SA07280032B1 - Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses - Google Patents

Abstract

Abstract: Compounds of formula (I) possess muscarinic M3 receptor catalytic activity where A is an oxygen atom or a group (R1, N(R12) is C1-C6 the C1-C6-alkyl or a hydrogen atom and R2 is a hydrogen atom or Group :-1, Z-Y-R6, -r5 -Z-NR9-CO-RS CO-NR9R10 , -Z-NR9R10 or Z-CO2-J and R3 carries a positive charge r3-R1 together with attached nitrogen They form a heterocycloalkyl ring and R2 forms a hydrogen atom, and a -Z-NR9-CO group : R5 , Z-CO-NR9R10, -Z-NR9R10 , -Z-Y-R5, R5 or a Z-CO2- group H - In cases with hydrogen attached to them, they are quaternary nitrogen and carry a positive charge or r2, R1 together with the nitrogen attached to them. M, -ZNR9R10 , Z-Y- R5 , Y-R5 -Z-N-R9CO-R6 or -R3 , Z VO2H is a lone pair or a Cl-C6 alkyl C1-C6-alkyl in which case the nitrogen atom attached to them is a quaternary nitrogen nitrogen carries a positive charge. R4 is the formula group C-B-A or D. The alkyl group is C1-C6-alkyl C1-C6 aryl, aryl-fused heterocycloalkyl, aryl-fused heteroaryl-cycloalkyl C1-C6-alkyl heteroaryl heteroaryl , aryl (aryl(C1-C8-alkyl). Define it in the description.

Description

Y

Het-7-ylamine and its uses [1,7,7] Dicyclic derivatives

Bicyclo[2.2.1]hept-7-ylamine derivatives and their uses Bicyclo [Methods of preparing it « pharmaceutical compositions » 7-ylamine for example » 143 muscarinic diseases and its use in the treatment of intermediate diseases in the future of m? Muscarini. Respiratory oo inhibits the passage of © or effects resulting from the passage of anticholinergic agents; anticholinergic impulses through the parasympathetic nerves. This represents a result of the ability of these compounds to inhibit by blocking their binding to cholinergic receptors (Ach) acetylcholine action of acetylcholine. muscarinic cholinergic receptors muscarinic acetylcholine Distinctive and every gen is produced by Jia gen; each is MI-MS; called receptors (mAChRs) distribute mAChRs . pharmacological properties of which display unique pharmacological properties; And those receptors can mediate all vertebrate organs in an extensive manner in the vertebrate organs of the inhibitory and exciting effects. for example; In smooth muscle found in the airways + bladder M3mAchRs + mediate responses to gastrointestinal-tract disorder and the gastrointestinal tract Vo

Pharmac. Ther. Pharmaceuticals ¢ 15957 ¢ Caulfield contractile (Revised by Caulfield .) (Yya-vy 5 pages) OA has been shown to be significant M3 and 112 muscarinic receptors (M1) in the lungs; submucosal muscarinic receptors saallbronchi ¢ trachea and locates in the trachea v (Edited by Fryer parasympathetic ganglia and submucosal glands part ?); ©) 018 « Am by Resp.

Crit Care Med.” Y449A ¢ Fryer and Jacoby and J. J. C. over the smooth muscle pathway mediates contraction and M3 (pp. S 1107108). Receptors Stimulate 13 receptors located in the submucosal glands. Therefore, it is considered a bronchodilator. ' Causes mucus secretion ©

Excess signaling through muscarinic acetylcholine receptors has been observed in a variety of different pathophysiological states including asthma and COPD (chronic obstructive pulmonary disease)0 in the case of COPD; vagal tone can either increase (Chest 1434 « Grosse et al ¢ 11: pp. 4/87-4840-00) and/or can induce a higher degree of interference for engineering reasons when applied to The upper part of the walls of the airways laden with oedema or mucus (Grosse et al., Am Rev.

Respir.

Dis.; 179: pp. 4556 to 7 AD). in addition; Inflammatory conditions can lead to loss of M2 receptor inhibition efficacy, causing increased rates of acetylcholine release in response to peal nerve stimulation (Frayer et al.; 0 1233 Life Sci; (Y=) TE; pp. £9-£00). The resulting increased activation of M3 receptors leads to an improvement in airway obstruction. Therefore, the identification of effective muscarinic receptor-1 antagonists is considered useful for the pharmaceutical treatment of these pathological conditions Cus Including improved activity of the M3 receptor Indeed, contemporary treatment strategies support the regular use of 143 anti-bronchodilators as initial treatment in COPD patients (Powles and colleagues, Am.

Rev.

Respir.

Crit.

Care Med. ¢ 0010 ¢ 1¥:

. ) 17976-176 pages

¢ Urinary incontinence due to excessive contraction of the bladder has also been shown to be mediated by increased stimulation of 1034055. Therefore, M3mACHR antagonists could be considered useful as pharmaceutical therapies in MAChR-intermediate diseases. Although there is ample evidence to support the use of antimuscarinic 200© receptor therapy for the treatment of pathological conditions of the airways; Relatively few anti-muscarinic compounds are used in hospitals for pulmonary indications. So ; There is a permanent dala for new and innovative compounds that are qualified to be soli on intercepting muscarinic receptors 143 muscarinic receptors; Especially those compounds with extended action; (Sy) from a diet for a single dose per day 0 Since the muscarinic receptors Ve are widely distributed throughout the body; the ability to release anticholinergic drugs directly into the respiratory tract is considered advantageous as it allows taking Low doses The structure and use of long-acting topically active drugs that remain on the receptor or in the lung will allow to reduce the unwanted side effects that can be seen with regular administration of the same drugs. Spiriva™ Tiotropium (Spiriva) is a bias muscarinic antagonist marketed for the treatment of chronic obstructive pulmonary disease » administered by inhalation. None N — = a SN A H 5 A 0 J oH 2 Tiotropium

° further ol ipratropium is a muscarinic antagonist market COPD gal .

Wl0 ig

Ipratropium Other muscarinic receptor regulators cited eg: US Patent © No. 07977; describe muscarinic regulators based on a ring system of compound (YY) 1) azabicycloheptane [2.2.1] azabicycloheptane. EP No. 189715 and US No. 17 describe various dla systems of compounds (? 7 1) azabicyclooctane [3.2.1.] azabicyclooctane [2.2.2 Jazabicyclooctane] [3.2.1.] ¥ 7 7 azabicyclohexane systems 0 and ISBN 0011/1177 have been described by, for example, in US Patent No. (quinuclidines) [3.2.1.] azabicyclohexane; systems (? +( azabicyclohexane 0 1 ) 1 YF) and the systems are described in 30787 [eT] in eg ISPM No. 30787.

CAYO Y [on eg in International Patent No. 1 [3.2.1 Jazabicyclooctane] 10 class of solid ¥ adrenergic receptor agonists 82 is well known. Many B2-agonists Y = information; Especially the long-acting B2-1 agonists, for example salmeterol and formoterol, “have a role in the treatment of asthma and COPD. These compounds generally handle load by inhalation. Compounds present under evaluation as slugs LY 802-28001555 Single daily dose labeled in

0 (VY) 04 Expert Open. Invest. Drugs (Yeo) VAT-VVO pages on

HN

NH

0 It is also known in the field of pharmaceutical compositions that contain both antimuscarinics and a beta-agonist ¥ 02-8005 for use in the treatment of respiratory diseases. eg muscarinic antagonist © agrees with P2agonist 7 ; American Patent 8/18 does not describe the beta anode; and ipratropium ¢oxotropium antagonists tiotropium ¢ tiotropium describing compatibility of 0110577 [oY other; and ISPM No. muscarinic antagonist 10677 [0X] and ISPM No. B2-agonists with beta-agonists - ?ipratropium and other compatibility. p2-agonists 7- With oxotropium beta antagonists describing compatibility of Ve and 015784 [ug described in International Patent No. 2-agonist and M3 beta agonist from antagonists. The 1-alkal [oF muscarinic intn. Also known in the field are compounds with both muscarinic receptor antagonist activity and beta-agonist activity? 82-2800158 located in the same molecule. These receptor antagonists are bifunctional molecules that provide expansion of the bronchi through two separate modes of action while obtaining ve. This molecule should be easy to synthesize for use. Jie. The pharmacokinetics of the single therapeutic molecule compared to the separate binary compounds and can be formulated more easily by means of those molecules described, for example, in International Patent No. steroid 0 Wie third active content; / 05 International No. 1001 [eo-] International No. 83447 [og 4746 no; International No. 4

7740; and International No. 774500075; They all use different bonding moieties for the covalent bonding of anti-3 with the beta-7 B2-agonist. General description of the invention According to the invention, a compound of the formula ( ): R? A m) 0 is presented where M is an oxygen atom. oxygen atom or NR group?) « R' (i) is a 1-6(carbon atom) C-Ceralkyl or a halogen atom R? halogen atom is 53 hydrogen atom or R® group; or the Z-Y-R® range; or set -7_ NRRY ; or group “2-00-1828; ~Z-NR-CO-R® group; or -7_ CO-R® group 0; or group 2-0011; 183 is a single pair; or an alkyl (1-1 carbon atom) 0,0-m-arole to which the nitrogen atom attached to which led is quaternary nitrogen and carries a positive charge; or (=) Li and 183 Ls with nitrogen attached to them form a heterocycloalkyl ring R? heterocycloalkyl ring form a hydrogen atom or group "2"; or group 10 2-785; or group -ZNRR" ; or -Z-CO-NRRY ensemble ; or _ZNR'- 60-8 ensemble ; or -8:2-00 ensemble ; or —Z-COMH ensemble ; and 183 Ble for a pair Single; or Alk-1 (carbon atom) anal-m©-,© Alls in which the nitrogen atom attached to it is quaternary nitrogen and carries a positive charge ; or

A

(z)Li and R? together with the nitrogen attached to them form a 7-7-8 heterocyclic alkyl ring; or a group of Y-R¥ic ganas; The aforementioned ring is replaced by a heterocycloalkyl ring; or set to 21808- ; or ~Z-CO-NR'R'® combination; or 2180-00-85 ¢ Series J 87-:2-00- Series ; or group 2-00:11-; and 183 is a singular pair; or an Ally Cr-Coralkyl with the nitrogen atom attached to it being quaternary nitrogen and Lind carries a positive charge ¢ or doc cba Tinal closes ge als SR 7a R® I 7 . rR" ow * 8 9 ll 8b lm a blk nh #0 mo (a) (b) (c) (d) 2 be the alkylene group (111 carbon atoms) Cp-Crealkylene alkenylene 117 carbon atoms) Cp-Cye-alkenylene 0 or alkenylene (1-7 carbon atoms) counting “dissolving” 0-j; it is a bond or an oxygen atom oxygen atom; 5p is the alkyl group (1-1) carbon atom Cr-Coralkyl » aryl carl aryl = fused - JS cycloalkyl 1 arylfused-cycloalkyl aryl fused - heterocyclic aryl-fused- aryl(Cy-Cg-alky) atom carbon) A=) aryl (alkyl) ¢ heteroaryl heteroaryl “heterocycloalkyl carbon atom” (Wll.©- (161:21) cyclo-alkyl A-) (alkyl) heteroaryl aie aryl “Ve cheterocycloalkyl or heterocycloalkyl be an alkyl (1-Y) 33 carbon) C1-Ce-alkyl or 3 hydrogen atom ¢ 75 be an alkyl group (1-6 atoms) carbon) Ci-Ce-alkyl or halogen iss moon on 710 ja sa or ?;

q aryl fused to an alkyl + aryl are independently selected from the group composed of aryls R® and R® alkyl (1-1 atom “heteroaryl ¢ aryl-fused-heterocycloalkyl heterocyclic ¢ cycloalkyl carbon) wala-m0-.© ; Cycloalkyl carbon) 83 1-1 (carbon atom) anola-m6-,© ; 1-1 hydroxy-alkyl) ; alkyl OH is 8” hydrogen atom group 01185 or hydrogen atom ¢ nitrile; hydroxy nitrile C;-Ce-alkyl © ' ¢ hydrogen atom or hydrogen atom C-Cg-alkyl carbon atom (1-1) The alkyl RY©,- carbon atom (1-1) and the alkyl group (hydrogen atom) are independently a hydrogen atom LGR? ¢ aryl-fused-heterocycloalkyl » aryl » aryl » Ce-alkyl 1-1; aryl (alkyl) heteroaryl » aryl-fused-cycloalkyl (ls) 0 carbon atoms (alo-0-1616:0210; 1-1) or a heteroaryl (arylCi-Coalkyl carbon) attached to them form a mitrogen atom together with £3 nitrogen RS RO or nitrogen atom Lyla) having from 4 -/ 5 ¢ heterocyclic ring foxygen atom ¢ hydrogen atom or 30 C;-C¢-alkyl carbon atom (-01) Crown is a ve cycloalkyl or a heteroaryl cycloaryl s aryl that is Ar; and a cycloalkyl or heteroaryl is a heteroaryl aryl that is Independently, an aryl ¢ or a bond of CH,CH,,CH, « oxygen atom is 50 oxygen © oxide + dissolved solvate + pharmaceutically acceptable salt. or a drug generator derived therefrom nitrogenous N-oxide 0 : in a subset of the compounds of the invention and the N(R'?) or an oxygen atom group being an oxygen atom A

01 82 and hydrogen atom or hydrogen atom Ci-Cealkyl is not an alkyl (1-1 carbon atom) 7- or hydrogen atom group (carbon atom) Alola-m0-0 + hydrogen atom 1- 1 alkyl (contiguous being nitrogen together with nitrogen RZ or group 2085879 or 1 and 7-8 ¢ heterocycloalkyl ring late cycloalkyl ring in this case nitrogen atom x carbon) -m©-,© 83 1-1) be a lone pair or an alkyl RP 0 and carry a positive charge quaternary nitroten attached to them is a nitrogen atom attached to them form a ring nitrogen ignites together with nitrogen SR! or carries a positive charge; Positive charge nitrogen atom This case a nitrogen atom ¢ charge of bs a is one of the groups of the formula RE M5 8a R® Ar * 1 . r > ben ct R% 7b . 0 0 (Rn (a) (b)

Co carbon) 33 A=Y) alkynylene « Cy-Calkylene carbon) 83 A=Y) the alkylene group is 7 ¢ Cp-Cg-alkynylene carbon atom (A—Y) or the alkynylene Cs-alkenylene ¢" oxygen atom form a bond or oxygen atom 7 ve carbon atom) A=) aryl (alkyl) ¢ heteroaryl; -alkyl carbon atom) A=) ajala-:©0-,010 e or hetero-aryl (alkyl(; hydrogen atom or hydrogen atom C;-Ce-alkyl carbon atom) 1-1 The alkyl (6 halogen carbon atom) is primary -m©-,© or the 1-6 halogen “p and 17” are independently the alkyl group (al

11

EF or 7 60 0 and “be isosterone equal to zero” aryl hetero “aryl” and “18 be isochrome chosen from the group composed of an aryl, RS ¢ cycloalkyl carbon atom) and an alvo- ; Cycloalkyl 1-1 (alkyl ¢ heteroaryl carbon atom) anole-m6-,©; hydroxyalkyl (1-1 83 carbon) 1-1 ; an alkyl(OH is 8” ¢ hydrogen atom or 33 hydrogen hydroxyC,-Ce-alkyl 0 1-1); an alkyl hydrogen atom group that independently forms a hydrogen atom RY SR carbon atom) 1-1 aryl (alkyl(0 heteroaryl ¢ aryl carbon atom) anole.m©-.© ; aryl or that the heteroaryl C;-Ce-alkyl carbon) 83 1-1 or the heteroaryl (alkyl) arylCy-Ce-alkyl attached to them form a mixed ring having a nitrogen atom with a nitrogen atom LR something and another oxygen atom or nitrogen atom of 4-8 atoms; optionally containing a 0 nitrogen atom and .hydrogen atom; or 5 hydrogen (C1-Coralkyl carbon atom) 6-1 Alkyl formation (RP? anti and syn) The compounds of the invention exist in the forms A, Bm, R*m, R* syn- anti-

Endo Exo either in the directive AR The compounds of the invention are also present as the group 1 we we

R R oF

AlR*H endo-exo-

VY

. Predominantly anti-endo of an invention in order 1 currently preferably 1 M rR “N compounds

H

The Al R* anti-, endo- systems Cus of the compounds of the invention can also exist as 5-substituted optical cyclocyclic cyclic isomers that can lack a level of symmetry. The order can be defined for each mode. In order for 8, R to determine the absolute Cahn-Ingold-Prelog label of the molecule using © . To avoid confusion the ring numbering used below has been used as 7 1 and 543 enantiomers "racemates" though; The compounds of the invention include racemates of all these Cus forms in any ratio; individual racemates and mixtures of enantiomers 105. In varying degrees muscarinic possesses muscarinic 3 receptor inclusion activity 0 quaternary The preferred class of compounds of the invention consist of quaternary ammonium salts in formula (1) being neutral nitrogen according to formula (1) wherein nitrogen is ammonium salts. carrying a positive charge quaternary nitroten The compounds of the invention may be useful in treating or preventing diseases involving activation of muscarinic receptors; For example, the current compounds are useful for treating a range of conditions, including but, 1 chronic obstructive pulmonary disease; Jie inflammation is not limited to disorders of the chronic bronchial respiratory system of all kinds (including associated hoarseness); asthma (allergic/acute respiratory distress syndrome”) wheezy-infant and non-allergic; Infant whistling syndrome

Adult YRA (41809) ¢ Chronic obstructive pulmonary disease; bronchial hyperactivity + pulmonary fibrosis » emphysema and allergic sinusitis - » exacerbation of airway hyperactivity resulting from JA therapy; In particular, treatment with an inhaled drug, Al Pneumoconiosis (for example, “aluminosis, anthracosis, asbestosis sims} 0, silicosis 55, feather silicosis, 55, mourning, siderosis, sciatica silica 0 5 tabacosis ; byssinosis ; Disorders of the digestive system MD Jie Irritation of the bowel Irritable bowel syndrome « Ulcerative colitis Spasmodic colitis; gastroduodenal ulcers de J} “gastrointestinal convulsions or hyperactivity” 0 blockages, diverticulitis; pain accompanying spasms of gastrointestinal smooth musculature; Urinary system disorders associated with urination disorders, including neurogenic urination, neurogenic bladder, nocturnal enuresis, psychosomatic bladder, incontinence associated with bladder spasms, or bursitis. chronic cystitis » urinary urgency or pollakiuria; Motion sickness and cardiovascular disorders Jie vagal induced bradycardia. to treat respiratory conditions; Often, inhalation will be preferred, and in these cases, compounds (1) that are quaternary ammonium salts will be preferred. In many cases, the activity period of the inhaled quaternary ammonium salts of the invention may be more than VY or more than YE hour for a typical dose.For the treatment of irritable bowel disorders

Oral V¢ We May Cardiovascular Imbalances; Injecting drug syndrome Another aspect of the invention is a pharmaceutical composition comprising the compound of the invention and a carrier or excipient. The activity of the muscarinic receptor includes: Terms As long as they are not described in the context in which they are used, the following terms have the following meanings: The following alkyl group is Cua CO- alkyl group means the alkyl group “Acyl Jud” - 00 .COCH(CHs), 5, COCH; as described here. Ideal acyl groups include acyl and acyl R where —NR- acyl group means “Acylamino acyl amino” =

N(CH;) 5, NHCOCH; Idealism includes acylamino by their definition here. acyl amino groups .COCH; Where -O-alkyl group means “alkyloxy group SSI” and “Alkoxy” means alkoxy-0 methoxy includes an alkyl be as described below examples of alkoxy groups. -OC;Hs) ethoxy And ethoxy (-0011:) methoxy where -000- alkyl group means “alkoxycarbonyl” alkoxycarbonyl group - alkoxycarbonyl alkyl is as defined below. Examples of alkoxycarbonyl groups are .ethoxycarbonyl and methoxycarbonyl includes methoxycarbonyl 0 of a group denoting a hydrocarbon group en as a group. or alkyl” JSF - to + 1 atoms; preferably VY to 1 saturated straight or branched endowed with hydrocarbon

Yvyi

Vo-1 «ethyl; Ethyl methyl Examples of alkyl groups include methyl ALL carbon + V. And? To + 11 straight or branched chain atoms possessing whom? to hydrocarbon series Examples of groups carbon - carbon carbon and carbon double bond = carbon © 2-propenyl . propenyl —Y and 1-propenyl leniporb-1 » ethenyl alkynyl includes ethinyl as a group or fraction From a group denoting a hydrocarbon group “Alkylamino Jolt - preferably? to + straight or branched VY atoms holding from? to a hydrocarbon including an alkynyl carbon and a carbon-carbon triple bond in the chain are examples of alkynyl groups 2- propenyl and? The highest examples of alkyl amino groups include methylamino. -) , CH, Alkylene already included Examples of alkylene groups Vo as alkenyl in which the alkenyl Alkenyl group means "Alkenylene" Alkenylene -

CH2CH= CH- , alkenylene examples include alkenylene groups 0 already defined

CH=CHCH2- , CH=CH- are as alkynyl; Where alkynyl the "Alkynylene" group means the alkynylene - and CH,CC-, CCCHy, -CC- were previously defined. Examples of alkynylene groups include Y.

- “Alkylsulfiny] means the alkyl group -50-, where the alkyl is as defined above. Examples of alkylsulfinyl groups include methylsulfinyl and ethylsulfinyl. Jai - sulfonyl “Alkylsulfonyl” means an alkyl group -,50- where the alkyl is as defined above. Examples of alkyl groups Alkylsulfonyl sulfonyl includes _methylsulfonyl and ethylsulfonyl .ethylsulfonyl “Alkylthio sb Ji - means the alkyl group -5- where the alkyl is as defined above. Examples of alkylthio groups include methylthio and ethylfer .cthylthio - 0-acyl “aminoacyl” means CO-NRR group where R is as described here. Examples of aminoacyl groups aminoacyl include 0011112 , CONHCHj.5 - “Aminoalkyl” means NH, alkyl group, where the alkyl is as previously described. Examples of aminoalkyl groups include CH,NH , and -aminosulfonyl means -502-0808 group, where R is as described as Vo here. Examples of aminosulfonyl groups include SO;NH, and SO,NHCH;. "Aryl dul - as a group or part of a group denoting oi cyclic carbon whe monocyclic or ape cyclic optionally substituted from + to 14 carbons; preferably 1 to 0 atoms Jie carbon is phenyl or naphthyl. The aryl group may be substituted with one or more substituted groups. xe - arylalkyl means aryl group - alkyl where The aryl dus alkyl moieties are as described above. The preferred arylalkyl alkyl groups contain an alkyl moiety (1-4 carbon atoms). Examples of arylalkyl alkyl groups include benzyl;

11 _ of it aryl may be a part of _aryl. naphthlenemethyl and phenethyl phenethyl. substituted by one or more substitute groups

- “Arylalkyloxy” means aryl-alkyloxy group Cus aryl-alkyloxy the aryl and alkyloxy parts are as described previously 0 aryl groups ° alkyloxy preferred aryl-alkyloxy contain an alkyl part ( 1-; a carbon atom). Examples of aryl-alkyloxy groups include benzyloxy (ej). benzyloxy aryl aryl of it may

be replaced by one or more substituted groups. Aryl-fused-cycloalkyl means Jie monocyclic aryl ring phenyl combined with a cycloalkyl group where 10 aryl and cycloalkyl are the same They are described here Examples of cycloalkyl-dof groups include tetrahydronaphthyl and indanyl The aryl and cycloalkyl rings may be substituted with one or more substituent groups The aryl-fused-cycloalkyl group may be attached to the rest of the compound by any atom

Carbon available. ve - “aryl-fused-heterocycloalkyl” means a monocyclic aryl ring, Jie monocyclic aryl ring, phenyl fused to a heterocycloalkyl ila alkyl group, where the aryl and the alkyl heterocycloalkyl be as described here 0 Examples of aryl groups incorporated with a heterocycloalkyl include tetrahydroquinolinyl “indolinyl 10801071 ¢ benzodecynyl Y. 5602001001 + benzodioxolyl | benxodioxolyl + dihydrobenzofuranyl and isoindolonyl . The aryl rings and the heterocycloalkyl rings may each be substituted with one or more substituent groups.

VA

May be attached to the rest of the compound heterocycloalkyl aryl group combined with heterocyclic alkyl available. nitrogen atom with any carbon or nitrogen atom. They are as described above. aryl dul means aryl group -0- where “Aryloxy” - aie aryl is the aryl part. phenoxy Aryloxy includes examples of aryloxy groups. It may be substituted with one or more substituted groups ° heterocycloalkyl heterocyclic (Als JST is a special case of "Cyclic amine" - heterocyclic A members "means a monocyclic cyclic alkyl ring system with whom? to ye or optionally substituted in which one of the carbon atoms of the ring is replaced by a nitrogen which may contain (where 18 is NR optionally an additional selected heterodimer of oxygen 0; sulfur 5 or “pyrrolidine” including cyclic pyrrolidine amines are examples of cyclic amines (0 as described here) 1 and 11-methyl piperazine; piperazine morpholine; piperidine morpholine piperidine may be substituted by a group of cyclic amines with the cyclic amine group N. -methylpiperazine One or more substituents bicyclic or monocyclic means a monocyclic "cycloalkyl Jit" system - preferably from “to carbon atom” 11 saturated carbon atom optionally substituents from? to 8 carbon atoms preferably more than * to + carbon atoms Examples of monocycloalkyl rings A cyclohexyl ¢ cyclopentyl cyclopropyl Cyclopropyl Cyclopropyl may be the cycloalkyl group of the cycloalkyl group. cycloheptyl and cyclohexyl . substituted with one or more cycloalkyl-alkyl substituent groups alkyl - ila JU “Cycloalkylalkyl group means git - ve as previously described. Examples of alkyl groups are kyl where the cycloalkyl and alkyl parts are bentyl Cyclo« cyclopropylmethyl is a monocyclic cycloalkyl that includes cyclomethyl propyl

cyclopentylmethyl; cyclohexylmethyl and Jie cycloheptylmethyl. The cycloalkyl moiety of the derivative may be substituted with one or more substituent groups. aw - alkyl “dialkylamino sud” means L1 (alkyl) group? where the alkyl is as ° defined above. Examples of dialkylamino groups include AU methylamino Al dimethylamino diethylamino . - “Halo” or “halogen” means fluoro ¢ chloro; bromo ag or iodine 1000. The preferred is fluoro or chloro-’haloalkoxy Haloalkyl means an Ally -O-alkyl group in which the alkyl 0 is replaced by one or more halogen atoms.The typical haloalkyl groups are Gaal trifluoromethoxy and JG .difluoromethoxy - 'haloalky] means an alkyl group which is replaced by one or more halo atoms. Typical haloalkyl groups include the 10-aryl trifluoromethyl "heteroaryl" as a group or as part of a group expressing a substituted aromatic monocyclic or polycyclic 0-4 moiety. cyclic 0 and in preference to 01-© a cyclic atom in which one or more of the cyclic atoms is an element(s) other than carbon ¢, for example, nitrogen, oxygen, or sulfur ABN. Of these groups include the groups | indolizinyl ; isoxazolyl » isoquinolinyl ¢ f

1 isothiazolyl oxazolyl ¢ oxadiazolyl « pyrazinyl

pyrazinyl ¢ pyridazinyl ; pyrazolyl « pyridyl ; pyrimidinyl

¢ quinolinyl » quinazolinyl quinazolinyl + pyrrolyl ¢ pyrimidinyl

¢ thiazolyl thiazolyl ¢ 1,3,4-thiadiazolyl thiazolyl — £0 7 + 0 tetrazolyl

© thienyl and triazolyl . The heteroaryl aryl group can be substituted

with one or more substituted groups. The heteroaryl aryl group can attach to the rest

The compound of the invention is about Bub any carbon or nitrogen atom available.

-"Heteroarylalkyl alkyl arylalkyl" means dc gene hetero-aryl-alkyl alkyl-aryl

In which the heteroaryl and 1a-alkyl moieties are as described before. Typical heteroarylalkyl 0-aryl groups contain a primary alkyl moiety. alkyl aryl groups

Typical heteroarylalkyl heteroaryls include pyridylmethyl . hetero-aryl moiety

A derivative can be replaced by one or more of a substituted group.

-'alkyloxy-aryl hetero-' means hetero-alkyloxy-aryl group

aryl-alkyloxy, in which the heteroaryl and alkyloxy moieties are as described from 0 before . The preferred heteroarylalkyloxy alkyloxy groups contain the alkyl moiety

Ole0 alkyloxy aryl groups typical heteroarylalkyloxy slide includes pyridyl

pyridylmethyloxy . The derived hetero-aryl moiety may be substituted by one or more

from a substituted group.

- “heteraryloxy” means heteroaryloxy group led Alls heter aryl 160081 is 0 as described before . Typical heteroaryloxy groups include pyridyloxy. part

A derived heteroaryl can be substituted by one or more of a substituted group.

