equivalents of a compound of formula R ¹ -Y ¹ -C (O) L, or a protected derivative thereof, in which 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, piperid-4-yl or HN (R ³ ) - (C 1-8) alkyl and each R ¹ , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ is as defined in the Summary of the Invention and then deprotection when necessary to prepare a compound of Formula I in which R ^{1 is} equal to R ² ; X ² and / or X ⁸ is 1,4-piperazinylene or 1,4-piperidylene; X ¹ is -C (O) -, -OC (O) -, or -N (R ³ ) C (O) -; and X ⁹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) - and / or wherein X is ² and / or X ⁸ (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 ) -;

(f) reacting a compound of Formula 3 or a protected derivative thereof, with two or more mole equivalents of an isocyanate of formula R ¹ -NC (O) or a protected derivative thereof, and then removing the protection when necessary to prepare a a compound of Formula I wherein R ^{1 is} equal to R ² ; X ² and / or X ⁸ is 1,4-piperazinylene or 1,4-piperidylene; X ¹ is -NHC (O) - and / or X ⁹ is -NHC (O) - and / or wherein X is ² and / or X ⁸ (C 1-4 alkylene and X ¹ is -NHC (O) N ( R ³ ) - and / or X ⁹ is -NHC (O) N (R ³ ) -;

(g) reacting an amine of formula R ¹ -N (R ³ ) H or a protected derivative thereof, with a compound of Formula 4:

LC (O) -Y ^l -X ² -X ³ -Xl ^ x ⁵ r ² -x ⁹ -x ⁸ -x ⁷ -x ^6X ^ or a protected derivative thereof, wherein L is a prominent group, Y ¹ is 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 is as defined in

Summary of the invention and then removal of the protection when necessary to prepare one

-30 a compound of Formula I in which X ^{1 is} -N (R ³ ) C (O) -, -N (R ³ ) C (O) O- or -N (R ³ ) C (O) N (R ³ ) -;

(h) reacting a compound of formula R ¹ -X ¹ -Y ^2, or a protected derivative thereof, with a compound of Formula 5:

LC (O) -Y ³ -X <

r ² -x ⁹ -x ⁸ -x ⁷ -x ⁶

X ⁵ or a protected derivative thereof, wherein L is a protruding group, Y ³ is a bond, -O or -N (R ³ ) -, Y ² is piperazin-1-yl, piperid-4-yl or HN (R ³ ) - (C 1-8) alkyl, singly, 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 is, as defined in the Summary of the Invention and then deprotection when necessary to prepare a compound of Formula I in which X ^{2 is} 1,4-piperazinylene or 4,1-piperidylene and X ³ is -C (0) -, -C (O) O- or -C (O) N (R ³ ) -, or in which X ² (C _1-8 ) is alkylene and X ³ is -N (R ³ ) C (O) -, -N (R ³ ) C (O) O- or -N (R ³ ) C (O) N (R ³ ) -;

(i) reacting 2 or more mole equivalents of a compound of formula R ¹ -X ¹ -Y ² or a protected derivative thereof, with a compound of Formula 6:

ιχχο) -Υ ³ -χ *> ⁵

LCCO) Y ⁷ -X * or a protected derivative thereof, in which L is a prominent group, Y ³ and Y ⁷ are independently a bond, -O-or -N (R ³ ) -, Y ² is piperazine-1- yl, piperid-4-yl, HN (R ³ ) - (C 1-8) alkyl or HN (R ³ ) -hetero (C _1-8 ) alkyl and each R ¹ , X ¹ , X ⁴ , X ⁵ and X ⁶ is, as defined in the Summary of the Invention, and then deprotection when necessary to prepare a compound of Formula I wherein X ² and X ^{8 are} each 1,4-piperazinylene or 4,1-piperidylene and X ³ and X ⁷ are independently -C (O) -, -C (O) O- or -CfOjNiR ³ ) -, or wherein X ² and X ^{8 are} each (C ₁ , ₈ ) alkylene or hetero (C., _ ₈ ) alkylene and X ³ and X ² are independently -N (R ³ ) C (O) -, -N (R ³ ) C (O) O- or -N (R ³ ) C (O) N (R ³⁾ ) -, individually;

-31 (j) optionally reacting a compound of Formula I in which R ^{4 is} amino with cyanamide to prepare a compound of Formula I in which R ^{4 is} guanidino;

(k) optionally further converting the compound of Formula I into a pharmaceutically acceptable salt;

(l) optionally further converting the salt form of the compound of Formula I to the non-salt form;

(m) optionally further converting the non-oxidized form of a compound of Formula I to some pharmaceutically acceptable / V-oxide;

(n) optionally further converting an AA oxide form of a compound of Formula I into its non-oxidized form;

(o) optionally further converting a non-derivatized compound of Formula I into a pharmaceutical prodrug; and (p) optionally further converting the prodrug derivative of a compound of Formula I into its non-derivatized form.

In all the above procedures, the reference to Formula I refers to such Formula, wherein 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 , as defined in their broadest definitions, explained in the Summary of the Invention, with reference to methods that are particularly well used in the present preferred embodiments.

-32 EXAMPLES:

EXAMPLE 1 / erobutyl 4-aminobenzylcarbamate hydrochloride

4-Aminobenzylamine (50.34 g, 0.412 mol) in dichloromethane (200 mL) was placed in a 1-liter, 3-neck round bottom flask equipped with a mechanical stirring device and cooled to 0 ° C. To the solution, di- / e? -Butyl dicarbonate (89.9 g, 0.412 mol) in dichloromethane (200 mL) was added dropwise over 30 minutes and the resulting suspension was stirred for 2 hours at 0 ° C, which gave a nearly homogeneous solution. The dichloromethane solution was then washed with aqueous sodium hydroxide (1.0 M, 500 mL) and then with water (500 mL). The organic layer was dried (MgSO4, filtered and concentrated in vacuo to give a yellow oil. The oil was taken up in ethyl ether: methanol (2: 1, 225 mL) and the solution cooled to 0 ° C, acidified with hydrogen chloride in dioxane (4.0 M, 115 mL, 0.412 mol) and combined with ethyl ether (200 mL) to give a dense light yellow precipitate. The precipitate was collected by filtration and washed with additional ethyl ether (500 mL). gave / ere-butyl 4-aminobenzylcarbamate hydrochloride (100.23 g, 0.387 mol, yield 94%) as a light yellow solid; ¹ H-NMR (300MHz, DMSO-dg): 10ΛΟΙ 0.20 (brs, 3H) , 7.40 (tr, 1H), 7.30 (s, 4H), 4.10 (d, 2H), 1.40 (s, 9H).

EXAMPLE 2 ere-Butyl 4-guanidinobenzylcarbamate

Cyanamide (100 g, 2.4 mol) was placed in a 500 mL round bottom flask and heated to a temperature between 60 and 65 ° C until the material was completely melted and then / ero butyl 4-aminobenzylcarbamate hydrochloride (25.3 g , 97.8 mmol), prepared as in Example 1, was added directly to the liquid cyanamide, which gave some yellow solution. The solution was stirred for 2 hours at a temperature between 60 and 65 ° C and then water (100 mL) was added. The aqueous mixture was cooled to room temperature and washed with ethyl ether (1 L). The organic phase was back-extracted with water (2x, 100 mL) and the combined aqueous layers washed with ethyl ether (500 mL), cooled in an ice-water bath and then basified with aqueous sodium hydroxide (10 M, 100 mL) to give insoluble oil that slowly crystallized. The crystals were collected by filtration and washed with water. Vacuum drying gave N-butyl 4-guanidinobenzylcarbamate (18.3 g, 69.24 mmol, yield 70.8%) as a colorless

-33crystalline 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 3 te / p-butyl 4-chlorocarbonyl-1-piperazinecarboxylate

Trifosgene (25 g, 84.2 mmol) was added to dichloromethane (200 mL) and the resulting solution cooled to 0 ° C. A tert-butyl mixture was then added dropwise to the triphosgene solution

Of 1-piperazinecarboxylate (40 g, 214.8 mmol) and pyridine (35 mL, 432.7 mmol) in dichloromethane (100 mL) and allowed to warm to room temperature for 30 minutes. The mixture was quenched with aqueous hydrochloric acid (0.1 N, 200 mL) and the aqueous phase was washed with dichloromethane (50 mL). The combined organic layers were dried (MgSO ₄ ) and filtered. Concentration in vacuo gave tert-butyl 4-chlorocarbonyl-1piperazinecarboxylate (45.6 g, 71.6 mmol, 85% yield) as a 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 4 butyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate

Tert-butyl 4-guanidinobenzylcarbamate (41.77 g, 0.158 mol), prepared as in Example 2, was treated with trifluoroacetic acid (TFA) (100 mL) for 30 minutes at room temperature. The resulting colorless liquid was concentrated in vacuo at 45 ° C and the residue triturated with ethyl ether (3x, 400 mL) and dried in vacuo to a colorless foam. The residue was dissolved in methanol (200 mL) and then DIEA (55 mL, 0.32 mol, amount based on estimated excess TFA present) was added to the solution. The mixture was cooled to 0 ° C and then tert -butyl 4-chlorocarbonyl-1-piperazinecarboxylate (39.3 g, 0.158 mol) was prepared as in Example 3 in dichloromethane (120 mL). An additional amount of DIEA (30 mL) was added and the reaction was allowed to warm to room temperature, stirred for 12 hours and concentrated in vacuo to give an orange oil. The oil was combined with water (200 mL) to give a dense precipitate. Recrystallization of the precipitate from acetonitrile and ether gave therobutyl 4- (4-guanidinobenzylcarbamoyl) -1piperazinecarboxylate trifluoroacetate (62.0 g, 0.126 mol, 80% yield) 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); LRMS

-34with electrospray (Electrospray LRMS), [LRMS = Low Resolution Mass Spectrometry = Op. prev.]: calculated for ^c 13 ^H 20 ^N 6 ^{O: mh +: 277} · ⁴ ; MH2 ⁺² / 2: 139.2, Found: MH ⁺ : 277.4; MH2 ⁺² / 2: 139.3.

EXAMPLE 5 c / s-1,5-cyclooctylene di (chloroformate)

C / S-1,5-cyclooctanediol (20.2 g, 0.14 mol) was added to acetonitrile (250 mL) and potassium carbonate (41.4 g, 0.3 mol) was added to the mixture to give some suspension. . The suspension was cooled to 0 ° C under a nitrogen atmosphere and then phosgene (1.9M in toluene, 220 mL, 0.42 mol) was added dropwise over one hour. The suspension was warmed to room temperature and stirred for 12 hours and then ether (1 L) was added. The suspension was filtered to be insoluble and concentrated. P recrystallization of the hexane residue gave c / s-1,5-cyclooctylene di (chloroformate) as a colorless crystalline solid. Further purification may be carried out by flash chromatography on silica gel using hexamethyl ether (10: 1) as eluent;

¹ H-NMR (300MHz, CDCl ₃ ): 5.00-4.85 (m, 2H), 2.20-1.60 (m, 12H).

EXAMPLE 6 c / s-1,5-Cyclooctylene Chloroformate 4-Therobutoxycarbonyl-1-piperazinecarboxylate

C / S-1,5-cyclooctylene di (chloroformate) (1.91 g, 7.1 mmol) prepared as in Example 5 in dichloromethane (25 mL) was added dropwise to a mixture of tert-butyl 1-piperazinecarboxylate (1.3 g, 7.1 mmol) and DIEA (1.3 mL, 7.1 mmol) in dichloromethane (25 mL). The mixture was stirred for 15 minutes at room temperature and then treated with 0.1 M aqueous hydrochloric acid. The dichloromethane layer was dried (MgSO4, filtered and concentrated. Purification from the residue by flash chromatography with silica gel using ethyl ether and hexanes as eluent gave c / s-1,5-cyclooctylene chloroformate 4-terbutoxycarbonyl-1piperazinecarboxylate (660 mg, 1 mg) , 6 mmol, yield 22%) as a colorless oil;

¹ H-NMR (300MHz, CDCl3): 5.00-4.90 (m, 1H), 4.80-4.70 (m, 1H), 3.40 (S, 8H), 2.05-1 , 40 (m, 12), 1.40 (s, 9H).

-35 EXAMPLE 7 cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (O-butoxycarbonyl-1-piperazinecarboxylate)

7erc-Butyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate (383.7 mg, 1.06 mmol), prepared as in Example 4, was treated with neat trifluoroacetic acid (1 mL) for 10 minutes at room temperature. The mixture was concentrated in vacuo to give a colorless oil. The oil was then placed in water (15 mL) and the pH of the aqueous solution adjusted between 7 and 8 with 5M aqueous sodium hydroxide added dropwise. C / s-1,5-cyclooctylene chloroformate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (444.7 mg, 1.06 mmol), prepared as in Example 6, in THF (10 mL) was added to the aqueous solution. were adjusted with 1M aqueous sodium hydroxide added dropwise until no further change in pH was observed. The mixture was concentrated in vacuo removing most of the THF and then ethyl ether (5 mL) and 5M aqueous sodium hydroxide (sufficient to adjust the pH to 14) were added to give a dense white suspension. The suspension was allowed to stand for 15 to 30 minutes at room temperature and then the precipitate was collected by filtration and washed with water (2x, 15 mL). Vacuum drying gave c / s-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazine-carboxylate 4-tert-butoxycarbonyl-1 piperazinecarboxylate (527 mg, 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-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate (Compound 1)

The following is a preparation of a compound of Formula I in which R ^{1 is} 4-guanidinobenzyl, R ² is

2-piperid-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 covalent bond and X ⁵ is c / s-1,5-cyclooctylene.

Cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (818 mg, 1.24 mmol) prepared as in Example

-367, was treated with undiluted TFA (2 mL) for 10 minutes. The mixture was concentrated in vacuo to give a colorless oil. The residue was triturated with ethyl ether (2x, 10 mL) and dried in vacuo to give a colorless foam. The residue was then added to DMF (2 mL) and then DIEA (700 mL, 4.0 mmol) and phenylbutyl 4- (2isocyanatoethyl) -1-piperidinecarboxylate (3.2 mL, 0.39 M in DMF) were added. , 1.25 mmol). The mixture was stirred for 12 hours and then concentrated in vacuo. The residue was triturated with water (2x, 5 mL) and dried in vacuo to give a yellow solid. The solid was then treated with TFA (2 mL) and the mixture was concentrated in vacuo. We put the rest in the water. Purification from the aqueous mixture by preparative reverse phase HPLC gave c / 1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1 piperazinecarboxylate as an amorphous colorless solid substance; Plasma desorption LRMS (Plasma Desorption LRMS); calculated for θ35 ^ 55 ^ 10θ6 · MH ⁺ : 712.9, found; MH ⁺ : 713.2.

