UA77301C2 - Tetrahydro-naphthalene derivatives - Google Patents

Abstract

This invention relates to tetrahydro-naphthalene derivatives and salts thereof which is useful as an active ingredient of pharmaceutical preparations. The tetrahydro-naphthalene derivatives of the present invention have an excellent activity as VR1 antagonist and useful for the prophylaxis and treatment of diseases associated with VR1 activity, in particular for the treatment of urge i urinary incontinence, overactive bladder, chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritic pain, neuralgia, neuropathies, algesia, nerve injury, ischaemia, neurodegeneration, stroke, incontinence, inflammatory disorders such as asthma and COPD.

Description

Description of the invention

The present invention relates to derivatives of hydroxytetrahydronaphthalenylurea, which are useful as an active ingredient in pharmaceutical formulations. Hydroxytetrahydronaphthalenylurea derivatives of the presented invention have the activity of vanilloid receptor (VR) antagonists and can be used for the prevention and treatment of diseases caused by the activity of VR, in particular, for the treatment of urinary incontinence, overactive bladder, chronic pain, neuropathic pain, postoperative pain, pain in rheumatoid arthritis, neuralgia, neuropathy, algesia nerve damage, ischemia, neurodegeneration, stroke, incontinence 70 or inflammatory disorders such as asthma and chronic obstructive pulmonary disease (COPD).

Urinary incontinence (UI) is the involuntary loss of urine. Urinary incontinence (US) is one of the most common types of urinary incontinence, along with stress urinary incontinence (SUI), which usually results from disorders of the urethral closure mechanism. NUS is often caused by neurological disorders or diseases that result in neuronal damage, such as dementia, Parkinson's disease, multiple sclerosis, stroke, and diabetes, although 12 individuals who do not have these disorders are common. One of the common causes of UBS is overactive bladder (OVB), which is a medical condition that refers to symptoms of frequency and urgency that originate from abnormal contraction and instability of the detrusor muscle.

Today, there are a number of medicines on the market for the treatment of urinary incontinence and mainly for the treatment of NUS. Therapy of NASM is focused on drugs that act on peripheral nervous control mechanisms or on drugs that act directly on the contraction of the smooth muscle of the bladder detrusor, with the main emphasis on the development of anticholinergic agents. These agents may inhibit the parasympathetic nerves that control bladder emptying or may cause a direct spasmolytic effect on the bladder detrusor muscle. This leads to a decrease in intravesical pressure, an increase in capacity and a decrease in the frequency of contractions of the bladder. with

Orally active anticholinergic drugs such as propantheline (ProBantin), tolterodine (He) tartrate (Detrol), and oxybutynin (Ditropan) are the most commonly prescribed drugs. However, their most serious drawback is unacceptable side effects such as dry mouth, visual disturbances, constipation and central nervous system disorders. These side effects lead to reduced enjoyment of use.

Dry mouth is responsible for 7,095 complaints when using oxybutynin. The inadequacy of the existing therapy reveals the need for new, effective, safe, orally available drugs with fewer side effects.

Vanilloid compounds are characterized by the presence of a vanillyl group or a functionally equivalent group. at

Examples of several vanilloid compounds or modulators of vanilloid receptors are vanillin cha (4-hydroxy-3-methoxybenzaldehyde), guaiacol (2-methoxyphenol), zingerone 3o (4-(4-hydroxy-3-methoxyphenyl)-2-butanone), eugenol ( 2-methoxy4-(2-propenyl)phenol) and capsaicin in (8-methyl-M-vanillyl-b-nonenamide).

Among other things, capsaicin, the main spicy ingredient in "hot" chili peppers, is a specific neurotoxin that desensitizes the C processes of afferent neurons. Capsaicin interacts with vanilloid receptors (VR), which are mainly expressed on cells of the dorsal root ganglion (DKG) or nerve endings of 70 afferent sensory fibers, including C-appendages of nerve endings. , gray N, 5Kippeg K, Kashtapp VE, Vazrasht AIiY, Oshiz 0: Te siopeid

Iz» sarzaisip geseriog ipiedgaez tiSrie raip-rgodisipuo vity. Meygop. 21:531-543, 1998). The VRI receptor was recently cloned |Saiegipa Mu, Zspitaspeg MA, Totipada M, Kozep TA, Iemipe 90, Ushiiv 0: Myshge 389:816-824, (1997)| and identified as a non-selective cation channel with six transmembrane domains that are structurally similar to the TKR (transient potential receptor) family of channels. and Binding of capsaicin to BP1 is allowed by sodium, calcium and possibly potassium ions to reduce their concentration gradients -I, which leads to initial depolarization and release of neurotransmitters from nerve endings.

VRI can therefore be considered as a molecular integrator of chemical and physical stimulation that causes neuronal signals in pathological conditions or diseases. aw! 20 In excess, there is direct and indirect evidence showing a relationship between VRI activity and diseases such as pain, ischemia, and inflammation (eg, MUO 99/00115 and 00/50387). In addition, BP1 has been shown to convert reflex signals generated in an overactive bladder by pathways that are damaged or abnormal spinal reflex pathways ): 36-52, 1997).Desensitization of 29 afferent nerves by depletion of neurotransmitters using BP agonists such as capsaicin,

GF) showed promising results in the treatment of bladder disorders caused by spinal cord damage and multiple sclerosis ((Maddi SA: ТПпегарециис роииепияИ ои сарздаисип-ИиКе о тоиестиев - Бицаиев ип апитаив apa pitapv. She Zsiepsev 51:1777-1781, 1992) and ( OeKidaeg OYU; Spapaigatapi M;.

Oazdiria R; MapRorre! N; Vaen !/; RoumleLeg Su: Ipigamevisa! sarzaiisip az a igeaitepi yTog geitasiogu deygivog 60 NureitepPehia: A atsai! sepieg vischau myp Iopd-gegt ToPouir. 9. Wow. 158:2087-2092, 1997)|.

It is expected that antagonism of the BP1 receptor will lead to the blocking of the release of neurotransmitters, which will lead to the prevention and treatment of conditions and diseases caused by the activity of BP1.

Therefore, it is expected that BP1 receptor antagonists can be used for the prevention and treatment of conditions and diseases including chronic pain, neuropathic pain, postoperative pain, rheumatoid arthritis pain, neuralgia, neuropathy, algesia, nerve damage, ischemia, neurodegeneration, stroke, incontinence,

inflammatory disorders such as asthma and COPD, urinary incontinence (UI) such as urge incontinence (UPI) and/or overactive bladder.

MO 00/50387 describes compounds having vanilloid agonist activity and represented by the general formula: pe

Ko zt: Shchi - 70 and sia; who t; E t lvt, zh u Z: ih t Yad ke de ya

Nd her SBYDYA not s Kegt koe siv de tn IV ok che

SHE; son of Same VO EE

Shi she shchi a s I g z au Ya She: i radu tota rn

With EM in which:

XP is an oxygen or sulfur atom;

AR is -MNSON»- or -CH»-;

BZ is substituted or unsubstituted C1-4 alkyl, or KU CO-; where

B2! is alkyl with 1-18 carbon atoms, alkenyl with 2-18 carbon atoms, or substituted or unsubstituted aryl with 6-10 carbon atoms;

RE? is hydrogen, alkyl with 1-6 carbon atoms, alkoxy with 1-6 carbon atoms, haloalkyl with 1-6 carbon atoms or a halogen atom;

KE: is hydrogen, alkyl with 1-4 carbon atoms, aminoalkyl, diacid monoester or A-alkyl acid; and (8) an asterisk 7" denotes a chiral carbon atom, and pharmaceutically acceptable salts thereof.

MO 2000/61581 describes amine derivatives represented by the general formula:

Gee and -

Zo Shi s o

From the village

Kisova

Eh I'm naked -

B tity ke Ne Soni wine g y. ethers

Ki zh za I i pl tsk V yat , " zva shrshe JHE o shoyai in 0 Kvi Z s NI Niit p tt SEP o shЖ re gЕ Z ! t 15 and F -

Be ev 0 J oon K-T,

Nreya zhe tey 7 te FOR what ach s skonn dk cho all is Bu p de this PC che Here i » sk: I the same

times

And i - nin: KE

Shi. pe; le "lava -I Already -I Ш in which o (KU E") represent (Р, РЕ), (СЕ», H) or (irg, iRg) o 20 as agents useful in the treatment of diabetes, hyperlipidemia, atherosclerosis and cancer

MO 00/75106 describes compounds represented by the general formula: - scan m psa ay y

I am ;

GF) tt yat che go aa because horror

I'm Ed. and so on

Don't know where DE ET is. 65 pr pd pa M in which 7 represents

SE wild melons WE DRINK t and tak dir: I V tt

Mk eat- even t. ve mya x kis VE toy

I am

- sa

Cat o i and what kind of juice ks tya I zy: x NI zhi vv oi ze - Y ze food; Shh!

In VE: where 290 is hydrogen, C..4" alkyl, C. i. cycloalkyl or similar, and KU! is amino-C. 6 alkyl, aminocarbonyl-C-6 alkyl or hydroxyaminocarbonyl C..6 alkyl; and

VO Her 1 is independently selected from the group containing H, C..6 alkyl, C4.6 alkylthio, C 6 alkoxy, fluorine, chlorine, bromine, iodine and nitro; which are useful agents in the treatment of MMP-mediated diseases in mammals.

MO 00/55152 describes the compounds represented by the general formula: с что (о) ой хх и зт : "m Vs vin z ЖЙ oral still A ж "-

Why not | "c) in which

Ag is a heterocycle; (ze)

Ago is tetrahydronaphthyl; and my O are as defined in this application; which are useful agents in the treatment of inflammation, immune-dependent diseases, pain and diabetes. uh-

However, none of these references describe simple derivatives of hydroxytetrahydronaphthalenylurea having antagonistic activity against BP1.

It is desirable to develop a compound that has effective antagonistic activity against BRI1 and can "be used for the prevention and treatment of diseases caused by the activity of BRI, in particular, for the treatment of urinary incontinence, urge incontinence, overactive bladder, as well as pain and/or - with inflammatory diseases, such as asthma and COPD. a This invention provides a hydroxytetrahydronaphthalene derivative of formula (I), its tautomeric and "» stereoisomeric form and its salts: which:

The same

ZE

- and WE. F I with: B MORE: y ry - weigh it

ОО шучка з о тен В; She

SI. i r i

Es NE I) Zh vit still -x still And still - in which 99 X represents S. in alkyl, la ee Y o U NI she ko SCHE By and and de dit vo vaj rn still in pri

AI." about Iv

Not y y ke- More TES M tya ss Z ІЙ t (incl. is u still dn ZK V so pn sna Ve o, sen na s Y a r va tya h . Uk de 65 U represents a simple connection,

M. Ki i ze zh a OO 2 PE zh y shir v zyh Uzh 2 I ikh she «s o

B", 2 and KZ independently represent hydrogen, halogen, hydroxy, nitro, carboxy, amino, C 4.6 70 alkylamino, di(C-.v alkyl)amino, C 3.1 cycloalkylamino, C 4.6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C4-6 alkanoyl, C4-6 alkanoylamino, carbamoyl, C4-6 alkylcarbamoyl, cyano, C4-6 alkyl, optionally substituted with cyano, C4-6 alkyloxycarbonyl or mono-, di- or tri-halogen, C.i.6 alkoxy, optionally substituted with mono-, di- or tri-halogen, phenoxy, optionally substituted with halogen or C 4.6 alkyl, or C 1-6 alkylthio, optionally substituted with mono-, di- or tri-halogen; 2", e5, 29 and B" independently represent hydrogen, C-6 alkyl or phenyl; and represent hydrogen or C-6 alkyl; and 72 represent hydrogen, halogen or C-6 alkyl .

Hydroxytetrahydronaphthalenylurea derivatives of formula (I), their tautomeric and stereoisomeric forms, and their salts unexpectedly show good antagonistic activity against BRI. Therefore, they are particularly suitable for the prevention and treatment of diseases caused by BP activity, in particular, for the treatment of urinary incontinence and/or overactive bladder.

Preferably, derivatives of hydroxytetrahydronaphthalenylurea of formula (I) are compounds in which

X represents a reason

ZD yaya , "A o is ShK - tzhE ee is Koka se same SCHI Z i Yan nn o "EE and t 0. BY un ie san e oj pe i. -- x nak ev y

Bya and o de Ge)

U represents a simple bond or its m. C.6 alkyl)amino, C3 cycloalkylamino, C6 alkoxycarbonyl, phenyl, benzyl, sulfonamide, C6 alkanoyl, C6 alkanoylamino, carbamoyl, C6 alkylcarbamoyl, cyano, C6 alkyl, neoob' optionally substituted by cyano, C4.6 alkyloxycarbonyl or mono-, di- or tri-halogen, C.i.6 alkoxy, optionally substituted by mono-, di- or tri-halogen, phenoxy, optionally substituted by halogen or C 4.65 alkyl, or C. 6 alkylthio, - optionally, substituted with mono-, di- or tri-halogen; -And B and 2? independently represent hydrogen or C. in alkyl; and sa 77172 each represents hydrogen.

In another embodiment, derivatives of hydroxytetrahydronaphthalenylurea of formula (I) can be compounds in which av! 20 X represents itself

He zorya KE zt Bya i zi ay schy NK Schy y rod sshrya chhe IN in Z shk di ten z At sy tv i B ny sykh kraihy

GF) Z Kene - ra Aeneas R I - and a frog: where where

U represents a simple connection or 60 lion that i yur i 65 B

B", 82 and BZ are independently hydrogen, halogen, di(C 4.6 alkyl)amino, C 4.6 cycloalkylamino, C 4.6 alkoxycarbonyl, C 1.6 alkyl, optionally substituted with cyano, C 45 alkoxycarbonyl or mono -, di- or tri-halogen, C.6 alkoxy, optionally substituted by mono-, di- or tri-halogen, phenoxy, optionally substituted by halogen or C. 5 alkyl, or C. 6 alkylthio, optional optionally substituted with mono-, di- or tri-halogen;

At 2? each represents hydrogen; and 71 77 each represents hydrogen.

In another embodiment, hydroxytetrahydronaphthalenylurea derivatives of formula (I) can be compounds in which

X is also a g. scheme of rotation Yake Kl p ko kV de

U represents a simple connection or ev shr, where p

B" and B? independently represent hydrogen, chlorine, bromine, fluorine, cyclopentylamino, trifluoromethyl or --(3 trifluoromethoxy;

VU, are you two? each represents hydrogen; and 77172 each represent hydrogen. "- zo In another embodiment, hydroxytetrahydronaphthalenylurea derivatives of formula (I) can be compounds in which

X represents o so y, I her- y. still vyya i ev MY, which PE xx "where 70 U represents a simple connection or as s m;" Well

IS

Because, oh, how IZHNE - and

Se -I (95) where at 20 V i 2? are independently hydrogen, chlorine, bromine, fluorine, cyclopentylamino, trifluoromethyl or trifluoromethoxy; - With VU, are you 2? each represents hydrogen; and 77172 each represent hydrogen.

More preferably, the mentioned hydroxytetrahydronaphthalenylurea derivative of formula (I) is selected from the group containing:

HF) IM-(4-chloro-3-"-trifluoromethyl)phenyl|-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea;

M-(3-chlorophent)-M'-(7-pdroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea; o IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-III-"trifluoromethyl)phenyl|urea;

IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(4-trifluoromethyl)phenyl|urea; 60 Ethyl. 3-((7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)amino|carbonyl)amino)benzoate;

M-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-"1-naphthyl)urea;

M-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-ME(2-naphthyl)urea;

IM-(3,4-dichlorophenyl)-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea;

IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(4-isopropylphenyl)urea; for IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(4-phenoxyphenyl)urea;

M-(4-chloro-3-"-trifluoromethyl)phenyl/|-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl|urea;

M-(4-chloro-3--trifluoromethyl)phenyl|-M'-K75)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl|urea;

IM-(4-chloro-3-trifluoromethyl)phenyl|-M'-K7K)-7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea;

IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-phenylurea;

M-(4-chlorophenyl)-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea;

IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(2-trifluoromethyl)phenyl|urea;

IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(4-trifluoromethyl)phenyl|urea;

IM-(3,4-dichlorophenyl)-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea; 70 IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(4-trifluoromethoxy)phenyl|urea;

IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-I4--trifluoromethoxy)benzyl|urea;

IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(2,4,6-trimethoxybenzyl)urea;

IM-(2,6-difluorobenzyl)-M'-(7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea;

M-K7PO-7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl|-M'-I4-"-trifluoromethyl)benzyl|urea;

M-K75)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl|-M'-I4-(trifluoromethyl)benzyl|urea;

M-K7PO-7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl|-M'-I4-"-trifluoromethoxy)benzyl|urea;

M-K75)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl|-M'-I4-"(trifluoromethoxy)benzyl|urea;

IM-(2-(4-chlorophenyl)ethyl|-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea; and

IM-III-fluoro-4-trifluoromethyl)benzyl|d-M'-(7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea.

In the context of the present invention, the substituents, unless otherwise indicated, usually have the following meanings:

Alkyl, by itself, and "alk" and "alkyl" in alkoxy, alkanoyl, alkylamino, alkylaminocarbonyl, alkylaminosulfonyl, alkylsulfonylamino, alkoxycarbonyl, alkoxycarbonylamino, and alkanoylamino represents a linear or branched alkyl radical having from 1 to 6, preferably from 1 up to 4 and especially preferably from 1 to 3 carbon atoms, which is illustratively and preferably methyl, ethyl, n-propyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxy is illustrative and preferably methoxy, ethoxy, n-propoxy, iso-propoxy, i) tert-butoxy, n-pentoxy and n-hexoxy.

Alkanoyl is illustratively and preferably acetyl and propanoyl.

Alkylamino is an alkylamino radical having one or two (independently selected) alkyl "-zo substituents, which illustratively and preferably represent methylamino, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamino, n-hexylamino, M ,M-dimethylamino, M,M-diethylamino, o

M-ethyl-M-methylamino, M-methyl-M-n-propylamino, M-isopropyl-M-n-propylamino, M-t-butyl-M-methylamino, c

M-ethyl-M-n-pentylamino and M-n-hexyl-M-methylamino.

Alkylaminocarbonyl or alkylcarbamoyl is an alkylaminocarbonyl radical having one y- or two (independently selected) alkyl substituents, which illustratively and preferably are y-methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, n-pentylaminocarbonyl, n- hexylaminocarbonyl, M,M-dimethylaminocarbonyl,

M,M-diethylaminocarbonyl, M-ethyl-M-methylaminocarbonyl, M-methyl-M-n-propylaminocarbonyl,

M-isopropyl-M-n-propylaminocarbonyl, /M-t-butyl-M-methylaminocarbonyl, M-ethyl-M-n-pentylaminocarbonyl |i «

M-n-texyl-M-methylaminocarbonyl. z c Alkoxycarbonyl is illustratively and preferably methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-pentoxycarbonyl and n-hexoxycarbonyl. ; » Alkoxycarbonylamino is illustratively and preferably methoxycarbonylamino, ethoxycarbonylamino, n-propoxycarbonylamino, isopropoxycarbonylamino, tert-butoxycarbonylamino, n-pentoxycarbonylamino and n-hexoxycarbonylamino. -Alkanoylamino is illustrative and preferably represents acetylamino and ethylcarbonylamino.

Cycloalkyl, by itself, and in cycloalkylamino and cycloalkylcarbonyl, is a cycloalkyl

Ш- a group having usually 3-8 and preferably 5-7 carbon atoms, which are illustrative and preferably represented by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Cycloalkylamino is a cycloalkylamino radical having one or two (independently selected) cycloalkyl substituents, which are illustratively and preferably cyclopropylamino, such as cyclobutylamino, cyclopentylamino, cyclohexylamino, and cycloheptylamino.

Halogen is fluorine, chlorine, bromine and iodine.

Preferably, the medicine of the present invention also contains one or more pharmaceutically acceptable carriers and/or excipients.

Hydroxytetrahydronaphthalenylurea derivatives of formula (I), their tautomeric and stereoisomeric forms and their salts (F) are effective in the treatment or prevention of diseases selected from the group consisting of urinary incontinence, overactive bladder, chronic pain, neuropathic pain, postoperative pain, pain in rheumatoid arthritis, neuralgia, neuropathy, algesia, nerve damage, ischemia, neurodegeneration and/or stroke, as well as inflammatory diseases such as asthma and COPD as well as diseases that also depend on BP activity.

The compounds are also used in the treatment and prevention of neuropathic pain, which is a form of pain that is often caused by shingles and postherpetic neuralgia, severe diabetic neuropathy, neuropathic low back pain, post-traumatic and postoperative neuralgia, neuralgia due to nerve entrapment and other neuralgias, phantom pain, complex regional pain syndrome, infectious or parainfectious neuropathy similar to that due to NTM infection, pain due to central nervous system disorders such as multiple sclerosis or Parkinson's disease or spinal cord injury or brain injury, and post-stroke pain.

In addition, the compounds are useful in the treatment of musculoskeletal pain, a form of pain often caused by osteoarthritis or rheumatoid arthritis or other forms of arthritis, and back pain.

In addition, the compounds are useful in the treatment of pain due to cancer, including visceral or neuropathic pain associated with pain or cancer treatment.

The compounds are also useful in the treatment of internal pain, for example, pain due to obstruction of internal organs such as gallstone colic, pain due to irritable bowel syndrome, pelvic pain, vulfodynia, orchialgia or prostatodynia.

The compounds are also useful in the treatment of pain due to inflammatory lesions of the joints, skin, muscles or nerves.

The compounds are useful in the treatment of orofacial pain and headache, such as migraine or tension-type headache.

Compounds of formula (I) of the presented invention can be, but are not limited to, obtained by methods of TSA,

ИБ, ИВИ, ИП, ИД, ЭЕ) or |ЕЙ, below. In some embodiments, one or more substituents such as an amino group, a carboxyl group, and a hydroxyl group of compounds used as starting materials or intermediates are preferably protected with a protecting group known to one skilled in the art.

Examples of protective groups are described in "Rgoiesime OSgocrz ip Ogdapis Zupipevziv (Zga Eaiiop)" by the editors

Steepe apa MUtsiv, dUopp Umieu apa Zopv, Mem Mogk 1999. ' honorary rn sch

Be b

BUT sk yo Ve so Mys: zhk ; what about

Met Sl. some I, and what Beck. Jan that ddKya and still I I and t ve t schi -- Zvee I melons and gr tygy'

A compound of formula (I) (where X, 77 and 77 are as defined above) can be prepared by reacting a compound of formula (II) (where 77 and 77 are as defined above) and isocyanate (II) (where X is such as it was - from 5 Defined above). Cha

The reaction can be carried out in a solvent, which is, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as M,M-dimethylformamide (DMF), M,M-dimethylacetamide (DMAC) and M-methylpyrrolidone (MMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); sulfoxides, such as dimethyl sulfoxide (DMSO); and stv) with others. Optionally, two or more solvents selected from the above list can be mixed and used. ;" The reaction can be carried out in the presence of an organic base such as pyridine or triethylamine.

The reaction temperature may, optionally, vary depending on the reacting compounds. The reaction temperature is usually, but not limited to, from about room temperature to 100°C. The reaction can and does occur during, as a rule, from 30 minutes to 48 hours and preferably from 1 to 24 hours.

The compound of formula (I) and isocyanate (I) are commercially available or can be obtained using known methods. at

VEINS ME with | z - y 7 seyy E and y shi . weight - pa her shk I yad "es" se: es ZV 7 uran se svv sho Z A vk: sect t I 000 her nt:

With ; - -- Those 60 MORE of them Vk it

A compound of formula (I) (wherein X, 77 and 77 are as defined above) can be prepared by reacting a compound of formula (II) (wherein 77 and 72 are as defined above) with phosgene, diphosgene, triphosgene, 1, 1-carbonyldiimidazole (KDI) or 1,1"-carbonyldi(1,2,4-triazole) (KDT), and subsequent addition to 65 of the reaction mixture of the compound of formula (IM) (where X is as defined above).

The reaction can be carried out in a solvent, which is, for example, halogenated hydrocarbons such as dichloromethane,

chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as M,M-dimethylformamide (DMF), M,M-dimethylacetamide (DMAC) and M-methylpyrrolidone (MMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); other. Optionally, two or more solvents selected from the above list can be mixed and used.

The reaction temperature may, optionally, vary depending on the reacting compounds. The reaction temperature is usually, but not limited to, from about 202 to 502C. The reaction can proceed for, as a rule, from 30 minutes to 10 hours and preferably from 1 to 24 hours. 70 Phosgene, diphosgene, triphosgene, KDI and KDT are commercially available and the compound of formula (IM) is commercially available or can be obtained using known techniques. Ше а ЗБШЯй still di

WITH.

NO, what did I say? ek t M n de iIKy VN i sia ply skh y No No

Yad I don't have wings, I'm a woman

DE I o mak ME sn en is ibn ifiki lez NA and ih i

WICKED, this time, I ate 2 more times

Ko i: B pn duv I de i i "I

The compound of formula (I) (where X, 77 and 77 are as defined above) can be obtained by reaction with 172 ! compounds of formula (II) (where 27 and 7- are as defined above) and compounds of formula (M) (where I 4 represents (o) a halogen atom such as chlorine, bromine or iodine) and subsequent addition to the reaction mixture compounds of formula (IM) (where X is as defined above).

The reaction can be carried out in a solvent, which is, for example, halogenated hydrocarbons, such as dichloromethane, «- 20 chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as (a) acetonitrile; amides such as M,M-dimethylformamide (DMF), M,M-dimethylacetamide (DMAC) and M-methylpyrrolidone c (MMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); other. Optionally, two or more solvents selected from the above list can be mixed and used. - with The reaction temperature may, optionally, vary depending on the reacting compounds. The temperature M of the reaction is usually, but not limited to, from about 309C to 12092C. The reaction can take place during, as a rule, from 1 hour to 48 hours and preferably from 2 to 24 hours.

The reaction can preferably be carried out in the presence of a base, which is, for example, organic amines, such as pyridine, triethylamine and M,M-diisopropylethylamine, dimethylaniline, diethylaniline, 4-dimethylaminopyridine and others. The compound of formula (M) is commercially available or can be prepared using known techniques. with

We are with NU asan. same

B NO: 5 tya ZONE YOU

BE Pevne ha same Be v n sel shk; And: SI and : - | ko ag S Z Ey 2 iya y v ke y -i mezh o TIY zykyh Ne U ziynvnya, sn NE shko y I E hek y KN sna - pe kh povi VN: sce Y rya GO: i g. SHE sieeini pelee-y ron she V Her - M Ir not. s: DYNY sia i ie 7 She neck dreams

These are the two MES

I spin two tek Y z y

GF) A compound of formula (I) (where X, 77 and 77 are as defined above) can be prepared by reacting a compound of formula (II) (where X is as defined above) with phosgene, diphosgene, triphosgene, ime) 1,1-carbonyldiimidazole (CDI) or 1,1"-carbonyldi(1,2,4-triazole) (CDT), and subsequent addition to the reaction mixture of the compound of formula (II) (where 77 and 77 are as determined above).

The reaction can be carried out in a solvent, which is, for example, halogenated hydrocarbons such as dichloromethane, chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as M,M-dimethylformamide (DMF), M,M-dimethylacetamide (DMAC), and M-methylpyrrolidone 65 (MMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); other. Optionally, two or more solvents selected from the above list can be mixed and used.

The reaction temperature may, optionally, vary depending on the reacting compounds. The reaction temperature is typically, but not limited to, from about 302°C to 100°C.