1 cycloalkyl combined with a heteroaryl "means a monocyclic heteraryl group; for example"-lead; which cycloalkyl or furanyl; Combined with a pyridyl cycloalkyl group the example pyridyl and the cycloalkyl groups are as described before. Typical heteroaryl cycloalkyl groups include tetrahydroquinolinyl and tetraheteroaryl combined with a heteroaryl aryl. Heteroaryl and cycloalkyl rings can each be substituted by one or more than one substituent group. A cycloalkyl group combined with a heteroaryl can attach to a residue. Available nitrogen compound by means of any carbon or nitrogen atom combined with a heteroaryl "means the aryl group heterocycloalkyl part" -; combined with a monocyclic dibs or pyridyl group heterodimer; eg pyridyl and hetroaryl cycloalkyl; In which the aryl heterocycloalkyl heterocycloalkyl 0 they are as described before. incorporated heterocycloalkyl groups heterohydrodeoxynopyridinyl ; Dihydropyrrolidopyridinyl di JE is an aryl hetero-containing_ rufuranopyridinyl and dioxolopyridinyl . Heteroaryl rings and heterocyclic alkyl rings can each be substituted with one or more of a substituted group. heterocycloalky group! part with the rest of the compound via any Gab atom the heterocyclic alkyl combined with a heteroaryl can ve . available nitrogen carbon or nitrogen or "heterocyclic" means a cycloalkyl group heterocycloalkyl heterocycloalkyl - a cycloelement which contains one or more mixed atoms Amt of the cycloalkyl cycloalkyl group Cycloalkyl 1) NR or “sulfur” (examples of these CONRCO and CONR) have cycloelement groups (LY a) of 874 Includes succinimidyl and 7-oxopyrrolidinyl).The heterocycloalkyl group may be substituted with one or more substituted groups.Heterocycloalkyl group part

YY

It can be attached to the rest of the compound by any heterocycloalkyl atom (heterocycloalkyl part). Available nitrogen Carbon, nitrogen, or heterocycloalkyl Heterocycloalkylalkyl heterocycloalkyl gant - alkyl alkyl group — heterocycloalkyl means heterocycloalkyl 'heterocycloalkyl' as Tkyl and the heterocycloalkyl alkyl in which The heterocyclic alkyl fractions group ° have been previously described. Other; Hydrocarbon group SY as a group means if “Lower alkyl primary alkyl” - to; 1 atoms of jad may be straight or branched aliphatic hydrocarbon propyl propyl (propyl or isopropyl) “ethyl methyl Jie carbon in chain iso-butyl or bytyl or iso-propyl 01 ¢ (tertbutyl WS description) Where the alkyl is -SO- alkyl group Means the alkyl group "Sulfonyl" - - Methanesulfonyl includes sulfonyl here Examples of sulfonyl and sulfonyl groups R means sulfonyl group 118 - where "Sulfonylamino" Amino Judd - 111150011 Includes sulfonyl amino as described here Examples of sulfonylamino groups Vo As described here heteroaryl means hydrogen ¢ alkyl « aryl or heteraryl © - means physiologically tolerable salt "pharmaceutically acceptable salt" is a pharmaceutically acceptable salt - or toxically, and includes, when appropriate, the salts of adding a pharmaceutically acceptable base; acceptable quaternary ammonium salts 1777 z

YY

When the compound of the invention contains one or more acidic groups ¢, for example, groups (I), then the salts of the addition of a pharmaceutically acceptable base, which may carboxy groups, carboxy, calcium, such as serum ¢ potassium, potassium, ¢ sodium, are formed that include sodium salts or salts containing organic amines « ammonium 0

N- and 17- diethylamine diethylamine Jie organic amines ° or amino acids diethanolamine _diethanolamine 1 methyl-glucamien and the like and lysine (for example, lysine amino acids Amino group, the salts of addition of Jia when the compound of the invention contains a basic group (II) “pharmaceutically acceptable acid hydrochlorides that may be formed include acetate hydrochlorides phosphates; phosphate sulfates hydrobromides 01 mesylates + tartrates; Quaternary (III) sulfates + bromides bromide ¢ chlorides chloride Mia the opposite accepted may be vo benzenesulfonates benzene sulfonates methanesulfonates methanesulfonates ¢ sulfates phosphate + toluenesulfonates (tosylates) toluene sulfonates ( tosilat) 0 cha) » lactates; and similar Y succinates succinates. It will be understood that as used here; The references to the vehicles of the invention are intended to include . Also, pharmaceutically acceptable salts

Ve refers to a compound that is metabolically convertible in vivo (eg 'prodrug' -

Sie of the compound of the invention (oxidation or oxidation, reduction and hydrolysis by hydrolysis may be capable of hydroxy ester generator of the compound of the invention containing a hydroxy group for conversion by hydrolysis in the neighborhood of the parent part - esters suitable for the compounds of the invention containing a group ¢ lactate catates ¢ citrates ¢ acetates For example: hydroxy hydroxy acetate ° ¢ salicylates salicylates ¢ oxalates oxalates oxalates “malonates tartrates tartrates maleates maleates” fumarates fumarates succinates succinate ¢ propionates propionate ¢ methylene-bis-B-hydroxynaphthoates -hydroxynaphthoates Gar methylene-bis' di-p--para-toluyl tartrate AW ¢ isothionates Isothiones 1 gentisates ethanesulfonates ethanesulfonates » methanesulfonates methanesulfonates ¢ toluoyltartrates 01 ¢ p-toluenesulfonates para -toluene sulfonates » benzenesulfonates 0 z for Al generator as an example. Quinates and quinates, cyclohexylsulfamates, cyclohexylsulfamates, an ester drug, according to the compound of the invention, containing a carboxy group, may be formed convertible by in vivo hydrolysis of the parent molecule. Examples of ester drug precursors are those described by H YA ¢ Fat Drug metab, res Line Weber F.J by Vo It will be understood that as used herein references to the compounds of the invention are intended to also include forms. Pharmaceuticals - 'saturated' refers to compounds and/or groups that do not contain any carbon-carbon double bonds or carbon-carbon triple bonds. “0 - “pla substituent) means optionally substituted up to four substituents. The optionally substituted groups include acyl (eg “(COCH; alkoxy) (eg (-OCH; ; alkoxycarbonyl) alkoxycarbonyl (eg-COOCH; ¢ alkylamine) alkylamine (eg (NHCH); alkyl-la

Yo

alkylsulfinyl (eg -SOCH; ; alkylsulfonyl (eg {(-S0,CH; -S0,CH; alkyl-in) alkylthio (eg (SCH; 11112.aminoacyl amine) eg (CON(CHs); ¢ an aminoalkyl alkyl amine (eg -111 :07): arylalkyl (eg —CH,Ph or _CH,- 1120© ) « cyano a dialkylamino sil alkyl (eg ¢(N(CHa)halo °), a haloalkoxy (eg OCF; or sla (-OCHF; -haloalkyl) (eg CFs « alkyl (eg CH or NO2 « OH » (CHyCH; ; Jul (optionally substituted with an alkoxy; alkoxy + halogen; an alkyl or a halo) alkyl dul 0 (haloalkyl heteroaryl) (optionally substituted with an alkoxy halogen + alkyl or haloalkyl ¢ (haloalkyl) heterocycloalkyl Ve; aminoacyl (eg “(CONHCH; , CONH, aminosulfonyl” (SO;NHCH; , SO,NH, Sie) aminosulfonyl acylamino (eg (NHCOCH; ; sulfonyl amino) (eg (NHSO) ,CH; “heterocycloalkyl 0-alkyl amine (eg morpholine)” arylooxy; Heteroaryl aryl + aryl alkyloxy

. (eg benzyloxy) and aryl heterokyloxy

0 - alkylene radicals; Alkenylene or alkenylene may be optionally substituted by optionally substituted groups in the preceding radicals that include an alkoxy (eg (LOCH; alkyl amino (eg and 2071011)) alkylsulfinyl (eg Jit (SOCH; sulfonyl (SO,CH; Sti) Alkylsulfonyl ¢ alkylthio sb (eg “NH, + (SCH; + aminoalkyl” (-CHoNH, Sie) aminoalkyl aryl alkyl CH,CH,- 5} ~ CH, Ph Sia) arylalkyl

“(Ph Ye _cyano; dialkylamino (-N(CHs), 364) dialkylamino ae alkoxy (eg -OCF; or ((OCHF, haloalkyl) (eg Alkyl CFs (eg CH, or NO, 5 OH¢ (CH,CH;

The compounds of the invention may exist in one or more geometric shapes; visual; enantiomeric 56 diastereomeric and tautomeric; Including, but not limited to, the shapes “worse” and “trans”; Figures 8, 2 RIK - 8, meso, and Figures 10 and enol. Unless Sy is otherwise, the reference for a particular compound includes all isomeric forms, including racemic mixtures and those derived from them. When appropriate, these isomers are separated from their mixtures by applying or condensing known methods (eg chromatographic techniques and recrystallisation techniques). When appropriate, these isomers can be prepared by applying or adapting known methods (eg asymmetric fabrication). Groups ER aay — 0 three combinations of groups 1-12 or 183. In combination (1) RY the alkyl (1-1 carbon atom) is C-Ce-alkyl or atom hydrogen atom and R? is 83 hydrogen atom or group 187 - or group Z-Y-R® or -Z-NRR" dc sane or group ZNR'-CO-R' ; or ~Z-COpR'® group ; or .7 COM group ; and RP is a C-Coralkyl unpaired + or (1-6 carbon) C-Coralkyl in this case 10 The nitrogen atom attached to it is a quaternary nitroten and carries a positive charge. In combination RI(Y) and 183 together with the nitrogen atom attached to them form a heterocyclic alkyl R ® is a heterocycloalkyl hydrogen atom or group 15 or group 7-7-3853 - or group —Z-NR'R' or group Z-CO-NR'R'® or group -7- 0 1187-0 or group 87-:200- or group 2-00:11- in these cases the nitrogen atom 0 attached to them is quaternary nitrogen 108 and carries a positive charge. In particular R' and 183 together with the nitrogen attached to them may form a ring

Xv to 7 ring atoms where the hetero-atoms are nitrogen monocyclic Yon composed of - piperidinyl piperidinyl > » azetidinyl . Examples of these rings include azetidinyl . nitrogen for example methylpiperazinyl nitrogen substituted for nitrogen dishes piperazinyl piperazinyl .pyrrolidinyl ring and the attached methylpiperazinyl rings form a cycloalkyl nitrogen ring with nitrogen Low and 182 R' (2) phylotella in ©

Heterocycloalkyl ¢ said ring is substituted with a Y-R® group or a Z-Y-R' group or a "!2-0828" group or a —Z-CO-NR'R' group or a 2180-00-85 group or group 8 -:2-00 or group 11 -:2-00- and 182 be a lone pair or an alkyl (1-1 carbon atom) A Cy-Ce-alkyl in this case) 3 nitrogen 0 connected to them be nitrogen tetranitrogen together with nitrogen R? carries a positive charge, particularly A18- and quaternary #0 ring atoms where the hetero-atoms 1 connected to them may be a monocyclic ring composed of ? to piperidinyl piperidinyl ¢ azetidinyl rings include azetidinyl .nitrogen, Die nitrogen, Jaf piperazinyl, piperazinyl 0” pyrrolidinyl ring, and methylpiperazinyl rings.

7 when group 8 or group 2-7-87- or group of -22087-8 or group 10 -2-00:-11 or group 2-0008 or group -ZNR-CO-R' or group 10 is present 00-2188 : related to nitrogen and nitrogen RAR! in 182 or the ring is from a carbon in the chain ld may be for example .,(0112); The last is optionally replaced by up to three 2

methyl

ve is not a ligand or -0- and

It may be:

Ya

and propyl ethyl; ethyl methyl eg methyl ¢ Ci-Ce-alkyl carbon atom (2-1 alkyl) en-,sec- or tertbutyl AG; normal butyl; secondary or 0-© isopropyl or isopropyl combined with an alkyl dof or naphthyl or optionally substituted phenyl aryl naphyl eg phenyl eg “,4-methylenedioxyphenyl + 7,;-ethylene heterocycloalkyl heterocyclic Aryl ¢ dihydrobenzofuranyl or dihydrobenzofuranyl 3,4-ethylenedioxyphenyl dioxyphenyl © pyrimidinyl ¢ pyrrolyl pyridyl pyridyl Jie optionally substituted heteroaryl hetero-benzoisoxazolyl “isoxazolyl” oxazolyl oxazolyl pyrimidinyl benzo thiazolyl - + thiazolyl thiazolyl “benzoxazolyl ¢ furyl benzothienyl benzothienyl ¢ thienyl Jul” quinolyl quinolyl ¢ thiazolyl isothiazolyl + benzimidazolyl; benzimidazolyl imidazolyl benzofuryl ¢ imidazolyl 0 isothiazolyl ¢ pyrazolyl benzisothiazolyl isothiazolyl thiadiazolyl benztriazolyl benztriazolyl triazolyl isothiazolyl indo lyl; indolyl triazinyl triazinyl ¢ pyridazinyl pyridazinyl « oxadiazolyl oxadiazolyl ; indazolyl and indazolyl carbons) the first of them ©-,© such as those for which the aryl part is (3 170 dl) optionally substituted aryl 0 0 -6 carbon atom) 6-1 specifically possesses any of the aryl groups mentioned above and the (alkyl) part; optionally substituted aryl cyclo ¢ 1,2,3,4-tetrahydronaphthalenyl tetrahydronaphalenyl carbon atom)-(ano-0,-0) for example /-1) optionally substituted (alkyl heteroaryl heteroaryl 00 or from heteroaryl aryl groups example those where the heteroaryl aryl part

Yq or CH, is Ci-Coralkyl carbon) 83 1-1 previously mentioned specifically and the (alkyl) part heteroaryl; CH,CH; cyclopropyl butyl cyclopropyl Jud optionally substituted eg cycloalkyl cycloalkyl; or cyclohexyl or cyclopentyl cyclopentyl cyclobutyl cyclopentyl (C1-Cg- carbon) Bd A=) optionally substituted (alkyl( heterocycloalkyl Heterocyclic Jif oe heterocycloalkyl part ie those where the heterocycloalkyl part is - piperazinyl piperidinyl piperidinyl azetidinyl is an azetidinyl or “methylpiperazinyl” substituted Pentrogen + eg piperazinyl methyl or - CHy having C-Cealkyl carbon atom (1-1) Ji and a pyrrolidinyl moiety ¢ CH,CH, 1:

Cy-Coralkyl may be independently selected from hydrogen » alkyl (1-1 carbon) RY, RO; n- or isopropyl or normal propyl ¢ ethyl ethyl » methyl e.g. aryl methyl -fused- or any of the optionally substituted aryl groups; aryl-fused-cycloalkyl + aryl-fused-cycloalkyl » heterocycloalkyl mentioned specifically in the description of aryl(Cr-Ca-alkyl)- carbon atom (/-1) or an aryl (alkyl heteroaryl 0; or their related UR may be a nitrogen atom bonded together with a nitrogen atom optionally having an Agila acyclic atom and preferably 1-4 AE in it from heterocyclic ring piperidinyl piperidinyl ™ azetidinyl aritinyl Je or other oxygen nitrogen atom nitrogen Jie ¢ nitrogen atom piperazinyl piperazinyl ¢ piperazinyl 0 morpholinyl morpholinyl ¢ pyrrolidinyl Pyrrolidinyl » methylpiperazinyl .thiomorpholinyl ring and thiomorpholinyl v. or methyl methyl RY currently preferred are the compounds of the invention where in group 1081283 and group 2-7-85 - as explained above especially When 18 group 187 “ethyl ethyl benzyl benzyl” phenyl e.g. cyclic lipophilic phenyl does not form a bond or -0- and -2- forms a straight alkylene radical © phenylethyl ethyl Jad or by chain up to - YR® nitrogen or branched up to nitrogen alkylene radical © so that methyl Je and can be - carbon atoms up to 9 carbon atoms Se VY .carries a positive charge quaternary nitrogen : radical (radical) mm alkyl formation(1-1 3 carbon) R where N(R) or group oxygen atom be an oxygen atom, A hydrogen atom or 2 not be a hydrogen atom (ethyl or ethyl methyl) (for example, methyl C-Cealkyl 0 -0- in which the A of which the currently preferred Ala is . : 184 group and l; cob » groups formula m al to be selected from 18 - 5m R® M 9 R™

R® Ar * 8b * * 8b Dh B W TE

J p0 0 with 6) 0 0) (d) methyl (ise eg C;-Co-alkyl carbon) 33 1-1 may be an alkyl) 8” : a in group ¢ hydrogen atom or) 8-hydrogen ethyl or ethyl, for example, heteroaryl; Heteroaryl phenyl group De Jol de gana May be Ar! such as cycloalkyl hexyl or cycloalkyl group 2-thienyl in particular "- thienyl thienyl: or cyclopropyl; cyclopentyl cyclopentyl - cyclohexyl 1

The cyclobutyl ¢ ring substituents R™ and RP 8 are independently an alkyl group (1-1 carbon) Ci-Coalkyl e.g. methyl; ethyl ¢ tertbutyl AG or Se halogen fluoro chlorine chloro or bromo; and m and “may be independently yellow OY 7 or CY in groups 5 and 8; The FR R® are independently selected from any of the groups dole dof Als fused-heterocycloalkyl Ju aryl-fused-heterocycloalkyl cycloalkyl Jul ¢ aryl-fused-cycloalkyl heteroaryl ¢ Alkyl (1-1 30 carbon) Ci- Co-alkyl or the cycloalkyl groups specifically mentioned in the LR description. 1 0 may be OH; A hydrogen atom “alkyl (1-1 carbon atom) Ola-M0-0,0 Mia methyl or ethyl Jil; hydroxy - to an alkyl () 1 carbon atom) first m0- Sie hydroxy methyl nitrile Jaf « hydroxymethyl or Cus CONRY- group; each RY is independently an alkyl ( 1-1 22 carbon) Ci-Co-alkyl e.g. methyl or ethyl or hydrogen atom .Vo preferred Wa is a state where RE is OH. Preferred combinations of 18# and R®, especially when RY is an OH, include those combinations where: Both 8 and RP are a monocyclic heteroaryl optionally substituted by © or 6 cyclic atoms, for example, pyridyl pyridyl; oxazolyl ¢ thiazolyl ¢ furyl and especially thienyl Juul e.g. —Y thienyl 2-thienyl ¢ phenyl Jad (I) Ye optionally substituted and

YY

optionally substituted and the other being a cycloalkyl phenyl being R® 5 phenyl one of *8 (IID) or especially cyclobutyl ; And cyclopropyl cyclobutyl Jug Se cycloalkyl and ¢ cyclohexyl or cyclopentyl cyclohexyl one of 18** and 18 be a monocyclic aryl heterocyclic optionally substituted from © or + atoms (IV) Thiazolyl “oxazolyl + thienyl” pyridyl ring, for example, pyridyl °, for example, cycloalkyl, and the other is a furyl or furyl “thiazolyl” or cyclopentyl cyclohexyl;_cyclopentyl cyclobutyl cyclopropyl cyclobutyl . cyclohexyl 1-11 alkyl (¢ hydrogen atom; a hydrogen atom OH may be RC in group “; the alkyl-hydroxy; ethyl or ethyl methyl e.g. methyl Ci- Ceralkyl carbon atom 0 or nitrile hydroxymethyl Sie Ci-Ce-alkyl carbon (823 -1)

Mie is isosterically an alkyl (1-1 carbon atom) Walala-m©-© RY group 01154 where all is currently the preferred case. hydrogen atom yd, ethyl Jiu, methyl or heteroaryl alkyl Jol being an aryl ring; AFP; each OH is RY which has a cycloalkyl Al 0 ; Alkyl (1-1 atom heteroaryl, any of these aryl rings »heteroaryl Wie may be . above RY mentioned specifically in the description of cycloalkyl carbon) anole-m©-,© or cycloalkyl The -0- ¢ ten AP is the bridge © - between the two loops. Favorites include phenyl lila. CH, CH, Jl. » be a set of 5 d or RY, it is currently preferred that RAJ d; » and bea of options 7 The preferred sub-class of compounds to which the invention relates consists of compounds of formula

JA

L (a) (CH) x \ \ la Y— (CH), R8a en 25 R8b (1A) J where the A ring is an optionally substituted phenyl ring Or a monocyclic heterocyclic ring with © or 1 cyclic atoms or a Gus phenyl hetero-alkyl ring system The hetero-alkyl ring is a monocyclic heterocyclic ring with © © or 1 cyclic atoms; R® is phenyl; thynyl

“phenyl R®” cyclohexyl or cyclopentyl phenyl is “thienyl”

thienyl; cyclopentyl or cyclohexyl ¢ (YoYo)

git VY dot zero (fice 46 ee) 1 7 provided it is 8+4 not

More than 1 0 ¢ 7 is a bond or -©0- and X- is a pharmaceutically acceptable anion 0 . in TA compounds; Preferably, the Wa loop should be:

(I phenyl optionally substituted, where the selective substituents are selected from the 0-alkoxy halo, especially fluoro or chloro; alkyl (1-? carbon atom) Ci- Cs-alkyl ¢ amino (1-? carbon atom) amino C;-Cs-alkyl acyl (1-?8 carbon) acyl Cp-Ca-alkyl + amino alkyl (YY) 83 carbons) Cp -Cialkyl and Aminosulfonyls

aminosulfonyl Ve or ve where the alkyl phenyl ring is combined with heterocycloalkyl phenyl heterocycloalkyl ring system (11 + a heterocyclic with a monocyclic heterocyclic of © or heterocycloalkyl part heterocycloalkyl dihydrobenzofuranyl dehyde Sie ring atoms The other preferred subclass of compounds to which the invention relates consists of compounds

IB Formula 0 (CHa), X \ \ +

He 0 0 (IB) 0 OH An optionally substituted H or monocyclic heterocyclic phenyl ring is a phenyl ring B in which the aryl-fused: fade aryl-fused ring has 1 or © cyclic atoms or a ring Cycloalkyl or -0-:--7-1 - 0 or not [ be -0- 4-3-1-1 ; 5 is heterocycloalkyl ; It does not form a bond or -0- and 2 is a pharmaceutically acceptable anion in 01, provided that 5 + 7 does not exceed * 0 IB compounds. Where the optional substituents are selected from the alkoxy-halo, especially fluoro or 5,55 chloro « alkyl (1-? carbon atom) C-Cs-alkyl - aminoacyl amino alkyl and aminosulfonyl or (ii) 0 phenyl-combined-cycloalkyl heteroalkyl where the cycloalkyl is a mono-heterocyclic of © or 1 atoms of the Jie ring dihydrobenzofuranyl yyy

Yo or 7 and may appear -+-”-;-*--1 Mia may be 517 - 1B, 1A in both families -؛-3-?-1 and 1-7-*- -# or <- and 8 is 0 1 Whe 5, 1 in suitable combinations of

SR is when 7 is 5, Y, 1 the currently preferred combination of IB, JA compounds BY or —1-0

JY is STT is bond and Y is ? And it is not -0- another preferred combination at the present time, as 2.0, as in the compounds of the invention, in general, it is preferred that the compounds be IB, 18 in both families. Primarily ank-endo, in order, a brief explanation of the drawings. It shows the results of obtaining the catalyst and the comparative compound tiotropium: 1 Detailed description figure 0 . Examples of the compounds of the invention include those here: The preferred compounds of the invention include (HPT-7-yl)-di-1 7 anti-ammonium salts - ?(biphenyl-7-yl carbamoyloxy(bicyclo)?methyl) ?-phenoxy-propyl). - AE Ye (-7-(7-hydroxy-7 2R ¢ 1S)] anionic ammonium salts acetoxy)-bicyclo(?)01(hpt-7-yl)-dimethyl-(©-phenyl) anti-{(1$,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo [2.2.1Thept-7-y1]- dim¥ thyl-(3-phenyl-propyl)-ammonium salts (+)-7-("-hydroxy-? + 7-di-thiophene-"-yl-acetoxy)- . hepten-7-yl )-dimethyl-(3-phenyl-propyl) (1-bicyclo(" ?

Al anti-(+)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2. 1]hept-7-yl]- dimethyl-(3-phenyl-propyl)-ammonium salts -thiophene-7-yl- SEY -7-(7-hydroxy-7 ) 28 « IS ( - salts counteract ammonium

Acetoxy)-bicyclo(?71)HPT-1-yl)-dimethyl-(©-phenoxy-propyl). $,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2 2.17hept-7-yl]- #1 dimethyl-(3-phenoxy- propyl)-ammonium salts [ ( 18 28 ) -7-(7-hydroxy-7;7-di-thiophene-?"-yl-

Acetoxy)-bicyclo (1 7 Y) (HPT-1-yl)-dimethyl-phenethyl. anti-[(1S,2R)-2-(2-Hydroxy-2, 2-di-thiophen-2-yl-acetoxy)-bicyclo [2.2.17hept-7-yi]- diméthyl-phenethyl-ammonium salts anti-[ ( 5 +28 )-7-(7-hydroxy-7,1-7-di-thiophene-7-yl-acetoxy)-bicyclo("1,7)hpt-"-yl )-dimethyl-(©-phenyl-butyl). anti-[(1 $.2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1Thept-7-y1]- dimethyl-(4 -phenyl-butyl)-ammonium salts 0 (2R 18 )-7-(7-hydroxy-?SU Ye -thiophene -dr Y —acetoxy)-bicyclo(? 0 (hpt-la-yl)-trimethyl . anti-[(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1 Thept-7-ylJ- trimethyl-ammonium salts Ammonium salts (7"-benzyloxy-ethyl)-antagonist [ ( 5 > 2R )-7-(7-hydroxy-?SEY 0-thiophene-1-yl-acetoxy)-bicyclo(?? 1)HPT-7-yl)-dimethyl.(2-Benzyloxy-ethyl)-anti-[(1S 2R)-2-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy) )-bicyclo[2.2.1 Thept-7-yl}-dimethyl-ammonium salts

Yv(7-(7-hydroxy-?17-diphenyl-acetoxy)-2R + 18(-0(hpt-7-yl)-dimethyl-(*-phenoxy-propyl) ammonium salts ‎ 1 YY) anti-(1S, 2R) 2-(2-Hydroxy-2,2-diphenyl-acetoxy)-bicyclo[2.2. 1]hept-7-yl]-dimethyl- (3-phenoxy-propyl)-ammonium salts -H 9(-7) anionic ammonium salts -(15 ¢ 28 )-dimethyl-("-phenoxy- propyl)-[0.(li-l-tpe)-1 7-carbonyloxy)-bicyclo(? anti-(1S, 2R) Dimethyl-(3-phenoxy-propyl)-[2-(9H-) xanthene-9-carbonyloxy)-bicyclo[2.2.1]hept-7-yl]-ammonium salts -xanthine-1-carbonyloxy)- H )-7-(1-hydroxy-4 2R « 1S) Anti-ammonium salts (HPT-7-yl)-dimethyl-(©-phenoxy-propyl) 1-bicyclo(?0) anti-(1S, 2R) 2-(9-Hydroxy-9H-xanthene- 9-carbonyloxy)-bicyclo[2.2.1 Jhept-7-yll- dimethyl-(3-phenoxy-propyl)-ammonium salts ‏ )-7-(7-hydroxy-7.17-_di-thiophene-?7-yl - 2R 1 1S) anti-ammonium salts-[.acetoxy(-bicyclo(?)1)hpt-no-yl)-indan-7-yl-dimethyl antiy¢1S,2R(-2-) 2-Hydroxy-2,2-di-thiophen-2 -yl-acetoxy)-bicyclo[2.2.1]Thept-7-yl]- indan-2-yl-dimethyl-ammonium salts (-7-(7-) hydroxy-?2R > 18 ([ammonium salts -(benzyloxcarbamoyl-methyl)-antagonist .hpt-l7-yl)-dimethyl (OY Y) di-thiophene-7-yl-acetoxy)- Bicyclo Yo (Benzylcarbamoyl-methyl)-anti-[(1S,2R)-2-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicytlo[2.2.1]hept-7 -yl]-dimethyl-ammonium salts

-) 28 2 18 ( [-dihydro-benzofuran-*-yl)-ethyl] -(-(-7) Te(-)ammonium salts-)li-l-tpe(1YY) di-thiophene -7-yl-acetoxy)-bicyclo-71 To -(1-hydroxy [2-(2,3-Dihydro-benzofuran-5 -yl)-ethyl]-anti-[(1 S,2R) -2-(2-hydroxy-2,2-di-thiophen-2- yl-aetoxy)-bicyclo[2.2.1 Jhept-7-yl]-dimethyl-ammonium salts as referred to in the background of the invention with the highest dual activity compounds Harmful to the M3 receptor, the adrenergic receptor cushion, the adrenoreceptor agonist 82 is known, and the treatment of a respiratory disease with this dual-activity ALSA is a known type of treatment - the known strategy to provide compounds with a dual activity mechanism that is a simple co-bond of a compound with an antagonist activity of the receptor 143 of a compound.. This co-coupling - B2 adrenoreceptor agonist with excitatory adrenergic receptor agonist activity Ve as defined and explained above and excitatory adrenergic receptor agonist (I) 143 of the receptor agonist complex for this Sie-activated coupling is also part of the invention. ‎ 02 adrenoreceptor agonist x R? ~SL—B

A (im

The double Al R* includes compounds of formula (1) as defined and explained above by replacing group 82 with group LB, where L is a connecting root and 3 is ed. 2 Structurally, these dual activity conjugates can be represented by the formula [11], where RAR and RY are as defined and explained above in relation to the compounds of the invention, 1 is a bivalent junctional radical, and 3 is a part that has activity of the adrenergic receptor agonist B2

Pharmacopoi Jie Paragraph 52 referred to above in the background of the invention These compounds 111 constitute another facet of the present invention. An example of these compounds is Example No. 1; here. The present invention also relates to pharmaceutical formulations that include as an active substance - the compound of the invention can synthesize other compounds with the compounds of this invention to prevent and treat inflammatory diseases of the lung - so the present invention also relates to pharmaceutical formulations to prevent and treat respiratory disorders such as chronic obstructive rheumatic disease and bronchitis Chronic - asthma, chronic obstructive pulmonary disease - fibrosis, pulmonary emphysema and allergic sinusitis It includes a therapeutically effective amount of the compound of the invention and one or more other therapeutic substances. Other compounds may be combined with the compounds of this invention to prevent and treat inflammatory diseases in ai 0 - therefore the invention includes a combination of the substance of the invention as previously described herein with one or more anti-inflammatory substances - a bronchodilator - an antihistamine - a decongestant or an antitussive - The aforementioned substances of the invention described above and the aforementioned combination materials present in similar or different pharmaceutical formulations - they are administered separately or at the same time - the preferred combinations may have two or three different pharmaceutical formulations - therapeutic materials suitable for combination therapy with 0. The compounds of the invention include one bronchodilator or Jie ST inhibitor 70123. ie Methyl xanthines Theophylline Other muscarinic receptor antagonists Nie corticosteroid Fluticasone propionate — ciclesonide — mometasone furoate or 91 A gut budesonide 00 — or the steroids described in ip. [oF

$e

CYYORY [oF ; International No. 34448 [iF; International No. 17784 [or; International No. FOTIA

INA [of and International No. FRAY [ot International No

A non-steroidal glucocorticoid receptor agonist B2-adrenoreceptor agonist B2- metaproterenol Metaproterenol — salmeterol Salmeterol — albuterol (salbutamol) Carmoterol — procaterol Procaterol — fenoterol Fenoterol — terbutaline terbutaline fenoterol Arformoterol — formoterol Formoterol — indacaterol Indacaterol — carmoterol - GSK —Y03A+Y — GSK L-BCL-4A- GSK 165/ 47 — procaterol picometerol - and also compounds EP No. TA —Y + 00= GSK:4No 09 — AGSK 147440-00

JY; US No. 180097 [AT Japanese No. 90785648 – International No. NEE. ATT; American No. 1005 // 774197; US No. 015445/7006; International 01511 [oY]; International No. 01 [47197; International No. 0/ 87497; International No. 4 [ooo 1110/07; ISN 714773 [0X ; intn 704460 [oY intn + 7; int. 1704 [oT int. 07/ 417134; International No. 07/ 77594; Intl No. ve [of Intl No. OTT) /04 - Intl No. 1874 [of Intl No. +54 [oY]

CEVVAA [og ; International No. ©7417 [og; International No. 27417 [of ; International No. 7047; International No. +73 997 767; International No. TVALY /+4; Intl No. 37797 [o£] Intl No. 087/0 4 - Intl No. 50718 [uf; International No. 4766 4 A; 3/14; International No. 4 0/ 80574; European No. 1450054 » International No. VITALLY

CAYEYIYY / 001; European No. 59/9/1377; US No. 85457 [eg Intl No. Ctltat [of Intl No. 1 tal#0] [uf??? ; International No. 04 / ¥ 4 0 American No

1; International No. 20 [47,897; International 40107 [eo; International No. 71 [ro / 39 hum »; International No. [ro; International No. 08743 [ro No. 4 0/1784 no; international number [+0; International No. 0+[06 – International No. 0+[04; International No. 0 [0 [vod]; Intl 37870 [eo - Intl No. 47441 [roo; international 6 [eo; International No. 1074848 [vo; International No. 74511 [+0; International No. 7487 0 American No. TAIT [eo ie; international no [ro do not like international no; International 178976 [eo; US No. 00901971149; International No. 7091861; International No. 200017 feo; International No. 01798540; Deutsch No. 79773711 [eo no. ; International No. 7777234 [Yao; US No. 001846 [eo M©e International No. 0184/18 00 ; International No. 16-171 [he; US No. 04341 [Yeo; International No. [on 1745; International No. 7 [ 04 ; International No. 21587/05; International No. 47 [ 77771 ; US No. [YT #No. 01”; US No. 7005/03717; Int. No. 05/017977; International No. 4 [66111; — montelukast Wie — leukotriene modulator leukotriene modulator protease inhibitors pranlukast or pratlukast zafirlukast 0

TACE and MMP12 substrates, for example, matrix metalloprotease inhibitors, for example, metal protease inhibitors. 017-333 0002333 and marimastat such as maristat Jie Human neutrophil elastase inhibitors sivelestat and those described in: [ro International No. 14 ¢ [0]; IPM No. 17 [rt IPM No. 0 [rf] IPM No. 153174/15 IPM No. 1721177 [ro; Int. 7 / 4 Int. #0470 [of Int. 14701 [of Int. No. TEV

Bell 7 + International No. [io 409/7; intn [io 87437 intn 15/4+; International No. 00/07 1747 AD; Phosphodiesterase-4 inhibitors;- “ie Phosphodiesterase-4 (PDE4) inhibitors (PDE4) roflumilast - arofylline — cilomilast - 171 ?- ONO 0 or 10485. Phosphodiesterase inhibitors Phosphodiesterase-7 inhibitors Y= antipruritic agent on Je codeine or dextramorphan and kinase inhibitors especially PB8 MAPKINASE 01 P2X7 anticonvulsants iNOS inhibitors INOS A non-steroidal anti-inflammatory agent NSATD Sie (NSAID) ibuprofen or ketoprofen dopamine receptor antagonist and TNF-X inhibitors For example, monoclonal antibodies against CDP- 5 Remicade — TNF 0, receptor immunoglobulin molecules, Jie TNF receptor, Enbrel, Jie agonists AZA, those described in European Patent No. SEP 00157774, European No. 1175411177 and 7 A2b antagonists such as those described in International Patent No. Y [EYYAA 00] and components of the function of a chemokine receptor ie chemokine agonists: CXCR2 - CCR3 - CCR2 — CCRA- CXCR3 - CX3CR1, CCR ty Alef SB <DEM - SB —-Y101Y: — SB - A scribble ¢“ SB- 112 Jie .INCB -YYA¢{ — MLN =\VY“Y — RS -. 4147 — MCP-1 (4

PGD2 Sie prostanoid receptors Compounds that act as prostanoid receptors antagonist Ramazoban P eg A2 thromboxane or thromboxane antagonist (CRTH, or DPI) ramatrobant© . Vehicles that modify a function. Kineret like Interleukin 1 receptor antagonists 1 llodecakin Jie Interleukin 10 agonists 01 interleukin antagonists

HMG-CoA reductase inhibitors (statins) (statins) HMG-COA inhibitors or reducers - lovastatin Mevastatin 2067881800 — lovastatin - rosuvastatin eg rosuvastatin 0 fluvastatin and fluvastatin pravastatin pravastatin - simvastatin - diquafosol INS - 377117 Jie Mucus regulators Mucus regulators gefitinib MSI- 1956 — DNK-333 — talnetant — 05-003 - sibenadet .gefitinib Antiinfective agents (antibiotic For infections (antibiotics or antivirals) Vo included, but not limited to antiallergic drugs (and anti-allergic drugs or antiviral). for each . Material in general - an effective dose will be used from each of them. Any suitable route can be used to give my mammals, especially a human, an effective dose of a compound.