The following compounds of Formula I were prepared by the procedure as in Example 8 and by substituting various starting materials:

czs-1,5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 2); calculated for ^C 35 ^H 5 ^{O N} 10 ^O 6 ^{: mh +: 707} ' ⁹ ' found: MH ⁺ : 707.7;

cvs-1,5-cyclooctylene 4- {4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperidylmethylcarbamoyl) -1-piperazinecarboxylate (Compound 3); calculated for ^C 34 ^H 53 ^N 10 ^O 6 ^{: mh +: 698} ' ⁹ ' found: MH ⁺ : 699.7;

cis-1,5-cyclooctylene 4 - ((ra) 7S-4-aminocyclohexylmethylcarbamoyl) 1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 4); Calculated for C35H ₅₅ N _1Q O _6: MH ^+: 712.9, Found: MH ^+: 713.6;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

3- piperid-4-ylpropylcarbamoyl-1-piperazinecarboxylate (Compound 5); calculated for ^C 36 ^H 58 ^N 10 ° 6 ^{: mh +: 727} > ⁹ <found: MH ⁺ : 727.9;

4- [4- (2-Piperid-4-ylethylcarbamoyl) piperazin-1-ylcarbonyl] benzyl

4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 6); calculated for ^C 34 ^H 48 ^N 10 ° 5 ^{: mh +: 677} ' ⁸ - found: MH ⁺ : 677.6;

4- [4- (3-Piperid-4-ylpropylcarbamoyl) piperazin-1-ylcarbonyl] benzyl

4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 7); calculated for

-37 ^C 35 ^H 5 ^{O N} 10 ° 5 ^{: mh +: 691} ' ⁹ · found: MH ⁺ : 691.5;

4- [4- (4-piperid-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-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 9); calculated for ^C 34 ^H 48 ^N io ° 5 ^{: mh +: θ77} ' ^θ > found: MH ⁺ : 677.7;

4- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] benzyl 4- (3-piperid-4-ylpropylcarbamoyl) -1-piperazinecarboxylate (Compound 10); calculated for ^C 35 ^H 5 ^{O N} 10 ^O 5 ^{: mh +: 691} - ⁹ - found: MH ⁺ : 691.3;

4- [4- (2-piperid-4-ylethylcarbamoyl) piperazin-1-ylcarbonylmethylbenzyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 11); calculated for ^C 35 ^H 50 ^N w ° 5 ^{: mh +: 691} ′ ⁹ · found: MH ⁺ : 692.1;

4- [4- (3-piperid-4-ylpropylcarbamoyl) piperazin-1-ylcarbonylmethylbenzyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 12); calculated for ^C 36 ^H 52 ^N 10 ° 5 ^{: mh +: 705} - ⁹ - found: MH ⁺ : 705.6;

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

cis-), 5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 14); calculated for ^C 35 ^H 55 ^N 9 ° 6 ^{: mh +: 698} - ⁹ - found: MH ⁺ : 698.2;

cis-), 5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (3-piperid-4-ylpropylcarbamoyl) -1-piperazinecarboxylate (Compound 15); calculated for ^C 36 ^H 57 ^N 9 ° 6 ^{: mh +: 712} - ⁹ - found: MH ⁺ : 712.3;

cis-), 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-imidazol-1-ylbutylcarbamoyl) -1-piperazinecarboxylate (Compound 16); calculated for ^C 35 ^H 53 ^N 11 ° 6 ^{: mh +: 724} ' ⁹ ' found: MH ⁺ : 724.5;

cis-), 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-imidazolin-2-ylaminobutylcarbamoyl) -1-piperazinecarboxylate (Compound 17); calculated for C ₃₅ H ₅₆ N ₁₂ O ₆ : MH ⁺ : 741.9, found; MH ⁺ : 741.7;

cis-), 5-cyclooctylene 4 - ((N- [5-4-aminocyclohexylmethylcarbamoyl) 1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound

18); calculated for C ₃₅ H ₅₆ N ₁₀ O ₆ : MH ⁺ : 713.9, found: MH ⁺ : 714.1;

-38c / s-1,5-cyclooctylene 2- (1-tert-butyryloxymethoxycarbonylpiperid-4-yl) ethylcarbamoyl-1 piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -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-methylpiperid-4-yl) ethylcarbamoyl] -1-piperazinecarboxylate (Compound 20); calculated for C ₃₆ H ₅₈ N _w O ₆ : MH ₂ ²⁺ / 2; 364.0 found: MH ₂ ²⁺ / 2: 364.3;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazolin-2-ylaminopropylcarbamoyl) -1-piperazinecarboxylate (Compound 21); calculated for 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) piperid-4-ylmethylcarbamoyl] -1-piperazinecarboxylate (Compound 22); calculated for C ₃₆ H ₅₇ N ₁₁ O _S : MH ⁺ : 740.9, found: MH ⁺ : 740.5;

cis-1,5-cyclooctylene 4- (4-guanidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 23); calculated for ^C 36 ^H 57 ^N 9 ° 6 ^{: mh +: 712} - ⁹ - found: MH ⁺ : 711.6;

cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate

2- (1-Methoxycarbonylpiperid-4-yl) ethylcarbamoyl-1-piperazinecarboxylate (Compound 24);

calculated for C ₃₇ H ₅₇ N _g O ₈ : MH ⁺ : 756.9, found: MH ⁺ : 756.7; and

3- {4- [2- (4- {cis-5- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyloxy] cyclooxyloxycarbonyl} piperazine-1-ylcarbonylamino) ethyl] piperid-1-ylcarbonylpropionic acid (Compound 25); calculated for C _3g H ₆₀ N _g O _g : MH ⁺ : 799.0, found: MH ⁺ : 798.6.

The following compounds of Formula I were prepared by the procedure as in Example 8 and by replacing the isocyanate with an activated ester:

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- imidazol-4-ylacetyl-1-piperazinecarboxylate (Compound 26); calculated for 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- (F-3-imidazol-4-ylacryloyl) -1-piperazinecarboxylate (Compound 27); calculated for ^C 33 ^H 46 ^N 10 ^O 6 ^{: mh +: 679} - ⁹ - found: MH ⁺ : 679.8;

c is-A, 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- (3-imidazol-4-ylpropionyl) -1-piperazinecarboxylate (Compound 28); calculated for ^C 33 ^H 48 ^N 10 ° 6 ^{: mh +: 681} > ⁸ - found: MH ⁺ : 681.7;

-39 cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (5-imidazol-1-ylvaleryl) -1-piperazinecarboxylate (Compound 29); calculated for ^C 35 ^H 52 ^N 10 ^O 6 ^{: mh +: 709} ' ⁹ · found: MH ⁺ : 709.5;

cis-A, 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (Compound 30); calculated for ^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-piperazinecarboxylate (Compound 31); calculated for ^C 39 ^H 52 ^N 10 ^O 6 ^{: mh +: 757} ' ⁹ ' found: MH ⁺ : 757.2;

cis-A, 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-imidazol-1-ylmethylbenzoyl) -1-piperazinecarboxylate (Compound 32); calculated for ^C 38 ^{H 5 O N} 10 ^O 6 ^{: mh +: 743} ′ ⁹ · found: MH ⁺ : 743.7;

cis-A, 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylmethylbenzoyl) -1-piperazinecarboxylate (Compound 33); calculated for ^C 38 ^{H 5 O N} 10 ^O 6 ^{: mh +: 743} ′ ⁹ · found: MH ⁺ : 743.6;

cis-A, 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (7-imidazol-1-ylheptanoyl) -1-piperazinecarboxylate (Compound 34); calculated for ^C 37 ^H 56 ^N 10 ° 6 ^{: mh +: 737} > ⁹ > found: MH ⁺ : 737.6;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- [6- (2-methylimidazol-1-yl) hexanoyl] -1-piperazinecarboxylate (Compound 35); calculated for ^C 37 ^H 56 ^N 10 ° 6 ^{: mh +: 737} - ⁹ - found: MH ⁺ : 737.3;

cis-A, 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-imidazol-1-ylphenoxyacetyl) -1-piperazinecarboxylate (Compound 36); calculated for ^C 38 ^{H 5 O N} 10 ° 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-A, 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- [6- (5-Methylimidazol-1-yl) hexanoyl] -1-piperazinecarboxylate as a 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-piperid-4-ylbutyryl) -1-piperazinecarboxylate (Compound 38); calculated for C ₃ gH ₅₇ N _g O ₆ :

MH ⁺ : 712.9 Found: MH ⁺ : 712.4;

cis-A, 5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate

4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (Compound 39); calculated for C ₃₆ H ₅₆ N ₉ O ₆ :

-40ΜΗ ⁺ : 697.9, Found: ΜΗ ⁺ : 697.5;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- (2-piperid-4-ylethyl) (methyl) carbamoyl-1-piperazinecarboxylate (Compound 40); calculated for ^C 36 ^H 58 ^N 10 ° 6 ^{: mh +: 727} ' ⁹ - found: MH ⁺ : 727.6;

cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethyl) (methyl) carbamoyl-1-piperazinecarboxylate (Compound 41); calculated for ^C 36 ^H 57 ^N 9 ° 6 ^{: mh +: 712} ' ⁹ ' found: MH ⁺ : 712.7;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethoxycarbonyl) -1-piperazinecarboxylate (Compound 42); calculated for ^C 35 ^H 55 ^N 9 ° 7 ^{: mh +: 714} ' ⁹ · found: MH ⁺ : 714.5;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-imidazol-1-ylphenylacetyl) -1-piperazinecarboxylate (Compound 43); calculated for ^C 38 ^{H 5 O 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 (Compound 44); calculated for ^ε 36 ^Η 53 ^Ν 9θ6 ^{: MH +: 708} - ⁹ - found: MH ⁺ : 708.8;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-pyrid-4-ylthiopropionyl) -1-piperazinecarboxylate (Compound 45); calculated for ^C 35 ^H 49 ^N 9 ° 6 ^{: mh +} ' ⁷²⁴ - ⁹ - found: MH ⁺ 724.4;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbonyl) -1-piperazinecarboxylate 4-pyrid-4-ylthioacetyl-1-piperazinecarboxylate (Compound 46); calculated for ^ 34Η ₄₇ Ν ₉ Ο ₆ : MH ⁺ : 710.9, Found: MH ⁺ : 710.8;

cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (3-pyrid-4-ylthiopropionyl) -1-piperazinecarboxylate (Compound 47); calculated for ^C 35 ^H 48 ^N 8 ° 6 ^{: mh +: 709} - ⁹ - found: MH ⁺ : 709.3;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (6-imidazol-4-ylhexanoyl) -1-piperazinecarboxylate (Compound 48); calculated for ^C 36 ^H 54 ^N 10 ^O 6 ^{: mh +: 723} · ⁹ 'found: MH ⁺ : 723.5;

cis-1,5-cyclooctylene 4- (benzoimidazol-6-ylcarbonyl) -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 49); calculated for ^C 35 ^H 47 ^N 10 ° 6 ^{: mh +: 703} ′ ⁸ - found: MH ⁺ : 703.4;

cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- (6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (Compound 50); calculated for ^C 36 ^H 53 ^N 9 ° 6 ^{: mh +} : 708.9, found: MH ⁺ : 708.6;

-41cisG, 5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- (6-imidazol-4-ylhexanoyl) -1-piperazinecarboxylate (Compound 51); calculated for ^C 37 ^H 54 ^N 8 ° 6 ^{: mh +: 707} - ⁹ · found: MH ⁺ : 707.5;

cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (6-imidazol-4-ylhexanoyl) -1-piperazinecarboxylate (Compound 52); calculated for ^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-pyrid-4-ylcarbamoylacetyl-1-piperazinecarboxylate (Compound 53); calculated for ^C 35 ^H 47 ^N 9 ° 7 ^{: mh +: 706} - ⁸ 'found ·. MH ⁺ : 706.3;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-pyrid-4-ylaminopropionyl) -1-piperazinecarboxylate (Compound 54); calculated for C ₃ 5 ^H 5 ^{o n} io ° 6 ^{; mh +;} 707.9 found: MH ⁺ : 707.3;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

3- [pyrid-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;

czs-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- (3-piperazin-1-ylcarbonylpropionyl) -1-piperazinecarboxylate (Compound 56); calculated for ^C 35 ^H 54 ^{N 1} O ° 7 · ' ^{mh +: 727} ' ⁹ 'found: MH ⁺ : 727.5;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-piperid-1-ylcarbonylaminoacetyl-1-piperazinecarboxylate (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- (5-imidazol-4-ylvaleryl) -1-piperazinecarboxylate (Compound 58); calculated for ⁽ -'35 ^Η 52 ^Ν ιοθ6 ^{: mh +: 708} ' ⁹ ' found: MH ⁺ : 709.4;

cis-1,5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- (3-piperazin-1-ylcarbonylpropionyl) -1-piperazinecarboxylate (Compound 59); calculated for ^C 36 ^H 54 ^N 8 ° 7 ^{: mh +: 711} - ⁹ 'found: MH ⁺ : 711.4;

cis-1,5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4-piperid-4-ylcarbonylaminoacetyl-1-piperazinecarboxylate (Compound 60); calculated for ^C 36 ^H 54 ^N 8 ° 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 ° 6 ^{: mh +: 7θθ} · ^θ - found: MH ⁺ : 708.4;

cis-1,5-cyclooctylene 4- [3- (6-aminopyrid-3-yl) propionyl] -1-piperazinecarboxylate

-424- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 62); Calculated for C35H50N1 ₀ O ^_6: MH ^+: 707.8, Found: MH ^+: 707.4;

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- [4- (4-pyrid-4-ylthio) butyryl] -1-piperazinecarboxylate (Compound 63); calculated for C ₃₆ H ₅₁ Ν ₉ Ο _θ : MH ⁺ : 738.9, Found: MH ⁺ : 738.4;

c / s-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 ° 8 ^{: mh +: 725} - ⁸ · found: MH ⁺ : 725.2;

cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (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-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (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-amidinopiperid-4-ylacetyl) -1-piperidinecarboxylate 4- (6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (Compound 67); calculated for ^C 35 ^H 57 ^N 9 ° 6 ' ^{mh +: 7θθ} - ^θ - found: MH ⁺ : 700.5;

cis-1,5-cyclooctylene 4- (1-amidino-4-piperidylacetyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (Compound 68); calculated for C ₃₅ H ₆₀ N ₈ O ₆ : MH ⁺ : 689.9, found: MH ⁺ : 689.4;

cis-1,5-cyclooctylene 4- (1-amidino-4-piperidylacetyl) -1-piperazinecarboxylate 4- (6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (Compound 69); calculated for ^ 35 ^Η 57 ^Ν 9θ6 ^{; MH +: 700-9>} Found: MH ^+: 700.4;

cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (6-imidazol-4-ylhexanoyl) -1-piperazinecarboxylate (Compound 70); calculated for θ36 ^Η 53 ^ 9θ6 ^: 708.9, found: MH ⁺ : 708.4;

cis-1,5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- (6-imidazol-4-ylhexanoyl) -1-piperazinecarboxylate (Compound 71); calculated for ^C 37 ^H 54 ^N 8 ° 6 ^{: mh +: 707} · ⁹ · found: MH ⁺ : 707.4;

cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate

4- (6-imidazol-1-ylhexanoyl) -1-piperazinecarboxylate (Compound 72); Calculated for ^C 36 ^H 52 ^N 8 ° 6 ^{: mh +: θθ3} ′ ^θ > found: MH ⁺ : 693.4;

cis-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate

-434- (4-Piperid-4-ylbutyryl) -1-piperazinecarboxylate (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. (Compound 74); calculated for ^C 36 ^H 52 ^N 8 ° 6 ^{: MH +: 693} - ^{θ MH +: 693} -4; ^and cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- [4- (2- (1-te / 'C ^L butilkarboniloksimetoksikarbonil) piperid-4-ylethylcarbamoyl) 1 -piperazinecarboxylate (Compound 75); calculated for θ42 ^Η 65 ^Ν 9θιο · ^{MH +: θ57} –θfunded: MH ⁺ : 856.6.

EXAMPLE 9 c / s-1,5-cyclooctylene di (4- / erobutoxycarbonyl-1-piperazinecarboxylate)

C / S-1,5-cyclooctylene di (chloroformate) (3.69 g, 13.7 mmol) prepared as in Example 5, and DIEA (7.2 mL, 41 mmol) was added to DMF (25 mL) and terobutyl 1piperazinecarboxylate (5.1 g, 27.4 mmol) was added. The mixture was stirred for 12 hours at room temperature and then concentrated in vacuo to give a semi-solid residue. The residue was partitioned between dichloromethane (50 mL) and water (50 mL) and the dichloromethane layer was washed with 0.1 N aqueous hydrochloric acid (2x, 25 mL), dried (MgSO ₄ ) and filtered. Concentration in vacuo gave c / s-1,5-cyclooctylene di (4-tert-butoxycarbonyl-1-piperazinecarboxylate) as an amorphous solid; ¹ H-NMR (300 MHz, CDCl 3); 4.80 (m, 2H), 3.40 (br s, 16H), 2.001.40 (m, 12H), 1.40 (s, 18H).

EXAMPLE 10 cis-1,5-cyclooctylene di [4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate] (Compound 76)

The following is a preparation of a compound of Formula I wherein R ¹ and R ^{2 are} each 2-piperid-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 covalent bond and X ⁵ is c / s-1,5-cyclooctylene.

