WO2011079103A1 - Spiropiperidine benzylamines as beta-tryptase inhibitors - Google Patents

Abstract

The present invention discloses and claims a series of substituted spiropiperidine benzylamines of formula (I) wherein R is as described herein. More specifically, the compounds of this invention are inhibitors of β-tryptase and are, therefore, useful as pharmaceutical agents for treating joint inflammation, including arthritis, rheumatoid arthritisand other arthritic condition such as rheumatoid spondylitis, gouty arthπtis, traumatic arthritis, rubella arthritis, psoriatic arthritis, osteoarthritis or other chronic inflammatory joint disease, or diseases of joint cartilage destruction, ocular conjunctivitis, vernal conjunctivitis, inflammatory bowel disease, asthma, allergic rhinitis, interstitial lung diseases, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, hypertrophic scars, various dermatological conditions, for example, atopic dermatitis and psoriasis, myocardial infarction, stroke, angina or other consequences of atherosclerotic plaque rupture, as well as periodontal disease, diabetic retinopathy, macular degeneration, acute macular degeneration, wet macular degeneration, tumour growth, anaphylaxis, multiple sclerosis, peptic ulcers, or a syncytial viral infection.

Description

SPIROPIPERIDINE BENZYLAMINES AS BETA-TRYPTASE INHIBITORS

BACKGROUND OF THE INVENTION

Field of the Invention

The present invention relates to a series of substituted spiropiperidine benzylamines. The compounds of this invention are inhibitors of β-tryptase and are, therefore, useful as pharmaceutical agents. Additionally, this invention also relates to methods of preparation of substituted spiropiperidine benzylamines and intermediates therefor.

Description of the Art

Mast cell mediated inflammatory conditions, in particular asthma, are a growing public health concern. Asthma is frequently characterized by progressive development of hyper-responsiveness of the trachea and bronchi to both immunospecific allergens and generalized chemical or physical stimuli, which lead to the onset of chronic inflammation. Leukocytes containing IgE receptors, notably mast cells and basophils, are present in the epithelium and underlying smooth muscle tissues of bronchi. These leukocytes initially become activated by the binding of specific inhaled antigens to the IgE receptors and then release a number of chemical mediators. For example, degranulation of mast cells leads to the release of proteoglycans, peroxidase, arylsulfatase B, chymase, and tryptase, which results in bronchiole constriction.

Tryptase is stored in the mast cell secretory granules and is the major protease of human mast cells. Tryptase has been implicated in a variety of biological processes, including degradation of vasodilator/ and bronchodilatory neuropeptides (Caughey, et al., J. Pharmacol. Exp. Ther., 1988, 244, pages 133-137; Franconi, et al., J. Pharmacol. Exp. Ther., 1988, 248, pages 947-951 ; and Tarn, et al., Am. J. Respir. Cell Mol. Biol., 1990, 3, pages 27-32) and modulation of bronchial responsiveness to histamine (Sekizawa, et al., J. Clin. Invest., 1989, 83, pages 175- 179).

As a result, tryptase inhibitors may be useful as anti-inflammatory agents (K Rice, P.A. Sprengler, Current Opinion in Drug Discovery and Development, 1999, 2(5), pages 463-474) particularly in the treatment of chronic asthma (M.Q. Zhang, H. Timmerman, Mediators Inflamm., 1997, 1 12, pages 31 1 -317), and may also be useful in treating or preventing allergic rhinitis (S. J. Wilson et al, Clin. Exp. Allergy, 1998, 28, pages 220-227), inflammatory bowel disease (S.C. Bischoff et al, Histopathology, 1996, 28, pages 1 -13), psoriasis (A. Naukkarinen et al, Arch. Dermatol. Res., 1993, 285, pages 341 -346), conjunctivitis (A.A.Irani et al, J. Allergy Clin. Immunol., 1990, 86, pages 34-40), atopic dermatitis (A. Jarvikallio et al, Br. J. Dermatol., 1997, 136, pages 871 -877), rheumatoid arthritis (L.C Tetlow et al, Ann. Rheum. Dis., 1998, 54, pages 549-555), osteoarthritis (M.G. Buckley et al, J. Pathol., 1998, 186, pages 67- 74), gouty arthritis, rheumatoid spondylitis, and diseases of joint cartilage destruction.

In addition, tryptase has been shown to be a potent mitogen for fibroblasts, suggesting its involvement in the pulmonary fibrosis in asthma and interstitial lung diseases (Ruoss et al., J. Clin. Invest., 1991 , 88, pages 493-499).

Therefore, tryptase inhibitors may be useful in treating or preventing fibrotic conditions (J.A. Cairns and A.F. Walls, J. Clin. Invest., 1997, 99, pages 1313-1321 ) for example, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas and hypertrophic scars.

Additionally, tryptase inhibitors may be useful in treating or preventing myocardial infarction, stroke, angina and other consequences of atherosclerotic plaque rupture (M. Jeziorska et al, J. Pathol., 1997, 182, pages 1 15-122).

Tryptase has also been discovered to activate prostromelysin that in turn activates collagenase, thereby initiating the destruction of cartilage and periodontal connective tissue, respectively.

Therefore, tryptase inhibitors could be useful in the treatment or prevention of arthritis, periodontal disease, diabetic retinopathy, and tumour growth (W.J. Beil et al, Exp. Hematol., (1998) 26, pages 158-169). Also, tryptase inhibitors may be useful in the treatment of anaphylaxis (L.B. Schwarz et al, J. Clin. Invest., 1995, 96, pages 2702-2710), multiple sclerosis (M. Steinhoff et al, Nat. Med. (N. Y.), 2000, 6(2), pages 151 -158), peptic ulcers and syncytial viral infections.

Such a compound should readily have utility in treating a patient suffering from conditions that can be ameliorated by the administration of an inhibitor of tryptase, e.g., mast cell mediated inflammatory conditions, inflammation, and diseases or disorders related to the degradation of vasodilatory and bronchodilatory neuropeptides, and have diminished liability for semicarbazide-sensitive amine oxidase (SSAO) metabolism. β-tryptase is located solely in mast cell granules as the most abundant serine protease and is released following stimulation of the IgE receptor by allergen. In experimental animals, β-tryptase release provokes inflammation and bronchoconstriction characteristic of human asthma. It is also thought to cause fibroblast activation and therefore to have a role in airways remodeling. Levels of β- tryptase are elevated in bronchoalveolar lavage fluid (BALF) from asthmatic patients. Clinical proof-of-concept (bronchial allergen challenge) for asthma has been reported with an inhaled β-tryptase inhibitor (APC-366 - since terminated due to bronchial irritation), β-tryptase inhibitors have the potential to impact the symptoms and pathogenesis of a number of proinflammatory indications, in particular, asthma and potentially COPD.

Benzylamine containing tryptase inhibitors, as one popular class of serine protease inhibitors, are also recognized as substrates for amine oxidases, especially SSAO.

WO 2009067202 discloses a series of compounds, including substituted spiropiperidines, useful as tryptase inhibitors. But the compounds disclosed therein do not include the spiropiperidine benzylamines of the present invention.

Costanzo, M. J. et al., "Potent, nonpeptide inhibitors of human mast cell tryptase: Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives", Bioorganic & Medicinal Chemistry Letters, 2008, vol. 18, pp. 21 14-2121 , discloses a series of compounds, including substituted spiropiperidines, useful as tryptase inhibitors. But the compounds disclosed therein do not include the spiropiperidine benzylamines of the present invention.

All of the references described herein are incorporated herein by reference in their entirety.

Accordingly, it is an object of this invention to provide a series of substituted spiropiperidine benzylamines that are inhibitors of β-tryptase.

It is also an object of this invention to provide processes for the preparation of the substituted spiropiperidine benzylamines as disclosed herein.

Other objects and further scope of the applicability of the present invention will become apparent from the detailed description that follows. SUMMARY OF THE INVENTION

The present invention provides substituted spiropiperidine benzylamines of fornnula (I), and the stereoisomers, enantiomers, racemates and tautomers of said compounds and the pharmaceutically acceptable salts thereof, as inhibitors of β- tryptase, and methods of using the compounds of formula (I) as pharmaceutical agents for the treatment of diseases and disorders.

Thus in accordance with the practice of this invention there is provided a compound of formula (I):

wherein

wherein

R1 is alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl;

R2 and R3 are each independently H, halo, alkoxy, haloalkoxy, alkyl, amido, ureyl, carboxyl, sulfonyl amido, sulfonyl urea or alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

W1 , W2, W3 or W4 is each independently N, CH, CR2 or CR3.

