MX2008001836A - Azole and thiazole derivatives and their use - Google Patents

Abstract

Compounds of formula (I) are useful in the treatment of diseases where enhanced M3 receptor activation is implicated, such as respiritory tract diseases:wherein (i) R1is C1-C6-alkyl or hydrogen;and R2is hydrogen or a group -R7, -Z-Y-R7, -Z-NR9R10;-Z-CO-NR9R10, -Z-NR9-[AE11]C(O)O-R7, or -Z-C(O)-R7;and R3is a lone pair, or C1C6-alkyl;or (ii) R1and R3together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R2is a lone pair or a group -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-[AE12]C(O)O-R7;or;-Z-C(O)-R7;or (iii) R1and R2together with the nitrogen to which they are attached form a heterocycloalkyl ring, said ring being substituted by a group -Y-R7, -Z-Y-R7, -Z-NR9R10;-Z-CO-NR9R10;-Z-NR9-[AE13]C(O)O-R7;or;-Z-C(O)-R7;and R3is a lone pair, or C1-C6-aIkyl;R4and R5are independently selected from the group consisting of aryl, arytfused-heterocycloalkyl, heteroaryl, C1-C6-alkyl, cycloalkyl;R6is -OH, C1-C6-alkyl, C1-C6-alkoxy, hydroxy-C1-C6-alkyl, nitrile, a group CONR82or a hydrogen atom;A is an oxygen or a sulfur atom;X is an alkylene, alkenylene or alkynylene group;R7is an C1-C6-alkyl, aryl, aryl-fused-cycloalkyl, aryl-ffused-heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, cycloalkyl or heterocycloalkyl group;R8is C1-C6-alkyl or a hydrogen atom;Zis a C1-C16-alkylene, C2-C16-alkenylene or C2-C16-alkynylene group;Y is a bond or oxygen atom;R9and R10are independently a hydrogen atom, C1-C6-alkyl, aryl, aryl-fused-heterocycloalkyl, aryl-fused-cycloalkyl, heteroaryl, aryl(C1-C6-alkyl)-, or heteroaryl(C1-C6-alkyl)- group;or R9and R10together with the nitrogen atom to which they are attached form a heterocyclic ring of 48 atoms, optionally containing a further nitrogen or oxygen atom.

Description

DERIVATIVES OF AZOL AND TIAZOL AND THEIR USES FIELD OF THE INVENTION This invention relates to oxazole and thiazole derivatives, pharmaceutical compositions, methods for their preparation and use in the treatment of diseases where the activation of the increased M3 receptor is involved.

BACKGROUND OF THE INVENTION Anti-cholinergic agents prevent the passage of, or the effects resulting from the passage of, impulses through the parasympathetic nerves. This is a consequence of the ability of such compounds to inhibit the action of acetylcholine (Ach) by blocking its binding to muscarinic cholinergic receptors. There are five subtypes of muscarinic acetylcholine receptors (AChRs), called M1-M5, and each is the product of a different gene and each exhibits unique pharmacological properties. The mAChRs are widely distributed in vertebrate organs, and these receptors can mediate both inhibitory and exciting actions. For example, in smooth muscle found in the respiratory tract, bladder and gastrointestinal tract, M3 mAChRs mediate contraction responses (reviewed by Caulfield, 1993, Pharmac.Ther., 58, 319-379). Ref .: 190075 In the lungs, muscarinic receptors Ml, M2 and M3 have been shown to be important and are located in the trachea, bronchi, submucosal glands and parasympathetic ganglion (reviewed in Fryer and Jacoby, 1998, Am J Resp Crit Care Med., 158 (5 part 3) S 154-160). The M3 receptors in the smooth muscle of the respiratory tract mediates contraction and therefore bronchoconstriction. The stimulation of M3 receptors that localize submucosal glands results in the secretion of mucus. Increased signaling through muscarinic acetylcholine receptors has been noted in a variety of different pathophysiological states including asthma and COPD. In COPD, the vagal tone may either increase (Gross et al 1989, Chest 96: 984-987) and / or cause a greater degree of obstruction for geometric reasons if applied to the upper part of the walls of the respiratory tract. edematous or mucus-laden (Gross et al., 1984, Am Rev Respir Dis; 129: 856-870). In addition, inflammatory conditions can lead to loss of inhibitory M2 receptor activity resulting in increased levels of acetylcholine released after vagus nerve stimulation (Fryer et al, 1999, Life Sci., 64, (6-7) 449 -455). The increased activation resulting from the M3 receptors leads to increased airway obstruction. Thus, the identification of potent muscarinic receptor antagonists would be useful for the therapeutic treatment of those disease states where the enhanced activity of the M3 receptor is involved. Indeed, contemporary treatment strategies currently support the regular use of M3 antagonist bronchodilators as first-line therapy for COPD patients (Pauwels et al 2001, Am Rev Respir Crit Care Med; 163: 1256-1276). Incontinence due to hypercontractibility of the bladder has also been shown to be mediated through the increased stimulation of M3 mAChRs. In this way the M3 mAChR antagonists may be useful as therapeutic in these mAChR-mediated diseases. Despite the large body of evidence supporting the use of anti-muscarinic receptor therapy for the treatment of respiratory disease states, relatively few anti-muscarinic compounds are in use in the clinic for pulmonary indications. In this way, a need is maintained for new compounds that are capable of causing blockage in muscarinic M3 receptors, especially those compounds with a long duration of action, which allow a once-a-day dose regimen. Since muscarinic receptors are widely distributed throughout the body, the ability to administer anticholinergic drugs directly to the respiratory tract is advantageous since it allows smaller doses of the drug to be administered. The design and use of topically active drugs with a long duration of action and that remain in the recipient or in the lung, would allow the reduction of unwanted side effects that will be appreciated with the systemic administration of the same drugs. The tiotropium (Spiriva ™) is a long-lasting muscarinic antagonist currently marketed for the treatment of chronic obstructive pulmonary disease, administered by the inhaled route.

Tiotropium Additionally, ipratropium is a muscarinic antagonist marketed for the treatment of COPD.

Ipratropium Chem. Pharm. Bull. 27 (12) 3149-3152 (1979) and J. Pharm. Sci 69 (5) 534-537 (1980) describes puryl derivatives as having atropine-like activities. Med. Chem. Res 10 (9), 615-633-12001) describes isoxazoles? -isoxazolines as muscarinic antagonists. O97 / 30994 describes oxadiazoles and thiadiazoles as muscarinic receptor antagonists. EP0323864 describe oxadiazoles linked to a mono- or bicyclic ring as modulators of the muscarinic receptor. The class of β2 adrenergic receptor agonists is well known. Many of the β2 agonists, in particular, long-acting β2-agonists such as salmeterol and formoterol, have a role in the treatment of asthma and COPD. These compounds are also generally administered by inhalation. Compounds currently under evaluation as ß2 agonists once a day are described in Expert Opin. Investig. Drugs 14 (7), 775-783 (2005). A well known β2-agonsite pharmacophore is the portion: Also, pharmaceutical compositions containing both a muscarinic antagonist and a β2-agonist for use in the treatment of respiratory disorders are known in the art. For example, US2005 / 0025718 describes a β2 agonist in combination with tiotropium, oxotropium, ipratropium and other muscarinic antagonists; O02 / 060532 describes the combination of ipratropium with ß2 agonists and WO02 / 060533 describes the combination of oxotropium with ß2 agonists. Other M3 antagonist / β2 agonist combinations are described in O04 / 105759 and WO03 / 087097. Also, compounds that possess both antagonist and β2-agonist activity of the muscarinic receptor present in the same molecule are known in the art. Such bifunctional molecules provide bronchodilation through two separate modes of action while possessing single molecule pharmacokinetics. Such a molecule should be easier to formulate for therapeutic use compared to two separate compounds and should be co-formulated more easily with a third active agent, for example a steroid. Such molecules are described in for example, WO04 / 0742 6, WO04 / 089892, O05 / 111004, O06 / 023457 and O06 / 023460, all of which use different linker radicals to covalently link the M3 antagonist to the β2 agonist, indicating that The structure of the linker radical is not critical to preserve both activities. This is not surprising since the molecule does not require to interact with the M3 and ß2 receptors simultaneously.

BRIEF DESCRIPTION OF THE INVENTION According to the invention, a compound of the formula (I) is provided: wherein (I) R1 is Ci-C- alkyl or hydrogen; and R2 is hydrogen or a group -R7, -Z-Y-R7, -Z-NR9R10; -Z-CO-NR9R10, -Z-NR9-C (0) 0-R7, or; -Z-C (0) -R7; and R3 is a single pair, or C? -C6 alkyl; or (II) R1 and R3 together with the nitrogen to which they are bound form a heterocycloalkyl ring, and R2 is a single pair or a group -R7, -ZY-R7, -Z-NR9R10, -Z-CO-NR9R10, - Z-NR9-C (0) 0-R7; or -Z-C (0) -R7; or (III) R1 and R2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, the ring is substituted by a group -Y-R7, -Z-Y-R7, -Z-NR9R10; -Z-CO-NR9R10; -Z-NR9-C (0) 0-R7; or; -Z-C (0) -R7; and R3 is a single pair, or Ci-Ce alkyl; R4 and R5 are independently selected from the group consisting of aryl, heterocycloalkyl fused to the aryl, heteroaryl, Ci-Cß alkyl, cycloalkyl; R6 is -OH, Ci-Cß alkyl, Ci-Cß alkoxy, hydroxyC C ~Calkyl, nitrile, a CONR82 group or a hydrogen atom; A is a sulfur or oxygen atom; X is an alkylene, alkenylene or alkynylene group; R7 is Ci-Cß alkyl, aryl, cycloalkyl fused to aryl, heterocycloalkyl fused to aryl, heteroaryl, aryl (C?-C8 alkyl), heteroaryl (Ci-C alquilo alkyl), cycloalkyl or heterocycloalkyl group; R8 is C], C6 alkyl or a hydrogen atom; Z is a C? -C? 6 alkylene, C2-Ci6 alkenylene or C2-Ci6 alkynylene group, - And it is a bond or atom of oxygen; R9 and R10 are independently a hydrogen atom, C? -C6 alkyl, aryl, heterocycloalkyl fused to the aryl, cycloalkyl group fused to the aryl, heteroaryl, aryl (C? -C6 alkyl), or heteroaryl (C? -C6 alkyl); or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing an additional nitrogen or oxygen atom; or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof. In a subset of the compounds of the invention: R 1 is C 1 -C 6 alkyl or a hydrogen atom; R2 is C? -C6 alkyl, a hydrogen atom or a group -ZY-R7 and R3 is a single or C? -C6 alkyl, or R1 and R2 together with the nitrogen to which they are attached represent a heterocycloalkyl ring, or R1 and R3 together with the nitrogen to which they are attached represent a heterocycloalkyl ring; R4 and R5 are independently selected from the group consisting of aryl, heteroaryl, Ci-Cß alkyl, cycloalkyl; R6 is -OH, halogen, C? -C6 alkyl, hydroxyC? -C6 alkyl or a hydrogen atom; A is a sulfur or oxygen atom; X is an alkylene, alkenylene or alkynylene group; Z is an alkylene, alkenylene or alkynylene group; And it is a bond or atom of oxygen; R7 is aryl, heteroaryl, heterocycloalkyl. It will be appreciated that the carbon atom to which R4, R5 and R6 are linked may be an asymmetric center of compounds of the invention, they may be in the form of single enantiomers or mixtures of enantiomers. A preferred class of compounds of the invention consists of quaternary ammonium salts of the formula (I) wherein the nitrogen shown in the formula (I) is quaternary nitrogen, bearing a positive charge. The compounds of the invention may be useful in the treatment or prevention of diseases in which the activation of muscarinic receptors are involved, for example the present compounds are useful for the treatment of a variety of indications, including but not limited to disorders of the tract Respiratory diseases such as chronic obstructive pulmonary disease, chronic bronchitis of all types (including dyspnea associated with them), asthma (allergic or non-allergic; infantile wheezing syndrome), acute respiratory distress syndrome in adults (ARDS), obstruction chronic respiratory disease, bronchial hyperactivity, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis, exacerbation of hyperactivity in the respiratory tract as a consequence of other drug therapies, particularly other inhaled drug therapies, pneumoconiosis (eg aluminosis, anthracosis, asbestosis, calicosis, ptilosis, siderosis, silicosis, tobacco is and bisinosis); Gastrointestinal tract disorders such as irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal seizures or hyperanacinesia, diverticulitis, pain accompanied by spasms of smooth gastrointestinal musculature; urinary tract disorder accompanied by urination disorders including neurogenic polaquisuria, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urgency or polaquisuria; dizziness; and cardiovascular disorders such as vagally induced breast bradycardia. For the treatment of respiratory conditions, administration by inhalation will often be preferred, and in such cases administration of the compounds (I), which are quaternary ammonium salts, will often be preferred. In many cases, the duration of action of the quaternary ammonium salts of the invention administered by inhalation may be more than 12, or more than 24 hours during the typical dose. For the treatment of gastrointestinal tract disorders and cardiovascular disorders, administration by the parenteral route, usually the oral route, may be preferred.

Another aspect of the invention is a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or excipient. Another aspect of the invention is the use of a compound of the invention for the manufacture of a medicament for the treatment or prevention of a disease or condition in which muscarinic M3 receptor activity is involved.

BRIEF DESCRIPTION OF THE FIGURE Figure 1 shows the results obtained in this test for the compound of Example 32 (0.1, 0.3 and 1 μg / kg in) 4 hours before for MCh-induced bronchoconstriction (10 μg / kg iv), and the compound of comparison tiotropium.

DETAILED DESCRIPTION OF THE INVENTION As long as the qualifiers are not otherwise indicated in the context in which they are used, the following terms have the following meaning when used herein: The "Acyl" means a -CO-alkyl group in which the alkyl group is as described herein. Exemplary acyl groups include -COCH3 and -COCH (CH3) 2. "Acylamino" means a group -NR-acyl in which NR and acyl are as described herein. Exemplary acylamino groups include -NHCOCH3 and -N (CH3) COCH3. The "Alkoxy" and "Alkyloxy" mean an -O-alkyl group in which the alkyl is as described below. Exemplary alkoxy groups include methoxy (-OCH3) and ethoxy (-OC2H5). The "alkoxycarbonyl" means a -COO-alkyl group in which the alkyl is as defined below. Exemplary alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. "Alkyl" as a group or part of a group refers to a straight or branched chain saturated hydrocarbon group having from 1 to 12, preferably from 1 to 6 carbon atoms, in the chain. Exemplary alkyl groups include methyl, ethyl, 1-propyl and 2-propyl. "Alkenyl" as a group or part of a group refers to a straight or branched chain hydrocarbon group having from 2 to 12, preferably from 2 to 6, carbon atoms and a carbon-carbon double bond in the chain . Exemplary alkenyl groups include ethenyl, 1-propenyl, and 2-propenyl. "Alkylamino" means a -NH-alkyl group in which the alkyl is as defined above. Exemplary alkylamino groups include methylamino and ethylamino. "Alkylene" means an alkyl group in which the alkyl group is as defined above. Exemplary alkylene groups include -CH2-, - (CH2) 2- and -C (CH3) HCH2-. "Alkenylene" means an alkenyl group in which the alkenyl is as defined above. Exemplary alkenylene groups include -CH = CH-, -CH = CHCH2-, and CH2CH = CH-. "Alkynylene" means an alkynyl group in which the alkynyl refers to a straight or branched chain hydrocarbon group having from 2 to 12, preferably 2 to 6 carbon atoms and a triple carbon-carbon bond in the chain. Exemplary alkynylene groups include ethynyl and propargyl. "Alkylsulfinyl" means an -SO-alkyl group in which alkyl is as defined above, exemplary alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl. "Alkylsulfonyl" means a -S02-alkyl group in which the alkyl is as defined above. Exemplary alkylsulfonyl groups include methylsulfonyl and ethylsulfonyl. "Alkylthio" means a -S-alkyl group in which the alkyl is as defined above. Exemplary alkylthio groups include methylthio and ethylthio. "Aminoacyl" means a group -CO-NRR in which R is as described herein. Exemplary aminoacyl groups include -CONH2 and -CONHCH3. The "Aminoalkyl" means an alkyl-NH2 group in which the alkyl is as described above. Exemplary aminoalkyl groups -CH2NH2. "Aminosulfonyl" means a group -S02-NRR in which R is as described herein. Exemplary aminosulfonyl groups include -S02NH2 and -S02NHCH3. The "Aryl" as a group or part of a group denotes an optionally substituted monocyclic or multicyclic aromatic carbocyclic portion of 6 to 14 carbon atoms, preferably 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group can be replaced by one or more substituent groups. "Arylalkyl" means an aryl-alkyl group in which the aryl and alkyl portions are as described above. Preferred aryloalkyl groups contain a C? _4 alkyl portion. Exemplary aryl alkyl groups include benzyl, phenethyl and naphthlenomethyl. "Aryloalkyloxy" means an aryl-alkyloxy group which aryl and alkyloxy portions are as described above. Preferred aryloalkyloxy groups contain a C? -4 moiety. Exemplary aryl alkyl groups include benzyloxy. "Cycloalkyl fused to aryl" means a monocyclic aryl ring, such as phenyl, fused to a cycloalkyl group, in which the aryl and cycloalkyl are as described herein. Exemplary aryl fused cycloalkyl groups include tetrahydronaphthyl and indanyl. The aryl and cycloalkyl rings can each be replaced by one or more substituent groups. The cycloalkyl group fused to the aryl can be bound to the remainder of the compound by any available carbon atom. "Heterocycloalkyl fused to aryl" denotes a monocyclic aryl ring, such as phenyl, fused to a heterocycloalkyl group, in which the aryl and heterocycloalkyl are as described herein. Heterocycloalkyl groups fused to aryl include tetrahydroquinolinyl, indolinyl, benzodioxinyl, benxodioxolyl, dihydrobenzofuranyl and isoindolonyl. The aryl and heterocycloalkyl rings can each be replaced by one or more substituent groups. The heterocycloalkyl group fused to aryl can be linked to the remainder of the compound by any available carbon or nitrogen atom. "Aryloxy" means an -O-aryl group in which the aryl is described above. Exemplary aryloxy groups include phenoxy. The "cyclic amine" means a system of the optionally substituted 3 to 8 membered monocyclic cycloalkyl ring wherein one of the ring carbon atoms is replaced by nitrogen, and which may optionally contain an additional heteroatom selected from O, S or NR ( where R is as it is written in the present). The amines 1 Cyclics include pyrrolidine, piperidine, morpholine, piperazine and N-methylpiperazine. The cyclic amine group can be replaced by one or more substituent groups. "Cycloalkyl" means an optionally substituted bicyclic or monocyclic ring system of 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl. The cycloalkyl group can be substituted by one or more substituent groups. "Cycloalkylalkyl" means a cycloalkyl-alkyl group in which the cycloalkyl and alkyl portions are as described above. Monocyclic cycloalkylalkyl groups include cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl. The "Dendrimer" means a multifunctional basic group with a branched group linked to each functional site. Each branched site can be linked to another branched molecule and this process can be repeated several times. "Dialkylamino" means a group -N (alkyl) 2 in which the alkyl is as defined above. Exemplary dialkylamino groups include dimethylamino and diethylamino. "Halo" or "halogen" means fluoro, chloro, bromo or iodo. Preferred are fluoro or chloro.

The "haloalkoxy" means an -O-alkyl group in which the alkyl is substituted by one or more halogen atoms. Exemplary haloalkyl groups include trifluoromethoxy and difluoromethoxy. The "haloalkyl" means an alkyl group which is substituted by one or more halo atoms. Exemplary haloalkyl groups include trifluoromethyl. "Heteroaryl" as a group or part of a group denotes an optionally substituted aromatic monocyclic or monocyclic organic portion of 5 to 14 ring atoms, preferably 5 to 10 ring atoms, in which one or more of the ring atoms they are elements other than carbon, for example nitrogen, oxygen or sulfur. Examples of such groups include benzimidazolyl, benzoxazolyl, benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl group , tetrazolyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl. The heteroaryl group can be replaced by one or more substituent groups. The heteroaryl group can be linked to the remainder of the compound of the invention by any available carbon or nitrogen atom. "Heteroarylalkyl" means a heteroaryl-alkyl group in which the heteroaryl and alkyl portions are as described above. Preferred heteroarylalkyl groups contain a lower alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl. "Heteroarylalkyloxy" means a heteroaryl-alkyloxy group in which the heteroaryl and alkyloxy portions are as described above. Preferred heteroaryl alkyloxy groups contain a lower alkyl moiety. Exemplary heteroaryloalkyloxy groups include pyridylmethyloxy. "Heteroaryloxy" means a heteroaryloxy group in which the heteroaryl is as described above. Exemplary heteroaryloxy groups include pyridyloxy. "Cycloalkyl fused to aryl" means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a cycloalkyl group, in which heteroaryl and cycloalkyl are as described above. Exemplary aryl fused heterocycloalkyl groups include tetrahydroquinolinyl and tetrahydrobenzofuranyl. The heteroaryl and cycloalkyl rings can each be substituted by one or more substituent groups. The cycloalkyl group fused to the heteroaryl can be linked to the remainder of the compound by any available carbon or nitrogen atom. "Heterocycloalkyl fused to heteroaryl" means a monocyclic heteroaryl group, such as pyridyl or furanyl, fused to a heterocycloalkyl group, in which the heteroaryl and heterocycloalkyl are as described above. Exemplary heterocycloalkyl fused heterocycloalkyl groups include dihydrodioxinopyridinyl, dihydropyrrolopyridinyl, dihydrofuranopyridinyl, and dioxolopyridinyl. The heteroaryl and heterocycloalkyl rings can each be replaced by one or more substituent groups. The heteroheterocycloalkyl group fused to the aryl can be linked to the remainder of the compound by any available carbon or nitrogen atom. "Heterocycloalkyl" means: (I) an optionally substituted cycloalkyl group of 4 to 8 ring members which contain one or more heteroatoms selected from O, S or NR; (II) a cycloalkyl group of 4 to 8 ring members which contain CONR and CONRCO (examples of such groups include succinimidyl and 2-oxopyrrolidinyl). The heterocycloalkyl group can be substituted by one or more substituent groups. The heterocycloalkyl group can be linked to the remainder of the compound by any available carbon or nitrogen atom. "Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl- group in which the heterocycloalkyl and alkyl portions are as described above.