The reaction can proceed for, as a rule, from 30 minutes to 40 hours and preferably from 1 to 24 hours. Roma et o

Iov YN r y p: : to venu ME a: in "y N.. gu 5 shh

Nya nifhah ery sty DE: doeh ya ke sv Zhe x shchih BEK vka i: t po i v yah iye dishe SHE « Y : still z i a; t Shok koe Br.

I am not 7 and I pOshchichnokh Zovni, - and: In po nn deya kos syh ERI shk ee | 1 r pe i sa ey VX thing a. reaction in Bk Kk A men t : rn How : : Om k

A compound of formula (I) (where X, 77 and 77 are as defined above) can be obtained by reacting a compound of formula (IM) (where X is as defined above) and a compound of formula (M) (where I 4 represents itself a halogen atom, such as chlorine, bromine or iodine) and subsequent addition to the reaction mixture of a compound of formula (II) (where 7 and 72 are as defined above). c 29 The reaction can be carried out in a solvent, which is, for example, halogenated hydrocarbons, such as dichloromethane, he) chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; nitriles such as acetonitrile; amides such as M,M-dimethylformamide (DMF), M,M-dimethylacetamide (DMAC) and M-methylpyrrolidone (MMP); urea such as 1,3-dimethyl-2-imidazolidinone (DMI); other. Optionally, two or more solvents selected from the above list can be mixed and used. at

The reaction temperature may, optionally, vary depending on the reacting compounds. The reaction temperature is typically, but not limited to, from about 302°C to 120°C. and,

The reaction can proceed during, as a rule, from 1 hour to 48 hours and preferably from 2 to 24 hours. what

The reaction can preferably be carried out in the presence of a base, which is, for example, organic amines, such as 3o pyridine, triethylamine and M,M-diisopropylethylamine, dimethylaniline, diethylaniline, 4-dimethylaminopyridine and others. in - . a - and - and (95) (ав) -M ko bo b5

Masses 9 I: . ki seni nd nan in ZMK naya vla sud zhi pad NOT I I about Kg V rents

ME AS sleep not Y cy anti nya . pad cunning o DV zo khz N Ye pava recttk t tin pany Z eV ZOS I. and where ani so E Not y

Mshcha eV r SHOBY. tn 19 shk; I and and and her

M No Z riv your BZh a, outside: 1 6 I - I sit

WITH

; re. that 25 le

SAME sao ; van: still VE ee

I 3 Mr. SHE: yaho - .. she juices "-0Yk TE ni zhi sni zh zi s ele M s NE ery higher Me sne nya s - r pe 0 BEJ ! pc i |. Il,

DV ke schu Baeh ta -- ro ah

Her | "c) ace and so in: that kn

What's more - what's going on in U about Kant Z

ShK. with ah 2 "age

From I sh . ste a nd: i-

And we. Ba. DN Cheeks TI Beka s s zadnvh, V 5 v she PEJHO ssh

SHY Sho shi « ke PISK PEN tin Ya y

Bank still And I ZV ZIZ their and nn ket nny -

G Z x - y?

The compound of formula (I) (where X and 72 are as defined above) can be obtained by the following method;

In Stage E-1, a compound of formula (MII) (where X and 77 are as defined above) can be obtained by a method similar to that described in Method (A), (B), IVI, (GP or ID) to obtain compounds of formula (I) by -I using a compound of formula (MI) (wherein 77 is as defined above) instead of a compound of formula (II). c In Step E-2, a compound of formula (MI) (wherein X and 77 are as defined above) can be prepared via 5p by reacting a compound of formula (MII) (wherein X and 72 are as defined above) with an acid, such as (α) hydrochloric acid.

The reaction can be carried out in a solvent, which is, for example, halogenated hydrocarbons, such as dichloromethane, - chloroform and 1,2-dichloroethane; ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; alcohols such as methanol, ethanol; water and others. Optionally, two or more solvents selected from the above list can be mixed and used.

The reaction temperature may, optionally, vary depending on the reacting compounds. The temperature (F) of the reaction is usually, but not limited to, from about 202C to 1002C. The reaction can proceed for, as a rule, from 30 minutes to 10 hours and preferably from 1 to 24 hours.

In Step E-3, a compound of formula (I) (where X and 77 are as defined above) can be prepared by reacting a compound of formula (III) (where X and 77 are as defined above) with a reducing agent , such as sodium borohydride or lithium aluminum hydride.

The reaction can be carried out in a solvent, which is, for example, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aliphatic hydrocarbons such as n-hexane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; alcohols such as methanol, ethanol, 65 isopropanol and others. Optionally, two or more solvents selected from the above list can be mixed and used. The reaction temperature may, optionally, vary depending on the reacting compounds. The reaction temperature is usually, but not limited to, from about -202 to 502C. The reaction can proceed for, as a rule, from 30 minutes to 10 hours and preferably from 1 to 24 hours.

A compound of formula (I") (where X and 77 are as defined above and 77 is C6 alkyl) can be prepared by the following two-step process.

In Step E-4, a compound of formula (IX) (where X and 72 are as defined above and 7 is hydrogen or C 5 alkyl) can be prepared by reacting a compound of formula (MI!) (where X and 72 are as defined above) with a tri(C 1-6 alkyl)oxosulfonium salt such as trimethyloxosulfonium iodide.

The reaction can be carried out in a solvent, which is, for example, ethers such as diethyl ether, isopropyl 70 ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aliphatic hydrocarbons such as n-hexane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; other. Optionally, two or more solvents selected from the above list can be mixed and used.

The reaction temperature may, optionally, vary depending on the reacting compounds. The reaction temperature is usually, but not limited to, from about -2029 to 502C. The reaction can proceed for, as a rule, from 30 minutes to 10 hours and preferably from 1 to 24 hours.

In Step E-5, a compound of formula (I") (where X, 77 are as defined above and 7 is C1-6 alkyl) can be prepared by reacting a compound of formula (IX) (where X and 72 are as defined above and 73 is hydrogen or C 1-6 alkyl) with a reducing agent such as sodium borohydride or lithium aluminum hydride.

The reaction can be carried out in a solvent, which is, for example, ethers such as diethyl ether, isopropyl ether, dioxane and tetrahydrofuran (THF) and 1,2-dimethoxyethane; aliphatic hydrocarbons such as n-hexane, cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; other. Optionally, two or more solvents selected from the above list can be mixed and used.

The reaction temperature may, optionally, vary depending on the reacting compounds. The reaction temperature is usually, but not limited to, between about 202°C and 5090°C.

The reaction can proceed for, as a rule, from 30 minutes to 10 hours and preferably from 1 to 24 hours. at

The compound of formula (MI) is commercially available or can be prepared using known techniques.

Es nat

ZE chNi and more EK "- ke t (c) spi ZI what where and ik same vroda with Shi i, OO o two pek V I zal ak s pai pnrsma. she and the same Vye X s il TA clever and ol Ves Es zon Vajkd

The same is also E and t KS elenia visy x pen with still and h- 4: so se se sam In code 1: From she: Novykh s - Kk ZED: same neck with t that zoyam bach No

Pa) NO oh heh

UoOya shi Yad " pPiya - and aty "" U

YV

DE, : shk i tt KKU te miy v na ho EN 5 I - zvi te Y she YANA MV Language sch sh shi

JAK res in Noni district JAK "mouths of braids KZ ZY SHISHNA

TEI I ZT dnk sir vntya era eflbva Zheto v. as 1 that BUT he with M and Keszy made the rest of the face of the face I DE x M. Shck (95) but one thing Eh Z Ese

Ks And her EK poshi and she. SHNTNNyat Vo; ps ie v: -z s: SHY Zh

The stereoisomeric form of the compound (I), B form (I-4) (where X, 77 and 77 are as defined above) can be obtained by a method similar to that described in Method |AI, (B), IV), (GP or |D)| to obtain a compound of formula () by using a compound of formula (II-a) (where 7, 7 and 77 are as defined above) instead of a compound of formula (I).

The stereoisomeric form of compound (I), C form (1-a) (where X, 77 and 72 are as defined above) can be obtained by a method similar to that described in Method |AI, (BI, IVI, IGI or ID) for obtaining a compound of formula () by using a compound of formula (II-a) (wherein 7 and 77 are as defined above) instead of a compound of formula (I).

Compound (II-a) or (II-a") can be obtained using known methods. dB When the compound represented by formula (I) or its salt has an asymmetric atom in the structure, its optically active compounds and racemic mixtures are also included in the scope of the present invention.

Typical salts of the compound represented by formula (I) are salts obtained by the interaction of the compounds of the present invention with inorganic or organic acids or inorganic or organic bases. Such salts are known as acid additive and basic additive salts, respectively.

Acids that form acid addition salts include inorganic acids such as, but not limited to, sulfuric acid, phosphoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, and the like, and organic acids such as, but not limited to, p-toluenesulfonic acid acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid and the like. 70 Basic addition salts are salts derived from inorganic bases such as, without limitation, ammonium hydroxide, alkali metal hydroxide, alkaline earth metal hydroxides, carbonates and bicarbonates and the like, and organic bases such as, without limitation, ethanolamine , triethylamine, tris(hydroxymethyl)aminomethane and the like. Examples of inorganic bases are sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate and the like.

The compound of the present invention or its salt, depending on its substituents, can be modified to form lower alkyl esters or known other esters; and/or hydrates or other solvates. These esters, hydrates and solvates are included within the scope of the present invention.

The compounds of the present invention can be administered in the form of oral forms, such as, without limitation, normal and enteric coated tablets, capsules, pills, powders, granules, elixirs, tinctures, 20 solutions, suspensions, syrups, solid and liquid aerosols and emulsions. They may also be administered in parenteral forms such as, but not limited to, intravenous, intraperitoneal, subcutaneous, intramuscular, and similar forms well known to one of ordinary skill in the art. The compounds of the present invention can be administered intranasally by topical application of suitable intranasal solvents, or transdermally using transdermal delivery systems well known to one of ordinary skill in the art.

The dosage regimen using the compounds of the present invention is selected by one skilled in the art in consideration of i) various factors including, without limitation, the age, weight, gender and medical condition of the recipient, the complexity of the condition being treated, the route of administration, the metabolic rate and excretory functions of the recipient, used dosage form, individual compound and its used salt. Compounds of the present invention are preferably formulated immediately before administration together with one or more pharmaceutically acceptable excipients. Excipients include inert substances such as, but not limited to, carriers, diluents, flavors, sweeteners, lubricating agents, solubilizers, suspending agents, binding agents, disintegrants, and encapsulating material.

Another embodiment of the present invention is a pharmaceutical formulation containing a compound according to the invention and one or more pharmaceutically acceptable excipients that are compatible with other ingredients of the formulation and are not harmful to the recipient. Pharmaceutical formulations of the invention are obtained by combining a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically acceptable excipients. When preparing the compositions of the present invention, the active ingredient can be mixed with a diluent or included in a carrier, which can be in the form of a capsule, small bag, paper or other container. The carrier may act as a diluent, which may be a solid, semisolid, or liquid material that acts as a solvent, or may be in the form of tablets, pills, powders, etc. lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols, ointments containing, for example, up to 1Ovag. 95 active compounds, soft and hard gelatin capsules, suppositories, sterile solutions for injections and sterile packaged powders.

For oral administration, the active ingredient may be combined with an orally non-toxic and pharmaceutically acceptable carrier such as, without limitation, lactose, starch, sucrose, glucose, sodium carbonate, mannitol, sorbitol, calcium carbonate, calcium phosphate, calcium sulfate , methylcellulose and the like; together with, optionally, disintegrating agents such as, but not limited to, corn starch, methylcellulose, 2) agar, bentonite, xanthan gum, alginic acid, and the like; and, optionally, binding agents such as, without limitation, gelatin, natural sugars, beta-lactose, corn sweeteners, natural and synthetic resins, acacia, tragacanth, sodium alginate, carboxymethyl cellulose, polyethylene glycol, waxes and the like; and, optionally, lubricating agents such as, but not limited to, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.

In powder forms, the carrier may be a finely divided solid which is mixed with the finely divided active ingredient. The active ingredient can be mixed with a carrier having binding properties in suitable proportions and compressed into tablets of the desired shape and size. Powders and tablets

F) preferably contain from about 1 to about 99 percent by weight of the active ingredient and which are a new composition of the present invention. Suitable solid carriers are magnesium carboxymethyl cellulose, low-melting waxes and cocoa butter. Sterile liquid formulations are suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, a sterile organic solvent, or a mixture of sterile water and a sterile organic solvent.

The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions may be prepared by dispersing the finely ground active ingredient in an aqueous starch or sodium carboxymethylcellulose solution or in a suitable oil.

The formulation may be in unit dosage form, which is a physically discrete unit containing a unit dose suitable for administration to a human or other mammal. The unit dosage form may be a capsule or tablet, or a series of capsules or tablets. "Unit dose" is a predetermined amount of the active compound of the present invention, calculated to achieve the desired therapeutic effect, in combination with one or more excipients. The amount of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particularities of the treatment.

Typical oral dosages of the present invention, when used for the purposes indicated, will range from about 0.01 mg/kg/day to about 10 mg/kg/day, preferably from about 70 0.1 mg/kg/day to 30 mg/kg/day. day, and most preferably from about 0.5mg/kg/day to about 10mg/kg/day. In the case of parenteral administration, an amount of from about 0.001 to 100 mg/kg/day, preferably from 0.01 mg/kg/day to 1 mg/kg/day, is usually administered. The compounds of the present invention may be administered as a single daily dose or the total daily dose may be administered as divided doses, two, three or more times per day. When the release occurs using transdermal forms, the administration is continuous.

Examples

The present invention is described in the form of examples, but they should not be construed as limiting the present invention.

In the examples below, all quantitative data, unless otherwise indicated, refer to percentages by weight.

Mass spectra were recorded using electrospray (ES) ionization techniques (Misgotazz Riayogt IS).

Melting points were not adjusted. Liquid chromatography-mass spectroscopy (LC-MS) data were recorded on

Misgotazz Riayogt I!S with a Zpitadg2y Rpepotepeh 005 column (4.bmmehZOMmm) washing with a mixture of acetonitrile-water (9:1-1:9) at a flow rate of Timl/min. TLC was performed with silica gel plates (Merck silica gel 60 R-254). Silica gel (UMAKO-de! C-200 (75-150μm)) was used for all separations using column chromatography. All substances had a reagent degree of purification and were obtained from Zidt-Aiagisa, UUako p

Riga SNpetisai! Ipdyzigiev, Tsea., Tokuo Kagzei Koduo So. Tsa., Agsp Sogrogaiyop.

All starting materials are commercially available or can be obtained using the methods given in the literature.

The action of the presented compounds was investigated with the help of the following studies and pharmacological tests.

IMeasurement of capsaicin-induced influx of Ca 27 in the BRI-transfected human CHO cell line) "- (Study 1) (1) Creation of the БР1-CHO|со9aea human cell line o

cDNA of the human vanilloid receptor (LVR'I) was cloned from the library of axotomized ganglion of the spinal cord (UMO 00/29577). The cloned cDNA of lVRI1 was combined with the rsOMAZ vector and transfected with this construct into the cell line SNOichisOaeed. The cell line contains aequorin and SKE-luciferase reporter genes as readout signals. - Transfectants were cloned by limited dilution in the selected medium (OMEM/E12 medium ich- (Sirso VKI) supplemented with 1095 SET, 1.4 mM sodium pyruvate, 20 mM NEREB, 0.1595 sodium bicarbonate, 100U/ml penicillin, 1OOμg/ml streptomycin, 2MM glutamine, unimportant amino acids and 2 mg/ml 418). Inflow

Sa?! was studied on capsaicin-stimulated clones. Clones with a high response were selected and used for subsequent project experiments. VRI-SNOIShsOaed human cells were stored in the selected medium and passaged every 3-4 days at 1-2.5x10 cells/flask (75mm2). o) c (2) Measurement of Ca influx using ROZ 5-3000 z» VRI-SNOInsOaed human cells were suspended in a culture medium that was the same as the selected medium except (3418) and seeded at a density of 1000 cells per well in 384-well plates (black walls and transparent bottom/Mayide Mips Ipiegpaiopa!) After 48 hours, the medium in the cultures was replaced with 49 2 μM Bisho-3 AM (Moiiesciag Rgorevs) and 0.0295 Rygopis E-127 in test buffer (balanced saline and Hank's solution (HB55), 17mM NEREZ (pH 7.4), 1mM probenecid, 0.195 BSA) and the cells were incubated for 10 min at -I 2520. After washing twice with the test buffer, the cells were incubated with the test compound, this or solvent for 20 min at 252. The mobilization of cytoplasmic Ca was measured using

ROZ5-3000 (with ec 18vnm, lem 22Onm/Natataiyvy RPoipisv) for 10 seconds after stimulation of TONNM of capsaicin. ("in") 20 The integral K was calculated and compared with the control. shk IMeasurement of capsaicin-induced Ca influx in primary cultured rat spinal cord ganglion neurons) (Study 2) (1) Preparation of rat spinal cord ganglion neurons 5B Newborn Wistar rats (5-11 days old) were killed and dorsal root ganglion cells were removed ( Eyes were incubated with 0.195 trypsin (Sibso VKI) in RVO(-) (Sirso VKI) for ZOh at 3729, then

F) added half the volume of calf embryo serum (CET) and cells were precipitated by centrifugation. OKO ko neuronal cells were resuspended in Nat E12/5956 SET/5965 horse serum (Sirbso VKI) and dispersed by repeated pipetting and passed through a 7µm mesh (Rysop). The culture plate was incubated for 3 hours at 372C to remove contaminating Schwann cells. Non-adherent cells were recovered and further cultured in 384-well plates supplemented with laminin (Mips) at 1x10"cells/5µl/well for 2 days in the presence of 5ng/ml recombinant rat MORE (Zidta) and 5µM 5-fluorodeoxyuridine (Zidta). (2) Research mobilization of Sa?"

Cells of OKO neurons were washed twice with NVZ5 supplemented with 17 mM NEREBZ (pH 7.4) and 0.195 BSA. After 65 incubation with 2 μM Yano-ZAM (Moiiesshciag Rgorevs), 0.0295 PE127 (Sirso VKM) and 1 mM probenecid (Zidta) for 4 hours at 372C, the cells were washed 3 times. Cells were incubated with BRI antagonists or solvent

(dimethyl sulfoxide) and then with iM capsaicin in GOzZ5-6000 (x2k548Onm, Hem-92O0nm/Natataivy Roopisv).

Changes in fluorescence at 480 nm were monitored for 2.5 minutes. The integral K was calculated and compared with the control.

I Bath organ study to measure capsaicin-induced bladder contraction) (Study 3)

Male Wistar rats (10 weeks old) were anesthetized with ether and killed by neck torsion. The entire bladder was removed and an oxygen-containing modified Krebs-Henseleit solution (pH 7.4) with the following composition (112 mM Masi, 5.9 mM KSI, 1.2 mM Mdei", 1.2 mM Man»oRo, 2 mM Sasi", 2 ,5mM Manso", 12mM glucose). Bladder contractions were studied as previously described by Maddi SA ei ai: Vg.).Ripagtasoi. 108: 70 801-805, 1993). The isometric tension was recorded when the food was loaded using the longitudinal tapes of the detrusor muscle of the rat. Bubble tapes were equilibrated for 2 min before each stimulation.

The contraction response to the 80MM KSI was determined at 15-minute intervals until reproducible responses were obtained.

The response to KSI was used as an internal standard to estimate the maximal response to capsaicin.

The effect of the compounds was studied by incubating the strips with the compounds for 30 h before stimulation with μm 75 kcapsaicin (solvent: 8095 saline, 1096 EUN and 1095 Hmeep 80). One study was performed with the same animal and used as a control, while other animals were used to evaluate the compounds.

The ratio of each capsaicin-induced contraction to the internal standard (ie, KSI-induced contraction) was calculated and the effect of the test compounds on capsaicin-induced contraction was evaluated.

Measurement of Ca influx into P2X1-transfected human CHO cell line) (1) Preparation of P2X1-transfected human CHO cell line P2X1-transfected human CHO cell line was obtained and maintained in Dulbecco's medium modified with Needle (OMEM/E12) supplemented with 7,590 SET, 20MM HERE5 -KOH (pH 74), 1.4 mM sodium pyruvate, 100 U/ml penicillin, 100 ng/ml streptomycin, 2 mM glutamine (Sirso VKI) and 0.5 Units/ml apyrase (class I, Zidta). The suspended cells were seeded in each of wells of 384-well black clear-bottom plates (Maide Myps Ipiegpaiopa!) with 3x103/5µl/well. SM cells were cultured for an additional 48 hours before adhering to the plates. (5) (2) Measurement of intracellular levels of Ca?"

The P2X1 receptor agonist-mediated increase in Ca" levels in the cytosol was measured using the fluorescence of chelated Bicho-3 AM (Moiesciag Rgobe5) Ca". The cells attached to the plate were washed twice with washing buffer (HB55, 17 mM HERE8-KOH (pH 7.4), 0.195 BSA and 0.Bodynits/ml of apyrase) and (7) were incubated in 40 μl of supplemented buffer (1 μM Richo-3 AM, iM probenecid, 1 µM cyclosporin A, 0.0195 (BU Pluronic (MoiIesciag Rgobez) in wash buffer) for 1 hour in the dark. Plates were washed twice with 40 µL of wash buffer and 35 µL of wash buffer was added to each well with 5 µL of test compounds, i. or 2 ",3'-0o-(2,4,6-trinitrophenyl)adenosine-5'-triphosphate (Moiesciag Rgorevs) as a comparison. After the next incubation for 10 minutes in the dark, 200 nm of the agonist A,B-methyleneATP was added to initiate mobilization 30 s. Fluorescence intensity was measured using gO55-6000 - (boi MOnm, Hem?1Onm/Natataiyvy Rioyupisv) with 250 msec intervals. Calculated from the data integral ratio and compared with the control.

Measurement of Capsaicin-Induced Bladder Contraction in Anesthetized Rats) (Study 4) (1) Animals Female Sprague-Dawley rats (200-250g/Snagiez Rameg darap) were used. (2) Insertion of the implant Rats were anesthetized with intraperitoneal injection of urethane (Zidta) in the amount of 1.2 g/kg.

The abdomen was opened through a median incision and a polyethylene catheter (VESTOM BISKIMZOM, PE5O) was implanted into the bladder through the cap. In parallel, the inguinal area was cut and a catheter (Nibiki, size 5) filled with 2 IU/ml of heparin (Momo Neragip, Amepiiz Rpagta) in saline (Oyivika) was inserted into the common iliac artery. (3) Cystometric studies - The bladder catheter was connected through a T-tube to a pressure sensor (Middo-Zresigatei Rietza, OT-XXAO) and to a microinjection pump (TEKOMO). Saline was infused at room temperature into the bladder at a rate of 2.4 ml/h.

Intravesical pressure was recorded continuously on a tape recorder (UoKodauga). At least three reproducible micturition cycles, corresponding to 20-minute periods, were recorded before the administration of the compound under study and sk were used as baseline values. (4) Administration of test compounds and bladder stimulation with capsaicin The saline infusion was stopped before the administration of the compounds. The studied compound was dissolved in a mixture of ethanol, Tmeep 80 (ISM Vioteadisaiv Ips.) and saline 5B (1:1:8, o/0/0o) and was administered intraarterially in the amount of 1Omg/kg. 2 minutes after the introduction of the compound, 1 µg of capsaicin (Masaii Tezdce) dissolved in ethanol was injected intraarterially. (F) (5) Analysis of cystometric parameters based on the cystometric data, the relative increase in capsaicin-induced intravesical pressure was analyzed. Capsaicin-induced bladder pressure was compared with maximal bladder pressure 60 due to micturition without capsaicin stimulation. Compound-mediated inhibition of bladder pressure was evaluated using Student's i-test. A probability of less than 595 was taken as a significant difference.

IMeasurement of overactive bladder in anesthetized rats with cystitis) (Study 5) (1) Animals 65 Female Sprague-Dawley rats (200-250g/Snpagez Rameg darap) were used. Cyclophosphamide (SCHUR) dissolved in saline was administered intraperitoneally at a dose of 15 Ω/kg 48 hours before the experiment.

(2) Implant insertion

Rats were anesthetized with intraperitoneal injection of urethane (Zidta) in the amount of 1.25 g/kg.

The abdomen was opened through a median incision and a polyethylene catheter (VESTOM BISKIMZOM, PE5O) was implanted into the bladder through the cap. In parallel, the inguinal region was cut and a polyethylene catheter (VESTOM BISKIMZOM, RE5O) filled with saline (OizyKa) was inserted into the femoral vein. After emptying the bladder, the rats were left for 1 hour to recover from the operation. (3) Cystometric studies

The bladder catheter was connected through a T-tube to a pressure sensor (Middo-Zresigatedi Rietsa, OT-XXAV) and a 70 microinjection pump (TECOMO). Saline was infused at room temperature into the bladder at a rate of 3.bml/g for 20 minutes. Intravesical pressure was recorded continuously on a tape recorder (MoKodama). At least three reproducible micturition cycles corresponding to 20-minute periods were recorded before administration of the test compound. (4) Administration of test compounds

The studied compound was dissolved in a mixture of ethanol, Tmeep 80 (CM Vioteadisaiv Ips.) and saline (1:1:8, v/v/v) and was administered intravenously in the amount of 0.05 mg/kg, 0.5 mg/kg or Bbmg/kg . Saline (Masaiai Tezdpce) was infused through Zhv after the introduction of the compound into the bladder at a rate of 3.bml/g at room temperature. (5) Analysis of cystometric parameters

Cystometric analyzes were analyzed as previously described (essi A ei ai: Eytsg. 9). Rpaptosai 259: 129-135, 1994). The frequency of urination was calculated from the interval between urinations and the bladder capacity was calculated from the volume of infused saline before the first urination and analyzed from cytometric data. Test compound-mediated inhibition of micturition frequency and test compound-mediated increase in bladder capacity were assessed using unpaired Student's t-test.

A probability of less than 595 was taken as a significant difference. The data were analyzed as the mean SDR from 4-7 rats. high school

(Measurement of acute pain)

Mainly, acute pain was measured in rats on hot plates. Two options were used i) testing on hot plates. In the classic version, the animals were placed on a hot surface (52-56 2) and the latency time was measured until the moment when the animals show nociceptive behavior, such as stepping or licking paws. Another option is to increase the temperature of the hot plate, where experimental "-- animals were placed on a surface with a neutral temperature. Later, this surface was slowly, but not continuously, heated until the moment when the animals began to lick the hind paw. The temperature at which the animals began to lick the hind paw was measured to determine the pain threshold. co

The compounds were tested against a control fupa that was treated with a solvent. The introduction of the substance was carried out at different times with the help of different routes of administration (int.v., v.ch., p.0., i.t., V.PpP., P.Sh, -

Intradermal, transdermal) before pain testing. what

(Measurement of chronic pain)

Chronic pain was measured using the formalin or capsaicin test, mainly in rats.

A solution of 1-595 formalin or 10-100 μg of capsaicin was injected into the bandaged paw of the experimental animal.

After the introduction of formalin or capsaicin, animals show nociceptive reactions similar to shivering, licking and "biting" of the affected paw. The number of nociceptive reactions was measured within a time of up to 90 minutes hsh with determining the intensity of pain. and Compounds were tested against a solvent-treated control group. Introduction of substances and? performed at different times using different routes of administration (i.v., i.c., p.0., i.t., v.PpP., p.Sh, intradermal, transdermal) before the introduction of formalin or capsaicin.