C / s-1,5-cyclooctylene di (4-tert-butoxycarbonyl-1-piperazinecarboxylate) (47.9 mg, 0.088 mmol) prepared as in Example 9 was treated with undiluted TFA (1 mL) for 10 minutes. , which gave some colorless oil. The mixture was concentrated in vacuo and

-44 The residue was triturated with ethyl ether (2x, 5 mL) and dried again in vacuo to give an amorphous solid. A solid residue was added to DMF (5 mL) and DIEA (100 mL, 0.5 mmol) was added to the solution followed by tert-butyl 4- (2-isocyanatoethyl) -1-piperidinecarboxylate (460 mL, 0.39 M in DMF). 0.18 mmol). The mixture was stirred for 12 hours and concentrated in vacuo. The residue was triturated with water (2x, 5 mL) and dried in vacuo to give a yellow solid. The solid was treated with TFA (2 mL) and the mixture was concentrated in vacuo. We put the rest in the water. Purification from the aqueous mixture by preparative reverse phase HPLC followed by lyophilization gave c / s-1,5-cyclooctylene di [4- (2-piperid-4ylethylcarbamoyl) -1-piperazinecarboxylate] as a colorless amorphous solid; Electrospray LRMS: calculated for C34H ₆₀ N ₈ O ₆ : MH ⁺ : 677.9, found: MH ⁺ :

677,6.

By treating Example 10 and substituting various starting materials, cis-3,5-cyclooctylene di [4- (4-methylaminomethylbenzylcarbamoyl) -1-piperazinecarboxylate (Compound 77) was prepared; calculated for C ₃₈ H ₅₆ N ₈ O ₆ : MH ⁺ : 721.9, found: MH ⁺ : 721.7.

The following compounds of Formula I were prepared by the procedure as in Example 10 and by replacement of the isocyanate with an activated ester:

cis-1,5-cyclooctylene di [4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (Compound 78); calculated for C ₃₆ H ₆₂ N ₆ O ₆ : MH ⁺ : 675.9, found: MH ⁺ : 675.6; and para-dimethylenephenylene di [4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate (Compound 79); calculated for 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

Tert-Butyl 4-chlorocarbonyl-1-piperazinecarboxylate (188 mg, 0.76 mmol), prepared as in Example 3, was added to dichloromethane (10 mL) and DIEA (150 mL, 0.86 mmol) was added. 1- (3-Aminopropyl) imidazole (100 mL, 0.84 mmol) was added with the injection needle and the mixture was stirred for 12 hours. Dichloromethane (10 mL) was added to the mixture and the organic layer was washed with water (1x, 10 mL), dried (MgSO ₄ ) and filtered. Concentration gave tert-butyl 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (230 mg, 0.68 mmol, 90% yield) as

-45barless 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-benzenecarbamate hydrochloride

4-Aminobenzylamine (5.56 g, 45.6 mmol) was added to water (45 mL) and citric acid (9.63 g, 50 mmol) was added to the solution. Di-tert-butyl dicarbonate (9.94 g, 45.5 mmol) in dioxane (20 mL) was added dropwise to the solution, and the mixture was stirred for 48 hours at room temperature to give a yellow suspension. The suspension was filtered and the aqueous solution basified with an excess of solid sodium carbonate and extracted with ethyl acetate (3x, 35 mL). The combined extracts were washed with saturated aqueous sodium chloride, dried (MgSO ₄ ), filtered and concentrated in vacuo to give a white solid. The solid was added to methanol (30 mL), the solution acidified with hydrogen chloride in dioxane (4M, 8.4 mL, 33.6 mmol) and then ethyl ether (100 mL) was added, which gave some suspension. The particulate matter was isolated by filtration. Vacuum drying gave tert-butyl 4-aminomethyl-1-benzenecarbamate hydrochloride (7.2 g, 27.8 mmol, yield 61%) as a colorless solid; ¹ H-NMR (300MHz, DMSO-,θ): 9.43 (S, 1H), 8.20 (br s, 3H), 7.40 (dd AB, 4H), 3.92 (m, 2H) , 1.50 (s, 9H).

EXAMPLE 13 tert-butyl 4-isocyanatomethyl-1-benzenecarbamate:

Tert-Butyl 4-aminomethyl-1-benzenecarbamate hydrochloride (3.39 g, 13.1 mmol), prepared as in Example 12, was added to dichloromethane (120 mL) at 0 ° C and pyridine (4.3 mL, 53 mmol) was added. ) and triphosgene (1.3 g, 4.4 mmol). The mixture was allowed to warm to room temperature for 30 minutes and aqueous hydrochloric acid (0.5N, 100 mL) was added, the organic layer was dried (MgSO ₄ ) and filtered. Concentration gave tert-butyl 4isocyanatomethyl-1-benzenecarbamate (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).

-46 EXAMPLE 14 cis-1,5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (CompoundSO)

The following is a preparation of a compound of Formula I wherein R ^{1 is} 4-aminobenzyl, R ² is 3imidazol-1-ylpropyl, 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 covalent bond and X ⁵ is cis-A, 5-cyclooctylene.

(a) 7-Ethyl-butyl 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (225 mg, 0.67 mmol), prepared as in Example 11, was treated with undiluted TFA (1 mL) for 10 minutes. The mixture was concentrated in vacuo and the residue was taken up in dichloromethane (10 mL) and an excess of DIEA (1.0 mL) was added to the solution. To the solution was added cis-1,5-cyclooctylene chloroformate 4-tert-butoxycarbonyl-1-piperazinecarboxylate (279 mg, 0.67 mmol), prepared as in Example 6, in dichloromethane (5 mL) and the mixture was stirred 1 hour. Additional dichloromethane (10 mL) was added and the organic layer was washed with saturated aqueous sodium bicarbonate (1x, 10 mL), dried (MgSO ₄ ) and filtered. Concentration gave the crude adduct of cisA, 5-cyclooctylene 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate and te / c-butoxycarbonyl-1-piperazinecarboxylate as a colorless foam.

(b) The adduct prepared in part (a) was treated with undiluted TFA (1 mL) for 10 minutes and then the mixture was concentrated in vacuo. The residue was taken up in DMF (10 mL) and excess DIEA (1.5 mL) and tert-b ut I 4-isocyanatomethyl-1-benzenecarbamate (165 mg, 0.67 mmol) prepared as in Example 13 were added. stirred for 12 hours and concentrated in vacuo. The residue was treated with undiluted TFA and the mixture was concentrated in vacuo. The residue was taken up in water (15 mL) and the aqueous solution extracted with ethyl ether (1x, 15 mL). The aqueous layer was basified with 1.0 M aqueous sodium hydroxide and then extracted with dichloromethane. The dichloromethane was dried (MgSO ^ and filtered. Concentration in vacuo gave cis-A, 5-cyclooctylene 4- (4-aminobenzilkarbamoil) -1piperazinkarboksilat 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate as a colorless foam; ¹ H-NMR (300MHz, CDCI _3): 7.45 (s, 1H), 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).

The following compounds of Formula I were prepared by the procedure as in Example 14 and by substituting various starting materials:

-47c / s-1,5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-pyrid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 81);

cis-N, 5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-piperid-4-ylpropyl) -1-piperidinecarboxylate (Compound 82); and, cis-1,5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyl) -1-piperidinecarboxylate (Compound 83).

EXAMPLE 15 cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (Compound 84)

The following is a preparation of a compound of Formula I in which 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 are each 1,4-piperazinylene, X ³ and X ⁷ are each -C (O) O-, X ⁴ and X ⁶ are each covalent bond and X ⁵ is cis-1,5-cyclooctylene.

Cis-1,5-cyclooctylene 4- (4-aminobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate prepared in Example 14 was added to methanol and ethyl ether and excess hydrogen chloride were added (4M in dioxane). The mixture was concentrated and dried in vacuo. An excess of cyanamide (1.0 g) was added and the mixture was heated at 65 ° C for two hours, giving a yellow solution. The mixture was allowed to cool to room temperature and triturated with ethyl ether (3x, 10 mL). The insoluble residue was placed in water. Purification from the aqueous mixture by preparative reverse phase HPLC gave c / s-1,5-cyclooctylene

4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) 1-piperazinecarboxylate as a colorless amorphous solid; Electrospray LRMS: calculated for Ο ^ Η ^ Ν ^ Οθ: MH ⁺ : 710.9, found: MH ⁺

710,6.

The following compounds of Formula I were prepared by the procedure as in Example 15 and by substituting various starting materials:

cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

4- (2-pyrid-4-ylethylcarbamoyl) -1-piperazinecarboxylate '(Compound 85); calculated for ^C 35 ^H 5 ^{O N} 10 ^O 6 ^{: mh +: 707} ' ⁹ ' found: MH ⁺ : 707.6;

-48c / s-1,5-cyclooctylene 3-piperid-4-ylpropyl-1-piperidinecarboxylate 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate (Compound 86); and cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4-piperid-4-ylbutyl-1-piperidinecarboxylate (Compound 87); calculated for ^ 37 ^ 60 ^ 8θ5 ^: MH ⁺ : 697.9, Found: MH ⁺ : 697.7.

EXAMPLE 16 c / s-1,5-Cyclooctylene Chloroformate 4-Benzyloxycarbonyl-1-piperazinecarboxylate

Benzyl 1-piperazinecarboxylate (1.0 g, 4.53 mmol, 1.0 equiv) and DIEA (0.88 mL, 4.98 mmol, 1.1 equiv) in dichloromethane (25 mL) were added dropwise. vc / s-1,5cyclooctylene di (chloroformate) (1.2 g, 4.53 mmol, 1.0 equiv), prepared as in Example 5, in dichloromethane (25 mL) at 0 ° C. The reaction mixture was stirred for 22 hours while allowing it to warm 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 (Na ₂ SO ₄ ) and concentrated. Purification of the residue by flash column chromatography eluting with 20 and 30% ethyl acetate in hexanes gave c / 1,5,5-cyclooctylene chloroformate 4-benzyloxycarbonyl-1-piperazinecarboxylate (0.81 g, 1.81 mmol, 40%) as yellow oil;

IR: 2939 (s), 2863 (m), 1770 (s), 1732 (s), 1696 (s); ¹ H NMR (300 MHz, 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 17

1- [cis-5- (4-Benzyloxycarbonylpiperazin-1-ylcarbonyloxy) cyclooctyloxycarbonyl] 4-piperidinecarboxylic acid

Isonipecotinic acid (75 mg, 0.58 mmol, 1.1 equiv) and DIEA (0.23 mL, 1.33 mmol,

2.5 eq.) Was added in c / s-1,5-cyclooctylene chloroformate 4-benzyloxycarbonyl-piperazinecarboxylate (0.24 g, 0.53 mmol, 1.0 equiv.), Prepared as in Example 16, in dichloromethane ( 10 mL) at 0 ° C, which gave some white suspension. The suspension was stirred for 18 hours while allowing it to warm to room temperature. The reaction mixture was partitioned between dichloromethane and 0.05N aqueous hydrochloric acid. Concentration of the organic layer gave crude 1- [cis-5- (4-benzyloxycarbonylpiperazin1-ylcarbonyloxy) cyclooxyloxycarbonyl] -4-piperidinecarboxylic acid (0.36 g) as

-49barless oil; ¹ H NMR (300 MHz, 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-t-butoxycarbonylpiperid-4-yl) ethylcarbamoyl] -1-piperidinecarboxylate

1-hydroxybenzotriazole hydrate (80 mg, 58.3 mmol, 1.1 equiv), tert-butyl 4- (2-aminoethyl) 1-piperidinecarboxylate hydrochloride (0.14 g, 0.53 mmol, 1.0 equiv.). ) and 4-methylmorpholine (0.15 mL, 1.33 mmol, 2.5 equiv) were added to a solution of crude 1- [c / s-5- (4-benzyloxycarbonylpiperazin-1-ylcarbonyloxy) cyclooxyloxycarbonyl] -4-piperidinecarboxylic acid ( 0.36 g, 0.53 mol, 1.0 equiv) prepared as in Example 17 in DMF (5 mL). 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.13 g, 0.66 mmol, 1.25 eq) was added to the reaction mixture at 0 ° C. The solution was stirred for 1.5 hours at 0 ° C and 3 days at 23 ° C. The reaction mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate, water (two portions) and saturated aqueous sodium chloride. The organic layer was dried (Na ₂ SO ₄ ) and concentrated. Purification from the residue by flash column chromatography eluting with 3% methanol in dichloromethane gave c / s-1,5-cyclooctylene 4-benzyloxycarbonyl-1-piperazinecarboxylate 4- [2- (1-tefobutoxycarbonylpiperid-4-yl) ethylcarbamotyl] -1-piperidinecarboxylate (0.15 g, 0.2 mmol, 37% over two steps) as a yellow oil; ¹ H NMR (300 MHz, 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); Electrospray LRMS: calculated for ^C 40 ^H 62 ^N 5 ° 9 ( ^{mh +} ) ^: 756.97, found: 757.0.

EXAMPLE 19 c / s-1,5-Cyclooctylene 1-Piperazinecarboxylate 4- (2- (1-tert-butoxycarbonylpiperid-4-yl) ethylcarbamoyl] -1-piperidinecarboxylate

V cis-1,5-cyclooctylene 4-benzyloxycarbonyl-1-piperazinecarboxylate 4- (2- (1-tetrobutoxycarbonylpiperid-4-yl) ethylcarbamoyl] -1-piperidinecarboxylate (0.15 g, 0.20 mmol, 1. 0 equiv.) Prepared as in Example 18, ethanol (3 mL) and palladium (5%) on charcoal (5% palladium on carbon) (75 mg, 0.50 mass equiv.) Were added. The mixture was stirred under hydrogen (1 atm) for 17 hours at 23 ° C. The reaction mixture was placed under nitrogen.

-50in filtered. Concentration of the filtrate gave cis-1,5-cyclooctylene 1-piperazinecarboxylate 4- [2 (1-tert-butoxycarbonylpiperid-4-yl) ethylcarbamoyl] -1-piperidinecarboxylate (110 mg, 0.18 mmol, 90 %) as a colorless oil; ¹ H NMR (300 MHz, CDCl ₃ ): 5.5 (m, 1H), 4.9 (m, 2H), 4.75 (m, 1tH), 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); Electrospray LRMS: calculated for ^C 32 ^H 56 ^N 5 ° 7 ( ^{mh +} ) ^: 622.83, found: 622.7.

EXAMPLE 20 cis -), 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperidinecarboxylate (Compound 88)

The following is a preparation of a compound of Formula I wherein R ^{1 is} 4-guanidinobenzyl, R ² is ² -piperid-4-ylethyl, X ¹ and X ⁹ are each -NHC (O) -, X ² is 1,4-piperazinylene, X ⁸ is 4,1-piperidylene, X ³ and X ⁷ are each -C (O) O-, X ⁴ and X ⁶ are each covalent bond and X ⁵ is cis-), 5-cyclooctylene.

In cis-), 5-cyclooctylene 1-piperazinecarboxylate 4- (2- (1-tert-butoxycarbonylpiperid-4yl) ethylcarbamoyl] -1-piperidinecarboxylate (0.11 g, 0.18 mmol, 1.0 equiv) prepared as in Example 19, in dichloromethane (2 mL) at 0 ° C, triphosgene (30 mg, 0.10 mmol, 0.58 equiv.) and pyridine (30 mL, 0.39 mmol, 2.1) were added. The reaction mixture was stirred for 3 hours at 0 [deg.] C. The mixture was partitioned between dichloromethane, 0.05N aqueous hydrochloric acid and saturated aqueous sodium chloride. The organic layer was dried (Na2SO4) and concentrated to give a brown oily residue. 4-guanidinobenzylamine dihydrochloride (43 mg, 0.20 mmol, 1.1 equiv) and DIEA (0.16 mL, 0.90 mmol, 5.0 equiv) in DMF (2 mL) were added to the residue. The suspension was stirred for 18.5 hours at 23 [deg.] C. and concentrated, the residue was taken up in 50% TFA in dichloromethane (4 mL) and the mixture was stirred for 45 minutes at 23 [deg.] C. The reaction mixture was concentrated and the residue triturated. with ether and vacuum dried from the residue by preparative reverse phase HPLC and lyophilization, cis-, 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperidinecarboxylate was prepared as a colorless solid; Electrospray LRMS: calculated for ^C 36 ^H 58 ^N 9 ° 6 ( ^{mh +} ): 712.91, found: 712.8.