The "lower alkyl" as a group means unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched having from 1 to 4 carbon atoms in the chain, ie, methyl, ethyl, propyl (propyl or iso-propyl) or butyl (butyl, isobutyl or tert-butyl). The "sulfonyl" means an S02-alkyl group in which the alkyl is as described herein. Exemplary sulfonyl groups include methanesulfonyl. "Sulfonylamino" means a group -NR-sulfonyl in which R and sulfonyl are as described herein. Exemplary sulfonylamino groups include -NHS02CH3. The R means alkyl, aryl, or heteroaryl as described herein. "Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable basic addition salts, pharmaceutically acceptable acid addition salts, and pharmaceutically acceptable quaternary ammonium salts. For example (I) wherein a compound of the invention contains one or more acidic groups, for example carboxy groups, pharmaceutically acceptable basic addition salts which may be formed including sodium, potassium, calcium, magnesium and ammonium salts, or salts with amines organic, such as, diethylamine, M-methyl-glucamine, diethanolamine or amino acids (for example lysine) and the like; (II) wherein a compound of the invention contains a basic group, such as an amino group, pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, maleates , fumarates, succinates and the like; (III) where a compound contains an acceptable ion counter of the quaternary ammonium group which may be, for example, chlorides, bromides, sulfates, methanesulfonates, benzenesulfonates, toluenesulfonates (tosylates), phosphates, acetates, citrates, lactates, tartrates, mesylates , maleates, fumarates, succinates and the like. It will be understood that, as used herein, referring to the compounds of the invention is meant to also include the pharmaceutically acceptable salt. "Prodrug" refers to a compound which is converted in vivo by metabolic means (for example by hydrolysis, reduction or oxidation) to a compound of the invention. Suitable groups for forming pro-drugs are described in "The Practice of Medicinal Chemistry, 2nd Ed. Pp561-585 (2003) and in FJ Leinweber, Drug Metab. Res., 18, 379. (1987) It will be understood that, as is used herein, referring to the compounds of the invention is understood to also include the prodrug forms.The "saturated" belongs to compounds and / or groups which do not have any of the carbon-carbon double bonds or triple bonds carbon-carbon The cyclic groups referred to above, to name a few, aryl, heteroaryl, cycloalkyl, cycloalkyl fused to the aryl, heterocycloalkyl fused to the aryl, heterocycloalkyl, heterocycloalkyl fused to the aryl, heterocycloalkyl fused to heteroaryl and cyclic amine can be replaced by one or more substituent groups Suitable optional substituent groups include acyl (for example -C0CH3), alkoxy (for example, -OCH3), alkoxycarbonyl (for example -COOCH3), uilamino (for example -NHCH3), alkylsulfinyl (for example -SOCH3), alkylsulfonyl (for example -S02CH3), alkylthio (for example -SCH3), -NH2, aminoacyl (for example -C0N (CHa)), aminoalkyl (for example -CH2NH2), arylalkyl (for example -CH2Ph or -CH2-CH2-Ph), cyano, dialkylamino (for example -N (CH3) 2), halo, haloalkoxy (for example -OCF3 or -0CHF2), haloalkyl (for example -CF3), alkyl (for example -CH3 or -CH2CH3), -OH, -CHO, -N02, aryl (optionally substituted with alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted with alkoxy, haloalkoxy), halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl (for example -CONH2, -CONHCH3), aminosulfonyl (for example -S02NH2, -S02NHCH3), acylamino (for example -NHCOCH3), sulfonylamino (for example -NHS02CH3), heteroarylalkyl, cyclic amine (for example morpholine), aryloxy, heteroaryloxy, arylalkyloxy (for example benzyloxy) and heteroarylalkyloxy. The alkylene or alkenylene groups may be optionally substituted. Suitable optional substituent groups include alkoxy (eg, -OCH3), alkylamino (for example -NHCH3), alkylsulfinyl (for example -SOCH3), alkylsulfonyl (for example -S02CH3), alkylthio (for example -SCH3), -NH2, aminoalkyl (for example -CH2NH2), arylalkyl (for example -CH2Ph or -CH2-CH2-Ph), cyano, dialkylamino (for example -N (CH3) 2), halo, haloalkoxy (for example -OCF3 or -OCHF2), haloalkyl (for example -CF3), alkyl (for example -CH3 or -CH2CH3), -OH, -CHO, and -N02. The compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis and trans forms, E and Z forms, R, S and meso forms, keto, and enol forms. While not otherwise indicated a reference to a particular compound including all such as isomeric forms, including racemic and other mixtures thereof. Where such appropriate isomers can be separated from their mixtures by the application or adaptation of known methods (for example chromatographic techniques and recrystallization techniques).

Where such suitable isomers can be separated by the application of adaptation of known methods (for example asymmetric synthesis).

The groups R1, R2 and R3 There are three combinations of groups R1, R2 and R3 In combination (I) R1 is C6-C6 alkyl or hydrogen; and R2 is hydrogen or a group -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C (0) 0-R7 or -Z-C (0) -R7; and R3 is a single pair, or C C ~ alkyl, in which case the nitrogen atom to which it is bonded is a quaternary nitrogen and carries a positive charge. In combination (II) R1 and R3 together with the nitrogen to which they are bound form a heterocycloalkyl ring, and R2 is a single pair (this is the substituent R2 is absent) or a group -R7, -ZY-R7, -Z- NR9R10, -Z-CO-NR9R10, -Z-NR9-C (O) O-R7 or -ZC (0) -R7. In this case, of course, when R2 is different from a single pair, the nitrogen atom to which it bonds is a quaternary nitrogen and carries a positive charge. In particular R1 and R3 together with the nitrogen to which they are attached can form a monocyclic ring of 3 to 7 ring atoms, in which the heteroatoms are nitrogen. Examples of such rings include azetidinyl, piperidinyl, piperazinyl, N-substituted piperazinyl such as methylpiperazinyl and pyrrolidinyl rings. In combination (III) R1 and R2 together with the nitrogen to which they are bonded form a heterocycloalkyl ring, the ring is substituted by a group -Y-R7, -ZY-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C (0) 0-R7 or -ZC (0) -R7 and R3 is a single pair (that is, the substituent R3 is absent), or C6-C6 alkyl especially methyl. In particular R1 and R2 together with the nitrogen to which they are linked can form a monocyclic ring of 3 to 7 ring atoms, in which the heteroatoms are nitrogen. Examples of such rings include azetidinyl, piperidinyl, piperazinyl, Piperazinyl substituted with N such as methylpiperazinyl rings, and pyrrolidinyl. Of course, when R3 is different from a single pair, the nitrogen atom to which it binds is a quaternary nitrogen and carries a positive charge. Where a group -R7 or -Y-R7, -Z-Y-R7, or a group -Z-NR9R10; or a group -Z-CO- NR9R10; or a group -Z-NR9-C (O) O-R7 or a group -Z-C02-R7; is present in R2, or the ring formed by R1, R2 and the nitrogen to which they are linked: Z may be, for example - (CH2)? _ g the latter being optionally substituted in a maximum of three carbons in the chain by methyl; And it is a bond or -O-; R7 may be Ci-Ce alkyl, such as methyl, ethyl, n or isopropyl, n, sec or tertbutyl; The optionally substituted aryl such as phenyl or naphthyl, or heterocycloalkyl fused to the aryl such as 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, or dihydrobenzofuranyl; Optionally substituted heteroaryl such as pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzothiazolyl, quinolyl, thienyl, benzothienyl, furyl, benzofuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benzotriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl and indazolyl; The optionally substituted aryl (Ci-C alquilo alkyl) such as those in which the aryl part is any of the above-mentioned aryl groups specifically mentioned and the part (C?-C6 alkyl) - is -CH 2 - or -CH 2 CH 2 -; Cycloalkyl fused to the optionally substituted aryl such as indanyl or 1, 2, 3, 4-tetrahydronaphthalenyl; The heteroaryl (Ci-Cß alkyl) optionally substituted such as those in which the heteroaryl part is any of the above-mentioned heteroaryl groups specifically mentioned and the part (C?-C6 alkyl) - is -CH 2 - or -CH 2 CH 2 -; The optionally substituted cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; or optionally substituted heterocycloalkyl (C 1 -C 8 alkyl), such as those in which the heterocycloalkyl part is azetidinyl, piperidinyl, piperazinyl, piperazinyl substituted with N such as methylpiperazinyl or pyrrolidinyl and the part (C 6 -C 6 alkyl) is CH2- or -CH2CH2-; R9 and R10 can be independently selected from hydrogen; Ci-Cd alkyl such as methyl, ethyl or n or isopropyl; or any of those optionally substituted aryl, heterocycloalkyl fused to the aryl, heteroaryl or aryl groups (Ci-Cs alkyl) - specifically mentioned in the discussion of R7 above; or R9 and R10 together with the nitrogen atom to which they are linked can form a heterocyclic ring of 4-8 ring atoms, preferably 4-6 ring atoms which optionally contain an additional nitrogen or oxygen atom, such as azetidinyl, piperidinyl , piperazinyl, piperazinyl substituted with N such as methylpiperazinyl, pyrrolidinyl, morpholinyl, and thiomorpholinyl. In a preferred embodiment of the invention, in the group -NR1R2R3, R1 is methyl or ethyl, R2 is -Z-NR9R10 or -ZY-R7 as defined and discussed above, and is a bond or -O- and -Z- is straight or branched radical alkylene linked to nitrogen and -NR9R10 or -YR7 by a chain above 16, for example above 10, carbon atoms, and R3 is methyl, so that the nitrogen is quaternary and carries a positive charge . In these cases, R7 is preferably a cyclic lipophilic group such as phenyl, benzyl, dihydrobenzofuryl or phenylethyl and R9 and R10 are as defined and discussed above. In another preferred embodiment of the invention, in the group -NR1R2R3, R2 is -Z- NR9R10 or -ZY-R7 as defined and discussed above, Y is a bond or -0-, and -Z- is a straight alkylene radical or branched linked to nitrogen and -NR9R10 or -YR7 by a chain above 16, for example above 10, carbon atoms, and R1 and R3 together with the nitrogen to which they are bound form a heterocyclic ring of 4-8 atoms of the ring, preferably 4-6 ring atoms which optionally contains a further nitrogen or oxygen atom, such as azetidinyl, piperidinyl, piperazinyl, N-substituted piperazinyl such as methylpiperazinyl ring, pyrrolidinyl, morpholinyl, or thiomorpholinyl, such that nitrogen It is quaternary and carries a positive charge. In these cases, R7 is preferably a cyclic lipophilic group such as phenyl, benzyl, dihydrobenzofuryl or phenylethyl; R9 and R10 are as defined above. In a subset of compounds of this embodiment, R1 and R3 together with the nitrogen to which they are bound form a piperidinyl or pyrrolidinyl ring.

The groups R4, R5 and R6 R4 and R5 can be independently selected from any of those aryl, heterocycloalkyl fused to the aryl, cycloalkyl fused to the aryl, heteroaryl, Ci-Ce alkyl, or cycloalkyl groups specifically mentioned in the discussion of R5 above. R6 can be -OH, a hydrogen atom, C? -C6 alkyl such as methyl or ethyl, C? -C6 alkoxy such as methoxy or ethoxy, hydroxy C? -C6 alkyl such as hydroxymethyl, nitrile, or a CONR82 group wherein each R 8 is independently Ci-Cβ alkyl such as methyl or ethyl, or a hydrogen atom. Currently preferred is the case where R6 is -OH. Preferred combinations of R4 and R5, especially when R6 is -OH, include those wherein (I) each of R4 and R5 is optionally substituted monocyclic heteroaryl of 5 or 6 ring atoms such as pyridyl, oxazolyl, thiazolyl, furyl and specifically thienyl as a 2-thienyl; (II) each of R 4 and R 5 is optionally substituted phenyl; (III) one of R4 and R5 is optionally substituted phenyl and the other is cycloalkyl such as cyclopropyl, cyclobutyl, or especially cyclopentyl or cyclohexyl; and (IV) one of R4 and R5 is optionally substituted monocyclic heteroaryl of 5 or 6 ring atoms such as pyridyl, thienyl, oxazolyl, thiazolyl, or furyl; and the other is cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

The ring of the atom A A can be an oxygen or sulfur atom The substituent R8 Although R8 can be Ci-Cß alkyl, such as methyl or ethyl, it is currently preferred that R8 is a hydrogen atom.

The Radical X Although X may be an alkylene, alkenylene or alkynylene radical, at present it is preferred that it be alkylene, for example ethylene or methylene. A preferred subclass of compounds with which the invention is interested consists of those of the formula (IA) where A is -0- or -S-; m is 1 or 2; ring A is an optionally substituted phenyl ring, or monocyclic heterocyclic ring of 5 or 6 ring atoms, or a heterocycloalkyl ring system fused to phenyl wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; R 4 is phenyl, thienyl, cyclopentyl or cyclohexyl; R5 is phenyl; thienyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 with the condition that s + t is not greater than 16; Y is a bond or -O-, and X ~ is pharmaceutically acceptable anion. Another preferred subclass of compounds with which the invention is concerned consists of those of the formula (IB) where A is -0- or -S-; m is 1 or 2; ring B is a pyrrolidinium or piperidinium ring; ring A is an optionally substituted phenyl ring, or monocyclic heterocyclic ring of 5 or 6 ring atoms, or heterocycloalkyl ring system fused to phenyl wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms; R 4 is phenyl, thienyl, cyclopentyl or cyclohexyl; R5 is phenyl; thienyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, , 6 or 7 with the condition that s + t is not greater than 16; Y is a bond or -0-, and X "is a pharmaceutically acceptable anion.

Another preferred subclass of compounds with which the invention is concerned consists of those of the formula (IC) where A is -0- or -S-; m is 1 or 2; Ring B is a pyrrolidinium or piperidinium ring; R 4 is phenyl, thienyl, cyclopentyl or cyclohexyl; R5 is phenyl; thienyl, cyclopentyl or cyclohexyl; R9 and R10 are independently hydrogen atom, or optionally substituted Ci-Cd alkyl or aryl, such as optionally substituted phenyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 with the condition that s + t is not greater than 16; Y is a bond or -O-, and X "is a pharmaceutically acceptable anion In the compounds (IA) and (IB), it is currently preferred that ring A is (I) phenyl optionally substituted, wherein the optional substituents are selected from alkoxy, halo especially fluoro or chloro, Ci-Ce alkyl, C? -C3 aminoacyl, C? -C3 amino alkyl, and, or (II) a fused heterocycloalkyl ring system of phenyl wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms, such as dihydrobenzofuranyl. In each of the subclasses (IA), (IB) and (IC), s + t can be, for example 1, 2, 3, 4, 5, 6, or 7 and can arise from appropriate combinations of tys such as where t is 0, 1, 2, 3, 4, 5 or 6 and s is 1, 2, 3, 4, 5, 6 or 7. In compounds (IA) and (IB), a currently preferred combination of t, And this is where t is 0, s is 3, and Y is -O-. A currently preferred additional combination is where Y is a bond and s + t is 2, 3 or 4.