IMeasurement of neuropathic pain) -I Neuropathic pain was induced by various variants of unilateral damage to the sciatic nerve, mainly in rats. The operation was performed under anesthesia. The first option is damage to the buttock

On the nerve, the application of compression bandages around the sciatic nerve (Veppei apa Hie, Raiip 33 (1988):

Ge) 87-107). The second option is a tight bandage around half the diameter of the sciatic nerve (Zei(7eg ei a!., Raip 43 (1990): 205-218). In the next option, a group of models is used in which tight bandages or transverse o cuts are made along either the I 5 or I 6 spinal nerves, or only across the I 5 spinal nerve (KIM ZN; SNOMO OM, - AM EHREKIMEMTASG-MOOEGY ROK REKIRNEKAG MEOKORATNU RKOVBIOSEO VU BESMEMTAYIG 5RIMAG MEKME

HYZATIOM in TNE KA, RATM 50 (3) (1992): 355-363). A fourth option involves axotomy of two of the three terminal branches of the sciatic nerve (the fibular and peroneal nerves) while leaving the fibular nerve intact, where the last option also involves axotomy of only the tibial branch and leaving the fibular and common nerves intact. Control animals are subjected to iF) sham operation. After surgery, an animal with damaged nerves develops chronic mechanical allodynia, cold allodynia, as well as thermal hyperalgesia. Mechanical allodynia is measured using a pressure sensor. Thermal hyperalgesia is measured using an infrared radiation source (Riapiag Tezi, Odo Vavziie, Sotegio, Mau), or using a cold plate 5-102C7, where the nocifensive reaction of the affected hind paw is counted, thereby determining the intensity of pain. In the following cold pain test, the nocifensive response or duration of 65 nocifensive responses to a plantar injection of acetone into the hind paw is counted. Usually, chronic pain is assessed by recording the activity of daily rhythms (Zy!igio and Atai, Opimegeiag 2y Koip, Soiodpe, (zeptapu), and by counting withdrawals during the course (oi rgipi racegpiz; EOOTRKIMTZ rgodgat, Kiardog ei aI., 1997. A Iom/ sovi teiioi (about apaiuze Tooirgipi racTsegpv. 9. Meshygovzsi. Meipodz 75, 49-54).

Compounds were tested against a solvent-treated control group. The introduction of the substance was carried out at different times using different routes of administration (IV, IV, PO, IT, V.P., P.Sh, intradermal, transdermal) before pain testing.

IMeasurement of inflammatory pain)

Basically, inflammatory pain was induced in rats by injecting 0.75 mg of tsafraginan or complete Freund's adjuvant into the hind paw. Animals developed edema with mechanical allodynia, as well as thermal 7/0 piperalgesia. Mechanical allodynia was measured using a pressure sensor

PTS Ips.-Yi be Zsiepse Ipsigitepiv, UUoodiapa Niiv, ZA, O5A). Thermal hyperalgesia was measured with the help of a source of ultraviolet radiation (Riapiag Tezvi Odo Vaziiye, Sogpegio, Mamu, Ramzhm/ Štegtai viitshi|ayog, o. Ogaki, Opimegeyu oi SaiIyogpia, OBA). Two methods were used to measure edema. In the first method, the animals were killed and the hind legs were sectioned and weighed. The second method involves measuring 7/5 of the paw volume difference using water displacement in plethysmometry (to Vavziye, Sotegio, Nash).

Compounds were tested against a solvent-treated control group. The substance was administered at different times using different routes of administration (i.v., i.c., p.0., i.t., v.p.p., p.sh., intradermal, transdermal) before pain testing.

(Measurement of diabetic neuropathic pain)

Rats were administered 50-8mg/kg of streptozotocin by one intraperitoneal injection, causing the development of severe hyperglycemia and mechanical allodynia for 1-3 weeks. Mechanical allodynia was measured using a pressure sensor (EIesigopis mop Egeu Apezipeziotegyeg, ETS Ips.-I Ge Zsiepse Ipvigitepiv, UUosai|agpa Niiyiv, BA, OA).

Compounds were tested against a solvent-treated control group. The introduction of the substance was carried out at different times using different routes of administration (IV, IV, PO, IT, VP, P.Shsh, SC Intradermal, transdermal) before pain testing.

IC results of capsaicin-induced Ca influx in BP1-transfected CHO human cell lines are shown in i9) in the Examples and Tables of Examples, below. The data correspond to compounds obtained using solid-phase synthesis and thus purity levels of approximately 40-9095. For practical purposes, compounds were grouped into four classes by activity, as follows: "-

ISvuo-A("or-)0.1 μM"B("or-)0.5μM "B("or-)1μMeH

The compounds of the present invention also show good selectivity and significant activity in other studies (2)-(5) described above. co

Methods of obtaining initial compounds: и What do you eat? eto - lk ate what dakavi i t sV still ate ";" KK lyh mr. To a stirred solution of 8-amino-2-naphthol (50.0 g, 31.4 mmol) in tetrahydrofuran (1000 mL) was added di-tert-butyl dicarbonate (68.6 g, 314 mmol). The mixture was stirred at 702C for 18 hours. After cooling the mixture to room temperature, the solvent was removed under reduced pressure. Ethyl acetate was added to the residue and the mixture was washed with a saturated aqueous solution of sodium carbonate and then with water. The extracted organic layer was dried over NaCl, filtered and concentrated under reduced pressure. Diisopropyl ether was added to the obtained residue and the precipitate was filtered and dried to obtain M-t-butoxycarbonyl-8-amino-2-naphthol (64.2 g, yield 7996)

MS (ESI) t/2 259|M and F) TN nNMR (DMSO-aub) 5 1.48 (r. 9H), 7.07 (dd, 9U-2.2Hz and 8.85Hz, 1H), 7, 20 (t, 9U-7.9Hz, 1H), 7.24 (d, ime) 3-2.2Hz, 1H), 7.36 (d, 9-7.25Hz, 1H), 7.60 (d , U-8.2Hz, 1H), 7.75 (d, U-8.8Hz, 1H), 8.92 (c, 1H).

Next, to a mixture of M-t-butoxycarbonyl-8-amino-2-naphthol (64.0 g, 247 mmol) and cesium carbonate (161 g, 49 mmol) in 30 ml of anhydrous DMF at room temperature was added iodethane (42.3 g, 272 mmol). The mixture was stirred at 6°C for 2 hours. Water was added to the mixture and the product was extracted with ethyl acetate.

The organic layer was washed with water and brine, dried over Ma»5O), filtered and concentrated under reduced pressure. Isopropyl ether was added to the resulting residue and the precipitate was collected and dried to obtain (7-ethoxynaphthalen-1-yl)carbamic acid t-butyl ester (47.9g, 67.595 yield). 65 MS (ESI) t/2 287 (MI "YAN NMR (DMSO-yv) 5 1.41 (T, U-6.95Hz, ZN), 1.50 (s, 9H), 4.16 (k, 9U-6.95HZ, 2H), 7.15 (dd, 9-2.55 and

8.8Hz, 1), 7.28 (t, U-8.8Hz, 1H), 7.36 (d, 9U-2.2Hz, 1H), 7.54 (d, 9U-7.25Hz, 1H ), 7.61 (d, U-8.2Hz, 1H), 7.80 (d, U-8.85Hz, 1H), 9.12(s, 1H).

Next, to (7-ethoxynaphthalen-1-yl)ucarbamic acid t-butyl ester (47.9g, 167mmol) in 100ml of anhydrous 1,4-dioxane was added 4M CARRIER in 1,4-dioxane (M/bOml) at 02С. The mixture was stirred at room temperature for 2 hours. Isopropyl ether was added to the reaction mixture and the precipitate was filtered. Saturated sodium bicarbonate was added to the obtained solid and the product was extracted with ethyl acetate.

The organic layer was dried over NaCl5O), filtered and concentrated under reduced pressure to give 7-ethoxy-naphthalene-1-ylamine (27.0g, 86.395 yield). 70 MS (ESI) p/2 187 (MI

TN NMR (DMSO-ab) 5 1.39 (T, U-11.3 GHz, ZN), 4.15 (k, 9-11.3 Hz, 2H), 5.52 (s(w), 2H), 6.64 (dd, 9U-3.75 and 10.05Hz, 1), 7.01-7.07 (m, ZN), 7.39 (d, 9-3.8HzC, 1H), 7.63 (d, U-14.45Hz, 1H).

Next, to a flask containing 7-ethoxynaphthalene-1-ylamine (1.80g, 9.bimol) and t-butanol (2.13g, 28.8mmol) in tetrahydrofuran (20ml), liquid ammonia (300ml) was collected at -782С . Lithium (0.200 g, 28.8 mmol) was added to the mixture within 30 minutes and stirred at -782C for 1 hour. Methanol and water were added and the mixture was stirred at room temperature for 16 hours allowing the ammonia to evaporate. Ethyl acetate was added to the obtained residue. The organic layer was washed with water, dried over NaCl, filtered and concentrated under reduced pressure to obtain 7-ethoxy-5,8-dihydronaphthalene-1-ylamine (1.37g, 7695 yield). dk ev, speknevyh Bk re i y y ;

ANOTHER residential complex. Be ok he)

To a stirred solution of 7-ethoxy-5,8-dihydronaphthalene-1-ylamine (1.077, 5.bmol) in tetrahydrofuran (30ml) was added 2M aqueous solution of HC (10ml) and stirred at 402C for 1 hour.

The mixture was neutralized by adding sodium bicarbonate and the product was extracted with ethyl acetate. The organic layer was washed with water, dried over NaCl5O), filtered and concentrated under reduced pressure to obtain 8-amino-3,4-dihydro-THIAN-naphthalene-2-one (0.71 g, 7890 yield). (av)

MS (ESI) t/2 162IMeNI p

TN NMR (SOSIzv) 5 2.62-2.65 (w 2H), 3.07 (t, 9U-7.25Hz, 2H), 3.34 (s, 2H), 6.65 (d, U- 7.85, 1H), 6.70 (d,

U-7.25 Hz, 1H), 7.07 (T, 9-7.55 Hz, 1H). -

Next, sodium borohydride (0.030g, O0.175 mmol) was added to 8-amino-3,4-dihydro-THN-naphthalen-2-one (0.050g, O0.318mmol) in methanol (1Oml) at 02С and the mixture stirred for 1 hour. The mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was dried over Ma»5O), filtered and concentrated under reduced pressure to give 8-amino-1,2,3,4-tetrahydronaphthalen-2-ol (0.037g, 7195 yield).

MS (ECI) n/2 163 (M) "

TN NMR (DMSO-α) 5 1.53-1.57 (nsh. 1), 1.81-1.85 (m, 1H), 2.16 (dd, U-7.7 and 16.4 Hz, 1H), 2.61-2.74 (m, - s ZN), 3.89-3.90 (m, 1H), 4.65 (s, 2H), 4.72 (d, 9U-41HC, 1), 6.28 (d, 9U-7.45Hz, 1H), 6.28 (d, 9-7.45Gu, and 1H), 6.41 (d, 9-1.1Hz, 1H) , 6.76 (t, U-7.55Hz, 1H). and

University of

Beige ve i- -y o 20 A stirred solution of benzeneruthenium (I) chloride dimer (31Omg, 0.0Obmmol) and (15, 2H)-(-)-cis-1-amino-2-indanol (3.7mg , O0.025mmol) in degassed isopropanol was heated at 802 for 20-6 minutes under argon. The mixture was added to a solution of 8-amino-3,4-dihydro-AN-naphthalen-2-one (5mg, 0.3100mmol) in isopropanol (3ml) at room temperature. A solution of potassium hydroxide (3.48mg, 0.062mmol) in isopropanol (mL) was added and the mixture was stirred at 459 for 1 hour. The mixture was passed through silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to obtain the chiral enantiomer

GF) 8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (33.Omg, 6590 yield). 7 MS (ECI) n/2 163 (M)

TN nMR (DMSO-a6) 5 1.53-1.57 (sho 1H), 1.81-1.85 (m, 71H), 2.16 (dd, 9U-7.7 and 164Gu, 1H), 2.61-2.74 (m, in ZN), 3.89-3.90 (m, 1H), 4.65 (s, 2H), 4.72 (d, 9U-4.1HC, 1) , 6.28 (d, 9U-7.45Hz, 1 N), 6.28 (d, 9-7.45Hz, 1

NU, 6.41 (d, 9-7.7Hz, 1H), 6.76 (T, 9-7.55Hz, 1H). b5

Yar: shrre quieted as za pae with Z "y i N kla t I iy xx sf ih id nanis ze pn ke VN s St "v MIZH a

A stirred solution of benzeneruthenium (II) chloride dimer (1.55 g) and (15,2K)-(-)-cis-1-amino-2-indanol (1.85 g) in degassed isopropanol (500 ml) was heated at 8092 for 20 minutes under argon and then cooled to room temperature. The mixture was added to a solution of 8-amino-3,4-dihydro-THN-naphthalen-2-one (25.0 g) in isopropanol (70 Oml) at room temperature, after which the resulting solution of potassium hydroxide (1.74 g) 75 in ZbOml isopropanol ( obtained by dissolution at 45 oC and then cooled to room temperature). After stirring at 452C for 30 minutes, the mixture was cooled to room temperature and passed through a layer of silica gel and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting solid was dissolved in dichloromethane and treated with activated carbon for 10 minutes.

After filtering through a layer of silica gel, the mixture was concentrated under reduced pressure. The obtained product was recrystallized from dichloromethane to obtain red crystals of (H)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (14 g, 5695 yield).

MS (ECI) t/x2 163 |MI"

TN nMR (DMSO-a6) 5 1.53-1.57 (sho 1H), 1.81-1.85 (m, 71H), 2.16 (dd, 9U-7.7 and 164Gu, 1H), 2.61-2.74 (m,

ЗН), 3.89-3.90 (m, 71Н), 4.65 (с, 2Н), 4.72 (d, 9-41ГЦц, 71Н), 6.28 (д, 9У-7.45ГЦц, 1). at

(5)-8-amino-1,2,3,4-tetrahydronaphthalen-2-ol is obtained using (1K, 28)-()-cis-1-amino-2-indanol.

Next, a solution of (K)-8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (36.2g) and pyridine (18.5ml) in THF (850ml) was cooled at 02С and phenylchloroformate (28, 8ml). The mixture was stirred for 3 hours at room temperature and then poured into ethyl acetate. The mixture was washed with aqueous MNACI, then with water and -- the organic layer was dried over Ma»5O), filtered and concentrated under reduced pressure. Acetonitrile was added to the obtained "23 residue, and the precipitate was collected and washed with a mixture of acetonitrile and isopropyl ether (2:3), obtaining "K)-7-Pdroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ucarbamic acid phenyl ester ( 33, OGg). co

MS (ESI) t/2 284 (MANI - "IN NMR (DMSO-ab) 5 1.59-1.64 (n, 1H), 1.83-1.89 (m, 1H), 2.68- 2.99 (m, 4H), 3.90-3.92 (m, 1H), 4.84 (dd, im

U-z.8Hz and 29.9Hz, 1H), 6.75 (d, U-7.9Hz, 1H), 7.07-7.25 (m, 6H), 7.42 (T, 9-7 .85Hz, 1H), 9.29 (s, 1H).

Example 1-1

IM-(4-chloro-3-"-trifluoromethyl)phenyl|-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea VNY

Co | shezhuh p » naz pn, dya sen

I t, TE t How -i I I 5 that her -I Neo o eya

This example was carried out according to the general method E: o To a stirred solution of 7-ethoxy-5,8-dihydronaphthalene-1-ylamine (0.1 bg, 0.84 mmol) in (a) 50 tetrahydrofuran (15 ml) was added 4- chloro-3-trifluoromethylphenyl isocyanate (0.22 g, 1.0 mmol). The mixture was stirred at room temperature for 1.5 hours and poured into water. The product was extracted with ethyl acetate and the organic layer was dried over NaCl5SO4, filtered and concentrated under reduced pressure to give

M-(4-chloro-3-trifluoromethyl-phenyl)-M'-(7-ethoxy-5,8-dihydronaphthalen-1-yl)urea (0.31 g, 8990 yield). Next, to a solution of M-(4-chloro-3-trifluoromethyl-phenyl)-M'-(7-ethoxy-5,8-dihydronaphthalen-1-yl)urea (0.21 g, 0.5 mmol) in 59 tetrahydrofuran ( 20ml) an aqueous solution of hydrochloric acid (bml) was added and the mixture was stirred at 409С

GF) within 45 minutes. The mixture was neutralized by adding 1095 aqueous sodium bicarbonate solution and extracted

HF with ethyl acetate. The organic layer was dried over NaCl3O), filtered and concentrated under reduced pressure to give /M-(4-chloro-3-fluoromethylphenyl)-M'-(7-oxo-5,6,7,8-tetrahydronaphthalene-1- il) of the extract (0.16g, 8590 output). Further, to M-(4-chloro-3-trifluoromethylphenyl)-M'-(7-oxo-5,6,7,8-tetrahydronaphthalen-1-yl)urea (0.07g, 60 : и и ; и и

0.18mmol) in methanol (10ml) was added sodium borohydride (0.04g, 0.09mmol) at 09C and the mixture was stirred for 30 minutes. The mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was dried over

Ma»5zO,, was filtered and concentrated under reduced pressure and the product obtained was recrystallized from a mixture of ethyl acetate/hexane (1/2) to obtain VE IM-(4-chloro-3-trifluoromethyl)phenyl|-M'-(7-hydroxy- 5,6,7 8-tetrahydro-1-naphthalenyl)urea (41 mg, 5995 yield) "YAN NMR (DMSO-ав6) 5 1.57-1.58 (shо 71), 1.87-1.90 (m , 1H), 2.36-2.42 (m, 1H), 2.63-2.76 (m, 1H), 2.83-2.87

(m, 2H), 3.91-3.96 (m, 1), 4.87 (d, 9U-4.1Hz, 1), 6.82 (d, 9U-7.6Hz, 1), 7 .06 (t, 9U-1.6Hz, 1), 7.58 (d,

U-7.6 Hz, 1H), 7.61-7.62 (m, 2H), 7.93 (s, 1H), 8.09 (s, 1H), 9.47 (s. 1H).

Molecular weight: 384.8

Me (MN): 384

Tel.: 227-2289S

IP migo activity class: A

Example 1-2

IM-(4-Chloro-3-(trifluoromethyl)phenyl|-M'-(K)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthapinyl) truncated g; ssssvy sv ras and skh gl s. no;

She: She re m U shchi o y Ya

A racemic mixture of /M-(4-chloro-3--trifluoromethyl)phenyl|-M'-(7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea (30.0mg) was separated by chiral HPLC (column of UOaisei, n-hexane:2-propanol--98:2) to the corresponding

K-isomer (8.3 mg). K-isomer and chiral HPLC (column SpPigaiSe! OO 0.49cmx25cm, n-hexane/'ethanol--97/3, flow rate 1.5ml/min) was detected at 20.1 minutes.

Molecular weight: 384.8

Me (Man): 384 p

Example 1-3 Go)

IM-(D-chloro-3-"-trifluoromethyl)phenyl|-M'-((8)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl) truncated

Zo ak yan s ikh o rn SHY. I vh En oun I I Ek a : yan VN

In 0OMUy: -

A racemic mixture of /M-(4-chloro-3--trifluoromethyl)phenyl|-M'-(7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea (30.0mg) was separated by chiral HPLC (Oaise column! O0, n-hexane:2-propanol--98:2) to the corresponding

C-isomer (2.2 mg). 5-isomer and chiral HPLC (column SpPigaiSe! OO 0.49cmx25cm, n-hexane/ethanol--97/3, flow rate 1.5ml/min) was detected at 17.6 minutes. "

Molecular weight: 384.8 shsh s Me (MH): 384 g Example 2-1 "" M-phenyl-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea

DO MORE

EK se Ya i95) re sne sem ek " ni o r -M Ne: oey

This example was carried out according to the general method of A.

To a solution of 8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (20.0 mg, 0.1233 mmol) in 1,4-dioxane (1.0 ml) was added phenyl isocyanate (14.0 mg, 0.1233 mmol) at room temperature. The mixture was stirred for 16 hours and then diisopropyl ether and hexane were added. The precipitate was filtered and dried to give iF) M-phenyl-M'-(7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea (17.8 mg, 51905 yield). co Molecular weight: 282.3

Me (MAN): 283 in Tpl.: 198-1999S

Activity class: B

Using starting material B and according to methods similar to example 2-1, above, the compounds of Examples 2-2-2-41 were synthesized and tested. b5 one thing is VI ENN

CANCER

MoU Chek ote s kur nrvsyan. EE PE Oi nn KATA t, KON Ken Kn TA ect n ey

Con Is x gg Vo o xs nia mn: Shnn nyn: o shya PV Koi nnya LA KE tkte oo KI IY

ZI Enr i ee partu ili ili ko av re i tutov ka aa nia ny kove pyv 5

PA Irina ony t i i A V ne nn i v a IN.

ONE "ZE V s PAN ze her o pa Von V. Nancy nina

M! tiy Go ma p va OO AV sr: zr I pe yiv o

Oh, and that in the city of Konevi. kit vii ti lot Shi te ze Y ih he ZK

N:NYA : ZD NYA How Y I her: se sht ke : 1 "ee" Hn : NU SCHE WITH CHE and I'm angry and I "KV; ШЭ that o r N Kene: o E and 1st I U I Z r: Ey sh: i Z p SVY sh. HERE ik cha Ko EV

Those ZDU li '- Z 5 and oh SI AK STILL those

I g t Zh Zk. sch te Y V and I

SYA ke "kis ZHK I KV I STILL eat and her wool YOU Ko THIS Not I Still; more

Like TE and NE KE shchi. 1 in I tA Bey

In still Net Z VNT rya 25 I IC Ei re a Ks I and hey KV Kg w schu i that scha She 7 zh STE sia NYA "I vh dhi di nach Z ve y her KE E ni ZE sia na kh Ж.. And Ko o (y Pe Z M. still Eh "ped at v. Z K iy I; EY fi y iyi "eV: Z i Sche; CHE Ж M i. i. shЯ ii ii I: R: Y Ne ШЭ I Ж r : Z sY Not I and ki DE Z yet

NYA : M fa Va 7: I "No No Z Zh

Z Z Ben I still M I y

EY is ZE NO: Z. Kch J. V: I "Vo PO et ih WOLA NA KU oo m MD o: A ID Z id Z t "V

Ken vk va vnsiv siv BANK eta: PC chna shin Zheren este I: cht dere tras rn tk nis ntn v bt NI ry scher schi nan o vv U Ist peki ti kt sti PO vv o ru DAV i i Vk i t in. z Bey sote tra i y J 8 ET she k ex t t

Set oOB: and cook, and Zno g va No, and what: if would KRY 0 ZDUKeVNNENAE IN MK More

Z: A V. SYA :: Y M y I KE IY

Me her SHK rayu TOK Ya. and "I Hey yah - 4. r and still more z. ge I same |: YAN and r lovi x Where In her

With ; I skh Because In " their dock I Not -Y And Still. still R her EY rya T sii: her Battle Ж Y г чн Y pvh still Кк: НИ у ий rad le Ж. pory. s shchy y: -E shchi

B: and I: in; a ЖЯХ Y TE Ka EE "I Z pashisya 2 her r: ZU ih Zm r Z r Ш) шх V sh o re SE hu in ME ШЭ iv

Y SY UA ono syh: ШЭ Eh U «4 ey te vya tya Z OA ie: sche Ki te I Ei, r I - iheet. g s rya ha ry VE 1 I: "VE I sche r Na sche YAE.. sche i, Ve sina ke Ku me 1 otv li Yak. BE dn lov ra V Not I GT Bk s her erooilnon root reno sr autumn washing ost de r sne enisnn by sand ME we go ik ss In nav tv in pesvanny I ker netn ee TERTKU zai (o)

Pre ee NKY CHEN WU ti en NE NN NT i i MI or Eco UE:

IN! and vk NI PTK MNN and MY NN kn ENN VT and

From ss SHE EU vana: an: SE Kk NN to Ex

M I Z: r, I Z. Ks Y S SCHE: r i Z: iy s: i r More and How;

Still I SCHO and z Ж ra ZI in sh Z os shii x. che and Ch; Co

ZD, This. I'm sorry for her

ZE and Vyk yr KI And her ac --

MORE I. Be more with: EE and gi

B her KU sh 2. still Ya tse -k Ya. ECO, TE those: still gi Ka

Zk I. You are not in That I t and Ei (av)

Ж s ша 3.00 Kiy ZHE, вх and another spring in. And you are SN. where am I and how

ZA и и и ок в: что вх Э У Іі ря

Same as shi: s zh ZU ve I Still o still To « s: Z s Z B i g ro.

LE Cl, SCHE KS: in SCHE. NN Hey and I'm better; be nava Ž ve z ri v sa "Bor Do kedi wai chl E : g u ME -

ТР де ши и Ж Ne: v sya и ne

І І ТЕ Р s Кы НЫ рН офеют Uzh s ect lit Y

Zk fai SBK Ber kin i a 0 AN SN y eh khan shchi NU o. B: B sni vv Ki Y MALA p I o kn ay Z Y Sl: che yi gYA DI KA re ne Lived tim Shev osn sis Where

Le Ir re Y, Else What and Else From Shrnya This DK ore AN j y y y y y y y yy ryy TE p Ne. NOT yet r: still with and o. s B och A B 2 E i «

Z. still behind Beseya Z I Z I still

I'm Kh.-paska: i same still s i still -

BC With St. El. i Zh: Kn y "Z Ni z so la SCHE: B I sche Y Ya r s Z SCHO svv "KE via Key SCHE SCHE (Z KZ

The same. o V ŽY sna Ka B ZE i ; КИ I I кри они Шщ "more Z z more " N. ШЧе rea zhk si hu Y; TK i і s з" 5: ий венен I: еще ц І 4! еще ий я tA КЙ I I I Не BE и I I

Ж It's me V I sh ! Tr; g ii Es y I Ko HES y pk: г 1 zy p a rr No I y y yav v s, How ris-sya I t t t her Y SCHE y

Bi; ой екв оважеия выдах Б -ых "Price real lady signs VN zas is NO PAM i

Vanya Tanya in nado ENN S kodi Rome I I re di EE sna KT LE yatYA live became g pis Y

Yar i ve vo i rache nov -i o I res act i ren NE ZI i sov. 25 IN: mm; and

YavoO i o zhen RIK ro I she ha ON shi "e ta still SE: sa SHE I EE o Ei still shcha Z vi WHAT z TE g V JHE Eh "r -I I Z zy vv o i k- Eh ze and more

Z B: ZY Shi tia Z; le te z "v y: En B IV Ko ) vi E i y poyau. ZE Zh. a Z wk). and another 1 s: Y Ka as g y V y V her re i still Z n: shchi still Z i still she t in EE: I J 2 But y and teh i z as -still Z s: "MV y y I Ж pe SHOE schi. not yet ; B "B ЧО m r s Still you N Z

Where is it? yah Ya: more "B, r 5 i - M "NEK. and a B More Ko ki. y y

THIS AND; Zo: What else is there? What else is there?

