TW201136938A - 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. Additionally, this invention also discloses methods of preparation of substituted spiropiperidine benzylamines.

Description

201136938 VI. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to a series of substituted spiropiperidinamides. The compound of the present invention is an inhibitor of ?-tryptase' and thus can be used as a medicament. Furthermore, the invention relates to a process for the preparation of substituted spiropiperidinamides and intermediates thereof. [Prior Art] Mast cell-mediated inflammatory conditions, especially asthma, are a public health problem of concern. The hallmark of asthma is often described as the progressive development of the excessive response of the trachea and bronchus to immune-specific allergens and general chemical and physical stimuli. This progressive development leads to the development of chronic inflammation. Leukocytes containing IgE receptors, especially mast cells and basophils, are present in the epithelial and inferior smooth muscle tissues of the bronchi. These leukocytes are initially activated by the binding of specific IgE receptor antigens inhaled and then release many chemical mediators. For example, the degranulation of mast cells results in the release of proteoglycans, peroxidases, arylsulfatase B, chymase and tryptase, resulting in contraction of the bronchioles. Tryptase is stored in the secretory granules of mast cells and is the main protease of human mast cells. Tryptase involves a variety of biological processes, including the degradation of neuropeptides that cause vasodilation and bronchial relaxation (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 Tam, et al" Am. J. Respir. Cell Mol. Biol., 1990, 3, pages 27-32) and for the bronchi The regulation of histamine response (sekizawa, et 201136938 al., J. Clin. Invest., 1989, 83, pages 175-179). Therefore, tryptase inhibitors can be used as anti-inflammatory drugs (KRice, PA Sprengler, Current Opinion in Drug Discovery and Development, 1999, 2(5), pages 463_474), especially in the treatment of chronic asthma (MQ Zhang, H. Timmerman, Mediators Inflamm., 1997, 112, pages 311-317), and may be used to treat or prevent allergic rhinitis (SJ Wilson et al, Clin. Exp. Allergy, 1998, 28, pages 220-227), Inflammatory bowel disease (SC Bischoff et al, Histopathology, 1996, 28, pages 1-13), psoriasis (a. Naukkarinen et al, Arch. Dermatol. Res, 1993, 285, pages 341-346), conjunctivitis ( AAIrani 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), class Rheumatoid arthritis (LC Tetlow et al, Ann. Rheum. Dis., 1998, 54, pages 549-555), osteoarthritis (MG Buckley et al, J. Pathol 1998, 186, pages 67-74), Gouty arthritis, rheumatoid spondylitis, and various diseases of articular cartilage damage.

In addition, tryptase has been shown to be a strong fibroblast mitogen, indicating involvement in pulmonary fibrosis, asthma and interstitial lung disease (RU0SS et al., J. Clin. Invest) 1991, 88, pages 493 -499) Therefore, tryptase inhibitors can be used to treat or prevent fibrotic disorders (JA Cairns and AF Walls, J. Clin. Invest., 1997 99 pages 1313-1321 ), such as fibrosis, scleroderma, lung Fibrosis, cirrhosis, myocardial fibrosis, neurofibromatosis, and proliferative lesions. In addition, tryptase inhibitors can be used to treat or prevent myocardial infarction, 4 201136938 Stroke 'angina pectoris and other consequences of atherosclerotic plaque rupture (Μ.

Jeziorska et al, J. Pathol·, 1997, 182, pages 115_122). It has also been found that tryptase activates the pro-stromal lysin, which in turn activates collagenase to cause damage to cartilage and periodontal connective tissue, respectively. Thus, tryptase inhibitors can be used to treat or prevent arthritis, periodontal disease, diabetic retinopathy, and tumor growth (WJ Beil et al, Exp. Hematol, (1998) 26, pages 158-169). Moreover, tryptase inhibitors can be used to treat allergies (LB Schwarz et al, J. Clin. Invest., 1995, 96, pages 2702-2710), multiple sclerosis (M. Steinhoff et al, Nat. Med. ( NY), 2000, 6(2), pages 15M58), peptic ulcer and syncytial virus infection. Such compounds should be readily available for the treatment of patients with symptoms that are ameliorated by the administration of tryptase inhibitors, such as mast cell-mediated inflammatory symptoms, inflammation, and processes associated with the degradation of neuropeptides that cause vasodilation and bronchial relaxation. A disease or disorder that is not easily metabolized by the aminourea-sensitive amine oxidase (SSAO) metabolic mechanism. As the most abundant serine protease, β-tryptase is only present in mast cell granules and is released after stimulation of the IgE receptor by allergens. In experimental animals, the release of beta-tryptase causes inflammation and bronchial tightening, a feature of human asthma. It is also believed to cause activation of fibroblasts and thus play a role in the remodeling of the respiratory tract. The concentration of β-tryptase in bronchoalveolar lavage fluid (BALF) in asthma patients increased. A clinical proof of asthma (bronchial allergen stimulation) with an inhaled sputum-tryptase inhibitor (APC_366_ terminated due to bronchial irritation) has been reported for 201136938. Beta-tryptase inhibitors have the potential to affect the symptoms and pathogenesis of many pro-inflammatory signs, especially asthma and potential C〇PD. A trypsin inhibitor containing benzylamine, as a universal serine protease inhibitor, is also recognized as a substrate for amine oxidase, especially SSAO. WO 2009067202 discloses a range of compounds, including substituted spiropilottes, which can be used as tryptase inhibitors. However, the compounds disclosed herein do not include the snail D-benzylamine of the present invention.

Costanzo, MJ et al. in "Potent, nonpeptide inhibitors of human mast cell tryptase.* Synthesis and biological evaluation of novel spirocyclic piperidine amide derivatives" ("The efficacy of human mast cell tryptase, non-peptide inhibitors: novel spiro rings Synthesis and Biological Evaluation of Piperidamine Derivatives, ά C/iem 如/TkMeri1, 2008, vol. 18, pp. 2114-2121) - A series of compounds, including substituted spiropyridae, are disclosed Used as a membrane-like protease inhibitor. However, the compounds disclosed herein do not include the spiropiperidine benzylamine of the present invention.

All references cited herein are incorporated by reference in their entirety. It is an object of the invention to provide a series of substituted spiropiperidine T amines which are inhibitors of beta-tryptase. Another object of the present invention is to provide a method of making a replacement "shirt" as disclosed herein. Other objects of the present invention and further scope of applicability will become apparent from the following detailed description. 6 201136938 SUMMARY OF THE INVENTION The present invention provides substituted spiropiperidinylamines of formula (I), stereoisomers, enantiomers, racemates and tautomers of the compounds And a pharmaceutically acceptable salt thereof, as an inhibitor of β-tryptase, and a method of treating diseases and disorders using the compound of the formula (I) as a pharmaceutical preparation. Thus, in accordance with an embodiment of the present invention, a compound of formula (I) is provided:

Vn:

R (I) where R=

R2 Corpse R3 R1 wherein R1 is alkyl, which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl Alkenyl, optionally substituted aryl, heteroaryl and optionally substituted heteroaryl; R2 and R3 are each independently H, halo, alkoxy, haloalkyl 201136938 oxy, alkyl, decylamino a ureido group, a carboxyl group, a sulfonyl decylamino group, a sulfonyl urea or an alkyl group optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, an alkoxy group, a halogenated alkoxy group, and a ring-burning group. a group, a heterocyclic group, an aryl group, and a heteroaryl group; W1, W2, W3 or W4 are each independently N, CH, CR2 or CR3. The invention further encompasses various salts of the compounds of formula (I), including the various enantiomers or diastereomers of the compounds of the formula. A further embodiment of the invention relates to a method of inhibiting 0-type trypsin activity in a patient' comprising administering to said patient a therapeutic amount of a β-membrane protease inhibiting sword. Another embodiment of the present invention relates to a method of inhibiting tryptase activity in a patient' comprising administering to the patient a therapeutic amount of a compound of formula (1). Another embodiment of the present invention relates to a A method of treating a patient having a disease or disorder ameliorated by inhibition of Ρ-membrane protease comprises administering to the patient a therapeutically effective amount of a compound of formula (I). In other aspects of the invention, there are also provided various pharmaceutical compositions containing one or more compounds of formula (I), and their therapeutic use in alleviating various diseases which are ameliorated by inhibition of ρ-like ceramide. DETAILED DESCRIPTION OF THE INVENTION The terms used herein have the following meanings: As used herein, the expression "(Ci-C4)alkyl" includes fluorenyl and ethyl, 8 201136938 and straight or branched propyl and butyl. . Preferred alkyl groups are methyl, ethyl, n-propyl, isopropyl and t-butyl. The extended expressions such as "(crc4) alkoxy", "(CrC4) alkoxy (CrC4) alkyl", or "hydroxyl (CrCO alkyl)" should also be interpreted accordingly. The expression used herein (crc6 "Perfluoroalkyl" means that all hydrogen atoms in the alkyl group are substituted by fluorine atoms. Illustrative examples include trifluoromethyl and pentafluoroethyl, and linear or branched heptafluoropropyl, nonafluoro Butyl, undecafluoropentyl and decafluorohexyl. The extended expression "(Q-C6) perfluoroalkoxy" should also be understood accordingly. "Tooth" or "_base" means fluorine i, chlorine The term "patient" as used herein means a warm-blooded animal such as a rat, a mouse, a dog, a cat, a guinea pig, and a primate such as a human. The expression "pharmaceutical acceptable carrier" as used herein. By means of a non-toxic solvent, dispersant, excipient, adjuvant, or other material in admixture with a compound of the present invention, is used to form a pharmaceutical composition, i.e., a pharmaceutical form suitable for administration to a patient. An example of a carrier is a pharmaceutically acceptable oil, usually for parenteral administration. The term "pharmaceutically acceptable salt" means that the salt of the compound of the present invention can be used for pharmaceutical preparation. However, certain other salts can also be used in the preparation of the compound of the present invention and a pharmaceutically acceptable salt thereof. Suitable pharmaceutically acceptable salts of the compounds of the invention include acid addition salts which can be prepared by mixing a solution of a compound of the invention with a solution of a pharmaceutically acceptable acid, such as hydrochloric acid, hydrochloric acid , nitric acid, amine acid, sulfuric acid, acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, fumaric acid, maleic acid, hydroxymaleic acid, 201136938 Rhyme lk bad blood I, fine acid , glutaric acid, acetic acid, C, 2: stupid, basal formic acid, benzoic acid, phenylacetic acid, hawthorn: 柠 豕酉 豕酉 豕酉 文 文, glycolic acid, lactic acid, propionic acid, malonic acid Acidic metal salts such as sodium hydrogen hydride and hydrogen sulphate can also be formed. =, such a salt can be present in the form of monoacid salt or in the form of anhydrous salt or hydrated salt. In addition, when the compound of the present invention itself contains a hetero group, pharmacy Acceptable salts may include alkali metal salts 'salt or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; and salts with suitable organic ligands, such as quaternary ammonium salts. Stereoisomers - The expression is a generic term for all isomers of various molecules differing only in the orientation of the atomic space. Usually, it includes the mirror image isomer (enantiomer) which is often formed in the presence of at least one asymmetric center. When the compounds of the invention have two or more asymmetric centers, they may also exist as diastereomers, and some molecules may also exist as geometric isomers (cis/trans) Similarly, certain compounds of the present invention may exist as a mixture of two or more different compounds but in a fast-blind manner, i.e., a tautomer which is usually referred to as a tautomer. Representative examples of the body include: a homologous isomerized L-keto tautomer, a heteropolyisomereomer, a _-diamine tautomer, and the like. It is to be understood that all such isomers and mixtures thereof are intended to be within the scope of the invention. As commonly used in organic chemistry, the terms "r," and "s," are used herein to mean a particular configuration of a chiral center. The symbol "R" (right) refers to the net prioritization of the group along the lowest priority of the bond r, the configuration of the chiral center from the stomach ^ high times 201136938 for the clockwise relationship. Symbol " s" (left) refers to the configuration of the chiral center in which the group priority (from highest to second lowest) is counterclockwise when viewed along the key to the lowest priority group. The priority of the group is It is determined according to the order rule, which first determines the priority according to the size of the atomic number (the order in which the atomic numbers are decremented). For a list of priorities and paradigms, see Stereochemistry of Organic Compounds. , Ernest L. Eliel, Samuel H. Wilen and Lewis N. Mander, editors, Wiley-Interscience, John Wiley & Sons, Inc" New York, 1994. In addition to the (R)-(S) system, earlier DL The system can also be used herein to indicate the absolute configuration' especially for amino acids. In this system the Fischer projection is oriented such that the number 1 carbon atom on the primary bond is at the top. The prefix "D" is used to represent the functionalities in the structure. The decision is that the group is the absolute configuration of the isomer at the right of the chiral center carbon atom and the prefix "L" is used in the structure. The functional (determination) group is the isomer of the chiral center carbon atom to the absolute In a broad sense, the term "substituted" is intended to include substituents for all acceptable organic compounds. In certain embodiments disclosed herein, the term "substituted" means independently Substituted by one or more substituents selected from the group consisting of (CrC6) alkyl, (CVC6) fluorenyl, (qu perfluoroalkyl, phenyl, hydroxy-, -C〇2H, vinegar , amidino group, (Ci_C6) alkoxy A, (C "C6) thioalkyl, (crc6) perfluoroalkoxy, ΝΗ2, c, Br>, b, -NH-lower alkyl, and -N (lower alkyl) 2. However, it should be understood that any other suitable substituents known to those skilled in the art can also be used in these examples. Earth 201136938 "Therapeutically effective amount" means a specific disease, The dose of a compound that is effective in the treatment of a disorder or symptom. The term "treatment" refers to: (i) prevention a disease, disorder, or condition that occurs in a patient who is prone to, but has not been diagnosed with, the disease, disorder, and/or symptom; (ii) inhibits the disease, disorder, or symptom, ie, inhibits its development; and (iii) reduces The disease, disorder or symptom, ie, the regression of the disease, disorder and/or symptom. Thus, in accordance with an embodiment of the present invention, a compound of formula (I) is provided: (I)

VN:

R where

Wherein R1 is alkyl, which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, i-alkoxy, cycloalkyl, heterocycloalkyl, aryl, optionally substituted Aryl, heteroaryl and optionally substituted heteroaryl; 12 201136938 _ R2 and R3 are each independently H, H, alkoxy, dentate, alkyl, decyl, county , silk, bis-indenylamino, hydrazinyl or, optionally, substituted by one or more substituents selected from the group consisting of an alkyloxy group, an alkyl group, a ring group, a hetero-wei group, Aryl and hetero-spray; or ^. , W2 pin W4_Kizaki's n, ch, cr2 The present invention further includes the respective exemplified or diastereomers of the compound t of the formula (1) as described above in the example of 3, all Salts that can be formed, including those that are pharmaceutically acceptable, and which, as described above and below, (iv) (4) (d) and diastereomeric substituted diradicals, provide a compound of formula (1) The ruler is 1 - (7 · fluoro · Η 2 · methoxyethyl) · heart three gas methoxy oxime D - - ^ ^ ^ ^ 娜 benzo [bH. acid: chaos ... A Oxyethyl)-indol-3-yl)-carbonyl-5,-amine manicure A snail [taste bit-4,3, tune)_stupid [b]biting] hydrochloride; soil methane H7 · 曱 曱 曱 + + ( ( ( ( ( ( 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘 秘)_7_Methyl·!Η_ πBiluo[3,2_b]. Bite Winter 13 201136938 Base)-Carbonyl-5'-Aminothiol [Piperidine-4,3,-(2H)-Benzene And [b]furan]hydrochloride 0 Wherever possible, all of the above compounds may also include their corresponding salts, including pharmaceutically acceptable salts. The compounds of the invention can be synthesized by any procedure known to those skilled in the art. In particular, several starting materials for the preparation of the compounds of the invention are known or are commercially available per se. The compounds of the present invention, as well as several precursor compounds, can also be prepared as reported in the literature and as further described herein for the preparation of analogous compounds. For example, see R·. C. Larock, “Comprehensive Organic Transformations”, VCH publishers, 1989. It is also well known that in a wide variety of organic reactions, it may be necessary to protect certain reactive functional groups such as amine groups from the unnecessarily participating in these reactions. Conventional protecting groups can be used in accordance with standard practice and are well known to those skilled in the art. For example, see T W. Greene and p. GM Wuts, Protecting Groups in Organic Synthesis, John Wiley & Sons, Inc., 1991. For example, suitable amine protecting groups include, but are not limited to, sulfonyl (e.g., anthracene), sulfhydryl (e.g., benzyloxyindenyl or tert-butoxymethyl), and arylalkyl (such as benzyl). They can then be removed by suitable hydrolysis or hydrogenation. Other suitable (four) amine Baoxian County includes the trifluoroethylene group [-C(=0)CF3], or the solid phase resin combined with (4) group, such as the 2,6-dimethoxy group combined with Xinxiangxiang resin. a benzyl group (Ellman linker) or a 2,6-dimethoxy-4-[2-(polystyryloxy)ethoxy] group, which can be catalyzed by, for example, TFA acid for 201136938 It is removed by hydrolysis. In another aspect of this specific embodiment, the particular disease, disorder, or condition that can be prevented and/or treated with a compound of the invention includes, but is not limited to, an inflammatory disease, such as joint inflammation, including arthritis, rheumatoid Arthritis and other joint symptoms such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, osteoarthritis or other chronic inflammatory joint diseases or articular cartilage damage, conjunctivitis , spring conjunctivitis, inflammatory bowel disease, asthma, allergic rhinitis, interstitial lung disease, fibrosis, scleroderma, pulmonary fibrosis, cirrhosis, myocardial fibrosis, neurofibromatosis, hyperplastic lesions, various Skin diseases such as atopic dermatitis and psoriasis, myocardial infarction, stroke, angina pectoris or other consequences of rupture of atherosclerotic plaque, as well as periodontal disease, diabetic retinopathy, macular degeneration, acute macular degeneration, wet macular degeneration , tumor hyperplasia, allergic reactions, multiple sclerosis, peptic ulcer, or syncytial virus infection. As explained below by way of specific examples, the compound of formula (I) inhibits beta-tryptase and exhibits an anti-inflammatory effect. Therefore, the compound of the present invention can be used for the treatment of a disease or condition which is permeable to inhibition of ?-tryptase. Accordingly, in one aspect of the invention, there is provided a method of treating a condition in a patient, the condition comprising an inflammatory disease, such as joint inflammation, including arthritis, rheumatoid arthritis, and other joint symptoms such as rheumatoid spondylitis, Gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, osteoarthritis or other chronic inflammatory joint diseases or articular cartilage damage, conjunctivitis, spring conjunctivitis, inflammatory bowel disease, asthma, allergies 15 201136938 f Raw nose & interstitial lung disease, fibrosis, scleroderma, pulmonary fibrosis, cirrhosis. Muscle fibrosis, neurofibromatosis, hyperplastic scars, various skin diseases such as atopic dermatitis and psoriasis, muscle infarction, stroke, other consequences of reading pain or rupture of atherosclerotic plaque, and periodontal disease, Diabetic retinopathy, plaque degeneration, acute macular degeneration, wet macular degeneration, tumor hyperplasia 1 allergic reaction, multiple sclerosis, peptic ulcer, or syncytial virus infection' This method involves administering a therapeutic effect to the patient The compound of the formula (1). It will be readily understood by those skilled in the art that the conditions and conditions that are specifically described herein are not intended to be limiting, but rather to illustrate the efficacy of the compounds of the present invention. Thus, it will be appreciated that the compounds of the invention are useful in the treatment of any disease caused by the effects of beta-like trypsin. In other words, as described above, the compound of the present invention is an inhibitor of ?-tryptin, and is effective for improving any condition caused wholly or partially by ?-tryptin. It will be readily understood by those skilled in the art that the conditions and conditions that are specifically described herein are not intended to be limiting, but are intended to exemplify the efficacy of the compounds of the present invention. Thus, it will be appreciated that the compounds of the invention are useful in the treatment of any disease caused by the effects of beta-like trypsin. In other words, as described above, the compound of the present invention is an inhibitor of ?-tryptin and is effective for improving any condition mediated entirely or partially by ?-tryptin. All of the examples of the compounds of the invention disclosed herein can be used in methods of treating the various diseases described herein. As described herein, the compounds used in the methods of the present invention are capable of inhibiting the action of tryptin and thereby reducing the effects and/or conditions caused by sputum-tryptase activity. 201136938 In a further aspect of the method of the invention, the compounds of the invention may be administered by any method known in the art. In particular, the compounds of the invention may be administered via the oral, intramuscular, subcutaneous, rectal, tracheal, nasal, peritoneal or topical routes. Finally, in the present invention, a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula (1), including enantiomers and stereoisomers of the compound, is also provided. And tautomers, and pharmaceutically acceptable salts, solvates or derivatives thereof, and which have the structural formula shown by formula (I) as described herein. As described herein, the pharmaceutical composition of the present invention is characterized by its β-tryptase inhibitory activity and can be used for the treatment of any disease, symptom or disorder caused by the influence of β-tryptase on a patient. Likewise, as noted above, all of the preferred embodiments of the compounds of the invention disclosed herein can be used in the preparation of the pharmaceutical compositions described herein. These pharmaceutical compositions preferably take the form of tablets, pills, capsules, powders, granules, sterile injectables or suspensions, metered aerosols or liquid sprays, drops, ampoules, automatic injection devices Or a suppository; for oral, parenteral, intranasal, sublingual or rectal administration, or for inhalation or insufflation. Alternatively, the pharmaceutical composition may be administered once a week or once a month in a suitable form; for example, an insoluble salt of the active compound (e.g., citrate) may be modified to form an intramuscular depot preparation. It is conceivable to employ a tactile polymer comprising an effective pharmaceutical ingredient. When preparing a solid pharmaceutical composition such as a tablet, the main active ingredient is mixed with a pharmaceutical carrier such as the commonly used tablet ingredients corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, 17 201136938 Dicalcium phosphate, gums and other pharmaceutical diluents such as water to form a solid preformed pharmaceutical composition comprising a homo-mixture of a compound of the invention or a pharmaceutically acceptable salt thereof. When we say that the pharmaceutical composition is uniform, it means that the active ingredient is uniformly dispersed in the pharmaceutical composition, so that the pharmaceutical composition can be easily divided into the same effective unit dosage form, such as a tablet. , pills and capsules, etc. Then, this solid state portion 6 is divided into the above unit dosage forms containing 0.1 to about 5 mg of the active ingredient of the present invention. The flavored unit dosage form comprises from j to 1 mg of the active ingredient, such as tablets 2, 5, 1 , 25, 5 or just mg. The tablet or pill of the novel pharmaceutical composition may be coated or otherwise The ingredients are complexed to provide a dosage form with the advantage of a time delay. For example, a tablet or pill may comprise an inner dosage portion and an outer dosage portion, the outer dosage portion being a layer outer shell surrounding the inner dosage portion. The two parts can be separated by a layer of casing so that the inner dose portion is not broken down in the stomach, thereby completely entering the ten-&intestine or delayed release. A wide variety of materials can be used to make this layer of casing or coating, including mixtures of some polymeric acids and polymeric acids with shellac, cetyl alcohol and cellulose acetate. :r: package: 2 f of Xinling pharmaceutical composition for oral or injectable oil suspension, containing edible culvert = suitable flavor (four), aqueous suspension of flavored emulsion, and Xi'an seed sesame oil, coconut oil or peanut Suitable dispersion or class (IV) drugs (4). Water-suspended suspension: arbor gum, sea salt, scented synthetic and natural colloids such as tearing, A · Polyethyl condensed base fine, ^ fresh base _ money, edge cellulose 201136938 The pharmaceutical composition of the present invention can be Any method known in the art is administered. In general, the pharmaceutical compositions of this invention may be administered via the oral, intramuscular, subcutaneous, rectal, tracheal, nasal, peritoneal or topical routes. The preferred mode of administration of the pharmaceutical compositions of this invention is by oral and nasal routes of administration. Any known method of administering a pharmaceutical composition via the oral or nasal route can be used for the administration of the pharmaceutical composition of the present invention. In the treatment of the various diseases described herein, a suitable dosage level is from about 0.01 to 250 mg/kg per guanidine, preferably from about 0.05 to 100 mg/kg per guanidine, especially from about 0.05 to 20 mg per day. /kg. The compound can be used 1 to 4 times a day. The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention in any way. [Examples] Examples (Overview) "kg" means kilograms, "g" means grams, "mg" means milligrams, >g" means micrograms, "pg" means picograms, and "lb" means Pounds, "oz" means ounces, "mol" means moles, "mmol" means millimolar, "μιηοίε" means micromolar, "nmole" means nanomolar, "L" means liter, "mL" Or ''ml' means milliliters, 'μ!/' means microliters, "gal" means gallons, "°C" means degrees Celsius, "Rf" means retention factors, "mp" or "mp" Refers to the melting point, "dec" means decomposition, "bp" or "bp" means boiling point, "mm of Hg" means pressure in millimeters of mercury, "cm" means centimeters, and "nm" means nanometers. "abs." means absolute, "cone." means concentrated, "c" means concentration in g/mL, "DMSO" means dimercaptosulfoxide, "DMF" 19 201136938 means N, N-dimercaptocaramine, "CDI, means u, carbonyldiimidazole, DCM" or "CH2C12" means di-methane, "DCE" means di-ethane, HC1 means hydrochloric acid, "Et〇Ac Means ethyl acetate, "pBS," means phosphate buffered saline '"IBMX" means 3-isobutyl-1 fluorenylxanthine, and "PEG" means polyethylene glycol '"MeOH" Methanol, "MeNH2" is a nail amine, ''n2,, a nitrogen, iPrOH" refers to isopropyl alcohol, "2" refers to the scale, 'ah, refers to lithium aluminum hydride," Heptane, refers to n-heptane, "HMBA_AM, resin refers to 4-secret phenyl hydrazine g" amine fluorenyl resin, "pdcl2 (dppf^,, refers to bis(diphenylphosphino)) ferrocene Iron-palladium (II) divaporate DCM complex, "HBTU" means 2-(1Η_benzotriwaxyl (3)-tetradecyl hydrourea hexafluorophosphate" "DIEA" means diisopropyl Ethyl ethylamine, ''CsF,' means fluorinated ''MeI'' means methyl iodide' 'AcN', 'MeCN' or 'CH3CN' means acetonitrile, TFA" means trifluoroacetic acid, '' THF, means tetrahydrofuran, "NMp" means 1-mercapto-2-pyrrolidone, "H2〇" means water, "B〇c" means t-butoxycarbonyl, and "saline" means saturated chlorine. Aqueous sodium solution, "M" means mol/L," "mM" means mmol/L, "μΜ" means micromol/L, and "nM" means Namol/L 'N" means equivalent 'TLC' means thin layer chromatography, "HPLC" Refers to high performance liquid chromatography, "HRMS" refers to high resolution mass spectrometry, "lod" refers to loss on drying ' '>Ci, refers to microcurie' 'iP' refers to intraperitoneal, "iv , means intravenous, anhyd=anhydro; aq=water; min=minute; hr=hour; d=day; sat.=saturated; “s” = single peak; “士,=双峰, t = three peaks; q = four peaks; m = multiple peaks; dd = double doublets; br = broad peaks; rt = room temperature; LC = liquid chromatography; MS = mass spectrometry; ESI / MS = electrospray ion Chemical/mass spectrometry; RT = retention time; m = molecular ion, "~,, 20 201136938 = approx. Usually the reaction is carried out in nitrogen. The solvent was dried over magnesium sulfate and evaporated in vacuo on a rotary evaporator. TLC analysis was performed on EM Science's Silicone 60F254 plate and developed by UV irradiation. Rapid analysis was performed using a prefilled silica gel column from Alltech. Unless otherwise stated, '4 NMR spectral analysis was performed on a Gemini 300 or a Varian Mercury 300 spectrometer equipped with an ASW 5 mm probe at 3 〇〇 MHz and usually at ambient temperature in deuterated solvents such as d2o, dmso-d6 Or recorded in cdci3. The chemical shift value (δ) is expressed in parts per million (ppm) with tetradecyl decane (TMS) as an internal standard. High-pressure liquid chromatography-mass spectrometry (LCMS) experiments for determining retention time (RT) and associated mass ions were performed using one of the following methods: Mass spectrometry (MS) was recorded using a Micromass mass spectrometer. Usually, the method used is electrospray ionization with a scan mass m/z of 100 to 1000. Liquid chromatography was performed on a Hewlett Packard 1100 series binary pump and degasser; the auxiliary detectors were: Hewlett Packard 1100 Series UV Detector, Wavelength = 220 nm and Sedere SEDEX 75 Evaporative Light Scattering Detector (ELS), Temperature = 46. (:, nitrogen pressure = 4 bar. LCT: gradient (AcN + 0.05% TFA): (H20 + 0.05% TFA) = 5: 95 (minutes) to 95: 5 (2.5 minutes) to 95: 5 (3 minutes) Column: YMC Jsphere 33x2 4 μΜ, 1 ml/min MUX: Column: YMC Jsphere 33x2, 1 ml/min Gradient (AcN+0.05% TFA) : (H20+0.05% TFA) = 5:95 (〇 Minutes) to 95:5 (3.4 minutes) to 95:5 (4.4 minutes). 21 201136938 LCT2 : YMC Jsphere 33x2 4 μΜ > ( AcN+0.05% TFA): (H20+0.05% TFA) = 5:95 ( 0 minutes) to 95:5 (3.4 minutes) to 95:5 (4.4 minutes) QU: YMC Jsphere 33x2 lml/min, (AcN+0.08% formic acid): (H2O+0.1% formic acid)=5:95 (0 Minutes) to 95:5 (2.5 minutes) to 95:5 (3.0 minutes) The following examples illustrate the procedures used to prepare certain compounds of the invention.Example 1 1-(7-fluoro-1-(2-decyloxy) Ethyl)-4-difluoromethoxyl n--3-yl)-carboyl-5'-aminoindolyl snail [piperidine-4,3'-(2H)-benzo[b Furan] hydrochloride