This invention further includes various salts of the compounds of formula (I) including various enantiomers or diastereomers of compounds of formula (I). A further embodiment of the present invention relates to a method for inhibiting β-tryptase activity in a patient comprising administering to said patient a therapeutically effective amount of an inhibitor of β-tryptase.

Another embodiment of the present invention relates to a method for inhibiting β-tryptase activity in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula (I).

Another embodiment of the present invention relates to a method for treating a patient suffering from a disease or disorder ameliorated by inhibition of β-tryptase comprising administering to said patient a therapeutically effective amount of a compound of formula (I).

In other aspects of this invention there are also provided various pharmaceutical compositions comprising one or more compounds of formula (I) as well as their therapeutic use in alleviating various diseases which are ameliorated by inhibition of β-tryptase.

DETAILED DESCRIPTION OF THE INVENTION

The terms as used herein have the following meanings:

As used herein, the expression "(Ci-C )alkyl" includes methyl and ethyl groups, and straight-chained or branched propyl, and butyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl and tert-butyl. Derived expressions such as "(Ci-C₄)alkoxy", "(C C₄)alkoxy(Ci-C₄)alkyl", or "hydroxy(C C₄)alkyl" are to be construed accordingly.

As used herein, the expression "(CrC6)perfluoroalkyl" means that all of the hydrogen atoms in said alkyl group are replaced with fluorine atoms. Illustrative examples include trifluoromethyl and pentafluoroethyl, and straight-chained or branched heptafluoropropyl, nonafluorobutyl, undecafluoropentyl and tridecafluorohexyl groups. Derived expression, "(Ci-C6)perfluoroalkoxy", is to be construed accordingly.

"Halogen" or "halo" means chloro, fluoro, bromo, and iodo.

As used herein, "patient" means a warm blooded animal, such as for example rat, mice, dogs, cats, guinea pigs, and primates such as humans.

As used herein, the expression "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant, or other material which is mixed with the compound of the present invention in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is pharmaceutically acceptable oil typically used for parenteral administration.

The term "pharmaceutically acceptable salts" as used herein means that the salts of the compounds of the present invention can be used in medicinal preparations. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfamic acid, sulfuric acid, methanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, malic acid, ascorbic acid, succinic acid, glutaric acid, acetic acid, propionic acid, salicylic acid, cinnamic acid, 2- phenoxybenzoic acid, hydroxybenzoic acid, phenylacetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, carbonic acid or phosphoric acid. The acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate can also be formed. Also, the salts so formed may present either as mono- or di- acid salts and can exist substantially anhydrous or can be hydrated. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts, and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.

The expression "stereoisomers" is a general term used for all isomers of the individual molecules that differ only in the orientation of their atoms in space. Typically it includes mirror image isomers that are usually formed due to at least one asymmetric center, (enantiomers). Where the compounds according to the invention possess two or more asymmetric centers, they may additionally exist as diastereoisomers, also certain individual molecules may exist as geometric isomers (cis/trans). Similarly, certain compounds of this invention may exist in a mixture of two or more structurally distinct forms that are in rapid equilibrium, commonly known as tautomers. Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. It is to be understood that all such isomers and mixtures thereof in any proportion are encompassed within the scope of the present invention.

As used herein, 'R' and 'S' are used as commonly used terms in organic chemistry to denote specific configuration of a chiral center. The term 'R' (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The term 'S' (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group. The priority of groups is based upon sequence rules wherein prioritization is first based on atomic number (in order of decreasing atomic number). A listing and discussion of priorities is contained in Stereochemistry of Organic Compounds, Ernest L. Eliel, Samuel H. Wilen and Lewis N. Mander, editors, Wiley-lnterscience, John Wiley & Sons, Inc., New York, 1994.

In addition to the (R)-(S) system, the older D-L system may also be used herein to denote absolute configuration, especially with reference to amino acids. In this system a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top. The prefix 'D' is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon at the chiral center and 'L', that of the isomer in which it is on the left.

In a broad sense, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a few of the specific embodiments as disclosed herein, the term "substituted" means substituted with one or more substituents independently selected from the group consisting of (Ci-C6)alkyl, (C2- C6)alkenyl, (Ci-C6)perfluoroalkyl, phenyl, hydroxy, -CO2H, an ester, an amide, (Ci- C₆)alkoxy, (CrC₆)thioalkyl, (CrC₆)perfluoroalkoxy, -NH₂, CI, Br, I, F, -NH-lower alkyl, and -N(lower alkyl)₂. However, any of the other suitable substituents known to one skilled in the art can also be used in these embodiments.

"Therapeutically effective amount" means an amount of the compound which is effective in treating the named disease, disorder or condition. The term "treating" refers to:

(i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder and/or condition, but has not yet been diagnosed as having it;

(ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and

(iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.

Thus, in accordance with the practice of this invention there is provided a compound of the formula (I):

wherein

wherein

R1 is alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl;

R2 and R3 are each independently H, halo, alkoxy, haloalkoxy, alkyl, amido, ureyl, carboxyl, sulfonyl amido, sulfonyl urea or alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

W1 , W2, W3 or W4 is each independently N, CH, CR2 or CR3. This invention further includes various salts of the compounds of formula (I) including various enantiomers or diastereomers of compounds of formula (I). As noted hereinabove and by way of specific examples hereafter all of the salts that can be formed including pharmaceutically acceptable salts are part of this invention. As also noted hereinabove and hereafter all of the conceivable enantiomeric and diastereomeric forms of compounds of formula (I) are part of this invention.

In one of the embodiments, there is provided the compounds of formula (I) wherein R is indolyl that is optionally substituted.

In a further aspect of this invention the following compounds encompassed by the scope of this invention without any limitation may be enumerated:

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-indole-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; 1 -(7-Fluoro-1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-aminomethyl- spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride;

1 -(7- Trifluoromethoxy -1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; and

1 -(1 -(2-Methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride. All of the above compounds may also include corresponding salts wherever possible including the pharmaceutically acceptable salts thereof.

The compounds of this invention can be synthesized by any of the procedures known to one skilled in the art. Specifically, several of the starting materials used in the preparation of the compounds of this invention are known or are themselves commercially available. The compounds of this invention and several of the precursor compounds may also be prepared by methods used to prepare similar compounds as reported in the literature and as further described herein. For instance, see R. C. Larock, "Comprehensive Organic Transformations," VCH publishers, 1989.

It is also well known that in various organic reactions it may be necessary to protect reactive functional groups, such as for example, amino groups, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice and known to one of skilled in the art, for example, see T. W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, Inc., 1991 . For example, suitable amine protecting groups include without any limitation sulfonyl (e.g., tosyl), acyl (e.g., benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g., benzyl), which may be removed subsequently by hydrolysis or hydrogenation as appropriate. Other suitable amine protecting groups include trifluoroacetyl [-C(=O)CF₃] which may be removed by base catalyzed hydrolysis, or a solid phase resin bound benzyl group, such as a Merrifield resin bound 2,6-dimethoxybenzyl group (Ellman linker) or a 2,6-dimethoxy- 4-[2-(polystyrylmethoxy)ethoxy]benzyl, which may be removed by acid catalyzed hydrolysis, for example with TFA.

In another aspect of this embodiment, a specific disease, a disorder or a condition that can be prevented and/or treated with the compound of this invention include, without any limitation the following: an inflammatory disease, for example, joint inflammation, including arthritis, rheumatoid arthritis and other arthritic condition such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, osteoarthritis or other chronic inflammatory joint disease, or diseases of joint cartilage destruction, ocular conjunctivitis, vernal conjunctivitis, inflammatory bowel disease, asthma, allergic rhinitis, interstitial lung diseases, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, hypertrophic scars, various dermatological conditions, for example, atopic dermatitis and psoriasis, myocardial infarction, stroke, angina or other consequences of atherosclerotic plaque rupture, as well as periodontal disease, diabetic retinopathy, macular degeneration, acute macular degeneration, wet macular degeneration, tumour growth, anaphylaxis, multiple sclerosis, peptic ulcers, or a syncytial viral infection.

As described herein below by way of specific examples, the compounds of formula (I) inhibit β-tryptase and demonstrate anti-inflammatory effects. Therefore, the compounds of this invention may have utility in the treatment of diseases or conditions ameliorated by inhibition of β-tryptase.