By proceeding as in Example 20 and substituting various starting materials, we are

-51 prepared the following compounds of Formula I:

cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (3-imidazol-4-ylpropylcarbamoyl) -1-piperazinecarboxylate (Compound 89); Calculated for ^ 34 ^H 5O ^N 1O ° ^{6: MH +: θθ5> 9} · Found: MH ^+: 695.4;

cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (2-imidazol-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 90); calculated for θ33 ^Η 48 ^Ν ιο ° 6 ^{: MH +: 681} ' ³ > found: MH ⁺ : 680.9;

cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (Compound 91); calculated for ^C 34 ^{H 5 O N} 10 ^O 6 ^{: mh +: θθ5} - ⁹ - found: MH ⁺ : 694.9;

cis-1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1-piperazinecarboxylate 4- (4-imidazol-1-ylbutylcarbamoyl) -1-piperazinecarboxylate (Compound 92); calculated for θ35 ^Η 53 ^Ν ΐ0θ6 ^{: MH +:} 709.9, Found: MH ⁺ : 709.4; and cis-1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (3-imidazol-1-ylpropylcarbamoyl) -1-piperazinecarboxylate (Compound 93); calculated for ^C 35 ^H 51 ^N io ° 6 ^{: mh +: 7θθ} ′ ⁹ · found: MH ⁺ : 710.4.

EXAMPLE 21

3-Piperid-4-ylpropionic acid hydrochloride

4-Pyridinacrylic acid hydrochloride (12.0 g; 64.6 mmol) and 1.37 g of platinum oxide were suspended in acetic acid (80 mL) and hydrogenated for 12 hours at 50 to 60 psi. The mixture was diluted with water and filtered through a pad of celite. The solids were washed with water (200 mL) and the combined filtrates and washings were concentrated in vacuo to give a white solid. The solid was suspended in a small amount of methanol and the mixture was diluted with diethyl ether (200 mL). The particulate matter was isolated by filtration and washed with diethyl ether and hexane. Air drying gave 3-piperid-4-ylpropionic acid hydrochloride (11.3 g; 58.1 mmol, 90%) as a colorless solid; ¹ H-NMR (300 MHz; DMSO-d ₆ ): 8.75 (br s, 2H), 3.15 (d, 2H), 2.75 (t, 2H), 2.2 (t, 2H) , 1.75 (d, 2H), 1.45 (t, 2H), 1.25 (br q, 2H).

-52PRIMER 22

3- (1-tert-butoxycarbonylpiperid-4-yl) pyopionic acid

3-Piperid-4-ylpropionic acid (5.07 g; 26.2 mmol), prepared as in Example 21, was dissolved in 2N aqueous NaOH (40 mL; 80 mmol). THF (40 mL) was added followed by di (terobutyl) dicarbonate (6.21 g; 28.4 mmol) to give some suspension. The suspension was stirred for 22 hours, diluted with water and concentrated in vacuo. The residue was washed with diethyl ether (2x, 100 mL) and the aqueous phase acidified to pH 2-3 with 1.0N aqueous KHSO ₄ and extracted with ethyl acetate (3x, 200 mL). The combined organic phases were washed with brine and dried (Na ₂ SO ₄ ). Concentration in vacuo gave 3- [4- (1-c-butoxycarbonyl) -4piperidylpropionic acid (6.21 g; 24.1 mmol, 92%) as a colorless oil which crystallized upon condition; ¹ H-NMR (300 MHz, CDCl ₃ ): 4.10 (br d, 2H), 2.65 (br t, 2H), 2.35 (t, 2H), 1.70-1.50 (m , 3H), 1.45 (s, 9H), 1.20-0.95 (m, 2H).

EXAMPLE 23 Ezc-Butyl 4-Benzyloxycarbonyl-1-piperazinecarboxylate

7e / c-butyl 1-piperazinecarboxylate (2.01 g; 10.8 mmol) and DIEA (2.0 mL; 1.48 g; 11.5 mmol) in 50 mL of ice-cold dichloromethane were treated with benzyl chloroformate (2 , 0 mL; 2.39 g; 14.0 mmol). The mixture was stirred for 42 hours and then partitioned between ethyl acetate and 0.5N KHSO ₄ . The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water and brine, dried (MgSO4 and concentrated. Purification from the residue by chromatography over silica gel (ethyl acetate: hexane, 1: 3) afforded terobutyl 4-benzyloxycarbonyl-1- piperazinecarboxylate (3.33 g; 10.4 mmol, 96%) as a colorless solid; ¹ H-NMR (300 MHz, CDCl ₃ ): 7.35 (brs, 5H), 5.13 (s, 2H). 3.55-3.25 (m, 8H), 1.45 (s, 9H).

EXAMPLE 24 Benzyl 1-piperazinecarboxylate hydrochloride

N-c-Butyl 4-benzyloxycarbonyl-1-piperazinecarboxylate (1.01 g; 3.16 mmol), prepared as in Example 23, was suspended in 4 mL of ethyl acetate. The suspension was cooled in an ice-water bath and 4N hydrogen chloride (12 mL in 1,4-dioxane) was added to give some solution. The solution was stirred for 30 minutes in an ice bath and then at room temperature for 30 minutes. The reaction mixture was diluted with diethyl ether (75 mL), which gave one

-53precipitate. The precipitate was isolated by filtration and washed with diethyl ether. Vacuum drying gave benzyl 1-piperazinecarboxylate hydrochloride (740 mg; 2.78 mmol, 88%) as a colorless solid; ¹ H-NMR (300 MHz, DMSO-d ₆ ): 9.25 (br s, 2H), 7.33 (s, 5H), 5.06 (s, 2H), 3.58 (br s, 4H) ), 3.04 (t, 4H). «

EXAMPLE 25 Tert-Butyl 4- [2- (4-Benzyloxycarbonylpiperazin-1-ylcarbonylamino) ethyl] -piperidinecarboxylate

3- (4- (1-tert-butoxycarbonyl) -4-piperidyl] propionic acid (2.16 g; 8.4 mmol), prepared as in Example 22, in dry benzene (28 mL) was treated with triethylamine ( 1.35 mL; 951 mg; 9.40 mmol) and diphenylphosphoryl azide (2.05 mL; 2.62 g; 9.53 mmol) The reaction mixture was gradually warmed to reflux and held at reflux for 3.5 hours. was cooled to room temperature and then added dropwise to a suspension of benzyl 1-piperazinecarboxylate hydrochloride (2.44 g; 9.19 mmol) prepared as in Example 24 and triethylamine (1.40 mL; 1.02 g; 10 , 0 mmol) in dry dichloromethane (10 mL) The reaction mixture was stirred for 43 hours and diluted with ethyl acetate and 0.5N KHSO _{4. The} organic layer was washed with water, aqueous sodium bicarbonate and brine, dried (Na ₂ SO ₄ ). Purification from the residue by chromatography on silica gel (ethyl acetate-hexane, 4: 1; then pure ethyl acetate) gave tert-butyl 4- [2- (4-benzyloxycarbonylpiperazin-1-ylcarbonylamino) ethyl] -1-piperidinecar boxylate (3.84 g; 8.1 mmol, 96%) as a white solid; ¹ H-NMR (300 MHz, CDCl ₃ ): 7.35 (s, 5H), 5.15 (s, 2H), 4.50 (bps, 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-terbutoxycarbonylpiperidin-4-yl) ethylcarbamoyl] -1-piperazinecarboxylate

7cri> butyl 4- [2- (4-benzyloxycarbonylpiperazin-1-ylcarbonylamino) ethyl-1-piperidinecarboxylate (2.03 g; 4.28 mmol), prepared as in Example 25, and palladium (10%) on charcoal (570 mg) suspended in ethanol (19 mL) was hydrogenated at atmospheric pressure overnight. The reaction mixture was filtered and the catalyst was washed with ethanol. The filtrate and washings were concentrated in vacuo and the residue dissolved in dichloromethane

-54 (30 mL) and treated with DIEA (500 mL). The solution was added dropwise to cis-1,5-cyclooctylene di (chloroformate) (4.15 g; 15.4 mmol), prepared as in Example 5, in ice-cold dichloromethane (75 mL). The reaction mixture was stirred overnight and diluted with 0.5N aqueous KHSO ₄ and dichloromethane. The aqueous phase was extracted with dichioromethane and the combined organic layers washed with brine, dried (Na2 O4 and concentrated. Purification from the residue by chromatography on silica gel (ethyl acetate-hexane, 3: 1; then pure ethyl acetate) gave c / s -1,5-cyclooctylene chloroformate 4- (2- (4- (ero-butoxycarbonylpiperidin-4-yl) ethylcarbamoyl) -1-piperazinecarboxylate (1.02 g; 1.8 mmol, 42%) as a light yellow oil; ¹ H -NMR (300 MHz, CDCI ₃ ): 5.00-4.90 (m, 1H), 4.85-4.75 (m, 1H), 4.35 (bh, 1H), 4.05 ( br d, 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 27

4-cyanophenylacetic acid

2- (4-cyanophenyl) ethanol (5.00 g; 34.0 mmol) was dissolved in acetone (140 mL) and cooled to 10-15 ° C. While maintaining the internal temperature below 30 ° C, a solution of CrO ₃ in aqueous H ₂ SO ₄ was added dropwise until it remained amber, which gave some suspension. The suspension was stirred for 45 minutes and filtered. The solids were washed with acetone (150 mL) and the combined filtrates and washings were stirred with 2propanol (20 mL) for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and the solution was washed with 0.5N aqueous KHSO ₄ , water and brine and concentrated. The residue was dissolved in dichloromethane and the solution was treated with sodium hydroxide (1.56 g) in water (100 mL). The aqueous phase was extracted with dichloromethane and acidified to pH 1-2 with concentrated aqueous hydrochloric acid, which gave some precipitate. The precipitate was washed with water and air-dried. Vacuum drying afforded 4-cyanophenylacetic acid (3.36 g; 20.7 mmol, 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 te / o-butyl 4- (4-cyanophenylacetyl) -1-piperazinecarboxylate

A mixture of 4-cyanophenylacetic acid (890 mg; 5.52 mmol) prepared as in Example 27, ethylene dichloride (1.16 g; 6.07 mmol) and 1-hydroxybenzotriazole hydrate (820 mg; 6.07

-55mmol) was suspended in THF (18 mL) and tert-butyl 1-piperazinecarboxylate (1.04 g; 5.60 mmol) and DIEA were added to give a homogeneous solution. The solution was concentrated in vacuo and the residue was treated with 0.2N KHSO ₄ . The mixture was filtered and the collected solid was washed with water. Vacuum drying gave tert-butyl 4- (4cyanophenylacetyl) -1-piperazinecarboxylate (1.68 g; 5.1 mmol, 92%) as a solid;

¹ H-NMR (300 MHz, 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 29 tert-Butyl 4- [4 - ((N-hydroxyamidino) phenylacetyl] -1-piperazinecarboxylate

Tert-butyl 4- (4-cyanophenylacetyl) -1-piperazinecarboxylate (1.68 g; 5.1 mmol), prepared as in Example 28, in dry ethanol (10 mL) was treated with hydroxylamine hydrochloride (461 mg; 6 , 63 mmol) and triethylamine (924 mL, 671 mg; 6.63 mmol). The mixture was refluxed for 3.5 hours, cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethanol, filtered and the filtrate cooled overnight to give a crystalline product. The crystals were isolated by filtration and washed with cold ethanol. Air drying afforded tert-butyl 4- [4 / N-hydroxyamidino) phenylacetyl] -1-piperazinecarboxylate (1.62 g; 4.5 mmol, 88%); ¹ H-NMR (300 MHz, 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 (br s, 4H), 3.25 (br s, 4H), 1.40 (s, 9H).

EXAMPLE 30

4-piperazin-1-ylcarbonylmethylbenzamidine bis (trifluoroacetate)

Tert-Butyl 4- [4 - ((N-hydroxyamidino) phenylacetyl] -1-piperazinecarboxylate (653 mg; 1.81 mmol) prepared as in Example 29 and palladium (10%) on charcoal (200 mg) was suspended in acetic acid (12 mL) and the suspension overnight was bubbled with hydrogen in bubbles. The reaction mixture was filtered and the catalyst was washed with acetic acid. The combined filtrates and washings were concentrated in vacuo and the residue dissolved in TFA. The solution was allowed to stand for 1 hour and then concentrated in vacuo. The residue was co-evaporated from a mixture of dichloromethane and methanol and then suspended in diethyl ether. The particulate matter was collected by filtration. Drying gave 4-piperazin-1-ylcarbonylmethylbenzamidine bis (trifluoroacetate) (1.04 g; 1.81 mmol, 100%) as a white solid, ¹ H-NMR (300 MHz, DMSO-dg); 9.30 (d, 4H), 9.15 (brs, 2H), 7.70 (d, 2H), 7.40 (d,

-562Η), 3.85 (S, 2H), 3.65 (brd, 4H), 4.20-3.90 (m, 4H).

EXAMPLE 31 cis-1,5-cyclooctylene 4 ₇ (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 94)

The following is a preparation of a compound of Formula I wherein R ^{1 is} 4-amidinobenzyl, R ² is 2piperid-4-ylethyl, X ¹ is -C (O) -, and X ⁹ is -NHC (O) -, X ² and X ⁸ is each 1,4-piperazinylene, X ³ and X ⁷ are each -C (O) 0-, X ⁴ and X ⁶ are each covalent bond and X ⁵ is c / s-1,5-cyclooctylene.

4-Piperazin-1-ylcarbonylmethylbenzamidine bis (trifluoroacetate) (80 mg; 0.17 mmol), prepared as in Example 30, was dissolved in DMF (1.0 mL) and the solution treated with DIEA (150 mL). 4- [2- (4-tert-Butoxycarbonylpiperazin-1-yl) ethylcarbamoyl] -1-piperazinecarboxylate (100 mg), prepared as in Example 26, was added c / s-1,5-cyclooctylene chloroformate in DMF (1. 0 mL) and the mixture was stirred overnight and concentrated in vacuo. The residue was dissolved in dichloromethane and TFA (1: 1) and the mixture was concentrated in vacuo. The residue was triturated with diethyl ether to give some foamy residue. Purification from the residue by preparative reverse phase HPLC and lyophilization of the pure fractions afforded c / s-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1-piperazinecarboxylate 4- (2-piperid4-ylethylcarbamoyl) -1-piperazinecarboxylate a colorless solid; Electrospray LRMS: calculated for C ₃₅ H ₅₄ N ₈ O ₈ : MH ⁺ : 683.9; MH2 ⁺² / 2: 342.5, found MH ⁺ : 683.8; MH2 ⁺² / 2: 342.3.

