SA07280031B1 - Azole and thiazole derivatives and their use in the treatment of diseases where enhanced M3 receptor activation is implicated - Google Patents

Abstract

Azole and thiazole derivatives and their use in the treatment of diseases where enhanced M3 receptor activation is implicated Example: tract diseases (I) where (1) R1 is a C1-C6-alkyl (1-6 carbon) or hydrogen; and R2 is hydrogen, or the R7 group, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C(O)O-R7, or; - Z-C(O)-R7; and R3 is a lone pair, or C1-C6-alkyl; or (ii) R1 and R3 together with their attached nitrogen form a heterocycloalkyl ring, and R2 is a lone pair or combination of R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10 , -Z-NR9-C(O)O-R7 , or ; -Z-C(O)-R7;(3)R1 and R3 together with a nitrogen atom attached to it form a heterocycloalkyl ring, said ring replaced by a Y-R7 group, -Z-Y-R7, -Z-NR9R10, - Z-CO-NR9R10; - Z-NR9-C(O)O-R7; or Z-C(O)-R7; R3 is a lone pair, or C1-C6-alkyl; R4 and R5 separately select from the group consisting of aryl, fused heterocycloalkyl fused aryl, aryl fused, C1-C6-alkyl, cycloalkyl ; R6 is an OH, C1-C6-alkyl

Description

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Azole and thiazole derivatives and their use in the treatment of diseases where enhanced M3 receptor activation is implicated. Combinations of thiazole and thiazole oxazole The current invention is concerned with oxazole derivatives, ways to prepare them and use them in a pharmaceutical composition. Improved M3 diseases, where they include activation of the M receptor. Anti-cholinergic factors prevent the passage of  or effects resulting from the passage of  parasympathetic impulses through the parasympathetic nerves. This represents a result of the ability of these compounds to inhibit the action of acetylcholine (AS) by blocking its binding with muscarinic cholinergic receptors. muscarinic of muscarinic acetylcholine receptor subtypes due to types o there va called 111-315; Each of them represents a product of unique cholinergic receptors (mAchRs), each of which displays unique pharmacological characteristics, distinct gene, widely distributed in mAChRS vertebrate organs. Pharmacological properties can mediate each of the receptors and those vertebrate organs Vo inhibitory and excitatory actions. for example; in the 2x Jsmooth muscle in the airways bladder the gastrointestinal tract 113 in mAchRs mediate contractile responses v¢; Pharmaceutical treatment 0997 abil S revised by ( mediate contractile responses . ) Mm Moth 113 and 112 « Ml muscarinic receptors ¢ Jungs in the knees; The bronchi, the trachea, have proven to be important and are localized in the trachea and the parasympathetic ganglia, the submucosal glands, the submucosal glands. smooth muscle pathway M3 part ? (E-S;01-<11). receptors (YoA

M3 stimulate receptors. bronchi is a constrictor of the bronchial tubes SUN mediates contraction and mucus causes the secretion of mucus localized submucosal glands in the submucosal glands .secretion 0 0 through acetylcholine receptors increased signaling it was discovered that pathophysiological states increased signals Muscarinic in a variety of pathophysiological conditions

LJ vagal tone; COPD is in the state of . COPD asthma The different types of asthma, including; 456 : 287-444) and/or Chest «1384» et al. usa) can affect the obstruction for geometric objection for Jef at 59 degrees or oedematous La YU when Applied to loaded airway walls reasons —A0T pages: 1794 ¢ Am Rev. Respir. Dis. 14484 ¢ 550k) mucus (Gross) can lead to loss of inflammatory conditions in addition to AV conditions, causing increased rates of release of M2 inhibitory receptor inhibitory activity (Frayer et al.; vagal nerve according to stimulation of the nerve acetylcholine ve;p49 ;-0©;). 143 receptors lead to an improvement in airway obstruction. Therapeutic identification of effective muscarinic receptor antagonists is useful for pharmacological treatment.

¢ treatment for those disease states, which includes improved M3 receptor activity. actually ; Contemporary treatment strategies support the regular use of M3 antagonist bronchodilators as first-line therapy for patients with COPD (Powells and Zmla, Tt. Am. Rev.

Respir.

Crit.

Care Med. ;; VAY : pp. 776-1175976 ). © Enuresis incontinence due to excessive bladder contraction. Bladder mAchRs have also been shown to mediate through increased stimulation 113 the hypercontractility in MACHR. M3mAchRs therefore antagonists can be considered useful as pharmacotherapy. mediated diseases.

0 . 1016:050 “For the treatment of airway conditions.” Relatively few antimuscarinic compounds are used in hospitals for pulmonary indications. So ; There is an ever-present need for innovative new compounds capable of causing M3 muscarinic receptor blocking - especially those with long duration of action; Manage one de jal diet in

0 pel Vo Since the muscarinic receptors (gmuscarinic receptors & extensively throughout the body) - the ability to release the anticholinergic drug directly in the respiratory tract is distinctive as it allows low doses of intake. The structure and use of topically active long-acting drugs that remain on the receptor or in the lung will allow the reduction of unwanted side effects.

,. Which can be seen when regularly taking the same drugs _ 0 commercial) is a prolonged muscarinic antidote Ale) Tiotropium spiriva™ chronic Market for the treatment of long-acting muscarinic obstructive disease .inhaled ¢ obstructive pulmonary disease

Oo \ L N 55 AHA SSA H 5 0 Pr OHU 0 Tiotropium Additionally, ipatropium is a muscarinic antagonist marketed for the treatment of COPD. M \ N on 2 0 0 Ipratropium YV Chem.

Pharm. Bull. © ) b pp. 148 167-1194 ) and Journal of Pharmaceutical Sciences 0(14) pp. 87-5074 (VAAL) describes furyl derivatives as activities similar to atropine. Med.

Chem.Res. 10(1); pp. 177-7156 (0011) describes isoxazoles and isoxazolines as muscarinic antagonists. ISBN 1777454 describes Oxadiazoles and Thiadiazoles as Muscarinic Receptor Antagonists EP No. 017774854 describes oxadiazoles attached to a mono-or bicyclic ring as muscarinic receptor modulators. 32 Adrenaline agonists are well known.A lot of known B2-7 beta antagonists ¢, especially long-acting ¥ beta antagonists 52 long-acting

For example, salmeterol and formoterol play a role in the treatment of asthma and COPD. These compounds are also dealt with dale 0 inhalation. Compounds currently under evaluation as beta ¥ mono agonists « (Y) 01 Expert Opin. Invest. Drugs prescribed at once- daily daily dose

Y— Uw agonist, pharmacophore, pharmacophore . (Ye +0) 2877/7/5 © pages: It is well known that it is the half.

color

HN pa

NH

0 Also known in the field are pharmaceutical compositions that contain both muscarinic antagonists and a beta-Y agonist for use in the treatment of respiratory diseases. for example; US Patent 7065 // 0759718 describes a beta-7 moiety in agreement with tiotropium ¢ oxotropium; ipratropium and other antimuscarinics; International Patent No. 17/1105877 describes the compatibility of ipratropium with beta-agonists - ? and International Patent No. 100677 [oY] describes the compatibility of oxotropium with beta-7 anion. Other compatibility of 0 1043 antagonists and a beta agonist "described in International Patent No. 015754 [uf and International No. [oF] Lakh Lal. Also known in the field are compounds related to both the muscarinic receptor antagonist and the activity of the beta agonist - Present in the same molecule, these bifunctional molecules provide bronchodilation in two separate modes of influence during obtaining the pharmacokinetics of the single molecule.

molecule. Such a molecule should be easier to synthesize for therapeutic use compared to separate binary compounds and can be formulated more easily by means of a third active content; se; Steroids 9:0:010. These molecules are described, for example, in Patent 4/04 (VEY ET intl [ut 844957]; All of them use Asha bond moieties, to covalently bond M3 antibody with β-momentum General Description of the Invention According to the present invention, a compound according to formula 1 8 is provided for Re R°® A New TR 0) Ye where (0) 1 is an alkyl C;-Ce-alkyl or hydrogen ¢ and be R2 3 is a hydrogen; or a group means mineralization ¢ -ZNR°R® ¢ -2-. Ce-alkyl; or R? and 8 together with its attached nitrogen form a mixed cycloalkyl ring; and 8 (1) 0

Z-CO- «ZNRR'" is formed from a single pair or group of a bole TM-TrH-2-01 with attached 'NR°R'" tormy forming a cycloalkyl nitrogen ring together With Nitrogen Atom 18 SR! (Y) 7-0. -Z-NR°R'® ¢ .Z-Y-R7 ¢ -Y-R7 mixed; The aforementioned episode is replaced by the group #00 #Al-At'ar; -ZNR-C(O)O-R'; or -ZCO)MR' ; and p is a lone pair; or JI longitude-m0- ; with me

A

RY 5 187 separately choose from the combination of Arylaz; aryl-fused heterocycloalkyl » aryl scrambled heteroaryl ¢ alkyl C,-Co- ¢ cycloalkl cycloalkl » (alkyl ¢ Cy-Ce-alkyl alkyl) 1-1 carbon atom) « halogen is 011- « halogen RS 1-1) JSI-C; C° alkoxy hydroxy 1-1 alkoxy (33° alkoxy carbon) C1-Co-alkyl ; nitrile; conr®'y group; or a hydrogen atom ¢ hydrogen atom ¢ sulfur or an oxygen atom is an A alkynylene atom alkenylene; An alkylene is an alkylene group X “Ye RT is a C-Coralkyl (303 carbon) (VY) alkyl; aryl “aryl” fused cycloalkyl aryl; alkyl ila scrambled - aryl fused; ariel mixed; aryl (alkyl A=) carbon atom) caryl(C.Caalkyl aryl (alkyl A=) carbon atom) heteroaryl(C; Cs. heterocycloalkyl or alkyl group ¢ cycloalkyl Cycloalkyl “alkyl) ¢ group 05 hydrogen or a hydrogen atom Ci-Ce-alkyl for the alkyl (1-1 553 carbon) 5 le RP ¢ atom 7 is an alkylene V1) carbon atom ) C;.C.alkenylene » 5,3-carbon (11-Y) alkylene) C,.Cig-alkenylene or the alkynylene group (7-17 carbons) -0-y alkynylne group 0 ; ¢ oxygen atom or oxygen atom bond is a Y bond to g and "ie on saa is a 0 hydrogen atom an alkyl (1-1 carbon atom); yf is a mixed cycloalkyl - fused aryl » alkyl ila fused with aryl; methylated aryl nepi q or methylated aryl (alkyl (1 carbon atom)) « Cp-Coalkyl carbon) 303 3-1 aryl (alkyl 0 with attached nitrogen atom It forms a mixed cyclic baw RO; or that "8 and; optionally contains a nitrogen atom or 4-8 atoms a carbon atom AE composed of additional oxygen; oxide ¢ solvate dissolved » pharmaceutically acceptable salt Ly a

Nitrogenous N-oxide or a precursor thereof. In one of the subgroups of the compounds of the invention: R is a C-coalkyl (1-1 carbon) alkyl or hydrogen atom; 12 is a 1-7-alkyl (carbon atom) alleleh-m©-,© ; A hydrogen atom or ic sane 2-7-87- f

0 8 is a lone pair or an alkyl (032835017) wala-m©-,©; or 82 together with its attached nitrogen atom represents a mixed cycloalkyl ring; or SRY 3 together with its attached nitrogen atom represents a cyclic mixed cycloalkyl SR 8 separately choose from the group consisting of aryl + aryl scrambled 1-6 (Jl carbon atom) cycloalkyl

1-1) a carbon atom); 1-hydroxy-alkyl (is a 1-011 halogen; an alkyl 866 Ve carbon atom) or a hydrogen atom; sulfur is an oxygen or sulfur atom A alkynylene or alkenylene « an alkylene is an alkylene group X '

0 2 is an alkylene group » alkynylene or alkynylene ; 7 is a bond or oxygen atom; sole RT for dif mixed aryl + mixed cycloalkyl .

‎YEYV

Ye connected can represent the center of R®; 5" and RY, it will be realized that the carbon atom in which it is asymmetric. Therefore, the compounds of the present invention can be in the form of single enantiomers. Mixtures of enantiomers or mixtures of enantiomers, single enantiomers. Cus ammonium salt of formula (I) 0 nitrogen carrying a positive Cus ammonium salt of formula (I) charge Detailed description Compounds of the invention may be useful In the treatment of or from diseases that contain compounds, muscarinic receptors, including activation of muscarinic receptors. Bronchial — chronic obstructive lung disease (associated chronic obstructive lung disease) asthma dyspnoea all of the 2 (including aorta) wheezy-infant syndrome - allergic and non-allergic (sensitization and non-improvement) 0 chronic respiratory Ocular chronic obstructive respiratory disease (ARDS) / sla Shortness of breath 6 s— fibrosis - bronchial hyperactivity - obstruction and sinusitis — pulmonary emphysema pulmonary fibrosis Exacerbation of airway hyperactivity due to treatment — allergic rhinitis His nose sensitive to another medication especially to treatment with another inhaled medication: 0

11

Pneumoconiosis ptilosis , chalicosis , asbestsis , anthracosis , aluminosis , hyssinosis, tabacosis, silicosis , siderosis gastrointestinal-tract disorders spasmodic colitis irritable bowel Diverticulitis, hyperanakinesia pain accompanying spasms of gastrointestinal smooth urinary- tract disorders ¢ musculature — neurogemic bladder, neurogenic polakisuria For disorders of urination including psychosomatic bladder — urinary incontinence — neurogenic bladder agnostic thiol 0 chronic cyst - urgency (alg) associated with bladder spasms or nocturnal enuresis vagally seasickness and Cardiovascular disorders such as pollakiuria or urination. induced sinus bradycardia For the treatment of respiratory conditions inhalation administration will often be preferred to the formation of ammonium salts (I) and in these cases the administration of VO compounds will be preferred in many cases - activity period of els ammonium salts quaternary ammonium salts of the invention Those that are taken by inhalation may be more than - typical dose for the treatment of imbalances - typical dose YE or more than - cardiovascular disorders of the digestive system and cardiovascular imbalances oral route often via the parenteral route of abuse by injection 0 . may be preferred -

YY

Another aspect of the invention is a pharmaceutical composition that includes the compound of the invention and a bearer of the invention is the use of a compound to manufacture a drug or a pharmaceutically acceptable excipient. 113 Including Alls muscarinic receptor activity to treat or prevent disease or: Terms As long as they are not described in the context in which they are used, the following terms °: have the following meanings

Ac gana where the co-alkyl group is acyl "reu means alkyl group" -

COCH(CH3); , alkyls as described herein ideal acyl groups include . COCHj3; Where # and acyl nracyl group stands for acyl group acylamino "sid" acyl -0

N(CH3) of acyl amino groups including Tid are as defined herein 1 means an alkyl group -0- where an alkyloxy and an alkoxy - an alkyl are as described below. Examples of groups Alkoxy includes methoxy. (OC;Hs) ethoxy and (-O-CHs) methoxy Vo means alkyl group -000- where alkoxycarbonyl “alkoxycarbonyl” — alkyl is as defined below Examples of alkoxycarbonyl and methoxycarbonyl groups methoxycarbonyl includes alkoxycarbonyl .ethoxycarbonyl carbonyl “alkyl”: as a group or part of a group denoting a 1 - Yn hydrocarbon group; Preferably 11 to 1 saturated straight or branched hydrocarbon

YEYY

a

to > carbon atoms - in the chain - examples of alkyl groups include Jie ethyl -1 methyl ethyl propyl "- propyl .

asl - as a group or part of a group denoting a straight or branched-chain hydrocarbon group having from ? to VY and preferably ? to 1 atoms

° carbon and a carbon «00::» double bond - carbon in the chain Abd

The alkynyl groups include ethinyl-1-propenyl and 7-propenyl.

- “Alkynyl” as a group or part of a group denotes a straight or branched-chain hydrocarbon group possessing whom? to 11 and preferably * to + carbon atoms and a carbon - carbon triple bond in the chain are examples of groups

,. Propanyyl and 7-propynyl-01-alkynyl include ethanyl Ve

- “alkyl” snd means alkyl group NH - where alkyl is as defined above. Examples of alklamino groups include smethylamino ethylamino sis.

cls - means an alkyl group where the alkyl group is as previously defined

Vo for alkylene groups include C(CH;) HCH,- (CH2); 2 CH, w

- "Alkynyline" means an alkynyl group - where the alkynyl is as previously defined. Examples of alkynylene groups include CH,CH= CH- , CH=CHCH,- , CH-CH

- "Alkynyline" means -alkynyle group - where alkynyl is as previously defined. Examples of alkynylene groups include -CH2CC- , CCCHy, -CC- and

1 where alkyl is -50- JS means alkylsulfing group] "alkylsulfinyl" - as defined by the highest examples of alkylsulfinyl groups including methylsulfinyl. ethylsulfonyl and methylsulfonyl mean alkyl group -502 where the alkyl is as alkylthio - defined by higher examples of alkylsulfonyl groups including methylsulfonyl °. And ethyl sulfonyl “alkyl thio” means the 5-alkyl group - where the alkyl is as defined above - 0 thio including methyl thio and ethyl thio JS are examples of the be groups as described by R where CO-NRR means aminoacyl group "amino-acyl" - and CONH, and CONHCH; acyl The sine here includes examples of 1 groups where the alkyl is as previously described NH, alkyl de pana "amino-alkyl" Means - examples of alkyl amino groups include 013:11 and -where # is as described here SO,-NRR "aminosulfonyl" means group - and SO,NHCH3, 50211135 Examples of aminosulfonyl groups include “Aryl” as a group or part of a group denotes a multicyclic aromatic carbocyclic or monocyclic 10 to 1 carbon atom - preferably optionally substituted VE From + to the aryl group may be naphthyl or naphthyl phenyl phenyl Jie carbon substituted with one or more aryl substituent groups "meaning an aryl - alkyl group - where the alkyl and aryl parts are dF - Te and aryl as previously described - preferred alkyl aryl groups containing part

YEYVY yo benzyl phenethyl Examples of alkyl aryl groups include benzyl Cp JS the aryl part of which may be naphthlenemethyl and naphthlene methyl substituted with one or more substituent groups and means aryl-alkyloxy group where arylalkyloxy is 'aryl' Alkyloxy" - aryl and alkyloxy parts are as previously described. Arylalkyloxy groups 0. Preferred Cy aryl groups contain an alkyl part, the arylalkyloxy part, of which the aryl part may be substituted by benzyloxy. The alkyloxy includes benzyloxy. By one or more substituent groups means an aryl-fused-cycloalkyl ring “aryl-fused-cycloalkyl” mono-as phenyl-fused with a cycloalkyl group where aryl and cycloalkyl > 0 are as described Here are examples of aryl-combined-cycloalkyl-indanyl and indanyl tetrahydronaphthyl groups including tetrahydr and phayl-aryl and cycloalkyl groups that may be substituted with one or more substituted groups an aryl-combined-cycloalkyl group may be connected the rest of the compound in any atom. Available Carbon Vo “Aryl-combined-cycloalkyl-dissenting” means a mono aryl ring such as phenyl-dissubstantial with a cycloalkyl group, where the aryl and cycloalkyl dissenters are as done for aryl-compact-cycloalkyl dissenting groups including AB 0 Describe them here - indolinyl enchodinyl — tetrahydroquinolinyl —benxodioxolyl Js —u€ 13 ¢ 3 — benzodioxinyl Y. isoindolonyl dihydrobenzofuranyl dihydrobenzofuranyl and

- - Aryl and cycloalkyl ligands, each of which may be substituted with one or more substituent groups. An aryl-combined-cycloalkyl group may be attached to the rest of the compound with any available carbon or nitrogen atom. aryloxy means aryl group -0- where aryl is as described above examples of aryloxy groups include phenoxy the aryl part of which may be substituted by one or more substituent groups and - "cyclic amine" Sila is a special case of "cyclic" Transal alkyl" or 'transterocyclic' means a cyclic and monoalkyl system from © to A optionally substituted 01 members where one carbon atom of the ring is replaced by nitrogen by nitrogen which may optionally contain an additional offending atom selected from 0 ,8 or NR (where R is as described by La) Examples of cyclic amines include pyrrolidine — piperidine — morpholine piperazine and 11 — methylpiperazine methylpiperazine - The cycloamine yo-group may be substituted by one or more substituent groups - “Cycloalkyl” means a monocyclic, dicyclic or dicyclic system optionally substituted from © to 11 carbon atoms - preferably from * to +8 Carbon atoms preferably more than © to +7 carbon atoms - Examples of monocyclic alkyl rings include cyclopropyl - cyclopentyl - cyclohexyl Y and cycloheptyl - cyclopropyl group may be substituted with one or more substituent groups

No - “cycloalkylalkyl” means a Sf-alkyl group where the cycloalkyl and alkyl parts are as previously described - Abid for monocycloalkyl alkyl groups including cyclopropylmethylcyclomethyl J—iicyclopropylmethyl cyclopentylmethyl - cyclohexylmethyl ° and cycloheptylmethyl cyclohexylmethyl - the cyclohexyl part of it may be substituted with one or more substituted groups - "sind" means NealkyD? (alkyl) group, - where the alkyl is as It is identified by the highest examples of dialkylamino groups including St methyl sud, diethylamino, and 1- “halo” or “halogen” means fuoro-chloro — bromo Or Iodo 1000 - preferred is fluoro or chloro and - "haloalkoxy" means alkyl -8- where Js is substituted by one or more halogen atoms - including halo-alkyl groups haloalkyl Ve includes DB trifluoromethoxy and sot difluoromethoxy - "halo alkyl" means an alkyl group inferred from one or more halo atoms Examples of haloalkyl groups include tri Fluoromethyl and - "other aryl" as a group or part of a group refers to an organic moiety Ye aromatic monocyclic or multicyclic moiety optionally substituted from 10 VE atoms ring atoms of Eden preferably 0 to ‎ 01

Ya

Ring atoms where one or more of the ring atoms is an element other than that of IBN. sulfur carbon filled with nitrogen, oxygen or sulfur benzimidazolyl, benzoxazolyl, the _ groups include benzothiazolyl, benzofuranyl, benzothienyl, furyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxazolyl, 8 oxadiazolyl, py razinyl, pyridazinyl, pyrazolyl, pyridyl , pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, tetrazolyl, 1,3,4-thiadiazolyl, mixed aryl groups can substitute for Ltriazolyl thiazolyl, thienyl . With one or more substituted groups the methylated aryl group may be attached to the rest of the compound of the present invention with any atom 0 . Carbon or Nitrogen available. “Scattered aryl” means a scrambled alkyl-aryl group in which the scrambled aryl JH and the alkyl moieties are as described before. Preferred mixed alkyl-aryl groups contain a primary alkyl moiety. Typical groups of . pyridylmethyloxy methylated alkyl aryl include vo ; means methylated alkyloxyaryl group heteroaryloxy methylated aryl "they are as described from heteroaryl in which the methylated aryl and the alkyloxy moieties

Jf mixture includes heteroaryloxy moiety before . Primary arylalkyloxy groups. Nmung groups of aryl mixtures of alkyloxy include, . pyridylmethyloxy. 0

YEVY

"Michelated aryloxy" means a chelated aryloxy group in which the chelated aryl is as described before. Typical examples include pyridyloxy. From pg. a carbon atom) or a hydrogen; and “18 is a hydrogen; or a group of T-fill -Z-CO-NRR' ¢ -ZNR°R”; 0 swell-*<2; or 7(0 )©-2- ; and RP _is a mono pair or an alkyl (= carbon atom) in which case the attached nitrogen atom is a quaternary nitrogen atom with a positive charge. In compatibility (7) SR 83 together_with the attached nitrogen with which it forms a mixed cycloalkyl ring; and 182 is a single pair or group of W8 78 ¢ ZNRR' «¢ D -Z-CO-NR'R'®; TWRM-289-.; or; 0(7 )-- In this case, of course, when 12 is not a lone pair, the nitrogen atom attached to it is a quaternary nitrogen and carries a positive charge. In particular RY and 183 together with the nitrogen atom attached to it can form a monocyclic ring of VY is a ring atom in which the mixed atoms are nitrogen Examples of such rings include azetidinyl 22600101 piperidingl 00 piperazinyl N-substituted piperazinyl “eg 5s methylpiperazin pyrrolidinyl rings.

Phil in Compatibility©; GRY “18 together with its attached nitrogen atom forms a scrambled cycloalkyl ring ¢ said ring is replaced by a group of “YR 277-87 ¢ swelling-23- Z-NR°R'®, -Z-CO-NR °R, or 5-Z-C(O)-R' 83 is a lone pair (ie; variant RP is absent ); or an alkyl 1-3 carbon atom) and in particular methyl .mrthyl© and in particular; 8 and 182 together with the nitrogen atom attached to it can be a monocyclic ring of V=F cyclic atom ; Which led mixed atoms is nitrogen. Examples of such rings include azetidine; piperidinil; piperazinil; nitrogen-substituted piperazinil; For example the methylpiperazinyl and pyrrolidinyl rings; Of course when 13 is not a lone pair; The attached nitrogen atom is 0 nitrogen quaternary and carries a positive charge. where set 187; or 7-87-a; 2-7-87- or FRO group; or combination -2- CO-NR°R' .; or —~Z-NR9-C(O)O-R7 ic sane or combination 2-002-87- ; located in ff « R2 ring formed by « RY 82 ; and the nitrogen atom attached to it: Z; Dee can represent ; 1 (10© )- ; The latter is even optionally replaced? 1 carbon atoms in the chain via methylation; 7 is a bond or oxygen 0; 7 can be an alkyl (1-1 carbon atom); eg methyl methyi - ethyl rethyi ; ordinary propyl; isopropyl alcohol; secondary or tertiary butyl gale; yo aryl optional e.g. phenyl or naphthyl or JS cyclo-mixed aryl on Ju ww Article -3,4 3,4-methylenedioxyphenyl, ethylenedioxyphenyl, a dihydrobenzofuranyl; ; YEYY

A mixed aryl optionally substituted on Jaw eg 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, indoly© and indazolyl; (TY) alkyl carbon atom) optionally substituted aryl for example those where the aryl moiety Any aryl groups specifically mentioned above and the 1-1 alkyl moiety (carbon atom) is -CH,CH,CHy- ; 0 alkyl ila fused optionally substituted aryl dar eg indanyl or -1,2,3,4 tetrahydronaphthalenyl ¢ (4-1 carbon atom JST) optionally substituted aryl dar for example where that the scrambled aryl moiety is any of the aforementioned scrambled aryl groups and the alkyl moiety (AY (carbon atom)) is CH, or -CH,CHy; 0 optionally substituted cycloalkyl e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl ; or (alkyl A=) carbon atom) an optionally substituted mixed cycloalkyl e.g. those wherein the mixed cycloalkyl moiety is azetidinyl, piperidinyl, piperazinyl, N-substituted piperaziny e.g. pyrrolidingl § methylpiperazinyl, Ys and the 1-1 alkyl moiety (carbon atom) is CH or CH,CH, ; RO and 810 hydrogen can be selected separately; an alkyl (1 carbon atom) eg methyl; Ethyl 0Nd Propyl ; isopropyl alcohol; or any of the substituted aryls

YY

carbon atom) AY optionally ¢ aryl scrambled cycloalkyl scrambled aryl or aryl (previous alkyl; or RT mentioned earlier in discussion in together with its attached nitrogen atom can be a cyclic scalded ring RYO SRC a cyclic atom; and preferably; - a cyclic atom optionally containing an additional nitrogen AE from azetidinyl, piperidinyl, piperazinyl or an additional oxygen atom eg methylpiperazinyl, pyrrolidinyl, nitrogen substituted piperazinyl for example ». thiomorpholinyl and morpholinyl, in a preferred embodiment of the present invention, in group 1188283, 1 is methyl or ethyl 182 is 2-08789- or 2-7-87- as specified in the foregoing discussion for It is a bond or oxygen and -2- is a straight or branched alkylene moiety connected 0 01 to She an 11 carbon atom with nitrogen and "20858 or to 2718- by up to and carrying quaternises carbon atoms + and 183 are methyl, so that the nitrogen has a positive charge.In those cases ¢ 187 preferentially is a cyclic lipophilic group over their RO eg phenyl, benzyl, dihydrobenzofuryl; or phenylethylene; and “18r. as specified and discussed before 1-7- is 182 « -NR'R'R? ; in the Mall group in another embodiment according to the invention - is a bond or an oxygen and Yo or 2-7-87- as defined and discussed by NR°RY -7187 is a straight or branched alkylene moiety attached to nitrogen and “01878” or Z- carbon atoms; and for 18 and 18 together with 10 carbon atoms; For example, up to 11 by preferentially gc the nitrogen atom attached to it forms a rotating mixed ring of ; +8 cyclic atom Yo ?-1 cyclic atom optionally containing an additional nitrogen or oxygen atom; for example; Nitrogen-substituted piperazinyl for azetidingl, piperidinyl, piperazinyl eg v¢yy © thiomorpholinyl and methylpiperazinyl, pyrrolidinyl, morpholinyl eg

YY

It carries a positive charge. in those cases; C quaternises so that the nitrogen atom is preferentially a cyclic lipophilic group, for example, phenyl; benzyl; They are also defined and discussed before. in RY GR hydrobenzofuryl; or phenylethylene; and together with the nitrogen atom 183 HR a subset of the compounds of this embodiment; the . attached to it forms a piperidinyl or pyrrolidinyl ring. 0 ascribed to the Cg R* groups and 7C separately can choose from any of the aryl groups; mixed cycloalkyl + carbon atom); OR 1-1 (Aryl cycloalkyl + aryl chelated; alkyl -011 RO. The cycloalkyl groups specifically mentioned in the previous discussion 18 could represent a carbon atom) eg methyl; or ethyl; For example methoxy or ethoxy; hydroxy 1-1(alkoxyalkyl)17 carbon) eg hydroxymethyl; nitrile; or an alkyl group apart (1-1 carbon atom) eg methyl; R® where each “CONRY,” or ethyl or hydrogen atom. Currently preferred is the case where 86 is a ¢ “OH is an R® and especially when ¢ RS is the preferred harmonics of 84 and . -0117 1 -: include those where 6 is an optionally substituted monocyclic cyclic aryl of 85 SRY each of ( ) or >cyclic atoms eg pyridyl; oxazolyl; thiazolyl; furyl and, in particular, thienyl eg 7-thienyl; of “8 and 8 is an optionally substituted vinyl; JS (Y Ye is an optionally substituted vinyl and the other is an alkyl RP”) both of “ 8 and cyclo for example cyclopropyl; cyclobutyl; or particularly cyclobenyl or

YEYY cyclohexyl; and

8) One of SR? 185 is a monocyclic cyclic cyclic aryl optionally substituted by a © or + cyclic atom e.g. pyridyl; thienyl “oxazolyl” or “thiazolyl” or furyl; and The other is a cycloalkyl, for example cyclopropyl, cyclobutyl, cyclohexyl or cyclohexyl The ring stom A can represent an oxygen atom or a sulfur. substituent R® although R® can represent an alkyl (1 carbon atom); eg methyl or 0-ethyl; It is currently preferred that 18 is a hydrogen atom. the radical X (all) Although X can represent the alkylene moiety; Subclasses of compounds according to the present invention are of the formula TA re N > (CHa) a) cn ) Sn (CH,) — nebulae "A 2/m / 2/5 Re (1A) yo, where A is oxygen or sulfur; equals 1 or 7; Addl is an optionally substituted phenyl ring; or a monocyclic mixed ring of © or 6 cyclic atoms; or a vinyl fused scrambled cycloalkyl ring where the scrambled cycloalkyl ring is a scrambled Y ring with a monocyclic heterocyclic of © or 6+cyclic atoms; RY is vinyl; einyl; YEYY

Yo; einyl; Cyclopentyl or Hexyl Jud Cyclopentyl + or Cyclohexyl; 187 phrases

YoY 0 or 7 where; equals row 126 0 4 oY oY oy goose toroid; 7 is a bond or 11 is not greater than sit such that V or 11 is © 6 . It is a pharmaceutically acceptable anion X oxygen; and

IB The other preferred subcategory is compounds of the form ©

Rs N 1 x (CH), -( Bohm Cell Sudam it (CHa), —

RS © (IB) that Cus is a Badal ring or ? 1 is oxygen or sulfur; A is equal to z is a loop of A; the piperidinium or pyrrolidinium phenyl ring optionally substituted; or a scrambled monocyclic ring of © or 6 atom cyclocyclic; Ve or a scrambled cycloalkyl ring combined with vinyl where the scrambled cycloalkyl ring is ¢ is a phenyl RY scrambled monocyclic ring of © or + atoms cyclic thynyl Cyclopentyl or Jud-Thinyl; cyclopentyl; or to cyclohexyl; 5" is (Ve; or 7 is equal to zero 3 © cE TY) cyclohexyl; 8 is equal to; 7 is a bond or 11 is not greater than sat so that V Jie 4 .197 Ne Oxygen + is a pharmaceutically acceptable anion

IC The other preferred subclass according to the present invention is formula

Y1

X: So

R4 IN (CHp), no duration (Cnt (CH), — Pio

fo m where that is a Badal episode or ? 1 is oxygen or sulfur; equals A is vinyl; einyl; cyclopentyl; or hexyl RY pyrrolidinium or piperidinium © on cyclic RO GRY; 18 is vinyl; einyl; cyclopentyl or cyclohexyl; carbon atom) optionally substituted; or Ariel; on 1-1) hydrogen atom unit; or alkyl or 7 since 216 9 ct 7 7 oY eg optionally substituted phenyl; 8 equals

ET is not greater than sat such that 17 or 1 0 cE FY 0); equals yellow. X is a pharmaceutically acceptable anion; X is a bond or oxygen; and 7 0 phenyl substituted (1) is A that ring Wa; IB is preferred in compounds e and optionally; since the optional substituents are chosen from alkoxy; halo and especially fluorine; or ?2-1 (carbon atom); alkyl amino (TY) carbon atom); aminoacyl (YY) chlorine; an alkyl carbon atom); and or phenyl moiety where the moiety cycloalkyl ring ila cycloalkyl system (1) 0 is a monocyclic moiety ring composed of © or 6 cyclic atoms; e.g. a dihydrobenzofuran Anil

Vol 2 can represent such as tts lie IC, 18 and IA in each of the subclasses of suitable combinations of ; and # eg La and can 7 Jeo ا++

YEYV

wrap where ( is yellow se dO 046 7 1 is TOE YY) or 1 . In compounds 1A and IB the currently preferred compatibility of ot 7 and 5 is where © is zero; 8 equals ©; And Y is oxygen. The additional preferred fit is where © 7 is an association and set equals OY “or ;. In compounds according to formula IC; currently preferred compatibility of +; 5Y 5 is where y is a bond and st equals + ; 9 or 01 . It will be realized that the given fits of R* ; 185 and 8 can increase the optical enantiomers in these cases; All enantiomers according to the present invention generally show affinity for the My receptor; Although, in general, a single enantiomer is preferred by the criterion of potency in the My receptor and/or selective against the 142 receptor. In some embodiments of the present invention; The absolute stereochemistry of the preferred enantiomer is known. then no ; In one of my favorite incarnations; RY is vinyl; 8 is cyclohexyl or cyclopentyl; RO is a hydroxyl group; The carbon atom attached to it 1 has an absolute distribution of -1 as determined by the cahn-, ingold-prelog rules. Examples of compounds of the present invention include those here. Each of the examples is an object of the present invention and where the corresponding ion is specified in the example of the present invention provides a compound with a substituent corresponding ion as described herein. The preferred compounds of the present invention include: [2-(Hydroxy-diphenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)- ammonium salts [2-( (R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl] -dimethyl-(3- Ysvy phenoxy-propyl)-ammonium salts

Ya

[2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl- phenethyl-ammonium salts [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]-dimethyl-ammonium salts [2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(6- methyl-pyridin-2-ylmethyl)-ammonium salts [2-(Cyclopentyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium salts Ye 1-[2-( Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-1-(3-phenoxy- propyl)-pyrrolidinium salts [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl ]-dimethyl-(4-phenoxy-butyl)-ammonium salts (2-Benzyloxy-ethyl)-[2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- '° ylmethyl]-dimethyl- ammonium salts [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(4- phenyl-butyl)-ammonium salts [2-(((R)-Cyclohexyl-hydroxy- phenyl-methyl)-oxazol-5-ylmethyl]-[3-(4-fluoro-phenoxy)-propyl]-dimethyl-ammonium salts | 01 [2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3- phenyl-propyl)-ammonium salts [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- | ylmethyl]-dimethyl-ammonium salts [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[3-(3,4- dichloro-phenoxy)-propyl]-dimethyl-ammonium salts | 0

YEYV

‎[2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(8- methylamino-octyl)-ammonium salts [2-((R)-cyclohexyl -hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-[2-(4- methylaminomethyl-phenyl)-ethyl]-ammonium salts {2-[2-(Cyclohexyl-hydroxy-phenyl- methyl)-oxazol-5-yl]-ethyl }-dimethyl-(3- 0 phenoxy-propyl)-ammonium salts {2-[2-(Hydroxy-diphenyl-methyl)-oxazol-5-yl] -ethyl } -dimethyl-(3-phenoxy- propyl)-ammonium salts [2-(Hydroxydiphenylmethyl)thiazol-5-ylmethyl]dimethyl-(3- phenoxypropyl)ammonium salts ~~ 0 (3 -Benzyloxypropyl)-[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- ylmethyl]-dimethyl-ammonium salts [2-(4-Chloro-benzyloxy)-ethyl]- [2-((R)-cyclohexyl-hydroxy-phenyl-methyl)- oxazol-5-ylmethyl]-dimethyl-ammonium salts 0 is also preferred in the aforementioned background of the invention; Compounds with M3 receptor antagonist activity and a beta-adrenergic receptor agonist? considered information; And for the treatment of respiratory diseases, as these two-acting compounds are a cognizant form of treatment. The known strategy of the compounds through the dual activity mechanism is a simple covalent bond of the compound with the 143 receptor antagonist activity with the compound having beta-adrenergic receptor antagonist activity? . Those 0 covalent conjugates of the M3 (1) receptor agonist complex as previously identified and discussed and a beta-adrenergic receptor agonist? also form part of the present invention. for example; These bi-active conjugates include compounds of Formula 1- as defined and discussed previously; Modified by Dla) the R group? by the LB group where LJ is a linker moiety and 3 is a moiety containing beta-adrenergic receptor agonist activity? . constructively; These bi-reactive Yo conjugates can be represented as in the formula I YEYV

Yes 8

RA "1 rl A located | R

L—8 am Whereas and discussed before in proportion to compounds 20a they are as R® Lee as Le and as Boy as Le bivalent bonding moiety according to the invention The current 1 formula for example 1 part contains the activity of an adrenaline receptor agonist :00m©0:©00:60-beta © by in the background section led) Referred to 1 beta-agonist The pharmacophor example constitutes another target according to the present invention. An example of that is TIT invention. those vehicles. 1/7 compounds is Example No. active Ji. The present invention also relates to pharmaceutical formulations; included; As the content of the compound of the present invention. Other compounds can be combined with cingredient compounds 0 The current invention to prevent and treat inflammatory diseases in the lung. Therefore, the present invention is concerned with pharmaceutical formulations for the prevention and treatment of respiratory diseases, for example, La; chronic bronchitis; chronic obstructive chronic obstructive pulmonary disease; pulmonary fibrosis; chronic obstructive respiratory disease asthma allergic rhinitis comprising; And allergic rhinitis, pulmonary emphysema Vo, and one or more of a therapeutic agent (Jal) therapeutically from the compound of the invention, Aled, including a quantity. Al other compounds can be combined with compounds of the current invention to prevent and treat inflammatory diseases of the lung. Accordingly, the present invention includes a compatibility of the agent according to the present invention as previously described with one or more anti-inflammatory agents; People's Expansion 0