Step A 3-Bromo-4-hydroxybenzylamine hydrobromide

The title compound was prepared according to the procedure described in this document: Smith, L.H. ·.. Mei C/zem. 1977, vol. 20, ρρ· 1254-1258, using 4-hydroxy stilbene as the starting material. NMR (300 MHz, DMSO-m) δ 8.0 (bs ' 2Η ), 7.6 ( m, 1H) ' 7.3 (m, 1H), 7.0 (m, 1H) ' 6.8 (m ' 1H), 3·9 ( m, 2H). 22 201136938

Step B (3-Bromo-4-hydroxybenzyl)-amino decanoic acid tert-butyl ester

DIEA (32 ml, 195 mmol) and Boc-Sf (16. 6 g) were added to a solution of 3-ox-4-yl hydroxy hydrazide > succinate (18.4 g, 65 mmol) in CH2C12 (600 mL) , 78 mmol). The reaction mixture was stirred for 4 hours and diluted with CH.sub.2Cl.sub.2 (300 mL). The reaction mixture was washed with water and brine, dried over EtOAc EtOAc The crude residue was purified with EtOAc EtOAc elut elut elut elut elut ^NMROOOMHz' CDCl3)S7.4(m' 1H), 7.l5(m,1H), 7.0 (m,1H),6.8 (m,1H),5.5 ( m ' 1H),4.2 ( m,2H) ,

1.5 (s, 9H). Step C 1-Benzyl-5'(tert-butoxymethylamino)-spirobin _4,3, stupid [匕] furan]

The title compound was prepared in a similar manner according to the procedure described in this patent: Allerton, C. et al" WO 075775, 2007, using (1_th sense-1,2,3,6-tetrahydro 0 to 0 - 4-yl)methanol and (3-di-4-trabenzylidene)-amino decanoic acid 23 201136938 tert-butyl ester as starting material. 1hnmr(300MHz' CDC13) 3 7.4(m,5H),7.1 (m, 2H), 6.7 (m, 1H), 4.8 (bs, 1H), 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); LCN1S vn/z · [ΝΙίΉ]+=4〇9 °

Step D 5 (tert-butoxycarbonylaminoindenyl)-spioxidine _4,3,-(2H)-benzo[b]furan]

1-benzyl-5,(tert-butoxycarbonylaminomethyl)-spiro[piperidine-4,3'-benzo[b]furan] (6.0 g, 14.7 mmol) and at 50 psi* H2 A solution of 10% Pd/C (1 g) in 60 ml MeOH and acetic acid (1 ml) for 5 h. The reaction mixture was filtered through celite and concentrated in vacuo. The reaction mixture was taken with EtOAc EtOAc EtOAcjjjjjjjjjjj 'HNMR ( 300 MHz > CDC13) 57.1 ( m > 2H) 5 6.8 (m » 1H) »

4.8 (bs ' 1H) ' 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- disorder-5-dioxanoxycarbonyl group)-amino phthalic acid ethyl hydrazine 24 201136938

Ethyl formate was added dropwise to a solution of 2-fluoro-5-nonylphenylamine (50.72 g, 0.26 mol) and pyridine (27.3 mL, 0.34 mol) in THF (500 mL) over 30 min. (32.2 mL, 0.39 mol). After 1 hour, both LC/MS and TLC indicated that the reaction was complete. The reaction mixture was partitioned between H20 andEtOAc. The two phases were separated and the organic phase was washed with EtOAc EtOAc EtOAc. The crude product was purified on silica gel eluting with EtOAc/EtOAc (EtOAc:EtOAc:EtOAc HNMR ( 300 MHz » CDC13) δ 8.11 ( br s » 1H) » 7.07 ( dd > /= 9. 9.3 Hz, 1H), 7.00-6.80 (m, 2H), 4.27 (q, "7=7.1 Hz, 2H), 1.33 (t '7.1 Hz, 3H); 19FNMR (CDC13, 300 MHz) δ-57.84 (s, 3F), -134.01 (br s, IF);

LC Rt: 5.03 min; MS 309 (M+CH3CN+1 > 100%)» 268 (M+l) 〇Step F (6-fluoro-2-iodo-3-indolylphenyl)-amino decanoic acid Ethyl ester

201136938 at -78. (: sec-BuLi (1.4) was added dropwise to a solution of (2-fluoro-5-trifluorodecyloxyphenylamino decanoic acid ethyl ester (31.34 g' 117.2 mmol) in THF (180 mL) over 1 hour. Μcyclohexane solution, 200 mL, 280 mmol). After 20 min, add 1⁄4 (44.6 g, 175.8 mmol) of THF (i5 〇mL) solution over 30 min. Then mixture at -78 °C Stir for 30 min. Add saturated 〇4〇η, and remove the cold bath. The reaction mixture was partitioned between h2 EtOAc and EtOAc. The phases were separated and the organic phase was washed with 1% NajO3, HaO and brine. Drying with MgSO4, EtOAc (EtOAc) (EtOAc m.) The layers, 39%) and air dried. The filtrate was concentrated in vacuo and the residue was suspended in heptane (200 mL). More product was obtained by purifying the filtrate by silica gel chromatography. NMR (300 MHz » CDCI3) δ 7.30-17.10 (m , 2 Η) > 6.16 (br s,1 Η), 4.26 ( q, J = 7.1 Hz, 2 Η) 1.32 (t,7=7·1 Hz, 3H); 19F NMR (300 MHz, CDC13) δ -56.90 ( s,3F ), 14.35 ( d, J = 8.5 Hz » IF); LC Rt 3.01 min, MS 394 (M+l '100%), 374, 364, 321, 267.