Appropriate methods of administration are known to the skilled in the industry, and they include oral, intravenous, parenteral, rectal, topical, injected, external into the eye, ocular, nasal, oral, buccal, and pulmonary. The amount of the preventive or curative dose of a compound The formula will of course vary according to a range of factors including activity of the specific compound used - age - body weight - diet - general health - sex of the patient - time of administration - route of administration - rate of excretion - use of any other drugs - severity of the disease being treated - generally the daily dose range for inhalation It would fall in the range of about 1.1 µg to about 10 mg per kg of body weight for a human - preferably 11 µg to about 15 mg per kg - more preferably 11 µg to 50 micrograms per kg - in divided doses or a single dose Elsewhere it may be necessary to use doses outside these limits in some cases and known formulations suitable for inhalation - and may include carriers and/or diluents known for use in these formulations - Composition It may contain 0.00 - 794 by weight active compound - preferably = one dose includes the active compound in an amount from 1 microgram to 100 mg for oral administration and appropriate doses are 01 microgram per kilogram to 001 mg per kg - preferably £0 μg per 0 kg to ; mg per kg. Another aspect of the present invention presents pharmaceutical formulations that include the compound of the invention and a pharmaceutically acceptable carrier. The term 'combination' as in pharmaceutical formulation, pharmaceutically, means that it includes a product that includes active substances and inactive ingredients (pharmaceutically acceptable excipients) that are the carrier. Ye also means any product that results directly or indirectly from the amalgamation or combination of any two or more components, or from the dissociation of one or more components, or from other types of reactions of one or more components.

{0} Therefore, the pharmaceutical compositions of the present invention include any composition manufactured by adding the compound of the invention - additional active substances and pharmaceutically acceptable excipients - the pharmaceutical compositions of the present invention include the compound of the invention as an active substance or a pharmaceutically acceptable salt thereof, and it may also contain a pharmaceutically acceptable carrier and optionally other therapeutic materials - the term.

° 'pharmaceutically acceptable salts' refers to salts prepared from non-toxic, pharmaceutically acceptable bases or acids that include inorganic bases or acids and organic bases or acids - and salts of quaternary ammonium compounds with pharmaceutically acceptable counter-ions For inhalation delivery, the active compound is preferably in the form of fine particles. They can be prepared by a variety of techniques, including dilution by spray.

. Lyophilization and micronization 0 For example, the composition of the invention can be prepared as a suspension for delivery from an aerosol as an aerosol solution PMD propellants in a liquid propellant eg for use in a pressurized metered-dose inhaler - HFA134A CFC-12 Known to a skilled craftsman and including PMD ] Suitable for use in isobutane (and wet) and isobutane HFA-152, (and 66.2) HCFC022- HFA-227 for conductivity Gila in a preferred embodiment of the invention. The composition of the invention is in powder form Yo. Known DPI Many types of DPI Using a dry powder inhaler Microparticles can be formulated for delivery by administration with excipients that aid delivery and excretion For example in a dry powder form Microparticles can be formulated with large carrier particles The occasion is known It includes Jalal lactose particles) to the lung - DPI particles outflow from . - It may have a mean aerodynamic mass diameter of more than 0 μm: 0 in the case of an aerosol based formula, an example is . His right [YE compound of the invention]

£1 - Lecithin (ze), Y NFLLIQ-CONC Lecithin M 43a - Trichlorofluoromethane 170 NF Trichlorofluoromethane g / tq. - Dichlorofluoromethane 1,1 NF Dichlorodifluoromethane g / dose. The dose of active compounds can be determined as described according to the inhaler device used 0 In addition to the active compounds - forms of administration may additionally contain excipients, for example, propellants 0, for example, Figen in alls aerosols (divided doses) surfactants = emulsifiers - Stabilizers - preservatives - flavorings - fillers (for example, lactose in Alla, withdrawn inhalers) or, if appropriate, other active compounds. For inhalation purposes a large number of oad are available - with which aerobic states of optimal particle size can be generated and administered using appropriate inhalation technique for the patient - in addition to the use of conditioners (separators - expanders) and pear-shaped containers (nebulator® Si) Volumatic® and automatic devices dispensing a spray inflator (autohaler®) for divided-dose air solutions - especially in the case of powder inhalers of a number of technical solutions available (eg turbohaler® rotadisk® diskhaler® or inhalers, for example, as described in 0606771 District (A) 10 additionally, the compounds of the invention can be connected in multi-chamber devices, thus allowing the connection of the synthesized materials.Manufacturing methods: The compounds of the invention can be prepared according to the following schemes and examples using a suitable wad, which is more represented by the following specific examples, in addition to using the described methods. With the disclosure found here and the ordinary skilled in the workmanship can easily prepare additional compounds 0 A of the present invention protected herein The compounds illustrated in the examples cannot, however, be considered to be the only type considered as an invention ABH explains in more detail the preparation of the compounds of the present invention having skill in workmanship ty

They will readily understand that known variations of the conditions and processes of the following preparatory methods may be used for the preparation of these compounds. The compounds of the invention may be separated in the form of pharmaceutically acceptable salts such as those previously described.

It may be necessary to protect the interacting functional groups (eg hydroxy-amino-thio

© or carboxy) in the mediums used in the preparation of the compounds of the invention to avoid third party involvement

A reaction leading to the formation of compounds is desired and conventional protective groups can be used, for example those described by TW Green and PGM Watts in Protective groups in organic chemistry John Wiley and Sons 1144 — John Wiley and Sons.

The compounds of the invention can be prepared according to the methods described in Scheme 1.

M R® » bag ma WR RNY and H A m od Ee — =« or Br (IV-a) OH (1X-a) (VIli-a) | 00 RR: RA R* | | then 0 nm-0 (a) (Ila) mg wa R® b IR Ho N NR NR H ' p 0 0.0 Br CH (XV) (XIV-b ) (X1il-b) |R? 1 R® 1 rR Ve vr 0 oh ss A ss A fm 0 Ope Ogre (Ib) (lI-b) (Xi-b) Scheme (1) : Compounds of formula (1-2) and (la) where RG RP, RY and RD are as defined for 832-82-8 and 87 in compounds of formula (1) can be prepared from compounds of formula (I-A) or (1B) b 0-4 (11-a) R °

Mr. Dr

By reaction with a compound of formula (I-A).

: R%-X (III-A)

where X is a leaving group of Jie halogen — tosilates- mesylates - the reaction can be performed in a range of solvents Jie acetonitrile - chloroform DMF or

DMSO © optionally in the presence of an amine base DIPEA die (DB) at a temperature from 0 °C to

The return of the solvent preferably from the surrounding Hla to the return heat of the solvent.

Compounds of formula (I-A) and (1113) where RB- RA and RD are as defined (for 8-182 and 8) in compounds of formula (1) can be prepared from compounds of formula (IFA) or ( 11-8) H- Cus RB in reaction with a compound of formula (II-B).

: RB-CHO (III-B) 01 Especially “ metal borohydride Jie In the presence of a suitable reducing agent the reaction can be performed in — sodium triacetoxyborohydride acetoxa borohydride oN sodium chloroforum - 1,2-dichloroethane chloroethane A -0117 Jie uses a range of optionally in the presence of — alcohols alcohols — dichloromethane dichloromethane — chloroform 0 degrees on the return temperature of the solvent preferably from 0 When heated from - acetic acid 10 is well known at (IIB) and (ITA) degrees to the ambient temperature of the solvent and formula compounds

The workmanship is easily available, or it can be prepared in known ways. Appropriate methods for preparing compounds of formula (I-A) or (II-B) where H=RB involve the reaction of (H-11) or (II-B) where 18 = benzyl with hydrogen hydrogen in the presence of palladium on yo carbon or palladium hydroxide on carbon in suitable solvents such as methanol — ethanol — acetic acid -> ethyl acetate and its mixtures of which are interchangeable - (I-A) or (II-B) reaction where R6 = methyl or benzyl

benzyl with -1-chloroethyl chloroformate in a suitable solvent -Y,Y (Jie 1,2-dichloroethane) at the return heat of the solvent and then the next reaction with methanol It is a preferred method for the preparation of compounds of formula (I-A) or R6- Cus (II-B) 1° Compounds of formula (I-A) and (II-B) exist in two imaginary forms that can be separated by HPLC Preparatory impractical using conditions known to the skilled in the workmanship and represented below alternately because the absolute order of the compound (I-A) or (1113) is inscribed with the absolute order of the compounds (XV, X) in the order and the compounds of (XV.

X) be known in publication (see 20007485682) A skilled craftsman will understand that the use of homochiral primers will deliver a homochiral product of a definite ys stereoscopic shape. Compounds of formula (II-A) where (for 18 the group of formula (A) and R6 - be H as defined above for formula (I) can be prepared from compounds of formula (IV-A) where RB, RA are as defined above by the reaction with the compound of formula (7). The reaction may take place in a range of non-nucleophilic organic solvents DMF Jie or toluene in a range of temperatures - preferably between 0° and the boiling temperature of the solvent - compounds of formula (V) that are well known in the manufacture and are readily available or can be Prepare it in known ways. A Compounds of formula (I-A) where RD is the group of formula (3) as defined above can be prepared from compounds of formula (IV-A) by reaction with the compound of formula (VI).

88 EGP LG, Faj Aleppo

R® vp© be a leaving group eg Igy (1) be as defined for the formula RC and RP, RM where the reaction is carried out in - I-imidazolyl imidazolyl -1 group -0 - Alkyl-halogen or THF toluene dichloromethane Jie cule NAH Jie Having a strong base. The solvency and heat of return of the solvent 0 at a range of temperatures preferably between © dichloromethane be LG, (I) be as defined for the formula RPC RP, RY wherein (VI) the compounds of the formula may be prepared I-imidazolyl compounds (© - alkyl-halogen group) or = imidazolyl. By known methods (VII) Formula Rr “oN nafj Rr vip © is well known in manufacture and readily available or can be prepared (VII) Compounds of formula \K WO compounds can be prepared 0 1 / 0 those described in Jie prepared by known methods where (for 1 the group of formula © as defined above are compounds of formula (I-A) of formula (VIA) by reaction with a compound of formula (T1) -A) for LG Ar?0 RS (Vl-a) to be a leaving group eg the LG group and (I) be as defined for the formula Ar2 where the reaction 1-imidazolyl takes place Imidazolyl -1 or halogen -O-alkyl group alkyl or dichloromethane THF - toluene Jie in a NAH solvent in the presence of a strong base such as the temperature and return temperature of the solvent 0 in a range of temperatures, preferably between dichloromethane oY

HO © oR” (VII-a) is LG, 1 is as defined for formula RC RP where (IV-A) compounds of formula 1-imidazolyl halogen OR = imidazolyl - O-alkyl ©0-alkyl group . By known methods (VILA) © are well known in their manufacture and are readily available or (VIA) formula compounds can be prepared by known methods.

Seb The group of formula (0) is as defined - RD where (I-A) the compounds of formula (171-3) in reaction with the compound of formula (IV-A) can be prepared from the compounds of formula L (VI-b) 0

THF toluene Jie in NAH Jie solvent The reaction is carried out in the presence of a strong base. Celsius or heat of return of the solvent 0 in a range of temperatures preferably between DMSO preferably well known in the workmanship and readily available or possible (IV-B) compounds of formula . Prepared by known methods Reacting with (VIIA) Prepared from compounds of formula (Say (IV-A) Compounds of formula Vo The reaction is carried out in LIATH (DBU)3 Jie A suitable reductant, preferably a bulk reductant m up to VA in a range of temperatures preferably from THF a polar organic solvent preferably Return heat of the solvent in reaction with (IX-A) compounds of formula (VIIA) preparation of compounds (Sa) The reaction can be performed in a range of solvents AIBN preferably tin 811351111 and a root starter preferably 0

Prison 2000 preferably toluene in a range of temperatures preferably between Hla ambient and the return heat of the solvent. (Se) Preparation of compounds of formula (IX-A) from compounds of formula (X) by reaction with amine formula RARBNH - (XI). ° The reaction is performed in a range of solvents preferably 0014/1117 in the temperature range preferably between 0 and 100 degrees.Compounds of formula (X) are known in the formula (Y4V®) J.Chem.soc.

Perkin trans] - 1/979 in (Y44V) synthesis “Mamahet Tal. Compounds of formula (XI) are well known in the manufacture and can be prepared by known methods or made commercially. Compounds of formula (I-B) can be prepared from compounds of formula (II-B) in a similar way as compounds of formula (IA) from compounds of formula (IFA) above Compounds of formula (I1B) can be prepared from compounds of formula (2013) Reacting with a tin reactant - preferably 31035011 and a root initiator - preferably AIBN, the reaction can be performed in a range of solvents, preferably toluene Vo, in a range of temperatures, preferably between Biba ambient and the return heat of the solvent. Compounds of formula (701-3) can be prepared from compounds of formula (IV-B) by reacting with a brominating substance, preferably triphenylphosphine, in carbon tetrabromide as a solvent. (Se) preparation of compounds of formula (IV-B) from compounds of formula (XHI-B) by reaction with a suitable reductant (sale Yo) preferably amiga sodium borohydride - the reaction is carried out in a polar organic solvent preferably THF in a range of temperatures, preferably from -78°C to the return heat of the solvent.

ot By similar methods (XIV-B) from compounds of formula (XII-B) preparation of compounds of formula (Sa. (Iv-A) from compounds of formula (1I-A) to those used to prepare compounds of formula (XV) From compounds of formula (XIV-B) compounds of formula can be prepared

H

O (XV) Br H The reaction is performed in a range of solvents preferably (XI) by reaction with an amine of formula ° . C Yeo and 0 in a range of temperatures preferably between DCM/THF. 082075503 described in XV compounds of formula a a Rr?

RAL, RA RNY { a i 0 N~OH NH, (XIX-a) (Vill-a) (XX-a) b g 8 8 7 m 0 ine 8 3

H R® N N A H =< R® H =< R®

H R HO R' 0 (XVl-a) (XVIl-a) (XVlil-a): (Y) Scheme Formation of the -118- group is given in the scheme? A Cua (I) Preparation of compounds of formula 01 By methods similar to those (XVI-A) of formula (XVIA) compounds (Say. [1]-4) are prepared from formula (I-A) compounds used to prepare formula compounds by treatment (XVII -A) From compounds of formula (XVIA) compounds of formula (XXI-A) can be prepared with an organometallic reactant of the formula

00 R-M (XXI-A) . Where M is the type of metal Jie lithium lithium or alls - MG — especially the Jiegenar reactant in a suitable inert solvent THF serum or diethyl ether at a temperature between VA Celsius Shas The return of the solvent is preferable Between 0°C and ambient temperature, compounds of formula (XXI-A) are known in the industry or can be prepared according to a known party. (Say) Preparation of a compound of formula (XVII-A) from compounds of formula (XIX-A). The sum is 0, where X is a leaving group, especially a halogen group. Optionally, in the presence of a suitable solvent, SU Sie. Dichloromethane dichloromethane in the absence or presence of the SU Jie base 0 isopropyl diisopropylethylamine “ethyl amine” and compounds of the formula (XIX-A) are experimentally available or readily prepared according to the publication. Compounds of formula (XIX-A) from compounds of formula (XX-A) by reducing aloxime with a suitable reducing substance Jie borohydride reactant - specifically NABHA/NICL2 in a suitable solvent Jie methanol methanol at a suitable temperature 01 Jie. (Sa Vo) Preparation of compounds of formula (XX-A) from compounds of formula (7111-8) by treatment with hydroxylamine or its salt in the presence of a suitable solvent Jie methanol optionally in the presence of a base Jie sodium acetate at a temperature between 0°C and the return temperature of the solvent, preferably at ambient temperature.The following non-specific examples explain the invention.0 General experimental details: All reactions are carried out in the presence of a nitrogen atmosphere if no SY otherwise.

04 Lave compounds purified by columnar silica chromatography and flash silica gel for chromatography indicates silica gel chromatography - 1,075 to 0.070 mm (70 ? to 0 mesh) Nia 0 Silica Gel ( FLUKA 60 silica gel and nitrogen pressure up to 01 PSI elution column accelerator When thin layer chromatography (TLC) 0 is used it indicates TLC silica gel using plates typically ?7 6 cm silica Gel on Aluminum Foil Plates (FLUKA60778) Die (FLUKA60778) All commercial solvents and reactions were used as received. All compounds containing base centers that were purified by ©1101 were obtained as al TFA unless otherwise indicated. 01 HPLC preparatory conditions. HPLC1: YY,0 X 001 reverse phase column (CIS mm LD GENCSIS column, particle size V µm) Rinse Gradient of A: Water + 75.1 B TFA acetonitrile TFA 750.1 + with a flow rate of © ml/min and a scale of 711 minutes in excess of [3] UV detection at YY.

Ne nm. Apparatus: HPLC2 phenylhexyl column (column 71.01 77550 Luna mm particle size #*µm) with a gradual elution of: : water + B « TFA 6.1 acetonitrile TFA 70.1 + acetonitrile at a flow rate of 0 milli / min with UV detection at 4 79 nm. 0 LC/MS devices: Liquid chromatography mass spectrometers (LC/MS) used: 0/10/51 method:

ov

Higgins 0.1 mm X 001 (C18 with reverse phase column) Micromass platform LCT formic acid 760.11 + particle size © µm) and rinse with: water clypeus 'Gradient z=) « formic acid Formic acid 71.1 + acetonitrile: B «acid 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 (in line) UV method m detector MS μl divided into 001 (UV-ELS, MS detection ° .method - Electrospray (positive ion) ionization 5- Electrospray (positive ion): LC-MS2 method mm 41 X Yi) 018 with reverse phase column Micromass platform LCT formic acid 7 0.1 + particle size ¥ µm) and rinse with: water Phenomenex luna; Graduation of formic acid 71.1 formic acid + acetonitrile: B « formic spark plug 0

Gradient 5 95 2.0 0.00 5 95 2.0 0.50 95 5 2.0 4.50 95 5 2.0 5.50 oA 6.00 2.0 95 in line) UV with MS detector (microliter divided into 001) UV- LES, MS detection 0 (positive and negative ion) Ionization method 5 - with an electronic device (positive and negative ions): LC-MS3 yb

Phenomenex £.1 mm X 1 (C18 with reverse phase column Wasters micromass ZQ ° « formic acid 7 0.1 + water: A: particle size ¥ µm) and rinse with 8 Gradient: Graduation » formic acid Formic acid 7 1,1 + acetonitrile: 8 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 (in line) UV with MS detector 1 microliter divided into 001) UV- LES, MS detection MS ionisation method Electron (positive and negative ions) ) - MS ob method 0

Electrospray (positive and negative ion): LC-MS4 method

04 as Wasters micromass ZQ reverse phase column (Higgins clypeus) C18 © micron X 548 001 mm, or equivalent) and rinse with A: water + 70.1 formic acid « B: acetonitrile 1 + acetonitrile / formic acid ; Gradient: 0.00 1.0 95 5 1.00 1.0 95 5 15.0 1.0 5 95 20.0 1.0 5 95 22.0 1.0 95 5 25.0 1.0 95 5 Detection (001) UV- LES, MS μL divided into MS with detector UV in line) 0 MS ionization method - Electron (positive and negative ion) - MS ionisation method Electrospray (positive and negative ion) Abbreviations used in the experiments section: AS = DCM: chloromethane ely - THF - dichloromethane hydrofuran - MEOH = methanol ETOH — methanol = ethanol Jive JS = DMSO — ethanol 0 sulfoxide — ETOAC = ethyl acetate DIPEA - ethyl acetate = diisopropyl ethylamine -©(-1 = EDCI dimethylaminopropyl) -3- ethylcarbo SB imide hydrochloride die SW = DMAP -aminopyridine - RT = temp V) =o = HATU - azazotriazole - NUN, N,N = (dr) = tetramethyluronium hexafluorophosphate - TFA = DEfluoroacetic acid RT = retention time; Satd = saturated. 1 Example (1).

Te (¥)-anti-Biphenyl-2-yl-carbamic acid 7-dimethylamino-bicyclo[2.2.1]hept-2-yl ester. (II-a): R®, R® = CH;, R? = biphenyl-2-ylcarbamyl 0

Br: (A) the compound a. (+)-anti-5-Bromo-7-dimethylamino-bicyclo[2.2.1]heptan-2-one. (IX-a): R®, R°=CH; 0 sh VY (+(°C) of a solution of 0 (mL) ice-cold 0 ( DCM) to a solution of the dimethyl solution THE-76-one heptane was added to a solution of [YY] bromo- bi-cyclo.mM) by drip 16.9 A 8.7 6 M Y)amine The reaction was allowed to slowly bring to ambient temperature over several . And filtered B20 in the LE hour the reaction mixture was concentrated and removed 117 hours - after 0 on chromatography the filtrate was absorbed over terrestrial diatoms and chromatographically

CAA was extracted by 775 2620 in bitane solution to give silica gel. (745) grams of the compound labeled as an orange solid (H NMR (020_) (H NMR) 400 MHz): 0 1.70 (1H, ddd, J = 14.2 Hz, NMR 4.4 Hz, 1.3 Hz), 2.18 ( 6H, s), 2.2 (1H, m), 2.47 (1H, d, J = 1.2 Hz), 2.60 (1H, d, J = 4.8 0

Hz), 2.80 (3H, m), 4.66 (1H, m).

Ne od : (B) compound b. (+)-anti-7-Dimethylamino-bicyclo[2.2.1]heptan-2-one. (VIII-a): CH patches, before the reaction with nitrogen gas toluene the gas in the liberated toluene was removed for a minute and the toluene Yo that was pumped hard through it for a minute was removed from the nitrogen gas -heptane [VY] dimethylamino-bicyclo (Y= ms) gas to (+) 0-bromo A) mg QLA 001 (£)-5-bromo-7-dimethylamino- bicyclo[2.2.1]heptan-2-one ?-on © mmol) in atmosphere 007 mg (VY) azoisobutyronitrile mmol) and azoisobutyronitrile-nitrogen of nitrogen μl and (YY) tributyltin hydride To this mixture was added tributyltin hydride (Av at nitrogen mmol) and the solution was stirred under nitrogen atmosphere for 7 hours and labeled. 0 μl tributyltin hydride hydride (Yo) toluene azoisobutyronitrile solution (mmol) and a few slices of azoisobutyronitrile 1.11 0 μL (1 °C) for an hour and a half - the Av mixture was evaporated, they were added, and the reaction was heated at of a yellow liquid that has been dyed (chromatographic aba 0,8 reaction in order to give

Et20 778, which was extracted by pentane and was silica gel on silica gel (chromatography 0 brown residue 7100 > (714 mg. to provide us with colorless oil 1520 7008 in pentane to: contaminated) ‎ Et20 IN PENTANE) 7110 : RF, 0.25 (50 1H NMR (CDCl;, 400 MHz): including signals for tin residues. TWN NMR 00.90 3H, t, J = 7.4 Hz), 1.35 (6H, m ), 1.61 (2H, m), 1.98 (2H, m), 2.09 2H, m), 0 2.18 (6H, 5), 2.25 (1H, 5), 2.53 (1H, t, ] = 4.4 Hz), 2.58 (1H, d, J = 4.8 Hz).