NO Mr. I pe She What in "TYA I r v ve; SCHI V. Come here. oo cm ZDU son. Saint Sean toyum WHAT

NED obsya Kos s y ev i s si ie pin v Ann PE deya s Z sni p tith set ON B siru Tsary dusstnv kl

Betsi ny she en vh si V p Ky v pr nn kyt r nni nn ktiv r: same Vi iii

Y. more n 6. og chini tt . Prof. Tityai Tsi. No 1 -- you - -- o. what are you

Bod r uses tvs as: M NNA vessyat nov KI in EE and use fol stok nn tekla in EE EN

EN. ShErTe sshakn nn shk ss: I still IY yy en I

BONN вх са ге ED и EI: г нм I Не І: Bern ked s bisa

Bosh vin sh yu Jason t Sv NA ee KEDY: WASH Your seams Shi on o i V VO i ni ZIO V V unhssy nroonor and onnsvnch he and day tv p rensonini ka nninnn s nina an nn kv U Vi EN Z nene i o et Nr ionic skwonnny

AND WE PREIKI OKA AL TV ANYA Mt se vy i oh v g shcha u et BYK Ann 0 DYAN I still J i es oAshiE i pen nn KK 0 rent ' i

En "SHE ZHK ooslne and t more. Kk r

Ha RIII xYa v tr VI oh m M 2: svy vi i tr: Yu) o I i v er, IT. Bk Ki nak Sh-: r. z B Z o Uh eV he is U: Y v! AND

KE, I vat ee хх и г zu I She ДН 7, Z "5 I и гия ; And Be; "a N Z t V shk DE z. i CHE D: B.

A, Shchi no ke Ko i 5 C 5: N.

UA 7 ryu o VE VA s Z v Z Z SCHE

As V Ye sla soi still still in: And Zh still Be; r Mn "a Ne. Mk BR A "B r ZE. Ei V shchi KE B.

EE B Z "AB z REY Z Z z i . IN

M ZE VV. гри и сн Pe: I: U 70.7 Not all VK ks y "I re y y y sce Х N rya V: I A Ne: U Kk r "EE KY "A i Я v ШЭ yy Z E mi OK u zani si sch NO. ZK Also: Z

I WHAT? in and I to her 1;

I V I TK urine: vyshne I, -k B. siv K -AK chu oku yati konk Z I Ig: u SCHE g and her: ts

What Z Na si xx N.Y "And how am I Zh

Ii Z i p: i s I V K: Ve Ni UA. With Ya

В и He и и я ие в "В как Швы вен и g: я те B У 2 и,

I that "wa t still ih zhk Ya. from 15." And kopradeatiyh Ryzhik --knnt Ves es and p vh

Essay ee Bon vin avu MOR zhenization li RIV Ole Il TK PEN Kit o LAKU rev TAKI p in in,

KO del ekt: ves rea a o ut v pos i sys so NN I VZ vva; V MN rez cho B u hi tyat zha B ryu he li 79 V Ya sne Ne z, sh TE v shi: yad shi ! and I: SHE and SYA How. Ya. slya even as far as V B Z

Ж TE p so s VVE s, these are EE I: shcha

MORE Even r in KI ke in the same Bo B) and | Pih stvnn:, aiv KO k: pi; Ki Ya re -

More V V Me I x "y RK t More kh :Z Ex 15 dk Zhe I I che s t Z ke KE sia MORE: V "more

BE U KZ i YaiE Ki m EE still Ka

And with the same... and I Es te still and iE I o: still ih KIN not yet) "a Z Dol shk In in Ky B I JH: Ш -7E Shchy vish tova si Y r: SYA: V t i: 2 I: "no

Yes Mo EMV a: Not YET from Za B

I'm in! gtYae s: V le y Ya Ya

I'm still in: ZD NO; r God Z a a I: OV A i: MORE. Another 250 ZK ooskvssyov he o o norov ven zro svv cache shina vi roi den jay MIV) yad i Dan i and I how

Z Yanu A rt non he AN. KE Bru posyuknn MN NE I h she. -y tm de SYA NE "z Esh and I kt V g; r; Z

E pev With her sleep. t i ha ru K- I and her Y CHE Z zd y Z: 1 A shi i. still sia «r did same. HOW else with: me. Eh I Y tt ah liy t » 1 th 3 I u re v, as. NE I r I p B gu ERY ney y che More B I 2 4 How yours Щ I I sat with -- lk tk No Ж z a kg Же зо же ех Же І КИ Ж. I и Che I KE; I F Ir I Sh: shchi o -D; From inv that: iz ZE: zr: -N

More KU AT IE sen y How Z rij z LE ZHEO B V LE z y o -k - I A KE Z «A Kk Z so

Also ЖХ: sv s, More: ves N more: I on "B Zla naik AK. Shchi IN Be r. By I and Ey "Eh r, ia Z Z: Z oz r sh u

In Siky: DEC. х г I a: TK I and MORE How about szash: ZK 1. i rya VI Ai ti

I: I: ste hm t i: -YIV zhk i a. they are still I" 3B E I ON and still ee Z SCHA lishi: ANYA sesoetv zi: KK sia zhk sao Mk sksivku opuedtn usno "what - PA LA MT i sidk wl West koney In idnv r ovnk hliv raft o v n

Di i mn p i vini ni ah two g y t same NN S more. V y ssh iv ky "Vre KN nn Ya. t I "v ona: Still En y GivnnnknYa vie eny ShZhejetitaye NDU sy Me. t

HE IN M this 2 like me B Y

BA TU and NIKY. even THIS "In v and How

Ka; "higher ay: - "IJ E I Shchy " to her and V 1 is dya Be VE; Я ие Ж. г и ии ІЈ "ЯН В НЕ Я. : - ије е. "kish Ky I BE fi How t І: ny y: ! her her Fo sh-

SE i sarchan, - i Z pre B i

BE sa g: z NE ho: Y i 1 Kiya ve Z z i VE OO i z. and Oh I UVE. BOJ s still h 7 ож VE" S X "KE te re: Zh. iya y zak: y. ) MORE. In I How

B Y ki NN y I Ge More poison. y sv MY R NE -AE r I: "» I in M nya and s ih KE s: Ai Sche SCHE, Ba i ia Z : ii lek I Beh SV Sche Z VE Bokya K.

MORE:. her B; TAY CE s "Y va de SCHE: ii « in: Ko

I am; a Not shr i Her I : mya With No

How -Y no var Hey shcha: si Z. Te EK I g! VE en oi I: and V. for r yan; -N zny Kn ni im ros: y Be V 5 Y ETIY -i y t De y Ni: Her Va t: KI hi KE Eh Z si: DY X TYA u. ! cher 1 (y -I ah y There is more: With How Her child didyao o sh0Y

How "V tyr SNY Z r Z Y Eh: DESTROY IN EOM I i i i i ii DEC W pesen ef em: Tv n st y Casey iv synov in nya Fr s V nya Mowing clay akstEt grtshnle other Ek IY

Ha shi r NI I si YN o SHEU

De snya Ki 5 DYSHY zva kul in KO saliva ION gene B I 5o V E J: NK pav -Yalru Z Z I same: EV

KI i o Ve MNN che DK KI Sha: h v i Cl 1 av) How I DE ZHY MK ORD o KE : V y ve Zhe r : Й и и ше я КА E B Ne B - V I We Yan Ki E action And more

I'm 1 with: B and Z in C. I'm 2 and I'm singing. ZK still and Bi E ay BI i Z a and still yi Ve re. re y : ON I: her and "NOT JH KV i o ZE eh 7 tv Te: her

I sh Kk sani s Z ta z NE -I NYA rk re her

I BOKY Z E EN M. Zh

In her I: Vede: Ne h "SHE "VNU; also E Z Z as o sn Y ' 14 EN Z y E y. I va SCHE: r; "Mk he dy is I u y OS: vyko V KN vi "more about Jacques: the law of r. z ts nei NO, NIJ nn dod nn nir rinin nir rinci nynk porni pro tru p poennprtyt V Ya ped o ne V V sn NI oven v ivan kn nn kon Viv Pi viv sr Ya g в en vysh - r kN: Syak Podkanitdn se impressions ac Mk tt sluh inn nya i B Se NK sect VE NI NI I TV IN. o Noya Ka ikh Petr j EE r kN SCHE

TOO, I put a samovar on her, and Zach still carried medicine to her

Dr Kom IC s A NOYA Yavy VO KEKV as ZY ee I mia ne nn dk ia ray, V: av p sinatt t kVA Contacts zrod dit nits NOT VYK VZ DYADEIN no o EAKEMy

NE NK I OSH nki INNA NA he IN ok piku Y

V gai Zheto Bi ni nn teh ED r NIKY V ti. TAY Hey

Pe KZ -:- MD V hin nni: beat nya ZE VIDY VNS still i te 7 DS MN; SI pi EE ZO ee; ШЧе p vyy eh kh ko y. Щ: и же же де "ar re Evans VEN де : r VE газ шчи N Z Ше ОО же s Bi Z GE "I ZE sy: Z Es This, y ry y "VE

And "y vro she ho Yay - even K; ZE: IZ Ya pa «Sche PEOM Mshazh ND) g Ya r M ki r Z She. and Oh Z KI x 5 pods

SHI SHE Tya: I What. IZ x still Br

B t EV. "It's not her

N. Z I p 45 5 still re re

With s IJ and y in R d Be KV

Tek Z with Ne, IV and: y, Z with S

M: Zh sna K-t Ya re r. VZ .

Not Ka - ; but still B B "I still have more.

I and he lo Bo dn about him this s: I KN and re. vo vo: kwain vk ZE che a ro (and Kene -Zh5

Z She -Sh s I "Zh g u: sa y Se ty p ii SI i y Z un I ISHCHE VC: 78 KZ "ee re her i r V S "VE : ke IN Z i; m z KE

Ai BK and did they erase 1 IF of them: in ЖЖ Ko: mine

Z her den t Vey 13 and i te E v es ie nni sonnet s p y U Kt Z KK fiions po nin there fu niknatnlne nn Na b EE: Z

OE ZINDNY E tt Y a Ya ky m rey

Ken OK I sishrvh Z za Koli Bu se svi TE y

ON Z as well as Te "V Be tn ME yani KMT sign liy Kn ry IN BE MORE:

To a Ge Y a. 7 YOU IN; and 2 essays aes yakvavA 1 oyu Izh p Y Ptya ih ve "In tss i This "a

ЖЭ ШЧе lok v I Ш Ш Ш Ш Ш Ш Ш Ш Ш Ш Ш

NE Kg gav shk B zhk Se her: MORE

More Kr and more Ei t. and t Ky

This is sa and pen JAN 5; ZU and sY as ie KE -

ZT. ZI g NN TI! Yai g 1I Uch pe ey, pe

I "ZI ZE is I. KM tn KA Nk ke: Z

In B GU "became: I AM NOT I hin zn gi C is I

What; in fra NI: Ser yar 5 IC Y: : В тя Z есть Р Х еще ЖЖ е :3

Be: trze v a vo scha ST Ya y

What r t se VE s: IY fe Ya che Y shchi Ya

With Zk, start Es Her: y Z V. and also y p Nis via de tv Z DZ -SHE "Not woven VK YN Bo K o i Kr

I gu cho s: Z: as ih Still i Ne: y

What BE ie Eh v shch g: Y A a

KE nn I: zha, pe i u. I 1 and B Be kovii B also I soy with a

I "VE o Le E sia V! i and r; WITH

WHAT I m: s. BYAN A sv tek as Uk sa M ZD.

OS JE ota: sensiv si pover, sy ts 2 i still in "y "Znedunyan MK ny V M s vse v is Kok oev o vnnv ni uni nu kin ozh zmu sidtko ovnashno I, - і Y, issued і kit Myr u ry suk on TEM assistant tet LEK vin ELINA tiv V ee sv y a r NIC i vin N nts Comets nut Ates still Z p NI AN ZY Mr. I nya verno svi. BE VVE; VINY 7 256YDTSH Bi: A Es S i i: he zvinann Bin Borna: still Ki se

KE Railway in A; KOHN: and J.: "KE

LI shk y R p Ka ih as z yy I s re EE: he Codes soaYY yar a in I "I g)

With B I only AS from outside and IN I r

KE I Sho How with in and I still rich NO; tr Ya ge still Y and Z

What else is there? и г -kNe Ko zve Che Y I Y I z SCHI i Bsnnia Z i: also Y V; from "V zedeyan svyani SHE esche TI esce i Pe. Z

What "How kA ve KI zu ze I Still

Zo y V: terta shchi i still r TE: E "K h- 14 KE Takes in neo still 1 still Ж "r

KE LENT t NI tN Sya r V : U "Ne "Yak ger AV "m Sho BE Z B y i z i in SHCHEYA se eV V y t shCE

Not: s - NE da YOU and и хг KE Ko a r p v : a ve gZ ve. o ssh i TL Z I KE A tv sapky for Menu sl OV: PY v ANU AN iy U V;

UNN it ov a i oksryti Po IN in in v nn EV EN SYA

Dod te BYY pd KE NE DY v v V

HE her I lh NEYANI shen nipple o Y I gi kl: nn p i:

PAS. tav s U vely Ba sv nok TI ie BO uzi ach u g" V Ne

Kt - ry M t, EI dni lady Nis ay ХВ vyl zi ZASHNK p :n what NYA A eV: V V I NYA ele VE still

MORE WITH MORE. more I, I, I, I - y: CHI, re kove I o y a F Ne Z ih se ZY o. more I and more

Not even sl EV ШЭ и "ВЕ Ж ТЕ in her Her I gZ In 8. those and PV Ve s: Y "IN Ei :

But: V es V B : Na Sh le V. i: sh: I Z iz Kk

But" and sv with Z Vi: I. that Z and I Eto Bei ih Ts a Z "Z and TV : TOD s: in I a and ly

EE t as 5007 Ki zn Z Koty A ie "V in te p. Ve BO NI A 1 Eh i Z o pln zhk g se her 46 BE se r ev more and for ich Kk « more -5) ly a Te De : Be p

NO I ate Z ba. me Zk I Te s NK

As and B Z I: and so E: 9 EY EE Ka

Not What I. NK Z ONE s Nd I and still pe ) 73 "y Best tvi yat STILL and B sY p F 1 d vn zhk. ZHI A OK and I eV EKS x t

From the foot of the fin kn NA MK tik hung the news and oon I ryu vszhvto Bey ryn DI NNYA ch et ele ava u ki nk ch i ovet v NEK, nave nev cad I o go you A fi zenitni kunya Ix KN z" Ko NI y rad Bo nn S Ne yav sk vieko: TK I p ri SHY i y, Ko shk ryky M ryk u kuri V ana: NE ENN Z z lecho EK Kp zhna BK rt lek A ELinya a Vr v ry s VE Z KI KE ий ШЕ : г: Я и и п Y shinvn ny She stv ne Z VSH and z EI; Z SYA che I Te B s- Z izh -V M s sce Ж I "y, y TV "ih No: Prati A y Mov U "I sce Ve 7 5 pi SV y t y "DE t 7 dr s: I WHERE ARE I STILL: s I N I V Not V

Woman SCHI Bi I i Still MORE - in KE s y t I Ey U 2 m I o, Be: I ey 7. -y ih I Ne A, in - even Her Not with g t YOU: y y i I t What -I V B I'm old I hr: y re: w 2

K «V Mi sv sooh sce y DE D I her rya od t t: Zk yi Y TE NYA: so yi Z o KK AI B : liy Щ "ШЭ

E: вк ster Va і- В: З: ц KN З g: вс; I I CHE U Z I No z zay t I. zones I I Ben . sh With av! GE o x NE la I Te i A I I

N still oh and is Bes s and I "In them h Be own svv still 2 I EV Still De p Noah SE schu y E: "pIIY DE SCHI Z

Gazy iya fin tr non v ins Z i YN valova B: ZK ee: iy dev d VA A. "bokiv nan ks i i nn i Vrt i i nya Ya skseznstve dv o vvi ev a v i Vas - sn; es: Vin av o i nya i AK time stik "VV Z

S ee I NN lived sk She obreyestEm s Vo MN IK I

Don I lex vv oo A and Z rakh KASI E testu v

Z Ves E Y I ANYA UELECchiYasV Essay Ne Y y I Cohen -Zh

Ii ha v I a: Eh I Z I "Zh

Their EE Pt ey ST t: rei i vh Z E iK Z VE OO pere u wo i Schi NE

I Z riya Tone STILL I shcha Still Z ii "V Still U as y u r "v

B EE is guilty: KEM M prasch si |: r "B NE sly, IY Ne M YAK Schy I; s 5 Shk srvke ih: p ZK: i BU i and pre "EE I . NV still N Ko IY Щ M, "V - in styar: to her I and EV same -yK I Te IVANE: which I I ; ray 15 "KK ke se and un ZK as: y Y Ne N. Ж KU r g sere NI 7 YIV y KEY p: KK; in J I SE Se In Still and With and Not k.

B V As Yav still s Id I B g BE ra

VE KE s es SCHE I Ky her rea bo ssh. he V. Zh. Moss ss not B I z: still y

Y slia tuti: S senna aso klnin tv kov V y sah Y - "not nav tannia zan En ilni E itv lE in zhkvaminiki VA sni yanm ni slototoyut ore, y Y still z Ul lavy I. BE

Bolts pe ethos KET so zovn navan panna kntsnsni i no VA kn vinye penya aspires is vozan nok givenness nanny pev v i vker B pis I na - ov nanis st ska vve sy vv tozhnit a en kla IN vu

Kern Eynotu t LEVA vk s kn EE PES aug Fan V tyu I I K-t it g Khtiaek EL, gitinvko

What eh pev Eopetstt dvory And des I and VISIT ON OA KE AEN BYNCHNE AND

Pih lo ble MU ET hv SO jan v i rani I v ee et pre Vache UA AHA: ns KL: I: ZAVDNYCH p prav

Also to her Zv z son in uuvay pany Yae PANDa y: OPO siy ar vi p NIZHNYK i i EY t How a daws DE I HOW na i NKY z i I NN x sy i shchi ionni Be. r E og mkyaya NE VE Olya a na vylitie ie: lys fa BAS o con en o M p rol; the life of VK non Tsar asny Y nnia piv a sao one on

Koshova Z Vyno ve ON inini ni inni ZB bila viv H.

From us knony r pk ze, ZV Ol v s zhk Y u vyt V stzhy v A, : her PE sao By stu no Ж ody i zhme shK t ener: res v | Chi

What is 5 in IJ pra siva: NAM h Yasya rve SCHI 7 EK TI

EK g SE, m: In the year of her seni: Ti Bonn ZE pnia Ai. VE and iy

Ж Ж «ol not s1 in shchi I bl ak

What: And when iisnyak still ik Like juice ZE

Still ее r: ше хх EE in Zhe BE sya o ,ja y SYA B: ze s: ЕВ re et R dk Net li ak I sho baths KE g ve NE Ій iE A dev В ke ж 5 y "also and I go there li still t sh 155 es y; Sg V: shko s Y sche Sche KE - Sche.

EE En i, adek Oh SCHE che yar VD Sche I

Be: This is prkvyvyh tr Be 5; Tia Ki: more «

Ki ZE NO; Z: I t I -D B

M: and in She a s eV Ku he YAN. B I MU ne 2 y t EE va i still iya Z. y Z cho TAI I B VI Na I Ei ii 2Ж

IY 2 ED es t zu I I NI zi ke

Ne I BV Y i: y I: What M I "NO CHE popu we still ate CHI Ii tk ge E I KE OKU. still Ku y "Z I

ZNE Ks I RI; Other things: y es, str pk ne poksvKen pd stad Issuing raU and r oo M fen ko o pini nn vyrinsnya cal gran UDOMA m skver h B E pechu EE PEMAZHEEV NN uvrya takel nyti t cate AEN tk eYU MI Zove neti v i Ya E

ED Ko, ten and "RKO and not and V dyk U

Be se set ze ZM. Y Y Chk sia and Koshty ay ay «y. SHANY KN khz "I NI x SI I called ana sk Twin Z fari re VI si Ne

NOT "B: vk ni rovetttthh LIVE No Y i KR TI SCHE on y "a

Kk I: In Dr. Tk KN Ya Ya ry schi Bilo "y Sh Dou: Ki BK still sia Zh

Her Ge KE GO ZHYAYAN Ke I M Z a

NO ee and "DB p i: Es I hЖ te ei t dv U Udeyaikh llkva y r: y i y gyi "M B I

Also I io. fell YAKE and shk in No

KE "ME well Be I HER EVIL VE re ri res EE I si Z Y voy V I

Be "V KE pn tia KZ SCHI I. and Zhe gi rez BEN i. KU E I: I -E 4: ": «shi KM z IN AN - "Where else B. zle: E.A i. Shchi. Z hi IN t |V he i VE semi BI I ZV 1 shk re s og c LY V o: TV d: i and ZE

EE Ak A VVE: MY B U Y to Vr that I "EE V I Beh stbnvn iy ki Y 5-Y IN "Also; YAE KO MYASHA ke: From her E ZHE g JAK - Ba xx SODOI I I Zhe i TU ha BI - "y av: V. Z M "y "ye t g

Зк I am: SNY -i y y :y pe sce

L2Depoz lk lahnen gene ikh ser t estyuyutya doza lyut i mzhik DY hi VE | With you ia vi V рН SE NEK KE In NE NeKe CHE ENYAKKNO Na ID . h, and KE

Wed MMK on VN ce ru ru ty rik tyny MKK i RVE OO V ZHY VYAI Men t Z a Ж KY TM El Ta Ve M even EN EE on o A KI NK Ash U u t shk pp porve

ON ee 0 kA Ba V I ia y I MV is: -. IN;

Ks NI shi Z her ee "SHHI and zhi ep below AJ DA sti ik. THIS is kva ih sh I ! and, Zhe and VK - G: de sia V s

TE TE ST and ZK lk Z. r A le p

J t EV. Copy of this copy

I have DRAIN nt I Because I'm STILL here

Bk I 28 zv tv liny la I: 13 I De I

KN 29 What else Kg: za ey uk iy " Y yin - go ha y: I y y hg, I ze, y Bu

TE and PE se hu : s H I EE o 5 I NI I Z |U B hv TV ks "V r: NE reg Fe r Bug "a Shko yar: BE: z liu i and Gu E; No, from Or.

Ko I Z ZY B S still Shchi y: i

V Z Y Nk pa i. EI hi Bo -Z SHE x ih B OD z - EI B: Z B

Not ZHEO and the same E: yet

K Z "I B an s sv, vi so teY Z i i i E i i Be E (od zi i: shk l li: Va y v y 5 Ku iz zo Ш B Ш. Ochne t ! sce y r -

NK KI se ZK Z 5» KE Shche" i CHA

Noah cried out: "4 more

I and: ZY ooettya sht se Z It is not Te with BT "VK probably I nntesi against I JE iy s SE ro anny shop of villages Us sryutet ovi SHE appeared t se DA oon sheoma yo se sel. I scan still av) still iteoh ve el et not at EK A i TEN POLYA S i VK a cover NOT about KK PKT te V pak r oo a i i od No inii and All These Times fon y rya U nin Z o NN R DT u r KU he zCYY vysakh

In ef | ZK Kp and SH Ach Baly S IN "VN 4 or doc: YOU, FROM TKU,. you A "ZHY: zh ZBYV 5 a

Her and ke and DT KA towers of the wall OB r nyu V ee Be

LE min peri BY M: t- t B: "NN Y p KE 7 I

Kt and Dan du eV I W SCHA her t

ZI EE: A KZ i Ke I s mya gYa ee i Kona: sf o V y Yak E mi

She eu Wes still with me. KE. 2 i |: t -

BE KYA, Z Sho g Bo SCHI v. I have them Z and "SHHI in also Bin and K. and E

EVEN MORE and. vshashet vy che E Kei I she se CHE r: NM I t |: b I " de i - sce y: ee De E I K I "i y - Eh. Ana E: SCHE e re "sche zav: en KK and ps "I vga and Bey Kat Y Ko: te te Tk

Schi CHE shi p ZV I what and NOT and how ELSE

VV GKI I z: NINI Y Che E su I KE reg y "CHE NO san oi Ei : r Z s Z lo her NK: zay: Fe B: Z. V ah KE REA y "e still SN Z; B U v y Ba yiv V. EN i ee - : Y z zar 1 SCHI I tovose J ey E B I i e "M TE s Kom . I'm ALL VI and SCHE yaeklyai ЖВ 4. ak i sg v t KE i ni You suk zhiktatya s i - Vu u 27 sen, i. Sito Di I V... And " Svianm foaming we ot-ot, - OKLY pElIg and vnyh. REVE KN psnvya ni PE MES so v swop Y Yadkeriya nen ura v ZNA VAD sya fi j fenttij: V shcha h sr du otit YAN

SCHI ezetestitya klyari ner vn pn KE pa EE i a I Shust v SE ni t pdnnya s p KE zey v o. VH Vone po ikan i sot ve V: MN nina sn

M I sake VSYA for Da Verby N.Yu for EN A. I rek Nu r sya p t 19 REK z is Z. SCHE tetvneevede s: Mer u KZHNNya SCHE sny Pes t- Na g (Y y and Sche B ih E y with PESTKe yam Vu och NO

In k Zh IZ with I "M. I: c: I 4 a v y ziv 2 A roza and her I Kz 1 KE zoryana: KK o» І ШЧЭ B ech ЧЭ EE sa: Bey s V E KE g ЩЭ Zo SYA rasi Z r: Z z via 45YD" in Ya A s y s : y ne -E -5 I s y y ' y 74 Bas her still oh AN ryh | still Gai. se - | Still in NN sive, ky Ysva; r «v Z ya. g Be ok Ko y Boyan ky S "Ж E Ne 2 Hek "Ж я я -Щ Zv g: Я ne В г: VI re zr o Ya r Lk t More U Y, shk y Bi

Hey No G and. n Zh KU iy Kos EN

In ev Vkris faith I |; I tA her e y o ZYABEh K Я 5 Bkrya 1 tr. ren YIV NINA tik kt S ET ASV y pu ih post vh sera s ve kpk go Vk dev, av) pi Z "Ah iv eh i zhary o: I tk t t pu hy YOU ia PI puzzles i nn Z Shkaya How actions td zasn Z; ko (y g What Zo: "y

ZE C) I - o YOU Not ta SCHE SI Sche x I still p i. oh : che re o - EE eat: De, S Es: Z NO N re. (In «i y li De y: "Z i: M ikh Sche vo : in: z 1eЯ Be "lei rya U ZB is N Sche s: Y ee UZH Kz NE SCHE pi g; E EE sei

What is U I: r p v ih o M SE: what I I: Also: si VEK him Telya E as tv re and o with Du her Che still still ik I IK . s, Be, 5 « -zhE "Ж 2 - W KI Genya NA VEL LE E yet - NOT a

Y ze ho ON St - M U I everything

A « BT koki, 1 st M. zi i t -V Zh net en kiy a: m Zh vu S

GF) I TZ r y y r. Be v r g BE Nor "Y I 71 S slerny DV Zhe IH khz shk "No

NE I ee o nyka Y 1 a ak a r: y t I lovy pe Ii Still still Ж ih) in Ж ех KE io ; r V Still oi t AY nn ay pr i vono tinyy svoe: Vsny Best vydne v net nt eV AZH bones one thing Prim sya

PTO ZY i EN V M KK TE Ua NN ZBE naya sk v o nat test uch tv vann vne U U DY PI MEN vna PINA shana; si Ko EvShN i Men Kdetnva akva tus ti tyri yunya et "y tez zv dey i; ЕК В Жех п ше веж ж НН 2 ев Z NI dike deli ukh niv z AY. f; ze tii il era mi ia tesynyi i

IV ex vu M EV s ED i; lan I DENO un and sny zoli r u

I'm going on Du o Zmi and Yasna i t nya i I i peak oto rosa pk prinya edevvnai nd kiv vani en i KN ko ne pariv ee oon ev rzvan It is important ve se vv

BOSH sh vyv nevy so un U o KN kyu ZA z vy, vovyh im Ye Beredyan ek: "pon ev

NK COFFEE Let in NK "WE NOT ME. KK: KE

TYA TE yan ON si Be act J BAN: MK osv Z and ZY

Bk SYA -iV ry vi. Nkh t "y KE V. E Z "Be 7 ee. ro ZHE t Ne "Y Se Zh: E vusi re CHE soy se sey Ii. y tor ge I. Zh t NE I - B: s LA s I, sho ke and yane B

MN Ne Z i Ko soleioi Sh schu i Ri: Z ve- ey

LYA and; you " ee гЯ Ж U ES Эй "o. ee «TK ож ОК Доти в Те В NE I ш- Эй

Where EI U ZU py tya, kny Z oh and same "Ж ME in p 2

Y N.U redit kety M NU -K v, I re: and:

Vr Not yet STILL in "Z I Be I r r ti DYA Y "Ve yi Z. Tseh "y :

ШЧИ -Э и i З ШЭ И Ии: и M: З |?