The following compounds of Formula i were prepared by the procedure as in Example 31 and by substituting different starting materials:

cis-1,5-cyclooctylene 4- (1-amidinopiperid-4-ylacetyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 95); calculated for ^C 34 ^H 59 ^N 9 ° 6 ^{: mh +: 6θθ} - ⁹ · found: MH ⁺ : 690.6;

cis-1,5-cyclooctylene 4- (4-amidinobenzoylaminomethyl) -1-piperidinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 96); calculated for ^C 36 ^H 56 ^N 8 ° 6 ^{: mh +: 697} - ⁹ - found: MH ⁺ : 697.7;

cis-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate

-574- (2-piperid-4-yl) ethylcarbamoyl] -1-piperazinecarboxylate (Compound 97); calculated for ^C 35 ^H 55 ^N 9 ° 6 ^{: MH +: θθθ} ' ^θ · Found: MH ⁺ : 698.7;

cis-T, 5-cyclooctylene 4- (4-amidinophenylsulfonylaminomethyl) -1-piperidinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 98); calculated for ^C 35 ^H 56 ^N 8 ° 7 ^{: MH +: 733} - ⁹ <found: MH ⁺ : 733.4;

cisA, 5-cyclooctylene 4- (2- (1-amidinopiperid-4-yl) ethylcarbamoyl] 1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 99) calculated for θ35 ·% 2 ⁶ ιοθ6 ^{: MH +: 719} - ⁹ > found: MH ⁺ : 719.5;

cis-A, 5-cyclooctylene 4- (4-amidinophenylcarbamoylmethyl) -1-piperidinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 100); calculated for ^C 36 ^H 56 ^N 8 ° 6 ^{; mh +} ' ⁶⁹⁷ - ⁹ - found: MH ⁺ : 695.6;

cis-A, 5-cyclooctylene 4- (4- (N-methoxycarbonylamidinobenzylcarbamoyl) 1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate (Compound 101); calculated for ¢ 37 ^ 57 ^ 0 ^ MH ⁺ : 756.9, Found: MH ⁺ : 756.4; and cisA, 5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate

3-piperid-4-ylpropyl-1-piperidinecarboxylate (Compound 102); Calculated for C ₃₆ H ₅₈ N ₈ O ₅ : MH ⁺ : 683.9, Found: MH ⁺ : 683.3.

EXAMPLE 32

1,5-pentamethylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate] (Compound 103)

The following is a preparation of a compound of Formula I wherein R ¹ and R ^{2 are} each ⁴ -guanidinobenzyl, 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- and X ⁴ -X ⁶ -X ⁵ together are 1,5-pentamethylene.

7erobutyl 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate trifluoroacetate (306 mg, 0.62 mmol) was treated with undiluted trifluoroacetic acid (1 mL) at room temperature for ten minutes to prepare a colorless homogeneous solution. The liquid was concentrated and the oily residue triturated with diethyl ether (3 x 10 mL), followed by drying in vacuo to some colorless foam. The deprotected piperazine salt was then added to DMF (2.5 mL), followed by the addition of diisopropylethylamine (0.5 mL, 3.1 mmol) and 1,5-n-pentylene di (chloroformate) (70 mg, 0 , 31 mmol) and the mixture was allowed to stir at room temperature for one hour. The reaction mixture was concentrated and

-58 The residue was triturated with diethyl ether (3x 10 mL) followed by drying in vacuo. The crude material was placed in water (5 mL) and purified by preparative reverse phase HPLC and lyophilization to afford 1,5-n-pentiene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate] as a colorless amorphous solid; Electrospray LRMS: calculated for C ₃₃ H ₄₈ N ₁₂ O ₆ : MH ⁺ : 709.8, found: MH ⁺ : 709.3.

The following compounds of Formula I were prepared by the procedure as in Example 32 and by substituting various starting materials:

1,4-tetramethylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate] (Compound 104); calculated for C ₃₂ H ₄₆ N ₁₂ O ₆ : MH ⁺ : 695.8, found: MH ⁺ : 695.8;

4-guanidinobenzyl

4- {5- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] valeryl} -1-piperazinecarboxamide (Compound 105); calculated for θ32 ^Η 46 ^Ν ΐ2θ4 ^{: MH +: θθ3} - ⁸ - found: MH ⁺ : 663.4;

4-guanidinobenzyl

4- {6- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] hexanoyl} 1-piperazinecarboxamide (Compound 106); calculated for C ₃ 3 ^H 48 ^N 12 ° 4 ^{: MH +: 677} · ⁸ found: MH ⁺ : 677.4;

4-guanidinobenzyl

4- {7- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] heptanoyl} 1-piperazinecarboxamide (Compound 107); calculated for C ₃ 4 ^H 50 ^N 12 ° 4 · ^{MH +: 691} - ⁹ found: MH ⁺ : 691.5;

4-guanidinobenzyl

4- {8- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] octanoyl} 1-piperazinecarboxamide (Compound 108); calculated for ^C 37 ^H 57 ^N 9 ° 8 ^{: MH +: 756} - ⁹ found: MH ⁺ : 756.4;

4-guanidinobenzyl

4- {9- [4- (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] nonanoyl} 1-piperazinecarboxamide (Compound 109); calculated for θ 36 ^ 54 ^ 12 ^ 4 'MH ⁺ : 719.9, found: MH ⁺ : 719.5;

4-amidinobenzyl

4- {7- [4- (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] heptanoyl} 1-piperazinecarboxamide (Compound 110); calculated for C _{3 4} H 48 ^N 10 O 4: MH ⁺ : 661.8,

-59 done: MH ⁺ : 661.3;

1,5-pentamethylene di [4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl] (Compound 111); calculated for θ33Η ₄₆ Ν ₁₀ Ο ₄ : MH ⁺ : 647.8, found: MH ⁺ : 647.3;

1.6-Hexamethylene di [4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl] (Compound 112); calculated for C ₃₄ H ₄₈ N ₁₀ O ₄ : MH ⁺ : 661.8, found: MH ⁺ : 661;

1.7-heptamethylene di [4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl] (Compound 113); calculated for C ₃₅ H _5Q N _1Q O ₄ : MH ⁺ : 675.9, found: MH ⁺ : 675.4; and 3-oxa-1,5-pentamethylene di [4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl] (Compound 114); calculated for C ₃₂ H ₄₄ N ₁₀ O ₇ : MH ⁺ : 681.8, Found: MH ⁺ : 681.4,

EXAMPLE 33

In Vitro tryptase inhibition test

Mixtures of human tryptase (15 pg / mL) and test compounds (variable concentrations) in Tris buffer (containing: NaCl, 100 mM; Tris, 50 mM; 2- [AAmorpholine] ethane sulfonic acid, 2.5 mM, CaCI ₂ . 0.5 mM; DMSO, 10%; glycerol, 5%; polyoxyethylene sorbitan monolaurate (Tween-20), 0.05%; heparin, 25 ng / mL; and pH 8.2) were incubated for one hour at room temperature and then tosyl-Gly-Pro-Lys-para-nitroanilide was added so that the final concentration of the test mixture was 0.5 mM. The hydrolysis of the substrate was monitored spectrophotometrically at (405 nm) for 5 minutes. The apparent inhibition constants (Kj) were calculated from the enzyme development curves using standard mathematical models.

Human tryptase can be purified from human lung samples and skin tissue samples (e.g., see Smith et al. (1984) J. Biol. Chem. 59: 11046-11051; and Braganza et al. (1991) Biochem. 30: 4997-5007) and from the human mast cell type or obtained commercially (e.g., ICN Biomedicals, Irvine California; Athens Research & Technology, Athens, Georgia). Swine intestinal mucosal heparin and tosyl-Gly-Pro-Lys-pa /? -Nitroanilide can be obtained from Sigma Chemical Company.

The following compounds of Formula I were prepared as described in this application or by methods known to one of ordinary skill in the art and tested for tryptase inhibitory effect:

Compound 1, Κ ₍ = 0.003µΜ; Compound 2, Kj = 0.8pM; Compound 3, Κ ₍ = 0.07µΜ;

-60 Compound 4, Kj = 0.001 μΜ; Compound 5, Κ ^ Ο ^ μΜ; Compound 6, Κ ₍ = 1μΜ;

Compound 7, Kj = 0.3pM; Compound 8, Kj = 4pM; Compound 9, Κ | = 0.4μΜ;

Compound 10, Κ-ΙμΜ; Compound 11, Κ ₍ = 0.09μΜ; Compound 12, Κ | = 0.2μΜ;

Compound 13, Kj = 0.02pM; Compound 14, Kj = 0, .004pM; Compound 15, Kj = 0.5pM;

Compound 16, Kj = 0.9pM; Compound 17, Kj = 1pM; Compound 18, Kj = 0.08pM;

Compound 19, Κ ₍ = 1.2μΜ; Compound 20, Κ | = 3.4μΜ; Compound 21, Κ ^ Ο, δμΜ;

Compound 22, Kj = 0.2pM; Compound 23, Kj = 4pM; Compound 24, Kj = 0.3pM;

Compound 25, Kj = 0.002pM; Compound 26, Kj = 19pM; Compound 27, Kj = 2pM;

Compound 28, Kj = 4pM; Compound 29, Κ, = 1μΜ; Compound 30, Kj = 0.031pM;

Compound 31, Kj = 1pM; Compound 32, Kj = 2pM; Compound 33, Kj = 1pM;

Compound 34, Kj = 3pM; Compound 35, Κ · = 0.8μΜ; Compound 36, Kj = 0.6pM;

Compound 37, Kj = 0.07pM; Compound 38, Κ _} = 0.004µΜ; Compound 39, Κ · = 0.004µΜ;

Compound 40, Κ ₍ = 4μΜ; Compound 41, K _f = 0.7pM; Compound 42, Kj = 0.02pM;

Compound 43, Kj = 0.4pM; Compound 44, Kj = 0.02pM; Compound 45, Kj = 0.08pM;

Compound 46, Kj = 1pM; Compound 47, Kj = 0.3pM; Compound 48, Kj = 0.09pM;

Compound 49, Kj = 2pM; Compound 50, Κ ₍ = 0.08μΜ; Compound 51, Kj = 1pM;

Compound 52, K _i = 0.04 pM; Compound 53, Kj = 6pM; Compound 54, Kj = 0.1pM;

Compound 55, Kj = 2pM; Compound 56, Kj = 10pM; Compound 57, Kj = 2pM;

Compound 58, Κ, = 0.1μΜ; Compound 59, Κ ^ Ο, δμΜ; Compound 60, Kj = 5pM;

Compound 61, Kj = 41pM; Compound 62, Kj = 0.2pM; Compound 63, Κ ₍ = 2μΜ;

Compound 64, Kj = 1pM; Compound 65, Kj = 0.001pM; Compound 66, Kj = 0.02pM;

Compound 67, Kj = 3pM; Compound 68, Kj = 0.04pM; Compound 69, Kj = 0.5pM;

Compound 70, Kj = 0.05pM; Compound 71, Kj = 0.8pM; Compound 72, Κ — Ο, ΙμΜ;

Compound 73, Κρ0,002μΜ; Compound 74, Kj = 0.04pM; Compound 75, Kj = 0.01pM;

Compound 76, Κ = 0.1μΜ; Compound 77, Kj = 6pM; Compound 78, Kj = 0.1pM;

Compound 79, Kj = 1pM; Compound 84, Κ ₍ = 0.06μΜ; Compound 85, Kj = 0.9pM;

Compound 86, Κ-Ο, ΟδμΜ; Compound 87, Κ-Ο, ΟδμΜ; Compound 88, Kj = 0.1pM;

Compound 89, Kj = 0.1pM; Compound 90, Kj = 1pM; Compound 91, Kj = 0.1pM;

Compound 92, Kj = 0.1pM; Compound 93, Kj = 0.02pM; Compound 94, Kj = 0.007pM;

Compound 95, Κ, · = 0.02μΜ; Compound 96, Κ, · = 0.02μΜ; Compound 97, Kj = 0.0009pM;

Compound 98, 1 ^ = 0.03μΜ; Compound 99, Kj = 0.05pM; Compound 100, Κρ0,009μΜ;

Compound 101, Kj = 0.04pM; Compound 102, Kj = 0.08pM; Compound 103, Kj = 0.001pM; Compound 104, Κ · = 0.003µΜ; Compound 105, Kj = 0.04pM; Compound 106, Κ · = 0.004µΜ; Compound 107, ΚρΟ, ΟΟΟΙμΜ; Compound 108, Kj = 0.0005pM; Compound 109, Kj = 0.0007pM;

-61 Compound 110, Kj = 0.0008pM; Compound 111, Kj = 0.3pM; Compound 112, Kj = 0.09pM;

Compound 113, Κ | = 0.005µΜ; and Compound 114, Κ _ί = 0.058µΜ.

EXAMPLE 34 In Vivo Asthma Test

Allergic sheep characterized as double reacting. orig .: responders] (i.e., indicating early and late stages of bronchoconstriction) are challenged with an antigen (e.g., Ascaris suum}. A test compound or solvent is administered to the sheep with aerosol inhalation 0.5 hours before and 4 and 24 hours after challenge. Specific lung resistance (SR _L ) is monitored using an esophageal balloon catheter just before treatment with the first test compound or solvent and every 0.5 hours to 1 hour thereafter.

In addition, airway susceptibility is monitored 1 to 2 days before challenge with the antigen and right after administration of the test compound or solvent 24 hours after challenge with the antigen. For the purposes of this application, airway susceptibility is defined as the cumulative carbachol dose required to increase SR _L by 400% (PC ₄₀₀ ). PC ₄₀₀ values are obtained by administering 0 to 30 respiratory units of 1% carbachol (10 mg in 1 mL PBS) by aerosol inhalation until SR _l is increased by 400%.

Solvent-treated sheep show an early phase of bronchoconstriction 0 to 4 hours after challenge with antigen and a late phase of bronchoconstriction 4 to more than 8 hours after challenge with antigen. Solvent-treated sheep also exhibit an over-susceptibility to carbachos (ie, a 60% decrease in PC _{400 is} observed).

Sheep treated with tryptase inhibitors show no late stage of bronchoconstriction (ie, at 4 to 8 hours after challenge with the antigen, SR _l remained at baseline). Furthermore, sheep treated with tryptase inhibitors do not show any over-susceptibility to carbachos.

-62 EXAMPLE 35

Typical pharmaceutical preparations containing a compound of Formula I.

Compound of Formula I Citric Acid Monohydrate Sodium hydroxide Aroma

Water

ORAL PREPARATION

10-100 mg 105 mg 18 mg

q.s. up to 100 mL

INTRAVENIC PREPARATION

Compound of Formula I 0.1-10 mg

Dextrose monohydrate q.s., to make isotonic

Citric acid monohydrate 1.05 mg

Sodium hydroxide 0,18 mg

Water for injection q.s. to 1.0 mL

TABLET PREPARATION

Compound of Formula I 1%

Microcrystalline cellulose 73%

Stearic acid 25%

Colloidal silica 1%.