In compounds (IC) a currently preferred combination of t, Y and s is where Y is a bond and s + t is 8, 9 or 10. It will be appreciated that certain combinations of R4, R5 and R6 may give rise to optical enantiomers. In such cases, both enantiomers of the invention generally exhibit affinity to the M3 receptor, although one enantiomer is generally preferred on M3 receptor potency criteria and / or selectivity against the M receptor. In some embodiments of the invention, the absolute stereochemistry of the preferred enantiomer is known. For example, in a preferred embodiment R 4 is a phenyl group; R5 is a cyclohexyl or cyclopentyl group; R6 is a hydroxyl group; and the carbon atom to which they are bonded has the absolute configuration R as dictated by the Cahn-lngold-Prelog rules. Examples of compounds of the invention include those of the Examples herein. Preferred compounds of the invention include: [2- (Hydroxy-diphenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium salts [2- ((R) -cyclohexyl] salts -hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium [2- ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] salts ] -dimethyl-phenethyl-ammonium [2- ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (4-methyl-pent-3-enyl) -ammonium salts [2- ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] - [2- (2,3-dihydro-benzofuran-5-yl) -ethyl] -dimethylammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (6-methyl-pyridin-2-ylmethyl) -ammonium [2- (Cyclopentyl-hydroxy-phenyl-methyl) salts] -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium salts of 1- [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -1- (3-phenoxy) propyl) -pyrrolidinium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (4-phenoxy-butyl) -ammonium salts of (2-Benzyloxy-ethyl) - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-ammonium salts of [2 - ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (4-phenyl-butyl) -ammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl ) -oxazol-5-ylmethyl] - [3- (4-fluoro-phenoxy) -propyl] -dimethyl-ammonium [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] salts ] -dimethyl- (3-phenyl-propyl) -ammonium [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (2-phenoxy-ethyl) -ammonium salts [2- ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-p-tolyloxy-propyl) -ammonium salts [3- (4-Chloro-phenoxy]] salts ) -propyl] - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-ammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] - [3- (3, -dichloro-phenoxy) -propyl] -dimethyl-ammonium [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethi] salts l] -dimethyl- (8-methylamino-octyl) -ammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- [2- (4-methylaminomethyl- phenyl) -ethyl] -ammonium salts of. { 2- [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-yl] -ethyl} -dimethyl- (3-phenoxy-propyl) -ammonium salts of. { 2- [2- (Hydroxy-diphenyl-methyl) -oxazol-5-yl] -ethyl} -dimethyl- (3-phenoxy-propyl) -ammonium salts of [2- (hydroxydiphenylmethyl) thiazol-5-ylmethyl] dimethyl- (3-phenoxypropyl) ammonium salts of (3-benzyloxypropyl) - [2- ((R) - cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-ammonium [2- (4-Chloro-benzyloxy) -ethyl] - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl] salts ) -oxazol-5-ylmethyl] -dimethyl-ammonium As referred to in the context to the previous section of the background of the previous invention, compounds with dual M3 receptor antagonist activity and β2-adrenoreceptor agonist are known, and the treatment Respiratory disease with such dual activity compounds is a recognized form of treatment. The known strategy for the provision of compounds with such dual activity mechanisms is a simple covalent binding of a compound with M3 receptor antagonistic activity to a compound with a β2 adrenoreceptor agonist activity. Such covalent conjugates of a compound (I) of the M3 receptor agonist as defined and discussed above and a β2 adrenoreceptor agonist also forms part of the invention. For example. , such conjugates of dual activity include compounds of the formula (I), as defined and discussed above, modified by replacing the group R2 with a group LB where L is a linking radical and B is a portion having β2-adrenoceptor agonist activity . Structurally, such conjugates of dual activity can be represented as in formula (III): wherein R1, R3, R4, R5, R6 and R8 are as defined and discussed above in relation to the compounds (I) of the invention, L is a divalent linking radical and B is a moiety having β2-adrenoreceptor agonist activity, such as the β2-agonist pharmacophor is referred to above in the context of the invention section. Such compounds (III) form another aspect of the present invention. An example of such a compound is Example No. 77 herein. The present invention also relates to pharmaceutical formulations comprising, as an active ingredient, a compound of the invention. Other compounds can be combined with compounds of this invention for the preparation and treatment of inflammatory lung diseases. Thus, the present invention also concerns pharmaceutical compositions for preventing and treating airway disorders such as chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, pulmonary fibrosis, pulmonary emphysema, and allergic rhinitis comprising a therapeutically effective amount of a compound of the invention and one or more of the other therapeutic agents. Other compounds can be combined with compounds of this invention for the prevention and treatment of inflammatory diseases of the lung. According to the invention, it includes a combination of an agent of the invention as described hereinbefore with one or more anti-inflammatories, bronchodilator, antihistamine, decongestant or anti-tressive agents, the agents of the invention described hereinbefore and Combination agents exist in the same or different pharmaceutical compositions, administered separately or simultaneously. Preferred combinations would have two or three different pharmaceutical compositions. Suitable therapeutic agents for combination therapy with compounds of the invention include: One or more of the other bronchodilators such as PDE3 inhibitors; Methyl xanthines such as theophylline; Other antagonists the muscarinic receptor; A corticosteroid, for example fluticasone propionate, ciclesonide, mometasone furoate or budesonide, or steroids described in WO02 / 88167, O2 / 12266, WO02 / 100879, WO02 / 00679, WO03 / 35668, WO03 / 48181, O03 / 62259, O03 / 64445, WO03 / 72592, O04 / 39827 and WO04 / 66920; A non-steroidal glucocorticoid receptor agonist; A β2 adrenoreceptor agonist, for example albuterol (salbutamol), salmeterol, metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, picumeterol, GSK-159797, GSK-597901, GSK-159802, GSK-64244, GSK- 678007, TA-2005 and also compounds of EP1440966, JP05025045, WO93 / 18007, WO99 / 64035, US2002 / 0055651, US2005 / 0133417, US2005 / 5159448, WO00 / 075114, O01 / 42193, WO01 / 83462, O2 / 66422, O02 / 70490, WO02 / 76933, O03 / 24439, WO03 / 42160, WO03 / 42164, O03 / 72539, O03 / 91204, WO03 / 99764, WO04 / 16578, O04 / 016601, WO04 / 22547, WO04 / 32921, WO04 / 33412 , O04 / 37768, WO04 / 37773, O04 / 37807, WO0439762, WO04 / 39766, O04 / 45618, O04 / 46083, WO04 / 71388, WO04 / 80964, EP1460064, WO04 / 087142, WO04 / 89892, EP01477167, US2004 / 0242622 , US2004 / 0229904, WO04 / 108675, O04 / 108676, WO05 / 033121, WO05 / 040103, WO05 / 044787, WO04 / 071388, WO05 / 058299, WO05 / 058867, WO05 / 065650, WO05 / 066140, WO05 / 070908, WO05 / 092840, O05 / 092841, O05 / 092860, WO05 / 092887, WO05 / 092861, WO05 / 090288, WO05 / 092087, WO 05/080324, O05 / 080313, US20050182091, US20050171147, WO05 / 092870, O05 / 077361, DE10258695, WO05 / 111002, WO05 / 111005, WO05 / 110990, US2005 / 0272769 WO05 / 110359, WO05 / 121065, US2006 / 0019991, WO06 / 016245, WO06 / 014704, 06/031556, WO06 / 032627, US2006 / 0106075, US2006 / 0106213, 06/051373, WO06 / 056471; A leukotriene modulator, for example montelukast, zafirlukast or pranlukast; protease inhibitors, such as inhibitors of the metalloprotease matrix for example MMP12 and TACE inhibitors such as marimastat, DPC-333, GW-3333; Inhibitors of human neutrophil elastase, such as sivelestat and those described in WO 04/043942, WO05 / 021509, WO05 / 021512, O05 / 026123, O05 / 026124, WO04 / 024700, O04 / 024701, O04 / 020410, WO04 / 020412, WO05 / 080372, WO05 / 082863, WO05 / 082864, O03 / 053930; Inhibitors of phosphodiesterase-4 (PDE4), for example roflumilast, arofilino, cilomilast, ONO-6126 or IC-485; Phosphodiesterase-7 inhibitors; An antitussive agent, such as codeine or dextramorphan; Kinase inhibitors, particularly P38 MAPKinase inhibitors; Antagonists P2X7; INOS inhibitors; A non-steroidal anti-inflammatory agent (NSAID), for example ibuprofen or ketoprofen; A dopamine receptor antagonist; TNF-α inhibitors, for example anti-TNF monoclonal antibodies, such as Remicade and CDP-870 and TNF receptor immunoglobulin molecules, such as Enbrel; A2a agonists such as those described in EP1052264 and EP1241176; Antagonists A2b such as those described in WO2002 / 42298; Modulators of chemokine receptor function, for example CCR1, CCR2, CCR3, CXCR2, CXCR3, CX3CR1 and CCR8 antagonists, such as SB-332235, SB-656933, SB-265610, SB-225002, MCP-K9- 76), RS-504393, MLN-1202, INCB-3284; The compounds which modulate the action of prostanoid receptors, for example a PGD2 (DPI or CRTH2), or a thromboxane A2 antagonist for example ramatrobant; The Compounds which modulate the Th1 or Th2 function, for example, PPAR agonist; 1-interleukin receptor antagonist, such as Kineret; Interleukin 10 agonists, such as decaine; HMG-CoA reductase inhibitors (statins); for example rosuvastatin, mevastatin, lovastatin, simvastatin, pravastatin and fluvastatin; Mucus regulators such as INS-37217, diquafosol, sibenadet, CS-003, talnetant, DNK-333, MSI-1956, gefitinib; Anti-infective agents (antibiotic or antiviral), and antiallergic drugs including, but not limited to, anti-histamines. The weight ratio of the first and second active ingredients can be varied and will depend on the effective dose of each ingredient. Generally, an effective dose of each will be used. Any suitable route of administration can be employed to provide a mammal, especially a human, with an effective dosage of a compound of the present invention, in therapeutic use, the active compound can be administered by any convenient, adequate or effective route. Suitable routes of administration are known to those of skill in the art, and include oral, intravenous, rectal, parenteral, topical, ocular, nasal, buccal, and pulmonary. The magnitude of prophylactic or therapeutic dose of a compound of the invention, of course, will vary depending on a range of factors, including the activity of the specific compound being used, the age, body weight, diet, general health and sex of the patient, time of administration, route of administration, route of excretion, use of any of the other drugs, and the severity of the disease under treatment. In general, the range of daily dose for inhalation will fall within the range of about 0.1 μg to about 10 mg per kg of body weight of a human, preferably 0.1 μg to about 0.5 mg per kg, and more preferably 0.1 μg up to 50μg per kg, in single or divided doses. On the other hand, it may be necessary to use doses outside these limits in some cases. Compositions suitable for administration by inhalation are known, and may include carriers and / or diluents that are known for use in such compositions. The composition may contain 0.01-99% by weight of the active compound. Preferably, a dose unit comprises the active compound in an amount of 1 μg to 10 mg. For oral administration, suitable doses are 10 μg per kg up to 100 mg per kg, preferably 40 μg per kg up to 4 mg per kg. Another aspect of the present invention provides pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier. The term "composition", as a pharmaceutical composition, is intended to encompass a product comprising the active ingredients, and the inert ingredient (pharmaceutically acceptable excipients) that make the carrier, as well as any product which results, directly or indirectly, from the combination, complexation or Aggregation of any of two or more of the ingredients, or of the dissociation of one or more of the ingredients, or of other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by administering a compound of the invention, additional active ingredients, and pharmaceutically acceptable excipients. The pharmaceutical compositions of the present invention comprise a compound of the invention as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or acid bases and organic or acid bases, and salts of quaternary ammonium compounds with pharmaceutically acceptable ion counter. For delivery by inhalation, the active compound is preferably in the form of microparticles. They can be separated by a variety of techniques, including dried sprayer, frozen spray and micronisation. By way of example, a composition of the invention can be separated as a suspension for delivering a nebulizer or as an aerosol in a liquid propellant, eg for use in a pressurized medium dose inhaler (PMDI). Propellants suitable for use in a PMDI are known to those of skill, and include CFC-12, HFA-134a, HFA-227, HCFC-22 (CCI2F2) and HFA-152 (C2H4F2) and isobutane. In a preferred embodiment of the invention, a composition of the invention is in dry powder form, for release using a dry powder inhaler (DPI). Many types of IPR are known. Microparticles for delivery by administration can be formulated with excipients that aid delivery and delivery. For example, in a dry powder formulation, the microparticles can be formulated with large carrier particles that aid the current of the DPI in the lung. Suitable carrier particles are known, and include lactose particles; these can have an average mass aerodynamic diameter of greater than 90 μm. In the case of an aerosol-based formulation, an example is: Compound of the invention 24 mg / tank Lecithin, NF Liq. With e . 1.2 mg / tank Trichlorofluoromethane, NF 4.025 g / tank Dichlorodifluoromethane, NF 12.15 g / tank. The active compounds can be dosed as described depending on the inhaler system used. In addition to the active compounds, the administration forms may additionally contain excipients, such as, for example, propellants (for example Frigen in the case of medium aerosols), active substances of surfactants, emulsifiers, stabilizers, preservatives, flavorings, fillers. (for example lactose in the case of powder inhalers) or, if appropriate, additional active compounds. For inhalation purposes, a large number of systems are available with which aerosols of optimum particle size can be generated and administered, using an inhalation technique which is appropriate for the patient. In addition to the use of adapters (spacers, expanders) and pear-shaped containers (for example Nebulator®, Volumatic®), and automatic devices that emit a spray by blow (Autohaler®), for medium aerosols, in particular in the case of powder inhalers, a number of technical solutions are available (eg Diskhaler®, Rotadisk®, Turbohaler® or inhalers for example as described in EP-A-0505321). Additionally, the compounds of the invention can be delivered in multi-chamber devices thus allowing for release of combination agents.

Synthesis Methods The compounds of the invention of the present invention can be prepared according to the procedures of the following reaction schemes and examples, using appropriate materials, and are further exemplified by the following specific examples. Additionally, by using the methods described with the description contained herein, one of ordinary skill in the art can readily prepare additional compounds of the present invention claimed herein. The compounds illustrated in the examples are not, however, constructed to form only the genus that is considered to be the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those of ordinary skill in the art will readily appreciate that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The compounds of the invention can be isolated in the form of their pharmaceutically acceptable salts, such as those previously described herein. This may be necessary to protect the reactive functional groups (eg, hydroxy, amino, thio or carboxy) in intermediates used in the preparation of compounds of the invention to avoid their unwanted participation in a reaction leading to the formation of the compounds. Conventional protecting groups, for example those described by T. W. Greene and P.M. Wuts in "Protective groups in organic chemistry" John Wiley and Sons, 1999, may be used. The compounds of the invention can be prepared according to the routes illustrated in Reaction Schemes 1-4.

Reaction scheme 1 Reaction scheme 2 (VI) (XVII) (XX) Reaction Scheme The compounds of the formula (Ib) wherein Rc, Rd and Re are as defined for R1, R2 and R3 and are not a hydrogen atom can be prepared from the compounds of the formula (Ia) by reaction with an alkylating agent of the formula (XXI): Re-W (XXI) wherein W is a leaving group such as halogen, tosylate, mesylate. The reaction can be carried out in a range of solvents, preferably DMF, chloroform or acetonitrile at a temperature from 0 ° C to the reflux temperature of the solvent. In a similar manner, the compounds of the formula (Ie), (Ig), (Ii), (Ik) and (In) can be prepared from the compounds of the formula (Id), (If), (Ih), (Ij) and (Im) respectively. It will be appreciated that some compounds may contain a chiral center and thus exist in enantiomeric forms which can be separated by chiral preparative HPLC techniques using conditions known to those of ordinary skill in the art and exemplified below. The compounds of the general formula (I-a) can be prepared from the compounds of the general formula (II): by reaction with a compound of the general formula (XXII): RbM (XXII) wherein Ra and R are as defined for R4 and R5 in the general formula (I) and M represents a metal counterion such as Li or MgBr. The reaction can take place in an aprotic organic solvent such as THF or diethyl ether at a temperature range, preferably between -78 ° C and the reflux temperature of the solvent. The compounds of the general formula (XXII) are well known in the art and are readily available or can be prepared by known methods. The compounds of the general formula (II) can be prepared from the compounds of the general formula (III): r (|||) by reaction with an amine of the formula (XXIII): RcRdNH (XXIII) wherein Rc and Rd are as defined for R1 and R2 in the general formula (I). The reaction is carried out in a range of solvents, preferably THF / DCM at a temperature range, preferably between 0 and 100 ° C. The compounds of the general formula (XXIII) are well known in the art and can be prepared by known methods, or are commercially available. The compounds of the formula (III) can be prepared from the compounds of the general formula (IV): - by reaction with a brominating agent such as N-bromosuccinimide in the presence of a radical initiator such as AIBN or benzoyl peroxide. The reaction can be carried out in suitable solvents, such as CC14, at a range of temperatures, preferably between room temperature and the reflux temperature of the solvent. The compounds of the formula (IV) can be prepared from the compounds of the general formula (V): by reaction with an acid such as hydrochloric acid, sulfuric acid, methanesulfonic acid or trifluoromethanesulfonic acid in a range of solvents such as THF, DCM, water, and preferably 1,4-dioxane at a temperature range, preferably between room temperature and temperature to reflux of the solvent. Alternatively the compounds of the formula (IV) can be prepared from the compounds of the general formula (V) by palladium catalyzed cyclization using palladium catalyst such as bis (dibenzylideneacetone) palladium in the presence of a ligand such as triphenylphosphine and a base such as sodium tert-butoxide in a solvent such as THF from room temperature to the reflux temperature of the solvent. Alternatively, the compounds of the formula (IV) can be prepared from the compounds of the formula (XVI): according to the method described in J. Chem. Soc. 1948, 1960. The compounds of the general formula (XVI) are known in the art and can be prepared by known methods such as those described in Tetrahedron 2002, 58 (14), 2813. Alternatively, the compounds of the formula (IV) can be prepared from the compounds of the formula (XVII): according to the method described in J. Org. Chem., 1938, 2, 319. Compounds of the general formula (XVII) are well known in the art and can be prepared by known methods such as those described in GB2214180. The compounds of the general formula (V) can be prepared from the compounds of the general formula (VI): by reaction with propargylamine in the presence of a suitable coupling agent, such as DCC / HOBt or many other known coupling methodologies. Alternatively, the compounds of the formula (VI) can be converted to, for example, the acid chloride and amide formation optionally carried out in the presence of a suitable non-nucleophilic base and the compatible solvent under well-known conditions. The compounds of the general formula (VI) are readily available or can be prepared by known methods. Alternatively, the compounds of the general formula (I-a) can be prepared from the compounds of the general formula (VII): according to methods described above for the preparation of the compounds of the formula (II) of the compounds of the formula (III) The compounds of the general formula (VII) can be prepared from the compounds of the formula (VIII): according to methods similar to those used to prepare the compounds of the formula (III) of the compounds of the formula (IV) as described above. The compounds of the general formula (VIII) can be prepared from the compounds of the formula (IV) using methods described above for the preparation of the compounds of the formula (I-a) of the compounds of the formula (II). Alternatively, the compounds of the formula (VIII) can be prepared from the compounds of the formula XIX When using the methods described above for the preparation of the compounds of the formula (IV) of the compounds of the formula (XVII). The compounds of the general formula (XIX) can be prepared by known methods such as those described in GB2214180. Alternatively, the compounds of the formula (VIII) can be prepared from the compounds of the formula (XX): using methods described above for the preparation of the compounds of the formula (IV) of the compounds of the formula (V). The compounds of the general formula (XX) can be prepared from the compounds of the formula (XVIII) using methods described above for the preparation of the compounds of the formula (V) of the compounds of the formula (VI). Alternatively, the compounds of the formula (I-b) can be prepared directly from the compounds of the formula (VII) by quaternization with a suitably substituted tertiary amine as described above.

Alternatively compounds of the formula (Ia) wherein -NRcRd is a secondary amine (this is one of Rc or Rd is a hydrogen atom) can be prepared from the compounds of the formula (Ia) wherein -NRcRd is a group -NH2 by reductive alkylation with an appropriately substituted aldehyde. The reaction is carried out in the presence of a reducing agent such as sodium cyanoborohydride or sodium borohydride, preferably sodium triacetoxyborohydride in a range of organic solvents, preferably dichloroethane. The compounds of the formula (Id) and (Ie) can be prepared from the compounds of the formula (Ic) by reductive alkylation or alkylation methods as described above and in accordance with standard methods well known to those skilled in the art. . The compounds of the formula (I-c) can be prepared from the compounds of the general formula (IX): by reaction with a reducing agent such as lithium aluminum hydride, diisobutyl aluminum hydride, or borane in a range of aprotic solvents such as diethyl ether, or THF or preferably by hydrogenation in the presence of a catalyst such as Raney Nickel in a suitable solvent such as EtOAc or EtOH at a temperature range from room temperature to the reflux temperature of the solvent. The compounds of the general formula (IX) can be prepared from the compounds of the general formula (VIII) by reaction with a source of ion cyanide such as acetone cyanohydrin or an inorganic cyanide, preferably sodium cyanide, in the presence of a non-nucleophilic base such as tetramethyl guanidine, in a range of solvents, preferably ethanol, at a range of temperatures, preferably between room temperature and the reflux temperature of the solvent. The compounds of the formula (If) can be prepared from the compounds of the formula (Ia) by reaction with a reducing agent such as triethylsilane in the presence of an acid such as trifluoroacetic acid in a solvent such as DCM from room temperature to temperature of reflux of the solvent. The compounds of the formula (Ih) can be prepared from the compounds of the formula (Ia) by reaction with an alkylating agent of the formula (XXIV): RfY (XXIV) wherein Rf is as defined for R6 in the general formula (I) and Y is a starting group such as halogen, tosylate, mesylate. The reaction is carried out in the presence of a base such as sodium hydride in a solvent such as THF from 0 ° C to the reflux temperature of the solvent.

The compounds of the general formula (I-m) can be prepared from the compounds of the formula (1-1) using methods described above for the preparation of the compounds of the formula (I-d) of the compounds of the formula (I-c). The compounds of the general formula (1-1) can be prepared from the compounds of the formula (XIV) using methods described above for the preparation of the compounds of the formula (I-c) of the compounds of the formula (IX). The compounds of the general formula (XIV) can be prepared from the compounds of the formula (XIII) using methods described above for the preparation of the compounds of the formula (IX) of the compounds of the formula (VII). Alternatively, the compounds of the formula (I-k) can be prepared directly from the compounds of the formula (XIII) by quaternization with a suitably substituted tertiary amine as described above. The compounds of the general formula (I-j) can be prepared from the compounds of the formula (XIII) using methods described above for the preparation of the compounds of the formula (I-a) of the compounds of the formula (VII).

The compounds of the general formula (XIII) can be prepared from the compounds of the formula (XII) using methods described above for the preparation of the compounds of the formula (III) of the compounds of the formula (IV). The compounds of the general formula (XII) can be prepared from the compounds of the general formula (XI): by reaction with a reducing agent such as Raney Nickel in a solvent such as ethanol at a temperature from room temperature to the reflux temperature of the solvent according to the method described in J. Org. Chem. 2006, 71 (8), 3026. The compounds of the general formula (XI) can be prepared from the compounds of the general formula (X): RV (R9 KR Rb R (X) by reaction with 1- (methylthio) acetone in the presence of trifluoromethanesulfonic anhydride in a solvent such as DCM at a temperature from 0 ° C to the reflux temperature of the solvent according to the method described in J Org. Chem. 2006, 71 (8), 3026. Compounds of the general formula (X) are well known in the art and can be prepared by known methods, or are commercially available.

(XXIX) (XXVIII) Reaction Scheme The compounds of the formula (XXIX) can be prepared from the compounds of the formula (XXVI) by employing a similar sequence of reactions as are used to prepare the compounds the formula (I-b) of the compounds of the formula (VIII) in Reaction Scheme 1 above. The compounds of the formula (XXVI) wherein Ra and Rb are the same can be prepared from the compounds of the formula (XXV) wherein R is a suitable alkyl group (such as ethyl or methyl) by treatment with an appropriate organometallic reagent such as a Grignard reagent, in a suitable solvent such as THF or diethyl ether. The compounds of the formula (XXVI) wherein Ra and Rb are dissimilar can be prepared from the compounds of the formula (XXV) by converting to an intermediate amine, preferably a Weinreb amide, and the introduction of Ra and Rb is carried out through their respective organometallic reagents in a stepwise manner.

The compounds of the formula (XXV) are known in the - for example, Helv. Chim. Acta 1946, 29, 1957. The following non-limiting Examples illustrate the invention.

General Experimental Details: All reactions were carried out under a nitrogen atmosphere unless otherwise specified. The NMR spectra were obtained on a Varian Unity Inova 400 spectrometer with a 5mm reverse sensing triple resonance probe operating at 400MHz or on a Bruker Avance DRX 400 spectrometer with a 3mm reverse sense triple resonance TXI probe operating at 400MHz or on a Bruker Avance DPX 300 spectrometer with a standard 5mm dual frequency probe operating at 300MHz. The changes are given in ppm relative to tetramethylsilane. Where the products were purified by column chromatography, 'flash silica' refers to silica gel for chromatography, 0.035 to 0.070 mm (220 to 440 mesh) (eg, Fluka 60 silica gel), and an applied nitrogen pressure up to 10 psi (25.4 kg / cm2) which accelerates the elution column. Where thin layer chromatography (CCD) has been used, it refers to CCD on silica gel using plates, typically 3 x 6 cm of silica gel on aluminum foil plates with a fluorescence indicator (254 nm), (e.g. , Fluka 60778). All commercial solvents and reagents were used as received. All compounds containing basic centers, which were purified by HPLC, were obtained as the TFA salt unless otherwise stated.

Preparative HPLC conditions: Reverse phase column C18 (100 x 22.5 mm i.d Genesis column with 7 μm particle size). UV detection at 230 nm.