By the fact that O DN SYNY I I. "YAK VZ also: t y xx y rovy KEN se TIV - Kg de: ІХ y хз pl chi ZK; More. ZE B in 1

NK Ya -a pok : well I'm the whole "V NYA: TYA

PE este V medi svi Kt, - same t: SVY iE and HNN dis

V tit UMA Kl DE VIV JAK nny cation j YAKU. From pe F; VI

NK per half peta in us Kupe tovrya vyti chiv polu tyny is Kt, utre elluk Mi | Mr. Kin Iovnya VANEK i nen in o sdi and greetings A hi pra no OIV NN MY NIC: t

Y Z Z. i. Me: Oh Ki. in re ty 7 te man and i yat r Her

Ye B. Ya. I - 55: STILL THE SAME

M " ke sht s K ШЭ Кг t Ж Ko "A р сты nosik He цио ЗЕ "а пт BE.

V r sy uv B, sii How STILL this nev

BI "V Bi rn TEN t Fa I r: Kk Hm them

Koh Ba z leszvk: t. nn Ky M x V Z KENE V Beh; with ah Kri -E no I: yes VE: fii 1

DM ZHE and EE I and I EE; Ex and tre

AJ .-: ry. Y Z a. and Qing De

Z i i z i I: A and E3ya for

Ko Ya t VE and Maty t y v h I HER Z sce V ii z - MAV ah t ve ee sx sx sce s

M G: I li: DNA 5 I t Sai Ex

TI Ne B tA m TV Still No

Ж я Е НА И В - I schu: and rii s not yet I in ШЭ r yet «NO :u ШЭ EE t che soy pe ah Kat v : idu 2 | ЩНЯ "YA LE SkUMt i KYU, k IZ i 15 more KE vok eYA NYA g. nYA im Kg Z more

But. ZKYDYI ZY u o Anna St. I sesquinonsya NK Z shcha 1; pev Po TE VE Wrong uv o o vet I EE YN I yan. Meklakaya t AN yE at nn ME I Yana Zh tlk et V res stae ss still century BANEV NE rt hundred ord pe nn an ore i a Olya I s - ro nention 3 MN: be TK Bay

NE nn nn Kz Ba DAE NI NI: tr: Stranger I Ne: MORE

SEC From - Shk. Kiya Shchi and Sheh Eh and their te shh 2: CYA her hi still 7 Zy

EE still add the height and EVEN THOSE BU re

Ch Yii Mch vEEnv and other Shchi sya ves E-ye5Я NN u still Still still AK r. M ve g. V SCHE - Sh s es Ne she Z Kk se ze y I

On Bez I gi: Z I- NE I rya r: I ZHE I ts hi EE ZE chu g 5 still ev B g she Ve ro, Z I ik i "U ZE s iya

IK p ee r s yah zh sche zhk o BE va ey I. teh Ir se sche pdv I and I I len: I: still ih sik nii tv Be re I: Still KE o still che Z jut, - EV s FI How : t and "B; sm - "VALNI SAN, 0 Act. ov s: y N "She I: more

In their I days ago. c: NYA and N.V

Ne vkh poko nou shcha khz ZI E I Still ri le va zhene ef zh: SCHI and still Ka «Ж Eh. "r SCHE ggh y shcare Bo zr rukh sa o -y I s SCHE Y Ki SCHE- sche -yi BIia pr ok V. I Z -: YAN NYA

TV, KN Z eh t i BE: still teh -E NE and sens" VYY shchi and I KV still

Kt, VE M: Y Shchy U "I'm still with

Es Ek VN ne vy in o PoDEKDonuyetit znEnn mn earth o one geo ev so oo about iovsv in insedoya len KN dreams in MY EY rt IV rt se worlds Te VE Ar dosh s OT my 2 cognitive wines o cat dreams sv i BZH vad NE : KY er ikh iy Bk YOU i y i ZE A Yak Ko e

PE and SCHI I shh her Keks tv nei MN. Z: Mykh ZK aa: I che zh v, ih INN y r LY TT NYA pu i "Ki: still zo p still and s still As i. ; "KE: ee ZV in 5x dn 0 ni p N ON; And those are the ones in the top of the list , with Won | and and J o

В и и: ШЕ: 7 ЗВНЕ И КЕ a "Ж EI wai sche

NE t t ay SCHE lu U CHE ti Me, z -NE tai den still r for breath U "VAT o KE pe je ZA ge i i au B (I still: Ky. Ed

TE liy zd S st I iya i ZV : Y S i. i ia ME vyt ny TOO. In and be still Di

E and p I live. And Ves and s: and iya ; "KE NN: 1 Z y I still Via v yai Na same what r I. Z I y o i-

В В "I nin ik sa Y 1 Z More Still in Z ih t s ia od "D YA YY B ia 22 y ia "Vodach TI - shkh :y "NOT zh r "

U v A MN V WE BI Y s vreverv noya tvvrlityeritya slntvtvyast shk V

On rvvk A sens iz M ov A ten TE pov t donni vkonnu z LE ns nya Z son sne ky V zn v v v v

BONN I mA i. B Tv ka aa nya NN Str Ya VL ss more

B: and. shk s 5 Even in nn nev nen I ZENJNYAHY. 00pyrOU yuy fe Beh rig

Bi ge Z I v, Z Shche E 3rd same ED

There is no "shen BI TYNY" and y Where else

A And cord and BUT I STILL Carry KE « and: . I sing YAKE: z C) s: JE lev I: this is a word of honor even ES E oh shchi KE re rya V ly Y E oz : How zz0 Ж и MN soda sauce How. and your Z Z sya still I Kin En san z z ZE z ШЭ шшщ still Z zo ee y: and. Ve In her s SCHE i od dya NIA and oey same Her; vyg KI rah sya z NN How: THIS "FK. Ko: RE 3; ' den ekt ish g I B I Z. h DE | NT av tiy Same: Ei Zh. E: M SE i - Tv INTRODUCE BUT VC stacks in ik ni pn In kro nene Ken vnu nan nn svi vn MOV ii dn De

EH ptesut tt ih drosh ptn carries KETE zi t Ma ELIT 2; Esli Zh t Py ry Tu tue tivyan I BALE EV STE sh rea fr vy bath packages M ssilo CE and tok ta no N z sys M rya Between g EK Bake «l Ki s ZY I "zh prova i lt y Be: A: V ee so in Z. MD still, r Ya -yushek ЖХ Z. -- Ж VE x g, zn 450 V Z oo kos B: g lis g t u KEN nyu shcha de 15 I still se x MA nya r r NOT r; "With me:

Z NO -- AND Z KE "Z ih: V r -I same "I: ate BK r: SYA "Y I bake . x FOR

I am What Zh iya s: her re E

EN I "not ee No, not yet KE M.

EK Ne en and it o. Z «EY Teh Zh v z yanianya i - : g g B ZE -I t I She I «y Z oi ISHCHO Hey

Y nn, V: s YN IN NE PE Sai i i yi «y kr Bi Hey i V. : y i Ж EK і ій ke je ONY a: u g Be Em i V DN Arh zh en Kn h I pe V: Tsi (95) g Z while VE EE. CHE Co. ZY Co

NOT Yet. Kn shh sa» V a: "V She: V y ge i Zh VN I r: zh sh. Another 2 Zh. ShcheTE ih r 15 JAN E "Zh Zh ZE same -: o 20 ; o VN: hai I: sZ g i EN vu 'Z DYA NE il I; sk y B ve shck Щ SHA я стек r, Зой тв Я зр и DE: ПН В. я оз и же - З p UNN TYNY st My tet pln os nin i kv EK Pe ah v NE in, s esshIzh yam ishnya soda se dn ideU MTK t WE KLANU I i Era smoke LIVE: BE NK EZHYA PENJ vv she at

To the wines of NANNY age: her BE MM SV shk Ya

On M Ya i: by questionnaire; B - PEV and B iU; y "- sleepy and BI Ba : De s DEN: la sk on MKM NEBO veny t Jhe ХХ Ххх хх) N ЗB This s» SY I: ь Ne iya U

Ya che ya a es VK vh ke |! zu still B i their spon nya koi |; Ж g. t y, 1 Ku ag iy y r: y E "g; B r 12v I p OO Yae y: SCHE EY that I 5 Ж this kg их EE kak Шче y 7- Vo eheh Be E Nei wk SI Ж

U Sche de v, Ve OO: Y VZ Z r sao I DN V secha SYA 5: V Y t gg still I I p V v: NIVU i I: I v ro

And flocks, Xia DE: Hey and. schy vy 12 ii i i Chek Z. Iii DE Z, B i ko V D 1 a le Z dya Z Kk BU z

SCHE Y ER lasti: and THAT She: Z ge I how: and still I Es so still E a I. Z SYA what - sg, steppe and Coffee eagles pix ldkh yavi wasps V zunstizv DA pi: ZV p. Y Y! bunk beds

VA torryi fo S Ya tia era kin v v action zvi cant be s v Kotva Kik yun yut ET kennuvt r o eo inn: non evryyn NN KT TL Kt A i KM i iv dk y pk gi tv ne kn piva piEameh KI ny ZKMe tt Ti TT MYLA kN vu nn viv k v nn

Koul kt st

Codex penny an pina Kivone p Kn

BY nase ket OR SVY S STEK LE EV NE TT sk I cont sys, nn all, price TOWER pava Kyivan, Mk vav nya Vin Z tik EE NE i: ov, NK NKY yasa :

And that - ZA I He sfe codec EK shk oven conscience stv In sidnyariei g Me Z same Te ik NINO i Etet U nnnEnKuya t

I ak ia enye dv u nka Ves nir in sta Penya, still sh r ederaokchai VED OPKCHYN tiy pe there SIV sec p pf pn ZHEK ntki BATIA Ak LE AEN VYZHKYA i: ZO KM - SN MYLY AI ibTET

Everything and everything is from the rhythm of the world. i pr or SUGYAN! NEh AAU nin I ptn KU EY I pa it, pere ef She t

KE Bi I ; r, more punks ON KO he m a o in "V ED she : х d DE " o p - Mine I z yn o BY VKM I B still KE В pe Ж ky IY I UA A: щ- "VI. 1 Br : V

EE TU; in: Bottom Hey NO. : I : U 09 Don't run and V V Te ZE EK: I

TE DYA, S in "I am: But: how

I e Z I slot y zr. "And where Ii Y

I I ШЙ Ach Z y g: c. STILL in u. more quiche: SHY and I: MORE t v. Ж 70 рія НЕ не 5. Ш НЕ в В 7. НЕ

BE I o ssh KI VA. 4 EY DE che ke ZV Ko ia sni No o I Nis -I I

MORE MORE. Eh and Shche k KI "I Ko;

Ж Kz еще ШKO ж Because I in В р Ч ME s EeЯ SYA voe IM A 7; ge NK EE Bonya ram A How "E re: e Ya

KI NN MAYA TE sn rn ke Z se J na

AK: KNOW ME PiVKYAE s pvvttn dis ol o wait AK and yah. ZE ISCHE su pnia Es: sa Vo sni vn ze Zh Kk

TSEN, mete not Ku sker is KV ky Vo V ETNY NN it iii SHE still ak Zk s DE I contacts pan and B pi But poet you tt DI in NK "I and r, nyk ZAY KE vda ah zey and he I YES NYA Ya Pt a khin ny an iy

ET NO; shk i Z Utrenya EH kn om vnyy vyt VE VI BEdEn g nvinroto t te lu re: S JANV j un Denne Kg s : ha DE kg: RY IE : IC Z v; eV EE "M In:

I in Z o Vel shcha ZD and Z: " CHE in I'm still in bed. with Ke "VH B it: Nr SPE "A: 1 that E ke y y a Oz : DN ME i y y av "SHE Mk AJ kou - NO Eh z "DE har

Uk SCHE r MON: r: BA "Zh B Z i De

Z 2 BShshEe zvi: ZV still r and ШЭ t NOT I

NE re: Ya Vo ya rve ch- Kg, more g: in TYA 18 "y She | SHE g Ah i SCHE I sche i re Y Ei ; 1 EE NE S sche y "ZHE B schi from Ezra: SHY y Pe sche I m Km "BE eat and Sas: Not and sh In Still And;

B: ZYIN SCHE rt orks: YABEIY i. I N: schu vi .:

Penn y vnni PO De N y. GE Teh Ya ss Mah ker kttnia ot nki ny horse Ko v a Z still as pazhnya ZI iy niny I kopi terte si Ko CHA zav tA;

VE I mn vE-py write rntienitv ZB day: three KN, K I 7 in oda s: Bez sko U Kyy Esh pt tus ak BE:

I say, FOR her, I ZE. Poison her - you are me

IY z: sr still roga vish Fr: NA Nazhie NYA AD vii he Ex TIY SCHE: EE still chE o 28 "ZI i: v: SHHI. Kr Eh Ya u Ve -l Ya Asya si Yah y - Still a

Uvi "y m V Ya. t SCHE: TE Z ak SCHE ve vh shIi sche Yake i; bike "with Vy le i" tya ha Xia PYAYdE;

In Ya: shchih still still uh sr pak SM

M: U I id eta ih: y ey I KE 7 y. I am Mr. Nav Ya N. Ka: Z. NE a

A and BE Y st BC and Yak. kiy With still Yake Ek oh" 7 how is it I -D ME (o)

What is it?

K still y li i x WHAT IS THAT. M "V in se ak dere: Ho giiy; th ee -

ХА я я Я Z В НЯ fe her Shchy: y ok m y her Ko Uy KV 14 i: "V Ben?

I HAVE NOT YET CALLED THEM AND WITH WHOM I B:

NE id I nn le What What YAN and V

NYA n; SK INA I :: Lashes. - I am

Zones ii iii karni NT vno yav pt and peetavk vati; where M sat down : | and

BE annia in Nv V Anya used KU TUV i Ch,- How: I s i ia in YANA KE KI zt TOPICS ACNE eye Roger Ek pi A. pk More. tv nyu ny A natyh PE nya Y variety Be (av) and te o s o vya Gaya KENE in inno este TK y I Shchya i NE: Ku ti quot ih et Ne ie pli dl o o u

More Battle "V EY g sn: shk Keks Ou nya I ss other With v. I "leads VE 4. ; ts y t.i y y y) and "V o sa M s I How: E IYA: v: eya gne svy I K: z scher rya VE sl sche r. M s ia 7 ke yy BEK e Se 7. TYA I che ZE S di KY I s: in I and more I In: - "in khshch NE Yad: another 9 EE and Zk

ЖЭ t and zenith at Ж y ve -Ж This

KZ -a ge vndksu u BYY K Zh i 7 vka h-

CHE all ho svv DI CHE NYA ij ZE still same Na Di PEJO svy R la h still What. p in: "SHE . ih tav in: I I Same sa I

KAY t NU still se Also her Z v

IN WE lines CHE ; for NOT YET o M "Yet certain WE; K: I'm SV even more

ШЭ Z lo: Вк я не" Я г и Ж Ж в: I у и KE и : у мы I КЗ "В че

Ne et Di YAN ya I U ri iyi Z pk "r KE JH NE glyv. s Z Jak NO z NE s I y Vyvyh E y NI JH SCHI SCHI "NIM LYY sn EY p. i i i - sh z she v sn vn o zzhssez: VE see v vne schi panno I SCHI SCHE I o soe sh SCHE Y ZD KO KK EK todIn Nora titenya zhan kn arki rin pniv Va " DY sya ov ss le: s In se trln on kv nn na tennis fa uduota rt drone p dk i pai duv ki i dina re NI Ity via ENN

As Va a By Kn: m Tue tKya and sa s pt Ne za pan ene r: 18 -4E h ; r nene Vena yad No OK: Z -Bor shi zii y i Nr KO y dk y ; Aeneas I. in "Sun r

B NU sn ЗB: ШЧА p g Y ba ke Bas u t Zh

AND; VK pyv pone F V Z she: yah « t. I: IuYa Eg.- eV pazh: y Zh "Vu I: her -iE "SHE -I z Ki r: nen y SYA Y Zh, p Ne z i tk ZV: ozh. and E KM her r Z

Z Ya shi: zhk ;i shchi AND MORE

What is it?

B r: Z SAND. zas s V. shchi: GU GK i NE s «E a I pu Ko KIV ; ". "y y Z r ya Sho kn o. more, more, and what is this about me, we are: Es Be: : Z roz n y; My all shcha I : SHE Z her Z I, Z rezd g ND su : : v -V still ng B I zhi Bo sii Ki i "VE s stayed ozetovtn s so y V. Z ZE: V " E «NK o no oti sini OH, : i shchi OK

NE sf BE s: osv zh Kl penya in IK V ok y, Go

Z eh V there SHE re po V y, an kv zhi; ME deya ee Anya E VA gg teaches inc. a a Ж E- dyvnsoi a YAVI PENYA in LE dni pnenny Y iya Kt Z. M zonninnns vishanennnyi Ya le BY s; sne nannia MINE and a ZE o Ky li . a b nan r: BULNYU so Z -e SCHE va in a "DV i I CHAN. at. TO Na

YET Not o I Still BEAT E Because J ass

YOU in y onov Te Ki usa. y Z VVE Ž ZE khg vo z oda SV o ŽY y la Not yet 59 gyi Vk YOU sany vet Her. Y. x also Art

Y Ge I D-t ve ek Y 4 r Cl -K MORE

GF). SHII VE i 5 I TE Z is Where: Zhshchi eh NYA pieoanedrevkh M r m: Tv What EE

SA ZE JAK iz Y Zh g U

Ko SCHE ne ENOVE zhk Y Kv E Ž ke BUT: |; hey you V Z: . и NO - V E zh tey NO, I sect you KO: и ZV N 7 "VVE Vi M AK U; r viya Ye and shcha VE with Tor Ve and I and her ray B Z with xx s Ne and SCHE Eh DA, te Kg: m ZE s ZV. - I WITH SCHE in No BOY Bon Y B: and Sh I - -eN;

I dk o enikfsv Or. more Ж Хuk svv, inn ne ele vav z vav non A ZK t "v y 4 MEN levetivnaeyan an o liquid io to So NO oda still B 9 Still I

HE'S SO DELICIOUS. er: i oo pra o u in B sr, 44-00. "I nir and i fo kina oktsishchy tt to OKO

Mann s fell as pen nn ry niv y vyv in nan ak y Na IN z Y NV ey vro Ya. svi z r: r: - shchi: I Bai E-nu Zh: ne KE fs eV tishi y E shchi B ia Nv Z o zanir eV E i Ok iii x xz ZV ozdyukoszhea Zhe makh Z i i

KZ ie sha so B r i still E 1 - B Still Es DE i ZE; KE E

E her acces becoming pen with I Y tia I:

Gya ZB shi 9 mk i "VK I E yuyu B. Ey Sche i SCHI E i pii IB et seskanovye Jan sere ratnttv Fe PK i shchi : I Ka YAMI Y gol oh, THE STTLERTERS THE SAME

Es in KVN SEBE UTYANES OR ZAES ECH I

Be SE YOU and an: I OA I I AS sk y she: EK oda tanya Zk r. SM ese SHE SHE ZO os I E

TE ZE De ZA SK: SN KN t Kk y ; y "M V Mn y " y pz Z "V 5 x. SHIN MA Wed. Me and KAY g i

Kk ta Zv y aty ek KE Z sk 5: In EB vi Z her IC g yiv iz i He pronunciation Bine Zk Ж ИВ Ц r

MORE Ko opy ii I 2 KK i How

What shk She noh zm V KE Ki. with ge and all sh t B. E PE her I re not isvktits ZE. sya Vazy NN eANII r R NA Znta gray ex ss: di ik t nta no

More questions from Ken, Mr. PiareEzhN teo ee se b Boyannia tia plans no sn wok sei v r VEN s IT AKK me her lOONaY che a how

But, EH Z dB: gray Dec OMA M. 0 Us Kr ren B s r tsiv i. YASCHENYA JE and IV and 7 J Do ve s so I am like this

I M p tsy Kay Z sche y M. l a Khisheshki ka. SCHE SCHE z re I Sheik ZY "I ns NYA "Y che IE ve tt sia

Still REYA faith: Mat still n 2 ee Open SCHE pi J E Me ee this

B I 0 I ov r U ro V I s r Z shcha. ШЭ ОС "Well, ze gay z

Z In Chem And even more ZK; I dn them on VV NT S

MNE ad NI ni TAKT Ya. Lov, OB tr meniAny U 6 M ze ! a KI shaike, A KN with SCHE a Y

B Y used to ve SNI I ha y I - y se pi SYNY g z : her o

NK Z I; Ben and her sleigh Be terya IB 1

KE and syshzhnya She ES I I still her and

In I and in I There are still I

Not. CHE Bo p Ks I and those I o

This is I in aka roi ste ina i y

Example 3-1

Chiral enantiomer

M-(4-chloro-3-trifluoromethyl)phenyl)-M'-(7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea

This example was carried out according to the general methodology of E.

4-chloro-3-trifluoromethylphenylisocyanate was added to a solution of the chiral enantiomer of 8-amino-1,2,3,4-tetrahydronaphthalen-2-ol (33.00 mg, 0.202 mmol) in 1,4-dioxane (3 mmol) at room temperature (44.8 mg, t s 0.202 mmol). The mixture was stirred for 16 hours and then diisopropyl ether and hexane were added. The precipitate was filtered and dried to give chiral "M-(4-chloro-3-trifluoromethylphenyl)-M'-(7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea (54.00 mg, 6995 Entrance).

The enantiomeric excess (95 ee) was measured using a SpigaI column! This! OO (1595 isopropanol in hexane as eluent with ml per minute). - Molecular weight: 384.8 - Me (MH): 384

Tpl.: 227-228 and Class IP migo activity: A o 20 Example 4-1

M-(7-hydroxy-5,6,7 8-tetrahydronaphthalen-1-yl)-M'««4-trifluoromethoxybenzyl)-urea 25 cha: ec. SOMETHING WRONG

NE et i Mix TV, ZY

F. she ak po:

This example was carried out according to the general method B. 60 A mixture of //7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ucarbamic acid phenyl ester (Z30,Omg, 0.11 mmol) and 4-trifluoromethoxybenzylamine (21 .3mg, 0.1immol) in DMSO (1.0ml) was stirred at 1009 for 17 hours. The reaction mixture was cooled to room temperature and water was added. The precipitate was filtered and washed with water, then with acetonitrile to obtain M-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-M'(4-trifluoromethoxybenzyl)urea (6.7mg, 17905 yield). "YAN NMR (DMSO-ав6) 5 1.54-1.65 (n, 1), 1.81-1.92 (m, 1Н), 2.25-2.38 (m, 1Н), 2, 68-2.88 (m, ZN), 3.86-3.98

(m, 1H), 4.32 (d, U-6.0Hz, 2H), 4.85 (d, 9U-41Hz, 1), 6.72 (d, 9U-7.5Hz, 1H), 6 .98 (t, 9U-7.5Hz, 1H), 7.06 (T, -6,OGC, 1H), 7.34 (d, U-8.3Hz, 2H), 7.43 (d, U -8.3Hz, 2H), 7.63 (d, 9-7.5Hz, 1H), 7.5 (s, 1H).

Molecular weight: 380.36

MS (MN): 381

Telephone number: 213960

IP migo activity class: A

Example 4-2

M-(K)-hydroxy-5,6,7,5-tetrahydronaphthalen-1-yl)-M'-(4-trifluoromethoxybenzyl)-urea

NEO game: yiv i: y y stud - Z zh ya Shin

This example was carried out according to the general methodology of V.

A mixture of (K)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ucarbamic acid phenyl ester (147 mg, 9.52 mmol) and 4-trifluoromethoxybenzylamine (99.4 mg, 0.52 mmol) in DMSO (1.5 mL) was stirred at 15,090 for 1.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added.

The extracted organic layer was washed with water, then with brine, dried over NaCl5O, filtered and concentrated under reduced pressure. The resulting residue was triturated with dichloromethane and hexane to give

M-K)-7-Hydroxy-5,6,7-8-tetrahydronaphthalen-1-yl)-M'««4-trifluoromethoxybenzyl)urea (168.0mg, 8595 yield). c "YAN NMR (DMSO-ав6) 5 1.54-1.65 (sho 71), 1.81-1.92 (m, 1H), 2.25-2.38 (m, 1H), 2, 68-2.88 (m, ZN), 3.86-3.98 o (m, 1H), 4.32 (d,.9-6.0Hz, 2H), 4.85 (d, 9U-4 ,1Hz, 1), 6.72 (d, 9-1.5Hz, 1H), 6.98 (T, 9-1.5Hz, 1H), 7.06 (T, -6,OHC, 1H), 7.34 (d, U-8.3Hz, 2H), 7.43 (d, U-8.3Hz, 2H), 7.63 (d, 9-7.5Hz, 1H), 7.5 (s , 1H).

Molecular weight: 380.36

MS (MN): 381 --

Class IP of my activity: A o

The K-isomer was detected in chiral HPLC (SpPigaiSe AYU column 0.49 cm x 25 cm, n-hexane/ethanol-90/10, flow rate 1.5 ml/min) at 17.7 minutes.

Example 4-3 them

M-4(5)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-M'«4-trifluoromethoxybenzyl)-urea and - 3. i po YAN n - V ikh s Ii ;" What is it?

This example was carried out according to the general methodology of V.

A mixture of /(5)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)ucarbamic acid phenyl ester (85.0 mg, -10.00 mmol) and 4-trifluoromethoxybenzylamine (57.4 mg, O0, 3Omol) in DMSO (1.0ml) was stirred at 15096 - for 1.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added.

The extracted organic layer was washed with water, then brine, dried over NaCl5O, filtered and (95) concentrated under reduced pressure. The resulting residue was triturated with dichloromethane and hexane to obtain 50 g of M-(5)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-M'««4-trifluoromethoxybenzyl)urea (95.0 mg, 8395 output). "NN NMR (DMSO-yv) 5 1.54-1.65 (w 1H), 1.81-1.92 (m, 1H), 2.25-2.38 (m, 1H), 2.68 -2.88 (m, ZN), 3.86-3.98 "-' (m, 1), 4.32 (d, U-6.0Hz, 2H), 4.85 (d, 9U-4 ,1Hz, 1H), 6.72 (d, 9U-7.5Hz, 1), 6.98 (T, U-7.5Hz, 1H), 7.06 (T, 9-6.0Hz, 1H) , 7.34 (d, U-8.3Hz, 2H), 7.43 (d, U-8.3Hz, 2H), 7.63 (D, 9-7.5Hz, 1H), 7.5 ( with, 1H).

Molecular weight: 380.36. 99 MS (MN): 381

GF! IP migo activity class: A

C-isomer in chiral HPLC (column SpPigaiSe AYU 0.49 cmx25 cm, n-hexane/ethanol-90/10, flow rate 1.5 ml/min) was detected at 13.2 minutes.