Claims (41)

PATENT REQUIREMENTS A compound of formula I: κ'-χ'-χυχλχ ⁴ ^ X ⁵ R ² -X ⁹ -X ⁸ -X ⁷ -X ⁶ ^ in which: X is ⁵ (C _{3. 14)} cycloalkylene, hetero (C _{3. 14)} cycloalkylene, (C _{6. 14)} arylene or hetero (C _{5. 14)} arylene; X ⁴ and X ⁶ are independently (C ₀ _ ₂₎ alkylene; X ¹ and X ⁹ are independently covalent bond, -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 ³ is independently hydrogen, (C ₁ _ ₃₎ alkyl or (C _{3. 8)} cycloalkyl, with the proviso that X ¹ and X ⁹ are not both 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) 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 ³ is as defined above; X ² and X ⁸ are independently (C 7-8) alkylene, hetero- (S) alkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -; wherein X ¹⁰ (C0_4) alkylene or hetero (C3-4) alkylene and X ¹¹ is (C3_ ₈₎ cycloalkylene or hetero (C _{3. 8)} cycloalkylene; R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ -, in which: R ^{4 is} amino, amidino, guanidino, 1-iminoethyl or methylamino, X ¹² is (C _{4. 6)} alkyl, hetero (C _{4. 6)} alkylene, heterooxo (C _{4. 6)} alkylene, oxo (C _{4. 6)} alkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ - in wherein X is ¹⁵ (C3-6) cycloalkylene, hetero (C5-6) arylene, hetero (C3-6) cycloalkylene or phenylene, X ¹⁴ is (Cn14) alkylene and X ¹⁶ is (C _n16) alkylene, wherein the sum nl4inn16 0 , 1,2, 3 or 4, R ⁵ is a group selected from the following, such as: azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-ii, imidazol-2-yl, imidazol-4-yl, 2-imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, -645-methylimidazol-1-yl, 1-methylpiperid-3-yl, 1-methylpiperid-4-yl, piperid-3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid -3-yl, pyrid-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 any carbocyclic ketone or thioketone derivative thereof, the group being optionally substituted by one or more radicals selected from the following, such as: halo, hydroxy, mercapto, (C ₁ _ ₈₎ alkyl, (C _{3. 14)} cycloalkyl, (C ₆ _ ₁₄₎ Ar, (C _{6. 14)} aryl (C _{first 4)} alkyl, (C _V8) alkanoyl, (C ₁ _ ₈ ) alkyloxy, (C _{6 14)} aryloxy, (C _{3. 14)} cycloalkyloxy, (C ₁ _ ₄₎ alkyloxy, (C, _ ₈₎ alkylthio, (C _{3. 14)} cycloalkylthio, (C ₆ _ ₁₄₎ arylthio and -NR ⁶ R ⁷ wherein R ⁶ and R ^{7 are} independently selected from hydrogen, (C 1-6 alkyl, (C 1-8) alkanoyl, (C 3-14) cycloalkyl or (C 6-14) aryl, and X ¹³ is (C 0. ₆₎ alkylene, hetero _{(C2. 6)} alkylene, heterooxo _{(C3. 6)} alkylene, oxo _{(C2. 6)} alkylene or -X ¹⁷ -X ¹⁸ -X ¹⁹ -, wherein X ¹⁸ is as defined above for X ¹⁵ , X ¹⁷ is (C _n ¹⁷ ) alkylene and X ¹⁹ is (C _{n 19} ) alkylene, wherein the sum of n 17 and n 19 is 0, 1 or 2; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, in which: ^R8 is amino, 1-iminoethyl or methylamino, X ²⁰ is (C4.6) alkylene, hetero (C4.6) alkylene, heterooxo (C4-6) alkylene, oxo (C4.6) alkylene, or -X ²² -X ²³ -X ²⁴ -, wherein X ²³ is as is defined above for X ¹⁵ , X ²² is (Cn ²² ) alkylene and X ²⁴ is (Cn ²⁴ ) alkylene, wherein the sum of n ^{22 and} n ²⁴ is 0, 1, 2, 3 or 4, with the proviso that when R ^{8 is} amino, then X ²⁰ is not (C4.g) alkylene or oxa (C _{4. 6)} alkylene and n22 is not 1,2,3 or 4, R ⁹ is as defined above for R ⁵ and X ²¹ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.6) alkylene or -X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ²⁶ , as defined above for X ¹⁵ , X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (C _n ²⁷ ) alkyl, in which the sum of n 25 and n 27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, optionally substituted by one or more radicals chosen from halo, hydroxy, mercapto, (C., _ ₈₎ alkyl, (C ₃ _i ₄₎ cycloalkyl, (C _{6. 14)} aryl, (C ₆ _ ₁₄₎ aryl (C _{first 4)} alkyl, (C ^ gjalkanoil, (C ₁ _ ₈₎ alkyloxy, (C _{6. 14)} aryloxy, (C _{3. 14)} cycloalkyloxy, (C ₁ _ ₄₎ aikiloksi, (C ^ gjalkiltio, (C _{3. 14)} cycloalkylthio, (C _{6. 14)} arylthio, and -NR ⁶ R ^7, wherein R R ⁶ and R ⁷ as defined above, with the proviso that the covalent bonds do not occur between the hetero atoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any hetero atoms contained in X ³ , X ⁵ , X ⁷ and X ⁹ ; in -65Pharmaceutically acceptable salts, / V-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 1, wherein: X ^{5 is} cis-), 5-cyclooctylene and X ⁴ and X ⁶ are each covalent bond or X ^{5 is} 1,4-phenylene and X ⁴ and X ⁶ are (C 1-6 alkylene; X ¹ and X ⁹ are independently covalent bond, -C (O) -, -NH (C (O) -, -C (O) NH-, -N (CH ₃ ) C (O) - or -S (O ) ₂ NH-; X ³ and X ⁷ are independently -C (O) - or -C (O) O-; X ² and X ⁸ are independently -X ¹⁰ -X ¹¹ -, in which: X ^{10 is a} covalent bond or methylene and X ¹¹ is 4,1-piperidylene or 1,4-piperazinylene; R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ -, in which: 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-piperidylene, X ¹⁴ is (Cn14) alkylene and X ¹⁶ is (Cn16) alkylene, wherein the sum of n14 and n16 O, 1, or 2, R ⁵ is piperid-4-yl and X ¹³ is (C _{2nd 3)} alkylene; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, in which: R ⁸ is amino, methylamino or 1-iminomethyl X ²⁰ is -X ²² -X ²³ -X ²⁴ -, wherein X ^{23 is} Ma / 1,2-cyclohexylene, 1,4-phenylene, 4,1-pyridylene, 1,4-piperidylene, X ²² is (Cn22) alkylene and X ²⁴ is (Cn24) alkylene, wherein the sum of n22 and n24 is 1 or 2, R ⁹ is benzoimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-4 -yl, piperid-4-yl, piperazin-1-yl, pyrid-3-yl, pyrid-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl, or 1,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl X ²¹ is (C 1-6) alkylene, w-aza (C2.5) alkylene, 2-aza-3-oxotrimethylene, 3-aza-2oxotrimethylene, 3-oxotrimethylene, o-thia (C2.4) alkylene or -X ²⁵ - X ²⁶ -X ²⁷ -, wherein X ^{26 is} 1,4-phenylene, X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (C _{n 27} ) alkylene, wherein the sum of n 25 and n 27 is O or 1; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 2, wherein X ^{5 is} cis-), 5-cyclooctylene and X ⁴ and X ⁸ are each a covalent bond; X ¹ and X ⁹ are independently covalent bond, -C (O) -, -NHC (O) -, -C (O) NH-66 or -S (O) 2NH-; X ³ and X ⁷ are independently -C (O) - or -C (O) O-; R ¹ is R ⁴ -X ¹² -, wherein R ^{4 is} amidino or guanidino; and R ² is R®-X ²⁰ - or R ⁹ -X ²¹ -, wherein R ^{8 is} amino or methylamino, X ²³ is transA, 4-cyclohexylene or 1,4-phenylene, R ⁹ is imidazol-1-yl , imidazol-4-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, piperid-4-yl or pyrid-4-yl, and X ²¹ is (C _1-5 ) alkylene or 3-azatrimethylene; and pharmaceutically acceptable salts, ΛΑ-oxides, prodrug derivatives and protected derivatives thereof. A compound of claim 3 wherein X ¹ and X ^{9 are} independently -C (O) - or -NHC (O) -, X ³ and X ⁷ are each -C (O) O-; X ² and X ⁸ are each -X ¹⁰ -X ¹¹ -, wherein X ^{10 is a} covalent bond and X ¹¹ is 1,4-piperazinylene; R ¹ is R ⁴ -X ¹² -, wherein R ^{4 is} amidino or guanidino and X ¹² is -X ¹⁴ -X ¹⁵ -X ¹⁶ -, in which 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 4 -X ²⁴ -, wherein X ^{23 is} transA, 4-cyclohexylene, X ²² is a covalent bond and X ²⁴ is methylene, R ⁹ is piperid-4-yl and X ²¹ is ethylene or trimethylene; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4, wherein X ¹ and X ^{9 are} each -NHC (O) -, R ¹ is 4-amidinobenzyl and R ² is 2-piperid-4-ylethyl, namely c / s-1,5- cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4, wherein X ^{1 is} -NHC (O) -, X ⁹ is -C (O) -, R ¹ is 4-amidinobenzyl and R ² is 3-piperid-4-ylpropyl, namely c / s-1,5-cyclooctylene 4- (4-amidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4, wherein X ¹ and X ^{9 are} each -NHC (O) -, R ¹ is 4-guanidinobenzyl and R ² is / racs-4-aminocyclohexylmethyl, namely c / s-1,5-cyclooctylene trans-4- {4aminocyclohexylmethylcarbamoyl) -1-piperazinecarboxylate 4- (4-guanidinobenzylcarbamoyl) 1-piperazinecarboxylate; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4, wherein X ¹ and X ^{9 are} each -C (O) -, R ¹ is 4-amidinobenzyl and R ² is 3-piperid-4-ylpropyl, namely c / s-1,5- cyclooctylene 4- (4-amidinophenylacetyl) -1-67piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate; and pharmaceutically acceptable salts, oxides, prodrugs and protected derivatives thereof. The compound of claim 4, wherein X ¹ and X ^{9 are} each -NHC (O) -, R ¹ is 4-guanidinobenzyl and R ² is 2-piperid-4-ylethyl, namely c / s-1,5- cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4, wherein X ^{1 is} -NHC (O) -, X ⁹ is -C (O) -, R ¹ is 4-guanidinobenzyl and R ² is 3-piperid-4-ylpropyl, namely cis- 1,5-cyclooctylene 4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4, wherein X ^{1 is} -C (O) -, X ⁹ is -NHC (O) -, R ¹ is 4-guanidinobenzyl and R ² is 2-piperid-4-ylethyl, namely cis- 1,5-cyclooctylene 4- (4-guanidinophenylacetyl) -1piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4, wherein X ¹ and X ^{9 are} each -C (O) -, R ¹ is 4-guanidinobenzyl and R ² is 3-piperid-4-ylpropyl, namely c / s-1,5- cyclooctylene 4- (4-guanidinophenylacetyl) -1 piperazinecarboxylate 4- (4-piperid-4-ylbutyryl) -1-piperazinecarboxylate; and pharmaceutically acceptable salts, / U-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 4, wherein X ^{1 is} -C (O) -, X ⁹ is -NHC (O) -, R ¹ is 4-amidinobenzyl and R ² is 2-piperid-4-ylethyl, namely c / s-1,5-cyclooctylene 4- (4-amidinophenylacetyl) -1piperazinecarboxylate 4- (2-piperid-4-ylethylcarbamoyl) -1-piperazinecarboxylate; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with a pharmaceutically acceptable excipient. -6815. Compound of Formula I: ιόχ'-χ ^ χ'-χν ^ X r ² -x ⁹ -x'-x ⁷ -x ^{6 /} in which: X is ⁵ (C _{3. 14)} cycloalkylene, hetero (C _{3. 14)} cycloalkylene, (C _{6. 14)} arylene or hetero (C _{5. 14)} arylene; X ⁴ and X ⁶ are independently (C _{is 0. 2)} alkylene; X ¹ and X ³ are independently covalent bond, -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 ^{3 is} independently hydrogen, (C 3-3) alkyl or (C 3-8) cycloalkyl; X ⁷ and X ⁹ are 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 ³ is as defined above; X ² and X ⁸ are independently (C1-8) alkyl, hetero ^ .8) alkylene ^-Χ 1θ -Χ ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ (C0. ₄₎ alkylene or hetero (C _{third 4)} alkylene and X ¹¹ is (C _{3. 8)} cycloalkylene or hetero (C _{3. 8)} cycloalkylene; R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ -, in which: R ^{4 is} amino, amidino, guanidino, 1-iminoethyl or methylamino, X ¹² ΐθ (C _{4. 6)} alkyl, hetero (C _{4. 6)} alkylene, heterooxo (C _{4. 6)} alkylene, oxo (C _{4. 6)} alkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ - in wherein X ^{15 is} (C3.6) cycloalkylene, hetero (C5.6) arylene, hetero (C3.6) cycloalkylene or phenylene, X ¹⁴ is (Cn14) alkylene and X ¹⁶ is ( _C16 ) alkylene, sum n14 and n16 0,1,2, 3 or 4, R ⁵ is a group selected from the following, such as: azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2- imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, piperid-3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-4-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1.4.5.6-tetrahydropyrimidin-2-yl, 1,4,5,6-tetrahydropidin-4-yl and 1.4.5.6- Tetrahydropyrimidin-5-yl and any carbocyclic ketone or thioketone derivative thereof, the group being optionally substituted by one or more -69radikali selected from, halo, hydroxy, mercapto, (C -, _ ₈₎ alkyl, (C _{3. 14)} cycloalkyl, (C _{eighth 14)} aryl, (C ₆ _ ₁₄₎ aryl (C ., _ ₄₎ alkyl, (C ₁ _ ₈₎ alkanoyl, _{(C1. 8)} alkyloxy, (C ₈ _ ₁₄₎ aryloxy, (C _{3. 14)} cycloalkyloxy, (C _{1. 4)} alkyloxy, (C ₁₈ ) alkylthio, (C _{3. 14)} cycloalkylthio, (C _{eighth 14)} arylthio, and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are independently selected from the following such as: hydrogen, (C, _{first 8)} alkyl , (C.,. ₈₎ alkanoyl, (C ₃ _ ₁₄₎ cycloalkyl or (C _{8. 14)} aryl, and X ¹³ is (C0.g) alkylene, hetero (C2.8) alkylene, heterooxo (C3.6) alkylene, oxo (C2.g) alkylene or -X ¹⁷ -X ¹⁸ -X ¹⁹ -, wherein X ¹⁸ , as defined above for X ¹⁵ , X ¹⁷ is (Cn ¹⁷ ) alkylene and X ¹⁹ is (C _{n 19} ) alkylene, wherein the sum of n 17 and n 19 is 0, 1 or 2; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, in which: ^R8 is amino, 1-iminoethyl or methylamino, X ²⁰ is (C4-6) alkylene, hetero (C4.6) alkylene, heterooxo (C4.6) alkylene, oxo (C4.6) alkylene or -X ²² -X ²³ -X ²⁴ -, wherein X ²³ is as is defined above for X ¹⁵ , X ²² is (Cn ²² ) alkylene and X ²⁴ is (C _n ²⁴ ) alkylene, wherein the sum of n ²² and n ²⁴ is 0, 1, 2, 3 or 4, with the proviso that when R ⁸ is amino, then X ²⁰ is (C _{4. 8)} alkylene or oxa (C _{4. 6)} alkylene and n22 is not 1, 2, 3 or 4, R ⁹ is as defined above for R ⁵ and X ²¹ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.6) alkylene or -X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ²⁶ , as defined above for X ¹⁵ , X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (C _{n 27} ) alkylene, wherein the sum of n 25 and n 27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, optionally substituted by one or more radicals chosen from halo, hydroxy, mercapto, (C, _{first 8)} alkyl , ^{(C3-i4) cycloalkyl, cycloalkyl, alkyl} · (c 6-14) aryl, (c 6-14) aryl (c., _ 4) alkyl, ^(c i_e) alkanoyl, _{(C1. 8)} alkyloxy, (c _{sixth 14)} aryloxy, (C _{3. 14)} cycloalkyloxy, (C ₁ _ ₄₎ alkyloxy, (C ₁ _ ₈₎ alkylthio, (C _{3. 