Ty he a (©) the compound ©. (£)-anti-7-Dimethylamino-bicyclo[2.2.1]heptan-2-ol. (IV-a): R®, R= CH; lithium tri-tert-lithium tri-butoxyaluminohydride-01 ((; mm) ice-cold THF mol) was added to a solution of 0.49 ¢ mg YAY) butoxyaluminohydride 0 (0)-7 - == dimethylamino-bicyclo[1,7,7]-17-heptane (+) (°C) composed of

VO of or equal to Safar and Jil 70 mg (one dimethylamino-bicyclo[2.2.1]heptan-2-one mmol) and the reaction mixture was stirred at zero degrees Celsius for an hour and a half, then it was lithium tri-tert- from lithium tri-teret - biotex aluminohydride AT (dill fraction (mg - ©a,1_mol) and the reaction mixture was stirred for an hour and a half (V4+) butoxyaluminohydride 0 d. Others and is evaporated directly over terrestrial diatoms DCM The reaction mixture is diluted by the silica gel is purified on a container of silica gel (hromatography) and stained (chromatographic) with 77.5 methyl hydroxide gradually to DCM in the MeOH by 75 methyl hydroxide from the substance (compound 77000) mg 0181 methyl hydroxide in the 0014 to give 7270 0 This substance was shown by spectroscopy 1 - a Labeled NMR) as a white solid as the 1 M2-8-(.) isomer of the labeled product and (£)-7- epiisomer 17 of the solid as a mixture of ?4:. TLC: RF 01) in pentane E20 7975 (isomer does not dissociate ay:l' H NMR (d¢-MeOH, 400 MHz): 0 0.96 (1H, dd, J = 4.0 Hz, MR 13.2 Hz), 1.31 ( 1H, m), 1.56 (1H, m), 1.80 (1H, m), 1.93 (1H, m), 2.01 (1H, m), 2.17 (1H, m), 2.28 (8H, s), 4.14 (1H , m).

ne 0,

JY

(D) Compound 0 d. ()-anti-Biphenyl-2-yl-carbamic acid 7-dimethylamino-bicyclo[2.2.1]hept-2-y] ester Biphenyl -Y and Molecular sieves J Add some powder from? 0.0 angstroms (DMF mg + 997 mmol) to a solution of YAS ) 2-biphenylisocyanate dimethylamino-bicyclo isocyanate (Y= (2) mM) consisting of (10) mM toluene ) and toluene mg and VY) (+)-7-dimethylamino-bicyclo[2.2.1]heptan-2-ol heptan -?- first [VY] 0 for an hour and a half and then Ake degrees 00 mmol) The reaction mixture was stirred at +,V0 (Na2SO4) and dried ale. It was diluted with 24080 and washed twice with water and was done with a solution in an aun container. This product was 0 mg of A colorless solution TOA that was filtered and evaporated to give methyl hydroxide ZE-Y and was removed (extracted or removed) by silica gel of silica gel (mg) with different purity - the purest part was collected (91 mg) VE) was done to give two parts DCM in the 0 and silica gel was extracted from the silica gel eles on chromatography re-chromatography containing the compound entitled free ei by 7780 2020 in pentane to give three purer parts. In pentane (2720 700) 8: TLC (137) of (£) -7- isomer tubing and 47 mg

'H NMR (CDCls, 400 MHz): 0 1.11 (1H, dd, J = 3.6 Hz, 13.6 NMR

Hz), 1.25 (1H, m), 1.62 (2H, m), 3 (1H, m), 2.05 2H, m), 2.13 (IH, t, J = 4.4 Hz), 2.18 (6H, s), 2.56 (1H, m), 4.95 (1H, m), 6.60 (1H, bs), 7.13 (1H, dt, J = 1.2 Hz, 7.4

Hz), 7.22 (1H, dd, J = 1.6 Hz, 7.6 Hz), 7.33-7.44 (4H, m), 7.49 (2H, m), 8.09 (1H, d, J = 8.0Hz). ° (Y) Example anti-Biphenyl-2-yl-carbamic acid 7-dimethylamino-bicyclo[2.2.1]hept-2-yl ester. (1I-a): R®=CH;, RY = biphenyl-2-ylcarbamyl (first eluting enantiomer)

N>

N + 5 t) 1 tert butyl 1 (eg 43) chiral HPLC The titled compound was separated from preparations of Ve [MH]+ : NMR eptane \ 0.25 , — ( chiralpacia Yo X 01 mind 5 ZY methyl ether . LC-MS (Method ) RT VY, Y M/Z Yo\,Y diethylaunine , 14 ml \ min, RT 20.6 min 1 As obtained from Example (1) Example 3 0 anti-Biphenyl- 2-yl-carbamic acid 7-dimethylamino-bicyclo[2.2.1]hept-2-yl ester. (II-a): patches R"=CHj, RY = biphenyl-2-ylcarbamyl (second eluting enantiomer)

no

N~

H/a

N T° (JS

Chiral pac A 250 x 1 For example, Chiral HPLC, the entitled compound was separated after preparations of tert butyl methyl ether/heptane 17 20 mmid, ml/min, at room temperature for ; 7 min 04 diethylamine (pal diethylamine 58 and o

LC — MS (Method1) : Rt, 7.07 m/z 351.2 [MH] + (¢) Ex. (£)-anti-[2-(B iphenyl-2-ylcarbamoyloxy)-bicyclo[2.2.1 Jhept- 7-yl]-trimethyl-ammonium iodide. (I-a): cat cat R® = CHa, RY = biphenyl-2-ylcarbamyl lh. _

Ni

NO

(JY 0-Dimethylamino-17) A solution of () biphenyl-7-yl-carbamic acid (+)-biphenyl-2-yl-carbamic acid 7- hept-7-yl-ester was stirred [V,Y,Y] methyl iodide in an aqueous solution of dimethylamino-bicyclo[2.2.1]hept-2-yl ester .YY sad clock 50 degrees Celsius (,? mL ) When Ve the active mixture was evaporated and the resulting solid was stained on a container of silica gel 1) to give DCM of methyl hydroxide in the 701 and it was removed (reduced) by silica gel. Of the compound entitled as a weak yellow solid (LEY) mg

13.6' H NMR (CDCl, 400 MHz): 0 1.13 (1H, dd, J = 3.2 Hz, Hz), 1.60 (1H, m), 1.81 (1H, m), 1.99 (2H, m), 2.06 (1H, s), 2.41 (1H, m), 2.78 (1H, s), (1H, t, J = 3.8 Hz), 3.52 (9H, 5), 4.00 (1H, 5) , 5 .02 (1H, m), 6.63 (1H, s), 7.13 (1H, 3.11 dt, J = 0.8 Hz, 7.2 Hz), 7.22 (1H, dd, J = 1.6 Hz, 8.0 Hz), 7.31-7.51 (6H, m), 7.95 (1H, d,J=64Hz). ° Example (0) (+)-syn-Biphenyl-2-yl-carbamic acid 7-dimethylamino-bicyclo[2.2.1]hept-2-yl ester. R® = CHj; RY = biphenyl-2 -ylcarbamy] bug (Il-b): / N \ | 0 OH Ve compound (A) = kbc a. (+) — 7-Dimethylamino-5 -hydroxy-bicyclo[2.2.1 lheptan-2-one.(XIV-b): CH; A solution of dimethylamine (7©m, YE m, $A mmol) was added in a solution of THE to a solution of 7-bromo-bicyclo [VF]-3-ol heptate (4.00 00g and 05.9ml (Use in acetone solution) 0£ml) At zero degrees Celsius, the mixture was allowed to reach ambient temperature for one hour and was stirred at ambient temperature overnight.The orange solution was filtered and the filtrate was evaporated to dryness and purity was achieved by Column chromatograpy on silica gel. using l methyl hydroxide in

Tv

LC-MS (Mehtod2): From the compound as brown powder (731) aba 2.00 to produce DCM solution of

RT 0.37 Min, m\z 170.09 [MH]+ /

N

0 > () 1 + 0 : (B) component b. (£) — syn- Biphenyl-2-yl-carbamic acid 7-dimethylamino-5-oxo-bicyclo[2.2.1]hept- 2-yl ester. (XHI-b): Lebel's dip = biphenyl-2-ylcarbamyl (mmol) to a solution of 0.57 7-biphenyl isocyanate (0 μl) and heptane-7-en were added. 40 mg [0,7,7] dimethylamino-*-hydroxy-bicyclo-17 at 71 mC) and the mixture was heated at 1 (mmol toluene) in toluene 00 «. Overnight 0 1710010 the solvent was removed in vacuum and the residue was purified by Coleman chromatography using 1 to produce the compound as a white powder DCM methyl hydroxide in L / 1 followed by DCM (RVC) mg: LC- MS (Mehtod') : RT 6.50 Min, m\z 365.15 [MH]+ / t \ 1 Ho") 0 Vo : )6 ( Compound C. (+)-syn -Biphenyl-2-yl-carbamic acid 7-dimethylamino-5-hydroxy- bicyclo[2.2.1]hept-2-y] ester (IV-b): R® = CHy; R° = biphenyl- 2-ylcarbamyl

TA

(Use mg and 148 mM YO) sodium borohydride Sodium borohydride was added to a solution of biphenyl == yl-carbimic acid -7-dimethylamino-5-oxo-bi mg; 100+ mmol) in methyl solution (You) hept-?-yl-ester[1,7,7] cyclo-hydroxide at 0°C and the reaction was allowed to reach ambient temperature for the residue By Coleman chromatography AES and phil hour - the solvent was removed at 0 by DCM methyl hydroxide in a solution of JX followed by DCM ZY ++ using chromatography: from the product as a white powder (ZY ) mg 194 to produce LC- MS (Mehtod') : RT 6.31 Min, m\z 367.16 [1111[7 : 0 0]

Br 2 5 ) since 0 : (D) compound 0 d. (£)-syn-Biphenyl-2-yl-carbamic acid 5-bromo-7-dimethylamino-bicyclo[2.2.1}hept- 2-yl ester. (XII-b): R®, R® = biphenyl RY = biphenyl-2-ylcarbamyl —o— gud A colloidal solution of biphenyl-7-yl-carbamyl-7-dimethyl (Uso mg ¢ 554 mM VAY) hydroxy-bicyclo[7,?,0] hept-7-yl-ester (Use Fortified Triphylphosphine Polymer (?18? mmol/g +4,” +1, g 37 mm (10 mmol) in 1.51 mg (IY) mmol) and imidazole 4,770 tetrabromethane (1.07 g) °C overnight - ©0 removed Acetonitrile solution (£ mm) were stirred gently at - HPLC solvent in vacuum, and the residue was purified using (System 2 : flow rate 18 ml/min , gradient 010.257 min increasing in B)

The resulting TFA salt was converted to the free basic salt by loading it over SCX2 CARTIDGE followed by purification (allyl) using 3 to give £0 mg (771) of the entitled compound. LC-MS (Mehtod3) : RT 2.25 Min, m\z 429.19\431.14 [MH]+ : a. \ £3) with 0° compound (E): e. (+)-syn-Biphenyl-2-yl-carbamic acid 7-dimethylamino-bicyclo[2.2.1]hept-2-yl ester A solution of tributyltin hydride (£1 µl - 115 mL) was added (Use in a solution of anhydrous toluene (Yoo) (μl) to a solution of biphenyl-7-yl-carbimic acid 0 om bromo Vm dimethylamino-bicyclo[1,7,7]hept-7- Lyle Esther (£0 mg; 10 mmol) and 10-7.7 isobars (TY) methylpropionitrile) 01 (mg © 1056 mmol) in anhydrous toluene solution (lle +A) at 00 °C Before stirring at Ae, apple, for 60 minutes, the solvent was removed in vacuum, and the residue was purified using 11010. min increasing in B uv detection at /System 2 : flow rate 18 ml/min , gradient of 4 nm) Ve 210 YA mg (AV) of the compound entitled . LC-MS (Method 1): Rt 7.18, m/z 351.19 [MH]; . (1H, m), 1.36 (2H, m), 1.66 (2H, m), 2.13 (1Ht, J =4.3Hz), 2.24 1.09 8 (J0y) (TH, s), 2.34 (1H, m ), 2.54 (1H, t, J = 4.0Hz), 5.26 (1H, m), 6.58 (1H, s), 7.11 (1H, 0

7 0 td, J = 7.5, 1.2Hz), 7.21 (1H, dd, Gl 7.5, 1.6Hz), 7.34 (1H, m), 7.38 (2H, m), 7.41 (1H, m), 7.49 2H , m), 8.11 (1H, at night 8.2Hz). (1) Example: syn-Biphenyl-2-yl-carbamic acid 7-dimethylamino-bicyclo[2.2.1]hept-2-yl ester. (II-b): R’=CHj; R? = biphenyl-2-ylcarbamyl (first eluting enantiomer) ° / ) > 1 (example 0 for example ©) under conditions mentioned. Chiral HPLC The titled compound was separated after preparations. min) 19 In an example? (room temperature for: LC-MS (Mehtod1) : RT 7.16 Min, m\z 351 [MH]+. * As obtained in NMR example 1 (7) Example syn-Biphenyl-2 -yl-carbamic acid 7-dimethylamino-bicyclo[2.2.1]hept-2-yl ester.(II-b): bug R®=CH;; RY = biphenyl-2-ylcarbamyl (second eluting enantiomer) / 5 5 \ 1 o~" 0 for example © under the conditions under which Chiral PHLC separates the titled compound after Vo preparations: room temperature for 0.4 ? min (dap) is mentioned for Mithqal?

LC-MS (Mehtodl) : RT 7.14 Min, m\z 351 [MH] + NMR

Vv) e Jud as obtained (A) example (+-3711-[2-3 iphenyl-2-ylcarbamoyloxy)-bicyclo[2 2,1]hept-7-yl]-trimethyl- ammonium iodide. (I-b): R%R®, R= CH;, RY = biphenyl-2-ylcarbamyl

VQ

\ 1) With 0 ° the titled compound was prepared using the conditions described for the example preparations;

LC-MS (Method 1): Rt 7.02, m/z 365 [M]+; (CDCL3) 8 1.43 NMR (1H, m), 1.50 (1H, dd, J = 15.1, 3.8Hz), 1.78 (1H, m), 1.88 (1H, m), 2.04 (1H, m) , 2.51 (1H, m), 2.73 (1H, t, J = 4.0Hz), 2.96 (1H, J =3.9Hz), 3.54 (9H, s), 4.31 (1H, s), 5.33 (1H, m) , 6.65 (1H, s), 7.17 (1H, m), 7.25 (1H, m), 7.37 (3H, m), 7.43 (1H, 10 m), 7.50 (2H, m), 7.99 (1H, d, br). 1 The following examples have been prepared in a manner similar to that described for an example

Name Structure 'H NMR (400MHz) Rt/min (Method 1); [MH+ or [M}+ vy anti-Biphenyl-2- N (CDCl3) 6 1.09 (1H, dd, J = 8.63; 471 yl-carbamic Au 13.6, 3.6Hz), 1.16 (1H, m), acid-7 -{methyl- 1.57 2H, m), 1.79 (1H, m), (3-phenoxy- 1.90 (2H, pent, J = 6.6Hz), propyl)- 2.05 (1H, m), 2.14 (1H, t, J = amino]bicyclo[2.4.4Hz), 2.16 3H, s), 2.29 (1H, 2.17hept-2-yl s), 2.51 (2H, m), 2.56 (1H, t,J ester. =4.0Hz ), 3.98 2H, t,J=

Enantiomer 1.6.6Hz), 4.93 (1H, m), 6.57 (1H, s), 6.88 (2H, m), 6.92 (1H, m), 7.12 (1H, m), 7.21 (1H, m), 7.26 (2H, m), 7.36 (3H, m), 7.41 (1H, m), 7.48 (2H, m), 8.08 (1H, d, br, J = 8.0Hz)

l anti-Biphenyl-2- N (CDCl) 8 1.09 (1H, dd, J = 8.60; 471 yl-carbamic A 1 13.6, 3.6Hz), 1.16 (1H, m), col 5 acid- 7-[methyl- 1.57 (2H, m), 1.79 (1H, m), (3-phenoxy- 1.90 (2H, pent, J = 6.6Hz), = propyl)-amino]- 2.05 (1H, m), 2.14 (1H, bicyclo[2.2.1]he 4.4Hz), 2.16 (3H, s), 2.29 (1H, pt-2-yl ester.s), 2.51 (2H, m), 2.56 (1H, t,J Enantiomer 2. =4.0Hz), 3.98 2H, t,J= 6.6Hz), 4.93 (1H, m), 6.57 (1H, s), 6.88 (2H, m), 6.92 (1H, m), 7.12 (1H, m), 7.21 (1H, m), 7.26 (2H, m), 7.36 s 7.48 (3H, m), 7.41 (1H, m), (2H, m), 8.08 (1H, d, br,J = 8.0Hz) vo anti-2- Bt ' ~ (CDCl;) 1.10 (1H, dd, J = 8.84; 485

A

(Biphenyl-2- ox A 13.7, 3.4Hz), 1.58 (1H, m), ylcarbamoyloxy) 1.80 (1H, m), 2.00 (2H, m), bicyclo[2.2.1]he 2.37 (3H, m), 2.77 (1H, t, br, J pt-7-yl]- =3.8Hz), 3.11 (1H, t, br, J = dimethyl-(3- 3.8Hz), 3.39 3H, s), 3.41 (3H, phenoxy- 5), 3.87 (1H, s), 3.90 (2H, m), propyl)- 4.11 2H, t,J =5.4Hz), 5.02 ammonium (1H, m), 6.63 (1H, s), 6.90 iodide . (2H, m), 6.93 (1H, m), 7.13

Enantiomer (1H, td, J = 7.5, 1.2Hz), 7.24 prepared from (3H, m), 7.34 (3H, m), 7.42 example 9. (1H, m), 7.49 (2H, m), 7.98 (1H , d, br, 1 = 7.4Hz)

vi anti-2- 5 2 (CDCly) 6 1.10 (1H, d, J = 8.81; 485 (Biphenyl-2- d 13.7Hz), 1.58 (1H, m), 1.80 ylcarbamoyloxy) (1H, m), 2.00 (2H, m), 2.37 bicyclo[2.2.1]he (3H, m), 2.77 (1H, s, br), 3.11 pt-7-yl]- (1H, s br), 3.39 (3H, 5 ), 3.40 dimethyl-(3- (3H, 5), 3.87 (1H, s), 3.90 phenoxy- (2H, m), 4.12 2H, t, 5l 4Hz), propyl)- 5.02 (1H, m) , 6.63 (1H, s), ammonium 6.90 (2H, m), 6.93 (1H, m), iodide. 7.13 (1H, t, J = 7.5Hz), 7.24

Enantiomer (3H, m), 7.34 (3H, m), 7.42 prepared from (1H, m), 7.49 (2H, m), 7.98 example 10. (IH, d, l 7.4Hz) z )( Example anti-[(1 $,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)bicyclo[2.2.1]hept-7-yl]- dimethyl-(3-phenylpropyl)ammonium bromide: (II-a): cat R® = Me, R® = 3-Phenyl-propyl, R? = 2,2-di-thiophen-2-yl-acetoxy.

A

A, : (A) the compound a. anti-(1S.2R.)-7-(Benzylmethylamino )-bicyclo[2.2.1]heptan-2-ol:

vv dibromo-bicyclo-TY (1S, 2R, 3R) The titled compound of heptate = unone-methylbenzylamine was prepared using similar methods to the methods in example [+.Y.Y] 2D

LC-MS (Mehtod2) : RT 0.76 Min, m/z 232 [MH] + NMR

A

55%

OH, 0 7 5 : (B) compound b. _ anti-Hydroxy-di-thiophen-2-yl-acetic acid (1S.2R)-7-(benzylmethylamino)- bicyclo[2.2.1]hept-2-yl ester: - (benzylmethylamines) -7 - (1S, 2R) = to a cold (0 °C) solution of anti (mmol) sodium hydride £F was added - 1 gram (heptane-7-ol [YY] bicyclo) 0. Partially (in parts) (Use 0018 mg of 760 mg colloidal solution in £1 mineral oil) The mixture is allowed to come to ambient temperature for ten minutes and then re-cooled to -day- Thiophene -7- yl acyl acid hydroxy 0 degrees Celsius, hydroxy acid (Av mmol) was added in parts, then the mixture was heated at oY - 1 g (Ya) dd. Selzie for two hours, Ve, after allowing the mixture to cool to the ambient temperature, and the mixture was irrigated by adding ammonium chloride aqueous dropwise (drop by drop) (concentrated 00 ml), and then the associated organic compounds were extracted - ( MeV ve * ( ethyl acetate by ethyl acetate. Drying it using sodium sulfate - filtered and evaporated to yellow color oil

VA

By using 770-05 ethyl silica gel purified by flash Coulomb on silica gel in hexane analyzers as a purifying agent, flash Coulomin was continuously used ethyl acetate acetate aba 0.11 This gives DCM in the A solution ethyl acetate 796 - 0 using . From the compound entitled as yellow oil (FOV)

LC-MS (Mehtod2) : RT 2.44 Min, m\z 454 [MH] + scramble ©

HX

5%6OH. 0 | J : (C) c.anti-Hydroxy-di-thiophen-2-yl-acetic acid (1 S.2R)-7-methylaminobicyclo[2.2.1]hept- 2-yl ester: )18- 2R) to a solution of anti-hydroxy-di-thiophene-1-yl-acetic acid 1 mg ©trap fo) z -- (benzylmethyl-imno)-bicyclo[1,7,7]hept -1- chloroethyl chloro-lyl ester -1-dichloroethane (© mmol) - 1.1 mmol) was added in a solution of A hours °C for a period of Ae mmol) The mixture was heated at 8.7 °C (0 OV) and the chloroethyl chloroformate was removed under reducing pressure to leave 1- the solvent and the excess of VO. Yellow / brown oil (ml) and it was stirred at a temperature ©) methanol This product has been re-dissolved in methanol. Surrounded for an hour, then evaporated to a yellow foam via and converted to alkali using sodium (Ge Ve). The residue was suspended in water 10 x 4 ( ethyl acetate hydroxide )00 + Normal) and then It was extracted by ethyl acetate. The associated organic compounds were dried using sodium sulfate and filtered. And evaporate it to a brown solid material © 10-0 using silica gel. Refining by flash rheumatograph on silica gel as a purifying agent (lye) is given as 1 mg (55%) of DCM in a methanol solution. The compound entitled as a yellow solid

LC-MS (Mehtod2): RT 2.20 Min, m/z 351 [MH] + NMR

Jo

Ner

A Ye 0 oA 0 / Ya (0) Compound d. anti-Hydroxy-di-thiophen-2-yl-acetic acid (1S.2R)-7-[methyl-(3-phenyl-propyl)- amino]-bicyclo[2.2.1Thept-2-yl ester: phenylpropanol (00 µL ¢ 41 mmol) to a solution of Anti-V added hydroxy-di-thiophene-7-ylacetic acid (18-28)-7-methylamino-bicyclo-V di = Y mg; 6.41 mmol) in a solution of 5 1) lyl esters TY Hept [071]. 01 mm (01) chloroethane. The mixture was stirred at ambient temperature for ten minutes, after which it was added. The mixture was stirred at (Use 1174 mg; 87 ml) sodium triacetoxy borohydride. The ambient temperature for two hours was 0.

As ml) and the mixture was separated within 10 minutes. Aqueous sodium hydrogen carbonate (concentrate) was added. DCM. Washing the aqueous phase by means of the Phase Separation Cartridge. The associated organic compounds were evaporated to a yellow-colored oil 6-10 Using silica gel purification by flash chromatography on silica gel from (7 V1) 00 mg in 4 lysate as a purifying agent given ethyl acetate © the compound entitled

LC- MS (Mehtod2) : RT 2.65 Min, m\z 482 [MH] + NMR (8) e. anti-[(1S,2R)-2~) 2-Hydroxy-2.2-di-thiophen -2-yl-acetoxy )-bicyclo[2.2.1]hept-7-y1]- dimethyl-(3-phenyl-propyl)-ammonium bromide: 0 ok 9 8

A Lor 0 / -17- (1S-2R) solution of antihydroxy-di-thiophene-7-yl-acetic acid 104) hept-?-yl ester [0,7,7][methyl] - )= phenyl-propyl)-amino]-bicyclo of a solution of methylbromide in acetonitrile (©mM) WW 7780 mg-mmol) at °C Te for leakage) for ? days at ile) heated in an airtight tube 10 ilica the solvent was removed and the residue was purified by flash chromatography on silica gel as a purifying agent by DCM in a solution as methanol by (using) 0—+) 7 methanol gel. mg (£10) of the compound labeled as a white solid 001 to give

AN

LC-MS (Method 1): Rt 8.43 min, m/z 496 [M}+; IH 11807 NMR (DMSO, 400 MHz) 0 1.01 (1H, dd, J = 13.4 Hz, 3.1 Hz), 1.35 (1H, m), 1.69 (2H, m), 1.95 (1H, m), 2.04 2H, m), 2.19 (1H, m), 2.61 (3H, m), 2.93 (1H, t, br, J = 3.5 Hz), 3.07 (3H, s), 3.06 3H, s), 3.39 (2H , m), 3.53 (1H, s), 5.0 (1H, m), 7.01(2H, m), 7.10 (2H, m), 7.22 (1H, m), 7.27 (2H, m), 7.32 (2H, m), 7.39 (1H, 5), 7.51 2H, m). © (Yo and 1;) eg trans-1-anti-{(1 §,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2 . 2.1]hept- 7-yl]-1-methyl-4-phenylpiperidinium bromide and cis-1-anti-[(1S,2R)-2-(2-Hydroxy- 2,2-di-thiophen-2-yl- acetoxy)-bicyclo[2.2.1 Jhept-7-yl]-1 -methyl-4-phenylpiperidinium bromide: (11-a): NR?R® = piperidinyl, R® = Me, RY = 2,2-di- thiophen-2-yl-acetoxy.

Ja 8 6 0 Hy 0 ِ / : Compound (H) a. anti-Hydroxy-di-thiophen-2-yl-acetic acid (1S.2R)-7-(4-phenyl-piperidin-1-yl)-bicyclo[2.2.1]hept-2-yl ester: dibromo- Bicyclo TY (IS2R-3R) The compound entitled was prepared from vo[?,?,..]heptane-71-on and 4-phenylbipyridine using methods similar to those in Examples 10’ and 1.

LC-MS (Mehtod2) : RT 2.60 Min, m/z 4 [MH] + NMR

AMAR

AY

JBr

NT

1 0 and 05 0 / : (B) compound b. trans-1-anti-[(1S,2R)-2-( 2-Hydroxy-2.2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl |-1-methyl- 4-phenyl-piperidinium bromide and cis-1-anti- [(1S2R)-2A 2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy )-bicyclo[2.2.1Thept-7-yl]-1 - methyl-4-phenyl-piperidinium bromide: The compound entitled was prepared from anti-hydroxy-di-thiophene-7-yl-heptate-?-yl [DY]yl) bycyclo-1-pyridine sb di =f) is an acid (15-28) -2a-, then it is separated using colline chromatography on 11 ester using a method similar to the example as a buffering agent DCM in a methanol solution using 0- 5 71 methanol silica gel : methyl-4-phenylpadepyrdene bromide -1-[dV Hbt [LY XY] acipoxy) by cyclo

LC-MS (Method 1): Rt 8.06 min, m/z 508 [M]+; (CDCl) 6 NMR 1.27 (1H, m), 1.57 (1H, m), 1.77 (1H, m), 1.86 (1H, m), 2.06 (3H, m), 2.20 (2H, d, J = 15.3Hz), 2.40 (1H, m), 2.86 (1H, t, br, J = 3.7Hz), 3.03 (1H, t, br, J =3.7Hz), 3.42 0 (1H, m), 3.61 3H, s), 3.65 (1H, y J = 13.6Hz), 3.69 (1H, s), 3.82 (1H, y J = 13.6Hz), 4.50 (2H, m), 4.66 (1H, s) ), 5.16 (1H, m), 7.00 2H, m), 7.17 (2H, m), 7.23 (2H, m), 7.26 (1H, m), 7.33 (4H, m).

AY

-hydroxy-7,7-dithiophene-?-yl (TY)-7- (1S-2R)[-ant-10-cis-acetoxy)bicyclo[0,7,7]hept mV yl] -0-methyl -; - Vinyl by pyridene bromide. NMR (1: LC-MS (Method).

Rt 8.10 min, m/z 508 [M]+; (:l00) 5 1.16 (1H, dd, l = 13.8, 3.0Hz), 1 52 (1H, m), 1.72 (2H, m), 2.08 (SH, m), 2.59 (1H, m) ), 2.86 (1H, tbr, J= 4.0Hz), 3.09 (1H, m), 3.20° (1H, s, br), 3.36 (3H, 5), 3.82 (2H, d, J = 12.2H2), 3.99 (2H, t, J = 12.2Hz), 4.63 (1H, s), 5.01 (1H, s), 5.32 (1H, m), 6.96 (2H, m), 7.16 (2H, m), 7.24 (5H , m), 7.31 (2H, m). The following examples have been prepared in a style similar to the methods described for Examples 6-132 1.

At

Name Structure 'H NMR (400MHz) Rt/min (Method 1); [MH]J+ or [M]+

Ao 0 (1) anti- ~ (CDCl) 8 1.08 (1H, m), 8.16; 498

Hydroxy-di- AS, 1.10 (1H, dd, J = 13.7, 0 A thiophen-2- 3.4Hz), 1.40 (1H, m), 1.56 yl-acetic acid (1H, m), & 1.77 (1H , m), 7-[methyl-(3- 1.89 (2H, pent, J = 6.5Hz), phenoxy- 2.09 (1H, m), 2.15 (3H, s), propyl)- 2.19 (1H, m), 2.28 (1H, s), amino]- 2.50 (2H, m), 2.52 (1H, m), bicyclo[2.2.1] 3.98 (2H, t, J = 6.5Hz), hept-2-yl 5.07 (1H , m), 6.87 (2H, m), ester 6.93 (1H, m), 6.98 (2H, m), 7.16 (1H, dd, J = 3.7, 1.3Hz), 7.19 (1H, dd, J = 3.7, 1.3Hz), 7.27 (4H, m)

tam 0 5 (+) anti-2-(2- RG (CDCl3) 8 1.10 (1H, dd, J = 8.20; 512

Hydroxy-2,2- Ae, 13.6, 2.5Hz), 1.45 (1H, m), di-thiophen- YO | 13 (1H, m), 1.75 (1H, m), 2-yl-acetoxy)- 1.88 (1H, m), 2.28 (2H, bicyclo[2.2.1] m), 2.37 (IH, m), 2.67 hept -7-yl]- (1H, s, br), 3.07 (1H, s, br), dimethyl-(3- 3.23 (3H, s), 3.24 (3H, 9), phenoxy- 3.70 (2H, m) , 3.87 (1H, s), propyl)- 4.04 (2H, ,A J = 5.1Hz), ammonium 5.14 (1H, m), 6.85 (2H, m), acetate 6.94 (3H, m), 7.14 ( 2H, m), 7.24 (4H, m)

AY p - anti-(1R,2S)- ~~, (CDCl) 0 1.24 (1H, m), 8.15; 2 2-(2- Ae, 1.57 (1H, m), 1.68 (1H, m),

Hydroxy-2,2- 5 A |1.76 (1H, m), 1.97 (1H, m), di-thiophen- 2.38 (2H, m, br), 2.53 (1H, 2-yl-acetoxy)- m) , 2.82 (1H, t, br, J = 0 bicyclo[2.2.1] Hz), 3.13 (1H, t, br, J] = 0 hept-7-yl]- Hz), 3.38 (3H, s), 3.39 (3H, dimethyl-(3- s), 3.95 (2H, m), 4.05 (1H, phenoxy- 5), 4.15 (2H, t, J = 4.8 Hz), propyl)- 4.62 (1H, s), 5.21 (1H, m), ammonium 6.89 (2H, m), 6.99 3H, m), iodide 7.16 (1H, dd, J=3.7, 1.3 Hz) 7.18 (1H, dd, J= 3.7, 3

Hz), 7.29 (4H, m).

AA hk anti-(+)-2-(2- PS 9 (CD;0D) © 1.16 (1H, dd, J 8.28; 496

Hydroxy-2,2- LJ = 13.7, 3.3 Hz), 146 (1H, di-thiophen- m), 1.70 (1H, m), 1.80 (1H, 2-yl-acetoxy)- m), 1.97 (1H, m), 2.15 (2H, bicyclo[2.2.1] m), 2.26 (2H, m), 2.62 (1H, hept-7-yl}- t, J =42 Hz), 2.71 2H, t, J dimethyl- (3- - 7.5 Hz), 2.94 (1H, , J = 4 phenyl- Hz), 3.12 (6H, s), 3.41 (2H, propyl)- m), 3.50 (1H, s), 5.05 (1H, ammonium m), 7.0 2H, m), 7.15 (ZH, bromide m), 7.20 (1H, m), 7.29 (4H, m), 7.40 (2H, m).