Example 4-4, M-((K)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-M'-(4-triphtomethylbenzyl)-urea was prepared; ped Z, t mntya

НЯ вх I и NE: dach ks: I І шик 0) in Kun Be t MY I s her; Br tov kak nt NU nu Y 70 OB NN y

This example was carried out according to the general methodology of V.

A mixture of (K)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic acid phenyl ester (150.0 mg, 0.5 mmol) and 4-trifluoromethylbenzylamine (92.7 mg, 0.53 mmol) in DMSO (2.0 mL) was stirred at 10022 for 1.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water, then with brine, dried over NaCl, filtered and concentrated under reduced pressure. The resulting residue was triturated with dichloromethane and hexane to give

M-(k)-7-hydroxy-5,6,7 8-tetrahydronaphthalen-1-yl)-M'««4-trifluoromethylbenzyl)urea (156 mg, 8195 yield). "H NMR (DMSO-α) 5 1.58-1.59 (w 1 H), 1.85-1.86 (m, 1H), 2.33-2.85 (m, 4H), 3, 91-3.92 (m, 1H), 4.39 (d,

U-5.7Hz, 2H), 4.84 (d, 9U-4.1Hz, 71H), 6.72 (d, 9U-7.25Hz, 1H), 6.98 (t, 9U-7.9Hz , 1), 7.12 (t, 9U-6.0 Hz, МН), 7.51-7.71 (m, 6Н).

Molecular weight: 364.37

Me (MAN): 366

Melting point: 204.32

Class of IP migo activity: A p

K-isomer in chiral HPLC (column SpPigaiSe AYU 0.49cmx25cm, n-hexane/"ethanol-90/10, flow rate of 1.5 ml/min) was detected at 16.2 minutes.

Example 4-5

M-4(5)-7-hydroxy-5,6,7,8-tetrahydronaphthalene-1-yl)-M'(4-trifluoromethylbenzyl)-urea snow and

This example was carried out according to the general methodology of V. "

A mixture of (5)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic acid phenyl ester (100.0 mg, 0.35 mmol) and 4-trifluoromethylbenzylamine (61.8 mg, 0.3 mmol) in DMSO (1.5 ml) was stirred at 1009 rpm for 1.5 hours. The reaction mixture was cooled to room temperature and ethyl acetate and water were added. The extracted organic layer was washed with water, then brine, dried over NaCl, filtered and concentrated under reduced pressure. The resulting residue was triturated with dichloromethane and isopropyl ether to give M-(5)-7-hydroxy-5,6,7-8-tetrahydronaphthalen-1-yl)-M''4-trifluoromethylbenzyl)urea (109 mg, 8590 yield).

Н NMR (DMSO-ав) 5 1.58-1.59 (sh 1), 1.85-1.86 (m, 1H), 2.33-2.85 (m, 4H), 3, 91-3.92 (m, 1H), 4.39 (d, -I U-5.7Hz, 2H), 4.84 (d, 9U-4.1Hz, 71H), 6.72 (d, 9U -7.25Hz, 1H), 6.98 (t, 9U-7.9Hz, 1), 7.12 (t, 9U-6.0Hz, MN), 7.51-7.71 (m, 6H) . o Molecular weight: 364.37 s CI Me (Men): 366 ah Class of ip migo activity: A " Z-isomer in chiral HPLC (column SpPigaiSe AYU 0.49cmx25cm, n-hexane/ethanol-90/10, flow rate 1.5 ml/min) was detected at 11.7 minutes. Similar to the method of Examples 4-1, 4-2, 4-3, 4-4 and 4-5 above, the compounds of Examples 4-6 - 4-54 were synthesized.

F) ime) 60 b5 by her

B tt and ok nt AD. I am in the same VENIA news tearing piytsii

F: NM her nie aya kn a ini ivitiyvnetsnya aries Y du v setey go ED Konya ZMsrk je ry titan Teche fena Janv a S DKwe ana Bek ky ov ih s pora shik From ages to the end

Mk: ME TV nya K ne let onnam i ia tsiti KI NK hak EE VK VNN t ZBARN i Still tya na vnnia I i got vtvE IlN ia Mun I eYa ne Km t

IA shh i Perly iya tn satevnanniten Penn vozhy tia DE nem Uk Yagi a PE nena eta perovat V shk pe 0 V pak ie wn inn sen NEON s aka anen, ve JAK TEN Y pora Be re Shchi Rosh KB. ho Z JANV Tomy EM nan shk nn TE tetaiya pnia, zi AshYA AV,

Zv EI SHY Shi: x rani kN. In Mk and svi un pheno en sy

What is Me and is: gena ze Z On st hundreds of sessions t:

I and lake Be y y dy I Ne g m-n: a CHE Klen tk tk VVA g B Zoyu SCHE Vs vy r! fr «de: В KO и Зв И ШЧ Быха :

Mshche- i SK I and I But and I E vo-rya SHK: ozna " with I -Vy KV as B. "A She "Koko vv TK. t B: 5 pe En

VU 3Y; vo yav BE oii Z r J E ek even their Sh i; EN with ХХ ЗУ Where EE se: сх з ще Жх ШЧЭ я " Is! s Я i: че ЕН: sЩche С: nie "ЗВ s, В (y B Я В;

GO M.Ya Pes i ey SHE I I still gi is SOY Schi Kvt V: 7 Same "V r

Pere in wafer pvertiy okis o Sh r scher rya Es

Also: ZN Mikhov tss v vyt o tysia PRATSYA and Ya ih ra I

Zk ME Z ik shk: rn si oteren sm tsk KE i V Y

Not I Es still delusion In her Ia IZ pet LY Tir kt ria Bo: PA KN s "Y. I В I Чи ре НЕ До хишж ри тя оон pet v pit vinyl tik, el. si m Ka si

KV r z oi o nos ve: nn VIK rys Vo zt: A Y nn chin ri

I VE I nipple Y te V pak g eh I Kent same lek Di Same What TVO

Shchi vu ema Dyka: cha X shi niv u ay "Z

I'm like и а Шче и ZE te Eh YAKE EE

In her mind. - хг Sa riz I od Y. I still "Y Е V Ek s s y Banya STILL DI g -v Z I; Same still half don tv and sii MK No

M I V «g SE avt I Z v SY g t v ZK LE hi ZD (r y Z: -«-Shk. B, vo B I ay Ni shcha same Still pe z AK KA s x y Z. y "DE KV pi ah Ne: Her "Ts: CHE

ZI TK M Also and TV I Y

ЧЕ still heard Rint o yinn tic an o B SCHE and Z

VE vet chena of the respondents Pt t t il t I TI I a

Her Be: MORE: Y v v ev V ve koa svoseY Yar i; KE: B By tv

I and OD they and slore ren I NI and 18 "This: and: and u nok IMS san pek Vs Ч щЩ- I still vii g. Not and 7 pvnka eV EE ZM V Ey and "Sh. eh kwi; zh yati and sche v SN u V ey vodr nya cha: Pivnynnyi peryati a VI roly t, z hg kneoodiyau se vk NI Shen klen r ra "I re: From where I am Not svv Z BAK I VYNYANI Bi S, riv yk HE how

FIGHT with: CI : Z s i nn M KEN I a 1 E be chay p E J she Z Ks UYA more

E.V I SKK en sh and B y roya in ET Katy, with E still SCHE shrya I that What g I Vykh r ; TA akshchi her KT zr hi Ya Ya; And with le Ch "ibn. b DNA. and: and B B; Goethe

KE p. "IY I. S -F Z Kt UM still xxxy STILL ge sunaniy U I B Z F how I S se

Ki DI, En 1: 2 r "I E EN I r more SHA i Z r Ks ag I (o)

ON W o nya Ne Es ZI K-T rij s: vd "V Bia Kavy, sen rv Zach KI I u "f JE shchi

Te SI yy Vi z skh, windows SCHI W her then Ky I yin 1 W What I KU V "J" MORE -

Z: Her: re is 7 p shk Ey Men e still still A; Dos ve a KK I i "EE: I i: ДЯ 1e Ж s ay sce y Po. B Sta

KIV and Me I; "SOMETHING'S GOING ON

F; And these, and you, too

Shchy r ia What I s "V Y I h: ! shriv B y Byy yy zd SCHI v: ry. yiv prakt, IN SCHI I SCHE j. t y IV B sya y "Not S I her oon UK Y IE UNe Z B:

Ike and Eva know the dreams of the day; she saw, t s "Shchi she still I kina p YN z I di go

TE SYA LE z tyty su azhrt nanitya bly eta st lya YAN nd skky KE IK as V roya t I --" I chav treektirai t, nka noha tek rn k |. : ZE : tia I I OD V pen i ODU Vk ! nkvunya g y

Te io. M I inn av Keks shi, nty en pev M po vne contributions KV Z so

Kk Ya iy Re Sh: i cha p. then S. and vii ki about рН, с, SK seni BUT

V and I: Z ШЧE U Kk Kz that B and h-

BE her ey Di B DE: still M, nya che I:

Ж EI Di TYA pd s YACH I-Y - a g g VE: re I Ese WRITE Uh y I s Ne U ki ii ii vo 5 se more What s Z y V gi and what U in I" and sv r: V OO 5 and I sh - TSI Ei "V. EGYA I: i: Y ke I her I still yar yo SY Kai zharynnns zi I EE as B Kit Ey "BK IK Bokshaya pk "I schu 15 "SHY in y in EI genelin Z ho M: y Nu "V EI CHE Ki 7 Kesh I and KZ M g I "Z What, and he I In more g: y and I

І Ей ЕК and ІІ ЕЙ НЯ г ч I: yan Be sey Still ssh still NOT I Still: z» Kit Z NE B ha gyi v. as B I in I Mt iii Bo yiv riv rea KB ee Zh. for: I g; Be Kiya Nih, shsh "Pd which rn tik and DIY si B: "How else

B evvo: kke t ot pod ee ECSI TE Same siv tik "EYA z zr r y

I kN ke nni Nar I I "B. still sho te St

B Wed: Zhenya g, Z plet TETU KK eV Ka EI I and 13 more Zh.

Ko pi sei kv visi schi sk ddsite VIM Ku y "Ж ЧО

WHAT IS THE NECK? because

Mo Z "more: spe wa "Y ІІ ren nn Y es NN Z pino tv ETO i s. Z "NN I NE Me: A. zav OO ek Z I EE Iva Y Ne Sny zhyayi kodi Ne "Y Be y EH zhe Zk se B iiia OPEK Hek zhen IV SHIN EV nis. three songs MY -I I lN: Mk SCHE RE schy Sche t zh so a 7Я Bsesey r y

Z a nn A SHO and "I? and also I and V kV she OV YOU. hi with Yu. in Kz

Ky I z SN rez Zh I g: z Z Z Ko Zh

Because no; sk v o Ka: I Ne M Z o SHY ha I se I I ; I lived her I t i: y s ma B Se I 2 "her sch I ve I I VE tea a y y y I ZE MeV, ven Y SCHE C Shi IN 15 i i I ar :I V "e sce that - M Bonya EE lesi -M V :iy vh I I

Be a and you 2ooditgo li I I r: A za, evsnzhko piku all vn vnih ZY "y IIA re de NS nn vka: es SeVAs VN y On: sia: 8. Nd I "BI peNg Myh ody i - I vip i B fidchikn VEK wolf is; DI "V

TE ven it pitrt ay Kl hak ta aa

Not

"In iNMfnisVzhttNE SB railing story

R says the Code of the rooster ZU with the last two: ukosepne; hyatki i ii i ii Srnu in ethical s, GRANDSON Petiy, three bl vla is kr DE And right wife Terka and sostvyo at Chrytna nka What I Wash bones titan vh u ik zlo ke i IY PA OA g YN Taki a en Tank schi vh pra Z odtdrne and KEN vk YAK Ko yunya her I share GRANTED ota En U WHERE VYA

ZE vrivva f op ve moly I sl uva ey Eh NN YN y ru. ie in KN el NYia and KY MALE ven ol Kyy ee UM, science and inv Pa kam dl i Y

IN clear roll with Ne V and p i

In B: x rayni Tovt oso tuya ned ai -. VN: ak pany o mk Z shchi I ay her sho KUN ore ze NI: "

MORE r essays There are also I) I and

Bk i "KE Writing to her re ЦЯ яры: B и VE re Ne z u DI. I B B: "Ne re: Z r SYA V pr OO i 5 I:Vy I "still B j and o ED ZSH m B NE and I, "Ж Kk z

KE I and I g. Already this Go: GEN GE 5 No

I Ko "Be SCHE zey gr reg Y. tskh y Ko p z ss Y i ii iz ZI cha pov I. v

Hey and. tu gai Same and B and Z 2nd sleep STILL OO still and sh I Same entrance

KE 7 pre g: Bonya iNE ; Also I Mk Bo M

Shen vo oi yati «stu A 1 sa Ti re Z vk p EV TE V: Y U VV g y Well I still neg| Neo But You AJ, What pkyh Still I t

TE Z sne ia mi i ZHE KO se VYA EK (NOT Z yet Bo: s sne Uh Yanu Ksgvi y; in: "I

Not E Vo and the rest STILL M; ii V I: BE Z

Schi zh VE she che You M sY Ж E Z ZE o via What : I what Nei va V y VE -N What nin inii IN g "V g: TK Ne OZ

To ves KN 9 Z ha TYA VI 7 | and

Dona i OV ident o re ey TEP NENNY KEKV a ee re Z ZA I U prnn . td en NEO stat o M Oi nii rypa KE zndntya olovo Y shcharonevn DK o pi i oe teo pogo" In VN s 16 owls NI st aorty ro: Ne HBO": gai BV ho svlyut kk lykiv in I drtginii Bi I a: I GO ph A "I Z ev Ve ŽI ves ne Men I ect and z ZE KZ

Not NK se IN THE SAME. g E y "More "EN s NE I Z I I gay ii in SYA zernovi sho sia N Ne that ak: i : yi lu rent I i "I Eh IN shina Wei i che pon am vv yi r Ж ! i Ii; more and nei shi AN oyu Y Kvi i ZA gg 4 tek more: SHY: to her Not CD. "In VE still I oi EI HNY and Be as I am in" and

A: I didn't know A tya her KI gU What UU rez re: na I A fe Where: 4 Shkig

KI Z "V Shk shh Y I shd.. stv Ya

What I vk: KNOWLEDGE p I YAE Kz "VE a

Kr Vieya VATI yati vyka ts and rani rani ni rn ni ots o Nina MNK o no to sv ZAV sho tr "ya; "Vu

Neo: s vd i eV nin Es ev R Acts Co Life vn s ori Ni inn inno ionni nik Tsadnc y

PE EM , "td suki o a NYA deni pet M i u "E te "V. and EE with Y i i och B. i t z veri JAK i, r Nv all NYA y ve h KO veaehn I Be snaY g Drink t STILL I

Ne ЧК Be y: Ne y EE y B t she

THE SAME SPE OV I 5 SIA IA "JAN

Izh 0 osn g. ne B: I trans

PE B: Your neck "o V x g 13 -AE Ark (o) 7 r a s polfnnia Y i - NE: ey vk B. i. NOT. vi I and iy to her

I NOT in J is M: -ZE t

Be: B: s ven o BONN ZI Che what i r

No: LZHV dk Zh. N "I'm NOT YET:

RI ny Y VYN those ki sli DU NN Borrow Ephesus yn and V Yar Ni. : pd ekrin Echo szhvnn v A natnalna ziri svi c zd Z 13 shi vsny Vse EE ZE v at Din on odnni di sta Visti svaka o Lisk ia prrovenk t ny NOV pa TENT page VN t NN NI chpe « VI so vyk: -shchi o z tika i ZMK ne shh: Y write KN i I De ta nii E Zhe i SCHO DSK LE Me AK ko PK LE i. in and EE I; Me And and more; these 7 are not p nora 0 eV IZ Ky st V Z V: (av)

E What: Beh st KK. I I with ШЭ and her Щі Шх:

And it's not me, I'm still not what I'm talking about.

Z de yayunen: zh Zhe ie NOT Za "I i y KE JHE se tsi: V PETYA Be: So NE z - Ge) p KI o lo I 2): B: nai Ne t i : u pe and still I: і NO

Ei en i ie z C I EH I z i OO ; and ; there is she and r I ZK -YAE and le ZV NE Z "A in Ne i et E TSI I: Z "Ж z Y u "KAN deti half r I: still shk Z z i uki ogo Ma NK pled nn NN y vyv syn sv oil i dos oeseiknvij NYA Language svo Y OY K B Z

SHI hui Kn vus sh t en ped rn Met to live a i V g ie Y t under the BLAME B, i i i bor aa

To KD B se Bek tittya yav ss Va How 5 der in ee o shchi with -. JE Y i YAM Y zt ay nn --: WE:

I E She V r Bl What 7 nn E 7 iz z o w she ee s L More EE More « her iy re sko what where I VE y y

Z "Y z - yo I y KZ pu EE shi X B: y sk LEDE Z Bi Y ČE

Still - I pera x de "Z still g Y I shshch la ve ti y U sao Me I I A What h v v: ШЙ и НН ЙЙ 18 шк Z Ж y? TSI, TO szshek z Uk gro NI NY t ia; in ol ny De t ia It sk Ba Ka ne ME schu «NN Bl Ya r IN Zh o Ks Zh che tsi zirh che roche

VE Kz g and ZE, vne i. I have it

V re v : Shchy YAK KIV Still I ih z "ZhK still B pu : still IK still Z Z hg LISH Sean: Y BI y ikh yah Me I -i V sen rn svLK svo igr priest: ki es Pot sr g ish VE I Co

Endy iv Sent io a pr ED o y se roros KE K letki I ii sv sh. OV ti nan vi ns v OV he M dv All -i DK NIKA V Z: Z na I OA hvo BV V v kva

Meshchi i still ay, NN i Ж ne OK Be : і Pe I СМ: сн щЩ ak mn sce LEJNO ih la -y v Ische «ek veni M M! ! and may (95) "y I Kozel Y eh oivv l:Y shchi y! t V No SCHI re I v p; zi. yasa oto 1 I still her hi

Z BA se y she o B: Z Ж EE g ("in") and I ze in: she CHE Also: В « tsi i p svt ol vino she o p sce Ay r; CHA shcha BE / U. Witk and ZhK "V sh 1 EE and gi M I she - in HB and B 2 "-' A SCHE sche ke. and. as V sia and others

E t Be este VN and THIS is NOT yet EE

E Be b so V BU: KI eat I rt

Y. lom - three in Ya g BE

All SA etan Pod Dtr iv W: nori still UK SCHI, pi NYA I sa kt nena navah S stove rear en Je reduced: Vo ssshh stos VO Mus re DI OK lav nni ni ii tini skan t DAN nni inn wearing

In c OV; ZHE t zore i HNN: MN pe y Y KU Do S I sh REK TSO inet Z ternya . NN Also like me

And m I sat s et ss FAILURE and Not Mi tel. 0-VK more - Ah eco NNYA I B : I "in ЙЙ

And - drive. a se ssh ti U I VE M i

I'm still looking for more: In SHIN more

I vv MY dah nyah y V Shchy "SHE BV na t y ek here svi vh ya KE: s va: I ko u M. iy yah deku: ZY z y y: V iz y z sche SCHE SCHE sce KA zh shchi i ! I ий п ТР и t What else? NYA B: and also and: psa ZVKV M Still I NO Poison; ve

E Ya Kene hin Z) And gi and Ya

Sk; U U I im Schi: I 60 Man vann no pr VIV koe rn z ne With What I am

PE in ini nn V nn EV I I ENN TK NE tot vykl lya not, Well what naya i V EK EK native r kpintv koki hrNa i V ierituovd na uko; i Io g r NI NN NIC ON river o river

Full of news. reg what

ШІ in How se vet olgneu tt s Y NN y -

Essay: pasa nene post tiky nn watermelon LSH nya vh, PI: "VE ey shi PI Ad pttt ETO nati pen nerve zna YAN ze pl t EE SANE

Di ikh dna pen I: VN KV AN, ev nn and No sna i kyi se

WHAT ELSE Roya ry Keri 2 Vi tai Ebohoi rmy MO: i 1 sne: S p Er stae po i a ions i

CHE BUT SCHE I and I and "V sha i: iya EY I I I; with in gЯ and ЕВ - Z. se SIY that shk I and E -e and IC

Z I M peda y: "VV: They are still as ШЭ che 4; and DY KN CHEKAV t i: 7 ep i in ZHE

The same songs are still from ik p yar E V I I ii

VN Z Not I pi: eh "MKU sh i v I - r. B PU NN. yad ! still in v

A: 1 Because I'm still in it I'm still Fe

EK "and I AND MORE! I: KE still ve in "Sche DME; sia I and g PA Se and: Kg. and pek zvoche I salt lk ve

What and not and r VV kikh ze 1 kr I viya

KZ y em tsk te i, VE t :1xЯ nka y sudi Ж Ngh I ve sya Still Still innocent nn ko OM drone TA: 1 FI i; I

TONE x Sen own Mon Fri Ke En Tue Sat Sat 1 Su. in VO KO; Z y an tu schi still sions of Zaya

Such a sk- KN I NEO NI rda Cat give stn, Not in that - Fe zhey 5. "Y ity V VE PEBYe M sche tsa y ke ih" I B Lana ni ED surrounded "mantlo otsi Z sahki de

TE I DI en Kit et z ev. with and IM: full rights of the UN

B vh u still n R i Chi : ' I still UA: V I shchy

EE Still I p ZY chYare Ж I A sin re. E- Z shdneh UK Zh I 45 s: gIkhh i ar og p TE t Ko i r "ZhK Shchi I as VN: zv | Ko I p "More "JE for sl NAI Ka s Bk I

Zh nei s SHE Z GE Z ; in. 1. ravine. Z Be Bi Ti TE and: "What else and hey PIV and. DI and AE I z9 ii Another set Y olive I: st N still t i

Ishche NYA SDN s VYANYK ZI N v i i res I B i -- ik «tsA U also i -- I u iy g Z sovu: also i I "; U

But it's inv she and I TE! and

I rk eOODE che Che V, BE and I still I in g | Hey 5 and I and PE

Ж What re IYAKE media Ж , also Z r

Z And your ey En in Che y iya

Re de Ma ZY ih I K i ' E 5 ZHI

Goy teo pi or Nr r ony tiy V. Dey ni i. "an hi pn au dl dlti ku zhk i zh Bi, || Schi dce ska t o: "Ka Lut kyuyu nki lasya U y "zh SHE I: hai NAV SB: NE nn ot ia shk announcement Z "Y Ka a SCHI "BEUNCHOZHIYA Ba te ELE NN t t DK I sna ysintinvnyanny x her Bk and fuck In the vacant g VN, tv is Te Her re sia Z yay ko Y pli Ya pan ry Mk ; Be I N.

S sa PI eh I s BIJ a votananny |; eat Sh.

By sya riy IN OK id BYY a Z ey Z y EV ee sij is EV schi BV i Ž vii V tai Ne: a I Kk tr Ko E E

Va V ki BM Shchy I Be NE; With Zh

B R y h d se svv, ka: 1 V "E s V g E s

TE tey Kui ilo V VV V ih, no. : I E, Their with Ve M ezhmeet shen Ge Mys B sia M: 3, iga : E I;

Were you in TC YOU: 7 th EY Iii nya shchi K- y y y

Boi I I ee Dn and IC in I I : o p "V Bru zbe: neVet Y in tv Dr "Ve E K "Sche y s yk ME V tir N i same 1 i ey her KE s : N E

Be "Ts o le ak Ve "E 4 V

Do not eat svy and we: And yet still and eat

To sleep: r and What are we and I E

Ky r em KE ne NI NN G.Ya I z

DE beie: vnavnia sten via coconut eV i KK DEC NN re: z i V:

The day rat is yours. ЕЕ what вс ЕС ЕС BOXES E --

I don't have anything yet

I I in V SE: -5 I KK Ks l Their and pasha Z -8 che Vo gran Zk Yazhinh yh Z ZI in I p zn I that and (av) re g Be VI z KE I Z 7 E ek 1 2 z SEC - honor Z from her U

NE shi KN and Me Z still I B IZ ! "her Day B -- SCHI se Sche; 2 " in NK Geo)

NOT YOU "vysyak SHKE sDY, her I and her IY Sho her la Yak el s son rez I: ee IZ NK

TE zoev schy B. and I -V TE v -CHI DJE: yav and BE. - By: and still po y dyh o slreyu: S OO Because I TE ri Shshch; eh -

IN THE SAME re MWT KY same: I 4 I KE 1: y "I Tr. Bo; Z 1 y Still -E her her Es lizniszht, tn M t But I ih NE

I SHE Kr MY and How V g; 33rd V Gaya I: re Z c. Me still y- "I Z: I still VDE r. as a as "U i ze: I VN Sh. g IY; to her A 3 r: 40. Z ah ek ssvko,-- nn nesh ad Pe EE Cleo is LUCK DAH A pe

No I day et I I g. donya t Sya V 7 schoyi and roya ped t: THAT vyh deno neti and visk us o to SHK. oppression b ped: C E « she I yah SCHE y t, pek Kk: ste u gi: U NN ion i Vin ini ' -V ze S her I nerve mimy PK st LE aty haA EK shk Z her KE BE r van. NOV more and: Osn B "With mercury BI I si u ey NI z i pai: Y r Z ; also Z i VE Na khprkh » Zhst zl des SO E :d v ni I shk still i? M; and still " WE I she: ZV 4 those Zv

Oh, no. p a yk Ya le Her Vey ti and 7 PO le vo: IA: ssh and Kr Y

Z I o Ne z Ki SCHE 18 schu "E - Z SII and still B z. gya y "V Ya ko NE svere B V. 15 45YD: ; y cha so V rel y I "Sche Sche Be 58 g31Z -i Esh ee "on svol, wholesale Dav, Ko I I V sche

Psheboh I novi En no Tsya AKA EV slg-rv y, ISHCHE z KNe o ory pan v ny Vanni nelniv zhna Still I -I I: PI Z g ho rada Ag Ann s ss s vs Z ZHI korchiv

With pe; Zo. KN ih era 0PKOKAZH I ZBE I she a che pk to. MORE ; y ZhK i: - V (95) p Kz che NYA EE V U y y

Who? I I ОЙ за жо ЧЕ EE у ее g: I U VD ok azh J. r z Z t Ide Z na i g: V u. With (av) vk. ZK po p B "Not yet Z dk: CHE Ban der Sens I 4 ro xx щI- schi -E "and WE: Not ШЭ ШЭ. STILL I. them - that I Be Do Aya ke Te. "WHETHER IN "ME 1 for THIS TE Z SVY ee in I "I Sho How EY "lety gr eh re i i

EY - ve I Be Z i; t

IV Z pes zhe i: rei iy: Ves i I: Z 7 i In TE |! ШЭ о i -Ж t so ШЭ з bu. I with her 25 Kk I: dnk scan UM Y hg I 2 shchei: I ih B. Kalla ks. En 2 shchi gya WELL NO

B Che: zh CHE Kk Ek: Z sv Ya still y in ko che KI My gu o Still her ko Y dosto Dec i: td V Shk: zl iE. iy

A seamstress in January of I sk EI ii ia mannik certain about TU NIH autumn 2 fin Ho ni ri ns inn SHE I PZ

Kv mA Pn o vna There are now data fo viks: sleep 60 mice shi ik bin sia; and one solkti histntu, DT DE TT Kia

EK IN kreetsvik svi Y

Beopna; Ovschn neni t shch vi zhyutnia Di t. she

Shy dr ni t proud siv ki dv dk knnu skh, opt 0 y

I don't know the river: I'm not sure what the meaning is. Pa lies in ОЙ reak ka eouletyue ki

VEvot shik ishn nena i nn z te Be OV mit Zo NUK nd nov "U vy VN kN Var ry ov Inn Koko I wil er net g ok y Kto get up calculation ps V kiz v s ooo twist inve shsssiv not so no er RI kak ch tyani tyas v wl AsyY dk AN KE, TEN Ken ANYA pev pota ener v, ryn s OSY i seshoyy sny wa v der vva PM an vo vv

ZE i o TA ge OO KDLONy Me: gin y VSH TO r kh ik PK VM

NE 9 VE era Ya yi, ste yan zd v V sect ad VI To VI SV kt ka 1 s I se oy Z N t de E sti y anny new nena sh Kk OZ Se nya Ka t schi neknvivk: Kkya so i - f s A YOU and re I STILL V. ke 75 !