LC / MS system The liquid chromatography mass spectroscopy (LC / MS) systems used: CL-EM method 1 CLT Waters Platform with a C18 reverse phase column (100 x 3.0 mm Higgins Clipeus with 5 μm particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient: Gradient - Flow time ml / min% A% B 0.00 1.0 95 5 1.00 1.0 95 5 15.00 1.0 5 95 20.00 1.0 5 95 22.00 1.0 95 5 25.00 1.0 95 5 Detection - EM, ELS, UV (100 μl split for EM with in-line UV detector at 254 nm) EM ionization method - Electrorocium (positive ion) CL-EM method 2 CL Waters Platform with a C18 reverse phase column (30 x 4.6 mm Phenomenex Luna 3 μm particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient: Gradient - Flow time ml / 'min% A% B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5 Detection - EM, ELS, UV (100 μl split for EM with UV detector online) EM ionization method - Electrorocium (positive and negative ion) CL-EM Method 3 Waters Micromass ZQ with a C18 reverse phase column (30 x 4.6 mm Phenomenex Luna 3 μm particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient: Gradient - Flow time ml / min% A% B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5 Detection - EM, ELS, UV (100 μl split for EM with on-line UV detector) EM ionization method - Electrorocium (positive and negative ion) CL-EM Method 4 Waters ZMD with a C18 reverse phase column (30 x 4.6 mm id Phenomenex Luna with 3 μm particle size), elution with solvent A (water with 0.1% formic acid) and solvent B (acetonitrile with acid 0.1% formic). Gradient: Gradient - Flow time mL / min% A% B 0.00 2.0 95 5 0.50 2.0 95 5 4.50 2.0 5 95 5.50 2.0 5 95 6.00 2.0 95 5 Detection - EM, ELS, UV (200μL / min split for MS with Waters 996 DAD detection online). EM ionization method - Electrorocium (positive and negative ion). CL-EM 5 Waters Micromass ZQ method with a C18 reverse phase column (100 x 3.0 mm Higgins Clipeus with 5 μm particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient: Gradient - Flow time ml / min% A% B 0.00 1.0 95 5 1.00 1.0 95 5 15.00 1.0 5 95 20.00 1.0 5 95 22.00 1.0 95 5 25.00 1.0 95 5 Detection - EM, ELS, UV (100 μl split for EM with in-line UV detector at 254 nm) EM ionization method - Electrorocium (positive ion) CL-EM method 6 Waters Micromass ZQ with a C18 reverse phase column (100 x 3.0 mm Higgins Clipeus with 5 μm particle size), elution with A: water + 0.1% formic acid; B: acetonitrile + 0.1% formic acid. Gradient: Gradient - T: Lempo fluj or ml / min% A% B 0.00 1.0 95 5 1.00 1.0 95 5 15.00 1.0 5 95 20.00 1.0 5 95 22.00 1.0 95 5 25.00 1.0 95 5 Detection - EM, ELS, UV (100 μl split for EM with in-line UV detector at 254 nm) EM ionization method - Electrorocium (positive ion) Abbreviations used in the experimental section DCM = dichloromethane DIPEA = di-isopropylethylamine DMAP = dimethylaminopyridine DMF = dimethylformamide EtOAc = ethyl acetate EtOH = ethanol IMS = industrial methylated distillate MeOH = methanol TA = room temperature Tr = retention time TFA = trifluoroacetic acid THF = tetrahydrofuran Sat = saturated Preparation of intermediaries Intermediary 1 2-Oxo-2-phenyl-N-prop-2-ynyl-acetamide. (V): Ra = Ph oxalyl chloride (6.1 g, 48 mmol) was added to a solution of phenylglyoxylic acid (6.0 g, 40 mmol) and 3 drops of DMF in dry DCM (50 ml). The reaction mixture was stirred at room temperature for 3 hours then the solvent was removed. The residue was taken up in dry DCM (50 ml) and the solution was cooled to 0 ° C. A mixture of propargyl amine (2.2 g, 40 mmol) and triethylamine (4.05 g, 40 mmol) was carefully added over a period of 10 minutes then the mixture was allowed to warm to room temperature. Stirring was continued for 2.5 hours then water (10 ml) was added. The mixture was washed with 1 M HCl (2x20ml), saturated sodium acid carbonate (aq.) (2x20ml) then brine. The organic phase was then dried (Na2SO) and the solvent was removed. The residue was crystallized from cyclohexane to give the product as a light brown solid. Yield: 5.75 g, 76% LC-MS (Method 3): Tr 2.47 min, m / z 188 [MH +].

Intermediary 2 (5-Methyl-oxazol-2-yl) -phenyl-methanone. (IV): Ra = Ph The methanesulfonic acid (10 g, 104 mmol) was added dropwise to a solution of 2-oxo-2-phenyl-N-prop-2-inyl-acetamide.

(Intermediary 1) (2.4 g, 12.83 mmol) in 1,4-dioxane (20 ml). The resulting solution was heated at 90 ° C for 66 hours. The reaction mixture was cooled and the solvent was removed. The dark residue was divided between DCM and water. The DCM fraction was washed with 1 M HCl (2x), saturated sodium hydrogen carbonate (2x) then brine. The solution was dried (Na2SO4) and the solvent was removed to give the crude product. Purification was achieved by column chromatography, eluting with 4: 1 cyclohexane: ethyl acetate. This gave the product as a dull white solid. Yield: 1.0 g (41%) LC-MS (Method 3): Tr 2.94 min, m / z 188 [MH +] Intermediary 3 (5-Bromomethyl-oxazol-2-yl) -phenyl-methanone. (III): Ra = Ph A mixture of (5-methyl-oxazol-2-yl) -phenyl-methanone (Intermediate 2) (0.8g, 4.28 mmol), N-bromosuccinimide (0.9 g, 5.06 mmol) and 2, 2'-azobis (2-methylpropionitrile) (56mg, 0.34 mmol) in carbon tetrachloride (8 ml) was heated to reflux for 1.5 hr. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with DCM (20 ml) and washed with water, saturated sodium hydrogen carbonate and brine. This was dried (Na2SO4) and the solvent was removed. Purification was achieved by column chromatography eluting with 4: 1 cyclohexane: ethyl acetate. This gave the product as a yellow solid. Yield: 0.9g (79%) LCMS (Method 3): Tr 3.26 min, m / z 266, 268 [MH +] Intermediary 4 (5-Dimethylaminomethyl-oxazol-2-yl) -phenyl-methanone. (II): Ra = Ph, Rc, Rd = CH2 (5-Bromomethyl-oxazol-2-yl) -phenyl-methanone (Intermediate 3) (0.18g, 0.68mmol) was dissolved in a 2M solution of dimethylamine in THF ( 3 ml, 6 mmol). The mixture was stirred at room temperature for 1 h with a precipitate formed almost instantaneously. The solvent was removed and the residue partitioned between DCM and saturated sodium hydrogen carbonate (ac, 5ml). The aqueous phase was extracted with DCM and the combined organic phase was dried (Na2SO4) and the solvent was removed to give the product as an orange oil which crystallized on standing. Yield: 0.16 g (99%) LC-MS (Method 2): Tr 1.22 min, m / z 231 [MH +] Also prepared by a similar method by reaction of Intermediate 3 with methylamine was Intermediate 5 (5-Methylaminomethyl-oxazol-2-yl) -phenyl-methanone. (II): Ra = Ph, Rc = CH3, Rd = H Yield: 2.37g (83%) CLEM (Method 3): Tr 0.26 and 1.44min, m / z 217 [MH +] Intermediary 6 Cyclohexyl- (5-methyl-oxazol-2-yl) -phenyl-methanol. (VIII): Ra = Ph, Rb = c-Hexyl A solution of (5-methyl-oxazol-2-yl) -phenyl-methanone (intermediate 2) (3.0 g, ldmmol) in dry THF 32 mL at 0 ° C under nitrogen it was treated dropwise for 10 minutes with a 2M solution of cyclohexylmagnesium chloride in diethyl ether (10 ml, 20 mmol). The resulting deep yellow solution was stirred at 0 ° C for about 30 minutes during which time a precipitate formed, and then at room temperature for 1.5 hours. The reaction mixture was cooled to 0 ° C again and carefully treated with saturated ammonium chloride solution (aq) (10 mL). The mixture was stirred at room temperature for 10 minutes then diluted with water (10 mL). The phases were separated and the organic phase was washed with brine. The combined aqueous phase was extracted with DCM (3 x 20 mL) and the combined organic phase was dried (MgSO 4) and concentrated in vacuo to give the crude product which was triturated with ether (10 mL), filtered thoroughly and dried . Yield: 3.65g (84%) LCMS (Method 3): Tr 3.78 min, m / z 272 [MH +] Also prepared by a similar method by reaction of Intermediate 2 with cyclopentyl magnesium chloride was Intermediary 7 Cyclopentyl- (5-methyl-oxazol-2-yl) -phenyl-methanol. (VIII): Rs Ph, Rb = c-Pentyl Yield: 3.82 g (70%) LC-MS (Method 2): Tr 3.68 min 258 [MH +] Also prepared by a similar method by reaction of Intermediate 2 with phenylmagnesium bromide was Intermediary 8 (5-Methyl-oxazol-2-yl) -diphenylmethanol. (VIII): Ra. Rb = Ph Yield: 2.06g (73%) LC-MS (Method 3): Tr 3.78 min 272 [MH +] Intermediary 9 (5-Bromomethyl-oxazol-2-yl) -cyclohexyl-phenyl-methanol. (VII): Ra = Ph, Rb = c- Hexyl A solution of cyclohexyl- (5-methyl-yl-oxazol-2-yl) -phenyl-methanol (Intermediate 6) (3.0 g, 11.1 mmol) in 1, 2 - Dichloroethane (22mL) was treated with N-bromo-succinimide (2.16g, 12.2mmol) followed by 2,2'-a-zobis (2-methylpropioni trilo) (0.18g, 2.1 mmol). The mixture was heated at 80 ° C for 2.5h and then allowed to cool to room temperature. The saturated sodium hydrogen carbonate solution was added and the phases separated. The organic layer was washed with brine and the combined aqueous layers were extracted with DCM. The combined organic phase was dried (MgSO 4) and concentrated in vacuo to give the crude product as a brown oil. Purification was achieved by column chromatography eluting with 33-100% DCM / cyclohexane followed by 25% EtOAc / DCM. Yield: 1.85g (48%) LCMS (Method 3): Tr 4.27 min, m / z 350, 352 [MH +] Also prepared by a similar method from Intermediary 7 was Intermediary 10 (5-Bromomethyl-oxazol-2-yl) -cyclopentyl-phenyl-methanol. (VII): Ra = Ph, Rb = c-Pentil Yield: 10.7g (83%) LCMS (Method 3): Tr 3.90 min, m / z 336, 338 [MH +] Also, prepared by a similar method from Intermediary 8 was Intermediary 11 (5-Bromomethyl-oxazol-2-yl) -diphenylmethanol. (VII): Ra, Rb = Ph Yield: 1.63g (63%) LCMS (Method 4): Tr 3.53 m / z 326, 328 [MH + -H20] Intermediary 12 [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-yl] -acetonitrile. (IX): Ra = Ph, Rb = c-Hexyl To a solution of ± - (5-bromomethyl-oxazol-2-yl) -cyclohexyl-phenyl-methanol (Intermediate 9) (1.05 g, 3.0 mmol) in IMS ( 15 mL) was added sodium cyanide (169 mg, 3.45 mmol). The mixture was heated at 70 ° C for 1 hour then concentrated in vacuo and partitioned between ethyl acetate (30 mL) and water (30 mL). The aqueous was extracted with ethyl acetate (2 x 30 mL) and the combined organics were dried over sodium sulfate, filtered and evaporated to an orange oil. Purification by flash column chromatography on silica gel using a mixture 40% ethyl acetate: 60% cyclohexane as eluent then recrystallization from DCM using hexane gave the title compound as a white crystalline solid. Yield: 700 mg (79%) LC-MS (Method 3): Tr 3. 66 min, m / z 279 [MH + -H20].

Also, prepared by a similar method of Intermediary 11 was Intermediary 13 [2- (Hydroxy-diphenyl-methyl) -oxazol-5-yl] -acetonitrile. (IX): Ra, Rb = Ph Yield: O.llg (54%) LC-MS (Method 3): Tr 2.96 min m / z 291 [MH +] Intermediary 14 2- (1,1-Diphenyl-ethyl) -5-methyl-4-methylsulfanyl-oxazole. (XI): Ra, Rb = Ph, Rg = CH3 To a colorless solution of l-methylthio-2-propanone (0.98mL, 9.7mmol) in 13mL dry DCM at 0 ° C under nitrogen a solution was added dropwise of trifluoromethanesulfonic anhydride (1.62mL, 9.7mmol) in 10 mL dry DCM. The resulting yellow solution was stirred at 0 ° C for 1 h then a solution of 2,2-diphenylpropionitrile (lg, 4.8 mmol) in 10 mL dry DCM was added dropwise rapidly. The reaction mixture was stirred at 0 ° C for 2 h then between 0 ° C and room temperature for 5 days, becoming dark red. The reaction mixture was cooled to 0 ° C and carefully treated with saturated sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted with DCM (x2). The combined organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried (Na2SO4) and evaporated to a dark viscous oil (1.67 g). The crude product was purified by chromatography on silica gel eluting with diethyl ether / cyclohexane % (Rf = 0.25) to give the title compound as a pale yellow oil which crystallized on standing. Performance: 0.79g (53%) CLEM (Method 2): Tr 4.37 min m / z 310 [MH +] Intermediary 15 2- (1, 1-Diphenyl-ethyl) -5-methyl-oxazole. (XII): Ra, Rb = Ph, Rg = CH3 A suspension of 2- (1,1-diphenyl-ethyl) -5-methyl-4-methylsulfanyl-oxazole (Intermediate 14) (0.70 g, 2.3 mmol) in 15 mL IMS was warmed to dissolve. The Raney Nickel 2800 (~ 3g) was added causing a rapid evolution of a gas. The reaction mixture was stirred under reflux under nitrogen. After 1.25 h, CLEM indicated a 1: 1 mixture of starting material: product and no change after an additional 1 h. Other 3 g of Raney nickel 2800 was added and the reaction mixture was stirred at reflux for lh. The Tic indicates that all the starting material has reacted. The catalyst was completely filtered through high flow and the volatiles were evaporated to give a viscous, colorless oil. (0.57g). The oil was purified by chromatography on silica gel eluting with 15% EtOAc / cyclohexane (Rf = 0.36) to give the title compound as a colorless oil. Yield: 0.57g (89%) LCMS (Method 2): Tr 3. 96min m / z 264 [MH +] Intermediary 16 -Brcmomethyl-2- (1, 1-diphenyl-ethyl) -oxazole. (XIII): Ra, R * 3 = Ph, Rg = CH3 Prepared by Intermediary 15 in accordance with the method used to prepare Intermediary 9. Yield: 0.75g (quant.) CLEM (Method 2): Tr 4.06 min m / z 342, 344 [MH +] Intermediary 17 8-methoxy-octyl ester of methanesulfonic acid. Diisopropylethylamine (170 mg, 1.49 mmol) was added to a solution of 8-methoxy-octan-1-ol (217 mg, 1.35 mmol) in dry DCM (1 mL). The solution was cooled in an ice bath and methanesulfonyl chloride (170 mg, 1.49 mmol) was added under nitrogen. The solution was allowed to warm to room temperature overnight. The Tic showed the presence of some starting material. More methanesulfonyl chloride (231 mg, 2.01 mmol) was added and the solution was stirred at room temperature overnight. The reaction mixture was treated with water and the phases were separated. The organic layer was dried (MgSO 4) and the solvent was evaporated. The crude product was purified by chromatography on silica gel eluting with diethyl ether: cyclohexane (1: 1) and then with diethyl ether: cyclohexane (2: 1) to give the title compound as an oil. 8-Methoxy-octan-l-ol can be prepared according to the methods described in Synthesis 2004, 4, 595. Yield: 135 mg (42%) LCMS (Method 2): Tr 3.14 min, no observed mass ion Intermediary 18 8- (Tert-butoxycarbonyl-methyl-amino) -octyl ester of methanesulfonic acid. The title compound was prepared according to the procedure described for the preparation of Intermediate 17 using (8-hydroxy-octyl) -methylcarbamic acid tert-butyl ester in place of 8-methoxy-octan-i-ol. The tert-butyl ester of (8-hydroxy-octyl) -methylcarbamic acid can be prepared according to the methods described in US2005277688 or US2004254219. Yield: 225mg (71%) XH NMR (CDC13): d 1.20-1.57 (m, 19H), 1.75 (m, 2H), 2.83 (s, 3H), 3.01 (s, 3H), 3.19 (t, 2H) , 4.22 (t, 2H).

Intermediary 19 ~ J »2- (4-Bromomethyl-phenyl) -ethanol. A solution of 4- (bromomethyl) phenyl acetic acid (458mg, 2.0mmol) in 10mL toluene and 8mL THF under nitrogen was treated with a 2M solution of borane-dimethylsulfide complex in THF (2mL, 4.0mmol) and the mixture of The reaction was stirred at room temperature overnight. There is no reaction by CLEM. An additional 1.5mL (3.0mmol) borane-dimethylsulfide complex was added and the reaction was stirred for 2 h. The EtOAc and water were added and the phases were separated. The organic layer was dried (MgSO) and the solvent was evaporated to give the title compound. Yield: 347 mg (81%) XH NMR (CDC13): d 2.89 (t, 2H), 3.49 (s, 1 H), 3.86 (t, 2H), 4.49 (s, 2H), 7.21 (d, 2H) 7.35 (d, 2H). Intermediary 20"° ~ XL: O 2- {4- [(Benzyl-methyl-amino) -methyl] -phenyl} -ethanol A solution of 2- (4-bromomethyl-phenyl) -ethanol (Intermediate 19) (347mg, 1.6mmol) in 15 mL acetonitrile was treated with potassium carbonate (557 mg, 4.0 mmol) followed by N-methyl benzylamine (293 mg, 2.4 mmol) The reaction was stirred under reflux for 6 h when CLEM indicated the Complete conversion of the starting material The reaction was allowed to cool to room temperature and the solvent was evaporated The residue was partitioned between EtOAc and water and the phases were separated The organic layer was dried (MgSO.sub.4) and the solvent was evaporated. crude product was purified by chromatography on silica gel eluting with DCM to 1% MeOH / DCM to give the title compound as an oil Yield: 258mg (63%) 1 H NMR (CDC13): d 2.09 (br s, 1 H ), 2.16 (s, 3H), 2.81 (t, 2H), 3.48 (s, 2H), 3.50 (S, 2H), 3.79 (t, 2H), 7.15 (d, 2H), 7.20-7.25 (m, 1 H), 7.26-7.37 (m, 6H).

Intermediary 21 2- (4-Methylaminomethyl-phenyl) -ethanol. A solution of 2-. { 4 - [(benzyl-methyl-amino) -methyl] -phenyl} Ethanol (Intermediate 20) (258 mg, 1.0 mmol) in 10 mL IMS was treated with 20% palladium hydroxide on carbon (50 mg). The reaction mixture was stirred under a hydrogen atmosphere for 3 h when CLEM indicates complete conversion of starting material. The reaction mixture was filtered through celite and the solvent was evaporated. The crude product was loaded onto an SCX-2 cartridge using 10% MeOH / DCM and the impurities were removed by wetting the column with MeOH / DCM. The column was eluted with 1: 1 2M / DCM methanolic ammonia and the solvent was removed to give the title compound. Yield: 91 mg (55%) X H NMR (MeOD): d 2.35 (s, 3 H), 2.79 (t, 2 H), 3.65 (s, 2 H), 3.72 (t, 2 H), 7.18-7.25 (m, 4 H) ).

Intermediary 22 [4- (2-Hydroxy-ethyl) -benzyl] -methyl-carbamic acid. A solution of 2- (4-methylaminomethyl-phenyl) -ethanol (Intermediate 21) (91 mg, 0.55mmol) in 3mL dry DCM at 0 ° C was treated dropwise with a solution of di-tert-butyl carbonate ( 144mg 0.66mmol) in 2mL dry DCM and the reaction mixture was allowed to warm to room temperature. After 2 h water was added and the mixture was stirred for 10 minutes. The two layers were separated and the organic layer was dried (MgSO4) and the solvent was evaporated to give the title compound. Yield: 146mg (quant.). XH NMR (CDC13): d 1.48 (s, 9H), 2.81 (br s, 3H), 2.86 (t, 2H), 3.86 (br t, 2H), 4.40 (br s, 2H), 7.14-7.22 (m , 4H).

Intermediary 23 Ester of 2-. { 4- [(tert-butoxycarbonyl-methyl-amino) -methyl] -phenyl} -methylsulfonic acid ethyl ester. The title compound was prepared according to the procedure described for the preparation of Intermediate 17 using Intermediary 22 instead of 8-methoxy-octan-1-ol. Yield: 106 mg (50%) XH NMR (CDC13): d 1.48 (s, 9H), 2.75-2.84 (br s, 3H), 2.87 (s, 3H), 3.04 (t, 2H), 4.36-4.44 ( m, 4H), 7.15-7.22 (m, 4H).