Ad anti-(1S,2R)- A | (CDCl) 0 1.24 (1H, m), 8.25; 512 / == 2-2- Ae, 1.57 (1H, m), 1.68 (1H, m), 5

Hydroxy-2,2- o Ga |176 an, m), 1.97 (1H, m), di-thiophen- 2.38 (2H, m, br), 2.53 (1H, 2-yl-acetoxy)- m) , 2.82 (1H, t, br, J = 3.0 bicyclo[2.2.1] Hz), 3.13 (1H, t, br, J = 3.0 hept-7-yl]- Hz), 3.38 (3H, s), 3.39 (3H, dimethyl-(3- s), 3.95 (2H, m), 4.05 (1H, phenoxy- s), 4.15 2H, t, J = 8 Hz), propyl)- 4.62 (1H, s), 5.21 ( 1H, m), ammonium 6.89 (2H, m), 6.99 3H, m), iodide 7.16 (1H, dd, J = 3.7, 1.3

Hz) 7.18 (1H, dd, J = 3.7, 1.3 Hz), 7.29 (4H, m)

m anti-(1S, 2R) HAN re (CDCL) 0 1.13 (1H, dd, J = 8.25; 512 2-(2- pS 2 13.6, 3.1 Hz), 1.47 (1H, m), 0 oH

Hydroxy-2,2- 6 ly» [1.63 (1H, m), 1.71 (1H, m), di-thiophen- 1.91 (1H, m), 2.29 (3H, s), 2-yl-acetoxy)- 2.29 (2H, m), 2.41 (1H, m), bicyclo[2.2.1] 2.72 (1H, t, br, J = 3.5 Hz), hept-7-yl]- 3.09 (1H, a br, J = 3.5 Hz), dimethyl-(3- 3.30 (3H, s), 3.31 (3H, s), phenoxy- 3.79 (2H, m), 3.86 (1H, s), propyl)- 4.00 2H, t, J = 5.3 Hz), ammonium 4.83 (1H, s), 5.13 (1H, m), toluene-4- 6.82 (2H, m), 6.95 (1H, m), sulfonate 6.98 (2H, m), 7.09 (2H, d , J = 8.1 Hz), 7.15 (2H, m), 7.25 (2H, m), 7.29 (2H, m), 7.74 (2H, m)

Ph. ~~ Br anti-[(1S,2R)- | _\¢ (de-DMSO) 0 1.03 (1H, dd, 7.87; 482 / —

NO, 2-(2- es J = 13.4 Hz, 3.1 Hz), 1.37 E

Hydroxy-2,2- o “7 | (1H, m), 1.72 H, m), 2.00 di-thiophen- (1H, m), 2.22 (1H, m), 2.70 2-yl-acetoxy)- (1H, t, br, J = 3.5 Hz) , 3.01 bicyclo[2.2.1] (1H, tbr, J = 3.5 Hz), 3.09 hept-7-yl]- (2H, m), 3.15 (3H, s), 3.17 dimethyl- (3H, s), 3.59 (3H, m), 5.03 phenethyl- (1H, m), 7.01 (2H, m), 7.10 ammonium (2H, dd, J = 3.6, 1.3 Hz), bromide 7.29 (1H, m), 7.36 (4H, m) ), 7.39 (1H, 5), 7.51 (2H, m)

YY Ya

AY

Br

Benzyl-anti- a ) (dg-DMSO) 5 1.05 (1H, dd, 7.38; 468 —N / = [(1S,2R)-2- A 2 12 13.4, 3.2Hz), 1.37 (1H, 0 OH (2-hydroxy- 5 | m), 1.67 (1H, m), 1.78 2,2-di- (IH, m), 2.02 (1H, m), thiophen-2- 2.18 (1H, m), 2.63 (iH, t, : yl-acetoxy)- br, J = 4.0Hz), 2.98 (1H, t, bicyclo[2.2.1] br, J = 4Hz), 3.00 (6H, s), hept-7-yl ]- 3.59 (1H, s), 4.60 (2H, s), dimethy!l- 4.98 (1H, m), 7.01 (2H, m), ammonium 7.10 (2H, m), 7.40 (1H, s), bromide 7.53 (5H, m), 7.60 (2H, m)

The anti-[(1S,2R)- Br (CDCl;) 8 1.14 (1H, dd, J = Method 4: 7.73; 510—N- ) 3.1Hz), 1.48 (1H, m), ,13.9 2 1 / -2(-2 JOH n Hydroxy-2,2- > 1.62 (1H, m), 1.73 (5H, m), 0 di-thiophen- 1.91 (1H, m) , 2.44 (1H, 2-yl-acetoxy)- m), 2.70 GH, m), 8 bicyclo[2.2.1] (1H, t, br, J = 3.8Hz), 3.29 hept- 7-yl}- (3H, s), 3.30 (3H, s), 3.66 dimethyl-(4- (2H, m), 4.04 (1H, s), 4.80 pheny!- (1H, s) , 5.15 (1H, m), 6.98 butyl)- (2H, m), 7.17 (SH, m), ammonium 7.26 (2H, m), 7.29 (2H, m) bromide Br a (d-DMSO) 6 1.04 (1H, dd, 6.35; 392 = a / anti-[(1S,2R)- 5 OH Le, J =13.4, 3.3Hz), 1.35 ( 1H, -2(-2 o Ly Hydroxy-2,2- m), 1.68 2H, m), 1 .96 di-thiophen- (1H, m), 2.17 (1H, m), 2.67 2-yl-acetoxy)- (1H, t, br, J = 4.0Hz), 2.98 bicyclo[2.2.1] (1H t, br, J = 3.9Hz), 3.13 hept-7 -yl}- (9H, s), 3.55 (1H, s), 4.97 trimethyl- (1H, m), 7.01 (2H, m), ammonium 7.10 (2H, m), 7.39 (1H, s) ), bromide 7.51 (2H, m).

(2- B ar (CD;0D) of 1.11 (1H, dd, J Method 4: 7.35; 512 —_— N-

Benzyloxy-! ) 0 = 13.6 Hz, 3.3 Hz), 1.47 oO. JOH ethyl)- khanasa | > (1H, m), 1.75 (1H, m), 1.81 0 [(1S,2R)-2- (1H, m), 2.00 (1H, m), 2.15 (2-hydroxy- (1H, m), 2.66 (1H, t, J = 4.1 2,2-di- Hz), 3.01 (1H, t, J= 3.9 Hz), thiophen-2- 3.204 (3H, s), 3.20 (3H, 9), yl- acetoxy)- 3.57 (1H, s), 3.70 (2H, m), bicyclof2.2.1] 3.95 (2H, a br, J = 4.0 Hz), hept-7-yl]- 4.58 (2H, s), 4.90 (1H, m), dimethyl- 7.00 (2H, m), 7.14 (2H, m), ammonium 7.26-7.38 (5H, m), 7.40 bromide (2H, m).

{0 0 anti-[(1S,2R)- (dg-DMSO) 8 1.01 (1H, dd, 6.78; 490

Br 2-(2- —N- _ J = 13.4, 3.2Hz), 1.23 (2H,

ANE

Hydroxy-2,2- o__kOH 1m), 1.35 (1H, m), 1 (1H, o ly di-thiophen- m), 1.60 (2H, d, J = 2-yl-acetoxy)- 13.1Hz), 1.68 (4H, m), bicyclof2.2.1] 1.97 (1H, m), 2.20 (1H, m), hept-7-yl]- 2.64 (1H, t, br, J = 3.7Hz), dimethyl-[2- 2.96 (1H, t, br, J = 3.5Hz), (tetrahydro- 3.04 (3H, s), 3.05 (3H, s), pyran-4-yl)- 3.27 (2H, m), 3.39 (2H, m) ), ethyl]- 3.50 (1H, s), 3.84 (2H, m), ammonium 5.01 (1H, m), 7.01 (2H, bromide m), 7.10 (2H, dd, J = 3.6, 1.3Hz), 7.39 (1H, s), 7.51 (2H, m)

anti-(1S, 2R) A 30 (CDCl) 6 1.09 (2H, m), Method 4: 7.48, 508

Hydroxy-di-Te 1.19 (2H, m), 1.44 (2H, m), thiophen-2- 1.59 (3H, m), 1.76 (3H, yl-acetic acid m), 2.06 (1H, m), 2.10 7 -(4-benzyl- (1H, s), 2.15 (1H, t, J = piperidin-1- 4.3Hz), 2.51 (3H, m), 2.81 yl)- (2H, d, J = 11.4Hz), 4.76 bicyclo[2.2.1] (1H, s), 5.05 (1H, m), 6.98 hept-2-yl (2H, m), 7.12 (2H, m), ester 7.18 3H, m), 7.27 (4H, m) anti-(1S, 2R) Cy (CDCl) & 0.97 (2H, m), | Method 4:7.91, 496

Hydroxy-oy Kom | 120 (3H, m), 1.51 (SH, m) ydaroxy : f M), mM), diphenyl- 1.73 (3H, m), 2.04 (1H, acetic acid 7- m), 2.09 (1H , s), 2.11 (1H, (4-benzyl- t, J = 4.4Hz), 2.48 (1H, m), piperidin-1- 2.49 (2H, d, J = 7.0Hz), yb)- 2.79 (1H , m), 4.26 (1H, s), bicyclo[2.2.1] 5.07 (1H, m), 7.12 2H, m), hept-2-yl 7.18 (1H, m), 7.26 (2H, ester m), 7.33 (6H, m), 7.42 (4H, m)

av = cis-4-Benzyl- Oh, (CDCl3) 6 1.02 (1H, dd, J = Method 4: 8.30; 510

Ph 1-[anti- 0K 13.8, 3.0Hz), 1.30 (1H, m), 0 (1S,2R)-2-(2- 1.45 (2H, m), 1.74 (SH, hydroxy-2,2- ) 2.00 (1H, m), 5 diphenyl- (1H, m), 2.62 2H, d, J = acetoxy)- 7.0Hz), 2.74 (1H, t, br, J = bicyclo[2.2.1] 4, 0Hz), 3.08 (1H, a br, J = hept-7-yl}-1- 4.0Hz), 3.25 (3H, s), 3.66 methyl- (4H, m), 4.20 (1H, s), 4.55 piperidinium (1H, s), 5.28 (1H, m), 7.11 bromide (2H, m), 7.20 (1H, has 7.27 (2H, m), 7.33 (8H, m), 7.41 (2H, m) )

aA — trans-4-” f) 5 1.09 (1H, dd, J =| Method 4: 8.24; 510

Ph

Benzyl-1- by 13.8, 3.0Hz), 1.35 (1H, m), [anti-(1S,2R)- 1.57 (4H, m), 1.92 (3H, 2-(2-hydroxy-m), 2.36 2H, m), 2.70 2,2-diphenyl- (3H, m), 2.93 (1H, Babr, J = acetoxy)- 4.0Hz), 3.39 (3H, ss), 3.58 bicyclo[2.2.1 ] (1H, d, br, J = 13.0Hz), hept-7-y1]-1- 3.74 (2H, m), 4.05 (1H, s), methyl- 4.07 2H, m), 5.16 (1H, m ), piperidinium 7.17 (2H, m), 7.21 (1H, bromide m), 7.28 QH m), 7.38 (10H, m)

and anti-(1S, 2R) 7 A on (CDCl;) 8 0.95 (1H, m), 8.62; 486

Hydroxy- ox 0.99 (IH, dd, J = 13.5, diphenyl- 3.3Hz), 1.21 (1H, m), 1.47 acetic acid 7- (1H, m), 1.70 (1H, m), [methyl-(3- 1.88 (2H, pent, J = 6.5Hz), phenoxy- 2.05 (1H, m), 2.11 (1H, m), propyl)- 2.13 BH, s), 2.26 (1H, s), amino}- 2.48 (3H , m), 3.96 2H, t, J bicyclo[2.2.1] = 6.5Hz), 4.26 (1H, s), 5.09 hept-2-yl (1H, m), 6.87 2H, m), 6.93 ester (1H , m), 726 (2H, m), 7.33 (6H, m), 7.42 (4H, m)

Yeo pro. 8 anti-(1S, 2R) PS 1 8 1.08 (1H, dd, J = 8.69; 500 2-(2- on 13.8, 3.2Hz), 1.36 (1H, m),

Hydroxy-2,2- 1.51 (2H, m), 1.87 (1H, m), diphenyl- 2.36 (2H, m), 2.47 (1H, acetoxy)- m), 2.75 (1H, a br, J = bicyclo[2.2.1] 4.0Hz), 3.08 (1H, abr, J = hept-7-yl}- 4.0Hz), 3.38 (3H, 5), 3.40 dimethyl-(3- (3H, s) , 3.93 (2H, m), 4.11 phenoxy- (4H, m), 5.23 (1H, m), propyl)- 6.87 (2H, m), 6.97 (1H, m), ammonium 7.27 (2H, m), 7.35 (8H, bromide m), 7.42 (2H, m)

Yvyi

for 110 mm anti-(1S, 2R) 7 A O 1 (precipitation) 5 0.83 (1H, dd, J = 9.29; 484 9H-Xanthene- LT 13.7, 3.4Hz), 0.96 (1H, m) , 9-carboxylic 1.26 (1H, m), 1.44 (1H, acid 7- m), 1.69 (1H, m), 1.86 [methyl-(3- (2H, pent, J = 6.5Hz), 1 93 phenoxy- (1H, m), 2.05 (1H, t, J = propyl)- 4.0Hz), 2.10 3H, s), 2.18 amino}- (1H, s), 238 (1H, ,a J = bicyclo[2.2 .1] 4.0Hz), 2.44 2H, m), 3.95 hept-2-yl (2H, t, J = 6.5Hz), 4.83 ester (1H, m), 4.94 (1H, s), 6.86 (2H, m ), 6.93 (1H, m), 7.07 (2H, m), 7.14 (2H, m), 7.28 (6H, m)

1 i 0 ~ anti-(1S, 2R) 7 A OC (CDCl3) 6 0.62 (1H, dd, J = 2.53; 500 0 0 9-Hydroxy- 1 50] 13.8, 3.0Hz), 0.66 (1H, m) , 9H-xanthene- 0.77 (1H, m), 1.25 (1H, 9-carboxylic m), 1.55 (1H, m), 1.83 acid 7- (3H, m), 1.96 (1H, Ba br, J = [methyl-(3- 4.0Hz), 2.05 3H, s), 2.11 phenoxy- (1H, s), 2.28 (1H, t, br, J = propyl)- 4.0Hz), 2.40 (2H, m), 3.91 amino]- (2H, t, ] = 6.4Hz), 4.79 (1H, bicyclo[2.2.1] m), 4.90 (1H, s), 6.84 b hept-2-y! m), 6.93 (1H, m), 7.13 ester (2H, m), 7.19 (2H, m), 7.26 (2H, m), 7.35 (2H, m), 7.50 (2H, m)

Vey rh Br anti-(1S, 2R) A: 0 (:000) 5 0.91 (1H, dd, J = 9.26; 499

AC

Dimethyl-(3- 0 13.7, 3.2Hz), 1.37 (1H, m), 0 phenoxy- 1.58 (2H, m), 1.89 (1H, propyl)-[2-m), 2.27 3H, m), 2.68 ( 1H, (9H- t, J = 4.0Hz), 2.89 (1H, t, J xanthene-9- = 40Hz), 3.32 (3H, s), carbonyloxy)- 3.35 (3H, s), 3.75 (1H, s) ), bicyclo[2.2.1] 3.86 (2H, m), 4.07 2H, t,J hept-7-yl]- = 5.5Hz), 4.90 (1H, m), ammonium 4.96 (1H, s), 6.84 ( 2H, m), bromide 6.95 (1H, m), 7.09 (2H, m), 7.15 (2H, m), 7.28 (6H, m)

Yof oo" . Br anti-(1S, 2R) 0 0 (CDCl3) 0.72 (1H, dd, J =| Method 4: 7.55; 514 0 (0.0 2-9 1 50) 13.8, 3.0Hz ), 1.13 (1H, m),

Hydroxy-9H- 1.22 (1H, m), 1.37 (1H, xanthene-9-m), 1.77 (1H, m), 2.23 carbonyloxy)- (1H, m), 2.30 (2H, m), 2.62 bicyclo[2.2 .1] (1H, t, br, J = 4Hz), 2.83 hept-7-yl}- (1H, t, br, J] = 4.0 Hz), 3.31 dimethyl-(3- (3H, s), 3.33 3H, s), 3.88 phenoxy- (2H, m), 3.92 (1H, 5), 4.08 propyl)- (2H, t, J = 5.4Hz), 4.79 ammonium (1H, s), 4.94 (1H, m) , 6.83 bromide (2H, m), 6.96 (1H, m), 7.18 (4H, m), 7.26 (2H, m), 7.37 2H, m), 7.50 (1H, dd, 12 7.8, 1.6Hz), 7.54 (1H, dd, J = 17.8, 1.6Hz)

Yeo anit-[(1S,2R)- 2 (CDCl) B 1.16 (1H, m), Method 4: 7.42, 494

Br 2-(2- m _ 1.52 (1H, m), 1.74 (2H, t),

Pye

Hydroxy-2,2- 0 OH 2.03 (1H, m), 2.47 (1H, m), o ly di-thiophen- 2.81 (1H, m), 3.11 (1H, m), 2-yl-acetoxy)- 3.34 -3.46 (8H, m), 3.48- bicyclo[2.2.1] 3.58 (2H, m), 4.07 (1H, s), hept-7-yl]- 474-481 (2H, m), 0 indan-2 -yl- (1H, m), 6.97 (2H, m), 7.14- dimethyl- 7.30 (8H, m). ammonium bromide

Yel

HO

Hydroxy-di- , (CDCl;) with 1.20 (1H, m), Method 4: 6.53, 422 7 == thiophen-2- Ae, 1.24-1.32 (1H, m), 1.56 yl-acetic acid o Ly (2H, m), 1.80 (1H, m), 2.11- anti-(1S,2R)- 2.22 (2H, m), 2.37 (3H, s), 7- 2.58 (1H, br s), 2.73 (1H , br (carboxymeth s), 3.20 (2H, m), 5.08 (1H, yl-methyl-m), 6.99 2H, q), 7.18 (2H, amino)-m), 7.30 (2H, m). bicyclo[2.2.1] hept-2-yl ester (£0) eg anti-(1S, 2R) 2-(2-Hydroxy-2,2-diphenyl-ethoxy)-bicyclo[2.2. 1]hept-7-yl]-dimethyl-(3-phenoxy-propyl)-ammonium bromide.

PhO—""\

PpN

A Ph 0K : : Compound (e) a. 2-{anti-(1S.2R,)-7-[Methyl-(3-phenoxy-propyl)-amino ]-bicyclo[2.2.1Thept-2-yloxy}- 1,1-diphenyl-ethanol

L solution of ante = [(18-28) -7-[methyl = (3-phenoxy-propyl)-amino]-bicyclo[0,7,7]heptane == ole (7 mg; 14 mL) (Use in ml of DMSO solution stirred under nitrogen atmosphere at ambient temperature. Sodium hydride was added (£0 mg ¢ 770 suspension in oil) and the reaction was warmed to Ve©° abu for <1 min before being cooled to oe °C. -1,1-diphenylethylene oxide (You) mg added; 0.71 mmol) to the (negative) anion and the heating continued for 1 minute. The reaction was cooled to ambient temperature and the reaction was quenched by adding water - it was extracted with L-200 and the associated organic extracts were washed with brine, dried with 0 magnesium sulfate and concentrated in vacuum. Compound (8): b. anti-(1S, 2R) 2-(2-Hydroxy-2.2-diphenyl-ethoxy )-bicyclo[2.2.1]hept-7-yl]-dimethyl- (3-phenoxy-propyl)-ammonium bromide 1 | Br Woom Para 2 Ph . Gel A solution of methylamine (171 mm and ¥ m) was added to a solution of (1-bromo-nonyloxy)-teibert-butyl-dimethyl-silane (41.4 YT “aba mmol) in ( lle Yo) IMS at -01 °C and the reaction was allowed to reach room temperature overnight.

01 The material was removed, diethyl acetate Ji, the solvent, and the residue was crushed by a di-pad, after the filtrate was concentrated in the solid HBR chicks by filtration, in order to display the compound entitled as the salt of Al-Ghalq N 12003 (aqueous * and it was done Extract it with the 0014 associated organic layers were dried - filtered and concentrated to display the compound entitled as oil (MgSO2) Yield: 774 g mm salt of 118 and 1 (1718 aba? 4,1) °

LC-MS (Mehtod2): RT 2.80 Min, lead 288 [MH] + NMR: (B) methyl-(?-phenoxy[-7-(IS2R)-) compounds were prepared from 7 - (Anti-diphenylethanol-1,1) hept-?- yloxy [VY] propyl)-amino | By Cyclo

DAY to those described in Allee's example using methods 0

LC-MS (Method 1): Rt 8.69 min, m/z 486 [M]+; (CDCl) § NMR 1.07 (1H, dd, J = 13.3, 3.4Hz), 1.60 (2H, m), 9 (1H, m), 2.09 (1H, m), 2.30 (1H, m) , 2.37 (2H, m), 2.66 (1H, t, br, J = 4.0Hz), 2.93 (1H, t, br, J = 4.0Hz), 3.22 (1H, s), 3.37 (3H, 5), 3.38 3H, s), 3.09 (2H, 5), 3.97 (2H, m), 4.07 (1H, s), 4.14 CH, t,J = 5.5Hz), 4.17 (1H, m), 6.86 (2H, m) ), 6.96 (1H, m), 7.26 (3H, m), 7.31 (5H, m), 7.40 Ne (4H, m) (£1) Example Hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S,7S)-7-({9-[(R)-2-hydroxy-2-(8- hydroxy-2-oxo-1,2-dihydro-quinolin-5 -yl)-ethylamino }-nonyl}-methyl-amino)-bicytlo[2.2.1]hept-2-yl ester

Bra So N ° 5 b

4< Compound (A) a. (9-Bromo-nonyloxy )-tert-butyl-dimethyl-silane. tert-butyl-dimethylsilyl chloride (1 mg VATA - aha YAN) was added in parts to a solution of TY bromo-nonyl -1 first (77.8 174.76 aba © mol) and imidazole (0.0 g) - 377 ml (Use in dry DCM) £00 (lle at Vom °C under nitrogen atmosphere, the reaction was allowed to reach room temperature overnight, the solids were removed by filtration, the filtrate was washed with 701 citric acid (aqueous) and the brine was dried by 140504 filtrate and concentrated to dryness To display (to produce) 0 the compound entitled as a yellow color oil - yield 41.4 grams = 98. Diethyl cther \ cyclohexane)/. (TLC : RF 0.91 -50) After an hour and a half at °C, another amount of lithium tert biotoxy aluminum hydride (VE g; 04 mmol) was added after an hour and a half at 07 °C. The reaction was quenched with a concentrated solution. of ammonium chloride (aqueous) and was divided between acyl acetane and anhydrous.Yo solids were removed by filtration and washed with ethyl acetate The phases were separated and the aqueous layer was extracted by ethyl acetane The associated organic layers were washed with a concentrated solution of Ibe 1100603 and brine and dried. Na2sod was filtered and concentrated to dryness to display a cloudy yellow oil - the raw material was purified by Column chromatography on silica gel using 0 Gradient of 0— DCM/ HEOH 701. As a purifying agent, after evaporating the volatile substances, a yellow / light brown lime oil was obtained.

0: yield YT - g; TOV LC- MS (Mehtod2): RT 2.95 Min, m/z 398 [MH] + NMR compound 0 (: sodium hydride added) ¢ YO mg I colloidal solution in mineral oil 1.70 mmol) to a solution of (2R-48-7S) -15) == }1 = (tert-butyldimethylsilyloxy)nonyl[methylamino] - bicyclo[YY]heptane-7-ol (1.0 g; 7.54 lle mol) in dry toluene (Gl 001) at 0 degrees Agha under 0 nitrogen atmosphere once The gas movement is stable and hydroxy-di-thiamine Y = lyl acetic acid Ji estide (La (A) mg + 7.04 mmol) was added in parts and when the gas movement stopped the reaction mixture was heated At Ar degree Celsius in ples of pre-heated sand 0 after evaporation of the volatiles, the compound entitled as light yellow oil / Ch yield: 1,197 grams - 7464 was obtained. LC- MS (Mehtod3): RT 4.83 Min, m\z 474+476 [MH] N IIT A 10 Compound (D) tert-Butyl-dimethyl-silanyloxy)-nonyl ]-methyl-amino}-bicyclo- -7-119-(15.45,75)_L[2.2.1]heptan-2-one.tri-N-butylene hydride (Y0,1 mM + £10,mmol) was added to A solution of (15-45-75)-5-bromo =V= ( [-(tert-butyl-dimethyl-oxysilyl)-0_nonyl]-methyl-amino)-bicyclo DY] Heitan-7-on (1,597g + 4,7ml

111 (Use and AIBN) 0 mg Ale 1.475 mol) toluene 6 free gases (40 lle) under an atmosphere of nitrogen.nitrogen and heated at 88 degrees Celsius In a previously heated sand bath, after two hours at A °C, the bagasse mixture was concentrated in vacuum and purified by 0 Column chromatography on silica gel using a gradient of 7140-1 of diethyl ether. / pentane as a purifying agent After evaporation of the volatile substances, the entitled compound was obtained as a light yellow oil / Yield: 3.41 grams - Quantitative (containing butyltin residues) LC-MS (Mehtod3): RT 3.10 Min, m\z 396 [ MH] FSaantte: |OH Compound (E): (1S.2R 4S.7S)-7-{[9-(tert-utyldimethylsilanyloxy )nonyl]methylamino}bicyclo-8 [ 2.2.11heptan-2-ol vo to a solution of (15-48-78) -7- {1-4-tert-butyl-dimethylsilanyloxy)nonyl[methylamino{bicyclo[YY]heptane) Y = Un[)£9gm - 0.4mmol max (in dry THF solution (£1mL) at -© celsite degree under nitrogen atmosphere 5 with the addition of lithium tri- Tert-Biotxi-aluminum hydride (7.44 grams 6,135 mmol).

11° After two and a half hours, the reaction mixture was poured over a concentrated aqueous solution of ammonium chloride AN chlorides - the layers were separated and the aqueous layer was extracted by ether and the accompanying organic layers were washed with brine and dried with

,. It was filtered and concentrated to dryness to display a light brown viscous oil (Na2SO4).

° The raw material was purified by Column chromatography on silica gel using a Gradient of 1-56 / from JAN ethyl acetate in a solution of DCM as a purifying agent to display the compound. It is a viscous oil with a very light brown color.

Yield VT 0 g ¢ TEN LC-MS (Mehtod3) : RT 3.44 Min, m/z 620 [MH] N NSS si' | Cs HO 0 Ns © 01 Compound (6): g.

Hydroxy-di-thiophen-2-yl-acetic acid (1S.2R.4S.7S)-7-[(9-hydroxy-nonyl)-methyl- amino]-bicyclo[2.2.1]hept-2- yl ester. solution of hydroxyl-dala-thiophene-7-yl--17-acetic acid (1S-2R-3S-7S) 7A 1}0 tert-butyl-di-methyl-oxycyclanyl) - ‎ [dis methyl-amino)bicyclo[",]hept-7-yl-ester (.91; g ¢ 87 mmol) in THF solution (V) mM) was treated with 1 Molar of HCl (3.5 mM) and Al was dissolved at room temperature for £0 min.

ny The reaction mixture was neutralized by an aqueous solution of saturated sodium bicarbonate and extracted ethyl acetate by means of ethyl acetate The accompanying organic layers were dried by sodium sulfate and rocks were filtered to . Drying in order to produce a light brown oil that was used from Ain Takiyah. 716 Production: 777 We are v °

LC-MS (Mehtod3): RT 2.39 Min, m\z 506 [MH+]

N SSO

HO 0 ab 0 : (11) the compound h. _Hydroxy-di-thiophen-2-yl-acetic acid (1S.2R.4S,78)-7-[methyl-(9-oxo-nonyl) -amino]-bicyclo[2.2.1}hept-2-yl ester.0 mmol) was added to a solution of 0.056 des-Martin Brideaux Nan (£04 mg)-hydroxy-dithiophene-7- yl = acetic acid (15-25-45-75)-NO-[(5-hydroxy-hept-7-yl-ester (70 mg [VY] nonyl)-methyl-amino]-bicyclo dry (¥ mL) at zero degrees Celsius, and the reaction was allowed, DCM, mmol, in the +, VYY solution, in the room, after an hour at room temperature, the reaction mixture was treated, ahs, until it reached 10 ethyl acetate JAN An aqueous solution of saturated sodium bicarbonate was extracted by washing the organic layer with brine, dried (8102504), filtered, and concentrated to acetate. Drought

1 "And the solids were removed by filtration, and the ether was crushed (removed) by the residue by the concentration of the filtrate in order to produce a viscous oil of brown / orange color, and it is used directly without purification again. mmol (mmol) max) +, VY yield: 9 mg; each | q oN

NSS SSN

0 OH Ni = 0 OR” © 1 (1) Compound i. Hydroxy-di-thiophen-2-yl-acetic acid (1S,2R,4S.78)-7-({9-[(R)-2-(tert-butyldimethylsilanyloxy)-2-(8-hydroxy-2- oxo-1,2-dihydroquinolin-5- ylethylamino]nony|}methylamino)bicyclo[2.2.1]hept-2-yl ester.=v (1S-2R-4S-7S) yl-acetic acid=Y- mixture of hydroxy-di-thiophene Ve yl-ester (max. Y= [methyl- )= oxo-30amino]bicyclo[1,7,7]hept (tert-butyldimethylsilanyloxy) -1- mmol) ©- [ (8) -?-amino 7" and sodium (Use mM +, VY 6 mg YEO) hydroxy-111-conillon-7-on -86- [di mmol) and acetic acid (2 drops) in GAA mg and VAT) triacetoxyborohydride A dry solution of 1,?- dichloroethane was stirred overnight at ambient temperature. 0. After concentrating in vacuum, a light brown oil was obtained

LAY production: 50 mg

Example LC-MS (Mehtod3) : RT 2.04 Min, m\z 708 [MH] (£Y)

11 (Benzylcarbamoyl-methyl)-anti-[(1S,2R)-2-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1 Ihept-7-ylJ-dimethyl ammonium bromide. 7 OH.6 / | 0 P(A) a.Hydroxy-di-thiophen-2-yl-acetic acid _anti-(1S,2R)-7-[(benzylcarbamoyl-methyl)- 0 methyl-amino]-bicyclo[ 2.2.1]hept-2-yl ester solution of anti--hydroxy-di-thiophene-7-ylacetic acid ~V= (1S-2R) methylamino-bicyclo[1,1,7]hept- 7- yl-ester (04 mg ») + mL (Use) was formed in acetonitrile solution (¥ mL). DIPEA (9; μl » YA, + mmol) and n0-benzyl-7-bromo-acetamide $A) mg ; (1.71 mol dle) were added and the mixture was stirred at 00 °C for two hours. The solvent was evaporated and purified by Coulman flash chromatography on silica gel using a Gradient of 701-101 ethyl ethyl acetate in a solution of DCM as a purifying agent to give the compound entitled as oil a pale yellow color 101 (mg + 784) 1. LC-MS (Mehtod2): RT 2.83 Min, m\z 511 [ [MH] the reaction mixture was partitioned between the DOM and a saturated aqueous solution of saturated sodium bicarbonate - the organic layer was dried (NA2SO4) filtered and concentrated in vacuum to produce a brown/dark green rubber that hardens with the leave that was purified by the Prepared HPLC (B 0 ak) 0 + 8 721 min).