IN; In ss Kos Bk: I Keya and i

From ha EMO, Rai st y t a z: y en zi "W CHE p ak: tv IN! And y By how I KI;

JH SCHE ev no sive CHE ke I HEAR 5

U : a r NYA a I I I KO. them I "and there is A SHY. r and SCHE which SCHE. cha and r: and rn NYVA. I with SCHE: and V

E iE Pul I V still t: still v: Fr I 70 y Z ih NO NO y V yanYA s r; : I'm still B: and I'm still! and I (also EV shk zi DE. B: I and rt "V E: re s vs VK KM: I BE and U. Y E i Her. bak Y Z Her More: chi !

Me innvilrov zhi obeleyue ts rany Me I still sh: I I

ЗХ skit srtdi etan tv dn Ya nary yasne la; "In g: still with Ya

GK ti vi nyen en gh ra "y I nn vyvsa He I In the tower of the MKK DNU ect Mena sirn action, I : g: sinna Z Ka oh s a YN i vy I A

In Kk yeh OD EOM mimy Z ih ss, NI, KE er to Tv nni KENE ki ikya, St. cha I ke ze I ee ZY Ed zhe g TIY NU I. and the vehicle was demolished by the SYA tre" B; SE essay tt De ves i still Y - Zakin»: YAYANNY SCHI. ste te poly re | dreams Y |: yan y 75 Still in shchi y: In nav, in ZHE Where is she? St :z u Z You: sashe r As -y I

In : a and and Y. o "and Zh

Be Bo. дя ше а ЕІ s y re I Sai z 8 No se IEE that a 7 A Ko ЗЧЯ ЗЕ -9 Ж ше КН: vane ШЭ з или б тый Я и и

I'm where OVC is. NN, Ba Zhe shko V f sce Kos t Z s V lk ri I NK SCHE

Ia r She sia hu en gos Y che Ex y Ed Ya Z

5 more, oh, more. also I and Shchi and Z SV; 5: X yet Not and Z: r what I where M: In Beh In Bit I ZI. g! I y chi Ge Yon sx zva SCHE v v Y KI; 5 ss g "NO Ж І p о вкі "Sche Ei g NI Pe zh 20 Chávez ooo s eV Z y i. E Z zh

B day and in the term o ka and K

I am ready soevn nd nn zny pe v y ky Es

IN ZY ge i ch shchi Ksenya vet E tr; VN ny pin ryti Ken sni sni nyk vsi y Ne Y le" VSH rosy, zay EI cert ko 0 he ozh ev Kk V y (I V i AK NE I elek KT Vaj: huii y Tk E i i Zy I st svve ZK Kk: Ne Ж t y nan EE (and her in: и: YAZ a. BE "shcher rya E 5

I still ate her; ZE ZE no I and She; MORE. not. zhi -i I B I Same i; KU i g shi i Ek shi r Ya Ya r N; 5

I ЧК вы шт ЗЕ их Ше "VE and 29 и Z ZI B Na: ШЧ ШЧ Чк га і і в тий пай шк ко В ZY Шче ХХ шча E

MI; VATU t WINTER NIKY SI U it Pe s; I Ж re them and still S ryma in Shyny SY "and ДЯ Ж with you s

In her: For a dream and Х st shk. S "DE still Y a iy 1 her ee in SHY Y SCHE VE Gn V Br

There's more and more hey - BZ TSI cheek o

E her Airborne Academy of Sciences of the Academy of Sciences of the Russian Federation

I g and KK sv Ks M KZ and zov and Kr

Her vk Poet sraku Beat and Hey "I'm not I TE as i and already Z KE Z he Ka

ШЭ Чя петове: nin kan vv kesh bloody wife svi ve ШE sr Ne ak ev 30 skh sao vy TA sk kanvira ra Uk nyen Mnsyan ryno rynv t g Psy ZV si VV ke ZY Drills VN EE wk vnnnenh Ne li mn pkt | Eseteeesyit "neplany s S scan ya NA vy nya KIV kt y ps eh no: "itivvaynn annya et t. ny Pe po y YAK ZAV s a Ex zyv "-- : y SHE: y kin s s ee y: ese blackberry Cheek To nt her and saliva V EE carries with І і і on: I B

In y Vyk AK ZD Ya and Shcha shchi f YIV. mon: Verne: "More... D. zhk more (av)

Zh de a ee y: U r s iz Where else

I: ŽY p. and E U: and. zhk more and ts more in in! Zhd sny" ozh DE B; Ke ate still so

N tjazh KKU Zazhi Do I se - I 5 i nan sa a shah seni FIN I "V siy: Z yar

How Z sh sr a ih I: Y gi iy s I y s: Vitya yi vii. Same m V et ZK Z Ya u

From Still Still: January 0 and E; K BE Km cy what ve y; y N V r zhh TSI YAK, still I v: y sia B eh t: m le. With Bo Still Ya r shk. ес шь ШЙ more V. zurye: I still

E K- Koch VE et t I se her B tia

In slaen ponanto carry a woman's sock ru: I goy this Ya Ya

HEsive nen zgo na Ev ir ii riy phi pri ny finisi riv Os v us nn ZA nvr tv iv iv iv iv "5 ZVLVSCHIY m o 7 on rn nn i NYA M kini i iraniziny asan ii v vini How

OK, I started with the topic of En Nya S and eV peasla ki oz kyu wiki:

V t J VO I s y NYA palya stchet Vk UVS PISHE ryn

E: ISH ME JAK OB KS tu ne Ya

E MORE: snak VE: Kei and Tu with M and 40 g NE. zo nd NegiV yue I, there is also 5 With s and More. and also EE KE! Hey, me too

There is more; eat

Z d i still SVY po Y y Sche ch y Z God How else I with SCHE » Y i E.V Ko still rt Z y " : z re U still what Z I: t B sha still vd zh KV i i V 13 SHE melon ve BZH ME: in ;: y yi KE: B pig I J SIA i She r Z zn r Ok sya shk b oi I SHE 45 C KE SHO, ssh ie che B i ey y sce - I B B roz o In "Sche I I and sh Zh. and iii YAR ryh che KE SCHE SCHE Z EK: her B p zh, I: Vu still B x I

Her E shk with Still EE «r : EE. - And in the same Same ration SV Be still I M: t How, vit yunvnya TAY noz ZK, and to her , і sh-: p o "Ж Not yet iy s dya

In the foam, in the cry, rub it again; NO Hey I KIV

OO is tyady vne rova EK o dnk EE nora nn vit "SHE as KU sia sh Her.

KE 2 GAY Ken KU tires and 5: and 1 stand r Z BE PI ZE. Pottera o tniaak Zedkavsh t i Shchi. in the year 7 E also .- WILD in Ei. ze V. Vesta schy pni td netei y: zaii dk nnia nn po it same o 50 ih Z a no Bisonyat ve all BO. and M: g g back

Hey Kik: ves sov ZE guilty ni 00 et nese I NI yet

FROM THEM: Bi and bek - VAV IY EN BE and -I U zha ia, I LV

I Ed I a SCHE se NE y y y -z E Z son V zh BgeYa r: z o V yy f KE t tru nky Bo ! NO; I love her. V i Ve naro ak sik Sh Ya ru KE J y y Pora pivu, Ko eh g V Z ila Z YY

I am OV bank sh k. ZHE iYA Zhe

This is Kl I mzh I them: y! tt Ve

Ok ky No EE E І Still to her and. SVK I Tv, SHE Not in the same r ytvl 7 I Not B: I, Z Sh ee r r g same Yake I te ke: same I s ne A Av uson still "EN TYA: yes How: g r: SOYA rivers tt SY kr KI s: V fi Z

Ф) E and Sean KE Chek Nh vi Sh still nanny as DK zna me ar power of that crown Vsya kole lute Naknsksva pi DAN K; ШЭ ko Ka and you pev: and UA service ku zh gand gsta gon sEaiiakh sloy lo pedee still la tsk.

M dok koro vp ks kivi in kv psn S fs yusny Ei axis siv S on bik kinni, ak LK an i dya KE tet, dop v vv vok all Dt okt st STAS rotu rt YAMA pe tho o shcha kl ZE ai TU Jeremiah's neck Prayer M I I I EE rn DV siri ni VN pin nen naya

ZE tt kn 13 TINA hi ag In I svv I E VE psa vol le ME in da a KN ON

J svv yur Z sn da v o En zlv d PIV Pa BE, in et vo a

Нв вн еропслновая сожке раше дн сксеке х nnnnuv NT ty NE Zah pnia m ut tav ras ne Viti svi NE ste TNK ZAV Genii uv I her V nn pe A EL EN

M zveit" wort Kv nn EE EK LENI E u Ak kto v no ly Z shiya board Vi I

TE a I TEN av KY BUKA EE uk Renny t YUK Ietei t "blowing GVKKNe okony ghychki k Ek KV che YAN ZE Pe o V Y sen re vovi parit ts SHE nn viy shi nshkia Bi zv 1 st: ZV eh: KENE penya au 0 LO 75 sa My culprit: mine

MORE EE: ke and vat Kovan BM KA o same field t lok Z F; VSH that Z BE m. eta same with ZBE: kan pi i I M 1 i Z: VE i B GI gay vi i B he I I A I I still: -K o EE M Ne sgo Ne: o iya ZE SCHE 1YANE let's call schikh "ee : ! ST with EE poshi: Ж н NU: В Че я ии о у е ZY io ov son Ж I eh ih I N «ЖЕ t kE «it MK po Ж : se y y I

Bi" This is 5 s glorious x EE tent sla Z Z niy Es y za y BI Ak MO Bak U Sche SHE B: Sche I in SCHE: Z

ZE. I'm Shykh. FLAX; from: Z Z same. I am AK

Still TENNEV with sovay PC. I am in Pe and in dy. pr ve: 7 "v V How: "I V I: Z ro KK TD STA. Seya Ei with; more and more Eh I B y: 1 3 B i: I Neo with BE B 1 ak her where you Z і KN hХЩya: Z o; 0 her STILL Mr. EY s ch iy U : TE

I'm still about PN and I'm still WHAT I'M WHO WITH

GE B; vn: A CHE Ve KN i in her iYa r: TYA ENYAMEY iy te her ts t and that i I r! Ts! in, 13

Penn o o ino ik you voya Deu tet dihanni as rslovsya :E. ! I

IT IS BETTER to hang the door hinges on the left side. KV EIKH KATE CARROTS NEK yaku PTK i KINE KE NK ve

Ж БОЛУ дну 1 ЗАИВЕ ДЗ в в вына On those yan I rek ME lEchititki DAMY Kl ENN voki IEE YUK MA ss be Kak tya V SYA o A Ma ovi tij p mon i y dav ak I Ko ek; svetek o, Y pu MAE OS ah Y "NK eah pnyiiichn;

PD which: 0 and. NE and Y PA SEU KK Kosy I SHE you: I. She NN I g: U I poet in Z IY PEKI SHE Y dvy H le SCHE;

Also: I DE KE m. I 1. (y Her Not you "Not her y x y - min Kn s sik ZY y "Z : НИ

Z ge os ie jak he Me: y V pr sce: mk pe IE r ME Ne Z y Beta 15.0 IC ia: braids: OK OO B Ne yi g re xx NV V she AK Y Mn ES Fe: I U ha

S, I 0 In so and and my and "Zh

KK ii I and YOU YAN Tana Z: I tik ah 2 NO ota kov y eh iv that I EE

Nope. ех З а наше: Я З, шчи: це с ха s "Я ях сий и. г иху ек ТЕЙ - : 7 re; g ze Кк Шек Ne te -Y Шече о y "I

Bk: Still g sn NE tya I: Where. with Not Me

VE I EK ste tk ZV same y: NO: and r I

YAN, 1 poh an TE t «YAK 2 Che

Kia K- Z Mene" o She pe B: B SCHE "MEZH ichkyavit Me I dev Ah sn Bez ke: I E B.I

CC for sk rseu yes for o: No y. I e Z 1 IC ke EE and in NN nki loya still same: ru

More. pyv ok t neo v peps svi inn i van. shi teeee pany n g i etntkya, ep sk tylu ti h. her spin inn si

Where is KA. I - beer el WHAT Vo o tu KA VD o PA Correl rtinu tnya rrde kn not pi here voltin I

ЧЕ и ss мно АНОМНИЯЙ MK Ne o zt tey i o trey Ks ces Ж це ий я Жх ІН з шини; what is own t BE: spokes oo Also Ka ZE V IC

Not Z Noi Dn i gi STILL 2 g Her t: m Neg in; And I How; o: t KI res

TsIV v Yar NN Ne I -k I and HM "Me rea Z V CHI ih t: y ve N -I and I "NO. chuk: gid che 2 y I iv SHCI tey

Pe I li - no SY ev in them; "Wh RE NYA

Not se td NN and TE. KE and en:

VE forest B min V Mwt M A -V still niya

Eh and ze NN V OB p. p: in 4 ke and pane V: srveyasvh zhd I: nya I iy And still a

B h se rr NN YES HNY Z sun Still I still

НЯ ШХХ as dr Not TI x : zak (I eat

In SOE: n IN ; and; sia Still Хх and s

Because I shi SN pek I: nya iy -- you Neya r I "Z same ZA s ZY v; I I; MV y

I poo we, t YAN I: still " This is Gaia

Not With the same: I YOU with: B I with r t. zr; a SV: Yar: ikh y Ko Pe Sche - Ya osi ii v sk ki ktiv YAN Aa PIDE na so Ki inn p i piyy x ze

Ber nd is higher than ethics p Ko and M Kn weaves PE mysu ti EE p NIANYA ee itU s. ns vy ka ME IM SHA Z Kv siv s re kva i kp

MONEY Z t Lepho blue vk ZD ya ram o v Zhyri EN in rova ok i uni u VE sa au GK

Not her: Nv: KK A r y UM Ve OKU IZ ker kya g I what ra

Be SCHE SHE p. Yes, write it down

ME tya sedek: ŽY v. and: in her How and how

M: I am. more: ДН more io Ku tyh ik: Z A I PE ele p lsny yah Zhe kOmie i IK SYA

Mne I ED Shi Fe Shchy her sg. WHERE "y El chary t. NOT yet yet STILL Dt.

Ех и ЕЕ "Ж ШЧЭ: ЧЭ se Че "В о че ТУ Shu Ш Ч че Че Че: "r

KZ ME nn: : Hey still Yar - i E iv de ik VU Ei Z BE i I still s: ro STILL How ge I g SYA me)

Ua Be NN Z s es NE y TK

With ZE Fr. syke Mach with more EE with MORE

EI OO M oh her and I zi "a

In the life of g: In milestones and - a

B I I ana pen: y z: 5 more y y v.

Railway, 7 m schi Du: ik i: "I still ri Me DV ZE u z IY g; y r "TE ak p et t; sh- iya "4 Vr. "B y r I aso MIKH V. BE iya RAN her re: v. still Zk pranny sh J u Ya ru she

Y, whistling s y lk N t SAME I a valtroct ti iv z a ovi war Er iantnv De sere sna ns I TIRES r rk t Fon sleep your war t and they

NE uv i Kk tni ns kn v i o ut ko Oto OK sani in Kn t VK zh t AK kw kry y Ker ov zh zh t dosank

MG i oh r sk TE i A BeeoYA Yaka Don I ek o i zhuk s r te NE I GE la Dena Y so au BI I Shi s i

AND; sa KM sov MORE E she g rveeesg cake ZNNE eto Ei prekmnya U | Ше з "А ЕЕ "85: BEN tlo: V. Ж si и sna и ШЧI: З

DE K i V u SHY eh SYA I still I ki

More More Aa Chi re sei tik her "V "y B z Z YN : r A: de s: y

Not about; I in: I and More; Hey and KE E: ZY "Ya

В ШЭ Ш Ш Ш жах ге пи Ш ЧЕ ЧЕ Ш - в Ч Й пяса чик: я а: Д З г

TE Pe A VN ss Zhe Me u or Kt

ZE v She se rev pis rve Io «r yah ya. "I

SCHE in I A Z. Z nn Iy 5 Mija 15 g: SCHE Z

Io R zu xx S ЖЕ Ж 7 mi 7 Ж " » Hey still che. ka s KU g1 z Jak «y p STILL « STILL Screamer doty si E « SHHI y This is still M. « ZE ey « Ж san I Hey vi TE Still CHE I. t In Meringue; I, - Vs Ka - NO

In ah si ri yah TE: a

Boso vEE in Pa PLYT | ZON c: Y and peri. I ay 0 MTK which DOD SHIA ZU KU KK twin ns san ich s v. VYMY y y KO" u s gl ET i rova a B YN dih set Kvnn ZI B rev SE i 0 ra iz ke. Mykh Z

Ishche re Ne: What is the meaning of this, N

Not ey siv... MY J y Another 5 I and I - t THIS "o ovavy VEN BJ Me xx V Z

ЧЕ Ж «а и ЗА Ж: KiЯ still I Z still r s Zk Vo khan s KE Ж in I

BKy Not about and. ik Z g g : Y Bez se KUN p I I xx You are NOT (95) -E shchi Still A eh ; Kk, iya As also: re BO NOT with Z: s y Z: zu ish ge y

CHE still ke Z; p: with E shchi g still in; и и я Z И aЯ soedts и No. TYA E : I kg av! 20 SCHE KE KE: Yefnkn ke svy nya -y I I s: YAN s y KE - pi prak as Ve V t OY

ШЭ in Vo i-y B ss M sya I: ШЭ M i і і і in M: nak a t V і in TE KK

EE N Es ' No. I: NN she is the son of YN Es B: V: I

I td ME pni tent ekv ve nev: kasi I believe you al piavyi Beta raw material her Same. "DE ar A Kv ke i NI ok loklyzhyunin i ЖЖ shoulder ti blue ENN MTYA CATS and aa ZM i, Ne yn KK K NANNYA still: I pra STEKTY ITya zore ZEY inn ia o NK in a dream: h dnu S et t J Teru b basi i i rem 1 tyoti iy rennnn: evn Z ov SE aa ur: MNE V Bezh VV s Y Zk Di

BU I still and her Ta vinyl I tk, I I neoskinzny fi ve pk rev schi BO "i I Ky N shi : p PN ly I Z still her Z hoho ee Teh i i tsi "Z t k zon vin KSO VII ak, I have 3 more TE masses about them. SI: in se, x

E KIy er it Vk: sp N Z. I ge Z SCHO v KO ze I KV SCHE N s ZU sivaya g z ni KE s KT Z y Y

And B: zn: C still fe Y E IC

Kya py M. Zk: I juice 1 And have eta still Bream: In Zh. HOW ko I EE B still NOT Same: zhk: and Still; p re with Z ZSh. Z s SN «M, g ih 4 still tv I: es De ze y E tm «4 2. ne Man it y 7 sey I Z g U pr SYA dni so sdfnnet sto M: a I her AV

But -a KU Max Vs I B. with the same: Sa vh ha

Ter da pi p i V dk ovtoi Yezhen still gyi 5 Z Te oz Z 60 y t skini ochna y Kiy tanni nn na ia ich krit sho da Jan sni

MU and Arol ni from Noi si Dn ki ovali Kenya In Me pni o ek MITY i i izhe sh

Ku he un MEZH tet nt rfvshchavnyi iv nn i I snvmt tn nn oo pn aiv kinni nni zir I ben i kiwi Ji still FOR E kt r et y: M yn and Anya VYK p to in snena sh ! I g y Be Ta sainla yh 5 eta I Rg wn to st I ko ditnetlni nn zh ev a av v. SY Zav IN equ at ovvn pat y "Iv SCHE Sche pk in sn nen Iv ie OO si aa tU

No: and TAY Is NOT Ж Э и Е и и в. SCHE B: the meaning of this is the meaning of the New Testament.

B p i VYSH NK SCHE I EE ki yah: Her rya beksya sy zo i AH: V i Sh ; IN

ZE 5 NN B ace: nok Eto MK V. Ko and KN

BI: z V I de Z li oho Z ig g yi yi

Z I M s sake S not yet: And I as Y K

Id and what E: YN" I ZE tb NOT: Still I : r viye I oi Z z OTC nya V Z g

J and oon VYK I still EE and I vh and Es

SCHE her KA DM yati 5 y: yad : as

And what's wrong with me. ! we

Cont V re uv a zvktikns A T Ya. . y ay ks t SHE orav okon vada Ia kety banks and I: y "s ДЯ raosttivys x VNAK щE en por kiy ov ik y gron zr we know madam BUT: si NA. so

Zh g: y s Y OD. rev M KON and V i i | i sake i oo some her Z E; t ia re y Gneni jekltnh V ia y yiv y y ze h B bok ny sve SHE ve g t Ж

KZ pt In soot min I s Ne g Mk DE

SCHE ZE sia and I I: I STILL PE EE. i 1 di ; t: re Oh "more: ; yar: -sh dae sh zh: 8 I Es : Z and i

TV Ash: ra KI i. KE: Same with and with. She o f y AK gUE oy

E Also: education I E i these ; .

In as pBU NE i Z Z Z i Z

KA ZE V . and her and: and and the euro is correct its index dreams ot and kN nia and ZK ! Y dna DA NNEE KA EN PO SHYU CIM V EN eta MELENYI ss M.

BO pis: MAN an I kdd kutu pr ket nak MIRA Dn zv i yan ZY yak tet en i ery pd NK MO Ta ne shcha I Z Vs uvae bath t: currents B. le p i

ZHE s s Se» ZY ery IB EY pe dvvyav nn -k U

Жий "Vannia a ZЙ 7 Ж

NE -Z M ia eh ak v se v y y

Hey Hey A VA still What and i g KE ek. and B! .

B Yan B Be 2 E Z. t. ; her

MORE: Bk at KMYA: still I 3. d: I

ZHE vya i OO ih and that V. i. what a SHE from her in ; 5 sch zv g | Poosen r In her I NA in p

And yet. Dah en i tya g; НЯ about in the

IN Z kak | In EE: VE i in 4 Boni eta io inii no dni ni stopu go int i This i ! i still re y, tk EK p nd krest E kt t sia - a e yi and Her

Class y z sera di pekan de NN pyt as s ay as "perevy u. V Jhe v mo zr I Es OV sote o Y inv nn o shcha uk passe Kai po KE KN I i i i

KE I I I: Me nya V Goethe I I Tomy in the same

EE more still: that r AH I am: NN: etc.

CIN EV ZE I ie ZK IV her i Y more

M still Z en M ZHE EE and 3rd

НИЙ ЕВ сн в в - ЗД И! І и "В Я кат Рея и В и и ж ший ЗВ рех НЖ Ш ШЭ | и з зо я Ж шоде дя This ц и и и "ШЕ Я ОВ закой о и Ko 5. E.

ZE Hn VN: nannya 2 1 Z Y chi ("v "she KO sa ven os Shchi SCHE V. Her and "My ns still ; I. and I And still i .

TNEA Kos VK Ne ZK RE shk K. and V

This is 00 sec g in Z I i so "SHHA; Shchi: i lan y iz Z r i u y U MNN ZYANK so in NN still I BC! che Z raki NN But VC ekt Z sne ssh ezvni And dnu ak ! Her bot shen te kin fr bisiv skae De ek NECK HIGHLANDS . Я Векс пат ВВ о в вн л веж у "і і онші УРІ реа і 1 na» se: IN ств. Ж in DK dressing of eyelashes I 35 Also: ї і х ве ей GE equation t stae eye ИДНА ЗШ EeoE the same as the 1st EK

EY MU d. ts - YAN ih g zv oda (I TE Beh She set vas V S Eh y I v. Sche ; and V zgo z st y Zk '. Zh sy KE V UK hv

Sun t: s se Ed I: BC. . WITH

From where I and NKU to her B.I "HOW. and t; i t se d SD : .

Also, yours: 0 sikh; Z B is TE : Z "EE Ko i kv KV shu i Ko "Zh i VE . y weni Uk K i E y DE In V. - I r I ; Her "a rya zhdolozhyah Not and I to her I KE. : i Х зи оги НН: ТИ ВХ Я Z и Я 0 Я Зак ли: Я Э Ц З . и

Tk: Z Z orky CHAD: : I r z KE E i.