Intermediary 24 4- (3-Bromo-propoxy) -benzenesulfonamide. A suspension of 4-hydroxybenzenesulfonamide (4.1 g, 23 mmol), 1,3-dibromopropane (6.83 g, 34 mmol) and potassium carbonate (3.17 g, 23 mmol) in acetonitrile (35 mL) was heated at 55 ° C overnight. The mixture was allowed to cool to room temperature and filtered. The filtrate was evaporated to give a residue which was partitioned between DCM and 0.1 M NaOH (aq). The organic layer was dried (MgSO 4) and the solvent was evaporated. Purification was carried out by column chromatography on silica gel eluting with cyclohexane and then with diethyl ether, followed by recrystallization from isopropanol. Yield: 483mg (7%) LCMS (Method 2): Tr 3.01 min, no observed mass ion Intermediary 25 Bromide of (9-hydroxy-nonyl) -methyl-ammonium. To a solution of 9-bromo-l-nonanol (10.2 g, 45.7 mmol) in IMS (50 mL) at 0 ° C was added a methylamine solution (57 mL, 8 M in EtOH, 456 mmol). After 30 minutes at 0 ° C the reaction mixture was allowed to warm to room temperature and was stirred for 26 h. The solvent was evaporated to give a white solid, which was triturated with diethyl ether to give the title compound as a white solid. Yield: 9.97 g, 86%. LC-MS (Method 3): Tr 1.51 min, m / z 174 [MH +].

Intermediary 26 9 ~. { [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -methyl-amino) -nonan-1-ol. (5-Bromomethyl-oxazol-2-yl) -cyclohexyl-phenyl-methanol (1.0 g, 2.86 mmol) was added to a solution of (9-hydroxy-nonyl) -methyl-ammonium bromide (686 mg, 2.86 mmol) and N, N-diisopropylethylamine (1.0 mL, 5.7 mmol) in dry DCM. After stirring the mixture at room temperature for 4 h saturated NaHCO3 (aq) was added. The phases were separated and the aqueous layer was extracted with DCM. The combined organic layers were dried (Na2SO4), filtered, and concentrated to dry to give a yellow oil. Purification by column chromatography on silica gel using a gradient of 5-10% MeOH / DCM as eluent to provide the title compound as a colorless oil. Yield: 0.80 g, 63%. LC-MS (Method 2): Tr 2.42 min, m / z 443 [MH +].

Intermediary 27 9-. { [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -methyl-amino} -nonanal A solution of DMSO (0.17 mL, 2.3 mmol) in dry DCM (3 mL) was added dropwise to a solution of oxalyl chloride (94 μL) in dry DCM (3 mL) at -78 ° C under a nitrogen atmosphere. Then a solution of 9-. { [2- (cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -methyl-amino} -nonan-1-ol (0.49 7 g, 1.1 mmol) in dry DCM (5 mL) was added and the reaction mixture was stirred at -78 ° C for 15 min. Triethylamine (0.62 mL, 4.4 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 1 h saturated NaHCO3 (aq) was added, the phases were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated to dry to give a viscous yellow / brown oil. The crude product was reapplied under the same reaction conditions until further conversion of the starting material to provide a viscous yellow oil plus solids, this was triturated with diethyl ether and the supernatant was concentrated to dry to provide a solid foam, which was used without further purification. Yield: 0.59 g. LC-MS (method 2): Tr 2.74 min, m / z 441 [MH +].

Intermediary 28 - [(R) -l- (tert-Butyl-dimethyl-silanyloxy) -2- (9- { [2- (cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -methyl-amino} ) -non i lamino) -ethyl] -8-hydroxy-lH-quinolin-2-one A mixture of 9-. { [2- (cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -methyl-amino} -nonanal (0.49 g, 1.1 mmol), 5- [(R) -2-amino-l- (tert-butyl-dimethyl-silanyloxy) -ethyl] -8-hydroxy-lH-quinolin-2-one (0.37 g , 1.1 mmol), and sodium triacetoxyborohydride (0.33 g, 1.6 mmol) in dry DCE (10 mL) was stirred under a nitrogen atmosphere at room temperature for 19 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography on silica gel using a mixture of DCM / MeOH / acetic acid / water (120: 15: 3: 2) as eluent to give the product as a brown gum very light. The residue was taken in MeOH, passed over an SCX-2 cartridge, and released using 2M ammonia solution in MeOH. Evaporation of the solvent in vacuo afforded the title compound as a mixture of diastereomers as a yellow / green gum. Yield: 78 mg, 9%. LC-MS (method 2): Tr 2.64 min, m / z 760 [MH +].

Intermediary 29 -Methylthiazole-2-carboxylic acid ethyl ester Prepared in accordance with Helv. Chim. Acta., 1946 (29), 1957.

Intermediary 30 Methanol of (5-methylthiazol-2-yl) diphenyl To an ice-cooled solution of Intermediary 29 (0.24 g, 1,402 mmol) in anhydrous THF (7 ml) under a nitrogen atmosphere was added, dropwise, a 3M solution of bromide phenylmagnesium in diethyl ether (0.934 ml, 2.80 mmol). Once the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 20 minutes. After this period, the solution was emptied into 1 M HCl and extracted twice with diethyl ether. The combined organic layers were washed with saturated sodium hydrogen carbonate (aq.), Water and brine, dried (MgSO4) and evaporated. The residue was subjected to column chromatography (SiO2, 40 g) eluting with 10% EtOAc in iso-hexane to give the desired material. Yield = 0.27 g (67%) LC-MS (Method 6): Tr 3.20 min, m / z 282 [MH] +. 1 H NMR, 400 MHz, DMS0-d 6: 7.4 (1 H, m), 7.3 (4 H, m), 7.3-7.2 (6 H, m), 7.1 (1 H, s) and 2.4 (3 H, d).

Intermediary 31 Ester of 2- (4-methyl-benzyloxy) -ethyl methanesulfonic acid Prepared in a manner similar to the procedure described in J. Am. Chem. Soc. 2002, 124 (28), 8206. LC-MS (Method 4): Tr 2.44 minutes, observed non-molecular ion.

Intermediary 32 Ester 2- (4-chloro-benzyloxy) -ethyl methanesulfonic acid Prepared in a manner similar to Intermediary 31. LC-MS (Method 2): Tr 3.34 minutes, observed non-molecular ion.

Intermediary 33 2- (4-Chloro-benzyloxy) -ethyl methanesulfonic acid ester Prepared in a manner similar to Intermediate 31.

LC-MS (Method 4): Tr 3.59 minutes, observed non-molecular ion.

Intermediary 34 l-Benzyloxy-3-methyl-3-phenoxybum To a solution of (3-methyl-but-3-enyloxymethyl) -benzene (4.22 g, 23.9 mmol) and phenol (2.25 g, 23.9 mmol) in 20 mL dry DCM BF3 Et20 (0.582 mL, 4.78 mmol) was added under nitrogen. The solution was stirred at room temperature overnight, H20 was added, and the phases were separated. The aqueous phase was extracted with DCM (x2) and the organic layer was dried (MgSO4) and the solvent was removed to give an oil. The crude product was purified by column chromatography on silica gel eluting with a gradient of cyclohexane to 5% diethyl ether in cyclohexane. Yield: 0.9 g (14%) LC-MS (Method 4): Tr 4.47 min, non-molecular ion observed.

Intermediary 35 3-Methyl-3-phenoxy-butan-1-ol The palladium (II) hydroxide on carbon (20% by weight) (150 mg) was added to a flask under an inert atmosphere, followed by cold IMS (5 ml) and (3 ml). -benzyloxy-1, 1-dimethyl-propoxy) -benzene (0.73 g, 2.7 mmol). The flask was purged with hydrogen (x3) and the mixture was stirred at room temperature overnight under a hydrogen balloon. The mixture was filtered through celite under inert atmosphere and the filtrate was evaporated to give the crude product which was purified by column chromatography using a gradient of cyclohexane at 50% diethyl ether in cyclohexane. Yield: 71 mg, 14% LC-MS (Method 4): Tr 2.87 min, non-molecular ion observed.

Intermediary 36 3-Methyl-3-phenoxybutyl ester of methanesulfonic acid The title compound was prepared according to the procedure described for the preparation of Intermediate 17. Yield: 37mg, 37% LC-MS (Method 2): Tr 3.45 min , non-molecular ion observed.

Intermediary 37 [2- (Cyclopentyl-hydroxy-phenyl-methyl) -oxazol-5-yl] -acetonitrile. (IX): Ra = Ph, Rb = c-Pen il Prepared in accordance with the method used for the preparation of Intermediary 12. Yield: 0.75 g (57%) LC-MS (Method 4): Tr 3.47 min, m / z 265 [MH + -H20].

Examples Reaction Scheme The following compounds were prepared using the route shown in Reaction Scheme 5.

Example 1 (5-Dimethylaminomethyl-oxazol-2-yl) -diphenyl-anol. (Ia): Ra, Rb = Ph, Rc, Rd = CH3 Phenylmagnesium bromide (0.75 ml of a 1 M solution in THF, 0.75 mmol) was added dropwise to a cold (0 ° C) solution of (5- dimethylaminomethyl-oxazol-2-yl) -phenyl-methanone (Intermediate 4) (0.15g, 0.65mmol) in dry THF (1.5ml). The mixture was stirred cold for 1.5 h then additional phenylmagnesium bromide (0.4 ml of a 1 M solution in THF, 0.4 mmol) was added dropwise. The mixture was stirred at 0 ° C for 0.5 h and then treated with excess saturated ammonium chloride solution (aq). The mixture was extracted with DCM (x2) and the combined organic phase was washed with brine, dried (Na2SO4) and the solvent was removed to give the crude product. Purification was achieved by HPLC eluting with 5-70% acetonitrile / water containing 0.1% TFA for 18.5 minutes. Yield: 0.19 g (69%, as its TFA salt) LC-MS (Method 1): Tr 5.56 min, m / z 309 [MH +] LC-MS (Method 3): Tr 1.72 min, m / z 309 [MH + ] XH NMR (DMSOd6): d 2.74 (s, 6H), 4.48 (s, 2H), 7.25-7.37 (m, 10H), 7.40 (s, 1 H), 10.23 (br s, 1 H). A sample of this material was converted to the free base by passing through an SCX-2 cartridge eluting with MeOH (x3) and then 2M ammonia / MeOH (x3) to give the desired compound as a white solid. LC-MS (Method 1): Tr 5.68 min, m / z 309 [MH +] ^ NMR (DMSO-de): d 2.12 (s, 6H), 3.47 (s, 2H), 6.98 (s, 1H), 7.02 (s, ÍH) 7.22-7.34 (m, 10H).

Formate of [2- (hydroxy-diphenyl-yl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium. (I-b): Ra = Rb = Ph, Rc, Rd = CH3, Re = 3-Phenoxypropyl. A solution of (5-dimethylaminomethyl-oxazol-2-yl) -diphenyl-methanol (Example 1) (24mg, 0.078mmol) in acetonitrile (0.3mL) and chloroform (0.5 mL) was treated with 3-phenoxypropyl bromide (37μL, 0.23mmol) and the reaction mixture was stirred at room temperature overnight and then at 50 ° C for 42 h. The volatiles were evaporated and the crude product was purified by preparative HPLC eluting with 25-75% acetonitrile / water containing 0.1% formic acid for 30 minutes to give the product as a colorless gum. Yield 24mg, 63% LC-MS (Method 1): Tr 7.56 min m / z 443 [M +] 1 H NMR (MeOD): d 2.29 (m, 2H), 3.11 (s, 6H), 3.45 (m, 2H), 3.98 (t, 2H), 4.79 (S, 2H), 6.85-6.90 (m, 2H), 6.93-6.98 (m, 1 H), 7.24-7.38 (m, 12H), 7.56 (S, 1 H), 8.51 (br s, 1 H).

Also prepared by a similar method using the route shown in Reaction Scheme 2 were the following compounds: Reaction scheme 6 The following compounds were prepared using the route shown in Reaction Scheme 6.

Example 4 Cyclohexyl- (5-dimethylaminomethyl-oxazol-2-yl) -phenyl-methanol. (Ia): Ra, = Ph, Rb = c-Hexyl, Rc, Rd = CH3 A solution of (5-bromomethyl-oxazol-2-yl) -cyclohexyl-phenyl-methanol (Intermediate 9) (3.2g, 9.2mmol ) in 40 mL THF was treated with a 2M solution of dimethylamine in THF (40 mL, 80 mmol). A suspension formed after being stirred for a few minutes. The reaction mixture was kept at room temperature overnight and then the solid was completely filtered and discarded. The filtrate was concentrated under reduced pressure and the residue partitioned between DCM and saturated sodium hydrogen carbonate solution. The organic layer was dried (Na2SO4) and evaporated to give the title compound as a solid. Yield: 2.74 g (95%) LC-MS (Method 1): Tr 6.57 min, m / z 315 [MH +] 1 H NMR (DMS0-d 6): d 0.92-1.29 (m, 6H), 1.42-1.74 (m , 4H), 2.10 (s, 6H), 2.22 (m, 1 H), 3.45 (s, 2H), 5.90 (s, 1 H), 6.98 (s, 1 H), 7.18-7.22 (m, 1 H) ), 7.27-7.34 (m, 2H), 7.40-7.46 (m, 2H). The two enantiomers of cyclohexyl- (5-dimethylaminomethyl-oxazol-2-yl) -phenyl-ethanol (Example 4) (2.74 g) were separated by preparative chiral HPLC using a 250x20 mm chiralpak® IA column packed with tris amylase (3, 5-dimethylphenylcarbamate) immobilized on 5 μm silica gel. The column was eluted with 5% ethanol in heptane buffered with 0.1% diethylamine at 15 ml / min. The first eluant enantiomer (Tr 8.5 min) gave (S) -cyclohexyl- (5-dimethylaminomethyl-oxazol-2-yl) -phenyl-methanol (Ia): Ra, = Ph, Rb = c-Hexyl, Rc, Rd = CH3 (Example 5) as a white solid.

Example 5 Yield: 0.73g (27%) LC-MS (Method 1): Tr 6.50 min, m / z 315 [MH +] XH NMR (CDC13): d 1.12-1.39 (m, 7H), 1.62-1.76 (m, 3H ), 2.25 (S, 6H), 2.29-2.32 (m, 1 H), 3.54 (dd? B, 2H), 3.70 (br.s, 1 H), 6.84 (s, 1 H), 7.24 (t, 1 H), 7.33 (t, 2H), 7.64 (d, 2H).

The second elution enantiomer (Tr 10.3 min) gave (R) -cyclohexyl- (5-dimethylaminomethyl-oxazol-2-yl) -phenyl-methanol (Ia): Ra, = Ph, Rb = c-Hexyl, Rc, Rd = CH3. (Example 6) as a white solid.

Example 6 Yield: 1.04 g (38%) LC-MS (Method 1): Tr 6.48 min, m / z 315 [MH +] H NMR (CDC13): d 1.10-1.39 (m, 7H), 1.62-1.76 (m, 3H ), 2.25 (s, 6H), 2.29-2.35 (m, 1 H), 3.54 (ddAB, 2H), 3.70 (br.s, 1 H), 6.84 (s, 1 H), 7.24 (t, 1 H) ), 7.33 (t, 2H), 7.64 (d, 2H).

Example 7 Bromide of [2- ((S) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium, (Ib): Ra = Ph, Rb = c- Hexyl Rc, Rd = CH3, Re = 3-Phenoxypropyl. A solution of (S) -cyclohexyl- (5-dimethylaminomethyloxazol-2-yl) -phenyl-methanol (Example 5) (0.060 g, 0.19 mmol) and 3-phenoxypropyl bromide (0.215 g, 1 mmol) in acetonitrile (1.33 ml. ) and chloroform (2 ml) was allowed to stand at room temperature for 5 days. The solvent was removed to give the crude product. Purification was achieved by column chromatography eluting sequentially with DCM, 2.5%, 5%, 10% then 20% methanol in DCM. Yield: 50mg (43%) LC-MS (Method 1): Tr 8.32 min, m / z 449 [M +] XH NMR (CDC13): d 1.06-1.17 (m, 3H), 1.23-1.36 (m, 4H) , 1.52-1.85 (m, 3H), 2.28-2.35 (m, 3H), 3.32 (s, 3H), 3.33 (s, 3H), 3.63 (dd, 2H), 4.04 (t, 2H), 5.23 (ddAB, 2H), 6.85 (d, 2H), 6.98 (t, 1 H), 7.20 (t, 1 H), 7.26-7.30 (m, 4H), 7.55-7.58 (m, 3H).

Example Bromide of [2- ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl-dimethyl- (3-phenoxy-propyl) -ammonium, (Ib): Ra = Ph, Rb = c-Hexyl , Rc, Rd = CH3, Re = 3-Phenoxypropyl A solution of (R) -cyclohexyl- (5-dimethylaminomethyloxazol-2-yl) -phenyl-methanol (Example 6) (98 mg, 0.31 mg) and 3- bromide phenoxypropyl (740 mg, 3.44 mmol) in chloroform (1.5 mL) and acetonitrile (1.5 mL) was heated at 50 ° C for 22 h. The RM was concentrated to dry to give a colorless viscous oil, which was triturated with diethyl ether to give a white gum. This was purified by column chromatography eluting with 2.5-25% MeOH / DCM to give the product as a cloudy viscous oil. Dry under vacuum at 45 ° C for 1-2 days provided a white solid. Yield: 142 mg (86%) LC-MS (Method 1): Tr 8.41 min, m / z 449 [MH +]? H NMR (CDC13): 'd 1.06-1.16 (m, 3H), 1.21-1.37 (m , 4H), 1.59-1.74 (m, 3H), 2.32 (m, 3H), 3.32 (s, 3H), 3.33 (s, 3H), 3.61 (dd, 2H), 4.03 (t, 2H), 4.14 ( br.s, 1 H), 5.20 (ddAB, 2H), 6.85 (d, 2H), 6.98 (t, 1 H), 7.19 (t, 1 H), 7.26-7.30 (m, 4H), 7.55-7.58 (m, 3H).

Example 9 [2- ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium tosylate. (I-b): Ra = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 3-Phenoxypropyl. Prepared in accordance with the method used in Example 8 but using 3-phenoxypropyl tosylate in place of 3-phenoxypropyl bromide. Yield: 80% LC-MS (Method 5): Tr 7.72 min, m / z 449 [MH] +. X H NMR (DMSO-de): d 0.96-1.25 (m, 6H), 1.54-1.71 (m, 4H), 2. 18-2.27 (m, 3H), 2.28 (s, 3H), 3.03 (s, 3H), 3.04 (s, 3H), 3. 33-3.39 (m, 2H), 3.99 (t, 2H), 4.76 (s, 2H), 6.10 (s, 1 H), 6. 92 (d, 2H), 6.96 (t, 1 H), 7.11 (d, 2H), 7.22 (t, 1 H), 7.31 (dt, 4H), 7.45-7.49 (m, 4H), 7.54 (s, 1 H).

Example 10 [2- ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium (Z) -3-carboxy-acrylate. (I-b): Ra = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 3-Phenoxypropyl. A mixture or silver oxide (I) (59 mg, 0.25 mmol) and [(R) -2- (cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy) bromide. propyl) -ammonium (Example 8) (265 mg, 0.500 mmol) in water (10 mL) was stirred at room temperature for 5 h. Maleic acid (58 mg, 0.50 mmol) was added to the reaction mixture, followed by MeOH (10 mL). The suspension was stirred vigorously at room temperature for 1 h, then filtered over Celite and lyophilized to give the title compound as a white solid. Yield: 97% LC-MS (Method 5): Tr 7.92 min, m / z 449 [M +] H NMR (CDC13): d 1.05-1.42 (m, 7H), 1.59-1.72 (m, 3H), 2.23- 2.33 (m, 3H), 3.13 (s, 6H), 3.53 (m, 2H), 4.00 (m, 2H), 4.89 (ddAB, 2H), 6.20 (s, 2H), 6.83 (d, 2H), 6.96 (t, 1 H), 7.19 (t, ÍH), 7.25-7.30 (m, 4H), 7.47 (s, ÍH), 7.55 (d, 2H).

Example 11 Prepared according to the method used in Example 10 but using succinic acid instead of maleic acid was: 3-carboxy-propionate of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium. tifa): Ra = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 3-Phenoxypropyl Yield: 97% LC-MS (Method 5): Tr 7.90 min, m / z 449 [M +] XH NMR ( CDCI3): d 1.03-1.35 (m, 6H), 1.42-1.45 (m, 1 H), 1.59-1.73 (m, 3H), 2.22-2.33 (, 3H), 2.46 (s, 4H), 3.14 (s) , 6H), 3.52 (m, 2H), 4.00 (m, 2H), 4.93 (ddAB) 2H), 6.84 (d, 2H), 6.97 (t, 1 H), 7.19 (t, 1 H), 7.26- 7.30 (m, 4H), 7.48 (s, 1 H), 7.55 (d, 2H).