The fractions containing the pure product were concentrated and neutralized by an aqueous solution to obtain a brown/green oil. Production: Ala Majm “101 / . LC-MS (Mehtod3) : RT 2.51 Min, m\z 822 [MH] ° Q DL “_Nehlam H” LS M0 0 / A 0 Compound (0) b. (Benzylcarbamoyl- methyl)-anti-[(1S.2R)-2-(2-hydroxy-2.2-di-thiophen-2-yl- acetoxy)-bicyclo[2.2.1 lhept-7-yl |-dimethyl-ammonium bromide 1 The compound entitled was prepared from hydroxy-di-thiophene-7-yl-acetic-anti-acid - (18-28) -7-[(benzylcarbamoylmethyl)methylamino] bycyclol [YY] heat - "- YL-Ester using Allee's methods to those described in Example 17. _ NMR (1H, dd), 1.45-1.52 1.12 8 (000i) LCMS (method 4): Rt 7.53 mins, m/z 525 [M+]; (1H, m), 1.63 (1H, m), 1.72-1.80 (1H, m), 1.88-1.97 (1H, m), 2.28 (1H, m) , 2.74 (14, 0 br, t), 3.06 (1H, br t), 3.34 (3H, s), 3.36 (3H, s), 4.17 (1H, s), 4.41 (2H, d), 4.68 (2H, dd), 4.79 (1H, s), 5.60 (1H, m), 6.98 (2H, m), 7.15 (2H, m), 7.19-7.23 (1H, m), 7.25 - ( 4H, m), 7.36 (2H, d), 9.55 (1H, t). 7.31 The following example is prepared in a manner similar to that described for the £Y example.

A Name Structure 'H NMR (400 MHz) Rt/min (Method 4); [MH]+ or [M]+ 0 pe (CDCl) 6 1.16 (1H, dd), 7.39; 524 -2,3(-2[ Dihydro- i Br 1.46-1.54 (1H, m), 1.68- —N benzofuran-5- 'A Le, 1.75 (2H, m), 1.90-1.99 JOH, .0 (1H, m), 2.45 (1H, m), 2.76 |ma l)-ethyl]-anti- [(1S,2R)-2-(2- ( 1H, s), 3.05-3.11 (3H, m), hydroxy-2,2-di- 3.16 (2H, t), 3.39 (3H, s), thiophen-2-yl- 3.41 (3H, s), 3.86 (2H, m), f (acetoxy)- 4.17 (1H, s), 4.52 (2H, bicyclo[2.2.1]h 4.81 (1H, s), 5.16 (1H, m) , ept-7-yl}- 6.69 (1H, d), 6.97 (2H, m), dimethyl- 7.03 (1H, d), 7.15 (2H, dd), ammonium 7.24-7.30 (3H , m). -yl]- dimethyl-(3-phenoxy-propyl)-ammonium bromide

There is no God CN 0 YO Compound (H): a. anti-(1S, 2R) Oxo-phenyl-acetic acid _7-[methyl-(3-phenoxy-propyl)-amino]- ‎bicyclo[2.2.1]hept-2-yl ester (1S2R)-7-[methyl-()=phenoxy-propyl)amino]bicyclo[0,7,7]heptane-7-ol (aba +, vV)-7,8 mmol) in The SLO THE (alle 01) at ambient temperature under an atmosphere of nitrogen with a solution of sodium hydride (£0 1 mg of 770 suspended in oil) for a period of ? hours . Oxo-vinyl-acetyl chloride (TY) (mg - 3.14 mmol) was added and 0 _ the reaction was allowed to remain for 20 hours - the reaction was irrigated by adding a saturated solution of ammonium chloride and extracted by ETOAC and then Jue associated organic extracts using brine, dried by 1406504 and concentrated in vacuum. The reaction was purified by chromatography on a silica gel using a Gradient of 0 - 75 of 2120 cyclohexane as a purifying agent to give the compound as a yellow color oil 10 (100 mg). NMR 1.20-1.30(2H, m), 1.63-1.71 (2H, m), 1.78-1.88 (1H, m), 1.88-1.96 (2H, 8(J00) .m), 2.14-2.25 (5H, m), 2.35-2.37 (1H, m), 2.50-2.58 (2H, m), 2.66-2.70 (1H, m), 3.97- (2H, m), 5.20-5.26 (1H, m) ), 6.85-6.95 (3H, m), 7.24-7.30 (2H, m), 7.48-7.54 (2H, 4.03 m), 7.63-7.69 (2H, m), 7.95-8.00 (2H, m). ‏

0 is critical

A 2 0 (a) the compound a. anti-(1S, 2R) Cyclohexyl-hydroxy-phenyl-acetic acid 7:[methyl-(3-phenoxypropyl)- amino]-bicyclo[2.2.1]hept-2-yl ester to a stirred solution of anti-(IS2R) ) oxo-phenyl-acetic acid -7-[methyl-(7-phenoxy-propyl) = amino]-bicyclo [YY] Het-7-yl-ester You) mg ; Ale 4 mol) in anhydrous THF (0 mM) was added cyclohexylmagnesium chloride 15 (mM) 1.94 mmol) under nitrogen atmosphere 0100860. The reaction was heated at 0 © Political degree for VA hour. 1 The cold reaction was irrigated by adding a saturated ammonium chloride solution - extracted by ETOAC, and the accompanying organic extracts were dried using MGS54 and concentrated in vacuum. The reaction was purified by chromatography on a silica gel using a scale of 1 of ©20-2120 purified complete cyclohexane to yield a product as pure oil 177 (0 mg). LC-MS (Mehtod1) : RT 2.86 Min, m\z 492 [MH+]

1

Br 0 a N Z a A 0 0 : (C) the compound c. anti-(1S.2R)[2-(2-Cyclohexyl-2-hydroxy-2-phenyl-acetoxy)-bicyclo[2.2.1]hept-7- yl]dimethyl-(3-phenoxy-propyl)-ammonium bromide - cyclohexyl — hydroxyphenyl (18-2R) - The compound entitled was prepared from ante °[methyl-(*-phenoxypropyl)-amino]bicyclo[1,7,7]hept-1-yl 1- Acetic acid: CVF ester using methods explained in an example (£9) for example anti-(1S, 2R) 2-Hydroxy-3,3-dimethyl-2-phenyl-butyric acid 7 -[methyl-(3-phenoxy-propylamino]bicyclo[2.2.1]hept-2-yl ester 0 N

A OH

0-oxo-phenyl-acetic acid -7-[methyl (IS2R)- The compound entitled antihept-7-yl-ester was prepared using the [VY]phenoxy-propyl)-amino]-bi methods cyclo-" which has been explained as an example; nuclear magnetic resonance ve

111 (CDCl) 6 0.97-1.05 (9H, s), 1.07-1.28 (2H, m), 1.68-1.79 (2H, m), 1.81-1.96 (3H, m), 2.1-2.24 (5H, m), 2.31 (1H, s), 2.49-2.61 (3H, m), 3.80 (1H, s), 3.97-4.03 (2H, m), 5.02-5.11 (1H, m), 6.86-6.95 (3H, m), 7.23-7.34 (5H, m), 7.69-7.74 (2H, m). LCMS (method 4): Rt 8.29 mins, m/z 466 [MH+]. (£1) Example © anti-(1S, 2R) [2-(2-tert-Butyl-2-hydroxy-2-phenyl-acetoxy)-bicyclo[2.2.1]hept-7yl]- dimethyl-( 3-phenoxy-propyl)-ammonium bromide

Br og x

Oh

0 The compound entitled was prepared from ant-(1S2R) 7-hydroxy-7,7-dimethyl-0 ?-phenyl-butyric acid -7-[methyl=)=phenoxypropylamino]bicyclo]0 ,7,7[ hept -7- yell steadily using the methods described in Example 17 . LC- MS (Mehtod2) : RT 2.82 Min, m\z 480 [M+] ( £Y) Example [anti-(1R,2R)-2-(2-Hydroxy-2,2-diphenyl- acetylamino)-bicyclo[2.2.1]hept-7-yl}- diméthyl-(3-phenoxy-propyl)-ammonium bromide

Oy AN

J NH, (A) the compound a. (1R.7S)-N’-Methyl-N’-(3-phenoxy-propyl)-bicyclo[2.2.1]heptane-2,7-diamine

YY

A solution of (18.78) -7-[methyl-(=phenoxy-propyl)-amino]-bicyclo methanol mmol) was formed in methanol (5.9 ¢ aha 1,70) heptane-7-en ],,7[ (let) followed by hydroxylamine (Use 6 mg 7.9 ml TEA) Sodium acetate was added

VA The mixture was stirred at room temperature for . (se mM AY hydrochloride) 07 mg © . hour was added, followed by the addition of (Use milligrams A = 1.11 grams) of nickel (VY) chloride hexahydrate 5, mmol) tam = aba, 148) on parts sodium borohydride . hour VA stirring the mixture at room temperature for ethyl acetate between ethyl acetate LEN the solvent was removed under buffer pressure and fractionated Ye . and sodium aqueous hydroxide organic phases It was dried with sodium sulfate, filtered, and evaporated into rubber. This was then purified with methanol. It was washed with methanol. SCX CARTIRIDGE. It was loaded into 385 material using colmen - methanol in methanol. Lise using molar. ,

DCM methanol in the 01-210 of Gradient by cellulometric chromatography using a Ve scale. ) 799 - mg OY) as a purifying agent to produce the compound entitled as brown oil

LC-MS (Mehtod2) : RT 0.34 Min, m\z 275 [MH+]

ON

0 : (B) the compound

1 b. N-{(1R,75)-7-[Methyl-(3-phenoxy-propyl)-amino]-bicyclo[2.2.1]hept-2-yl}-2-0x0- 2-phenyl-acetamide methyl - 07<-(©-phenoxy-propyl)-bicyclo-N7 - (IR-7S) solution of (¥) DCM (mmol) formed in YF + compound (Yoo) diamine =, Y= heptat [0,7] . mmol) = (ev YO) 0.47 (mmol) with diisopropylethylamine (© mmol) in -0.095 mg VAS) a solution of oxo-vinyl-acetylchloride was added . Drop by drop (drip) DCM The mixture was stirred at room temperature for ¥ hours silica gel The solvent was evaporated and the residue was purified by chromatography on silica gel with DCM in ethyl acetate solution Ethyl acetate 7701-1 from Gradient using scale 01 (0) - to give the compound entitled as colorless oil (04 mg)

LC- MS (Mehtod2) : RT 2.28 Min, m\z 407 [MH+] yo 0 ht, 1 op: (0) compound c. 'eo 2-Hydroxy-N-{anti-(1R) .,2R)-7-[methyl-(3-phenoxy-propyl)-amino]-bicyclo[2.2.1]hept-2-y1}-2,2-diphenyl-acetamide =) methyl- =V= (IR-7S)}- A cold solution (0 °C) of N-hept-?-yl)-7-oxo-7-phenyl [YY] phenoxy-propyl)-amino]-bicyclo A solution of phenylmagnesium THF (Sle©) mmol) in the 1.75 - mg 001 (acetamide - mmol) THF = 1.57 chloride (773" mm - ¥ M in the 0

114 mm 197 mm - ¥ molar in the 1117 and 177 (a solution of vinylmagnesium chloride .mol) was added and the solution was stirred for an hour at zero degrees Celsius. The reaction was allowed to reach room temperature for another hour. 01 mm) The reaction was irrigated by adding aqueous ammonium chloride (saturated), then the organic materials were dried, ethyl acetate, the mixture was extracted by ethyl acetate °, accompanied by the use of sodium sulfate, filtered, and evaporated from Gradient By using gradient silica gel purification by chromatography on silica gel ane color in order to give the compound entitled as DCM oil from methanol 608001 in the 25-0 (FIV = mg 01)

LC-MS (Mehtod2) : RT 2.55 Min, m\z 485 [MH+] Br 9 AA_H 0

A =

FC

: (D) compound d. [anti-(1R,2R)-2-(2-Hydroxy-2.2-diphenyl-acetylamino)-bicyclo[2.2.1]hept-7-yl]- dimethyl-(3-phenoxy-propyl)-ammonium bromide - Methyl[-7-(IR-2R)hydroxy-N- } you —Y The compound entitled was prepared from -yl)-7,7-diphenyl Y= hept [VY] phenoxy- propyl)-amino[bicyclo-”)11 acetamide using methods similar to those in the NMR example.

'Yo

LCMS (method 1): Rt 7.88 mins, 499 m/z [M+]; (CD;0D) 6 1.27 (1H, m), 1.66-1.75 (1H, m), 1.85 (2H, t), 2.05 (1H, m), 2.22-2.38 (3H, m), 2.73 (1H, m) ), 3.00 (1H, s), 3.20 (6H, s), 3.60-3.68 (3H, m), 4.11 (3H, m), 6.92-6.96 (3H, m), 7.25-7.34 (8H, m), 7.40-7.45 (4H, m). (8A) Joe 0

Hydroxy-di-thiophen-2-yl-acetic acid anti-(1S,2R)-7-[(3-dimethylamino-propyl)- methyl-amino]-bicyclo[2.2.1]hept-2-yl ester: 2 A << A —

AS, 6 OH, 0 ÷ / The compound entitled Ante—hydroxy-di-thiophene-7- ylacetic acid (methane =F) methylamino-bicyclo[1,7,7-hept-7-] was formed. Lylester of -7- (15-28) 0 sulfonyl-oxy-propyl) dimethyl-ammonium chloride using methods similar to those in Example. Magnetic resonance nuclear

LCMS (method 1): Rt 5.02 mins, 449 m/z [MH+]; ))00:0( 6 1.07-1.18 (2H, m), 1.50 (2H, m), 1.77 (3H, m), 2.10 (1H, m), 2.17 3H, s), 2.32 (1H, s), 2.42 (2H, t), 2.54 0 (1H, s), 2.61 (6H, s), 2.79 (2H, m), 4.57 (1H, br s), 5.02 (1H, m), 6.98 (ZH, m) , 7.14 (2H, m), 7.38 (2H, m). (£9) Example (3-Dimethylamino-propyl)-[anti-(1S,2R)-2-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)- bicytlo[ 2.2.1]hept-7-yl]-dimethyl-ammonium bromide:

l 71 0 N NN N — LS 0 OH, 0 7 a 0 Compound (e): a.

Hydroxy-di-thiophen-2-yl-acetic acid _anti-(1S.2R)-7-{[2-( 1,3-dioxo-1,3-dihydro- isoindol-2-yl)-ethyl} -methyl-amino}-bicyclo[2.2.1]hept-2-yl ester ° The compound entitled was formed from anti-hydroxy-di-tyophene-7-yl-acetic acid (IS-2R) -7-methyl amino-bicyclo[0,7,7] hept-7-yl estide and of (N-=Y)bromoethyl)phenatimide (Phthamimide) using methods similar to those in Example 47 LC-MS ( Mehtod2) : RT 2.70 Min, m\z 537 [MH+] HNN = LS Hy 0 0 J a 0 0 Compound (b) : _Hydroxy-di-thiophen-2 -yl-acetic acid _anti-(1S.2R)-7-[(2-amino-ethyl)-methyl- .amino}-bicyclo[2.2.1]hept-2-yl ester hydroxy- di — thiophen -7- yl - satiic acid ante — (1S2R) - Y, 1 ) -Y ] } -Y _- dioxo — Y, 1 _ dihydro _- isanodole -Y —- yl ( _ethyl] at dine _ 0 -amino ) bycyclo [0,7,7] hept-7-yl-ester Av) mg -10+ mM (Use Done It was formed in ethanol (7 ml).Hydrazine monohydrate (YY) μl - 0.44 ml (Use) was added and the mixture was heated at 80 degrees Celsius for an hour, then allowed to reach a temperature of the room.

17 The resulting white precipitate was ethanol filtered and the filtrate was washed with ethanol. Evaporation of the filtrate in order to produce the raw material from the entitled compound

LC-MS (Mehtod3): RT 2.03 Min, m\z 407 [MH+]

OG

“Ag, 6 011 0 7 : (©) Compound 0 c. Hydroxy-di-thiophen-2-yl-acetic acid _anti-(1S,2R)-7-[(2-benzoylamino-ethyl)- methyl- amino]-bicyclo[2.2.1]hept-2-yl ester 15-( The raw material of hydroxy-di-thiophene-7-yl-acetic acid- you are hept-?- yl-ester [0,7] has been dissolved ,7[amino-ethyl)-methyl-amino]bicyclo-7[-7-(2R.mM)(0 mmol) DCM) in a solution of (0 (00 mmol)+ followed by benzoyl 177 - μl ©1 (diisopropylethylamine added . mmol) 1.15 - μl (YY) chloride. Fe min. The mixture was stirred at room temperature for a period of

Phase — separation (mL) and the organic matter was separated by 0) ola was added using silica gel and evaporated - chromatography on silica gel cartridge 0 as a DCM agent in ethyl acetate solution of ethyl acetate 7700 —+ of Gradient (IT) - in order to give the compound entitled as a colorless oil (0? mg iis

LC-MS (Mehtod3) : RT 2.47 Min, m\z 51 [MH+]

YYA

9A:

NN = art6OH, 0 | / (D) compound d. (2-Benzoylamino-ethyl)-anti-[(1S,2R)-2-(2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]- dimethyl-ammonium bromide The entitled compound was prepared from hydroxy-di-thiophene-7-yl-acetic acid [VY] ?-benzoyl amino-ethyl)-methyl-amino [bicyclo] [-7- (1S2R) - You. 0 hept-7- ly Esther using methods similar to those for example nuclear magnetic resonance.

LCMS (method 1): Rt 5 sls, m/z 525 [M+]; (CD;0D) 6 1.18 (1H, dd), 1.47-1.55 (tH, m), 1.74-1.90 (2H, m), 1.99-2.09 (1H, m), 2.31 (1H, m), 2.80 (1H , m), 3.12 (1H, 0 m), 3.27 (3H, s), 3.27 (3H, s), 3.64-3.69 (3H, m), 3.89 (2H, t), 5.09 (1H, m), 7.00 (2H, m), 7.14 (2H, m), 7.40 (2H, m), 7.45-7.50 (2H, m), 7.54-7.58 (1H, m), 7.85-7.88 (2H, m). 1A example anti4[€1S,2R)-8-(tert-Butoxycarbonyl-methyl-amino)-octyl]-[2-(2-hydroxy-2,2-di- thiophen-2-yl-acetoxy) )-bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium bromide iN he

Br

14 Compound (E): a. anti-(1S)-7-(Benzyl-methyl-amino)-5-bromo-bicyclo[2.2. 1 ]heptan-2-one == heptane [YY] dibromo - bicyclo - 7,7 - (IS) A solution of DCM was stirred under nitrogen atmosphere 151 ml of the grams - 76.5 mmol) in VY) on . mol) drip lle 7,57 - aba V, 01) and it was added that - benzylmethylamine nitrogen © - an hour before washing with water YY the reaction was stirred at ambient temperature for a period of time. The brine was dried (148504) and concentrated in vacuum. The silica gel of ISCO Copanion was purified by chromatography on a vessel of (IVA) aba 6,74 cyclohexane to give - ET20 716 —+ remove (purify) by . Titled compound as yellow solid 0 NMR 'H NMR (CDCls;, 400 MHz): 0 1.77-1.80 (1H, m), 2.10 (3H, s), 2.20-2.30 (1H, m), 2.65-2.73 (1H, m), 2.80-3.00 (4H, m), 3.40-3.60 (2H, m), 4.75-4.85 (1H, m), 7.20-7.40 (5H, m).

A

A

\o : (B) compound b. (1S)-7-(Benzyl-methyl-amino)-bicyclof2.2.1]heptan-2-one (benzyl-methyl-amino)-5-bromo-bicyclo-7-(IS)-solution from you toluene mM Av in (Use 1.7 mM-heptane-?-un-) 0 grams [V,V,Y]

Ww. - mg (YUU) methoxypropionitrile (Y) -azops ¥ - 1 was degassed before adding . mmol) 1 The reaction was heated to 88 °C for an hour and a half and allowed for the reaction to reach . To ambient temperature, the reaction was extracted by Normal of hydrochloric acid (100 ml was washed °). Then it was cooled in an ice bath and neutralized with sodium carbonate steel ET20 using Al-01, followed by the addition of sodium hydroxide (Normal) to give a pH equal to . The reaction was extracted by ethyl acetate, filtered, and concentrated to an oil of color (Na2S04). 400MHz): 0 1.37-1.52 (2 H, m), 2.00-2.29 (7 H, m), 2.60-2.71 (3

H, m), 3.49 2 H, dd, J = 13, 42 Hz), 7.21-7.34 (5 H, m).

A

A, : (C) compound c. anti-(1S.2R,)-7-(Benzylmethylamino)-bicyclo[2.2.1]heptan-2-ol [0,7,7] (benzyl-methylamino)-bicyclo-7 - (1S) A solution of (1S) was cooled in an ice bath. THF mmol) in a solution of 19,748-On (5,? g -7-

111 (se) added lithium tri (1-butoxy) aluminum hydride (0.4 grams = 77.5 ml). 11 minutes sad, in parts, the reaction was stirred at zero degrees Celsius for an hour and a half, then the reaction was watered. ml) and the solids were removed by filtration (01) with ammonium chloride, and the filtrate was washed with water. As an agent - ATOAC 770-710 by chromatography using dal (gram).Yr) purified to give the compound entitled as pale oil.

LC-MS (Mehtod2) : RT 0.76 Min, m\z 232 [MH+]

A

The 6 OH 0 | 7 Ve : (D) compound d. anti-(1S, 2R)-Hydroxy-di-thiophen-2-yl-acetic acid (1S,2R)-7-(benzylmethylamino)-bicyclo[2.2.1]hept-2-y] ester: (benzylmethylamino) amino)-7- (IS2R) = to a cold (0°C) solution of ANTE g = “,4 mmol) sodium hydride 1 (heptate-7-ol [VY] bye) was added cyclo - .mmol) in 08 fractions (77 mg; 770 mg colloidal solution in mineral oil) the mixture was allowed to reach ambient temperature for ten minutes and then re-cooled to .0°C

(1.74 grams - 5.7 ml) was added to the hydroxy-di-thiophene-7-yl-acetic acid ethyl-estide (Use) in parts, then the mixture was heated at Av °C for two hours. After allowing For the reaction to reach ambient temperature, the reaction was irrigated with the addition of aqueous ammonium chloride (saturated and 00 ml) dropwise and extracted by ethyl acetate (#3,0101 ml).The associated organic materials were dried by 182504 filtered and evaporated to Yellow oil Purification by Coleman flash on silica gel using 7090-0 ethyl acetate in DCM solution to give VY gram (7597) of the compound labeled as 00 yellow oil LC- MS (Mehtod2) : RT 2.44 Min, m\z 454 [MH+] 02 Ag, OH, 5 7 0 Compound (BE): e. anti-Hydroxy-di-thiophen-2-yl -acetic acid (1S,2R)-7- methslaminobicyclo[2.2.1]hept-2-yl ester: to a solution of anti-hydroxy-di-thiophen-7-yl-acetic acid (18 28) ) -7-(benzylmethyl-amino) bicyclo [YY] hept-7-yl ester (£00 g - AN + mmol 4 in 1,1-dichloroethane (©mL) ). -1 chloroethyl chloroformate (+07 mm and 5.9 lla mol) was added and the mixture was heated at 80 degrees gla for A hours).

The solvent and excess of 1-chloroethyl chloroformate were removed under reducing pressure, leaving a brown/yellow oil. This is aly reconstituted in methanol (©mL) and stirred at ambient temperature for an hour and then evaporates to a yellowish foam. The residue was suspended in water (Glo 10) and converted to basic using sodium hydroxide (+ Norman) and extracted with ethyl acetate (; 01 x mm). The associated organic materials were dried on sodium sulfate (Gad) and evaporated to a brown solid. Purification by flax chromatography on silica gel using 0-0 1 methanol in DCM solution as purifying agent to give 188 mg (£01) of the compound labeled as lia yellow. LC- MS (Mehtod?2) : RT220 Min, m\z 364 [MH+] Ae A nA == Tag OH_ 6 lJ 0 Compound (F) : anti-Hydroxy -di-thiophen-2-yl-acetic acid _ 7-{[8-(tert-butoxycarbonyl-methyl-‏ 1 amino)-octyl]-methyl-amino}-bicyclo[2.2.1]hept-2-yl ester: to a solution of anti-hydroxy-di-thiophene-7-yl-acetic acid (1S-2R) -L7-methylamino-bicyclo-YY]hept-7-yl-ester (6 mg) and 1217 mmol) in acetonitrile (© mm) methane sulfonic acid 4-(tert-butoxy Yvyi) was added

carbonyl - methyl - amino) - octyl ester (Vo) mg = 100 mmol) and triethylamine (YY) μl - 1.74 mmol) the mixture was heated at A °C for 11 hours. (Al) solvent was done in vacuo and then the residue was purified by flash chromatography on silica gel using 1-0001 ethyl acetate in DCM solution as a ie agent followed by further purification by flash chromatography on silica gel using of 700001-10 ethyl acetate in cyclo-hexane as a purifying agent to give the compound titled Yo) mg and (AYA) NMR MHz: 0 1.07-1.15 (2 H, m), 1.20-1.31 ( 8 H, m), 1.35-1.53 (14 400, R2)) 'H NMR (H, m), 1.56-1.65 (1 H, m), 1.76-1.85 (1 H, m), -2.04 2.16 (5 H, m), 2.23 (1 H, 5), 2.28 (2 H,t),2.51 (1H, m), 2.83 (3H, s),3.18(2H, m),4.77(1 H,s), 5.07 (1H, m), 6.99 2H, 0 m), 7.17-7.21 (2 H, m), 7.27-7.30 (2 H, m). Adm by NNN Go to PN LS not Br / | 0

Compound (6): Yanti-[(1S,2R)-8-(tert-Butoxycarbonyl-methyl-amino)-octyl]-[2-(2-hydroxy-2,2-di-p-thiophen) 2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium bromide Solution from you (IS2R) hydroxy - di - thiophen == yl - acetic acid - no - ( [ /- tert-butoxycarbonyl-methylamino) = octyl]-methyl-{sisal-bicyclo[7,] hept-7-yl-ester (Yo) mg - 17 mmol) in 7700 solution of methyl bromide in acetonitrile (©mL) heated in an airtight tube for ? days at Te degrees Celsius

\Yo silica gel was removed from the solvent and the residue was purified by flash chromatography on silica gel from the compound (FAY) mg Yo as a purifying agent to give DCM methane in the 7200-0 using . Entitled: Yellow foam (Nuclear magnetic resonance).

LC-MS (Method 1): Rt 9.14 min, m/z 619 [M]+; 'H NMR (CDCl, 400 MHz) (0 1.20- © 1.82 (25 H, m), 1.92-2.02 (1H, m), 2.48-2.59 (1 H, m), 2.79 (1 H, s), 2.81 (3 H, m), 3.08 (1 11, 9), 3.18 (2) 11, 0, 3.33 (3H, s), 3.39 (3H, s), 3.60-3.75 (2 H, m), 4.16 (1 H , 5), 4.70 (1 H, s), 5.21 (1 H, m), 6.95-7.02 (2 H, m), 7.12-7.19 (2 H, m), 7.27-7.30 (2 H, m). . 18 The following examples are prepared in a manner similar to that described in Example 1

Ex. Name Structure 'H NMR (400MHz) Rt/min (Method 1); (M]+

2a| anti-(1S,2R)-[2-(2- ) } Br (CDCL3) 6 1.01 (1 H,| 8.42;484

3b dd), 1.25-1.35 (1 H, m), l Hydroxy-2,2- diphenyl-acetoxy)- 0 ® 1.40-1.52 (2 H, m), bicyclo[2.2. 1]hept-7- 1.73-1.84 (1 H, m), yl]-dimethyl-(3- 2.13 (2 H, m), 2.42 (1 phenyl-propyl)- H, m), 2.61 (1 H, m), ammonium bromide 2.73 (2 H, m), 2.91 (1 H, m), 3.28 3 H, 5), H, s), 3.61-3.76 3 3.31 H, m), 4.01 (1 H, s), 2( H, 5), 5.20 (1 H, 1( 4.14 m), 7.19-7.23 (3 H, m), H, m 12 (7.25-7.41).

3a| anti-(1S,2R)-[2-(2- 0 (CDCl;) § 1.00-1.10 (1 | 8.28;498)

Hydroxy-2,2- 3, 3 11, m), 1.20-1.40 (2 H, diphenyl-acetoxy)- oN m), 1.40-1.50 (2 H, m), see bicyclo[2.2.1] hept-7- 1.70-1.90 (4 H, m), yl]-dimethyl-(4- 235-250 (1 H, m), phenyl-butyl)- 2.60-2.65 (1 H, ,l ammonium bromide 2.70-2.80 (2 H, m), 2.90-3.00 (1 H, m), 3.25 (3 H,s),3303H, s), 3.60-3.80 (2 H, m), 4.03 (1H, s) , 4.10 (1 H, s), 5.10-5.20 (1 H, m), 7.10-7.20 (3 H, m), 7.23-730 (3 H, m), 7.30-7.40 (7 H, m), 7.40 -7.50 (2H, m).

YYA

4a anti-(1S,2R)-[2-(9- D i Br (d6-DMSO) 5 0.43 (1 7.76; 498 3 3

Hydroxy-9H-o | H, dd), 0.89 (1 H, m), 0 xanthene-9- 1.18 (1 H, m), 1.48 (1 carbonyloxy)bicyclo[ H, m), 1.80 (1 H, m), 2.2.1Thept- 7-yl]- 1.90-2.02 (3 H, m), dimethyl-(3-phenyl- 243 (1 H, m), 2.55 (2 propyl)-ammonium H, m), 2.69 (1H, m), bromide 2.98 (6 H, s), 3.29 (2H, m), 3.38 (1 H, s), 3.71 (IH, m), 7.09 (1 H, s), 7.18733 (© H, m), 739-746 ( 2H, m), 7.56-7.63 (2H, m).