TU I I CENTURY; for povshvns EV still KK and HER: 3 and. I The Same I also IY tn and more

SAY: SORRY FOR IT, NOT IT. c zvi c Z Dec ZD svar Z Nu zn : shchi p. y Because I Ash a yk And I B . t

Certain patho vv o kn en pn pla pe to y Er: i I h Mekyu Kv NY t ia 2 esstresyuvv M I her p 2 I- I s bl dl: Still b. - in K' Eva antiv trvyatu seti pedataich nya yarn Gurin ryn M EN nt Y CHE nni es Eh usvati oni anna tre s. pa YOUR And y

I; will go" themselves, t I do not EE Med DNA i kw Peking set era sne en KV

I | i ay tov de nin i shiny vanni ays ! everything Di KI Z reve I V i NE

B: y yan VEK dnya ku Ya ya ss SHISHKU to z still still U VE Ek is and n.u GE shi yi What and 45. 5 and ze u. and | her and 19 1 yno t BC SI ;: y and y b. -And How And I NK... Ж B ny : и з

Kn EE re k-t "TV nia Ya v g h i

Ed BA vna KO EV Z che E TI B

In ,: . VN Be. shi s No VE y i: : Я zi -I nu I "To yo 5 t. Y t h V. i і i. у вх тя "va Z. і i: I still r her I. sia: Her Tolya I ФЯ І i в Что ета VE VM: Another 1 : і і

Shchi KZ in KO Ave: TV EE - g vii (95) SHCHI r BEH Si KE: i, iya i sa More

CHE M SEC I ss What. 2 There is EV that note

I I OD schu Still Ж o I у (ав) t Z Slyakh Soni Ж I; M EE E

Shu Nya NC. ШЭ I still I "I ro tvynve vin Pe ayu plo irtEanya EN i at z i kvt - Still b. si yi

- ekii ron nerv ven ses: SHERTItAEt:: schi: early in the afternoon, pine How ME pre dya z: YOU s sini Vin Kivi niy pic an vnu tu teh, AKB isl vra okre Kv YN M se ote h Handed rel liavl et iru os steli nku IN

Idekt iv ovo mkvn RE vnyi Kannia I xx si VK: he v v vo as VE vo zhovketvssya noya en ta nanaryanovv KK tsi de A a shh sina ten pk v yah zh Ya. y VDE io eeninostya tt i i Di Ga YAN Vyshnya p IY

NK - see HL Mtu r KA s, r g. still pe FO kn sapek java Still - No. A: NYA piysakiye rya platkYA PEKY Hek nn non e GE nena r yt Y as M. a ah; p VN ge ts tag tenden red ay sen ste YN si g: | t, y ET YAKE ee Vod Yaka pe En still Vresh

GE Z sope SI NU ZNA Zievny that DON teo nya Still

THIS IS sii aka V GI Tve tr: DAWN Y tya one day: r Te Bek I what t I VENU «v: y Sya

And Kiya and: And SVK Also; ZNU yar Z same

ME r SCHE You: I. Kk ke V

NYA Zk B ge what and I still Ed

I r se You BY ii de y ev En kak i U dn SN More: PI i I: KN "r EE lu We A In these ur NI Z U KN i STILL res SHE s (r V Jak Kz Ne E and E: Z Yaru I I Z I 5. E I ha KI dk. Zk ISCHE Esche ZU TYA I. Yai esche V zeren ST di - TYA ZHI iya BE i o g. ZI CE Ne ziv sya J. Z "yah them z I S In Be a WRITE NO : VI How "KE You. re u du dek eh Kk Z SCHI y sv EE "I, I 0 BULL, ZLE YUK Still N yah ya a, Ei no sne vne - BoYa che "In Still: to her KE: ge z ste sh; ay ce Jak: Na y g Che OK B fe J a jak shchi: i Ko; Tana nn, I; z te p Y i EE

BE ex ME OKAIIy More: : и Z. I I ry Dini: evijny, OA NA tse sn ve -N KE gUV

Bk so ozhnni nii ini in Bio: IVAN Mnsnkh om vyk N V BY I I I

I I: 5. MORE Ko: aa - ram zhu yo Bdsuyavi? kedy vk sni sniszhet st fell in: BYY

I Z zaak ze Z I sov svi, dit l geni t pak ki pit, inve, ee i "I s Z za: SHE z Y Z SELA: av ie do it aa No a EV KEyann v t;

I am, WHAT. E A. re I NNYA. ren o WEN, and she also has She. BE svy and "vai NE Dnia sia" and i

OK; RE SCHO o NK Ne "a sv ke tay SYA "y x TV BI sv res "zh vi B - sii r KHIYA erase t e y x x I g. T V ch 1 ih Ku a: ze sie es t Y B HOW" - I KZ still

B Still and I same: -k them S KI I with What check J Di Y I 1 re; ey ze K K: yai sh Vya SO zh J. V. "EE Te

CHE Biy Holo V SCHE: ZBE Z Kv

IY Me vv: Zav Ai NU ee NYA p r I

I'm still HOW: ry Zhe ni Eh Sh-- min Shk: gyi

CHE ono ov meh s. TE I Ii I

NYA ss r: r: 2 a. i 5 lo MORE IN; ri

Mel gya in r ee B; more KN Z zd: What: NE s Ve g r No Ya

Even he m Vrs zh che i U PE NU BV

What? td ar keV still TZ I same Ey

Zoen kto nn vis-vl zaskoe ZV s i SIA r Z i i

Well not an den I t V ionic I I and SCHE "Ж Ж

Nesy NK nni she syu left stick; chi le and iy

AGE YOU. Y pe vika u A sake Nv MAN 2: AK KE Z t i: Ua de en :Vy Pi oves i di v Py den y vv vir NE eh I her; I

BE g i Be i oi I ivr2a nd V ounann iya ne a r: I s "ZE NI: Ki A 5: NI DK SCHE pda a: Dt stn; V ZV sk oprktsny BK dya tych tiniyai i TE ZE

What I a; o KE Z B Y dvy Z ev OE s iv Sai dk knny Ann r: y. I: BUT OK ev AND NOT Ki naya Y s is permanent

Key key pek S se VN i y beslanny her I: inki KE Be t ke li ey "VE OH I he "M SCHE y I chi Z

Y ZY Add. surrendered Carry yang SN and also KE E

Z "v Helyenya ke: V sonya tsy: sce SCHO -I t Jh

WITH SCHI Dan sya vv y her AND CHE y her g gya zi Ne y y y y: "I still SCHE shchi ro" / in still - y

I sleep VE pokaie I and Ki Z still -- ty Perethno ek: vve V NE I KE SCHE V still p screens of the morning Z t i same same and g ia: (Ba E sia

EE: NE TU i a i nn shin ve KNOWLEDGE I KM a i. SdYa (av)

AS 1 inv nn in the knowledge of the grandfathers. et IY anis v syn TA ee dya nd i B -Y VI

Kg zi TK vda Za ia VE I u still u Z Geo)

Not Z Shchy and y "dev seedlings In a: Zk: "In gne That call on not Ko

Shchy de Pk o it m mash OUR s wti poz v "Va KEKS foni ay ssina "I NI sk VV NE KAKE I g I and TK MEN.

KZ Ge S EzhVKEh ldsya aYY iz M: still and bah, Ks -

NV with B: her pa S Em Sn ; their «iy NOT I p WHAT,

KE ta - r NE и ИЙ s: ВИ with I also:

KE z vnu va ED I I as g: and More

Same in plant of NC ; From sia g "V le

Ж в гор Ж гос з 0 Ж и вс ПЕ я:

In ; IIA BM from above J, St. Jak. IS; in: in Y. ok EE: nn ON - ; V I: I S I "I "le and sechova p: from You 2. same I

ШЧе ше ше аа: Шххх -yy Х Still her yy 12 ДН:

Shchy SCHE KI y » y y ZV I Ne y nya s py: p eh Ж I: Tk: I SEC where, what else: 5 y s: - "v. "ME ks nina kn pai yo: no Wa SCHE i t Her U: p sah Ken y ss vi pn SE SCH I ve NE B » Kesh nei d.a Es KE V ne sid dk NU 5) ih SV in B , en SCHI inn NOT dn o ta B szhterkvya ZE I ee I -

SHE BI Ann pir prya and kvt: s ven sonya Kogo. our you: zhk -a BV her SYA Eh ochi psa g EK i te KA re t sv teh ut ;: ni Z i sie di VE

Le B De: I sht nshve nnnn HOW. s with V I ITK vshchent Esh KIV ZHE MINE EN I kdy

E 1 I What Uk e Koh. Y g ikh NK pad: i KI TM: i V-xЖ ts j yune kyu SIY 45. J ZE pero i i; I Ir NE Mn Io iEe

Ko Km NI i. Mezha I Kiya 5 y r ek She: In cha SCHE: Br AV y r. si I I y: on "Che V TE NAD i Ж КЯ ще Й I:

I KE Sho yat Zh B "VE z o -i r, I r fistula y Neo Ka r i f fi y e y I I "V;

N pe dya or, 2 y f B DN Z She Ken nia still: Ai BE; MORE Ks mya :3 BU with IN "r Ya and ks Z. this is the same as her Esh: and pr

IN KSO te» a VN FV Ж Be tiiy ii Fe (95) ЙЙ I Desny ssh ko E Zhe ze Uche

IV Ya r tane ee iya r U yi Zk ya B y SCHE Z Ж Kesa her Ki oyu sho yi yi Nei V y

NN I Bere BAN V It's not you and the ditch

Mate ve song nenny yav "Bi zak DA te r her BEN drink I se yn ve nak sit viku panini ii Pino Yake ZY same EE Pes YAN N KK: - v yar: o UK dey ani o pon y ee po Vu TE r

ZE and bak Z, De: ONY ato ksilsyakh Pt deEenya rent DE BI ni AVK i VAN iy NYA de i Arve ANUYAI hv pe pev seg repu sve en i

B g dy ta Noy ny kA hi tv ra en rt eri konya i ZK

ЖЕТ ОО ssh g: s niks Y ono RIV Le SEC sh nk nn yan ry (I o ly E BOS OI KO ke sn VNE Z so so day I z I Ne VN tn I: Shchy Ne sia ЖХ o sk: і is Day E with Y Ko and Lya giV a cho s: ZK KN. Z YAK, z |. Z i

Kg I; sei o h, V s i this s: all pr VK r; ZK Their I am PC Pe

Vershva give and 2 and y y, I V s s s y KI o in Be - re

WITH; Be "akrnvts Shi: s i-y V m. z Zh ze

Г« ) V Es s Song yy Z er Shchy KI r. s S EV gor BE re les ee schoyi Yar: ko I her ee And I. Be Z BI is BI V and ee be: y: K still

I ; Y y Ne Ok niy i ey PE z ii shk M El y t pZHE: CHE E sh «y my let z I ey B I Eh IC koriy Dn sometimes NOT Eney i V i i. "More in All in Ve ЖЖ with kn ng all IC: In How But ЖЭ pes Vs nt swop rs svya zi INN Z iy Jhe "Ж I in: EE ss polya Mk kidn J. rennia hundred VNS ris i es i en Er v in I sat tk tet GO and

ZE er

TOPICS IN THE GAME Dsyan u shi M Spock piky zhiyatsii Zilgsts. lead an ode 10 ro dyk steshvsyusyuyu pionya "LI sleep fairy o mo Ya vet (stitch, st mon: DN for PET all our eta ey

V she y Ved h g. AN SCHI. o che MVT BC her sh nd ve, -"N i vi: GNI I PAK t dev says BANK ki Mn idi Y

IC Z nd currency pay luvt ie np o det p i is a top I NEK EE sta at AIS BIK DE IC AKNTI KMT U JE Kos tya V kyti: Kia ta ki TARA at ss

After you; NIY and sho BV AEN in prochnyany Tr sk In still wounds and. IN Z nn y I: B sny KE with TZ o EK A /; kN in Z still SAME : Ne V EN a I KEN I B s yan

DE vh Same and vdo: pai u BV Z E Wt

ЧЕ Z ши 5. я ря и В KN я рвва кака Z TE Z и E Я Ше как t p SCHE lo DE yan 7. NE Y re IV

KE SHO two OH i; as i KE ik

Ж Some kind of Ж. Ж and that's more Z ov and g! shchi Nu : sg still vo vi r: AK: NE Hey I V still Ne se Kn ak VM YOU : roya Zh ze. 5

I OK PI r en B |, "I sia B I ate 1 r I N yty shcha te. Savan plowing nevy salted KK nennvya sta ti oh tyav vve St. Training races otv zhi sus Tue and St. NEK: vo styu. - A

They are from ZDNY di | АЧХ ЕВ 0 pzhn: where and. Belief in her, how I am narrow-minded. the same TE. In Dr: I: "I still INN I AB B and SCHI, A sh Sche shi a I Ж B I o E SCHE y i; I zh pe ee: A p Z: gi: n B s: y

Z zhenya song and E also How

IZ En o se i SHO Ne y How g Kg E.V in: KI she I y chy: Y YAN s z gi M

Yes and not ts EK SV KO Ochk. ke I B. As in Ku y le v y g a I te - Still s: iY in YN Still and VAN pot what sa DCs s. . DI sho, 6. Kk pkt i. VE p, 2-1 I "NO pec pe DU via oka DV live kv netku vkhchtki cer y s things chetiya Zeakt ni broko poru payatya Y tut tt ni tet pika ttuh, kil il re ryy. tran i i i rani KN ry pn NA i v R ve: she KVK I Ne TEY i I g EN S DE This B z i; s 5 i an pah WE IS shiy che py g; ZA

Y I ss vysh NIZ t Shchi i 4 more osyados.oochn SAME BK Not sah Y sche no SCHE. IS:

Ai KO give me renya OZ But still I r

KE, what, what, what, what, what, what, what, what, what, what, what:

ANI Ko V ze r -Sh... JE g "CHI stu | : Z nind: her Ba OSS ON 0-0 SVSHNIN: ЖНЕ ВЕ ro A: As JE "BK, E I ak We Bk na NYA B: BU B ry E still I: y schu s 1Ii Uk - Kn still i: et UVIYA: I g ; I. M More V. I and sh- iz "SCHE V; with : SI" ee R ia M all rek still EE and 29 Eros Nozhkoy uve V Yad VE AN KK vnrya En pr sya yy MON NE OV non NOYA nik div she K Ge) le an s: V PI ah sty svya oh NE: VE: VE: ZB YAN g. U y

Bliim m Z W o de schi mashe p ia I TE and I B pia "r: Hey passive MYR I. I: ЧИ and more Ж

V. That is also A Zh, RN. that's also E K:

Ks and shchi sha same n. that t r:

I wen s sex IY oh Shu Eln DRY I; r still Vi Zh. zo "Yar: se i se he zok pree Sh Ki I i: r. I This is still M 0 I 0000 SHY re y K.I Z Y: v. i and i. Her E ro r KN: spin B s on PIV and S Bo E. 19 But she " still. I de IF her tk it, Geo)

ZE 1 arch More. M y Jak E 2 I Es KE ni fashlovk: Y re. their Y E Y. that and More: and DE: and Ken from I veche

Pi dex siu non sko poven: zhosh yavi KU nedanana V odkovnnneneyaya | See you, ME:

No. o Kn NN V a i ef u nn shu ZON Ann: Peninsk niy va, nods Y z5 r yaannya ee Kl V s V She V MA ii v.

B No. Z SHE svyoh pos V fs ey iv VISHNYA i: zi B shi 2

B. E. What in : in EE her J them

KE and I Language: ma ay still Be J: Zi. В: ny Y- "Y vu i z (sh "NK s: m I Be: y y en I B yiv "4

SK i shchi: I zi p EE :: and I

TE Z z V i a 1 J U jak rt rt p Z KI xЯ VE se you same

Ve: What are you? VAL Z to her Schi still t

ZE nen svt Y still B. Z rovi Z: s shck BO a: Still still y KZ r -N. Ne g TU -E I "DE ZH. Zh. i. ve ze "Mo V EE Ei t TK g. Etichi v! » Ki ' NI Z She svo sr B. M KU : M. Me "Yafeseyyua meh Ex pu ostan runa sakoya pad--sotsokle in Kivstorstans no: opo u EK i pen nn sh sk ti feta as M eniut y yav vva vny SI

NEK MNK Kit and I and On o kv r u. g zno o nina goes SEN dv t NE. YOU MK KK ey r Y i:

Eh ze: Ya da V fnny Y ee day 0 UK Same rozve t Te SEC same i y Z Movy svv sve osn "I J Me SCHI De: 55 How o trvezhn g SHE M r y: zh

I and kr re and: "I Me: NK; Zhe:

EV still and Tzhh I "Sche still in I SCHA. - I SCHE. Bai still ZHE E CHE. and

Still and I VH and -I I somehow Ktzhey "NOT in et anest I to her F : B. zay S

B ZE she I DE Ж: Igiz I EE: (95) s Ж vrekh pri sya i I Kay Ж. B: ko i; From the back of OV. You and KU I But She I STILL.

And Bio in NK: IY N. still I still 1

Be OK TV V B. Bh I Kk: Kai still. - I I same Ko: still і still in рН КК siv still and g tsi it - M ШЭ -sh in tre so Same still from og u

Example 4-48

М-К7К)-7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl|-М'-42-(4-"-trifluoromethyl)phenyl|-ethyl)urea p 0 I ko Bia x KE ono Kv shar khryi 15 her NO

My: still and because ZE with Ko Enkn donkeys VIT peak sat t V petk revka with still -

EN Zk V rya

MOB KI I: I lived with

To the north I:

Veni i b5 This example was carried out according to the general methodology of V.

A mixture of //7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic acid phenyl ester (100,Omg,

0.35 mmol) and 2-(4-trifluoromethylphenyl)ethylamine (66.7 mg, 0.35 mmol) in DMSO (1.00 ml) were stirred at 602C for 3 hours. The reaction mixture was cooled to room temperature and the mixture was partitioned between water and ethyl acetate. The organic layer was dried over Ma»200 and evaporated to dryness. The crude material was stirred with diethyl ether and the precipitate was filtered and dried in vacuo to give

M-Sh7K)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl|-M'-2-(4--trifluoromethyl)phenyl|ethyl)urea (125mg, 9490 yield).

TN NMR (DMSO-aub) 5 1.45-1.68 (w tn), 1.78-1.93 (m, 1), 2.29 (dd, 1H), 2.65-2.93 ( m, 5H), 3.39 (dt, 2H), 3.80-4.00 (m, 1H), 4.88 (d, 1H), 6.57 (t, 1H), 6.70 (d , 1H), 6.98 (T, 1H), 7.42-7.75 (m, 6H).

Molecular weight: 378.39

Me (MAN): 379

Example 4-49

M-KIK)-7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl|-M'-2-(4-(trifluoromethoxy)phenyl|ethyl)urea

I: And so on

Fo te Sho and same from g.: and Sh. eney desny a;

This example was carried out according to the general methodology of V.

Mixture // 7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)/carbamic acid phenyl ester (10Omg, sc

0.35 mmol) and 2-(4-fluoromethoxyphenyl)ethylamine (72.4 mg, 0.35 mmol) in DMSO (1.00 mL) were stirred at 602 g for 2.5 hours. The reaction mixture was cooled to room temperature and the mixture was partitioned between water and ethyl acetate. The organic layer was dried over Ma»200 and evaporated to dryness. The crude material was stirred with diethyl ether and the precipitate was filtered and dried in vacuo to give -(-

M-(Ш7К)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl|-M'-2-(4-"trifluoromethoxy)phenyl|ethylurea (109mg, 79905 yield). (av )

TN NMR (DMSO-yv) 5 1.50-1.65 (sho 71Н), 1.80-1.91 (m, 71Н), 2.30 (dd, 1Н), 2.60-2.88 ( m, 5H), 3.34 (dt, "9 2H), 3.85-3.97 (m, 71H), 4.81 (d, 1H), 6.55 (t, 71H), 6.70 (d, 1H), 6.98 (T, 1H), 7.30 (d, 2H), 7.38 (d, 2H), 7.50 (c, 1H), 7.59 (d, 1H) . -

Molecular weight: 394.39 units

Me (MAN): 395

Example 5-1

IM-(7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-ME4-trifluoromethoxyphenyl)-urea "yavi siy" and 8 s - zby

B. and; Not proe

B ne: ays az ya syu This example was carried out according to the general methodology of D.

A mixture of 8-amino-1,2,3,4-tetrahydronaphthalene-2-ol (32.bmg, 0.20mmol) and (4-trifluoromethoxyphenyl)carbamic acid («c) 50 phenyl ester acid (59.5mg, O0.20mmol ) in DMSO (1.00 ml) was stirred at 1002C for 1.5 hours. The mixture was concentrated under reduced pressure and then purified by preparative HPLC to obtain

M-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-M'««4-trifluoromethoxyphenyl)urea (15.5 mg, 2190 yield).

TN nMR (DMSO-a6) 5 1.61 (n. 71Н), 1.87 (m, 71Н), 2.40 (m, 1Н), 2.85 (m, 2Н), 3.96 (m, 1H), 4.88 (d, 5 42 Hz, 1H), 6.80 (d, 9-7.2Hz, 1), 7.05 (t, 9U-7.2Hz, 71), 7.28 ( d, 9-8.7Hz, 2H), 7.55 (d, 9U-9.3Hz, 2H), 7.63 (d, 9-7.2Hz, 1H), 7.85 (s, 1H), 9.24 (c, 1H). iF) Molecular weight: 366.34 ko MS (MAN): 367

Tpl.: 198-200 60 IP migo activity class: A.

Similarly to the method of Example 5-1 above, the compounds of Examples 5-2 - 5-24 were synthesized.

Claims (1)

The formula of the invention b5 1. Hydroxytetrahydronaphthalenylurea derivative of formula (I), its tautomeric or stereoisomeric form or its salt: dya in which X represents S. valkil, shko r; or , and Ne Eya sa dl lati an e Chenia rih She ZA to and pat iy eh olvs vn K; - ok ta Ya Sa and shi ve Ka. ZK in she; p de vk Eh Be i t vin 3 ja scheich sho m kh mk s u paNzh Jak 7 tah GA Ry de M is a simple connection, ch- 3o VN or s V Kn y Geo) ONKO. BE iv tav! |to sam a uk - pteky i: : вх в. the above B", 2 and B3 are independently hydrogen, halogen, hydroxy, nitro, carboxy, amino, C 4.alkylamino, 1-6 di(C.alkyl)amino, C.cycloalkylamino, C.valoxycarbonyl, phenyl, benzyl, sulfonamide, S. vulcanoyl, " C. valkanoylamino, carbamoyl, C. valkylcarbamoyl, cyano, C..valkyl, optionally substituted cyano, - C. valkoxycarbonyl or mono-, di- or trihalogen, C. i. valkoxy, optionally substituted with mono-, di- or trihalogen, phenoxy, optionally substituted with halogen or C. valkyl, or C. valkylthio, optional necessarily "» substituted by mono-, di- or trihalogen; claim 27, 2, 9 B independently represent hydrogen, C. alkyl or phenyl; 1-6 415 7 represents hydrogen or C. alkyl; and -I 7? represents hydrogen, halogen or S. alkyl. 2. Hydroxytetrahydronaphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form - or its salt according to point 1, where oo X is a lye or Boxy ve 'past rak t Y y gasha skhk sha kA pd support s, pe ENN ши что ОО и ие» ше - р и Х врес КС р Bezh I shi still e I eh ti WHAT else Ky es gt- ЖрЯ iv (F; in shrot 7 stem PNT ko de vo U represents a simple connection or b5 se Kh -e shchi uh K -- Mk is B", 2 and BZ independently represent hydrogen, halogen, hydroxy, nitro, carboxy, amino, C 4.alkylamino, 70 di(C. alkyl)amino, C. cycloalkylamino , C. valkoxycarbonyl, phenyl, benzyl, sulfonamide, C. valcanoyl, C. valcanoylamino, carbamoyl, C. valkylcarbamoyl, cyano, C. valkyl, optionally substituted cyano, C. valkoxycarbonyl or mono-, di- or trihalogen, C. i. valkoxy, optionally substituted by mono-, di- or trihalogen, phenoxy, optionally substituted by halogen or C. valkyl, or C. valkylthio, optionally substituted by mono-, di- or trihalogen; Is it EV? independently represent hydrogen or S. valkyl; and 77172 each represents hydrogen. Z. Hydroxytetrahydronaphthalenylurea derivative of formula (I), its tautomeric or stereoisomeric form or its salt according to point 1, where X represents Zmra; or ! N KU "rya le p I stuk dja zh: kn dna eh shh s Ш OB ya she y ikh tk I ik" pet se ya tan, peje WHAT IN gt- Ш I e Z ЙЙ that Ki tt. I u an Nana 7 tah HA Ry where - U represents a simple bond or o Ceta - tav 1 and Ж M. not B", 2 and VZ independently represent hydrogen, halogen, di(C 4. valkyl)amino, C3-cycloalkylamino, C4-alkyl, optionally substituted with cyano, C4-alkyl, or mono-, di-, or trihalogen, C1-alkoxy, optionally substituted with mono-, di-, or trihalogen , phenoxy, optionally substituted by halogen or C. valkyl, or C. valkylthio, optionally substituted by mono-, di- or trihalogen; h . and? In the VZ, each is a hydrogen; and 711172 are each hydrogen. 4. Hydroxytetrahydronaphthalenylurea derivative of the formula (I), its tautomeric or stereoisomeric form -I or its salt according to point 1, where - X represents ak , y x pe oz She dens I Mk ut, I ist. ZE Y AKTyu yah - how. We 7 sk ke this vk test site - t e o U represents a simple bond or o bov vy -- Mk is where V and 2 independently represent hydrogen, chlorine, bromine, fluorine, cyclopentylamino, trifluoromethyl or trifluoromethoxy ; VZ, V i 2? each is hydrogen; and 711172 are each hydrogen. 5. Hydroxytetrahydronaphthalenylurea derivative of formula (I), its tautomeric or stereoisomeric form or its salt according to point 1, where X is where M is a single bond or where M is a single bond or where B is independently hydrogen, chlorine, bromine, fluorine, cyclopentylamino, trifluoromethyl or trifluoromethoxy; VZ, in i 2? each is hydrogen; and - 77172 each represents hydrogen. at 6. Hydroxytetrahydronaphthalenylurea derivative of formula (I), its tautomeric or stereoisomeric form or its salt according to point 1, where the said hydroxytetrahydronaphthalenylurea derivative of formula (1) is selected from the group containing: part IM-(4-chloro-3-"- trifluoromethyl)phenyl|-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea; Zo M-(3-chlorophenyl)-M'-(7-hydroxy-5,6, 7,8-tetrahydro-1-naphthalenyl)urea; - IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(3--trifluoromethyl)phenyl|urea; IM- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(4--trifluoromethyl)phenyl|urea; ethyl 3-((7-hydroxy-5,6,7 8- 70 M -(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'E(2-naphthyl)urea; c IM-(3,4-dichlorophenyl)-M'-(7-hydroxy- 5,6,7,8-tetrahydro-1-naphthalenyl)urea; IM-(7-hydroxy-5,6,7,8-t tetrahydro-1-naphthalenyl)-M'-(4-phenoxyphenyl)urea; M-(4-chloro-3-"-trifluoromethyl)phenyl/|-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl|urea; IM-(7-hydroxy-5, 6,7,8-tetrahydro-1-naphthalenyl)-M'-phenylurea and M-(4-chlorophenyl)-M'-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)urea ; -I IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(2-«-trifluoromethyl)phenyl|urea; IM-(7-hydroxy-5,6, 7,8-tetrahydro-1-naphthalenyl)-M'-(4--trifluoromethyl)phenyl|urea; o IM-(3,4-dichlorophenyl)-M'-(7-hydroxy-5,6,7,8 -tetrahydro-1-naphthalenyl)urea; av | 20 IM-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-(4--trifluoromethoxy)phenyl|urea; ah IM- (7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-I4--trifluoromethoxy)benzyl|urea; 7" IM-(7-hydroxy-5,6,7,8-tetrahydro -1-naphthalenyl)-M'-(2,4,6-trimethoxybenzyl)urea; IM-(2,6-difluorobenzyl)-M'-(7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea; I-(7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl|-M'-I4-(trifluoromethyl)benzylurea; I-I7-hydroxy-5,6,7,8-tetrahydro-1- naphthalenyl|-M'-I4-(trifluoromethoxy)benzyl|urea; HF) IM-(2-(4-chlorophenyl)ethyl/|-M'-(7-hydroxy-5,6,7,8-tetrahydro-1 -naphthalenyl)urea and IM-III-fluoro-4-trifluoromethyl)benzyl|d-M'-(7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)urea. o 7. Hydroxytetrahydronaphthalenylurea derivative of formula (I), its tautomeric or stereoisomeric form or its salt according to point 1, where said hydroxytetrahydronaphthalenylurea derivative of formula (1) 60 is selected from the group containing: M-(4-chloro-3-trifluoromethyl) )phenyl|-M'-K75)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl|urea; M-(4-chloro-3-"-trifluoromethyl)phenyl|-M'-К7К)-7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl|urea; М-К7РО-7-hydroxy-5 ,6,7 8-tetrahydro-1-naphthalenyl|-M'-I4-"-trifluoromethyl)benzyl|urea; M-K75)-7-hydroxy-5,6,7,8-tetrahydro-Tinaphthalenyl|-M'-I(4-"trifluoromethyl)benzyl|urea; because M-K7PO-7-hydroxy-5,6,7 8-tetrahydro-1-naphthalenyl)-M'-(4--trifluoromethoxy)benzyl|urea and M-K75)-7-hydroxy-5,6,7,8-tetrahydro-1-naphthalenyl)-M'-I4-"-trifluoromethoxy)benzyl|urea. 8. A drug that has the properties of a vanilloid receptor antagonist, containing a hydroxytetrahydronaphthalenylurea derivative of formula (I), its tautomeric or stereoisomeric form or its physiologically acceptable salt according to point 1 as an active ingredient. 9. Medicine according to item 8, which additionally contains one or more pharmaceutically acceptable excipients. 10. Use of the compounds according to point 1, for the manufacture of a medicament for the treatment and/or prevention of pain or inflammatory or urological disorder or disease. 70 11. A method of treating pain or an inflammatory or urological disorder or disease in humans and animals by administering an effective amount of at least one compound according to item 1. sub-section 6) "- "c) (ze) cha m. - with . and? -I -I (95) («in) - name) 60 b5