Yevy

AR

; Mucolytics or antihistamine agents ¢ bronchodilator airway such agents according to the present invention ¢ decongestant or anti-tussive agents antitussive the same pharmaceutical formulations or La described before and other combinatorial agents various pharmaceutical formulations; Take alone or simultaneously. Preferred combinations include different pharmaceutical formulations. Therapeutic agents suitable for therapeutic compatibility with * JY 0 compounds of the present invention include: one or more other bronchodilators eg PDE3 inhibitors; methyl xanthines eg theophylline; other muscarinic antagonists; fluticasone propionate, ciclesonide, mometasone furoate ¢ corticosteroid ¢ mtca 0

WO02/88167, WO02/12266, described in steroids or budesonide or WO002/100879, WO02/00679, WOO03/35668, WO03/48181, WO03/62259, -WO004/66920 and WO03/ 64445, W003/72592, W0O04/39827 Nonsteroidal glucocorticoid receptor agonist; albuterol (salbutamol), salmeterol, bega-? For example Ve metaproterenol, terbutaline, fenoterol, procaterol, carmoterol, indacaterol, formoterol, arformoterol, picumeterol, GSK-159797, GSK-597901, GSK-159802,

EP1440966, Compounds in accordance with Lead patents, GSK-64244, GSK-678007, TA-2005

JP05025045, W093/18007, W099/64035, US2002/0055651, US2005/0133417,

US2005/5159448, WO00/075114, WOO01/42193, WO01/83462, W002/66422, 00

WO002/70490, WO02/76933, WO03/24439, WO03/42160, WO03/42164,

WO03/72539, WO03/91204, WO03/99764, WO04/16578, WO04/016601, 1 WO04/22547, WOO04/32921, WOO04/33412, WOO04/37768, WO04/37773,

WO004/37807, 11700439762, WO04/39766, WO04/45618, WO04/46083,

WO004/71388, WO004/80964, EP1460064, WO04/087142, WO04/89892,

EP01477167, US2004/0242622, US2004/0229904, WO004/108675,

W004/108676, W005/033121, WO05/040103, WO05/044787, W004/071388,

WO005/058299, WO05/058867, WOO05/065650, WO05/066140, WO05/070908, ©

WO005/092840, WO05/092841, WO05/092860, W005/092887, WO05/092861,

WO005/090288, WO05/092087, WO05/080324, WO05/080313, US20050182091,

US20050171147, WO05/092870, WO05/077361, DE10258695, W005/111002,

WO005/111005, WO05/110990, US2005/0272769 WO05/110359, WO05/121065,

US2006/0019991, W006/016245, WO006/014704, WO006/031556, 0

WO006/032627, US2006/0106075, US2006/0106213, WO006/051373, . WO06/056471; ¢ pranlukast montelukast, zafirlukast i ¢ Modified Leukotriene 101012 Protease Inhibitors; For example inhibitors of tissue metalloprotease 1 and TACE inhibitors eg Jus 617-3333 marimastat, DPC-333, ; Human neutrophil elastase inhibitors ¢ eg sivelestat such as those described in WO004/043942, WO05/021509, WO05/021512, WO05/026123, WO005/026124, WO04/024700, WO04/024701, W004 020410, W004/020412, WO05/080372, WO05/082863, WO05/082864, 0 . 0 Phosphodiesterase inhibitors-;- ¢ roflumilast, arofylline, cilomilast, ONO-6126 ia or 10-485 ¢ phosphodiesterase inhibitors-; antitussive agent; eg codeine or dextramorphan; a

YY

¢ kinase P38 MAP kinase inhibitors ¢ especially inhibitors P2X7 antagonists INOS inhibitors; eg ibuprofen or metoprofen non-steroidal non-steroidal non-inflammatory agent dopamine A receptor antagonist © Mie ¢ TNF —a Wl inhibitors; monoclonal antibodies against TNF—antibodies “eg remicade, CDP-870, and immunoglobulin molecules TNF receptor” on the Jaw article in April; Ve A2 agonists eg those described in EP No. 64, 51197 0; A2 bald eg those described in International Patent No. 001 / 7794; chemokine receptor activity modifiers Dia antagonists of CCR1, CCR2, CCR3, SB-332235, SB- wt ¢ CCR8 and CXCR2, CXCR3, CX3CR1 1° 656933, SB-265610, SB-225002, MCP- 1(9-76), RS-504393, MLN-1202, INCB- ¢ 3284 or (orth? or 401 (pgd2) Compounds that modulate the effect of prostanoid receptors ¢ like ¢ ramatrobant Jie Ay antagonist thromboxane ¢ PPAR eg Th2 or Thi agonist Compounds that modulate the activity of 0 ¢ Kineret eg Y = interleukin receptor antagonists Tlodecakin IL-10 agonist eg example

Ye rosuvastatin, mevastatin, lovastatin, (statins) ¢ eg HMG-Co A reductase inhibitors ¢ fluvastatin s simvastatin, pravastatin Anti-infective agents (antibiotic or antiviral)© and antiallergic drugs Antiallergic Les in it without limitation Antihistamines © Histamines The weight ratio of the first and second active ingredients can vary and will depend on the effective dose of each content General The effective dose of each will be used Any route Suitable for ingestion It can be used to provide to live animals providing a mammal ¢, especially humans, with an effective dose of the compound of the present invention. Experience in the “convenient” intestine ¢ rectal rectal intravenous vein oral field; including – mouth; tongue and lungs nasal – nose ocular (pad) eyeball “topical topical ¢ parenteral buccal and pulmonary Vo the magnitude of prophylactic or therapeutic dose value of the compound of the present invention will; naturally ; Vary rate dependent on a number of factors; including the potency of the specific compound used; age Body weight ¢ general health and sex of patient + time of administration ¢ the route of administration; The rate of excretion. ; the use of any other real estate; And the severity of the treated disease of excretion Y:

CY in general; The average daily dose will fall within the range of approximately 0.11 mg/kg of human body weight; with a preference of 10 μg to approximately mg/kg ; in preference to the largest µg of approximately 1.5 µg of nb to approximately yo of µg kg; in single or divided doses. On the other hand; It may become necessary to use doses outside these limits in some cases. The compositions suitable for inhalation are known; It may include carriers and/or diluents 1 which are indicated for use in such formulations. The composition may contain an amount of 1 0 mg / kg. Appropriate oral doses are Vom micrograms © . mg/kg; preferably 6 µg/kg up to; 001 mg / kg until the other objective according to the present invention provides pharmaceutical formulations that include a compound according to the present invention and a pharmaceutically acceptable carrier. The term “composition” as in pharmaceutical formulation is intended to include the product containing the active content(s); the inactive content(s) (pharmaceutically acceptable excipients) that are pregnant; In addition to any product produced; 0 directly or indirectly; who agree; the complexity or agglomeration of any of two or more Contents or the decomposition of one or more Contents; or from other types of interactions or interactions 0 between one or more of the . according to; Pharmaceutical compositions according to the present invention include any composition prepared by mixing a compound according to the present invention with additional content(s). Pharmaceutically acceptable actives and excipients Vo Pharmaceutical compositions according to the present invention include the compound of the present invention as an active content or a salt derived from it Pharmaceutically acceptable 0 It may also contain a pharmaceutically acceptable carrier and pharmaceutically "Pharmacologically acceptable Zo Optionally contents Other active The expression pharmaceutically acceptable or non-toxic refers to salts prepared from acceptable salts bases including acids including inorganic bases or inorganic acids and organic bases or Ye quaternary with ammonium ions organic acids; And salts of ammonium compounds

By means of JB the composition according to the present invention may be prepared of as a suspension to release a nebuliser or aerosol 01 into a liquid propellant ¢ eg for use in a pressurized inhaler and dose meter 214001. Propellants suitable for use in PMDI are known to experts in The range includes CFC-12, HFA-134a, HFA-227, HCFC-22 (CCLEF,)© and (WillArch) 118-152 and isobutane. in a preferred embodiment according to the present invention; The composition of the present invention is in the form of a dry powder; For release using a dry powder inhalation method. Many types of DPI are known. Fine particles for ingestion release may be formulated with excipients that aid release and release. for example; in a dry powder formulation; The fine particles can be formulated with large particulate matter that aids in the influx of DPT into the lung. Appropriate particle carriers are known; These include lactose particles; They can include an average mass aerodynamic diameter greater than 900 µm. In the case of an aerosol formulation; An example is the VO compound of the invention Jal 74 mg/canister lecithin; liquid center. 0.1 mg/canister mg/canister trichlorofluoromethane NF = 4.075 g/canister mg/canister dichlorofluoromethane 07.06 = ¢ NF g/canister mg/canister The active ingredients can be dosed as described depending on the inhalation system 0 “©” used. In addition to active compounds; Pictures taken may contain additional excipients; For example ; for example; Propellants (Jie; firgen in the case of metered aerosols ¢ surface-active substances ¢ emulsifiers - stabilizers » preservatives ¢ flavorings ¢ my tower b

Fillers (Jia lactose in the case of powdered inhalers J) powder inhalers when appropriate Other active compounds Purposes of inhalation A large number of systems are available in which Lexa particle size aerosols are available Ideally, Lan can administer and administer using an aspiration technique appropriate to the patient, as well as the use of adapters (spacers ¢ extenders) and pear-shaped containers (such as + Nebulizer®, Volumatic®) ¢ and automatic means that deliver a balanced spray (Autohaler®). For calibrated aerosols, particularly in Alla powdered inhalers ¢ A number of technical solutions are available (for example filling Diskhaler®, Rotadisk®, Turbohaler® or inhalers as described in EP No. 505771). The compounds of the present invention can be released in multi-cavity media thus permitting the combinatorial agents to be released.Methods of synthesis The compounds according to the present invention may be prepared according to the methods in the following diagrams and the following examples, using suitable materials  further embodied by the following specified examples. 0 on top of that, using the methods described from the discussion mentioned here; An expert in the field can prepare the additional compounds according to the protection requirement mentioned in the present invention. The compounds shown in the examples; in any case; It is not considered to be constituent of the sex only, but it is considered according to the invention. The examples further illustrate the details for the preparation of the compounds of the present invention. Experts in the field will immediately understand that the known variations in conditions and processes according to the following preparation methods can be used to prepare these compounds. The compounds according to the present invention can be dissociated in the form of pharmaceutically acceptable salts; For example those described before. It may be necessary to protect reactive functional groups (eg, +0-hydroxy amino ¢ thio or carboxy) in the stepson

TA

The media used to prepare the compounds of the present invention to avoid sedimentation that is not required in the . A reaction that causes compounds tw greene to form conventional protective groups; for example; Those described by TW Green "" in Protective Groups in Organic Chemistry gm WAP JM Watts Cad ¢ 1959484 0 John Willey & Sons protective groups in organic chemistry . Vehicles of the present invention can be prepared according to the illustrated routes. £7) No. of schemes Yevy

° 0 2 N

R NO 0 in “NH = R he

OH —= l N 0 9 a 0 m o Mm “>

N N A

! Gel Lom or J ro Re > HO Re

RO N-R 0 m (R® 010) (vii) (1-9)

N

RY 0 8 A Ao a A, ay | HoT, Br f , -R®

CR A (Vil) (I-h) NL N Tamal gets excited.”

HO go a NY) ws Ao ~~ HO ON

R®

NT N (IX) bow of Section (0) (1-b) EN mA

HO R°NH,

N (ic) er . 0 NR

R R" R° N a (-9) So R°

HO Re No (I-d)

Nts A F,

HO Ls Ne (le) Work 1 Chart No

SMe

Ri__CN la a[la d la a a wT; — Po - Ao I om

R® to R R® = To Br 00

N i Lom Aj RP rR

NT

0) | ts or 883 cn

R° [la (XIV) a ws Ao :

R71, 0718

R R Qom (1-k) (>

Ro

RS R® NH, (H)ts Ao R°

RI, © N

R Re (I-m) iN 84 Cc > Nr

R ry

(I-n) Chart number?

YEYY

1

No NH o RN oe (XV) 0 ~~ (XV) N » ll 0 6 . I: 1! 7 (Iv) 0 o "vi 0/1 0

RA

HO RP "6 ~~ 0 L A 5 0 HM A Sr

R° HO RP (XVII) ~__ 0 7 (vin

Az

Ho ge H (XX)

Y chart number and R? ¢R! Jay they are as specified by R® RY ¢ R® -b) where 1) compounds according to formula C and not a hydrogen atom can be prepared from compounds of formula (1-a) by reaction with 71 alkylation agents According to the formula © (XXI) RW tosilates ¢ halogen leaving eg halogen de gana as 177 the reaction can be carried out in a range of solvents; And preferably. mesylate; tosylate at zero temperature acetonitrile or chloroform acetonitrile; Chloroform DMF « similar manner. solvent For the reflux temperature of the solvent, Gye, 0 degrees, to be prepared from the compounds of the formula (Sa (Ins Le), (Ig), (IH), (Ik) compounds of the formula . successively) 1- - - ). (I- .ivy (Im (I-d), (I), (I-h), )1]

£y It will be highlighted that some compounds can contain a chiral center and thus generate enatiomeric images that (Sa) can be separated by preparative chiral HPLC techniques using conditions known to experts in the field and are represented below. Compounds According to the general formula (Te), it can be prepared from compounds of the general formula [1

N

“ro 0 N 0 aN =R° (Ir) 0 by means of a complex reaction according to the general formula XXII (XXII) R°M wherein 188 and 85 are as defined for 84 and 185 in the general formula 1 and 1) represent Os) against a metallic eg lithium li or magnesium bromide: 1488. The reaction can take place in an aprotein organic cule eg THF or diethyl ether in a range of temperatures preferably between YAS °C and the reflux temperature of the solvent. Compounds according to the general formula 7071 are considered well known in the field and are available directly or can be prepared in known ways. Compounds of the general formula IT can be prepared from compounds of the general formula TI

N

AI

0 (an 0 Br yo by a reaction with an amine according to the formula XXII (XXII) R°RINH wherein 88 and RY are as specified for 18 and 182 in the general formula 1. The reaction takes place in the range of solvents ' and preferentially') (1111 /10 in the range of temperatures ' and preferably Ye between zero and 100 degrees Celsius.

The compounds according to the general formula XXII are well known in the field and can be prepared by known methods; Or commercially available co Compounds according to formula 111 can be prepared from compounds according to the general formula IV N Aon, nv © oe © through the reaction of a brominating agent, for example, N Jad - N-bromosuccinimide in the presence of a radical initiator eg AIBN or benzoyl peroxide. The reaction can be carried out in suitable solvents; for example CCL ; in a range of temperatures, preferably between the ambient temperature and the reflux temperature of the solvent. 0 Compounds according to the formula TV can be prepared from compounds of the general formula V 0 N “SN having 0 0 by reacting with an acid, for example hydrochloric acide; sulfuric acid; fue-sulfonic acid or trifluoromethansulfonic acid in a range of solvents eg THF-DCM; Water, Ve and preferentially 01-?dioxan in a range of temperatures; And with a preference between the ambient temperature and the reflux temperature of the solvent. Alternately, compounds of formula IV can be prepared from compounds of general formula V by gyrolysis of sisspalladium by using a palladium catalyst, for example, Dbis(dibenzylideneacetone)palladium * and the presence of a third ligand, for example, Ye. Triphenylphosphine and a base eg sodium tributoxide

sodium tert-butoxide in a solvent eg THF from room temperature to the reflux temperature of the solvent. Alternately 0 compounds of formula IV can be prepared from compounds of formula XVI NH Hoe xvyy © according to the method described in Chemical Society Journal 6014448 1970 . Compounds of general formula XVI are known in the art and may be prepared by known methods eg those described in (VE)OA 001 Tetrahedron 77 . Alternatively, compounds of formula IV can be prepared from compounds of formula XVII 0 hot" (XVII) o Mo 0 according to the method described in the Journal of Organic Chemistry ¢ 157748 YA 0 Yc. Compounds of general formula 3311 are considered It is well known in the field and can be prepared by known methods, for example those described in British Patent No. 77114186. Compounds of general formula V You can be prepared from compounds of general formula VI 0 mAb (V1) © ‎ Ve is reacted with propargylamine in the presence of a suitable conjugating agent, eg DCC/HOBt, or several other known conjugate methods. Compounds of formula VI can be interchangeably converted, for example, to acid chloride and The formation of an amide is optionally affected in the presence of a suitable non-nucleophilic base and compatible solvent YEYY

¢0 under well known conditions. Compounds of general formula VI are readily available or may be prepared by known methods. Alternatively, compounds of the general formula Tra can be prepared from compounds of the general formula [171 N lo 0 Na HO (VII) R Br o according to the previously described methods for preparing compounds of formula 11 from compounds of formula JI compounds of general formula 711 can be prepared from compounds of formula VII N RA J \ Soon, HO 1, (VIN R described by. > Compounds of general formula 37111 can be prepared from compounds of formula IV using Gohl described previously to prepare compounds of formula 1-8 from compounds of formula [1]. Alternatively, compounds of formula 7111 can be prepared from compounds of formula XIX 0 RA nol NY ( XIX) 8 0 using the previous methods for preparing compounds of formula 11 from compounds of formula XVII. Vo compounds of general formula XIX can be prepared by known methods, for example those described in British Patent No. 77114186. Interchangeably 0 Compounds of formula [1711] can be prepared from compounds of formula XX 0 N ANF sans 8 a 1 HO (XX) R

By using the previously described methods for preparing compounds of formula IV from compounds of formula 1, compounds of general formula XX can be prepared from compounds of formula XVII, using the previously described methods for preparing compounds of formula 1 from compounds of formula VI. . © Interchangeably; Compounds of formula Tb can be prepared directly from compounds of formula VIT by quaternisation with a suitable substituted tertiary amine as described above. Alternately ¢ compounds of formula Ta where 10898 is a secondary amine (i.e. one of R® or RY is a hydrogen atom) can be prepared from compounds of formula Ta where - NRRY is a group NH, reductive alkylation by aldehyde substituted appropriately by 0 . The reaction takes place in the presence of a reducing agent for example sodium cyanoborohydride or sodium borohydride and preferably sodium triacetoxyborohydride in a range of oraganic solvents; In preference to dichloroethane (jG), compounds of formula 1-4 and Te can be prepared from compounds of formula Tc by alkylation or 1-reductive alkylating methods as previously described and according to standard methods well known to experts in the field for compounds of formula p10 It can be prepared from compounds of the general formula IX (IX) 10 Re 9 oN by reaction with a reducing agent, for example lithium aluminum hydride 00 diisobutyl aluminum hydride » or borane in a range of non-polar solvents eg 0 diethyl ether or THF or preferably hydrogenated in the presence of a catalyst eg nickel vevy ramen (J

P nickel is a suitable solvent for example ethyl acetate EtOAc or ethanol 21011 at se from room temperature to the reflux point of the solvent. Compounds of general formula IX may be prepared from compounds of general formula [711] by reaction with a cyanide ion source for example acetone cyanohydrin or an inorganic cyanide; © and preferably sodium cyanide; in the presence of a non-nucleophile base eg tetramethylguanidine ¢ in a range of solvents; and preferably ethanol; in a range of temperatures; And with a preference between the ambient temperature and the reflux temperature of the solvent. Compounds of formula Lf can be prepared from compounds of formula Ta by reacting with a reducing agent, for example, triethylsilane, in the presence of an acid, for example, trifluoroacetic acid, in a solvent, for example, DCM, from room temperature to reflux of the solvent. Compounds of formula Ih can be prepared from compounds of formula 18 by reaction with an alkylating agent according to formula 17' km (XXIV) 0 where RE is as defined for 186 in general formula 1 and Y is the term About a group leaving eg halogens; Tosilat ¢ mesylate. The reaction takes place in the presence of a base eg sodium hydride in ade eg THF from zero reflux temperature of the solvent. Compounds of general formula Tom can be prepared from compounds of formula 1-1 using the previously described methods for preparing compounds of formula 1-4 from compounds of formula p1. Compounds of general formula 1-1 can be prepared from compounds of formula XIV by using the previously described methods for preparing compounds of formula Tc from compounds of formula IX 01°

I

M. Compounds of general formula XIV can be prepared from compounds of formula 70111 using the previously described methods for preparing compounds of formula IX from compounds of formula VII. Alternately 0 compounds of formula Tk may be prepared directly from compounds of formula XT by quaternisation with a suitably substituted tertiary amine as described above. © Compounds of general formula 1 can be prepared from compounds of formula XII using the previously described methods for preparing compounds of formula 1-8 from compounds of formula VII . Compounds of general formula XT can be prepared from compounds of formula XII using Gohl. Compounds of general formula 011 can be prepared from compounds of general formula XI SMe of la . The duration of the (XI) R Ve reaction by reacting with a reducing agent, for example Raney nickel, in a solvent, for example

Gy ethanol at room temperature to the reflux temperature of the solvent 210 (AY 10 Yeo) for the method described in The Journal of Organic Chemistry

X can be prepared from compounds of the general formula XT compounds of the general formula

RX\_CN

RT, (X) R eo by reaction with 1-(methylthio) acetone in the presence of trifluoromethanesulfonic anhydride at a temperature of 0 °C to the reflux temperature of DCM, a solvent for example. 172 (A) (VY) 00013 to the solvent according to the method described in the Journal of Organic Chemistry. Compounds of general formula 7 are well known in the art and can be prepared by: information or commercially available

£9 RO BE oo AEE oo RL rs s s (XXV) Ho (XX V1) Ho (XXVII) Br © FL Hs Nec Boh 5 HO R* le R RY R {(XXIX) (XXVIIN) Scheme No.: compounds of formula (Say XXIX) to be prepared from compounds of formula XXVI using a similar sequence of reactions as was used to prepare compounds of formula Ib from compounds of formula 1 in scheme No. 1 Previous Compounds of formula Cus XXVI that Ra and Rb isotropics (Sa) can be prepared from compounds of formula XXV where 18 is a suitable alkyl group (eg ethyl or methyl) by treating an organic reagent suitable metallic eg reagent 0 Grenard; in a suitable solvent eg THE or diethyl ether 0 compounds of formula XXVI as Ra and Rb are not the same and can be prepared from compounds of formula XXV by amine conversion intermediate, preferably by an amide of Weinrib, and the completion of the recruitment of Ra and Rb through dependent organometallic reagents in a serial manner. Compounds of formula XXV are known in the study - eg Helv.Chim.

Acta D (Yq) Here are the unspecified examples to illustrate the invention. General empirical details YEYV

All reactions take place in a nitrogen environment unless otherwise specified. NMR spectrometers over Whe Varian Unity Innova foe with inverted detection triple-Of probe operating at 500MHz over Bruker Avance DRX 00 spectrometer with 0mm detection inverted resonance probe operating at 40860MHz Hertz or above © Broker Avance DBX 01 Spectrometer with Dual Frequency Probe © MM Standard operating at Yor MHz. Changes are available c / m relatively with tetramethylsilane. where compounds were purified by column chromatography + “silica and mesh” denotes silica gel for chromatography; 2.25 eae Vom mm (0 £€0 = YY mesh) (eg; fluka silica gel (Te) and applied pressure of nitrogen up to 10 psi accelerator column clarifiers. Where 0 is used, thin layer chromatography (Te) TLC ); it refers to TLC using silica gel plates, typically “+36 cm silica gel on aluminum foil plates with a fluorescent indicator (YO£)+nm (eg; Fluca. 0977/8). All commercial solvents and reagents are used as received. all compounds containing a base center(s); that can be purified by HPLC; It is obtained as TFA salt unless SY otherwise. HPLC preparation conditions Inverted column state 0-18 (0 360100 77.8 mm inner diameter of the column and a particle size of 1 μm). UV detection at YY nanometers. LC/MS Systems Yee 1 way LC-MS Waters platform LCT with inverted column 6-18 VX Ver (mm Hagens Klepios particle size © µm); Clarification with 0.1 M water + 0.1 6 formic acid Bo = acetonitrile + 100% formic acid. sloping YEYY

%B %A flow ml/min Gradient — Time 95 1.0 0.00 5 95 1.0 1.00 95 5 1.0 15.00 95 5 1.0 20.00 ° 5 95 1.0 22.00 5 95 1.0 25.00 It has an ultraviolet detector MS 001 microliters divided into (UV) + ELS-MS—detection) nanometers YO! Direct in ) ionization method 145 - electrospray (positive ion 0

LC-MS method? from with inverted column Case 6-18 (20 76 .7 mm Phenomenon Luna The LCT Waters Platform 3 ¢ Formic Acid 96 +N + Water A Particle Size 7 µm) » Lacqueration by ‎ acetonitrile + 96 01 formic acid. Gradient = %B %A flow ml/min Gradient — Time Vo 5 95 2.0 0.00 5 95 2.0 0.50 95 5 2.0 4.50 95 5 2.0 5.50 5 95 2.0 6.00 Ye) It has an ultraviolet detector MS Divide into 001 microliters (UV ¢ ELS « MS— Detection) Ionization Method 145 - Electrostatic spraying (positive and negative ions)

LC-MS method? of 1 mm Phenominx X Ya) C-18 Waters Micromass ZQ with inverted column acid ov) + water A clarification by 0” μm) Y particle size Lgl Yo Formic acid. Boring % 100 + acetonitrile = B formic; and %B %A flow m/min Gradient — Time of 95 2.0 0.00 5 95 2.0 0.50 95 5 2.0 4.50 95 5 2.0 5.50 5 95 2.0 6.00 8 It contains a microliter MS ultraviolet detector divided into 001 (UV – ELS “MS— direct detection) Electrospray (positive and negative ions - MS ionization method)

LC-MS method; of with inverted column Case 6-18 (30 x 36 x 4.67 mm Phoenix Luna size ZMD Waters 0 - 8 formic acid; 101% Fela A particulate * µm); denaturation with formic acid. Boiler 96 000 + acetonitrile %B %A flow mL/min Gradient — Time 5 95 2.0 0.00 5 95 2.0 0.50 Vo 95 5 2.0 4.50 95 5 2.0 5.50 5 95 2.0 6.00 (997 Watts DAD per μl per division In detection (ELS 001) UV; “MS” detection (electro-spraying) of positive and negative ions - MS ionization method

LC-MS method © from MM Hagens Klepios VX 000 (6-18 Watts 20 μM with inverted column formic acid; 0.1 Yo + water A particle size * μm) » Lacturation by acetonitrile + ) + % formic acid. The gradient = 8 %B %A flow m/min Gradient — Time Yo 5 95 1.0 0.00 01 5 95 1.0 1.00 oy 95 5 1.0 15.00 95 5 1.0 20.00 95 1.0 22.00 5 95 1.0 25.00 It has an ultraviolet detector MS Micro lt Divide into 001 (UV ¢ ELS; MS—detection © ) direct at 4*7 nm) ionization method 145 - electrospraying (positive ion)

LC-MS method > from M. Haggins Klepios VX Ver) 06-18 Aad with inverted column ZQ Waters Micromass ¢ formic acid Bo 06.1 + water A particle size #6 μm) » Lacquering with Ye acetonitrile + )+% formic acid. Gradient = B %B %A flow ml/min 5 Gradient — Time 5 95 1.0 0.00 5 95 1.0 1.00 95 5 1.0 15.00 'o 95 5 1.0 20.00 5 95 1.0 22.00 5 95 1.0 25.00 It has an MS ultraviolet detector Divide 001 microliters into 001 (UV – ELS “MS—detection) direct at 794 nm Yo) ionization method 145 - electrospraying (positive ion) Abbreviations used in the experimental part Dichloromethane DCM Diisopropylethylamine DIPEA Methylaminopyridine SG DMAP of Dimethylformamide DMF Ethyl acetate EtOAc

Js) EtOH Industrial methyl alcohol 5 Abbreviations used in the experimental part Chloromethane SB DCM Diisopropylethylamine DIPEA Dimethylaminopyridine DMAP Dimethylformamide DMF Ethyl acetate BroAc

Js EtOH Synthetic Methyl Alcohol 5 Methanol MeOH Room Temp RT _Residence Time ©: Trifluoroacetic Acid TFA Tetrahydrofuran THF Saturated Sat. Media Preparation 1 Media No. o0 0

NH

2-Oxo-2-phenyl-N-prop-2-ynyl-acetamide. (V): R® = Ph Oxalyl chloride (11 g ¢ 58 mmol) was added to a dry solution of phenylglyoxylic acid (01 mL) DCM DMF mixture (g ¢ 56 mmol) and ¥ points from 7) The reaction was stirred at room temperature for 2 hours and then the solvent was separated. The remaining 0 dry (1*mL) was taken and the solution was cooled to 0°C. C. A mixture of DCM amine in perboargel (7.7 g; 56 mmol) and triethylamine (4.05 g ¢ 46 mmol) was mixed for 10 minutes and then allowed to warm to room temperature for 10 minutes. Stirring continues for 7.6 hours, and then water (10 ml) is added.The mixture is washed with 0

Vo) mL twice); saturated (aqueous) sodium hydrogen carbonate 01 (1 M HCl 0 mL twice) and then brine. The organic phase was then dried (sodium sulfate) and the solvent was separated. The remainder crystallizes with cyclohexane to provide the product in the form of a solid. Light brown colour. 96776 6 Productivity 5.75 g

LC-MS (Method 3): Rt 2.47 min, m/z 188 [MH"]. Yo 1 Argument No.

N

0 2 7 (5-Methyl-oxazol-2-yl)-phenyl-methanone. (IV): R* = Ph

01 methanesulfonic acid 01 (c 0154 mmol) was added dropwise to a solution of -2-0*0 2-phenyl-N-prop-2-ynyl-acetamide (median Y.£) ) 1 g ¢ 17.87 mmol) in 1©-dioxane (Yr) mL). The resulting solution was heated at 90 °C for 17 hours. The reaction mixture was cooled and the solvent was separated. The dark residue is separating between DCM and water. Output Jury 00 © by 1 M HCl (times); Saturated sodium hydrogen carbonate (for once) and then brine. The solution (ada) (sodium sulfate) 6 and the solvent was separated to provide the crude product. Purification is done by column chromatography + and clarification by a ratio of 1 rE of cyclohexane: ethyl acetate. The product is available as a semi-white solid. 0 Productivity 1 g (9641). LC-MS (Method 3): Rt 2.94 min, m/z 188 [MH] Median No. ? N TL Br (5-Bromomethy!l-oxazol-2-yl)-phenyl-methanone. (lil): R? = Ph 1 mixture of (5-methyl-oxazol-2-yl)-phenyl-methanone (median A)) 1 g ; l mmol) and A1-bromosuccinimide (3,00 g) 2.01 mmol) + f-2,2 azobis(2-methylpropionitrile) )071 mg (deeds VE 1 in carbon tetrachloride (Je A) And heated to reflux for 0.59 hours.The reaction mixture was cooled to ambient temperature and filtered.The filtrate was diluted with DCM (10ml) and washed with water -Ye saturated sodium hydrogen carbonate and brine.And dried (sodium sulfate) and YEYY

ov the solvent is separated. Then, purification by column chromatography and clarification by 10 ¢ cyclohexane:ethyl acetate. The product is available as a yellow solid. Yield 0.9 g( 674( LC-MS (Method 3): Rt 3.26min, m/z 266, 268 [MH] © Media No. N 0 7 1 N \ (5-Dimethylaminomethyl-oxazol-2-yl)-phenyl-methanone.(II): 58 = Ph, R®, R% = CHs vA) (¥ Luss) (5-Bromomethyl-oxazol- 2-yl)-phenyl-methanone “TA can 0 mmol) in solution? Molar of dimethylamine in THF (? ml; 6 mmol). The mixture was stirred at ambient temperature for 1 hour with the formation of a precipitate. The solvent separated and the residue partitioned between DCM and saturated sodium hydrogen carbonate (aqueous (Ja © «). The aqueous phase was extracted by DCM and the combined organic phase was dried (sodium sulfate) and the solvent separated to provide the product as an orange-colored oil that crystallized by precipitation 8 . Productivity: 0.13 gm (9699). LC-MS (Method 2): Rt 1.22min, m/z 231 [MH"] Also, mediator © is prepared by a similar method by reacting mediator © with methylamine. N , 0 H 4 0 N AEA RY \ oA (5-Methylaminomethyl-oxazol-2-yl)-phenyl-methanone.(Il): R* = Ph, R°=

CHa, R*=H (BAY) in Y.TV Throughput LCMS (Method 3): Rt 0.26 and 1.44min, m/z 217 [MH] 6 Median ©

HO N

0

Cyclohexyl-(5-methyl-oxazol-2-yl)-phenyl-methanol. (VIII): R* = Ph, RP = c-

Hexyl

V1 g ¥) ) tesula ((5-methyl-oxazol-2-yl)-phenyl-methanone A solution of dry at zero degrees Celsius under nitrogen treats a drop of THF ml of YY mmol) in 0 minutes with lotion? A molar of cyclohexylmagnesium chloride in the second 0 point through zero degrees ls (mmol). The resulting dark yellow solution (Yoo ml Ye) ethyl ether min. During this period a precipitate is formed; And then at a temperature of Ve Celsius for about an hour. The reaction mixture was cooled to zero degrees Celsius again and treated with a 0.5 room solution for a period of time at a temperature of 0 lf the mixture. (Je Ye) with a saturated ammonium chloride solution (aqueous) (Yo) phases were separated and phase (Je) for 10 minutes and then diluted with water for 10 minutes in a room for organic DCM washed with brine. Combined aqueous phase It was extracted by ml for three times) and the combined organic phase was dried (magnesium sulfate) and concentrated in Ye.. Filtered and dried (Ja Ye) in vacuum to provide the raw product that was ground with ether (9684) Productivity 2.725 g Ye 01/5 (Method 3): Rt 3.78 min, m/z 272 [MH]

Yevv

049 Lad Mediator 1 is prepared in a similar way by reaction of mediator ? With cyclopentyl magnesium chloride. H N 01 Cyclopentyl-(5-methyl-oxazol-2-yl)-phenyl-methanol. (VII): R® = Ph, RY = c-Pentyl© Yield 7.87 g (9670) .

LC-MS (Method 2): Rt 3.68 min 258 [MH] in a similar way with the reaction of mediator No. ? With vinyl bromide A also the intermediate is prepared with magnesium

Ho Nos

Ya (5-Methyl-oxazol-2-yl)-diphenyl-methanol. (Vil): cat, cat = Ph. (9677) Productivity 7.05 g

LC-MS (Method 3): Rt 3.78 min 272 [MH"] 4 Argument No.

HO N oA

BrVo (5-Bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol. (VII): R? = Ph,

RP = c-Hexy!

Yevyev

A solution of cyclohexyl-(5-methyl-oxazol-2-yl)-phenyl-methanol (median 1 (9 g) YY mmol) in f “-dichloroethane (Je YY) treated with (1,11 g 0.70 0 mmol) followed by (02001001018|l2,2-220515)2-01817 ().+a” ¢ 11 mmol). The mixture was heated to As 4 gia degree for 0.0 hours » and then allowed to cool to room temperature. A saturated sodium hydrogen carbonate solution was added and the phases were separated. The organic layer was washed with brine and the combined aqueous phases were extracted by DCM. The combined organic phase (magnesium sulfate) was dried and concentrated in vacuums to provide the crude product as brown oil. Purification is by column chromatography and clarification by DCM 96 001-"“” / cyclohexane followed by 90675 0-ethyl acetate / DCM. Yield 0.88 g (9648)

LCMS (Method 3): Rt 4.27 min, m/z 350, 352 [MH*]. 7 In a similar way, media No. 01 is also prepared from medium No

HO N

2

Br (5-Bromomethyl-oxazol-2-yl)-cyclopentyl-phenyl-methanol. (VII): R* = Ph, 00

R® = c-Pentyl (YAY g(‎01.11) Productivity (Method 3): Rt 3.90 min, m/z 336, 338 [MH*] 01/5 A Also prepare median No. 11 In a similar manner from argument number 4.

HO N ose

Br 5-Bromomethyl-oxazol-2-yl)-diphenyl-methanol. (VII): a cat a cat = Ph . (9677) 0.17 gm Productivity

LCMS (Method 4): Rt 3.53 m/z 326, 328 [MH*-H.O]

VY median number 0

N

7 A = ( CN [2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-acetonitrile.(IX): R® =

Ph, R® = c-Hexyl +-(5-bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol to a solution of cyanide (Ja Yo ) IMS mmol) in Yo a. (5 g) q (medium No. IK 1 °C for 71 sodium (114 mg 7.45 mmol). The mixture is heated in . ml) and water (0 ml) of between ethyl acetate. Tan for an hour and then concentrated in vacuum and the aqueous phase was extracted with ethyl acetate (10 ml for two times) and the combined organic phases were dried over sodium sulfate; Filtered and evaporated into orange colored oil. By purification by flash chromatography over silica gel using a mixture of 96460 ethyl acetate Vo and 1660 cyclohexane as a diffuser and then repeated crystallization with DCM using hexane, the entitled compound is available as a white crystalline solid. Yield ‎re 7 mg 0 (%v4).

LC-MS (Method 3): Rt 3.66 min, m/z 279 [MH*-H,0].