Step G (6-Fluoro-3-indolyl-2-trimethylglyoxiphonylethynyl)-ethyl carbamate 26 201136938

(6-Fluoro-2-indol-3-methylphenyl)-amino decanoic acid ethyl ester (H ig, 45.9 mmol), Et3N ( 12.8 mL, 91.9 mmol), Pd(PPh) 2Cl2 (1.6 g, Mixture of 5% mol), Cul (0.7 g, 8% mol) and TMS-acetylene (19.6 mL, 137.8 mmol) in degassed THF (180 mL) at 6 Torr.加热 Heat overnight. The mixture was cooled to room temperature then partitioned between H20 and EtOAc. This mixture was filtered through diatomaceous earth to remove insolubles. The two phases of the solution were separated and the organic phase was washed with hydrazine and brine, dried, filtered and concentrated in vacuo. The crude product was purified on silica gel eluting with EtOAc/EtOAc eluting to afford 15.6 g (93%) of product as a beige solid. NMR ( 300 MHz, CDC13) δ 7.15-7.00 (m, 2 Η), 6 4ι (brs, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7l Hz, 3H), 0.27 (s, 9H); 19F NMR (300 MHz» CDC13) δ-57.59 ( s * 3F ) , -118.15 (s, IF); LC Rt 4.11 min; MS 364 (M+l, 100%).

Step H 7-Fluoro-4-trifluorodecyloxy-1Η-Π引引朵27 201136938

(6-Fluoro-3-indolyl-2-tridecyldecylethynylphenyl)-amino decanoic acid ethyl ester (28.9 g, 79.6 mmol) and hydrazine (35.7 g, 636.7 mmol) in degassed The mixture in tert-butanol (300 mL) was heated at 70 °C overnight. LC/MS indicated the reaction was complete. The mixture was cooled to room temperature and then partitioned between H20 and Et2. The two phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were washed with EtOAc (EtOAc)EtOAc. The crude product was purified on silica gel eluting with EtOAc/EtOAc (EtOAc (EtOAc) !H NMR ( 300 MHz > CDC13) δ 8.47 ( br sj 1H) > 7.35-7.20 (m,1H) ' 6.95-6.80 ( m,2H), 6.68 ( d, "/= 2.5 Hz, 1H); 19FNMR (300MHz, CDC13) δ-57.63 (s, 3F), -136.10 (d, J = 8.5 Hz » IF);

LC Rt 3.55 min; MS 220 (M+l, 100%). Step I 7-Fluoro-1-(2-decyloxyethyl)-4-trimethoxymethoxy-1H-0 bow 丨0

A mixture of 7-fluoro-4-trifluorodecyloxy-1H-indole (16.0 g, 72.8 mmol) and powder KOH (20.4 g, 364.2 mmol) in DMSO (150 mL) was stirred at room temperature for 10 min. 2-Methoxyethyl bromide (10.3 mL, 109.2 mmol) was added. The mixture was stirred at room temperature overnight. LC/MS indicated that the reaction was complete. This mixture was partitioned between H20 and Et20. The two phases were separated and the aqueous phase was extracted with EtOAc (2×). The combined organics were washed with EtOAc (EtOAc)EtOAc. The crude product was purified on silica gel eluting with heptane/EtOAc (100/0 to 50/50) to yield 19.3 g (95%) of product as a yellow liquid. WNMR ( 300 MHz, CDC13) δ 7.15 (d, 2.1 Hz, 1H), 6.90-6.75 (m, 2H), 6.56 (t, "/= 2.5 Hz, 1 H), 4.44 (t, «/= 5.2 Hz , 2H), 3.72 (t, "/= 5.2 Hz, 2H), 3.31 (s, 3H); 19F NMR (300 MHz, CDC13) δ -57.54 ( s, 3F ), -137.00 ( d, 11.3 Hz, IF LC Rt 3.61 min; MS 278 (M+b 100%).

Step J 2,2,2-Trifluoro-1-[7-fluoro-1-(2-decyloxyethyl)-4-trifluorodecyloxy-111-called 朵0--3-yl]- Acetylene

To 7-fluoro-1-(2-decyloxyethyl)-4-trifluoromethoxy-1H-. TFAA (26.2 mL, 188.2 mmol) was added to a mixture of hydrazine (19.3 29 201136938 g, 69.7 mmol) in DMF (135 mL). The mixture was heated at 4 ° C overnight. TLC indicated the reaction was complete. The mixture was cooled to room temperature and then partitioned between h2 〇 and EkO. The two phases were separated and the aqueous was washed with EtOAc EtOAc EtOAc. The crude product was purified on silica gel eluting with EtOAc/EtOAc (EtOAc/EtOAc) NMR ( 300 MHz, CDC13) δ 8.03 ( d, J = 1.4 Hz, 1H), 7.20-6.95 (m, 2H), 4.54 (t,··=4.9 Hz, 2H), 3.76 (t, J = 4.8 Hz) , 2H), 3.33 (s, 3H); 19FNMR (300 MHz, CDC13) δ-57.74 (s, 3F), _71.10 (s, 3F), -134.95 (d, "/= 11.5 Hz, IF);

LC Rt 3.88 min ; MS 374 ( M+l ♦ 100%) 〇 Step K

7-fluoro-1-(2-decyloxyethyl)-4-trifluoromethoxy-iH-indole-3-carboxylic acid 2,2,2-trifluoro-l-[7-fluoro- 1-(2-decyloxyethyl)_4·trifluoromethoxy-1H-indol-3-yl]-ethanone (23.4 g' 62.6 mmol) in MeOH (100 mL) and 5 M NaOH (100 mL The mixture in the mixture was heated to 8 Torr and heated overnight. LC/MS indicated the reaction was complete. The reaction mixture was cooled to room temperature, 201136938. The residue was dissolved in H20, then

It was then concentrated in vacuo to remove most of the Me〇H and washed with EhO. The aqueous phase was slowly acidified to ~2 with concentrated HCl. The acidified _ float was extracted with Et20 and the organic phase was washed with H.sub.2G and brine. The residue was suspended in heptane (10/90). The white powder (i9 4 g, 96%) in the suspension was collected by suction filtration and air dried. H NMR ( 300 MHz, CDC13) δ 8.02 ( s, 1H), 7.15-7.05 ( m ' 1Η) ' 7.00-6.90 ( m ' 1Η) ' 4.49 ( t, "/ = 5.0 Hz, 2 Η), 3.75 (t ,·/= 4.9 Hz, 2H), 3.33 (s, 3H); 19F NMR (300 MHz, CDC13) δ -57,74 ( s,3F ), -135.65 ( d, ·/= 11.3 Hz, IF); LC </ RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt;

Step L 1-(7-Fluoro-1-(2-methoxyethyl)-4-trifluoromethoxyindolyl)-carbonyl-5'-(tert-butoxymethylamino) - snail [σ辰π定_4,3'-(2H)-benzo[b]furan]

In 7-mercapto-1-(2-morpholinyl-yl-ethyl)-1Η-indole-3-carboxylic acid (642 mg, 2.0 mmol), 5'-(tert-butoxycarbonylamino) )-嫘[piperidine-4,3'-(2H)-benzo[b]0-propanol] (636 mg, 2.0 mmol), 1-(3-didecyl 31 201136938 aminopropyl)-3 To a solution of ethyl carbodiimide hydrochloride (46 〇 mg, 24 mm 〇 1) in ch2ci2 was added triethylamine 56 m Bu 4 0 rmn 〇l). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (EtOAc)EtOAc. Flash chromatography on <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; bNMROOOMHz' CDC13) S7.4(s,1H),7.1 (m,2H), 6.9 (m,2H) ' 6.8 (m,1H),4.8 (bs,1H),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 Μ 1-(7-Fluoro-1-(2-decyloxyethyl)-4-trifluorodecyloxyindol-3-yl)-carbonyl-5-aminomethylspiro[piperidine-4, 3 '-(2H)-benzo[b]furan] hydrochloride

In 1-C7-fluoro-1-(2-decyloxyethyl)-4-trifluorodecyloxyindol-3-yl)-carbonyl-5 '-(tert-butoxycarbonylaminomethyl) -Spirulina [piperidin-4,3 '-(2H)- benzo[b] 0 furan] (430 mg, 0.69 mmol) in 2 ° smolder (5 mL) solution was added 2MHC1 dioxin solution ( 10 mL ' 20.0 mmol). The reaction mixture was stirred for 2 h then concentrated in vacuo. The residue was triturated with diethyl ether for 2 h and EtOAc (EtOAc) NMR (300 MHz, DMSO-m) δ 8.2 (bs, 2H), 7.7 (s, 1H), 7.3 (m, 2H), 7.1 (m, 2H), 6.8 (m, 1H), 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 w&quot; : [M+H]+=522. Example 2 1-(7-Fluoro-1-(2-methoxyethyl)-indole-3-yl)-carbonyl_5,-aminomethyl snail [Biridine-4,3 '-(2H )-benzo[b]furan]hydrochloride

Step A 7-Fluoro-1-(2-decyloxyethyl)_1H-indole

The title compound was prepared in a similar manner to Step 1 of Example 1 using 7-fluoro-1H-indole as starting material. H NMR ( 300 MHz ' CDC13 ) δ 7.36 ( d, J = 8.1 Hz, 1H) U1 (d '"/= 3 Hz ' 1H) ' 7.00-6.95 (m,1H), 6.86 (dd, 7.11 (d, "7 = c/ = 8· 1 Hz, 1H ), 33 201136938 1H), 6.48 (m, 1H), 4.45 (t, J = 5.7 Hz, 2H), 3.73 (t ' J = 5.7 Hz, 2H), 3.30 (s, 3H); 19F NMR (300 MHz, CDC13) δ-135.93 (d, 3F).