Thus in one aspect of this invention there is provided a method of treating a disease in a patient, said disease selected from the group consisting of an

inflammatory disease, for example, joint inflammation, including arthritis, rheumatoid arthritis and other arthritic condition such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, osteoarthritis or other chronic inflammatory joint disease, or diseases of joint cartilage destruction, ocular

conjunctivitis, vernal conjunctivitis, inflammatory bowel disease, asthma, allergic rhinitis, interstitial lung diseases, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, hypertrophic scars, various

dermatological conditions, for example, atopic dermatitis and psoriasis, myocardial infarction, stroke, angina or other consequences of atherosclerotic plaque rupture, as well as periodontal disease, diabetic retinopathy, macular degeneration, acute macular degeneration, wet macular degeneration, tumour growth, anaphylaxis, multiple sclerosis, peptic ulcers, or a syncytial viral infection, comprising administering to said patient a therapeutically effective amount of a compound of formula (I).

One of skill in the art readily appreciates that the pathologies and disease states expressly stated herein are not intended to be limiting rather to illustrate the efficacy of the compounds of the present invention. Thus it is to be understood that the compounds of this invention may be used to treat any disease caused by the effects of β-tryptase. That is, as noted above, the compounds of the present invention are inhibitors of β-tryptase and may be effectively administered to ameliorate any disease state which is mediated all or in part by β-tryptase.

One of skill in the art readily appreciates that the pathologies and disease states expressly stated herein are not intended to be limiting rather to illustrate the efficacy of the compounds of the present invention. Thus it is to be understood that the compounds of this invention may be used to treat any disease caused by the effects of β-tryptase. That is, as noted above, the compounds of the present invention are inhibitors of β-tryptase and may be effectively administered to ameliorate any disease state which is mediated all or in part by β-tryptase.

All of the various embodiments of the compounds of this invention as disclosed herein can be used in the method of treating various disease states as described herein. As stated herein, the compounds used in the method of this invention are capable of inhibiting the effects of β-tryptase and thereby alleviating the effects and/or conditions caused due to the activity of β-tryptase.

In another embodiment of the method of this invention, the compounds of this invention can be administered by any of the methods known in the art. Specifically, the compounds of this invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal or topical route.

Finally, in yet another embodiment of this invention, there is also provided a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula (I), including enantiomers, stereoisomers, and tautomers of said compound and pharmaceutically acceptable salts, solvates or derivatives thereof, with said compound having the general structure shown in formula (I) as described herein.

As described herein, the pharmaceutical compositions of this invention feature β-tryptase inhibitory activity and thus are useful in treating any disease, condition or a disorder caused due to the effects of β-tryptase in a patient. Again, as described above, all of the preferred embodiments of the compounds of this invention as disclosed herein can be used in preparing the pharmaceutical compositions as described herein.

Preferably the pharmaceutical compositions of this invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. An erodible polymer containing the active ingredient may be envisaged. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Flavored unit dosage forms contain from 1 to 100 mg, for example 1 , 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The pharmaceutical compositions of this invention can be administered by any of the methods known in the art. In general, the pharmaceutical compositions of this invention can be administered by oral, intramuscular, subcutaneous, rectal, intratracheal, intranasal, intraperitoneal or topical route. The preferred administrations of the pharmaceutical composition of this invention are by oral and intranasal routes. Any of the known methods to administer pharmaceutical compositions by an oral or an intranasal route can be used to administer the composition of this invention.

In the treatment of various disease states as described herein, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 20 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day. This invention is further illustrated by the following examples which are provided for illustration purposes and in no way limit the scope of the present invention.

Examples (General)

As used in the examples and preparations that follow, the terms used therein shall have the meanings indicated: "kg" refers to kilograms, "g" refers to grams, "mg" refers to milligrams, Vg" refers to micrograms, "pg" refers to picograms, "lb" refers to pounds, "oz" refers to ounces, "mol" refers to moles, "mmol" refers to millimoles, mole" refers to micromoles, "nmole" refers to nanomoles, "L" refers to liters, "ml_" or "ml" refers to milliliters, "μΙ_" refers to microliters, "gal" refers to gallons, "°C" refers to degrees Celsius, "R_f " refers to retention factor, "mp" or "m.p." refers to melting point, "dec" refers to decomposition, "bp" or "b.p." refers to boiling point, "mm of Hg" refers to pressure in millimeters of mercury, "cm" refers to centimeters, "nm" refers to nanometers, "abs." refers to absolute, "cone." refers to concentrated, "c" refers to concentration in g/mL, "DMSO" refers to dimethyl sulfoxide, "DMF" refers to N,N- dimethylformamide, "CDI" refers to 1 ,1 '-carbonyldiimidazole, "DCM" or "CH₂CI₂" refers to dichloromethane, "DCE" refers to 1 ,2-dichloroethane, "HCI" refers to hydrochloric acid, "EtOAc" refers to ethyl acetate, "PBS" refers to Phosphate Buffered Saline, "IBMX" refers to 3-isobutyl-1 -methylxanthine, "PEG" refers to polyethylene glycol, "MeOH" refers to methanol, "MeNH₂" refers to methyl amine, "N₂" refers to nitrogen gas, "iPrOH" refers to isopropyl alcohol, "Et₂O" refers to ethyl ether, "LAH" refers to lithium aluminum hydride, "heptane" refers to n-heptane, "H MBA-AM" resin refers to 4-hydroxymethylbenzoic acid amino methyl resin, "PdCI₂(dppf)₂" refers to 1 ,1 '-bis(diphenylphosphino)ferrocene-palladium (II) dichloride DCM complex, "HBTU" refers to 2-(1 H-benzotriazol-1yl)-1 ,1 ,3,3-tetramethyluronium hexafluorophosphate, "DIEA" refers to diisopropylethylamine, "CsF" refers to cesium fluoride, "Mel" refers to methyl iodide, "AcN," "MeCN" or "CH₃CN"refers to acetonitrile, "TFA" refers to trifluoroacetic acid, "THF" refers to tetrahydrofuran, "NMP" refers to 1 -methyl-2- pyrrolidinone, "H₂O" refers to water, "BOC" refers to t-butyloxycarbonyl, "brine" refers to a saturated aqueous sodium chloride solution, "M" refers to molar, "mM" refers to millimolar, "μΜ" refers to micromolar, "nM" refers to nanomolar, "N" refers to normal, "TLC" refers to thin layer chromatography, "HPLC" refers to high performance liquid chromatography, "HRMS" refers to high resolution mass spectrum, "L.O.D." refers to loss on drying, "μΟ^'\" refers to microcuries, "i.p." refers to intraperitoneally, "i.v." refers to intravenously, anhyd = anhydrous; aq = aqueous; min = minute; hr = hour; d = day; sat. = saturated; s = singlet, d = doublet; t = triplet; q = quartet; m = multiplet; dd = doublet of doublets; br = broad; r.t. = room temperature; LC = liquid chromatograph; MS = mass spectrograph; ESI/MS = electrospray ionization/mass spectrograph; RT = retention time; M = molecular ion, "~" = approximately.

Reactions generally are run under a nitrogen atmosphere. Solvents are dried over magnesium sulfate and are evaporated under vacuum on a rotary evaporator. TLC analyses are performed with EM Science silica gel 60 F254 plates with visualization by UV irradiation. Flash chromatography is performed using Alltech prepacked silica gel cartridges. The ¹ H NMR spectra are run at 300 MHz on a Gemini 300 or Varian Mercury 300 spectrometer with an ASW 5 mm probe, and usually recorded at ambient temperature in a deuterated solvent, such as D₂O, DMSO-D₆ or CDCI3 unless otherwise noted. Chemical shifts values (δ) are indicated in parts per million (ppm) with reference to tetramethylsilane (TMS) as the internal standard.

High Pressure Liquid Chromatography-Mass Spectrometry (LCMS) experiments to determine retention times (RT) and associated mass ions are performed using one of the following methods:

Mass Spectra (MS) are recorded using a Micromass mass spectrometer. Generally, the method used was positive electro-spray ionization, scanning mass m/z from 100 to 1000. Liquid chromatography was performed on a Hewlett Packard 1 100 Series Binary Pump & Degasser; Auxiliary detectors used were: Hewlett Packard 1 100 Series UV detector, wavelength = 220 nm and Sedere SEDEX 75 Evaporative Light Scattering (ELS) detector temperature = 46°C, N₂ pressure = 4 bar.

LCT: Grad (AcN+0.05% TFA):(H₂O+0.05% TFA) = 5:95 (0 min) to 95:5 (2.5 min) to 95:5 (3 min). Column: YMC Jsphere 33x2 4 μΜ, 1 ml/min

MUX: Column: YMC Jsphere 33x2, 1 ml/min

Grad (AcN+0.05% TFA):(H2O+0.05% TFA) = 5:95 (0 min) to 95:5 (3.4 min) to 95:5 (4.4 min).