YEYV

+7. 11 In a similar manner from argument No. 1, also prepare argument No

HO N

2

CN

[2-(Hydroxy-diphenyl-methyl)oxazol-5-yl]-acetonitrile. (IX): R?, R° = Ph. (9654) g 0011 Throughput LC-MS (Method 3): Rt 2.96min m/z 291 [417] °

VE Median No

N SMe

RSS

2-(1,1-Diphenyl-ethyl)-5-methyl-4-methylsulfanyl-oxazole. (XI): R*R® = Ph, R® = CH; 0 To a colorless solution of “I-methylthio-2-propanone) (9A) ml « 5.7 mmol) in VY ml dry DCM at 0 °C under nitrogen a solution of trifluoromethanesulfonic anhydride was added dropwise 0.17 (ml; 9.7 mmol) in 01 ml of dry DCM. The resulting yellow solution was stirred at 0°C for 1 hour and then a solution of 7 (SEY phenypropionitrile 1 (g; 4.8 mmol) in 01 ml of dry DCM Ve was added dropwise. The reaction was stirred at 0 °C for an hour between 0 °C and room temperature for a day ¢ to become dark red in color The resulting mixture was cooled to 0 °C Ja and treated carefully with saturated sodium bicarbonate solution The phases were separated and the aqueous layer was extracted by DCM (Y 3). The organic phase is washed with water ¢ saturated sodium bicarbonate solution and YeYV

Brine ; (Sodium sulfate) was dried and evaporated to a viscous oil 0.77 (Gale). The crude product was treated by silica gel chromatography and clarified by 0% diethyl ether/cyclohexane (RE = ©?..) to provide the entitled compound as a pale yellow oil that crystallizes by precipitation. © Yield 0.749 g (7657). LCMS (Method 2): Rt 4.37min m/z 310 [1111] Median No. Vo t) N 04 R” = Ph, R® = CH; 2-(1, 1-Diphenyl-ethyl)-5-methyl-oxazole. (XII): 0 suspension of Jas s1)2-(1,1-diphenyl-ethyl)-5-methyl-4-methylsulfanyl-oxazole (nl) 4 g; 7.7 mmol) in V0 ml lay IMS to dissolve. Raney nickel 0 (approximately * (pa) was added causing rapid gaseous fizzing. The reaction mixture was stirred until reflux under nitrogen. After 0.76 hours, the value of 1.0145 indicates that it is mixed in a 1:1 ratio of starting material: product and not Change after 1 hour. Add another 0.71880 grams of Raney nickel and stir the reaction mixture until reflux for 1 hour. TLC analysis indicates that all the starting material has reacted. The catalyst is filtered through a high flow and the materials The volatile was evaporated to obtain a viscous colorless oil (0.0897 g).The oil was purified by silica gel chromatography and clarified by ethyl acetate/cyclohexane 9615 (Rf = 0.776) to obtain the compound labeled as colorless oil. © _yield 0.57g (9684) . LCMS (Method 2): Rt 3.96min m/z 264 [MH"] YEYV

Intermediate No. 01 Ro N OH Br Ph, RY = cat cat 5-Bromomethyl-2-(1,1-diphenyl-ethyl)-oxazole. (XII): Wanna © is prepared from medium 11 according to the method used to prepare medium number 4. Productivity 00975 g (amount). LCMS (Method 2): Rt 4.06min m/z 342, 344 [MH"] Mediator No. 17 BY Oa 0 0 Methanesulfonic acid 8-methoxy-octyl ester 0 0 diisopropylethylamine added 170 mg (0.45 mmol) for a solution of 8-YVV (methoxy-octan-1-ol mg ¢ V.Y0 mmol) in dry DCM (Je 1). It was cooled in an ice bath and methanesulfonyl chloride 170 (mg; 0.44 mmol) was added under nitrogen The solution was allowed to warm to ambient temperature overnight TLC Ve indicates that a portion of the starting material is present Added More methanesulfonyl chloride (YY) mg 1.00 mmol) and the solution was stirred at ambient temperature overnight. + The reaction mixture was treated with water and the phases were separated. The organic layer was dried (magnesium sulfate) and the solvent was evaporated. The crude product was purified Silica gel chromatography and clarification by diethyl ether: cyclohexane (1:1) and then diethyl ether: cyclohexane (1:1) Ye to provide the titled compound in the form of oil. 8-Methoxy-octan- [1-0] according to the methods described in the preparation 0010144498 .Ag 7

Yield 8 mg 7 (Yt LCMS (Method 2): Rt 3.14min, no mass ion observed Median VA 0 0 WN 0 INNS Je N Ao A 0 Methanesulfonic acid 8-(tert-butoxycarbonyl-methyl-amino)-octyl ester.© The entitled compound was prepared according to the method described for preparing medium No. VY using 8(hydroxy-octyl)-methyl-carbamic acid tert-butyl ester instead of 8-methoxy-octan-1-ol.. |(8-Hydroxy-octyl)-methyl-carbamic acid tert-butyl ester Gg can be prepared by methods described in US Patent Ay 0000579775488 LE, 200114 01 yield = YYO mg ) 96971 . 'H NMR (CDCl,): 8 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). Median No. VA HO Ol Br Vo 2-(4-Bromomethyl-phenyl)-ethanol. solution of £0A) 4-(bromomethyl)phenyl acetic acid mg ¢ Y mmol) in 10 ml of toluene and A ml of THF under nitrogen treated with a 1 M solution of borane-dimethyl sulfide complex in day (THF + mmol) and The reaction mixture was stirred at room temperature overnight. No interaction occurred with 10145. An additional 1.0 mL (¥ mmol) of Baeborane-dimethylsulfide was added and the reaction was stirred for ? hour . Ethyl acetate and water were added and the phases were separated. The organic layer was dried (sulfate

. (7A ) mg TEV = Yield “H NMR :(J00) 62.89 ) 2H), 3.49 (s, 1H), 3.86 ( 2H), 4.49 (s, 2H), 7.21 (d, 2H) ), 7.35 (d, 2H).01 Median No

HO

OL for no o 2-{4-[(Benzyl-methyl-amino)-methyl]-phenyl } ethanol. A solution of (medium VEY) (V4 mg ¢ 011 mmol) in 11 mL acetonitrile treated with potassium carbonate (Y) OO (mg ¢ mmol) and followed with N-methyl (YAY) benzylamine 0 mg ¢ 7.4 mmol). The reaction was stirred up to reflux for 7 hours. Laie denotes 1.015, then the transformation of the starting material. The reaction is allowed to be cooled to room temperature and the solvent is evaporated. The residue was partitioned between ethyl acetate and water and the phases were separated. The organic phase was dried (magnesium sulfate) and the solvent was evaporated. The crude product was purified by silica gel chromatography and clarified by DCM to 1 96_methanol / DCM to obtain the compound entitled Ve as oil. ,. (%Y) mg YOA = Yield 'H NMR (CDCl3): §2.09 (brs, 1H), 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, 1H), 7.26-7.37 (m, 611). YY Argument No. 0 HO CL H

N~2-(4-Methylaminomethyl-phenyl)-ethanol.

YeYV

in a solution of 2-{4-[(benzyl-methyl-amino)-methyl]-phenyl}-ethanol (medium NO. TOA) (0 mg 1 1 mmol) in 10 mL of IMS Treated with 96710 palladium hydroxide per carbon (Yo) mg). The reaction mixture was inverted under a hydrogen environment for ? Hours when the LCMS indicates complete transformation of the starting material. The reaction mixture was filtered through the silite and the solvent by evaporation. The crude product is carried over the SCX-2 cartridge using 9600 methanol / DCM and the impurities are separated by flowing through the column using methanol / DCM. The column was liquified with 1 0 ¥ M methanolic ammonia/DCM and the solvent was evaporated to obtain the titled compound. Yield = A) mg (00%) “HNMR (MeOD): 6 2.35 (s, 3H), 2.79 (t, 2H), 3.65 (s, 2H), 3.72 (t, 2H), ( m, 4H). 2-(4-methylaminomethyl-phenyl)-ethanol (median DN) 71 mg; 105 mmol) in *mL of dry DOM at 0 °C treated drop by drop with a solution of VEE) A mixture of 2 + 5 (salle) was mixed in ¥ ml dry DOM and the reaction mixture was allowed to warm to room temperature. After ¥ an hour, water and the mixture were added and the mixture was stirred for 10 minutes. The two layers separated and the organic layer was dried (sulfate Mg) and “0” solvent evaporated to obtain the titled compound. Yield = VET mg (quantitatively). (s, 9H), 2.81 (br s, 3H), 2.86 (t, 2H), 3.86 (br t HNMR (2H): 1.48 6 (f 20i), 4.40 (br s, 2H), 7.14-7.22 (m, 4H). Argument No. YEYY YY

TA

0 to 0

tu

tk

0

Methanesulfonic acid 2-{4-[(tert-butoxycarbonyl-methyl-amino)-methyl]- phenyl}-ethyl ester. Using 17 the entitled compound was prepared according to the method described for the preparation of medium No. 0 . 8-218010*7-00870-1-01 instead of YY Median No. . (%o+) mg Yo = Yield “TH NMR :(J020) 5 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).

Y ¢ Median No. Ya

Br._~_70

This is 4-(3-Bromo-propoxy)-benzenesulfonamide. (+7-di(00 mmol) (YW) 4.1 mg {4-hydroxybenzenesulfonamide) suspended from

YY « 1 V g (mmol) and potassium carbonate ve Cox 1. AY) bromopropane Heat at 00 °C overnight. The mixture (de TO) mmol) in acetonitrile No was allowed to cool to ambient temperature and filtered. The filtrate is evaporated to obtain a residue which is molar sodium hydroxide (aqueous). The organic layer was dried 10 and DCM was partitioned between (magnesium sulfate) and the solvent by evaporation. Purification by silica gel column chromatography and clarification with cyclohexane and then diethyl ether; followed by recrystallization. with isopropanol Ye mg) b EAY = Yield LCMS (Method 2): Rt 3.01min, no mass ion observed

YeYV Yo Mediator No

. 8 HN ~~~ OH (9-Hydroxy-nonyl)-methyl-ammonium bromide. To a solution of O-bromo-1-nonanol (0011 g ¢ £0.Y mmol) in IMS (50 © .mL) at 0°C a solution of methylamine (oY) mL Ae was added molar in ethanol (to millimoles). After Vv minutes at zero degrees Celsius the reaction mixture was allowed to warm to room temperature for YO hours. The solvent evaporates to provide a white solid; which were triturated with diethyl ether to provide the compound entitled as a white solid. . 9687 6 Productivity = 9.99 g

LC-MS (Method 3): Rt 1.51 min, m/z 174 [MH+]. 1 YT intermediate of [ H HO 0 Noe SO 9-{[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-methyl-amino}-nonan-1-ol . 0 ¢ ax Y)(5-Bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol _mmol) was added to a solution of (9-hydroxy-nonyl)-methyl-ammonium bromide TAT) mg ¢ Y.AT mmol) and N,N-diisopropylethylamine (1 mL ¢ ¥.© mmol) in dry 0014. After stirring the mixture at room temperature for a period of time; Hours Added, Ye, saturated sodium bicarbonate (aqueous). The phases were separated and the aqueous layer was extracted by DCM. United organic layer dried (sodium sulfate); Nominated and focused until and

A Ye dryness to the availability of yellow oil. Purification by column chromatography over silica gel using a denaturant of 7000-8 methanol / DCM as a propeller. The entitled compound is available as a colorless oil. Yield - 08 g (NY) LC-MS (Method 2): Rt 2.42 min, m/z 443 [MH+]. ° Medium No. VV HO A Nee S20 9-{[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl}-methyl- amino}-nonanal 0 solution of 107 (DMSO ml ¢ 7.7 mmol) in dry DCM (YY ml) was added dropwise to a solution of oxalyl chloride (28 μl) in dry DCM (¥ ml) at VA= °C under ambient of nitrogen. Hence a solution of Ge (89 g ; 011 mmol) in (de©)ila DCM was added and the reaction mixture was stirred at -8 °C Ne for 1 min. Triethylamine (+ 4.4 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 1 hour saturated sodium bicarbonate (aqueous) was added ¢ the phases were separated; And the aqueous layer is extracted by DCM. United organic layers washed with brine; desiccated (sodium sulfate); Filtered and concentrated to dryness to provide a yellow/brown viscous oil. The crude product is reintroduced through the same reaction conditions, Ye, for further transformation of ead, to provide yellow viscous oil plus solids 0, and then YEYV.

Ya

triturated with diethyl ether and the supernatant concentrate until dry to provide a solid foam; which. It is used without additional purification. Productivity = 04 + gm

LC-MS (method 2): Rt 2.74 min, m/z 441 [MH+].

YA Median No. © Al N oA

CAA nl “0 0 NNN

Oh

NH

0 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 0 9-{[2-(cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- mixture of 5-]) 8(-2-200100-1-)1611- mmol) + f 011 ¢ g +.£4) methyl-amino}-nonanal ¢ aa +.YV) butyl-dimethyl-silanyloxy)-ethyl]- 8-hydroxy-1H-quinolin-2-one (g a mmol) in (0 vv) mmol) and sodium triacetoxyborohydride Ya 19 for dd yall was stirred under a nitrogen environment at a temperature (Je 0) Dry DCE Yo 1 hour. The solvents were evaporated in air and the residue was purified by chromatography over silica gel (1: 19: 071) methanol / acetic acid / water / DCM using a mixture of as a thinner to provide the product in the form of very light brown gum. The residue is taken in methanol It is passed and released using a ¥ M ammonia solution in methanol by evaporating the SCX-2 over a cartridge.

YY

The solvent in vacuo is available as a mixture of diastereomers in the form of gum. Yellow/green in colour. 9649 ¢ mg YA = throughput LC-MS (method 2): Rt 2.64 min, m/z 760 [MH+].

YA Mediator No. © 7 0 5-Methylthiazole-2-carboxylic acid I ester . Either 0 (Y 4 ) 14736 « Helv. Chim. Acta. Attended according to 01 Median No

N don

HO S g va (5-Methylthiazol-2yhdiphenyl methanol

THF mmol) in 10.17 +” of medium No. 95) .. g elie to a cold solution of ¢ BY of nitrogen was added 4 drop drop 4 solution 7 mo yy induce (Je V) anhydrous when 0 mmol) YA (phenylmagnesium bromide in diethyl ether) 4. ml 0 min. after 70 addition; The reaction mixture was allowed to warm to room temperature, stirred for 1 molar time, and extracted twice with 1 110 diethylene! this period; The solution is poured over ether. The combined organic layers were washed with saturated sodium hydrogen carbonate with water and brine, dried (magnesium sulfate) and evaporated. The remainder displays 0 (water).

Ethyl acetate in 9600 g) and leaching by Er 0 for column chromatography (silica).

LC-MS (Method 6): R; 3.20 min, m/z 282 [MH].” “H NMR, 400 MHz, DMSO-dg: 7.4 (1H, m), 7.3 (4H, m), 7.3-7.2 (6H, m), © 7.1 (1H) , s) and 2.4 (3H, (0

YY median number 0 9:

Methanesulfonic acid 2-(4-methyl-benzyloxy)-ethyl ester 3007 Prepared in a manner similar to that described in Journal of the American Chemical Society 0 L (Y A) 06 +

LC-MS (Method 4): Rt 2.44 mins, no molecular ion observed.

YY Median No

Cl 0 5

Methanesulfonic acid 2-(4-chloro-benzyloxy)-ethyl ester '© . 1? Prepared in a manner similar to medium No. ; No molar ion observed LC-MS (Method 2): Rt 3.34 mins

YY Median No

Cl

To b 0 5

Cl ~"0"0

Methanesulfonic acid 2-(4-chloro-benzyloxy)-ethyl ester | 00 . 31 Prepared in a manner similar to the mediator

LC-MS (Method 4): Rt 3.59 mins, no molecular ion observed.

Yevyev

m of intermediate VE number 1-Benzyloxy-3-methyl-3-phenoxybutane: to a solution of aa £. YY ) (3-methyl-but-3-enyloxymethyl)-benzene ¢ © 77.4 mmol) and phenol (7.75 g - 77.5 mmol) in 01 ml Cala DCM was added under 1.887 ( BF3. E20 ( pas sal ml; £.YA mmol). The solution was stirred at ambient temperature overnight; water was added or the phases were separated. The aqueous phase was extracted by (Y) DCM once) and the organic layer was dried (magnesium sulfate) and the solvent was separated. To save oil. The crude product was purified by silica gel column chromatography and clarification by malt from 0 cyclohexane to 706 diethyl ether in cyclohexane. Yield = 0.4 g (£9611 . LC-MS (method no.): residence time 4.49 min; No molar ion was observed. Intermediate No. Yo SG. 2# 3-Methyl-3-phenoxy-butan-1-0l 0 Palladium hydroxide was added. (7) supercarbon (BY) by weight (150 mg) of a flask under an inert environment; Tracked by cold IMS (© (Je) and 3-benzyloxy-1,1- +.YY) dimethyl-propoxy)-benzene 1 g 7.7 mmol) sys El. Cleaned with hydrogen ( times) and the mixture was stirred at ambient temperature overnight under a Te balloon of hydrogen . The mixture was filtered through celite through an inert environment and the filtrate was evaporated to provide VO of the crude product, which was purified by column chromatography using a slant from cyclohexane to . Diethyl ether in cyclohexane 0 . 96 VE mg VY = yield method number; ): survival time 7.89 min; No molar ion was observed. (LC-MS 77 argument number 0

CL Mo2 7 0 0 0

Methanesulfonic acid 3-methyl-3-phenoxy-butyl ester . 17 The named compound is prepared according to the method described for the preparation of mediator No. . 96797 mg = 71 yield per minute; No molar ion was observed. YEO Method No. ? : residence time (LC-MS 0

YY Median No

N

2 1

HO 0 ا ه ه ه 9-{[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-methyl- amino}-nonanal 0 . 11 It is prepared according to the method used to prepare the medium No. (9659) gm = 0.75 throughput .min; VEY method No. : residence time (LC-MS) Examples a!

N N N

Ra | A no blah | P8 and RA! > 1 9 HOT Hol, © “To Hol, © _ NR 0 Re RP Rr” R® C Re (In (I-a) (I-b) 0 Scheme No. 0. The following vehicles are to be brought using the lane Shown in chart No. 1 is an example of No

HO N

0 duck N \ Oo (5-Dimethylaminomethyl-oxazol-2-yl)-diphenyl-methanol. (I-a): R®, R® =

Ph, R°, RY = CH, molar THF in 1 ml of a solution (+.¥e) Phenylmagnesium bromide was added (-5) from (Ruste) AE (5"._mmol) (median no. ) dimethylaminomethyl-oxazol-2-yl)-phenyl-methanone | 0 1015© Cold for ls the mixture. (Ja \ .0) dry THF mmol) in Je (5 0 1 0 0 g) THE molar in 1 hour and then add phenylmagnesium bromide (+08 ml) of solution; . mmol) point by point. The mixture was stirred at zero degrees Celsius for half an hour, and then treated with an excess of saturated (aqueous) ammonium chloride solution. the mixture was extracted by bitter) and the combined organic phase was washed with brine; Sulfate 7 (DCM Vo and Sodium HPLC) was dried; the solvent was separated to provide the crude product. Purification was performed by .18.5 min over TFA 96 +) with 9676-5 acetonitrile/water. contains. ) TFA g (9679; as salt = 014) Throughput LC-MS (Method 1): Rt 5.56 min, m/z 309 [MH"] LC-MS pips (Method 3): Rt 1.72 min, m/z 309 [MH] AR vy 'H NMR (DMSO-dg): 6 2.74 (s, 6H), 4.48 (s, 2H), 7.25-7.37 (m, 10H), 7.40 (s, 1H), 10.23 (br s, 1H) For SCX-2, a sample of this substance is converted to a free base by passing through a cartridge of molar / methanol (7 times) to provide compound 1 through methanol (once), and then ammonia Requirement as a white solid © Residency time 0.28 minutes: (Method No. 1) LC-MS

LC-MS (Method 1): Rt 5.68 min, m/z 309 [MH] '"H NMR (DMSO-dg): § 2.12 (s, 6H), 3.47 (s, 2H), 6.98 (s, 1H) , 7.02 (s, 1H) 7.22-7.34 (m, 10H).Example No. 0

N 0 Mousse Gel 0 Solution HO / JA.

J a [2-(Hydroxy-diphenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium formate. (I-b): R* = R° = Ph, 89 = CHa, 85 = -3

Phenoxypropy|. 1 (Example No. 5-dimethylaminomethyl-oxazol-2-yl)-diphenyl-methanol a solution of 0 (de +20) mL) and chloroform (oF) mmol) in acetonitrile (178 ¢ aaa YE) mmol) and stirred a mixture of “YY 0 µl ¥V) 3-phenoxypropyl bromide treated with ¥Y hour for Angie reaction at room temperature overnight and then at 00 °C preparatory and decantation By HPLC the volatile substances are evaporated and the crude product is purified by 0. Yo-Yo oY.% acetonitrile/water containing 000% formic acid during Yo min yield = 4 mg LC-MS (Method 1): Rt 7.56 min m/z 443 [11]

}

Ya

H NMR (MeOD): § 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, 1H), 7.24-7.38 (m, 12H), 7.56 (s, 1H), 8.51 (brs, 1H).

CLS all is prepared by a similar method using the following procedure shown in Scheme No. ? Lia: oo

N.R

3 (5- L (CDCl3): 2.31 (s, | (Method

Methylaminometh 3H), 3.06 (br s, 3): Rt No HON 2H), 3.68 (d, 2H), | 1.44min yl-oxazol-2-yl)- CJ 2 6.81 (s, 1H), - 7.25 , m/z diohenvi-8 7.36 (m, 10H). 217 p l [MH] methanol. (I-a):

R? RP = Ph, R® =

H, RY = CHa.

N NT N wo Jom 0 very much ts A 6

HoT, Br 07100 OE HoT gh (vi) R (I-a) (I-b) . + The following vehicles are to be brought using the lane shown in Scheme No. ¢ Example No. 1 0

HO N

+

N

\

Cyclohexyl-(5-dimethylaminomethyl-oxazol-2-yl)-phenyl-methanol. (I-a):

R?, = Ph, R® = ¢c-Hexyl, R® = CH,

YEYY va (5-bromomethyl-oxazol-2-yt)-cyclohexyl-phenyl-methanol solution of

Y was treated with a solution of THF (g ¢ 9.7 mmol) in £0 ml of (YY) 9 (medium No. mmol). The suspension is formed after Av; 56 mL (56 M THF) of dimethylamine in the reaction mixture is kept at room temperature overnight and then ALE is stirred for minutes. The solid is filtered and discarded. The filtrate is concentrated under pressure Reduced and the residue is divided between 0 (and a saturated sodium hydrogen carbonate solution. The organic layer is dried DCM. Sodium sulfate) and evaporated to provide the titled compound as a solid. (9695) Yield = 7.74 g

LC-MS (Method 1): Rt 6.57min, m/z 315 [MH] 'H NMR (DMSO-de): 8 0.92-1.29 (m, 6H), 1.42-1.74 (m, 4H), 2.10 (s , 01 6H), 2.22 (m, 1H), 3.45 (s, 2H), 5.90 (s, 1H), 6.98 (s, 1H), 7.18-7.22 (m, 1H), 7.27-7.34 (m, 2H) , 7.40-7.46 (m, 2H). cyclohexyl-(5-dimethylaminomethyl-oxazol-2-yl)-phenyl- enantiomers from chiral preparative HPLC (Example #4) (7.74 g) are separated by 01800 tris amylase (3,5-) by Lie 1 mm Yo X You using a Keralbak Vo column (the column like Wh) fixed on top of © 1 micromol dimethylphenylcarbamate gel). 11 ml/min diethyl ether in 96 100 by 960 ethanol in heptane equilibrated with: (© min) providing (example number Ao = first leaching enantiomer) (residence time). As a white solid © Example No. 0 9 (3

AN

71. (9671) EGP 0.77 = productivity

Ae

R)-cyclohexyl-(-5 min) provides 0017 = second larval enantiomer (residence time dimethylaminomethyl-oxazol-2-yl)-phenyl-methanol (I-a): R®, = Ph, R° = c- . White solid (+1) Example Hexyl number, RS, R%= CH, + number be

H...N 0

N

> Hat. (%¥A) g 1 ". ¢ = Yield 'H NMR (CDCls): 8 1.10-1.39 (m, 7H), 1.62-1.76 (m, 3H), 2.25 (s, 6H) , 2.29-2.35 (m, 1H), 3.54 (ddas, 2H), 3.70 (br.s, 1H), 6.84 (s, 1H), 7.24 (t, 1H), 7.33 (t, 2H), 7.64 (d , 2H).1 1 Example No

N.A

C0, 0 / A

Br

QO ~) [2-((S)-Cyclohexyl-hydroxy-phenyi-methyl)-oxazol-5-yimethyi]-dimethyl-(3- phenoxy-propyl)-ammonium bromide. (I-b): R* = Ph, cat = c-Hexyl, R® = p

CHa, R® = 3-Phenoxypropyl. 0 (S)-cyclohexyl-(5-dimethylaminomethyloxazol-2-yl)-phenyl- a solution of 3-phenoxypropyl mmol) and 114 ¢ aa v.07) (© No. Ji) methanol

Y) and chloroform (de 01"(mmol) in acetonitrile 1 ¢ g .71©) bromide was allowed to stand at room temperature for 1 day. The solvent was separated to obtain (Ja

YeXVY

A)

Y 0 DCM Crude product. Purification is done by 5 column chromatography by serial clarification. DCM methanol at 90 0 ; Hence, 96011 AD. (9647) productivity = 04 mg

LC-MS (Method 1): Rt 8.32 min, m/z 449 [M*] 'H NMR (CDCla): § 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 (das, 2H), 6.85 (d, 2H), 6.98 ) 1H), 7.20 (t, 1H), 7.26-7.30 (m, 4H), 7.55-7.58 (m, 3H).

A Example No

N

BL / wo © SN

Br ~) 1 [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yimethyll-dimethyl-(3- phenoxy-propyl)-ammonium bromide. (I-b): Ph = 88, cat = c-Hexyl, R® = p

CHa, R® = 3-Phenoxypropyl (R)-cyclohexyl-(5-dimethylaminomethyloxazol-2-yl)-phenyl-(3-phenoxypropyl mmol) and 0.71 mg (1A) ( TA (eg methanol 00 and acetonitrile (Je V1.0) mg + 2.44 mmol) in chloroform VEL) bromide until dryness RM 1 h. The concentration of YY (ml) is heated at 00 degrees 4540 for a period of (9). To provide a sticky oil without color; Which is grinded with diethyl ethyl ester to provide a white gum, to provide DCM / methanol %Yo-Y.0, and purified by column chromatography and clarification by day. 1-7 °C is available for a period of time. . Air dry at 00. White solid substance. (96876) mg VEY Throughput for LC-MS (Method 1): R; 8.41 min, m/z 449 [MH"]

AY

'H NMR (CDClz): 5 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 (1, 2H), 4.14 (br.s, 1H), 5.20 (ddag, 2H), 6.85 (d, 2H), 6.98 (i, 1H) , 7.19 (t, 1H), 7.26-7.30 (m, 4H), 7.55-7.58 (m, 3H). q Example No. ©

N

but a / : 0 ¥

HO' A Wei 00 Je [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3- phenoxy-propyl)-ammonium tosylate. (I-b): R* = Ph, R® = c-Hexyl, R® = CHs.,

R® = 3-Phenoxypropyl. 3-phenoxypropyl But using A for the method used in Example No. Why 0 is present. 3-phenoxypropyl bromide instead of tosylate. 96860 Productivity

LC-MS (Method 5): R; 7.72 min, m/z 449 [MH]". (s, 3H), 3.03 (s, 3H), 3.04 (s, 3H), 3.33-3.39 (m, 2H), 3.99 (t, 2H), 0 4.76 (s, 2H), 6.10 (s, 1H) , 6.92 (d, 2H), 6.96 (t, 1H), 7.11 (d, 2H), 7.22 (t, 1H), 7.31 (dt, 4H), 7.45-7.49 (m, 4H), 7.54 (s, 1H).1 Example No

N

: 6 Ny

HO" CC NO TJ 0 0

Ho—{ _0

AY

[2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl})-oxazol-5-yimethyll-dimethyl-(3-phenoxy-propyl)-ammonium (Z)-3-carboxy-acrylate. (I-b): R* = Ph, p = cat R® = 3-Phenoxypropyl. Roa = R® cat, aporoic silver oxide mixture (1)04 mg ¢ + .Y0 mmol) and [(R)-2-(cyclohexyl- hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-© (LM01) mg ¢ 20 + mmol) in water (Y10) (A (Example No. ammonium bromide tC mg; 8 A) at room temperature for ½ hours. Malic acid (ls mmol) was added to the reaction mixture; and followed up with methanol (10 ml). The suspension was stirred vigorously at room temperature for 1 hour, and then filtered through celite and lyophilized to provide the labeled compound as ala 1 0 white in colour. ,. 9 AY = Throughput LC-MS (Method 5): Rt 7.92 min, m/z 449 [M*] 'H NMR (CDCls): § 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 (ddag, 2H), 6.20 (s, 2H), 6.83 ( d, 2H), 6.96 (t, 1H), 7.19 (1, 1H), 7.25-7.30 (m, 4H), 7.47 (s, 1H), 10 7.55 (d, 2H). Example No. 11 is prepared according to the method used in Example No. 01, but by using succinic acid in place of maleic acid representing / 1 bH HO Be Sala TT 0 0 Ye

YEVY

How much [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yimethyl]-dimethyi-(3- phenoxy-propyl)-ammonium 3-carboxy-propionate. (I-b): R? =Ph, RP = c- R® = CHa, R® = 3-Phenoxypropyl C Hexyl, yield = 96997 . LC-MS (Method 5): Rt 7.90 min, m/z 449 [M*] ° '"H NMR (CDCls): 8 1.03-1.35 (m, 6H), 1.42-1.45 (m, 1H) , 1.59-1.73 (m, 3H), 2.22-2.33 (m, 3H), 2.46 (s, 4H), 3.14 (s, 6H), 3.52 (m, 2H), 4.00 (m, 2H) , 4.93 (ddag, 2H), 6.84 (d, 2H), 6.97 (t, 1H), 7.19 (1, 1H), 7.26-7.30 (m, 4H), 7.48 (s, 1H), 7.55 (d , 2H). OH ~ 0 0 [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yimethyl]-dimethyi-(3- phenoxy-propyl)-ammonium (S)-3- carboxy-2-hydroxy-propionate (I-b): R?1 =Ph, R® = c-Hexyl, R°, 88 = CHa, R® = 3-Phenoxypropyl yield 8 970. LC-MS ( Method 5): Rt 7.90 min, m/z 449 [M*] 'H NMR (CDCl3): 5 1.02-1.34 (m, 6H), 1.38-1.47 (m, 1H), 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 (brs, 0 2H), 3.98-4.10 (m, 3H) , 4.85 (br.s, 2H), 6.84 (d, 2H), 6.96 (t, 1H), 7.18 (1, 1H), 7.25-7.29 (m, 4H), 7.47 (s, 1H), 7.54 (d, 2H). Example number VY rm YEYY

Ao

HO0SN+

Cyclohexyl-(5-{[methyl-(3-phenoxy-propyl)-amino]-methyl }-oxazol-2-y1)- phenyl-methanol. (I-a): R®, = Ph, R® = c-Hexyl, Ki = CH, R¢ = 3-Phenoxypropyl (intermediate No. (5-bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl- methanol mixed with (©Y¥) N-methyl-3-phenoxy-propylamine 0 mmol) +. YAT plural VY) (4 ©

CY (mmol) + diisopropylethylamine (10 µl) 1.74 mg ; h. Mixture 0178 at room temperature for li (Je Y) THF mmol) in the reaction is treated with saturated sodium hydrogen carbonate solution (aqueous) and the organic phase The combined organic layers are washed. DCM season. The aqueous layer is extracted with brine; desiccant (sodium sulfate); Filter and concentrate until dry to provide a pale brown 0 oil. Purification by column chromatography over silica gel using a fluid from . As a thinner, the compound entitled DCM Colorless Oil / Ethyl Acetate 9670-0 is available. 9660 Throughput LC-MS (Method 1): Rt 8.61 min, m/z 435 [1/[ 'H NMR (CDCl): 6 1.09-1.39 (m, 7H), 1.61-1.74 (m, 3H) , 1.96 (p, 2H), Vo 2.27-2.33 (m, 4H), 2.53 (t, 2H), 3.67 (s, 3H), 3.99 (t, 2H), 6.83 (s, 1H), 6.89 (d, 2H), 6.94 (t, 1H), 7.20-7.33 (m, 5H), 7.63 (d, 2H).

VE Ex. cyclohexyl-(5-{[methyl-(3-phenoxy-propyl)-amino]- in narimoytnyala; they dissociate in a similar way) 11 (Ex. methyl}-oxazol-2- yl)-phenyl-methanol 00 heptane + ) + 96 diethyl ethanol Jed 9600 for example No.; and amelioration by a minute) AY = Amen. The first mesenteric enantiomer (residence time).

AT

(S)-Cyclohexyl-(5-{[methyi-( 3-phenoxy-propyl)-amino]-methyl}-oxazol-2-yl)-phenyl-methanol. (I-a): R? = Ph, cat = c-Hexyl, 88 = CH, RY = 3-

Phenoxypropyl.

N

O.D

0

HO:SN©~)

LC-MS (Method 1): Rt 8.44 min, m/z 435 [MH] ° "H NMR (CDCl): 5 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, 1H), 6.89 (d, 2H), 6.94 (t , 1H), 7.20-7.33 (m, 5H), 7.63 (d, 2H).

Yo example number min) provides Ve.q4 = second enantiomer (residence time Ye (R)-Cyclohexy!-(5-{[methyl-(3-phenoxy-propyl)-amino |-methyl}- oxazol-2- yh-phenyl-methanol (I-a): R?, = Ph, R° = c-Hexyl, R® = Rona RY = 3-

Phenoxypropyl

N

sans mo © A ~) 1 ©

LC-MS (Method 1): Rt 8.51 min, m/z 435 [MH] '"H NMR (CDCla): 6 1.09-1.39 (m, 7H), 1.61-1.74 (m, 3H), 1.96 (p, 2H), 2.27-2.33 (m, 4H), 2.53 (1, 2H), 3.67 (s, 3H), 3.99 (t, 2H), 6.83 (s, 1H), 6.89 (d, 2H), 6.94 (i , 1H), 7.20-7.33 (m, 5H), 7.63 (d, 2H).y using the path shown in Scheme No. ¢ Ailes The following example compounds are prepared by Ye 7" HNMR] ToS method

AY mpl p 16 Cyclohexyl-(5- (CDCl3): 6 1.05- | (Method 3): 1.42 (m, 7H), | Rt2.13 and methylaminometh HoJ__N 1.57-1.81 (m. 2.20min, yl-oxazol -2-yl)- 54 3H), 2.31 (m, m/z 301 "1H), 2.42 (s, [MH] phenyl-methanol. 3H), 8.30 (d (1-a): R* = Ph, Qom 2H), 6.85 (s, 1H), 7.21-7.27 = c-Hexyl, R® = on 1H), 7.31-

CHa, 5" - 7.37 (m, 2H), 7.60-7.66 (m, 2H). Rt2.1min, imethylaminome HON 225 (6H,s),|m/z301 thyl-oxazol-2-yl)-oy / 2.95-3.07 (1H, [MH]

N m), 3.46-3.60 phenyl-methanol. (2h. 2xd). 3.72 (1-a): 88 - Ph, R° (1H, bs), 6.84 1H, s), 7.19- = c-Pentyl, 07 = 2s i m)

RY = CH, 7.28-7.36 (2H, m), 7.59-7.65 (2H, m). 18 | Cyclopentyl-(5- (CDCl): § 1.14- | (Method 2): ; ; 1.76 (9H, m), | Rt2.1min, dimethylaminome HON 2.25 (6H.5) m/z 301 thyl-oxazol-2- yl)-L 2 2.95-3.07 (1H, [MH] \ m), 3.46-3.60 phenyl-methanol QH. 2xd), 3.72 — first eluting (1H, bs), 6.84 enantiomer (1-a): itm,

R*= Ph, 85 = c- 7.28-7.36 (2H,

Pentyl, R° = km = m), ot

CHj 191 Cyclopentyl-(5- (CDCls): 8 1.14- | (Method 2): ; : 1.76 (OH, m), | Rt2.1min, dimethylaminome HOJ MN 2.25 (6LL 5), m/z 301 thyl-oxazol -2-yl)- 61 / 2.95-3.07 (1H, [MH] viv N m), 3.46-3.60

AA phenyl-methanol (2H, 2xd), 3.72 4 eluti (1H, bs), 6.84 — second eluting (1H, 5), 7.19- enantiomer (1-a): 7.28 (1H, m), 7.28-7.36 (2H) ,

R®=PhR=c-m), Ti0565

Pentyl, R= R% = (2H, m).

CHs

Cyclohexyl- (CDCl): § 1.04- | (Method 2): henyl-(5- 1.50 (10H,m), | Rt2.21 and pheny HOS N 1.50-1.85 (6H. | 2.35min, piperidin-1- 64 Oy m), 2.23-2.51 m/z 355. (SH, [MH"] ylmethyl-oxazol- m)3.61QH.5) 2-yl)-methanol. 3.67 (1H,s), 6.82.phg _ b (1H, s), 7.19- ( 1-a): R®=Ph, R 7.28 (1H, m), = ¢-Hexyl, R® = 7.28-7.37 (2H,

RC = Piperidinyl m), [rt 21 Cyclohexyl- (CDCl): § 1.04- | (Method 2): i 1.50 (10H,m), | Rt2.21 and phenyl-(5b N 1.50-1.85 (6H. | 2.35min, piperidin-1- J,his l 2232511 5 ylmethyl-oxazol- ~ (SH, m),3.54- (MH) 3.70 (3H, 2xs), 2-yl)-methanol - 6.82 (1H, s), first eluting gids enantiomer.(1-a): (2H, m), 7.60-

R® — Ph, RP = C- 7.67 (2H, m).

Hexyl, R° = 89 =

Piperidinyl 22 Cyclohexyl- (CDCl): 3 1.04- | (Method 2):

JE. 1.50 (10H,m), | Rt2.21 and phenyl-(5 HOS AN 1.50-1.85 (6H, 2.35min, piperidin-1- 2g m), 2.23-2.51 m/z 355 + ylmethyl-oxazol- 390.1381 aes [MI] 2-yl)-methanol - 6.82 (1H, s), vey 7.19-7.28 (1H,

mouth (second eluting m), 7.28-7.37 enantiomer. (1-a): oi Ph, 85 = c- Co = ch Hexyl, R®=R%= Piperidinyl Cyclohexyl- (CDCl5): 8 1.04- | (Method 2): 23 sr 6. =o Lm | ls pyrrolidin-1- Ue m), 2.23-2.37 m/z 341 ylmethyl-oxazol- Certo [MH] 2-yl)-methanol. 3.65 (1H, s), (1a): Re = Ph, B° 685 (IHL). c-Hexyl, R® = 7.20-7.28 (1H, = RY = Pyrrolidiny! on. [ely] (2H, m).7.66 Cyclohexyl- (CDCl): & 1.04- | (Method 2): 24 me wim A 6 sar pyrrolidin-1- J Ao m), 2.23-2.37 m/z 341 ylmethyl-oxazol- Cer cit om, [MH] 2-yl)-methanol - 3.69 (2H, s), first eluting b5).6.85 (IF.5). enantiomer . (1-a): 7.20-7.28 (1H, =m es BS Hexyl, R®= 89 - 7.66 (2H,m). Pyrrolidinyl Cyclohexyl- (CDCl): 8 1.04- |( Method 2): 25 i ar 6 Fe pyrrolidin-1- Lo m), 2.23-2.37 m/z 341 ylmethyl-oxazol- eit om [MH'} 2-yl}- methanol - 3.67-3.77 GH, second eluting ne 08 On Vey enantiomer. (1-a): (1H, m), 728 q.

R* = Ph, 45 2 6- 7.36 (2H, m), 7.59-7.66

Hexyl, R® = R%= (2H,m).

Pyrrolidinyi 26 [5-(4-Phenoxy-© (CDCl;): 6 1.82 | (Method 1):

Co (m, 2H), 1.97 | Rt 7.89min, piperidin-1- HON (m, 2H), 2.34 m/z 441 ylmethyl)-oxazol- L 5 (re (m, 2H), 2.71 [MH] 2-01-0060 N TA (m, 2H), 3.65 (s, -yl]-diphenyl- 2H), 4.17-4.33 methanol.(1-a): (m, 2H), 6.87 (d, a_nb_ 0 2H), 6.93 (,

R*=R"=Ph,R 2H), 7.24-7.38 =RY=4- (m, 12H).