Step B 2,2,2-Trifluorofluoro-1-(2-methoxyethyl)-lH-indol-3-yl]-B

The title compound was prepared in a similar manner to Step J of Example 1 using 7-fluoro-1-(2-methoxyethyl)-1? ^NMRUOOMHz, CDCl3)5 8.00(d,1H), 7.96(s,1H), 7.30-7.25 (m,1H),7.05 (dd,1H),4.53 (t,5.1 Hz, 2H),3.77 (t, J = 5.1 Hz, 2H), 3.32 (s, 3H); 19F NMR (300 MHz ' CDC13) δ -72.25 ( s, 3F ), -134.23 ( s, IF). Step c 7-Fluoro-1-(2-decyloxyethyl)-1Η-吲π朵-3_acid

The title compound was prepared in a similar manner to the procedure of Example i, using </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -Base]-Ethyl ketone is the starting material. NMR (300 MHz, DMSO-do) δ 12.17 ( s, 1H), 8, 04 ( s, 1 Η), 7.83 (d, J = 7.5 Hz, 1 Η), 7.18-7.11 (m, 1 Η), 7.08-7.01 (m,1H), 4.50 (t, "/= 5.1 Hz, 2H), 3.69 (t, */= 5.1 Hz, 2H), 3.22 (s, 3H); 19FNMR (300 MHz, DMSO-i/6) Δ-134.07 (d, IF).

Step D 1-(7-Fluoro-1-(2-methoxyethyl)-indol-3-yl)-carbonyl-5,-(tert-butoxycarbonylaminoindenyl)-spiro -4,3 ' -(2H)-stupid [b]furan]

The title compound was prepared in a similar manner to Step L of Example 1 using 7-fluoro-1-(2-methoxyethyl)- s- s s s s s s s s s s s s s s s The amino group fluorenyl)-spiro [piperidine-4,3'-(2Η)-benzo[b]furan] is the starting material. ΗΝΜ Ι Ι (300 ΜΗζ, CDC13) δ 7.5 (m, 2H), 7.1 (m, 3H), 6.9 (m, lH) '6.75 (d, 1H), 4.8 (bs, 1H), 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 35 201136938 ΗΊΐ-(2-decyloxyethyl)-π 哚 哚 I base) ^ carbon _5, _ aminomethyl snail [piperidine-4,3 '-(2H)-benzo[ b]furan]hydrochloride

The title compound was prepared in a similar manner to the step of Example 1 using 1-(7-fluoro^-1-(2-decyloxyethyl)- s. Oxytoxylaminoindenyl)-spiro [piperidine-4,3'-(2H)·benzo[b]furan] is the starting material. !HNMR (300 MHz, DMSO-Min) δ 8·2 (bs, 2H), 7.8 (s, 1Η) ' 7.5 (m ' 2Η), 7.4 (m, 2Η), 7.2 (m, 1Η), 6 8 (d, 1H), 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),! 7(m,4H); LCMS m/z: [M+H]+= 438. Example 3 1_(7-Difluoroi-methoxy-1-(2-decyloxyethyl)-°b -3_yl)_ylamino_5,_aminomercaptospiro[piperidine-4,3,-(2H)-benzo[b]furan] hydrochloride

201136938

Step A (2-Trifluoromethoxyphenyl)-aminocarboxylate

On · 5. (: (ice/salt bath) Sodium hydride (3.6 g, 60% by weight '0.09 mol) was added portionwise in a solution of 2-(trifluoromethoxy)aniline (15.9 g, 0.09 mol) in DME (300 mL) The suspension was warmed to room temperature and ethyl chloroacetate (7.5 mL '0.08 mol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hr then heated to reflux and heated for 1.5 hr. The reaction was quenched with EtOAc (2 mL, EtOAc (EtOAc)EtOAc. Purification with EtOAc/Heptane (1-5%) elute elute elute elute elute elute 8.1 Hz, 1H), 7.30-7.22 ( m, 2H), 7, 07 ( app t, 1H), 6.90 ( br s, 1H), 4.25 ( q, "/= 7.2 Hz ' 2H), 1.34 ( t, */= 7.2 Hz, 3H); 】9F NMR (300 MHz, CDC13) δ -57.32 (s, 3F);

LC Rt: 2.96 min; LCMS m/z: [M+H]+=250. Step B (2-Moth-6-Tri-Itoxyphenyl)-Ethyl Carbamate

201136938 Add sec-BuLi (1.3 Μ Cyclohexane) to a solution of (2-trifluoromethoxyphenyl)-carbamic acid ethyl ester (11. 〇g '44.2 mmol) in THF (200 mL) at -78 °C The burning solution '71.4 mL, 92.8 mmol). After 1 hour, a solution of ι 2 (11.22 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 NH4C1 (200 mL) was added and the cold bath was removed. The reaction mixture was partitioned between Η&quot; and diethyl ether. The two phases were separated and the organic phase was washed with 50% Na.sub.2SO.sub.3, H.sub.2 and brine. solid. NMR ( 300 MHz, CDC13) δ 7.81 ( d, 8.1 Hz, 1H), 7·29 (m, 1H) ' 7.05 (app t ' 1H), 6.10 (br s, 1H), 4.24 (q ' 7.2 Hz ' 2H) ' 1.33 ( t, "/ = 7.2 Hz, 3H); 19F NMR (300 MHz, CDC13) δ -57.28 ( s, 3F);

LC Rt 2.93 min; LCMS m/z: [M+H]+= 375 〇 Step C (2-trifluoromethoxy-6-tridecylalkylethynylphenyl)-amino decanoic acid ethyl ester

To the bis(dibasic scale), (II) monochloride (210 mg, 0.30 mmol) and Cul (57 mg, 0.30 mmol) were added to TEA (110 mL), heated to 80 °C and heating was continued for 20 min. The mixture was cooled to room temperature, then (2-exchange-6-tri-IL-methoxyphenyl)-aminoacetic acid ethyl acetate (n.2 g, 29.9 38, 2011 369 38 mmol) was added and the mixture was stirred for 3 min. Then, TMS b (4.0 mL, 28.4 mmol) was added dropwise to the reaction mixture, and the resulting solution was stirred at room temperature for 15 hours. The triethylamine was removed in vacuo and the residue was partitioned between water and Et.sub.2. The organic phase was washed with 1 NHCI and brine and dried over EtOAc EtOAc. The crude product was purified on EtOAc EtOAc (EtOAc) 'HNMR (300 MHz ^ CDC13) 6 7.41 (d »/=7.5 Hz &gt; 1H), 7.29-7.13 ( m,2H), 6.32 (br s,1H), 4.23 ( q,7.2 Hz, 2H) ' 1.30 (t, "/= 7.1 Hz, 3H), 0.26 (s, 9H);

LC Rt 3, 56 min; LCMS m/z: [M+H]+=346 » Step D 7-trifluoromethoxy-1H-indole

Bright. (2-Trifluoromethoxy-6-tridecyldecylethynylphenyl)-carbamic acid ethyl ester (5.214 g, 15.1 mmol) was added to this solution and heated to 8 ° C and heating was continued 2 hour. The residue was removed between Et 2 〇 and water by removing the scouring in a vacuum towel. The organic phase was washed with brine, dried over EtOAc EtOAc m. The crude product was purified on silica gel eluting with EtOAc EtOAc (EtOAc) , H NMR (300 MHz ' CDC13) δ 8.40 (br s,1H), 7.58-7.55 201136938 (m,1H),7·25 (m,1H),7.09-7.07 (m,2H),6.62-6.60 ( m,1H); 19F NMR (300 MHz, CDC13) δ -57.50 ( s, 3F);

CHN: Theoretical value: C 53.74% 'H 3.01%, N6.96%. Actual values: C 53.86%, H 3.14%, N 6.97%.

Step E 1-(2-decyloxyethyl H-trifluoromethoxy-1H-indole

The title compound was prepared in a similar manner to Step 1 of Example 1 using 7-trifluoromethoxy-1H-indole as starting material. hNMR ( 300 MHz, CDC13) δ 7.50 (d, 1H), 7.15 (d, · / = 3.0 Hz, 1H), 7.05-7.03 (m, 2H), 6.51 (d, */= 3.3 Hz, 1 H) , 4.46 (t, "/= 5.4 Hz, 2H), 3.70 (t, 5.4 Hz, 2H), 3.30 (s, 3H); 19F NMR (300 MHz, CDC13) δ -56.45 ( s, 3F); LCMS m /z : [M+H]+=260.