5a| anti-(1S,2R)-[2-(9- 4 L (d6-DMSO) 0.62 (1| 7.92;498)

Hydroxy-9H- Hy 3 H, dd), 0.91-1.01 (1 H, fluorene-9- 0 m), 1.19-1.27 (1 H, m), 0 oH) carbonyloxy)bicyclo[ 1.51 (1 H, m) , 1.81 (1 2.2.1]hept-7-yl}- H, m), 2.06 (1 H, m), dimethyl-(3- 2.15 (2H, m), 2.53 (1 phenoxy-propyl)- H, m), 2.74 (1 H, m), ammonium bromide 3.02 (6 H, s), 3.42-3.50 (3 H, m), 4.01 2 H, m), 4.80 (1 H, m), 6.75 (1

H, s), 6.90-6.99 (3 H, m), 7.27-7.38 (4 H, m), 741-748 (2 H, m), 7.49-7.52 (2 H, m), 7.80-7.83 (2 H, m).

18 anti-(1S,2R)-[2-(1,3- .0 (CDCl3) 8 1.14-1.20 (1 | 7.55;551)

N

Dioxo-1,3-dihydro- | 3 > H, m), 1.48-1.58 (1H, / = isoindol-2-yl)-ethyl]- A %, m), 1.70-1.75 (2H, m), [2-(2-hydroxy- 2,2-di- 0 Ma 1.91-2.06 (1 H, m), thiophen-2-yl- 2.50 (1 H, m), 2.89 (1 acetoxy)bicyclo[2.2.1 H, s), 320 (1 H, s),

Jhept-7-y1]-dimethyl- 3.57 (3H,s),3.59 3H, ammonium bromide s), 4.05 2H, m), 4.30, (2H,m), 4.39 (1H, 5), 4.90 ( 1H, s),523 (1H, m), 6.93-6.99 (2 H, m), 7.12-7.18 (2 H, m), 7.26-7.30 (2 H, m), : 7.71-7.78 (2 H, m), 7.80-7.87 (2 H, m).

Ye 0 anti-(1S,2R)-(3- Jy (d6-DMSO) & 1.02 (1 | 7.22;492 / = L Wa Ethoxycarbonyl- 0 LO H, dd), 1.20 3 H, Na propyl)-[2-(2- 1.31-1.40 (1 H, m), hydroxy-2,2-di- 1.64-1.77 (2 H, m), thiophen-2-yl- 1.90-2.02 (3 H, m), acetoxy)- 2.20 (1 H, m), 2.40 (2 bicyclo[2.2.1}hept-7- H, t), 2.67 (1 H, yl]-dimethyl- 2.98 (1 H) , m), 3.04 (3 ammonium bromide H, s), 3.06 3 H, s), 3.30-3.39 (2 H, m), 3.57 (1 H, s),4.09 (2H, q), 5.01 (1 H , m), 7.00- 7.02 (2 H, m), 7.10- 7.12 2 H, m), 7.39 (1

H, s), 7.50-7.55 2 H, m).

11

N anti-(1S,2R)-9- A 002 (AQ) 0.55-0.70 21 8 0

Hydroxy-9H- 1X H, m), 0.75-0.85 (1 H, xanthene-9-m), 1.20-1.40 3 H, m), carboxylicacid 7- 1.40-1.70 (4 H, m), [methyl-( 4-phenyl- 1.80-1.90 (1 H, m), butyl)- 1.90 (1 H, s), 2.00 3 H, amino]bicyclo[2.2.1] s), 2.05 (1 H, s), 1.15- hept-2-yl ester 2.25 3 H, m), 2.50- 2.60 (2 H, m), 4.70- 4.80 (1 H, m), 4.90 (1

H, s), 7.10-7.30 (9 H, m), 7.30-7.40 (2 H, m), 7.40-7.60 (2 H, m).

VEY

— 9a anti-(1S,2R)-[2-(9- SN (CDCl3) 8 1.60-1.70 (1 8.62; 512)

Hydroxy-9H- Evel H, m), 1.05-1.40 (4 H, 0 ol) xanthene-9-m), 1.60-1.80 (4 H, m), carbonyloxy)bicyclo[ 2.15-2.05 (1 H, m) , 2.2.1]hept-7-yl]- 2.50 (1 H, m), 2.65- dimethyl-(4-phenyl- 2.75 (3 H, m), 3.20 (3 butyl)-ammonium H, s), 325 (3 H, s), bromide 3.50-3.70 (2 H, m), 3.85 (1 H, s),4.75 (1 H, s), 4.80-4.90 (1 H, m), 7.10-7.30 (9 H , m), 735-740 2 H, m), 7.50-7.60 (2 H, m).

<7 108 anti-(1S,2R)-[9- py 0 (CDCl) 81.60-1.75 (2|102 0

Hydroxy-9H- 10% H, m), 1.75-1.85 (1 H, xanthene-9- m), 1.20-1.40 (6 H, m), carboxylic acid 7- 1.50-1.60 (2 H, m), [ methyl-(S-phenyl- 1.80-1.90 (1 H, m), pentyl)-amino}- 1.90 (1 H, s), 2.0 3 H, bicyclo[2.2.1]hept-2- s), 2.10 ( 1 H, s), 2.50- yl ester 2.60 (2 H, m), 4.75- 4.80 (1 H, m), 4.90 (1

H, s), 7.10-7.20 (7 H, m), 7.20-7.30 (2 H, m), 7.30-7.40 (2 H, m), 7.40-7.60 (2 H, m).

Veo

Br [la| anti-(1S,2R)-[2-(9- 3 (CDCl3) 3 0.65-0.70 (1 8.92; 526)

Hydroxy-9H- VT 9 IH m), 1.05-1.40 (6 H, xanthene-9- m), 1.60-1.80 (4 H, m), carbonyloxy)- 2.15225 (1 H, m), bicyclo[2.2.1 ]hept-7- 2.55-2.63 (3 H, m), yl]-dimethyl-(5- 2.70-2.75 (1 H, and (phenyl-pentyl)- 3.15-3.30 (6 H, m), ammonium bromide 2.45-2.60 (2 H, m), 3.90 (1 H, s),4.85(1 H, s), 4.90-4.95 (1 H, m), 7.10-7.20 (7 H, m), 722 730 (2 H, m), 735-740 (2 H, m), 7.50-7.58 (2 H, m).on 8 12a|anti-(1S,2R)-[2-(2- 2 (CDCl) & / b 2 Hydroxy-2,2-di- and JOH 6 Na thiophen-2-yl- acetoxy)bicyclo[2.2.1 Thept-7-yl}-(4- ‎hydroxy-4-phenyl- ‎butyl)-dimethyl- ammonium bromide

Br anti-(1S,2R)-[2-(2- 7 + _ (CD;0D) § 1.19 (1 H,| 8.25;506)

A

Hydroxy-2,2-di- o LOX |dd), 1.46-1.57 (1 H, m), NaL thiophen-2-yl- 1.64-191 (2 H, m), acetoxy)- 2.00-2.12 (1 H, m), bicyclo[2.2.1]hept-7- 2.24236 (1 H, m), yl]-dimethyl-(4- 1.78 (1 H, m), 3.07- phenyl-but-3-ynyl )- 3.12 3 H, m), 3.23 (3 ammonium bromide H, s), 324 3 H, s), 3.64 (1H, s), 3.75 (2 H, t), 5.09 (1 H, m), 6.98 - 7.01 (2 H, m), 7.12- 7.16 (2 H, m), 7.27- 737 (3 H, m), 7.39- 7.41 (4 H, m).

VEY

14a| anti-(1S,2R)-[2-(9- a - (d6-DMSO) 8 0.6111 6

Hydroxy-9H- pS (|H dd), 090-099 (LH, fluorene-9- a m), 1.17-1.24 (1 H, m), carbonyloxy)- 1.43-1.58 (3 H, m), bicyclo[2.2.1hept-7- 1.62-1.73 (2H, m), yl]-dimethyl-(4- 1.76-1.84 (1 H, m), phenyl-butyl)- 1.98-2.08 (1 H, m), ammonium bromide 2.60 2 H, t), 2.67 (1 H, m), 2.95 (6 H, s), 3.23- 3.35 (4 H, m), 4.70- 4.77 (1 H, m), 6.73 (1

H, s), 7.14-720 (3 H, m), 7.22-7.28 (2 H, m), 7.30-7.37 (2 H, m), 741-746 (2 H, m), 7.48-7.52 (2 H, ,l 7.82 (2 H, d).

YEA

1 15a anti-(1S,2R)-9- 0 2 A ® 0 2.9

Hydroxy-9H- (method 3) xanthene-9- carboxylic acid 7-{[4-(4-cyano- phenyl)-but-3-y nyl]-methyl-amino}-bicyclo[2.2.1]he pt- 2-yl ester

N

16a anti-(1S,2R)-9- J A OC o (CDCl) 8 1.60 -| 2.60;523 0

Hydroxy-9H-Fo) 1.75(2H, m), 1.78-1.83 | (method 3) xanthene-9- (1H, m), 1.20-1.43 (4H, carboxylic m), 1.80-2.10 (6H, m), acid 7-{[4-(4-cyano-2.18-2.30 (3H) , m), phenyl)-butyl]- 2.60-2.70 (3H, m), methyl-amino}- | 4.78-4.80 (1H, m), 4.90 bicyclo[2.2.1]hept-2- (1H, s), 7.10-7.40 (8H, yl ester m), 7.45-7.60 (4H, m).

Ved un 17a anti-(1S,2R)-9-L 27 2 (CDCl) & 0.70-0.75| 2.68;524

Hydroxy-9H- Fo (1H, m), 0.80-0.85 (1H, | (method 2) xanthene-9-m), 1.10-1.40 (2H, m), carboxylic 1.65-1.80 (2H, m), 2.18 acid 7-{[4-(4- (3H, s), 2.19- 2.28 (1H, methoxy-phenyl)- m), 2.50-2.55 (1H, m), but-3 2.75-2.80 (3H, m), 3.20 -ynyl]-methyl- (BH, s), 3.25 (3H, s), amino}- 3.70-3.85 (2H, m), 3.90 bicyclo[2.2.1] (1H, s), 4.75 (1H, s) ), hept-2-yl ester 4.85-4.95 (1H, m), 7.10-7.20 (4H, m), 7.30-7.40 (4H, m), 7.50-7.60 (4H, m).

You. LSR 18a anti-(1S,2R)-9- N 2 2 (CDCl) & 0.60-0.857 4

Hydroxy-9H- 0 Ra(3H, m), 1.25-1.40 (1H, | (method 2) xanthene-9- m), 1.60-1.70 (1H, m), carboxylic 1.80-1.90 (1H, m) , 2.0- acid 7-{[4-(4- 2.05 (1H, m), 2.15 (3H, methoxy-phenyl)- s), 2.25 (1H, s), 2.26- but-3 2.35 (1H, m) , 2.40-2.50 -ynyl]-methyl- (2H, m), 2.55-2.60 (2H, amino}-m), 3.80 (3H, s), 4.75-bicyclo[2.2.1] 4.85 (1H, m), 4.90 (1H, hept-2-yl ester s), 6.75-6.85 (2H, m), 7.10-7.40 (8H, m), 7.50-7.60 (2H, m).

011 o 19a anti-(1S,2R)- (CDCl3) 6 1.07-1.15 (2 | 2.68; 6

Hydroxy-di-i H, m), 1.40-1.48 (3 H, | (Method 2) thiophen-2-yl-acetic 0 l m), 1.51-1.64 (3 H, m), 0 0 5 acid 7-{[4-(4- 6 Na|1.76-1.85 (1 H, m), methoxy-phenyl)- 2.04-2.15 (5 H, m), butyl]-methyl- 223(1H, s) ,231 2H, amino}- t), 2.49-2.57 3H, m), bicyclo[2.2.1]hept-2- 3.78 (3H,s),4.77 (1H, yl ester s), 5.04-5.09 ( 1 H, m), 6.80-6.84 (2 H, m), 6.97-7.00 (2 H, m), 7.06-7.09 (2 H, m), 7.17-7.21 (2 H, m), 7.27-7.30 ( 2 H, m). (20A) anti-(1S,2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-[methyl-(4-pyrimidin-5-yl-but-3-ynyl)-amino] -bicyclo[2.2.1]hept-2-yl ester

H 1 H 1 hy A 0 2 0 9 | no oH]

P(A) compound 0

YoYa. anti-(1S,2R)-9-Hydroxy/methoxy-9H-xanthene-9-carboxylic acid 7-methylamino- bicyclo[2.2.1]hept-2-yl ester m and +,4Y) 1-chloroethyl chloroformate 1-chloroethyl chloroformate - (mmol) was added to a solution of 4-hydroxy-114-xanosene-4-carboxylic acid 85 0.56 - mg (TAT) (benzy-methyl-amino) -bicyclo[1,19] hept-7-yl-ester -7# 1 °C for Av and the mixture was heated at 0 dichloroethane (7 mM) YY in (Ue mL) l-chloroethyl chloroethyl chloroformate 1- The solvent and excess were removed from le lod under reducing pressure leaving a brown / yellow oil (ml chloroformate) and stirred at the temperature (©) methanol This was re-dissolved in methanol the surroundings for an hour, then evaporated into a soft (yellow butter) 0 ml) and converted to basic using hydroxide 01 (the residue was suspended in water ml) organic matter 70074 (sodium (0 + normal) and extracted By concomitant ethyl acetate it was dried by the 1182504 filtrate and evaporated to a brown solid. Methanol 77-0 using silica gel purification by flash chromatography on silica gel as a purifying agent to give 7705 mg (747) From the mixture of the compound entitled DCM in the methanol 0 as a rubber - nuclear magnetic resonance

NMR (CDCls, 400 MHz) : 0 0.54-0.6 (1 H, m), 0.70-0.82 (1 H, m), 0.90-1.03 (1 H, m), 1.13-1.23 (1 H, m), 1.45 -1.55 (1 H, m), 1.80-1.89 (2 H, m), 2.15-2.20 (1 H, m), 2.23 (3 H, s), 2.52-2.55 (1 H, m), 4.73-4.82 (1 H, m), 7.10-7.21 (4 H, m), 7.30-7.40 (2

H, m), 7.49-7.55 (2 H, m). LC-MS (Method 2): Rt 2.24 min, m/z 366 [MH]+. Methoxy | 0 tbl NMR (CDCls, 400 MHz) : 0 0.54-0.6 (1 H, m), 0.70-0.82 (1 H, m), 0.90-1.03 (1 H, m), 1.13-1.23 (1 H, m), 1.45-1.55 (1 H, m), 1.80-1.89 (2 H, m), 2.15-2.20 (1 H, m),

yor 2.23 (3H, 5), 2.52-2.55 (1 H, m), 2.28 3H, s), 4.73-4.82 (1 H, m), 7.10-7.21 (4 H, m), 7.30-7.40 (2 H, m), 7.49-7.55 (2 H, m). LC-MS (Method 2): Rt 2.44 min, m/z 380 [MH]+. 0 0 ° oH] : (B) the compound 0 b. _anti-(1S.2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-(but-3-ynyl-methyl- amino)-bicyclo[2.2.1]hept-2-yl ester

SV - A solution of 4-hydroxy/methoxy-114-zansene-4-carboxylic acid mg; 774 mmol) and (- AY) methylamino-bicyclo[1,7,7] hept-7-yl-ester mmol) and triethylamine (110 μL 0.905 » mg Tou ) where -1- bromo-but 0 h at VA mmol) in acetonitrile (1 mL) in a sealed tube heated for 0.960 F. 0 °C silica The solvent was removed and the residue was purified by flash chromatography on silica gel Purified laboratory - The compound DCM was dissolved in methanol Methanol 7 +0 - 0 using molar hydrochloric acid gel (1 ml) and was stirred for a period of 1 and (lle 1) THF produced in the ve. hours and then evaporated into rubber. (aqueous) NaHCO3 and DCM the residue was partitioned between the The organic layers were collected and dried using 8504/14 and the solvent was removed to give .(717) mg of the compound entitled as a rubber material VY NMR 0

14 'H NMR (real) 400 MHz): 000.59-0.75 (2 H, m), 0.79-0.91 (1 H, m), 1.23-1.38 (1

H, m), 1.50-1.65 (1 H, m), 1.70-1.92 (2 H, m), 1.94-2.00 (1 H, m), 2.08 (3 H, s), 2.18- 2.30 (4 H, m), 2.47-2.55 (2 H, m), 4.75-4.83 (1 H, m), 4.90 (1 H, s), 7.10-7.22 (4 H, m), 7.31-7.40 (2 H, m) , 7.48-7.55 (2 H, m).

P N

~ ® 0.9

N 0 0n © [=] : (0 c. anti-(1S.2R)-9-Hydroxy-9H-xanthene-9-carboxylic acid 7-[methyl-(4-pyrimidin-5-) yl-but-3-ynyl)-amino]-bicyclo[2.2.1]hept-2-yl ester zansine -4-carboxylic acid -7- (but-3?- - H 4- a solution of -4 Hydroxychloroquine mg -* 065 mM (YY) hept-7-yl ester [0,7,7] [benyl-methyl-amino) bi-cyclo 0 0.003 bromopyrimidine (10 mg - 20997 mmol) ) and cupryodide (7 mg; -© (Use ml) was liberated from the gas by 1 (mL) acetonitrile (1 mmol) in triethylamine (cgay) after that it was added and then sealed a Argon plasma Tetrix (no mg-cl mmol) for a period of time; Hours was done gia 0 degree © and freed from gas using argon - the reaction was heated at 1485804 and washed with water and dried by DCM The solvent was removed and the residue was dissolved in a ve silica gel solution The solvent was removed The residue was purified By flash chromatography on silica gel 11 mg of compound 11 as a purifying agent to give DCM in methanol 71-0 using labeled as a rubber solid

LC-MS (Mehtod2) : RT 2.28 Min, m\z 407 {[MH+] : Ex. M21 00

Yoo anti-(1S,2R)-Hydroxy-di-thiophen-2-yl-acetic acid 7-{methyl-[3-(3-methyl-[1,2.4]oxadiazol-5-yl)-propyl]-amino }-bicyclo[2.2.1]hept-2-yl ester <3 Br

P(A) compound 0 a. 5-(3-Bromo-propyl)-3-methyl-[1,2,4]oxadiazole (Use mg - 14.0 mM VAL) A solution was formed > (N-Hydroxyacetamdine mM) Sodium was added hydride (0.0 mg of 7160 in oil (Yi) THF in a solution of (--mol) in parts, then the mixture was stirred at room temperature for an hour. Ale (1.6-mmol) was done. Strain and grow the mixture. The mixture was heated at 1.6 - 1 mL (A) ethyl -;- bromo-butyrate at 0°C for ½ hours and the reaction was allowed to reach room temperature - 0 mL was irrigated) and extracted 001 (The mixture was carefully diluted with aqueous ammonium chloride solution, then diluted with water (ml) 001 XY) with ethyl acetate. The accompanying organic materials were dried by means of sodium sulfate, filtered, and evaporated. gel for silica gel Isco companion column Residue purification over 10 minutes in cyclohexane ethyl acetate 2001-1 from Gradient by calibration

CY - mg YY) to give the labeled compound as a pale yellow oil. NMR "TH NMR (CDCls, 400 MHz): 002.34-2.41 (5 H, m), 3.06 (211 1), 3.52 (2) H, 1).

ENN B A$ 6 OH 0 Š / (22A) anti-(1S.2R)-[2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo [2.2.1]hept-7-yl]- dimethyl[3(3-methyl-1,2.4-oxadiazol-5-yl)-propyl]-ammonium bromide

N-o Br / ble ~~ AON __

A Ye

Oh, o what. -hydroxy-di-thiophen-7-yl-acetic acid-7-(methyl(1S-2R)you[©-(©-methyl-[1,1,7]-ocadiazole -*-yl) propyl]-amino)-bicyclo[YY]hept-7-yl ester was reacted with methyl bromide (2-Benzyloxy-ethyl)-[2-(cyclopentyl-hydroxy-phenyl-methyl)-thiazol-5 -ylmethyl]-dimethyl-ammonium ~~ bromide. ~ (from first to the one in Example 18 to give the compound entitled ales using enantiomer methods) | 0 white solid compress. 'H NMR (d6-DMSO, 400 MHz) Na 1.02 (1 H, dd), 1.32-1.40 (1 H, m), 1.64-1.78 (2 H, m), 1.91-2.01 (1 H, m), 2.18-2.23 (3 H, m), 2.31 (3 H, 5), 2.67 (1 H, m), 2.95-3.00 (3 H, m), 3.08 3 H, s), 3.09 3 H, s), 3.42-3.49 2 H, m), 3.57 (1 H, 5), 4.99-5.04 (1 H, m), 0 7.00-7.02 (2 H, m), 7.09-7.11 (2 H, m), 7.39 (1 H, 5), 7.48-7.52 (2 H, m). biological examples

10 The inhibitory effects of the compounds of this invention on 143 mental receptors (in the case of an example: the parietal receptors (of the parietal gland) and were determined by the following related articles B2 and 61): Muscarinic ligation [muscarinic receptors - Y] H])-N-methylscobalamine Y[H] Radio logand hinding studies use human Muscarinic and adjacent cell membranes expressing muscle receptors (NMS©).

M3, muscarinic antagonists are used to assess the susceptibility of receptor antagonists (M3, MC). 2

NMS in 47- enriched dishes with [11]? TRIS membranes that were found in buffer and anti-143 were incubated at different concentrations for ? The clocks of the radioactive membranes and ligaments are done. 0 . After that, they were harvested by filtration and allowed to dry overnight. Ye After that, the bound radioactive ligands were counted using scintillation. The liquid of AS was added - half-life of antigens at Canberra Packard top count scintillation counter and acclimated [ H3] — QNB measured using the radioligand reciprocal muscarinic receptors. On the previous susceptibility, the ki is higher than (Fold higher Y=) The antigens were incubated (cultivated) for ¥ hours at a concentration of human Muscarinic Vo. All receptors appear with membranes [H3] - QNB As specified with an association. At the end of this time for the kd acceptor (Fold higher Yo-) to a concentration of [113] - QNB membranes, 1081 min was added to the 15 that was studied and the incubation continued. For several periods of time, the bound radionuclides were then harvested by filtration and allowed to dry 0 overnight.

018

The scintillation liquid was then added and the radioligand bound was counted using the Canberra Packard topcount sciotillation counter.

The rate at which [H3]-QNB was known to bind to the muscarinic J 65 receptors is close to the rate at which the antibody degrades from the receptors.

.antagonists on the receptors © : Results oe

14 Forgive

Yo

NT 3 yi yy: In the previous table, the estimator is 143 on the correlation (values 161), indicated as follows: 1 + 1 01 g greater than 1 01 4 ++ -1 nm +++ 1 g less than

Suva nM is less than af. All tested compounds showed

NT= Not tested Obtained on VA nm for ki As another explanation for this invention, binding capacity °

A, for example, 1.70 nM va, for example: and the adrenal adrenal adrenergic radiological bonding. B Testing iodocyanopendulol receptors and membranes = [17© 1] Radiological bonding studies using . Human adrenergic EVA cellular receptors displaying 32 adrenoceptors.

B2 iodocyanopendulol and anti [VY] then incubated with SPA- BEADS for membranes and J Ve

Tris bufler at different concentrations for a period of time? Hours at local temperature in the wallac, the test in 97 pustular dishes, which is read using the (shal), a microbeta counter was made. In this test, 001 nM is less than 11: it displays the value of 41 examples.

Analysis of Inhibition of AL-143 Receptor Activity CHO cells expressing human L3 receptors were collected and incubated overnight in 46 collagen-coated umbilical plates (black wall - pure bottom) at density 0005©/VO μl of medium in 77 from plasma. The following days, the calcium-sensitive formulation (Beal) calcium fraction (cat #r Ave©) was prepared in HBSS buffer with the addition of 41 Pronecid (Aquarium pH 4,). An equal volume of the formulation (VO) solution (μL) was added. into cells and was incubated for 0©; minutes, followed by the addition of 0 © μl of anti-Muscarinic. After 10 minutes, the plate was read on Flexstation TM (excitation £AA nano jie release ovo nanometer) for 15 seconds to determine the main fluorescence line, then muscarinic agonist carbachol 0 was added. at E YA+ . The concentration and fluorescence that was measured for 0 sec. The signal was calculated by subtracting (Ail) of the response from the average of the main line of fluorescence in the control well in the absence of the antigen - the percentage of the maximum response in the presence of the antigen was then calculated to produce Kraft [50]. The inhibitory effect of the compounds of this invention on the muscarinic M3 receptors can develop 0 in the ex-viva and the following invivo tests: Evolution in the ability and time (period) to work in a pig cast and isolate: the experiments were done At TV °C in a solution of krebs-hanseieit evolving (variable) - VY E nM sodium chloride and 15814 sodium bicarbonate (magnesium sulfate, 0.7 calcium chloride, £,Y potassium chloride And 11.0 glucose and kh2pod 0.7 pH (V, 0) gas was placed by 755 Jo oxygen carbon dioxide Cop Indomethacin was added to the final concentration of ? micro meter.

Vig dunkin harhey cuinea pigs 8 trachea were removed from a young male from . Dissected free from adhesive tissue before opening longitudinally in an anticline, individual strips of 7-7 rings of cartilage crosswise were cut and suspended using a force transducer in a water bath and attached to 01 mm. Cotton thread in. Two platinum electrodes © ) MP 100 w\a ckowledge data acquisition system Response was recorded by . PC attached to the tape was neutralized for an hour under stable pressure (tone) body, after which it was subjected to a monopolar pulse (ms +,)) with pulses intended for Jim Av stimulation electric field at a frequency It was prepared for each tissue, and then each piece was sheathed with voltage-response, and a 0 curve was alerted every minute according to the response of each piece to the intensity of the current. The submaximal boltage of the tissue was washed with water. with Krebs' solution and allowed to settle under a stimulus before adding the test compound Concentration response curves were obtained from the cumulative addition of the test compound half — log quantities - Once the response for each addition reaches the peak of the curve, the other addition is made vo The catalyst was calculated for each concentration of each compound that was added and the EFS curves for the percentage of inhibition of contractility were calculated for each Eco and grophpad prism software dose response were constructed using . A compound that has been identified by Eco Studies on the event period has been conducted by adding a concentration of . (Degree of stability) Plateau contracture and response until it reaches the EFS of the compound to tissue 0 . onset time The time required to reach 756 of this response is determined to be all

YVY1

The tissues were then washed to become ox from the compounds by ales Flushing the tissue with freshly prepared Krebsey's solution and the time required for the contraction process in response to EFS to return to 7500 after the response that was measured in Ala and the presence of this compound Bimi the event duration on the example in this combined test for the example Yo has nM 1.8 Eco and the event duration is +08 min. ° appropriate to explain this invention is an example Cus ca that the binding capacity of ki is 57 nM obtained against the MY receptor together with the 16 500 whose value is 1,8 014 in an isolated trachea of a pig Giuinea. Methacholine stimulation of Broncho formation in tissue: Givinea pigs, male, Dunkin Hartley (weighing 00 to 00 aba), reared in 0 groups, each group © pigs, where they are identified individually. The animals are allowed to acclimate to The surrounding environment for at least a period of days during this cl and study the time allowed the animals to take an increase in water and food adlibitum Giuinea pigs were anesthetized by inhaling the anesthetic halothane 75 the test compound was administered through the nose. Vo animals were placed in a heated area and allowed to recover before returning to their cages. After YE an hour after ingestion of Giuinea pigs, they are finally anesthetized with urethane (YO) micrograms / ml and ? ml/kg). At the point of surgical anesthesia - the jugular vein was diverted into a canal by 7:00 Wal was infused with heparinised saline (hpBS) 0 (mL) 01 uf for intravenous administration For methacholine - the trachea was exposed and changed by a rigid portex tube, and the pharynx was switched through the mouth to a flexible portex tube for feeding.

The breathing animal was connected to a hants MMS, UK pulmonometer, which consisted of an airflow (gaseous) and a pressure conductor. The trachea was connected to the gas facility and the 000018 of the pharynx was connected to the pressure connector. ° The nasopharyngeal canal was exposed to give the basic resistance between 07 emH = 0.1 20\mL\s. The baseline reading was recorded two minutes before intravenous ingestion of OS (Fo) 170 μg / kg lle / kg). The stimulated contraction was recorded at two minutes from the point of intravenous administration. The peak of 0 resistance and the area of resistance under the Auc gail were calculated by the devices during the two minutes of the recording time that was used for analysis. Effects of warming up the broncho of the tested compound. The results were obtained in this test for a compound, for example, Ye (= © f / μg / kg (Veh); hours before 01 (34011) μg / mg (VV). The stimulated beoncho contraction and the comparative compound tiotropium were recorded in Figure (1).