Phenoxy- piperidinyl 27 {5-[(Benzyl- (CDCl3) 6 1.36, | (Method 4) methyl-amino)- 1 (1H, m), 1.44- Rt 2.63 min, fa 1 on or m/z 377 yl}-cyclopentyl-0 / . , S), MH" phenyl-methanol. Bh" | 3020Hm) (MH) (I-a): R*=Ph,R" = 3.49 (2H, 5), c-Pentyl, R° = CHj, 3.64 ( 2H, s),

RY = Benzyl 3.69 (1H, s), 6.84 (1H, s), 7.24-7.35 (8H, m), 7.65 (2H, m). 28 {5-[(Benzyl- (DMSO-dg) 6 | (Method 1): methyl-amino)- 1.19, (1H, m), | Rt 7.54min, methyl]-oxazol-2-HO. MN 1.37 (2H, m), m/z 377 yl }-cyclopentyl- 64 / 1.51 (3H, m), [MH] phenyl-methanol - “) 1.63 (2H, m), second eluting 2.08 (3H, s) , enantiomer. (I-a): 2.94 (1H, m),

R*=Ph,R’=c- 3.41 (2H, d,J =

Pentyl, R = CHj, 2.7Hz), 3.58

R? = Benzyl (2H, s), 5.99 (1H, s), 7.02 (1H, s), 7.24, (4H, m), 7.31 (4H, m), 7.46 (2H, m).

29 {5-[(Benzyl- (DMSO-dg) 8 | (Method 1): methyl-amino)- 1.19, (1H, m), | Rt7.29min, methyl]-oxazol-2- HOS N 138 2H, m),| m/z377 yl}-cyclopentyl- 0 54 / 1.51 (3H, m), [MH] phenyl-methanol - Hb” 1.63 (2H, m), first eluting 2.08 (s, 3H), enantiomer. (I-a): 2.94 (1H, m),

R*=Ph, R® =c- 3.41 (2H,d,J =

Pentyl, R° = CHj, 2.8Hz), 3.58

RY= Benzyl (2H, s), 5.99 (1H, s), 7.02 (1H, s), 7.23, (4H, m), 7.32 (4H, m), 7.46 (2H, m). | [2-(1,1-Diphenyl-a (CDCl3) 82.17 | (Method 1):

N (s, 3H), 2.21 (s, | Rt 6.57min, - -5- ethyl)-oxazol-5 BYR 6H). 3.51 (s,| m/z 307 yimethyl]- IY 2H), 6.91 (s, [MH] dimethyl-amine 1H), 7.15 (m, ' 4H), 7.21-7.32 (I): R*=R° = (m, 6H).

Ph, R°= R= Qm = CHs 31 [2-((S)- Q (CDCl3) 8 1.01- | (Method 1): ِ N= NL 1.39 (m, 7H), | Rt 8.05min ,

Cyclohexyl HO 8 Hsam 1 65 (m, 3H), m/z 419 hydroxy-phenyl- 0 or 2.30 (m, 2H), [M'] B 3.13 (t, 2H), methyl)-oxazol -5 3.32 (5.3H), yimethyl]- 3.33 (s, 3H), ] 3.66 (m, 2H), dimethyl 5.21 (dd, 2H), phenethyl- 7.16-7.32 (m, .8H), 7.53 (m , ammonium 3H). bromide. (I-b): R® = Ph, 85 = p Hexyl, 85, R® = ©, R® = 2 -

Phenethyl

YeYY

32 [2-((R)- (CDCl5) § 1.02- | (Method 1): } N | 1.38 (m, 8H), | Rt 7.93min,

Cyclohexyl on CX On 166 (m, 3H), | mz419 hydroxy-phenyl- 2.30 (brs, 1H), 17 ] = Br 3.12 (br s, 2H), methyl)-oxazol-5 3.32 (brs. 6H), yimethyl]- 3.67 (brs, 2H), : Z 5.21 (br dd, 2H), dimethyl 7.16-7.32 (m, phenethyl- 8H), 7.53 (m, ammonium 3H). bromide. (I-b): R? =Ph, R®=c-

Hexyl, 85, 88 =

CHa, R® = 2-

Phenethyl 33 [2-((R)- (MeOD): § | (Method 1):

N 1.04-1.40 (m, | Rt 8.12min, - I, s

Cyclohexy! wor A oh | 6m, 1.52-1.81 m/z 397 hydroxy-phenyl-a (m, 10H), 2.41 [M'] thvl)-5.(m,1H), 2.49- methyl)-oxazol-5 2.59 (m.2H) , ylmethyl]- 3.06 (s, 3H), dimethyl-(4- 3.07 (s, 3H), 3.17 (dt, 2H), methyl-pent-3- 4.72 (s, 2H), enyl)-ammonium 4.99 (m , 1H), 7.22-7.28 (m, bromide. (I-b): R? 1H), 7.29-7.36 =Ph, RP = ¢- (m, 2H), 7.48- 7.54 (mm, 3H).

Hexyl, 35, R® =

CHa, R® = 4-

Methyl-pent-3- enyl 34 [2-((R)- (CDCl3): 8 1.07- | (Method 1):

N : 0 clohe I- N / \ >“ | + 1 36 (m, 8H), Rt 8.14 min, y xy HO ANAT 1.59-1.72 (m, m/z 461 hydroxy-phenyl- Br 0 3H), 2.29 (m, [M'] 1H), 3.04 (t, methyl)-oxazol-5- (except 2H), 3.16 (t,

ylmethyl]-[2-(2,3- 2H), 3.32 (s, dihydro- 561 benzofuran-5-yl)- 2H), 4.53 (1, ethyl]-dimethyl- 2a ammonium 1H), 6.96 5 bromide. (I-b): R? ry “iD 754 = Ph, 85 = ¢- (m, 3H).

Hexyl, Rc = R%

CHa, R® = 2-(2,3-

Dihydro-benzofuran-5-yl)- ethyl [2-((R)- (MeOD): § | (Method 1): 0 AA with hydroxy-phenyl- (m, 3H), 1.68 [M7] methyl) -oxazol-5- A Ti 26 ylmethyl]-di 3H), 3.06 (s, methyl-(6-methyl- 3 on o pyridin-2-ylmethyl 2H), 7.25 (tt, )-ammonium oy Sy 739 formate. ( I-b): R® (dd, 2H) 7.50- =Ph, 89 p 3260 (5, 11D,

Hexyl, R®, R® = 7.81 (t, 1H),

CHa, R® = 6- 8.53 (brs, 1H).

Methyl-pyridin-2-ylmethyl 36 | [2-(Cyclopentyl- (CDCl3) 6 1.24- | (Method 1): Lk a |B methyl)-oxazol-5- 0 or m), 2.32 (2H, M7] nar J

Ys dimethyl-(3- 3.64 (2H, m),

p8 phenoxy-propyl)- 4.03 (2H, m), (2H, m), 5.22 . ammonium 6.85 (2H.d), bromide (I-b): R® 6.88 (1H, 1), 7.b_ A 20 (1H, t), 7.25 - =Ph, 8-0 7.32 (5H, m), Pentyl, 85, R® = 7.52-7.60 (3H, CHa, R® = 3- m). Phenoxypropyl [2-(Cyclopentyl- (CDCl3) 8 1.20- | (Method 1): 37 (8H), 2.14 | Rt 7.96min, 1.80 bah N. - hydroxy-pheny! = Hoy (2H.m), 3.00 fg 436 methyl)-oxazol- 5- or (1H, m), 3.35 [M'] (6H, s), 3.64 . yimethyl] (3H, m), 4.04 dimethyl-(3- (2H, s), 5.21 (2H, m), 6.85 ] ] phenoxy-propyl (211.d), 6.98 ammonium (1H, 1), 7.17- (5H, m), 7.32 pH Lh. bromide (I-b): R 7507.62 (3H.=Ph, 89 = ¢-m). , 85, RY = CHa, R® = 3- Phenoxypropyl 1-[2-(Cyclohexyl- 3 (CDCl3) 8 1.01- | (Method 1): |38 i N . 1.38 (8H , m), | Rt 8.77min, - ‎hydroxy-phenyl 0: oro 1.56-1.99 (8H, | m/z 489 methyl)-oxazol-5- 8 m), 2.35-2.38 (M'] (3H, m), 3.41- -3(-1- ylmethyl]-1-(3 3.57 (4H, m), phenoxy-propyl)- 3.65 (1H, s), Cn 3.78- 4.03 piperidinium (4H.m), 5.19 bromide (I-b): R® (1H, d), 5.34 —Ph.

R® = c- (1H, d), 6.81 R© (2H, m), 6.97 Hexyl, R®, RY = (1H, 1), 7.17- Piperidinyl, R® = rena, 3-Phenoxypropy! m).

39 | 1-[2-(Cyclohexyl-Q©.(CDCl3) § 1.01-|(Method 1):

N. 1.38 (8H, m), | Rt 8.78min, hydroxy-phenyl- Ho hoy 1.56-1.99 (8H, rz 489 methyl)-oxazol-5- O o m), 2.35-2.38 [M*] (3H, m), 3.41- ylmethyl]-1-( 3- 3.57 (4H.m), phenoxy-propyl)- 3.71-4.10 (5H,), iperidinium 5.19 (1H, d), pip 5.34 (1H, d), bromide. (I-b): R® 6.81 (2H, m), for o_ 6.97 (1H, 1), 250,11 - © 7.17-7.31 (5H,

Hexyl, R%, R = m), 7.50-7.60

Piperidinyl, R® = (3H, m). 3-Phenoxypropyl | 1-[2-(Cyclohexyl- A (CDCl3) § 1.03- | (Method 1):

N , 1.39 (8H, m), | Rt 8.75min, hydroxy-phenyl- 0 hoy 1.53.1.80 (2H.w/z 475 methyl)-oxazol-5- or m), 2.05-2.44 [M'] -1-)9- (7H, m), 3.48 ylmethyl}-1-(3 (2H.m). 3.62 phenoxy-propyl)- (2H, m), 3.80

Ce (1H, s), 3.99- pyrrolidinium 4.18 (4H, m), bromide. (I-b): 8 5.16 (1H, 4d), - b_ A 5.29 (1H, d), =Ph,R"=c 6.84 (2H,m),

Hexyl, 85, R? = 6.99 (1H, t), i. o 7.19-7.34 (5H,

Pyrrolidinyl, 47 = m). 7.54-7.60 3-Phenoxypropyl (3H,m). 41 | 1-[2-(Cyclohexyl- Q a (CDCl5) 6 1.03- | (Method 1): .N .1.39 (8H, m), | Rt 8.57min, hydroxy-pheny!o>oy 153.1.80 OH ae methyl )-oxazol-5- 0 - m), 2.05-4 [M*] -1-(3- (7H, m), 3.48 ylmethyl]-1-(3 (2H.m), 3.62 phenoxy-propyl)- (2H, m), 3.80

CL (1H, 5), 3.99- pyrrolidinium 4.18 (4H, m), bromide. (I-b): cat 5.16 (1H, d), _b_ 5.29 (1H, d), =Ph, R=c 6.84 (2H,m),

Ye Hexyl, R%, R® = 6.99 (1H, 1),

Pyrrolidinyl, R= | 7.19-7.34 (5H,

EE [TE 42 [2-((R)- (CDCl) 8 0.99- | (Method 1):

Crh Bn 204m | Ron hydroxy-phenyl-m), 2.29 (1H, M*] methyl)-oxazol-5- J an as ylmethyl]-(8- 3.46 (5H,m), methoxy-octyl)- Tiernan dimethyl-m), 7.43 (1H, ammonium m), lb 9 formate. (I-b): Qm = Ph, 85 = ¢-

Hexyl, R, 89 =

CHjs, R® = 8-

Methoxyoctyl 43 [2-((R)- (CDCl3) § 1.05- | (Method 1): cro.a sn hydroxy-phenyl- - (2H,m), 2.34 [M1] methyl)-oxazol-5 - ( Leis 0 yimethyl]- 3.44-3.59 (2H, dimethyi-(4- m), 378 ax > phenoxy-butyl)- 5.15 (1H, ,f( ammonium pp OH > bromide. (I-b): R ® 6.97 (1H, 1), =Ph, R= c- "152766

Hexyl, 85, R% = (3H, m).

CHa, R® = 4-

Phenoxybutyl

YEYV

Vv 44 (2-Benzyloxy-(CDCl)6 1.04- (Method 5):

MLL 1.83 (10H, m), | Rt 7.52min, ethyl)-[2-((R)- HO Noy 2.31 (1H, m), m/z 499 cyclohexyl- - 3.30 (6H, s), [M"] 3.72 (1H.s) .8 ), hydroxy-phenyl- 3.82-4.00 (4H, methyl)-oxazol-5- m), 4.56 (2H, s), 4.98-5.26 (2H, ylmethyl]-m), 7.20- dimethy!- 7.41(8H, m), i 7.44 (1H, s), ammonium 7.56 2H.d), bromide (I-b): R? = Ph, R® = p Hexyl, p = p

CHs, R® = 2-

Benzyloxyethyl [2-((R)- N (CDCl3) 8 1.04- (Method 5): } but “1.85 (14H, m), t 7.79min,

Cyclohexyl HO™ 231 (1H, m), m/z 447 hydroxy-phenyl- a 2.70 (2H, v), (M"] ] = 3.12-3.44 (8H, methyl)-oxazol-5 m), 3.65 (1H, 5), ylmethyl]- 5.10 (1H, 4d), : A 5.28 (1H, 4d), dimethyl-(4 7.11-7.37 (8H, phenyl-butyl)-m), 7.46 (3H, ammonium m ).bromide (I-b): R? = Ph, 85 = p Hexyl, 85, RY =

CHs, R® = 4-

Phenylbutyl 46 [2-((R)- N (CDCl3) § 1.01- (Method 5): ] Na, 1.41 (8H, m), | Rt7.51min,

Cyclohexyl 00 MST 1.56-1.80 (2H.m/z 467 hydroxy-phenyl- or F m), 2.25-2.39 [M'] 0b" (3H, m), 3.34 methyl)-oxazol-5 ( 6H.5).3.50.

Y sy ylmethyl]-[3-(4- 3.70 (2H, m),

fluoro-phenoxy)- 3.92-4.05 (3H, propyl]-dimethyl- mw), a rh o ammonium 6.75-6.82 (2H, bromide. (I-b): 8 om oo! =Ph, R® = c- 7.33 (3H) m),

Hexyl, FC, RE = 7.51-7.60 cH, and R® = 3-(4-

Fluorophenoxy)- propyl 47 [8-(tert- (CDCl3) 8 1.02- | (Method 5): suoearbon Bok lt my | Reso methyl-amino)- M 2.70 (3H, s), [M+] octylH2-( (R)- 297335 (101 cyclohexyl-m), 4.82-5.06 hydroxy-phenyl- Om methyl)-oxazol-5- 7.43-7.64 (3H, yimethyl]-m). dimethyl-ammonium methanesulfonate. (I-b): R® = Ph, R® = c-hexyl, R®, RY = Me, R® = 8- (tert- butoxycarbonyl- methyl-amino)- octyl.

Yevy

48 [2-((R)- (CDCl3) §0.98- | (Method 1): 1.35 (6H, m), | Rt 8.27min, - N cyclohexyl for 10 nm 1.46-1.80 (4H, m/z) 433 hydroxy-phenyl- 0 m), 1.88-2.06 [M'] 0 (2H, m), 2.28 methyl)-oxazol-5 Ao (1H 5). 2.55 ylmethyl]- (2H, bs), 2.97 a (6H, 5), 3.07- dimethyl-(3 3.27 (2H, m), phenyl-propyl)- 4.47-5.04 2H, b . s), 7.06-7.39 ammonium (9H, m), 7.46-formate. (I-b): R? 7.61 (2H, m), = Ph, 8.67 (1H, 0)

Hexyl, 85, R% =

CHa, R® = 3-

Phenylpropyl. 49 [2-((R)- (CDCl3) 8 0.98- | (Method 1): ] N 3 1.35 (6H, m), 1 Rt 8.09min, cyclohexyl HO" Sok JL 150-177 (4H, | ~~ m/z 435 hydroxy-phenyl- 1 m), 2.29 (1H, [M"] - 5. H oO m), 3. 14 (6H, 5), methyl)-oxazol-5 3.86 2H. bs), ylmethyl]- 4.35 (2H, bs), : : d 4.93 (2H, bs), dimethyl-(2 6.87 (2H.d), phenoxy-ethyl)- 6.96-7.03 (1H, .m) , 7.13- ammonium 7.19 (SH.m), formate. (I-b): R? 7.44 (1H, s), _ b_ A 7.54 (2H, 4d), =Ph.R"=c 8.64 (Hb s)

Hexyl, 88, R% =

CHa, R® = 2-

Phenoxyethyi (2-{4-[(Tert- (CDCl3) 6 1.00- | (Method 5):

N. - What is 1.80 (19H, m), | Rt 8.11min, butoxycarbon! - A 0 2.29 (1H, m), m/z 562 methyl-amino)- 6 l M 2.73 (3H, 5), [M'] hvil- 0 2.80 (3H, s), methyl]-phenyl} 3.09 (2H.1). vey ethyl)-[2-((R)- 3.18 (6H, s),

Yau cyclohexyl- 3.43-3.58 (2H, ]m), 4.34 (1H, s), hydroxy-phenyl 438 (2H.5), methyl)-oxazol-5- 4.95 (1H, d), 5.05 (1H, d) , ylmethyl]- 7.16-7.29 (TH, dimethyl-m), 7.51-7.57 . (3H, m). ammonium methanesulfonate. (I-b): 88 = Ph, R® = c-Hexyl, C8 R® = CHs, R® = 2-{4- [(Tert- butoxycarbonyi- methyl-amino)- methyl]-phenyl}- ethyl [ 3-(4-Carbamoyl- (DMSO-d¢) | (Method 5): i i AEN 6 0.90-1.30 (6H, | Rt 6.11min, phenoxy) propyl] HO CI ho m), 1.49-1 75 m/z 792 [2-((R)- 8 aala|(4H, m), 2.17- [M'] 0 2.31 (3H, m), cyclohexyl 3.04 (6H.5).hydroxy-phenyl- 3.28-3.43 (2H, =.m), 4.06 (2H, t), methyl)-oxazol-5 477 2H. 8), ylmethyl}- 6.09 (1H, s), . 6.93-6.99 (2H, dimethyl m), 7.15-7.26 ammonium (2H, m), 7.27-ide. (1b): pH 7.35 (2H, m), bromide. ( ) R 7.44-7.50 (2H, =Ph, 9 =c-m), 7.54 (1H, s),

Hexy! Re Re = 7.77-791 (3H, for 3 m).

CHs, R® = 3-(4-

Carbamoyl-phenoxy)propyl

YEVY

011 52 [2-((R)- (CDCl3) 8 0.99- | (Method 1): — Hot im, | wos hydroxy-phenyl- 0 " 3.44 (6H, s), [IM] methyl)-oxazol-5 - 2 OH > ylmethyl]- 5.16-5.27 (2H, fsoazos eT ylcarbamoyimeth m), 7.27-7.33 yI)-dimethyl- Se OM, oo, ammonium 8.21 (1H, 4d), bromide.(I-b): R® 11.40 ( 1H, 5).=Ph, R° = p Hexyl, 85, RY =

CHs, R® =

Isoxazol-3-ylcarbamoylmeth yi 53 [2-((R)- (CDCl3) § 1.02- | (Method 1):

Crane ok a hydroxy-phenyl- - ul m), 2.26-2.42 [M1] methyl)-oxazol-5-© CH RN yimethyl]-[3-(4- | 3.76 (2H, m), methoxycarbonyl- Sp 0 Ky phenoxy)-propyl]- 4.03-4.14 (2H, amot ae ammonium 6.87 (2H, d), bromide. (I-b): R® as _Ph, B® = c- (2H, m), 7.53 -

Hexyl, 86, 89 = an 1 R® = 3-(4-

Methoxycarbonyi-

YsY phenoxy)propy!

01 54 [2-((R)- (MeOD) 8 1.02- | (Method 1): ] dl 1.42 (6H, m), | Rt7.05min,

Cyclohexyl HO" Aor ° 1 5 1 _ 1 82 (4H, m/z 528 hydroxy-phenyl- 8 SL m), 2.27-2.46 [M7] methyl)-oxazol-5- oF py sh and MM), 3.34 - ylmethyl]- 3.54 2H, m), dimethyl-[3-(4- 4.04-4.17 (2H, m), 4.78 (2H, s), sulfamoyl- | 6.98-7.07 (2H, henoxv)-oropvil-m) , 7.17-7.35 phenoxy)-p Py] (3H, m), 7.47- ammonium .54 (3H, m), bromide.(I-b): R? 7.78-7.88 Ny m).=Ph, R® = p Hexyl, 85, RY =

CHa, R® = 3-(4-

Sulfamoyl-phenoxy)propyl [2-((R)- (CDCl3) 8 1.00- | (Method 5):

N ;

Cvclohexvl- NU EAN 1.39 (7H, m), 1 Rt 7.88min, NO NO HO EMAT 1.50-1.77 (3H, m/z 463 hydroxy-phenyi- or m), 2.22-2.37 M'] methyl) -oxazol-5- Cn 5 > »S), J. ylmethyl]- (3H, 5), 3.57 dimethyl-(3-p- (2H, m), 3.75 (1H, s), 3.94- tolyloxy-propyl) - 4.02 (2H, m), ammonium 5.17 (1H, d), 5.34 (1H, d), bromide. (I-b): R® 6.71 (2H, d), —Ph, RP = c- 7.05 (2H, 4d), 6 7.15-7.30 (3H,

Hexyl, R®, 89 = m), 7.51-7.57

CHa, R® = 3-p- (3H, m),

Tolyloxypropyl

YEYY

101 56 [3-(4-Chloro- (CDCl3) § 1.02- | (Method 1): reno son Hokey Lit | ikon [2-((R)- 8 0 m), 2.58-2.38 [M] cyclohexyl- GH oh hydroxy-phenyl- 3.70 (2H, m), methyl)-oxazol-5- 18 ylmethyl]- 5.30 (1H, d), aime a ammonium (5H, m), 7.53- bromide. (I-b): R? 7.59 BH, m). =Ph, R°=c-

Hexyl, 85, R = and R® = 3-(4-

Chloro- phenoxy)propyl 57 [2-((R)- (CDCl3) § 1.02- | (Method 5): — NO wad hydroxy-phenyl- i TL 2.26-2.39 (3H, [M*] methyl) )-oxazol-5- 5 2 ylmethyl]-[3-(3,4- m), 3.86 (1H, s), dichloro- S20 OE phenoxy)-propyl]- 5.33 (1H, 4d), amet E ammonium 7.19 -7.36 (4H, bromide. (I-b): R? m), To = Ph, 85 = p Hexyl, R®, R% =

CHs, R® = 3-(3,4-

Dichloro-phenoxy)propyl

Yevy

Yet: Is it also prepared using the path shown in diagram No.? in

OA Example No. 920 N 0

SUSRS

HO0N

Br 1-[2-(Hydroxy-diphenyl-methyl )-0xazol-5-ylmethyl]-1-methyl-4-phenoxy-piperidinium bromide. (I-b): R* = R® = Ph, Keys R? = Piperidinyl, Co =CH, 0 [5-(4-phenoxy-piperidin-1-ylmethyl)-oxazol-2-yl]-diphenyl- to a solution of mL acetonitrile v.00 mmol was added) in 0.01 mg vo)( Yad, (eg methanol approximately © mmol) of a 96460 by weight solution of methyl bromide in ) de 5

VA acetonitrile. The reaction mixture was heated at 50 °C in a tightly closed vial for 2 hours

Ji for an hour, during which a white precipitate is formed. The solvent is evaporated and the residue is triturated with binary 0 excitation. The solid is recrystallized with acetonitrile to provide the entitled compound as a mixture of 0 of cis: trans isomers as a white solid 1:48 in a ratio of . 961 pounds) yield = 1 mg

LCMS (Method 1): Rt 7.93min, m/z 455 [M*] 'H NMR (CDCl3) 6 2.11-2.37 (m, 4H), 3.15 (s, 3H, minor isomer), 3.30 (s, Vo 3H) ), 3.58 (br s, 4H), 3.67 (br 5, 4H, minor isomer), 4.67 (brs, 1H), 4.71 (brs, 1H, minor isomer), 5.04 (br s, 2H), 5.23 (br s , 2H, minor isomer), 6.87 (d, 2H), 6.91 (d, 2H, minor isomer), 7.02 (t, 1H), 7.26-7.38 (m, 12H), 7.58 (br s, 1H), 7.63 ( br s, 1H, minor isomer). oq No. Je Ye. instead of YA but using Example No. oA prepared according to the method used in Example No. Example No. 17? and represent

YEYY

101 None !L / Br > 0 *

HO N ;

Benzyl-[2-( cyclopentyl-hydroxy-phenyl-methyl )-0xazol-5-ylmethyl] -dimethyl- ammonium bromide. (I-b): R* = Ph, R” = c-Pentyl R®, RY = CH3, R® = Benzyl . (96197) mg 11 = Yield LC-MS (Method 1): Rt 6.70min, m/z 391 [M*]} ° 'H NMR (DMSO-d) 6 1.22 (1H, m), 1.38 (2H, m), 1.52 (3H, m), 1.68 (2H, m), 2.88 (3H, s), 2.92 (3H, $s) 2.97 (1H, m), 4.55 (2H, 50, 4.70 ( 2H, 5), 6.18 (1H, s), 7.25 (1H, m), 7.34, (2H, m), 7.48-7.58 (7H, m).

Te is Example No. but using Example No. 91 instead of oA is prepared according to the method used in Example No. Ye. Example No. 71 represents “Nebo 0 +.”

HO”, N

Benzyl-[2-( cyclopentyl-hydroxy-phenyl-methyl )-oxazol-5-yImethyi]- dimethyl-ammonium bromide. (I-b): R* = Ph, RP = c-Pentyl, R® = 88 = CH,

R® 2 Benzyl (Yoo A ) mg YV= Yield LC-MS (Method 1): Rt 7.30min, m/z 391 [M*]} "H NMR (DMSO-de) § 1.23 (1H) , m), 1.37 (2H, m), 1.52 (3H, m), 1.67 (2H, m), 2.88 (3H, s), 2.92 (3H, 5( 2.97 (1H, m), 4.55 (2H, Ss) ), 4.70 (2H, s), 6.18 (1H, s), 7.25 (1H, m), 7.34, (2H, m), 7.48-7.58 (7H, m).0 +1 Example number \EARY

1 l l

HO", 0 N NNT N and 9 H 5-0 H-ClI 0 [2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(8- methylamino) -octyl)-ammonium methanesulfonate hydrochloride salt.(I-b): R* =

Ph, R = c-Hexyl R® = R® = CH3, R® = 8-Methylamino-octyl 0 [8-(tert-butoxycarbonyl-methyl-amino)-octyl]-[2-((R)-cyclohexyl- Dissolve hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-ammonium 1 110! ml of +1 mg; 008+ mmol) at (01) (8V) (Ex. Molar methanesulfonate in dioxane). The solution was stirred at ambient temperature overnight. The solvent was separated and the crude product was purified by silica gel column chromatography ¢ and clarified by Ve gradient. To provide the entitled compound as a solid DCM / methanol 96710 up to DCM from (%tY) mg YY = throughput LC-MS (Method 1): Rt 5.50, m/z 456 [ M"] 'H NMR (CDCl) § 1.01-2.19 (22H, m), 2.33 (1H,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- 0 7.36 (3H, m), 7.46-7.60 (3H, m), 9.31 (2H, s).

Ty example number uh a

TO

0 no no _ — 5 -0 Cl 0 but using Example No. A replaces IR according to the method used in Example No. asd and represents EV sold Example No. 0

101 [2-((R )-cyclohexyl-hydroxy-phenyl-methyl )-0xazol-5-ylmethyl [-dimethyl-[2-(4- methylaminomethyl -phenyl)-ethyl}-ammonium methanesulfonate hydrochloride. (I-b): R* = Ph, R® = c-Hexyl, R®, RY = CH, R® = 2-(4-Methylaminomethyl- phenyl)-ethyl . 96 51 = Productivity oe

LC-MS (Method 5): Rt 4.64min, m/z 462 [M*] “HNMR (MeOD) 6 1.01-1.41 (6H, m), 1.50-1.81 (4H, m), 2.39 (1H, m) , 2.69 (3H, s), 2.71 (3H, s), 3.08-3.27 (8H, m), 3.39-3.57 (2H, m), 4.19 (2H, 5), 7.20-7.35 (3H, m), 7.39 -7.59 (7H, m).1 0

N N N ra A Solve A Solve R°

HO 0 CN Si HO 0 NH, J 0 N

RP R® 2 HO R® Re (1X) (to) (1-d)

N i Ad m HO b ml (l-e) 17 chart no

LY Vehicles for the following example are brought using the route shown in Scheme No. > Example No

HO. yale 0 NH,

Vo[5-(2-Amino-ethyl)-oxazoi-2-yl l-cyclohexyl-phenyl-methanol. (I-c): R® = Ph,

R® = c-Hexyl [2-(cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yI}- to a solution of preheated mL) Yo) THF mg; ? mmol) in 101 (VY (median No. 86 rrpy oY) at 00 °C a solution of the borane-dimethylsulfide Ye complex was added dropwise

01 minutes from 00 ; ; mmol). The mixture is heated until reflux for a period of THF from? Molar V was then allowed to cool to room temperature. The mixture was then cooled in an ice bath and quenched in a standard 1) and followed with hydrochloric acid (Je 0) by adding methanol drop by drop and then equilibrated with sodium carbonate Yo This mixture was stirred for 0 (Je 1 (Jo Av) and ethyl acetate (da Av) saturated aqueous hydrogen. The mixture is partitioned between water © twice) and the combined organic layers are dried Jeo) ethyl acetate is extracted all ; SCX for oil. The residue was purified by a DAD cartridge over sodium sulfate, filtered, washed with methanol, and then clarified with ammonia; Standard in methanol to provide . The compound entitled as colorless oil. (9677) productivity = 500 mg 0

LC-MS (Method 2): Rt 2.18 min, m/z 283 [MH*-H,0] 'H NMR (CDCls) 5 1.10-1.38 (7 H, m), 1.54-1.77 (3 H, m) , 2.28 (1H, m), 2.80 (2H, 1), 2.98 (2H, 1), 3.67 (1H, br s), 6.72 (1H, s), 7.24 (1H, m), 7.34 (2H, m) , 7.62 (2H, m). 1¢ Example number Yo

N

= 1.

HO 0 NT

Cyclohexyl-[5-(2-dimethylamino-ethyl)-oxazol-2-yl l-phenyl-methanol. (I-d): Cat = Ph, R® = c-Hexyl, R® = 89 = CH; of [5-(2-amino-ethyl)-oxazol-2-yl]-cyclohexyl-phenyl-methanol to a solution of chloroethane (5 mL) ary ¢ mg + k mmol) in You. ( ) iy (example AC number in water - mmol) and a third % vv ml of 9 0 solution was added formaldehyde 7 $ Y 7 mmol). This mixture was stirred in 1 . Y ¢ mg Ye sodium acetooxyborohydride) a

0 mL) and 10 DCM carbonate for 1 hour and then add 0 at room temperature for a period of time and mix gently. The organic substances are isolated through (a) +) saturated aqueous sodium hydrogen peroxide phase separation cartridge and evaporation for oil. By purification by flash column chromatography over a gel as a propagator, 4% DCM is obtained. : Methanol 960 silica using a mixture of . The compound entitled as a white solid © . (%VY) yield at 7 mg

LC-MS (Method 2): Rt 2.20 min, m/z 329 [MH]. 67 The nuclear magnetic lung corresponds to Example No

To example number

N

SOONG

24 No. 7 \

Br Ye {2-] 2:(Cyclohexyl-hydroxy-phenyl-methyl )-oxazol-5-yl]-ethyi}-dimethyl-(3-bhenoxy-propyl)-ammonium bromide. (I-e): 88 = Ph, R® = c-Hexyl, R® = R = CHj, R® = 3-Phenoxypropyl cyclohexyl-[5-(2-dimethylamino-ethyl)-oxazol-2-yl]-phenyl- A solution of J mmol) in a mixture of acetonitrile 1.01 + mg Vie) 16 (Example No. methanol 00©+) 3-phenoxypropyl bromide (Ja 0.75) and chloroform ( Je .5 (1 °C for 0 mmol hours). This mixture was heated in 0.77 “ily Sua. Then the solvent was separated in vacuum 76 01-17 by flash column chromatography over a silica wrecker. Using a denaturant of . as a promoter, the compound entitled as a white solid DCM is obtained as methanol in 0. (% oo¥) mg Al = Productivity 071 LC-MS (Method 1): Rt 8.66 min , m/z 463 [M*]

10' H NMR (MeOD) 6 1.06-1.35 (6H, m), 1.66 (4H, m), 2.24 (2H, m), 2.37 (2H, m), 3.17 (6H, s), 3.29 (1H, m) ), 3.59 (2H, m), 3.66 (2H, m), 4.06 (2H, 1), 6.91-6.97 (3H, m), 6.99 (1H, s), 7.20-7.33 (5H, m), 7.50 ( 2H, m). 17 Example No

N

. 1.

HO 0 NT

Oo[5-(2-Amino-ethyl)-oxazol-2-yI]-cyclohexyl-phenyl-methanol. (I-d): 88 = Ph, c-Hexyl crack, R°=RY = CH (first eluting enantiomer)

Lg is a chiral preparatory postexample No. HPLC of the titled compound isolated by

Yo 0.0 ola 9698 ethanol; residence time 11 diethyl ether ; 0

LC-MS (Method 1): Rt 6.74 min, m/z 9 [MH] "HNMR (CDCls) 8 1.10-1.37 (7H, m), 1.61-1.76 (3H, m), 2.26 (6H, s), 2.57 (2H, (, 2.81 (2H, t), 3.66 (1H, s), 6.69 (1H, 8), 7.24 (1H, m), 7.34 (2H, 1), 7.63 (2H, d).

Y Example No. Ve

N

1.

HO 0 NT [5-(2-Amino-ethyl)-oxazol-2-yI |-cyclohexyi-phenyi-methanol. (I-d): R? = Ph,

RP = c-Hexyl, R° = R® = CH; (second eluting enantiomer) a chiral preparation according to Example No. 4+ using HPLC the titled compound is isolated by following . min) 1.5 = the conditions noted for Example 176; (remaining time 0

LC-MS (Method 1): Rt 6.76 min, m/z 329 17

1 . 17 NMR corresponds to Example No

TA Example No

N

[1 _ night 2 0 No 7 \

Br {2-[2-(Cyclohexyl-hyd roxy-phenyl-methyl)-oxazol-5-yl]-ethyl }-dimethyl- (3-phenoxy-propyl)-ammonium bromide (I-e): R* = Ph, RP = c-Hexyl, R= ee rwa = cat R® = 3-phenoxypropyl — Enantiomer 1 The named compound was prepared from the compound in Example No. 16 using the method in Example No. . lo

LC-MS (Method 1): Rt 8.54 min, m/z 463 [M7] "H NMR (DMSO-d¢) 0.95-1.28 (6H, m), 1.48-1.70 (4H, m), 2.12 - 01 2.28 (3H, m), 3.11 (6H, s), 3.20 (2H, 0, 3.51 (2H, m), 3.61 (2H, m), 4.03 (2H, 1), 5.89 (1H, s), 6.92-6.98 (3H, m), 7.00 (1H, s), 7.20-7.24 (1H, m), 7.28-7.34 (4H, m), 7.43-7.47 (2H, m).14 Example No. > N {1 0

HO 0 text im << 2 bk” Br Yo {2-[2( Cyclohexyl-hydroxy-phenyl-methyl )-0xazoi-5-yl]-ethyl}-dimethyl- (3-phenoxy-propyl) -ammonium bromide (I-e): 88 = Ph, R® = c-Hexyl, R® =

RY = Mela R® = 3-phenoxypropyl — Enantiomer 2 using the method in Example No. TV The titled compound is prepared from the compound in Example No. H - LC-MS (Method 1): Rt 8.62 min , m/z 463 [M*]

101 . 148 NMR corresponds to Example No

Vo Example No. 2

CN

[5-(2-Amino-ethyl)-oxazol-2-yl l-diphenyl-methanol. (I-c): 88 = 89 = Ph intermediate ( [2-(hydroxy-diphenyl-methyl)oxazol-5-yl]-acetonitrile to a solution of No. ov) c. VY mmol) in 5 (de VY) Raney nickel (catalytic quantity) was added and the suspension was stirred under a hydrogen gas environment (in a balloon) at room temperature overnight. The reaction mixture was filtered through the celite ‘ washed with 5 and the filtrate was concentrated in a vacuum to provide a brown oil; which is used without additional purification.

LC-MS (Method 2): Rt 1.85 min, m/z 295 Ve 'H NMR (CDCls) §2.66-2.73 (m, 2H), 2.81-2.86 (m, 2H), 6.64 (s, 1H), 7.25 -7.37 (m, 10H). The compounds for the following example are prepared in a similar manner; Using the path shown in the diagram No. Exam Name Structure HNMR | LCMS ple 71 [5-(2- 3 (CDCl3): 82.23 | (Metho inG- N (s, 6H), 2.55 (t, | d 5): Rt

Dimethylamino 07h | 20280 oH), | 5.03 ethyl)-oxazol-2-§) | 4.50 (br.s, 1H), min, yil-diphenyl- 6.76 (s, 1H), 7.27-m/z 7.37 (m, 10H). 323 methanol. (I-d): [MH]

R®=R"= Ph, R° - 89 - CH,

WY

72 {2-[2-(Hydroxy-0 : Ramah-001150) 6 | (Metho i i � N 2.17 (m, 2H), | d 1): Rt diphenyl-methyl)- | = AJ 312s. OF 3.28 | 743 oxazol-5-yl]- a a (t, 2H), 3.52 (m, min, di . Br 2H), 3.64 (m, m/z ethyl}-dimethyl 2H), 4.04 (t, 2H) , | 457 (8-phenoxy- 6.95 (m, 3H), [M'] ] 6.99 (s, 1H), 7.04 propyl) Gs, 1H), 7.24-7.34 ammonium (m, 12H). bromide. (I-e): 8 =R°=Ph,R°=

R% = CHs, R® = -3

Phenoxypropyl. 6+ The vehicles of the following example are brought using the lane shown in Scheme No

N N N a | without | 8 blah a blah 8 R R 0 N-gpt yed ami 0 yall 0 toc ro ml NO min Dro Jee (-a) (-f) (and-a) A chart no

VY Example No

OE

/ EL 0 AN

W, (2-Benzhydryl-oxazol-S-ylmethyl)-dimethyl-amine. (I-f): R* = R® = Ph, Ki = RY

CH; A third (-5 μl + (£0 mmol) of a solution of 0) silane Ji was added.