Example 12 Prepared according to the method used in Example 10 but using (S) -malic acid instead of maleic acid was (S) -3-carboxy-2-hydroxy-propionate of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium. (Ib): Ra = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 3-Phenoxypropyl Yield: 89% LC-MS (Method 5): Tr 7.90 min, m / z 449 [M +] XH NMR (CDC13): d 1.02-1.34 (m, 6H), 1.38-1.47 (m, ÍH), 1. 58-1.72 (m, 3H), 2.17-2.35 (m, 3H), 2.60-2.71 (m, 2H), 3.09 (br.s, 6H), 3.44 (br.s, 2H), 3.98-4.10 (m, 3H), 4.85 (br.s, 2H), 6.84 (d, 2H), 6.96 (t, 1 H), 7.18 (t, 1 H), 7.25-7.29 (m, 4H), 7.47 (s, 1 H), 7.54 (Cl, 2H).

Example 13 Cyclohexyl- (5-. {[[Methyl- (3-phenoxy-propyl) -amino] -methyl] -oxazol-2-yl) -phenyl-methanol. (Ia): Ra, = Ph, Rb = c-Hexyl, Rc = CH3, Rd = 3-Phenoxypropyl A mixture of (5-bromomet-1-oxazol-2-y1) -cyclohexy-1-phenyl-1-methanol ( Intermediate 9) (102 mg, 0.286 mmol), N-me t -yl-3-phenoxy-propylamine (57 mg, 0.34 mmol), and diisopropylethylamine (65 μL, 0.37 mmol) in THF (2 mL) was stirred at room temperature Environment for 1.75 h. The reaction mixture was treated with saturated sodium hydrogen carbonate solution (aq.) And the organic phase was separated. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried (Na 2 SO), filtered, and concentrated to dry to give a pale brown oil. Purification by column chromatography on silica gel using a gradient of 25-30% ethyl acetate / DCM as eluent to give the title compound as a colorless oil. Yield: 60% LC-MS (Method 1): Tr 8.61 min, m / z 435 [M +] X H NMR (CDCl 3): d 1.09-1.39 (m, 7H), 1.61-1.74 (m, 3H), 1.96 ( p, 2H), 2.27-2.33 (m, 4H), 2.53 (t, 2H), 3.67 (s, 3H), 3.99 (t, 2H), 6.83 (s, 1 H), 6.89 (d, 2H), 6.94 (t, 1 H), 7.20-7.33 (m, 5H), 7.63 (d, 2H).

Example 14 The two enantiomers of cyclohexyl- (5. {[[Methyl- (3-phenoxy-propyl) -amino] -methyl] -oxazol-2-yl) -phenyl-methanol (Example 13) were separated in a manner similar to those of Example 4 eluting with 10% EtOH / heptane + 0.1% diethylamine. The first eluted enantiomer (Rt 8.3 min) gave (S) -Cyclohexyl- (5-. {[[Methyl- (3-phenoxy-propyl) -amino] -methyl] -oxazol-2-yl) -phenyl- methanol (I-a): Ra, = Ph, Rb = c-Hexyl, Rc = CH3, Rd = 3-Phenoxypropyl.

LC-MS (Method 1): Tr 8.44 min, m / z 435 [MH +] XH NMR (CDCl 3): d 1.09-1.39 (m, 7H), 1.61-1.74 (m, 3H), 1.96 (p, 2H) , 2.27-2.33 (m, 4H), 2.53 (t, 2H), 3.67 (s, 3H), 3.99 (t, 2H), 6.83 (s, ÍH), 6.89 (d, 2H), 6.94 (t, 1 H), 7.20-7.33 (m, 5H), 7.63 (d, 2H).

EXAMPLE 15 The second elution enantiomer (Tr 10.9 min) gave (R) -Cyclohexyl- (5- {[[methyl- (3-phenoxy-propyl) -amino] -methyl} - oxazol-2-yl) -phenyl-methanol. (I-a): Ra, = Ph, Rb = c-Hexyl, Rc = CH3, Rd = 3-Phenoxypropyl LC-MS (Method 1): Tr 8.51 min, m / z 435 [MH +] XH NMR (CDC13): d 1.09-1.39 (m, 7H), 1.61-1.74 (m, 3H), 1.96 (p, 2H) , 2.27- 2.33 (m, 4H), 2.53 (t, 2H), 3.67 (s, 3H), 3.99 (t, 2H), 6.83 (s, 1 H), 6.89 (d, 2H), 6.94 (t, 1 H), 7.20-7.33 (m, 5H), 7.63 (d, 2H). The following example compounds were prepared in a similar manner, using the route shown in Reaction Scheme 3. eleven Also prepared using the route shown in Reaction Scheme 3 were: Example 5 1- [2- (Hydroxy-diphenyl-methyl) -oxazol-5-ylmethyl] -1-methyl-4-phenoxy-piperidinium bromide, (Ib) Ra = Rb = P, Rc, Rd = Piperidinyl, Re = CH3 To a solution of [5- (4-phenoxy-piperidin-1-ylmethyl] oxazol-2-yl] -diphenylmethanol (Example 26) (35 mg, 0.08 mmol) in 0.5 mL acetonitrile was added 1.5mL (~ 5 mmol) of a 40% by weight solution of methyl bromide in acetonitrile The reaction mixture was heated at 40 ° C in a sealed vial for 18 h during which a white precipitate formed.The solvent was evaporated and the residue was triturated. with diethyl ether The solid was recrystallized from acetonitrile to give the title compound as an 8: 1 mixture of cis: trans isomers as a white solid Yield: 6mg (14%) LCMS (Method 1): Tr 7.93min, m / z 455 [M +]? H NMR (CDC13) d 2.11-2.37 (m, 4H), 3.15 (s, 3H, minor isomer), 3.30 (s, 3H), 3.58 (br s, 4H), 3.67 ( br s, 4H, minor isomer), 4.67 (br s, 1 H), 4.71 (br s, 1 H, minor isomer), 5.04 (br s, 2 H), 5.23 (br s, 2H, minor isomer), 6.87 (d, 2H), 6.91 (d, 2H, minor isomer), 7.02 (t, 1 H), 7.26-7.38 (m, 12H), 7.58 (br s, 1 H), 7.63 (br s, 1 H, minor isomer).

Example 59 Prepared according to the method used in Example 58 but using Example 28 instead of Example 26 was Benzyl- [2- (cyclopentyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-ammonium bromide. (Ib): Ra = Ph, Rb = CH3 Pentyl Rc, Rd = CH3, Re = Benzyl Yield: 11 mg, (17%) LC-MS (Method 1): Tr 6.70 min, m / z 391 [M +] XH NMR (DMS0-d6) d 1.22 (1 H, m), 1.38 (2 H, m), 1.52 (3 H, m), 1.68 (2 H, m), 2.88 (3 H, s), 2.92 (3 H, s) 2.97 (1 H, m), 4.55 (2H, s), 4.70 (2H, s), 6.18 (1 H, s), 7.25 (1 H, m), 7.34, (2H, m), 7.48-7.58 (7H , m).

Example 60 Prepared according to the method used in Example 58 but using Example 29 instead of Example 26 was Benzyl- [2- (cyclopentyl-hydroxy-phenyl-methyl) -oxazo [-5-ylmethyl] -dimethyl-ammonium bromide, (Ib): Ra = Ph, Rb = c-Pentyl, Rc = Rd = CH3, Re = Benzyl Yield: 27 mg, (58%) LC-MS (Method 1): Tr 7.30 min, m / z 391 [M +] XH NMR (DMSO-d6) d 1.23 (1 H, m), 1.37 (2H, m), 1.52 (3H, m), 1.67 (2H, m), 2.88 (3H, s), 2.92 (3H, s) 2.97 (ÍH, m), 4.55 (2H, s), 4.70 (2H, s) , 6.18 (1 H, s), 7.25 (1 H, m), 7.34, (2H, m), 7.48-7.58 (7H, m) Example 61 Methanesulfonate hydrochloride salt of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (8-methylamino-octyl) -ammonium. (Ib): Ra = Ph, Rb = c-Hexyl Rc = Rd = CH3, R6 = 8-Methylamino-octyl Methanesulfonate of [8- (tert-butoxycarbonyl-methyl-amino) -octyl] - [2- ((R ) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-ammonium (Example 47) (60 mg, 0.09 mmol) was dissolved in 6 mL of 1 M HCl in dioxane. The solution was stirred at room temperature overnight. The solvent was removed and the crude product was purified by column chromatography on silica gel, eluting with a DCM gradient up to 20% MeOH / DCM to give the title compound as a solid. Yield: 21 mg (42%) LC-MS (Method 1): Tr 5.50, m / z 456 [M +] 1 O NMR (CDC13) d 1.01-2.19 (22H, m), 2.33 (1 H, m), 2.64 (3H, s), 2.69 (3H, s), 2.21 (2H, m), 3.16 (6H, s), 3.35-3.50 (2H, m), 4.78-5.08 (2H? M), 7.16-7.36 (3H , m), 7.46-7.60 (3H, m), 9.31 (2H, s).

Example 62 Prepared according to the method used in Example 61 but using Example 50 in place of Example 47 was methanesulfonate hydrochloride [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl - [2- (4-methylaminomethyl-phenyl) -ethyl] -ammonium, (Ib): Ra = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 2- (4-Methylaminomethyl-phenyl) -ethyl Yield: 51% LC-MS (Method 5): Tr 4. 64 min, m / z 462 [M +] 1 H NMR (MeOD) d 1.01-1.41 (6H, m), 1.50-1.81 (4H, m), 2.39 (HH, m), 2.69 (3H, s), 2.71. (3H, s), 3.08-3.27 (8H, m), 3.39-3.57 (2H, m), 4.19 (2H, s), 7.20-7.35 (3H, m), 7.39-7.59 (7H, m).

Reaction Scheme 7 The following example compounds were prepared using the route shown in Reaction Scheme 7 Example 63 [5-Amino-ethyl) -oxazol-2-yl] -cyclohexyl-phenyl-methanol. (I-c): Ra = Ph, Rb = c-Hexyl To a solution of [2- (cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-yl] -acetonitrile (Intermediate 12) (600 mg, 2.0 mmol) in THF (20 mL ) a solution of borane-dimethylsulfide complex (2 mL of 2 M in THF, 4 mmol) was added dropwise to it at 55 ° C. The mixture was heated to reflux for 90 minutes then allowed to cool to room temperature. The mixture was then cooled in an ice bath and quenched by the dropwise addition of methanol (5 mL) followed by hydrochloric acid (1 N, 2 mL). This mixture was stirred for 30 minutes then neutralized with saturated aqueous sodium hydrogen carbonate. The mixture was partitioned between water (80 mL) and ethyl acetate (80 mL), the aqueous was extracted with ethyl acetate (2 x 50 mL) and the combined organics were dried over sodium sulfate, filtered and evaporated to a oil. The residue was purified by SCX cartridge, washing with methanol then eluting with 4N ammonia in methanol to give the title compound as a colorless oil. Yield: 400 mg (67%) LC-MS (Method 2): Tr 2.18 min, m / z 283 [MH + -H20] XH NMR (CDC13) d 1.10-1.38 (7 H, m), 1.54-1.77 (3 H, m), 2.28 (H, m), 2.80 (2 H, t), 2.98 (2 H, t), 3.67 (1 H, br s), 6.72 (1 H, s), 7.24 (1 H, m) , 7.34 (2H, m), 7.62 (2H, m).

Example 64 Cyclohexyl- [5- (2-dimethylamino-ethyl) -oxazol-2-yl] -phenyl-methanol. (I-d): Ra = Ph, Rb = c-Hexyl. Rc = Rd = CH3 To a solution of [5- (2-amino-ethyl) -oxazol-2-yl] -cyclohexyl-phenyl-methanol (Example 63) (250 mg, 0.83 mmol) in 1,2-dichloroethane ( 5 mL) was added formaldehyde (0.3 mL of 37% solution in water, 4.0 mmol) and sodium triacetoxyborohydride (352 mg, 1.7 mmol). This mixture was stirred at room temperature for 6 hours then DCM (10 mL) and saturated aqueous sodium acid carbonate (10 mL) were added and mixed thoroughly. The organics were isolated through a phase separation cartridge and evaporated to an oil. Purification by flash column chromatography on silica gel using a mixture of 10% methanol: 90% DCM as eluent gave the title compound as a white solid. Yield: 200 mg (73%) LC-MS (Method 2): Tr 2.20 min, m / z 329 [MH +] NMR corresponds to Example 66.

Example 65 Bromide of. { 2- [2- (Cyclohexyl-hydroxy-f-enyl-methyl) -oxazol-5-yl] -ethyl} -dimethyl- (3-f-enoxy-propyl) -ammonium. (Ie): Ra = Ph, Rb = c-Hexyl, Rc = Rd = CH3, Re = 3-Phenoxypropyl To a solution of cyclohexyl- [5- (2-dimethylamino-ethyl) -oxazol-2-yl] -phenyl -methanol (Example 64) (10.5 mg, 0.03 mmol) in a mixture of acetonitrile (0.5 ml.) and chloroform (0.75 L) was added 3-phenoxypropyl bromide (50 μL, 0.32 mmol). This mixture was heated to 50 ° C for 6 hours then the solvent was removed in vacuo. Purification by flash column chromatography on silica gel using a gradient of 2-10% methanol in DCM as eluent gave the title compound as a white solid. Yield: 8.6 mg (53%) LC-MS (Method 1): Tr 8.66 min, m / z 463 [M +] 1 H NMR (MeOD) d 1.06-1.35 (6H, m), 1.66 (4H, m), 2.24 (2H, m), 2.37 (2H, m), 3.17 (6H, s), 3.29 (HI, m), 3.59 (2H, m), 3.66 (2H, m), 4.06 (2H, t), 6.91- 6.97 (3H, m), 6.99 (1 H, s), 7.20-7.33 (5H, m), 7.50 (2H, m). [5- (2-Amino-ethyl) -oxazol-2-yl] -cyclohexyl-f-enyl-methanol. (I- d): R = Ph, Rb = c-Hexyl, Rc = Rd = CH3 (first eluted enantiomer) The title compound was isolated following preparative chiral HPLC of Example 64. (Chiralpax LA, 250 x 20mm id; % ethanol / 95% heptane / 0.1% diethylamine, 15 mL / min, Tr 12 minutes). LC-MS (Method 1): Tr 6.74 min, m / z 329 [MH +] * H NMR (CDC13) d 1.10-1.37 (7H, m), 1.61-1.76 (3H, m), 2.26 (6H, s) , 2.57 (2H, t), 2.81 (2H, t), 3.66 (1H, s), 6.69 (1H, S), 7.24 (1H, m), 7.34 (2H, t), 7.63 (2H , d).

Example 67 [5- (2-Amino-ethyl) -oxazol-2-yl] -cyclohexyl-phenyl-methanol. (I-d): Ra = Ph, Rb = c-Hexyl, Rc = Rd = CH3 (second enantiomer eluted) The title compound was isolated following preparative chiral HPLC of Example 64 using the conditions reported by Example 66; (Tr 13.5 minutes). LC-MS (Method 1): Tr 6.76 min, m / z 329 [MH +] NMR corresponds to Example 66.

Example 68 Bromide of. { 2- [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-yl] -ethyl} -dimethyl- (3-phenoxy-propyl) -ammonium (Ie): Ra = Ph, Rb = c-Hexyl, Rc = Rd = CH 3, Re = 3-phenoxypropyl-Enantiomer 1 The title compound was prepared from the compound in Example 66 using the method in Example 65. LC-MS (Method 1): Tr 8.54 min, m / z 463 [M +] XH NMR (DMSO-de) d 0.95-1.28 (6H, m), 1.48- 1.70 (4H, m), 2. 12-2.28 (3H, m), 3.11 (6H, s), 3.20 (2H, t), 3.51 (2H, m), 3. 61 (2H, m), 4.03 (2H, t), 5.89 (1H, s), 6.92-6.98 (3H, m), 7. 00 (1 H, s), 7.20-7.24 (1 H, m), 7.28-7.34 (4H, m), 7.43-7.47 (2H, m).

Example 69 Bromide. { 2- [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-yl] -ethyl} -dimethyl- (3-f-enoxy-propyl) -ammonium (Ie): Ra = Ph, Rb = c-Hexyl, Rc = Rd CH3, Re = 3-f enoxopropyl-Enantiomer 2 The title compound was prepared from the compound in Example 67 using the method in Example 65. LC-MS (Method 1): Tr 8.62 min, m / z 463 [M +] NMR corresponds to Example 68.

Example 70 [5- (2-Amino-ethyl) -oxazol-2-yl] -dif-enyl-methanol (Ic): Ra = Rb = Ph To a solution of [2- (hydroxy-dif-enyl-methyl) -oxazole-5- il] -acetonitrile (Intermediary 13) (0.36 g, 1.2 mmol) in IMS (7 mL) was added Raney Niquel (catalytic amount) and the suspension was stirred under an atmosphere of hydrogen gas (balloon) at room temperature overnight. The reaction mixture was filtered over Celite, washed with IMS and the filtrate was concentrated in vacuo to give a brown oil, which was used without further purification. LC-MS (Method 2): Tr 1.85 min, m / z 295 [M +] XH NMR (CDC13) d 2.66-2.73 (m, 2H), 2.81-2.86 (m, 2H), 6.64 (s, ÍH), 7.25-7.37 (m, 10 H). The following example compounds were prepared in a similar manner, using the route shown in Reaction Scheme 7.

The following compounds, eg, were prepared using the route shown in Reaction Scheme 8.

Reaction scheme 8 Example 73 (2-Benzhydryl-oxazol-5-ylmethyl) -dimethyl-amine. (If): Ra = Rb = Ph, Rc, Rd = CH3 Triethylsilane (720 μL, 4.51 mmol) was added to a solution of (5-dimethylaminomethyl-oxazol-2-yl) -diphenylmethanol (Example 1) ( 100 mg, 0.325 mmol) in DCM (0.7 mL), followed by TFA (0.7 mL), and heated to reflux for 6 h. The reaction mixture was concentrated, passed over an SCX-2 cartridge and freed with 2M ammonia solution in methanol. After evaporation of the volatiles the residue was purified on silica using a gradient of 1-5% MeOH / DCM as eluent to give the title compound as a colorless oil Yield: 74 mg (78%) LC-MS (Method 5 ): Tr 5.03 min, m / z 293 [MH +] 1 H NMR (CDC 13): d 2.24 (s, 6 H), 3.50 (s, 2 H), 5.59 (s, 1 H), 6.91 (s, 1 H), 7.22- 7.33 (m, 10H).

Example 74 Bromide (2-Benzhydryl-oxazol-5-ylmethyl) -dimethyl- (3-phenoxy-propyl) ammonium, (I-q): Ra = Rb = Ph, Rc, Rd = Me, Ra = 3-Phenoxypropyl. The title compound was prepared from Example 73 in accordance with the method used to prepare the Example Yield: 87% LC-MS (Method 1): Tr 8.05 min, m / z 427 [M +] XH NMR (CDC13): d 2.32 (m, 2H), 3.39 (s, 6H), 3.59 (m, 2H) , 3.93 (m, 2H), 5.30 (s, 2H), 5.62 (s, 1 H), 6.79 (d, 2H), 6.97 (t, 1 H), 7.20-7.32 (m, 12H), 7.61 (S , 1 HOUR) .

Example 75 [2- (Methoxy-diphenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-amine. (Ih): Ra = Rb = Ph, Rc = Rd = R £ = Me A solution of (5-dimethylaminomethyl-oxazol-2-yl) -diphenylmethanol (Example 1) (100 mg, 0.32 mmol) in 3 mL DMF under nitrogen was added sodium hydride (60% dispersion in oil, 16 mg, 0.40 mmol) and the reaction mixture was stirred for 5 minutes. The iodomethane (40μL, 0.65mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The water and EtOAc were added and the phases were separated. The organic layer was dried (Na2SO4) and the solvent was evaporated. The crude product was purified using a 10 g NH 2 isolute cartridge eluting with 5-10% EtOAc / cyclohexane to give the title compound. Yield: 56mg (53%) LCMS (Method 4): Tr 2.22min, m / z 323 [MH +] XH NMR (CDC13): d 2.21 (s, 6H), 3.27 (s, 3H), 3.55 (s, 2H ), 6.99 (s, 1 H)? 7.23-7.37 (m, 6H), 7.43-7.52 (m, 4H).

Example 76 [2- (Methoxy-diphenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium bromide. (I-j): Ra = Rb = Ph, Rc, Rd = Me, Re = 3-Phenoxypropyl. Rf = Me. The title compound was prepared from Example 75 in accordance with the method used to prepare Example 8.

Yield: 40mg (45%) LCMS (Method 5): Tr 7.46min, m / z 457 [M +] 1 H NMR (MeOD): d 2.27 (m, 2H), 3.09 (s, 6H), 3.23 (s, 3H) ), 3.42 (m, 2H), 3.98 (t, 2H), 4.78 (s, 2H), 6.88 (dd, 2H), 6.96 (m, 1 H), 7.25-7.34 (m, 8H), 7.47 (m , 4H), 7.62 (s, l H).