Claims (1)

Viv Claims: (I) The formula Wh A compound is a compound 1 -1 x z A 00 "re (NR) or an oxygen atom group where 8m is 33 oxygen + R? and hydrogen atom or halogen atom (C1-Ce-alkyl carbon) 33 1-4) is an alkyl R! ( i ) ; —7- or group 8; or group 7-7 -8 ; or a hydrogen atom group that is 53 hydrogen © -27- ; or a group ~Z-NR*-CO-R® ; or a group “2-00-0858; or a group NRR + phrase of a single pair » or alkyl (1-1 carbon) RP ; or 2-0011- group ; and COR' »” = attached to it is a nitrogen atom in which the nitrogen atom is Ci-Co- alkyl A; or carries a positive charge and attached quaternary nitrogen 4 is a heterocyclic alkyl ring nitrogen 83 together with nitrogen (<)0 or group 8; or hydrogen atom and 182 is 309 hydrogen heterocycloalkyl ring yy -; ~Z-CO-NR'R' group 2-7-8 ¢ group or ".2-828 group; or 1y group of ble 183 pair OR 8-:2-00-GROUP OR 2-0011-GROUP OR 2280-00-83 0+nitrogen atom in which the nitrogen atom is Ci-Cealkyl carbon (1-Y) single; or an alkyl 4′ with a positive charge attached to it is quaternary nitrogen 1; or a positive charge 4 together_with the nitrogen attached to them is a heterocycloalkyl ring 82 SR (c) ay 7-7-8; said ring is replaced by a 7-78 group; or a heterocycloalkyl ring yA group VIA; or ~“ZNR-CO-R®; or combination ~Z-CO-NR'R' ; or combination ~Z-NRR' or combination + 4 1-0) is a single pair; or alkyl RP; and Z-COH Series 2-0028; or a group of |, attached to which is a nitrogen atom (led to which Ci-Cealkyl carbon atom) yy ; or carries a positive charge quaternary nitrogen yy d 8 be one of the groups of formula 8; 5; ©; or .]” 2 la xlr moi 0” dw ® vo 0 m (a) (b) (© (d) 0 is the alkylene group (1-11 carbon) 106 and ala-”:© -© ; alkenylene (7-16 carbon) 2 1" ¢ Cp-Cyg-alkynylene group ( iS 53 1-7 or alkynylene (C,-Cis-alkenylene YA toXygen atom * ? | 7) form a bond or Oxygen atom aryl = fused - with alkyl «aryl The alkyl group (1-1 carbon atom) is atolmm©-.© ¢ aryl 85 T° aryl-fused- aryl fused - with heterocyclic alkyl 1 aryl-fused -cycloalkyl (12 carbon atoms) -:0-:0)aloe A=) aryl (¢ heteroaryl Jul 1 heterocycloalkyl A carbon atom) -(ole- and 0-©) + Cycloalkyl A=) (alkyl (heteroaryl ¢ alkyl) ¢ heterocycloalkyl group or cycloalkyl ve thydrogen atom or 353 hydrogen C1-Ce-alkyl forming an alkyl (1-1 atom) carbon) 86 TC; hydrogen or halogen C1-Ce-alkyl four being the alkyl group (1-1 carbon atom) T° or “+”; SPR being zero apart; m + 8 vv a R®© and 28 are independently selected from the group made up of aryls; aryl-fused-heterocycloalkyl lie » heteroaryl » alkyl (1-33,0 carbon) oleic-m0-0; cycloalkyl 1? 8# is OH; Jl (1-1 carbon atom) anole-m6-©; hydroxy -alkyl (1-1 "© carbon atom) ala-m©-,© ; nitrile; CONR™M group or hydrogen atom (thydrogen atom of RY) is alkyl-1) 83 carbon) anola-m0- or hydrogen atom 4 8 and 8" can independently form a hydrogen atom and an alkyl group (1-1 carbon) Ci- Ce-alkyl ~~ © » Ariel Jul ¢ aryl - heteroaryl + aryl cycloalkyl » aryl heteroaryl aia £1 ¢ aryl (alkyl) 1-6 carbon) Ci-Ce-alkyl or heteroaryl gy (alkyl 1-1 83 carbon) or bits - ©; or SR “l together with the nitrogen atom £4 attached to them form a heterocyclic ring with 4-8 atoms » containing lia £9 nitrogen atom or oxygen; or 2c the alkyl-1 (83 carbons) is Ci-Ce-alkyl or hydrogen atom ¢)© it is aryl - heteroaryl or cycloalkyl ¢ oY is independently aryl aryl » heteroaryl or cycloalkyl ; and “©” is a 33 oxygen CH,CHy, CH, 0 oxygen atom or a  Sot bond a pharmaceutically acceptable salt pharmaceutical acceptable salt —Y 1 is an A compound as mentioned in claim 1, where: A Y is an oxygen atom or an N(R” group 0 and p hydrogen atom is a carbon atom) ally-m©-,© or 53 hydrogen 1-1) lg is a 0” alkyl or hydrogen atom group is a hydrogen atom ¢ C;-Ce-alkyl carbon) 3 6-1 is an alkyl(3 nitrogen atom and 182) together with nitrogen R' or group 23200828 or ZYR® 0 0 ¢ heterocycloalkyl ring ila attached to them form an alkyl ring 1 50 and in this case the “+” C-Cealkyl carbon atom (1-1) of L8 is a lone pair or alkyl 0” bearing quaternary nitrogen attached to them is nitrogen atom nitrogen A And 83 together with the nitrogen attached to them R' or carries a positive charge q carbon) 83 1-1 be an alkyl R? and a heterocycloalkyl ring form a heterocycloalkyl ring 0 is tetrameric and carries a charge of nitrogen atom primordial -,©; in this case the nitrogen atom 11 ¢ carries a positive charge VY and i a is one of the groups of the formula 87 ay m5 ge 1 R® Ar * 8b Moi IF and 85 0 (a) (b) A= (carbon atom) or alkynylene (A=Y) carbon atom); Alkenylene AY) be the alkylene group 7 00 carbons); aryl is an aryl group 8 A “(C1-Cy-alkyl) carbon atom) 1-4 (la) heteroaryl or aryl heteroaryl aryl(C-Cy-alkyl)- 4thhydrogen atom or hydrogen atom ‎ Ci-Ce-alkyl carbon atom) 1-4 is an alkyl( 6 0 11971*T8 and P are independently an alkyl group (1-6 £5 carbon) the machine-M©-© or the halogen 0” thalogen YY CF; or 1 and © is independent of zero ; 8 7 ; Heteroaryl aryl and 18 are independently selected from the group composed of aryl, RE ve ¢ cycloalkyl cycloalkyl (Ci-Ce-alkyl carbon atom) 1-1) alkyl ¢ heteroaryl Yo; Hydroxyalkyl (1-1 C-Coralkyl atom carbon atom) 11-(to chelate “1 M OH” is a thydrogen atom or 3) hydroxy-C;-Ce-alkyl for the carbon) -1) an alkyl group ¢ hydrogen atom that independently forms a hydrogen atom. 83 1 1 carbon) we have 0-© or 33 1-6 alkyl ( ) heteroaryl or heteroaryl (C-Cs-alkyl carbon) A attached to them forming a nitrogen atom with the nitrogen atom LR? SR that v) nitrogen atoms » optionally contain 8) nitrogen AE in it from the heterocyclic ring and another 7 oxygen atom or oxygen atom YY hydrogen atom or 333 hydrogen ¢ C-Ce -alkyl carbon) 83 1-1 constitutes an alkyl (2 ve) or protection element? Where 8! is 1 as mentioned in the protection element A compound? R? hydrogen atom or ethyl methyl v . 711898!" or 7-7-8 group or hydrogen atom group ; methyl as mentioned in the claim ¥, where 1! is a methyl A compound =) Z- or a group Z-CO-NR°R! It is an R* group and a hydrogen atom or an ethyl hydrogen atom with you ,. 2-0011 or combination 1187-08 Y a 1©— A compound as stated in the claim “or claimant; Where 83 is methyl Jie ¥ so that the nitrogen atom connected to them is quaternary nitrogen v and carries a positive charge 1 +- A compound as mentioned in the claim. 1 or alc protection A R! Cus , P or Y L RZ together with the nitrogen atom attached to them form a monocyclic heterocyclic ring ¥ with 1 UY cyclic atoms where the heterocyclic atoms are ¢ nitrogen .hetero -atom(s) are nitrogen =V 1 A compound as mentioned in claim © where R , 83 or RL RY together with the Y nitrogen attached to them form an azetidine ring azetidinyl » piperidinyl and "| piperazinyl and N -_methylpiperazinyl or pyrrolidinyl .pyrrolidinyl ¢ —A 1 WS A compound mentioned in claim > or claim V where the nitrogen atom attached to H,83 or A,82 is a quaternary nitrogen nitrogen ¥ and carries a positive charge. Arr has been reported for 7; the 2 Ikon 6-(yl©) Jase optionally up to three carbon atoms in the chain by means of methyl 8. sy 1 bond or -0- and v p is methyl « ethyl ; n- or isopropyl « A n-butyl; secondary butyl or butyl 38 n-, sec- or tertbutyl « or 1-phenyl ; 7 ¢ 4 — methylenedioxyphenyl €,Y ¢ 3,4-methylenedioxyphenyl ethylene 0-deoxyphenyl 4-ethylenedioxyphenyl 3 » Ro-benzofuryl dehydride 3,4-methylenedioxyphenyl, ¢3,4-ethylenedioxyphenyl, dihydrobenzofuranyl, “1 naphthyl 0 VY pyridyl – pyrrolyl; pyrimidinyl » + oxazolyl; “isoxazolyl » benzisoxazolyl » benzoxazolyl + thiazolyl « benzthiazolyl » quinolyl ¢ thienyl +- benzthienyl Jab 0 - furyl » benzfuryl ¢ imidazolyl ¢ 1 benzimidazolyl + isothiazolyl ¢ benzisothiazolyl — 'V - « pyrazolyl » isothiazolyl » triazolyl 0 YA benztriazolyl » thiadiazolyl ¢ oxadiazolyl « M0 pyridazinyl » triazinyl ; indolyl or indazolyl or 0-aryl alkyl Cus arylalkyl that the aryl part is phenyl 1” + phenyl = methylene 7-deoxyphenyl “YY” 3 4-methylenedioxyphenyl ?- ethylenedioxyphenyl-3,4 SD ' 3,4-ethylenedioxyphenyl ethylenedioxyphenyl vy dihydrobenzofuranyl "" or naphthyl; and the alkyl moiety (1-3 carbon atoms) is Ci-Ce-alkyl “!| is CH” or ¢—CH,CH, or Ni Yo aryl alkyl Cus heteroarylalkyl that the heteroarylalkyl aryl part is pyridyl g pyridyl « pyrrolyl ¢ pyrimidinyl » oxazolyl « isoxazolyl b » benzisoxazolyl « benzoxazolyl ¢ benzthiazolyl m benzthiazolyl » quinolyl ; thienyl Jil ¢ benzthienyl » furyl ¢ and benzfuryl ¢ imidazolyl » benzimidazolyl » benzimidazolyl » isothiazolyl m isothiazolyl » benzisothiazolyl » pyrazolyl » isothiazolyl » triazolyl Yell pm triazolyl ¢ benztriazolyl ¢ thiadiazolyl  oxadiazolyl “oy pyridazinyl” triazinyl  indolyl  any indazolyl  m and where of a part The alkyl (1-1 carbon) primary -m©-,© is —CH, or CH,CH, ; Or ve indanyl or 1 + 7 + ? ¢ 4- ely 1,2,3,4-tetrahydronaphthalenyl 1,2,3,4-tetrahydronaphthalenyl ¢ 0 om heterocycloalkyl group (1-3-alkyl carbon) an-m©-,©; where ry the heterocycloalkyl part is azetidinyl ¢ piperidinyl mm piperidingl ; piperazinyl; piperazinyl substituted with nitrogen ¢ eg methylpiperazinyl tetrahydropyrrolyl The -1 alkyl moiety (1m C) C-Coalkyl is —CHy- or -CH ,CH, + or b cyclopropyl « cyclobutyl ; cyclopentyl or b-cyclohexyl; and + 187 and "l separately le for hydrogen; methyl" ethyl, + propyl, n- or isopropyl; Dla to phenyl - 7 4 — methylenedioxyphenyl 34-methylenedioxyphenyl ¢ 4,7 ethylene 0; 3,4-ethylenedioxyphenyl ¢ dihydrobenzofuranyl aldehyde » naphthyl gv or A pyridyl ¢ pyrrolyl ¢ pyrimidinyl ¢ oxazolyl » 4; isoxazolyl; benzisoxazolyl » benzoxazolyl o. + thiazolyl » benzthiazolyl » quinolyl + thienyl ; 1e benzthienyl Jilin ¢ furyl ; benzfuryl; imidazolyl; ox to 0 521201 .+ isothiazolyl + benzisothiazolyl ev — e pyrazolyl » isothiazolyl » triazolyl “of benztriazolyl » thiadiazolyl » oxadiazolyl ; De-pyridazinyl » triazinyl » indolyl or indazolyl or on arylalkyl where ek aryl is phenyl Jud + 7 ¢ 4- methylene ov dioxy «Yo 34-methylenedioxyphenyl Jud 4-ethylenedioxyphenyl -3,4 3,4-ethylenedioxyphenyl ethylenedioxyphenyl oA 'dihydrobenzofuranyl dihydrobenzofuranyl 4 » or naphthyl » and the alkyl part 1 -1 (carbon atom) Ci-Ce-alkyl 1. -CHp- is -CH,CH, ; R® and RY together with its attached +1 nitrogen atom form an azetidinyl ring “piperidinyl” piperazinyl + methyl “+ methylpiperazinyl substituted with nitrogen; pyrrolidinyl ring » morpholinyl 1; or thiomorpholinyl ring .-01 .1 compound M as mentioned in claim 1 or claim ?where in ¥ group 8283 NR ! “No methyl or ethyl no and 82 can be -27-7- group v and (SSR? methyl) so that the nitrogen connected to them is quadruple 'and carries a positive charge. 01 where D18 is phenyl or v-phenyl (alkyl( 6-1 83 carbon) phenyl(C,-Cs-alkyl « 7 is bond or -0- » Z- - v is a straight or branched alkylene radical that connects nitrogen and YR® with a ¢ chain up to 0 or Ja 4 carbon atoms VY carbon atoms A compound as Mentioned in any of the previous claims, where A is an oxygen atom. (NR group) - where 187 is methyl or ethyl or hydrogen atom .-064 1 A compound as mentioned in any of the previous claims where RY v be RC group, (a) be methyl or ethyl or a hydrogen atom Ar' “hydrogen atom ¢ phenyl be thienyl Jib ¢ phenyl ¢ cyclohexyl cyclohexyl cyclopentyl « cyclopropyl or cyclobutyl ¢ m R™ and R™ independently form “ethyl Jif” methyl propyl or isopropyl n-or isopropyl 0 ; butyl gale; secondary butyl and n-, sec- or tertbutyl JS ; fluoro « 7 chloro or bromo ; nog and © are independent of zero; 110 or XY 'VY 1- A compound as mentioned in any of claims 1 to 11 where RY x is group (i) and RY, + and can be independently selected from methyl methyl; ethyl propyl n ¢ is isopropyl alcohol; butyl gale; secondary butyl n- or isopropyl, n-, sec- , or tertbutyl ©¢ phenyl ; ¥ 46 -3,4-methylenedioxyphenyl ¢ ¥ + ?; pyridyl 0 pyridyl pyrrolid • isoxazolyl – oxazolyl – oxazolyl + pyrimidinyl pyrimidinyl » pyrrolyl – thiazolyl – benzoxazolyl – benzisoxazolyl – benzisoxazolyl 1; quinolyl ¢ benzthiazolyl benzthiazolyl vy “benzimidazolyl benzimidazolyl ¢ imidazolyl imidazolyl” benzfuryl benzfuryl “furyl furyl v ¢ pyrazolyl pyrazolyl +” benzisothiazolyl » isothiazolyl isothiazolyl ¢ thiadiazole yell « benztriazolyl benzotriazolyl + triazolyl triazolyl » isothiazolyl oo ¢ triazinyl triazinyl » pyridazinyl pyridazinyl » oxadiazolyl + » thiadiazolyl 1 46-tetra Yoo Ye 1 and indanyl July) ; indazolyl or indolyl indolyl vy; cyclopropyl 1,2,3,4-tetrahydronaphthalenyl hydronaphthalenyl A cyclohexyl cyclopentyl cyclobutyl 4 ethyl methyl methyl + hydrogen atom “ OH is R¥ 1 where CONRY, nitrile 010116 or the group “ methyl methyl + hydrogen atom 11 . hydrogen atom or hydrogen atom ethyl ethyl « methyl is a methyl RM that all yy RY where WY or © to 1 as mentioned in any of the claims A compound 11-ethyl; methyl may be independently selected from RY methyl; and “8 and (d) be the ¥ or butyl group n- or isopropyl, n-, sec normal propyl; isopropyl alcohol; ordinary butyl; secondary butyl of ¢ 3,4-methylenedioxyphenyl; -methylene dioxyphenyl 7 « phenyl ¢ tertbutyl ; Tert-Dihydrwenzofuranyl « 34-ethylenedioxyphenyl M “© 6;-ethylenedioxyphenylpyrimidinyl » pyrrolyl; pyridyl pyridyl naphthyl “dihydrobenzofuranyl — < benzoxazolyl + isoxazolyl oxazolyl A” + isoxazolyl “ pyrimidinyl 0 benzothiazolyl ¢ thiazolyl “ benzoxazolyl “ benzisoxazolyl A” furyl; furyl benzthienyl “thienyl” quinolyl quinolyl “benzthiazolyl 4-isothiazolyl” benzimidazolyl “imidazolyl”; imidazolyl benzfuryl 0 isothiazolyl » pyrazolyl pyrazolyl + benzisothiazolyl benzizothiazolyl » isothiazolyl 01 “ thiadiazolyl thiadiazolyl » benztriazolyl benzotriazolyl » triazolyl triazolyl » isothiazolyl 0 or indoly l Indolyl » triazinyl triazinyl » pyridazinyl; pyridazinyl oxadiazolyl oxadiazolyl 1 +” 1,2,3,4- 46-tetrahedranivalinyl 7 + Yo 1 and indanyl ; indanyl indazolyl ve bentyl + cyclobutyl ; cyclopropyl cyclobutyl tetrahydronaphthalenyl cyclopropyl D + OH ; 2 is cyclohexyl and cyclopentyl cyclohexyl yy; hydroxymethyl nitrile 1 ethyl ethyl » methyl ¢ hydrogen atom d or ethyl methyl » or group 0011859 where all 1859 is methyl » nitrile 0 . hydrogen atom 4 85 where 11 or claim 11 as mentioned in claim A compound 17-01. 011 be VA is a compound, A compound, as mentioned in sf from claims Ve to 11, where ([) both “L and R® have pyridyl optionally substituted ¢ oxazolyl” thiazolyl + + thienyl Juli “furyl” or phenyl; or (I) one of 12088 and R8b is an optionally substituted phenyl and JAY is a cyclopropyl ¢ cyclobutyl (Als; cyclopentyl or hexyl cyclohexyl ; or (ID), one of R® and R® is optionally substituted pyridyl « thienyl ¢ oxazolyl » thiazolyl ¢ 04-0 Compound A as mentioned in any of the claims 11 to 11 where each RV oe v and GRP ?- 2-thienyl or phenyl or One of “18 and RY is phenyl + and the other is ?”- 2-thienyl. 11 where 184 x is (C) group and R* is — OH; hydrogen atom ¢ methyl « + ethyl ¢ hydroxymethyl » Nitrile nitrile or CONRY group, where each “85 is a methyl (ethyl Ji) methyl or a chydrogen atom APS _is selected from Yoo phenyl 6;-methylene dioxyphenyl - 34 1 methylenedioxyphenyl 7 6 -ethylenedioxyphenyl 3,4-ethylenedioxyphenyl « dihydrobenzofuranyl dibhyd + naphthyl ¢ pyridyl + pyrrolyl 1 + pyrimidinyl + oxazolyl oxazolyl » isoxazolyl ¢ mouth 4 benzisoxazolyl ¢ benzoxazolyl « thiazolyl ; 0 benzthiazolyl « quinolyl ¢ thienyl ; benzthienyl « yy furyl ¢ benzfuryl ¢ imidazolyl ; benzimidazolyl « VY isothiazolyl ; benzisothiazolyl » pyrazolyl » yy isothiazolyl » triazolyl ; benztriazolyl » thiadiazolyl b » oxadiazolyl » pyridazinyl » triazinyl ; 1 indolyl or indazolyl ¢ cyclopropyl (Als “butyl Gils cyclobutyl 4’ cyclopentyl +6 and cyclohexyl; and 0 is between yy The two AF rings are CH, -0- Ar CH,CH; . -71 1 A compound, as mentioned in the claim Cus Ye, each AP ring forms a phenyl y ring. R¥ Cus 71 or the protection element Yo as mentioned in the protection element A compound - NY 1 . 011 be 1A has the formula 1 protection aie as mentioned in A compound —VY 1 YAN (ar (CHy), X Y \ \ 4 Y— (CH), N , ) 88 has Y R8b IA (IA) 1 1 Optionally substituted or monocyclic hetero-ring phenyl ring form phenyl ring A Where the ring is cyclic atoms or a combined heterocyclic alkyl ring system 1 of © or monocyclic heterocyclic ring : Cus phenyl-fused-heterocycloalkyl ring 'monocyclic heterocyclic ring sil' is a planall heterocycloalkyl ring A ¢ thienyl “phenyl” 5 or 6 ring atoms phenyl is phenyl 18. ¢ cyclohexyl or cyclohexyl cyclopentyl ils 0 a Yo) Ss ¢ cyclohexyl or cyclohexyl cyclopentyl ala pentyl “thienyl 6” or 7, provided that it is 8+4 not more than 0 9 4+7 +7 +1 ha A 1 is free pharmaceutically acceptable X- is a bond or -0- and 7 + 0 vy .anion 0 B Where the IB ring has formula 1 as mentioned in the claim A compound An optionally substituted 1-740 compound or a monocyclic heterocyclic phenyl ring A phenyl ring B Where the ring " or a ring Alkyl 5 or 6 ring atoms 1 of © or monocyclic heterocyclic ring © (CH), X- \ \ + Y— (CH), oN button 0 0 8 OH 0 V YAY -0-:?-?-?7-1 is 5 + phenyl-fused-heterocycloalky! ring heterocyclic combined with aryl oe is 57 Ve from stan provided that it is not 17 or 7 and + is + - 1-?”-”-;-e-+- or - . bond or -0-and “.” Pharmaceutically acceptable anion. Of the group consisting of 1, as mentioned in the claim, A compound - ? Bicyclo(?7 -methyl (©-phenoxy-propyl). " anti€2-(Biphenyl-2-ylcarbamoyloxy)bicyclo[2.2.1]hept-7-yl]-dimethyl-(3-phenoxy- propyl)- ammonium salts ( 18 + 28 )-7-(7-hydroxy-7;7-di-dimethyl-(*-phenyl-propyl)). 7-tpeh(1,1-acetoxy)-bicyclo(? antiq(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1 [hept-7-yl1]- ‎dim@thyl-(3-phenyl-propyl)-ammonium salts (+)-7-(7-hydroxy-7;7-di-thiophene-7-yl-) acetoxy)-0 0 hepten-7-yl)-dimethyl-(7-phenyl-propyl) (1 1 psi(? 11 anti'(%)-2-(2-Hydroxy-2,2) -di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1 ]hept-7-yl]- dimethyl-(3-phenyl-propyl)-ammonium salts VAY anionic ammonium salts -( 15 + 28 ) -7-(7-hydroxy-7 107-di-thiophene-7-yl-0-acetoxy)-bicyclo(7 1)hept-la-yl)-di Methyl-(©-phenoxy-propyl).0 anti¥(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept- 7-yl]-diméthyl-(3-phenoxy-propyl)-ammonium salts [ ( 15 ¢ 28 ) -7-(7-hydroxy-7;7-di-thiophene-7-yl-0A (hpt-la-yl)-dimethyl-phenethyl.1-acetoxy)-bicyclo(?0 anti¥[(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2- yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]- dim&thyl-phenethyl-ammonium salts ( )-7-(7-hydroxy-7-17-di-thiophene-7-yl-28 + 1S ) Ammonium salts anti-[YY (HPT-7a-yl)-dimethyl-(?-phenyl-butyl).1-acetoxy)-bicyclo(??vy antiY[{1$,2R)-2 -(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2,2. 1]hept-7-yl]- dim&thyl-(4-phenyl-butyl)-ammonium salts -7-yl-nevoith-yanth-71 7-iscorde-7(-7-)2R + 1S) [ Antagonist ammonium salts © . (HPT-7-yl)-trimethyl 1 1-acetoxy)-bicyclo(?TY antiYf1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)- bicyclo[2.2.1]hept-7-y1]-trimefhyl-ammonium salts SUEY (-7-(7-hydroxy-7 2R » 15) | (7-benzyloxy-ethyl)-antagonist © . (HPT-7-yl)-dimethyl 1 1-thiophene-7-yl-acetoxy(-bicyclo)? TY (2-Beenzyloxy-ethyl)-anti-[(1S,2R)-2-( 2-hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicy<Yo[2.2.1]hept-7-yl]-dimethyl-ammonium salts phenyl-acetoxy)- SEY Y= S008 Y (=Y) 2R + 15 (- anionic ammonium salts Te .methyl- (?-phenoxy-propyl) enanth-(li-1-tpeh) VY bicyclo(?To How much (2R) 2-(2-Hydroxy-2,2-diphenyl-acetoxy)-bicyclo[2.2.1]hept-7-yl]-dimethyl- ,15-(3-ph¥énoxy-propyl)- ammonium salts YA anti -(15 ¢ 28 )-dimethyl-(7-phenoxy-propyl)-[ 7-(4 11 -xanthine-™ 4-carbonyloxy)-bicyclo(?1 1) hept-7-yl). -ammonium salts "; 1 YY) fy (HPT-7-yl)-dimethyl-(3-phenoxy-propyl) anti{dS, 2R) 2-(9-Hydroxy-9H-xanthene-9-carbonyloxy)-bicyclo[2.2 .1]hept-7-yl]- diméthyl-(3-phenoxy-propyl)-ammonium salts 3d £1 anti-ammonium-[ ) 2R + 1S (-7-(7-hydroxy-7) 17-_di-thiophene-7-yl-EV acetoxy)-bicyclo(?1)hpt-no-yl)-indan-7-yl-dimethyl . anti{{1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept-7-yl]- indah2-yl- dimethyl-ammonium salts -Biscyclo (?(VY-HPT-7-yl)-dimethyl . (Besdylcarbamoyl-methyl)-anti-[(1S,2R)-2-(2-hydroxy-2,2-di-thiophen-2) -yl-acetoxy)- bicytYo[2.2.1]hept-7-yl]-dimethyl-ammonium salts of [ (7-(7 ye)-dihydro [f=(Jro= chisisdir -anti[)18 «—Y=(2R eo (7-hydroxyYe Yo di-thiophene-7-yl-acetoxy)-bicyclo(?1)1)hpt-7-yl )-dimethyl . YAO [2-(2)3-Dihydro-benzofuran-5-yl)-ethyl]-anti-[(1S,2R)-2-(2-hydroxy-2,2-di-thiophen-2-yl-aéetoxy )-bicyclo[2.2.1]hept-7-yl]-dimethyl-ammonium salts ; Which has an anti-salt of 1 as mentioned in claim No. A compound compound 1-717 Y) thiophene-7-yl-acetoxy) bicyclo SUEY (-7-(7-hydroxy-7) 28 + 1S) of the compound "anti-(1S,2R)-2-(2-Hydroxy-2,2- hept-la-yl)-dimethyl-(7-phenylpropyl)ammonium)1 1 |" ; di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]}hept-7-yl]-dimethyl-(3-phenoxy-propyl)- ammonium salt © or solvate or nitrogen oxide N-oxide thereof 1 derivative “78- A compound as mentioned in claim No. 1; which is an anti-salt of Compound (1S) « 28)-7-(7-hydroxy-?SEY thiophene-7-yl-acetoxy (bicycloYY) (VT hept-no-yl)-dimethyl-( ?-phenoxy-propyl)ammonium anti-(1S,2R)-2-(2- ; Hydroxy-2,2-di-thiophen-2-yl-acetoxy)-bicyclo[2.2.1]hept- 7-yl]-dimethyl-(3-phenoxy- propyl)-ammonium salt © or solvate or nitrogen oxide -N-oxide thereof (Fide 1 4?- A compound as Mentioned in claim No. 1; which Jia is an antisalt of Syd (1S) “« 28)-7-(7-hydroxy-7SEY thiophene-7-yl-acetoxy(bicyclo)7 1 (VY HPT-7-yl)-trimethyl-ammonium anti-[(1S,2R)-2-(2-Hydroxy-2,2-di-thiophen-2-yl- ?); acetoxy)-bicyclo[2.2.1]hept-7-yl]-trimethyl-ammonium salt or solvate or nitrogenous oxide derivative (N-oxide thereof =F) A compound as mentioned in claim 1; which represents an antisalt of "_ compound 1S)-28)-7-(7-hydroxy-?SEY phenyl-acetoxy(bicyclo(?1)1)hpt- anti-(1S, 2R) 2-2-Hydroxy-2,2- 7-yl)-dimethyl-(7-phenoxypropyl)ammonium ¥ diphenyl-acetoxy)-bicyclo[2.2.1]hept-7 -yl]-dimethyl-(3-phenoxy-propyl)-ammonium | ¢ -N-oxide thereof solvate or dissolved salt © —TY 1 A compound as mentioned in claim 1; Which Jig is an anti-salt of "compound (18 + 28)-7-(4-hydroxy-4 H-xanthine-4-carbonyloxy)-bicyclo (1)1-9" hept-la-yl)- Dimethyl-(7-phenoxy-propyl)-ammonium anti-(1S, 2R) 2-(9-Hydroxy-9H-; xanthene-9-carbonyloxy)-bicyclo[2.2.1]hept-7-yl ]-dimethyl-(3-phenoxy-propyl)- ammonium salt© or solvate or nitrogen oxide derivative -N-oxide thereof —FY 1 A compound as mentioned in any of the elements The previous protection was modified by replacing 17, group 82, with group 1-3, where L is a connecting root and 3 is a part that has activity ald ¥ adrenoreceptor agonist activity 82 . 1 7©- A compound, as mentioned in any of the preceding claims for use in treatment ¥. 1 4 “- pharmaceutical composition includes a compound as stated in any of the elements of protection 1 to YY and a pharmaceutically acceptable carrier or excipient ~Yo .1 pharmaceutical composition As stated in claim 9 ?YX in a form suitable for inhalation. no 1 ¥1- A combination comprising a compound as described in any of Claims 7 No. 7-1 and one or more anti-inflammatory agents; a bronchodilator, an antihistamine, a decongestant, or antitussive agents, where the aforementioned compound is as mentioned in any of © Claims No. 7-1 * The aforementioned lay agents exist in similar or different pharmaceutical formulations and may be taken separately or simultaneously. A combination Gilg -*7 1 according to claim No. 7, whereby the aforementioned combination includes “a compound as mentioned in any of claim No. 77-1 and an adrenaline-adrenergic agonist? -b2-adrenoreceptor agonist ¥ –¥A 1 | Compound as mentioned in any of the claims 1 to YY for use in the treatment of or prevention of a disease or condition in which the activity of the M3 muscarinic receptor is involved – F4 1 Compound, as mentioned in claim 1, where the disease or condition is a defect in the “respiratory-tract disorder.” 1 46- Compound, as mentioned in the claim FPA, where the disease or condition is a disorder of the “gastrointestinal-tract disorder.” CompoundeSye -; YAA —EY 1 WS Compound mentioned in claim YA where the disease or condition is chronic obstructive lung disease “condition is chronic obstructive lung disease” “chronic” asthma respiratory obstruction bronchial hyperactivity ¢ ¢ pulmonary fibrosis » pulmonary emphysema©; or allergic sinusitis .allergic rhinitis 1 7;- Compound as mentioned in the claim YA where the disease or condition is ¥ syndrome and condition is irritable bowel syndrome; gastric ulcers spasmodic colitis ¥ “duodenal ulcers” gastroduodenal ulcers gastrointestinal convulsions ~~ ¢ or hyperanakinesia spasms accompanied by diverticulitis pain in the smooth muscles of the gastrointestinal tract pain accompanying spasms urinary system disorders 1 Accompanying disorders including neurogenic bladder | urinary-tract disorders accompanying micturition disorders including neurogenic pollakiuria Vv; Involuntary urination Bodily bladder itself A Urinary incontinence associated with bladder contraction or chronic cystitis — characteristic of urination or pollakiuria 4 Seasickness and cardiovascular disorders vagalyinduced sinus bradycardia Jie « 1400;- WS Compound mentioned in protective element YA where the disease or Ala is vagally induced sinus bradycardia.