14)} cycloalkylthio, (C _{eighth 14)} arylthio, and -NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are as defined above: with the proviso that the covalent bonds do not occur between the heteroatoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any heteroatoms contained in X ³ , X ⁵ , X ⁷ and X ⁹ ; or a pharmaceutically acceptable salt, / V-oxide, prodrug derivative or protected derivative thereof, for the treatment of a disease in an animal in which tryptase action contributes to the pathology and / or symptomatology of the disease by administering to the animal a therapeutically effective amount of a compound of Formula -7016. The compound of claim 15, wherein the disease is selected from the following, such as: asthma, allergic rhinitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczema dermatitis, anatyloxia, hyperpenolysis, hyperpenolysis peptic ulcers, inflammatory bowel disease, eye and spring conjunctivitis, and inflammatory skin conditions. The compound of claim 16, wherein the disease is asthma. The compound j _of claim 17, wherein the compound is administered in an aerosolized pharmaceutically acceptable carrier suitable for administration as an inhaler. The compound of claim 18, wherein the compound is administered in combination with a therapeutically effective amount of a β-adrenergic agonist, a methylxanthine, a chromoglycate or a corticosteroid, The compound of claim 19, wherein the β-adrenergic agonist is selected from the following, such as: albuterol, terbutaline, formoterol, fenoterol and prenalin, methylxanthine is selected from the following: caffeine, theophylline, aminophylline and theobromine, chromoglycate is selected from cromoline and necromyl, and a corticosteroid selected from beclomethasone, triamcinolone, flurisolid and dexamethasone. A compound of claim 16 wherein the disease is rheumatoid arthritis or conjunctivitis. The compound of claim 21, wherein the compound is administered in some pharmaceutically acceptable carrier suitable for topical administration. 23. A compound of formula I: ιόχ'-χ ^ -χ ⁴ ^ r ² -x ⁹ -x ⁸ -x ⁷ -x ^6zX X ⁵ in which: X ⁴ -X ⁵ -X ⁶ together are (C _{2nd 12)} alkylene or hetero (C _{3. 12)} alkylene; -71X ¹ and X ⁹ are independently covalent bond, -C (O) -, -C (O) O-, -0C {0) -, -C (O) N (R ³ ) -, -N (R ³ ) CO-, -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 ³ is independently hydrogen, (C ₁ _ ₃₎ alkyl or (C _{3. 8)} cycloalkyl, with the proviso that X ¹ and X ⁹ are not both 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) 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 ³ is as defined above; X ² and X ⁸ are independently (C1 _8) alkyl, hetero (CV8) alkylene, -X ¹⁰ -X ¹¹ - or -χ ^{11 -χΐ} θ - in £ _whereby j _e χΐθ (c _{Q. 4)} alkylene or hetero (C _{3. 4)} alkylene and X ¹¹ is (C ₃ _ ₈₎ cikloaikilen or hetero (C ₃ _ ₈₎ cycloalkylene; R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ , in which: R ^{4 is} amino, amidino, guanidino, 1-iminoethyl or methylamino, X ¹² is (C _{4. 8)} alkylene, hetero (C _{4. 6)} alkylene, heterooxo (C _{4. 6)} alkylene, oxo (C _{4. 6)} alkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ - in wherein X ^{15 is} (C3.6) cycloalkylene, hetero (C5.6) arylene, hetero (C3.6) cycloalkylene or phenylene, X ¹⁴ is (Cn14) alkylene and X ¹⁶ is ( _C16 ) alkylene, sum n14 and n16 0, 1, 2, 3 or 4, R ⁵ is a group selected from the following, such as: azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2- imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-3-yl, 1-methylpiperid- 4-yl, piperid-3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-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 any carbocyclic ketone or thioketone derivative thereof, the group being optionally substituted by one or more radicals selected from the following, such as: halo, hydroxy, mercapto, (C -, _ ₈₎ alkyl, (C _{3. 14)} cycloalkyl, (C ₆ _ ₁₄₎ aryl, (C _{6. 14)} aryl (C _{first 4)} alkyl, (C, _ ₈₎ alkanoii ( C, _ ₈₎ alkyloxy, (C _{6. 14)} aryloxy, (C _{3. 14)} cycloalkyloxy, (C _{first 4)} alkyloxy, (C ₁ _ ₈₎ alkylthio, (C _{3. 14)} cycloalkylthio, (C _{6. 14} ) arylthio and -NR ⁶ R ⁷ , wherein R ⁶ and R ^{7 are} independently selected from hydrogen, (C _1-8 ) alkyl, (C 1-6 alkanoyl, (C 3-8 cycloalkyl) or (C _{6. 14)} aryl, and X ¹³ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.g) alkylene or -X ¹⁷ -X ¹⁸ -X ¹⁹ -, wherein X ¹⁸ is as defined above for X ^15, X ¹⁷ is (Cn17) alkylene and X ¹⁹ is (C _N19) alkylene, wherein the sum of n17 and N19 is 0, 1 or 2; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, in which: -72 is R ⁸ as defined above for R ⁴ , X ²⁰ ΐθ (C4.6) alkylene, hetero (C4.6) alkylene, heterooxo (C4.6) alkylene, oxo (C4.6) alkylene or -X ²² -X ²³ -X ²⁴ -, wherein X ²³ , as defined above for X ¹⁵ , X ²² is (Cn ²² ) alkylene and X ²⁴ is (C _n ²⁴ ) alkylene, wherein the sum of n ²² and n ²⁴ is 0, 1, 2, 3 or 4, R ⁹ is as defined above for R ⁵ and X ²¹ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.6) alkylene or -X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ²⁶ , as defined above for X ¹⁵ , X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (C _{n 27} ) alkylene, wherein the sum of n 25 and n 27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, is optionally substituted by one or more radicals selected from the following, such as: halo, hydroxy, mercapto, (C ₁ _ ₈ ) alkyl, _{(C3. 14)} cycloalkyl, (C _{6. 14)} aryl, (0 ₆ _ ₁₄₎ 3πΙ (0 _η _ ₄₎ 3ΐΚΐΙ, (C.,. ₈₎ alkanoyl, _{(C1. 8)} alkyloxy , (C _{6. 14)} aryloxy, (C _{3. 14)} cycloalkyloxy, (C _{first 4)} alkyloxy, (C ^ alkylthio, (C _{3. 14)} cycloalkylthio, (C _{6. 14)} arylthio, and -NR ⁶ R ⁷ , wherein R ⁶ and R ⁷ are as defined above: with the proviso that the covalent bonds do not occur between the heteroatoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any hetero atoms, contained in X ³ , X ⁵ , X ⁷ and X ⁹ ; and pharmaceutically acceptable salts, N-oxides, prodrugs and protected derivatives thereof. The compound of claim 23, wherein: X ⁴ -X ⁵ -X ⁶ together are (C _{2nd 10)} alkylene or hetero (C _{3. 10)} alkylene; X ¹ and X ⁹ are independently covalent bond, -C (O) -, -NHC (O) -, -C (O) NH-, -N (CH ₃ ) C (O) - or -S (O) ₂ NH-; 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 or methylene, and X ¹¹ is 4,1-piperidylene or 1,4-piperazinylene; R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ -, in which: 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-piperidylene, X ¹⁴ is (Cn14) alkylene and X ¹⁶ is (Cn16) alkylene, wherein the sum of n14 and n16 0, 1, or 2, R ⁵ is a piperid-4-yl, and X ¹³ is (C _{2nd 3)} alkylene; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, in which: -73je R ⁸ amino, amidino, guanidino, methylamino or 1-iminoethyl, X ²⁰ is -X ²² -X ²³ -X ²⁴ -, wherein X ^{23 is} fc3 / 7S-1,4-cyclohexylene, 1,4-phenylene, 4,1-pyridylene, 1,4-piperidylene, X ²² is (Cn22) alkylene and X ²⁴ is (Cn24) alkylene, wherein the sum of n22 and n24 is 1 or 2, R ⁹ is benzoimidazol-5-yl, imidazol-1-yl, imidazol-4-yl, 2-imidazolin-2-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-4 -yl, piperid-4-yl, piperazin-1-yl, pyrid-3-yl, pyrid-4-yl, 1,4,5,6-tetrahydropyrimidin-5-yl, or 1,4,5,6-tetrahydro-2-dioxopyrimidin-5-yl X ²¹ is (C 1-6 alkylene, c 1 -aza (C 2-5) alkylene, 2-aza-3-oxotrimethylene, 3-aza-2 oxotrimethylene, 3-oxotrimethylene, w-thia (C2.4) alkylene or X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ^{26 is} 1,4-phenylene, X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (C _{n 27} ) alkylene, wherein the sum of n 25 and n 27 is O or 1; and pharmaceutically acceptable salts, / V-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 24, wherein X ⁴ -X ⁵ -X ^{6 are} together (C ^{4 8} ) alkylene or hetero (C 4-10) acylene; X ¹ and X ⁹ are independently covalent bond, -C (O) -, -NHC (O) -, -C (O) NH- or -S (O) 2NH-; X ³ and X ⁷ are independently -C (O) - or -C (O) O-; R ¹ is R ⁴ -X ¹² -, wherein R ^{4 is} amidino or guanidino; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, wherein R ^{8 is} amino, amidino, guanidino or methylamino, X ²³ is trans-A, 4-cyclohexylene or 1,4-phenylene, R ⁹ is imidazol-1-yl, imidazol-4-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, piperid-4-yl or pyrid-4-yl, and X ²¹ is (C _v5 ) alkylene or 3-azatrimethylene; and pharmaceutically acceptable salts, AA oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 25, wherein X ¹ and X ^{9 are} 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 each -X ¹⁰ -X ¹¹ -, wherein X ^{10 is a} covalent bond and X ¹¹ is 1,4-piperazinylene; 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 -, wherein R ^{8 is} amidino or guanidino and X ²⁰ is -X ²² -X ²³ -X ²⁴ -, in which X ^{23 is} 1,4-phenylene, X ²² is a covalent bond and X ²⁴ is methylene; and pharmaceutically acceptable salts, AA oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 26, wherein X ⁴ -X ⁵ -X ^{6 are} together hexamethylene; X ¹ and X ⁹ are each -NHC (O) -, X ³ and X ⁷ are each -C (O) - and R ¹ and R ² are each 4-guanidinobenzyl, namely 4-guanidinobenzyl 4- {7- [4 - (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] heptanoyl} -741-piperazinecarboxamide; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 26, wherein X ⁴ -X ⁵ -X ^{6 are} together heptamethylene; X ¹ and X ⁹ are each -NHC (O) -, X ³ and X ⁷ are each -C (O) - and R ¹ and R ² are each 4-guanidinobenzyl, namely 4-guanidinobenzyl 4- {8- [4 - (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] octanoyl} 1-piperazinecarboxamide; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 26, wherein X ⁴ -X ⁵ -X ^{6 are} together octamethylene; X ¹ and X ⁹ are each -NHC (O) -, X ³ and X ⁷ are each -C (O) - and R ¹ and R ² are each 4-guanidinobenzyl, namely 4-guanidinobenzyl 4- {9- [4 - (4-guanidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] nonanoyl} 1-piperazinecarboxamide; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 26, wherein X ⁴ -X ⁵ -X ^{6 are} together hexamethylene; X ¹ and X ⁹ are each -NHC (O) -, X ³ and X ⁷ are each -C (O) - and R ¹ and R ² are each 4-amidinobenzyl, namely 4- {7- [4- (4 -amidinobenzylcarbamoyl) piperazin-1-yl carbonyl] heptanoyl} -1-piperazine carboxamide; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 26, wherein X ⁴ -X ⁵ -X ^{6 are} together pentamethylene; X ¹ and X ⁹ are each -NHC (O) -, X ³ and X ⁷ are each -C (O) O- and R ¹ and R ² are each 4-guanidinobenzyl, namely 1,5-pentamethylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate]; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 26, wherein X ⁴ -X ⁵ -X ^{6 are} together tetramethylene; X ¹ and X ⁹ are each -NHC (O) -, X ³ and X ⁷ are each -C (O) O- and R ¹ and R ² are each 4-guanidinobenzyl, namely 1,5-tetramethylene di [4- (4-guanidinobenzylcarbamoyl) -1-piperazinecarboxylate]; and pharmaceutically acceptable salts, / Oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 26, wherein X ⁴ -X ⁵ -X ^{6 are} together pentamethylene; X ¹ and X ⁹ are each -NHC (O) -, X ³ and X ⁷ are each -C (O) - and R ¹ and R ² are each 4-guanidinobenzyl, namely 4-guanidinobenzyl 4- {6- [4 - (4-amidinobenzylcarbamoyl) piperazin-1-ylcarbonyl] hexanoyl} -751-piperazinecarboxamide; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. The compound of claim 26, wherein X ⁴ -X ⁵ -X ^{6 are} together 3-oxatetramethylene; X ¹ and X ⁹ are each -C (O) -, X ³ and X ⁷ are each -C (O) - and R ¹ and R ² are each 4-amidinobenzyl, namely 3-oxa-1,5-pentamethylene di [4- (4-guanidinophenylacetyl) piperazin-1-ylcarbonyl]; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 23 in combination with a pharmaceutically acceptable excipient. 36. Compound of Formula I: κ'-χ'-χ ^ χ ^ χ ^ r ² -x ⁹ -x'-x ⁷ -x ^6zX I in which: X ⁴ -X ⁵ -X ⁶ together are (C _{2nd 12)} alkylene or hetero (C _{3. 12)} alkylene; X ¹ and X ⁹ are independently covalent bond, -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 ^{3 is} independently hydrogen, (C ₁₃ ) alkyl or (C 3-8) ^c * chloalkyl, with the proviso that X ¹ and X ⁹ are not both 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) 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 ³ is as defined above; X ² and X ⁸ are independently (C1-8) alkyl, hetero ^ .8) alkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ (C0. ₄₎ alkylene or hetero (C _{3. 4)} alkylene and X ¹¹ is (C _{3. 8)} cycloalkylene or hetero (C _{3. 8)} cycloalkylene; R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ -, in which: -76 is R ⁴ amino, amidino, guanidino, 1-iminoethyl or methylamino, X ¹² is (C4-6) ^{alkyl | a>} hetero (C4. ₆₎ alkylene, heterooxo (C _{4. 6)} alkylene, oxo (C _{4. 6)} alkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ - in wherein X ^{15 is} (C3.6) cycloalkylene, hetero (C5.6) arylene, hetero (C3.6) cycloalkylene or phenylene, X ¹⁴ is (Cn14) alkylene and X ¹⁶ is ( _C16 ) alkylene, sum n14 and n16 0,1, 2, 3 or 4, R ⁵ is a group selected from the following, such as: azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2- imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-3-yl, 1-methylpiperid- 4-yl, piperid-3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-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 any carbocyclic ketone or thioketone derivative thereof, wherein this group is optionally substituted by one or more radicals selected from the following, such as: halo, hydroxy, mercapto, (C.,. ₈₎ alkyl, (C ₃ _ ₁₄₎ cycloalkyl, (C _{6. 14)} aryl, (C ₆ _ ₁₄₎ aryl (C ₁ _ ₄₎ alkyl, (C ^ gjalkanoil, (C ₁ _ ₈ ) alkyloxy, (C _{6. 14)} aryloxy, (C _{3. 14)} cycloalkyloxy, (C ₁ _ ₄₎ alkyloxy, (C ^ gjalkiltio, (C _{3. 14)} cycloalkylthio, (C _{6. 14)} arylthio, and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are independently selected from the following such as: hydrogen, (C, _{first 8)} alkyl, (C ^ gjalkanoil, (C _{3. 14)} cycloalkyl or (C _{6. 14)} aryl, and X ¹³ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.6) alkylene, or -X ¹⁷ -X ¹⁸ -X ¹⁹ -, wherein X ¹⁸ , as defined above for X ¹⁵ , X ¹⁷ is (Cn ¹⁷ ) alkylene and X ¹⁹ is (C _{n 19} ) alkylene, wherein the sum of n 17 and n 19 is 0, 1 or 2; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, in which: R ⁸ is as defined above for R ⁴ , X ²⁰ is (C4.6) alkylene, hetero (C4.6) alkylene, heterooxo (C4.6) alkylene, oxo (C4.6) alkylene, or -X ²² -X ²³ -X ²⁴ -, wherein X ²³ , as defined above for X ¹⁵ , X ²² is (Cn ²² ) alkylene and X ²⁴ is (C _n ²⁴ ) alkylene, wherein the sum of n ²² and n ²⁴ is 0, 1, 2, 3 or 4, R ⁹ is as defined above for R ⁵ and X ²¹ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.6) alkylene or -X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ²⁶ , as defined above for X ¹⁵ , X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (C _{n 27} ) alkylene, wherein the sum of n 25 and n 27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heteroaikylene, heterocycloalkylene, phenylene, arylene and heteroarylene as defined above is optionally substituted by one -77ali more radicals chosen from halo, hydroxy, mercapto, (C ·, .G) alkyl, _{(C3. 