LCT2: YMC Jsphere 33x2 4 μΜ, (AcN+0.05%TFA):(H2O+0.05%TFA) = 5:95 (0 min) to 95:5 (3.4 min) to 95:5 (4.4 min) QU: YMC Jsphere 33x2 I ml/min, (AcN+0.08% formic acid):(H2O+0.1 % formic acid) = 5:95 (0 min) to 95:5 (2.5min) to 95:5 (3.0min)

The following examples describe the procedures used for the preparation of some of the compounds of this invention.

Example 1

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-indole-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride

Step A

3-Bromo-4-hydroxybenzylamine hydrobromide

The title compound was prepared according to the procedure by Smith, L.H. J. Med. Chem. 1977, vol. 20, pp. 1254-1258, using 4-hydroxybenzylamine as the starting material.

¹ H NMR (300 MHz, DMSO-c/6) δ 8.0 (bs, 2H), 7.6 (m, 1 H), 7.3 (m, 1 H), 7.0 (m, 1 H), 6.8 (m, 1 H), 3.9 (m, 2H).

Step B

(3-Bromo-4-hydroxy-benzyl)-carbamic acid tert-butyl ester

To a solution of 3-bromo-4-hydroxybenzylannine hydrobromide (18.4g, 65 mmol) in CH2CI2 (600 mL) was added DIEA (32 ml, 195 mmol) and Boc-anhydride (16.6 g, 78 mmol). The reaction mixture was stirred for 4 h and diluted with CH₂CI₂ (300 mL). The reaction mixture was washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by S1O₂ chromatography eluting with 2% MeOH/CH₂CI₂ to yield 19 g (96%) of the titled compound.

¹ H NMR (300 MHz, CDCI₃) δ 7.4 (m, 1 H), 7.15 (m, 1 H), 7.0 (m, 1 H), 6.8 (m, 1 H), 5.5 (m, 1 H), 4.2 (m, 2H), 1 .5 (s, 9H).

Step C

1 -Benzyl-5'(tert-butyloxycarbon l-aminomethyl)-spiro[piperidine-4,3'-benzo[b]furan]

The title compound was prepared in a similar manner according to the procedure by Allerton, C. et al., WO 075775, 2007 using (1 -benzyl-1 ,2,3,6- tetrahydropyridin-4-yl)methanol and (3-bromo-4-hydroxy-benzyl)-carbamic acid tert- butyl ester as the starting materials.

¹ H NMR (300 MHz, CDCI₃) δ 7.4 (m, 5H), 7.1 (m, 2H), 6.7 (m, 1 H), 4.8 (bs, 1 H), 4.4 (s, 2H), 4.2 (m, 2H), 3.5 (s, 2H), 2.9 (m, 2H), 2.0 (m, 4H), 1 .7 (m, 2H), 1 .4 (s, 9H); LCMS m/z: [M+H]⁺=409.

Step D

5'-(tert-butyloxycarbonyl-aminomethyl)-spiro[piperidine-4,3'-(2H)-benzo[b]furan]

A solution of 1 -Benzyl-5'(tert-butyloxycarbonyl-aminomethyl)-spiro[piperidine- 4,3'-benzo[b]furan] (6.0 g, 14.7 mmol) and 10% Pd/C (1 g) in 60 ml MeOH and acetic acid (1 ml) was subjected to H₂ at 50 psi for 5h. The reaction mixture was filtered through Celite and was concentrated down in vacuo. The reaction mixture was taken up in EtOAc and was washed with saturated NaHCO₄ (2X), brine, dried with Na₂SO , filtered and was concentrated in vacuo to give 4.54 g (97% yield) of the title compound.

¹ H NMR (300 MHz, CDCI₃) 5 7.1 (m, 2H), 6.8 (m, 1 H), 4.8 (bs, 1 H), 4.4 (s, 2H), 4.2 (m, 2H), 3.3 (s, 2H), 2.7 (m, 2H), 1 .8 (m, 2H), 1 .4 (s, 9H).

Step E

(2-Fluoro-5-trifluoromethoxy-phenyl)-carbamic acid ethyl ester

To a solution of 2-fluoro-5-methyl-phenylamine (50.72 g, 0.26 mol) and pyridine (27.3 mL, 0.34 mol) in THF (500 mL) at 0 °C was added ethyl chloroformate (32.2 mL, 0.39 mol) dropwise over a 30 min period. After 1 h, both LC/MS and TLC indicated that the reaction was completed. The reaction mixture was partitioned between H2O and EtOAc. The two layers are separated and the organic layer was washed with 1 M HCI, H₂O, and brine, dried over MgSO , filtered, and concentrated in vacuo. The crude material was purified on silica gel with heptane/EtOAc (95/5 to 70/30) as eluent to give 69.23 g (99%) of the product as a clear colorless liquid.

1 H NMR (300 MHz, CDCI₃) 5 8.1 1 (br s, 1 H), 7.07 (dd, J = 9.1 , 9.3 Hz, 1 H), 7.00-6.80 (m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1 .33 (t, J = 7.1 Hz, 3H);

1⁹F NMR (CDCI3, 300 MHz) 5 -57.84 (s, 3F), -134.01 (br s, 1 F);

LC Rt: 5.03 min; MS 309 (M+CH₃CN+1 , 100%), 268 (M+1 ).

Step F (6-Fluoro-2-iodo-3-methyl-phenyl)-carbannic acid ethyl ester

To a solution of (2-fluoro-5-trifluoromethoxy-phenyl)-carbamic acid ethyl ester (31 .34 g, 1 17.2 mmol) in THF (180 mL) at -78 °C was added sec-BuLi (1 .4 M in cydohexane, 200 mL, 280 mmol) dropwise over a 1 h period. After 20 min, a solution of I2 (44.6 g, 175.8 mmol) in THF (150 mL) was added dropwise over a 30 min period. This mixture was then stirred at -78 °C for 30 min. Saturated NH CI was added, and the cooling bath was removed. The reaction mixture was partitioned between H₂O and EtOAc. The two layers are separated, and the organic layer was washed with 10% Na₂SO3, H₂O, and brine, dried over MgSO₄, filtered, and concentrated in vacuo. The residue was suspended in CH2CI2 (50 mL), and heptane (300 mL) was added. The white powder (18.1 g, 39%) from the resulting suspension was collected by suction filtration and air-dried. The filtrate was concentrated in vacuo, and the residue was suspended in heptane (200 mL). Another batch of product (3.8 g, 8%) was collected by suction filtration and air-dried. More product can be obtained by purifying the filtrate via silica gel chromatography.

1 H NMR (300 MHz, CDCI₃) δ 7.30-17.10 (m, 2H), 6.16 (br s, 1 H), 4.26 (q, J = 7.1 Hz, 2H), 1 .32 (t, J = 7.1 Hz, 3H);

1⁹F NMR (300 MHz, CDCI₃) δ -56.90 (s, 3F), -1 14.35 (d, J = 8.5 Hz, 1 F);

LC Rt 3.01 min; MS 394 (M+1 , 100%), 374, 364, 321 , 267.

Step G

(6-Fluoro-3-methyl-2-trimethylsilanylethynyl-phenyl)-carbamic acid ethyl ester

A mixture of (6-fluoro-2-iodo-3-methyl-phenyl)-carbamic acid ethyl ester (18.1 g, 45.9 mmol), Et₃N (12.8 mL, 91 .9 mmol), Pd(PPh)₂CI₂ (1 .6 g, 5% mol), Cul (0.7 g, 8% mol), and TMS-acetylene (19.6 mL, 137.8 mmol) in degassed THF (180 mL) was heated at 60 °C overnight. The mixture was cooled to r.t., and then partitioned between H₂O and EtOAc. This mixture was filtered through Celite to remove the insoluble material. The two layers of the filtrate are separated, and the organic layer was washed H₂O and brine, dried over MgSO₄, filtered, and concentrated in vacuo. The crude material was purified on silica gel with heptane/EtOAc as eluent to give 15.6 g (93%) of the product as a beige solid.

¹ H NMR (300 MHz, CDCI₃) δ 7.15-7.00 (m, 2H), 6.41 (br s, 1 H), 4.26 (q, J = 7.1 Hz,

2H), 1 .31 (t, J = 7.1 Hz, 3H), 0.27 (s, 9H);

¹⁹F NMR (300 MHz, CDCI₃) δ -57.59 (s, 3F), -1 18.15 (s, 1 F);

LC Rt 4.1 1 min; MS 364 (M+1 , 100%).