Veo) ) 1 (Ex. No. dimethylaminomethyl-oxazol-2-yl)-diphenyl-methanol 0' (Ja 0 -v) TFA traced by ' (Je LY ) DCM mmol) at +0.10 mg YEVY and heated until reflux for 7 hours. the reaction mixture concentrated; passes over the cartridge

YY ¢ and liberated with a ¥ M ammonia solution in methanol. After evaporating the SCX-2 volatile materials as a thinner to provide IDEM / methanol 9659-1, the residue was purified over silica using a slurry of . The compound entitled as colorless oil. ( 9678) mg VE = Yield LC-MS (Method 5): Rt 5.03 min, m/z 293 [MH"] °' H NMR (CDCl): § 2.24 (s, 6H), 3.50 ( s, 2H), 5.59 (s, 1H), 6.91 (s, 1H), 7.22-7.33 (m, 10H).

VE Example No

N

FN un, / BAN

Br

QJ ~) (2-Benzhydryl-oxazol-5-ylmethyl)-dimethyl-(3 -phenoxy-propyl)-ammonium 01 bromide. (I-g): R* = R® = Ph, R, R? = Me, R® = 3-Phenoxylpropyl. According to the method used to prepare Example No. yy, the named compound is prepared from Example No. . A

BAY = daily)

LC-MS (Method 1): Rt 8.05 min, m/z 427 [M*] Yo 'H NMR (CDCls): § 2.32 (m, 2H), 3.39 (s, 6H), 3.59 (m, 2H), 3.93 (m, 2H), 5.30 (s, 2H), 5.62 (s, 1H), 6.79 (d, 2H), 6.97 (t, 1H), 7.20-7.32 (m, 12H), 7.61 (s, 1H) .

Yo Example No

NA or) _

MeO / i 76 a

11 [2-(Methoxy-diphenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-amine. (I-h): 18 = RP =Ph,R°=R*=R'=Me (eg (5-dimethylaminomethyl-oxazol-2-yl)-diphenyl-methanol to a solution of DMF added under nitrogen mmol) in 7 ml 77 0 mg 001 ( ) 1 mixture number la mg “¢.0 mmol) and 01 Ju) sodium hydride (8 dispersed in 5 mmol) and Mixed lo min. Iodomethane (1 μl) was added to baal, and the reaction was hr. Water, ethyl acetate and VA were added and the reaction was stirred at room temperature for a period of time. The phases were separated. the organic layer is dried (sodium sulfate); And the solvent evaporates. The product, Acetate 9600-8, was isolated and clarified by NH2, Cartridge 01 g. Crude purified using . Ethyl / cyclohexane for the availability of the titled compound 0 . (9657) productivity = 0% mg

LCMS (Method 4): Rt 2.22min, m/z 323 [1117] “H NMR (CDCls): § 2.21 (s, 6H), 3.27 (s, 3H), 3.55 (s, 2H), 6.99 (s, 1H), 7.23-7.37 (m, 6H), 7.43-7.52 (m, 4H).74 Example 1

N

®! cel 0 +

MeOFO

Br "-) [2-(Methoxy-diphenyl-methyl)-0xazol-5-ylmethyl] -dimethyl-(3-phenoxy-propyl)- ammonium bromide. (I-i): R* = R® = Ph, R®, R? = Me, R® = 3-Phenoxypropyl, R =

Me. According to the method used to prepare Example No. Vo, the compound entitled is prepared from Example No. YL 6. (% to ) Yield = c mg “HNMR (MeOD): 6 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, 1H), 7.25-7.34 (m, 8H), 71 7.47 (m, 4H), 7.62 (s,1H).

101

VV Example No

NOH

/ the | 0

HO 0 No

Oh

NH

0 5-[(R)-2-(9-{[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yimethyl]- methyl-amino}-nonylamino)-1-hydroxy-ethyl]-8 -hydroxy-1H-quinolin-2-one. 0 solution of 5-[(R)-1-(tert-butyl-dimethyl-silanyloxy)-2-(9-{[2-(cyclohexyi- hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- methyl-amino}-nonylamino)-Vo)ethyl]-8-hydroxy-1H-quinolin-2-one mg ¢ (+ mmol) in dry THF (1 ml) under a nitrogen environment treated pe (8; μl; 1.7 mmol) . After bin "stirring on day at room temperature throughout Jal; the reaction mixture is neutralized with saturated sodium bicarbonate (aqueous) and extracted by DCM, _ the combined organic phases washed with brine; dried (sodium sulfate) ¢ filtered And the dryness Ja is concentrated to provide green/brown gum 0 and purified by preparative HPLC (system 90675 b + 10 b/min). Cartridge Ve 5902 Released using a ¥ M ammonia solution in methanol Evaporating the solvent in a vacuum Titled compound available as yellow glue 0% vy < mg Y 1 = yield LC-MS (method 2 ): Rt 2.22 min, m/z 645 [MH].

YA Example No

YEVY

A N SEs 5 HO No SI (5-Dimethylaminomethylthiazol-2-yl)diphenyl methanol. (XXVIII): R? = Ph, Me = cat R® = Ph, R° = Me, (Je 9 DCE to a mixture of AIBN ) 8.4 mg + [mmol ethmide] was added « N — ° bromosuccinimide YAY ax .0 (Y) millimoles) and the median is 0. 1 ) Ye g + “Yoo mmol) . The suspension is placed in an oil bath preheated at 980 °C. After 560 minutes, the reaction becomes complete according to LC-MS analysis. The solution is poured over a mixture of J ether and saturated sodium hydrogen carbonate and the layers are separated. The organic phase was washed with water and brine (ada magnesium) and evaporated. The residue was dissolved in (Se Y) THF 0 – cooled to -01 °C under a nitrogen environment and treated with a ¥ molar solution of dimethylamine in VA (ol) THF ml ¢ Yoo mmol) 0. After heating to room temperature; evaporated solvent; The residue was subjected to column chromatography (silica; A g) and clarified by 0 160 ethyl acetate in iso-hexane to obtain the required material. Throughput = 1 ra g (51 %). LC-MS (Method 6): Rt 2.84 min, m/z 325 [MH]+. Vo 1H NMR, 400 MHz, DMSO-dg: 7.5 (1H) , s), 7.4 (4H, m), 7.3-7.2 (7H, m), (2H, s) and 2.1 (6H, s). 3.6 Example No. Va but N AS NO / Mahalem © L

A [2-(Hydroxydiphenylmethyl)th iazol-5-ylmethylldimethyl-(3-Ph, R® = Me, = cat phenoxypropyl)ammonium bromide. (XXIX): 88 = Ph, Me, R® = 3-phenoxy-1-propyl = €YA) Phenoxypropylbromide aul.+g; 0.74_mmol) for a solution of © median ¥ (2.200 an 1097 mmol) in 011013 (1 mL) and MeCN (1 mL). The solution was heated at 00 °C for 1 hr; Later, TLC (01%) methanol in DCM indicates near completeness of the reaction. The solvents are evaporated and the residue is subjected to column chromatography (silica A g) and clarification by \o-o% methanol in DCM to provide the required material as a solid. White in color.Ye Yield: 0.051 g (TY 96). LC-MS (Method 1): Rt 2.39 min, m/z 459 [M-Br]+. 1H NMR, 400 MHz, DMSO-d6: 8.0 (1H, s), 7.5 (1H, s), 7.4 (4H, m), (8H, m), 6.9 (3H, m), 4.9 (2H, s), 4.0 (2H, s), 3.4 (2H, m), 6.1 (6H, -7.3 7.2 s) and 2.2 (2H, m).Vo Ae N HO" FI Br (3-Benzyloxy-propyl)-[2-((R )-cyclohexyl (-hydroxy-phenyl-methyl)-oxazol-5-R® ylmethyl]-dimethyl-ammonium bromide (I-b): R* =Ph, R® = c-Hexyl, CHa, R® = 3-Benzyloxy-propyl = Ye. The compound entitled was prepared according to the method used to prepare Example A. LC-MS (Method 5): Rt 7.26 min, m/z 68 1 'H NMR (DMSO- dg): & 0.90-1.29 (m, 6H), 1.50-1.74 (m, 4H), 2.04 (m, 2H), 2.26 (m, 1H), 2.98 (s, 3H), 2.99 (s, 3H) ), 3.27 (m, 2H), 3.45 (t, 2H), 4.46 (s,

1 2H), 4.72 (s, 2H), 6.08 (s, 1H), 7.24 (t, 1H), 7.28-7.39 (m, 7H), 7.46 (d, 2H), 7.52 (s, 1H).

AY example number except HO 5” 1m mm - p -5-0 0 [2-(4-Chloro-benzyloxy)-ethyl]-[2-((R)-cyclohexyl-hydroxy -phenyl-methyl)- ° oxazol-5-yimethyl]-dimethyl-ammonium methanesulfonate. (I-b): R? =Ph, cat = c-Hexyl, 85, R® = CH,, R® = 2-(4-Chloro-benzyloxy)-ethyl . The entitled compound was prepared according to the method used to prepare Example No

LC-MS (Method 1): Rt 8.73 min, m/z 483 [M+]. ‘” H NMR (CDCl): 6 1.02-1.49 (7H, m), 1.56-1.79 (3H, m), 2.21-2.34 (1H, 01 m), 2.67 (3H, s), 3.14 (611, 3.64 ( 2H, bs), 3.88 (2H, b 5), 4.49 (2H, 8), 4.79- 4.99 (3H, m), 7.16-7.36 (7H, m), 7.43 (1H, s), 7.51-7.58 (2H , m).

Example No. AY > , Br 0 [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yimethyll-dimethyl-(2- Vo 0x0-2-phenyl-ethyl)-ammonium bromide . (I-b): 83 = Ph, RP = c-Hexyl, ©

RY = CHj, R® = 2-Oxo0-2-phenyl-ethyl . A according to the method used to prepare Example No. an entitled compound

LC-MS (Method 2): Rt 2.53 and 2.60 min, m/z 433 [M+]. H NMR (CDCl): 6 1.02-1.87 (10H, m), 2.17-2.32 (1H, m), 3.59 Ye. (38H, s), 3.60 (3H, s), 3.89 (1H, bs), 5.28 (1H, d), 5.47 (1H, d), 5.76 (2H,

Ss), 7.17-7.33 (3H, m), 7.42 (1H, S), 7.45-7.54 (4H, m), 7.61-7.67 (1H, m),

YeXV 8.05-8.11 (2H, m).

YY.

AY Example No

N\-

Br

HO" >) /

IS

[2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl methyl]-dimethyl-(2- phenethyloxy-ethyl)-ammonium bromide. (I-b): R* = Ph, Qm = c-Hexyl, R°, © Ph = CHa, R® = 2-Phenethyloxy-ethyl

A according to the method used to prepare Example No. an entitled compound

LC-MS (Method 1): Rt 8.51 min, m/z 463 [M+]. H NMR (CDCl): 6 1.07-1.40 (m, 7H), 1.60-1.80 (m, 3H), 2.32 (m, 1H), 2.87 (t, 2H), 3.12 (s, 6H), 3.72-3.87 (m, 6H), 4.17 (s, 1H), 4.91 (dd, Ye 2H), 7.16 (m, 3H), 7.20-7.28 (m, 3H), 7.29-7.37 (m, 3H), 7.57 (d, 2H).84 Example No

N

no / ) 0 +

HO'A 0

Oh

[3-(4-Carboxy-phenoxy)-propyl]-[2-(((R)-cyclohexyl-hydroxy-phenyl-methyl )- oxazol-5-ylmethyl]-dimethyl-ammonium bromide. (I-b): R? = Ph, RP = c-Hexyl, Yo

RS, R'=CH;,R°= 3-(4-Carboxy-phenoxy)-propyl [2-(((R)-Cyclohexyl-) to a solution of (Jo +.Y 1) Molar 1 hydroxide was added sodium hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[3 -(4-methoxycarbonyl-phenoxy)- mg; 064 mmol) £1) (oF No. Jl) propyl]-dimethyl-ammonium bromide

Yevy Y The solution was stirred at ambient temperature for | (Ja 9 and methanol (Ja ¥) in water 90.

YY

Molar (7 ml). The solution was freeze-dried and the crude product 1 HO day; And then I add

DCM was purified by column chromatography and clarification by 9670 methanol in . To obtain the titled compound, which is assumed to be a bromide salt. (0%) Yield = 6 mg

LC-MS (Method 1): Rt 7.35 min, m/z 493 [M+]. © “HNMR (CD3;0D): 6 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).

Ao Example No

N

ruble for 0 yen

HO / B 1 RIA - F 0 0 [2-(((R)-cyclohexyl-hydroxy-phenyl-methyl )-0xazol-5-ylmethyl]-dimethyl-[2-(4- methyl-benzyloxy)- ethyl]-ammonium methanesulfonate. (I-b): R? =Ph, Hexyl moiety, R®, RY = CH;, R® = 2-(4-Methyl-benzyloxy)-ethyl . A The entitled compound was prepared according to the method used to prepare Example No

LC-MS (Method 1): Rt 8.67 min, m/z 463 [M+]. \o '" H NMR (CDCl): 6 1.03-2.07 (10H, my), 2.22-2.43 (4H, m), 2.69 (3H, s), 3.14 (6H, 5), 3.64 (2H, b 5) , 3.86 (2H, b s), 4.48 (2H, 5), 4.60 (1H, b 5), 4.82-5.02 (2H, m), 7.04-7.37 (7TH, m), 7.42 (1H, s), 7.55 ( 2H, d).

AT Example No

N

No a / 0 0 y "0 MN NL o Cl oo 0 Y.

YEVY

[2-(((R)-cyclohexyl-hydroxy-phe nyl-methyl)-oxazol-5-ylmethyl}-[2-(3,4- dichloro-benzyloxy)-ethyll-dimethyl-ammonium methanesulfonate. (I-b): R® = Ph, RP = c-Hexyl, R® = CH, R® = 2-(3.,4-Dichloro-benzyloxy)-ethyl . For the method used to prepare the example No. lady of the compound entitled present

LC-MS (Method 1): Rt 9.09 min, m/z 517 [M+]. © “H NMR (CDCl3): 6 1.03-1.39 (7H, m), 1.58-1.80 (3H, m), 2.23-2.35 (1H, m), 2.71 (3H, s), 3.17 (6H, s), 3.71-3.77 (2H, m), 3.89-3.98 (2H, m), 4.42 (1H, 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).

AY Example 1 0 mt N _ bla / 0 wo] © “R / 0 N- (2-benzyloxy-ethyl)-[2-((R) - cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyll-dimethyl-ammonium toluene-4-sulfonate. (I-b): R® = Ph, R® = ¢-

Hexyl, 53,88 = CHa, R® = 2-Benzyloxy-ethyl . Using the entitled compound A, it was prepared according to the method used to prepare Example No. Ye

LC-MS (Method 2): Rt 2.60 m/z 449 [M+]. HNMR (CDCl3): 6 1.02-1.76 (10H, m), 2.22-2.37 (4H, m), 3.19 (6H, S), 3.69 (2H, bs), 3.86 (2H, b s), 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) .

AA Example No. 0

N

HO { PR 0 NH, [5-(2-Amino-ethyl)-oxazol-2-yl |-cyclopentyl-phenyl-methanol. (Ic): R? =

Ph, 85 = c-Pentyl.

YeYY

177. 0 Bring documentation of the method used to prepare Example 3

LC-MS (Method 2): Rt 2.03 min, m/z 287 [MH"] "H NMR (CDCls) § 1.28-1.71 (m, 11H), 2.78 (t, 2H), 2.97 (m, 3H), 6.72 (s, 1H), 7.22-7.28 (m, 1H), 7.30-7.36 (m, 2H), 7.59-7.64 (m, 2H). o

AS Example No

N

. 1

HO 0 NT

Cyclopentyi-[5-(2-dimethylamino-ethyl)-oxazol-2-yl}-phenyl-methanol. (I-c):

R® = Ph, R® = c-Pentyl, R° = RY = Wa© Cg according to the method used to prepare Example No. any 01

LC-MS (Method 2): Rt 2.05 min, m/z 315 [MH] '"H NMR (CDCl) 6 1.29-1.70 (m, 8H), 2.26 (s, 6H), 2.57 (m, 2H), 2.80 (t, 2H), 2.97 (m, 1H), 3.68 (brs, 1H), 6.69 (s, 1H), 7.21-7.27 (m, 1H), 7.33 (t, 2H), 7.62 (d, 2H) 4. Example Yo number

N

11 btm al

HO ; NL © oo) 8-0 0 [2-((R )-cyclohexyl-hydroxy-phenyl-methyl )-0xazol-5-yimethy| l-dimethyi-(3-methyl-3-phenoxy-butyl)-ammonium methanesulfonate. (I-b): 38 = Ph, RC - c-Hexyl, R°, 88 = Rona R® = 3-Methyl-3-phenoxy-butyl . A The entitled compound was prepared according to the method used to prepare Example No. 1

16 . (1%) Productivity © mg

LC-MS (Method 4): Rt. 2.85 min, m/z 477 [M+]. 'H NMR (CDCl): 6 0.70-2.00 (16H, m), 2.02-2.13 (2H, m), 2.16-2.30 (1H, 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). © Waseet 1 a 0

NH

© 2-Ox0-2-phenyl-N-prop-2-ynyl-acetamide. mmol) to a solution of phenylglyoxylic acid (£A ¢ g LY) add oxalyl chloride (1g 0 (£4 mmol) and ? Drops of DMF in dry DCM (0 (Je). The reaction mixture was stirred at room temperature for ¥ hours and then the solvent was separated. The residue was taken in dry DCM (+ (Je) and the solution was cooled to 0 degrees C. A mixture of propardylamine (1 g (6.06 mmol) and triethylamine (260 g Ee mmol) was added at a rate of 0 over a period of 10 minutes and then the mixture was allowed to warm to room temperature. Stirring continues for 7.5 hours, and then water (01 ml) is added. The mixture was washed with 1,110 M 71 (ml twice) and saturated (aqueous) sodium hydrogen carbonate (107 ml twice) and then Brine 0 organic phase and then ada (sodium sulfate) and the solvent Season . The residue crystallizes with cyclohexane to provide the product as a light brown solid. b productivity = 5.75 g; 1 90 . LC-MS (Method 3): Rt 2.47 min, m/z 188 [MH]. mediator number? a

01 © pe Al (5-Methyl-oxazol-2-yl)-phenyl-methanone

01 methanesulfonic acid (g Ve f mmol) was added dropwise to a solution of 2-0X0-

2-phenyl-N-prop-2-ynyl-acetamide intermediate 1a (7.4 g - 17.87 mmol) in oo 0;-dioxane (107 mL). The resulting solution was heated at 0 °C for 67 hours.

The reaction mixture was cooled and the solvent was separated. The bold remainder is the partition between the DOM and the water. The resulting

DCM washed with 1 M HCI; Saturated sodium hydrogen carbonate (7 times)

And then brine. The solution was dried (sodium sulfate) and the solvent was separated to provide the product

raw. Purification is by column chromatography; and promotion by; : 1-hexane 0-cyclo:ethyl acetate. This provides the product as an off-white solid.

Productivity = gm (9641).

LC-MS (Method 3): Rt 2.94 min, m/z 188 [111] fy mean B 0

Cyclohexyl-(5-methyl-oxazol-2-yl)-phenyl-methanol.

Vo

solution of (5-methyl-oxazol-2-yl)-phenyl-methanone ) intermediate (VY) ¥ g ;

11 mmol) in 7 ml of Gils THF at zero degrees Celsius under nitrogen treatment

Drop by drop in 10 minutes with a solution? Molar of VY) ml ; 01 mmol).

The resulting yellow solution was stirred at zero degrees Celsius for approximately 0 * minutes, during which time it was thought to be a god?

17 hours. The reaction mixture was cooled to the point of Yoo precipitate 6 and then at room temperature for 0 (01 lm) zero Celsius seconds and treated carefully with saturated ammonium chloride solution (Je Ye) for 1 minute and then diluted with water 01 sad The mixture was stirred at room temperature, the phases were separated and the organic phase was washed with brine. (magnesium) and concentrated in Fara 2 to provide the raw product that was ground with ether and dried (AL) Productivity = 7.66 g

LCMS (Method 3): Rt 3.78 min, m/z 272 [MH"] (6-methyl-oxazol-2-yl)-phenyl- is also prepared in a similar way by reacting 0 with cyclopentyl magnesium chloride to form IY (median 068 median no. A

HO N

7

Cyclopentyl-(5-methyl-oxazol-2-yl)-phenyl-methanol. . (96,760 g) YAY = Yield Ve

LC-MS (Method 2): Rt 3.68 min, m/z 258 [MH] Median © A :

HO N

7 7

Cyclobutyl-(5-methyl-oxazol-2-yl )-phenyl-methanol.

AEA RY

YYV

to a suspension of magnesium (0.18 g - 5.71 mmol) in 10 mL of dry ether under argon; Cyclobutyl bromide (TY) (total 5.7 mmol) was added at this rate so that it remained in the reflux. The resulting mixture was stirred at room temperature for 1 hour; Then a solution of (intermediate £.YF) (IY total 77.76 mmol) in Av mL dry ether and ©71 mL 2115 at -01°C was added. The mixture was allowed to warm to room temperature + stirred for VT 1 hour; Then it was cooled to Yom °C and treated with aqueous ammonium chloride. Ethyl acetate and water are added to the reaction mixture. the organic layer separated; dried (magnesium sulfate) and evaporated to dryness. By chromatographic purification (Rediscip cartridge) and clarification with DCM-/dla-hexane, the entitled compound is available as 0 white solid. Yield = 7.1 grams (BTA).

LC-MS (Method 4): Rt 3.10 min, m/z 226 [M-H,O+H}* median no + a b 5

Br (6-Bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol. Vo solution of Jeyclohexyl-(5-methyl-oxazol-2-yl)-phenyl-methanol intermediate ©a)

N-bromo- treated with (Je YY) 1,2-dichloroethane mmol) in 10 g ¥):

YO 1 g YA (mmol) followed by VY.Y ¢ g YA (succinimide mmol). The mixture was heated up to Av °C for 7.6 hours and then allowed to cool down to room temperature. Saturated sodium hydrogen carbonate was added and the phases were separated. The organic layer was washed with brine and the combined aqueous layers were extracted by 1 4717

YYA

The combined organic phase was dried (magnesium sulfate) and concentrated in vacuum to provide . 4 The crude product is brown in color. Purification is done by column chromatography and clarification / cyclohexane followed by 9675 ethyl acetate / DCM % V + oY by . DCM (EA) gm 0.85 = Yield 0

LCMS (Method 3): Rt 4.27 min, m/z 350, 352 [MH] : median 7a

HO N

74

Br (5-Bromomethyl-oxazol-2-yl)-cyclopentyl-phenyl-methanol. 0 01 g (m6) / 0 of productivity per year

LCMS (Method 3): Rt 3.90 min, m/z 336, 338 [MH] Median No. 8a

HO N

:oL_

Br (5-Bromomethyl-oxazol-2-yl )-cyclobutyl-phenyl-methanol. Yo. (96 001) Productivity = 7.9 g

LCMS (Method 4): Rt 3.33 min, m/z 304, 6 [M-H0OJ* argument #9a

18 N ( 0 0 (5-Bromomethyl-oxazol-2-yl)-phenyl-methanone . 1 according to the method used to prepare medium as . (0 67) (yield = 1.4 g 'H') NMR (CDCl) 6 4.57 (s, 2H), 7.36 (s, 1H), 7.53 (m, 2H), 7.66 (t, 1H), 8.45 (m, © 2H).

N

4 nal o © a (5-Dimethylaminomethyl-oxazol-2-yl)-phenyl-methanone. (14 (intermediate (5-bromomethyl-oxazol-2-yl)-phenyl-methanone) solution of 0 treated with a solution of ?molar of di-THF ml of 0 mmol) in 11110 g 1.5 (mmol). The reaction mixture was stirred at 110 °C + 0 ml) THF methylamine in an hour and concentrated through reducing pressure. The remainder is partitioned between 1 ethyl acetate at room temperature for . ? My caliber. The aqueous layer was treated basicly with aqueous potassium carbonate solution HCI and Vo. The organic layer was separated and washed with brine; (magnesium sulfate) was dried and evaporated to provide the entitled compound as a brown solid. Yield = 1.0 g (%o¥). 'H NMR (CDCl3) 6 2.35 (s, 6H), 3.69 (s, 2H), 7.25 (s, 1H), 7.52 (m, 2H), 7.64 (t, 1H), 8.46 (m, 2H). A 11 Median No. Ys

10

No Ion

HO 0 C [2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-acetonitrile. To a solution of (5-bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol (intermediate 0 0) (IN g * mmol) in IMS (10 mL) sodium cyanide (8) 14 was added mg + 7.8 mmol). The mixture was heated at no degrees Celsius for 1 hour, then concentrated in vacuum and partitioned between ethyl acetate (1 * ml) and water (W (ml). The aqueous layer was extracted by ethyl acetate (Ja) (twice) and the combined organic layers were dried over sodium sulfate; Filter and evaporate the orange-colored oil. Purification by flash column chromatography over silica gel using a mixture of 96400 ethyl acetate: 96768 00 cyclohexane as a translucent and then recrystallization with DCM / hexane to provide the titled compound as a white crystalline solid. Yield < 7000 mg (9674).

LC-MS (Method 3): Rt 3.66 min, m/z 279 [MH*-H,0]. A 11 Median No

A SMe

JL

Yo 2-(1,1-Diphenyl-ethyl)-5-methyl-4-methylsulfanyl-oxazole. To a solution of 1-methylthio-2-propanone (+.9A) ml « 5.7 mmol) in 11 ml of dry DOM at 0 °C under nitrogen a solution of 0.57 trifluoromethanesulfonic anhydride was added dropwise (ml; 9.7 mmol) in 01 ml dry DCM 171

111 . The resulting yellow solution was stirred at 0°C for 1 hour and then a solution of 1 (2,2-diphenylpropionitrile g ¢ £.A mmol) in 0 mL of dry DCM was rapidly added dropwise . The reaction mixture was stirred at 0 °C for ¥ h and then between ,. f room temperature for a day; It becomes dark red in color, Ashe, degree Lia. The reaction mixture is cooled to 0 degrees Celsius and treated carefully with a saturated sodium bicarbonate solution. The phases were separated and the aqueous layer was extracted by (Y) DCM once). The combined organic phase is washed with water; saturated sodium bicarbonate solution and saline solution; Dry (Sodium sulfate) 0 and evaporate _ to dark viscous oil (VY) g). _The crude product was purified by silica gel chromatography and clarification by 965 diethyl ether / hexane (Rf) ila 75-0) to obtain the compound entitled as a pale yellow oil that crystallizes upon precipitation. Yield = 0.74 g (9657). LCMS (Method 2): Rt 4.37min m/z 310 [MH*] A 11” Argument No.

J

N

04 2-(1,1-Diphenyl-ethyl)-5-methyl-oxazole. A suspension of 2-(1,1-diphenyl-ethyl)-5-methyl-4-methylsulfanyl-oxazole (median ad, 17) (IVY g 7.7 mmol) in 0 mL of By IMS to dissolve Raney nickel 05 (approximately ¥ g) was added causing rapid fizzing of the gas The reaction mixture was stirred in reflux under Ys nitrogen After 0.75 hours measurements of 101458 indicate a mixture of a 1:1 ratio of a substance Starting: the product and without changing after an additional 1 hour * an extra gm of Raney nickel 728 vevy was added

The reaction mixture was stirred in reflux for 1 hour. TLC indicates that all of the starting material has reacted. The catalyst is filtered through a hi-flu and the volatile substances are evaporated to obtain a colorless viscous oil (V (.., g). The oil was purified by silica gel chromatography and clarified by 70516 ethyl acetate: (RE = 1.76 cyclohexane) to obtain the compound labeled as colorless oil. Yield = 0.81 g (BAR) LCMS (Method 2): Rt 3.96min m/z 264 [MH*] Median No. 14 A N JL Br 5 - Bromomethyl-2-(1,1-diphenyi-ethyl)-oxazole.

Ye Prepare medium No. VY {according to the method used to prepare medium No. Yield = 0.75 g (quantity) 0 LC-MS (Method 2): Rt 4.06min m/z 342, 344 [MH*] Median No. 11a N 1 7b yo Cyclohexyl-(5-methyl-thiazol-2-yl )-phenyl-methanol. solution of Y.0) 5-methyithiazole g Yo VY mmol) in 50 mL of anhydrous THF and cooled to VAS °C under a nitrogen environment. 11 ordinary butyl lithium (0.3 mL of a solution in hexanes) was added dropwise over 0 minutes. Interaction heart for prp?

0 minutes before adding a converter of ila phenyl ketone hexyl in 50 ml of anhydrous THE drop by drop. The reaction was stirred for ve min at VAS °C and then allowed to warm to ambient temperature before quenching by adding saturated sodium carbonate and extracted with diethyl ether | The combined organic extracts were washed with brine + dried (magnesium sulfate) and concentrated. By chromatographic purification using Zero-1096 (JAY) acetate/heptanes, the compound entitled 0. Yield-2015 g (16/85) is available. NMR (CDCls) § 1.05-1.3 (5 H, m), 1.35-1.45 (2 H, m), 1.6-1.8 (3 H, m), 2.30-2.40 (4 H, m), 3.8 (1 H, s), 7.15-7.40 (4 H, m), 7.6-7.7 (2 H, m). 00 Mediator No. 11a N 1/yna Cyclohexyl-(5-methyl-thiazol-2-yl)-phenylmethanol. Prepared according to the method used for mediator 11a using a substitute. (CDCl) 6 1.37-1.67 (m ,8H), 2.38 (s, 3H), 2.39 (s, 3H), 3.09 (m, Yo 117 1H), 3.94 (s, 1H), 7.22 (t, 1H), 7.26 (m, 1H), 7.32 (m, 2H), 7.66 (m, 2H). 0 . solution of Y) 3-phenoxy-propan-1-ol g; £7 (Jsanlle and triethylamine V) mL ; 0 mmol) in 001 mL of dichloromethane cooled to ©°C under an environment of VEYY

The nitrogen ¢ was treated with benzenesulfonyl chloride (4 mL + £1.Y mmol) drop by drop. After stirring at room temperature for 1 hour, water was added to the reaction mixture. The aqueous phase is extracted with dichloromethane; United organic layers washed with brine; (magnesium sulfate) was dried and concentrated to obtain a pale brown oil. The oil © was purified by silica gel chromatography and clarified by ‎DCM% 001-7”©*/pentane to obtain the compound labeled as a colorless oil. Productivity = 0.17 gm (9679). 'H NMR (CDCl3) § 2.13 (dt, 2H), 3.96 (t, 2H), 4.27 (t, 2H), 6.77 (d, 2H), 6.94 (t, 1H), 7.25 (m, 2H ), 7.46 (m, 2H), 7.58 (t, 1H). 0011 (g ¢ 19 mmol) and ethylene glycol (11 mL 0 mmol) heated at 171°C for ? hours . The reaction mixture was allowed 0 to cool to room temperature to 1 (aa ¥) 4-methoxybenzyl chloride mmol) was added. The solution was heated at Yo °C for a period of VT an hour under a nitrogen environment. Add water and ethyl acetate; the organic layer separated; dried (magnesium sulfate) and concentrated. By chromatography (Rediscip cartridge) and denaturation with ethyl acetate/cyclohexane, the entitled compound is available as oil. Yield = .1 g 6717(0 1 + 5 (method 1) : residence time = 7.24 min; molar ion not observed Median 11a

115 0 LT 00

Methanesulfonic acid 2-(4-methoxybenzyloxy) ethyl ester 1714 6 g YY) (1 VA) (Intermediate No. 2-(4-methoxybenzyloxy)ethanol) solution of

DCM ml 16 ml ; 7.7 mmol) in LY (mmol) and diisopropylethylamine, dry; Cool to zero degrees Celsius under a nitrogen environment; Treat drop by drop with a solution © mixed. DCM (10 mmol) in VAY of methanesulfonyl chloride (1.0 ml h) And then add water. Layer VT room temperature for da reaction inverted in organic matter separated + dried (magnesium sulfate) and concentrated. By chromatographic purification (Rediscip cartridge) and decantation by means of ethyl acetate / cyclohexane, the compound is available. Entitled as oil 0 . (%VY) yield = 7.5 g/min; The molar ion is not observed. YAY = (method no. ): residence time 15a 01 number parameter j Lo Lr o ©

Methanesulfonic acid 2-(4-methylbenzyloxy) ethyl ester 06 2-(4-methyl-) but using 119 prepared according to the method used for intermediate No. - 2-(4-methoxybenzyloxy)ethanol replacing benzyloxy)ethanol (method No. ): survival time = 7.44 min; The molar ion is not observed. 1-5a 11 argument no

HO

2-(2,3-Dihydro-benzofuran-5-yl)-ethanol

Borane-1117 complex (1 M) 0 mL was slowly added; © mmol) for a solution of -2,3

THF ml of 0151 g ¢ 79.4 mmol) in £.7Y) dihydro-5-benzofuranacetic acid dry cooled to 0°C under a nitrogen environment. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. Added water (00) and stirred the mixture oo (ye sad) for a minute. Ethyl acetate was added and the phases were separated. The aqueous layer was additionally extracted with ethyl acetate; the combined organic layers were dried (magnesium sulfate) and concentrated to provide the labeled product as a light brown viscous oil Colour. Yield = 4.7 g (96000) (Method No. ?): Residence time = 7.77 CAREY. Molar ion not observed. 0 Mediator No. ?? a

Br

TD

5-(2-Bromo-ethyl)-2,3-dihydro-benzofuran to a solution of 2-(2,3-dihydro-benzofuran-5-yl)-ethanol (medium #1a)YY) g VY mmol) in 100 ml dry DCM added carbon tetrabromide (EY) g (15.7 “Vo mmol) and triphenylphosphine (YTV) g; VEY millimoles). The reaction mixture was stirred for hours at room temperature; Then more carbon tetrabromide (1.92 (pa) and triphenylphosphine (3.74 g) + were added and the reaction mixture was stirred for 101 hours. The reaction mixture was then concentrated; the remaining was triturated with diethyl ether and filtered. The filtrate was purified by chromatography silica gel and clarification by DOM to provide the compound entitled as oil 0 is light yellow in color; which crystallizes by standing. Yield = 7.478 g (TAL 'H NMR (CDCl3) § 3.07 (t, 2H), 3.19 (t, 2H), 3.51 (t, 2H), 3.55 (t, 2H), 6.72 (d, 2H), 6.92 (d, 2H), 7.04 (s, 1H).

AEA RY

What is the broker number?? a Clo H To AN (4-Benzyloxy-benzyl)-methyl-amine suspension of 4-benzyloxybenzaldehyde (¥ g ¢ 05.7 mmol) in 01 mL methanol © treated with solution ? Molar of methylamine in THF (VE) ml © YA mmol). Angstrom molar shakers and sodium borohydride (0.1 g + 7 mmol) were added to the solution, which was stirred at room temperature for 11 hours. The mixture is filtered and evaporated, and the resulting residue is separated between ethyl acetate and water. the organic layer separated; Washed with saline solution 0 dried (sodium sulfate) and evaporated. The resulting oil was dissolved in methanol and purified 0 with a 50-2 cartridge and clarified with methanol and then with Y-Nm ammonia; the availability of the compound entitled as an amber-colored oil; which crystallizes standing. . (%A g (0.51 = yield (method no. )) : residence time).

Yo 0 (4-Benzyloxy-benzyl)-methyl-carbamic acid tert-butyl ester solution of (4-benzyloxy-benzyl)-methyl-amine (Medium No. YY 1) (7.91 g; .1 mmol ), + tributyl dicarbonate (YAN g 17.5 mmol) and triethylamine (5.4 mL; YAY mmol) in 100 mL dichloromethane and allowed

d by standing at room temperature for 11 hours. The solution was then washed with brine, dried (sodium sulfate) and evaporated to obtain a compound labeled as amber oil. Yield = a 1g (4v%). LC-MS (Method 4): Rt 3.93 mins, m/z 350 [M+Na]". butyl ester vial containing a mixture of (4-benzyloxy-benzyl)-methyl-carbamic acid tert- butyl ester 0 (medium No. (TYE (0.; g ¢ VY.0 mmol)) and A catalytic volume of 7008 palladium over charcoal in 110 mL ethanol fluxed with nitrogen; then filled with hydrogen 0 The reaction mixture was stirred at room temperature for yE hours ¢ and then the flask was cleaned with nitrogen; the mixture was filtered through Silite, evaporate to dryness, chromatographic purification (AssoluteCell Cartridge) and liquefaction with Zero-17 96 0 ethyl acetate/pentane. 4): Rt 3.03 mins, m/z 236 [11-11] 0 Median FY No. E 0 [4-(3-Bromo-propoxy)-benzyl]-methyl-carbamic acid tert-butyl ester 000

Prepared according to the method used for medium £0a but using (4-hydroxy-benzyl)- methyl-carbamic acid tert-butyl ester (median (1Y®) substituted for 2-chloro-4-hydroxy- benzonitrile (method no. ): residence time = YLAY min., molar ion not observed. 0 Mediator No. 71?a Sg LO ~0 0 Methanesulfonic acid 3-phenoxy-propyl ester prepared according to method used for intermediate A but using 3-phenoxy-propanol in place of 2-(4-methoxy-benzyloxy)-ethanol. NMR (CDCls): § 2.23 (dt, 2H), 2.99 (s, 3H) , 4.09 (t, 2H), 4.45 (t, 2H), 6.90 Yera (d, 2H), 6.96 (t, 1H), 7.29 (m, 2H). Median No. 78 A H 5 NH, A 0 4-(3-Bromo-propoxy)-benzamide Vo Gig was prepared for the method using the intermediate £0a but by using 4-hydroxy-benzamide in place of 2-chloro-4-hydroxy-. benzonitrile LC-MS (Method 2): Rt 2.77mins, m/z 258, 260 [M+] intermediate #79a CL | 5.0 Cl 4-(3-Bromo-propoxy)-1, 2-dichloro-benzene | 00 was prepared according to the method used for the medium £0a but using 3,4-dichlorophenol in place of 2-chloro-4-hydroxy-benzonitrile.

Yee 'H NMR (CDCl3): 6 2.31 (mm, 2H), 3.58 (m, 2H), 4.08 (m, 2H), 6.76 (dd, 1H), 7.00 (d, 1H), 7.32 (m, 1H) . A 91 Median No

CA oy \ 4-Bromomethyl-N,N-dimethyl-benzenesuifonamide mmol) 17.7 ¢ g £.710) 4-bromomethyl-benzenesulfonyl chloride solution of

Cad DCM (01 mmol) in 17.7 g; V0) and methylamine hydrochloride. ml + 4.;? (5.548 mmol) DIPEA nitrogen at zero degrees Celsius treated with ¢ and water. The organic layer was separated by DCM for an hour; then 1 solution was added, inverted for a period of bull (magnesium sulfate) dried and evaporated. The remainder was purified ion Molarity not observed. 1+5a ©1 argument no. vo

O.L

0% \ 4-(2-Hydroxy-ethoxymethyl)-N,N-dimethyl-benzenesulfonamide using 4- unacceptable A but 18 is prepared according to the method used for medium No. 4- replacing (01) (medium No. bromomethyl -N,N-dimethyl-benzenesulfonamide .methoxy-benzyl chloride | 0 (Method No. ?): residence time = 7.74 minutes; molar ion was not observed. 11 15 YY Median No.