14)} cycloalkyl, (Cg_j ₄₎ aryl, (Cg. ^ ₄₎ aryl, (Cj_ ₄₎ alkyl, (C ^ g) alkanoyl, (Cj.gJalkiloksi, (C ₆ _ ₁₄₎ aryloxy, (C _{3. 14)} cycloalkyloxy, (C ₁ _ ₄₎ alkyloxy, (C, _{first 8)} alkylthio, (C ₃ _ ₁₄₎ cycloalkylthio, (C _{6. 14)} arylthio, and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are as defined above; with the proviso that covalent bonds do not occur between heteroatoms contained within R ^1, X ² , Χ ⁴ , Χ ^θ , X ⁸ and R ² and any heteroatoms contained in Χ ³ , X ⁵ , X ⁷ and X ⁹ ; or a pharmaceutically acceptable salt, N-oxide or prodrug derivative thereof. for treating a disease in an animal in which the action of tryptase contributes to the pathology and / or symptomatology of the disease by administering to the animal a therapeutically effective amount of a compound of Formula I. The compound of claim 36, wherein the disease is selected from the following, such as: asthma, allergic rhinitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, rheumatoid arthritis, arthritic conditions in general, urticaria, angioedema, eczema dermatitis, anaphylaxis, hyperphylaxis, hyperphylaxis skin, peptic ulcers, inflammatory bowel disease, eye and spring conjunctivitis, and inflammatory skin conditions. The compound of claim 37, wherein the disease is asthma. The compound of claim 38, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I in an aerosolized pharmaceutically acceptable carrier suitable for administration as an inhaler. The compound of claim 39, wherein the pharmaceutical composition further comprises a therapeutically effective amount of a β-adrenergic agonist, a methylxanthine, a chromoglycate or a corticosteroid. The compound of claim 40, wherein the β-adrenergic agonist is selected from the following, such as: albuterol, terbutaline, formoterol, phenoterol and prenalin, methylxanthine is selected from the following, such as: caffeine, theophylline, aminophylline and theobromine, chromoglycate is selected from cromoline and necromyl, and a corticosteroid selected from beclomethasone, triamcinolone, flurisolid and dexamethasone. The compound of claim 37, wherein the disease is rheumatoid arthritis or conjunctivitis. -7843. The compound of claim 42, wherein the pharmaceutical composition comprises a therapeutically effective amount of a compound of Formula I in a pharmaceutically acceptable carrier suitable for topical administration. 44. A process for the preparation of a compound of Formula I: R ^l -X'-X ² -X ³ -X ^ / X ⁵ R ² -X ⁹ -X ⁸ -X ⁷ -X ⁶ ^ in which: X is ⁵ (C3-14) cycloalkylene, hetero (C3-14) cycloalkylene, (C 6-14) aryl or hetero (C5-14) aryl, and X ⁴ and X ⁶ are independently (C0_ ₂₎ alkylene or X ⁴ -X ⁵ -X ⁸ together are (C ₂ _ ₁₂₎ alkylene or hetero (C _{3. 12)} alkylene; X ¹ and X ⁹ are independently covalent bond, -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R ³ ) -, -N (R ³ ) CO-, -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 ³ is independently hydrogen, (C ₁ _ ₃₎ alkyl or (C _{3. 8)} cycloalkyl, with the proviso that X ¹ and X ⁹ are not both 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) 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 ³ is as defined above; X ² and X ⁸ are independently (C, _ ₈₎ alkylene, hetero (C, _ ₈₎ alkylene, -X ¹⁰ -X ¹¹ - or -X ¹¹ -X ¹⁰ -, wherein X ¹⁰ (C0_4) alkylene or hetero (C3-4) alkylene and X ¹¹ is (C3. ₈₎ cycloalkylene or hetero _{(C3. 8)} cycloalkylene; R ¹ is R ⁴ -X ¹² - or R ⁵ -X ¹³ -, in which: R ^{4 is} amino, amidino, guanidino, 1-iminoethyl or methylamino, X ¹² is (C _{4. 6)} alkyl, hetero (C _{4. 6)} alkylene, heterooxo (C _{4. 6)} alkylene, oxo (C _{4. 6)} alkylene or -X ¹⁴ -X ¹⁵ -X ¹⁶ - in wherein X ¹⁵ (C _{3. 6)} cycloalkylene, hetero (C _{5. 6)} arylene, hetero (C _{3. 6)} cycloalkylene or phenylene, X ¹⁴ is (Cn14) alkylene and X ¹⁸ is (Cn16) alkylene, with the sum of n14 and n16 0, 1,2, 3, or 4, -79R ⁵ is a group selected from the following, such as: azetidin-3-yl, benzoimidazol-4-yl, benzoimidazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-4-yl, 2 -imidazolin-2-yl, 2-imidazolin-3-yl, 2-methylimidazol-1-yl, 4-methylimidazol-1-yl, 5-methylimidazol-1-yl, 1-methylpiperid-3-yl, 1-methylpiperid -4-yl, piperid-3-yl, piperid-4-yl, piperazin-1-yl, piperazin-2-yl, pyrid-3-yl, pyrid-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 any carbocyclic ketone or thioketone derivative thereof, the group being optionally substituted by one or more radicals selected from the following, such as: halo, hydroxy, mercapto, (C ₁ _ _s) alkyl, (C _{3. 14)} cycloalkyl, (C _{6. 14)} aryl, (C _{6. 14)} aryl (C _{first 4)} alkyl, (C _V8) alkanoyl, (C _ ₈₎ alkyloxy, (C _{6. 14)} aryloxy, (C _{3. 14)} cycloalkyloxy, (C _{first 4)} alkyloxy, (C, _ ₈₎ alkylthio, (C _{3. 14)} cikloalkiitio, (C _{6. 14)} arylthio and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ are independently selected from the following such as: hydrogen, (C ₁ _ ₈₎ alkyl, (C., _ ₈₎ alkanoyl, (C _{3. 14)} cikioalkil or (C _{6. 14)} aryl, and X ¹³ is (C0,6) alkylene, hetero (C2.6) alkylene, heterooxo (C3-6) alkylene, oxo (C2.6) alkylene or -X ¹⁷ -X ¹⁸ -X ¹⁹ -, wherein X ¹⁸ is as defined above for X ^15, X ¹⁷ is (Cn17) alkylene and X ¹⁹ is (C _N19) alkylene, wherein the sum of n17 and N19 is 0, 1 or 2; and R ² is R ⁸ -X ²⁰ - or R ⁹ -X ²¹ -, in which: ^R8 is amino, 1-iminoethyl or methylamino, X ²⁰ is (C4.6) alkylene, hetero (C4.6) alkylene, heterooxo (C4.6) alkylene, oxo (C4.g) alkylene or -X ²² -X ²³ -X ²⁴ -, wherein X ²³ , as defined above for X ¹⁵ , X ²² is (Cn ²² ) alkylene and X ²⁴ is (Cn ²⁴ ) alkylene, wherein the sum of n ^{22 and} n ²⁴ is 0, 1, 2, 3 or 4, with the proviso that when R ⁸ amino, then X ²⁰ is not (C4.g) alkylene or oxa (C _{4. 6)} alkylene and n22 is not 1, 2, 3 or 4, R ⁹ is as defined above for R ⁵ and X ²¹ is (C0.6) alkylene, hetero (C2.6) alkylene, heterooxo (C3.6) alkylene, oxo (C2.g) alkylene, or -X ²⁵ -X ²⁶ -X ²⁷ -, wherein X ²⁸ , as defined above for X ¹⁵ , X ²⁵ is (Cn ²⁵ ) alkylene and X ²⁷ is (C _{n 27} ) alkylene, wherein the sum of n 25 and n 27 is 0, 1 or 2; wherein each alkylene, cycloalkylene, heterocycloalkylene, phenylene, arylene and heteroarylene, as defined above, is optionally substituted by one or more radicals selected from the following, such as: halo, hydroxy, mercapto, (C 1-6 alkyl, ( C _{3. 14)} cycloalkyl, (C _{6. 14)} aryl, (Οθ ^ ₄₎ aryl (C _{first 4)} alkyl, (C _V8) alkanoyl, (C _V8) alkyloxy, (C _{6. 14)} aryloxy, ( C _{3. 14)} cycloalkyloxy, (C ₁ _ ₄₎ alkyloxy, (C ₁ _ ₈₎ alkiitio, (C _{3. 14)} cycloalkylthio, (C _{6. 14)} arylthio, and -NR ⁶ R ⁷ wherein R ⁶ and R ⁷ as is -80defined above; with the proviso that the covalent bonds do not occur between the hetero atoms contained in R ¹ , X ² , X ⁴ , X ⁶ , X ⁸ and R ² and any hetero atoms contained in X ³ , X ⁵ , X ⁷ and X ⁹ ; and pharmaceutically acceptable salts, N-oxides, prodrug derivatives and protected derivatives thereof, the process comprising: (a) reacting a compound of Formula 1: r'-x'-x ² -x ³ -x ⁴ Y ⁸ -X ⁷ -X ⁶ 'or a protected derivative thereof, with a compound of formula R ² -Y ⁹ -C (O) L, or a protected derivative thereof, wherein L is a protruding group, Y ⁹ is a bond, -O- or -N (R ³⁾ -, Y ⁸ is a piperazin-1-yl, piperid-4-yl or HN (R ³⁾ - (C, _{first 8)} alkyl, respectively, and each of R ^1, R ² , R ³ , X ¹ , X ² , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ is as defined in the Summary of the Invention and then deprotection when necessary to prepare a compound of Formula I , in which X ⁸ 1,4-piperazinylene or 1,4-piperidylene and X ⁹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) -, or in which X ⁸ (C _{1 8} ) alkylene and X ⁹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) -; (b) reacting a compound of Formula I or a protected derivative thereof, with an isocyanate of Formula R ² -NC (O) or a protected derivative thereof, and then deprotecting when necessary to prepare a compound of Formula I, in which X ⁸ 1,4-piperazinylene or 1,4-piperidylene and X ⁹ is -NHC (O) -, or in which X ^{8 is} (C 1-6 alkylene and X ⁹ is -NHC (O) N (R ³ ) -; (c) reacting a compound of Formula 2: Υ ² -Χ ³ -Χ ⁴ χ R ² -X ⁹ -X ⁸ -X ⁷ -X ^6xX X ³ or a protected derivative thereof, with a compound of formula R ¹ -Y ¹ -C (O) L or protected -81 derivative thereof, wherein L is a prominent group, Y ¹ is a bond, -O- or -N (R ³ ) -, Y ² is piperazin-1-yl, piperid-4-yl or HN (R ³ ) - (C |. ₈₎ alkyl, respectively, and all 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, and then deprotecting when necessary to prepare a compound of Formula I wherein X is ² 1,4-piperazinylene or 1,4-piperidylene and X ¹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) -, or in which X ² (C _{1 8} ) alkylene and X ¹ is -C (O) N (R ³ ) -, -OC (O) N (R ³ ) - or -N (R ³ ) C (O) N (R ³ ) -; (d) reacting a compound of Formula 2 or a protected derivative thereof, with an isocyanate of formula R ¹ -NC (O), or with a protected derivative thereof, and then deprotecting when necessary to prepare a compound of Formula I, in which X ² 1,4-piperazinylene or 1,4-piperidylene and ^X1 is -NHC (O) -, or wherein X ² (C ₁ _g) alkylene and ^X1 is -NHC (O) N (R ³⁾ -; (e) reacting a compound of Formula 3: Y ² -X ³ -X \> ⁵ Y ^with -X ⁷ -X ^{6 /} or a protected derivative thereof, with 2 or more molar equivalents of a compound of formula R ¹ -Y ¹ -C (O) L or a protected derivative thereof, wherein L is a prominent group, Y ¹ is a bond, -O- or -N (R ³ ) -, Y ² and Y ⁸ are independently piperazin-1-yl, piperid-4-yl or HN (R ³ ) - (C 1-8) alkyl and each R ¹ , R ³ , X ³ , X ⁴ , X ⁵ , X ⁶ and X ⁷ is as defined in the Summary of the Invention and then deprotection when necessary to prepare a compound of Formula I in which R ^{1 is} equal to R ² ; X ² and / or X ⁸ is 1,4-piperazinylene or 1,4-piperidylene; X ¹ is -C (O) -, -OC (O) -, or -N (R ³ ) C (O) -; and X ⁹ is -C (O) -, -OC (O) - or -N (R ³ ) C (O) - and / or in which X ² and / or X ⁸ (CV ⁸ ) is 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 ) -; (f) reacting a compound of Formula 3 or a protected derivative thereof, with two or more mole equivalents of an isocyanate of formula R ¹ -NC (O) or a protected derivative thereof, and then removing the protection when necessary to prepare a compound of Formula I, wherein R ^{1 is} equal to R ² ; X ² and / or X ⁸ is 1,4-piperazinylene or 1,4-piperidylene; X ¹ is -NHC (O) - and / or X ⁹ is -NHC (O) - and / or in which X ² and / or X ⁸ (C _{1 is} alkyl) and X ¹ is -NHC (O) N ( R ³ ) - and / or X ⁹ is -NHC (O) N (R ³ ) -; -82 (g) reacting an amine of formula R ¹ -N (R ³ ) H or a protected derivative thereof, with a compound of Formula 4: LC (O) -Y'-X ² -X ³ -X ⁴ : x ³ R ² -X ⁹ -X ⁸ -X ⁷ -X ⁶ ', or with a protected derivative thereof, wherein L is a protruding 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 is as defined in the Summary of the Invention and then deprotection when necessary to prepare a a compound of Formula I in which X ¹ -N (R ³⁾ C (O) -, -N (R ³⁾ C (O) O- or -N (R ³⁾ C (O) N (R ³⁾ -; (h) reacting a compound of formula R ¹ -X ¹ -Y ^2, or a protected derivative thereof, with a compound of Formula 5: LC (O) -Y ³ -X \ r ² -x ⁹ -x ⁸ -x ⁷ -x ⁶ '^ or with a protected derivative thereof, in which L is a prominent group, Y ³ is a bond, -0 or -N (R ³ ) -, Y ² is piperazin-1-yl, piperid-4-yl or HN ¹ R 4 -fC 4 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 is as defined in the Summary of the Invention and then deprotection, when necessary, to prepare a compound of Formula I in which X ^{2 is} 1 , 4-piperazinylene or 4,1-piperidylene and X ³ is -C (O) -, -C (O) O- or -C (O) N (R ³ ) -, or in which X ² (C ^ alkylene and X ³ is -N (R ³ ) C (O) -, -N (R ³ ) C (O) O- or -N (R ³ ) C (O) N (R ³ ) -; (i) reacting 2 or more mole equivalents of a compound of formula R ¹ -X ¹ -Y ^2, or a protected derivative thereof, with a compound of Formula 6: -83LC (O) -Y ³ -X ⁴ j ^X x ^{5 1} LC (O) Y ⁷ -X ⁶ ^ or with a protected derivative thereof, in which L is a prominent group, Y ³ and Y ⁷ are independently a bond, -O- or -N (R ³ ) -, Y ² is piperazine -1 -ii, piperid-4-yl, HN (R ³ ) - (C 1-8) alkyl or HN (R ³ ) -hetero (C _1-8 ) alkyl and each R ¹ , Χ ¹ , X ⁴ , X ⁵ and X ⁶ is as defined in the Summary of the Invention and then deprotection when necessary to prepare a compound of Formula I in which X ² and X ^{8 are} each 1,4-piperazinyl or 4,1-piperidylene and X ³ and X ⁷ are independently -C (O) -, -C (O) O- or -C (O) N (R ³ ) -, or in which X ² and X ^{8 are} each (Ο _ν8 ) alkylene or hetero (C.,. ₈₎ alkylene and X ³ and X ² are each independently -N (R ³⁾ C (O) -, -N (R ³⁾ C (O) O- or -N (R ³⁾ C (O) N (R ³ ) -, singly; (j) optionally reacting a compound of Formula I in which R ^{4 is} amino with cyanamide to form a compound of Formula I in which R ^{4 is} guanidino; (k) optionally further converting the compound of Formula I into a pharmaceutically acceptable salt; (l) optionally further converting the salt form of the compound of Formula I to the non-salt form; (m) optionally further converting the non-oxidized form of the compound of Formula I into a pharmaceutically acceptable / V-oxide; (n) optionally further converting the / V-oxide form of the compound of Formula I into its non-oxidized form; (o) optionally further converting a non-derivatized compound of Formula I into a pharmaceutical prodrug; (p) optionally further converting the prodrug derivative of the compound of Formula I into its non-derivatized form.