Step H

7-Fluoro-4-trifluoromethoxy-1 H-indole

A mixture of (6-fluoro-3-methyl-2-trimethylsilanylethynyl-phenyl)-carbamic acid ethyl ester (28.9 g, 79.6 mmol) and KOH (35.7 g, 636.7 mmol) in degassed t-butanol (300 mL) was heated at 70 °C overnight. LC/MS indicated the reaction was completed. The mixture was cooled to r.t., and then partitioned between H₂O and Et₂O. The two layers are separated, and the aqueous layer was extracted with Et₂O (2x). The combined organic layers are washed with H₂O and brine, dried over MgSO₄, filtered, and concentrated in vacuo. The crude material was purified on silica gel with heptane/EtOAc (100/0 to 60/40) as eluent to give 16.0 g (91 %) of the product as a yellow liquid.

¹ H NMR (300 MHz, CDCI₃) δ 8.47 (br s, 1 H), 7.35-7.20 (m, 1 H), 6.95-6.80 (m, 2H), 6.68 (d, J = 2.5 Hz, 1 H);

¹⁹F NMR (300 MHz, CDCI₃) δ -57.63 (s, 3F), -136.10 (d, J = 8.5 Hz, 1 F);

LC Rt 3.55 min; MS 220 (M+1 , 100%), 200.

Step I

7-Fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-1 H-indole

A mixture of 7-fluoro-4-trifluoromethoxy-1 H-indole (16.0 g, 72.8 mmol) and powder KOH (20.4 g, 364.2 mmol) in DMSO (150 mL) was stirred at r.t. for 10 min. 2- Methoxyethyl bromide (10.3 mL, 109.2 mmol) was added. This mixture was stirred at r.t. overnight. LC/MS indicated the reaction was completed. The mixture was partitioned between H₂O and Et₂O. The two layers are separated, and the aqueous layer was extracted with Et₂O (2x). The combined organic layers are washed with H₂O and brine, dried over MgSO , filtered, and concentrated in vacuo. The crude material was purified on silica gel with heptane/EtOAc (100/0 to 50/50) as eluent to give 19.3 g (95%) of the product as a yellow liquid.

¹ H NMR (300 MHz, CDCI₃) δ 7.15 (d, J = 2.1 Hz, 1 H), 6.90-6.75 (m, 2H), 6.56 (t, J = 2.5 Hz, 1 H), 4.44 (t, J = 5.2 Hz, 2H), 3.72 (t, J = 5.2 Hz, 2H), 3.31 (s, 3H);

1⁹F NMR (300 MHz, CDCI₃) δ -57.54 (s, 3F), -137.00 (d, J = 1 1 .3 Hz, 1 F);

LC Rt 3.61 min; MS 278 (M+1 , 100%).

Step J 2,2,2-Trifluoro-1 -[7-fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-1 H-indol-3-yl]- ethanone

To a mixture of 7-fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-1 H-indole (19.3 g, 69.7 mmol) in DMF (135 ml_) was added TFAA (26.2 ml_, 188.2 mmol). This mixture was heated at 40 °C overnight. TLC indicates the reaction was completed. The mixture was cooled to r.t., and then partitioned between H₂O and Et₂O. The two layers are separated, and the aqueous layer was washed with saturated NaHCO3 (2x), H₂O and brine, dried over MgSO , filtered, and concentrated in vacuo. The crude material was purified on silica gel with heptane/EtOAc (100/0 to 50/50) as eluent to give 23.4 g (89%) of the product as a slightly green solid.

1 H NMR (300 MHz, CDCI₃) δ 8.03 (d, J = 1 .4 Hz, 1 H), 7.20-6.95 (m, 2H), 4.54 (t, J = 4.9 Hz, 2H), 3.76 (t, J = 4.8 Hz, 2H), 3.33 (s, 3H);

¹⁹F NMR (300 MHz, CDCI₃) δ -57.74 (s, 3F), -71 .10 (s, 3F), -134.95 (d, J

1 F);

LC Rt 3.88 min; MS 374 (M+1 , 100%).

Step K

7-Fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-1 H-indole-3-carboxylic acid

A mixture of 2,2,2-trifluoro-1 -[7-fluoro-1 -(2-nnethoxy-ethyl)-4-trifluoronnethoxy- 1 H-indol-3-yl]-ethanone (23.4 g, 62.6 mmol) in MeOH (100 mL) and 5 M NaOH (100 mL) was heated at 80 °C overnight. LC/MS indicates that the reaction was completed. The reaction mixture was cooled to r.t. and then concentrated in vacuo to remove most of the MeOH. The residue was dissolved in H₂O and then washed with Et₂O. The aqueous layer was slowly acidified to pH ~2 with cone. HCI. The acidified suspension was extracted with Et₂O and the organic layer was washed with H₂O and brine, dried over MgSO₄, filtered, and concentrated in vacuo. The residue was suspended in CH₂CI₂/heptane (10/90). The white powder (19.4 g, 96%) in the suspension was collected by suction filtration and air-dried.

¹ H NMR (300 MHz, CDCI₃) δ 8.02 (s, 1 H), 7.15-7.05 (m, 1 H), 7.00-6.90 (m, 1 H), 4.49

(t, J = 5.0 Hz, 2H), 3.75 (t, J = 4.9 Hz, 2H), 3.33 (s, 3H);

¹⁹F NMR (300 MHz, CDCI₃) δ -57.74 (s, 3F), -135.65 (d, J = 1 1 .3 Hz, 1 F);

LC Rt 3.06 min; MS 363 (M+CH3CN+1 ), 322 (M+1 , 100%).

Step L

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-indole-3-yl)-carbonyl-5'-(tert- butyloxycarbon l-aminomethyl)-spiro[piperidine-4,3'-(2H)-benzo[b]furan]

To a solution of 7-methyl-1 -(2-morpholin-4-yl-ethyl)-1 H-indole-3-carboxylic acid (642 mg, 2.0 mmol), 5'-(tert-butyloxycarbonyl-aminomethyl)-spiro[piperidine-4,3'- (2H)-benzo[b]furan] (636 mg, 2.0 mmol), 1 -(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (460 mg, 2.4 mmol) in CH₂CI₂ was added triethylamine (0.56 ml, 4.0 mmol). The resulting mixture was stirred at r.t. overnight. The mixture was diluted with EtOAc and washed with water, brine, dried over MgSO₄, filtered and concentrated in vacuo. Purification by flash chromatography on SiO₂ eluting with 80% ethyl acetate / heptane gives 0.43g (35% yield) of the titled compound. ¹ H NMR (300 MHz, CDCI₃) δ 7.4 (s, 1 H), 7.1 (m, 2H), 6.9 (m, 2H), 6.8 (m, 1 H), 4.8 (bs, 1 H), 4.4 (m, 4H), 4.3 (m, 2H), 3.8 (m, 2H), 3.3 (s, 3H), 3.1 (m, 2H), 1 .9 (m, 2H), 1 .8 (m, 2H), 1 .5 (m, 2H), 1 .4 (s, 9H);

LCMS m/z: [M+H]+=622.

Step M

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-indole-3-yl)-carbonyl-5'- aminomethyl-s iro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride

To a solution of 1 -(7-fluoro-1 -(2-methoxy-ethyl)-4-thfluoronnethoxy-indole-3-yl)- carbonyl-5'-(tert-butyloxycarbonyl-aminonnethyl)-spiro[pipehdine-4,3'-(2H)- benzo[b]furan] (430 mg, 0.69 mmol) in dioxane (5 mL) was added 2M HCI in dioxane (10 mL, 20.0 mmol). The reaction mixture was stirred for 2h then concentrated in vacuo. The residue was triturated with ether for 2h and the resulting solid collected to give 325 mg (84%) of the titled compound.

¹ H NMR (300 MHz, DMSO-c/6) δ 8.2 (bs, 2H), 7.7 (s, 1 H), 7.3 (m, 2H), 7.1 (m, 2H), 6.8 (m, 1 H), 4.5 (m, 4H), 3.9 (m, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 3.3 (s, 3H), 3.1 (m, 2H), 1 .8 (m, 2H), 1 .8-1 .6 (m, 4H);

LCMS m/z: [M+H]⁺=522.

EXAMPLE 2

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-aminomethyl-spiro[piperidine-

4,3'-(2H)-benzo[b]furan] hydrochloride

Step A

7-Fluoro-1 -(2-methox -ethyl)-1 H-indole

The title compound was prepared in a similar manner as in Example 1 , Step I, using 7-fluoro-1 H-indole as the starting material.

¹ H NMR (300 MHz, CDCI₃) δ 7.36 (d, J = 8.1 Hz, 1 H), 7.1 1 (d, J = 3 Hz, 1 H), 7.00- 6.95 (m, 1 H), 6.86 (dd, 1 H), 6.48 (m, 1 H), 4.45 (t, J = 5.7 Hz, 2H), 3.73 (t, J = 5.7 Hz, 2H), 3.30 (s, 3H);

¹⁹F NMR (300 MHz, CDCI₃) δ -135.93 (d, 3F).