YEN

Bra 0 CL / s-N \ 4-(2-Bromo-ethoxymethyl)-N,N-dimethyl-benzenesulfonamide 4-(2-hydroxy- a) but using YY prepared according to the method used for medium No. 2-a) replaced VY (intermediate No. ethoxymethyl)-N,N-dimethyl-benzenesulfonamide . (2,3-dihydro-benzofuran-5-yl)-ethanol. ©

LC-MS (Method 2): Rt 3.37 mins, m/z 322, 324 [M]".

A 0 AD 0 OC

Phenethyloxy-acetic acid tert-butyl ester mmol); Tetrabutylbromoacetate #11 to a mixture of ?-phenylethanol (1.0 ml; 0 ¢ g 7.4) tetrabutylammonium hydrogen sulfate s mmol) 001 + ml (11 ml) of aqueous sodium hydroxide Yoo mmol) in 7 + mL toluene; 0 hours added. Aqueous layer 11 The reaction mixture was stirred at room temperature for 0. standard and then extracted with ; parts of ethyl acetate; (magnesium sulfate) was dried and evaporated. The remainder was re-dissolved in cyclohexane; The resulting precipitate was filtered and the filtrate was purified by chromatography over silica and clarified with cyclohexane; For the availability of the titled compound. Clear oil. (£1%) g Yo = Yield “HNMR (CDCl3) 6 1.47 (s, 9H), 2.95 (t, 2H), 3.74 (t, 2H), 3.97 (s, 2H), -7.18 7.25 (m, 3H), 7.26-7.31 (m, 2H).Ye Median #34a

AEA

2-Phenethyloxy-ethanol Part of a solution of eda (Usedle YY gm LAA) added Lithium aluminum hydride mmol) at 0°C | The reaction was allowed to be o.V «0.10 gm ({79) medium No. Ye dwelling for an hour; before it was cooled to 11 degrees by heating to room temperature and stirred for 1 titer time and diluted by 1 (ee) and quenched by adding © ml of sodium hydroxide Min © the mixture is filtered; and the filter is evaporated Ye ml diethyl ether. After stirring for 0. To provide the compound entitled (9611 0 0) productivity 0.926 g 'H NMR (CDCl3) 682.90 ) 2H), 3.55 (m, 2H), 3.67-3.73 (m, 4H), 7.18-7.25 (m, 3H), 7.27-7.32 (m, 2H). Ve median No. 5a “0 [2-(2-Bromo-ethoxy)-ethyl]-benzene 2-phenethyloxy- was prepared according to the method used for intermediate No. A but using 2-(2,3-dihydro-benzofuran-5). -yl)-ethanol instead of ethanol Ve 'H NMR (CDCl) 82.91 (t, 2H), 3.44 (t, 2H), 3.71 (t, 2H), 3.76 (t, 2H), 7.18- 7.24 (m , 3H), 7.26-7.31 (m, 2H).

PY Median No

HO. _~ 0 CL 2-[(4-Methylphenyl)methoxy}-ethanol | 0 1-bromomethyl-4- was prepared according to the method used for intermediate A, but using . 4-methoxy-benzyl chloride instead of methyl-benzene 'H NMR (CDCl3) § 2.33 (s, 3H), 3.58 (m, 2H), 3.74 (m, 2H), 4.52 (s, 2H), 7.16 ( m, 2H), 7.24 (m, 2H).

Yevyev

For intermediate YY CL 0 lbsb'8 1-(2-Bromo-ethoxymethyl)-4-methyl-benzene was prepared according to the method used for intermediate YY but using -4([-2 methylphenyl) methoxy]-ethanol © instead of 2-(2,3-dihydro-benzofuran-5-yl)-ethano '” H NMR (CDCl) 8 2.35 (s, 3H), 3.47 (t, 2H), 3.76 (6 2H), 4.55 (s, 2H), 7.16 (m, 2H), 7.24 (m, 2H). Argument #8/?a Cl N > 1 0 4- Chloromethyl-N,N-dimethyl-benzamide was prepared according to the method used for medium No. Ve, but using 4-chloromethyl- benzoyl chloride instead of 4-bromomethyl-benzenesulfonyl chloride. LC-MS (Method 2 ): Rt 2.58 mins, m/z 198 [MH]". benzamide was prepared according to the method used for IVA mediator, but using 4-chloromethyl-N,N- dimethyl-benzamide (median No. (fra) instead of 4-methoxy-benzyl chloride. x LC-MS (Method 2): Rt 1.88 mins, m/z 224 [MH]". Ye. Argument No. Tee

Yee

N ~ 0 4-(2-Bromo-ethoxymethyl)-N,N-dimethyl-benzamide was prepared according to the method used for intermediate 7?a but using 4-2-hydroxy- 2-(2,3-dihydro-) instead of (iva (intermediate ethoxymethyl)-N,N-dimethyl-benzamide .benzofuran-5-yl)-ethano ©

LC-MS (Method 2): Rt 2.75 mins, m/z 386, 388 [M]". -hydroxy-ethyl ester in zero DMF ml 001 mmol) in 764 do V2.0) solution of ethylene glycol 0°C under nitrogen; treated dropwise with sodium hydride 907680 in 0 YY oil) 6 £8 mmol) the mixture was kept at room temperature for 1 hour; then 4-chloromethyl-benzoyl chloride (1.€ g ¢ Y€ mmol) was added. The mixture was stirred at room temperature for 1 hour, then 0% aqueous ammonium chloride was added, followed by water and ethyl acetate. The organic layer was separated, dried (magnesium sulfate) 6 and evaporated. The raw material was purified over silica (Rediscip cartridge). ) and liquefaction with ethyl acetate / cyclohexane to provide the titled compound as oil Yield = Y.0 g (95677) LC-MS (Method 2): Rt 1.98 mins, molecular ion not observed Median No. 9a To suck

© 1010

HO~0 M©- 0 4-(2-Hydroxy-ethoxymethyl)-benzoic acid solution of -(2-hydroxy-ethoxymethyl)-benzoic acid 2-hydroxy-ethyl este (medium No. 41a ( V0) g; 2.758 mmol) in 10 ml of dioxane treated with 100 ml of 1 N ° sodium hydroxide ald ge at room temperature for 11 hours. diethyl ether was added; The layers were separated and the organic layer was discarded. The aqueous layer is acidified to a pH of Y= by means of aqueous HCl© and ethyl acetate is extracted. The organic layer (magnesium sulfate) 0 was dried and evaporated to provide the titled compound as a white solid. 0 > Yield < 0.97g (9677).

LC-MS (Method 2): Rt 1.88 mins, molecular ion not observed

EF Median No

HO

~~ 0 Ha H

N ~ 0 4-(2-Hydroxy-ethoxymethyl)-N-methyl-benzamide

Ae) (1 €Y (median No. 4-(2-hydroxy-ethoxymethyl)-benzoic acid) solution of 0 mg + gal mmol)' methylamine hydrochloride (1/6 mg « 6.74 mmol) and A) DIPEA 6;.! ml VEY mmol) in 0 ml of DMF treated with A) 4 g (5.71 mmol) 0. The solution was stirred at room temperature for 11 hours; And then concentrate until dry. Residue purified over silica (rediscip cartridge) and clarified by JAN YS acetate/cyclohexane; To provide the titled compound. ,. (%AA a AA = Yield Yevy (BAS) g

1

LC-MS (Method 2): Rt 1.67 mins, m/z 210 [MH]". £8 Argument No.

Bro H

N ~ 0 4-(2-Bromo-ethoxymethyl)-N-methyl-benzamide 4-2-hydroxy- | But by using YY for the method used for the intermediate Gy, © prepares 2-(2,3-dihydro- (intermediate No. 4) instead of ethoxymethyl)-N-methyl-benzamide . benzofuran-5-yl)-ethanol.

LC-MS (Method 2): Rt 2.57 mins, m/z 373 [MH]". Argument #45a

Bra_~_ 0 TX Cl 1. CN 4-(3-Bromo-propoxy)-2-chloro-benzonitrile 1 mmol) + 0.8 1 g (Y.0A) 2-chloro-4-hydroxy- benzonitrile mixed from (g; FUER) ml; 87.7 mmol) and potassium carbonate (AO) bromopropane HET. 1 hour VA Stir and heat to reflux for (Je YO) mmol) in YOY acetonitrile

Cd ye The solvent evaporates and the residue is partitioned between ethyl acetate and water. The aqueous layer Yo is extracted by ethyl acetate. Conjugated ethyl acetate extracts were washed (water; brine), dried over magnesium sulfate, and the solvent separated by evaporation in air. Purification + chromatography using a silica gel isolate cartridge (1*g) and clarification with ethyl acetate in cyclohexane. color 01 . (01%) yield = 7.88 g

TH NMR (J20) 6 2.34 (dt, 2H), 3.59 ) 2H, 4.17 ) 2H), 6.88 (dd, 1H),

YEYY 7.03 (d, 1H), 7.58 (d, 1H).

0

PET Median No

CL

That is, 0 1-{2-(2-Bromo-ethoxy)-ethyl]-4-methoxy-benzene is prepared according to the method used for intermediate number YY a, but using 2-[2-(4-methoxy-) phenyl)-ethoxy]-ethanol © instead of 2-(2,3-dihydro-benzofuran-5-yl)-ethanol . LC-MS (method no. 1): residence time 7.77 minutes; No 0 molar ion observed in intermediate No. 497 a 0 s 0 NH, 0 4-(2-Hydroxy-ethoxymethyl)-benzamide 4-chloromethyl- but using NVA prepared according to the method used for median number 0 . 4-methoxy-benzyl chloride instead of benzamide 'H NMR (CD;OD) 83.59 (m, 2H), 3.72 ) 2H), 4.61 (s, 2H), 7.46 (d, 2H), 7.85 (d, 2H).

EA Broker No

TL 8 nt x 0 0 o ' 0 NH, 0 Yo

Toluene-4-sulfonic acid 2-(4-carbamoyl-benzyloxy)-ethyl ester : ¢ aa +.00) (1£Y lagu gl)4-(2-hydroxy-ethoxymethyl)-benzamide | A solution of mmol) in 7 ml of pyridine treated with para-toluenesulfonyl chloride (280+ gm) for 87 hours. The solvent was evaporated (VT a mmol) and left to remain at room temperature for f

YEA

It was dried over “VY” and washed with copper sulfate “DCM” in vacuum, and the residue was taken in magnesium sulfate, and evaporated to dryness, to provide the compound entitled as oil. (9671) mg = 01 yield LC-MS (Method 4): Rt 2.98 mins, m/z 350 [MH"] 169 Median © 0 Mad p “OL !

Cl [2-(3,4-Dichloro-phenyl)-ethoxy]-acetic acid tert-butyl ester 2-3,4- | But by using IY it is prepared according to the method used for argument No. . 2-phenylethanol instead of dichlorophenyl)ethanol "H NMR (CDCl3) § 1.47 (s, 9H), 2.88 (t, 2H), 3.72 (t, 2H), 3.95 (s, 2H), 7.09 Ve (dd, 1H), 7.34 (m, 2H).

Cl

CX

Cl 2-[2-(3,4-Dichloro-phenyl)-ethoxy]-ethanol [2-(3,4-dichloro-phenyl)- was prepared according to the method used for intermediate 4a but using 101-phenethyloxy- instead of ( i £9 (Medium No. ethoxy]-acetic acid tert-butyl ester . No.?? a) Jas sl)acetic acid tert-butyl ester "H NMR (CDCls) § 2.85 (t, 2H), 3.55 ( m, 2H), 3.68 (t, 2H), 3.72 (m, 2H), 7.06 (dd, 1H), 7.32 (d, 1H), 7.35 (d, 1H).

Cl oY

Cl 4-[2-(2-Bromo-ethoxy)-ethyl]-1,2-dichloro-benzene

YEVY

084 2-[2-(3 4-dichloro-) but using YY prepared according to the method used for mediator No. 2-(2,3-dihydro-benzofuran- instead of) 0 (medium No. phenyl)- ethoxyl-ethanol 5-yl)-ethanol. “H NMR (CDCl3) 6 2.85 (t, 2H), 3.44 ( ) 2H), 3.69 (t, 2H), 3.75 (t, 2H), 7.07 (dd, 1H), 7.34 (m, 2H). °oY mediator no

Oh

2-[4-(3-Bromo-propoxy)-phenyl]-ethanol used for medium £0 a and medium no.; “A, but by using (3 hall prepared according to 2-010:0-4- from Yay 4-hydroxy-phenyl)-methyl-carbamic acid tert-butyl ester Ye . hydroxy-benzonitrile

LC-MS (Method 2): Rt 3.17 mins, m/z 241, 243 [M-H,0]" a oF Median No.

HO N

2

N

>»

Vo

Cyclohexyl-(5-dimethylaminomethyl-oxazol-2-yl}-phenyl-methanol (intermediate 5-bromomethyl-oxazol-2-yl)-cyclohexyl-phenyl-methanol solution of 0 treated with a solution of ?molar of THF total 9.7 mmol) in 560 ml (IN No. 7).

p-dimethylamine in Jo 0 (THF 80 mmol). Suspension formed after stirring for minutes AL . The reaction mixture was kept at room temperature overnight, and then the solid was filtered off. The filtrate was concentrated through a reducing pressure and the residue was partitioned between the DCM and a saturated sodium hydrogen carbonate solution. The organic layer was dried (0 sodium sulfate) and evaporated to provide the titled compound as a solid. Productivity = 7.74 g (9695). LC-MS (Method 1): Rt 6.57min, m/z 315 [MH"] 'H NMR (DMSO-dg): 6 0.92-1.29 (m, 6H), 1.42-1.74 (m, 4H) , 2.10 (s, 6H), 2.22 (m, 1H), 3.45 (s, 2H), 5.90 (s, 1H), 6.98 (s, 1H), 7.18-7.22 (m, 1H), ( m, 2H), 7.40-7.46 (m, 2H). (Y.VE) g) was separated by preparative chiral HPLC using a Yo X You mm Keralpack column primed with a © μmol silica gel stabilizer. The column was liquified by 965 ethanol in heptane buffer with 100 76 diethyl 10 Amine at a rate of 15 mL/min.The first leaching enantiomer (residence time = 8.58 min) provides (S)-cyclohexyl-(5-dimethylaminomethyl-oxazol-2-yl)-phenyl-methanol (median ¢). 0 as a white solid Median 54 a N & J oy / N \ Y Yield = .0.77 g (96797) LC-MS (Method 1): Rt 6.50 min, m/ z 315 [MH*].

Yo) 'H NMR (CDCly): § 1.12-1.39 (m, 7H), 1.62-1.76 (m, 3H), 2.25 (s, 6H), 2.29-2.32 (m, 1H), 3.54 (dds, 2H) , 3.70 (br.s, 1H), 6.84 (s, 1H), 7.24 (t, 1H), 7.33 (1, 2H), 7.64 (d, 2H).

R)-cyclohexyl-min) Provides compound 0017 = larval enantiomer II (residence time) I 00 (median No. (5-dimethylaminomethyl-oxazol-2-yl)-phenyl-methanol 0 . as a white solid Color Intermediate No. 85 A

HO i, N 2

N

\ . 9677) c 11 Productivity = § b

LC-MS (Method 1): Rt 6.48 min, m/z 315 [MH"] Ve 'H NMR (CDCl): 6 1.10-1.39 (m, 7H), 1.62-1.76 (m, 3H), 2.25 (s , 6H), 2.29-2.35 (m, 1H), 3.54 (dds, 2H), 3.70 (br.s, 1H), 6.84 (s, 1H), 7.24 (t, 1H), 7.33 (t, 2H), 7.64 (d, 2H). Argument No. 576a

Cl

HOT 0 2-(3,4-Dichloro-benzyloxy)-ethanol 3,4-dichlorobenzyl mmol) was added to 1.0776 potassium hydroxide (7 g mol) and heated in YT ml; VEY) glycol (li) ml) in 2.04 (aa 0) chloride . VT watch for Aggie °C for 'hours; Hence at 50 degrees 0 . The mixture was allowed to cool to room temperature and then water and diethyl ether 0 were added; Dried (magnesium sulfate) and evaporated. The remainder is purified by the Bib clad organic layer

11 and liquefaction with cyclohexane ¢ and from IST chromatographically released SPE (cartridge) then 9670 diethyl ether / cyclohexane to provide the titled compound as colorless oil. (%VY) yield = 5014 g 'H NMR ((J00)) 5 1.75-2.00 (br s, 1H), 3.60 ) 2H), 3.78 (t, 2H), 4.52 (s, 2H), 7.14-7.19 (m, 1H), 7.39-7.46 (m, 2H) ° Parameter No. uh a y 0 ar 0 Cl 4-(2-Bromo-ethoxymethyi)-1,2-dichloro-benzene 104 cpa £94) (107 (parameter No. 2-(3) A solution of 4-dichloro-benzyloxy)-ethanol (ml) was stirred at room temperature. carbon (? .1 g h. VY sad mmol) and the reaction mixture stirred at room temperature oe YY + was triturated with diethyl ether and filtered. The filtrate was purified, 5c, the reaction mixture was concentrated in vacuum and decantation by means of cyclohexane to provide (IST dallas SPE chromatographic) cartridge. The compound entitled Ye . 961 0 0 (yield = 0.1¢ g’ H NMR :(wa0600) 8 3.50 (t, 2H), 3.80 (t, 2H), 4.54 (s, 2H), 7.16-7.20 (m, 1H) , 7.39-7.47 (m, 2H) Intermediate #58a 2 OH 4-[2-(2-Hydroxy-ethoxy)-ethyl]-phenol

Yevy

YoY

YALA 0.3 g) 2-[2-(4-benzyloxy-phenyl)-ethoxy]-ethanol palladium/carbon solution (amount approximately covering the peak of 9600 mmol treated with IMS) in 0 ml of an hour another part of 0.5 spatulas) and the mixture is hydrogenated under a balloon of hydrogen. After indicating that all TLC catalyst was added and the mixture was hydrogenated overnight. Start readings have reacted. The catalyst is filtered through a hi-flu and the volatile substances are evaporated. Product 0 (Cyclohexane 1:1 crude purified by silica gel chromatography and clarification with ethyl acetate. To obtain compounds labeled as oil without hazy color) RE = 1.79. (%A4) = 0.0 g Throughput LC-MS (Method 2): Rt 1.91 min, no molecular ion observed.

Pod number 0

Br 0 cl

Oh

4-[2-(2-Bromo-ethoxy)-ethyl]-phenol The entitled compound is prepared using the same method as for intermediate No. 7?a, but using . jo A mediator . (9687) yield = 3.25 g Vo

LC-MS (Method 2): Rt 3.03 min, no molecular ion observed a+1 mediator for gr 0 1-(2Bromo-ethoxymethyl)-4-tert-butoxy-benzene

1 The titled compound is prepared by using methods corresponding to the mediator No. © a; mediator A 717 and median No. YE No. . (9687 g) FLV = Yield 1H NMR (CDCls) 6 1.34 (s, 9H), 3.49 (t, 2H), 3.79 (t, 2H), 4.54(s, 2H)? 6.94-7.00 ( m, 2H), 7.22-7.28 (m, 2H). mmol) formed in V4.0 ¢ mg N-hydroxy acetamidine (VAL) partial solution of metallic; Cu) sodium hydride (000 mg) of 96760 in Canal. (Je 01 ( THE 0 . hour 1 mmol) part by part and then the mixture was stirred at room temperature for 7 or mmol) and the mixture was heated in 116 ¢ 018 ml (Ethyl 4-bromobutyrate) was added for hours and then allowed to cool to a temperature Room The mixture was quenched Badd © °C carefully with aqueous ammonium chloride and then diluted with water (100 ml) and extracted with ethyl acetate (ml twice). The residue was purified through an Escco Companion column of silica gel and clarification with a malt of ethyl acetate in cyclohexane to obtain the compound entitled as yellow oil 96000-RV. Pale color (PN + mg) 701 = yield 01 "TH NMR (CDCls, 400 MHz): § 2.34-2.41 (5 H, m), 3.06 (2 H, 1), 3.52 (2H, 1).

MY Median No

This 1 0 HO Cl 2-Chloro-4-hydroxy-benzamide (YY) 2-Chloro-4-hydroxy-benzonitrile (g ¢ V4.0 mmol) was added (in fractions of transmethylated sulfuric acid) 0 9657-4 - (Je 01). The dark reddish solution was stirred repeatedly at room temperature ° for T day 0 The reaction mixture was slowly poured over ice (Je Yeo with stirring and then extracted) 79 times) ethyl acetate Conjugated ethyl acetate extracts were washed (53a ¥ clad ¢ brine 1 time) and dried over Cady 0 magnesium sulfate and evaporated. The residue was purified by chromatography using a silica gel cartridge, Yo g, and clarified with a molality of 0-0000096 ethyl acetate in cyclohexane to obtain compound 0 labeled as a solid. Productivity = Can 17/7 9671 . 'H NMR (DMSO-dg): 5 6.73 (dd, 1H), 6.81(d, 1H), 7.32(d, 1H), 7.37 (s, 1H), 7.63(s, 1H), 10.16 (bs, 1H) The median is the PAY number. 0 Br'yo~ 0 0 4-(3-Bromo-propoxy)-2-chloro-benzamide Prepared according to the method used for intermediate No. 160 but using 2-chloro-4-hydroxy-benzamide 2-chloro-4-hydroxy-benzonitrile and heating for VE an hour. Yield = YY gm < 9747 . LC-MS (Method 2): R; 2.90 min m/z 292,294 [MH] Ye Example 1a

111

N

7 11 +

HO” nl + 0 N ~ 0 1 0 0”

H A 0 [2-(R)-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-[2-(4-methoxy-benzyloxy)-ethyl]-ammonium formate.

R)-cyclohexyl-(5-dimethylaminomethyloxazol-2-yl)-phenyl-methanol A solution of methanesulfonic acid (medium No. 00 )) © mg ¢ +17 mmol) and -4)-2 © mmol) 10974 mg (YY) (119 (intermediate no. methoxy-benzyloxy)-ethyl ester 460°C for 00 and acetonitrile (1ml) heated at (de015) in chloroform hr. The reaction mixture Concentrate to dryness and purify by column chromatography and clarification

HPLC The resulting oil is purified by . DCM / by ethyl acetate and 906780 methanol acid 96 101 preparatory and laxative by 9648-85 acetonitrile / water containing 0. Formic to provide the titled compound as a solid. (% ¢Y Yield - 7 mg).

LC-MS (Method 1): R; 7.33, m/z 479 [M"] 1H NMR (CDCl3) 8 1.13 (m, 3H), 1.28 (m, 3H), 1.44 (m, 1H), 1.63 (m, 2H), 1.74 (m, 1H) , 2.29 (m, 1H), 3.12 (s, 6H), 3.65 (m, 2H), 3.82 (s, SH), 4.45 (s, \o 2H), 4.90 (m, 2H), 6.89 (d, 2H ), 7.21 (m, 3H), 7.29 (m, 2H), 7.37 (s, 1H), 7.55 (d, 2H), 8.60 (bs, 1H).

Cyclopentyl-(5- (CDCl3): 8 1.14-1.76 | (Method 2): : : (m, 9H), 2.25 )6, 6H), | Rt2.1min, dimethylamine 2953.07 (m, 1H), | m/z 301 thyl-oxazol-2-yl)- 0-1 n 3.46-3.60 (dd, 2H), [MH] 0/ 3.72 (bs, 1H), 6.84 (s, phenyl-methanol. 6 LH) 7.19.7.58 (mn 1H), 7.28-7.36 (m,

YEYV 2H), 7.59-7.65 (mm,

YoVv

Cyclopentyl-(5- (CDCl): §1.14-1.76 | (Method 2): : (m, 9H), 2.25 (s, | Rt 2.1min, dimethylaminome HON 6H), 2.95-3.07 (m, m/z 301 thyl-oxazol-2-yl)- 2 1H), 3.46-3.60 (dd, [MH] phenyl-methanol 2 AA - first eluting | 8 7.28 (m.1H), 7.28- : 7.36 (m, 2H) ), 7.59- enantiomer 7.65 (m, 2H).

Cyclopentyl-(5- (CDCl): 6 1.14-1.76 | (Method 2): : .(m, 9H), 2.25 (s, 6H), Rt 2.1min, dimethylaminome HO 2 2.95-3.07 (m. 1H). m/z 301 thyl-oxazol-2-yl)-6 3.46-3.60 (dd, 2H), [MH] phenyl-methanol 1 | 3.72 (bs, 1H), 6.84 Gs,

Intermediate 3a 1H), 7.19-7.28 (m, — second eluting | ——————————— 1H), 7.28-7.36 (m, .2H), 7.59-7.65 (m, enantiomer 2H).

Cyclobutyl-(5- (CDCl3)6 1.65-1.77 | (Method 4): dimethylaminomet (m, 2H), 1.78-1.89 | Rt 2.09min, hyl-oxazol-2-yl)- HON (m, 2H), 2.04 -2.15 m/z 287 phenyl-methanol 2 / | (m, 2H), 2.23 (s, 6H), [MH] b" 3.37 (m, 1H), 3.50

Intermediate 4a er 10, 7.24 (t, 1H), 7.31 (t, 2H), 7.48 (d, 2H)

Cyclobutyl-(5- (CDCls): § 1.65-1.76 | (Method 1): : (m, 2H), 1.79-1.88 | Rt 5.55 min, .|dimethylaminome HON (m, 2H),2.05-2.14 |m/ z 7 thyl-oxazol-2-yl)- 20 (m, 2H), 2.23 (s, 6H), [MH ohenyl-methanol | 3.38 1H), 3.50 . . Intermediate 5a (dds, 2H), 3.61 (bs, — first eluting | ———————=———=% 1H), 6.86 (s, 1H), : 7.24 (m, 1H), 7.31 enantiomer ( m, 2H), 7.48 (m, 2H).

Cyclobutyl-(5- (CDCl): §1.65-1.76 | (Method 1): : : (m, 2H), 1.79-1.88 | Rt 5.43 min, dimethylaminome HO 2 (m.2H), 2.05-2.14 m/z 287 thyl-oxazol-2-yl)- Ay fn, 2). 223 5, GH), [MH] ygyy phenyl-methanol (dda, 2H), 3.61 (bs,

1001 — second eluting | Intermediate 6a 1H), 6.86 (s, 1H), : 7.24 (m, 1H), 7.31 enantiomer (m, 2H), 7.48 (m, 2H). (2-Benzyloxy- (CDCl3) 6 1.28 (m, | (Method 1): ethyl)-[2- MN 1H), 1.43 (m, 2H), | Rt 8.00 min, (cyclopentyl- | 8 AN 1.50-1.67 (m, SH), 2. m/z 435 hydroxy-phenyl- 0 OO 95 (m, 1H), 3.21 (s, [M'] methyl)-oxazol -5- ol 6H), 3.70-3.88 (m, ylmethyl]- Examole 1a 4H), 4.52 (s, 2H), dimethyl- | =X@mple fa 5.00 (dag, 2H), 7.18 ammonium (t, 1H), 7.23-7.30 (m, formate. (from 4H), 7.31-7.38 (m, second enantiomer) 3H), 7.40 (s, 1H) ), 7.52 (d, 2H), 8.55 (bs, 1H) [2-(Cyclopentyl- (CDCls) 6 1.31-1.66 | (Method 1): hydroxy-phenyl- (m, 8H), 3.01 (m, | Rt 7.89 min, methyl)-thiazol-5- 1 y!1H), 3.40 (s, 6H), m/z 421 ylmethyl]- 7 a Ny 2 4.19 (m, 2H), 4.47 + dimethyl-(2- | “© AN (m, 2H), 5.24 (dda, IM] phenoxy-ethyl)- Br” 2H), 6.88 (d, 2H), ammonium 7.05 (t, 1H), 7.22 (t, bromide. (from Example 2a 1H), 7.32 (m, 4H), second enantiomer) 7.56 (m, 3H).[2-(Cyclopentyl- (CDCl3) 6 1.25-1.65 | (Method 1): hydroxy-phenyl- (m, 8H), 2.99 (t, 1H), | Rt 7.74min, methyl)-oxazol-5- N : 3.04 (t, 2H), 3.18 (t, m/z 447 ylmethyl]-[2-2,3- | Ma 1 dmn 2H), 3.33 (s, 6H), [M*) dihydro- LY | 3.63 (m 2H), 4.56 benzofuran-5-yl)- Br 2H), 5.24 (ddAB, ethyl]-dimethyl- 2H), 6.71 (d, 1H), ammonium Example 8 , 1H).(3-{4-[(tert- (CDCl3) 8 1.12 (m, | (Method 4):

Butoxycarbonyl- | slander CAN Lo 3H), 1.31 (m, 3H), | Rt 2.83min, methyl-amino)- ° [Ce 1.47 (s, 9H), 1.54- m/z 592 methyl]-phenoxy}- 8 o 1.77 (m, 4H), 2.31 [M'] propyl)-[2 -(R)- Intermediate 7a (m, 2H), 2.40 (m, (cyclohexyl- | — sca 1H), 2.79 (s, 3H), hydroxy-phenyl- 3.12 (s, 6H), 3.45 (m ,

Vy methyl)-oxazol-5- 2H), 4.03 (m, 2H),

1001 ylmethyl}- 4.36 (s, 2H), 4.78 (s, dimethyl- 2H), 6.90 (d, 2H), ammonium 7.19 (m, 3H), 7.29 bromide. (m, 2H), 7.52 (m, 3H) [2-(Cyclobutyl- (CDCl3) 8 1.59 (m, | (Method 1): hydroxy-phenyl- 1H), 1.71 (m, 1H), | Rt 7.08min , methyl)-oxazol-5- 1 1.78 (m, 1H), 1.95 m/z 407

Sine. or AN 0 oo 230 on, phenoxy-ethyl)- . 3.30 (m, 1H), 3.39 (s, ammonium Br 3H), 3.40 (s, 3H), bromide. (from Example 4a 4.11 (t, 2H), 4.42 (m, second enantiomer) 2H), 4.85 (s, 1H), 5.12 (ddas, 2H), 6.87 (d, 2H), 7.02 (t, 1H), 7.19 (m, 1H), 7.25 (m, 2H), 7.30 (m, 2H), 7.40 (m, 2H), 7.56 (s, 1H). (2-Benzyloxy- (CDCl3) 8 1.60 (m, | (Method 1): ethyl)-[2- 1H), 1.72 (m, 1H), | Rt 7.27min, (cyclobutyl- N 1.78 (m, 1H), 1.92 m/z 421 hydroxy-phenyl-1 mah (m, 1H), 2.06 (dt, [M'] methyl)-oxazol-5 Example 5a 3.87 (m, 2H), 4.53 (s, bromide) (from 2H), 4.73 (s, 1H), second enantiomer) 5.00 (s, 2H), 7.20 (t, 1H), 7.23-7.30 (m, 4H), 7.31-7.41 (m, 5H), 7.43 ( s, 1H). - 1 1.77 (m, 1H), 1.90 m/z 433 ylmethyl]-[2-(2,3- | [oN To (m, 1H), 2.06 (dt, [M'] dihydro- 0 1H), 2.24 (dt, 1H), benzofuran-5-yl)- TCR 2.99 (dd, 2H), 3.16 (t, ethyl]-dimethyl- 2H), 3.29 (s, 3H), ammonium | Example 6a 3.30 (s, 3H) , 3.33 (m, bromide. (from 1H), 3.61 (m, 2H), second enantiomer) 4.53 (t, 2H), 4.58 (s, 1H), 5.05 (dds, 2H), 1 6.66 (d, 1H) , 6.93

Yq. (dd, 1H), 7.15 (s, 1H), 7.18-7.28 (m, 3H), 7.39 (m, 2H), 7.52 (s, 1H) [3-(4-Carbamoyl- (CD30OD) 8 1.33 (m , |(Method 1): phenoxy)-propyl]- 1H), 1.44 (m, 2H), | Rt 6.22min, [2-(cyclopentyl- a 1.51-1.76 (m, 5H), m/z 478 hydroxy-phenyl- | “87 M RAR” 2.34 (m, 2H), 3.08 [M'] methyl) -oxazol-5-Br I" | (m, 1H), 3.13 (s, 3H), ylmethyl]- 3.14 (s, 3H), 3.46 (m, dimethyl- | Example 7a 2H), 4.09 (m, 2H), ammonium 4.80 (s, 2H), 6.98 (m, bromide. (from 2H), 7.20 (t, 1H), second enantiomer) 7.29 (m, 2H), 7.51 (m, 2H), 7.54 (s, 1H), 7.86 (mm, 2H). [2-(Cyclopentyl- (CD;0D) 61.34 (m, | (Method 1): hydroxy-phenyl- 1H), 1.44 (m, 2H), | Rt 8.82min, methyl)-oxazol-5- 1 | 1.54-1.76 (m, SH), m/z 503 ylmethyl]-[3-(3,4- Ho Hoy 2.30 (m, 2H), 3.07 [MT] dichloro-phenoxy)- or a | (m, 1H), 3.11 (s, 3H), propyl]-dimethyl- 3.12 (s, 3H), 3.42 (m, ammonium | Example 8a 2H), 4.00 (m, 2H), bromide. (from 4.77 (s, 2H), 6.88 second enantiomer) (dd, 1H), 7.11 (d, 1H), 7.21 (t, 1H), 7.29 (t, 2H), 7.42 (d, 1H), 7.51 (m , 3H). [3-(4-Carbamoyl- (CD50D)6 1.57-1.73 | (Method 1): phenoxy)-propyl}- (m, 2H), 1.77 (m, | Rt 5.80min, [2-(cyclobutyl- 1 1H) ), 1.82 (dt, 1H), m/z 464 hydroxy-phenyl- with a load of 1.99 (m, 1H), 2.21 [M7] methyl)-oxazol-5-i (dt, 1H), 2.33 ( m, ylmethyl]- 9 0 2H), 3.12 (s, 3H), dimethyl- 3.13 (s, 3H), 3.45 (m, ammonium mt 8 3H), 4.07 (m, 2H), bromide. (from 4.77 (s, 2H), 6.98 (m, second enantiomer) 2H), 7.21 (t, 1H), 7.28 (m, 2H), 7.39 (m, 2H), 7.52 (s, 1H), 7.86 (m , 2H). [2-(R)- (CDCl3) 8 1.13 (m, | (Method 1): (Cyclohexyl- 3H), 1.21-.1.39 (mm, | Rt 8.16min, y ¢ yy fydroxy-phenyl- 5H), 1.67 (m, 2H), |m/z 556

011 methyl)-oxazol-5- 2.32 (m, 1H), 2.72 (s, [M1] ylmethyl]-[2-(4- CM Nk 6H), 3.27 (s, 3H), dimethylsulfamoyl- "0 A Cy _ 3.28 (s, 3H), 3.94 (m, benzyloxy)-ethyl]- Br JN 2H), 4.00 (m, 2H), dimethyl- 4.67 (s, 2H), 5.14 ammonium (t, bromide. 1H), 7.32 (t, 2H), 7.48 (m, 3H), 7.56 (d, 2H), 7.76 (d, 2H). [2-(Cyclopentyl- (CD;0D) § 1.35 ( m, | (Method 1): pols. 1H), 1.46 (m, 2H), | Rt 8.33min, methyl)-oxazol-5- Nol 1.54-1.75 (m, 5H), m/z 449 ylmethyl]- Ho Sk 2.89 (t, 2H), 2.94 (s, [117] dimethyl-(2- Br 6H), 3.08 (m, 1H), henethyloxy-

RIE | ani 11a man $7 bromide. (from 4.56 (dag, 2H), 7.11 second enantiomer) (m, 1H), 7.20 (m, 4H), 7.25 (t, 1H), 7.33 (m, 2H), 7.37 (s, 1H), 7.53 (m , 2H). [2-(Cyclobutyl- (CDs0D) § 1.64 (m, | (Method 1): ry phony 1H), 1.72 (mm, 1H), | Rt 7.91min, methyl)-oxazol-5- N 1.85 (dt, 1H) ), 1.99 m/z 435 MH (m, 1H), 2.07 (dt, [M'] methyl-(2-

Shenton. Br 2. 88 oth os ethyl)-ammonium Example 12a 6H), 3.41 (m, 1H), bromide. (from 3.47 (m, 2H), 3.77 (t, second enantiomer) 2H), 3.85 (m, 2H), 4.55 (dda, 2H), 7.12 (m, 1H), 7.21 (m, 4H), 7.25 (t , 1H), 7.32 (m, 2H), 7.37 (s, 1H), 7.40 (m, 2H). [2-(R)- (CDCl3) 61.14 (m, | (Method 1): (Cyclohexyl- 3H), 1.23-1.40 (m, | Rt 6.88min, hyd -phenyl- N - ammon Q mi we ; y ons > o b , 3H, 2.32 (m, 1H), [M7] yimetnyl]-| 2-(4- ~ 97 (s, 3H), 3.11 (s, dimethylcarbamoyl 9© 3H), 3.26 (s , 3H), -benzyloxy)-ethyl]- Example 13a 3.27 (s, 3H), 3.93 (m, dimethyl- 4H), 4.58 (s, 2H), ammonium 5.06 (d, 1H), 5.19 (d, 11 1H) ), 7.24 (t, 1H),

11 bromide. 7.32 (m, 4H), 7.41 (d, 2H), 7.47 (s, 1H), 7.57 (d, 2H). [2-(R)- (CDCl) 81.14 (m, | (Method 1): (Cyclohexyl- 3H), 1.24-1.40 (m, | Rt 6.63min, hydroxy-phenyl-m 4H), 1.65 (m , 2H), m/z 506 methyl)-oxazol-5- HO CA Wn 1 1.76 (m, 1H), 2.32 [MT] ylmethyl]-[2-(4-i a© (m, 1H), 3.01 (d) , methylcarbamoyl- > 0 3H), 3.23 (s, 3H), benzyloxy)-ethyl]- | Example 14a 3.24 (s, 3H), 3.88 (m, dimethyl- 4H), 4.08 (s, 1H), ammonium 4.58 (s, 2H), 5.05 (d, bromide. 1H), 5.13 (d, 1H), 6.73 (m, 1H), 7.24 (t, 1H), 7.32 (m, 4H), 7.45 (s, 1H), 7.77 (d, 2H), 7.56 (d, 2H). [3-(3-Chloro-4- (CDCl) 81.03-1.26 | (Method 5): cyano-phenoxy)- (m, 3H), 1.26-1.38 1 Rt 8.10min, propyl]-[2-(R) - N (m, 3H), 1.55-1.78 m/z 508 (cyclohexyl- | wo I mM (m, 4H), 2.29-2.45 [M*] hydroxy-phenyl- TL, (m, 3H), 3.11 (s, 3H), methyl)-oxazol-5- > 3.12 (s, 3H), 3.42 (m, ylmethyl]- | Example 15a 2H), 4.11 (m, 2H), dimethyl- 4.77 (s, 2H) , 7.02 ammonium (dd, 1H), 7.21 (m, bromide. 2H), 7.30 (m, 2H), 7.52 (m, 3H), 7.74 (d, 1H). [2-(R)-(CDCl3) $1.05-1.28 | (Method 5): (Cyclohexyl- (m, 3H), 1.33 (m, | Rt 8.27min, hydroxy-phenyl- : N o| 3H), 1.54 (m, 1H), m/z 493 methyl)-oxazol- 5-| wo Ae ST 1.68 (m, 2H), 1.77 [MT] ylmethyl]-{2-[2-(4- (m, 1H), 2.40 (m, methoxy-phenyl)- or 1H), 2.83 (t, 2H) ), ethoxy]-ethyl}- | Example 16a 2.95 (s, 6H), 3.45 (m, dimethyl- 2H), 3.70 (s, 3H), ammonium 3.73 (t, 2H), 3.85 (mm, bromide. 2H), 4.55 (s, 2H), 6.78 (m, 2H), 7.13 (m, 2H), 7.25 (m, 1H), 7.33 (m, 3H), 7.53 (m, 2H).