Example 77 - [(R) -2- (9- { [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -methyl-amino} -.-nonylamino) -1-hydroxy-ethyl ] -8-hydroxy-lH-quinolin-2-one. A solution of 5- [(R) -1- (tert-butyl-dimethyl-silanyloxy) -2- (9- { [2- (cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] - methyl-amino.}. -nonylamino) -ethyl] -8-hydroxy-1H-quinolin-2-one (75 mg, 0.10 mmol) in dry THF (1 mL) under a nitrogen atmosphere was treated with triethylamine trihydrofluoride ( 48 μL, 0.30 mmol). After stirring at room temperature overnight the reaction mixture was neutralized with saturated NaHC03 (aq) and extracted with DCM. The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated to dry to provide a green / brown gum. This was purified by preparative HPLC (system 1, 25% B + 1.7% B / min). The product fractions were concentrated, the residue was taken up in MeOH / DCM, passed over an SCX-2 cartridge, and released using 2 M ammonia solution in MeOH. Evaporation of the solvent in vacuo afforded the title compound as a yellow gum. Yield: 21 mg, 33%. LC-MS (method 2): Tr 2.22 min, m / z 645 [MH +].

Example 78 (5-Dimethylaminomethylthiazol-2-yl) diphenylmethanol. (XXVIII): Ra = Ph, Rb = Ph, Rc = Me, Rd = Me The DCE (3ml) was added to a mixture of AIBN (5.84 mg, 0.036 mmol), N-bromosuccinimide (0.070 g, 0.391 mmol) and Intermediary 30 (0.1 g, 0.355 mmol). The suspension was placed in an oil bath preheated to 90 ° C. After 40 minutes the reaction was judged complete according to the LC-MS analysis. The solution was poured into a mixture of diethyl ether and saturated sodium hydrogen carbonate and the layers were separated. The organic phase was washed with water and brine, dried (MgSO 4) and evaporated. The residue was dissolved in THF (2 ml), cooled to -10 ° C under a nitrogen atmosphere and treated with a 2M solution of dimethylamine in THF (0.178 ml, 0.355 mmol). After warming to room temperature, the solvent was evaporated, and the residue was subjected to column chromatography (Si02, 8g) eluting with 50% EtOAc in iso-hexane to give the desired material. Yield = 0.06 g (51%) LC-MS (Method 6): Tr 2.84 min, m / z 325 [MH] +. H NMR, 400 MHz, DMSO-d6: 7.5 (H, s), 7.4 (4H, m), 7.3-7.2 (7H, m), 3.6 (2H, s) and 2.1 (6H, s).

Example 79 Bromide of [2- (hydroxydiphenylmethyl) thiazol-5-ylmethyl] dimethyl- (3-phenoxypropyl) ammonium. (XXIX): Ra = Ph, Rb = Ph, Rc = Me, Rd = Me, Re = 3-phenoxy-1-propyl Phenoxypropylbromide (0.438 g, 2.034 mmol) was added to a solution of Intermediary 3 (0.055 g, 0.170) mmol) in CHC13 (1 ml) and MeCN (1 ml). The solution was heated at 55 ° C for 20 h, which TLC (10% MeOH in DCM) indicated pure completion of the reaction. The solvents were evaporated and the residue was subjected to column chromatography (Si02, 8g) eluting with 5 to 15% MeOH in DCM to give the desired material as a white solid. Yield = 0.061 g (66.7%) LC-MS (Method 1): Tr 2.39 min, m / z 459 [M-Br] +. H NMR, 400 MHz, DMSO-d6: 8.0 (H, s), 7.5 (1 H, s), 7.4 (4 H, m), 7.3-7.2 (8 H, m), 6.9 (3 H, m), 4.9 ( 2H, s), 4.0 (2H, s), 3.4 (2H, m), 6.1 (6H, s) and 2.2 (2H, m).

Example 80 Bromide (3-benzyloxy-propyl) - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-ammonium, (Ib): Ra = Ph, Rb = c- Hexyl, Rc, Rd = CH3, Re = 3-Benzyloxy-propyl The title compound was prepared according to the method used to prepare Example 8. LC-MS (Method 5): Tr 7.26 min, m / z 463 [ M +] H NMR (DMS0d6): d 0.90-1.29 (m, 6H), 1.50-1.74 (m, 4H), 2.04 (m, 2H), 2.26 (m, 1 H), 2.98 (s, 3H), 2.99 (s, 3H), 3.27 (m, 2H), 3.45 (t, 2H), 4.46 (s, 2H), 4.72 (s, 2H), 6.08 (s, 1 H), 7.24 (t, 1 H), 7.28-7.39 (m, 7H), 7.46 (d, 2H), 7.52 (s, 1 H).

Example [2- (4-Chloro-benzyloxy) -ethyl] - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethylammonium methanesulfonate. (Ib): Ra = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 2- (4-Chloro-benzyloxy) -ethyl The title compound was prepared according to the method used to prepare Example 8. LC-MS (Method 1): Tr 8.73 min, m / z 483 [M +]. XH NMR (CDC13): d 1.02-1.49 (7H, m), 1.56-1.79 (3H, m), 2.21-2.34 (1H, m), 2.67 (3H, s), 3.14 (6H, s), 3.64 (2H, bs), 3.88 (2H, bs), 4.49 (2H, s), 4.79-4.99 (3H, m), 7.16-7.36 (7H, m), 7.43 (ÍH, s), 7.51-7.58 (2H , m).

Example 82 Bromide of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl) -dimethyl- (2-oxo-2-phenyl-ethyl) -ammonium, (Ib): Ra = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 2-Oxo-2-phenyl-ethyl The title compound was prepared according to the method used to prepare Example 8. LC-MS (Method 2): Tr 2.53 and 2.60 min, m / z 433 [M +] • 1 H NMR (CDC13): d 1.02-1.87 (10H, m), 2.17-2.32 (1 H, m), 3.59 (3H, s), 3.60 (3H, s), 3.89 (HH, bs) , 5.28 (HH, d), 5.47 (HH, d), 5.76 (2H, s), 7.17-7.33 (3H, m), 7.42 (1 H, s), 7.45-7.54 (4H, m), 7.61- 7.67 (1 H, m), 8.05-8.11 (2H, m).

Example 83 Bromide of [2- ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (2-f-eethyloxy-ethyl) -ammonium, (Ib): R = Ph, Rb = c -Hexyl, Rc, Rd = CH3, Re = 2-Phenethyloxy-ethyl The title compound was prepared according to the method used to prepare Example 8. LC-MS (Method 1): Tr 8.51 min, m / z 463 [M +] H NMR (CDCl 3): d 1.07-1.40 (m, 7H), 1.60-1.80 (m, 3H), 2.32 (m, 1 H), 2.87 (t, 2H), 3.12 (s, 6H), 3.72- 3.87 (m, 6H), 4.17 (s, 1 H), 4.91 (dd, 2H), 7.16 (m, 3H), 7.20-7.28 (m, 3H), 7.29-7.37 (m, 3H), 7.57 (d , 2H).

Example 84 [3- (4-Carboxy-phenoxy) -propyl] - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-ammonium bromide, (-b): Ra = Ph, Rb = c-Hexyl. Rc, Rd = CH3, R? = 3- (4-Carboxy-phenoxy) -propyl 1 M NaOH (0.209mL) was added to a solution of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl bromide] ] - [3- (4-methoxycarbonyl-phenoxy) -propyl] -dimethyl-ammonium (Example 53) (41 mg, 0.069 mmol) in H20 (3 mL) and MeOH (3 mL). The solution was stirred at room temperature for 2 days, and then 1 M HCl (2mL) was added. The solution was dried by freezing and the crude product was purified by column chromatography eluting with 20% MeOH in DCM to give the title compound which was assumed to be the bromide salt. Yield: 40mg (100%) LC-MS (Method 1): Tr 7.35 min, m / z 493 [M +]. XH NMR (CD3OD): d 1.02-1.39 (6H, m), 1.53-1.79 (4H, m), 2.22-1.46 (3H, m), 3.12 (6H, s), 3.39-3.52 (2H, m), 4.05-4.16 (2H, m), 4.77 (2H, s), 6.93-7.01 (2H, m), 7.16-7.35 (3H, m), 7.48-7.56 (4H, m), 7.95-8.02 (2H, m) ).

Example 85 [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl-dimethyl- [2- (4-methyl-benzyloxy-ethyl] -ammonium methanesulfonate (Ib): R = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 2- (4-Methyl-benzyloxy) -ethyl The title compound was prepared according to the method used to prepare Example 8. LC-MS (Method 1) : Tr 8.67 min, m / z 463 [M +]. XH NMR (CDC13): d 1.03-2.07 (10H, m), 2.22-2.43 (4H, m), 2.69 (3H, s), 3.14 (6H, s), 3.64 (2H, bs), 3.86 (2H, bs), 4.48 (2H, s), 4.60 (1 H, bs), 4.82 - 5.02 (2H, m), 7.04-7.37 (7H, m), 7.42 (1H, s), 7.55 (2H, d).

Example 86 [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] - [2- (3, 4-dichloro-benzyloxy) -ethyl] -dimethylammonium methanesulfonate. (Ib): Ra = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 2- (3,4-Dichloro-benzyloxy) -ethyl The title compound was prepared in accordance with the method used to prepare the Example 8. LC-MS (Method 1): Tr 9.09 min, m / z 517 [M +]. 1 H NMR (CDC13): d 1.03-1.39 (7H, m), 1.58-1.80 (3H, m), 2. 23-2.35 (ÍH, m), 2.71 (3H, s), 3.17 (6H, s), 3.71-3.77 (2H, m), 3.89-3.98 (2H, m), 4.42 (1 H, s), 4.49 (2H, s), 4.87-5.04 (2H, m), 7.11-7.33 (4H, m), 7.36-7.49 (3H, m), 7.53-7.59 (2H, m).

Example 87 Toluene-4-sulfonate (2-benzyloxy-ethyl) - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-ammonium. (Ib): Ra = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 2-Benzyloxy-ethyl The title compound was prepared according to the method used to prepare Example 8 using 2- (benzyloxyethyl) -p-toluenesulfonate. LC-MS (Method 2): Tr 2.60 m / z 449 [M +].

X H NMR (CDCl 3): d 1.02-1.76 (10H, m), 2.22-2.37 (4H, m), 3.19 (6H, s), 3.69 (2H, bs), 3.86 (2H, bs), 4.25 (1H, bs), 4.48 (2H, s), 4.89-5.07 (2H, m), 7.05-7.15 (2H, m), 7.16-7.43 (9H, m), 7.55 (2H, d), 7.73 (2H, d) . [5- (2-Amino-ethyl) -oxazol-2-yl] -cyclopentyl-phenyl-methanol. (I-c): Ra = Ph, Rb = c-Pentyl. Prepared according to the method used to prepare Example 70. LC-MS (Method 2): Tr 2.03 min, m / z 287 [MH +] XH NMR (CDCI3) d 1.28-1.71 (m, 11 H), 2.78 ( t, 2H), 2.97 (m, 3H), 6.72 (s, 1 H), 7.22-7.28 (m, 1 H), 7.30-7.36 (m, 2H), 7.59-7.64 (m, 2H).

Example 89 Cyclopentyl- [5- (2-dimethylamino-ethyl) -oxazol-2-yl] -phenyl-methanol. (I-c): Ra = Ph, Rb = c-Pentyl. R ° = Rd = CH3 Prepared in accordance with the usadp method to prepare Example 64. LC-MS (Method 2): Tr 2.05 min, m / z 315 [MH +] XH NMR (CDC1) d 1.29-1.70 (m, 8H ), 2.26 (s, 6H), 2.57 (m, 2H), 2.80 (t, 2H), 2.97 (m, 1 H), 3.68 (br S, 1 H), 6.69 (s, 1 H), 7.21-7.27 (m, 1 H), 7.33 (t, 2H), 7.62 (d, 2H).

Example 90 [2- ((R) -cyclohexyl-hydroxy-f-enyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-methyl-3-phenoxy-butyl) -ammonium methansulfonate. (Ib): R = Ph, Rb = c-Hexyl, Rc, Rd = CH3, Re = 3-Methyl-3-phenoxy-butyl The title compound was prepared according to the method used to prepare Example 8. Performance : 5mg (6%) LC-MS (Method 4): Rt. 2.85 min, m / z 477 [M +]. X H NMR (CDCl 3): d 0.70-2.00 (16H, m), 2.02-2.13 (2H, m), 2.16-2.30 (1 H, m), 2.62 (3H, s), 3.07 (6H, s), 3.44. -3.55 (2H, m), 4.77-4.91 (2H, m), 6.83 (2H, d), 6.97-7.27 (5H, m), 7.43-7.52 (4H, m).

BIOLOGICAL EXAMPLES The inhibitory effects of the compounds of the present invention on the M3 muscarinic receptor and (in the case of Example 77) the β2 adrenergic receptor, were determined by the following tests: Radioligand Linkage Assays of the Muscarinic Receptor Radioligand binding studies using [3H] -N-methyl scopolamine ([3H] -NMS) and commercially available cell membranes expressing human muscarinic receptors (M2 and M3) were used for evaluate the affinity of muscarinic antagonists for M2 and M3 receptors. Membranes in TRIS buffer solution were incubated in 96-well plates with [3 H] -NMS and M3 antagonist at various concentrations for 3 hours. The membranes and linked radioligand were then harvested by filtration and allowed to dry overnight. The scintillation fluid was then added and the bound radioligand is counted using the Canberra Packard Topcount scintillation counter. The half-life of the antagonists at each muscarinic receptor was measured using the alternative radioligand [3 H] -QNB and an adaptation of the previous affinity assay. The antagonists were incubated for 3 hours at a concentration 10 times greater than their Ki, as determined with the ligand [3 H] -QNB, with membranes expressing the human muscarinic receptors. At the end of this time, [3 H] -QNB was added at a concentration 25 times greater than its Kd for the receptor to be studied and the incubation continued for several periods of time from 15 minutes to 180 minutes. The membranes and linked radioligand were then harvested by filtration and allowed to dry overnight. The scintillation fluid was then added and the radioligand is counted using a Canberra Packard Topcount scintillation counter. The relationship at which [3H] -QNB is linked to muscarinic receptors is related to the relationship at which the antagonist dissociates from the receptor, that is, to the half-life of the antagonists at the receptors. The following compounds were tested in the receptor binding assay: 10 15 25 10 15 20 25 Compounds with a Ki linked to M3 < 1 nM are indicated +++ '; those with Ki between 1 and lOnM as? ++ 'and those with more than lOnM as' +'. All tested compounds have Ki values < 5μM. The compounds marked 'T' were not tested in this assay.

Radioligand Linkage Assays of the Adrenergic Receptor ß Radioligand binding studies using [1251] -iodocyanopenindolol and commercially available cell membranes expressing the human β2 adrenergic receptor were used to assess the affinity of the antagonists for the β2 adrenergic receptor. The SPA membranes and beads were incubated with [1251] -iodocyanopenindolol and the β2 antagonist at various concentrations for 3 hours at room temperature in TRIS buffer. This assay was performed on 96-well plates that are read using the Wallac Microbeta counter. Example 77 exhibits a Ki value of < 100nM in this trial.

Inhibition Analysis of M3 Receptor Activation by Calcium Mobilization CHO cells expressing the human M3 receptor were seeded and incubated overnight in 96-well collagen coated plates (black wall, clear bottom) at a density of 50000 / 75μl of 3% serum medium. The next day, the calcium sensitive pigment (Molecular Devices, Cat # R8041) was prepared in HBSS buffer with the addition of 5mM probenecid (pH 7.4). An equal volume of the pgmento solution (75μl) was added to the cells and incubated for 45 minutes followed by the addition of 50μl of muscarinic antagonists or vehicle. After an additional 15 minutes the plate was read on a FLEXstation ™ (488nm excitation, 525nm emission) for 15 seconds to determine the baseline fluorescence. The muscarinic agonist Carbachol was then added at an EC8o concentration and the fluorescence is measured for an additional 60 seconds. The signal was calculated by subtracting the peak response from the baseline fluorescence mean in control wells in the absence of antagonist. The percentage of the maximum response in the presence of the antagonist was then calculated in order to generate IC50 curves.

Evaluation of power and duration of action in tracheas of isolated guinea pigs The experiments were carried out at 37 ° C in solution Modified Krebs-Henseleit, (114mM NaCl, 15mM NaHC03, lmM MgSO4, 1.3mM CaCl2, 4.7mM KCl, 11.5mM glucose and 1.2mM KH2P0, pH 7. 4) gasified with 95% 02/5% C02. Indomethacin was added to a final concentration of 3μM. The tracheae were removed from adult male Dunkin Hartley guinea pigs and dissected from the tissue before opening longitudinally in a line opposite the muscle. Individual strips of 2-3 rings of cartilage were cut across and are suspended using cotton yarn in organ baths jacketed in lOml water and linked to a force transducer that ensures that the tissue is located between two platinum electrodes. The responses were recorded by means of an MPlOOW / Ackowledge data acquisition system connected to a PC. The tissues were equilibrated for one hour under a latent tone of lg and then subjected to electric field stimulation at a frequency of 80Hz with a pulse width of O.lms, a unipolar pulse, fired every 2 minutes. A "voltage response" curve was generated for each tissue and a submaximal voltage is then applied to each tissue port according to its own voltage response. The tissues were washed with Krebs solution and allowed to stabilize under stimulation before the addition of the test compound. The response curves to the concentration are obtained by cumulative addition of the test compound in increments of log medium. Once the answer to each addition has reached a plateau, the following addition is made. The percentage of contraction inhibition stimulated by EFS is calculated for each concentration of each compound added and the dose response curves are constructed using the Graphpad Prism software and the EC50 is calculated for each compound. The time-onset studies and the duration of action were performed by adding the previously determined EC50 concentration of the compound to the tissues contracted with EFS and the response allowed in the panicie. The time it takes to reach 50% of this response was determined to be the beginning of time. The tissues were then completely washed from the composite by flowing the tissue bath with fresh Krebs solution and the time taken for the contraction in the response to EFS to return to 50% response in the presence of the compound is measured. This is called the duration of action.

Methacholine induced bronchoconstriction in vivo Male guinea pigs (Dunkin Hartley), weighing 500-600g housed in groups of 5, were individually identified. The animals were allowed to acclimate to their surrounding location for at least 5 days. During this time and study time, animals were allowed access to water and food ad libitum. The guinea pigs were anesthetized with halothane (5%) inhaled anesthetic. The test compound or vehicle (0.25-0.50 ml / kg) was administered intranasally. The animals were placed on a heating pad and allowed to recover before returning to their housing cages. Up to 72 hours after dosing, the guinea pigs were terminally anesthetized with Urethane (250μg / ml, 2ml / kg). At the point of surgical anesthesia, the jugular vein was cannulated with an i.v. cannula. portex filled with heparinized phosphate buffered saline (hPBS) (10U / ml) for i.v. of methacholine. The trachea was exposed and cannulated with a rigid portex cannula and the esophagus was transiently cannulated with a flexible portex infant feeding tube. Spontaneous animal respiration was then connected to a pulmonary measurement system (EMMS, Hants, UK) consisting of a flow pneumothorax and a pressure transducer. The tracheal cannula was connected to a pneumothorax and the esophageal cannula is connected to a pressure transducer. The esophageal cannula was placed to give a baseline resistance of between 0.1 and 0.2cmH20 / ml / s. A baseline reading of 2 minutes was recorded before i.v. administration. of methacholine (up to 30μg / kg, 0.5ml / kg). A 2-minute record of induced constriction was taken from the i.v. administration point. The software calculates the peak resistance and an area of resistance under the curve (AUC) during every 2 minutes of recorded period that were used to analyze the bronchoprotective effects of the test compounds. The results obtained in this test for the compound of Example 32 (0.1, 0.3 and 1 μg / kg in) 4 hours before for MCh-induced bronchoconstriction (10 μg / kg iv), and the tiotropium comparison compound, are shown in the Figure 1.

Inhibition of salivation induced by pilocarpine by compounds administered i.n. Guinea pigs (450-550g) are supplied by Harían RU or David Hall, Staffs UK and are acclimated to accommodation facilities for a minimum of three days before use. The guinea pigs were randomized into treatment groups and weighed. Each animal was lightly anesthetized (4% halothane) and the compound or vehicle was administered intransally (0.5ml / kg) for up to 24 hours before stimulating with pilocarpine. At the test time point, the guinea pigs were terminally anesthetized with urethane (25% solution in H20, 1. 5g / kg). Once sufficient anesthesia has been developed (absence of finger prick reflex) each animal has an absorbent pad placed in the mouth for 5 minutes to dry residual saliva, this pad was removed and replaced with a new pre-weighed pad for 5 minutes. minutes to establish a reading of the baseline saliva production. At the end of this x period of 5 minutes, the pad was removed and weighed. A new pre-weighed pad was inserted into the mouth before each animal received s. c. pilocarpine administered under the skin on the back of the neck (0.6mg / kg @ 2ml / kg). The pad was removed, weighed and replaced with a new pre-weighed pad every 5 minutes up to 15 minutes. Saliva production was calculated by subtracting the previously weighed weight of the pad every 5 minute period after weighing the pad and these numbers are aggregated together to produce an accumulation of saliva for 15 minutes. Each 5-minute period should be analyzed in addition to the full 15-minute registration period. The baseline production of saliva is assumed to be constant and multiplied by three to produce a reading for the production of baseline saliva for 15 minutes. The inhibition of saliva produced by the compound should be calculated using the following equation: (1- (baseline test) / (baseline Veh)) * 100. It is noted that with respect to this date, the best known method for carrying out the aforementioned invention is that which is clear from the present description of the invention.