Step B

-Trifluoro-1 -[7-fluoro-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-ethanone

The title compound was prepared in a similar manner as in Example 1 , Step J, using 7-fluoro-1 -(2-methoxy-ethyl)-1 H-indole as the starting material. ¹ H NMR (300 MHz, CDCI₃) δ 8.00 (d, 1 H), 7.96 (s, 1 H), 7.30-7.25 (m, 1 H), 7.05 (dd, 1 H), 4.53 (t, J = 5.1 Hz, 2H), 3.77 (t, J = 5.1 Hz, 2H), 3.32 (s, 3H);

1⁹F NMR (300 MHz, CDCI₃) δ -72.25 (s, 3F), -134.23 (s, 1 F).

Step C

7-Fluoro-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid

The title compound was prepared in a similar manner as in Example 1 , Step K, using 2,2,2-trifluoro-1 -[7-fluoro-1 -(2-methoxy-ethyl)-1 H-indol-3-yl]-ethanone as the starting material.

¹ H NMR (300 MHz, DMSO-c/6) δ 12.17 (s, 1 H), 8.04 (s, 1 H), 7.83 (d, J = 7.5 Hz, 1 H), 7.18-7.1 1 (m, 1 H), 7.08-7.01 (m, 1 H), 4.50 (t, J = 5.1 Hz, 2H), 3.69 (t, J = 5.1 Hz, 2H), 3.22 (s, 3H);

¹⁹F NMR (300 MHz, DMSO-c/6) δ -134.07 (d, 1 F).

Step D

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-(tert-butyloxycarbonyl- aminometh l)-spiro[piperidine-4,3'-(2H)-benzo[b]furan]

The title compound was prepared in a similar manner as in Example 1 , Step L, using 7-fluoro-1 -(2-methoxy-ethyl)-1 H-indole-3-carboxylic acid and 5'-(tert- butyloxycarbonyl-aminomethyl)-spiro[piperidine-4,3'-(2H)-benzo[b]furan] as the starting materials. ¹ H NMR (300 MHz, CDCI₃) δ 7.5 (m, 2H), 7.1 (m, 3H), 6.9 (m, 1 H), 6.75 (d, 1 H), 4.8 (bs, 1 H), 4.5 (m, 4H), 4.4 (m, 2H), 4.3 (m, 2H), 3.8 (t, 2H), 3.3 (s, 3H), 3.2 (m, 2H), 1 .9 (m, 2H), 1 .8 (m, 2H), 1 .4 (s, 9H);

LCMS m/z: [M+H]+=538.

Step E

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-aminomethyl-spiro[piperidi

4 3'-(2H)-benzo[b]furan] hydrochloride

The title compound was prepared in a similar manner as in Example 1 , Step M, using 1 -(7-fluoro-1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-(tert- butyloxycarbonyl-aminomethyl)-spiro[piperidine-4,3'-(2H)-benzo[b]furan] as the starting material.

¹ H NMR (300 MHz, DMSO-c/6) δ 8.2 (bs, 2H), 7.8 (s, 1 H), 7.5 (m, 2H), 7.4 (m, 2H), 7.2 (m, 1 H), 6.8 (d, 1 H), 4.5 (m, 4H), 4.2 (m, 2H), 3.9 (m, 2H), 3.7 (m, 2H), 3.3 (m, 2H), 3.2 (s, 3H), 1 .83 (m, 2H), 1 .9-1 .7 (m, 4H);

LCMS m/z: [M+H]⁺=438.

EXAMPLE 3

1 -(7- Trifluoromethoxy -1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-aminomethyl- spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride

Step A

(2-Trifluoromethox -phenyl)-carbannic acid ethyl ester

To a solution of 2-(thfluoromethoxy)aniline (15.9 g, 0.09 mol) in DME (300 mL) at -5 °C (ice/salt bath) was added sodium hydride (3.6 g, 60% by weight, 0.09 mol) in portions. The suspension was warmed to r.t. and ethyl chloroformate (7.5 mL, 0.08 mol) was added dropwise. The reaction mixture was stirred for 2 h at r.t. then heated to reflux for 1 .5 h. The mixture was then cooled to r.t. and water (150 mL) was slowly added to quench the reaction. The phases are separated and the water layer was extracted with EtOAc (2x100 mL). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified on silica gel with EtOAc/heptanes (1 -5%) as eluent to give 1 1 .0 g (49%) of the titled product as an amber oil.

¹ H NMR (300 MHz, CDCI₃) δ 8.20 (d, J = 8.1 Hz, 1 H), 7.30-7.22 (m, 2H), 7.07 (app t, 1 H), 6.90 (br s, 1 H), 4.25 (q, J = 7.2 Hz, 2H), 1 .34 (t, J = 7.2 Hz, 3H);

1⁹F NMR (300 MHz, CDCI₃) δ -57.32 (s, 3F);

LC Rt: 2.96 min; LCMS m/z: [M+H]⁺=250.

Step B

(2-lodo-6-trifluoromethoxy-phenyl)-carbamic acid ethyl ester

To a solution of (2-trifluoromethoxy-phenyl)-carbamic acid ethyl ester (1 1 .0 g, 44.2 mmol) in THF (200 mL) at -78 °C was added sec-BuLi (1 .3 M in cyclohexane, 71 .4 mL, 92.8 mmol) dropwise. After 1 h, a solution of I2 (1 1 .22 g, 44.2 mmol) in THF (42 mL) was added dropwise. The resulting orange mixture was stirred at -78 °C for 40 min then saturated NH CI (200 mL) was added, and the cooling bath was removed. The reaction mixture was partitioned between H₂O and diethyl ether. The two layers are separated, and the organic layer was washed with 50% Na₂SO3, H₂O and brine, dried over MgSO , filtered, and concentrated in vacuo to give 14.9g (90%) of a yellow/orange solid as the titled product.

¹ H NMR (300 MHz, CDCI₃) δ 7.81 (d, J = 8.1 Hz, 1 H), 7.29 (m, 1 H), 7.05 (app t, 1 H), 6.10 (br s, 1 H), 4.24 (q, J = 7.2 Hz, 2H), 1 .33 (t, J = 7.2 Hz, 3H);

1⁹F NMR (300 MHz, CDCI₃) δ -57.28 (s, 3F);

LC Rt 2.93 min; LCMS m/z: [M+H]⁺=375.

Step C

(2-Trifluoromethoxy-6-trimeth lsilanylethynyl-phenyl)-carbamic acid ethyl ester

Bis(triphenylphosphine)palladium (II) dichloride (210 mg, 0.30 mmol) and Cul (57 mg, 0.30 mmol) was added to TEA (1 10 mL) and heated to 80 °C for 20 min. The mixture was cooled to r.t. then (2-iodo-6-trifluoromethoxy-phenyl)-carbamic acid ethyl ester (1 1 .2 g, 29.9 mmol) was added and stirred for 30 min. TMS-acetylene (4.0 mL, 28.4 mmol) was then added dropwise to the reaction mixture and the resulting solution was stirred at r.t. for 1 .5 h. Triethylamine was removed in vacuo and the residue was partitioned between water and Et₂O. The organic layer was washed with 1 N HCI, brine and dried over MgSO , filtered and concentrated in vacuo. The crude material was purified on silica gel with EtOAc/heptane (5-6 %) as eluent to give 8.4 g (81 %) of the titled product as a yellow solid.

¹ H NMR (300 MHz, CDCI₃) δ 7.41 (d, J = 7.5 Hz, 1 H), 7.29-7.13 (m, 2H), 6.32 (br s, 1 H), 4.23 (q, J = 7.2 Hz, 2H), 1 .30 (t, J = 7.1 Hz, 3H), 0.26 (s, 9H);

LC Rt 3.56 min; LCMS m/z: [M+H]⁺=346.

Step D

7-Trifluoromethoxy-1 H-indole

KOH (1 .95 g, 34.8 mmol) was heated to 80 °C in t-butanol (55 ml_) for 2 hr during which time the solution becomes homogeneous and clear. (2- Trifluoromethoxy-6-trimethylsilanylethynyl-phenyl)-carbamic acid ethyl ester (5.214 g, 15.1 mmol) was added to the solution and heated at 80 °C for 2h. The solvent was removed in vacuo and the residue partitioned between Et₂O and water. The organic layer was washed with brine, dried over MgSO₄, filtered and concentrated in vacuo. The crude material was purified on silica gel with EtOAc/heptanes (1 -5%) as eluent to give 1 .82 g (60%) of the titled product as a yellow liquid.