benzyloxy)-ethyl]- (m, 3H), 1.26-1.37 | Rt 6.93min, [2-(R)-(cyclohexyl- 0 a (m, 3H), 1.55 (m, m/z 492 hydroxy-phenyl- om, TO 1H), 1.67 (m, 2H), [ M] methyl)-oxazol-5- 15 malsen 1 2 1.75 (m, 1H), 2.39 ylmethyl}- (m, 1H), 3.11 (s, 6H), dimethyl- | Example 17a 3.55 (m, 2H), 3.96 ammonium (m, 2H), 4.65 (s, 2H), format. 4.78 (s, 2H), 7.24 (1, 1H), 7.31 (d, 2H), 7.43-7.53 (m, SH), 7.88 (d, 2H), 8.40 (bs, IHx 1.5 formate). [2-(R)- (CD3;0D)6 1.07-1.24 | (Method 5): (Cyclohexyl- (m, 3H), 1.28-1.38 | Rt 8.60min, hydroxy-phenyl- N cl (m, 3H), 1.58 (m, m/z 503 methyl)-oxazol-5- | wo EY Ne JL 1H), 1.67 (m, 2H), [M1] ylmethyl]-[2-(3,4- - 1.77 (m, 1H), 2.42 dichloro-phenoxy)- (m, 1H), 3.16 ( s, 6H), ethyl}-dimethyl- Example 18a 3.76 (m, 2H), 4.49 ammonium (m, 2H), 4.84 (s, 2H), bromide. 6.96 (dd, 1H), 7.22 (d, 1H), 7.25 (t, 1H), 7.33 (m, 2H), 7.46 (d, 1H), 7.53 (m, 3H). [2-(R)-(CDsOD)6 1.05–1.27 | (Method 1): (Cyclohexyl- (m, 3H), 1.28-1.40 | Rt 9.20min, hydroxy-phenyl- N cl (m, 3H), 1.57 (m, m/z 531 methyl)-oxazol-5- | Ho CY Me m|d 1H), 1.68 (m, 2H), (M1) dition. l * 0 phenyl)-ethoxy]- Example 19a 2.98 (s, 3H), 2.99 (s, ethyl}-dimethyl- 3H), 3.48 (m, 2H), ammonium 3.75 (t, 2H), 3.87 (m , bromide.2H), 4.62 (s, 2H), 7.17 (dd, 1H), 7.25 (t, 1H), 7.33 (t, 2H), 7.39 (t, 2H), 7.41 (d, 1H), 7.53 ( m, 2H). [2-(R)- (CD;0D) 6 1.03-1.22 | (Method 5): (Cyclohexyl- (m, 3H), 1.23-1.39 | Rt 7.18min, hydroxy-phenyl- (m, 3H), 1.57 (m, m/z 493 methyl)-oxazol-5- 1H), 1.65 (m, 2H), [M'] ylmethyl]-{3-[4-(2- 1.74 (m, 1H), 2.29 17/4 hydroxy-ethyl)- (m, 2H), 2.40 (m,

phenoxy]-propyl}- 1H), 2.76 (t, 2H), dimethyl- NOT NL 3.11 (s, 6H), 3.44 (m, ammonium | Ao 2H), 3.70 ) 2H), bromide. Br 4.01 (mm, 2H), 4.77 (s,

OH 2H), 6.84 (m, 2H), 7.15 (m, 2H), 7.21 (t,

Example 8

Example 20a 1H), 7.30 (m, 2H). 7.52 (m, 3H). [2-(R)-(CDs0D)8 1.05-1.27 | (Method 5): (Cyclohexyl- (m, 3H), 1.28-1.40 | Rt 8.08min, hydroxy-phenyl- N (m, 3H), 1.57 (m, m/z 449 methyl)-oxazol-5- HO™ ao JT 1H), 1.67 (m, 2H), [M™] ylmethyl]- 1.77 (m, 1H), 2.28 (s, dimethyl-(2-p- 9 3H), 2.41 (m, 1H), tolyloxy -ethyl)- Example 21a 3.16 (s, 6H), 3.73 (1, ammonium 2H), 4.44 (m, 2H), bromide. 6.88 (m, 2H), 7.13 (d, 2H), 7.25 (t, 1H), 7.33 (m, 2H), 7.53 (m, 3H). [2-(Cyclopentyl- (CD;0D): § 1.22- | (Method 5): hydroxy-phenyl- 1.76 (m, 8 H), 2.98- | Rt 8.60 min, methyl)-oxazol-5- \ 3.12 ( m, 1H), 3.08 (s, m/z 503 ylmethyl]-[2-3,4- | wo J Me ~, a | 6H), 3.49-3.56 (m, [M'] dichloro- 1a 2H), 3.87-3.96 (m, benzyloxy)-ethyl]- Br 2H), 4.54 (s, 2H), dimethyl-amm | Example 22a 4.76 (s, 2H), 7.16-onium bromide. 7.22 (m, 1H), 7.24- (from second 7.31 (m, 3H), 7.43 (s, enantiomer) 1H), Taso [2-(Cyclopentyl- (CD;OD): 8 1.27- | (Method 5): hydroxy-phenyl- 1.78 (m, 8H), 2.33 (s, | Rt 8.30 min, methyl)-oxazol-5- \ 3H), 3.02-3.14 (m, m/z 449 ylmethyl)- 1 mo I Me_~, 1H), 3.08 (s, 6H), [M*] dimethyl-[2-(4- 11 3483.54 (m, 2H), methyl-benzyloxy)- 9 3.86-3.94 (m, 2H), ethyl]-ammonium | Example 23a 4.53 (s, 2H), 7.16- bromide (from 7.34 (m, 7TH), 7.43 (s, second enantiomer) 1H), 7.48-7.54 (m, 2H) [2-(4- (CD;OD) : § 1.27- (Method 5):

Chlorophenoxy)- 1.81 (m, 8H), 3.04- | Rt 8.28 min, p" ethyl]-[2- 3.14 (m, 1H), 3.08 (s, m/z 455)

Yio (cyclopentyl- 6H), 3.79 (t, 2H), [M7] hydroxy-phenyl- ML 0 ] 4.48 (t, 2H), 4.88 (s, methyl)-oxazol-5- no 2 fm, ylmethyl }- Br , 7.20 -7.36 (m, dimethyl- Example 24a 5H), 7.49-7.60 (m, ammonium Example 8 3H) bromide (from second enantiomer) [2-(Cyclopentyl- (CDs0D): 8 1.26- | (Method 5): hydroxy-phenyl- 1.80 (m, 8H), 2.27 (s, | Rt 8.22 min, methyl)-oxazol-5- 1 3H), 3.02-3.14 (m, m/z 435 ylmethyl]- Ho ok JT 1H), 3.18 (s, 6H), [M'] dimethyl-(2-p- l 3.76 (t, 2H), 4.44 (1, tolyloxy-ethyl)- Br 2H), 4.87 (s, 2H) , ammonium | Example 25a 6.87 (d, 2H), 7.12 (d, bromide 2H), 7.31 (t, 1H), (from second to 2 enantiomer) .50-7.56 (m, 3H) [2-((R)- (CD;0OD): 8 1.04- (Method 1):

Cyclohexyl- 1.42 (m, 6H), 1.48- | Rt 7.86 min, hydroxy-phenyl- N oH 1.85 (m, 4H), 2.34- m/z 479 methyl)-oxazol-5- | ox 1 Ne ST 2.47 (m, 1H), 2.80 (t, [M'] ylmethyl]-{2-[2-(4- - 2H), 2.95 (s, 6H), hydroxy-phenyl)- 3.42-3.46 (m, 2H), cthoxyl-ethy! 1 Example 26a 3.72 (t, 2H), 3,81-imethyl- 3.87 (m, 2H), 4.58 (s, ammonium 2H), 6.65-6.70 (m, bromide 2H), 7.00-7.05 (m, 2H), 7.23-7.28 (m, 1H), 7.31-7.36 (m, 2H), 7.38 (s, 1H), 7.50-7.55 (m, 2H). [2-((R)- (CD3;0D) 6 1.01- | (Method 1) ~ ydrony 182 (m. 41D, 2.19. | Rt 7-24min - .82 (m, ,2.19-phenylmethyl)- | on Ibo 2.33 (m, 2H), 2.35-m/z 465 oxazol-5-on |2.48 (m, 1H), 3.10 (s, [M] ylmethyl]-[3-(4- Br 6H), 3.38-3.57 (m, hydroxy-phenoxy)- 2H), 3.89-4.05 (m : Example 27a ' ' propyl}-dimethyl 2H), 4.77 (s, 2H), ammonium 6.66-6.81 (m, 4H), bromide 7.17-7.37 ( m, 3H), 7.47-7.59 (m, 3H).

Yevy

1 [2-((R)- (CDCl3) 5 0.99-1.49 | (Method 1):

Cyclohexyl- (m, 7H), 1.53-1.78 | Rt 8.44min, hydroxy-phenyl-bd (m, 3H), 3.07 (t, 2H), m/z 443 methyl)-oxazol-5- | To am << 3.38 (s, 3H), 3.40 (s, [M7] yimethyl)- TN 3H), 3.72 (t, 2H), dimethyl-(4- Br 5.21-5.40 (m, 2H), phenyl -but-3-ynyl)- 7.16-7.40 (m, 8H), ammonium | Example 28a 7.52-7.62 (m, 3H). bromide [2-(4-Chloro- (CDCl3) §0.94-1.36 | (Method 1): phenoxy)-ethyl]-[2- (m, 6H), 1.46-1.78 | Rt 8.58min, ((R)-cyclohexyl- 0© | (m, 4H), 2.28 (s, 1H), m/z 469 hydroxy-phenyl- | To) be LT 3.15 (s, 6H), 3.87 (S , (M"] methyl)-oxazol-5- 2H), 4.34 (s, 2H), yimethyl) or 4.92 (s, 2H), 6.80 (d, imethyl- 2H), 7.13-7.30 (m, ammonium | Example 29a 5H), 7.39-7.58 (m, bromide 3H).[2-(4-tert-Butoxy- (CDCl3) 8 1.10-1.43 | (Method 5): benzyloxy)-ethyl]- (m, 15H), 1.47 -1.61 | Rt 9.19min, [+ {R®) ayctahet: = Ag[(m, 3H), 1.86 (s, 1H), m/z > - - " 0 - ydraxy pheny 0 Ok 2.22-2.40 ( m, 1H), [M'} met. nt - 3.60 (s, 6H), 3.67- ylmethyl]- 3.88 (m, 4H), 4.15 (s, dimethyl- | Example 30a 1H), 4.45 (s, 2H), ammonium 5.04-5.26 (m, 2H), bromide 6.85-7.04 (m, 2H), 7.13-7.38 (m, SH), 7.44 (s, 1H), 7.52- 7.62 (m, 2H). [2-((R)- (CDCl3)8 1.01-1.51 | (Method 1):

Cyclohexyl- (m, 8H), 1.55-1.81 | Rt 7.15min, hydroxy-phenyl-N o-N (m, 3H), 2.02-2.53 m/z 439 methyl)-oxazol-5- | Tamesta Lidem | (m, 21), 2.37 (s, 3H), [M*] ylmethyl]- 2.91 (t, 2H), 3.29 (s, dimethyl-[3-(3- Br 6H), 3.53-3.71 (m, methyl) - 2H), 5.04-5.23 (m, [1,2,4]oxadiazol-5- | Example 31a 2H), 7.19-7.25 (m, yD)-propyl]- 1H), 7.30 (t, 2H), ammonium 7.49-7.59 (m, 3H). bromide [3-(4-Carbamoyl-3- (CD;0D) 6 1.04- | (Method 1): ys yy|__chloro-phenoxy)- 1.79 (m, 10H), 2.34 yy propyl ]-[2-( R)- (m, 2H), 2.41 (m, | Rt 7.13min, cyclohexyl- N00 Ne o 0 1H), 3.13 (s, 6H), L hydroxy-phenyl-mo "6 Tm, 3.44 (m, 2H), 4.07 526017 methyl)-oxazol-5- or 5 (m, 2H), 4.56 (bs, ylmethyl]- 1H), 4.79 (s, 2H), dimethyl- | Example 32a 6.93 (dd, 1H) ), 7.04 ammonium (m, 1H), 7.23 (m, bromide 1H), 7.31 (m, 2H), 7.54 (m, 4H) {2-[2-(4-Chloro- or (CD;0D) § 1.10 - Method 5 phenyl)-ethoxy]- “A 1 Ne 1.82 (m, 10H), 2.42 | (t, 2H), HR, cyclohexyl- Br 2.97 (s, 6H), 3.47(m, m/z hydroxy-phenyl- 2H), 3.75 (t, 2H), 497M] methyl)-oxazol-5- Example 33a 3.86 (m, 2H), 4.60 (s, ylmethyl]- 2H) 7.18-7.39 (m, dimethyl- 8H), 7.54 (d, 2H) ammonium bromide yo Example A 1 B 2 NJ

HO 10 H 0 Br BH [2-(R)-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-[3-(4- methylaminomethyl-phenoxy)-propyl]- ammonium dibromide. (3-{4-[(tert-Butoxycarbonyl-methyl-amino)-methyl]-phenoxy }-propyl)-[2-treat ° (R)-(cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5 -ylmethyl]-dimethyl- Combine 715 mmol) with 00 ml of VAC (a) 0 (ammonium bromide medium) The solution is left to remain at 0 degrees. (J 0) mani » followed by methanol HBr 00 hours and then freeze-dried to obtain an amber gum 'which is dissolved 11 chambers for 11 minutes to provide the compound entitled as a glial yellow foam in methanol / 0014 and evaporated to 0. fading YEYY '

Ya

. (%) os mg(‎11795 = throughput LC-MS (Method 1): Rt 5.81min, m/z 492 [11] 'H NMR (CD3),SO 6 0.92-1.13 (m, 3H) , 1.13-1.28 (m, 3H), 1.58 (m, 3H), 1.68 (m, 1H), 2.19-2.30 (m, 3H), 2.53 (m, 3H), 2.72 (s, 1H), 3.05 (s , 3H), 3.06 (s, 3H), 3.39 (m, 2H), 4.02 (t, 2H), 4.07 (t, 2H), 4.80 (s, 2H), 6.98 (d, 2H), 7.22 (t, ° 1H), 7.31 (t, 2H), 7.45 (m, 4H), 7.55 (s, 1H), 8.74 (bs, 2H).Example 36a

Doc

HO" 0 N HA Br [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(4- 0x0-4-phenyl-butyl)-ammonium bromide Ve (R)-cyclohexyl-(5-dimethylaminomethyloxazol-2-yl)-phenyl- a solution of 2-(3-bromopropyl)-2- (intermediate No. 100 ( )+1 mg + 14 mmol) and methanol mg ¢ “8 mmol) in chloroform (¥ ml) and 717) phenyl-[1,3]dioxolane °C for 1 hour. The reaction mixture was concentrated in 50 acetonitrile (ml) heated in 1

HMN and acetonitrile © adsorbed over DCM until dryness; Re-dissolved in a mixture of absolute and purified by chromatography using © GM absolute silica gel cartridge and clarification. The material was treated with tetrahydrofuran. DCM with a ratio of 0-967 methanol in the mixture. (Je £) and water (Sa fc YEA ) HBr ml mixed of Y.o and (Ja 7.5) stirred at room temperature for ? day. The reaction mixture was concentrated in vacuum and treated with absolute 0 and hmn in methanol; it is absorbed in cull (once) the remaining (Y) in methanol and evaporates again Purified by chromatography using a ©g absolute silica gel cartridge and clarification by

118 mm of Y = ia % methanol in dom . It provides a glassy substance which is ground by diethyl ether to provide the entitled compound as a white solid. productivity = 57.7 mg (1687).

LC-MS (Method 1): Rt 8.08min, m/z 461 [11] 'H NMR CD;0D.' [J1.03-1.39 (m, 6H), 1.55-1.79 (m, 4H), 2.23 (m, 2H), 2.40° (m, 1H), 3.13 (m, 8H), 3.28 (m, 2H), 4.76 (s, 2H), 7.20 (m, 1H), 7.30 (m, 2H), 7.54 (m, SH), 7.64 (m, 1H), 8.00 (m, 2H). Mediator No. 1 a

HON

+

N

\

Cycloheptyl-(5-methyl-oxazol-2-yl)-phenyl-methanol. Ye suspension of magnesium bicyclate (/?7 mg “l mmol) 9 YoY-dibromoethane) 01 µl; 1.8851 mmol) in 1 mL of dry ether under nitrogen; warms slowly until initiation occurs; Then it was stirred at room temperature for ye min oe and cooled to 0°C. 0.05 (g - 1.51 mmol) cycloheptyl bromide was added and the mixture was stirred for 1 min at 0°C. The resulting solution is filtered. and add dropwise to a solution of (5-dimethylaminomethyl-oxazol-2-yl)-phenyl-methanone (intermediate (IVs) (*g YAY mmol) in .£0 ml of dry THF. Mixed The reaction was stirred at room temperature for 1.0 h, and then carefully quenched with saturated aqueous ammonium chloride. Ethyl acetate was added; the organic layer was separated and the aqueous layer was extracted with * parts of ethyl acetate. The combined organic layers were washed with brine; Dried (magnesium sulfate) and evaporated Chromatographic purification over silica gel and clarification by 71-001 ethyl acetate/cyclohexane Provide colorless oil Fraction of oil 717?

0 does not crystallize with cyclohexane. 0. The resulting solid and the rest of the oil combine © to provide the compound entitled “in a mixture with the starting material (medium No. 01a) as a white solid. Yield = 486 mg. LC-MS (Method) 4): Rt 2.33 min, m/z 329 [MH]" ° enantiomer cycloheptyl-(5-dimethylaminomethyl-oxazol-2-yl)-phenyl- Oe methanol (Meaning No. (IVY)£04) mg) separated by preparative chiral HPLC using a 01 X YOu mm Keralpack Lime column with a fixative over 0 µm silica gel The column was liquefied by 0% ethanol in heptane buffered by 011 0 96 diethylamine At a rate of VA ml/min The first enantiomer was diluted (remaining time = 7 minutes «analytical batch) (Medicine No. (IVY) obtained as a white solid. Median No. VY H N 2 N > Cycloheptyl-(5-dimethylaminomethyl-oxazol-2-yl)-phenyl-methanol — first eluting enantiomer Vo yield = 001 mg) ¢ (oN LC-MS (Method 5): Rt 6.41 min, m/z 329 [MH"] "HNMR (CDCls): 0 1.25-1.39 (m, 4H), 1.40-1.57 (m, 7H), 1.69 (m, 1H), (s, 6H), 2.56 (m, 2H), 3.53 (dda, 2H), 3.68 (bs, 1H), 6.83 (s, 1H), 7.23 (m, 2.24 1H), 7.33 (m, 2H), 7.64 (m, 2H ). 0 Lacrimal enantiomer II (residence time = 14 min; analytical batch) (medium No. VF) is obtained as a white solid.

Did the broker tell him the number? A HO N of N “> Cycloheptyl-(5-dimethylaminomethyl-oxazol-2-yl )-phenyl-methanol — second eluting enantiomer © yield = 11 mg ( 9618) . LC-MS (Method 5): Rt 6.28 min, m/z 329 [1111] 'H NMR (CDCl3): 0 1.25-1.39 (m, 4H), 1.40-1.57 (m, 7H), 1.69 ( m, 1H), (s, 6H), 2.56 (m, 2H), 3.53 (dd as, 2H), 3.68 (bs, 1H), 6.83 (s, 1H), 7.23 (m, 2.24 1H ), 7.33 (m, 2H), 7.64 (m, 2H). 0 On a 0 OH ~ Br (Cycloheptyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-2[ phenoxy-propyl)-ammonium bromide. (from first enantiomer) 88g is prepared for the method used in example i but using cycloheptyl-(5- dimethylaminomethyl-oxazol-2-yl)-phenyl-methanol 0 (median number (iv Y) (R)-cyclohexyl-(5-dimethylaminomethyloxazol-2-yl)-phenyl-methanol (Medium No. 505).LC-MS (Method 1): Rt 8.03min, m/z 463 [11]. (m, 12H), 2.32 (m, 2H), 2.56 (m, 1H), 3.33 (s, 3H), 3.34 1.24-1.74 No (CDCl): (s, 3H), 3.64 (dd, 2H), 4.00 (s, 1H), 4.03 (t, 2H), 5.19 (d, 1H), 5.30 (d, 1H), Ye (d, 2H), 6.97 (t, 1H), 7.19 ( t, 1H), 7.25-7.31 (m, 4H), 7.57 (m, 3H). 6.85 The following example compounds are prepared in a manner similar to that described below.

Cyclooctyl-(5- (CDCl3): L 1.24 (m, dimethvlami ' 2H), 1.35 (m, 2H), fmetilylaninome 1.38-1.62 (m, 10H), hyl-oxazol-2-yl)- HO N 2.25 (s, 6H), 2.65 (m,

Co 1H), 3.54 (ddag, 2H), phenyl-methanol - Ay 3.71 (bs, 1H), 6.83 (s, first eluting 1H), 7.24 (m, 1H), enantiomer | Intermediate 8a 7.33 (m, 2H), 7.65 (m, 2H).

Cyclooctyl-(5- (CDCl): L 1.24 (m, dimethvlami 1 2H), 1.35 (m, 2H),

Hmetylamine | 1.38-1.62 (m, 10H), hyl-oxazol-2-yl)- HO N 2.25 (s, 6H), 2.65 (m,

C 1H), 3.54 (ddag, 2H), phenyl-methanol - SW 3.71 (bs, 1H), 6.83 (s, second eluting 1H), 7.24 (m, 1H), enantiomer | Intermediate 9a 7.33 (m, 2H), 7.65 (m, 2H). [2 (Cycloheptyl- (CDCl3): No 1.24-1.74 hydroxy-phenyl- (m, 12H), 2.32 (m, methyl)-oxazol-5- N Cl 0 2H), 2.56 (m, 1H), ylmethyl ]- (Sov © 3.33 (s, 3H), 3.34 (s, dimethyl-(3- or 3H), 3.64 (dd, 2H), phenoxy-propyl)- Br 4.00 (s, 1H), 4.03 (t, ammonium Example 34a 2H), 5.19 (d, 1H), bromide (from 5.30(d, 1H), 6.85 (d, second enantiomer) 2H), 6.97 (t, 1H), 7.19 (t, 1H), 7.25- 7.31 (m, 4H), 7.57 (m, 3H).[2 (Cyclooctyl- (CDCl,): 0 1.17-1.37 hydroxy-phenyl- (m, 4H), 1.38-1.65 methyl)-oxazol-5- NN ° ) (m, 10H), 2.32 (mm, ylmethyl]- - Ra 2H), 2.67 (m, 1H), dimethyl-(3- i 3.32 (s, 3H), 3.34 (s, phenoxy-propyl)- > 3H), 3.64 (m, 2H), ammonium Example 35a 3.97 (s, 1H), 4.04 (t, bromide. (from 2H), 5.17 (d, 1H), first enantiomer) 5.32 (d, 1H), 6.85 (d, 2H), 6.97 (t, 1H), 7.20 (t, 1H), 7.25- 7.31 (m, 4H), 7.58 , 3H).

Ye (m, 3H)

(Cyclooctyl- (CDCl): 0 1.17-1.37 2[ hydroxy-phenyl- (m, 4H), 1.38-1.65 (m, 10H), 2.33 (m, 0 l methyl)-oxazol -5- N 2H), 2.67 (m, 1H), ~~ doy ylmethyl]- dimethyl-(3- .32 (s, 3H), 3.34 (s, phenoxy-propyl) )- 9 3H), 3.65 (m, 2H), ammonium Example 36a 3.91 (s, 1H), 4.04 (t, bromide (from 2H), 5.18 (d, 1H), second enantiomer) 5.33 (d, 1H), 6.85 (d, 2H), 6.98 (t, 1 H), (t, 1H), 7.25- 7.20 (m, 4H), 7.58 7.31 (m, 3H).1.30-1.79 No t, 2H), (s, 6H), 3.76 (t, 3.11 d-#.__ ylmethyl]- 1 dimethyl-(2- “on © 2H), 3.83 (m, 4H), phenethyloxy- Br 3.94 (bs, 1H), 4.87 ethyl)-ammonium (d, 1H), 4.96 (d, 1H), bromide. (from | Example 37a 7.17 (m, 3H), 7.24 second enantiomer) (m, 3H), 7.33 (m, 3H), 7.58 (m, 2H). 1.19-1.73 no [2-( Cyclooctyl- (CDCls): hydroxy-phenyl- (m, 14H), 2.66 (m, methyl)-oxazol-5- CO] ims 2m, (s, 6H), 3.77 (t, 3.11 ylmethyl }- dimethyl-(2- on © 2H), 3.84 (m, 4H), phenethyloxy- Br 4.84 (d, 1H), 4.95 (d, ethyl)-ammonium 1H), 7.17 (m, 3H), bromide (from | Example 38a 7.25 (m, 3H), 7.34 second enantiomer) (m, 3H), 7.59 (m, 2H).[2-( 4-tert-Butoxy- (CDCl3) J1.08-1.71 ‎benzyloxy)-ethyl]- (m, 23H), 2.45-2.70 ‎[2-((R)-cyclooctyl- Be | (m, 1H) , 3.25 (s, 6H), hydroxy-phenyl- | "07 CL Lk 3.68-3.92 (m, 4H), methyl)-oxazol-5- 0 4.23 (s, 1H), 4.45 (s, ylmethyl]- 9 2H), 5.00-5.22 (m, dimethyl- 30a 2H), 6.85-6.96 (m, ammonium HT 2H), 7.06-7.25 (m, bromide (from 5H), 7.42 (s, 1H), second enantiomer) 7.45-7.58 (m, 2H). A I YeYW

Ca hydroxy-phenyl- (m, 14H), 2.33 (s, methyl)-oxazol-5- = 1 hn, 3H), 2.60-2.70 (m, ylmethyl)- 0 CL 1H), 3.26- 3.36 (d, dimethyl-[2-(4- Br” 6H), 3.77-3.91 (mm, methyl-benzyloxy)- 4H), 4.30 (br s, 1H), ethyl]-ammonium Example 40a 4.47 (s, 2H), 5.07- bromide (from 5.24 (dd, 2H), 7.12- second enantiomer) 7.23 (m, SH), 7.28 (t, 2H), 7.46 (s, 1H) ), (d, 2H).7.57 [2-(4-carbamoyl- (CDCl) [J0.79-1.66 benzyloxy)-ethyl]- (m, 12H), 1.75 (s, [2-(cyclooctyl- ML 3H), 2.28 (s, 3H), hydroxy-phenyl- HO PII 2.58-2.67 (m, 1H), methyl)-oxazol-5- 0 1 2 3.04 (d, 6H), 3.55- ylmethyl]- 5° 3.67 (m, 2H), 3.70- dimethyl- Je 3.81 (m, 2H), 4.43 Gs, ammonium tosylate 2H), 4.63 (s, 1H), (from second | Example 41a 4.74-4.91 (dd, 2H), enantiomer) 7.06 (d, 2H), 7.14- (m, 5H), 7.32 (s, 7.30 1H), 7.56 ( d, 2H), (d, 2H), 7.79 (d, 7.68 2H). Argument No. 76 A Oa | El 7 7 0 [2-(1,1-Diphenyl-ethyl)-oxazol-5-ylmethyl]-dimethyl-amine. A solution of 5-bromomethyl-2-(1,1-diphenyl-ethyl)- oxazole (intermediate V¢ a) (collectively 7.7 mmol) in 0.£ ml of THF was added dropwise to a 1 Mol solution of dimethylamine in (AA) THF filled with 17. 5 mmol) at zero degrees Celsius. The reaction mixture was allowed to warm to room temperature and left to remain overnight. The solid was filtered and thrown away. The filtrate was concentrated through a reducing pressure and the residue was partitioned between the ethyl acetate and

May the water. The Ald layer was extracted by Y part of JAY acetate and the combined organic layers were washed with a saturated aqueous sodium bicarbonate solution; dried (sodium sulfate) and evaporated. The residue was purified by chromatography over silica gel and clarification by ‎Ye: Ya : © : ? From DCM: methanol / acetic acid / water to provide colorless oil. © This substance is converted to the free base by passing through a 2-50 cartridge and leaching with methanol and then ammonia / 1M methanol to provide the entitled compound as a colorless oil with some solid matter. Yield = £0 mg(9660). LC-MS (Method 1): Rt 6.57min, m/z 307 [MH"] 'H NMR (CDCl3) [1 2.17 (s, 3H), 2.21 (s, 6H), 3.51 (s, 2H) ), 6.91 (s, 1H), Ve (m, 4H), 7.21-7.32 (m, 6H). )-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)- ammonium bromide Yo solution of [2-(1,1-diphenyl-ethyl)-oxazol-5-ylmethyl]-dimethyl- amine (intermediate £A) (IVT mg ¢ 371 + mmol) and +.1Y) 3-phenoxypropyl bromide ml ¢ 74 mmol) in chloroform (+19 ml) and acetonitrile (0 ml) heated in 00 ° s.d. A gh 90 h. Mixed Jeli) concentrated to dryness oo and the residue purified © by column chromatography and clarified by zero-967 methanol / DCM to provide the product as a colorless gum Drying in vacuum at £ 0 °C for 11 hours

A productivity = 14 mg (9684). LC-MS (Method 1): R; 8.47 min, m/z 441 [M"] NMR (CDCl): O 2.18 (s, 3H), 2.27 (m, 2H), 3.09 (s, 6H), 3.42 (m, yz 2H), 3.96 (m, 2H), 4.77 (s, 2H), 6.85 (m, 2H), 6.95 (t, 1H), 7.15 (m, 4H), 7.20- 7.32(m, 8H), 7.55 (s, 1H). -hydroxy-phenyl-methyl)-oxazol-5-yl]-acetonitrile 0 (medium No. 001 ( (VY mg ¢? mmol) in THF (10 mL) heated at 00 °C added Drop by drop solution of the borane-dimethyl sulfide complex (? ml of a Molar Y solution in THF; 4 mmol) The mixture Ja The reflux was heated for 0 min and then allowed to cool to room temperature The mixture was then cooled in an ice bath and quenched by adding dropwise of methanol (©)Jo followed by hydrochloric acid (1 N (Yc ml) 10. This mixture was stirred for 10 minutes and then neutralized with saturated aqueous sodium hydrogen carbonate The mixture was partitioned between water (A) ml) and ethyl acetate (80 (Jo); the aqueous layer was extracted with ethyl acetate (00 ml twice) and the combined organics were dried over sodium sulfate ¢ filtered and evaporated to oil. The residue is purified with the SCX cartridge; washed with methanol and then clarified with ammonia; Standard because the compound is labeled as a colorless oil. Yo yield = fen mg (PY) LC-MS (Method 2): Rt 2.18 min, m/z 283 [M+H-H,0]" YeeYV

Wa H, m), 1.54-1.77 (3 H, m), 2.28 (1H, m), 7( 01.10-1.38 (J020)) NMR Tra (2H, 1), 2.98 (2H, t ), 3.67 (1H, br s), 6.72 (1H, s), 7.24 (1H, m), 7.34 (2H, m), 2.80 (2H, m). 7.62 Median IVA N o J HO 0 NT o Cyclohexyl-[5-(2-dimethylamino-ethyl)-oxazol-2-yl]-phenyl-methanol. to a solution of [5-(2-amino) -ethyl)-oxazol-2-yl]-cyclohexyl-phenyl-methanol (median number AF ¢ aaa You ( (VV + mmol) in 1-71 dichloroethane (Jo) formaldehyde added ©107 (ml in a solution of 9697 in water; 4 mmol) and tri-0,0 sodium acetooxyborohydride (YOY) mg ¢ 017 mmol). This mixture was stirred at room temperature for 7 hours, then 10 ml (DCM) and saturated aqueous sodium hydrogen carbonate (Se 0) were added and gently mixed. The organic substances were separated through a phase separation cartridge and evaporated to oil. Purification by column chromatography Flash over silica gel using a mixture of 90010 methanol and 90960 DCM as a thinner. Titled compound 10 is available as a white solid. Yield = 0000 mg (9677).LC-MS (Method 2): Rt 2.20 min , m/z 329 [MH"] NMR corresponds to what is the parameter ?6a. Median 74a

VA

N i 1.

HO 0 N ~~ [5-(2-Amino-ethyl)-oxazol-2-yl]-cyclohexyl-phenyl-methanol (first eluting enantiomer) chirality of intermediate No. diethylamine;

LC-MS (Method 1): Rt 6.74 min, m/z 329 [MH] '"H NMR (CDCl3) 01.10-1.37 (7TH, m), 1.61-1.76 (3H, m), 2.26 (6H, s) , 2.57 (2H, 1), 2.81 (2H, 1), 3.66 (1H, s), 6.69 (1H, S), 7.24 (1H, m), 7.34 (2H, t), 7.63 (2H, 4d) 0

IAs Median No

N

1.

HO 0 N ~~ [5-(2-Amino-ethyl)-oxazol-2-yl]-cyclohexyl-phenyl-methanol. (second eluting enantiomer) using preparative chiral IVA for mediator No. HPLC glib, the titled compound separates No: . min) 13.5 = residence time (IVA) conditions noted for median No

LC-MS (Method 1): Rt 6.76 min, m/z 329 [MH]

IVA nuclear magnetic resonance as it is for the parameter Fey No. Example No. YH

N 0 » NT ©

Sn

Oh

Br{2-[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl}-ethyl}-dimethyl-(2-phenoxy-ethyl)-ammonium bromide. [5-(2-amino-ethyl)-oxazol-2-yl}-cyclohexyl-phenyl-methanol solution of mmol) f-2 1016 ¢ 50 mg (((second lacrimation enantiomer)) intermediate No. 80a) © mg ¢ 28 mmol) in chloroform (+28 ml) and 151) phenoxyethyl bromide at °C for 48 hours. The reaction mixture was concentrated at 00 heated in (Je 07) acetonitrile / Methanol 9610 = sim until dryness and purified by column chromatography and clarification by -1 - to provide the product as a colorless oil by drying in a vacuum at 00 °C for DCM a day white foam is available 0 7 (%Y 1) mg OA= Yield LC-MS (Method 5): Rt 7.98 min, m/z 449 [11] 'H NMR (CDCl3) 01.03-1.23 (m, 3H), 1.24-1.38 (m, 3H) ), 1.54 (m, 1H), 1.66 (m, 2H), 1.74 (m, 1H), 2.36 (m, 1H), 3.26 (s, 6H), 3.36 (m, 2H), 3.76 (m, 2H) , 3.89 (m, 2H), 4.46 (m, 2H), 6.94-7.03 (m, 4H), 7.22 (m, 1H), 7.26-7.33 (m, 0 4H), 7.49 (m, 2H). The following example compounds are prepared in a similar manner using the method described below

AVR] Tov (2-Benzyloxy- (CDCl3) 01.07-1.22 | (Method 5): ethyl)-{2-[2- (m, 3H), 1.23-1.36 | Rt 8.10min, (cyclohexyl- BS (m, 3H), 1.53 (m, | m/z 463 hydroxy-phenyl- IN "absorbent 1H), 1.66 (m, 2H), [M'] methyl)-oxazol -5- “between 0 1.74 (m, 1H), 2.35 yl]-ethyl}- 5 (m, 1H), 3.17 (s, 6H), dimethyl- 8 le 42 3.26 (m, 2H), 3.66 ammonium | 6 222 (m, 4H), 3.89 (m, bromide. (from 2H), 4.55 (m, 2H), 07 6.84 (s, 1H), 7.22 (m,

second enantiomer (1H), 7.27-7.34 (mm, 7H), 7.49 (m, 2H) grew. {2-[2-(Cyclohexyl- (CDCl5) 01.05-1.22 | (Method 1): hydroxy-phenyl- (m, 3H), 1.23-1.36 | Rt 8.50min, methyl)-oxazol-5- ~~) (m, 3H), 1.55 (m, m/z 477 1H), 1.65 (m, 2H), [M*] 8 "ben yl]-ethyl}- dimethyl-(2- o 1.74 (m, 1H), 2.37 phenethyloxy- (m, 1H), 2.85 ( m, ethyl)-ammonium Example 43a 2H), 3.03 (s, 6H), bromide. (from 3.18 (m, 2H), 3.55 second enantiomer) (m, 4H), 3.73 (m, 2H), 3.81 (m, 2H), (s, 1H), 7.13 (m, 6.93 1H), 7.16-7.24 (m, 5H), 7.30 (m, 2H), ( m, 2H). cyclohexyl-(5-methyl-thiazol-2-yl)-phenyl-methanol ) intermediate Yo 1 ( an V.0Y) © ¢ 00.¥ mmol) and N-bromo-succinimide ) 79.+ g ¢ 7.5 mmol) in carbon tetrachloride (10*mL) treated with (10 mg); under nitrogen. The mixture was refluxed into a preheated flask for 0.5 h and then allowed to cool to room temperature. By filtration Ir Highflo; And to concentrate until dryness, there is Kadr oil, which is dissolved in THF © ml; Cool to -01 degree Adie under a nitrogen environment and treat with 0 ¥ molar solution of dimethylamine in 11978 (THF ml 1 7285 mmol). The solution was allowed to stand at room temperature for yt hours; And then focus on the void. DCM and sodium hydrogen carbonate solution were added. phases separated; Cory

YAY

The organic layer (magnesium sulfate) was dried and concentrated in Fara 2 to provide the crude product as yellow oil. Purification by column chromatography (Rediscip cartridge); To provide the titled compound in the form of DOM oil / and to liquefy by zero-10 methanol. (% tA) mg 0 O° - Yield ©

LC-MS (Method 4): Rt 2.31min, m/z 331 [MH"] 'H NMR ((CD3),SO) 0 0.99-1.22 (m, SH), 1.26-1.35 (m, 2H), 1.52 -1.69 (m, 3H), 2.11 (s, 6H), 2.38 (m, 1H), 3.53 (s, 2H), 7.18 (dd, 1H), 7.29 (dd, 2H), 7.53 (s, 1H), 7.65 (d, 2H).i AY Argument No. 01

N

= y

HO J .No Cyclohexyl-(5-dimethylaminomethyl-thiazol-2-yl )-phenyl-methanol. first eluting enantiomer) TAY column chiral preparatory mediator HPLC glib titled compound separates

CN mm I.D.; 7.58 96 ethanol / 997.5 96 heptane (Yo X You oY Keralpax 10: .) ml/min; 9.74 min residence time 19 diethylamine; 6' H NMR (F020) 1.05-1.42 (m, 7H), 1.60-1.78 (m, 3H), 2.33 (s, 6H), 2.37 (m, 1H), 3.56 (s,[0 2H), 3.86 (bs, 1H), 7.22 (t, 1H), 7.33 (m, 2H), 7.42 (s, 1H), 7.68 (m, 2H).