Step F 2,2,2-Trifluoro-l-[l-(2-methoxyethyl)_7_trifluoromethoxy_1H_0 哚-3-yl]-acetamidine 201136938

To a mixture of 1-(2-decyloxyethyl)-7-trifluoromethoxy-1H-indole (1.898 g, 7.32 mmol) in DMF (14 mL), TFAA (1.2) mL, 8.63 mmol). After the dropwise addition was completed, the reaction mixture was stirred at 0 ° C for 3.5 hours, and then poured into ice water (50 mL). The solid precipitate was collected and used in the subsequent step, or dissolved in water/EtOAc to further refine as described below. The two phases were separated and the organic phase was washed with w~~~ The crude orange solid (2.6 g, 100%) was used in the next step without further purification. iHNMR ( 300 MHz, CDC13) δ 8.35 (d, 9 Hz, 1H), 8.01 (s, 1H), 7.33 (appt, 1H), 7.26 (m, 1H), 4.55 (t, · / = 6 Hz, 2H ), 3.75 (t, /= 6 Hz, 2H), 3.32 (s, 3H); 19FNMR (300 MHz, CDC13) δ -56.41 (s, 3F), -72.16 (s, 3F);

LC </RTI> </RTI> </RTI> <RTI ID=0.0></RTI> Step G 1-(2-decyloxyethyl)-7-trifluoromethoxy-1Η-η 哚-3-carboxylic acid

201136938 2,2,2-Trifluoromethane [2-(oxy)ethyl-7-trifluoromethoxy-1Η-°哚-3-yl]-ethanone ( 1.655) at 90 °C g, 4.66 mmol) in 5N NaOH (20 mL) was heated for two days. The reaction mixture was cooled to room temperature then washed with CH.sub.2 C.sub.2 (3.times.30 mL). The aqueous phase was slowly acidified to pH~4 with cone. EtOAc (m.). H NMR ( 300 MHz &gt; CDC13) δ 8.17 ( d &gt; J = 6 Hz &gt; 1H)» 7.97 (s, 1H), 7.27-7.22 (m, 1H), 7.18-7.15 (m, 1H), 4.52 (t, J = 6 Hz, 2H), 3.74 (t, "/= 6 Hz, 2H), 3.32 (s, 3H); 19F NMR (300 MHz, CDC13) δ _56.34 (s, 3F);

LC Rt 3.17 min; MS 345 (M+CH3CN +1) &lt;&quot;&&&&&&&&&&&&&&&&&&吲哚_3_yl)-carbonyl-5'-(tert-butoxycarbonylaminomethyl)-spiro[piperidine-4,3,-(2H)-benzo[b]furan]

The title compound was prepared in a similar manner as Example 1 Step L using 1-(2-decyloxyethyl)-7-trifluorodecyloxy </RTI> </RTI> <RTI ID=0.0> Oxycarbonylaminoindenyl)-spiro[Biridine-4,3,-(2H)-benzo[b]furan] is the starting material. 42 201136938 ^NMR ( 300 MHz, CDC13) δ 7.7 (d, 2H), 7.5 (s ' 1H) ' 7.1 (m, 4H), 6.8 (d, 1H), 4.8 (bs, 1H), 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-Trifluorodecyloxy-1-(2-decyloxyethyl)-indol-3-yl)-carbonyl-5'-aminoindolyl snail [piperidine-4,3 '-(2H)-benzo[b]furan]hydrochloride

The title compound was prepared in a similar manner to the step of Example 1 using 1-(7-trifluoromethoxy-1-(2-methoxyethyl)-indole. '·(tert-Butoxycarbonylaminomethyl)-spiro[Biridine-4,3'-(2H)-benzo[b]furose] was used as the starting material.丨HNMR ( 300 MHz ' CDC13) δ 8.1 (bs, 2H), 7.8 ( s, 1H), 7.7 (m ' 1H) ' 7.4 (m ' 1H), 7.2 (m, 3H), 6.8 (d, 1H) ' 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-Methyllacylethyl)-7-methyl·; IH-0 嘻 and 43 201136938 yl)-carbonyl-5 '-aminomethylspiro[piperidine-4, 3 '-(2H)-benzo[b]furan]hydrochloric acid

Step A 7-Mercapto-1H-pyrrolo[3,2_b]pyridine

The title compound was prepared according to the procedure described in this document: C/zem/W; % 2002, vol. 67(7), ρρ· 2345-2347 NMR NMR ( 300 MHz, CDC13) δ 11.4 ( bs, 1H), 8.2 (d, 1H), 7.6 (d, 1H), 6.9 (d, 1H), 6.5 (d, 1H), 3.3 (s, 3H); LCMS m/z: [M+H]+=133.

Step B 3-iodo-7-indolyl-1H-pyrrolo[3,2-b]° pyridine

To a solution of 7-methyl-1H-pyrrolo[3,2-b]pyridine (0.5 g, 3.79 mmol) in THF (30 mL), N-iodosuccinimide (0.337 g, 4.2 mmol). The reaction mixture was stirred for 2 h and concentrated in vacuo. Fast chromatography on Si02 at 201136938, elution with 50% ethyl acetate / heptane to give 〇% g, (94%) desired product. !HNMR (300 MHz, DMSO_t/〇δ 11.9 (bs, m), 8 2 (d 1H), 7.8 (s ' 1H), 7.0 (d, 1H), 6.5 (d, 1H), 3.3 (s, 3H LCMS w/z: [M+H]+=259.

Step C is more than [3,2-b]. Bisidine 3-magnetic-1-(2-decyloxyethyl)-7-mercapto·ιη

Ή NMR (300 MHz &gt; DMSO-H NMR (300 MHz, DMSO cancer) δ 8 4 , using 3-, 1H), 7.4 (s,

3H; &gt; 2.7 Cs &gt;3H);3H;&gt; 2.7 Cs &gt;3H);

LCMS m/z : [M+H]+=317 〇

Step D

Trifluoroacetate 45 201136938

The OH title compound was in a similar manner as described in this document. Lefoix, M. et al., (10)*5·, 2005, vol • pp. 3581-3588 'Use 3-峨 small (2-曱The oxyethyl)-7-methyl] group [3,2 -b] ° is defined as the starting material.咕NMR (300 MHz, DMSO-m) δ 8.7 (s, 1H), 8.5 (d, 1H) ' 7.6 (d ' 1H), 4.75 (t, 2H), 3.75 (t, 2H), 3 9 r 3H )&gt;2.95(s&gt;3H); (S' LCMS m/z: [M+H]+=235.

Step E 1-(1-(2-Methoxyethyl)-7-methylpyrido[3,2-b]pyridyl)-yl-5--(tert-butoxyamino) Methyl)^[fl bottom bite_4,3,_(2h)_stupid [b]furan]trifluoroacetate

F with examples! Step L Prepare the title compound in a similar manner, using K2-methoxyethyl and (10) clocks of singular-domain acid trifluoro 46 201136938 acetate and 5'·(tert-butoxycarbonylamino) snail [ Piperidine_4,3,_(2H)_benzo[b]furan] is the starting material. The product was purified by rp-HPLC eluting with a gradient of 10% CH.sub.3CN/H.sup. The corresponding fractions were combined and lyophilized to give the title compound. ^NMROOOMHz, CDC13) δ8·6(ιη,1H), 8.2(m,1H), 7.4 (m,1H),7.1 (m,2H), 6.8 (m,1H),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-Methoxyethyl)-7-indolyl-iH-pyrrolo[3,2-b]pyridin-3-yl)-carbonyl-5 '-aminoindenyl snail [piperidine _4,3 '-(2H)_ benzo[b]furan]hydrochloric acid