¹ H NMR (300 MHz, CDCI₃) δ 8.40 (br s, 1 H), 7.58-7.55 (m, 1 H), 7.25 (m, 1 H), 7.09-

7.07 (m, 2H), 6.62-6.60 (m, 1 H);

¹⁹F NMR (300 MHz, CDCI₃) δ -57.50 (s, 3F);

CHN: Theoretical: C 53.74%, H 3.01 %, N 6.96%. Found: C 53.86%, H 3.14%, N 6.97%.

Step E

1 -(2-Methoxy-eth l)-7-trifluoromethoxy-1 H-indole

The title compound was prepared in a similar manner as in Example 1 , Step I, using 7-trifluoromethoxy-1 H-indole as the starting material.

¹ H NMR (300 MHz, CDCI₃) δ 7.50 (d, 1 H), 7.15 (d, J = 3.0 Hz, 1 H), 7.05-7.03 (m, 2H), 6.51 (d, J = 3.3 Hz, 1 H), 4.46 (t, J = 5.4 Hz, 2H), 3.70 (t, J = 5.4 Hz, 2H), 3.30 (s, 3H);

¹⁹F NMR (300 MHz, CDCI₃) δ -56.45 (s, 3F);

LCMS m/z: [M+H]⁺=260.

Step F

2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indol-3-yl]-ethanone

To a mixture of 1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole (1 .898 g, 7.32 mmol) in DMF (14 mL) at 0 °C was added TFAA (1 .2 mL, 8.63 mmol) dropwise. After addition was completed, the reaction mixture was stirred at 0 °C for 3.5h and then poured into ice water (50 mL). The solid precipitate was collected and can be used in subsequent steps or taken up in water/EtOAc and further worked up as follows. The two layers are separated, and the organic layer was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude orange solid (2.6 g, 100%) can be taken on to the next step without further purification.

1 H NMR (300 MHz, CDCI₃) δ 8.35 (d, J = 9 Hz, 1 H), 8.01 (s, 1 H), 7.33 (app t, 1 H), 7.26 (m, 1 H), 4.55 (t, J = 6 Hz, 2H), 3.75 (t, J = 6 Hz, 2H), 3.32 (s, 3H);

1⁹F NMR (300 MHz, CDCI₃) δ -56.41 (s, 3F), -72.16 (s, 3F);

LC Rt 3.59 min; LCMS m/z: [M+H]⁺=356.

Step G

1 -(2-Methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic acid

2,2,2-Trifluoro-1 -[1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indol-3-yl]- ethanone (1 .655 g, 4.66 mmol) in 5 N NaOH (20 mL) was heated at 90 °C for two days. The reaction mixture was cooled to r.t., and then washed with CH2CI2 (3x30 mL). The aqueous layer was slowly acidified to pH ~4 with cone. HCI and the white powder was collected by suction filtration and air-dried to give the titled product (0.923 g, 65%). ¹ H NMR (300 MHz, CDCI₃) δ 8.17 (d, J = 6 Hz, 1 H), 7.97 (s, 1 H), 7.27-7.22 (m, 7.18-7.15 (m, 1 H), 4.52 (t, J = 6 Hz, 2H), 3.74 (t, J = 6 Hz, 2H), 3.32 (s, 3H);

1⁹F NMR (300 MHz, CDCI₃) δ -56.34 (s, 3F);

LC Rt 3.17 min; MS 345 (M+CH₃CN+1 ), 304 (M+1 , 100%).

Step H

1 -(7-Trifluoromethoxy-1 -(2-nnethoxy-ethyl)-indole-3-yl)-carbonyl-5'-(tert- butyloxycarbon l-aminomethyl)-spiro[piperidine-4,3'-(2H)-benzo[b]furan]

The title compound was prepared in a similar manner as in Example 1 , Step L, using 1 -(2-methoxy-ethyl)-7-trifluoromethoxy-1 H-indole-3-carboxylic acid and 5'-(tert- butyloxycarbonyl-aminomethyl)-spiro[piperidine-4,3'-(2H)-benzo[b]furan] as the starting materials.

¹ H NMR (300 MHz, CDCI₃) δ 7.7 (d, 2H), 7.5 (s, 1 H), 7.1 (m, 4H), 6.8 (d, 1 H), 4.8 (bs, 1 H), 4.5 (m, 4H), 4.4 (m, 2H), 4.3 (m, 2H), 3.7 (t, 2H), 3.3 (s, 3H), 3.2 (m, 2H), 1 .9 (m, 2H), 1 .8 (m, 2H), 1 .4 (s, 9H);

LCMS m/z: [M+H]⁺=604.

Step I

1 -(7- Trifluoromethoxy -1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-aminomethyl- spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride

The title compound was prepared in a similar manner as in Example 1 , Step M, using 1 -(7-trifluoromethoxy-1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-(tert- butyloxycarbonyl-aminomethyl)-spiro[piperidine-4,3'-(2H)-benzo[b]furan] as the starting material.

¹ H NMR (300 MHz, CDCI₃) δ 8.1 (bs, 2H), 7.8 (s, 1 H), 7.7 (m, 1 H), 7.4 (m, 1 H), 7.2 (m, 3H), 6.8 (d, 1 H), 4.5 (m, 4H), 4.2 (m, 2H), 3.9 (m, 2H), 3.7 (m, 2H), 3.3 (m, 2H), 3.2 (s, 3H), 1 .83 (m, 4H);

LCMS m/z: [M+H]⁺=504.

EXAMPLE 4

1 -(1 -(2-Methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-yl)-carbonyl-5'- aminomethyl-s iro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride

Step A

7-Methyl-1 H- rrolo[3,2-b]pyridine

The title compound was prepared according to the following procedure: Journal of Organic Chemistry, 2002, vol. 67(7), pp. 2345-2347.

1 H NMR (300 MHz, CDCI₃) δ 1 1 .4 (bs, 1 H), 8.2 (d, 1 H), 7.6 (d, 1 H), 6.9 (d, 1 H), 6.5 (d, 1 H), 3.3 (s, 3H);

LCMS m/z: [M+H]⁺=133.

Step B

3-lodo-7-methyl-1 H-pyrrolo[3,2-b]pyridine

To a solution of 7-methyl-1 H-pyrrolo[3,2-b]pyridine (0.5 g, 3.79 mmol) in THF (30 mL) was added N-iodosuccinimide (0.337 g, 4.2 mmol). The reaction mixture was stirred for 2 h and concentrated in vacuo. Purification by flash chromatography on S1O2 eluting with 50% ethyl acetate/heptane gives 0.92 g, (94%) of the desired product.

¹ H NMR (300 MHz, DMSO-c/6) δ 1 1 .9 (bs, 1 H), 8.2 (d, 1 H), 7.8 (s, 1 H), 7.0 (d, 1 H), 6.5 (d, 1 H), 3.3 (s, 3H);

LCMS m/z: [M+H]⁺=259.

Step C

3-lodo-1 -(2-methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine

The title compound was prepared in a similar manner as in Example 1 , Step I, using 3-iodo-7-methyl-1 H-pyrrolo[3,2-b]pyridine as the starting material.

1 H NMR (300 MHz, DMSO-c/6) δ 8.4 (d, 1 H), 7.4 (s, 1 H), 6.9 (d, 1 H), 4.45 (t, 2H), 3.65 (t, 2H), 3.3 (s, 3H), 2.7 (s, 3H);

LCMS m/z: [M+H]⁺=317.

Step D

1 -(2-Methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-carboxylic acid trifluoro- acetic acid salt

The title compound was prepared in a similar manner according to the procedure by Lefoix, M. et al., Synthesis, 2005, vol. 20, pp. 3581 -3588 using 3-iodo- 1 -(2-methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine as the starting material.

1 H NMR (300 MHz, DMSO-c/6) δ 8.7 (s, 1 H), 8.5 (d, 1 H), 7.6 (d, 1 H), 4.75 (t, 2H), 3.75 (t, 2H), 3.2 (s, 3H), 2.95 (s, 3H);

LCMS m/z: [M+H]⁺=235.

Step E

1 -(1 -(2-Methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-yl)-carbonyl-5'-(tert- butyloxycarbonyl-aminomethyl)-spiro[piperidine-4,3'-(2H)-benzo[b]furan]

trifluoroacetic acid salt

The title compound was prepared in a similar manner as in Example 1 , Step L, using 1 -(2-methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-carboxylic acid trifluoro-acetic acid salt and 5'-(tert-butyloxycarbonyl-aminomethyl)-spiro[piperidine- 4,3'-(2H)-benzo[b]furan] as the starting materials. The product was purified by RP- HPLC eluting in a gradient of 10% CH₃CN/H₂O (adjusted with TFA to pH=3.5) to 100% CH₃CN. The appropriate fractions are combined and lyophilized to give the title compound. ¹ H NMR (300 MHz, CDCI₃) δ 8.6 (m, 1 H), 8.2 (m, 1 H), 7.4 (m, 1 H), 7.1 (m, 2H), 6.8 (m, 1 H), 4.7 (m, 2H), 4.5 (m, 2H), 4.2 (m, 4H), 3.6-3.8 (m, 5H), 3.3 (s, 3H), 3.2 (s, 3H), 1 .9 (m, 2H), 1 .8 (m, 2H), 1 .4 (s, 9H);

LCMS m/z: [M+H]⁺=535.