PAY Broker No. Yo

N

: 0

HO J No

YeVV

YAY

Cyclohexyl-(5-dimethylaminomethyl-thiazol-2-yl)-phenyl-methanol. (second eluting enantiomer) a (column 81 chiral preparation of mediator No. HPLC glib compound titled separating vA heptane 96 Aveo) ethanol % 7.5 Jala mm diameter Ye X Yoo Keralpax 1a ; ) min 00111 = ml/min; Residence time VA Diethylamine; 96 0 'H NMR (CDCl3) [J 1.05-1.42 (m, 7H), 1.60-1.78 (m, 3H), 2.33 (s, 6H), 2.37 (m, 1H) ), 3.56 (s, 2H), 3.86 (bs, 1H), 7.22 (t, 1H), 7.33 (m, 2H), 7.42 (s, 1H), 7.68 (m, 2H). jo. Example No

N

/>” | +

HO J HAL TJ

Br 3 0. [2-(Cyclohexyl-hydroxy-phenyl-methyl)-thiazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)-ammonium bromide. (from first enantiomer) cyclohexyl-(5-) prepared according to the method used in Example 1a but using the (AY) substitute (median no. dimethylaminomethyl-thiazol-2-yl)-phenyl-methanol (median no. cyclohexyl) -(5-dimethylaminomethyl-oxazol-2-yl)-phenyl-methanol |06. (jee

LC-MS (Method 1): Rt 8.80min, m/z 465 [M] z NMR (CD;0D) OU 1.05-1.42 (m, 7H), 1.69 (m, 3H), 2.34 (m, 2H) ), 2.59 (m, 1H), 3.11 (s, 3H), 3.12 (s, 3H), 3.51 (m, 2H), 4.09 (t, 2H), 4.85 (s, 2H), 6.91 (m, 2H) , 6.96 (t, 1H), 7.21 (t, 1H), 7.24-7.33 (mm, 4H), 7.71 (m, 2H), 8.00 (s, 1H). Yo

AE] ow [2-(Cyclohexyl- (CDCl3) L 1.04-1.19 | (Method 5): hydroxy-phenyl- (m, 3H), 1.22-1.36 | Rt 8.32min, methyl)-thiazol-5- ( m, 4H), 1.57-1.74 m/z 465 ylmethyl]- (m, 3H), 2.33 (m, [MT] dimethyl-(3- 2H), 2.48 (m, 1H),

YAY phenoxy-propyl)- Ns 3.30 (s, 6H), 3.70 (mm, ammonium “NA HY 2H), 4.01 (s, 1H), bromide. (from Br 4.06 (t, 2H), 5.37 (s, second enantiomer) 2H), 6.82 (d, 2H), 6.95 (t, 1H), 7.20 (t, 1H), 7.25 (m, 2H), 7.30 ( m, 2H), 7.72 (d,

Example 44a 2H), 8.06 (s, 1H).

Cyclopentyl-(5- (CDCl3): 1.28-1.78 | (Method 1): dimethylaminomet Rt 6.40min, hyl-thiazol-2-yl)- NT (8H, m), 2.23 (6 H, m/z 317 phenyl- methanol. “ANS $),3.03-3.10 (1 H, [MH”] (first eluting m), 3.56 (2 H, 5), enantiomer) 3.9800 (1 H,s),7.23 (1H,d,J= 7.32 Hz),

Intermediate 10a 7.30-7.35 (2 H, m), 2 - 1, A, 11, 1 (7.40)

Hz), 7.65-7.69 (2 H, m).

Cyclopentyl-(5- (CDCl3): 1.28-1.78 | (Method 1): dimethylaminomet Rt 6.48min, hyl-thiazol-2-yl)- f Hm®),2236H | 7 phenyl-methanol. Ho { Jon s),3.03-3.10 (1 H, [MH"] (second eluting m), 3.56 2 H, 5), enantiomer) 3.980 (1 H,s),7.23 (1 H,d,J=732Hz ),

Intermediate 11a 7.30-7.35 2H, m), 740 (1H,t,J=0.92

Hz), 7.65-7.69 (2 H, m). [2-(Cyclopentyl- (CDCl3) L 1.33-1.68 | (Method 5): hydroxy-phenyl- . (m, 8H), 2.34 (m, | Rt 8.03min, methyl)-thiazol-5- 2H) , 3.17 (dt, 1H), m/z 451 ylmethyl}dimethyl- 3.33 (s, 6H), 3.73 (m, (M*] (3-phenoxy- 2H), 3.87 (s, 1H), propyl)-ammonium 4.09 (t, 2H), 5.37

Y £YV| bromide. (from first (dda, 2H), 6.83 (d,

enantiomer) , 2H), 6.97 (t, 1H), N Nod ' YN ALO 7.22 (t, 1H), 7.24-

AOC 7.33 (m, 4H), 7.70 (d, 2H), 8.04 (s, 1H)

Example 45a [2-(Cyclopentyl- (CDCl3) L 1.33-1.68 | (Method 5): hydroxy-phenyl- (m, 8H), 2.34 (m, | Rt 8.03min, methyl)-thiazol-5- YN ° 2H), 3.17 (dt, 1H), m/z 451 ylmethyl]dimethyl- Hoy TY TU 3.33 (s, 6H), 3.73 (m, [M'] (3-phenoxy- Br 2H), 3.87 (s, 1H), propyl)-ammonium 4.09 (t, 2H), 5.37 bromide. (from (ddag, 2H), 6.83 (d, second enantiomer) 2H), 6.97 (t, 1H),

Example 46a 7.22 (t, 1H), 7.24- 7.33 (m, 4H), 7.70 (d, 2H), 8.04 (s, 1H) (2-Benzyloxy- (CDCl3): 1.20-1.70 | (Method 1): ethyl )-[2- Rt 8.40min, (cyclopentyl SIR (8 H, m), 3.10-3.20 m/z 451 hydroxy-phenyl- Hoy vs” 7 a (1 H, m), 3.30 (6 H, [MF] methyl)-thiazol-5- or $).3.80 (1 H. 5) ylmethyl}- > +8), dimethyl- 4.85-4.95 (4 H, m), ammonium bromide. (from first | Example 47a 4.55 )2 for 5302 enantiomer) H,s), 7.2-7.4 (8 H, m), 7.70-7.75 2 H, m), 7.95 (1 H, s). Examples laa The inhibitory effects of the compounds of this invention on M3 mental receptors (in Alla example (VY and B2 parietal receptors (of the parietal gland) and were determined by binding assays aul): © muscle receptors Muscarinic radiolucency:

YAO

-N-methylscopal Y[H] is used for radio logand hinding — studies and economically adjacent cell membranes show (NMS - Y[H]) amines are used to assess the susceptibility of (M3, MC) Muscarinic receptors for humans. M3, 112 for Mucarinic receptors, antagonists of the ° A membranes located in TRIS buffers were incubated in dishes composed of MN, sampled with 0 nMS Y[H] and antagonist M3 at different concentrations for a period of time. ? The membrane clocks and bound radioligands were then harvested by filtration and allowed to dry overnight. The scintillation liquid was added after that, and the radioligands 0 bound were counted using “sai Canberra Packard top count scintillation counter.” The age of the antagonists at the AS of the a muscarinic receptors was measured using the reciprocal radioligand [H3] - QNB and adapt to the previous ability. The antigens were incubated via al hours at a concentration (Fold Y =) (higher than ki) as determined with the association of QNB - [113] with membranes that show 0 muscarinic receptors. human populations at the end of this time. QNB - [113] was added to the concentration of Fold higher Yo~) for its L of the acceptor that was studied and incubation continued for several intervals from VO min to VAL min The membranes and bound radioligands were then harvested by filtration and allowed to dry overnight.

Leaching of the scintillation liquid was then added and the bound radioligand was bac using a canbera Packard topcount sciotillation counter The rate at which [H3] - QNB binding to muscarinic © receptors was known - close to the rate at which the antibody is degraded from Receptors This means the half-life of antagonists on the receptors. Results: AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

YAY

YAA

AA

Yevy

neighborhood we ww sw ww Ce Cw

1 20a++

50a +++

Ce

Cw in the previous table is estimated to be 143 on binding (KI values) indicated as follows: Less than 1 nm +++ g HEM 01 -1 g and greater than 1 + M 01 © All tested compounds showed ad The Ki is less than nM and not tested NT= All the tested compounds show correlation values: 16 > 50 nmol in this titration. Specifically, example number “a” contains a value of 1655 equal to 8.04 nmol and example number 1”a contains a Ki value of 0.056 nmol. : adrenergic radioligand binding Ye adrenoceptors 5 test Ye radioligand binding studies using Y = [Ye 1] iodocyanopendolol and membranes cellular viability (displaying 52 adrenalgic adrenergic receptors) 43,4 The membranes and SPA- BEADS were incubated with [VV0] iodocyanopendolol VO and antagonist 32 at different Fadl concentrations for 3 hours at local temperature. In Tris bufler the test was done in dishes of 976 holes (eyes) that are read using a Wallace counter 1. wallac microbeta counter us Sue

Yay. In this assay, 001 nM is less than 11: displays the value of YY, an example of exchanged CHO, M3 cells, analysis of inhibition of the activity of the receptors, exposure of the 143 human receptors, collected and incubated throughout Night in 2.2... black - pure bottom (at density jaa) 96-hole plates coated with collagen. Microliter of medium in 96” of plasma Vo / 1 a (cat # 2 80 4 next days) Calcium-sensitive formula (partial preparations) Vo Proencid (tub grade) OmM with the addition of HBSS buffer Prepare it in μl) was added to the cells with an equal volume of formula solution (V0) μl of anti-L antibody 50 Adal min followed by £0 Baal and incubated with Muscarinic | 0 nano£AA (stirring) Flexstation TM After 10 minutes, the plate was read on a second to determine the main fluorescence line. Vo (015 nm emission meter) was done for a period of E YA + at muscarinic agonist carbachol, after that a second was added, and the signal was calculated for 01 The concentration and fluorescence that were measured for a period by subtracting the peak of the response from the average of the main line of fluorescence in the well of 1 control in the absence of the antibody - the percentage of the maximum response in the presence of 1050. The antibody was then calculated to produce curves for the compounds. This invention at 103 day A receptors Effect: The following invivo and ex-viva tests can develop in the muscarinic: The development in the ability and time (period) to work in a pig cast and isolated Ye.

17 krebs- hanseieit Experiments done at 1? degrees Celsius in a solution of sodium chloride and 15134 sodium chloride VV E OM - developed (variable) calcium chloride and 2 pounds potassium chloride 01 “bicarbonate (magnesium sulfate) and gas was placed by (Vf) pH 102004 017 glucose and 1116 and oxygen 965 carbon dioxide Indomethacin was added to the concentration 9650 0. micrometers Final Vd Dunkin harhey guinea pigs The trachea was removed from a young male from Individual strips of 7-7 rings of cartilage crosswise were cut and forcefully placed in any 10 mm water bath and suspended using a cotton thread in 0. The tissue is located between two platinum electrodes, ASU transducer

MP 100 w\a ckowledge data The response was recorded by . Associated PC acquisition system The tapering was equalized for an hour under stable pressure (tone) then it was Hertz with pulses whose purpose was Ae It was exposed to a stimulatory electric field at a frequency of 0 m voltage-response A unipolar pulse and it is detected every minute. Curve 108 1) A submaximal piece of tissue is prepared by JS for each tissue, then it is sheathed according to the response of each piece to the current intensity, and the tissue is washed with Krebs solution. And they were allowed to settle under a stimulus before adding the test compound Concentration response curves were obtained from the cumulative addition Y. half — log of the test compound in quantities

1 Once the response to each addition reached the peak of the curve, the stimulus was made. The EFS was calculated for each concentration. The other addition — the rate of inhibition of contractility for each compound that was added. Dose-response curves were constructed using . Calculated for each Eco compound and grophpad prism software

° Studies on the event period were conducted by adding the concentration of the Eco that was determined for the compound to the BFS contractile tissue and the response until it reached Plateau (degree of stability). The time required to reach 986 of this response is determined to be the start time.

The tissue was then washed to become free of the compounds by flowing 0 tissue bath with freshly prepared Krebsey's solution and the time required for the contraction process in response to 2158 to return to 9690 after the response that was measured in the case of the presence of this compound in the period of the event on the occasion of the example in this The composite test for example 01 has an A+ Eco 01 and event duration of 0406 minutes. Appropriate to explain this invention is example 08 where the binding capacity of 0 ki is 1 pM.” Jit wed salle 14 was obtained together with the 90 10 of 018 018 in an isolated trachea of the Giuinea pig. Methacholine stimulation of Broncho formation in tissue: Giuinea pigs, male, Dunkin Hartley (weighing from 500 to 1 ter grams), breeder in groups, each group © pigs, where they are identified individually 6 000 YEYY

05 sido The surroundings for at least a period of time aid Allow the animals to acclimatize to the environment during this time and study the time allowing the animals to take in extra water and food. adlibitum %0 By inhaling the anesthetic halothane, Giuinea, pigs were anesthetized. The test compound was administered intranasally 0 The animals were placed in a heated area and allowed to recover before returning to their cages Anesthetized Tal Givinea pigs Jb 1 hour from YE after . ml / kg) Y micrograms / ml and YOu) urethane by the

01 at the point of surgical anesthesia - the jugular vein was diverted into a canal by portexl.y the cannula was filled with ale neutral solution of (hpBS) heparinised phosphate (ml / n) 01 For intravenous administration of mechacholine - the trachea was exposed and changed by a rigid portex channel, and the pharynx was replaced by mouth to a flexible portex tube for feeding.

hants MMS, UK The breathing animal was connected to a Vo lung monitor. Which consists of an air flow (gas) and a pressure conductor

The trachea was connected to the gas attachment and the pharyngeal tube was connected to the pressure connector. BLE was exposed to the pharyngeal plac with a primary resistance of between 2.1 - 20\mL\s 0.1 cmH | 0 . YEYY

Ya The baseline reading was recorded two minutes before taking mechacholine by means of . Milligrams / kg) Yo micrograms / kg Vein (to) The stimulated contraction was recorded at two minutes from the point of intravenous administration, by means of devices, according to the Auc of resistance and the area of resistance under the curve dad calculation During the two minutes of the recording time that was used for the analysis, the 0 warm-up effects of the tested compound, broncho

LF =) Ye The results were obtained in this test for an example compound / μg 01 (14011; hours before the) 0181 w / μg / kg stimulus and the comparator tiotropium beoncho contraction of the Ve (V+ mg) (1) Recorded as 0 Inhibition of pilocarpine induced salivation by nasal compounds Guinea pigs (9;-8©50 g in weight) Available from NHS Laboratories Harlan Ald British or David Hall; UK staff and acclimatized in supplies for at least a 7 day period prior to use. Guinea pigs are allocated (about 1 764 randomly) to treatment groups and weighed. Each animal is dilutely anesthetized until (aS / halothane) and compound or excipient administered intranasally (20+ ml at the time of the test; pigs are anesthetized 0. hour before competition with pilocarpine YE kg). When fama 018 1120% in YO guinea has finally been treated with urethane (solution) sufficient amount of anesthetic has been administered (absence of toe-pinch reflex), each animal has an absorbent pad placed in the mouth for ¾ minutes to dry up remaining saliva This and yay pad is removed and replaced with a new, pre-weighed pad for 0 minutes to demonstrate the baseline saliva production reading At the end of the 5 minutes, the pad is separated and weighed A new, pre-weighted pad is inserted into the mouth before receiving every animal under the skin

Y Pilocarpine administered subcutaneously in the back of the neck (+01 mg/kg at a rate of 0 ml/kg per minute). jacket separation; Weigh and replace with a new pre-weighed blanket each © . 11 minutes until saliva production is measured by subtracting the pre-weighted weight of the mantle from each minute of the weighted mantle later, and these numbers are added together to produce saliva pool min vod min. Each period e minutes can be further analyzed into Yo by constant and multiplied aly as a whole as a recording period. Basic production of saliva is assumed to be 0 . Min Vo by ¥ yields the reading for basal saliva production during The inhibition of saliva produced by the compound can be estimated using the following equation: . 001# (-Basic Veh (/) Basic Test-1)

Claims (1)

Y4A Claims 1 Compound pursuant to claim No. 1 - 1 C 8 of a son “R® Le A Ne for R 0 wherein or R'; ¢ hydrogen or C- hydrogen Coalkyl carbon atom (1-1) a is an alkyl (1); -2-00- « -ZNR°R 27 ¢ -R7 ; or hydrogen group is hydrogen © _ is 1 pair or alkyl RP or 0(87)-2- and -ZNR*-C(O)O-R' « NR°R"® 1; or C1-Cgalkyl carbon atom) 1-1) attached to form an alkyl cycloalkyl ring mixed nitrogen together with nitrogen sR'(Y) A -¢ -72-7-87 ¢ R7 and 1 is a single pair or group of heterocycloalkyl ring 9 ¢ -Z-C(O)-R" ¢ § « -Z-NR*-C(O)O-R' « -Z-CO-NR°R!® « Z-NR°R!® 0 connected to it forms a ring alkyl cycloalkyl nitrogen mixed together with a nitrogen atom RP SR! 2-; or 207; and 83 are carbon atoms) states:0-6; 1=V) lone pair; or a 14-alkyl mixed cycloalkyl ¢aryl separately chosen from the aryl group RS and RY Vo atom 1-1(alkyl 0 heteroaryl aryl scrambled « aryl-fused aryl heterocycloalkyl 1' cycloalkyl carbon) tola M-6, » cycloalkyl 11 ¢ C- Cg alkyl alkyl (1-1 carbon atom) » halogen Halogen-011 K is a VA hydroxy-alkyl (1 carbon atom) with C1-Cs (a carbon atom) and T =) alkoxy alkoxy 4 18 group 00108577 + ¢ nitrile « hydeoxy-Ci-Ce-alkyl 0 ¢ hydrogen atom 71 ¢ oxygen or a sulfur atom YY or alkenylene + alkylene is an alkyl group XO YY ; Aryl C-Coalkyl (carbon atom) 1-1 (O is an alkyl Yo fused aryl - heterocycloalkyl group 0 aryl-fused-cycloalkyl aryl Y1 aryl fused + C) -Cg-alkyl carbon atom) AY) aryl (alkyl ¢ heteroaryl de; aryl scrambled YY; or cycloalkyl ils carbon atom) i.e. -»©-,©; Alkyl A=) (alkyl YA ¢ heterocycloalkyl group mixed 4 ¢ hydrogen atom carbon atom)alkyl from or hydrogen atom 1-1) is an alkyl 5© carbon atom) 1 carbon atom ) from -,,.©-, ¢ alkynylene (1-7a 11-1 ) is a Zz 1 alkylene group; C,-Cjg-alkynylene group (1-7) carbon atom or an alkynylene group Cp-Cpgalkylene TY ¢ oxygen atom 0 bond is a Y YY bond 33 1) Alkyl + hydrogen atom separately RY 4 R® r¢ « aryl-fused-cycloalkyl Mixed cycloalkyl-fused aryl “aryl carbon)(lolamme- + aryl Yo atom NY aryl (alkyl heteroaryl) mixed aryl 0 combined with aryl - cycloalkyl cycloalkyl 1 or cycloaryl (alkyl) = 30 carbon ¢ aryl (C;-Cg-alkyl) carbon) Tv nitrogen atom together with a nitrogen atom RI (Tg-2)) of 161 s or Ng and YA composed of ;- + 33 carbon heterocyclic ring mixed dda ring attached to it forming TH or oxygen oxygen optionally containing a nitrogen atom « heterocyclic ring of 4-8 atom 0 AEA RY ¢ extra oxygen atom 5 You or solvent wee pharmaceutically acceptable salt; Nitrogen oxide N-oxide 7 1?- Composite according to what was mentioned in Claim No. 1, whereby "L is for Alk ?” yl) 1-1 carbon atom) C,-Cg-alkyl or a hydrogen atom (R? ¢ hydrogen atom) ; It is an alkyl (1-1 carbon atom) C-Ce-alkyl « hydrogen atom or © group 27-38 R* y is a lone pair or an alkyl 1-1 (carbon atom) C-Ce-alkyl 1 “or VY Liu argonically with the nitrogen atom attached to it represents a mixed heterocycloalkyl ring A” or Alo R® together with the nitrogen atom attached to it 9 represents a heterocycloalkyll ring ¢ heterocycloalkyll ring RYO: and 87 separately choose from the group consisting of “aryl dif aryl heteroaryl 1-alkyl-1 (carbon atom) talla-m0-. ©; The cycloalkyl Als ¢ R® 1 is 011- ; halogen « alkyl (171 carbon atoms) C-Calkyl ¢ OY hydroxy -alkyl. 2-1(553 carbon) CrCealkyl or hydrogen atom ¢ hydrogen atom 4 ¢ a sulfur atom or sulfur oxygen is an oxygen atom A 0 * is an alkylene group or alkenylene alkynylene VV; 0 2 is an alkylene group “alkylene” or “alkenylene” in alkynylene 4; 11 7 is a bond or an oxygen atom ; 1 “© is an aryl 0 aryl a mixed aryl heteroaryl ¢ a mixed cycloalkyl ,. alkynylene group YY or No. 7; Whereas !18 is 1 compound according to claim No. * 1 is hydrogen R? ; ) the alkyl ¢ hydrogen ¥ is R? and ¢ ZCO)R ' J NRR', -Z-CO-NR°R, -Z-NR*-C(O)O-R” ¢ and in those state C-Coalkyl nitrogen atom 1 -quaternary nitrogen and carries a positive charge V ;- compound as stated in claim ¥ ; wherein 13 is a methyl 1 attached to which is a nitrogen atom wherein the nitrogen atom is 0 methyl Y and carries a positive charge quaternary nitrogen YF 0 carries a positive charge ¢ or number ". Whereas or 82 together 1 is a compound as mentioned in claim number -* 1 connected to it forming a monocyclic mixed cyclic alkyl ring nitrogen with a nitrogen atom "¢ 3 to 7 ring atoms V=Y of a monocyclic heterocycloalkyl ring 0 is a lone pair R? and ¢ nitrogen; in which the mixed atoms are nitrogen Yevy l © or alkyl 1-1 (carbon atom) il ©-© ; or combination - 21180800 7-2-7-5 Z-NR’-C(O)O-R” 1 a +0 . for mT) is a compound as mentioned in claim No. © or No. 76 wherein SR 83 together with “the nitrogen atom attached to it forms an azetidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl 0 ring Or pyrrolidinyl 1 7- A compound as mentioned in claim No. * or No. +, where the nitrogen atom ¥ attached to it is R! quaternary nitrogen 7 and carries a positive charge ¢ .mA) compound as mentioned in any of the previous claims where; in any group - 17 Y-R', -Z-Y-R ,-Z-NR°RY, -Z-CO-NR°R'', -Z-NR'-C(O)O-R" ¥ or 2-0-¢ "2 are <(CHyys); optionally substituted up to “* carbons by methyl ~~ ¢ « Y© is a Jbond bond oxygen O; 187 is a methyl Jie « ethyl propyl n-isopropyl orisopropyl VY; butyl gale; secondary or tertiary n-, sec- or tert-butyl + or phenyl, 3,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, A dihydrobenzofuranyl, naphthyl 4 or pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, YEYY l isoxazolyl, benzisoxazolyl, benzoxazolyl, thiazolyl, benzthiazolyl, quinolyl, 0 thienyl, benzthienyl, furyl, benzfuryl, imidazolyl, benzimidazolyl, isothiazolyl, 11 benzisothiazolyl, pyrazolyl, isothiazolyl, triazolyl, benztriazolyl, thiadiazolyl, 01 indazolyl 0 oxadiazolyl, pyridazinyl, pyridazinyl, triazinyl, indolyl 0 or Gua Arylalkyl 01 the aryl part is -3,4 phenyl, methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, 01 or naphthyl 1 « and the 1-1 (carbon atom) alkyl moiety C-Coalkyl is CH, or - CH,CH, 117 ; or 0-aryl alkyl mixed arylalkyl where the mixed aryl part is pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, 14 thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, 0 imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, 71 triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, YY triazinyl, indolyl 0 or 1008 2011 Whereas the alkymel part). 1-6 carbon) C -Coalkyl Y¢ is —CH, or <CH,CH, ; or indanyl Yo or ,2,3,4-tetrahydronaphthalenyl 1; or 0 heterocycloalkyl (1-4 alkyl C) 0 heterocycloalkylC;-Cs alkyl where the vy heterocycloalkyl is azetidinyl, piperidinyl, Jai ua piperazinyl « piperazinyl , YA nitrogen N-substituted ex 4 methylpiperazinyl i.e. tetrahydropyrrolyl and the alkyl moiety 1-1 (carbon atom) C-Coalkyl© is CH, or CHCH;; or YEYY r cyclopropyl, cyclobutyl, cyclopentyl 1 or cyclohexyl ; ¥Y C and C separately are hydrogen “ethyl Jf” methyl or VY propyl n- or isopropyl gle or isopropyl ethyl or n-or isopropyl ¢ phenyl ,3,4-methylenedioxyphenyl,3,4-ethylenedioxyphenyl, vi dihydrobenzofuranyl, naphthyl; furyl, benzfuryl, YV imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, = YV 0 © Ariel Alky_L Cus arylalkyl the aryl part is phenyl, 3.,4-methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, £Y dihydrobenzofuranyl — ¢¥ or naphthyl and the alkyl part) 1-1 carbon atom ) Ci-Cg.alkyl tf is -CHy or -CH,CH,- ; or R® sR' together with the attached nitrogen atom 5 le form azetidinyl , piperidinyl, piperazinyl, N- Adda thiomorpholinyl sf » methylpiperazinyl, pyrrolidinyl, morpholinyl 7 . RO 5 RY 67 separately selected from hydrogen « alkyl (1-1 carbon atom) 4; Cr-Coalkyl » or any of the aryls Optionally Jans aryl ¢ aryl scrambled cycloalkyl 4-merged substituent aryl-fused-heterocycloalkyl heteraryl Jib or aryl © (1-4 alkyl C) C-Caalkyl specifically specified for 87 in this requirement; 51 or Y.0 oY C and R'® - together with the attached nitrogen atom form an oY heterocyclic ring composed of 4-4 to 8 ring atoms 4 optionally contained Sle ot An extra nitrogen atom is an oxygen atom. 1 4- A compound as mentioned in Claim No. 1, where ; in group 1,088,283; then "Lg is methyl or ethyl; 82 is -ZNR°R'"- or ZY- Y "RTT is an - bond and Z is an alkylene moiety straight or branched alkylene radical linking nitrogen “!21878 or 787 ce by a chain formed up to 11 8 carbon atoms R? 4 ¢ carbon atoms is .methyl Jue 0 is a compound phenyl; RT is a compound as stated in claim No. 9 wherein 1-01 Jo or phenyl > dihydrobenzofury + benzyl benzyl " . phenylethyl ¥ 1-11-1 is a compound as stated in claim No. q or claim No. Ye where “8” and RY are as specified in claim No. +.; VY 1 is a compound as stated in claim 1 where ¢ is in the group NR'R?’R*- ; ld "82 is ZNRR" or 2-7-8 ; No _ is an oxygen bond or oxygen T + and — Z is an alkylene radical straight 0 branched up; nitrogen and “!1898 or 787 by a chain of up to 11 carbon atoms And The Yo attached to it forms a nitrogen ring together with the nitrogen atom R' 5R' - and carbon atoms © ¢ 4 to 8 ring atoms made up of 8-4 5,0 heterocyclic ring mixed with cyclic 1 oxygen atom or optionally nitrogen oxygen containing a nitrogen atom 7 . Additional + and 83 together with the RD atom that um 07 compounded according to claim number -1“ 4 azetidinyl, piperidinyl, piperazinyl, N- attached to it form a nitrogen ring 0 0 thiomorpholinyl 0 methylpiperazinyl, pyrrolidinyl, morpholinyl, 1 where 18 is preferably 11 or No. 11 compound as mentioned in Claim No. 14-1 phenyl Jad) for example_ cyclic lipophilic group is a cyclic lipophilic group Y or phenylethyl dihydrobenzofuryl dihydrobenzofuryl « benzyl benzyl ¢ phenyl ¥ .phenylethyl ; they RY SR? Whereas, 117-14 is a compound as mentioned in any of Claims No. 1-1#1. + As specified in the claim No. “a compound as specified in any of the previous claims, as “8 and 185 choose 1-11 “n- or isopropyl; isobutyl gale – propyl ethyl ethyl” methyl apart from methyl v phenyl, 3,4- 6 n-, sec- and tertbutyl; secondary »+ or tertary butyl gale oY methylenedioxyphenyl, 3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, naphthyl; ¢ YEYY 1 pyridyl, pyrrolyl, pyrimidinyl, oxazolyl, isoxazolyl, benzisoxazolyl, benzoxazolyl, © thiazolyl, benzthiazolyl, quinolyl, thienyl, benzthienyl, furyl, benzfuryl, 1 imidazolyl, benzimidazolyl, isothiazolyl, benzisothiazolyl, pyrazolyl, isothiazolyl, 1-triazolyl, benztriazolyl, thiadiazolyl, oxadiazolyl, pyridazinyl, pyridazinyl, A 1,2,3,4-tetrahydronaphthalenyl; 5 indanyl ¢ indazolyl or triazinyl, indolyl * “ —OH is RS ¢ cyclohexyl and cyclopropyl, cyclobutyl, cyclopentyl 0 0M hydrogen atoms ¢ methyl “ ethyl “ethyl hydroxylmehyl 0 ¢ nitrile 0 nitrile or group 0011855 “where all 85 units VY is a methyl” ethyl or hydrogen atom -117-1 compound as mentioned in any of the foregoing claims; where (1) each of the J wid and th ann is RY; or (7) each of the thienyl is a thienyl 5 RY X phenyl ¥; or 7) one of the RY and 85 is phenyl Jud and the other is cyclo-Jin; ~~ cyclopentyl or cyclohexyl; or (4) one of “# and 5 is 0-thienyl ¢ and oe tetra AY cyclopentyl cyclopentyl cyclohexyl .cyclohexyl 1 ,. -011 is RO wherein 11 is a compound as stated in claim No. 1 —VA 1 -11-1 is a compound as mentioned in any of the preceding claims where RE is 'hydrogen' 1" Yevy A 1 70- A compound according to what was mentioned in any of the previous claims, where X is - CH, Y a -CH,CH,- . -71-1 is a compound of claim 1 having Y of formula IA re N 7 (CHa) ~n) ot Lon ) Ah (CH). —Y A 2/m / 2/s RS (18) ; dus that A© is oxygen or sulfur 5 ; ““ is equal to 1 or ? ; The ring is 1 optionally substituted phenyl ring + or + Vv monocyclic heterocyclic ring of © or 1 ring atoms 5106 ¢ or + scrambled cycloalkyl ring heterocycloalkyl ring fused to phenyl where the a phenyl-fused-heterocycloalkyl ring is a 0 monocyclic heterocyclic ring of © or + cyclic atoms 6 0 5 ring atoms); 18 is phenyl « thienyl ¢ cyclopentyl 1 » or cyclohexyl ; 185 is phenyl « thienyl 0 cyclopentyl cyclopentyl or cyclohexyl ; 8 is equal to (Yo) 007 s 2 0 or 7 where is zero; 7+ 9+ 4 5 11 or 7 where + 0 is not greater than 11 ; Y is a bond or oxygen, and X is a pharmaceutically acceptable anion 0 pharmaceutically acceptable anion Yevy Y.4 containing Formula 1 Compound pursuant to claim No. 77-1 IB ¥ Rs N \ x (CH,), a) i (Cr), — COE v ; Where © M is oxygen or sulfur 5 ; equals 1 or ? ; Ring 1 8 is an Ada pyrrolidinium or piperidinium ring; Ring M is a ring Aas we phenyl ring Jed optionally + or A monocyclic heterocyclic ring 4 of © J + 3,0 cyclic ads J ¢ 510 6 ring atoms alkyl Cua phenyl 0 mixed heterocycloalkyl ring The 11-alkyl heterocycloalkyl ring is a dali ring. Rotation 1" monocyclic heterocyclic ring from © or + i dl atoms 5to6ringatoms OV; R' is phenyl-thienyl phenyl; cyclopentyl 04" or cyclohexyl 5¢ is phenyl ¢ Ve thienyl ; cyclopentyl or Jr Sa cyclohexyl ; 1 #iso (YY) 2109 aa where is sr 9 110 cg 1" or 7 so that sit is not greater than 11 ; No precipitate 108 or oxygen ¢ and X is a pharmaceutically acceptable ion .pharmaceutically acceptable anion 4 YEYY 0 YY compound SOLS in claim No. 1? or No. YY where the ring is “for” (1) an optionally substituted phenyl; wherein the optionally substituent is chosen from the alkoxy v (1 -?carbon atom) b “libero” halo ¢ alkyl (1-? carbon atom) taldene. ¢ ; aminoacyl (1-?500 carbon) aminoCiCaacyl 5-aminoalkyl (1-?30 % carbon) aminoC; Monocyclic heterocyclic ring consisting of © or 1 + Jed Jaw Jeo ring atoms Dihydrobenzofuryl .dihydrobenzofuranyl q IC containing formula 1;7- a compound as stated in claim No. 1 * ure mg N (CH,), —N mL ) +_ (CH,) — Rio A 2m ~~ (CH) CE XY v SEEN © They are oxygen or sulfur 5 ; ““ is equal to 1 or ? ; Basal is 1 pyrrolidinium ring or piperidinium ring 18” is Jud phenyl 1-; thienyl; cyclopentyl + or cyclohexyl Ala ; + T is phenyl Jud « thienyl ; cyclopentyl cyclohexyl ; “1 and “J has the unit of a hydrogen atom 0 hydrogen or an alkyl” YY) e.g. phenyl aryl m©-,© optionally substituted or aryl alkyl carbon) 0 500 where © is 7 fT eof FY oY optionally substituted; 8 is equal to phenyl) Y ; 11 or 7 such that + is not greater than 119 46” +7 +1 ha OY Wasa is an acceptable anion X and + oxygen is an OY bond or oxygen .pharmaceutically acceptable anion 084 Yo A compound as mentioned in any of Claims No. 17-7?? whereas ; be zero -Yo 1 stt or VY or 0 co cE YY) be se JOE YoY oY "CY deo cE avy) be ' is zero; t where YY or Compound YY number as mentioned in claim No. (YT) oxygen is oxygen 7 oF equal to 8 "whereas 7 is a YY phrase or a compound YY number according to what was mentioned in claim No. - 77 1 . for the and ++ bond equals 7 ? or Y; wherein 37 is a YE bond compounded according to claim No. -7*-" .01 and ++ equals 9 6 or ¢ Selected from constituent group 1 compound as stated in claim No. 74-1 of 1 And [2-(Hydroxy-diphenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3-phenoxy-propyl)- ¥ ammonium salts ¢ [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol -5-ylmethyl]-dimethyl-(3- s phenoxy-propyl)-ammonium salts 1 [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl- L phenethyl-ammonium salts A [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(4- 4 methyl-pent-3-enyl)-ammonium salts Ye [2- ((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-[2-(2,3-dihydro-11 benzofuran-5-yl)-ethyl]-dimethyl-ammonium salts VY [2- ((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(6- " methyl-pyridin-2-ylmethyl)-ammonium salts Vi[2-(Cyclopentyl-hydroxy-phenyl-methyl) )-oxazol-5-ylmethyl]-dimethyl-(3- Vo phenoxy-propyl)-ammonium salts 1 [2-(Cyclopentyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3- no ‎ phenoxy-propyl)-ammonium salts YA 1-[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-1-(3-phenoxy- 4 propyl)-pyrrolidinium salts Ye. [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(4- AR phenoxy-butyl)-ammonium salts YY A\EARY (2-Benzyloxy-ethyl)-[2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5- YY ylmethyl]-dimethyl-ammonium salts Yi [2-((R)-Cyclohexyl-hydroxy- phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(4- Yo phenyl-butyl)-ammonium salts 1 [2-((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- [ 3-(4-fluoro- Yv phenoxy)-propyl]-dimethyl-ammonium salts YA [2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-(3- Ya phenyl-propyl)-ammonium salts ve [2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl}-dimethyl-(2- 1 phenoxy-ethyl)-ammonium salts ry [2(( R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl [-dimethyl-(3-p-ry tolyloxy-propyl)-ammonium salts AR [3-(4-Chloro-phenoxy)-propyl}-[ 2-(((R)-cyclohexyl-hydrox y-phenyl-methyl)- Yo oxazol-5-ylmethyl]-dimethyl-ammonium salts 71 [2-(((R)-Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5 -ylmethyl]-[3-(3,4- 9 dichloro-phenoxy)-propyl]-dimethyl-ammonium salts TA [2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]- dimethyl-(8- va methylamino-octyl)-ammonium salts ge [2-(((R)-cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-ylmethyl]-dimethyl-[2-(4- 3 methylaminomethyl-phenyl) )-ethyl]-ammonium salts l AREA {2-[2-(Cyclohexyl-hydroxy-phenyl-methyl)-oxazol-5-yl]-ethyl }-dimethyl-(3- ey phenoxy-propyl)-ammonium salts £4 {2-[2-(Cyclohexyl) -hydroxy-phenyl-methyl)-oxazol-5-yl]-ethyl }-dimethyl- to (3-phenoxy-propyl)-ammonium salts, and £1 {2-[2-(Hydroxy-diphenyl-methyl)-oxazol -5-yl}-ethyl } -dimethyl-(3-phenoxy- tv propyl)-ammonium salts Hand [2-(Hydroxydiphenylmethyl)thiazol-5-ylmethyl]dimethyl-(3- £9 phenoxypropyl)ammonium salts © (3-Benzyloxypropyl)-[2-((R)-cyclohexyl-hydrox y-phenyl-methyl)-oxazol-5- 51 ylmethyl]-dimethyl-ammonium salts oY [2-(4-Chloro-benzyloxy)-ethyl] -[2-((R)-cyclohexyl-hydroxy-phenyl-methyl)- oy oxazol-5-ylmethyl]-dimethyl-ammonium salts of R? A compound as mentioned in any of the previous claims, modified by substituting a group *10 1 to be a connecting root and 3 to be a part that has a receptor aberrant activity 1. Cus LB with a group “0 82 adrenoreceptor agonist” adrenergic activity 7 . Compound as stated in any of the claims prior to use in treatment TY 1—FY 1 A pharmaceutical composition, a pharmaceutical Includes a compound as mentioned in any of the claims 1 to Jala Y4 or a pharmaceutically acceptable excipient Pharmaceutically acceptable and 10 Contains VY, as mentioned in the claim, a pharmaceutical formulation —FY 1 . Any form suitable for inhalation 7