The title compound was prepared in a similar manner to the step of Example 1 using 1-(1-(2-methoxyethyl)-7- hydrazinobi[3,2 </ RTI> <RTIgt; The base 5-'-(tert-butoxycarbonylaminoguanidino)-spiro[piperidine-4,3,-(2Η)-benzo[b]furan]trifluoroacetate is the starting material.丨HNMR (300 MHz, CD3OD) 3 8.5 (m, 2H), 7.6 (m, 1H), 47 201136938 'call, 4.6 (m, 4H), s, 3H), 3.2 (s, 3H) ' 7.4 (m ' 1H), 7·3 (m ' 1H), 6.8 (m 4.1 (m' 2H), 3.8-3.6 (m, 8H), 3.3 (2.1 (m ' 2H), 1.9 (m, 2H); LCMS: [m+h]+=435. Biological activity: 1) Its β-like pancreas The properties of the compounds of the present invention demonstrate the protease inhibitory potency (IC50 and heart value) by the following results. In vitro test procedures for the preparation of '_ eggs (four) It is dependent on nature, therefore, compounds that inhibit their catalytic activity will likely inhibit the action of pancreatic egg (IV). This inhibition of catalytic activity can be measured by in vitro enzyme analysis and cell analysis. Human lung-like proteases or expression of recombinant human β-like genotypes in yeast cells were confirmed. Substantial results were obtained using isolated proenzymes or expressed enzymes. The assay procedure used 96-well microplates (Costar 359). 〇), using L_pyroxylaminopurine _L_脯aminomercapto_L_arginine-p-nitrophenylamine (S2366: Quadratech) as a substrate (essentially as McEuen et. al. Bioch Em Pharm, 1996, 52, pages 331-340. The analysis was performed with 0.5 mM substrate (2 x Km) at room temperature and the microplate was read at 405 nm with a microplate reader (Beckman Biomek Plate reader). Materials and methods for primary tryptase screening (chromogenic assay) Analysis buffer 50 mM Tris (pH 8.2), 100 mM NaC 0.05% Tween 20, 50 pg/mL heparin 48 201136938 Substance S2366 (2.5 mM reserve Liquid) Enzyme-purified recombinant β-tryptase 310 pg/mL stock solution Analytical protocol (single point assay) • Add 60 pL of diluted substrate to each well (final concentration of 500 μΜ in assay buffer) • Add compound re-sampling, final concentration 20 μΜ, volume 20 pL • Add enzyme, final concentration 50 ng/mL, volume 20 μί • Total volume per well 100 kl Short agitation to mix, and at room temperature Incubate for 30 minutes in the dark • Read absorbance at 405 nM. The following controls are available for each plate: Total: 60 gL of substrate, 20 pL of buffer (containing 0.2% final DMSO concentration), 20 gL of enzyme non-specific: 60 pL Acceptance, 40 pL buffer (containing 0.2% DMSO) Total: 60 eL substrate, 20 Μί buffer (without DMSO), 20 pL enzyme non-specific: 60 pL substrate, 40 pL buffer (without DMSO) analysis protocol (IC5G and &amp; assay) Analytical procedures are basically the same as above, the difference is Compound refills were added at the following concentrations: 0.01, 0.03, 0.1, 0.3, 1, 3, 10 μΜ (all dilutions were performed manually). For each analysis, either a single point analysis or an ic50 assay, one standard compound was used in order to obtain an ic50 for comparison. Using the IC50 value, the Ki value can be calculated using the following formula: = + [by 49 201136938 quality] / Km). The compound of the present invention shows β-tryptase inhibition in the range of 1 Μ to &lt; 1 nM. Although the present invention has been described by the foregoing examples, it is understood that the invention is not limited thereto, but it is understood that the invention covers the general scope disclosed above. Various modifications and embodiments may be made without departing from the spirit and scope of the invention. [Simple diagram description] None [Main component symbol description] None

Claims (1)

201136938 VII Patent application scope: 1. A compound of formula (I): (I) where R1 calcining group, optionally substituted by one or more substituted molybdenum selected from the group consisting of a hydroxyl group, an alkoxy group, a dentate group, a cycloalkyl group, a heteroalkyl group, an aryl group, optionally substituted Aryl, heteroaryl and optionally substituted heteroaryl; R2 and R3 are independently of each other, halo, halo, alkoxy, halo alkoxy, alkyl, amidino, ureido, carboxy, A sulfonyl decylamino group, a hydrazinyl urea or an alkyl group optionally substituted with one or more substituents selected from the group consisting of a hydroxyl group, an alkoxy group, a functional alkoxy group, a cycloalkyl group, a heterocycloalkyl group And aryl and heteroaryl; Wl 'W2, W3 or W4 are each independently N, CH, CR2 or CR3; or a salt thereof or an enantiomer or diastereomer thereof. 2. A compound according to the term "Patents", wherein r is a thiol group which is optionally substituted by 201136938. 3. A compound of claim 1 which is selected from the group consisting of: 1((7-fluoro-1-(2-methoxyethyl)-4-trifluoromethoxy) is phenyl)-ylidene-5'-aminoindolyl snail [Brigade. 3'-(2H)-benzo[b] scream] hydrochloride; 1-(7-fluoro-1-(2-decyloxyethyl)-indol-3-yl)-carbonyl _5, _Aminomethylspiro[pyridin-4,3,-(2H)-benzo[b]furan] hydrochloride; 1-(7-trifluoromethoxy-1-(2-decyloxy) Base)·吲哚_3_yl)-carbonyl-5,aminomercaptospiro[piperidine-4,3,-(2H)-benzo[b]furan] hydrochloride; oxiranylethyl) _7_Mercapto-1H-pyrrolo[3,2-b]acridine_3_yl)-monoyl_5'-aminomethylspiro[pyridinyl-4,3,_(2h)benzo(8) Furose] hydrochloride; or a salt thereof or an enantiomer or diastereomer thereof. 4. A pharmaceutical composition comprising a compound of formula (1): Of which 52 201136938 R1 is alkyl, optionally substituted by one or more substituents selected from the group consisting of hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl, optionally substituted Aryl, heteroaryl and optionally substituted heteroaryl; R2 and R3 are independently of each other, i, alkoxy, haloalkoxy, alkyl, amidino, ureido, carboxy, Sulfhydryl decylamino, sulfonyl urea or optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, haloalkoxy, cycloalkyl, heterocycloalkyl, aryl And a heteroaryl group; W1, W2, W3 or W4 are each independently N, CH, CR2 or CR3; or a pharmaceutically acceptable salt thereof or an enantiomer or diastereomer thereof, and At least one pharmaceutically acceptable excipient, diluent or combination of carriers. 5. The composition of claim 4, wherein the compound is selected from the group consisting of: 1_(7-fluoro-1 -(2-methoxyethyl)-4-trifluoromethane 。 朵 朵-3-yl)-carbonyl-5'-aminoindolyl snail [piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; 1-(7 -Fluoro-1-(2-decyloxyethyl)-°11-11-3-yl)-mono-5--amino group 53 201136938 Methylspiro[piperidine-4,3 '-(2H) -benzo[b]furan] hydrochloride; 1-(7-trifluorodecyloxy-1-(2-decyloxyethyl)-indol-3-yl)-carbonyl-5 '-amino Mercapto [Piperidine-4,3 '-(2H)-benzo[b]furan] hydrochloride; and 1-(1-(2-decyloxyethyl)-7-indenyl-1H- Pyrrolo[3,2-b].pyridin-3-yl)-carbonyl-5'-aminomercaptospiro[piperidine-4,3'-(2H)-benzo[b]furan] Hydrochloric acid a salt; or a pharmaceutically acceptable salt thereof. 6. A method of treating a disease in a patient selected from the group consisting of arthritis, rheumatoid arthritis, and other joint disorders such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriasis joints Inflammation, osteoarthritis or other chronic inflammatory joint disease or articular cartilage damage, conjunctivitis, spring conjunctivitis, inflammatory bowel disease, asthma, allergic rhinitis, interstitial lung disease, fibrosis, scleroderma, lung fiber Chemotherapy, cirrhosis, myocardial fibrosis, neurofibromatosis, hypertrophic scars, various skin diseases such as atopic dermatitis and psoriasis, myocardial infarction, stroke, angina, or other consequences of rupture of atherosclerotic plaque, and periodontal disease , diabetic retinopathy, macular degeneration, acute macular degeneration, wet macular degeneration, tumor hyperplasia, allergic reaction, multiple sclerosis, peptic ulcer, or syncytial virus infection, the method comprising administering to the patient a therapeutic amount Compound of formula (I): 54 (i) (i)201136938 among them Wherein R 1 is an alkyl group, optionally substituted with one or more substituents selected from the group consisting of a light group, an alkoxy group, a halogenated gas group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, Optionally substituted aryl, heteroaryl and optionally substituted heteroaryl; R 2 and R 3 are independently of each other, halo, alkoxy, halo alkoxy, alkyl, amidino, Urea group, carboxyl group, sulfonyl decylamino group, sulfonyl urea or, as the case may be optionally substituted by one or more substituents selected from the group consisting of an alkyl group, a methoxy group, a halogenated oxygen group a group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, and a heteroaryl group; W1, W2, W3 or W4 are each independently of hydrazine, CH, CR2 or CR3; or a pharmaceutically acceptable salt thereof or a complex thereof Isomers or diastereomers, optionally in combination with at least one pharmaceutically acceptable excipient, diluent 55 201136938 or carrier. Base)--ylamino-5-aminomethyl spigot bite · 4,3 '_ (called benzo (9) bite] salt such as Shenzhan Zhiyi A τε column acid salt; 1-(7- Fluor-1-(2-methoxyethyl)_吲哚_3_yl)-carbonyl_5, aminomethylspiro[piperidine-4,3'-(2H)-benzo[b]furan Hydrochloride; 1-(7-trifluorodecyloxy·ι·(2_methoxyethyl)_吲哚_3_yl)-carbonyl-5 '-aminoindolyl snail [pyridinyl] 4,3'-(2Η)-benzo[b]furan] hydrochloride; and 1-(1-(2-methoxyethyl)-7-mercapto-1Η-η ratio [3, 2-b]Acridine-3-yl)-carbonyl-5'-aminomethylspiro[piperidine-4,3'-(2H)-benzo[b]furan] hydrochloride; or pharmaceutically thereof Acceptable salt 56 201136938 IV. Designation of representative drawings: (1) The representative representative of the case is: (No). (2) Simple description of the symbol of the representative figure: None 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (I) 2