Step F

1 -(1 -(2-Methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-yl)-carbonyl-5'- aminonnethyl-spiro ipendine-4,3'-(2H)-benzo[b]furan] hydrochloride

The title compound was prepared in a similar manner as in Example 1 , Step M, using 1 -(1 -(2-methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-yl)-carbonyl-5'- (tert-butyloxycarbonyl-aminomethyl)-spiro[piperidine-4,3'-(2H)-benzo[b]furan] trifluoroacetic acid salt as the starting material.

¹ H NMR (300 MHz, CD₃OD) δ 8.5 (m, 2H), 7.6 (m, 1 H), 7.4 (m, 1 H), 7.3 (m, 1 H), 6.8 (m, 1 H), 4.6 (m, 4H), 4.1 (m, 2H), 3.8-3.6 (m, 8H), 3.3 (s, 3H), 3.2 (s, 3H), 2.1 (m, 2H), 1 .9 (m, 2H);

LCMS m/z: [M+H]⁺=435.

Biological Activity

The properties of the compound of the present invention are demonstrated by: 1 ) its beta-Tryptase Inhibitory Potency (IC₅o and K, values).

IN VITRO TEST PROCEDURE

As all the actions of tryptase, as described in the background section, are dependent on its catalytic activity, then compounds that inhibit its catalytic activity will potentially inhibit the actions of tryptase. Inhibition of this catalytic activity may be measured by the in vitro enzyme assay and the cellular assay.

Tryptase inhibition activity is confirmed using either isolated human lung tryptase or recombinant human beta tryptase expressed in yeast cells. Essentially equivalent results are obtained using isolated native enzyme or the expressed enzyme. The assay procedure employs a 96 well microplate (Costar 3590) using L- pyroglutamyl-L-prolyl-L-arginine-para-nitroanilide (S2366: Quadratech) as substrate (essentially as described by McEuen et. al. Biochem Pharm, 1996, 52, pages 331 - 340). Assays are performed at room temperature using 0.5mM substrate (2 x K_m) and the microplate is read on a microplate reader (Beckman Biomek Plate reader) at 405 nm wavelength.

Materials and Methods for Tryptase primary screen (Chromogenic assay)

Assay buffer

50 mM Tris (pH 8.2), 100 mM NaCI, 0.05% Tween 20, 50 μg/mL heparin.

Substrate

S2366 (Stock solutions of 2.5 mM).

Enzyme

Purified recombinant beta Tryptase Stocks of 310 μg mL.

Protocol (Single point determination)

• Add 60 μΙ_ of diluted substrate (final concentration of 500 μΜ in assay buffer) to each well

• Add compound in duplicates , final concentration of 20 μΜ, volume 20 μΙ_

• Add enzyme at a final concentration of 50 ng/mL in a volume of 20 μΙ_

• Total volume for each well is 100 μΙ_

• Agitate briefly to mix and incubate at room temp in the dark for 30 minutes

• Read absorbencies at 405 nM

Each plate has the following controls:

Totals : 60 μΙ_ of substrate, 20 μΙ_ of buffer (with 0.2% final concentration of

DMSO),

20 μΙ_ of enzyme

Non-specific: 60 μΙ_ of substrate, 40 μΙ_ of buffer (with 0.2% DMSO) Totals: 60 μΙ_ of substrate, 20 μΙ_ of buffer (No DMSO), 20 μΙ_ of enzyme

Non-specific: 60 μΙ_ of substrate, 40 μΙ_ of buffer (No DMSO)

Protocol (ICgn and K, determination)

The protocol is essentially the same as above except that the compound is added in duplicates at the following final concentrations: 0.01 , 0.03, 0.1 , 0.3, 1 , 3, 10 μΜ (All dilutions carried out manually). For every assay, whether single point or IC₅o determination, a standard compound is used to derive IC₅o for comparison. From the IC₅o value, the K, can be calculated using the following formula: K, = IC₅o/(1 + [Substrate]/K_m).

The compounds of this invention display beta-Tryptase inhibition in the range of 1 μΜ to <1 nM.

Although the invention has been illustrated by certain of the preceding examples, it was not to be construed as being limited thereby; but rather, the invention encompasses the generic area as hereinbefore disclosed. Various modifications and embodiments can be made without departing from the spirit and scope thereof.

Claims

CLAIMS What is claimed is:

1 . A compound of formula (I)

wherein

R1 is alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl;

R2 and R3 are each independently H, halo, alkoxy, haloalkoxy, alkyl, amido, ureyl, carboxyl, sulfonyl amido, sulfonyl urea or alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

W1 , W2, W3 or W4 is each independently N, CH, CR2 or CR3; or

a salt thereof or an enantiomer or a diastereomer thereof.

2. The compound according to claim 1 , wherein R is indolyl that is optionally

substituted.

3. The compound of claim 1 selected from the group consisting of:

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-indole-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; 1 -(7-Fluoro-1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-aminomethyl- spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride;

1 -(7- Trifluoromethoxy -1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; and

1 -(1 -(2-Methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-yl)-carbonyl-5'- anninonnethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; or a salt thereof or an enantiomer or a diastereomer thereof.

4. A pharmaceutical composition comprising a compound of formula (I):

wherein

R1 is alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl;

R2 and R3 are each independently H, halo, alkoxy, haloalkoxy, alkyl, amido, ureyl, carboxyl, sulfonyl amido, sulfonyl urea or alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

W1 , W2, W3 or W4 is each independently N, CH, CR2 or CR3; or a pharmaceutically acceptable salt thereof or an enantiomer or a diastereomer thereof in combination with at least one pharmaceutically acceptable excipient, diluent or a carrier.

5. The composition according to claim 4, wherein the compound is selected from the group consisting of:

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-indole-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; 1 -(7-Fluoro-1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-aminomethyl- spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride;

1 -(7- Trifluoromethoxy -1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; and

1 -(1 -(2-Methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; or a pharmaceutically acceptable salt thereof.

6. A method of treating a disease in a patient, said disease selected from the group consisting of joint inflammation, including arthritis, rheumatoid arthritis and other arthritic condition such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, osteoarthritis or other chronic inflammatory joint disease, or diseases of joint cartilage destruction, ocular conjunctivitis, vernal conjunctivitis, inflammatory bowel disease, asthma, allergic rhinitis, interstitial lung diseases, fibrosis, sceleroderma, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, neurofibromas, hypertrophic scars, various dermatological conditions, for example, atopic dermatitis and psoriasis, myocardial infarction, stroke, angina or other consequences of atherosclerotic plaque rupture, as well as periodontal disease, diabetic retinopathy, macular degeneration, acute macular degeneration, wet macular degeneration, tumour growth, anaphylaxis, multiple sclerosis, peptic ulcers, or a syncytial viral infection; comprising administering to said patient a therapeutically effective amount of a compound of formula (I):

(I)

wherein

R1 is alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl;

R2 and R3 are each independently H, halo, alkoxy, haloalkoxy, alkyl, amido, ureyl, carboxyl, sulfonyl amido, sulfonyl urea or alkyl optionally substituted by one or more groups selected from hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl and heteroaryl;

W1 , W2, W3 or W4 is each independently N, CH, CR2 or CR3; or

a pharmaceutically acceptable salt thereof or an enantiomer or a diastereomer thereof optionally in combination with one or more pharmaceutically acceptable excipient, diluent or a carrier.

7. The method according to claim 6, wherein the compound is selected from the group consisting of:

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-4-trifluoromethoxy-indole-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride;

1 -(7-Fluoro-1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'-aminomethyl- spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; 1 -(7- Trifluoromethoxy -1 -(2-methoxy-ethyl)-indole-3-yl)-carbonyl-5'- aminonnethyl-spiro[pipendine-4,3'-(2H)-benzo[b]furan] hydrochloride; and

1 -(1 -(2-Methoxy-ethyl)-7-methyl-1 H-pyrrolo[3,2-b]pyridine-3-yl)-carbonyl-5'- aminomethyl-spiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; or a pharmaceutically acceptable salt thereof.