Claims (41)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A compound of the formula (I): characterized in that (i) R1 is Ci-Cß alkyl or hydrogen; and R2 is hydrogen or a group -R7, -Z-Y-R7, -Z-NR9R10; -Z-CO-NR9R10, -Z-NR9-C (O) O-R7, or -Z-C (0) -R7; and R3 is a single pair, or C? -C6 alkyl; or (ii) R1 and R3 together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R2 is a single pair or a group -R7, -ZY-R7, -Z-NR9R10, -Z-CO-NR9R10, - Z-NR9-C (O) O-R7; or; -Z-C (0) -R7; or (iii) R1 and R2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, the ring is substituted by a group -Y-R7, -Z-Y-R7, -Z-NR9R10; -Z-CO-NR9R10; -Z-NR9-C (0) 0-R7; or; -Z-C (0) -R7; and R3 is a single pair, or C? -C6 alkyl; R4 and R5 are independently selected from the group consisting of aryl, heterocycloalkyl fused to the aryl, heteroaryl, Ci-Cß alkyl, cycloalkyl; R6 is -OH, C?-C6 alkyl, Ci-Cd alkoxy, hydroxyC C ~C6 alkyl, nitrile, a CONR82 group or a hydrogen atom; A is an oxygen or a sulfur atom; X is an alkylene, alkenylene or alkynylene group; R 7 is a C 1 -C 6 alkyl, aryl, cycloalkyl fused to aryl, heterocycloalkyl fused to aryl, heteroaryl, aryl (Ci-Cs alkyl), heteroaryl (C 1 -C 8 alkyl), cycloalkyl or heterocycloalkyl group; R8 is C6-C6 alkyl or a hydrogen atom; Z is an alkylene group Ci-Cie, C2-Ci6 alkenylene or C2-Ci6 alkynylene, "Y is an oxygen bond or atom, R9 and R10 are independently a hydrogen atom, Ci-Cß alkyl, aryl, heterocycloalkyl group fused to aryl, cycloalkyl fused to aryl, heteroaryl, aryl (Ci-Cd alkyl) -, or heteroaryl (C? -C6 alkyl); or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, which optionally contains additional oxygen or nitrogen atoms, wherein any aryl, heteroaryl, cycloalkyl, cycloalkyl fused with aryl, heterocycloalkyl, and heterocycloalkyl fused with aryl may be substituted by one or more substituents selected from acyl, alkoxy, alkoxycarbonyl, alkoxycarbonyl-N- (alkyl) aminoalkyl, alkylamino, alkylsulfinyl, alkylsulfonyl, alkylthio, -NH2, aminoacyl, aminoalkyl, alkylaminoalkyl, arylalkyl, cyano, dialkylamino, halo, haloalkoxy, haloalkyl, alkyl, -OH, -CHO, -COOH, -N02, aryl (optionally substituted by alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heteroaryl (optionally substituted by alkoxy, haloalkoxy, halogen, alkyl or haloalkyl), heterocycloalkyl, aminoacyl, aminosulfonyl, acylamino, sulfonylamino, cyclic heteroarylalkyl, aryloxy, heteroaryloxy, arylalkyloxy and heteroarylalkyloxy; or a pharmaceutically acceptable salt, solvate, N-oxide or prodrug thereof.
2. 2. The compound according to claim 1, characterized in that: R1 is C6-C6 alkyl or a hydrogen atom; R2 is Ci-Ce alkyl, a hydrogen atom or a group -ZY-R7 and R3 is a single pair or C? -C6 alkyl, or R1 and R2 together with the nitrogen to which they are attached represents a heterocycloalkyl ring, or R1 and R3 together with the nitrogen to which they are attached represents a heterocycloalkyl ring; R4 and R5 are independently selected from the group consisting of aryl, heteroaryl, Ci-Ce alkyl, cycloalkyl; R6 is -OH, halogen, Ci-Cd alkyl, hydroxyCi-Cd alkyl or a hydrogen atom; A is an oxygen or a sulfur atom; X is an alkylene, alkenylene or alkynylene group; Z is an alkylene, alkenylene or alkynylene group; And it is a bond or atom of oxygen; R7 is aryl, heteroaryl, heterocycloalkyl, which aryl, heteroaryl or heterocycloalkyl can be substituted by one or more substituent groups as defined in claim 1.
3. 3. The compound according to claim 1 or 2, characterized in that R1 is methyl or ethyl, or a hydrogen atom; R2 is hydrogen, C? -C6 alkyl, or a group -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-CO-R7 or; -Z-C (0) -R7; and R3 is a single pair, or Ci-Cß alkyl, in which case the nitrogen atom which is bonded is a quaternary nitrogen and carry a positive charge.
4. 4. The compound according to claim 3, characterized in that R3 is methyl, so that the nitrogen atom is bonded is a quaternary nitrogen and carries a positive charge.
5. The compound according to claim 1 or 2, characterized in that R1 and R3 together with the nitrogen to which they are attached form a monocyclic heterocycloalkyl ring from 3 to 7 ring atoms, in which the hetero atoms are nitrogen; and R2 is a single pair or C? -C6 alkyl, or a group -R7, -Z-Y-R5, -Z-NR9R10, -Z-NR9-C (0) 0-R7 or -Z-C (0) -R7.
6. 6. The compound according to claim 5, characterized in that R1 and R3 together with the nitrogen to which they are bound form an azetidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, or pyrrolidinyl ring.
7. The compound according to claim 5 or 6, characterized in that the nitrogen atom in which R1 and R3, or R1 and R2, are linked is a quaternary nitrogen and carry a positive charge.
8. 8. A compound according to any of the preceding claims, characterized in that in any group it is -R7, -Y-R7, -ZY-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C (0) 0-R7 or; -Z-C (0) -R7: Z is - (CH2)? _ 8-, optionally substituted up to three carbons per methyl, Y is a bond or -0-; R7 is methyl, ethyl, n- or isopropyl, n-, sec- or tertbutyl; or phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl; or pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl. , pyridazinyl, triazinyl, indolyl or indazolyl; or arylalkyl wherein the aryl part is phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, or naphthyl, and the part - (C 1 -C 6 alkyl) -is -CH 2 - or -CH 2 CH 2 -; or heteroarylalkyl wherein the hetroaryl part is pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or indazolyl, and the part - (C 1 -C 6 alkyl) - is -CH 2 - or -CH 2 CH 2 -; or indanyl or 1, 2, 3, 4-tetrahydronaphthalenyl; or heterocycloalkyl (Ci-Cß alkyl) -, wherein the heterocycloalkyl part is azetidinyl, piperidinyl, piperazinyl, substituted N-piperazinyl such as methylpiperazinyl, or tetrahydropyrrolyl and the part - (C?-C6 alkyl) - is -CH 2 - or - CH 2 CH 2 -. or cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; and R9 and R10 are independently hydrogen; methyl, ethyl or n- or isopropyl; phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl; pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or indazolyl; or arylalkyl wherein the aryl part is phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, or naphthyl, and the part - (- Ci-Ce alkyl) - is -CH 2 - or -CH 2 CH 2 -; or R9 and R10 together with the nitrogen atom to which they are attached form an azetidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl ring. R9 and R10 are independently selected from hydrogen; C? -C6 alkyl; or any of those optionally substituted aryl, heterocycloalkyl groups fused to the aryl heteroaryl or aryl (Ci-Cß alkyl) - especially defined by R7 in this claim; or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 ring atoms optionally containing an additional oxygen or nitrogen atoms, and when R7 is a heteroaryl, cycloalkyl, cycloalkyl, fused with aryl group , heterocycloalkyl, or heterocycloalkyl fused with aryl, this can be replaced by one or more substituent groups as defined in claim 1.
9. 9. The compound according to claim 1, characterized in that in the group -NR1R2R3, R1 is methyl or ethyl, R2 is -Z-NR9R10 or -ZY-R7, Y is a bond or -0-, and -Z- is a straight or branched alkylene radical linked to nitrogen and -NR9R10 or -YR7 by a chain of up to 16 atoms of carbon, and R3 is methyl.
10. The compound according to claim 9, characterized in that R7 is phenyl, benzyl, dihydrobenzofuryl or phenylethyl, which phenyl, dihydrobenzofuryl or phenylethyl can be replaced by one or more substituent groups as defined in claim 1.
11. 11. The compound according to claim 9 or 10, characterized in that R9 and R10 are according to claim 8.
12. 12. The compound according to claim 1, characterized in that in the group -NRXR2R3, R2 is -Z-NR9R10 or -ZY -R7, Y is a bond or -O-, and -Z- is a straight or branched alkylene radical linked to nitrogen and -NR9R10 or -YR7 by a chain of up to 16 carbon atoms, and R1 and R3 together with nitrogen to which they are bonded form a heterocyclic ring of 4-8 atoms in the ring, optionally containing an additional oxygen or nitrogen atom.
13. 13. The compound according to claim 12, characterized in that R1 and R3 together with the nitrogen to which they are bound form an azetidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, pyrrolidinyl, morpholinyl, or thiomorpholinyl ring.
14. The compound according to claim 12 or 13, characterized in that R7 is preferably a cyclic lipophilic group such as phenyl, benzyl, dihydrobenzofuryl or phenylethyl, which phenyl, benzyl, dihydrobenzofuryl or phenylethyl group can be substituted by one or more substituent groups as defined in claim 1.
15. 15. A compound according to any of claims 12 to 14, characterized in that R9 and R10 are as defined in claim 8.
16. 16. The compound as claimed in any of the claims, characterized in that R4 and R5 are independently selected. of methyl, ethyl, n- or isopropyl, n-, sec- and tertbutyl; phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl; pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl or indazolyl; indanyl and 1, 2, 3, 4-tetrahydronaphthalenyl; cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and R6 is -OH, a hydrogen atom, methyl, ethyl, hydroxy methyl, nitrile, or a group CONR82 wherein each R8 is independently methyl, ethyl, or a hydrogen atom.
17. 17. The compound according to any of the preceding claims, characterized in that (i) each of R4 and R5 is thienyl; or (ii) each of R4 and R5 is phenyl; or (iii) one of R4 and R5 is phenyl and the other is cyclopentyl or cyclohexyl; or (iv) one of R4 and R5 is thienyl, and the other is cyclopentyl or cyclohexyl.
18. 18. The compound according to claim 17, characterized in that R6 is -OH.
19. 19. The compound according to the preceding claims, characterized in that R8 is hydrogen.
20. 20. The compound according to the preceding claims, characterized in that X is -CH2- or -CH2CH2-.
21. 21. The compound according to claim 1, characterized in that it has the formula (IA) where A is -O- u -S-; m is 1 or 2; ring A is an optionally substituted phenyl ring, or monocyclic heterocyclic ring of 5 or 6 atoms in the ring, or system in the heterocycloalkyl ring fused with phenyl wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 atoms in the ring ring; R 4 is phenyl, thienyl, cyclopentyl or cyclohexyl; R5 is phenyl; thienyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 with the condition that s + t is not greater than 16; Y is a bond or -O-, and X "is a pharmaceutically acceptable anion
22. 22. The compound according to claim 1, characterized in that it has the formula (IB) where A is -O- u -S-; m is 1 or 2; Ring B is a pyrrolidinium or piperidinium ring; ring A is an optionally substituted phenyl ring, or monocyclic heterocyclic ring of 5 or 6 atoms in the ring, or system in the heterocycloalkyl ring fused with phenyl wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 atoms in the ring ring; R 4 is phenyl, thienyl, cyclopentyl or cyclohexyl; R5 is phenyl; thienyl, cyclopentyl or cyclohexyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 with the condition that s + t is not greater than 16; Y is a bond -O-, and X 'is a pharmaceutically acceptable anion.
23. 23. The compound according to claim 21 or 22, characterized in that the ring A is (i) optionally substituted phenyl, wherein the optional substituents are selected from C?-C3 alkoxy, halo, C?-C3 alkyl, amino acyl C? ~ C3, and amino C? -C3 alkyl, or (ii) a heterocycloalkyl ring system fused to a phenyl wherein the heterocycloalkyl ring is a monocyclic heterocyclic ring of 5 or 6 ring atoms, such as dihydrobenzofuranyl.
24. 24. The compound according to claim 1, characterized in that it has the formula (IC) where A is -0- u -S-; m is 1 or 2; Ring B is a pyrrolidinium or piperidinium ring; R 4 is phenyl, thienyl, cyclopentyl, cyclohexyl; R- is phenyl; thienyl, cyclopentyl or cyclohexyl; R and R 10 are independently a hydrogen atom, or optionally substituted C 1 -C 6 alkyl or aryl, such as optionally substituted phenyl; s is 1, 2, 3, 4, 5, 6 or 7 and t is 0, 1, 2, 3, 4, 5, 6 or 7 with the condition that s + t is not greater than 16; Y is a bond or -0-, and X 'is a pharmaceutically acceptable anion.
25. 25. A compound according to any of claims 21 to 23, characterized in that t is 0, 1, 2, 3, 4, 5 or 6 and s is 1, 2, 3, 4, 5, 6 or 7 and s + t is 1, 2, 3, 4, 5, 6, or 7.
26. 26. The compound according to claim 21 or 22, characterized in that t is 0, s is 3, and Y is -O-.
27. 27. The compound according to claim 21 or 22, characterized in that Y is a bond and s + t is 2, 3 or 4.
28. 28. The compound according to claim 24, characterized in that Y is a bond and s + t is 8, 9 or 10.
29. 29. The compound according to claim 1, characterized in that it is selected from the group consisting of salts of [2- (hydroxy-diphenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3- phenoxy-propyl) -ammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium salts of [2- (( R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-phenethyl-ammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] - dimethyl- (4-methyl-pent-3-enyl) -ammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] - [2- (2,3-dihydro) -benzofuran-5-yl) -ethyl] -dimethylammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (6-methyl-pyridin-2-ylmethyl) ) -ammonium salts of [2- (Cyclopentyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxy-propyl) -ammonium salts of [2- (Cyclopentyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (3-phenoxypropyl) -ammonium salts of 1- [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -1- (3-phenoxy-propyl) -pyrrolidinium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl) -methyl) -oxazol-5-ylmethyl] -dimethyl- (4-phenoxy-butyl) -ammonium salts of (2-Benzyloxy-ethyl) - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazole -5-ylmethyl] -dimethyl-ammonium salts of [2- ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazoi-5-ylmethyl] -dimethyl- (4-phenyl-butyl) -ammonium salts of [2 - ((R) -Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] - [3- (4-fluoro-phenoxy) -propyl] -dimethyl-ammonium salts of [2- ((R) -cyclohexyl) -hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl] - (3-phenyl-propyl) -ammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazole-5- ilmethyl] -dimethyl- (2-phenoxy-ethyl) -ammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl-dimethyl- (3-p-tolyloxy-propyl) -ammonium salts of [3- (4-Chloro-phenoxy) -propyl] - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethylamine onium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] - [3- (3,4-dichloro-phenoxy) -propyl] -dimethyl-ammonium salts of [2 ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- (8-methylamino-octyl) -ammonium salts of [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl- [2- (4-methylaminomethyl-phenyl) -ethyl] -ammonium salts of. { 2- [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-yl] -ethyl} -dimethyl- (3-phenoxy-propyl) -ammonium salts of. { 2- [2- (Cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-yl] -ethyl} -dimethyl- (3-phenoxy-propyl) -ammonium, and salts of. { 2- [2- (Hydroxy-diphenyl-methyl) -oxazol-5-yl] -ethyl} -dimethyl- (3-phenoxy-propyl) -ammonium salts of [2- (hydroxydiphenylmethyl) thiazol-5-ylmethyl] imethyl- (3-phenoxypropyl) ammonium salts of (3-benzyloxypropyl) - [2- ((R) - cyclohexyl-hydroxy-phenyl-methyl) -oxazol-5-ylmethyl] -dimethyl-ammonium salts of [2- (4-Chloro-benzyloxy) -ethyl] - [2- ((R) -cyclohexyl-hydroxy-phenyl-methyl] ) -oxazol-5-ylmethyl] -dimethylammonium
30. 30. The compound according to the preceding claims, characterized in that it is modified by the replacement of the group R2 by a group -LB where L is a linked radical and B is a portion having activity ß2 adrenoceptor agonist.
31. 31. The compound according to the preceding claims, characterized in that it is for use in therapy.
32. 32. A pharmaceutical composition characterized in that it comprises a compound according to any of claims 1 to 29 and a pharmaceutically acceptable carrier or excipient.
33. 33. A pharmaceutical composition according to claim 31, characterized in that it is a suitable form for inhalation.
34. 34. The use of a compound according to any of claims 1 to 29, for the manufacture of a medicament for use in the prevention treatment of a disease or condition in which muscarinic M3 receptor activity is involved.
35. 35. A method for the treatment of a disease or condition in which the activity of the muscarinic M3 receptor is characterized in that it comprises administering to a subject in need thereof an effective amount of a compound according to any of claims 1 to 29
36. 36. The use according to claim 33 or a method of treatment according to claim 34, wherein the disease or condition is a disorder of the respiratory tract.
37. 37. The use according to claim 33 or a method of treatment according to claim 34, wherein the disease or condition is a disorder of the gastrointestinal tract.
38. 38. The use according to claim 33 or a method of treatment according to claim 34, wherein the disease or condition is a cardiovascular disorder.
39. 39. The use according to claim 33 or a method of treatment according to claim 34, wherein the disease or condition is chronic obstructive pulmonary disease, chronic bronchitis, asthma, chronic respiratory obstruction, bronchial hyperactivity, pulmonary fibrosis, emphysema. pulmonary or allergic rhinitis;
40. 40. The use according to claim 33 or a method of treatment according to claim 34, wherein the disease or condition is irritable bowel syndrome, spasmodic colitis, gastroduodenal ulcers, gastrointestinal seizures, or hyperanakekinesia, diverticulitis, spasms accompanied of gastrointestinal smooth muscle pain, urinary tract disorders accompanied by urination disorders including neurogenic frequency, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms or chronic cystitis, urinary urgency or frequency; dizziness; and cardiovascular disorders such as vagally induced breast bradycardia.
41. 41. The use according to claim 33 or a method of treatment according to claim 34, wherein the disease or condition is vagally induced breast bradycardia. SUMMARY OF THE INVENTION Compounds of the formula (I) are described which are useful in the treatment of diseases where the activation of the increased M3 receptor is involved, such as diseases of the respiratory tract: wherein (i) R1 is alkyl? -C? or hydrogen; and R2 is hydrogen or a group -R7, -Z-Y-R7, -Z-NR9R10; -Z-CO-NR9R10, -Z-NR9-C (O) O-R7, or -Z-C (0) -R7; and R3 is a single pair, or Ci-Ce alkyl; or (ii) R1 and R3 together with the nitrogen to which they are attached form a heterocycloalkyl ring, and R2 is a single pair or a group -R7, -ZY-R7, -Z-NR9R10, -Z-CO-NR9R10, - Z-NR9-C (O) O-R7; or; -Z-C (0) -R7; or (iii) R1 and R2 together with the nitrogen to which they are attached form a heterocycloalkyl ring, the ring is substituted by a group -Y-R7, -Z-Y-R7, -Z-NR9R10; -Z-CO-NR9R10; -Z-NR9-C (O) O-R7; or; -Z-C (0) -R7; and R3 is a single pair, or C? -C6 alkyl; R4 and R5 are independently selected from the group consisting of aryl, heterocycloalkyl fused to the aryl, heteroaryl, Ci-Ce alkyl, cycloalkyl; R6 is -OH, Ci-Ce alkyl, Ci-Ce alkoxy, hydroxyC1-C6 alkyl, nitrile, a CONR82 group or a hydrogen atom; A is an oxygen or a sulfur atom; X is an alkylene, alkenylene or alkynylene group; R 7 is a C 1 -C 6 alkyl, aryl, cycloalkyl fused to aryl, heterocycloalkyl fused to aryl, heteroaryl, aryl (C 1 -C 8 alkyl), heteroaryl (C 1 -C 8 alkyl), cycloalkyl or heterocycloalkyl group; R8 is C6-C6 alkyl or a hydrogen atom; Z is a C? -C? 6 alkylene group, C2-Ci6 alkenylene or C2-C? 6 alkynylene; And it is a bond or atom of oxygen; R9 and R10 are independently a hydrogen atom group, Ci-Ce alkyl, aryl, heterocycloalkyl fused to the aryl, cycloalkyl fused to the aryl, heteroaryl, aryl (C?-C6 alkyl) -, or heteroaryl (d-C6 alkyl); or R9 and R10 together with the nitrogen atom to which they are attached form a heterocyclic ring of 4-8 atoms, optionally containing one additional oxygen or nitrogen atom.